Rare Diseases of the Orbit.

1 General Introductory Remarks

Oto-rhino-laryngologists and ophthalmologists regularly have to deal with diseases of the orbit. The complex anatomy of this small region of the body and the multitude of different tissues it encompasses entail a high heterogeneity of pathologies. In addition to numerous systemic diseases associated with the orbit, various malformations can arise from a complex embryology, and treatment of orbital diseases must be considered a prime example for interdisciplinary cooperation. The central facial position and close topographic association with the nose and paranasal sinuses, skull base, cranial skull, and temporal region can even require interdisciplinary surgical care.

The orbit serves as protection for the eye and its adnexae. The relatively stable bony frame with the corpus adiposum orbitae provides protection, but because of the confined space, volume expansion can rapidly lead to problems. These features are responsible for the fact that most pathological processes of the orbit primarily manifest ophthalmologically. Exophthalmos, diplopia, and loss of vision are the most frequent clinical signs, and ophthalmologists play a crucial role in detecting and managing these conditions.

Many orbital diseases, such as endocrine orbitopathy, are well known yet still can follow atypical and rare courses. Other conditions are truly rare and so numerous that a complete overview of them all is beyond the scope of this manuscript. Most clinicians likely will never encounter many of the diseases described here yet will still find this comprehensive series of synopses useful. Our intention for this article is to sharpen the clinical perspective and provide preparation for first encounters with possibly unfamiliar manifestations.

In addition, this article does not deal with periorbital (preseptal) diseases. Thus, it does not cover pathologies of the eyelids and the draining lacrimal ducts or traumatology of the orbit. Furthermore, solely ocular diseases are not within the scope of this overview, as these conditions expand beyond the ocular border structures (e. g., to the sclera) or cause concomitant orbital reactions.

2. Interdisciplinarity and “What is rare, What is frequent?” – A Dilemma?

Different disciplines vary in perspective on the orbit and perception of the incidence of related conditions, as is also reflected in the literature. Because pathogenic processes related to the orbit are not common, precise incidences are difficult to pinpoint in the different patient populations treated or co-treated within different disciplines. Furthermore, large randomized trials are lacking, and most published studies are comparative with small case numbers or are non-comparative analyses or case reports.

The orbit is a quite limited region of the human body, encompassing numerous tissues that fall under the care of clinicians in the head and neck disciplines. When surgery is indicated, neurosurgeons, maxillofacial surgeons, oto-rhino-laryngologists, and ophthalmologists can be crucially involved. Furthermore, numerous other disciplines also have a role in good management of these diseases, including internal medicine, pediatrics, radiology, and hemato-oncology. Finally, pathologists make essential contributions to diagnosis by means of modern methods (e. g., molecular pathology).

3. History-taking and Diagnostics

3.1 History-taking

For conditions involving the area of the orbit, structured history-taking must always precede targeted diagnostics and therapy. It is useful to identify and assess key symptoms, quantify manifestations, and prioritize pathological changes in accordance with symptoms.

After the patient interview, leading symptoms must be retrieved and classified (by duration, intensity, or progression) (infobox 1) .

The history-taking also should include the patient’s background regarding general diseases as well as social and family history. In these cases, the focus must be placed on autoimmune diseases (e. g., autoimmune thyroid disease), other chronic inflammatory diseases (e. g., granulomatosis with polyangiitis), malignancies (e. g., prostate, breast, or bronchial cancer including existing genetic predisposition), and current medications (especially anticoagulants, among others). Known previous diseases of the orbit and neighboring structures (nose, paranasal sinuses, neurocranium) may give hints about recurrent conditions.

Because diseases of the orbit may lead to vision loss and frequently manifest primarily ophthalmologically, taking an eye-related history is of highest importance. Also important is an examination to determine if both eyes are functionally equal and to identify any amblyopia, to establish whether previous surgeries have been performed in the area of the eyes, and to try to determine how visual acuity and refraction (refractive power rates) have developed in the context of possible orbital disease. The leading symptom of “exophthalmos” might be confused with pseudo-exophthalmos (e. g., upper eyelid retraction) or enophthalmos of the contralateral side.

3.2 Ophthalmological diagnostics 1

The diagnostic approach to assessing for orbit-related conditions includes the following:

Inspection, palpation, and measurement of the palpebral fissure, determination of the repositioning of the eyeballs, testing of corneal sensitivity and intraocular pressure;

Determination of vision, including refraction;

Perimetry assessments, including visual field examination with determination of the stimulus threshold and measurement of the visual field limits and the blind spot;

Exophthalmometry and orthoptics; and

Split lamp examination and ophthalmoscopy with assessment of the papilla.

For detailed descriptions regarding ophthalmological history-taking and examination techniques, a recent continuing medical education article covers the specific information 2 .

3.3 Radiological diagnostics (MRI, CT, ultrasound)

Radiological procedures allow for:

Differential diagnostic classification,

Determination of extent,

Display of possible infiltration of surrounding structures,

Surgery planning (CT scan/MRI for navigation), and

Radiation planning.

Ultrasound can give initial hints about the type of tumoral mass but is limited regarding measurement of depth. MRI is superior to CT scan in cases of unclear inflammatory lesions and tumors. T1- and T2-weighted and T2 fat-saturated sequences (which afford excellent visualization of the optic nerve and the eye muscles) are performed. The additional application of contrast agents is suitable for examinations associated with tumors and inflammatory processes.

A CT scan allows for the best identification of calcified and bony structures with sufficient significance for soft tissue structures. Thus, this modality plays an important role in surgery planning. In cases of unclear masses and inflammation, the application of contrast agents may give additional information concerning the tissue type and vascularization. One disadvantage is radiation exposure, which can damage the eye lens and therefore should be applied sparingly in young patients.

Angiography, scintigraphy, PET, and SPECT are reserved for exceptional cases. For documentation and planning of reconstructions, photography, 3D photography, and perhaps surface scans also may be relevant 3 .

3.4 Histopathological diagnostics

If a clinical diagnosis cannot be made based on the above-mentioned examination techniques, biopsy with histopathological examination is important and suitable, in particular in the context of unclear or advanced findings, recurrence, or therapy failure. In these cases, the risks of iatrogenic damage should not outweigh the benefit. For targeted planning of biopsy, adequate clinical examination and imaging with subsequent interdisciplinary discussion are advised. The following recommendations should be considered regarding biopsies:

Intake of systemic corticosteroids and other immunosuppressants should be avoided in the weeks before biopsy, if possible.

Incisional or excisional biopsies can be taken for formalin fixation or examinations of fresh material.

The biopsy should afford sufficiently large specimens, as morphological examination of fine needle aspirates is not always possible (and may be sufficient only in cases of lymphoma or metastasis).

Biopsy samples should be taken from different areas of a lesion.

Damage to the examination material should be avoided.

Material should be compared to previous biopsy samples of other organs, if available, for better identification of systemic diseases.

3.5 Laboratory diagnostics

For a multitude of rare orbital diseases, further examinations are useful, in particular adequate laboratory diagnostics. Readers interested in specific details can refer to 4 .

In the following sections, we systematically illustrate the various rarely occurring structural, inflammatory, degenerative, and neoplastic changes involving the orbit.

4. Structural Lesions of the Orbit

Structural lesions of the orbit include congenital and acquired changes. The first category comprises hamartomas, choristomas, teratomas, and tissue ectopy and the large group of bone anomalies. Acquired alterations largely involve post-inflammatory and post-traumatic conditions.

4.1 Cysts and cystic lesions

Cystic lesions may occur as isolated or multiple findings. They are usually more or less spherical and can have different consistencies (e. g., serous, sebaceous, solid, mixed). In general, these lesions are painless masses that grow quite slowly. In the context of secondary inflammatory reactions, a local granulomatous tissue reaction may occur, leading to severe reactive changes and to osteolysis in the area of bone structures.

Below are some aspects that contribute to classification:

Timing of manifestation (congenital or acquired)

Number (isolated or multiple)

Tissue type (epithelial or non-epithelial)

Location

subperiostal

extraconal

conal

intraconal

Etiology

vascular/hematogenous

neurogenic

infectious

metastatic

4.1.1 Congenital cysts and cystic lesions of epithelial origin: dermoids 5 6 7 8

Epidemiology

3–9% of the orbital masses

Etiology

congenital as choristoma

Location

mostly extraorbital (preseptal) in a temporal-superior location, along the frontozygomatic suture (70–90%) ( Fig. 1 )

less frequently in the area of the medial upper eyelid

rarely as intraorbital dermoids

Clinical

well-delimited cystic lesion with slow progression

displacement of adjacent structures

sonographically well-defined, anechoic, oval/round lesion with hyperreflective echoes as an indication of epidermal differentiation (adnexa structures, sebum, cellular detritus), or secondary calcifications

fibrous capsula

Cave : ruptured dermoid cysts induce granulomatous inflammation; acute and chronic courses are known; And transsutural growth is possible (sandglass configuration)

Therapy

complete excision with preservation of the cystic wall; proliferation-active areas (mostly near the bone) especially have to be removed

marsupialization

Cave : incomplete excisions may – although rarely – lead to recurrences; more rare are malignant transformations in the sense of squamous cell carcinomas

Important differential diagnoses

temporal

primary and secondary lacrimal gland tumors

medial

retention cysts and mucoceles (history regarding bone lesions)

meningoceles; encephaloceles

choristomas of the nasal mucosa

general

each solid, non-infiltrative mass with cystic shape

further cystic lesions are conjunctival cysts, epidermoids, and cysts originating from tissue ectopy (e. g., ectopic tissue of Rathke’s pouch), cholesterol granulomas, and cholesteatomas

Note

If a cystic structure is found within the tissue (e. g., the external eye muscle), a secondary process (infection, metastasis) may be suspected.

4.1.2 Acquired cysts and cystic lesions

4.1.2.1 Mucoceles 9 10 11

Epidemiology

3–4% of orbital masses

age peak in the 4 th to 6 th decades of life

Etiology

missing ventilation of the affected paranasal sinus

previous trauma/surgery in 50%

common in children with cystic fibrosis

Location

medial to medial-superior in the orbit, accordingly originating from the ethmoid or frontal sinus

rarely originating from the sphenoid sinus

subperiostal to diffusely intraorbital as a complication of, e. g., orbital phlegmons

Clinical

exophthalmos/bulbar displacement, diplopia ( Fig. 2 )

pain only in the context of secondary inflammatory changes of the orbit; otherwise, often initially painless

displacing growth and secondarily compression of the optic nerve, the ocular bulb, or the draining lacrimal pathways

Cave: enophthalmos is a possible rare complication; possible osteolysis of the orbital floor in the context of “silent sinus syndrome” of the maxillary sinus; opticus atrophy possible with chronic course

Therapy

restoration of adequate ventilation of the affected sinus

excision of the cystic mass

complication management (incision, drainage, intravenous antibiotics)

Note

In cases of fronto-ethmoid location, meningocele/encephalocele must be considered. Hypertelorism and increased size during Valsalva maneuver are additional indicators.

CaveBilateral fronto-ethmoid mucoceles also induce Hypertelorism .

4.1.2.2 Dacryops 12 13

Epidemiology

0.5–2% of orbital masses

usually in the 2 nd to 5 th decades of life

Etiology

occlusion of the glandular excretory duct (after inflammation/trauma)

multifactorial

idiopathic

Location

mostly palpebral part of the lacrimal gland (less frequently: orbital part, accessory lacrimal glands, cysts in the ectopic lacrimal gland tissue, or cysts of glandular tissue of the caruncle; Fig. 3 )

isolated, rarely multiple and bilateral occurrence

Clinical

more or less pronounced paragraph shape of the upper eyelid (temporal pseudoptosis)

foreign body sensation

rapidly increasing size possible in the context of emotional reflex secretion or following bleeding (color change)

depending on the size, astigmatism and/or diplopia

Cave : rarely, secondary bacterial colonization

Therapy

complete excision of cyst(s)

marsupialization, laser photocoagulation

wait-and-see, tear substitute, avoiding cold wind/water

Important differential diagnoses

rarely dacryops as sequela of trachoma, pemphigoid, or dacryolith

4.1.2.3 Orbital implantation cysts 14 15

Epidemiology

heterogeneous data depending on the etiology (most frequently after enucleation with an incidence of 2–7% of cases)

Etiology

posttraumatic (e. g., strabismus surgery, peri- and intraocular surgery, penetrating orbital trauma, enucleation, orbital fracture) because of dissemination of (conjunctival) epithelium

Clinical

slowly growing cystic tumor

Cave : rupture leading to granulomatous inflammation

Therapy

complete surgical excision

4.2 Neurogenic cysts

These rare anomalies are associated with congenital disorders of the eye, optic nerve, or meninges.

4.2.1 Congenital cystic eye 16 17 18

Synonym

anophthalmos with orbital cyst

Epidemiology

quite rare

Etiology

consequence of non-invagination of the primary optic vesicle

multifactorial

Location

central to superior in the orbit (protruded upper eyelid)

Clinical

mostly isolated, rarely syndromic (Orbeli syndrome)

cyst, sometimes lined by neuroglia

missing ocular bulb

possible contralateral occurrence of microphthalmos

mostly associated with systemic pathologies

agenesis of corpus callosum, basal encephaloceles, heterotopia of the gray matter

facial clefts, saddle nose, choanal atresia, sphenoid anomalies

genital malformations

finger malformations

Cave : possible connection to the arachnoid space

Therapy

depending on cyst size, indication for surgical excision

in cases of small, constant cysts, wait-and-see is justified

in cases of high surgical risk, cyst puncture should be considered

Important differential diagnoses

teratomas with a solid component in addition to the cystic part and showing (sometimes rapid) growth

4.2.2 Microphthalmos, microphthalmos with cyst, and anophthalmos 16 17 18 19 20 21 22 23 24

Epidemiology

anophthalmos: 1–4:100 000

microphthalmos: 2–20:100,000; among them 2–5% with additional cysts

microphthalmos with cyst in 2% of cystic orbital lesions

Etiology

sequela of incomplete invagination of the primary optic vesicle

multifactorial

SOX2 gene on chromosome 3 with anophthalmos; additional associated genes (e. g., PAX6, OTX2, CHS10, FOXE3, and RAX)

microphthalmos/anophthalmos, isolated or in the context of syndromic malformations (>30% syndromic;>57% multiple congenital malformations)

predisposing factors

pregnancy-related (vitamin A deficiency, radiation exposure)

infections (e. g., rubella)

diabetes mellitus

substance abuse

medications

consanguinity

Location

unilateral:bilateral ratio, 2:1 for anophthalmos

mostly unilateral microphthalmos

microphthalmos with inferior cyst and protruding lower eyelid (compare delimitation of cystic eye)

Classification of microphthalmos/anophthalmos ( Table 1 , infobox 2 )

unilateral vs. bilateral

with or without other ocular pathologies

with or without systemic manifestation

syndromic or non-syndromic

Clinical

severe malformations and functional blindness of the contralateral eye in 12.5% of unilateral microphthalmos cases and 34.0% of unilateral anophthalmos cases

cerebral pathologies, mainly malformations in the area of the corpus callosum, occurring in cases of bilateral anophthalmos (70%), unilateral anophthalmos (20%), and unilateral microphthalmos (12.5%)

association with clefts

possible association with different internal diseases (cardiovascular, pulmonary, renal, gastrointestinal)

rare associations

Waardenburg syndrome (inner ear hearing loss)

congenital ectodermal dysplasia

Therapy

indication for surgical excision depending on cyst size

in cases of small, stable cysts, wait-and-see is justified

in cases of high surgical risk, cyst puncture possible

enlargement of the hypoplastic orbit with volume expanders

Important differential diagnoses

teratomas, cryptophthalmos ( infobox 3 ) and bulbar phthisis as degenerative (post-inflammatory) alteration (bulbus quadratus)

Note

A continuum has been described, from sighted, severely hyperopic microphthalmos to anophthalmos. The orbit with adnexa structures (eyelids and extraocular muscles) may show near-normal development. Bulbar rudiments that are in part microscopically small can be present so that true anophthalmos can be extremely difficult to define. Some authors diagnose (true, complete) anophthalmos only when histological examination of the orbital contents confirms the absence of ocular tissue. This gray area is why the term ‘clinical anophthalmos’ or ‘incomplete anophthalmos’ was coined

4.2.3 Orbital cephaloceles 16 25 26

Epidemiology

cephaloceles: overall 0.8–5:10,000; occipital in>70% of cases

overall<1% of orbital masses in children

Etiology

deficient separations of neuroectoderm and ectoderm

persisting connections between the neurocranium and the orbit

Classification

anterior (frontal bone, ethmoid bone, lacrimal bone, maxilla)

posterior (sphenoid bone)

Clinical

hypertelorism, pulsatile exophthalmos

painless (pulsatile) tumor

frontal sinus aplasia

rarely bilateral, but if so, then associated with hypertelorism

differentiation between meningoceles (meninges) and meningoencephaloceles (meninges and brain tissue) depending on contents

further skull anomalies possible (sphenoid), hydrocephalus

association with neurofibromatosis

Cave: possible secondary ulceration and infection of the cephaloceles

Therapy

excision and closure of the bone defect

duraplasty

Note

Generally, these lesions are present at birth but sometimes will manifest only later in life (especially when located dorsally).

4.2.4 Other neurogenic cysts 27

Primary arachnoid cysts may be found in combination with ipsilateral ocular colobomas. Nerve sheath cysts as a further entity are associated with other anomalies of the central nervous system (CNS).

4.3 Congenital tumors and tissue ectopy

4.3.1 Dermolipoma 28

Epidemiology

about 2% of orbital tumors in children

Etiology

choristoma

ectopic ectoderm disseminated as epidermal tissue of the eyelids in the area of the conjunctiva and frequently in an intraorbital direction

Location

temporal palpebral area

rarely along the inferior and superior conjunctival fornix

Clinical

often asymptomatic

possibly keratinizing

partly bearing hair follicles

foreign body sensation

Therapy

surgical excision with preservation of the conjunctiva, lacrimal gland, and exterior ocular muscles (lateral rectus muscle) if desired (esthetic) or in cases of irritation of the ocular surface

superficial removal without preparation into the depth of the orbit is sufficient in most cases

Important differential diagnoses

lymphoma

orbital fat hernia ( Fig. 4 )

4.3.2 Ectopic lacrimal gland tissue and other tissue ectopy 29 30

Accessory lacrimal gland tissue is regularly found in the area of the conjunctival fornices (Wolfring’s and Krause’s glands). In the posterior areas of the orbit, this tissue is rarely found. However, it may induce chronic scarring inflammation where it occurs that requires surgical intervention.

In addition, heterotopic cranial tissue and cartilage structures have been described in the orbit.

4.3.3 Orbital teratoma 31 32 33

Epidemiology

6.6% of pediatric tumors, mostly located outside the orbit

quite rare orbital occurrence

Etiology

neoplasm of two or all three germ layers (pluri- to totipotent embryonic stem cells)

Clinical

progressive, unilateral, mostly cystic tumor

proptosis

possible enlargement of the bony orbit by a factor 2 or 3

strongly heterogeneous tissue

complete teratoma as orbital fetus-in-fetu (orbitopagus parasiticus)

incomplete second fetus with parts of a spinal cord

teratoma with evidence of all three germ layers

dermoid tumor with evidence of two germ layers

Therapy

surgical excision

Important differential diagnoses

dermoid, rhabdomyosarcomas, or vascular anomalies

cave :

malignant teratoma of the orbit (in 2% of cases)

intracranial extension

4.4 Bone anomalies and mesodermal defects

4.4.1 Accessory bones and sutures, osseous variations, aberrant foramina 34 35 36

Epidemiology

some types are frequent (duplication of the fronto-zygomatic suture in 7 of 400 skulls)

significant regional differences

found in about 1–2% of the orbits

Etiology

disturbed ossification

classification into variations and congenital deformities

orbit mostly self-determined regarding development (independently from the eye)

anatomical pathways are only secondarily surrounded by bone; nerve and vessel duplications precede bone variations

Clinical

partly clinically completely unapparent

association with dysostoses of the skull

exophthalmos

facial asymmetry

hyper- or hypotelorism

4.4.1.1 Examples of bone variations 34

Accessory sutures and bone fragments (e. g., duplication of the fronto-zygomatic suture, fragmented zygomatic bone with ossiculum infraorbital marginale)

Missing involvement of the maxilla in the development of the inferior orbital margin (incidence of 1:2250)

Malformations of the ethmoid bone where the frontal bone forms the medial orbital wall

Frequent dehiscence of the lamina papyracea

Incomplete presence up to complete absence of the lacrimal bone; variations of the lacrimal hamulus and thus variations of the lacrimal sac and nasolacrimal duct

Accessory ossicles in the area of the frontal maxillary process

Maxillary hypoplasia

Duplication of the anterior lacrimal crest

4.4.1.2 Examples of foramina variations 34

Supra- and infraorbital foramina in form of channels, incisions/sulcus, multiple primordia

Duplication of the optic canal/missing optic foramen in cases of anophthalmos

Up to four-fold primordium of the zygomatico-facial foramen

Up to five-fold primordium of the infraorbital foramen (double primordium in>10%)

Trochlear spine (simple, double, or as ring)

Bony separation of the inferior orbital fissure by an accessory bone bridge

4.4.1.3 Examples of wall defects 34

Unilaterally missing development of the frontal bone and the maxilla (frontal lobe covered only by meninges and skin; clinically also without presence of cephaloceles with downward displacement of the eyeball and divergence)

Cave : association with cyclopia and arhinencephaly, rare coincidence with phacomatoses, e. g., in cases of neurofibromatosis (malformations in the area of the sphenoid bone)

4.4.1.4 Examples of wall dehiscence 34

Infantile and sometimes senile physiological occurrence

Especially in the area of the maxilla and the ethmoid bone

More rarely in the area of the lacrimal bone, palatine bone, or sphenoid bone

Cave :

optic canal variation because of absent parts of bone surrounding the optic nerve and the resulting direct communication between the dural sheath and sphenoid mucosa

association of orbital varices with bone dehiscence or misinterpretation of phleboliths

4.4.2 Cribra orbitalia 34 35

Thinning of the orbital roof with exposed diploe and contained venous plexus because of a bone development disorder (differential diagnosis of vitamin D deficiency, anemia).

4.4.3 Familial hypoplasia of the orbital margin (Urrets-Zavalia syndrome) 34

Epidemiology

extremely rare (<1:1 000 000; described in two families to date)

Etiology

genetic agenesis of the orbital margin and parts of the ocular adnexa structures

dominant inheritance (high penetration, constant expression)

involves tissue of the paraxial and visceral mesoderm

Clinical

missing bony orbital frame

hypoplasia of the eyelid skin and palpebral tarsus

variable defects with disorders of the draining nasolacrimal pathways, eyelid coloboma, vertical strabismus

Note

Accessory bones and sutures or aberrant foramina often have no pathological significance but sometimes must be considered in the context of sinus, orbital, and lacrimal duct surgery.

4.4.4 Facial clefts, facial dystrophy, craniofacial dysostoses, and malformations of the skull 34 37 38

Complex facial deformities originating from a disorder of embryogenesis in the area of the first and second pharyngeal arches.

4.4.4.1 Rare facial clefts (including Tessier clefts) 37 38 39

Epidemiology

1–5:100 000

Etiology

lack of fusion of embryonic tissues of the first pharyngeal arch (association with malleus and incus malformations)

early developmental stage (embryonic weeks 5–8)

in later stages because of umbilical cord trauma (atypical cleft, amniotic band syndrome)

Typical type

oro-ocular or oro-orbital facial cleft

transverse and diagonal clefts

clinical

numerous manifestations

partly medial eyelid colobomas

Atypical type

oro-temporal facial cleft

clinical

temporal eyelid colobomas

association with dermoids, ear adnexae, other facial deformities (cleft lip and palate)

anophthalmos, microphthalmos, uveal coloboma

Tessier clefts 38 40

15 types (0–14), possible course from the maxilla via the orbit to the frontal bone

Groups

midline clefts

paramedian clefts

orbital clefts

lateral clefts ( Fig. 5 )

Therapy

plastic reconstruction by maxillofacial surgeons to close the soft tissue and bone defect, orthodontic treatment

phoniatrics/pedaudiological involvement

if needed, oculoplastic intervention for eyelid correction or coloboma closure

4.4.4.2 Facial dystrophy, craniofacial microsomia 37 41

Epidemiology

1:3000 to 1:5000

Etiology

disturbed embryogenesis (concerning the first pharyngeal arch)

Clinical

jaw bones

asymmetric midfacial hypoplasia

ankyloses

micrognathia

eye

dermoid (epibulbar)

upward or downward displacement of the globe

anophthalmos/microphthalmos

eyelid coloboma

mouth

macrostomy (clefts)

facial clefts

skeletal system

changes in the spine

cranial nerves

facial nerve palsy

sensory hearing loss

palatal lift disorder

ocular muscle paresis

ear

ear adnexae

microtia/anotia

auricular canal atresia

conductive hearing loss

Cave : rare association with tetralogy of Fallot, ventricular septum defect, transposition of the major vessels, aortic arch anomalies, kidney malformations (absence of one kidney, duplicate ureter, renal ectopy), hydronephrosis, hydroureter, anomalies of the extremities (ulna, radius), microcephaly, encephalocele, hydrocephaly, corpus callosum hypoplasia, Arnold-Chiari malformation, holoencephaly

present as syndromes: VA(C)TER(L) – v ertebral a nomalies, anal atresia, c ardiac anomalies, t racheo e sophageal atresia, r enal anomalies, and l imb anomalies; or CHARGE – c oloboma, h eart, a tresia choanae, r etardation of growth and development and g enitourinary and e ar anomalies

Types ( Table 2 )

otocephaly

mandibulo-facial dysostosis

oto-mandibular dysostosis

oculo-auricular dysplasia

mandibulo-oculo-facial dyscephaly

oculo-vertebral dysplasia

microgenia and glossoptosis

4.4.4.3 Facial (hemi)atrophy (Parry-Romberg) 42 43

Synonym

progressive facial trophoneurosis

Epidemiology

1:700 000

females more frequently affected than males

Etiology

uni- or rarely bilateral disorder of the soft tissue and bone because of missing/insufficient innervation (cranial nerves V and VII)

Clinical

slowly progressive, generally unilateral atrophy of the facial soft tissue including muscles as well as some of the bony-cartilaginous structures

facial asymmetry

highly variable disease activity over 2 to 20 years until self-limiting stagnation

malformation of the external auricle (misplaced ear, auditory canal atresia, adnexae, reduced ossicles, small tympanum)

unilateral micrognathia

hypoplastic mastoid

atrophic facial muscles, yellowish skin (possible hypo- and hyperpigmentation), lanugo hairiness with otherwise alopecia

temporally sloping axis of the eyelid, enophthalmos, lagophthalmos, pseudoptosis (differential diagnosis of associated Horner’s syndrome)

exposed facial nerve in the middle ear

atrophy of soft palate and tongue (speaking and swallowing disorders)

saber-like scleroderma along the medial orbital skin

heterochromia, blepharophimosis, coloboma, oculo-motor paresis, partly nystagmus

Cave:

rare hemiatrophy of the entire body

frequent occurrence of orbital tumors (among others neurinomas)

Therapy

systemic medication (including glucocorticoids, cyclophosphamides, methotrexate) and local therapies (among others PUVA, botulinum toxin, phototherapy)

surgical therapy options for stabilization or reconstruction in cases of periocular changes

Important differential diagnoses

facial hemihypertrophy

unilateral hypertrophy of one side of the body

exophthalmos with megalophthalmos

congenital facial nerve palsy (Möbius syndrome)

4.4.4.4 Craniofacial dysostoses 44 45 46 47 48

Extreme heterogeneity of diseases with different nomenclature

Epidemiology

syndromic and non-syndromic

3–10:10,000

syndromic types occur 10–50 times more rarely; extremely rare types<1:1,000,000 (e. g., Boston syndrome)

most frequent syndromes

Crouzon syndrome

Pfeiffer syndrome

Saethre-Chotzen syndrome

rare syndromes

Boston syndrome

Cole-Carpenter syndrome

Herrmann-Opitz craniosynostosis

craniosynostosis, Philadelphia type

cardio-cranial syndrome, Pfeiffer type

Jackson-Weiss syndrome

Hunter-McAlpine craniosynostosis

Lopez-Hernandez syndrome

Baller-Gerold syndrome

Etiology

primordial disorder of the bone, premature closure of affected sutures

increased volume expansion in one direction because of expansive cranial growth and blockage in the other direction (Virchow’s rule: blockage perpendicular to the synostosis and compensatory growth along the synostosis)

metopic suture (physiologically open up to the 8th month of life), sagittal suture, lambdoid suture, coronal suture not open until adulthood

manifestation of the disease typically in the 1 st to 4 th years of life

Clinical

skull deformity with or without orbital involvement

exophthalmos, hyper- and hypotelorism, strabismus

increased intracranial pressure (headaches, papillary edema, opticus atrophy)

encephalocele

syndactyly

ear malformations (auricle, external auditory canal, middle ear)

association with metabolic disorders (hyperthyroidism, vitamin D–resistant hypophosphatemia, mucopolysaccharidosis [associated with dysmorphia of the head, formerly called gargoylism], and mucolipidosis), chondro- and osteodystrophies (e. g., achondroplasia)

4.4.4.4.1 Cleidocranial dysostosis 44 49

Hypoplastic dysostosis of the skull with brachy- or platycephaly ( Fig. 6 )

Dental anomalies

Pseudoarthrosis, hypoplasia or aplasia of one or both clavicles

Hypoplasia of the nasal bone and maxilla

Elevated palate

Possible deformities of thorax, pelvis, and extremities

Spina bifida

4.4.4.2 Oxycephaly (acrocephaly, tower skull) 44 45 46 47 48

Male:female ratio, 4:1

Vertical elongation of the skull

Transverse and sagittal shortening

Coronary and facial synostoses

Reduction of the skull base

Prominent nose, hypoplastic maxilla, narrow palate

Flat orbits with small volume

Supraorbital pronounced exophthalmos, strabismus, motility disorders, nystagmus, exposition keratopathy, mild hypertelorism

Papillary edema, opticus atrophy

Retinal vascular stasis, tortuositas vasorum

Eyelid edema

Rare associations: cataract, corneal dystrophy, eyelid coloboma, orbital encephaloceles

Often minor impairment of intelligence ( Cave : apparent intellectual disability often possibly a consequence of psychosocial stigmatization and not biological)

Classic syndrome: Apert syndrome (acrocephalo-syndactyly)

Oxycephaly with exophthalmos, exposition keratopathy, ophthalmoplegia, papillary edema, opticus atrophy

Syndactyly (second to fourth fingers/toes); synarthroses (shoulder, elbow)

4.4.4.3 Scaphocephaly (sphenocephaly) 44 45 46 47 48

Synostosis of the sagittal suture

Long small shape of the head

Low width of the skull with hypotelorism

Sagittal synostosis

4.4.4.4 Brachycephaly 44 45 46 47 48

Synostosis of the coronal or lambdoid sutures

Short, broad skull

Intermediate between scaphocephaly and oxycephaly

4.4.4.5 Dolichocephaly 44 45 46 47 48

Prominent frontal skull

Coronal, sagittal, and/or lambdoid synostoses

Coronal representative: Crouzon syndrome

prominent front, typical shape of the nose (parrot beak)

hypoplastic maxilla, prognathism, malpositioned teeth, elevated palate, partly with cleft formation

diverging strabismus, lacrimal duct stenosis, papillary edema, opticus atrophy, exposition keratopathy, ocular coloboma, glaucoma, ectopia lentis

ear anomaly (auditory canal atresia, auricular anomaly)

4.4.4.4.6 Plagiocephaly 44 45 46 47 48

Sagittal asymmetry

Unilateral synostosis of different sutures

Classified into:

anterior type

unilateral synostosis of the coronal suture

hypoplastic ipsilateral orbit

orbital roof with declining axis in temporal direction

posterior type

closure of the lambdoid suture

to be delimited against acquired positional plagiocephalus by differential diagnosis

4.4.4.4.7 Hemicraniosis 44 45 46 47 48

Prominent frontal bone, parietal bone, and zygomatic bone

Significant asymmetry

Exophthalmos and opticus atrophy

4.4.4.4.8 Trigonocephaly 44 45 46 47 48

Frontal cranial dysplasia (synostosis of the metopic suture) with occipital compensation

Also with coronary synostosis

Hypotelorism

Opticus atrophy

Narrow anterior cranial fossa

Hypoplastic ethmoid sinus

4.4.4.4.9 Platycephaly (clinocephaly) 44 45 46 47 48

Increased posterior cranial fossa with overriding of the cervical spine

Synostosis of the superior sutures

Therapy:

conservative by changing the skull position, i. e., through physiotherapy or helmet wearing

correction or prevention of increased intracranial pressure

treatment of the head deformity (functional/psychosocial indication)

surgery techniques:

open or minimally invasive suturectomy

suturectomy and removal or remodeling of single bone fragments, if needed as fronto-orbital advancement

cranial distraction

4.4.4.5 Hypertelorism 37 44 45

Interorbital distance of>30 mm

Association with craniosynostosis or cleft formation in the maxillary and facial area, but also isolated

Rare occurrence of frontal or frontobasal encephaloceles

Classification

primary

morphogenetic (habitual) because of disproportional growth

embryonic because of developmental disorders (e. g., Apert and Crouzon syndrome) with nasal cleft (rarely duplicate nasal septum, dermoid)

secondary

developmental disorder attributable to environmental factors (trauma, encephaloceles, diseases of the cartilage or bone)

4.4.4.6 Median cleft face syndrome 50

Synonym/manifestation

cyclopia, holoprosencephaly, arhinencephaly, otocephalic anomalies

Epidemiology

1:16 000 live births

Etiology

complex cerebral malformation with missing hemisphere separation

cyclopia from disturbed balance of excitation and inhibition processes of development and concerning the entire cranial position

Clinical

sometimes presence of proboscis as rudiment of the nasal apparatus

malformations such as completely missing eyes (anophthalmos) or face (aprosposus, i. e., missing eyes and olfactory and gustatory organs) as well as presence of one (cyclopia or synophthalmia) via three (diprosopus triophthalmus, cephalotheracopagus) or four separated eyes (tetrophthalmus) possible

starting at the optic nerve, possible separated presentation of both eyes and orbits from posterior in anterior direction (for example, a single cornea with otherwise duplicated tissues)

many clinical variations with fluent transition, e. g., median facial clefts, microphthalmos, anophthalmos, cyclopia, hypotelorism (facial dysmorphia correlating with cerebral anomaly)

isolated or in the context of syndromes (including CHARGE, Smith-Lemli-Opitz syndrome, Rubinstein-Taybi syndrome, Meckel syndrome, Lambotte syndrome, Steinfeld syndrome)

complications

neurological: epilepsy, hydrocephalus, developmental intellectual disability, hypotonia, spasms

craniofacial: microcephaly, hypo- or hypertelorism, median and lateral clefts (concerning lips, maxilla, and palate), arhinia, hypoplasia of the piriform aperture

endocrinological: diabetes insipidus, growth hormone deficiency, hypoplasia of the adrenal cortex, hypogonadism

otomotor dysfunction: speaking and swallowing disorders, gastroesophageal reflux, necessity for gastrostomy

vegetative dysfunctions: temperature regulation, heart and respiratory rate control

life expectancy

unfavorable prognosis, lethal in early childhood (mean mortality at age 4 years; 15% between ages 10 and 19 years)

Therapy

symptom-based

4.4.5 Developmental disorders of the bones

4.4.5.1 Fibrous dysplasia 51

Etiology

mesenchymal defect of the bone spongiosa and the bone marrow and replacement by fibrous tissue

Clinical

subtypes:

affecting only one bone (monostotic)

affecting several bones (polyostotic)

McCune-Albright syndrome (severest type of microsomia, endocrine and pigment disorders of the skin)

possibly affecting skull

in cases of cranial location, orbital involvement in>40%

atypical facial pain and headache

sinusitis

hearing disorders

exophthalmos

facial asymmetry

Therapy

surgical decompression (optic channel, orbit) in cases of clinical complaints such as optic neuropathy

surgical excision of involved areas with consideration of functional aspects (curative surgery is not possible; basically, a benign disease)

Cave : radiation therapy contraindicated because of the high risk of malignant transformation

4.4.5.2 Osteopetrosis 52

Epidemiology

1:250 000 to 5:100 000 (dominant inheritance)

Etiology

disturbed differentiation of osteoclasts

increasing bone substance with reduced stability

Clinical

macrocephaly, craniofacial dysmorphia

fractures, microsomia

nerve compressions (blindness, deafness, facial palsy)

osteomyelitis

hydrocephalus, pituitary hypoplasia, cerebral demyelination

choanal atresia

dental anomalies, double tooth series, palatal cleft, caries

disturbed calcium balance, secondary hyperparathyroidism

retinal atrophy, cataract

disorder of the hematopoiesis with risk of pancytopenia, hepatosplenomegaly

manifestations; types:

autosomal recessive osteopetrosis (ARO) (malignant type)

neuropathic type of ARO

association with renal tubular acidosis (i. e., RTA)

X-linked osteopetrosis with lymph edema, anhidrotic ectodermal dystrophy, and immune deficiency (i. e., OLE-DAID)

common variable immune deficiency (i. e., CVID)

leukocyte adhesion deficiency syndrome (i. e., LAD-III)

autosomal dominant type (Albers-Schönberg disease)

pyknodysostosis

dysosteosclerosis

osteopoikilosis (with occurrence of connective tissue naevi as Buschke-Ollendorff syndrome)

osteopathia striata (with or without cranial sclerosis)

Therapy

symptomatic, depending on the manifestation of the functional disorder or complication (e. g., surgical decompression of the optic nerve)

multi- and interdisciplinary approach

vitamin D substitution

transfusion if needed

4.4.5.3 Cherubism 53

Etiology

different inheritance pathways, probably mainly dominant with high penetration

cystic proliferation of the mandible and maxilla

Clinical

disease onset in early childhood (2nd to 5th years of life)

various courses, sometimes clinically almost undetectable

prominent chin and cheeks, irregular tooth position

eyes displaced in upward direction, proptosis, diplopia

coarse bone swellings

occasional association with regional lymphadenopathy

spontaneous involution after bone growth (at about age 30 years)

Cave : dysarthria, dysphagia, and dyspnea possible

association with Ramon syndrome, neurofibromatosis type 1, and fragile X syndrome

Therapy

surgical resection of the affected region under functional aspects

Cave:

possible activation of disease by surgery

radiotherapy contraindicated (osteoradionecrosis, malignancy induction)

Note

Cleft formation and other craniofacial malformations show a broad variation. They may appear as isolated or as syndromic findings. Clinically, the courses are sometimes highly complex with vital risks. The early detection and treatment of these complication-associated conditions are the major challenge in this group of diseases. The interdisciplinary approach is multimodal; often several surgical interventions are necessary.

4.5 Conclusion

In cases of structural anomalies of the orbit, orbital bone malformations have to be delimited from ocular pathologies. The first category encompasses mainly craniosynostoses that may occur as isolated findings or in the context of syndromes. Ocular malformations may be associated with orbital lesions (e. g., Goldenhar syndrome) or lead to them. The development of the orbit can occur completely independently from ocular organogenesis. Dermoids are the most frequently observed congenital lesions of the orbit. The major challenges are complications that require the attention of members of the neurological and/or neurosurgical disciplines (e. g., encephaloceles, hydrocephalus).

The acquired structural anomalies include mainly posttraumatic changes or sequelae of surgeries and/or radiation. These changes are highly variable and occur rather frequently.

Knowledge of possible structural changes is essential for successful therapy. The observation of the close neighborhood of the orbit to the skull is extremely important. Regarding diagnostics, appropriate imaging procedures for further topographic assessment are essential. For therapy, often an interdisciplinary exchange with neuro- and ophthalmic surgeons is necessary, initiated by the primarily treating discipline (usually ENT/maxillofacial surgery).

5. Inflammatory Diseases of the Orbit

There are many inflammatory lesions of the orbit. Below, an overview is given with classification into infectious and non-infectious types.

5.1 Infectious orbital inflammation

Infectious cellulitis is the most frequent cause of orbital inflammation. It develops mainly from inflammatory processes of the paranasal sinuses, face, oropharynx, and ocular adnexa structures, but sometimes can arise because of foreign bodies or septic dissemination. The causes are a large spectrum of bacterial and viral pathogens, fungi, and parasites.

5.1.1 Bacterial inflammation (orbital cellulitis)

The most frequent origins of infectious orbital inflammation are orbital complications of purulent sinusitis, which will not be dealt with in this article on rare orbital diseases. For reviews of their classification, pathogenesis, diagnostics, and management, see 54 55 56 57 58 59 60 61 62 63 64 65 66 67 .

The identification of rare pathogens may be a challenge but is crucial for affected patients because the diseases can entail a high local and systemic morbidity, independent of their rarity. Opportunistic infections must be considered especially in immunocompromised and previously affected patients 58 . The keys to successful management are a high index of suspicion, prompt diagnosis, and adequate therapy of the underlying disease.

5.1.1.1 Tuberculosis

In recent years, the incidence of tuberculosis has increased because of resistant strains and the distribution of immunosuppressant agents.

Pathogenesis: in cases of tuberculosis, the involvement of the orbit may occur via two different pathways:

hematogenic dissemination with two manifestation types in the orbit:

periostitis (more frequent): slow course with cold abscess, sequesters, and fistulas; mainly young patients affected; mostly located in the zygomatic bone

tuberculoma (rarer): infiltrative orbital mass, sometimes associated with neurosensory deficit

direct spread from contagious neighboring structures (paranasal sinuses or lacrimal gland); causes necrotizing infiltrative lesions, partly with cutaneous fistulas 60

Clinical

painful movement impairment, no intraocular lesions, rather non-specific symptoms leading to late diagnosis

very rarely also atypical mycobacteria (mycobacterium hominis; mycobacterium avium)

Cave : especially in cases of cold abscess, wet cavities or (very rarely) complicated sphenoid osteomyelitis because of optic neuropathy, clinical suspicion often more important than blood culture for diagnosis 58

Diagnostics

biopsy with caseating granulomas, culture of acid-proof rods (gold standard) is difficult 61

additional diagnostics: skin test (tuberculin test) and serology (interferon-γ release assay [IGRA] as well as molecular pathological PCR diagnostics from biopsies) 60]

Therapy

timely tuberculostatic triple therapy (isoniazid, rifampicin, ethambutol) by specialists (not only after evidence of positive culture; the associated constellation of clinical and molecular pathological findings is crucial)

indication of surgical intervention for symptom relief, e. g., in cases of vision loss 58

in cases of interaction between HIV and tuberculosis, sometimes complex management 60

5.1.1.2 Syphilis

This venereal disease, which currently affects mainly immunosuppressed patients and men who have sex with men, is caused by Treponema pallidum and can involve the orbit because of post-primary hematogenic dissemination. In the orbit, it manifests as painful periostitis or a soft tissue lesion after latency 61 .

Clinical

in cases of posterior manifestation, painful apex orbitae syndrome

focal or diffuse syphilitic periostitis into the orbital bone

occurrence of intraconal soft tissue lesions, in the extraocular muscles, or the lacrimal gland

Diagnostics

serological confirmation of the diagnosis by means of a fluorescence Treponema antibody absorption test

Therapy

complete healing with antibiotic therapy with penicillin G 61

5.1.1.3 Necrotizing fasciitis

Necrotizing fasciitis of the orbit is an ophthalmological emergency but quite rare because of the good blood supply. Because of rapid progression, it can lead to death when the diagnosis is made too late 58 .

Epidemiology

incidence of 0.24:100 000 62

Classification 63

type I: polymicrobial, e. g., aerobic and anaerobic bacteria (especially in patients with multiple morbidities) ( Fig. 7a–d )

type II: at about 80%, the most frequent type 64 (single bacterial pathogens, mostly beta-hemolyzing streptococci of group A; superantigens and exotoxins as most important virulent factors)

type III: mainly vibrio bacteria; rarely occurring in Europe

type IV: fungi

Etiology

penetrating traumas are the most frequent triggers (35%), along with surgeries as well as acute infections of the paranasal sinuses, efferent lacrimal ducts, or skin, and pharmaceutical immune suppression or malignancies

unknown trigger in 25% of cases 64

Risk factors

greater age, alcohol and drug abuse, diabetes mellitus, collagenosis, and cardiovascular disease

in 50% of cases, no risk factors present 64

Clinical

early detection possible because of thin skin near the eye

severe pain possible even prior to skin changes (“pain out of proportion”) 62

fever and intensive sweating

gangrene development within a few hours with livid, blistering skin discoloration

risk of blindness in cases of central artery closure 58

toxic shock syndrome in 30% of cases

Diagnostics

based on clinical symptoms

scores, e. g., LRINEC 65 , imaging for rapid diagnosis and delimitation of other infections such as mucormycosis possibly helpful

Therapy

intensive debridement (mainly subcutaneous near the eye, sometimes repeatedly performed 66 up to exenteration as ultima ratio 67 ) in combination with broad spectrum antibiotics (mostly broad-spectrum penicillin or cephalosporins plus clindamycin/vancomycin; see 2009 DGHNO consensus paper 68 )

exclusively additive effect of hyperbaric oxygen therapy and immunoglobulins 63

Prognosis

mortality varies between 8 and 14%, especially high in cases of systemic complications such as toxic shock syndrome with multi-organ involvement, periorbital necrotizing fasciitis with blindness, or involvement of facial soft tissue 64 66

reduction in mortality possible through high index of suspicion and immediate therapy 58

5.1.1.4 Non-infectious (non-bacterial) osteomyelitis in childhood

Epidemiology

very rare, non-infectious inflammation with multifocal bony lesions and periodic exacerbations of painful swellings

synonym: chronic recurrent multifocal osteomyelitis (CRMO)

pediatric equivalent of SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis)

prevalence: 1–2:1,000,000

age peak around 10 years 69

Etiology

multifocal bony lesions

frequent association with other chronic inflammatory diseases, e. g., rheumatoid arthritis (RA), Crohn’s disease, sacroiliitis, psoriasis, or gangrenous pyoderma 70

Clinical findings in cases of orbital involvement

cephalgia

hyperemic swelling

Diagnostics

CT scan: osteolytic findings

scintigraphy: focus with increased uptake

histology: lesions with osteoblastic/osteoclastic remodeling, granulomatous infection infiltrates with giant cells

biopsy of involved bone needed for confirmation of diagnosis and exclusion of differential diagnoses (e. g., Langerhans cell histiocytosis, osteoblastoma, osteosarcoma)

Therapy

first choice: NSAIDs (e. g., naproxen)

alternative: bisphosphonate or biologicals such as TNF antagonists (etanercept) or IL-1 inhibitors (anakinra)

Prognosis

unfavorable course of CRMO is possible (in contrast to earlier opinions) with persistent chronic pain and physical impairment in up to 50% of cases 71

Important differential diagnosis: infectious osteomyelitis of the orbit

another rare disease in the area of the orbit

etiology: mostly after previous trauma, inflammation (paranasal sinuses, dentogenic, or secondary after bacteremia in the context of intravenous drug abuse or leukemia) 72

Clinical: in acute stages, fever and swelling; in chronic courses, sequesters and fistulas

many other possible differential diagnoses, including bacterial cellulitis, atypical pathogens (tuberculosis), neoplasms as in Ewing sarcoma

5.1.2 Orbital fungal infections

Fungal infections as the origin of orbital inflammation are quite rare; however, this aspect should always be considered in immunocompromised patients. The most frequent infections are caused by Phytomycetes ( Mucor spp.) and Ascomycetes ( Aspergillus spp.).

5.1.2.1 Rhino-orbital mucormycosis

Mucormycosis is a rare infectious disease with high mortality. There often is a delay to diagnosis, and the disease is characterized by quick deterioration. Rapid surgical and medical treatment may be lifesaving 73 .

Pathogenesis

ubiquitously occurring pathogen that leads to endothelial damage, ischemia, and the typical necrotic eschar (missing in early stages) because of angioinvasion

affecting the lung, skin, and gastrointestinal tract, but most frequently the paranasal sinuses with involvement of the orbit and finally also intracranial involvement via the orbital apex/lamina cribrosa

Etiology

almost always associated with another factor, e. g., uncontrolled diabetes mellitus (especially in cases of ketoacidosis), malignancies, burn injuries, hemochromatosis, post kidney or stem cell transplantation, intake of the chelating agent deferoxamine, AIDS

Clinical

general symptoms: fever, fatigue, pharyngitis

rhino-orbital symptoms: acute pansinusitis with purulent rhinorrhea, pain, and massive crust formation (black crusts at the nose and palate), subsequent apex-orbital syndrome with sudden loss of vision and ophthalmoplegia, stupor with intracranial extension with cavernous sinus thrombosis 58

Diagnostics

suspected mucormycosis and rapid biopsy examination in cases of unclear facial complaints, paresthesia, swellings, and rapidly progressive sinusitis in patients with relevant comorbidities 74

Therapy

pharmacotherapy of first choice: liposomal amphotericin B

other pharmacotherapy: isavuconazole and posaconazole, especially for salvage therapy 73 75

repeated and extensive debridement almost always required

exenteration necessary when the orbital apex is affected, but not mandatory in cases of affected anterior orbital parts 76

Prognosis

formerly almost always lethal, but survival rate of ~70% with the introduction of amphotericin B 58

in recent years, lethal courses observed in immune-healthy patients – especially after injuries or insect bites in warm climates – because of mucor infections caused by a new pathogen strain ( Apophysomyces elegans ) 58

5.1.2.2 Aspergillosis of the orbit

Aspergillus spp. are ubiquitous and generally colonize the mucosa of the upper airways as harmless saprophytes. As opportunistic pathogens, they play a major role in immunocompromised patients (e. g., after kidney transplantation).

Classification: two types of courses are differentiated regarding infections of the head and neck:

non-invasive

because of a pre-existing lesion of the mucosa (mostly in the context of chronic sinusitis), colonization with formation of so-called fungus balls or chronic allergic rhinosinusitis

occurrence also in healthy patients

rarely affecting the orbit 77

invasive

in cases of impaired immune competence (e. g., because of leukemia or AIDS), rapid distribution by vascular invasion with tissue necrosis, via ethmoid and sphenoid sinus into the orbital apex, the cavernous sinus, and in the intracerebral direction; development of thromboses and aneurysms with high mortality 78 79 80

possible hematogenous dissemination from pulmonary infection foci or because of contaminated needles with heroin abuse 61

Clinical

invasive type: similarly fulminant manifestation as for mucormycosis

non-invasive type: mostly slowly progressive indolent mass developing in the paranasal sinuses with extension in direction of the orbit, often pre-existing sinusitis

isolated involvement of the sphenoid sinus with optic neuritis without involvement of the orbit is possible 81 82

Diagnostics

rather low sensitivity and specificity of the single test procedures, warranting identification by a combination of imaging (CT scan, MRI), microbiological examinations (direct microscopy, culture, PCR, biomarker), and histopathology (branch-like septated hyphae, chronic-fibrous granulomatous inflammation) 83

because of non-specific symptoms (minor sinusitis, retrobulbar, partly neuropathic pain, apical orbital inflammation difficult to identify by imaging), particular attention is needed in the context of diagnostic procedures 59

Important differential diagnoses

bacterial cellulitis, cavernous sinus thrombosis, Tolosa-Hunt syndrome

tumors of the orbital apex or the sphenoid sinus

Therapy

antifungal therapy with liposomal amphotericin B until exclusion of mucormycosis, followed by a shift to the more effective voriconazole 84

extensive debridement of the infected tissue, especially in the context of the invasive type

Prognosis

good in immunocompetent people and localized, non-invasive type with adequate therapy 85 ( Fig. 8a-d )

poor in invasive type

almost always lethal in cases of intracranial extension in immunocompromised patients 86

5.1.2.3 Other mycoses

Outside of Europe, other pathogens may be responsible for fungal infections of the orbit 58 59 , including:

North American blastomycosis

Fusariosis

African histoplasmosis

Sporotrichosis

Rhinosporidiosis

Coccidioidomycosis

Candidiasis

Bipolaris hawaiiensis

5.1.3 Viral infections

Orbital effects from viruses are rare; however, these microbes may cause diseases based on infection or secondary immune phenomena, including:

Varicella zoster virus (VZV): acute myositis, optic neuritis

Mumps virus: acute dacryoadenitis

Epstein-Barr virus (i. e., EBV): acute dacryoadenitis, some cases associated with T cell lymphomas of the orbit and the paranasal sinuses 61

5.1.4 Parasitoses

Infestation of the orbit is also possible by larvae of different parasitic worms. In Germany, echinococcosis ranks among these rare diseases of the orbit.

5.1.4.1 Cystic echinococcosis

Epidemiology

occurring worldwide, especially when humans and animals live in close proximity

mainly patients between the 1 st and 4 th decades of life 59

endemic distribution in Central and South America, Middle East, North Africa, China, and Russia

Pathogenesis

excretion with feces of eggs of adult tapeworms from the gut of carnivores (e. g., dogs)

intake of eggs by herbivores (e. g., sheep, cattle) as intermediate hosts or humans via the consumption of contaminated vegetables

distribution of the eggs in intermediate host via the blood circulation into the tissue and intake by the final host with food

growing in the final host until the final larval stage

effects in the lung and liver are most frequent, with orbital involvement in 1% of cases 88 89

Clinical

slowly progressive, indolent, intraconal mass

increasing proptosis and motility disorder 88 89

possible thinning of the orbital wall with intracranial extension

rupture of the cystic wall (spontaneous or in the context of surgical excision) may lead to fulminant inflammatory or anaphylactic reaction 61

Diagnostics

well-defined cystic structure by ultrasound and CT scan with contrast-enhancing margin 90

hemagglutination and enzyme-linked immunosorbent assays for antibodies available but with sensitivity of only 50% in cases of isolated orbital involvement 61

Therapy

classic: surgical excision

alternative: different recommendations 91 92 , e. g.:

monotherapy with albendazole over 3 months; in cases of concomitant inflammation additionally systemic corticosteroids

combination of albendazole, praziquantel, and surgical excision

in cases of unclear diagnosis or compression-induced loss of vision, surgical excision required 61 , fine needle aspiration may be applied for diagnostics and therapy (albendazole injection) 59

5.1.4.2 Cysticercosis

Epidemiology

endemic occurrence in countries with poor sanitary conditions (Latin America, parts of Asia, and in South Sahara)

Pathogenesis

caused by the parasite Taenia solium (pork tapeworm)

intake of eggs via underdone pork and hematogenous distribution

formation of encapsulated larvae with preferential colonization in the eye and brain (neurocysticercosis, life-threatening) 61

Clinical

at the eye, often subconjunctival, intravitreal, and retinal involvement

in the area of the orbit, mainly extraocular muscles affected 93 94

Therapy

surgical excision and pharmacotherapy with albendazole or praziquantel

reduction of the concomitant inflammation by steroids 95

5.1.4.3 Trichinosis

Pathogenesis

intake of encapsulated larvae by ingestion of underdone pork

in the gut, development of larvae into roundworms, development of new larvae, and hematogenous distribution

development of cysts in the striated muscles

Clinical

first manifestation often in the extraocular muscles

preseptal edema, chemosis, and painful myopathy

Therapy

pharmacotherapy with thiabendazole 59 61

5.1.4.4 Ophthalmomyiasis

Etiology

caused by botfly larvae in tropical regions

Clinical

the symptoms vary from mild conjunctivitis to destruction of the entire orbit

Therapy

removal of the larvae

disinfection up to exenteration in cases of severe disease

5.1.4.5 Other parasitoses and fly larvae with possible eye involvement 96

Cestodes

Dirofilaria

Loa loa

Onchocerca volvulus

Oxyuris

Plasmodia

Porocephalus armillatus

Schistosoma

Thelazia

Wuchereria bancrofti

5.2 Non-infectious orbital inflammation

5.2.1 Introduction

In the proper sense of the word, orbital inflammation is not a diagnosis 97 . The inflammation corresponds to the adaptive response of the immune system to a cause, e. g., an infection or injury, and to autoimmune disease. In 20% of tumoral lesions of the orbit, an association with inflammation is found 98 . The detection of the underlying disease is often a major challenge. Common characteristics are signs of clinical inflammation as well as the histological manifestation of a polymorphic inflammatory cell infiltration 59 . With regard to occurrence and intensity, a significant variability is observed 99 . Endocrine orbitopathy as the most frequent non-infectious inflammatory change in the orbit will not be discussed because it falls outside the scope of this article covering rare diseases of the orbit.

5.2.2 Idiopathic orbit inflammation

Idiopathic orbit inflammation (IOE) was formerly known as ‘pseudotumor orbitae’. encompasses a heterogeneous group of diseases characterized by orbital inflammation without an identifiable local or systemic cause. It is a rare entity as well as an exclusion diagnosis 100 , characterized by an increase in mass of orbital structures, which may be caused by non-specific inflammatory, sometimes fibrotic, and rarely even destructive lesions 61 . The pathophysiology is not fully clarified; an autoimmune genesis that might be triggered by infections has been proposed 99 . Several classifications have been suggested, but none are generally acknowledged because of the highly variable clinical and pathologic properties 101 102 103 .

IOE may affect every orbital structure, and the first manifestation varies from acute onset to a slowly progressive course.

Depending on the location, the following differentiations can be made 61 :

Idiopathic dacryoadenitis: isolated and affecting the lacrimal gland (most frequent variant)

Idiopathic orbital myositis: limited to one or more extraocular muscles

Diffuse IOE affecting different orbital structures (rare)

Idiopathic perineuritis of the optic nerve (very rare): involvement of the optic nerve sheath

Anterior IOE: listed as an independent entity by some authors 103

The list of differential diagnoses is long and encompasses almost all types of infectious and non-infectious orbital inflammation as well as a multitude of neoplastic and vascular lesions 99 . The diagnosis can be made only based on histology so that biopsies play a major role, especially in cases of advanced disease and recurrences, to exclude relevant differential diagnoses. Exceptions are idiopathic myositis with its characteristic clinical and radiological appearance as well as lesions in the area of the orbital apex where the risks of iatrogenic injuries are higher than the expected benefit. Good response to corticosteroids is observed in numerous different orbital lesions including endocrine orbitopathy and malignancies, so that this response should not be used for confirming the diagnosis.

Histological characteristics 100 102

classic orbital pseudotumor

broad inflammatory substrate of lymphocytic, granulocytic, and sometimes histiocytic infiltrates, organized into lymph follicles with germinal centers

increased connective tissue with edema and fibrosis

early visible destruction of the lacrimal gland acini or muscle fibers

delimitation to lymphoproliferative diseases is important

idiopathic sclerotic type

tissue sclerosis and hyalinization dominant

poor inflammatory infiltrate, similarity to retroperitoneal fibrosis

diagnostics based on IgG4-associated diseases recommended 104

rarely granulomatous (histiocytic giant cell infiltration) and vasculitic (vasculitis of the minor vessels) inflammatory reactions

possible transition of classic orbital pseudotumors to the sclerotic subtype 100

Clinical

highly variable, typically unilateral occurrence with disease history of several days to weeks, ranging from mild signs of inflammation to severe pain and increased orbital pressure with the risk of optic nerve compression; often recurrences in cases of classic pseudotumors as well as the sclerotic type 100

depending on the location, painful (swelling-related) pseudoptosis, chemosis, exophthalmos, and (mostly pain-related) impaired ocular motility

sclerotic type: pain frequent, rather notable swelling of the eyelid, impaired ocular mobility, loss of vision ( Fig. 9a, b )

Imaging and serologic diagnostics

idiopathic dacryoadenitis/idiopathic myositis: increase in affected structures with unchanged differentiation

sclerotic type: homogeneously enhancing, poorly delimited infiltrates of different orbital structures (initially mostly lateral with involvement of the lacrimal gland), in the further course, possible extension in the direction of the cavernous sinus and pterygopalatine fossa; in addition, possible multifocal fibrosclerosis (in particular retroperitoneal) ( Fig. 9c, d )

broad laboratory and serological diagnostics for differential diagnosis and assessment of the inflammatory activity possibly useful (among others, kidney and thyroid values, ANCA, ACE, rheumatoid factors, IgG4 serum level)

Therapy

in cases of a high level of suffering, immediate therapy is required

different levels of anti-inflammatory therapy, from antibiotic therapy, NSAIDs, or steroids to application of immunosuppressants 100

mostly good response to systemic high-dose therapy with corticosteroids, although response can be poor to corticosteroids and irradiation in cases of sclerotic type

with rapid diagnosis and onset of combination therapy consisting of corticosteroids and immunosuppressants (in cooperation with rheumatologists), delayed progression at least possible in cases of the sclerotic subtype 59

in cases of refractory and chronic courses, systemic application of immunosuppressants (e. g., methotrexate and azathioprine), biologicals such as rituximab, and a combination with radiation of the orbit

surgery such as debulking in the lacrimal type, decompression of the orbit in cases of optic nerve compression, orbital exenteration as ultima ratio in persistent severe pain 99

5.2.2.1 Tolosa-Hunt syndrome

Epidemiology

rare idiopathic granulomatous inflammation of the cavernous sinus and the orbital apex with compression of the neighboring cranial nerves (III–VI)

incidence of 1:1,000,000 per year 105

Clinical

unilateral ophthalmoplegia and (partly migrating) pareses of the cranial nerves running along the cavernous sinus and the superior orbital fissure (the oculomotor nerve most frequently affected)

often associated with constant retrobulbar facial pain

Diagnostics

confirmation of the diagnosis by means of MRI or biopsy to exclude differential diagnosis (sarcoidosis, malignancies, cavernous sinus thrombosis, cavernous carotid fistula) 106

Therapy

initially high-dose glucocorticoid boost therapy, then slowly reducing over at least 4–6 weeks (even longer if needed)

further options: radiotherapy and immunosuppressants (e. g., infliximab) 107 108

Prognosis

rapid pain relief from corticosteroids

Cave : even in cases of malignancies, high-dose corticosteroid application may lead to temporary improvement of the complaints; see case report in Fig. 10a–f

regression of neuropathies often only after several months, sometimes persisting

recurrence possible 109 110

Case report 1

History

79-year-old male patient with right-sided periorbital headaches progressing for months: intermitting neuralgic character in the area of the ophthalmic nerve, touch-sensitive

trochlear and abducent paresis on the right side for weeks (diplopia)

Diagnostics

MRI of the orbit: contrast-enhancing structure in the extraconal space at the orbital roof (most likely thickened supraorbital nerve) reaching into the superior orbital fissure, focal contrast enhancement in the orbital apex and into the cavernous sinus ( Fig. 10a–c )

PET-CT: no glucose consumption typical for malignancy, in particular in the area of the orbit

lumbar puncture: no hint of a florid inflammatory reaction of the CNS, no local immunoglobulin synthesis, no oligoclonal bands, no hint on serology of acute infection with neurotropic pathogens

Further course

working diagnosis: suspected Tolosa-Hunt syndrome; differential diagnostics in direction of infectious genesis, systemic granulomatous inflammation, or neoplasm

interdisciplinary board: therapy attempt with systemic glucocorticoid application (also because of the significant periprocedural risk in case of biopsy), and analgesics

initial improvement (in particular of the bulbar motility) and regressive MRI findings; differential diagnosis of autoimmune genesis, malignancy could not be excluded with certainty

continuation of glucocorticoid therapy

because of pre-damaged lung (fibrosis) with immunosuppressive therapy, repeated pneumonia and/or influenza pneumonitis

after 3 months, indication for biopsy because of persistent complaints despite regressive MRI findings

histological diagnosis: poorly differentiated adenocarcinoma

further staging diagnostics without clear findings, thus most likely primary tumor location

Therapy

radiotherapy (with consideration of the comorbidities and patient’s wishes)

Note

Even in cases of inflammatory processes of the orbit, malignant disease must be considered. Improvement with glucocorticoid therapy does not exclude malignancy.

5.2.2.2 IgG4-associated orbitopathy

Definition

subacute to chronic courses of immunological systemic disease with coarse lymphocytic infiltrates and fibrotic lesions 111

Locations and clinical

most frequent manifestations are autoimmune pancreatitis, sclerotic cholangitis, nephritis and renal fibrosis, and involvement of the lacrimal glands, salivary glands, and lymph nodes 111

manifestations in the area of the orbit are typical, each structure may be affected, but in particular:

lacrimal gland: IgG4-associated dacryoadenitis with mostly painless swelling, mostly bilateral manifestation and with sicca symptoms 112

orbital nerves and muscles: mainly infraorbital nerve; mostly painless with diplopia

orbital fatty tissue: associated with increased lacrimal glands 112 113

rarely, destructive lesion with enophthalmos 113 114 , affecting ocular structures or the bony limits

in more than 70% of patients extraocular manifestations 111

visual disorders as leading symptom 111

Diagnostics

imaging

diffusely increased lacrimal gland, muscles (mainly lateral), infraorbital nerve, partly with swelling of the bone channel ( Fig. 11a, b )

often ipsilateral effect on the paranasal sinuses 112

histology

lymphoplasmacellular infiltration with obliterating phlebitis and eosinophilic inflammation

percentage of IgG4-positive plasma cells>40% (triggering stimulus for differentiation of B lymphocytes in IgG4-producing plasma cells still unknown)

fibrosis in the further course

histologic diagnostic criteria: IgG4/IgG ratio>50% as well as>30% IgG4-positive cells per high-power field 115

laboratory

increased IgG4 serum level, although non-specific (increased also in Churg-Strauss syndrome, sarcoidosis, allergic diseases) and not identifiable in particular in limited orbital involvement

otherwise, no signs of systemic inflammation 99

Therapy

first choice: traditionally oral glucocorticoid application (30–40 mg/d) as induction therapy, low-dose maintenance therapy over years, regression of complaints often observed

recommendation from recent studies: application of rituximab not only in recurrences but also in first-line therapy, leading to significantly better outcome rates than other disease-modifying anti-rheumatic drugs (DMARDs), such as methotrexate, mycophenolate, and azathioprine 116

surgical debulking and radiotherapy only rarely indicated 116 117

Case report 2

History

75-year-old patient, condition after functional endoscopic sinus surgery (FESS) in 2007

6 months prior, right eye swelling and diplopia for 6 months, re-FESS in a new location with a clinical finding of “orbital abscess”

3 months later, re-FESS with polypous pansinusitis with orbital involvement, also performed alio loco

at first in domo presentation, persistent diplopia, loss of vision, eyelid edema, hypoesthesia

Diagnostics

MRI: extraconal mass at the orbital floor not delimited from the inferior rectus muscle with contrast enhancement ( Fig. 11a, b )

after biopsy via a transconjunctival access, diagnosis of IgG4-associated orbital inflammation

Therapy (in cooperation with rheumatologists)

glucocorticoids and methotrexate, leading to full recovery

5.2.3 Vasculitis of the orbit

Orbital inflammation is often part of a systemic disease that cannot always be identified initially, even though it can have far-reaching consequences. Vasculitis plays a particular role. Vasculitic diseases encompass numerous pathologies; for the orbit, these are mainly orbital granulomatosis with polyangiitis (GPA, formerly called Wegener’s disease) as well as polyarteritis nodosa. These and other related diseases are listed below with their main characteristics.

5.2.3.1 Small and medium-sized vessel diseases

5.2.3.1.1 Orbital granulomatosis with polyangiitis (GPA)

Definition

necrotizing granulomatous inflammation of the respiratory tract and necrotic vasculitis of small and medium-sized vessels of the airways and kidneys

Epidemiology

rare disease, incidence of 3:100 000 118

orbital involvement in about 50% of cases 111 (almost every structure may be affected)

Classification into two clinical types 119

limited form

mostly affecting the upper airways

mostly no identification of ANCA

systemic form

affecting the airways, kidneys, other organs

often associated with c-ANCA (90%) and p-ANCA increase (20%) 111

formerly high mortality: currently up to 90% remissions because of early combination therapy 120

Symptoms 111

proptosis as a key characteristic (in combination with pulmonary and renal symptoms, groundbreaking for correct diagnosis)

painful ophthalmoplegia because of extension of the orbital mass into neighboring structures (e. g., cavernous sinus)

epiphora from obstruction of the efferent lacrimal ducts in cases of sinus involvement, diplopia caused by vasculitis of the extraocular muscle vessels, inflammation of the lacrimal gland, bulb perforation caused by necrotic scleritis, xanthelasma-like staining of the eyelids (“yellow lid sign”)

vision-threatening compression of the optic nerve in cases of infiltration of the neighboring structures

mostly subacute onset, mostly bilateral in the further course, episodes with significant progression of findings in the context of chronic disease

possibly dramatic deterioration during the disease course because of fibrosis and orbital atrophy with enophthalmos, motility disorders, and chronic pain 118 121

Diagnostic imaging (CT and MRI) 122

extraconal infiltrates, mainly infero-medial in close proximity to the affected sinuses with bone destruction and septum perforation

possible isolated effect on the orbital apex (partly with intracranial extension) or isolated effect on the lacrimal gland (diffuse enlargement)

diffuse extension in intra- and extraconal direction (“wall-to-wall” tumor) as a pathognomonic sign of advanced stage

MRI suitable for identification of granulomatous inflammatory reaction

Pathology

classic histological triad of vasculitis, necrosis, and granulomatous inflammation in the orbit in 50% of patients

other characteristics: polymorphic inflammatory infiltrates, degeneratively changed granules/collagen as well as increased number of IgG4-positive plasma cells in many cases 123

also in ANCA-negative GPA: additional immunohistochemical examination of IL-17 and IL-23 for differentiation of sarcoidosis 111

Therapy

management of orbital GPA similar to that for systemic GPA

current standard: combination of corticosteroids with cyclophosphamide, methotrexate, or azathioprine; early therapy start may avoid fatal local or systemic courses 118

in refractory cases: rituximab 124 (more favorable side-effect profile with comparable effect)

surgical debulking in cases of persistent proptosis, uncontrollable pain, or compressive neuropathy of the optic nerve 121

5.2.3.1.2 Allergic granulomatosis (Churg-Strauss syndrome)

Definition

allergic systemic disease; initial manifestation with asthma and rhinosinusitis, and in the course, necrotic vasculitis of small and medium-sized vessels and eosinophilic granulomatous inflammation 118

orbit rarely affected

Location

predominantly involving the lung, paranasal sinuses, and peripheral nerve system

Clinical

ischemic vasculitis or orbital inflammatory pseudotumor with dacryoadenitis, myositis, periscleritis, perineuritis

may be a first manifestation of the syndrome 125 ( Fig. 12a–c )

in the course, proptosis, diplopia, ophthalmoplegia, loss of vision from optic nerve compression

in the stage of vasculitis, life-threatening complications possible (peritonitis from gut perforation, eosinophilic myocarditis with myocardial infarction 127

Diagnostics

biopsy of affected structures

main histological features: necrotizing vasculitis with extravascular Infiltrates ( Fig. 12d )

seropositive pANCA in 70% of patients 126

imaging (CT, MRI): non-specific changes with increased retrobulbar space, swelling of lacrimal gland and extraocular muscles (EOM)

diagnostic criteria of American College of Rheumatology (1990; 4 of 6 must be applicable): asthma, paranasal sinus abnormalities, pulmonary infiltrates, eosinophilia greater than 10% of white blood cell differential, extravascular eosinophils, presence of a mononeuropathy or polyneuropathy 127

Therapy

first-line therapy: systemic corticosteroids (oral, intravenously applied), additional methotrexate and cyclophosphamide as steroid-saving measure in cases of critical organ involvement

biologicals in case of recurrence or refractory disease: rituximab, infliximab, mepolizumab, or omalizumab 118 128 ; in general, permanent pharmacotherapy needed

Prognosis

before the era of biologicals: mortality in up to 50% of cases if two or more organs affected 129

5.2.3.1.3 Polyarteritis nodosa

Definition

necrotic vasculitis of small and medium-sized arteries and sometimes of the accompanying veins

segmental effects characteristic (typically bifurcations)

typically thromboses and nodular aneurysms 59

histological characteristics: fibrinoid necrosis of the media and simultaneous occurrence of different inflammatory stages

Epidemiology

mostly male patients in the 4 th and 5 th decades of life

association with hepatitis B

orbit involved in about 10% of patients 118 , sometimes as the first manifestation of the disease

Location

predilection for kidney, heart, liver, gastrointestinal tract, peripheral nerves, and CNS, and also bones and joints

Clinical

typical ophthalmological lesions: retinal vasculitis, choroidal infarction with exudations, ischemic optic neuropathy

secondary phenomena of vasculitis: ischemia of the EOM with ophthalmoplegia, diffuse orbital inflammation with exophthalmos, impaired motility, chemosis

Diagnosis based on the combination of orbital inflammation with other disease symptoms, non-specific inflammation signs on labs, biopsy, and imaging (sometimes angiographic confirmation of aneurysms)

Therapy

systemic corticosteroids and cyclophosphamide

application of other DMARDs such as methotrexate, azathioprine, and rituximab also reported 118

Prognosis

5-year survival rate of about 80% 118

5.2.3.2 Vasculitis of the major vessels

5.2.3.2.1 Giant cell arteritis (temporal arteritis)

Definition

idiopathic vasculitis of the middle and major arteries of the head and neck

histologically segmental inflammation with giant cells, lymphocytes, plasma cells, and eosinophils 118

Epidemiology

age peak in the 7 th to 8 th decades of life

mostly female patients 111

orbital involvement rarely observed

Etiology

combination of genetic predisposition (European ancestry) and environmental factors (association with virus infection, e. g., VZV, CMV, parvovirus 19) 130

Clinical

general symptoms

headaches, jaw claudication

B symptoms such as fever, fatigue, weight loss

polymyalgia rheumatica, scalp tenderness 111

ophthalmological symptoms

loss of vision because of ischemia of the optic nerve (anterior ischemic opticus neuropathy [i. e., A-AION]: urgent treatment indicated)

further diplopia, choroidal and retinal ischemia signs 111

orbital symptoms

ophthalmoplegia and diplopia (because of ischemia and inflammation) 131

Diagnostics

diagnosis by means of combination of typical symptoms (headache, scalp tenderness), laboratory parameters (increased erythrocyte sedimentation rate (ESR), radiological findings (contrast enhancement of the orbit in MRI), and biopsy of the temporal artery (biopsy of the orbital lesion is rarely necessary) 118

Therapy

first-line therapy: high-dose corticosteroids ( Cave : undesired long-term effects)

current study results with tocilizumab (anti-IL-6) quite promising 132

5.2.3.2.2 Takayasu arteritis

Definition

granulomatous panarteritis affecting the aorta and its main branches

Epidemiology

first description in middle-aged female Japanese patients

current investigations: all ethnic groups affected with increasing prevalence 133

Clinical

vasculitic destruction of the carotid artery with collateral blood supply to the eye

possible loss of vision because of ischemic ocular complications

initially, amaurosis fugax or progressive permanent loss of vision possible 134

Diagnostics

fluorescence angiography to confirm critical perfusion of the retina

in recent years, replaced by MR angiography and FDG-PET

Therapy

primary glucocorticoids

in steroid refractory cases: leflunomide and tocilizumab 135

5.2.3.3 Vasculitis of vessels with variable size

5.2.3.3.1 Cogan’s syndrome

Definition

rare inflammatory systemic disease

main involvement of the visual and audiovestibular system as well as vessels of variable size 111

Epidemiology

affects mostly young adults

age peak at 29 years

to date, about 250 cases published 136

orbital involvement extremely rare

Etiology and pathogenesis

autoimmune genesis with origin in the inner ear

triggered by initial virus infection

identification of different autoantigens (CD 148, connexin 26) 137

Classification

typical type

non-infectious interstitial keratitis with Menière-like vestibulo-cochlear disorder within 2 years after first manifestation 111

atypical type

different ocular symptoms such as conjunctivitis, episcleritis, glaucoma, uveitis; labyrinthine affection about two years after first manifestation

partly severe hearing loss, bilateral deafness in 60% of the patients 138

Clinical

resulting from necrotic vasculitis in about 70% of cases, systemic involvement with manifestation in the blood vessels (aorta, renal, and coronary vessels), neurological and gastrointestinal symptoms; severe, sometimes life-threatening course

in cases of orbital involvement (only case reports): hearing loss, vertigo, enophthalmos, and orbital inflammation (however, without biopsy confirmation of the genesis) 118

Diagnostics

neurotological, ophthalmological, and angiological diagnostics to exclude differential diagnoses

Differential diagnoses

congenital syphilis, Susac’s syndrome, Vogt-Koyanagi-Harada syndrome

other vasculitis diseases, e. g., granulomatosis with polyangiitis 136

Therapy

first-line therapy: systemic high-dose glucocorticosteroids, often leading to improvement in vestibulo-cochlear and ocular symptoms 139

prophylaxis against recurrence: biologicals such as infliximab (application also as first-line pharmaceutic in combination with glucocorticoids at an early stage of the disease to avoid irreversible damage) 140

5.2.3.3.2 Behcet’s disease

Definition

idiopathic systemic vasculitis of blood vessels of variable size with episodic course 141

Epidemiology

highest prevalence in the Middle East and Asia

male:female ratio, 3.5:1

orbital involvement extremely rare

Etiology and pathogenesis

strong association with HLA-B51

non-specific increase in CRP and BSG 118

Clinical

general symptoms

aphthous lesions of the oral mucosa and genitals

skin lesions and intraocular inflammation

further organ manifestations in the gastrointestinal tract, lung, muscles, joints, and CNS 111

in cases of ocular involvement

mostly uveitis with hypopyon, retinal vasculitis

rarely, anterior ischemic optic neuropathy (i. e., AION)

Cave : ocular involvement requires particular attention because of the high morbidity

in cases of orbital involvement (single case reports)

affecting EOM and/or lacrimal gland (however, without biopsy confirmation) 142

Diagnostics

definition of HLA-B51, CRP, and BSG 118

diagnosis of orbital involvement based on the combination of clinical symptoms and lab parameters in accordance with Behcet’s disease and orbital inflammation 118

Therapy

first-line therapy: corticosteroids

second-line therapy: azathioprine, ciclosporin, infliximab or adalimumab; in severe cases with vision-threatening retinitis, combination therapy also possible 143

promising current study results with application of IL-1 inhibitors (anakinra, canakinumab) 144

5.2.3.3.3 Kawasaki syndrome

Definition

systemic autoimmune vasculitis, preferentially affecting medium-sized vessels, in particular the coronary vessels

Epidemiology

children younger than 5 years

incidence: in Japan 240:100 000; in those of European descent, 9:100 000 145

Etiology and pathogenesis

histopathologically six typical lesions: endothelial degeneration, necrotic arteritis, granulomatous inflammation, media degeneration, scarring, development of aneurysms 118

Clinical

cardinal symptoms: fever (>5 days), palmar and plantar erythema, polymorphic exanthema, bilateral conjunctival injection and chemosis, erythema of the oral mucosa, cervical lymphadenitis, aneurysms of the coronary vessels

ophthalmological symptoms

bilateral non-purulent conjunctivitis in 80% of cases with conjunctival injection and chemosis

anterior uveitis 145

orbital inflammation (single case reports) confirmed by biopsy; otherwise, by diagnosis in the context of further symptoms of the disease 146 147 148

Diagnostics

typical clinical constellation

important: cardiological diagnostics with heart echocardiogram, and coronary angiography if needed

lab: non-specific increase in ESR, CRP, alpha-1 antitrypsin, thrombocytes

Therapy

standard: high-dose intravenous application of immunoglobulins plus aspirin for symptom reduction and prevention of aneurysms of the coronary arteries 118

therapy-refractory cases: infliximab 149

application of corticosteroids is controversially discussed (administration only in refractory cases) 147

5.2.3.3.4 Collagenosis-associated vasculitis: systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), dermatomyositis (DM)

Definition

vasculitis as typical sign in patients with collagenoses

mostly affecting minor vessels in form of leukocytoclastic vasculitis (perivascular infiltration with apoptotic degeneration of neutrophilic granulocytes) 59 118

Epidemiology

occurrence in about 30–40% of SLE patients and 5–15% of RA patients 59 118

ocular involvement in 20% of the patients with SLE

orbital involvement much rarer 150

Etiology and pathogenesis

immunocomplex-mediated pathogenesis

Clinical

frequently: cutaneous lesions, involvement of the mesenterial, coronary, and pulmonary arteries, the arteries of the lower extremities, and the CNS

ocular involvement: mostly retinopathy, keratoconjunctivitis sicca, uveitis

single publications about symptoms of orbital inflammation (infarction, myositis, exophthalmos)

orbital inflammation symptoms together with according general symptoms and typical serological findings of SLE and RA (increased ANA and ds-DNA-AB) 151 152 153

very rare orbital involvement in DM: case report of delayed bilateral orbital involvement with exophthalmos by increased EOM, associated with muscle weakness, and typical EMG changes (without confirmation by biopsy) 154

Therapy

SLE and RA: glucocorticoids intravenous or oral; alternatively, azathioprine and biologicals (rituximab, infliximab, belimumab)

DM: glucocorticoids intravenous; also immunoglobulins as first-line therapy as well as methotrexate and azathioprine have been described 118

5.2.4 Granulomatous inflammation of the orbit

5.2.4.1 Sarcoidosis

Sarcoidosis is a chronic inflammatory systemic disease. The term ‘sarcoid’ was introduced by Caesar W. Boeck because these lesions are histologically similar to sarcomas without being malignant. Effects in the lung with bihilary lymphadenopathy as well as skin and eyelid lesions are typical findings 155 156 157 .

Etiology and pathogenesis

increased inflammatory reaction to some pathogens (not precisely identified) with increased cellular immune response and formation of non-caseating granulomas

genetic component (higher familial incidence)

Epidemiology

peak between the 30 th and 40 th years of life

women more frequently affected

in about 30% of cases, limited orbital sarcoidosis with isolated effects on orbital structures 102 158

Location

ocular involvement (including the most frequent extrapulmonary symptoms): conjunctivitis, uveitis, chorioretinal lesions, vitreous body changes

orbital involvement possible as first manifestation: mostly lacrimal gland (often bilateral involvement); furthermore, orbital fatty tissue, optic nerve sheath (as part of neurosarcoidosis), efferent lacrimal ducts, or eye muscles 155 156 159 160 161

Clinical

depending on the affected structure, palpable tumor mass, eyelid swelling, ptosis, diplopia, exophthalmos, epiphora, sicca symptoms, or painful ophthalmoplegia 156 161

depending on size and location, possible central artery obstruction and loss of vision 159 161

Diagnostics

biopsy essential for confirmation of the diagnosis; because of the histological similarity with other lesions such as idiopathic orbital inflammation or lymphoproliferative diseases, diagnosis can be difficult

serology: angiotensin converting enzyme and liver values; possibly inconspicuous serological findings

imaging

MRI: if affected, the lacrimal gland is diffusely increased with homogeneous enhancement, with further manifestations as a poorly delimited mass, swelling of the optic nerve sheath, or diffusely increased muscles

thoracic X-ray for pulmonary assessment

Therapy

intravenous corticosteroids to improve the functional prognosis (essential)

interdisciplinary care with rheumatologists is important

surgical excision or debulking if needed, but only in combination with previous systemic therapy 159 161

in refractory cases or recurrence: immunosuppressive combination therapy, e. g., with methotrexate or azathioprine, or with biologicals such as infliximab or adalimumab 156 161

5.2.4.2 Melkersson-Rosenthal syndrome

Definition

neuromucocutaneous granulomatous dermatosis

Epidemiology

incidence of 0.08% 162

first manifestation mostly in young adults

Etiology

autosomal dominant inheritance with variable expression 163

Clinical

classic symptom triad: lingua plicata, cheilitis granulomatosa, peripheral facial nerve palsy; mono- or oligosymptomatic appearance quite frequent

often diffuse edematous facial swellings, rarely isolated in the area of the eyelids (thus a difficult diagnosis, especially when other characteristics are missing; imaging and biopsy may facilitate the delineation)

rare involvement of other cranial nerves 162 163 164 165 (e. g., diplopia because of oculomotor paresis 162 166 )

Therapy

intralesional and systemic glucocorticosteroids

excision and plastic-reconstructive facial surgery in cases of functional as well as cosmetic problems 59

systemic therapy approaches with immunosuppressants (e. g., azathioprine), hydroxychloroquine, and thalidomide 162 163 167

Prognosis

variable chronic course with spontaneous remissions and recurrences

5.2.4.3 Foreign body granulomas and idiopathic lipogranulomas

Definition

granulomatous inflammatory reaction caused by foreign bodies

Classification according to the type of foreign body

ruptured dermoid cyst ( Fig. 13a–d )

most frequent intrinsic cause of foreign body granulomas (partly with inflammatory reaction)

mostly inhomogeneous lesion with irregular borders on CT scans

therapy: excision (possibly complete removal without damaging neighboring structures; if small fibrotic parts remain, treatment with intralesional corticosteroids)

herbal foreign bodies

further source of granulomatous inflammatory reaction, exact history-taking is important

slowly progressive course and fistulation possible

paraffin-induced sclerotic lipogranuloma

mostly as consequence of application of moisturizing nasal ointments after endoscopic sinus surgery (with intraoperative damage of the lamina papyracea) 168 169

accidental leakage of intraocular silicone oil in the context of ophthalmological interventions

after autologous fat injection in plastic surgery

idiopathic lipogranuloma

in cases of missing trigger

only single case reports in the literature, unclear etiology

histologically orbital fatty tissue necrosis 170

Clinical

eyelid swelling

subcutaneously palpable nodes

in cases of tumoral lesions: exophthalmos, impaired oculomotor function, and bulb deviation are possible

Diagnostics

classic inflammatory signs because of concomitant vasculitis 168 171 172

CT scan and/or MRI: partly poorly delimited, partly diffusely configured lesion 171

Therapy

complete surgical removal with subsequent systemic glucocorticoid application is most effective 170

optionally: triamcinolone injection or debulking

Prognosis

spontaneous remission as well as recurrences observed 171 172 173 174

5.2.5 Sjögren’s syndrome (SS)

Definition

chronic autoimmune disease characterized by inflammation of the lacrimal and salivary glands as well as the epithelia

keratoconjunctivitis sicca as one of the leading diagnostic criteria (inflammation of the accessory conjunctival lacrimal glands) 61

Epidemiology

age peak in the 4 th to 5 th decades

affects mainly women

Classification

primary SS: independent disease with ocular and oral symptoms (Sicca syndrome)

secondary SS (more frequently observed): in the context of other autoimmune diseases (RA, SLE, systemic sclerosis)

Etiology and pathogenesis

environmental and hormonal factors as well as genetic predisposition

lymphocytic infiltration and sclerosis of the lacrimal and salivary glands by T cells and autoantibodies; B cells presumably also pathogenetically significant 175

Clinical

slowly progressing, painless swelling of the lacrimal gland (and sometimes of the salivary glands)

in the further course, glandular atrophy, often bilateral, xerostomia, xerophthalmia (rather in the atrophic stage)

other ocular and orbital symptoms: uveitis, episcleritis/scleritis, optic neuropathy 155 176 , myositis of the EOM 177

extraglandular symptoms: fatigue, pain, polyneuropathy, vasculitic skin lesions, pulmonary changes, musculoskeletal, renal, and gastrointestinal manifestations 175

Diagnostics

CT/MRI: orbitally enlarged lacrimal glands with enhancement, difficult to delimit to lymphoproliferative diseases 178

lab: increased specific antinuclear antibodies (SS-A and SS-B, the latter highly specific for SS)

biopsy: confirmation of the diagnosis and exclusion of lymphoma (SS patients have a 20-fold increased risk for lymphoma, in particular in the head and neck 175 179 180 )

Therapy

interdisciplinary therapy is necessary because SS is relatively resistant against pharmacotherapy with corticosteroids and other anti-rheumatics

symptomatic therapy of sicca symptoms by ophthalmologists and systemic rheumatological medication consisting of steroids and immunosuppressants, application of biologicals, e. g., rituximab, mostly recommended in SS with extraglandular manifestation 181

5.2.6 Kimura syndrome

Definition

benign chronic inflammatory disease of the subcutaneous tissue, of unknown genesis, also called angiolymphoid hyperplasia with eosinophilia

first description by Kimura in 1948 182

Epidemiology

mainly observed in males of Asian origin between the 20 th and 30 th years of life

orbit rarely affected

Histopathology

circumscribed skin lesion with a mixture of blood vessels with coarse endothelial cells and areas of polymorphic inflammatory infiltrates with abundant eosinophils, regularly structured multiple lymph follicles and development of eosinophilic abscesses 182 183 184 185

Clinical

inflammatory angiomas of the head and neck with regional lymphadenitis

possible involvement of the salivary glands as well as oral and nasal mucosa

orbit (rarely): well-delimited mass of the eyelids, lacrimal glands, or anterior orbit 184 186 , exophthalmos, loss of vision, and diplopia

Diagnostics

typical findings: increased serum IgE and blood eosinophilia

Therapy

systemic and topical glucocorticoids (leading to tumor reduction and spontaneous remission)

local excision in cases of well-delimited unifocal lesions as therapy of choice

in cases of incomplete excision, adjuvant radiotherapy for local control 186 187 194

5.2.7 Histiocytic diseases

Orbital xanthogranulomatous diseases are characterized by proliferation of histiocytes and summarized within the term ‘non-Langerhans cell histiocytosis’. In contrast, Langerhans cell histiocytosis has its origin in dendritic cells, associated with the Rosai-Dorfman syndrome and monocytes/macrophages. These diseases are described below.

5.2.7.1 Non-Langerhans cell histiocytoses

5.2.7.1 Juvenile xanthogranuloma

Definition

benign proliferative cutaneous disease, mainly affecting the eyes and skin

primary effects on the orbit with proptosis quite rare

Numerous differential diagnoses in childhood

Diagnostics: biopsy confirmation of diagnosis required

Therapy and prognosis

mostly spontaneous remission

in symptomatic patients with non-resectable lesions, corticosteroids and chemotherapeutics are applied

5.2.7.1.2 Adult-onset xanthogranuloma (AOX) and adult-onset asthma with periocular xanthogranuloma (AAPOX)

Etiology and pathogenesis

unknown, probably autoimmune genesis with deposits of immune complexes and subsequent foreign body reactions in the tissue

unknown cause of the affinity for orbital adnexa structures 188

Clinical

yellowish infiltrates in the area of the conjunctiva and eyelids (xanthelasmas)

bilateral occurrence possible

Diagnostics

confirmation of the diagnosis by biopsy: histologically lipid-charged macrophages (xanthoma cells) in the dermis and deeper tissue layers, along with foreign body giant cells and Touton giant cells

association with hematological diseases (lymphoproliferative lesions, hepatosplenomegaly) possible, requiring thorough physical evaluation

determination of the orbital extension by CT to assess infiltration of the orbital fat, EOM, and lacrimal gland

in cases of association with asthma, the term ‘adult-onset asthma with periocular xanthogranuloma (AAPOX)’ is used 189

Therapy

surgical debulking and plastic reconstruction

irradiation

systemic corticosteroids and other immunosuppressants ( Fig. 14a, b )

intralesional triamcinolone highly effective 190

Prognosis

progressive disease

vision-threatening course without therapy

5.2.7.1.3 Necrobiotic xanthogranuloma

Epidemiology

rare disease occurring in patients between the 5 th and 6 th decades of life

Pathogenesis

foreign body giant cell reactions to deposits of lipid serum immunoglobulin complexes in the skin 188

necrobiosis as histopathological key characteristic: eosinophilic degeneration of collagen in a granulomatous inflammation reaction with foamy histiocytes, foreign body giant cells, Touton giant cells, and lymphocytes

Location

development of infiltrates at the eyelids and ocular adnexa structures as well as the extremities

effects on inner organs and hematological neoplasms also possible 61

Clinical

reddish-yellow lesions or flesh-colored nodules with extension into the anterior orbit with subsequent proptosis, ptosis as well as scar-related lagophthalmos

Therapy

many different therapeutic alternatives in use, including surgery, radiation, plasmapheresis, intralesional and systemic steroid application as well as cytostatic agents

case reports describing successful application of thalidomide in combination with dexamethasone 191

overall, pharmacotherapy superior to radiation and surgical debulking

Prognosis

progression after biopsy or debulking possible

lifelong follow-up because of increased risk of hematological malignancy

5.2.7.1.4 Erdheim-Chester disease

Definition

rare type of non-Langerhans cell histiocytosis with progressive course, characterized by bone pain, retroperitoneal fibrosis, and infiltrations in the face

pathological characteristics: wide-spread infiltration of foamy (lipid charged) non-Langerhans cell histiocytes

Epidemiology

first manifestation mostly between the 5 th and 7 th decades of life

predominantly in males

more than 600 cases described since 1930 192

Etiology

not completely understood

association with different immunological diseases as hint for abnormal interaction between T cells and macrophages (uncontrolled activation of the macrophages by functional disorders of natural killer (NK)-T cells or cytotoxic T cells)

Clinical

characteristic: bone pain, especially in the distal lower extremities because of osteosclerosis of the long bones

often bilateral orbit effects: xanthogranulomas with partly deep retrobulbar infiltration, thus ophthalmoplegia and compressive optic neuropathy also possible in addition to exophthalmos

general symptoms such as fever and weight loss

severe disorders possible, including diabetes insipidus, cerebellar and pyramidal tract signs, cranial nerve paresis, adrenal insufficiency, pulmonary fibrosis, and cardiac decompensation 192 193 194

variable course that can include fulminant organ failure

Therapy

interdisciplinary treatment essential in cases of orbital involvement

systemic therapy with, e. g., interferon, glucocorticoids, cladribine, imatinib, anakinra

since 2012, also infliximab and vemurafenib

orbital decompression in cases of compressive neuropathy of the optic nerve 192 194 195

Prognosis

poorest among all non-Langerhans cell histiocytosis with mortality rates of>60% within 3 years 196

5.2.7.1.5 Disseminated xanthogranuloma

Definition

very rare, non-familial, histiocytic, infiltrative disease primarily affecting skin, mucosa, and hypothalamus

Epidemiology

about 100 cases reported

disease onset mostly in young adults 197

male:female ratio, 2:1

Etiology and pathogenesis

causes or risk factors not known

characteristic: accumulation of histiocytes at the entire integument and CNS with accumulation of cholesterol and other lipids, leading to a histologically foamy appearance (typical for xanthomatous lesions)

Clinical

reddish cutaneous nodes, mainly at the surface of the flexors

cornea, conjunctiva, and eyelids affected (20%)

dysphagia or dysphony because of involvement of the upper airways (40%)

diabetes insipidus from meningeal involvement (40%)

Diagnostics

pathognomonic: triad of typical skin alterations, dysphagia, and diabetes insipidus 198

bone marrow biopsy and serum electrophoresis required to exclude myeloid melanoma (observed in more than 50% of the patients)

histologically, not differentiable from Erdheim-Chester disease

Therapy

currently, causal therapy not possible

therapy attempts with numerous different medications, e. g., corticosteroids, lipid reducers, and several immunosuppressants; cladribine (purine-nucleoside analogue) currently most promising 199

Prognosis

possible local control by surgical excision or CO 2 laser ablation

5.2.7.2 Langerhans cell histiocytosis

Definition

spectrum of diseases characterized by skeletal or soft tissue infiltration with Langerhans cells (synonym: Langerhans cell granulomatosis, histiocytosis X) 200 201

Epidemiology

rare, predominantly occurring in children and adolescents

prevalence of 4–5:1,000,000

involvement of the orbit in 25% of cases

Etiology and pathogenesis

unclear, presumably clonal proliferation of phenotypically abnormal Langerhans cells

expression of atypical surface proteins and deposits in the tissue where Langerhans cells otherwise are not present (e. g., bones)

Types

unifocal manifestation: eosinophilic granuloma (most frequent type)

multifocal manifestation: Hand-Schüller-Christian disease with the triad of exophthalmos, diabetes insipidus, and osteolysis, very rarely Letterer-Siwe syndrome with progressive involvement of bone marrow and other organs 202

Clinical

typical orbital findings: proptosis, ptosis, and papillary edema, bone destruction or the temporal orbital part

additional inflammatory reaction

Diagnostics

CT scan for detection of bone lesions

MRI to assess the cranial extension 203

diagnosis based on typical clinical lesion, immunohistochemical identification of the surface markers of CD1a and CD207 as well as electron microscopic evidence of typical Birbeck granulae

Differential diagnoses in pediatric patients

acute infections (eyelid edema), inflammatory pseudotumor, dermoid cyst, rhabdomyosarcoma, Ewing sarcoma, osteosarcoma, or neuroblastoma, Erdheim-Chester disease

Prognosis

better with increasing age at first diagnosis

rather poor in cases of multifocal involvement

5-year survival rate maximum of 50% in cases of Letterer-Siwe syndrome despite modern chemotherapeutics

Therapy

local excision as therapy of choice in cases of isolated orbital involvement

intralesional injection of corticosteroids (prompt resolution described)

low-dose radiation in cases of lesions that cannot be approached surgically

systemic therapy for incomplete resection or with recurrence

prednisone for disseminated disease

chemotherapeutics in cases of poor response

hormone substitution in cases of hypopituitarism 61

5.2.7.3 Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorman syndrome)

Definition

rare disease with massive infiltration of S-100 positive histiocytes in the tissue and cervical lymph nodes 204

Etiology and pathogenesis

possibly viral genesis and genetic component

histopathologically characteristic: emperipolesis with phagocytosis of lymphocytes, erythrocytes, and neutrophilic granulocytes by large S-100 positive histiocytes

Epidemiology

age peak in adolescents between 15 and 20 years

increased occurrence in people with darker skin 204 205 206

Clinical

first manifestation mostly as indolent cervical lymph node swelling with accompanying fever, weight loss, and night sweats

extranodal manifestations in>40% of patients: eye, salivary glands, nose, bones, skin, or CNS 204 207 , necessitating systemic examination

in cases of massive lymph node swelling, possible life-threatening compression of the upper airways 208

orbital manifestation: proptosis, swelling of eyelids or lacrimal glands

intra- or extranodal involvement: possible compressive neuropathy of the optic nerve and uveitis 208

Therapy

generally self-limiting, indication for treatment mainly in cases of airway obstruction resulting from sudden size progression of massive cervical lymph node swellings

first-line pharmacotherapy: systemic high-dose therapy with corticosteroids

surgical intervention (excision or debulking) according to the severity of the orbital manifestation, further functional and esthetic corrections possible

in cases of idiopathic eyelid edemas, systemic corticosteroids or other immunosuppressants

in cases of life-threatening obstruction of the airways: surgical therapy or emergency radiation inevitable

chemotherapy if needed in cases of severe orbital involvement with optic neuropathy 204 209

5.2.8 Castleman’s disease

Definition

rare lymphoproliferative disease

Classification in two clinical categories

monocentric type

benign localized hyperplasia of lymphatic tissue

curative treatment by excision of the affected lymph nodes

multicentric type

systemic disease with potentially life-threatening symptoms

classification in HHV-8-associated type and idiopathic multicentric type (pathogenetic cytokine dysregulation) 210 211

Classification into three histological categories

hyaline vascular type (80–90%)

plasma cell type (10–20%)

rare mixed type

Location

extranodal involvement of the orbit quite rare, with few cases reported

monocentric variant with hyaline vascular type in more than 90% of the orbital cases

Clinical

mostly indolent swelling (proptosis)

in some cases, B symptoms

Diagnostics

histological confirmation 211 212

imaging procedures for orbital assessment and for exclusion of a multicentric occurrence recommended

Therapy

primary therapy option: surgical excision 211 212

in cases of multicentric variant, an interdisciplinary treatment approach required

monoclonal antibodies, if needed combined with cytostatics 211 213 214

5.3 Conclusion

The large spectrum of possible diagnoses and the frequently overlapping clinical and radiological presentations of orbital inflammation emphasize the significance of biopsies for identifying the cause. In addition to the many infectious diseases that can entail possibly severe complications, autoimmune diseases often present initially in the orbit and must be assessed accurately with regard to serology and clinical manifestation. Among non-infectious inflammatory lesions, idiopathic orbital inflammation is most frequently observed. IgG4-associated diseases have gained in importance in recent years as a cause of orbital inflammation. Because of their similarity to lymphoproliferative diseases, non-infectious diseases of the orbit require thorough assessment. Histiocytic diseases remain important rare conditions that cause inflammation and fibrosis of the orbit and can lead to severe organ failure.

6. Degenerative Diseases: Orbital Amyloidosis

6.1 Orbital amyloidosis

The term ‘amyloidosis’ describes a heterogenic group of diseases characterized by extracellular accumulation of insoluble proteins in the β leaflet structure. Organ function may be disturbed by compression or direct cytotoxicity. Amyloidosis may present as a primary condition or secondarily as sequela of another disease. A genetic predisposition has been described 215 for this rare systemic or localized disease.

Location

deposits of amyloid possible in all structures of the orbit and the ocular tissue 216 217 218

cases described with involvement of the lacrimal gland, eyelids, conjunctiva, and eye muscles including the palpebral levator muscle ( Fig. 15a, b )

Clinical

ptosis, exophthalmos, motility impairment with diplopia, bulbus deviation, ectropium or entropium, palpable tumor 218

Differential diagnoses

chronic inflammatory gut diseases, tuberculosis, multiple myeloma

examinations required of heart, kidneys, gastrointestinal tract, and CNS 215

Diagnostics

difficult diagnosis because of a lack of typical symptoms

MRI: inhomogeneous and contrast-enhancing deposits

CT scan: calcifications

histopathology: amyloid-typical apple-green staining as well as polarization with microscopically double-refractive properties

in cases of localized involvement, exclusion of a systemic variant required

Therapy

depending on the type, ranging from systemic chemotherapy with cortisone application to transplantation of the affected organs

in cases of localized orbital amyloidosis: surgical removal as therapy of choice if needed correcting interventions, e. g., for eyelid malpositions 215 216 218 219

radiotherapy as prophylaxis against recurrence recommended by some authors 216 220

Prognosis

highly variable course in cases of orbital involvement, from complication-free localized findings to severe organ damage with loss of vision 215

6.2 Storage diseases 221 222 223 224 225

Patients with storage diseases like Pompe’s disease or Gaucher’s disease have a high prevalence of clinically significant ophthalmological symptoms such as ptosis, bulbar motility disorders, strabismus, myopia, and astigmatism, in particular in classic infantile manifestations. These symptoms are mainly the result of the accumulation of glycogen (Pompe’s disease) or glucocerebroside (Gaucher’s disease), especially in the EOM, which may affect other ocular adnexa structures.

6.3 Mitochondrial diseases

6.3.1 Chronic progressive external ophthalmoplegia (CPEO)

Definition

very rare systemic muscle disease with slowly progressive paresis of all external eye muscles

Epidemiology

in addition to Leber’s hereditary optic neuropathy, the most frequently observed mitochondrial disease of adults with eye involvement

prevalence: about 12:100 000 226

onset mostly between the 20 th and 50 th years of life

Clinical

ptosis often the first symptom 227

Differential diagnoses

other mitochondrial diseases, e. g., Kearns-Sayre syndrome (also ptosis and external ophthalmoplegia, onset mostly before the age of 20 years, additionally cardiac conduction disorders, cerebellar ataxia, and/or increased liquor albumin)

MELAS syndrome, (ocular) myasthenia gravis, oculopharyngeal muscle dystrophy

Diagnoses

MRI: atrophy of the extraocular muscles 228

skeletal muscle biopsy: evidence of numerous “ragged red fibers” and COX-negative fibers

6.3.2 Leigh syndrome

Definition

neurodegenerative disease (mitochondriopathy) in children

Epidemiology

most frequent pediatric presentation of mitochondriopathy

onset mainly in the 2 nd year of life

prevalence: about 1:40 000 229

in rare cases, occurrence in adults also possible 230

Etiology

genetically very heterogenic, up to now identification of mutations in 75 genes 231

Clinical

highly variable symptoms

in the context of infection, development of neurological symptoms such as ataxia and dystonia and also ophthalmological symptoms, mainly strabismus, melanotic retinopathy, optic nerve atrophy, ptosis, and nystagmus 232

later symptoms in other organs such as heart, liver, kidneys, or gastrointestinal tract

Prognosis

progress in phases, mostly with death in the 3 rd year of life

7. Tumors of the Orbit 2 201 233

7.1 General remarks

With an incidence of 6–10 per 1 million people, orbital neoplasms are rare, but they encompass a multitude of different entities that can lead to difficulties in the context of diagnostics. About 60% in adults are benign and 40% are malignant. “True” orbital neoplasms have to be differentiated from inflammatory orbital lesions without identifiable origin (idiopathic orbital inflammation, formerly called pseudotumors). They represent about 5–7% of all orbital masses and respond well to steroids and immunosuppressants. In the context of history-taking and diagnostics, the exact location, invasiveness, and status should be clarified. Diagnostics and therapy are often performed in an interdisciplinary context.

7.1.1 Symptoms

Neoplasm of the orbit may be classified as described below.

Because of the anatomical circumstances, typically the following symptoms are observed (with decreasing incidence) 201 :

Exophthalmos/bulbus protrusion (key symptom)

Bulbus dislocation

Motility disorders, diplopia

Pain

Loss of vision

Impaired visual field

Intraconal lesions tend to lead to axial exophthalmos, whereas extraconal masses tend to lead to bulbus dislocation to the contralateral side of the tumor (e. g., a tumor of the lacrimal gland leads to dislocation into the inferior nasal direction).

7.1.2 Classification and overview 2 201

Neoplasms of the orbit may be classified as follows:

Neoplasms of epithelial origin

Neoplasms of non-epithelial origin

Neoplasms of lymphatic tissue

In each category, benign and malignant entities are found. The only epithelial structure in the orbit is the lacrimal gland , and primary epithelial neoplasms thus occur there. Vascular lesions are sometimes not considered to be neoplasms but instead are viewed as malformations and have a special status. However, they may behave clinically like “true” neoplasms.

7.1.3 General therapeutic principles of benign neoplasms of the orbit 2 201

In general, the following therapy options are possible:

“Watch-and-wait” in cases of asymptomatic benign neoplasms without diagnostic uncertainty (e. g., incidentally discovered hemangioma)

Surgical resection as most frequently performed therapy in cases of symptomatic benign lesion

Other treatment strategies such as radiotherapy or chemotherapy in the context of specific entities

In the context of symptomatic benign processes, a thorough weighing of the expected therapeutic benefit against the risk of functional damage is necessary. Resection of an optic sheath meningioma, for example, is associated with a high risk of optic nerve atrophy.

7.2 Particularities

7.2.1 Neoplasms of the lacrimal gland

Epidemiology 233 234 235 236

incidence: 0.6–1:1 000 000 people per year; about 80 newly diagnosed diseases per year in Germany

tumors of the lacrimal gland encompass about 25% of orbital neoplasms

the distribution of tumors of different tissue types in the lacrimal gland is as follows 237 :

epithelial origin:>50–65%

lymphatic origin (special type of mesenchymal neoplasm): about 30–35%

mesenchymal origin or metastases: 10–15%

ratio of benign to malignant epithelial neoplasms is almost 1:1

Differential diagnoses 233

inflammatory diseases

acute dacryocystitis

chronic dacryocystitis

idiopathic orbital inflammation (formerly called pseudotumor orbitae, dacryoadenitic type, representing about 20–40% of all cases)

structural changes (e. g., lacrimal gland cyst)

secondary tumors (not originating from glandular tissue, e. g., metastases, schwannomas)

General therapeutic strategies 235 236

for suspected epithelial tumor of the lacrimal gland, incision biopsy is contraindicated because of association with significantly worse prognosis of benign as well as malignant tumors

e. g., pleomorphic adenoma: 5-year recurrence rate of 32% after biopsy vs. 3% without biopsy prior to tumor resection

in addition, possible malignant degeneration of locally recurrent pleomorphic adenomas

lacrimal gland malignancy: 5-year survival rate of 29% after biopsy vs. 70% in cases of initially complete resection

precise preoperative diagnostic assessment desirable, based in part on symptom duration, pain, and radiological characteristics

the most effective and safe therapy in cases of epithelial tumors: complete resection during the first surgical intervention

complete resection indicated for encapsulated and well-circumscribed processes, without prior incision biopsy

surgical access via lateral orbitotomy and rarely in combination with coronal incision

7.2.1.1 Benign neoplasms of the lacrimal gland

Table 3 summarizes the most important benign neoplasms of the lacrimal gland. Because of their specific characteristics, lymphoid neoplasms are also dealt with in the section on malignant diseases even if they are, strictly speaking, neoplasms of mesenchymal origin.

7.2.1.1.1 Benign epithelial neoplasms of the lacrimal gland

7.2.1.1.1.1 Pleomorphic adenoma 233 234 236 238 239 240 241 242 243 244

Epidemiology

most frequent epithelial tumor of the lacrimal gland (<50%)

about 20% of all lacrimal gland tumors 237

manifestation in the 4 th to 5 th decades of life

male : female ratio, 1:1

Typical clinical findings

very slow growth

bulbus dislocation in inferior nasal direction (95%), impaired motility, sometimes with diplopia (40%), epiphora

Diagnostics

CT scan as diagnostic measure of choice

MRI provides only minor additional information (hyperintense signal in T2 weighting)

extraconal round-oval, sharply delimited lesion in the lateral superior quadrant of the orbit, inhomogeneous structure, displacing growth, dilation of the bony lacrimal gland fossa (81% in CT scan), calcifications as possible hint of malignant transformation

ultrasound: well-delimited, hypoechoic mass with dorsal sound amplification, low internal echo; on color duplex sonography, vascularization and perfusion identified only in the area of the capsule

Other diagnostic criterion

score for differentiation between pleomorphic adenoma and carcinoma of the lacrimal gland according to Rose and Wright 242 ( Table 4 )

Biopsy

risk of incision biopsy doubted by some authors; however, most authors confirm this risk

benefit and risk of fine needle aspiration cytology are controversially discussed

Therapy

complete tumor extirpation without opening the tumor capsule with a margin of glandular tissue (access: lateral orbitotomy, palpebral glandular parts should be preserved)

after previous biopsy: enbloc resection of the scar with the biopsy pathway as well as the lacrimal gland

Prognosis

in cases of incomplete resection and incision biopsies or untreated status, risk of recurrence (32% within 5 years after incision biopsy vs. 3% after complete capsule-preserving resection) or malignant transformation (20% within 30 years)

7.2.1.1.1.2 Warthin’s tumor (cystadenolymphoma) 245 246

One of the monomorphic adenomas

synonyms: adenolymphoma, cystadenolymphoma, papillary cystadenoma lymphatosum (however, to avoid confusion with malignant lymphomas or lymphadenomas, the term ‘Warthin’s tumor’ should be used)

Epidemiology

second most frequent benign tumor of the parotid gland, sometimes also found in periparotid lymph nodes

rarely in other salivary glands

extremely rare in the lacrimal gland (until now, fewer than 10 cases described worldwide)

Therapy

complete surgical resection via lateral orbitotomy

7.2.1.1.1.3 Oncocytoma 247 248 249 250 251 252 253 254

Synonyms

oxyphilic adenoma, oncocytic adenoma, Hürthle cell adenoma

Epidemiology

extremely rare in the lacrimal gland (MEDLINE analysis of the literature between 1959 and 2004 provided only 5 well-documented cases 248 )

more frequently in salivary glands, kidney, adenohypophysis, (para)thyroid gland, caruncle, and conjunctiva of the eye

affects older women especially

Etiology

development probably from a mutation in the mitochondrial DNA

Histology

benign, slowly growing tumor originating from the epithelia of the excretory glandular ducts; malignant transformation extremely rare

granulated, large, eosinophilic, mitochondria-rich tumor cells, so-called oncocytes (“Hürthle cells”)

Therapy of choice

complete surgical resection

7.2.1.1.1.4 Myoepithelioma 241 255 256 257 258 259

One of the monomorphic adenomas

Epidemiology

extremely rare in the area of the lacrimal glands: 2 of 272 (<0.01%) histologically examined lacrimal gland tumors 241 ; elsewhere, up to 2005, only 7 case reports 255 )

other occurrences in the head and neck: salivary glands (<1% of parotid tumors), palate

Imaging

on CT, well-delimited encapsulated mass

in other locations, difficult to differentiate from other soft tissue tumors or sarcomas by clinical radiology

Therapy

complete and intact resection via orbitotomy, if needed, combined with coronal incision 255

Follow-up

radiological follow-up recommended

Prognosis

local recurrence rate of 20%

7.2.1.1.1.5 Cystadenoma 260 261 262 263

Epidemiology

rare in the lacrimal gland

mainly found in the bile duct, pancreas, ovaries, epididymides, and kidneys

rare in the salivary glands (<1% of the salivary gland tumors)

Pathology

papillary and mucinous subtypes (the latter may degenerate)

first report in 2002 describing a bilateral cystadenoma of the lacrimal glands 260

Differential diagnosis

papillary cystadenoma histologically similar to the papillary cystadenoma lymphomatosum (i. e., Warthin’s tumor)

7.2.1.1.1.6 Sclerotic polycystic adenosis (SPA) 264 265

Definition

new entity in the current WHO classification of epithelial salivary gland tumors

formerly considered as inflammatory/reactive change, current term ‘neoplasm’ controversially discussed but favored by most authors

Synonym

sclerotic polycystic adenoma

Epidemiology

first case report of SPA of the lacrimal gland in 2013 264

60 cases described to date (involvement mostly of the parotid gland, sometimes of the minor salivary glands)

Differential diagnoses

pleomorphic adenoma, adenoidcystic carcinoma, mucoepidermoid carcinoma, acinic cell carcinoma (often histopathological misinterpretation and confusion)

Prognosis

recurrence in 30% of cases

no metastatic spread or disease-related increased mortality because of SPA

7.2.1.1.2 Benign non-epithelial neoplasms of the lacrimal duct

7.2.1.1.2.1 Mesenchymal tumors

Solitary fibrous tumor {266–271]

Epidemiology

quite rare overall, regardless of location

2.8 cases per 100,000 patients in a Mayo Clinic population 268

about 10 case reports of lacrimal gland involvement

typical locations: most frequently the pleura, more rarely abdomen, pelvis

Pathology

in the area of the lacrimal glands, possibly originating from periductal connective tissue

mostly benign, but malignant appearance (10–37%) as well as recurrences and metastases observed

slow, displacing growth

Differential diagnosis

in the area of the lacrimal gland, similar clinical and radiological appearance to pleomorphic adenoma

Therapy

complete resection via lateral orbitotomy

no clear evidence for benefit of radiotherapy or chemotherapy in cases of residual tumor

Prognosis

correlation between confirmed microscopically non–tumor-free surgical margins and increased development of local recurrences and distant metastases

local recurrences and distant metastases described mainly for tumors>10 cm, largely in the thorax or abdomen

extra-thoracic location linked to increased risk for local recurrences but not to the development of distant metastases

7.2.1.1.2.1.1 Myxoma 272 273 274 275 276

Definition

neoplasm of mesenchymal/connective tissue origin

Epidemiology

1 case report involving the lacrimal gland

other locations at the eye: conjunctiva, cornea, orbit

other locations: predominantly heart, and also bones, skin, skeletal muscles, urogenital tract

Pathology

histologically few cells and vessels with abundant myxoid (mucus-like) matrix rich in hyaluronic acid

Diagnostics

well-circumscribed oval isodense mass on CT

Therapy

complete surgical resection (with excellent prognosis)

radiotherapy without relevant effect

7.2.1.1.2.1.2 Fibrous histiocytoma 261 277

Epidemiology

report on fibrous histiocytoma of the lacrimal gland in an 11-year-old girl, no other published case reports 277

more frequent in the orbit of adults

Pathology

classification of benign, locally aggressive, and malignant types

7.2.1.1.2.2 Benign lymphoid tumors – reactive lymphoid hyperplasia 278

Definition

benign lymphoproliferative disease

not a “true” neoplasm, being neither monoclonal nor autonomous

polyclonal lymphocytic proliferation

formerly called pseudolymphoma

atypical lymphoid hyperplasia as special type (borderline lesion between reactive lymphoid hyperplasia and lymphoma; today mostly classified as low-grade B cell lymphoma)

Epidemiology

about 6% of all lesions of the lacrimal gland 279

similar incidence in conjunctiva, lacrimal glands, and other locations of the orbit (mostly extraconal), rarely in the eyelid

rarely bilateral or additionally outside the eye region (e. g., parotid, lung)

Clinical

slowly growing mass with minor functional impairment, only rarely reddening or pain

in the lacrimal gland, sometimes palpable as a rather solid, elastic mass with smooth or nodulous surface

Therapy 237

high-dose glucocorticoids and/or radiotherapy (about 25 Gy)

rituximab for therapy-resistant cases

Prognosis

malignant transformation possible

7.2.1.2 Malignant neoplasms of the lacrimal gland

Table 5 summarizes the malignant neoplasms of the lacrimal gland.

7.2.1.2.1.Malignant epithelial neoplasms of the lacrimal gland

Comparing all types of carcinomas of the lacrimal and the major salivary glands, tumors with similar histology seem to have a less favorable prognosis when they appear in the lacrimal glands. For carcinomas of the lacrimal gland, a classification exists in the current TNM classification of malignant tumors of the UICC. According to this classification, preauricular, submandibular, and cervical lymph nodes are considered as regional lymph nodes. Assignment to the T categories T1–3 is based on tumor size; depending on the involvement of the periosteum and/or bone, the subcategories a–c are differentiated. An involvement of neighboring structures, e. g., paranasal sinuses, cavernous sinus, or brain, leads to categorization as T4 280 .

A singular histopathological classification for lacrimal gland tumors does not exist. Instead, many authors consider the lacrimal gland as a minor salivary gland and classify tumors based on the system for salivary glands.

Table 6 shows a proposal for a classification of malignant epithelial lacrimal gland tumors , modified according to Weis et al., in analogy to the WHO classification of salivary gland tumors and with updates of the current version 237 261 285 286 . It is worth mentioning that still some years ago primary adenocarcinomas of the lacrimal as well as salivary glands were not further subclassified. Meanwhile, it is known that they form a group of tumors with different morphologies and biological behaviors, and hence with different prognoses.

7.2.1.2.1.1 Adenoid cystic carcinoma (ACC) 279 287 288 289 290 291 292 293 294 295

Epidemiology

second most frequent epithelial lacrimal gland tumor 296

most frequent malignant tumor of the lacrimal gland (20–30%) 237

mean age at disease onset: about 40 years

male:female ratio, 1:1

Pathology

perineural invasion of the tumor as a typical sign

frequently hematogenous metastatic spread (more typical than regional lymph node metastasis), even after several years (mainly in the lung, besides bones, liver, and brain)

Clinical

bulbus dislocation, proptosis, S-shaped ptosis, diplopia, epiphora

pain (in 38–79% of cases) and hypesthesia in the frontotemporal area (indicating the presence of an aggressive tumor)

symptom duration at first presentation typically<6 months

Diagnostics

high-resolution CT scan: bone erosion, irregular margins of the mass, possibly focal calcifications within the tumor

MRI: best option to identify involvement of the cavernous sinus, brain, and bone marrow

Therapy

still no clarity and no consensus regarding optimal therapy; mostly resection with safety margins and adjuvant radiotherapy

surgical options

according to extension, local resection, exenteration, or radical exenteration (with resection of the orbital roof, lateral orbital wall, and parts of the temporal muscle)

radical surgery without clear advantage for local tumor control up to T2, exenteration in cases of tumors at T3 or greater appears beneficial 297

(elective) neck dissection: the rate of regional lymph node metastases (including the intraparotid lymph nodes) appears low in ACC (especially of the lacrimal gland) [297, 298); elective neck dissection appears unjustified in most cases (but should be discussed in advanced stages, solid histological subtypes, or high-grade malignant degeneration) 298 ; higher lymphogenic metastasis rate with ACC of the salivary glands, with elective neck dissection thus leading to longer survival in advanced stages 299 .

radiotherapy

in some trials, no significant survival benefit with additional radiation 288 ; improved local control after adjuvant radiotherapy in larger tumors, per other studies 297

particle therapy: satisfactory outcomes in ACC of the lacrimal gland with proton and heavy ion radiation 300 301 302 303

brachytherapy may be part of the therapeutic concept, e. g., for treatment of patients after R1 resection 304 305

chemotherapy: hints at improved prognosis with intraarterial cytoreductive chemotherapy (IACC) before (and after) therapy by means of surgery and radiation 289 290 ; furthermore, confirmed higher rate of eye-preserving surgeries after neoadjuvant IACC 306

Prognosis

high rate of local recurrence

poor long-term prognosis: median survival of 5 years, 10-year survival rate of 20%

ACC of the lacrimal gland mainly involves high-grade phenotypes with aggressive behavior and shorter median survival (2.5 years) 297

often death because of intracranial tumor growth or pulmonary metastases

7.2.1.2.1.2 Carcinoma in pleomorphic adenoma 252 261

Definition

according to the WHO classification of salivary gland tumors of 2017, the term ‘carcinoma in pleomorphic adenoma’ is only used together with the histological subtype 265

Synonyms

pleomorphic (adeno-)carcinoma, malignant mixed tumor (misleading because only the epithelial (carcinoma) and not the mesenchymal part degenerates; different situation for carcinosarcoma (“true” malignant mixed tumor), also described in the lacrimal gland 282

Epidemiology

second most frequent malignant epithelial tumor of the lacrimal gland (4–18%) 279 291 307 308 309

appears typically in the 6 th /7 th decades of life (about 10 years later than pleomorphic adenoma)

adenocarcinomas more frequently observed in males, adenoid-cystic carcinomas more frequent in females 287

Classification

non-invasive (intracapsular relation to pleomorphic adenoma)

minimally invasive (<4–6 mm above the capsula)

invasive (>4–6 mm above the capsula) 265

Histology

mostly poorly differentiated adenocarcinoma or undifferentiated carcinoma, more rarely adenoidcystic carcinoma

also possible: differentiated squamous cell carcinoma and spindle cell sarcomas 235 261 308 310

Clinical

sudden development of tumor recurrence after incomplete removal of a pleomorphic adenoma or significant sudden progress (possibly with accompanying pain) of a tumor that has been symptom-free for several years

Therapy

tumor resection (possibly radical orbitectomy including bone areas, depending on extent) with removal of regional (parotid) and cervical lymph nodes (adenocarcinomas may metastasize early lymphatically)

adjuvant radiotherapy afterwards as a useful completion of treatment 296 311

Prognosis

mostly considered unfavorable but depends on several factors such as histological subtype and invasiveness

non-invasive and minimally invasive types: very good prognosis after complete surgical resection (without adjuvant therapy)

invasive type: very aggressive tumors with poor prognosis but favorable prognostic effect of adjuvant therapy 312 313

causes of death: intracranial spread, distant metastases (lung, thoracic wall, bones)

7.2.1.2.1.3 Adenocarcinoma (not otherwise specified, NOS) 233

Annotation: In the current WHO classification of salivary gland tumors, the number of entities was reduced from 39 to 33 to reduce complexity and make the classification clearer. Among others, this change led to the inclusion of several, sometimes extremely rare entities under the term “adenocarcinoma NOS” 285 .

Epidemiology

third most frequent malignant epithelial tumor of the lacrimal gland (5–10%) 237 279

Etiology

de novo or within pleomorphic adenoma

Pathology

highly malignant

earlier metastasis comparison to adenoidcystic carcinomas

early lymphatic and hematogenous metastasis, mainly in the lung, brain, and mediastinum 314

Therapy

frequently in an advanced stage at first presentation so that adequate surgical resection is difficult or even impossible

surgical therapy, if needed with orbital exenteration or craniofacial orbitectomy and regional lymph node dissection 291 315

adjuvant radiotherapy 306 315 316

with observed Her-2 overexpression in some adenocarcinomas of the lacrimal gland, pharmaceuticals such as lapatinib are possible therapeutic options 317

Prognosis

shorter survival rates in comparison to adenoidcystic carcinoma

7.2.1.2.1.4 Mucoepidermoid carcinoma

Epidemiology

fourth most frequent malignant epithelial tumor of the lacrimal gland (2–3%) 237 279

until 2000, fewer than 30 case reports published 318

mean age at disease onset: 49 years

males a little more frequently affected 291 319 320

Clinical

typically indolent, slowly growing mass

Differential diagnosis

often confused with pleomorphic adenoma 296 319 320

Therapy

high-grade tumors: exenteration (with resection of affected bones)/orbitectomy, and adjuvant radiation

low-grade tumors: tumor extirpation (with or without radiation) 296 319

regional lymph node dissection (parotidectomy and neck dissection), mainly in higher grading and/or tumor size

Prognosis 314

tumor-free survival and overall prognosis mainly grading dependent (classification into grades I–III based on histopathological characteristics)

Thorvaldsson et al. (1970): mean follow-up of 12 years in cases of mucoepidermoid carcinomas of the major salivary glands; survival rates of 100% or 97% in patients with grade I or grade II tumors, but only 43% in grade III tumors (high-grade) 314 321

7.2.1.2.1.5 Ductal adenocarcinoma

Epidemiology

first described by Katz et al. in 1996 322

very rare, 2% of all epithelial lacrimal gland tumors 286

Yang et al. (2018): review of 24 cases in the literature and two of their cases 323

male:female ratio, 3–4:1 237 323

Etiology

possible development as carcinoma in pleomorphic adenoma 324

Pathology

equivalent of ductal adenocarcinoma of the salivary gland, histopathological similarities with ductal breast cancer

metastases most frequently observed in cervical lymph nodes, brain, bones, lung, and liver

androgen receptor positive in 46–83% of cases; Her-2 positive in 35–67% 237 323 325

Therapy 317 323 326

therapy recommendations along the same lines as for ductal salivary gland carcinoma

surgical resection, if needed with adjuvant radio(chemo)therapy

orbital exenteration in>50% of the patients undergoing surgery

primary radiochemotherapy in non-resectable tumors

chemotherapy in palliative settings with response rates of 15–20%

if needed, pharmaceutical androgen deprivation therapy in the recurrent or metastatic setting, e. g., bicalutamide for androgen receptor–positive tumors or trastuzumab or lapatinib with Her-2/neu expression

Prognosis

aggressive tumor, with more than one third of patients dying even after aggressive therapy 237 323

high recurrence rate, with more than half of patients developing metastases (58%), sometimes very early 323 327

7.2.1.2.1.6 Acinar cell carcinoma 328 329 330 331

Epidemiology

very rare in the area of the salivary glands (2–4% of parotid tumors)

even more rare in the area of the lacrimal gland, with only single case reports in the literature

females appear more frequently affected

age of manifestation: 6 th decade of life

Diagnostics/differential diagnosis

uncharacteristic in CT/MR imaging, resulting in a high risk of confusion with pleomorphic adenoma

Therapy

surgical resection, eye preservation depending on the extent of the lesion, if needed, exenteration or advanced exenteration (in cases of bone infiltration)

7.2.1.2.1.7 Primary sebaceous carcinoma 332 333 334 335

Epidemiology

extremely rare, only single case reports

Hypotheses of pathogenesis

originating from heterotopic tissue

malignant transformation and sebaceous-like differentiation of other epithelial tumors of the lacrimal gland

originating from degenerated pluripotent cells

Pathology

highly malignant tumor often identified very late (high-grade)

Differential diagnoses

must be differentiated from secondary invasion (e. g., originating from upper eyelid carcinoma) and metastasis

histologically sometimes difficult to delimit from other entities such as squamous cell carcinoma or basal cell carcinoma (40–75% of sebaceous carcinomas of the lacrimal gland confused initially with squamous cell carcinoma; special staining for fat can avoid this confusion)

Therapy

surgical therapy, if needed, orbital exenteration or advanced exenteration

parotidectomy/neck dissection depending on the extension (infiltration of surrounding structures, e. g., the upper eyelid)

adjuvant radiotherapy (local recurrence rate after resection: 9–36%)

radiotherapy alone in cases of non-resectable tumors

particle therapy (e. g., heavy ions, C 12 ) 336

7.2.1.2.1.8 Myoepithelial carcinoma 337 338 339 340 341

Epidemiology

very rare in the head and neck region, mostly affecting the parotid gland

extremely rare in the lacrimal gland; in larger case series,<1% of all lacrimal gland tumors 286

Mahdi et al. (2018): at the time of their writing, only 9 published case reports 324

Pathology

difficult histopathological diagnostics, misinterpretation occurs because of the rarity of the disease and histological polymorphism 286 342

Therapy

overall, so rare that no therapy concept established

surgical therapy

wide surgical excision, if needed, orbital exenteration

cervical lymph node metastases are rather rare so that elective neck dissection is not routinely recommended 341 343

radiotherapy

applied in myoepithelial tumors of the lacrimal gland at least in the palliative setting 344 ; if the parotid gland or other locations of the head and neck involved, adjuvant therapy after surgical resection in half of cases 341

primary radiotherapy if surgical resection not possible

significance of adjuvant radiation unknown; several authors report no effect on local recurrence rate 345

chemotherapeutics partly described as effective, but systematic data are lacking

Prognosis

high-grade malignancy with poor prognosis and high recurrence rate 286 341

myoepithelial carcinoma of the head and neck: 5-year survival rate of 32% 341

distant metastasis rate of 35% (mainly pulmonary metastases) 341

distant metastases with primary tumor in the lacrimal gland rarely described ( cave : low number of cases) 342

7.2.1.2.1.9 Squamous cell carcinoma

Epidemiology

according to a review by Weis et al. (2009), only 8 case reports published at the time of their writing 286

Etiology/pathogenesis

development of a few cases on the floor of a lacrimal gland cyst lined with epithelium (dacryops) 346 347

Therapy

surgical resection (if needed, orbital exenteration) and adjuvant radio(chemo)therapy 346 347 348

7.2.1.2.1.10 Oncocytic carcinoma 349 350

Epidemiology

according to Kalantzis et al. (2013), at the time of their writing, four published cases with involvement of the lacrimal gland 350

Pathology

high-grade tumor with infiltrative growth pattern, tendency to local recurrences and distant metastases

Therapy

radical resection (if needed, orbital exenteration) followed by adjuvant radio(chemo)therapy

7.2.1.2.1.11 Polymorphic adenocarcinoma 265 351

Formerly used term (until 2017)

polymorphic low-grade adenocarcinoma

Epidemiology

according to Selva et al. (2004), at the time of their writing, four published cases with involvement of the lacrimal gland 351

appears almost exclusively in the minor salivary glands, mainly at the palate (female:male ratio, 2:1)

Differential diagnosis

often confused with adenoidcystic carcinoma

Pathology

infiltrative growth and perineural invasion

metastases in regional lymph nodes relatively rare (6.5–10%), distant metastases extremely rare

Therapy

surgical resection (if needed, orbital exenteration); because of the relatively favorable prognosis according to Selva et al. 351 , eye-preserving procedures to be considered

necessity of adjuvant radiation questionable 351

Prognosis

clearly better compared to other adenocarcinomas of the salivary gland (overall survival of ≥95%)

if salivary glands involved, local recurrence in 5–33% of cases (generally well controllable with re-resection)

7.2.1.2.1.12 Secretory carcinoma 265 352 353

Definition

new entity, first described in 2010 in the head and neck as mammary analogue secretory carcinoma, designated as “secretory carcinoma” by the WHO

previously assigned to other entities despite not always typical histopathological characteristics (e. g., granule poor acinic cell carcinoma)

first described in 2018 in the lacrimal gland 352 353

Pathology

similar to the secretory carcinoma of the breast, also identification of the specific ETV6-NTRAK3 fusion gene

occurring in the head and neck mainly in the parotid gland (70%), and also in the buccal, lip, and palatal mucosa, rarely in the submandibular or sublingual glands

regional lymph node metastases in up to 25% of cases

Therapy

surgical resection

tropomyosin receptor kinase (TRK) inhibitors (larotrectinib, entrectinib) as future therapy options for tumors with NTRK fusion

Prognosis

overall, not very aggressive tumor with relatively favorable prognosis (survival exceeding 95%)

7.2.1.2.2 Malignant non-epithelial tumors of the lacrimal gland

Malignant non-epithelial tumors of the lacrimal gland are summarized in Table 7 . Lymphomas of the lacrimal gland are discussed specifically in section 7.2.1.2.3.

7.2.1.2.3 Malignant lymphoproliferative diseases – lymphomas of the lacrimal gland 233 237 365 366

Definition

belongs to ocular adnexa lymphomas

Epidemiology

lymphomas are the most frequent orbital malignancies 365

37% of all malignant tumors of the lacrimal gland are lymphomas 366

predominantly older people affected; mean age of 60 (+) years

female:male ratio, 2.4:1

Classification: by decreasing incidence, the following entities are found in the lacrimal gland

extranodal marginal zone lymphoma

follicular lymphoma

diffuse large cell B cell lymphoma (DLBCL)

Etiology/pathogenesis

in rare cases, development on the floor with chronic inflammatory diseases (Sjögren’s syndrome, IgG4-associated diseases, reactive lymphatic hyperplasia)

Clinical

main symptoms: mass, bulbus dislocation, diplopia

pain rarely reported (in the context of bone infiltration in cases of highly malignant types)

salmon-colored tumor in the area of the neighboring conjunctiva 233

in 20–25% of cases, bilateral involvement 365 367 368

typically, involvement of the orbital and palpebral part of the gland 233

Diagnostics

imaging procedures

CT scan or MRI: smooth and homogeneous mass, mostly without infiltration of the surrounding tissue (but possible bone erosion in highly aggressive types 365 )

clear morphological differentiation among reactive lymphatic hyperplasia, lymphoma, and non-specific inflammation of the lacrimal gland not possible with clinical assessment or imaging, so biopsy required (incision biopsy preferable to fine needle aspiration cytology) 233

further diagnostics (for assessment of systemic involvement)

bone marrow biopsy, whole body CT scan/MRI or PET

Ann Arbor classification and TNM staging apply

Therapy

radiotherapy, especially in localized types (Ann Arbor stage IE)

polychemotherapy, especially in cases of systemic spread (stages IIE-IVE), in cases of DLBCL also in an early stage 369

antibody therapy, e. g., anti-CD-20 rituximab

stem cell transplantation, if needed

surgical therapy: surgical therapy alone generally not justified 233

Prognosis

at the time of first diagnosis, about 80% at a localized stage (IE), and 20% showing systemic involvement in the context of staging (stage IIE–IVE) 233

for patients with stage IE at first diagnosis, secondary generalization in the further course in 22–42% of cases 233

Rasmussen et al. (2011): 5-year survival rate of 70% in 27 patients with lymphoma of the lacrimal gland 366

7.2.1.2.3.1 Extranodal marginal zone B-cell lymphoma

Epidemiology

most frequent subtype in the lacrimal gland, with 40% of all lymphomas 366

Therapy

early stage (stage IE/IIE, no systemic involvement): radiotherapy (about 30–40 Gy) 370

in cases of systemic involvement or high tumor charge: pharmaceutical combination therapy, e. g., rituximab+cyclophosphamide+hydroxydaunorubicin+vincristine+prednisone (R-CHOP) ->3-year progression-free survival in 70–80%

rituximab applied for a further 2 years as maintenance dose

Prognosis

low-grade lymphoma: 5-year survival rate of 75% 366 , more favorable in salivary glands (95–100%)

7.2.1.2.3.2 Follicular lymphoma

Epidemiology

with about 28% of all lymphomas, second most frequent subtype in the lacrimal gland 365 366

Therapy

early stage (stage IE/IIE): radiotherapy ->5-year survival rate of about 100% 366

in cases of systemic involvement or high tumor charge: pharmaceutical combination therapy, e. g., R-CHOP ->3-year progression-free survival in 70–80%

rituximab applied for a further 2 years as maintenance dose

Prognosis

low-grade lymphoma with favorable prognosis (5-year survival of about 80–90%)

7.2.1.2.3.3 Diffuse large-cell B cell lymphoma (DLBCL)

Epidemiology

with 15% of all lymphomas, third most frequent subtype in the lacrimal gland 365 366

Pathology

destructive growth in neighboring structures (e. g., ethmoid, intracranial) observed in 6 of 27 patients 365

Therapy

already in stage I (only involvement of the lacrimal gland): R-CHOP

in patients younger than 60 years with high risk profile (IPI score≥2 or increased LDH), etoposide added to R-CHOP (R-CHOEP)

in stage IE and absence of B symptoms, additional radiotherapy

Prognosis

high-grade lymphoma; 5-year survival rate: 55–73%

7.2.1.2.3.4 Mantle cell lymphoma

Therapy

primary therapy: R-CHOP

in patients younger than 65 years, additional cytarabine and stem cell transplantation

Unfavorable prognosis

Annotation: The WHO classification of lymphoid neoplasms encompasses more than 80 lymphoma categories. They are subdivided into three groups: B cell neoplasms, T and NK cell neoplasms, and Hodgkin lymphomas. Lymphomas as well as lymphoid leukemia are included. At this point, only the most important entities are mentioned 371 . The incidence distribution of the subtypes in the lacrimal gland corresponds to that for the salivary glands 366 .

7.2.1.3 Metastases in the lacrimal gland

Epidemiology

a malignant disease already known in 80% of cases at the time of first diagnosis of an orbital mass 233

presence of orbital metastases (mostly unilateral) in an estimated 2–3% of all patients with malignancies 233

location in the lacrimal gland quite rare 233 372

7.2.2 Neoplasms of the orbit (without lacrimal gland neoplasms)

7.2.2.1 Benign neoplasms

7.2.2.1.1 Benign epithelial neoplasms

See Section 6.2.1.1.1, “Benign epithelial neoplasms of the lacrimal gland.”

7.2.2.1.2 Benign non-epithelial neoplasms

Tumors of non-epithelial origin are even more numerous in type than epithelial tumors of the orbit.

7.2.2.1.2.1 Fibro-osseous processes of the orbit

There are several fibro-osseous lesions that can appear in the periorbital region and may lead secondarily to involvement of the orbital soft tissue, including an aneurysmal bone cyst, giant cell granuloma, and cholesterol granuloma. However, in the literature, these lesions are often called ‘reactive bone lesions’ and included in the list of bone tumors of the orbit.

7.2.2.1.2.1.1 Fibroma, ossified fibroma, fibromatosis 201 373

Fibroma

Epidemiology

quite rare in the orbit

7 fibromas in 2210 orbital tumors in four case series 373 374 375

occurrence mostly in adolescence and early adulthood

Pathology

mostly originating from the cranial periorbita or muscle conus

Ossified fibroma

Epidemiology

occurring mainly in younger patients

Pathology

slowly growing benign tumors, but destructive growth and recurrence possible after incomplete resection

location also in the paranasal sinuses of maxillary bones

Diagnostics

radiological differentiation from fibrous dysplasia necessary

Fibromatosis

May have an intermediate character

Therapy

generally surgical resection

7.2.2.1.2.1.2 Aneurysmal bone cyst

Definition

locally expansive osteolytic lesion consisting of blood-filled cavities with surrounding reactive fibro-osseous tissue

Location

predilection site: metaphysis of the long bones and spine

rare in the skull 377

orbital occurrence in less than 1% of cases 378 379 , then mostly orbital roof 380

Epidemiology

preferred occurrence in childhood and adolescence up to the 20th year of life

Etiology and pathogenesis

association with other bone lesions (fibrous dysplasia, chondroblastoma, osteoblastoma, giant cell tumors) that precede development of aneurysmal bone cyst and may be predisposing for the development as a reactive phenomenon 382 383

focal hemodynamic changes with secondary venous hypertonia or preexisting trauma discussed as causes 381

current oncogenetic study results: clonal neoplastic lesion with specific genetic rearrangement (USP6 gene upregulation in spindle cells) 384 , leading to possible differentiation of similar lesions without USP rearrangement (e. g., osteosarcoma, chondroblastoma, giant cell tumors)

Clinical

initially indolent swelling or bulbar protrusion

often slow growth over weeks and months, then episodes of rapid growth and painful exophthalmos, ptosis, diplopia, and further ophthalmological symptoms 378

Diagnostics

CT scan and MRI (characteristic changes, see Fig. 16a, b ): polylobulated mass with multiple cystic areas, separated by connective tissue septa; furthermore, solid areas, thinning of the surrounding cortex, liquid level in the cystic areas because of non-coagulated blood; clear contrast enhancement, the dura respected in cases of intracranial extension 378 385

histology: cystic cavities lined with endothelial-like cells; solid parts consisting of spindle-shaped fibroblasts with singular multinucleated giant cells, hemosiderin-charged macrophages, granulation tissue, and extravasal erythrocytes; septa frequently with newly developed bone; no atypical mitoses or other histological malignancy criteria

Differential diagnoses

other bone tumors (e. g., osteoblastomas, osteoclastomas, brown tumors)

reparative giant cell granuloma and giant cell tumors

examination by pathology reference centers required 378

Therapy

first choice: surgical excision and (depending on the extension and local destruction) reconstruction of the bone defect

in extended cases: intralesional curettage and partial removal with adjuvant radiotherapy

in cases of high intraoperative risk of bleeding: preoperative embolization or stereotactic radiosurgery

Prognosis

recurrence rate of 10–30%

malignant transformation possible but extremely rare 384

follow-up recommended 379 380 386

7.2.2.1.2.1.3 Giant cell granuloma 387 388 389 390 391

Definition

rare, reactive benign mass with locally aggressive growth

Epidemiology

mostly in females in the 1st to 3rd decades 392

Location

epiphyses in the long bones (>90% of cases)

skull (about 2% of cases): mostly mandible and maxilla, more rarely sphenoid and petrous bone, ethmoid, or orbit 387 391

Pathogenesis

still unknown

inflammation, trauma, and intraosseous hemorrhages are possible causes

because of the association with other symptoms such as Noonan syndrome, neurofibromatosis type I, and cherubism, a still unidentified chromosomal anomaly appears possible 393

Clinical

symptoms mostly the result of processes involving masses: swelling, deformity, sometimes pain

exophthalmos, visual impairment, diplopia as first clinical symptoms

Diagnostics

CT scan: mostly sharply delimited osteolytic process with expansive character, but highly variable and non-specific

histopathology: characteristic accumulation of multinucleated large osteoclast-like giant cells with a tendency to cluster around hemorrhagic foci

Differential diagnoses

osteoclastoma, osteosarcoma, eosinophilic granuloma, aneurysmal bone cyst, “brown tumors” in cases of hyperparathyroidism, non-ossified fibroma, Langerhans cell histiocytosis (radiological differentiation sometimes difficult)

differentiation of giant cell tumors is controversially discussed in the literature 394 : in the described cases, definite diagnosis of orbital giant cell granuloma was only possible by biopsy or surgical excision

Therapy

first choice: complete resection

not always possible as radical intervention in the area of the skull

radiation: controversially discussed in cases of resistance to radiation and possible malignant cell degeneration; however, recommended by some authors after partial resection

medication for adjuvant therapy: corticosteroids, calcitonin, bisphosphonates, imatinib, and interferon-α 393 395

denosumab (monoclonal antibody): neutralization by binding to the RANK ligands produced by the tumor cells in cases of unresectable or locally advanced findings 391

Prognosis

recurrence in 10–50% of cases

7.2.2.1.2.1.4 Cholesterol granuloma

Definition

rare benign lesion developing because of foreign body reaction to cholesterol crystals

Epidemiology

occurring typically in middle-aged males 396

Etiology and pathogenesis

presumed development from traumatic genesis or intrinsic anomaly of diplopia

inflammatory reaction against degradation products of blood components or in cases of hypoxic tissue destruction

granulomatous inflammatory reaction on cholesterol with subsequent erosion of the surrounding bone 397 398

Location

mostly in the temporal bone

possible also in the area of the facial skull

rarely orbital, but if so, typically in the area of the frontal bone above the lacrimal fossa (superotemporal or superior) because the weakest connection of the periorbita to the bone is found with frequent occurrence of trauma 399 400 401 ; in cases of unclear lesions of the orbit from imaging, location, and often positive trauma history, cholesterol granuloma to be considered 401

Clinical

exophthalmos, diplopia, visual impairment

more rarely periorbital pain or ptosis

Diagnostics

CT scan: osteolytic lesions of the frontal diploe with erosion of the adjacent cortex and sometimes expansion into the extradural space

MRI: differentiation of other soft tissue tumors is possible; typically high signal intensities in the T1- and T2-weighted sequences because of liquid content 402

histology: cholesterol crystals surrounded by multinucleated giant cells; differentiation of epidermoids and dermoid cysts because of absence of epithelial elements; differentiation of aneurysmal bone cyst or giant cell tumors by the prominent xanthomatous component

Differential diagnoses

difficult clinical and CT morphological differentiation of dermoid or epidermoid cyst

others: neoplasms of the lacrimal gland, metastases, aneurysmal bone cyst, or chondroma 61

Therapy

first choice: drainage of the lesion contents and meticulous removal of the cyst wall as well as surrounding bone ->minimization of recurrence risk

different techniques, depending on the size and location of the lesion 400 401 403

7.2.2.1.2.1.5 Osteoma 201

Epidemiology

most frequently a tumor originating from the orbital bone (often also from the paranasal sinuses)

Diagnostics

CT scan: bone-dense, well-delimited mass (often incidental finding)

Therapy

surgical resection, only in symptomatic/progressive cases

7.2.2.1.2.1.6 Chondroma 201 404

Annotation: The trochlea is the only cartilaginous structure of the orbit, and the sphenoid has cartilaginous precursor structures.

Epidemiology

Garrity and Henderson (2007) 405 and Shields et al. (2004) 279 : only one case each out of 1373 and 627, respectively, of mesenchymal orbital tumors

Rootman et al. (2004): one case out of 62 primary tumors of the orbital bone in a period of 24 years 405 406 407

in the area of the facial skull, mainly occurring in adolescents and young adults

Clinical

often asymptomatic

in cases of progression, ptosis/proptosis

Location

superior nasal quadrant

Pathology

histopathological differentiation of low-grade chondrosarcomas is difficult

partly aggressive behavior of chondrogenic tumors of the facial skeleton (discrepancy between histological appearance and biological behavior)

Therapy

resection, with a safety margin if possible

long-term follow-up recommended 404

7.2.2.1.2.2 Neuroma 201 408

Synonyms

schwannoma, Schwann cell tumor

Epidemiology

0.7–2.3% of orbital tumors

usually singular occurrence

in up to 18% of cases, association with neurofibromatosis

Pathology

benign tumor of the peripheral nerves

Therapy

surgical resection, especially in symptomatic processes

7.2.2.1.2.3 Neurofibroma 201 409

Plexiform neurofibroma

Epidemiology

most frequent subtype in the orbit

often congenital or in early childhood

neurofibromatosis type I is often the primary disease

Pathology

multinodular mass with infiltrative behavior (eyelid, skull base, periorbita) and relatively strong vascularization

degeneration rate (transformation into malignant peripheral nerve sheath tumor): 2–4%

Clinical

severe visual impairment is typical

Therapy

surgical resection

difficult because of irregular borders, often multiple intervention until exenteration

Localized neurofibroma [ 409 , 410 ]

Epidemiology

rarely associated with neurofibromatosis

manifestation peak: 3rd-5th decades of life

Location and pathology

typically cranial location in the orbit (frontal nerve), less vascularized, better encapsulated

Therapy

surgical resection

Pathology

in contrast to schwannomas, additionally fibroblasts and perineural cells are found, higher contents of connective tissue substance, not (well-)encapsulated, cannot be separated surgically from the nerve, requiring sacrifice of the nerve

7.2.2.1.2.4 Meningioma 201 411

Epidemiology

according to estimations, about 4–8% of all orbital neoplasms

age of manifestation: typically around the 45th year of life, optic nerve sheath meningioma in younger patients

women significantly more frequently affected than men

Risk factors

previous radiotherapy of the head region

neurofibromatosis type 2

Typical locations

lateral orbital wall, orbital roof (“primary ectopic meningiomas,” only single cases)

optic nerve sheath meningioma (most frequent optic nerve sheath tumor), in 90% of cases, already growth through the optic nerve canal in direction of the chiasma at diagnosis 412

ingrowth of meningiomas of the cavernous sinus or the medial sphenoid wing (optic nerve compression)

Pathology

orbital meningiomas usually grade 1 meningiomas according to the WHO grading for meningiomas (grade 1: benign; grade 2: anaplastic; grade 3: malignant) 413

Clinical

leading symptoms

slowly progressive, painless loss of vision (key symptom)

visual field defects

transient obscurations

protrusion or motility disorders (with diplopia) often in advanced stage

Therapy 411 412 414 415

with small and/or less impairing findings: “watch-and-wait” and initially half-yearly MRI controls

therapy indication 412 : progressive visual impairment, visual decline to 0.4; increasing visual field disorders, endangered chiasma

optic nerve sheath meningioma

therapy of first choice: fractionated radiotherapy (50–55 Gy) with probably best functional outcome (vision)

surgical therapy, especially in cases of extension in intracranial direction or blindness and disfiguring protrusion

in cases of growth into the optic canal, optic nerve decompression, if needed

surgical resection (if necessary, embolization prior to surgery), possibly with adjuvant radiotherapy

7.2.2.1.2.5 Opticus glioma 201 412

Definition

special type of pilocystic astrocytoma (juvenile pilocystic astrocytoma, WHO grade I) 412

Epidemiology

manifestation in 90% of cases before the 20th year of life, in 50% of cases before the age of 5 412

underlying neurofibromatosis type I possible and should be excluded

Differential diagnosis

optic nerve schwannoma 416 (observed, even though extremely rare [fewer than 10 cases have been described], even if the myelin sheath of the optic nerve does not contain Schwann cells; most probably originating from small sympathetic nerve fibers)

Clinical

bilateral location possible (especially in neurofibromatosis)

slow growth

exophthalmos

squint position of the affected eye

visual and visual field impairment

phase-wise increase of the complaints in cases of bleeding

nystagmus

endocrinological accompanying symptoms possible (e. g., diabetes insipidus, obesity, precocious puberty)

Therapy 417 418 419

controversial because a spontaneous course is not predictable, spontaneous remission is possible, and all procedures have some significant side effects

proximity to the optic canal is crucial for the course

follow-up by means of MRI and visual/visual field examinations (more decisive for the therapy indication than radiologically found increase) in cases of newly diagnosed gliomas

(partial) resection, especially in cases of large, progressive intraorbital gliomas with blindness, growth in direction of the chiasma, or disfiguring exophthalmos

probably transection of the optic nerve in front of the chiasma to avoid extension to the contralateral side

fractionated radiotherapy was former therapy of choice, but in children, especially age<7 years, associated with the risk of neurological-cognitive deficits and later secondary tumors (in particular with neurofibromatosis), so currently indicated mainly in progressing chiasma-near tumors in older children or adults

chemotherapy to reduce tumor size and growth and to delay other therapies

first-line therapy in cases of loss of vision/tumors requiring action especially in small children: pharmaceuticals such as carboplatin combined with vincristine

Case report 3

History

18-year-old female patient

increasing exophthalmos for about 4 months and visual impairment for 5 days, left side

Diagnostics

ophthalmological examination

vision: right side 1.25, left side 0.6

Hertel exophthalmometry: right side 20, left side 24 mm

congestive papilla, left side

MRI ( Fig. 17 )

suspected optic nerve glioma measuring 28×17 mm

no intracerebral growth

Procedure

transnasal endoscopic medial orbital decompression with biopsy

histopathology: optic nerve glioma

definitive fractionated stereotactic radiotherapy (50.4 Gy)

Course

initially fluctuating but good vision (around 0.8–0.9)

about 6 months after radiation: ophthalmological optic nerve atrophy, clearly deteriorated vision of the left eye (0.25), increasing edema of the papilla, secondary strabismus divergens, cosmetically disturbing progressive exophthalmos ( Fig. 18 ), and insufficient eyelid closure

further deterioration during the following 3 months (vision 0.1, Hertel exophthalmometry on the left side 27 mm, increasing suffering, fundoscopy findings ( Fig. 19 )

bulbus enucleation and tumor resection, implantation of Guthoff implant, later prosthesis

genetic assessment to exclude neurofibromatosis

7.2.2.1.2.6 Myxoma 272 273 274 275 276

Definition

neoplasm of mesenchymal/connective tissue origin

Epidemiology

few case reports published about the orbital area

men and women equally affected

Pathology

histologically containing few cells and vessels with abundant myxoid (mucus-like) hyaluronic acid-rich matrix

other locations: predominantly heart, along with bones, skin, skeletal muscles, urogenital tract

Diagnostics

association of orbital myxomas with Carney syndrome (familial myxoma syndrome), Mazabraud syndrome, McCune-Albright syndrome

should be considered in patients with increased numbers of chloasma, cardiac history, and orbital mass

a well-circumscribed, oval, isodense mass seen on CT

radiotherapy without relevant effect

Further examples of benign non-epithelial orbital neoplasms are listed in Table 8 .

7.2.2.2 Malignant neoplasms

7.2.2.2.1 Malignant epithelial neoplasms

See Section 7.2.2.2.3, “Malignant epithelial tumors of the lacrimal gland.”

7.2.2.2.2 Malignant non-epithelial neoplasms

Annotation: Lymphomas of the orbit are described in Section 6.2.2.2.3.

7.2.2.2.2.1 Rhabdomyosarcoma 434

Epidemiology

most frequent orbital malignancy in children

embryonic subtype: most frequent, about 60–70% of all pediatric rhabdomyosarcomas

alveolar subtype: 30% of all pediatric rhabdomyosarcomas, in 80% associated with specific gene translocation/-fusion (PAX3 on chromosome 2 or PAX7 on chromosome 1 with FOXO1 on chromosome 13)

Clinical

rapidly progressing exophthalmos

eyelid swelling/reddening

ptosis, possibly palpable tumor

Diagnostics

biopsy

Therapy

standard: chemotherapy+radiotherapy

exenteration not to be performed primarily, only with confirmation of residual tumor/recurrence in the biopsy after chemotherapy+radiotherapy

Prognosis

key problem of local recurrence

unfavorable prognosis in cases of confirmed gene translocation/fusion

7.2.2.2.2.2 Fibrosarcoma 435 436 437]

Epidemiology

mean age at manifestation: 50 years

men preferentially affected (independent of location)

several case reports of orbital involvement in children

Etiology and pathogenesis

occurrence as post-radiogenic secondary tumor in the orbit (e. g., after radiotherapy of retinoblastoma)

increased risk after implantation of foreign material

Pathology

aggressive tumor (in more than 80% grade 2/3 according to FNCLCC)

metastases mainly in the lung, bones, and regional lymph nodes

only single case reports of orbital fibrosarcomas after application of modern diagnostic procedures

in recent years, improved histopathological diagnostic procedures and classification systems for sarcomas have led to a rare diagnosis of exclusion (<1% of all adult soft tissue sarcomas)

Therapy

resection with wide safety margins up to exenteration

exenteration especially in cases of local recurrences

significance of postoperative radio- or chemotherapy unknown, in particular in cases of rare locations in the orbit

Prognosis

5-year survival rate of about 55%

7.2.2.2.2.3 Retinoblastoma 438 439 440

Definition

malignant tumor in the retina; precondition for its development are mutations in both alleles of the retinoblastoma gene (located on chromosome 13, band q14)

Epidemiology

incidence of about 1:20 000 live births

most frequent intraocular malignancy in children

male:female ratio, 1:1

usually occurring before the age of 5 years

Types

45% inherited

heterozygous for mutations in the retinoblastoma gene, with an additional mutation arising in the second allele

both eyes usually affected

mean age at the time of diagnosis: 12 months

55% non-inherited

both mutations occurring in the same cell

mainly unilateral

mean age at the time of diagnosis: 23 months

75% unilateral, 25% bilateral

Clinical

leukocoria, strabismus, more rarely: painful reddening of the eye, glaucoma, visual impairment

Diagnostics

ophthalmological examination: unifocal or multifocal whitish, vascularized retinal mass, sometimes with tumor dissemination

ultrasound

MRI (for evaluation of optic nerve involvement and possible extraocular extension)

gene diagnostics (differentiation between hereditary and non-hereditary type)

generally no biopsy

lumbar puncture in cases of extension in direction of the CNS

possibly bone scintigraphy/bone marrow puncture if bone metastasis is suspected

Therapy

objective: preservation of life (primary objective), preservation of function (secondary objective)

laser/cryocoagulation, transpupillary thermotherapy (especially in small tumors)

chemotherapy as one of the most important options: allows avoiding radiotherapy or enucleation in a significant number of cases

enucleation including resection of the optic nerve (especially in advanced unilateral tumors)

radiotherapy (former standard therapy with high radiation sensitivity, but significant risk for post-radiogenic secondary tumors – about 36% within 50 years in the hereditary type – so reserved for specific indications such as metastatic spread or response failure on chemotherapy)

brachytherapy: primary therapy option in cases of solitary tumors ventral to the equator (in 2/3 of cases with good visual function) or after failure of other therapeutic strategies, adjuvant therapy option

adjuvant chemotherapy, especially after enucleation if certain risk factors are present (e. g., choroid invasion, optic nerve invasion, extension into the orbit, dissemination into the anterior chamber)

Prognosis

5-year survival rate: about 96% in developed countries

in the hereditary type: increased risk for secondary (extraorbital) tumors

7.2.2.2.2.4 Malignant glioma of the optic nerve 412 441 442

Definition

corresponds to anaplastic astrocytoma, WHO grade III, or glioblastoma, WHO grade IV; no association with neurofibromatosis

Epidemiology

extremely rare

manifestation peak: middle-aged adults

Symptoms

initially similar to acute neuritis of the optic nerve

retroorbital pain

at time of diagnosis, chiasma involvement already present in 75%, early CNS infiltration

rapidly progressive loss of vision up to blindness

possibly other neurological symptoms such as seizures

Therapy 442 443

no effective therapy

combined radiochemotherapy with temozolomide

surgical resection only in single cases, e. g., strictly unilateral involvement without chiasma involvement

Prognosis

death usually within one year

Further examples for non-epithelial malignant neoplasms of the orbit are listed in Table 9 .

7.2.2.2.3 Lymphoproliferative diseases of the orbit

7.2.2.2.3.1 Orbital lymphomas 365 463 464 465

Annotation: See Section 7.2.1.2.3, “Lymphomas of the lacrimal gland.”

Epidemiology of lymphomas

the most frequent malignant orbital masses (about 50–55% of all orbital malignancies are non-Hodgkin lymphomas)

the most frequent primary orbital tumors in older patients (>60 years)

lymphoid tumors encompass about 10–20% of orbital masses

ocular adnexae (conjunctiva, eyelids, lacrimal gland, orbital soft tissue) affected in 1–2% of all lymphomas and about 8% of all extranodal lymphomas

secondary orbital involvement in an estimated 5% of all patients with non-Hodgkin lymphomas

mainly older people affected

Frequency in lymphoma types

B cell lymphomas, 97%

(extranodal) marginal zone (B cell) lymphomas, about 50–60%

follicular lymphoma, about 9–23%

DLBCL, about 8–23%

mantle cell lymphoma, about 5%

Locations

orbital soft tissue: 32–60%

conjunctiva: 15–42%

lacrimal gland: 14–20%

external eye muscles: 9%

lacrimal sac: 2–11%

bilateral occurrence: 11–32%

Clinical

lymphomas of the conjunctiva: typically smooth and salmon-colored

morphologically sometimes difficult to differentiate from idiopathic orbital inflammation by imaging (formerly so-called orbital pseudotumor) ->biopsy

mostly locally limited ocular adnexa lymphomas at the time of diagnosis (exception: mantle cell lymphomas)

Therapy

in localized manifestation: radiotherapy ->good local control and healing rate

in cases of bilateral or systemic disease and aggressive subtypes (e. g., DLBCL): chemotherapy

immunotherapy with anti-CD-20 antibodies

Prognosis

low-grade lymphoma (marginal zone lymphoma, follicular lymphoma): good

high-grade lymphoma (DLBCL, mantle cell lymphoma): poor

Case report 4

History

first presentation of a 58-year-old male patient in the Department of Ophthalmology of the University Hospital of Halle, Germany

complaints for 2 years

Symptoms

left eye protruded and reddened

current visual impairment

Fig. 20a, b shows preoperative findings

Previous measures and course

intensive diagnostics (including MRI examination) and therapy by ophthalmologists in cooperation with a general hospital

transconjunctival biopsy of the orbit performed elsewhere: on histopathology, a lymphoplasmacellular infiltrate without a conspicuous IgG4 ratio

working diagnosis: idiopathic inflammatory orbitopathy, left more than right

therapy-refractory course with high-dose glucocorticoids for about 1.5 years (80 mg prednisolone at the time of first presentation), obvious Cushing symptoms, steroid-induced diabetes mellitus, arterial hypertonia, NYHA III heart failure, liver steatosis

Diagnostics/clinical findings (relevant aspects)

no relative afferent pupillary defect, impaired bulbus motility (especially adduction) on the left, diplopia when looking upwards and to the side

anterior segments of the eye

congested conjunctival/episcleral vessels

lid-parallel conjunctival folds (LIPCOF)++

fundoscopy

left papilla temporally faint

retina and choroid folds

vision

right: 1.0

left: 0.4

Hertel exophthalmometry (mm)

23–123–28

tension

right: 15 mmHg

left: 15 mmHg

CT scan ( Fig. 21a, b )

on the left, evidence of four polylobulated, homogenously moderately contrast enhancing, intra- and extraconal lesions, the largest one measuring 18.5×26×18 mm

on the right, significantly smaller intramuscular lesions

Course

first, change in medication to cortisone-saving immunomodulated therapy initially with methotrexate, but because of intolerance shifted to mycophenolate mofetil; additional rheumatological care

because of no improvement, ENT-specific consultation and indication of balanced orbital decompression with intraorbital re-biopsy ( Fig. 22 ) for verification of the diagnosis; transfer to the department of otolaryngology

Therapy

balanced medial and lateral orbital decompression on the left and biopsy of a mass (mostly intraconal location protruding in extraconal direction) via lateral orbitotomy

stepwise reduction of pharmacotherapy

Histopathological diagnosis

extranodal marginal zone lymphoma

Further course

postoperatively, slight visual improvement (0.5)

staging by means of whole-body CT scan and cMRT without hint of further manifestation of the lymphoma

case presentation to the tumor board and therapy by the departments of hemato-oncology and radiotherapy

local radiotherapy up to 30.6 Gy (ED 1.8 Gy) of the right and left orbits

cooperation with the department of hemato-oncology

7.2.2.2.3.2 Leukemia

Epidemiology

orbital manifestation in comparison to lymphomas clearly more rare

percentage of leukemias in malignant lymphoid orbital adnexa diseases: ~4% 365

occurrence mostly during the first decade

Types

orbital manifestation possible in acute and chronic leukemias

most frequent subtype: acute myelic leukemia 466 467 468

mostly secondary orbital involvement (e. g., as recurrence), orbital manifestation also a possible first symptom

bilateral occurrence possible

orbital involvement mostly a hint of an advanced disease stage

Therapy

chemotherapy and radiotherapy of the affected eye (better outcome compared to chemotherapy alone) 469

7.2.2.2.4 Metastases 59 470 471

Epidemiology

7–8% of all orbital neoplasms

in up to 25% of cases, evident before identification of the primary tumor

Differential diagnoses

clinically and morphologically, confusion with other diseases possible, for example, abscesses or parasitosis 471

Location of the primary tumor

in adults mainly in the breast, lung, gastrointestinal tract, prostate, kidney, skin

in adults with involvement of the external eye muscles in the breast, skin (melanoma) 471

in children mainly neuroblastoma, Ewing sarcoma

Therapy and management

identification of the primary tumor

depending on the tissue type

radiotherapy as significant therapeutic pillar (at least for symptom control)

Case report 5

History

62-year-old male patient

for 4 days, aqueous rhinorrhea, epiphora, increasing periorbital swelling and reddening, increasing pain in the left eye

no infection of the upper airways

Findings

reddening and swelling of the left upper and lower eyelid with extension to the cheek

exophthalmos

chemosis with conjunctival hyperemia

motility impairment of the bulb

reduced vision (0.6)

intraocular pressure: 14 mmHg on right, 20 mmHg on left

leukocytes and CRP slightly increased

CT scan (with contrast agent; Fig. 23a, b )

lesion 12×11×10 mm, strongly contrast enhancing in the area of the inferior rectus muscle, slightly displacing the optic nerve

regularly ventilated paranasal sinuses

Course

because of the suspicion of intraorbital abscess, transnasal, transethmoid endoscopic orbitotomy with opening of the lesion releasing only limited turbid secretions; swab and biopsy performed

histology: neuroendocrine tumor

diagnosis after identification of the primary tumor, and staging (among others DOTA-TOC PET-CT): neuroendocrine tumor (G2) of the ileum with hepatic, orbital, and lymph node metastases

7.2.2.2.5 Secondary orbital tumors 59 472

Origin

paranasal sinuses

classification: grade I (infiltration of the orbital bone), grade II (infiltration of the periorbita), grade III (infiltration of the orbital soft tissue by transgression of the periorbita)

therapy: multimodal approach required (among others R0 resection, which is crucial for prognosis)

prognosis: with grade III, improved survival by orbital exenteration compared to organ preservation

intracranial

eyelid (e. g., basal cell carcinoma)

conjunctiva (e. g., melanoma)

7.2.3 Vascular anomalies

Vascular anomalies have a special position and can be classified into vascular tumors and malformations .

7.2.3.1 Vascular tumors

Vascular tumors have the following characteristics:

“True” neoplasms with endothelial proliferation and angiogenesis

Capacity for regression (at least partly) with increasing age

Differentiation of benign, locally aggressive (borderline), and malignant subtypes

7.2.2.2.5 Infantile hemangioma 2 473 474 475 ’

Synonym: capillary hemangioma (former term)

Epidemiology

most frequent vascular orbital tumor in childhood

manifestation typically in the first weeks of life (not at birth) with progression during the first 3–6 months

spontaneous regression typically from the 6th month to the 9th year of life (75–90% gone by the age of 7 years 476 ), rarely only during puberty

in general harmless, but in cases of unfavorable location (e. g., orbit, oral cavity), possible functional impairment and permanent deformity (e. g., irreversible amblyopia, astigmatism)

Location and appearance ( Fig. 24a, b )

ranging from small and circumscribed to large and multifocal

most frequently extraconal, mostly ventral to the bulbus in the area of the eyelids; extraocular muscles and lacrimal gland also possibly affected

more rarely, intraconal, e. g., in the area of the orbital fat body 477

in cases of retrobulbar location, risk of compression of the optic nerve (especially with rapid growth)

Clinical

raspberry-like appearance, especially with superficial location

Differential diagnosis

congenital hemangioma

much rarer, absolute rarity in the orbit

present already at birth and completely developed (no further growth after birth)

Therapy 478

spontaneous remission in 85–90% of cases

treatment only in symptomatic hemangioma cases necessary; in cases of optic nerve compression, therapy urgently needed

propranolol 2–3 mg/kg body weight per day applied in 2–4 single doses for 6 months (therapy of first choice in cases of complex infantile hemangiomas; response rate of 98%)

meanwhile, systemic steroid application reserved for exceptional cases (e. g., airway obstruction, non-response to other therapeutic procedures)

cytostatics (vincristine) and interferon-alpha are obsolete

laser/cryotherapy: in small, plain, easily accessible hemangiomas (e. g., eyelid)

surgical resection: indicated rather rarely in the area of the orbit because of the risk of damaging surrounding structures

7.2.3.1.2 Hemangiopericytoma 479 480

Definition

tumor originating from the pericytes of the vascular wall or pluripotent perivascular cells

Epidemiology

only single reports of orbital occurrence 480

Diagnostics 480

no pathognomonic clinical or radiological characteristics

biopsy required

Pathology

histologically, the whole spectrum of benign to malignant characteristics ->classification into benign, borderline, and malignant

behavior rather unpredictable, with even seemingly benign lesions sometimes showing malignant behavior

metastasis in about 15% of cases

hemangiopericytoma and solitary fibrous tumors overlapping considerably in histology and immunohistochemistry, and according to some authors, possibly representing an independent entity 479

Therapy

complete surgical resection

if needed, adjuvant radiotherapy

if needed, chemotherapy

follow-up

Prognosis

local recurrences in about 30% of cases

Table 10 lists examples of other vascular tumors of the orbit. Most are absolute rarities in the orbit, and only single case reports are available 475 . Meanwhile, many authors classify tufted angioma as a borderline tumor and an independent entity together with Kaposi-form hemangioendothelioma – with a histopathological spectrum that has more or less aggressive characteristics, depending on the individual case 494 495 .

7.2.3.2 Vascular malformations 2 473 474 475 495

Vascular malformations have the following characteristics:

Mesenchymal vasculogenetic developmental disorders with low proliferative activity

Always present at birth but apparent only later (growth triggered, for example, by hormones or mechanical impact)

Progressive

No spontaneous remission

The classification of vascular malformations and therapeutic options is listed in Table 11 . The percentages are general and not specific for the orbit 2 475 ( Fig. 25a, b ).

7.2.3.2.1 Venous malformation 201 412

Synonym

former ‘cavernous hemangioma’, and according to the current ISSVA classification of vascular anomalies 494 , to be called ‘slow-flow venous malformation’ (however, the former term is still widely used)

Epidemiology

one of the most frequent benign masses of the orbit in adults (5–7% of all orbital lesions)

typical age of manifestation: 30–50 years

women more frequently affected

Clinical

often incidental finding

slow growth (exophthalmos developing over years)

increased growth during pregnancy

typical location: intraconal

Therapy

“watch-and-wait” in smaller/asymptomatic findings

sclerotherapy

complete surgical resection, e. g., via lateral orbitotomy

Differential diagnosis

‘orbital varicosities’

the term ‘orbital varicosities’ is no longer used, and they are classified as venous malformations

pathogenesis: congenital weakness of the venous walls of the valve-less orbital vein ->massive dilation

diagnostics: exophthalmos during Valsalva maneuver

Clinical: in cases of bleeding, rapid and painful increase in exophthalmos

therapy: in general, not required

7.2.3.2.2 Lymphatic malformation 412 473

Synonym (no longer used)

lymphangioma

Epidemiology

occurring mainly in childhood and adolescence

Clinical

periorbital swelling

slowly progressive, indolent exophthalmos

motility disorders

bulbus displacement

complication: acute exacerbation because of bleeding or infection possible (significant increase within hours or days also possible)

no capsula, diffusely infiltrating, compartment borders not respected

filled with lymphatic fluid or blood

Therapy

complete extirpation usually not possible

“watch-and-wait”

in cases of risk of vision loss, volume-reducing measures such as partial resection, injection of sclerotizing substances, mTOR inhibitors

7.2.3.2.3 Arteriovenous malformation (AVM) 473 475 495 496

Location

mainly in the head and neck, including brain ( Fig. 26 )

extremities

more rarely, inner organs (e. g., liver, lung)

Characteristics

clinically quite diverse and challenging

unexceptionally life-long progressive growth (destructive)

reacts to stimuli such as hormonal changes, trauma (e. g., possible increased proliferation after incomplete invasive therapy) 474

Clinical classification (Schobinger classification, shortened) 497

stage I: clinically inactive

stage II: expansion, pulsation

stage III: destructive AVM with ulcerations, necrosis, bleeding, pain, infection

stage IV: decompensated AVM with heart failure

Therapy

often quite difficult and risky

“watch-and-wait” in cases of asymptomatic AVM

possibly complete closure by embolization (several sessions) with subsequent resection (if the location allows) to avoid recurrence

mTOR inhibitors not effective

Prognosis

high tendency to recurrence in cases of incomplete therapy

Case report 6

History

emergency presentation of a 9-month-old boy with acute right-sided exophthalmos

no relevant previous diseases

Diagnostics

inspection: right-sided exophthalmos, increased vascular injection, incomplete eyelid closure ( Fig. 27 )

ultrasound at first presentation: suspicion of retrobulbar, acutely bleeding, cavernous venous malformation, MRI for further clarification recommended

MRI ( Fig. 28 ): retrobulbar bleeding with suspected ruptured, partly thrombosed aneurysma spurium with additional venous malformation portions, DD AVM

angiography: high-flow AVM in the right-sided orbit, mainly fed from the right ophthalmic artery, dominant venous outflow via dilated venous aneurysms (type II according to the WHO classification), venous drainage via the cavernous sinus

Course

progressive exophthalmos, right-sided

increasing defense of the child

severe right-sided loss of vision

Therapy

embolization of the AVM with onyx18 (interventional radiology) ->complete closure of the inflow via the ophthalmic artery and another feeder from the maxillary artery ->AVM considered operable

because of progressive exophthalmos and onset of corneal ulceration of the right eye, interdisciplinary case discussion and indication for surgery

bulbus enucleation, resection of the intraconal AVM after embolization, implantation of a Guthoff implant (16 mm) with tenon and conjunctiva plasty (interdisciplinary by ophthalmologists and otolaryngologists; Fig. 29 )

later epithetic treatment

Histology

AVM with condition after embolization

no hint of malignancy

7.3. Conclusion

Neoplasms of the orbit are rare but diverse. Based on symptoms alone, they cannot be differentiated from structural or inflammatory lesions, and differentiated ophthalmological, radiological, and paraclinical diagnostics are important. In most cases, however, histopathological examination of the excisional biopsy is decisive. Exceptions are tumors of epithelial origin of the lacrimal gland, in which incision biopsies may significantly worsen the overall prognosis. The classification of orbital tumors consists of neoplasms of epithelial and non-epithelial origin as well as neoplasms of the lymphatic tissue, whereas the lacrimal gland is the only organ of the orbit with epithelial structures. Vascular malformations are a special case because they have a highly variable clinical behavior. In addition to watch-and-wait in asymptomatic benign processes, surgical resection of symptomatic benign neoplasms is mainly considered. However, especially in the area of the orbit, the expected benefit must be weighed against the possible functional deficits. The access pathways mainly depend on the location of the lesions. Radiotherapy as well as systemic therapies with chemotherapeutics and biologicals are important therapeutic pillars and in recent decades have reduced morbidity with orbital tumors. Nonetheless, malignant orbital tumors are mostly associated with a poor prognosis.

Lymphoproliferative lesions of the orbit are indolent so that patients often have a good quality of life after remission. However, mortality rates can be quite high, for example in cases of NK/T cell lymphomas. A better understanding of the molecular genetic correlations will certainly lead to more precise application of targeted therapeutics and thus to a better prognosis with orbital lymphomas. An essential condition, however, is conducting biopsies that are actually representative.

Bone tumors of the orbit encompass highly variable entities, and fibro-osseous lesions have fascinating pathogenetic and pathological properties. Imaging allows differentiation among the possible diagnoses, but biopsy is often necessary for confirmation. These evaluations are reserved mainly for referral centers. Treatment decisions should always be made with consideration of the systemic effects of the disease and new approaches with targeted therapies.

Because of their rarity and diversity, tumors of the lacrimal gland are challenging not only for pathologists but also for clinicians. History and symptom assessment are crucial for the diagnosis but can vary enormously, and even imaging is rarely pathognomonic. Furthermore, controversies exist with regard to the most appropriate therapies, especially in the context of malignant epithelial tumors that generally have a poorer prognosis compared to malignancies of the salivary glands.

Primary and secondary neurogenic tumors are often located in the orbit, presumably because of the high density of nerves in this region. Diagnostics and therapy represent a challenge given that the etiology, pathogenesis, and natural course of the diseases are still not clear.

Tumors of the orbital fatty and connective tissues as well as the striated muscles are mostly heterogeneous neoplasms that are nonetheless similar with regard to clinical symptoms, histogenetics, molecular biology, and prognosis.

Metastases of the orbit are another heterogeneous group of neoplasms with a high variation in presentation, depending on the disease extent and biology of the primary tumor. Most metastases occur in patients with an unknown primary tumor and become apparent because of displaced bulbus, strabismus, and pain. In cases of suspicion, imaging and biopsy are necessary to plan multidisciplinary treatment aimed at preserving vision, reducing pain, and improving quality of life. In some cases, a curative approach is possible.

Vascular anomalies are subdivided into vascular tumors and vascular malformations. Although the former are “true” neoplasms with endothelial proliferation and angiogenesis, malformations are vasculogenetic developmental disorders. They have a low proliferative activity and are already present at birth but become apparent only later and do not show spontaneous remission. The heterogenous clinical presentation of vascular tumors requires clarification of various differential diagnoses. Therapeutic alternatives span a large spectrum that includes pharmacotherapy, laser, and classic surgical interventions so that most patients might benefit from one of these options. Dural AV fistulas and carotid cavernous fistulas may have variable orbital manifestations. Despite differences in the lesions, the same examination procedures are applied. Characterization of a lesion and therapy planning require conventional catheter angiography. In benign cases, the therapeutic strategy is conservative, but in rapidly progressing and severe cases, neuroendovascular management is preferred.

Infobox 1

Leading orbital symptoms

Exophthalmos/enophthalmos

Ptosis/eyelid retraction

Disorders of the eye motility/diplopia

Periocular/ocular reddening and swelling

Periocular congestion/chemosis

Periorbital/orbital pain

Foreign body sensation/epiphora

Retrobulbar pressure sensation

Bulbar movement pain

Bulbar repulsion pain/difficult repulsion

Elevated intraocular pressure

Choroid folds/papilledema

Visual field loss

Loss of vision

Infobox 2

Anophthalmos

Complete absence of ocular tissue

primary anophthalmos – development of neither eye nor orbit

secondary anophthalmos – non-viable malformations in combination with cranial malformations

degenerative anophthalmos – ocular primordium present but degenerated

Frequently hypoplastic and thus size-reduced orbit but with enormous self-differentiation capacity

agenesis

complete anophthalmos, also secondarily possible

presence of mesodermal tissue

presence of ectodermal tissue

presence of meso- and ectodermal tissue

Possibly involving malformations of the visual pathway and agenesis of the corpus callosum

Malformations of the skull, meningoceles, orbital dermoids, deafness

Infobox 3

Cryptophthalmos

Absence of eyelids in combination with microphthalmos/anophthalmos

Hypoplastic orbit

Eyebrow hairiness incomplete or completely missing

Mostly bilateral

In cases of unilateral occurrence, severe malformations of the orbit and of the contralateral eye

Orbital roof absent, malformation of the sphenoid bone, auricular anomalies, syndactyly, facial clefts, laryngeal atresia, anal atresia, genital malformations, meningo-encephaloceles, hydrocephalus, persistent craniopharyngeal duct (orbital cyst formation from residues of Rathke’s pouch), pituitary gland disorders, adrenal aplasia

8. Danksagung

Die Autoren möchten sich ganz herzlich bei Herrn Prof. H.-J. Welkoborsky, Frau Dr. C. Adderson-Kisser, Herrn Dr. I. Seiwerth, Frau A. Gey, Herrn Prof. W. Wohlgemuth, Frau A. Troch und Herrn Prof. S. Plontke für ihre Unterstützung bei der Erstellung des Manuskripts bedanken.

Interessenkonflikt Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Literatur

1 Poloschek C M Lagreze W A Ridder G J [Clinical and neuroradiological diagnostics of orbital tumors] Ophthalmologe 2011 108 510 518 21695605 10.1007/s00347-010-2190-z

2 Plontke S K Glien A Kisser U [Diseases and Surgery of the Orbit] Laryngorhinootologie 2020 99 896 917 33307575 10.1055/a-1263-6285

3 AWMF. Rekonstruktion von Orbitadefekten (S2e-Leitlinie), Registernummer: 007/099. In: Arbeitsgemeinschaft medizinisch wissenschaftlicher Fachgesellschaften (AWMF); 2013

4 Fay A, Dolman PJ. Laboratory Serologic Investigations.In Fay A, Dolman PJ , Hrsg. Diseases and Disorders of the Orbit and Ocular Adnexa E-book. Elsevier; 2017: 57–77

5 Bonavolonta G Tranfa F de Conciliis C Dermoid cysts: 16-year survey Ophthalmic Plast Reconstr Surg 1995 11 187 192 8541260 10.1097/00002341-199509000-00005

6 Jordan D R Spitellie P Brownstein S Orbital cholesterol granuloma and cholesteatoma: significance of differentiating the two Ophthalmic Plast Reconstr Surg 2007 23 415 417 17881999 10.1097/IOP.0b013e318137a6fe

7 Sherman R P Rootman J Lapointe JS Orbital dermoids: clinical presentation and management Br J Ophthalmol 1984 68 642 652 6466593 10.1136/bjo.68.9.642 PMC1040432

8 Shields J A Kaden I H Eagle R C Orbital dermoid cysts: clinicopathologic correlations, classification, and management. The 1997 Josephine E. Schueler Lecture Ophthalmic Plast Reconstr Surg 1997 13 265 276 9430304

9 Delfini R Missori P Iannetti G Mucoceles of the paranasal sinuses with intracranial and intraorbital extension: report of 28 cases Neurosurgery 1993 32 901 906 discussion 906 8327090 10.1227/00006123-199306000-00003

10 Heichel J Struck H G Hammer T [Pediatric acute dacryocystitis due to frontoethmoidal mucocele] HNO 2019 67 458 462 31065761 10.1007/s00106-019-0671-1

11 Nicollas R Facon F Sudre-Levillain I Pediatric paranasal sinus mucoceles: etiologic factors, management and outcome Int J Pediatr Otorhinolaryngol 2006 70 905 908 16293319 10.1016/j.ijporl.2005.10.002

12 Holtmann C Brachert M Spaniol K [Dacryolith in a lacrimal duct] Ophthalmologe 2016 113 244 247 26160103 10.1007/s00347-015-0085-8

13 Tanaboonyawat S Idowu O O Copperman T S Dacryops - A review Orbit 2020 39 128 134 31512543 10.1080/01676830.2019.1608564

14 Junemann A Holbach LM [Epithelial giant inclusion cyst 50 years after enucleation without orbital implant] Klin Monbl Augenheilkd 1998 212 127 128 9577816 10.1055/s-2008-1034848

15 Kalantzis G K Verity D H Rose GE Periocular implantation cysts: a late complication of ophthalmic surgery Eye (Lond) 2014 28 1004 1007 24924444 10.1038/eye.2014.111 PMC4135250

16 Gupta R Seith A Guglani B Congenital cystic eye: features on MRI Br J Radiol 2007 80 e137 140 17704309 10.1259/bjr/31817019

17 Guthoff R Klein R Lieb WE Congenital cystic eye Graefes Arch Clin Exp Ophthalmol 2004 242 268 271 14676958 10.1007/s00417-003-0820-8

18 Kuchle H J Normann J Lubbering I [Congenital cystic eye] Klin Monbl Augenheilkd 1986 188 239 241 3713096 10.1055/s-2008-1050620

19 Schittkowski M P Guthoff RF Injectable self inflating hydrogel pellet expanders for the treatment of orbital volume deficiency in congenital microphthalmos: preliminary results with a new therapeutic approach Br J Ophthalmol 2006 90 1173 1177 16707526 10.1136/bjo.2006.092478 PMC1857413

20 Schittkowski M P Guthoff RF Systemic and ophthalmological anomalies in congenital anophthalmic or microphthalmic patients Br J Ophthalmol 2010 94 487 493 19822908 10.1136/bjo.2009.163436

21 Badtke G, Tost M. Anophthalmus congenitus.In Velhagen K , Hrsg. Der Augenarzt, Band XI. Leipzig: VEB Georg Thieme; 1986: 328–344

22 Badtke G, Tost M. Mikrophthalmus congenitus.In Velhagen K , Hrsg. Der Augenarzt, Band XI. Leipzig: VEB Georg Thieme; 1986: 312–328

23 Chaudhry I A Arat Y O Shamsi F A Congenital microphthalmos with orbital cysts: distinct diagnostic features and management Ophthalmic Plast Reconstr Surg 2004 20 452 457 15599246 10.1097/01.iop.0000143716.12643.98

24 Oguz H Ozturk A San I Congenital nasolacrimal duct occlusion with clinical anophthalmos: a possible new association Ophthalmic Genet 2003 24 181 185 12868037 10.1076/opge.24.3.181.15611

25 Pejic M Luecke K Meoded A Pediatric Cephaloceles: A Multimodality Review Appl Radiol 2020 49 26 32

26 Terry A Patrinely J R Anderson R L Orbital meningoencephalocele manifesting as a conjunctival mass Am J Ophthalmol 1993 115 46 49 8420377 10.1016/s0002-9394(14)73523-8

27 Vashisht S Ghai S Hatimota P Cystic lesions of the orbit : A CT spectrum Indian Journal of Radiology and Imaging 2003 13 139

28 Modi P Shah N A Bhalodia J N ORBITAL TUMORS IN CHILDREN: A DESCRIPTIVE STUDY AT TERTIARY CARE CENTRE The Journal of medical research 2013 3 362 366

29 Green W R Zimmerman LE Ectopic lacrimal gland tissue Report of eight cases with orbital involvement. Arch Ophthalmol 1967 78 318 327 6040007 10.1001/archopht.1967.00980030320010

30

31 Damato P J Damato FJ Neonatal Orbital Teratoma Br J Ophthalmol 1962 46 685 691 18170834 10.1136/bjo.46.11.685 PMC510268

32 Herman T E Vachharajani A Siegel MJ Massive congenital orbital teratoma J Perinatol 2009 29 396 397 19399001 10.1038/jp.2008.205

33 Sesenna E Ferri A Thai E Huge orbital teratoma with intracranial extension: a case report J Pediatr Surg 2010 45 e27 31 10.1016/j.jpedsurg.2010.01.031 20438911

34 Duke-Elder S Anomalies of the Bony Orbit. In: Duke-Elder S, Hrsg. System of Ophthalmology Vol III: Normal and abnormal Development Part 2, Congenital Deformities: Henry Kimpton 1964 942 949

35 Exner S Bogusch G Sokiranski R Cribra orbitalia visualized in computed tomography Ann Anat 2004 186 169 172 15125048 10.1016/S0940-9602(04)80035-9

36 Islam N Mireskandari K Rose GE Orbital varices and orbital wall defects Br J Ophthalmol 2004 88 833 834 15148222 10.1136/bjo.2003.024547 PMC1772180

37 Duke-Elder S. Deformities of the Face.In Duke-Elder S , Hrsg. System of Ophthalmology Vol III: Normal and abnormal Development Part 2, Congenital Deformities: Henry Kimpton. 1964; 1007–1035

38 Kawamoto H K The kaleidoscopic world of rare craniofacial clefts: order out of chaos (Tessier classification) Clin Plast Surg 1976 3 529 572 788997

39 Fearon JA Rare craniofacial clefts: a surgical classification J Craniofac Surg 2008 19 110 112 18216674 10.1097/SCS.0b013e31815ca1ba

40 Tessier P Anatomical classification facial, cranio-facial and latero-facial clefts J Maxillofac Surg 1976 4 69 92 820824 10.1016/s0301-0503(76)80013-6

41 Heike C L Hing A V Aspinall C A Clinical care in craniofacial microsomia: a review of current management recommendations and opportunities to advance research Am J Med Genet C Semin Med Genet 2013 163C 271 282 24132932 10.1002/ajmg.c.31373

42 Dupont S Catala M Hasboun D Progressive facial hemiatrophy and epilepsy: a common underlying dysgenetic mechanism Neurology 1997 48 1013 1018 9109892 10.1212/wnl.48.4.1013

43 Fea A M Aragno V Briamonte C Parry Romberg syndrome with a wide range of ocular manifestations: a case report BMC Ophthalmol 2015 15 119 26340917 10.1186/s12886-015-0093-0 PMC4560931

44 Duke-Elder S. Deformities of the Skull.In Duke-Elder S , Hrsg. System of Ophthalmology Vol III: Normal and abnormal Development Part 2, Congenital Deformities: Henry Kimpton. 1964: 1035–1072

45 Freudlsperger C Castrillón-Oberndorfer G Hoffmann J Isolierte, nichtsyndromale Kraniosynostosen Der MKG-Chirurg 2013 6 301 313

46 Governale LS Craniosynostosis Pediatr Neurol 2015 53 394 401 26371995 10.1016/j.pediatrneurol.2015.07.006

47 Kotrikova B Muhling J [Surgery of craniofacial deformities] Klin Monbl Augenheilkd 2004 221 970 977 15562363 10.1055/s-2004-813654

48 Wilkie AO M Johnson D Wall SA Clinical genetics of craniosynostosis Curr Opin Pediatr 2017 29 622 628 28914635 10.1097/MOP.0000000000000542 PMC5681249

49 Mundlos S Cleidocranial dysplasia: clinical and molecular genetics J Med Genet 1999 36 177 182 10204840 PMC1734317

50 Dubourg C Bendavid C Pasquier L Holoprosencephaly Orphanet J Rare Dis 2007 2 8 17274816 10.1186/1750-1172-2-8 PMC1802747

51 Lustig L R Holliday M J McCarthy E F Fibrous dysplasia involving the skull base and temporal bone Arch Otolaryngol Head Neck Surg 2001 127 1239 1247 11587606 10.1001/archotol.127.10.1239

52 Stark Z Savarirayan R Osteopetrosis Orphanet J Rare Dis 2009 4 5 19232111 10.1186/1750-1172-4-5 PMC2654865

53 Lannon D A Earley MJ Cherubism and its charlatans Br J Plast Surg 2001 54 708 711 11728115 10.1054/bjps.2001.3701

54 Grass S Welkoborsky H J Mobius H [Orbital complications] HNO 2018 66 800 811 30315347 10.1007/s00106-018-0569-3

55 Lehnerdt G Peraud A Berghaus A [Orbital and intracranial complications of acute sinusitis. Diagnostics and therapy in children and adolescents] HNO 2011 59 75 86 quiz 87-78 21085922 10.1007/s00106-010-2162-2

56 Stammberger H [Complications of inflammatory paranasal sinus diseases including iatrogenically-induced complications] Eur Arch Otorhinolaryngol Suppl 1993 1 61 102 8374351

57 Welkoborsky H J Grass S Deichmuller C Orbital complications in children: differential diagnosis of a challenging disease Eur Arch Otorhinolaryngol 2015 272 1157 1163 25056021 10.1007/s00405-014-3195-z

58 Hamed-Azzam S AlHashash I Briscoe D Rare Orbital Infections ~ State of the Art ~ Part II J Ophthalmic Vis Res 2018 13 183 190 29719648 10.4103/jovr.jovr_202_17 PMC5905313

59 Rootman J. Diseases of the orbit.Second edition Aufl. Lippincott Williams & Wilkins; Philadelphia: 2003

60 Madge S N Prabhakaran V C Shome D Orbital tuberculosis: a review of the literature Orbit 2008 27 267 277 18716964 10.1080/01676830802225152

61 Fay A, Dolman PJ. Diseases and Disorders of the Orbit and Ocular Adnexa Expert Consult. In Fay A, Dolman PJ (eds). Elsevier; 2017

62 Heichel J Griebsch M Siebolts U [Bilateral periocular necrotizing fasciitis with unilateral orbital involvement] Ophthalmologe 2020 117 1121 1125 32130503 10.1007/s00347-020-01078-6

63 Huber L Budjan J Rotter N [Necrotizing fasciitis in the head and neck region-three case reports and a review of the literature] HNO 2020 68 935 943 32617608 10.1007/s00106-020-00899-w

64 Amrith S Hosdurga Pai V Ling WW Periorbital necrotizing fasciitis -- a review Acta Ophthalmol 2013 91 596 603 22520175 10.1111/j.1755-3768.2012.02420.x

65 Wong C H Chang H C Pasupathy S Necrotizing fasciitis: clinical presentation, microbiology, and determinants of mortality J Bone Joint Surg Am 2003 85 1454 1460 12925624

66 Lazzeri D Lazzeri S Figus M Periorbital necrotising fasciitis Br J Ophthalmol 2010 94 1577 1585 19897473 10.1136/bjo.2009.167486

67 Wladis E J Levin F Shinder R Clinical Parameters and Outcomes in Periorbital Necrotizing Fasciitis Ophthalmic Plast Reconstr Surg 2015 31 467 469 25675166 10.1097/IOP.0000000000000390

68 Federspil P German Society of Oto-Rhino-Laryngology H, Neck S. [Guidelines: Antibiotic treatment of infections of the head and neck: consensus report on behalf of the presidency of the German Society of Oto-Rhino-Laryngology, Head and Neck Surgery edited by P. Federspil, Homburg/Saar] . HNO 2009 57 377 394 19333568 10.1007/s00106-009-1895-2

69 Barrani M Massei F Scaglione M Unusual onset of a case of chronic recurrent multifocal osteomyelitis Pediatr Rheumatol Online J 2015 13 60 26653878 10.1186/s12969-015-0058-0 PMC4676857

70 Dagan O Barak Y Metzker A Pyoderma gangrenosum and sterile multifocal osteomyelitis preceding the appearance of Takayasu arteritis Pediatr Dermatol 1995 12 39 42 7792218 10.1111/j.1525-1470.1995.tb00122.x

71 Huber A M Lam P Y Duffy C M Chronic recurrent multifocal osteomyelitis: clinical outcomes after more than five years of follow-up J Pediatr 2002 141 198 203 12183714 10.1067/mpd.2002.126457

72 Hu A C Ng WKY Orbital Osteomyelitis in the Pediatric Patient J Craniofac Surg 2021 32 206 209 32881821 10.1097/SCS.0000000000006801

73 Cornely O A Alastruey-Izquierdo A Arenz D Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium Lancet Infect Dis 2019 19 e405 e421 31699664 10.1016/S1473-3099(19)30312-3 PMC8559573

74 Bakhshaee M Bojdi A Allahyari A Acute invasive fungal rhinosinusitis: our experience with 18 cases Eur Arch Otorhinolaryngol 2016 273 4281 4287 27272179 10.1007/s00405-016-4109-z

75 van Burik J A Hare R S Solomon H F Posaconazole is effective as salvage therapy in zygomycosis: a retrospective summary of 91 cases Clin Infect Dis 2006 42 e61 65 16511748 10.1086/500212

76 Songu M Unlu H H Gunhan K Orbital exenteration: A dilemma in mucormycosis presented with orbital apex syndrome Am J Rhinol 2008 22 98 103 18284868 10.2500/ajr.2008.22.3121

77 Nicolai P Lombardi D Tomenzoli D Fungus ball of the paranasal sinuses: experience in 160 patients treated with endoscopic surgery Laryngoscope 2009 119 2275 2279 19688860 10.1002/lary.20578

78 Johnson T E Casiano R R Kronish J W Sino-orbital aspergillosis in acquired immunodeficiency syndrome Arch Ophthalmol 1999 117 57 64 9930161 10.1001/archopht.117.1.57

79 Levin L A Avery R Shore J W The spectrum of orbital aspergillosis: a clinicopathological review Surv Ophthalmol 1996 41 142 154 8890440 10.1016/s0039-6257(96)80004-x

80 Siddiqui A A Shah A A Bashir SH Craniocerebral aspergillosis of sinonasal origin in immunocompetent patients: clinical spectrum and outcome in 25 cases Neurosurgery 2004 55 602 611 discussion 611-603 15335427 10.1227/01.neu.0000134597.94269.48

81 Nielsen E W Weisman R A Savino P J Aspergillosis of the sphenoid sinus presenting as orbital pseudotumor Otolaryngol Head Neck Surg 1983 91 699 703 6420754 10.1177/019459988309100620

82 Sivak-Callcott J A Livesley N Nugent R A Localised invasive sino-orbital aspergillosis: characteristic features Br J Ophthalmol 2004 88 681 687 15090423 10.1136/bjo.2003.021725 PMC1772124

83 Lamoth F Calandra T Early diagnosis of invasive mould infections and disease J Antimicrob Chemother 2017 72 i19 i28 28355464 10.1093/jac/dkx030

84 McCarthy M Rosengart A Schuetz A N Mold infections of the central nervous system N Engl J Med 2014 371 150 160 25006721 10.1056/NEJMra1216008 PMC4840461

85 Green W R Font R L Zimmerman LE Asperillosis of the orbit Report of ten cases and review of the literature. Arch Ophthalmol 1969 82 302 313 5806054 10.1001/archopht.1969.00990020304002

86 Denning DW Therapeutic outcome in invasive aspergillosis Clin Infect Dis 1996 23 608 615 8879787 10.1093/clinids/23.3.608

87 Robert Koch-Institut. Infektionsepidemiologisches Jahrbuch meldepflichtiger Krankheiten für 2019 Berlin Robert Koch-Institut 2020

88 Gomez Morales A Croxatto J O Crovetto L Hydatid cysts of the orbit. A review of 35 cases Ophthalmology 1988 95 1027 1032 3068605 10.1016/s0161-6420(88)33067-8

89 Xiao A Xueyi C Hydatid cysts of the orbit in Xinjiang: a review of 18 cases Orbit 1999 18 151 155 12045979 10.1076/orbi.18.3.151.2705

90 Kars Z Kansu T Ozcan O E Orbital echinococcosis. Report of two cases studied by computerized tomography J Clin Neuroophthalmol 1982 2 197 199 6217224

91 Chtira K Benantar L Aitlhaj H The surgery of intra-orbital hydatid cyst: a case report and literature review Pan Afr Med J 2019 33 167 31565128 10.11604/pamj.2019.33.167.18277 PMC6756819

92 Senyuz O F Yesildag E Celayir S Albendazole therapy in the treatment of hydatid liver disease Surg Today 2001 31 487 491 11428598 10.1007/s005950170106

93 Pushker N Bajaj M S Balasubramanya R Disseminated cysticercosis involving orbit, brain and subcutaneous tissue J Infect 2005 51 e245 248 15904962 10.1016/j.jinf.2005.04.011

94 Walrath J D Lalin S C Leib ML Cysticercosis isolated to the orbit Ophthalmic Plast Reconstr Surg 2003 19 243 244 12918564 10.1097/01.iop.0000064991.06048.dd

95 Sotelo J Escobedo F Rodriguez-Carbajal J Therapy of parenchymal brain cysticercosis with praziquantel N Engl J Med 1984 310 1001 1007 6708975 10.1056/NEJM198404193101601

96 Nentwich M M Pleyer U Schaller U C [International ophthalmology and travel medicine] Ophthalmologe 2016 113 83 94 26631047 10.1007/s00347-015-0158-8

97 Mombaerts I Rose G E Garrity JA Orbital inflammation: Biopsy first Surv Ophthalmol 2016 61 664 669 26994870 10.1016/j.survophthal.2016.03.002

98 Ben Simon G J Yoon M K Atul J Clinical manifestations of orbital mass lesions at the Jules Stein Eye Institute, 1999-2003 Ophthalmic Surg Lasers Imaging 2006 37 25 32 16468548

99 Nölle B, Both M. Idiopathische Orbitaentzündung.In Pleyer U , Hrsg. Entzündliche Augenerkrankungen. Berlin, Heidelberg: Springer- Verlag; 2016: 48–57

100 Swamy B N McCluskey P Nemet A Idiopathic orbital inflammatory syndrome: clinical features and treatment outcomes Br J Ophthalmol 2007 91 1667 1670 17620331 10.1136/bjo.2007.124156 PMC2095535

101 Fujii H Fujisada H Kondo T Orbital pseudotumor: histopathological classification and treatment Ophthalmologica 1985 190 230 242 4011135 10.1159/000309523

102 Mombaerts I Goldschmeding R Schlingemann R O What is orbital pseudotumor? Surv Ophthalmol 1996 41 66 78 8827931 10.1016/s0039-6257(97)81996-0

103 Rootman J Nugent R The classification and management of acute orbital pseudotumors Ophthalmology 1982 89 1040 1048 7177569 10.1016/s0161-6420(82)34683-7

104 Rootman J McCarthy M White V Idiopathic sclerosing inflammation of the orbit. A distinct clinicopathologic entity Ophthalmology 1994 101 570 584 8127579 10.1016/s0161-6420(94)31298-x

105 Iaconetta G Stella L Esposito M Tolosa-Hunt syndrome extending in the cerebello-pontine angle Cephalalgia 2005 25 746 750 16109058 10.1111/j.1468-2982.2005.00924.x

106 Speth M M Metternich F U Mina R Tolosa-Hunt-Syndrom, das sich als migrierende, auf Kortikosteroid reagierende CN3- und CN6-Lähmung bei verschatteten Keilbeinhöhlen darstellt forum hno omnimed Verlag 05/2020

107 Halabi T Sawaya R Successful Treatment of Tolosa-Hunt Syndrome after a Single Infusion of Infliximab J Clin Neurol 2018 14 126 127 29629550 10.3988/jcn.2018.14.1.126 PMC5765250

108 Mormont E Laloux P Vauthier J Radiotherapy in a case of Tolosa-Hunt syndrome Cephalalgia 2000 20 931 933 11304029 10.1046/j.1468-2982.2000.00147.x

109 Perez C A Evangelista M Evaluation and Management of Tolosa-Hunt Syndrome in Children: A Clinical Update Pediatr Neurol 2016 62 18 26 27473647 10.1016/j.pediatrneurol.2016.06.017

110 Zhang X Zhang W Liu R Factors that influence Tolosa-Hunt syndrome and the short-term response to steroid pulse treatment J Neurol Sci 2014 341 13 16 24703581 10.1016/j.jns.2014.03.031

111 Espinoza G M Liu JL Orbital Vasculitides-Differential Diagnosis Curr Rheumatol Rep 2019 21 54 31486966 10.1007/s11926-019-0853-6

112 Tiegs-Heiden C A Eckel L J Hunt C H Immunoglobulin G4-related disease of the orbit: imaging features in 27 patients AJNR Am J Neuroradiol 2014 35 1393 1397 24627453 10.3174/ajnr.A3865 PMC7966591

113 Erdei A Steiber Z Molnar C Exophthalmos in a young woman with no graves' disease - a case report of IgG4-related orbitopathy BMC Ophthalmol 2018 18 5 29329570 10.1186/s12886-018-0672-y PMC5766976

114 Jurkov M Olze H Klauschen F [IgG4-Related Orbitopathy as an Important Differential Diagnosis of Advanced Silent Sinus Syndrome. German version] HNO 2020 68 864 868 32060570 10.1007/s00106-019-00798-9 PMC7653796

115 Mulholland G B Jeffery C C Satija P Immunoglobulin G4-related diseases in the head and neck: a systematic review J Otolaryngol Head Neck Surg 2015 44 24 26092582 10.1186/s40463-015-0071-9 PMC4482182

116 Detiger S E Karim A F Verdijk R M The treatment outcomes in IgG4-related orbital disease: a systematic review of the literature Acta Ophthalmol 2019 97 451 459 30734497 10.1111/aos.14048

117 Plaza J A Garrity J A Dogan A Orbital inflammation with IgG4-positive plasma cells: manifestation of IgG4 systemic disease Arch Ophthalmol 2011 129 421 428 21482868 10.1001/archophthalmol.2011.16

118 Perumal B Black E H Levin F Non-infectious orbital vasculitides Eye (Lond) 2012 26 630 639 22361845 10.1038/eye.2012.28 PMC3351059

119 Sfiniadaki E Tsiara I Theodossiadis P Ocular Manifestations of Granulomatosis with Polyangiitis: A Review of the Literature Ophthalmol Ther 2019 8 227 234 30875067 10.1007/s40123-019-0176-8 PMC6513923

120 Mukhtyar C Flossmann O Hellmich B Outcomes from studies of antineutrophil cytoplasm antibody associated vasculitis: a systematic review by the European League Against Rheumatism systemic vasculitis task force Ann Rheum Dis 2008 67 1004 1010 17911225 10.1136/ard.2007.071936

121 Holle J U Voigt C Both M Orbital masses in granulomatosis with polyangiitis are associated with a refractory course and a high burden of local damage Rheumatology (Oxford) 2013 52 875 882 23293138 10.1093/rheumatology/kes382

122 Perry S R Rootman J White VA The clinical and pathologic constellation of Wegener granulomatosis of the orbit Ophthalmology 1997 104 683 694 9111264 10.1016/s0161-6420(97)30251-6

123 Chang S Y Keogh K A Lewis J E IgG4-positive plasma cells in granulomatosis with polyangiitis (Wegener's): a clinicopathologic and immunohistochemical study on 43 granulomatosis with polyangiitis and 20 control cases Hum Pathol 2013 44 2432 2437 23993777 10.1016/j.humpath.2013.05.023

124 Martinez Del Pero M Chaudhry A Jones R B B-cell depletion with rituximab for refractory head and neck Wegener's granulomatosis: a cohort study Clin Otolaryngol 2009 34 328 335 19673980 10.1111/j.1749-4486.2009.01968.x

125 Takanashi T Uchida S Arita M Orbital inflammatory pseudotumor and ischemic vasculitis in Churg-Strauss syndrome: report of two cases and review of the literature Ophthalmology 2001 108 1129 1133 11382641 10.1016/s0161-6420(01)00557-7

126 Cottin V Cordier JF Churg-Strauss syndrome Allergy 1999 54 535 551 10435467 10.1034/j.1398-9995.1999.t01-1-00091.x

127 Masi A T Hunder G G Lie J T The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis) Arthritis Rheum 1990 33 1094 1100 2202307 10.1002/art.1780330806

128 Vaglio A Moosig F Zwerina J Churg-Strauss syndrome: update on pathophysiology and treatment Curr Opin Rheumatol 2012 24 24 30 22089097 10.1097/BOR.0b013e32834d85ce

129 Guillevin L Lhote F Gayraud M Prognostic factors in polyarteritis nodosa and Churg-Strauss syndrome. A prospective study in 342 patients Medicine (Baltimore) 1996 75 17 28 8569467 10.1097/00005792-199601000-00003

130 Nagel M A White T Khmeleva N Analysis of Varicella-Zoster Virus in Temporal Arteries Biopsy Positive and Negative for Giant Cell Arteritis JAMA Neurol 2015 72 1281 1287 26349037 10.1001/jamaneurol.2015.2101 PMC5110206

131 Borruat F X Bogousslavsky J Uffer S Orbital infarction syndrome Ophthalmology 1993 100 562 568 8479716 10.1016/s0161-6420(93)31606-4

132 Stone J H Tuckwell K Dimonaco S Trial of Tocilizumab in Giant-Cell Arteritis N Engl J Med 2017 377 317 328 28745999 10.1056/NEJMoa1613849

133 Seyahi E Takayasu arteritis: an update Curr Opin Rheumatol 2017 29 51 56 27748689 10.1097/BOR.0000000000000343

134 Tugal-Tutkun I Systemic vasculitis and the eye Curr Opin Rheumatol 2017 29 24 32 27662569 10.1097/BOR.0000000000000345

135 Misra D P Wakhlu A Agarwal V Recent advances in the management of Takayasu arteritis Int J Rheum Dis 2019 22 01 60 68 30698358 10.1111/1756-185X.13285

136 Iliescu D A Timaru C M Batras M Cogan's Syndrome Rom J Ophthalmol 2015 59 6 13 27373108 PMC5729811

137 Tayer-Shifman O E Ilan O Tovi H Cogan's syndrome--clinical guidelines and novel therapeutic approaches Clin Rev Allergy Immunol 2014 47 65 72 24385257 10.1007/s12016-013-8406-7

138 Grasland A Pouchot J Hachulla E Typical and atypical Cogan's syndrome: 32 cases and review of the literature Rheumatology (Oxford) 2004 43 1007 1015 15150435 10.1093/rheumatology/keh228

139 Gluth M B Baratz K H Matteson E L Cogan syndrome: a retrospective review of 60 patients throughout a half century Mayo Clin Proc 2006 81 483 488 16610568 10.4065/81.4.483

140 Padoan R Cazzador D Pendolino A L Cogan's syndrome: new therapeutic approaches in the biological era Expert Opin Biol Ther 2019 19 781 788 31056972 10.1080/14712598.2019.1611779

141 Kokturk A Clinical and Pathological Manifestations with Differential Diagnosis in Behcet's Disease Patholog Res Int 2012 2012 690390 22191082 10.1155/2012/690390 PMC3236321

142 Hammami S Yahia S B Mahjoub S Orbital inflammation associated with Behcet's disease Clin Exp Ophthalmol 2006 34 188 190 16626443 10.1111/j.1442-9071.2006.01181.x

143 Urruticoechea-Arana A Cobo-Ibanez T Villaverde-Garcia V Efficacy and safety of biological therapy compared to synthetic immunomodulatory drugs or placebo in the treatment of Behcet's disease associated uveitis: a systematic review Rheumatol Int 2019 39 47 58 30421105 10.1007/s00296-018-4193-z

144 Bettiol A Silvestri E Di Scala G The right place of interleukin-1 inhibitors in the treatment of Behcet's syndrome: a systematic review Rheumatol Int 2019 39 971 990 30799530 10.1007/s00296-019-04259-y

145 Hedrich C M Schnabel A Hospach T Kawasaki Disease Front Pediatr 2018 6 198 30042935 10.3389/fped.2018.00198 PMC6048561

146 Demirsoy S Gucuyener K Olgunturk R A case of Kawasaki syndrome associated with preseptal cellulitis in orbita Turk J Pediatr 1988 30 55 59 3232225

147 Felz M W Patni A Brooks S E Periorbital vasculitis complicating Kawasaki syndrome in an infant Pediatrics 1998 101 E9 10.1542/peds.101.6.e9 9606251

148 Sheard R M Pandey K R Barnes N D Kawasaki disease presenting as orbital cellulitis J Pediatr Ophthalmol Strabismus 2000 37 123 125 10779274 10.3928/0191-3913-20000301-15

149 Son M B Gauvreau K Burns J C Infliximab for intravenous immunoglobulin resistance in Kawasaki disease: a retrospective study J Pediatr 2011 158 644 649 e641 21129756 10.1016/j.jpeds.2010.10.012

150 Read RW Clinical mini-review: systemic lupus erythematosus and the eye Ocul Immunol Inflamm 2004 12 87 99 15512979 10.1080/09273940490895308

151 Arthurs B P Khalil M K Chagnon F Orbital infarction and melting in a patient with systemic lupus erythematosus Ophthalmology 1999 106 2387 2390 10599676 10.1016/S0161-6420(99)90544-4

152 Nabili S McCarey D W Browne B A case of orbital myositis associated with rheumatoid arthritis Ann Rheum Dis 2002 61 938 939 12228169 10.1136/ard.61.10.938 PMC1753915

153 Sanchez I J Finger D R Bradshaw DJ Orbital inflammatory syndrome and systemic lupus erythematosus J Clin Rheumatol 1995 1 295 298 19078001 10.1097/00124743-199510000-00008

154 Kokotis P Theodossiadis P Bouros C Bilateral ocular myositis as a late complication of dermatomyositis J Rheumatol 2005 32 379 381 15693104

155 Lokdarshi G Pushker N Bajaj MS Sclerosing Lesions of the Orbit: A Review Middle East Afr J Ophthalmol 2015 22 447 451 26692715 10.4103/0974-9233.167807 PMC4660530

156 Petrarolha S M Rodrigues B S Filho F D Unilateral Eyelid Edema as Initial Sign of Orbital Sarcoidosis Case Rep Ophthalmol Med 2016 2016 6.912927E6 10.1155/2016/6912927 PMC4889789 27298746

157 Rosenbaum J T Choi D Wilson D J Parallel Gene Expression Changes in Sarcoidosis Involving the Lacrimal Gland, Orbital Tissue, or Blood JAMA Ophthalmol 2015 133 770 777 25880323 10.1001/jamaophthalmol.2015.0726 PMC5021543

158 Mavrikakis I Rootman J Diverse clinical presentations of orbital sarcoid Am J Ophthalmol 2007 144 769 775 17869205 10.1016/j.ajo.2007.07.019

159 Demirci H Christianson MD Orbital and adnexal involvement in sarcoidosis: analysis of clinical features and systemic disease in 30 cases Am J Ophthalmol 2011 151 1074 1080 e1071 21457924 10.1016/j.ajo.2010.12.011

160 McNab AA The 2017 Doyne Lecture: the orbit as a window to systemic disease Eye (Lond) 2018 32 248 261 29125145 10.1038/eye.2017.224 PMC5811731

161 Pasadhika S Rosenbaum JT Ocular Sarcoidosis Clin Chest Med 2015 36 669 683 26593141 10.1016/j.ccm.2015.08.009 PMC4662043

162 Aluclu M U Keklikci U Guzel A Melkersson-Rosenthal syndrome with partial oculomotor nerve palsy Ann Saudi Med 2008 28 135 137 18398275 10.5144/0256-4947.2008.135 PMC6074525

163 Shapiro M Peters S Spinelli HM Melkersson-Rosenthal syndrome in the periocular area: a review of the literature and case report Ann Plast Surg 2003 50 644 648 12783021 10.1097/01.SAP.0000069068.03742.48

164 Cocuroccia B Gubinelli E Annessi G Persistent unilateral orbital and eyelid oedema as a manifestation of Melkersson-Rosenthal syndrome J Eur Acad Dermatol Venereol 2005 19 107 111 15649204 10.1111/j.1468-3083.2004.01084.x

165 Pierre-Filho Pde T Rocha E M Natalino R Upper eyelid oedema in Melkersson-Rosenthal syndrome Clin Exp Ophthalmol 2004 32 439 440 15281985 10.1111/j.1442-9071.2004.00852.x

166 Khandpur S Malhotra A K Khanna N Melkersson-Rosenthal syndrome with diffuse facial swelling and multiple cranial nerve palsies J Dermatol 2006 33 411 414 16700832 10.1111/j.1346-8138.2006.00097.x

167 Rawlings N G Valenzuela A A Allen L H Isolated eyelid edema in Melkersson-Rosenthal syndrome: a case series Eye (Lond) 2012 26 163 166 22056858 10.1038/eye.2011.285 PMC3259600

168 Ramaswamy B Singh R Manusrut M Sclerosing lipogranuloma of the eyelid: unusual complication following nasal packing in endoscopic sinus surgery. BMJ Case Rep 2015 2015 10.1136/bcr-2014-208093 PMC4369014 25750223

169 Witschel H Geiger K Paraffin induced sclerosing lipogranuloma of eyelids and anterior orbit following endonasal sinus surgery Br J Ophthalmol 1994 78 61 65 8110702 10.1136/bjo.78.1.61 PMC504693

170 Herrmann B Rozot P Baylac F [Lipogranuloma of the orbit Apropos of a case]. J Fr Ophtalmol 1996 19 780 784 9033904

171 AlGhafri L Galindo-Ferreiro A Maktabi A Idiopathic orbital lipogranuloma Int J Ophthalmol 2017 10 494 496 28393047 10.18240/ijo.2017.03.28 PMC5360791

172 Jakobiec F A Rai R Rashid A Bilateral Eyelid Pseudoptosis From Lipogranulomas of the Preaponeurotic Fat Pads Ophthalmic Plast Reconstr Surg 2015 31 e125 131 24841730 10.1097/IOP.0000000000000157

173 Paik J S Cho W K Park G S Eyelid-associated complications after autogenous fat injection for cosmetic forehead augmentation BMC Ophthalmol 2013 13 32 23841959 10.1186/1471-2415-13-32 PMC3717022

174 Park J Y Kim N Periorbital Lipogranuloma after Facial Autologous Fat Injection and Its Treatment Outcomes Korean J Ophthalmol 2016 30 10 16 26865798 10.3341/kjo.2016.30.1.10 PMC4742640

175 Cafaro G Croia C Argyropoulou O D One year in review 2019: Sjogren's syndrome Clin Exp Rheumatol 2019 37 118 3 15 31464675

176 Mathews P M Hahn S Hessen M Ocular complications of primary Sjogren syndrome in men Am J Ophthalmol 2015 160 447 452 e441 26093285 10.1016/j.ajo.2015.06.004

177 Danlos F X Daoued F Seror R Orbital Myositis and Primary Sjogren Syndrome J Rheumatol 2015 42 1536 1537 26233955 10.3899/jrheum.141318

178 Tonami H Matoba M Kuginuki Y Clinical and imaging findings of lymphoma in patients with Sjogren syndrome J Comput Assist Tomogr 2003 27 517 524 12886135 10.1097/00004728-200307000-00011

179 Luemsamran P Rootman J White V A The role of biopsy in lacrimal gland inflammation: A clinicopathologic study Orbit 2017 36 411 418 28816552 10.1080/01676830.2017.1352608

180 Ohshima K Matsuo N Yokoe S [A case of lacrimal gland malignant lymphoma, associated with Sjogren's syndrome] Nippon Ganka Gakkai Zasshi 1991 95 386 392 1877413

181 Carubbi F Cipriani P Marrelli A Efficacy and safety of rituximab treatment in early primary Sjogren's syndrome: a prospective, multi-center, follow-up study Arthritis Res Ther 2013 15 R172 24286296 10.1186/ar4359 PMC3979092

182 Kimura T On the unusual granulations combined with hyperplastic changes of lymphatic tissue Trans Soc Pathol Jpn 1948 37 179 180

183 Buder K Ruppert S Trautmann A Angiolymphoid hyperplasia with eosinophilia and Kimura's disease - a clinical and histopathological comparison J Dtsch Dermatol Ges 2014 12 224 228 24580875 10.1111/ddg.12257_suppl

184 Claros P Fokouo V Nyada F Kimura's disease of the orbit: A modern diagnostic challenge Eur Ann Otorhinolaryngol Head Neck Dis 2017 134 287 289 28330644 10.1016/j.anorl.2017.02.006

185 Googe P B Harris N L Mihm M C Kimura's disease and angiolymphoid hyperplasia with eosinophilia: two distinct histopathological entities J Cutan Pathol 1987 14 263 271 3680714 10.1111/j.1600-0560.1987.tb00498.x

186 Kodama T Kawamoto K Kimura's disease of the lacrimal gland Acta Ophthalmol Scand 1998 76 374 377 9686859 10.1034/j.1600-0420.1998.760327.x

187 Monzen Y Kiya K Nishisaka T Kimura's Disease of the Orbit Successfully Treated with Radiotherapy Alone: A Case Report Case Rep Ophthalmol 2014 5 87 91 24748872 10.1159/000360789 PMC3985780

188 Bullock J D Bartley G B Campbell R J Necrobiotic xanthogranuloma with paraproteinemia Case report and a pathogenetic theory. Ophthalmology 1986 93 1233 1236 10.1016/s0161-6420(86)33605-4 3101022

189 Shams P N Rasmussen S L Dolman PJ Adult-Onset Asthma Associated With Simultaneous Conjunctival, Eyelid, and Orbital Xanthogranulomatosis Responsive to Systemic Immunosuppression Ophthalmic Plast Reconstr Surg 2015 31 e162 163 24833457 10.1097/IOP.0000000000000191

190 Elner V M Mintz R Demirci H Local corticosteroid treatment of eyelid and orbital xanthogranuloma Ophthalmic Plast Reconstr Surg 2006 22 36 40 16418663 10.1097/01.iop.0000192645.24814.e8

191 Efebera Y Blanchard E Allam C Complete response to thalidomide and dexamethasone in a patient with necrobiotic xanthogranuloma associated with monoclonal gammopathy: a case report and review of the literature Clin Lymphoma Myeloma Leuk 2011 11 298 302 21658660 10.1016/j.clml.2011.03.020 PMC3390934

192 Cives M Simone V Rizzo F M Erdheim-Chester disease: a systematic review Crit Rev Oncol Hematol 2015 95 1 11 25744785 10.1016/j.critrevonc.2015.02.004

193 Estrada-Veras J I O'Brien K J Boyd L C The clinical spectrum of Erdheim-Chester disease: an observational cohort study Blood Adv 2017 1 357 366 28553668 10.1182/bloodadvances.2016001784 PMC5446206

194 Merritt H Pfeiffer M L Richani K Erdheim-Chester disease with orbital involvement: Case report and ophthalmic literature review Orbit 2016 35 221 226 27322549 10.1080/01676830.2016.1176211

195 Manousaridis K Casper J Schittkowski M P [Erdheim-Chester disease of the orbit with compressive optic neuropathy] Ophthalmologe 2010 107 266 269 19777245 10.1007/s00347-009-2041-y

196 Veyssier-Belot C Cacoub P Caparros-Lefebvre D Erdheim-Chester disease. Clinical and radiologic characteristics of 59 cases Medicine (Baltimore) 1996 75 157 169 8965684 10.1097/00005792-199605000-00005

197 Altman J Winkelmann RK Diffuse normolipemic plane xanthoma Generalized xanthelasma. Arch Dermatol 1962 85 633 640 13860747 10.1001/archderm.1962.01590050063012

198 Zak I T Altinok D Neilsen S S Xanthoma disseminatum of the central nervous system and cranium AJNR Am J Neuroradiol 2006 27 919 921 16611791 PMC8133973

199 Khezri F Gibson L E Tefferi A Xanthoma disseminatum: effective therapy with 2-chlorodeoxyadenosine in a case series Arch Dermatol 2011 147 459 464 21173305 10.1001/archdermatol.2010.378

200 Minkov M Lehrnbecher T S1-Leitlinie 025/015 „Langerhanszell-Histiozytose (LCH) im Kindesalter In 2017

201 Bertelmann E Minko N Lohneis P Benigne Neoplasien der Orbita Klin Monatsbl Augenheilkd 2011 228 1113 1130 10.1055/s-0031-1280223 21913166

202 Maccheron L J McNab A A Elder J Ocular adnexal Langerhans cell histiocytosis clinical features and management Orbit 2006 25 169 177 16987763 10.1080/01676830600669486

203 Esmaili N Harris GJ Langerhans Cell Histiocytosis of the Orbit: Spectrum of Disease and Risk of Central Nervous System Sequelae in Unifocal Cases Ophthalmic Plast Reconstr Surg 2016 32 28 34 25689784 10.1097/IOP.0000000000000402

204 Vemuganti G K Naik M N Honavar SG Rosai dorfman disease of the orbit J Hematol Oncol 2008 1 7 18588698 10.1186/1756-8722-1-7 PMC2474646

205 Bothra N Kaliki S Gowrishankar S Isolated unilateral eyelid Rosai-Dorfman disease Oman J Ophthalmol 2018 11 300 302 30505131 10.4103/ojo.OJO_26_2018 PMC6219329

206 Rosai J Dorfman RF Sinus histiocytosis with massive lymphadenopathy. A newly recognized benign clinicopathological entity Arch Pathol 1969 87 63 70 5782438

207 Foucar E Rosai J Dorfman R Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): review of the entity Semin Diagn Pathol 1990 7 19 73 2180012

208 McClellan S F Ainbinder DJ Orbital Rosai-Dorfman disease: a literature review Orbit 2013 32 341 346 23895540 10.3109/01676830.2013.814689

209 Ezeanosike E Ezeanosike O B Akpan S I Rhabdomyoblastic differentiation in rosai dorfman disease of the orbit in a 12-year-old male Niger J Clin Pract 2018 21 1670 1673 30560834 10.4103/njcp.njcp_262_17

210 Fajgenbaum D C van Rhee F Nabel CS HHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy Blood 2014 123 2924 2933 24622327 10.1182/blood-2013-12-545087

211 Goel R Raut A Agarwal A A Rare Presentation of Orbital Castleman's Disease Case Rep Ophthalmol Med 2020 2020 1.012759E6 10.1155/2020/1012759 PMC6964713 31984145

212 Schrock A Gutgemann I Keiner S [Castleman's disease in ear, nose, and throat practice] HNO 2007 55 01 E29 32 17262216 10.1007/s00106-006-1415-6

213 Talat N Belgaumkar A P Schulte KM Surgery in Castleman's disease: a systematic review of 404 published cases Ann Surg 2012 255 677 684 22367441 10.1097/SLA.0b013e318249dcdc

214 van Rhee F Wong R S Munshi N Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial Lancet Oncol 2014 15 966 974 25042199 10.1016/S1470-2045(14)70319-5

215 Kesper C Viestenz A Siebolts U [Orbital Amyloidosis - Comparison of Two Different Clinical Courses] Klin Monbl Augenheilkd 2020 237 35 40 31968364 10.1055/a-1078-1274

216 Leibovitch I Selva D Goldberg R A Periocular and orbital amyloidosis: clinical characteristics, management, and outcome Ophthalmology 2006 113 1657 1664 16828514 10.1016/j.ophtha.2006.03.052

217 Mora-Horna E R Rojas-Padilla R Lopez V G Ocular adnexal and orbital amyloidosis: a case series and literature review Int Ophthalmol 2016 36 281 298 26466598 10.1007/s10792-015-0138-7

218 Naxer S Behnes C L Schittkowski MP [Amyloidosis--a rare differential diagnosis of an orbital tumour] Klin Monbl Augenheilkd 2011 228 555 564 20725885 10.1055/s-0029-1245462

219 Ladner-Merz S Muller-Ladner U [Amyloidoses] Z Rheumatol 2008 67 677 682 quiz 683 19011876 10.1007/s00393-008-0385-3

220 Khaira M Mutamba A Meligonis G The use of radiotherapy for the treatment of localized orbital amyloidosis Orbit 2008 27 432 437 19085298 10.1080/01676830802350216

221 Eghbali A Hassan S Seehra G Ophthalmological findings in Gaucher disease Mol Genet Metab 2019 127 23 27 31047801 10.1016/j.ymgme.2019.02.002

222 Prakalapakorn S G Proia A D Yanovitch T L Ocular and histologic findings in a series of children with infantile pompe disease treated with enzyme replacement therapy J Pediatr Ophthalmol Strabismus 2014 51 355 362 25139343 10.3928/01913913-20140813-01 PMC4413912

223 Slingerland N W Polling J R van Gelder C M Ptosis, extraocular motility disorder, and myopia as features of pompe disease Orbit 2011 30 111 113 21438734 10.3109/01676830.2010.546932

224 Winter A W Salimi A Ospina L H Ophthalmic manifestations of Gaucher disease: the most common lysosomal storage disorder Br J Ophthalmol 2019 103 315 326 30612093 10.1136/bjophthalmol-2018-312846

225 Yanovitch T L Banugaria S G Proia A D Clinical and histologic ocular findings in pompe disease J Pediatr Ophthalmol Strabismus 2010 47 34 40 20128552 10.3928/01913913-20100106-08

226 Wabbels B Ali N Kunz W S [Chronic progressive external ophthalmoplegia and Kearns-Sayre syndrome : interdisciplinary diagnosis and therapy] Ophthalmologe 2008 105 550 556 18373100 10.1007/s00347-007-1643-5

227 Pfeiffer MJ [Chronic Progressive External Ophthalmoplegia Ptosis: Problems with Diagnostics and Treatment] Klin Monbl Augenheilkd 2018 235 31 33 29373868 10.1055/s-0043-124370

228 Pitceathly R D Morrow J M Sinclair C D Extra-ocular muscle MRI in genetically-defined mitochondrial disease Eur Radiol 2016 26 130 137 25994195 10.1007/s00330-015-3801-5 PMC4666274

229 Rahman S Blok R B Dahl H H Leigh syndrome: clinical features and biochemical and DNA abnormalities Ann Neurol 1996 39 343 351 8602753 10.1002/ana.410390311

230 McKelvie P Infeld B Marotta R Late-adult onset Leigh syndrome J Clin Neurosci 2012 19 195 202 22273117 10.1016/j.jocn.2011.09.009

231 Lake N J Compton A G Rahman S Leigh syndrome: One disorder, more than 75 monogenic causes Ann Neurol 2016 79 190 203 26506407 10.1002/ana.24551

232 Han J Lee Y M Kim S M Ophthalmological manifestations in patients with Leigh syndrome Br J Ophthalmol 2015 99 528 535 25351680 10.1136/bjophthalmol-2014-305704

233 Fichter N Schittkowski M Guthoff R Erkrankungen der Tränendrüse Ophthalmologe 2005 102 399 425 15782290 10.1007/s00347-005-1190-x

234 Moreiras J Tumors of the lacrimal gland - Orbit – examination, diagnosis, mircrosurgery, pathology 2004

235 Font R, Gamel J. Epithelial tumours of the lacrimal gland: an analysis of 265 cases.In Jakobiec F (ed) Ocular and adnexal tumours. Aesculapius, Birmingham. 1978

236 Riedel K Markl A Hasenfratz G Epithelial tumors of the lacrimal gland: Clinico-pathologic correlation and management Neurosurg Rev 1990 13 289 298 2177857 10.1007/BF00346367

237 Andreasen S Esmaeli B Holstein L An Update on Tumors of the Lacrimal Gland. Asia-Pac J Ophthalmol 2017 6 159 172 10.22608/APO.201707 28399336

238 Cates C Manners R Rose G Pleomorphic adenoma of the lacrimal gland in a 10 year old girl Br J Ophthalmol 2002 86 249 250 11815361 10.1136/bjo.86.2.249 PMC1771012

239 Faktorovich E Crawford J Char D Benign mixed tumor (pleomorphic adenoma) of the lacrimal gland in a 6-year-old boy Am J Ophthalmol 1996 122 446 447 8794728 10.1016/s0002-9394(14)72082-3

240 Mercado G Gunduz K Shields C Pleomorphic adenoma of the lacrimal gland in a teenager Arch Ophthalmol 1998 116 962 963 9682721 10.1001/archopht.116.7.962

241 Ni C Kuo P Dryja T Histopathological classification of 272 primary epithelial tumors of the lacrimal gland Chin Med J 1992 105 481 485 1333391

242 Rose G Wright J Pleomorphic adenoma of the lacrimal gland Br J Ophthalmol 1992 76 395 400 1320923 10.1136/bjo.76.7.395 PMC504299

243 Stefko S DiBernardo C Green W Pleomorphic adenoma of the lacrimal gland with extensive calcification Arch Ophthalmol 2004 122 778 780 15136329 10.1001/archopht.122.5.778

244 Stupp T Pavlidis M Buchner T Pleomorphic Adenoma of the Lacrimal Gland in a Child After Treatmentof Acute Lymphoblastic Leukemia Arch Ophthalmol 2004 122 1538 1540 15477468 10.1001/archopht.122.10.1538

245 Bonavolontà G Tranfa F Staibano S Warthin Tumor of the Lacrimal Gland Am J Ophthalmol 1997 124 857 858 9402842 10.1016/s0002-9394(14)71713-1

246 Ghosh D Ekka J Adenolymphoma of the lacrimal gland: A very rare case report Int J Ocul Oncol oculoplasty 2018 4 144 145

247 Bartoletti-Stella A Salfi N Ceccarelli C Mitochondrial DNA Mutations in Oncocytic Adnexal Lacrimal Glands of the Conjunctiva ARCH OPHTHALMOL 2011 129 664 666 21555623 10.1001/archophthalmol.2011.95

248 Calle C Castillo I Eagle R Oncocytoma of the Lacrimal Gland: Case Report and Review of the Literature Orbit 2006 25 243 247 16987774 10.1080/01676830600575543

249 Cameron J Barras C Oncocytoma of the eyelid ACTA OPHTHALMOL SCAND 2004 83 125 10.1111/j.1600-0420.2005.00346.x 15715577

250 George E Swanson P Newman B Oculocutaneous oncocytic tumors: clinicopathologic and immunohistochemical study of 2 cases with literature review Am J Dermatopathol 2007 29 279 285 17519627 10.1097/DAD.0b013e318053d87c

251 Morand B Bettega G Bland V Oncocytoma of the eyelid: an aggressive benign tumor Ophthalmology 1998 105 2220 2224 9855150 10.1016/S0161-6420(98)91219-2

252 Shields C Shields J Tumors of the conjunctiva and cornea Survey of Ophthalmology 2004 49 3 24 14711437 10.1016/j.survophthal.2003.10.008

253 Shields C Shields J Arbizo V Oncocytoma of the caruncle Am J Ophthalmol 1986 102 315 319 3752196 10.1016/0002-9394(86)90004-8

254 Surakiatchanukul T Sioufi K Pointdujour-Lim R Caruncular Oncocytoma Mimicking Malignant Melanoma Ocul Oncol Pathol 3 320 323 10.1159/000468524 PMC5757591 29344489

255 Bolzoni A Pianta L Farina D Benign myoepithelioma of the lacrimal gland: report of a case Eur Arch Otorhinolaryngol 2005 262 186 188 15138773 10.1007/s00405-004-0787-z

256 Font R Garner A Myoepithelioma of the lacrimal gland: report of a case with spindle cell morphology Brit J Ophthalmol 1992 76 634 636 1329939 10.1136/bjo.76.10.634 PMC505248

257 Grossniklaus H Wojno T Wilson M Myoepithelioma of the Lacrimal Gland Arch Ophthalmol 1997 115 1588 1590 9400797 10.1001/archopht.1997.01100160758017

258 Heathcote J Hurwitz J Dardick I A Spindle-Cell Myoepithelioma of the Lacrimal Gland Arch Ophthalmol 1990 108 1135 1139 2166496 10.1001/archopht.1990.01070100091041

259 Nickol T Kleinsasser O Myoepitheliome der Parotis. Jahresversammlung der Deutschen Gesellschaft für HNO-Heilkunde 1998

260 Bajaj M Pushker N Kashyap S Cystadenoma of the lacrimal gland Orbit 2002 21 301 305 12610770 10.1076/orbi.21.4.301.8556

261 Bernardini F Devoto M JO C. Epithelial tumors of the lacimal gland: an update Curr Opin in Ophthalmol 2008 19 409 413 10.1097/ICU.0b013e32830b13e1 18772674

262 Silbert J Braich P Misra R Basal cell cystadenoma of the lacrimal gland: diagnostic pitfalls of a basaloid pattern in lacrimal tumours. Internat Ophthalmol 2011 DOI: 43-46 10.1007/s10792-010-9392-x 20878449

263 Wang L Zhang S K Ma Y Papillary cystadenoma of the parotid gland: A case report World J Clin Cases 2019 7 366 372 30746378 10.12998/wjcc.v7.i3.366 PMC6369395

264 Pfeiffer M Yin V Bell D Sclerosing Polycystic Adenosis of the Lacrimal Gland Ophthalmology 2013 120 873 23552085 10.1016/j.ophtha.2012.10.039

265 Speight P Barrett A Salivary gland tumours: diagnostic challenges and an update on the latest WHO classification Diagn Histopathol 2020 26 147 158

266 Brunnmann R Ro J Ordonez N Extrapleural Solitary Fibrous Tumor: A Clinicopathologic Study of 24 Cases Mod Pathol 1999 12 1034 1042 10574600

267 Mupas-Uy J Kitaguchia Y Takahashia Y Solitary Fibrous Tumor in the Lacrimal Gland Fossa: A Case Report Case Rep Ophthalmol 2016 7 398 403 27721790 10.1159/000448164 PMC5043291

268 Okike N Bernatz P Woolner L Localized mesothelioma of the pleura. Benign and malignant variants J Thorac Cardiovasc Surg 1978 75 363 372 633933

269 Scott I Tanenbaum M Rubin D Solitary fibrous tumor of the lacrimal gland fossa Ophthalmology 1996 103 1613 1618 8874434 10.1016/s0161-6420(96)30455-7

270 Vallat-Decouvelaere A Dry S Fletcher C Atypical and malignant solitary fibrous tumor in extrathoracic locations; evidence of their comparability to intra-thoracic tumors Am J Surg Pathol 1998 22 1501 1511 9850176 10.1097/00000478-199812000-00007

271 Woo K Suh Y Kim Y Solitary fibrous tumor of the lacrimal sac Ophthalmic Plast Reconstr Surg 1999 15 450 453 10588259 10.1097/00002341-199911000-00018

272 Bielory B P Turbin R E Mirani N M Radiographic and histological findings in an atypical orbital myxoma Ophthalmol Eye Dis 2011 3 55 23861624 10.4137/OED.S7498 PMC3661435

273 Demirci H Shields C L Eagle RCJ Report of a conjunctival myxoma case and review of the literature Arch Ophthalmol 2006 124 735 738 16682598 10.1001/archopht.124.5.735

274 Kini Rao A Nayal B Conjunctival myxoma-a case report Malays J Med Sci 2013 20 92 94 23613661 PMC3629886

275 Parikh D Mukherjee B Lacrimal gland myxoma Indian J Ophthalmol 2017 65 887 889 28905841 10.4103/ijo.IJO_226_17 PMC5621280

276 Rambhatla S Subramanian N Gangadhara Sundar J K Myxoma of the orbit Indian J Ophthalmol 2003 51 85 87 12701871

277 Bajaj M Pushker N Fibrous SK histiocytoma of the lacrimal gland Ophthal Plast Reconstr Surg 2007 23 145 147 10.1097/IOP.0b013e318030f5dd 17413632

278 Andrew N Coupland S Pirbhai A Lymphoid hyperplasia of the orbit and ocular adnexa: A clinical pathologic review Survey of Ophthalmology 2016 61 778 790 27127077 10.1016/j.survophthal.2016.04.004

279 Shields J Shields C Scartozzi R Survey of 1264 patients with orbital tumors and simulating lesions: the 2002 Montgomery lecture, part 1. Ophtalmology 2004 DOI: 997-1008 10.1016/j.ophtha.2003.01.002 15121380

280 Wittekind C TNM-Klassifikation maligner Tumoren. Achte Auflage. Aufl WILEY-VCH 2017

281 Devoto M Croxatto J Primary cystadenocarcinoma of the lacrimal gland Ophthalmology 2003 110 2006 2010 14522780 10.1016/S0161-6420(03)00490-1

282 Takahira M Nakamura Y Shimizu S Carcinosarcoma of the Lacrimal Gland Arising From a Pleomorphic Adenoma Am J Ophthalmol 2005 140 340 341 16086968 10.1016/j.ajo.2005.02.030

283 Daisuke Y Toshiyuki O Shuichi Y Case of primary neuroendocrine carcinoma in lacrimal gland Acta Ophthalmol 2013 91 252

284 Gess A Silkiss R A merkel cell carcinoma of the lacrimal gland. Ophthal Plast Reconstr Surg 28 11 13 10.1097/IOP.0b013e3182127cb5 21743373

285 El-Naggar A Chan J Grandis J World Health organization classification of head and neck tumours 2017 DOI:

286 Weis E Rootman J Joly T Epithelial lacrimal gland tumors: pathologic classification and current understanding Arch Ophthalmol 2009 127 1016 1028 19667339 10.1001/archophthalmol.2009.209

287 Gamel J Font R Adenoidcystic carcinoma of the lacrimal gland: the clinical significance of a basaoid histologic pattern Human Pathol 1982 13 219 225 6281163 10.1016/s0046-8177(82)80180-9

288 Friedrich R Bleckmann V Adenoid cystic carcinoma of the salivary and lacrimal glands origin: localization, classification, clinical pathological correlation, treatment results and long-term follow-up control in 84 patients Anticancer Res 2003 23 937 940 12820326

289 Goldberg R Intraarterial chemotherapy. A welcome new idea for the management of adenoidcystic carcinoma of the lacrimal gland Arch Ophthalmol 1998 116 372 373 9514492 10.1001/archopht.116.3.372

290 Hamper K Lazar F Dietel M Prognostic factors for adenoid cystic carcinoma of the head and neck: a retrospectiv evaluation of 96 cases J Oral Pathol Med 1990 19 101 107 2160530 10.1111/j.1600-0714.1990.tb00806.x

291 Henderson J In Orbital Tumors New York: Raven Press; 1994 323 342

292 Lee D Campbell R Waller R A clinicopathologic study of primary adenoid cystic carcinoma of the lacrimal gland Ophthalmology 1985 92 128 134 2983279 10.1016/s0161-6420(85)34081-2

293 Strianese D Baldi G Staibano S Expression of apoptosis-related markers in malignant epithelial tumors of the lacrimal gland and their relation to clinical outcome Br J Ophthalmol 2007 91 1239 1243 17431014 10.1136/bjo.2007.118661 PMC1954920

294 Tse D Benedetto P Dubovy S Clinical analysis oft he effect on intraarterial cytoreductive chemotherapy in the treatment of lacrimal gland andoid cystic carcinoma Am J Ophthalmol 2006 141 44 53 16386975 10.1016/j.ajo.2005.08.068

295 Wright J Rose G Garner A Primary malignant neoplasms of the lacrimal gland Br J Ophthalmol 1992 76 401 407 1320924 10.1136/bjo.76.7.401 PMC504300

296 Karcioglu Z Orbital Tumors. Diagnosis and Management New York Springer 2005

297 Ahmad S Esmaeli B Williams M American Joint Committee on Cancer classification predicts outcome of patients with lacrimal gland adenoid cystic carcinoma Ophthalmology 2009 116 1210 1215 19395039 10.1016/j.ophtha.2008.12.049

298 GROUP IHANS. Cervical lymph node metastasis in adenoid cystic carcinoma of the sinonasal tract, nasopharynx, lacrimal glands and external auditory canal: a collective international review. J Laryngol Otol 2016 130 1093 1097 10.1017/S0022215116009373 PMC5535774 27839526

299 Xiao R Sethi R Feng A The role of elective neck dissection in patients with adenoid cystic carcinoma of the head and neck Laryngoscope 2019 129 2094 2104 30667061 10.1002/lary.27814

300 Bördlein I Mit schweren Ionen gegen hartnäckige Tumoren Deutsches Ärzteblatt 2004 101 1718 1720

301 Hayashi K Koto M Ikawa H Efficacy and safety of carbon-ion radiotherapy for lacrimal gland carcinomas with extraorbital extension: a retrospective cohort study Oncotarget 2018 9 12932 12940 29560121 10.18632/oncotarget.24390 PMC5849185

302 Lesueur P Rapeaud E De Marzi L Adenoid Cystic Carcinoma of the Lacrimal Gland: High Dose Adjuvant Proton Therapy to Improve Patients Outcomes Front Oncol 2020 10 135 32133287 10.3389/fonc.2020.00135 PMC7041626

303 Wolkow N Jakobiec F Lee H Long-term Outcomes of Globe-Preserving Surgery With Proton Beam Radiation for Adenoid Cystic Carcinoma of the Lacrimal Gland. Am J Ophthalmol 2018 195 10.1016/j.ajo.2018.07.024 30071211

304 Shields J Shields C Freire J Plaque radiotherapy for selected orbital malignancies: preliminary observations: hte 2002 Montgomery Lecture, part 2 Ophthal Plast Reconstr Surg 2003 19 91 95 10.1097/01.IOP.0000056020.66654.33 12644752

305 Tyl J Blank L Koornneef L Brachytherapy in orbital tumors Ophthalmology 1997 104 1475 1479 9307644 10.1016/s0161-6420(97)30113-4

306 Gündüz A Yesiltas Y Shileds C Overview of benign and malignant lacrimal gland tumors Curr Opin Ophthalmol 2018 29 458 468 30028745 10.1097/ICU.0000000000000515

307 Ashton N Epithelial tumors of the lacrimal gland Mod Probl Ophthalmol 1975 14 306 323 170512

308 Perzin K Jakobiec F Lovolsi V Lacrimal gland malignant mixed tumors (carcinomas arising in benign mixed tumors): a clinicopathologic study Cancer 1980 45 2593 2606 7378993 10.1002/1097-0142(19800515)45:10<2593::aid-cncr2820451019>3.0.co;2-s

309 Shields C Shields J Eagle R Clinicopathologic review of 142 cases of lacrimal gland lesions Ophthalmology 1989 96 431 435 2726173 10.1016/s0161-6420(89)32873-9

310 Henderson J Farrow G Primary malignant mixed tumors of the lacrimal gland Report of 10 cases. Ophthalmology 1980 87 466 475 7413135 10.1016/s0161-6420(80)35206-8

311 Jakobiec F Bilyk J Font R Ophthalmic Pathology. An Atlas and Textbook. Aufl. Philadelphia 4th ed. WB Saunders 1996

312 Chen A Garcia J Bucci M The role of postoperative radiation therapy in carcinoma ex pleomorphic adenoma of the parotid gland Int J Radiat Oncol Biol Phys 2007 67 138 143 17049183 10.1016/j.ijrobp.2006.07.1380

313 Takahira M Minato H Takahashi M Cystic carcinoma ex pleomorphic adenoma of the lacrimal gland Ophthal Plast Reconstr Surg 2007 23 407 409 10.1097/IOP.0b013e3181238dc2 17881995

314 Hwang S Kim K High-grade Mucoepidermoid Carci- noma of the Lacrimal Gland Korean J Ophthalmol 2018 32 426 427 30311467 10.3341/kjo.2018.0026 PMC6182204

315 Heaps R Miller N Albert D Primary adenocarcinoma of the lacrimal gland Ophtalmology 1993 100 1856 1860 10.1016/s0161-6420(93)31385-0 8259287

316 von Holstein S Coupland S , D B. Epithelial Tumors of the Lacrimal Gland: a clinical, histopathological, surgical, and oncological survey Acta Ophthalmol 2013 91 195 206 22471335 10.1111/j.1755-3768.2012.02402.x

317 Dennie T Metastastic her-2 amplified lacrimal gland carcinoma with response to lapatinib treatment Case Rep Oncol Med 2015 2015 1 3 10.1155/2015/262357 PMC4332983 25722902

318 Totuk O Demir M Yapicier O Low-Grade Mucoepidermoid Carcinoma of the Lacrimal Gland in a Teenaged Patient. Case Rep Ophthalmol Med 2017 10.1155/2017/2418505 PMC5727657 29318070

319 Eviatar J Hornblass A Mucoepidermoid carcinoma of the lacrimal gland: 25 cases and a review and update of the literature Ophthal Plast Reconstr Surg 1993 9 170 181 10.1097/00002341-199309000-00002 8217958

320 Sofinski S Brown B Rao N Mucoepidermoid carcinoma of the lacrimal gland. Case report and review of the literature Ophthalmic Plast Reconstr Surg 1986 2 147 151 3154555 10.1097/00002341-198601060-00006

321 Thorvaldsson S Beahrs O Woolner L Mucoepidermoid tumors of the major salivary glands Am J Surg 1970 120 432 438 5507327 10.1016/s0002-9610(70)80002-2

322 Katz E Rootman J Dolman P Primary Ductal Adenocarcinoma of the Lacrimal Gland Ophthalmology 1996 103 157 162 8628547 10.1016/s0161-6420(96)30746-x

323 Yang H Wu C Tsai C Primary ductal adenocarcinoma of lacrimal gland: Two case reports and review of the literature Taiwan J Ophthalmol 2018 8 42 48 29675349 10.4103/tjo.tjo_3_18 PMC5890584

324 Ishida M Hotta M Kushima R Case of ductal adenocarcinoma ex pleomorphic adenoma of the lacrimal gland Rinsho Byori 2009 57 746 751 19764409

325 Andreasen S Grauslund M Heegaard S Lacrimal gland ductal carcinomas: clinical, morphological and genetic characterization and implications for targeted treatment Acta Ophthalmol 2017 95 299 306 27808478 10.1111/aos.13310

326 Jaspers H Verbist B Schoffelen R Androgen Receptor–Positive Salivary Duct Carcinoma: A Disease Entity With Promising New Treatment Options J Clin Oncol 2011 29 473 476 21422415 10.1200/JCO.2010.32.8351

327 See T Stålhammar G Tang T Primary ductal adenocarcinoma of the lacrimal gland: A review and report of five cases Survey of Ophthalmology 2020 65 371 380 31837385 10.1016/j.survophthal.2019.11.002 PMC7215120

328 Anesi A Negrello S Lucchetti D Clinical Management of Acinic Cell Carcinoma of the Lacrimal Gland Case Rep Oncol 2019 12 777 790 31762749 10.1159/000503557 PMC6872994

329 De Rosa G Zeppa P Tranta F Acinic Cell Carcinoma in a Lacrimal Gland: first case report Cancer 1986 57 1988 1991 3955504 10.1002/1097-0142(19860515)57:10<1988::aid-cncr2820571018>3.0.co;2-n

330 Jang J Kie J Lee S Acinic cell carcinoma of the lacrimal gland with intracranial extension Ophthalmic Plast Reconstr Surg 2001 17 454 457 11766029 10.1097/00002341-200111000-00014

331 Rosenbaum P Mahadevia P Goodman L Acinic cell carcinoma of the lacrimal gland Arch Ophthalmol 1995 113 781 785 7540387 10.1001/archopht.1995.01100060107044

332 Briscoe D Mahmood S Bonshek R Primary sebaceous carcinoma of the lacrimal gland Br J Ophthalmol 2001 85 625 626 11351970 10.1136/bjo.85.5.625 PMC1723953

333 Harvey P Parsons M Rennie I Primary sebaceous carcinoma of lacrimal gland: a previously unreported primary neoplasm Eye 1994 8 592 595 7835459 10.1038/eye.1994.143

334 Kiratli H Tarlan B Fırat P Primary sebaceous carcinoma of the lacrimal gland Orbit 2012 31 352 354 22906082 10.3109/01676830.2012.678921

335 Park H Choi S Primary sebaceous carcinoma of lacrimal gland: A case report and review of literature World J Clin Cases 2018 6 1194 1198 30613681 10.12998/wjcc.v6.i16.1194 PMC6306633

336 Yamamoto N Mizoe J Hasegawa A Primary sebaceous carcinoma of the lacrimal gland treated by carbon ion radiotherapy Int J Clin Oncol 2003 8 386 390 14663642 10.1007/s10147-003-0348-2

337 Herrera G Light microscopic, ultrastructural and immunocytochemical spectrum of malignant lacrimal and salsivary gland tumors, including malignant mixed tumors Pathobiology 1990 58 312 322 1706602 10.1159/000163603

338 Iida K Shikishima K Okido M A case of malignant myoepithelioma in the lacrimal gland Nippon Ganka Gakkai Zasshi 2001 105 42 46 11210787

339 Larbcharoensub N Pangpunyakulchai D Aroonroch R Lacrimal myoepithelial carcinoma ex recurrent pleomorphic adenoma: A clinicopathological report and review of the literature Mol Clin Oncol 2018 8 209 213 29387416 10.3892/mco.2017.1488 PMC5769277

340 Nagao T Sugano I Ishida Y Salivary gland mmalignant myoepithelioma: a clinicopathologic and immunohistochemical study of ten cases Cancer 1998 83 1292 1299 9762928 10.1002/(sici)1097-0142(19981001)83:7<1292::aid-cncr4>3.0.co;2-l

341 Xu T Liao Z Tang J Myoepithelial carcinoma of the headand neck: A report of 23 casesand literature review. Cancer Treatment Communications 2014 2 24 29

342 Mahdi Y Azami M Daoudi R Diagnostic pitfall: primary myoepithelial carcinoma of the lacrimal gland, case report and literature review BMC Clinical Pathology 2018 18 1 7 30123086 10.1186/s12907-018-0073-4 PMC6090953

343 Yu G Ma D Sun K Myoepithelial carcinoma of the salivary glands: behavior and management Chin Med J 2003 116 163 165 12775221

344 Soumarová R Lovasová Z Vaňková M Radiotherapy in malignant myoepithelioma of the soft palate – case report Case Rep Oncol 2009 2 116 120 20740173 10.1159/000228546 PMC2918858

345 Nieder C Schneller F Grosu A Radiotherapy and chemotherapy for myoepithelioma of the sellar region Strahlenther Onkol 2005 181 260 263 15827697 10.1007/s00066-005-1356-0

346 Fenton S Srinivasan S Harnett A Primary squamous cell carcinoma of the lacrimal gland Eye 2003 17 424 425 12724709 10.1038/sj.eye.6700323

347 Su G Patipa M Font R Primary squamous cell carcinoma arising from an epithelium-lined cyst of the lacrimal gland Ophthal Plast Reconstr Surg 2005 21 383 385 10.1097/01.iop.0000176263.07921.22 16234706

348 Hotta K Arisawa T Mito H Primary squamous cell carcinoma of the lacrimal gland Clin Experiment Ophthalmol 2005 33 534 536 16181286 10.1111/j.1442-9071.2005.01043.x

349 Bernardini F Orcioni G Croxatto J Oncocytic carcinoma of the lacrimal gland in a patient with neurofibromatosis Ophthal Plast Reconstr Surg 2010 26 486 488 10.1097/IOP.0b013e3181df6b22 20700068

350 Kalantzis G Norris J El-Hindy N Oncocytic adenocarcinoma of the lacrimal gland: an unusual presentation Eye 2013 27 104 105 23174753 10.1038/eye.2012.200 PMC3545375

351 Selva D Davis G Dodd T Polymorphous Low-Grade Adenocarcinoma of the Lacrimal Gland ARCH OPHTHALMOL 2004 122 915 917 15197069 10.1001/archopht.122.6.915

352 Bortz J Zhang P Eagle R Secretory Carcinoma of the Lacrimal Gland: A Rare Case Report Ophthalmic Plast Reconstr Surg 2018 34 154 157 10.1097/IOP.0000000000001173 30059394

353 Hyrczaa M Andreasen S Melchiorc L Primary Secretory Carcinoma of the Lacrimal Gland: Report of a New Entity Am J Ophthalmol 2018 193 178 183 29963997 10.1016/j.ajo.2018.06.019

354 Kadir S. Synovial Sarcoma involving lacrimal gland: A rare clinical entity. Int J Ocu Oncol Oculoplast. 1: 14–18

355 Likhvantseva V Safonova T Kuzmin K Primary granulocytic sarcoma of lacrimal gland Vestn Oftalmol 2016 132 82 89 28635826 10.17116/oftalma2016132382-89

356 Yilmaz A Saydam G Sahin F Granulocytic sarcoma: a systematic review Am J Blood Res 2013 3 265 270 24396704 PMC3875275

357 Rajabi M Riazi H Hosseini S Malignant Peripheral Nerve Sheath Tumor of Lacrimal Nerve: A Case Report Orbit 2015 34 41 44 25264927 10.3109/01676830.2014.959610

358 Stark A Hugo H Buhl R Tumoren peripherer Nerven Dtsch Arztebl 2002 99 928 933

359 Gündüz K Shields J Eagle R. Malignant Rhabdoid Tumor of the Orbit Arch Ophthalmol 1998 116 243 246 9488282 10.1001/archopht.116.2.243

360 Johnson L Sexton F Goldberg S Poorly differentiated primary orbital sarcoma (presumed malignant rhabdoid tumor): radiologic and histopathologic correlation Arch Ophthalmol 1991 109 1275 1278 1656924 10.1001/archopht.1991.01080090101031

361 Orphanet. Rhabdoidtumor. In: Orphanet; 2020

362 Rootman J Damji K Dimmick J Malignant rhabdoid tumor of the orbit Ophthalmology 1989 96 1650 1654 2694050 10.1016/s0161-6420(89)32666-2

363 Walford N Deferrai R Slater R Intraorbital rhabdoid tumour following bilateral retinoblastoma Histopathology 1992 20 170 173 1313784 10.1111/j.1365-2559.1992.tb00948.x

364 Niffenegger J Jakobiec F Shore J Adult extrarenal rhabdoid tumor of the lacrimal gland Ophthalmology 1992 99 567 574 1374874 10.1016/s0161-6420(92)31948-7

365 Ferry J Fung C Zukerberg L Lymphoma of the ocular adnexa: A study of 353 cases 2007 31 170 184 10.1097/01.pas.0000213350.49767.46 17255761

366 Rasmussen P Ralfkiaer E Prause J Malignant lymphoma of the lacrimal gland. A nation-based study Arch Ophthalmol 2011 129 1275 1280 21987669 10.1001/archophthalmol.2011.270

367 Johnson T Tse D Byrne G Ocular adnexal lymphoid tumors: a clinicopathologic and molecular genetic study of 77 patients Ophthal Plast Reconstr Surg 1999 15 171 179 10355835

368 Polito E Galieni P Leccisotti A Clinical and radiological presentation of 95 orbital lymphoid tumors Graefes Arch Clin Exp Ophthalmol 1996 234 504 509 8858356 10.1007/BF00184859

369 Aranow M Ocular adnexal lymphoma: evidence-based treatment approach Int Ophthalmol Clin 2015 55 97 109 25436496 10.1097/IIO.0000000000000049

370 König L Stade R Rieber J Radiotherapy of indolent orbital lymphomas: two radiation concepts Strahlenther Onkol 2016 192 414 421 27160291 10.1007/s00066-016-0962-3

371 de Leval L Jaffe E Lymphoma Classification Cancer J 2020 26 176 185 32496451 10.1097/PPO.0000000000000451

372 Shields J Shields C Eagle R Metastatic renal cell carcinoma to the palpebral lobe of the lacrimal gland Ophthal Plast Reconstr Surg 2001 17 191 194 10.1097/00002341-200105000-00008 11388385

373 Fowler J Terplan K Fibroma of the Orbit Arch Ophthalmol 1942 28 263 271

374 Mortada A Fibroma of the orbit Brit J Ophthal 1971 55 350 5579169 10.1136/bjo.55.5.350 PMC1208308

375 Rong A Ulloa-Padilla J Blessing N Subperiosteal fibroma of the orbit Orbit 2018 37 378 380 29303383 10.1080/01676830.2017.1423348

376 Rabelo N da Silva V do Espírito Santo M Orbit ossifying fibroma – Case report and literature review Surg Neurol Int 2020 11 35 32257561 10.25259/SNI_492_2019 PMC7110299

377 Sheikh BY Cranial aneurysmal bone cyst “with special emphasis on endovascular management” Acta Neurochir (Wien) 1999 141 601 610 discussion 610-601 10929725 10.1007/s007010050349

378 Glien A Meyer B Wernert N [Orbital aneurysmal bone cyst in a 2-year-old child] HNO 2007 55 281 286 17237961 10.1007/s00106-006-1472-x

379 Wang J C Zhang M Zhao XX Aneurysmal bone cyst of the orbit Chin Med J (Engl) 2015 128 562 563 25673465 10.4103/0366-6999.151120 PMC4836266

380 Yu J W Kim K U Kim S J Aneurysmal bone cyst of the orbit : a case report with literature review J Korean Neurosurg Soc 2012 51 113 116 22500206 10.3340/jkns.2012.51.2.113 PMC3322208

381 Ruiter D J van Rijssel T G van der Velde EA Aneurysmal bone cysts: a clinicopathological study of 105 cases Cancer 1977 39 2231 2239 265751 10.1002/1097-0142(197705)39:5<2231::aid-cncr2820390541>3.0.co;2-q

382 Biesecker J L Marcove R C Huvos A G Aneurysmal bone cysts. A clinicopathologic study of 66 cases Cancer 1970 26 615 625 5458269 10.1002/1097-0142(197009)26:3<615::aid-cncr2820260319>3.0.co;2-i

383 Schajowicz F Tumors and tumorlike lesions of bone 2. Aufl Berlin-Heidelberg-New York Springer-Verlag 1994

384 Oliveira A M Chou MM USP6-induced neoplasms: the biologic spectrum of aneurysmal bone cyst and nodular fasciitis Hum Pathol 2014 45 1 11 23769422 10.1016/j.humpath.2013.03.005

385 Fay A, Dolman PJ. Laboratory Serologic Investigations.In Fay A, Dolman PJ , Hrsg. Diseases and Disorders of the Orbit and Ocular Adnexa E-book. Elsevier; 2017: 314

386 Mallen J R Caranfa J T Zimmerman D Atypical presentation of a solid-variant orbital aneurysmal bone cyst with a literature review Neurochirurgie 2018 64 431 433 30413280 10.1016/j.neuchi.2018.10.001

387 Chawla B Khurana S Kashyap S Giant cell reparative granuloma of the orbit Ophthalmic Plast Reconstr Surg 2013 29 e94 95 23511994 10.1097/IOP.0b013e31827bdac3

388 Kamoshima Y Sawamura Y Imai T Giant cell tumor of the frontal bone in a girl: case report Neurol Med Chir (Tokyo) 2011 51 798 800 22123486 10.2176/nmc.51.798

389 Smolarz-Wojnowska A Essig H Gellrich N C [Orbital tumours in children and adolescents. Differential diagnostics and clinical symptoms] Ophthalmologe 2010 107 543 548 20393733 10.1007/s00347-009-2068-0

390 Vernet O Ducrey N Deruaz J P Giant cell tumor of the orbit Neurosurgery 1993 32 848 851 8492864 10.1227/00006123-199305000-00022

391 Yip C M Lee H P Hsu S S Left orbital roof giant cell tumor of bone: A case report Surg Neurol Int 2018 9 127 30034918 10.4103/sni.sni_467_17 PMC6034354

392 Yamaguchi T Dorfman HD Giant cell reparative granuloma: a comparative clinicopathologic study of lesions in gnathic and extragnathic sites Int J Surg Pathol 2001 9 189 200 11584315 10.1177/106689690100900304

393 de Lange J van den Akker H P van den Berg H Central giant cell granuloma of the jaw: a review of the literature with emphasis on therapy options Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007 104 603 615 17703964 10.1016/j.tripleo.2007.04.003

394 Auclair P L Cuenin P Kratochvil F J A clinical and histomorphologic comparison of the central giant cell granuloma and the giant cell tumor Oral Surg Oral Med Oral Pathol 1988 66 197 208 3174054 10.1016/0030-4220(88)90094-1

395 de Lange J van Rijn R R van den Berg H Regression of central giant cell granuloma by a combination of imatinib and interferon: a case report Br J Oral Maxillofac Surg 2009 47 59 61 18656288 10.1016/j.bjoms.2008.05.013

396 Roman-Romero L Gonzalez-Garcia R Cholesterol granuloma of the orbit. Report of cases and analysis of controversial treatment J Maxillofac Oral Surg 2011 10 166 169 22654372 10.1007/s12663-010-0120-x PMC3177526

397 Loeffler K U Kommerell G Cholesterol granuloma of the orbit--pathogenesis and surgical management Int Ophthalmol 1997 21 93 98 9405991 10.1023/a:1005838915787

398 Selva D Phipps S E O'Connell J X Pathogenesis of orbital cholesterol granuloma Clin Exp Ophthalmol 2003 31 78 82 12580900 10.1046/j.1442-9071.2003.00605.x

399 Daus W Voges J Schwechheimer K [Cholesterol granuloma of the orbits--clinicopathologic study] Klin Monbl Augenheilkd 1988 193 195 199 3054259 10.1055/s-2008-1050246

400 Hsu H T Liao W C Wu C C Cholesterol granuloma of the orbit Kaohsiung J Med Sci 2017 33 422 423 28811012 10.1016/j.kjms.2017.04.007

401 Rong A J Erickson B P Blessing N W Orbital cholesterol granuloma: A report and discussion of orbital findings Am J Ophthalmol Case Rep 2019 15 100468 31198882 10.1016/j.ajoc.2019.100468 PMC6556881

402 Arat Y O Chaudhry I A Boniuk M Orbitofrontal cholesterol granuloma: distinct diagnostic features and management Ophthalmic Plast Reconstr Surg 2003 19 382 387 14506423 10.1097/01.IOP.0000083644.62765.70

403 Aferzon M Millman B O'Donnell T R Cholesterol granuloma of the frontal bone Otolaryngol Head Neck Surg 2002 127 578 581 12501112 10.1067/mhn.2002.129735

404 Kabra R Patel S Shanbhag S Orbital Chondroma: A rare mesenchymal tumor of orbit Indian J Ophthalmol 2015 63 551 554 26265654 10.4103/0301-4738.162638 PMC4550997

405 Garrity J, Henderson J. Henderson’s Orbital Tumors.In 4th ed. Aufl. USA: Lippincott Williams and Wilkis; 2007: 103–104

406 Rootman J Connell J Primary bone tumors of orbit Surv Ophthalmol 2004 49 328 342 15110669 10.1016/j.survophthal.2004.02.011

407 Shields J Bakewell B Augsburger J Classification and incidence of space-occupying lesions of the orbit. A survey of 645 biopsies Arch Ophthalmol 1984 102 1606 1611 6497741 10.1001/archopht.1984.01040031296011

408 Pushker N Meel R Sharma S Giant orbital Schwannoma with fluid-fluid-levels Br J Ophthalmol 2010 95 1168 10.1136/bjo.2009.170829 20657016

409 Misra S Gogri P Misra N Recurrent neurofibroma of the orbit Australas Med J 2013 30 189 191 10.4066/AMJ.2013.1660 PMC3650310 23671464

410 Lee L Gigantelli J Kincaid M Localized neurofibroma of the orbit: a radiographic and histopathologic study Ophthal Plast Reconstr Surg 2000 16 241 246 10.1097/00002341-200005000-00013 10826767

411 Turbin R Thompson C Kennerdell J A long-term visual outcome comparison in patients with optic nerve sheath meningioma managed with observation, surgery, radiotherapy, or surgery and radiotherapy Ophtalmology 2002 109 890 899 10.1016/s0161-6420(02)01017-5 11986093

412 Schittkowski M Fichter N. Orbitale Neoplasien Teil I Einführung, vaskuläre und neurogene Neoplasien Ophthalmologe 2012 109 1033 1046 23053338 10.1007/s00347-012-2664-2

413 Jain D Ebrahimi K Miller N Intraorbital meningiomas: a pathologic review using current World Health Organization criteria Arch Pathol Lab Med 2010 134 766 770 20441509 10.5858/134.5.766

414 Eddleman C Liu J Optic nerve sheath meningioma: current diagnosis and treatment Neurosurg Focus 2007 23 E4 10.3171/FOC-07/11/E4 18004966

415 Saeed P Rootman J Nugent R Optic nerve sheath meningiomas Ophthalmology 2003 110 2019 2030 14522782 10.1016/S0161-6420(03)00787-5

416 Ramey W Arnold S Chiu A A Rare Case of Optic Nerve Schwannoma: Case Report and Review of the Literature Cureus 2015 7 e265 26180689 10.7759/cureus.265 PMC4494577

417 Gnekow A Low-grade chiasmatic-hypothalamic glioma-carboplatin and vincristine chemotherapy effectively defers radiotherapy within a comprehensive treatment strategy - report from the multicenter treatment study for children and adolescents with a low grade glimoa - HIT-LGG 1996 - of the Society of Paediatric Oncology and Hematology (GPOH) Klin Padiatr 2004 216 331 342 15565548 10.1055/s-2004-832355

418 Sharif S Second primary tumors in neurofibromatosis 1 patients treated for optic nerve glioma: substantial risks after radiotherapy J Clin Oncol 2006 24 2570 2575 16735710 10.1200/JCO.2005.03.8349

419 Wilhelm H Primary optic nerve tumors Curr Opin Neurol 2009 22 11 18 19155759 10.1097/WCO.0b013e32831fd9f5

420 Emesz M Arlt E Krall E Granularzelltumor der Orbita. Der Ophthalmologe 2014 111 866 870 24173669 10.1007/s00347-013-2972-1

421 Huang N Rayess H Svider P Orbital Paraganglioma: A Systematic Review J Neurol Surg B Skull Base 2017 79 407 412 30009123 10.1055/s-0037-1615750 PMC6043173

422 Makhdoomi R Nayil K Santosh V Orbital paraganglioma--a case report and review of the literature Clin Neuropathol 2010 29 100 104 20175960 10.5414/npp29100

423 Al-Khiary H Ayoubi A Elkhamary S Primary orbital ganglioneuroma in a 2-year-old healthy boy Saudi J Ophthalmol 2010 24 101 104 23960884 10.1016/j.sjopt.2010.03.003 PMC3729488

424 Cannon T Brown H Hughes B Orbital Ganglioneuroma in a Patient With Chronic Progressive Proptosis Arch Ophthalmol 2004 122 1712 1714 15534137 10.1001/archopht.122.11.1712

425 Hatsukawa Y Furukawa A Kawamura H Rhabdomyoma of the orbit in a child Am J Ophthalmol 1997 123 142 144 9186119 10.1016/s0002-9394(14)71014-1

426 Li Y Li N Zang W Rhabdomyoma of the orbit J Pediatr Ophthalmol Strabismus 2008 45 113 115 18404960 10.3928/01913913-20080301-15

427

428 Gündüz K Günalp I Erden E Orbital leiomyoma: report of a case and review of the literature Surv Ophthalmol 2004 49 237 242 14998695 10.1016/j.survophthal.2003.12.010

429 Merani R Khannah G Mann S Orbital leiomyoma: a case report with clinical, radiological and pathological correlation Clin Exp Ophthalmol 2005 33 408 411 16033356 10.1111/j.1442-9071.2005.01034.x

430 Shah N Chang W White V Orbital lipoma: 2 cases and review of literature Ophthalmic Plast Reconstr Surg 2007 23 202 205 17519657 10.1097/IOP.0b013e318050ca52

431 Franchi G Sleilati E Soupre V Melanotic neuroectodermal tumour of infancy involving the orbit and maxilla: surgical management and follow-up strategy Br J Plast Surg 2002 55 526 529 12479433 10.1054/bjps.2002.3910

432 Koob M Fayard C Pariente D Prenatal diagnosis of orbital melanotic neuroectodermal tumor in infancy Ultrasound Obstet Gynecol 2015 46 247 252 25594399 10.1002/uog.14787

433 Soles B Wilson A Lucas D Melanotic Neuroectodermal Tumor of Infancy Arch Pathol Lab Med 2018 142 1358 1363 30407852 10.5858/arpa.2018-0241-RA

434 NIH. Childhood Rhabdomyosarcoma Treatment (PDQ®)–Health Professional Version. In: National Cancer Institute at the National Institutes of Health; 2020

435 Al-Bargi H Al-Maiman M Orbital fibrosarcoma: a case report and literature review Egypt J Oral Maxillofac Surg 2012 3 45 48

436 Bahrami A Folpe A Adult-type fibrosarcoma: A reevaluation of 163 putative cases diagnosed at a single institution over a 48-year period Am J Surg Pathol 2010 34 1504 1513 20829680 10.1097/PAS.0b013e3181ef70b6

437 Scruggs B Ho S Valenzuela A Diagnostic challenges in primary orbital fibrosarcoma: a case report Clin Ophthalmol 2014 8 2319 2323 25429202 10.2147/OPTH.S70843 PMC4242685

438

439 Cassoux N Lumbroso L Levy-Gabriel C Retinoblastoma: Update on Current Management. Asia-Pac J Ophthalmol 2017 6 290 295 10.22608/APO.201778 28558178

440 WHO. RETINOBLASTOMA - 2014 Review of Cancer Medicines on the WHO List of Essential Medicines. In: Union for International Cancer Control; 2014

441 Caignard A Faguer R Mercier P Optic nerve and visual pathways primary glioblastoma treated with radiotherapy and temozolomide chemotherapy Eur J Ophthalmol 2014 24 637 640 24366773 10.5301/ejo.5000416

442 Waheed S Huang B Zamora C Glioblastoma involving the optic nerve Am J Neuroradiol 2018 41 e

443 Alireza M Amelot A Chauvet D Poor prognosis and challenging treatment of optic nerve malignant gliomas: Literature review and case report series World Neurosurg 2017 97 e1 e6 10.1016/j.wneu.2016.10.083 27793766

444 Ashour O Stalling M Ramsey J Intraocular Medulloepithelioma RadioGraphics 2018 38 194 199 29320332 10.1148/rg.2018170160

445 Verdijk R On the Classification and Grading of Medulloepithelioma of the Eye Ocul Oncol Pathol 2016 2 190 193 27239464 10.1159/000443963 PMC4881278

446 Hei Y Kang L Yang X Orbital alveolar soft part sarcoma: A report of 8 cases and review of the literature Oncol Lett 2018 15 304 314 29285193 10.3892/ol.2017.7286 PMC5738708

447 Inci E Korkut N Erem M [Alveolar soft tissue sarcoma] HNO 2004 52 145 149 14968318 10.1007/s00106-003-0872-4

448 Rose A Kabiru J Rose G Alveolar soft-part sarcoma of the orbit Afr J Paediatr Surg 2011 8 82 84 21478594 10.4103/0189-6725.78936

449 Dirksen U Jürgens H S1-Leitlinie: Ewing-Sarkome des Kindes- und Jugendalters Stand 06/2014, DOI: AWMF-Register Nr. 025/006

450 Kaliki S Rathi S Palkonda V Primary orbital Ewing sarcoma family of tumors: a study of 12 cases Eye 2018 32 615 621 29219959 10.1038/eye.2017.278 PMC5848293

451 Chaugule S Putambekar A Gavade S Primary Orbital Leiomyosarcoma in an Adult Male Ophthal Plast Reconstr Surg 2019 35 e27 e29 10.1097/IOP.0000000000001293 30601462

452 Klippenstein K Wesley R Glick A Orbital Leiomyosarcoma After Retinoblastoma. Ophthalmic Surg Lasers Imaging Retina 1999 30 579 583 10929985

453 Yeniad B Tuncer S Peksayar G Primary Orbital Leiomyosarcoma. Ophth Plast Reconstr Surg 2009 25 154 155 10.1097/IOP.0b013e31819aaef4 19300170

454 Cai Y McMenamin E Geoff R Primary liposarcoma of the orbit: A clinicopathologic study of seven cases Ann Diagn Pathol 2001 5 255 266 11598853 10.1053/adpa.2001.27911

455 Garrity J, Henderson J, Cameron J. Henderson's Tumors of Primitive Mesoderm, Striated muscle, Adipose Tissue and Smooth muscle.In Garrity JA HJ, Cameron JD , Hrsg. Henderson's orbital tumors. 4th edition. AuflPhiladelphia: Lippincott Williams and Wilkins; 2007: 123–141

456 Alkatan H Chaudhry I Al-Qahtani A Epithelioid sarcoma of the orbit Ann Saudi Med 2011 31 187 189 21242638 10.4103/0256-4947.75589 PMC3102481

457 Inazawa N Hatakeyama N Hori T Primary orbital neuroblastoma in a 1-month-old boy Pediatr Int 2014 56 122 125 24548201 10.1111/ped.12239

458 Vallinayagam M Rao V Pandian D Primary orbital neuroblastoma with intraocular extension Indian J Ophthalmol 2015 63 684 686 26576531 10.4103/0301-4738.169784 PMC4687200

459 Zhang N Lin L Presumed primary orbital neuroblastoma in a 20-month-old female Ophthal Plast Reconstr Surg 2010 26 383 385 10.1097/IOP.0b013e3181cc8598 20622692

460 Rose A Luthert P Jayasena C Primary Orbital Melanoma: Presentation, Treatment, and Long-term Outcomes for 13 Patients Front Oncol 2017 7 316 29326884 10.3389/fonc.2017.00316 PMC5741819

461 Kiratli H Balci K Güler G Primary orbital endodermal sinus tumor (yolk sac tumor) J AAPOS 2008 12 623 625 18835732 10.1016/j.jaapos.2008.06.011

462 Mogaddam A Memar B Aledavood A Isolated Orbital Endodermal Sinus Tumor Ophthal Plast Reconstr Surg 2007 23 477 479 10.1097/IOP.0b013e31815928de 18030121

463 Eckardt A Lemound J Rana M Orbital lymphoma: diagnostic approach and treatment outcome. World J Surg Oncol 2013 DOI: 73 10.1186/1477-7819-11-73 PMC3616859 23506357

464 Olsen T Heegaard S Orbitla Lymphoma Surv Ophthalmol 2019 64 45 66 30144455 10.1016/j.survophthal.2018.08.002

465 Sharma T Kamath M Diagnosis and Management of Orbital Lymphoma. Ophthalmic Pearls 2015 DOI: 37-39

466 Bidar M Wilson M Laquis S Clinical and imaging characteristics of orbital leukemic tumors Ophthalmic Plast Reconstr Surg 2007 23 87 93 17413619 10.1097/IOP.0b013e3180333a85

467 Hatton M Rubin P Chronic Lymphocytic Leukemia of the Orbit Arch Ophthalmol 2002 120 990 991 12096979

468 Maka E Lukáts O Tóth J Orbital tumour as initial manifestation of acute myeloid leukemia: granulocytic sarcoma: case report Pathol Oncol Res 2008 14 209 211 18431695 10.1007/s12253-008-9028-x

469 Taylor C Taylor R Kinsey S LEUKEMIC INFILTRATION OF THE ORBIT: Report of Three Cases and Literature Review Pediatr Hematol Oncol 2005 22 415 422 16020132 10.1080/08880010590964390

470 Pausch N Sterker I Bauer U Maligner intraorbitaler Tumor: Primum oder Metastase? HNO 2016 64 262 264 26992382 10.1007/s00106-016-0139-5

471 Schenke T Lehmann G Kunze C Eine abszessverdächtige Raumforderung in der extraokulären Augenmuskulatur. HNO 2020 10.1007/s00106-020-00856-7 32240325

472 Suarez C Ferlito A Lund V Management of the orbit in malignant sinunasal tumors Head Neck 2008 30 242 250 18023029 10.1002/hed.20736

473 Evert K Kühnel T Weiß K Diagnostik und Management von Gefäßanomalien. Der Pathologe 2019 40 422 430 31243549 10.1007/s00292-019-0625-0

474 Müller-Wille R Wildgruber M Sadick M Vascular Anomalies (Part II): Interventional Therapy of Peripheral Vascular Malformations Fortschr Röntgenstr 2018 190 927 937 10.1055/s-0044-101266 29415296

475 Sadick M Müller-Wille R Wildgruber M Vascular Anomalies (Part I): Classification and Diagnostics of Vascular Anomalies Fortschr Röntgenstr 2018 190 825 835 10.1055/a-0620-8925 29874693

476 Wassef M Blei F Adams D Vascular Anomalies Classification: Recommendations From the International Society for the Study of Vascular Anomalies Pediatrics 2015 136 e203 e214 26055853 10.1542/peds.2014-3673

477 Fay A Nguyen J Jakobiec F Propranolol for Isolated Orbital Infantile Hemangioma ARCH OPHTHALMOL 2010 128 256 258 20142556 10.1001/archophthalmol.2009.375

478 Grantzow R Schmittenbecher P Höger P S2k-Leitlinie 006/100: Infantile Hämangiome im Säuglings- und Kleinkindesalter. AWMF online 2015 DOI: 1-13

479 Goldsmith J van de Rijn M Syed N Orbital Hemangiopericytoma and Solitary Fibrous Tumor: A Morphologic Continuum Internat J Surg Pathol 2001 9 295 302 10.1177/106689690100900406 12574845

480 Pacheco L Fernandes B Miyamoto C Rapid growth of an orbital hemangiopericytoma with atypical histopathological findings Clin Ophthalmol 2014 8 31 33 24353402 10.2147/OPTH.S47901 PMC3862697

481 Westerfeld C Allen C Mihm M Non-Involuting Congenital Hemangioma Presenting as an Orbital Mass in a Newborn Investigative Ophthalmology & Visual Science 48 3582

482 Gbolahan O Fasina O Adisa A Spindle cell hemangioma: Unusual presentation of an uncommon tumor J Oral Maxillofac Pathol 2015 19 406 10.4103/0973-029X.174634 PMC4774302 26980977

483 Budimir I Demirović A Iveković R Epithelioid hemangioma of the orbit: case report Acta Clin Croat 2015 54 92 95 26058249

484 McEachren T Brownstein S Jordan D Epithelioid hemangioma of the orbit Ophtalmology 2000 107 806 810 10.1016/s0161-6420(00)00011-7 10768347

485 Stiefel H Ng J Wilson D Orbital Cellular Epithelioid Hemangioma Ocul Oncol Pathol 2019 5 424 431 31768366 10.1159/000496207 PMC6873054

486 Kamano H Noguchi T Yoshiura T Intraorbital lobular capillary hemangioma (pyogenic granuloma) Radiat Med 2008 26 609 612 19132492 10.1007/s11604-008-0280-5

487 Häußler S Uecker F Knopke S Tufted angiomas of the head and neck HNO 2018 66 S1 S6

488 Benesch M Lackner H Sorantin E Medikamentöse Therapie vaskulärer Anomalien Paediatr Paedolog 2020 55 21 27

489 Cho W Kim S Park S Intracranial kaposiform hemangioendothelioma: proposal of a new malignant variant J Pediatr Ophthalmol Strabismus 2009 3 147 150 10.3171/2008.11.PEDS08171 19278316

490 Li B Li Y Tian X Unusual multifocal intraosseous papillary intralymphatic angioendothelioma (Dabska tumor) of facial bones: a case report and review of literature Diagn Pathol 2013 8 160 24063649 10.1186/1746-1596-8-160 PMC3852300

491 Collaco L Goncalves M Gomes L Orbital Kaposi’s Sarcoma in Acquired Immunodeficiency Syndrome Eur J Ophthalmol 2000 10 88 90 10744212 10.1177/112067210001000114

492 Siddens J Fishman J Jackson I Primary orbital angiosarcoma: a case report Ophthalmic Plast Reconstr Surg 1999 15 454 459 10588260 10.1097/00002341-199911000-00019

493 Lyon D Tang T Kidder T Epithelioid Hemangioendothelioma of the Orbital Bones Ophtalmology 1992 99 1773 1778 10.1016/s0161-6420(92)31723-3 1480392

494 ISSVA. ISSVA Classification of Vascular Anomalies ©2018. In: International Society for the Study of Vascular Anomalies

495 Wildgruber M Sadick M Muller-Wille R Vascular tumors in infants and adolescents Insights Imaging 2019 10 30 30868300 10.1186/s13244-019-0718-6 PMC6419671

496 Gilbert P Dubois J Giroux F New Treatment Approaches to Arteriovenous Malformations Semin Intervent Radiol 2017 34 258 271 28955115 10.1055/s-0037-1604299 PMC5615391

497 Schobinger R A Fontaine R Periphere Angiodysplasien