Educational Case: Atypical presentation of primary hyperparathyroidism with brown tumor.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see https://doi.org/10.1016/j.acpath.2023.100086 . 1

Primary objective

Objective EN7.1: Hyperparathyroidism. Describe the causes and clinicopathologic features of primary, secondary, and tertiary hyperparathyroidism including potential effects on bone.

Competency 2: Organ System Pathology; Topic: Endocrine (EN); Learning Goal 7: Hyperparathyroidism and Hypoparathyroidism.

Secondary objective

Objective CHEM1.3: Endocrine Disorders. Discuss the efficient use of laboratory tests to identify and manage patients with endocrine disorders, to define the pathogenesis of these disorders, and to help distinguish among diseases in the differential diagnosis.

Competency 3: Diagnostic Medicine and Therapeutic Pathology; Topic: Chemistry (CHEM); Learning Goal 1: Pathogenesis, Diagnosis, and Treatment of Common Disorders.

Patient presentation

A 54-year-old woman presents to the clinic with lower left arm pain. The pain began four months ago and has progressed to a constant, moderately severe, aching pain that is worse at night and mildly improves with ibuprofen. During this time, she also describes having mild fatigue. She has no significant past medical history, recent trauma or infectious disease. Her last visit with a healthcare provider was 10 years ago. Besides ibuprofen and over the counter antacids, she does not take any other medications or supplements. The patient has a family history of renal cell carcinoma in her mother and hypertension in her father. Her social history is noncontributory as she has never smoked, enjoys one glass of red wine weekly, and does not use marijuana or other recreational drugs.

Diagnostic findings, Part 1

The patient’s vital signs are 98.2 °F, blood pressure at 140/94 mmHg, heart rate at 78 beats per minutes, and respiratory rate at 14 breaths per minute with 98 % oxygen saturation on room air. Physical examination demonstrates distal radius tenderness of the left arm with a lack of overlying erythema, discoloration, swelling, or warmth. There is normal range of motion of the left wrist, elbow, and upper extremity. Head, ears, eyes, and neck including thyroid and throat are unremarkable. There is no thyromegaly or lymphadenopathy. Cardiopulmonary exam has a normal S1, S2 with no S3, S4, rubs, gallops, or murmurs. Her lungs are clear to auscultation bilaterally. The abdomen has positive bowel sounds and is soft and non-tender to palpation with no masses or organomegaly.

Questions/discussion points, Part 1

What is the differential diagnosis and next tests to order?

The differential diagnosis for chronic forearm pain and fatigue is broad. Traumatic causes include remote injury to the forearm and osteoporotic fracture. Infectious causes include chronic osteomyelitis. Inflammatory causes are tendonitis, enthesitis, arthritis of the wrist joint, and polymyalgia rheumatica. Vascular causes include arterial entrapment and vascular occlusion. Neurologic causes such as nerve entrapment in carpal tunnel syndrome or cervical radiculopathy can also lead to forearm pain. Metabolic etiologies like hypothyroidism, hyperparathyroidism, hypophosphatemia, acidosis, and renal failure may result in bone pain. Neoplastic causes include multiple myeloma, primary and metastatic bone tumors. 2 , 3 , 4

To narrow the differential, a complete blood count (CBC) is ordered to look for hematologic abnormalities, infection, inflammation, and malignancy. A basic metabolic panel (BMP) is ordered to rule in or out any metabolic or electrolyte disturbances. A thyroid-stimulating hormone (TSH) is ordered to test for hypothyroidism. An x-ray of the left forearm is ordered to see whether there is a bone or soft tissue abnormality.

Diagnostic findings, Part 2

Findings from the BMP, CBC, and TSH lab tests are listed in Table 1 . The x-ray of the forearm is shown in Fig. 1 . Table 1 Initial laboratory values. Table 1 Basic metabolic panel (BMP) Result Reference Range Glucose, serum (mg/dL) 83 70–110 Calcium, serum (mg/dL) 13.2 8.4–10.2 Sodium, serum (mEq/L) 140 135–147 Potassium, serum (mEq/L) 3.8 3.5–5.0 Bicarbonate, serum (mEq/L) 27 22–28 Chloride, serum (mEq/L) 99 95–105 Blood urea nitrogen (mEq/L) 12 7–18 Creatinine, serum (mEq/L) 1.0 0.6–1.2 Complete blood count (CBC) RBC (red blood cells) (million/mm 3 ) 4.2 3.5–5.5 Hemoglobin (g/dL) 10.8 12.0–16.0 Hematocrit (%) 33 36–46 MCV (mean corpuscular volume) (μm 3 ) 82 80–100 RDW (red blood cell distribution width) (%) 15.1 11.7–15.4 Platelet count (/mm 3 ) 260,000 150,000–400,000 WBC (white blood cells) (/mm 3 ) 7000 4500–11,000 Neutrophils (%) 58 40–60 Lymphocytes (%) 31 20–40 Monocytes (%) 7 2–8 Eosinophils (%) 3 1–4 Basophils (%) 1 0.5–1 Additional laboratory testing TSH (uIU/mL) 3.5 0.27–4.2 MCV: mean corpuscular volume. RBC: red blood cells. RDW: red blood cell distribution width. TSH: thyroid-stimulating hormone. WBC: white blood cells. Fig. 1 A radiograph of the left radius. Courtesy of Al Salam H, Case study, Radiopaedia.org . Accessed on 21 Nov 2024. https://doi.org/10.53347/rID-12460 . This figure is republished in its original form in accordance with CC BY-SA 4.0. Fig. 1

Radiographic findings: Well-defined radiolucent bone lesion located centrally within the diaphysis with benign-appearing periosteal reaction, cortical expansion and thinning, and no cortical destruction.

Questions/discussion points, Part 2

How do the findings from the initial laboratory and radiological testing narrow the differential?

The CBC and BMP show elevated calcium and normocytic anemia with no other diagnostic abnormalities, while the x-ray shows a radiolucent bone lesion. Together, these findings increase the likelihood of multiple myeloma, metastasis, primary bone malignancy, and hyperparathyroidism. The normal BMP findings help rule out acidosis, severe kidney dysfunction, and other causes of fatigue such as diabetes, hyponatremia, and other electrolyte disturbances. The normal white blood cell and platelet count in the CBC decrease the likelihood of acute infectious or inflammatory processes and hematologic malignancies. The x-ray findings make traumatic fracture and soft tissue etiologies less likely while pointing toward a disease process that directly involves the bone. Together, the laboratory and radiologic testings significantly narrow the differential diagnosis for this patient.

What additional tests are indicated to confirm the patient’s hypercalcemia?

To confirm the patient’s hypercalcemia, free, ionized calcium, or total calcium corrected for albumin should be ordered. The value of calcium measured in the BMP is total calcium which measures the three forms of calcium present in the serum—50 % calcium bound to protein, 10 % calcium complexed to anions, and 40 % free ionized calcium. 5 However, only free ionized calcium is biologically active and causes the physiological effects of hypocalcemia and hypercalcemia. 6 So, to confirm that the patient has clinically significant hypercalcemia and not only an elevation in bound or complexed calcium, one should order confirmatory tests. Free ionized calcium is preferred in patients with kidney disease, acid base disorders, and anion disturbances because the formula correcting total calcium for albumin may be inaccurate in these instances. 7 Since the serum calcium level is primarily regulated by parathyroid hormone (PTH), a PTH should also be ordered.

How is the level of calcium in the blood regulated in normal physiology?

The concentration of calcium in the blood is primarily regulated by parathyroid PTH and vitamin D. When there is a decrease in calcium in the blood, the calcium sensing receptor (CaSR) on chief cells in the parathyroid gland senses this decrease and responds by increasing the secretion of active PTH. 7 In the skeletal system, the net effect of PTH is bone resorption which increases the amount of calcium and phosphate in the blood. In bone, PTH stimulates osteoblasts to express RANKL which interacts with RANK on osteoclasts causing increased osteoclast maturation and thus bone resorption. 8 Parathyroid hormone also acts on osteoblasts stimulating their proliferation and decreased apoptosis which increases bone formation. 9

Parathyroid hormone also has a direct and indirect effect on calcium uptake from the renal and gastrointestinal (GI) systems, respectively. In the renal system, PTH stimulates calcium reabsorption in the thick ascending limb and the distal convoluted tubule of the nephron. Parathyroid hormone also inhibits the reabsorption of phosphate in the proximal convoluted tubule (PCT), therefore increasing the excretion of phosphate. Also, in the PCT, both hypocalcemia and PTH activate 1α-hydroxylase to convert the inactive form of vitamin D to the active form of vitamin D (calcitriol). 8 , 9 Calcitriol acts on intestinal epithelial cells of the GI tract to increase absorption of calcium and phosphate. Additionally, calcitriol increases the reabsorption of calcium and phosphate in the kidney and resorption of these minerals from bone. 7 , 8 , 9 In contrast, the effects of PTH and vitamin D are suppressed in response to high blood calcium, and the hormone calcitonin inhibits bone resorption and stimulates calcium excretion at the kidney. 9

What is the differential diagnosis of the patient’s hypercalcemia given her presentation and findings?

The differential diagnosis of hypercalcemia can be organized into categories based on pathophysiology—PTH-mediated, malignancy, vitamin D mediated, drug-related, and miscellaneous other causes. Of these causes, 90 % of cases of hypercalcemia are the result of primary hyperparathyroidism or malignancy. 10 In primary hyperparathyroidism, PTH is inappropriately secreted from the parathyroid glands and stimulates an increase in calcium above the upper limit of normal. The most common presentation of primary hyperparathyroidism in the United States is an asymptomatic patient who has mild hypercalcemia discovered incidentally on routine lab work. 7 , 11 , 12 However, rarely, patients can present with symptoms, most commonly unexplained bone pain, fragility fractures, nephrolithiasis or other signs of renal dysfunction. 11 , 12 Lytic bone lesions occur only very rarely in patients with primary hypercalcemia in the United States, who usually show generalized osteopenia and subperiosteal bone resorption. In contrast, hypercalcemia of malignancy tends to occur in patients with previously known malignancy who develop moderate-to-severe hypercalcemia and are more likely to initially present with hypercalcemic symptoms. 7

There are two forms of hypercalcemia of malignancy. In the first, humoral hypercalcemia of malignancy, solid tumors secrete parathyroid-related peptide (PTHrP) that is similar in structure to PTH such that it stimulates the PTH receptors in the body to cause hypercalcemia. 7 Common types of these tumors include squamous cell carcinoma of the lung, head or neck, urothelial carcinomas, breast cancers, and renal cell carcinoma. 11 , 12 , 13 Given this patient’s family history, anemia, and bone pain, renal cell carcinoma with potential metastasis to bone is in the differential diagnosis. However, the patient’s lack of hematuria, flank plain, and palpable abdominal mass make this option less likely. 11 , 12 The second form of malignancy-associated hypercalcemia is local osteolysis of the bone caused by hematologic malignancy or metastasis. The most common tumors that cause this are breast cancer and multiple myeloma. 13 Since the patient has anemia and bone tenderness, multiple myeloma is in the differential (using the mnemonic CRAB which stands for calcium elevated, renal failure, anemia, and bone lytic lesions), but the patient does not have signs of renal insufficiency. 11 Osteolytic bone lesions that are frequently multiple are commonly seen in hypercalcemia of malignancy, particularly when associated with myeloma, breast carcinoma, or renal cell carcinoma.

There are multiple drug-induced causes of hypercalcemia including calcium carbonate antacids, thiazide diuretics, and lithium. If the patient took calcium carbonate antacids in excess, she could have developed milk–alkali syndrome. This syndrome consists of hypercalcemia, metabolic alkalosis, and acute kidney injury. Yet, given the patient’s normal bicarbonate and creatinine, this is a less probable cause. 11 Thiazide diuretics can cause hypercalcemia by increasing the reabsorption of calcium by the kidney. 7 Lithium acts on the parathyroid gland to increase the level of calcium needed to prevent the release of PTH, thus causing hypercalcemia while also generally affecting thyroid gland function. 14 Vitamin D–mediated causes include vitamin D intoxication, granulomatous disease, and Hodgkin’s lymphoma, which all increase the amount of vitamin D causing hypercalcemia. 7 , 10 , 11 , 12 In order to narrow the differential, the PTH levels should be measured. If the PTH level is low, then PTHrP, alkaline phosphatase, serum protein, or vitamin D should be tested depending on the patient’s symptoms. 10 , 11

Diagnostic findings, Part 3

The patient was asked to stop taking calcium carbonate antacids. Serum intact PTH, ionized calcium, and inorganic phosphorous were ordered for two weeks later. The result was increased PTH of 185 pg/mL (normal: 15–65 pg/mL), increased serum ionized calcium of 8.0 mg/dL (4.5–5.6 mg/dL), and decreased serum phosphorous of 1.9 mg/dL (3.5–4.9 mg/dL). After the lab tests showed an elevated PTH, 24-h urine calcium and urinary calcium/creatinine clearance ratio was ordered, and the result was 440 mg/24 hr (normal 100–300 mg/24 hr) and 0.03, respectively.

Questions/discussion points, Part 3

Interpret the laboratory investigations and correlate with the differential diagnosis?

The elevated PTH and ionized calcium suggest that the patient has a PTH-mediated cause of hypercalcemia. In this setting, normal to elevated PTH would be considered abnormal since hypercalcemia should cause suppression of PTH to less than <20 pg/mL, especially in the case of malignancy. 7 , 15 This narrows the differential to primary hyperparathyroidism and familial hypocalciuric hypercalcemia (FHH). 10 , 15 In FHH, there is a loss of function of the CaSR in the parathyroid and renal tissue. This results in elevated PTH in 20 % of patients, moderate hypercalcemia, and low calcium excretion in the urine. 16 In FHH, the urinary calcium is < 200 mg/day and urinary calcium/creatinine clearance ratio is < 0.01, which makes FHH unlikely in this patient but important to rule out as it is not treated surgically. 10 , 15 Therefore, the final diagnosis based on laboratory findings is primary hyperparathyroidism. To confirm the diagnosis, these lab results need to be present two times at more than 2 weeks apart. Other processes that can cause elevated PTH and calcium include tertiary hyperparathyroidism, lithium, thiazide, and very rarely ectopic PTH production by tumors. 17

What are the differences among primary, secondary, and tertiary hyperparathyroidism? Summarized in Table 2

Primary hyperparathyroidism is an abnormal increase in PTH secreted from one or more of the parathyroid glands in absence of external physiologic changes. This causes high serum calcium, mild decrease in serum phosphate, and increased urinary calcium. The most common cause of primary hyperparathyroidism is a single-gland adenoma (75–85 %), multigland disease (5–-10%), and rarely parathyroid carcinoma (1%). 18 , 19 , 20 , 21 Table 2 Pathophysiology and laboratory findings in primary, secondary, and tertiary hyperparathyroidism. 18 , 19 Table 2 Primary hyperparathyroidism Secondary hyperparathyroidism Tertiary hyperparathyroidism Pathophysiology - Abnormal intrinsic overactivity of a parathyroid tissue causes increased production and release of PTH - Extrinsic hypocalcemia and/or hyperphosphatemia causes a physiologic overproduction of PTH by the parathyroid gland in response - Prolonged renal failure results in autonomous overproduction of PTH by the parathyroid gland leading to hypercalcemia Etiology - Parathyroid adenoma - Parathyroid hyperplasia - Parathyroid carcinoma - Vitamin D deficiency - Intestinal calcium malabsorption - Chronic kidney disease - End-stage renal disease Lab values Calcium (serum) High Low-normal or low High Phosphorous (serum) Low Variable High 25-hydroxyvitamin D (serum) Normal Normal or low Normal 1,25-dihydroxyvitamin D (serum) High-normal or high Variable Low Alkaline phosphatase (serum) High High High PTH (serum) High High Very high 24 hour calcium (urinary) Normal or high Usually low Low PTH: parathyroid hormone.

In contrast, secondary hyperparathyroidism is increased secretion of PTH from the parathyroid glands in response to persistently low serum calcium. While many diseases can cause this, the most common are chronic kidney disease and vitamin D deficiency. 18 , 20 In chronic kidney disease (CKD), there is progressive decrease in renal function which starts with the decrease of 1,25-dihydroxyvitamin D due to the loss of renal 1α-hydroxylase enzyme. As CKD progresses, hyperphosphatemia develops which stimulates increased PTH. The combination of decreased vitamin D–mediated calcium absorption and increased binding of serum calcium to phosphate, eventually cause hypocalcemia. 18 , 20

Tertiary hyperparathyroidism occurs when there is prolonged secondary hyperparathyroidism which leads to hyperplasia of the parathyroid gland and eventually autonomous PTH secretion that leads to elevated serum calcium. 18 , 20 , 21 While CKD is the most common cause, it also can develop with X-linked and adult onset hypophosphatemic rickets and oncogenic osteomalacia. 21

How does primary hyperparathyroidism in the United States typically present today compared to fifty years ago?

Before the 1970s, primary hyperparathyroidism in the United States typically presented as a symptomatic disease. However, in the mid-1970s, screening with chemistry panels started to become routine and in the late 1990s, earlier screening guidelines were implemented for osteoporosis. As a result, the most common presentation of primary hyperparathyroidism today is an asymptomatic patient with elevated calcium found on routine blood work. 22 Asymptomatic patients are further categorized phenotypically with the presence or absence of end target organ damage upon further testing. 23 Today, the patients in the U.S. who present symptomatically are often pediatric patients since routine calcium screening starts in adulthood, patients with parathyroid carcinoma since it causes a rapid and severe increase in serum calcium, and those with limited access to healthcare. 24 , 25

The classic signs and symptoms of primary hyperparathyroidism are a result of both the elevated PTH and hypercalcemia. The renal and skeletal involvements are causally linked to primary hyperparathyroidism. The renal features of this disease are decreased renal function, polyuria, nephrolithiasis, and nephrocalcinosis. The skeletal features include bone pain, osteitis fibrosa cystica, osteoporosis, fractures, and pseudogout. 23 In contrast, the cardiovascular, gastrointestinal, neurobehavioral, and neuromuscular involvements in this disease are associated but not causally linked with primary hyperparathyroidism. The cardiovascular features include atherosclerosis, cardiac arrhythmias, hypertension, vascular stiffness, left ventricular hypertrophy, and increased cardiovascular risk factors such as insulin resistance and elevated cholesterol. Vascular stiffness is diagnosed with increased pulse wave velocity along the aortic tree and is used with traditional blood pressure measurements to estimate cardiac risk. 26 The gastrointestinal features are anorexia, nausea, vomiting, constipation, cholelithiasis, pancreatitis, and peptic ulcer disease. The neurobehavioral features are depression, anxiety, reduced quality of life and in severe cases, altered mental status, and impaired cognition. Finally, the neuromuscular features of primary hyperparathyroidism are myopathy and impaired neuromuscular function. 23

Diagnostic findings, Part 4

A radionucleotide bone scan is performed that showed increased uptake in the left radius and no other evidence of bone disease. 26 A bone scan was completed instead of a skeletal survey. Since solitary isolated lytic bone lesions are so rare in primary hyperparathyroidism, a bone biopsy is done to confirm the diagnosis ( Fig. 2 , Fig. 3 ). 27 Fig. 2 Bone. Early bone changes of hyperparathyroidism. High-power view showing burrowing of osteoclasts (arrows) into the bone matrix giving the lesion a tunneled (or “moth-eaten”) appearance associated with patchy fibrosis (arrowheads). (H&E). Fig. 2 Fig. 3 A, B. Bone. A. Osteolytic lesion filled by giant cells (arrowheads), macrophages, plump fibroblasts, and hemorrhage (arrows) (called “brown tumors of hyperparathyroidism” on gross examination) is seen in this patient's biopsy. (H&E). B. Higher magnification showing multiple osteoclasts in the osteolytic lesion with hemorrhage and reactive fibrous tissue, a feature of severe hyperparathyroidism. (H&E). Fig. 3

Questions/discussion points, Part 4

Describe the microscopic bone changes associated with primary hyperparathyroidism as seen in Fig. 2 , Fig. 3

The pathologic findings are a reflection of PTH-mediated bone resorption and represent a spectrum of severity from the earliest changes to osteitis fibrosa cystica. The earliest changes in primary hyperparathyroidism are paratrabecular fibrovascular proliferation in areas previously occupied by bone marrow. Additionally, there is a gradual increase in the number and activity of morphologically normal osteoclasts. 28 Over time, this increase in osteoclast activity causes the edges of the bony trabecula to become scalloped from merging of Howship lacunae–the depressions in bone created when osteoclasts are in the process of resorbing. 28 , 29 Osteoclasts also expand the system of Haversian canals in bone and create tunneling resorption starting in the subperiosteal and endosteal surfaces and burrowing into the cortex. 28 , 30 , 31 Normally, the Haversian canal is formed by osteoclasts boring a large diameter cylinder through bone with osteoblasts following behind and adding lamellae to narrow the diameter. 29 However, in primary hyperparathyroidism, osteoclasts predominate and act to resorb the bone in these tunnels from the inside out. When this is produced in a cancellous bone, it forms radially expanding tunnels through the center of the trabecula resulting in dissecting osteitis characteristic of primary hyperparathyroidism ( Fig. 2 ). 28 , 30 , 32

Following these changes, the fibrovascular stroma further proliferates to completely surround the remaining trabecular bone segments. 28 , 31 The overall decrease in bone mass during this process results in microfractures and hemorrhage. 30 , 31 In an attempt to repair the tissue, brown tumors form. They consist of clusters of osteoclast-like giant cells in areas of hemorrhage, hypervascular fibrous tissue composed of mostly reactive appearing spindle cells and hemosiderin-laden macrophages, and extravasated red blood cells ( Fig. 3 ). 28 , 29 , 32 These clusters are divided from each other by septae formed from reactive fibrous tissue and trabecula of reactive woven bone. 32 If hyperparathyroidism persists, the lesion can undergo cystic degeneration which causes osteitis fibrosa cystica. 28 , 31 On gross examination, these tumors are well-circumscribed, brown, hemorrhagic lesions with a spongy internal appearance from its clustered architecture and cystic degeneration. Peripherally, the cortex is thinned and expanded and there is a possible shell of reactive bone. 32 These lesions are called brown tumors because they are brown grossly due to hemosiderin deposition from old hemorrhage. 28 , 31

Based on the histology, what other conditions are considered in the differential diagnosis of this patient’s bone lesion ( Fig. 3 )?

The histologic differential diagnosis includes many bone lesions that contain numerous osteoclasts or osteoclast-like giant cells and is nearly indistinguishable from some lesions including giant cell reparative granulomas and solid aneurysmal bone cysts. For this reason, correlation with clinical, radiologic, and laboratory findings is crucial in determining correct diagnosis, even after tissue sampling. The most important clinical features are age and skeletal maturity as many lesions in the histologic differential occur only or almost always in children, adolescents or young adults and would not be seen in a patient this age such as the following: chondroblastoma, aneurysmal bone cyst, non-ossifying fibroma, Langerhans cell histiocytosis, fibrous dysplasia, and telangiectatic osteosarcoma. 32 , 33

Despite these clinical and radiologic considerations, the lesions that are considered on the histologic differential diagnosis are giant cell tumor of bone, aneurysmal bone cyst, giant cell reparative granuloma, and metastatic carcinoma. 28 , 32 Giant cell tumors (GCTs) of bone differ from brown tumors in cellular distribution, nuclear characteristics, and relationship between giant cells and mononuclear cells. In GCTs, giant cells are evenly distributed among mononuclear cells in contrast to brown tumors where they are clustered. 28 , 32 Additionally, in GCTs, the mononuclear cells in the stroma are neoplastic with high mitotic rate, plump, and have indistinct cell borders in contrast to the non-neoplastic spindled fibroblasts, which comprise the stroma of brown tumors. This causes the giant cells to be less distinguishable from mononuclear cells in GCTs compared to brown tumors. 28 , 32 Finally, in GCTs, many osteoclast-like giant cells are larger than normal with more than 20 nuclei, whereas they are morphologically normal in brown tumors. 28 , 34

In solid aneurysmal bone cysts (ABCs), small samples are similar to brown tumors; however, ABCs do not have the lobular pattern of clustered giant cells. 32 In addition, the solid variant of ABCs is very rare and most ABCs show areas of classic cystic change unlike brown tumors. 34 Since brown tumors are a repair reaction, they are also very similar histologically to giant cell reparative granulomas. However, these tumors are most common in the craniofacial skeleton and do not have other bone manifestations of hyperparathyroidism. 28 , 32 Lastly, metastatic carcinoma is on the differential especially when there are multiple lytic lesions on radiologic imaging. Metastatic carcinoma is distinct from brown tumors on biopsy because they contain neoplastic cells consistent with carcinoma or myeloma, neither of which have large numbers of giant cells.

Describe the classic radiologic bone findings of primary hyperparathyroidism

The classic radiologic bone findings of primary hyperparathyroidism are subperiosteal, subchondral and subligamentous bone resorption, focal lytic lesions, and osteopenia. Subperiosteal bone resorption on plain radiograph is most commonly found at the radial aspects of second and third middle phalanges. It also classically occurs along the medial segment of the proximal tibia, humerus and femur, and at the lamina dura of the teeth and spine. 35 , 36 Acroosteolysis—the subperiosteal resorption of the distal phalanges of hands and feet—is another classic finding and radiolucent bands that cross the distal phalanges. 35 , 36 , 37 In contrast, subchondral resorption is present in areas subject to shearing stresses that develop resorptive changes at sites of attachment such as the acromioclavicular joint, sternoclavicular joints, pubic symphysis, and sacroiliac joints. 28 , 35 Similarly, subligamentous and subtendinous resorption can develop at the femoral trochanter, ischial and humeral tuberosities, elbow, and inferior aspect of distal clavicle. 35 Focal lytic lesions such as brown tumors can occur in almost any part of the axial or appendicular skeleton—especially the long bones, pelvis, mandibles, ribs, and vertebrae. In the skull, many focal lytic lesions can occur from the resorption of trabecular bone and are interspersed with normal bone and sclerotic regions of reactive bone, giving the skull a classic “salt and pepper” appearance on plain radiograph. 35 , 36

Although historically these findings have been classic for primary hyperparathyroidism, the most common skeletal finding on imaging today is osteopenia. 36 In the work up for skeletal complications, asymptomatic patients are recommended to have a dual-energy x-ray absorptiometry (DEXA) scan at the lumbar spine, hip, and distal 1/3 radius to look for decreased bone mineral density. 17 In modern times, between 39 and 63 % of patients with primary hyperparathyroidism have been shown in some studies to have bone mineral densities consistent with osteoporosis. 13 , 36 Interestingly, in contrast to postmenopausal osteoporosis, DEXA scans in patients with primary hyperparathyroidism and concomitant osteoporosis show preferential bone resorption at a cortical bone rather than a cancellous bone. So, the distal radius often shows more bone resorption than the lumbar spine in patients with hyperparathyroidism—the opposite of what happens in postmenopausal osteoporosis. 38

Diagnostic findings, Part 5

Scans of the neck were acquired immediately after IV injection of technetium 99 m sestamibi ( Fig. 4 ). Additionally, an ultrasound of the thyroid gland showed a 4.5 × 3.5 × 2.0 cm hypoechoic nodule along the posterior inferior aspect of the left lobe of the thyroid gland, consistent with the region of abnormal uptake on parathyroid scan. Fig. 4 Technetium 99m sestamibi scan. The scan is performed to localize the parathyroid neoplasm prior to surgery. The scan demonstrates increased uptake in the region of the left inferior parathyroid gland (black arrow). Used with permission of Elsevier, Figure 24.24 Maitra A. The Endocrine System. In:Kumar V, Abbas AK, Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease 10th ed. Elsevier; 2021; 1093, permission conveyed through Copyright Clearance Center, Inc. Fig. 4

Questions/discussion points, Part 5

Describe why the sestamibi scan was performed, the procedure, and findings of the scan ( Fig. 4 )

The sestamibi scan is used to localize the tumor for surgical planning, neither for the diagnosis of primary hyperparathyroidism nor for the decision to perform surgery. Localization helps the surgeon determine whether to perform a minimally invasive parathyroidectomy for a single hypersecreting gland versus a bilateral exploration when there is a multigland disease. 39 Technetium 99 m sestamibi is a radioactive isotope that is taken up by the parathyroid tissue and can be used to identify hyperfunctioning parathyroid tissue and ectopic parathyroid tissue on nuclear imaging. In Fig. 4 , there is an area of increased uptake in the region of the left inferior parathyroid gland suggesting a solitary adenoma.

What is the recommended treatment of the patient’s primary hyperparathyroidism and bone lesion?

The definitive treatment for primary hyperparathyroidism is surgical resection of the parathyroid tumor. Parathyroidectomy is recommended for all symptomatic patients who have no contraindications to surgery. 17 , 39 Since this patient has overt symptoms of primary hyperparathyroidism with a brown tumor and fatigue and is otherwise healthy, she is recommended to have this procedure. If she declines or is not able to have surgery, her primary hyperparathyroidism could be managed medically with the calcimimetic cinacalcet to lower her serum calcium and PTH levels and with bisphosphates or denosumab to increase her bone mineral density. Additionally, her calcium, vitamin D, PTH, renal function, and bone mineral density should be monitored regularly. 17

For asymptomatic patients, surgery is an option for all patients and is recommended in patients less than 50 years old. The other indications are based on subclinical biochemical, skeletal, and renal manifestations of the disease. Surgery is recommended for patients with serum calcium more than 1 mg/dL above the upper limit of normal. It is also recommended if a patient has a vertebral fracture by x-ray, computed tomography, magnetic resonance imaging, or vertebral fracture assessment, or has a bone mineral density T-score less than or equal to −2.5 at any location. 17 , 39 A T-score value in this context refers to the standard deviation of the patient’s bone mineral density from mean in young adults. Osteoporosis is diagnosed with a bone mineral density T-score of less than or equal to −2.5, while osteopenia is between −1 and −2.5. 40 Surgery is also recommended if patients have any of the following renal manifestations—creatinine clearance or estimated glomerular filtration rate <60 mL/min, nephrocalcinosis or nephrolithiasis on imaging, or hypercalciuria above 250 mg/day in women or above 300 mg/day in men. 17 , 39

The treatment of the patient’s brown tumor is parathryoidectomy. Once the patient’s primary hyperparathyroidism resolves, brown tumors become sclerotic and then spontaneously regress. 41 Further surgical management of the brown tumor should be considered if the lesion does not regress after parathyroidectomy or there is extensive expansion of the tumor into adjacent structures. 36

Diagnostic findings, Part 6

The patient is subsequently consented for surgery. The risks and benefits are discussed. The risks include infection, hemorrhage, the risk of re-surgery, and the risk of damage to surrounding structures. In the event of acute bleed intraoperatively, the patient wishes to receive blood. The consent was written clearly in black pen, time-stamped, and uploaded to the patient’s electronic medical record prior to surgery.

The surgeon resects the left inferior parathyroid gland ( Fig. 5 ). Intraoperative PTH levels are monitored and drop to within normal range 15 minutes after the parathyroid tumor was removed. No intraoperative complications were observed and the estimated blood loss was 50 mL. Postoperative serum calcium levels were within normal limits 3 days, 4 weeks, and 6 months after surgery, indicating surgical cure. Fig. 5 The cut surface of a parathyroid adenoma. This 4.5 × 3.5 × 2.0 cm parathyroid tumor was resected from the neck of the patient. The red-brown parathyroid gland is enlarged with focal hemorrhage on gross examination. Fig. 5 Fig. 6 Parathyroid gland. Microscopically, the tumor (asterisk) is well circumscribed and encapsulated. A rim of residual, compressed normal parathyroid tissue containing fat cells can be identified adjacent to the tumor. (H&E, Original magnification 2x). Fig. 6 Fig. 7 Parathyroid gland. The tumor is composed of a uniform population of chief cells without increased mitotic activity, hemorrhage, or necrosis. (H&E, Original magnification 20x). Fig. 7

Questions/discussion points, Part 6

Comparing the gross and microscopic features of this tumor ( Fig. 5 , Fig. 6 , Fig. 7 ) to normal parathyroid tissue, what type of tumor does the patient have?

On gross pathology, normal parathyroid glands are approximately 4–6 mm × 2–4 mm, weigh 20–40 mg, and are ovoid, smooth and pale-tan to yellow in appearance. In contrast, parathyroid adenomas most commonly appear grossly as a reddish-brown mass in an enlarged, single gland that is encapsulated with occasional hemorrhagic or cystic changes and possible borders of a normal parathyroid tissue ( Fig. 5 ). 42 , 43

Microscopically, normal parathyroid glands are composed of two main epithelial cell types—chief cells and oxyphil cells. Chief cells secrete PTH and appear as small, polygonal cells with a centrally located nucleus, mildly acidophilic cytoplasm, and well-defined cytoplasmic membranes. Oxyphil cells are larger, round cells, with more acidophilic cytoplasm and many mitochondria. In adult parathyroid glands, adipose tissue makes up 10–30 % the parathyroid glands. There is also a thin, fibrous capsule that surrounds each parathyroid gland and has septae that divide the internal structure into lobules. 44 , 45

In parathyroid adenomas, there is a benign proliferation of chief, oncocytic (oxyphil), transitional, clear cells, or a mixture of cells in one parathyroid gland or ectopic parathyroid tissue. 42 , 46 They are well circumscribed by a pseudocapsule and have a rim of a compressed, atrophic, normal parathyroid tissue that is sometimes separated from the rest of the gland by the capsule ( Fig. 6 ). 42 , 43 , 46 In this case, the resected neoplasm is hypercellular with a proliferation of chief cells and lack of stroma and fat cells ( Fig. 7 ), which represents the most common type of parathyroid adenoma. In parathyroid adenomas, the cells can be arranged in many distributions including solid, follicular, rosette, acinar, nests, and cord pattern. 42 , 46 In distinguishing parathyroid adenomas from carcinoma, adenomas only have a few cells with nuclear atypia, multiple nuclei, or mitotic figures (<5 per 10 HPF) and have no invasive growth features. 42 , 46 Overall, based on the gross and microscopic findings, this patient has a benign parathyroid adenoma.

What are the primary parathyroid tumors in the differential diagnosis for this lesion?

The differential diagnosis for the parathyroid tumor includes parathyroid hyperplasia, atypical parathyroid adenoma and parathyroid carcinoma. Parathyroid hyperplasia is the proliferation of parenchymal parathyroid cells in more than one gland without atypical features. 47 Primary hyperplasia arises intrinsically within the parathyroid gland, is very rare, and is still being characterized. In the past, it was thought that hereditary endocrine syndromes gave rise to primary hyperplasia; however, it is now thought that they instead give rise to many microadenomas in the setting of multiple parathyroid glands, not hyperplasia. 47 Secondary hyperplasia is the proliferation of cells due to chronic external stimulus—most commonly hypocalcemia, hyperphosphatemia, and low vitamin D due to chronic kidney disease. If prolonged, this causes autonomous production of PTH from tissue becoming neoplastic via the hyperplasia-neoplasia pathway and represents tertiary hyperparathyroidism. 47 Microscopically, parathyroid hyperplasia is almost identical to parathyroid adenomas and clinical–pathologic correlation must be evaluated to make either of these diagnoses. 46 , 47 Atypical adenomas and parathyroid carcinoma both show atypical features concerning for malignancy; however, parathyroid carcinoma involves growth into adjacent structures. 48 , 49 , 50 , 51

What hereditary syndromes are associated with primary hyperparathyroidism?

The hereditary syndromes associated with primary hyperparathyroidism are multiple endocrine neoplasia type 1 (MEN1), MEN2, MEN4, and hyperparathyroidism jaw tumor syndrome (HPT-JT). While all of these syndromes are autosomal dominant, they differ in their impacted genes, associated tumors, and effect on the parathyroid gland. MEN1 is caused by a loss-of-function mutation in the MEN1 gene, which encodes for the tumor suppressor protein menin. This syndrome is characterized by the development of multiple endocrine tumors, classically parathyroid adenomas or multigland disease, anterior pituitary adenomas, and gastroenteropancreatic neuroendocrine tumors. 22 , 52 , 53 , 54 , 55 The parathyroid tumors of MEN1 are most commonly multiglandular parathyroid disease in a nodular distribution with multiple parathyroid microadenomas that can develop in different parathyroid glands at different times. 52 , 55 , 56 , 57 Similarly, MEN4 presents with the same spectrum of endocrine disorders and is almost identical histologically; however, it has decreased disease severity, later-onset, and a slightly higher rate of single-gland parathyroid disease. 52 , 56 MEN4 is caused by a loss-of-function mutation in the CDKN1B gene that encodes for p27. 52 , 53

In contrast, MEN2 rarely presents with primary hyperparathyroidism, rather it presents with different endocrine tumors. It is characterized by the development of medullary thyroid carcinoma, pheochromocytoma, and primary hyperparathyroidism. Even one of these diseases should alert the physician to discuss family history with the patient to determine if further testing is necessary. Medullary thyroid cancer is caused by an activating mutation in the RET gene that produces the RET tyrosine kinase receptor, which acts aberrantly in this disease process. 22 , 52 , 53 The effect on the parathyroid gland is that it causes multiglandular disease with milder and smaller proliferations of cells and with an increased prevalence of single-gland disease than MEN1. 55 , 56

Hyperparathyroidism jaw tumor syndrome is unique in that it preferentially causes single-gland tumors, benign and atypical adenomas that can develop asynchronously instead of multigland disease. Hyperparathyroidism jaw tumor syndrome is caused by an inactivating mutation in the CDC73 gene which encodes the protein parafibromin and is a part of the polymerase-associated factor 1 transcriptional-regulatory protein complex. 52 The syndrome is characterized by primary hyperparathyroidism and ossifying fibromas of the maxilla and mandible. However, the second most common finding besides primary hyperparathyroidism is uterine tumors with some studies having shown that more than 50 % of women with the syndrome are affected—often in their 20s to 40s. 58 , 59 Approximately 25–30 % of patients also develop renal tumors. 52 Primary hyperparathyroidism in HPT-JT is caused by benign adenomas, atypical adenomas, and parathyroid carcinoma. Somatic CDC73 mutations are seen in 40–75 % of sporadic parathyroid carcinomas and thus patients with HPT-JT have a much higher chance of developing parathyroid carcinoma. 52 The parathyroid tumors of patients with CDC73 mutations have distinguishing histologic characteristics of sheet-like growth pattern, enlarged nuclei with mostly normal N:C ratios, eosinophilic cytoplasm with perinuclear clearing, microcystic change, and loss of parafibromin on immunohistochemistry. 57 , 60

What are the potential complications following parathyroidectomy?

Postoperative complications following parathyroidectomy include hyperparathyroidism or hypoparathyroidism, hypocalcemia, hungry bone syndrome, nerve injury, neck hematoma, or parathyromatosis. The most common postoperative complication is failure to surgically resolve the patient's hyperparathyroidism. A patient is considered to have persistent hyperparathyroidism if their calcium has not returned to normal within 6 months of surgery. If they develop hypercalcemia after 6 months, this is considered recurrent hyperparathyroidism. 61

Another potential complication of surgery is temporary or permanent hypoparathyroidism. Temporary hypoparathyroidism often occurs in the days following surgery since the suppressed normal parathyroid glands take a few days to return to regular functioning. Permanent hypoparathyroidism results from the surgical removal of all parathyroid tissues. 61 , 62 Hypoparathyroidism causes mild-to-severe hypocalcemia. The symptoms of mild hypocalcemia are perioral and distal extremity paresthesias, whereas the symptoms of severe hypocalcemia are muscle cramping, tetany, and seizures. The classic signs of hypocalcemia are Chvostek and Trousseau signs. 61 , 62 Additionally, patients with bone disease on imaging have a 25–90 % chance of developing hungry bone syndrome compared to those without bone disease who have a less than 6 % chance. 63 In hungry bone syndrome, there is an increase in bone forming activity after parathyroidectomy that results in severe hypocalcemia, hypophosphatemia, hypomagnesemia, and normal PTH for more than four days after surgery. 61 , 63 , 64

During surgery, damage can occur to the recurrent laryngeal nerve (RLN) or superior laryngeal nerve (SLN). The RLN innervates almost all of the intrinsic laryngeal muscles. So, damage to one causes hoarseness or voice change, whereas damage to both causes bilateral vocal cord paralysis, dyspnea, and potential airway compromise. The external branch of the SLN innervates the cricothyroid muscle involved in vocal cord tightening. Damage to this nerve causes more subtle symptoms such as voice fatigue. 61 , 62 Neck hematoma is another potential complication. When this occurs, it is considered a surgical emergency because an expanding neck hematoma can cause airway compromise. 61 , 62 Rarely, parathyroidectomy can cause parathyromatosis with seeding of the parathyroid gland into the surrounding tissue resulting in many small functional areas of parathyroid tissue in the neck. 61

Teaching points

• Primary hyperparathyroidism is an intrinsic, abnormal increase in PTH secreted from the parathyroid gland with a subsequent rise in serum calcium to levels above normal. It is due to a parathyroid adenoma, parathyroid hyperplasia, or parathyroid carcinoma. • Parathyroid hormone increases serum calcium by directly increasing calcium reabsorption at the kidneys and resorption from bone, as well as indirectly by increasing activation of vitamin D that causes increased absorption of calcium from the intestines. • While primary hyperparathyroidism is the most common cause of hypercalcemia, other conditions in the differential include hypercalcemia of malignancy, excess vitamin D, drug-induced, milk–alkali syndrome, familial hypocalciuric hypercalcemia, and secondary or tertiary hyperparathyroidism. • Secondary hyperparathyroidism is caused by extrinsic metabolic changes, most commonly hypocalcemia caused by chronic kidney disease. • Tertiary hyperparathyroidism occurs when parathyroid cells start secreting PTH autonomously leading to hypercalcemia and is most commonly caused by end-stage renal disease. • The typical presentation of primary hyperparathyroidism today in the United States is asymptomatic hypercalcemia detected on routine biochemical screening. • As the disease progresses, symptoms include skeletal, renal, cardiovascular, gastrointestinal, neurobehavioral, and neuromuscular symptoms. • The classic radiologic bone findings are subperiosteal, subchondral, subligamentous bone resorption, focal lytic lesions including brown tumors, and osteopenia. • Radiologically, brown tumors appear as benign-looking lytic lesions that commonly occur in the diaphysis of long bones. • Histologically, brown tumors are a reparative process in response to osteoclastic resorption of bone. They are characterized by lobules of osteoclast-like giant cells, hypervascular and reactive fibrous tissue, and areas of hemorrhage. • The treatment of symptomatic primary hyperparathyroidism is parathyroidectomy. • The potential complications of parathyroidectomy are persistent hyperparathyroidism, hypoparathyroidism, recurrent or superior laryngeal nerve injury, neck hematoma, and parathyromatosis. • After the parathyroid tumor is resected, it can be diagnosed as a benign adenoma, atypical adenoma, parathyroid hyperplasia, multigland disease, or parathyroid carcinoma. • Multigland disease is associated with the hereditary endocrine syndromes MEN1, MEN2, MEN4, and hyperparathyroidism jaw tumor syndrome. • Benign adenomas are histologically characterized by proliferation of parenchymal cells that causes a hypercellular appearance with minimal fat cells and a compressed rim of normal parathyroid tissue. There are few atypical cellular features and no invasion.

Funding

The article processing fee for this article was funded by an Open Access Award given by the Society of ‘67 , which supports the mission of the Association for Academic Pathology to produce the next generation of outstanding investigators and educational scholars in the field of pathology. This award helps to promote the publication of high-quality original scholarship in Academic Pathology by authors at an early stage of academic development.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

References

1 Knollmann-Ritschel B.E.C. Huppmann A.R. Borowitz M.J. Conran R. Pathology competencies in medical education and educational cases: Update 2023 Acad Pathol 10 3 2023 100086 10.1016/j.acpath.2023.100086 PMC10366624 37496887

2 Gennari C. Gonnelli S. Differential diagnosis: bone pain and fractures Geusens P. Sambrook P. Lindsay R. Osteoporosis in Clinical Practice: A Practical Guide for Diagnosis and Treatment Second ed. 2004 Springer 125 140

3 Bergman R. Kaiser K. Stress Reaction and Fractures. StatPearls 2025 StatPearls Publishing Updated April 3, 2025. https://www.ncbi.nlm.nih.gov/books/NBK507835/ 29939612

4 Jayarangaiah A. Kemp A.K. Kariyanna P.T. Bone Metastasis. StatPearls 2023 StatPearls Publishing Updated July 31, 2023. https://www.ncbi.nlm.nih.gov/books/NBK507911/ 29939688

5 Fraser W.D. Alter D.N. Bone and metabolism Rifai N. Chiu R.W.K. Young I. Burnham C.D. Wittwer C. Tietz Textbook of Laboratory Medicine Seventh ed. 2023 Elsevier 766

6 Shane E. Rosen C.J. Mulder J.E. Diagnostic Approach to Hypercalcemia 2022 UpToDate Updated March 19, 2025. https://www.uptodate.com/contents/diagnostic-approach-to-hypercalcemia

7 Walker M.D. Shane E. Hypercalcemia: a review JAMA 328 16 2022 1624 1636 10.1001/jama.2022.18331 36282253

8 Vautour L. Goltzman D. Regulation of calcium homeostasis Bilezikian J.P. Bouillion R. Clemens T. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism 2019 Wiley 163 172

9 Molina P.E. Parathyroid gland and Ca 2+ and PO 4 - regulation Molina P.E. Endocrine Physiology 6e. 2023 McGraw Hill https://accessmedicine.mhmedical.com/content.aspx?bookid=3307&sectionid=275922040

10 Carroll M.F. Schade D.S. A practical approach to hypercalcemia Am Fam Physician 67 9 2003 1959 1966 12751658

11 Cifu A.S. Hypercalcemia Stern D.C. Cifu A.S. Altkorn D. Symptom to Diagnosis: An Evidence-based Guide Fourth ed. 2020 McGraw-Hill Medical 381 390

12 Walker M.D. Silverberg S.J. Primary hyperparathyroidism Nat Rev Endocrinol 14 2 2018 115 125 10.1038/nrendo.2017.104 28885621 PMC6037987

13 Guise T.A. Wysolmerski J.J. Cancer-associated hypercalcemia N Engl J Med 386 15 2022 1443 1451 35417639 10.1056/NEJMcp2113128

14 Szalat A. Mazeh H. Freund H.R. Lithium-associated hyperparathyroidism: report of four cases and review of the literature Eur J Endocrinol 160 2 2009 317 323 10.1530/EJE-08-0620 19001061

15 Silva B.C. Cusano N.E. Bilezikian J.P. Primary hyperparathyroidism Best Pract Res Clin Endocrinol Metabol 32 5 2018 593 607 10.1016/j.beem.2018.09.004 30449543

16 Lee J.Y. Shoback D.M. Familial hypocalciuric hypercalcemia and related disorders Best Pract Res Clin Endocrinol Metabol 32 5 2018 609 619 10.1016/j.beem.2018.05.004 PMC6767927 30449544

17 Bilezikian J.P. Khan A.A. Silverberg S.J. Evaluation and management of primary hyperparathyroidism: summary statement and guidelines from the fifth international workshop J Bone Miner Res 37 11 2022 2293 2314 10.1002/jbmr.4677 36245251

18 Maitra Anirban The endocrine system Kumar V. Abbas A.K. Aster J.C. Robbins and Cotran Pathologic Basis of Disease Tenth ed. 2021 Elsevier 1065 1132

19 Insogna K.L. Primary hyperparathyroidism N Engl J Med 379 11 2018 1050 1059 10.1056/NEJMcp1714213 30207907

20 Fraser W.D. Hyperparathyroidism Lancet 374 9684 2009 145 158 10.1016/S0140-6736(09)60507-9 19595349

21 Marcocci C. Cetani F. Clinical practice. Primary hyperparathyroidism [published correction appears in N Engl J Med. 2012 May 31;366(22):2138] N Engl J Med 365 25 2011 2389 2397 10.1056/NEJMcp1106636 22187986

22 Minisola S. Arnold A. Belaya Z. Epidemiology, pathophysiology, and genetics of primary hyperparathyroidism J Bone Miner Res 37 11 2022 2315 2329 10.1002/jbmr.4665 36245271 PMC10092691

23 El-Hajj Fuleihan G. Chakhtoura M. Cipriani C. Classical and nonclassical manifestations of primary hyperparathyroidism J Bone Miner Res 37 11 2022 2330 2350 10.1002/jbmr.4679 36245249

24 Alagaratnam S. Kurzawinski T.R. Aetiology, diagnosis and surgical treatment of primary hyperparathyroidism in children: new trends Horm Res Paediatr 2015 10.1159/000381622 25966652

25 Salcuni A.S. Cetani F. Guarnieri V. Parathyroid carcinoma Best Pract Res Clin Endocrinol Metabol 32 6 2018 877 889 10.1016/j.beem.2018.11.002 30551989

26 Marshall A.G. Neikirk K. Afolabi J. Update on the use of pulse wave velocity to measure age-related vascular changes Curr Hypertens Rep 26 3 2024 131 140 10.1007/sl1906-023-01285-x 38159167 PMC10955453

27 Xie C. Tsakok M. Taylor N. Partington K. Imaging of brown tumours: a pictorial review Insights Imaging 10 1 2019 75 10.1186/s13244-019-0757-z 31359305 PMC6663953

28 Klein M.J. Bonar S.F. Freemont T. Metabolic bone diseases Klein M.J. Bonar S.F. Freemont T. Atlas of Nontumor Pathology: Non-Neoplastic Diseases of Bones and Joints, First Series, Fascicle 9 2011 American Registry of Pathology 881 964

29 Wojciech P. Bone Wojciech P. Ross M.H. Histology: A Text and Atlas with Correlated Cell and Molecular Biology Eighth ed. 2020 Wolters Kluwer 232 273

30 Horvai A. Bones, joints and soft tissue tumors Kumar V. Abbas A.K. Aster J.C. Robbins and Cotran Pathologic Basis of Disease Tenth ed. 2021 Elsevier 1171 1215

31 Garcia R.A. Klein M.J. Schiller A.L. Bones and joints Rubin R. Strayer D.S. Rubin's Pathology: Clinicopathologic Foundations of Medicine Sixth ed. 2012 Wolters Kluwer Health/Lippincott Williams & Wilkins 1199 1272

32 Nielsen G.P. Rosenberg A.E. Brown tumor Nielsen G.P. Rosenberg A.E. Diagnostic Pathology: Bone Third ed. 2021 Elsevier 270 273

33 Orosz Z. Athanasou N.A. Giant cell-containing tumors of bone Surg Pathol Clin 10 3 2017 553 573 10.1016/j.path.2017.04.004 28797502

34 Yoshida A. Giant cell tumor of bone Folpe A.L. Nielsen G.P. Bone and Soft Tissue Pathology Second ed. 2023 Elsevier 538 543

35 Resnick D. Jacobson J.A. Chung C.B. Parathyroid disorders and renal osteodystrophy Resnick D. Jacobson J.A. Chung C.B. Kransdorf M.J. Pathria M.N. Resnick's Bone and Joint Imaging Fourth ed. 2025 Elsevier 600 615

36 Bennett J. Suliburk J.W. Morón F.E. Osseous manifestations of primary hyperparathyroidism: imaging findings Internet J Endocrinol 2020 2020 3146535 10.1155/2020/3146535 PMC7054819 32148487

37 Botou A. Bangeas A. Alexiou I. Sakkas L.I. Acro-osteolysis Clin Rheumatol 36 1 2017 9 14 10.1007/s10067-016-3459-7 27796661

38 Minisola S. Gianotti L. Bhadada S. Silverberg S.J. Classical complications of primary hyperparathyroidism Best Pract Res Clin Endocrinol Metabol 32 6 2018 791 803 10.1016/j.beem.2018.09.001 30665547

39 Wilhelm S.M. Wang T.S. Ruan D.T. The American Association of Endocrine Surgeons guidelines for definitive management of primary hyperparathyroidism JAMA Surg 151 10 2016 959 968 10.1001/jamasurg.2016.2310 27532368

40 Porter J.L. Varacallo M.A. Osteoporosis. StatPearls 2023 StatPearls Publishing Updated August 4. https://www.ncbi.nlm.nih.gov/books/NBK441901/ 28722930

41 Helms C.A. Vinson E.N. Benign lucent bone lesions Klein J.S. Brant W.E. Helms C.A. Vinson E.N. Brant and Helms' Fundamentals of Diagnostic Radiology Fifth ed. 2019 Wolters Klewer 1278 1297

42 Nose V. Erickson L.A. Tischler A.S. Parathyroid adenoma Nose V. Erickson L.A. Diagnostic Pathology: Endocrine Third ed. 2023 Elsevier 404 411

43 Merino M.J. Quezado M. The endocrine system Rubin R. Strayer D.S. Rubin's Pathology: Clinicopathologic Foundations of Medicine Sixth ed. 2012 Wolters Kluwer Health/Lippincott Williams & Wilkins 1199 1272

44 Pawlina W. Endocrine organs Histology Pawlina W. A Text and Atlas with Correlated Cell and Molecular Biology Eighth ed. 2018 Wolters Kluwer 784 831

45 Ovalle W.K. Nahirney P.C. Endocrine system Ovalle W.K. Nahirney P.C. Netter's Essential Histology Third ed. 2021 Elsevier 231 261

46 Asa S.L. Baloch Z.W. de Krijger R.R. WHO classification of tumours: endocrine and neuroendocrine tumours. Volume 10 WHO Series on Histological and Genetic Typing of Human Tumours Fifth ed. 2025 International Agency for Research on Cancer/World Health Organization https://tumourclassification.iarc.who.int/chaptercontent/53/68

47 Asa S.L. Baloch Z.W. de Krijger R.R. WHO classification of tumours: endocrine and neuroendocrine tumours. Volume 10 WHO Series on Histological and Genetic Typing of Human Tumours Fifth ed. 2025 International Agency for Research on Cancer/World Health Organization https://tumourclassification.iarc.who.int/chaptercontent/53/169

48 Rivera M. Roh M. Endocrine pathology Fadi W.A. Sturgis C.D. Differential Diagnoses in Surgical Pathology Tumors and their Mimickers 2024 Elsevier 592 635

49 Asa S.L. Baloch Z.W. de Krijger R.R. WHO classification of tumours: endocrine and neuroendocrine tumours. Volume 10 WHO Series on Histological and Genetic Typing of Human Tumours Fifth ed. 2025 International Agency for Research on Cancer/World Health Organization https://tumourclassification.iarc.who.int/chaptercontent/53/70

50 Asa S.L. Baloch Z.W. de Krijger R.R. WHO classification of tumours: endocrine and neuroendocrine tumours. Volume 10 WHO Series on Histological and Genetic Typing of Human Tumours Fifth ed. 2025 International Agency for Research on Cancer/World Health Organization https://tumourclassification.iarc.who.int/chaptercontent/53/71

51 Nose V. Erickson L.A. Tischler A.S. Parathyroid carcinoma Nose V. Erickson L.A. Diagnostic Pathology: Endocrine Third ed. 2023 Elsevier 422 431

52 Jha S. Simonds W.F. Molecular and clinical spectrum of primary hyperparathyroidism Endocr Rev 44 5 2023 779 818 10.1210/endrev/bnad009 36961765 PMC10502601

53 Blau J.E. Simonds W.F. Familial hyperparathyroidism Front Endocrinol 12 2021 623667 10.3389/fendo.2021.623667 PMC7947864 33716975

54 Nosé V. Gill A. Teijeiro J.M.C. Perren A. Erickson L. Overview of the 2022 WHO classification of familial endocrine tumor syndromes Endocr Pathol 33 1 2022 197 227 10.1007/s12022-022-09705-5 35285003

55 Duan K. Mete O. Familial hyperparathyroidism syndromes Diagn Histopathol 22 2016 92 100 10.1016/j.mpdhp.2016.02.003

56 Nose V. Erickson L.A. Tischler A.S. Multiple endocrine neoplasia type 1 Nose V. Erickson L.A. Diagnostic Pathology: Endocrine Third ed. 2023 Elsevier 754 761

57 Erickson L.A. Mete O. Juhlin C.C. Overview of the 2022 WHO classification of parathyroid tumors Endocr Pathol 33 2022 64 89 10.1007/s12022-022-09709-1 35175514

58 Torresan F. Iacobone M. Clinical features, treatment, and surveillance of hyperparathyroidism-jaw tumor syndrome: an up-to-date and review of the literature Internet J Endocrinol 2019 1761030 10.1155/2019/1761030 PMC6935818 31929790

59 Iacobone M. Carnaille B. Palazzo F.F. Hereditary Hyperparathyroidism—a consensus report of the European society of endocrine surgeons (ESES) Langenbecks Arch Surg 400 2015 867 886 10.1007/s00423-015-1342-7 26450137

60 Asa S.L. Baloch Z.W. de Krijger R.R. WHO classification of tumours: endocrine and neuroendocrine tumours. Volume 10 WHO Series on Histological and Genetic Typing of Human Tumours Fifth ed. 2025 International Agency for Research on Cancer/World Health Organization https://tumourclassification.iarc.who.int/chaptercontent/53/67

61 Rodgers S.E. Carty S.E. Primary hyperparathyroidism Ellison E.C. Upchurch G.R. Fischer's Mastery of Surgery Eighth ed. 2024 Elsevier 347 360

62 Karzai S. Prescott J.D. Primary hyperparathyroidism Cameron J.L. Cameron A.M. Current Surgical Therapy Fourteenth ed. 2023 Elsevier 860 866

63 Witteveen J.E. van Thiel S. Romijn J.A. Hamdy N.A. Hungry bone syndrome: still a challenge in the post-operative management of primary hyperparathyroidism: a systematic review of the literature Eur J Endocrinol 168 3 2013 R45 R53 10.1530/EJE-12-0528 23152439

64 Cartwright C. Anastasopoulou C. Hungry Bone Syndrome. Statpearls 2025 StatPearls Publishing Updated February 6 https://www.ncbi.nlm.nih.gov/books/NBK549880 31751070