Background
Laennec was the first one to report on an intrabronchial tumor mass, published posthumously in 1881. This was the first description of a bronchial carcinoid tumor [ 1 ]. The first detailed description of a so-called bronchial adenoma, which was probably a carcinoid tumor too, was adduced by Mueller in 1882 [ 2 ]. The term "Karzinoid" was introduced by the German pathologist Oberndorfer in 1907 for tumors of the ileum, although Lubarsch had described a similar case of two patients with ileal carcinoid tumors in 1888 [ 3 , 4 ]. Carcinoids represent approximately 2% of all lung tumors. 25-30% of all neuroendocrine tumors appear in the bronchopulmonary system. The age-adjusted incidence rates of bronchopulmonary carcinoids and neuroendocrine tumors in general have increased over the last 30 years for all genders and races. This increase may be due to improvements in histopathological diagnosis and classification and to the more frequent use of endoscopic procedures [ 5 - 7 ]. The average age of diagnosis is at 60 years. Modlin et al. and others described a female predominance [ 8 , 9 ], whereas Quaedvlieg et al. described a female predominance only for patients under the age of 50 years, suggesting hormonal influence [ 10 ]. Typical carcinoids are the most common lung tumors in children. Misdiagnosis of typical carcinoid tumors of the lung as SCLC has been reported previously [ 11 , 12 ]. We report of a patient with a typical bronchopulmonary carcinoid tumor, which was initially misdiagnosed as an adenocarcinoma of the lung and also treated as such. This led to serious postoperative consequences for the patient. The tumor described in our case report showed almost no progression in 5 years. GnrH receptors and the associated Raf-1/MEK/ERK-1/2-pathway are potential targets for analogs in cancer treatment. We suspected a correlation between the lack of tumor growth, application of leuprolide and the Raf-1/MEK/ERK-1/2-pathway. Therefore, we examined GnrH receptor status in the examined specimen.
Case report
In March 2010 a 77 year-old male patient was shown to have a tumor mass of about 1.7 cm diameter in the inferior lobe of the left lung (see Figure 1 ). Since 2005, this asymptomatic tumor mass had hitherto been known with a diameter of approximately 1.7 cm. It showed almost no increase in size and could therefore be classified as "stable disease". The patient suffered from prostate cancer 4 years ago and was treated with TUR-P, radiation therapy and the application of leuprolide. Other pre-existing conditions were arterial hypertension and chronic obstructive lung disease. The physical examination was without pathological findings. A preoperative PET/CT scan was not performed due to the fact that neither a positive nor a negative PET/CT scan result rules out a surgical intervention. Therefore, we conducted a left anterolateral thoracotomy with atypical segment resection for curative tumor treatment. The pathological examination of the resected tissue revealed a malignant tumor with a diameter of 1.5 cm. As a first histological diagnosis, a metastasis of prostate cancer with lymphangiosis carcinomatosa was assumed. Further immunohistochemical studies for PSA, CK7, CK20 and TTF1 were performed. Stainings for PSA and CK20 were both negative, stainings for TTF1 showed a strong nuclear and for CK7 a strong cytoplasmatic reaction (see Figure 2 ). Therefore, the initial diagnosis of a metastasis of prostate cancer was changed to adenocarcinoma of the lung. Relying on this new diagnosis, we conducted a re-thoracotomy with lobectomy and systematic lymphadenectomy as an adequate treatment 12 days after the above-mentioned operation. The resection margins were free of tumor cells. To this point, the tumor stage was pT1 N0 MX G2 L1 V0. Further immunohistochemical studies were performed. These revealed cytoplasmatic expression of chromogranin A and synaptophysin, plasma membrane associated expression of CD56 and a Ki-67 labelling index of approximately 5% (see Figure 2 ). After re-evaluation of all results and particularly with regard to the little progress in tumor size, the diagnosis was ultimately changed to typical bronchopulmonary carcinoid tumor. A re-examination of the sample showed no invasion of tumor cells in lymphatic vessels. The patient recovered well from surgery and received postoperative rehabilitation therapy. In addition lung function testing revealed no evidence of impairment. Follow-up care is carried out by our department of oncology. The typical carcinoid tumor described in our case report showed almost no progression in 5 years. We suspected a correlation between the lack of tumor growth, application of leuprolide and the Raf-1/MEK/ERK-1/2-pathway. Therefore, we examined GnrH receptor status in the examined specimen. An expression of GnrH receptor could not be detected.
Discussion
It is generally assumed that carcinoids arise from Kulchitsky cells disseminated in the bronchopulmonary mucosa [ 13 ]. Typical carcinoids (TCs) are usually well-differentiated tumors of histologically ordered structure, which are larger than 5 cm with less than 2 mitoses per 10 high power fields and without necrosis. A minority of carcinoids show an atypical appearance with 2-10 mitoses per 10 high power fields, necrosis and they tend to be more aggressive than typical carcinoids. They also show a higher probability to metastasize, to recur and have a worse outcome and prognosis. These are referred to as atypical carcinoids (ACs) [ 14 - 16 ]. The division of neuroendocrine tumors into different subgroups is nowadays based on the WHO classification of 2004 [ 16 ]. Other systems like the embryogenetic classification proposed by Wiliams and Sandler in 1963, which differentiated between carcinoids of the foregut (lung, stomach, duodenum, pancreas, upper jejunum), midgut (lower jejunum, ileum, appendix, caecum) and hindgut (colon, rectum), were too inaccurate and therefore could not prevail [ 17 ]. 75-90% of all bronchopulmonary carcinoids are localized central, 10-25% peripheral [ 18 , 19 ]. 70-90% are identified as typical and 10-30% as atypical carcinoids [ 8 , 20 ]. TCs are primarily found central and show nodal involvement in 3-20%, whereas ACs are mostly localized in the periphery of the tracheobronchial tree and show nodal involvement in 48-75% [ 8 , 21 ]. ACs are more often associated with smoking than TCs (62-80%). In this regard, a correlation between typical carcinoid histology and smoking is not very likely [ 6 , 8 , 22 , 23 ]. The combination of tumor size and mean nuclear area can be used to predict the presence or absence of regional lymph node metastases in 80% and 94% of all cases, respectively [ 24 ]. At the time of diagnosis, ACs usually present at a more advanced stage than typical ones. Therefore, an accurate histological diagnosis is essential for further treatment [ 25 ]. Mineo et al. published in 2005 that ACs have a higher probability for developing micrometastases, thus explaining the more aggressive clinical behavior. Nodal micrometastases do not correlate with tumor size and stage, implying that even small tumors located in the periphery of the tracheobronchial tree may metastasize. Immunohistochemical detection of micrometastases by using chromoganin A and cytokeratin as markers can help to identify patients with a high risk of recurrence, allowing a more accurate staging [ 26 ]. Atypical and typical carcinoid tumors are characterized by a frequent deletion of 11 q material including the MEN1 gene locus. Losses of 10 q and 13 q sequences are more often associated with atypical than with typical carcinoids, making further cytogenetic differentiation possible and probably explaining the more aggressive behavior of ACs [ 27 ].
TTF1 is a transcription factor with a molecular weight of 38 kDa, which plays an important role in lung morphogenesis and the expression of surfactant factor. It is considered as a dependable marker in distinguishing between primary and metastatic lung adenocarcinomas and can also be helpful in discerning pulmonary neuroendocrine tumors from gastrointestinal ones. The diagnostic value seems to depend on the used antibody clone [ 28 - 30 ]. According to the literature, the expression rate in adenocarcinomas of the lung varies between 73-92% [ 31 - 34 ]. The described expression rate of TTF1 in bronchopulmonary carcinoids also shows a high variability. Rugge et al. and Sturm et al. were not able to detect TTF1-expression in either TCs or ACs. Furthermore, Sturm et al. showed a positive TTF1-expression in 85.5% and 49% of all studied SCLCs and LCNECs, respectively. According to the authors, this could imply that carcinoids derive from different stem cells than SCLCs and non-SCLCs including LCNECs [ 35 , 36 ]. In this context it is worth mentioning a study published by Sampietro et al., which revealed no relation between carcinoids and small-cell lung carcinomas in gene product immunophenotyping. The authors pointed out that ACs and LCNECs should not be construed as intermediate forms of these two tumor entities [ 37 ]. Folpe et al. were able to detect TTF1 in 35% of all cases in TCs, in 100% in ACs, in 75% in LCNECs and in 95% in SCLCs. The authors also concluded that these results suggest a common cell line origin of SCLCs and TCs [ 38 ]. Du et al. described that TTF1 is expressed by neuroendocrine cell hyperplasia in 72.7%, by TCs in 27.8%, by ACs in 29.4% and by LCNECs in 37.5% of all cases. They also demonstrated that extrapulmonary neuroendocrine tumors are negative for TTF1, rating it to be 100% specific but not very sensitive for bronchopulmonary carcinoids and possibly also LCNECs [ 39 ]. The predominance of TTF1 in carcinoids of bronchopulmonary origin was confirmed by other studies [ 40 - 42 ]. In contrast to these and other publications, Cai et al. gave an account of positive TTF1-expression in 69% of their studied carcinoid cases, all tumors except one were TCs [ 40 ]. In addition, immunohistochemical detection of Mib1 and Bcl2 can be useful to differentiate between recurrent and non-recurrent bronchopulmonary carcinoid tumors [ 35 ]. The expression of CDX2 and PDX1 is highly specific for identifying neuroendocrine tumors of intestinal origin, since bronchopulmonary carcinoids seem to be negative for these two markers. CK7 is predominantly found in adenocarcinomas of the lung. It is also expressed by 63% of bronchopulmonary carcinoid tumors and by 11% of gastrointestinal carcinoids. CK20 is mainly found in adenocarcinomas of the gastrointestinal tract, but not in bronchopulmonary carcinoid tumors. Together with NESP-55, these mentioned markers can help to discriminate between neuroendocrine tumors or adenocarcinomas of pulmonary and such of extrapulmonary origin [ 34 , 40 - 43 ]. Chromoganin A (CgA) and synaptophysin are commonly used neuroendocrine markers in immunohistochemical analysis [ 44 ]. Overdiagnosis of typical carcinoid tumors of the lung as SCLCs has been reported previously [ 11 , 12 ]. In our case report, the first diagnosis was metastasis of prostate cancer. After initial immunohistochemical stainings and due to the therein reported expression of TTF1, CK7 and the lack of CK20, this diagnosis was changed to primary adenocarcinoma of the lung. Further immunohistochemical stainings were performed. In consideration of the slow tumor progression, the low Ki-67 labelling index and the expression of CgA and synaptophysin, the diagnosis was ultimately changed to TC. Up to this time, we had already conducted a lobectomy to treat the previously suspected adenocarcinoma. As Pelosi et al. stated, careful evaluation of hematoxylin and eosin sections, together with the Ki-67 labelling index, remains the most important tool in discriminating between carcinoids and SCLCs. An index below 20% is typical for carcinoid tumors, whereas an index above 50% is usually found in SCLCs.
GnrH receptors and the associated Raf-1/MEK/ERK-1/2-pathway are potential targets for analogs in cancer treatment. Activation of the Raf-1/MEK/ERK-1/2-pathway by leflunomide and teriflunomide can inhibit proliferation and growth of BON carcinoid cells in vitro and in vivo and also decrease expression of neuroendocrine markers in both BON and H727 carcinoid cells [ 45 ]. Similar effects have been reported for estradiol, ZM336372 and tautomycin [ 46 - 50 ]. Kidd et al. detected GnrH receptor expression in H720, but not in H727 cells and GHRH receptor expression in H727, but not in H720 cells. According to their results for H720 cells, GnrH+doxorubicin conjugate is a more effective proliferation inhibitor in vitro than doxorubicin alone. In H727 cells, this difference was not observed. Furthermore, GHRH receptor antagonists have an antiproliferative effect in H727 but not in H720 cells [ 51 ]. The signaling mechanisms of GnrH receptors differ significantly from cell type to cell type. For example, signaling in COS7 cells is not dependent on PKC. Since GnrH receptor expression has not been studied in larger patient collectives with carcinoid tumor disease, this raises the question whether there is an association with the above mentioned Raf-1/MEK/ERK-1/2-pathway and if its activation is dependent on GnrH receptors [ 52 ]. If there is such a context, the effects of agonists like leuprolide as a GnrH receptor agonists may become of interest. Although we could not detect GnrH-receptors in the examined specimen, there may be individual differences in expression. In this regard, GnrH receptor profiles in TCs and ACs should be scrutinized. Further investigations could lead to new therapeutical options in the treatment of TCs and especially ACs, since the GnrH receptor has been described as located on the latter [ 51 ]. Clinically tested and approved drugs such as leuprolide could come to use.
According to an analysis of eight studies by Gustafsson et al., approximately 58% of all patients show unspecific symptoms: cough in 32%, hemoptysis in 26%, pneumonia in 24% of all cases and, to a lesser extent, fever, dyspnoe and chest pain. A carcinoid syndrome occurs seldomly in approximately 1-3% [ 53 ]. Long term obstruction typical for centrally localized tumors can cause multiple bronchiectases in 19% of all patients [ 22 ]. Young and adult patients should undergo further examination if they show long-standing pulmonary symptoms without any response to drug therapy [ 54 , 55 ]. To date there is no laboratory test available that could always detect a carcinoid reliably. Several serum markers are used. CgA is a maker of carcinoids in general with a high sensitivity (85.7%) and specificity (67.9%), although it can also be detected in SCLCs depending on the clinical stage [ 56 , 57 ]. The elevation of CgA can indicate the recurrence of radically operated midgut carcinoid tumors in 85% of all cases. The measurement of CgA can be recommended for the continuous surveillance of carcinoid patients [ 57 , 58 ]. However, CgA is also known to be false positive in some cases, for example in patients with multiple myeloma, renal impairment, atrophic gastritis or proton pump inhibitor therapy [ 59 ]. The measurement of 5-HIAA and, according to the clinical symptoms, of ACTH, MSH, GH etc. is only useful if a carcinoid syndrome is suspected. Various diagnostic methods are used in combination. Only 75% of all patients show a suspicious chest X-ray. Despite a lack of sensitivity and specificity, high resolution CT scans of the abdomen and thorax are used most commonly for an initial localization of the tumor. Carcinoid tumors are known to be highly vascularized and may show a strong contrast agent enhancement. MRI can provide additional information. 68 Ga-DOTA-peptide PET/CT scans are currently the most accurate imaging procedures for the diagnosis of NETs such as bronchial carcinoids with a sensitivity of 97% and a specificity of 92%. Even the detection of tumors smaller than 1 cm is possible. According to a study published by Ambrosini et al., 68 Ga-DOTANOC PET/CT either affected stage or caused a therapy modification in more than 50% of the NET patients, proving its superiority to conventional imaging [ 60 ]. In this context it should be noted that it can be distinguished between endobronchial carcinoid and inflammatory myofibroblastic tumors by combining 18 F-FDG PET and 68 Ga-DOTATOC PET/CT [ 61 ]. Prior to this new method, somatostatin receptor scintigraphy was used in imaging, which was not very specific for bronchial carcinoids. A recently published study showed that 68 Ga-DOTANOC PET/CT is superior to 111 In-pentetreotide in the detection of CUP-NETs, with a localization rate of the primary tumor of 59% vs. 39%, respectively. The authors concluded that this method can play a major role in the management of patients with CUP-NETs [ 62 ]. Bronchial carcinoids are known to be highly vascularized. Nevertheless they show a high rate of false negative results in 18 F-FDG PET, although solitary cases of carcinoids with high 18 F-FDG uptake have been reported [ 63 - 65 ]. Interestingly, combined diagnostic imaging with 131 I-MIBG and 111 In-pentetreotide achieved an overall sensitivity of 95% for localization of carcinoid tumors. However, this approach was not further pursued [ 66 ]. According to the current ACCP guidelines, transthoracic needle biopsy, bronchoscopy or even surgical resection are appropriate means of diagnosis for solitary pulmonary nodules of at least 8-10 mm diameter. VATS, thoracotomy and mediastinoscopy can be used in combination or as sole diagnostic procedures [ 67 ]. Endo- and epibronchial ultrasound can also provide further valuable information [ 68 , 69 ]. In this regard, it is important to mention that transthoracic fine needle aspiration biopsy bears the risk of nondiagnostic biopsies. It is dependant on many different factors like tumor size or needle diameter [ 67 , 70 ]. Also, there are several reports on implantation metastasis caused by fine needle aspiration biopsy. Although FNAB is considered to be a well-established diagnostic procedure, we think the above mentioned limitations and complication threaten the success of any curative therapy and should not be ignored [ 71 ]. 18 F-FDG PET/CT scan is known to be highly sensitive, yet has its limitations due to a lower specifity. Like the above mentioned FNAB, a negative PET/CT scan does not rule out the possiblity of malignancy of a solitary pulmonary nodule and cannot replace surgical resection [ 70 ]. Therefore, we did not see the necessity to perform a preoperative PET/CT scan. Since surgical resection is still considered to be the most reliable diagnostic test [ 67 , 70 ], we prefer surgical diagnostic procedures, if they are feasible. Histological analysis with further immunohistochemical differentiation still remains the gold standard in diagnosing bronchopulmonary carcinoid tumors, with markers like TTF1, CK7, CK20, chromogranin A, synaptophysin and Ki-67 being used routinely.
Surgical resection is still considered to be gold standard in treatment. Nowadays, tissue-sparing procedures become more and more popular, since they show no great difference in long-term survival and a better postoperative quality of life. For this purpose, early diagnosis is essential. The extents of surgical resection and lymph node dissection are still a matter of ongoing debate. Some authors concluded that parenchyma sparing procedures in ACs should be avoided because of a higher recurrence rate [ 25 , 72 ] and are suitable especially for TCs. Others prefer more invasive procedures such as lobectomy in combination with radical lymphadenectomy for any histological kind of carcinoid tumor [ 20 , 22 ]. Endobronchial typical carcinoids with strictly endoluminal growth and small tumor base are reported to be treatable by bronchoscopic resection, showing excellent long term results [ 69 ]. Wedge bronchoplasty with large margins should be avoided due to the risk of kinking of the tracheobronchial tree [ 73 ]. Some authors pointed out that lymph node dissection should be performed in any patients with atypical carcinoids [ 74 , 75 ], whereas others recommended systematic lymphadenectomy in any carcinoid case [ 20 , 22 , 24 , 75 ]. Octreotide and chemotherapy are normally used if a carcinoid syndrome or metastases are present. Kaplan et al. even recommended postoperative radiochemotherapy for patients with atypical carcinoids at stage I, reasoning it with higher locoregional failure and distant metastasis rates as compared to patients with typical carcinoids [ 76 ]. According to the ACCP guidelines, there is level 2 C evidence for a conservative and observant approach in case of a new diagnosed pulmonary tumor mass without growth in the last 2 years. However, this strategy is not used very often in practice, because tumors greater than 1.5 cm in diameter show high potential for malignancy [ 67 ]. This approach should therefore be used with caution. Even after radical resection, distant metastases can occur in 8% of all TC cases and are associated with a worsening of prognosis.
The 10-year survival rate for typical carcinoids ranges from 82% to 93%, for atypical carcinoids from 56% to 64% [ 8 , 69 , 72 , 75 ]. Modlin et al. described a 5-year survival rate of 73,5% for all stages [ 6 ]. The various forms of surgical resection techniques used nowadays normally show excellent long-term results. Histology, evidence of invasive growth, nodal status and the presence or absence of distant metastases were identified as the most important prognostic factors for long term survival [ 6 , 7 , 26 , 72 , 75 ]. At the time of diagnosis, ACs usually show a more advanced stage than TCs. According to a recently published study, nodal invasion in TCs has no influence on prognosis [ 9 ]. In contrast, Martini et al. reported in 1994 that long term survival is independent of lymph node metastases for both TCs and ACs and that recurrence seems to depend more on cell type than nodal status. However, this study only consisted of 25 patients [ 77 ]. In case of metastatic disease, TCs may show a similar clinical course like ACs. If the metastases are not resectable, the disease is considered to be incurable [ 53 , 78 , 79 ].
Conclusion
Misdiagnosis of bronchopulmonary carcinoid tumors with surgical overtreatment can cause serious consequences for the patient like intra- and postoperative complications with further possible serious limitations of lung function. The use of several immunohistochemical markers and careful evaluation of hematoxylin and eosin sections together with the Ki-67 labelling index are important tools in discriminating between carcinoids and other bronchopulmonary carcinomas. Simultaneously, the pre-operative progression of the disease should be considered before defining the extent of initial surgical resection. In case of metastatic disease, TCs may show a similar clinical course like ACs and a significant worsening of prognosis. Therefore, we think that even small TCs which are considered as "stable disease" like our reported case should be resected. Also, a 10-year follow up is recommended.
GnrH receptors and the associated Raf-1/MEK/ERK-1/2-pathway are potential targets for analogs in cancer treatment. Activation of the above mentioned pathway can inhibit proliferation and growth of various carcinoid cell types. The typical carcinoid tumor described in our case report showed almost no progression in 5 years. The patient suffered from prostate cancer 4 years ago and was treated with TUR-P, radiation therapy and the application of leuprolide. We suspected a correlation between the lack of tumor growth, application of leuprolide and the Raf-1/MEK/ERK-1/2-pathway. Therefore, we examined GnrH receptor status in the examined specimen. Although we could not detect GnrH-receptors in the examined specimen, there may be individual differences in expression. In this regard, GnrH receptor profiles in TCs and ACs should be scrutinized. Further investigations could lead to new therapeutical options in the treatment of TCs and especially ACs, since the GnrH receptor has already been described on the latter. Clinically tested and approved drugs such as leuprolide could come to use.
Consent
Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
List of abbreviations
TCs: typical carcinoid tumors; ACs: atypical carcinoid tumors; CgA: Chromogranin A; SCLC: small cell lung carcinoma; LCNECs: large cell neuroendocrine carcinomas.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
ID: preparation and drafting of the manuscript, literature research; SH: editing of the manuscript; AK: editing of the manuscript; BK: immunohistochemical staining and examination of the specimen, editing of the manuscript; MF: editing of the manuscript; HJ: editing of the manuscript. All authors read and approved the final manuscript.
Laennec RTH Traite de l'auscultation mediate et des maladies des poumons et du coer Paris: J.S. Chaudé 1831
Mueller H Zur Entstehungsgeschichte der Bronchialerweiterungen MD thesis 1882 University of Halle, Faculty of Medicine
Lubarsch O Über den primären Krebs des Ileums nebst Bemerkungen über das gleichzeitige Vorkommen von Krebs und Tuberkulose Virchows Arch Pathol Anat Physiol Klin Med 1888 111 280 317 10.1007/BF01966242
Oberndorfer S Karzinoide Tumoren des Dünndarms Frankf Z Pathol 1907 1 426 430
Maggard MA O'Connell JB Ko CY Updated population-based review of carcinoid tumors Ann Surg 2004 240 117 22 10.1097/01.sla.0000129342.67174.67 15213627 PMC1356383
Modlin IM Lye KD Kidd M A 5-decade analysis of 13,715 carcinoid tumors Cancer 2003 97 934 59 10.1002/cncr.11105 12569593
Yao JC Hassan M Phan A Dagohoy C Leary C Mares JE Abdalla EK Fleming JB Vauthey JN Rashid A Evans DB One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States J Clin Oncol 2008 26 3063 72 10.1200/JCO.2007.15.4377 18565894
Fink G Krelbaum T Yellin A Bendayan D Saute M Glazer M Kramer MR Pulmonary carcinoid: presentation, diagnosis, and outcome in 142 cases in Israel and review of 640 cases from the literature Chest 2001 119 1647 51 10.1378/chest.119.6.1647 11399686
García-Yuste M Matilla JM Cueto A Paniagua JM Ramos G Cañizares MA Muguruza I Typical and atypical carcinoid tumours: analysis of the experience of the Spanish Multi-centric Study of Neuroendocrine Tumours of the Lung Eur J Cardiothorac Surg 2007 31 192 7 10.1016/j.ejcts.2006.11.031 17196822
Quaedvlieg PF Visser O Lamers CB Janssen-Heijen ML Taal BG Epidemiology and survival in patients with carcinoid disease in The Netherlands. An epidemiological study with 2391 patients Ann Oncol 2001 12 1295 300 10.1023/A:1012272314550 11697843
Pelosi G Rodriguez J Viale G Rosai J Typical and atypical pulmonary carcinoid tumor overdiagnosed as small-cell carcinoma on biopsy specimens: a major pitfall in the management of lung cancer patients Am J Surg Pathol 2005 29 179 87 10.1097/01.pas.0000149690.75462.29 15644774
Valente M Catena L Milione M Pusceddu S Formisano B Bajetta E Common Diagnostic Challenges in the Histopathologic Diagnosis of Neuroendocrine Lung Tumors: A Case Report Case Rep Oncol 2010 3 202 207 10.1159/000317313 20740197 PMC2920000
Gould VE Linnoila RI Memoli VA Warren WH Neuroendocrine components of the bronchopulmonary tract: hyperplasias, dysplasias, and neoplasms Lab Invest 1983 49 519 37 6138458
Arrigoni MG Woolner LB Bernatz PE Atypical carcinoid tumors of the lung J Thorac Cardiovasc Surg 1972 64 413 21 5054879
Hamperl H Über gutartige Bronchialtumoren (Cylindrome und Carcinoide) Virchows Arch Pathol Anat Physiol Klin Med 1937 300 46 88 10.1007/BF01888109
Travis WD Brambilla E Müller-Hermelink HK Harris CC Kleihues P, Sobin LH Pathology and genetics of tumours of the lung, pleura, thymus and heart World Health Organization classification of tumours 2004 Lyon: IARC Press
Williams ED Sandler M The classification of carcinoid tumours Lancet 1963 1 238 9 14000847 10.1016/s0140-6736(63)90951-6
Alp M Uçanok K Doğan R Kaya S Cetin G Unlü M Yorulmaz F Moldibi B Surgical treatment of bronchial adenomas: results of 29 cases and review of the literature Thorac Cardiovasc Surg 1987 35 290 4 10.1055/s-2007-1020249 2447671
Rekhtman N Neuroendocrine tumors of the lung: an update Arch Pathol Lab Med 2010 134 1628 38 21043816 10.5858/2009-0583-RAR.1
Davini F Gonfiotti A Comin C Caldarella A Mannini F Janni A Typical and atypical carcinoid tumours: 20-year experience with 89 patients J Cardiovasc Surg (Torino) 2009 50 807 11 19935614
Marty-Ané CH Costes V Pujol JL Alauzen M Baldet P Mary H Carcinoid tumors of the lung: do atypical features require aggressive management? Ann Thorac Surg 1995 59 78 83 10.1016/0003-4975(94)00630-P 7818364
Daddi N Ferolla P Urbani M Semeraro A Avenia N Ribacchi R Puma F Daddi G Surgical treatment of neuroendocrine tumors of the lung Eur J Cardiothorac Surg 2004 26 813 7 10.1016/j.ejcts.2004.05.052 15450578
Valli M Fabris GA Dewar A Hornall D Sheppard MN Atypical carcinoid tumour of the lung: a study of 33 cases with prognostic features Histopathology 1994 24 363 9 10.1111/j.1365-2559.1994.tb00538.x 8045525
Thunnissen FB Van Eijk J Baak JP Schipper NW Uyterlinde AM Breederveld RS Meijer S Bronchopulmonary carcinoids and regional lymph node metastases. A quantitative pathologic investigation Am J Pathol 1988 132 119 22 3394795 PMC1880615
Ferguson MK Landreneau RJ Hazelrigg SR Altorki NK Naunheim KS Zwischenberger JB Kent M Yim AP Long-term outcome after resection for bronchial carcinoid tumors Eur J Cardiothorac Surg 2000 18 156 61 10.1016/S1010-7940(00)00493-0 10925223
Mineo TC Guggino G Mineo D Vanni G Ambrogi V Relevance of lymph node micrometastases in radically resected endobronchial carcinoid tumors Ann Thorac Surg 2005 80 428 32 10.1016/j.athoracsur.2005.02.083 16039178
Walch AK Zitzelsberger HF Aubele MM Mattis AE Bauchinger M Candidus S Präuer HW Werner M Höfler H Typical and atypical carcinoid tumors of the lung are characterized by 11 q deletions as detected by comparative genomic hybridization Am J Pathol 1998 153 1089 98 10.1016/S0002-9440(10)65653-2 9777940 PMC1853037
Compérat E Zhang F Perrotin C Molina T Magdeleinat P Marmey B Régnard JF Audouin J Camilleri-Broët S Variable sensitivity and specificity of TTF-1 antibodies in lung metastatic adenocarcinoma of colorectal origin Mod Pathol 2005 18 1371 6 10.1038/modpathol.3800422 15861215
La Rosa S Chiaravalli AM Placidi C Papanikolaou N Cerati M Capella C TTF1 expression in normal lung neuroendocrine cells and related tumors: immunohistochemical study comparing two different monoclonal antibodies Virchows Arch 2010 457 497 507 10.1007/s00428-010-0954-0 20694477
Matoso A Singh K Jacob R Greaves WO Tavares R Noble L Resnick MB Delellis RA Wang LJ Comparison of thyroid transcription factor-1 expression by 2 monoclonal antibodies in pulmonary and nonpulmonary primary tumors Appl Immunohistochem Mol Morphol 2010 18 142 9 10.1097/PAI.0b013e3181bdf4e7 19887917 PMC2828524
Bakir K Koçer NE Deniz H Güldür ME TTF-1 and surfactant-B as co-adjuvants in the diagnosis of lung adenocarcinoma and pleural mesothelioma Ann Diagn Pathol 2004 8 337 41 10.1053/j.anndiagpath.2004.08.003 15614737
Hecht JL Pinkus JL Weinstein LJ Pinkus GS The value of thyroid transcription factor-1 in cytologic preparations as a marker for metastatic adenocarcinoma of lung origin Am J Clin Pathol 2001 116 483 8 10.1309/NL4Y-FHG8-2XBC-F9XH 11601132
Moldvay J Jackel M Bogos K Soltész I Agócs L Kovács G Schaff Z The role of TTF-1 in differentiating primary and metastatic lung adenocarcinomas Pathol Oncol Res 2004 10 85 8 10.1007/BF02893461 15188024
Su YC Hsu YC Chai CY Role of TTF-1, CK20, and CK7 immunohistochemistry for diagnosis of primary and secondary lung adenocarcinoma Kaohsiung J Med Sci 2006 22 14 9 10.1016/S1607-551X(09)70214-1 16570563 PMC11918202
Rugge M Fassan M Clemente R Rizzardi G Giacomelli L Pennelli G Mescoli C Segat D Rea F Bronchopulmonary carcinoid: phenotype and long-term outcome in a single-institution series of Italian patients Clin Cancer Res 2008 14 149 54 10.1158/1078-0432.CCR-07-1631 18172265
Sturm N Rossi G Lantuejoul S Papotti M Frachon S Claraz C Brichon PY Brambilla C Brambilla E Expression of thyroid transcription factor-1 in the spectrum of neuroendocrine cell lung proliferations with special interest in carcinoids Hum Pathol 2002 33 175 82 10.1053/hupa.2002.31299 11957142
Sampietro G Tomasic G Collini P Biganzoli E Boracchi P Bidoli P Pilotti S Gene product immunophenotyping of neuroendocrine lung tumors. No linking evidence between carcinoids and small-cell lung carcinomas suggested by multivariate statistical analysis Appl Immunohistochem Mol Morphol 2000 8 49 56 10.1097/00022744-200003000-00008 10937049
Folpe AL Gown AM Lamps LW Garcia R Dail DH Zarbo RJ Schmidt RA Thyroid transcription factor-1: immunohistochemical evaluation in pulmonary neuroendocrine tumors Mod Pathol 1999 12 5 8 9950155
Du EZ Goldstraw P Zacharias J Tiffet O Craig PJ Nicholson AG Weidner N Yi ES TTF-1 expression is specific for lung primary in typical and atypical carcinoids: TTF-1-positive carcinoids are predominantly in peripheral location Hum Pathol 2004 35 825 31 10.1016/j.humpath.2004.02.016 15257545
Cai YC Banner B Glickman J Odze RD Cytokeratin 7 and 20 and thyroid transcription factor 1 can help distinguish pulmonary from gastrointestinal carcinoid and pancreatic endocrine tumors Hum Pathol 2001 32 1087 93 10.1053/hupa.2001.28245 11679943
Lin X Saad RS Luckasevic TM Silverman JF Liu Y Diagnostic value of CDX-2 and TTF-1 expressions in separating metastatic neuroendocrine neoplasms of unknown origin Appl Immunohistochem Mol Morphol 2007 15 407 14 10.1097/01.pai.0000210416.53493.0f 18091383
Srivastava A Hornick JL Immunohistochemical staining for CDX-2, PDX-1, NESP-55, and TTF-1 can help distinguish gastrointestinal carcinoid tumors from pancreatic endocrine and pulmonary carcinoid tumors Am J Surg Pathol 2009 33 626 32 10.1097/PAS.0b013e31818d7d8b 19065104
Chu P Wu E Weiss LM Cytokeratin 7 and cytokeratin 20 expression in epithelial neoplasms: a survey of 435 cases Mod Pathol 2000 13 962 72 10.1038/modpathol.3880175 11007036
Al-Khafaji B Noffsinger AE Miller MA DeVoe G Stemmermann GN Fenoglio-Preiser C Immunohistologic analysis of gastrointestinal and pulmonary carcinoid tumors Human pathology 1998 29 992 999 10.1016/S0046-8177(98)90206-4 9744317
Cook MR Pinchot SN Jaskula-Sztul R Luo J Kunnimalaiyaan M Chen H Identification of a novel Raf-1 pathway activator that inhibits gastrointestinal carcinoid cell growth Mol Cancer Ther 2010 9 429 37 10.1158/1535-7163.MCT-09-0718 20103603 PMC2820603
Greenblatt DY Kunnimalaiyaan M Chen H Raf-1 activation in gastrointestinal carcinoid cells decreases tumor cell adhesion Am J Surg 2007 193 331 5 10.1016/j.amjsurg.2006.09.016 17320529 PMC1838566
Kunnimalaiyaan M Chen H The Raf-1 pathway: a molecular target for treatment of select neuroendocrine tumors? Anticancer Drugs 2006 17 139 42 10.1097/00001813-200602000-00004 16428931
Kunnimalaiyaan M Ndiaye M Chen H Neuroendocrine tumor cell growth inhibition by ZM336372 through alterations in multiple signaling pathways Surgery 2007 142 959 64 10.1016/j.surg.2007.09.020 18063082 PMC2180346
Pinchot SN Adler JT Luo Y Ju J Li W Shen B Kunnimalaiyaan M Chen H Tautomycin suppresses growth and neuroendocrine hormone markers in carcinoid cells through activation of the Raf-1 pathway Am J Surg 2009 197 313 9 10.1016/j.amjsurg.2008.10.007 19245907 PMC2664746
Van Gompel JJ Kunnimalaiyaan M Holen K Chen H ZM336372, a Raf-1 activator, suppresses growth and neuroendocrine hormone levels in carcinoid tumor cells Mol Cancer Ther 2005 4 910 7 10.1158/1535-7163.MCT-04-0334 15956248
Kidd M Schally AV Pfragner R Malfertheiner MV Modlin IM Inhibition of proliferation of small intestinal and bronchopulmonary neuroendocrine cell lines by using peptide analogs targeting receptors Cancer 2008 112 1404 14 10.1002/cncr.23303 18224665
Kraus S Naor Z Seger R Intracellular signaling pathways mediated by the gonadotropin-releasing hormone (GnRH) receptor Arch Med Res 2001 32 499 509 10.1016/S0188-4409(01)00331-9 11750725
Gustafsson BI Kidd M Chan A Malfertheiner MV Modlin IM Bronchopulmonary neuroendocrine tumors Cancer 2008 113 5 21 10.1002/cncr.23542 18473355
Andersen JB Mortensen J Damgaard K Skov M Sparup J Petersen BL Rechnitzer C Borgwardt L Fourteen-year-old girl with endobronchial carcinoid tumour presenting with asthma and lobar emphysema Clin Respir J 2010 4 120 4 10.1111/j.1752-699X.2009.00149.x 20565486
Emeryk J Czekajska-Chehab E Korobowicz E Korbel M Wegrzyn-Szkutnik I Milanowski J Bronchial carcinoid in a 39-year-old man treated for bronchial asthma: a case report Cases J 2008 2 7414 20119517
Bajetta E Ferrari L Martinetti A Celio L Procopio G Artale S Zilembo N Di Bartolomeo M Seregni E Bombardieri E Chromogranin A, neuron specific enolase, carcinoembryonic antigen, and hydroxyindole acetic acid evaluation in patients with neuroendocrine tumors Cancer 1999 86 858 65 10.1002/(SICI)1097-0142(19990901)86:5<858::AID-CNCR23>3.0.CO;2-8 10463986
Seregni E Ferrari L Bajetta E Martinetti A Bombardieri E Clinical significance of blood chromogranin A measurement in neuroendocrine tumours Ann Oncol 2001 12 Suppl 2 S69 72 10.1093/annonc/12.suppl_2.S69 11762355
Welin S Stridsberg M Cunningham J Granberg D Skogseid B Oberg K Eriksson B Janson ET Elevated plasma chromogranin A is the first indication of recurrence in radically operated midgut carcinoid tumors Neuroendocrinology 2009 89 302 7 10.1159/000179900 19176944
Nobels FR Kwekkeboom DJ Coopmans W Schoenmakers CH Lindemans J De Herder WW Krenning EP Bouillon R Lamberts SW Chromogranin A as serum marker for neuroendocrine neoplasia: comparison with neuron-specific enolase and the alpha-subunit of glycoprotein hormones J Clin Endocrinol Metab 1997 82 2622 8 10.1210/jc.82.8.2622 9253344
Ambrosini V Campana D Bodei L Nanni C Castellucci P Allegri V Montini GC Tomassetti P Paganelli G Fanti S 68Ga-DOTANOC PET/CT clinical impact in patients with neuroendocrine tumors J Nucl Med 2010 51 669 673 10.2967/jnumed.109.071712 20395323
Jindal T Kumar A Dutta R Kumar R Combination of (18)-FDG and (68)Ga-DOTATOC PET-CT to differentiate endobronchial carcinoids and inflammatory myofibroblastic tumors J Postgrad Med 2009 55 272 4 10.4103/0022-3859.58932 20083875
Prasad V Ambrosini V Hommann M Hoersch D Fanti S Baum RP Detection of unknown primary neuroendocrine tumours (CUP-NET) using (68)Ga-DOTA-NOC receptor PET/CT Eur J Nucl Med Mol Imaging 2010 37 67 77 10.1007/s00259-009-1205-y 19618183
Chong S Lee KS Chung MJ Han J Kwon OJ Kim TS Neuroendocrine tumors of the lung: clinical, pathologic, and imaging findings Radiographics 2006 26 41 58 10.1148/rg.261055057 16418242
Jadvar H Segall GM False-negative fluorine-18-FDG PET in metastatic carcinoid J Nucl Med 1997 38 1382 3 9293792
Suemitsu R Maruyama R Nishiyama K Okamoto T Wataya H Seto T Ichinose Y Pulmonary typical carcinoid tumor and liver metastasis with hypermetabolism on 18-fluorodeoxyglucose PET: a case report Ann Thorac Cardiovasc Surg 2008 14 109 11 18414349
Taal BG Hoefnagel CA Valdés Olmos RA Boot H Combined diagnostic imaging with 131I-metaiodobenzylguanidine and 111In-pentetreotide in carcinoid tumours Eur J Cancer 1996 32A 1924 32 8943676 10.1016/0959-8049(96)00241-9
Gould MK Fletcher J Iannettoni MD Lynch WR Midthun DE Naidich DP Ost DE Evaluation of patients with pulmonary nodules: when is it lung cancer?: ACCP evidence-based clinical practice guidelines (2nd edition) Chest 2007 132 Suppl 3 108S 130S 17873164 10.1378/chest.07-1353
Belak J Kudlac M Zak V Cavarga I Kocan P Böör A Stebnicky M Somos A Tkacova R Surgical management of bronchopulmonary carcinoid tumors: experience over 8 years and review of the literature Tumori 2010 96 84 9 20437863 10.1177/030089161009600114
Fuks L Fruchter O Amital A Fox BD Abdel Rahman N Kramer MR Long-term follow-up of flexible bronchoscopic treatment for bronchial carcinoids with curative intent Diagn Ther Endosc 2009 2009 782961 20169101 10.1155/2009/782961 PMC2821777
Wahidi MM Govert JA Goudar RK Gould MK McCrory DC American College of Chest Physicians Evidence for the treatment of patients with pulmonary nodules: when is it lung cancer?: ACCP evidence-based clinical practice guidelines (2nd edition) Chest 2007 132 3 Suppl 94S 107S 17873163 10.1378/chest.07-1352
Yoshikawa T Yoshida J Nishimura M Yokose T Nishiwaki Y Nagai K Lung cancer implantation in the chest wall following percutaneous fine needle aspiration biopsy Jpn J Clin Oncol 2000 30 450 2 10.1093/jjco/hyd120 11185892
Mezzetti M Raveglia F Panigalli T Giuliani L Lo Giudice F Meda S Conforti S Assessment of outcomes in typical and atypical carcinoids according to latest WHO classification Ann Thorac Surg 2003 76 1838 42 10.1016/S0003-4975(03)01194-9 14667595
Kurul IC Topçu S Taştepe I Yazici U Altinok T Cetin G Surgery in bronchial carcinoids: experience with 83 patients Eur J Cardiothorac Surg 2002 21 883 7 10.1016/S1010-7940(02)00089-1 12062280
Cardillo G Sera F Di Martino M Graziano P Giunti R Carbone L Facciolo F Martelli M Bronchial carcinoid tumors: nodal status and long-term survival after resection Ann Thorac Surg 2004 77 1781 5 10.1016/j.athoracsur.2003.10.089 15111186
Rea F Rizzardi G Zuin A Marulli G Nicotra S Bulf R Schiavon M Sartori F Outcome and surgical strategy in bronchial carcinoid tumors: single institution experience with 252 patients Eur J Cardiothorac Surg 2007 31 186 91 10.1016/j.ejcts.2006.10.040 17140801
Kaplan B Stevens CW Allen P Liao Z Komaki R Outcomes and patterns of failure in bronchial carcinoid tumors Int J Radiat Oncol Biol Phys 2003 55 125 31 10.1016/S0360-3016(02)03796-3 12504044
Martini N Zaman MB Bains MS Burt ME McCormack PM Rusch VW Ginsberg RJ Treatment and prognosis in bronchial carcinoids involving regional lymph nodes J Thorac Cardiovasc Surg 1994 107 1 7 8283871
Naalsund A Rostad H Strøm EH Lund MB Strand TE Carcinoid lung tumors-incidence, treatment and outcomes: a population-based study Eur J Cardiothorac Surg 2011 39 565 9 10.1016/j.ejcts.2010.08.036 20888248
Warren WH Gould VE Long-term follow-up of classical bronchial carcinoid tumors. Clinicopathologic observations Scand J Thorac Cardiovasc Surg 1990 24 125 30 10.3109/14017439009098055 2166332