Luigi Insabato, Marialaura Del Basso De Caro, Elena Caramanna, Gaetano De Rosa

Department of Biomorphological and Functional Science, Section of Anatomic Pathology, University Federico II of Naples, Faculty of Medicine, Naples, Italy

TABLE OF CONTENTS

1. Abstract

2. Introduction

3. Problems with terminology

4. Neuroendocrine tumors are now recognized in almost all sites in the body

5. Diagnostic criteria

5.1. Immunohistochemical markers

6. Molecular features of NET

7. Multiple endocrine neoplasia syndromes

8. Conclusions/Perspectives

9. References

1. ABSTRACT

Here we review the pathologic features of a specialized tumor subset, collectively referred to as neuroendocrine tumors. These tumors arise almost anywhere in the body but many issues regarding their diagnosis and classification remain to be settled. Recent technical improvements, have increased the rate of detection, and have contributed to better diagnosis and classification of these tumors.

2. INTRODUCTION

The evolution of the concept of the neuroendocrine cell and the definition of the neuroendocrine tumours (NET) are one of the most fascinating and only partially clarified issues in the literature. The identification of Kulchitsky's cells and the description of a special type of intestinal tumor, i.e. carcinoid, by Oberndorfer in the German literature in 1907, represent early scientific contributions to the elucidation of carcinoid tumours (1); few years later in 1914 Pierre Masson studying carcinoid tumours of the appendix observed that the neoplastic cells contained abundant secretory granules strongly stained with silver nitrate, and he showed that Kulchitsky's cells had the same features as the cells of carcinoid tumours (2). The work of Friedrich Feyrter and later Anthony Pearse established the concept of a diffuse endocrine cell system (3-4). NET arise from the neuroendocrine system, a diffuse system composed of the endocrine and the nervous systems interacting each other. More specifically, the endocrine system is primarily a network of glands producing hormones, along with cells that belong to the disseminated neuroendocrine system (DNS), scattered throughout other organs (5-6). As a matter of fact a wide variety of cells that are present in the central and peripheral nervous system and in many classic endocrine organs made the disseminated neuroendocrine cell system. Cells and tumours of the DNS may be divided in two principal groups: neural type, including neuroblastoma, pheochromocytoma, and paraganglioma; and epithelial type which include carcinoid and NET from many sites.

3. PROBLEMS WITH TERMINOLOGY

The broad heterogeneity characterizing NET has posed problems regarding their correct classification. NET can develop in any organ or district of the body; most of them arise from the gastroenteropancreatic (GEP) district, hence the distinction in GEP and non-GEP neuroendocrine tumours previously referred to as carcinoids. They occur most frequently in the gastrointestinal system, where they are most common in the small intestine, appendix, and rectum, and in the bronchi as the most frequent extragastrointestinal site. NET are defined nowadays as endocrine tumors (ET), and they are divided into functional and non-functional tumours. Functional tumours are classified based upon the hormones they produce and the associated endocrine syndrome. The more common functional tumours are listed in table 1. Nonfunctioning tumours are either an incidental finding or are associated with an expanding mass (7). These two groups of NET are often histologically indistiguishable. Most NET are carcinoid, pheochromocytoma, medullary thyroid carcinoma, parathyroid tumors, and pituitary tumours. The rest of NET is composed of poorly differentiated tumours with a more aggressive behavior, including Merkel cell carcinoma. The new WHO classification, divided NET into the followings categories: 1. well-differentiated endocrine tumors, 2. well-differentiated endocrine carcinomas, formerly defined as carcinoids and malignant carcinoids respectively, 3. poorly differentiated endocrine carcinomas and 4. mixed exocrine-endocrine tumours on the basis of their location, tumor size, histologic features (angioinvasion and Ki-67 index), and biologic behavior. (8). This classification enables NET in the gastroenteropancreatic tract to be clearly diagnosed, but unfortunately this is not applied to lung tumours. The classification of NET of the lung is evolving and complex; they are currently classified in typical carcinoid, atypical carcinoid, small-cell lung carcinoma (SCLC), and large-cell neuroendocrine carcinoma (LCNEC) (9). Their separation rests primarily on mitotic rate and the presence or absence of necrosis, and, in the case of separating SCLC from LCNEC, cell morphology.

SCLC account for 20% to 25% of primary carcinomas of the lung and it is now widely acknowledged that they form the aggressive end of the spectrum of neuroendocrine lung tumours. Extrapulmonary small cell carcinomas in comparison are rare, however the clinical behavior of these tumours is generally aggressive, similar to their pulmonary counterparts (10).

Pretty nearly two thirds of all neuroendocrine tumors (NET) are located in the gastroenteropancreatic tract. They originate from the diffuse neuroendocrine cells distributed throughout the gut, and from the pancreatic islet cells. They usually produce bioactive substances and show immunoreactivity to neuroendocrine markers; based on their endocrine secretion, they are functional active or inactive. Functionally active NET present with clinical symptoms because of excessive hormone release from the tumor cells; examples of such events are insulinomas, gastrinomas, VIPomas, somatostatinomas , glucagonomas, ACTH producing tumours.

Finally, goblet cell carcinoid of the appendix is a distinct entity, it arise from a pluripotent cell with divergent neuroendocrine and mucinous differentiation. The dual endocrine and glandular differentiation has led to confusion in the nomenclature (adenocarcinoid, crypt cell carcinoma, and mucinous carcinoid. These tumours frequently have signet ring cell morphology. They are more similar to a adenocarcinoma of the colon, indeed they are widely invasive, with a high cellular proliferation rate and dysregulation of the cell cycle with up-regulation of cyclin Dl and p21, and down-regulation of p16 (11).

4. NEUROENDOCRINE TUMORS ARE NOW RECOGNIZED IN ALMOST ALL SITES IN THE BODY

The diverse extragastrointestinal sites where NET have been reported to occur are shown in table 2 (12-28).

Redarding the genital system, NETs are more common in the female than male genital tract; most are uterine small cell carcinomas or ovarian carcinoids. Most male genital tract NET are prostatic small cell carcinomas or testicular carcinoids. The prostate contains the largest number of neuroendocrine cells of any genitourinary organ. Most of these cells contain chromogranin A (Figure 1B) and serotonin (29). In histologically typical prostate adenocarcinoma, particular attention has been given to the presence of eosinophilic neuroendocrine cells which stained positively with chromogranin A. The term Paneth cell-like has been used to describe these neuroendocrine cells (30). More than ten years ago it has been demonstrated that androgen-deprivation therapy is associated with an increased number of neuroendocrine cells in hormonally treated prostate carcinoma (31).

5. DIAGNOSTIC CRITERIA AND IMMUNOHISTOCHEMICAL MARKERS

The hallmark of well-differentiated endocrine tumour is the presence of small cells containing regular, well-rounded nuclei, frequently arranged in a neuroendocrine growth pattern, i.e. well-defined nests of tumour cells separated by thin fibrovascular septa, or they show strands of tumour cells arranged in trabeculae, ribbons or festoons (Figure 1A).

Well-differentiated endocrine carcinomas share many of the features of the above described tumour, however they are distinguished by more pronounced cytologic atypia, increased mitotic activity and frequent foci of necrosis, and vascular invasion.

Poorly differentiated endocrine carcinomas represent the more aggressive end of the spectrum of NET, with significant morbidity and mortality, and one of the most common histological subtypes in the lung (Figure 2). In these tumours the patterns of growth above described as ribbon-like, trabecular or festoons arrangement of tumour cells are rarely seen.

Merkel cell carcinoma deserves a mention apart, also called neuroendocrine carcinoma of the skin, most often develops in older people (Figure 3A). Long-term sun exposure or having a weak immune system may increase the risk of developing Merkel cell carcinoma. Because of its diffuse pattern of growth, and of its uniform small tumor cells, Merkel cell carcinoma is potentially mistaken for lymphoma. Histologically the dermis is diffusely involved by monotonous sheets of tumour cells, with a narrow band of intact papillary dermis (Figure 3B). The diagnosis of Merkel cell carcinoma can be reliably made even on cytological specimens obtained by fine needle aspiration biopsy (Figure 3C); the smears are usually highly cellular, the neoplastic cells have scanty cytoplasm, and the nuclei are round and vesicular, with a typically fine granular (dusty) chromatin and small multiple nucleoli often located in proximity of the nuclear membrane. High mitotic activity, and numerous apoptotic bodies are frequently seen (32).

The diagnosis of NET is a challenge even for pathologists dealing with cytological specimens, and in proper hands a reliable cytological diagnosis can be made (33-34).

5.1 Immunohistochemical markers

Immunohistochemically NET express positive reactions to neuroendocrine markers, including neuron specific enolase (NSE), synaptophysin, and chromogranin A (Figure 1B). NSE is a very sensitive, albeit no too specific marker for NET, reacting with some nonneuroendocrine tumours. NSE should be used only with other broad-spectrum markers of neuroendocrine cells in the diagnosis of NET.

Many endocrine tumours express somatostatin receptors, and very recently a scoring system for somatostatin receptor type 2A has been proposed in NET (35).

CD56 or neural cell adhesion molecule (NCAM) has become the antibody of choice in many laboratories being one of the most sensitive marker in this context (36-37).

The homeobox gene products such as thyroid transcription factor 1 (TTF1) and CDX-2 might be inappropriately expressed in NET.

CDX-2 expression can be highly specific in identifying NET of intestinal origin whereas TTF-1 expression could be helpful in identifying NET of pulmonary origin (38-39).

Immunohistochemically Merkel cell carcinoma shows immunoreactivity for both neuroendocrine and epithelial markers being positive for NSE, CD56, synaptophysin, chromogranin A, and showing a distinct perinuclear dot-like positivity for CK20 and neurofilaments (Figure 3D) (40).

It should be kept in mind that the immunohistochemical profiles are not specific for a particular NET, however the combination of the various antibodies can be helpful for diagnosis, prognosis, and therapy.

6. MOLECULAR FEATURES OF NET

The molecular pathogenesis of NET is still largely unknown. Recently authors underlined that the malignant progression of GEP endocrine tumors seems to be associated with complex allelotypes and chromosomal instability (41). More recently in a review of NET of the lung it has been suggested that a molecular classification of NET should be integrated to morphology, for a better definition of the different histological types and a more appropriate selection of the therapeutic strategy (42).

Hormones and neuropeptides may influence the activities of lymphoid organs and neuroendocrine cells. Somatostatin (SS) and cortistatin (CST) are two hormones sharing marked amino acidic sequence homology, as a result of a probable primordial gene duplication in chromosomes 3 and 1, respectively (43). The current literature supports a strong association between high level of SS expression and neuroendocrine tumours, including pituitary adenomas, endocrine pancreatic tumours, gastrointestinal and lung carcinoids, paragangliomas, pheochromocytomas, small cell carcinomas, Merkel cell carcinomas, neuroblastomas and medullary thyroid Carcinomas (44-46). While the role of SS in neoplastic conditions has been extensively studied, establishing the usefulness of SS analogs in the control of hormonal secretion and neoplastic growth in several neuroendocrine tumours, less clear remains the role of CST in the same tumours. Interestingly, in a very recently review, authors conclude that CST analog might open new interesting perspectives in the treatment of neuroendocrine tumours (43).

7. MULTIPLE ENDOCRINE NEOPLASIA SYNDROMES

Multiple endocrine neoplasia (MEN) syndromes consist of 2 categories, MEN 1 and MEN 2. MEN 1 is a relatively uncommon inherited disease: individuals who inherit the gene for MEN 1. The endocrine glands most commonly affected by MEN 1 are the parathyroid, pancreas, and pituitary glands. (the endocrine glands which start with the letter "P"). Hyperparathyroidism is the most common manifestation of MEN 1, caused by hyperplasia of multiple parathyroid glands. Penetrance is almost 100% by age 50 years. In patients with MEN1, parathyroid hyperplasia or multiple adenomas occur in approximately 90-95%. (47). MEN 2 is a rare autosomal dominantly inherited familial cancer syndrome caused by RET proto-oncogene germline mutations. It is associated with an increased risk for medullary carcinoma of the thyroid (onset in early adulthood), pheochromocytoma and parathyroid adenoma/hyperplasia. Medullary thyroid carcinoma is a well-differentiated thyroid tumor that maintains the typical features of parafollicular C cells, and somatic RET mutations have been found in 40-50% of these tumours. Very recently authors demonstrated that point mutations in RET, at the germline level in (virtually all) MEN 2 patients and, at the somatic level, in about half of the sporadic cases, characterize medullary thyroid carcinoma, suggesting that these patients might benefit of novel treatments based on RET inhibition (48).

8. CONCLUSIONS AND PERSPECTIVE

Very recently authors, in evaluating the usefulness of WHO classification of NET for selecting an appropriate treatment, suggested that some clinicopathological parameters, i.e. the site of the primary tumour, liver involvement, high MIB-1 levels, and a long disease free survival could be important, although they conclude that the clinical and prognostic impact of each of these variables remains to be established (49).

Finally although at present the knowledge of the genetic background of NET may have not direct bearing on treatment and outcome, distinction on genetic analysis could become important to establish targeted therapeutic strategies for future treatment of neuroendocrine tumours.

9. REFERENCES

1. G. Klöppel: Oberndorfer and his successors: from carcinoid to neuroendocrine carcinoma. Endocr Pathol 18, 141-144 (2007)
doi:10.1007/s12022-007-0021-9
PMid:17960501

2. A. Gosset, P. Masson: Le tumeurs endocrines de l'appendice. Press Med 22, 237-240 (1914)

3. F. Feyrter: Uber die these von den peripheren endokrinen drusen. Wien Z Innere Med Grenzgeb 10, 9-36 (1946)

4. A.G.E. Pearse: The cytochemistry and ultrastructure of polypeptide hormone-producing cells of the APUD series and the embryologic, physiologic amd pathologic implications of the concept. J Histochem Cytochem 17, 303-313 (1969)

5. R. Day, M. Salzet: The neuroendocrine phenotype, cellular plasticity, and the search for genetic switches: redefining the diffuse neuroendocrine system. Neuro Endocrinol Lett 23, 379-384 (2002)

6. S.B. Baylin: Neuroendocrine differentiation: a prognostic feature of non-small-cell lung cancer? J Clin Onco l7, 1375-1376 (1989)

7. K.A. DeLellis, K.V. Lloyd, P.U. Heitz, C. Eng: Tumours of Endocrine Organs. Lyon France IARC Press, 2003. World Health Organization Classification of Tumours. Lyon France IARC Press (2004)

8. E. Solcia, G. Klöppel, L.H. Sobin: Histological typing of endocrine tumours. World Health Organization. International Histological Classification of Tumours. Blackwell Publishing Second edition. Springer Verlag, Berlin (2000)

9. E. Brambilla, W.D. Travis, T.V. Colby, B. Corrin, Y. Shimosato: The new World Health Organization classification of lung tumours. Eur Respir J 18, 1059-1068 (2001)
doi:10.1183/09031936.01.00275301
PMid:11829087

10. J. Vrouvas, D.V. Ash: Extrapulmonary small cell cancer. Clin Oncol (R Coll Radiol) 7, 377-381 (1995)
doi:10.1016/S0936-6555(05)80009-3
PMid:8590700

11. R. Kanthan, A. Saxena, S.C. Kanthan: Goblet cell carcinoids of the appendix: immunophenotype and ultrastructural study. Arch Pathol Lab Med 125, 386-390 (2001)

12. A. Ferrero, C. Gallino, G. D'Aloisio, G. Gandini, M. Garavoglia: Primary neuroendocrine carcinoma of the liver: difficult diagnosis of a rare neoplasm. Acta Chir Belg 99, 299-302 (1999)

13. H. Sethi, M. Madanur, P. Srinivasan, B. Portmann, N. Heaton, M. Rela: Non-functioning well-differentiated neuroendocrine tumor of the extrahepatic bile duct: an unusual suspect? Hepatobiliary Pancreat Dis Int 6, 549-552 (2007)

14. D.E. Hansel, J.I. Epstein, E. Berbescu, S.W. Fine, R.H. Young, J.C. Cheville: Renal carcinoid tumor: a clinicopathologic study of 21 cases. Am J Surg Patho l31, 1539-1544 (2007)
doi:10.1097/PAS.0b013e31802e290d
PMid:17667548

15. M. Mascolo, V. Altieri, C. Mignogna, G. Napodano, G. De Rosa, L. Insabato: Calcitonin-producing well-differentiated neuroendocrine carcinoma (carcinoid tumor) of the urinary bladder: case report. BMC Cancer 5, 88-91 (2005)
doi:10.1186/1471-2407-5-88
PMid:16048646    PMCid:1190163

16. L. Insabato, G. De Rosa, L.M. Terracciano, G. Lupoli, D. Montedoro, C. Ravetto: A calcitonin-producing neuroendocrine tumor of the larynx: a case report. Tumori 79, 227-230 (1993)

17. G.X. Papacharalampous, S. Korres, M. Tzagaroulakis, I. Segas, E. Ferekidis: Paraganglioma of the larynx: A case report. Med Sci Monit 13, 145-148 (2007)

18. M. Capelli, G. Bertino, P. Morbini, C. Villa, S. Zorzi, M. Benazzo: Neuroendocrine carcinomas of the upper airways: a small case series with histopathological considerations. Tumori 93, 499-503 (2007)

19. R.J. Lapoint, P.A. Bourne, H.L. Wang, H. Xu: Coexpression of c-kit and bcl-2 in Small Cell Carcinoma and Large Cell Neuroendocrine Carcinoma of the Lung. Appl Immunohistochem Mol Morphol 15, 401-406 (2007)

20. K.A. Vidulich, S.E. Donley, M. Duvic: Multinodular cutaneous spread in neuroendocrine tumor of the breast: an unusual presentation. Am J Clin Dermato l8, 379-383 (2007)

21. K.M. Webb, J.J. Laurent, D.O. Okonkwo, M.B. Lopes, M.L. Vance, E.R. Jr Laws: Clinical characteristics of silent corticotrophic adenomas and creation of an internet-accessible database to facilitate their multi-institutional study. Neurosurgery 53, 1076-1084 (2003)
doi:10.1227/01.NEU.0000088660.16904.F7
PMid:14580274

22. A. Dham, A.M. Truskinovsky, A.Z. Dudek: Thymic carcinoid responds to neoadjuvant therapy with sunitinib and octreotide: a case report. J Thorac Oncol l3, 94-97 (2008)
doi:10.1097/JTO.0b013e31815eb7a2
PMid:18166847

23. K. Cupisti, A. Wolf, A. Raffel, M. Schott, D. Miersch, Q. Yang, C.F. Eisenberger, H.D. Röher, W.T. Knoefel: Long-term clinical and biochemical follow-up in medullary thyroid carcinoma: a single institution's experience over 20 years. Ann Surg 246, 815-821 (2007)

24. S.A. Boikos, C.A. Stratakis: Molecular mechanisms of medullary thyroid carcinoma: current approaches in diagnosis and treatment. Histol Histopathol 23, 109-116 (2008)

25. C.A. Koch, N. Azumi, M.A. Furlong, R.C. Jha, T.E. Kehoe, C.H. Trowbridge, M.T. O'Dorisio, G.P. Chrousos, S.C. Clement: Carcinoid Syndrome Caused by an Atypical Carcinoid of the Uterine Cervix. J Clin Endocrinol Met 84, 4209-4213 (1999)
doi:10.1210/jc.84.11.4209

26. Z. Bing, L. Levine, J.A. Lucci, S.S. Hatch, M.A. Eltorky: Primary Small Cell Neuroendocrine Carcinoma of the Vagina: A Clinicopathologic Study. Arch Pathol Lab Med 128, 857-862 (2004)

27. P. Dursun, M.C. Salman, C. Taskiran, A. Usubutun, A. Ayhan: Primary neuroendocrine carcinoma of the fallopian tube: A case report. Am J Obst Gynecol 190, 568-571 (2004)
doi:10.1016/j.ajog.2003.07.030
PMid:14981411

28. K. Behnam, D. Kabus, M. Behnam: Primary ovarian undifferentiated non-small cell carcinoma, neuroendocrine type. Gynecol Oncol 92, 372-375 (2004)
doi:10.1016/j.ygyno.2003.09.031
PMid:14751189

29. P.A. Abrahamsson: Neuroendocrine cells in tumour growth of the prostate. Endocr Relat Cancer 6, 503-519 (1999)
doi:10.1677/erc.0.0060503
PMid:10730904

30. M.G. Weaver, F.W. Abdul-Karim, J.R. Srigley: Paneth cell-like change and small cell carcinoma of the prostate. Two divergent forms of prostatic neuroendocrine differentiation. Am J Surg Pathol 16, 1013-1016 (1992)
doi:10.1097/00000478-199210000-00013
PMid:1329569

31. A.G. Aprikian, C. Cordon-Cardo, W.R. Fair, V.E. Reuter: Characterization of neuroendocrine differentiation in human benign prostate and prostatic adenocarcinoma. Cancer 71, 3952-3965 (1993)
doi:10.1002/1097-0142(19930615)71:12<3952::AID-CNCR2820711226>3.0.CO;2-X
PMid:7685237

32. G. Pettinato, A. De chiara, L. Insabato, P. Angrisani, J. Saurel, J.L. Monard, V. Ruocco, F. Quarto: Neuroendocrine (Merkel Cell) Tumor of the skin: Fine-needle aspiration cytology, histology, electron micrscopy and immunohistochemistry of 12 cases. Appl Pathol 6, 17-27 (1988)

33. R. Arora, S.R. Mathur, M. Aron, K. Verma, V.K. Iyer, V.K. Arora, M.C. Sharma: Oncocytic carcinoid tumor of the lung: a case report of diagnostic pitfall in filter membrane preparation of bronchial washings. Acta Cytol 51, 907-910 (2007)

34. J.M. Prosser, D. Dusenbery: Histocytologic diagnosis of neuroendocrine tumors in the liver: A retrospective study of 23 cases. Diagn Cytopathol 16, 383-391 (1997)
doi:10.1002/(SICI)1097-0339(199705)16:5<383::AID-DC2>3.0.CO;2-D
PMid:9143838

doi:10.1002/(SICI)1097-0339(199705)16:5<383::AID-DC2>3.3.CO;2-2
PMid:9143838

35. M. Volante, M.P. Brizzi, A. Faggiano, S. La Rosa, I. Rapa, A. FerreroA, G. Mansueto, L. Righi, S. Garancini, C. Capella, G. De Rosa, L. Dogliotti, A. Colao, M. Papotti. Somatostatin receptor type 2A immunohistochemistry in neuroendocrine tumors: a proposal of scoring system correlated with somatostatin receptor scintigraphy. Mod Pathol 20, 1172-1182 (2007)
doi:10.1038/modpathol.3800954
PMid:17873898

36. S. Lantuejoul, D. Moro,R.J. Michalides, C. Brambilla, E. Brambilla: Neural cell adhesion molecules (NCAM) and NCAM-PSA expression in neuroendocrine lung tumors. Am J Surg Pathol 22, 1267-1276 (1998)
doi:10.1097/00000478-199810000-00012
PMid:9777989

37. O. Kaufmann, T. Georgi, M. Dietel: Utility of 123C3 monoclonal antibody against CD56 (NCAM) for the diagnosis of small cell carcinomas on paraffin sections. Hum Pathol 28, 1373-1378 (1997)
doi:10.1016/S0046-8177(97)90226-4
PMid:9416693

38. M. Barbareschi, C. Roldo, G. Zamboni, P. Capelli, A. Cavazza, E. Macri, M.G. Cangi, M. Chilosi, C. Doglioni: CDX-2 homeobox gene product expression in neuroendocrine tumors: its role as a marker of intestinal neuroendocrine tumors. Am J Surg Pathol 28, 1169-1176 (2004)
doi:10.1097/01.pas.0000131531.75602.b9
PMid:15316316

39. X. Lin, R.S. Saad, T.M. Luckasevic, J.F. Silverman, Y. Liu: Diagnostic value of CDX-2 and TTF-1 expressions in separating metastatic neuroendocrine neoplasms of unknown origin. Appl Immunohistochem Mol Morphol 15, 407-414 (2007)
doi:10.1097/01.pai.0000210414.15375.47

40. G. Pettinato, A. De Chiara, L. Insabato: Diagnostic significance of intermediate filament buttons in fine needle aspirates of neuroendocrine (Merkel cell) carcinoma of the skin. Acta Cytol 33, 420-421 (1989)

41. D. Furlan, R. Cerutti, S. Uccella, S. La Rosa, E. Rigoli, A. Genasetti, C. Capella: Different molecular profiles characterize well-differentiated endocrine tumors and poorly differentiated endocrine carcinomas of the gastroenteropancreatic tract. Clin Cancer Res 10, 947-857 (2004)
doi:10.1158/1078-0432.CCR-1068-3
PMid:14871972

42. L. Righi, M. Volante, I. Rapa, G.V. Scagliotti, M. Papotti: Neuro-endocrine tumours of the lung. A review of relevant pathological and molecular data. Virchows Arch 451, 51-59 (2007)
doi:10.1007/s00428-007-0445-0

43. M. Volante, R. Rosas, E. Allia, R. Granata, A. Baragli, G. Muccioli, M. Papotti: Somatostatin, cortistatin and their receptors in tumours. Mol Cell Endocrinol 286, 219-229
doi:10.1016/j.mce.2007.12.002
PMid:18248880

44. M. Papotti, S. Croce, L. Macri, A. Funaro, C. Pecchioni, M. Schindler, G. Bussolati: Correlative immunohistochemical and reverse transcriptase polymerase chain reaction analysis of somatostatin receptor type 2 in neuroendocrine tumours of the lung. Diagn Mol Pathol 9, 47-57 (2000)
doi:10.1097/00019606-200003000-00008
PMid:10718213

45. M. Papotti, S. Croce, M. Bello, M. Bongiovanni, E. Allia, M. Schindler, G. Bussolati: Expression of somatostatin receptor types 23 and 5 in biopsies and surgical specimens of human lung tumours. Correlation with preoperative octreotide scintigraphy. Virchows Arch 439, 787-797 (2001)

46. M. Papotti, U. Kumar, M. Volante, C. Pecchioni, Y.C. Patel: Immunohistochemical detection of somatostatin receptor types 1-5 in medullary carcinoma of the thyroid. Clin Endocrinol 54, 641-649 (2001)
doi:10.1046/j.1365-2265.2001.01175.x
PMid:11380495

47. M.L. Brandi, R.F. Gagel, A. Angeli, J.P. Bilezikian, P. Beck-Peccoz, C. Bordi, B. Conte-Devolx, A. Falchetti, R.G. Gheri, A. Libroia, C.J. Lips, G. Lombardi, M. Mannelli, F. Pacini, B.A. Ponder, F. Raue, B. Skogseid, G. Tamburrano, R.V. Thakker, N.W. Thompson, P. Tomassetti, F. Tonelli, S.A. Wells Jr, S.J. Marx.: Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 86, 5658-5671 (2001)
doi:10.1210/jc.86.12.5658

48. M. Santoro, A. Fusco: New drugs in thyroid cancer. Arq Bras Endocrinol Metabol 51, 857-861 (2007)
doi:10.1590/S0004-27302007000500025

49. E. Bajetta, L. Catena, G. Procopio, E. Bichisao, L. Ferrari, S. Della Torre, S. De Dosso, S. Iacobelli, R. Buzzoni, L. Mariani, J. Rosai: Is the new WHO classification of neuroendocrine tumours useful for selecting an appropriate treatment? Ann Oncol 16, 1374-1880 (2005)
doi:10.1093/annonc/mdi258
PMid:15939719

Key Words: Neuroendocrine, Tumour, Cancer, Neoplasia, Pathology, Classification, Review