Diagnostic and prognostic implications of the World Health Organization classification of neuroendocrine tumors.

BACKGROUND: Neuroendocrine differentiation of tumors is often difficult to establish. In the same manner, the evaluation of the prognostic role of neuroendocrine differentiation may constitute a relevant clinical problem. Although different classifications are used for neuroendocrine tumors (NET) of different origin, the last World Health Organization (WHO) classification of NET, originally proposed for gastroenteropancreatic tumors, has proved to be a practical tool to allow pathologists to uniform the diagnoses and re-classify these tumors into 3 main categories. AIM: The present study was carried out in order to evaluate diagnostic and prognostic implications of NET reclassification according to the last WHO classification of NET. MATERIALS AND METHODS: Thirty-one tumors with an initial diagnosis referable to a NET achieved before 1999 were independently evaluated by 3 pathologists on the basis of the 2000 WHO classification of NET. Immunohistochemistry for panneuroendocrine markers and Ki-67 was also performed in all cases. RESULTS: Twelve, 14, and 4 tumors were respectively reclassified as well-differentiated NET, well-differentiated neuroendocrine carcinoma and poorly differentiated neuroendocrine carcinoma; 1 tumor was reclassified as mixed endocrine-exocrine tumor. Two or more neuroendocrine markers were expressed in all NET regardless of histotype, differentiation degree, and site of primary tumor. After revision, 10 of the 31 tumors under study (32%) changed histo-prognostic category when compared to the initial diagnosis. Ki-67 score was the best predictor of survival at the multivariate analysis. CONCLUSION: The WHO classification is suitable to accurately reclassify tumors with an initial diagnosis referable to a NET and to separate these tumors in 3 well-distinct histo-prognostic categories with relevant clinical implications. Ki-67 score seems to be a better predictor of survival than the degree of differentiation.

Pancreatic endocrine tumors: recent advances.

Pancreatic endocrine tumors (PET's) can be divided on a clinical and pathologic basis into ten classes [insulinomas, gastrinomas (Zollinger-Ellison syndrome), VIPomas (Verner-Morrison syndrome, WDHA, pancreatic cholera), glucagonomas, somatostatinomas, ACTH-releasing tumors (ACTHomas), growth hormone-releasing factor secreting tumors (GRFomas), nonfunctioning or pancreatic polypeptide secreting tumors (non-functioning PET), PET's causing carcinoid syndrome and PET's causing hypercalcemia)]. Recent reports suggest calcitonin-secreting PET's also rarely occur but whether they cause a distinct clinical syndrome is unclear. PET's resemble carcinoid tumors histologically; in their ability to synthesize and frequently secrete multiple peptides such as neuroendocrine cell markers (chromogranins); their biologic behavior and their tumor growth patterns. Both groups of tumors are highly vascular, have high densities of somatostatin receptors and similar tumor localization studies including somatostatin receptor scintigraphy are used for both. PET's, similar to carcinoids causing the carcinoid syndrome, require two separate treatment options be considered: treatment directed against the hormone-excess state and treatment directed against the tumor per se because of their malignant nature. In the last few years there have been advances in tumor diagnosis, localization methods, treatment approaches particularly related to the use of synthetic somatostatin analogues, and the definition of the role of surgical procedures in these diseases. Important other advances include insights into the long-term natural history of PET's particularly from studies of gastrinomas, which allow prognostic factors to be identified and the timing of treatment options to better planned, as well as insights into the molecular basis of these disorders. The latter includes both a description of the molecular basis of the genetic inherited syndromes associated with PET's or carcinoid tumors, as well as an increased understanding of the molecular basis for sporadic PET's or carcinoid tumors. Each of these areas will be briefly highlighted in this presentation.

[Endocrine-cell stomach tumors]. / Endokrinnokletochnye opukholi zheludka.

Screening of the endocrine cell participation in the stomach carcinoma has been performed. Endocrine cells are found in all stomach tumors and those in which these cells occupy more than 75% of the surface are distinguished as endocrine cell carcinomas (ECC). They are subdivided into well (WD), moderately (MD) and poorly differentiated (PD). ECC are more frequently observed in males, their predominant location is cardia and fundus. The growth in the deep parts of mucosa and submucosa (this determines late clinical symptoms) is characteristic for these tumors. Alveolar, trabecular and glandular structural variants are observed in WD ECC and MD ECC, while PD ECC corresponded to small cell carcinoma (iat cell and intermediate types). Prognosis is unfavorable in MD ECC and PD ECC. Apart from this amacrine and combined tumors with an endocrine component are described. The authors emphasize the necessity to single out ECC from whole group of stomach carcinoma.

[The systematization of APUD tumors]. / Kum sistematizatsiiata na APUD-tumorite.

The mechanisms involved in neuroendocrine transmission of peptides, underlying the so-called classification of multiple endocrine neoplasms (MEN), are described. Three cases from the clinical practice are followed up where facilitation of the diagnosis and the results of treatment are related to the tumor markers' values.

[Neuroendocrine system and its tumors]. / Neuroendokrines System mit seinen Tumoren.

The original classification of neuroendocrine tumours proposed by Pearse was based on a common embryologic origin in the neuroectoderm. The term, carcinoid, literally means carcinoma-like, was coined in 1907 to describe the histologic similarity of these tumors to carcinomas on the one hand and their generally indolent biologic behaviour on the other hand. Neuroendocrine tumours represent a group with complex biological, histological, ultrastructural and immunocytochemical properties. This concept was replaced by another classification based on results of modern techniques (electron microscopy, immunocytochemistry, molecular and DNA analyses). This permits a more reliable classification of tumours, that can be used to determine their biological behaviour and prognosis.

Apudomas / Apudomas

Se revisa la literatura mundial y se actualizan los conceptos sobre las celulas APUD y sus lesiones por hiperfuncion, tanto neoplasias como hipertroficas. Se acompana el articulo con algunas fotografias.

[Potentials and limits for the histologic diagnosis of apudomas]. / Vozmozhnosti i ogranicheniia gistologicheskoi diagnostiki apudom.

One should differentiate apudomas, two-component tumors (a combination of apudoma with a non-endocrine tumor), apudoma-like tumors and non-endocrine ones with admixture of APUD cells among the tumors with cells possessing the properties of APUD cells. Apudomas in their turn are represented by microapudomas and high- and low-differentiated macroapudomas. Routine light microscopy in most cases provides for apudoma verification, estimation of its differentiation and tissue origin, occasional identification of a secreted hormone.

Monoamine and diamine oxidase activity in the diagnosis of carcinoid tumors.

This study determines if one could distinguish foregut from midgut carcinoid tumors by quantitative measurement of the monoamine oxidase (MAO) and diamine oxidase (DAO) activities in homogenates of tumors. The MAO activity of 16 foregut carcinoid tumors (1850 +/- 342 pmol/mg/minute) was significantly higher than the MAO activity of 11 midgut carcinoid tumors (407 +/- 43 pmol/mg/minute, P less than 0.01) with no overlap between the groups. Although all ten of the midgut carcinoids had measurable DAO activity (720 +/- 190 pmol/mg/minute), with the exception of one duodenal carcinoid tumor (33 pmol/mg/minute) the nine foregut carcinoid tumors evaluated did not have detectable DAO activity. The MAO activity of all of the foregut carcinoids was higher than that of 6 islet cell tumors, 28 paragangliomas, and 12 medullary carcinomas of the thyroid. Quantitative MAO and DAO activity may be useful in distinguishing foregut carcinoid tumors from other related tumors.

[APUD system (problems of structural and functional organization, histogenesis and pathology)]. / APUD-sistema (voprosy strukturno-funktsional'noi organizatsii, gistogeneza, patologii).

The aspects of structure and function of the APUD-system under normal and pathological conditions are analysed. New terms and concepts (apudocyte, apudoblast, apudogenesis, apudopathies) applicable to the APUD-system are introduced. It is suggested that some apudocytes originate from polypotential stem cells. The dysfunctions of the APUD-system (apudopathies) are described, their classification is suggested, and the role of apudocytes in the endogenous mechanisms of oncogenesis is analysed.

[Immunocytochemistry of pancreatic and pancreatico-duodenal apudomas]. / Immunocytochimie des apudomes pancréatiques et pancréatico-duodénaux.

Immunocytochemical techniques, applied to material fixed with Bouin's fluid and using immune sera specific to various hormonal polypeptide(s), give a classification of pancreatic and pancreatico-duodenal apudomas based upon cellular functional activity. With a rane containing a minimum of five antibodies (gastrin, insulin, glucagon, somatostatin and pancreatic polypeptide), 15 tumours could be identified amongst the 22 tested. They were either "monohormonal" tumours (10 cases) or "bi- or polyhormonal" tumours (5 cases). In the remaining 7 cases, only rare cells were immunoreactive. A large number of immunoreactivities thus revealed in histological sections are clinically silent or are present in a "forme fruste".

APUD cells and the apudomas. A concept relevant to anaesthesia and endocrinology.

A variety of cells found in the pituitary and pineal glands, sympathetic nervous system and adrenal glands, the gut, pancreas, thyroid (C-cells), chemoreceptors (type I-Cells), lungs (P-cells), skin (melanocytes) and the urogenital tract have a common origin from the neural crest. These cells are programmed for neuro-endocrine function and, as a group, can be regarded as one of the physiological control systems. They secrete a variety of amine and peptide hormones and have common cytochemical characteristics from which the term APUD cell is derived. Tumours of these cells are referred to as 'apudomas' and may synthesise not only their own hormones but also those which are normally produced by other APUD cells. The relevant physiological properties of some of the peptides which have been described relatively recently are discussed and the principal clinical syndromes produced by the APUDomas are described.