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Publications and source records attributed to C Capella.
In this article new classifications of the neuroendocrine tumours of the lung, pancreas and gut are proposed. These classifications use a common frame work and attempt to consider the morphological, functional as well as biological features of the tumours.
This review summarizes knowledge on pathology of proliferative lesions of the pituitary gland in multiple endocrine neoplasia syndrome type 1 (MENS 1). When compared with sporadic tumors occurring in general population, pituitary adenomas associated with MENS 1 show the following distinguishing features: (1) they are more often endocrinologically functional, (2) they are more often GH or PRL-producing and (3) they are more frequently plurihormonal. The study of autoptic cases discloses that pituitary PRL or mixed GH-PRL cell adenomas in MENS are multiple and are associated with PRL or GH cell hyperplasia of the peritumoral parenchyma.
BACKGROUND: Low-grade gastric MALT lymphoma is an uncommon tumour for which a close association with chronic Helicobacter pylori infection has been suggested. However, given the rarity of MALT lymphoma of the stomach despite the high prevalence of H. pylori infection, it seems plausible that genetic host factors might play a fundamental role in gastric lymphomagenesis. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 83 patients with low-grade gastric MALT, all of whom resided in a geographic area (southern Switzerland and northern Italy) where the incidence of gastric tumours appears to be uncommonly high. RESULTS: One or more additional cancers were observed in 17 of 83 patients (20%, 95% CI 12% to 31%) for a total of 23 tumours. Of these, 5 were diagnosed prior to, 12 concomitantly with, and 7 after the gastric MALT lymphoma. Eleven patients had a single additional solid tumour (13%, 95% CI 7% to 22%); 3 patients had non-Hodgkin's lymphoma and one had Hodgkin's disease. Multiple additional cancers were present in 3 cases. Nine of 83 patients have died and 8 of them of a second cancer. CONCLUSIONS: Unexpectedly an extraordinarily large number of patients with other malignancies was observed in this series. The reasons for this finding are still unknown, but genetic alterations are speculated to play an important role.
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Endocrine cells of the gastric oxyntic mucosa, and especially the enterochromaffin-like (ECL) cells, are the progenitors of gastrin-promoted proliferative lesions whose tumorigenic potential largely depends on the background condition in which they arise. Hypertrophic gastropathy due to the familial multiple endocrine neoplasia (MEN-1)-associated or sporadic Zollinger-Ellison syndrome (ZES), diffuse chronic atrophic gastritis restricted to the corpus-fundus (type A CAG), with or without associated pernicious anemia, and Helicobacter pylori-related multifocal chronic atrophic gastritis are the usual background for such growths. The endocrine cell lesions have been classified as pseudohyperplasia (cell clustering unassociated with cell proliferation), hyperplasia (diffuse, linear, micronodular, adenomatoid), dysplasia (enlarged, adenomatous or fused micronodules, microinfiltration, nodular growth), and neoplasia (intramucosal or invasive carcinoids). The entire spectrum of endocrine cell proliferation, from hyperplasia to dysplasia and neoplasia, has been observed in MEN-ZES and diffuse type A CAG. Both hyperplastic and pseudohyperplastic changes occur with some frequency in the H. pylori-related chronic gastritis associated with ulcer disease or dyspepsia. However, because no progression to dysplastic or neoplastic lesions has thus far been documented in these latter conditions, their role in gastric endocrine cell tumorigenesis appears negligible.
Intraductal papillary growth of mucin producing hypersecreting, columnar cells characterizes a group of rare pancreatic exocrine neoplasms which we propose to call intraductal papillary-mucinous tumors (IPMT). We analysed the histopathology of 26 IPMT in relation to gastro-enteropancreatic marker expression, genetic changes and biology. Four IPMT showing only mild dysplasia were considered to be adenomas. Nine tumours displayed moderate dysplasia and were regarded as borderline. Severe dysplasia-carcinoma in situ changes were found in 13 IPMT which were therefore classified as intraductal carcinomas. Six of these carcinomas were frankly invasive and two of these had lymph node metastases. The invasive component resembled mucinous non-cystic carcinoma in all but one tumour which showed a ductal invasion pattern. Immunohistochemically, an intestinal marker type was found in most carcinomas, while gastric type differentiation prevailed among adenomas or borderline tumours. K-ras mutations (seven at codon 12 and one at codon 13) were found in 31% of IPMT (2 adenomas, 1 borderline, 5 carcinomas). Nuclear p53 overexpression was detected in 31% of IPMT (6 carcinomas and 2 borderline IPMT) and correlated with p53 mutations (one at exon 8 and the other at exon 5) in two carcinomas. p53 abnormalities were unrelated to K-ras mutation. c-erbB-2 overexpression was observed in 65% of IPMT, with various grades of dysplasia. Twenty-two of 24 patients are alive and well after a mean post-operative follow-up of 41 months. Only two patients, both with invasive cancer at the time of surgery, died of tumour disease. It is concluded that pancreatic IPMT encompass neoplasms which, in general, have a favorable prognosis, but are heterogeneous in regard to grade of dysplasia and marker expression. Adenoma, borderline tumour, intraductal carcinoma and invasive carcinoma can be differentiated. p53 changes but not K-ras mutation or c-erbB-2 overexpression are related to the grade of malignancy. Most IPMT differ in histological structure, marker expression and behaviour from ductal adenocarcinoma.
The syndrome of multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant tumour disease of the neuroendocrine system with manifestations in the parathyroids, pancreas, duodenum and pituitary gland and rarely also in the stomach and thymus. Recently, the MEN 1 gene locus has been mapped to the long arm of chromosome 11. This gene most likely belongs to the tumour suppressor genes, the allelic loss of which causes tumour development. The pancreatic and duodenal tumours may metastasize, but usually have a low malignant potential. Clinically, most MEN 1 patients present between the age of 20 and 35 with hyperparathyroidism and/or Zollinger-Ellison syndrome.
The general use of the term carcinoid for the classification of neuroendocrine tumors has become increasingly difficult during recent years. First, its definition and prognosis varies from site to site. Second, its traditional definition does not cover the whole morphological and biological spectrum of neuroendocrine tumors known today. We therefore propose new classifications of the neuroendocrine tumors of the lung, pancreas, stomach, duodenum, jejunum-ileum, appendix and colorectum. These classifications use a common framework and attempt to consider the morphological, functional and biological features of these tumors.
To clarify the mechanisms of the gastric mucosal immune--inflammatory response to Helicobacter pylori infection, surgical and biopsy specimens from asymptomatic uninfected, gastritis-free individuals and from H. pylori-positive ulcer patients with chronic gastritis were investigated using light and electron microscopy. Activation of the antigen-transporting endocytic--endosomal system, enhanced expression of the antigen-processing enzyme cathepsin E and de novo expression of antigen-presenting human leukocyte antigen (HLA)-DR molecules have been detected in H. pylori-colonized gastric epithelium. These findings may be crucial in the production of a mucosal immune-inflammatory response to H. pylori infection. Cytoplasmic swelling and vacuolation, micropapillary change, mucin loss, erosion of the juxtaluminal cytoplasm and cell desquamation were the main effects of bacterial cytotoxicity on gastric surface-foveolar epithelium. Activated macrophages and granulocytes (partly linked to the mucosal IgG immune response) concentrate in the foveolar-neck region of the mucosa, where they may enhance damage and impair regeneration of the epithelium. Both direct bacterial cytotoxicity and inflammatory cell aggression against gastric epithelium may predispose the patient to peptic ulcer disease.
A specific rabbit anti-human serum was used selectively to localize the aspartic proteinase cathepsin E to follicle associated epithelium (FAE) of human and rat intestine, including jejunum, ileum, appendix, colon and rectum, as well as of human palatine, pharyngeal and lingual tonsils. Coexpression of class II histocompatibility antigen HLA-DR antigen has been observed in some of the cathepsin E-positive epithelial cells. In addition, cathepsin E has been detected in a few mononuclear cells of intestinal lymphoid structures and tonsils resembling interdigitating reticulum cells of lymph nodes. Another aspartic proteinase, cathepsin D, has been found to be poorly represented in FAE and intensely expressed by macrophages. Electron immunocytochemistry localized cathepsin E to endosomal vesicles and endoplasmic reticulum of M cells in rat and human ileum as well as of M-like cells in human palatine tonsil. The results suggest a possible role of endosomal cathepsin E in the processing of macromolecules and microorganisms transported by M cells and related epithelial cells to mucosal associated lymphoid tissue (MALT).
BACKGROUND: Enterochromaffinlike (ECL) cell carcinoids recently observed in rats stimulated new interest in gastric endocrine tumors arising in humans. METHODS: Paraffin-embedded sections of 55 endocrine tumor cases were stained with H&E, mucin tests were performed, and immunoperoxidase was used for detecting endocrine markers; 23 cases were also investigated ultrastructurally. RESULTS: Forty-five argyrophil carcinoids, 9 neuroendocrine carcinomas, and 1 gastrinoma were identified. Three clinicopathologic subtypes of carcinoids were characterized: (1) twenty-eight cases, none metastatic, arose in a background of body-fundus atrophic gastritis and hypergastrinemia; (2) seven cases, 2 locally metastatic, were associated with hypertrophic gastropathy and hypergastrinemia due to multiple endocrine neoplasia/Zollinger-Ellison syndrome; and (3) ten were sporadic cases, 7 of which were deeply invasive, 6 metastatic, and 5 histologically atypical. All carcinoids showed histochemical and ultrastructural patterns of ECL cells. The 9 neuroendocrine carcinomas, all deeply invasive and metastatic, were composed of anaplastic, small- to intermediate-sized cells with high mitotic index and focal necrosis. CONCLUSIONS: Gastrin-promoted carcinoids represent a benign or low grade tumor disease, whereas sporadic carcinoids and neuroendocrine carcinomas are life-threatening neoplasms, independent of gastrin promotion.
A specific rabbit anti-human cathepsin E serum detected this aspartic proteinase in Langerhans cells of the skin, in interdigitating reticulum cells of lymph nodes and spleen and in histiocytosis X cells, but not in macrophages. Immunoblotting of tissue extracts confirmed the presence of cathepsin E in skin and lymph nodes. Electron immunocytochemistry with the protein A gold technique localized cathepsin E in the endoplasmic reticulum and in endosomal vesicles of both interdigitating and Langerhans cells, likely involving Birbeck bodies. A role of endosomal cathepsin E in antigen processing is suggested.
Among endocrine tumors occurring in the gastrointestinal tract, midgut argentaffin EC cell carcinoids, gastric argyrophil ECL cell carcinoids, duodenal gastrin cell tumors, and rectal trabecular L cell carcinoids (in order of decreasing frequency) are those occurring more frequently. Together, they account for more than 80% of such tumors. Duodenal somatostatin cell tumors, gangliocytic paragangliomas, and differentiated neuroendocrine carcinomas are also well-defined tumor entities. The carcinoid syndrome, either classical, with intermittent flushing, hypotension, and diarrhea, or atypical, with persistent histamine-type red flushing, bronchospasm, and no diarrhea, and Zollinger-Ellison syndrome, with severe peptide ulcer disease, are the only hyperfunctional syndromes consistently found in association with these tumors. The carcinoid syndrome occurs in about 10% of gastrointestinal carcinoids, usually in their advanced, metastatic stage. The Zollinger-Ellison syndrome occurs in association with about 40% of intestinal gastrin cell tumors, including small intramural growths. Tumor prognosis depends on the mode and site of presentation, histology, cell type(s), size, level of invasion, metastases (especially distant metastases), and associated clinical syndrome or background disease. Hormones, trophic factors, inherited genetic traits, somatic mutations, and some chronic inflammatory processes are pathogenetically important in a large proportion of cases.
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Two hundred and nineteen (33 GH, 21 GH-PRL, 38 PRL, 16 ACTH, 1 TSH cell functioning and 38 FSH-LH, 17 alpha-chain, 8 mixed, 27 minimal glycoprotein--MIN-GLYC--, 11 small argyrophil granule--SAG--, 4 silent TSH-sTSH--and 5 silent ACTH-sACTH--cell nonfunctioning) adenomas were investigated immunohistochemically with antibodies against ACTH, GH, PRL, TSH, FSH, LH alpha-hCG, chromogranin A (CgA) and chromogranin B (CgB). For immunostaining of CgB a novel monoclonal (B 11) antibody was employed. All types of adenomas were positive for CgB. CgA was widely expressed in nonfunctioning FSH-LH, MIN-GLYC, SAG, MIXED, alpha-chain adenomas and in the single TSH cell functioning adenoma. CgA was lacking both in PRL and ACTH functioning adenomas and was poorly expressed in GH and GH-PRL functioning adenomas. The distribution of Grimelius' silver paralleled that of CgA-IR, but not that of CgB-IR. We conclude that: 1) CgB may be considered as an universal granular marker for pituitary adenomas, 2) CgA is an important marker for nonfunctioning adenomas, 3) the pattern of distribution of CgA and CgB for most nonfunctioning ("null cell" according to Kovacs et al.) adenomas favors their origin from glycoprotein producing (FSH/LH, TSH) cells.
A series of 3 tumourlets (TLs), 81 typical carcinoids (TCs), 14 atypical carcinoids (ACs) (well-differentiated neuroendocrine carcinomas, WDNCs) and 24 small cell-intermediate cell carcinomas (SCC-ICCs) of the lung were studied. Histopathological features were correlated with amine and peptide hormone immunoreactivity and with clinical data. All types of tumours expressed general neuroendocrine (NE) markers: Grimelius positivity and chromogranins were detected more frequently in well-differentiated (TLs, TCs) than in less well differentiated tumours [ACs (WDNCs) and SCC-ICCs] whereas neuron specific enolase (NSE) was prominent in the latter tumours. TLs and peripheral TCs were benign, often showing a paraganglioid pattern and frequently expressing gastrin-releasing peptide (GRP), which is present in the peripheral airways of normal lung. Central TCs were associated with lymph node metastases in 8.5% of the cases, frequently had a trabecular architecture, often associated with human milk fat globule 2 (HMFG2)-positive acinar and rosette-like structures, and were mainly immunostained for the alpha-subunit of human chorionic gonadotrophin (alpha-hCG) and serotonin. ACs (WDNCs) were associated with intrathoracic and/or extrathoracic metastases in 57.1% of the cases with a mortality rate of 35.7%. Their histological and cytological features were intermediate between those of TCs and SCC-ICCs. ACs (WDNCs) expressed serotonin and alpha-hCG less frequently than TCs. All SCC-ICCs were surgically treated and displayed a mortality rate of 91.6% with a mean survival of 10.2 months after operation. These tumours were characterized by high expression of HMFG2 and NSE, while the expression of both orthotopic (serotonin, GRP) and ectopic (ACTH) specific NE substances was very low. Since all TCs (either central or peripheral) had a favourable outcome, while about 36% of ACs (WDNCs) were fatal, the latter seem more appropriately designated "well-differentiated NE carcinomas". The differential diagnosis between different NE tumours of the lung is important and is mainly based on morphology. Both panendocrine and specific immunohistochemical markers are helpful in distinguishing the less aggressive, mostly benign varieties from the more malignant varieties.
We report eight cases of neuroendocrine carcinomas found within inguinal (five cases), axillary (two cases), and submandibular (one case) lymph nodes. The patients underwent extensive investigations, but no primary tumor was found in any case. Although the existence of an occult or regressed primary cannot be ruled out, the possibility of a lymph node origin should be considered on the basis of epithelial inclusions or anomalous carcinomatous differentiation of stem cells of the lymphoreticular system.
Immunohistological analysis of the expression of lactase protein in adults with hypolactasia has been carried out using monoclonal antibodies. Eight different antibodies that recognize at least three distinct epitopes on the lactase protein each gave the same result. Strong brush border staining was observed in all the lactase-persistent adults. No staining at all was detected in 9 of the hypolactasic subjects. In the remaining 12 individuals a mosaic pattern of expression was observed: small patches of enterocytes stained strongly, whereas the surrounding areas showed no staining at all. Sucrase-isomaltase, in contrast, showed no such mosaicism in these or in any of the other individuals. The mosaicism observed in the 12 hypolactasic individuals suggests that the differentiation of the columnar cells along the villus is not homogeneous. Furthermore, the existence of two patterns of expression of the lactase protein in the lactase-deficient individuals (i.e., absence of protein and mosaicism), if characteristic of the entire length of the intestine of the individuals tested, would suggest the existence of two phenotypes of adult-type hypolactasia in the population studied.