Fausto Sessa

Intraductal papillary-mucinous tumours represent a distinct group of pancreatic neoplasms: an investigation of tumour cell differentiation and K-ras, p53 and c-erbB-2 abnormalities in 26 patients

Intraductal papillary growth of mucin producting 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 noncystic 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.

Prognostic criteria in nonfunctioning pancreatic endocrine tumours.

To identify prognostic subgroups among nonfunctioning (nonsyndromic) pancreatic endocrine tumours, a series of 61 tumours were analysed systematically for macroscopic, histopathological and immunohistochemical variables potentially predictive of malignancy. High-grade nuclear atypia, elevated mitotic rate and multifocal necrosis allowed us to separate 5 poorly differentiated carcinomas from 56 well differentiated tumours. Among the latter, 29 well-differentiated carcinomas showing gross local invasion or metastases were identified. Vascular or perineural microinvasion, Ki67 proliferative index >2%, mitotic rate ≥2, size ≥4 cm, capsular penetration, nuclear atypia, lack of progesterone receptors and presence of calcitonin were among the variables correlated with malignancy. The first two were the most sensitive and specific. Their presence or absence was used in the 27 tumours lacking evidence of malignancy at the time of surgery to separate 11 cases with increased risk of malignancy (in 2 of which metastases developed during follow-up) from 16 cases with limited risk. The resulting four prognostic groups of nonfunctioning pancreatic endocrine tumours (limited- and increased-risk tumours, well-differentiated carcinomas and poorly differentiated carcinomas) showed distinct survival curves, which were significantly affected by vascular microinvasion, Ki67 proliferative index and metastases.

Gastric Carcinoids and Related Endocrine Growths

A series of 30 gastric endocrine tumours has been revised in the light of available available cytologic and clinicopathologic information. Among 24 well differentiated endocrine tumours-16 with and 8 without chronic atrophic gastritis (CAG)-3 gastrin cell tumours have been distinguished from 21 argyrophil carcinoids, 15 of which showed light- and/or electronmicroscopy patterns of enterochromaffin-like (ECL) cell tumours, 2 of EC cell tumours and 1 of D1/P cell tumour. One case of mixed carcinoid/adenocarcinoma and 5 cases of endocrine carcinomas, 4 poorly and 1 moderately differentiated, were also identified. Achlorhydria, due to type A CAG or HCl-suppressing drugs, and bombesin hyperstimulation are among possible factors inducing G cell hyperfunction and/or hyperplasia. Hypergastrinaemia is among causative agents of argyrophil ECL cell hyperplasias and, possibly, of tumours of the oxynticopeptic mucosa, while chronic inflammation and gland atrophy with or without concomitant hypergastrinaemia are important factors in inducing both hyperplastic and tumour argyrophil growths in CAG mucosa.

Early and multifocal tumors in breast, salivary, Harderian and epididymal tissues developed in MMTY-Neu transgenic mice

Transgenic mice carrying various oncogenes driven by mammary gland specific enhancers develop mammary tumors usually arising in a stochastic way. The only exception is a mouse lineage (TG.NF) carrying an activated rat Neu oncogene driven by the murine mammary tumor virus long terminal repeat (MMTV-LTR) that gave rise to rapid and multifocal mammary tumors interpreted as a result of a single-step neoplastic transformation. The effect of the oncogene appeared to be specific for breast tissue, since salivary and Harderian glands as well as epididymis expressed high levels of Neu but only developed hyperplasia (Muller et al., Cell, (1988) 54, p. 105). Here we describe a transgenic mouse lineage for the MMTV-Neu, analysed up to third generation. Multifocal tumors involving mammary glands arose very rapidly in all females independently from pregnancy and in some males. Moreover, multifocal neoplasias occurred also in salivary and Harderian glands and in the epididymis at a very high rate. These data demonstrate that the Neu oncogene can induce tumors in all the tissues where it is expressed at high levels.

Histopathology, hormone products, and clinicopathological profile of endocrine tumors of the upper small intestine: A study of 44 cases

Forty-two duodenal and 3 upper jejunum tumors from 44 patients were investigated. All tumors were tested immunohistochemically for gastroenteropancreatic hormones and general endocrine cell markers. Twenty-eight of the 45 tumors (62%) proved to be gastrin cell tumors, with (12 cases) or without (16 cases) associated Zollinger-Ellison syndrome. Zollinger-Ellison syndrome was part of type 1 multiple endocrine neoplasia syndrome in 3 cases. Twenty-three of the 28 gastrin cell tumors (82%) were from proximal duodenum, 2 were from the second part of the duodenum, and 3 were from the upper jejunum. Seven cases were somatostatin cell tumors, 6 of which were from the ampullary region; 5 cases were associated with biliary tract disease and 2 with associated cutaneous neurofibromatosis. Four ganglioneuromatous paragangliomas, from the ampullary region or nearby duodenum, showed somatostatin cells, coupled with pancreatic polypeptide cells in 2 cases. Two serotonin-producing argentaffin carcinoids were also identified. In addition to the main cell type, 30 tumors showed one or more, usually minor, cell populations producing somatostatin, serotonin, cholecystokinin, pancreatic polypeptide, insulin, neurotensin, or the alpha chain of human chorionic gonadotropin. Only 3 tumors lacked hormone immunoreactivity. Some correlation has been noted between histological structure and hormone content of tumor cells, with prevalence of broad gyriform trabeculae and vascular pseudorosettes among gastrin cell tumors, tubuloacinar patterns among somatostatin cell tumors, thin parallel trabeculae among PP cell growths, and a solid nest pattern among argentaffin carcinoids. Deep infiltration of the intestinal wall was observed in 22 tumors, 6 of which also had metastases to local lymph nodes. All metastatic cases were among ZES tumors or ampullary somatostatin cell tumors. Ganglioneuromatous paragangliomas and nonfunctioning gastrin cell tumors had essentially benign behavior, even when involving deep strata of the intestinal wall. Post operative follow-up study of 36 cases, including all metastatic tumors, showed no evidence of tumor-related death or progressive tumor disease.

The Clinicopathologic Heterogeneity of Grade 3 Gastroenteropancreatic Neuroendocrine Neoplasms: Morphological Differentiation and Proliferation Identify Different Prognostic Categories

Background/Aims: Gastroenteropancreatic (GEP) neuroendocrine carcinomas (NECs) are defined as neuroendocrine neoplasms (NENs) with a Ki-67 index >20% according to the 2010 WHO classification. Some reports suggest that this category is heterogeneous. We retrospectively studied a series of 136 patients affected by grade 3 GEP-NECs with the aim to clarify the prognostic role of tumor morphological differentiation, proliferation, defect in mismatch repair proteins (MMRd), CD117 expression, and site of origin. The primary endpoint was the correlation between these parameters and the overall survival (OS). Methods: Univariate and multivariable Cox proportional hazards regression analyses were used to assess the prognostic significance of various clinical and histopathologic features. Results: With a median follow-up of 81 months, the median OS was 12.9 months. At multivariate analysis, morphological differentiation, Ki-67 index, MMRd, stage, and CD117 expression were independent prognostic markers in NECs. Three different prognostic categories of NECs were identified according to the degree of morphologic differentiation (well vs. poorly differentiated) and Ki-67 index (<55% vs. ≥55%). On this basis, median OS was 43.6 months in well-differentiated neoplasms with a Ki-67 index 20-55% (named type A), 24.5 months in poorly differentiated neoplasms with a Ki-67 index 20-55% (type B), and 5.3 months (p < 0.0001) in poorly differentiated neoplasms with a Ki-67 index ≥55% (type C). Conclusions: The present study suggests that GEP-NECs represent a heterogeneous group of neoplasms which can be better classified in different prognostic categories using both tumor morphology and Ki-67 index.

Pancreatic polypeptide (PP) cells in the PP-rich lobe of the human pancreas are identified ultrastructurally and immunocytochemically as F cells

SummaryThe ultrastructure of immunohistochemically identified PP cells has been investigated by applying the serial semithin/thin section technique to the human pancreas, with special reference to the posterior part of the head, reputed to originate from the ventral primordium. PP cells of this area differ from those already identified in the rest of the pancreas and correspond to a cell, not yet described in the human pancreas, characterized by larger granules of very variable shape and structure. Such granules resemble those of so-called “F cells”, i.e. the PP cells of dog uncinate process and cat duodenal lobe, also coming from the ventral primordium. Thus, human “ventral lobe” PP cells have peculiar potentialities which are expressed in distinctive structural patterns of presently unknown functional meaning.

Glucagon- and PP-related peptides of intestinal L cells and pancreatic/gastric A or PP cells. Possible interrelationships of peptides and cells during evolution, fetal development and tumor growth

The immunohistochemical detection of six distinct sequences of proglucagon and its derivatives (GRPP, glicentin, glucagon-37, glucagon-29, GLP1, GLP2 and MPGF) in both intestinal L cells and pancreatic or gastric A cells of some mammals (dog, man, guinea pig) confirms that the two cell types produce the same proglucagon molecule, although the final step of its post-translational processing differs in the two cells. Immunohistochemical and ultrastructural patterns of glucagon/glicentin cells in the pancreas of lower vertebrates and early human fetuses, as well as tumor cell studies, suggest an evolution of gastropancreatic A cells from L cells. On the contrary, the PP-related peptide PYY of intestinal L cells, and PP with its C-terminal icosapeptide extension of pancreatic PP cells, likely originate from different prohormones. Although intermediate patterns of peptide expression can be observed, including some F-type PP cells of the dog pancreas (uncinate process) and pyloric mucosa showing PYY immunoreactivity or rare PYY and/or HPP immunoreactive cells of the human rectum lacking glicentin reactivity, no obvious relationship can be established between L cells and pancreatic (F-type) PP cells. However, some evolutionary, embryogenetic and oncogenetic link may exist between L cells and human D1-type PP cells, a minor population of PP cells scattered in the pancreatic tissue of dorsal pouch origin and a major fraction of tumor PP cells.

Expression of acidic fibroblast growth factor (aFGF) and fibroblast growth factor receptor 4 (FGFR4) in breast fibroadenomas

Background/Aim—Fibroadenomas are benign tumours composed of both glandular and fibrous tissue. The mechanisms regulating the growth of these tumours and the relation between the stromal and epithelial cells are poorly understood. Acidic fibroblast growth factor (aFGF) is a well known fibroblast activator, which acts through four specific cell surface receptors, among which, fibroblast growth factor receptor 4 (FGFR4) is highly specific. The aim of this study was to evaluate the distribution of aFGF and FGFR4 in specific cell types of fibroadenomas to understand their possible role in the growth of these breast lesions. Methods—Formalin fixed and paraffin wax embedded tissues from 15 fibroadenomas and peritumoral normal breasts were investigated for the expression of aFGF and FGFR4 using immunohistochemistry. The presence of aFGF mRNA was also investigated using in situ hybridisation. Results— Immunoreactivity for aFGF and FGFR4 was seen in epithelial cells, but it was lacking in myoepithelial cells of both normal tissues and fibroadenomas. Strong FGFR4 immunoreactivity was found in stromal fibroblasts, which were also weakly positive for aFGF. aFGF mRNA was detected in epithelial cells and in some stromal fibroblasts. Conclusions—These results suggest a paracrine/autocrine modulation of epithelial and stromal cells of fibroadenomas through an aFGF–FGFR4 interaction. This interaction might regulate various cell functions and the growth of fibroadenomas.

Idiopathic hepatic copper toxicosis in a child

A 10-year-old Italian boy with chronic liver disease and copper overload is described. Biological and histopathological findings are similar to those described in children with Indian childhood cirrhosis. This report suggests that a disease akin to Indian childhood cirrhosis but different from Wilson disease can be found in non-Indian children probably representing a new, possibly inherited, disease of copper metabolism leading to copper overload in the liver.