Tiziana D’Adda

Carcinoid (ECL Cell) Tumor of the Oxyntic Mucosa of the Stomach: A Hormone-Dependent Neoplasm?

In 1969 Rubin1 described a proliferation of endocrine cells in the atrophic oxyntic (or fundic) mucosa of patients with pernicious anemia (PA). Shortly thereafter, Solcia et al.2 also noted hyperplasia of fundic endocrine cells associated with chronic atrophic gastritis (CAG), even in the absence of PA, and, in addition, they reported a case of severe proliferation of the same cells in a patient with Zollinger—Ellison syndrome (ZES). These findings were confirmed in our laboratory,3,4 and we observed that hypergastrinemia is the common feature of the two otherwise opposite pathologic conditions of the oxyntic mucosa of the stomach. Considering the trophic effects of gastrin, therefore, we proposed that hypergastrinemia is responsible for the hyperplastic response of endocrine cells of the oxyntic mucosa in both CAG and ZES.4 The subsequent study of single cases of fundic carcinoid tumors extended this hypothesis by linking hypergastrinemia to the development of neoplasms from the same endocrine cell population.5,6

Association Between Recurrence of Sporadic Colorectal Cancer, High Level of Microsatellite Instability, and Loss of Heterozygosity at Chromosome 18q

PURPOSE:Microsatellite instability and loss of heterozygosity of chromosomes 18q, 8p, and 4p are genetic alterations commonly found in colorectal cancer. We investigated whether these genetic markers allow for the stratification of patients with Stage II to III colorectal cancer into groups with different recurrence risks, and with different prognoses.METHODS:Tumors of 113 patients were evaluated for loss of heterozygosity of chromosomes 18q, 8p, and 4p and for microsatellite instability by use of six microsatellite markers. Genetic alterations involving each of these genetic markers were examined for association with disease recurrences and survival.RESULTS:Loss of heterozygosity of chromosomes 18q, informative in 96 percent of cases, in Stage III tumors was associated with higher risk of overall recurrence (P < 0.001), local recurrence (P < 0.001), distant metastases (P < 0.001), decreased overall survival (P = 0.002), and disease-free survival (P < 0.001). The recurrence rates and survival rates among patients with Stage II colorectal cancer were independent of loss of heterozygosity of chromosome 18q. Stage III and loss of heterozygosity of chromosome 8p also were associated with a higher risk of recurrences when these factors were considered individually. In multivariate analysis, only loss of heterozygosity of chromosome 18q was independently associated with risk of recurrences (P < 0.001) and with disease-free survival (P = 0.001). No correlation was observed between microsatellite instability and recurrence rates. However, microsatellite instability was associated with improved overall survival (P = 0.04) and with a longer disease-free interval (P = 0.002). Only in five cases (16.7 percent) was it possible to perform resection of recurrences; two of these patients had microsatellite instability tumor. In no cases was it possible to resect recurrence of tumors with loss of heterozygosity of chromosome 18q.CONCLUSIONS:Loss of heterozygosity of chromosome 18q is an informative genetic marker, which in resected Stage III colorectal cancer can be used to predict recurrences and survival. Microsatellite instability identified cases that, even in the case of recurrence, have a more favorable prognosis.

Structure and Function of Endocrine Cells in the Oxyntic (Acid-secreting) Mucosa of Human Stomach

The morphological and functional characteristics of the endocrine cells of the oxyntic (acid-secreting) mucosa of the human stomach, a target of the trophic effect of gastrin, are reviewed. In healthy subjects these cells account for 0.90 +/- 0.35% of the volume of the entire mucosa and for 1.21 +/- 0.44% of the volume of the epithelial mucosal component alone. The cells show no extension to the glandular lumen and show an intimate anatomic relationship with contiguous non-endocrine epithelial cells. This configuration indicates undefined local functions of the paracrine type not influenced by the gastric lumen content. Seven cell types were identified ultrastructurally, three of which (enterochromaffin-like (ECL), P and D) cumulatively account for more than 75% of the total endocrine cell mass. The secretory product(s) of the endocrine cells has not been demonstrated definitively with the exception of minor cell populations producing glucagon (only in the fetal life), somatostatin and 5-HT. Recently, production of histamine and glycoprotein hormone alpha-subunit by oxyntic endocrine cells of man have been reported. However, histamine seems to occur in these cells normally, whereas the production of glycoprotein hormone alpha-subunit appears to be virtually restricted to cells of patients with hypergastrinaemic conditions.

Two cases of low-grade endometriod carcinoma associated with undifferentiated carcinoma of the uterus (dedifferentiated carcinoma): a molecular study.

Dedifferentiated carcinoma (DC) is an uterine neoplasm containing both low-grade endometrioid carcinoma (LGEC) and undifferentiated carcinoma (UC). DC is an aggressive tumour even when the UC component represents only 20% of the entire neoplasm. In this paper, two cases DCs at different stages of development, in 61- and 83-year-old women respectively were reported. In addition, in these uterine malignancies microsatellite instability (MSI) and loss of heterozygosity (LOH) were investigated in order to explain its aggressive behavior, in both components. Case #1 presented metastases at diagnosis, while case #2 was at a lower stage. LGEC component was invasive in case #1 and intramucous in case #2. In both cases, UC components were characterized by a high degree of instability, in accordance of its aggressive behaviour and its architectural heterogeneity. Further studies with more numerous cases are mandatory to confirm these data.

Involvement of HER-2/neu and metastasis-related proteins in the development of ileal neuroendocrine tumors

HER-2/neu overexpression and/or gene amplification occurs in several human malignancies, frequently correlates with tumor aggressiveness, and provides the basis for treatment with trastuzumab. Among neuroendocrine neoplasms (NEN) of the gastroenteropancreatic (GEP) tract, ileal neuroendocrine tumors show peculiar features of malignancy with frequent metastases at the diagnosis. We investigated the overexpression and/or amplification of HER-2/neu and the involvement of the metastasis-related proteins c-Met, MTA-1, and VEGF in 24 primary ileal NEN by immunohistochemistry and fluorescence in situ hybridization (FISH). Data were compared with those of 43 GEP endocrine tumors of other sites. All primary ileal NEN showed an intense membranous and cytoplasmic immunostaining for HER-2/neu. According to the breast cancer scoring system, 17% of ileal carcinoids showed a score of 3+ and 71% with a score of 2+ with a significant difference respect the non-ileal GEP endocrine tumors (p < 0.0000). FISH analysis revealed chromosome 17 polysomy in 33% of 2+/3+ ileal tumors but not HER-2/neu gene amplification. The c-Met and MTA-1 but not VEGF were overexpressed in almost all ileal NEN, whereas VEGF presented more frequently a normal staining. The comparisons with the other GEP NEN demonstrated significant differences for all the three proteins (p < 0.0000, p < 0.0002, and p < 0.001, respectively). These findings suggest that in ileal NEN, HER-2/neu overexpression plays a role in the carcinogenetic process and by triggering the altered expression of c-Met and MTA-1, may activate the molecular pathway(s) promoting tumor progression and metastasis development. Ileal HER-2/neu overexpressing neuroendrocrine tumors may constitute potential candidates for target therapy with specific humanized monoclonal antibodies.

Primary moderately differentiated neuroendocrine carcinoma (atypical carcinoid) of the larynx: A case report with immunohistochemical and molecular study.

Neuroendocrine tumours are the second most common laryngeal neoplasms, following squamous carcinoma. In this paper, we report the case of a moderately differentiated neuroendocrine carcinoma NEC (atypical carcinoid) of the larynx in a heavy smoker 67-year-old woman, with a history of hoarseness, dysphagia and dyspnea. The lesion was biopsied and microscopic examination revealed moderately differentiated NEC; thus the patient underwent supraglottic laryngectomy with lymphadenectomy. Here, we emphasized the morphological criteria for a correct pathological diagnosis. Moreover, because it has been demonstrated that many neuroendocrine neoplasms and malignant lesions of the larynx can be related to human papilloma virus (HPV), for the first time, we probed to verify if laryngeal neuroendocrine carcinoma could be due to an HPV infection by using polymerase chain reaction amplification (PCR) of tumoural DNA. On immunohistochemical analysis, the lesion characteristically revealed both neuroendocrine and epithelial differentiation with diffuse staining for chromogranin A, synaptophysin and neuron-specific enolase (NSE) and epithelial membrane antigen (EMA) and overexpression of p53 protein. PCR of NEC DNA did not show any signal for HPV DNA. Thus, this neoplasm is not due to an HPV infection, but a mutation of p53 gene which could cause immunohistochemical overexpression of p53 protein.

Pancreatic polypeptide-related tumors

PP-producing tumors are mostly located in the pancreas and may present as three pathologic lesions: pure PP-omas, mixed tumors with minor PP cell population, and PP-cell hyperplasia. These tumors are among the most common multiple adenomas frequently found in patients with multiple endocrine neoplasia type 1. Hypersecretion and high circulating levels of PP are frequently found. They are symptomless but may be useful for the identification of the pancreatic tumors. Numerous types of extrapancreatic endocrine tumors are able to synthesize and secrete PP. They occur mostly but not exclusively in the gastrointestinal tract, particularly in the rectum. The inactivation of the MEN 1 gene at 11q13 appears to be involved in the development of pancreatic but not of rectal PP-producing tumors.

Adenomatous polyposis coli gene involvement in ileal enterochromaffin cell neuroendocrine neoplasms

The adenomatous polyposis coli gene is a key tumor suppressor gene. Alterations in this gene have been found in most sporadic colon cancers; associated with familial adenomatous polyposis; and found in neoplasms of other organs, such as the liver, stomach, lung, breast, and cerebellar medulloblastoma. In the heterogeneous group of neuroendocrine neoplasms of the gastrointestinal tract, the involvement of adenomatous polyposis coli is debated, and only occasional reports found adenomatous polyposis coli alterations in foregut and midgut neuroendocrine neoplasms, with adenomatous polyposis coli mutations only in the latter. To elucidate the penetrance of adenomatous polyposis coli alterations in ileal neuroendocrine neoplasms, we performed DNA fragment analysis (loss of heterozygosity for 5q22-23 and 5q23) and sequencing on the mutation cluster region of the adenomatous polyposis coli gene on 30 ileal enterochromaffin cell neuroendocrine neoplasms. Adenomatous polyposis coli gene mutations were detected in 23% of cases (7/30); in particular, 57% were missense and 14%, nonsense/frameshift, all novel and different from those reported in colorectal or other cancers. Loss of heterozygosity analysis demonstrated a deletion frequency of 15% (4/27). No association was found with features of tumor progression. Our observations support the involvement of somatic adenomatous polyposis coli alterations in tumorigenesis of ileal enterochromaffin cell neuroendocrine neoplasms; the mechanisms of adenomatous polyposis coli gene inactivation appear to be different from those reported in other tumor types.

Endocrine cell replacement of oxyntic glands in Zollinger-Ellison syndrome: A role for female sex hormones?

A 48-year-old woman with Zollinger-Ellison syndrome (ZES), but no evidence of multiple endocrine neoplasia (MEN)-1 syndrome, developed an unusually florid evolution of enterochromaffin-like (ECL) cell hyperplasia, which led to extensive replacement of oxyntic glands by endocrine tissue and resulted in the disappearance of the patient’s gastric acid hypersecretion with antisecretory treatment no longer required. The patient’s previous history included breast cancer, treated with surgery and 5 years of antiestrogen therapy, and bilateral granulosa-thecal cell tumor of the ovary. In addition, increased circulating levels of 17 β-estradiol (17βE) and progesterone, possibly depending on concomitant development of liver cirrhosis, were also found. On the basis of these associations, it is suggested that abnormalities in the domain of female sex hormones, with a potential synergistic role of liver dysfunction, may be involved in the florid evolution of hypergastrinemia-driven proliferation of ECL cells observed in the present case.

Primary alveolar soft part sarcoma of uterine corpus: a case report with immunohistochemical, ultrastructural study and review of literature

BackgroundAlveolar soft part sarcoma (ASPS) is a rare mesenchymal malignancy. ASPS usually occurs most commonly in the deep soft tissues of the thigh and buttock or the head and neck regions.ASPS that originate from the uterine corpus are even more rare, with only 10 previous cases reported in the English literature.Case presentationIn our case, the alveolar features were completely lost and the tumour shows a solid, non-alveolar pattern and the nuclei have marked variation in nuclear size, and multinucleation. The correct pathological diagnosis has been made by immuno- histochemical and ultrastructural features, which rvealed overexpression of TFE3 and peculiar cytoplasmic crystalline inclusions.In this paper, an additional case of primary ASPS of uterine corpus is reported with immunohistochemical, ultrastructural study and review of literature in the effort to delineate its clinical and pathological features. In this unusual site, the diagnosis can be problematic because ASPS can mimic other primary or metastatic uterine neoplasms.ConclusionsThus, in this unusual presentation an essential diagnostic marker is the nuclear over-expression of TFE3 as well as ultrastructural study, which reveals the presence of peculiar cytoplasmic crystalline inclusions.