Endoscopic ultrasound guided fine-needle aspiration diagnosis of duodenal high grade neuroendocrine carcinoma underlying a villous adenoma: report of a case.

Endoscopic ultrasound guided fine-needle aspiration biopsy is a reliable and accurate method for the diagnosis of submucosal lesions of the gastrointestinal tract. We report the cytopathologic findings of a case of duodenal high-grade neuroendocrine carcinoma in a 68-year-old woman who presented with melena and marked anemia, 45 years after kidney transplantation. Imaging studies performed in the work-up of melena showed a duodenal mass, which on endoscopy proved to be an exophytic, villous duodenal lesion, 3 cm from the ampulla. Forceps biopsy of the exophytic lesion showed a villous adenoma. Endoscopic ultrasound additionally revealed an underlying submucosal lesion and EUS-guided fine needle aspiration of this submucosal mass and of the enlarged mesenteric lymph nodes was diagnostic of a high-grade neuroendocrine carcinoma. The aspirates showed abundant cellularity with tumor cells arranged in sheets and occasional loose clusters. The neoplastic cells had a moderate amount of pale cytoplasm and large round to oval hyperchromatic nuclei with focally prominent nucleoli. Mitoses, apoptotic bodies and necrotic debris were also present. The tumor cells were strongly and diffusely positive for cytokeratin AE1/AE3, synaptophysin and chromogranin and showed a very high proliferative fraction on Ki67 staining, supporting the diagnosis of a high-grade neuroendocrine carcinoma. This is to our knowledge the first case of high-grade neuroendocrine carcinoma of the duodenum diagnosed by EUS-FNA. This case also emphasizes the diagnostic value of EUS-FNA sampling of the submucosal and intramural component of villous tumors of the gastrointestinal tract when mucosal forceps biopsies show only benign findings.

Immunohistochemical expression of prostatic antigens in adenocarcinoma and villous adenoma of the urinary bladder.

Adenocarcinomas of the bladder are rare, with the diagnosis dependent on exclusion of secondary involvement by direct extension or metastatic spread from other sites. The recent description of an unusual form of urothelial-type mucinous prostatic adenocarcinoma raises a novel differential diagnosis between adenocarcinomas of the prostate and bladder, and investigation into the utility of classic prostatic immunohistochemical antigens in bladder adenocarcinoma is warranted. We identified 37 primary infiltrating adenocarcinomas of the bladder, which included signet ring cell carcinomas (n=11), urachal adenocarcinomas (n=5), and enteric adenocarcinoma (n=21). Also included for comparison were 3 cases, each of bladder villous adenomas and bladder adenocarcinoma in situ. Tissue microarrays were constructed from each case, with each specimen represented by multiple 1.0-mm cores to assess for tumor protein heterogeneity. Immunohistochemistry for prostate-specific antigen (PSA), prostate specific acid phosphatase (PSAP), P501S (prostein), and prostate specific membrane antigen (PSMA) was performed, and moderate to strong immunoreactivity was considered a positive result. Of the 37 adenocarcinomas, all were negative for PSA and PSAP (0/37; 0%). In contrast, a minority of bladder adenocarcinomas was labeled with the prostate antigens P501S and PSMA. P501S showed moderate diffuse cytoplasmic staining in 4/37 cases (11%), including 3 enteric-type adenocarcinomas and 1 mucinous adenocarcinoma. Additionally, 1 case of adenocarcinoma in situ demonstrated diffuse cytoplasmic staining for P501S. The granular perinuclear staining pattern of P501S typically seen in prostatic adenocarcinoma was absent in all cases of bladder adenocarcinoma. PSMA showed diffuse cytoplasmic staining in 4/37 (11%) infiltrating adenocarcinomas (including 1 signet ring carcinoma and 3 enteric-type adenocarcinomas), and in 1 case of adenocarcinoma in situ. Membranous PSMA staining was evident in an additional 3 tumors, 1 urachal mucinous adenocarcinoma, 1 nonurachal mucinous and signet ring cell adenocarcinoma, and 1 nonurachal villous adenoma. In conclusion, although all cases of bladder adenocarcinoma examined were negative for PSA and PSAP, the surprising finding that a subset of invasive and in situ adenocarcinomas of the bladder demonstrated immunoreactivity for P501S and PSMA should warrant caution when using these markers in differentiating prostatic from bladder adenocarcinomas. The lack of granular perinuclear staining for P501S and the absence of membranous PSMA staining both favor a bladder adenocarcinoma, although rare cases of villous adenoma and adenocarcinoma did show PSMA membranous staining indistinguishable from that seen in prostate cancer. Although the novel antigens P501S and PSMA are fairly specific and more sensitive in the differential diagnosis of prostate and urothelial carcinoma, care must be taken when adenocarcinomas of the bladder are considered within this differential diagnosis.

Inverse correlation between HLA-DR antigen expression and CD4 positive lymphocytic populations in normal mucosa, tubulovillous adenoma, and invasive carcinoma of the colon.

BACKGROUND: HLA-A,B,C and HLA-D molecules present antigenic peptides to the antigen-specific receptor of autologous T lymphocytes. T-cell-mediated host-versus-tumor response might therefore depend on the presence of these molecules on tumor cells, although the absence of HLA-A,B,C determinants on a cell has been shown to increase its susceptibility to lysis by natural killer cells. The prognostic role of tumor stage and grade is well- established in colorectal cancer. In this study we used immunohistochemistry to analyse the expression of HLA-DR on epithelial cells of normal colonic mucosa, tubulovillous adenoma, and invasive carcinoma, as well as the magnitude of the stromal T lymphocytes at the relevant sites. HLA-DR expression was correlated to histological grade and Dukes stage in the cases of invasive cancer. Yet, we investigated the association of HLA-DR plus DQ genes and adenoma or carcinoma by PCR. MATERIALS AND METHODS: 31 cases of normal colonic mucosa, 12 cases of tubulovillous adenoma, and 39 cases of invasive carcinoma were surveyed for the detection of HLA-DR monoclonal antigen, and the T helper (TH) marker (CD4) in the stroma (lamina propria) of the relevant cases. RESULTS: HLA-DR was expressed in 20 of 31 normal colonic mucosas (64.5%), 4 of 12 adenomas (33.3%), and in 10 of 39 invasive carcinomas (25.6%). A strong relation of HLA-DR expression and histological grade was found (p < 0.001), but no association with Dukes stage (p = 0.141). No significant correlation between HLA-DR plus DQ genes and adenoma or cancer of the colon was found. CD4 positive cells were found in 9 of 31 normal colonic mucosas (29%), 5 of 12 adenomas (42%), and in 26 of 39 invasive carcinomas (67%). CONCLUSIONS: The results showed an inverse correlation between the expression of HLA-DR and the number of CD4 positive cells as the lesion progressed to malignancy. HLA-DR was significantly associated with tumor grade but not with Dukes stage in colonic cancer hosts. HLA-DR and DQ genes do not contribute to a susceptibility to adenoma or carcinoma.

Expression of HLA-DR antigen and characterization of the lymphocytic infiltrate in normal mucosa, tubulo-villous adenoma and invasive carcinoma of the colon.

Prognosis of colonic carcinoma is poor. The two most important factors having the greatest effect on survival are pathologic stage of disease and histologic grade of the tumor. Our study points towards the value of HLA-DR antigen in the prognosis of colonic carcinoma. We studied 31 cases of normal colonic mucosa, 12 cases of tubulo-villous adenoma, and 39 cases of invasive carcinoma for the detection of HLA-DR monoclonal antigen. Yet, we investigated the association of HLA-DR and DQ genes and adenoma and carcinoma by PCR. We also studied the T helper (TH) marker (CD4) in the lamina propria of the relevant cases, given that the dependence of immune responsiveness on the class II antigens reflects the central role of these molecules in presenting antigen to TH cells. HLA-DR was expressed in 20 of 31 normal colonic mucosa (64.5%), 4 of 12 adenomas (33.3%), and in 10 of 39 invasive carcinomas (25.6%). No significant correlation between HLA-DR and DQ genes and adenoma or cancer of the colon was found. CD4 was expressed in 9 of 31 normal colonic mucosa (29%), 5 of 12 adenomas (42%), and in 26 of 39 invasive carcinomas (67%). The results showed decreased expression of HLA-DR and increased expression of CD4 as the lesion progressed to malignancy. HLA-DR and DQ genes do not contribute to a susceptibility to adenoma or carcinoma. The immune attract mechanism by low HLA-DR signaling seems to be of minor importance in the malignant and metastatic potential of the colonic carcinoma.

[Tissue expression of carbohydrate antigen 19-9 (CA 19-9) in adenomatous lesions of the colorectum]. / Espressione tissutale dell'antigene carboidrato 19-9 (CA 19-9) nelle lesioni adenomatose del colon-retto.

Serum levels of tumor markers almost not detectable in precancerous states or early cancer, the behavior of the tumor associated antigen CA 19-9 in colorectal carcinogenesis was analysed. In order to investigate the adenoma-carcinoma sequence, tissue antigenic expression was measured in adenomas, characterized by different size and histology, and compared with that found in normal colonic mucosa. Tissue content of CA 19-9 was determined by an immunoperoxidase technique (ABC-POD) in 88 colonic polyps, and correlated to the degree of histological dysplasia, and dimension of adenoma. Tissue content of CA 19-9 was also evaluated in non-adenomatous mucosa obtained by endoscopic biopsy. Among the 88 polyps, 50 showed the tubular histological type, while 31 resulted tubulovillous and 7 villous. High degree of dysplasia was present in 7 adenomas (7.9%) and focal carcinoma was observed in 6 (6.8%). Positivity for CA 19-9 was registered in 60.2% of adenomas. No correlation was found between tissue-CA 19-9 and degree of dysplasia, size of adenoma and villous component. However, a statistically significant correlation was observed between expression and cellular distribution of the antigen (chi 2 = 98.07, p < 0.00001). Our data confirmed CA 19-9 expression in adenomas, but it is unlikely this tissue antigen proves to be a reliable marker of adenoma-carcinoma sequence.

Expression of adhesion molecules in the host response to colon carcinoma.

Expression of the adhesion molecules LFA-1, ICAM-1, and VCAM-1 was studied in five resected colon carcinomas, one villous adenoma, and normal colon mucosa to determine whether expression of these markers is increased in response to tumor. Frozen tissue samples were stained by a labeled avidin-biotin technique using primary antibodies to LFA-1 (CD11a), CD2, CD4, CD8, CD20, CD68, HLA-DR, ICAM-1 (CD54), and VCAM-1. For each marker, the number of positive mononuclear cells was graded semiquantitatively, and stromal and endothelial cells were scored as either positive or negative. Overall grade of inflammation was increased in tumor compared with normal mucosa in five cases. Cells positive for LFA-1, CD2, CD4, CD8, and CD20 were increased in the tumors in the same cases. ICAM-1 was expressed in vessels, inflammatory cells, and stromal cells in normal mucosa. It was markedly increased in tumor stroma in all six cases. VCAM-1 was negative in normal mucosa, and focally expressed in tumor vessels and stroma. We conclude that increased expression of adhesion molecules occurs around colon neoplasms, particularly in stromal cells, and may be a mechanism for the recruitment of activated leukocytes as part of the inflammatory response to colon carcinomas.

Incidence and pathogenesis of villous tumors of the gallbladder, and their relation to cancer.

The aim of this study was to investigate the incidence and pathogenesis of villous tumors of the gallbladder, and their relation to cancer. Five hundred and thirty-three cases of cholecystectomy and 1300 randomly selected autopsy cases, mainly elderly individuals, were investigated. Gallbladders were fixed in 10% formalin after operation or at autopsy, followed by macroscopic study. In cases of villous tumors, the entire gallbladder was cut into 5-mm-thick serial sections, embedded in paraffin, cut to 4-microns, stained with hematoxylin and eosin (H&E), and histologically studied. To investigate cancer-associated antigens, i.e., carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9, deparaffinized sections were examined by the peroxidase-antiperoxidase (PAP) immunohistochemical technique with anti-CEA and anti-CA 19-9 antibodies. Villous tumor was found in two resected cases (0.38%) and in one autopsy case (0.08%). Histologically, one of the villous tumors consisted mainly of a proliferation of lining epithelia; the other two consisted mainly of a proliferation of glands. In all three cases, the patients had had accompanying chronic or acute inflammation and two were accompanied by cholecystolithiasis, which made us aware of the importance of inflammation or trauma from stones in the pathogenesis of such neoplasms. Although no apparent cancerous epithelium was observed in any of these tumors by studying H&E specimens, moderate structural and cellular atypism was found in one of them. The atypical epithelium in this case was positively stained for CEA and CA 19-9. It was concluded that villous tumor should be considered to be a premalignant lesion.