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Despite duodenal-type follicular lymphoma (DTFL) being morphologically, immunophenotypically and genetically indistinguishable from nodal FL (nFL), this entity typically shows a significantly better prognosis. Here, we analysed the tumour immune microenvironments of diagnostic specimens from patients with DTFL (n = 30), limited-stage FL (LSFL; n = 19) and advanced-stage FL (ASFL; n = 31). The mean number of CD8 + tumour-infiltrating lymphocytes (TILs) in the neoplastic follicles was higher in DTFL (1,827/mm 2 ) than in LSFL (1,150/mm 2 ) and ASFL (1,188/mm 2 ) (P = 0·002, P = 0·002, respectively). In addition, CD8 + PD1 -  T cells with non-exhausting phenotype were more abundant in the peripheral blood (PB) of DTFL than in LSFL and ASFL, indicating that DTFL may exhibit a better and longer-lasting T cell-mediated immune response. Moreover, whereas FOXP3 + CTLA-4 + effector regulatory T cells (eTregs) were rarely observed in the neoplastic follicles of DTFL (mean: 12/mm 2 ), they were more abundant in LSFL (78/mm 2 ) and ASFL (109/mm 2 ) (P = 2·80 × 10 -5 , P = 4·74 × 10 -8 , respectively), and the numbers of eTregs correlated inversely with those of CD8 + TILs (r = -0267; P = 0·018). Furthermore, DTFL showed significantly fewer circulating FOXP3 hi CD45RA - CD25 hi eTregs (0·146%) than ASFL (0·497%) and healthy controls (0·639%) (P = 0·0003, P = 6·79 × 10 -7 , respectively). These results suggest that the augmented anti-tumour immune reactions may contribute to a better prognosis on DTFL., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Duodenal-type follicular lymphoma (DTFL) is a rare and highly indolent follicular lymphoma (FL) variant. It is morphologically and immunophenotypically indistinguishable from typical FL, characterized by restricted involvement of intestinal mucosa, and lacks extraintestinal manifestations. The molecular determinants of this distinct clinical behavior are largely unknown. Thirty-eight diagnostic biopsies from patients with DTFL were evaluated. The 10-year overall survival rate was 100% in clinically evaluable patients (n = 19). We compared the targeted mutation profile of DTFL (n = 31), limited-stage typical FL (LSTFL; n = 17), and advanced-stage typical FL (ASTFL; n = 241). The mutation frequencies of recurrently mutated genes, including CREBBP , TNFRSF14 / HVEM , and EZH2 were not significantly different. However, KMT2D was less commonly mutated in DTFL (52%) and LSTFL (24%) as compared with ASTFL (79%). In ASTFL, 41% of KMT2D- mutated cases harbored multiple mutations in KMT2D , as compared with only 12% in LSTFL ( P = .019) and 0% in DTFL ( P < .0001). Whole exome and targeted sequencing of DTFL revealed high mutation frequencies of EEF1A1 (35%) and HVCN1 (22%). We compared the immune microenvironment gene expression signatures of DTFL (n = 8) and LSTFL (n = 7). DTFL clearly separated from LSTFL by unsupervised, hierarchical clustering of 147 chemokines and cytokines and was enriched for a chronic inflammation signature. In conclusion, the mutational landscape of DTFL is highly related to typical FL. The lower frequency of multiple mutations in KMT2D in DTFL and LSTFL indicates an increasing selection pressure for complete KMT2D loss in ASTFL pathogenesis. The highly dissimilar immune microenvironment of DTFL suggests a central role in the biology of this disease., (© 2018 by The American Society of Hematology.)

Aims: PD-1/PD-L1 checkpoint immunotherapy has been proposed recently as a promising treatment in relapsed/refractory disease, used eventually in combination with traditional chemotherapy in different cancer settings. To date, no data are available concerning PD-L1 expression in ampulla of Vater carcinoma and its pre-invasive lesions., Methods and Results: We assessed the immunohistochemical expression of PD-L1 in a series of 26 ampullary adenocarcinomas, 50 ampullary dysplastic lesions and 10 normal duodenal mucosa samples. Moreover, in all cases DNA mismatch repair proteins status was investigated. PD-L1 was expressed in seven of 26 (26.9%) invasive carcinomas and three of 50 (6.0%) dysplastic samples. Most of the PD-L1-positive tumours (seven of 10) were intestinal-type and poorly differentiated (G3). The number of PD-L1-positive stromal lymphoid cells was significantly higher in dysplastic and invasive lesions than in the normal samples (P = 0.011). Nineteen dysplastic lesions and eight invasive carcinomas did not show any evident epithelial or stromal PD-L1 expression. Four of the carcinomas were mismatch repair-deficient and two of these were PD-L1-positive. Furthermore, mismatch repair-deficient lesions showed a significantly higher average of PD-L1-positive stromal lymphoid cells than those of neoplastic PD-L1-negative samples (62.8 versus 21.6; P < 0.001)., Conclusions: The present results suggest a role of the PD-1/PD-L1 axis in ampullary adenocarcinomas, and therefore this may also prompt consideration of checkpoint immunotherapy as a novel promising treatment for these tumours., (© 2017 John Wiley & Sons Ltd.)

Objectives: Nutritional deficiencies and immune dysfunction in cancer patients may contribute to postoperative septic morbidity. This trial compared the effects of perioperative enteral immunonutrition (EIN) versus standard enteral nutrition (SEN) on systemic and mucosal immunity in patients undergoing pancreaticoduodenectomy for periampullary cancer., Methods: Thirty-seven patients were randomized (EIN, n = 17; SEN, n = 20) to receive feed for 14 days preoperatively and 7 days postoperatively. Mediators of systemic immunity (interleukin 1α, tumor necrosis factor α, lymphocytes subsets, and complement components) and of mucosal immunity in duodenal biopsies, nutritional markers and parameters were evaluated., Results: The groups were comparable for demographics, the concentrations of mediators of systemic and mucosal immunity at time of recruitment, and for the duration and amount of feed received. Preoperative EIN rather than SEN was associated with significant reductions in plasma tumor necrosis factor α and total hemolytic complement. Enteral immunonutrition-fed patients had significantly higher total lymphocyte count on the third postoperative day and significantly greater rise in CD4/CD8 ratio from day 3 to day 7 postoperatively compared with SEN-fed patients., Conclusions: The perioperative administration of EIN rather than SEN is associated with a favorable modulation of the inflammatory response and enhancement of systemic immunity in patients undergoing pancreaticoduodenectomy for periampullary cancer.

Extra-ampullary duodenal adenocarcinomas are rare, and when studied, frequently have been grouped with jejunoileal adenocarcinomas. Nevertheless, anecdotal experiences suggest that these neoplasms may present 2 or more distinct phenotypes. To better characterize these neoplasms, we performed a retrospective review of 38 cases with a special focus on the morphologic and immunophenotypic characteristics and their clinicopathologic significance. Our cohort of extra-ampullary duodenal adenocarcinomas was classified on the basis of the morphologic features into gastric type (n=19, 50%), intestinal type (n=14, 37%), pancreaticobiliary type (n=2, 5%), and others (n=3, 8%). Most gastric-type adenocarcinomas (n=18, 95%) developed in the proximal duodenum, whereas the other types were located equally in the proximal and distal duodenum. Intestinal-type dysplasia was present at the periphery of 8 (57%) intestinal-type adenocarcinomas, and 8 (42%) gastric-type adenocarcinoma were associated with gastric-type dysplasia. Gastric foveolar metaplasia (n=12) and Brunner gland hyperplasia (n=10) were exclusively recognized adjacent to gastric-type adenocarcinomas. Notably, intestinal-type histology and the absence of lymph node metastasis were significantly associated with favorable disease-free survival in univariate and multivariate analyses. In summary, this study demonstrated that 2 major subsets of extra-ampullary duodenal adenocarcinoma, intestinal type and gastric type, are associated with distinct histopathologic features and clinical behavior.

We have reported previously that duodenal follicular lymphoma (FL) is distinct from nodal FL and showed more resemblance to mucosa-associated lymphoid tissue lymphoma, and that FL frequently involved the duodenal second portion. In the present study, we examined duodenal FLs and gastric/colonic FLs to clarify the clinicopathological and immunological differences between the tumor types. We analyzed 8 samples of gastric FL, 17 of duodenal ones, and 5 of colonic/rectal ones, and characterized them by immunohistochemistry, immunogenotyping, and histology. Gastric and colonic FLs presented in submucosal to subserosal areas, whereas duodenal ones presented in the mucosal to submucosal layers. Immunohistochemical analysis revealed that duodenal FLs exhibited the following phenotypes: CD10 (+), B-cell lymphoma 2 (BCL-2) (+), BCL-6 (+), activation-induced cytidine deaminase (AID) (-), BACH2 (+), CD27 (+), MUM-1 (-), Blimp-1 (-), and loose CD21 network (duodenal pattern). Gastric/colonic FLs exhibited the following phenotypes: CD10 (+), BCL-2 (+), BCL-6 (+), AID (+), BACH2 (+), CD27 (-), MUM-1 (-), Blimp-1 (-), and a dense CD21 network (nodal pattern). Expression of AID and CD27 in lymphoma cells and the CD21 network pattern were considerably different between duodenal FLs and gastric/colonic ones. Moreover, in situ hybridization revealed that, in the duodenal FLs, BACH2 was expressed at the periphery of the tumor follicle and tumor villi. The number of immunoglobulin heavy-chain variable domains VH4 and VH5 were higher in duodenal follicular lymphomoas than in gastric FLs. The lymphoma cells of duodenal FLs are different from those of gastric/colonic FLs, and duodenal FL is distinct even within the gastrointestinal tract. Somatic hypermutation in immunoglobulin genes and CD27 expression are hallmarks of memory B cells. We suggest that duodenal FL cells are in the memory B-cell stage, and require BACH2 instead of AID for ongoing mutation.

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., (Copyright © 2010 Wiley Periodicals, Inc.)

Background: Despite having a dramatically larger surface area than the large intestine, the small intestine is an infrequent site for the development of adenocarcinoma. To better understand the molecular abnormalities in small bowel adenocarcinoma (SBA), we characterised a number of candidate oncogenic pathways and the immunophenotype of this rare cancer., Methods: Tissue microarrays were constructed from tumour samples from 54 patients with all stages of the disease. Immunohistochemistry and microsatellite instability (MSI) testing were conducted., Results: The profile of cytokeratin 20 and 7 coexpression was variable, but expression of caudal type homeobox transcription factor 2 (CDX2) was present in 70% of cases. In this young population (median age 54 years), loss of mismatch repair (MMR) proteins occurred in 35% of patients, with confirmed MSI in 100% of tested cases. Expression of vascular endothelial growth factor-A (VEGF-A) and epidermal growth factor receptor (EGFR) was common, occurring in 96 and 71% of patients, respectively. Only one case showed HER2 expression and none showed loss of phosphatase and tensin homologue mutated on chromosome 10 (PTEN)., Conclusions: These results suggest that alterations in DNA MMR pathways are common in SBAs, similar to what is observed in large bowel adenocarcinomas. Furthermore, the high percentage of tumours expressing both EGFR and VEGF suggests that patients with this rare cancer may benefit from therapeutic strategies targeting EGFR and VEGF receptor (VEGFR).

Aim: To investigate the association of gastric histological and endoscopic findings in patients with Helicobacter pylori (H. pylori), according to presence of seropositivity to 12 bacterial virulence antigens., Methods: This is a cross-sectional single-center study of 360 consecutive outpatients referred in the period of one year to upper gastrointestinal endoscopy because of dyspeptic complaints. Patients sera were tested by Western blot method to determine the presence of serum antibodies to bacterial virulence antigens--p120 (CagA--cytotoxin-associated antigen), p95 (VacA - vacuolating cytotoxin), p67 (FSH--flagellar sheath protein), p66 (UreB--urease enzyme heavy subunit), p57 (HSP homologue--heath shock protein homologue), p54 (flagellin), p33, p30 (OMP--outer membrane protein), p29 (UreA--urease enzyme light subunit), p26, p19, and p17. Upper gastrointestinal endoscopy was performed, endoscopic diagnosis recorded, and 4 mucosal biopsy samples were obtained and assessed according to Updated Sydney protocol., Results: The sera of 207 patients were analyzed. Thirty patients had gastric adenocarcinoma, 126 peptic ulcers, and 51 normal finding. p120 (CagA) seropositivity was significantly more often present in patients with higher activity grade in the antrum (P = 0.025), p30 in patients with greater inflammation in the antrum (P = 0.025) and the corpus (P = 0.010), p33 in patients with greater inflammation in the corpus (P = 0.050), and p19 (OMP) in patients with lower intestinal metaplasia grades in the corpus (P = 0.025). Seroreactivity to all other bacterial proteins showed no association with the histological status of the stomach mucosa. Except for the seropositivity to protein p95 (VacA), which was more often present in patients with duodenal ulcer (P = 0.006), there was no difference in seroreactivity to other bacterial proteins and upper gastrointestinal endoscopic findings., Conclusions: p120 (CagA), p33, p30 (OMP), and p19 (OMP) seropositivity was more often present in patients with higher grades of the histological parameters of gastritis and seropositivity to protein p95 (VacA) with endoscopic presence of duodenal ulcer. Histological parameters of gastritis are more associated with bacterial virulence than endoscopic findings.

Aims: We report herein an additional case of primary malignant fibrous histiocytoma (MFH) in the duodenum and provide a review of the existing literature., Methods and Results: A 61-yr-old Chinese man was admitted to our hospital with symptoms of melena, anorexia, and weight loss. An abdominal computed tomography (CT) and gastrointestinal barium meal examination demonstrated a tumor of the duodenum suggestive of primary malignancy. The tumor was successfully treated by pancreaticoduodenectomy. It was histopathologically and immunohistochemically diagnosed to be a storiform-type primary MFH of the duodenum. There have been a total of 40 cases of primary malignant fibrous histiocytoma of the small bowel documented in the literature including our Chinese cases., Conclusion: Primary malignant fibrous histiocytoma of the small bowel, especially in the duodenum is extremely rare. The final diagnosis is made only after pathological and immunopathological examination of the tumor. The malignant potential of such tumors is high. The prognosis may be mainly dependent on the invasion and metastasis of tumor, while tumor size is irrelevant. The treatment should be surgery if possible. Early surgical intervention may be the best form of management that may offer the patient good result.

A 49-yr-old Japanese woman underwent upper gastrointestinal endoscopy because of nonspecific dyspepsia. Endoscopy revealed a flat elevated lesion about 15 mm in diameter adjacent to the duodenal papilla, the surface of which was uneven and covered with whitish granules. Based on the results of histological examination with immunohistochemistry (positive for CD10, CD20, CD79a, and bcl-2 protein, negative for CD5 and cyclin D1), a diagnosis of grade 1/3 follicular lymphoma was established. Systemic staging examinations suggested the lymphoma was restricted to the mucosa and superficial portion of the submucosa in the duodenal wall. The patient was treated with a combination of CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisolone) and monoclonal anti-CD20 antibody (rituximab), in addition to radiotherapy. After six courses of this combination chemotherapy, complete regression of the lymphoma was observed. Although reports of small duodenal lymphoma (<20 mm or localized to the mucosa or submucosa) are extremely rare, the features of this case are characteristic of small duodenal lymphoma in terms of evolution around the ampulla of Vater, low-grade follicular type, occurrence in a women, occurrence in the fourth decade of life, and favorable outcome, and this type of tumor may need to be distinguished by pathogenesis and clinical behavior from various other gastrointestinal lymphomas.

In general, metastases to the small intestine are rare, and mostly occur in melanoma. CCR9 has been shown to be the principal chemokine receptor for the thymus expressed chemokine (TECK), a chemokine selectively expressed in the small intestine and thymus. Here we show that CCR9 is highly expressed on melanoma cells and all melanoma cell lines isolated from small intestinal metastases, and on a proportion of cell lines from other sites. Only melanoma cells and cell lines from small intestinal metastases, however, were responsive to the CCR9 ligand TECK, as assessed by receptor downregulation and by actin polymerization. CCR9 expression was also found on the adenocarcinoma cell line CaCo-2 expressing characteristics of enterocytic differentiation, but not on any other cell line isolated from colorectal, breast, and lung cancer. Our data provide evidence that the aberrant functional cell surface expression of an organ-specific chemokine receptor is associated with metastasis to this site. The regulation of receptor function seems to be a critical step in the metastatic process.

We report the regression of coexisting mucosa-associated lymphoid tissue (MALT) lymphomas in the duodenal bulb and gastric corpus brought about by Helicobacter pylori eradication. During an endoscopic examination, multiple polyps in the duodenal bulb were observed in a 62-year-old woman. The pathology of the duodenal polyps was low-grade B-cell MALT lymphoma. Gastric MALT lymphoma was also detected in biopsies of rough mucosa from the gastric corpus. Southern blot analysis showed rearranged bands of DNA immunoglobulin heavy chain J portion (IgH-J) in both lesions, but the positions of these bands were different in the two lesions. H. pylori was recognized in the gastric mucosa by positive serum H. pylori antibody and urease tests, while bacterial bodies were not found in the duodenal bulb. With 1 year after the successful eradication of H. pylori, both the lesions, that in the duodenal bulb and that in the gastric corpus, had disappeared. Furthermore, positive rearrangement of IgH-J was not found at either of the lesion sites. In May 2000, 3 years after the treatment, endoscopic surveillance failed to find any recurrence of these malignant lymphomas.

Aims and Methods: Digestive stromal tumors are the most frequent undifferentiated mesenchymal tumors. The prognosis of these tumors is difficult to predict and the histogenesis is still subject to controversy. However, the frequent and specific expression of CD117 (c-kit) by these tumors could suggest an origin from interstitial cells of Cajal. The aim of this study was to analyse the histological and immunohistochemical characteristics of 46 digestive stromal tumors surgically resected, with comparaison of CD34 and CD117 expression in these tumors. Sixteen tumors were analyzed on electron microscopy., Results: Sixty three and 74% of the stromal tumors were positive for CD117 and CD34 respectively. While CD117 expression was similar in all locations, on the contrary, there was a decreasing gradient of CD34 expression between gastric (87%) and jejunal (33%) tumors. All tumors with skeinoid fibers expressed CD117. Focal expression of smooth muscle actin was noted in 43% of the cases. The ultrastructural study showed no correlation with the immunohistochemical results., Conclusion: Digestive stromal tumors show an immunophenotypic and ultrastructural heterogeneity. CD117 expression is frequent, but not constant.

A 52-year-old Tunisian patient had fever, impaired health and several opportunistic infections (Campylobacter jejuni, Mycobacterium hominis, Herpes virus, Giardia intestinalis, Vibrio metschnikovii). Lymphocytopenia was noted (348/mm3; CD4+: 2.2%; CD4+/CD8+: 0.1). Polymerase chain rection search for HIV was negative in serum and in tumor tissue. Diagnosis of primary digestive Kaposi sarcoma was established at autopsy due to the deep location of the lesions. There was an ulcerofungating tumor spreading over 1.3 m of the duodenojejunum. This is the fourth reported case of CD4+ lymphocytopenia, a new and very rare immunodeficiency syndrome recently defined by the Centers for Disease Control. We detected human herpes virus 8 by immunohistochemistry of tumor tissue. Human herpes virus 8 is implicated in the pathogenesis of Kaposi sarcoma.

The influence of a human CD4(+) T cell response in anti-carcinoma immune reactions remains largely uncharacterized. Here, we made use of a major histocompatibility complex (MHC) class-II-restricted, anti-ras oncogene-specific CD4(+) T cell line produced previously in vivo from a patient with metastatic carcinoma in a peptide-based phase I trial. Using this patient-derived T cell line as a potentially relevant cell type, we examined the consequences of the anti-carcinoma CD4(+) T cell response, with emphasis on specific lymphokines potentially important for the regulation of Fas/Fas ligand (FasL) interactions. Antigen (Ag)-specific CD4(+) T cells produced substantial amounts of IFN-gamma following recognition of MHC class-II-matched Ag-presenting cells expressing the cognate peptide. The IFN-gamma promoted significant upregulation of Fas on the surface of colon carcinoma cells and sensitized these targets to Fas-mediated apoptosis and Ag-specific CD8(+) cytotoxic T lymphocyte (CTL)-mediated lysis involving a Fas-based effector mechanism. Moreover, Ag-stimulated CD4(+) T cells secreted soluble FasL (sFasL), which induced the death of TNF-resistant/refractory colon, breast, and ovarian carcinoma cells. Interestingly, although CD4(+)-derived sFasL expressed cytotoxic activity, the recovery of carcinoma cells which resisted Fas-mediated lysis displayed enhanced metastatic ability in vivo, compared with the unselected parental population, in an athymic mouse model. Thus, a tumor-specific CD4(+) T cell response may have both positive and negative consequences in human carcinoma via the production of proinflammatory cytokines such as IFN-gamma and/or sFasL that may (1) improve or facilitate CTL-target engagement, contact-independent effector mechanisms, and the overall lytic outcome and (2) potentially select for Fas-resistant tumor cells that escape immune destruction, which may thus impact the metastatic process.

The incidence of indolent lymphomas in the lymph nodes and extranodal regions is quite different. Follicular lymphoma (FL) is most common in the nodes, and it seems to be least common in the gastrointestinal (GI) tract, where mucosa-associated lymphoid tissue lymphoma arises most frequently. The authors report that the incidence of FL is unexpectedly high in the duodenum compared with other portions of the GI tract. FL was detected in only eight of 222 cases of GI lymphoma (3.6%). However, five cases of FL arose in the duodenum, which accounted for 38.5% of 13 duodenal lymphomas. Only in two patients did FL arise in either the stomach or the colorectum, and in the remaining patients FL was widespread with lymphomatous polyposis. Duodenal FL was composed of neoplastic follicles with small cleaved cells in dominance, and the immunophenotype of the lymphoma cells was CD10+, BCL-2+, CD20+, CD75+, CD79+, CD3-, CD5-, cyclin D1-, CD23-, and CD45RO-. All the patients were women age 37 to 66 years (average age, 52.4 yrs). In all patients the lymphoma was present around the ampulla of Vater, and four of five patients showed multiple small-size polyps. Although lymphoma cell infiltration was confined to the submucosa in the four patients examined, the regional lymph nodes were involved partially in two patients without distant metastasis. All patients are alive at 2 to 50 months of follow up (average, 27 mos), which is comparable with the prognosis for indolent nodal lymphomas. These results suggest that the duodenum has a distinct background of histogenesis of the lymphomas and that biopsy specimens from the duodenum with multiple polyps should be examined carefully.

As recently described, Ki-1 anaplastic large cell lymphoma is a distinctive subtype of non-Hodgkin's lymphoma. We report a Ki-1 anaplastic large cell lymphoma of the duodenum in a 62-year-old man. He received modified CHOP therapy and was in complete remission at 18 months. To our knowledge, this is the first report of primary Ki-1 anaplastic large cell lymphoma of the duodenum.

A case of duodenal gangliocytic paraganglioma (DGP) arising in the ampulla of Vater of an 84 year old male is reported. The present case shows the typical histological features with a mixture of epitheliold, ganglion-like and spindle cells. Immunohistochemically, the spindle cells were positive with antibodies to neuron specific enorse, S-100 protein and neurofilament (NF), but negative for anti-glial fibrillary acidic protein (GFAP), synaptophysin and myelin basic protein (MBP). Both anti-Leu-7 and -chromogranin A antibodies gave positive reactions with a fine granular pattern in the epithelioid cells. Most ganglion-like cells showed the cytoplasmic immunoreaction with GFAP and a few with NF and synaptophysin. In these three tumor components, no reactivity was detected in the antibodies to the neurohormonal peptides tested. The present data are fundamentally in keeping with those previously reported, but add the immunohistochemical positivity of ganglion-like cells for GFAP, suggesting different neuroglial differentiation.

Weekly injections of dimethylhydrazine (DMH) (25 mg/kg), or azoxymethane (AOM) (8 mg/kg) to young adult male CDI mice for 1-2 months produced generalized intestinal crypt hyperplasia, which we measured in duodenum in terms of number of interphase and mitotic cells present in crypts. As shown earlier, the crypts expanded because of the presence of a hyperproliferative "initiated" crypt subpopulation which was also sensitive to natural killer (NK) cells. Hyperplasia was thus present as long as NK activity was suppressed by the carcinogen treatment. After interruption of the treatment for periods of 1, 2, 3, 6 and 10 months in the various groups, hyperplasia soon regressed as a result of elimination of the subpopulation by the recovering NK cells. When NK activity was once again eliminated during the terminal days of these "interruption periods" (by injections of anti-asialo GM-I antibody, alpha AGM-I), the original hyperplasia was fully reconstituted, apparently from stem cells of the subpopulation which survived up to 10 months in their crypt base location. These "initiated stem cells" represented, then, the original carcinogenic insult during the pre-cancerous period. They also appeared to be the source of the eventual neoplasia, as treating the animals with mutagens during the interruption periods produced specific changes in crypt base histology: new "crypt base basophilic" (CBB) cells appeared which produced large accumulations as well as microscopic tumors when NK activity was suppressed (by alpha AGM-I). Some of the initiated stem cells were apparently transformed into neoplastic ones which remained under NK control, the NK cells preventing the establishment of their progeny. Further experiments indicated that, although the initiated stem cells are not eliminated by normal NK activity, activated NK cells can kill them, thereby eliminating the potential source of neoplasia.

12 cases of duodenal carcinoma were studied for nuclear DNA ploidy patterns, the proliferation index (PI), proliferating cell nuclear antigen (PCNA) positive score (1 = 0-25%, 2 = 26-50%, 3 = 51-75%, 4 = 76-100%) and PCNA positive rate. DNA aneuploidy was observed in 9 cases (75%) and PCNA staining was positive in 11 cases (91.6%). DNA ploidy patterns, PI, PCNA positive scores and positive rates were not related to each other. No relationship DNA ploidy patterns for PCNA positive scores and PCNA positive rates could be found. The relationship between PI and PCNA positive score was found not to be significant (P less than 0.10). PI was revealed to correlate significantly (P less than 0.05) to PCNA positive rate.

The authors report the clinical, pathological and immunological features of a case of T-lymphoblastic lymphoma presenting with protein-losing enteropathy. There was extensive multifocal involvement of the duodenum, jejunum and ileum. The mediastinum was not enlarged; the peripheral blood picture and bilateral bone marrow trephine biopsies were unremarkable. The tumor cells were positive for terminal deoxynucleotide transferase, CD3, CD2, CD7 and CD10; they were negative for CD1, CD5, CD4, CD8 and HLA-DR. The immunophenotype was that of an immature thymic T-cell. Monocytic and B-cell markers were negative. Despite initial dose reduction in chemotherapy, the patient still developed massive intestinal hemorrhage and succumbed 2 wks after treatment. Postmortem examination confirmed absence of thymic involvement. The overall picture strongly suggests a primary intestinal origin of this T-lymphoblastic lymphoma which contradicts the conventional wisdom that T-lymphoblastic lymphoma arises in the thymus from primitive cortical lymphocytes before rapidly disseminating.

Forty cases of carcinomas in the pancreatoduodenal region (carcinoma of the ampulla of Vater: 11 cases, carcinoma of the pancreas head (CPH): 12 cases, carcinoma of the inferior common bile duct (CIBD): 17 cases) and its non-malignant counterparts were examined immunohistochemically, using monoclonal antibodies against four Lewis (Le) blood group-related antigens and sialyl Tn antigen. TKH-2 (anti-sialyl Tn) reactivity, which is almost negative in non-malignant counterparts except for goblet cells in the duodenum, is highly positive in carcinomas, therefore, sialyl Tn antigen can be an excellent tumor marker in this region. Lex and sialyl Lex-i antigens have been regarded as pancreatic cancer-associated antigens, however, this study suggests that Lex and sialyl Lex-i are more useful markers for CIBD than CPH. Above findings imply that altered regulation of glycosyltransferase activity is associated in malignant state of the pancreas and inferior common bile duct.

Primary malignant lymphoma located in the duodenum is a rarity. A case of primary lymphoma of the duodenum in a 27-year-old man, in which the 2 discrete masses of duodenal bulb and the second portion with pancreatic head invasion was found, is reported here. Immunohistochemical evaluation of the present case showed that lymphoma cells expressed the T-cell markers MT1 and UCHL1. Treatment consisted of pancreaticoduodenectomy followed by antineoplastic chemotherapy.

The possible regulatory role of NK cells on early events in chemical carcinogenesis remains undefined. The present study examined whether NK cells control 1,2-dimethylhydrazine (DMH)-induced hyperplasia of the duodenal crypt in CD1 mice. Mice receiving chronic DMH treatment showed a dose-dependent hyperplasia confined to the proliferative zone, with a parallel increase in mitotic and 3H-TdR-labelled cells and significant suppression of splenic NK activity. Complete ablation of splenic NK activity with anti-asialo GM-I antibody (alpha AGM-I) treatment slightly enhanced hyperplasia. Halving of the DMH dose for 2 weeks led to regression of hyperplasia, which was totally prevented by alpha AGM-I treatment. The alpha AGM-I treatment alone did not influence crypt size in normal mice. Finally, a stimulation of NK activity with Poly I:C treatment in DMH-treated mice caused regression of the DMH-induced hyperplasia. Our results suggest that hyperplastic cells with possible genetic alterations induced by the carcinogen express target structures for NK cells, but that simultaneous carcinogen-induced suppression of NK activity hampers their containment, allowing progression of hyperplasia to neoplasia, possibly owing to additional genetic changes.

Gastric M1 antigens were previously shown to be oncofetal markers for the colon in man and in the rat. They were observed very early during carcinogenesis in goblet cells of precancerous colonic mucosa; using an immunohistological method, we found that M1 were produced in 68% (41/60) of colonic adenocarcinomas and in 33% (21/63) of duodenal adenocarcinomas. M3C antigen has been described as being associated with human colonic mucus; in the rat it is restricted to the proximal colon. We found that M3C was produced in 91% (55/60) of colonic adenocarcinomas and in 15% (8/53) of duodenal adenocarcinomas. Before tumor appearance, M3C was sometimes expressed by goblet cells of the distal colon. We could not find it during fetal life. We have concluded that mucus-associated antigens can characterize modifications in cell differentiation in rat colonic carcinomas.

A 39-year old Asian with multiple duodenal villous adenomas and an adenocarcinoma arising from one of these tumors is described. The rarity of villous adenomas at this site is stressed and their tendency to undergo malignant change reviewed. Immunoperoxidase studies using carcinoembryonic antigen (CEA) antiserum were positive in high dilutions (1 in 8,000) in the carcinoma and the largest adenoma. This stain would appear to show functional malignancy before histological evidence of malignancy is found.

A case of duodenal somatostatinoma is reported. The patient, a 54-year-old male, had complained of an epigastric pain due to gastric ulcer and a duodenal polyp was unexpectedly found at a gastrectomy. The polyp showed basically tubular adenocarcinoma, with negative argyrophil and argentaffin reactions. By an indirect immunofluorescent examination almost all of the tumor cells were revealed as somatostatin-immunoreactive. Big somatostatin was also positive. Radioimmunoassay of the tumor indicated 6400 pg of somatostatin-like immunoreactivity per milligram of wet tissue. This seems to be the second case of duodenal somatostatinoma, following the case reported by us previously.

The clinicopathologic features of 11 cases (8 in men) of duodenal gangliocytic paraganglioma are presented. The patients averaged 56 years of age; none showed evidence of phakomatosis. Ten tumors occurred in the second portion of the duodenum, and one arose in the third portion. All tumors were polypoid, and half presented with gastrointestinal bleeding. The neoplasms were composed of paraganglioma and carcinoid-like elements, neurons, and Schwann as well as sustentacular cells. All tumors behaved in a benign fashion after local resection or snare polypectomy; long-term follow-up (1-25 years; mean, 8.3 years) showed no recurrence in any case. Immunocytochemical examination demonstrated the presence of somatostatin, serotonin, and human pancreatic polypeptide within endocrine cells and neurons.

A case report is given of a 32 year old patient harboring an immunoblastoma of the duodenum. Immunoglobulins could be demonstrated histologically in the tumor cells for the first time by a special technique. Clinical and morphological findings are discussed.