Overrepresentation of HLA-DQ2 in small intestinal neuroendocrine tumor patients.

PURPOSE: To investigate whether celiac disease risk haplotypes HLA-DQ2 and DQ8 also increase the risk for developing small intestinal neuroendocrine tumor (SI-NET). METHODS: Thirty-five patients with serotonin-producing jejunal and ileal SI-NET were examined with HLA-DQ genotyping and serology for IgA anti-tissue transglutaminase (tTG) antibodies. RESULTS: Twenty-one patients (60 %) carried HLA-DQ2 or DQ8, twice the frequency of the general population (P < 0.001). In particular DQ2 was overrepresented (P = 0.013). Gender, age, disease stage, histopathological grade, or multifocality of primary tumor did not differ between patients with DQ2 or DQ8 and patients with other HLA-DQ haplotypes. No patient in the study was diagnosed with celiac disease (latent or symptomatic) as anti-tTG antibodies were negative in all 35. CONCLUSION: HLA-DQ haplotypes associated with celiac disease are overrepresented also in patients with SI-NET, in particular HLA-DQ2.

[Type II enteropathy-associated T-cell lymphoma: a clinicopathologic study].

OBJECTIVE: To study the clinicopathologic features, immunohistochemical findings, differential diagnosis and prognosis of type II enteropathy-associated T-cell lymphoma (EATL). METHODS: Fourteen cases of type II EATL encountered in Department of Pathology, Nanjing General Hospital were retrospectively reviewed. The clinical data, histologic features, immunohistochemical findings and follow-up information were analyzed, with literature review. RESULTS: There were altogether 12 males and 2 females. The median age of patient was 49 years. The sites of involvement included jejunum (10 cases) and ileum/colon (4 cases). The patients often presented with an abdominal mass, abdominal pain, diarrhea and constitutional symptoms such as fever, night sweating and cachexia. There was no clinical evidence of gluten-sensitive enteropathy. Histologically, the lymphoma cells showed full-thickness infiltration of the intestinal wall. They contained round hyperchromatic nuclei and pale cytoplasm. The stroma was minimally inflamed, with or without associated coagulative necrosis. A remarkable finding was the presence of villous atrophy, cryptal hyperplasia and intraepithelial lymphocytosis. Immunohistochemical study showed that the tumor cells expressed CD3, CD43 and CD8 (14/14). Some of them were also positive for CD56 (11/14) and CD30 (2/14). The staining for CD4, CD20, CD79a and myeloperoxidase was negative. A high proliferation index was demonstrated by Ki-67 immunostain. In-situ hybridization for EBER was negative. Follow-up data were available in 9 cases. The duration of follow-up ranged from 6 months to 36 months. Seven patients died within 14 months. CONCLUSIONS: EATL is a rare type of lymphoma with intestinal involvement. Associated enteropathy is not demonstrated, in contrast to cases encountered in Nordic countries. A correct diagnosis requires evaluation of clinical manifestations, pathologic features and ancillary study results.

NK cells engineered to express a GD2 -specific antigen receptor display built-in ADCC-like activity against tumour cells of neuroectodermal origin.

Treatment of high-risk neuroblastoma (NB) represents a major challenge in paediatric oncology. Alternative therapeutic strategies include antibodies targeting the disialoganglioside GD(2) , which is expressed at high levels on NB cells, and infusion of donor-derived natural killer (NK) cells. To combine specific antibody-mediated recognition of NB cells with the potent cytotoxic activity of NK cells, here we generated clonal derivatives of the clinically applicable human NK cell line NK-92 that stably express a GD(2) -specific chimeric antigen receptor (CAR) comprising an anti-GD(2) ch14.18 single chain Fv antibody fusion protein with CD3-ζ chain as a signalling moiety. CAR expression by gene-modified NK cells facilitated effective recognition and elimination of established GD(2) expressing NB cells, which were resistant to parental NK-92. In the case of intrinsically NK-sensitive NB cell lines, we observed markedly increased cell killing activity of retargeted NK-92 cells. Enhanced cell killing was strictly dependent on specific recognition of the target antigen and could be blocked by GD(2) -specific antibody or anti-idiotypic antibody occupying the CAR's cell recognition domain. Importantly, strongly enhanced cytotoxicity of the GD(2) -specific NK cells was also found against primary NB cells and GD(2) expressing tumour cells of other origins, demonstrating the potential clinical utility of the retargeted effector cells.

A case report with plasmablastic lymphoma of the jejunum.

Plasmablastic lymphoma (PBL) is a recently identified entity that is considered to be a type of diffuse large B-cell lymphoma with a unique immunophenotype and a predilection for the oral cavity of patients with the human immunodeficiency virus (HIV). Although its clinical features may help in the differential diagnosis, an extraoral location in a patient without HIV makes it more difficult to suspect clinically. This case report is the first to describe a patient with PBL originating from the jejunum in a 60-yr-old, HIV-seronegative man. Computed tomography of the face, chest and abdomen showed about a 9.4 x 9.0 cm mass of the proximal jejunum, multiple masses in the musculoskeletal soft tissue, and multiple lymphadenopathies. The histological examinations demonstrated a large cell lymphoma with plasmablastic differentiation. The neoplastic cells were diffusely positive for MUM1, epithelial membrane antigen and lambda light chains, and focally positive for CD79a; but negative for CD3, CD20, CD30, CD34, CD45RO, CD56, CD99, and CD117. The proliferation index by Ki-67 immunohistochemistry was approximately 70%. These findings were compatible with the diagnosis of PBL. The findings in this case suggest that PBL should be included in the differential diagnosis of a small bowel mass even in a HIV-negative patient.

Immune modulation by non-hodgkin lymphoma in a patient with two primary intestinal T-cell lymphomas and long-standing celiac disease.

Tumors may influence immunologic reactions. Here, we report on a 72-year-old patient who suffered from celiac disease (CD) that had been diagnosed 20 years before. Under a normal diet but without any evidence of enteropathy or CD-associated antibodies, the patient developed a jejunal T-cell lymphoma. It was resected due to perforation and four courses of IMVP-16 were added. The patient started and kept a strict gluten-free diet (GFD). Two years later, he presented with weight loss and a clonally divergent refractory sprue type II with loss of antigen (CD8; T-cell receptor-beta) expression in intraepithelial lymphocytes. At this time point, he showed high titers of CD-associated antibodies, although he was on a strict GFD. This case report highlights several questions: the missing enteropathy under a gluten-containing diet supports the notion of immune suppression in malignant diseases, especially non-Hodgkin lymphoma. Secondly, the patient developed an early form of a second independent T-cell lymphoma (refractory sprue type II) under a strict GFD, then with CD-associated antibodies, which raises the question whether the clonal intraepithelial lymphocytes were stimulating antibody production. Thus, the single detection of CD-associated antibodies in patients with CD is not itself proof of noncompliance with GFD.

Immunophenotype and molecular characterisation of adenocarcinoma of the small intestine.

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).

A Case Report with Plasmablastic Lymphoma of the Jejunum

Plasmablastic lymphoma (PBL) is a recently identified entity that is considered to be a type of diffuse large B-cell lymphoma with a unique immunophenotype and a predilection for the oral cavity of patients with the human immunodeficiency virus (HIV). Although its clinical features may help in the differential diagnosis, an extraoral location in a patient without HIV makes it more difficult to suspect clinically. This case report is the first to describe a patient with PBL originating from the jejunum in a 60-yr-old, HIV-seronegative man. Computed tomography of the face, chest and abdomen showed about a 9.4x9.0 cm mass of the proximal jejunum, multiple masses in the musculoskeletal soft tissue, and multiple lymphadenopathies. The histological examinations demonstrated a large cell lymphoma with plasmablastic differentiation. The neoplastic cells were diffusely positive for MUM1, epithelial membrane antigen and lambda light chains, and focally positive for CD79a; but negative for CD3, CD20, CD30, CD34, CD45RO, CD56, CD99, and CD117. The proliferation index by Ki-67 immunohistochemistry was approximately 70%. These findings were compatible with the diagnosis of PBL. The findings in this case suggest that PBL should be included in the differential diagnosis of a small bowel mass even in a HIV-negative patient.

Functional CCR9 expression is associated with small intestinal metastasis.

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.

[Immunohistochemical and ultrastructural heterogeneity of gastrointestinal stromal tumors]. / Hétérogénéité immunohistochimique et ultrastructurale des tumeurs stromales digestives.

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.

[Primary digestive tract Kaposi sarcoma with idiopathic CD4+ lymphocytopenia, HIV negative, HHV8 positive]. / Sarcome de Kaposi digestif primitif avec lymphocytopénie CD4 idiopathique, VIH négatif, HHV8 positif.

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.

[Fatal outcome of Strongyloides stercoralis infection in a patient with no previously known immunosuppression]. / Fatalt forløbende Strongyloides stercoralis-infektion hos patient uden forudgående kendt immunsuppression.

A case of fatal infection with Strongyloides stercoralis in a previously healthy young African with no known immunosuppression is reported. The patient suffered severe gastrointestinal bleeding and despite intensive treatment died of multiorgan failure. Postmortem, signs of ulcerating T-cell lymphoma were found in a jejunal specimen, and the patient was found to be infected with HTLV-1. Gastrointestinal bleeding in relation to infection with Strongyloides stercoralis is discussed as well as possible relations between the severity of infection, lymphoma and HTLV-1.

[Primary intestinal T lymphoma with massive eosinophilia]. / Linfoma T primario de intestino asociado a intensa eosinofilia.

Primary intestinal T lymphoma with eosinophilia is an infrequent tumour. Its rarity account for the paucity of similar cases recorded in the literature. It affects predominantly middle-aged men and may be associated with ulceration, fistula formation and intestinal perforation with an abdominal mass. Lesions of the intestine with massive tissue eosinophilia may be a difficult diagnostic problem, but this entity displays distinctive histological features. The presence of intense tissue eosinophilia is a T-cell dependent lymphomas response. We describe a case of T lymphoma involving small intestine with massive eosinophilia.

[Immunoproliferative disease of the small intestine. A case of polymeric IgA with evolution to lymphoma]. / Enfermedad inmunoproliferativa del intestino delgado. A propósito de un caso de IgA polimérica con evolución a linfoma.

Immunoproliferative disease of the small intestine (IPDSI) is rare and although it is more frequent in mediterranean countries it has more exceptionally been described in Western countries. IPDSI is characterized by diffuse infiltration of the small intestine mucose by lymphoblastic cells and over time may evolve to the development of lymphoma, generally of an immunoblastic nature. Another peculiarity of the disease is its association with heavy alpha chain disease (HACD). Several types of paraproteinemia may appear in the serum of patients, very seldom in the form of polymeric IgA, with the evolution of the cases reported in the literature not leading to the development of heavy chain disease or lymphoma. We herewith present an exceptional case of IPDSI in whom the association of HACD was discarded and in whom polymeric IgA paraproteinemia which evolved to the development of lymphoma was observed.

Molecular analysis of T-cell clonality in ulcerative jejunitis and enteropathy-associated T-cell lymphoma.

Ulcerative jejunitis (UJ) and enteropathy-associated T-cell lymphoma (EATL) are closely related conditions both associated with celiac disease. Benign-appearing inflammatory ulcers are seen in both, which has led to the suggestion that UJ is a manifestation of EATL. The aim of this study was to investigate this relationship using the polymerase chain reaction (PCR) to detect T-cell gene rearrangement. PCR amplification of the T-cell receptor gamma-chain gene was performed on DNA extracted from lymphoma, associated inflammatory ulcers, and intervening mucosa in six EATL cases and from ulcers and intervening mucosa of seven cases of UJ. In two of these cases, DNA from a subsequent lymphoma was also studied. The PCR products from the tumor and an ulcer from one EATL case, two ulcers from one case of UJ, and one ulcer and subsequent cutaneous lymphoma from one UJ case were sequenced. Twenty-five ulcers from twelve cases of Crohn's disease, twenty sections of normal bowel, and nine celiac biopsies were included as controls. A monoclonal T-cell population defined by a dominant band equal in size to that amplified from the lymphoma was identified in at least one ulcer from four informative EATL cases and from intervening mucosa in three. Monoclonality was demonstrated in at least one, and up to thirteen, ulcers from all seven cases of UJ, in intervening mucosa in five, and in the two subsequent lymphomas. Sequencing showed the same clone was present in the tumor and the ulcer in the EATL case, in two of three ulcers from the UJ case, and in an ulcer and subsequent cutaneous lymphoma in one UJ case. All Crohn's disease ulcers and all sections of normal bowel were polyclonal. One of nine celiac biopsies showed a dominant band. In conclusion, we have shown that T-cell monoclonality is a feature of the ulcers in both UJ and EATL and that the same clone is present in EATL and its associated inflammatory ulcers and in UJ and subsequently developing lymphoma.

Malignant gastrointestinal stromal tumor of the small intestine: radiologic-pathologic correlation.

Neoplasms of the small intestine are very rare. Gastrointestinal stromal tumors (GISTs) are one of the new undifferentiated stromal tumors of the gastrointestinal tract diagnosed by immunohistochemistry. We present a case of a malignant GIST arising from the small intestine and report the radiologic characteristics of the tumor and pathological correlation. CT showed a very large, enhancing mass with extensive central necrosis located on the mesenteric side of the jejunum. A perforation into the jejunal lumen was observed by upper GI series. MRI showed a very large tumor which was hypointense on T2-weighted images. Ultrasound revealed a mixed solid and cystic mass. Grossly, the tumor was solid peripherally with extensive central necrosis. Microscopically, it consisted of spindle and epithelioid cells. Immunohistochemically, the cells stained positive for CD34, which is diagnostic of GIST.

Single jejunoileal and right colonic carcinoids as midgut tumors. A study collating immunophenotypes and histogenesis.

The jejunoileum and the right colon, both of which are located in the midgut, have some histologic similarities such as the presence of Paneth cells and intraepithelial endocrine cells (IEECs). Since gastrointestinal (GI) carcinoids arise from the same stem cells as GI endocrine cells, the question was whether or not there might also be similarities in the histogenesis of jejunoileal carcinoids (JICs) and right colonic carcinoids (RCCs). Ten single JICs and 3 RCCs together with their respective controls were stained using various neurohormonal immunoreagents. Our results showed that neither the JICs nor the RCCs appeared to arise from a background of diffuse IEEC hyperplasia. Furthermore, in the jejunoileum, serotonergic progenitor cells appear to have a proclivity for neoplastic transformation, as do cells of the pancreatic polypeptide and glucagon lineage in the right colon.