Vascular endothelial growth factor-A is an Immunohistochemical biomarker for the efficacy of bevacizumab-containing chemotherapy for duodenal and jejunal adenocarcinoma.

BACKGROUND: The efficacy and safety of bevacizumab-containing chemotherapy for patients with metastatic duodenal and jejunal adenocarcinoma (mDJA) are unclear. The present study aimed to evaluate the efficacy of bevacizumab and to explore immunohistochemical markers that can predict the efficacy of bevacizumab for patients with mDJA. METHODS: This multicentre study included patients with histologically confirmed small bowel adenocarcinoma who received palliative chemotherapy from 2008 to 2017 at 15 hospitals. Immunostaining was performed for vascular endothelial growth factor-A (VEGF-A), TP53, Ki67, ß-catenin, CD10, MUC2, MUC5AC, MUC6, and mismatch repair proteins. RESULTS: A total of 74 patients were enrolled, including 65 patients with mDJA and 9 with metastatic ileal adenocarcinoma. Patients with mDJA who received platinum-based chemotherapy with bevacizumab as first-line treatment tended to have a longer progression-free survival and overall survival than those treated without bevacizumab (P = 0.075 and 0.077, respectively). Multivariate analysis extracted high VEGF-A expression as a factor prolonging progression-free survival (hazard ratio: 0.52, 95% confidence interval: 0.30-0.91). In mDJA patients with high VEGF-A expression, those who received platinum-based chemotherapy with bevacizumab as a first-line treatment had significantly longer progression-free survival and tended to have longer overall survival than those treated without bevacizumab (P = 0.025 and P = 0.056, respectively), whereas no differences were observed in mDJA patients with low VEGF-A expression. CONCLUSION: Immunohistochemical expression of VEGF-A is a potentially useful biomarker for predicting the efficacy of bevacizumab-containing chemotherapy for patients with mDJA.

Multicenter retrospective analysis of the clinicopathologic features of monomorphic epitheliotropic intestinal T-cell lymphoma.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a provisional entity in the 2017 World Health Organization classifications. To further elucidate the clinicopathologic features of this new disease, we carried out a retrospective, multicenter analysis of 42 patients with MEITL. The median age of the patients was 59 years (range, 20-84 years), and 27 patients (64 %) were male. Thirty-two patients (76 %) were Ann-Arbor stages I-II and 28 (67 %) were Lugano stages I-II1&2. The most frequent site of involvement was the jejunum (N = 21). Most cases expressed CD8 (79 %) and CD56 (95 %) and did not express CD30 (5 %) or EBER (0 %). The median progression-free survival was 6.9 months (95 % CI 4.3-9.6); the median OS was 14.8 months (2.4-27.2). Thirty-two patients (76 %) underwent surgery and 37 (88 %) received chemotherapy. A complete response (CR) rate was 38 %. Sixteen patients had undergone autologous stem cell transplantation (ASCT). Relapse or progression was documented in 24 cases, most frequently in the primary site (N = 23). Four cases showed central nervous system relapse. Age over 55 years, poor performance scale, advanced Lugano stage (IIE-IV), not achieving CR, and not receiving ASCT were associated with inferior OS. While the optimal management of MEITL remains undetermined, achieving CR and consolidative ASCT seem essential. As CHOP might be insufficient for achieving CR, more efficient combinations should be investigated. Additionally, considering the frequent local failure and CNS relapse, novel therapeutic approaches are required to improve survival.

Clusterin in Neuroendocrine Epithelial Neoplasms: Absence of Expression in a Well-differentiated Tumor Suggests a Jejunoileal Origin.

Clusterin, a widely expressed, tissue-specific glycoprotein, is a diagnostic marker of several tumor types, including anaplastic large cell lymphoma, follicular dendritic cell sarcoma, and tenosynovial giant cell tumor. A recent study has suggested it is highly expressed by well-differentiated neuroendocrine tumors (NET) arising at most anatomic sites, with the exception of jejunoileal tumors, and that it is similarly not expressed by poorly differentiated neuroendocrine carcinomas (NEC). We sought to validate this result in a large cohort of NETs and NECs. Clusterin immunohistochemistry was performed on tissue microarrays of 255 NETs [45 lung, 4 stomach, 8 duodenum, 75 pancreas (62 primary, 13 metastatic), 107 jejunoileum (69 primary, 38 metastatic), 16 appendix] and 88 NECs (43 visceral, 45 Merkel cell). Extent (%) and intensity (0, 1+, 2+, 3+) of staining were assessed and an H-score (extent x intensity) calculated. An average H-score >5 was considered positive. Clusterin expression was noted in 82.4% of 148 nonjejunoileal NETs (average H-score 183) and only 8.4% of 107 jejunoileal NETs (average H-score, 31), as well as 19.3% of NECs (average H-score, 36). Clusterin is frequently, strongly expressed by NETs of diverse anatomic sites, with the exception of jejunoileal tumors, in which it is only rarely, weakly expressed. It is occasionally, weakly expressed by NECs. Most metastatic NETs of occult origin arise in the pancreas or the jejunoileum. For cases in which an initial site of origin immunopanel (eg, islet 1, PAX6, CDX2) is ambiguous, addition of clusterin may be diagnostically useful, with absence of expression suggesting a jejunoileal origin.

Prognostic Significance of CD44v6, CD133, CD166, and ALDH1 Expression in Small Intestinal Adenocarcinoma.

BACKGROUND: Small intestinal adenocarcinoma (SIAC) is a rare human malignant tumor. According to the cancer stem cell (CSC) hypothesis, only a small subpopulation of tumor cells has the ability to initiate and increase tumor growth. CD44v6, CD133, CD166, and ALDH1 have been proposed to be putative CSC markers in gastrointestinal malignancies. However, their implications in SIAC still remain unclear. We aimed to investigate the expressions of CD44v6, CD133, CD166, and ALDH1 and evaluate their relationships with clinicopathologic parameters including the survival data in SIACs. MATERIALS AND METHODS: Immunohistochemical analysis for CD44, CD133, CD166, and ALDH1 was performed using tissue microarrays for 191 surgically resected SIACs. RESULTS: CD44v6, CD133, CD166, and ALDH1 expression was found in 25 (13.5%), 58 (30.7%), 82 (44.1%), and 63 (33.3%) cases, respectively. CD44v6(+) was correlated with vascular tumor invasion (P=0.023). CD133(+) was marginally correlated with the histologic subtype of the tumors (P=0.085). Combined CD44v6(+)/CD133(+) was observed in 11 (5.9%) and was associated with a significantly worse survival rate by univariate (P=0.016) and multivariate (P=0.048; Cox hazard ratio, 2.403) analyses. . CONCLUSIONS: Evaluation of the combined CD133 and CD44v6 expression could be a useful tool for predicting a poor outcome in patients with SIAC.

Gastrointestinal autonomic nerve tumour of jejunum presenting as a perforated mass.

Gastrointestinal autonomic nerve tumour (GANT) is a rare mesenchymal neoplasm of the gastrointestinal tract arising from the neural plexus of the intestinal wall. Herein, we present a 70-year-old male patient presenting with a clinical picture of acute abdomen. Examination of the specimen obtained from the small bowel by means of complete resection revealed a relatively soft submucosal mass measuring 4.5 x 3 cm in size with spindle morphology and high mitotic activity (> 10 mitoses per 50 high-power fields). The tumour cells were strong positive for c-kit (CD117), S-100 protein and glial fibrillary acidic protein (GFAP), but did not harbour mutations in the c-kit and PDGFR genes. The diagnosis was based on light microscopy and immunohistochemical verification. We started tyrosine kinase inhibitor 400 mg/day. The patient is currently alive without metastasis at 28 months postoperatively. He is under close follow-up and survival data of the patient will be presented in the later studies.

[Undifferentiated carcinoma of the jejunum producing granulocyte colony-stimulating factor].

An 80-year-old man presented with abdominal fullness and vomiting. Laboratory data revealed severe anemia, an inflammatory response, and elevated white blood cell counts. Abdominal computed tomography indicated ileus caused by a jejunal tumor measuring 8cm in diameter. Although small-bowel endoscopy enabled visualization of the tumor, adequate biopsy specimens could not be obtained for accurate diagnosis. The patient's condition rapidly deteriorated, because of which surgical treatment could not be initiated. The patient died approximately 3 weeks after admission. High serum granulocyte colony-stimulating factor (G-CSF) levels were detected at autopsy. Immunohistochemical staining of the autopsy specimen indicated positive G-CSF levels in the jejunal tumor. On the basis of these findings, a final diagnosis of undifferentiated carcinoma of the jejunum producing G-CSF was made.

Crohn enteritis-associated small bowel adenocarcinomas exhibit gastric differentiation.

Primary small bowel adenocarcinoma is rare. Although generally similar to colonic adenocarcinoma, some small bowel adenocarcinomas exhibit unique morphologic features, particularly those arising in association with Crohn disease. In this study, 15 sporadic small bowel adenocarcinomas and 11 Crohn enteritis-associated small bowel adenocarcinomas were examined for histology and immunohistochemical profile including cytokeratins (CK) 7 and 20, intestinal markers CDX2 and MUC2, and gastric epithelial markers MUC5AC and MUC6. We found that Crohn enteritis-associated small bowel adenocarcinomas frequently resemble gastric tubular adenocarcinoma histologically. In addition, when compared to sporadic small bowel adenocarcinoma, the former expressed MUC5AC and MUC6 with much higher frequency (82% vs. 7% and 73% vs. 0%, respectively). Ten of 11 Crohn enteritis-associated small bowel adenocarcinomas (91%) were positive for at least one gastric-type marker (MUC5AC or MUC6). Expression of CK7 was also more frequent in Crohn enteritis-associated small bowel adenocarcinoma (73% versus 27%) while expression of CK20 was less frequent (64% vs. 100%). There was no difference between sporadic and Crohn enteritis-associated small bowel adenocarcinoma in expression of CDX2 (100% vs. 91%) and MUC2 (93% vs. 73%). These observations suggest that there is a difference in the morphologic and immunohistochemical characteristics of sporadic versus Crohn enteritis-associated small bowel adenocarcinoma, particularly in their expression of gastric-type mucin. The findings also suggest that gastric differentiation in Crohn enteritis-associated small bowel adenocarcinoma is related to gastric metaplasia, a common phenomenon in Crohn disease.

Significance of decreased apoptosis, role of Bid expression and Bcl-Xl/Bid ratio in human jejunal stromal tumors.

Given that the studies on human small intestinal stromal tumors are very limited, our study was designed to determine the significance of apoptosis, the role of some apoptosis-related proteins, including Bax, Bad, Bid, Bcl-2, Bcl-Xl, and Bcl-W, in jejunal stromal tumors (JST). For this purpose, 52 samples were examined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and immunohistochemistry, including 40 cases from normal jejunum and 12 cases from the JST. The results showed that a significantly decreased apoptosis was observed in JST compared with normal jejunum (median of apoptotic index, 0.13% vs 15.17%, p < 0.001). In univariate analysis, statistically significant differences were shown in percentage of positive-expression of Bid (0.0% vs 77.5%, p < 0.001), Bcl-2 (91.7% vs 42.5%, p = 0.003), and Bcl-Xl (75.0% vs 35.0%, p = 0.014), but not in Bax, Bad, and Bcl-W. Moreover, Bcl-Xl was an independent parameter associated with JST by multivariate Logistic analysis. For the role of ratios of anti-apoptotic proteins to pro-apoptotic proteins, Bcl-Xl/Bid ratio was the most preferable index. In conclusion, decreased apoptosis and expression of Bid, increased level of Bcl-Xl may play some important roles in human JST, and Bcl-Xl/Bid ratio may be as a new potentially associated index, although they should be validated in more studies.

Melanoma markers-negative primary melanoma with melanoma markers-positive metastasis.

Concordant loss of all 3 commonly used melanocytic markers (ie, S-100, HMB-45, and Melan-A) in a primary malignant melanoma with expression of the same in the metastatic lesion is very rare. To the best of the authors' knowledge, they documented the second case of this unusual and rare phenomenon.

Epidemiology of small bowel carcinoids in a defined population.

BACKGROUND: This retrospective study describes the epidemiology of small bowel carcinoids in a geographically defined population, with no other selection bias. METHODS: All patients (n = 145) resident in Jönköping County when diagnosed with carcinoid in the jejunum or ileum from 1960 to 2005 were included. Medical records were reviewed in detail, and tumor specimens were histopathologically and immunohistochemically reexamined when required (n = 44). RESULTS: The annual age-adjusted incidence of small bowel carcinoids was 1.12 (95% confidence interval 0.95-1.31) per 100,000 persons. Median age at diagnosis was 69 years. The predominating presenting symptom was uncharacteristic abdominal pain (50%), whereas a smaller number suffered from typical flushes (13%). Surprisingly, 14% presented with overt gastrointestinal hemorrhage. Most of the patients diagnosed based on their symptoms had metastases at diagnosis (44% regional, 40% distant). Metastasized tumors by definition belong to World Health Organization (WHO) histopathologic group 2; and when reexamined, most (83%) of the localized tumors were also found to belong to WHO group 2. CONCLUSIONS: In comparison to previous reports, a higher age-adjusted incidence of small bowel carcinoids was observed, and the patients were clearly older at the time of diagnosis. Even with metastatic disease, the presenting symptoms were usually uncharacteristic, and the carcinoid syndrome was infrequently seen.

Hepatic angiomyolipoma and intramural small intestinal schwannoma: a coincidence or a relationship?

We report a case of hepatic angiomyolipoma associated to a small bowel schwannoma in a 40-years old woman. Both lesions were asyntomatic. Histologically, hepatic angiomyolipoma showed oncocytic features and scanty adipose tissue, the tumor cells expressed desmin, smooth muscle actin, S-100 protein and HMB45. The tumor cells of intramural small intestinal mass were positive for S-100 protein and GFAP and negative for CD117, CD34 and desmin. To the best of our knowledge, no case of hepatic angiomyolipoma has been previously reported in association with intestinal schwannoma.

Jejunojejunal intussusception secondary to metastasis from adenocarcinoma of the lung--a case report.

Small intestine metastasis from primary lung cancer is uncommon and jejunojejunal intussusception secondary to metastatic lung cancer is extremely rare. We report a case presenting with a one-week history of abdominal pain associated with poor appetite, vomiting and absent defaecation. Physical examination revealed abdominal distention with decreased bowel sounds. Chest roentgenogram showed a mass lesion in the right upper lung zone. Biopsy of the lung mass lesion confirmed adenocarcinoma of the lung. Computed tomography (CT) of the abdomen demonstrated a "target mass" lesion in the right lower abdomen, representing a small intestinal intussusception. Emergency segmental resection of the affected small intestine with jejunojejunal anastomosis was performed. Histological examination of the specimen revealed metastatic adenocarcinoma of lung origin. The patient had an uneventful postoperative course and was discharged home two weeks after surgery.

[Review of 32 gastro-intestinal stromal tumours with CD117 antigen]. / Revision de 32 tumeurs mesenchymateuses gastro-intestinales avec le CD117.

AIM: The aim of this study is to review clinical data, histological and immunohistochemical findings and prognosis of stromal gastrointestinal tumors. METHODS: A retrospective Study of 32 cases of stromal gastrointestinal tumors diagnosed in the Department of Pathology of Mongi Slim Hospital of Tunis from 1991 to 2004. RESULTS: The average age of the patients was of 54.4 years, equal for sex. Tumors were essentially gastric (50%) and of the small intestine (37.5%). All the patients had surgical treatment. Gastro-intestinal Stromal Tumors or GIST represent the most frequent stromal tumor with 56.2% of cases. CONCLUSION: After immunohistochimestry study, using CD117 antigen, this revision allows better management of GIST. Glivec is the standard treatment of advanced GIST.

Adenomyoma of the jejunum.

Adenomyoma of the small intestine is an extremely rare condition characterized by abnormal glandular structures surrounded by smooth muscle. We report a case of adenomyoma of the jejunum. The patient was a 61-year-old female with cancer of the sigmoid colon and multiple liver cysts, who was sent to the operation room for exploratory laparotomy and sigmoidectomy. At surgery, a polypoid lesion was incidentally found in the lower jejunum, which was resected. On histologic examination, the morphologic features were typical of adenomyoma. However, new histopathological and immunohistochemistry features are described here, providing evidence that adenomyoma of the jejunum is a form of intestinal epithelial hamartoma.

Metastatic liposarcoma in the jejunum causing intussusception: report of a case.

We report a case of metastatic liposarcoma in the jejunum manifesting as intestinal intussusception. A 75-year-old man underwent wide excision of a dedifferentiated liposarcoma in his left thigh, followed by adjuvant radiation therapy. He was referred to our department 7 months later with colicky abdominal pain and vomiting. Abdominal radiography showed an intussusception of the small intestine. Laparotomy revealed an antegrade jejunojejunal intussusception, and we resected the jejunum containing the tumor without attempting manual reduction. Histological examination confirmed that the tumor was a metastasis of the liposarcoma. The patient died of pulmonary metastasis 3 months later.

Down-regulated in adenoma Cl/HCO3 exchanger couples with Na/H exchanger 3 for NaCl absorption in murine small intestine.

BACKGROUND & AIMS: Electroneutral NaCl absorption across small intestine contributes importantly to systemic fluid balance. Disturbances in this process occur in both obstructive and diarrheal diseases, eg, cystic fibrosis, secretory diarrhea. NaCl absorption involves coupling of Cl(-)/HCO(3)(-) exchanger(s) primarily with Na(+)/H(+) exchanger 3 (Nhe3) at the apical membrane of intestinal epithelia. Identity of the coupling Cl(-)/HCO(3)(-) exchanger(s) was investigated using mice with gene-targeted knockout (KO) of Cl(-)/HCO(3)(-) exchangers: Slc26a3, down-regulated in adenoma (Dra) or Slc26a6, putative anion transporter-1 (Pat-1). METHODS: Intracellular pH (pH(i)) of intact jejunal villous epithelium was measured by ratiometric microfluoroscopy. Ussing chambers were used to measure transepithelial (22)Na(36)Cl flux across murine jejunum, a site of electroneutral NaCl absorption. Expression was estimated using immunofluorescence and quantitative polymerase chain reaction. RESULTS: Basal pH(i) of DraKO epithelium, but not Pat-1KO epithelium, was alkaline, whereas pH(i) in the Nhe3KO was acidic relative to wild-type. Altered pH(i) was associated with robust Na(+)/H(+) and Cl(-)/HCO(3)(-) exchange activity in the DraKO and Nhe3KO villous epithelium, respectively. Contrary to genetic ablation, pharmacologic inhibition of Nhe3 in wild-type did not alter pH(i) but coordinately inhibited Dra. Flux studies revealed that Cl(-) absorption was essentially abolished (>80%) in the DraKO and little changed (<20%) in the Pat-1KO jejunum. Net Na(+) absorption was unaffected. Immunofluorescence demonstrated modest Dra expression in the jejunum relative to large intestine. Functional and expression studies did not indicate compensatory changes in relevant transporters. CONCLUSIONS: These studies provide functional evidence that Dra is the major Cl(-)/HCO(3)(-) exchanger coupled with Nhe3 for electroneutral NaCl absorption across mammalian small intestine.

Undifferentiated carcinoma of the jejunum with extensive rhabdoid features. Case report and review of the literature.

Malignant rhabdoid tumor, first described in the kidney of young infants, is a rare and highly aggressive neoplasm of controversial histogenesis that has been reported at many other sites, including the gastrointestinal tract. However, malignant rhabdoid tumor of the small intestine is very rare, with only seven cases published to date. We report a 70-year-old man who presented with abdominal pain and weight loss, and showed a perforated jejunal mass with disseminated metastases by imaging. The patient underwent partial jejunectomy and biopsy of a liver metastasis. Microscopically, the tumor was characterized by neoplastic cells with vesicular nuclei, large nucleoli and abundant eccentric cytoplasm with hyaline globular intracytoplasmic inclusions. Immunohistochemically, the neoplasm coexpressed vimentin and epithelial antigens (AE1/AE3, Cam 5.2, CK34betaE12, CK19 and EMA), most of them showing a peculiar immunostaining pattern in relation to the globular inclusions. Ultrastructurally, the inclusions corresponded to paranuclear whorls of intermediate filaments. The patient received postoperative chemotherapy but died 9 months after surgery. In summary, we report the exceptional case of an undifferentiated carcinoma of the jejunum with rhabdoid phenotype. As with tumors at other sites, recognition of rhabdoid morphology in small intestine neoplasms is of significance because the prognosis is extremely poor.