DNA mismatch repair deficiency but not ARID1A loss is associated with prognosis in small intestinal adenocarcinoma.

Small intestinal adenocarcinoma is an uncommon neoplasm with poor prognosis. It is clinically approached similarly to colorectal carcinoma (CRC). The prognostic value of DNA mismatch repair protein deficiency (dMMR) in CRC is well established, but its role in small intestinal adenocarcinoma remains inconclusive. Recently, loss of expression of ARID1A, a tumor suppressor gene product, by immunohistochemistry (IHC) was linked to dMMR and poor outcome in small intestinal adenocarcinoma, suggesting that it may be an emerging prognostic biomarker. We hypothesized that dMMR and/or ARID1A loss may be associated with clinical outcome in small intestinal adenocarcinoma. We examined dMMR and ARID1A loss by IHC in 120 surgically resected, nonampullary small intestinal adenocarcinomas collected from 2 tertiary centers. ARID1A loss was detected in 6 (7%) of 92 ARID1A-stained adenocarcinomas, whereas 21 (18%) of 120 adenocarcinomas demonstrated dMMR. ARID1A loss was not associated with survival or dMMR. dMMR adenocarcinomas had no distant metastasis, whereas 22 (22%) of 99 MMR-proficient adenocarcinomas had (P = .01). dMMR was an independent, positive predictor of disease-free survival (P = .035, hazard ratio: 0.2). Compared with dMMR CRC, dMMR small intestinal adenocarcinomas more frequently demonstrated loss of MSH2 and MSH6 and less often showed loss of MLH1 and PMS2 (both P < .001). In summary, ARID1A loss by IHC is uncommon in small intestinal adenocarcinomas. dMMR small intestinal adenocarcinomas are nonmetastatic tumors, frequently demonstrate loss of MSH2 and MSH6, and have superior disease-free survival. Our results suggest that all small intestinal adenocarcinomas should be tested for MMR protein deficiency.

Pancreatic Paraganglioma: A Case Report.

Background: Paraganglionic neoplasms that originate in the adrenal medullas are referred to as pheochromocytomas, but if they arise from other paraganglia scattered throughout the body, they are referred to as paragangliomas. Pancreatic paragangliomas are an extremely rare entity as only 20 cases have been reported in the literature. They tend to be nonfunctional and typically occur in the fourth to fifth decade of life without a gender predilection. We describe in this study a case of a pancreatic paraganglioma and its CT appearance. Case Presentation: A 62-year-old woman undergoing presurgical evaluation for an olfactory groove meningioma resection was incidentally found to have a pancreatic mass. Multiple fine needle aspirations of the mass through endoscopic ultrasound yielded only atypical epithelial cells. The mass demonstrated avid enhancement on serial CTs with mild interval growth over a period of 5 years. No lymphadenopathy was ever found. The patient's complete blood count, complete metabolic panel, and plasma carcinoembryonic antigen levels were all within normal limits. Urine catecholamine metabolite levels were never checked as the patient demonstrated no symptoms of catecholamine excess. The patient underwent a laparoscopic distal pancreatectomy and splenectomy, and the mass was eventually diagnosed as a pancreatic paraganglioma through pathology. While the patient tolerated the surgery well, she did require a biliary sphincterotomy and placement of a pancreatic duct stent postoperatively for treatment of a pancreatic duct leak, which completely resolved. She showed no evidence of disease recurrence on multiple subsequent CTs and continues to do well. Conclusion: Pancreatic paragangliomas are usually incidentally discovered and typically demonstrate avid homogenous enhancement on contrast-enhanced CT or MR. Aggressive surgical resection is necessary to maximize the chances of disease-free survival. Pancreatic paragangliomas are similar histologically, whether benign or malignant, to paragangliomas that occur anywhere else in the body, with ∼70% in the abdomen and 30% in the chest.

Prevalence of a hobnail pattern in papillary, poorly differentiated, and anaplastic thyroid carcinoma: a possible manifestation of high-grade transformation.

Papillary thyroid carcinoma is the most common thyroid carcinoma and has a generally favorable prognosis. There are several well-characterized variants, some of which are associated with more aggressive clinical behavior. Hobnail is a recently described rare variant that appears to behave more aggressively. Initial reports characterizing this variant focused on primary tumors and excluded other recognized variants, as well as poorly differentiated and anaplastic thyroid carcinomas, from analysis. Here, we evaluate the frequency of hobnail features in both primary and metastatic papillary thyroid carcinomas, including in association with other known variants, and also in poorly differentiated and anaplastic thyroid carcinomas. Primary and metastatic papillary thyroid carcinomas from a 5-year period (2007 to 2011) and all available anaplastic and poorly differentiated thyroid carcinomas from a 22-year period (1989 to 2011) were retrieved from the files. Tumors from 478 papillary, 26 anaplastic, and 18 poorly differentiated thyroid carcinomas were reviewed for hobnail features present in >10% of each tumor. Hobnail features were most commonly observed in association with poorly differentiated thyroid carcinoma (4 of 18 cases, 22%) and were seen in only 1.3% of papillary thyroid carcinoma patients (6 of 478). One of 26 anaplastic carcinomas had hobnail features (3.8%). Among the papillary thyroid carcinomas, hobnail features were often associated with other histologic variants that are known to be more clinically aggressive, had increased mitotic activity, and/or necrosis and lymph node metastases at presentation. These findings suggest that hobnail features may be a manifestation of higher-grade transformation.

Next-generation sequencing of salivary high-grade neuroendocrine carcinomas identifies alterations in RB1 and the mTOR pathway.

Salivary gland high-grade neuroendocrine carcinomas are rare, aggressive tumors that are morphologically and immunohistochemically similar to cutaneous high-grade neuroendocrine (Merkel cell) carcinomas. The majority of Merkel cell carcinomas harbor Merkel cell polyomavirus, while the virus is rare or absent in salivary high-grade neuroendocrine carcinomas. Inactivation of retinoblastoma 1 (RB1) has been implicated in the pathogenesis of both virus-positive and -negative Merkel cell carcinomas but by different mechanisms. In virus-positive tumors, a portion of the viral genome, the large T antigen, may inactivate RB1, and in virus-negative Merkel cell carcinomas truncating mutations in the RB1 gene have been identified. The molecular genetics of salivary high-grade neuroendocrine carcinomas are not well understood. Here, we performed targeted next-generation sequencing of 151 cancer-related genes on 4 four Merkel cell polyomavirus-negative primary salivary gland high-grade neuroendocrine carcinoma cases. Somatic mutations were predominantly found within tumor suppressor genes [TP53 (3 cases), PTEN (2 cases), RB1 (1 case)]. Truncating RB1 mutations, as seen in virus-negative Merkel cell carcinomas, were not identified. However, 3 of 4 cases had RB1 deletions by copy number variation analysis. The 4th case had loss of heterozygosity for RB1. Fluorescence in situ hybridization confirmed RB1 deletions in 2 of 3 cases, and the absence of RB1 deletion in the 4th case that had loss of heterozygosity. All 4 cases showed loss of RB1 protein expression by immunohistochemistry, indicating that RB1 inactivation is important. However, the mechanism of RB1 inactivation appears different than that seen in Merkel cell carcinomas. In addition, copy number variation consistent with activation of the PI3KCA/AKT/mTOR pathway was also observed in all 4 cases. The mTOR pathway may be a potential therapeutic target in these tumors as mTOR inhibitors are currently used to treat other tumor types.

Mcl1 downregulation sensitizes neuroblastoma to cytotoxic chemotherapy and small molecule Bcl2-family antagonists.

Neuroblastoma (NB) is a common, highly lethal pediatric cancer, with treatment failures largely attributable to the emergence of chemoresistance. The pro-survival Bcl2 homology (BH) proteins critically regulate apoptosis, and may represent important therapeutic targets for restoring drug sensitivity in NB. We used a human NB tumor tissue microarray to survey the expression of pro-survival BH proteins Mcl1 and Bcl2, and correlated expression to clinical prognostic factors and survival. Primary NB tumors heterogeneously expressed Mcl1 or Bcl2, with high expression correlating to high-risk phenotype. Co-expression is infrequent (11%), but correlates to reduced survival. Using RNA interference, we investigated the functional relevance of Mcl1 and Bcl2 in high-risk NB cell lines (SK-N-AS, IMR-5, NLF). Mcl1 knockdown induced apoptosis in all NB cell lines, while Bcl2 knockdown inhibited only NLF, suggesting functional heterogeneity. Finally, we determined the relevance of Mcl1 in resistance to conventional chemotherapy (etoposide, doxorubicin) and small molecule Bcl2-family antagonists (ABT-737 and AT-101). Mcl1 silencing augmented sensitivity to chemotherapeutics 2- to 300-fold, while Bcl2 silencing did not, even in Bcl2-sensitive NLF cells. Resistance to ABT-737, which targets Bcl2/-w/-x, was overcome by Mcl1 knockdown. AT-101, which also neutralizes Mcl1, had single-agent cytotoxicity, further augmented by Mcl1 knockdown. In conclusion, Mcl1 appears a predominant pro-survival protein contributing to chemoresistance in NB, and Mcl1 inactivation may represent a novel therapeutic strategy. Optimization of compounds with higher Mcl1 affinity, or combination with additional Mcl1 antagonists, may enhance the clinical utility of this approach.