Immunotactoid hepatopathy: A novel entity with histologically proven recurrence post liver transplantation.

Immunotactoid deposition is a rare fibrillary deposition disease that is primarily seen in the kidney and is associated with paraproteinemia. Here, we report a case of hepatic immunotactoid deposition in a 67-year-old male with a history of smoldering myeloma and chronic kidney disease who underwent liver transplantation for metabolic dysfunction-related cirrhosis. Immunotactoid deposition was first identified in the explanted liver and recurred in the allograft within only 7 weeks following transplantation, presenting as ascites with normal liver function tests. The patient's posttransplant course was complicated by proteinuria and renal failure requiring dialysis. Histologic examination of both native and allograft livers demonstrated pink amorphous material occupying sinusoidal spaces that were Congo-red negative and immunoglobulin M Kappa-restricted. Electron microscopy revealed characteristic deposits of electron-dense bundles of hollow microtubules with a 40 nm diameter within the sinusoids and space of Disse, consistent with immunotactoids. Therapy of the patient's underlying plasma-cell dyscrasia utilizing a daratumumab-based regimen showed decreased serum paraproteins, resolution of ascites, and improved kidney function, no longer requiring dialysis, without inducing rejection. The patient continues to respond to treatment 10 months posttransplant.

Loss of SATB2 Expression in Colorectal Carcinoma Is Associated With DNA Mismatch Repair Protein Deficiency and BRAF Mutation.

The special AT-rich sequence binding protein (SATB2) has been reported to be a specific immunohistochemical marker for colorectal carcinoma; however, correlation of SATB2 expression with molecular alterations commonly assessed in colorectal carcinoma has not been performed. We examined the immunohistochemical expression of SATB2 in 586 adenocarcinomas of the gastrointestinal (GI) tract and pancreas to assess its utility in diagnosis and analyze the clinicopathologic and molecular characteristics of colorectal carcinoma stratified by SATB2 expression. SATB2 and CDX2 expression were evaluated in 266 adenocarcinomas of lower GI tract origin (246 colorectal and 20 appendiceal mucinous), 208 adenocarcinomas of upper GI tract and small intestinal origin (74 esophagus/esophagogastric junction, 103 stomach, 20 duodenal, and 11 jejunoileal), and 112 pancreatic ductal adenocarcinomas. SATB2 expression was more frequently identified in adenocarcinomas of lower GI tract origin (222/266, 83%) compared with upper GI tract, small intestinal, or pancreatic origin (26/320, 8%) (P<0.001). Compared with CDX2 alone, dual positive expression for SATB2 and CDX2 (SATB2/CDX2) has a significantly higher specificity for adenocarcinoma of lower GI tract origin (94% vs. 57%, P<0.001). In colorectal carcinoma, loss of SATB2 expression was more frequently observed in DNA mismatch repair (MMR) protein deficient tumors (31%) compared with MMR protein proficient tumors (13%) (P<0.01). A BRAF V600E mutation was more frequently identified in colorectal carcinomas with loss of SATB2 expression compared with those with positive SATB2 expression (29% vs. 3%) (P<0.001). In summary, SATB2 expression is a relatively specific marker of lower GI tract origin; however, loss of SATB2 expression is more commonly seen in colorectal carcinoma with MMR protein deficiency and BRAF mutation.

Histologic Features Do Not Reliably Predict Mismatch Repair Protein Deficiency in Colorectal Carcinoma: The Results of a 5-Year Prospective Evaluation.

Most major professional medical organizations advocate universal screening for Lynch syndrome in colorectal carcinoma; however, some allow for a selective screening approach based on clinicopathologic factors including assessment of histologic features of mismatch repair protein deficiency (MMRD). We performed a prospective evaluation for histopathologic features of MMRD in colorectal carcinomas that underwent universal screening for Lynch syndrome to evaluate the ability of histology to predict MMRD. In total, 947 resected colorectal carcinomas over a 5-year period were prospectively analyzed for histologic features of MMRD and for DNA mismatch repair protein abnormalities. Histologic features of MMRD were reported as present in 281 of 947 (30%) tumors with only 109 (39%) cases demonstrating MMRD by immunohistochemistry. Histologic features of MMRD had a sensitivity of 74% [95% confidence interval (CI), 66%-80%], specificity of 78% (95% CI, 75%-81%), positive predictive value of 39% (95% CI, 32%-44%), and negative predictive value of 94% (95% CI, 92%-96%). Histologic features of MMRD in left colon/rectal tumors had a significantly lower sensitivity of 56% (95% CI, 41%-77%) compared with right colon tumors (P=0.02). Histologic rereview identified that tumor-infiltrating lymphocytes (TILs) were most likely to be incorrectly reported as absent, and 72% of cases incorrectly assessed as lacking TILs demonstrated MMRD by immunohistochemistry. We demonstrate that histologic features of MMRD do not reliably predict the presence of MMRD by immunohistochemistry. Interpretative errors in the assessment of histologic features of MMRD occur, particularly for TILs and in tumors of the left colon/rectum.

Colorectal poorly differentiated neuroendocrine carcinomas frequently exhibit BRAF mutations and are associated with poor overall survival.

The molecular alterations in colorectal poorly differentiated neuroendocrine carcinoma remain incompletely characterized, particularly with respect to mutations in BRAF and KRAS. We analyzed 32 colorectal poorly differentiated neuroendocrine carcinomas and 40 colorectal poorly differentiated conventional adenocarcinomas for mutations in KRAS and BRAF and for DNA mismatch repair protein abnormalities to correlate histopathology with molecular alterations and survival. Compared with poorly differentiated conventional adenocarcinoma, poorly differentiated neuroendocrine carcinoma frequently harbored BRAF mutations (59% versus 5%; P < .001) and less frequently demonstrated KRAS codon 12 or 13 mutations (17% versus 43%; P = .03). BRAF mutations were identified in both pure poorly differentiated neuroendocrine carcinoma (60%) and poorly differentiated neuroendocrine carcinoma associated with a signet ring cell adenocarcinoma component (82%). Most (93%) poorly differentiated neuroendocrine carcinomas demonstrated proficient DNA mismatch repair by either microsatellite instability polymerase chain reaction or DNA mismatch repair immunohistochemistry. Patients with poorly differentiated neuroendocrine carcinoma had a significantly worse overall survival compared with patients with poorly differentiated conventional adenocarcinoma (P < .001). There was no significant difference in overall survival between patients with pure poorly differentiated neuroendocrine carcinoma and patients with both poorly differentiated neuroendocrine carcinoma and adenocarcinoma components (P = .5). In conclusion, colorectal poorly differentiated neuroendocrine carcinomas frequently harbor BRAF mutations and are associated with poor overall survival.