AimsMetaplastic breast carcinoma (MBC) is a rare subtype of breast carcinoma less responsive to conventional chemotherapy than ductal carcinoma. In molecular terms, MBCs usually cluster with triple-negative breast cancers (TNBCs), but have a worse prognosis than TNBCs. Studies investigating MBCs for specific biomarkers of therapy response are rare and limited by the methodological approaches. The aim of the present study was to characterise MBCs on a molecular level and test programmed death-ligand 1 (PD-L1) biomarker expression in MBCs for future therapeutic interventions.MethodsWe profiled 297 samples (MBC (n=75), TNBC (n=106), human epidermal growth factor receptor 2 (HER2)-positive breast cancers (n=32) and hormone-positive breast cancers (n=84)) by next-generation sequencing. Immunohistochemistry for PD-L1 and programmed cell death 1 (PD-1) expression was performed using automated procedures.ResultsThe most commonly mutated genes in MBCs included TP53 (56%) and PIK3CA (23%). Pathogenic mutations in other genes, including HRAS, FBXW7, PTEN, AKT1 and SMAD4, were rare. PD-L1 expression was detected in a significantly higher proportion of MBCs (46%) than in other subtypes (6% each in hormone-positive and HER2-positive breast cancers, and 9% in TNBC, not otherwise specified, p<0.001). PD-1-positive tumour infiltrating lymphocytes (TILs) varied greatly in MBCs.ConclusionsComprehensive profiling of a large cohort of this rare subtype of breast carcinoma highlighted the predominance of TP53 mutation and increased PD-L1 expression in carcinoma cells. These results can be exploited in clinical trials using immune checkpoint inhibitors.

Background and Objectives Despite routine inclusion of lymphovascular invasion (LVI) status in pathologic reports of resected pancreatic ductal adenocarcinomas (PDA), the clinical implications of LVI have not been well characterized. Methods This study is a retrospective review of 2640 patients who underwent a pancreatectomy for PDA at Thomas Jefferson University Hospital, Massachusetts General Hospital, or Johns Hopkins Hospital (2003-2014). Clinical and pathologic records were extracted from institutional databases. Results The median post-resection survival for the total cohort was 19.2 months with a 5-year survival rate of 15.2%. In a multivariate Cox proportional hazards model including conventional pathologic features, LVI was an independent predictor of survival (HR = 1.14, P = 0.017). In a stratified Kaplan-Meier survival analysis, patients with N0, LVI- PDA had a significantly improved overall survival compared to those with N0, LVI+ PDA (median 31 vs 24 mo, P = 0.020). Similarly, patients with N1, LVI- PDA had superior survival to patients with N1, LVI+ disease (18.6 vs 16.5 mo, P = 0.001). Conclusions As the first large scale study focused on the clinical impact of LVI status in PDA, these data indicate that this routinely reported pathologic feature is a bona fide and independent adverse prognostic factor.

Blockade of the interaction between PD-1 and its ligands PD-L1 has shown clinical efficacy across several tumor types, especially in mismatch-repair-deficient colorectal carcinoma. The aim of this study was to examine the pattern and cellular localization of PD-L1 expression in the different molecular subtypes of mismatch-repair-deficient colorectal cancers vs. their mismatch-repair-proficient counterparts. PD-L1/SATB2 double-antibody-immunohistochemistry was utilized to distinguish tumor cell from immune cell staining. We observed in our series of 129 colorectal adenocarcinomas that PD-L1 expression occurred primarily in tumor-associated-immune cells and most prominently at the tumor-stroma-interface of the invasive front. The level of invasive front immune cell staining was significantly higher in mismatch-repair-deficient tumors compared to mismatch-repair-proficient tumors (p < 0.001), but no difference was observed among the different subtypes of mismatch-repair-deficient tumors: Lynch syndrome-associated vs. MLH1-methylated vs. unexplained. While selected mismatch-repair-proficient tumors exhibited unusually high tumor-infiltrating-lymphocytes and had high level immune cell PD-L1 expression, a positive correlation between PD-L1 expression and high lymphocyte count was detected only in mismatch-repair-deficient tumors (r = 0.39, p < 0.001) and not in mismatch-repair-proficient tumors. Notably, true tumor cell PD-L1 expression in colorectal carcinoma was rare, present in only 3 of 129 tumors (2.3%): 2 MLH1-methylated and 1 mismatch-repair-proficient with high tumor-infiltrating-lymphocytes; and the staining in the tumor cells in all 3 was diffuse (>=50% of the tumor). These findings may serve to inform further efforts aiming to evaluate PD-L1 immunohistochemistry vis-à-vis molecular sub-classification as predictive biomarkers in the treatment of colorectal carcinoma.

-Lesions with secretory features described in this review show a pathologic spectrum, sometimes even within the same lesion. As a consequence, one should employ a low threshold for recommending reexcision on a core biopsy containing benign-appearing hypersecretory glands and use all ancillary data, including clinical presentation, imaging findings, morphology, immunohistochemistry, and molecular pathology, to render a final diagnosis.

Hypophysitis is a rare inflammatory condition of the pituitary gland that has three main histologic subtypes: lymphocytic hypophysitis (LH), granulomatous hypophysitis (GH), and xanthomatous hypophysitis (XH). Among these, LH is the most common and is strongly associated with the postpartum state, while XH is the least common. Many hypophysitis cases have been reported in the literature but only a few cases of postpartum GH have been discussed. Here, we describe a case of GH in a 24-year-old female presenting eleven days postpartum. We also review the current literature on postpartum GH and discuss the possible alterations in the immune environment during and after pregnancy that could explain this phenomenon. With more cases of GH being reported, the commonalities of female predominance, postpartum time of presentation, and occasional spontaneous resolution between LH and GH lend support to the theory that these two diseases likely represent spectrums of a single immunologic disorder.