Faculty Bibliography

BACKGROUND:Uterine undifferentiated (UEAC)/dedifferentiated (DEAC) carcinomas are rare malignant neoplasms. They appear to pursue an aggressive clinical course with an advanced stage at presentation. Recently, it was discovered that the use of immunotherapeutic drugs targeting programmed cell death protein 1 (PD1)/programmed death ligand-1 (PD-L1) was associated with improved survival in several types of cancer (especially in patients with mismatch-repair (MMR) deficient patients). Whether these findings can be applied to UEAC/DEAC remains a question. Herein, the aim of this study is to evaluate the expression of PD-L1/PD-1 in UEAC/DEAC and its relationship to MMR status. This could offer useful therapeutic information. DESIGN/METHODS:Review of endometrial carcinoma (EC) diagnosed over the period of 2011 to 2017 in our institution identified 14 UEAC/DEAC cases (n=14). All cases had immunohistochemistry performed for MMR (MLH1, PMS2, MSH2 and MSH6), PD-L1 and PD-1. The protein expression was examined and in DEAC cases both the undifferentiated component and the low grade component were recorded separately. The expression of PD-L1 and PD-1 was scored in both the tumor and the peritumoral lymphocyte infiltration. RESULTS:Overall variable degrees of tumoral or immune stromal PD-L1 staining (from 1% to 5%), was present in 50.0% (7/14) of UC/DEACs. Seven cases (50%) were PD-1 positive (immune stromal). Five cases (35.7%) showed co-expression of PD-1 and PD-L1 (Figure 1). Worth noting is that PD-1 staining was exclusively present in peritumoral immune cells. Following this the 14 cases were further divided into MMR deficient and MMR proficient groups (Table 1). A total of 8 cases had MMR deficiency (57.1%). There was a statistically significant association for PD-L1 positivity in the MMR deficiency group (p=0.05). However there was no statistically significant differences regarding PD-1 positivity between MMR groups. CONCLUSIONS:PD-L1 and PD-1 were expressed in majority of MMR-deficient UEAC /DEAC cases. PD-L1 was not expressed in MMR-proficient carcinomas. These findings might help support potential immunotherapy trials in MMR-deficient UEAC /DEAC.

BACKGROUND:Death domain-associated protein 6 (DAXX) is involved in regulating apoptosis via subcellular localization. The presence of DAXX point mutations correlates well with loss of nuclear expression on immunohistochemistry (IHC). In this study, we sought to determine (1) whether DAXX expression pattern is the same across different uterine carcinoma subtypes, and (2) which uterine carcinomas show loss of nuclear DAXX IHC. DESIGN/METHODS:We studied 65 uterine carcinomas of the following histologic types: 30 endometrioid (12 FIGO [The International Federation of Gynecology and Obstetrics] grade 1, 12 FIGO grade 2, and 6 FIGO grade 3), 8 serous, 14 clear cell, and 13 undifferentiated/dedifferentiated type (UEC/DDEC). Nuclear DAXX IHC was assessed in each tumor and was graded semi-quantitatively as follows: 0% to 50%, 50% to 75%, and greater than 75% of lesional cells react. RESULTS: = .0001), where DAXX expression was cytoplasmic. In addition, in the 11 DDEC cases, all the differentiated components showed loss of nuclear DAXX compared with the undifferentiated components which retained nuclear DAXX expression. CONCLUSIONS:We demonstrate that loss of nuclear DAXX is present in low-grade endometrial carcinomas and the differentiated components in UEC/DDEC, but not in high-grade ones, suggesting DAXX's role in tumor progression and its potential as a therapeutic target in high-grade endometrial carcinomas.

Here we report a fatal case of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) due to methimazole use in a 64-year-old woman. She was initially hospitalized for abdominal pain and possible colitis, and subsequently developed hematuria, renal failure, and hemoptysis. The serologic work-up revealed positive antinuclear antibody (ANA) and perinuclear-antineutrophilic cytoplasm antibodies (p-ANCA), with positive antimyeloperoxidase. Three weeks following admission, the patient was found to be pulseless, and expired. At autopsy, microscopic review included widespread transmural necrotizing vasculitis and crescentic glomerulonephritis in the kidney, and diffuse pulmonary alveolar hemorrhage; focal coronary artery intimal vasculitis and necrotizing pericarditis were also noted. Several drugs have been associated with the development of ANCA-positive diseases, including propylthiouracil, hydralazine, allopurinol, penicillamine, and levamisole in cocaine. Association of ANCA vasculitis with methimazole exposure is less known, and severe presentation with fatal outcome, as seen in our patient, is exceedingly rare. We reviewed clinical and histopathologic features of drug-induced ANCA vasculitis associated with methimazole to raise awareness of this potentially life-threatening complication associated with this agent.