Murali, Rajmohan

Abstract Purpose: To identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes. Experimental Design: We profiled 421 primary CCOCs that passed quality control using a targeted deep sequencing panel of 163 putative CCOC driver genes and whole transcriptome sequencing of 211 of these tumors. Molecularly defined subgroups were identified and tested for association with clinical characteristics and overall survival. Results: We detected a putative somatic driver mutation in at least one candidate gene in 95% (401/421) of CCOC tumors including ARID1A (in 49% of tumors), PIK3CA (49%), TERT (20%), and TP53 (16%). Clustering of cancer driver mutations and RNA expression converged upon two distinct subclasses of CCOC. The first was dominated by ARID1A-mutated tumors with enriched expression of canonical CCOC genes and markers of platinum resistance; the second was largely comprised of tumors with TP53 mutations and enriched for the expression of genes involved in extracellular matrix organization and mesenchymal differentiation. Compared with the ARID1A-mutated group, women with TP53-mutated tumors were more likely to have advanced-stage disease, no antecedent history of endometriosis, and poorer survival, driven by their advanced stage at presentation. In women with ARID1A-mutated tumors, there was a trend toward a lower rate of response to first-line platinum-based therapy. Conclusions: Our study suggests that CCOC consists of two distinct molecular subclasses with distinct clinical presentation and outcomes, with potential relevance to both traditional and experimental therapy responsiveness. See related commentary by Lheureux, p. 4838

Context. —Patients with pneumothorax occasionally require limited lung resections to control persistent air leaks. In some patients, especially smokers, histopathologic findings suggest that a ruptured bulla or bleb caused the pneumothorax. Other patients only exhibit histopathologic changes related to the physical trauma of acute, and likely occult recurrent, peripheral lung injury in the setting of “spontaneous,” or idiopathic, lung rupture. Sometimes, pneumothorax occurs secondary to an underlying localized or diffuse parenchymal lung disease. A comprehensive description of the morphologic findings that may be seen in these specimens will help the surgical pathologist distinguish patients with more common and indolent occurrences of pneumothorax from those requiring additional workup or treatment. Objective. —To develop a diagnostic approach for surgical pathologists encountering lung specimens obtained in the context of pneumothorax repair. Data Sources. —Literature review and consultation experience of the authors. Conclusions. —Two general categories of histopathologic changes can be identified: (1) nonspecific changes, reflecting the lung's acute and chronic response to localized injury, and (2) changes suggesting an underlying lung disease that may have played an etiologic role in the development of pneumothorax. The latter changes are important to recognize because they may require additional workup or treatment of clinically occult lung disease. Difficulty arises when nonspecific histopathologic changes overlap with those of an underlying lung disease. Awareness of these diagnostic challenges and pitfalls, together with clinicoradiographic correlation, is essential in these situations and will help guide the surgical pathologist toward an accurate diagnosis and the appropriate management of clinically occult disease.

AbstractTo determine cytologic features of epithelioid hemangioendothelioma (EHE) that would enable accurate diagnosis, we evaluated fine-needle aspiration biopsy (FNAB) smears from 11 histologically confirmed EHEs. The variably cellular smears comprised dispersed single cells and occasional cell aggregates. Dense stromal fragments were present in association with some tissue fragments. The cells were epithelioid, containing moderate or large amounts of dense cytoplasm. Nuclei exhibited mild pleomorphism, and nuclear grooves were identified in all cases. At least occasional intranuclear pseudoinclusions (INPIs) and intracytoplasmic lumina (ICLs) were present in all cases and in 9 cases (82%), respectively, and rare erythrocytes were seen within ICLs in 5 cases (45%). Mitotic figures were identified in 4 cases (36%). The background was bloody in 6 cases (55%) and contained hemosiderin and/or hemosiderin-laden macrophages in 5 cases (45%). The combination of the following features in FNAB samples should raise strong suspicion for EHE: predominantly dispersed single cells with occasional cohesive cell clusters; epithelioid cytomorphology; dense cytoplasm with well-defined cytoplasmic borders; ICLs (with or without erythrocytes), INPIs, and nuclear grooves. The presence of these features should prompt correlation with clinical, radiologic, and histologic features and immunohistochemical evaluation using vascular markers.