Molecular Evaluation of Low-grade Low-stage Endometrial Cancer With and Without Recurrence.

Low-grade, low-stage endometrioid carcinomas (LGLS EC) demonstrate 5-yr survival rates up to 95%. However, a small subset of these tumors recur, and little is known about prognostic markers or established mutation profiles associated with recurrence. The goal of the current study was to identify the molecular profiles of the primary carcinomas and the genomic differences between primary tumors and subsequent recurrences. Four cases of LGLS EC with recurrence and 8 cases without recurrence were evaluated via whole-exome sequencing. Three of the 4 recurrent tumors were evaluated via Oncomine Comprehensive Assay. The resulting molecular profiles of the primary and recurrent tumors were compared. Two of the 3 recurrent cases showed additional mutations in the recurrence. One recurrent tumor included an additional TP53 mutation and the other recurrent tumor showed POLE and DDR2 kinase gene mutation. The POLE mutation occurred outside the exonuclease domain. PIK3CA mutations were detected in 4 of 4 primary LGLS EC with recurrence and in 3 of 8 disease-free cases. LGLS EC with recurrence showed higher MSIsensor scores compared with LGLS without recurrence. The level of copy number gains in LGLS EC with recurrence was larger than LGLS EC without recurrence. This pilot study showed 1 of 3 recurrent cases gained a mutation associated with genetic instability (TP53) and 1 of them also acquired a mutation in the DDR2 kinase, a potential therapeutic target. We also noted a higher level of copy number gains, MSIsensor scores and PIK3CA mutations in the primary tumors that later recurred.

Molecular Profiles of Mixed Endometrial Carcinoma.

Mixed endometrial carcinomas are defined as a combination of 2 or more distinct histologic subtypes, one of which must be a type II tumor comprising at least 5% of the tumor volume. The oncogenesis of these tumors remains unclear, particularly in light of the increasingly appreciated morphologic overlap among subtypes, as well as evolving molecular data. We evaluated 8 cases of mixed endometrial carcinoma, including 4 endometrioid (EC)/serous (SC), 1 SC/clear cell (CC), and 3 EC/CC cases, to study the underlying molecular features and oncogenic mechanisms at play. Each component was analyzed by a targeted next-generation sequencing assay. All tumors shared mutations in both components. In 6 cases, one component showed additional mutations. Two EC/SC cases showed shared mutations and mutations unique to each component. When present, unique mutations were typically seen in the SC component, including variants in POLE and TP53, as well as potentially targetable genes DDR2, MAP2K1, and CCNE1. In EC/SC tumors, ERBB2 abnormalities were seen in 2 cases. EC/CC cases showed FGFR2 activating mutations in the EC component only. No fusion drivers were identified. Our data suggest that the majority of these tumors begin as a single clone and diverge along 2 pathways: (1) tumor progression, with one component showing additional mutations, and (2) tumor divergence, in which tumor components have both shared mutations and mutations unique to each component. In addition, the findings suggest a component of morphologic mimicry in these tumors. Our findings are clinically relevant since targetable mutations may be present in only one component of mixed tumors.

Adenomyoepithelial tumors of the breast: molecular underpinnings of a rare entity.

Adenomyoepitheliomas (AMEs) of the breast are uncommon and span the morphologic spectrum of benign, atypical, in situ, and invasive forms. In exceptionally rare cases, these tumors metastasize to regional lymph nodes or distant sites. In the era of genomic characterization, data is limited regarding AMEs. The aim of this study was to provide insight into the molecular underpinnings of a spectrum of AMEs. Seven cases of AMEs of the breast (benign-1, atypical-2, in situ-1, invasive-3) were identified in our files. The seven samples were interrogated using the Oncomine Comprehensive Assay v3 (ThermoFisher). Two atypical AMEs and the malignant in situ AME harbored the same gain-of-function PIK3CA mutation. The malignant in situ AME also showed EGFR amplification, not described previously. Both a benign AME and a malignant invasive AME shared the same gain-of-function AKT1 variant. The benign AME also showed a GNAS mutation. Moreover, the same gain-of-function HRAS mutation was present in an atypical AME and a malignant invasive AME. We also identified co-occurring HRAS and PIK3CA mutations in an ER-positive atypical AME, which has not been previously described. No fusion drivers were detected. We describe the molecular characteristics of the spectrum of AME tumors of the breast, which harbor alterations in the PI3K/AKT pathway. Our findings are clinically relevant with respect to the current options of targeted therapy in the rare instances where malignant AME tumors of the breast progress.

Recurrent TERT promoter mutations in urothelial carcinoma and potential clinical applications.

Increased telomerase activity is associated with almost all types of advanced human cancers with unknown molecular mechanism(s). Two recurrent point mutations in the promoter region of telomerase reverse transcriptase (TERT)--the key subunit of telomerase--have recently been identified in melanoma as well as a small sample of bladder cancer cell lines. However, the incidence and clinical-pathological significance of these mutations in urothelial carcinoma have not been well established yet. We collected 86 specimens of urothelial carcinoma including upper and lower urinary tract: high grade and low grade, invasive and noninvasive, and primary and metastatic. We also included some matched benign urothelium and common benign bladder lesions: cystitis, nephrogenic adenoma, and inverted papilloma. In addition, we collected urine samples for urothelial carcinoma workup; blood samples from patients underwent cystectomy with extensive lymphovascular invasion. All specimens were subject to polymerase chain reaction amplification and bidirectional Sanger sequencing for the TERT promoter mutations: C228T and C250T. We found that 64 (74%) of 86 carcinoma samples harbored 1 of the 2 TERT promoter mutations (C228T, n = 54; C250T, n = 10); the incidences were roughly equal regardless of site of origin, histologic grade, and invasive status. All matched benign and benign lesion samples showed wild-type sequence. These TERT promoter mutations are the most common genetic alterations in urothelial carcinoma and are not associated with tumor locations, grade, or invasiveness. Importantly, the feasibility of detecting these mutations in urine samples may provide a novel method to detect urothelial carcinoma in urine.

Benign Multicystic Peritoneal Mesothelioma: AIRP Best Cases in Radiologic-Pathologic Correlation.

RadioGraphics continues to publish radiologic-pathologic case material selected from the American Institute for Radiologic Pathology (AIRP) "best case" presentations. The AIRP conducts a 4-week Radiologic Pathology Correlation Course, which is offered five times per year. On the penultimate day of the course, the best case presentation is held at the American Film Institute Silver Theater and Cultural Center in Silver Spring, Md. The AIRP faculty identifies the best cases, from each organ system, brought by the resident attendees. One or more of the best cases from each of the five courses are then solicited for publication in RadioGraphics. These cases emphasize the importance of radiologic-pathologic correlation in the imaging evaluation and diagnosis of diseases encountered at the institute and its predecessor, the Armed Forces Institute of Pathology (AFIP).

Heterogeneity of TERT promoter mutations status in squamous cell carcinomas of different anatomical sites.

Squamous cell carcinoma (SCC) can arise from different anatomical sites including the skin, head and neck, lung, esophagus, genital area, and so on. Despite the same histopathologic features and immunohistochemistry profile, the SCCs of different body sites can show tremendous differences in their presenting symptoms, risk factor associations, natural history, prognosis, and response to treatment. This may reflect the fact that SCCs are heterogenous and likely have unique molecular characteristics at different anatomical sites. Recurrent somatic mutations in the TERT promoter region were first reported in human melanomas. Subsequently, other tumors including cutaneous SCC were found to demonstrate high frequencies of the same mutations. However, the incidences of TERT promoter mutation in noncutaneous SCCs have not been systemically studied. We investigated the TERT promoter mutation status among SCCs from different sites. We collected 84 cases of SCC from the skin (27), head and neck (12), lung (25), and cervix (10), as well as 10 cases of urothelial carcinoma with squamous differentiation (UC-SqD). We found that the frequencies of TERT promoter mutation among SCC of different sits are quite heterogenous: ~70% in skin SCC and UC-SqD, 16.67% in head and neck SCC, and 0% in lung and cervix SCC. These results may support the hypothesis of different carcinogenesis mechanisms of SCC in different sites. It also indicates that TERT promoter mutation could be a biomarker for distinguishing skin SCC or UC-SqD vs pulmonary SCC.

Upper urinary tract urothelial carcinoma with intratubular spread.

Upper urinary tract urothelial cell carcinomas (UUT-UCs) are uncommon and are defined as urothelial carcinoma involving the urinary tract from the renal calyces, renal pelvis to the distal ureter. One well-known an peculiar histopathological finding in UUT-UC is urothelial carcinoma with intratubular spread (retrograde spread within renal tubules). However, this special feature has not been systematically studied. We therefore collected a total of 53 consecutive cases of upper urinary tract urothelial carcinomas (UUT-UCs), and studied the clinical and pathological features of intratubular spread (IS). A cocktail stain comprised of antibodies PAX8 and p63 together with PAS was validated and employed to facilitate the study of intratubular spread. Seventeen cases (31.5%) showed intratubular spread demonstrated by either H&E stain and/or the cocktail stain. All of the 17 cases wit intratubular spread had tumor involvement of the renal calyx; the majority of these (14/17, 82.4%) were high grade urothelial carcinoma and the remainder (3/17, 17.6%) were low grade. 4 of 17cases (23.5%) were non-invasive. We classified intratubular spread into 4 different types, based on histopathological patterns: pagetoid, typical, florid, and secondary invasion from intratubular spread. In conclusion, study shows intratubular spread of urothelial carcinoma is fairly common phenomenon in UUT-UC and is associated with a variety of clinical-pathological features. High grade UUT-UC tends to have more extensive intratubular spread and secondary invasion into renal parenchyma. Distinct morphological characteristics as well as the staining pattern from a unique cocktail stain help to identify and evaluate intratubular spread of urothelial carcinoma. Recognizing these different types of intratubular spreading (IS) is crucial for accurate staging of some upper urinary tract urothelial carcinomas (UUT-UCs).

Case report: verapamil-induced subacute cutaneous lupus erythematosus.

Calcium-channel blockers (CCB), including verapamil, nifedipine, and diltiazem, are one of the most widely prescribed class of drugs in the treatment of cardiovascular disease. In the last several years, CCBs have been linked with a distinct cutaneous subset in the lupus spectrum, subacute cutaneous lupus erythematosus (SCLE), and we describe a case induced by verapamil.

Primary cutaneous B-cell lymphoma in a 74-year-old Caucasian male.

Primary cutaneous B-cell lymphoma is an uncommon neoplasm with classification schemes that may be confusing, but with clinical presentations that are relatively consistent. Clinical exam and history can raise the index of suspicion for this condition, although the diagnosis is confirmed only by pathological evaluation. We report such a scenario in the case of a 74-year old male with a slowly expanding oval plaque on his right upper arm.