Joseph T Rabban

Practical roles for molecular diagnostic testing in ovarian adult granulosa cell tumour, Sertoli–Leydig cell tumour, microcystic stromal tumour and their mimics

Within the last decade, molecular advances have provided insights into the genetics of several ovarian sex cord–stromal tumours that have otherwise been enigmatic. Chief among these advances are the identification of FOXL2, DICER1 and CTNNB1 mutations in adult granulosa cell tumours, Sertoli–Leydig cell tumours (SLCTs), and microcystic stromal tumours (MCSTs), respectively. As access to molecular diagnostic laboratories continues to become more widely available, the potential roles for tumour mutation testing in the pathological diagnosis of these tumours merit discussion. Furthermore, links to inherited cancer susceptibility syndromes may exist for some women with SLCT (DICER1 syndrome) and MCST [familial adenomatous polyposis (FAP)]. This review will address practical issues in deciding when and how to apply mutation testing in the diagnosis of these three sex cord–stromal tumours. The pathologist's role in recommending referral for formal risk assessment for DICER1 syndrome and FAP will also be discussed.

NTRK fusion cervical sarcoma: a report of three cases, emphasising morphological and immunohistochemical distinction from other uterine sarcomas, including adenosarcoma

AimsA unique fibrosarcoma‐like tumour of the uterine cervix harbouring a rearrangement of a neurotrophic tyrosine kinase receptor (NTRK) gene (NTRK1 or NTRK3) has recently been described in 11 young women, some with recurrence and/or metastasis. The aims of this study were to expand the morphological spectrum of this tumour by reporting three additional cases that showed adenosarcoma‐like features not previously described, one of which is the first reported to respond to targeted therapy, and to evaluate 19 conventional uterine adenosarcomas for evidence of NTRK rearrangement.Methods and resultsThree patients presented with a polyp or mass confined to the cervix. The constellation of polypoid growth, spindle cell morphology, entrapped endocervical glands and intraglandular stromal projections raised diagnostic consideration for adenosarcoma with stromal overgrowth. Deep cervical wall invasion was present in two cases at hysterectomy, and the third was removed by polypectomy. All three stained for S100 and pan‐Trk, but were negative for a spectrum of other diagnostic markers. All three harboured NTRK rearrangements (TPM3–NTRK1, TPR–NTRK1, and SPECC1L–NTRK3). One patient developed pleural metastases at 16 months, received the NTRK inhibitor larotrectinib, and is free of disease 15 months later. Two others are alive without disease. None of the uterine adenosarcomas showed any S100 or pan‐Trk staining, or rearrangement of NTRK1, NTRK2 or NTRK3 on next‐generation sequencing.ConclusionsUnusual adenosarcoma‐like spindle cell neoplasms of the cervix may represent an NTRK fusion sarcoma, which can be detected by S100 and pan‐Trk staining and confirmed by NTRK molecular testing. Conventional uterine adenosarcomas do not harbour NTRK rearrangements.

International Feasibility of Applying Diagnostic Essential Criteria of the Fifth Edition World Health Organization Classification of Female Genital Tumors: Evidence for a Global Gap in Health Care Equity

The new categories of diagnostic essential criteria and desirable criteria in the fifth edition World Health Organization Classification of Female Genital Tumors (fifth WHO FGT) aim to standardize the classification of gynecologic tumors worldwide. As some essential criteria require biomarkers (immunohistochemistry [IHC] or molecular tests), we hypothesized that the applicability of the fifth WHO FGT criteria may be limited by access to these tests due to local resource constraints. After defining the essential biomarkers in the fifth WHO FGT, we conducted an international survey of pathologists to determine accessibility to essential biomarkers and then evaluated access as a function of the pathologist's country income category. A total of 37 IHC and 6 molecular tests are considered essential for diagnosing a spectrum of common and less common tumors. Among 480 respondents from 76 countries, access to the printed or online version of the fifth WHO FGT was associated with country income (P < .0001); 62.5% of low-income country respondents reported no access to either version. Routine access to IHC in general and routine access to each of the essential IHC were significantly associated with the country income category (P < .0001). Only 12.5% of low-income country respondents reported routine access to IHC in general, and none reported routine access to any essential molecular tests. Short tandem repeat genotype testing for molar pregnancy diagnosis was the least accessible essential molecular test worldwide, available to only 26.6% of the respondents, most of whom were in high-income countries. Additional essential criteria for some tumors consisted of one of 18 different specific types of tumor differentiation for which no morphologic definition was provided; high-income country respondents were more likely to routinely use IHC in these settings than lower-income country respondents (P < .0001). Conversely, the patient bore the direct responsibility for paying for IHC when used in lower-income countries compared with high-income countries (P < .0001). This survey demonstrates a global gap in health care equity due, in part, to limited access to biomarkers deemed as essential for diagnosis by the fifth WHO FGT and to the lack of diagnostic criteria adaptable to resource-limited environments. Based on the survey results, we offer several practical strategies for narrowing this gap in future editions of the WHO FGT, chief among them being a move toward resource-stratified diagnostic criteria.