Sertoli-Leydig cell tumors are characterized by the presence of somatic DICER1 hotspot mutations. In this study, we sought to define the association between DICER1 hotspot mutations and different morphologic subtypes of ovarian Sertoli-Leydig cell tumors. Furthermore, we aimed to assess whether DICER1 hotspot mutations occur in other ovarian sex cord-stromal tumors, testicular sex cord-stromal tumors, or other female genital tract tumors with rhabdomyosarcomatous differentiation. We subjected a series of ovarian Sertoli-Leydig cell tumors (n=32), Sertoli cell tumors (n=5) and gynandroblastomas (n=5), testicular sex cord-stromal tumors (n=15) and a diverse group of female genital tract tumors with rhabdomyosarcomatous morphology (n=10) to DICER1 hotspot mutation analysis using Sanger sequencing. We also tested 2 gynandroblastomas for the presence of FOXL2 hotspot mutations (p.C134W; c.402C>G). Twenty of 32 (63%) Sertoli-Leydig cell tumors harbored a DICER1 hotspot mutation, of which 80% had the p.E1705K mutation. No association was found between DICER1 mutation status and the presence of heterologous or retiform differentiation in Sertoli-Leydig cell tumors. DICER1 mutations were found at similar frequencies in gynandroblastoma (2/5; 40%) and ovarian Sertoli cell tumors (5/8; 63%; p>0.1), and all mutated tumors harbored a p.E1705K mutation. DICER1 hotspot mutations were also identified in a single cervical rhabdomyosarcoma and in the rhabdomyosarcomatous component of a uterine carcinosarcoma. No DICER1 mutations were detected in testicular sex cord-stromal tumors. Two DICER1 wild-type gynandroblastomas harbored a p.C134W FOXL2 hotspot mutation in both tumor components. In this study we confirmed that DICER1 hotspot mutations occur in over half of ovarian Sertoli-Leydig cell tumors, and are unrelated to tumor differentiation. We also widened the spectrum of ovarian sex cord-stromal tumors with sertoliform differentiation, in which DICER1 mutations are known to occur, to include Sertoli cell tumors and gynandroblastomas. Our results suggest that DICER1 mutations may not play a role in testicular sex cord-stromal tumorigenesis.
Small cell carcinoma of ovary, hypercalcemic type (SCCOHT) is a rare ovarian neoplasm that occurs in young women and has a poor prognosis. The histologic diagnosis of SCCOHT can be challenging due to its rarity and relatively non-specific histologic features, which range from the classic, first-described small cell morphology to a pattern in which there are large cells with abundant eosinophilic cytoplasm. Many entities can be in the differential diagnosis and to date, immunohistochemical stains have shown no distinctive profile and have been of limited aid. SMARCA4 (also known as BRG1) mutations have recently been reported at high frequency in these tumors. SMARCA4 is an important component of the SWI/SNF complex which regulates gene expression through alteration of nucleosome conformation. Studies to date have suggested that immunohistochemical loss of expression of SMARCA4 is associated with the presence of a SMARCA4 mutation in most cases. In this study, the sensitivity and specificity of the immunohistochemical loss of SMARCA4 expression for the diagnosis of SCCOHT is examined in the context of the differential diagnosis with other primary or metastatic ovarian tumors. All but one of the SCCOHT showed loss of SMARCA4 expression (16/17; 94%), while of 279 other tumors tested, only two tumors (one clear cell carcinoma and one ovarian melanoma) showed loss of SMARCA4 expression. We conclude that SMARCA4 immunohistochemistry is highly sensitive and specific for a diagnosis of SCCOHT and is of clinical utility in the differential diagnosis of poorly differentiated ovarian tumors.
Cervical clear cell carcinoma (CCC) is a rare human papillomavirus-independent adenocarcinoma. While recent studies have focused on gastric-type endocervical adenocarcinoma (GTA), little is known about CCC. A total of 58 (CCCs) were collected from 14 international institutions and retrospectively analyzed using univariable and multivariable methods and compared with 36 gastric-type adenocarcinomas and 173 human papillomavirus-associated (HPVA) endocervical adenocarcinoma (ECA) regarding overall survival (OS) and recurrence-free survival (RFS). Most cases were FIGO stage I (72.4%), with Silva C pattern of invasion (77.6%), and the majority were treated with radical surgery (84.5%) and adjuvant therapy (55.2%). Lymphovascular invasion was present in 31%, while lymph node metastasis was seen in 24.1%; 10.3% were associated with abdominopelvic metastases at the time of diagnosis; 32.8% had recurrences, and 19% died of disease. We did not find statistically significant differences in OS and RFS between CCC and GTA at 5 and 10 years (P = 0.313 and 0.508, respectively), but there were significant differences in both OS and RFS between CCC and HPVA ECA (P = 0.003 and 0.032, respectively). Also, OS and RFS in stage I clear cell and GTA were similar (P = 0.632 and 0.692, respectively). Multivariate analysis showed that OS is influenced by the presence of recurrence (P = 0.009), while RFS is influenced by the FIGO stage (P = 0.025). Cervical CCC has poorer outcomes than HPVA ECA and similar outcomes to human papillomavirusindependent GTA. Oncologic treatment significantly influences RFS in univariate analysis but is not an independent prognostic factor in multivariate analysis suggesting that alternative therapies should be investigated.
AimsThe depth of invasion is an important prognostic factor for patients with vulvar squamous cell carcinoma (SCC). The threshold of 1 mm distinguishes between FIGO stages IA and ≥IB disease and guides the need for groin surgery. Therefore, high interobserver agreement is crucial. The conventional and the alternative method are described to measure the depth of invasion. The aims of this study were to assess interobserver agreement for classifying the depth of invasion using both methods and to identify pitfalls.Methods and resultsFifty slides of vulvar SCC with a depth of invasion approximately 1 mm were selected, digitally scanned and independently assessed by 10 pathologists working in a referral or oncology centre and four pathologists in training. The depth of invasion was measured using both the conventional and alternative method in each slide and categorised into ≤1 and >1 mm. The percentage of agreement and Light’s kappa for multi‐rater agreement were calculated, and 95% confidence intervals were calculated by bootstrapping (1000 runs). The agreement using the conventional method was moderate (κ = 0.57, 95% confidence interval = 0.45–0.68). The percentage of agreement among the participating pathologists using the conventional method was 85.0% versus 89.4% using the alternative method. Six pitfalls were identified: disagreement concerning which invasive nest is deepest, recognition of invasive growth and where it starts, curved surface, carcinoma situated on the edge of the tissue block, ulceration and different measurement methods.ConclusionsPathologists reached only moderate agreement in determining the depth of invasion in vulvar SCC, without a notable difference between the two measurement methods.
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