Mutational spectrum in clinically aggressive low-grade serous carcinoma/serous borderline tumors of the ovary-Clinical significance of BRCA2 gene variants in genomically stable tumors.

OBJECTIVE: The mutational spectra of low-grade serous carcinomas (LGSCs) and serous borderline tumors (SBTs) of the ovary are poorly characterized. We present 17 cases of advanced or recurrent LGSC/SBT patients who underwent molecular profiling. METHODS: Thirteen LGSCs and four SBTs underwent targeted gene panel testing by massively parallel sequencing. Microsatellite stability and tumor mutation burdens (TMBs) were determined based on panel sequencing data. RESULTS: The mean TMB was 5.2 mutations/megabase (range 3-10) in 14 cases. Twelve of twelve (12/12) cases were microsatellite stable. Clear driver mutations were identified in 11 cases, namely KRAS (5/17), BRAF (2/17), NRAS (2/17) and ERBB2 (2/17). Five cases harbored BRCA2 alterations (allele fractions: 44-51%), including two classified as likely benign/benign variants, and three classified as variants of uncertain significance (VUSs), with two variants being confirmed to be germline. The three BRCA2 VUSs were missense variants that were assessed to be of unlikely clinical significance, based on family cancer history and expected impact on protein function. Two patients received PARP inhibitors during their disease course, with neither of the patients demonstrating appreciable response. CONCLUSIONS: The mutational spectra in 17 clinically aggressive SBT/LGSC cases demonstrate genomically stable tumors, frequently driven by the RTK/RAS/MAPK pathway. While BRCA2 variants were identified, our data demonstrate BRCA2 gene variants are at most VUSs and of dubious clinical significance, in contrast to disease-associated BRCA1/2 variants that may be identified in high-grade serous carcinoma. Germline testing and PARP inhibitors are thus expected to provide limited benefit to patients with LGSC/SBTs.

Ectopic Prolactin Secretion From a Uterine Leiomyoma.

Ectopic hormone production is well recognized, but ectopic production of prolactin has been reported infrequently. We report here the case of a 47-year-old woman who had hyperprolactinemia (213-224 ng/mL) causing galactorrhea and hypogonadism. Cabergoline treatment, 1.0 mg twice a week, did not lower the prolactin level at all, but excision of a large uterine leiomyoma corrected the hyperprolactinemia and the hypogonadism. The excised leiomyoma tissue exhibited immunostaining for prolactin, confirming by this method for the first time that a uterine leiomyoma was the cause of hyperprolactinemia. This case illustrates the need to consider an ectopic source of prolactin in a patient who has hyperprolactinemia that is not associated with a large sellar mass and is completely resistant to cabergoline.

Cervical cancer biopsy reporting: a review.

The terminology for reporting human papillomavirus-associated squamous lesions in the cervix, both in tissue samples and cytology specimens, has suffered from many changes throughout the last years creating confusion in interpreting cervical biopsy and cytology reports by clinicians. This review presents a summary and discussion of the current terminology for reporting results of cervical biopsies and cytology with emphasis in the lower anogenital squamous terminology consensus recommendations for tissue specimens and the 2001 Bethesda Workshop for reporting cytology results. Microscopic features of cervical lesions in tissue samples and cytology specimens are presented. Biomarkers, including p16 and Ki-67, are discussed and how they can help the pathologist when dealing with difficult cases.

Urothelial carcinoma involving the gynecologic tract: a morphologic and immunohistochemical study of 6 cases.

Spread of urothelial carcinoma (UC) to the female genital tract occurs in a small subset of women with UC. We studied 6 patients with involvement of various gynecologic (GYN) sites and detailed natural history and pathologic features. Four patients initially presented with bladder lesions, including 1 high-grade pTa tumor, 2 pT1 tumors, and 1 pT2 tumor; 1 patient presented with pT2 disease of the renal pelvis and 1 with GYN involvement in the form of vulvar Paget's disease. For the 5 patients presenting with UC, time to GYN involvement was 2 to 8 years; vaginal bleeding (n=4) was the main presenting symptom, and the first site of involvement was the vagina (n=4) or cervix (n=1). GYN sites displayed an array of morphologies and growth patterns that may be seen in both UC and GYN primary tumors. The presence or absence of invasion in the original UC did not dictate whether GYN sites would exhibit invasive disease or whether disease would present as continuous or "skip" lesions. Immunohistochemistry for at least 1 GYN site per patient revealed diffuse, strong CK7 and focal to diffuse strong CK20 positivity in all cases, as well as at least focal p16 positivity in 5 of 6 cases. HPV in situ hybridization was negative in all cases. At last follow-up, 3 patients had died from UC and 3 were alive with recurrent disease/documented metastasis. Our findings highlight the morphologic and immunohistochemical overlap between primary GYN squamous lesions and GYN involvement by UC and hence the importance of clinical history in ensuring an accurate diagnosis.