Androgen Insensitivity Syndrome with Bilateral Gonadal Sertoli Cell Lesions, Sertoli-Leydig Cell Tumor, and Paratesticular Leiomyoma: A Case Report and First Systematic Literature Review.

Androgen insensitivity syndrome (AIS) is a rare Mendelian disorder caused by mutations of the androgen receptor (AR) gene on the long arm of the X chromosome. As a result of the mutation, the receptor becomes resistant to androgens, and hence, karyotypically male patients (46,XY) carry a female phenotype. Their cryptorchid gonads are prone to the development of several types of tumors (germ cell, sex cord stromal, and others). Here, we report a 15-year-old female-looking patient with primary amenorrhea who underwent laparoscopic gonadectomy. Histologically, the patient's gonads showed Sertoli cell hamartomas (SCHs) and adenomas (SCAs) with areas of Sertoli-Leydig cell tumors (SLCTs) and a left-sided paratesticular leiomyoma. Rudimentary Fallopian tubes were also present. The patient's karyotype was 46,XY without any evidence of aberrations. Molecular genetic analysis of the left gonad revealed two likely germline mutations-a pathogenic frameshift deletion in the AR gene (c.77delT) and a likely pathogenic missense variant in the RAC1 gene (p.A94V). Strikingly, no somatic mutations, fusions, or copy number variations were found. We also performed the first systematic literature review (PRISMA guidelines; screened databases: PubMed, Scopus, Web of Science; ended on 7 December 2023) of the reported cases of patients with AIS showing benign or malignant Sertoli cell lesions/tumors in their gonads (n = 225; age: 4-84, mean 32 years), including Sertoli cell hyperplasia (1%), Sertoli cell nodules (6%), SCHs (31%), SCAs (36%), Sertoli cell tumors (SCTs) (16%), and SLCTs (4%). The few cases (n = 14, 6%; six SCAs, four SCTs, two SLCTs, and two SCHs) with available follow-up (2-49, mean 17 months) showed no evidence of disease (13/14, 93%) or died of other causes (1/14, 7%) despite the histological diagnosis. Smooth muscle lesions/proliferations were identified in 19 (8%) cases (including clearly reported rudimentary uterine remnants, 3 cases; leiomyomas, 4 cases). Rudimentary Fallopian tube(s) were described in nine (4%) cases. Conclusion: AIS may be associated with sex cord/stromal tumors and, rarely, mesenchymal tumors such as leiomyomas. True malignant sex cord tumors can arise in these patients. Larger series with longer follow-ups are needed to estimate the exact prognostic relevance of tumor histology in AIS.

Combined anti-HER2 and hormonal treatment in a patient with HR+HER2+ clear-cell uterine carcinoma: A case report.

Clear-cell carcinoma (CCC) of the uterus is an aggressive disease. Current international guidelines on the treatment of uterine carcinomas predominantly cover cancer with endometrioid histology, and clinicians tend to use the same approach for patients with non-endometrioid histology due to the absence of separate guidelines for these rare tumor types. At present, molecular analysis enables the assessment of novel and non-standard treatment options based on the individual characteristics of a tumor. The present report presents a clinical case of successful treatment of a patient with clear cell uterine carcinoma with HER2 and ER expression. Non-toxic targeted treatment was used based on immunohistochemistry (IHC) data. The patient received anti-HER2 and hormonal treatment and demonstrated an excellent response. The follow-up period was 47 months and the patient remained stable during treatment without significant toxicity. Therefore, this approach demonstrated the potential for selecting highly-specific therapy for rare tumors, which lack distinct recommendations for their treatment.

Highly differentiated follicular carcinoma arising from struma ovarii: a report of 3 cases, a review of the literature, and a reassessment of so-called peritoneal strumosis.

Struma ovarii has elicited considerable interest because of its many unique features since Ludwig Pick first elucidated its relationship to teratoma in the early part of the 20th century. The most common thyroid-type malignancies to arise in struma ovarii are papillary and follicular carcinomas. In this article, we describe a newly recognized neoplasm originating from struma ovarii that we interpret as follicular carcinoma with a high degree of differentiation. By definition, all of these cases have an innocuous appearance resembling that of nonneoplastic thyroid tissue in both the ovary and sites of dissemination. Including our own, 14 cases in the literature spread to the peritoneum, and 4 metastasized to more distant sites. The peritoneal involvement more often was diagnosed at the same time as the ovarian struma; however, the systemic dissemination occurred subsequent to oophorectomy. Our index patient with highly differentiated follicular carcinoma (HDFCO) developed peritoneal dissemination and para-aortic lymph node metastases 26 years after excision of ovarian struma. Vascular invasion was not identified in any of the cases; however, the primary neoplasm extended to the surface of the ovary in 2 cases with peritoneal involvement. Because of its harmless histological appearance, this form of follicular carcinoma characteristically cannot be diagnosed until the neoplasm spreads beyond the ovary, thus, showing evidence of aggressive behavior. The corollary of this observation is that cases having the histological appearance of ordinary struma ovarii can rarely behave in a malignant fashion. Although cases of typical thyroid-type carcinoma with extraovarian dissemination are relatively easy to diagnose, those with an innocuous histological appearance present nosological and diagnostic difficulties. The differential diagnosis of peritoneal dissemination of struma includes HDFCO, the typical types of thyroid cancer, and so-called strumosis. We have studied the relationship of HDFCO to cases reported as peritoneal strumosis or similar terms and doubt the existence of the latter as a distinct clinicopathologic entity. The treatment of choice for patients with HDFCO is local resection of the extraovarian tumor with subsequent thyroidectomy followed by radioactive iodine ablation.

Tamoxifen overrides autophagy inhibition in Beclin-1-deficient glioma cells and their resistance to adenovirus-mediated oncolysis via upregulation of PUMA and BAX.

Autophagy is an evolutionarily conserved process regulating cellular homeostasis via digestion of dysfunctional proteins and whole cellular organelles by mechanisms, involving their enclosure into double-membrane vacuoles that are subsequently fused to lysosomes. Glioma stem cells utilize autophagy as a main mechanism of cell survival and stress response. Most recently, we and others demonstrated induction of autophagy in gliomas in response to treatment with chemical drugs, such as temozolomide (TMZ) or oncolytic adenoviruses (Ads). As autophagy has been implicated in the mechanism of Ad-mediated cell killing, autophagy deficiency in some glioma tumors could be the reason for their resistance to oncolysis. Despite the observed connection, the exact relationship between autophagy-activating cell signaling and adenoviral infection remains unclear. Here, we report that inhibition of autophagy in target glioma cells induces their resistance to killing by oncolytic agent CRAd-S-5/3. Furthermore, we found that downregulation of autophagy inducer Beclin-1 inhibits replication-competent Ad-induced oncolysis of human glioma by suppressing cell proliferation and inducing premature senescence. To overcome the autophagy-deficient state of such glioma cells and restore their susceptibility to oncolytic Ad infection, we propose treating glioma tumors with an anticancer drug tamoxifen (TAM) as a means to induce apoptosis in Ad-targeted cancer cells via upregulation of BAX/PUMA genes. In agreement with the above hypothesis, our data suggest that TAM improves susceptibility of Beclin-1-deficient glioma cells to CRAd-S-5/3 oncolysis by means of activating autophagy and pro-apoptotic signaling pathways in the target cancer cells.

CMV70-3P miRNA contributes to the CMV mediated glioma stemness and represents a target for glioma experimental therapy.

Glioblastoma multiforme (GBM) is a rapidly progressive brain tumor with a median survival of 15-19 months. Therapeutic resistance and recurrence of the disease is attributed to cancer stem cells (CSC). Here, we report that CMV70-3P miRNA encoded by CMV increases GBM CSC stemness. Inhibition of CMV70-3P expression using oligo inhibitors significantly attenuated the ability of primary glioma cells to proliferate and form neurospheres. At the molecular level, we show that CM70-3P increases expression of cellular SOX2. Collectively, these findings indicate that CMV70-3P is a potential regulator of CMV- mediated glioma progression and cancer stemness.

Nuclear Protein of the Testis Midline Carcinoma Masquerading as a Primary Mediastinal Seminoma.

Nuclear protein of the testis (NUT) midline carcinomas are rare aggressive carcinomas characterized by chromosomal rearrangements that involve the gene encoding the NUT. This article reviews the clinicopathologic features and the differential diagnosis of these malignancies.