Ovarian-type (ie, Mullerian) epithelial tumors occurring in the testicular and paratesticular regions are exceptionally rare, with only a handful reported worldwide. Serous tumors are the most frequently encountered subtype among these rare tumors. The pathogenesis of these tumors within the testicular and paratesticular regions remains a subject of intrigue and debate, with various hypotheses attempting to explain their presence in the paratestis region, where most tumors occur. However, our understanding of the pathogenesis of intratesticular tumors is limited. To date, 11 known examples of intratesticular serous Mullerian tumors have been reported globally. In this report, we present an extraordinary tumor, an intratesticular Mullerian serous borderline tumor with foci of microinvasion, in a 38-year-old male patient. This tumor exhibits histological features similar to their ovarian counterparts and is confirmed through an immunohistochemical panel. Our report underscores the extreme rarity of these tumors, emphasizes the importance of heightened awareness among clinicians and pathologists, and provides valuable insights into their complex development and histogenesis. This contribution aims to enhance diagnostic precision and optimize therapeutic strategies for similar tumors.

Paratesticular cystadenomas remain a very rare entity, typically presenting as a painless mass, often indistinguishable from the testicle. As such, the predominant management seems to be complete excision via various approaches, which often proves curative. Given its rarity, post-operative surveillance has not been standardized; most patients and providers elect a more conservative surveillance approach. Based on the available literature, this seems appropriate, given the lack of morbidity or recurrence associated with these types of tumors.

Low-grade serous ovarian cancer (LGSOC) is a rare form of epithelial ovarian cancer that generally exhibits a protracted course and is less sensitive to chemotherapy than high-grade serous ovarian cancer. Over the past decade, it has become clear that patients with LGSOC have a clinically distinct course and are molecularly and histologically unique from patients with high-grade serous ovarian cancer.
Endocrine therapy is frequently used for the treatment of patients with recurrent LGSOC and is now also part of the standard upfront treatment of this disease, with an ongoing phase III clinical trial seeking to determine if chemotherapy can be eliminated altogether from the initial treatment of LGSOC. Tumors are frequently found to exhibit alterations affecting the mitogen-activated protein kinase (MAPK) pathway, recently leading to developments in the use of targeted treatments for those patients with recurrent disease. LGSOC is a clinically, histologically, and molecularly unique form of epithelial ovarian cancer. Recent advances in the understanding of endocrine and molecular drivers of this disease have led to changes in both the treatment of newly diagnosed and recurrent disease, with ongoing studies focused on refining upfront therapy and seeking novel targeted combinations for those patients with recurrent disease.

Ovarian serous neoplasms are thought to arise from the fallopian tube or from the ovarian surface epithelium. The possibility of a third pathway-involving the mesenchymal-epithelial transition and mimicking the formation of the Müllerian duct-arose from observations gathered from our routine cases. The purpose of this study is to determine the association of precursors in the ovarian stroma with different types of ovarian serous neoplasms. Three hundred neoplasms, benign (25), borderline (63), and malignant ovarian serous neoplasms (40 low-grade serous carcinomas [LGSCas] and 172 high-grade serous carcinomas [HGSCas]), were reviewed. Clinicopathologic features analyzed included patient\'s age, tumor size, stage, histologic pattern, and possible precursors in the ovarian parenchyma (endosalpingiosis, inverted macropapillae, polyploid giant cancer cells, and simple cysts). All benign and borderline cases showed continuity with benign serous cysts or endosalpingiosis. In LGSCas, continuity with serous cysts was found in 29 (72%) of 40 cases, and inverted macropapillae were found in 12 (30%) of 40 cases. In untreated HGSCas, there was continuity with simple cysts in 42% of cases. In addition, these HGSCas contained polyploid giant cancer cells in 20% of cases. There were no different features in the ovaries in cases with or without serous tubal intraepithelial carcinoma. Our study shows that in a subset of cases, ovarian serous neoplasms and the Müllerian duct develop in similar fashion, originating from epithelial cells derived from the mesothelium, or occur de novo from structures derived from mesenchymal-epithelial transition.

BACKGROUND: The heterogeneous subtypes and stages of epithelial ovarian cancer (EOC) differ in their biological features, invasiveness, and response to chemotherapy, but the transcriptional regulators causing their differences remain nebulous.
METHODS: In this study, we compared high-grade serous ovarian cancers (HGSOCs) to low malignant potential or serous borderline tumors (SBTs). Our aim was to discover new regulatory factors causing distinct biological properties of HGSOCs and SBTs.
RESULTS: In a discovery dataset, we identified 11 differentially expressed genes (DEGs) between SBTs and HGSOCs. Their expression correctly classified 95% of 267 validation samples. Two of the DEGs, TMEM30B and TSPAN1, were significantly associated with worse overall survival in patients with HGSOC. We also identified 17 DEGs that distinguished stage II vs. III HGSOC. In these two DEG promoter sets, we identified significant enrichment of predicted transcription factor binding sites, including those of RARA, FOXF1, BHLHE41, and PITX1. Using published ChIP-seq data acquired from multiple non-ovarian cell types, we showed additional regulatory factors, including AP2-gamma/TFAP2C, FOXA1, and BHLHE40, bound at the majority of DEG promoters. Several of the factors are known to cooperate with and predict the presence of nuclear hormone receptor estrogen receptor alpha (ER-alpha). We experimentally confirmed ER-alpha and PITX1 presence at the DEGs by performing ChIP-seq analysis using the ovarian cancer cell line PEO4. Finally, RNA-seq analysis identified recurrent gene fusion events in our EOC tumor set. Some of these fusions were significantly associated with survival in HGSOC patients; however, the fusion genes are not regulated by the transcription factors identified for the DEGs.
CONCLUSIONS: These data implicate an estrogen-responsive regulatory network in the differential gene expression between ovarian cancer subtypes and stages, which includes PITX1. Importantly, the transcription factors associated with our DEG promoters are known to form the MegaTrans complex in breast cancer. This is the first study to implicate the MegaTrans complex in contributing to the distinct biological trajectories of malignant and indolent ovarian cancer subtypes.

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.

Sarcomatoid or anaplastic carcinomas arising within epithelial ovarian neoplasms are rare, particularly within serous tumors of the ovary, and carry a poor prognosis. Here we present the case of a patient initially diagnosed with low grade serous ovarian carcinoma arising within a serous borderline tumor (atypical proliferative serous tumor). She underwent rapid progression of disease and was found to have anaplastic/sarcomatoid carcinoma on biopsy of recurrence. These findings prompted pathologic re-review of the original neoplasm, which demonstrated a microscopic focus of sarcomatoid/anaplastic carcinoma.

To investigate the computed tomography (CT) and magnetic resonance imaging (MRI) characteristics of ovarian serous borderline tumors (SBTs), and evaluate whether CT and MRI can be used to distinguish micropapillary from typical subtypes.
We retrospectively reviewed the clinical features and CT and MR imaging findings of 47 patients with SBTs encountered at our institute from September 2013 to December 2019. 30 patients with 58 histologically proven typical SBT and 17 patients with 26 micropapillary SBT were reviewed. Preoperative CT and MR images were evaluated, by two observers in consensus for the laterality, maximum diameter (MD), morphology patterns, internal architecture, attenuation or signal intensity, ADC value, enhancement patterns of solid portions (SP), and extra-ovarian imaging features.
The median age were similar between typical SBT and SBT-MP (32.5 years, 36 years, respectively, P>0.05). Morphology patterns between two subtypes were significantly different on CT and MR images (P < 0.001). Irregular solid tumor (21/37, 56.76%) was the major morphology pattern of typical SBT tumor, while unilocular cyst with mural nodules (14/20, 70%) was the major morphology pattern of SBT-MP on CT images. Similarly, papillary architecture with internal branching (PA&IB) (17/21, 80.95%) was the major morphology pattern of typical SBT tumor, while unilocular cyst with mural nodules (4/6, 66.67%) was the major pattern of SBT-MP on MR images. PA&IB all showed slightly hyperintense papillary architecture with hypointense internal branching on T2-weighted MRI. More calcifications were found in typical SBT (24/37, 64.86%) than SBT-MP mass lesion (6/20, 30%) (P < 0.05). Hemorrhage was less frequently visible in (20/37, 54.05%) typical SBT lessons than SBT-MP mass lesion (18/20, 90%) (P < 0.05). The ovarian preservation is more seen in typical SBT (38/58, 65.52%) than SBT-MP (12/28, 42.86%) in our series (P < 0.05). Mean ADC value of solid portions (papillary architecture and mural nodules) was 1.68 (range from 1.44 to 1.85) × 10-3 mm2/s for typical SBT and 1.62 (range from 1.45 to 1.7) × 10-3 mm2/s for that of SBT-MP. The solid components of the two SBT subtypes showed wash-in appearance enhancements after contrast injection both in CT and MR images except 2 of SBT-MP with no enhancement as complete focal hemorrhage on MR images.
Morphology and internal architecture are two major imaging features that can help to distinguish between SBT-MP and typical SBT.

BACKGROUND: Serous borderline tumors (SBT) are the most common subtype of ovarian borderline tumors with excellent clinical course. However, they can recur or progress to low-grade serous carcinoma (LGSC) in a small proportion of the cases. Beside BRAF and KRAS mutations, copy number alterations (CNA), particularly loss of chromosome 9p21 locus which results in deletion of genes CDKN2A and MTAP, have been suggested to be involved in disease progression. MTAP immunohistochemistry recently has been introduced for mesothelioma as a reliable surrogate marker for the homozygous deletion of chromosome 9p21 locus. Therefore, in the current study, we aimed to evaluate the MTAP loss of expression in serous borderline tumors and low-grade serous carcinomas to identify if it can be used as a marker for prognosis and progression.
METHODS: Eighty-four total cases of ovarian serous lesions, including 21 cases of serous cystadenomas, 21 cases of serous borderline tumors, 12 cases of low-grade serous carcinomas and 30 cases of high-grade serous carcinomas were selected. MTAP immunohistochemistry was performed on the representative blocks and cytoplasmic staining was used for interpretation. The cases were labeled as positive (retained) if MTAP showed cytoplasmic granular staining and negative (loss of expression) if negative cytoplasmic staining was observed in the presence of positive internal control.
RESULTS: Ten of 21 cases of serous borderline tumors showed loss of MTAP expression (48%). Among those, 7 cases were bilateral, 2 cases had micropapillary features, one case had supraclavicular and cervical lymph node involvement by serous borderline tumor and 2 cases had progression to low-grade serous carcinoma, including one of micropapillary tumors. Also 8 out of 12 cases of LGSCs showed MTAP loss of expression (66%). Only 4 of 30 cases of high-grade serous carcinomas (13%) and none of the serous cystadenoma cases showed loss of expression of MTAP.
CONCLUSIONS: To our knowledge, this is the first description of MTAP immunohistochemistry in serous borderline tumors and low-grade serous carcinomas. Our study was limited due to small sample size. However, it showed an association between MTAP loss of expression and adverse clinical behavior in ovarian serous borderline tumors. This supports the role for further investigations in larger series to evaluate the role of MTAP stain as a prognostic marker in these neoplasms.

BACKGROUND: Patients with 46, XY disorder of sex development (DSD) are predisposed to the development of gonadal tumors, particularly germ cell tumors and gonadoblastoma. However, to the best of our knowledge, there are no publications in the existing literature that refer to the coexistence of 46, XY DSD and serous tumors in the ovary.
METHODS: Here, we report the case of a 23-year-old female (social gender) patient with 46, XY DSD presenting with primary amenorrhea. Imageology revealed a huge mass in the left adnexa. Subsequent pathological analysis revealed a serous borderline tumor of the ovary.
CONCLUSIONS: Gonadal tumors of patients with 46, XY DSD are not necessarily malignant tumors and can coexist with borderline tumors with primitive corded gonads. The coexistence of DSD and serous borderline tumors is rare. Clearly, an early and accurate diagnosis plays an important role in the treatment of these patients. Although there may not be a clear correlation between the two lesions, it is vital that we specifically analyze the mechanisms involved so that we can determine whether patients with DSD are associated with an increase of developing serous borderline tumors of the gonad.