Atypical (Symplastic) Leiomyoma Arising in Pararectal Endometriosis Associated With Metastatic Ovarian Clear Cell Carcinoma: A Case Report

<div>Abstract<p><b>Purpose:</b> To identify therapeutic targets in ovarian clear cell carcinomas, a chemoresistant and aggressive type of ovarian cancer.</p><p><b>Experimental Design:</b> Twelve ovarian clear cell carcinoma cell lines were subjected to tiling path microarray comparative genomic hybridization and genome-wide expression profiling analysis. Regions of high-level amplification were defined and genes whose expression levels were determined by copy number and correlated with gene amplification were identified. The effects of inhibition of PPM1D were assessed using short hairpin RNA constructs and a small-molecule inhibitor (CCT007093). The prevalence of <i>PPM1D</i> amplification and mRNA expression was determined using chromogenic <i>in situ</i> hybridization and quantitative real-time reverse transcription-PCR in a cohort of pure ovarian clear cell carcinomas and on an independent series of unselected epithelial ovarian cancers.</p><p><b>Results:</b> Array-based comparative genomic hybridization analysis revealed regions of high-level amplification on 1q32, 1q42, 2q11, 3q24-q26, 5p15, 7p21-p22, 11q13.2-q13.4, 11q22, 17q21-q22, 17q23.2, 19q12-q13, and 20q13.2. Thirty-four genes mapping to these regions displayed expression levels that correlated with copy number gains/amplification. <i>PPM1D</i> had significantly higher levels of mRNA expression in ovarian clear cell carcinoma cell lines harboring gains/amplifications of 17q23.2. PPM1D inhibition revealed that PPM1D expression and phosphatase activity are selectively required for the survival of ovarian clear cell carcinoma cell lines with 17q23.2 amplification. <i>PPM1D</i> amplification was significantly associated with ovarian clear cell carcinoma histology (<i>P</i> = 0.0003) and found in 10% of primary ovarian clear cell carcinomas. PPM1D expression levels were significantly correlated with <i>PPM1D</i> gene amplification in primary ovarian clear cell carcinomas.</p><p><b>Conclusion:</b> Our data provide strong circumstantial evidence that <i>PPM1D</i> is a potential therapeutic target for a subgroup of ovarian clear cell carcinomas.</p></div>

<div>Abstract<p><b>Purpose:</b> To identify therapeutic targets in ovarian clear cell carcinomas, a chemoresistant and aggressive type of ovarian cancer.</p><p><b>Experimental Design:</b> Twelve ovarian clear cell carcinoma cell lines were subjected to tiling path microarray comparative genomic hybridization and genome-wide expression profiling analysis. Regions of high-level amplification were defined and genes whose expression levels were determined by copy number and correlated with gene amplification were identified. The effects of inhibition of PPM1D were assessed using short hairpin RNA constructs and a small-molecule inhibitor (CCT007093). The prevalence of <i>PPM1D</i> amplification and mRNA expression was determined using chromogenic <i>in situ</i> hybridization and quantitative real-time reverse transcription-PCR in a cohort of pure ovarian clear cell carcinomas and on an independent series of unselected epithelial ovarian cancers.</p><p><b>Results:</b> Array-based comparative genomic hybridization analysis revealed regions of high-level amplification on 1q32, 1q42, 2q11, 3q24-q26, 5p15, 7p21-p22, 11q13.2-q13.4, 11q22, 17q21-q22, 17q23.2, 19q12-q13, and 20q13.2. Thirty-four genes mapping to these regions displayed expression levels that correlated with copy number gains/amplification. <i>PPM1D</i> had significantly higher levels of mRNA expression in ovarian clear cell carcinoma cell lines harboring gains/amplifications of 17q23.2. PPM1D inhibition revealed that PPM1D expression and phosphatase activity are selectively required for the survival of ovarian clear cell carcinoma cell lines with 17q23.2 amplification. <i>PPM1D</i> amplification was significantly associated with ovarian clear cell carcinoma histology (<i>P</i> = 0.0003) and found in 10% of primary ovarian clear cell carcinomas. PPM1D expression levels were significantly correlated with <i>PPM1D</i> gene amplification in primary ovarian clear cell carcinomas.</p><p><b>Conclusion:</b> Our data provide strong circumstantial evidence that <i>PPM1D</i> is a potential therapeutic target for a subgroup of ovarian clear cell carcinomas.</p></div>

To identify therapeutic targets in ovarian clear cell carcinomas, a chemoresistant and aggressive type of ovarian cancer. Twelve ovarian clear cell carcinoma cell lines were subjected to tiling path microarray comparative genomic hybridization and genome-wide expression profiling analysis. Regions of high-level amplification were defined and genes whose expression levels were determined by copy number and correlated with gene amplification were identified. The effects of inhibition of PPM1D were assessed using short hairpin RNA constructs and a small-molecule inhibitor (CCT007093). The prevalence of PPM1D amplification and mRNA expression was determined using chromogenic in situ hybridization and quantitative real-time reverse transcription-PCR in a cohort of pure ovarian clear cell carcinomas and on an independent series of unselected epithelial ovarian cancers. Array-based comparative genomic hybridization analysis revealed regions of high-level amplification on 1q32, 1q42, 2q11, 3q24-q26, 5p15, 7p21-p22, 11q13.2-q13.4, 11q22, 17q21-q22, 17q23.2, 19q12-q13, and 20q13.2. Thirty-four genes mapping to these regions displayed expression levels that correlated with copy number gains/amplification. PPM1D had significantly higher levels of mRNA expression in ovarian clear cell carcinoma cell lines harboring gains/amplifications of 17q23.2. PPM1D inhibition revealed that PPM1D expression and phosphatase activity are selectively required for the survival of ovarian clear cell carcinoma cell lines with 17q23.2 amplification. PPM1D amplification was significantly associated with ovarian clear cell carcinoma histology (P = 0.0003) and found in 10% of primary ovarian clear cell carcinomas. PPM1D expression levels were significantly correlated with PPM1D gene amplification in primary ovarian clear cell carcinomas. Our data provide strong circumstantial evidence that PPM1D is a potential therapeutic target for a subgroup of ovarian clear cell carcinomas.

ObjectiveTo compare the incidence and survival rates of primary ovarian clear cell carcinoma (OCCC) and ovarian serous carcinoma (OSC) from a nationwide collected database.MethodsWe extracted information of patients with primary OCCC and OSC from the Korea Central Cancer Registry recorded between 1999 and 2018, including age at diagnosis and the Surveillance, Epidemiology, and End Results summary stage. Age-standardized incidence rates (ASRs) and annual percent changes (APCs) were calculated. Baseline characteristics and overall survival (OS) were compared between the OCCC and OSC groups.ResultsOverall, the incidence rate of primary OCCC increased markedly from 1999 (ASR, 0.16/100,000) to 2018 (0.76/100,000) (APC, 7.85%; P<0.0001). Patients with OCCC were significantly younger and had early-stage disease more frequently than those with OSC. Patients diagnosed with OCCC before the age of 50 showed better OS than those diagnosed after the age of 50 (P=0.0048). The 5-year OS of the OCCC group did not differ by study period [73.5% (1999–2008) vs. 75.4% (2009–2018), P=0.3187], whereas the 5-year OS of the OSC group improved from 54.4% to 58% (P=0.0003).ConclusionsOur nationwide registry-based study demonstrated that the incidence of OCCC in Korea increased significantly from 1999 to 2018. Early-stage OCCC had a relatively good prognosis, but advanced-stage OCCC had a worse OS than advanced-stage OSC. Therefore, the development of optimal treatment strategies for OCCC is warranted.

Objective: To assess the expression level of targeting drug-based molecular biomarkers in ovarian clear cell carcinoma (OCCC) tissues and its clinical significance. Methods: A total of 63 OCCC patients included 40 primary OCCC and 23 recurrent OCCC for secondary cytoreductive surgery (SCS), who had received primary surgeries at Fudan University Shanghai Cancer Center between January, 2008 and December, 2015 were enrolled, and immunohistochemistry SP method was used to test human epidermal growth factor receptor (EGFR), human epidermal growth factor receptor-2 (HER2), aurora kinase A (AURKA), breast cancer susceptibility gene 1 (BRCA1), BRCA2 and programmed death-ligand 1 (PD-L1)protein expression in paraffin-embedded tissues. Results: The positive rates of EGFR, HER2, AURKA,BRCA1, BRCA2 and PD-L1 in primary and recurrent tumor tissues were respectively 20% (8/40) vs 30% (7/23) , 22% (9/40) vs 35% (8/23) , 38% (15/40) vs 35% (8/23) , 42% (17/40) vs 39% (9/23) , 20% (8/40) vs 22% (5/23) , 25% (10/40) vs 17% (4/23) , and there were no significant differences between primary and recurrent OCCC (all P>0.05). χ(2)-test or Fisher exact analysis revealed that HER2 expression in recurrent tumor tissues had a relationship with chemoresistance (P<0.05), while the expression of other biomarkers showed no significant relationship with chemoresistance (all P>0.05). Further, Kaplan-Meier survival analysis showed that patients with HER2 and AURKA-positive expression had a significantly shorter progression-free survival time in primary OCCC (4 months vs 10 months, log-rank test, P<0.05 for HER2; and 4 months vs 10 months, P<0.05 for AURKA); and a shorter overall survival time after SCS in recurrent OCCC (10 months vs 44 months, P<0.05 for HER2; and 13 months vs 43 months, P<0.05 for AURKA). However, multivariate Cox proportional hazards regression analysis indicated that none of these 6 biomarkers was independent risk factor of progression-free survival time of primary OCCC or overall survival time after SCS for recurrent OCCC (P>0.05). Conclusion: HER2 and AURKA could serve as prognostic factors in ovarian clear cell carcinoma.

The diagnosis of primary clear cell carcinoma of the ovary or kidney is usually straightforward. However, problems in ascertaining the site of the primary tumor may arise when there is widespread metastatic disease or when clear cell carcinoma is present in both the ovary and kidney. In this study, the value of a panel of antibodies in distinguishing between an ovarian and renal clear cell carcinoma was evaluated. The panel comprised cytokeratin (CK)7 and 20, vimentin, estrogen receptor (ER), CD10, and renal cell carcinoma (RCC) marker. Ovarian clear cell carcinomas (n=14) were positive with CK7 (14/14), vimentin (6/14), ER (2/14), and RCC marker (2/14). All were negative with CD10 and CK20. Renal clear cell carcinomas (n=14) were positive with CD10 (14/14), RCC marker (14/14), vimentin (7/14), CK7 (2/14), and CK20 (1/14). All were negative with ER. This panel allows clear cell carcinomas of the ovary and kidney to be distinguished with a high degree of certainty and is a useful adjunct to histologic examination. Primary ovarian clear cell carcinomas are characterized by CK7 positivity, whereas primary renal neoplasms are characterized by positivity for CD10 and RCC marker and negative staining with CK7.

Clinicopathologic and biological analysis of PIK3CA mutation in ovarian clear cell carcinoma

Metastatic lung carcinomas with clear cell morphology can be confused with primary ovarian clear cell carcinomas. We performed immunohistochemical stains in 14 cases of non-small cell lung carcinomas with clear cell features and 14 cases of ovarian clear cell carcinomas using a panel of markers, including thyroid transcription factor 1 (TTF-1), carcinoembryonic antigen (CEA), Wilms tumor gene 1, octamer-binding transcription factor 4 (OCT-4), cancer antigen 125 (CA-125), estrogen receptor, and progesterone receptor. Among non-small cell lung carcinomas with clear cell features, 87.5% of adenocarcinomas (or 50% overall frequency in lung carcinomas) were positive for TTF-1, whereas none of the ovarian clear cell carcinomas were positive (P = 0.002). All 14 ovarian clear cell carcinomas stained for CA-125 as compared with 1 non-small cell lung carcinoma (P < 0.001). On the other hand, 85% of non-small cell lung carcinomas stained for CEA, whereas none of the ovarian clear cell carcinomas did (P < 0.001). Interestingly, 4 ovarian clear cell carcinomas (28%) showed positive staining for the germ cell marker OCT-4. Either lung or ovarian carcinomas stained for Wilms tumor gene 1, estrogen receptor, or progesterone receptor very infrequently; and the difference between the 2 groups was not statistically significant. Our results suggest that an immunohistochemical panel consisting of TTF-1, CEA, CA-125, and OCT-4 is helpful in distinguishing most pulmonary and ovarian carcinomas with clear cell features.

Prognosis of Japanese Patients with Ovarian Clear Cell Carcinoma Associated with Pelvic Endometriosis: Clinicopathologic Evaluation

BackgroundMolecular aberrations occurring in primary ovarian clear cell carcinoma (OCCC) can be of diagnostic, predictive, and prognostic significance. However, a complex molecular study including genomic and transcriptomic analysis of large number of OCCC has been lacking.Methods113 pathologically confirmed primary OCCCs were analyzed using capture DNA NGS (100 cases; 727 solid cancer related genes) and RNA-Seq (105 cases; 147 genes) in order to describe spectra and frequency of genomic and transcriptomic alterations, as well as their prognostic and predictive significance.ResultsThe most frequent mutations were detected in genes ARID1A, PIK3CA, TERTp, KRAS, TP53, ATM, PPP2R1A, NF1, PTEN, and POLE (51,47,27,18,13,10,7,6,6, and 4%, respectively). TMB-High cases were detected in 9% of cases. Cases with POLEmut and/or MSI-High had better relapse-free survival. RNA-Seq revealed gene fusions in 14/105 (13%) cases, and heterogeneous expression pattern. The majority of gene fusions affected tyrosine kinase receptors (6/14; four of those were MET fusions) or DNA repair genes (2/14). Based on the mRNA expression pattern, a cluster of 12 OCCCs characterized by overexpression of tyrosine kinase receptors (TKRs) AKT3, CTNNB1, DDR2, JAK2, KIT, or PDGFRA (p < 0.00001) was identified.ConclusionsThe current work has elucidated the complex genomic and transcriptomic molecular hallmarks of primary OCCCs. Our results confirmed the favorable outcomes of POLEmut and MSI-High OCCC. Moreover, the molecular landscape of OCCC revealed several potential therapeutical targets. Molecular testing can provide the potential for targeted therapy in patients with recurrent or metastatic tumors.

ObjectivesPrevious study showed that patients with Ovarian clear cell carcinoma (OCCC) are at increased risk for developing secondary malignancy (SM). Objectives: To identify and compare germline and somatic mutations in...

We report the first documented case of primary ovarian clear cell carcinoma harboring an ETV6::NTRK3 fusion gene. A 49-year-old woman presented with a rapidly growing ovarian cyst that was diagnosed as stage IC1 clear cell carcinoma following primary debulking surgery. Molecular analysis revealed an ETV6::NTRK3 fusion gene, confirmed by RT-PCR and Sanger sequencing. The tumor also contained an ARID1A variant (p.P1326Rfs*155), exhibited low tumor mutation burden (3.7 Muts/Mbp), and showed stable microsatellite status. Following standard surgical and chemotherapeutic treatment, the patient remained disease-free at 2.5years post-surgery. This case demonstrates that NTRK fusion gene, in conjunction with ARID1A mutation, may contribute to clear cell carcinoma development, highlighting the need for further investigation into the prevalence and significance of NTRK fusions in ovarian clear cell carcinomas. The identification of this actionable genetic alteration provides potential targeted therapeutic options should disease recurrence occur.

Previous studies have evaluated the utility of estrogen receptor (ER) and progesterone receptor (PR) immunohistochemistry (IHC) in differentiating uterine versus extrauterine leiomyosarcomas (LMS). At best, these studies have shown only modest sensitivity and specificity for these markers in this context. In our own practice, we have noticed that retroperitoneal LMS, such as those arising in the wall of the inferior vena cava, frequently exhibit a remarkable resemblance not to uterine LMS, but rather to uterine leiomyomas (LM) with bizarre nuclei, formerly known as symplastic LM. This includes areas with bland nuclear cytology, punctuated by the presence of cells with large bizarre nuclei but a paradoxically low mitotic index. We refer to these areas in retroperitoneal LMS as "symplastic-like." It has been our experience that these "symplastic-like" areas are frequently the predominant or exclusive component in small core biopsies of retroperitoneal LMS, even when the resection of these tumors reveals the presence of more conventional high-grade LMS morphology. In female patients, symplastic-like morphology in a smooth muscle tumor at an intra-abdominal site raises the possibility of iatrogenic dissemination of a uterine LM with bizarre nuclei from a prior myomectomy or morcellation procedure. We hypothesized that negative staining for ER and PR by IHC could effectively exclude a uterine origin, given the high sensitivity of these markers for all variants of uterine LM. After successfully using ER and PR IHC in our clinical practice on a few index cases, we decided to study a larger cohort of carefully selected cases to systematically determine the sensitivity and specificity of these markers in this very specific context. Confining our search to include only female patients, we identified 8 cases of retroperitoneal LMS that had been confirmed radiologically, intraoperatively and/or histologically to originate from a retroperitoneal source and 6 cases of uterine-based LM with bizarre nuclei, all diagnosed at our institution over an 8-year period. We tested only whole slides for ER and PR IHC. ER and PR were both completely negative in all 8 cases of retroperitoneal LMS and were both strongly expressed in all 6 cases of LM with bizarre nuclei. In conclusion, despite conflicting data in the literature regarding the utility of ER and PR in distinguishing uterine versus extrauterine smooth muscle tumors, we endorse the use of these markers for the specific distinction of retroperitoneal LMS with symplastic-like features from disseminated uterine LM with bizarre nuclei in female patients.

PIK3CA overexpression is a possible prognostic factor for favorable survival in ovarian clear cell carcinoma

Loss of heterozygosity (LOH) at the 3p region is found in up to 50% of epithelial ovarian neoplasms. The von Hippel-Lindau (VHL) gene at the 3p25 locus is one of the tumor-suppressor genes located at 3p. The role, if any, of the VHL gene locus is not clear in ovarian carcinogenesis. We analyzed primary and metastatic ovarian clear-cell carcinomas (OCCC) for LOH at 3p25 to determine its frequency and its diagnostic utility as an adjunctive tool in the differential diagnosis of metastatic clear-cell carcinomas. Microdissection followed by single-step DNA extraction and polymerase chain reaction (PCR) amplification, using two polymorphic markers flanking the VHL gene locus, was done on archival histology and cytology samples from 9 patients with metastatic OCCC. Of the informative cases, 43% of the metastatic and 50% of the primary OCCC showed LOH. LOH at the VHL gene locus is not uncommon in clear-cell ovarian carcinoma. LOH at 3p25 in cytologic specimens may be a valuable adjunct in the diagnosis of OCCC metastasis in cytologically equivocal cases. OCCC should enter the differential in clear-cell carcinomas of unknown primary that show LOH at 3p25. Published 2001 Wiley-Liss, Inc.