Dataset Information

Clear Cell Adenocarcinoma of Urethra: Clinical and Pathologic Implications and Characterization of Molecular Aberrations.

ABSTRACT:

Purpose

This study aimed to evaluate the molecular features of clear cell adenocarcinoma (CCA) of the urinary tract and investigate its pathogenic pathways and possible actionable targets.

Materials and methods

We retrospectively collected the data of patients with CCA between January 1999 and December 2016; the data were independently reviewed by two pathologists. We selected five cases of urinary CCA, based on the clinicopathological features. We analyzed these five cases by whole exome sequencing (WES) and subsequent bioinformatics analyses to determine the mutational spectrum and possible pathogenic pathways.

Results

All patients were female with a median age of 62 years. All tumors were located in the urethra and showed aggressive behavior with disease progression. WES revealed several genetic alterations, including driver gene mutations (AMER1, ARID1A, CHD4, KMT2D, KRAS, PBRM1, and PIK3R1) and mutations in other important genes with tumor-suppressive and oncogenic roles (CSMD3, KEAP1, SMARCA4, and CACNA1D). We suggest putative pathogenic pathways (chromatin remodeling pathway, mitogen-activated protein kinase signaling pathway, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin pathway, and Wnt/β-catenin pathway) as candidates for targeted therapies.

Conclusion

Our findings shed light on the molecular background of this extremely rare tumor with poor prognosis and can help improve treatment options.

SUBMITTER: Song B

PROVIDER: S-EPMC10789969 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Publications

Clear Cell Adenocarcinoma of Urethra: Clinical and Pathologic Implications and Characterization of Molecular Aberrations.

Song Boram B Lee Seok Hyun SH Park Jeong Hwan JH Moon Kyung Chul KC

Cancer research and treatment 20230911 1

<h4>Purpose</h4>This study aimed to evaluate the molecular features of clear cell adenocarcinoma (CCA) of the urinary tract and investigate its pathogenic pathways and possible actionable targets.<h4>Materials and methods</h4>We retrospectively collected the data of patients with CCA between January 1999 and December 2016; the data were independently reviewed by two pathologists. We selected five cases of urinary CCA, based on the clinicopathological features. We analyzed these five cases by who ...[more]

PMID: 37697729

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Project description:BackgroundPrimary clear cell adenocarcinoma of the urethra (CCAU) is a kind of extremely rare genitourinary cancer. Despite the similarity in the clinical manifestations of these reported cases, diagnosis and determination of standard therapy remain challenging due to the rarity of findings and similarity with other urethral tumors.Case presentationHerein, we reported two cases of CCAU with the same chief complaint of hematuria: a 71-year-old female and a 66-year-old male. The male patient reported concomitant symptoms of frequent and painful urination. CT scans show abnormal enhancements. After a cystoscopy examination, both patients are diagnosed with malignant urethral tumors. Surgical resections and additional pathological examinations support the diagnosis of CCAU (palliative resection for case 1 and transurethral resection for case 2). Case 1 undergone progression 6 months after initial treatment with transurethral resection and chemotherapy with a 15-month overall survival. In contrast, the prognosis of case 2 remained uneventful 10 months after surgery without recurrence. After presenting our cases, we launched a literature review that included 23 articles and 33 cases of CCAU to summarize the characteristics of the disease.ConclusionPrimary clear cell adenocarcinoma of the urethra is a rare malignant urethral tumor with controversial histological origins. Primary symptoms include hematuria and changes in voiding habits. Middle-aged and elderly females are more susceptible to primary clear-cell adenocarcinoma of the urethra. Unfortunately, it is difficult to differentiate primary clear-cell adenocarcinoma of the urethra from other urethral tumors due to similar clinical features. However, imaging tools such as CT, MRI, and cystoscopy are adjunctive in confirming diagnoses. Even though surgical resection is the primary treatment to relieve clinical symptoms, prevent recurrence, and confirm diagnosis, no standard surgical protocol is available. The therapeutic effect of postoperative adjuvant therapies remains unclear. Future investigations on CCAU are necessary to advance clinical knowledge and to provide treatment guidance.

Project description:BACKGROUND:Historically, VHL was the only frequently mutated gene in clear cell renal cell carcinoma (ccRCC), with conflicting clinical relevance. Recent sequencing efforts have identified several novel frequent mutations of histone modifying and chromatin remodeling genes in ccRCC including PBRM1, SETD2, BAP1, and KDM5C. PBRM1, SETD2, and BAP1 are located in close proximity to VHL within a commonly lost (approximately 90%) 3p locus. To date, the clinical and pathologic significance of mutations in these novel candidate tumor suppressors is unknown. OBJECTIVE:To determine the frequency of and render the first clinical and pathologic outcome associated with mutations of these novel candidate tumor suppressors in ccRCC. DESIGN, SETTING, AND PARTICIPANTS:Targeted sequencing was performed in 185 ccRCCs and matched normal tissues from a single institution. Pathologic features, baseline patient characteristics, and follow-up data were recorded. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:The linkage between mutations and clinical and pathologic outcomes was interrogated with the Fisher exact test (for stage and Fuhrman nuclear grade) and the permutation log-rank test (for cancer-specific survival [CSS]). RESULTS AND LIMITATIONS:PBRM1, BAP1, SETD2, and KDM5C are mutated at 29%, 6%, 8%, and 8%, respectively. Tumors with mutations in PBRM1 or any of BAP1, SETD2, or KDM5C (19%) are more likely to present with stage III disease or higher (p = 0.01 and p = 0.001, respectively). Small tumors (<4 cm) with PBRM1 mutations are more likely to exhibit stage III pathologic features (odds ratio: 6.4; p = 0.001). BAP1 mutations tend to occur in Fuhrman grade III-IV tumors (p = 0.052) and are associated with worse CSS (p = 0.01). Clinical outcome data are limited by the number of events. CONCLUSIONS:Most mutations of chromatin modulators discovered in ccRCC are loss of function, associated with advanced stage, grade, and possibly worse CSS. Further studies validating the clinical impact of these novel mutations and future development of therapeutics remedying these tumor suppressors are warranted.

Project description:BackgroundIt has long been appreciated that different subtypes (serous, clear cell, endometrioid and mucinous) of epithelial ovarian carcinoma (EOC) have distinct pathogenetic pathways. However, clinical management, especially chemotherapeutic regimens, for EOC patients is not subtype specific. Ovarian clear cell carcinoma (CCC) is a rare histological subtype of EOC, which exhibits high rates of recurrence and low chemosensitivity. We assessed potential therapeutic targets for ovarian CCC patients through analyzing the variation of drug-based molecular biomarkers expression between ovarian CCC and high-grade serous carcinoma (HGSC).MethodsSeven candidate drug-based molecular biomarkers, human epidermal growth factor receptor (EGFR), human epidermal growth factor receptor-2 (HER2), phosphatase and tensin homolog deleted on chromosome ten (PTEN), aurora kinase A (AURKA), breast cancer susceptibility gene 1 (BRCA1), breast cancer susceptibility gene 2 (BRCA2) and programmed death-ligand 1 (PD-L1) were measured in 96 ovarian CCC and 113 HGSC by immunohistochemistry in paraffin embedded tissues. The relationship between these biomarkers and clinicopathological factors were explored.ResultsThe expression level of four of the seven drug-based molecular biomarkers was markedly different between HGSC and CCC. High expression levels of HER2 and PD-L1 were more commonly observed in CCC patients (12.6% vs 2.7%, 21.1% vs 11.6%, P = 0.006, 0.064, respectively), while loss of BRCA1 and BRCA2 expression were more frequently occurred in HGSC patients (72.6% vs 54.3%, 89.4% vs 79.8%, P = 0.007, 0.054, respectively). Survival analysis showed that five of seven biomarkers had prognostic values but varied between subtypes. Furthermore, EGFR expressed frequently in CCC patients with endometriosis than in HGSC patients (44.4% vs 8.3%, P = 0.049). AURKA and PD-L1 correlated with the resistance to platinum-based chemotherapy in CCC patients (P = 0.043, 0.028, respectively) while no similar results were observed in HGSC patients.ConclusionOvarian CCC showed a markedly different expression map of drug-based molecular biomarkers from HGSC, which suggested a new personalized target therapy in this rare subtype.

Dataset Information

Clear Cell Adenocarcinoma of Urethra: Clinical and Pathologic Implications and Characterization of Molecular Aberrations.

Purpose

Materials and methods

Results

Conclusion

Publications

Clear Cell Adenocarcinoma of Urethra: Clinical and Pathologic Implications and Characterization of Molecular Aberrations.

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