OBJECTIVE: Metastatic Leydig cell tumors (LCT) are rare, difficult-to-treat malignancies without known underlying molecular-genetic events. An index case of metastatic LCT showed an LDLR-TERT gene fusion upon routine genetic profiling for detection of therapeutic targets, which was then followed by an investigation into a cohort of additional LCTs. PATIENTS AND METHODS: Twenty-nine LCT (27 male and 2 female patients) were profiled using next-generation sequencing and immunohistochemistry. RESULTS: TERT gene fusions were detected only in testicular metastatic LCTs, in 3 of 7 successfully analyzed cases (RMST:TERT, LDLR:TERT, and B4GALT5:TERT). TOP1 and CCND3 amplifications were identified in the case with a B4GALT5:TERT fusion. A TP53 mutation was detected in 1 metastatic tumor without a TERT fusion. Five primary (4 testicular and 1 ovarian) LCTs showed multiple gene amplifications, without a consistent pattern. A single metastatic ovarian LCT showed BAP1 mutation and copy number amplifications affecting the NPM1, PCM1, and SS18 genes. At the protein level, 4 of 7 metastatic and 6 of 10 primary testicular LCTs overexpressed Topo1. Androgen receptor was overexpressed in 10 of 13 primary testicular tumors and 2 of 5 metastatic testicular LCTs (without detectable ARv7 messenger RNA or ARv7 protein). Only 1 metastatic testicular LCT exhibited a high tumor mutational burden; all tested cases were microsatellite instability stable and did not express programmed cell death ligand 1. CONCLUSIONS: Our study for the first time identified TERT gene fusions as a main genetic alteration and a potential therapeutic target in metastatic LCTs. Topo1 and androgen receptor may guide decisions on chemotherapy and/or hormone therapy for selected individual patients.
- MeSH
- fúze genů MeSH
- imunohistochemie MeSH
- lidé MeSH
- nádor z Leydigových buněk * MeSH
- nádorové supresorové proteiny MeSH
- telomerasa * genetika MeSH
- testikulární nádory * genetika MeSH
- thiolesterasa ubikvitinu MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Primary Extra-mammary Paget's disease (EMPD) is a very rare cutaneous adenocarcinoma affecting anogenital or axillary regions. It is characterized by a prolonged course with recurrences and eventually distant metastatic spread for which no specific therapy is known. METHODS: Eighteen EMPD (13 vulvar and five scrotal) and ten mammary Paget's disease (MPD) cases were comprehensively profiled for gene mutations, fusions and copy number alterations, and for therapy-relevant protein biomarkers). RESULTS: Mutations in TP53 and PIK3CA were the most frequent in both cohorts: 7/15 and 5/15 in EMPD; 1/6 and 4/7 in MPD HER2 gene amplification was detected in 4/18 EMPD (3 vulvar and 1 scrotal case) in contrast to MPD where it was detected in the majority (7/8) of cases. TOP2A gene amplification was seen in 2/12 EMPD and 1/6 MPD, respectively. Similarly, no difference in estrogen receptor expression was seen between the EMPD (4/15) and MPD (3/10). Androgen receptor was also expressed in the majority of both cohorts (12/16 EMPD) and (7/8 MPD).Here ARv7 splice variant was detected in 1/7 EMPD and 1/4 MPD cases, respectively. PD-L1 expression on immune cells was exclusively observed in three vulvar EMPD. In contrast to MPD, six EMPDs harbored a "high" tumor mutation burden (≥10 mutations/Mb). All tested cases from both cohorts were MSI stable. CONCLUSIONS: EMPD shares some targetable biomarkers with its mammary counterpart (steroid receptors, PIK3CA signaling pathways, TOP2A amplification). HER2 positivity is notably lower in EMPD while biomarkers to immune checkpoint inhibitors (high TMB and PD-L1) were observed in some EMPD. Given that no consistent molecular alteration characterizes EMPD, comprehensive theranostic profiling is required to identify individual patients with targetable molecular alterations.
- MeSH
- amplifikace genu MeSH
- cílená molekulární terapie MeSH
- dospělí MeSH
- extramamární Pagetova nemoc farmakoterapie genetika patologie MeSH
- individualizovaná medicína MeSH
- kůže patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mikrosatelitní nestabilita MeSH
- mutace MeSH
- nádorové biomarkery antagonisté a inhibitory genetika metabolismus MeSH
- nádory kůže farmakoterapie genetika patologie MeSH
- nádory prsu farmakoterapie genetika patologie MeSH
- Pagetova nemoc prsu farmakoterapie genetika patologie MeSH
- protokoly antitumorózní kombinované chemoterapie farmakologie terapeutické užití MeSH
- prsy patologie MeSH
- retrospektivní studie MeSH
- sekvenční analýza DNA MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- skrotum patologie MeSH
- variabilita počtu kopií segmentů DNA MeSH
- vulva patologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
The characteristic morphologic spectrum of tubulocystic renal cell carcinoma (TC-RCC) may include areas resembling papillary RCC (PRCC). Our study includes 15 RCCs with tubulocystic pattern: 6 TC-RCCs, 1 RCC-high grade with tubulocystic architecture, 5 TC-RCCs with foci of PRCC, 2 with high-grade RCC (HGRCC) not otherwise specified, and 1 with a clear cell papillary RCC/renal angiomyoadenomatous tumor-like component. We analyzed aberrations of chromosomes 7, 17, and Y; mutations of VHL and FH genes; and loss of heterozygosity at chromosome 3p. Genetic analysis was performed separately in areas of classic TC-RCC and in those with other histologic patterns. The TC-RCC component demonstrated disomy of chromosome 7 in 9/15 cases, polysomy of chromosome 17 in 7/15 cases, and loss of Y in 1 case. In the PRCC component, 2/3 analyzable cases showed disomy of chromosome 7 and polysomy of chromosome 17 with normal Y. One case with focal HGRCC exhibited only disomy 7, whereas the case with clear cell papillary RCC/renal angiomyoadenomatous tumor-like pattern showed polysomies of 7 and 17, mutation of VHL, and loss of heterozygosity 3p. FH gene mutation was identified in a single case with an aggressive clinical course and predominant TC-RCC pattern. The following conclusions were drawn: (1) TC-RCC demonstrates variable status of chromosomes 7, 17, and Y even in cases with typical/uniform morphology. (2) The biological nature of PRCC/HGRCC-like areas within TC-RCC remains unclear. Our data suggest that heterogenous TC-RCCs may be associated with an adverse clinical outcome. (3) Hereditary leiomyomatosis-associated RCC can be morphologically indistinguishable from "high-grade" TC-RCC; therefore, in TC-RCC with high-grade features FH gene status should be tested.
- MeSH
- dospělí MeSH
- hybridizace in situ fluorescenční MeSH
- karcinom z renálních buněk genetika MeSH
- leiomyomatóza genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- lidské chromozomy, pár 17 genetika MeSH
- lidské chromozomy, pár 7 genetika MeSH
- lidský chromozom Y genetika MeSH
- molekulární biologie MeSH
- nádorový supresorový protein VHL genetika MeSH
- nádory ledvin genetika MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Synchronní prezentace benigních a maligních nádorů ledviny je velmi vzácná. Představujeme případ 63leté ženy, která podstoupila bilaterální parciální nefrektomii poté, co jí bylo vysloveno podezření na oboustranný výskyt renálního tumoru sonografickým vyšetřením a CT. Histopatologické vyšetření levé ledviny prokázalo chromofobní renální karcinom. V resekátu pravé ledviny byl nalezen světlobuněčný karcinom z renálních buněk společně s malým angiomyolipomem a renomedulárním intersticiálním nádorem. Následná chemoterapie nebyla indikována. V současnosti je pacientka bez známek relapsu a udržuje normální renální funkce.
Synchronous occurrence of benign and malignant kidney tumours is very rare. We present the case of a 63-year-old female patient who underwent a bilateral partial nephrectomy after being diagnosed with bilateral kidney tumours by ultrasonography and a computed tomography scan. Histopathological analysis of the left kidney tumour mass revealed a chromophobe renal cell carcinoma. In the right kidney specimen clear cell renal cell carcinoma was found along with a small angiomyolipoma and renomedullary interstitial cell tumour. There were no indications for subsequent chemotherapy. At present, three years after the surgery, the patient has had no signs of relapse and maintains normal renal function.
- Klíčová slova
- oboustranné nádory ledvin,
- MeSH
- angiomyolipom * chirurgie patologie MeSH
- karcinom z renálních buněk * chirurgie patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mnohočetné primární nádory * chirurgie patologie MeSH
- nádory ledvin chirurgie patologie MeSH
- nefrektomie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
