Leiomyoma with bizarre nuclei (LBN) is an uncommon variant of uterine smooth muscle neoplasm. Involvement of fumarate hydratase (FH) has been suggested in the pathogenesis of a subset of LBN. The goal of our study is to assess the clinicopathological, morphological, immunohistochemical and molecular findings focusing on FH in LBNs (n = 108) and compare it with the findings in usual leiomyomas (UL; n = 50) and leiomyosarcomas (LMS; n = 42). Immunohistochemically, loss of FH expression was found in 67/108 of LBN, 1/50 of UL and in no LMS. Class 4/5 FH mutations were detected in 15/53 LBN with sufficient DNA quality for molecular analysis. Pathogenic variants of the FH gene were detected in neither UL nor LMS. Local recurrence after surgery was present in 18/92 of LBN patients, 7 of which were histologically verified and 2 of which were found to be LBN. Our results confirmed that LBN behave in a benign fashion, although they may relapse. FH gene mutations were a common finding only in LBN, but not in UL and LMS. Immunohistochemistry with an antibody against FH seems to have a good sensitivity (87%) and moderate specificity (58%) with regard to predicting FH gene mutations and could be used as a screening method in tumors with features suggestive of FH alterations to identify patients who are at risk for the FH aberrations.
- MeSH
- buněčné jádro patologie MeSH
- dospělí MeSH
- fumarasa genetika MeSH
- leiomyom genetika patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mutace MeSH
- nádorové biomarkery genetika MeSH
- nádory dělohy genetika patologie MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Klíčová slova
- syndrom hereditární leiomyomatózy a renálního karcinomu, syndrom mnohočetné kožní a děložní leiomyomatózy,
- MeSH
- dědičné nádorové syndromy diagnóza genetika komplikace MeSH
- fumarasa genetika MeSH
- karcinom z renálních buněk etiologie genetika patologie MeSH
- leiomyom * diagnóza etiologie patologie MeSH
- leiomyomatóza * diagnóza patologie vrozené MeSH
- lidé MeSH
- nádory dělohy genetika MeSH
- nádory kůže diagnóza etiologie genetika MeSH
- senioři MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Autorky prezentují případ mladého muže s bolestivými mnohočetnými tumory, které byly histologicky diagnostikovány jako mnohočetné piloleiomyomy. Jsou diskutovány typy leiomyomů včetně mnohočetného výskytu piloleiomyomů v rámci syndromu leiomatosis cutis et uteri (Reedův syndrom).
The authors present a case of a young man with multiple painful tumours that were diagnosed histologically as multiple pilar leiomyomas. Leiomyoma types are discussed including the occurence of multiple pilar leiomyoma as a part of familial leiomyomatosis cutis et uteri (Reed's syndrome).
- MeSH
- dědičné nádorové syndromy MeSH
- dospělí MeSH
- fumarasa genetika MeSH
- karcinom z renálních buněk diagnóza genetika MeSH
- leiomyom * diagnóza genetika chirurgie MeSH
- lidé MeSH
- nádorová bolest MeSH
- nádory kůže diagnóza chirurgie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Renal medullary carcinomas (RMCs) and collecting duct carcinomas (CDCs) are rare subsets of lethal high-stage, high-grade distal nephron-related adenocarcinomas with a predilection for the renal medullary region. Recent findings have established an emerging group of fumarate hydratase (FH)-deficient tumors related to hereditary leiomyomatosis and renal cell carcinoma (HLRCC-RCCs) syndrome within this morphologic spectrum. Recently developed, reliable ancillary testing has enabled consistent separation between these tumor types. Here, we present the clinicopathologic features and differences in the morphologic patterns between RMC, CDC, and FH-deficient RCC in consequence of these recent developments. This study included a total of 100 cases classified using contemporary criteria and ancillary tests. Thirty-three RMCs (SMARCB1/INI1-deficient, hemoglobinopathy), 38 CDCs (SMARCB1/INI1-retained), and 29 RCCs defined by the FH-deficient phenotype (FH/2SC or FH/2SC with FH mutation, regardless of HLRCC syndromic stigmata/history) were selected. The spectrum of morphologic patterns was critically evaluated, and the differences between the morphologic patterns present in the 3 groups were analyzed statistically. Twenty-five percent of cases initially diagnosed as CDC were reclassified as FH-deficient RCC on the basis of our contemporary diagnostic approach. Among the different overlapping morphologic patterns, sieve-like/cribriform and reticular/yolk sac tumor-like patterns favored RMCs, whereas intracystic papillary and tubulocystic patterns favored FH-deficient RCC. The tubulopapillary pattern favored both CDCs and FH-deficient RCCs, and the multinodular infiltrating papillary pattern favored CDCs. Infiltrating glandular and solid sheets/cords/nested patterns were not statistically different among the 3 groups. Viral inclusion-like macronucleoli, considered as a hallmark of HLRCC-RCCs, were observed significantly more frequently in FH-deficient RCCs. Despite the overlapping morphology found among these clinically aggressive infiltrating high-grade adenocarcinomas of the kidney, reproducible differences in morphology emerged between these categories after rigorous characterization. Finally, we recommend that definitive diagnosis of CDC should only be made if RMC and FH-deficient RCC are excluded.
- MeSH
- biopsie MeSH
- diferenciální diagnóza MeSH
- dítě MeSH
- dospělí MeSH
- dřeň ledvin enzymologie patologie MeSH
- fenotyp MeSH
- fumarasa nedostatek genetika MeSH
- genetická predispozice k nemoci MeSH
- imunohistochemie MeSH
- karcinom z renálních buněk klasifikace enzymologie genetika patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mutace MeSH
- mutační analýza DNA MeSH
- nádorové biomarkery nedostatek genetika MeSH
- nádory ledvin klasifikace enzymologie genetika patologie MeSH
- prediktivní hodnota testů MeSH
- retrospektivní studie MeSH
- sběrací ledvinové kanálky enzymologie patologie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- stupeň nádoru MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
- Geografické názvy
- Austrálie MeSH
- Brazílie MeSH
- Evropa MeSH
- Kanada MeSH
- Spojené státy americké MeSH
An emerging group of high-grade renal cell carcinomas (RCCs), particularly carcinomas arising in the hereditary leiomyomatosis renal cell carcinoma syndrome (HLRCC), show fumarate hydratase (FH) gene mutation and loss of function. On the basis of similar cytomorphology and clinicopathologic features between these tumors and cases described as tubulocystic carcinomas with poorly differentiated foci (TC-PD) of infiltrative adenocarcinoma, we hypothesized a relationship between these entities. First, 29 RCCs with morphology of TC-PD were identified retrospectively and assessed for FH expression and aberrant succination (2SC) by immunohistochemistry (IHC), with targeted next-generation sequencing of 409 genes-including FH-performed on a subset. The 29 TC-PD RCCs included 21 males and 8 females, aged 16 to 86 years (median, 46), with tumors measuring 3 to 21 cm (median, 9) arising in the right (n=16) and left (n=13) kidneys. Family history or stigmata of HLRCC were identifiable only retrospectively in 3 (12%). These tumors were aggressive, with 79% showing perinephric extension, nodal involvement in 41%, and metastasis in 86%. Of these, 16 (55%) demonstrated loss of FH by IHC (14/14 with positive 2SC). In contrast, 5 (17%) showed a wild-type immunoprofile of FH+/2SC-. An intriguing group of 8 (28%) showed variable FH± positivity, but with strong/diffuse 2SC+. Next-generation sequencing revealed 8 cases with FH mutations, including 5 FH-/2SC+ and 3 FH±/2SC+ cases, but none in FH+/2SC- cases. Secondly, we retrospectively reviewed the morphology of 2 well-characterized cohorts of RCCs with FH-deficiency determined by IHC or sequencing (n=23 and n=9), unselected for TC-PD pattern, identifying the TC-PD morphology in 10 (31%). We conclude that RCCs with TC-PD morphology are enriched for FH deficiency, and we recommend additional workup, including referral to genetic counseling, for prospective cases. In addition, based on these and other observations, we propose the term "FH-deficient RCC" as a provisional term for tumors with a combination of suggestive morphology and immunophenotype but where genetic confirmation is unavailable upon diagnosis. This term will serve as a provisional nomenclature that will enable triage of individual cases for genetic counseling and testing, while designating these cases for prospective studies of their relationship to HLRCC.
- MeSH
- dědičné nádorové syndromy patologie MeSH
- dospělí MeSH
- fumarasa nedostatek genetika MeSH
- imunohistochemie MeSH
- karcinom z renálních buněk enzymologie genetika patologie MeSH
- leiomyomatóza patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- multiplexová polymerázová řetězová reakce MeSH
- nádory dělohy patologie MeSH
- nádory kůže patologie MeSH
- nádory ledvin enzymologie genetika patologie MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- vysoce účinné nukleotidové sekvenování MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cell carcinomas (RCC) are difficult to diagnose prospectively. We used immunohistochemistry (IHC) to identify fumarate hydratase (FH)-deficient tumors (defined as FH negative, 2-succinocysteine [2SC] positive) in cases diagnosed as "unclassified RCC, high grade or with papillary pattern," or "papillary RCC type 2," from multiple institutions. A total of 124 tumors (from 118 patients) were evaluated by IHC for FH and 2SC. An FH deficiency was found in 24/124 (19%) cases. An indeterminate result (only 1 marker abnormal) was found in 27/124 (22%) cases. In a tissue microarray of 776 RCCs of different types, only 2 (0.5%) tumors, initially considered papillary type 2, were FH deficient. FH mutations were found in 19/21 FH-deficient tumors (with confirmed germline mutations in 9 of 9 tumors in which germline status could be assessed) and in 1/26 FH-indeterminate tumors identified by IHC. No FH mutations were found in 2/21 FH-deficient RCCs, 25/26 FH-indeterminate RCCs, and 10/10 RCCs demonstrating FH expression by IHC. Patients with FH-deficient RCC had a median age of 44 years (range, 21 to 65 y). Average tumor size was 8.2 cm (range, 0.9 to 18 cm). FH-deficient RCCs were characterized by at least focal macronucleoli and demonstrated 2 or more growth patterns in 93% cases. Papillary was the most common (74%) and dominant (59%) pattern, whereas other common patterns included: solid (44%), tubulocystic (41%), cribriform (41%), and cystic (33%). At presentation, 57% were stage ≥pT3, 52% had positive nodes, and 19% had distant metastases. After a mean follow-up of 27 months (range, 1 to 114 mo), 39% of patients were dead of disease, and 26% had disease progression. We conclude that FH and 2SC are useful IHC ancillary tools, which allow recognition of FH-deficient RCC.
- MeSH
- čipová analýza tkání MeSH
- cystein analogy a deriváty analýza biosyntéza MeSH
- dědičné nádorové syndromy diagnóza genetika patologie MeSH
- dospělí MeSH
- fumarasa nedostatek genetika MeSH
- imunohistochemie MeSH
- karcinom z renálních buněk diagnóza etiologie MeSH
- leiomyomatóza diagnóza genetika patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- nádory dělohy diagnóza genetika patologie MeSH
- nádory kůže diagnóza genetika patologie MeSH
- nádory ledvin diagnóza etiologie MeSH
- psychomotorické poruchy komplikace MeSH
- senioři MeSH
- svalová hypotonie komplikace MeSH
- vrozené poruchy metabolismu komplikace MeSH
- zárodečné mutace MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome secondary to germline fumarate hydratase (FH) mutation presents with cutaneous and uterine leiomyomas, and a distinctive aggressive renal carcinoma. Identification of HLRCC patients presenting first with uterine leiomyomas may allow early intervention for renal carcinoma. We reviewed the morphology and immunohistochemical (IHC) findings in patients with uterine leiomyomas and confirmed or presumed HLRCC. IHC was also performed on a tissue microarray of unselected uterine leiomyomas and leiomyosarcomas. FH-deficient leiomyomas underwent Sanger and massively parallel sequencing on formalin-fixed paraffin-embedded tissue. All 5 patients with HLRCC had at least 1 FH-deficient leiomyoma: defined as completely negative FH staining with positive internal controls. One percent (12/1152) of unselected uterine leiomyomas but 0 of 88 leiomyosarcomas were FH deficient. FH-deficient leiomyoma patients were younger (42.7 vs. 48.8 y, P=0.024) and commonly demonstrated a distinctive hemangiopericytomatous vasculature. Other features reported to be associated with FH-deficient leiomyomas (hypercellularity, nuclear atypia, inclusion-like nucleoli, stromal edema) were inconstantly present. Somatic FH mutations were identified in 6 of 10 informative unselected FH-deficient leiomyomas. None of these mutations were found in the germline. We conclude that, while the great majority of patients with HLRCC will have FH-deficient leiomyomas, 1% of all uterine leiomyomas are FH deficient usually due to somatic inactivation. Although IHC screening for FH may have a role in confirming patients at high risk for hereditary disease before genetic testing, prospective identification of FH-deficient leiomyomas is of limited clinical benefit in screening unselected patients because of the relatively high incidence of somatic mutations.
- MeSH
- čipová analýza tkání MeSH
- dospělí MeSH
- fenotyp MeSH
- fumarasa nedostatek genetika MeSH
- genetická predispozice k nemoci MeSH
- imunohistochemie MeSH
- leiomyomatóza enzymologie genetika patologie chirurgie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mutace MeSH
- mutační analýza DNA MeSH
- nádorové biomarkery nedostatek genetika MeSH
- nádory dělohy enzymologie genetika patologie chirurgie MeSH
- nádory kůže enzymologie genetika patologie chirurgie MeSH
- prognóza MeSH
- syndrom MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- hodnotící studie MeSH
- práce podpořená grantem MeSH
Zhoubné nádory ledvin tvoří přibližně 2 % všech nádorových onemocnění.Papilární renální karcinom je podle klasifikace WHO z roku 2004 samostatnou skupinou renálních karcinomů. Rozlišujeme 2 subtypy, papilární renální karcinom typ 1 a typ 2, které se vzájemně liší histologicky, geneticky, svým chováním i prognózou. Mimo sporadický výskyt jsou známy hereditární formy, jejichž studium přispívá k rozvoji nové cílené léčby. Současná cílená léčba u papilárních renálních karcinomů je obecně výrazně méně úspěšná než u konvenčního světlobuněčného karcinomu ledviny.
Malignant tumours of kidney form about 2 percent of the all malignancies. Papillary renal cell carcinoma (PRCC) is discrete group of renal cancers according to WHO 2004 classification. The papillary renal cell carcinomas are divided into two subtypes, type 1 and type 2. Both types differ from each other in histology, genetics, their behaviour and prognosis. There are hereditary forms of the papillary renal cell carcinomas except for sporadic forms of the PRCCs. Study of the hereditary forms contributes to discovery of new targeted therapy. Current targeted therapy is significantly less effective in patients with papillary renal cell carcinoma in comparison to patients with clear cell histology.
- MeSH
- fumarasa genetika MeSH
- geny p16 MeSH
- karcinom z renálních buněk * diagnóza epidemiologie genetika klasifikace patologie MeSH
- lidé MeSH
- mutace genetika MeSH
- nádory ledvin * diagnóza epidemiologie genetika klasifikace patologie MeSH
- přežití po terapii bez příznaků nemoci MeSH
- prognóza MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
