ACCME/Disclosures. M31078/07 Ondřej Hes 4/13/2016

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1 M31078/07 Ondřej Hes Department of Pathology Charles University and University Hospital Plzeň Bioptická laboratoř Plzeň Czech Republic ACCME/Disclosures The USCAP requires that anyone in a position to influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. Dr. Ondrej Hes declares no conflict(s) of interest to disclose. A 44 year old male. Tumor of the right kidney. Pleural effusion and fluid with malignant cells were revealed. CT scans showed retroperitoneal and mediastinal lymphadenopathy. Radical nephrectomy was performed. Tumor located in pole of the kidney, whitish on gross section. Diameter 8 cm, pt2. 1

2 Immunohistochemical and cytogenetical profile Diffusely positive: EMA, racemase (AMACR) Focally positive: CK 7, vimentin CANH 9, CK 20 negative VIM FISH: gains of chromosomes 7, 17, loss of Y AMACR 2

3 My diagnosis in 2007: high grade tubulocystic renal cell carcinoma Years passed Around new hot topic appeared in GU area HL RCC IHC: analyses using antibodies 2SC (S (2 succino) cysteine) and FH (fumarate hydratase) showed surprising results Analysis of FH gene was performed: Tumor showed a mutation of the FH gene: c.911_917delcttttgt, p.(phe305leufs*22). Kruger National Park, South Africa 2013 New diagnosis of hereditary leiomyomatosis associated RCC has been finally established Hereditary leiomyomatosis associated RCC Hereditary leiomyomatosis associated renal cell carcinoma (HLRCC) is not a new entity it was listed in the 2004 WHO classification (section hereditary renal cell carcinoma) Suggestion that HLRCC is a hereditary counterpart of type II PRCC. New informations Merino ( Am J Surg Pathol) 2007, Grubb ( J Urol) 2007 Everglades, Florida 3

4 Hereditary leiomyomatosis Leiomyoma associated with familiar leiomyomatosis Fumarate hydratase gene germline mutations (1q42), AD Associated with cutaneous and uterine leiomyomas (usually under age of 30) AND (OR?) HLRCC: Aggresive tumor with early metastatic activity Hereditary leiomyomatosis associated RCC HLRCC mostly papillary pattern, however spectrum is much more broader!!!! Tubulocystic, cribriform, alveolar and even cystic or solid 4

5 Eosinophilic macronucleoli with perinucleolar halo (immunophenotype and mutations in FH gene) Courtesy Dr. Jose Lopez, Bilbao Terminology Fumarate hydratasedeficient RCC (Trpkov Am J Surg Pathol 2016, Smith 2016?) FH, 2SC 2+ (associated with FH mutation) Close relationship of TC RCC and HL RCC? Possible HL RCC (Fumarate hydratase deficient RCC )? RCC with variable architecture, cca eosinophilic cells Prominent red nucleoli with halo (could be focal finding) Time to call genetist High likelihood of syndromic disease 5

6 Differential diagnostics vs urothelial lesion vs tubulocystic carcinoma vs collecting duct carcinoma vs conventional papillary RCC vs metastasis VS TCC Urothelial carcinoma of the renal pelvis with glandular differentiation CK 7, CK 20 (GATA 3, Uroplakin, PAX 8, ) High grade urothelial carcinomas are frequently associated with urothelial surface papillary component and/or show in situ carcinoma/dysplasia in the renal pelvis (sampling!) The presence of squamous or glandular differentiation are features favoring TCC. VS Tubulocystic RCC Usually Low grade lesion No prominent deeply red nucleoli More uniform architecture HL RCC Different immunoprofile (2Sc, FH) Absent FH gene mutation TC RCC 6

7 VS Collecting duct RCC High grade lesion with hobnail cells (mostly), triangular tubules Desmoplasia and inflammatory infiltrate Location in renal medulla Immunohistochemistry (2SC, FH) and lack of FH gene mutation VS Conventional PRCC Difficult Age + From morphology and IHC (2SC and FH) only suspect dg FH gene analysis is the most reliable tool VS Metastasis Other kidney tumors, where we have to call genetist Anamnesis IHC panel Again molecular genetics Translocation RCC, namely TFE3 (Xp11) SDH def RCC Tumors in BHD syndrome 7

8 Final remark 2007 patient was treated with 6cycles of gemcitabine and cisplatin chemotherapy. CT scans after 3rd treatment cycle showed disease stabilization. However, patient experienced disease progression after the 6th cycle in all affected area patient underwent treatment with sunitinib malate. After 2nd cycle of therapy, CT scan revealed regression of lymphadenopathy, pleural mass and effusion patient is alive (!) with residual disease (retroperitoneal lymph nodes) 9 years after nephrectomy. No signs of cutaneous leiomyomas (not yet) Fumarate hydratase deficient RCC? No VEGF, VHL, mtor, Hif1, Hif2!!!!!!!!!!!!!!! Thank you for your attention Around Čerchov, Czech Republic 8