Collecting Duct Renal Cell Carcinomas

Transcription

1 Collecting Duct Renal Cell Carcinomas Gabriel G. Malouf, MD, PhD Department of Medical Oncology Pitié-Salpêtrière Hospital Paris, France Fourteenth International Kidney Cancer Symposium Miami, Florida, USA November 6-7,

2 Renal cell carcinoma subtypes Conventional (clear cell) * (~75%) Non-clear cell * (~25%) Papillary 1 & 2 Chromophobe Translocation (TFE3/TFEB) Unclassified Oncocytoma Mucinous tubular and spindle cell, thyroid-like follicular carcinoma of the kidney (<1%) Renal medullary (<1%) Collecting duct (Bellini s tumor) (<1%) * Sarcomatoid dedifferentiation

3 Imaging features of CDC Pickhardt et al. (2001) (n=17) 1 Medullary involvement (94%) Infiltrative appearance (65%) Cystic component (35%) Yoon et al. (2006) (n=18) 2 Medullary location (94%) Weak (69%) and heterogenous (85%) enhancement Involvement of the renal sinus (94%) and infiltrative growth (50%) Preserved renal contour (61%) and cystic component (50%) 1 Pickhardt et al. AJR Yoon et al. Eur J Radiol. 2006

4 Ontogeny of renal cell carcinomas subtypes Oosterwijk et al. Eur Urol, 2011

5 How to diagnose CDC? Gold standard of diagnosis remains pathology. Several markers have been recently described as differentially expressed between CDC and upper-tumor urothelial carcinomas (UTUC) as GATA3, P63 and PAX8, however few of them were assessed in published clinical series which report natural history of the disease and patients outcome. PAX8+/GATA3- or p63- CDC (sens. 94% - specif.100%) PAX8-/GATA3+ or p63+ UTUC (sens. 84% - specif.100%) Gonzalez-Roibon et al. Hum Pathol. 2013

6 Natural history and outcome No risk factor for CDC has been identified. ~400 cases reported in the literature including 1/3 from Japan. CDC represent a lethal subtypes of RCC which often present at an advanced stage with up to 54% of cases showing metastatic spread at initial presentation (Kwon et al. 2014) Overall survival is estimated to be less than one year in metastatic setting. Efficacy of targeted agents is poor, although there have been reports suggesting efficacy of VEGF-targeted agents. However, the rational behind is lacking (Pecuchet et al. 2013) As compared to other RCC subtypes which genetics have been extensively analyzed, no report so far investigated genome-wide genetic and epigenetic driving genetic and epigenetic alterations in this disease.

7 Korean Cancer Study Group Patients characteristics Overall Survival Kwon et al. Cancer Res Treat, 2014

8 French-Italien Study Group Karakiewicz et al. Eur Urol, 2007

9 French multicenter study Seventeen patients with pathological diagnosis of CDC centrally reviewed were identified from 7 French institutions. Median age was 61.5 years (range: years) similar to classical clearcell RCC. There were male predominance with sex ratio male/female of 2:1. The majority of primary tumors (n=13/17) were located in the right kidney. All except two patients had radical nephrectomy. All but one patient were stage III-IV, with a total of 44% of them presenting with distant metastasis at initial presentation. Out of those, we succeeded in extracting RNA of good quality from 11 cases which were suitable for RNAseq

10 Unique transcriptomic profile of CDC as compared to upper-tumor urothelial carcinomas and normal kidneys Malouf et et al. submitted

11 Unique signature of CDC as compared to other RCC subtypes and bladder carcinomas Malouf et et al. submitted

12 Differentially expressed genes between collecting duct carcinomas and upper-tumor urothelial carcinomas Up-regulated genes (n=1,886)* Down-regulated genes (n=823) *Up-regulated genes were those with fold change 2 in CDC vs UTUC, FDR<0.05 Down-regulated genes were those with fold change 2 in CDC vs UTUC, FDR<0.05 Malouf et et al. submitted

13 Activation of mesenchymal signature in collecting ducts carcinomas CHARAFE_BREAST_CANCER_LUMINAL_VS_MESENCHYMAL_UP P=0.006 Malouf et et al. submitted

14 Conclusion CDC is an orphan subtype of RCC which often presents at an advanced stage. Diagnosis of CDC might be challenging hampering description of the natural history of the disease. The majority of series reported to data did not include central pathological review of the tumors with appropriate immuhistochemical staining. CDC display a unique gene expression pattern as compared to upper-tumor urothelial carcinomas. Up-regulated genes in CDC are related to response to wounding and activation of the immune system. Targeting immune checkpoints and/or TFG-β pathway might represent new avenues for patients in this setting. International collaborative studies are urgently needed to decipher genetic and epigenetic alterations of this orphan disease.

15 Acknowledgments Pitié-Salpêtrière Hospital, Paris, France Pr David Khayat Pr Jean-Philippe Spano Dr Eva Compérat Pr Morgan Rouprêt Fondation AVEC laboratory Dr Roger Mouawad, PhD Frédérick Allanick Dr Souheyla Bensalma, PhD Dr Linda Denaise, MD, PhDc Dr Marion Classe, MD, PhDc Dr Ronan Flippot, MD CHU Lille, France Pr Xavier Leroy Necker Hospital, Paris, France: Dr Virginie Verkarre CHU Bordeaux, France Dr Jean-Christophe Bernhard CHU Rennes, France: Pr Nathalie Rioux-Leclercq CHU Grenoble, France: Dr Valentin Arnoux CHU Strasbourg: Dr Véronique Lindner Dr Philippe Barthélémy MD Anderson Cancer Center, Houston, USA Pr Nizar M. Tannir (medical oncology) Dr Xiaoping Su (Bionformatics) Dr Hui Yao (Bionformatics) The patients and their families