Updated Recommendations on the Diagnosis, Management, and Clinical Trial Eligibility Criteria for Patients With Renal Medullary Carcinoma

Abstract

Renal medullary carcinoma (RMC) is one of the most aggressive renal cell carcinomas. It predominantly afflicts young adults and adolescents with sickle cell trait and other sickle hemoglobinopathies, and is refractory to targeted and anti-angiogenic therapies used in patients with clear-cell renal cell carcinoma. Platinum-based cytotoxic chemotherapy is the mainstay for RMC treatment. Based on recent advances in the diagnosis, management, and clinical trial development for RMC, a panel of experts met in October 2017 and developed updated consensus recommendations to inform clinicians, researchers, and patients. Because RMC often aggressively recurs while patients are still recovering from nephrectomy, upfront chemotherapy should be considered for the majority of patients, including those with localized disease. After safety and dosing information have been established in adults, phase II and III trials enrolling patients with RMC should allow patients aged 12 years and older to be accrued. Patients with the very rare unclassified renal cell carcinoma with medullary phenotype variant should be included in RMC trials. Medical providers should be aware that RMC can afflict subjects of all races, and not only those of the African descent, and that the presence of sickle cell trait, or of other sickle hemoglobinopathies, can impact drug responses and toxicity.

Molecular hallmarks of renal medullary carcinoma: more to c-MYC than meets the eye

“…Renal medullary carcinoma (RMC) is a lethal renal cell carcinoma (RCC) that predominantly afflicts young individuals of African descent with sickle cell trait or other sickle hemoglobinopathies. 1 All RMC tumors demonstrate loss by immunohistochemistry of the potent tumor suppressor SMARCB1 (also known as INI1, hSNF5 or BAF47), a subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex. 2 The targeted therapies used for other RCCs are typically ineffective against RMC and the best available cytotoxic chemotherapies achieve a greater than 3 year overall survival in less than 5% of patients diagnosed with RMC.…”

“…2 The targeted therapies used for other RCCs are typically ineffective against RMC and the best available cytotoxic chemotherapies achieve a greater than 3 year overall survival in less than 5% of patients diagnosed with RMC. 1 There is clearly a need to develop new therapies informed by a deeper understanding of the biological pathways that drive RMC. We accordingly investigated the molecular landscape of RMC by performing comprehensive genomic and transcriptomic profiling of untreated primary RMC tisses.…”

“…CDC arises from the same anatomical epicenter within the renal medulla and is morphologically very similar to RMC but expresses SMARCB1 by immunohistochemistry and is not associated with sickle hemoglobinopathies. 1 – 3 UTUC originates anatomically close to the renal medulla and is treated with similar platinum-based cytotoxic chemotherapy regimens to those used for RMC. 1 MRT is negative for SMARCB1 by immunohistochemistry and can often arise from the kidney but morphologically appears like an undifferentiated rhabdoid malignancy, whereas RMC manifests as a high grade adenocarcinoma.…”

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“…The clinical presentation of RMC is more reminiscent of aggressive hematological malignancies, which often require a combination of drugs to achieve potent and durable responses. Indeed, the combination of bortezomib with cytotoxic chemotherapy achieved gratifying and durable responses in two pediatric patients with RMC [5], thus providing clinical evidence that combining proteasome inhibition with chemotherapy should be further investigated. Novel regimens combining Editorial proteasome inhibitors with gemcitabine and doxorubicin have recently been developed for the treatment of urothelial carcinoma [10].…”

“…This high penetrance and rapid transformation is rarely observed with the inactivation of other single genes in cancer biology and underscores the potent tumor suppressor role of SMARCB1. Inactivation of SMARCB1 is found in all cases of renal medullary carcinoma (RMC) and renal cell carcinoma unclassified with medullary phenotype (RCCU-MP); in the majority of malignant rhabdoid tumors (MRT), atypical teratoid/rhabdoid tumors (ATRT), and epithelioid sarcomas (ES); and in aggressive variants of pancreatic carcinomas, extraskeletal myxoid chondrosarcomas, sinonasal carcinomas, and primitive neuroectodermal tumors [3][4][5]. Notably, the two prototypical SMARCB1deficient malignancies, RMC and MRT, have very low mutation rates with SMARCB1 loss being the only recurrent event, suggesting that SMARCB1 inactivation is sufficient to drive these highly malignant tumors [3,6].…”