Amin MB, Smith SC, Agaimy A, et al. hemoglobinopathies, and if positive, SMARCB1/INI1 loss should be confirmed by immunohistochemistry. The majority of patients with RMC are diagnosed with metastatic disease. Upfront radical nephrectomy should be considered in patients with good performance status and low metastatic burden or after response to systemic therapy. Currently, cytotoxic, platinum-based chemotherapy provides the best, albeit brief, palliative clinical benefit. Vascular endothelial growth factorCdirected therapies and mammalian target of rapamycin inhibitors are ineffective in RMC as monotherapy. Therapeutic trials of novel agents are now available for RMC, and every effort should be made to enroll patients in clinical studies. INTRODUCTION Renal medullary carcinoma (RMC) is a rare and particularly devastating disease that affects adolescents and young adults. In April 2016, a small international group of investigators that represented pathology, pediatric and medical oncology, urology, nephrology, hematology, cancer genomics, and therapeutic development interests in RMC gathered in Nashville, Tennessee, to discuss the status Rabbit polyclonal to ANKRD45 of this disease biologically and clinically to take the next steps in developing diagnostic and treatment algorithms for RMC. EPIDEMIOLOGY AND NATURAL HISTORY Sickle cell trait (SCT) affects 300 million people worldwide, with the largest number in sub-Saharan Africa.1 However, prevalence rates vary widely, from 8% in African Americans to 10% to 20% in India, 20% in the Middle East, and as high as 20% to 40% in some parts of Africa.2,3 Life expectancy with SCT has been similar to that of unaffected individuals in American cohorts.4 However, SCT is a risk factor for several conditions, including chronic kidney disease,5 venous thromboembolism,6 and sudden death.7 The kidney is perhaps the organ most affected by SCT. In 1974, Berman8 described six nephropathies in SCT: hematuria secondary to bleeding beneath the renal pelvic urothelium, papillary necrosis, nephrotic syndrome, renal infarction, hyposthenuria, and pyelonephritis. In 1995, Davis et al9 described a distinctive subtype of renal cell carcinoma, RMC, that occurs almost exclusively in patients with SCT and termed it the seventh sickle cell nephropathy. Since, RMC has been recognized as a highly aggressive neoplasm almost exclusively associated with SCT (hemoglobin AS [HbAS]), although a few cases have been reported in individuals with homozygous SS disease (sickle cell anemia),10,11 HbS/-thalassemia,12 and HbSC.10,12 RMC is an extremely rare tumor Apixaban (BMS-562247-01) and comprises 0.5% of all renal carcinomas. However, its prevalence may be underestimated because underdiagnosis occurs as a result of difficulty in differentiating RMC from collecting duct carcinoma and other aggressive renal malignancies on the basis of standard histology evaluation (Table 1).13 RMC is increasingly recognized in the Americas and Europe, but no information exists about its prevalence in sub-Saharan Africa, where SCT is endemic. Table 1. Differential Diagnosis of RMC Open in a separate window RMC affects primarily adolescents and young adults. Most patients present between the ages of 11 and 39 years and either already have a diagnosis of SCT or are given a diagnosis of SCT during work-up for RMC.14 The most common presenting symptoms for RMC are gross hematuria, flank pain, and abdominal masses.15 Males are disproportionately affected in a ratio of 2:1.11,16 For unknown reasons, RMC has a predilection for the right-side kidney.8,14 RMC is characterized by early and widespread metastases, and thus, most cases are diagnosed in late stages, and prognosis is poor.16 In the initial series by Davis et al,9 the median survival was 4 months. Even with chemotherapy and surgery, outcomes remain dismal, with a median survival of approximately 13 months. BIOLOGY RMC is believed to arise from the renal papillae or calyceal epithelium and may be triggered by chronic medullary hypoxia as a result of sickled red cells in individuals with HbS and is suggested by strong expression of vascular endothelial growth factor and hypoxia-inducible factor,17 although the mechanism has not been demonstrated conclusively. A critical finding in RMC is the loss of SMARCB1/INI1 in the switch/sucrose nonfermentable (SWI/SNF) complex, a key mediator of chromatin remodeling and modulation of transcriptional activity.18-20 Biallelic loss of SMARCB1/INI1 is a hallmark feature in several childhood cancers, including malignant rhabdoid tumor.[PubMed] [Google Scholar] 14. with RMC are diagnosed with metastatic disease. Upfront radical nephrectomy should be considered in patients with good performance status and low metastatic burden or after response to systemic therapy. Currently, cytotoxic, platinum-based chemotherapy provides the best, albeit brief, palliative clinical benefit. Vascular endothelial growth factorCdirected therapies and mammalian target of rapamycin inhibitors are ineffective in RMC as monotherapy. Therapeutic trials of novel agents are now available for RMC, and every effort should be made to enroll patients in clinical studies. INTRODUCTION Renal medullary carcinoma (RMC) is a rare and particularly devastating disease that affects adolescents and young adults. In April 2016, a small international group of investigators that represented pathology, pediatric and medical oncology, urology, nephrology, hematology, cancer genomics, and therapeutic development interests in RMC gathered in Nashville, Tennessee, to discuss the status of this disease biologically and clinically to take the next steps in developing diagnostic and treatment algorithms for RMC. EPIDEMIOLOGY AND NATURAL HISTORY Sickle cell trait (SCT) affects 300 million people worldwide, with the largest number in sub-Saharan Africa.1 However, prevalence rates vary widely, from 8% in African Americans to 10% to 20% in India, 20% in the Middle East, and as high as 20% to 40% in some parts of Africa.2,3 Life expectancy with SCT has been similar to that of unaffected individuals in American cohorts.4 However, SCT is a risk factor for several conditions, including chronic kidney disease,5 venous thromboembolism,6 and sudden death.7 The kidney is perhaps the organ most affected by SCT. In 1974, Berman8 described six nephropathies in SCT: hematuria secondary to bleeding beneath the renal pelvic urothelium, papillary necrosis, nephrotic syndrome, renal infarction, hyposthenuria, and pyelonephritis. In 1995, Davis et al9 described a distinctive subtype of renal cell carcinoma, RMC, that occurs almost exclusively in patients with SCT and termed it the seventh sickle cell nephropathy. Since, RMC has been recognized as a highly aggressive neoplasm almost exclusively associated with Apixaban (BMS-562247-01) SCT (hemoglobin AS [HbAS]), although a few cases have been reported in individuals with homozygous SS disease (sickle cell anemia),10,11 HbS/-thalassemia,12 and HbSC.10,12 RMC is an extremely rare tumor and comprises 0.5% of all renal carcinomas. However, its prevalence may be underestimated because underdiagnosis occurs as a result of difficulty in differentiating RMC from collecting duct carcinoma and other aggressive renal malignancies on the basis of standard histology evaluation (Table 1).13 RMC is increasingly recognized in the Americas and Europe, but no information exists about its prevalence in sub-Saharan Africa, where SCT is endemic. Table 1. Differential Diagnosis of RMC Open in a separate window RMC affects primarily adolescents and young adults. Most patients present between the ages of 11 and 39 years and either already have a diagnosis of SCT or are given a diagnosis of SCT during work-up for RMC.14 The most common presenting symptoms for RMC are gross hematuria, flank pain, and abdominal masses.15 Males are disproportionately affected in a ratio of 2:1.11,16 For unknown reasons, RMC has a predilection for the right-side kidney.8,14 RMC is characterized by early and widespread metastases, and thus, most cases are diagnosed in late stages, and prognosis is poor.16 In the initial series by Davis et al,9 the median survival was 4 months. Even with chemotherapy and surgery, outcomes remain dismal, with a median survival of approximately 13 months. BIOLOGY RMC is believed to arise from the renal papillae or calyceal Apixaban (BMS-562247-01) epithelium and may be triggered by chronic medullary hypoxia as a result of sickled red cells in individuals with HbS and is suggested by strong expression of vascular endothelial growth factor and hypoxia-inducible factor,17 although the mechanism has not been demonstrated conclusively. A critical finding in RMC is the loss of SMARCB1/INI1 in the switch/sucrose nonfermentable (SWI/SNF) complex, a key mediator of chromatin remodeling and modulation of transcriptional activity.18-20 Biallelic loss of SMARCB1/INI1 is a hallmark feature in several childhood cancers, including malignant rhabdoid tumor of the kidney and atypical teratoid/rhabdoid tumor.21-23 Furthermore, next-generation sequencing of many human neoplasms offers revealed biallelic loss, loss of heterozygosity, or a high mutational frequency of various subunits of the SWI/SNF complex, which suggests a tumor suppressor part for SWI/SNF complex function.24,25 Loss of SWI/SNF activity may be one step along the pathogenesis of RMC, but whether it is by itself sufficient for transformation remains unclear. Given the prevalence of this genomic alteration like a defining feature of the disease, the loss of SMARCB1/INI1 is almost certainly a major traveling.