Although all sickle hemoglobinopathies are associated with RMC, the vast majority of patients with RMC have sickle cell trait (SCT) and only a handful of cases have been documented in patients with homozygous sickle cell disease, hemoglobin SC disease, or sickle beta thalassemia. This may be due to the much higher population genotype rates of SCT (8.3% in the United states) compared with sickle cell disease (0.15%). Approximately 1 in 14 African Americans have SCT, and between 1/20,000 to 1/39,000 will develop RMC. SCT is found in approximately 300 million individuals worldwide.
RMC is more likely to arise from the right (~70% of cases) compared with the left kidney. Notably, other renal manifestations of sickle cell trait such hematuria predominantly arise from the left kidney due to the compression of the left renal vein between the aorta and superior mesenteric artery which causes relative anoxia in the renal medulla and thus promotes sickling, an effect known as the nutcracker phenomenon. One explanation for this discrepancy in the laterality of sickle nephropathies and RMC may be that the driver of RMC pathogenesis is regional ischemia induced by red blood cell sickling in the medullary vasa recta. Anatomical differences in the right vs. the left renal artery may result in reduced blood flow and increased viscosity from red blood cell sickling in the right renal inner medulla. Sex differences in the propensity for regional ischemia among individuals with sickle hemoglobinopathies may also explain why RMC is two times more frequent in men than women.
Renal medullary RMC occurs in young patients (<50 years old) with SCT who most commonly present with hematuria and/or flank pain in ~66% cases, and about half will have constitutional symptoms such as unintentional weight loss or, less commonly, night sweats (read more here). Histologically, RMC presents as a high-grade, poorly differentiated adenocarcinoma containing focal anastomosing tubules and cords with a reticular and cribriform appearance, as well as a myxoid highly desmoplastic stroma with neutrophil infiltrates and microabscess-like foci. Sickle red blood cells in the tumor specimen confirm the diagnosis. Immunohistochemistry demonstrates loss of INI1 (also known as SMARCB1, BAF47 and hSNF5) and, in many cases, expression of the stem cell marker OCT3/4. CT imaging at presentation will demonstrate an ill-defined heterogeneous mass, arising from the renal medulla, more frequently in the right kidney, with intratumoral necrosis, an average size of 6-7 centimeters, and lower contrast enhancement than the renal cortex and medulla during all phases.
RMC should be part of the differential diagnosis in all young patients with sickle cell hemoglobinopathy who present with a renal cell carcinoma. It is particularly important to distinguish RMC from other kidney malignancies because RMC is refractory to targeted therapies that are effective in clear cell renal cell carcinoma or other non-clear cell renal cell carcinomas. The histologic and clinical similarities between RMC and collecting duct carcinoma may also pose diagnostic difficulties. Because SMARCB1 loss can be seen in other malignancies, absence of SMARCB1 expression cannot on its own be the defining characteristic of RMC. On the other hand, intact SMARCB1 nuclear expression by immunohistochemistry should exclude the diagnosis of RMC in all cases. The major difference between collecting duct carcinoma and RMC is that the latter occurs only in patients with a sickle cell hemoglobinopathy. Therefore, a diagnosis of RMC can be made on the basis of appropriate histological findings (including loss of SMARCB1 expression) in patients with sickle cell hemoglobinopathy.
Furthermore, it has been proposed that patients with no evidence of hemoglobinopathy who present with high-grade renal adenocarcinomas with loss of SMARCB1 expression (and/or presence of OCT3/4 expression) should be diagnosed with “unclassified renal cell carcinoma with medullary phenotype” (RCCU-MP).
A diagnostic algorithm for RMC and RCCU-MP (adapted from here) is shown below:
Additional information regarding our current recommendations on the diagnosis, management, and clinical trial eligibility criteria for patients with renal medullary carcinoma can be found in the following articles: