Renal Medullary Carcinoma in an Adolescent with Homozygous Hemoglobin SS
Authors: Marsh Anne M. , Quirolo Keith C. , Golden Carla , Vichinsky Elliott 
Published: October 2019

Abstract
Abstract 4774
Renal medullary carcinoma (RMC) is a highly aggressive malignant neoplasm originally thought to be unique to individuals with sickle cell trait (SCT). Common symptoms include hematuria, abdominal pain, and weight loss. The disease is usually metastatic at presentation and is almost universally fatal within months of diagnosis. Herein, we describe an adolescent with homozygous hemoglobin SS (Hgb SS) and RMC. This is the third case of RMC reported in Hgb SS, and the first case with prior hydroxyurea therapy (Dimashkieh Arch Pathol Lab Med 2003 and Swartz Urology 2002). In addition to five reported cases in individuals with hemoglobin SC, it now appears that RMC is not unique to individuals with SCT and should instead be considered more inclusively related to the family of sickle hemoglobinopathies (Davis Am J Surg Pathol 1995, Luthra Intern Med 2010, Baig J Natl Med Assoc 2006, Swartz Urology 2002).
A 13 year-old African American male with Hgb SS, treated with hydroxyurea since 2 months of age, presented with a several month history of recurrent abdominal pain and microscopic hematuria. An abdominal ultrasound demonstrated normal appearing kidneys that measured 8.4 cm and 9.7 cm on the right and left sides, respectively. He continued to have abdominal pain, often associated with intermittent sickle cell extremity pain. A repeat sonogram was obtained 9 months after the initial ultrasound due to a new complaint of scrotal pain. The formerly normal left kidney now had a 5 cm mass in the mid-to-lower pole, along with moderate caliceal dilation and cortical thinning of the superior pole. Computed tomography (CT) and positron emission tomography scans confirmed the renal mass along with local invasion into the psoas muscle, liver metastases, pulmonary metastases, and retroperitoneal lymphadenopathy.
Multiple core needle biopsy specimens were obtained from the left kidney, diagnostic of RMC. Histopathology showed widespread areas of necrosis with only a few areas of viable tumor. The viable tumor cells formed gland-like structures and had infiltrating sheets with rhabdoid features, eosinophilic cytoplasm, and prominent nucleoli. Immunohistochemical analysis demonstrated strong positivity for EMA, P53 (>95%), and PAX8. CD117 was mostly negative, however there were focal areas of weak cytoplasmic reactivity. ALK-1 immunostain, INI-1, p63, and hepar-1 were all negative. Fluorescence in situ hybridization showed no evidence of t(9;22) BCR;ABL rearrangement but did show extra copies of the BCR gene in 73% of cells.
Neoadjuvant chemotherapy with 3 cycles of carboplatin, gemcitabine, and paclitaxel and one cycle of carboplatin, gemcitabine and bortezomib resulted in an improvement on imaging in the primary tumor and metastatic sites. A left radical nephrectomy and lymph node dissection were then performed. Pathology showed 10–20% focally viable renal medullary carcinoma within the kidney with evidence of vascular invasion and positive margins. The sampled lymph nodes were free of tumor. Several weeks later he underwent thoracoscopic resection of left pleural and pulmonary nodules, both of which were positive for metastatic disease.
Over the next 11 months, he received 5 cycles of chemotherapy consisting of alternating cycles of carboplatin, gemcitabine, paclitaxel and carboplatin, gemcitabine and bortezomib, followed by 5 additional cycles of methotrexate, vinblastine, doxorubicin and cisplatin. Palliative radiation therapy delivered to the psoas muscle for pain management was beneficial. After a brief initial response to therapy, interval imaging studies demonstrated stable disease followed by subsequent florid progression. Given disease progression, his therapy was changed to the tyrosine kinase and vascular endothelial growth factor receptor antagonist, axitinib. Sixteen months from the time diagnosis, he is ambulatory but with widespread metastatic disease.
This case highlights the need for a heightened index of suspicion for RMC in all patients with sickle hemoglobinopathies, not just those with SCT. The lack of sensitivity of renal ultrasound in this case and two others suggests that CT may be required for early diagnosis of RMC (Blitman AJR 2005 and Wesche Pediatr Pathol Lab Med 1998). While hydroxyurea is an effective medication with an excellent safety margin in sickle cell disease, the carcinogenic risk of long-term exposure in sick cell disease remains unknown.

Disclosures:
Off Label Use: Hydroxyurea for sickle cell disease modulation.