Diagnostic challenges of renal medullary carcinoma and the role for cytologic assessment: Case report and literature review

Abstract Background Renal medullary carcinoma (RMC) is a diagnostically challenging, aggressive primary renal malignancy associated with abysmal survival. Delays in diagnosis contribute to most patients having diffusely metastatic disease at the time of initial presentation. Methods We present the case of a 13‐year‐old African American male with sickle cell trait who presented with a renal mass and hematuria. Evaluation included imaging, fluid cultures, and cytologic assessment. Results Patient was diagnosed with RMC based on cytologic assessment of sub‐centimeter fluid collections aspirated from the left kidney at the time of cortical biopsy for suspected renal mass. The additional fluid aspiration in conjunction with renal biopsy was an atypical but crucial step in early diagnosis. Conclusion Cytomorphologic evaluation of fluid biospecimens is not currently part of the standard work‐up for patients with renal masses but, when available, can provide crucial information that reduces time to diagnosis. Prompt symptom recognition and treatment initiation may improve patient outcomes.

However, follow-up CT scan 6 months later revealed progression of his pulmonary metastases. Subsequently, he was started on oral erlotinib and intravenous bevacizumab, with decreased size and reduced fluorodeoxyglucose avidity of the pulmonary nodules on his most recent scans 20 months from diagnosis.

| DISCUSS ION
Patients with RMC most often present in the second to third decade of life. 6,7 In the pediatric age group, the median age at diagnosis is 13 years. 8 The large majority of patients with RMC have sickle cell trait or other related hemoglobinopathies. The pathophysiologic mechanism driving RMC tumorigenesis remains elusive. A leading hypothesis posits that a chronically hypoxic environment in the renal pelvis exacerbates the sickling of cells, triggering local inflammation, necrosis, cellular damage, and eventually the development of RMC from the calyceal epithelium. 4,9 The hallmark molecular alteration seen in RMC is inactivation of the SMARCB1 (INI) tumor suppressor gene on chromosome 22 due to chromosomal translocations or deletions. 6,[9][10][11][12] The typical presenting symptoms of RMC include hematuria, flank pain, and/or an abdominal mass. 4 Given the aggressive nature of the disease, systemic symptoms such as weight loss and fatigue are common findings. 24 Most patients present with evidence of metastatic disease at diagnosis. In a pooled analysis of 166 patients, 71% had at least localized metastasis. 24 The regional lymph nodes, liver, lungs, bone, and adrenal glands comprise the most common sites of metastasis. Some patients may have a suspected renal abscess or urinary tract infection and may present without a clinically recognizable mass.
Due to this variable presentation, full body screening remains imperative to staging RMC. The diagnostic work-up typically consists of radiographic imaging with CT of the chest, abdomen, and pelvis often demonstrating a unilateral renal mass with distant metastatic spread. However, the lack of clearly defined radiographic features and the absence of a standardized imaging approach complicates the diagnosis of RMC. 8,13 Lesions often appear as hypovascular, infiltrative, poorly defined solid masses occupying the renal medulla and lying adjacent to the pelvicalyceal system. 14  positive for PAX8, broad-spectrum keratins, epithelial membrane antigen, and vimentin. They were also negative for INI1, though they are certainly not the only tumor (nor the only renal tumor) to show INI1 loss. 15 The differential diagnosis of RMC can be organized based on age, 16 location, 9 cytologic features, 17     Previous "unclassified renal cell carcinoma with medullary phenotype" morphologically identical to renal medullary carcinoma but without any hemoglobinopathy (now regarded as a subtype of SMARCB1-deficient renal cell carcinoma with medullary-like features or phenotype) Renal medullary carcinoma: loosely cohesive or two-dimensional clusters and individual cells (no true papillary structures) with an epithelial appearance, high nuclear: cytoplasmic ratio, often eccentrically placed nuclei, marked nuclear pleomorphism, irregular nuclear membranes, finely granular to vesicular chromatin, one to several prominent nucleoli, and dense, frequently vacuolated cytoplasm with sharp cytoplasmic borders Collecting duct carcinoma: two-or three-dimensional groups of cells with papillary configuration, moderate nuclear pleomorphism, irregular nuclear membranes, coarse chromatin, prominent nuclei, and vacuolated cytoplasm

ACK N OWLED G M ENTS
We express gratitude to Kathy Zeblisky and Angela Garcia for their meaningful contributions throughout the manuscript preparation and revision process.

CO N FLI C T O F I NTE R E S T S TATE M E NT
No authors have conflicts of interest to declare.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.