Renal Cell Carcinoma: A Great Masquerader

Kidney and renal pelvis cancer is the twelfth leading cause of cancer death in the United States (1). Renal cell carcinoma (RCC) accounts for 85% of all renal neoplasms, with the clear cell subtype being identified in almost 4 out of 5 cases of RCC (2,3). The American Cancer Society predicts that there will be 81,610 new cases of kidney and renal pelvis cancer in 2024, and an estimated 14,390 people will die of this disease (1,4). Majority of the cases are  asymptomatic and often diagnosed on incident imaging studies done for a variety of other reasons (5). Hematuria or flank pain is the most common presenting symptom but is present in less than half of the cases of RCC, and 25% of symptomatic patients tend to have locally advanced or metastatic disease. 

A recent clinic case made me wonder if these patients are truly asymptomatic or if RCC is a “great masquerader.” A 56-year-old Caucasian gentleman with a history of hypertension was diagnosed as having secondary polycythemia (Hct 56-60% and elevated EPO levels) thought to be due to the use of testosterone supplementation and negative workup for polycythemia vera. Polycythemia persisted despite reducing the dose of testosterone supplementation. He had been undergoing periodic phlebotomies under the care of his hematologist for more than five years until he reported gross hematuria. At that time, he underwent an MRI of the kidneys, which showed an 11.6 cm mass involving the lower pole of the kidney with invasion of the left collecting renal system and associated retroperitoneal lymphadenopathy. He subsequently underwent radical left nephrectomy with retroperitoneal lymph node dissection and received tyrosine kinase inhibitor, axitinib and targeted immunotherapy with pembrolizumab. Interestingly, after tumor resection and subsequent immunotherapy, he was noted to have a resolution of polycythemia to the point that he no longer requires phlebotomy. “Could this be a case of delayed diagnosis, or is it a great masquerade by RCC?”

Paraneoplastic syndromes have been reported in 20-40% of cases of RCC (6), and the most common presentations include uncontrolled hypertension, hypercalcemia, and polycythemia ( defined as Hgb >16.5 g/dL/Hct >49% in euvolemic men or Hgb >16 g/dL/Hct >48% in euvolemic women). Almost 40% of patients with RCC manifest with hypertension, and 20% with hypercalcemia (7). Only less than 5% of all cases of RCC manifest with polycythemia,although 30-40%% of RCC may have elevated EPO levels without polycythemia and could be due to underlying iron deficiency or chronic inflammation that cause EPO hyporesponsiveness (8,9).The etiology of polycythemia in clear cell RCC is due to inactivating mutation of VHL gene, that results in upregulation of hypoxia inducible factorα (HIFα), even under non hypoxic conditions causing increased EPO production in the renal proximal tubule, causing increased blood production and, eventually, polycythemia (10).The majority of RCCs that present with polycythemia have the clear cell cancer subtype (4), which is the type this patient had on pathologic diagnosis. The presence of polycythemia in patients with RCC despite normal EPO levels has been reported and could be due to the production of the inactive form of EPO or due to significant tumor necrosis, thereby decreasing the EPO production (11,12).

Although it is common knowledge among nephrologists to evaluate for RCC in CKD/ESRD patients with polycythemia, it is often overlooked due to lack of symptoms and misattribution to other etiologies such as testosterone use, COPD or obstructive sleep apnea. Therefore, a thorough workup for secondary polycythemia should include imaging studies (US/CT/MRI of the abdomen and pelvis and/or MRI of the brain) to unmask cancers such as RCC, which are potentially curable, if detected early. 

References:

1. “Key statistics about kidney cancer.” Accessed: May 19, 2024. [Online]. Available: 

2. K. Garfield and C. A. LaGrange, Renal Cell Cancer. StatPearls Publishing, 2023.

3. “Cancer of the kidney and Renal Pelvis - Cancer stat facts,” SEER. Accessed: May 19, 2024. [Online].

4. A. M. Kase, D. J. George, and S. Ramalingam, “Clear Cell Renal Cell Carcinoma: From Biology to Treatment,” Cancers , vol. 15, no. 3, Jan. 2023, doi: 10.3390/cancers15030665.

5. K. M. Krajewski and I. Pedrosa, “Imaging Advances in the Management of Kidney Cancer,” J. Clin. Oncol., vol. 36, no. 36, p. JCO2018791236, Oct. 2018.

6. D. G. Skinner, R. B. Colvin, C. D. Vermillion, R. C. Pfister, and W. F. Leadbetter, “Diagnosis and management of renal cell carcinoma. A clinical and pathologic study of 309 cases,” Cancer, vol. 28, no. 5, pp. 1165–1177, Nov. 1971.

7. P. J. Gold, A. Fefer, and J. A. Thompson, “Paraneoplastic manifestations of renal cell carcinoma,” Semin. Urol. Oncol., vol. 14, no. 4, pp. 216–222, Nov. 1996.

8. K. Pepper et al., “Renal cell carcinoma presenting with paraneoplastic hypercalcemic coma: a case report and review of the literature,” J. Gen. Intern. Med., vol. 22, no. 7, pp. 1042–1046, Jul. 2007

9. J. L. Da Silva et al., “Tumor cells are the site of erythropoietin synthesis in human renal cancers associated with polycythemia,” Blood, vol. 75, no. 3, pp. 577–582, Feb. 1990.

10. C. L. Cowey and W. K. Rathmell, “VHL gene mutations in renal cell carcinoma: role as a biomarker of disease outcome and drug efficacy,” Curr. Oncol. Rep., vol. 11, no. 2, pp. 94–101, Mar. 2009.

11. K. Ito, T. Asano, S. Tominaga, H. Yoshii, H. Sawazaki, and T. Asano, “Erythropoietin production in renal cell carcinoma and renal cysts in autosomal dominant polycystic kidney disease in a chronic dialysis patient with polycythemia: A case report,” Oncol. Lett., vol. 8, no. 5, pp. 2032–2036, Nov. 2014.

12. J. Kopel, P. Sharma, I. Warriach, and S. Swarup, “Polycythemia with Renal Cell Carcinoma and Normal Erythropoietin Level,” Case Rep. Urol., vol. 2019, p. 3792514, Dec. 2019