What is Paraneoplastic Polycythemia?
Paraneoplastic polycythemia is a true increase in red blood cell mass caused by autonomous, pathologic production of erythropoietin (EPO) by malignant or benign tumors, independent of the body's normal oxygen-sensing mechanisms. 1
Mechanism and Pathophysiology
Paraneoplastic polycythemia represents a hypoxia-independent form of secondary polycythemia where tumors produce EPO autonomously, leading to unregulated erythropoiesis regardless of tissue oxygen levels. 1 This distinguishes it from hypoxia-driven secondary polycythemia (chronic lung disease, sleep apnea, high altitude) where EPO production is an appropriate physiologic response to low oxygen. 1
The key mechanistic feature is that tumor cells synthesize and secrete EPO or EPO-like substances that stimulate bone marrow erythroid progenitors, resulting in excessive red blood cell production. 1, 2 Some tumors may produce molecules with biological activity similar to EPO but with different molecular structures that may not be detected by standard radioimmunoassay. 2
Tumors That Cause Paraneoplastic Polycythemia
Malignant Tumors
- Renal cell carcinoma (most common malignant cause) 1, 2, 3
- Hepatocellular carcinoma 1, 4
- Parathyroid carcinoma 1
- Cerebellar hemangioblastoma 3
- Testicular seminoma (rare) 5
Benign Tumors
Clinical Context: Patient Over 40 with Elevated RBC Count and Hoarse Voice
In a patient over 40 presenting with polycythemia and hoarse voice, the combination strongly suggests renal cell carcinoma as the underlying malignancy. 1 Hoarseness can result from laryngeal nerve involvement by mediastinal lymphadenopathy from metastatic disease or direct tumor extension.
The diagnostic workup should include:
- Serum EPO level - typically elevated or high-normal in paraneoplastic polycythemia 1, 2
- Abdominal ultrasound or CT scan to screen for renal cell carcinoma, hepatocellular carcinoma, and other EPO-producing tumors 1
- JAK2 V617F mutation testing - should be negative (this mutation is present in >95% of polycythemia vera cases, helping exclude primary polycythemia) 1
- Chest X-ray or CT to evaluate for lung masses, mediastinal adenopathy explaining hoarseness, and to exclude hypoxia-driven causes 1
Diagnostic Pitfalls to Avoid
Do not assume polycythemia vera without checking EPO levels. 1 The presence of elevated hemoglobin/hematocrit with a suspected tumor requires measurement of serum EPO to distinguish primary from secondary polycythemia, as missing this distinction could lead to inappropriate treatment with phlebotomy or cytoreductive therapy when the underlying cause is tumor-related EPO production. 1
Be aware that EPO levels may be elevated, high-normal, or even within normal range in paraneoplastic polycythemia. 1, 2, 4 In one study of hepatocellular carcinoma, 23% of patients had elevated serum EPO concentrations, but only one of these patients had overt erythrocytosis, suggesting that advanced malignancy can inhibit erythropoiesis despite high EPO levels. 4 Additionally, tumor-produced EPO may not always be biologically active. 4
The overlapping EPO values between healthy patients, polycythemia vera, and secondary polycythemia can create diagnostic confusion. 2 Therefore, EPO levels must be interpreted in conjunction with clinical context, imaging findings, and JAK2 mutation status rather than in isolation.
Treatment Implications
Treatment of paraneoplastic polycythemia is directed at the underlying tumor. 2, 5 Surgical resection of the EPO-producing tumor typically results in spontaneous resolution of the polycythemia. 5 In the case of renal cell carcinoma with hoarseness suggesting advanced disease, oncologic evaluation for staging and treatment planning (surgery, targeted therapy, immunotherapy) takes priority over managing the polycythemia itself.