What are the paraneoplastic manifestations of renal cell carcinoma (RCC)?

From the Guidelines

Paraneoplastic manifestations of renal cell carcinoma (RCC) include hypercalcaemia, unexplained fever, erythrocytosis, and Stauffer’s syndrome, which are relatively frequent and can resolve after kidney tumour resection. These manifestations are systemic symptoms and signs that occur due to substances released by the tumor rather than direct tumor invasion or metastasis. According to the ESMO clinical practice guidelines for diagnosis, treatment, and follow-up of RCC 1, suspicion of RCC should prompt laboratory examinations to identify these paraneoplastic syndromes. The guidelines recommend testing for serum creatinine, haemoglobin, leukocyte and platelet counts, lymphocyte to neutrophil ratio, lactate dehydrogenase, C-reactive protein (CRP), and serum-corrected calcium, which can help identify patients with paraneoplastic syndromes.

Some key paraneoplastic manifestations of RCC include:

• Hypercalcaemia
• Unexplained fever
• Erythrocytosis
• Stauffer’s syndrome, which is characterized by signs of cholestasis unrelated to tumour infiltration of the liver or intrinsic liver disease These manifestations can be prognostic for survival and are used for risk assessment, as stated in the guidelines 1. Recognition of these paraneoplastic syndromes is crucial, as they may be the presenting feature of RCC, can help in early diagnosis, and may serve as markers for disease recurrence during follow-up. Treatment primarily involves addressing the underlying cancer, and symptom-specific management may be necessary to improve patient outcomes.

From the Research

Paraneoplastic Manifestations of Renal Cell Carcinoma (RCC)

The paraneoplastic manifestations of RCC are diverse and can be present in up to 20% of patients with RCC 2. These manifestations can be categorized into:

• Endocrine paraneoplastic syndromes, such as ectopic production of parathyroid hormone-related protein or erythropoietin 2
• Nonendocrine paraneoplastic syndromes, including:
  • Constitutional symptoms: fever, cachexia, and weight loss 3
  • Metabolic and biochemical abnormalities: hypercalcemia, nonmetastatic hepatic dysfunction, amyloidosis 3
  • Other manifestations: anemia, polycythemia, recent-onset hypertension, and liver dysfunction 4

Incidence and Prognosis

The incidence of paraneoplastic syndromes in RCC varies, with some studies reporting:

• Hypercalcemia in 6.9% of patients 5
• Stauffer's syndrome in 11.9% of patients 5
• Hypertension in 15.8% of patients 5
• Anemia in 60.4% of patients 5
• Elevated erythrocyte sedimentation rate (ESR) in 55.4% of patients 5
• Persistent leukocytosis in 3.0% of patients 5 The presence of paraneoplastic syndromes has been associated with adverse prognosis in some studies, with patients having worse oncologic outcomes compared to those without paraneoplastic syndromes 4, 5. However, other studies have found that the adverse outcome associated with paraneoplastic syndromes may be largely explained by adverse pathologic features of the tumors 4.

Clinical Significance

Paraneoplastic syndromes can be the initial clinical presentation of RCC in a significant number of patients, and recognition of these syndromes may facilitate early diagnosis 2, 3. Furthermore, the presence of paraneoplastic syndromes can be used as a "neoplastic tumor marker" to aid in the diagnosis and management of RCC, particularly in cases of recurrence 6.