Background: Secondary erythrocytosis (SE) refers to elevated hemoglobin (>160 g/L in women or >165 g/L in men) not due to an underlying myeloproliferative neoplasm. Paraneoplastic or tumor-associated erythrocytosis (TAE) is a rare cause of SE, with limited data on associated tumor types, management, and outcomes such as thrombosis. We conducted a systematic review of the literature on TAE to describe its diagnosis, management, and outcomes.

Methods: This systematic review was a substudy of a preregistered review in PROSPERO (CRD42024508643) and followed PRISMA guidelines. A systematic search was conducted in MEDLINE, EMBASE, CENTRAL (via Ovid), and Google Scholar. We included studies involving adult patients (≥18 years) published between January 2005 and February 2025. Titles and abstracts were independently screened by two reviewers, with disagreements resolved by a third reviewer. Data on diagnosis, management and outcomes of TAE were extracted and synthesized following SWiM (synthesis without meta-analysis) guidelines.

Results: Of 3,231 eligible records, 14 met the inclusion criteria, including 10 case reports/series and 4 retrospective cohort studies, comprising a total of 100 reported cases of TAE. 50% of patients were female, with a mean age of 47.4 years, among patients with available data. Tumor types included 79 cases of hepatocellular carcinoma (HCC), 8 hemangioblastomas, 3 uterine leiomyomas, 3 renal cell carcinomas (RCC), 2 Leydig cell tumors, and 2 paragangliomas. Single cases were identified for pheochromocytoma, plasma cell neoplasm, colorectal adenocarcinoma, and growth hormone secreting pituitary adenoma. Among patients with available follow-up data, the mortality rate was 15.4% at median follow-up of 30 months (range, 7-180 months). Only 2 patients experienced thrombosis during follow up, though thrombotic outcomes were not reported for the remaining 98 patients. Interventions for erythrocytosis included phlebotomy in 9% of cases, cytoreductive therapy in 2%, antiplatelet therapy in 2%, anticoagulation in 2%, and surgical tumor resection in 75% of reported cases.

Management and outcomes varied by tumor type. Among the 79 cases of HCC, 1 patient received phlebotomies, hydroxyurea, and aspirin. All 8 reported hemangioblastoma cases underwent surgical tumor resection, which consistently resolved the erythrocytosis. In the 3 cases of uterine leiomyomas, median hemoglobin was 184 g/L (range, 174-213 g/L); 1 patient received phlebotomy and hydroxyurea, and all 3 underwent surgical resection of the leiomyoma, leading to resolution of erythrocytosis. 3 cases of RCC had a median hemoglobin of 176 g/L (range, 172-180 g/L), with 2 managed using phlebotomy; 2 had surgical tumor resections and 1 received systemic therapy that resolved the erythrocytosis. Erythrocytosis recurred in 1 patient alongside metastatic disease and persisted until death. In the 2 cases of Leydig cell tumor, median hemoglobin was 165 g/L (range, 160-170 g/L). 1 patient underwent pre-operative phlebotomy for erythrocytosis, and both underwent surgical tumor resection, which resolved erythrocytosis. 2 paraganglioma cases were reported, with a median hemoglobin of 210 g/L (range, 200-220 g/L), one occurring alongside a pheochromocytoma. Both were managed with phlebotomy; one underwent surgical resection and the other systemic therapy. Erythrocytosis persisted in both cases.

Conclusion: TAE is a rare condition seen across several tumor types, with the most common reported in the literature being hepatocellular carcinoma and hemangioblastoma. In nearly all documented cases, resolution of erythrocytosis was achieved with definitive tumor treatment, either through surgical resection or systemic therapy. Death was primarily driven by the underlying malignancy, with few reported cases of thrombosis. Clinicians should remain aware of TAE as a rare cause of SE, and management should focus on treating the underlying tumor; the role of additional strategies such as phlebotomy, cytoreduction, and antithrombotic therapy remains uncertain.

Disclosures: No relevant conflicts of interest to declare

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2025
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