JAK2 unmutated erythrocytosis: 2023 Update on diagnosis and management

Abstract

Disease Overview JAK2 unmutated or non‐polycythemia vera (PV) erythrocytosis encompasses a heterogenous spectrum of hereditary and acquired entities. Diagnosis Foremost in the evaluation of erythrocytosis is the exclusion of PV through JAK2 (inclusive of exons 12–15) mutation screening. Initial assessment should also include gathering of previous records on hematocrit (Hct) and hemoglobin (Hgb) levels, in order to streamline the diagnostic process by first distinguishing longstanding from acquired erythrocytosis; subsequent subcategorization is facilitated by serum erythropoietin (Epo) measurement, germline mutation screening, and review of historical data, including comorbid conditions and medication list. Hereditary erythrocytosis constitutes the main culprit in the context of longstanding erythrocytosis, especially when associated with a positive family history. In this regard, a subnormal serum Epo level suggests EPO receptor mutation. Otherwise, considerations include those associated with decreased (high oxygen affinity Hgb variants, 2,3‐bisphosphoglycerate deficiency, PIEZO1 mutations, methemoglobinemia) or normal oxygen tension at 50% Hgb saturation (P50). The latter include germline oxygen sensing pathway (HIF2A–PHD2–VHL) and other rare mutations. Acquired erythrocytosis commonly results from central (e.g., cardiopulmonary disease, high‐altitude habitat) or peripheral (e.g., renal artery stenosis) hypoxia. Other noteworthy conditions associated with acquired erythrocytosis include Epo‐producing tumors (e.g., renal cell carcinoma, cerebral hemangioblastoma) and drugs (e.g., testosterone, erythropoiesis stimulating agents, sodium‐glucose cotransporter‐2 inhibitors). Idiopathic erythrocytosis is an ill‐defined terminology that presumes the existence of an increased Hgb/Hct level without an identifiable etiology. Such classification often lacks accounting for normal outliers and is marred by truncated diagnostic evaluation. Management Current consensus treatment guidelines are not supported by hard evidence and their value is further undermined by limited phenotypic characterization and unfounded concerns for thrombosis. We are of the opinion that cytoreductive therapy and indiscriminate use of phlebotomy should be avoided in the treatment of non‐clonal erythrocytosis. However, it is reasonable to consider therapeutic phlebotomy if one were to demonstrate value in symptom control, with frequency determined by symptoms rather than Hct level. In addition, cardiovascular risk optimization and low dose aspirin is often advised. Future Directions Advances in molecular hematology might result in better characterization of “idiopathic erythrocytosis” and expansion of the repertoire for germline mutations in hereditary erythrocytosis. Prospective controlled studies are needed to clarify potential pathology from JAK2 unmutated erythrocytosis, as well as to document the therapeutic value of phlebotomy.

Contribution of lowered hemoglobin threshold value in the diagnosis of polycythemia vera: Comparison of 2016 and 2008 WHO criteria

“…When assessing the epidemiology of erythrocytosis, the evolution of its classification and the relatively new identification of molecular tests (that are now among diagnostic criteria) affect the epidemiology of disease, with direct effects on prevalence and incidence, and indirect effects on prognosis and survival. [9] Although the prevalence estimates can vary widely, the prevalence of PV was reported as 0.044 to 0.057% in the USA, while the prevalence of erythrocytosis was found to be 0.3% according to the 2008 WHO criteria and 3.4% according to the 2016 criteria. [10,11] The importance of reaching a precise diagnosis will help to resolve the underlying pathology causing erythrocytosis, and therefore, its potential clinical outcomes.…”

Erythropoietin‐secreting metanephric adenoma presenting as erythrocytosis

“…Serum EPO concentration and JAK2 mutation testing are critical to differentiate PV from secondary erythrocytosis in the vast majority of cases. Furthermore, a thorough review of the diagnostic approach to JAK2 unmutated erythrocytosis was recently published 1 . Despite a lack of symptoms or exam findings, as in this patient, imaging is a crucial next step in the evaluation of secondary erythrocytosis.…”

“…Erythrocytosis, or red blood cell (RBC) concentration above age‐ and gender‐specific reference ranges, 1 is typically diagnosed by increased hemoglobin concentration or hematocrit level, and is unusual in young patients such as this. Initial workup includes repeating the hemoglobin to ensure that this value is accurate and not hemo‐concentrated from dehydration.…”

“…At the very least, abdominal and pelvic imaging is useful to exclude EPO‐secreting tumors or conditions inducing local renal hypoxia. Other EPO‐secreting tumors associated with erythrocytosis can be seen in Table 1, 4–6,8–28 and include meningiomas, uterine leiomyomas, and parathyroid adenomas 1 …”

“…The use of therapeutic phlebotomy, low‐dose aspirin, and cardiovascular risk optimization may be advised in certain cases (such as those with high hematocrit and symptoms), but there is no strong evidence to support or refute these practices. Furthermore, the goal hematocrit is unknown 1 . In a 2023 clinical update on the diagnosis and management of JAK2 unmutated erythrocytosis, 1 the authors do not recommend use of cytoreductive therapy or indiscriminate use of phlebotomy to treat patients without an MPN.…”