Determination of accuracy of polycythemia vera diagnoses and use of the JAK2V617F test in the diagnostic scheme.

In 2005, three independent research groups described the presence of a specific mutation in the JAK2 gene, JAK2V617F, in patients with a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN). The percentage of patients with the mutation varied according to specific disease with >98 % of polycythemia vera (PV) patients having the mutation. In 2008, the World Health Organization issued new diagnostic criteria for PV including use of the JAK2V617F test as a major diagnostic criterion. The goal of the present study is to determine the accuracy of diagnosing PV in a community practice and reporting of PV to cancer registries, as well as assessing the integration of molecular testing into diagnostic paradigms. Using Geisinger Medical Center's electronic medical records (EMR), patients with a PV diagnosis being seen by a hematologist/oncologist during 2004-2009 were identified. Records were reviewed by a single hematologist/oncologist to determine accuracy of the treating physician's diagnosis and use of the molecular test for the JAK2V617F mutation. There was a diagnosis of PV from the treating physicians in 121 of the 204 evaluable patients (59 %) and another MPN in 21 (10 %). However, we confirmed a PV diagnosis in only 90 patients (44 %). Of the 90 confirmed PV patients, 64 were JAK2V617F-mutation positive while 24 were not tested. While JAK2V617F testing has made a major impact in facilitating the successful delineation of the type of polycythemia (PV versus secondary polycythemia) in patients evaluated in a large, community-based Hematology/Oncology practice, physician usage of other critical tests is inconsistent leading to errors in diagnosis. JAK2V617F mutation testing in combination with other diagnostic criteria may help reduce diagnostic errors.

Spleens of myelofibrosis patients contain malignant hematopoietic stem cells.

Cancer stem cell behavior is thought to be largely determined by intrinsic properties and by regulatory signals provided by the microenvironment. Myelofibrosis (MF) is characterized by hematopoiesis occurring not only in the marrow but also in extramedullary sites such as the spleen. In order to study the effects of these different microenvironments on primitive malignant hematopoietic cells, we phenotypically and functionally characterized splenic and peripheral blood (PB) MF CD34+ cells from patients with MF. MF spleens contained greater numbers of malignant primitive HPCs than PB. Transplantation of PB MF CD34+ cells into immunodeficient (NOD/SCID/IL2Rγ(null)) mice resulted in a limited degree of donor cell chimerism and a differentiation program skewed toward myeloid lineages. By contrast, transplanted splenic MF CD34+ cells achieved a higher level of chimerism and generated both myeloid and lymphoid cells that contained molecular or cytogenetic abnormalities indicating their malignant nature. Only splenic MF CD34+ cells were able to sustain hematopoiesis for prolonged periods (9 months) and were able to engraft secondary recipients. These data document the existence of MF stem cells (MF-SCs) that reside in the spleens of MF patients and demonstrate that these MF-SCs retain a differentiation program identical to that of normal hematopoietic stem cells.

A multidisciplinary investigation of a polycythemia vera cancer cluster of unknown origin.

Cancer cluster investigations rarely receive significant public health resource allocations due to numerous inherent challenges and the limited success of past efforts. In 2008, a cluster of polycythemia vera, a rare blood cancer with unknown etiology, was identified in northeast Pennsylvania. A multidisciplinary group of federal and state agencies, academic institutions, and local healthcare providers subsequently developed a multifaceted research portfolio designed to better understand the cause of the cluster. This research agenda represents a unique and important opportunity to demonstrate that cancer cluster investigations can produce desirable public health and scientific outcomes when necessary resources are available.

Use of molecular testing to identify a cluster of patients with polycythemia vera in eastern Pennsylvania.

BACKGROUND: The role of the environment in the origin of polycythemia vera has not been well documented. Recently, molecular diagnostic tools have been developed to facilitate the diagnosis of polycythemia vera. A cluster of patients with polycythemia vera was suspected in three countries in eastern Pennsylvania where there have long been a concern about environment hazards. METHODS: Rigorous clinical criteria and JAK2 617V>F testing were used to confirm the diagnosis of polycythemia vera in patients in this area. Participants included cases of polycythemia vera from the 2001 to 2005 state cancer registry as well as self- and physician-referred cases. FINDING: A diagnosis of polycythemia vera was confirmed in 53% of 62 participants using WHO criteria, which includes JAK2 617V>F testing. A statistically significant cluster of cases (P < 0.001) was identified where the incidence of polycythemia vera was 4.3 times that of the rest of the study area. The area of the cluster contained numerous sources of hazardous material including waste-coal power plants and U.S. Environmental Protection Agency Superfund sites. INTERPRETATION: The diagnosis of polycythemia vera based solely on clinical criteria is frequently erroneous, suggesting that our prior knowledge of the epidemiology of this disease might be inaccurate. The JAK2 617V>F mutational analysis provides diagnostic clarity and permitted the confirmation of a cluster of polycythemia vera cases not identified by traditional clinical and pathologic diagnostic criteria. The close proximity of this cluster to known areas of hazardous material exposure raises concern that such environmental factors might play a role in the origin of polycythemia vera.