MPDs and myelodysplastic disorders may have the functional caveat of producing extramedullary hematopoietic (EMH) tissue when the liver and spleen launch into hematopoietic production in a proliferative and disordered state. EMH is induced by a chronic state of low hemoglobin that triggers the proliferation of new sites for hematopoiesis. These tissues can become significantly enlarged and impinge on surrounding organs. Paraspinal, liver, and splenic sites are the most commonly involved sites for EMH production. Other sites have been noted but are less common, such as lymph nodes, pleura, lungs, GI tract, brain, skin, breast, kidneys, and adrenal glands. EMH production may occur in the MPDs such as CML, PV, essential thrombocythemia, myelofibrosis (MF), and myeloid metaplasia. Additionally, hemoglobinopathies such as sickle cell disease and thalassemia may produce EMH sites (Ünsal, Yirmibeşoğlu, Okar, Karakuş, & Pak, 2013).

EPIDEMIOLOGY

A U.S. cancer registry for chronic MPDs and myelodysplastic disorders began data collection in 2001. Data reviewing average annual age-adjusted incidence rates of chronic MPDs (with myelodysplastic disorders included) in 2001 through 2003 were 3.3 and 2.1 per 100,000, respectively. Incidence rates increased with age for both MDS and chronic MPDs (CMD; p <.05) and were highest among Whites and non-Hispanics. Surveillance, Epidemiology, and End Results (SEER) program data through 2004 showed that the overall relative 3-year survival rates for MDS and CMD were 45% and 80%, respectively, with males experiencing poorer survival than females (Rollison, Howlader, Smith, & Strom, 2008). Within these data, approximately 9,700 patients with MDS and 6,300 patients with CMD were estimated for the entire United States in 2004 (Rollison et al., 2008). However, because reporting of these disease states began so close to the time of this analysis, the numbers may be underrepresented.

Considering the relationship between MPDs and aging, there may be an association with the acquisition of DNA damage over time by natural aging or by accumulated toxins or stressors (Malcovati & Nimer, 2008). From a public health perspective, MPDs contribute to the morbidity and health care burden faced by an aging population.

DIAGNOSTIC CRITERIA

The major MPDs are generally classified by chromosomal abnormalities such as the Philadelphia chromosome (BCR-ABL) or Janus-associated kinase-2 (JAK-2; JAK2V617F) mutations. When chromosomal mutations occur, they interfere with the normal controls imposed on the orderly proliferation and longevity of particular hematopoietic cells. For example, a CML diagnosis is confirmed by identifying the BCR-ABL fusion also known as the Philadelphia chromosome. BCR-ABL negative MPDs include the disorders in which JAK2V617F mutations are often found. PV cases are found to have the JAK2V617F mutation approaching 100% of the time. By contrast, JAK2V617F mutations are found in ET and MF only about 50% of the time. Morphologic evidence in the bone marrow aspirate and biopsy will further support diagnosis in these cases. Pathologists and hematologists will utilize chromosomal testing and bone marrow aspirate and biopsies to confirm or rule out a proliferative diagnosis prior to initiating definitive treatment strategies. As bone marrow biopsy, genetic, and flow-cytometric testing is expensive, if there is a suspicion of these disorders in the primary care setting, a hematologist is best equipped to determine an appropriate approach to testing.

MDSs are a heterogeneous group of disorders characterized by impaired peripheral blood cell production reflected in cytopenias and most commonly a hypercellular dysplastic-appearing marrow (Nimer, 2008). Hallmark features at presentation will be anemia, thrombocytopenia, and frequently pancytopenia with all cell lines being reduced. The main prognostic factors in MDS are chromosomal abnormalities, the proportion of blasts in bone marrow, and number and degree of cytopenias.

Workup for MDS will include analysis of a peripheral smear and bone marrow, which reveals a varying presentation of immature myeloid and erythroid cells, macrocytosis, atypical megakaryocytes, blast cells, and at times ringed sideroblasts. Ringed sideroblasts are erythroblasts that have iron-loaded mitochondria most clearly visualized as perinuclear granules when stained with Prussian blue (Malcovati et al., 2009). Monocytosis may be apparent in some cases. Aspirate from the bone marrow will be sent for cytogenetic studies and flow cytometry that may help eliminate some diagnoses and identify markers for prognostic scoring.

Primary care settings are often the first point for clinical suspicion of hematologic disorders when patients are otherwise presenting for routine preventive care and screening. Hematologic disorders are often found incidentally when a blood count is ordered for a physical examination or preoperative assessment. Alternatively, patient complaints of unusual fatigue or other constitutional symptoms may prompt a search for suspected anemia. Sustained or advancing changes in one or more cell lines that do not correlate with secondary causes increase the probability of an MPD or MDS. These patients suffer from a significant burden of fatigue and constitutional symptoms that are frequently in excess of what may be expected based on overt disease manifestations or level of anemia (Keohane, Radia, & Harrison, 2013). Patient history may often reveal an unaccountable decrease in quality of life from fatigue and other diverse symptoms.

MPD, myeloproliferative disorders; MPN, myeloproliferative neoplasms.

Thrombotic pathology may be a presenting sign prompting a review of blood counts and finding of a proliferative disorder. One analysis of large selected studies showed that prevalence rates for major thrombosis, at time of diagnosis, range from approximately 34% to 39% for PV and 10% to 29% for ET. Arterial thrombotic events were more frequent than venous events. In both PV and ET, advanced age and history of thrombosis are independent predictors of recurrent thrombosis. In addition, leukocytosis, but not thrombocytosis, has been identified as a potential risk factor for thrombosis in both diseases (Vannucchi et al., 2009). Constitutional symptoms are always a red flag for hematologic and/or oncologic problems and should prompt a thorough hands-on clinical and laboratory investigation. A focused review of systems, family medical history, and occupational exposures provide useful baseline of information.

CVA, cerebral vascular accident; DVT, deep vein thrombosis; GI, gastrointestinal; MF, myelofibrosis; MI, myocardial infarction; PLT, platelets; PV, polycythemia vera.

         Red blood cell (RBC): If the red cell line is elevated, the main goal is to determine if the erythrocytosis is PV or not, as there are therapeutic considerations based on the risk level. Length of time and trend of the elevation should be assessed. Causes for secondary polycythemia can be congenital or acquired. Acquired polycythemia may be erythropoietin (EPO) mediated where elevated EPO levels have been stimulated by a physiological process. Chronic lung disease with a chronic reduction in oxygen will stimulate elevated EPO secretion and may induce erythrocytosis. The elevation will be more marked with increased volume of smoking. The presence of an EPO-secreting tumor causing high EPO levels is rare, but in this scenario, the erythrocytosis will not be hypoxia driven. Any physiological state that creates a lower oxygen environment, such as carbon monoxide inhalation, smoking, sleep apnea, and living or training at high altitudes, may lead to EPO production increase. Consider occupational exposure in poorly ventilated areas: auto-repair garages, discharge of CO₂ fire extinguishers prior to refilling, or portable and home-heating systems. Checking an EPO level and a carboxyhemoglobin level may narrow diagnostic considerations. Patients who are body builders or distance competitive runners may not be forthcoming about EPO “doping” or use of androgens because of regulatory standards in the competitive sporting world. Additionally, some athletes may train in high altitudes to purposefully stimulate higher RBC production. Therapeutic testosterone replacement may contribute to RBC production particularly if testosterone levels become high. JAK2V617F mutation testing has a very high sensitivity and specificity (approaching 100%) for detecting PV, but mutation testing is expensive and may require a hematologist’s order in any given institution. If PV or other myeloproliferative diagnosis is likely, a bone marrow biopsy will be encouraged to obtain baseline information on cytogenetics and level of fibrosis in the marrow microenvironment.

         Platelets (PLTs): As with other cell-line investigation, alternative diagnoses to a MPD should be considered. There are a number of etiologies for an elevated PLT count, many of which are reactive. Reactive thrombocytosis is not always associated with an increased risk for either bleeding or thrombosis. Reactive thrombocytosis should subside when the cause is brought under control, either naturally or with therapeutic assistance such as in inflammation, iron deficiency, or treatment for infection. If chronic circumstances will keep the PLT count high over time and there are other considerations elevating thrombotic risk, antiplatelet therapy such as aspirin may be used.

DIAGNOSTIC STUDIES

         Bone marrow aspirate and trephine core biopsy: Bone marrow morphology analysis is central in identifying various subtypes of myeloid neoplasms. Bone marrow biopsy may confirm a suspected diagnosis by excluding reactive conditions or serous atrophy. Marrow evaluation generally increases diagnostic accuracy and helps in refining the IPSS in MDSs. Other important findings relative to prognosis and treatment are the presence of aggregates or clusters of immature myeloid precursor cells such as myeloblasts and promyelocytes. Bone marrow biopsy is the only means of identifying and quantifying reticulin fibrosis in the marrow microenvironment. Aspirate can be difficult or impossible to obtain with extensive MF and analysis of the core with reticulin staining is important to secure the diagnosis. Serial evaluations can help analyze disease progression and/or treatment efficacy.

         Immunohistochemical staining (IHS): Utilizes antibodies that react with antigens present in tissue and thus identifies particular cell types found to be common in particular cancerous cells.

         Flow cytometry: A laser-based technology used in cell identification.

         Cytogenetic studies: Molecular cytogenetic testing, otherwise known as fluorescence in situ hybridization (FISH), may be utilized to address specific, focused clinical questions and is provided for a variety of clinical applications, including the assessment of both constitutional and acquired chromosomal aberrations. FISH testing is a method by which an assessment is made for the presence, absence, relative positioning, and/or the copy number of specific DNA segments by fluorescence microscopy.