A 67-year-old man comes to the office due to severe fatigue for the past several months. The patient cannot eat as much as he used to and has lost nearly 10 kg (22 lb) in the past 6 months. Physical examination shows mucosal pallor, hepatomegaly, and massive splenomegaly. Further evaluation reveals a gain-of-function mutation of a non-receptor tyrosine kinase protein in hematopoietic cells, leading to persistent activation of signal transducers and activators of transcription (STAT) proteins. This patient is most likely suffering from which of the following disorders?
Chronic myeloproliferative disorders | ||
Disorder | Diagnostic features | Mutation |
Chronic myelogenous leukemia | Constitutional symptoms (eg, fatigue, weight loss, excessive sweating), splenomegaly & leukocytosis with marked left shift (eg, myelocytes, metamyelocytes, band forms) | Philadelphia chromosome t(9:22) BCR-ABL fusion protein |
Essential thrombocytosis | Hemorrhagic & thrombotic symptoms (eg, easy bruising, microangiopathic occlusion), thrombocytosis & megakaryocytic hyperplasia | JAK2 |
Polycythemia vera | Pruritus, erythromelalgia, splenomegaly, thrombotic complications, erythrocytosis & thrombocytosis | |
Primary myelofibrosis | Severe fatigue, splenomegaly (often causing early satiety/abdominal discomfort), hepatomegaly, anemia & bone marrow fibrosis | |
The chronic myeloproliferative disorders are bone marrow diseases characterized by overproduction of myeloid cells. Primary myelofibrosis is caused by atypical megakaryocytic hyperplasia, which stimulates fibroblast proliferation, resulting in progressive replacement of the marrow space by extensive collagen deposition. In the early stages, there is marrow hypercellularity with minimal fibrosis, but as the disease progresses, pancytopenia can result. Hepatomegaly and massive splenomegaly develop because the loss of bone marrow hematopoiesis is compensated for by extramedullary hematopoiesis. The peripheral smear characteristically shows teardrop-shaped red blood cells (dacrocytes) and nucleated red blood cells.
With the exception of chronic myelogenous leukemia, the chronic myeloproliferative disorders (especially polycythemia vera) frequently harbor a mutation in the nonreceptor cytoplasmic tyrosine kinase, Janus kinase 2 (JAK2). This mutation results in constitutive tyrosine phosphorylation activity, and consequently, in the cytokine-independent activation of the signal transducers and activators of transcription (STAT) pathway. Once they are activated, STAT proteins translocate to the nucleus and promote transcription. A JAK2 inhibitor (ruxolitinib) has been approved for treatment of primary myelofibrosis.
(Choice A) In acute promyelocytic leukemia, t(15;17) leads to the formation of a fusion gene between the promyelocytic leukemia (PML) and the retinoic acid receptor alpha (RARA) genes. The abnormal PML/RARα fusion protein blocks differentiation of myeloid precursors.
(Choice B) Chronic lymphocytic leukemia is a lymphoproliferative disorder involving B lymphocytes. The most significant laboratory finding is marked lymphocytosis, with "smudge cells" seen on peripheral blood smear. The majority of cases exhibit increased expression of the proto-oncogene BCL2; a similar finding occurs in follicular lymphomas.
(Choices C and D) Several high-grade non-Hodgkin lymphomas (NHLs) are associated with cytogenetic abnormalities. The t(8;14) translocation involves the c-Myc oncogene and is common in Burkitt lymphoma, which is associated with Epstein-Barr virus infection and classically has a "starry sky" histological appearance. Mantle cell lymphoma is a low grade NHL characterized by t(11;14), leading to cyclin D1 overexpression.
Educational objective:
The chronic myeloproliferative disorders (polycythemia vera, essential thrombocytosis, and primary myelofibrosis) often have a mutation in Janus kinase 2 (JAK2), a cytoplasmic tyrosine kinase. This results in constitutive tyrosine kinase activity, and consequently, in the cytokine-independent activation of signal transducers and activators of transcription (STAT) proteins (JAK-STAT signaling pathway).