A 65-year-old man comes to the office due to several months of severe fatigue that limits his ability to do daily activities. He has also had upper abdominal fullness, early satiety, and unintentional weight loss but no fever, night sweats, cough, or rash. The patient has not seen a physician for many years. He does not use tobacco, alcohol, or illicit drugs and is a retired chemical engineer. Physical examination shows mucosal pallor with no scleral icterus. The lungs are clear on auscultation, and heart sounds are normal. There is mild hepatomegaly, and the spleen tip is palpable close to the midline of the abdomen. Laboratory evaluation reveals pancytopenia. Peripheral blood smear shows immature granulocytes, nucleated erythrocytes, and teardrop cells. Bone marrow aspiration is attempted but yields no marrow. Which of the following histopathological features is most likely to be present in this patient's spleen?
Primary myelofibrosis | |
Pathogenesis | Chronic myeloproliferative disorder with clonal megakaryocytes → secrete transforming growth factor-ß → stimulates fibroblasts in BM to produce collagen → BM fibrosis → hematopoietic stem cells migrate to liver & spleen → extramedullary hematopoiesis |
Manifestations |
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BM = bone marrow. | |
Primary myelofibrosis is a chronic myeloproliferative disorder marked by the clonal expansion of atypical megakaryocytes. These atypical cells produce transforming growth factor-beta, which stimulates fibroblasts in the bone marrow to lay down collagen, leading to subsequent bone marrow fibrosis. Because fibrotic bone marrow is inhospitable to hematopoietic stem and progenitor cells, these precursor cells migrate out of the bone marrow to the liver and spleen, the primary sites of extramedullary hematopoiesis.
The proliferation of erythroid, myeloid, and megakaryocytic progenitor cells in the spleen leads to a marked expansion of the splenic red pulp and usually results in dramatic splenomegaly. Nucleated red cells and immature granulocytes spill into the circulation and can be identified on peripheral blood smear. Dacrocytes are also common due to erythrocyte membrane damage during red blood cell production in the spleen or fibrotic marrow. Because extramedullary hematopoiesis is less efficient than medullary hematopoiesis, patients typically have one or more cytopenias.
The diagnosis of primary myelofibrosis requires bone marrow evaluation. Aspiration of bone marrow is frequently unsuccessful (dry tap) due to fibrosis. Therefore, bone marrow biopsy is generally required and usually shows hypocellular marrow with significant fibrosis and atypical megakaryocytes. A minority of primary myelofibrosis cases have been linked to chemical exposure (eg, toluene, benzene).
(Choice A) Gaucher disease is an autosomal recessive lysosomal storage disease associated with hepatosplenomegaly and pancytopenia due to the accumulation of glucocerebroside within the cytoplasm of macrophages (crumpled-paper appearance). However, most cases present in childhood. In addition, a dry tap on bone marrow aspirate and dacrocytes on peripheral smear would be atypical.
(Choice B) Acute infections of the spleen (eg, septic emboli from infective endocarditis) are typically associated with diffuse neutrophilic infiltration. Follicular necrosis is also common if the infection is due to group A Streptococcus. A dry tap, dacrocytes, and lack of fever make this less likely.
(Choice C) Congestive splenomegaly due to portal hypertension (eg, from liver cirrhosis) is associated with dilated sinusoids, fibrosis of the red pulp, and hemosiderin-laden macrophages. A dry tap and dacrocytes would not be seen.
(Choice E) Splenic noncaseating granulomas are common in sarcoidosis, some malignancies, and some infectious disorders. However, a dry tap and dacrocytes make primary myelofibrosis far more likely.
Educational objective:
Primary myelofibrosis is a chronic myeloproliferative disorder associated with bone marrow fibrosis. Extramedullary hematopoiesis leads to marked expansion of the splenic red pulp with hematopoietic progenitor cells, resulting in massive splenomegaly. Patients also usually have hepatomegaly, cytopenias, and peripheral smear abnormalities (eg, dacrocytes, nucleated red cells, immature granulocytes).