A 68-year-old man presents to the clinic with progressive fatigue, a 15-lb weight loss, and discomfort in his left upper abdomen. Past medical history is significant for hypertension which is managed with losartan. Vital signs are within normal limits. On physical examination, he has massive splenomegaly extending 10 cm below the left costal margin and hepatomegaly. There is no peripheral lymphadenopathy.
Laboratory studies show the following:
Hemoglobin: 8.4 g/dL
White blood cell count: 14,000/μL
Platelet count: 90,000/μL
Peripheral blood smear: Numerous teardrop-shaped red blood cells, nucleated red blood cells, and immature myeloid cells (metamyelocytes and myelocytes).
Bone marrow aspiration: Dry tap with no marrow obtained despite multiple attempts.
Which of the following is the most likely underlying mechanism for this patient's bone marrow findings?
The correct answer is:
C: Release of fibroblast growth factors by neoplastic megakaryocytes.
This patient is presenting with primary myelofibrosis (PMF), a chronic myeloproliferative neoplasm. The core pathophysiology involves a clonal proliferation of hematopoietic stem cells, particularly atypical megakaryocytes. These neoplastic megakaryocytes release profibrotic cytokines, such as transforming growth factor-beta (TGF-β) and platelet-derived growth factor (PDGF). These factors stimulate non-neoplastic fibroblasts to lay down excessive collagen and reticulin, leading to progressive bone marrow fibrosis. This results in the characteristic clinical findings:
Dry tap on bone marrow biopsy: The fibrotic marrow cannot be aspirated.
Extramedullary hematopoiesis: As the marrow becomes a scar, blood production shifts to the liver and spleen, causing massive splenomegaly.
Leukoerythroblastic peripheral smear: Immature red and white cells are squeezed out of the fibrotic marrow or released from extramedullary sites.
Dacrocytes (teardrop cells): Red blood cells are physically damaged as they attempt to maneuver through the fibrotic marrow.
Answer choice A: Neoplastic proliferation of plasma cells causing lytic bone destruction, is incorrect. This describes multiple myeloma (MM). While MM can involve the marrow, it typically presents with lytic lesions and hypercalcemia rather than massive splenomegaly and teardrop cells.
Answer choice B: Overexpression of Bcl-2 preventing apoptosis of follicular B-cells, is incorrect. This is the hallmark of follicular lymphoma t(14;18). It presents with painless lymphadenopathy, not myelofibrosis.
Answer choice D: Replacement of marrow by metastatic small cell lung carcinoma, is incorrect. While metastatic cancer can cause a dry tap and a leukoerythroblastic smear (known as myelophthisic anemia), the presence of massive splenomegaly and the constitutional symptoms in an elderly patient more strongly point toward a primary myeloproliferative process.
Answer choice E: T-cell mediated destruction of hematopoietic stem cells, is incorrect. This is the mechanism for aplastic anemia. Aplastic anemia presents with a dry tap due to an empty, fatty marrow (hypocellularity), but it does not cause splenomegaly or teardrop cells.
Key Learning Point
Primary myelofibrosis is characterized by marrow fibrosis triggered by megakaryocyte-derived cytokines (TGF-β). It presents with massive splenomegaly, a dry tap on bone marrow aspiration, and teardrop cells on peripheral smear. Like other myeloproliferative neoplasms, it is frequently associated with the JAK2 V617F mutation (approx. 50% of cases).
