Primary myelofibrosis (formerly known as chronic idiopathic myelofibrosis), has the lowest incidence amongst the chronic myeloproliferative neoplasms and is characterized by a rather short median survival and a risk of progression to acute myeloid leukemia (AML) noted in a small subset of the cases, usually as a terminal event. As observed with other chronic myeloproliferative neoplasms, the bone marrow biopsy may harbor small lymphoid aggregates, often assumed reactive in nature. In our paper, we present a 70-year-old Caucasian male who was diagnosed with primary myelofibrosis, and after 8 years of followup and therapy developed an AML. The small lymphoid aggregates noted in his bone marrow were neoplastic in nature and represented bone marrow involvement by a CD5-negative mantle cell lymphoma (MCL) that presented without any associated lymphadenopathy. We reviewed the English medical literature to identify a single case report of simultaneous association of AML and a MCL in the bone marrow. The unusual association presented here suggests an increase in observer awareness to apparently benign lymphoid aggregates in chronic myeloproliferative neoplasms.
A 70-year-old male patient with a past medical history of left hip replacement and depression presented with arthralgias involving the neck, hips, and knees. The complete blood count (CBC) had significant changes from normal indices noted on a previous examination performed 2 months earlier and showed leukocytosis (White blood cell (WBC) count 16.7 × 109/L; normal range 3.5–11.0 × 109/L) with neutrophilia (absolute neutrophil count 13.2 × 109/L; normal range 1.5–7.5 × 109/L) and thrombocytosis of 1,346 × 109/L (normal range 150–400 × 109/L)). The white blood cell differential included segmented neutrophils 78%, monocytes 5%, lymphocytes 11%, and basophils 6%. His red blood cell (RBC) count was 4.72 × 1012/L (normal range 4.2–5.5 × 1012/L), hemoglobin 13.8 g/dL (normal range 13.5–16.0 g/dL), and the RDW was 15.9% (normal range 11.5–14.5%) (Table
Sequential analysis of peripheral blood and bone marrow changes.
Diagnosis | ||||
---|---|---|---|---|
Prefibrotic stage of primary myelofibrosis |
JAK 2-positive primary myelofibrosis (IPSS score 1; DIPSS score 1 [ |
JAK 2-positive primary myelofibrosis and atypical B-lymphoid aggregates (IPSS score 3, DIPSS score 4) | Acute myeloid leukemia and CD5-negative mantle cell lymphoma | |
Time elapsed | Onset | 2 years | 7 years | 7 years and 9 months |
| ||||
Peripheral Blood | ||||
WBC (×109/L) | 16.7 | 16.4 | 59.3 | 40.3 |
Hgb (g/dL) | 13.8 | 10.1 | 12.6 | 11 |
Platelets (×109/L) | 1346 | 575 | 303 | 202 |
Blasts (%) | 0 | 0 | 5% | 69% |
| ||||
Bone Marrow | ||||
Cellularity | 50% | 95% | 95% | 95% |
Reticulin | 2+/4 | 4+/4 | 4+/4 | 4+/4 |
Blasts (%) | <5% | <5% | 9% | 73.4% |
| ||||
Description | Megakaryocytic hyperplasia, dysmegakaryopoiesis | Dysmegakaryopoiesis | Dysmegakaryopoiesis | Blasts, dysmegakaryopoiesis |
| ||||
Lymphoid aggregates | None | Single small aggregate Cyclin D1 negative IgH negative | CD20+, CD5 negative, BCL2+, A few cells are Cyclin D1+ IgH positive | Lymphoid aggregates 10%, CD5 negative, CD20+, BCL2+ Cyclin D1+ IgH positive FISH positive for t(11;14) |
Primary myelofibrosis, prefibrotic stage: (a) peripheral blood, thrombocytosis with giant platelets, Wright-Giemsa stain, Ob. 100x, immersion oil. (b) bone marrow biopsy with mildly hypercellular bone marrow, hematoxylin and eosin stain, Ob. 40x. (c) bone marrow aspirate, dysmegakaryopoiesis, Wright Giemsa stain, Ob. 100x, immersion oil. (d) Reticulin stain, mildly increased reticulin deposition. Ob. 50x.
Two years later the patient had a cerebrovascular accident. A second bone marrow examination showed increased cellularity, megakaryocytic hyperplasia, dysmegakaryopoiesis, and marked fibrosis (4+/4). A small intertrabecular lymphoid aggregate composed of small mature appearing lymphocytes was also noted and favored to be reactive in nature. The CBC and peripheral blood smear were similar to those noted in 2003 except for anemia; lymphadenopathy was not observed and a CT scan of the abdomen detected mild splenomegaly. Therapy was switched to hydroxyurea, then restarted and titrated to maintain platelet counts in the range of 450–550 × 109/L. A PCR analysis performed on a blood sample detected the presence of the JAK 2-V617 mutation. Notable changes in the CBC and peripheral blood smear morphology were detected in August 2010 when the WBC reached
Primary myelofibrosis, fibrotic stage: (a) peripheral blood smear, Wright-Giemsa stain, blast (arrow), Ob. 100x immersion oil. (b) Hypercellular bone marrow biopsy, Hematoxylin and eosin stain, Ob. 50x (c) bone marrow biopsy with markedly increased reticulin deposition. Ob. 50x, (d) Anti-CD20 antibody highlights a large subset of positive lymphoid cells in a lymphoid aggregate, Ob. 50x. (e) Anti-CD3 antibody highlights a small subset of CD3+ T-cells in a lymphoid aggregate, Ob. 50x. (f) Anti-Cyclin D1 antibody highlights a small subset of positive nuclei in a lymphoid aggregate, Ob. 50x.
In 2011, while presenting with symptoms suggestive of a respiratory infection, the CBC showed leukocytosis (WBC 40.3 × 109/L), hemoglobin of 11 g/dL, MCV 115 fL, platelets 215 × 1012/L (Table
Acute myeloid leukemia and associated bone marrow involvement by mantle cell lymphoma: (a) peripheral blood smear, Wright-Giemsa stain, blasts, Ob. 100x, immersion oil. (b) Bone marrow biopsy, Ob. 20x, anti-CD34 antibody highlights positive blasts; the lymphoid cells are negative. (c) Bone marrow biopsy, hematoxylin and eosin stain, Ob. 50x, lymphoid aggregate and blasts. (d) Bone marrow biopsy, anti-CD20 antibody highlights a large subset of positive cells in a lymphoid aggregate, Ob. 20x. (e) Bone marrow biopsy, anti-CD3 antibody highlights a small subset of positive cells in a lymphoid aggregate, Ob. 20x. (f) Bone marrow biopsy, anti-Cyclin D1 antibody highlights a large subset of positive cells in a lymphoid aggregate, Ob. 20x.
PMF is a Philadelphia chromosome-negative chronic myeloproliferative neoplasm characterized by a clonal proliferation of hematopoietic cells with variable morphologic maturity and efficiency [
A recent study evaluating 1000 patients verified a prognostic scoring system for these patients as well as provided valuable clinical and demographic information [
Mantle cell lymphoma (MCL) is a mature, aggressive B-cell lymphoma with a CCND1 translocation, usually presenting at an advanced clinical stage, and commonly involving the lymph nodes, spleen, bone marrow, and extranodal sites (includes the gastrointestinal tract and Waldeyer ring) [
The unusual simultaneous association of an AML and MCL has been previously described in a single case report [
Our case highlights the rare occurrence in a bone marrow replaced by JAK 2-positive PMF of an unusual variant of MCL, CD5 negative, and also the later “coexistence” of the MCL with an AML. While the association noted here might be merely coincidental, it brings attention to the mechanisms of a B-cell clone expansion in a clearly fibrotic marrow and to the underlying cell-to-cell interactions. Of note, this CD5-negative mantle cell lymphoma had a lowproliferation rate and was not associated with lymphadenopathy on repeated imaging studies. While a few prior studies [
Myelofibrosis has been described in association with non-Hodgkin lymphomas [
While benign lymphoid aggregates have been described in bone marrow biopsies in association with chronic myeloproliferative disorders [