Case Workshop of Society for Hematopathology and European Association for Haematopathology
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1 Case Workshop of Society for Hematopathology and European Association for Haematopathology Robert P Hasserjian Department of Pathology Massachusetts General Hospital Boston, MA
2 Clinical history 55 year old woman presented with asymptomatic neutropenia on routine physical exam in July 2000 Previous CBCs had been normal Bone marrow biopsy and aspirate were performed July 2000 No clinical intervention Neutropenia persisted and skin and mouth ulcers developed in December 2001 Patient otherwise well, on no medications, no exposure to toxins and only occasional alcohol use Repeat bone marrow biopsy and aspirate were performed January 2002 and March 2003
3 Jul 00 bone marrow
4 Jul 00 bone marrow
5 Results of bone marrow examinations (2000, 2002, 2003) Hypocellular-normocellular marrow with multiple nonparatrabecular and paratrabecular lymphoid aggregates Immunohistochemistry on 2000 and 2002 samples Mixture of T cells (CD4 > CD8), B cells and polytypic plasma cells Low-grade lymphoma suspected Flow cytometry on 2003 bone marrow sample No monoclonal B-cell population or increased blasts Normal T-cells Flow cytometry on peripheral blood (March 03) Polyclonal B-cells (CD20+: 5%) Unremarkable T-cells (CD4+: 42%, CD8+: 30%, CD16+/CD3-: 17%) Only occasional large granular lymphocytes and atypical lymphocytes were noted on morphologic review or peripheral smear
6 Clinical course ( ) Date HGB g/dl WBC x 10 9 /L (ANC cells/μl) PLT x 10 9 /L Spleen (costal margin) Bone marrow Jul 00 Normal Neutropenia Normal 30% cellular, myeloid hypoplasia Jan (110) % cellular, myeloid hypoplasia Mar (280) 232 Possible tip palpated 60% cellular, normal M:E ratio
7 Diagnostic work-up Elevated serum IgA level (634 mg/dl) with normal IgM and IgG No monoclonal paraprotein detected ANCA titer positive at 1:2560 ANA negative HIV negative Parvovirus serology negative
8 Clinical course ( ) Date HGB g/dl WBC x 10 9 /L Apr 03 PLT x 10 9 /L Spleen Bone marrow (ANC cells/μl) (costal margin) G-CSF started (Neulasta 6 mg every 3 weeks) in April 2003 ulcers resolved and WBC improved Mar (510) cm 95% cellular Apr 05 Erythropoietin started (Procrit 50,000 U weekly, then Aranesp 300 mg weekly) Jun (4,620) cm 95% cellular Jun 06 First RBC transfusion Oct (3,080) 76 90% cellular
9 Jun 05 bone marrow
10 Jun 05 bone marrow reticulin stain
11 Jun 05 bone marrow
12 Jun 05 bone marrow
13 Jun 05 blood Jun 05 blood Jun 05 bone marrow Jun 05 bone marrow
14 PAX5 CD2 CD34 IHC: no increase in blast cells
15 Data from ancillary studies Flow cytometry Blood (Sept 05): Negative CD4+: 38%, CD8+: 24%, CD20: 3% Blood (Jun 07): Negative CD4+: 25%, CD8+: 31%, CD20: 1% PNH screen negative Bone marrow cytogenetics normal on multiple occasions Molecular studies on blood No clonal IgH or TCR rearrangement detected by PCR Negative for JAK2 V617F mutation
16 Diagnoses entertained Suspicious for low grade lymphoma (July 00) Idiopathic neutropenia (Mar 03) Progressive myelodysplastic syndrome on a background of myelofibrosis (May 05) Possible low grade T cell lymphoma (Jun 05) Myelofibrotic spent-phase MDS/MPD (Jun 06) Myeloproliferative disorder with lymphocytic infiltration (June 07)
17 Treatments considered 5-azacitidine (Vidaza) Allogeneic stem cell transplant (matched unrelated donor) Given her relatively good response to growth factors, modest transfusion requirements and uncertain diagnosis, the patient was continued on supportive care only
18 A non-neoplastic etiology? Lymphoma No neoplastic B-cell or T-cell population detected by flow cytometry or PCR Myeloproliferative neoplasm Does not fulfill WHO 2008 criteria of PMF Lack of characteristic megakaryocyte morphology Lack of prominent granulocytic proliferation in earlier biopsies JAK2 negative Myelodysplastic syndrome with fibrosis (MDS-F) Morphologic dysplasia is minimal Prolonged clinical course not typical of MDS-F (median survival 10 months) Presentation with isolated neutropenia and relatively good response to growth factors would be unusual for MDS Tefferi and Vardiman Leukemia 2007 Maschek Eur J Haematol 1992
19 Autoimmune myelofibrosis Bone marrow reticulin fibrosis associated with cytopenias has been reported in patients with systemic lupus erythematosus Reversal of fibrosis and cytopenias in response to steroids favors an autoimmune etiology Marrow fibrosis has also been reported in association with other autoimmune diseases Polyarteritis nodosa, scleroderma, psoriatic arthritis, Sjögren's, Hashimoto s thyroiditis, ulcerative colitis, primary biliary cirrhosis Rizzi et al. Leuk Lymph 2004
20 Autoimmune myelofibrosis in patients without a known autoimmune disease? Proposed diagnostic criteria Grade 3-4 reticulin fibrosis of bone marrow, without osteosclerosis Lack of clustered, atypical megakaryocytes Lack of significant dysplasia Lymphoid infiltration of bone marrow (+/- lymphoid aggregates) Absent or mild splenomegaly Presence of autoantibodies Excellent response to corticosteroid therapy CR in 6 patients, PR in 1 patient?role of dysregulated TGFβ production by CD4+ T-cells and monocytes Pullarkat et al Am J Hematol 2003 Bass et al. AJCP 2001 Rizzi et al Leuk Lymph 2004 Paquette et al. Medicine 1994
21 Clinical course ( ) Date HGB g/dl WBC x 10 9 /L Oct 06 - Jul 07 (ANC cells/μl) PLT x 10 9 /L Spleen (costal margin) cm; stable on CT scan Bone marrow Sep cm Not performed Anti-platelet antibodies positive, diagnosed with autoimmune thrombocytopenia Started on 50 mg prednisone daily
22 Most recent clinical course (2007) Date HGB g/dl WBC x 10 9 /L PLT x 10 9 /L Spleen Bone marrow (ANC cells/μl) (costal margin) Sept cm Not performed Sept 20 Steroids started (Prednisone 50 mg daily) Sept Oct cm
23 Conclusions Favored diagnosis is autoimmune myelofibrosis This disease may occur in patients with no documented diagnosis of autoimmune disease Potential for misdiagnosis as lymphoma, MDS, MPN, or MDS/MPN disease Exclusion of lymphoma through ancillary studies and careful assessment of bone marrow morphology can help avoid misdiagnosis
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