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Journal of Clinical Oncology, Vol 26, No 7 (March 1), 2008: pp. 1171-1174 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.8106
Lung Cancer Presenting With Amegakaryocytic ThrombocytopeniaDivision of Hematology, Department of Internal Medicine, Stanford University School of Medicine, Stanford, CA
Division of Oncology, Department of Internal Medicine, Stanford University School of Medicine, Stanford, CA
A 71-year-old woman presented with complaints of easy bruising and epistaxis for several weeks. She denied fevers, sweats, weight loss, shortness of breath, cough, or bony pain. Five years before presentation, the patient had a normal complete blood count. The WBC was 11,600/mL, with 78% neutrophils, 12% lymphocytes, 5% monocytes, 3% eosinophils, and 0.4% basophils. Hemoglobin was 11.4 g/dL with a mean corpuscular volume of 90 µm3. The platelet count was 6,000/µL. Coagulation studies revealed no evidence of disseminated intravascular coagulation. Blood smear demonstrated normochromic, normocytic red cells without increased polychromasia, spherocytes, or schistocytes. There was no significant dysplasia. Several large granular lymphocytes were noted. Platelets were decreased in number, but normal in morphology. Remaining bloodwork was normal, including metabolic and hepatic panels, and negative HIV, hepatitis C virus, and antinuclear antibody studies. No B-cell clone was detected by molecular testing, though a clonal T-cell population was identified. There was no immunophenotypic evidence of paroxysmal nocturnal hemoglobinuria. A bone marrow biopsy exhibited 20% to 30% cellularity with a mild decrease in erythroid precursors and adequate erythroid maturation. Myeloid forms were left-shifted with poor maturation, but no increase in blasts. Notably, there was a near-absence of megakaryocytes (Fig 1). No dysplasia was present. There was an increase in plasma cells, with approximately 20% of core biopsy staining positive for CD138 (Fig 2). However, the plasma cells were polyclonal by both flow cytometry and in situ
Fifteen days after initial presentation, the patient complained of prominent fatigue and a new productive cough. She denied shortness of breath, fevers, sweats, anorexia, or gross bleeding. Physical examination revealed newly developed, bilateral, 2-cm supraclavicular adenopathy. Lungs were clear to auscultation bilaterally. The WBC was 3,500/mL, with 70% neutrophils and 21% lymphocytes. Hemoglobin was 7.5 g/dL, with a reticulocyte count of 0.69%. Platelets were not improved after the IV Ig and remained at 3,000/µL. Computed tomography of the chest, abdomen, and pelvis revealed extensive mediastinal, supraclavicular, and hilar adenopathy, innumerable bilateral pulmonary nodules (the largest was 2.2 cm), and no adenopathy in the abdomen or pelvis (Fig 3). The patient required multiple packed RBC and platelet transfusions, and developed worsening hypoxemia, for which she was hospitalized. She was intubated electively for biopsy of the 2-cm left supraclavicular lymph node. A bronchoscopy revealed bloody secretions throughout the airways with no visible masses. Bronchopulmonary lavage was negative for any infectious or malignant process. Pathology from the excisional biopsy revealed near effacement of the lymph node by a poorly differentiated neoplasm showing marked nuclear pleomorphism and numerous mitotic figures, including atypical forms (Fig 4). Multiple areas of necrosis were identified. Immunohistochemical studies showed positive staining for CK7, CKCAM5.2, CKAE1, and TTF1, supporting an epithelial neoplasm consistent of lung origin. The patient was extubated the day after the node biopsy, and she died several days later as a result of progressive hypoxemia.
This case represents severe amegakaryocytic thrombocytopenia as the initial presentation of lung cancer. Myelodysplastic syndrome (MDS) has rarely been described as a possible paraneoplastic process complicating solid tumors, including lung cancer.1 Although varying degrees of thrombocytopenia are seen in approximately 25% of patients with MDS, it is unusual for the disease to present with isolated, severe thrombocytopenia.2 MDS has been reported to evolve from a pure thrombocytopenia.3-5 However, the lack of marrow megakaryocytes is quite atypical for MDS. The severe thrombocytopenia with a near absence of megakaryocytes is consistent with acquired amegakaryocytic thrombocytopenia, a rare disease that has been reported to progress to both MDS and aplastic anemia.6-10 In addition, amegakaryocytic thrombocytopenia has been described as a paraneoplastic syndrome complicating thymoma and a CD5+ non-Hodgkin's lymphoma.11,12 The significance of the clonal T-cell process in this case report is not clear. Four previously described patients with amegakaryocytic thrombocytopenia have demonstrated concurrent clonal T-cell populations.13-16 Indeed, acquired amegakaryocytic thrombocytopenia is believed to be a result of cell-mediated destruction of megakaryocytes, possibly provoked by a clonal population of lymphocytes.17,18 High titers of antithrombopoietin IgG antibodies have been described in patients with acquired amegakaryocytic thrombocytopenia, and thus humoral immunity is also believed to be contributory to the disease process.19,20 Immunosuppression can be effective as treatment, although interestingly, therapies designed predominantly to suppress lymphocytes (antithymocyte globulin, cyclosporine) seem to have the greatest activity.17,21-25 The marrow plasmacytosis is another unusual finding in this case. An increase in polyclonal plasma cells can been seen in numerous processes, including HIV and other infections, Sjögren's syndrome, Still's disease, large granular lymphocyte syndrome, secondary polycythemia, acute myelogenous leukemia, and as a result of certain medications.26-36 To our knowledge, we propose that this represents the first report of lung carcinoma presenting as severe thrombocytopenia, due most likely to paraneoplastic acquired amegakaryocytic thrombocytopenia with a concurrent clonal T-cell process. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
ACKNOWLEDGMENTS We thank Jon Fukomoto, MD, and John Cupp, MD, for their assistance with preparing the pathology photographs. REFERENCES 1. Sans-Sabrafen J, Buxo-Costa J, Woessner S, et al: Myelodysplastic syndromes and malignant solid tumors: Analysis of 21 cases. Am J Hematol 41:1-4, 1992[Medline] 2. French Registry of Acute Leukemia and Myelodysplastic Syndromes: Age distribution and hemogram analysis of the 4496 cases recorded during 1982-1983 and classified according to FAB criteria—Groupe Francais de Morphologie Hematologique. Cancer 60:1385-1394, 1987[CrossRef][Medline] 3. Najean Y, Lecompte T: Chronic pure thrombocytopenia in elderly patients: An aspect of the myelodysplastic syndrome. Cancer 64:2506-2510, 1989[CrossRef][Medline] 4. Qian J, Xue Y, Pan J, et al: Refractory thrombocytopenia, an unusual myelodysplastic syndrome with an initial presentation mimicking idiopathic thrombocytopenic purpura. Int J Hematol 81:142-147, 2005[CrossRef][Medline] 5. Sashida G, Takaku TI, Shoji N, et al: Clinico-hematologic features of myelodysplastic syndrome presenting as isolated thrombocytopenia: An entity with a relatively favorable prognosis. Leuk Lymphoma 44:653-658, 2003[CrossRef][Medline] 6. Zafar T, Yasin F, Anwar M, et al: Acquired amegakaryocytic thrombocytopenic purpura (AATP): A hospital based study. J Pak Med Assoc 49:114-117, 1999[Medline] 7. Antonijevi 8. King JA, Elkhalifa MY, Latour LF: Rapid progression of acquired amegakaryocytic thrombocytopenia to aplastic anemia. South Med J 90:91-94, 1997[Medline] 9. Slater LM, Katz J, Walter B, et al: Aplastic anemia occurring as amegakaryocytic thrombocytopenia with and without an inhibitor of granulopoiesis. Am J Hematol 18:251-254, 1985[Medline] 10. Meytes D, Levi, Virag I, et al: Acquired amegakaryocytic thrombocytopenia with rapid progression into aplastic anemia. Harefuah 106:509-510, 1984[Medline] 11. Maslovsky I, Gefel D, Uriev L, et al: Malignant thymoma complicated by amegakaryocytic thrombocytopenic purpura. Eur J Intern Med 16:523-524, 2005[CrossRef][Medline] 12. Lugassy G: Non-Hodgkin's lymphoma presenting with amegakaryocytic thrombocytopenic purpura. Ann Hematol 73:41-42, 1996[CrossRef][Medline] 13. Colovic M, Pavlovic S, Kragulijac N, et al: Acquired amegakaryocytic thrombocytopenia associated with proliferation of gamma/delta TCR T-lymphocytes and a BCR-ABL (p210) fusion transcript. Eur J Haematol 73:372-375, 2004[CrossRef][Medline] 14. Ergas D, Tsimanis A, Shtalrid M, et al: T-gamma large granular lymphocyte leukemia associated with amegakaryocytic thrombocytopenic purpura, Sjogren's syndrome, and polyglandular autoimmune syndrome type II, with subsequent development of pure red cell aplasia. Am J Hematol 69:132-134, 2002[CrossRef][Medline] 15. Kouides PA, Rowe JM: Large granular lymphocyte leukemia presenting with both amegakaryocytic thrombocytopenic purpura and pure red cell aplasia: Clinical course and response to immunosuppressive therapy. Am J Hematol 49:232-236, 1995[CrossRef][Medline] 16. Lai DW, Loughran TP Jr, Maciejewski JP, et al: Acquired amegakaryocytic thrombocytopenia and pure red cell aplasia associated with an occult large granular lymphocyte leukemia. Leuk Res [Epub ahead of print on October 1, 2007]. 17. Benedetti F, de Sabata D, Perona G: T suppressor activated lymphocytes (CD8+/DR+) inhibit megakaryocyte progenitor cell differentiation in a case of acquired amegakaryocytic thrombocytopenic purpura. Stem Cells 12:205-213, 1994[Medline] 18. Gewirtz AM, Sacchett MK, Bien R, et al: Cell-mediated suppression of megakaryocytopoiesis in acquired amegakaryocytic thrombocytopenia. Blood 68:619-626, 1986 19. Katai M, Aizawa T, Ohara N: Acquired amegakaryocytic purpura with humoral inhibitory factor for megakaryocytic colony formation. Intern Med 33:147-149, 1994[CrossRef][Medline] 20. Shiozaki H, Miyawaki J, Kuwaki T, et al: Autoantibodies neutralizing thrombopoietin in a patient with amegakaryocytic thrombocytopenia purpura. Blood 95:2187-2188, 2000 21. Trimble MS, Glynn MF, Brain MC: Amegakaryocytic thrombocytopenia of 4 years duration: Successful treatment with antithymocyte globulin. Am J Hematol 37:126-127, 1991[CrossRef][Medline] 22. Quintás-Cardama A: Acquired amegakaryocytic thrombocytopenia purpura successfully treated with limited cyclosporin A therapy. Eur J Haematol 69:185-186, 2002[CrossRef][Medline] 23. Azuno Y, Yaga K: Successful cyclosporin A therapy for acquired amegakaryocytic thromboctopenic purpura. Am J Hematol 69:298-299, 2002[CrossRef][Medline] 24. Peng CT, Kao LY, Tsai CH: Successful treatment with cyclosporine A in a child with acquired pure amegakaryocytic purpura. Acta Paediatr 83:1222-1224, 1994[Medline] 25. Chaudhary UB, Eberwine SF, Hege KM: Acquired amegakaryocytic thrombocytopenia purpura and eosinophilic fasciitis; a long relapsing and remitting course. Am J Hematol 75:146-150, 2004[CrossRef][Medline] 26. Min JK, Cho CS, Kim HY, et al: Bone marrow findings in patients with adult Still's disease. Scand J Rheumatol 32:119-121, 2003[CrossRef][Medline] 27. Lee J, Chang JE, Cho YJ, et al: A case of reactive plasmacytosis mimicking multiple myeloma in a patient with primary Sjogren's syndrome. J Korean Med Sci 20:506-508, 2005[Medline] 28. Thiele J, Kvasnicka HM, Zankovich R, et al: The value of bone marrow histology in differentiating between early stage polycythemia vera and secondary (reactive) polycythemias. Haematologica 86:368-374, 2001 29. Shtalrid M, Shvidel L, Vorst E: Polyclonal reactive peripheral blood plasmacytosis mimicking plasma cell leukemia in a patient with staphylococcal sepsis. Leuk Lymphoma 44:379-380, 2003[CrossRef][Medline] 30. Gawoski JM, Ooi WW: Dengue fever mimicking plasma cell leukemia. Arch Pathol Lab Med 127:1026-1027, 2003[Medline] 31. Korolev AM: Reactive plasmacytosis with lytic lesions of the bone system in tuberculosis. Sov Med 32:151-152, 1969[Medline] 32. Gürsoy M, Haznedaroglu IC, Celik I, et al: Agranulocytosis, plasmacytosis, and thrombocytosis followed by a leukemoid reaction due to acute acetaminophen toxicity. Ann Pharmacother 30:762-765, 1996[Abstract] 33. Gorden L, Smith C, Graber SE: Marked plasmacytosis and immunoglobulin abnormalities following infusion of streptokinase. Am J Med Sci 301:186-189, 1991[Medline] 34. Rosenthal NS, Farhi DC: Reactive plasmacytosis and lymphocytosis in acute myeloid leukemia. Hematol Pathol 8:43-51, 1994[Medline] 35. Agnarsson BA, Loughran RP Jr, Starkebaum G, et al: The pathology of large granular lymphocyte leukemia. Hum Pathol 20:643-651, 1989[CrossRef][Medline] 36. Thiele J, Arenz B, Klein H, et al: Differentiation of plasma cell infiltrates in the bone marrow: A clinicopathological study on 80 patients including immunohistochemistry and morphometry. Virchows Arch A Pathol Anat Histopathol 412:553-562, 1988[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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staining. There was no significant increase in lymphocytes. Bone marrow cytogenetics were 46,XX in 20 metaphases. One hour after the patient received an apherised unit of platelets, the patient's platelet count increased from 8,000 to 65,000/µL and remained at 49,000/µL the next day. Seven days later, the WBC was 5,300/µL, hemoglobin was 9.2 g/dL, and platelet count was 3,000/µL. For a likely diagnosis of amegakaryocytic thrombocytopenia, the patient was given a 2-day course of intravenous immunoglobulin (IV Ig). 
N, Terzic T, Jovanovic V, et al: Acquired amegakaryocytic thrombocytopenia: Three case reports and a literature review. Med Pregl 57:292-297, 2004
