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Journal of Clinical Oncology, Vol 24, No 36 (December 20), 2006: pp. 5783-5784 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.08.4673
Hemophagocytic Alveolar RhabdomyosarcomaDepartment of Pediatrics, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan
Department of Pathology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan A 16-year-old Japanese boy presented with a 5-month history of an enlarging nontender lump on the hypothenar eminence of his left hand. The mass was firm and elastic in consistency, with normal skin color and no fluctuation. Magnetic resonance imaging of the left hand confirmed the presence of a well-delineated, homogeneous solid mass, 20 x 30 mm in size. The mass was hypointense relative to muscle on T1-weighted imaging and heterogeneously hyperintense on T2-weighted imaging, suggestive of internal necrosis or hemorrhage (Fig 1A). Magnetic resonance imaging with gadolinium enhancement indicated the tumor was encapsulated (Fig 1B).
A complete blood picture showed: leukocyte count, 4,300/mL; hemoglobin, 7.9 g/dL; and platelet count, 67,000/µL. Bone marrow examination revealed a nucleated cell count of 73,000/µL with 68.6% of mononuclear blastic cells characterized by large hyperchromatic nuclei and vacuolated cytoplasm. Clumps of blastic cells were present and infiltrated with phagocytic macrophages (Fig 2A; x400 magnification). Cytometric studies indicated the cells lacked common leukocyte antigens (CD45), but were solely immunoreactive for CD56, suggesting a nonhematologic cell origin. Representative spectral karyotyping showed hyperdiploid with an aberrant karyotype, 66, XY, –X, –1, t(2;13)(q35;q14)x2, –3, +5, der(5)t(1,5)(q21;q22)x2, del(11)(p15), +12, +del(15)(q15), –16, –17, –18, –19, +20, +21, –22. Biopsy sections of the left hand mass demonstrated small, round tumor cells arranged in nests with spaces and surrounded by a fibrous stroma, exhibiting an alveolar pattern (Fig 2B; x200 magnification). Cells were immunoreactive for desmin and myogenin. Using reverse transcriptase polymerase chain reaction techniques, PAX3-FKHR fusion gene products were amplified in both bone marrow and biopsy specimens. A diagnosis of alveolar rhabdomyosarcoma (ARMS) was established.
Additional laboratory data showed the presence of tumor lytic syndrome and hypercalcemia (14.3 mg/dL) without apparent disseminated intravascular coagulopathic manifestations. The patient received immediate interventions with hydration, alkalization, and administration of allopurinol and bisphosphonates. Abrupt onset of spiking fever and pancytopenia refractory to transfusion were noted on hospital day 2. Hyperferritinemia (1,906 ng/mL; normal, 39.9 to 465 ng/mL) and elevated concentrations of circulating soluble interleukin-2 receptor (1,140 U/mL; normal, 220 to 530 U/mL) and serum neopterin (81 nmol/L; normal, < 10 nmol/L) were suggestive of active hemophagocytic syndrome (HPS). Repeated bone marrow examination demonstrated unusual features showing phagocytosis of leukocytes, erythrocytes, platelets, and other cellular debris by tumor cells (Fig 2C; x1,000 magnification), in addition to visually increased numbers of phagocytic macrophages. The patient underwent administration of methylprednisolone sodium succinate (30 mg/kg) for 2 consecutive days, which promptly resolved symptoms associated with HPS. The patient subsequently received five courses of intensive chemotherapy comprising vincristine, actinomycin-D, cyclophosphamide, etoposide, pirarubicin, cisplatin, and ifosfamide, followed by radiotherapy (41.4 Gy) to the left hand. Despite complete remission in bone marrow after the fifth course of chemotherapy, a pulmonary metastatic nodule (diameter, 9 mm) was found on computed tomography of the chest (Fig 3; arrows). High-dose chemotherapy comprising melphalan and thiotepa, in conjunction with autologous peripheral blood stem-cell transplantation was administered and the residual metastasis was surgically resected. The patient remains alive, 10 months after first admission.
ARMS is an aggressive soft tissue malignancy occurring in children and adolescents.1 Most ARMS patients express PAX3-FKHR or PAX7-FKHR gene fusions resulting from specific chromosomal translocations of t(2;13) or t(1;13), respectively.2-4 Although fewer than 25% of children with rhabdomyosarcoma present with metastatic disease,1 the initial presentation of ARMS with bone marrow metastasis mimicking acute leukemia is rare.5 However, morphologic resemblance of cells to lymphoblasts may often lead to misdiagnosis in cases with leukemic rhabdomyosarcoma until additional information is provided including immunophenotypic and cytochemistric features, characteristic chromosomal changes and molecular analyses. Hemophagocytosis by leukemic blasts has been described and is characteristic in acute myeloid leukemia with t(8;16)(p11;p13), inv(8)(p11q13), or t(16;21)(p11;q22).6 However, the finding of hemophagocytosis in ARMS is extremely rare,7 and concurrent HPS has not previously been reported. HPS may develop in association with malignant diseases (malignancy-associated hemophagocytic syndrome), in which activated macrophages and released cytokines, including interferon-  ,8 soluble interleukin-2 receptor,8 neopterin,9 and interleukin-18,10 are known to play major roles. Only pathologic evidence is available to indicate that both mature and immature human muscle fibers exhibit phagocytic capacities to eliminate apoptotic muscle cells,11 and the precise mechanisms and pathophysiology of this unusual behavior of ARMS warrant further investigation. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES 1. Wexler LH, Meyer WH, Helman LJ: Rhabdomyosarcoma and the undifferentiated sarcomas, in Pizzo PA, Poplack DG (eds): Principles and Practice of Pediatric Oncology (ed 5). Philadelphia, PA, Lippincott Williams & Wilkins, 2006 2. Barr FG, Galili N, Holick J, et al: Rearrangement of the PAX3 paired box gene in the paediatric solid tumour alveolar rhabdomyosarcoma. Nat Genet 3:113-117, 1993[CrossRef][Medline] 3. Shapiro DN, Sublett JE, Li B, et al: Fusion of PAX3 to a member of the fork head family of transcription factors in human alveolar rhabdomyosarcoma. Cancer Res 53:5105-5112, 1993 4. Davis RJ, D'Cruz CM, Lovell MA, et al: Fusion of PAX7 to FKHR by the variant t(1;13)(p36;p14) translocation in alveolar rhabdomyosarcoma. Cancer Res 54:2869-2872, 1994 5. Sandberg AA, Stone JF, Czarnecki L, et al: Hematologic masquerade of rhabdomyosarcoma. Am J Hematol 68:51-57, 2001[Medline] 6. Imashuku S, Hibi S, Sako M, et al: Hemophagocytosis by leukemic blasts in 7 acute myeloid leukemia cases with t(16;21)(p11;q22). Cancer 88:1970-1975, 2000[CrossRef][Medline] 7. Tosi WC, Feng CS: Hemophagocytosis by rhabdomyosarcoma cells in bone marrow. Am J Hematol 54:340-342, 1997[CrossRef][Medline] 8. Janka G, Imashuku S, Elinder G, et al: Infection- and malignancy-associated hemophagocytic syndromes: Secondary hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am 12:435-444, 1998[CrossRef][Medline] 9. Hamerlinck FF: Neopterin: A review. Exp Dermatol 8:167-176, 1999[CrossRef][Medline] 10. Larroche C, Mouthon L: Pathogenesis of hemophagocytic syndrome (HPS). Autoimmun Rev 3:69-75, 2004[CrossRef][Medline] 11. Fidzianska A, Goebel HH: Phagocytic capacity of human muscle fibers. Hum Pathol 23:1044-1047, 1992[CrossRef][Medline]
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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