—  SHORT COURSE #52  —

Soft Tissue Tumors in Children and Adolescents:
A Morphologic Pattern Oriented Approach with Molecular and Genetic Correlations

Section 7 - Inflammatory Myofibroblastic Tumor

Cheryl M. Coffin, M.D.
David M. Parham, M.D.


Clinical History:
A 7-year old girl with anemia and thrombocytosis was found to have a large abdominopelvic mass. Laboratory abnormalities included anemia, thrombocytosis, elevated erythrocyte sedimentation rate, and elevated C-reactive protein. She underwent resection of an 11 cm tan, whorled mass with focal necrosis. The laboratory abnormalities resolved after surgery.

Discussion and Differential Diagnosis:
This case represents an example of inflammatory myofibroblastic tumor with thrombocytosis, megakaryocytic hyperplasia, and a unique chromosomal translocation with ALK rearrangement. The points for discussion are the clinicopathologic and molecular genetic features of IMT, its classification, and differential diagnosis.

The 300 g, 11.0 cm, tan, whorled mass had a predominantly spindled inflammatory cellular pattern with unusual histologic features of coagulative necrosis, foci of high cellularity with a herringbone pattern, and clusters of multinucleated giant cells within the tumor. Immunohistochemical staining revealed cytoplasmic reactivity for smooth muscle actin and ALK1 in the spindle cells and strong membranous cytoplasmic CD61 reactivity in the multinucleated giant cells, indicative of megakaryocytic differentiation. The cytogenetic analysis revealed a complex tumor karyotype including a translocation t(1;2)(q21;p23).

In the current WHO Classification, IMT is defined as a distinctive neoplasm of intermediate grade with a low risk of metastasis. It is composed of myofibroblastic spindle cells accompanied by an inflammatory infiltrate of plasma cells, lymphocytes, and eosinophils. Although primarily a visceral and soft tissue tumor of children and young adults, the age range extends throughout life and the abdominopelvic region is a common site. Up to one-third of patients experience the clinical syndrome of fever, growth failure, malaise, weight loss, anemia, thrombocytosis, polyclonal hyperglobulinemia, and elevated erythrocyte sedimentation rate. A variety of cytogenetic and molecular genetic abnormalities have been reported in IMT and these have in common clonal cytogenetic arrangements that involve the ALK-receptor tyrosine kinase gene at chromosome 2p23. Immunohistochemical reactivity for ALK-1 correlates well with the presence of ALK gene rearrangements detectable by fluorescent in situ hybridization, cytogenetics, or RT-PCR. Fusion oncogenes with ALK include tropomyosin 3, tropomyosin 4, clathrin, and other genes. Local recurrence develops in 25% of cases, fewer than 5% metastasize to distant sites, and rare cases undergo histologic evolution to a high-grade spindle cell or round cell neoplasm. At present surgery is the principal treatment, although regression and response to various pharmacologic agents have been reported in individual cases. Reliable prognostic indicators remain elusive; absence of an ALK rearrangement may portend a higher risk of metastasis.

The differential diagnosis of inflammatory myofibroblastic tumor includes infectious and reactive processes, dendritic cell neoplasms, lymphoma, fibromatoses, nodular fasciitis, fibrous histiocytoma, smooth muscle neoplasms, sarcomatoid carcinoma, melanoma, rhabdomyosarcoma, and other spindle cell neoplasms. Distinction between IMT and these lesions depends in part on the histologic appearance of IMT, which can have a variety of histologic patterns including a myxoid vascular pattern, a compact inflammatory fascicular pattern, and a collagenized scar-like pattern. Usually histology and immunohistochemistry are sufficient to establish the diagnosis. ALK abnormalities are found in approximately one-half to two-thirds of cases, but may also be seen in a anaplastic large cell lymphoma and rhabdomyosarcoma. Inflammatory pseudotumor of lymph nodes and spleen is a separate entity from IMT.

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