Case 12 -

Inflammatory Myofibroblastic Tumor D. Ashley Hill, M.D. Mihaela Onciu M.D.

Case History: 18-year-old boy who presented with symptoms of esophageal dysfunction. Radiographic studies showed a lung/mediastinal mass. Gross Examination: The specimens were received in two parts representing mediastinal tumor with left lower lobe of lung and the lesser curvature of the stomach. Sections of lung and mediastinal soft tissue showed a 7.5 x 5.5 x 4.6 cm white fibrous mass with a pushing border. The tumor did not involve the bronchial structures. Sections of the stomach showed a white-tan mass extending from the serosa into the gastric wall. The gastric mucosa over the lesion was ulcerated. Microscopic Examination: Both the lung and gastric portions of the tumor had similar morphologic features. Sections showed a cellular spindle cell proliferation with a prominent inflammatory infiltrate consisting primarily of lymphocytes and plasma cells. The central regions of the tumor were less cellular and more collagenous and showed dystrophic calcification. The spindle cells had morphologic features of myofibroblasts with bland regular nuclei. Although macroscopically the tumor had a pushing border, infiltration of the lung parenchyma at the periphery of the mass was seen. Diagnosis: Inflammatory myofibroblastic tumor Discussion Inflammatory myofibroblastic tumor (IMT) is a mesenchymal neoplasm composed of proliferating myofibroblasts with a background lymphoplasmacytic infiltrate. Most patients are young (9-10 years) but the age range is broad with cases in young infants and octogenarians reported. Most patients present with a mass, with or without constitutional manifestations including fever, weight loss, night sweats and malaise. Laboratory abnormalities such as an elevated erythrocyte sedimentation rate, anemia, thrombocytosis and hypergammaglobulinemia are present in 15-30% of patients. These systemic manifestations typically disappear with resection of the lesion. IMT's are found in many sites including lung, mesentery, gastro-intestinal tract, omentum, head and neck, retroperitoneum, liver, bladder, kidney, heart and mediastinum. Extrapulmonary tumors appear to affect a younger group of patients and are more likely to be multinodular. Surgical removal is the treatment of choice but a complete excision may be limited by site considerations and multifocality of the tumor. The recurrence rate of extrapulmonary tumors is reported to range from 10% to 25%. Most of these recurrent tumors involve the mesentery, omentum and retroperitoneum. Pathologic Features Grossly, IMTs are typically rubbery, nodular white-tan tumors ranging from 2 to 20 cm (average 5-10 cm). Some tumors, particularly intra-abdominal examples can be multifocal (e.g. multiple separate nodules in the mesentery or omentum). Three histologic patterns of IMT have been described: 1) a myxoid/vascular pattern where stellate and spindled cells are arranged in a loose, myxoid background with vascular proliferation and inflammatory cells resembling nodular fasciitis or granulation tissue; 2) a compact spindle cell pattern with hypercellular areas of spindle cells in a storiform or fascicular arrangement resembling a variety of spindle cell neoplasms including smooth muscle, fibrohistiocytic and gastrointestinal stromal tumors; and 3) a hypocellular fibrous pattern with residual spindle cells and scattered inflammatory cells in a collagenous background resembling a scar or desmoid fibromatosis. Any given tumor may have a predominance of one or another pattern. These patterns are not predictive of clinical behavior. Mitotic figures may be numerous but no atypical forms should be seen. The inflammatory component contains predominantly plasma cells and lymphocytes, the latter may form lymphoid aggregates or follicles. Malignant change appears to be an uncommon event. Many of the tumors showing malignant transformation have a distinctive morphologic appearance in which the typical spindle cells are accompanied by polygonal cells with large round nuclei, prominent nucleoli and abundant eosinophilic cytoplasm resembling ganglion cells. Atypical mitotic forms may be seen in association with this change. Differential Diagnosis Because IMTs can be confused with both reactive processes as well as potentially malignant neoplasms, distinguishing them from their histologic mimics is important in assuring appropriate patient management. The variety of patterns in IMT results in a broad differential diagnosis including nodular fasciitis, desmoid fibromatosis, gastrointestinal stromal tumor, smooth muscle neoplasms, inflammatory fibroid polyps and idiopathic fibrosclerosing lesions. Many of these entities can be distinguished by clinical and macroscopic features. Idiopathic fibrosclerosing lesions such as sclerosing mediastinitis, idiopathic retroperitoneal fibrosis and Riedel's thyroiditis are typically seen in adults and usually form ill-defined masses with entrapment of normal structures. Inflammatory fibroid polyps are typically solitary, submucosal lesions in the stomach or ileum that is characterized by stellate cells in a myxoid stroma and an eosinophil-rich inflammatory infiltrate. Immunohistochemistry and molecular genetics can be helpful in some cases. The myofibroblasts in IMTs are positive for vimentin and usually positive for smooth muscle actin (92%). Muscle-specific actin is positive in 89% of cases. Desmin staining can be seen in 69% and is usually focal. About 1/3 are positive for cytokeratin and 1/4 are positive for CD68. Focal reactivity for CD30 was seen in 6% of cases. ALK immunohistochemistry is positive in approximately 60% of IMTs and is thus helpful when it is positive. ALK-positivity is seen with higher frequency in intra-abdominal IMTs from young patients. Spleen and lymph node IMTs are typically negative. The relationship of the IMT to the inflammatory fibrosarcoma described by Meis and Enzinger is still unclear although by WHO classification, both tumors are grouped together. There is clearly clinical and morphologic overlap between the two lesions as initially described, and the potential for local recurrence and less commonly metastatic disease in both entities is recognized. Neither morphologic features nor genetic aberrations have been reliably predictive of outcome in either entity. Perhaps more important than the preferred designation is the appropriate communication with the surgeons and treating physicians regarding the potential aggressive behavior of these lesions with the assurance of appropriate long-term follow-up. Clinical Course While most IMTs follow a non-recurring clinical course after complete surgical excision, a subset of cases may be locally aggressive, recurrent, or rarely metastatic. In rare instances where tumors have metastasized, the lungs and brain appear to be the favored sites. Adjuvant therapy for IMTs with malignant transformation is unproven although rare reports describing good responses to chemotherapy and/or radiation therapy exist. Pathogenesis IMTs were originally lumped in the category of "inflammatory pseudotumor" which designates a variety of tumefactive lesions whose basic morphologic composition is spindle cells and a lymphocytic or lymphoplasmacytic infiltrate. Some inflammatory pseudotumors are represented by reparative lesions both idiopathic and post-operative (e.g. post-operative spindle cell tumor of the bladder). Another subset of inflammatory pseudotumors has been associated with a variety of infectious agents including Epstein-Barr virus (EBV), Actinomyces, Pseudomonas species, mycobacteria, and human herpesvirus-8. The follicular dendritic cell or spindled histiocyte is the principal type of spindle cell involved in some of the infection-associated lesions, particularly those in the liver and spleen. IMT's represent a third subset of inflammatory pseudotumors, characterized clinically by a potential for aggressive local growth, multifocality, and occasional malignant transformation. The discovery of clonal cytogenetic aberrations involving the anaplastic lymphoma kinase gene on chromosome band 2p23 led to reclassification of this subgroup as a neoplasm of myofibroblasts rather than infections or reactive process. ALK gene fusions with either of two related tropomyosin genes TPM3 and TPM4, the clathrin heavy chain gene, CLTC or Ran-binding protein 2, RANBP2, among other gene fusion partners confirms that these lesions are truly neoplastic. ALK is a member of the insulin receptor family of receptor tyrosine kinases and its expression is normally restricted to the nervous system. ALK gene fusions were first identified in anaplastic large cell lymphomas (ALCL), in which most commonly a t(2;5) chromosomal translocation generates an NPM-ALK gene fusion and a constitutively activated chimeric protein. Interestingly, both TPM3-ALK and CLTC-ALK fusions have also been described in anaplastic large cell lymphoma, indicating that the identical fusion proteins are involved in the pathogenesis of both mesenchymal and lymphoid neoplasms. The sole common characteristic shared by the various ALK fusion partner proteins is the presence of a known or putative N-terminal oligomerization motif. The fusion of various N-terminal oligomerization motifs from partner proteins to a truncated tyrosine kinase (ALK) leads to unregulated constitutive activation of the kinase catalytic domain. Diagnostically, these gene fusions are useful in that they typically result in overproduction of the ALK protein which can be detected by immunohistochemical means. Recommended Reading Coffin CM, Watterson J, Priest JR, Dehner LP. Extrapulmonary inflammatory myofibroblastic tumor (inflammatory pseudotumor). A clinicopathologic and immunohistochemical study of 84 cases. Am J Surg Pathol 1995;19:859-72. Coffin CM, Humphrey PA, Dehner LP. Extrapulmonary inflammatory myofibroblastic tumor: a clinical and pathological survey. Semin Diagn Pathol 1998;15:85-101. Meis-Kindblom JM, Kjellstrom C, Kindblom LG. Inflammatory fibrosarcoma: update, reappraisal, and perspective on its place in the spectrum of inflammatory myofibroblastic tumors. Semin Diagn Pathol 1998;15:133-43. Coffin CM, Dehner LP, Meis-Kindblom JM. Inflammatory myofibroblastic tumor, inflammatory fibrosarcoma, and related lesions: an historical review with differential diagnostic considerations. Semin Diagn Pathol 1998;15:102-10. Dehner LP. The enigmatic inflammatory pseudotumours: the current state of our understanding, or misunderstanding. J Pathol 2000;192:277-9. Cook JR, Dehner LP, Collins MH et al. Anaplastic lymphoma kinase (ALK) expression in the inflammatory myofibroblastic tumor: a comparative immunohistochemical study. Am J Surg Pathol 2001;25:1364-71. Cessna MH, Zhou H, Sanger WG et al. Expression of ALK1 and p80 in inflammatory myofibroblastic tumor and its mesenchymal mimics: a study of 135 cases. Mod Pathol 2002;15:931-8. Hussong JW, Brown M, Perkins SL, Dehner LP, Coffin CM. Comparison of DNA ploidy, histologic, and immunohistochemical findings with clinical outcome in inflammatory myofibroblastic tumors. Mod Pathol 1999;12:279-86. Cheuk W, Chan JKC, Shek T, et al. Inflammatory pseudotumor-like follicular dendritic cell (IP-FDC) tumor: A distinctive low-grade malignant intra-abdominal neoplasm with consistent Epstein-Barr virus association. Am J Surg Pathol 2001;25:721-31. Neuhauser TS, Derringer GA, Thompson LDR, et al. Splenic inflammatory myofibroblastic tumor (inflammatory pseudotumor): A clinicopathologic and immunophenotypic study of 12 cases. Arch Pathol Lab Med 2001; 125:379-385. Kutok JL, Pinkus GS, Dorfman DM, Fletcher CD. Inflammatory pseudotumor of lymph node and spleen: an entity biologically distinct from inflammatory myofibroblastic tumor. Hum Pathol 2001;32:1382-7. Kapusta LR, Weiss MA, Ramsay J, Lopez-Beltran A, Srigley JR. Inflammatory myofibroblastic tumors of the kidney: a clinicopathologic and immunohistochemical study of 12 cases. Am J Surg Pathol 2003 May; 27(5): 658-66. Morris SW, Naeve C, Mathew P, et al. (1997) ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin's lymphoma encodes a neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK). Oncogene 1997;14:2175-2188. Griffin CA, Hawkins AL, Dvorak C, et al. Recurrent involvement of 2p23 in inflammatory myofibroblastic tumors. Cancer Res 1999;59:2776-2780. Drexler HG, Gignac SM, von Wasielewski R, et al. Pathobiology of NPM-ALK and variant fusion genes in anaplastic large cell lymphoma and other lymphomas. Leukemia 2000;14:1533-1559. Lawrence B, Perez-Atayde A, Hibbard MK, et al. TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors. Am J Pathol 2000;157:377-384. Ma Z, Hill DA, Collins MH et al. Fusion of ALK to the Ran-binding protein 2 (RANBP2) gene in inflammatory myofibroblastic tumor. Genes Chromosomes Cancer 2003;37:98-105. Bridge JA, Kanamori M, Ma Z et al. Fusion of the ALK gene to the clathrin heavy chain gene, CLTC, in inflammatory myofibroblastic tumor. 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