Case 1 -

Inflammatory Myofibroblastic Tumor of the Uterus Marisa R. Nucci Brigham and Women's Hospital Boston, MA

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Clinical history: Myomectomy specimen from a 37 year old woman with menorrhagia and fibroids. Case 1 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 1 - Figure 1 Intramyometrial mass with predominantly rounded, pushing borders. Case 1 - Figure 2 In one area there is a slightly irregular interface with the myometrium. Note the prominent chronic inflammatory infiltrate. Case 1 - Figure 3 The tumor is composed of fascicular spindle cells set within a myxoid matrix. Case 1 - Figure 4 The spindle cells have palely eosinophilic cytoplasm and elongated nuclei with dispersed chromatin and occasional nucleoli. Case 1 - Figure 5 Chronic inflammatory cells, particularly plasma cells, are scattered throughout the tumor. Case 1 - Figure 6 Mitotic activity was scarce, but focally numbered up to 2 per 10 high power fields (arrows indicate mitotic figures). Diagnosis: Inflammatory Myofibroblastic Tumor of the Uterus Inflammatory myofibroblastic tumor (IMT) is a cellular, fascicular myofibroblastic/fibroblastic neoplasm with a variably myxoid to collagenous stroma and associated prominent lymphoplasmacytic infiltrate. [1, 2] Although first described in the lung, it is now well known that IMT can occur at a variety of anatomic sites with lung, mesentery, omentum and retroperitoneum representing the most common locations. IMT was recently recognized to also occur in the uterus, with a series of 6 cases reported. [3] Since this tumor has a wide anatomic distribution, a number of terms have been used historically to describe this entity; however, based on clinical and morphologic overlap, the majority of lesions formerly known as inflammatory pseudotumor, plasma cell granuloma, inflammatory fibrosarcoma, and omental-mesenteric myxoid hamartoma are now recognized to be IMTs. Clinical Features [1, 2, 3] IMT may occur at any age although they have a predilection for children and adolescents. Of the six cases that have been described in the uterus, the patients' ages ranged from 6 to 46 years. At extrauterine sites, patients typically present with non-specific symptoms related to its location such as cough and chest pain for pulmonary IMT or vague abdominal pain and discomfort for intraabdominal IMT. A constitutional syndrome consisting of fever, weight loss and malaise may be seen in 15-30% of patients. The most common symptoms of the patients with uterine IMT were menorrhagia and abdominal pain; one patient presented with weight loss and fever. Pathologic Features [1, 2, 3] Gross Features Uterine IMTs typically occur as a polyp extending from the lower uterine wall or as a circumscribed myometrial mass. On gross examination, IMTs may appear fibrous, fleshy or gelatinous. Uterine IMTs range in size from 1 to 12 cm (median 5 cm, mean 6 cm); this mean size at presentation is similar to extrauterine IMTs. Microscopic Features Histologically, IMT is characteristically a cellular, fascicular myofibroblastic/fibroblastic proliferation in a variably myxoid to collagenous stroma with an associated prominent lymphoplasmacytic infiltrate. Three patterns of IMT have been described: [1] 1) myxoid/vascular pattern 2) compact spindle cell pattern 3) fibromatosis-like pattern The myxoid/vascular pattern is composed of plump spindle cells in an edematous to myxoid matrix, having an appearance akin to fasciitis. The compact spindle cell pattern typically has spindle cells arranged in a fascicular or storiform pattern set in a more collagenous appearing stroma. The fibromatosis-like pattern is hypocellular with a densely collagenous to sclerotic, hyalinized matrix containing elongate (and less plump appearing) spindle cells. Uterine IMTs typically have rounded pushing borders with the myometrium but they may also have focally irregular borders; two of the six cases from the series of Rabban et al [3] infiltrated the endometrium and entrapped benign glands. Useful Diagnostic Criteria for recognition in the uterus Fasciitis-like, storiform, and/or fascicular appearance Typically pushing borders Myxoid to collagenous stroma Lymphoplasmacytic infiltrate Molecular Genetics [2] Cytogenetic and molecular genetic analyses have shown that approximately 50% of IMTs have rearrangements involving the ALK gene on chromosome 2p23. These abnormalities are more common in pediatric patients and have been described in tumors at both pulmonary and extrapulmonary sites. The case presented herein is the first description of ALK gene rearrangement (by FISH) in a uterine IMT. Immunohistochemical Profile [2, 3, 4] ALK gene rearrangement typically results in overexpression of ALK protein, which can be diagnostically useful. Approximately 50% of extrauterine IMTs will be positive for ALK by immunohistochemistry; however, ALK positivity is not entirely specific for IMT as it can be positive in other mesenchymal neoplasms, particularly MPNST and rhabdomyosarcoma. All uterine IMTs described to date (including the case presented herein) were positive for ALK (cytoplasmic) by immunohistochemistry. Behavior [2, 3, 5] According to the most recent WHO, IMTs are defined as a tumor of intermediate biologic potential because of their risk for local recurrence and metastasis. The risk of recurrence depends on site and ability for a complete resection. Tumors within the lung for example have a low risk of recurrence (of about 2%) as compared to tumors arising in the retroperitoneum (that tend to be multinodular), which have a recurrence risk of up to 25%. Histologic features however do not reliably predict which IMTs will behave in an aggressive fashion. In the four patients with uterine IMT with followup, all are alive with no evidence of disease at 1.5 - 5 years; two patients were treated with hysterectomy (NED at 2.5 and 5 years) and two patients were treated with hysteroscopic resection (NED at 1.5 and 3 years). Distant metastasis of IMT is rare but may occur years (up to a decade) after initial excision. Differential Diagnosis: Leiomyosarcoma, myxoid variant [6, 7, 8, 9, 10] Similar to the conventional spindle cell type of uterine leiomyosarcoma, this variant also typically affects women in their sixth decade who may present with abnormal vaginal bleeding, pelvic pain and/or a pelvic mass. However, in contrast, myxoid leiomyosarcoma usually will have a more gelatinous gross appearance with a glistening cut surface, although this may vary in extent depending on the amount of extracellular myxoid matrix deposition. The tumor cells may be spindled or stellate and the degree of (Alcian blue positive) extracellular matrix deposition may obscure the tumors fascicular architecture. Although the majority of the tumor may have a bland cytomorphologic appearance, tumor cells typically exhibit at least focal moderate atypia. Diagnostic criteria separating myxoid leiomyosarcoma from myxoid leiomyoma is not well established since this type of tumor is rare. Atkins et al. have suggested that a mitotic rate in excess of 2 per 10 high power fields, regardless of the presence or absence of either atypia or necrosis, will separate benign and malignant myxoid tumors. For practical purposes, the diagnosis of myxoid leiomyosarcoma should be considered if any of the following is present: 1) There is moderate to marked cytologic atypia. 2) There is coagulative tumor cell necrosis. 3) Mitotic activity exceeds 2 per 10 high power fields. 4) There is destructive infiltration of the surrounding myometrium. Inflammatory myofibroblastic tumor [3] can be distinguished from myxoid leiomyosarcoma by its 1) typically pushing border without vascular invasion, 2) its prominent lymphoplasmacytic infiltrate and 3) its immunohistochemical expression of ALK. Leiomyoma, myxoid variant Because uterine IMTs typically have a rounded, pushing border and may have a fascicular growth pattern and myxoid appearance, myxoid leiomyoma may be considered in the differential diagnosis. On gross examination this extremely uncommon variant of leiomyoma typically appears gray and gelatinous although this feature depends on the extent of myxoid change within the tumor. Histologically, an abundant pale blue myxoid matrix separates the bland appearing smooth muscle bundle fibers. Features helpful in the recognition of IMT vs a myxoid leiomyoma is the presence in the former of 1) a fasciitis-like growth pattern, 2) a storiform growth pattern (if present), 3)a lymphoplasmacytic infiltrate and 4) positive staining for ALK by immunohistochemistry. Endometrial Stromal Sarcoma, Myxoid Variant Similar to IMT, the myxoid variant of endometrial stromal sarcoma [11] also may present as a polypoid endometrial mass however, it, 1) has a characteristic multinodular or tongue-like pattern of myometrial infiltration, 2) at least focally exhibits the presence of typical endometrial stromal neoplasia with its characteristic growth pattern and prominent (arteriolar) vascular component, and 3) is negative for ALK-1 by immunohistochemistry. Take Home Message 1) The myxoid variant of leiomyosarcoma should be considered if any one of the following histologic features are present in a myxoid smooth muscle tumor: moderate to severe nuclear atypia (i.e. discernible at 4X), tumor cell necrosis, mitotic activity > 2 per 10 high power fields, and destructive infiltration of the myometrium. 2) Myxoid leiomyoma is uncommon and should only be considered if a myxoid smooth muscle tumor is well circumscribed, lacks significant cytologic atypia, lacks tumor cell necrosis, and has a mitotic count of < 2 per 10 high power fields. References 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. Gleason B, Hornick J. Inflammatory myofibroblastic tumours: where are we now? J Clin Pathol 2007. Rabban JT, Zaloudek CJ, Shekitka KM, Tavassoli FA. Inflammatory myofibroblastic tumor of the uterus: a clinicopathologic study of 6 cases emphasizing distinction from aggressive mesenchymal tumors. Am J Surg Pathol 2005;29:1348-55. 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. Coffin CM, Hornick JL, Fletcher CD. Inflammatory myofibroblastic tumor: comparison of clinicopathologic, histologic, and immunohistochemical features including ALK expression in atypical and aggressive cases. Am J Surg Pathol 2007;31:509-20. King ME, Dickersin GR, Scully RE. Myxoid leiomyosarcoma of the uterus. A report of six cases. Am J Surg Pathol 1982;6:589-98. Kunzel KE, Mills NZ, Muderspach LI, d'Ablaing G, III. Myxoid leiomyosarcoma of the uterus. Gynecol Oncol 1993;48:277-80. Chang E, Shim SI. Myxoid leiomyosarcoma of the uterus: a case report and review of the literature. J Korean Med Sci 1998;13:559-62. Atkins K, Bell S, Kempson RL, Hendrickson MR. Myxoid smooth muscle tumors of the uterus [abstract]. Mod Pathol 2002;14:132A. Vigone A, Giana M, Surico D, Leutner M, Surico N. Massive myxoid leiomyosarcoma of the uterus. Int J Gynecol Cancer 2005;15:564-7. Oliva E, Young RH, Clement PB, Scully RE. Myxoid and fibrous endometrial stromal tumors of the uterus: a report of 10 cases. Int J Gynecol Pathol 1999;18:310-9.