Case 5 -

(Inflammatory) Pseudosarcomatous Myofibroblastic Proliferation of the Bladder Sharon W. Weiss Emory University School of Medicine Atlanta, GA

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Clinical History The patient is a 48-year-old male with a history of NF1 who presented with a nodular lesion of the bladder which was incompletely excised. Over a period of 3 months, three additional surgeries were necessary to control disease. Finally, because of progressive symptoms, the urologist elected to perform a total cystectomy. The specimen revealed an ulcerating lesion which extended through the bladder wall into perivesical fat. The patient died 2 years later of complications of NF1 but was not noted to have evidence of the recurrent bladder tumor. Case 5 - Figure 1 - Low-power view of bladder lesion showing ulcerated surface. Case 5 - Figure 2 - Irregularly intersecting fascicles of spindled cells associated with myxoid stroma characterize the lesion. Case 5 - Figure 3 - Arborizing vasculature is a prominent feature of the lesion. Case 5 - Figure 4 - Lesion involves muscularis propria of the bladder. Case 5 - Figure 5 - Lesion consists of myofibroblastic cells associated with inflammatory cells. Case 5 - Figure 6 - High-power view shows myofibroblastic cells associated with myxoid stroma. Areas like this closely resemble nodular fasciitis. Case 5 - Figure 7 - High-power view illustrating myofibroblastic features of lesions including amphophilic cytoplasm and vesicular nuclei. Note presence of mitotic figure. Diagnosis (Inflammatory) Pseudosarcomatous Myofibroblastic Proliferation of the Bladder Discussion Pseudosarcomatous myofibroblastic proliferation (PMP) was first described as a bladder-specific, fasciitis-like lesion by Roth, who termed it a "reactive pseudosarcomatous response." [8] Since that description, numerous reports have appeared attesting to the fact that the lesion, while appearing worrisome on a number of counts, is invariably benign and that similar lesions may occur in other submucosal locations such as the vagina, ureter, urethra, and prostate. The various terms applied to this lesion have included inflammatory fibromyoxid (pseudo) tumor, pseudomalignant spindle cell proliferation and inflammatory pseudotumor. "Post operative spindle" cell tumor," [5] a reactive lesion occurring in various organs following surgical trauma, probably represents a variation on the theme of PMP, rather than a distinct entity. PMP is a relatively uncommon lesion with greater than 100 cases reported in the literature. Its principal significance lies in the fact that it is easily confused with more common malignant lesions (e.g., sarcomatoid carcinoma). PMP occurs anytime from childhood to late adult life with the majority of patients experiencing hematuria and/or dysuria. [2, 4, 6] Efforts to identify the pathogenetic mechanism for those lesions which apparently occur in the absence of surgical trauma have not proved fruitful, although some patients have experienced urinary tract infections. The lesion develops as a nodular or polypoid mass in the bladder, ranging from a few to several centimeters in size (average of approximately 4-5 cm) and frequently complicated by mucosal ulceration. Grossly, the lesions appear variably myxoid. In the superficial or submucosal regions, spindled or multipolar, haphazardly-arranged myofibroblastic cells are associated with a myxoid-edematous stroma containing scattered inflammatory cells. In the deeper reaches of the lesion, edema and myxoid change are less striking and the cells tend to be aggregated in short fascicles around an intricate, branching vasculature. In some cases, the proliferation may involve blood vessels, muscularis propria and, in exceptional cases, the perivesical fat. Even in these cases with extensive growth, the overall appearance of the lesion remains unchanged in that the cells continue to resemble benign myofibroblasts, possessing neither cytologic atypia nor significant mitotic activity. Their immunohistochemical profile is consistent in most respects with myofibroblastic differentiation in that they express vimentin, actin, and desmin. An unexpected (and potentially confounding) finding is the common expression of cytokeratin by these cells. In our experience, this occurs in over three quarters of cases [2] and thus limits one's ability to use this antigen as a discriminator between carcinomas and PMP. Recently, expression of the ALK protein has been identified within a subset of PMP, but FISH has not confirmed that 2;5 translocation that characterizes the inflammatory myofibroblastic tumor (IMT) of childhood is present, suggesting that the two lesions are unrelated. [3] The outcome of patients with PMP is invariably excellent. Recurrences develop in about one quarter of patients, but no recurrence has resulted in destructive growth or death of a patient. Most importantly, there has been no recorded instance of metastasis. Whereas these outcome studies do not resolve the lingering question as to whether these lesions are reactive or neoplastic, they certainly underscore the need for a conservative approach for managing patients. Complete excision of the lesion is the ideal therapy, recognizing that in some cases, particularly those with mural extension, partial or even complete cystectomy is necessary. In this case a complete cystectomy was performed. Approximately 2 years after cystectomy the patient died of other complications related to neurofibromatosis, but there was no evidence of recurrence of the PMP. The differential diagnosis of PMP includes notably sarcomatoid carcinoma and leiomyosarcoma in adult patients and IMT and embryonal rhabdomyosarcoma in children. The fundamental observation in making the distinction between PMP and the various malignancies is that the latter always display varying degree of nuclear atypia and nuclear hyperchromasia, usually significant levels of mitotic activity, and often necrosis independent of areas of ulceration. In contrast, PMP contains typical myofibroblastic-appearing cells with regular round-oval nuclei with vesicular nuclear chromatin. Obviously, overlying in situ carcinoma and focal areas of epithelial differentiation are important ancillary observations in establishing a diagnosis of carcinoma. Although considerable immunophenotypic overlap exists among the various lesions in the differential diagnosis, leiomyosarcomas usually express desmin more strongly and diffusely than PMP, and rhabdomyosarcomas express the skeletal muscle-specific nuclear regulatory proteins myoD1 and myogenin. Perhaps the most problematic histologic distinction is the PMP from IMT. IMT is also characterized by a proliferation of myofibroblastic cells associated with inflammation. However, IMT also contains large rounded ganglion-like cells which show a varying degree of nuclear atypia. The inflammatory component is typically plasmacytic and lymphocytic, and there is often a prominent degree of hyalinization and even calcification. [1] Most IMT display clonality either in the form of translocations or other rearrangements targeting chromosome 2 short arm which create fusions between the ALK gene and the tropomyosin (TPM3 and TPM4) gene, which result in constitutively active ALK tyrosine kinase receptor. Fusions between ALK and the clathrin heavy chain (CTLC) have also been reported. Since IMT is associated with paraneoplastic symptoms and in some cases undergoes malignant transformation, the distinction is of more than academic interest. Perhaps the most intriguing question about PMP is whether they are reactive or neoplastic. The preponderance of evidence suggests a reactive process. This evidence includes their occurrence following trauma and their close resemblance to other reactive myofibroblastic proliferations such as nodular fasciitis. Nonetheless, it should be emphasized that their potential for extension through the bladder wall is at variance with the local growth potential of conventional nodular fasciitis, which seldom invades other structures and rarely achieves a size over 3 cm. Moreover, their common expression of keratin again contrasts with other reactive myofibroblastic proliferations. Although at least one report attesting to clonality of these lesions exists, it remains to be confirmed on a larger scale. References Coffin CM, Watterson J, Priest JR, Dehner LP. Extrapulmonary inflammatory myofibroblastic tumor (inflammatory pseudotumor). Am J Surg Pathol 1995; 19:859-872. Harik LR, Merino C, Coindre JM, Amin MB, Weiss SW. Pseudosarcomatous myofibroblastic proliferations of the bladder: a clinicopathologic study of 42 cases. Mod Path (abst), accepted 2004. Hirsh MS, Dal Cin P, Fletcher CDM. ALK expression in reactive, pseudosarcomatous myofibroblastic proliferation of the genitourinary tract. Mod Pathol 152A, 2003. Jones EC, Clement PB, Young RH. Inflammatory pseudotumor of the urinary bladder: a clinicopathological, immunohistochemical, ultrastructural, and flow cytometric study of 13 cases. Am J Surg Path 1993; 17:264-274. Proppe KH, Scully RE, Rosai J. Post-operative spindle cell nodules of genitourinary tract resembling sarcomas: report of eight cases. Am J Surg Pathol 1984; 8:101-108. Ro JY, El-Naggar A, Amin MB, Sahin AA, Ordonez NG, Ayala AG. Pseudosarcomatous fibromyxoid tumor of the urinary bladder and prostate: immunohistochemical, ultrastructural, and DNA flow cytometric analyses of nine cases. Hum Pathol 1993; 24:1203-1210. Roth JA. Reactive pseudosarcomatous response in the urinary bladder. J Urol 1980; 16:635-637.