Case 9 -

Pseudosarcomatous ('Reactive') Myofibroblastic Proliferation Christopher D.M. Fletcher, M.D., FRCPath Department of Pathology Brigham and Women's Hospital and Harvard Medical School Boston, MA 02115

Clinical History A 33-year-old female presented with haematuria. At cystoscopy, the urologist identified a fleshy, focally necrotic 3 cm mass in the dome of the bladder. Transurethral resection was performed. Case 9 - Figure 1 Click to view with ImageScope Click to view with a Web-Based Viewer Pathologic Findings The specimen was received as multiple fragments of soft pinkish tissue, measuring in aggregate approximately 2 cm. These tissue fragments show a notably cellular submucosal spindle cell proliferation, covered in areas by intact non-dysplastic urothelium. There is focal surface ulceration and large areas of the lesion have a loose oedematous stroma. The spindle cells have eosinophilic cytoplasm and plump vesicular nuclei with variably prominent nucleoli. Notably, however, there is no nuclear hyperchromasia nor any significant degree of pleomorphism. In the more solidly cellular areas of the lesion, the tumour has a fascicular growth pattern, focally simulating leiomyosarcoma. Elsewhere, the lesional cells are very elongated and have a strap-like appearance, reminiscent of rhabdomyoblasts, although they are not as brightly eosinophilic as the latter. Throughout the tumour, even away from areas of ulceration, there is a prominent interstitial infiltrate of inflammatory cells, in this case consisting mostly of neutrophil polymorphs. At the deep aspect of the lesion, the tumour infiltrates between bundles of muscularis propria. Immunostaining shows multiple small foci of positivity for smooth muscle actin (SMA), more diffuse and striking positivity for desmin, diffuse positivity for keratin AE1/AE3 and, in addition, there is diffuse cytoplasmic positivity for ALK-1. Diagnosis: Pseudosarcomatous ('Reactive') Myofibroblastic Proliferation Lesions with histologic features similar to nodular or proliferative fasciitis have been recognized increasingly over the past two decades to occur also at visceral locations, especially the genitourinary tract and particularly the bladder. [1, 2, 3, 4, 5, 6, 7] Other rare locations in my experience include the peritoneal cavity, larynx and sinonasal tract. Although originally believed to be mainly post-traumatic (usually postoperative) in origin, it is now realized that most such cases are apparently spontaneous. These clinically benign lesions occur most often in young adults and sometimes in children. Sex incidence is approximately equal. Lesions in the bladder typically present with haematuria. In my experience, less than 50% of cases are clearly associated with a prior history of instrumentation or surgery of some kind – such cases are sometimes known as 'postoperative spindle cell nodule'. These lesions may be large, often measuring around 5 cm and sometimes larger and, when associated with a short history and dramatic symptoms, may be clinically very worrisome, making their pathologic interpretation especially anxiety-provoking. Local recurrence is very uncommon, is non-destructive and is usually associated with incomplete excision. Often, because of symptoms, limited partial cystectomy is necessary for bladder lesions – in such cases local recurrence almost never occurs. Histologically this group of lesions is characterised by fasciitis-like features but, because of mucosal ulceration and frequent involvement of the muscle coat (particularly in the bladder), there is often diagnostic concern for rhabdomyosarcoma, leiomyosarcoma or spindle cell (sarcomatoid) carcinoma. Such concern is enhanced by the frequent presence of elongated eosinophilic strap-like cells or plumper bizarre fibroblasts, similar to those seen in proliferative fasciitis. Morphologic clues to the correct diagnosis are the invariable presence of loose oedematous stroma as well as a mixed inflammatory infiltrate (even away from areas of mucosal ulceration). Furthermore, the spindle cell component does not show nuclear hyperchromasia nor significant pleomorphism. In addition, there is no evident origin from urothelium nor any urothelial dysplasia. Immunohistochemistry may not be so helpful in differential diagnosis since, in addition to consistent SMA positivity, these lesions are keratin positive in around 50% of cases and are also desmin positive in 30-40%, a phenotype entirely consistent with myofibroblastic differentiation but nevertheless unnerving on occasion ! Important pointers in the differential diagnosis are clinical context (spindle cell TCC would be very rare under age 40, while vesical rhabdomyosarcoma would be rare over age 10), the discohesive distribution of lesional cells in a prominent fibromyxoid stroma, the diffuse stromal inflammatory infiltrate (most often neutrophils and lymphocytes) and the absence of significant nuclear pleomorphism or hyperchromasia. Mitoses are variable in number but have normal morphology. Staining for myf-4 (myogenin) is consistently negative. These lesions are distinguished from inflammatory myofibroblastic tumor (IMT) by clinical context and the fact that the latter tends to have a much more prominent chronic inflammatory component, especially plasma cells, and may show some degree of nuclear atypia. Confusingly, however, it is now recognised that as many as 50% of these lesions may show immunopositivity for ALK-1, [8, 9] although this is usually focal. Having said that, in contrast to IMT, these lesions do not show ALK gene rearrangement [9] and, to date, they have never been shown to be locally aggressive nor to metastasise, whereas the latter biologic potential is well documented in around 5% of IMTs. References Proppe KH, Scully RE, Rosai J. Postoperative spindle cell nodules of genitourinary tract resembling sarcomas. A report of eight cases. Am J Surg Pathol 1984; 8: 101-108 Young RH, Scully RE. Pseudosarcomatous lesions of the urinary bladder, prostate gland and urethra. Arch Pathol Lab Med 1987; 111: 354-358 Albores-Saavedra J, Manivel JC, Essenfeld H et al. Pseudo-sarcomatous myofibroblastic proliferations in the urinary bladder of children. Cancer 1990; 66: 1234-1241 Lundgren L, Aldenborg F, Angervall L et al. Pseudomalignant spindle cell proliferations of the urinary bladder. Hum Pathol 1994; 25: 181-191 Hollowood K, Fletcher CDM. Pseudosarcomatous myofibroblastic proliferations of the spermatic cord ("proliferative funiculitis"). Am J Surg Pathol 1992; 16: 448-454 Ro JY et al. 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 Hojo H et al. Pseudosarcomatous myofibroblastic tumor of the urinary bladder in children: a study of 11 cases with review of the literature. Am J Surg Pathol 1995; 19:1224-1236 Tsuzuki T, Magi-Galluzzi C, Epstein JI. ALK-1 expression in inflammatory myofibroblastic tumor of the urinary bladder. Am J Surg Pathol 2004; 28:1609-1614 Hirsch MS, Dal Cin P, Fletcher CDM. ALK expression in pseudosarcomatous myofibroblastic proliferations of the genitourinary tract. Histopathology 2006; 48:569-578