Inflammatory Myofibroblastic Tumor of the Bladder

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1 Inflammatory Myofibroblastic Tumor of the Bladder We illustrate a case of an inflammatory myofibroblastic tumor (IMT) involving the bladder in a woman with dysuria and review the literature and differential diagnosis. Inflammatory myofibroblastic tumor, also referred to as pseudosarcomatous myofibroblastic proliferation, is a rare lesion that can arise in the genitourinary system and is characterized by a fascicular arrangement of myofibroblasts with admixed inflammatory cells and slitlike vessels. Urinary bladder IMT can be a diagnostic pitfall because its histologic features (brisk mitoses, invasion into muscularis propria, and prominent nucleoli) can mimic malignancy. The differential diagnosis of urinary bladder IMT includes sarcomatoid carcinoma and leiomyosarcoma. Diagnostic features such as bland nuclear chromatin, ganglion-like cells, pale eosinophilic cytoplasm with long processes, overexpression of anaplastic lymphoma kinase (immunohistochemistry or gene rearrangement studies), and the absence of atypical mitoses help distinguish IMT from its malignant mimics. Current controversies regarding postoperative spindle cell nodule and IMT are discussed. (Arch Pathol Lab Med. 2014;138: ; doi: /arpa CC) STUDY CASE A 38-year-old woman with no previous surgical history was seen with dysuria and pelvic pain. A computed tomographic scan showed a nodular-appearing bladder mass, and the patient underwent a transurethral resection of the mass. The urinary bladder transurethral resection showed the lamina propria expanded by a spindle cell proliferation (Figure 1, A and B). The architecture varied from areas of hypocellular spindle cells arranged in loose fascicles with background myxoid to edematous stroma to more cellular areas with compact spindle cells. The spindle cells had ovoid to fusiform nuclei with eosinophilic cytoplasm and elongated, delicate cytoplasmic processes. Most nuclei had finely dispersed chromatin with variably prominent nucleoli. Mitotic figures and necrosis were not readily apparent. The background showed prominent Accepted for publication June 2, From the Department of Pathology, University of Michigan Medical School, Ann Arbor. The authors have no relevant financial interest in the products or companies described in this article. Presented in part at New Frontiers in Pathology: An Update for Practicing Pathologists; September 28, 2013; Ann Arbor, Michigan. Reprints: Megan Alderman, MD, Department of Pathology, University of Michigan Medical School, 1301 Catherine St, Mail Stop I4232, Ann Arbor, MI ( malderm@umich.edu). Megan Alderman, MD; Lakshmi P. Kunju, MD vasculature, including small, slitlike vessels with interspersed inflammatory cells. The fascicles of spindle cells focally entrapped thick smooth muscle bundles consistent with muscularis propria (Figure 1, C). The spindle cells showed cytoplasmic positivity with anaplastic lymphoma kinase 1 (ALK-1) and expressed smooth muscle actin (SMA). In addition, the spindle cells were negative for CK903 and desmin. The final diagnosis was inflammatory myofibroblastic tumor (IMT). This case will be used to discuss the diagnostic features of IMT, to present the differential diagnosis of spindle cell lesions arising in the urinary bladder, and to review the immunoprofile of such tumors and their molecular findings. COMMENT Inflammatory myofibroblastic tumor is an enigmatic, uncommon spindle cell lesion that can occur in the urinary bladder and multiple other sites and has gone by different names over the years (inflammatory pseudotumor, pseudosarcomatous fibromyxoid tumor, and nodular fasciitis). The pathogenesis of IMT remains obscure, with possible etiologies including autoimmune disease and infectious organisms. Controversy still exists as to whether an IMT is truly a neoplastic process, although recent molecular discoveries, as will be discussed herein, suggest a clonal process. Inflammatory myofibroblastic tumor has been reported with some frequency in both sexes across a wide spectrum of ages (7 days to 88 years). 1,2 A recent review article showed that most IMTs arising in the genitourinary tract occur in the fourth to fifth decades of life, with a male predilection (1.33:1 ratio). 1 In the genitourinary tract, IMT most frequently arises in the bladder, although it has been documented in the kidney, urethra, prostate, ureter, and rete testis. 3 The most common clinical finding at presentation is hematuria. Other less common clinical presentations include infection, abdominal/pelvic pain, and obstructive symptoms. Rarely, patients are seen with systemic symptoms such as fever and weight loss, which have been attributed to cytokine production. 4 The distinction, or potential lack thereof, between IMT and postoperative spindle cell nodule (PSCN) is controversial. Originally described in 1984 by Proppe et al, 5 PSCN represents a benign reactive myofibroblastic proliferation of the genitourinary tract that arises uniquely after instrumentation, usually a surgical procedure. Both PSCN and IMT share significant histologic and immunohistochemical overlap. Some authors who believe that IMT is biologically a distinct entity with malignant potential prefer the term pseudosarcomatous myofibroblastic proliferation to encompass PSCN and similar lesions. 6 Most recently, the term low Arch Pathol Lab Med Vol 138, October 2014 Inflammatory Myofibroblastic Tumor of the Bladder Alderman & Kunju

2 Figure 1. A, Inflammatory myofibroblastic tumor typically shows a loose, fascicular architecture with tapered myofibroblasts and lightly eosinophilic elongated cytoplasmic processes. Background slitlike blood vessels are present, as well as mixed inflammation, shown here as eosinophils, lymphocytes, and scattered plasma cells. B, Variably prominent delicate nucleoli may be present, but no significant cytologic atypia are seen. C, Urinary bladder inflammatory myofibroblastic tumor can invade underlying muscularis propria, but, most important, this does not signify malignancy. D, Smooth muscle actin is positive (cytoplasmic, as shown here with a tram-track pattern) in most inflammatory myofibroblastic tumors. E, Inflammatory myofibroblastic tumors are negative for high-molecular-weight cytokeratins (CK903 shown here). F, Desmin is diffusely positive in approximately 50% of inflammatory myofibroblastic tumors. G, ALK-1 is expressed in 50% of inflammatory myofibroblastic tumors (typically cytoplasmic expression). H and I, Postoperative spindle cell nodule is characterized by a fasciitis-like architecture with more poorly formed fascicles than inflammatory myofibroblastic tumors and delicate granulation tissue type vascularity (hematoxylin-eosin, original magnifications 3200 [A, D, E, H, and I], 3400 [B], and 3100 [C, F, and G]). grade myofibroblastic proliferation has been used to encompass all related myofibroblastic lesions. 1 In the urinary bladder, IMT most commonly manifests as a polypoid mass or a submucosal nodule with a firm, whorled, or gelatinous cut surface with or without surface ulceration. Tumors may macroscopically extend into detrusor muscle. Most vesical IMTs are less than 2 cm in size with no specific site predilection, 3 but these tumors can range significantly in size from 1.5 to 13 cm. 7 Inflammatory myofibroblastic tumor is classically associated with 3 histologic patterns. The first is a myxoid/vascular pattern resembling fasciitis with loosely arranged plump cells in an edematous or myxoid stroma with prominent vasculature. The inflammatory infiltrate often contains more neutrophils and eosinophils and fewer plasma cells. The second is a compact spindle cell pattern characterized by a cellular proliferation of spindle cells with a fascicular or storiform architecture. Numerous plasma cells and lymphocytes are commonly intermixed with the spindle cells. The third is a hypocellular fibrous pattern resembling a fibromatosis with elongated rather than plump spindle cells in a densely collagenous stroma containing scattered lymphocytes, plasma cells, and eosinophils. 8 Inflammatory myofibroblastic tumor may contain all 3 histologic patterns or a predominance of 1 or 2 patterns. None of these patterns have shown an association with clinical outcomes. The cell type common to all 3 patterns is the myofibroblast with a predominantly spindled morphology, plump ovoid or tapering vesicular nuclei with fine evenly distributed chromatin, variably prominent nucleoli, pale eosinophilic cytoplasm, and delicate long cytoplasmic processes (Figure 1, A and B). The spindle cells display minimal Arch Pathol Lab Med Vol 138, October 2014 Inflammatory Myofibroblastic Tumor of the Bladder Alderman & Kunju 1273

3 Figure 2. The differential diagnosis of inflammatory myofibroblastic tumor includes sarcomatoid carcinoma and leiomyosarcoma. A, Pure sarcomatoid carcinoma may closely mimic inflammatory myofibroblastic tumor with myxoid change, vaguely fascicular background, and admixed inflammatory cells. However, the high cellularity and marked cytologic atypia are helpful in diagnosing this entity. B, Most sarcomatoid carcinomas will have epithelial differentiation (invasive carcinoma, as present here, or an in situ component), which is helpful in distinguishing them from inflammatory myofibroblastic tumor. C and D, p63 (C) and CK903 (D) are expressed (nuclear and cytoplasmic, respectively) in sarcomatoid 1274 Arch Pathol Lab Med Vol 138, October 2014 Inflammatory Myofibroblastic Tumor of the Bladder Alderman & Kunju

4 cytologic atypia; although mild pleomorphism can be seen, nuclear hyperchromasia is uncommon. Ganglion-like cells are seen in about 50% of IMTs. These tumors show areas of variable cellularity with zonation (ie, hypocellular areas) superficially and foci with higher cellularity in deeper portions of tumor. Mitoses and focal necrosis may be present 6 ; however, atypical mitoses are absent. Most important, invasion into muscularis propria has been reported in up to 40% of cases 9 and does not denote malignancy (Figure 1, C). The morphologic features arguing against the diagnosis of IMT include significant nuclear atypia with prominent nuclear hyperchromasia, pleomorphism, and/or atypical mitoses. Inflammatory myofibroblastic tumors express SMA (often with a tram-track staining pattern) in 90% of cases (Figure 1, D). They can express pancytokeratin focally (.50% cases). Low-molecular-weight cytokeratin (CAM 5.2) is usually positive, while high-molecular-weight cytokeratin, p63, and epithelial membrane antigen are typically negative (Figure 1, E). Desmin can show variable expression (approximately 50% of cases are positive) (Figure 1, F), and h-caldesmon can similarly show focal expression. 10 Anaplastic lymphoma kinase overexpression by immunohistochemistry (a diffuse cytoplasmic pattern is most common 11 ) is variable and seen in approximately 50% of cases (range, 20% 89% of urinary bladder IMTs 2,6,10,12 14 ) (Figure 1, G). This fairly specific but somewhat insensitive marker reliably predicts ALK gene rearrangement in most cases. Clonal rearrangements involving the ALK gene located on chromosome 2p23 have been confirmed by fluorescence in situ hybridization (FISH) in approximately 50% of IMTs. 8,15 Several ALK fusion partners have been identified, including TPM3, TPM4, CLTC, RANBP2, and ATIC. 15 Of these, ALK-ATIC rearrangements have been reported in vesical IMT. 16 Inflammatory myofibroblastic tumors of the urinary bladder have documented ALK rearrangement by FISH in 67% to 72% of cases. 2,6,9,13 The preliminary data indicate that an ALK-1 immunostaining pattern may potentially correlate with specific gene fusions, although this has yet to be validated in a large series of ALK-positive IMT cases. Localization of ALK-1 within the cell seems to be determined by its fusion partner, leading to diffuse cytoplasmic staining for ALK-1 with TPM3, TPM4, CARS, and ATIC and SEC31L1 fusion partners (all of which are cytoplasmic proteins), nuclear staining with the RANBP2 fusion partner (encoding a nuclear pore protein), and granular cytoplasmic staining with the CLTC fusion partner (encoding a structural protein of coated vesicles). 15 The distinction between IMT and PSCN can be challenging because of morphologic and immunohistochemical overlap; hence, clinical history can be helpful. Postoperative spindle cell nodules are typically small (,1 cm), are associated with a history of instrumentation, and morphologically show a fasciitis-like appearance with spindle cells in a loose fascicular arrangement with edematous to myxoid stroma and granulation tissue type vasculature (Figure 1, H and I). In contrast, IMTs are usually larger tumors, with no history of prior instrumentation. Morphologically, IMT contains haphazard fascicles of spindle cells with a more varied cellularity, including hypocellular fibrous areas, and more dense inflammation, including plasma cells, compared with PSCN. The immunoprofile of PSCN may be identical to that of IMT (low-weight cytokeratin, SMA, desmin positive, and HMWCK and p63 negative). Similar to IMT, some studies 6,17 have described ALK-1 overexpression in a subset of PSCN cases, although corresponding genetic rearrangements in PSCN have not been documented with as clear an association as IMT. 15 Most IMTs follow an indolent course after surgical resection, with the main concern being local recurrence, which occurs in 10% of cases. 7 Most cases tend to stay stable or regress even with incomplete resection. No metastases have been reported to date in urinary bladder IMT except for a single case of malignant genitourinary IMT/fibrosarcoma with an unusual history that occurred after irradiation. 9 Inflammatory myofibroblastic tumor and other spindle cell lesions of the urinary bladder represent one of the most difficult diagnostic dilemmas in genitourinary pathology because of significant overlap between benign and malignant processes in terms of clinical presentation, gross findings, morphology, and immunoprofile. When considering a diagnosis of urinary bladder IMT, the most common differential diagnosis includes sarcomatoid carcinoma and leiomyosarcoma (LMS). Inflammatory myofibroblastic tumor may mimic sarcomatoid carcinoma, which represents only 0.1% to 0.3% of vesical carcinomas. 18 According to the World Health Organization urothelial classification, the term sarcomatoid carcinoma encompasses all biphasic malignant neoplasms exhibiting morphologic and/or immunohistochemical evidence of epithelial and mesenchymal differentiation. The 2 components (epithelial and mesenchymal) can be intermixed. The epithelial component is most commonly urothelial carcinoma, with squamous cell carcinoma being the next most frequent. Small cell carcinomas and adenocarcinomas may also occur. Occasionally, the epithelial component consists only of carcinoma in situ. The mesenchymal component of sarcomatoid carcinoma usually has a high-grade spindle cell morphology composed of tumor cells in poorly formed fascicles (Figure 2, A and B). Heterologous elements may also be noted, including chondrosarcoma (most frequent), osteosarcoma, or rhabdomyosarcoma (least common). Grossly, both IMT and sarcomatoid carcinoma may manifest as polypoid lesions. Histologically, IMT can mimic sarcomatoid carcinoma with increased mitoses, dense cellularity, invasion into muscularis propria, and cytokeratin positivity. Although prominent myxoid change is more common in IMT, focal myxoid stroma can be seen in sarcomatoid carcinoma. The main histologic features that distinguish IMT from sarcomatoid carcinoma are minimal cytologic atypia and the absence of atypical mitoses. In addition, most sarcomatoid carcinomas will show evidence of epithelial differentiation (usually carcinomas of the urinary bladder, whereas inflammatory myofibroblastic tumors will be negative (see Figure 1, E). E, Leiomyosarcomas of the urinary bladder are typically high grade with atypical mitoses, hyperchromasia, and cellular pleomorphism in contrast to inflammatory myofibroblastic tumor, which should not display significant atypia (see Figure 1, A through C). F, Desmin is diffusely expressed in most leiomyosarcomas. G and H, Leiomyosarcoma is frequently characterized by myxoid changes (G), which may cause confusion with the myxoid changes typical of inflammatory myofibroblastic tumor in small biopsy specimens (H). The prominent cytologic atypia seen in leiomyosarcoma are critical for the distinction (hematoxylin-eosin, original magnifications 3200 [A, B, and E] and 3100 [C, D, F, G, and H]). Arch Pathol Lab Med Vol 138, October 2014 Inflammatory Myofibroblastic Tumor of the Bladder Alderman & Kunju 1275

5 Immunoprofile of Inflammatory Myofibroblastic Tumor and Its Mimics Variable Inflammatory Myofibroblastic Tumor Sarcomatoid Carcinoma Leiomyosarcoma Cytokeratin cocktail Positive (.50%) Positive (.90%) Negative (10% aberrant) LMW cytokeratin Positive Positive Positive HMW cytokeratin Negative Positive (25% 30%) Negative p63 Negative Positive (.50%) Negative Smooth muscle actin Positive (90%) Negative/positive (50% typically focal staining) Positive Desmin Positive/negative (50%) Negative Positive ALK-1 Positive (50%) Negative Negative (,5% positive) Abbreviations: ALK, anaplastic lymphoma kinase; HMW, high-molecular-weight; LMW, low-molecular-weight. traditional urothelial carcinoma and/or in situ disease) in resection specimens. 18 The spindle cell component of sarcomatoid carcinoma tends to express pancytokeratin at least focally, 12 although some cases may completely lack cytokeratin expression. While low-molecular-weight cytokeratins can be expressed in both IMT and sarcomatoid carcinoma, high-molecularweight cytokeratin (CK5/CK6) and p63 positivity strongly favor a diagnosis of sarcomatoid carcinoma over IMT (Figure 2, C and D). Desmin is usually negative in sarcomatoid carcinoma; hence, diffuse expression of desmin and SMA favors a diagnosis of IMT over sarcomatoid carcinoma, although focal SMA expression is frequently seen in sarcomatoid carcinoma (documented in 52% of cases). 2,12 14,20 ALK-1 expression by immunohistochemistry or FISH is virtually diagnostic of IMT in this setting because these genetic rearrangements have not been documented in bladder sarcomatoid carcinomas. 2,12 14 However, the absence of ALK-1 expression does not exclude the diagnosis of IMT. Histologic features of IMT can mimic LMS, the most common sarcoma arising in the urinary bladder of adults. Most urinary bladder LMSs are of intermediate to high grade 10 with characteristic nuclear hyperchromasia, atypical mitoses, and variably prominent necrosis (Figure 2, E). In addition, LMSs typically have cigar-shaped nuclei with a compact, fascicular architecture that is distinct from the round to oval nuclei in IMT with a looser arrangement of spindle cells. Leiomyosarcomas commonly show detrusor muscle invasion and expression of smooth muscle markers (Figure 2, F). Leiomyosarcomas can show myxoid change (Figure 2, G), which can mimic IMT (Figure 2, H) in small biopsy specimens. Once again, it is the lack of significant nuclear pleomorphism, cytologic atypia, and abnormal mitoses that most clearly separates IMT from its malignant mimics. The slitlike vascularity typical of IMTs is not seen in LMSs. Smooth muscle markers, SMA and desmin, are diffusely expressed in both IMT and LMS, although a tram-track SMA pattern, when present, may favor a diagnosis of IMT. 14 Another potential pitfall in differentiating IMT from LMS is that approximately 10% of LMSs have expression of lowmolecular-weight cytokeratin (CAM 5.2), 2,12 which can mimic both IMT and sarcomatoid carcinoma. ALK-1 antibody expression supports a diagnosis of IMT in this context, but notably a small subset (,5%) of LMSs can show ALK-1 expression (usually focal). 2,11 14,21 Interestingly, the ALK rearrangements by FISH and truncated/chimeric ALK transcripts by reverse transcription polymerase chain reaction typical of IMT have not been documented in LMS. 11,21 Instead, ALK gene amplification with full-length ALK transcripts has been detected by FISH and reverse transcription polymerase chain reaction, 11,21 suggesting another mechanism by which ALK may contribute to tumorigenesis. The Table summarizes the immunophenotype of IMT and its distinction from morphologic mimics. CONCLUSIONS Inflammatory myofibroblastic tumor is a rare spindle cell tumor with a complex historical nomenclature (inflammatory pseudotumor, pseudosarcomatous myofibroblastic tumor, inflammatory pseudosarcomatous fibromyxoid tumor, etc) that reflects its unclear etiology. In general, the term inflammatory pseudotumor is best avoided. Inflammatory myofibroblastic tumor has been documented in numerous sites and typically occurs in the urinary bladder as a polypoid lesion. The histology of IMT is characterized by loose fascicles of spindled myofibroblasts with delicate processes, which lack nuclear hyperchromasia and pleomorphism, surrounded by a myxoid and/or collagenous stroma with associated mixed inflammation and slitlike vascular channels. These tumors can show zonation characterized by hypocellularity superficially and denser cellularity in deeper portions. The immunohistochemical profile of IMT includes positive staining with SMA and lowmolecular-weight cytokeratin and variable positivity with desmin. ALK-1 expression is variable and has been documented in approximately 50% of urinary bladder IMTs, with ALK gene rearrangement confirmed in most cases. Inflammatory myofibroblastic tumor, which typically should be a diagnosis of exclusion in the urinary bladder, can cause a diagnostic dilemma because many of its morphologic and immunohistochemical features, when viewed in isolation, may mimic malignant spindle lesions such as sarcomatoid carcinoma and LMS. This distinction has clinical consequences because IMT is generally considered benign and treated with conservative management. The main factor distinguishing IMT from its malignant mimics is minimal cytologic atypia with a lack of nuclear hyperchromasia and the absence of abnormal mitoses. ALK-1 protein expression and/or ALK gene rearrangements favor the diagnosis of IMT over sarcomatoid carcinoma and LMS but are helpful only when present. High-molecularweight cytokeratins and p63 expression favor the diagnosis of sarcomatoid carcinoma. References 1. Alquati S, Gira FA, Bartoli V, et al. Low-grade myofibroblastic proliferation of the urinary bladder. Arch Pathol Lab Med. 2013;137(8): Sukov WR, Cheville JC, Carlson AW, et al. Utility of ALK-1 protein expression and ALK rearrangements in distinguishing inflammatory myofibroblastic tumor from malignant spindle cell lesions of the urinary bladder. Mod Pathol. 2007;20(5): Cheng L, Foster SR, MacLennan GT, et al. Inflammatory myofibroblastic tumors of the genitourinary tract: single entity or continuum? J Urol. 2008;180(4): Arch Pathol Lab Med Vol 138, October 2014 Inflammatory Myofibroblastic Tumor of the Bladder Alderman & Kunju

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