Pathology of Inflammatory Myofibroblastic Bladder Tumor

Most benign spindle cell tumors of the urinary bladder are an inflammatory myofibroblastic tumor (IMT). ^{[1, 2, 3]}  Although the urinary bladder and rarely, the ureter, are affected, this lesion has been described in numerous other locations. ^{[2, 4, 5, 6]}  Postoperative spindle cell nodule (PSCN) is usually described as histologically identical to IMT, except that a history of instrumentation or trauma to the bladder can be elicited, and plasma cells are often less prominent. ^[7]

Most cases of IMT of the bladder are idiopathic, but in some cases, there is a history of inflammation or irritation of the bladder.

The male-to-female ratio ranges from 2:1 to 3:1. ^{[4, 8, 9]} The first large series of 38 cases was comprised of patients aged 2.5 months to 87 years. ^[9] Among the 38 cases, the mean age of patients was 38 years for pseudotumor (age range, 15-74 years), 65 years for postoperative spindle cell nodule, 51 years for sarcoma, and 76 years for carcinoma. ^[9] Later series involved 46 patients and 42 patients. ^{[4, 8]}

Williamson et al discuss inflammatory myofibroblastic tumors in pediatric and young-adult patients, noting that IMTs may be a source of differential diagnostic complexity. According to the authors, the molecular characteristics and clinical behavior of pediatric bladder tumors are, with the exception of rhabdomyosarcoma, less well understood than those in adults. ^[10]

The most common presenting symptom is hematuria, followed by bladder outlet obstruction and dysuria. In a large series of 38 cases, after review and immunohistochemical workup, 17 patients had inflammatory pseudotumor (myofibroblastic tumor), 4 patients had postoperative spindle cell nodule, and 1 patient had leiomyoma. ^[9]

Gross features

The size of the inflammatory myofibroblastic tumor/pseudotumor averages about 4 cm (range, 1.5-13 cm), ^{[4, 9]} which is similar to sarcoma at 4 cm (range, 0.5-7 cm). ^[8] The mass is soft and fleshy.

Microscopic features

The usual appearance of inflammatory myofibroblastic tumor/pseudotumor is illustrated in the image below (see Image 1 in the figure below). Spindle cells are without atypia and have many stromal microvessels. On higher power, there are spindle cells without atypia, loose matrix, and frequent plasma cells—hence the synonym plasma cell granuloma, although it has been defined differently by some authors. Up to 50% of cases have muscularis propria invasion, but so do 50% of sarcomas. ^[9]  The degree of atypia is minimal, often with loose matrix and plasma cells (see Image 2 in the figure below).

Although necrosis has been described in 30% or more of inflammatory myofibroblastic tumors, the presence of necrosis at the tumor-detrusor muscle interface in muscle-invasive cases was one criterion present in sarcoma that distinguished it from inflammatory pseudotumor (see Image 3 in the figure below). ^{[8, 9]}

Other findings specific to sarcoma were more nuclear atypia, less prominent microvasculature, less variable cellularity, consistently ≥1 mitotic figure per 10 high-power fields (see Image 4 in the figure below), and predominant acute inflammation without plasma cells. In some cases, there is myxoid degeneration with cell dropout (see Image 5 in the figure below). ^{[8, 9]}

The separation from sarcoma can be made in most cases, although an inflammatory myofibroblastic tumor has overlap with sarcoma in presentation, age range, and size. Key histologic findings that favored pseudotumor were as follows:

1. No necrosis at the tumor-detrusor muscle interface, even with muscularis propria invasion

2. Less nuclear atypia

3. Minimal to absent p53 immunoreactivity

4. Mitotic rate ≤1 per 10 high-power fields. ^[9]

No tumor recurrence after resection also favored pseudotumor. ^{[8, 9]}

Making a meaningful separation between inflammatory pseudotumor (a term used since 1937) ^[2]  and inflammatory myofibroblastic tumor (IMT), a term introduced in 1990 for lung lesions, is more difficult. ^[11]  The oldest large series of 38 spindle cell tumors in the urinary bladder included 17 pseudotumors, 4 postoperative spindle cell nodules (PSCNs), and 13 sarcomas. ^[9]  The 17 patients in the pseudotumor group had no recurrence. ^[9]  The term IMT is now used more often than pseudotumor, but IMT may include a more aggressive but overlapping set of lesions.

Whether ALK-1 rearrangements are detected in 8% of cases or over one half of cases perhaps depends on whether the lesions being studied are inflammatory pseudotumors or IMT. ^{[4, 11, 12, 13]}  The ALK-1 reactivity correlates with local recurrence ^[13]  and muscle invasion. ^[4]  IMT includes tumors with necrosis in up to 30% of cases and also encompasses tumors with recurrence in up to 31% of cases, so it is tempting to suggest that, of the tumors classified in 2001 as sarcoma (at least the 7 low-grade ones), most may have been considered by others as IMT or, conversely, that IMT is truly a low-grade sarcoma. ^{[4, 9]}

If the four criteria for inflammatory pseudotumor are applied, as listed above, the calls to discourage the use of this term might be premature. ^[14]  Thus, although the terms inflammatory pseudotumor and IMT represent more reactive or more neoplastic points on a spectrum leading to malignancy, there remains at least some histologic factors that predict behavior and there is some rationale to retain the use of both terms.

No single definitive immunostain can make the differential diagnosis of inflammatory pseudotumor compared to other entities, such as sarcoma and sarcomatoid carcinoma.

In a 2001 study, p53 protein nuclear immunostaining of sarcoma was moderate, unlike the rare to absent staining in pseudotumors (see image 6 in the figure below and in Microscopic Findings). ^[9] Because all 12 sarcomas were desmin-negative, they were not called leiomyosarcoma; the frequencies of reactivity overlapped with benign tumors in epithelial (cytokeratins, EMA), mesenchymal (vimentin, desmin), and actin (muscle-specific actin and smooth muscle actin) immunostaining.

Anaplastic lymphoma kinase (ALK) has emerged as a fairly specific but not too sensitive marker for IMT, with reactivity in 57% (20/35) of cases, ^[4] 62% (13/21) of cases, ^[15] and 46% (12/26) of cases. ^[8] Moreover, ALK rearrangements could be identified in more than one half of cases, ^{[4, 15]} generally in all cases that were also ALK-immunoreactive. ^{[15, 16]} Fluorescent in situ hybridization detected ALK rearrangement in another study in 56% of cases, versus 69% by immunostaining, for a combined 75% detection of ALK abnormalities. ^[17]

A review by Teoh et al reported that ALK-positive inflammatory myofibroblastic tumors of the urinary bladder had a female predilection, appeared to occur more frequently in younger patients, and had different immunohistochemical staining patterns when compared with ALK-negative inflammatory myofibroblastic tumors. The review also reported that regardless of its ALK status, inflammatory myofibroblastic tumors of the urinary bladder has a good prognosis after surgical resection. ^[18]

Westfall and colleagues confirmed the finding that p53 protein was rare to absent in pseudosarcomatous myofibroblastic proliferation (pseudotumor) of the bladder. ^[19] They obtained the following immunostaining results: cytokeratin OSCAR, 70% (7/10); cytokeratin AE1/AE3, 78% (7/9); cytokeratin 34βE12, 0% (0/10); cytokeratin 5/6, 0% (0/9); p63, 0% (0/9); SMA, 100% (10/10); and ALK, 20% (2/10). ^[19]

Anaplastic lymphoma kinase (ALK) rearrangements have been identified in more than one half of cases, generally in all cases that were also ALK-immunoreactive. ^{[4, 15]}

A case report exists of a novel fusion of HNRNPA1-ALK in a middle-aged Japanese man with inflammatory myofibroblastic bladder tumor. ^[20] The novel transcript fusion was on exon 2 of HNRNPA1 and exon 18 of ALK, which caused ALK protein overexpression.

In one study, no pseudotumors recurred after transurethral resection or partial cystectomy, ^[9] although one patient, 5 months after transurethral resection, had a histologically identical pseudotumor that the surgeon considered residual. Rare recurrences were described in another study. ^[8]