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Low-grade myofibroblastic proliferations of the urinary bladder.

BACKGROUND AND AIMS

In human pathology, mesenchymal fibroblastic/myofibroblastic spindle cell proliferations constitute an exceedingly broad and heterogeneous category of disorders, ranging from indolent lesions to highly aggressive neoplasms. In this setting, and especially when dealing with reactive and low-grade lesions, the differential diagnosis is often challenging. (1)

In 1980, Roth (2) reported a particular spindle cell proliferation arising in the urinary bladder of a 32-year old woman. This lesion shared several similarities with nodular fasciitis, so it was classified as a reactive proliferation because of the absence of malignant epithelial elements, its benign clinical course, and the patient's well-known history of chronic cystitis. (2) Four years after the Roth (2) initial description, Proppe et al (3) reported on 8 cases of similar spindle cell lesions that occurred 5 weeks to 3 months after genitourinary tract interventions. These benign reactive lesions resembling a sarcoma were called postoperative spindle cell nodules (PSCN). (3) Later on, several authors reportedcases of PSCN that had occurred up to 15 months (usually about 3 months) after urinary bladder surgery or instrumentation. (4-6)

Over time, these myofibroblastic proliferations have had a number of designations, such as inflammatory pseudotumor, inflammatory pseudosarcomatous fibromyxoid tumor, pseudosarcomatous myofibroblastic tumor, fibromyxoid pseudotumor, plasma cell granuloma, plasma cell pseudotumor, and xanthomatous pseudotumour. (6,7) Although most of the abovementioned terms are now considered outdated, the nosology and definition of these lesions are still a matter of debate. Inflammatory myofibroblastic tumor (IMT) of the urinary bladder is probably still the most frequent designation (8-19); however, some authors prefer the term pseudosarcomatous myofibroblastic proliferation (PMP) for a fraction of these myofibroblastic proliferations. These authors believe that, both morphologically and biologically, there are sufficient reasons to distinguish IMT and PMP. In addition to histopathologic differences (see below) and even though PMPs seem to be clonal proliferations with a potential for aggressive, local growth and recurrence, they are characterized by an excellent outcome and do not have the same malignant potential as IMT. These same scientists also group PSCNs with PMPs. (20,21)

This review will focus on what is currently known about these low-grade myofibroblastic proliferations (LGMPs) of the urinary bladder--which is the term we have chosen to embrace all of the above designations and entities.

A PubMed (US National Library of Medicine, Bethesda, Maryland) search was carried out to identify original articles focusing on this subject. We have based our review of the literature on selected study articles and textbooks, recently published review articles, editorials from peer-reviewed journals, and the reference list of each searched publication. All of these manuscripts were full-text, English-language, and published between 1980 and 2012. When necessary, we contacted by e-mail the corresponding authors of the article to obtain clarifications and/or details about the cases on which they had reported.

Because of the rarity of LGMPs affecting this anatomic site, we obtained most of the clinicopathologic features from an overall patient population composed of the most-relevant cases reported in the English-language literature (Table 1). (2-6,8,12,15,17-50) Because of the relative paucity of specific articles dealing with PMP and/or PSCN, fewer data were available regarding these entities, compared with those dealing with IMT. Information regarding tumor designation, patients' characteristics, primary symptoms, tumor size, urinary bladder infiltration, treatment, and follow-up was obtained from each selected publication. The LGMPs shown in the various figures are unpublished and are selected from files belonging to our Section of Pathology and the Department of Pathology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Arcispedale Santa Maria Nuova (Reggio Emilia, Italy).

EPIDEMIOLOGY AND CLINICAL PRESENTATION

Among the LGMPs, IMT, which was first described in the lung, is the most-frequently reported entity. (51) In the genitourinary tract, the urinary bladder is the most common anatomic site of origin of this lesion; additional locations include the kidney, urethra, prostate, ureter, and rete testis. (52)

Our review of the most-salient literature concerning cases of LGMP occurring in the urinary bladder (Table 1) showed that most of those cases occur during the fourth and fifth decades of life, with men more frequently affected than women (1.33:1 ratio), and without any perceptible difference between IMT and PMP. Overall, this male predominance seems to be less evident when considering patients younger than 18 years. The case distribution during the various decades of life is shown graphically in Figure 1.

In LGMPs, painless hematuria was the most-common symptom, whereas dysuria, pelvic pain, and symptoms related to obstruction or infections occurred more rarely (Table 1). Unlike extragenitourinary tract IMT, systemic symptoms--such as fever and weight loss--are uncommon in urinary bladder locations. (53) In only one case were myalgia, fatigue, and fever reported; however, at least in part, these signs and symptoms could have been secondary to an underlying systemic lupus erythematosus. (48)

PATHOLOGIC AND IMMUNOHISTOCHEMICAL FINDINGS

Grossly, LGMPs of the urinary bladder may be either polypoid masses or, less frequently, rather flat nodules, with or without surface ulceration. On cut section, their color is gray-white to yellow with a macroscopic appearance from fascicular to myxoid. (7,20,52) In the cases reported (Table 1), at first diagnosis, the tumor's greatest diameter was between 1 and 11 cm (median, 4 cm), with no difference between patients aged older than or younger than 18 years, and no site predilection.

Three main histopathologic patterns of IMT have been described: (1) a myxoid/vascular pattern (Figure 2, A) characterized by spindle/stellate myofibroblasts with abundant eosinophilic cytoplasm and vesicular nuclei; (2) a compact, spindle cell proliferation (Figure 2, B)--sometimes with some ganglion-like cells--arranged in fascicular or storiform patterns, with varying degrees of cellularity; and (3) a hypocellular, fibrous pattern (Figure 2, C), displaying abundant collagen, plasma cells, lymphocytes, and eosinophils (similar to desmoid fibromatosis). (52)

These patterns are also typically characterized by varying amounts of acute (with neutrophils and/or eosinophils), chronic (lymphoplasmacellular), or mixed inflammatory infiltrates (Figure 2, D). Myofibroblasts show elongated-to-oval nuclei, often with prominent nuclei, and do not exhibit clear-cut atypia. The reported mitotic index ranges from 0 to 20 mitoses/10 high-power fields with most IMTs having a mitotic count of less than 5. (20) Based on Table 1, muscularis propria infiltration is common (about 60% of the whole patient population), whereas perivesical soft tissue invasion is not frequent (about 5% of the cases, without any apparent difference between IMT and PMP).

Necrosis is usually quite rare to absent in LGMPs of the urinary bladder (Figure 2, E). Iczkowski et al (5) found no necrosis in any of their cases and, in addition, suggested it as key to a diagnosis of sarcoma. Montgomery et al (6) detected necrosis in 30% of their patient population with IMT, whereas Harik et al (20) found it in 22 of 42 lesions (52%), even though it was mainly focal, minimal, and confined to the surface. Seven of those 22 cases (32%) showed necrosis (extensive in 2 of 7; 29%) in the deep urinary bladder wall and were associated with muscularis propria invasion. (20) Overall, when present, necrosis in LGMPs is rarely extensive and/or is located at the tumor-detrusor interface. Lesions with these findings should be carefully evaluated to rule out any malignancy.

Some authors (20,21,46,54) claim that, in the urinary bladder, IMT and PMP should be considered separate entities with sufficiently different clinical behavior to warrant their distinction on morphologic grounds. According to these scientists, the distinguishing histologic features of PMPs are haphazard-to-loose, fascicular arrangements of spindle cells, many of which have elongated, bipolar cytoplasmic processes that are often eosinophilic (rhabdomyoblast-like) (Figure 2, F); edematous-to-myxoid stroma with prominent vascularity and a variably dense, acute, and/or chronic inflammatory infiltrate; occasionally, focal, more-cellular fascicular areas, particularly in the deeper portions; rare occurrences of storiform and hypocellular, fibrous patterns; and inflammatory infiltrates that are generally less dense than they are in IMT. (54) The malignant potential of IMT of the genitourinary tract is seen in anecdotal cases of transformation into true inflammatory fibrosarcoma, which is characterized by increasing atypia and cellularity in a background superimposable on that of classic IMT (see index case in Figure 3, A through C). (6)

Moreover, the synchronous occurrence of a transitional-cell carcinoma, as either a separate nodule or admixed, has been reported sporadically (Table 1). (7) Interestingly, metastatic urothelial carcinoma may exhibit a similar myofibroblastic proliferation, whereas the corresponding primary tumor may not. (55)

In the LGMPs of the urinary bladder, there is significant immunohistochemical overlap between myofibroblastic proliferations diagnosed as IMT or PMP. In fact, they express vimentin (95%-100% of cases), smooth-muscle actin (48%-100%; Figure 4, A), AE1/3 (73%-78%; Figure 4, B), desmin (5%-80%; Figure 4, C), muscle-specific actin (62%), clone OSCAR keratin (70%), and CAM 5.2 (70%), whereas CK5/6 and 34PE12 seem not to be expressed. (1,6,10,52,54) Bladder IMT is more prone to express keratins than is IMT occurring in other genitourinary tract locations, and, rarely, findings are positive for myogenin or MyoD1. (52) Unlike bladder sarcomas, in IMT, p53 nuclear positivity is weak or even negative. (5)

Immunohistochemical analysis with an antianaplastic lymphoma kinase-1 (ALK-1) antibody is specific but only slightly sensitive for IMT (provided that myogenin and MyoD1 findings are negative because rhabdomyosarcoma may seldom express these markers). (1) Results for ALK-1 were found to be positive in 20% to 89% of urinary bladder IMTs (Figure 4D). (1,6,10,20,42,43,46)

The pathologic differential diagnosis of bladder LGMPs is summarized in Table 2.

IMAGING FINDINGS

Radiologic imaging plays a key role in the preoperative management and follow-up of patients with LGMP. Ultrasound, contrast-enhanced computed tomography, and magnetic resonance images provide valuable information on tumor size and infiltration of the urinary bladder wall. (56) On ultrasound, according to the particular case, LGMP can appear as either a well-defined, nonspecific mass or as simple bladder-wall thickening with variable echogenicity, and the lesion being described as hypoechoic or hyperechoic. On ecocolor Doppler (or ecopower Doppler), and especially on contrast-enhanced ultrasound examinations, LGMPs may appear as hypervascular nodules. (57-59) Computed tomography (Figure 5) may show either a focal or diffuse bladder-wall thickening and, more rarely, a polypoid mass; the lesion may be hypodense, isodense, or hyperdense and well enhanced after intravenous contrast medium administration. On magnetic resonance imaging, LGMP is characterized by low T1 signal intensity and nonhomogeneous high T2 signal intensity. In some cases, on T2 imaging, LGMP may show high signal intensity centrally, reflecting central necrosis, and low signal peripherally. Postcontrast, T1-weighted magnetic resonance imaging demonstrates heterogeneous enhancement with nonenhanced areas of necrosis. (59)

MOLECULAR GENETICS

Clonal genetic aberrations in the short arm of the chromosome 2 (region 21-23 of the long arm) have been described in approximately 50% to 60% of IMTs. This rearrangement involves the 2p23 region that contains the ALK gene, which encodes a tyrosine kinase receptor expressed predominantly in the central nervous system and is a member of the superfamily of insulin growth-factor receptors. (60) Although fluorescence in situ hybridization (FISH) in many IMTs has shown ALK gene rearrangement, in most cases, the fusion partner has not been identified. The ALK gene rearrangements identified that have led to fusion with other genes include ATIC, (41) CARS, (61,62) TPM3, (63-65) TPM4, (63,65,66) TPM3 and TPM4, (67) CLTC, (60,65,68) RANBP2, (60,69) and SEC31L1 (SEC31A). (70) The ALK-ATIC rearrangement has been reported in bladder IMTs. (41)

In normal ALK signaling, ligand-induced homodimerization of the extracellular domains brings the tyrosine kinase domains into sufficient proximity to enable transphosphorylation and kinase activity, whereas translocations resulting in pathogenic fusion partners provide dimerization domains that are ligand-independent, leading to unregulated constitutive kinase activity. (71)

Fluorescence in situ hybridization analysis can be used to detect ALK gene break-apart rearrangements in IMT (Figure 6). The FISH kits are a mixture that consists of 2 fluorophore-labeled DNA probes in hybridization buffer containing ALK-upstream and ALK-downstream probes characterized by 2 different colors. The hybridization targets of these 2 probes are situated on opposite sides flanking the breakpoint of the ALK gene. Nuclei with ALK gene rearrangement display the normal ALK region as a 2-color fusion signal, whereas, if a breakapart has occurred, the 2color signals split, separating them. (52) Using FISH analysis, rearrangements of the ALK gene have been detected in 67% to 72% of IMTs of the urinary bladder. (6,20,43,46) Some PMPs and PSCNs show positive immunohistochemistry for ALK and/or express ALK gene rearrangements. (20,52) Detection of ALK gene rearrangements by FISH is fundamental to distinguishing IMTs from other spindle cell proliferations of the urinary bladder, especially when the immunohistochemical analysis is not conclusive. (46)

PATHOGENESIS

Some studies on extragenitourinary tract IMT have investigated its etiology; however, its pathogenesis remains obscure. In addition, no studies have clarified the pathogenesis of genitourinary IMT. An underlying infection has long been thought to be the primum movens of this spindle cell proliferation. Various infectious agents have been detected in IMTs, such as bacteria (Bacteroides corrodens, Klebsiella pneumoniae, Mycobacterium avium, Corynebacterium jejuni, Bacillus sphaericus, Escherichia coli, and Coxiella burnettii) and viruses, the most-frequently reported being Epstein-Barr virus and human herpesvirus 8. (52,72,73)

An autoimmune etiology of IMT has been postulated based on single reports. In one case, an IMT of the submandibular gland was found in a patient with polyclonal hypergammaglobulinemia, high titers of antinuclear antibody, but without any signs of known autoimmune disease. (74) Additional reports described cases of IMT of the spleen with thrombocytopenic purpura and IMT with Riedel thyroiditis. (52)

In 20 LGMPs listed in Table 1, previous urinary bladder instrumentation was ascertained, so that they were labeled as PSCN.

TREATMENT

As shown in Table 1, 65% (185 of 285) of the reported cases were treated with transurethral resection (TUR), 27% (77 of 285) with partial cystectomy, 6% (16 of 285) with total cystectomy, and 3% (7 of 285) with other surgical procedures. In fact, surgical management is a sign of the controversy surrounding the nature of LGMPs, the consequent limited workload of such lesions for a single surgeon, and the anecdotal and subjective judgments. (6,12,20,45)

Based on available data from the literature, even though the malignant potential of LGMP of the genitourinary tract is still uncertain and is sometimes difficult to evaluate, the indolent and often benign clinical course that characterizes most of the cases does not warrant aggressive therapy (radical cystectomy, radiation, or chemotherapy). (52) On the other hand, follow-up cystoscopy and biopsies are mandatory to detect potential recurrences early on, especially in large, multinodular, and/or incompletely resected lesions. (75)

OUTCOME

The World Health Organization classification of soft tissue tumors classifies IMTs as neoplasms of intermediate malignancy, subtype rarely metastasizing. (76) According to this classification, extrapulmonary IMTs have a recurrence rate of approximately 25% (related to location, resectability, and multinodularity), whereas only a few cases (<5%) metastasize. (53) In most cases, it is difficult to predict the recurrence and/or malignant potential on the basis of histopathologic findings alone. (76)

In our review of the literature (Table 1), data on patients' follow-up were available in 218 cases. Only 7% (15 of 218) of patients with urinary bladder myofibroblastic proliferations experienced local recurrence: 5% (10 of 218) with IMT, or similar designations, and 2% (25 of 218) with myofibroblastic lesions clearly labeled as PMP. None of them developed metastases or died from the disease.

In 5 of 218 cases (2.3%) there was a synchronous carcinoma (4 urinary bladder transitional-cell carcinomas and 1 renal clear-cell carcinoma). Of 9 deaths, 1 patient (of 9; 11%) died from urosepsis, 1 (of 9; 11%) from postoperative infection, 3 (of 9; 33%) from unrelated causes, 1 (of 9; 11%) of inflammatory fibrosarcoma, 2 (of 9; 22%) from synchronous bladder transitional-cell carcinoma, 1 (of 9; 11%) from neurofibromatosis complications, and 1 (of 9; 11%) from unknown causes.

We need more data to explore ALK-1 as a prognostic factor in IMT and related myofibroblastic lesions of the urinary bladder.

UNSOLVED QUESTIONS

Although more than 30 years have passed since its first description, several questions remain unanswered regarding LGMP of the urinary bladder. The most urgent problem seems to be both the nomenclature and the real nature of these lesions.

Some authors feel that PMP and PSCN represent the same entity, which should be separated from true IMT. Grounds for this classification are a fairly distinct histopathologic picture and the quite different clinical behavior, with IMT representing proliferations with some malignant potential. (20,21,46,54) At the opposite end of that spectrum, the inflammatory fibrosarcoma shares a similar background with clearly malignant spindle cells and, above all, a much worse prognosis. (6) A widespread unifying theory hypothesizes that such lesions would be part of a single continuum, ranging from benign pseudosarcomatous lesions to low-grade sarcomas. (52) Molecular genetics does not yet help us to solve the arcana of these LGMPs. In fact, only a fraction of these cases (but a fraction that includes IMT, PMP, and PSCN cases) harbor ALK gene rearrangements with evidence of clonal proliferation, whereas the remaining LGMPs are either reactive or due to an unknown genetic abnormalities. (20,52) Unfortunately, so far, ALK expression and ALK gene rearrangements are unable to predict prognosis. In addition, in most cases, the histopathologic appearance alone does not help us forecast the clinical behavior of a given myofibroblastic proliferation of the urinary bladder.

CONCLUSIONS

The LGMPs of the urinary bladder include different lesions extending from benign, pseudosarcomatous entities to low-grade, inflammatory fibrosarcomas, and they mainly affect patients in their middle decades. With the exception of frank sarcomas, these lesions should be considered of uncertain clinical behavior, even though no metastatic cases in this anatomic location have been reported in the English-language literature. However, in view of the indolent clinical course, in most cases, aggressive treatments (such as radical cystectomy, chemotherapy, and radiotherapy) are probably unjustified. (52)

Further investigations dealing with the molecular genetics in LGMPs of the urinary bladder will certainly help us to clarify their nature and to establish more-sound classifications and prognostic criteria.

Caption: Figure 1. Number and distribution during the various decades of life of the urinary bladder low-grade myofibroblastic proliferation cases published in the English-language literature. This graph is based on manuscripts with sufficient information on the ages and genders of single patients. Black columns, males; gray columns, females.

Caption: Figure 2. Histopathology. A, The myxoid/vascular pattern shows spindled myofibroblasts, which usually lack clear nuclear hyperchromasia and pleomorphism. These elements seem to float in a markedly myxoid stroma containing some thin-walled blood vessels. B, Some cases are more compact and cellular. The myofibroblasts are arranged in medium-sized fascicles and placed in a stroma rich in collagen. C, Sometimes, these lesions are hypocellular with an abundant, fibrous stroma. D, There are different degrees of admixed, inflammatory cells, such as lymphocytes, plasma cells, and granulocytes. E, Occasionally, limited areas of tumor necrosis (asterisk) may be found throughout the spindle cell proliferation. F, Some lesions may be characterized by spindled and/or round, rhabdomyoblast-like myofibroblasts (hematoxylin-eosin, original magnifications X10 [A through C], X20 [D], X4 [E], and X40 [F]).

Caption: Figure 3. Malignant transformation. A 45-year-old woman with a twice-recurring inflammatory myofibroblastic tumor (IMT) of the urinary bladder, which, at follow-up, turned into a lethal inflammatory fibrosarcoma (unpublished index case). A, The original IMT was composed of a spindle cell proliferation in an extremely loose stroma. These elongated cells displayed myofibroblastic morphology without clear-cut atypia. B, The first recurrence (8 months later), with a more cellular pattern, where the neoplastic cells showed a hyperchromatic nucleus and some atypical mitotic figures. C, The second recurrence (6 months after first recurrence) consisted of a highly cellular proliferation, where the neoplastic elements are clearly atypical and pleomorphic (hematoxylin-eosin, original magnifications X40 [A through C]).

Caption: Figure 4. Immunohistochemistry. A, Immunohistochemical analysis showing marked and diffuse positivity for smooth muscle actin. B, Keratin AE1/ AE3 may be mildly and focally positive (arrowhead). C, Occasionally, desmin may display sparse positivity (arrow; the arrowhead shows muscularis propria infiltration). D, Intense positivity for ALK-1. Immunohistochemical reactions were revealed with 3,3'- diaminobenzidine and mildly counterstained with hematoxylin (original magnifications X20 [A through D]).

Caption: Figure 5. Contrast-enhanced tomography. Triphasic, contrast-enhanced, axial, multidetector computed tomography of the pelvis (arterial phase) showing an irregular thickening of the right-hand side of the urinary bladder wall (arrow), which also involves the homolateral ureter outlet.

Caption: Figure 6. Fluorescence in situ hybridization (FISH) for the anaplastic lymphoma kinase (ALK)-1 gene. This analysis has been carried out using dual-color, breakapart probes. Rearrangement of the above gene is confirmed by the presence of cells with separate red and green signal (arrows), whereas some myofibroblasts show normal fusion signal (arrowheads) (image courtesy of William R. Sukov, MD, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota). The FISH analysis of a bladder inflammatory myofibroblastic tumor is achieved with a breakapart strategy that uses probes flanking both telomeric and centromeric sides of the ALK locus (original magnification X100).

We are indebted to Gabriella Becchi, B. Tech, for her competent technical assistance. In addition, we would like to express our gratitude to the various authors who provided additional information on their published cases. Lastly, a special thank to William R. Sukov, MD, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, for providing Figure 6; to Alberto Cavazza, MD, Department of Pathology, IRCCS, Arcispe dale Santa Maria Nuova, Reggio Emilia, Italy, for his precious help in retrieving adequate histologic material and to Augusto Vaglio, MD, PhD, Department of Nephrology, University Hospital, Parma, Italy, for his critical review of this manuscript.

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(46.) 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):592-603.

(47.) Spiess PE, Tuziak T, Tibbs RF, et al. Pseudosarcomatous and sarcomatous proliferations of the bladder. Hum Pathol. 2007;38(5):753-761.

(48.) Hoene KA, Kaufman MR, Cates JM, Chang SS. Inflammatory myofibroblastic tumor of the urinary bladder in a 27-year-old woman with systemic lupus erythematosus. Int J Urol. 2008;15(2):182-184.

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(76.) Coffin C, Fletcher J. Inflammatory myofibroblastic tumour. In: Fletcher C, Unni KK, Mertens F, eds. Pathology and Genetics of Tumours of Soft Tissue and Bone. Lyon, France: IARC Press; 2002:91-93. World Health Organization Classification of Tumours; vol 4.

Sara Alquati, MD; Federica Alessandra Gira, MD; Veronica Bartoli, MD; Sandro Contini, MD; Domenico Corradi, MD

Accepted for publication September 27, 2012.

From the Department of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Arcispedale Santa Maria Nuova, Reggio Emilia, Italy; the Department of Surgical Sciences, Section of Radiology, University of Parma, Parma, Italy (Dr Gira); the Department of Clinical and Experimental Medicine, Section of Occupational Medicine, University of Parma (Dr Bartoli); the Department of Surgical Sciences, University of Parma (Dr Contini); and the Department of Biomedical, Biotechnological, and Translational Sciences, Section of Pathology, University of Parma (Dr Corradi).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Domenico Corradi, MD, Department of Biomedical, Biotechnological, and Translational Sciences, Section of Pathology, University of Parma Via Gramsci 14, 43126 Parma, Italy (e-mail: domenico.corradi@unipr.it).

Table 1. Review of the Literature Regarding Cases of Low-Grade
Myofibroblastic Proliferations Occurring in the Urinary Bladder

                       Designation,
                       No. of Cases
                       (% of all Cases),                   Sex,
Source, y              N = 287 (a)         Age, (b) y      M/F

Roth, (2) 1939         IP, 1 (0.4)         32              0/1
Proppe et al,          IP, 1 (0.4)         29              1/0
  (3) 1984
Olsen, (22) 1984       IP, 1 (0.4)         24              0/1
Nochomovitz et         IP, 2 (0.7)         22; 73          1/1
  al, (8) 1985
Ro et al, (23) 1986    PFT, 2 (0.7)        52; 56          0/2
Young et al,           IP, 1 (0.4)         59              1/0
  (24) 1987
Wick et al,            IP, 2 (0.7)         55; 60          2/0
  (25) 1988
Stark et al,           IP, 2 (0.7)         19; 16          1/1
  (26) 1989
Albores-Saavedra       PMP, 10 (3.5)       7 (2-16)        2/8
  et al, (19) 1990
Huang et al,           PSC, 1 (0.4)        45              1/0
  (4) 1990
Hughes et al,          PL, 4 (1.4)         48 (41-56)      1/3
  (27) 1991
Dietrick et            IP, 2 (0.7)         18; 37          1/1
  al, (28) 1992
Lamovec et al,         IP, 1 (0.4)         2               0/1
  (29) 1992
N'Dow et al,           IP, 1 (0.4)         18              0/1
  (30) 1993
Ro et al, (17) 1993    PFT, 8 (2.8)        56 (40-58)      3/5
Jones et al,           IP, 13 (4.5)        33 (19-60)      5/8
  (15) 1993
Lundgren et al, (18)   PSC, 12 (4.2)       50 (14-80)      4/8
Angulo et al,          PMP, 2 (0.7)        16; 49          1/1
  (31) 1994
Koirala et al,         IP, 1 (0.4)         47              1/0
  (32) 1994
Weidner, (33) 1995     IP, 1 (0.4)         61              1/0
Hojo et al,            PMT, 11 (3.8)       8 (3-19)        7/4
  (12) 1995
Horn et al,            IP, 3 (1.0)         39 (35-49)      0/3
  (34) 1997
Netto et al,           IP, 5 (1.7)         7 (2-12)        3/2
  (35) 1999
Gardner et al,         IMT, 1 (0.4)        3               1/1
  (36) 1999
Asanuma et al,         IP, 1 (0.4)         7d              1/0
  (37) 2000
Iczkowski et           IP, 17 (5.9);       44 (15-83)      15/6
  al, (5) 2001           PSC, 4 (1.4)
Schneider et           IP, 2 (0.7)         3; 14           2/0
  al, (38) 2001
Watanabe et            PMT, 3 (1.0)        38 (10-47)      2/1
  al, (39) 2001
Gyftopoulos et         PSC, 1 (0.4)        24              1/0
  al, (40) 2002
Debiec-Rychter et      IMT, 1 (0.4)        46              1/0
  al, (41) 2003
Tsuzuki et             IMT, 14 (4.9)       41 (18-76)      9/5
  al, (42) 2004 (d)
Freeman et             IMT, 9 (3.1)        36 (13-51)      5/4
  al, (43) 2004
Mergan et              IMT, 3 (1.0)        7 (6-15)        1/2
  al, (44) 2005
Montgomery et          IMT, 39 (13.6)      46 (3-86)       26/13
  al, (6) 2006 (d)
Hirsch et              PMP, 21 (7.3)       39 (18-76)      6/15
  al, (21) 2006
Harik et               PMP, 42 (14.6)      avg 47 (7-77)   32/10
  al, (20) 2006
Houben et              IMT, 1 (0.4)        10              0/1
  al, (45) 2007
Sukov et               IMT, 21 (7.3)       42 (26-88)      8/13
  al, (46) 2007
Spiess et              PFT, 7 (2.4);       62 (37-85)      6/11
  al, (47) 2007          PSC, 10 (3.5)
Hoene et al,           IMT, 1 (0.4)        27              0/1
  (48) 2008
Lekas et               PL, 1 (0.4)         36              0/1
  al, (49) 2008
Lecuona et             IMT, 1 (0.4)        3               1/0
  al, (50) 2012

                                              Major
                                              Dimension, (b)
Source, y              Symptoms               cm

Roth, (2) 1939         Cystitis, hematuria    1.5
Proppe et al,          NA                     NA
  (3) 1984
Olsen, (22) 1984       Cystitis               1
Nochomovitz et         Hematuria              5; 5
  al, (8) 1985
Ro et al, (23) 1986    Hematuria              2; 4
Young et al,           Hematuria              2
  (24) 1987
Wick et al,            Hematuria              3; 3
  (25) 1988
Stark et al,           Hematuria              3; 3
  (26) 1989
Albores-Saavedra       Hematuria,             3 (2-5)
  et al, (19) 1990       strangury, dysuria
Huang et al,           NA                     NA
  (4) 1990
Hughes et al,          Hematuria cystitis     NA
  (27) 1991
Dietrick et            Hematuria, dysuria     8; 4
  al, (28) 1992
Lamovec et al,         Dysuria                3.5
  (29) 1992
N'Dow et al,           Hematuria              2
  (30) 1993
Ro et al, (17) 1993    Hematuria              4 (2-8)
Jones et al,           Hematuria,             5 (2-7)
  (15) 1993              recurrent cystitis
Lundgren et al, (18)   Hematuria,             3 (1.5-6)
                         cystitis, dysuria
Angulo et al,          Hematuria, pain,       3.5; 4.5
  (31) 1994              dysuria
Koirala et al,         Hematuria              4
  (32) 1994
Weidner, (33) 1995     Hematuria              2
Hojo et al,            Hematuria, dysuria     5 (3-9)
  (12) 1995
Horn et al,            Pain, hematuria        2 (1.5-3)
  (34) 1997
Netto et al,           Suprapubic pain,       4.5; 2 (size
  (35) 1999              hematuria,             available in
                         irritative             2 cases)
                         voiding symptoms
Gardner et al,         Dysuria, abdominal     4.7
  (36) 1999              pain, increased
                         urinary frequency
Asanuma et al,         Hematuria              1.5
  (37) 2000
Iczkowski et           Hematuria, urinary     3.2 (1.3-13)
  al, (5) 2001           obstruction,
                         irritation
Schneider et           Hematuria              4.3; 6
  al, (38) 2001
Watanabe et            NA                     3 (2.5-4)
  al, (39) 2001
Gyftopoulos et         Increased urinary      11
  al, (40) 2002          frequency
Debiec-Rychter et      Hematuria              4
  al, (41) 2003
Tsuzuki et             NA                     NA
  al, (42) 2004 (d)
Freeman et             NA                     5 (2-7.5)
  al, (43) 2004
Mergan et              Hematuria              NA
  al, (44) 2005
Montgomery et          Hematuria              avg 4.2
  al, (6) 2006 (d)                              (1.2-12)
Hirsch et              Hematuria, dysuria,    4 (0.6-12)
  al, (21) 2006          abdominal pain
Harik et               Hematuria, pelvic      avg (1-10)
  al, (20) 2006          pain, obstructive
                         symptoms
Houben et              Dysuria, voiding       5.5
  al, (45) 2007          symptoms
Sukov et               NA                     NA
  al, (46) 2007
Spiess et              Hematuria, dysuria     NA
  al, (47) 2007
Hoene et al,           Myalgias, fatigue,     6.5
  (48) 2008              fever
Lekas et               Hematuria,             2.4
  al, (49) 2008          abdominal pain
Lecuona et             Hematuria              8.2
  al, (50) 2012

                       Bladder                Treatment, (c)
                       Infiltration           No. (%),
Source, y              (No.)                  n = 285

Roth, (2) 1939         Muscularis propria     PC, 1 (0.4)
Proppe et al,          NA                     TUR, 1 (0.4)
  (3) 1984
Olsen, (22) 1984       NA                     TUR, 1 (0.4)
Nochomovitz et         NA                     PC, 1 (0.4);
  al, (8) 1985                                  TUR, 1 (0.4)
Ro et al, (23) 1986    NA                     TUR, 1 (0.4);
                                                PC, 1 (0.4)
Young et al,           NA                     TUR, 1 (0.4)
  (24) 1987
Wick et al,            NA                     NA, 1 (0.4)
  (25) 1988
Stark et al,           Muscularis             PC, 2 (0.7)
  (26) 1989              propria (2)
Albores-Saavedra       Muscularis propria     PE, 1 (0.4);PC, 2
  et al, (19) 1990       (6); perivesical       (0.07); TUR, 6
                         fat (2);NA (2)         (2.1); CYS,
                                                1 (0.4)
Huang et al,           NA                     CYS, 1 (0.4)
  (4) 1990
Hughes et al,          Muscularis             TUR, 3 (1.1);
  (27) 1991              propria (4)            CYS, 1 (0.4)
Dietrick et            Muscularis             CYS, 1 (0.4);
  al, (28) 1992          propria (2)            TUR, 1 (0.4)
Lamovec et al,         Perivesical and        CYS, 1 (0.4)
  (29) 1992              periurethral
                         tissue
N'Dow et al,           Muscularis propria     PC, 1 (0.4)
  (30) 1993
Ro et al, (17) 1993    Muscularis propria     TUR, 6 (2.1);
                         (3); lamina            CYS, 2 (0.7)
                         propria (5)
Jones et al,           Muscularis propria     TUR, 8 (2.8);
  (15) 1993              (10); perivisceral     PC, 5 (1.8)
                         fat (2); lamina
                         propria (1)
Lundgren et al, (18)   NA                     TUR, 11 (3.9);
                                                TAR, 1 (0.4)

Angulo et al,          NA                     PC, 2 (0.7)
  (31) 1994
Koirala et al,         Muscularis propria     TUR, 1 (0.4)
  (32) 1994
Weidner, (33) 1995     Muscularis propria     PC, 1 (0.4)
Hojo et al,            NA                     PC, 3 (1.1); TUR,
  (12) 1995                                     2 (0.7); TUR-PC,
                                                6 (2.1)
Horn et al,            Muscularis propria     PC, 2 (0.7);
  (34) 1997              (1); lamina            TUR, 1 (0.4)
                         propria (2)
Netto et al,           NA                     TUR, 5 (1.8)
  (35) 1999
Gardner et al,         Fibroadipose tissue    PC, 1 (0.4)
  (36) 1999
Asanuma et al,         Muscularis propria     OE, 1 (0.4)
  (37) 2000
Iczkowski et           Lamina propria (3);    TUR, 13 (4.6);
  al, (5) 2001           muscularis propria     PC, 8 (2.8)
                         (15); NA (3)
Schneider et           Muscularis             PC, 2 (0.7)
  al, (38) 2001          propria (2)
Watanabe et            NA                     PC, 3 (1.1)
  al, (39) 2001
Gyftopoulos et         Muscularis propria     SEA, 1 (0.4)
  al, (40) 2002
Debiec-Rychter et      Muscularis propria     CYS, 1 (0.4)
  al, (41) 2003
Tsuzuki et             Muscularis             TUR, 14 (4.9)
  al, (42) 2004 (d)      propria (2)
Freeman et             NA                     CYS, 3 (1.1); PC,
  al, (43) 2004                                 5 (1.8);
                                                TUR, 1 (0.4)
Mergan et              NA                     PC, 3 (1.1)
  al, (44) 2005
Montgomery et          Muscularis             PC, 7 (2.5);
  al, (6) 2006 (d)       propria (16)           CYS, 1 (0.4);
                                                TUR, 38 (13.3)
Hirsch et              Muscularis propria     TUR, 3 (1.1); PC,
  al, (21) 2006          (13); muscularis       9 (3.2);
                         mucosae (4)            NA, 1 (0.4)
Harik et               Muscularis propria     TUR, 30 (10.5);
  al, (20) 2006          (28 of 32; 88%);       CYS, 3 (1.1);
                         muscularis mucosae     PC, 9 (3.2)
                         (32 of 38; 84%);
                         perivisceral fat
                         (3 of 8; 38%)
Houben et              Perivesicular soft     PC, 1 (0.4)
  al, (45) 2007          tissues
Sukov et               NA                     PC, 2 (0.7); TUR,
  al, (46) 2007                                 19 (6.7)
Spiess et              Muscularis propria     TUR, 17 (6.0)
  al, (47) 2007          (7); NA (10)
Hoene et al,           Muscularis propria     CYS, 1 (0.4)
  (48) 2008
Lekas et               NA                     TUR, 1 (0.4)
  al, (49) 2008
Lecuona et             Perivisceral fat       SEA, 1 (0.4)
  al, (50) 2012

                       Follow-up (b)
Source, y              (mo)                    Additional Data

Roth, (2) 1939         NED (12)
Proppe et al,          Re-excision of a        Preexisting TCC-UB;
  (3) 1984               recurrence after        can be labeled PSCN
                         6 wk; NED (36)
Olsen, (22) 1984       NED (36)
Nochomovitz et         NED (36; 3)             73-y-old patient
  al, (8) 1985                                   died of unrelated
                                                 causes with no
                                                 evidence of disease
Ro et al, (23) 1986    NED (12;24)
Young et al,           NED (42)                15 mo after surgery,
  (24) 1987                                      in situ TCC-UB;
                                                 can be labeled PSCN
Wick et al,            NA                      55-y-old patient had
  (25) 1988                                      previous surgery
                                                 for TCC-UB;
                                                 60-y-old patient
                                                 had previous TUR;
                                                 both labeled PSCN
Stark et al,           NED (24;17)
  (26) 1989
Albores-Saavedra       Follow-up data
  et al, (19) 1990       available for 8
                         pts; NED (24;
                         18-72)
Huang et al,           NED (48)
  (4) 1990
Hughes et al,          NED (60; 48-108)        Synchronous, invasive
  (27) 1991                                      TCC-UB in 1 case
Dietrick et            NED (12; 18)
  al, (28) 1992
Lamovec et al,         NED (8)
  (29) 1992
N'Dow et al,           NED (9)
  (30) 1993
Ro et al, (17) 1993    NED (51;24-108)
Jones et al,           NED (24; 6-64)          1 patient had surgery
  (15) 1993                                      for TCC-UB at 15
                                                 mo; 1 case labeled
                                                 PSCN
Lundgren et al, (18)   NED (60;1-180)          1 patient died from
                                                 postoperative
                                                 infection; 1 died
                                                 of unknown cause;
                                                 synchronous TCC-UB
                                                 in 2 cases; 1 case
                                                 labeled PSCN
Angulo et al,          NED (144;228)
  (31) 1994
Koirala et al,         NED (10)
  (32) 1994
Weidner, (33) 1995     NED (12)                Synchronous renal
Hojo et al,            NED (15;2 wk-42)          cell carcinoma
  (12) 1995
Horn et al,            NED (18; 12-23)         2 cases labeled PSCN
  (34) 1997
Netto et al,           NED (18, 18, 42);2 NA
  (35) 1999
Gardner et al,         NED (3)
  (36) 1999
Asanuma et al,         NED (12)
  (37) 2000
Iczkowski et           Follow-up data          1 patient died of
  al, (5) 2001           available for 20;       urosepsis;
                         residual tumor in       synchronous
                         2; NED (24; 5-132)      low-grade TCC-UB
                                                 in 1 case; TCC in
                                                 situ at 1 y in 1
                                                 case; 4 cases
                                                 labeled PSCN
Schneider et           NED (NA)
  al, (38) 2001
Watanabe et            NED (96; 72-156)
  al, (39) 2001
Gyftopoulos et         NED (12)
  al, (40) 2002
Debiec-Rychter et      NA                      AL[K.sup.+] with
  al, (41) 2003                                  both IHC and FISH.
Tsuzuki et             NA                      Generic local
  al, (42) 2004 (d)                              recurrence in 2
                                                 cases; ALK in 10
                                                 cases with IHC
Freeman et             NED (16;5-48);          ALK: IH[C.sup.+] in
  al, (43) 2004          follow-up data          8 cases,
                         available for 6 pts     [FISH.sup.+] in 4
                                                 (out of 6; 67%).
Mergan et              NED (24; 2-60)          AL[K.sup.+] with IHC
  al, (44) 2005
Montgomery et          Follow-up data          ALK: IH[C.sup.+] in
  al, (6) 2006 (d)       available for 32;       18, [FISH.sup.+]
                         recurrence in 9,        in 12;8 cases
                         with 2 recurrences      labeled PSCN
                         in 2 cases; 2
                         lethal, synchronous
                         sarcomatoid TCC; 1
                         lethal case
                         diagnosed as
                         inflammatory
                         fibrosarcoma; NED
                         in remaining cases
                         (24; 3-120)
Hirsch et              Recurrence in 2 cases   ALK: IH[C.sup.+] in
  al, (21) 2006          with 2 recurrences      10 (of 19; 53%),
                         in 1; NED               FISH-in the 6
                         (27;3-108)              cases evaluated;
                                                 4 cases labeled
                                                 PSCN
Harik et               Follow-up data          ALK: IH[C.sup.+] in
  al, (20) 2006          available for 28        12, [FISH.sup.+]
                         pts; recurrence in      in 4 (of 6 cases;
                         3 cases; 3 alive        67%); 9 labeled
                         with disease;           PSCN; 1 patient
                         NED (24)                with
                                                 neurofibromatosis
                                                 died of its
                                                 complicacy
Houben et              NED (6)                 AL[K.sup.+] with IHC
  al, (45) 2007
Sukov et               NED (34; 7-70)          ALK: IH[C.sup.+] in
  al, (46) 2007                                  13; [FISH.sup.+]
                                                 in 14
Spiess et              NED (36; 2-157)         2 pts died from other
  al, (47) 2007                                  diseases
Hoene et al,           NED (6)                 Systemic lupus
  (48) 2008                                      erythematosus;
                                                 AL[K.sup.+] with
                                                 IHC, [FISH.sup.-]
Lekas et               NED (36)                AL[K.sup.+] with IHC
  al, (49) 2008
Lecuona et             NED (7)                 AL[K.sup.+] with IHC
  al, (50) 2012

Abbreviations: ALK, anaplastic lymphoma kinase; avg, average;
CYS, cystectomy; FISH, fluorescence in situ hybridization; IHC,
immunohisto-chemistry; IMT, inflammatory myofibroblastic tumors;
IP, inflammatory pseudotumor; NA, not available; NED, no evidence
of disease; OE, open excision; PC, partial cystectomy; PE, pelvic
exenteration; PFT, pseudosarcomatous fibromyxoid tumor;
PL, pseudosarcomatous lesion; PMP, pseudosarcomatous
myofibroblastic proliferations; PMT, pseudosarcomatous
myofibroblastic tumor; PSCN, pseudomalignant spindle cell nodule;
pts, patients; SEA, suprapubic extraperitoneal approach; TAR,
transabdominal resection; TCC, transitional-cell carcinoma; TUR,
trans-urethral resection; UB, urinary bladder.

(a) Cases by designation, No. (%), n = 287: IMT, 91 (31.7);
IP, 57 (19.9); PFT, 17 (5.9);PL, 5 (1.7); PMP, 75 (26.1); PMT,
14 (4.9); PSC, 28 (9.8).

(b) When multiple cases are reported, data are expressed as
median value with its range.

(c) Cases by treatment, No. (%), n = 285: CYS, 16 (5.6); NA, 2 (0.7);
OE, 1 (0.4); PC + TUR-PC, 77 (27.0); PE, 1 (0.4); SEA, 2 (0.7);
TAR, 1 (0.4); TUR, 185 (64.9).

(d) These data may be slightly different than those in the
original article because they were directly obtained after
contacting the corresponding authors.

Table 2. Differential Diagnosis

                  IMT (a)          PMP/PSCN (a)     LM

Cell atypia       Absent or        Absent or        Absent or
                    minimal          minimal        minimal
Mitoses           Few              Few              Absent or rare
Necrosis          Absent or        Absent           Absent
                    superficial
                    (minimal if
                    present)
Stroma            Myxoid or        Mainly           Scarce
                    fibrous          myxoid
Inflammation      Present          Present          Absent
Muscularis        Frequent         Frequent         In the
  propria                                             muscularis
  infiltration                                        propria
ALK-1             [+ or -]         [+ or -]         -
CD34              -                -                [+ or -]
c-Kit (CD117)     -                -                -
Cytokeratin       [+ or -]         [+ or -]         -
Desmin            [+ or -]         [+ or -]         +
DOG-1             -                -                -
EMA               -                -                Rare
h-Caldesmon       -                -                +
Muscle-specific   [+ or -]         [+ or -]         +
  actin
MyoD1             Rare             -                -
Myogenin          Rare             -                -
p63               -                -
SMA               [+ or -]         [+ or -]         +
S100              -                -
Vimentin          +                +                +

                  LG-LMS                SC               LG-IFS

Cell atypia       Minimal or            Moderate or      Minimal or
                    moderate              severe           moderate
Mitoses           Frequent              Frequent to      Frequent
                                          diffuse
Necrosis          Focal                 Frequent         Focal or
                                                           zonal
Stroma            Scarce                Scarce           Myxoid or
                                                           fibrous
Inflammation      Absent                Absent or        Present
                                          minimal
Muscularis        In the muscularis     Frequent         Frequent
  propria           propria often
  infiltration      with whole
                    wall infiltration
ALK-1             -                     -                [+ or -]
CD34              [+ or -]                               -
c-Kit (CD117)     -                                      -
Cytokeratin       Rare                  +                [+ or -]
Desmin            +                     [+ or -]         [+ or -]
DOG-1
EMA               -                     +                -
h-Caldesmon       +                                      -
Muscle-specific   [+ or -]              [+ or -]
  actin
MyoD1
Myogenin          -                     -
p63                                     [+ or -]         -
SMA               +                     [+ or -]         [+ or -]
S100              -                                      -
Vimentin          +                     [+ or -]         +

                  EGIST

Cell atypia       Minimal to
                    severe
Mitoses           Rare to
                    frequent
Necrosis          Absent to
                    diffuse
Stroma            Scarce to
                    fibrous
Inflammation      Absent

Muscularis        Frequent
  propria
  infiltration
ALK-1             -
CD34              [+ or -]
c-Kit (CD117)     +
Cytokeratin       -
Desmin            Rare
DOG-1             +
EMA               Rare
h-Caldesmon       [+ or -]
Muscle-specific   [+ or -]
  actin
MyoD1
Myogenin
p63
SMA               [+ or -]
S100              [+ or -]
Vimentin          +

Abbreviations: ALK-1, anaplastic lymphoma kinase-1; EMA, epithelial
membrane antigen; IMT, inflammatory myofibroblastic tumor; EGIST,
extragastrointestinal gastrointestinal stromal tumor; LG-IFS,
low-grade inflammatory fibrosarcoma; LG-LMS, low-grade
leiomyosarcoma; LM, leiomyoma; PMP, pseudosarcomatous myofibroblastic
proliferation; PSCN, postoperative spindle cell nodules; SC,
sarcomatoid carcinoma; SMA, smooth muscle actin.

(a) See text "Pathologic and Immunohistochemical Findings" section
for detailed treatment.


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Author:Alquati, Sara; Gira, Federica Alessandra; Bartoli, Veronica; Contini, Sandro; Corradi, Domenico
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Report
Geographic Code:1USA
Date:Aug 1, 2013
Words:8545
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