Multi-centers clinicopathological prognosis study of inflammatory myofibroblastic tumors of urogenital system in China

Purpose: We aimed at investigate a series of inflammatory myofibroblastic tumors (IMTs) of urogenital Materials at West China Hospital of Sichuan University and the Third People’s Hospital of Chengdu, we identified 33 individuals with IMTs from May 2009 to January 2019 Results: A total of 33 patients with IMTs of urogenital system were identified. The median age of all the individuals was 39.5 years (range 0-74 years). The most common presentations were hematuria (13patients), pain (12 patients), and mass (12 patients). In addition, other clinical symptoms included dysuria, urinary frequency, and fever. Fourteen individuals were diagnosed with anemia, including 10 mild anemia patients and 4 moderate anemia cases. Moreover, neutrophil was the dominant inflammatory cell type. The main positive markers of immunohistochemistry staining included SMA (22/25), MSA (8/9), CD34 (15/17), and CD68 (3/3). Surgery resection was the sole treatment for all the patients. Follow- up was available in 23 patients during a median follow-up period of 78.3 months (range 19.2-118.8 months), and either recurrence or metastasis was detected in any patients except one patients died from retroperitoneum IMTs. Conclusion: This study confirmed that urogenital system IMTs, with potential of recurrence or metastasis, are extremely rare. In summary, although favorable prognosis was observed in IMTs of urogenital system, closely follow-up is essential and needed.

years). The most common presentations were hematuria (13patients), pain (12 patients), and mass (12 patients). In addition, other clinical symptoms included dysuria, urinary frequency, and fever. IMTs. Conclusion: This study confirmed that urogenital system IMTs, with potential of recurrence or metastasis, are extremely rare. In summary, although favorable prognosis was observed in IMTs of urogenital system, closely follow-up is essential and needed.

Background
Inflammatory myofibroblastic tumors (IMTs), a rare entity of spindle cell tumors, composed of myofibroblastic mesenchymal spindle cells with an inflammatory infiltrate of plasma cells, lymphocytes, and eosinophils [1] . According to World Health Organization (WHO) classification, IMTs are intermediate tumors with potential for recurrence. The first report of IMTs was demonstrated by Brunn on two cases of "myoma of the lung" in 1939, and IMTs of urinary system was firstly described by Roth in 1980 [2] . The lung is the most common site (95%) of IMTs, and other potential sites (5%) including abdomen, retroperitoneum, pelvic cavity, head, neck, trunk, and limbs [3] . What's more, urinary bladder is the most common site of IMTs. Nevertheless, IMTs comprise less than 1% of all bladder neoplasms [4] .
Nevertheless, IMTs of urinary system couldn't be recognized precisely because of clinical symptoms, laboratory test results and imaging lacking specificity for the diagnosis of IMTs. So far, surgical resection is the dominant and preferred therapy for IMTs. In addition, steroids, nonsteroidal antiinflammatory drugs (NSAIDs), chemotherapy, and radiotherapy have been used as adjuvant therapy if necessary [5] . Up to now, there are only several studies [3,[6][7][8] of urinary system IMTs relied on enormous population. Unfortunately, these studies described mainly the clinicopathological characteristics so that all of them maybe not illustrate the incidence, survival, mortality and prognosis of urinary system IMTs.
In this study, we are aiming to retrospectively investigate the clinic characteristics, pathological features, treatment, survival and prognosis of urinary system IMTs in China.

Methods
We searched pathologic databases at the West China Hospital of Sichuan University and the Third People's Hospital of Chengdu from May 2009 to January 2019. Our search terms included inflammatory myofibroblastic tumor, inflammatory pseudosarcoma, and spindle cell lesion. Finally, 33 patients were included in our study.
Patients characteristics including age, sex, signs and symptoms (including pain, dysuria, urinary frequency, anemia level, tumor size in maximal dimension, tumor location, treatment given, and presence of any tumor recurrence or distant metastases were recognized. Hematuria was defined as red blood cell of urine more than 3/HP.

Baseline characteristics
Thirty-three patients diagnosed with urogenital system IMTs were identified, which met the eligibility criteria for our study from May 2009 to January 2019. The baseline characteristics are shown in Table   1
Among those patients who had TURBT performed, specifically, 3 (42.9%) patients had further partial cystectomy. Therefore, among patients with bladder IMTs, 3 (30.0%) patients were treated with TURBT plus partial cystectomy. In addition, among other sites IMTs patients, 3 (30.0%) patients underwent orchiectomy, and other patients (70.0%) were treated with pure tumor resection. What's more, all the patients didn't undergo additional therapy apart from surgery.

Discussion
IMTs, a rare subtype with unique clinical and pathologic characteristics, in which the dominant components is spindle cells, and other components including alterable extracellular collagen, lymphocytes, and plasma cells [9] . IMTs, originally reported in the lung, has been recognized at multiple extrapulmonary sites, particularly the soft tissue and solid organs of children and young adults [1,3,8] . The the most common site of IMTs of genitourinary system is the urinary bladder. The alternative terminologies of IMTs, including plasma cell granuloma, inflammatory pseudotumor, pseudosarcomatous fibromyxoid tumor, and inflammatory myofibroblastic tumor, demonstrated that further studies are needed to explore the pathogenesis of IMTs. Nevertheless, a crowd of studies, including our study, agree with the myofibroblastic nature of IMTs with expression of SMA, desmin, vimentin, CD34, and CD68. At the same time, we found that the significant inflammatory cell types of IMTs included neutrophil, eosinophil, plasma cell, and lymphocyte, which supported the prior reports [10] . According to the current WHO Classification of Tumors of Soft tissue and Bone [11] , moreover, IMTs are categorized as intermediate grade tumors in view of the potential for local recurrence and distant metastasis.
The first case report of IMTs of the kidney was published in 1976, closely followed by a series of case reports and rare studies [9,[12][13][14][15][16] . The median age of kidney IMTs 39 years (range 6-74 years) in our study doesn't consist with the mean age 57.1 years in a large study [9] , but consists with the mean age 43.3 years of literatures review in the 13 case reports. In addition, it agrees with other reports that the age of onset, concentrated in 25-72 years (median 51.5 years), and the most common symptom is hematuria with more than half of them being anemia upon presentation of bladder IMTs in our study [6,8,17] . Sarcomatoid urothelial carcinoma et al are the most significant subtypes in the differential diagnosis of IMTs. What's more, both IMTs and sarcomatoid urothelial carcinoma exhibit similar biological characteristics resulting in the differential diagnosis becoming the most difficult [6] .
According to the study of Liang et al [18] , however, the good news is that contrast-enhanced CT may be valuable in the diagnostic imaging of the urinary system IMTs.
The ALK gene translocation was detected by FISH in 2/3 (67.7%) individuals, which is consistent with 30%-67% ALK gene rearrangements of IMTs on FISH testing in other studies [6,17,19,20] . As is wellknown, more than half of anaplastic large cell lymphoma (ALCL) patients presented ALK gene translocation accompanied with tyrosine kinase activation. Moreover, ALK gene rearrangement was confirmed in testis IMTs too [21] . Therefore, IMTs were considered as neoplastic rather than reactive in mature on the basis of ALK gene rearrangement. In 2014, Chun et al [10] published a systematic review in which they demonstrated that had a marked female predilection (male: female=1: 1.67) was recognized in ALK-positive IMTs.
Nowadays, surgical resection is the dominant therapy of urogenital system IMTs. In 2003, a 12 kidney IMTs cases study was published in which all the patients underwent kidney resection, was administrated with no adjuvant treatment, and no recurrent tumors was recognized in the patients available for follow-up [9] . Our study happened to coincide with this series [9] on kidney IMTs patients' prognosis.
In terms of the urinary bladder IMTs, according to previous reports, partial or radical cystectomy can insure no residual IMTs [10] . In consideration of benign behavior of the urinary bladder IMTs, nevertheless, TURBT maintained as a selection in reserve for patients who are unwilling to received partial or radical surgery. Studies including our series demonstrated that local management can make patients acquire favorable recurrence free survival and overall survival [3,6,17] . Until now, although extremely rare recurrence was reported in fewer individuals, no distant metastasis was illustrated in literatures already. In our study, one patient with retroperitoneum IMTs appeared poor prognosis after retroperitoneum tumor resection. In addition, a systematic review published in 2014 also demonstrated local tumor recurrence in five bladder IMTs cases [10] . Therefore, although further chemotherapy or radiotherapy is not needed, close follow-up, regular cystoscopy and imaging tests are necessary for the early diagnosis of tumor recurrence and metastasis.

Conclusion
This study confirmed that urogenital system IMTs, with potential of recurrence or metastasis, are extremely rare. In summary, although favorable prognosis was observed in IMTs of urogenital system, closely follow-up is essential and needed. The research was based on a retrospective study. Ethics approval was not needed because the study is a secondary analysis of an existing public internal database of our hospital.

Consent for publication
Not applicable Availability of data and materials All data on which the conclusions of the manuscript rely are available from reasonable request.