Inflammatory myofibroblastic tumors (IMTs), which are rare tumors, exhibit myofibroblastic differentiation, often with anaplastic lymphoma kinase (ALK) gene rearrangements. A subset of IMTs identified in the urinary tract have been shown to harbor a fibronectin 1 (FN1)-ALK gene fusion. In this case report, a case of an IMT with FN1-ALK fusion in the urinary bladder was presented, and its clinicopathological characteristics were reviewed. A 45-year-old female was referred to Chungbuk National University Hospital with gross hematuria. Cystoscopy revealed a solid mass in the bladder. The patient subsequently underwent transurethral resection of the lesion. The mass comprised stellate and spindled myofibroblastic cells that were arranged in loose fascicles, with a myxoid background and a mixed inflammatory infiltrate. Immunohistochemical analysis revealed that the tumor cells were positive for vimentin, cytokeratin AE1/AE3 and ALK, and focal-positive for desmin. Targeted next-generation sequencing was subsequently employed to identify the FN1-ALK fusion. To date, the patient has undergone outpatient follow-up for 18 months, with no signs of tumor recurrence. To conclude, in total, FN1 has been identified as an ALK fusion partner almost exclusively in cases of genitourinary IMTs [13 bladder IMTs (including the present case) and two uterine IMTs]. In the present case, the FN1-ALK fusion was found to involve ALK exon 19 and FN1 exon 23. By contrast, the majority of the other IMTs with an ALK fusion have involved ALK exon 20, whereas ALK fusion involving ALK exon 18 or 19 has been reported only in genitourinary IMTs. Therefore, the FN1-ALK fusion involving ALK exon 18 or 19 may be specific to a subset of IMTs arising in the urinary bladder.
Inflammatory myofibroblastic tumors (IMTs) are rare mesenchymal neoplasms with myofibroblastic differentiation. IMTs can occur at any age, although the disease has a predilection for children, adolescents and young adults (
~50% of IMTs harbor anaplastic lymphoma kinase (ALK) gene rearrangements, resulting in constitutive gene activation and cytoplasmic ALK protein expression (
The majority of urinary tract IMTs with an ALK gene rearrangement harbor a fibronectin 1 (FN1)-ALK gene fusion (
A 45-year-old woman was referred to the Chungbuk National University Hospital institute with a 1-week history of gross hematuria. Computed tomography (CT) revealed the presence of a 2.2×2 cm, heterogeneously enhancing round mass located in the anterior/superior wall of the urinary bladder (
IMT of the urinary bladder is a rare tumor that follows an indolent clinical course. IMTs are often associated with ALK gene rearrangement, and the FN1 gene is the most common fusion partner in the urinary bladder (
Overall, the recurrence rate for IMTs is ~20%, although it is markedly higher for abdominal and pelvic IMTs (up to 85%), and lower for IMTs of the lung (<2%) and bladder (<4%) (
The current RNA sequencing results revealed the presence of FN1-ALK fusion. In cases of IMT of the urinary bladder, the most common fusion partner is FN1 (
FN1 is located at chromosome 2q35, and encodes fibronectin, a glycoprotein widely distributed in plasma and the extracellular matrix.
In the present case study, the FN1-ALK fusion involved ALK exon 19 and FN1 exon 23. The majority of previously reported ALK fusions have featured a common breakpoint between exons 19 and 20 (
Tumors with FN1-ALK fusion have shown different treatment responses, depending on the type of ALK inhibitors used to treat the patient. Reinhart
It is unclear why the FN1-ALK fusion has different sensitivities, depending on the type of ALK inhibitor used for the therapy. Childress
In conclusion, a rare case of an IMT with FN1-ALK fusion in the urinary bladder was reported in the present case study. The presence of FN1-ALK fusions with ALK with exon 18 or 19 rearrangement may be specific to a subset of IMTs, wherein ALK is inhibited upon treatment with second-generation ALK inhibitors, but not with crizotinib. This could be of importance both in the neoadjuvant and in the palliative settings, particularly in terms of negating the need for radical surgery. Therefore, the detection of a distinct FN1-ALK fusion not only assists the diagnosis of IMTs, but also helps to determine the most appropriate course of treatment. However, since only one case was reported, the current conclusions are limited and may not represent all patients. Considering the rarity of this condition, gathering data from all cases of urinary bladder IMTs with FN1-ALK fusion will help to confirm the molecular characteristics and the efficacy of ALK TKIs in the treatment for IMTs.
Not applicable.
The data analyzed during the current study is available at
SMS and HCL made substantial contributions to the conception and design of the work, and drafted and revised the manuscript. CGW and OJL interpreted the pathological data. YJK analyzed the patient data. SMS and CGW confirm the authenticity of all the raw data. All authors have read and approved the final manuscript.
The present study adhered to the guidelines established by the Declaration of Helsinki and was approved (approval no. 2022-11-018) by the Institutional Review Board of Chungbuk National University Hospital (Cheongju, Korea).
Written informed consent for the publication of anonymous case information was provided by the patient.
The authors declare that they have no competing interests.
Enhanced abdominopelvic computed tomography image showing an enhanced 2.2×2 cm bladder mass (yellow arrow).
Cystoscopy, revealing a single solid erythematous tumor in the anterior/superior wall of the urinary bladder.
(A) The mass comprised stellate and spindled myofibroblastic cells arranged in a ‘tissue culture-like’ pattern, with a myxoid background and a mixed inflammatory infiltrate comprising neutrophils, eosinophils and lymphocytes (original magnification, ×200; scale bar, 100 µm). (B) The tumor cells had a pale eosinophilic cytoplasm, with long tapering processes. The nuclei were elongated, ovoid or round, with a bland appearance and containing delicate chromatin and small-to-inconspicuous nucleoli (original magnification, ×400; scale bar, 50 µm).
The tumor cells showed strong immunoreactivity for (A) cytokeratin AE1/AE3 and (B) ALK protein. The immunoreactivity for (C) desmin was focal (original magnification, ×400; scale bar, 50 µm). ALK, anaplastic lymphoma kinase.
Clinical features of previously reported cases of a primary retroperitoneal mucinous cystic neoplasm with borderline malignancy.
First uthor, year | Age, years | Sex | Size, cm | Clinical symptoms | Treatment | Outcome | Fusion | ALK IHC | (Refs.) |
---|---|---|---|---|---|---|---|---|---|
Lovly |
8 | F | 3 | ND | ND | ND | Exon 23 of FN1 Intron 18 of ALK | ( |
|
Lovly |
26 | F | 3 | ND | ND | ND | Exon 23 of FN1 | Positive | ( |
Intron 18 of ALK | |||||||||
Ouchi |
12 | M | ND | Gross hematuria | Neoadjuvant treatment (meloxicam) + partial | NED, 12 months | Exon 20 of FN1 | Positive | ( |
cystectomy | Exon 19 of ALK | ||||||||
Bertz |
64 | F | ND | ND | TUR-B | ND | ND | Positive | ( |
Reinhart |
43 | F | 7 | Dysuria and macrohematuria | Neoadjuvant therapy (crizotinib → lorlatinib) | NED, 12 months | Exon 36 of FN1 | Positive | ( |
+ partial cystectomy | Exon 19 of ALK | ||||||||
Present case | 45 | F | 2.2×2 | Gross hematuria | TUR-B | NED, 18 months | Exon 23 of FN1 | Positive | |
Exon 19 of ALK |
F, female; IHC, immunohistochemistry; M, male; ND, not described; NED, no evidence of disease; TUR-B, transurethral resection of the bladder; ALK, anaplastic lymphoma kinase; FN1, fibronectin.