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Background: Inflammatory myofibroblastic tumor (IMT) is an indolent tumor mainly affecting children and young adults. As a rare mesenchymal tumor with unknown etiology and pathogenesis, IMT has a predilection for the lung and abdominopelvic region. Previous literature featuring IMT in the central nervous system (IMT-CNS) is rare. The clinical symptoms and radiologic features of IMT-CNS are not specific; therefore, the diagnosis is predominately based on the histopathologic and immunohistochemical analysis of the specimen., Case Description: We herein present a case of a 21-year-old woman who complained of bilateral blurred vision for 15 days. Head magnetic resonance imaging demonstrated a round-shaped and irregular lesion located in the right frontal lobe. The boundary of the lesion was clear, and the lesion was homogeneously enhanced. Peripheral edema of the lesion was observed, and the mass effect was obvious. Supratentorial craniotomy tumor resection was performed. Histopathologic and immunohistochemical analysis revealed IMT, which had negative expression of anaplastic lymphoma kinase., Conclusions: Remission of her symptoms was observed, and no recurrence was recorded during a 6-month follow-up., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Although inflammatory myofibroblastic tumors (IMTs) are seen in the lower respiratory tract in the pediatric population, few cases occurring in the larynx have been reported in the literature. Treatment of choice is complete surgical excision because of risk of recurrence. We describe a case of pediatric subglottic IMT presenting with progressive hoarseness and symptoms of persistent reactive airway treated with potassium titanyl phosphate laser. We also enumerate the number of pediatric cases of IMT that occur in the larynx and subglottis compared with those which occur in the upper respiratory tract, specifically the trachea and bronchi. To the best of our knowledge, this is the first reported case of respiratory tract IMT excision using a potassium titanyl phosphate laser and the second reported case of a pediatric laryngeal IMT showing anaplastic lymphoma kinase-1 immunoreactivity., (Copyright © 2014 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: To study the clinical and pathologic features of primary cardiac inflammatory myofibroblastic tumor., Methods: A total of 4 patients with primary cardiac inflammatory myofibroblastic tumor were encountered during the period from 1993 to 2013 in National Center for Cardiovascular Disease. The clinical features, imaging findings and outcomes of the 4 patients were evaluated. ALK protein expression and ALK gene status were studied using the archival tumor tissues., Results: There were 1 female and 3 male patients. The age of patients ranged from 5 months to 30 years (mean = 16 years). The tumor was located in right ventricle (n = 2), right atrium (n = 1) or pericardium (n = 1). Histologic patterns included 2 cases of fibrous histiocytoma type, 1 case of granulomatous type and 1 case of sclerosing type. Immunohistochemical study showed that 2 cases expressed ALK protein. Fluorescence in-situ hybridization however did not reveal any ALK gene rearrangement., Conclusions: Inflammatory myofibroblastic tumor of the heart is rarely encountered and easily misdiagnosed. It carries distinctive clinical and pathologic features. ALK protein expression is helpful in arriving at the correct diagnosis.

Inflammatory myofibroblastic tumours (IMTs), also known as inflammatory pseudotumours, include a diverse group of lesions characterised by inflammatory cell infiltration and variable fibrotic responses. Their occurrence in the breast is unusual. We present a case of an IMT of the breast in a 46-year-old woman who complained of a breast mass with palpable axillary lymph node. The initial clinical diagnosis was breast cancer, and the patient underwent a conservative excision with apparently negative margins and an axillary lymph node excisional biopsy. A histopathological examination showed the presence of myofibroblastic spindle cells with mixed inflammatory infiltrates, and the pathological diagnosis was IMT. Significantly, the case we present here is unique in showing anaplastic lymphoma kinase 1 (ALK1) overexpression and ALK1 gene amplification in IMT of the breast. Therefore, our case suggests that ALK1 gene amplification in IMT of the breast has important diagnostic and therapeutic implications.

Purpose of Review: Inflammatory myofibroblastic tumors (IMTs) are indolent mesenchymal neoplasms associated with a small risk of aggressive behavior and metastasis. Surgery is the mainstay of treatment and until recently there have been limited effective treatment options for unresectable disease. This review describes the identification of anaplastic lymphoma kinase (ALK) fusion genes in approximately 50% of IMTs and the role of ALK inhibition in the treatment of this disease., Recent Findings: A recent phase I dose-escalation trial of the selective MET/ALK inhibitor crizotinib showed a long-term partial response in a patient with IMT carrying an ALK translocation but not in a patient with ALK-negative disease. Emergence of resistance to crizotinib occurs approximately 5-8 months after initiation of therapy and has been shown to be driven by different mechanisms. Multiple second-generation ALK inhibitors are currently being investigated in the preclinical and clinical trial setting., Summary: ALK-directed therapy has emerged as a highly effective treatment option for a subset of patients with IMT and pulmonary adenocarcinoma. A number of additional malignancies, including rhabdomyosarcoma, neuroblastoma, anaplastic large cell lymphoma, renal cell carcinoma, and inflammatory breast cancer, have been shown to activate ALK expression by means of ALK fusion proteins, ALK mutations, or increased ALK copy number. Development of more selective ALK inhibitors, which can overcome emergent crizotinib resistance mutations, as well as development of combination treatments with drugs targeting compensatory pathways, will be key to achieving therapeutic success in targeting this potent and prevalent oncogenic driver.

The inflammatory myofibroblastic tumor (IMT) is a rare neoplastic lesion with a high incidence in children and young people, and may arise in lungs, soft tissue, or viscera. It is recognized as a borderline tumor with the possibility to recur, undergo malignant transformation, and metastasize. IMT is composed of fascicles of bland myofibroblastic cells admixed with an inflammatory infiltrate consisting of lymphocytes, plasma cells, and eosinophils. We reviewed pulmonary IMT diagnosed at Garrahan Hospital in Buenos Aires, Argentina, during 12 years and examined the clinical, laboratory, and pathological features as well as molecular genetics. Eight pediatric cases were evaluated with a male-to-female ratio of 5:3 and a median age of 6 years at diagnosis. The most common lung localization was the upper lobe. All cases underwent surgical excision and no local recurrences were found. Five out of eight patients, including two cases with metastatic/multifocal lesions in the central nervous system (CNS), are alive and disease free after a median follow-up of 30 months. Anaplastic lymphoma kinase (ALK) expression was negative in all pulmonary samples by immunohistochemistry (IHC), however, rearrangement for ALK locus by fluorescence in situ hybridization was found in one lung and in two CNS samples. These findings may reflect higher sensitivity of the molecular biologic procedure compare to traditional IHC practice. In our pediatric experience, 25% of patients with lung IMT developed CNS lesions; therefore we consider that CNS screening in these patients should be considered, at diagnosis and later during follow up.

Background and Objective: Cytochrome P450 arachidonic acid epoxygenase 2J2 (CYP2J2) is a new metabolic pathway of arachidonic acid. However, its biological effects, especially pathophysiologic significance in human beings, remain to be further recognized. This study was to determine the expression of CYP2J2 in human tumor tissues and cell lines., Methods: The expression of CYP2J2 mRNA and protein in 130 specimens of human carcinoma and related adjacent normal tissues, four specimens of inflammatory pseudotumor tissues, eight human tumor cell lines and two normal cell lines (as control) was detected by reverse transcription-polymerase chain reaction (RT-PCR), western blot and immunohistochemistry., Results: CYP2J2 was highly expressed in 101 (78%) carcinoma tissues, but was not detected in adjacent normal tissues and inflammatory pseudo-tumor tissues. Its mRNA level was obviously correlated to its protein level (r = 0.613, p < 0.01). Immunohistochemistry analysis showed the same results as RT-PCR and western blot. Furthermore, CYP2J2 was only expressed in cancer cells but not in interstitial and inflammatory cells. CYP2J2 was highly expressed in all carcinoma cell lines, but not in two normal cell lines., Conclusion: CYP2J2 is highly and selectively expressed in human tumor tissues and cell lines and may be a novel biomarker of human tumors.

Inflammatory myofibroblastic tumor (IMT) of the urinary tract, also termed postoperative spindle cell nodule, inflammatory pseudotumor, and pseudosarcomatous fibromyxoid tumor, is rare and in the past was believed to reflect diverse entities. We reviewed a series of 46 IMTs arising in the ureter, bladder, and prostate, derived primarily from a large consultation practice. There were 30 male and 16 females aged 3 to 89 years (mean 53.6). Lesions were 1.2 to 12 cm (mean 4.2). There was a history of recent prior instrumentation in 8 cases. Morphology was similar to that previously described for IMT occurring in this region, with the exception of 1 case that focally appeared sarcomatous. Polypoid cystitis coexisted in 5 patients (11%). Mitoses were typically scant (0 to 20/10 hpf, mean 1). Necrosis was seen in 14 (30%) cases. Invasion of the muscularis propria was documented in 19 (41%). By immunohistochemistry (IHC), lesions at least focally expressed anaplastic lymphoma kinase (ALK) (20/35, 57%), AE1/3 (25/34, 73%), CAM5.2 (10/15, 67%), CK18 (6/6, 100%), actin (23/25, 92%), desmin (15/19, 79%), calponin (6/7, 86%), caldesmon (4/7, 57%, rare cells), p53 (10/13, 77%), and most lacked S100 (0/14), CD34 (0/13), CD117 (2/13, 15%), CD21 (0/5), and CD23 (0/3). ALK gene alterations were detected by fluorescence in situ hybridization (FISH) in 13/18 (72%) tested cases, including 2 with prior instrumentation; 13/18 (72%) showed agreement between FISH ALK results and ALK protein results by IHC. Most bladder IMTs were managed locally, but partial cystectomy was performed as the initial management in 7 cases and cystectomy in 1 (1 IMT was initially misinterpreted as carcinoma, 1 IMT was found incidentally as a separate lesion in a cystectomy specimen performed for urothelial carcinoma). Follow-up was available in 32 cases (range 3 to 120 mo; mean 33; median 24). There were 10 patients with recurrences (2 with 2 recurrences). Recurrences were unassociated with muscle invasion or with ALK alterations. In 2 cases, tumors of the urinary tract (TURs) showing IMT preceded (1 and 2 mo, respectively) TURs showing sarcomatoid carcinoma with high-grade invasive urothelial carcinoma accompanied with separate fragments of IMT. Even on re-review the IMT in these 2 cases were morphologically indistinguishable from other cases of IMT, with FISH demonstrating ALK alterations in the IMT areas in one of them. Both these patients died of their carcinomas. Lastly, there was 1 tumor with many morphological features of IMT and an ALK rearrangement, yet overtly sarcomatous. This case arose postirradiation for prostate cancer 4 years before the development of the lesion, with tumor recurrence at 4 months and death from intra-abdominal metastatic disease at 9 months. In summary, urinary tract IMTs are rare and share many features with counterparts in other sites, displaying similar morphology and immunogenotypic features whether de novo or postinstrumentation. Typical IMTs can be locally aggressive, sometimes requiring radical surgical resection, but none of our typical cases metastasized, although they can rarely arise contemporaneously with sarcomatoid urothelial carcinomas. For these reasons, close follow-up is warranted.

Inflammatory myofibroblastic tumor is a rare spindle cell lesion of indeterminate malignant potential occurring in both pulmonary and extrapulmonary tissues. This report describes an unusual presentation of an unusual tumor at an unusual location: an intramural ileal case of inflammatory myofibroblastic tumor presenting with intussusception in a 29-year-old woman. We characterize this tumor through microscopic and ultrastructural analysis, extensive immunohistochemical analysis, ploidy analysis, and Epstein-Barr virus in situ hybridization, and we report the finding of an ALK/TPM3 fusion using fluorescence in situ hybridization.

Background/purpose: Inflammatory myofibroblastic tumor (IMT) is considered as an intermediate neoplasm that may present malignant features. Differential diagnosis with other tumor processes is sometimes difficult. Similar anaplastic lymphoma kinase (ALK) gene abnormalities as in anaplastic large cell lymphoma have been reported. Human herpesvirus 8 (HHV-8) DNA sequences have been described in adult pulmonary IMTs and Epstein-Barr virus (EBV) has been reported in splenic and hepatic IMTs, suggesting the importance of both viruses in IMT development. This article aims to evaluate ALK, EBV, and HHV-8 expression in children with IMT and to correlate our findings with clinical features., Methods: Sixteen children (range, 1-15 years) who had surgery for IMT between 1978 and 2003 were evaluated retrospectively. Formalin-fixed, paraffin-embedded archival tissues were stained for HHV-8 and ALK with immunohistochemistry. Epstein-Barr virus was detected by in situ hybridization (EBER probes)., Results: Tumors were located in the pulmonary lobe (n = 4), urinary tract (n = 4), mesentery or bowel (n = 4), hepatic lobe (n = 1), vena cava (n = 1), spinal cord (n = 1), and soft tissue (n = 1). Five children were treated with steroids and/or antibiotics before surgery, with no substantial result. IMT was excised totally in all but 2 cases. Four patients presented aggressive IMT with recurrence or metastasis requiring new surgery. ALK was positive in 3 (18.8%) cases and EBV in 1 pulmonary and 1 bladder tumor, all of them without recurrence or metastasis. None of the cases were positive for HHV-8. All patients are now disease-free with a mean follow-up of 4.2 years., Conclusions: Considering the present lack of efficient medical treatment, surgery should still be considered as the mainstay therapy in IMT, even in cases of recurrence or metastases. Larger multicentric studies would be necessary to understand the prognostic significance of ALK, EBV, and HHV-8 and their relationships with the origins of the tumor.

Inflammatory myofibroblastic tumours (IMFT) may arise at any anatomical site, including lung, soft tissues, retroperitoneum and bladder. Although morphologically similar, these lesions encompass a spectrum of entities with differing aetiology, ranging from reactive/regenerative proliferations to low-grade neoplasms with a risk of local recurrence, but no significant metastatic potential. Vesical IMFT usually presents as a polypoid mass with a pale firm cut surface and can be of considerable size, mimicking a malignant tumour clinically and radiologically. Its good outcome, however, warrants conservative surgical excision, emphasising the importance of identification and distinction from malignant tumours of the bladder that may require more radical surgery and/or adjuvant therapy. We conducted a preliminary retrospective, comparative immunocytochemical study of 20 bladder tumours, including nine IMFTs, five spindle cell (sarcomatoid) carcinomas, two rhabdomyosarcomas, two leiomyosarcomas and two neurofibromas. The results confirmed IMFT positivity for smooth muscle actin, desmin and cytokeratin in 78-89% cases, resulting in potential confusion with sarcomatoid carcinoma or leiomyosarcoma. In contrast, cytoplasmic anaplastic lymphoma kinase (ALK 1) staining was present in eight IMFT (89%), but was not seen in any other lesion examined. The ALK 1 staining was confirmed by fluorescence in situ hybridisation, with translocation of the ALK gene present in 15-60% tumour cells in four of six IMFT examined, but not in four cases of sarcomatoid carcinoma or three of leiomyosarcoma. In conclusion, ALK 1 staining may be of value in the distinction of vesical IMFT from morphologically similar entities, and often reflects ALK gene translocations in these lesions., (Copyright 2004 USCAP, Inc.)

We report a case of an intraocular inflammatory myofibroblastic tumor nearly filling the vitreous cavity of the eye of a 50-year-old man. The tumor was composed of a mixture of spindle cells and mixed inflammatory elements, including numerous plasma cells. The differential diagnosis included inflammatory pseudotumor and neoplastic mimics of this condition. Further investigation with immunohistochemistry revealed the mass to be composed of myofibroblasts, positive for smooth muscle actin stains and with weak anaplastic lymphoma kinase (ALK) expression in some tumor cells. Evaluation by fluorescence in situ hybridization revealed the tumor cells to have multiple copies of chromosome 2 and ALK but no rearrangement of the ALK gene. The authors propose that multiple copies of the ALK gene may be involved in inflammatory myofibroblastic tumor tumorigenesis, in addition to ALK gene rearrangements.

Inflammatory myofibroblastic tumor (IMT), synonymously referred to as inflammatory pseudotumor, is a distinctive mesenchymal lesion composed of spindle cells displaying morphological features of myofibroblasts admixed with considerable numbers of inflammatory cells. Recent genetic and molecular studies have shown that a subset of IMT is characterized by the expression of altered anaplastic lymphoma kinase (ALK) protein mostly resulting from rearrangements of the ALK gene such as TPM3-ALK, TPM4-ALK and CLTC-ALK fusion genes. We analyzed the ALK status in nine cases of IMT arising in various anatomical locations. Six cases showed immunohistochemical expression of the ALK protein, and two ALK-positive lesions examined by reverse transcription-polymerase chain reaction and a subsequent sequencing analysis harbored the TPM4-ALK fusion gene. Of note, the majority of ALK-positive tumor cells in four of the six lesions lacked the coexpression of myogenic markers including alpha-smooth muscle actin, a cytoskeletal protein indicating myofibroblastic differentiation, whereas a substantial number of tumor cells in the remaining two cases coexpressed ALK and alpha-smooth muscle actin and/or desmin. In an ultrastructural study of the lesion with predominant ALK-positive/actin-negative cells, spindle cells failed to demonstrate features of myofibroblasts such as intracytoplasmic bundles of thin filaments and dense bodies. The current findings suggest that ALK-positive cells in IMT are not always myofibroblastic but might be immature primitive mesenchymal cells.

We report two cases of gingival plasma cell granuloma in a 34-yr-old and 40-yr-old two male renal transplant recipients with cyclosporine A (CsA)-induced gingival overgrowth (GO). Histologically, these lesions were composed of mature plasma cells, showing polyclonality for both lambda and kappa light chains and fibrovascular connective tissue stroma. In addition to the fact that CsA-induced plasma cell granuloma is rare, the salient features of our cases were the secretion of interleukin-6 and overexpression of phospholipase C- gamma 1 of the tumor cells, which may explain the mechanisms of CsA- induced GO.

ALK-positive anaplastic large-cell lymphoma (ALCL) has been recognized as a distinct type of lymphoma in the heterogeneous group of T/Null-ALCL. While most of the ALK-positive ALCL (ALKomas) are characterized by the presence of the NPM-ALK fusion protein, the product of the t(2;5)(p23;q35), 10-20% of ALKomas contain variant ALK fusions, including ATIC-ALK, TFG-ALK, CLTC-ALK (previously designated CLTCL-ALK), TMP3-ALK, and MSN-ALK. TMP3-ALK and TMP4-ALK fusions also have been detected in inflammatory myofibroblastic tumors (IMTs), making clear that aberrations of the ALK gene are not associated exclusively with the pathogenesis of ALK-positive ALCL. Here we report results of molecular studies on two lymphoma cases and one IMT case with variant rearrangements of ALK. Our study led to the detection of the CLTC-ALK fusion in an ALCL case and to the identification of two novel fusion partners of ALK: ALO17 (KIAA1618), a gene with unknown function, which was fused to ALK in an ALCL case with a t(2;17)(p23;q25), and CARS, encoding the cysteinyl-tRNA synthetase, which was fused to ALK in an IMT case with a t(2;11;2)(p23;p15;q31). These results confirm the recurrent involvement of ALK in IMT and further demonstrate the diversity of ALK fusion partners, with the ability to homodimerize as a common characteristic., (Copyright 2002 Wiley-Liss, Inc.)

Inflammatory pseudotumors (IPTs) of the lymph node and spleen are an uncommon, benign cause of lymphadenopathy and/or splenomegaly that often bear striking clinicopathologic similarities to the inflammatory myofibroblastic tumors (IMTs) found in soft tissues. These tumors have classically been grouped together under the umbrella category of "inflammatory pseudotumor." Recent evidence shows that IMTs are in fact neoplastic processes that often harbor balanced chromosomal translocations involving the ALK kinase gene. These translocations result in expression of ALK kinase in IMTs as assessed by immunohistochemical studies. However, the relationship between IMT and IPT of the lymph node and spleen is uncertain. To determine if ALK tyrosine kinase expression is also present in IPT, 13 cases of IPT (9 involving lymph nodes, 4 splenic lesions) were examined for the presence of ALK tyrosine kinase by immunohistochemical staining on paraffin-embedded tissue. In addition, in situ hybridization studies for Epstein-Barr virus--encoded RNAs (EBER) and immunoperoxidase studies for human herpesvirus-8 (HHV8)--specific proteins were performed. All cases had clinical, morphologic, and immunophenotypic findings typical of IPT and had varying proportions of fibroblastic and inflammatory components. Age ranged from 11 to 75 (median, 40) years; 8 subjects were male, and 5 were female. None of the cases (0 of 13) had positive staining for ALK kinase or HHV8, and in 1 a lymph node (1 of 13) was focally positive for EBV (EBER) by in situ hybridization. The absence of ALK kinase as detected by immunohistochemical studies in IPT of the lymph node and spleen suggests that this entity is biologically distinct from the histologically similar IMT., (Copyright 2001 by W.B. Saunders Company)

Inflammatory myofibroblastic tumor (IMT) is an uncommon mesenchymal neoplasm with a variable histologic appearance that may mimic other spindle cell processes, particularly nodular fasciitis, desmoid tumor, and in intra-abdominal locations, gastrointestinal stromal tumor. Recently, gene fusions involving ALK at chromosome 2p23 have been described in IMTs. The resultant ALK protein overexpression in the myofibroblastic component of these tumors is detectable by immunohistochemistry. We examined 73 IMTs, 20 cases of nodular fasciitis, 15 desmoid fibromatoses, and 15 gastrointestinal stromal tumors by immunohistochemistry using ALK-11, a rabbit polyclonal antibody that recognizes the C-terminus of the protein. ALK positivity was detected in 44 of 73 (60%) IMTs. All cases of nodular fasciitis, desmoid fibromatosis, and gastrointestinal stromal tumors were ALK negative (p < 0.001). These findings demonstrate that ALK positivity is common in IMTs, and immunohistochemistry using anti-ALK antibodies can be helpful in the differential diagnosis of these neoplasms. In addition, anti-ALK staining seems to correlate with those IMTs that have the typical tri-patterned histologic appearance and clinical presentation, providing additional support to the premise that IMT is a distinctive clinicopathologic entity within the broad category of inflammatory pseudotumors.

Calcifying fibrous pseudotumor (CFT) is a rare benign soft tissue lesion composed of dense hyalinized fibrous tissue containing bland spindle-shaped cells admixed with a lymphoplasmacytic infiltrate and foci of dystrophic and often psammomatous calcifications. It has been suggested that CFT represents a late sclerosing stage of inflammatory myofibroblastic tumor (IMT). Recently, clonal cytogenetic abnormalities involving the anaplastic lymphoma kinase (ALK) gene on chromosome 2p have been identified in IMT, particularly those arising in deep soft tissue sites. We evaluated seven cases of deep soft tissue CFT diagnosed at the Cleveland Clinic Foundation and the University of Florida with available paraffin-embedded blocks using a monoclonal antibody to ALK (Dako, Carpenteria, CA) and a modified avidin-biotin complex method. The cohort included six women and one man with a median age at diagnosis of 43 years (range, 26 to 67 years). Sites of CFT included mesentery (3), peritoneum (1), omentum (1), serosa of small bowel (1), and anterior mediastinum (1). Immunohistochemically, only one case showed focal staining for ALK. The remaining six cases were negative, with appropriate positive and negative control staining. In conclusion, unlike IMT, CFT in deep soft tissue locations rarely expresses ALK by immunohistochemistry, suggesting that CFT is a different clinicopathologic entity than IMT, as opposed to representing a "burned out" IMT. Ann Diagn Pathol 5:10-14, 2001., (Copyright 2001 by W.B. Saunders Company)