Spectrum of kinase gene rearrangements in a large series of paediatric inflammatory myofibroblastic tumours.

INTRODUCTION: Inflammatory myofibroblastic tumours (IMTs), being an exceptionally rare category of paediatric neoplasms, often contain druggable gene rearrangements involving tyrosine kinases. METHODS AND RESULTS: This study presents a large consecutive series of IMTs which were analysed for the presence of translocations by the PCR test for 5'/3'-end ALK, ROS1, RET, NTRK1, NTRK2 and NTRK3 unbalanced expression, variant-specific PCR for 47 common gene fusions and NGS TruSight RNA fusion panel. Kinase gene rearrangements were detected in 71 of 82 (87%) IMTs (ALK: n = 47; ROS1: n = 20; NTRK3: n = 3; PDGFRb: n = 1). The test for unbalanced expression had 100% reliability in identifying tumours with ALK fusions, but failed to reveal ROS1 rearrangements in eight of 20 (40%) ROS1-driven IMTs; however, ROS1 alterations were detectable by variant-specific PCR in 19 of 20 (95%) cases. ALK rearrangements were particularly common in patients below 1 year of age (10 of 11 (91%) versus 37 of 71 (52%), P = 0.039). ROS1 fusions occurred more often in lung IMTs than in tumours of other organs (14 of 35 (40%) versus six of 47 (13%), P = 0.007). Among 11 IMTs with no kinase gene rearrangement identified, one tumour demonstrated ALK activation via gene amplification and overexpression, and another neoplasm carried COL1A1::USP6 translocation. CONCLUSIONS: PCR-based pipeline provides a highly efficient and non-expensive alternative for molecular testing of IMTs. IMTs with no detectable rearrangements need further studies.

Inflammatory myofibroblastic tumors: recent progress and future of targeted therapy.

An inflammatory myofibroblastic tumor is a rare component of bone and soft-tissue sarcomas that has distinct pathological features as a lymphoplasmacytic inflammatory infiltrate. As is the case for other non-small round cell sarcomas, surgical resection remains the standard treatment strategy for inflammatory myofibroblastic tumors, but recurrence is possible. Concerning systemic therapy, the available data for conventional chemotherapy (such as those of doxorubicin-based regimens) are limited, and case reports of anti-inflammatory inflammatory myofibroblastic tumor treatments describe some degree of symptom relief and efficacy against tumor progression. However, as more information about cancer genomics accumulates, the potential for molecularly targeted therapies for inflammatory myofibroblastic tumors has become more promising. Approximately half of inflammatory myofibroblastic tumors harbor anaplastic lymphoma kinase (ALK) fusion genes, and the other half could have potentially targetable fusion genes or mutations such as ROS1, NTRK and RET; case reports demonstrating the clinical efficacy of treatments targeted to inflammatory myofibroblastic tumor have been published, as have several prospective clinical trials. Few drugs are approved for the treatment of inflammatory myofibroblastic tumor, and most of them were approved for tumor-agnostic indications. Drugs that could be used for pediatric indications and dosing in inflammatory myofibroblastic tumor have also not been established. To provide effective targeted therapy for rare diseases such as inflammatory myofibroblastic tumor, it is necessary to obtain clinical evidence by designing and performing clinical trials and to find a path toward regulatory approval.

Inflammatory myofibroblastic tumor of the lung involving the central nervous system in pediatric patients.

INTRODUCTION: The inflammatory myofibroblastic tumor (IMT) is a very rare lesion with an incidence of less than 0.1% of total neoplasms and with main affection in the lungs. Involvement in the central nervous system is extremely rare, but with a much more aggressive course than IMT diagnosed in the rest of the body. We report the 2 cases presented in our neurosurgery department to date; both were treated satisfactorily without intercurrences in 10 years of follow-up. HISTORICAL BACKGROUND: The World Health Organization described the IMT as a distinctive lesion composed of myofibroblastic spindle cells accompanied by an inflammatory infiltrate of plasma cells, lymphocytes, and eosinophils. CLINICAL PRESENTATION: Clinical manifestations of patients with CNS IMT vary and may consist of headache, vomiting, seizures, and blindness. Seizures are the most common symptom in patients with focal lesions. DIAGNOSIS: The true origin of this entity remains to be elucidated, but to date, etiologies ranging from chromosomal alterations to autoimmune or postinfectious mechanisms have been described. Due to its rarity and non-specificity in imaging, the final diagnosis of IMT in the brain parenchyma relies on pathological examination. MANAGEMENT: Treatment options are controversial and include total or subtotal removal, high-dose steroids, and radiation therapy. In the last decade, the development of ALK Tyrosine Kinase Inhibitors allows the possibility of chemotherapy in those patients harboring ALK mutations. CONCLUSION: IMT is a rare tumor that can exceptionally be found in the CNS. The cause is still unknown although the different studies focus on a neoplastic origin. The diagnosis is based in the use of different modalities of imaging and with histological confirmation. Optimal management is gross total resection whenever possible, is the only established curative treatment. Further research with longer follow-up is needed to clarify the natural history of this rare tumor.

Cutaneous inflammatory myofibroblastic tumor with CARS-ALK fusion: Case report and literature review.

Cutaneous inflammatory myofibroblastic tumors (IMT) constitute a rare entity, generating a diagnostic pitfall when diagnosing spindle cell proliferation within the dermis. Raising awareness of this tumor among dermatopathologists remains vital in differentiating it from common cutaneous tumors such as fibrous histiocytoma, atypical fibroxanthoma, melanoma, poorly differentiated carcinoma, and other more aggressive tumors. Accurate diagnosis of IMT aids in ensuring appropriate management and follow-up for patients while preventing unnecessary harm and overtreatment. Here we report a case of a 38-year-old female with a painless, slow-growing nodule of the left posterior scalp initially diagnosed as a dermatofibroma. The histopathological examination revealed an ill-defined dermal nodule of spindled cells without connection or infiltration of the epidermis. At high power, the cells were arranged in fascicles with a prominent background of lymphocytic infiltrate. Immunohistochemical analysis showed strong diffuse immunoreactivity for anaplastic lymphoma kinase (ALK), and targeted RNA sequencing identified a CARS-ALK fusion ultimately confirming the accurate diagnosis of a cutaneous IMT.

Infantile Inflammatory Myofibroblastic Tumor of Spleen.

Background: Inflammatory myofibroblastic tumor (IMT) is a mesenchymal neoplasm with unknown etiology and recurrent potential. They are widely reported in children and young adults. Nearly 50% of inflammatory myofibroblastic tumor harbor rearrangement in anaplastic lymphoma kinase (ALK) gene with the majority expressing ALK protein. ALK-negative IMTs harbor alteration in ROS1 gene in a subset of cases. Few reports have shown association of IMT with Epstein-Barr virus (EBV). Case report: We report a case of IMT of the spleen in an 18-month-old infant presenting with abdominal distention and failure to thrive. Workup for ALK-1, ROS1, and EBV small-encoded RNA in-situ hybridization using immunohistochemistry was negative. Conclusions: IMT can arise in an infant spleen.

Rare presentation of inflammatory myofibroblastic tumor on a digit.

Inflammatory myofibroblastic tumors (IMTs) are rare soft tissue neoplasms consisting of a mixture of spindle-shaped myofibroblasts or fibroblasts and a variable inflammatory infiltrate composed of eosinophils, plasma cells, and lymphocytes. Associations with trauma and infectious agents have been proposed, but the etiology is unknown. While IMT predominantly develops in the lungs of pediatric patients or young adults, extrapulmonary IMT is well documented and may occur anywhere. Cutaneous IMT is rare and few have been reported on the hand in the English language. The mean age of onset is 10 years, with a slight female predilection. IMT demonstrates intermediate malignant potential, with a tendency to recur locally. Metastases are rare. According to a recent review, anaplastic lymphoma kinase (ALK) positivity on immunohistochemistry is related to local recurrence, but not distant metastases. We report an unusual case of a 36-year-old male, with a lesion on the right second digit, displaying classic histopathologic and immunohistochemical features of IMT, including ALK staining, and confirmatory fluorescence in situ hybridization-proven ALK gene rearrangement.

Molecular Alterations in Pediatric Fibroblastic/Myofibroblastic Tumors: An Appraisal of a Next Generation Sequencing Assay in a Retrospective Single Centre Study.

BACKGROUND: Pediatric fibroblastic/myofibroblastic tumors (PFMTs) can be challenging to definitively classify. Large case series or diagnostic updates have not been recently published despite identification of molecular alterations that could improve diagnostic accuracy. Our review of the literature found that over two-thirds of the more than 30 types of PFMTs harbor recurrent molecular alterations. We performed an institutional review of PFMTs to highlight limitations of a predominantly morphological classification, and evaluated the utility of a next-generation sequencing assay to aid diagnosis. METHODS: PFMTs identified over a period of 12 years were reviewed, categorized per the new WHO classification, and tested using the Oncomine Childhood Cancer Research Assay. RESULTS: Eighty-seven specimens from 58 patients were reviewed; 50 were chosen for molecular analysis, 16 (32%) lacking definitive classification. We identified alterations, some novel, in 33% of assayed cases. Expected alterations were identified for most known diagnoses and mutations were identified in 6 of 16 tumors (38%) that were initially unclassified. CONCLUSION: We confirmed a significant subset of PFMTs remain difficult to classify using current criteria, and that a combined DNA/RNA assay can identify alterations in many of these cases, improving diagnostic certainty and suggesting a clinical utility for challenging cases.

DCTN1-ALK gene fusion in inflammatory myofibroblastic tumor (IMT) of the CNS.

PURPOSE: Inflammatory myofibroblastic tumor (IMT) is a rare neoplastic tumor type of intermediate biological potential, only recently distinguished from the non-neoplastic category of inflammatory pseudotumor (IP). The literature describes very few cases of IMTs arising in the central nervous system (CNS), and the distinguishing clinical, pathological, and molecular features of IMT-CNS are not well understood. Our purpose is to publish a case of an IMT-CNS with a novel DCTN1-ALK gene fusion, furthering in the literature's characterization of a rare tumor type. METHODS: Review of the literature included a PubMed Database search of articles found by the following searches: "Inflammatory myofibroblastic tumor;" "Inflammatory myofibroblastic tumor central nervous system;" "ALK gene fusion;" and "DCTN1-ALK gene fusion." Inclusion of articles discovered by these search terms was determined through critical appraisal of article relevance, number of citations, cross-citation within articles of interest, and rare findings with conflicting conclusions in an effort to reduce publication bias. RESULTS: We present a case of IMT-CNS with several distinctive molecular features including a DCTN1-ALK gene fusion, the first of its kind described in an intracranial IMT. CONCLUSION: IMT is an infrequent tumor type and its presentation within the CNS is exceedingly rare. The paucity of cases, along with the ambiguity of terminology in the literature, has stunted accurate clinical, pathological, and molecular characterization of IMT-CNS. Our case report improves the characterization of the recently appreciated category of IMT-CNS so that connections between phenotype and prognosis, and between genotype and treatment, can eventually be made.

[Clinicopathological features of inflammatory myofibroblastic tumor].

Objective: To investigate the clinicopathological diagnosis and differential diagnosis of inflammatory myofibroblastic tumor (IMT). Methods: Thirty-two cases of IMT collected at the People's Hospital of Jiangsu Province from May 2010 to May 2020 were evaluated for their clinical, histologic, immunohistochemical and genomic features, and relevant literature was reviewed. Results: There were 19 male and 13 female patients, with age ranging from 5 to 65 years (mean, 37 years). The tumors were located in the lung and mediastinum (10 cases), gastrointestinal tract and mesentery/omentum (12 cases), urinary bladder (5 cases), head and neck (3 cases), somatic soft tissue (1 case), and retroperitoneum (1 case). Four cases of epithelioid inflammatory myofibroblastic sarcoma (EIMS) were all located intra-abdominally. Histologically, the tumor cells were myofibroblasts and fibroblasts arranged in predominantly fusiform pattern, with variably edematous to myxoid background or sclerotic collagenized stroma, and variably mixed chronic or acute inflammatory cells infiltration. EIMS were composed mainly of epithelioid tumor cells, with myxoid stroma and numerous neutrophils. Immunohistochemically, the tumor cells expressed cytoplasmic ALK (25/32, 78%), whereas the four EIMS showed nuclear membrane ALK staining pattern. The tumor cells also expressed CKpan (8/19), SMA (24/32, 75%) and desmin (12/32, 38%); all four EIMS also showed strong positivity for desmin. Fluorescence in situ hybridization (FISH) for ALK gene rearrangement showed split apart signals in 12 of 15 cases, most commonly with atypical signals. Next-generation sequencing (NGS) was performed in three tumors and showed that one case of lower leg IMT harbored a novel CLIP2-ALK fusion, and two cases of EIMS harbored RANBP2-ALK fusion. Follow-up data were available in 29 patients. Twenty-two patients were alive with no evidence of tumor, four patients had tumor recurrences (three patients were treated with crizotinib and were alive with tumor), and three patients died of the disease (including two patients with EIMS). Conclusions: IMTs show a wide morphologic spectrum, and should be differentiated form a variety of benign or malignant tumors. Immunohistochemistry (ALKp80, ALKD5F3) and FISH (ALK break-apart probe) could assist the diagnosis of IMT, with NGS recommended for the atypical cases.

Lorlatinib for the treatment of inflammatory myofibroblastic tumour with TPM4-ALK fusion following failure of entrectinib.

Inflammatory myofibroblastic tumour (IMT) is a rare malignancy with limited responses to corticosteroids and chemotherapy. About half of cases have activating rearrangements in the ALK gene which could be targeted with ALK inhibitors. A 40-year-old man presented with a large right lung mass and nodal, trapezius and cerebral metastases. Biopsy confirmed IMT with TPM4-ALK fusion. He was treated with prednisolone without clinical benefit. He received the Trk/ROS1/ALK inhibitor entrectinib in a clinical trial but his disease progressed in less than 3 months. Ifosfamide and etoposide in addition to radiotherapy to the brain and chest were administered. Transient improvement in the radiotherapy-treated areas was observed but his disease progressed shortly afterwards on all sites including the development of new adrenal metastasis. Compassionate use of the third-generation ALK inhibitor lorlatinib resulted in excellent partial response on all disease sites after 2 months, followed by a further 6 months of disease stabilisation. Repeat imaging showed slight increase in size of the cerebral metastasis but stable disease elsewhere, for which he was given stereotactic radiotherapy. His disease progressed 3 months later and lorlatinib was substituted with another ALK inhibitor brigatinib but he deteriorated and died shortly afterwards. Our patient tolerated lorlatinib well for 11 months with minimal toxicities, although he developed unilateral right-sided lung consolidation that was probably related to a combination of infection, radiotherapy and lorlatinib, which needed treatment with antibiotics and corticosteroids. This case demonstrates a role of lorlatinib in the treatment of TPM4-ALK-rearranged IMT despite failure of entrectinib.

Calcifying fibrous tumor and inflammatory myofibroblastic tumor are epigenetically related: A comparative genome-wide methylation study.

Based on histological findings, calcifying fibrous tumor (CFT) may be a late (burned out) stage of inflammatory myofibroblastic tumor (IMT). This concept, however, has not been proven by molecular means. Five CFTs were analyzed for IMT-related rearrangements in ALK, ROS1 and RET using fluorescence in situ hybridization (FISH). Additionally, genome-wide methylation patterns were investigated and compared with IMT (n = 7), leiomyoma (n = 7), angioleiomyoma (n = 9), myopericytoma (n = 7) and reactive soft tissue lesions (n = 10) using unsupervised hierarchical cluster analysis and t distributed stochastic neighbor embedding. CFT patients, 4 females and 1 male, had a median age of 20 years ranging from 7 to 43 years. Two patients were younger than 18 years old. The tumors originated in the abdomen (n = 4) and axilla (n = 1). Histologically, all lesions were (multi) nodular and hypocellular consisting of bland looking (myo)fibroblasts embedded in a collagenous matrix with calcifications. FISH analysis brought up negative results for ALK, RET and ROS1 rearrangements. However, genome-wide methylation analysis revealed overlapping methylation patterns of CFT and IMT forming a distinct homogeneous methylation cluster with exception of one case clustering with myopericytoma/angioleiomyoma. In conclusion, DNA methylation profiling supports the concept that CFT and IMT represent both ends of a spectrum of one entity with CFT being the burn out stage of IMT.

Pseudosarcomatous myofibroblastic proliferations of the genitourinary tract are genetically different from nodular fasciitis and lack USP6, ROS1 and ETV6 gene rearrangements.

AIMS: Pseudosarcomatous myofibroblastic proliferations of the genitourinary tract have a debatable relationship with inflammatory myofibroblastic tumour (generally lacking ALK rearrangement); however, they share several overlapping features with nodular fasciitis of soft tissue. As rearrangement of the USP6 gene has been recently recognised as a recurrent alteration in soft tissue nodular fasciitis, and several other alternative gene fusions have been recently recognised in inflammatory myofibroblastic tumour, the aim of this study was to investigate whether USP6, ROS1 or ETV6 rearrangements were present in these lesions (12 cases). METHODS AND RESULTS: Fluorescence in-situ hybridisation analysis was performed by the use of bacterial artificial chromosome-derived break-apart probes against USP6, ROS1, and ETV6. Two cases with adequate genetic material from recent paraffin tissue blocks were also tested by use of a solid tumour gene fusion detection assay via next-generation sequencing, targeting >50 known genes involved in recurrent fusions. None of the genitourinary pseudosarcomatous myofibroblastic proliferations was found to harbour USP6 (0/12), ROS1 (0/8) or ETV6 (0/7) rearrangements, and no gene fusions were detected in two cases studied by sequencing. CONCLUSIONS: Despite overlap in histological and immunohistochemical features between pseudosarcomatous myofibroblastic proliferation and nodular fasciitis, these tumours lack the recently recognised USP6 rearrangements that occur in nodular fasciitis, as well as alternative fusions found in ALK-negative inflammatory myofibroblastic tumours. At present, this diagnosis remains based primarily on clinical, histological and immunohistochemical features.

Frank Stinchfield Award: Identification of the At-risk Genotype for Development of Pseudotumors Around Metal-on-metal THAs.

BACKGROUND: Once touted as the future of hip arthroplasty, metal-on-metal (MoM) bearing surfaces have fallen sharply from favor with the emergence of a strong body of evidence demonstrating unacceptably high premature implant failure rates. The previously unpredictable development of adverse local tissue reactions (ALTRs) has been a substantive contributor to this. Although the underlying pathophysiology of these so-called "pseudotumors" is now well understood, the fundamental predisposing patient risk factors have remained elusive. QUESTIONS/PURPOSES: The aim of this research, as a clinical-genotype correlation analysis, was to identify specific alleles (genes) associated with the development of ALTRs in patients with in situ MoM THAs. METHODS: A case-control study of patients who received a large-head, primary MoM THA between 2005 and 2008 was performed with a minimum followup of 5 years. Twenty-six patients who had undergone revision of a primary MoM THA secondary to symptomatic ALTRs were recruited. The mean timeframe from primary MoM THA to symptomatic revision was 5.5 years (range, 1-10 years). Twenty-eight control subjects were randomly selected asymptomatic patients with no evidence of ALTRs on protocol-specific screening. Baseline demographics and high-resolution genotype (human leukocyte antigen [HLA] Class II) were collected for all patients. Cohorts were similar with respect to age at the time of primary MoM THA (mean, 54.8 versus 54.9 years, p = 0.95) and serum cobalt (mean, 5.5 versus 8.5 µg/L, p = 0.09) and chromium concentrations (mean, 2.9 versus 4.2 µg/L, p = 0.27). The association between genotype and revision surgery secondary to ALTRs was determined with gender as a covariate. RESULTS: The prevalence of the risk genotype was 30% (16 of 54) among the entire cohort. Adjusting for sex, the odds of revision were 6.1 times greater among patients with the risk genotype present than among patients without (95% confidence interval [CI], 1.5-25.4; p = 0.01). Among females, the specificity of the risk genotype was 1.0 (95% CIexact, 0.5-1.0; pexact = 0.03), and for males, it was 0.8 (95% CIexact, 0.6-0.9; pexact < 0.01). CONCLUSIONS: The findings of this study suggest that, among patients with a primary MoM THA, allelic variation within the HLA Class II loci may be a strong, independent risk factor associated with the need for subsequent revision surgery secondary to pseudotumor formation. CLINICAL RELEVANCE: Given the hypothesis-generating nature of this novel undertaking, confirmatory prospective clinical studies are required to further elucidate this correlation and to explore the clinical utility of targeted genetic screening in this specific population. This research may, however, represent a key missing piece in the puzzle that is metal ion-induced pseudotumor formation.

Dramatic response to alectinib in inflammatory myofibroblastic tumor with anaplastic lymphoma kinase fusion gene.

Inflammatory myofibroblastic tumor (IMT) is a neoplasm characterized by the proliferaton of myofibroblasts with the infiltration of inflammatory cells. There is no standard treatment for patients with recurrent or metastatic IMT. We describe here a patient with hyper-progressive IMT with an anaplastic lymphoma kinase (ALK) fusion gene that dramatically responded to alectinib without adverse events. His dramatic and enduring response supports the observation that alectinib may be considered a good treatment option for rare aggressive ALK-positive tumors.

Immunology of IgG4-related disease.

Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory condition that derives its name from the characteristic finding of abundant IgG4(+) plasma cells in affected tissues, as well as the presence of elevated serum IgG4 concentrations in many patients. In contrast to fibrotic disorders, such as systemic sclerosis or idiopathic pulmonary fibrosis in which the tissues fibrosis has remained largely intractable to treatment, many IgG4-RD patients appear to have a condition in which the collagen deposition is reversible. The mechanisms underlying this peculiar feature remain unknown, but the remarkable efficacy of B cell depletion in these patients supports an important pathogenic role of B cell/T cell collaboration. In particular, aberrant T helper type 2 (Th2)/regulatory T cells sustained by putative autoreactive B cells have been proposed to drive collagen deposition through the production of profibrotic cytokines, but definitive demonstrations of this hypothesis are lacking. Indeed, a number of unsolved questions need to be addressed in order to fully understand the pathogenesis of IgG4-RD. These include the identification of an antigenic trigger(s), the implications (if any) of IgG4 antibodies for pathophysiology and the precise immunological mechanisms leading to fibrosis. Recent investigations have also raised the possibility that innate immunity might precede adaptive immunity, thus further complicating the pathological scenario. Here, we aim to review the most recent insights on the immunology of IgG4-RD, focusing on the relative contribution of innate and adaptive immune responses to the full pathological phenotype of this fibrotic condition. Clinical, histological and therapeutic features are also addressed.

Inflammatory myofibroblastic tumor as a second neoplasm after Wilms tumor.

We report two survivors of Wilms tumor (WT) who developed inflammatory myofibroblastic tumor (IMT). The first patient had IMT in the mainstem bronchus 1 year after WT therapy that included vincristine, dactinomycin, doxorubicin (VDA) and whole lung radiation therapy (XRT). The second patient had IMT in the cecum 7 years after WT therapy consisting of VDA and abdominal XRT. The unlikely co-occurrence of WT and IMT suggests a genetic link between these tumors or that IMT can arise as a complication of cancer therapy. IMT should be considered in WT survivors who develop secondary tumors, especially at unusual sites.

FN1: a novel fusion partner of ALK in an inflammatory myofibroblastic tumor.

Inflammatory myofibroblastic tumors (IMTs) are rare tumors characterized as low-to-intermediate grade sarcomas. Rearrangements of the anaplastic lymphoma kinase (ALK) gene have been reported in IMT. Here, we describe a novel fusion gene in an IMT tumor specimen. A 12-year-old male was admitted to our hospital with a bladder tumor. We identified the fibronectin 1 gene (FN1) as a fusion partner of ALK using 5'RACE. This novel fusion, FN1-ALK, resulted in ALK overexpression in the IMT. This finding should clarify the causes of IMT and facilitate development of novel therapeutics.

[Inflammation, malignancy and immunology in gastrointestinal spindle cell tumors: what is beyond GIST?]. / Entzündung, Malignität und Immunologie gastrointestinaler Spindelzelltumoren : Was gibt es abgesehen von GIST noch?

Many mesenchymal tumors and tumefactions associated with the gastrointestinal tract feature prominent inflammatory cells but the mechanisms for the inflammation and the processes themselves remain poorly understood. Such classic lesions include Kaposi sarcoma, inflammatory fibroid polyp, sclerosing mesenteritis and inflammatory myofibroblastic tumor but, more recently, the recognition of IgG4-related fibrosclerosing disease has resulted in modification of the views on pathogenesis and treatment of such inflammatory lesions in many anatomical sites. In some lesions the inflammation may reflect viral influences (Kaposi sarcoma) or a bacterial infectious trigger (IgG4-related fibrosclerosing disease) whereas in others such an interaction is unclear and alterations in various genes have been detected, such as anaplastic lymphoma receptor tyrosine kinase gene rearrangements in inflammatory myofibroblastic tumor and platelet-derived growth factor receptor alpha (PDGFRA) gene mutations in inflammatory fibroid polyp and some gastrointestinal stromal tumors (GIST). Even the inflammatory milieu of GISTs may have an impact on the outcome. This article discusses the practical diagnostic considerations as well as the theoretical background.

[Clinicopathologic features of extrapulmonary inflammatory myofibroblastic tumor].

OBJECTIVE: To investigate the clinicopathologic features, immunohistochemic phenotypes and genetic alterations of extrapulmonary inflammatory myofibroblastic tumor (IMT) and the correlation with prognosis. METHODS: Thirty cases of IMT with follow-up were analyzed morphologically and immunohistochemically. ALK FISH was also performed to determine the ALK gene status. RESULTS: Patients ranged in age from 12 to 73 years (mean 43.4 years). The male-to-female ratio was 1.0: 1.1. The tumors were located in various anatomical sites including gastrointestinal tract, liver, spleen, kidney, pelvic, retroperitoneum, mediastinum etc. Histologically, the majority of cases were composed of spindled fibroblastic and myofibroblastic cells accompanied by an inflammatory infiltrate of plasma cells, lymphocytes, and eosinophils. Most cases with aggressive behavior had features including prominent nucleoli and edematous myxoid background. Lymphohistiocytic reactions were usually absent. Some cases showed multinucleation, nuclear pleomorphism and mitoses. One case demonstrated epithelioid morphology with round-to-epithelioid cells. The immunohistochemical study showed vimentin, SMA, CK, desmin, and ALK were expressed in 100% (30/30), 70% (21/30), 13% (4/30), 27% (8/30), and 27% (8/30) of IMT, respectively. Diffuse cytoplasmic ALK staining was detected in seven cases. One case (containing round-to-epithelioid cells) demonstrated ALK nuclear membrane staining, coupled with positive reaction for CD30 and negative reaction for LCA. EMA, CD34, CD117 and S-100 protein, and MyoD1 were negative for all cases. Six ALK protein positive cases harbored ALK gene rearrangement, but not the remaining 22 cases. Follow-up data were available in 21 patients. After initial resection, 14 patients were alive with no evidence of disease, while 4 patients were alive with tumor recurrence and 3 patients died of the disease. CONCLUSIONS: Most IMT with aggressive behavior have features including prominent nucleoli, edematous myxoid background, and positive expression of ALK. Lymphohistiocytic reaction is usually absent. ALK may be a potential novel therapeutic target for IMT.