Potential pathogenetic link between angiomyofibroblastoma and superficial myofibroblastoma in the female lower genital tract based on a novel MTG1-CYP2E1 fusion.

Angiomyofibroblastoma and superficial myofibroblastoma are distinctive benign mesenchymal tumors occurring in the female lower genital tract. Despite their significant overlapping clinicopathologic features, including the presence of bland-looking spindle or oval cells with myofibroblastic or myoid differentiation, the tumors have been regarded as separate entities. Although subepithelial, hormone-sensitive mesenchymal cells of the female lower genital tract are considered as their potential common progenitor cells, their potential kinship or pathogenetic similarities remain elusive. Based on the identification of a novel RNA sequencing-based MTG1-CYP2E1 fusion transcript in an angiomyofibroblastoma index case, we investigated an additional ten samples of the tumor and its site-specific histological mimics, including eight superficial myofibroblastomas, four deep angiomyxomas, four cellular angiofibromas, three fibroepithelial stromal polyps, and eight non-site-specific mesenchymal tumors occurring in the female lower genital tract. Using reverse transcription-polymerase chain reaction, we showed that the MTG1-CYP2E1 fusion transcripts were consistently detectable in angiomyofibroblastomas (5/5, 100%) and often in superficial myofibroblastomas (3/5, 60%) but were not detected in the other examined site-specific or non-site-specific mesenchymal tumors. Our immunohistochemical experiments showed that CYP2E1, an isoenzyme belonging to the cytochrome P450 superfamily, exhibited increased positivity in tumors with MTG1-CYP2E1 than was observed in fusion-negative tumors (RR = 6.56, p = 0.001). The results of our study provide further evidence supporting the assertion that angiomyofibroblastoma and superficial myofibroblastoma represent phenotypic variants of site-specific mesenchymal tumors and share a common oncogenic mechanism.

Infantile inflammatory myofibroblastic tumors: clinicopathological and molecular characterization of 12 cases.

Inflammatory myofibroblastic tumors arising in infants are rare, poorly investigated and mostly reported as isolated cases or as a part of larger series thus, their clinicopathological and molecular features are essentially unknown. Archival files from two large pediatric institutions and a tumor registry were queried for pediatric inflammatory myofibroblastic tumors. Available material from patients ≤12 months of age was reviewed. Additional immunostains (ALK-1, D240, WT1) and ALK-FISH studies were performed as needed. Targeted anchored multiplex PCR with next-generation sequencing was done in all cases. A total of 12 of 131 infantile cases (mean 5.5 months) were identified (M:F of 2:1). Anatomic locations included intestinal/mesenteric (n = 6), head/neck (n = 3), and viscera (n = 3). Half of tumors showed a hypocellular myxoid pattern, perivascular condensation, and prominent vasculature with vague glomeruloid structures present in four of them. The remaining cases exhibited a more cellular pattern with minimal myxoid component. ALK-1 immunohistochemistry was positive in most cases (11/12) with cytoplasmic-diffuse (n = 6), cytoplasmic-granular (n = 2), and dot-like (n = 3) staining patterns. ALK fusion partners identified in five cases included EML4, TPM4, RANBP2, and a novel KLC1. Three inflammatory myofibroblastic tumors showed fusions with other kinases including TFG-ROS1 and novel FN1-ROS1 and RBPMS-NTRK3 rearrangements. Favorable outcome was documented in most cases (10/11) with available follow-up (median 17 months) while three patients were successfully treated with crizotinib. In summary, infantile inflammatory myofibroblastic tumors are rare and can exhibit paucicellular, extensively myxoid/vascular morphology with peculiar immunophenotype mimicking other mesenchymal or vascular lesions. All tumors harbored kinase fusions involving ALK, ROS1, and NTRK3 including three novel fusion partners (KLC1, FN1, and RBPMS, respectively). A favorable response to crizotinib seen in three cases supports its potential use in infants as seen in older patients. Awareness of these unusual morphologic, immunophenotypic, and molecular features is critical for appropriate diagnosis and optimized targeted therapy.

Crizotinib in ALK+ inflammatory myofibroblastic tumors-Current experience and future perspectives.

Inflammatory myofibroblastic tumor (IMT) and its subtype epithelioid inflammatory myofibroblastic sarcoma (EIMS) are rare soft-tissue tumors. As about 50% of IMT and 100% of EIMS contain activating rearrangements of the anaplastic lymphoma kinase (ALK) gene, targeted kinase inhibition of ALK by compounds such as crizotinib is a potential treatment option. We performed a literature review and analyzed a total of 30 patients with IMT/EIMS treated with crizotinib. A total of 12 patients achieved complete or partial remission. As preliminary data are promising, a prospective study evaluating crizotinib treatment in patients with unresectable/multifocal ALK+ IMT/EIMS is warranted.

Long-term efficacy update of crizotinib in patients with advanced, inoperable inflammatory myofibroblastic tumour from EORTC trial 90101 CREATE.

PURPOSE: European Organisation for Research and Treatment of Cancer (EORTC) 90101 (CREATE) was a prospective, multicentric, non-randomised, open-label phase II basket trial to assess the efficacy and safety of crizotinib in patients with different types of cancers, including advanced inflammatory myofibroblastic tumour (IMT) with or without anaplastic lymphoma kinase (ALK) rearrangements. Here, we report updated results with long-term follow-up. PATIENTS/METHODS: After central reference pathology, eligible ALK-positive and ALK-negative patients with advanced/metastatic IMT deemed incurable with surgery, radiotherapy or systemic therapy received oral crizotinib 250 mg twice daily. The ALK status was assessed centrally using immunohistochemistry and fluorescence in situ hybridisation. The primary end-point was the proportion of patients who achieved an objective response (i.e. complete or partial response). If ≥6 ALK-positive patients achieved a confirmed response, the trial would be deemed successful. RESULTS: At data cut-off on 28th January 2021, we performed the final analysis of this trial. Of the 20 eligible and treated patients (19 of whom were evaluable for efficacy), with a median follow-up of 50 months, five were still on crizotinib treatment (4/12 ALK-positive and 1/8 ALK-negative patients). The updated objective response rate (ORR) was 66.7% (95% confidence interval [CI] 34.9-90.1%) in ALK-positive patients and 14.3% (95% CI 0.0-57.9%) in ALK-negative patients. In the ALK-positive and ALK-negative patients, the median progression-free survival was 18.0 months (95% CI 4.0-NE) and 14.3 months (95% CI 1.2-31.1), respectively; 3-year overall survival rates were 83.3% (95% CI 48.2-95.6) and 34.3% (95% CI 4.8-68.5). Safety results were consistent with previously reported data. CONCLUSION: These updated results confirm previous findings that crizotinib is effective, with durable responses, in patients with locally advanced or metastatic ALK-positive IMT. With further follow-up after the original primary analysis, the ORR increased, as patients derived long-term benefit and some responses converted from stable disease to partial responses. CLINICAL TRIAL NUMBER: EORTC 90101, NCT01524926.

Anaplastic lymphoma receptor tyrosine kinase-negative inflammatory myofibroblastic tumor of triceps brachii: Case report.

Inflammatory myofibroblastic tumor (IMT) is a non-neoplastic benign lesion comprising various inflammatory cells, including myofibroblasts and vascular tissues. It is a rare tumor that sometimes shows similar signs and progression as malignant tumors. The anatomical sites of IMTs include the lungs, liver, orbit, skin, mesentery, and maxillary sinus, but they rarely occur in the limb musculoskeletal system. To our knowledge, no case of neurological symptoms caused by the tumor in the triceps brachii muscle has been reported. In this article, we report the case of a 42-year-old male patient with an IMT that grew rapidly in the triceps brachii muscle and consequently caused symptoms of ulnar nerve lesion owing to its increasing size. The patient showed no ulnar nerve lesion symptoms after undergoing wide excision and was diagnosed with anaplastic lymphoma receptor tyrosine kinase- negative IMT.

Characterization of a unique muscle cell line.

A clonal cell line derived from a mouse neoplasm is described which shares many properties with smooth muscle. The cells have electrically excitable membranes capable of generating overshooting action potentials, and they contract both spontaneously and with electrical stimulation. They respond to the iontophoretic application of acetylcholine with a depolarizing response, and to norepinephrine with a hyperpolarizing response. Electron microscopy reveals that the cells have a morphology similar in many, but not all, respects to that of smooth muscle cells in vivo. The cells secrete soluble collagen-like molecules in addition to several proteins of undefined function. Finally, there is an increase in the specific activities of creatine phosphokinase and myokinase associated with increased cell density and the cessation of cell division.

Progressive decrease of phosphocreatine, creatine and creatine kinase in skeletal muscle upon transformation to sarcoma.

In vertebrates, phosphocreatine and ATP are continuously interconverted by the reversible reaction of creatine kinase in accordance with cellular energy needs. Sarcoma tissue and its normal counterpart, creatine-rich skeletal muscle, are good source materials to study the status of creatine and creatine kinase with the progression of malignancy. We experimentally induced sarcoma in mouse leg muscle by injecting either 3-methylcholanthrene or live sarcoma 180 cells into one hind leg. Creatine, phosphocreatine and creatine kinase isoform levels decreased as malignancy progressed and reached very low levels in the final stage of sarcoma development; all these parameters remained unaltered in the unaffected contralateral leg muscle of the same animal. Creatine and creatine kinase levels were also reduced significantly in frank malignant portions of human sarcoma and gastric and colonic adenocarcinoma compared with the distal nonmalignant portions of the same samples. In mice, immunoblotting with antibodies against cytosolic muscle-type creatine kinase and sarcomeric mitochondrial creatine kinase showed that both of these isoforms decreased as malignancy progressed. Expressions of mRNA of muscle-type creatine kinase and sarcomeric mitochondrial creatine kinase were also severely downregulated. In human sarcoma these two isoforms were undetectable also. In human gastric and colonic adenocarcinoma, brain-type creatine kinase was found to be downregulated, whereas ubiquitous mitochondrial creatine kinase was upregulated. These significantly decreased levels of creatine and creatine kinase isoforms in sarcoma suggest that: (a) the genuine muscle phenotype is lost during sarcoma progression, and (b) these parameters may be used as diagnostic marker and prognostic indicator of malignancy in this tissue.

ALK-negative urachal inflammatory myofibroblastic tumor in an elderly female: A case report.

RATIONALE: Inflammatory myofibroblastic tumor (IMT) is a rare soft tissue lesion, originally reported in the lungs. Occurrence of the IMT was also documented in the digestive system, but rare in the urinary system, especially in the urachus, and little is presently known about IMT. PATIENT CONCERNS: This study reported a very rare case of urachal IMT in an elderly female patient at the age of 77 who was diagnosed with a lower abdominal mass 2 months ago. DIAGNOSIS: The preoperative diagnosis was urachal carcinoma, which was confirmed to be anaplastic lymphoma kinase (ALK) negative urachal IMT by postoperative histopathology and immunohistochemistry tests. INTERVENTIONS: Laparoscopic radical urachal carcinoma resection and partial bladder resection was performed under general anesthesia, and the tumor was completely removed. OUTCOMES: There was no recurrence and metastasis over 22 months of follow-up. LESSONS: The urachal IMT occurs mainly in males and nonelderly people with ALK positive while in females with ALK negative. The most common clinical manifestations of urachal IMT are lower abdominal masses; it is very important to distinguish whether the tumor originates from the bladder or the urachus, because the surgical treatment options are completely different. Currently the complete surgical removal of the tumor is the best treatment option for urachal IMT. No other adjuvant therapy is required after operation. All urachal IMT after follow-up showed no recurrence and metastasis, suggesting a good prognosis. However, IMT has malignant potential and it requires a long-term close follow-up check.

Targeting ALK With Crizotinib in Pediatric Anaplastic Large Cell Lymphoma and Inflammatory Myofibroblastic Tumor: A Children's Oncology Group Study.

Purpose Fusions involving the ALK gene are the predominant genetic lesion underlying pediatric anaplastic large cell lymphomas (ALCL) and inflammatory myofibroblastic tumors (IMTs). We assessed the activity of the ALK inhibitor crizotinib in patients who had no known curative treatment options at diagnosis or with relapsed/recurrent disease. Methods In this study, 26 patients with relapsed/refractory ALK-positive ALCL and 14 patients with metastatic or inoperable ALK-positive IMT received crizotinib orally twice daily. Study objectives were measurement of efficacy and safety. Correlative studies evaluated the serial detection of NPM-ALK fusion transcripts in patients with ALCL. Results The overall response rates for patients with ALCL treated at doses of 165 (ALCL165) and 280 (ALCL280) mg/m2 were 83% and 90%, respectively. The overall response rate for patients with IMT (treated at 100, 165, and 280 mg/m2/dose) was 86%. A complete response was observed in 83% (five of six) of ALCL165, 80% (16 of 20) of ALCL280, and 36% (five of 14) of patients with IMT. Partial response rates were 0% (none of six), 10% (two of 20), and 50% (seven of 14), respectively. The median duration of therapy was 2.79, 0.4, and 1.63 years, respectively, with 12 patients ceasing protocol therapy to proceed to transplantation. The most common drug-related adverse event was decrease in neutrophil count in 33% and 70% of the ALCL165 and ALCL280 groups, respectively, and in 43% of patients with IMT. Levels of NPM-ALK decreased during therapy in most patients with ALCL. Conclusion The robust and sustained clinical responses to crizotinib therapy in patients with relapsed ALCL and metastatic or unresectable IMT highlight the importance of the ALK pathway in these diseases.

Inflammatory myofibroblastic tumor of the larynx with anaplastic lymphoma kinase (ALK) protein overexpression. A case report.

Inflammatory myofibroblastic tumor is an uncommon lesion which mainly develops in the lung and is extremely rare in the larynx. It may be easily misinterpreted as a malignant epithelial or mesenchymal spindle cell neoplasm. Histological and clinical knowledge of this lesion is important to exclude misdiagnosis and inappropriate treatment. We report a case of inflammatory myofibroblastic tumor arising on the right vocal cord of a 23-year-old man. The tumor was composed of a mixture of spindle cells and inflammatory elements. Immunohistochemical investigation revealed that the neoplastic cells expressed anaplastic lymphoma kinase (ALK) protein.

Management of anaplastic lymphoma kinase positive orbito-conjunctival inflammatory myofibroblastic tumor with crizotinib.

Inflammatory myofibroblastic tumor (IMT) is a distinct mesenchymal neoplasm of myofibroblastic spindle cells associated with an inflammatory infiltrate formed by lymphocytes, eosinophils, and plasma cells in a myxoid or collagenous stroma. This tumor has a predilection for children and young adults and most commonly occurs in the lungs, retroperitoneum, abdomen, and pelvis. Ocular and orbital involvement is exceedingly rare. We describe a case of IMT in a 7-year-old girl involving the cornea, conjunctiva, and the anterior orbit treated with crizotinib, resulting in complete tumor remission.

Coordinate cell-surface expression of matrix metalloproteinases and their inhibitors on cancer-associated myofibroblasts from malignant ascites in patients with gastric carcinoma.

PURPOSE: The crucial role of tumor stroma in cancer cell invasion has been described in human carcinoma tissues. However, myofibroblastic invasion remains largely unexplored in malignant ascites. Purpose of this study is to investigate the spatial localization or regulation of matrix metalloproteinases (MMP-2, -7 -9, MT1-MMP) and their inhibitors (TIMP-2 and -4) on myofibroblasts from malignant ascites in 20 patients with gastric carcinoma. METHODS: The quantitative flow cytometric analysis of MMPs or TIMPs on myofibroblasts was based on the percentage of double positive cells defined by anti MMPs or anti TIMPs, and anti alpha-smooth muscle actin (alpha-SMA) antibodies. RESULT: The results clearly showed that the coordination of the high level of cell-surface expression of secreted MMPs and TIMPs was noted on the alpha-SMA+ myofibroblasts. The finding suggests the possible formation of ternary complex, MT1-MMP/TIMPs/MMPs on the cells. The events might be a cause and result of activation processing of MMPs on the cells. CONCLUSION: This study provides the presence of invasive myofibroblasts with activated MMPs in close association with MMPs+ and TIMPs+ cancer cells and tumor-infiltrating lymphocytes from malignant ascites, emphasizing the importance of molecular cross-talk in tumor-host microenvironment for cancer invasion, metastasis and progression.

ALK positive inflammatory myofibroblastic tumour of the pineal region.

Inflammatory myofibroblastic tumours (IMTs) are an uncommon spindle cell neoplasm with a dense inflammatory infiltrate, usually encountered in children. IMTs of the central nervous system are extremely rare. This report describes the case of an IMT in a 61 year old man, in the pineal region. The tumour was completely excised, and immunohistochemistry demonstrated anaplastic lymphoma kinase 1 expression. There was no tumour recurrence during 18 months of follow-up. Our case extends both the age range and sites of occurrence of this rare tumour.

Inflammatory myofibroblastic tumor of the posterior mediastinum: an older adult case with anaplastic lymphoma kinase abnormalities determined using immunohistochemistry and fluorescence in situ hybridization.

Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm that usually occurs in children and young adults. Anaplastic lymphoma kinase (ALK) abnormalities in IMT, determined using immunohistochemistry and/or molecular genetic studies, including fluorescence in situ hybridization (FISH), have almost been limited to children and young adults. In elderly cases of IMT, these ALK abnormalities are very rare. We report on a case of IMT arising in the posterior mediastinum of a 59-year-old Japanese man that showed ALK abnormalities determined using immunohistochemistry and FISH, suggesting the neoplastic nature of a subset of IMTs in older patients similar to those in younger ones and the presence of an additional mechanism(s) that allows them to start to grow late.

Detection and diagnostic utilization of placental alkaline phosphatase in muscular tissue and tumors with myogenic differentiation.

Placental alkaline phosphatase (PLAP) is normally produced by primordial germ cells and syncytiotrophoblasts, and the detection of its expression has been useful in the diagnosis of germ cell tumors. We have recently observed PLAP immunoreactivity in normal human adult and fetal muscle tissue. Based on this observation, we explored the possible role of PLAP in the diagnosis of soft tissue tumors. A total of 271 tumors were studied. These included tumors with myogenic, neural, fibrous, myofibroblastic, lipomatous, neuroepithelial, perivascular, and epithelial differentiation. A formalin-fixed, paraffin-embedded section from each tumor was stained with PLAP monoclonal antibody using standard immunohistochemical methods preceded by antigen retrieval. In addition, western blotting with PLAP monoclonal antibodies was performed on fresh samples from a uterine leiomyoma, grossly normal myometrium, and placenta. Also, formalin-fixed sections of fetal skeletal muscle were labeled with double immunohistochemistry techniques using antibodies to myogenin and PLAP. Cytoplasmic PLAP reactivity was detected in all leiomyomas and rhabdomyosarcomas (100%), 7 of 15 (46%) leiomyosarcomas, 15 of 19 (79%) desmoplastic small round cell tumors, 2 of 15 (13%) gastrointestinal stromal tumors, 1 of 8 (13%) Wilms' tumors, 1 of 9 synovial sarcomas (9%), and 2 of 7 (29%) myofibroblastic tumors. No PLAP reactivity was detected in hyperplastic scars, nodular fasciitis, or the other remaining soft tissue and epithelial tumors. Double immunohistochemistry studies showed coexpression of myogenin and PLAP in fetal skeletal muscle cells, and western blot analysis showed a 70-kDa band in samples derived from grossly normal placenta, benign myometrium, and a uterine leiomyoma. PLAP immunoreactivity is detected in soft tissue tumors with known myogenic differentiation. PLAP immunoreactivity seems to relate to the degree of myogenic differentiation in soft tissue tumors and is more frequently expressed in cells with skeletal muscle differentiation and least in those with myofibroblastic features. The biologic function of PLAP in muscle and tumors with myogenic differentiation is unknown and merits further investigation. In addition to its role as a germ cell marker, PLAP may also be used as a myogenic marker in the diagnosis of soft tissue tumors.

Immunohistochemical observation of S-100 protein and neuron specific enolase in the tumour cells of granular cell tumour.

An immunohistochemical technique for the detection of S-100 protein, neuron specific enolase (NSE), carcinoembryonic antigen (CEA) and muramidase (lysozyme) was applied to a case of the granular cell tumour. S-100 protein was detected both in the nuclei and cytoplasma of the granular cells, and NSE was weakly positive in their cytoplasms. CEA and lysozyme were negative in the tumour cells. Our results supports the concept that granular cell tumours are derived from Schwann cells.

ALK negative inflammatory myofibroblastic tumor of the orbit: a masquerading entity.

Inflammatory myofibroblastic tumor is a biologically distinct neoplasm of intermediate grade, which can affect every possible tissue of the human body. It is a 'masquerading tumor' as the presenting complaints vary with the affected site. Occurrence of this tumor as an orbital mass is rare and is challenging for both the clinician as well as the pathologist, due to a varied number of lesions sharing a similar picture clinically and histologically. We discuss a rare case of inflammatory myofibroblastic tumor presenting as an orbital mass and the importance of immunohistochemistry in arriving at the diagnosis, which helps dictate the treatment and prognosis of the patient.