Abdominal inflammatory myofibroblastic tumour: Clinicopathological and molecular analysis of 20 cases, highlighting potential therapeutic targets.

AIMS: Inflammatory myofibroblastic tumour (IMT) is a rare mesenchymal neoplasm of intermediate malignant potential, occurring at any age and at multiple sites. Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is an aggressive subtype of IMT, typically involving the abdomen. Most IMTs harbour kinase gene fusions, especially involving ALK and ROS1, but 20-30% of IMTs show no detectable translocations. The aim of this study is to further delineate clinicopathological and molecular characteristics of abdominal IMT and discover potential new therapeutic targets. METHODS AND RESULTS: In 20 IMTs, including four EIMS, RNA fusion analysis was performed, followed by multiplex DNA analysis if no ALK or ROS1 fusion was detected. Fourteen IMTs (70.0%) had an ALK translocation and the fusion partner was identified in 11, including a RRBP1::ALK fusion, not previously described in classical (non-EIMS) IMT. RANBP2::ALK fusion was demonstrated in all EIMS. One IMT had a ROS1 fusion. In all ALK/ROS1 translocation-negative IMTs mutations or fusions - as yet unreported in primary IMT - were found in genes related to the receptor tyrosine kinase (RTK)/PI3K/AKT pathway. Three of four patients with EIMS died of disease [mean survival 8 months (4-15 months)], whereas only one of 14 classical IMT patients succumbed to disease [mean follow-up time 52 months (2-204 months); P < 0.01]. CONCLUSION: This study shows the wide clinical spectrum of abdominal IMTs and affirms the poor prognosis of EIMS, raising discussion about its status as IMT subtype. Furthermore, the newly detected alterations of the RTK/PI3K/AKT pathway expand the molecular landscape of IMTs and provide potential therapeutic targets.

ALK oncoproteins in atypical inflammatory myofibroblastic tumours: novel RRBP1-ALK fusions in epithelioid inflammatory myofibroblastic sarcoma.

ALK oncogenic activation mechanisms were characterized in four conventional spindle-cell inflammatory myofibroblastic tumours (IMT) and five atypical IMT, each of which had ALK genomic perturbations. Constitutively activated ALK oncoproteins were purified by ALK immunoprecipitation and electrophoresis, and were characterized by mass spectrometry. The four conventional IMT had TPM3/4-ALK fusions (two cases) or DCTN1-ALK fusions (two cases), whereas two atypical spindle-cell IMT had TFG-ALK and TPM3-ALK fusion in one case each, and three epithelioid inflammatory myofibroblastic sarcomas had RANBP2-ALK fusions in two cases, and a novel RRBP1-ALK fusion in one case. The epithelioid inflammatory myofibroblastic sarcoma with RRBP1-ALK fusion had cytoplasmic ALK expression with perinuclear accentuation, different from the nuclear membranous ALK localization in epithelioid inflammatory myofibroblastic sarcomas with RANBP2-ALK fusions. Evaluation of three additional uncharacterized epithelioid inflammatory myofibroblastic sarcomas with ALK cytoplasmic/perinuclear- accentuation expression demonstrated RRBP1-ALK fusion in two cases. These studies show that atypical spindle-cell IMT can utilize the same ALK fusion mechanisms described previously in conventional IMT, whereas in clinically aggressive epithelioid inflammatory myofibroblastic sarcoma we identify a novel recurrent ALK oncogenic mechanism, resulting from fusion with the RRBP1 gene. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

A case report of epithelioid inflammatory myofibroblastic sarcoma with RANBP2-ALK fusion gene treated with the ALK inhibitor, crizotinib.

Epithelioid inflammatory myofibroblastic sarcoma is a variant of inflammatory myofibroblastic tumor with aggressive clinical course associated with RANBP2-ALK fusion. The present report describes a case of a 22-year-old Japanese man with a pelvic mesenchymal neoplasm. The feature of the neoplasms, including epithelioid morphology, anaplastic lymphoma kinase staining on the nuclear membrane, and results from the reverse transcriptase-polymerase chain reaction, led to diagnosis of epithelioid inflammatory myofibroblastic sarcoma with RANBP2-ALK fusion. Despite two surgical excision procedures, local recurrence rapidly occurred, and the tumor developed resistance to conventional chemotherapy with doxorubicin. Subsequent administration of crizotinib, an oral anaplastic lymphoma kinase inhibitor, resulted in tumor shrinkage. Distinguishing epithelioid inflammatory myofibroblastic sarcoma from conventional inflammatory myofibroblastic tumor is important, and crizotinib is a promising treatment for this aggressive tumor.

Thoracic epithelioid inflammatory myofibroblastic sarcoma: a rare and aggressive disease with case report and literature review.

Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is a rare subtype of inflammatory myofibroblastic tumor, characterized to be an aggressive disease with high frequency of ALK rearrangement, rapid recurrence, and poor prognosis. Primary EIMS of thoracic origin is rarely observed. Herein, we described a case of 28-year-old female developed primary EIMS in the anterior mediastinum with hepatic metastasis. The EIMS displayed sheet-like growth of epithelioid and spindle cells with enlarged nuclei, abundant and eosinophilic cytoplasm, and infiltration of inflammatory cells. Immunohistochemical staining revealed positive expression of ALK in the nuclear membrane, and ALK rearrangement was identified by polymerase chain reaction assay. Alectinib showed partial response, and achieved a meaningful survival benefit for four months. Based on this case report and literature review, ALK inhibitor reveals promising activity on the rare but aggressive EIMS. Awareness of EIMS in thoracic disease and its clinicopathological features is essential to avoid erroneous diagnosis.

Radiologic findings of an adolescent epithelioid inflammatory myofibroblastic sarcoma.

Epithelioid inflammatory myofibroblastic sarcoma, a variant of the inflammatory myofibroblastic tumor, is a rare tumor that is not well described in the radiologic literature. We present a case of a 14-year-old male adolescent who presented with fever, fatigue, and weight loss symptoms and was found to have an abdominal mass on contrast enhanced CT. Initial differentials included lymphoma, pheochromocytoma, desmoid, and sarcoma, and pathological evaluation revealed an epithelioid inflammatory myofibroblastic sarcoma. The mass was separate from the surrounding structures of the left upper abdomen with unique radiologic features not previously described in the literature. Prior literature examples of epithelioid inflammatory myofibroblastic sarcoma described a heterogenous, enhancing lobulated mass, and our case was a lobulated, avidly enhancing homogenous mass on CT with surrounding inflammation and avid uptake on PET/CT. In addition to the imaging features, we describe the surgical findings, the pathologic features of the tumor, and the oncologic treatment of this patient. This case highlights the importance of including rare tumors such as epithelioid inflammatory myofibroblastic sarcoma as a potential differential consideration of an avidly enhancing homogenous abdominal mass in an adolescent.

Primary epithelioid inflammatory myofibroblastic sarcoma of the brain with EML4::ALK fusion mimicking intra-axial glioma: a case report and brief literature review.

An aggressive subtype of inflammatory myofibroblastic tumor, epithelioid inflammatory myofibroblastic sarcoma occurs primarily inside the abdominal cavity, followed by a pulmonary localization. Most harbor anaplastic lymphoma kinase (ALK) gene rearrangements, with RANBP2 and RRBP1 among the well-documented fusion partners. We report the second case of primary epithelioid inflammatory myofibroblastic sarcoma of the brain, with a well-known EML4::ALK fusion. The case is notable for its intra-axial presentation that clinico-radiologically mimicked glioma.

Inflammatory myofibroblastic tumor from molecular diagnostics to current treatment.

Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm with intermediate malignancy characterized by a propensity for recurrence but a low metastatic rate. Diagnostic challenges arise from the diverse pathological presentation, variable symptomatology, and lack of different imaging features. However, IMT is identified by the fusion of the anaplastic lymphoma kinase (ALK) gene, which is present in approximately 70% of cases, with various fusion partners, including ran-binding protein 2 (RANBP2), which allows confirmation of the diagnosis. While surgery is the preferred approach for localized tumors, the optimal long-term treatment for advanced or metastatic disease is difficult to define. Targeted therapies are crucial for achieving sustained response to treatment within the context of genetic alteration in IMT. Crizotinib, an ALK tyrosine kinase inhibitor (TKI), was officially approved by the US Food and Drug Administration (FDA) in 2020 to treat IMT with ALK rearrangement. However, most patients face resistance and disease progression, requiring consideration of sequential treatments. Combining radiotherapy with targeted therapy appears to be beneficial in this indication. Early promising results have also been achieved with immunotherapy, indicating potential for combined therapy approaches. However, defined recommendations are still lacking. This review analyzes the available research on IMT, including genetic disorders and their impact on the course of the disease, data on the latest targeted therapy regimens and the possibility of developing immunotherapy in this indication, as well as summarizing general knowledge about prognostic and predictive factors, also in terms of resistance to systemic therapy.

A case report: Pathological complete response to neoadjuvant lorlatinib for Epithelioid inflammatory myofibroblastic sarcoma with EML4-ALK rearrangement.

Inflammatory myofibroblastic tumor (IMT) is a rare tumor originating from mesenchymal tissue. Epithelioid inflammatory myofibroblastic sarcoma (EIMS) represents a rare and particularly aggressive variant, associated with a worse prognosis. Almost all EIMS cases exhibits activating anaplastic lymphoma kinase (ALK) gene rearrangements, which suggests that EIMS patients may potentially benefit from treatment with ALK tyrosine kinase inhibitors (TKIs). We presented a case involving a 34-year-old woman who was diagnosed with mediastinal EIMS and had a rare echinoderm microtubule-associated protein-like 4 (EML4) -ALK fusion. Following 15 months of neoadjuvant lorlatinib treatment, the patient underwent a complete surgical resection, resulting in a pathological complete response. Given the heightened risk of postoperative recurrence associated with EIMS, the patient's treatment plan included ongoing adjuvant therapy with lorlatinib. As of the present moment, the patient has achieved an overall survival of over 2 years with no observed tumor recurrence. Consequently, the case offers valuable clinical evidence supporting the potential benefits of neoadjuvant lorlatinib treatment for ALK-positive locally mediastinal EIMS patients, with a demonstrated tolerable safety profile.

Mediastinal epithelioid inflammatory myofibroblastic sarcoma with the EML4-ALK fusion: A case report and literature review.

Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is an aggressive subtype of inflammatory myofibroblastic tumour which rarely affects the chest cavity. We, for the first time, report a case of mediastinal EIMS with the EML4-ALK fusion. A young woman presented to our hospital with cough, chest tightness and shortness of breath. Computed tomography (CT) showed a mixed attenuation soft-tissue mass in the right middle and upper mediastinum. Negative results were obtained from bronchoscopy forceps biopsy and endobronchial ultrasound-guided transbronchial fine needle aspiration. CT-guided percutaneous biopsy was finally performed. However, due to the rapidly progressed EIMS that compressed the trachea and right main bronchus, the patient died of respiratory failure 1 day before diagnosis. EIMS progresses rapidly, and an early diagnosis is important. For mediastinal EIMS, CT-guided percutaneous biopsy may be useful. Next-generation sequencing of blood may be instructive to EIMS patients who are intolerant to invasive biopsy.

Epithelioid inflammatory myofibroblastic sarcoma treated with Alectinib: a case report and literature review.

Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is an extremely rare and aggressive form of inflammatory myofibroblastic tumor. Clinically, it has a high risk of relapse and peripheral organ infiltration, and it responds poorly to conventional chemotherapy. Anaplastic lymphoma kinase (ALK) inhibitors are currently the most effective targeted therapy for EIMS. This report discusses a typical case of abdominal EIMS in a 43-year-old woman. The tumors recurred rapidly within one month after surgery. Alectinib was promptly administered upon diagnosis. However, the patient developed a severe allergic reaction to the medication. After a comprehensive assessment and symptomatic treatment, her condition stabilized, leading to a favorable prognosis. This study summarizes cases of abdominal EIMS, highlights the successful use of Alectinib for treatment, and discusses the management of medication-related complications.

Case Report: Ensartinib for gastric epithelioid inflammatory myofibrosarcoma with STRN-ALK fusion.

Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is a highly aggressive malignant subtype of inflammatory myofibroblastoma (IMT) associated with poor prognosis. IMT can occur in various parts of the body, most frequently in the lungs, followed by the mesentery, omentum, retroperitoneum, and pelvis, among other areas; however, it is exceptionally rare in the stomach. Anaplastic lymphoma kinase (ALK) is a critical driver of lung cancer development and is currently the "gold standard" target for non-small cell lung cancer treatment. However, there are few reports on the use of ALK inhibitors for EIMS, necessitating further investigation. A male patient with postoperative inflammatory myofibroblastic sarcoma of the stomach received postoperative chemotherapy and had a stable outcome. However, a repeat CT scan performed 11 months later revealed disease progression. The patient later underwent immunohistochemistry testing that indicated ALK positivity, and next-generation sequencing revealed STRN-ALK fusion. Ensartinib 225 mg qd was administered as recommended, and the patient experienced only mild pruritus and no adverse effects such as rash. Eight months after CT follow-up, the patient's subseptal soft tissue nodules had decreased, and the outcome was assessed as a partial response. The findings of this case report introduce a novel strategy for treating ALK-positive EIMS that utilizes ensartinib, a drug with previously demonstrated success in the treatment of ALK-positive cancer.

Epithelioid inflammatory myofibroblastic sarcoma: a pitfall in the differential diagnosis of ALK-positive anaplastic large cell lymphoma.

An 18-year-old female presented with a 4.5 cm abdominal mass. Biopsy showed sheet-like growth of large tumor cells with round to oval nuclei, 1-2 nucleoli, and abundant cytoplasm. Immunohistochemistry showed strong, uniform CD30 staining and cytoplasmic ALK staining. B-cell markers (CD20, CD79a, PAX5, kappa/lambda) and T-cell markers (CD2, CD3, CD4, CD5, CD43, granzyme B, T-cell receptor-ß) were negative. Other hematopoietic markers (CD45, CD34, CD117, CD56, CD163, EBV) were negative, but CD138 was positive. Non-hematopoietic markers showed desmin positivity and negativity for S100, melan A, HBM45, PAX8, PAX2, WT1, MYO-D1, myogenin, pancytokeratin, and CAM5.2. Sequencing identified PRRC2B::ALK fusion. A diagnosis of epithelioid inflammatory myofibroblastic sarcoma (EIMS) was made. EIMS is a rare, aggressive form of inflammatory myofibroblastic tumor typically presenting in children and young adults. The tumor comprises large epithelioid cells that express ALK and often CD30. ALK-positive ALCL has a similar age range and also is a large-cell tumor expressing CD30 and ALK. Other ALK-positive neoplasms (e.g., carcinomas, ALK-positive large B-cell lymphoma, ALK-positive histiocytosis) typically lack CD30 and have distinct clinicopathologic features that aid diagnosis. Hematopathologists need to distinguish EIMS from ALK-positive ALCL, which frequently shows loss of pan-T-cell antigens. Careful morphologic evaluation for the hallmark cells of ALCL and comprehensive phenotyping are critical to avoid this diagnostic pitfall. If known, the ALK rearrangement partner gene may also provide diagnostic clues; for example PRRC2B::ALK and RANBP2::ALK occur in EIMS but not ALCL.

Case report: Epithelioid inflammatory myofibroblastic sarcoma treated with an ALK TKI ensartinib.

Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is an aggressive variant of inflammatory myofibroblastic tumor (IMT) and has a poor prognosis. EIMS is characterized by epithelioid morphology, neutrophilic infiltrate and specific fusion partners of anaplastic lymphoma kinase (ALK). Despite no standard therapy for EIMS, ALK tyrosine kinase inhibitors (TKIs) are recommended for these tumors. The present case describes an abdominal mass that presented in a 31-year-old male. The patient suffered from recurrence and multiple metastases 2 months after surgery. Ensartinib was administered and RANBP2-ALK fusion was detected. A partial response has been observed for 4 months and there has been no recurrence. This study provided a successful case with sustained response of targeted therapy.

Pericardial Epithelioid Inflammatory Myofibroblastic Sarcoma: An Atypical Presentation.

Sarcomas are a diverse group of cancers of mesenchymal origin. Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is an uncommon and hardly reported neoplasm that is a malignant variant of the typically benign inflammatory myofibroblastic tumor (IMS). We discuss an exceedingly rare case of a 53-year-old patient with primary EIMS of the pericardium who presented in impending hemodynamic collapse. A transthoracic echocardiogram revealed a large circumferential pericardial effusion with tamponade physiology and an echogenic intrapericardial mass compressing the right ventricle to near obliteration. She underwent emergent sternotomy with resection and one cycle of chemotherapy with liposomal doxorubicin before having recurrent metastatic pericardial and pleural effusions, ultimately leading to her unfortunate passing.

Epithelioid inflammatory myofibroblastic sarcoma with VCL-ALK fusion of central nervous system: case report and brief review of the literature.

Epithelioid inflammatory myofibroblastic sarcomas are an aggressive variant of inflammatory myofibroblastic tumor described primarily in the abdomen and less commonly in pulmonary location. The anaplastic lymphoma kinase (ALK) fusion partners described in this tumor include RANB2, RRBP1 and EML4. While rare examples of inflammatory myofibroblastic tumors have been described in the central nervous system, the epithelioid variant has never been described. The ALK-VCL fusion has been described in renal cell carcinoma, high-grade glioma and epithelioid fibrous histiocytoma but has not been described in epithelioid inflammatory myofibroblastic sarcoma or even inflammatory myofibroblastic tumor. Herein, we report the first case of epithelioid inflammatory myofibroblastic sarcoma in the central nervous system as well as the first case with VCL as the fusion partner for ALK.

Inflammatory Myofibroblastic Tumour: State of the Art.

An inflammatory myofibroblastic tumor (IMT) is a neoplasm composed of myofibroblastic and fibroblastic spindle cells accompanied by inflammatory cells, including lymphocytes and eosinophils. It is an ultra-rare tumor, the optimal management of which remains to be defined. Surgery is the treatment of choice for localized tumors. The treatment of advanced disease is not precisely defined. Chemotherapy regimens result in an overall response rate of approximately 50% based on retrospective data. The latest pathophysiological data highlight the role played by tyrosine kinase fusion genes in IMT proliferation. Anaplast lymphoma kinase (ALK) oncogenic activation mechanisms have been characterized in approximately 80% of IMTs. In this context, data regarding targeted therapies are most important. The aims of this article are to review the latest published data on the use of systematic therapy, particularly the use of molecular targeted therapy, and to publish an additional case of an IMT with Ran-binding protein 2 (RANPB2)-ALK fusion showing a long response to a tyrosine kinase inhibitor.

Primary pulmonary epithelioid inflammatory myofibroblastic sarcoma: a rare entity and a literature review.

Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is an aggressive subtype of inflammatory myofibroblastic tumor (IMT) harboring anaplastic lymphoma kinase (ALK) gene fusions and is associated with high risk of local recurrence and poor prognosis. Herein, we present a young, non-smoking male who presented with complaints of cough and dyspnoea and was found to harbor a large right lower lobe lung mass. Biopsy showed a high-grade epithelioid to rhabdoid tumor with ALK and desmin protein expression. The patient initially received 5 cycles of crizotinib and remained stable for 1 year; however, he then developed multiple bony metastases, for which complete surgical resection was performed. Histopathology confirmed the diagnosis of EIMS, with ALK gene rearrangement demonstrated by fluorescence in situ hybridization. Postoperatively, the patient is asymptomatic with stable metastatic disease on crizotinib and has been started on palliative radiotherapy. EIMS is a very rare subtype of IMT that needs to be included in the differential diagnosis of ALKexpressing lung malignancies in young adults.

Durable Clinical Response to ALK Tyrosine Kinase Inhibitors in Epithelioid Inflammatory Myofibroblastic Sarcoma Harboring PRRC2B-ALK Rearrangement: A Case Report.

Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm and patients with IMT tend to have a favorable outcome after complete surgical resection. However, some tumors of IMT cases have recurred and grown rapidly after successful surgery. Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is a highly aggressive intra-abdominal IMT variant with epithelioid-to-round cell morphology. Currently, no standard therapy exists for recurrent or invasive IMTs and EIMS, but anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are recommended for those harboring ALK gene rearrangements. We herein report the first case of PRRC2B-ALK fusion associated IMTs with clinical and pathological manifestation matched the diagnosis criteria of EIMS and the durable clinical response of the sequential use of ALK TKIs (crizotinib, alectinib, ceritinib, and lorlatinib). A female patient with EIMS of the greater omentum was suffering from a rapid recurrence after cytoreductive surgery was done. Crizotinib was administered when PRRC2B-ALK fusion was detected, and partial response was achieved. The progression-free survival (PFS) of crizotinib was 5 months. Alectinib was administered based on the results of second next-generation sequencing (NGS) analysis, which identified the secondary mutation ALK R1192P. The best overall response of alectinib treatment was a partial response (PR) and the PFS was 5.5 months. Ceritinib was prescribed as third-line therapy after alectinib resistance with ALK L1196M mutation. PR was achieved and the PFS of ceritinib was 6 months. The patient was taking lorlatinib after ceritinib resistance and achieved a stable disease at 2 months with the PFS more than 5 months. The overall survival was more than two years as of the time of manuscript preparation. We describe an EIMS of greater omentum caused by PRRC2B-ALK fusion gene and showed durable clinical response to the sequential use of ALK TKIs.

A case report on epithelioid inflammatory myofibroblastic sarcoma in the abdominal cavity.

Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is a rare entity and a novel variant of the inflammatory myofibroblastic tumor (IMT). We report the occurrence and specific characteristics of EMIS in an adult woman. Eleven months after the operation, the patient had a recurrence and multiple metastases in the abdominal cavity. Since the tumor was spreading all over the abdominal cavity and ALK staining of the tumor was positive, crizotinib was suggested as adjuvant therapy. But she failed to respond to the crizotinib treatment and died of organ failure three months later.

ALK-G1269A mutation in epithelioid inflammatory myofibroblastic sarcoma after progression on crizotinib: A case report.

Epithelioid inflammatory myofibroblastic sarcoma (EIMS), a specific subtype of inflammatory myofibroblastic tumors (IMT), is a relatively rare malignant mesenchymal tumor with clinical features of positive anaplastic lymphoma kinase (ALK), high invasiveness, treatment resistance and poor prognosis. Therefore, ALK inhibitors represent specific effective drugs for patients with this type of tumor. However, acquired resistance remains inevitable without a clear mechanism of action and therapeutic strategy to counteract this. Herein, a chromosomal ALK-G1269A mutation was identified using next-generation sequencing (NGS) and the mutation was confirmed by Sanger sequencing in a patient with crizotinib-resistant EIMS who benefited from treatment with the second-generation ALK inhibitor AP26113. To the best of our knowledge, a few rare cases of crizotinib-resistance in IMTs have been reported, and there are no reported cases in EIMS. In this article, we present the case of a patient with a secondary mutation of ALK-G1269A in EIMS, and suggest that AP26113 (Brigatinib) may represent an ideal treatment for these patients.