Epithelioid inflammatory myofibroblastic sarcoma treated with ALK inhibitor: a case report and review of literature

Epithelioid inflammatory myofibroblastic sarcoma is extremely rare and belongs to a variant of inflammatory myofibrobalstic tumor with aggressive clinical course. We describe a case of a 22 years old man presented with an abdominal huge tumor. Microscopically, the neoplasm cells were rounded and epithelioid in shape. Abundant interstitial edema and less myxoid stroma were also present together with an inflammatory infiltrate. Fluorescence in situ hybridization revealed that ALK gene presented mutation. After surgery the patient received chemotherapy with an anaplastic lymphoma kinase (ALK) inhibitor, crizotinib. The patient continues to be alive with disease for 16 months and has no recurrence. Although EIMS has a poor prognosis, this is the few successful case with sustained response of targeted therapy.     

p53 Mutation and MDM2 amplification in inflammatory myofibroblastic tumours

AIMS: The pathogenic mechanism and predictive indicators of biological behaviour of inflammatory myofibroblastic tumour are poorly understood. We investigated molecular abnormalities of p53 and MDM2 in order to assess whether these play an important role in pathogenesis, and whether they also contribute to clinicopathological aggressive phenotype in inflammatory myofibroblastic tumour. METHODS AND RESULTS: We compared the immunohistochemical expression of calponin, h-caldesmon, ALK, and p53 gene mutation and MDM2 gene amplification with clinicopathological findings in 15 cases of inflammatory myofibroblastic tumour. Histologically, cellular atypia was observed in five (33.3%) out of 15 cases. Local recurrences were observed in two (14.3%) of 14 informative cases, but no distant metastasis was observed. The expression of calponin (9/14; 64%) but not h-caldesmon (0/14; 0%) was seen, which suggested myofibroblastic differentiation. ALK expression was seen in eight (53.3%) out of 15 cases, particularly in patients under 40 years old. Nuclear expression of p53 protein was recognized in only one (6.7%) of 15 cases, and polymerase chain reaction single-strand conformation polymorphism followed by direct sequencing revealed p53 gene missense mutations in two (13.3%) of 15 cases. Nuclear expression of MDM2 was seen in four (26.7%) of 15 cases, and the MDM2 gene amplification was observed in two of the four cases. CONCLUSION: Inflammatory myofibroblastic tumour shows a wide spectrum of cellular atypia and biological behaviour with p53 and MDM2 expression. However, the alterations in the p53 pathway seem not to play a major role in the pathogenesis of inflammatory myofibroblastic tumour.     

Cytology of fine‐needle aspiration of inflammatory myofibroblastic tumor

Inflammatory Myofibroblastic Tumor (IMT) is a rare spindle cell neoplasm with a relatively indolent course. Its morphology may be confused with both reactive processes and/or malignant neoplasms on FNA specimens. Herein we discuss the cytologic features and IHC studies of IMT. The archives of the Department of Pathology at the Johns Hopkins Hospital were searched for IMT. A total of 257 cases were identified over a period of 11 years. Among them, 20 cases had cytology material. The patients' ages ranged from 7 to 81 years old with a median age of 54 years. The locations of the tumor in descending order were: liver (9/20, 45%), lung (8/20, 40%), abdomen (1/20, 5%), pelvis (1/20, 5%), and kidney (1/20, 5%). On FNA, the majority of tumors consisted of bland spindle cells with oval nuclei and small prominent nucleoli in a background of lymphocytes and plasma cells. Focal cytological atypia and “ganglion‐like” cells were identified in 7 cases, likely related to the risk of metastases and malignant transformation. The lesional cells expressed ALK (8/17, 47.1%) and actin (10/10, 100%), but with variable expression of cytokeratin. Ki‐67 showed low proliferative indices. ALK gene rearrangement was detected by FISH in three out of three cases and correlated with ALK protein expression by IHC. The cytologic diagnosis of IMT is challenging. When encountering a spindle cell lesion with prominent inflammatory component, a high index of suspicion in combination with the use of ancillary studies increases the diagnostic yield of IMT. Diagn. Cytopathol. 2010. © 2010 Wiley‐Liss, Inc.     

Fine‐needle‐aspiration cytology of a proximal type epithelioid sarcoma: A case report

Epithelioid sarcoma is a rare mesenchymal neoplasm, with an as yet unidentified cell of origin. Two subtypes of epithelioid sarcoma, distal/classic and proximal/large cell type, are recognized in the literature; with the proximal‐type having a lower incidence amongst the two. Here, we present a case of proximal‐type epithelioid sarcoma in a previously healthy young man. Fine‐needle‐aspiration of a large axillary mass was performed for diagnosis. The cytologic findings included a dispersed population of large epithelioid to polyhedral cells with abundant cytoplasm. Immunohistochemical staining showed coexpression of keratin and vimentin, as well as loss of INI1 staining, consistent with an epithelioid sarcoma, proximal subtype. Diagn. Cytopathol. 2015;43:859–862. © 2015 Wiley Periodicals, Inc.     

Epithelioid inflammatory myofibroblastic sarcoma with recurrence after extensive resection: significant clinicopathologic characteristics of a rare aggressive soft tissue neoplasm

A case of epithelioid inflammatory myofibroblastic scarcoma (EIMS) developing in an 8-year-old boy who presented with a bulky intra-abdominal occupying lesion with recurrence undergoing a radical resection was reported. Histologically, the tumor cells arranged in cords, strands or sheets of round-to-epithelioid cells with a vesicular nuclear chromatin pattern, prominent nucleoli and weakly eosinophic or basophilic cytoplasm embedded in the abundant myxoid stroma with lymphocytes infiltration. They were positive for ALK, Desmin, SMA, CD30, but negative for AE1/AE3, LCA, CD2, CD3, CD5, CD7, S-100, CD34, CD31, EMA, MyoD1, and myogenin. An elevated proliferation index was demonstrated by Ki-67 comparing the first and the second lesion. Fluorescence in situ (FISH) showed the presence of chromosomal translocation involving ALK. This case show EIMS is a rare variant of inflammatory myofibroblatic tumor with aggressive biological behavior and unfavourable prognosis. To be familiar with its significant clinicopathologic characteristics could prompt us to take it into consideration when facing the relevant dieases.     

Vocal cord inflammatory myofibroblastic tumor with mucoid deposits harboring TIMP3–ALK fusion: A potential diagnostic pitfall

A 35‐year‐old Japanese man who had experienced hoarseness for 10 years presented with a vocal cord lesion. A gross examination revealed a left vocal cord polyp occupying two‐thirds of the vocal space. The endoscopically resected lesion contained scattered atypical fibroblastic, stellate, or ganglion‐like cells with mucoid stroma. Vacuolated cells were also seen. Lymphoplasmacytic infiltrate was largely undetectable. A vocal cord polyp was first suspected, but well‐differentiated liposarcoma and inflammatory myofibroblastic tumor (IMT) were included in the differential diagnoses. The tumor cells were positive for anaplastic lymphoma kinase (ALK), calponin, and vimentin, and negative for other smooth muscle markers by immunohistochemistry. Structures resembling myofibroblasts were not observed by electron microscopy, which confirmed abundant rough endoplasmic reticulum in the tumor cells and accumulated lipid droplets in some tumor cells. ALK gene rearrangement was detected by fluorescence in situ hybridization, and TIMP3–ALK fusion was confirmed by 5′ rapid ampli?cation of cDNA ends. We diagnosed the lesion as an IMT, and an ALK‐rearranged stellate cell tumor may be postulated. This is the first report of a fusion partner gene of ALK in a case of laryngeal IMT.     

Variant WWTR1 gene fusions in epithelioid hemangioendothelioma—A genetic subset associated with cardiac involvement

The genetic hallmark of epithelioid hemangioendothelioma (EHE) is a recurrent WWTR1‐CAMTA1 fusion, which is present in most cases bearing a conventional histology. A subset of cases is characterized by a distinct morphology and harbors instead of YAP1‐TFE3 fusion. Nevertheless, isolated cases lack these canonical fusions and remain difficult to classify. Triggered by an index case of a left atrial mass in a 76‐year‐old female with morphologic features typical of EHE, but which showed a WWTR1‐MAML2 fusion by targeted RNA sequencing, we searched our files for similar cases displaying alternative WWTR1 fusions. A total of 6 EHE cases were identified with variant WWTR1 fusions, four of them presenting within the heart. There were three females and three males, with a wide age range at diagnosis (21‐76 years, mean 62, median 69). The four cardiac cases occurred in older adults (mean age of 72, equal gender distribution); three involved the left atrium and one the right ventricle. One case presented in the vertebral bone and one in pelvic soft tissue. Microscopically, all tumors had morphologic features within the spectrum of classic EHE; two of the cases appeared overtly malignant. All cases were tested by FISH and four were investigated by targeted RNA sequencing. Two tumors harbored WWTR1‐MAML2 fusions, one WWTR1‐ACTL6A, and in three cases, no WWTR1 partner was identified. Of the four patients with follow‐up, two died of disease, one was alive with lung metastases, and the only patient free of disease was s/p resection of a T11 vertebral mass. Our findings report on additional genetic variants involving WWTR1 rearrangements, with WWTR1‐MAML2 being a recurrent event, in a small subset of EHE, which appears to have predilection for the heart.     

Undifferentiated round cell sarcomas with novel SS18‐POU5F1 fusions

Despite significant recent advances in characterizing the molecular pathogenesis of undifferentiated round cell neoplasms, rare cases remain unclassified. Here, we report two distinctive undifferentiated round cell tumors occurring in young adults. One tumor presented intrabdominally and the other arose within the abdominal wall. One patient died of disease following local and distance recurrence, despite aggressive chemotherapy and radiotherapy. Morphologically, both tumors were similarly composed of primitive round to epithelioid cells arranged in nests, sheets, and trabecular patterns. The cytoplasm was scant and amphophilic, while the nuclei were round and uniform with brisk mitotic activity. Focal necrosis was present. Immunohistochemically, both tumors were variably positive for S100 and EMA, and one case focally expressed cytokeratin and TLE1. Targeted RNA sequencing revealed in both an identical SS18‐POU5F1 fusion gene. Fluorescence in situ hybridization was performed which confirmed SS18 and POU5F1 gene rearrangements. Expression data, relative to over 200 other mesenchymal neoplasms that had undergone targeted RNA sequencing on the same platform, suggested the SS18‐POU5F1 tumors cluster with EWSR1/FUS‐POU5F1‐positive myoepithelial tumors. In view of our limited sample size, additional studies are needed to characterize the breadth of clinical and pathologic findings in these neoplasms. In addition, further investigation is necessary to determine whether this entity represents a clinically aggressive and phenotypically undifferentiated variant of myoepithelial tumors, or perhaps an altogether novel category of undifferentiated round cell sarcoma.