Epithelioid Inflammatory Myofibroblastic Sarcoma

Abstract

Inflammatory myofibroblastic tumor (IMT) is a mesenchymal neoplasm of intermediate biological potential, which may recur and rarely metastasize. Pathologic features do not correlate well with behavior. Approximately 50% of conventional IMTs harbor ALK gene rearrangement and overexpress ALK, most showing diffuse cytoplasmic staining. Rare IMTs with a distinct nuclear membrane or perinuclear pattern of ALK staining and epithelioid or round cell morphology have been reported. These cases pursued an aggressive clinical course, suggesting that such patterns may predict malignant behavior. We describe 11 cases of IMT with epithelioid morphology and a nuclear membrane or perinuclear pattern of immunostaining for ALK. Ten patients were male and 1 was female, ranging from 7 months to 63 years in age (median, 39 y). All tumors were intra-abdominal; most arose in the mesentery or omentum, measuring 8 to 26 cm (median, 15 cm). Six tumors were multifocal at presentation. The tumors were composed predominantly of sheets of round-to-epithelioid cells with vesicular nuclei, large nucleoli, and amphophilic-to-eosinophilic cytoplasm. In all cases, a minor spindle cell component was present. Nine tumors had abundant myxoid stroma. In 7 cases neutrophils were prominent and in 3 cases lymphocytes were prominent. Plasma cells were often absent. Median mitotic rate was 4/10 HPF; 6 tumors had necrosis. By immunohistochemistry, all tumors were positive for ALK, 9 tumors showing a nuclear membrane staining pattern and 2 tumors showing a cytoplasmic pattern with perinuclear accentuation. Other positive markers were desmin (10 of 11), focal smooth muscle actin (4 of 8), and CD30 (8 of 8). All tumors were negative for MYF4, caldesmon, keratins, EMA, and S-100. Fluorescence in situ hybridization was positive for ALK gene rearrangement in 9 cases, and in 3 cases tested, a RANBP2-ALK fusion was detected by reverse transcription polymerase chain reaction. Ten patients underwent surgical resection; 1 patient was inoperable. Follow-up was available for 8 patients and ranged from 3 to 40 months (median, 13 mo). All patients experienced rapid local recurrences; 4 patients had multiple recurrences. Eight patients were treated with postoperative chemotherapy; 2 patients received additional radiotherapy. Two patients also developed metastases (both patients developed metastases to the liver; 1 patient developed metastases to the lung and lymph nodes as well). Thus far, 5 patients died of disease, 2 patients are alive with disease, and 1 patient, treated with an experimental ALK inhibitor, has no evidence of disease. In summary, the epithelioid variant of IMT with nuclear membrane or perinuclear ALK is a distinctive intra-abdominal sarcoma with a predilection for male patients. Unlike conventional IMT, abundant myxoid stroma and prominent neutrophils are common. These tumors pursue an aggressive course with rapid local recurrences and are frequently fatal. We propose the designation "epithelioid inflammatory myofibroblastic sarcoma" to convey both the m...

Expression of ROS1 predicts ROS1 gene rearrangement in inflammatory myofibroblastic tumors

“…Ten of these tumors were previously confirmed to harbor ALK gene rearrangements (by FISH, next-generation sequencing, or reverse transcriptase-polymerase chain reaction), 7 with known fusion partners (4 RANBP2 and 1 each TPM3 , CLTC , and FN1 ). 5, 18 …”

“…18 The gene fusion status of 10 of these tumors was previously published. 5, 18 Archival samples from 60 other spindle cell neoplasms in the differential diagnosis with inflammatory myofibroblastic tumor were also evaluated, including 10 cases each of desmoid fibromatosis; myofibroblastic sarcoma; gastrointestinal stromal tumor, spindle cell type; leiomyosarcoma; follicular dendritic cell sarcoma; and dedifferentiated liposarcoma (5 morphologically low grade and 5 with the so-called “inflammatory MFH” pattern).…”

“…2 In general, histologic features do not correlate well with clinical behavior, 3 with the exception of an aggressive epithelioid variant ( epithelioid inflammatory myofibroblastic sarcoma ) that arises in the mesentery and omentum and shows distinctive histologic appearances, including myxoid stroma and a predominantly neutrophilic inflammatory infiltrate. 4, 5 …”

Molecular Characterization of Inflammatory Myofibroblastic Tumors With Frequent ALK and ROS1 Gene Fusions and Rare Novel RET Rearrangement

“…Generally pathologic features of IMT do not correlate well with behavior 10 . However, the epithelioid variant of IMT, which shows distinctive nuclear membrane or perinuclear ALK immunostaining pattern, has been associated with a more aggressive clinical outcome 11 . In a subset of these lesions a RANBP2-ALK fusion has been detected by RT-PCR.…”

An Unusual Case of Systemic Inflammatory Myofibroblastic Tumor with Successful Treatment with ALK-Inhibitor

“…However, cases lacking these histologic features have been found to behave in an aggressive manner, and conversely cases with worrisome histologic features have been found to behave indolently [22]. In recent years, a highly aggressive intra-abdominal variant of IMT has been described with epithelioid-to-round cell morphology with nuclear membrane or perinuclear ALK staining and predilection for male patients, which has been termed “epithelioid inflammatory myofibroblastic sarcoma” to convey the malignant nature of this tumor and close relation to IMT [27]. …”