Uterine Inflammatory Myofibroblastic Neoplasms With Aggressive Behavior, Including an Epithelioid Inflammatory Myofibroblastic Sarcoma: A Clinicopathologic Study of 9 Cases.

The experience with uterine inflammatory myofibroblastic neoplasms with an unfavorable outcome is limited. We present the clinicopathologic features of 9 such cases, including 8 inflammatory myofibroblastic tumors (IMTs) and 1 epithelioid inflammatory myofibroblastic sarcoma (EIMS). Median patient age for the IMT group was 50.5 years; the patient with EIMS was 43 years old. Patients presented with abnormal uterine bleeding, presumed fibroids, pelvic pain, arthralgia and low-grade fever, as well as an incidental finding. Median tumor size for the IMTs was 8.5 cm. The borders were either infiltrative or well-circumscribed. Histologically, IMTs were purely fascicular or myxoid or showed predominance of one or the other pattern. Seven tumors were spindled, and 1 was both spindled and epithelioid. Tumors had variable nuclear atypia, ranging from grade 1 to 3. All tumors had an inflammatory infiltrate-predominantly lymphocytic, majority had necrosis (62.5%) and none had lymphovascular invasion. 7/8 (87.5%) tumors were positive for ALK-1 by immunohistochemistry (IHC). One tumor was negative for ALK-1 by IHC but was positive for ALK fusion by fluorescence in situ hybridization and had TNS1-ALK fusion by next-generation sequencing (NGS). Three other tumors with NGS testing showed one of the following ALK-fusion partners: FN1, DCTN1, and IGFBP5. The EIMS had infiltrative borders, myxoid and hyalinized patterns, epithelioid cells, and no lymphovascular invasion. This tumor was ALK-1 positive by IHC, had ALK rearrangement by fluorescence in situ hybridization and RANBP2-ALK fusion by NGS. Extrauterine disease at time of diagnosis was noted in 2/8 (25%) of IMTs, and in the single case of EIMS. Seven patients had surgery as primary treatment, 1 patient had neoadjuvant chemotherapy and 1 patient declined treatment. Patients with recurrence were treated with a combination of chemotherapy, targeted therapy, radiotherapy or hormonal therapy. Most patients (71.4%) recurred within 24 months (mos). Two thirds of patients were alive with disease at last follow up (mean 43.6 mos). The patient with EIMS was alive with disease at 22 mos. IMT referral cases were initially diagnosed as smooth muscle tumors in 87.5% of cases; while the EIMS was diagnosed as high-grade endometrial stromal sarcoma. Lack of consideration of IMT in the differential diagnosis of smooth muscle tumors with myxoid features can result in misdiagnosis and under-utilization of targeted therapy in these patients.

Collins K ，Ramalingam P ，Euscher ED ，Reques Llanos A ，García A ，Malpica A ... -  《-》

Epithelioid inflammatory myofibroblastic sarcoma: An aggressive intra-abdominal variant of inflammatory myofibroblastic tumor with nuclear membrane or perinuclear ALK.

Mariño-Enríquez A ，Wang WL ，Roy A ，Lopez-Terrada D ，Lazar AJ ，Fletcher CD ，Coffin CM ，Hornick JL ... -  《-》

Epithelioid inflammatory myofibroblastic sarcoma: a clinicopathological, immunohistochemical and molecular cytogenetic analysis of five additional cases and review of the literature.

Yu L ，Liu J ，Lao IW ，Luo Z ，Wang J ... -  《Diagnostic Pathology》

Uterine inflammatory myofibroblastic tumor harboring novel NUDCD3-ROS1 and NRP2-ALK fusions: clinicopathologic features of 4 cases and literature review.

Inflammatory myofibroblastic tumor (IMT) is a mesenchymal neoplasm of intermediate biologic potential, which occurs mostly in the lung and abdomen cavity of children and young adults. Uterine IMTs are rare. Herein, we presented clinicopathologic features of 4 uterine IMTs. All four patients were initially diagnosed as leiomyosarcoma by other hospitals and corrected to uterine IMT after pathological consultation. Patient age ranged from 44 to 64 years old. Two cases demonstrated multiple masses. Microscopically, three tumors were composed of fascicular spindled cells with eosinophilic cytoplasm, and the other one was densely composed of spindled and epithelioid cells with bizarre and multinucleated cells. Tumor cells showed variable nuclear atypia, ranging from mild to severe. Prominent inflammatory cell infiltration was found in one case, and necrosis in two tumors. Immunochemistry staining revealed expression of smooth muscle markers in all four tumors, including a-SMA and desmin. Three tumors were positive for ALK protein expression. FISH analysis demonstrated ROS1 rearrangement in one tumor and ALK rearrangement in the other 3 tumors. NGS analysis showed novel NUDCD3-ROS1 and NRP2-ALK fusions in two tumors and TNS1-ALK fusion in the other two tumors. Gene aberrations involving p53 signaling pathway were identified in all four cases. All patients received surgery as primary treatment, and one had neoadjuvant chemotherapy. Three patients recurred within 12 months, and the other one recurred after 7 years. Patients with recurrence were treated with a combination of chemotherapy, targeted therapy, or surgery. In conclusion, the diagnosis of uterine IMTs can be challenging. Ancillary studies including ALK IHC, FISH, and NGS are helpful to establish diagnosis and to discover novel gene rearrangement potentially for targeted therapy.

Zhang L ，Luan L ，Shen L ，Xue R ，Huang J ，Su J ，Huang Y ，Xu Y ，Wang X ，Shao Y ，Ji Y ，Xu C ，Hou Y ... -  《-》

Leiomyoma-like Morphology in Metastatic Uterine Inflammatory Myofibroblastic Tumors.

Uterine inflammatory myofibroblastic tumors (IMTs) are rare mesenchymal neoplasms that frequently harbor ALK gene rearrangements and have a low risk of metastasis. We reported 3 of these tumors mimicking the appearance of leiomyoma in their recurrence. These patients were 34, 43, and 45 years old. Two uterine tumors demonstrated classic morphology, with combined myxoid, compact fascicular, and hyalinized patterns and spindled cells with bipolar cytoplasmic processes, moderate atypia, and lymphoplasmacytic inflammatory infiltrates. The third had a "leiomyoma-like" appearance, with fascicles of plump spindled cells and a sparse lymphoplasmacytic infiltrate. ALK immunohistochemistry was positive in all the tumors, and all demonstrated ALK rearrangements using fluorescence in situ hybridization (n = 2) and/or RNA sequencing (n = 2). Two classic IMTs recurred at 3 and 50 months in the lung and abdomen, respectively, and recurrent tumors had a "leiomyoma-like" appearance, with 0 and 1 mitosis per 10 high-power fields, no inflammation in 1, and a sparse lymphocytic infiltrate in the other. ALK was positive in both tumors; 1 with available tissue showed an IGFBP5::ALK fusion using RNA sequencing. The third patient, who had a "leiomyoma-like" uterine tumor, experienced multiple recurrences, first in the abdomen at 100 months showing a similar appearance. Subsequent recurrence at 105 months showed transmural invasion of the sigmoid colon and a similar microscopic appearance but with the addition of infiltrative borders, moderate cellularity, mild-to-moderate atypia, and 10 mitoses per 10 high-power fields. Both recurrences were positive for ALK, and RNA sequencing revealed the same ACTG2::ALK fusion transcript identified in the primary tumor. The patient was treated with crizotinib, resulting in prolonged clinical remission, with no evidence of disease at 168 months from the initial surgery. Although "leiomyoma-like" uterine IMTs have been recently described, to our knowledge, this is the first report of recurrence of these tumors and the first report of a "leiomyoma-like" appearance in the recurrences of conventional uterine IMTs. A low threshold for performing ALK immunohistochemistry on recurrent uterine tumors can identify patients who may benefit from tyrosine kinase inhibitors.

Devins KM ，Samore W ，Nielsen GP ，Deshpande V ，Oliva E ... -  《-》