Inflammatory myofibroblastic tumors of the uterus are rare, and although most have a favorable prognosis, a small subset exhibit extrauterine disease, recur, or cause death. In this study, we evaluated the morphology and immunoprofile of 13 uterine inflammatory myofibroblastic tumors, including four with aggressive behavior. ALK rearrangements were detected by fluorescence in situ hybridization and fusion partners by anchored multiplex assay. Patients ranged from 8 to 63 (mean 39) years and tumors from 2.5 to 20 (mean 7.4) cm. Myxoid, compact, and hyalinized patterns were noted in 13, 12, and 2 tumors, ranging from 1 to 100%, 5 to 99%, and 0 to 5%, respectively. Nuclear atypia was mild in six (46%), moderate in five (38%), and severe in two (15%), with ganglion-like cells in two tumors. Mitoses ranged from 0 to 24 (mean 5) per 10 high-power fields. Inflammation was mild in five (38%), moderate in three (23%), and marked in five (38%), consisting of a lymphoplasmacytic infiltrate that was lymphocyte-predominant in six (46%). Lymphovascular invasion was noted in two (15%) and necrosis in eight (62%). All but one tumor were ALK-positive by immunohistochemistry, with granular cytoplasmic staining in nine (82%). ALK rearrangements (tested in 10) were detected in eight and was absent in one. The remaining tumor showed an isolated green 5' ALK signal. Fusion partners were identified in 10 (77%) and included THBS1 (n=3), IGFBP5 (n=2), DES (n=2), SEC31 (n=1), TPM3 (n=1), and TIMP3 (n=1). Size ≥8 cm was predictive of aggressive behavior (P<0.01), with increased mitoses (≥7 per 10 high-power fields), lymphovascular invasion, and compact-predominance approaching statistical significance. These data show that inflammatory myofibroblastic tumors of the uterus are morphologically heterogenous with frequent ALK expression and a variety of ALK fusion partners. Recognition of this rare mesenchymal neoplasm is crucial as those with aggressive behavior can potentially be treated with tyrosine kinase inhibitors.

Uterine perivascular epithelioid cell tumors (PEComas) are rare neoplasms that may show overlapping morphology and immunohistochemistry with uterine smooth muscle tumors. In this study, we evaluated the morphologic, immunohistochemical, and molecular features of 32 PEComas, including 11 with aggressive behavior. Two distinct morphologies were observed: classic (n=30) and those with a lymphangioleiomyomatosis appearance (n=2). In the former, patients ranged from 32 to 77 (mean: 51) years and 13% had tuberous sclerosis. Tumors ranged from 0.2 to 17 (mean: 5.5) cm with 77% arising in the corpus. Epithelioid cells were present in 100% and a spindled component was seen in 37%. Nuclear atypia was low (53%), intermediate (17%), or high (30%). Mitoses ranged from 0 to 36 (mean: 6) and 0 to 133 (mean: 19) per 10 and 50 high-power fields, with atypical mitoses present in 30%. Thin and delicate vessels were noted in 100%, clear/eosinophilic and granular cytoplasm in 93%, stromal hyalinization in 73%, necrosis in 30%, and lymphovascular invasion in 10%. All tumors were positive for HMB-45, cathepsin K, and at least one muscle marker, with most expressing melan-A (77%) and/or MiTF (79%). A PSF-TFE3 fusion was identified in one while another showed a RAD51B-OPHN1 fusion. Follow-up ranged from 2 to 175 (mean: 41) months, with 63% of patients alive and well, 20% dead of disease, 13% alive with disease, and 3% dead from other causes. In the latter group (n=2), patients were 39 and 49 years old, one had tuberous sclerosis, while the other had pulmonary lymphangioleiomyomatosis. Both tumors expressed HMB-45, cathepsin K, and muscle markers, but lacked TFE3 and RAD51B rearrangements. The 2 patients are currently alive and well. Application of gynecologic-specific criteria (≥4 features required for malignancy: size ≥5 cm, high-grade atypia, mitoses >1/50 high-power fields, necrosis, and lymphovascular invasion) for predicting outcome misclassified 36% (4/11) of aggressive tumors; thus, a modified algorithm with a threshold of 3 of these features is recommended to classify a PEComa as malignant.

Several morphologic features have been reported to be predictive of abnormal expression of mismatch repair (MMR) proteins in endometrial and colon carcinomas. Although it is known that abnormal MMR expression is increased in frequency in ovarian endometrioid and clear cell carcinomas, no such histologic correlation has been identified. We reviewed 109 unselected ovarian clear cell carcinomas for specific tumor characteristics (architecture, nuclear atypia, signet ring cells, stromal hyalinization, background precursor) and inflammatory response (peritumoral lymphocytes found along the leading edge of the tumor, intratumoral stromal inflammation found within the tumor, percentage of plasma cells in the intratumoral stromal inflammation, tumor-infiltrating lymphocytes) and performed immunohistochemistry for all 4 MMR proteins. Abnormal MMR expression was identified in 6% of tumors and included MSH2/MSH6 (3), MLH1/PMS2 (1), MSH6 (1), and PMS2 (1). These patients had a mean age of 40 (range, 31 to 48) years, which contrasted with a mean of 53.2 (range, 28 to 82) years for the overall cohort. One had a concurrent diagnosis of endometrial carcinoma, whereas another had a family history of endometrial carcinoma. None had a personal/family history of colonic carcinoma. Tumors with diffuse intratumoral stromal inflammation and peritumoral lymphocytes were more frequently associated with MMR loss on univariate analysis (P<0.001 and 0.047, respectively) with diffuse intratumoral stromal inflammation remaining a significant independent predictor on multivariate analysis. None of the other morphologic features evaluated reached statistical significance. Although previous series have been unable to identify a relationship between histology and MMR expression, this study identified a correlation with diffuse intratumoral stromal inflammation and peritumoral lymphocytes, 2 features that potentially could be selected for MMR analysis if corroborated by other studies.