Uterine Inflammatory Myofibroblastic Tumor Research Articles

A Novel ALK–THBS1 Fusion in a Laryngeal Inflammatory Myofibroblastic Tumour: A Case Report and Literature Review

Inflammatory myofibroblastic tumor (IMT) is an uncommon neoplasm most frequently seen in the abdomino-pelvic region and lungs of children and young adults. Laryngeal tumors are rare. We present a case of a 23-year-old patient with a 5month history of laryngitis and aphonia unresolved by corticotherapy. Laryngoscopy revealed a small, non-ulcerated, subepithelial, polypoid mass arising from the right vocal cord. The diagnosis of IMT with ALK expression was supported by histopathologic and molecular analysis. The THBS1 fusion partner was identified by RNA-sequencing analysis for the first time in a laryngeal IMT. This fusion partner has only been identified in six uterine IMTs thus far. Conservative excision of the lesion yielded excellent functional results for the patient. The voice was preserved and no recurrences were seen after 6months of follow-up.

ALK-rearranged Tumors Are Highly Enriched in the STUMP Subcategory of Uterine Tumors.

Smooth muscle tumor of uncertain malignant potential (STUMP) is a rare diagnosis rendered when there is uncertainty concerning the biological potential of a smooth muscle tumor. The initial differential diagnosis is often broad, as tumors in this subgroup are morphologically heterogenous. Recent data suggest uterine inflammatory myofibroblastic tumors (IMTs) with anaplastic lymphoma kinase (ALK) rearrangement may be misclassified as STUMPs, but the extent to which this occurs has not been examined. We identified 60 female patients with tumors previously diagnosed as STUMP (48 cases) or prospectively considered for the diagnosis of STUMP (12 cases). Each case underwent histologic review, ALK immunohistochemistry (IHC) and confirmatory break-apart fluorescence in situ hybridization (FISH) for ALK if immunoreactive. Six of the 43 (14%) uterine and cervical tumors were ALK IHC positive, whereas tumors at all other sites were ALK IHC negative. Myxoid features, although limited in some cases, were present in all 6 ALK IHC positive tumors, representing 35% (6/17) of tumors displaying myxoid features at uterine and cervical sites. All ALK immunoreactive tumors were confirmed to have ALK rearrangements by FISH with 1 tumor showing numerous (3 to 8) 3' ALK signals, an unusual FISH pattern not previously described in uterine IMTs. Two patients developed recurrent disease and were treated with ALK-targeted therapy with initial response. Our data demonstrate that a significant proportion of uterine and cervical tumors considered to be STUMPs are ALK-positive by IHC and FISH. Future screening of all uterine and cervical mesenchymal tumors under consideration for the diagnosis of STUMP, particularly those with myxoid features, is recommended to identify ALK-rearranged IMTs that could potentially be treated with targeted therapy using tyrosine kinase inhibitors.

Immunohistochemical and selected genetic reflex testing of all uterine leiomyosarcomas and STUMPs for ALK gene rearrangement may provide an effective screening tool in identifying uterine ALK-rearranged mesenchymal tumors.

We examined the value of targeted molecular screening for the identification of uterine anaplastic lymphoma kinase (ALK)-rearranged mesenchymal tumors, including ALK immunohistochemistry followed by molecular genetic testing, in all uterine leiomyosarcomas and STUMPs (smooth muscle tumors of uncertain malignant potential). All leiomyosarcoma and STUMP cases diagnosed in a 10-year period (2006-2016) at Charles University Faculty of Medicine in Pilsen were retrieved and reviewed. Of 23 cases, one case (LMS [leiomyosarcoma]) was positive for ALK rearrangement, namely, PPP1CB-ALK fusion gene. No specific histologic features (i.e., lymphocytic infiltrate and stromal edema) were observed in this case. This suggests that inflammatory myofibroblastic tumor (IMT)-like histologic features may not be an initial reliable screening tool in identifying uterine IMT cases. Thus, we proposed a two-step IHC and molecular genetic testing (as a reflex test) for IMT in all uterine LMS and STUMP cases. This will enhance the proper detection of such tumors at the population level and ultimately offer patients available targeted therapies.

Myxoid Mesenchymal Tumors of the Uterus: An Update on Classification, Definitions, and Differential Diagnosis.

Tumors with a predominant myxoid stroma are rare in the uterus. When encountered, however, they pose a diagnostic challenge. Traditionally myxoid leiomyosarcoma has been the most important consideration in this category, given its adverse prognosis and deceptively bland morphology. Conventional features of malignancy are variably present; in contrast, an infiltrative tumor border is a consistent pathologic characteristic. More recently, previously under-recognized lesions have been identified, in part due to our growing knowledge of their underlying molecular alterations: uterine inflammatory myofibroblastic tumor frequently harbors ALK rearrangements and a novel ZC3H7B-BCOR gene fusion has been described in a subset of myxoid high-grade endometrial stromal sarcomas. These tumors need to be distinguished from myxoid leiomyosarcoma, as by comparison have a less aggressive course and are amenable to targeted treatments. In addition, uterine mesenchymal tumors with malignant potential need to be distinguished from benign tumors and epithelial and mixed malignancies. This review aims to discuss our current understanding of the most common uterine myxoid neoplasms: their clinical features, their distinguishing histopathologic, immunohistochemical, and molecular features and the clues and pitfalls in their diagnosis.

Inflammatory myofibroblastic tumor of the uterus: a clinicopathological, immunohistochemical, and molecular analysis of 13 cases highlighting their broad morphologic spectrum

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 Inflammatory Myofibroblastic Tumors Frequently Harbor ALK Fusions With IGFBP5 and THBS1.

Inflammatory myofibroblastic tumor (IMT) can occur in a number of anatomic sites, including the uterus. Like its soft tissue counterpart, uterine IMT frequently expresses ALK and harbors ALK genetic rearrangements. The aim of this study is to fully characterize the genetic fusions that occur in uterine IMT. We studied 11 uterine IMTs with typical histology and 8 uterine myxoid smooth muscle tumors (5 leiomyomas, 1 smooth muscle tumor of uncertain malignant potential, and 2 leiomyosarcomas) in which the differential of IMT was considered, using a RNA-sequencing-based fusion assay to detect genetic fusions involving ALK, ROS1, RET, NTRK1/3, and other genes. ALK was expressed in 10 of 11 IMTs and 1 tumor initially categorized as a myxoid leiomyoma (granular cytoplasmic staining with paranuclear accentuation). Fusion transcripts involving ALK were identified in 9 of 10 ALK immunopositive IMTs, with 3 harboring IGFBP5-ALK, 3 harboring THBS1-ALK, 2 harboring FN1-ALK, and 1 harboring TIMP3-ALK. Among the smooth muscle tumors, IGFBP5-ALK fusion transcript was identified in only 1 ALK immunopositive case. Further review revealed that although a diagnosis of IMT was considered for the ALK immunopositive myxoid leiomyoma, this diagnosis was not initially rendered only because fluorescence in situ hybridization analysis was interpreted as negative for ALK genetic rearrangement; this case is best reclassified as an IMT. Notably, all the ALK fusions identified in our study included the transmembrane domain-encoding exon 19 of ALK. Our findings confirm the high frequency of ALK fusions in uterine IMT, with an enrichment of novel 5' ALK fusion partners (IGFBP5, THBS1, and TIMP3) and exon 19-containing ALK fusion. Given that IGFBP5 and FN1 are both situated on the same chromosome as ALK, fluorescence in situ hybridization analysis for ALK rearrangement may not be reliable and a negative result should not exclude a diagnosis of uterine IMT if the histologic features and ALK immunostaining findings are supportive.

Inflammatory Myofibroblastic Tumor of the Uterus

Inflammatory myofibroblastic tumor is currently regarded as a neoplasm with intermediate biological potential and a wide anatomic distribution. Inflammatory myofibroblastic tumors of the female genital tract are rare, and to date reported cases behaved indolently. We describe, herein, 10 cases of uterine inflammatory myofibroblastic tumor, 3 of which had an aggressive clinical course. Subject age ranged from 29 to 73 years. Tumors were composed of spindle and epithelioid myofibroblastic cells admixed with lymphoplasmacytic infiltrates in a variably myxoid stroma. Two growth patterns, myxoid and fascicular (leiomyoma-like), were noted. All tumors were positive for ALK expression by immunohistochemistry, which was stronger in the myxoid areas. Smooth muscle marker and CD10 expression was variable in extent, but typically positive. Fluorescence in situ hybridization for ALK rearrangements was positive in both fascicular and myxoid areas in all 8 cases tested. Three subjects showed clinical evidence of tumor aggressiveness as defined by extrauterine spread, local recurrence, or distant metastasis. Aggressive tumors were larger, had a higher proportion of myxoid stroma, and higher mitotic activity than indolent tumors. Tumor cell necrosis was seen only in cases with adverse outcome. This is the first report to describe aggressive biological behavior in uterine inflammatory myofibroblastic tumor. This diagnosis is often underappreciated and merits inclusion in the differential diagnosis of myxoid mesenchymal lesions of the uterus, particularly because patients with an aggressive course may benefit from targeted therapy.

Inflammatory Myofibroblastic Tumor of the Uterus

Inflammatory myofibroblastic tumor (IMT) is an indolent spindle cell proliferation that can histologically resemble various malignant mesenchymal neoplasms; however, it generally behaves as a benign or locally recurrent tumor. Most IMTs involve the lung, mesentery, omentum, or retroperitoneum. We report the clinical and pathologic features of six IMTs of the uterus, one of which was included in a previous report, and emphasize the histologic and immunohistochemical features that distinguish IMTs from uterine spindle cell neoplasms that require aggressive treatment. Recently, translocations of the anaplastic lymphoma kinase (ALK) gene and immunohistochemical expression of ALK have been reported in IMTs of various anatomic sites. We compared ALK expression in uterine IMTs with that in uterine mesenchymal neoplasms with which it may be confused. Patients with IMT were between 6 and 46 years of age. None had a history of abdominal surgery; three were multiparous. The IMTs ranged from 1 to 12 cm in maximum dimension. Three grew as polypoid masses that arose in the lower uterine segment, and two of these prolapsed through the cervical os. The three other tumors grew as bulky myometrial masses with focally irregular borders and infiltrated the endometrium, parametrium, or cervical stroma. There were three main microscopic patterns: a hypocellular pattern, a fascicular pattern, and a hyalinized pattern. A lymphoplasmacytic infiltrate was present in all of the tumors, and most had a myxoid background. Mitotic activity ranged from 0 to 2 mitotic figures per 10 high power fields (HPF) except in one tumor that focally had up to 8 mitotic figures per 10 HPF. No nuclear atypia or necrosis was present. Immunohistochemical expression of ALK was present in a cytoplasmic pattern in all IMTs tested. No ALK expression was identified in uterine leiomyoma (n = 7), leiomyosarcoma (n = 6), carcinosarcoma (n = 4), endometrial stromal sarcoma (n = 4), or normal uterine tissues. Follow-up ranging from 1.5 years to 5 years in 4 patients with uterine IMTs revealed no recurrence or metastasis. IMTs should be differentiated from aggressive uterine mesenchymal tumors because they can be treated conservatively and have a more favorable prognosis. ALK expression appears to be of diagnostic value in conjunction with other immunohistochemical stains.