RESUMEN
Inflammatory myofibroblastic tumor (IMT) is a myofibroblastic/fibroblastic neoplasm of intermediate malignant potential. It is frequently characterized by genetic fusion of ALK with a variety of partner genes, which results in the activated ALK signaling pathway that can be targeted with kinase inhibitors. IMTs can occur in the gynecologic tract, with the uterus (corpus and cervix) being the most frequent site. Recent studies suggest that IMTs in the gynecologic tract are underrecognized, and a low-threshold for performing ALK immunohistochemistry has been proposed. The aim of this study was to evaluate the specificity of ALK immunohistochemistry for IMTs among uterine mesenchymal and mixed epithelial/mesenchymal tumors. We performed ALK immunohistochemistry on 14 molecularly confirmed uterine IMTs and 260 other uterine pure mesenchymal and mixed epithelial/mesenchymal tumors. Cases showing any positive cytoplasmic and/or membranous staining of the tumor cells were considered to be ALK positive. All 14 IMTs were confirmed to harbor ALK genetic fusion by RNA sequencing, and ALK immunostaining in the form of granular cytoplasmic positivity with paranuclear accentuation was observed in all 14 cases. ALK was negative (complete absence of staining) in all the other pure mesenchymal tumors and in all mixed epithelial/mesenchymal tumors examined. Our findings show that ALK is a highly specific diagnostic immunohistochemical marker for ALK fusion in uterine mesenchymal tumors. In the work-up of uterine mesenchymal tumors, particularly smooth muscle tumors showing myxoid stromal changes, a diagnosis of IMT should be strongly considered if ALK positivity is observed.
Asunto(s)
Quinasa de Linfoma Anaplásico/análisis , Biomarcadores de Tumor/análisis , Inmunohistoquímica , Neoplasias de los Tejidos Conjuntivo y Blando/enzimología , Neoplasias Uterinas/enzimología , Adulto , Anciano , Quinasa de Linfoma Anaplásico/genética , Biomarcadores de Tumor/genética , Femenino , Fusión Génica , Predisposición Genética a la Enfermedad , Humanos , Persona de Mediana Edad , Neoplasias de los Tejidos Conjuntivo y Blando/genética , Neoplasias de los Tejidos Conjuntivo y Blando/patología , Fenotipo , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Análisis de Secuencia de ARN , Análisis de Matrices Tisulares , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologíaRESUMEN
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.
Asunto(s)
Fusión Génica , Granuloma de Células Plasmáticas/genética , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/genética , Proteínas Tirosina Quinasas Receptoras/genética , Trombospondina 1/genética , Neoplasias Uterinas/genética , Adulto , Anciano , Quinasa de Linfoma Anaplásico , Femenino , Biblioteca de Genes , Granuloma de Células Plasmáticas/patología , Humanos , Inmunohistoquímica , Persona de Mediana Edad , ARN/aislamiento & purificación , Análisis de Secuencia de ARN , Neoplasias Uterinas/patologíaAsunto(s)
Proteínas de Unión al Calcio/genética , Hemangioendotelioma Epitelioide/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Transactivadores/genética , Neoplasias del Cuello Uterino/genética , Adulto , Femenino , Hemangioendotelioma Epitelioide/patología , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Factores de Transcripción , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Translocación Genética , Neoplasias del Cuello Uterino/patologíaRESUMEN
AIMS: To determine the frequency and distribution of Fallopian tube involvement in patients with ovarian metastases of non-gynaecological origin. METHODS AND RESULTS: All Fallopian tube tissue was processed for histological examination in a consecutive series of 31 patients with ovarian metastases of non-gynaecological origin. The most common primary sites were appendix (n = 10) colon (n = 7), stomach (n = 6) and breast (n = 4). Twenty cases (65%) showed at least one type of tubal spread. Mural involvement was most common (14 cases) but serosal, intra-vascular, intra-epithelial and intra-lumenal spread were also identified in 12, 9, 8 and 11 cases respectively. Intra-epithelial involvement was restricted to the fimbrial epithelium and mimicked tubal carcinoma in situ (CIS) architecturally. Pagetoid invasion was noted in two of the cases. CONCLUSIONS: The Fallopian tubes are commonly involved in patients who have neoplasms metastatic to the ovaries. Metastases may show a CIS-like pattern of intra-epithelial spread and therefore small serous CIS-type lesions may not represent proof of tubal tumour origin in patients who have high-stage pelvic serous carcinomas. The frequency of intra-lumenal tumour cells supports transtubal spread as a likely mechanism for mucosal involvement by metastatic tumours involving the lower genital tract.