Embryonal Rhabdomyosarcoma of the Uterine Cervix

Abstract

Embryonal rhabdomyosarcoma of the uterine cervix (cERMS) is rare and frequently associated with DICER1 mutations. We report 94 tumors that arose in patients aged 7 to 59 (median = 23) years and presented with vaginal bleeding (52), protruding vaginal mass (17), cervical polyp (8), or expelled tumor fragments per vagina (5). Nine had DICER1 syndrome, 8 of whom had other syndromic manifestations including ovarian Sertoli-Leydig cell tumor ( 7), multinodular goiter (3), pleuropulmonary blastoma (2), pineoblastoma (1), and osteosarcoma (1). Syndromic patients were younger than nonsyndromic patients (16 vs. 24 y). Tumor size ranged from 2 to 24 (median = 4.5) cm. Ninety-two tumors were polypoid, most being grapelike (77 of 92). They were characterized by aggregates of primitive cells, almost always exhibiting a cambium layer, within a variably myxoedematous stroma and were hypocellular (63), moderately cellular (22), or hypercellular (9). Entrapped glands, typically scant, were present in 84 tumors. Primitive hyperchromatic ovoid to spindled cells with minimal cytoplasm predominated but differentiated rhabdomyoblasts with abundant eosinophilic cytoplasm (having cross-striations in 30) were seen in 83 tumors; they were often sparse but predominated in three. Nine tumors showed areas of intersecting fascicles and 4 zones with densely cellular (solid) growth. Cartilage was present in 38. Anaplasia was seen in 15 tumors, as was necrosis. Mitotic activity ranged from 1 to 58/10 high-power fields (median = 8). The varied microscopic features resulted in a spectrum of differential diagnostic considerations, mainly typical and cellular forms of fibroepithelial polyps, Mullerian adenosarcoma, and other sarcomas. Follow-up was available for 79 patients ranging from 6 to 492 (median = 90) months. Treatment information was available in 62 and included polypectomy in 6 patients (2 also received chemotherapy), limited resection in 26 (14 also received chemotherapy), hysterectomy in 29 (15 with adjuvant chemotherapy), and biopsies only in 1 (with chemotherapy). Staging was possible in 56 tumors; according to the "uterine sarcoma" system (tumor size and extent) they were: stage I (10/56; could not be further subclassified as size not available), IA (22/56), IB (18/56), IIA (2/ 56), IIB 3/56), IIIC (1/56). According to the "adenosarcoma" system (depth of invasion and extent) they were: stage IA (26/56), IB (14/56), IC (10/56), IIA (2/56), IIB (3/56), IIIC (1/56). Eight patients had local recurrence following incomplete excision (10%). Eleven of 79 patients had extrauterine recurrences (14%) and 9 died of disease (11%). Older age was associated with extrauterine recurrence (median 44 vs. 22; P = 0.002) and decreased disease-specific survival (median 44 vs. 22; P = 0.02). For patients with tumors initially confined to the cervix, the adenosarcoma staging system was superior to the uterine sarcoma staging system for predicting survival (P = 0.02). Three patients with DIC-ER1 syndrome who underwent fertility-preserving surgery developed a...

Embryonal rhabdomyosarcoma of the female gynecologic tract: a retrospective clinical study of 14 cases

“…These patients were younger and only 3 patients ERMS in cervix was the rst presentation of the syndrome. Identi cation of ERMS in a patient of any age, but particularly if young, should prompt referral for genetic testing and consideration of germline DICER1 testing [19,26]. In our series, only three of the patients have a test for DICER-1, but negative.…”

“…Five-year OS rate was 68.4%; factors associated with better OS were younger age, absence of distant metastasis, embryonal histology, negative lymph nodes, and performance of surgery. Devins et al [19] and Minard-Colin et al [20] also showed older age was associated with extrauterine recurrence and decreased disease-speci c survival. While there was no association between age and PFS or DSS in our series, maybe due to the small size of the sample.…”

“…Patients are prone to multidirectional tumors, including pleuropulmonary blastoma, cystic renal tumor, ovarian Sertoli-Leydig cell tumor, multinodular goiter, thyroid carcinoma, cystic nephroma, Wilms tumor, and pituitary blastoma, among others [25]. A clinicopathologic study of 94 cases about ERMS in cervix by Devins et al [19] found nine patients had DICER1 syndrome, 8 of whom had other syndromic manifestations including seven with ovarian Sertoli-Leydig cell tumor, three with multinodular goiter, two with pleuropulmonary blastoma, one with pineoblastoma, and one with osteosarcoma. These patients were younger and only 3 patients ERMS in cervix was the rst presentation of the syndrome.…”

“…In further risk-stratifying tumors, TNM staging system for rhabdomyosarcoma [11,12], the FIGO "adenosarcoma" system and "uterine sarcoma" system were also applied in our series, but there was no association between staging system factors and PFS or DSS in IRSG stage I group. Devins et al [19] showed in further risk-stratifying stage I tumors, the FIGO "adenosarcoma" system based on depth of invasion was superior to the "uterine sarcoma" system based on tumor size, the latter showing no correlation with outcome. While this did not nd in our series maybe due to the small size of the sample.…”

Genomic characterization of DICER1-associated neoplasms uncovers molecular classes

“…In contrast, DICER1-associated sarcomas (SARC DICER1 and PIS DICER1) usually exhibit an overtly sarcomatous phenotype which is associated with frequent alterations in TP53, KRAS/NRAS and NF1 , high genomic index, as well as a global hypomethylation signature. In contrast to LGMT DICER1, DICER1-associated sarcomas may show a more aggressive clinical course 15 , 19 – 23 . Although the difference in the global methylomic profiles of these three classes may reflect their cell type composition, such as dominant epithelium component in LGMT DICER1, dominant sarcoma component in the other two classes and no epithelium in PIS DICER1, the identification of these DICER1-associated tumor classes from various anatomical sites will enable meaningful clinical trial stratification in the future and suggests that rational drug development addressing the differing molecular foundations of mesenchymal tumors with DICER1 alteration may be a plausible goal.…”