DICER1‐associated embryonal rhabdomyosarcoma and adenosarcoma of the gynecologic tract: Pathology, molecular genetics, and indications for molecular testing

Abstract

Gynecologic sarcomas are uncommon neoplasms, the majority occurring in the uterus. Due to the diverse nature of these, the description of “new” morphological types and the rarity of some of them, pathological diagnosis and treatment is often challenging. Finding genetic alterations specific to, and frequently occurring, in a certain type can aid in the diagnosis. DICER1 is a highly conserved ribonuclease crucial in the biogenesis of microRNAs and mutations in DICER1 (either somatic or germline) have been detected in a wide range of sarcomas including genitourinary embryonal rhabdomyosarcomas (ERMS) and adenosarcomas. Importantly, DICER1‐associated sarcomas share morphological features irrespective of the site of origin such that the pathologist can strongly suspect a DICER1 association. A review of the literature shows that almost all gynecologic ERMS reported (outside of the vagina) harbor DICER1 alterations, while approximately 20% of adenosarcomas also do so. These two tumor types exhibit significant morphological overlap and DICER1 tumor testing may be helpful in distinguishing between them, because a negative result makes ERMS unlikely. Given that germline pathogenic DICER1 variants are frequent in uterine (corpus and cervix) ERMS and pathogenic germline variants in this gene cause a hereditary cancer predisposition syndrome (DICER1 syndrome), patients diagnosed with these neoplasms should be referred to medical genetic services. Cooperation between pathologists and geneticists is crucial and will help in improving the diagnosis and management of these uncommon sarcomas.

Clinicopathologic and molecular analysis of embryonal rhabdomyosarcoma of the genitourinary tract: evidence for a distinct DICER1-associated subgroup

“…Despite a similar or in some instances even identical morphology, the presence of cartilaginous nodules has previously been described in DICER1-associated ERMS, a finding that is confirmed by the current study [7,20]. Similarly, we report osteoid formation in conjunction with DICER1 mutations in a uterine ERMS, which has previously been reported in two cases of DICER1-associated ERMS of the female genital tract [34,40]. Thus, identification of cartilaginous nodules and/or osteoid formation in ERMS of the genitourinary tract, including the uterus, may suggest a DICER1-association.…”

“…These results are in line with a recent report by de Kock et al who reported a series of 19 DICER1-associated uterine ERMS with a median age at diagnosis of 30 years [7]. In contrast, a younger median age of 16 years at diagnosis of patients with DICER1associated ERMS arising anywhere in the female genital tract was published in a recent meta-analysis [34]. Our results suggest that on the other hand most extrauterine ERMS, more specifically DICER1-wt ERMS, usually do not occur in older patients [5].…”

“…In combination with published evidence, our results suggest that ERMS of the inner female genital tract-maybe with the exception of most tumors arising in the vagina-are associated with DICER1 mutations, in contrast to other ERMS arising in the urinary tract which is usually DICER1-wt. In their recent paper, Appellaniz-Ruiz et al hypothesized that DICER1 mutations could predispose to tumor development in Müllerian-derived tissues [34]. The Müllerian ducts ontogenetically give rise to the upper portion of the vagina, the uterine cervix, and corpus, as well as the fallopian tubes, potentially providing a developmental explanation for the predilection of DICER1mut ERMS at these sites.…”

Rhabdomyosarcoma of the Cervix in a Post-Menopausal Woman—An Unparalleled Phenomenon

“…There have been studies that suggest that the DICER1 mutation which causes dysregulation of miRNA and activates oncogenes may play a part in this process [8,17,18]. A hypothesis has been formed, stating that the DICER-1 mutation is present in ERMS developing in tissues derived from Mulerrian ducts, i.e., the uterus, cervix, upper part of the vagina and the fallopian tubes [19]. Moreover, a study of 17 cases has proved that DICER-1 mutation occurs more often in older patients, while in younger ones, ERMS usually develops with no connection to that mutation.…”

Phenotypic Similarities Within The Morphologic Spectrum Of DICER1-Associated Sarcomas and Pleuropulmonary Blastoma -- Histopathologic Features Suggesting Genetic Testing and Counselling

“…While Apellaniz-Ruiz in their review showed that nearly all gynecologic ERMSs (except vaginal tumours) were DICER1 -associated, Doros et al detected DICER1 mutation in only 3.8% (2/52) cases of sporadic ERMS and the Children's oncology group cohort of pediatric rhabdomyosarcomas showedDICER1 germline mutation in 4.4%. 10,[17][18][19][20] DICER1 -associated central nervous system sarcomas also have a high association with rhabdomyosarcomatous differentiation. 8,21,22 Our CNS case mimicked mesenchymal chondrosarcoma, though it expressed ERMS markers.…”