DICER1-associated sarcomas at different sites exhibit morphological overlap arguing for a unified nomenclature

Abstract

In this issue of Virchows, Davidson et al. report an interesting uterine corpus neoplasm, an ectomesenchymoma, in a 72-year old containing a DICER1 mutation [1]. Ectomesenchymoma is an exceedingly rare multiphenotypic sarcoma and in the 5th edition of the World Health Organization (WHO) Classification of Soft Tissue and Bone Tumours, is included in the category of skeletal muscle tumours [2]. It is defined here as exhibiting both mesenchymal and neuroectodermal differentiation and composed of areas resembling rhabdomyosarcoma (prototypically embryonal rhabdomyosarcoma (ERMS)) admixed with variable neuronal/neuroblastic components [2]. The latter covers the entire spectrum of neuroblastic phenotype, ranging from ganglion cells to mature ganglioneuroma, intermediate ganglioneuroblastoma and primitive neuroblastoma [2]. The majority of affected patients are infants or young children (first two decades of life) and most common primary sites include the pelvis, abdomen, retroperitoneum and urogenital organs. The case reported by Davidson et al. exhibited morphological and immunohistochemical evidence of both rhabdomyoblastic and neuroectodermal differentiation and cartilaginous foci were present [1]. Ectomesenchymomas have never been reported to contain DICER1 mutations, although this has not been investigated previously. The presence of a DICER1 mutation in this neoplasm is intriguing, given the morphological features. A wide variety of DICER1-associated sarcomas have been reported in the literature [3]. While some of these are classified as ERMS, for example, those reported in the uterine cervix, corpus, ovary and fallopian tube [4, 5], many other names have been appended to DICER1-associated sarcomas (Table 1). These include pleuropulmonary blastoma (PPB), PPB-like peritoneal sarcoma, DICER1-associated central nervous system sarcoma, spindle cell sarcoma with rhabdomyosarcoma-like features (DICER1mutant), primary intracranial sarcoma (DICER1-mutant), DICER1 renal sarcoma, anaplastic sarcoma of the kidney and presacral malignant teratoid neoplasm in association with pathogenic DICER1 variation [6–9]. As we, and others, have pointed out previously, DICER1associated sarcomas in many locations exhibit a similar and characteristic morphology that resembles PPB, the prototypical DICER1-associated sarcoma [3, 7, 10]. The morphological features, not all of which are present in every case, include a subepithelial layer of malignant mesenchymal cells (cambium layer), areas of rhabdomyoblastic differentiation with positive staining with myogenin and myoD1, cellular/immature and occasionally malignant cartilage, foci of bone/osteoid and areas of anaplasia. While the case reported by Davidson et al. additionally contains “neuroectodermal” elements, this has also been reported in DICER1-associated neoplasms. Immature neuroepithelium has been reported inDICER1-associated sarcomas [9] and occasional primitive neuroectodermal tumours have been reported in DICER1 syndrome [11]. It is likely that DICER1-associated sarcomas have a propensity to exhibit multiple lines of mesenchymal differentiation. This ties in with the observation that DICER1-associated ERMS of the uterine cervix, corpus, ovary and fallopian tube typically exhibit cartilaginous and sometimes osseous differentiation [4, 5]. Intracranial ERMS have also been reported to contain DICER1 mutations [12] and it is likely that these represent the same tumour as those reported as primary intracranial sarcoma,DICER1-mutant [8]. A further important point is that, given the admixture of elements, tumours such as ectomesenchymoma and other DICER1-associated sarcomas may potentially be given different names depending on the individual pathologist and according to what these neoplasms at different sites have been termed previously. For example, the case reported by Davidson et al. could * W. Glenn McCluggage [email protected]