DICER1-associated sarcomas: towards a unified nomenclature

We read with interest the recent paper by Schultz et al. “Pleuropulmonary Blastoma-like Peritoneal Sarcoma: a Newly Described Malignancy Associated with Biallelic DICER1 Pathogenic Variation” [1Schultz KAP, Nelson A, Harris AK, Finch M, Field A, Jarzembowski JA, et al. Pleuropulmonary blastoma-like peritoneal sarcoma: a newly described malignancy associated with biallelic DICER1 Pathogenic Variation. Mod Pathol. 2020. https://doi.org/10.1038/s41379-020-0558-4.Google Scholar]. The spectrum of reported DICER1-associated sarcomas continues to expand, and in this paper the authors report 7 cases of a primitive sarcoma that resembles pleuropulmonary blastoma (PPB). The tumours exhibited DICER1 pathogenic variants (hereafter referred to as “mutations”), were located in the peritoneal cavity and occurred in children at a mean of age 13 years (range 3–14 years). It appears that two of these neoplasms (cases 1 and 4) represent the same tumours we recently reported as embryonal rhabdomyosarcomas of the fallopian tube associated with DICER1 mutations [2McCluggage WG Apellaniz-Ruiz M Chong AL Hanley KZ Velázquez Vega JE McVeigh TP et al.Embryonal rhabdomyosarcoma of the ovary and fallopian tube: rare neoplasms associated with germline and somatic DICER1 mutations.Am J Surg Pathol. 2020; 44: 738-74710.1097/PAS.0000000000001442Crossref PubMed Scopus (30) Google Scholar]; our paper would not have been published when the authors were putting together their series of cases. Both these tumours, in common with some of the other neoplasms reported by Schultz et al. (the exact number is difficult to determine from the limited pathological details), exhibited rhabdomyoblastic differentiation (myogenin and myoD1 positivity) and contained cartilaginous elements. Our purpose of writing this letter is to point out that DICER1-associated sarcomas in many anatomical locations, and not just the peritoneum, exhibit a very similar and characteristic histology and closely resemble PPB from a morphological point of view; the sites where these neoplasms have been reported continues to increase and is likely to expand in the future. We concur with the views of Warren et al., who, also publishing in Modern Pathology, presented three new cases of DICER1-associated sarcoma and undertook a comprehensive review of the literature of 83 other cases, and suggested that these neoplasms, regardless of their site of origin, exhibit characteristic morphological features that resemble PPB [3Warren M, Hiemenz MC, Schmidt R, Shows J, Cotter J, Toll S, et al. Expanding the spectrum of dicer1-associated sarcomas. Mod Pathol. 2019. https://doi.org/10.1038/s41379-019-0366-x.Google Scholar]. These include a subepithelial layer of malignant mesenchymal cells, areas of rhabdomyoblastic differentiation (embryonal rhabdomyosarcoma) with positive staining with myogenin and myoD1, cellular/ immature and sometimes overtly malignant cartilage, foci of bone/ osteoid and foci of anaplasia. Not all of these characteristic features are present in every case. Such neoplasms have a different terminology at different sites, for example PPB, PPB-like peritoneal sarcoma [1Schultz KAP, Nelson A, Harris AK, Finch M, Field A, Jarzembowski JA, et al. Pleuropulmonary blastoma-like peritoneal sarcoma: a newly described malignancy associated with biallelic DICER1 Pathogenic Variation. Mod Pathol. 2020. https://doi.org/10.1038/s41379-020-0558-4.Google Scholar], DICER1-associated central nervous system sarcoma, spindle cell sarcoma with rhabdomyosarcoma-like features, DICER1 mutant, primary intracranial sarcoma, DICER1-mutant [4Lee JC Villanueva-Meyer JE Ferris SP Sloan EA Hofmann JW Hattab EM et al.Primary intracranial sarcomas with DICER1 mutation often contain prominent eosinophilic cytoplasmic globules and can occur in the setting of neurofibromatosis type 1.Acta Neuropathol. 2019; 137: 521-52510.1007/s00401-019-01960-xCrossref PubMed Scopus (37) Google Scholar, 5Kamihara J, Paulson V, Breen MA, Laetsch TW, Rakheja D, Shulman DS, et al. DICER1-associated central nervous system sarcoma in children: comprehensive clinicopathologic and genetic analysis of a newly described rare tumor. Mod Pathol. 2020. https://doi.org/10.1038/s41379-020-0516-1.Google Scholar, 6Koelsche C Mynarek M Schrimpf D Bertero L Serrano J Sahm F et al.Primary intracranial spindle cell sarcoma with rhabdomyosarcoma-like features share a highly distinct methylation profile and DICER1 mutations.Acta Neuropathol. 2018; 136: 327-33710.1007/s00401-018-1871-6Crossref PubMed Scopus (84) Google Scholar], DICER1 renal sarcoma, anaplastic sarcoma of the kidney [7Wu MK Vujanic GM Fahiminiya S Watanabe N Thorner PS O'Sullivan MJ et al.Anaplastic sarcomas of the kidney are characterized by DICER1 mutations.Mod Pathol. 2018; 31: 169-17810.1038/modpathol.2017.100Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 8Doros LA Rossi CT Yang J Field A Williams GM Messinger Y et al.DICER1 mutations in childhood cystic nephroma and its relationship to DICER1-rEnal sarcoma.Mod Pathol. 2014; 27: 1267-128010.1038/modpathol.2013.242Abstract Full Text Full Text PDF PubMed Google Scholar] and presacral malignant teratoid neoplasm in association with pathogenic DICER1 variation [9Nakano Y Hasegawa D Stewart DR Schultz KAP Harris AK Hirato J et al.Presacral malignant teratoid neoplasm in association with pathogenic DICER1 variation.Mod Pathol. 2019; 32: 1744-175010.1038/s41379-019-0319-4Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar], to name a few. A further interesting and related point is that embryonal rhabdomyosarcomas of the uterine cervix, endometrium and ovary are established to be associated with DICER1 mutations [10de Kock L, Yoon JY, Apellaniz-Ruiz M, Pelletier D, McCluggage WG, Stewart CJR, et al. Significantly greater prevalence of DICER1 alterations in uterine embryonal rhabdomyosarcoma compared to adenosarcoma. Mod Pathol. 2020. https://doi.org/10.1038/s41379-019-0436-0.Google Scholar, 11de Kock L Druker H Weber E Hamel N Traubici J Malkin D et al.Ovarian embryonal rhabdomyosarcoma is a rare manifestation of the DICER1 syndrome.Hum Pathol. 2015; 46: 917-92210.1016/j.humpath.2015.02.008Crossref PubMed Scopus (37) Google Scholar] and these also often exhibit the characteristic morphological appearance described with subepithelial condensation of tumour cells, cartilaginous differentiation and areas of anaplasia. Intracranial embryonal rhabdomyosarcomas have also been reported to exhibit DICER1 mutations [12Sakaguchi M Nakano Y Honda-Kitahara M Kinoshita M Tanaka S Oishi M et al.Two cases of primary supratentorial intracranial rhabdomyosarcoma with DICER1 mutation which may belong to a “spindle cell sarcoma with rhabdomyosarcoma-like feature, DICER1 mutant”.Brain Tumor Pathol. 2019; 36: 174-18210.1007/s10014-019-00352-zCrossref PubMed Scopus (16) Google Scholar] and, as noted by the authors [12Sakaguchi M Nakano Y Honda-Kitahara M Kinoshita M Tanaka S Oishi M et al.Two cases of primary supratentorial intracranial rhabdomyosarcoma with DICER1 mutation which may belong to a “spindle cell sarcoma with rhabdomyosarcoma-like feature, DICER1 mutant”.Brain Tumor Pathol. 2019; 36: 174-18210.1007/s10014-019-00352-zCrossref PubMed Scopus (16) Google Scholar], it is likely that these represent the same tumour type as those reported as primary intracranial sarcoma, DICER1-mutant or as DICER1-associated central nervous system sarcoma [4Lee JC Villanueva-Meyer JE Ferris SP Sloan EA Hofmann JW Hattab EM et al.Primary intracranial sarcomas with DICER1 mutation often contain prominent eosinophilic cytoplasmic globules and can occur in the setting of neurofibromatosis type 1.Acta Neuropathol. 2019; 137: 521-52510.1007/s00401-019-01960-xCrossref PubMed Scopus (37) Google Scholar, 5Kamihara J, Paulson V, Breen MA, Laetsch TW, Rakheja D, Shulman DS, et al. DICER1-associated central nervous system sarcoma in children: comprehensive clinicopathologic and genetic analysis of a newly described rare tumor. Mod Pathol. 2020. https://doi.org/10.1038/s41379-020-0516-1.Google Scholar]. In an ideal situation, it would be desirable if a unified nomenclature could be used to reflect that these neoplasms in different organs are likely to be part of the same tumour spectrum and strongly associated with DICER1 mutations, whether germline (as part of DICER1 syndrome) or somatic (post-zygotic, and generally not syndromic). For example, unifying terms such as “primary intracranial sarcoma, DICER1-mutant”, “primary peritoneal sarcoma, DICER1-mutant” or primary cervical sarcoma, DICER1-mutant” could be used. However, we appreciate that in the real world, nomenclature changes have the potential to result in confusion for pathologists and clinicians given that it may not be apparent that these “new” terms refer to neoplasms, which are already referred to by established terms in the literature rather than newly defined tumour types. This could potentially result in “loss” of important information when new terms are used since the pertinent literature may not be reviewed. However, we think it would be desirable to somehow unify the nomenclature and this will require close cooperation between pathologists and clinicians dealing with these rare tumour types; this will be required to be followed by adoption by groups which are responsible for tumour classification, such as the International Agency for Research on Cancer (IARC), the organisation that is responsible for producing the World Health Organization (WHO) “Blue books” on tumour classification. When introducing such a new terminology, it may be prudent to initially use both the “new” and “old” names, for example “primary peritoneal sarcoma, DICER1-mutant (PPB-like peritoneal sarcoma)”, “primary pulmonary sarcoma, DICER1-mutant (PPB)” or “primary cervical sarcoma, DICER1-mutant (cervical embryonal rhabdomyosarcoma)”. A broader point to be appreciated by pathologists (and clinicians) is that, especially but not exclusively in a young patient, when dealing with a mesenchymal neoplasm with areas of skeletal muscle differentiation/ embryonal rhabdomyosarcoma, cellular cartilage and/or anaplasia, the potential involvement of DICER1 should be considered and appropriate tumour testing undertaken. This is important since some of these patients will have germline DICER1 mutations (DICER1 syndrome) and, if this is established, surveillance/ screening can be undertaken for other DICER1-associated neoplasms and family members can be tested. Any person whose tumour contains a DICER1 mutation should be considered to be at risk for DICER1 syndrome, until proven otherwise [3Warren M, Hiemenz MC, Schmidt R, Shows J, Cotter J, Toll S, et al. Expanding the spectrum of dicer1-associated sarcomas. Mod Pathol. 2019. https://doi.org/10.1038/s41379-019-0366-x.Google Scholar]. As molecular diagnostics increase in availability and sophistication, similar or identical molecular events are being identified in tumours arising at diverse sites which often go by different names but have similar morphology. A good example of this is SMARCA4 mutations in small cell carcinoma of the ovary of hypercalcaemic type (SCCOHT) [13Witkowski L Goudie C Foulkes WD McCluggage WG Small-cell carcinoma of the ovary of hypercalcemic type (Malignant Rhabdoid Tumor of the Ovary): a review with recent developments on pathogenesis.Surg Pathol Clin. 2016; 9: 215-22610.1016/j.path.2016.01.005Abstract Full Text Full Text PDF PubMed Google Scholar, 14Foulkes WD Clarke BA Hasselblatt M Majewski J Albrecht S McCluggage WG No small surprise- small cell carcinoma of the ovary, hypercalcaemic type, is a malignant rhabdoid tumour.J Pathol. 2014; 233: 209-21410.1002/path.4362Crossref PubMed Scopus (105) Google Scholar, 15Witkowski L Carrot-Zhang J Albrecht S Fahiminiya S Hamel N Tomiak E et al.Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type.Nat Genet. 2014; 46: 438-44310.1038/ng.2931Crossref PubMed Scopus (305) Google Scholar, 16Ramos P Karnezis AN Craig DW Sekulic A Russell ML Hendricks WP et al.Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4.Nat Genet. 2014; 46: 427-42910.1038/ng.2928Crossref PubMed Scopus (228) Google Scholar, 17Jelinic P Mueller JJ Olvera N Dao F Scott SN Shah R et al.Recurrent SMARCA4 mutations in small cell carcinoma of the ovary.Nat Genet. 2014; 46: 424-42610.1038/ng.2922Crossref PubMed Scopus (232) Google Scholar], as well as in a variety of other neoplasms, for example within the uterine corpus, lung, gastrointestinal tract, pancreas, head and neck and other sites. These are often characterised by a monotonous population of cells, sometimes with rhabdoid features, and a similar morphological appearance to SCCOHT [18Matsubara D Kishaba Y Ishikawa S Sakatani T Oguni S Tamura T et al.Lung cancer with loss of BRG1/BRM, shows an epithelial mesenchymal transition phenotype and distinct histologic and genetic features.Cancer Sci. 2012; 104: 266-27310.1111/cas.12065Crossref Scopus (93) Google Scholar, 19Agaimy A The expanding family of SMARCB1 (INI1)-deficient neoplasia: implications of phenotypic, biological, and molecular heterogeneity.Adv Anat Pathol. 2014; 21: 394-41010.1097/PAP.0000000000000038Crossref PubMed Google Scholar, 20Ramalingam P Masand RP Euscher ED Malpica A Undifferentiated carcinoma of the endometrium: an expanded immunohistochemical analysis including PAX-8 and basal-like carcinoma surrogate markers.Int J Gynecol Pathol. 2016; 35: 410-41810.1097/PGP.0000000000000248Crossref PubMed Scopus (64) Google Scholar, 21Hoang LN Lee Y-S Karnezis AN Tessier-Cloutier B Almandani N Coatham M et al.Immunophenotypic features of dedifferentiated endometrial carcinoma- insights from BRG1/INI1-deficient tumours.Histopathology. 2016; 69: 560-56910.1111/his.12989Crossref PubMed Scopus (41) Google Scholar, 22Tessier-Cloutier B, Schaeffer DF, Bacani J, Marginean CE, Kalloger S, Köbel M, et al. Loss of switch/sucrose non-fermenting complex protein expression in undifferentiated gastrointestinal and pancreatic carcinomas. Histopathology. 2020 https://doi.org/10.1111/his.14096.Google Scholar, 23Agaimy A Franchi A Lund VJ Skálová A Bishop JA Triantafyllou A et al.Sinonasal undifferentiated carcinoma (SNUC): from an entity to morphologic pattern and back again-a historical perspective.Adv Anat Pathol. 2020; 27: 51-6010.1097/PAP.0000000000000258Crossref PubMed Scopus (22) Google Scholar, 24Kolin DL Dong F Baltay M Lindeman N MacConaill L Nucci MR et al.SMARCA4-deficient undifferentiated uterine sarcoma (malignant rhabdoid tumor of the uterus): a clinicopathologic entity distinct from undifferentiated carcinoma.Mod Pathol. 2018; 31: 1442-145610.1038/s41379-018-0049-zAbstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 25Kolin DL Quick CM Dong F Fletcher CDM Stewart CJR Soma A et al.SMARCA4-deficient uterine sarcoma and undifferentiated endometrial carcinoma are distinct clinicopathologic entities.Am J Surg Pathol. 2020; 44: 263-27010.1097/PAS.0000000000001375Crossref PubMed Scopus (49) Google Scholar, 26Lin DI Allen JM Hecht JL Killian JK Ngo NT Edgerly C et al.SMARCA4 inactivation defines a subset of undifferentiated uterine sarcomas with rhabdoid and small cell features and germline mutation association.Mod Pathol. 2019; 32: 1675-168710.1038/s41379-019-0303-zAbstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar]; in different organs, these neoplasms have variably been designated as carcinomas or sarcomas. While it would be more correct to refer to these by a generic term such as SMARCA4 deficient malignancies, we also recognise that, like PPB, some of the terms, for example SCCOHT, are well established in the literature and are likely to remain; as such, using both the “new” and “old” terminologies may be advisable in the immediate future. The authors declare that they have no conflict of interest.