Expression of p53 is significantly associated with recurrence-free survival and overall survival in pleuropulmonary blastoma (PPB): a report from the International Pleuropulmonary Blastoma/DICER1 Registry

González, Iván; Mallinger, Paige; Watson, Dave; Harris, Adrienne; Messinger, Yoav; Schultz, Kris Ann P.; Field, Amanda; Hill, D. Ashley; Dehner, Louis P.

doi:10.1038/s41379-021-00735-8

Cited by 19 publications

(32 citation statements)

References 20 publications

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“…Of particular interest is PPB, a tumour that in some cases progresses over time from a cystic lesion (type I) to a mixed cystic and solid lesion (type II) and then to a highly aggressive solid neoplasm (type III) [ 8 , 48 ]. The mesenchymal component in the cyst walls of type I PPB represents an early malignant population that can develop sarcomatous overgrowth in types II and III PPB, manifesting the characteristic DICER1 mixed sarcoma phenotype including RMS, chondrosarcoma, fibrosarcoma, primitive blastemal cells, and large anaplastic cells.…”

Section: Discussionmentioning

confidence: 99%

PRAME protein expression in DICER1‐related tumours

Thorner

Chong

Nadaf

et al. 2022

The Journal of Pathology CR

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DICER1 syndrome is an autosomal dominant tumour predisposition syndrome usually affecting persons under 30 years of age. Many of the associated benign and malignant lesions occur almost exclusively in DICER1 syndrome. One such tumour, pituitary blastoma (pitB), overexpresses PRAME 500x above control levels. PRAME (PReferentially expressed Antigen in MElanoma) is expressed in malignancies that are not DICER1-related (e.g. melanoma). To address whether PRAME expression is part of the DICER1 phenotype, or simply a feature of pitB, a series of 75 DICER1-mutated specimens and 33 non-mutated specimens was surveyed using immunohistochemistry for PRAME, together with EZH2, which complexes with PRAME. In DICER1-mutated specimens, positive staining for PRAME was only seen in malignant tumours; 7 of 11 histological types and 34/62 individual tumours were positive, while non-tumourous lesions were always negative. Pleuropulmonary blastoma (PPB) showed a continuum in staining, with type I lesions being PRAME negative (n = 7) but all type II and type III lesions PRAME positive (n = 7). Similarly, cystic nephroma (CN) was negative (n = 8), with anaplastic sarcoma of the kidney being positive (n = 2). However, one atypical CN with mesenchymal cell proliferation was PRAMEpositive. Embryonal rhabdomyosarcoma (RMS) with DICER1 pathogenic variants (PVs) was positive for PRAME (5/6), but the same tumour type without DICER1 PVs was also positive (9/15). Staining for EZH2 corresponded to that seen with PRAME, validating the latter. This study leads us to conclude that (1) PRAME expression occurs in two-thirds of DICER1-related malignancies; (2) PRAME may be a marker for the progression that certain DICER1-related lesions are thought to undergo, such as PPB and CN; and (3) PRAME expression in some tumours, such as RMS, appears to be an intrinsic feature of the tumour, rather than specifically related to DICER1 PVs. Therapy directed against PRAME may offer novel treatment options in patients with the DICER1 syndrome.

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Section: Discussionmentioning

confidence: 99%

PRAME protein expression in DICER1‐related tumours

Thorner

Chong

Nadaf

et al. 2022

The Journal of Pathology CR

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“…Given the association of pCN and DICER1 carriers, and the rare progression to ASK- DICER1 renal sarcoma, an abdominal ultrasound is recommended during infancy at the time a chest CT is done for PPB surveillance and every 6 to 12 months until at least 8-years of age. After this age, an annual ultrasound could be considered until 12-years of age 32 .…”

Section: The Urinary Systemmentioning

confidence: 97%

“…6 ) 21 . More recently, it has been demonstrated that TP53 expression by IHC correlates with the prognosis in PPB independent of the three PPB types; this observation validated the hypothesis that other mutations are necessary for tumor progression from type I to type III PPB 32 . Furthermore, it was noted in the latter study that the presence of TP53 expression in the epithelial cells lining the cystic structures in most type II PPBs but in less than 50% of type I PPB and in less than 20% of type IR raised the question of the role that the epithelium plays in tumor progression independent of mutations in the mesenchymal-stromal cells.…”

Section: Pleuropulmonary Blastoma (Ppb)mentioning

confidence: 99%

“…However, as noted above in the pediatric population this frequency is significantly higher and thus a recommendation for screening for DICER1 mutations in pediatric DTC is warranted. Given this increased risk for the development of DTC, it is recommended that a thyroid ultrasound around 8-years of age in DICER1 carriers and then every 2 to 3 years, and in patients receiving chemotherapy, a baseline ultrasound is recommended and then annually for 5 years 32 .…”

Section: Head and Neckmentioning

confidence: 99%

“…In the case of the tumorigenesis pathway, the second somatic hit and its particular anatomic site determine where the primary DICER1 -associated neoplasm(s) presents in one or more organs or elsewhere. Additional mutations, such as in TP53 and other as yet unidentified genomic or epigenomic events 32 , facilitate the progression to a DICER1 -associated neoplasm with one or multiple morphologic patterns in a complex collage of rhabdomyoblasts with features of ERMS, spindle cells, blastemal islands with or without rhabdomyoblastic differentiation, nodules of cartilage with fetal or immature or sarcomatous features and a population of larger, pleomorphic cells with or without anaplasia in selected tumor types. Another feature is the presence of immature tubules resembling primitive tubules with neural or nephrogenic features are seen in those DICER1 -associated neoplasms with teratoid features which together with the other differentiated sarcomatous components may suggest or lead to the diagnosis of a germ cell neoplasm; these latter findings have been seen in the eye, thyroid, cervix, central nervous system and pre-sacral region.…”

Section: Commentary/conclusionmentioning

confidence: 99%

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DICER1 tumor predisposition syndrome: an evolving story initiated with the pleuropulmonary blastoma

et al. 2022

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DICER1 syndrome (OMIM 606241, 601200) is a rare autosomal dominant familial tumor predisposition disorder with a heterozygous DICER1 germline mutation. The most common tumor seen clinically is the pleuropulmonary blastoma (PPB), a lung neoplasm of early childhood which is classified on its morphologic features into four types (IR, I, II and III) with tumor progression over time within the first 4–5 years of life from the prognostically favorable cystic type I to the unfavorable solid type III. Following the initial report of PPB, its association with other cystic neoplasms was demonstrated in family studies. The detection of the germline mutation in DICER1 provided the opportunity to identify and continue to recognize a number seemingly unrelated extrapulmonary neoplasms: Sertoli-Leydig cell tumor, gynandroblastoma, embryonal rhabdomyosarcomas of the cervix and other sites, multinodular goiter, differentiated and poorly differentiated thyroid carcinoma, cervical-thyroid teratoma, cystic nephroma-anaplastic sarcoma of kidney, nasal chondromesenchymal hamartoma, intestinal juvenile-like hamartomatous polyp, ciliary body medulloepithelioma, pituitary blastoma, pineoblastoma, primary central nervous system sarcoma, embryonal tumor with multilayered rosettes-like cerebellar tumor, PPB-like peritoneal sarcoma, DICER1-associated presacral malignant teratoid neoplasm and other non-neoplastic associations. Each of these neoplasms is characterized by a second somatic mutation in DICER1. In this review, we have summarized the salient clinicopathologic aspects of these tumors whose histopathologic features have several overlapping morphologic attributes particularly the primitive mesenchyme often with rhabdomyoblastic and chondroid differentiation and an uncommitted spindle cell pattern. Several of these tumors have an initial cystic stage from which there is progression to a high grade, complex patterned neoplasm. These pathologic findings in the appropriate clinical setting should serve to alert the pathologist to the possibility of a DICER1-associated neoplasm and initiate appropriate testing on the neoplasm and to alert the clinician about the concern for a DICER1 mutation.

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DICER1‐mutated rhabdomyosarcoma of the ovary with teratoid features

Lethongsavarn,

Vieille,

Kikweta Makhama

et al. 2023

Genes Chromosomes & Cancer

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DICER1‐mutated rhabdomyosarcoma is a rare, emerging entity with a predilection for the gynecologic and genitourinary tracts. We report here a case of DICER1‐mutated rhabdomyosarcoma of the ovary in a 14 years old girl which displayed interspersed mature teratoid glands, neuroectodermal rosettes and immature blastematous‐like tubes. Morphologically the sarcomatous component predominated, corresponding to a high grade spindle cell rhabdomyosarcoma with botryoid features. Islets of cartilage were present. The sarcomatous proliferation encased the teratoid glands, forming cambium layer‐like arrangements. The sarcoma cells were Myogenin and MYOD1 positive, the neuroectodermal rosettes expressed SALL4 along with cytokeratins and EMA and were negative for Inhibin; immature blastematous‐like tubes were negative for SALL4 and Inhibin. Whole RNA‐ and targeted DNA‐sequencing revealed two DICER1 mutations in exon 26: c.5113G>A: p.(Glu1705Lys) and exon 12: c.1642C>T: p.(Gln548X). The sarcomatous component harbored a complex genetic profile while the teratoid component was diploid, none of the above displayed abnormality of 12p. DICER1‐mutated sarcomas display pathological features similar to embryonal rhabdomyosarcomas, botryoid type. They also display heterogeneous features combining cartilage foci, teratoid mature glands, immature blastematous‐like tubes and/or neuroectodermal components. Molecular testing remains necessary to confirm the diagnosis. Further studies need to clarify the nosology of DICER1‐mutated sarcomas and devise specific therapeutic strategies.

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Expression of p53 is significantly associated with recurrence-free survival and overall survival in pleuropulmonary blastoma (PPB): a report from the International Pleuropulmonary Blastoma/DICER1 Registry

Cited by 19 publications

References 20 publications

PRAME protein expression in DICER1‐related tumours

PRAME protein expression in DICER1‐related tumours

DICER1 tumor predisposition syndrome: an evolving story initiated with the pleuropulmonary blastoma

DICER1‐mutated rhabdomyosarcoma of the ovary with teratoid features

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