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Review
. 2022 Jan;35(1):4-22.
doi: 10.1038/s41379-021-00905-8. Epub 2021 Oct 1.

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

Iván A González  1 , Douglas R Stewart  2 , Kris Ann P Schultz  3   4 , Amanda P Field  5 , D Ashley Hill  3   5   6 , Louis P Dehner  7   8
Affiliations
Review

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

Iván A González et al. Mod Pathol. 2022 Jan.

Abstract

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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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Pleuropulmonary blastoma, type III.
A Pleuropulmonary blastoma, type III occurring in a 3-year-old male as a large solid thoracic mass. Piecemeal resection revealed a tan-white, myxoid and hemorrhagic neoplasm (one of the original 11 PPB cases). B Focus of embryonal type rhabdomyosarcoma and nodule of malignant cartilage. C Another focus of primitive sarcoma with individual anaplastic cells including bizarre mitotic figure.
Fig. 2
Fig. 2. Pleuropulmonary blastoma, type I presenting as a cystic lesion in the lung of a 1-year-old female.
A Septal markings and cysts are appreciated in this unbisected specimen whose multicystic structure is lost with bisection as the delicate septa collapse. B The peripheral multicystic lesion is composed of uniform septal structures abutting the pleural surface, a characteristic feature. C Uniformly expanded septa by primitive-appearing small, rounded and spindled-shaped cells, many showing desmin and myogenin positivity (not shown). D Cambium layer-like concentration of primitive small cells with adjacent fibrous stroma.
Fig. 3
Fig. 3. Pleuropulmonary blastoma, type I showing septal widening.
Pleuropulmonary blastoma, type I showing a focus of septal widening by primitive small cells as a feature of presumed progression before the formation of a grossly visible mass, as a requisite for the diagnosis of type II PPB.
Fig. 4
Fig. 4. Pleuropulmonary blastoma, type I showing a nodule of cartilage within a septum.
This finding is seen in 15% of type I PPBs, as one or several foci.
Fig. 5
Fig. 5. Pleuropulmonary blastoma, type II.
A Focus of PPB type I in a mass lesion in this 2-year-old male whose tumor was predominantly solid. B, C A cambium layer-like growth pattern in this transitional area from type I to the solid pattern. D Solid focus showing a mixture of small primitive round and spindle cells.
Fig. 6
Fig. 6. Pleuropulmonary blastoma, type IR.
Pleuropulmonary blastoma, type IR showing the characteristic multicystic architecture of type I, but in the absence of a primitive small cell or rhabdomyoblastic population only ascertained after a complete microscopic examination of the resected cyst.
Fig. 7
Fig. 7. Sertoli-Leydig cell tumor, moderately differentiated in an adolescent presenting with an abdominal mass.
A Solid foci of this solid and cystic mass showing groups of Sertoli cells and surrounding Leydig cells. B Cystic focus with a delicate septum with a cambium layer-like localization of Sertoli cells with its resemblance to PPB type I.
Fig. 8
Fig. 8. Sertoli-Leydig cell tumor, moderately differentiated in a 15-year-old female.
A A cystic focus showing a group of Sertoli cells beneath a low cuboidal epithelial surface. B Nests of Sertoli cells surrounded by malignant-appearing, primitive-appearing spindle and round cells in another cystic area of the tumor. C MyoD immunostaining showing intense nuclear positivity to corroborate heterologous rhabdomyosarcoma.
Fig. 9
Fig. 9. Embryonal rhabdomyosarcoma of the cervix.
A A polypoid “vaginal” tumor presented in a 9-year-old female showing scattered endocervical glands with variably prominent subepithelial concentration of small cells and nodules of cartilage. PPB-type IR was also detected in the lung and a pathogenic heterozygous germline DICER1 mutation was detected. B Endocervical gland encircled by embryonal rhabdomyosarcoma in an 11-year-old female with a cervical-vaginal mass. She subsequently developed a Sertoli-Leydig cell tumor at age 13 years and had a pathogenic heterozygous germline DICER1 mutation.
Fig. 10
Fig. 10. Cystic nephroma, pediatric type.
A Circumscribed multicystic renal lesion in this CT image from a 2-year-old male who presented with an abdominal mass. A similar-appearing lesion on CT was present in the lung (PPB type I not shown). B Several delicate septal structures display architectural similarities to PPB type IR. C Multiple cysts in a fibrous stroma and one larger cyst with a hypercellular subepithelial mantle of spindle cells with a resemblance to PPB type I. Overtly sarcomatous elements were not present.
Fig. 11
Fig. 11. Anaplastic sarcoma of kidney (DICER1 renal sarcoma) in the right kidney of a 4-year-old male.
A The solid and cystic neoplasm showing a focus of residual pCN and adjacent cysts with surrounding hypercellular mantles of primitive small cells with rhabdomyoblastic differentiation (not shown) (inset, focus of hyperchromatic cells beneath a cyst). B A focus of primitive small, round and spindle-shaped cells projecting into a cyst with a subepithelial mantle of similar-appearing cells. C Malignant-appearing spindle cells surrounding a focus of neoplastic cartilage. D Focus of undifferentiated round cells with adjacent neoplastic cartilage. As in the case of PPB types II and III, anaplasia is not present in every ASK despite the implication of its appellation.
Fig. 12
Fig. 12. DICER1 cystic hepatic neoplasm presenting as a cystic lesion of the liver in a 1-year-old male.
A 10.7 cm mass with a multicystic cut surface showing one of multiple cysts lined by biliary type epithelium with a subepithelial zone of primitive small cells extending into the surrounding stroma. These cells demonstrated desmin immunopositivity. A pathogenic heterozygous germline mutation in DICER1 was detected.
Fig. 13
Fig. 13. Hamartomatous polyp with juvenile polyp-like features.
Small intestinal polyp in a child with PPB showing an ulcerated surface with elongated crypts and a lamina propria with bands of smooth muscle.
Fig. 14
Fig. 14. PPB-like peritoneal sarcoma arising in the pelvis of an adolescent female.
A Cystic focus of the tumor demonstrating a hypercellular zone of primitive round cells with patchy myogenin positivity (not shown). B Solid areas of the tumor showing undifferentiated sarcoma with round and spindle cell features and an enlarged, anaplastic tumor cell.
Fig. 15
Fig. 15. Poorly differentiated thyroid carcinoma in a 22-year-old female with a past history of Wilms tumor at age 7 years and a peritoneal sarcoma with cystic and rhabdomyosarcoma at age 11 years who was a DICER1 heterozygous germline variant.
A The 3.5 cm, tan-pink, encapsulated mass showing tumor in the capsule and closely apposed small nests of uniforms tumor cells with dense nuclei and pale cytoplasm. B Trabecular and small follicular profiles of basophilic tumor cells demonstrating scattered mitotic figures.
Fig. 16
Fig. 16. Nasal chondromesenchymal hamartoma.
A This tumor demonstrating a well-differentiated nodule of cartilage with an accompanying spindle cell stroma without rhabdomyoblastic features. B Another example with a less cellular myxoid stroma and cartilaginous nodules with variation in differentiation.
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