DICER1 – risk management (child)

DICER1 syndrome is a rare, autosomal dominant tumour predisposition syndrome characterised by the development of specific rare types of benign and malignant tumours. The most frequently reported tumours are pleuropulmonary blastoma (PPB), cystic nephroma, multinodular goitre and certain rare types of ovarian tumours (see table).^r

• Unaffected known or obligate DICER1 gene pathogenic variant carrier under age 18 years.

Exclusion criteria

• A DICER1 gene pathogenic variant carrier already diagnosed with a relevant cancer/tumour.
• Individual under age 18 years at 50% risk of inheriting a DICER1 gene pathogenic variant (their screening and follow up should be individualised).
• Individual with a variant of uncertain significance.

The penetrance of phenotypes is not known and is variable between and within families; the peak age for presentation is early childhood and early data suggests that for any particular manifestation, penetrance is 15% or less. See Key clinical phenotypes associated with constitutional DICER1 pathogenic variants.

^ Source: Australian Institute of Health and Welfare (AIHW) 2023 Cancer Data in Australia; Canberra: AIHW. <https://www.aihw.gov.au/reports/cancer/cancer-data-in-australia/>. (2019 data, unadjusted for competing mortality)

The choice of risk management strategy should take into account current age, other health issues and age-related cancer risk. Risks and benefits of interventions should be discussed with an experienced medical professional.

The impact of lifestyle on cancer risk should be discussed e.g. exercise most days for at least 30 minutes at moderate or strenuous intensity, maintain a healthy weight, have a healthy diet, limit alcohol intake, do not smoke and avoid excess sun exposure.

* Transition to transvaginal ultrasound could be considered in older adolescents and adults when the ovaries are not visible with transabdominal ultrasound after a careful discussion of potential benefits and harms.
** With particular attention to examination of the thyroid, respiratory, gastrointestinal and neurological systems.
*** Including, but not limited to, hirsutism, virilisation, abdominal distension, pain, or mass and abnormal vaginal bleeding, symptoms of intracranial tumours and prompt reporting of unusual symptoms.

There is no international consensus on screening so enrolment in clinical trials and participation in the International Pleuropulmonary Blastoma/DICER1 Registry is encouraged whenever possible.

• Pleuropulmonary Blastoma DICER1 Syndrome Study
• DICER1-related Pleuropulmonary Blastoma Cancer Predisposition Syndrome: A Natural History Study
• The International Pleuropulmonary Blastoma/DICER1 Registry
• DICER1 Syndrome Information Network

There is no published evidence regarding the benefit of screening for unaffected individuals with a DICER1 pathogenic variant. Surveillance strategies have recently been proposed on the basis that manifestations of DICER1 such as pleuropulmonary blastoma (PPB) evolve from benign cystic lesions amenable to early detection and intervention towards malignant lesions with poorer prognosis.^rrr An analytic model of diagnostic imaging screening strategies for PPB screening predicts improved life expectancy in children screened for PPB with combined chest X-rays and CT-scans.^r Larger studies are needed to assess the clinical validity of screening in DICER1, particularly for rarer manifestations. Enrolment in clinical trials and participation in the International Pleuropulmonary Blastoma/DICER1 Registry is encouraged whenever possible.^r

Renal

The risk of Wilms tumour/kidney sarcoma is low and it is unclear if a normal ultrasound and/or resection of cystic nephroma in early childhood is associated with a lower risk of later renal malignancy. 

Female reproductive tract

Sertoli-Leydig cell tumour of the ovary (SLCT) can occur from early childhood to late adulthood with a peak incidence between age 10 and 25 years. Surveillance imaging may reduce higher stage presentation and the need for adjuvant therapy although the efficacy is still to be determined.^rr 

Thyroid

Multinodular goitre (MNG) is common in DICER1 syndrome. Differentiated thyroid cancer has been described in individuals with DICER1 syndrome, but the cumulative incidence is unknown.^r Neck palpation in combination with thyroid ultrasound has been recommended as surveillance modalities for DICER1 pathogenic variant carriers. Most thyroid cancers are indolent and confined to the thyroid. To date there is no evidence of benefit of thyroid ultrasounds and overdiagnosis and overtreatment remains a concern. Thyroid ultrasound should not be performed more than once every 3 years if baseline ultrasound does not show suspicious nodules. 

To date there is no evidence to suggest that treatment outcomes for individuals with germline DICER1 pathogenic variants differ from historical outcomes for the same diseases, although outcomes of therapy for the various tumours associated with DICER1 pathogenic variant have not been rigorously studied.

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Bibliography

Gonzalez, I. A., D. R. Stewart, K. A. P. Schultz, et al. 2022 "DICER1 tumor predisposition syndrome: An evolving story initiated with the pleuropulmonary blastoma." Mod Pathol 35(1): 4-22.

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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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