DICER1 – risk management (adult)

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, cystic nephroma, multinodular goitre and certain rare types of ovarian tumours (see table).^r

• Unaffected known or obligate DICER1 gene pathogenic variant carrier age 18 years and over.
• Individual age 18 years and over at 50% risk of inheriting a DICER1 gene pathogenic variant.

Exclusion criteria

• A DICER1 gene pathogenic variant carrier already diagnosed with a relevant cancer/tumour.
• 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.

Cancer/tumour type	Risk for DICER1 pathogenic variant carrier	General population risk
Any neoplasm (cancer/tumour)	By age 30 years: 12.4%r* By age 60 years: 31.5%r*	By age 30 years: 0.9%^ By age 60 years: 11.8%^
Female reproductive tract  (Sertoli-Leydig cell tumour of the ovary; cervix embryonal rhabdomyosarcoma)	Unknown but increased	Unable to obtain
Thyroid cancer	Unknown but increased	By age 70 years: 0.94%^

* The published data on risk of any cancer/tumour by Stewart et al^r is based on small numbers and has significant ascertainment bias.
^ 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 general cancer risks 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 excessive sun exposure.

Cancer/tumour type	Recommendations
		Age	Strategy and frequency
Pleuropulmonary blastoma (PPB)	Surveillance	Prenatally	Consider third-trimester US for foetus at 50% risk to detect large lung cysts that might require intervention soon after delivery
Female reproductive tract	Surveillance	From age 8 years to age 40 years	Consider annual US of the ovaries** (See evidence section below)
	Education	Potential signs and symptoms of menstrual irregularities
Thyroid	Surveillance	From age 8 years to age 40 years	Annual clinical examination Consider 3 yearly thyroid US (See evidence section below)
CNS	Surveillance	No evidence of benefit for screening
General	Education	Potential signs and symptoms of DICER1-associated tumours***

Abbreviation: US - ultrasound
** 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
*** 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

Enrolment in clinical trials and participation in the International Pleuropulmonary Blastoma/DICER1 Registry is encouraged whenever possible. In at-risk pregnant women, third trimester ultrasound should be considered to investigate pleuropulmonary blastoma in the foetus.^r

• Pleuropulmonary Blastoma DICER1 Syndrome Study opens in a new tab or window
• DICER1-related Pleuropulmonary Blastoma Cancer Predisposition Syndrome: A Natural History Study opens in a new tab or window
• The International Pleuropulmonary Blastoma/DICER1 Registry opens in a new tab or window
• DICER1 Syndrome Information Network opens in a new tab or window

A consensus of expert opinion regarding surveillance consideration was proposed,^r however there is currently no published evidence on the benefit of screening in adults with a DICER1 pathogenic variant.

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 with ~95% of cases being diagnosed before age 40 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.

Read 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.

Version 6

Date	Summary of changes
19/01/2024	Document reviewed at July 2023 paediatric cancer genetics reference committee meeting. Discussions continued via MS Teams. Approved for publication with the following changes made:  New eviQ cancer genetics risk management template changes applied - PDF of changes Summary: minor wording changes Target population: minor wording changes Lifetime risk of cancer/tumour: general population risk updated with AIHW 2019 data Evidence - Female reproductive tract section: minor wording changes. Version increased to V.6. Approved on 11/01/2024, changes published on 19/01/2024. Review in 2 years.
17/09/2024	Review due date updated as per consensus of the eviQ cancer genetics chairs.
20/02/2025	Accordion heading changed to "Risk of cancer/tumour". Per consensus of the eviQ cancer genetics chairs, footnote added below the table stating that the data for risk of all cancers/tumours is based on small numbers and has significant ascertainment bias.

Version 5

Date

Summary of changes

13/02/2023

The following sections of the document were updated to align with the new eviQ cancer genetics risk management template: Summary: template sentence updated Target population: added to exclusion criteria "Individual with a variant of uncertain significance" Cancer/tumour risk management guidelines: template sentence updated and lifestyle factors sentence moved above table Version number increased to V.5.

Version 4

Date

Summary of changes

22/12/2021

Protocol reviewed by paediatric cancer genetics reference committee at the July 2021 meeting. Discussions continued via email and MS Teams. Approved for publication with the following changes made: Lifetime risk of cancer table: risk for general population updated to include AIHW 2017 data Cancer risk management guidelines: table added Evidence for risk management guidelines: Paragraph added for female reproductive tract surveillance Paragraph added for thyroid surveillance. Version number increased to V.4. Approved on 22/12/2021, changes published on 28/02/2022. Review in 2 years.

Version 3

Date	Summary of changes
24/10/2019	Protocol reviewed by CG reference committee. Approved for publication with the following changes made: Lifetime risk of cancer: section reviewed to align with new protocol ID 3653 DICER 1 - risk management (child). Risk of cancer/tumour table added References: new reference added Stewart et al 2019 "Mutation" changed to "pathogenic variant" throughout document for consistency among eviQ cancer genetics protocols per agreement among the cancer genetics reference committees' chairs. Definition of "pathogenic variant" added as a pop-up Version number increased to V.3. Review at next scheduled review.
18/12/2020	The following sections of the protocol were updated to align with the revised eviQ cancer genetics risk management template: Lifetime risk of cancer table: risk for general population updated to include AIHW 2016 data Cancer risk management guidelines: heading changed to "Cancer/tumour risk management guidelines" Support and information: template wording updated.

Version 2

Date	Summary of changes
03/07/2019	Protocol ID 1911 - Risk management for DICER1 syndrome taken to the Nov 2018 RCM for review. Decision was made to divide ID 1911 into two separate protocols - adults and children. Therefore, this protocol (adults) developed and approved for publication.  Published as version 1. To be reviewed in two years.
28/08/2019	Protocol title changed from 'Risk management for DICER1 syndrome (adults)' to 'DICER1 – risk management (adult)' in accordance with Cancer Genetics Reference Committees' consensus. Version number increased to V.2.

As ID 3569 replaces an existing approved protocol (ID 1911), it's history section is also included below for consistency in documentation.

ID 1911 - Risk management for DICER1 syndrome
Date	Summary of changes
29/04/2016	New protocol discussed at March 2016 cancer genetics reference committee meeting. Approved and published on eviQ. Review second yearly.
31/05/2017	Transferred to new eviQ website. Version number changed to V.2.