Endocrinology · Medical Literature
DICER1 alterations in thyroid lesions: a systematic review and meta-analysis with clinicopathologic implications.
Abstract
DICER1 is a key RNase III endoribonuclease involved in microRNA biogenesis and is implicated in both constitutional DICER1-related tumor predisposition and sporadic thyroid tumorigenesis. In thyroid pathology, DICER1 alterations have been reported across a broad spectrum of lesions, but their reported frequency and clinicopathologic significance vary substantially across published series. We performed a systematic review of thyroid-focused studies published between 2020 and 2025. Studies were included in the quantitative synthesis only if they provided an interpretable lesion-level numerator and denominator for thyroid lesions harbouring DICER1 alterations. Additional thyroid-focused studies that refined the cytomorphologic, histologic, and lesion-spectrum interpretation of DICER1-associated thyroid disease, but lacked a suitable denominator for prevalence meta-analysis, were retained for qualitative clinicopathologic synthesis. Random-effects meta-analysis of logit-transformed proportions was used for the quantitative component. Seven studies met criteria for quantitative synthesis, comprising 16,831 thyroid lesions, of which 317 were reported as DICER1-altered. Study-level proportions ranged from 1.4% in a large adult consecutive molecular-testing cohort to 22.0% in a pediatric follicular-patterned tumor cohort. The pooled proportion of thyroid lesions harbouring DICER1 alterations was 5.76% (95% CI, 2.49%-12.78%), with substantial heterogeneity (I² = 96.94%). Exploratory stratification showed lower pooled proportions in predominantly adult cohorts and higher pooled proportions in pediatric or young-enriched cohorts. Qualitative synthesis showed that DICER1 alterations occur across a wide thyroid lesion spectrum, including multinodular and follicular nodular disease, follicular adenoma, NIFTP, follicular thyroid carcinoma, follicular-patterned papillary thyroid carcinoma, and rare higher-grade or primitive malignant tumors such as thyroblastoma. Cytologically and histologically, these lesions frequently show follicular-patterned architecture, often with macrofollicular or mixed follicular growth and relatively bland nuclear features.Seven studies met criteria for quantitative synthesis, comprising 16,831 thyroid lesions, of which 317 were reported as DICER1-altered. Study-level proportions ranged from 1.4% in a large adult consecutive molecular-testing cohort to 22.0% in a pediatric follicular-patterned tumor cohort. The pooled proportion of thyroid lesions harbouring DICER1 alterations was 5.76% (95% CI, 2.49%-12.78%), with substantial heterogeneity (I² = 96.94%). Exploratory stratification showed lower pooled proportions in predominantly adult cohorts and higher pooled proportions in pediatric or young-enriched cohorts. Qualitative synthesis showed that DICER1 alterations occur across a wide thyroid lesion spectrum, including multinodular and follicular nodular disease, follicular adenoma, NIFTP, follicular thyroid carcinoma, follicular-patterned papillary thyroid carcinoma, and rare higher-grade or primitive malignant tumors such as thyroblastoma. Cytologically and histologically, these lesions frequently show follicular-patterned architecture, often with macrofollicular or mixed follicular growth and relatively bland nuclear features. DICER1 alterations are uncommon in large unselected adult thyroid cohorts but enriched in pediatric, young-adult, and follicular-patterned settings. They should not be interpreted as isolated lesion-specific markers. Rather, their diagnostic significance lies in the integration of molecular findings with lesion type, cytomorphology, histology, patient age, and clinical context, including the selective recognition of cases in which constitutional DICER1-related tumor predisposition should be considered.
Clinical relevance
What is the pooled prevalence of DICER1 alterations across the spectrum of thyroid lesions in studies published between 2020 and 2025, and what are the associated clinicopathologic implications for diagnosis, lesion classification, and germline risk stratification? __SNAPSHOT__ {"studyDesign":"Systematic review with random-effects meta-analysis of proportions (logit-transformed) for the quantitative component, plus qualitative clinicopathologic synthesis for studies lacking a suitable denominator","setting":"International; multi-institutional published series (2020–2025); no single country or center specified","sampleSize":"Quantitative synthesis: n = 16,831 thyroid lesions across 7 studies, of which 317 were DICER1-altered. Additional studies retained for qualitative synthesis (exact number not reported in available abstract).","population":"Thyroid lesions across the full diagnostic spectrum — including multinodular and follicular nodular disease, follicular adenoma, NIFTP, follicular thyroid carcinoma, follicular-patterned papillary thyroid carcinoma, and rare higher-grade or primitive entities — spanning pediatric, young adult, and adult cohorts","intervention":"Detection and characterization of DICER1 alterations (germline and/or somatic) via molecular testing (e.g., next-generation sequencing panels, targeted hotspot analysis) applied to thyroid lesion specimens","comparator":"Not applicable (single-arm prevalence meta-analysis); exploratory subgroup stratification by age cohort (predominantly adult vs. pediatric/young-enriched)","primaryOutcome":"Pooled proportion (prevalence) of thyroid lesions harboring DICER1 alterations at the lesion level","followUp":"Not reported (cross-sectional prevalence data from included studies; no prospective follow-up period defined)","fundingSource":"Not reported"}
Key findings
Seven studies met criteria for quantitative synthesis, comprising 16,831 thyroid lesions, of which 317 were DICER1-altered. The pooled proportion of thyroid lesions harboring DICER1 alterations was 5.76% (95% CI: 2.49%–12.78%), derived using random-effects meta-analysis of logit-transformed proportions. Heterogeneity was substantial (I² = 96.94%), indicating that the pooled estimate should be interpreted with caution as a central tendency rather than a reliable point estimate applicable across clinical contexts. Study-level proportions ranged widely: from 1.4% in a large adult consecutive molecular-testing cohort to 22.0% in a pediatric follicular-patterned tumor cohort, reflecting the strong influence of patient age and lesion selection on observed prevalence. NNT/NNH: not applicable to this prevalence meta-analysis. Adverse events or oncologic outcomes: not formally analyzed in the quantitative component. Qualitative synthesis identified DICER1 alterations across a broad thyroid lesion spectrum including multinodular and follicular nodular disease, follicular adenoma, NIFTP, follicular thyroid carcinoma, follicular-patterned papillary thyroid carcinoma, and rare higher-grade or primitive entities (e.g., pediatric poorly differentiated thyroid carcinoma, thyroblastoma). Histomorphologic correlates in included source studies (synthesized qualitatively) included macrofollicular growth pattern, atrophic cellular changes, and papillary excrescences, predominantly in younger patients. Cytomorphologic features on FNA were frequently banal (bland nuclei, abundant colloid, macrofollicular architecture), often yielding Bethesda category II classifications, which may result in under-detection of DICER1-altered lesions on cytology alone. No comparative statistical outcomes (e.g., odds ratios, hazard ratios, malignant transformation rates) were reported in the available abstract.
Practice implications
This meta-analysis establishes that DICER1 alterations occur across the full morphologic spectrum of thyroid lesions, from benign follicular nodular disease to rare aggressive entities such as thyroblastoma and pediatric poorly differentiated thyroid carcinoma. The overall pooled prevalence of approximately 5.76% is heavily context-dependent: it is substantially lower (~1.4%) in unselected adult molecular-testing cohorts and substantially higher (~22%) in enriched pediatric or young-adult follicular-patterned tumor cohorts. This heterogeneity (I² = 96.94%) precludes application of a single prevalence figure across clinical settings and underscores the importance of patient age, referral pattern, and lesion selection in interpreting any local prevalence. The study did not establish malignant risk stratification thresholds, predictive validity of DICER1 alteration for histologic outcome, or survival/recurrence outcomes — these remain to be addressed in prospective or outcomes-focused studies. The qualitative synthesis corroborates emerging evidence that DICER1-altered lesions are frequently cytomorphologically bland on FNA and may be systematically under-classified as benign (Bethesda II), highlighting a diagnostic gap in routine cytopathology. Clinically, detection of a somatic DICER1 hotspot mutation — particularly with a high variant allele frequency suggestive of germline origin — should prompt consideration of germline testing and evaluation for DICER1 syndrome, especially in patients younger than 40 years, those with multinodular disease, or those with a family history of DICER1-related neoplasms. Patients not well-represented include those with purely sporadic adult-onset solitary nodules outside enriched molecular-testing programs, and populations outside the geographic and institutional distribution of the seven included studies. Because only the abstract was available, the full risk-of-bias assessment, funnel plot analysis, and detailed subgroup methodology could not be reviewed; this limits certainty in the reported estimates. __LIMITATIONS__ Extreme heterogeneity (I² = 96.94%) renders the pooled prevalence of 5.76% an unreliable summary estimate for direct clinical application; study-level variation (1.4%–22.0%) reflects fundamentally different populations and testing strategies rather than a single estimable parameter.,Only seven studies met quantitative inclusion criteria, limiting statistical power and the ability to perform robust subgroup or meta-regression analyses.,Inclusion restricted to studies published 2020–2025 may exclude foundational prevalence data from earlier series, potentially introducing temporal selection bias.,Lesion-level (rather than patient-level) denominators introduce potential for outcome unit mismatch across studies with different counting conventions (e.g., multinodular glands counted as one vs. multiple lesions).,The study design is a prevalence meta-analysis and does not permit inference about DICER1 alteration as a driver of malignant transformation, recurrence, or survival.,Cytomorphologic and histologic data were synthesized qualitatively without quantitative pooling, limiting statistical rigor for these clinicopathologic correlations.,Generalizability is constrained by the geographic, institutional, and age-distribution composition of the included series, which may not reflect unselected community-based thyroid practice.,Funding source is not reported, precluding assessment of potential industry or institutional sponsorship bias.,Only an abstract (truncated) was available for this summary; full text including risk-of-bias tables, PRISMA flow diagram, and sensitivity analyses could not be reviewed, which limits the certainty of this appraisal. __BOTTOM_LINE_CATEGORY__ potentially_practice_informing __BOTTOM_LINE__ DICER1 alterations are present in approximately 5.76% of thyroid lesions across pooled studies (95% CI: 2.49%–12.78%), but prevalence varies dramatically by age cohort and lesion selection, making this estimate population-specific rather than universally applicable. Clinicians should recognize that DICER1-altered thyroid lesions are frequently cytomorphologically bland and may be under-detected on routine FNA, particularly in younger patients with macrofollicular or multinodular disease. Detection of a DICER1 alteration — especially with features suggesting germline origin — should trigger consideration of formal genetic evaluation for DICER1 syndrome, but this meta-analysis does not itself establish malignant risk thresholds or guide surgical decision-making.