Primary Thyroid Neoplasm with Fetal Morphology Associated with DICER1 Mutations: Expanding the Diagnostic Profile of Thyroblastoma.

Introduction: Thyroblastoma, a primary thyroid neoplasm with histological features of primitive thyroid tissue has recently been described and is included as a distinct entity in the most recent edition of the World Health Organization (WHO) Classification of Tumors (5th edition). In this study, we expand the clinical, morphological, and molecular profile of this aggressive neoplasm. Patient Findings: The patients are females, 19 and 45 years of age, referred for large thyroid nodules. Tumor morphology is biphasic, composed of nests and follicles of epithelial cells, some with colloid-like secretions reminiscent of fetal thyroid follicles intertwined with a primitive stromal spindle cell component. By immunohistochemistry, the epithelial component is diffusely positive for PAX8 and TTF1 markers. Molecular studies showed DICER1 aberrations. Conclusion: A primary primitive thyroid malignancy reminiscent of early fetal embryology with no teratoid element, recently reported as thyroblastoma represents a unique entity, novel in its description, and is likely underdiagnosed.

The prevalence of germline DICER1 pathogenic variation in cancer populations.

BACKGROUND: The DICER1 syndrome is an autosomal dominant tumor-predisposition disorder associated with pleuropulmonary blastoma, a rare pediatric lung cancer. Somatic missense variation in "hotspot" codons in the RNaseIIIb domain (E1705, D1709, G1809, D1810, E1813) is observed in DICER1-associated tumors. Previously, we found the prevalence of germline pathogenic DICER1 variation in the general population is 1:10,600. In this study, we investigated the prevalence of pathogenic DICER1 germline variation in The Cancer Genome Atlas (TCGA; 32 adult cancer types; 9,173 exomes) and the Therapeutically Applicable Research to Generate Effective Treatment (TARGET; two pediatric cancer types; 175 exomes) cohorts. METHODS: All datasets were annotated and binned into four categories: pathogenic, likely pathogenic, variant of unknown significance, or likely benign. RESULTS: The prevalence of DICER1 pathogenic variants was 1:4,600 in TCGA. A single participant with a uterine corpus endometrial carcinoma harbored two pathogenic germline DICER1 (hotspot and splice-donor) variants, and a single participant with a rectal adenocarcinoma harbored a germline DICER1 stop-gained variant. In the smaller TARGET dataset, we observed no pathogenic germline variants. CONCLUSION: This is the largest comprehensive analysis of DICER1 pathogenic variation in adult and pediatric cancer populations using publicly available data. The observation of germline DICER1 variation with uterine corpus endometrial carcinoma merits additional investigation.

Type I pleuropulmonary blastoma: pathology and biology study of 51 cases from the international pleuropulmonary blastoma registry.

Pleuropulmonary blastoma (PPB) is a malignant neoplasm of the lung that presents in early childhood. The early form of the disease, cystic type I PPB, can be clinically and pathologically deceptive because of its resemblance to some developmental lung cysts. This study reviews 51 cases of type I PPB and 6 lung cysts from relatives of children with PPB. Type I PPB is a delicate multilocular cyst with variable numbers of primitive mesenchymal cells beneath a benign epithelial surface. Rhabdomyoblasts and cartilage nodules are seen in 49% and 40% of cases, respectively. Tumors in the youngest subset of patients, from birth to 2 months of age, are more uniform in composition and cellularity compared with those in older groups. Early tumors have a subtle transition between normal developing lung and tumor, showing bland interstitial mesenchymal cells uniformly expanding the alveolar septa. Presumed regressive changes including cyst wall necrosis are common. This phenomenon may explain the variable and sometimes sparse tumor cellularity seen in some type I PPBs. On a biologic level, this process supports the concept that not all type I PPBs are fated to progress to a type II or III PPB. Factors that control the balance between progression and regression may be important in predicting tumor behavior and determining which patients will benefit from adjuvant chemotherapy. In the meantime, recognition of this lesion as a neoplasm with malignant potential rather than a developmental cystic malformation is vital so the child can receive complete excision and appropriate follow-up care.