Macrofollicular Variant of Follicular Thyroid Carcinoma: A Rare Underappreciated Pitfall in the Diagnosis of Thyroid Carcinoma.

Background: Follicular-patterned thyroid nodules predominantly composed of macrofollicular structures without nuclear atypia are generally regarded as benign (i.e., hyperplastic nodules or follicular adenomas). In line with this concept, fine-needle aspiration cytology (FNAC) also assigns a benign connotation to the presence of macrofollicular structures, unless thyrocytes present papillary thyroid carcinoma (PTC)-related nuclear features that raise the possibility of a macrofollicular variant of PTC. However, cases showing macrofollicular architecture, capsular invasion, and no PTC features can also be observed. Methods: We describe the clinical, cytological, histological, and molecular genetic features of four cases of encapsulated follicular neoplasms that presented histologically with a predominant (>70%) macrofollicular architecture, but which also showed clear signs of capsular invasion, and thus were classified as macrofollicular variant of follicular thyroid carcinoma (MV-FTC). Results: Cytologically, macrofollicular structures were identified in all cases, leading to a benign FNAC diagnosis in three of the four cases. Due to increasing nodule size, thyroidectomy was performed in all cases. Histology showed focal and limited capsular invasion, without vascular invasion. Next-generation sequencing (custom 394 gene panel) of each tumor compared with matched normal DNA revealed a total of 7 somatic variants, including dual (likely biallelic) mutations in the DICER1 gene in 2 patients. The clinical outcome was excellent in all cases. Conclusions: Similar to the classical minimally invasive follicular thyroid carcinoma, MV-FTC appears to behave indolently. MV-FTC has a high rate of false-negative FNAC results, but MV-FTC is very rare (<0.05% of all thyroidectomies) and apparently has an indolent behavior. Further studies comprising larger series are necessary to better clarify the biology of this diagnostically challenging rare tumor.

Extensive biliary intraepithelial neoplasia (BilIN) and multifocal early intrahepatic cholangiocarcinoma in non-biliary cirrhosis.

Biliary intraepithelial neoplasia (BilIN), a preneoplastic condition that may precede invasive intrahepatic cholangiocarcinoma (ICC), has been compared to pancreatic intraepithelial neoplasia (PanIN), a precursor lesion of pancreatic carcinoma. Biliary tract carcinoma development and progression is associated with several gene alterations, but BilIN lesions have yet to be studied in detail by molecular techniques. We describe a case of extensive intrahepatic biliary dysplasia, with lesions ranging from BilIN-1 to BilIN-3 lesions, and multifocal microscopic ICC in hepatitis C virus (HCV)- and alcohol-related cirrhosis. The small ICC foci had remained undetected prior to transplantation. Fluorescence in situ hybridization (FISH) analysis was performed on three foci of BilIN-3 lesions and on three microinvasive ICC foci with a combination of three FISH probes directed against genes frequently altered in pancreatic and biliary tract carcinomas. FISH analysis revealed a CDKNA2 heterozygous deletion in one BilIN-3 focus, and in one non-contiguous ICC focus, although the deletion was just above the chosen threshold. No deletions were detected in the genomic regions encoding TP53 and SMAD4. This report documents for the first time the development of multifocal ICC in the setting of extensive biliary dysplasia in a patient with three risk factors, HCV infection, alcohol abuse, and cirrhosis, and suggests heterogeneous carcinogenesis in ICC and possible involvement of the CDKNA2 gene.

Macrofollicular variant of follicular thyroid carcinoma: a clinical, cytologic, morphologic, and image analysis study of a unique case.

Thyroid lesions composed of large follicles that contain abundant colloid are usually regarded as benign hyperplastic or adenomatous nodules both by fine-needle aspiration cytology and histology. In such cases, the pathologist is less likely to request a complete inclusion of the capsule into paraffin block and to look for vascular and/or capsular invasion, the only criteria that permit the differential diagnosis between a benign nodule and a follicular carcinoma. We report the first case of a follicular thyroid carcinoma composed predominantly (>90%) of macrofollicles with a surface area that was up to 5 times larger than the surface area of normal follicles, as calculated with an image analysis system. Capsular invasion was detected in 2 separate foci. The tumor was classified as a minimally invasive follicular carcinoma, macrofollicular variant. This case is detailed to highlight the potential pitfall that may arise from an incomplete histological analysis of a macrofollicular lesion, with particular attention paid to the differential diagnoses.