Benign Neoplasms of the Thyroid Gland

Gross Findings

FAs are usually solitary, well demarcated, and encapsulated masses identified in one lobe or in the isthmus ( Fig. 24.1 ). The capsule is usually thin but distinct ( Fig. 24.3 ); a thick capsule should raise suspicion for a follicular carcinoma. Adenomas are usually round to spherical, measuring about 1 to 3 cm on average, although this may be quite variable depending on clinical presentation (palpable versus incidental radiographic feature). The cut surface is rubbery to firm with a homogeneous solid appearance. Gray-white lesions are usually more cellular, while brown-tan lesions tend to have more colloid. Cystic change, degeneration, calcification, and infarction are common and may alter the physical appearance. The oncocytic adenoma (10% to 15% of FAs) tends to have a mahogany-brown cut surface with central scarring.

Thoroughly sampling the capsule for invasion (capsular or lymphovascular) is critical, as invasion leads to a diagnosis of follicular carcinoma rather than FA. It is our practice to submit the whole periphery. If this is not feasible, a minimum of three sections per 1 cm of tumor diameter should be submitted. If the tumor looks macroscopically homogeneous after being bivalved, then the center of the tumor is of less interest and should be sampled only representatively. The tumor is serially sectioned perpendicular to the capsule, making 2- to 3-mm thick sections. Then the very periphery of the tumor to capsule to parenchymal interface is embedded. As many as five sections, 3 mm thick and 2.5 cm long, can be placed side by side in the cassette. With this technique, most tumors can be placed in fewer than 10 blocks, allowing for complete evaluation of the capsule ( Fig. 24.4 ).

Microscopic Findings

A well-defined, variably thick fibrous connective tissue capsule encloses the neoplastic cells, separating them from the compressed or atrophic thyroid parenchyma ( Figs. 24.5 and 24.6 ). If the capsule is very thick, additional sections should be evaluated to exclude a carcinoma. Small to medium-sized smooth muscle–walled vessels can usually be seen within the fibrous connective tissue ( Fig. 24.7 ). A reticulin or elastic stain can highlight fibers in a true capsule. Invasion is absent by definition, although entrapped epithelium can be seen. FNA may result in iatrogenic defects in the capsule, but these are usually associated with a linear tract, extravasated erythrocytes, hemosiderin-laden macrophages, “reactive” fibrosis, and endothelial hyperplasia ( Fig. 24.8 ). The site of puncture often has a “sharp edge” of transgression, suggesting a mechanical device rather than biologic aggression.

The cells are arranged in a variety of patterns with a variable amount of colloid, usually distinctive from the surrounding parenchyma. While the patterns of growth have been given “type” or “variant” designations (normofollicular [ Fig. 24.9 ], macrofollicular, microfollicular, fetal, embryonal, solid, trabecular [ Fig. 24.10 ], spindled [ Fig. 24.11 ], insular, organoid, papillary), these terms are of no clinical consequence. The follicles are usually uniform with a single architectural pattern predominating. Colloid may be highlighted by a periodic acid–Schiff (PAS) stain if it is limited. Delicate capillaries are easily identified, but intratumoral fibrosis is uncommon. The cells are monotonous and only slightly enlarged. There is a low nuclear:cytoplasmic ratio with well-defined cell borders in the cuboidal to columnar cells. The nuclei are usually aligned in an orderly arrangement along the basal aspect of the cell. Ample cytoplasm, ranging from eosinophilic, oncocytic ( Fig. 24.12 ), amphophilic, granular to clear, or signet-ring ( Fig. 24.13 ), surrounds round and regular nuclei with a coarse to heavy nuclear chromatin distribution. Nucleoli are inconspicuous, although they may be prominent and centrally placed in an oncocytic FA ( Fig. 24.12 ). Profound nuclear pleomorphism may be seen but is usually focal ( Fig. 24.12 ). Mitotic figures are generally inconspicuous but may be increased, particularly in the post-FNA setting. Degenerative and cystic changes include edema, fibrosis, hemorrhage, cyst formation, and calcification, but tumor necrosis is not identified. Infarction, especially in oncocytic tumors, may be associated with prior FNA or decreased blood supply. Viable tumor cells may be limited to the periphery. Fat is rarely noted (lipid-rich adenoma) within the tumor cells and presents as intracytoplasmic, oil red O–positive vesicles ( Fig. 24.14 ). This is distinct from lipoadenoma, in which mature fat is interspersed between the follicular epithelial cells ( Fig. 24.15 ). Squamous metaplasia may be seen but is more common in papillary carcinoma.

Oncocytic (oxyphilic, Hürthle cell, Ashkenazi cell) adenoma typically has less colloid production, frequently resulting in inspissated colloid that can mimic psammoma bodies ( Figs. 24.12 and 24.16 , left). Tumor cells tend to have a greater degree of nuclear atypia ( Fig. 24.12 ), with vesicular nuclear chromatin, nuclear contour irregularity, and prominent nucleoli. The cytoplasm is eosinophilic and granular. However, oncocytic adenoma is a histologic description only and does not imply a different biologic potential. To be qualified as a clear cell variant , the tumor should be predominantly or exclusively composed of cells with clear cytoplasm ( Fig. 24.13 ). The nuclei are usually centrally situated and are hyperchromatic. Signet-ring cell adenoma is extremely rare but has cells with large intracytoplasmic vacuoles, which compress the nucleus to the side ( Fig. 24.13 ). These vacuoles contain diastase-resistant PAS-positive material, which is strongly thyroglobulin-immunoreactive, suggesting an abnormal thyroglobulin accumulation. Metastatic adenocarcinoma may rarely give a similar histologic appearance.

Immunohistochemical Findings

Immunohistochemistry is seldom necessary for the diagnosis, but in cases where the diagnosis is in question, the neoplastic cells will be immunoreactive to thyroglobulin ( Figs. 24.11, 24.13, and 24.16 ), TTF1 ( Figs. 24.11 and 24.14 ), PAX8, and keratin (CAM5.2, AE1/AE3, CK7). Oncocytic tumors must be interpreted with caution owing to high background and nonspecific staining.

Fine Needle Aspiration

FNA is the first-line evaluation technique. Unfortunately FNA does not reliably distinguish between a cellular and a dominant adenomatoid nodule, FA, or follicular carcinoma with any degree of certainty or reproducibility. After adequacy is assessed (five or six follicular epithelial groups of at least 10 epithelial cells per group), a follicular neoplasm may be favored over an adenomatoid nodule (colloid goiter). Features that favor a neoplasm are syncytial groups with a microfollicular arrangement in a cellular smear in which there is increased cellularity compared with the amount of colloid and uniform, monotonous cells that vary little from one another ( Fig. 24.17 ). The epithelial groups are arranged as small spherical aggregates surrounding a colloid droplet. Oncocytic adenomas have large polygonal cells with granular cytoplasm. The nucleoli tend to be more prominent. Adenomatoid nodules tend to have cellular variability and often show extensive degenerative changes. The diagnosis of “follicular neoplasm” or “suspicious for a follicular neoplasm” will result in appropriate surgery for a solitary thyroid mass (equivalent to Bethesda System for Reporting Thyroid Cytopathology category IV).

Intraoperative Frozen Section

Intraoperative consultation cannot reliably separate FA from follicular carcinoma because extensive sampling is needed to exclude invasion; therefore it is not helpful, and should be deferred.

Genetics

Numerical chromosome changes can be seen, with trisomy 7 seen in some 15% of FAs, while tetrasomy is seen in about 45% of oncocytic adenomas. Translocations involving 2p21 ( THADA ) and 19q13 ( ZNF331-RITA ) are seen in approximately 10% and 20%, respectively, of FAs. The PAX8-PRARγ rearrangement, characteristic of follicular carcinoma, is also found in less than 10% of FAs. PAX8-PRARγ -rearranged tumors often have thickened capsules, a feature worrisome for malignancy. Infrequent TERT promoter mutations have been associated with atypia and aggressive behavior. Thus, PAX8-PRARγ -rearranged and TERT -mutated FAs may represent follicular carcinoma precursors or, in some cases, undersampled follicular carcinomas. In these cases, more extensive sampling to identify invasion is advocated.

Activating point mutations of RAS genes (specifically NRAS and HRAS ) are most prevalent and detected in about 20% to 30% of cases overall, but they are less common in oncocytic adenomas. RAS mutations are not restricted to FA and occur in all types of thyroid neoplasms, including follicular, papillary, and medullary carcinomas and even occasionally in nodular hyperplasia. Somatic mutations in mitochondrial DNA (mtDNA) are found in oncocytic tumors. Thyroid-stimulating hormone (TSH) receptor gene mutations have been described in hyperfunctioning “toxic” adenomas.