The term goiter encompasses both nodular and diffuse enlargement of the thyroid, and clinically can be divided into toxic and nontoxic variants based on the clinical symptoms and thyroid function tests (hypothyroid, euthyroid, or hyperthyroid) and isotope uptake on scintigraphy [16, 17].

The cytology specimen from a benign nodule shows (depending upon the preparation method) abundant watery colloid, small, round to oval shaped follicular cells with scant cytoplasm (may contain small blue lysosome granules) and dark nuclei arranged in monolayer sheets, groups with follicle formation or as single cells [18] (Fig. 30.1). Macrophages are usually present and their number depends upon the presence or absence of degenerative changes or a cystic component [18, 19]. The aspirates from a hyperplastic/adenomatoid nodule tend to be more cellular and contain an admixture of follicular cells and oncocytic cells arranged in monolayer sheets in a background of watery colloid and macrophages [18–20].

Solitary papillary hyperplastic nodules frequently occur in children and teenagers and can be hyper-functioning on radionuclide scan. By histologic examination these lesions are encapsulated and often demonstrate cystic change, papillary architecture and the lesional cells lack nuclear cytology of papillary thyroid carcinoma [21, 22]. The FNA specimens of solitary papillary hyperplastic nodules tend to be cellular and show papillary clusters, nuclear atypia and pleomorphism, nuclear grooves, multinucleated giant cells, and cells with vacuolated cytoplasm. In view of these features, some of these cases could be misclassified as “suspicious of” or consistent with papillary carcinoma [23].

Papillary thyroid carcinoma (PTC) is the most common form of thyroid malignancy in non-endemic goiter regions. The classic variant of papillary carcinoma predominantly consists of true papillae, i.e., finger like projection with cores containing vessel(s) and connective tissue surrounded by tumor cells. The papillae are of different sizes and can display a complex branching pattern. It is not uncommon to encounter a few follicles intermixed with papillae in this variant of PTC. Minor cystic changes are common. By light microscopy, the tumor cells are larger and are cuboidal to short columnar and contain amphophilic to slightly eosinophilic cytoplasm. Nuclei are relatively large and oval in shape and show nuclear indentations/grooves and round intranuclear cytoplasmic pseudoinclusions. Nucleoli are usually small and situated close to the nuclear membranes (eccentric), and much of the interior of the nucleus to be “empty,” “clear,” or “ground glass” in appearance. Follicles may be colloid-filled or empty and occur as small or large follicles , i.e., micro- or macro-follicles [49].

The cytology diagnosis of PTC is based on major and minor cytologic criteria. The major diagnostic feature is the characteristic nuclear morphology regardless of cytoplasmic features and architecture. The FNA specimen of PTC is usually cellular and shows tumor cells arranged in papillary groups, three-dimensional clusters or as single cells in a background of watery or thick “ropy” colloid (i.e., chewing gum colloid), nuclear or calcific debris, macrophages and stromal fragments. The cell groups may show a typical concentric arrangement of lesional cells described as “cellular swirls” [5, 50].

The individual tumor cells are enlarged, elongated, i.e., oval in shape with eosinophilic cytoplasm (cytoplasmic eosinophilia is common in Romanowsky stained preparations but is usually indistinct in alcohol-fixed Papanicolaou stained preparations; this also holds true for monolayer preparations). The nuclei show elongation, membrane thickening, chromatin clearing, grooves, and inclusions. The nucleoli are usually small and eccentric. Intranuclear grooves and inclusions can be seen in other benign and malignant conditions of the thyroid (Fig. 30.4). These include Hashimoto’s thyroiditis , nodular goiter , hyalinizing trabecular neoplasm , oncocytic follicular tumors , and medullary carcinoma [22, 51].

Psammoma bodies occur in about 20 % of cases of papillary thyroid carcinoma. These are lamellated round to oval calcified structures that represent the “ghosts” of dead papillae. Multinucleated histiocytes are common in FNA specimens of papillary thyroid carcinoma [52, 53]. The cytologic features of papillary thyroid carcinoma may not be readily evident in monolayer preparations [54].

The follicular variant of papillary thyroid carcinoma (FVPTC) is the second most common variant of PTC. Its diagnosis may be made when more than 70 % of the tumor consists of neoplastic follicles lined by cells demonstrating diagnostic nuclear morphology of PTC. Three distinct types of follicular variant exist represented by: the infiltrative type, the diffuse follicular variant, and the encapsulated follicular variant. The encapsulated FVPTC is characterized by the presence of a capsule around the lesion and is associated with an excellent prognosis. In some cases the diagnosis of this particular variant of papillary carcinoma can be difficult due to the presence of multifocal rather than a diffuse distribution of nuclear features of papillary thyroid carcinoma . Because of this peculiar morphologic presentation, these tumors can be misdiagnosed as adenomatoid nodule or follicular adenoma. Due to their excellent prognosis, the noninvasive forms of FVPTC are now recommended to be designated as noninvasive follicular tumor with papillary like nuclei—NIFTP, i.e., neoplasms but not carcinomas [39].

The cytologic interpretation of FVPTC can be challenging due to a paucity of diagnostic nuclear features [55]. The cytologic samples from FVPTC usually show enlarged follicular cells arranged in monolayer sheets and follicular groups in a background of thin and thick colloid. The individual tumor cells show nuclear elongation, chromatin clearing and thick nuclear membranes. The intranuclear grooves in FVPTC are delicate and do not traverse the entire length of nucleus; however, nuclear grooves and inclusions are very scarce. Thus, a majority of cytologic samples of FVPTC are diagnosed as either follicular neoplasm or suspicious for papillary carcinoma [56, 57].

Cystic papillary thyroid carcinomas are often encapsulated and the cystic component usually ranges from 50 % to occupying most of the lesion. The papillary fronds lining the cyst wall may be visible on gross examination. FNA specimens of this tumor contain large numbers of hemosiderin-laden histiocytes and considerable cellular debris. Sheets of intact follicular cells may be seen, which resemble those from cellular adenomatoid nodules; however, these will demonstrate nuclear cytology suspicious or diagnostic of PTC. Squamous metaplasia has been reported in cases of cystic PTCs. Dense globules of pink-staining colloid may be present [58–60].

Tall cell variant of papillary thyroid carcinoma is an aggressive form of PTC and can lead to multiple local recurrences, distant metastases and even death. This tumor shows oncocytic cells which are at least three times as tall as their width [61]. The cytologic samples from this tumor contain elongated cells with sharp cytoplasmic borders, granular eosinophilic cytoplasm, and variably sized nuclei with nuclear features of papillary carcinoma [62, 63]. The diagnostic nuclear features of PTC are readily found in aspirates of this variant. The intranuclear inclusions can be multiple within the same nucleus giving rise to a “soap-bubble-like” appearance [63].