Colloid goiter is usually caused by hyperplasia of the thyroid gland induced by iodine deficiency. Its histologic appearance varies with the developmental stage of the disease. In the early stages, the changes are bilateral and there is a diffuse enlargement of the gland, made up of small follicles. Later on, some of the follicles may become distended and may coalesce to form nodules, with diameters ranging from less than 1 mm to several centimeters. Degenerative changes, such as hemorrhage, necrosis, cysts (actually pseudocysts) and scar formation, often occur in the nodules. The process may involve the entire gland or it may occur focally and produce a solitary nodule. On the scintiscan, such change is often labeled a “cold nodule,” which is difficult to distinguish from a true neoplasm. For this reason, the colloid goiter is the lesion most often referred for aspiration.

The make-up of a needle aspirate from colloid goiter depends on the type of the lesion. The aspirate may be solid, semisolid, or fluid. Solid or semi-solid aspirates often consist of amber colored colloid which, in Papanicolaoustained smears, appears as pink homogeneous material, usually surrounded by a few follicular cells (see Fig. 30-1A) and in Diff-Quik-stained smears, appears bluish-violet. On drying, the colloid may form a typical cracked geometric pattern (see Fig. 30-1B). This type of colloid is derived from distended inactive follicles containing dense central colloid (see Fig. 30-1C). Occasionally, aspirates of colloid goiters yield smears of almost pure colloid with few follicular cells and/or macrophages. Although such smears do not meet the proposed criteria of adequacy because they contain very few follicular cells, they are, in our experience, diagnostic of colloid goiter.

In most cases, however, the smears also contain small cuboidal follicular cells, occurring either singly or in flat sheets wherein the small, spherical nuclei are evenly spaced and honeycomb-forming cytoplasmic borders may sometimes be recognized (Fig. 30-2A). “Naked” follicular cell nuclei are often seen scattered throughout the smear and should not be confused with lymphocytes, which they resemble (Fig. 30-2B). The nuclei of lymphocytes are usually slightly smaller and upon close inspection, usually are surrounded by a very thin rim of blue cytoplasm, at least on one side of the cell. Sometimes entire follicles may be seen in the form of spherical clusters of cells, sometimes with a central deposit of colloid (Fig. 30-3). Swedish observers consider squashed follicles, wherein cell borders cannot be clearly seen as “syncytial balls” and characteristic of colloidal goiter (Fig. 30-3C). In posthemorrhagic nodules or cysts, numerous macrophages, usually containing phagocytized hemosiderin granules, may be observed (Fig. 30-4).

An important source of error is clusters or sheets of spindle-shaped cells of the fibroblastic type. This finding suggests that fibrosis has occurred within the goiter. Sometimes, young, growing fibroblasts from an area of active fibrosis are markedly atypical, with enlarged, irregularly outlined nuclei that may contain large nucleoli and abundant basophilic cytoplasm with multiple cytoplasmic extensions (Fig. 30-5). Mitotic figures may also occur. The atypical fibroblasts may be mistaken for malignant cells and must be interpreted within the context of the clinical situation and other cytologic findings. It is of note that, very rarely, exuberant fibrosis may also occur in papillary thyroid carcinomas (Chan et al, 1991; Us-Krašovec and Golough, 1999).

A fairly high proportion of aspirations in colloid goiter yield variable amounts of fluid which usually indicates degenerative cystic changes (see below). The fluid may be clear, yellow, or brown in color, the latter indicative of a prior hemorrhage. Although the microscopic examination of the cyst fluid is seldom useful, it is mandatory because, occasionally, cystic thyroid carcinomas may masquerade as cystic goiters.

Over time, goiters often become nodular, sometimes in the form of a solitary nodule, usually arising from focal hyperplasia. Such nodules, often of adenomatous nature, usually cannot be reliably differentiated on clinical or ultrasonographic grounds from a “true” adenoma or carcinoma. As a general rule, smears from nonneoplastic nodules contain much colloid and few cells. By contrast, in aspirates from neoplastic lesions, there is little colloid and numerous cells. However, on rare occasions, aspirates of hyperplastic adenomatous nodules are also very cellular and may be very difficult to interpret. Certain features of the smears are sometimes helpful. Thus, the follicular cells tend to form a dispersed pattern in adenomatous goiter, rather than tight clusters or rosettes as in true adenomas. Also, “balls” of follicular cells, representing squashed whole follicles (see Fig. 30-3), are more characteristic of colloid goiter than of follicular adenomas. One has to gauge all these features in order to arrive at a correct interpretation. Although most cases are straightforward, the distinction between a hyperplastic adenomatous nodule and follicular neoplasm can be difficult, as it is in histological sections(Zacks et al, 1998; Busseniers and Oertel, 1993). In such cases, the interpretations and recommendations may include a course of suppression therapy with exogenous thyroid hormones or repeat FNA. If the mass does not regress, a surgical removal must be considered. In such a case, a scintiscan may be helpful. If the mass is “cold,” one would favor surgery rather than medical therapy, since a “cold” nodule would more likely be a true tumor.

This is the most common form of thyroiditis observed in clinical practice. It most often affects middle-aged women and is thought to be an autoimmune disease. Antithyroid antibodies are often elevated in this condition and thyroid function may be reduced, normal, or elevated. Both lobes of the thyroid are usually affected, diffusely enlarged and firm, but asymmetry may occur, with localized nodular enlargement (Wong and Wheeler, 2000). In histologic sections, the thyroid is infiltrated with lymphocytes that may also form lymph follicles with germinal centers (see Fig. 30-8D). The acini are often destroyed or atrophic (see Fig. 30-9D). A major component of the disease is the presence of oncocytes (Hürthle cells). The oncocytes may line glandular structures or form solid sheets of various sizes. The characteristic features of oncocytes, namely, abundant, eosinophilic, granular cytoplasm and large, often pyknotic nuclei of variable sizes, are usually well represented in Hashimoto’s thyroiditis (see Fig. 30-9C,D). Sometimes the Hürthle cells appear as single large cells in otherwise normal follicular epithelium. The term Askanazy cells is sometimes used to describe this feature. Rarely, psammoma bodies may be seen in Hashimoto’s thyroiditis (Dugan et al, 1987). Thyroid carcinomas and malignant lymphomas
may occur in Hashimoto’s thyroiditis. There is a misperception that malignant lymphoma is the most common tumor seen in Hashimoto’s thyroiditis. In fact, from 5% to 10% of patients with this disease will develop papillary carcinoma, and less than 1% develop malignant lymphoma (Carson et al, 1996).

A recently described clinical entity known as subchemical hypothyroidism with antibody-negative chronic thyroiditis, usually occurs in women with symptoms of fatigue, malaise, and hair loss (Wikland, et al, 2003; Wikland et al, 2001). These women often have negative physical examinations and medical work-ups, but are found to have chronic thyroiditis on FNA of their thyroid gland, if the astute clinician considers it in his or her differential diagnosis. The symptoms usually respond dramatically to oral levothyroxine.

The aspiration smears are characterized mainly by the presence of a mixture of lymphocytes and oncocytes or Hürthle cells in various proportions. In some cases, the aspirates are dominated by lymphocytes at various stages of maturation, and the smear may resemble an aspirate of a hyperplastic lymph node (Fig. 30-8A). Further search will usually reveal the presence of oncocytes and scattered follicular cells in clusters (Fig. 30-8B). We have observed a case of Hashimoto’s disease in which the pattern was mistaken for a metastatic carcinoma to lymph node (Koss et al, 1992). In other cases, the presence of oncocytes is dominant. In aspirates, these large cells form sheets or gland-like structures. The striking, abundant, eosinophilic and granular cytoplasm and the variability in nuclear sizes are characteristic (Fig. 30-9A,B). Sometimes the nuclei contain fairly large nucleoli, and, very rarely, intranuclear cytoplasmic inclusions (see Fig. 30-8C). Because of nuclear abnormalities, these cells can be mistaken for malignant cells. On further search, lymphocytes and follicular thyroid cells can be observed. On rare occasions, the follicular cells in clusters may mimic a papillary carcinoma (MacDonald and Yazdi, 1999). Still less common is the presence of psammoma bodies (Dugan et al, 1987). These, fortunately very rare findings, may lead to an erroneous diagnosis of papillary carcinoma.

As a general rule, the cytologic features of Hürthle cells in Hashimoto’s thyroiditis can be differentiated from a Hürthle cell tumor. In thyroiditis the oncocytes are large, atypical, and pleomorphic, whereas Hürthle cell tumors usually show monotonous cells, as is the case in histologic sections (see below) (Chen et al, 1998; Ravinsky and Safneck, 1988).
Further, the presence of abundant lymphocytes is very uncommon in Hürthle cell tumors.

The recognition in cytologic samples of either carcinoma or lymphoma, occurring in Hashimoto’s thyroiditis, may be exceedingly difficult. If a carcinoma is suspected, a surgical biopsy should be suggested. If a lymphoma is suspected, flow cytometry studies performed on the aspirate may help in determining a definitive diagnosis without having to resort to surgery.