Benign Follicular Nodules

The cytologic term benign follicular nodule was coined to encompass a group of benign histopathologic entities that have identical cytologic features.⁵⁶ The most common are the nodule in multinodular goiter (MNG) and the macrofollicular type of follicular adenoma.

MNG is a common thyroid disorder characterized by an enlarged thyroid gland (goiter) with multiple areas of nodularity. Worldwide, it is the most common endocrine abnormality, affecting more than 500 million people.⁵⁷ Its prevalence varies depending on regional iodine intake: Lower dietary iodine correlates with an increased prevalence of MNG. In the United States, despite iodine supplementation, the prevalence of MNG is roughly 4% to 7%.

The pathogenesis of MNG is best understood in cases associated with iodine deficiency. Because iodine is required for thyroid hormone synthesis, a deficiency of iodine results in decreased thyroid hormone production and a compensatory elevation in serum TSH levels. Chronically elevated TSH levels stimulate a diffuse follicular cell hyperplasia. Over time, somatic mutations within the follicular cells (possibly as a result of hydrogen peroxide [H₂O₂] production and free radical generation that occurs with thyroid hormone synthesis) confer a survival advantage over selected clones, which results in nodule formation.⁵⁸ The mechanism of follicular cell hyperplasia in iodine-sufficient regions is less well understood but is likely to be related to other stimuli (e.g., smoking, radiation, drugs, naturally occurring goitrogens) superimposed on a genetic susceptibility.⁵⁸

MNG is 5 to 15 times more common in women than in men, and prevalence increases with age. Patients are usually asymptomatic and euthyroid, but 5% to 10% progress to hyperthyroidism (toxic MNG).⁵⁷ Most cases are discovered incidentally by palpation or imaging studies. MNG varies in severity, from the minimally enlarged, asymptomatic gland with only one or two nodules, to the extremely enlarged nodular gland that extends from the neck into the mediastinum. Patients with large goiters can have compressive symptoms (e.g., shortness of breath, cough, dysphagia), and large goiters can be disfiguring. The growth of nodules is unpredictable and highly variable, but, on average, MNG nodules grow by about 4.5% per year.¹⁶

The treatment of MNG is varied and individualized. Choices include thyroid surgery, ¹³¹ I (radioactive iodine) therapy, and TSH suppresion with exogenous thyroxine (T₄) administration. Surgery is generally recommended for younger patients and those with a large goiter.¹⁶

Histologically, the nodules of MNG (commonly referred to as adenomatous or adenomatoid nodules) are usually not encapsulated. The follicles within the nodules vary in size, but most are larger than normal follicles (macrofollicles) and filled with colloid. Some nodules are composed of such enormous macrofollicles that they are virtually all colloid (colloid nodules). Less commonly, a nodule may be very cellular, composed of smaller follicles that contain little colloid. The rapid growth of some nodules leads to hemorrhage, scarring, cystic degeneration, and dystrophic calcification. Uninodular MNG is a controversial entity, but some histopathologists acknowledge its existence.

Unlike MNG, a follicular adenoma is usually a solitary nodule that measures 1 to 3 cm in diameter, but it can be much larger.⁵⁹ The histologic distinction between an adenomatous nodule in MNG and a follicular adenoma is somewhat arbitrary. In general, follicular adenoma is a solitary nodule with a well-defined fibrous capsule, and the follicular cells within the nodule are morphologically distinct from those in the surrounding gland.⁵⁹ Capsular and vascular invasion are absent. Follicular adenomas have a wide variety of predominant histologic patterns: macrofollicular (large follicles distended by colloid); microfollicular (follicles smaller than normal); and trabecular (follicular cells are arranged in crowded ribbons).⁵⁹ Uncommon variants include follicular adenoma with papillary hyperplasia (mostly in children and adolescents), signet ring cell follicular adenoma, mucinous follicular adenoma, lipoadenoma, clear cell follicular adenoma, and follicular adenoma with bizarre nuclei. Only the predominantly macrofollicular follicular adenomas are interpreted as benign follicular nodules by FNA. The others are likely to be interpreted as suspicious because of their unusual architectural patterns.

MNG and macrofollicular follicular adenoma are essentially indistinguishable by FNA, but this is of no clinical consequence. Patients with a benign result are instructed to return for a follow-up examination at 6- to 18-month intervals for at least 3 to 5 years to ensure that the nodule is behaving in a benign fashion.43,46

By definition, benign follicular nodule applies to a sample that is adequate for evaluation and consists predominantly of colloid and benign-appearing follicular cells in varying proportions. The benign follicular nodule has a predominantly macrofollicular architecture. During aspiration and slide preparation, most macrofollicles break into fragments; intact macrofollicles are relatively uncommon (Fig. 10.3A). Instead, one commonly sees flat sheets that represent fragments of macrofollicles (Fig. 10.3B) A macrofollicle fragment is defined by its flatness and the even spacing of follicular cell nuclei. (If there is conspicuous cell crowding and overlapping, the sheet is not a macrofollicle fragment.) Although the term macrofollicle fragment implies large size, and many are indeed large, some macrofollicle fragments are small (10 or even fewer cells). A macrofollicular pattern is defined by architecture and not size. Evenly spaced follicular cells (not crowded or overlapped) constitute a macrofollicle fragment, no matter the size of the cell sheet.

The macrofollicle fragment is made up of medium-sized cells, each with a round nucleus, coarsely granular chromatin, an inconspicuous nucleolus, and scant or a moderate amount of cytoplasm (Fig. 10.4A and B). Cytologic atypia is generally absent, but some nuclear size variation can be seen, and in some cases the nucleoli are moderate in size. Some follicular cells contain hemosiderin pigment, which is golden brown with the Papanicolaou stain and blue with Romanowsky-type stains.⁶⁰ In a benign follicular nodule, finding a minority of the follicular cells arranged in microfollicles or crowded groups is acceptable.

Colloid is usually abundant and can take the appearance of dense blobs with a hyaline texture, hard edges, and cracking artifact (Fig. 10.5). These thick colloid chunks have a similar appearance on smears and liquid-based preparations. More often, colloid is mostly thin and watery, covering large areas of the smear as a translucent film with bubbles, folds, cracks, and a circular “chicken wire” artifact (Fig. 10.6A). On liquid-based preparations, this watery colloid has a characteristic “folded tissue paper” appearance²⁶ (Fig. 10.6B). Colloid stains pale pink, pale green, or orange with the Papanicolaou stain, and magenta with Romanowsky-type stains.

Because most of the volume of a benign follicular nodule is occupied by colloid and not follicular cells, cytologic preparations from them tend to be sparsely cellular. But exceptions occur, and a minority are moderately cellular, with numerous macrofollicle fragments.

Hürthle cells are seen in up to 50% of cases of MNG⁶⁰ (Fig. 10.7). Macrophages with foamy or hemosiderin-laden cytoplasm, including multinucleated giant cells, are often present and are a nonspecific finding indicating cystic degeneration⁶⁰ (see Fig. 10.2). A minor population of elongated, large “cyst lining cells” with pale and grooved nuclei are sometimes present. Because of their streaming (“tissue culture”) arrangement, they resemble reparative epithelial changes and likely represent altered follicular cells lining areas of cystic degeneration⁶¹ (Fig. 10.8).

The diagnosis of a benign follicular nodule can be made confidently when there is a mostly orderly macrofollicular architecture. Follicular carcinomas are virtually never composed of orderly macrofollicles, but instead have a preponderance of microfollicles and/or trabeculae of crowded, overlapping cells.

A minor population of crowded follicular cells and/or microfollicles is often present in benign follicular nodules and does not alter the benign interpretation. If macrofollicles (intact and/or fragmented) outnumber the crowded, microfollicular/trabecular groups, the findings are consistent with a benign nodule. Follicular cells trapped in fibrin clots are often disrupted and architecturally distorted, conferring a crowded appearance that may potentially lead to an erroneous suspicious interpretation. An interpretation should not be rendered on the basis of the presence of clotted follicular cells.⁶²

It is important to note that not all MNGs and follicular adenomas are predominantly macrofollicular. Some nodules in MNG and some follicular adenomas are comprised predominantly of microfollicles and/or trabeculae and are inevitably interpreted as suspicious by FNA. This is a well-known limitation. Of note, morphometry and image analysis have not demonstrated sufficient reliability for classifying individual cases.63–66 Although some separation of MNG, follicular adenoma, and carcinoma is possible,⁶⁷ these methods are not sufficiently accurate to be useful for clinical diagnosis.⁶⁸ Neither is DNA quantitation by flow cytometry useful, because 25% of follicular adenomas are aneuploid.^69–72 Immunohistochemistry for MIB-1 is of limited value because there is significant overlap in the proliferative activity between benign and malignant follicular nodules.⁷³ Early reports on the application of immunohistochemistry for galectin-3 appeared promising,⁷⁴ but subsequent studies have not been able to demonstrate reliable results for FNA. An understanding of the underlying genetics of these diseases may eventually provide the key to more accurate distinction, and encouraging inroads have been made. The translocation t(2;3) (q13;p25), which results in a PAX8-PPARγ gene fusion, is a relatively specific marker of follicular carcinoma that is virtually never present in follicular adenoma, MNG, or papillary carcinoma, but it has low sensitivity (26% by fluorescence in situ hybridization [FISH]).⁷⁵

Focal cytologic atypia is present in some benign nodules and may present diagnostic difficulties. Hürthle cell (oncocytic) metaplasia is common in MNG, and the Hürthle cells sometimes show marked nuclear atypia. Such changes raise the possibility of a Hürthle cell neoplasm. If Hürthle cells are admixed with ordinary follicular cells arranged in macrofollicles, particularly if there is abundant colloid, it is appropriate to interpret the findings as benign. By contrast, Hürthle cell neoplasms yield an exclusive population of oncocytic cells. A suspicious interpretation should be rendered only when the sample is composed exclusively (or virtually exclusively) of Hürthle cells, particularly when many isolated cells are noted.⁷⁶

The flat sheets of fragmented macrofollicles are reminiscent of the flat sheets of papillary thyroid carcinoma. The distinction between a benign nodule and papillary carcinoma depends primarily on careful examination of nuclear features. The distinction can be difficult in some cases, particularly with the macrofollicular variant of papillary carcinoma, in which the nuclear changes are often subtle and focal.77,78 Besides differences in the nuclei, the malignant cells of papillary carcinoma are arranged more haphazardly, with more crowding, than the follicular cells of benign nodules. In rare cases, macrophages in MNG can aggregate, and their large pale nuclei might be mistaken for papillary carcinoma.⁷⁹

The large, pale nuclei of cyst lining cells bear a resemblance to the cells of papillary carcinoma. When the nuclear changes are mild, and the great majority of the sample looks benign, the benign, reactive nature of these cells is easily recognized. In some cases, nuclear atypia is marked and papillary carcinoma cannot be excluded. Depending on the degree of atypia, such cases are reported as AUS or even “suspicious for PTC.”⁶¹

Chronic Lymphocytic (Hashimoto) Thyroiditis

Chronic lymphocytic (Hashimoto) thyroiditis (HT) is a common autoimmune disease in which thyroid follicles are destroyed by a marked lymphoid infiltrate. Almost 95% of HT occurs in women, with a peak incidence between the ages of 40 and 60 years. The disease results in a diffuse, painless goiter with or without nodularity. Ultrasonography reveals a gland with a heterogeneous appearance. Most patients are hypothyroid. Histologic examination reveals an intense, patchy lymphoid infiltrate with germinal centers, follicular atrophy, and Hürthle-cell metaplasia. Fibrosis is prominent in a minority of cases. The diagnosis is established by correlating clinical findings with serologic test results. One or more of a variety of circulating autoantibodies are identified in almost all patients. The most common are anti thyroglobulin and anti thyroid peroxidase (TPO). (TPO was originally called the microsomal antigen.) In a patient with HT, FNA is performed only if there is a suspicious nodule that raises the possibility of a coexisting malignancy.

The aspirate is usually very cellular, with numerous lymphoid cells, including small lymphocytes, centrocytes, centroblasts, and dendritic cells (Fig. 10.9A and B). With liquid-based preparations, the dispersed lymphoid component is admixed with the white blood cells from contaminating blood. Dendritic-lymphocytic aggregates (germinal center fragments containing dendritic cells) are also present, as are tingible-body macrophages. Colloid is usually absent or scant. Normal follicular cells are infrequent or absent altogether; instead, there may be occasional clusters of Hürthle cells (Fig. 10.9C). The Hürthle cells and any residual follicular cells occasionally display focal chromatin clearing and nuclear grooves. Multinucleated giant cells can be present but are usually not as numerous as in subacute thyroiditis.

The cytologic diagnosis of HT is usually straightforward and is confirmed clinically by serologic tests for antibodies against the afore-mentioned thyroid antigens. Pitfalls include aspiration of a reactive lymph node (unlikely if the FNA was ultrasound-guided) and MNG with prominent Hürthle cell changes. Prominent Hürthle cell change occurs in some cases of MNG, but a lymphoplasmacytic infiltrate is absent or sparse.

Primary thyroid lymphoma is an uncommon malignancy that must be considered in the differential diagnosis of HT. Almost all cases of thyroid lymphoma arise in patients with longstanding HT, and patients with HT have a significantly higher relative risk for developing thyroid lymphoma compared with the general population.⁸⁰ Histologically, primary thyroid lymphomas are either extranodal marginal zone B-cell lymphomas, diffuse large B-cell lymphomas, or a mixture of the two.⁵⁹ Cytologically, thyroid lymphomas are composed of a uniform population of either small or large lymphoid cells. Because lymphoma is uncommon, immunophenotyping is not performed routinely on cases of typical HT and might actually be counterproductive. Some HT specimens contain clonal B-cell populations (demonstrated by a restricted κ/λ light chain ratio by flow cytometry or an IgH gene rearrangement by the polymerase chain reaction) that do not equate to malignancy and thus can be misleading.^81,82 For this reason, immunophenotyping and/or molecular genetics are recommended only if the clinical presentation (rapid growth, large nodule) or cytomorphology (monomorphous and/or atypical lymphoid population) suggest lymphoma.

Hyperplastic Hürthle cell nodules occur in HT and mimic a Hürthle cell tumor. The cells of a Hürthle cell tumor, however, usually have a more prominent nucleolus than those of HT, and a prominent lymphoid infiltrate is absent. In a patient with a history of HT, a nodule is more likely to represent a hyperplasia of Hürthle cells rather than a Hürthle cell neoplasm. In a minority of cases this distinction may nevertheless be hard to make, and definitive classification may depend on histologic examination.

The Hürthle cells (and any residual follicular cells) of HT occasionally display focal chromatin clearing and nuclear grooves. When mild and focal, such changes usually do not correlate with a histologic papillary carcinoma and can be disregarded on an FNA. If they are widespread and associated with other features of papillary carcinoma, however, a suspicious or malignant interpretation is warranted.

Subacute (de Quervain) Thyroiditis

Subacute (de Quervain) thyroiditis (ST) is a rare, painful enlargement of the thyroid gland in which thyroid follicles are damaged by a chronic granulomatous reaction, possibly due to a viral infection. Early, transient hypothyroidism is very common, but permanent hypothyroidism occurs only in a minority of patients. ST usually lasts several months and is self-limited, but it can recur in about 4% to 9% of patients.83,84 Patients are treated with nonsteroidal anti-inflammatory medications and, in more severe cases, with corticosteroids. In most cases, FNA plays no role in the diagnosis, which is usually established clinically. Because the gland can appear inhomogeneous, however, an FNA is sometimes performed to rule out a malignant nodule.

Aspirates can be sparsely, moderately, or highly cellular.⁸⁵ Multinucleated giant cells are usually a prominent, striking finding. They are numerous and very large, with bizarre, angular shapes (Fig. 10.10A). In ST, they tend to have densely granular but not vacuolated cytoplasm, in contrast with the frothy cytoplasm typical of the multinucleated cells in MNG nodules with cystic degeneration.⁸⁶ Some multinucleated cells have ingested colloid droplets.⁸⁶ Granulomas (Fig. 10.10B) are the hallmark of the disease but are not always present. Granulomas are crowded aggregates of epithelioid histiocytes that have an oval, spindle-shaped, kidney bean-shaped, or curved (“boomerang”) nucleus and abundant granular or vacuolated cytoplasm. Cell membranes are poorly defined, and as a result, granulomas have a syncytium-like appearance. Granulomas, if present, are rare and need to be hunted for in most cases.⁸⁵ Scant unremarkable macrofollicle fragments and colloid are usually present.⁸⁵

Stay updated, free articles. Join our Telegram channel

Join