Thyroid
Katherine Berezowski, ... Mary K Sidawy, in Fine Needle Aspiration Cytology, 2007
CLINICAL FEATURES
Goiter is a clinical term that denotes enlargement of the thyroid, which occurs due to impaired synthesis of thyroid hormones. Clinically, goiter presents in a nodular or diffuse form, and is divided by the functional activity of the thyroid into the non-toxic and toxic variants. Non-toxic nodular goiter is the most common form in the United States, affecting approximately 5% of the population. In essence, it is a compensatory response of the gland for a decrease in hormone secretion. The specific cause of this form of goiter is usually unknown. The basic mechanism involves stimulation of the thyroid by TSH due to low levels of the thyroid hormones, which leads to follicular cell hyperplasia and involution. Nodular goiter is the end-stage of a diffuse goiter and is caused by the cyclic changes taking place during hyperplasia and involution.
NODULAR GOITER (ADENOMATOID NODULE) – DISEASE FACT SHEET
Incidence
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Affects 5% of population
Gender and Age Distribution
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Female predominance
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Occurs in adults
Clinical Features
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Asymptomatic, euthyroid
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Slow growing
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Sudden growth as result of hemorrhage
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Compressive symptoms
Nodular goiter is a disease of adults and shows a female predominance. Most patients are asymptomatic and, by definition, euthyroid. Multinodular goiter develops over many years and is detected on routine physical examination or by the patient noticing an enlargement in the neck. If the goiter is large enough, it can lead to compressive symptoms. Patients may complain of sudden pain caused by hemorrhage into a nodule.
CYTOPATHOLOGIC FEATURES
Cytologic nomenclature of nodular goiter includes adenomatoid, cellular adenomatoid, adenomatous, hyperplastic, and non-neoplastic nodule. The aspirates from nodular goiter are of low to moderate cellularity. They demonstrate an admixture of colloid and follicular cells in variable proportion, reflecting the different phases of evolution of the disease. During the hyperplastic stage, follicular cells are abundant and colloid is scant. As the disease progresses to the involutional stage, follicular cells become fewer and colloid becomes abundant.
The presence of abundant colloid and a high colloid to cell ratio are extremely helpful in the cytologic diagnosis of goiter. Macroscopically, smeared unstained colloid resembles varnish. Microscopically, colloid can appear as thick amorphous material with sharply circumscribed edges or as a thin translucent film in the background, often with folds and cracks. When diluted by blood, its appearance overlaps with serum. Colloid may be lost during processing, particularly with liquid-based preparations (see Fig. 2-1).
NODULAR GOITER (ADENOMATOID NODULE)–PATHOLOGIC FEATURES
Cytopathologic Findings
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High colloid to cell ratio
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Follicular cells arranged in honeycomb sheets, spherules, tissue fragments, or singly
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Small round nuclei, naked nuclei, delicate cytoplasm
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Hürthle cells
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Cystic change: macrophages (pigmented, multinucleated), cyst-lining cells
Differential Diagnosis and Pitfalls
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Cystic papillary carcinoma
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Follicular neoplasm
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Follicular variant of papillary carcinoma
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Parathyroid cyst
Follicular cell nuclei are 1.5–2 times the size of mature lymphocytes. The chromatin is finely granular and uniformly dispersed, with inconspicuous nucleoli. The nuclei are round and may show enlargement and variability in size. The cytoplasm is delicate with indistinct borders (Fig. 2-7). The follicular cells are arranged in groups, honeycomb sheets, spherules, and tissue fragments. A spherule represents an intact non-neoplastic macrofollicle with its basement membrane. It appears as a round structure, with smooth borders and evenly spaced nuclei. A spherule may mimic a giant cell, but the latter can be differentiated by its irregular outline and unevenly spaced, elongated nuclei (Fig. 2-8). Tissue fragments with supporting vascular stroma may be mistaken for papillary structures and suggest papillary carcinoma. However, attention to the arrangement of the follicular cells within the tissue fragments (spherules and honeycomb sheets with maintained nuclear polarity) should prevent such a pitfall (Fig. 2-9). The follicular cells may also be found dispersed singly and stripped of their cytoplasm (Fig. 2-10). Hürthle cells with enlarged nuclei showing variable degrees of pleomorphism are seen in nodular goiter.
In Diff-Quik-stained smears, the follicular cells may reveal abundant intracytoplasmic blue granules, which can obscure the nuclei. These granules are seen in cystic and hemorrhagic lesions, and represent hemosiderin pigments. They are not specific and may be seen in goiter, as well as in benign and malignant neoplasms (Fig. 2-11). These non-specific granules should be distinguished from a different type of granules, ‘paravacuolar granules’ (Fig. 2-12). The latter consist of small blue granules grouped within a vacuole close to the nucleus. They are frequently observed in non-lesional thyroid tissue and occasionally in Hashimoto's thyroiditis. When the majority of aspirated follicular cells display paravacuolar granules, the cytopathologist needs to consider that the targeted lesion (especially when small) was missed and only adjacent non-lesional thyroid tissue was sampled.
Hemorrhage and cystic change are quite common in aspirates from nodular goiters. Cytologically, they manifest by the presence of histiocytes and hemosiderin-laden macrophages (many multinucleated), cholesterol crystals, and cyst-lining cells (Fig. 2-13 & Fig. 2-14). Cyst-lining cells appear as flat sheets of spindled to polygonal (squamoid) cells with abundant, dense cytoplasm, enlarged pleomorphic nuclei, and prominent nucleoli (Fig. 2-15). Bi- and multinucleation are common.
ANCILLARY STUDIES
Ancillary techniques including morphometry, image analysis, DNA measurements by flow cytometry, telomerase activity (by polymerase chain reaction [PCR]), and immunocytochemistry for a variety of antigens have been advocated for discriminating between benign and malignant nodules; however, none of these methods is sufficiently reliable.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The differential diagnosis of nodular goiter depends on the stage of the disease. Cystic nodules must be differentiated from cystic papillary carcinomas, while the differential diagnosis of cellular adenomatoid (hyperplastic) nodules includes follicular neoplasms and follicular variant of papillary carcinomas.
CYSTIC PAPILLARY CARCINOMA
Thirty per cent of thyroid nodules are cystic, most of which are nodular goiter. It is also important to point out that a third of papillary carcinomas are cystic, while cystic degeneration is rare in follicular, medullary, and anaplastic carcinomas. The gross appearance of the fluid (yellow or hemorrhagic) is not reliable in distinguishing goiter from papillary carcinoma. To the uninitiated, the prominent cytologic atypia and squamoid appearance of the cyst-lining cells of nodular goiter may lead to the erroneous diagnosis of papillary carcinoma.
FOLLICULAR NEOPLASMS
The cytologic features of cellular adenomatoid nodules overlap with those of follicular neoplasms, making the distinction between the two entities unreliable. High cellularity, scant colloid, and follicular cells arranged in acini and occasional microfollicles are shared features of both entities. When the distinction is difficult, the aspirates fall in the indeterminate category and are classified as ‘cellular follicular lesions’. The risk of malignancy with indeterminate thyroid cytology is reported as 15–20%.
FOLLICULAR VARIANT OF PAPILLARY CARCINOMA
This is a well-known pitfall, and one of the major sources of false negative diagnoses in thyroid FNA. This variant of papillary carcinoma reveals neoplastic cells arranged in syncytial clusters and microfollicles, and should be considered in the differential diagnosis of cellular follicular lesions. Attention to the nuclear features may help in establishing the correct diagnosis, or at least including papillary carcinoma in the differential diagnosis.
PARATHYROID CYST
When crystal-clear fluid is aspirated, the possibility of a parathyroid cyst should be considered. Measuring the level of C-terminal/midmolecule parathyroid hormone in the fluid helps in confirming the diagnosis.