Fine Needle Aspiration Cytology

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Fine-needle aspiration should be performed on any solitary or dominant nodule more than 10 mm in diameter or in nodules as small as 8 mm with highly suspicious ultrasonographic characteristics. Where the nodule is palpable it can be aspirated under direct palpation in the first instance. In some places in Europe and the USA and in Japan, ultrasound guidance is used for all lesions. However, in view of the additional resource required, many centers would reserve its use for cases where standard FNA yields nondiagnostic material. It is also especially useful in complex cysts, in lesions that are difficult to palpate or are impalpable, and in targeting the dominant nodule(s) in multinodular goiter. Aspiration should be carried out by a clinician with an interest in thyroid disease, trained in good practice and performing aspirates regularly. This can be a cytopathologist, surgeon, endocrinologist, or radiologist. The cytopathol-ogist reporting the FNA should also have an interest in thyroid disease and report sufficient cases to maintain expertise. There should be the opportunity for cytology review, and correla tion with any subsequent histology is essential as part of audit. In most centers, a combination of wet and air-dried preparations is used. Additional material may be processed as cytospin slides, cell blocks or Millipore filter preparations for immunohistochemistry where appropriate, or processed for molecular genetic analysis. However, in most instances, the diagnosis is made on standard smears. The few publications on the use of liquid-based cytology for thyroid suggest that it is not as good as conventional smears [3,4].

Aspirates are usually divided into five categories: nondiagnostic; benign; follicular lesions (usually neoplasms); suspicious of malignancy (papillary, medullary or anaplastic carcinoma, or lymphoma); and diagnostic of malignancy (in the same range of tumors). A numerical grading system of Thyl to Thy5 has recently been proposed in the British Thyroid Association guidelines [5]. This should be coupled with a descriptive report. Published figures would suggest that inadequate/nondiagnostic (Thyl) FNA cytology should be about 5-15% of the total, the figure being lower in ultrasound-guided lesions. Aspirates in this category include those with insufficient thyroid epithelial cells and those that cannot be interpreted because of technical artifact. Specimens are usually considered adequate when they contain at least six groups of 10 to 20 cells each on slides from two different passes [6]. This is especially important when making a benign diagnosis. A diagnosis of malignancy may be made with fewer cells where the characteristic features are pronounced (e.g. papillary carcinoma).

The aspirate from nodular goiter usually shows abundant thin colloid, sometimes with a "cracking" artifact. The follicular cells lie in sheets, in follicles or singly. Foamy and hemo-siderin-laden macrophages are usually present, but their numbers will vary with the extent of degeneration. This will be classified as Thy2. Hyperplastic nodules may give rise to smears resembling those from follicular neoplasms (Thy3). Some would advocate that a benign diagnosis should be made confidently only on the basis of two aspirates, 3 to 6 months apart. However, others would not recommend a repeat if the first aspirate is adequate, the nodule is <20 mm in diameter, and is not increasing in size.

The third category (Thy3) comprises mainly follicular neoplasms. Follicular Hurthle cell tumors are included in this group. It is not possible to make the distinction between benign and malignant follicular tumors on cytology alone, and all cases in this group require lobec-tomy for definitive diagnosis. The majority of these lesions are follicular adenomas, with up to 15% reported as follicular carcinomas. These are cellular aspirates, comprising follicu-lar or Hurthle cells arranged in microfollicles or three-dimensional groups, with little colloid (Figure 9.1). Nuclear atypia may be seen, but is not important in defining the behavior of the lesion, as atypical adenomas may show pleomorphism. There has been recent interest in the application of immunohistochemical markers for the preoperative diagnosis of fol-licular carcinoma, particularly galectin-3. A large European study suggested a positive predictive value of 92% and a diagnostic accuracy of 99% for galectin-3 positivity in predicting malignancy [7]. However, more recent investigations have demonstrated focal expression of galectin-3 in follicular adenomas and in nodular goiter and a number of follicular carcinomas have been reported as negative [8,9]. This might lead to erroneous diagnosis on cytology preparations.

Oncocytic follicular lesions also fall into the Thy3 category. Galectin 3 immunostaining has been reported as less specific in assessing malignant potential in oncocytic tumors [10]. Aspi-

Figure 9.1 Fine-needle aspirate of a follicular neoplasm.The follicular epithelial cells are arranged in microfollicles and there is almost no colloid. It is not possible to distinguish adenoma from carcinoma on cytological examination. Histologically this was a minimally invasive follicular carcinoma.

Figure 9.1 Fine-needle aspirate of a follicular neoplasm.The follicular epithelial cells are arranged in microfollicles and there is almost no colloid. It is not possible to distinguish adenoma from carcinoma on cytological examination. Histologically this was a minimally invasive follicular carcinoma.

rates from Hashimoto's thyroiditis will also contain oncocytes, but will also have a chronic inflammatory cell population.

Smears from classical papillary carcinoma are usually highly cellular, and may contain branching papillary tissue fragments and cell clusters. The tissue fragments often have a regular outline and show nuclear palisading. The nuclei are usually large and irregular and have grooves and pseudoinclusions. Thick colloid (chewing gum or ropy) is characteristic and multinucleate giant cells and psammoma bodies may also be found. Depending on how marked the changes are, these smears will be Thy4 (suspicious for malignancy) or Thy5 (definite for malignancy).

Follicular variant of papillary carcinoma (FVPC) may be recognized on cytology if the nuclear changes are pronounced. The smears show cells lying in sheets, cellular groups, or microfollicles. Colloid is usually thin, with thick "chewing gum" colloid less common than in the classic variant. The nuclei are elongated and show clearing of chromatin and thickening of the nuclear membrane, but nuclear grooves and inclusions are said to be less common than in the classic variant. The presence of mulinucleate giant cells is a factor in favor of the diagnosis of FVPC [11] and psammoma bodies may occasionally be found. In the cases where a confident diagnosis can be made, these smears would be classified as Thy5. However, where the nuclear features are not prominent, the smear may be interpreted as a follicular neoplasm (Thy3) or as Thy4 if there is some clearing of chromatin and a thick nuclear membrane. Distinction of microfollicu-lar and macrofollicular variants has been attempted [12]. Attempts have also been made to identify tall cell [13] and columnar cell [14] variants on cytological examination. To increase the overall sensitivity of detection of papillary carcinoma on FNA, one group has used reverse-transcription polymerase chain reaction (RT-PCR) for the specific RET/PTC gene rearrangements that characterize a subset of these tumors and has identified tumor in specimens deemed inadequate for standard cytological assessment [15]. However, the RET/PTC gene may be found in benign tumors [16].

A cellular smear comprising small to intermediate sized cells with frequent mitotic

Dominant Thyroid Nodule
Figure 9.2 Fine-needle aspirate of medullary carcinoma. The cells are rather dys-cohesive. They have ovoid nuclei and a plasmacytoid appearance in places.

figures, little colloid, and evidence of necrosis raises the possibility of poorly differentiated carcinoma. However, specific diagnosis requires examination of the surgical specimen.

Anaplastic or undifferentiated carcinomas are usually cellular and often show significant pleomorphism and high mitotic activity. There is often evidence of necrosis and polymor-phonuclear leukocytes. Osteoclast-like giant cells may be present.

Medullary carcinoma also gives a hyper-cellular smear (Figure 9.2). The cells may be polygonal or spindle-shaped and often have a plasmacytoid appearance. They tend to be poorly cohesive. Amyloid is present in up to 70% of cases. The diagnosis can be confirmed by immunostaining for calcitonin. These cases will be Thy4 or Thy5.

Thyroid lymphoma needs to be distinguished from chronic thyroiditis and is usually characterized on the immunophenotype of the lymphoid cells. This may be achieved by immunostaining of cell blocks or cytospins or by fluorescence activated cell sorting (FACS) analysis.

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