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Cytologically suspicious follicular lesions

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Cytologic diagnostic features:

  • high cellularity
  • predominantly microfollicular or trabecular pattern
  • crowded, overlapping cells
  • cellular alterations (mild atypia, an uniform enlargement)
  • scanty or absent colloid

Several of all of these features should be present to diagnose a follicular lesion as ‘cytologically suspicious’. Marked nuclear atypia is uncommon, and so are mitosis. Macrophages are absent. Bare nuclei are usually few or absent.

No single criterion is sufficient to distinguish benign from suspicious nodules. The presence of several features increases the likelihood of malignancy, and that is the case for which a diagnosis of cytologically suspicious follicular nodule should be made. All the aspirates that are composed of a pure Hürthle cell population are suspicious by definition.

The differential diagnosis includes other thyroid neoplasms. Nuclear grooves and pseudoinclusions may be focally present in some follicular adenomas and carcinomas. If focal, they should not lead to a diagnosis of papillary carcinoma but will define the lesion as supicious. In the so-called hyalinizing trabecular adenoma, smears show oval or spindle cells in aggregates or isolated. Clues to the correct diagnosis are a whorling, parallel array of the cells, an amorphous hyaline material and a perinucleolar clear zone. The clear cell variant of follicular carcinoma may be confused with some parathyroid tumors or metastatic renal cell carcinoma, but cells are usually positive to immunostaining for thyroglobulin.

Only about 30-40% of cases diagnosed as ‘suspicious follicular nodules’ prove to be malignant. Among these, only 50-75% are follicular carcinomas, while the others prove to be follicular variants of papillary carcinoma.

The Thy classification has been devised clinically to separate lesions at higher risk of malignancy from the ones with a low risk. In both cases the surgeon will offer excision of the nodule but will point out that in the former (Th4 category) the risk is approximately 80% while in the latter  (Th3) is approximately 20%.
In patients with a diagnosis of ‘suspicious follicular nodule’ a lobectomy is usually performed; if a carcinoma is diagnosed by the hystological examination, a complete thyroidectomy is recommended.

Adjunctive techniques have been advocated to discriminate between benign and suspicious follicular lesions. Morphology and image analysis proved not to be sufficiently accurate for clinical purposes. DNA measurements by flow cytometry is also not useful; in fact, aneuploidy does not guarantee that a tumor is malignant. Immunocytochemistry for MIB-1 is not of great value, since the proliferative activity in adenomas and carcinomas can be similar. Immunocytochemistry for galectin-3 appears to be promising, since most carcinomas are positive and most adenomas are negative, but is not specific or sensitive enough in clinical practice. The distinction could be made also with genetic markers: the translocation t(2;3) is a specific marker of follicular carcinoma. 

Nuclei showing a coarse chromatin pattern and nuclear grooving. A follicular lesion with nuclei showing a coarser chromatin pattern and nuvlear grooving.
The same lesion confirming a coarsely granular chromatin, mild nuclear pleomorphism. A high power view showing a coarsely granular chromatin and mild nuclear pleomorphism. Although there is some nuclear overlapping this feature is not so reliable in thicker clusters of cells.
Cells exhibiting some crowding, mild pleomorphism and irregular chromatin –  An MGG stain showing a microfollicular pattern with cells exhibiting some crowding, mild pleomorphism and a more irregularly granular chromatin.
Changes can be very focal and admixed with otherwise unremakable areas. This a rather bland follicle; in suspicous follicular lesions changes can be very focal and admixed with otherwise unremakable areas.
A rather crowded group of thyrocytes showing mild pleomorphism. A rather crowded group of thyrocytes showing mild pleomorphism; although a follicular arrangement can be identified nuclei are overlapping thoughout the group. This does not appear to be dictated by thickness of the cluster but is rather an expression of a more disordered architecture.
A nuclear pseudoinclusion in one cells and a flake of dense colloid. A monolayered sheet of thyroid cells which appear uniform, however a nuclear pseudoinclusion is visible in one cell and a flake of dense colloid is present at the upper right corner of the field (MGG); these would qualify the lesion as suspicious. Elsewhere more obvious features of papillary carcinoma, follicular variant were present.
A crowded group with prominent nucleoli and obvious nuclear grooves. A group of overlapping thyroid cells with prominent nucleoli and obvious nuclear grooves (Pap) in a blood stained smear. These features are suspicious but quantitatively insufficient for a definitive diagnosis of malignancy: other findings must be present.
Two similar groups of thryoid cells with prominent nucleolus and mild nuclear pleomorphism. Two groups of thryoid cells with prominent nucleolus and mild nuclear pleomorphism.
Nuclear overlapping in the upper left corner of the fragment. This lower power view of a Papanicolaou stained microbiopsy still identifies sheets of monolayered uniform thyroid cells which elsewhere showed suspicious nuclear features. You may note the more disordered architecture with nuclear overlapping in the upper left corner of the fragment. This low power finding should prompt an accurate screening of the slides for confirmation of suspicious features, this architectural feature alone being insufficient for diagnosis of suspicion.
A group of cells with marked anisonucleosis. A high power view of an MGG stained smear showing a group of cells with marked anisonucleosis, again a finding which should prompt a thorough search for more diagnostic features of suspicion for malignancy.
A central nucleus is much larger, hyperchromatic and has an irregular contour. A group of thyrocytes: a central nucleus is much larger, hyperchromatic and has an irregular contour (MGG). This is a suspicious finding.

Follicular carcinoma

It represents the second most common thyroid cancer (5-15% of thyroid malignancies). It is usually a solitary nodule but, differently from follicular adenoma, it shows capsular infiltration and vascular invasion. Follicular carcinoma is usually divided into two histological subtypes: a minimally invasive with a very good prognosis and a widely invasive with poor prognosis, which tends to metastatize to lung and bones.

The cells of follicular carcinoma never show the nuclear features of papillary carcinoma, which helps to distinguish follicular carcinoma from the follicular variant of papillary carcinoma. 

An MGG stain of an FNA from a follicular carcinoma. This case was mistakenly thought to be a medullary carcinoma because of the presence of cytoplasmic granules; it proved to be a follicular carcinoma. The granules are not the fine metachromatic ones found in medullary carcinoma and probably represent lysosomes. In our experience the vast majority of follicular carcinomas are labelled as suspicious follicular lesions.
Groups of thyrocytes from a follicular carcinoma.


Hürthle cell tumours

Hürthle cells (oncocytes) are altered follicular cells which are very rich in mitochondria. In cytologic smears, they appear as polygonal cells, with large and finely granular cytoplasm, purple with MGG staining and orangeophilic with Papanicolaou staining. They can be binucleated, nuclei are enlarged and their size may be variable, often with prominent nucleoli.

Hürthle cells are common in Hashimoto`s thyroiditis and in multinodular goiter, where they can also form macroscopic nodules. Benign Hürthle cells are usually cohesive and do not have prominent nucleoli; a slight or moderate pleomorphism can sometimes be observed. In Hashimoto`s thyroiditis, they are admixed with numerous lymphoid cells. In nodular goiter, they are admixed with macrophages and colloid.

In Hürthle cell tumors the aspirate is generally composed of a pure Hürthle cell population. The cells are usually discohesive, but aggregates can be seen. Vesicular nuclei and prominent nucleoli are often present. In the case of a Hürthle cell neoplasm, normal follicular cells are usually absent and so are abundant lymphocytes; colloid may be present.

The differential diagnosis includes some variants of papillary carcinoma, such as tall/pink cell and oncocytic. Moreover, rare Hürthle cell tumors show papillary architecture (oncocytic papillary neoplasm). Variants of papillary carcinoma can be excluded by the absence of the characteristic nuclear features in almost all cases. Metastatic renal cell carcinomas may mimic Hürthle cell neoplasms, but immunocytochemistry for thyroid transcription factor 1 (TTF-1), which is positive in follicular and Hürthle cells, is negative in the cells of renal cell carcinoma. Medullary thyroid carcinoma shows a dispersed cell pattern and a cytologic appearance that can mimic a Hürthle cells neoplasm. Prominent nucleoli are usually absent in medullary carcinoma. With MGG stains, the granules of Hürthle cells are blue, the ones of the cells of medullary carcinoma are red. 

A low power view of a FNA from a Hürthle cell neoplasm (MGG). A pure population of Hürthle cells (MGG). Note the pleomorphism which is apparent even at low power; this is not diagnostic of malignancy as it is a common feature in these neoplasms, whether benign or malignant. In our experience it is rather monomorphism which is more commonly associated with malignancy. In all cases definitive criteria for malignancy are exclusively histological (capsular or vascular invasion). 
A group of rather pleomorphic Hürthle cell (Pap). The pleomorphism is striking, with very large nuclei, prominent nucleoli and multinucleations. The N/C ratio however is not high. 
A follicular group of Hürthle cells (Pap). A cohesive group of cells showing the typical features of Hürthle cells (Pap). Note the dense cytoplasm with well defined borders, vescicular nuclei and prominent nucleoli.
Discohesive Hürthle cells (Pap). Discohesive cells with marked pleomorphism but preserved N/C ratio. Cytoplasm is dense and nuclei are round, often eccentrically placed imparting a “plasmacytoid” appearance. This may mimic medullary carcinoma.
A rather pleomorphic collection of Hürthle cells (MGG) showing pleomorphic nuclei, nucleoli and dense cytoplasm, often containing coarse granules. These are different from the fine granularity of medullary carcinoma.