Cytological aspects of diagnocstic and non-diagnostic FNAB
  Thyroid FNAB smears can be classified as diagnostic or non-diagnostic. In the first group are comprised the majority of benign and malignant thyroid lesions that can be identified with high accuracy by standard cytological criteria. In the second group are comprised two subgroups: a) smears containing insufficient cellular material (inadequate samples); b) smears that cannot be reliably classified either in the benign or in the malignant group on the basis of standard cytological criteria (“indeterminate” lesions).

A detailed description of cytological features of thyroid lesions can be found elsewhere4,34,35. Herein we will focus on basic cytological aspects that allow identification of thyroid lesions and on the characteristics of “indeterminate” lesions, which represent a major limitation of thyroid FNAB.

Basically, the following aspects are of importance when examining a thyroid smear: a) presence of colloid; b) cell arrangement; c) nuclear and cytoplasmic features; d) additional background features.

For instance, the presence of moderate or large amount of colloid is suggestive of nodular goiter. In contrast, colloid is scanty or absent in neoplastic or inflammatory lesions. The evaluation of the cellular arrangement may give indications of the histological structure. Cytoplasmic and, especially, nuclear details may suggest a neoplastic lesion with a degree of accuracy depending on the tumor histotype. For instance, papillary carcinoma is characterized by relatively specific nuclear features that include ground glass cell nuclei, nuclear inclusions, groves34. Elongated “bipolar” nuclei suggest a medullary cancer36 while highly pleomorphic spindle-shaped or giant nuclei are compatible with an anaplastic cancer37. The presence of additional features such as psammoma bodies, inflammatory cells, cell necrosis, is of major relevance for the diagnosis of many types of lesions.

Major cytological findings of the most common thyroid lesions are summarized in Table 1.

  1. Diagnostic FNAB
    Benign lesions, such as nodular goiter and chronic thyroiditis, and malignant lesions, such as papillary, medullary and anaplastic carcinomas, mostly show specific cytological aspects (Table 1). They can be diagnosed with high accuracy and are included in this group.


  2. Non-diagnostic FNAB
    Inadequate sampling
    Cytological smears should contain a good number of well preserved and well stained cells with epithelial characteristics in order to be classified as benign. Aspiration of too few cells to reach a diagnosis is a major limitation of FNAB. In a recent review of seven large series, the mean inadequacy rate was 17% (range 2–21%)34. It is important to avoid making a diagnosis in the presence of a suboptimal sample, as this is a major cause of false negatives. In order to facilitate recognition of sample adequacy, some authors have proposed to follow quantitative criteria. Hamburger recommends that cancer cannot be excluded if the sample does not contain at least six benign follicular cell clusters, each containing 10–15 cells, in two specimens derived from two different aspirates5. Other authors have adopted less stringent criteria.

    Variables that may affect adequacy and quality of cytologic smears have been described above.

    “indeterminate” lesions
    Standard thyroid FNAB is unable to reliably classify as benign or malignant a proportion of nodules ranging 15–30 %. These lesions are variably indicated as “follicular” or “suspicious” or “indeterminate” and represent a heterogeneous group of lesions, either benign or malignant, that have overlapping cytomorphologic aspects:

    1. Follicular lesions: the most common component of the “indeterminate” group is represented by well differentiated lesions with follicular structure, which account for 10–15% of all thyroid nodules. The large majority of these nodules are benign tumors (follicular adenomas) or hyperplastic goiter nodules. However, approximately 1 out of 10–15 follicular lesions is malignant (well differentiated follicular carcinoma). These carcinomas differ from adenomas because have acquired the ability to invade the tumor capsule and/or blood vessels. On the basis of the extent of invasion follicular carcinomas are classified as minimally or widely invasive. Cytological atypias are present in widely invasive tumors but are rare in minimally invasive follicular carcinomas. This last category, therefore, can be only diagnosed at histopathology after examination of multiple sections.


    2. Papillary carcinomas: it is increasingly recognized that, especially in areas where follicular carcinomas are rare, papillary cancer is a significant component of malignancies diagnosed as “indeterminate” at cytology. Most papillary carcinomas classified as “indeterminate” lesions belong to the follicular variant (FVPTC). In FVPTC (approximately 20 % of all papillary carcinomas) a number of cytologic features characteristic of papillary cancer, such as psammoma bodies, nuclear clearing, grooves and pseudoinclusions, are poorly represented38,39. A small proportion of the classic variant of papillary cancer may also scarcely present these cytological characteristics40.


    3. Hurthle cell lesions: Hurthle cell lesions represent approximately 2–3% of all nodules and include neoplastic lesions (either benign or malignant) and non-neoplastic lesions, such as metaplastic changes observed the context of Hashimoto’s thyroiditis, or nodular goiter. Hurthle cell carcinomas represent less than 1% of all nodules and cannot reliably be differentiated from either benign Hurthle cell tumors or non-neoplastic lesions.


    4. Insular carcinoma: it is an unusual thyroid tumor, representing 4–7% of all thyroid carcinomas. This cancer is characterized by a growth pattern in nests of cells called “insulae” and by a high aggressiveness and early spread to distant sites41. Smears are often highly cellular and poor of colloid. However, microfollicles are rare and there is a predominance of single cells. Nuclei are predominantly round, monomorphic and with small nucleoli. Inclusion of insular carcinoma in the “indeterminate” group may result from the scarce signs of cellular atypia.


    5. Medullary carcinoma: medullary carcinoma represents approximately 5% of all thyroid carcinomas. Aspirates are often rich of cells with characteristic cytological features (Table 1). Different morphologic variants, however, exist42. Classification in the “indeterminate” group may result from lack of experience with all the variants of this infrequent malignancy.