Ultrasonography

See section nodular goiters

Cytology

Essentials

The greatest concern relating to thyroid cytology lies in the fact that the cytological investigation does not allow a differentiation between benign and malignant follicular tumors. From a cytological aspect, therefore, it seems reasonable to discuss follicular tumors in a common chapter, although these tumors behave absolutely differently. A huge effort has been made to find markers in order to discriminate between benign and malignant follicular tumors preoperatively, but with only very limited success. This is in no way a great surprise, when even a common interpretation of the golden standard, histopathology, is not clearly resolved (Saxen 1978). Moreover, a follicular pattern is often seen in smears from non-tumorous thyroid lesions, and the distinction between non-tumorous follicular thyroid lesions and follicular tumors therefore involves a similar problem, naturally to a lesser extent, but also within histopathological examinations (Rosai 1992).
The above-mentioned facts lead to two important consequences. First, a cytological diagnosis of follicular carcinoma is not accepted. Secondly, if we cannot achieve a cytological differentiation of benign and malignant follicular tumors, we need another aspect. US may have a great part to play in this field.

Theoretical reason for the difficulty in the differential diagnostics of follicular tumors

1. The cytological differential diagnostics of follicular tumors is based on a quantitative analysis of the cytological features. There is no other field in thyroid cytology where this quantitative analysis has such a great role in the differential diagnostic.
2. The only decisive sign in the histopathological diagnosis of a follicular tumor is the presence of a complete capsule surrounding a thyroid parenchyma; this is an absolutely qualitative sign.
3. The only decisive sign in the histopathological diagnosis of a follicular carcinoma is the demonstration of invasion of the tumor; this again is an absolutely qualitative sign.

The problem lies in the fact that, although the invasive nature of a follicular tumor is not independent of the cellular details (i.e. atypia, polymorphism or cluster formation), the relation between these features is primarily of statistical and not practical significance. Moreover, this relation is not linear as regards the various features investigated in cytology. This means that, except for the amount of colloid in the smear, there is no feature where the sequence nodular goiter-follicular adenoma-follicular carcinoma can be observed.

This chapter is surprisingly short as regards the occurrence of follicular tumors and the problems they cause. In our opinion there is no clear-cut evidence for or against a follicular tumor in most thyroid lesions. The greatest mistake that can be made is the cytological diagnosis of follicular carcinoma. We must be aware that the relation between the cellular atypia and the invasive nature of the tumor is uncertain, in contrast with most other human tumors, where a close relationship does exist between these features.

Cytological signs of follicular tumors

In a typical (theoretical case) a follicular tumor is characterized by a background without colloid, and by the presence of uniform follicular cells forming folliculi of various sizes. Within these cases, atypical follicular tumors (i.e. atypical adenoma and follicular carcinoma) are characterized by nuclear polymorphism and the presence of small abortive folliculi. On the other hand the cytological picture does not permit a differentiation either atypical adenoma from highly invasive follicular carcinoma or of minimally invasive follicular cancer from the very common follicular adenoma. Moreover, in a significant proportion of the cases, a clear distinction between nodular goiters and follicular tumors is difficult or even impossible, see.

Some clues to the differential diagnostics of follicular tumors

A given follicular tumor is a heterogeneous lesion as regards the well-preserved, cellular parts. Even in cases of follicular carcinoma we can find regions with macrofollicular structures. This heterogeneity differs absolutely from that of anaplastic cancer for instance. In the latter disease, the heterogeneity means that part of the tumor is well preserved, while other parts are necrotic. The heterogenity of a follicular tumor is reflected in the cytology in the form of different cell types and different cell groups.

Some features on which the cytological differential diagnostics can be discussed:

1. Background

The greater the amount the colloid in the smear, the lower the chance of a follicular tumor.

2. Follicular formation

The greater the proportion of cells forming folliculi, the greater the chance of a follicular tumor.
The greater the proportion of well-preserved microfolliculi, the greater the chance of microfollicular adenoma and minimally invasive follicular carcinoma.
The greater the proportion of small, irregular folliculi, the greater the chance of an atypical follicular tumor.

3. Cellular atypia

The greater the occurrence of polymorphic cells in the smears, the greater the chance of an atypical follicular tumor.
The greater the extent of anisonucleosis, the lower the chance of a follicular tumor (in cases without nuclear polymorphism).
The presence of enlarged cells without anisonucleosis is a very specific sign of a follicular tumor.

A follicular tumor or follicular variant of papillary cancer?

See Chapter on papillary cancer.