Thyroid nodular disorder is a frequent finding in everyday clinical practice, particularly in areas of endemic goiter and in some patient groupings (elderly women) (1, 2).  

The large majority of thyroid nodules are of the benign kind (colloidocystic formations, cystic formations, nodular formations, expressions of chronic and subacute thyroiditis) and most thyroid carcinomas present limited biological aggressiveness.   
In spite of this, however, a small proportion of the thyroid carcinomas can cause the patient's death, especially where there was an absence of adequate treatment in the initial stages of the disease (3).  

The several diagnostic procedures currently available allow a precise definition of the morphological, pathologic-anatomical and functional characteristics of the thyroid nodules.   
However, they can also provoke a significant and unjustified increase in costs, with very few diagnostic benefits, when not utilized rationally.  

The diagnostic approach outlined below is derived from the more than 25 years' experience of the Pathologic Anatomy and Nuclear Medicine Departments at the Ospedale di Circolo in Busto Arsizio (VA) and has been applied to some tens of thousands of patients (Table 1).  

Investigations in the diagnosis of thyroid nodule disorder  

Clinical examination  

The medical history-taking and clinical examination should always precede any instrumental investigations.  

Some of the information gleaned (age, place of origin, dietary habits, family history of thyroid disease, irradiation of the cervical zone) may be important for the subsequent diagnostic and therapeutic iter.   

The thyroid's inspection and palpation (which as a rule is carried out with the patient seated and then repeated with the patient in supine position) allows the overall size of the gland, its consistency, and the presence of any nodular formations to be ascertained. An expert clinician is able to detect the great majority of thyroid nodular formations having a diameter of more than 1.5 cm.   

The clinical examination is then extended to include the entire cervical region (to detect the possible presence of any adenopathies) and to other organs and apparatus (to discover any clinical signs of thyroid dysfunction). If no thyroid nodule formations are revealed, there is no justification for proceeding to instrument-based tests. The latter are instead indicated - even when there are no clinical findings - in those particular cases where the diagnosis of thyroid carcinoma is made on metastases that may be locoregional, regional, or at a distance from the neoplasia (Table 2).   
   
Cytology testing on fine-needle aspirates  

In the case where the clinical examination revealed thyroid nodule formations, it is necessary to establish their nature to be then able to apply the most appropriate therapy and follow-up.  

We have been cytologically testing aspirates for the diagnosis of thyroid neoplasia for more than 25 years now (4, 5, 6). It is a simple, fast, low-cost procedure and results in a sure definition of the nature of the thyroid nodule in a high percentage of cases.   

The needle-aspiration of thyroid nodules is carried out using a 20 ml syringe and 22-guage 11/4-inch needles, with transparent cone. In particular cases, 25-guage 5/8-inch needles are employed. The testing is performed personally by the Pathologic Anatomist with the guidance of the same clinician that had previously examined the patient. The nodule is immobilized by the clinician between the index and medial fingers of both hands (Fig. 1). The aspiration is accomplished by making some excursions within the nodule with the simultaneous drawing back of the syringe piston about 2/3 of the way, and stopping at the first sign of fluid appearing at the cone of the needle. Normally, the aspirating is twice repeated, without local anesthetic. In the case of cystic nodules, the fluid is completely aspirated and the sediment obtained after centrifuging is always examined. The material is smeared onto slides with a delicate pressure and then stained with the May-Grünwald-Giemsa and Papanicolaou methods (Fig. 2). 2-4 slides are usually spread per aspiration. An increased number of slides simply leads to a dilution of the aspirated material with a worsening of the preparations and no diagnostic advantages (Figg. 3, 4). In selected cases, immunocytochemical testing is done for calcitonin, carcinoembryonic antigen and thyroglobulin, in order to confirm a diagnosis of medullary thyroid carcinoma and of any metastases (7) (Figg. 5, 6). The preoperative diagnosis of medullary thyroid carcimoma is important for the timely recognition of familial forms (MEN 2A - 2B) and the possible presence of pheochromocytoma, which - if disregarded - would be a significant surgical risk factor (Fig. 7).  

Cytology testing of needle-aspirates is done on nodules that have already been characterized from a functional point of view by thyroid scintigraphy. In particular, the nodules having a scintigraphic picture of autonomous adenoma (“hot” nodules with a functional inhibition of normal thyroid parenchyma) are not examined cytologically, since such nodules are always benign, save for exceptional cases. On the contrary, all hypofunctioning or normofunctioning nodules are cytologically checked out.  

In other institutions, cytology testing is carried out before thyroid scintigraphy on all palpable nodules and the latter procedure only applied in cases with a cytological diagnosis of “adenomatous tumor or formation”.  

In the period 1980-1997, we examined some 37,895 patients through cytological tests on needle-aspirates of the thyroid. 1,240 (3.3%) resulted positive for thyroid carcinoma, 35,840 (94.6%) negative, with 194 (0.5%) suspect cases. The proportion of preparations that were unsuitable for a correct interpretation was limited to 1.6% of the tests carried out. The diagnostic accuracy of the cytology testing was then assessed by correlating this with the histological examinations on 4,069 patients who had undergone surgery, because of a positive or suspect cytology result, or because of the presence of hyperactive or voluminous struma. 98% of cytological diagnoses of malignity and 95.4% of benign adjudications were confirmed by the histology examinations (Table 3). Only in the case of the cytological diagnosis of “adenomatous formation” is it indispensable to resort to the histological test, since the differentiation between adenoma and capsulated follicular carcinoma is not based on the cytological features, but rather on the evidence of a going beyond of the capsule and vascular invasion: factors that are only detectable by histology. It is to be emphasized how, in these cases, the histological examination must deal with several sections in order to be capable of ascertaining the zones of invasion, also in the event of such zones being of limited dimensions. To be noted is how the need to examine multiple sections makes impromptu histology testing useless, since this may allow evaluation of few sections and make the subsequent, definitive histology testing more difficult because of alterations provoked in the histology sample (8). The recognition of capsulated follicular (or “minimally invasive”) carcinoma is important, since the risk of relapse or metastasis further along is significantly less compared to invasive follicular carcinoma, and the survival rate is significantly greater (Fig. 8). The low reoccurrence risk in the capsulated follicular carcinomas having a diameter less than 2.5 cm with onset in patients younger than 45 years permits the avoidance of radiometabolic therapy with post-op 131-I and the follow-up scintigraphy.   

Thyroid scintigraphy  

Thyroid scintigraphy is a simple procedure, rapidly performed and, with the limited dosimetric load for the patient, is not operator-dependent. It allows an assessment to be made of thyroid regional functioning and other, additional information (gland volume and morphology, degree of retrosternal extension). If carried out before the cytology tests, the number of non-conclusive cytological diagnoses is cut, since it makes the checking of the functioning adenomas superfluous, or it may facilitate the diagnosis thanks to the useful morpho-functional information about the area subjected to structural checking. The data provided by scintigraphy also allows seeing the uni- or multi-nodular goiter with greater precision, and thus to more appropriately calibrate the therapeutic options as well as the type and frequency of subsequent check-ups.   

Thyroid scintigraphy is executed with a linear scanner 15' after the i.v. administration of 70-200 MBq of 99m-pertechnetate.   
The scintigraphic map obtained with the scanner has the advantage of achieving 1:1 maps and of quickly and easily marking out the palpable nodules, facilitating the integration of the clinical and scintigraphic information. Thyroid scintigraphy carried out with a gamma-camera (especially if equipped with a pin-hole collimator) has the advantage of greater spatial resolution, faster execution (useful when dealing with pediatric patients) and the possibility of subsequent elaboration of the functional image. In the event of functioning nodules being found, thyroid scintigraphy with radio-iodine may be indicated (131-I, or [if available] 123-I), since some thyroid nodules capable of taking up the pertechnetate are not able to “organify” the iodine and therefore have to be subjected to cytology testing.   

Thyroid ultrasound  

Thyroid ultrasound is an examination means that allows an accurate morphological definition of the thyroid gland. On the other hand, it does not permit the formulation of a sufficiently reliable diagnosis of thyroid nodule, so that it is always necessary to resort to cytology testing of a needle-aspirate (9). The sensitivity of thyroid ultrasound is high and allows detection of the presence of thyroid nodular formations of just a few millimeters.   
The incidence of such small nodular formations is particularly high in some geographical areas and in certain age bands, whereas their clinical significance is modest, even in cases where it is a question of malign neoplastic lesions. In spite of the papillary microcarcinomas (size < 1 cm) being particularly frequent (3.2% in our experience [Table 4] and up to 30% in some autopsic case surveys), it is in fact known that the impact on survival of such small neoplasia is insignificant.   
Most of them do not reach dimensions of more than a centimeter during a patient's lifetime and only in exceptional cases do they give rise to metastasis long-term. Deferring the diagnosis of these neoplasia to when they would have reached the limits of clinical detection (about 1.5 cm) or even subsequently to regional lymph nodal metastatization, does not involve significant survival variations.   
From this it derives that the risk - although limited - of surgical complications and the potential side-effects of TSH-suppressive hormonal therapy, probably exceed the hypothetical benefits of early diagnosis.   
For such reasons the use of thyroid ultrasound at this diagnostic stage does nothing to improve the efficacy of the diagnostic iter but, on the contrary, induces the need for further investigations, because of the impossibility of attaining a definitive diagnosis by ultrasound alone.   
Cytology testing with ultrasound guidance is more demanding, both from the technico-interpretive standpoint and in terms of time and cost.   
Moreover, this option of arriving at a diagnosis of papillary microcarcinoma thanks to ultrasound-guided needle-aspirates does not translate into any effective benefit for the patient, but instead exposes the patient to the risks of surgical and hormonal treatments and to the negative psychological impact of a diagnosis of malignity (10).   

On the other hand, thyroid ultrasound can be very useful in selected cases where the clinical situation is difficult unclear and, combined with ultrasound of the cervical region, is an invaluable aid in ascertaining any possible metastatic adenopathies in the pre-op staging phase and in the follow-up of thyroid carcinomas.   

Laboratory tests  

In the large majority of cases, serum TSH assays in patients with thyroid nodular formations allows the level of thyroid activity to be established. Indeed, normal values mean the presence of a thyroid dysfunction can be excluded, high values indicate hypothyroidism and a suppressed TSH level is a sign of hyperthyroidism.  

Testing for anti-Tg and anti-TPO antibodies allow the presence of thyroid disorders of autoimmune origin to be determined.   
Such information is important for establishing any therapy and subsequent follow-up programs.   
  

A rational protocol for the diagnosis of thyroid neoplasia  

Our own protocol allows us to arrive at a definitive diagnosis and full appreciation of the clinical situation in less than one “in-office” morning. Immediately following the clinical examination (also carried out in the Nuclear Medicine unit), any patient with palpable thyroid nodular formations undergoes thyroid scintigraphy with 99m-TC and possible venous blood sampling for hormone assay and anti-thyroid antibodies.   
The non-functioning nodular formations are then directly subjected to needle-aspirated cytology testing.   
This investigation is carried out by the pathologist with the guidance of the same clinician who had previously assessed the patient.   
This permits a useful exchange of information between pathologist and clinician.   
With such a procedure it is possible to gather all the useful information needed for a full characterization of the thyroid nodule's nature and activity, with a contained commitment of economic and human resources.   
The citizen appreciates the chance to see the entire diagnostic iter finished off within a few hours, with a clear saving of time.   
  

Carlo Ravetto   
Primario U. O.  Anatomia Patologica Ospedale di Circolo di Busto arsizio (VA)   

Luigia Colombo   
Primario U. O. Medicina Nucleare Ospedale di Circolo di Busto Arsizio (VA)   

Massimo E. Dottorini   
Aiuto Corr. U. O. Medicina Nucleare Ospedale di Circolo di Busto Arsizio (VA)