Improving the prediction of malignancy in cytologically suspicious thyroid nodules.

BACKGROUND: Fine needle cytology aspirates (FNA) classified as THY4 are a heterogeneous group suspicious for malignancy [papillary thyroid cancer (PTC)], which is confirmed in 50-80% of cases after surgery. AIM: To better stratify THY4 FNA specimens for the relative risk of malignancy. METHODS: We retrospectively analyzed 78 thyroid nodules classified as THY4 because of the presence of atypical cells, hypercellular trabeculae and/or intranuclear inclusions (ICI), in the absence of papillae. Two subgroups were identified: group 1 (38 nodules), showing ICI with (no.=17) or without (no.=21) trabeculae and cellular atypia, and group 2 (40 nodules), showing trabeculae and atypia but without ICI. RESULTS: PTC was detected at histology in 56/78 of the patients (71.8%). Malignancy occurred in 36/38 (94.7%) of the patients in group 1 and in 20/40 (50.0%) of the patients in group 2. Therefore, the positive predictive value (PPV) for PTC was 97.3% in the ICI+ specimens (group 1), with a sensitivity of 64.3% and specificity of 95.2%. When only ICI was present, without atypia and trabeculae, the PPV and specificity were similar (95.0 and 95.2%, respectively), but the sensitivity was decreased (48.7%). In specimens without ICI (group 2), the PPV was only 50.0%; however, combined with young age (<40 yr) and male gender, it reached a value similar to that of group1. CONCLUSIONS: In ICI+ specimens compared to ICI-, the risk of PTC is nearly doubled, since PPV increases from 50.0% to 97.3%. This observation suggests that surgery should be considered mandatory in all lesions classified THY4 at FNA, although the relevant difference in terms of cancer risk between ICI- vs ICI+ nodules might be an useful information for both the clinician and the patient.

Aggressive fibromatosis of the neck initiated after thyroidectomy.

We describe the case of a 44-yr-old woman, who 2 yr after thyroidectomy for a multinodular goiter with a follicular adenoma showed a rapidly growing mass of the neck causing dysphagia and moderate pain. Fine needle aspiration biopsy revealed the presence of fibroblast-like cells, partially with atypical features and no colloid: the cytological diagnosis was suspicious for an indeterminate (mesenchymal) neoplasm. Histological diagnosis, after extensive surgery, indicated aggressive fibromatosis. Immunohistochemistry was positive for vimentin and negative for thyroglobulin. After surgery, nuclear magnetic resonance showed a persistent mass of approximately 2 cm; dysphagia and pain persisted. Therefore, the patient received external radiation therapy (total dose 60 Gy) with clinical benefit. The patient is without symptoms 1 yr after surgery.

Immunostaining for Met/HGF receptor may be useful to identify malignancies in thyroid lesions classified suspicious at fine-needle aspiration biopsy.

The receptor for hepatocyte growth factor (Met) is not expressed in the normal thyroid but it is overexpressed in most thyroid carcinomas. We evaluated whether Met immunostaining of cytological smears from fine-needle aspiration biopsy (FNAB) may be useful for the preoperative diagnosis of thyroid cancer. Notably, routine cytological examination often fails to distinguish well-differentiated follicular carcinomas and a proportion of papillary carcinomas (low-grade papillary carcinomas and papillary carcinomas follicular variant [FVPTC]) from benign lesions: all these lesions are usually classified as suspicious. We examined 80 thyroid lesions diagnosed as suspicious at cytology that had subsequently undergone surgery. The histologic diagnosis had been: papillary carcinomas (n = 14), FVPTC (n = 11), follicular carcinomas (n = 25), atypical follicular adenomas (n = 5), follicular adenomas (n = 20), and nodular goiters (n = 5). We also studied typical papillary carcinomas (n = 30) and nodular goiters (n = 10), all correctly diagnosed at cytology. In lesions classified suspicious at routine cytology, Met immunostaining was positive in 12 of 14 (85.7%) papillary carcinomas, 8 of 11 (72.7%) FVPTC, 7 of 25 (28%) follicular carcinomas, and 5 of 5 atypical adenomas. In contrast, none of the 25 lesions cytologically suspicious but benign at histology were positive. These data suggest that Met immunostaining of suspicious cytological smears are useful for identifying malignant lesions, especially those with a papillary histotype.

Fine-needle aspiration biopsy of the thyroid.

The routine use of thyroid FNAB caused profound changes in the management of thyroid nodules. FNAB allows a prompt identification and treatment of thyroid malignancies and avoids unnecessary surgery in patients with benign lesions, improving quality of life in patients with thyroid nodules. Furthermore, FNAB provides guidance for the type of surgery and reduces costs of care. On average, standard FNAB is nondiagnostic in 25% to 40% of cases, which include inadequate specimens and indeterminate (suspicious) diagnoses. In addition, a small percentage of false-negative diagnoses occur, which are unavoidable and raise concern of a late diagnosis of cancer. To minimize the limitations of FNAB, every center should reach and maintain a high standard of expertise in all of the steps of smear preparation and interpretation. Alternative modes of sampling or sample preparation may result in a reduction of nondiagnostic samples and better accuracy. Every center should set up clinical guidelines tailored to their own FNAB results and including the evaluation of clinical data. More work is needed to increase the accuracy of FNAB in suspicious cases. Toward this goal a variety of molecular markers have been evaluated; although none of them are ideal, some are promising. More studies need to be carried out in larger series to further evaluate the accuracy of these markers in identifying specific cancer histotypes within the group of suspicious lesions. It is hoped that, in the near future, the routine use of a combination of these markers will cost-effectively improve the diagnosis of malignant nodules classified as suspicious on traditional cytology. Statistical methods such as bayesian analysis or neural networks can be advantageously used to integrate different relevant information derived from family and personal history, clinical data, cytologic results, and evaluation of molecular markers.

[Iodine deficiency and iodine prophylaxis experience in Sicily]. / Carenza iodica ed esperienza di iodoprofilassi in Sicilia.

Twenty years ago we described an area of goiter endemia in North-Eastern Sicily. In this area endemic goiter was associated to a variable degree of iodine deficiency and, in some places, also to an increased thiocyanate urine excretion. Our studies have demonstrated a strict relationship between iodine deficiency and congenital hypothyroidism (both permanent and transient), an increased prevalence of autonomously functioning thyroid nodules and an increased prevalence of thyroid cancer (follicular and anaplastic histotypes). A number of cases of endemic cretinism have also been described. An active iodine prophylaxis program has been carried in the town of Troina in the years 1979-87, by iodinating the municipal water supply. This intervention caused the disappearance of goiter in schoolchildren in only five years. In the last 20 years the prevalence of goiter has decreased in all endemic areas probably because of the "silent prophylaxis", due to improved socio-economic conditions and industrial food consumption. Today the persistence of endemic goiter confirms the inadequacy of the silent iodine prophylaxis and the need to immediately introduce an active iodine prophylaxis in Sicily.

Cold thyroid nodule reduction with L-thyroxine can be predicted by initial nodule volume and cytological characteristics.

In a previous study we demonstrated that a 1-yr treatment with L-T4 induces substantial nodule volume reduction (> or = 50%) in approximately 40% of patients with a benign solitary cold thyroid nodule. The present prospective study investigated whether it is possible to identify, before starting L-T4 treatment, nodules with a high probability to shrink in response to L-T4. We recorded several clinical and cytological features in a continuous series of 42 patients with a cold nodule and related them to the nodule volume response to 1-yr treatment with L-T4. Fisher discriminant analysis showed that a combination of some cytological features (colloid, degenerative changes, cellular hyperplasia, and fibrosis) and initial nodule volume can be used for predicting nodule volume reduction. In fact, although only 33% of all nodules shrank, 62% of colloid nodules and 57% of small degenerative nodules shrank. None of the hyperplastic or fibrotic nodules shrank. These results were validated in a different retrospective series of 46 patients and allowed us to predict nodule reduction in over 80% of the cases.

Longitudinal study on goiter prevalence and goitrogen factors in northeastern Sicily.

A longitudinal study was carried out in an area of endemic goiter of north-eastern Sicily. Three different surveys (in 1977, 1983 and 1994) evaluated the epidemiological prevalence of goiter in schoolchildren of the endemic area (towns of Bronte, Troina and Maniaci) in comparison to an iodine sufficient control area (Catania). Biochemical studies were also performed on urinary iodine and thiocyanate (SCN) excretion and 131I thyroid uptake. In the town of Troina an experimental program of active iodine prophylaxis was carried out from 1979 to 1987 by iodinating the municipal water supply. The aim of this study was to evaluate the effect of an active iodine prophylaxis program in comparison to the "silent iodoprophylaxis" due to improved economic conditions and widespread introduction of industrially produced food. In the 1977-94 period a significant decrease of goiter prevalence in schoolchildren was observed in all areas where no active iodoprophylaxis had been introduced. An abnormal prevalence of goiter, however, was still present in Bronte (12.1%) and Maniaci (25.9%) schoolchildren in respect to Catania (0.7%). In Troina, goiter prevalence decreased from 52.2 to 6.1% after only five years of active iodine prophylaxis (1983). It increased to 8.4% seven years after the program was discontinued (1994). In all areas studied average urinary iodine excretion increased by 70-100 micrograms/day except in the more rural area at Maniaci. During the same period urinary SCN values decreased by 30-40% and were lower in Troina (non volcanic soil) than in other towns studied. The balance between iodine and SCN intake appears a relevant factor in the etiology of endemic goiter in these areas and the iodine/SCN ratio inversely correlated with goiter prevalence. The persistence of endemic goiter in spite of the important changes in life style and socio-economic conditions if compared to the dramatic amelioration obtained by an active iodine prophylaxis program, confirms the inadequacy of the silent iodine prophylaxis, and further supports the need of an immediate introduction of active iodine prophylaxis in the areas of endemic goiter in Sicily.

Levothyroxine and potassium iodide are both effective in treating benign solitary solid cold nodules of the thyroid.

OBJECTIVE: To determine the effectiveness of levothyroxine and potassium iodide in treating patients with benign solitary cold thyroid nodules. DESIGN: Randomized controlled study. SETTING: Outpatient clinic at a university hospital. PATIENTS: 80 patients with solitary solid cold thyroid nodules found to be benign at cytologic examination were randomly assigned to no treatment, suppressive levothyroxine (thyroid-stimulating hormone level, < 0.3 mU/L), or low-dose potassium iodide (2 mg every 2 weeks). Seventy patients completed the 1-year study. After 1 year, patients receiving treatment discontinued drug therapy and were re-evaluated 4 months later; patients receiving no treatment were given levothyroxine and were followed for a second year. MEASUREMENTS: Nodule volume was measured by ultrasonography at 4-month intervals by an observer masked to treatment assignment. RESULTS: Mean nodule volume decreased by 40% of the basal volume in the 23 patients receiving levothyroxine (P < 0.001) and by 23% of the basal volume in the 25 patients receiving potassium iodide (P = 0.053). Volume slightly increased in the 22 untreated patients (P = 0.085). A clinically relevant reduction in nodule volume (> or = 50%) was observed in 9 of 23 patients treated with levothyroxine, in 5 of 25 patients treated with potassium iodide, and in none of 22 untreated patients (P = 0.004). Only nodules with a volume of 10 mL or less were reduced; nodules with volumes of 5 mL or less shrank most frequently. Nodule volume did not relevantly increase in treated patients but did increase in 3 of the 22 untreated patients. Drug withdrawal resulted in an increased mean nodule volume (P = 0.004) after 4 months. CONCLUSIONS: Levothyroxine and, to a lesser extent, potassium iodide are effective in arresting the growth or in reducing the volume of benign solitary solid cold thyroid nodules, especially small ones; discontinuation of therapy may result in resumed nodule growth.

[Physiopathology of the autonomous thyroid nodule]. / Fisiopatologia del nodulo "autonomo" della tiroide.

"Autonomous" thyroid nodule is a localized nodular lesion of the thyroid gland characterized by growth, iodine uptake and function, all independent from TSH control. These nodules represent a heterogeneous anatomic and clinical entity. The clinical diagnosis is based upon a negative suppression of nodule iodine uptake and scan imaging by T3 administration. The nodule function is determined by high serum thyroid hormone levels and/or low TSH (measured by ultrasensitive assay). Etiology and pathogenesis of these nodules is not yet completely clarified. Both genetic and environmental factors determine nodule growth and function: thyroid cells, in fact, are genetically heterogeneous and may have intrinsic (congenital) characteristics that may promote the growth of cellular clones having mitotic and functional activity that is partially independent of TSH. In these particular cell clones, environmental factors like iodine deficiency or other goitrogens may favour the growth of autonomous nodules and also, by activating their function, may induce toxicity. The autonomous thyroid nodules need to be treated only when they become toxic: in this case both surgical excision or radioiodine may be used.

Cancer risk in patients with cold thyroid nodules: relevance of iodine intake, sex, age, and multinodularity.

PURPOSE: We evaluated the frequency of thyroid cancer in patients with cold thyroid nodules in relation to iodine intake, sex, age, and multinodularity in a consecutive series of patients with nodular thyroid diseases. PATIENTS: In the period from 1980 to 1990, 5,637 patients were studied: 4,176 patients were from an iodine-sufficient area (ISA) and 1,461 from an adjacent iodine-deficient area (IDA). Surgery was performed in 792 patients on the basis of a suspicious or malignant finding at fine-needle aspiration biopsy. RESULTS: The overall thyroid cancer frequency was 4.6% (259 patients had cancer). Iodine intake affected the cancer rate in patients with cold nodules. The frequency of cancer in patients with cold thyroid nodules was 5.3% in the ISA and 2.7% in the IDA. This difference, however, was significant only in females. Sex had a major influence on the malignant rate of cold nodules; although female patients were more frequently observed (n = 5,028) than male patients (n = 609), the frequency of cancer was significantly lower in female patients with cold nodules (4.2%) than in males (8.2%). Age was an important factor in both sexes. The proportion of nodules that were malignant was smallest in patients of the 4th decade and was greatest in patients younger than 30 years or older than 60 years. Multivariate analysis showed that sex and age interact in determining the cancer risk in patients with thyroid nodules. Finally, the frequency of thyroid cancer in patients with a solitary nodule was not different from the frequency in patients with multiple nodules. CONCLUSION: Our study indicates that thyroid cancer risk in a patient with a nodular goiter varies markedly according to iodine intake, sex, and age but not in relation to multinodularity, as assessed by clinical examination. The knowledge of these epidemiologic aspects of thyroid cancer may increase the accuracy of the preoperative selection of patients with cold nodules of the thyroid.

Effect of TSH in human thyroid cells: evidence for both mitogenic and antimitogenic effects.

The well-known mitogenic effects of TSH observed in vivo on the thyroid are not always reproducible of human thyroid cells in vitro where conflicting results have been obtained. In order to clarify this issue, we have used primary cultures of human thyroid cells obtained from normal tissue and maintained in serum-free medium for several days. In this in vitro model we have studied the effect of TSH on growth by measuring three different parameters: [3H]-thymidine incorporation, cell counts, and DNA measurement. Monolayer cultures were plated at both low and high cell density (2 x 10(4) and 8 x 10(4) cells/25 mm well, respectively). Although at either cell density cultures were equally able to functionally respond to TSH in terms of cAMP accumulation a significant growth response to TSH was observed only in low density cultures. In high density cultures TSH had an antimitogenic effect. Moreover, TSH potentiated the mitogenic effect of insulin only in low density cultures. In contrast to TSH, FCS induced a similar proliferative response at both high and low cell density. Following TSH stimulation, cAMP content was always increased, paralleling the effect of growth in low density but not in high density cultures. The cAMP analogues dibutyryl-cAMP and 8-bromo-cAMP, as well as cholera toxin and forskolin, did not mimic the mitogenic effect of TSH but had an antiproliferative effect. In addition, these agents blunted the proliferative effect of insulin. These data suggest that in thyroid cells TSH is able to elicit both a mitogenic and an antimitogenic effect depending on the environmental conditions such as cell density.(ABSTRACT TRUNCATED AT 250 WORDS)

Relation between steroid receptor status and body weight in breast cancer patients.

Obesity is known to adversely affect breast cancer prognosis. Since obesity is associated with increased oestrogen levels, and oestrogens are growth stimulators of oestrogen receptor (ER)-positive breast carcinomas, we evaluated the relationship between the ER and progesterone receptor (PR) status of the neoplastic tissue and obesity in a series of 615 breast cancer patients. Both ER and PR concentrations were significantly and positively correlated with obesity by multiple regression analysis. Furthermore, the estimated probability of having an ER+/PR+carcinoma was significantly higher in obese patients (odds ratio 2.65, 95% confidence interval 1.56-4.48). This association between receptor-positive status and obesity was observed both in premenopausal and postmenopausal patients. Our data suggest, therefore, that obesity plays a role in determining the ER status of breast cancer and raise the possibility that ER presence in breast carcinomas occurring in obese patients is not indicative of a favourable prognosis.

Evaluation of the fine needle aspiration biopsy in the preoperative selection of cold thyroid nodules.

From 1980 to 1988 the authors examined by fine needle aspiration biopsy (FNAB) 4609 patients with solitary thyroid nodules or multinodular goiters. A total of 5605 "cold" thyroid nodules were evaluated and classified, on the basis of the cytologic findings, as malignant, follicular lesions (probably malignant and probably benign) and benign. Then the authors compared the preoperative cytologic findings with the postoperative histologic results in 827 nodules from patients who underwent surgery. In the 805 thyroid nodules in which an adequate cytologic specimen was obtained, false-negative results were 2.3% and false-positive findings were 1.1% By comparing cytologic and histologic diagnoses, preoperative FNAB resulted in the ability to accurately assess the risk of cancer in a thyroid nodule; since 250 nodules were identified as malignant, the risk of a "cold" thyroid nodule being cancer was 4.46% in this series.

The morphometric analysis of cell nuclei from fine needle aspirates of thyroid follicular lesions does not improve the diagnostic accuracy of traditional cytologic examination.

In order to evaluate the usefulness of the morphometric analysis in improving the accuracy of the traditional cytologic examination of follicular thyroid lesions, fine needle aspirates from 17 adenomatous goiters, 19 follicular adenomas and 18 follicular carcinomas were examined. In each case 20-50 follicles, accounting from 100 to 200 thyroid cells, were studied by operators unaware of the histologic diagnosis. Nuclear areas (mean, maximum and minimum area) were derived by means of a semiautomatic system and follicular thyroid lesions were classified into three groups (goiter, adenoma and follicular carcinoma) utilizing cut-off values. The results were then compared to the cytologic diagnosis carried out according to traditional (optic microscopy) criteria. Mean values of nuclear areas showed significant differences among the three groups, but a considerable overlap occurred in the size distribution of cell nuclei. At present, therefore, planimetric measurements of cell nuclei in fine needle aspirates do not improve the accuracy of standard cytologic examination in the differential diagnosis of follicular thyroid lesions.

High frequency of cancer in cold thyroid nodules occurring at young age.

In order to evaluate the risk of malignancy of cold thyroid nodules occurring in young as compared with adult patients, we studied a consecutive series of 2327 patients with a solitary cold thyroid nodule over a 6-year period. None of these patients had been previously irradiated in the neck or head. Fine needle aspiration of the nodule and cytologic examination were carried out in all patients and, on the basis of this evaluation and clinical examination 391 patients were selected for surgery; 109 patients were 4-20 years old and 2218 patients were older than 20 years. Malignancy was found in 11 (10.1%) and in 112 (5.0%) of cold thyroid nodules occurring in young and adult patients, respectively. The annual incidence of cold thyroid nodules in the population of the area studied was 5.2 vs 55.9 (per 10(5) inhabitants) in the young and in the adult group, respectively, and the annual incidence of thyroid cancer was 0.53 vs 2.82 (per 10(5) inhabitants) in the young and in the adult patients, respectively. The present study indicates, therefore, that in the absence of head or neck irradiation, cold thyroid nodules are much less frequent in young age, but that the malignancy rate of cold nodules occurring in young patients is 2-fold higher than in adults patients.

Morphometric studies on fine-needle aspirates from follicular proliferative lesions of the thyroid.

A morphometric analysis was carried out on smears of fine needle aspirates obtained from proliferative follicular lesions of the thyroid. Mean values, range as well as histograms of nuclear areas were calculated in histologically-diagnosed cases of non-toxic goiters, follicular adenomas and well-differentiated follicular carcinomas. Mean nuclear areas were found to be significantly higher in carcinomas than in adenomas and in adenomas than in non-toxic goiters. In size-frequency distribution histograms, differences among corresponding classes of the three groups were not statistically significant. Linear discriminant analysis was ineffective in differentiating not only benign from malignant follicular tumors, but also non-toxic goiters from adenomas. Morphometric studies on nuclear areas of thyreocytes in fine needle aspirates do not appear to be able to differentiate between proliferative follicular lesions of the thyroid.

[Receptor status and ovarian function in carcinoma of the breast]. / Status recettoriale e funzione ovarica nel carcinoma della mammella.

The Authors have evaluated the relationship between the presence of estrogen (ER) and progesterone (PgR) receptors and the ovarian function in 321 consecutive and unselected women who have undergone surgery for breast cancer. A significant relationship was found between the presence and the concentration of steroid receptors (ER and PgR) in the neoplastic tissue and the ovarian function. The Authors confirm the importance of considering the menopausal status in the evaluation of the results of steroid receptor assay.

The frequency of cold thyroid nodules and thyroid malignancies in patients from an iodine-deficient area.

An analysis of thyroid cancer morbidity was carried out in two adjacent areas of Sicily differing in iodine intake. A consecutive series of 911 patients with "cold" nodules from an iodine-deficient area (IDA) and 2537 from a control area (CA) were examined by fine needle aspiration and selected for surgery and pathologic examination. Malignancies were found in 27 of the patients (2.96%) from the IDA and in 139 patients (5.48%) from the CA. Based on a population survey indicating that "cold" thyroid nodules were 2.5 times more frequent in the IDA with respect to the CA, we calculated a prevalence of 127 thyroid cancers per 10(5) inhabitants in the IDA versus 93 in the CA (P less than 0.001). Moreover, follicular and anaplastic carcinomas were three times more frequent in the IDA than in the CA (75 versus 24 cases per 10(5) inhabitants, respectively). These studies indicate that iodine deficiency may be one factor in the development of certain thyroid malignancies in man.