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We studied the feasibility of employing the measurement of thyroglobulin (Tg) in the washout of the needle used to perform the fine needle aspiration cytology (FNA-Tg) for the differential diagnosis of nonthyroidal neck masses of unknown etiology. We studied 35 patients presenting for 1 or more neck lumps outside the thyroid gland. A previous history of treated differentiated thyroid cancer (DTC) was given by 23 patients and of nonthyroidal malignancy by 3 patients. FNA-Tg was measured in the Tg-free serum used to wash out the needle employed for the cytology. Finally, all patients were treated by surgery. FNA-Tg was always detectable in 14 patients with thyroid cancer metastases demonstrated by histology, with a mean (+/- SD) of 27,087 +/- 37,622 ng/FNA (P less than 0.002) compared to patients without thyroid cancer metastases (mean +/- SD, 12.1 +/- 4.8 ng/FNA in 7 cases; undetectable in 14 cases). Assuming 21.7 ng/FNA (the mean +/- 2 SD of the negative patients) as the cut-off value, all patients with metastases from DTC were detected by FNA-Tg. FNA-Tg had better negative predictive value than cytology, since this last technique gave 10 inconclusive results, comprising 2 false negative results in patients with metastases from DTC. Our results indicate that elevated concentrations of FNA-Tg in nonthyroidal neck nodes strongly suggest the diagnosis of metastases from DTC.

The authors investigated the humoral and tissue expression of six antigens associated with medullary thyroid cancer (MTC): calcitonin (CT), calcitonin gene-related peptide (CGRP), carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), somatostatin (SRIF), and thyroglobulin (TG). The antigens were studied in the neoplastic C cells using immunohistochemistry with specific antisera and in the plasma using specific radioimmunoassay. Eighteen patients (8 male and 10 female patients, aged 12-72 years) were studied. Mean follow-up was 70.7 months (range, 2-179 months). Nine patients (50%) died of their disease after a mean follow-up of 47.2 months (range, 2-116 months). By immunostaining, primary tumors expressed CT and CEA in all cases and NSE was positive in 90%, CGRP in 66%, SRIF in 63%, and TG in 58%. Metastatic tissues were positive in all cases of CT staining, 92.8% of CEA, 71.4% of NSE, 73.3% of CGRP, 38.5% of SRIF, and only 13.3% of TG staining. In positive cases the percentage of positive cells and the degree of staining were variable among the different antigens. The expression of an antigen in the neoplastic cells was associated with the hypersecretion of the corresponding antigen in the circulation in the case of CT and CEA. The levels of these antigens were elevated in all patients with metastases and could accurately predict the appearance of new metastases or indicate the effective treatment of previous metastases by surgery. In the case of NSE, CGRP, and SRIF, few patients had increased plasma concentrations of the antigens and these usually occurred during very advanced phases of the disease. Detectable levels of serum TG were never observed. When the outcome of the disease was compared with the expression of CT, CEA, NSE, CGRP, and TG, no correlation could be found. On the contrary, SRIF expression in the primary tumor could differentiate two groups of patients with different survival rates. SRIF-positive patients had survival rates of 100% and 50% at five and seven years, respectively, whereas SRIF-negative patients had survival rates of 40% at five years and 25% at seven years.

We have investigated whether the alternatively spliced form of thyroid peroxidase (TPO), which has been shown clearly to occur in Graves' thyroid, is present in normal thyroid. We have performed a polymerase chain reaction on cDNAs prepared from normal thyroid mRNAs using primers 100 bases up-stream and down-stream from the 171 nucleotides that have been shown to be spliced out. Size analysis of the polymerase chain reaction products by agarose gel electrophoresis revealed bands at 0.2 and 0.37 kilobases (kb), sizes predicted to be obtained when the two forms of TPO cDNA are present. This was confirmed by hybridization with a 32P-labeled probe corresponding to the 20 nucleotides of the junction site. After stringent washing, the 0.2-kb band gave a clear positive signal, which was stronger than that of the 0.37-kb band despite the latter cDNA being more abundant. This demonstrates clearly that the alternatively spliced form of TPO exists in normal thyroid. Its significance is discussed.

In a previous work we characterized a major epitope of thyroid peroxidase (TPO), which was recognised by 66% of 157 patients with autoimmune thyroid disease (AITD) and 9 out of 50 patients with non-thyroidal autoimmune disease (NTAID) 6 of whom had antibodies to the gastric parietal cell antigen (PCA). In the present study we have affinity purified C2 antibodies and demonstrated that they bind to the native TPO enzyme in a radioimmunoassay (RIA). We have measured antibodies to the C2 peptide and a second TPO peptide, C21, in enzyme-linked immunosorbent assays (ELISA) in 30 patients with NTAID all of whom have antibodies to the gastric PCA, having first determined the incidence of antibodies to C21 in 98 patients with AITD who do not have antibodies to the gastric PCA. 58% of patients with AITD have antibodies to C21, a peptide of TPO which overlaps C2 by 21 amino acids in the region containing an 11 residue fragment which is very similar to a fragment of the H+ K+ ATPase, which has recently been shown to be a major component of the gastric PCA. In patients having NTAID and antibodies to the gastric PCA, 60% are positive for C2 Ab and 100% for C21 Ab, which is suggestive of an epitope shared by TPO and H+ K+ ATPase, corresponding to TPO 659----669 and H+ K+ ATPase 177----187. We conclude that C2 antibodies are heterogenous and comprise activities which bind to the intact enzyme and activities binding to an epitope which may be common to TPO and H+ K+ ATPase.

Serum thyroglobulin (Tg) measurements in patients with treated differentiated thyroid cancer are usually well correlated with the presence or absence of residual or metastatic thyroid tissue. However, it is not rare to find a patient with detectable serum Tg levels but negative 131I whole-body scan (WBS) and no evidence of disease activity. To clarify the reason for this discrepancy, we decided to perform the WBS after the administration of a therapeutic dose of 131I in 17 consecutive patients in whom serum Tg was detectable while the WBS performed with a 5 mCi tracer dose was negative (12.6% of 135 patients studied with both WBS and serum Tg). The result of this study demonstrated that after this procedure the WBS became positive for significant residual or metastatic areas of radioiodine uptake in all patients but one. Such data indicate that in our patients the presence of circulating Tg is not a false-positive Tg result, but is due to the presence of residual or metastatic tissue that is not detected in the conventional WBS, that can be visualized using therapeutic doses. Preliminary follow-up data indicate that this procedure may also have therapeutic effect, although the relevance of this aspect remains to be established.

In the present investigation we studied serum anti-thyroglobulin and anti-thyroid microsomal autoantibodies, measured by hemagglutination technique, in 600 patients with thyroid cancer seen by us from 1975 to 1985 (mean follow-up 46 months). Positive thyroglobulin antibodies and/or microsomal antibodies were found in 138 (23%) patients (23.9% with papillary, 25% with follicular, 16.1% with anaplastic, and 4.1% with medullary thyroid carcinomas). The incidence of positive tests was similar in each decade of life (ranging between 21.9% and 27.9%), whereas in a normal sex-matched population with no evidence of thyroid disease, the frequency of positive tests was very low in young people and increased to 23% in people older than 60. In 64 patients with no evidence of residual or metastasic thyroid tissue after surgery and radioiodine, initially positive antibody titres became negative in 54.6%, decreased in 32.8%, did not change in 3.1%, and increased in 9.3%. On the contrary, antibody titres of patients with persistent disease became undetectable in 8.3%, decreased in 16.6%, remained unchanged in 25%, and increased in 50%. The clinical course of differentiated thyroid cancer was unaffected by the presence of thyroid antibodies and no difference was found in the death rate between antibody-positive and antibody-negative patients (11.5% and 13.6%, respectively). In conclusion, our data indicate that: 1) autoimmune phenomena are not an infrequent finding in thyroid cancer; 2) as in non-malignant thyroid diseases, positive-antibody tests are more frequently observed in females than in males; 3) at variance with normal controls, no age-dependent increase in serum anti-thyroid antibodies was found in thyroid cancer; 4) the presence of metastatic thyroid tissue seems to be necessary to perpetuate the autoantibody synthesis, and 5) anti-thyroid autoantibodies are not a protective or worsening factor in the tumour outcome.

We report on 49 patients younger than 18 years at diagnosis, of 776 patients with thyroid cancer, seen in our institution in the last 17 years. Female/male ratio was 2.2:1. Histologic type was papillary in 44, follicular in 4, and medullary in 1. Initial treatment was near-total thyroidectomy with or without neck dissection. Surgical complications (vocal cord palsy, permanent hypoparathyroidism, or both) were found in 25 patients and were usually associated with more advanced primary tumors. At surgery, node metastases were present in 73% of the patients and lung metastases, detected by chest x ray films, in 6%. Patients were treated with thyroid suppressive therapy and, except the one with medullary cancer, with radioiodine (131I) therapy. After a mean follow-up of 7.7 +/- 4.4 years (range, 1 to 17 years), one patient with lung metastases died of respiratory failure. Of 36 patients who have been followed up more than 4 years, 22 (61.1%) are now cured, and 14 have metastases (to lymph nodes, 2; to nodes and lung, 10; and to lung, 2). Since 1977 serum thyroglobulin (Tg) was used routinely as a tumor marker for differentiated thyroid cancer. After operation, Tg was elevated in all patients both not receiving (mean +/- SE, 902 +/- 380 ng/ml) and receiving (44 +/- 15 ng/ml) suppressive therapy; after 131I treatment, serum Tg dropped to 104 +/- 50 and 7.3 +/- 1.7 ng/ml, without and with suppressive therapy, respectively. Of 11 patients with lung metastases treated with 131I, respiratory function, as assessed by means of spirometry, was normal in three, mildly reduced in six, and severely impaired in two (including the one who died). In conclusion, our study indicates that thyroid cancer in young patients is rather advanced at initial examination and usually associated with node and, less frequently, lung metastases. Total thyroidectomy, radioiodine treatment, and thyroid suppressive therapy represent an effective combination of treatments for this disease and allow a good quality of life. The most serious adverse effect is represented by the high incidence of surgical complications and by pulmonary restrictive disease in relation to lung metastases.

Thirty (3.8%) of 780 patients with differentiated thyroid cancer seen between 1970 and 1987 had bone metastases. The primary tumor was follicular in 26 patients and papillary in four. Mean age at diagnosis was 61 years. The manifestation of bone metastases was the presenting symptom in 18 patients (60%). Treatment included total thyroidectomy, levothyroxine sodium therapy, and radioactive iodine treatments. Twenty-seven patients had bone metastases from the initial observation, with 44 sites involved. Of the sites, 27 (61%) were shown both on iodine 131 whole-body scan (WBS) and on x-ray film, 11 (25%) only on WBS, and six (14%) only on x-ray film. Multiple involvement was observed in 11 patients. The radiologic appearance was invariably osteolytic. Serum thyroglobulin was elevated in all patients. After radioactive iodine, no WBS+/X-ray+ metastases showed a complete response, although a sclerotic border was noted in several cases, whereas six WBS+/X-ray- lesions were no longer detectable by WBS. Treatment with radioactive iodine and bone surgery resulted in a complete cure in three patients and in a reduction of tumor mass in three. Twenty-one (70%) of the patients died of thyroid cancer after a mean survival of 86 months. Of the nine patients still alive, two are free of disease, three have a good quality of life, and four have severe disability.

We report the incidence of thyroid cancer in a series of 1832 consecutive patients seen for thyrotoxicosis of any etiology during 1970 and 1985 in our department. Surgical treatment for thyrotoxicosis was selected as the treatment of choice in 179 patients (9.8%), 86 with toxic diffuse goiter (TDG), 21 with toxic nodular goiter (TNG) and 40 with toxic adenoma (TA). The presence of thyroid cancer was found in 11 patients for a total incidence of 6.1%. Six patients had TDG (percent incidence in this group 6.9%), 4 patients had TNG (7.5%) and 1 had TA (2.5%). While the presence of thyroid cancer was totally unsuspected in TNG and TA, in TDG 4 out of 6 patients found to have a cancer, had been suspected before surgery. When a thyroid nodule was present in a toxic diffuse goiter the possibility to face with a malignant lesion reached 22.2% of the cases (4 out of 18 cases), while only 2 out of 68 patients (2.9%) with TDG and no nodule had thyroid cancer. These results confirm recent other series reporting the frequent association of hyperthyroidism and thyroid cancer and suggest that in thyrotoxic patients any nodule must be screened carefully to rule out malignancy.

The utility of determining circulating neuron-specific enolase (NSE) in medullary thyroid carcinoma was assessed in 25 patients followed up for a mean period of 45.6 months. In 5 patients tested before any treatment serum NSE concentrations were in the normal range. After total thyroidectomy abnormally high serum NSE concentrations (more than 9.8 ng/ml) were found in 1/3 patients with normal calcitonin (CT) in remission, in 2/10 with elevated CT levels but no evidence of disease and in 9/12 with elevated CT levels and documented metastases. The mean (+/- SD) NSE value in this last group was 12.0 +/- 12.6 ng/ml, significantly higher than in the other groups (p less than 0.005). The time course of serum NSE in patients with long follow-up seems to indicate that serum NSE rises when a large tumor mass is present and usually parallels the pattern of circulating CT. Effective treatment of the metastases is usually followed by reduction of serum NSE. Thus, serum NSE can serve as an additional humoral marker for medullary thyroid carcinoma, its elevation being associated with important metastatic involvement and with a poor prognosis of the tumor.

The authors evaluated the presence of somatostatin (SRIF) in the plasma and in the tumor tissue of a total of 22 patients with medullary thyroid cancer (MTC) and studied the effect of exogenous SRIF administration on basal and pentagastrin (PG)-stimulated plasma calcitonin (CT) and carcinoembryonic antigen (CEA) levels. Mean plasma SRIF concentrations were significantly higher than those found in normal controls, with five of 15 patients having plasma SRIF levels above the mean + 2 SD of normal controls. High immunoreactive SRIF concentrations were found in the extract of three tumor tissues but not in one follicular thyroid cancer or in one toxic diffuse goiter. By immunoperoxidase staining seven of 11 (63.6%) primary MTC and five of 13 (38.5%) metastases expressed SRIF antigen in a low number of cells and with a weak degree of staining. As expected, CT was expressed in almost 100% of the cases with positivity in most of the cells and strong degree of staining. Patients with positive SRIF staining in the primary tumor had longer survival than SRIF negative patients. Infusion of synthetic SRIF (11 micrograms/minute/45 minutes) produced a significant reduction of plasma CT (but not CEA) levels in 12 of the 15 patients submitted to this test. Maximal percent decrease of plasma CT ranged from 10.8% to 72.7% of the basal value and was usually observed between 30 and 45 minutes from the beginning of the infusion. When infused together with the injection of PG, SRIF was able to significantly (P less than 0.05) inhibit the PG-induced CT release in five of six patients tested. These results demonstrate the following: SRIF is present in a few cells of many primary MTC and less frequently in their metastases; tentatively, the expression of SRIF antigen in the tumor seems to be associated with longer survival; increased SRIF concentrations are found in the plasma of some patients with metastatic involvement; and treatment with exogenous SRIF reduces the basal and PG-induced CT (but not CEA) release from the tumor.