Extrathyroidal Tissue Research Articles

Permanent hypocalcemia in patients operated for thyroid carcinoma

The incidence and risk factors for permanent hypocalcemia in thyroid carcinoma were investigated. The records of 417 patients were reviewed retrospectively at tertiary oncology referral center. Total or subtotal thyroidectomy patients constituted group I (n = 225), reoperative thyroid surgery patients constituted group II (n = 106), and therapeutic neck dissection cases constituted group III (n = 86). Age, gender, thyroid functions, pathologically verified tumor type, differentiation, localization and size, multicentricity, thyroid capsule invasion, extrathyroidal soft tissue invasion, coexistence of lymphocytic thyroiditis, metastatic lymph nodes dissected, incidental parathyroidectomy, and the type of surgery were investigated. RE SULTS: Permanent hypocalcemia was seen in 32 (7.7%) patients. The incidence of permanent hypocalcemia for each group was 1.7%, 10.3% and 19.7%, respectively. Related risk factors were hyperthyroidism for group I [adjusted relative risk (RR) = 21.1, 95% confidence interval (CI) = 2.6-165, p = 0.01] incidental parathyroidectomy for group II (RR = 7.8, 95% CI = 1.9-31.0, p = 0.004), and extrathyroidal soft tissue invasion (RR = 3.1, 95% CI = 1.1-9.5, p = 0.03) for group III. Permanent hypocalcemia rate was increased with reoperative thyroid surgery and neck dissection added to total thyroidectomy. Hyperthyroidism, incidental parathyroidectomy and extrathyroidal extension were related risk factors.

Review on the Occasion of a Decade of Recombinant Human TSH: Prospects and Novel Uses

The introduction of recombinant human thyroid-stimulating hormone (rhTSH) almost a decade ago represents a remarkable achievement in the history of clinical thyroidology. rhTSH now contributes substantially to the diagnostic approach to thyroid cancer, offering a reliable and safe alternative to thyroid hormone withdrawal by avoiding the morbidity of hypothyroidism. Several recent studies have also demonstrated the efficacy of radioiodine ablation of thyroid remnants after preparation with rhTSH. Moreover, the use of rhTSH in this context is associated with a lower whole body exposure to radiation compared to thyroid hormone withdrawal. Although not approved officially, rhTSH-assisted treatment of locoregional or distant metastatic disease may be the treatment of choice for patients in whom hypothyroidism may be relatively contraindicated, such as the very young and the aged, although additional efficacy studies are necessary. The compound has also been shown to be useful in the treatment of nontoxic multinodular goiter, especially when the radioiodine uptake is low. Finally, rhTSH may prove to be useful in studying the functional reserve of thyroid in the aging process, as well as the putative role of the TSH receptor in extrathyroidal tissue, such as lymphocytes, osteocytes, and adipocytes.

Hürthle Cell Neoplasms of the Thyroid

The purpose of this study was to determine the sonographic features of Hürthle cell neoplasms (HCNs) of the thyroid. We retrospectively analyzed the sonographic appearance of 15 histologically proven HCNs in 15 patients aged 16 to 70 years (mean age, 44 years). Sonographic features that were reviewed included the size and echogenicity of the tumors, the presence of cystic areas or calcifications, and detectable blood flow on color Doppler imaging. Correlation of sonographic findings with pathologic results was performed. The tumors ranged from 0.4 to 7 cm in diameter, but most were less than 3 cm in diameter. Four (27%) of the 15 tumors were homogeneously hypoechoic. Two tumors (13%) were predominantly hypoechoic with isoechoic areas to thyroid parenchyma. Two (13%) neoplasms were isoechoic to thyroid parenchyma. Four (27%) tumors were predominantly isoechoic, containing hypoechoic areas, and 3 (20%) tumors were hyperechoic. Three neoplasms contained cystic components. None of the tumors contained calcifications. One tumor was avascular on Doppler examination. One neoplasm showed only peripheral blood flow. Thirteen tumors showed internal vascularity, 7 of them with peripheral blood flow. Twelve HCNs were benign, and 3 were malignant on pathologic examination. Hürthle cell neoplasms show a spectrum of sonographic appearances from predominantly hypoechoic to hyperechoic lesions and from peripheral blood flow with no internal flow to extensively vascularized lesions. Pathologic criteria differentiating benign and malignant HCNs (absence or presence of a capsular breach, vascular or extrathyroidal tissue invasion, nodal involvement, and distant metastasis) are beyond the resolution of sonography and fine-needle aspiration biopsy and require removal of the entire lesion. This precludes diagnosis and characterization of HCNs by sonography.

Risk factors for permanent laryngeal nerve paralysis in patients with thyroid carcinoma

This study investigated the incidence of and risk factors for permanent recurrent laryngeal nerve paralysis for patients with thyroid malignancy. Retrospective chart review. Tertiary oncology referral centre. Records of 290 consecutive patients treated between 1997 and 2001 were reviewed. All patients who have had one or more operations. Patients with preoperative recurrent laryngeal nerve paralysis and patients who underwent thyroidectomy in conjunction with laryngectomy were excluded. The incidence of postoperative permanent cord palsy was calculated in relation to the number of patients. Age, gender, thyroid functions, tumour localisations and size, multicentricity, thyroid capsule invasion, extrathyroidal soft tissue invasion, differentiation, histological type, co-existence of lymphocytic thyroiditis, total number of dissected and metastatic nodes, type of surgery, the place of surgery and number of operations were the risk factors investigated for permanent recurrent laryngeal nerve paralysis. Univariate and multivariate analyses were performed. Permanent recurrent laryngeal nerve paralysis developed in 27 (9%) of 290 patients with thyroid carcinoma. Transient and permanent paralysis rates in total or subtotal thyroidectomy, completion thyroidectomy and neck dissection groups were 5/3%, 7/3% and 24/17% respectively. Cox regression analysis identified the type of surgery [adjusted relative risk (RR) = 2.1, 95% confidence interval (CI) = 1.1-4.0, P = 0.01], extrathyroidal soft tissue invasion (RR = 5.7, 95% CI = 2.0-15.7, P = 0.001) and number of metastatic nodes (RR = 1.6, 95% CI = 1.1-2.5 P = 0.01). The factors related with recurrent laryngeal nerve paralysis post-thyroid carcinoma surgery are linked to special features of the tumour and to the type of surgery.

Clinical Features and Prognostic Factors for Survival in Patients with Poorly Differentiated Thyroid Carcinoma and Comparison to the Patients with the Aggressive Variants of Papillary Thyroid Carcinoma

We performed this study to compare the clinicopathologic features and outcomes between the patients with poorly differentiated thyroid carcinoma (PDTC) and the patients with the aggressive variants of papillary thyroid carcinoma (PTC). To evaluate the prognostic factors for survival of the patients with PDTC, we selected 49 patients with PDTC and 23 patients with the aggressive variants of PTC from three hospitals during the recent 15 years. The five-year survival rate and clinicopathologic features of the patients with PDTC were not different from those of the patients with the aggressive variants of PTC. Univariate analysis revealed the significant poor prognostic factors for survival of the patients with PDTC and the aggressive variants of PTC as follows: 1) an age more than 45 years, 2) a tumor size larger than 4 cm, 3) the presence of tumor invasion to extrathyroidal tissue or the trachea, 4) the presence of cervical lymph node invasion, 5) the presence of distant metastasis, 6) the absence of high-dose radioactive iodine (RAI) therapy, and 7) TNM stage II, III and IV. Distant metastasis and high-dose RAI therapy were independent significant predictors for survival of the patients with PDTC and the aggressive variants of PTC on multivariate analysis. However, distant metastasis was the only independent significant predictors for survival of the patients with PDTC excluding patients with the aggressive variants of PTC.

Surgical Management of Thyroid Carcinoma

Thyroid carcinoma has a unique biologic behavior characterized by early spread to regional lymph nodes and occasional extrathyroidal soft tissue extension but a low incidence of distant metastasis and infrequent disease-related death. Therefore, controversy exists over the proper extent of thyroidectomy and regional lymph node dissection in patients with differentiated thyroid carcinoma (DTC) and medullary thyroid carcinoma (MTC). The modest disease-specific mortality makes it unlikely that the extent of surgery will ever be the subject of a prospective randomized trial. Although more extensive cervical surgery may have only a limited effect on the duration of survival in patients with DTC, it may significantly improve quality of life by minimizing cervical recurrence. The high rates of cervical recurrence in patients with DTC and MTC have alerted physicians to the importance of fine-needle aspiration biopsy and ultrasonography for the diagnosis, preoperative staging, and follow-up of thyroid cancer. In patients with MTC, death caused by disease is uncommon in the absence of radiographically evident distant metastasis at the time of thyroidectomy. Cervical recurrence is even more common with MTC, and the need for compartment-oriented lymphadenectomy is accepted as standard surgical treatment to minimize disease recurrence. Postoperatively, calcitonin (CT) levels can be used to guide clinical management, but basal CT levels should not be used to direct the timing of prophylactic thyroidectomy in affected high-risk patients with familial MTC.

Follicular thyroid carcinoma: histology and prognosis.

Follicular thyroid carcinoma (FTC) is the second most common thyroid malignancy after papillary thyroid carcinoma. The authors studied the clinical course of 132 patients with FTC to determine whether there was a direct relation between the histologic degree of invasion, tumor recurrence, and patient survival. The 132 patients in the study population underwent 182 thyroid carcinoma-related operations, and their mean follow-up was 7.5 years (median:,6 years; range, 0-39 years). The following criteria were used to define malignant follicular neoplasms: 1) minimally invasive, tumor invasion through the entire thickness of the tumor capsule; 2) moderately invasive, tumor with angioinvasion (with or without capsular invasion); and 3) widely invasive, broad area or areas of transcapsular invasion of thyroid and extrathyroidal tissue. Forty-five of 119 patients (37.8%) presented with minimally invasive FTC (capsular invasion only), 50 patients (42%) presented with moderately invasive FTC (angioinvasion with or without capsular invasion), and 24 patients (20%) presented with widely invasive FTC. At presentation, 12 patients (9%) had distant metastases, and 8 patients (6%) had lymph node metastases. Excluding 12 patients who presented with distant metastases, 21 patients (16%) developed recurrent metastases 6 months after their initial treatment. Among 45 patients with capsular invasion only, 6 patients (13%) developed recurrent or persistent disease, and 5 patients (11%) died. Of the 50 patients who had angioinvasion with or without capsular invasion, 10 patients (20%) developed recurrent or persistent disease, and 7 patients (14%) died. Patients who had angioinvasion with or without capsular invasion had a less favorable prognosis compared with patients who had capsular invasion only (P < 0.0001). Among patients who had widely invasive FTC, 9 of 24 patients (38%) developed recurrent disease, and 8 patients (33%) died; in addition, 7 of the other 24 patients (29%) had persistent disease and died. The overall death rate for patients with widely invasive FTC was 62%. Patients with persistent disease had a poorer prognosis compared with patients who had recurrent disease (P < 0.0001). Twenty-eight patients (21%) in the entire group died of FTC. In the current retrospective investigation, the authors demonstrate that patients with minimally invasive FTC (capsular invasion only) had a slightly better survival rate at 5 years (98%) compared with patients who had angioinvasion with or without capsular invasion (80%) and had better survival compared with patients who had widely invasive FTC (38%). Other (but not all) reports in the literature support the findings that FTC with angioinvasion is more aggressive than FTC with only capsular invasion yet is less aggressive than widely invasive FTC. The authors conclude that FTC no longer should be classified as either minimally invasive or widely invasive; rather, they recommend classifying FTC as minimally invasive, moderately invasive, or widely invasive, because prognosis varies according to these groupings.

Can we rely on pathologic parameters to define conservative treatment of papillary thyroid carcinoma?

Papillary thyroid carcinoma is the most common malignant tumor of the thyroid and usually behaves in an indolent fashion. At most institutions these tumors are treated by near-total or total thyroidectomy followed by radioactive iodine ablation. The 2 main reasons for this extensive treatment include high rate of multicentricity in papillary carcinoma and difficulty in ablating large thyroid remnants with radioactive iodine after partial thyroidectomy. Some authors believe, however, that this treatment protocol may not be justified in all cases of papillary carcinoma. We analyzed 253 total thyroidectomies performed for papillary thyroid carcinoma for the following pathologic variables: tumor size, presence of tumor capsular and/or vascular invasion, intrathyroidal spread, tumor in the contralateral lobe, and lymph node metastases. Tumors measuring less than 1 cm and those with extrathyroidal soft tissue extension were excluded from this study. Among 253 cases (197 females, 56 males, age range 14-88 years), the primary tumor size ranged from 1-9.5 cm; 162 cases were completely encapsulated. Tumor capsule invasion was seen in 139 (86%) and vascular invasion was present in 32 (13%) cases; of these 27 (11% of the total) patients showed both tumor capsule and vascular invasion. Seventy-four (29%) patients showed tumor in the contralateral lobe; in 35 (47%) of these cases the contralateral tumor measured less than 1.0 cm. Lymph nodes were sampled in 106 cases, metastases were present in 67 (67/106 = 63%) and only 16 cases with lymph node metastases showed contralateral tumors. No significant correlation was noted between tumor size, occurrence of contralateral tumors, and lymph node metastases. Seventy-one percent of cases included in this study failed to show contralateral tumors. Hence, pathologic parameters such as lack of vascular invasion and lack of multifocality may be used to identify patients who can benefit from conservative therapy alone.

Extrathyroidal manifestations of Graves' disease: the thyrotropin receptor is expressed in extraocular, but not cardiac, muscle tissues.

The existence of an autoantigen common to Graves' disease and its associated extrathyroidal manifestations has been proposed. As the TSH receptor (TSHR) is the primary target for autoimmunity against the thyroid in Graves' disease, much effort has gone into investigating the role of TSHR messenger ribonucleic acid (mRNA) transcripts in extrathyroidal tissue, particularly in the orbit. A high stringency RT-PCR technique had previously been employed by our laboratory to demonstrate the presence of full-length and splice variant TSHR mRNA in extraocular muscle (EOM). This technique demonstrated selective amplification of TSHR mRNA transcripts in thyroid and EOM, but not in abdominal muscle, kidney, or brain tissue. We used this technique in the present study to investigate the reported presence of TSHR mRNA transcripts in cardiac tissue. After removal of all visible fat from muscle tissues, high stringency RT-PCR was performed, and we found no TSHR transcripts in the muscle of any chamber of the normal human heart. In addition, in situ hybridization on fresh-frozen and paraffin-embedded sections confirmed the presence of TSHR transcripts in thyroid and EOM, but not in abdominal or cardiac muscle. These findings support the hypothesis that the TSHR is a shared antigen in the thyroid and EOM, but not in cardiac muscle.

Prophylactic completion thyroidectomy for differentiated thyroid carcinoma: prediction of extrathyroidal soft tissue infiltrates.

Controversy exists on the extent of completion surgery for differentiated thyroid carcinoma (DTC). Between November 1994 and October 1999, 88 consecutive DTC patients who had no evidence of residual tumor after primary surgery underwent completion total thyroidectomy in conjunction with a systematic en bloc resection of the cervicocentral lymph node compartment. To identify individual parameters predictive of occult residual tumor, three separate logistic regression analyses were fitted for intrathyroidal tumor, extrathyroidal soft tissue infiltrate and cervicocentral nodal metastasis. Altogether, occult residual tumor was found in 22% (19/88) of patients. Occult intrathyroidal tumor, extrathyroidal soft tissue infiltrate, and cervicocentral nodal metastasis were encountered in 11%, (10/88), 6% (5/88), and 10% (9/88), respectively. On logistic regression analysis, patients with multifocal DTC on primary surgery had a 17.4 times higher risk (p = 0.026) on reoperation to harbor extrathyroidal soft tissue infiltrates within the cervicocentral compartment. At least in multifocal DTC, a systematic en bloc resection of the thyroid remnant and cervicocentral lymph node compartment is warranted to ensure clearance of occult extrathyroidal soft tissue infiltrates, setting the stage for radioiodine therapy. Selective lymph node dissection alone does not seem capable of eliminating these soft tissue infiltrates from the cervicocentral compartment.

Comparison of Nuclear DNA Content in Locally Invasive and Noninvasive Papillary Carcinoma of the Thyroid Gland

Extrathyroidal invasion of papillary carcinoma of the thyroid gland has a very bad prognosis. A retrospective study was performed on 40 specimens from patients with papillary carcinoma of the thyroid gland to find out whether DNA ploidy correlated with aggressive tumor behavior. The nuclear DNA content of 20 locally aggressive papillary thyroid carcinomas was studied by flow cytometry. The results were compared with those of a matched control group of 20 patients with noninvasive papillary tumors. Forty percent of the tumors with spread to extrathyroid tissue were aneuploid, whereas all the tumors without such extension were diploid. This difference was statistically significant (p &lt; 0.003). The data suggest that the differentiation of locally noninvasive and invasive papillary thyroid carcinomas may be potentially possible by nuclear DNA determination.

Comparison of nuclear DNA content in locally invasive and noninvasive papillary carcinoma of the thyroid gland

Extrathyroidal invasion of papillary carcinoma of the thyroid gland has a very bad prognosis. A retrospective study was performed on 40 specimens from patients with papillary carcinoma of the thyroid gland to find out whether DNA ploidy correlated with aggressive tumor behavior. The nuclear DNA content of 20 locally aggressive papillary thyroid carcinomas was studied by flow cytometry. The results were compared with those of a matched control group of 20 patients with noninvasive papillary tumors. Forty percent of the tumors with spread to extrathyroid tissue were aneuploid, whereas all the tumors without such extension were diploid. This difference was statistically significant ( p < 0.003). The data suggest that the differentiation of locally noninvasive and invasive papillary thyroid carcinomas may be potentially possible by nuclear DNA determination. (Otolaryngol Head Neck Surg 1997;117:501-3.)

Functional Expression of Thyrotropin Receptor in Differentiated 3T3-L1 Cells: A Possible Model Cell Line of Extrathyroidal Expression of Thyrotropin Receptor

Thyrotropin receptor (TSHR) in extrathyroidal tissue, especially fat tissue, is supposed to have important roles in the development of extrathyroidal manifestations of Graves' disease. However, the molecular mechanism of TSHR expression is not known. Expression of TSHR mRNA and TSH-dependent cAMP production were observed in differentiated but not in undifferentiated 3T3-L1 cells. Maximal expression was obtained when the cells were differentiated in the presence of insulin, dexamethasone, and isobutylmethylxanthine (IBMX). Dexamethasone and IBMX were indispensable for the first three days. On the other hand, after day 4, insulin was indispensable for the expression of TSHR. 3T3-L1 cell is the first non-thyroidal cell line reported that expresses TSHR and whose expression can be induced. 3T3-L1 cell can be a good model to investigate the mechanism of expression of TSHR and extrathyroidal manifestations of Graves' disease.

Effect of Thyroidectomy of Immature Male Chickens on Circulating Thyroid Hormones and on Response to Thyroid-Stimulating Hormone and Chronic Cold Exposure

Previous studies in the author’s laboratory established that thyroidectomized (Tx) immature male chickens had significant levels of circulating thyroid hormones, and it was proposed that extrathyroidal tissue might be present. Three experiments were conducted to further investigate this possibility. In all experiments, thyroid glands were removed surgically at 3 wk of age. In the first experiment, birds were kept until 20 wk of age. It was found that only triiodothyronine levels were reduced significantly in the Tx birds. In the second experiment, Tx as well as sham-operated control groups received a single iv injection of bovine thyroid-stimulating hormone (TSH) to determine if extrathyroidal tissue in Tx birds would respond to exogenous TSH. It was found that circulating thyroxine (T4) concentrations in sham-operated control birds, but not Tx birds, were increased following TSH injection. In the third experiment, Tx and sham-operated birds were exposed chronically to cold (7 C), and only circulating T4 was found to be elevated in both groups. It was concluded that extrathyroidal tissue in Tx birds does not respond to TSH.

Affinity purification of orbital membrane antigens for the study of the pathogenesis of Graves' ophthalmopathy.

We characterized 22 human monoclonal antibodies (MCAB) reactive with human orbital antigens. Most of these monoclonal antibodies had variable degrees of reactivity with eye muscle, orbital connective tissue, thyroid, and extra-thyroid tissue preparations when tested in an enzyme-linked immunosorbent assay (ELISA). Eight of the MCABs, selected on the basis of their reactivity with human eye muscle or orbital connective tissue antigens, were used to affinity purify orbital membrane antigens. All purified fractions were tested in the ELISA for reactivity with the MCAB used for their purification. Four of the purified antigens with a high reactivity were not proteins. To increase the specificity of the reactivity of serum autoantibodies with affinity-purified antigens, we developed a competitive binding ELISA in which the MCAB-immunoglobulin was directly labeled with alkaline phosphatase. We tested the serum of 24 patients with Graves' ophthalmopathy, 10 patients with a history of Graves' hyperthyroidism and no eye disease, 14 patients with Hashimoto's thyroiditis without eye disease, 8 patients with other nonautoimmune thyroid disorders, and 20 normal subjects for reactivity with an affinity-purified nonprotein orbital antigen. The levels of serum autoantibodies against this antigen in patients with Graves' ophthalmopathy were significantly higher than those in normal subjects or patients with Graves' hyperthyroidism with no eye disease. Although unlikely to be of primary pathogenetic significance, it is possible that levels of this antibody in patients with Graves' ophthalmopathy may reflect the extent of orbital inflammation and, therefore, be useful as a clinical marker.

Malignant lymphoma of the thyroid gland: a clinicopathologic study.

This study reviews 21 cases of thyroid lymphoma diagnosed between 1969 and 1980. The thyroid gland was the primary site in all but two cases. The 20 patients with non-Hodgkin lymphoma had a mean age of 66 years, 75% were women, and all were Caucasian. A rapidly growing thyroid mass with hoarseness, dysphagia, and difficulty in breathing was the initial finding. Most patients had diffuse histiocytic lymphomas. Associated Hashimoto thyroiditis was found histologically in 57% of the cases. Using the immunoperoxidase stain method on tissue sections, intracytoplasmic monoclonal immunoglobulin was demonstrated in 5 of 15 cases. All but two patients received radiation therapy, and 13 received chemotherapy. The median survival was 8 months; 20% died of unrelated causes and 32% are alive (average duration: 27 months). Dissemination, after local control by radiation therapy, was the leading cause of death. The prognosis was better in men, in patients under the age of 65 years, and in those patients who, on biopsy, did not have involvement of the extrathyroid soft tissue or regional lymph nodes.

Calcitonin in extrathyroidal tissues of man.

Prior studies have demonstrated detectable immunoreactive calcitonin in the serum and urine of totally thyroidectomized humans, suggesting that the hormone may be secreted by extrathyroidal tissues. Accordingly, a study of the immunoreactive calcitonin content of human tissues was undertaken, utilizing autopsy material from 23 patients. Significant amounts of calcitonin were found in many extrathyroidal tissues, ranging up to 40 ng/g wet weight. The hormone was detectable with two antibodies having different region specificities for calcitonin. Gel filtration and subsequent radioimmunoassay demonstrated that extrathyroidal tissue has calcitonin fractions of the same molecular size and charge characteristics as do the serum and thyroid. The finding of large amounts of extrathyroidal calcitonin may explain why thyroidectomy in man is not accompanied by marked changes in calcium metabolism.

LARYNGEAL MALIGNANCY FOLLOWING IODINE-125 THERAPY FOR THYROTOXICOSIS

A 52-year-old woman presented with a laryngeal sarcoma eight years after receiving two doses, each of 30 mCi, of iodine-125 for thyrotoxicosis. That extrathyroidal tissue receives a higher radiation dose of low-energy photon radiation from iodine-125 than from an equivalent microcurie dose of iodine-131 and that the tumour was of a type which rarely arises spontaneously in the larynx suggest a possible link between the development of the tumour and iodine-125 therapy.

THYROID-PITUITARY RESPONSE TO CARDIOPULMONARY BYPASS

The effects of open heart surgery on various parameters of thyroid-pituitary function were studied in 11 patients. The pattern of hormonal changes was variable. T4 concentration increased during anaesthesia and bypass, following which it returned to normal once haemodynamic stability had been regained. The pattern of change in T3 concentration did not follow consistently that of T4 and the proportional increase in concentration was not as great. There was a significant reduction in T3 concentration with the onset of haemodynamic stability. For individual patients there was no obvious correlation between changes in the concentrations of TSH, T3 and T4. The increases may be explained by release of T3 or T4 from extrathyroid tissue.