Immediate causes of death in thyroid carcinoma: clinicopathological analysis of 161 fatal cases.

Most patients with thyroid carcinoma have a good prognosis. Due to the small number of fatal cases, it has not been clarified what conditions result in death for patients with thyroid carcinoma. To provide appropriate management for advanced thyroid carcinoma patients, we analyzed causes of death in 161 fatal cases. Clinical characteristics and immediate (final) causes of death based on pathological conditions were analyzed in 62 anaplastic carcinomas and 99 fatal differentiated carcinomas. Single fatal conditions could not be specified in 55 patients. In the remaining 106 patients, respiratory insufficiency (43%) was the most common specific fatal condition, followed by circulatory failure (15%), hemorrhage (15%), and airway obstruction (13%). Respiratory insufficiency due to remarkable pulmonary metastasis replacing lung tissue, massive hemorrhage and airway obstruction due to uncontrolled local tumors, and circulatory failure resulting from compression of the vena cava by extensive mediastinal or sternal metastases were found to be the most important immediate causes of death. Based on this knowledge, several palliative procedures may be worth considering to improve survival and quality of life in patients with advanced thyroid carcinoma.

Postoperative changes in thyrotropin-binding inhibitory immunoglobulin level in patients with Graves' disease: is subtotal thyroidectomy a suitable therapeutic option for patients of childbearing age with Graves' disease?

Thyroid-stimulating hormone (TSH)-binding inhibitory immunoglobulin (TBII) is thought to be one of the essential causes of Graves' disease, and most cases of neonatal hyperthyroidism can be explained by transplacental passage of TBII. Because surgery is often indicated for patients of childbearing age, it is important to elucidate how surgery reduces TBII levels. Between 1988 and 1991 a total of 946 female patients with Graves' disease underwent subtotal thyroidectomy. Follow-up examination was undertaken at 1, 2, 3, and 4 to 5 years after surgery. At 4 to 5 years after surgery, 76.8% of patients without recurrent overt hyperthyroidism had TBII < 20%. In patients with recurrent hyperthyroidism, TBII increased gradually during follow-up, and they had higher TBII levels than nonrecurrence patients. There were a few euthyroid and hypothyroid patients who had TBII > 60%, and the number of such patients decreased annually. In most of the patients, immunologic remission was obtained by subtotal thyroidectomy except for their having recurrent hyperthyroidism. To acquire immunologic remission, hormonal remission, at least, would be necessary. Because no definite factor other than the size of the thyroid remnant related to postoperative thyroid function was elucidated, near-total thyroidectomy rather than subtotal thyroidectomy is expected to be induced not only hormonal remission but also immunologic remission. It should be noted that a few patients achieved hormonal remission but not immunologic remission.

Anaplastic transformation of papillary thyroid carcinoma in recurrent disease in regional lymph nodes: a histologic and immunohistochemical study.

BACKGROUND AND OBJECTIVES: Although the prognosis of papillary thyroid carcinoma is favorable in most cases, recurrent disease in the regional lymph nodes is not uncommon, and some patients die of recurrent disease that ultimately becomes unresectable. We studied the proliferative activity of cancer cells in recurrent foci in lymph nodes to see whether repeated recurrences might result in anaplastic transformation of papillary thyroid carcinoma. METHODS: Fourteen patients with papillary thyroid carcinoma who underwent reoperation for recurrent disease in the regional lymph nodes more than once were the subjects of the study. The histologic findings and proliferative activity of carcinoma foci at each recurrence were studied histologically and immunohistochemically. RESULTS: There were higher incidences of histologic features of poorly differentiated thyroid carcinoma in the metastatic foci in the lymph nodes as it recurred repeatedly, and the labeling indexes of proliferating cell nuclear antigen (PCNA) and nuclear antigen Ki-67 (MIB-1) increased. CONCLUSIONS: These observations suggest that papillary thyroid carcinoma may become more malignant, even undergo transformation to an anaplastic variety, as metastatic disease in the regional lymph nodes recurs repeatedly.

Papillary microcarcinoma of the thyroid.

Papillary microcarcinoma of the thyroid has been often detected by aspiration biopsy cytology performed with ultrasonographic guidance. Autopsy studies also have often revealed small thyroid carcinomas, and it was concluded that most small thyroid carcinomas should not be regarded as a clinical matter. In this study, 112 patients with papillary microcarcinoma 10 mm or less in size treated between 1992 and 1995 were analyzed. There were 104 females and 8 males, with a mean age of 46.0 years. Diagnosis of papillary carcinoma was made preoperatively in 100 of these patients (89.3%), and 77 patients underwent aspiration biopsy cytology under ultrasound guidance. Seventy of these patients underwent modified neck dissection, and 63.8% of these patients had lymph node metastases. The number of lymph node metastasis increased as primary tumor size increased. There was no clear border or clinical differences between primary tumors 10 mm or less and tumors more than 10 mm. One patient had lymph node recurrence after surgery and another patient had recurrent nerve palsy at the first visit. Based on these findings, papillary microcarcinoma should be treated surgically.

Effect of subtotal thyroidectomy on natural history of ophthalmopathy in Graves' disease.

Graves' ophthalmopathy is a complex disease whose pathogenesis is thought to be autoimmune. The treatment of Graves' disease is considered to be related to the progression of Graves' ophthalmopathy. There have been no long-term prospective studies on the natural course of Graves' ophthalmopathy. In this study we assessed the influence of subtotal thyroidectomy on the outcome of Graves' ophthalmopathy, comparing it with that of radioactive iodine treatment. Altogether 287 untreated patients with Graves' disease referred to Ito hospital in 1989 were followed prospectively for 5 years. A group of 67 patients were treated with radioactive iodine, and 18 patients underwent surgery. Proptosis of the eyes was measured in all patients using Hertel's exophthalmometer. The mean value of proptosis in patients with untreated Graves' disease was 14. 8 +/- 0.2 mm (mean +/- SEM), and after 5 years it increased slightly to 15.0 +/- 0.2 mm. The mean changes of proptosis in patients treated surgically and patients given radioactive iodine were -0.01 +/- 0.22 and 0.93 +/- 0.28 mm, respectively (p < 0.05). In patients treated by subtotal thyroidectomy, ophthalmopathy did not change in 77.8%; it progressed in 5.6% and was alleviated in 16.7%. In patients treated with radioactive iodine, the ophthalmopathy did not change in 86.6%, progressed in 10.4%, and was alleviated in 3.0%. These findings indicate that surgery can be a better treatment than radioactive iodine for Graves' patients with ophthalmopathy.

Fiberoptic bronchoscopy in thyroid carcinoma with tracheal invasion.

Preoperative bronchoscopic findings of thyroid carcinoma with tracheal invasion were examined and compared with the histopathological findings. Tracheal sleeve resection was performed in 20 cases. The bronchoscopic findings were classified into 5 types: confirmed tumor in the tracheal lumen (5 cases), extramural compression of the trachea plus mucosal change (9 cases), extramural compression of the trachea (2 cases), mucosal changes only (3 cases), normal findings (1 case). Pathological findings revealed that the extent of invasion in the tracheal wall varied according to each of the above bronchoscopic types. The number of tracheal rings with adventitial invasion averaged 0.8 (maximum 2) more than preoperative bronchoscopic findings of the number of tracheal rings with mucosal invasion. This study demonstrated the necessity of resective 2 more tracheal rings than is indicated by the bronchoscopic findings.

Factors affecting thyroid function after subtotal thyroidectomy for Graves' disease: case control study by remnant-weight matched-pair analysis.

In order to determine whether there are any predictive factors, other than the amount of remnant thyroid tissue, for subsequent thyroid function after subtotal thyroidectomy for Graves' disease, thyroid function was assessed in 329 patients 3 years after surgery, and a case control study was carried out in euthyroid, hyperthyroid, and hypothyroid groups by remnant-weight matched-pair analysis. Factors that affected thyroid function 3 years after surgery were thyroid gland infiltration by lymphocytes and the thyrotropin binding inhibiting immunoglobulin (TBII) value in the hyperthyroid and euthyroid groups, and the free triiodothyronine (FT3) value at the time of surgery and lymph follicle formation in the thyroid gland in the hypothyroid and euthyroid groups. It is concluded that no single factor studied at surgery, other than the amount of remnant tissue, can predict thyroid function after subtotal thyroidectomy for Graves' disease.

Primary leiomyosarcoma of the thyroid gland.

Primary leiomyosarcoma of the thyroid gland is extremely rare, and to the best of our knowledge only five well-documented cases have been reported in the world literature. We herein report a 58-year-old female patient with primary leiomyosarcoma of the thyroid who was successfully treated by total thyroidectomy with a modified neck dissection. Immunohistochemically, the tumor cells showed positive reactivity to alpha-smooth muscle actin and vimentin. Radical surgery was thus considered to be essential in the treatment of this rare but rather aggressive malignancy.

Calmodulin purified from human and porcine thyroids inhibits thyrotropin binding to porcine thyroid cells.

A thyrotropin (TSH) binding inhibiting protein (TBIP) that inhibits TSH binding to the TSH receptor, as determined by the TSH receptor assay, was purified from human and porcine thyroid. The soluble fraction (100,000 x g supernatant of Graves' thyroid homogenate) was precipitated with ammonium sulfate between 1.75 to 2.5 mol/L. TBIP was eluted by 0.5 mol/L sodium chloride (NaCl) containing 20 mmol/L Tris buffer, pH 7.5 from a Q-sepharose column. The unbound fraction from concanavalin A (Con A) and blue-sepharose was gel-filtered using sephadex G-100, and finally purified by Resource Q column chromatography. Purified TBIP was confirmed as a single protein band of 17 kDa. The TBI activity in the purified TBIP was significantly decreased by either etnylene glycol tetraacetate (EGTA) (1 mmol/L) or antibody to calmodulin (CaM) in the TSH receptor assay. The TBIP was confirmed immunologically as CaM by the Ouchterlony method using antibody for CaM. These findings demonstrated that the TBIP purified from human and porcine thyroids was, in fact, CaM. We examined the effects of TBIP purified from human thyroid on bovine TSH (bTSH) or thyroid stimulating antibody (TSAb)-stimulated cyclic adenosine monophosphate (cAMP) production in porcine thyroid cells (PTC). TBIP itself did not increase basal levels of cAMP production, but inhibited bTSH (100 mU/L)-stimulated cAMP production. However, TBIP did not inhibit cAMP production stimulated by TSAb-IgG and various thyroid stimulators (GTPgammaS, forskolin and pituitary adenylate cyclase-activating polypeptide [PACAP, 27 and 38 amino acids]). Authentic CaM purified from bovine brain behaved in a manner similar to that of TBIP. These data showed that CaM differentially affects thyroid stimulation by TSH and TSAb in intact thyroid cell experiments.

Preoperative change of thyroid stimulating hormone receptor antibody level: possible marker for predicting recurrent hyperthyroidism in patients with Graves' disease after subtotal thyroidectomy.

To make the surgical treatment for Graves' disease more ideal, it is important to elucidate factors related to postoperative thyroid dysfunction in addition to thyroid remnant. Because TSH receptor antibody (TRAb) is thought to be one of the essential causes of Graves' disease, we investigated whether preoperative changes in serum TRAb levels are related to postoperative recurrent hyperthyroidism. Between 1987 and 1992 a total of 1520 patients with Graves' disease were treated by subtotal thyroidectomy. Of these patients 335 visited Ito Hospital with no history of drug treatment of their disease and were treated surgically after several courses of antithyroid drug (ATD) therapy. There were 68 males and 267 females with a mean age of 25.8 years. The mean follow-up period was 48 months (range 12-84 months). Factors analyzed by univariate and multivariate analysis were as follows: age, sex, duration of ATD treatment, weight of resected thyroid, weight of thyroid remnant, preoperative titer of MCHA, TRAb at the time of initial examination (TRAb1), TRAb at the time of surgery (TRAb2), and DeltaTRAb, the difference between TRAb1 and TRAb2 (DeltaTRAb = TRAb1 - TRAb2). The chi-square test was used for univariate analysis and a logistic model for multivariate analysis. Of this group, 119 patients were euthyroid (35.5%), 50 were hyperthyroid (14.9%), and 166 were hypothyroid (49.3%). Significant factors related to recurrent hyperthyroidism were weight of thyroid remnant and DeltaTRAb in both univariate and multivariate analyses. DeltaTRAb is a possible new marker for predicting postoperative recurrent hyperthyroidism. If the preoperative TRAb level is not improved by ATDs in patients with Graves' disease, the thyroid remnant should be made smaller.

Separation and determination of amino acids, creatinine, bioactive amines and nucleic acid bases by dual-mode gradient ion-pair chromatography.

A simple and fast high-performance liquid chromatography method for the analysis of amino acids and biological bases such as creatinine was developed using a technique termed "dual-mode gradient ion-pair chromatography". A butyl-silica reversed-phase column and water-acetonitrile eluent containing sodium dodecyl sulfate (SDS) and perchloric acid were used for the separation. A concentration gradient of acetonitrile from 15 to 35% provided a good separation of such organic cations. Since change in concentration of acetonitrile causes change in distribution equilibrium of SDS between mobile and stationary phases, a complete regeneration of the column to the initial state is required for the reproducible separations. Completion of the reequilibrium was indicated by a system peak appearing in the UV chromatogram and by conductivity measurements. The formation mechanism of the system peak was revealed. A flow-rate gradient from 1 to 2 ml/min was introduced in addition to the concentration gradient to shorten the cycle time of the chromatography. More than twenty kinds of amino acids, creatine and creatinine were simultaneously separated within 50 min and the cycle time was 80 min including the reequilibration time. A post-column derivatization fluorescence detection system was usable as well as UV detection. This elution system was also useful for the separation of bioactive amines and nucleic acid bases. The developed method was applied to the simultaneous determination of urinary creatinine and diagnostic amino acids due to inherited metabolic disorders.

Papillary carcinoma of the thyroid. Tall-cell variant with extensive lymphocyte infiltration.

Thirteen cases of tall-cell variant of papillary thyroid carcinoma (PTC) showing extensive lymphocyte and plasma cell infiltration within the fibrous stalks of the papillary architecture were compared with age-, sex-, and tumor size-matched cases of ordinary tall-cell variant without extensive lymphocyte infiltration and also with cases of PTC of the conventional type. All cases of the tall-cell variant of PTC with extensive lymphocyte infiltration exhibited the histologic features of chronic thyroiditis. Dissemination of tumor cells with the thyroid was significantly less frequent than in control cases, but there was no difference between the incidences of lymph node metastasis. Immunohistochemically, the lymphocytes infiltrating the carcinoma focus were mainly CD20+, CD45+, and CD45RO+ cells, that is, basically the same as those found in foci of chronic thyroiditis. No tumor recurrence was observed during the mean follow-up period of 3 years 8 months. The results of this study suggest that the tall-cell variant of PTC with extensive lymphocyte infiltration has less aggressive characteristics and a more favorable prognosis.

Thyroid carcinoma metastasized to the sternum: resection of the sternum and reconstruction with acrylic resin.

Recently we resected and reconstructed the sternum in two female patients with thyroid carcinoma metastatic to the sternum. Histological diagnosis of the metastatic lesion was follicular carcinoma in the first case and papillary carcinoma in the second case. Reconstruction of the sternum was accomplished by using an acrylic resin plate alone in the first case and an acrylic resin plate sandwiched between layers of Marlex mesh (Marlex sandwich procedure) in the second case. In the first case the acrylic resin plate was directly fixed to the ribs with metallic wires, most of which snapped off later, and a small amount of exudate accumulated around the plate for a short period of time. In contrast, the postoperative course in the second case was uneventful and the Marlex sandwich procedure seemed superior in the chest wall reconstruction following resection of the sternum.

Early recurrence of hyperthyroidism in patients with Graves' disease treated by subtotal thyroidectomy.

Prerequisites for surgical treatment of Graves' disease are that it can be done safely and that it is associated with a low incidence of recurrent hyperthyroidism. Early recurrence is especially undesirable. We studied 728 patients with Graves' disease treated by subtotal thyroidectomy using multivariate analysis in order to determine the factors related to early recurrence. The following factors were analyzed: age, sex, duration of medical treatment, weight of resected thyroid tissue, thyroid remnant size, preoperative level of thyroid-stimulating hormone (TSH) binding inhibitory immunoglobulin (TBII), and antimicrosomal hemagglutination antibody (MCHA). "Early recurrence" was defined as TSH suppression observed within the first year after surgery and continuing for at least 6 months. A total of 106 patients (14.6%) had early recurrence. Statistical analyses were performed by the chi-square test for univariate analysis and a logistic model for multivariate analysis. Significant factors were thyroid remnant size, MCHA, and TBII. These results indicated that TBII and MCHA are related to early recurrence of hyperthyroidism, and smaller remnant size is recommended for patients with a high MCHA titer or a high TBII level (or both) in order to avoid early recurrence.

Management of recurrent hyperthyroidism in patients with Graves' disease treated by subtotal thyroidectomy.

If the aim of surgical treatment for Graves' disease is not permanent hypothyroidism, it is difficult to avoid recurrent hyperthyroidism completely. The management of recurrent hyperthyroidism, however, is neither easy nor obvious. Improvement in the sensitivity of TSH assay has allowed the diagnosis of latent hyperthyroidism. Little is known about the clinical course of latent hyperthyroidism. We studied the management and outcome of recurrent hyperthyroidism in patients with Graves' disease treated by subtotal thyroidectomy. Between January 1988 and August 1991, 1115 patients with Graves' disease were treated by surgery. Postoperative thyroid function was evaluated by free T3, free T4 and TSH measurements. One hundred seventy-five patients with suppressed TSH secretion for at least 6 months were categorized as having recurrent hyperthyroidism. Eighty patients (45.1%) also had elevated thyroid hormone levels, (group 1). The remaining 95 patients (54.9%) had normal thyroid hormone levels with suppressed TSH values (group 2). In group 1, 58 patients were treated with antithyroid drug (ATD), 12 with iodine and 10 with radioiodine (RI). Remission of Graves' disease was obtained in 22 patients (11 by ATD, 1 by iodine and 10 by Ri). On the other hand, patients in group 2 were followed up without medication, and spontaneous remission was observed in 21 of theln (22.1%). It was difficult to induce remission of overt recurrent Graves' disease by ATD or iodine. In contrast spontaneous remission could be obtained in some patients with postoperative latent hyperthyroidism.

Surgery for patients with thyroid carcinoma invading the trachea: circumferential sleeve resection followed by end-to-end anastomosis.

BACKGROUND: Curative surgery can be accomplished by tracheal resection in patients with thyroid carcinoma invading the trachea; however, there is controversy regarding the extent of the tracheal resection. In this study we investigated by means of histologic examination the mode of tracheal invasion by thyroid carcinoma. METHODS: Twenty-one patients with thyroid carcinoma invading the trachea underwent circumferential sleeve resection of the involved trachea. The extent of invasion of the tracheal wall on the adventitial and mucosal sides was compared on histologic examination. RESULTS: Three to nine tracheal rings were resected. Assessment of longitudinal spread showed that one to six rings (mean; 3.1 rings) were invaded on the adventitial side but only zero to four rings (mean; 1.9 rings) on the mucosal side, with invasion on the mucosal side never exceeding invasion on the adventitial side. In contrast, examination of circumferential spread showed invasion on the mucosal side exceeding invasion on the adventitial side in five cases. CONCLUSIONS: Our results suggest that when the extent of invasion of the adventitia is considered, carcinoma tissue may be left behind on the mucosal side of the trachea when partial wedge resection is performed and that, whenever feasible, circumferential sleeve resection should be performed in patients with thyroid carcinoma invading the trachea.

Metastases to the regional lymph nodes, lymph node recurrence, and distant metastases in nonadvanced papillary thyroid carcinoma.

To investigate the biological characteristics of papillary thyroid carcinoma from the perspectives of lymph node metastasis, lymph node recurrence, and distant metastasis, 746 patients with nonadvanced papillary thyroid carcinoma were retrospectively studied. There were 76 men and 670 women with a mean age of 42.7 years. The rate of lymph node metastasis was significantly higher in young patients (aged less than 30 years). Lymph node recurrence was observed in 80 patients and distant metastasis in 13, being seen with significant frequency in the young and elderly (aged over 50 years) patients and in the men. The frequency of distant metastasis was significantly greater in the elderly patients and in those with lymph node recurrence. These findings indicate that the role of regional lymph nodes and the clinical meaning of lymph node recurrence differ between young and elderly patients.

Clinicopathological study of clear-cell tumors of the thyroid: an evaluation of 22 cases.

Twenty-two cases of partial or wholly composed clear-cell thyroid tumors were reviewed to differentiate between a primary nodule and metastatic clear-cell renal carcinoma in the thyroid. Pathological reevaluation of HE-stained specimens, immunohistochemical observation using anti-thyroglobulin (TG) antibody, and periodic acid-Schiff (PAS) staining were performed. The pathological characteristics in metastases from the kidney have a greater tendency to demonstrate a strikingly clear cytoplasm with small nuclei, rich vascularization, and a trabecular arrangement of tumor cells than do primary thyroid cases. The immunohistochemical TG staining in conjunction with PAS staining for the recognition of follicular colloid could provide much more reliable information of primary cases compared to that using TG staining alone. Clinically, in primary cases, the female:male ratio is substantially higher while the mean age is lower than in metastatic cases reflecting differentiated thyroid carcinoma. In conclusion, immunohistochemical staining for TG with PAS staining for the recognition of follicular colloid proved to be the most sensitive method for identifying primary clear cell thyroid tumors. In addition, a careful assessment of past and/or present kidney disorders to rule out metastatic renal cell carcinoma is advisable. Age, gender, and physiological findings are also informative when differentiating between them.

Thyroid carcinoma after radioactive iodine therapy for Graves' disease.

Although the causal relation between radioactive iodine therapy (RIT) for Graves' disease and the subsequent occurrence of thyroid carcinoma is not definite, surgeons may be faced with the treatment of such patients. We studied the clinicopathologic features of patients with thyroid carcinoma following RIT for Graves' disease. From January 1983 to December 1991, 11 patients with thyroid carcinoma occurring 1 year or more after RIT for Graves' disease underwent surgery at Ito Hospital. These 11 patients accounted for 0.51% of 2146 surgical cases of thyroid carcinoma and 0.17% of 6419 RIT cases of Graves' disease during the period. They were all women, and their mean ages at RIT and surgery were 44.3 and 51.4 years, respectively. The administered dose of RI was 222.1 MBq and the absorbed dose 45.3 Gy on average. Total thyroidectomy was performed in two patients, subtotal thyroidectomy in three, and lobectomy in six. Bilateral modified neck dissection (MND) was added in two patients, and ipsilateral MND in seven. Histology revealed 10 papillary and 1 follicular carcinoma. The mean diameter of the tumor was 18.5 mm. Intraglandular dissemination of the tumor was noted in only one case and solid growth pattern in two. Nodal metastasis was disclosed in six cases, but in five of them only one node was involved. The present study indicated that thyroid carcinoma occurring after RIT for Graves' disease is not an aggressive variety, and thyroid lobectomy with ipsilateral MND would be sufficient as surgical treatment for such patients.