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Squamous cell carcinoma (SCC) of the thyroid is thought to be rare. However, SCC not infrequently occurs in conjunction with other histologic types of tumor. We reviewed 67 thyroid cancer autopsy cases obtained from two institutions from 1969 to 1981 and from 1975 to 1992, respectively. SCC was found in 19 cases (28.4%): 2 SCCs as the only malignancy and of uniform histologic type, 9 cases of tumors mixed with papillary carcinoma, and 8 cases of SCC mixed with papillary and anaplastic carcinomas. In only four of these cases was the SCC component found in the surgical specimens. These results indicate that the presence of SCC component is more likely to be found at the later stage of the disease.

The resistance of malignant tumors to chemotherapy with anticancer drugs has been considered to be due partly to overexpression of the multidrug resistance gene (mdr1) and its gene product, P-glycoprotein (P-GP), which acts as a drug efflux pump for several chemotherapeutic agents. In order to elucidate the mechanism of anticancer drug resistance in anaplastic thyroid carcinoma with very poor prognosis, we examined the expression of mdr1 mRNA and P-GP, and analyzed their relationships to chemotherapy response. Twenty surgical samples from 16 patients with anaplastic thyroid carcinoma were used. The mdr1 mRNA expression was examined by reverse transcription and polymerase chain reaction, and P-GP expression was evaluated by an immunohistochemical method using JSB-1 monoclonal antibody. Of the 20 clinical samples, expression of mdr1 mRNA and P-GP was observed in three and four samples, respectively. Three of the patients from whom the samples were obtained had been given anticancer drugs before biopsy. Of 12 patients who received chemotherapy for clinically evaluable diseases, 2 responded well, but 10 showed no response. All except one patient died of cancer progression. There was no relationship between the response to chemotherapy and the expression of mdr1 and P-GP. The expression of mdr1 mRNA and/or P-GP was observed in 5 of 16 patients with anaplastic thyroid carcinoma. However, the appearance of anticancer drug resistance in anaplastic thyroid carcinoma may not be explained solely by the expression of mdr1 and P-GP.

In iodine rich areas the incidence of papillary carcinoma of the thyroid is extremely high but its prognosis is favorable. When papillary carcinoma is confined to one lobe, our standard surgical procedure has been total lobectomy with isthmusectomy rather than total thyroidectomy. Our followup study of 185 such patients reveals considerable difference in the outcome between the 85 patients with gross thyroid capsular invasion and the 100 patients without, regardless of the presence of cervical lymph node metastasis. In the latter group, the tumor could be completely resected in all patients; although 4 cases had recurrence and required reoperation, 3 patients are alive and well and one died of other disease. In contrast, 20 patients in the former group had incomplete resection of the tumor, 4 patients developed recurrence and needed to be reoperated and 7 patients eventually died of thyroid cancer. One hundred thirty three patients (71.9%) underwent modified neck dissection at the time of surgery to find lymph node metastasis in 37 of 59 cases (62.7%) without gross thyroid capsular invasion and 64 of 74 cases (86.5%) with such invasion. The difference is statistically significant (P < 0.05). From these results we conclude that for papillary thyroid cancer in iodine rich areas total lobectomy with isthmusectomy is the treatment of choice when gross thyroid capsular invasion is not recognized on the operation table. However, when gross thyroid capsular invasion is recognized, total or near total thyroidectomy has to be performed.

Thyroid scintigraphy with Tl in the evaluation of nodules was investigated. A Tl scan was performed on 55 patients with thyroid nodules previously scanned with Tc or I. In the case of 16 carcinomas, accumulation of Tl was shown in every case. In addition, some lymph node metastases were depicted. (Accumulation was noted also in some of the metastatic lymph nodes.) Cold defect was delineated in ten cases of colloid and fetal adenoma, although accumulation was shown in four cases of Hürthle and embryonal adenoma. Six cases of degenerative cysts were delineated as cold defect. As for colloid nodular goiter, the affinity to the individual nodule was not constant. In general, degenerative and cystic nodules showed less activity and hyperplastic solid nodules showed more activity than normal tissue. We concluded that although a Tl scan cannot differentiate between benign and malignant tumors satisfactorily, it is nevertheless useful for determining surgical indication, as the case showing Tl accumulation on the scan is malignant or benign tumor with poorly differentiated solid type and possiblility of further growth and malignant change.

A randomized evaluation of the effectiveness and toxicity of the combination of doxorubicin and cisplatin and of doxorubicin alone in patients with advanced thyroid carcinoma was carried out. Ninety-two patients were entered and 84 were evaluable. They were stratified according to histological classification, Eastern Cooperative Oncology Group (ECOG) performance status, and metastatic sites. Forty-one patients received doxorubicin as a single agent and seven had partial response (17%). Forty-three patients received the combination, and there were five complete and six partial responses (combined response rate of 26%). This difference for overall response rate is not significant (P greater than 0.1). However, five complete responses were seen in the combination-treatment group, whereas none were observed in the single-agent treatment group; a significant difference was obtained (P = 0.03). Four of these five complete responders survived for more than 2 years, and two patients remained in a complete response after the discontinuation of therapy and are still alive. None of the partial responses exceeded 2 years in duration. The life-threatening toxicities from chemotherapy occurred in five patients treated with the combination of drugs and two treated with doxorubicin alone. However, none of the toxicities were fatal. The study has shown clearly that the quality of response achieved by the combination of drugs is far superior to that achieved by single-agent chemotherapy.

With 612 cases of malignant thyroid tumor, the follow-up observations were conducted from 7 to 11 years after initial examination, and 512 cases were follow up. It was found that 46 cases died of the primary cancer, while 13 died of other causes. The prognosis proved to be favorable with adenocarcinoma but with anaplastic carcinoma or squamous cell carcinoma the disease proved to be ultimately fatal. The survival rates 5 and 10 years after diagnosis were 97.4% and 95.8% for papillary adenocarcinoma, 95.6% and 92.5% for follicular adenocarcinoma, 7.7% and 7.7% for anaplastic carcinoma, 0% for squamous cell carcinoma, and 66.9% and 66.9% for malignant lymphoma. As to the causes of death, the obstruction due to the neck tumor ranks first, indicating that respiratory deaths are numerous. However, as there are histologically many deaths due to the transformation from adenocarcinoma to squamous cell carcinoma or anaplastic carcinoma, it is desirable to perform radical surgery at an early stage.

Post-irradiation carcinoma of the thyroid is usually histologically well-differentiated. In general, those subjects who developed carcinoma had been exposed to low-to-moderate doses of irradiation for benign conditions. We reviewed the charts of 520 patients with Hodgkin's disease seen at Roswell Park Memorial Institute, and found 2 cases of anaplastic carcinoma amongst other thyroidal abnormalities. The existing reports of post-irradiation carcinoma are reviewed and suggestions are made for the management of heavily irradiated, potentially cured patients with Hodgkin's disease.

From the thyroid screening program at the Roswell Park Memorial Institute in Buffalo, New York, 85 patients with thyroid nodules who had received previous irradiation to the head and neck were identified. The diagnosis was confirmed microscopically by needle aspiration cytology and the patients were treated with thyroid replacement therapy. In 24 patients, the nodules disappeared completely; a partial response (more than 50% reduction in size) was seen in 26; 11 patients were improved (20% to 50% reduction in size); 14 had stable disease (less than 20% reduction in nodule size) and in 10 the condition progressed (an increase of more than 20% in nodule size). Six of 21 patients who underwent operation had well differentiated tumours. The number of cases of Hashimoto's thyroiditis (14) was high. Suppressive therapy will separate those patients whose nodules will disappear completely and who will thus be spared operation. Continued follow-up of such patients is essential. All other patients should be offered operation since thyroid nodules are malignant in 30% of cases.

Mucin-producing carcinoma of the thyroid is rare and its histogenesis has been debated. The first case was reported by Diaz-Perez et al. (1976). We herein report the sixth case of mucin-producing carcinoma of the thyroid which was discovered in a 72-year-old Japanese woman. This patient was admitted with a 10-year history of a lump in the right anterior neck, which started to grow suddenly two months before diagnosis. The pathological diagnosis at biopsy was anaplastic carcinoma. A course of radiation therapy followed by chemotherapy resulted in no response. She died of two months after admission. At autopsy, the main tumor was found in the right lobe of the thyroid with metastasis to the lungs and liver. Histologically, the tumor was composed of mucin-secreting glandular cells and nests of epidermoid cells with keratinization and infrequent formation of intercellular bridges. Mucin was demonstrated both intracellulary and extracellulary.

A case is presented of a 32-year-old black female who died from adult respiratory distress syndrome with disseminated intravascular coagulopathy. At autopsy she was found to have typical multiple endocrine neoplasia IIA, a combination of medullary carcinoma of the thyroid, bilateral adrenal pheochromocytoma and nodular hyperplasia of the parathyroid.

A patient with pathologically confirmed medullary carcinoma of the thyroid with lymph node metastases was noted to show uptake of radiothallium, radiopertechnetate, and radioiodine. A perchlorate washout test was markedly positive, indicating that the uptake was largely due to trapping.

A patient with malignant lymphoma developed goiter and thyrotoxicosis during the course of her disease. A thyroid biopsy revealed involvement of the thyroid gland with a malignant lymphoma. This was associated with the high levels of circulating thyroglobulin and thyroid hormones. The patient was treated with propylthiouracil, local radiotherapy, and nitrogen mustard and prednisone. The patient became euthyroid with the disappearance of goiter. Circulating levels of thyroglobulin and thyroid hormones returned to the normal range.

Involvement of the thyroid gland by plasma cell neoplasms is very rare. On review of 248 cases, we found 4 cases in which pathological evidence of plasma cell neoplasm in the thyroid was verified. This was a heterogeneous group of patients; the thyroid involvement was clinically recognized as a site of extramedullary plasma cell neoplasm in one patient and as a part of generalized disease in two patients. In another patient with generalized disease, the thyroid involvement was discovered at autopsy.

This is a prospective, randomized study of 431 patients with palpable thyroid nodules who had previous radiotherapy for benign disorders of the head and neck area to determine the response of the thyroid nodules to suppressive therapy and the incidence of thyroid cancer in patients who could not be suppressed and had surgery. A complete response was achieved within 6 months in 18.3 percent of the patients, and in an additional 26 percent of patients between 7 and 12 months postoperatively. Twenty percent of the patients showed complete disappearance of nodules after 1 to 2 years of suppressive therapy. Twenty-two percent who underwent surgery showed carcinoma. If suppressive therapy is to be used, a trial of 1 year rather than 3 or 6 months, as often recommended, may be appropriate.

Medullary carcinoma of the thyroid from a 43-year-old patient showed 4 types of unusual cytoplasmic inclusion bodies ultrastructurally. Type 1 inclusion is composed of rod and doughnut-shaped bodies aggregated in the cytoplasma and not enclosed by a limiting membrane. Typical neurosecretory granules are intermingled with the rod and doughnut-shaped bodies. The doughnut-shaped bodies often have an electron dense core which is similar to the neurosecretory granules. The rod-shaped bodies are bounded by trilaminar unit membrane and have a slightly electron dense matrix. A centriole is often found associated with this type of inclusion. Type 2 inclusion is composed of small secretory granules and clear vesicles. These inclusions can be found either with or without surrounding membrane. Type 3 inclusion is a large osmiophilic body, or secondary lysosome, in which some degenerated organelles are discernible. Type 4 inclusion is a fragmented nucleus with condensation and margination of the chromatin, so-called karyorrhexis. Routine hematoxylin and eosin sections did not show each type of inclusion but semithin sections stained with Paragon suggested 4 different types of inclusions. Type 3 and 4 inclusions represent forms of degeneration and cell death in the tumor cells and probably represent a remote effect of radiation. Type 1 inclusion is not commonly associated with cell death and may represent a unique organellar aberration in these tumor cells. Type 2 inclusion is simply an aggregation of secretory granules and clear vesicles.

Thyroid cancer is not a common cancer and consists of a variety of tumors with different biological characteristics. Diagnosis and therapeutic approaches differ considerably, depending on which subgroup the tumor belongs to. Differentiated carcinomas, which constitute the bulk of thyroid carcinoma, often retain the features of the thyroid gland, which can be taken advantage of in their management. The prognosis of these patients is usually excellent. Undifferentiated carcinoma, in contrast, is an aggressive tumor and usually is fatal within a year from the diagnosis. Therefore, an aggressive therapeutic approach is required. Transformation of differentiated carcinoma to undifferentiated carcinoma does occur, although infrequently. The importance of proper management of patients with differentiated carcinoma is obvious. Medullary carcinoma, which originates from the parafollicular cells, has various interesting biological characteristics and is a medium-grade malignancy.

Patients with thyroid cyst (TC), non-toxic nodular goiter (NNG), follicular adenoma (FA) and papillary carcinoma (PC) were given a tracer dose of 125I 40h prior to surgery. Tissue specimens were hydrolysed with Pronase and their labeled iodocompound distribution determined by paper or thin layer chromatography; they were then derivatized and their stable iodoamino acids (IAA) determined by gas liquid chromatography (GLC). Specific activity (SA) of MIT, DIT and T4 was within the same range in TC, FA and grossly normal part of a PC, and was markedly lower in two NNG. SA of T3 was very high in a TC, and higher than that of other IAA, in one NNG, indicating preferential synthesis. SA of MIT and DIT was very high in grossly normal part of a second PC but stable iodothyronines were undetectable. Specimen therefore was biochemically abnormal though grossly normal. In the two abnormal specimens of PC stable IAA were undetectable, even though type of distribution of labeled IAA in one specimen closely approximated that found in TC, FA and NNG. In a second abnormal PC specimen RAI uptake was too low for analysis to be carried out. By combining labeled and stable IAA measurements new parameters for studying human thyroids have been obtained.

The majority of well-differentiated carcinoma of the thyroid can be effectively treated by surgery and thyroid hormone administration, or in combination with radioiodine therapy. Occasional patients with well-differentiated carcinoma, and patients with medullary carcinoma and anaplastic carcinoma should be considered for chemotherapy. Doxorubicin has been shown to be active in this neoplasm. In addition, there are chemotherapeutic agents shown to be active in small numbers of patients with this disease, but most of them have not received an adequate trial. Multiple-agent chemotherapy has also been tried in this disease. However, average response rate of multiple-agent chemotherapy appears to be only slightly better than that of doxorubicin single-agent chemotherapy. The importance of group approach in evaluating chemotherapy program is presented.

Three cases of squamous cell carcinoma and 3 cases of mixed squamous and glandular carcinoma were reported. Pathologic differential diagnosis of these rare primary tumors of the thyroid gland were discussed. All except 1 case occurred in elderly patients; their clinical behavior was more aggressive than that of differentiated carcinoma. It is suggested that the tumor be treated more vigorously at its initial stage.

A rare case of hamartomatous adiposity of the thyroid gland was found incidentally in a 73 year old white female with adenocarcinoma of the rectum. Pressure symptoms related to the goiter (120 gms) were the only manifestations noted. Extensive laboratory investigations failed to reveal any demonstrable functional abnormality of the thyroid gland.

Since February, 1977, 735 patients having a history of receiving radiation therapy for benign conditions of the head and neck areas during infancy and childhood were examined in a thyroid screening program, and 159 patients were found to have palpable thyroid nodules. These patients had thyroid function tests and indirect laryngoscopy and were followed closely on suppression therapy consisting of either Cytomel or thyroid extract. Thyroidectomy was advised in those in whom the nodules persisted or increased in size. This study documents the incidence of carcinoma and other benign pathological changes and postoperative complications in this group of patients. So far, 49 patients had either a lobectomy with isthmusectomy or a total thyroidectomy. Eleven patients were found to have carcinoma (six had papillary, four had mixed papillary and follicular, and one had follicular carcinoma). Three patients had a therapeutic modified neck dissection following the documentation of microscopic involvement of paratracheal lymph nodes. A high incidence of chronic nonspecific thyroiditis, postradiation fibrosis, and follicular adenomas were also found in these patients. Three patients had temporary hypocalcemia (two weeks) and none had wound infection, hematoma, or postoperative nerve palsy. Of patients who had surgical resection, 22.4% showed thyroid carcinoma.

Needle aspirations of benign and malignant epithelial lesions of the thyroid were investigated in 265 patients. An 18-gauge needle connected to a 20-cc glass syringe was used to puncture each tumoral mass. Smears were stained by the Wright-Giemsa method. The material obtained consisted of 180 nontoxic goiters, 18 toxic goiters, 15 cases of thyroiditis and 52 malignant lesions. Aspirations taken from 21 patients (8%) were either blank or contained only blood and insufficient material for diagnosis. Results were correlated with clinical findings and laboratory tests. Biopsies were obtained only in selected patients to establish the final diagnosis. One false positive and one false negative were recorded. Although well-preserved follicular patterns can be seen on the cytologic specimens, the differentiation of thyroid adenoma from early follicular carcinoma based on cytologic criteria only if fraught with many difficulties. Cell density, nuclear structure and presence of nucleoli are sometimes helpful in making the cytologic diagnosis of thyroid carcinoma.

Two cases of primary squamous cell carcinoma associated with a thyroid cyst in the thyroid are described. The majority of squamous cell carcinomas reported so far have had some degree of co-existing adenocarcinoma, while the cases presented in this report had no glandular component at all. The histogenesis of squamous cell carcinoma is not clear, but at present, it is believed that most cases arise from the follicular epithelium. In our cases, in spite of an intensive examination of serially sectioned specimens, no areas of adenocarcinoma, squamous metaplasia from the follicular epithelium, or congenital squamous remnants could be found.

Radiation-associated thyroid carcinoma is of clinical importance in modern radiation therapy of both Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL), because anatomically the thyroid is often in the radiation field. We have reviewed the records of HD and NHL patients seen at Roswell Park Memorial Institute (RPMI) between 1910 and 1960 to determine associated occurrence of thyroid cancer. Radiation therapy was the major therapeutic modality with the occasional use of single agent chemotherapy with nitrogen mustard, triethylene melamine (TEM), chlorambucil and prednisone. There were 519 patients with HD and 863 with NHL. The thyroid glands of 439 (84%) HD and 544 (63%) NHL patients were included in the field of radiation. The mean age of patients with HD was 39 yr while for those with NHL, it was 53 yr. The mean survival in HD was 4.2 yr and in NHL 3.8 yr. There were three cases of thyroid cancer among the HD patients occurring 31, 44 and 48 yr, respectively, after radiation therapy. When compared with the number of thyroid cancers expected to develop, the incidence was significantly greater (p less than 0.005). In contrast, three NHL patients were found to have thyroid cancer at the time of surgery or postmortem examination. This number is again greater than expected in such a population (p less than 0.005); however, in only two cases could the cancer be considered as a sequela to NHL treatment. In all three cases the cancer turned out to be subclinical thyroid carcinoma, incidentally found at surgery or autopsy. One of the patients is still alive without evidence of either disease. The reason for this difference between patients with HD and NHL treated with a similar principle is unclear. Some of the factors contributing to this difference may include: the younger age of HD patients at diagnosis; the longer survival of patients with HD as compared with those with NHL; differences in the sites of radiation and type of treatment given; and possible differences in immunological status between the two groups.

Eight autopsy cases of thyroid carcinoma, in which adenocarcinoma and squamous cell carcinoma coexisted, and presented. In these adenosquamous cell carcinoma, pathological findings suggest direct transition from papillary adenocarcinoma to squamous cell carcinoma, rather than transformation to squamous cell carcinoma via squamous metaplasia. We believe that squamous cell carcinoma arises from adenocarcinoma of the thyroid in most cases.

Prognosis of well-differentiated carcinoma of the thyroid gland is generally favorable, while that of anaplastic carcinoma, extremely poor. Well-differentiated carcinoma may sometimes be fatal; the most common underlying cause is considered to be due to anaplastic transformation of the original well-differentiated carcinoma to a less differentiated form. We studied 27 consecutive autopsy cases of fatal thyroid cancer treated at the Ito Hospital, Tokyo, during a five-year period, 1969-1973. We found uniform histological features of anaplastic carcinoma in 10 cases and of well differentiated carcinoma in four cases. In addition, co-existence of well-differentiated and anaplastic carcinomas was observed in nine cases and well differentiated and squamous cell carcinomas in four. Circumstantial evidence strongly suggests that malignant transformation is a part of the natural history of thyroid carcinoma, from well-differentiated carcinoma to less differentiated forms, either squamous cell or anaplastic carcinoma.

Two patients with anaplastic carcinoma of the thyroid following irradiation for Hodgkin's disease are presented, and the previously reported cases briefly reviewed. The risk of late development of thyroid carcinoma is life-long and high-dose irradiation in patients with prolonged life expectancy may result in anaplastic carcinoma as well as less malignant histological forms.

This is a case report of a patient who had received radiation therapy for Hodgkin's disease and 48 years later developed adenosquamous carcinoma of the thyroid gland. Radiation associated thyroid carcinoma is usually of differentiated variety and carried no different prognosis than one not related to radiation. Coexisting adenocarcinoma and squamous cell carcinoma is a very rare event, but makes the prognosis of patients with thyroid carcinoma much poorer. As a result, this kind of patient requires early recognition and aggressive therapy.