Nobuo Murakami

Papillary carcinoma of the thyroid I. Developing pattern of metastasis

Seventy‐one cases of papillary adenocarcinoma of the thyroid were operated on from January 1967 to July 1968. in 14 cases, the diagnosis of carcinoma was established postoperatively, so that 57 patients underwent systematic lymph node excision. Among these 57 cases, 90% had evidence of metastasis. a majority of metastatic deposits were small, i.e., 57% of them were less than 3 mm in diameter. There was no relationship between the location of primary tumor and metastasis; the initial metastases were most commonly observed in the pre‐ and paratracheal nodes, and subsequently, metastases were noted in the deep inferior and lateral cervical nodes. in patients who had a small number of metastatic deposits, the metastases were concentrated in the following sequence: pre‐ and paratracheal nodes, deep lower and lateral, and deep upper submandibular nodes. in those who had extensive metastases, the sequence of concentration was as follows: pre‐ and paratracheal, paraglandular and deep upper cervical, deep lower and lateral, and submandibular. From these observations, it can be concluded that metastasis of papillary thyroid carcinoma occurs first in paratracheal nodes, regardless of the location of the primary tumor. in the early stages, metastases are more frequent in the lower part of the neck. in later stages, when lymphatic obstruction has occurred, metastases appear in upper and submandibular nodes.

The value of lymph-node dissection in patients with differentiated thyroid cancer.

The perithyroidal and ipsilateral cervical lymphatic system not only is commonly involved by thyroid cancer but also is a common site of recurrence. Modified radical neck dissection, with preservation of the sternocleidomastoid muscle and spinal accessory nerve, is the treatment of choice for patients with clinically evident lymph node metastases due to differentiated thyroid cancer. It is also recommended, by us, for patients over 40 years of age who have primary thyroid tumors greater than 1.5 cm in size whether or not nodes are clinically palpable. This is because at least 75 per cent of these patients have metastases, and their discernment at operation is unreliable. With more aggressive surgery, the recurrence-free survival rate can be improved substantially without cosmetic deformity or postoperative dysfunction.

Papillary carcinoma of the thyroid II. Value of prophylactic lymph node excision

Among 57 patients with papillary adenocarcinoma of the thyroid who underwent systematic excision of lymph nodes from January 1967 to July 1968, 90% were shown to have evidence of metastasis. the majority of metastatic deposits were small, i.e., 57% measured less than 3 mm in diameter. of the patients operated on before 1962, 39% revealed metastases before or during surgery; thus, a majority of small metastatic tumors might have been overlooked. Among those patients operated on before 1962 and judged not to have metastasis and who did not undergo lymph node excision, 83% are assumed to have undiagnosed metastasis. Survival without recurrence in those patients considered free from metastasis was as high as 77% after 15 years. Survival without recurrence in patients with diagnosed metastasis who received individual‐not systematic and not en bloc‐lymph node excision was 43% after 10 years. in those patients in whom metastatic deposits were microscopic, no malignant biologic effect has been demonstrable. in those patients in whom gross nodal involvement was present, small metastatic tumors did not regress after removal of both primary tumor and affected nodes, but enlarged and caused recurrence. Systematic excision of regional lymph nodes appears of less importance in cases with no gross nodal involvement at time of surgery. Radical excision is required, however, in cases with gross involvement.

CERVICAL THYMOMA and INCIDENCE OF CERVICAL THYMUS

A case of cervical thymoma in a 51‐year‐old female is reported. The tumor was located on the left side of the anterior neck just beneath the left lower lobe of the thyroid gland and there was no connection to the mediastinal thymus gland. It was well encapsulated and lobulated on the cut‐surface. Histologically, the tumor showed a mixed proliferation of lymphocytes and epithelial cells. Mitoses were frequently seen. Several tiny fragments of ectopic thymic tissue were found around the tumor. Cervical thymic tissue, considered to be the original site of the cervical thymoma, was studied and found macroscopically in 12 out of 657 patients with Basedows disease (1.8%).

LOSS OF INTRACELLULAR PEROXIDASE and ANAPLASTIC CHANGE OF DIFFERENTIATED CARCINOMA OF HUMAN THYROID GLAND

Ultrastructural localization of endogenous peroxidase (peroxidase) in differentiated thyroid carcinoma was studied in 2 cases of follicular carcinoma and 12 of papillary carcinoma. The reaction product for the enzyme was observed in cancer cells which had a round and smoothly‐contoured nucleus and rather few number of microvilli (positive cells) and the product localized mainly in the rough‐surfaced endoplasmic reticulum and perinuclear cisternae. The positive cells resembled normal follicular cells in localization sites of the reaction product and ultrastructural features. On the contrary, in cancer cells having an irregularly‐outlined nucleus with or without intranuclear cytoplasmic inclusion and many microvilli, no reaction product was visualized (negative cells). The positive cells were frequently found in 2 follicular carcinomas and 2 papillary carcinomas. Only a few number of positive cells presented in 2 papillary carcinomas. The remaining 8 papillary carcinomas were composed only of negative cells. Histologically, follicles with colloid were frequently found in carcinomas with abundant positive cells, whereas they were few in number in carcinomas containing only negative cells.

THYROID CARCINOMA IN BENIGN THYROID DISEASES An Analysis from Minute Carcinoma

The relative frequency of thyroid carcinoma in benign thyroid diseases such as toxic diffuse goiter (toxic goiter), adenomatous goiter (goiter), adenoma, and chronic thyroiditis (thyroiditis) was studied using 3,219 surgically removed thyroid glands. Coexistence of carcinoma and benign diseases was found in 257 glands. Among them, 157 glands had minute carcinoma (diameter of cancer nodule is smaller than 10 mm) and 100 glands had advanced carcinoma (larger than 10.1 mm in diameter). The incidence of carcinoma including minute carcinoma was 29.4% in goiter (98/333), 21.0% in thyroiditis (11/53), 8.6% in adenoma (55/638), and 5.3% in toxic goiter (98/1852). Chi‐square test also revealed that the rate of carcinoma not only advanced carcinoma but also minute carcinoma was higher in goiter than in the other diseases (P<0.01, respectively). Among the patients aged under 39, the incidence of advanced carcinoma and minute carcinoma in thyroiditis were the highest, respectively (83% and 100% in thyroiditis, 9.0% and 11.4% in goiter, 2. 6% and 1.9% in adenoma, and 0.7% and 3.4% in toxic goiter), however, among the patients aged over 40, they were secondary lower and the lowest, respectively (19% and 16.8% in goiter, 5.2% and 7.5% in adenoma, 4.2% and 6.7% in thyroiditis, and 1.4% and 7.5% in toxic goiter). We concluded that adenomatous goiter accompanies carcinoma more frequently than other benign thyroid diseases and the high incidence of carcinoma in chronic thyroiditis is probably due to a preoperative selection of the patients. ACTA PATHOL. JPN. 35: 781–788, 1985.

Ultrastructural Localization Of Endogenous Peroxidase In The Human Thyroid Gland Under Normal And Hyperfunctioning Conditions

Ultrastructural localization of human thyroid peroxidase in normal and hyperfunctioning states has been studied. Peroxidase activity was visualized ultrastructurally with a cytochemical reaction using 0.05% diaminobenzidine‐tetrahydrochloride, and hydrogen peroxide with a final concentration of 0. 0025%, 0.005%, or 0.01%, respectively, and 2% osmium tetroxide. Reaction product demonstrating the enzyme was clearly observed in cell organelles with a final concentration of hydrogen peroxide at 0.0025% or 0.005%. In the normal portion of thyroid, follicular cells demonstrated the reaction product, located mainly in rough‐surfaced endoplasmic reticulum and perinuclear cisternae and in addition a small amount of the product was found in Golgi cisternae and small vesicles dispersed throughout the subapical cytoplasm. The reaction product significantly increased in amount in the cell organelles described above and in addition, a characteristic heavy deposition of the product was observed at the external surface of the microvilli in the follicular cells of thyroid obtained from the patients with treated Basedows disease. ACTA PATHOL. JPN. 34: 553–561, 1984.

Effects of Dietary Iodine on Chemical Induction of Thyroid Carcinoma

Effects of dietary iodine on the induction of thyroid carcinoma using N‐nitrosobis(2 hydroxypropyl)amine (BHP) were studied. Male Wistar rats were fed with an iodine‐adequate diet (IAD group), an iodine‐rich diet (IRD group) and an iodine‐deficient diet (IDD group), respectively, until the time of sacrifice. From the 2nd experimental month, animals were injected with BHP once a week for 10 weeks. In the IAD and IRD groups, benign nodules and papillary carcinoma were found. The incidence of rats with benign nodules was 100% in both groups and animals with papillary carcinoma in the IAD and IRD groups comprised 33% and 29%, respectively. The area of the thyroid gland occupied by nodular lesions was much narrower in the IRD group than in the IAD group. In the IDD group, the thyroid showed marked enlargement due to multiple nodular proliferation of follicle cells. The incidence of rats with carcinoma was 100%, and not only papillary but also follicular carcinoma and one pulmonary metastasis were found. As the iodine content of the diet decreased, the nodular lesions increased in width and number, and the incidence of carcinoma in rats became higher. These effects of dietary iodine are probably related to the goitrogenic and/ or promoting effects of TSH. Acta Pathol Jpn 40: 705‐712, 1990.

MINUTE CARCINOMA OF THE THYROID and ITS DEVELOPMENT TO ADVANCED CARCINOMA

The relationship between the size of carcinomas and their histological characteristics such as encapsulation and sclerosis was studied using 157 cases of thyroid minute carcinomas with diameters less than 10 mm. When the diameter of the tumor was less than 1 mm, encapsulated carcinomas were not found, but they were presented in a group with a larger diameter. Sclerosing carcinomas were more frequently distributed in the group with a diameter less than 5 mm. With increasing tumor size, the carcinomas were reduced markedly in number and only two cases of sclerosing carcinoma were observed with a diameter more than 8 mm. It was concluded that thyroid minute carcinomas arise as nonencapsulated carcinoma, either sclerosing or nonsclerosing, followed by encapsulation at a later time and that some of the nonsclerosing carcinomas become apparent clinically, whereas most of the sclerosing carcinomas remain clinically silent throughout the entire life of the host. ACTA PATHOL. JPN. 35 : 377–383, 1985.

ULTRASTRUCTURAL LOCALIZATION OF ENDOGENOUS PEROXIDASE ACTIVITY IN BENIGN THYROID DISEASES

Ultrastructural localization of endogenous thyroid peroxidase under benign pathological conditions such as toxic diffuse goiter, non‐toxic multinodular goiter, and adenoma, and in normal tissue was studied. Peroxidase activity was visualized by a cytochemical reaction for electron microscopy. In toxic diffuse goiters and most non‐toxic multinodular goiters, reaction product for peroxidase was observed not only in the cytoplasm but also at the external surface of microvilli of follicular cells. In normal thyroid tissues and adenomas, peroxidase was visualized only in the cytoplasm. Peroxidase activity at the external surface of microvilli of the follicular cells was found in the tissues obtained from the goiters which showed “hot” radioidine scintigram. These findings suggest that follicles with peroxidase activity at the external surface of microvilli in non‐toxic multinodular goiter are “autonomous follicles” and that peroxidase at the external surface of microvilli plays some role in active iodine uptake.