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Malignant lymphoma of the thyroid (MLT) frequently arises in patients with a background of Hashimoto's thyroiditis (HT); however, the mechanisms underlying this chain of events are unknown, and there has been no experimental model. Recently, the development of malignant lymphoma has been reported to occur in peripheral blood lymphocytes engrafted into severe combined immunodeficient (SCID) mice. We xenografted human thyroid tissue from patients with HT or Graves disease (GD) into SCID mice to determine the frequency and nature of MLT in these grafts. Human thyroid tissues ( 12 HT, 1 GD, and 15 from normal [paranodular] tissue) were xenografted into 72 mice (43 mice with HT or GD tissue) within 2 hours after human surgery. Human peripheral blood mononuclear cells (PBMC; 4 autologous HT, I allogeneic HT, and 1 allogeneic GD) were injected intraperitoneally into 6 of the latter 43 mice. In addition, 16 additional SCID mice received normal PBMC injections (alone). The mice were killed 6 to 20 weeks after xenografting. In 4 of 33 SCID mice bearing HT thyroid grafts (without addition of PBMC), MLT developed in the HT graft between 8 and 16 weeks after xenografting. In addition, one spleen of a mouse xenografted with GD tissue alone developed a human malignant lymphoma, although the xenografted thyroid in that mouse did not manifest lymphoma. One additional mouse xenografted with HT thyroid tissue and allogeneic HT PBMC developed malignant lymphoma of both the xenografted thyroid and the mouse spleen. In this mouse, the clonality of these lesions in the two organs was different: the thyroid showed restricted expression of immunoglobulin A (IgA) kappa, whereas the spleen exhibited lambda light chain restriction. One human MLT was removed from a SCID mouse, and equal halves were rexenografted into a nude mouse and another SCID mouse. Thyroid antibodies and IgG levels increased in the second SCID mouse, and the MLT survived; in the nude mouse, however, thyroid antibodies and IgG gradually disappeared, and the MLT regressed, virtually to normal. No MLTs were found in the normal human thyroid xenografts. In SCID mice receiving normal PBMC alone, lymphomas tended to develop when more than 35 x 10 6 cells were engrafted (a number similar to that of the lymphocytes in the HT xenografts); thus, the MLTs may reflect merely the numbers (and perhaps density) of human lymphocytes present in the xenografts. It is possible that committment of many of the HT-infiltrating lymphocytes to the thyroid might add an additional factor. However, whether this model will prove useful to study the possible transition of HT to MLT remains problematic.

Metallothioneins (MTs) are a set of ubiquitous low molecular proteins with a high affinity for metal ions, such as zinc, copper, and cadmium. MT overexpression can be induced by these metal ions as well as by other endogenous and exogenous factors. In this study, normal, hyperplastic, and neoplastic thyroid tissues of both follicular and C-cell origin were immuno-histochemically investigated with a monoclonal antibody against I- and II-isoforms of MTs. MT immunoreactivity was demonstrated in the follicular epithelium of 19 normal thyroid glands and in all 32 cases of Graves' disease investigated; 26 of 30 follicular adenomas and 25 of 28 follicular carcinomas showed MT immunoreactivity, whereas only 7 of 20 papillary carcinomas were MT-positive (p < 0.0001 ). In 3 of the 7 positive samples, positivity was restricted to follicular areas of differentation. No MT could be immunolocalized in normal and hyperplastic C cells and medullary thyroid carcinomas (n = 20). In mixed medullary-follicular carcinomas (n = 4), MT staining patterns resembled those seen for thyroglobulin. In anaplastic carcinomas, MTs were mainly immunolocalized in nonspindle cell areas. MT expression in thyroid tumors may reflect the different biological behavior of follicular and papillary carcinomas. Antibodies to MTs may also serve as fairly specific immunohistochemical markers of follicular cell differentiation in thyroid neoplasia.

Samples from 2 different locations within the same euthyroid multinodular goiters (SMG) and normal (N) human thyroids were assayed for their content of DNA, thyroglobulin (Tg), and stable iodine ( 127 1), and determined the response of adenosine 3',5'-cyclic monophosphate (cAMP) to TSH and NaF. Quantitative morphological estimation of histological components in the thyroid was performed and correlated with functional parameters. Regardless the zonal evaluation, in SMG the mean (± SD) DNA content (⧎g/mg tissue) (1.04 ± 0.86) was not statistically different from that in N (1.13 ± 0.21). The mean 127 I concentration (⧎g/⧎g DNA) in N tissues (0.357 ± 0.091) was greater than that in SMG (0.176 ± 0.074). In these tissues, the Tg mean level (± SD) (⧎g/⧎g DNA) was lower (28.3 ± 21.5) than that in N (75.6 ± 41.1). The mean relative proportion (Vv) of epithelial cells in SMG (range, 6.0-30.6%) was statistically different (p <0.00) from that observed in N tissues (range, 10.4-18.2%). The meanbasal (± SD) cAMP level (pmol/⧎g DNA) in these tissues (0.11 1 ± 0.036) was different (p < 0.05) from that in SMG (0.231 ± 0.026). In response to TSH (10 mU), both SMG and N increased their cAMP contents to 0.454 ± 0.045 and 0.572 ± 0.020, respectively. A further elevation in cAMP levels was observed in N (1.154 ± 0.210) after 75 mU TSH, whereas in SMG tissues, no consistent increase (0.609 ± 0.496) occurred. Goiter and normal thyroid slices were unable to increase their cAMP concentrations in response to NaF in vitro. No correlation was found between functional and morphological data in SMG samples. In contrast, this relation was quite uniform in normal thyroids. The results are concordant with the intrathyroidal pathogenic processes often cited for the heterogeneity in human goiter.

Positive immunohistochemical staining for three metal binding proteins, ceruloplasmin, lactoferrin, and transferrin, has been suggested to be a reliable diagnostic marker of malignant but not benign thyroid neoplasms. We tested this hypothesis on a series of 9 nodular hyperplasias, 17 follicular adenomas, 54 papillary carcinomas, 20 follicular carcinomas, and 3 anaplastic carcinomas of thyroid using formalin-fixed paraffin-embedded tissues. We found focal staining for ceruloplasmin and lactoferrin in approximately 25% of follicular adenomas examined; focal ceruloplasmin positivity was also seen in nonneoplastic tissues surrounding thyroid neoplasms. No staining for these markers was found in malignant neoplasms or hyperplasias. Transferrin was found in 55% of papillary carcinomas, but more follicular adenomas (20%) than follicular carcinomas (11%) were positive using this antiserum. These findings show that immunostaining for these antigens is not a reliable method to distinguish benign from malignant thyroid lesions of follicular cell origin.

A case of localized adiposity of the thyroid in a 35-year-old woman with a long history of steroid therapy for nephrotic syndrome is reported. A well-demarcated yellowish mass measuring 2 cm in diameter was found in the upper portion of the right lobe of the thyroid. Microscopically, this lesion was composed of mature adipose tissue partially mixed with thyroid tissue and had no distinct capsule. The nontumorous thyroid tissue showed features of Hashimoto's thyroiditis. At least two factors-hamartomatous malformation and metabolic disturbance-may be involved in the histogenesis of this localized adiposity.

We have attempted to determine whether the administration of thyrotropin would have any different functional or histological effects on Graves' tissue as opposed to human normal thyroid tissue in an in vivo situation (i.e., after xenograft into nude athymic mice). A dosage of 0.03 units per mouse of bovine thyroid-stimulating hormone (b-TSH) was injected intraperitoneally daily for 6 consecutive weeks into xenografted mice. The parameters measured included the free T 4 index and thyroid autoantibodies during the course of b-TSH injections. Tritiated ( 3 H)-thymidine incorporation into thyroid epithelial cells (TECs) and TEC HLA-DR expression were measured in the thyroid tissue at the time of human surgery and at sacrifice; in addition, light-microscopical observations were made at those times. Although there was a decline in free T 4 index values during the course of the study, there was light-microscopical evidence suggestive of hyperplasia in both types of xenografted thyroid tissue. The TSH appeared to result in thyrocyte down-regulation, possibly of receptor or postreceptor origin. The administration of the b-TSH seemed to induce TEC HLA-DR expression in this study. Because these results differ from the effects of TSH on TEC in vitro with respect to TEC HLA-DR expression, it may be postulated that there are other factors liberated in vivo in the nude mice that interact with the TEC and TSH and initiate the TEC HLA-DR expression. We conclude that there are no significant differences between the responses of Graves' tissue and the normal human thyroid tissue in these studies.