Overview of surgical pathology of the thyroid gland.

The purpose of this overview is to provide timely information on selected topics on the surgical pathology of the thyroid gland. Selected publications of the author and his colleagues at the University of Michigan and the Maine Medical Center form the basis of this review. Information provided in our reports is updated by perusal of recent, pertinent publications. The following questions summarize the contents of the overview. What is a "lateral aberrant thyroid"? Does it always represent metastatic carcinoma? What are dyshormogenetic goiters? Can "focal thyroiditis" in thyroid glands removed for the treatment of Graves' disease and toxic nodular goiters be predictive of the development of postoperative hypothyroidism? What is the pathology of autonomously functioning (hot) nodules? Do tall-cell, columnar-cell, and diffuse sclerosing types of papillary carcinomas forbode bad prognoses? What is the controversy over Hurthle cell tumors? Does the presence of a better differentiated component in an anaplastic thyroid carcinoma modify its biologic behavior? Are poorly differentiated carcinomas unique histologic variants? Does their histology affect prognosis? What is the most common small-cell tumor of the thyroid gland? Has the Chernobyl nuclear disaster affected the incidence of childhood thyroid carcinoma? Are these radiation-induced tumors more aggressive? The answers, some of which are controversial, are found in this overview. The aims here were to provide information to surgeons and pathologists and to improve the care of patients with thyroid disease.

Another dissertation on poorly differentiated carcinomas: is it really necessary?

Descriptions of poorly differentiated thyroid carcinomas, tumors with outcomes midway between that associated with well-differentiated and anaplastic carcinomas, have been prominent in the literature of the recent past. The neoplasms are characterized by the finding of poorly differentiated areas within papillary and follicular carcinomas. The work of Sakamoto clearly separates a group of poorly differentiated carcinomas, based on outcomes, from well-differentiated and anaplastic forms by the identification of schirrous, solid, and trabecular areas within papillary and follicular carcinomas. However, the presence of similar areas within more "benign" forms of papillary and follicular carcinomas may obviate the easy identification of such neoplasms in daily practice. This article presents a refinement of Sakamoto's classification and although suffering from the same limitations, may be of some practical value.

Polymerase chain reaction-based microsatellite polymorphism analysis of follicular and Hürthle cell neoplasms of the thyroid.

Follicular and Hürthle cell carcinomas of the thyroid cannot be differentiated from adenomas by either preoperative fine needle aspiration or intraoperative frozen section examination, and yet there exist potentially significant differences in the recommended surgical management. We examined, by PCR-based microsatellite polymorphism analysis, DNA obtained from 83 thyroid neoplasms [22 follicular adenomas, 29 follicular carcinomas, 20 Hürthle cell adenomas (HA), and 12 Hürthle cell carcinomas (HC)] to determine whether a pattern of allelic alteration exists that could help distinguish benign from malignant lesions. Alterations were found in only 7.5% of informative PCR reactions from follicular neoplasms, whereas they were found in 23.3% of reactions from Hürthle cell neoplasms. Although there were no significant differences between follicular adenoma and follicular carcinoma, HC demonstrated a significantly greater percentage of allelic alteration than HA on chromosomal arms 1q (P < 0.001) and 2p (P < 0.05) by Fisher's exact test. The documentation of an alteration on either 1q or 2p was 100% sensitive and 65% specific in the detection of HC (P < 0.0005, by McNemar's test). In conclusion, PCR-based microsatellite polymorphism analysis may be a useful technique in distinguishing HC from HA. Potentially, the application of this technique to aspirated material may allow this distinction preoperatively and thus facilitate more optimal surgical management. Consistent regions of allelic alteration may also indicate the locations of critical genes, such as tumor suppressor genes or oncogenes, that are important in the progression from adenoma to carcinoma. Finally, this study demonstrates that Hürthle cell neoplasms, now considered variants of follicular neoplasms, differ significantly from follicular neoplasms on a molecular level.

Nuclear DNA analysis of hyperplastic parathyroid glands in multiple endocrine neoplasia type I.

Twenty-four hyperplastic parathyroid glands from 11 patients with multiple endocrine neoplasia type I (MEN-I), and 36 hyperplastic parathyroid glands in 15 patients with sporadic primary hyperparathyroidism, ie, not associated with MEN, were analyzed for DNA by flow cytometry. Sixteen of 24 hyperplastic parathyroid glands from patients with MEN-I were DNA diploid, and eight were DNA aneuploid. Thirty-three of 36 hyperplastic parathyroid glands from patients without MEN were DNA diploid, and only three were DNA aneuploid. The mean percentage of 4c level (a measure of the G2M phase of the cell cycle) of DNA diploid hyperplastic parathyroid glands taken from patients with MEN-I was 8.1% +/- 4.5%, which is significantly higher than the 3.5% +/- 3.4% for those taken from patients without MEN. Our results show that there is a difference in nuclear DNA content between hyperplastic parathyroid glands in patients with MEN-I and those in patients without MEN.

Single and multigland disease in primary hyperparathyroidism: clinical follow-up, histopathology, and flow cytometric DNA analysis.

Two-hundred seventy-four patients with primary hyperparathyroidism had selective removal of enlarged parathyroid glands. Biopsies were taken from all parathyroid glands. Normal-size glands were not resected irrespective of their histological appearance. After a mean follow-up of 13.5 years the rates of persistent and recurrent hyperparathyroidism were, respectively, 3.6% and 0.7%. Transient and permanent hypoparathyroidism occurred in 24% and 2.5% of the patients. The microscopic appearance of enlarged glands and of biopsies taken from normal-size glands were reviewed by two pathologists. Normal parathyroid glands were distinguished from abnormal glands fairly accurately (sensitivity 93%, specificity 80%). Microscopic classification of abnormal parathyroid glands as adenomas or hyperplastic glands correlated poorly with the gross classification as single or multigland disease. Flow cytometric DNA analysis of paraffin embedded parathyroid tissue showed significant differences for DNA index, % S-phase and % G2M (p less than 0.001). Differentiating single from multigland disease by means of DNA analysis was not possible. In conclusion, removal of only enlarged parathyroid glands results in acceptable rates of persistent and recurrent hyperparathyroidism. Biopsies should only be taken sparingly to prevent transient and permanent hypoparathyroidism. Microscopic examination and flow cytometric DNA analysis can differentiate normal from abnormal parathyroid glands but are unable to differentiate abnormal glands into single or multigland disease.

Effects of several commonly used fixatives on DNA and total nuclear protein analysis by flow cytometry.

Five commonly used fixatives (AZF, B-5, Bouin's, formalin, and Zenker's) were evaluated for their effect on the flow cytometric analysis of DNA and total nuclear protein (TNP) in solid tumors. Data were obtained with the use of colonic adenocarcinoma, squamous carcinoma of the lung, mammary adenocarcinoma, and spleen with a plasma cell leukemic infiltrate. The parameters examined were G0-G1 DNA staining intensity, %G0-G1, percent coefficient of variation (%CV), percent debris, and TNP staining intensity. The results showed that variations in the fixation of solid tumor significantly affected flow cytometric-derived parameters. In this study, paraffin-embedded tissue (PET) fixed in 10% (v/v) neutral buffered formalin (NBF) produced the best results, with a %CV below 4.7, whereas fixatives such as Zenker's and B-5 produced poor %CVs (above 6.0) or uninterpretable TNP and light scatter data. These data suggest that a portion of all tissue samples be fixed in NBF to allow for subsequent analysis by fixative-sensitive assays such as DNA in situ hybridization and flow cytometry.

Autoimmune thyroid disease: immunological, pathological, and clinical aspects.

Autoimmune thyroiditis, most notably Hashimoto's thyroiditis, appears to be increasing in prevalence and is now more easily detected by sensitive laboratory tests and more invasive procedures such as fine needle aspiration. During the last decade, marked progress has been made in the understanding of these diseases. There is a greater awareness of the interaction between the humoral and cell-mediated arms of the immune system in autoimmune thyroiditis. Recent studies implicate a subpopulation of suppressor T lymphocytes which have an antigen-specific defect, resulting in their suboptimal interaction with the helper T lymphocytes and subsequent autoimmune manifestations. There is some evidence that thyroid epithelial cells which inappropriately express HLA-DR may enhance presentation of thyroid antigens to the immune system, possibly significant in the initiation or enhancement of the autoimmune response. The presence of various antithyroid autoantibodies allows the use of laboratory assays to confirm the clinical diagnosis and predict the results of treatment. There appears to be predisposing genetic factors in the development of autoimmune thyroiditis, with some geographical and racial differences. Environmental factors, most notably dietary intake of iodine, have also been implicated in the pathogenesis of Hashimoto's thyroiditis. Several animal models have been developed addressing such issues. Ongoing studies in the areas of postpartum thyroiditis and childhood thyroiditis are helpful in clarifying their relationship with Hashimoto's thyroiditis. Graves' disease and postpartum thyroiditis are being investigated as possible causes of postpartum depression. The association of Hashimoto's thyroiditis and carcinoma of the thyroid gland is still controversial, but its relationship with malignant lymphoma is now well accepted. Thus, although the pathogenesis of autoimmune thyroiditis remains elusive, there has been significant refinement of the clinical diagnosis, and immunological abnormalities of specific intrathyroidal lymphocytes have been identified. Hopefully, these new areas of knowledge will assist in the treatment of these diseases and in the prevention of the development of malignant lymphomas of the thyroid gland.

Percutaneous tetracycline instillation for sclerosis of recurrent thyroid cysts.

Of 770 hypofunctioning thyroid nodules subjected to needle biopsy since 1977, the fluid of 172 cysts (22%) was aspirated. The fluid, cytologically examined, showed no evidence of carcinoma except in three instances: papillary carcinomas that were subsequently treated surgically. Of the cystic lesions, 19 (11%) recurred and were treated by reaspiration and the instillation of tetracycline hydrochloride into the cyst cavity. In all but one instance this resulted in obliteration of the cysts (95%). This is a considerably higher rate of success than that reported from aspiration alone (40% to 85%). The follow-up period ranged from 1 to 42 months, with no recurrence or subsequent development of a thyroid nodule in these patients. The one recurrent cyst was reaspirated and reinstilled a second time, which resulted in great reduction in size. Not considered for this procedure were patients in whom the cytologic condition of the fluid was abnormal or indicative of a malignancy. Also excluded were those in whom there was incomplete decompression of the cyst, manifested by a persistent nodule. No patients had a history of head or neck irradiation or cervical lymphadenopathy, both contraindications for this procedure. No patients had grossly bloody aspirates. Recurrence of thyroid cysts after aspiration was not thought to be, in itself, a criterion for surgical selection. The effective use of tetracycline hydrochloride as a sclerosing agent in the treatment of malignant pleural effusions is well documented. Its action in producing symphysis is thought to be related to its low pH (2.0). This procedure is safe, simple, cost effective, and well tolerated by patients. It obviates the need for excision in patients who fulfill the aforementioned criteria.

The efficacy of simultaneous fine-needle aspiration and large-needle biopsy of the thyroid gland.

Fine-needle aspirations and cutting needle biopsies were performed on 415 patients with solitary thyroid nodules. All nodules were considered hypofunctioning by scintiscans. Specimens were adequate in 399 patients. Ten percent of these patients had thyroid cancers documented by thyroidectomies. Results from either or both procedures were positive or suspicious in 58 patients (14.5%). Thyroid cancers were found in 40 of the 58 patients (69%). Aspirates alone detected 34 of 40 cancers (85%) and biopsy specimens alone detected 30 of 40 cancers (75%). All thyroid cancers were detected when both results were considered together, demonstrating that needle aspirates and cutting needle biopsies are complementary. The difficulty of making definitive diagnoses of follicular neoplasms by needle aspirates or cutting needle biopsies is reemphasized.

Secretory diarrhea with islet cell hyperplasia and increased immunohistochemical reactivity to serotonin.

Two patients with secretory diarrhea and signs and symptoms consistent with the Verner-Morrison syndrome and islet cell hyperplasia are described. Both patients responded well to subtotal pancreatectomies. The morphologic changes in the pancreata were characterized by proliferation of islets associated with periductal and interstitial fibrosis. Immunohistochemical stains demonstrated increased staining for serotonin in islet cells. A few islet cells also stained for vasoactive intestinal polypeptide. The significance of these results is discussed.

Five cases of parathyroid lipohyperplasia.

Lipoadenoma is the accepted diagnosis of a single enlarged parathyroid gland that contains large quantities of mature fat cells and focal myxoid stroma, all widely separating small parenchymal cell nests in patients with hyperparathyroidism. Here we are reporting, for the first time, on five cases of hyperparathyroidism in which all four parathyroid glands are enlarged and each gland is noted to have an admixture of fat and parenchymal cells. We will introduce the descriptive diagnosis of lipohyperplasia to name this condition and keep it in perspective with other forms of parathyroid disease. All five patients were women between the ages of 36 and 62 years who underwent neck exploration, at which time four enlarged light-tan parathyroid glands were observed. Three and one half gland resections were performed, and all patients returned to a normocalcemic state except one who had borderline serum hypercalcemia after operation. Most of the resected parathyroid glands weighed in the range of 100 to 200 mg. The largest measured gland weighed 820 mg. Parathyroid histology showed an admixture of mature fat cells with parathyroid parenchymal cells often in a 1:1 ratio. One patient who had renal failure exhibited a lower ratio of fat cells. Two patients had chronic lymphocytic thyroiditis that was severe enough to require synthetic thyroid hormone therapy. Two patients had a history of urinary tract infections. Three patients had hypertensive cardiovascular disease, and several patients had arteriosclerotic cardiovascular disease. One patient had diabetes mellitus, one had a history of pituitary adenoma, and one had polydipsia. All of these patients were first seen with parathyroid glands measuring an average of five times normal size, yet they showed the usual 50% fat/50% parenchyma pattern of normal mature parathyroid glands. This means that the enlarged glands contain a 500% increase in parathyroid tissue, justifying the diagnostic term "lipohyperplasia." This easily represents enough parathyroid tissue to generate excessive parathyroid hormone production. At this time, there is no explanation of the pathogenesis of lipohyperplasia or how it varies from other previously described forms of parathyroid hyperplasia.

Survival time and "cure" in papillary and follicular thyroid carcinoma with distant metastases: statistics following University of Michigan therapy.

Between 1947 and 1980, 103 patients with well-differentiated thyroid carcinoma with metastases outside the neck were treated with sodium iodide (I-131) after surgical treatment. Forty-one patients had distant metastases first detected an average of 7.44 yr after the initial operation establishing the diagnosis of thyroid carcinoma. Follicular and papillary carcinomas gave the same survival time in patients, matched for age and sex, who had metastases outside the neck. Those considered to be free of their metastatic disease after I-131 therapy survived three times as long as those with persistent disease. Patients freed of their metastases had a higher conformity rate with half of our ten procedures of "ideal" treatment, compared with patients not freed of their metastases.

Nesidioblastosis in adults. A surgical dilemma.

Nesidioblastosis is the leading cause of hyperinsulinemia in newborns and infants. To our knowledge, it has not been previously reported in adults unless associated with other diseases. Three males and three females, aged 11 to 57 years, are described. Pancreatic resections ranged from 50% to 100%. Postoperatively, three patients were normoglycemic, two were insulin-dependent diabetics, and one had recurrent hypoglycemia controlled by drugs. The histologic findings in adults were very similar to those in infants with nesidioblastosis. It appears that a minimum resection of 75% to 80% of the pancreas will benefit the majority of patients, alleviating hypoglycemia and preventing the development of diabetes.

Experimental renal infarcts: angiographic and histologic studies.

The renal arteries in three groups of four dogs were occluded to induce renal infarcts using Gelfoam, Gelfoam and steel coil, and barium suspension. Each agent was evaluated for its effect on renal renin output, arteriographic appearance, and the extent of renal infarct produced. Gelfoam embolization produced incomplete infarcts with hypertrophy of remaining viable tissue. Renal infarcts were more extensive with the combination of Gelfoam and coil than with Gelfoam alone. Barium embolization produced the most diffuse and extensive renal infarct. Renal vein plasma renin levels from the embolized kidney were significantly elevated in the Gelfoam-plus-coil dogs, but arterial pressures were significantly higher in only two of four of these dogs 10 weeks after embolization.

The detection of islet-cell antibodies by immunofluorescence in Bouin's-fixed, paraffin-embedded human pancreas.

Pancreatic islet-cell antibodies have been demonstrated in the sera of insulin-dependent diabetic patients, with or without polyendocrine disease, by immunofluorescent microscopy in which cryostat sections of fresh-frozen human pancreas were used as the substrate. In the present study we used sections of Bouin's-fixed, paraffin-embedded, trypsin-treated human pancreas as the islet-cell substrate and compared the results to those obtained with cryostat sections. Twenty-four sera from insulin-dependent diabetic patients, one serum from a non-insulin dependent diabetic patient and five sera from normal individuals were tested. With serum samples containing islet- cell antibodies, Bouin's-fixed, paraffin-embedded tissue produced a more intense fluorescence, was easier to use and was more sensitive than the conventional cryostat method.

Adrenal medullary disease in multiple endocrine neoplasia type II.

The diagnosis of multiple endocrine neoplasia type II (MEN-II) was made in 18 patients from 1966 through 1978 at the University of Michigan Medical Center. Eight patients had adrenal medullary disease. Seven had bilateral adrenal pheocyromocytomas (two with concomitant medullary hyperplasia) and one had a unilateral pheochromocytoma with contralateral medullary hyperplasia. No malignant or extraadrenal pheochromocytomas were found. Pheochromocytomas in patients with MEN-II are multiple and involve both adrenal glands. Adrenal venography is advocated as the primary diagnostic tool for localization of adrenal medullary disease in MEN-II patients.