Fine needle aspiration biopsy of the thyroid gland in patients with prior Graves' disease treated with radioactive iodine. Morphologic findings and potential pitfalls.

OBJECTIVE: To evaluate the morphologic findings and their potential pitfalls in fine needle aspiration biopsies (FNAB) of thyroid glands obtained following radioactive iodine (RaI) (131I) treatment for Graves' disease. STUDY DESIGN: Study of thyroid FNAB specimens from six patients with prior Graves' disease treated with RaI who developed palpable nodules and had subsequent thyroid resections. RESULTS: The cytologic changes attributed to radiation were quite variable among the six cases and were so pronounced in one case that a false positive diagnosis of papillary carcinoma was made even though a history of RaI had been provided. The FNAB specimen from the second case, submitted without a history of RaI treatment, was diagnosed as suspicious for papillary carcinoma. The smears from patient 3 were signed out descriptively because the pertinent clinical history had not been provided. The FNAB specimens from the last three patients were correctly interpreted because of the history of RaI therapy provided. All six thyroid surgical specimens showed changes consistent with radiation injury, and none contained evidence of malignancy. CONCLUSION: The study's findings demonstrate that the atypia produced by RaI may be severe, leading to an erroneous diagnosis of malignancy. Provision of the appropriate clinical history of Graves' disease treated with RaI may prevent this pitfall.

A comparative study of flow cytometry and histopathologic findings in thyroid follicular carcinomas and adenomas.

As a possible diagnostic aid in the often difficult histopathologic distinction of thyroid follicular carcinomas from adenomas based on invasion most flow cytometry studies have indicated a higher aneuploidy incidence in carcinomas. However, these reports often are difficult to analyze mainly due to nonuniformity of pathologic diagnostic criteria. The present study compares the flow cytometry results of 65 follicular tumors with pathologic findings based on the World Health Organization's specific diagnostic and staging criteria. Aneuploidy was significantly higher in the 28 cancers than in the 27 hypercellular (fetal and embryonal) adenomas (57% v 22%; P = .02). There was a high percentage of aneuploidy (75%; nine of 12 cases) in the widely invasive follicular carcinomas, compared with 40% (six of 15 cases) in the minimally invasive carcinomas, 22% (six of 27 cases) in the hypercellular adenomas, and 10% (one of 10 cases) in the normofollicular or macrofollicular adenomas. However, aneuploidy was not significantly different between the most difficult differential histopathologic diagnoses of minimally invasive follicular carcinoma (40%; six of 15 cases) and hypercellular adenoma (22%; six of 27 cases) (P = .12). Other data included relatively high frequencies of aneuploidy in hypercellular adenomas (29%; six of 21 cases) and diploid status of carcinomas (36%; 12 of 33 cases). In summary, although the overall findings show a trend toward increasing aneuploidy from well-differentiated and hypercellular adenomas to minimally and widely invasive follicular carcinomas, the aneuploidy data are inconsistent and indicative of its nonspecificity and limited diagnostic usefulness.

Loss of the retinoblastoma tumor-suppressor gene in parathyroid carcinoma.

BACKGROUND: The origin and molecular pathogenesis of parathyroid carcinoma are unknown. This life-threatening cause of primary hyperparathyroidism cannot be reliably distinguished from its benign counterpart on the basis of histopathological features alone. Because the PRAD1, or cyclin D1, gene, a cell-cycle regulator, has been implicated in a subgroup of benign parathyroid tumors, we examined the possibility that another cell-cycle regulator with possible functional links to PRAD1, the retinoblastoma tumor-suppressor gene (RB), might be involved in the molecular pathogenesis of parathyroid carcinoma. METHODS: Parathyroid carcinomas from 9 patients and adenomas from 21 were studied for evidence of tumor-specific loss of RB gene DNA (allelic loss) by analysis of four DNA polymorphisms and for evidence of altered expression oF RB protein by immunohistochemical staining. RESULTS: All of 11 specimens from 5 patients with parathyroid carcinoma and informative DNA patterns and 1 of 19 specimens from 19 patients with parathyroid adenoma and informative DNA patterns lacked an RB allele. Fourteen of 16 specimens (88 percent) from the nine patients with carcinoma had abnormal expression of RB protein (a complete or predominant absence of nuclear staining for the protein). None of the 19 adenomas, including the tumor with loss of an RB allele, had unequivocally abnormal staining for RB protein. CONCLUSIONS: Inactivation of the RB gene is common in parathyroid carcinoma and is likely to be an important contributor to its molecular pathogenesis. The presence of such inactivation may help to distinguish benign from malignant parathyroid disease and may have useful diagnostic, prognostic, and therapeutic implications.

Ras oncogene mutations in benign and malignant thyroid neoplasms.

Current models for tumorigenesis propose that a series of genetic alterations occur during the progression from the normal cell to the malignant phenotype. Mutations in each of the three ras genes (K-ras, H-ras, and N-ras) have been identified in many human neoplasms, including thyroid cancer. In this study we examined genomic DNA from benign and malignant thyroid neoplasms for mutations that are known to activate the ras oncogenes (codons 12, 13, and 61). DNA from frozen surgically excised tissue (n = 8) and from formalin-fixed paraffin-embedded tissue (n = 30) was amplified by the polymerase chain reaction and screened for mutations using oligonucleotide-specific hybridization. No mutations were identified in follicular adenomas (n = 9). In follicular carcinomas, 2 of 14 tumors contained mutations (N-ras 61, Gln to Arg), and both of these patients had bone metastases. One of 15 papillary carcinomas had a ras mutation (H-ras 12, Gly to Ser). In contrast to other studies, we found that ras mutations are relatively uncommon in both benign and malignant thyroid neoplasms. Studies of larger numbers of tumors and comparisons of different patient populations will be required to assess a possible association of mutations in N-ras 61 with clinically aggressive follicular cancer.

Adrenal pseudocyst: a clinical and pathologic study of eight cases.

Adrenal pseudocysts are cystic lesions arising within the adrenal gland surrounded by a fibrous tissue wall devoid of a recognizable lining layer. This study comprised eight adrenal pseudocysts surgically excised at the Massachusetts General Hospital. The median age of the patients was 41 years. Seven of the eight individuals were women. There was no apparent etiologic relationship to prior trauma or pregnancy. Half of the patients described symptoms that resolved following pseudocyst removal. The remaining individuals were asymptomatic with adrenal pseudocysts discovered incidentally during the work up of other medical problems. Adrenal pseudocyst size ranged from 1.8 to 10 cm. Pseudocyst size did not correlate with the presence of symptoms. The histologic and immunohistochemical findings in this study suggest that at least some adrenal pseudocysts are of vascular origin. In two lesions, small foci of residual cells lining the inner pseudocyst wall were found that expressed factor VIII antigen (also Ulex Europaeus lectin in one case) but not vimentin, keratin, or epithelial membrane antigen. In both cases, abundant elastic tissue was present in the pseudocyst wall, and in one lesion, adrenal vein smooth muscle was present as well. In both cases, dilated sinusoids were found at the periphery of the pseudocysts and, in one lesion, the sinusoids appeared to coalesce to form the pseudocyst cavity. In the majority of the remaining six cases there was also some histologic evidence to suggest a vascular origin. In five and three cases, respectively, abundant elastic tissue and adrenal vein smooth muscle were found within the pseudocyst wall. In two lesions, both elastic tissue and smooth muscle were present. In addition, adrenal sinusoids were prominently dilated at the periphery of four pseudocysts and, in one case, the sinusoids appeared to coalesce to form the pseudocyst cavity.

Functioning oxyphil cell adenomas of the parathyroid gland. A study of 15 cases.

Parathyroid adenomas composed predominantly of chief cells are the most frequent cause of primary hyperparathyroidism. Until as recently as 1978, the rare oxyphil cell parathyroid adenoma was generally considered nonfunctioning. A retrospective review of 500 consecutive patients at the Massachusetts General Hospital with a diagnosis of hyperparathyroidism associated with parathyroid adenoma during the years 1979-1987 yielded 15 (3.0%) oxyphil cell adenomas. A total of 65 case reports of hyperparathyroidism associated with a diagnosis of oxyphil cell adenomas were reviewed, applying the same diagnostic criteria used in case selection for the present series. These criteria include: (a) at least 90% composition of the adenoma by oxyphil cells; (b) biopsy or excision of a second histologically normal parathyroid gland to help rule out hyperplasia; and (c) postoperative alleviation of hypercalcemia. More than 50% of the previously reported cases did not conform to these criteria. The findings in the present study further document the entity of hyperparathyroidism caused by oxyphil cell parathyroid adenomas and suggest criteria guidelines for this rare diagnosis.

Epithelial-lined (true) cyst of the adrenal gland: a case report.

A case of an epithelial-lined (true) adrenal cyst is reported. Although over 300 adrenal cysts have been reported in the literature, true cysts are rare. In this case, a 4.0 cm cyst lined by cuboidal to flattened cells with bland cytologic features was incidentally found at autopsy. Immunologic studies performed on formalin-fixed, paraffin-embedded sections demonstrated that the cells expressed keratins (AE1/AE3+, CAM 5.2+, and MAK-6+) and were negative for epithelial membrane antigen, vimentin, factor VIII, and desmin. Normal adrenal cortical and medullary cells did not express keratins, suggesting that the cyst lining was not derived from either adrenal cortex or medulla. A mesothelial origin, with a pathogenesis analogous to the formation of primary cysts of the spleen, is proposed.

Pathologic features of prognostic significance in adrenocortical carcinoma.

There are currently no well-established pathologic prognostic factors helpful in distinguishing low versus high grade adrenocortical carcinomas. The effect of 11 pathologic parameters on survival was investigated in 42 cases of adrenocortical carcinoma. Only one variable, mitotic rate, had a strong statistical association with patient outcome. The 21 patients with carcinomas with greater than 20 mitoses per 50 high power fields (hpf) had a median survival of 14 months, whereas the 21 patients with carcinomas with less than or equal to 20 mitoses had a median survival of 58 months (p less than 0.02). The presence of atypical mitoses, capsular invasion, tumor weight greater than 250 g, and size greater than 10 cm each showed a marginal statistical association with poor survival (p less than 0.06), whereas other features assessed, such as nuclear grade, presence of necrosis or of venous or sinusoidal invasion, character of the tumor cell cytoplasm, or architectural pattern, showed no statistical significance in predicting survival. It is proposed that adrenal cortical carcinomas with greater than 20 mitoses be designated high grade, whereas tumors with less than or equal to 20 mitoses be designated low grade.

Multiple branchial cleft-like cysts in Hashimoto's thyroiditis.

We report two cases of multiple intrathyroidal cysts in women with Hashimoto's thyroiditis. The cysts were lined by squamous and focally columnar epithelium, and they were surrounded by follicular lymphoid tissue and a fibrous capsule. They appeared similar to branchial cleft cysts of the lateral neck and were distinct from previously reported types of thyroid cysts. Although the histogenesis of these lesions is unclear, they are probably derived from developmental rests. A relationship between the cystic enlargement of these rests and the Hashimoto's disease seems likely.

Treatment of intrathyroidal papillary carcinoma of the thyroid.

Among 237 patients with grossly noninvasive (intrathyroidal) papillary carcinoma of the thyroid treated by surgery at the Massachusetts General Hospital and followed for a median of 14 years, no patient had tumor recurrence either in the thyroid bed or opposite lobe. There were 12 metastatic recurrences with risks of recurrence 4.0% and 6.9% at 10 years and 20 years respectively. Eight of these recurrences were restricted to cervical lymph nodes and did not herald the development of more serious recurrent disease. The remaining recurrences were lung metastases in four patients, two of whom died, accounting for the only deaths from thyroid carcinoma in this series. Factors that influenced the risk of recurrence included lymph node metastases at initial surgery, large tumor size, and to a lesser extent, male sex. The majority of patients (176) had subtotal thyroidectomies, mostly lobectomy (131 patients). There was no evidence that the 61 patients who underwent total thyroidectomy fared better than those with similar patient and tumor characteristics on whom subtotal procedures were performed. The overall findings of this study strongly support the concept that intrathyroidal thyroid carcinoma can be successfully treated by conservative surgery.

Papillary carcinoma.

In addition to a description of the basic criteria for the diagnosis of papillary carcinoma, a review of discussions by all workshop participants on the illustrative cases is presented. Areas of consensus included the following: classification of mixed papillary and follicular carcinomas as papillary, regardless of follicular dominance; recognition of three morphological variants--follicular, encapsulated, and diffuse sclerosing; nonspecificity of individual histological criteria, with the necessity to utilize a combination of characteristic features as guidelines for establishing a diagnosis; citing of nuclear features as probably the most important diagnostic criteria, ie, increased N/C ratio, irregularity in outline, and paleness of staining (ground glass appearance); grading of tumors on the basis of either cytological or architectural characteristics remains of unproven prognostic value. (Gross extent of tumor at the first operation remains the most valuable single prognostic criterion.); defining small carcinomas by size rather than using the imprecise term "occult" with its variable definitions including some clinically evident tumors; classifying as undifferentiated those carcinomas presenting a mixed papillary and anaplastic appearance at the time of the first operation, and retaining the papillary designation for papillary cancers which later undergo dedifferentiation; and recognition that thyroglobulin is a constant and keratin an inconstant tumor cell marker, with the latter not specific for distinguishing papillary carcinomas from follicular carcinomas or from hyperplastic adenomas.

Thyroid papillary carcinoma. Pathological and philosophical controversies.

An encapsulated thyroid tumor with a papillary architecture is statistically much more likely to be a hyperplastic follicular adenoma than a papillary carcinoma, for the latter are uncommonly encapsulated. Hyperfunction of such a tumor is diagnostic of an adenoma. Various histopathologic features are useful in the differential diagnosis, but these are more accurately termed guidelines than criteria. The presence of psammoma bodies, fibrovascular stalks of papillae and pale nuclear changes are probably the most reliable histopathologic features of a carcinoma. The value of needle biopsy as a diagnostic tool for the screening of thyroid nodules is emphasized. Encapsulated variants of papillary carcinoma are discussed, including the rare pure follicular variant and those intermixed with adenomatous components, suggesting the possibility that some papillary carcinomas might arise in a preexisting adenoma. When the histopathologic diagnosis is equivocal, a benign interpretation is favored since encapsulated papillary carcinomas are very low grade, have an unusually favorable prognosis, and need no further resection. The polarization in past years of clinicians into radical and conservative operative fractions is reviewed. This stemmed from different interpretations of the presence of lymph node metastases in a majority of cases and the high frequency of intraglandular microscopic dissemination of neoplasm. It is clear that biological behavior of this unusual cancer is more important than a literal interpretation of the pathologic findings as a determinant for patient management. The surgical pathologist should be mindful that he plays an important role in patient management, not only by providing a diagnosis but also by serving as a consultant to the surgeon in pathologic correlation.

Congenital goiter and the development of metastatic follicular carcinoma with evidence for a leak of nonhormonal iodide: clinical, pathological, kinetic, and biochemical studies and a review of the literature.

We report a large kindred of patients with congenital goiter, followed for 15 yr, in which two siblings (one male and one female) developed metastatic follicular thyroid carcinoma. These two patients were evaluated by iodine kinetic analysis. None of the classical defects of T4 biosynthesis was present in either patient. Rather, both patients had extremely rapid rates of iodine turnover, with elevated 131I uptake and excessive spillage of iodide in the urine. Serum iodoalbumin was present, probably as a nonspecific result of glandular hyperplasia. Iodine kinetic analysis after the ingestion of potassium perchlorate and methimazole was compatible with a leak of nonhormonal iodide from the thyroid. It is not possible to determine whether this iodide leak is the primary pathogenetic defect or is secondary to another unidentified abnormality. The unprecedented development of metastatic thyroid cancer in patients with congenital goiter occurred, in both instances years after subtotal thyroidectomy without thyroid hormone replacement therapy, suggesting a role for TSH in the genesis of human thyroid cancer. On the basis of our study of these patients and a review of the literature, we conclude that TSH is likely to be a factor in the induction of human follicular thyroid carcinoma.

Papillary carcinoma of the thyroid, oxyphil cell type, "clear cell" variant: a light- and electron-microscopic study.

A unique case of papillary carcinoma of the thyroid having the combined features of three morphological subtypes--tall cell, clear cell and Hürthle cell--has been studied by light and electron microscopy. The distinctive neoplastic cells had an oxyphilic basal zone, a mid-placed nucleus and a clear apical region. Ultrastructurally, the cytoplasm was virtually filled with mitochondria, characteristic of Hürthle cells, but the unusual finding was the marked distention and emptiness of those mitochondria located in the apical zone, accounting for the clear phenomenon noted by light microscopy. In contrast, the mitochondria in the basal, or oxyphilic, part of the cells were intact. While a few cases of clear cell and papillary clear-cell carcinoma of the thyroid have been studied by electron microscopy previously, the clear change has never been attributed to dilated mitochondria, but rather to the presence of glycogen. The reason for the mitochondrial swelling is not answered, but it is probably an in vivo effect. Some of the other characteristics of papillary carcinoma of the thyroid described previously, such as microvilli, absence of colloid, infolded nuclei and nuclear bodies, were also present in this case. However, ground-glass nuclei, a frequently reported feature, were not found.