Quantitative assessment of promoter methylation profiles in thyroid neoplasms.

CONTEXT: Cancer-specific molecular markers are needed to supplement the cytopathological assessment of thyroid tumors, because a majority of patients with cytologically indeterminate nodules currently undergo thyroidectomy without a definitive diagnosis. OBJECTIVE: The aim of this study was the quantitative assessment of promoter hypermethylation and its relation to the BRAF mutation in thyroid tumors. DESIGN: Quantitative hypermethylation of Rassf1A, TSHR, RAR-beta2, DAPK, S100, p16, CDH1, CALCA, TIMP3, TGF-beta, and GSTpi was tested on a cohort of 82 benign and malignant thyroid tumors and five thyroid cancer cell lines. SETTING: The study was conducted at a tertiary research hospital. PATIENTS: Patients underwent surgical resection for a thyroid tumor from 2000 to 2003 at our institution. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURE: Final surgical pathology diagnosis was the main outcome measure. RESULTS: Thyroid tumors showed hypermethylation for the following markers: Rassf1A, TSHR, RAR-beta2, DAPK, CDH1, TIMP3, and TGF-beta. A trend toward multiple hypermethylation was evident in cancer tissues, with hypermethylation of two or more markers detectable in 25% of hyperplasias, 38% of adenomas, 48% of thyroid cancers, and 100% of cell lines. A rank correlation analysis of marker hypermethylation suggests that a subset of these markers is epigenetically modified in concert, which may reflect an organ-specific regulation process. Furthermore, a positive correlation was found between the BRAF mutation and RAR-beta2, and a negative correlation was found between the BRAF mutation and Rassf1A. CONCLUSIONS: Methylation-induced gene silencing appears to affect multiple genes in thyroid tissue and increases with cancer progression. Additional markers with better discriminatory power between benign and malignant samples are needed for the diagnostic assessment of cytologically indeterminate thyroid nodules.

Telomerase as drug and drug target for the treatment of thyroid cancer.

Telomerase is known to be activated in almost all cancer cells and is quiescent in almost all normal cells. Therefore, it follows that therapeutic strategies directed against cancer would include the targeting of telomerase, as well as the use of telomerase. Several approaches have been used both in vitro and in vivo and include the following: 1) antisense; 2) immunotherapy directed against hTERT; and 3) the use of telomerase promoter to direct cytotoxic therapy. Herein we review these approaches and discuss their potential applicability against thyroid cancer.

Human telomerase reverse transcriptase expression in Diff-Quik-stained FNA samples from thyroid nodules.

Fine-needle aspiration (FNA) is a highly sensitive method in the differential diagnosis of thyroid nodules. However, 10% of thyroid FNAs are indeterminate for cancer, and thus additional markers may be useful diagnostically. The authors have demonstrated previously that human telomerase reverse transcriptase (hTERT) gene expression is useful in the distinction of benign lesions from malignant lesions. They therefore wondered whether the detection of hTERT gene expression was feasible using archival slides. To establish an experimental system, ribonucleic acid was extracted from human anaplastic thyroid carcinoma cell line (ARO) in cytologic specimens, and reverse transcription-polymerase chain reaction (RT-PCR) for hTERT expression was performed. RT-PCR analysis for hTERT gene detection was then performed using 58 Diff-Quik-stained archival FNA samples collected retrospectively. RT-PCR for human thyroglobulin (hTg) or beta-actin gene expression served as a positive control. Successful PCR results were obtained from 48 of the 58 cases. All 10 slides in which no RT-PCR products were noted were older than 3 years. hTERT gene expression was demonstrated in FNAs from two of seven cases (29%) of hyperplastic nodule, one of one case (100%) of Hashimoto's thyroiditis, three of eight cases (38%) of follicular adenoma, three of eight cases (38%) of Hürthle cell adenoma, three of four cases (75%) of follicular carcinoma, two of two cases (100%) of Hürthle cell carcinoma, and 11 of 18 cases (61%) of papillary carcinoma. All but one of the available 33 corresponding frozen samples exhibited the same RT-PCR results. This study demonstrates that Diff-Quik-stained thyroid FNA specimens less than 3 years old can be used for the detection of hTERT gene expression by RT-PCR. This test, along with careful cytopathologic examination, may improve our ability to differentiate benign lesions from malignant lesions in indeterminate FNA samples from thyroid nodules.

Human telomerase reverse transcriptase (hTERT) gene expression in FNA samples from thyroid neoplasms.

BACKGROUND: Although fine-needle aspiration (FNA) is the most sensitive method for the detection of thyroid carcinoma, it cannot provide a definitive diagnosis of malignancy in 60% of the patients operated on for suspicious lesions. Recently, human telomerase reverse transcriptase (hTERT) has been found to be a diagnostic marker of malignancy. We therefore sought to determine whether hTERT gene expression could serve as an adjunct to FNA in the differential diagnosis of thyroid nodules. METHODS: Twenty-four FNA samples from thyroid nodules that were suspected of malignancy were collected. RNA was extracted, and hTERT gene expression was examined by RT-PCR. Cytologic and histologic examinations were also performed. RESULTS: Two of three follicular, three of three Hürthle cell, and eight of eight papillary thyroid carcinomas had corresponding FNA samples that were positive for hTERT. One of two Hürthle cell adenomas was hTERT positive. FNA samples from three follicular adenomas and five hyperplastic nodules were negative for hTERT. Positive and negative predictive values were 93% and 90%, respectively. CONCLUSIONS: The detection of hTERT gene expression in thyroid FNA samples holds promise as a diagnostic marker in the distinction of benign from malignant thyroid lesions. Its application could alter the surgical management of these patients.

Human telomerase reverse transcriptase (hTERT) gene expression in thyroid neoplasms.

Ten percent of fine-needle aspirations (FNAs) of the thyroid are deemed "indeterminate" or "suspicious" for malignancy by the cytopathologist, but most of these lesions are benign. Therefore, additional markers of malignancy may prove to be a useful adjunct. The catalytic component of telomerase, human telomerase reverse transcriptase (hTERT), has been found to be reactivated in immortalized cell lines. Reverse transcription-PCR of the hTERT gene revealed expression in 15 (79%) of 19 malignant thyroid neoplasms, including 6 of 6 follicular carcinomas and 9 of 13 papillary carcinomas. In contrast, hTERT gene expression was detected in only 5 (28%) of 18 benign thyroid nodules, including 2 of 7 follicular adenomas and 3 of 11 hyperplastic nodules. All five benign thyroids exhibiting hTERT gene expression had lymphocytic thyroiditis. No normal thyroids exhibited hTERT gene expression. Telomerase enzyme activity was examined in all 37 nodules and was found to correlate with hTERT gene expression in 35 (95%) nodules. The two cases in which telomerase activity and hTERT expression results were discrepant were in two papillary carcinomas that were telomerase activity negative and hTERT positive. Finally, we have demonstrated that hTERT gene expression can be measured in in vivo FNA samples. These results suggest that hTERT expression may be more accurate than telomerase activity in distinguishing benign from malignant and may be measured in FNA samples from suspicious thyroid lesions.

Cost implications of different surgical management strategies for primary hyperparathyroidism.

BACKGROUND: Controversy exists about optimal management of patients with primary hyperparathyroidism. To date, no studies have explored the cost implications of variation in practice. METHODS: Results from a national survey of endocrine surgeons were combined with results from a survey of endocrinologists and financial data from Medicare. Patterns of use of resources were identified, annual costs for the surgical management of primary hyperparathyroidism in the United States were calculated, and the financial impact of variation in practice was estimated. RESULTS: Survey respondents (n = 109) were experienced endocrine surgeons, performing an average of 33 parathyroidectomies annually. Seventy-five percent of patients undergo localization before initial exploration for primary hyperparathyroidism. In order of preference, these studies were sestamibi (43%), ultrasonography (28%), and sestamibi with single-photon emission computed tomography (26%). Although there is variation in preoperative and postoperative practice, in-hospital costs have the greatest influence on total cost. An estimated $282 million is spent annually in the United States on operations for primary hyperparathyroidism. National health expenditures could range by more than $70 million, depending on whether management strategies involving low or high use of resources are employed. CONCLUSIONS: Substantial variation among endocrine surgeons in the management of primary hyperparathyroidism has important cost implications. Implementation of evidence-based guidelines to optimize clinical and economic performance should be considered.

Overexpression of TTF-1 and PAX-8 restores thyroglobulin gene promoter activity in ARO and WRO cell lines.

BACKGROUND: In anticipation of developing gene therapy against thyroid carcinoma we created an expression vector using the thyroglobulin (Tg) gene promoter. The inhibition of both Tg and thyroid-specific transcription factor (TTF-1 and PAX-8) gene expression, however, has been well documented in thyroid carcinomas. We therefore examined the effects of overexpression of TTF-1 and PAX-8 on Tg gene promoter activity in the human thyroid carcinoma cell lines, ARO (anaplastic) and WRO (follicular). METHODS: ARO, WRO, and nonthyroid cells were transfected with an expression vector in which beta-galactosidase (beta-gal) is driven by the Tg gene promoter (beta-gal). Tg, TTF-1, and PAX-8 gene expression were also examined by reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: ARO and WRO exhibited decreased gene expression of Tg, TTF-1, and PAX-8. Transfection with TG--gal alone exhibited minimal beta-gal expression, whereas cotransfection with TTF-1 and PAX-8 resulted in markedly increased expression. There was no evidence of beta-gal expression with or without TTF-1 and PAX-8 in nonthyroid cells. CONCLUSIONS: Weak Tg gene promoter activity in ARO and WRO is associated with decreased expression of transcription factors TTF-1 and PAX-8 but can be restored with their overexpression. This model may serve as a template on which to further develop cell-specific gene therapy against thyroid carcinoma.

Somatic mutations of the PTEN tumor suppressor gene in sporadic follicular thyroid tumors.

The PTEN (MMAC1/TEP1) tumor suppressor gene was recently isolated and mapped to human chromosome band 10q23. Homozygous deletions and mutations of PTEN were observed in cell lines and sporadic cancers of the breast, kidney, and central nervous system. Germline mutations in PTEN were recently found in Cowden disease, an autosomal dominant inherited syndrome, previously mapped to chromosome bands 10q22-23. This disease is associated with a wide variety of malignancies and hamartomas of ectodermal, mesodermal, and endodermal origin. The most common neoplasms in Cowden disease patients arise in the breast, skin, and thyroid (follicular subtype). To determine the involvement of PTEN in sporadic follicular thyroid tumors, we first analyzed sporadic follicular adenomas and carcinomas for deletions of the PTEN gene. Loss of heterozygosity was found in 7/26 (27%) follicular carcinomas and 2/27 (7%) follicular adenomas, one of which was a small hemizygous deletion (approximately 3 cm). Sequence analysis of the entire PTEN coding region revealed two mutations in carcinomas with 10q loss. Our findings suggest that the PTEN tumor suppressor gene is occasionally inactivated in sporadic follicular thyroid tumors.

Profile of a clinical practice: Thresholds for surgery and surgical outcomes for patients with primary hyperparathyroidism: a national survey of endocrine surgeons.

A 1991 NIH Consensus Development Conference statement provided recommendations for the management of patients with asymptomatic and minimally symptomatic primary hyperparathyroidism (primary HPT), but adherence to these guidelines has not been documented. We conducted a cross-sectional survey of North American members of the American Association of Endocrine Surgeons inquiring about surgeon and primary HPT patient characteristics, thresholds for surgery, and clinical outcomes. Multivariate regression was used to assess the relationship of physician characteristics to practice patterns and outcomes. Of 190 surgeons surveyed, 147 (77%) responded; 109 provided complete responses (57%). These surgeons spend 66% of their time in patient care and perform an average of 33 (range, 1-130) parathyroidectomies/yr. More than 72% of primary HPT patients who underwent surgery were asymptomatic or minimally symptomatic. High volume surgeons (>50 cases/yr) had significantly lower thresholds for surgery with respect to abnormalities in preoperative creatinine clearance, bone densitometry changes, and levels of intact PTH and urinary calcium compared to their low volume colleagues (1-15 cases/yr). Overall reported surgical cure rates were 95.2% after primary operation and 82.7% after reoperation. Compared to high volume surgeons, low volume endocrine surgeons had significantly higher complication rates after primary operation (1.9% vs. 1.0% respectively; P < 0.01) and reoperation (3.8% vs. 1.5%; P < 0.001) as well as higher in-hospital mortality rates (1.0% vs. 0.04%; P < 0.05). Endocrine surgeons operate on a large number of asymptomatic or minimally symptomatic primary HPT patients. Even among a group of highly experienced surgeons who typically see patients after referral from endocrinologists, clinical outcomes and criteria for surgery vary widely and appear to be associated with surgeon experience. Their criteria for surgery diverge from NIH guidelines. These results implore the endocrine community to examine the evidential basis for decisions made in the management of primary HPT.

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.

Hürthle cell neoplasms of the thyroid: are there factors predictive of malignancy?

OBJECTIVE: To determine if any preoperative or intraoperative factors can reliably predict malignancy in patients with Hürthle cell neoplasms. SUMMARY BACKGROUND DATA: Most experienced surgeons recommend total thyroidectomy for Hürthle cell carcinomas and reserve thyroid lobectomy for Hürthle cell adenomas. However, delineation between Hürthle cell adenoma versus carcinoma often cannot reliably be made either before or during surgery. METHODS: Medical records from 57 consecutive patients who underwent thyroid resections for Hürthle cell neoplasms between October 1984 and April 1995 at The Johns Hopkins Hospital were analyzed to determine if any factors were predictive of malignancy. RESULTS: Of the 57 patients with Hürthle cell neoplasms, 37 had adenomas and 20 had carcinomas, resulting in a 35% prevalence of malignancy. Patients with adenomas did not differ from those with carcinoma with respect to age, sex, or history of head and neck irradiation. However, patients with Hürthle cell carcinomas had significantly larger tumors (4.0 +/- 0.4 cm vs. 2.4 +/- 0.2 cm, p < 0.005). Furthermore, although the incidence of malignancy was only 17% for tumors 1 cm or less and 23% for tumors 1 to 4 cm, tumors 4 cm or greater were malignant 65% of the time (p < 0.05). Both fine-needle aspiration and intraoperative frozen section analysis had low sensitivities in the detection of cancer (16% and 23%, respectively). With up to 9 years of follow-up, there has been no tumor-related mortality. CONCLUSIONS: These data demonstrate that the size of a Hürthle cell neoplasm is predictive of malignancy. Therefore, at the time of initial exploration for large Hürthle cell neoplasms (>4 cm), definitive resection involving both thyroid lobes should be considered because of the higher probability of malignancy.

Distinct patterns of E-cadherin CpG island methylation in papillary, follicular, Hurthle's cell, and poorly differentiated human thyroid carcinoma.

Expression of the invasion/metastasis suppressor, E-cadherin, is diminished or lost in thyroid carcinomas. Yet, mutational inactivation of E-cadherin is rare. Herein, we show that this loss is associated with hypermethylation of the E-cadherin 5' CpG island in a panel of human thyroid cancer cell lines. This aberrant methylation is evident in 83% of papillary thyroid carcinoma, 11% of follicular thyroid carcinoma, 40% of Hurthle's cell carcinoma, and 21% of poorly differentiated thyroid carcinomas. Contrary to previous reports, the majority of these poorly differentiated thyroid carcinomas express E-cadherin, but often within the cytoplasm rather than at the cell surface. Together, our data indicate that the invasion/metastasis suppressor function of E-cadherin is frequently compromised in human papillary, Hurthle's cell, and poorly differentiated thyroid carcinoma by epigenetic and biochemical events.

Association between extent of axillary lymph node dissection and survival in patients with stage I breast cancer.

BACKGROUND: The role of axillary lymph node dissection for stage I (T1N0) breast cancer remains controversial because patients can receive adjuvant chemotherapy regardless of their nodal status and because its therapeutic benefit is in question. The purpose of this study was to determine whether extent of axillary dissection in patients with T1N0 disease is associated with survival. METHODS: Data from 464 patients with T1N0 breast cancer who underwent axillary dissection from 1973 to 1994 were examined retrospectively. Kaplan-Meier estimates of overall survival, disease-free survival, and recurrence were calculated for patients according to the number of lymph nodes removed (<10 or > or = 10; <15 or > or = 15), and survival curves compared using the Wilcoxon-Gehan statistic. Cox proportional hazards regression modelling was used to adjust for confounding prognostic variables. RESULTS: Median follow-up time was 6.4 years. Patient groups were similar in age, menopausal status, tumor size, hormonal receptor status, type of surgery, and adjuvant therapy. There was a statistically significant improvement in disease-free survival in the > or = 10 versus <10 nodal groups (P <.01). Five-year estimates of survival were 75.7% and 86.2% for <10 nodes and > or = 10 nodes, respectively; 10-year estimates were 66.1% and 74.3%. There also was a notable improvement in the survival comparison of patients with <15 versus > or = 15 nodes (P < or = .05). These findings were confirmed in the multivariate analysis. CONCLUSIONS: These results may reflect a potential for misclassification of tumor stage among patients who had fewer nodes removed. The data, however, suggest that in patients with Stage I breast cancer, improved survival is associated with a more complete axillary lymph node dissection.

Absence of activating mutations of the genes encoding the alpha-subunits of G11 and Gq in thyroid neoplasia.

Activating mutations of the TSH receptor and alpha-subunit of Gs (G alpha s) that increase adenylyl cyclase activity have been identified in a subset of hyperfunctioning benign thyroid follicular adenomas and, less commonly, in hypofunctioning adenomas and carcinomas. In addition some thyroid tumors exhibit inappropriate activation of phospholipase C (PLC), a signaling pathway that has been implicated in the growth and dedifferentiation of thyroid cells. We therefore hypothesized that some thyroid tumors might be caused by somatic mutations in the genes encoding the alpha-chain of Gq or G11 that result in constitutive activation of the PLC pathway. We amplified regions of the alpha q and alpha 11 genes that encode amino acids, Q209 and R183, and we screened the DNA for mutations by sequence analysis and denaturing gradient gel electrophoresis. No mutations were identified after analysis of DNA from 38 thyroid tumors and 2 poorly differentiated thyroid carcinoma cell lines, including: 13 follicular adenomas, 10 follicular carcinomas, 5 papillary carcinomas, and 10 hyperplastic nodules from multinodular goiters. We conclude that activating mutations of alpha q and alpha 11 are absent or rare in hypofunctioning thyroid neoplasms and that other mechanisms must explain the elevated PLC activity reported in thyroid carcinoma.

Determination of transgene copy number and expression level using denaturing gradient gel electrophoresis.

Transgenic mice and cell lines are frequently developed to study human disease. Accurate determination of transgene copy number and levels of mRNA are necessary to understand the phenotypic changes observed in these models. Currently, transgene copy number and expression are estimated by Southern blot analysis of genomic DNA and Northern blot analysis of mRNA. We report a novel PCR-based method for determining transgene copy number and levels of transgene expression using competitive PCR between endogenous genomic genes and mutant transgenes followed by denaturing gradient gel electrophoresis (DGGE). We are able to accurately quantify a range of 1-10 copies of transgene incorporated per diploid genome. After reverse-transcribing RNA to cDNA, we are able to quantify levels of transgene mRNA that correlate with biochemical and histological evidence of transgene activity. In conclusion, resolving PCR and reverse transcription-PCR products by DGGE is a rapid and reproducible method that allows for accurate determination of transgene copy number and expression. This technique provides a more complete understanding of transgene effects.

Thyroid-specific expression of cholera toxin A1 subunit causes thyroid hyperplasia and hyperthyroidism in transgenic mice.

Thyroid cell growth and function are regulated by hormones and growth factors binding to cell surface receptors that are coupled via G proteins, Gs and Gq, to the adenylyl cyclase and phospholipase C signal transduction systems, respectively. Activating mutations of the TSH receptor and G alpha s have been documented in subsets of thyroid neoplasms. To test the oncogenic potential of activated G alpha s in transgenic mice, we used the cholera toxin A1 subunit that constitutively activates G alpha s and used the rat thyroglobulin gene promoter for targeting this transgene (TGCT) to thyroid follicular cells. Three (M1392, F1358, and F1286) of six founders identified were able to transmit the transgene to their offspring and thyroid glands from these mice contained elevated levels of cAMP. Concentrations of serum thyroxine were elevated as early as 2 months of age (M 1392 and F 1286). F1358 mice were euthyroid until 8 months of age, at which time they developed hyperthyroidism. All three TGCT lines developed thyroid hyperplasia independent of their thyroxine levels. DNA image analysis of thyroid follicular cells from both the hyper and euthyroid mice showed that DNA index and "S+G2/M" phase were increased compared with normal, changes similar to that seen in poor prognosis human carcinomas. These data suggest that the G alpha s-adenylyl cyclase-cAMP pathway has an important role in thyroid hyperplasia and the transgenic mouse models reported herein will allow further examination of the role of this pathway in thyroid oncogenesis.

Telomerase activity: a marker to distinguish follicular thyroid adenoma from carcinoma.

The inability to distinguish microinvasive follicular thyroid cancer from benign follicular tumors preoperatively presents an important surgical dilemma. We examined 44 follicular tumors and found telomerase activity in all 11 follicular carcinomas and in 8 of 33 benign follicular tumors. It was undetectable in 22 normal thyroid tissues adjacent to the tumors. Telomerase activity may thus provide a diagnostic marker distinguishing benign from malignant follicular thyroid tumors. The ability to identify invasive follicular thyroid tumors could avert over 14,000 thyroidectomies annually in the United States, thereby significantly decreasing morbidity and health care costs.

Papillary carcinoma of the thyroid: can operative management be based solely on fine-needle aspiration?

BACKGROUND: Fine-needle aspiration cytology is sensitive for detecting malignancies such as papillary carcinoma of the thyroid gland. Because fine-needle aspiration specificity for papillary carcinoma of the thyroid is variable, routine intraoperative frozen section is often advocated. STUDY DESIGN: To define the roles of fine-needle aspiration and frozen section in papillary carcinoma of the thyroid gland, we reviewed data from 82 patients who underwent thyroidectomy between August 1989 and August 1995 for papillary carcinoma of the thyroid cytology. Results of fine-needle aspirations were grouped into three categories: diagnostic of papillary carcinoma of the thyroid; diagnostic of follicular-variant of papillary carcinoma of the thyroid; or suspicious for papillary carcinoma of the thyroid. Definitive diagnoses were made on permanent histology. RESULTS: A fine-needle aspiration revealing papillary carcinoma of the thyroid was 98 percent specific for cancer or 100 percent specific for follicular-variant of papillary carcinoma of the thyroid. A fine-needle aspiration that was suspicious for papillary carcinoma of the thyroid (n = 24) was only 54 percent specific for cancer. On the basis of gross intraoperative findings, 5 of these 24 patients underwent total thyroidectomy without frozen section, and all had carcinoma. The other 19 had frozen section analysis. Of the 5 patients with cancer detected by frozen section, 4 had cancer on permanent histology. Findings on frozen section demonstrated a follicular neoplasm in the other 14 patients, of which 4 ultimately were cancer. CONCLUSIONS: When papillary carcinoma of the thyroid or follicular-variant of papillary carcinoma of the thyroid is definitively diagnosed on fine-needle aspiration, the surgeon can perform definitive thyroidectomy without frozen section because of the high specificity for cancer. If the fine-needle aspiration is suspicious for papillary carcinoma of the thyroid, the incidence of cancer is 54 percent, and patients with these conditions should undergo surgery with frozen section. When either gross findings or frozen sections suggest malignancy, definitive thyroidectomy can be performed because 90 percent of such cases will be cancer. If frozen section is not diagnostic of malignancy, a thyroid lobectomy/isthmusectomy is recommended because 71 percent have a benign lesion. This systematic approach to papillary carcinoma of the thyroid will obviate unnecessary frozen sections while maintaining excellent diagnostic specificity.