Management of thyroid nodules detected at US: Society of Radiologists in Ultrasound consensus conference statement.

The Society of Radiologists in Ultrasound convened a panel of specialists from a variety of medical disciplines to come to a consensus on the management of thyroid nodules identified with thyroid ultrasonography (US), with particular focus on which nodules should be subjected to US-guided fine needle aspiration and which thyroid nodules need not be subjected to fine-needle aspiration. The panel met in Washington, DC, October 26-27, 2004, and created this consensus statement. The recommendations in this consensus statement, which are based on analysis of the current literature and common practice strategies, are thought to represent a reasonable approach to thyroid nodular disease.

PPARgamma staining as a surrogate for PAX8/PPARgamma fusion oncogene expression in follicular neoplasms: clinicopathological correlation and histopathological diagnostic value.

The PAX8/PPARgamma (PPFP) fusion-oncogene is moderately specific for follicular thyroid carcinomas (FTC). It remains unknown whether this can be translated into improved diagnosis, classification, or outcome prediction. We studied a cohort of well-characterized follicular adenomas (FA), FTC, and Hurthle cell carcinomas (HCC) from patients with complete clinical follow-up, to determine whether PPARgamma immunohistochemistry (as a surrogate of PAX8/PPARgamma expression) helps to distinguish FA from FTC and to assess its diagnostic accuracy as an adjunct to frozen section. We also correlated PPARgamma staining with clinical outcomes to assess its role as a prognostic marker.PPARgamma staining was more common in FTC (31 of 54; 57%) than in HCC (one of 23; 4%) or FA (four of 31; 13%) (P < 0.000001). Adjunctive use of PPARgamma immunohistochemistry improved diagnostic sensitivity of intraoperative frozen section from 84% to 96% (P < 0.05) but reduced specificity from 100% to 90% (P < 0.05). PPARgamma staining was associated with favorable prognostic indicators (female gender, better tumor differentiation, and lesser risk of metastases).PPARgamma staining may be helpful in the differential diagnosis of FA, FTC, and HCC, particularly when diagnostic sensitivity of histomorphology is reduced (e.g. during intraoperative frozen section). PPARgamma staining also shows an association with favorable prognosis and may have a role in risk stratification.

Long-term trends in thyroid carcinoma: a population-based study in Olmsted County, Minnesota, 1935-1999.

OBJECTIVE: To determine whether there was a significant increase in the incidence of thyroid carcinoma in Olmsted County, Minnesota, that may be attributed to the widespread use of therapeutic head and neck irradiation between 1920 and the 1950s or to exposure to atomic fallout at the Nevada Test Site in the 1960s. METHODS: Rochester Epidemiology Project resources were used to identify potential cases of thyroid carcinoma among residents of Olmsted County between 1935 and 1984. We extended this earlier study through 1999. RESULTS: During the study period, thyroid carcinoma was newly diagnosed in 263 residents. In women, the age-adjusted incidence increased from 2.7 per 100,000 person-years (p-y) in 1935-1949 to 9.2 per 100,000 p-y in 1990-1999 (P = .001); In men, the rate increased from 0.8 to 5.0 per 100,000 p-y (P = .007). However, most of the increase occurred before 1965 and remained relatively stable thereafter. Similar trends were observed for papillary carcinoma alone. CONCLUSION: Although the Incidence of thyroid carcinoma increased significantly between 1935 and 1964, no significant Increases have been seen since 1965, suggesting that neither atmospheric atomic fallout from the Nevada Test Site nor use of ionizing radiation to treat conditions of the head and neck significantly affected the incidence of thyroid carcinoma in Olmsted County.

High resolution loss of heterozygosity mapping of 17p13 in thyroid cancer: Hurthle cell carcinomas exhibit a small 411-kilobase common region of allelic imbalance, probably containing a novel tumor suppressor gene.

There is strong evidence in many tumor types, including thyroid cancer, for a novel tumor suppressor gene (TSG) at 17p13. To identify the putative thyroid 17p13 TSG we mapped thyroid tumor loss of heterozygosity (LOH) at high resolution within this region. We examined 20 typical follicular thyroid carcinomas (FTC), 19 Hurthle cell carcinomas (HCC), 15 papillary thyroid carcinomas (PTC), and 7 follicular adenomas (FA) for LOH at 17p13 using 18 probes. Complete clinical follow-up data were available for all patients. We confirmed a high 17p13 LOH rate in FTC (18 of 20) and HCC (13 of 19) and showed an association between 17p13 LOH and advanced tumor grade. Only 4 of 15 PTC and 1 of 7 FA displayed 17p13 LOH. In the HCC we identified a narrow minimal common deleted region between D17S1308 (285 kb from the p-telomer) and D17S695 (696 kb from the p-telomer). This region was flanked centromerically by a breakpoint cluster, further suggesting nonrandom deletion. All but 1 of the PTC and FA with 17p LOH and 50% of the affected FTC also showed LOH in this region. These data suggest that a TSG, involved in HCC pathogenesis, is contained within the D17S1308-D17S695 interval. There are several potential candidate TSGs in this region that are worthy of further study.

Observer variation of encapsulated follicular lesions of the thyroid gland.

Although histologic definition of follicular thyroid lesions is readily available, application of the diagnostic criteria and personal experience may lead to disagreement among pathologists. To investigate interobserver variation in assessment of encapsulated follicular lesions, eight pathologists (four American and four Japanese) reviewed the same hematoxylin and eosin-stained slide of each of 21 cases of thyroid lesions showing encapsulation and follicular growth pattern. In 10% of the cases, there was complete agreement. At least seven pathologists agreed on the diagnosis in 29% of the cases, and at least six in 76% of the cases. American and Japanese pathologists agreed among themselves in 33% and 52% of cases, respectively. The frequency of diagnosis of adenomatous goiter among Japanese pathologists (31%) was considerably higher than that among American pathologists (6%). In contrast, the frequency of diagnosis (25%) of papillary carcinoma among American pathologists was considerably higher than that (4%) among Japanese pathologists. Our analysis revealed three main factors affecting observer variation: 1) interpretation of the significance of microfollicles intimately related to capillaries within the tumor capsule, 2) evaluation of what constituted the type of nuclear clearing indicative of papillary carcinoma, and 3) absence of clear morphologic criteria for separation of adenomatous goiter and follicular adenoma. To reduce observer variation of encapsulated follicular lesions, it will be necessary to provide more explicit criteria for diagnosis.

FHIT and TSG101 in thyroid tumours: aberrant transcripts reflect rare abnormal RNA processing events of uncertain pathogenetic or clinical significance.

OBJECTIVE: The chromosomal regions containing the two putative tumour suppressors, fragile histidine triad gene (FHIT) and tumour suppressor gene 101 (TSG101), are deleted frequently in thyroid tumours. We therefore analysed FHIT and TSG101 transcripts in a group of advanced thyroid tumours to establish their role in thyroid tumorigenesis. DESIGN: Retrospective analysis of FHIT and TSG101 mRNA transcripts and genomic DNA from cryo-preserved thyroid tumours. TP53, previously shown at the genomic level not to be mutated in this cohort of tumours, served as a control. PATIENTS: We analysed nine follicular thyroid carcinomas (FTC), six papillary thyroid carcinomas and six follicular adenomas (FA) and histologically normal thyroid tissue from four of the FA patients. MEASUREMENTS: Single stage and nested reverse transcription polymerase chain reaction (RT-PCR) products of FHIT, TSG101, and TP53 were analysed by agarose or polyacrylamide gel electrophoresis and sequenced. Genomic DNA was also analysed by polymerase chain reaction and sequencing (FHIT) or by Southern blotting (TSG101). Clinical data were correlated with the results of the mutation analysis. RESULTS: Truncated FHIT transcripts were observed frequently alongside full length transcripts with nested RT-PCR, most often in FTC, while single stage RT-PCR revealed only normal length transcripts in all tumours. Similar results were obtained for TP53, while abnormal TSG101 transcripts were detectable by single stage RT-PCR. Sequence analysis of the truncated FHIT and TSG101 transcripts revealed mainly exon skipping and alternate RNA processing events. Only a single point mutation (of TSG101) was found. Southern blotting for the TSG101 gene, and PCR amplification and sequencing of the FHIT gene showed no evidence of genomic abnormalities in either case, and there was no evidence of splice site mutations in the FHIT gene, suggesting that the truncated transcripts result from altered RNA processing. There was no relationship between tumour stage, grade or survival and the presence of FHIT or TSG101 abnormalities. CONCLUSIONS: Truncated FHIT and TSG101 transcripts in thyroid tumours reflect alternate mRNA splicing events, rather than genomic deletions. Such abnormal RNA processing seems to be common and widespread in thyroid neoplasms, as similar results were obtained by analysis of transcripts of TP53, which we had previously shown not to be mutated in these specimens. Although a pathogenetic role for these aberrant transcripts remains possible, no correlation was found with stage, histological grade or outcome in this small group of advanced thyroid malignancies. Relaxation of mRNA splice control appears to be a feature of follicular cell-derived thyroid neoplasms.

Rosai-Dorfman disease of the thyroid masquerading as anaplastic carcinoma.

Rosai-Dorfman disease (RDD), otherwise known as sinus histiocytosis with massive lymphadenopathy, is a rare histiocytic syndrome of unknown etiology, dominated by histiocytic and lymphocytic infiltration of enlarged lymph nodes. Thyroid involvement is rare and its impact unknown. We report a case of RDD involving the thyroid, initially diagnosed and managed as anaplastic carcinoma, and review the literature for previously reported cases of thyroid involvement. A 71-year-old woman sought further evaluation after treatment elsewhere for a 4-month history of a rapidly enlarging goiter causing local compression. Pathology was reported to show anaplastic thyroid carcinoma with prominent histiocytic infiltration. On review, we found characteristic features of RDD within the thyroid and cervical lymph nodes. The patient showed serologic evidence of autoimmune thyroid disease. Two years after thyroidectomy, there was no evidence of recurrent disease. We have identified only three previously reported cases of RDD involving the thyroid, all of them in women. In all cases, the patient has survived without evidence of disease progression, suggesting that thyroid involvement may not change the generally good prognosis of RDD. The description of autoimmune thyroid disease in our case and in two of the three previously reported cases, suggests a link with autoimmune thyroid disease.

Managing patients with papillary thyroid carcinoma: insights gained from the Mayo Clinic's experience of treating 2,512 consecutive patients during 1940 through 2000.

2,512 consecutive patients with papillary thyroid carcinoma (PTC) were managed during 1940 through 2000 at the Mayo Clinic. During that period, there were two significant therapeutic trends. The first was a change in surgical practice during 1940-69 from an initial unilateral lobectomy (UL) to a bilateral lobar resection (BLR). The second was the increasing use since 1970 of I-131 for radioactive-iodine remnant ablation (RRA). The advent of BLR resulted in significantly improved tumor recurrence (TR) rates in both low-risk (MACIS scores < 6) and high-risk (MACIS scores 6+) patients, and also reduced cause-specific mortality (CSM) in high-risk patients. By contrast, RRA did not significantly improve the outcome (either CSM or TR) in low-risk (MACIS < 6) patients previously treated with initial near-total or total thyroidectomy. These data encourage a more selective use of I-131 in PTC management and do not lend support to the current widespread use of RRA in low-risk PTC.

Potential absence of prognostic implications of severe preoperative hypercalcitoninemia in medullary thyroid carcinoma.

OBJECTIVE: To evaluate preoperative hypercalcitonine-mia further as a marker of prognosis in patients with medullary thyroid carcinoma (MTC). METHODS: We reviewed the clinical and laboratory data in six patients (four men and two women, 39 to 76 years old)--three with sporadic MTC, one with familial MTC, and two with multiple endocrine neoplasia type 2A--who had preoperative basal serum calcitonin levels of 400 to 16,000 pg/mL (normal, 0 to 19). Pentagastrin stimulation was performed in patients who had preoperative basal calcitonin levels less than 1,000 pg/mL, and responses ranged from 2,600 to 8,500 pg/mL. Thyroidectomy revealed intrathyroidal MTC in four patients; MTC and nodal metastatic lesions were present in two. The tumor cells were immunoreactive with anti-calcitonin immunoperoxidase staining. RESULTS: Serum calcitonin and carcinoembryonic antigen levels were normal postoperatively. In serial postoperative evaluation during a follow-up period of 2 to 9 years, stimulated peak plasma calcitonin levels after pentagastrin or calcium infusion were normal (in five patients) or near normal (in one patient), without clinical evidence of recurrent disease. The two patients with nodal metastatic disease have had normal calcitonin levels during a mean duration of follow-up of approximately 3 years. CONCLUSION: Pronounced preoperative hypercalci-toninemia does not necessarily preclude a favorable short-term outcome in patients with MTC.

Papillary thyroid microcarcinoma: a study of 900 cases observed in a 60-year period.

BACKGROUND: The study aims were to characterize patients with papillary thyroid microcarcinoma (PTM) and to describe post-surgical outcome. METHODS: Nine hundred PTM patients had initial treatment at Mayo Clinic during 1945-2004. Mean follow-up was 17.2 years. Recurrence and mortality details were derived from a computerized database. RESULTS: Median tumor size was 7 mm; 98% were intrathyroidal. 273 patients (30%) had neck nodal involvement; 3 (0.3%) had distant metastases at diagnosis. Seven-hundred and sixty-five (85%) underwent bilateral lobar resection (BLR; total-, near-total, or bilateral subtotal thyroidectomy). Regional nodes were removed by either "node picking" (27%) or compartmental dissection (23%). Tumor resection was incomplete in 5 (0.6%). Radioiodine remnant ablation (RRA) was performed in 155 (17%). Overall survival did not differ from expected for an age and gender matched control group (P = .96); 3 patients (0.3%) died of PTM. None of the 892 patients with initial complete tumor resection developed metastatic spread during 20 postoperative years. Twenty-year and 40-year tumor recurrence rates were 6% and 8%, respectively. Higher recurrence rates were seen with multifocal tumors (P = .004) and node-positive patients (P < .001). Neither more extensive surgery nor RRA reduced recurrence rates compared to unilateral lobectomy. CONCLUSION: More than 99% of PTM patients are not at risk of distant spread or cancer mortality. RRA after BLR did not improve postoperative outcome.

Management of thyroid nodules detected at US: Society of Radiologists in Ultrasound consensus conference statement.

The Society of Radiologists in Ultrasound convened a panel of specialists from a variety of medical disciplines to come to a consensus on the management of thyroid nodules identified with thyroid ultrasonography (US), with particular focus on which nodules should be subjected to US-guided fine needle aspiration and which thyroid nodules need not be subjected to fine-needle aspiration. The panel met in Washington, DC, October 26-27, 2004, and created this consensus statement. The recommendations in this consensus statement, which are based on analysis of the current literature and common practice strategies, are thought to represent a reasonable approach to thyroid nodular disease.

Prevalence and incidence of cytoplasmic yellow bodies in thyroid neoplasms.

CONTEXT: Cytoplasmic yellow bodies are a common and frequent histologic finding in hyalinizing trabecular adenoma of the thyroid gland, a morphologically distinctive neoplasm, and are visible in fine-needle aspiration biopsy of the tumor. OBJECTIVE: To determine the prevalence and frequency of cytoplasmic yellow bodies in common thyroid tumors. DESIGN: Microscopic slides of random cases of papillary carcinoma (61 cases), follicular adenoma (27 cases), and Hürthle cell adenoma (12 cases) were searched for cytoplasmic yellow bodies. SETTING AND PATIENTS: Slides were from patients who had undergone surgery at Mayo Clinic, Rochester, Minn, and were obtained from the Mayo Clinic Tissue Registry. MAIN OUTCOME MEASURE: Presence or absence of cytoplasmic yellow bodies. RESULTS: Cytoplasmic yellow bodies were found in papillary carcinoma (62%), follicular carcinoma (22%), and Hürthle cell adenoma (83%) but were very infrequent numerically in each tumor type. CONCLUSIONS: Cytoplasmic yellow bodies may be present in papillary carcinoma and in follicular and Hürthle cell adenomas, but because they are uncommon in these tumors, they are unlikely to be found in fine-needle aspiration biopsy smears. Therefore, cytoplasmic yellow bodies are a useful cytomorphologic indicator of hyalinizing trabecular adenoma of the thyroid gland.

Merkel cell carcinoma of the head and neck: a retrospective case series.

BACKGROUND: Eighty-five percent of all Merkel cell carcinomas appear on sun-exposed areas, with 50% to 55% occurring on the head and neck. METHODS: A chart review was performed on 22 patients treated for Merkel cell carcinoma of the head and neck between 1981 and 1998. RESULTS: Fifteen patients were men (68%). The average age at operation was 69.9 years (range, 24-84 years). The average duration of follow-up was 3.6 years (range, 3 days-8.6 years). Overall survival at 1, 2, and 3 years postoperatively was 78%, 68%, and 68%, respectively. The only independent predictor of survival was the type of surgical therapy. All patients who underwent wide local excision (WLE) of the primary tumor with dissection of the lymphatic drainage basin were alive at 2 years as opposed to 68% who had WLE alone and 33% who had Mohs surgery. CONCLUSIONS: WLE and dissection of the lymphatic drainage basin provided the best overall survival.

Papillary thyroid carcinoma managed at the Mayo Clinic during six decades (1940-1999): temporal trends in initial therapy and long-term outcome in 2444 consecutively treated patients.

It is uncertain whether more extensive primary surgery and increasing use of radioiodine remnant ablation (RRA) for papillary thyroid carcinoma (PTC) have resulted in improved rates of cause-specific mortality (CSM) and tumor recurrence (TR). Details of the initial presentation, therapy, and outcome of 2444 PTC patients consecutively treated during 1940-1999 were recorded in a computerized database. Patients were followed for more than 43,000 patient-years. The 25-year rates for CSM and TR were 5% and 14%, respectively. Temporal trends were analyzed for six decades. During the six decades, the proportion with initial MACIS (distant Metastasis, patient Age, Completeness of resection, local Invasion, and tumor Size) scores <6 were 77%, 82%, 84%, 86%, 85%, and 82%, respectively (p = 0.06). Lobectomy accounted for 70% of initial procedures during 1940-1949 and 22% during 1950-1959; during 1960-1999 bilateral lobar resection (BLR) accounted for 91% of surgeries (p <0.001). RRA after BLR was performed during 1950-1969 in 3% but increased to 18%, 57%, and 46% in successive decades (p <0.001). The 40-year rates for CSM and TR during 1940-1949 were significantly higher (p = 0.002) than during 1950-1999. During the last 50 years the 10-year CSM and TR rates for the 2286 cases did not significantly change with successive decades. Moreover, the 10-year rates for CSM and TR were not significantly improved during the last five decades of the study, either for the 1917 MACIS <6 patients or the 369 MACIS < 6 patients. Increasing use of RRA has not apparently improved the already excellent outcome, achieved before 1970, in low risk (MACIS <6) PTC patients managed by near-total thyroidectomy and conservative nodal excision.