AHNS Series: Do you know your guidelines? AHNS Endocrine Section Consensus Statement: State-of-the-art thyroid surgical recommendations in the era of noninvasive follicular thyroid neoplasm with papillary-like nuclear features.

The newly introduced pathologic diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) will result in less bilateral thyroid surgery as well as deescalation in T4 suppressive and radioactive iodine treatment. Although, NIFTP is a nonmalignant lesion that has nuclear features of some papillary malignancies, the challenge for the surgeon is to identify a lesion as possibly NIFTP before the pathologic diagnosis. NIFTP, due to its reduction of overall rates of malignancy, will result in the initial surgical pendulum swinging toward lobectomy instead of initial total thyroidectomy. This American Head and Neck Society endocrine section consensus statement is intended to inform preoperative evaluation to attempt to identify those patients whose final pathology report may ultimately harbor NIFTP and can be offered a conservative surgical plan to assist in cost-effective, optimal management of patients with NIFTP.

Thyroid cancer in Pacific women in New Zealand.

AIM: To describe trends in incidence rates of thyroid cancer in New Zealand between 1981-2004 with a particular focus on Pacific women. METHOD: Linked census-cancer registration data was used to calculate age standardised cancer incidence rates for thyroid cancer. Both trends over time amongst Pacific women, and differences in rates between Pacific and European/Other women in New Zealand, were assessed. RESULTS: Rates of thyroid cancer in New Zealand were higher for women than men. The highest rates of thyroid cancer in were observed amongst Pacific women with a pooled age-standardised incidence rate of 18.5/100,000 (95%CI 14.6-22.4/100,000) compared to 5.2/100,000 (95% 4.8-5.5/100,000) for European/Other; SRR 3.58 (95%CI 2.87-4.47). Sparse data mean it is difficult to clearly identify a trend over time for Pacific women but European women experienced a 73% increase from 4.0/100,000 (95%CI 3.3-4.6/100,000) in 1981=1986 to 6.9/100,000 (95%CI 5.9-7.8/100,000) in 2001-2004 (Ptrend=0.05). CONCLUSIONS: Pacific women in New Zealand have the highest rates of thyroid cancer among resident ethnic groups. Risk was highest for Pacific women over 45 years of age. More research needs to be done looking at which specific ethnicities are driving rates of thyroid cancer in New Zealand and whether the risk is influenced by birthplace and age at migration to New Zealand.

Multiple unrelated malignancies following renal transplantation: an evaluation of four cases.

The risk of de novo malignancy is significantly higher in patients who have undergone organ transplantation than in the general population. Long-term immunosuppressive treatment, in addition to age, genetic predisposition and infectious agents, plays a major role in the development of malignancy. Although skin and hemopoietic system cancers are common, atypical presentations of malignancies may occasionally be seen during long-term follow-up in patients with functioning allografts. In this report, four cases, each with more than one different primary malignancy (one patient with three malignancies and three patients with two malignancies), are presented.

New and old knowledge on differentiated thyroid cancer epidemiology and risk factors.

Differentiated thyroid cancer (DTC) represents 1-2% of all human malignancies. The annual incidence varies among countries and it is estimated that 1.2-2.6 men and 2.0-3.8 women/100,000 individuals are affected worldwide. This incidence has been increasing in the last decades, likely due to an "over-diagnosis" of small cancers that would have remained occult and that have been likely revealed because of an increased diagnostic scrutiny rather than a real increase of incidence. The annual mortality rate for DTC is 0.5/100,000 both in men and women. DTC is 2-4 times more frequent in females than in males. The mean age at diagnosis is 40-45 yr for papillary tumors (PTC) and 50-55 yr for follicular tumors (FTC). They are very rare in children. Ninety percent of DTC are represented by PTC hystotype, mainly follicular and classical variants. In the last years it has been observed an important change in the oncogenic pattern of PTC with a significant reduction of RET/PTC rearrangements and an increase of BRAFV600E mutation suggesting a change in pathogenic events. The unique well-demonstrated risk factor of DTC is the exposure to external radiation which is also correlated with the presence of RET/PTC rearrangements. Recently, other environmental factors (i.e. living in a volcanic area or in a iodine- either deficient or rich area) or some eating habits leading to obesity have been considered as potential DTC risk factors. However, at present, the favorite hypothesis is that a complex interaction between genetic and environmental factors is required to develop DTC.

Thyroid cancer and renal transplantation: a meta-analysis.

Kidney transplantation and the associated immune suppression are associated with a significantly increased risk of developing cancer during long-term follow-up. Thyroid cancer has been recognised as a potential post-transplant risk but has not yet been subject of a focused review. We therefore performed a meta-analysis on data of 50,861 patients with a total follow-up of 198 595 patient-years and identified a 6.9-fold higher standardised incidence ratio (95% confidence interval 5.6-8.7, P<0.001) of thyroid cancer post renal transplantation as compared with a non-transplant group. All such cancers were of papillary type as far as histopathology was known. The mean time to discovery was 6.0 years post transplantation. This puts thyroid cancer into the group of high cancer risk following solid organ transplantation which already includes cervical cancer, non-melanoma skin cancer, oral and lip cancer and haematological malignancies. It is unclear what causes the increased cancer incidence. Inclusion of thyroid ultrasound in long-term post-transplant evaluation may help to ensure timely recognition of this condition.

Thyroid nodules and cancers in children.

The incidence of thyroid nodules in children is estimated to be 1 to 1.5% based on clinical examination. Children with thyroid nodules, compared to adults with thyroid nodules, have a fourfold greater risk of developing malignant thyroid disease. Differentiated thyroid carcinoma is the most common pediatric endocrine tumor, constituting 0.5-3% of all childhood malignancies. The thyroid is one of the most frequent sites of secondary neoplasm in children who receive radiation therapy for other malignancies. Thyroid carcinoma has been studied extensively in adults. However, the pediatric literature on this subject is much less complete, owing to the rarity of its diagnosis. This article reviews the predisposing factors, genetics, pathology, pathogenesis , clinical presentation, detailed treatment and follow-up management of children with thyroid carcinoma. Additionally, a discussion regarding the controversial aspects of radioiodine therapy in children is included.

The paired box-8/peroxisome proliferator-activated receptor-gamma oncogene in thyroid tumorigenesis.

The American Cancer Society estimates 30,180 new cases of thyroid cancer in the United States in 2006. Of all thyroid cancers, 15-20% are follicular thyroid carcinoma (FTC), making this the second most common thyroid malignancy (after papillary carcinoma). A proportion of FTC has been found to be associated with a chromosomal translocation, t (2, 3)(q13;p25), which fuses the thyroid-specific transcription factor paired box-8 with the peroxisome proliferator-activated receptor-gamma nuclear receptor, a ubiquitously expressed transcription factor. This fusion event causes expression of a paired box-8/peroxisome proliferator-activated receptor-gamma fusion protein (PPFP). PPFP is detected in approximately 30% of FTC. In this report we review data on the role of PPFP in FTC, its mechanism of oncogenesis, and PPFP targeting as a strategy in thyroid cancer treatment.

AKT in thyroid tumorigenesis and progression.

AKT (protein kinase B) is a central signaling molecule in the phosphatidyl inositol 3-kinase pathway that is frequently activated in human cancer. AKT activation regulates energy metabolism, apoptosis, proliferation, and migration in many cell systems. In thyroid cancer, AKT activation is involved in tumorigenesis, particularly in both inherited and sporadic forms of follicular thyroid cancer. Phosphatidyl inositol 3-kinase and AKT signaling also appear to play an important role in progression of both papillary and follicular cancers. In this review, the role of AKT in thyroid cancer development and progression are discussed with a focus on areas of current debate in the literature.

Unexpected additional increase in the incidence of thyroid cancer among a recent birth cohort in Switzerland.

Data collected by the Swiss Cancer Registries Network (ASRT/VSKR) have been used to analyse trends in thyroid cancer during the last available 20 years, to make within-country geographical comparisons for current incidence rates. Age-standardized (European population) incidence rates per 100,000 for all morphologies combined ranges from 1.62 to 2.99 among males and from 2.13 to 8.09 among females in Switzerland. Regression analyses for both sexes combined detected an increase in time for papillary cases and a decrease for other types. Age-period-cohort analyses revealed that the youngest cohorts of men and women born after 1940 had an increased risk of all types of thyroid cancer while the cohort of people born between 1920 and 1939 were at increased risk of the papillary subtype. Assuming a higher sensitivity to ionizing radiation among the youngest people, a Chernobyl effect cannot be definitively excluded and continuous study of this topic should be encouraged.

Amiodarone-induced thyrotoxicosis and thyroid cancer: clinical, immunohistochemical, and molecular genetic studies of a case and review of the literature.

Amiodarone-induced thyrotoxicosis (AIT) is a well-known complication of amiodarone treatment found in 3% to 12% of patients. Two types of AIT have been described, each associated with a distinct histologic pattern of thyroid involvement. Type 1, which typically develops in the background of pre-existing thyroid disease, is due to iodine-induced excess thyroid hormone synthesis, whereas type 2 is due to destructive thyroiditis. The prevalence of thyroid cancer in patients with AIT is unknown. We report a case of papillary thyroid carcinoma associated with type 2 AIT.

The influence of dietary patterns on the development of thyroid cancer.

To elucidate the role of diet in the development of thyroid cancer, we conducted a case-control study of 113 persons with histologically-verified thyroid cancer and 138 controls, matched by age, gender and health unit. Socio-economic data, known risk factors and food consumption of more than 100 items were recorded by interviewer-administered prestructured questionnaire. Factor analysis was used to identify possible dietary patterns and logistic regression analysis was used to explore the effect of food items or dietary patterns on thyroid cancer. After adjustment for age, gender, body mass index (BMI), and total energy intake, significant positive associations were observed for pork consumption, while negative ones were observed for tomatoes, lemons and pasta. Dietary patterns of fruits, raw vegetables and mixed raw vegetables and fruits, led to a reduced risk (corresponding odds ratios (ORs) 0.68, 0.71, 0.73) for all thyroid cancers and similar figures were obtained for papillary thyroid cancers. A dietary pattern of fish and cooked vegetables led to an increased risk (OR 2.79) of follicular cancer.

[Reproductive history, contraceptives and cigarette smoke as risk factors for cancer of the thyroid in women. Case-control study]. / Storia riproduttiva, contraccettivi e fumo di sigaretta come fattori di rischio del cancro della tiroide nel sesso femminile.

BACKGROUND: Evaluation of the influence of hormonal and reproductive factors and the role of cigarette smoking in the onset of thyroid carcinoma. METHODS: Comparison between a group of 78 female patients all living in the district of Lazio, operated for thyroid follicular or papillary carcinoma at the Third Clinical Surgery Dept., Policlinico Umberto I, Rome (Italy) from 1990 to 1997, and a group of 150 women free from neoplastic and/or hormonal pathology, recruited by the compilation of a questionnaire. RESULTS: Cigarette smoking can be associated with risk reduction of developing thyroid neoplasia. On the contrary, no risk variation has been associated with the number of normal pregnancies, with pregnancy interruption both spontaneous and voluntary and with anthropometric characteristics of the analysed individuals. The first pregnancy at very young age and the use of contraceptives seem to determine a risk increase of thyroid cancer, at the limit of statistical significance. CONCLUSIONS: The antiestrogenic action of cigarette smoking exerts a protective action for thyroid carcinomas. Spontaneous or volontary interruption of pregnancy did not show a significant effect as risk factor.

Reproductive and hormonal risk factors for thyroid cancer in Los Angeles County females.

We conducted an individually matched case-control study (292 pairs) of female thyroid cancer patients to examine the role of reproductive history and exogenous hormones in this disease. Radiation treatment to the head or neck [28 cases and 2 controls exposed; odds ratio (OR), 14.0; 95% confidence interval (CI), 3.5-121.3] and certain benign thyroid diseases (including adolescent thyroid enlargement, goiter, and nodules or tumors) were strongly associated with thyroid cancer. Irregular menstruation increased risk (OR, 1.8; 95% CI, 0.9-3.7). Age at menarche and pregnancy history were not related to disease. Women with natural menopause and hysterectomized women without oophorectomy had no increase in risk, but disease risk was elevated in women with bilateral oophorectomy (OR, 6.5; 95% CI, 1.1-38.1). In general, use of oral contraceptives and other exogenous estrogens was not associated with thyroid cancer. However, risk increased with number of pregnancies in women using lactation suppressants (P = 0.03) and decreased with duration of breastfeeding (P = 0.04). These data provide only limited support for the hypothesis that reproductive and hormonal exposures are responsible for the marked excess of thyroid cancer risk in adult females.

Case-control study of thyroid cancer in Northern Italy: attributable risk.

BACKGROUND: The percentage of thyroid cancer cases attributable to specific risk factors can be calculated to focus preventive strategies. The per cent population attributable risks (PAR) for thyroid cancer were estimated in relation to history of benign thyroid diseases, history of radiotherapy, residence in endemic goitre areas and selected indicators of a poor diet, using data from a case-control study conducted between 1986 and 1992 in Northern Italy. METHODS: Cases were 399 histologically confirmed incident thyroid cancers and controls were 617 patients, admitted to hospital for a wide range of acute, non-neoplastic, non-hormone-related diseases. The PAR were computed on the basis of multivariate odds ratios (OR) and on the distribution of risk exposure among cases, assuming they are representative of the general population of cases. RESULTS: A history of benign thyroid disease accounted for 18.9% of cases, radiotherapy for 1.2%, residence for > or =20 years in endemic goitre areas for 2.4% of cases, and their combination for 21.7% of thyroid cancer cases; selected indicators of a poor diet accounted for 40.9% of thyroid cancer cases in this population. The combination of all factors considered explained over 57% of thyroid cancer cases in both sexes. The estimates for thyroid-related conditions were higher in women than men, whereas the opposite was true for dietary indicators. The overall PAR were somewhat higher in people aged > or =45 years (63.8%) than in younger subjects, and for follicular (69.1%) rather than papillary (53.7%) cancers. CONCLUSIONS: Exposure to a few simply identified and potentially modifiable risk factors or indicators (benign thyroid disease, residence in endemic goitre area and a poor diet) explained about 60% of thyroid cancer cases in this Italian population, indicating the theoretical scope for prevention.

Differential loss of heterozygosity at 7q31.2 in follicular and papillary thyroid tumors.

We analysed 42 differentiated thyroid tumors including 15 follicular adenomas (FA), 13 papillary thyroid cancers (PTC) and 14 follicular thyroid carcinomas (FTC) with 13 microsatellite markers specific for the long arm of human chromosome 7 within 7q31; this region is deleted frequently in several other tumor types. Overall, 20 of the 42 samples analysed (48%) displayed LOH with one or more of the markers tested. LOH was detected most frequently (78%) in FTC, the most malignant of the thyroid tumors. A smallest common deleted region (SCDR) was defined in this tumor type flanked by markers D7S480 and D7S490. This SCDR is distinct from D7S522, the most commonly deleted locus in many other tumors, which was deleted in only one FTC. D7S522 did show LOH in two of six informative PTCs. None of the PTC and only two of the FAs showed LOH in the FTC SCDR. Since FA is considered a premalignant stage of FTC, our results suggest that inactivation of a putative tumor suppressor at 7q31.2 may be acquired during adenoma to carcinoma progression. The absence of LOH at this locus amongst PTC suggests that inactivation of this tumor suppressor is specific for FTC. In conclusion, LOH at 7q31 is a frequent event in differentiated thyroid cancer, and we have defined a 2 cM SCDR specific for FTC.

Diet and the risk of papillary and follicular thyroid carcinoma: a population-based case-control study in Sweden and Norway.

A population-based case-control study was conducted in two regions of Sweden and Norway to investigate the association between dietary habits and the risk of thyroid cancer. The consumption of selected foods was reported in a self-completed food-frequency questionnaire by 246 cases with histologically confirmed papillary (n = 209) and follicular (n = 37) thyroid carcinoma, and 440 age- and gender-matched controls. Odds ratios (OR) and their 95 percent confidence interval (CI) were calculated as estimates of the relative risk using conditional logistic regression. High consumption of butter (OR = 1.6, CI = 1.1-2.5) and cheese (OR = 1.5, CI = 1.0-2.4) was associated with increased risks. Residence in areas of endemic goiter in Sweden was associated with an elevated risk, especially among women (OR = 2.5, CI = 1.3-4.9). High consumption of cruciferous vegetables was associated with increased risk only in persons who ever lived in such areas. A decreased risk was associated with consumption of iodized salt in northern Norway, and with use of iodized salt during adolescence among women (OR = 0.6, CI = 0.6-1.0). The results of this study suggest a role of diet and environment in the risk of thyroid cancer.

Diagnostic X-ray exposure and female papillary thyroid cancer: a pooled analysis of two Swedish studies.

The aim of the present study was to evaluate the risk for female papillary thyroid cancer from occupational and medical low level radiation exposure. The analyses are based on data from two Swedish case-control studies on determinants for thyroid cancer. One hundred and eighty six thyroid cancer cases, diagnosed during 1977-89 and aged 20-70 years, were collected from cancer registers. Twice as many population controls were selected. Questionnaires were mailed in 1990-91 to living cases and controls. A high risk was found for the occupational group of dentists/dental assistants, odds ratio (OR) = 13.1, 95% confidence interval (CI) = 2.1-389. For all occupational exposure to X-rays OR = 2.1, 95% CI = 1.0-4.4 was obtained. Diagnostic X-ray exposure was associated with increased risk, with a dose-response tendency yielding OR = 2.6, 95% CI = 1.5-5.1 for the highest absorbed thyroid dose (> 1.0 mGy). If only females of 50 years or less at diagnosis were considered, higher ORs were obtained. Increased risks were also found for some site-specific examinations, some of them giving very low radiation dose to the thyroid; more than 10 dental X-rays gave OR = 3.5, 95% CI = 1.6-7.6. A potentiated risk for prior X-rays was seen among women with three or more parities, with OR = 4.7, 95% CI = 1.5-14.8. Exposure to visual display units yielded OR = 2.3, 95% CI = 0.9-5.6. As in all questionnaire-based case-control studies possible recall bias must be considered but is unlikely to cause dose-response patterns and interaction as indicated in this study.

Carcinoma of the thyroid in children--a review.

Thyroid cancer is the third most common solid tumor in children and adolescents. A review was made of the data on 540 such patients reported from nine large centers renowned for their experience with thyroid cancer. In respect to the pathogenesis the only factor conclusively known to promote development of thyroid cancer in the pediatric age group is irradiation, as documented by the Chernobyl experience. The evidence indicates that thyroid carcinoma in the pediatric age group is a biologically independent and more aggressive entity than in adults; paradoxically the prognosis is good. In the great majority of cases the only presenting sign was a neck mass. In a high percentage (60-80%) there were also palpable lymph nodes. The findings regarding lung metastases were not clear-cut: in most series they were present in about 10%, with a high of 28% in one group and a low of 5% in another group. Papillary carcinoma or the follicular variant of papillary carcinoma were the dominant histologic types, pure follicular carcinoma being found much less frequently than among adults with thyroid cancer. Despite the relatively advanced stage of the disease upon diagnosis, only 13 patients died of the disease, 12 to 33 years postoperatively. Recurrence rates ranged between 10% to 35%, with involvement of the lateral neck, thyroidal bed or distant sites 3 to 33 years after treatment; most failures responded to further surgery or radioactive iodine. There is almost general agreement that surgical intervention should consist of total or near total thyroidectomy despite the high rates of recurrent laryngeal nerve paralysis and hypocalcemia. In regard to neck metastases less than radical surgery has proved during the years to be sufficiently effective. Radioactive iodine, used by all at some stage of management for treatment purposes, should be used prophylactically only after due consideration in view of possible teratogenicity.

Is residence in areas of endemic goiter a risk factor for thyroid cancer?

The association between an indicator of iodine deficiency and differentiated thyroid cancer has been investigated in a population-based case-control study. This included all incident cases (N = 484) of papillary and follicular thyroid cancer diagnosed during the years 1980-1992 in a Swedish Health Care Region among residents born in Sweden, and as many individually matched controls. Cases were included after a uniform review of their histopathological specimens. Residence in areas where goiter had been severely endemic in the 1930s was used as exposure indicator. Odds ratios (OR) and 95% confidence intervals as estimates of relative risk were calculated as a measure of association using logistic regression. A trend toward an association was found with a duration of residence in goiter areas between 21 and 40 years, most prominent among follicular cancer cases and in the group diagnosed at age > or = 50 years compared to not exposed. Exposure for the first time during adolescence (between 11 and 20 years) was associated with an increased risk of papillary cancer. This was especially evident among women, both when compared to not exposed and to those exposed during the first year of life; the association was strengthened after adjustment for duration of residence. These findings support the hypothesis of distinct causation patterns from iodine deficiency to the 2 most common histological types of thyroid cancer.