The role of angiogenesis and lymphangiogenesis in thyroid cancer pathogenesis has not been elucidated. Patterns for tumour behaviour and metastasic spread vary according to tumour type and whether differences in the angiogenic or lymphangiogenic phenotype influence the route for tumour metastases or determine a more aggressive behaviour has not been fully explored. The angiogenic and lymphangiogenic phenotypes of a large cohort of thyroid proliferative lesions (n=191) were studied. Using immunohistochemistry for CD34, lymphatic vessel endothelial receptor-1 (LYVE-1) (specific markers for vascular and lymphatic endothelium respectively), vascular endothelial growth factor (VEGF-A), VEGF-C and fibroblast growth factor-2 (FGF-2), this study analyses microvascular density (MVD), lymphatic vascular density (LVD), and expression of angiogenic and lymphangiogenic factors in normal thyroid (NT; n=19), multinodular goitre (n=25), toxic multinodular goitre (n=8), Graves’ hyperplasia (n=22), follicular adenoma (n=54), papillary carcinoma (PC; n=27), incidental papillary microcarcinoma (PMC; n=8), follicular carcinoma (FC; n=20) and medullary carcinoma (MC; n=8). MVD was decreased in proliferative lesions, benign and malignant, compared with NT (P<0.0001). In contrast, VEGF-A expression was increased in thyroid carcinomas (PC, FC and MC) when compared with PMC, benign lesions and NT (P<0.0001). LVD was higher in PC and PMC (P=0.001), and VEGF-C expression was increased in PC (P<0.0001). Despite higher LVD and increased expression of VEGF-A and VEGF-C in thyroid cancers, these markers were not related to poor prognosis in terms of tumour size, multifocality and/or presence of lymphatic or distant metastases. In conclusion, angiogenesis is reduced in thyroid proliferative lesions compared with NT tissue. However, VEGF-A expression is upregulated in thyroid cancers. Lymphangiogenesis and VEGF-C expression are increased in thyroid tumours prone to lymphatic metastases. This may be an important mechanism underlying the differences in metastatic behaviour between papillary and follicular thyroid cancer.
N Garcia de la Torre, I Buley, J A H Wass and H E Turner
D F√ºhrer, A Tannapfel, O Sabri, P Lamesch and R Paschke
In a 59-year-old patient, thyroid follicular cancer was diagnosed in two right-sided toxic thyroid nodules, which had presented clinically as unilateral thyroid autonomy. In addition, the patient had histologically proven lung metastases of thyroid cancer; however, these failed to exhibit iodine uptake and were resistant to radioiodine treatment. The functional activity of the thyroid nodules prompted us to screen for TSH receptor (TSHR) mutations, and the histological diagnosis of follicular carcinoma led us to search for the PAX8-PPARgamma1 rearrangement and mutations in the ras genes. Each thyroid nodule harboured a different TSHR mutation (large nodule, Asp633Tyr; small nodule, Phe631Ile). Presence of both mutations in one sample suggestive of local invasion of a thyroid carcinoma could not be demonstrated, although several specimens from different nodule locations were screened. Only the wild-type TSHR sequence was identified in the histologically normal left thyroid lobe, and no genetic alterations were found in the other investigated genes. No TSHR mutations were detected in the pulmonary metastases. This is the first case report of a patient with toxic follicular thyroid carcinoma harbouring two different TSHR mutations and presenting with non-functional lung metastases.
Julie A Ellerhorst, Aresu Sendi-Naderi, Marilyn K Johnson, Carolyn P Cooke, Shyam M Dang and A Hafeez Diwan
We have reported a high prevalence of hypothyroidism in the cutaneous melanoma population, suggesting that the pathologic hormonal environment of hypothyroidism promotes melanoma growth. The objective of this study was to test the hypothesis that TSH, which circulates at elevated levels in hypothyroid individuals, stimulates the growth of melanoma cells. Our results show that TSH receptors (TSHR) are expressed by virtually all cutaneous melanocytic lesions, including benign nevi, dysplastic nevi, and melanomas, with higher expression found in malignant and pre-malignant lesions. The finding of TSHR expression by human tumors is confirmed in cultured melanoma cells and melanocytes, in which TSHR expression is demonstrated by immunofluorescent staining, western blotting, and reverse transcriptase-PCR. Melanoma TSHR are functional, as evidenced by the ability of TSH to induce the formation of cAMP and to activate the mitogen-activated protein kinase (MAPK) pathway. Cultured melanoma cells, but not melanocytes, are induced to proliferate at a physiologically relevant concentration of TSH. Taken together, these data support the hypothesis that TSH is a growth factor for human melanoma. Our findings have broad clinical implications for the prevention of melanoma and the management of established disease.
J L Reverter, S Holgado, N Alonso, I Salinas, M L Granada and A Sanmartí
The effect of subclinical hyperthyroidism on bone mineral density is controversial and could be significant in patients with differentiated thyroid carcinoma who receive suppressive doses of levothyroxine (LT4). To ascertain whether prolonged treatment with LT4 to suppress thyrotropin had a deleterious effect on bone mineral density and/or calcium metabolism in patients thyroidectomized for differentiated thyroid cancer we have performed a cross-sectional study in a group of 88 women (mean ± SD age: 51 ± 12 years) treated with LT4 after near-total thyroidectomy and in a control group of 88 healthy women (51 ± 11 years) matched for body mass index and menopausal status. We determined calcium metabolism parameters, bone turnover marker N-telopeptide and bone mass density by dual-energy X-ray absorptiometry. No differences were found between patients and controls in calcium metabolism parameters or N-telopeptide except for PTH, which was significantly increased in controls. No differences were found between groups in bone mineral density in femoral neck (0.971 ± 0.148 gr/cm2 vs 0.956 ± 0.130 gr/cm2 in patients and controls respectively, P = 0.5). In lumbar spine, bone mineral density values were lower in controls than in patients (1.058 ± 0.329 gr/cm2 vs 1.155 ± 0.224 gr/cm2 respectively, P<0.05). When premenopausal (n = 44) and postmenopausal (n = 44) patients were compared with their respective controls, bone mineral density was similar both in femoral neck and lumbar spine. The proportion of women with normal bone mass density, osteopenia and osteoporosis in patient and control groups was similar in pre- and postmenopausal women. In conclusion, long-term suppressive LT4 treatment does not appear to affect skeletal integrity in women with differentiated thyroid carcinoma.
Jos√© I Botella-Carretero, Manuel G√≥mez-Bueno, Vivencio Barrios, Carmen Caballero, Rafael Garc√≠a-Robles, Jos√© Sancho and H√©ctor F Escobar-Morreale
To evaluate cardiovascular functionality in patients with thyroid cancer, we have performed echocardiography and ambulatory blood pressure monitoring in 19 women with differentiated thyroid carcinoma during thyroxine withdrawal, at three time points: the last day on TSH-suppressive thyroxine doses (subclinical or mild hyperthyroidism), 4-7 days after withdrawal (normal free thyroxine (FT4) and free triiodothyronine (FT3) levels), and before 131I whole body scanning (overt hypothyroidism). Twenty-one healthy euthyroid women served as controls. When compared with the values at visit 2, when patients had normal serum FT4 and FT3 levels, night-time systolic and mean blood pressure were increased when the patients were mildly hyperthyroid, and night-time systolic, diastolic and mean blood pressure were increased during overt hypothyroidism. The proportion of nondippers (absence of nocturnal decline in blood pressure) was markedly increased compared with healthy controls (7%), when patients were hyper- or hypothyroid (58% and 50% respectively), but not when patients had normal FT4 and FT3 levels (12%). No changes were observed in office blood pressure or in daytime ambulatory blood pressure readings. Diastolic function worsened during thyroxine withdrawal (E and A waves (early and late mitral flow) decreased, and the E/A ratio and the isovolumic relaxation time increased), and cardiac output decreased in parallel with the decrease in heart rate and systolic blood flow. In conclusion, the chronic administration of TSH-suppressive doses of thyroxine and the withdrawal of thyroxine frequently used for the management of differentiated thyroid carcinoma, are associated with undesirable cardiovascular effects.
Maya B Lodish and Constantine A Stratakis
Targeted therapy in oncology consists of drugs that specifically interfere with abnormal signaling pathways that are dysregulated in cancer cells. Tyrosine kinase inhibitors (TKIs) take advantage of unique oncogenes that are activated in certain types of cancer, and also target common mechanisms of growth, invasion, metastasis, and angiogenesis. However, many kinase inhibitors for cancer therapy are somewhat nonselective, and most have additional mechanisms of action at the cellular level, which are not completely understood. The use of these agents has increased our knowledge of important side effects, of which the practicing clinician must be aware. Recently, proposed endocrine-related side effects of these agents include alterations in thyroid function, bone metabolism, linear growth, gonadal function, fetal development, and glucose metabolism, and adrenal function. This review summarizes the most recent data on the endocrine side effects of TKIs.
Wassim Chemaitilly and Charles A Sklar
Endocrine disturbances are among the most frequently reported complications in childhood cancer survivors, affecting between 20 and 50% of individuals who survive into adulthood. Most endocrine complications are the result of prior cancer treatments, especially radiotherapy. The objective of the present review is to discuss the main endocrine complications observed in this population, including disorders of the hypothalamic–pituitary axis, disorders of pubertal development, thyroid dysfunction, gonadal dysfunction, decreased bone mineral density, obesity, and alterations in glucose metabolism with a special focus on recent findings reported from the Childhood Cancer Survivor Study.
Briseis Aschebrook-Kilfoy, Gila Neta, Alina V Brenner, Amy Hutchinson, Ruth M Pfeiffer, Erich M Sturgis, Li Xu, William Wheeler, Michele M Doody, Stephen J Chanock and Alice J Sigurdson
Relationships are unclear between polymorphisms in genes involved in metabolism and detoxification of various chemicals and papillary thyroid cancer (PTC) risk as well as their potential modification by alcohol or tobacco intake. We evaluated associations between 1647 tagging single nucleotide polymorphisms (SNPs) in 132 candidate genes/regions involved in metabolism of exogenous and endogenous compounds (Phase I/II, oxidative stress, and metal binding pathways) and PTC risk in 344 PTC cases and 452 controls. For 15 selected regions and their respective SNPs, we also assessed interaction with alcohol and tobacco use. Logistic regression models were used to evaluate the main effect of SNPs (P trend) and interaction with alcohol/tobacco intake. Gene- and pathway-level associations and interactions (P gene interaction) were evaluated by combining P trend values using the adaptive rank-truncated product method. While we found associations between PTC risk and nine SNPs (P trend≤0.01) and seven genes/regions (P region<0.05), none remained significant after correction for the false discovery rate. We found a significant interaction between UGT2B7 and NAT1 genes and alcohol intake (P gene interaction=0.01 and 0.02 respectively) and between the CYP26B1 gene and tobacco intake (P gene interaction=0.02). Our results are suggestive of interaction between the genetic polymorphisms in several detoxification genes and alcohol or tobacco intake on risk of PTC. Larger studies with improved exposure assessment should address potential modification of PTC risk by alcohol and tobacco intake to confirm or refute our findings.
J I Botella-Carretero, J M Gal√°n, C Caballero, J Sancho and H F Escobar-Morreale
We studied the psychological performance and the quality of life in patients with differentiated thyroid carcinoma, either during treatment with chronic suppressive doses of levothyroxine, or during the withdrawal of levothyroxine needed to perform whole-body scanning with radioactive iodine, with those of appropriate healthy controls. Eighteen women with differentiated thyroid carcinoma and 18 euthyroid age-matched healthy women were recruited. Patients were studied the day before levothyroxine withdrawal (when in chronic mild or subclinical hyperthyroidism), 4-7 days later (when most patients had normal serum free thyroxine and free triiodothyronine levels), and the day before scanning (when in profound hypothyroidism). Controls were studied at one time point. When compared with controls, patients presented with impairment of several indexes during chronic suppressive levothyroxine therapy (total score, emotional, sleep, energy and social of the Nottingham Health Profile; mental health, general health and social function of the SF-36, and total score on Wais Digit Span; P<0.05 for all comparisons). Also, quality of life indexes (19 of 21 scores), cognitive tests (6 of 12 scores), and affective and physical symptoms visual mental scales (18 of 19) worsened during profound hypothyroidism (P<0.05 for all comparisons). Quality of life and cognitive performance were almost comparable with those of euthyroid controls when most patients had normal free thyroxine and triiodothyronine levels. In conclusion, quality of life and psychometric functionality in patients with differentiated thyroid carcinoma is not only affected by withdrawal of levothyroxine but also by long-term treatment with supraphysiological doses of levothyroxine.
Dolly Thomas, Susan Friedman and Reigh-Yi Lin
Ongoing advances in stem cell research have opened new avenues for therapy for many human disorders. Until recently, however, thyroid stem cells have been relatively understudied. Here, we review what is known about thyroid stem cells and explore their utility as models of normal and malignant biological development. We also discuss the cellular origin of thyroid cancer stem cells and explore the clinical implications of cancer stem cells in the thyroid gland. Since thyroid cancer is the most common form of endocrine cancer and that thyroid hormone is needed for the growth and metabolism of each cell in the body, understanding the molecular and the cellular aspects of thyroid stem cell biology will ultimately provide insights into mechanisms underlying human disease.