Zakia Hafdi-Nejjari

Oncogenic alterations in papillary thyroid cancers of young patients.

BACKGROUND Papillary thyroid carcinoma (PTC) in young people usually has an aggressive initial presentation, though a good general prognosis despite recurrences in 10%-20% of patients. A number of genetic alterations that activate the mitogen-activated protein kinase (MAPK) pathway have been found in PTC. Some of these alterations have been identified as prognostic factors of PTC in adults. The objective of the current study was to comprehensively characterize all known oncogenic alterations of the MAPK pathway in young people. METHODS One hundred three PTCs removed from 9 children, 19 adolescents, and 75 young adults were submitted to molecular analyses. RESULTS Altogether, 57 alterations were found in 56 PTCs (55%) corresponding to V600E BRAF in 20.3%, RAS mutations in 12.6%, RET/PTC 1 in 11.6%, RET/PTC 3 in 8.7%, and rearrangement of NTRK in 1.9%. The prevalence of all alterations increased with age (22.2% in children; 52.6% in adolescents, 51.4% in adults 20-25 years, and 55.1% in adults 25-35 years). Prevalence increased from 39.2% earlier to 61.3% after 20 years mainly due to BRAF mutations. Classic-type PTC was associated with a larger prevalence of alterations, predominantly BRAF and RET/PTC, whereas the follicular variant was chiefly associated with RAS. RET/PTC (1 and 3) was significantly associated with extrathyroid extension (ET) and lymph node metastasis (es) (LNM). This association was found in the adult group. There were no associations of BRAF or RAS mutations with ET or LNM. A 3-year median follow up was available for 90 patients. RET/PTC 1 and 3 was associated with short-term disease dissemination (cervical lymph node recurrences and distant metastases) in young adults (p=0.001). Persistent illness was more prevalent in patients with (15%) than in patients without (7%) genetic alterations. CONCLUSION PTCs in young patients display a low prevalence of the already identified oncogenic alterations. The increasing prevalence with age is mainly due to V600E BRAF mutation. There is no relation between tumor aggressiveness and BRAF mutation. There is a relation between the presence of RET/PTC (1 and 3) and the histological and clinical short-term aggressiveness of PTC in the population of young adults. Such a relation is not found in children and adolescents.

Thyroid cancer: is the incidence rise abating?

OBJECTIVE The aim of the present study was to determine recent trends in thyroid cancer incidence rates and to analyze histopathological characteristics and geographical distribution. METHODS Histologically proven 5367 cases were collected over the period 1998-2006 in France from the Rhône-Alpes thyroid cancer registry. Geographical variations of incidence were analyzed using a mixed Poisson model. RESULTS The average incidence rates, age standardized to the world population, were 3.9/100,000 in men and 12.3/100,000 in women, higher than those previously reported in France. After an initial increase during the first 3 years, a steady level of incidence was observed for the period 2001-2006. The annual incidence rate of microcarcinomas was correlated with that of all cancers in men and women (r=0.78 and 0.89; P<0.01) respectively. Papillary microcarcinomas represented 38% of tumors and two-thirds of them measured less than 5 mm in diameter. They were fortuitously discovered after thyroidectomy for benign diseases in 64% of cases. Histological marks of aggressiveness differed according to the size of the tumor. Despite recent advances in diagnosis, 13% of tumors were diagnosed at advanced stage especially in men. Geographical distribution of incidence based on subregional administrative entities showed lower incidence rates in rural than in urban zones in men (relative rate: 0.72; 95% CI: 0.62-0.84) and women (relative rate: 0.85; 95% CI: 0.73-0.93). CONCLUSION The present study suggests that the rise in thyroid cancer incidence is now abating. It could reflect standardization in diagnostic procedures. Further studies, performed on a more prolonged period, are necessary to confirm these data.

Thyroid Cancers in Children, Adolescents, and Young Adults With and Without a History of Childhood Exposure to Therapeutic Radiation for Other Cancers

BACKGROUND The thyroid is highly sensitive to the carcinogenic effect of radiation in children. We compared, in patients with and without earlier childhood radiation, the features of papillary thyroid cancer (PTC) diagnosed in later childhood through young adulthood. METHODS Patients were from the Rhône-Alpes Thyroid Cancer Registry. Twenty-four patients (RAD group) had been treated by radiation therapy for nonthyroid neoplasms at the age of 8.0±6.0 years (mean±SD) and by surgery for PTC at the age of 17±6.4 years. They were compared with 413 patients with PTC but no radiation exposure (sPTC group, age 23±4.8 years). The two groups were subdivided into three subgroups, ages 8-14 (children), 15-20 (adolescents), and 21-29 years (adults) at time of PTC diagnosis, and compared to matched subgroups from 80 patients in the sPTC group (M-sPTC). Age in years at PTC diagnosis (RAD vs. M-sPTC) was 12±2 compared with 12±2 for children, 17±1 compared with 19±1 for adolescents, and 25±3.2 compared with 25±2.5 for adults. The matched subgroups had comparable pTNM, treatments, and follow-up. We compared the histopathological characteristics of the initial specimens and the outcome events. RESULTS The RAD group and the sPTC group were similar in terms of age when PTC was diagnosed. RAD tumors had significantly more lymph node metastases (p=0.007) and a higher proportion of invasive pTN3 stage tumors (p=0.01). The adult RAD subgroup (n=8) was more likely to have lymph node metastases (p=0.004) and a higher proportion of invasive pT3N+ stage tumors (p=0.01) than the adult sPTC subgroup (n=316). During the 6.5 years of follow-up, there was no difference in the risk of cervical recurrence between the RAD group and the M-sPTC groups. Risk of cervical recurrence was also similar for tumors that were high risk (pT3N+). CONCLUSION Young adults with PTC associated with radiation therapy for nonthyroid neoplasms in childhood have a more aggressive initial presentation than young adults with sporadic PTC. The risk of recurrent disease in patients who received radiation in early childhood through adolescence and who developed PTC in late childhood through early adulthood is similar to those who did not receive radiation.

Geographical correlation between incidence of benign disease and that of cancer of the thyroid among the population of the Rhône-Alpes région of France

OBJECTIVE To analyze, at a population level, the relation between the incidences of benign thyroid diseases in patients submitted to surgery and that of thyroid cancers based on their respective geographical distributions. METHODS The study included 3169 cases (691 cancers and 2478 benign diseases) operated on in 2002 in the Rhône-Alpes région, which is subdivided into eight départements and 311 cantons. RESULTS The total thyroid intervention rate was 54.6/100 000 (23.4 and 86.4), and the annual cancer incidence was 11.9/100 000 (4.7 and 13.8) for men and women respectively. The prevalence of cancer among thyroid surgery was 21.8% and that of cancer discovered in goiters increased with age (44% at 60 years). Intervention rates varied from départment to département. In women, the incidence of microcancers was correlated to the thyroid intervention for benign pathologies rate. In men, the incidence of supracentimetric cancers was related to the TIBR. At the canton level, the relative risk of benign diseases was correlated to that of cancers. TIBR and incidence of cancers were higher in urban cantons than in nonurban ones. The density of endocrinologists influenced the prevalence of cancers among all the cases submitted to surgery. CONCLUSION In the Rhône-Alpes population with high rates of thyroid cancer incidence and of thyroid surgery, a number of correlations were found according to gender and tumor size. However, the general incidence of cancer was not directly related to surgical activity. Geographical variability may be related to the heterogeneous medical and pathological practices.

Expression of CD133 in differentiated thyroid cancer of young patients

Aims CD133 expression in cancer is frequently associated with poor outcome. Thyroid carcinomas are rare in childhood and adolescence and are associated with a higher risk of recurrence and more metastases than the adult tumours. The aim of the study was to assess whether the expression of CD133 in thyroid carcinomas of children, adolescents and young adults was correlated with clinical prognostic factors. Methods Tissue microarrays were constructed with 235 tumours coming from 208 young adults with a median age of 28 years and 27 children with a median age of 13 years. An immunohistochemical study was performed with anti-CD133 antibody. CD133 expression was evaluated, using a semiquantitative score based on the percentage of positive cells. The mutation status of tumours was evaluated by reverse transcriptase PCR. Three cell lines were used to confirm CD133 expression by western blot. Results CD133 expression was found in 43% of adult and 37% of child tumours and was confirmed by western blot in cell lines. In young adults, the expression of CD133 was significantly more frequent in patients with tumours >3 cm (p=0.04) and in patients with lymph node metastases (p=0.02). The expression of CD133 was more frequent in patients in whom the tumour presented a BRAF mutation (p=0.03). Conclusions CD133 expression is correlated with tumour size, lymph nodes metastases and BRAF mutations in young adults. The presence of these cancer stem cells could offer new therapeutic alternatives for aggressive thyroid cancers.

Thyroid Carcinoma in Children and Adolescents Experience of the French Rhone Alpes Region Thyroid Cancer Registry

Thyroid cancer is a relatively uncommon disease within the pediatric population. It represents less than 3% of the cancers in children. It is exceptional before the age of 10, and the incidence increases in adolescents, with a difference between boys and girls leading to the preponderance of females affected by the disease similar to that observed in adults. By comparison, incidence rates in adults 20-24 years are 2.30/100 000 in men and 6.54/100 000 in women.

Impact of thyroid surgery volume and pathologic detection on risk of thyroid cancer: A geographical analysis in the Rhône-Alpes region of France

To investigate the impact of the volume of thyroid surgery and pathologic detection on the risk of thyroid cancer.