Sino-European Differences in the Genetic Landscape and Clinical Presentation of Pheochromocytoma and Paraganglioma.

CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) are characterized by distinct genotype-phenotype relationships according to studies largely restricted to Caucasian populations. OBJECTIVE: To assess for possible differences in genetic landscapes and genotype-phenotype relationships of PPGLs in Chinese versus European populations. DESIGN: Cross-sectional study. SETTING: 2 tertiary-care centers in China and 9 in Europe. PARTICIPANTS: Patients with pathologically confirmed diagnosis of PPGL, including 719 Chinese and 919 Europeans. MAIN OUTCOME MEASURES: Next-generation sequencing performed in tumor specimens with mutations confirmed by Sanger sequencing and tested in peripheral blood if available. Frequencies of mutations were examined according to tumor location and catecholamine biochemical phenotypes. RESULTS: Among all patients, higher frequencies of HRAS, FGFR1, and EPAS1 mutations were observed in Chinese than Europeans, whereas the reverse was observed for NF1, VHL, RET, and SDHx. Among patients with apparently sporadic PPGLs, the most frequently mutated genes in Chinese were HRAS (16.5% [13.6-19.3] vs 9.8% [7.6-12.1]) and FGFR1 (9.8% [7.6-12.1] vs 2.2% [1.1-3.3]), whereas among Europeans the most frequently mutated genes were NF1 (15.9% [13.2-18.6] vs 6.6% [4.7-8.5]) and SDHx (10.7% [8.4-13.0] vs 4.2% [2.6-5.7]). Among Europeans, almost all paragangliomas lacked appreciable production of epinephrine and identified gene mutations were largely restricted to those leading to stabilization of hypoxia inducible factors. In contrast, among Chinese there was a larger proportion of epinephrine-producing paragangliomas, mostly due to HRAS and FGFR1 mutations. CONCLUSIONS: This study establishes Sino-European differences in the genetic landscape and presentation of PPGLs, including ethnic differences in genotype-phenotype relationships indicating a paradigm shift in our understanding of the biology of these tumors.

miR-34b/c rs4938723 T>C Decreases Neuroblastoma Risk: A Replication Study in the Hunan Children.

Neuroblastoma is the most common seen solid neural tumor in children less than age one. As mutation in the miR-34b/c gene is observed in several types of human malignancies, there likely to be similar events that contribute to the pathogenesis of neuroblastoma. We hypothesize that polymorphism in the miR-34b/c gene might predispose to neuroblastoma. Here, we conducted this replication study by genotyping rs4938723 T>C from miR-34b/c in Hunan children (162 subjects with neuroblastoma and 270 control subjects) and examined its effect on the risk of neuroblastoma. We determined such association using logistic regression, adjusted for age and gender. Relative to those with TT genotype, subjects with C allele had reduced neuroblastoma risk (TC vs. TT: adjusted OR = 0.46, 95%CI = 0.30-0.71; additive model: adjusted OR = 0.64, 95%CI = 0.47-0.88; TC/CC vs. TT: adjusted OR = 0.49, 95%CI = 0.33-0.73). Stratified analysis revealed that rs4938723 TC/CC carriers were less likely to develop neuroblastoma for patients in the subgroups of age ≤ 18 months, age > 18 months, females, males, tumors in retroperitoneal, tumors in other sites, and clinical stages II, III, IV, and III+IV. Our findings verified miR-34b/c rs4938723 C variant allele as a protective factor for the risk of neuroblastoma. Further investigation of how miR-34b/c rs4938723 T>C might modify neuroblastoma risk is warranted.

Occurrence of Endocrine and Thyroid Cancers Among Alaska Native People, 1969-2013.

BACKGROUND: Nationwide, the incidence of thyroid cancer is lower among American Indian/Alaska Native (AI/AN) people than among U.S. whites (USW). However, little is known about the incidence of thyroid or other endocrine cancers specifically among Alaska Native (AN) people. METHODS: Data were examined from the National Cancer Institute's Surveillance, Epidemiology, and End Results Alaska Native Tumor Registry on endocrine cancers diagnosed among AN people from 1969-2013, with a specific focus on thyroid cancers. Frequencies of endocrine cancers by site and also of thyroid cancers by histology, size, and stage at diagnosis were evaluated. Distributions were compared to USW (Surveillance, Epidemiology, and End Results 9 Registries) using the chi-square test. Five-year average annual age-adjusted incidence rates of thyroid cancers were calculated, stratified by histology, age, and five-year period of diagnosis, and compared to those observed among USW. Five-year cause-specific survival was evaluated using cause of death data from the National Death Index Plus from the National Center for Health Statistics. RESULTS: During the 45-year period (1969-2013), 224 endocrine cancers were diagnosed among AN people, of which 210 (94%) were thyroid cancers. Compared to USW, AN people were diagnosed at a slightly younger age, had a higher proportion of thyroid cancers diagnosed with a size of 20-40 mm, and a larger proportion of patients with regional metastases. More than 85% of AN thyroid cancers were of papillary histology. The incidence of thyroid cancers was similar between AN people and USW, and appeared to increase among AN people over the period of surveillance. Finally, five-year cause-specific survival rate was 100% for papillary carcinoma patients and 86.3% [confidence interval 54.7-96.5] for follicular thyroid cancer patients. CONCLUSIONS: This study is the first report of endocrine cancers and the first detailed examination of thyroid cancer among AN people. The incidence of thyroid cancer was similar among AN people and USW. However, compared to USW, AN people appear to be at risk for diagnosis at a younger age, larger size, and higher stage. Further research is needed to explore the causes of these differences.

Different diagnostic cut-off values of urinary fractionated metanephrines according to sex for the diagnosis of pheochromocytoma in Korean subjects.

The diagnosis of pheochromocytoma depends on the documentation of catecholamine overproduction. The use of urinary fractionated metanephrines has recently become common for the diagnosis of pheochromocytoma. In order to avoid false positive and false negative results, optimal cut-off levels are necessary; however, there have been few published reports on whether different cut-off levels are needed to diagnose pheochromocytoma according to sex. We reviewed the medical records of 815 subjects (including 103 pheochromocytoma patients) whose of 24-h urinary fractionated metanephrine was measured using high-performance liquid chromatography methods and adrenal imaging at Samsung Medical Center. Receiver operating characteristic (ROC) curves were used to determine cut-off values according to sex. The upper limit values of fractionated metanephrine in healthy volunteers and the control group were significantly higher in male subjects compared with females. When we applied cut-off values according to sex, the diagnostic efficacies (defining a positive test as either metanephrine or normetanephrine levels above the cut-off value) were a sensitivity of 96% in male subjects and 98.1% in female subjects and a specificity of 88.6% in male subjects and 94.1% in female subjects. However, when we applied cut-off values without considering sex, the specificity decreased from 88.6% to 77.8% in male subjects. In this study, urinary fractionated metanephrines had a high level of sensitivity and specificity for the diagnosis of pheochromocytoma. However, diagnostic cut-off values were higher in male subjects than in female subjects. Therefore, different cut-off values may be needed according to sex to diagnose pheochromocytoma in Koreans.

[Mutation screening of VHL gene in a Chinese family with nonsyndromic pheochromocytoma].

OBJECTIVE: To detect the VHL gene mutations in a Chinese family with nonsyndromic pheochromocytoma. METHODS: Mutations of VHL gene were detected in a Chinese family with nonsyndromic pheochromocytoma. Five patients and fifteen relatives were involved in this study. Peripheral blood was collected and total genomic DNA was prepared for polymerase chain reaction (PCR). PCR products of all the three exons of VHL gene were purified and a direct gene sequence analysis was performed. RESULTS: All the five patients presented a codon 125 from Histidine (H) to Proline (P) change at nucleotide 587 (A --> C) in exon 2. Seven members of fifteen relatives were carriers with the same VHL gene mutation. Two carriers were detected with bilateral adrenal tumors and right renal cyst respectively by ultrasonic inspection. CONCLUSION: The novel VHL gene mutation detected in this kindred may be the causative gene. Genetic test can detect the carriers in an early period. It is recommended as a routine method of genetic test in nonsyndromic pheochromocytoma patients.

Morphological analysis of adrenal glands: a prospective analysis.

There is a lack of studies to document the weight range of normal adrenal glands. The aims of the current study are to find out the weight range of normal adrenal glands in Chinese patients and to analyze any potential factors affecting it. Adrenal glands not affected by disease were prospectively collected from autopsies on 333 Chinese patients (208 men, 125 women). The weight and longest dimension of each adrenal gland were noted. The impact of various clinicopathological factors on the adrenal weight was studied. In addition, the morphometric features of these adrenal glands were compared with that of 28 surgically resected adrenal glands with cortical adenomas. The mean combined weight of adrenal glands was 11.8 g (range = 5.8 g to 19.9 g). The left adrenal gland was often heavier than the right (mean weight = 6.1 g and 5.7 g respectively) and with a greater longitudinal length than the right (mean length = 5.2 cm and 4.8 cm respectively). Adrenal glands were often heavier in male, younger age group (less than 60-yr-old) and patients with history of hypertension or lung cancers. In comparison, the mean weight of right adrenal gland with cortical adenoma was 11.7 g (range = 6 g to 26 g) and that of left adrenal gland with cortical adenoma was 9.4 g (range = 4.6 g to 25 g). This is the first study in the English literature that provides data on the weight of normal adrenal glands in a solely Chinese population. Adrenal weight may be affected by patients' gender, age, laterality of adrenal gland and presence of systemic disease.

A review of clinicopathologic features of pheochromocytomas in Hong Kong Chinese.

Twenty-two Chinese patients with pheochromocytomas including 18 surgical and four autopsy cases were reported. The incidence at autopsy was 0.048%. The tumours were most common in the sixth and the fourth decades in males and females, respectively. There was no sex predilection. The incidence of bilaterality was 4.5% and the tumours were more common on the right side. 9.1% of the tumours were malignant and they were larger than their benign counterparts. Solid and diffuse pattern and mixed pattern were the most common histologic patterns. Minor histological features included hyaline globules (64%), nuclear pseudo-inclusions (55%), lipid degeneration (4.5%) and peri-adrenal brown fat (18%). All of them were strongly positive for the three pan-neuroendocrine markers (neuron-specific enolase, synaptophysin and chromogranin) confirming the usefulness of these markers in diagnosing pheochromocytoma.

The incidence and epidemiologic characteristics of neuroblastoma in the United States.

The incidence of neuroblastoma in the United States is described in relation to age, sex, race, and anatomic site, as well as population-derived indicators of socioeconomic levels, degree of urbanization, and farming activity. Incidence data were obtained for the years 1973-1978 from the Surveillance, Epidemiology and End Results Program of the National Cancer Institute. Based upon 265 cases, the overall incidence of neuroblastoma was 2.26 per million person-years. Approximately 60% of the cases were diagnosed under age two years, 75% under age five years and 84% under age 10 years. The incidence among males was 1.3 times that among females, but the male predominance was observed only among persons diagnosed under age five years. Although no difference in overall incidence was observed by race, the rate among whites was 1.6 times that among blacks and 1.5 times that among other nonwhites under age five years. Approximately 50% of all cases were diagnosed with tumors arising from the adrenals or soft tissues. No clear pattern of area-to-area variation in incidence was identified. Neuroblastoma incidence was inversely related to socioeconomic level as measured by per capita income (p = 0.05), as well as the proportion of county land devoted to farming (p = 0.034). No association was observed in relation to urbanization or population density.