Check for updates
Rare Cancers in Childhood and Adolescence in Brazil: First Report of Data From 19 Population-Based Cancer Registries
Nathalie V. Balmant, Msc1; Rejane de Souza Reis, PhD2; Marceli de Oliveira Santos, PhD3; Beatriz de Camargo, MD, PHD ID 1; and Gemma Gatta, MD4
BACKGROUND: Rare childhood cancer is challenging to define. The Italian Pediatric Rare Tumor (TREP) Study considers rare tumors to include solid malignancies characterized by an annual incidence rate of <2 cases per 1 million and not enrolled in clinical trials. The objective of the current study was to analyze the population incidence rate of rare tumors among children and adolescents (those aged birth-19 years) in Brazil. METHODS: Incidence data were obtained from 19 population-based cancer registries covering the 5 geographic regions in Brazil. Newly diagnosed cases were selected according to the TREP definition, using the International Classification of Diseases for Oncology. To calculate the crude incidence rate, the numbers of incident children and adolescents with a specific rare cancer were divided by the corresponding person-years lived for the population aged <20 years during the same period. RESULTS: Two tumors had an incidence rate that was >2 cases per 1 million (thyroid and skin cancers) in adolescents only. Several tumors demonstrated variations in incidence across the Brazilian regions. Adrenocortical carcinoma had a high incidence rate (4 cases per 1 million) in the south region among children aged <10 years. Thyroid and skin carcinoma had higher incidence rates in the midwest, southeast, and south regions. CONCLUSIONS: Due to the extraordinary rarity of these events, networking is important for improving basic research, clinical studies, and trials. Centralization of diagnosis is the only way to improve the diagnosis and treat- ment of children affected by these rare diseases. The registration and surveillance of rare pediatric cancers are crucial from a public health point of view, and therefore the quality of registration has to be improved. Cancer 2019;0:1-9. @ 2019 American Cancer Society.
KEYWORDS: adolescents, Brazil, childhood, population-based registries, rare tumors.
INTRODUCTION
Cancer in children and adolescents is a rare event, and a subset of such cancers are especially rare. The definition of rare childhood cancer includes both cancers that affect only children (eg, pancreatoblastoma, malignant rhabdoid tumors, and melanotic neuroectodermal tumors of infancy) as well as cancers that usually affect only adults (eg, cancers of the digestive system, thyroid, and adrenal gland).1
To the best of our knowledge, the first cooperative study of this group of rare tumors was undertaken in 2000 by the Italian Pediatric Rare Tumor Study (Tumori Rari in Eta Pediatrica [TREP]).2 TREP defines this group of rare tumors as any solid malignancy characterized by an annual incidence rate of <2 cases per 1 million and the patients are not enrolled in clinical trials.2,3 Groups from several other European countries (Italy, France, the United Kingdom, Poland, and Germany) later joined this initiative, and founded the European Cooperative Study Group for Pediatric Rare Tumors (EXPERT).2 EXPERT defines rare childhood cancers not only based on incidence rates but also on a lack of registries and very limited clinical studies. Together, these tumors account for approximately 5% of all childhood cancers.2,3
The Children’s Oncology Group (COG) in the United States defines rare tumors as those classified as other malig- nant epithelial neoplasms (including adrenocortical, thyroid, and nasopharyngeal carcinomas) and melanomas (subgroup XI from the International Classification of Childhood Cancer), predominantly adult cancers occurring in the pediatric age range, and other unspecified carcinomas. COG’s Rare Tumor Committee also includes 3 other tumor types: retino- blastoma, liver tumors, and germ cell tumors. These 4 categories account for 15% to 20% of all childhood malignancies.4,5
Initiatives to study rare childhood tumors also include the creation of international disease-specific registries and clinics.º These include registries for pleuropulmonary blastoma, pediatric adrenocortical carcinoma,8 nuclear pro- tein of the testis (NUT) midline carcinoma (http://www.nmcregistry.org/), and ovarian and testicular stromal tumors
Corresponding author: Beatriz de Camargo, MD, PhD, Postgraduate Program, Research Center, National Cancer Institute, Rio de Janeiro, RJ, Brazil; bdecamar@terra. com.br
1 Postgraduate Program, Research Center, Hospital Cancer Foundation, Tumor registry, Rio de Janeiro, Brazil; 2Hospital Cancer Foundation, Tumor registry, Rio de Janeiro, Brazil; 3 Surveillance and Prevention Coordination, National Cancer Institute, Rio de Janeiro, Brazil; 4IRCCS Foundation, Evaluative Epidemiology Unit, Evaluative Epidemiology Unit, National Cancer Institute, Milan, Italy.
The last 2 authors have contributed equally to this article.
We acknowledge all of the efforts made by Dr. Vilma Martins and Dr. Maria Paula Curado from the AC Camargo Cancer Center for the first meeting of the Brazilian Rare Tumor Network. We are grateful to all the coordinators of the population-based cancer registries in Brazil that contributed to this work.
| Rare Tumors in Childhood and Adolescents | ||
|---|---|---|
| Tumor Group | ICD-O-3 Morphology Codesª | ICD-O-3 Topography Codes |
| Pancreatoblastoma | 8971 | All sites |
| Non-germ cell gonadal tumors | 8600, 8620-8621, 8630, 8634, 8640 | C56, C62 |
| Pleuropulmonar blastoma | 8973 | All sites |
| Thymus tumors | 8010-8084, 8120-8157, 8190-8264, 8290, 8310, | C379 |
| 8313-8315, 8320-8325, 8360, 8380-8384, 8430-8440, | ||
| 8452-8454, 8480-8586, 8588-8589, 8940, 8941, 8983, | ||
| 9000, 9010-9016, 9020, 9030 | ||
| Gastrointestinal stromal tumor | 8936 | All sites |
| Pheochromocytoma and paraganglioma | 8680, 8700, 8711 | All sites |
| Epithelial tumors of appendix | 8010-8084, 8120-8157, 8190-8264, 8290, 8310, | C181 |
| 8313-8315, 8320-8325, 8360, 8380-8384, 8430-8440, | ||
| 8452-8454, 8480-8586, 8588-8589, 8940, 8941, 8983, 9000, | ||
| 9010-9016, 9020, 9030 | ||
| Breast cancer | 8010-8084, 8120-8157, 8190-8264, 8290, 8310, | C50 |
| 8313-8315, 8320-8325, 8360, 8380-8384, 8430-8440, | ||
| 8452-8454, 8480-8586, 8588-8589, 8940, 8941, | ||
| 8983, 9000, 9010-9016, 9020, 9030 | ||
| Carcinoid tumors | 8013, 8041, 8246 | All sites, except C07.9, C08.9, C11, C18.1, C37.9, C44, C50, C73 |
| Adrenocortical carcinoma | 8370-8375 | All sites |
| Salivary gland tumors | 8010-8084, 8120-8157, 8190-8264, 8290, 8310, | C079, C089 |
| 8313-8315, 8320-8325, 8360, 8380-8384, 8430-8440, | ||
| 8452-8454, 8480-8586, 8588-8589, 8940, 8941, 8983, 9000, 9010-9016, 9020, 9030 | ||
| Renal carcinoma | 8010-8589 | C64 |
| Nasopharyngeal carcinoma | 8010-8041, 8050-8075, 8082, 8083, 8120-8122, | C11 |
| 8130-8141, 8190, 8200, 8201, 8211, 8230, 8231, | ||
| 8244-8246, 8260-8263, 8290, 8310, 8320, 8323, 8430, | ||
| 8440, 8480, 8481, 8500-8576 | ||
| Skin tumors | 8720-8780, 8790 (melanoma) | C44 |
| 8010-8041, 8050-8075, 8078, 8082, 8090-8110, 8140, | C44 | |
| 8143, 8147, 8190, 8200, 8240, 8246, 8247, 8260, 8310, | ||
| 8320, 8323, 8390-8420, 8430, 8480, 8542, 8560, | ||
| 8570-8573, 8940, 8941 (skin carcinoma) | ||
| Thyroid carcinoma | 8020-8022, 8050, 8260, 8330, 8345, 8346, | C73 |
| 8430, 8480, 8510, 8588, 8589 | ||
Abbreviation: ICD-O-3, International Classification of Diseases for Oncology, 3rd Edition. ªIncluded behavior recode 3 for all morphology codes.
(http://www.otstregistry.org/), as well as an annual centralized clinic for pediatric gastrointestinal stromal tumor (https://ccr.cancer.gov/gist).
The objective of the current study was to analyze the population incidence rate of rare tumors among chil- dren and adolescents (those aged birth-19 years) in Brazil, according to the TREP proposal.
MATERIALS AND METHODS
For the current study, rare tumors were defined accord- ing to the TREP definition,9 using the International Classification of Disease for Oncology, Third Edition (ICD-O-3) (Table 1).10 We included only malignant tu- mors (fifth digit of the morphological code equal to 3). Incidence data were obtained from 19 population-based cancer registries (PBCRs) covering the 5 geographic regions of Brazil: north (Belem, Roraima, Manaus,
and Palmas), northeast (Fortaleza, Joao Pessoa, Recife, and Aracaju), midwest (Cuiaba, Goiania, and Campo Grande), southeast (Barretos, Sao Paulo, Jau, Grande Vitoria, Belo Horizonte, and Pocos de Caldas), and south (Curitiba and Florianopolis). These selected PBCRs cover approximately 23% of the total Brazilian population.
Figure 1 shows the period of coverage for each PBCR, the population coverage of children aged <20 years for each city providing PBCR data, and the distribution of skin color for each region. We did not evaluate skin color distribution according to individ- ual PBCR due to the very high percentage of missing data. Skin color distribution from the 5 Brazilian re- gions was obtained from the Brazilian Institute of Geography and Statistics (https://sidra.ibge.gov.br) based on self-reported categorization as white, black, yellow, brown, and Indian.
NORTH White - 22.6%
Roraima (2005-2010) Population: 1,164,548
Belém (2005-2014) Population: 6,764,101
NORTHEAST White - 29.1%
Black - 5.1 %
Yellow - 1.0 %
Black - 7.6 %
Brown - 68.7 %
Yellow- 1.1 %
Indian - 2.5 %
Brown - 61.7 %
Indian - 0.4 %
Fortaleza (2005-2009) Population: 4,586,261
Manaus (2005-2009) Population: 3,558,492
João Pessoa (2005-2013)
Population: 2,114,536
Palmas (2005-2013) Population: 785,964
Recife (2005-2012) Population: 3,915,427
Cuiabá (2005-2009) Population: 1,484,765
Aracaju (2005-2013)
MIDWEST
Population: 1,655,372
White - 40.3%
Black - 5.1 %
Yellow - 1.3 %
Goiânia (2005-2011) Population: 2,833,054
Belo Horizonte (2005-2011) Population: 5,066,550
Brown - 51.9 %
Indian - 1.4 %
Campo Grande (2008-2011) Population: 999,563
Poços de Caldas (2007-2011) Population: 220,711
Grande Vitória (2005-2012) Population: 4,539,575
Curitiba (2005-2012)
Population: 4,357,736
São Paulo (2005-2013) Population: 30,498,169
SOUTHEAST White - 51.8% Black - 6.7 %
Florianópolis (2008-2012) Population: 557,684
Yellow- 0.8 %
SOUTH White - 76.1%
Jaú (2005-2011) Population: 418,770
Brown - 40.6 % Indian - 0.1%
Black - 3.7 %
Yellow - 0.6 %
Brown - 19.3 %
Barretos (2005-2015) Population: 1,374,165
Indian - 0.4%
Table 2 presents data quality indicators. Unspecified diagnoses and those with unspecified morphology codes (8000, 8800, 9800, etc) were divided into subgroups based on the International Classification of Childhood Cancer, Third Edition. Of the 19 PBCRs, all had 0% of their cases ascertained by death certificate only. The rate of microscopically verified cases was >80% in 18 PBCRs, and 1 PBCR had a rate <75%. To estimate crude incidence rates, we divided the numbers of incident cases for a given entity during the period of diagnosis by the corresponding person-years lived within the general population during the same period for each PBCR.
RESULTS
Table 3 presents the crude incidence rates for each dif- ferent rare tumor according to TREP definition and region. Two tumors had an annual incidence rate of >2 cases per 1 million (thyroid and skin carcinoma). Several tumors demonstrated geographic variations in incidence. Thyroid carcinoma had higher incidence
rates in the midwest, southeast, and south regions (>6 cases per 1 million per year). Skin carcinoma had higher incidence rates in the midwest and southeast (>5 cases per 1 million per year). Adrenocortical car- cinoma had a higher incidence rate in the south region (2.2 cases per 1 million per year). Thyroid carcinoma, melanoma, and skin carcinoma had lower incidence rates in the north region. Some tumors demonstrated age-related variations in incidence (Table 4). Thyroid and skin carcinoma incidence rates increased with age, and were found to be highest among adolescents (those aged 15-19 years). The great majority of thyroid tumors included papillary carcinoma. Medullary carcinoma occurred in adolescents (5 cases) and in those aged 5 to 10 years (3 cases). Adrenocortical carcinoma had a higher incidence rate among children aged <10 years (Table 4). Figure 2 shows the annual incidence rates for the 4 major rare tumors according to patient sex and age. Skin and thyroid carcinomas had higher incidence rates in females, and nasopharyngeal carcinoma had a higher incidence rate among males. All 4 major rare
| Region | PBCR | No. of Cases | DCO, % | MV, % | NOS, % |
|---|---|---|---|---|---|
| North | Belem | 36 | 0.0 | 100.0 | 14.1 |
| Manaus | 13 | 0.0 | 92.3 | 16.6 | |
| Palmas | 7 | 0.0 | 100.0 | 10.2 | |
| Roraima | 3 | 0.0 | 100.0 | 20.3 | |
| Northeast | Aracaju | 33 | 0.0 | 93.9 | 5.0 |
| Fortaleza | 44 | 0.0 | 95.5 | 12.9 | |
| Joao Pessoa | 22 | 0.0 | 100.0 | 17.2 | |
| Recife | 42 | 0.0 | 92.9 | 10.9 | |
| Midwest | Campo Grande | 19 | 0.0 | 94.7 | 11.0 |
| Cuiaba | 14 | 0.0 | 100.0 | 13.2 | |
| Goiania | 61 | 0.0 | 72.1 | 3.2 | |
| Southeast | Belo Horizonte | 99 | 0.0 | 100.0 | 11.8 |
| Barretos | 22 | 0.0 | 100.0 | 3.4 | |
| Grande Vitoria | 16 | 0.0 | 100.0 | 10.1 | |
| Jahu | 7 | 0.0 | 85.7 | 0.0 | |
| Pocos de Caldas | 14 | 0.0 | 100.0 | 5.1 | |
| Sao Paulo | 616 | 0.0 | 100.0 | 22.6 | |
| South | Curitiba | 54 | 0.0 | 100.0 | 3.5 |
| Florianopolis | 24 | 0.0 | 100.0 | 4.1 | |
| Brazil | 1146 | 0.0 | 99.5 | 15.2 |
Abbreviations: DCO, cases ascertained from death certificate only; MV, microscopically verified cases; NOS, cases not otherwise specified (International Classification of Diseases for Oncology, 3rd Edition morphology codes: 8000-8005); PBCR, population-based cancer registry.
| Tumor Group | No. of Cases | North CR | Northeast CR | Midwest CR | Southeast CR | South CR | Brazil CR |
|---|---|---|---|---|---|---|---|
| Pancreatoblastoma | 0 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
| Non-germ cell gonadal tumors | 1 | 0.00 | 0.00 | 0.00 | 0.02 | 0.00 | 0.01 |
| Pleuropulmonary blastoma | 1 | 0.00 | 0.00 | 0.00 | 0.02 | 0.00 | 0.01 |
| Thymus carcinoma | 2 | 0.00 | 0.08 | 0.00 | 0.02 | 0.00 | 0.03 |
| GI stromal sarcoma | 3 | 0.00 | 0.08 | 0.00 | 0.02 | 0.20 | 0.04 |
| Pheochromocytoma and paraganglioma | 12 | 0.00 | 0.41 | 0.00 | 0.14 | 0.20 | 0.16 |
| Carcinoid tumor | 14 | 0.08 | 0.24 | 0.19 | 0.17 | 0.41 | 0.18 |
| Neuroendocrine tumor | 17 | 0.16 | 0.16 | 0.38 | 0.21 | 0.41 | 0.22 |
| Breast cancer | 24 | 0.16 | 0.49 | 0.38 | 0.31 | 0.20 | 0.31 |
| Salivary gland tumor | 35 | 0.24 | 0.57 | 0.56 | 0.47 | 0.41 | 0.46 |
| Adrenocortical tumor | 35 | 0.00 | 0.00 | 1.32 | 0.40 | 2.24 | 0.46 |
| Renal cell carcinoma | 39 | 0.33 | 0.33 | 0.38 | 0.55 | 1.22 | 0.51 |
| Nasopharyngeal carcinoma | 70 | 0.41 | 0.73 | 1.69 | 1.12 | 0.00 | 0.91 |
| Melanoma | 93 | 0.41 | 1.22 | 0.75 | 1.42 | 1.83 | 1.21 |
| Nonmelanoma skin cancer | 388 | 1.14 | 3.02 | 5.27 | 7.10 | 2.03 | 5.05 |
| Thyroid carcinoma | 412 | 1.87 | 4.07 | 6.39 | 6.48 | 6.51 | 5.36 |
| All tumors | 1146 | 4.81 | 11.41 | 17.30 | 18.47 | 15.66 | 14.90 |
Abbreviations: CR, crude incidence rates per 1 million; GI, gastrointestinal.
tumors had higher incidence rates among individuals aged >9 years.
DISCUSSION
To the best of our knowledge, there are few reports to date from PBCRs specifically regarding rare childhood tu- mors, and the current study is the first descriptive analysis of PBCR data regarding rare childhood cancers in Brazil,
covering approximately 23% of a population of 62,923,165 Brazilian children and adolescents (https://censo2010.ibge. gov.br). The objective of the current study was to describe the incidence rates of rare childhood tumors in Brazil ac- cording to the TREP definition. We excluded several rare tumor types, including rhabdoid tumors, liver tumors, and malignant germ cell tumors, because these tumors currently are being studied in specific clinical trials.
| Region | PBCR | Age Birth to 9 Years | Age 10 to 14 Years | Age 15 to 19 Years | |||
|---|---|---|---|---|---|---|---|
| No. | Rate | No. | Rate | No. | Rate | ||
| Adrenocortical tumors | North | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 |
| Northeast | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | |
| Midwest | 5 | 2.01 | 0 | 0.00 | 2 | 1.35 | |
| Southeast | 11 | 0.55 | 3 | 0.28 | 3 | 0.27 | |
| South | 9 | 3.99 | 0 | 0.00 | 2 | 1.44 | |
| Brazil | 25 | 0.69 | 3 | 0.15 | 7 | 0.34 | |
| Salivary gland tumors | North | 0 | 0.00 | 1 | 0.32 | 2 | 0.62 |
| Northeast | 0 | 0.00 | 3 | 0.95 | 4 | 1.18 | |
| Midwest | 0 | 0.00 | 1 | 0.74 | 2 | 1.35 | |
| Southeast | 2 | 0.10 | 10 | 0.92 | 8 | 0.71 | |
| South | 0 | 0.00 | 1 | 0.78 | 1 | 0.72 | |
| Brazil | 2 | 0.05 | 16 | 0.81 | 17 | 0.82 | |
| Renal carcinoma | North | 2 | 0.34 | 1 | 0.32 | 1 | 0.31 |
| Northeast | 0 | 0.00 | 1 | 0.32 | 3 | 0.88 | |
| Midwest | 0 | 0.00 | 2 | 1.49 | 0 | 0.00 | |
| Southeast | 5 | 0.25 | 6 | 0.55 | 12 | 1.07 | |
| South | 1 | 0.44 | 2 | 1.57 | 3 | 2.16 | |
| Brazil | 8 | 0.22 | 12 | 0.61 | 19 | 0.92 | |
| Nasopharyngeal carcinoma | North | 0 | 0.00 | 0 | 0.00 | 5 | 1.55 |
| Northeast | 0 | 0.00 | 3 | 0.95 | 6 | 1.77 | |
| Midwest | 0 | 0.00 | 3 | 2.23 | 6 | 4.06 | |
| Southeast | 0 | 0.00 | 19 | 1.75 | 28 | 2.49 | |
| South | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | |
| Brazil | 0 | 0.00 | 25 | 1.27 | 45 | 2.17 | |
| Melanoma | North | 2 | 0.34 | 0 | 0.00 | 3 | 0.93 |
| Northeast | 8 | 1.40 | 3 | 0.95 | 4 | 1.18 | |
| Midwest | 1 | 0.40 | 0 | 0.00 | 3 | 2.03 | |
| Southeast | 17 | 0.85 | 15 | 1.38 | 28 | 2.49 | |
| South | 1 | 0.44 | 2 | 1.57 | 6 | 4.33 | |
| Brazil | 29 | 0.80 | 20 | 1.01 | 44 | 2.12 | |
| Skin carcinoma | North | 8 | 1.35 | 3 | 0.96 | 3 | 0.93 |
| Northeast | 8 | 1.40 | 6 | 1.90 | 23 | 6.77 | |
| Midwest | 4 | 1.61 | 5 | 3.71 | 19 | 12.85 | |
| Southeast | 88 | 4.39 | 128 | 11.80 | 83 | 7.39 | |
| South | 4 | 1.77 | 2 | 1.57 | 4 | 2.88 | |
| Brazil | 112 | 3.07 | 144 | 7.30 | 132 | 6.37 | |
| Thyroid carcinoma | North | 0 | 0.00 | 3 | 0.96 | 21 | 6.51 |
| Northeast | 2 | 0.35 | 9 | 2.85 | 39 | 11.49 | |
| Midwest | 0 | 0.00 | 7 | 5.20 | 33 | 22.31 | |
| Southeast | 11 | 0.55 | 61 | 5.63 | 234 | 20.82 | |
| South | 0 | 0.00 | 11 | 8.63 | 25 | 18.02 | |
| Brazil | 13 | 0.36 | 91 | 4.61 | 352 | 16.98 | |
| All tumors with a CR >0.45 | North | 12 | 2.02 | 8 | 2.57 | 35 | 10.85 |
| Northeast | 18 | 3.15 | 25 | 7.91 | 79 | 23.27 | |
| Midwest | 10 | 4.01 | 18 | 13.37 | 65 | 43.95 | |
| Southeast | 134 | 6.69 | 242 | 22.32 | 396 | 35.24 | |
| South | 15 | 6.66 | 18 | 14.12 | 41 | 29.56 | |
| Brazil | 189 | 5.19 | 311 | 15.60 | 616 | 29.72 | |
Abbreviation: CR, crude incidence rate per 1 million; PBCR, population-based cancer registry.
Approximately 75% of rare tumors occur in ado- lescents (those aged 15-19 years).11 In the current series, incidence rates generally increased according to age. Among thyroid carcinoma cases, approximately 56.4% involved patients aged >14 years. Within the adolescent group (those aged 15-19 years), thyroid carcinoma had the highest incidence rate, follow by skin carcinoma. It is interesting to note that adrenocortical carcinoma oc- curred with a high incidence rate of 4 cases per 1 million
in the south region among children aged <10 years, con- stituting 51% of cases in all regions. Skin carcinoma also had a high incidence rate among children aged birth to 9 years.
Adrenocortical tumors represent approximately 0.2% of all pediatric tumors, with an annual incidence rate of 0.2 cases per 1 million children.12 A previous study has demonstrated a higher rate of this tumor type in Brazil, with Sao Paulo showing an incidence
20
Crude incidence rates per million
18
16
14
Melanoma
12
Skin carcinoma
Thyroid
10
Nasopharyngeal
8
6
4
2
0
0-9
10-14
15-19
0-9
10-14
15-19
Males
Females
rate of 1.5 cases per 1 million, which is >3 times the rate in most registries.13 Since the 1980s, there has been a clear cluster of pediatric adrenocortical carci- noma cases in several southern states of Brazil.14 In 1990, an International Pediatric Adrenocortical Tumor Registry was developed and 258 cases were registered in 11 years. The majority of these patients (79.5%) were from southern Brazil, whereas 13% were from the United States and 7.5% were from 9 other countries.8 A unique constitutional TP53 mutation (R337H) was identified in the Brazilian patients.15 This mutation has been detected throughout a region of Brazil extending from the state of Minas Gerais (southeast region) to the state of Rio Grande do Sul (south region).16 To the best of our knowledge, the origin of the R337H founder mutation is unknown and affected families are mostly distributed along a main route following the south, southeast, and midwest regions used by merchants of Portuguese origin in the 18th and 19th centuries.17 A screening program was implemented to detect the TP53 R337H mutation among newborns in Curitiba (south region), and this mutation was identified in 0.3% of all newborns.18 In the current study, the incidence rate followed the same pattern. The south region presented with the highest incidence rate (2.2 cases per 1 mil- lion), followed by the midwest (1.05 cases per 1 mil- lion) and southeast (0.41 cases per 1 million) regions. More specifically, the highest incidence rate was noted among children aged <10 years in the south region (4 cases per 1 million). It is difficult to find definite histopathological criteria to differentiate adrenocorti- cal carcinoma from adrenocortical adenoma, and the histopathological classification of adrenocortical car- cinoma in pediatric patients remains controversial.8,19
Unfortunately, in the current study, we did not have data regarding outcome, clinical characteristics, or pathological analysis. However, this is the first analy- sis, and the next steps will be to develop follow-up for these patients and revise the pathological reports from the PBCRs to improve the quality of registration and pathological reports.
The RARECAREnet database on the epidemiol- ogy of rare cancers in Europe provides incidence rates for many of the rare tumors reported in the current study; the youngest age categories were age <15 years and ages 15 to 29 years. For the majority of the rare en- tities in common with RARECAREnet, the Brazilian incidence rates (aged <20 years) are reported to be between age <15 years and ages 15 to 29 years.20 RARECAREnet also estimated survival for these exceptional tumors and demonstrated a good progno- sis for the majority of them, but with 5-year relative survival rates of <50% after 5 years for cases of adrenal gland carcinoma, some neuroendocrine tumors, and pancreatoblastoma. A comparative analysis between Brazilian and European data could be considered to enlarge the series of cases to study and to share the experience in treatment, protocols, and results.
Over the past decades, incidence rates for skin car- cinoma have been rapidly increasing in all white popu- lations worldwide. The risk of skin carcinoma increases with age but in the current series it was not clearly ob- served, especially in the southeast region, most likely due to the incomplete registration of skin cancers by all reg- istries. A report from the Automated Childhood Cancer Information System (ACCIS) presented skin carcinoma incidence rates of 0.3 cases per 1 million and 3.7 cases per 1 million among children and adolescents, respectively.21
Skin cancer data have been collected in all Brazilian PBCRs and follow Surveillance, Epidemiology, and End Results (SEER) rules, in which different topographical codes are considered multiple primary tumors.22 In a prior series of adolescents and young adults aged 15 to 29 years, the median incidence rate of skin carcinoma in Brazil was 18 cases per 1 million.23 Among children and adolescents aged <20 years with xeroderma pigmentosum, the rate of skin carcinoma in sunlight-exposed areas is reported to be 10,000 times higher than in the general population.24,25 A recent report has described a genetic cluster involving the POLH gene in families with xeroderma pigmentosum in a community in the state of Goias in the midwest re- gion of Brazil.26 In the current study, the incidence rate for skin carcinoma was highest in the midwest region, as has been previously reported among adolescents and young adults.22 Further investigations are necessary.
The incidence of melanoma among children in the United States is rapidly increasing by an average of 2% per year.27,28 According to the TREP definition, mela- noma is rare in children but not in adolescents.9 Several others countries also have reported increased incidence rates of melanoma, especially in adolescents aged 15 to 19 years and on sun-exposed areas of the body. Risk fac- tors for pediatric melanoma include being white, being female, increasing age, and environmental ultraviolet radiation exposure.28,29 Melanoma and skin carcinoma also demonstrated higher incidence rates in the south and southeast regions. The percentage of the popula- tion having white skin color is significantly higher in the south (76% of the population). Currently, improved edu- cation programs around the world are increasing aware- ness of the dangers of sun exposure among parents and adolescents.
Thyroid carcinoma has a low incidence rate among children aged <15 years (2.0 cases per 1 million).30 However, over the last decades, the incidence of thyroid cancer has markedly increased, especially among chil- dren aged 15 to 19 years.31-33 Moreover, thyroid cancer incidence rates are higher in white populations, at nearly twice those noted in black populations.34,35 In the cur- rent study, the highest thyroid cancer incidence rates were observed in the midwest, southwest, and south regions of Brazil, which have the highest percentages of white resi- dents. We also found a higher thyroid cancer rate among females, a finding that is in agreement with prior data.3
Nasopharyngeal carcinoma is very rare among chil- dren. Moreover, its incidence rates vary greatly in different populations, suggesting the influence of environmental factors such as exposure to Epstein-Barr virus.36 The SEER
database demonstrated an incidence rate of 0.5 cases per 1 million person-years among children and adolescents (aged birth-19 years).37 In the European population, rates were 0.3 and 1.3 in those aged <15 years and 15 to 24 years, respectively, with large variations noted across European countries and a high incidence in the southern countries.2º Single-institution data from Brazil have indi- cated that nasopharyngeal carcinoma accounts for 13% of head and neck tumors in children and adolescents (those aged birth-19 years).38 However, in the European popu- lation, the corresponding percentage was higher (30%).20 The incidence rate in the current study was 0.9 cases per 1 million, with the highest incidence noted in the mid- west followed by the southeast region.
It is interesting to note that in the north region, which has the lowest percentage of white individuals, the incidence of these tumors is the lowest, suggesting that some preventative factors are present in this population or that a diagnosis is difficult to reach because of the low availability of good diagnostic centers.
One of the first hurdles to overcome in study- ing rare cancers is diagnostic accuracy. Unexpectedly, some entities such as pancreatoblastoma, non-germ cell gonadal tumors, and pleuropulmonary blastoma had no cases or only one case diagnosed in all the Brazilian regions covered. Collaboration with the pathologist and clinician and the relevance of obtaining a sec- ond opinion for a correct diagnosis are important issues that must be discussed and organized. Central pathology currently is considered essential in all clini- cal trials.39 Unspecified cases are recorded in the regis- try in instances for which pathology reports could not be retrieved and no specific diagnosis could be made. A high percentage of unspecified neoplasms (not other- wise specified [NOS]) may distort the incidence rates in specific diagnostic groups or subgroups.40 Institutions of reference should be offered centralized histological review and the identification of these centers also is important. The RARECARE project found that after the revision of both morphology and topography NOS codes by PBCRs, the percentage of NOS cases was re- duced only marginally.41 Microscopically verified cases were not 100% in 7 PBCRs but this is not a reason for their exclusion because quality criteria are captured for new cases in all sources, including clinical and imaging examinations, and not only pathology reports.
The concept of disease rarity is a matter of controversy. One objective of the TREP project is to create a network to enable the development of diag- nostic and treatment recommendations for each rare
tumor.2 The establishment of a network of special- ists, including oncologists, pathologists, endocrinol- ogists, dermatologists, and surgeons, is essential for clinical trials, pathology review, and biological stud- ies. Partnerships with oncologists who treat adults are essential for developing new therapy. International collaboration is required to improve guidelines for diagnostic criteria, treatment, and research and trials performed among patients with rare tumors. It is well known that in patients with rare tumors, the diagnosis could improve after the establishment of such a group.
To the best of our knowledge, the current study is the first to report the incidence rates of this group of rare cancers in Brazil through population-based data to enlarge the collaboration with other Latin American countries. PBCRs can increase the robustness of the estimations and are useful to facilitate clinical collabo- rations. We believe the current study data can assist in the creation of a network of research groups to study rare tumors in children and adolescents, integrating special- ists from different areas of Brazil. In addition, the collab- oration between different cancer societies may improve the management of children with very rare cancers.
FUNDING SUPPORT
Nathalie V. Balmant has received a scholarship from CAPES/MS. Beatriz de Camargo is supported by a scholarly grant from CNPq 306291/2014-2.
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
AUTHOR CONTRIBUTIONS
Nathalie V. Balmant: Data collection, analysis, and interpretation and final approval of the article. Rejane de Souza Reis: Study conception and design, data analysis and interpretation, and final approval of the article. Marceli de Oliveira Santos: Study conception and design, data analysis and interpretation, and final approval of the article. Beatriz de Camargo: Study conception and design, data analysis and interpreta- tion, article writing, and final approval of the article. Gemma Gatta: Data analysis and interpretation, article writing, and final approval of the article.
REFERENCES
1. Pappo AS, Krailo M, Chen Z, Rodriguez-Galindo C, Reaman G. Infrequent tumor initiative of the Children’s Oncology Group: ini- tial lessons learned and their impact on future plans. J Clin Oncol. 2010;28:5011-5016.
2. Ferrari A, Bisogno G, De Salvo GL, et al; Italian Study on Rare Tumours in Paediatric Age (TREP); Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP). The challenge of very rare tumours in childhood: the Italian TREP project. Eur J Cancer. 2007;3:654-659.
3. Ferrari A, Schneider DT, Bisogno G; EXPERT Board. The found- ing of the European Cooperative Study Group on Pediatric Rare Tumors-EXPERT. Expert Rev Anticancer Ther. 2013;13:1-3.
4. Pappo AS, Furman WL, Schultz KA, Ferrari A, Helman L, Krailo MD. Rare tumors in children: progress through collaboration. J Clin Oncol. 2015;33:3047-3054.
5. Rodriguez-Galindo C, Krailo M, Frazier L, et al; COG Rare Tumors Disease Committee. Children’s Oncology Group’s 2013 blueprint for research: rare tumors. Pediatr Blood Cancer. 2013;60:1016- 1021.
6. Kotecha RS, Kees UR, Cole CH, Gottardo NG. Rare childhood cancers-an increasing entity requiring the need for global consensus and collaboration. Cancer Med. 2015;4:819-824.
7. Messinger YH, Stewart DR, Priest JR, et al. Pleuropulmonary blas- toma: a report on 350 central pathology-confirmed pleuropulmo- nary blastoma cases by the International Pleuropulmonary Blastoma Registry. Cancer. 2015;121:276-285.
8. Michalkiewicz E, Sandrini R, Figueiredo B, et al. Clinical and out- come characteristics of children with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry. J Clin Oncol. 2004;22:838-845.
9. Pastore G, De Salvo GL, Bisogno G, et al; TREP Group; CSD of Epidemiology Biostatistics, AIEOP. Evaluating access to pediatric cancer care centers of children and adolescents with rare tumors in Italy: the TREP project. Pediatr Blood Cancer. 2009;53:152- 155.
10. World Health Organization. International Classification of Diseases for Oncology. 3rd ed. Geneva, Switzerland: World Health Organization; 2000.
11. Ries L, Smith M, Gurney J, et al. Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975-1995. Bethesda, MD: National Cancer Institute; 1999.
12. McAteer JP, Huaco JA, Gow KW. Predictors of survival in pediat- ric adrenocortical carcinoma: a Surveillance, Epidemiology, and End Results (SEER) program study. J Pediatr Surg. 2013;48:1025- 1031.
13. Parkin DM, Stiller CA, Draper GJ, et al. International Incidence of Childhood Cancer. Lyon, France: International Agency for Research on Cancer; 1988.
14. Ribeiro RC, Figueiredo B. Childhood adrenocortical tumours. Eur J Cancer. 2004;40:1117-1126.
15. Ribeiro RC, Sandrini F, Figueiredo B, et al. An inherited p53 muta- tion that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma. Proc Natl Acad Sci U S A. 2001;98:9330-9335.
16. Achatz MI, Zambetti GP. The inherited p53 mutation in the Brazilian population. Cold Spring Harb Perspect Med. 2016;6(12).
17. Garritano S, Gemignani F, Palmero EI, et al. Detailed haplotype analysis at the TP53 locus in p.R337H mutation carriers in the pop- ulation of Southern Brazil: evidence for a founder effect. Hum Mutat. 2010;31:143-150.
18. Custodio G, Parise GA, Kiesel Filho N, et al. Impact of neona- tal screening and surveillance for the TP53 R337H mutation on early detection of childhood adrenocortical tumors. J Clin Oncol. 2013;31:2619-2626.
19. Gupta N, Rivera M, Novotny P, Rodriguez V, Bancos I, Lteif A. Adrenocortical carcinoma in children: a clinicopathological analy- sis of 41 patients at the Mayo Clinic from 1950 to 2017. Horm Res Paediatr. 2018;90:8-18.
20. RARECAREnet-Information Network on Rare Cancers. RARECAREnet study-data source and methods. http://www. rarecarenet.eu. Accessed September 10, 2018.
21. de Vries E, Steliarova-Foucher E, Spatz A, Ardanaz E, Eggermont AM, Coebergh JW. Skin cancer incidence and survival in European children and adolescents (1978-1997). Report from the Automated Childhood Cancer Information System project. Eur J Cancer. 2006;42:2170-2182.
22. Surveillance, Epidemiology, and End Results Program, National Cancer Institute. SEER Program Code Manual. 3th ed. Bethesda: National Cancer Institute; 1998. NIH publication n.98-2313.
23. Balmant NV, de Souza Reis R, Pinto Oliveira JF, Ferman S, de Oliveira Santos M, de Camargo B. Cancer incidence among adoles- cents and young adults (15 to 29 years) in Brazil. J Pediatr Hematol Oncol. 2016;38:e88-e96.
24. Sarasin A, Stary A. Human cancer and DNA repair-deficient dis- eases. Cancer Detect Prev. 1997;21:406-411.
25. Kraemer KH, DiGiovanna JJ. Forty years of research on xeroderma pigmentosum at the US National Institutes of Health. Photochem Photobiol. 2015;91:452-459.
26. Munford V, Castro LP, Souto R, et al. A genetic cluster of patients with variant xeroderma pigmentosum with two different founder mutations. Br J Dermatol. 2017;176:1270-1278.
27. Linabery AM, Ross JA. Trends in childhood cancer incidence in the U.S. (1992-2004). Cancer. 2008;112:416-432.
28. Strouse JJ, Fears TR, Tucker MA, Wayne AS. Pediatric melanoma: risk factor and survival analysis of the Surveillance, Epidemiology and End Results database. J Clin Oncol. 2005;23:4735-4741.
29. Wong JR, Harris JK, Rodriguez-Galindo C, Johnson KJ. Incidence of childhood and adolescent melanoma in the United States: 1973- 2009. Pediatrics. 2013;131:846-854.
30. Horner MJ, Ries LA, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2006. Bethesda, MD: National Cancer Institute; 2009.
31. Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA. 2006;295:2164-2167.
32. Vergamini LB, Frazier AL, Abrantes FL, Ribeiro KB, Rodriguez- Galindo C. Increase in the incidence of differentiated thyroid carci- noma in children, adolescents, and young adults: a population-based study. J Pediatr. 2014;164:1481-1485.
33. Alston RD, Geraci M, Eden TO, Moran A, Rowan S, Birch JM. Changes in cancer incidence in teenagers and young adults (ages 13 to 24 years) in England 1979-2003. Cancer. 2008;113:2807-2815.
34. Morris LG, Sikora AG, Myssiorek D, DeLacure MD. The basis of racial differences in the incidence of thyroid cancer. Ann Surg Oncol. 2008;15:1169-1176.
35. Dermody S, Walls A, Harley EH Jr. Pediatric thyroid cancer: an update from the SEER database 2007-2012. Int J Pediatr Otorhinolaryngol. 2016;89:121-126.
36. Stiller CA. International variations in the incidence of childhood car- cinomas. Cancer Epidemiol Biomarkers Prev. 1994;3:305-310.
37. Sultan I, Casanova M, Ferrari A, Rihani R, Rodriguez-Galindo C. Differential features of nasopharyngeal carcinoma in children and adults: a SEER study. Pediatr Blood Cancer. 2010;55:279-284.
38. Arboleda LPA, Hoffmann IL, Cardinalli IA, Santos-Silva AR, de Mendonca RMH. Demographic and clinicopathologic distribution of head and neck malignant tumors in pediatric patients from a Brazilian population: a retrospective study. J Oral Pathol Med. 2018;47:696-705.
39. Vujanic GM, Sandstedt B, Kelsey A, Sebire NJ. Central pathology review in multicenter trials and studies: lessons from the nephroblas- toma trials. Cancer. 2009;115:1977-1983.
40. International Agency for Research on Cancer. Indicators of data quality. http://iicc.iarc.fr/includes/results/chapters/QualityIndicators. pdf. Accessed July 14, 2018.
41. Trama A, Marcos-Gragera R, Sanchez Perez MJ, et al; RARECARE working group contributing to the data quality study. Data quality in rare cancers registration: the report of the RARECARE data quality study. Tumori. 2017;103:22-32.