Global frequency and distribution of head and neck cancer in pediatrics, a systematic review

Journal Pre-proof Global frequency and distribution of head and neck cancer in pediatrics, a systematic review ´ Lady Paola Aristizabal Arboleda, Regina Maria Holanda de ˜ Lopez, Anna Lu´ıza Damaceno Mendonc¸a, Eliana Elisa Munoz ´ ´ Natalia Rangel Palmier, Mariana de Pauli Paglioni, Jessica Araujo, Montenegro Fonseca, Iva Loureiro Hoffmann, Izilda Aparecida ˜ Cardinalli, Aline L.F. Chaves, Saray Aranda, Tha´ıs Bianca Brandao, Marcio Ajudarte Lopes, Ana Carolina Prado Ribeiro, Cristhian Camilo Madrid Troconis, Alan Roger Santos-Silva

PII:

S1040-8428(20)30030-5

DOI:

https://doi.org/10.1016/j.critrevonc.2020.102892

Reference:

ONCH 102892

To appear in:

Critical Reviews in Oncology / Hematology

Received Date:

13 November 2019

Revised Date:

25 January 2020

Accepted Date:

29 January 2020

´ ˜ Lopez EE, Please cite this article as: Aristizabal Arboleda LP, de Mendonc¸a RMH, Munoz ´ AL, Rangel Palmier N, de Pauli Paglioni M, Montenegro Fonseca J, Damaceno Araujo ˜ TB, Lopes MA, Prado Loureiro Hoffmann I, Cardinalli IA, Chaves ALF, Aranda S, Brandao Ribeiro AC, Madrid Troconis CC, Santos-Silva AR, Global frequency and distribution of head and neck cancer in pediatrics, a systematic review, Critical Reviews in Oncology / Hematology (2020), doi: https://doi.org/10.1016/j.critrevonc.2020.102892

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Title: Global frequency and distribution of head and neck cancer in pediatrics, a systematic review

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Authors: Lady Paola Aristizábal Arboleda*a DDS, MSc; Regina Maria Holanda de Mendonçab DDS, MSc, PhD; Eliana Elisa Muñoz Lopezc,d DDS; Anna Luíza Damaceno Araújoa DDS, MSc; Natalia Rangel Palmiera DDS, MSc; Mariana de Pauli Paglionia DDS, MSc, PhD; Jéssica Montenegro Fonsecaa DDS, MSc; Iva Loureiro Hoffmannb MD; Izilda Aparecida Cardinallib MD, PhD; Aline L. F. Chavese MD, MSc; Saray Arandaf DDS, MSc, PhD; Thaís Bianca Brandãog DDS, MSc, PhD; Marcio Ajudarte Lopesa, DDS, MSc, PhD; Ana Carolina Prado Ribeiroa,g DDS, MSc, PhD; Cristhian Camilo Madrid Troconish DDS, MSc; Alan Roger Santos-Silvaa, DDS, MSc, PhD

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Affiliations: aOral Diagnosis Department, Piracicaba Dental School, University of Campinas (UNICAMP), Piracicaba, São Paulo, Brazil; bBoldrini Children’s Center, Campinas, São Paulo, Brazil; cUniversidad Autónoma de Manizales (UAM), Manizales, Caldas, Colombia; dDental and Implant Center Smilingtek, Manizales, Caldas, Colombia; eDOM Oncologia, Divinopolis, Minas Gerais, Brazil; fUniversidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico; gSão Paulo State Cancer Institute (ICESP), São Paulo, Brazil; hDentistry Program, Health of Science Faculty, Corporación Universitaria Rafael Nuñez (CURN), Cartagena de Índias, Colômbia.

*

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Address correspondence to:

Lady Paola Aristizábal Arboleda* DDS, MSc. Oral Diagnosis Department

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Piracicaba Dental School, University of Campinas (UNICAMP) ORCID: 0000-0002-6090-1893

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Address: Av. Limeira, 901, Areão, Piracicaba, São Paulo – Brazil Postal code: 13414- 903 Phone number: (+5519) 98165 9751.0 E-mail: [[email protected]]

Highlights  

Lymphomas are the most prevalent head and neck cancer in pediatric patients. The distribution of head and neck cancer is impacted by geographic origin. 1

  

Neck and lymph nodes are hotspots for cancer in children. The incidence of head and neck cancer in pediatric patients is relatively low. Only a few studies on pediatric head and neck cancer were published so far.

Abstract Background: Incidence and mortality rates of childhood cancer represent a global public health issue, however, the worldwide prevalence of head and neck cancer

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in pediatric patients (HNCPP) is still unknown. Therefore, this study aimed to describe the frequency and distribution of HNCPP worldwide. Methods: A specific search strategy was performed using MEDLINE, Scopus, and EMBASE to include studies

based on hospital records, national cancer registries, and pathology files. Studies quality

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was assessed using the risk of bias checklist of the Joanna Briggs Institute Critical

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Appraisal. Results: Nineteen publications (15,970 cases) were included. Global frequency ranged from 0.25% to 15%. Male patients older than 10 years of age were

lymphoma, Hodgkin

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most affected by lymphomas, followed by carcinomas and sarcomas. Non-Hodgkin lymphoma, rhabdomyosarcoma, thyroid carcinoma,

and

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nasopharyngeal carcinoma were the main histopathological subtypes. Neck/lymph nodes were anatomical hotspots. Conclusions: This HNCPP global overview may guide

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secondary prevention strategies and future etiological studies.

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Keywords: Head; neck; cancer; malignancies; pediatrics; children; adolescents; epidemiology

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1. Introduction Worldwide, cancer represents one of the main causes of death among children

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and adolescents, and its overall incidence has been increasing (by 0.6% per year) since 1975. Despite leukemia representing the most frequent childhood cancer (29%), followed by central nervous system tumors (26%) and lymphomas (11%), some recent

reports have indicated an increase in the incidence of head and neck cancer in pediatric

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patients (HNCPP) [1-3]. In this context, some studies have demonstrated that head and

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neck cancer (HNC) ranges from 2% to 15% of all cancer cases in this segment of the population [3-6].

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HNC refers to a complex group of anatomical topographies that may be affected by a myriad of malignant tumors including squamous cell carcinoma, adenocarcinoma,

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lymphoma, rhabdomyosarcoma (RMS), neuroblastoma, nasopharyngeal carcinoma (NC), thyroid carcinoma (TC), and salivary gland carcinoma [7-9].

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The etiology of most HNCPP remains unknown. Thus, knowledge of the prevalence and distribution of certain types of malignancies in different regions of the

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world could generate new studies in search of the possible causes. However, only a few descriptive epidemiological studies have been published in the context of international literature [2-20]. Therefore, the aim of this systematic review was to synthesize the available literature to provide an actual summary of HNCPP worldwide, describing the frequency

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and clinicopathological distribution according to each geographic region, and thus to observe if there are any global differences. 2. Materials and methods This systematic review was reported accordingly by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines [21]. The study was registered with the PROSPERO database under the protocol number CRD42018088049(http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CR

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D42018088049). The review question defined was: “Are there any global differences in the distribution and prevalence of head and neck cancer in pediatric patients?” 2.1 | Inclusion and exclusion criteria

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Inclusion criteria comprised retrospective studies about HNCPP (0–19 years)

with demographic, histological type, and anatomic topography data. Studies published

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in the English, Portuguese, or Spanish language that were from a single referral

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institution, a national cancer registry, or a pathology archive were accepted. Exclusion criteria comprised studies focusing only on a histological subtype or anatomical site; malignant tumors located in different anatomical sites other than the head and neck;

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benign head and neck tumors; HNC in patients older than 19 years old; and tumors such as retinoblastomas, central nervous tumors, and metastases to the head and neck areas.

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Reviews, letters, personal opinions, book chapters, conferences, abstracts, posters,

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patents, case reports, and clinical trials were excluded. 2.2 | Information sources and search strategy The following electronic databases were assessed: PubMed/MEDLINE, Scopus,

and EMBASE. Regarding the search in the databases, three independent searches were done according to the following words: distribution OR frequency OR prevalence OR incidence; childhood OR children OR child OR adolescents OR pediatric*; 'head and

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neck cancer' OR 'head and neck malignant tumor*' OR 'head and neck malignancies' OR 'cancer of the head and neck' OR 'malignant tumor* of the head and neck'. Finally, the three options were mixed and the search strategy used was as follows: (((((((("head and neck cancer")) OR ("head and neck malignant tumor*")) OR ("head and neck malignancies")) OR ("cancer of the head and neck")) OR ("Malignant tumor* of the head and neck"))) AND (((((childhood) OR children) OR child) OR adolescents) OR Pediatric*)) AND ((((distribution) OR frequency) OR prevalence) OR incidence). All

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databases were searched up to September 2019. Reference lists of included articles were manually screened for additional potentially relevant studies. 2.3 | Study selection

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The titles and abstracts of all reports in the electronic searches were individually read by two investigators (L.P.A.A. and A.R.S.S.), excluding articles that clearly did not

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meet the eligibility criteria. The assessment of eligibility was guided by a flow diagram

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drawn on phase two of the quality assessment (Figure 1). The two reviewers proceeded with reading the full text of the articles screened to identify the eligible articles, and all the primary reasons for exclusions were registered for the composition of article

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selection flow. Rayyan QCRI was used as the reference manager to perform the screening of the articles, exclusion of duplicates, and registration of the primary reason

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for exclusion [22].

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2.4 | Data extraction We independently extracted the data from the studies through specific extraction

forms, utilizing the Microsoft Excel software. For each selected study, the following information was extracted (when available): year of publication, continent, country, study methodology, time period studied, number of cases, age range, mean age, the

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most affected age group, incidence of HNCPP, gender, histological tumor type, and anatomic topography. 2.5 | Risk of bias in individual studies The Joanna Briggs Institute has elaborated and validated a checklist for prevalence studies [23]. Therefore, the risk of bias was applied to all the selected articles; two reviewers (L.P.A.A. and A.R.S.S.) scored each item with “yes,” “no,” or “unclear,” and independently assessed each included study. Studies were characterized

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according to the following: (a) low risk of bias, if studies reached more than 70% scores of “yes”; (b) moderate risk of bias, if “yes” scores were between 50% and 69%; and (c) high risk of bias, if “yes” scores were below 49%.

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3. Results 3.1 | Literature search

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The study selection process is summarized in Figure 1. The searches in the

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databases initially resulted in 2,568 publications. Supplementary searching of the reference list generated 5 additional papers. A total of 772 papers were found to be duplicated and were therefore excluded. Following the assessment of the titles and

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abstracts, 1,730 papers were excluded, because they were not related to the subject. The analyses of the remaining 71 articles (by reading the full texts) resulted in the exclusion

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of 52 papers, because they did not meet the inclusion criteria. Therefore, a total of 19

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studies were included in the statistical analysis.

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Figure 1. Flow diagram of literature search adapted from PRISMA

3.2 | Risk of bias

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Seven studies fulfilled all the methodological criteria based on the sum of the 9

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applicable items by the Joanna Briggs Institute critical appraisal tool for prevalence studies. Thirteen of the studies were evaluated as low risk of bias [2-9,11,14-16,18]. Five studies were judged as moderate risk [10,13,17,19,20]. One study had a high risk of bias [12]. Limitations in some criteria, such as topographic description and the correlation between the demographic and tumor characteristics, were observed in most

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studies. Descriptions of the incidence of HNCPP was the main category absent in several studies. Details are described in Table 1. Q1 Q2 Q3 Q4 Q5 Q6

Q7

Q8

Q9

Abdulai et al.,10 2012 Das et al.,11 2011 Al Yamani et al.,12 2011 Fattahi et al.,13 2015 Khademi et al.,14 2009 Levi et al.,15 2017 Sengupta et al.,8 2009 Gosepath et al.,9 2007 Grønhøj et al.,16 2018 Rapidis et al.,4 1988 Lilja-Fischer et al.,6 2019 Arboleda et al.,5 2018 De Melo et al.,17 2010 Robinson et al.,7 1988 Cunningham et al.,18 1987 Schwartz et al.,3 2915 Albright et al.,2 2002 Hayes.,19 1937 Akinyele et al.,20 2012

Y Y N

Y Y U

Y Y N

Y Y Y

U Y Y

Y Y Y

U Y Y

U U U

Y Y Y Y Y Y Y Y

U Y Y Y Y Y Y Y

Y Y Y Y Y Y Y Y

Y Y Y Y Y Y Y Y

Y N Y N Y Y Y Y

Y Y Y Y Y Y Y Y

Y Y Y Y Y Y Y Y

U U Y U Y Y U Y

Y N Y Y

Y Y Y Y

Y N Y Y

Y Y Y Y

Y N Y Y

Y Y Y Y

Y Y Y Y

Y Y U Y

Y Y Y Y

Y Y U Y

Y Y N Y

Y Y Y Y

U Y Y Y Y Y Y Y

66.6 77.7 100.0 77.7 100.0 100.0 88.8 100.0

Moderate Low Low Low Low Low Low Low

Moderate Low High

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Y Y Y Y

100.0 55.5 88.8 88.8

Low Moderate Low Low

Y Y Y U

Y Y N U

Y Y Y U

100.0 100.0 55.5 66.6

Low Low Moderate Moderate

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Y Y Y Y

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Risk of bias

U U U

Total (% score yes) 55.5 77.7 44.4

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Study

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Note: Q1. Was the sample frame appropriate to address the target population? Q2. Were study participants sampled in an appropriate way? Q3. Was the sample size adequate? Q4. Were the study subjects and the setting described in detail? Q5. Was the data analysis conducted with sufficient coverage of the identified sample? Q6. Were valid methods used for the identification of the condition? Q7. Was the condition measured in a standard, reliable way for all participants? Q8. Was there appropriate statistical analysis? Q9. Was the response rate adequate, and if not, was the low response rate managed appropriately? Abbreviations: N, no; U, unclear; Y, yes.

Table 1. Risk of bias assessed by the Joanna Briggs Institute critical appraisal tool for prevalence studies

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3.3 | Description of the studies and demographic analysis Nineteen papers published from 1937 to 2019 were included in this systematic review and in the statistical analysis, representing a total of 15,970 patients. Each continent, with the exception of Oceania, was represented by HNCPP studies, including Africa, [10,20] Asia, [8,11-15] Europe, [4,6,9,16], and America [2,3,5,7,17-19]. Figure 2 shows the worldwide distribution of the 19 studies on HNCPP included in the

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systematic review. All studies were retrospective, 13 of them were performed in single institutions, and six were performed through national cancer registries. The time period analyzed in the studies ranged from 3 years to 41 years. The number of patients

analyzed in each study varied from 10 cases to 10,214 cases. The frequency of HNCPP

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was described by seven authors, and the percentage ranged from 0.25% to 15%. Male

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patients were more affected by HNC in 7 studies, one study showed equal gender results, and female patients were more affected in 2 studies. The mean age at diagnosis

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ranged from 5.2 years to 14 years, being analyzed in patients younger 19 years of age. In most studies, the main age group affected by HNC was pediatric patients over 10

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years of age, 4 studies were more prevalent for the age group of 10–14 years, 7 studies ranged from 10 years to 19 years, and HNC was more common in patients younger than

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2 years old in 1 study. The general descriptive characteristics of the included studies are

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summarized in Table 2.

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Figure 2. Worldwide distribution of HNCPP studies.

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Table 2. Summary of descriptive characteristics of included studies Source of the retrospective study

Time period (years)

No. of samples

Incide nce

Africa10 Africa20 Asia11 Asia12

Single institution Single institution Single institution Single institution

20 18 10 11

186 101 56 12

-

Asia13

Ghana Nigeria India Saudi Arabia Iran

Single institution

10

51

Asia14 Asia15

Iran Israel

7 41

136 357

Asia8

India

Single institution National Cancer Registry Single institution

Europe9

Germany

9

Europe16

Denmark

Europe6

Denmark

Europe4 South America5 South America17 North America7 North America18 North America3 North America2 North America19

Greece Brazil

National Cancer Registry National Cancer Registry National Cancer Registry Single institution Single institution

Brazil

Age range (years)

Mean age (years)

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Country

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Continent

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≤ 16 ≤ 15 ≤ 18 ≤ 18

The most affected age group (years)

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12-16 11-15 16-18

Gender Male (%) Female (%) 121 (65) 65 (35) 6 (50) 6 (50)

≤ 12

5.2 ± 3.9

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34 (66.7)

9.10% -

≤ 19 ≤ 19

12 12.5 ± 5.3

15-19 14-19

53

0.25%

≤ 12

-

10-12

215 (60.2) 34 (64.4)

370

7.3%

≤ 15

-

10-14

36

169

-

≤ 14

10

10-14

199 (53.8) 75 (44.3)

10

85

15%

≤ 15

6.1

-

49 (58)

17 (33.3) 142 (39.8) 19 (35.6) 171 (46.2) 94 (55.6) 36 (42)

20 30

308 367

2.39% 5.11%

≤ 19

9.35 ± 4.78

10-14

Single institution

5

23

-

2-17

13

13-18

241 (65.7) -

126 (34.3) -

USA

Single institution

15

147

-

≤ 18

-

<2

-

-

USA

Single institution

20

241

-

≤ 19

-

-

-

-

USA

National Cancer Registry National Cancer Registry Single institution

37

10,214

11.9%

≤ 15

-

-

-

-

23

3,050

12%

≤ 19

10.4

15-18

7

44

-

-

-

-

1,432 (47) -

1,618 (53) -

USA

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-

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3.4 | Histological types of HNCPP by continent Table 3 shows the histopathological distribution of HNCPP according to each geographic region. Two studies in Africa found that lymphoma was the main cancer type (102 [54.8%], 50 [49.5%],) [10,20]. Three out of six studies in Asia found lymphoma was the most common type of cancer (23 [43.4%], 27 [52.9%], and 83 [61%]) [8,13,14]; carcinomas were the main cancer type in two studies (45 [80.4%] and 179 [50.1%]) [11,15]. Sarcomas showed equal frequency with lymphomas in another

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Asian study (6 [50%]) [12]. Four studies were found in Europe, lymphoma was the main cancer type in two of them (160 [51.9%], 25 [29.4%]) [4,6], followed by sarcomas

(148 [40%]) [9], and carcinomas (96 [56.8%]) [16]. America was the continent with the

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most studies, five of them being from North America, while South America had two

studies. Carcinomas were the main cancer type (866 [28.4%], 3412 [33.4%], 11

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[47.8%], and 18 [40.9%]) [2,3,17,19] followed by lymphomas (194 [52.9%], 51

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[34.7%], and 143 [59.3%]) [5,7,18]. Figure 3 shows the main histopathological origin

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of each study.

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Figure 3. The main histopathological type of HNCPP per continent.

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Table 3. Histopathological distribution of HNCPP according with each geographic region.

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Israel15 No. (%) 74 (20.7) 0 0 0 0 0 0 0 0 0 179 (50.1) 0 0 0 0 0 0 0 0 0 0 0 0 0 40 (11.2) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 64 (17.9) 357 (100)

India8 No. (%) 23 (43.4) 9 (17) 14 (26.4) 0 0 0 0 0 0 0 15 (28.3) 8 (15.1) 4 (7.5) 3 (5.7) 0 0 0 0 0 0 0 0 0 0 11 (20.8) 11 (20.8) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 (3.8) 0 0 2 (3.8) 0 0 0 0 0 0 0 0 0 2 (3.8) 53 (100)

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Asia Iran13 Iran14 No. (%) No. (%) 27 (52.9) 83 (61) 13 (25.5) 38 (27.9) 14 (27.5) 45 (33) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 30 (22.1) 0 11 (8.1) 0 0 0 16 (11.8) 0 1 (0.7) 0 0 0 0 0 3 (2.2) 0 1 (0.7) 0 11 (8.1) 0 2 (1.5) 0 0 0 0 0 1 (0.7) 8 (15.7) 16 (11.8) 3 (5.9) 9 (6.6) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 (0.7) 0 0 0 0 0 0 0 4 (2.9) 0 0 0 2 (1.5) 5 (9.8) 0 8 (15.7) 7 (5.1) 0 2 (1.5) 0 0 8 (15.7) 5 (3.7) 0 0 0 2 (1.5) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 8 (15.7) 0 51 (100) 136 (100)

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India11 Saudi Arabia12 No. (%) No. (%) 0 6 (50) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 45 (80.4) 0 13 (23.2) 0 22 (39.3) 0 5 (8.9) 0 3 (5.4) 0 1 (1.8) 0 0 0 0 0 0 0 1 (1.8) 0 5 (8.9) 0 0 0 0 0 0 0 9 (16.1) 6 (50) 7 (12.5) 2 (16.7) 0 0 0 3 (25) 0 0 0 0 0 0 0 0 0 0 0 0 1 (1.8) 0 0 0 0 0 0 0 1 (1.8) 1 (8.3) 0 0 0 0 0 0 2 (3.6) 0 0 0 0 0 2 (3.6) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 56 (100) 12 (100)

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Africa Ghana10 Nigeria20 No. (%) No. (%) Lymphomas 102 (54.8) 50 (49.5) Hodgkin lymphoma 34 (18.3) 10 (9.9) Non-Hodgkin lymphoma 68 (36.6) 40 (39.6) Burkitt lymphoma 22 (11.8) 26 (25.7) Diffuse larg B-cell lymphoma 0 0 Lymphoblastic lymphoma 0 0 Anaplastic large B cell lymphoma 0 0 Follicular lymphoma 0 0 Peripheral T-cell lymphoma 0 0 Other lymphomas 0 14 (13.9) Carcinomas 47 (25.3) 25 (24.7) Nasopharyngeal Carcinoma 37 (19.9) 1 (0.9) Thyroid carcinoma 4 (2.2) 0 Salivary gland carcinoma 2 (1.1) 0 Mucoepidermoid carcinoma 1 (0.5) 5 (4.9) Acinic Cell Carcinoma 0 0 Sebaceous Adenocarcinoma 0 0 Adenoid Cystic Carcinoma 1 (0.5) 0 Epithelial-Myoepithelial Carcinoma 0 0 Adenocarcinoma, NOS 0 0 Squamous Cell Carcinoma 3 (1.6) 15 (14.8) Embryonal Carcinoma 0 0 Basal cell carcinoma 0 0 Other Carcinomas 1 (0.5) 4 (3.9) Sarcomas 30 (16.1) 25 (24.7) Rhabdomyosarcoma 26 (14.0) 18 (17.8) Rhabdoid sarcoma 0 0 Fibrosarcoma 1 (0.5) 0 Infantile fibrosarcoma 0 0 Infantile Myofibrosarcoma 0 0 Myxoid liposarcoma 0 0 Malignant histiocytoma 0 0 Malignant fibrohistiocytoma 1 (0.5) 0 Synovial sarcoma 0 0 Angiosarcoma 0 0 Leiomyosarcoma 1 (0.5) 0 Kaposi's Sarcoma 0 0 Neurogenic sarcoma 0 0 Ewing sarcoma 1 (0.5) 0 Chondrosarcoma 0 0 Osteosarcoma 0 6 (5.9) Other sarcomas 0 1 (0.9) Embryonal tumors 5 (2.7) 0 Primitive neuroectodermal tumor 2 (1.1) 0 Olfactory neuroblastoma 0 0 Neuroblastoma 2 (1.1) 0 Atypical teratoid / rabdoid tumour 0 0 Other embryonal tumors 1 (0.5) 0 Melanoma 0 1 (0.9) Germ cells 1 (0.5) 0 Immature teratoma 0 0 Malignant teratoma 1 (0.5) 0 Endodermal sinus tumor 0 0 Teratocarcinoma 0 0 Unspecified germ cell tumours 0 0 Other tumors 1 (0.5) 0 TOTAL 186 (100) 101 (100) Histologic Types

Germany9 No. (%) 79 (21.4) 2 (0.5) 77 (20.8) 17 (4.6) 0 0 0 0 0 0 135 (36.5) 23 (6.2) 102 (27.6) 0 0 0 0 0 0 0 0 0 0 10 (2.7) 148 (40.0) 103 (28.6) 0 0 0 0 0 0 0 0 0 0 0 0 0 1 (0.3) 0 0 7 (1.9) 0 0 0 0 7 (1.9) 0 1 (0.3) 0 0 0 0 1 (0.3) 0 370 (100)

Europe Denmark16 Denmark6 No. (%) No. (%) 0 25 (29.4) 0 13 (15.2) 0 12 (14.1) 0 5 (5.8) 0 0 0 0 0 0 0 0 0 0 0 0 96 (56.8) 3 (3.5) 5 (2.9) 0 47 (27.8) 3 (3.5) 23 (13.6) 0 17 (10.1) 0 3 (1.8) 0 0 0 3 (1.8) 0 0 0 0 0 3 (1.8) 0 0 0 0 0 18 (10.7) 0 73 (43.2) 20 (23.5) 48 (28.4) 6 (7.0) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 25 (14.8) 14 (16.4) 0 4 (4.7) 0 0 0 0 0 4 (4.7) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 33 (38.8) 169 (100) 85 (100)

Greece4 No. (%) 160 (51.9) 82 (26.6) 78 (25.3) 0 0 0 0 0 0 0 31 (10.1) 0 12 (3.9) 1 (0.3) 1 (0.3) 0 0 0 0 0 18 (5.8) 0 0 0 97 (31.5) 68 (22.1) 0 0 13 (4.2) 0 0 8 (2.6) 0 0 0 0 2 (0.6) 0 0 0 0 6 (1.9) 18 (5.8) 0 0 18 (5.8) 0 0 0 0 0 0 0 0 0 2 (0.6) 308 (100)

South America Brazil5 Brazil17 No. (%) No. (%) 194 (52.9) 4 (17.4) 90 (24.5) 0 104 (28.3) 4 (17.4) 61 (16.6) 1 (4.3) 17 (4.6) 1 (4.3) 13 (3.5) 1 (4.3) 7 (1.9) 0 2 (0.5) 0 1 (0.3) 0 3 (0.8) 1 (4.3) 83 (22.6) 11 (47.8) 47 (12.8) 5 (21.7) 23 (6.3) 0 11 (3) 1 (4.3) 5 (1.4) 1 (4.3) 2 (0.5) 0 1 (0.3) 0 1 (0.3) 0 1 (0.3) 0 1 (0.3) 0 1 (0.3) 2 (8.7) 1 (0.3) 0 0 2 (8.7) 0 1 (4.3) 70 (19.1) 8 (34.8) 47 (12.8) 7 (30.4) 2 (0.5) 0 0 0 2 (0.5) 0 1 (0.3) 0 1 (0.3) 0 0 0 0 0 1 (0.3) 0 0 0 0 0 0 0 0 0 6 (1.6) 0 5 (1.4) 0 2 (0.5) 0 3 (0.8) 1 (4.3) 10 (2.7) 0 5 (1.4) 0 2 (0.5) 0 2 (0.5) 0 1 (0.3) 0 0 0 5 (1.4) 0 4 (1.1) 0 2 (0.5) 0 0 0 1 (0.3) 0 1 (0.3) 0 0 0 1 (0.3) 0 367 (100) 23 (100)

USA7 No. (%) 51 (34.7) 31 (21.1) 20 (13.6) 8 (5.4) 0 1 (0.7) 0 0 0 0 2 (1.4) 1 (0.7) 1 (0.7) 0 0 0 0 0 0 0 0 0 0 0 32 (21.8) 26 (17.7) 0 0 0 0 0 0 0 0 0 0 0 0 2 (1.4) 0 0 4 (2.7) 14 (9.5) 0 0 14 (9.5) 0 0 0 0 0 0 0 0 0 48 (32.7) 147 (100)

USA18 No. (%) 143 (59.3) 85 (35.3) 58 (24.1) 7 (2.9) 0 29 (12) 0 0 0 22 (9.1) 42 (17.4) 12 (5) 24 (10) 6 (2.5) 4 (1.7) 0 0 0 0 2 (0.83) 0 0 0 0 42 (17.4) 31 (12.9) 0 1 (0.4) 0 0 0 0 1 (0.4) 1 (0.4) 0 0 0 1 (0.4) 2 (0.8) 3 (1.2) 1 (0.4) 1 (0.4) 12 (5) 0 0 12 (5) 0 0 0 2 (0.8) 0 2 (0.8) 0 0 0 0 241 (100)

North America USA3 USA2 No. (%) No. (%) 2432 (23.8) 816 (26.8) 1407 (13.8) 515 (16.9) 1025 (10) 301 (9.9) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 3412 (33.4) 866 (28.4) 0 0 2767 (27.1) 652 (21.4) 507 (5.0) 160 (5.2) 271 (2.7) 82 (2.7) 133 (1.3) 36 (1.2) 0 0 38 (0.4) 8 (0.3) 0 0 65 (0.6) 34 (1.1) 138 (1.4) 54 (1.8) 0 0 0 0 0 0 1273 (12.5) 428 -14 745 (7.3) 239 (7.8) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 76 (0.7) 20 (0.7) 45 (0.4) 13 (0.4) 98 (1.0) 21 (0.7) 309 (3.1) 135 (4.4) 257 (2.5) 209 (6.9) 0 0 0 0 115 (1.1) 48 (1.6) 0 0 142 (1.4) 161 (5.3) 526 (5.1) 132 (4.3) 70 (0.7) 18 (0.6) 0 0 0 0 0 0 0 0 0 0 2244 (21.9) 581 (16.3) 10214 (100) 3050 (100)

USA19 No. (%) 2 (4.5) 0 0 0 0 0 0 0 0 2 (4.5) 18 (40.9) 7 (15.9) 3 (6.8) 0 0 0 0 0 0 0 2 (4.5) 0 2 (4.5) 4 (9.1) 8 (18.2) 0 0 0 0 0 0 0 0 0 0 0 0 1 (2.3) 0 0 2 (4.5) 5 (11.3) 0 0 0 0 0 0 0 0 0 0 0 0 0 16 (36.3) 44 (100)

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According to histopathological subtypes, the most common diagnosis in Africa was nonHodgkin lymphoma (NHL) (68 [36.6%], 40 [39.6%]) [10,20], Asian studies showed a predisposition to three histopathological subtypes: NHL (14 [26.4%], 14 [27.5%], and 45 [33%]) [9,13,14], followed by fibrosarcoma (3 [25%]) [12], and TC (22 [39.3%]) [11]. RMS (103 [28.6%], (48 [28.4%]) [9,16] and Hodgkin lymphoma (HL) (82 [26.6%], 13 [15.2%]) [4,6] were the main category in the European studies. The most common histopathological subtypes in America were HL (31 [21.1%], 85 [35.3%]) [7,18], and TC (652 [21.4%]), 2767 [27.1%]) [2,3], followed by NHL (104

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[28.3%]) [5], RMS (7 [30.4%]) [17], and NC (7 [15.9%]) [19]. Figure 4 shows the main

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histopathological subtypes of each study.

Figure 4. The main histopathological subtype of HNCPP per continent

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3.5 | Anatomic topography of HNCPP by continent Neck and lymph nodes were the leading site category in Africa (74 [39.8%]) [10] followed by odontogenic and maxillofacial bone (30 [29%]) [20]. Asian studies showed different topographic distributions, including thyroid gland (23 [41.1%]) [11]; neck and lymph nodes (69 [50.7%]) [14]; and nasopharynx (151 [42.3%]) [15]. Two studies from Europe demonstrated higher prevalence for the thyroid gland (104 [28.1%]) [9], and neck and lymph nodes (180 [58.4%]) [4]. Neck and lymph nodes were the main anatomic topography in two American studies (152 [41.4%], 147 [61%]) [5;18].

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Oral cavity and mobile tongue (6 [26.1%]) [17], thyroid gland (673 [22.1%]) [2], and nasopharynx (7 [15.9%]) [19] were also prevalent topographies among American studies. Table 4 shows the topography distribution among the geographic regions. HL was the main cancer type affecting the

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neck and lymph nodes [4,5,14,18]. NC was the most frequent histopathological diagnosis in the nasopharynx [4,5,9,11,14,18]. RMS and NHL were the most frequent histopathological subtype in

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the nasal cavity, paranasal sinuses, and skull base category [4,5,9,14]. RMS, and NHL were the main

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cancer types in the odontogenic and maxillofacial bone [4,5,11,18]. Table 5 shows the correlation between histopathological subtypes and the main four anatomical topographies affected by each

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author.

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Table 4. Topography distribution of HNCPP among geographic region

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Israel15 No. (%) 0 151 (42.3) 0 0 0 0 0 0 0 48 (13.45) 0 73 (20.4) 0 85 (23.8) 0 0 0 0 0 0 0 0 0 0 357 (100)

Europe Germany9 Greece4 No. (%) No. (%) 0 180 (58.4) 63 (17) 35 (11.4) 104 (28.1) 12 (3.9) 11 (3) 24 (7.8) 2 (0.5) 0 1 (0.3) 0 8 (2.2) 6 (1.9) 28 (7.6) 6 (1.9) 0 9 (2.9) 40 (10.8) 0 0 10 (3.2) 12 (3.2) 1 (0.3) 79 (21.4) 0 15 (4.1) 5 (1.6) 4 (1.1) 0 3 (0.8) 0 0 0 5 (1.4) 0 0 0 3 (0.8) 0 0 0 5 (1.4) 20 (6.5) 0 0 2 (0.5) 0 370 (100) 308 (100)

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Asia Iran14 No. (%) 69 (50.7) 19 (14.0) 4 (2.9) 0 0 0 4 (2.9) 12 (8.8) 0 4 (2.9) 8 (5.9) 9 (6.6) 0 0 0 0 0 0 0 0 0 0 0 7 (5.1) 136 (100)

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India11 No. (%) 0 13 (23.2) 23 (41.1) 0 0 0 0 0 0 0 1 (1.8) 5 (8.9) 0 0 0 0 0 0 0 0 5 (8.9) 0 0 9 (16.1) 56 (100)

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Africa Ghana10 Nigeria20 No. (%) No. (%) Neck and lymph nodes 74 (39.8) 21 (21) Nasopharynx 23 (12.4) 30 (29) Thyroid gland 2 (1.1) 0 Pharynx 0 0 Larynx 0 0 Trachea 0 0 Nasal cavity 0 0 Paranasal sinus 0 0 Skull base 0 0 Oropharynx (base of tongue, Tonsils, Adenoids) 0 0 Odontogenic and maxillofacial bone 20 (10.8) 37 (37) Salivary glands 4 (2.2) 0 Orbit 0 0 Oral cavity and mobile tongue 0 0 Buccal mucosa 0 0 Palate 0 0 Nasolabial region 0 0 Tongue 0 0 Lips 0 0 Floor of the mouth 0 0 Parapharyngeal space 0 0 Ear 0 0 Skin 0 0 Not specified 63 (33.9) 13 (13) Total 186 (100) 101 (100) Anatomic topography

South America Brazil5 Brazil17 No. (%) No. (%) 152 (41.4) 0 84 (22.9) 5 (21.7) 24 (6.5) 0 0 0 0 0 0 0 12 (3.3) 0 7 (1.9) 1 (4.3) 2 (0.5) 0 21 (5.7) 2 (8.7) 21 (5.7) 3 (13) 17 (4.6) 4 (17.4) 9 (2.5) 1 (4.3) 6 (1.6) 6 (26.1) 3 (0.8) 1 (4.3) 2 (0.5) 1 (4.3) 1 (0.3) 0 0 3 (13) 0 1 (4.3) 0 0 5 (1.4) 0 4 (1.1) 1 (4.3) 3 (0.8) 0 0 0 367 (100) 23 (100)

North America USA18 USA2 USA19 No. (%) No. (%) No. (%) 147 (61) 0 1 (2.3) 37 (15.4) 143 (4.7) 7 (15.9) 24 (10) 673 (22.1) 3 (6.8) 0 9 (0.3) 0 0 4 (0.1) 0 0 3 (0.1) 0 0 20 (0.7) 0 0 45 (1.5) 1 (2.3) 0 0 0 0 54 (1.8) 1 (2.3) 6 (2.5) 0 5 (11.4) 7 (2.9) 124 (4.1) 2 (4.5) 14 (5.8) 120 (3.9) 2 (4.5) 2 (0.8) 65 (2.1) 3 (6.8) 0 0 0 0 0 2 (4.5) 0 0 0 2 (0.8) 0 1 (2.3) 0 0 0 0 0 0 0 0 0 4 (1.7) 15 (0.5) 0 0 0 5 (11.4) 0 1775 (58.2) 14 (31.8) 241 (100) 3050 (100) 44 (100)

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Table 5. Histopathological subtypes affecting the main four anatomical topographies in pediatric patients.

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USA18 Brazil5 Greece4 Germany9 Iran14 India11 No. (%) No. (%) No. (%) No. (%) No. (%) No. (%) 85 (35.3) 87 (23.7) 82 (26.6) 38 (27.9) 40 (16.6) 47 (12.8) 46 (14.9) 22 (16.2) 12 (5.0) 2 (0.5) 16 (5.2) 5 (3.7) 2 (0.8) 3 (0.8) 18 (5.8) 1 (0.7) 6 (2.5) 1 (0.3) 1 (0.3) 1 (0.7) -

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Topography/ Tumor type Neck and lymph nodes Hodgkin lymphoma Non-Hodgkin lymphoma Neuroblastoma Rhabdomyosarcoma Atypical teratoid / rabdoid tumour Squamous Cell Carcinoma Nasopharynx Nasopharyngeal Carcinoma Non-Hodgkin lymphoma Rhabdomyosarcoma Nasal cavity, paranasal sinuses and skull base Rhabdomyosarcoma Non-Hodgkin lymphoma Ewing sarcoma Chondrosarcoma Odontogenic and maxillofacial bone Rhabdomyosarcoma Osteosarcoma Non-Hodgkin lymphoma Ewing sarcoma Chondrosarcoma

(5.0) (6.2) (3.7)

2 1 1 1

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Pr

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12 15 9

47 (12.8) 13 16 (4.4) 6 16 (4.4) 11

(4.2) (1.9) (3.6)

23 12 21

(6.2) (3.2) (5.7)

11 6 1

(8.1) (4.4) (0.7)

13 (23.2) -

-

10 1 1 2

(2.8) (0.3) (0.3) (0.5)

11 3 0

(3.6) (1.0) -

23 4 1

(6.2) (1.1) (0.3)

6 5 2 -

(4.4) (3.7) (1.5) -

-

-

(0.8) (0.4) (0.4) (0.4)

2 1 7 4 2

(8.7) (0.3) (1.9) (1.1) (0.5)

4 -

(1.1) -

-

-

-

-

2 3 3 -

(1.5) (2.2) (2.2) -

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4. Discussion This is the first systematic review that investigates the worldwide demographic, clinicopathological distribution, and frequency of HNCPP. Throughout this review, we provide an overview of the different patterns of cancer that affect the head and neck region in the pediatric population of several places around the world. Epidemiological studies on pediatric cancer, which specifically cover the head and neck region, are scarce. In this way, only 19 studies met the inclusion criteria, and

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most of them presented heterogeneous results. Some methodological factors can generate important differences in the number of cases in each study; thus, studies

conducted within large national databases or studies from referring institutions covering

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a long period of time, have become key studies to assess the distribution and frequency of different types of cancer.

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Identifying the incidence of HNCPP presented a great challenge, as only a few

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studies have reported the incidence compared to the overall number of pediatric cancer [2-6,8,9,16]. Despite the low incidence found in the studies (0.25% to 15%), we can observe that specific anatomical regions such as neck/lymph nodes, nasopharynx and

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thyroid gland represent target topographies for the development highly frequent malignancies such as lymphomas, NC, and TC in American countries and Africa

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[2,3,5,10,16]. Future studies of HNCPP should be performed comparing the incidence

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with the overall cancer in pediatrics, and thus determine if HNC contributes to the increased incidence of whole childhood cancer. However, in the United States, it has been observed that the incidence rate of HNCPP has increased proportionally with the overall increase of childhood cancer [3]. Interestingly, the male gender was more prevalent in most studies, accounting for approximately 60% of the cases [5,8-10,13,15]. However, incidence increases in

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females between 10 to 14 years, unlike males, who are most affected between 0 and 9 years [9,16]. Only two studies showed a higher percentage in female patients, which was due to TC being predominant in females [2,16]. Regarding age, it is possible to conclude that patients between the ages of 10 and 19 are more likely to be affected by HNC. These results can be attributed to the high incidence of tumors such as HL and carcinomas [5,9,12,16,17]. The heterogeneity of studies regarding the classification of age groups, makes the analysis and comparison difficult; therefore, standardization in

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epidemiological studies of childhood cancer is necessary. Due to the incidence of some types of tumors in certain age groups, it is recommended to separate into the following groups: younger than 1 year old, 1–4 years old, 5–9 years old, 10–14 years old, and 15–

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19 years old [5,9,16,24].

America and Asia were the two continents with the highest number of studies;

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however, the distribution was concentrated in countries such as India, Iran, and the

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United States [2,3,7,8,11,13,14,18,19]. These results demonstrate the need to investigate HNCPP in other countries in order to correlate risk factors with the incidence of different types of HNC worldwide. Although Africa had only two studies according to

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the inclusion criteria, it is well recognized that there is a high incidence of lymphomas, mainly because Burkitt's lymphoma is endemic in this continent, with the orofacial

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region being the most affected [20,25].

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Europe had relevant studies on the incidence of HNCPP with national coverage for Germany and Denmark [6,9,16]. Of the 4 studies, 2 of them showed predominance for lymphomas [4,6]; however, the incidence of lymphomas may be underestimated, since the other two studies excluded this malignancy totally or partially, because they were nonspecific head and neck neoplasms [9-16]. Despite these results, we can observe that sarcomas, specifically the group of rhabdomyosarcomas, are responsible for a

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significant increase in incidence of HNCPP. Asia was a continent with very discrepant results among the six studies. Despite this, unlike Europe, Asian studies show a low prevalence for sarcomas, with lymphomas and carcinomas being the main types of cancer [8,11,13-15]. Similar to Africa, NHL seems to be the most common histological subtype in Asian pediatric patients [8,13,14]. Brazil was the only country in South America with 2 studies, they showed significant differences in sample and study time. Despite their methodological

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differences, lymphomas were more prevalent in both studies, followed by carcinomas and sarcomas [5,17] It is necessary to know the HNCPP profile in other countries in South America, where socioeconomic, cultural, environmental and genetic factors may

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be associated with the development of different types of HNC. All studies of North America were conducted in the United States, and most of them were carried out

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through national databases. The continent had a higher incidence of carcinomas,

two large studies [2,3].

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followed by lymphomas, and sarcomas. These results were due to the high TC index in

Regarding to the exclusion of topographies and some histological origins

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performed by some authors, we think that HNC studies should include all topographies that are part of this region, except for central nervous system tumors, since pediatric

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patients are affected by a myriad of histopathological subtypes, which should be

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considered. In addition, regardless of the clinical specialty involved in HNCPP, knowledge of the distribution and clinical characteristics in this population may be useful in early diagnosis. Although the etiology of many types of HNCPP is still unknown, there are certain geographical regions that have risk factors for some histopathological subtypes, such as NC in southern China and BL in Africa. These two malignancies are associated

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with Epstein-Barr virus; however, there is evidence that the virus needs genetic and environmental support factors for tumor development [26,27]. The hypothesis that a low socioeconomic condition increases Epstein-Barr virus associated BL in developing countries has been demonstrated in a Brazilian study [28]. Epidemiological studies from several countries are necessary to confirm the different known risk factors for each malignancy and to search for possible new causes of HNCPP. Restricted demographic data, old histopathological classifications, lack of

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standardization in age groups and anatomical topographies, and absence of HNCPP studies in other countries were some limitations of this systematic review. 5. Conclusions

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HNCPP has not yet been widely studied worldwide; however, this systematic review provides an overview of the frequency and distribution of these malignancies in

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several countries. Although there is a discrete difference in the most common types of

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cancer in each continent, histological subtypes such as HL, BL, RMS, TC, NC are still the most common malignancies in the head and neck region of this population.

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Therefore, this study becomes the starting point for future epidemiological studies.

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Author contributions

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Dr. Santos-Silva, MSc Aristizabal, Dr. Brandão, Dr. Ribeiro, and Dr. Lopes performed the searches in the databases (excluding articles that clearly did not meet the eligibility criteria), read the full text of the articles, screened and identified the eligible articles, coordinated and supervised data collection, and critically reviewed the manuscript for important intellectual content. Dr. Hoffmann, Dr. Cardinalli, MSc Paglioni, MSc Fonseca, and MSc Troconis designed the data collection, performed the data extraction, and revised the manuscript.

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Dr. Mendonça, Dr. Muñoz, Dr. Chaves, Dr. Aranda, MSc Damaceno, and MSc Palmier conceptualized and designed the study, drafted the initial manuscript, and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Conflicts of interest: None to declare

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Acknowledgements The authors would like to gratefully acknowledge the financial support of the Coordination for the Improvement of Higher Education Personnel (CAPES/PROEX,

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Brazil) and the National Council for Scientific and Technological Development (CNPq, Brazil). The authors thank Dr. Gilberto de Castro Junior and Dr. William Nassib

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William Junior, members of the Latin American Cooperative Oncology Group - Head

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and Neck, for valuable discussions during the preparation of this manuscript.

1.

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Authors Vitae

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Lady Paola Aristizabal Arboleda: Master in Stomatopathology and PhD student. https://orcid.org/0000-0002-6090-1893 Regina Maria Holanda de Mendonça: Dentist at the Boldrini Children's Center, Master in Oncology and PhD in Child and Adolescent Health. http://lattes.cnpq.br/7958274718321840 Eliana Elisa Muñoz Lopez: Specialist in Stomatology and oral pathology professor. https://orcid.org/0000-0001-8469-5142 Anna Luíza Damaceno Araújo: Master in Stomatopathology and PhD student. https://orcid.org/0000-0002-3725-8051 Natalia Rangel Palmier: Master in Stomatopathology and PhD student. https://orcid.org/0000-0001-9588-6227 Mariana de Pauli Paglioni: Master and PhD in Stomatopathology. https://orcid.org/0000-0002-6588-9651 Jéssica Montenegro Fonseca: Master in Stomatopathology and PhD student. https://orcid.org/0000-0002-1217-7298 Iva Loureiro Hoffmann: Oncologist at the Boldrini Children's Center. https://orcid.org/0000-0001-5087-031X Izilda Aparecida Cardinalli: Medical pathologist at the Boldrini Children's Center. http://lattes.cnpq.br/2926594291872185 Aline Lauda Freitas Chaves: Specialist in Clinical Cancerology. Master of Health Sciences with emphasis on head and neck cancer. http://lattes.cnpq.br/0280904901482481 Saray Aranda: Stomatologist. Master and PhD in Biomedical Sciences. https://orcid.org/0000-0002-0379-9626 Thaís Bianca Brandão: Master in Oral and Maxillofacial Prosthesis and PhD in Stomatopathology. https://orcid.org/0000-0001-9128-3138 Marcio Ajudarte Lopes: Master and PhD in Oral Biology and Pathology. Professor of semiology and oral pathology. https://orcid.org/0000-0001-6677-0065 Ana Carolina Prado Ribeiro: Stomatologist and Researcher at the São Paulo State Cancer Institute. PhD in Stomatopathology. http://lattes.cnpq.br/9493624333917492 Cristhian Camilo Madrid Troconis: Master and PhD student in Dental Materials. https://orcid.org/0000-0003-4058-1447 Alan Roger Santos-Silva: Specialist in Stomatology and Oral Pathology; Master and PhD in Pathology. Professor of semiology and oral pathology. https://orcid.org/00000003-2040-6617

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