Background: The objectives of this study were to determine the minimum incidence of penile cancer in the poorest Brazilian state, and to describe the epidemiologic and clinical characteristics of patients diagnosed with the disease. Methods: A retrospective study of 392 patients diagnosed with penile cancer in the three most important referral center in the state was conducted during 2004–2014. Results: The age-standardized incidence was 6.15 per 100,000 and the crude annual incidence was 1.18 per 100,000. More than half (61.1%) of the tumors were histological grades 2 and 3, and 66.4% of tumors were classified as at least stage T2. The average age of patients was 58.6 ± 15.7 years (range, 18 to 103 years), with 20.8% of patients ≤40 years of age at diagnosis. The vast majority underwent penectomy (93%). Only 41.8% underwent lymphadenectomy, 58 patients (14.8%) received chemotherapy, and 54 patients (13.8%) received radiotherapy. Stage 3/4 and vascular invasion were statically significant at disease-free survival analysis. Conclusion: The state of Maranhão has the highest incidence of penile cancer in Brazil and globally. Tumors are locally advanced and at the time of diagnosis, and there is a high frequency among young individuals. Patients have a low socioeconomic status, making it difficult to complete treatment and receive appropriate follow-up. Keywords: Carcinoma, Penis cancer, Age-standardized incidence, Penectomy, Squamous cell carcinoma Background cancer, poor hygiene, phimosis, human papillomavirus Penile cancer is a rare neoplasm in developed countries. (HPV) infection, use of tobacco, and risky sexual behav- However, the incidence in developing countries in Asia, ior, are the most highlighted [7–10]. The disease mainly Africa, and Latin America is high, accounting for up to affects individuals with low socioeconomic levels and 10% of malignant neoplasms in men [1–3]. Brazil stands low levels of education [11–15]. out among the countries with the highest incidences of Maranhão is the most rural state in Brazil, being his- penile cancer in the world, although no reliable data torically marked by great social inequality and extreme exist [4, 5]. In Brazil, the condition may account for poverty. Access to health care in the rural parts is poor, 2.1% of all neoplasias in men, and affects mainly inhabi- which leads the male population to seek medical atten- tants of the North and Northeast regions . Among tion in the capital city only when the disease is at an ad- the known risk factors for the development of penile vanced stage. According to the Ministry of Health, during the period 1992–2007, 6716 penectomies were * Correspondence: email@example.com performed in Brazil, out of which 419 (6.2%) in the state University Hospital of Federal University of Maranhão, Barão de Itapari of Maranhão. These data, albeit alarming, are underesti- Street, Centro, São Luís, Brazil 5 mated and insufficient for understanding the reality of Department of Radiology and Pathology, Ribeirão Preto Medical School of University of São Paulo, Bandeirantes Avenue, Monte Alegre, Ribeirão Preto penile cancer in Maranhão. Hence, the objectives of this 14049-900, Brazil study were to estimate the minimum incidence of penile Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Coelho et al. BMC Urology (2018) 18:50 Page 2 of 7 cancer in the state of Maranhão, and to describe the epi- year. This translates to an ASR of 13.89 per 100,000 demiologic and clinical characteristics of patients diag- men over an 11-year period, corresponding to an aver- nosed with the disease, in order to provide the basis for age ASR of 6.15 per 100,000 men over a 5-year period. the development of measures to confront this disease The crude incidence rate was 1.18 per 100,000 men per and to act as an impetus for future studies. year. Patients from rural areas comprised 82.1% of the sample (322/392). Most were farmers (71%) and most Methods (66,3%) reported being married. The average age of the A retrospective cohort study was conducted. The studied studied sample was 58.6 ± 15.7 years (range 18 to sample was of composed of 286 patients newly diagnosed 103 years), with 19.7% of patients aged ≤40 years at diag- with penile cancer from January 2004 to December 2014 nosis. The majority of our patients 29% (72/248) were at the Cancer Hospital Aldenora Bello (HCAB). HCAB is non-swokers. a high complexity oncology center in Maranhão and the All patients were diagnosed with squamous cell carcin- main referral center for the treatment of penile cancer in oma. Among 136 the cases with reviewed histological the state, which has an estimated population of 6,680,884 subtype, according to most recent WHO classification inhabitants, according to data from the Brazilian Institute (2016), 91 (66.9%) were of the subtypes of cancer that of Geography and Statistics (IBGE). are associated with the presence of HPV, which include Data were collected from physical and electronic re- warty, basaloid, or mixed carcinomas with warty or basa- cords of all patients classified by the Hospital Cancer loid components. More aggressive subtypes such as Record of HCAB as having penile cancer. The studied basaloid or sarcomatoid carcinoma was observed in 13 variables were age, marital status, education, occupation, cases (9.6%) and 01 case (0.7%), respectively. The pri- home town, tumor location, histological type and grade, mary location of the tumor was the glans in 74.0% (158/ tumor size, type of surgery, lymphadenectomy, staging 212216/292) of cases. More than half (66.1%) of the tu- (TNM system, 2010), chemotherapy, and radiotherapy. mors were histological grades 2 and 3. Using the TNM Data were stored in Microsoft Excel spreadsheet editor classification system, 66.4% (157/246) of tumors were and analyzed using Stata statistical software (Version classified as ≥T2. Lymph node involvement was present 7.0, StataCorp, College Station, Texas). in 54% (93/175) of patients, and was distributed as fol- Frequencies and percentages were used to express categor- lows: N1 in 8.6%, N2 in 28.7%, and N3 in 16.7%. Distant ical variables, while numerical variables were presented as metastases were detected in 9 of the 138 patients for means and standard deviations. Age-standardized incidence whom it was possible to search for metastatic disease rate (ASR) were calculated using the standard world popula- (Table 1). tion proposed by Segi and modified by Doll et al. This In terms of surgical procedures performed, the vast method was also applied in the Cancer Incidence in Five majority of patients (93%) underwent penectomy (210/ Continents series of the International Agency for Research 279): 74.7% partial, 17.3% total, and 1% complete emas- on Cancer (IARC), wherein the number of cases, in each culation. Lymphadenectomy was performed in 41.8% 5-year age-stratum was divided by the population size in (164/392) of patients overall; 64.2% underwent bilateral each age group . In addition, due to the unavailability of lymphadenectomy and 34.8% underwent unilateral ASR data in studies conducted in Brazil, we calculated an es- lymphadenectomy. Chemotherapy was administered to timated annual crude incidence rate in our sample, in order 21.9% (54/246) of patients. Of these, 65% received to compare with data from previous Brazilian studies. Since chemotherapy as palliative therapy, and 3.6% as adjuvant there are others small centers that receive patients with therapy. Almost all (92.3%) patients who received penile cancer in Maranhão, the incidence estimated from the chemotherapy had presented with advanced disease. Cis- data herein therefore provides only a minimum estimate. platin and 5-fluorouracil were the most frequently used Survival analysis was performed using the Kaplan-Meier chemotherapeutic agents. Radiotherapy was used in the method to determine disease-free survival. The Log Rank treatment of 27.1% (54/199) of patients, being adjuvant test was used to compare survival curves. The significance in 10 cases and palliative in the others. The radiation threshold use was p ≤ 0.05. This work was in accordance dose ranged from 20.2–60 Gy, with a dose of 50 Gy be- with the principles of the Declaration of Helsinki and ing most common (Table 2). approved by the Research Ethics Committee of the As shown in Figs. 1 and 2, Kaplan-Meier curves dem- Universidade Federal do Maranhão [process no. onstrated that stage 3/4 and vascular invasion were asso- 43774215.7.0000.5086] and informed consent was waived. ciated with decreased disease-free survival (recurrence, Lymph node or systemic metastasis). Histological grade, Results tumor thickness, perineural invasion and tumor subtype From 2004 to 2014, 392 patients were diagnosed with were not significant predictors for disease-free disease. penile cancer, resulting in an average of 36 cases per Due to great number of patients without follow-up, only Coelho et al. BMC Urology (2018) 18:50 Page 3 of 7 Table 1 Histologic features and staging of patients with penile Table 2 Treatment modalities in patients with penile cancer cancer % (N) % (N) Type of surgery Partial penectomy 74.7 (286/383) Histological subtype Total penectomy 17.3 (66/383) Epidermoid carcinoma 100 (392/392) Emasculation 1.0 (4/383) Others (postectomy, glansectomy and excision) 7.0 (27/383) Initial anatomic site Glans 74.0(216/392) Lymphadenectomy Undetermined 15.0 (44/392) Yes 41.8 (164/392) Foreskin 11.0 (32/392) No 58.2 (228/392) Histologic grade Chemotherapy Grade 1 38.9 (123/316) Yes 23.6 (58/246) Grade 2 54.1 (171/316) No 76.4 (334/246) Grade 3 7.0 (22/316) Radiotherapy Primary tumor (T stage) Yes 21.9 (54/246) Tis 0.6 (2/335) No 78.1 (145/246) T1(a, b) 33.0 (107/335) T2 44.6 (145/335) rates reported by IARC (Table 3). No previous Bra- T3 17.5 (57/335) zilian study used age-adjusted or age-standardized inci- T4 4.3 (14/335) dence rates. In these prior studies, only the cumulative incidence rates were reported for different time inter- Regional lymph nodes (N stage) vals, making it necessary to calculate the annual average N0 46.0 (107/233) for comparison. The annual crude incidence rate in the N1 8.6 (20/233) present study was 1.18 per 100,000 men, far higher than N2 28.7 (67/233) any previously reported national annual crude incidence rate (Table 4)[6, 12, 17, 18]. N3 16.7 (39/233) It is believed that incidence of penile cancer is even higher in the state of Maranhão, because a proportion of Distant metástasis the affected population seek treatment in the Southeast M0 45.9 (180/392) states, as reported by Favorito et al. , where 53.2% of M1 2.3 (9/392) their study participants were from the Northeast, par- Mx 51.8 (203/392) ticularly from Maranhão. Maranhão has a geographically isolated capital. Thus, the demand for health services in Staging neighboring states, that are more accessible, is high. Stage 0 26.0 (95/366) Moreover, there are other small care centers for patients Stage 1 30.0 (110/366) with penile cancer in the state of Maranhão; these were Stage 2 26.5 (97/366) not included in our study. Thus, the calculated cumula- tive incidence in this study is a lower range estimate of Stage 3 15.3 (56/366) the true incidence. Furthermore, the age-standardized Stage 4 2.2 (8/366) estimate of incidence was higher than the crude esti- advanced destructive lesions mate. This was due to the fact that the population of 111 cases were included in this analysis. Follow-up Maranhão is younger than the standard world popula- ranged from 01 to 39 months (median 13,4 months). tion of Segi modified by Doll . There was insufficient data on mortality for overall sur- A likely explanation for high penile cancer incidence vival analysis. in the state of Maranhão is the high HPV infection rate. An unpublished prospective study (with 57 penile cancer Discussion cases from Maranhão) reported an HPV infection rate of The ASR of 6.1 per 100,000 men (5-year interval) re- over 75% . These data are corroborated by the fact corded in this study exceeds the highest international that Maranhão has the highest cervical cancer incidence Coelho et al. BMC Urology (2018) 18:50 Page 4 of 7 Fig. 1 Kaplan-Meier estimated disease-free survival rate in available 111 patients according to American Joint Committee on Cancer (AJCC) stage (p ≤ 0.05) in Brazil , and the pathogenesis of cervical cancer is other studies, particularly those from developing regions directly related to HPV infection. Therefore, whose socioeconomic reality is similar to that of Maran- immunization of male adolescents is pivotal for disrupt- hão [1, 3, 6, 12, 17, 18]. The state of Maranhão has a ing the HPV transmission trail. Surprisingly, only three Human Development Index (HDI) of 0.639, considered patients were diagnosed with HIV/AIDS (human im- the lowest in Brazil. According to IBGE, 71.7% of the munodeficiency virus, acquired immune deficiency families in Maranhão earn less than USD 220.00 a syndrome). month. In this study, 71% of patients reported being The epidemiological and clinical characteristics of the farmers, and 82.1% were from rural areas. When com- patients in this study were similar to those reported in pared with other studies [3, 12], our patients have pretty Fig. 2 Kaplan-Meier estimated disease-free survival rate in available 111 patients according to presence of vascular invasion (p ≤ 0.05) Coelho et al. BMC Urology (2018) 18:50 Page 5 of 7 Table 3 Highest age-standardized incidence rates of penile than those found in studies conducted in developed cancer in geographical areas of the world countries, such as the United States (45.9 and 50.6%) Population Age-standardized incidence (per [26, 27] and Canada (36.4%) . 100,000) In this case series, penectomy was performed in 93% Brazil, Maranhão 6.1 of patients. Penectomy was partial, total, or involved Brazil, Goiania 3.3 complete emasculation in 74.7, 17.3, and 1% of cases, re- spectively. The frequency of penectomy in this series is USA, Montana: American 2.8 Indian higher than that reported by Paiva et al. (82%) , Koif- man et al. (80.9%) , Zhu et al. (75.8%) , and Cha- Brazil, Aracaju 2.7 lya et al. (73.9%) . These data demonstrate that Malawi, Blantyre 2.7 patients from Maranhão seek treatment late; hence, they Brazil, Cuiaba 2.5 require mutilating treatments. Treatment of penile can- Uganda, Kyadondo County 2.4 cer has a negative impact on welfare in up to 40% of pa- Colombia, Manizales 2.4 tients and results in psychiatric symptoms in about 50% India, Barshi 2.2 . The high frequency of more aggressive treatments in this study may contribute to a greater occurrence of Spain, Cuenca 2.1 psychological and sexual dysfunction. Brazil, Sao Paulo 2.0 Among patients who received chemotherapy, 92.3% had Thailand, Songkhla 1.9 advanced, unresectable disease and chemotherapy was USA, Puerto Rico 1.9 palliative. Only two patients received chemotherapy with Chile, Region of Antofagasta 1.8 adjuvant intent and, despite the large proportion of pa- India, Chennai (Madras) 1.8 tients with lymph node status N3, only one patient re- ceived chemotherapy with neoadjuvant intent. Cisplatin— Brazil, Fortaleza 1.8 alone as a radiosensitizing agent or in combination with Adapted from Forman et al.  5-fluorouracil—and 5-fluorouracil were the most fre- low smoking rates in the overall population. This would quently used drugs. The addition of a taxane or ifosfamide be consistent with the relatively low smoking rates in was not used as currently recommended . Maranhão State. Although the average age of 58.5 years Despite 34.2% of patients having lymph node involve- is similar to the majority of studies reported in the lit- ment at the time of undergoing surgical treatment, only erature, the Brazil series show a higher frequency of 19% of patients treated with radiotherapy were treated cases in young individuals [18, 19, 22, 23]. This study with adjuvant intent. The vast majority, 81%, received showed that 19.7% of patients diagnosed with penile radiotherapy because of local or regional recurrence and/ cancer were ≤ 40 years of age (Fig. 3). In young people or ineligibility for surgical rescue. Despite the poor level of with squamous cell carcinomas, tumor infiltrative evidence for adjuvant radiotherapy, European and Ameri- growth pattern perineural invasion, and recurrence are can guidelines recommend performing prophylactic radio- more likely . However, the literature and current therapy for patients at high risk of relapse [31, 32]. prognostic indicators do not include the age at diagnosis The number of patients undergoing lymphadenectomy as an important prognostic marker [8, 18, 24–26]. (41.8%) is much lower than that of patients with tumors In terms of the characteristics of the primary tumor, classified as ≥ T2 (66.4%) who should, in theory, be sub- the majority of patients presented with an advanced mitted to lymph node staging. The lower than expected stage of disease. Approximately 66.4% of tumors were number of lymphadenectomies is justified by the fact classified as TNM stage T2 or higher. These data are that many patients returned for evaluation only when similar to those presented by Couto et al. (63.6%) , there was local or regional recurrence. and slightly higher than those described by Favorito et The presence of recurrences, mainly lymph-node in- al. (57.9%) . However, these frequencies are higher volvement, is the most important prognostic factor for Table 4 Comparison of the incidence of previous studies in other states of Brazil and Maranhão State Number of cases Period Crude incidence rate (100.000 homens/ano) Maranhão 392 2004-2014 1,18 Bahia  378 1997-2007 0,72 Pará  208 1996-2006 0,46 Pernambuco  88 2007-2012 0,34 Rio de Janeiro  230 2002-2008 0,43 Coelho et al. BMC Urology (2018) 18:50 Page 6 of 7 Abbreviations ASR: Age-standardized incidence rate; HCAB: Cancer Hospital Aldenora Bello; HDI: Human Development Index; HPV: Human papillomavirus; IARC: International Agency for Research on Cancer; IBGE: Brazilian Institute of Geography and Statistics Funding This article was funded by the Research Support Foundation of Maranhão (Fundação de Amparo a Pesquisa do Maranhão – FAPEMA [grant number 00696/14]), Ministry of Education (grant number ProEXT 4482.2.6549.09042014) and the Study Group on Penile Cancer (Grupo de Estudos com Câncer de Pênis – GECAP). Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Authors’ contributions RWPC, LMF and GEBS are the principal investigators and wrote the first Fig. 3 A 42-year-old patient with advanced disease show auto- version of the manuscript. JDP, JSM, DVOG, JSL, LRN and AMTN participated penectomia and inguinal fistula in the care and management of the patient and preparation of the manuscript. LNZR and GEBS performed pathological analysis and interpretation. AAMS, JRRC contributed to critical revision of important intellectual content of the manuscript. All authors contributed to the writing survival in penile cancer . Several possible histo- process and read and approved the final manuscript. All authors read and logical parameters have been associated with recurrences approved the final manuscript. and penile cancer prognosis. These include, histological Ethics approval and consent to participate grade, tumor thickness, vascular embolization, perineu- This work was in accordance with the principles of the Declaration of ral invasion, tumor subtype and, clinical stage [18, 24– Helsinki and approved by the Research Ethics Committee of the Universidade Federal do Maranhão [process no. 43774215.7.0000.5086] and 26]. In our study, only tumor stage and vascular invasion informed consent was waived. were significant predictors for disease-free survival. Al- though, perineural invasion is an important predictor of Consent for publication nodal metastasis , our data show no significant in- Figure 1: Available for sending at any stage. crease in risk of disease recurrence. Competing interests This study has some limitations, mainly owing to The authors declare that they have no competing interests. missing data from medical records and the abandon- ment of treatment by patients. Many patients were rural Publisher’sNote residents, who had difficulty returning to the capital city Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. to continue treatment. When they again sought medical care, the presence of bulky local and/or regional recur- Author details rence—amenable only to palliative treatment—was com- Aldenora Bello Cancer Hospital, Seroa da Mota Street, Apeadouro, São Luís 65031-630, Brazil. Federal University of Pará, Brazil, Gov. José Malcher mon. Still, due to the limited patient follow-up, only the Avenue, Belém 66055-260, Brazil. Federal University of Maranhão, São Luís, deaths of those who died at HCAB were recorded. Fi- Brazil, dos Portugueses Avenue, Bacanga, São Luís 65080-805, Brazil. nally, the specimens were evaluated by different patholo- University Hospital of Federal University of Maranhão, Barão de Itapari Street, Centro, São Luís, Brazil. Department of Radiology and Pathology, gists, which may be considered as an inherent limitation Ribeirão Preto Medical School of University of São Paulo, Bandeirantes of multicenter studies. Avenue, Monte Alegre, Ribeirão Preto 14049-900, Brazil. 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Published: May 29, 2018