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Oral cancer in Fanconi anemia: Review of 121 cases
Critical Reviews in Oncology / Hematology 125 (2018) 35–40
Contents lists available at ScienceDirect
Critical Reviews in Oncology / Hematology journal homepage: www.elsevier.com/locate/critrevonc
Oral cancer in Fanconi anemia: Review of 121 cases a,⁎
a
T a
b
Camila Pinheiro Furquim , Allana Pivovar , José Miguel Amenábar , Carmem Bonfim , Cassius Carvalho Torres-Pereiraa a b
Graduate Program in Dentistry, Departament of Stomatology, Federal University of Paraná School of Dentistry, Curitiba, Paraná, Brazil Bone Marrow Transplantation Unit, Hospital de Clínicas, Federal University of Paraná, Curitiba, Paraná, Brazil
A R T I C LE I N FO
A B S T R A C T
Keywords: Fanconi anemia Oral cancer Squamous cell carcinoma Hematopoetic stem cell transplantation
Fanconi anemia (FA) is a rare autosomal recessive genetic disorder characterized by aplastic anemia, progressive pancytopenia, congenital anomalies, and increased risk of cancer development. After hematopoietic stem cell transplant (HSCT), patients have an estimated 500-fold increase in the risk of developing head and neck cancer compared to a non-affected, and the oral cavity is affected in one-third of cases. Thus, this study aimed to better understand the natural history of oral cavity cancer in patients affected by FA. After conducting a keyword search on MEDLINE, we found 121 cases of oral cavity cancer in patients who had been affected by FA. In conclusion, HSCT may increase the risks of oral cancer development, especially after 5 years after the transplant. In the normal population, the tongue is the most affected area. FA patients should be informed of the risks of oral malignant transformation and encouraged to be undergo medical surveillance.
1. Introduction
2. Methodology
Fanconi anemia (FA) is a rare autosomal recessive genetic disorder characterized by aplastic anemia, progressive pancytopenia, congenital anomalies such as short stature, hypoplastic thumbs, café-au-lait spots, cardiac and renal anomalies, and increased risk of cancer development (Alter, 2014; Auerbach, 2009). Despite the fact that hematopoietic stem cell transplantation (HSCT) is the main treatment for bone marrow failure, it increases the risk for solid tumors (Deeg et al., 1996; Curtis et al., 1997). Head and neck cancer risks, for instance, are estimated 500- to 700-fold more likely to develop in HSCT patients than in the normal population. Moreover, oral squamous cell carcinoma (OSCC) is the most common type of cancer developed in such patients (Alter, 2014; Kutler et al., 2003a; Rosenberg et al., 2003). The pathway to cancer development in this population has not been investigated thoroughly, and it remains unclear in the literature. The result of chromosomal instability associated with a defective repair of DNA damage is a possible explanation, since these patients do not have traditional behavioral risk factors such as tobacco and alcohol use (Dong et al., 2015). In light of the discussion presented, the aim of our literature review is to better understand the natural history of oral cavity cancer in patients affected by Fanconi Anemia (FA).
2.1. Selection of studies
⁎
Firstly, we conducted a keyword search on MEDLINE database using the following terms: squamous cell cancer Fanconi; head neck cancer Fanconi; oral malignancies Fanconi; oral cancer Fanconi and mouth cancer Fanconi. Inclusion criteria were limited to case reports; case series and clinical research describing patients with oral cancer and Fanconi anemia. Although data on this topic were not limited; we eliminated literature reviews; reports of non-oral sites; patients reported in previous publications; and publications that did not report oral cancer characteristics. Papers written in languages other than the ones understood by the authors were translated into English. Two people were responsible both for screening the titles and abstracts of the identified studies and for assessing full texts of potentially eligible studies under inclusion and exclusion criteria. Papers that referred to FA cases were read carefully to determine whether oral cancer was mentioned. Discrepancies were solved by team consensus. 2.2. Statistical analysis Data were analyzed, categorical variables were summarized by frequency (%), and quantitative variables were summarized by median and range. Disease-free survival outcomes were calculated considering
Corresponding author at: Department of Stomatology, Federal University of Paraná School of Dentistry, BR-80210-170, Curitiba, Paraná, Brazil. E-mail addresses: [email protected] (C.P. Furquim), [email protected] (A. Pivovar), [email protected] (J.M. Amenábar), [email protected] (C.C. Torres-Pereira).
https://doi.org/10.1016/j.critrevonc.2018.02.013 Received 23 July 2017; Received in revised form 5 January 2018; Accepted 25 February 2018 1040-8428/ © 2018 Elsevier B.V. All rights reserved.
Critical Reviews in Oncology / Hematology 125 (2018) 35–40
C.P. Furquim et al.
developed OSCC when they were younger than 25 years old, whereas 73% (n = 43) of non-HSCT patients developed oral cancer after their 25 years of age (Fig. 3b). There was no difference in the incidence of OSSC when gender was considered (p = 0.088)**. Notwithstanding, on the one hand, female patients tend to develop cancer when they are older (at age 28) than male patients (at age 23); the median age of cancer incidence in female patients is also higher than in male individuals (p = 0.011)*. On the other hand, female patients tend to develop more second primary tumors (31) than male patients (17). Furthermore, when HSCT was compared to second primary tumors, no statistic difference was found*(p = 0.064). * T-Test **Mann Whitney Test 3.3. Topography The tongue was the most affected site as confirmed by 73 cases (60%), followed by gingivae in 11 cases (9%), and by buccal mucosa and retromolar trigone in 7 cases (6%). Only female patients developed lip (n = 5) and mandible (n = 2) cancer. Cancer on the mandible and on the retromolar trigone area was reported only in patients who had not undergone hematopoietic stem cell transplantation. More details are presented in Table 2. Fig. 1. Study selection process on MEDLINE search.
3.4. Survival outcomes
the age of oral cancer and the time since the patient had undergone HSCT. Kaplan Meier method was used for survival analysis. IBM SPSS software (version 20.0; IBM Corp) was utilized for data analysis, which used Chi square, Pearson and Mann-Whitney tests.
The median of overall survival for patients with oral cancer was 26 years and the median of disease-free survival after transplantation was 10 years. (Fig. 4a and b): When we compared gender, it was possible to notice that female patients developed cancer later than male patients and it occurred after the transplant. This difference was statistically significant (p = 0.036) (Fig. 5a and b): Finally, the median time of disease-free survival for patients with oral cancer after the HSCT was 21 years and for patients who had not undergone HSCT was 29 years (p < 0.001). (Fig. 6.) Around 66% of transplanted individuals presented disease-free survival up to 18 years, while the same happened to 70% of non-transplanted patients.
3. Results 3.1. Included records A total of 249 studies were found in the search. The selection process is shown in Fig. 1. From these, we selected 47 studies published from 1970 to 2016. The characteristics of the studies used are summarized and described in additional supplementary Table S1.
4. Discussion 3.2. Patients’ characteristics Head and neck squamous cell carcinomas (HNSCC) in FA patients were most commonly located in the oral cavity (Kutler et al., 2015). Patients with FA display a marked predisposition for carcinomas of the mucous membranes of the anogenital and oral areas (Kennedy and Hart, 1982). Our study includes 121 cases of OSCC in patients with FA that have been reported on PubMed since 1970. FA-OSCCs are clinically and genetically similar to sporadic OSCCs, despite having a different etiology (van Zeeburg et al., 2008). While etiology is related to tobacco and alcohol use in the normal population, in FA patients its cause remains unclear. Some authors suggest that the local microbiome (bacteria and viruses) can contribute to oral cancer development; however there is not enough evidence to support this claim (Alter et al., 2013; Furquim et al., 2017; Park et al., 2013). The first review including oral cancer cases in FA patients described 17 head and neck cancer cases in patients younger than 30 years old, occurring equally in both females and males (Lustig et al., 1995). A review of oral transformation after HSCT that included several hematologic diseases presented a gender distribution of 19:5, in which males had a higher risk of developing secondary oral cancer than females. Yet, males are slightly more likely than females to undergo HSCT (62% to 56%) (Kruse and Grätz, 2009). Despite the above stated, some authors have indicated a high ratio of squamous cell carcinoma (SCC) occurring more in females than in males (Kennedy and Hart, 1982; Masserot et al., 2008; Reed et al., 1983). On that matter, a prospective study using 754 individuals by the
A total of one hundred twenty-one (121) individuals affected by FA and oral cancer were described in the papers selected. From this number, 69 (57%) were female and 52 (43%) were male, aged from 10 to 52 years old, at a median age of 26.5 years old. Considering the documented information, 56 (46%) cases reported individuals who had undergone HSCT at a median time of 10 years (ranging from 2 to 22); six cases (5%) showed no information about the transplant, and 59 (49%) cases did not go through the transplant procedure. Thirty-four (28%) patients developed more than one primary tumor. From these, 17 cases were detected exclusively in the mouth. Poor correlation was found between age and number of tumors (p = 0.023) ***. Older patients presented more cases of tumors. No correlation was found when comparing HSCT and number of tumors. Recurrence was observed in 14 (12%) patients. Four patients developed a third tumor, and all of them were located in the mouth. Regarding the treatment, 41 (34%) patients were treated exclusively due to excision of tumor and the other ones received treatment with radiotherapy and chemotherapy. Table 1 describes the subjects’ characteristics and Fig. 2, the time after HSCT of the cases included in this study. *** Pearson correlation coefficient Significant statistical differences were observed when age and HSCT were compared (p > 0.01). Patients with no HSCT developed OSCC later (31 years) in comparison with transplanted patients (20 years)* (Fig. 3a). More than 75% (n = 42) of the transplanted patients 36
Critical Reviews in Oncology / Hematology 125 (2018) 35–40
C.P. Furquim et al.
Table 1 Subjects’ characteristics.
GENDER FEMALE MALE AGE 18 YRS > 18 YRS TOTAL CASES 1 case of primary tumor > 1 case of primary tumor TREATMENT SURGERY RADIOTHERAPY AND OTHERS
HSCT(n)
NO HSCT (n)
RP
IC 95%
*
TOTAL
29 27
37 22
1.254046
1.8185627–0.86476673
0.236
57.40% 42.60%
25 31
3 56
2.50576
3.4171144–1.83746684
> 0.001
24.30% 75.70%
46 10
38 21
0.58906
1.0168128–0.34125471
0.032
73% 27%
28 13
12 25
0.488722
0.7940474–0.30079945
0.02
51.30% 48.70%
p
* Chi-square test. Table 2 Characteristics of oral cancer cases by topography.
Fig. 2. Distribution of sample by hematopoietic stem cell transplantation history.
LOCATION
NO HSCT
HSCT
NOT MENTIONED
Total
%
TONGUE GINGIVA BUCCAL MUCOSA ALVEOLAR RIDGE PALATE LIP FLOOR OF MOUTH RETROMOLAR TRIGONE ORAL CAVITY MANDIBLE TOTAL
32 5 2 6 3 2 2 4
38 4 5 1 2 2 2 0
3 2 0 0 0 1 0 0
73 11 7 7 5 5 4 4
60.3% 9.1% 5.8% 5.8% 4.1% 4.1% 3.3% 3.3%
1 2 59
2 0 56
0 0 6
3 2 121
2.5% 1.7% 100%
transplants, and in 117 patients with FA at the Saint Louis Hospital (SLH) cohort who did receive transplants. The results revealed that patients who had received HSCT have a 4.4-fold higher risk of developing SCC than those who had not (p = 0.003), and that SCC tends to develop at significantly younger ages (respective medians, 18 versus 33 years, p = 0.004). Rosenberg et al. (2005) corroborate these data when concluding that 50% of patients who receive transplants are prone to develop SCC by the age of 29, whereas 50% of patients who do not receive transplants are expected to develop SCC by the age of 45. Our literature review presented 56 cases in post-SCT patients at the median age of 20 and 59 cases in non-SCT patients at the median age of 31. The fifty-six (43%) patients who received HSCT had had a
International Fanconi Anemia Registry indicated that 19 patients (3%) had HNSCC. Patients’ age ranged from 15 to 49 years (median of 31 years), and there was a 2:1 female predominance (Kutler et al., 2003b). In our study, we observed that the median age of patients is 26 years and we did not find any statistically significant difference between genders. In the normal population, oral cancer tends to occur in men who demonstrate behavioral risk factors when they are over 45 years old (Scully and Bagan, 2009). One other study compared the risks of SCC in 145 patients with FA using the North American Survey (NAS) cohort who did not receive
Fig. 3. Age distribution of oral cancer development and HSCT history.
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Fig. 4. Disease-free survival for patients with oral cancer according to age and HSCT time.
radiation can be necessary. According to Masserot et al. (2008), radiotherapy may be useful in inoperable patients or at least may serve as a palliative treatment. They observed, for instance, that one patient who underwent a tongue cancer treatment, despite having died 14 months later, responded to radiotherapy. The longest follow-up time for patients with oral cancer treated with radiotherapy was 5 years and in this case report, the tumor was located in the base of the tongue (Bremer et al., 2003). Therefore, radiotherapy benefits must be better evaluated (Masserot et al., 2008). The prognosis was similarly poor after SCC for patients who did or did not receive the SCT. However, patients with FA who had received transplants and had SCC showed an increased risk of death of 66-fold when compared with no-HSCT patients whose risk was 30-fold and the overall mortality was 66% (Birkeland et al., 2011; Rosenberg et al., 2008). Survival after SCC had a median ranging from 13 to 33 months and the mean time of survival without the disease was from 7 to 15 months (Birkeland et al., 2011; Rosenberg et al., 2005). Unfortunately, our review was not able to determine the prognosis
malignancie at a median time of 10 years (ranging from 2 to 22). Even non-FA patients who underwent an HSCT have a higher risk of developing secondary solid tumors, in particular SCC, due to several risk factors, including donor gender, recipient age, full-body irradiation (TBI), chemotherapy, and chronic graft versus host disease (GVHD) (Bonfim et al., 2016; Grein Cavalcanti et al., 2015). Kruse and Grätz (2009) indicated that the latency time between having an HSCT and developing oral cancer range from 5 to 9 years (56.4%) (Kruse and Grätz, 2009). In their study, although the time of cancer transformation was similar to the ones previously shown in the literature, more than 23% of the cases of oral cancer in SCT patients occurred within a shorter period. The usual recommendation for treating oral cancer is surgery associated or not with radio and chemotherapy depending on the tumor’s stage of development (Kutler et al., 2015). Surgery is more indicated for patients affected by FA, since they are more sensitive to radio and chemotherapy (Alter, 2002). However, in some cases, tumors are larger and more aggressive. Since surgery is not possible for such cases,
Fig. 5. Disease-free survival for patients with oral cancer compared by gender.
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although the accuracy of MSE (mouth self examination) was poor, the motivation to include and train these patients to be aware of the risks is of utmost importance (Furquim et al., 2014). Future research should develop better strategies to guarantee diagnosis at an early stage, since these tumors cause morbidity and mortality. 5. Conclusion
• In patients affected by FA, HSCT was a risk factor for an earlier oral malignant transformation compared to non-transplanted patients. • The risk of oral cancer seemed to increase as a late complication both in transplanted and in non-transplanted individuals. • As in the general population, the tongue was the most affected site. • Patients with FA should be informed of the risks of oral malignant transformation and should be encouraged to go to the specialist regularly in order to be under medical surveillance.
Conflict of interest statement The authors have no conflict of interest to declare. Acknowledgments
Fig. 6. Disease-free survival for patients with oral cancer after the HSCT.
The authors would like to thank the Academic Publishing Advisory Center (Centro de Assessoria de Publicação Acadêmica, CAPA − www. capa.ufpr.br) of the Federal University of Paraná for assistance with English language editing.
and survival rates after SCC due to the lack of information about the treatment and follow up in the studies included. Yet, in recent systematic review, FA subjects presented worse overall survival when compared to other cases of head and neck cancer (Bhanu Prasad et al., 2017). The review presented here was limited to SCC located in the oral cavity. As described previously, the tongue was the most affected topography (n = 73), especially the lateral of the tongue, followed by gingivae (n = 11), and buccal mucosa and retromolar trigone (n = 7). Despite the fact that the most commonly affected area in the oral cavity of patients who underwent HSCT and had other diseases besides FA was the tongue, the number of salivary gland cancers is representative (28%). This result, however, did not happen in the FA oral cancer cases reported here. In fact, the results showed no differences in the oral cancer location when comparing the subgroups of patients who did and did not undergo HSCT, with the exception of mandibular and retromolar cancer that occurred only in non-HSCT patients. Patients affected by FA also had a tendency to develop multiple malignancies (Kutler et al., 2015). To illustrate, in this review we observed that 14 patients had cancer recurrence and 34 developed a new primary tumor. All the cases shown were subject to visual examination and early diagnosis. Specialists recommended their patients to have an oral examination every 6 months (Majhail et al., 2012). Accordingly, this population must be monitored very closely by a team of dentists and physicians. Regarding patients affected by FA with a history of precancerous leukoplakia or recurrent oral lesions, head and neck examinations are recommended every 6–8 weeks (Kutler et al., 2015). Therefore, although Kutler et al. (2015) suggested the screening of the oral cavity and oropharynx to start prior to 15 years of age, this review recommends that it must begin even earlier, since the first oral cancer case published occurred at the age of 10 years old, and in eight patients who were under 15 years of age (Kutler et al., 2015). Given the results shown, we acknowledge that this review has a limitation in the sense that many cases of oral cancer in FA patients have probably not been published, since unsuccessful treatment cases could be interpreted as less valuable for publication. Besides, there was the impossibility of excluding duplicated cases in the selected data due to the absence of information. Finally, considering that patients with FA present a very high risk for cancer, we suggest the thorough study of oral cancer prevention strategies to better assist this population. Moreover, mouth self-examination is recommended as a secondary prevention tool and,
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Contents lists available at ScienceDirect
Critical Reviews in Oncology / Hematology journal homepage: www.elsevier.com/locate/critrevonc
Oral cancer in Fanconi anemia: Review of 121 cases a,⁎
a
T a
b
Camila Pinheiro Furquim , Allana Pivovar , José Miguel Amenábar , Carmem Bonfim , Cassius Carvalho Torres-Pereiraa a b
Graduate Program in Dentistry, Departament of Stomatology, Federal University of Paraná School of Dentistry, Curitiba, Paraná, Brazil Bone Marrow Transplantation Unit, Hospital de Clínicas, Federal University of Paraná, Curitiba, Paraná, Brazil
A R T I C LE I N FO
A B S T R A C T
Keywords: Fanconi anemia Oral cancer Squamous cell carcinoma Hematopoetic stem cell transplantation
Fanconi anemia (FA) is a rare autosomal recessive genetic disorder characterized by aplastic anemia, progressive pancytopenia, congenital anomalies, and increased risk of cancer development. After hematopoietic stem cell transplant (HSCT), patients have an estimated 500-fold increase in the risk of developing head and neck cancer compared to a non-affected, and the oral cavity is affected in one-third of cases. Thus, this study aimed to better understand the natural history of oral cavity cancer in patients affected by FA. After conducting a keyword search on MEDLINE, we found 121 cases of oral cavity cancer in patients who had been affected by FA. In conclusion, HSCT may increase the risks of oral cancer development, especially after 5 years after the transplant. In the normal population, the tongue is the most affected area. FA patients should be informed of the risks of oral malignant transformation and encouraged to be undergo medical surveillance.
1. Introduction
2. Methodology
Fanconi anemia (FA) is a rare autosomal recessive genetic disorder characterized by aplastic anemia, progressive pancytopenia, congenital anomalies such as short stature, hypoplastic thumbs, café-au-lait spots, cardiac and renal anomalies, and increased risk of cancer development (Alter, 2014; Auerbach, 2009). Despite the fact that hematopoietic stem cell transplantation (HSCT) is the main treatment for bone marrow failure, it increases the risk for solid tumors (Deeg et al., 1996; Curtis et al., 1997). Head and neck cancer risks, for instance, are estimated 500- to 700-fold more likely to develop in HSCT patients than in the normal population. Moreover, oral squamous cell carcinoma (OSCC) is the most common type of cancer developed in such patients (Alter, 2014; Kutler et al., 2003a; Rosenberg et al., 2003). The pathway to cancer development in this population has not been investigated thoroughly, and it remains unclear in the literature. The result of chromosomal instability associated with a defective repair of DNA damage is a possible explanation, since these patients do not have traditional behavioral risk factors such as tobacco and alcohol use (Dong et al., 2015). In light of the discussion presented, the aim of our literature review is to better understand the natural history of oral cavity cancer in patients affected by Fanconi Anemia (FA).
2.1. Selection of studies
⁎
Firstly, we conducted a keyword search on MEDLINE database using the following terms: squamous cell cancer Fanconi; head neck cancer Fanconi; oral malignancies Fanconi; oral cancer Fanconi and mouth cancer Fanconi. Inclusion criteria were limited to case reports; case series and clinical research describing patients with oral cancer and Fanconi anemia. Although data on this topic were not limited; we eliminated literature reviews; reports of non-oral sites; patients reported in previous publications; and publications that did not report oral cancer characteristics. Papers written in languages other than the ones understood by the authors were translated into English. Two people were responsible both for screening the titles and abstracts of the identified studies and for assessing full texts of potentially eligible studies under inclusion and exclusion criteria. Papers that referred to FA cases were read carefully to determine whether oral cancer was mentioned. Discrepancies were solved by team consensus. 2.2. Statistical analysis Data were analyzed, categorical variables were summarized by frequency (%), and quantitative variables were summarized by median and range. Disease-free survival outcomes were calculated considering
Corresponding author at: Department of Stomatology, Federal University of Paraná School of Dentistry, BR-80210-170, Curitiba, Paraná, Brazil. E-mail addresses: [email protected] (C.P. Furquim), [email protected] (A. Pivovar), [email protected] (J.M. Amenábar), [email protected] (C.C. Torres-Pereira).
https://doi.org/10.1016/j.critrevonc.2018.02.013 Received 23 July 2017; Received in revised form 5 January 2018; Accepted 25 February 2018 1040-8428/ © 2018 Elsevier B.V. All rights reserved.
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developed OSCC when they were younger than 25 years old, whereas 73% (n = 43) of non-HSCT patients developed oral cancer after their 25 years of age (Fig. 3b). There was no difference in the incidence of OSSC when gender was considered (p = 0.088)**. Notwithstanding, on the one hand, female patients tend to develop cancer when they are older (at age 28) than male patients (at age 23); the median age of cancer incidence in female patients is also higher than in male individuals (p = 0.011)*. On the other hand, female patients tend to develop more second primary tumors (31) than male patients (17). Furthermore, when HSCT was compared to second primary tumors, no statistic difference was found*(p = 0.064). * T-Test **Mann Whitney Test 3.3. Topography The tongue was the most affected site as confirmed by 73 cases (60%), followed by gingivae in 11 cases (9%), and by buccal mucosa and retromolar trigone in 7 cases (6%). Only female patients developed lip (n = 5) and mandible (n = 2) cancer. Cancer on the mandible and on the retromolar trigone area was reported only in patients who had not undergone hematopoietic stem cell transplantation. More details are presented in Table 2. Fig. 1. Study selection process on MEDLINE search.
3.4. Survival outcomes
the age of oral cancer and the time since the patient had undergone HSCT. Kaplan Meier method was used for survival analysis. IBM SPSS software (version 20.0; IBM Corp) was utilized for data analysis, which used Chi square, Pearson and Mann-Whitney tests.
The median of overall survival for patients with oral cancer was 26 years and the median of disease-free survival after transplantation was 10 years. (Fig. 4a and b): When we compared gender, it was possible to notice that female patients developed cancer later than male patients and it occurred after the transplant. This difference was statistically significant (p = 0.036) (Fig. 5a and b): Finally, the median time of disease-free survival for patients with oral cancer after the HSCT was 21 years and for patients who had not undergone HSCT was 29 years (p < 0.001). (Fig. 6.) Around 66% of transplanted individuals presented disease-free survival up to 18 years, while the same happened to 70% of non-transplanted patients.
3. Results 3.1. Included records A total of 249 studies were found in the search. The selection process is shown in Fig. 1. From these, we selected 47 studies published from 1970 to 2016. The characteristics of the studies used are summarized and described in additional supplementary Table S1.
4. Discussion 3.2. Patients’ characteristics Head and neck squamous cell carcinomas (HNSCC) in FA patients were most commonly located in the oral cavity (Kutler et al., 2015). Patients with FA display a marked predisposition for carcinomas of the mucous membranes of the anogenital and oral areas (Kennedy and Hart, 1982). Our study includes 121 cases of OSCC in patients with FA that have been reported on PubMed since 1970. FA-OSCCs are clinically and genetically similar to sporadic OSCCs, despite having a different etiology (van Zeeburg et al., 2008). While etiology is related to tobacco and alcohol use in the normal population, in FA patients its cause remains unclear. Some authors suggest that the local microbiome (bacteria and viruses) can contribute to oral cancer development; however there is not enough evidence to support this claim (Alter et al., 2013; Furquim et al., 2017; Park et al., 2013). The first review including oral cancer cases in FA patients described 17 head and neck cancer cases in patients younger than 30 years old, occurring equally in both females and males (Lustig et al., 1995). A review of oral transformation after HSCT that included several hematologic diseases presented a gender distribution of 19:5, in which males had a higher risk of developing secondary oral cancer than females. Yet, males are slightly more likely than females to undergo HSCT (62% to 56%) (Kruse and Grätz, 2009). Despite the above stated, some authors have indicated a high ratio of squamous cell carcinoma (SCC) occurring more in females than in males (Kennedy and Hart, 1982; Masserot et al., 2008; Reed et al., 1983). On that matter, a prospective study using 754 individuals by the
A total of one hundred twenty-one (121) individuals affected by FA and oral cancer were described in the papers selected. From this number, 69 (57%) were female and 52 (43%) were male, aged from 10 to 52 years old, at a median age of 26.5 years old. Considering the documented information, 56 (46%) cases reported individuals who had undergone HSCT at a median time of 10 years (ranging from 2 to 22); six cases (5%) showed no information about the transplant, and 59 (49%) cases did not go through the transplant procedure. Thirty-four (28%) patients developed more than one primary tumor. From these, 17 cases were detected exclusively in the mouth. Poor correlation was found between age and number of tumors (p = 0.023) ***. Older patients presented more cases of tumors. No correlation was found when comparing HSCT and number of tumors. Recurrence was observed in 14 (12%) patients. Four patients developed a third tumor, and all of them were located in the mouth. Regarding the treatment, 41 (34%) patients were treated exclusively due to excision of tumor and the other ones received treatment with radiotherapy and chemotherapy. Table 1 describes the subjects’ characteristics and Fig. 2, the time after HSCT of the cases included in this study. *** Pearson correlation coefficient Significant statistical differences were observed when age and HSCT were compared (p > 0.01). Patients with no HSCT developed OSCC later (31 years) in comparison with transplanted patients (20 years)* (Fig. 3a). More than 75% (n = 42) of the transplanted patients 36
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Table 1 Subjects’ characteristics.
GENDER FEMALE MALE AGE 18 YRS > 18 YRS TOTAL CASES 1 case of primary tumor > 1 case of primary tumor TREATMENT SURGERY RADIOTHERAPY AND OTHERS
HSCT(n)
NO HSCT (n)
RP
IC 95%
*
TOTAL
29 27
37 22
1.254046
1.8185627–0.86476673
0.236
57.40% 42.60%
25 31
3 56
2.50576
3.4171144–1.83746684
> 0.001
24.30% 75.70%
46 10
38 21
0.58906
1.0168128–0.34125471
0.032
73% 27%
28 13
12 25
0.488722
0.7940474–0.30079945
0.02
51.30% 48.70%
p
* Chi-square test. Table 2 Characteristics of oral cancer cases by topography.
Fig. 2. Distribution of sample by hematopoietic stem cell transplantation history.
LOCATION
NO HSCT
HSCT
NOT MENTIONED
Total
%
TONGUE GINGIVA BUCCAL MUCOSA ALVEOLAR RIDGE PALATE LIP FLOOR OF MOUTH RETROMOLAR TRIGONE ORAL CAVITY MANDIBLE TOTAL
32 5 2 6 3 2 2 4
38 4 5 1 2 2 2 0
3 2 0 0 0 1 0 0
73 11 7 7 5 5 4 4
60.3% 9.1% 5.8% 5.8% 4.1% 4.1% 3.3% 3.3%
1 2 59
2 0 56
0 0 6
3 2 121
2.5% 1.7% 100%
transplants, and in 117 patients with FA at the Saint Louis Hospital (SLH) cohort who did receive transplants. The results revealed that patients who had received HSCT have a 4.4-fold higher risk of developing SCC than those who had not (p = 0.003), and that SCC tends to develop at significantly younger ages (respective medians, 18 versus 33 years, p = 0.004). Rosenberg et al. (2005) corroborate these data when concluding that 50% of patients who receive transplants are prone to develop SCC by the age of 29, whereas 50% of patients who do not receive transplants are expected to develop SCC by the age of 45. Our literature review presented 56 cases in post-SCT patients at the median age of 20 and 59 cases in non-SCT patients at the median age of 31. The fifty-six (43%) patients who received HSCT had had a
International Fanconi Anemia Registry indicated that 19 patients (3%) had HNSCC. Patients’ age ranged from 15 to 49 years (median of 31 years), and there was a 2:1 female predominance (Kutler et al., 2003b). In our study, we observed that the median age of patients is 26 years and we did not find any statistically significant difference between genders. In the normal population, oral cancer tends to occur in men who demonstrate behavioral risk factors when they are over 45 years old (Scully and Bagan, 2009). One other study compared the risks of SCC in 145 patients with FA using the North American Survey (NAS) cohort who did not receive
Fig. 3. Age distribution of oral cancer development and HSCT history.
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Fig. 4. Disease-free survival for patients with oral cancer according to age and HSCT time.
radiation can be necessary. According to Masserot et al. (2008), radiotherapy may be useful in inoperable patients or at least may serve as a palliative treatment. They observed, for instance, that one patient who underwent a tongue cancer treatment, despite having died 14 months later, responded to radiotherapy. The longest follow-up time for patients with oral cancer treated with radiotherapy was 5 years and in this case report, the tumor was located in the base of the tongue (Bremer et al., 2003). Therefore, radiotherapy benefits must be better evaluated (Masserot et al., 2008). The prognosis was similarly poor after SCC for patients who did or did not receive the SCT. However, patients with FA who had received transplants and had SCC showed an increased risk of death of 66-fold when compared with no-HSCT patients whose risk was 30-fold and the overall mortality was 66% (Birkeland et al., 2011; Rosenberg et al., 2008). Survival after SCC had a median ranging from 13 to 33 months and the mean time of survival without the disease was from 7 to 15 months (Birkeland et al., 2011; Rosenberg et al., 2005). Unfortunately, our review was not able to determine the prognosis
malignancie at a median time of 10 years (ranging from 2 to 22). Even non-FA patients who underwent an HSCT have a higher risk of developing secondary solid tumors, in particular SCC, due to several risk factors, including donor gender, recipient age, full-body irradiation (TBI), chemotherapy, and chronic graft versus host disease (GVHD) (Bonfim et al., 2016; Grein Cavalcanti et al., 2015). Kruse and Grätz (2009) indicated that the latency time between having an HSCT and developing oral cancer range from 5 to 9 years (56.4%) (Kruse and Grätz, 2009). In their study, although the time of cancer transformation was similar to the ones previously shown in the literature, more than 23% of the cases of oral cancer in SCT patients occurred within a shorter period. The usual recommendation for treating oral cancer is surgery associated or not with radio and chemotherapy depending on the tumor’s stage of development (Kutler et al., 2015). Surgery is more indicated for patients affected by FA, since they are more sensitive to radio and chemotherapy (Alter, 2002). However, in some cases, tumors are larger and more aggressive. Since surgery is not possible for such cases,
Fig. 5. Disease-free survival for patients with oral cancer compared by gender.
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although the accuracy of MSE (mouth self examination) was poor, the motivation to include and train these patients to be aware of the risks is of utmost importance (Furquim et al., 2014). Future research should develop better strategies to guarantee diagnosis at an early stage, since these tumors cause morbidity and mortality. 5. Conclusion
• In patients affected by FA, HSCT was a risk factor for an earlier oral malignant transformation compared to non-transplanted patients. • The risk of oral cancer seemed to increase as a late complication both in transplanted and in non-transplanted individuals. • As in the general population, the tongue was the most affected site. • Patients with FA should be informed of the risks of oral malignant transformation and should be encouraged to go to the specialist regularly in order to be under medical surveillance.
Conflict of interest statement The authors have no conflict of interest to declare. Acknowledgments
Fig. 6. Disease-free survival for patients with oral cancer after the HSCT.
The authors would like to thank the Academic Publishing Advisory Center (Centro de Assessoria de Publicação Acadêmica, CAPA − www. capa.ufpr.br) of the Federal University of Paraná for assistance with English language editing.
and survival rates after SCC due to the lack of information about the treatment and follow up in the studies included. Yet, in recent systematic review, FA subjects presented worse overall survival when compared to other cases of head and neck cancer (Bhanu Prasad et al., 2017). The review presented here was limited to SCC located in the oral cavity. As described previously, the tongue was the most affected topography (n = 73), especially the lateral of the tongue, followed by gingivae (n = 11), and buccal mucosa and retromolar trigone (n = 7). Despite the fact that the most commonly affected area in the oral cavity of patients who underwent HSCT and had other diseases besides FA was the tongue, the number of salivary gland cancers is representative (28%). This result, however, did not happen in the FA oral cancer cases reported here. In fact, the results showed no differences in the oral cancer location when comparing the subgroups of patients who did and did not undergo HSCT, with the exception of mandibular and retromolar cancer that occurred only in non-HSCT patients. Patients affected by FA also had a tendency to develop multiple malignancies (Kutler et al., 2015). To illustrate, in this review we observed that 14 patients had cancer recurrence and 34 developed a new primary tumor. All the cases shown were subject to visual examination and early diagnosis. Specialists recommended their patients to have an oral examination every 6 months (Majhail et al., 2012). Accordingly, this population must be monitored very closely by a team of dentists and physicians. Regarding patients affected by FA with a history of precancerous leukoplakia or recurrent oral lesions, head and neck examinations are recommended every 6–8 weeks (Kutler et al., 2015). Therefore, although Kutler et al. (2015) suggested the screening of the oral cavity and oropharynx to start prior to 15 years of age, this review recommends that it must begin even earlier, since the first oral cancer case published occurred at the age of 10 years old, and in eight patients who were under 15 years of age (Kutler et al., 2015). Given the results shown, we acknowledge that this review has a limitation in the sense that many cases of oral cancer in FA patients have probably not been published, since unsuccessful treatment cases could be interpreted as less valuable for publication. Besides, there was the impossibility of excluding duplicated cases in the selected data due to the absence of information. Finally, considering that patients with FA present a very high risk for cancer, we suggest the thorough study of oral cancer prevention strategies to better assist this population. Moreover, mouth self-examination is recommended as a secondary prevention tool and,
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