Pediatr Blood Cancer 2015;62:1024–1026
Oral Leukoplakia in Patients With Fanconi Anaemia Without Hematopoietic Stem Cell Transplantation Laura Grein Cavalcanti, DDS, MSc,1* Karine Fa´tima Lyko, DDS, MSc,1 Renata Lins Fuentes Arau´jo, DDS, MSc,1 Jose´ Miguel Amena´bar, DDS, PhD,2 Carmem Bonfim, Physician, PhD,3 and Cassius Carvalho Torres-Pereira, DDS, PhD2 Background. Fanconi anaemia is a genetic disease characterized by congenital abnormalities, progressive bone marrow failure, and a higher predisposition of oral squamous cell carcinoma. The purpose of this study was to evaluate the prevalence of oral mucosa lesions in patients with Fanconi anaemia without hematopoietic stem cell transplantation (HSCT). Procedure. Patients with Fanconi anaemia who had not undergone HSCT was cross-sectional evaluated for the presence of oral lesions. Results. The sample was composed of 78 male and 60 female patients, with a median age of 9 years. Of the 138 patients, approximately 45% manifested at least one oral mucosa abnormality: 35 patients (25%) presented with traumatic injuries, and 16 (12%) exhibited leukoplakia. The
Key words:
following lesions were observed in low prevalence: aphthous ulcers, atrophic tongue, petechiae and hematomas, gingival hyperplasia, mucoceles, herpes, hyperpigmentation, haemangioma, non-neoplastic proliferative lesions, neutropenic ulcers, papilloma, and candidiasis. Conclusion. There was a high prevalence of oral leukoplakias in patients with Fanconi anaemia who had not undergone HSCT. It highlights the need of regular oral screenings in this cohort of concern for head and neck malignancies and suggests that oral leukoplakias should be further investigated as art of the syndrome phenotype. Pediatr Blood Cancer 2015;62:1024–1026. # 2015 Wiley Periodicals, Inc.
diagnostics; Fanconi anaemia; oncology; oral cancer; oral manifestations
INTRODUCTION Fanconi anaemia (FA) is an autosomal recessive disease with a birth incidence of approximately one in 360,000 [1–3]. The basic defect in FA is faulty DNA repair and the disease is characterized by several congenital anomalies, such as progressive bone marrow failure, short stature, skin pigmentations (cafe´ au lait), renal malformations, abnormal thumbs, and an increased susceptibility to malignancies [2–8]. For the treatment of haematological disorders, patients with FA are often submitted to haematopoietic stem cell transplantation (HSCT), which is thought to increase the risk for squamous cell carcinoma, an adverse risk factor for death, even in patients with FA who did not receive transplants [1,9]. There are few reports describing the prevalence of oral lesions in patients with FA. Only three studies have evaluated FA subjects prior to HSCT, but both of these involved smaller samples and emphasized periodontal manifestations related to biofilm accumulation, such as gingivitis and periodontitis, while the present research focused on oral soft tissue lesions [5,10–11]. The evaluation of oral mucosa in patients with FA is important because of the bone marrow failure that is associated with this disease; in addition, because some patients with FA will be subjected to HSCT, they must undergo immunosuppression treatment that makes the patients prone to complications, including the development of new oral lesions [4]. Thus, the purpose of this study is to investigate the prevalence of soft tissue lesions in patients with FA who have not undergone HSCT.
patient, or his/her parent, was asked to sign an informed consent form. All patients were examined for the presence of oral lesions in a dental unit under reflective light at the Bone Marrow Transplantation Unit Dental Office in HC-UFPR. The oral mucosa was dried with gauze and an air syringe and was then observed for any alterations, excluding those compatible with normal oral structures or anatomic variations. A clinical diagnosis was established, by one oral medicine specialist, for each patient according to the International Classification of Diseases from the World Health Organization (WHO). Oral biopsies and exfoliative cytology were taken whenever indicated and according to systemic health status. The WHO classic definition of oral leukoplakia (“a white patch or plaque that cannot be characterized, clinically or pathologically as any other disease”) was used to classify white lesions [12]. A statistical analysis between the presence of leukoplakia and patients’ age was performed using the Mann– Whitney test.
RESULTS This study included 138 patients. Of these, 78 (57%) were male, 60 (43%) were female, and the median age was 9 years (range ¼ 1–38 years). The research revealed that 44% (n ¼ 61) of the study population expressed some form of abnormality in the oral mucosa, and 17% (n ¼ 27) of these individuals had more than one 1
Universidade Federal do Parana´, Curitiba, Parana´, Brazil; Department of Stomatology, Universidade Federal do Parana´, Curitiba, Parana´, Brazil; 3Bone Marrow Transplantation Service, Hospital de Clı´nicas, Universidade Federal do Parana´, Curitiba, Parana´, Brazil 2
SUBJECTS AND METHODS This cross-sectional study was performed between March, 2010 and April, 2014. All new patients, of both genders, who were admitted to the Bone Marrow Transplantation Unit of the Hospital de Clı´nicas of Universidade Federal do Parana´ (HC-UFPR), who had a confirmed FA diagnosis (positive diepoxy-butane [DEB] test), and who had not undergone to HSCT were evaluated. No age limits were established. This study was approved by the Ethics Committee in Research of the HC-UFPR, and prior to oral examination, each C
2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25417 Published online 15 February 2015 in Wiley Online Library (wileyonlinelibrary.com).
Conflict of interest: We certify that there is no conflict of interest with any financial organization in this paper.
Correspondence to: Laura Grein Cavalcanti, Universidade Federal do Parana´, Dom Pedro II st, Batel, Curitiba, Parana´ 80420-060, Brazil. E-mail: [email protected] Received 2 May 2014; Accepted 12 November 2014
Fanconi Anaemia and Oral Lesions lesion. Traumatic injuries were the most prevalent alteration, being observed in 35 patients (25%). Among the patients with traumatic injuries, 34 (25% of the total study population) presented erosion or ulcers, and 11 individuals (8% of the total population) exhibited lesions that were characterized as frictional hyperkeratosis. A high number of individuals (n ¼ 16; 12%) exhibited at least one leukoplakia according to WHO diagnostic criteria, and the hard palate was the location most affected by these lesions. Infectious lesions, such as papillomas, candidiasis, and herpes, were also observed. Aphthous lesions, petechiae/haematoma, gingival hyperplasia, atrophic tongue, and mucocele were noted in 7 (5%), 7 (5%), 3 (2%), 2 (1.5%), and 2 (1,5%) patients, respectively. Other oral lesions, such as tongue hyperpigmentation, haemangioma, nonneoplastic proliferative lesions, and neutropenic ulcers, were observed in one individual each (1%). These results are reported in detail in Table I. The overall occurrence of lesions was more frequent in females. More than 46% of the female patients exhibited some abnormality in the oral mucosa, while 42% of the males had oral lesions. Traumatic injuries were more prevalent in males (n ¼ 20; 57%), and the median age for patients with these injuries was 12 years. The observed injuries included lesions caused by cheek, lip and tongue biting, and frictional keratosis lesions, as shown in Table II. The group of individuals who manifested leukoplakia had higher median age (16.5 years) than the group of patients that did not present this lesion (9 years) (P < 0.001). Moreover, although the frequency of leukoplakia had been higher among males (n ¼ 10; 63%) than females (n ¼ 6; 37%), the median age of males with leukoplakia was lower (13.5 years) than the median age of female patients (22.5 years).
DISCUSSION A high prevalence of oral manifestations was observed in patients in this study. Almost 45% of the individuals presented with at least one oral mucosa lesion. Prior to this study, oral manifestations were described mostly in case reports, and only a few studies, with small samples, could be identified. Most of these publications described post-HSCT oral malignant transformation,
1025
but little is known about the oral mucosa status in this cohort of patients prior to the HSCT. Moreover, differently from other studies, the present research has focused exclusively on oral mucosa diseases. No attempt was made to describe dental abnormalities or dental biofilm-related conditions. Detailed comparisons with non-FA individuals are difficult because few epidemiological studies have described the prevalence of oral lesions in children and adolescents. The absence of a control group is a limitation of the present research. However, patients with FA of the present cohort seem to have presented a considerably higher prevalence (44%) of oral lesions when compared with a previous study conducted in children and adolescents with no haematological disorders, which reported a prevalence of 10.3% (n ¼ 10,030) [13]. The authors reported that approximately 2% of patients exhibited lip and cheek biting lesions, 1.4% presented with herpes, 0.1% had gingival hyperplasia, 0.1% had fistulae, and 0.04% presented mucoceles. Similarly, the most prevalent soft tissue alterations noted in the present cohort were traumatic injuries, especially cheek biting lesions. The others lesions observed were each found to have a similar prevalence to that reported in Shulman’s study [13], with the exception of herpes, which exhibited a higher prevalence. Otan et al. [2] reported two cases of aphthous ulcers in siblings with FA. In the present study, this lesion was observed in seven patients (5% of study participants). In addition, Arau´jo et al. [10] and Ac¸ikgoz et al. [5] reported the presence of aphthous lesions in 9.1% and 13.5% of patients, respectively. These numbers are high in a cross-sectional study, but must be interpreted with caution because aphthous ulcers have temporary manifestations with known spontaneous remission. On the other hand, the results add to the available evidence of a supposed higher susceptibility of apthous ulcers in FA. Arau´jo et al. [10] reported that 30.3% (n ¼ 10) of population of patients with FA exhibited petechiae and hematoma. However, in the present study, these alterations were observed in only seven patients (5%). The haematologic status was variable, and most of study participants did not require blood transfusion, although had lower level of leukocytes and platelets than a normal population. Most of the individuals were treated with androgens, and were
TABLE I. Prevalence and Distribution of Oral Lesions in Non-HSCT Treated Patients with Fanconi Anaemia Gender Lesion Traumatic lesions Leukoplakia Aphthous ulcers Petechiae/Hematoma Gingival hyperplasia Atrophic tongue Mucocele Herpes Hyperpigmentation Hemangioma Proliferative lesion Neutropneic ulcer Papilloma Candidiasis
Number of patients
Male (n)
Female (n)
Median age
Prevalent site
Number of lesions (n)
25% (n ¼ 35) 12% (n ¼ 16) 5% (n ¼ 7) 5% (n ¼ 7) 2% (n ¼ 3) 1.5% (n ¼ 2) 1.5% (n ¼ 2) 1.5% (n ¼ 2) 1% (n ¼ 1) 1% (n ¼ 1) 1% (n ¼ 1) 1% (n ¼ 1) 1% (n ¼ 1) 1% (n ¼ 1)
20 10 2 5 1 2 1 2 0 1 1 1 0 1
15 6 5 2 2 0 1 0 1 0 0 0 1 0
12 16,5 9 12 6 17,5 10.5 10 6 12 11 29 11 36
Buccal mucosa Hard palate Lip Generalized Anterosuperior Tongue dorsum Lip mucosa and soft palate Lip Tongue dorsum Tongue dorsum Buccal mucosa Buccal mucosa Ventral tongue Generalized
64 25 6 Not applicable 3 2 2 2 1 1 1 1 1 Not applicable
Pediatr Blood Cancer DOI 10.1002/pbc
1026
Cavalcanti et al.
TABLE II. Prevalence of Traumatic Lesions in Non-HSCT-Treated Patients With Fanconi Anaemia Traumatic lesion Cheek biting Tongue biting Lip biting Frictional keratosis
Percentage of patients (n) 20% (28) 9% (12) 4% (6) 8% (11)
Curitiba, Brazil. March, 2010–April, 2014.
clinically controlled or were not yet in an advanced stage of bone marrow failure. The annual malignant transformation rate of oral leukoplakias in healthy individuals is approximately 2% and patients with FA have a 700-fold higher risk to develop head and neck squamous cell carcinoma than the general population [14–15]. The number of white oral lesions that were not related to direct trauma to the oral mucosa was 12% in this sample. In a clinical setting for the treatment of patients with a presumably higher risk for oral malignant transformation, such as those with FA, the correct identification of oral mucosa alterations, particularly leukoplakia, is an important clinical endpoint and can define specific diagnostic, therapeutic, and proservation strategies. Tekcicek and co-workers [4] did not find leukoplakias or other potentially malignant oral lesions in a sample of 26 patients with FA. Similarly, Ac¸ikgo¨z et al. [5] and Arau´jo et al. [10] did not report oral leukoplakias in samples consisting, respectively, of 33 and 15 patients with FA who were not submitted to HSCT. The differences between the results reported in these previous studies and those reported herein, which identified a prevalence of 12% for leukoplakias in patients with FA, might be explained by the larger sample in the present cohort of patients with FA not subjected to HSCT (n ¼ 138). Also, these numbers could be influenced by the specific oral mucosa lesion-oriented approach of the present study, which could have identified oral lesions more frequently. Carrard et al. [16] observed leukoplakia associated with smoking and drinking habits in approximately 1% of their patients who lacked haematological disorders, and only one of those cases (0.2% of the study population) was observed in the younger group, who ranged from 14 to 29 years of age. Shulman [13] noted, in a population of children comparable in age to that of the present study, but lacking FA, one case (0.01%) of homogeneous leukoplakia and a 0.3% prevalence of frictional white lesions. The oral leukoplakia lesions that were diagnosed in the patients with FA of our study appeared to resemble the lesions that are commonly observed in Dyskeratosis Congenita, a syndrome for which oral leukoplakia is a frequently described characteristic [1,17–18]. Oral biopsies and cytology of these specimens failed to show high grade dysplasia and revealed a common finding of hyperkeratosis and acanthosis with none or non-specific
Pediatr Blood Cancer DOI 10.1002/pbc
pathological inflammatory response. Although the diagnosis of leukoplakia is a difficult and typical exclusion diagnosis, oral white patches can be distinguished in a comprehensive clinical oral examination context. The presence of these lesions is considered a relevant endpoint in screening strategies for oral cancer. The clinical significance of the presence of oral leukoplakias prior to HSCT and the relationship between pre-HSCT leukoplakias and subsequent oral malignant transformation in patients with FA, however, has not been established. Moreover, the prevalence of white hyperkeratotic frictional lesions that was observed in this study reinforces the need to establish this differential diagnosis, especially by non-oralmedicine specialists of the HSCT team, in order to establish appropriate strategies for therapeutics and prognoses. Future investigations should focus on longitudinal research designs of the oral mucosa to identify potentially malignant oral lesions in patients with FA. The present study demonstrates an important prevalence of oral lesions in patients with FA, especially non-traumatic oral white lesions, which could be classified clinically as leukoplakias. Our results suggest that oral leukoplakia could be an underreported feature of the FA syndrome phenotype.
REFERENCES 1. Masserot C, Peffault de Latour R, Rocha V, Leblanc T, Rigolet A, Pascal F, Janin A, Soulier J, Gluckman E, Socie´ G. Head and neck squamous cell carcinoma in 13 patients with Fanconi anemia after hematopoietic stem cell transplantation. Cancer 2008;113:3315–3322. ¨ zkan B. Recurrent aphthous ulcers in Fanconi’s anaemia: A case 2. Otan F, Ac¸ikgo¨z G, Sakallioglu U, O report. Int J Paediat Dent 2004;14:214–217. 3. Pasquini R, Zanis Neto J, Medeiros CR, Bitencourt MA, Bonfim CMS, Moreira VA, Setu´bal DC, Flowers MED, Kupka e, Arau´jo MV. Squamous cell carcinoma of the tongue due to Fanconi’s Anemia after bone marrow transplantation. Rev Bras Hematol Hemoter 2003;25:239–246. 4. Tekcicek M, Tavil B, Cakar A, Pinar A, Unal S, Gumruk F. Oral and dental findings in children with Fanconi anemia. Pediatr Dent 2007;29:248–252. 5. Ac¸ikgo¨z A, Ozden FO, Fisgin T, Ac¸ikgo¨z G, Duru F, Yarali N, Albayrak D. Oral and dental findings in Fanconi’s anemia. Pediatr Hematol Oncol 2005;22:531–539. 6. Alter BP. Diagnosis, genetics, and management of inherited bone marrow failure syndromes. Hematology Am Soc Hematol Educ Program 2007;29–39. 7. Gasparini G, Longobardi G, Boniello R, Di Petrillo A, Pelo S. Fanconi anemia manifesting as a squamous cell carcinoma of the hard palate: A case report. Head & Face Med 2006;2:1–5. 8. Torres-Pereira CC, Stramandinoli-Zanicotti RT, Amena´bar JM, Sassi LM, Galbiatti Pedruzzi PA, Piazzetta CM, Bonfim C. Oral squamous cell carcinoma in two siblings with Fanconi anemia after allogenic bone marrow transplantation. Spec Care Dentist 2013; doi: 10.1111/scd.12058. [Epub ahead of print]. 9. Rosenberg PS, Socie´ G, Alter BP, Gluckman E. Risk of head and neck squamous cell cancer and death in patients with Fanconi anemia who did and did not receive transplants. Blood 2005;105:67–73. 10. de Arau´jo MR, Ribas MO, Koubik ACGA, Mattioli T, de Lima AA, Franc¸a BH. Fanconi’s anemia: Clinical and radiographic oral manifestations. Oral Diseases 2007;13:291–295. 11. Lyko K, Bonfim C, Benelli EM, Torres-Pereira CC, Amena´bar JM. Salivary detection of periodontopathic bacteria in Fanconi’s anemia patients. Anaerobe 2013; Sep 19. pii: S 1075–9964 (13) 00153–4. [Epub ahead of print]. 12. WHO collaborating center for oral precancerous lesions. Definition of leukoplakia and related lesions. An aid to studies on oral precancer. Oral Surg Oral Med Oral Pathol 1978;4:518–539. 13. Shulman JD. Prevalence of oral mucosal lesions in children and youths in the USA. Int J Paediatr Dent 2005;15:89–97. 14. Van der Waal I. Potentially malignant disorders of the oral and oropharyngeal mucosa; terminology, classification and present concepts of management. Oral Oncol 2009;45:317–323. 15. Alter BP. Fanconı´’s anemia, transplantation, and cancer. Pediatric Transplantation 2005;9:81–86. 16. Carrard VC, Haas AH, Rados PV, Filho M, Oppermann R, Albandar J, Susin C. Prevalence and risk indicators of oral mucosal lesions in an urban population from South Brazil. Oral Diseases 2011;17: 171–179. 17. Atkinson JC, Harvey KE, Domingo DL, Trujillo MI, Guadagnini JP, Gollins S, Giri N, Hart TC, Alter BP. Oral and dental phenotype of dyskeratosis congenital. Oral Disease 2008;14:419–427. 18. Handley TP, McCaul JA, Ogden GR. Dyskeratosis congenita - Review article. Oral Oncol 2006;42: 331–336.
Oral Leukoplakia in Patients With Fanconi Anaemia Without Hematopoietic Stem Cell Transplantation Laura Grein Cavalcanti, DDS, MSc,1* Karine Fa´tima Lyko, DDS, MSc,1 Renata Lins Fuentes Arau´jo, DDS, MSc,1 Jose´ Miguel Amena´bar, DDS, PhD,2 Carmem Bonfim, Physician, PhD,3 and Cassius Carvalho Torres-Pereira, DDS, PhD2 Background. Fanconi anaemia is a genetic disease characterized by congenital abnormalities, progressive bone marrow failure, and a higher predisposition of oral squamous cell carcinoma. The purpose of this study was to evaluate the prevalence of oral mucosa lesions in patients with Fanconi anaemia without hematopoietic stem cell transplantation (HSCT). Procedure. Patients with Fanconi anaemia who had not undergone HSCT was cross-sectional evaluated for the presence of oral lesions. Results. The sample was composed of 78 male and 60 female patients, with a median age of 9 years. Of the 138 patients, approximately 45% manifested at least one oral mucosa abnormality: 35 patients (25%) presented with traumatic injuries, and 16 (12%) exhibited leukoplakia. The
Key words:
following lesions were observed in low prevalence: aphthous ulcers, atrophic tongue, petechiae and hematomas, gingival hyperplasia, mucoceles, herpes, hyperpigmentation, haemangioma, non-neoplastic proliferative lesions, neutropenic ulcers, papilloma, and candidiasis. Conclusion. There was a high prevalence of oral leukoplakias in patients with Fanconi anaemia who had not undergone HSCT. It highlights the need of regular oral screenings in this cohort of concern for head and neck malignancies and suggests that oral leukoplakias should be further investigated as art of the syndrome phenotype. Pediatr Blood Cancer 2015;62:1024–1026. # 2015 Wiley Periodicals, Inc.
diagnostics; Fanconi anaemia; oncology; oral cancer; oral manifestations
INTRODUCTION Fanconi anaemia (FA) is an autosomal recessive disease with a birth incidence of approximately one in 360,000 [1–3]. The basic defect in FA is faulty DNA repair and the disease is characterized by several congenital anomalies, such as progressive bone marrow failure, short stature, skin pigmentations (cafe´ au lait), renal malformations, abnormal thumbs, and an increased susceptibility to malignancies [2–8]. For the treatment of haematological disorders, patients with FA are often submitted to haematopoietic stem cell transplantation (HSCT), which is thought to increase the risk for squamous cell carcinoma, an adverse risk factor for death, even in patients with FA who did not receive transplants [1,9]. There are few reports describing the prevalence of oral lesions in patients with FA. Only three studies have evaluated FA subjects prior to HSCT, but both of these involved smaller samples and emphasized periodontal manifestations related to biofilm accumulation, such as gingivitis and periodontitis, while the present research focused on oral soft tissue lesions [5,10–11]. The evaluation of oral mucosa in patients with FA is important because of the bone marrow failure that is associated with this disease; in addition, because some patients with FA will be subjected to HSCT, they must undergo immunosuppression treatment that makes the patients prone to complications, including the development of new oral lesions [4]. Thus, the purpose of this study is to investigate the prevalence of soft tissue lesions in patients with FA who have not undergone HSCT.
patient, or his/her parent, was asked to sign an informed consent form. All patients were examined for the presence of oral lesions in a dental unit under reflective light at the Bone Marrow Transplantation Unit Dental Office in HC-UFPR. The oral mucosa was dried with gauze and an air syringe and was then observed for any alterations, excluding those compatible with normal oral structures or anatomic variations. A clinical diagnosis was established, by one oral medicine specialist, for each patient according to the International Classification of Diseases from the World Health Organization (WHO). Oral biopsies and exfoliative cytology were taken whenever indicated and according to systemic health status. The WHO classic definition of oral leukoplakia (“a white patch or plaque that cannot be characterized, clinically or pathologically as any other disease”) was used to classify white lesions [12]. A statistical analysis between the presence of leukoplakia and patients’ age was performed using the Mann– Whitney test.
RESULTS This study included 138 patients. Of these, 78 (57%) were male, 60 (43%) were female, and the median age was 9 years (range ¼ 1–38 years). The research revealed that 44% (n ¼ 61) of the study population expressed some form of abnormality in the oral mucosa, and 17% (n ¼ 27) of these individuals had more than one 1
Universidade Federal do Parana´, Curitiba, Parana´, Brazil; Department of Stomatology, Universidade Federal do Parana´, Curitiba, Parana´, Brazil; 3Bone Marrow Transplantation Service, Hospital de Clı´nicas, Universidade Federal do Parana´, Curitiba, Parana´, Brazil 2
SUBJECTS AND METHODS This cross-sectional study was performed between March, 2010 and April, 2014. All new patients, of both genders, who were admitted to the Bone Marrow Transplantation Unit of the Hospital de Clı´nicas of Universidade Federal do Parana´ (HC-UFPR), who had a confirmed FA diagnosis (positive diepoxy-butane [DEB] test), and who had not undergone to HSCT were evaluated. No age limits were established. This study was approved by the Ethics Committee in Research of the HC-UFPR, and prior to oral examination, each C
2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25417 Published online 15 February 2015 in Wiley Online Library (wileyonlinelibrary.com).
Conflict of interest: We certify that there is no conflict of interest with any financial organization in this paper.
Correspondence to: Laura Grein Cavalcanti, Universidade Federal do Parana´, Dom Pedro II st, Batel, Curitiba, Parana´ 80420-060, Brazil. E-mail: [email protected] Received 2 May 2014; Accepted 12 November 2014
Fanconi Anaemia and Oral Lesions lesion. Traumatic injuries were the most prevalent alteration, being observed in 35 patients (25%). Among the patients with traumatic injuries, 34 (25% of the total study population) presented erosion or ulcers, and 11 individuals (8% of the total population) exhibited lesions that were characterized as frictional hyperkeratosis. A high number of individuals (n ¼ 16; 12%) exhibited at least one leukoplakia according to WHO diagnostic criteria, and the hard palate was the location most affected by these lesions. Infectious lesions, such as papillomas, candidiasis, and herpes, were also observed. Aphthous lesions, petechiae/haematoma, gingival hyperplasia, atrophic tongue, and mucocele were noted in 7 (5%), 7 (5%), 3 (2%), 2 (1.5%), and 2 (1,5%) patients, respectively. Other oral lesions, such as tongue hyperpigmentation, haemangioma, nonneoplastic proliferative lesions, and neutropenic ulcers, were observed in one individual each (1%). These results are reported in detail in Table I. The overall occurrence of lesions was more frequent in females. More than 46% of the female patients exhibited some abnormality in the oral mucosa, while 42% of the males had oral lesions. Traumatic injuries were more prevalent in males (n ¼ 20; 57%), and the median age for patients with these injuries was 12 years. The observed injuries included lesions caused by cheek, lip and tongue biting, and frictional keratosis lesions, as shown in Table II. The group of individuals who manifested leukoplakia had higher median age (16.5 years) than the group of patients that did not present this lesion (9 years) (P < 0.001). Moreover, although the frequency of leukoplakia had been higher among males (n ¼ 10; 63%) than females (n ¼ 6; 37%), the median age of males with leukoplakia was lower (13.5 years) than the median age of female patients (22.5 years).
DISCUSSION A high prevalence of oral manifestations was observed in patients in this study. Almost 45% of the individuals presented with at least one oral mucosa lesion. Prior to this study, oral manifestations were described mostly in case reports, and only a few studies, with small samples, could be identified. Most of these publications described post-HSCT oral malignant transformation,
1025
but little is known about the oral mucosa status in this cohort of patients prior to the HSCT. Moreover, differently from other studies, the present research has focused exclusively on oral mucosa diseases. No attempt was made to describe dental abnormalities or dental biofilm-related conditions. Detailed comparisons with non-FA individuals are difficult because few epidemiological studies have described the prevalence of oral lesions in children and adolescents. The absence of a control group is a limitation of the present research. However, patients with FA of the present cohort seem to have presented a considerably higher prevalence (44%) of oral lesions when compared with a previous study conducted in children and adolescents with no haematological disorders, which reported a prevalence of 10.3% (n ¼ 10,030) [13]. The authors reported that approximately 2% of patients exhibited lip and cheek biting lesions, 1.4% presented with herpes, 0.1% had gingival hyperplasia, 0.1% had fistulae, and 0.04% presented mucoceles. Similarly, the most prevalent soft tissue alterations noted in the present cohort were traumatic injuries, especially cheek biting lesions. The others lesions observed were each found to have a similar prevalence to that reported in Shulman’s study [13], with the exception of herpes, which exhibited a higher prevalence. Otan et al. [2] reported two cases of aphthous ulcers in siblings with FA. In the present study, this lesion was observed in seven patients (5% of study participants). In addition, Arau´jo et al. [10] and Ac¸ikgoz et al. [5] reported the presence of aphthous lesions in 9.1% and 13.5% of patients, respectively. These numbers are high in a cross-sectional study, but must be interpreted with caution because aphthous ulcers have temporary manifestations with known spontaneous remission. On the other hand, the results add to the available evidence of a supposed higher susceptibility of apthous ulcers in FA. Arau´jo et al. [10] reported that 30.3% (n ¼ 10) of population of patients with FA exhibited petechiae and hematoma. However, in the present study, these alterations were observed in only seven patients (5%). The haematologic status was variable, and most of study participants did not require blood transfusion, although had lower level of leukocytes and platelets than a normal population. Most of the individuals were treated with androgens, and were
TABLE I. Prevalence and Distribution of Oral Lesions in Non-HSCT Treated Patients with Fanconi Anaemia Gender Lesion Traumatic lesions Leukoplakia Aphthous ulcers Petechiae/Hematoma Gingival hyperplasia Atrophic tongue Mucocele Herpes Hyperpigmentation Hemangioma Proliferative lesion Neutropneic ulcer Papilloma Candidiasis
Number of patients
Male (n)
Female (n)
Median age
Prevalent site
Number of lesions (n)
25% (n ¼ 35) 12% (n ¼ 16) 5% (n ¼ 7) 5% (n ¼ 7) 2% (n ¼ 3) 1.5% (n ¼ 2) 1.5% (n ¼ 2) 1.5% (n ¼ 2) 1% (n ¼ 1) 1% (n ¼ 1) 1% (n ¼ 1) 1% (n ¼ 1) 1% (n ¼ 1) 1% (n ¼ 1)
20 10 2 5 1 2 1 2 0 1 1 1 0 1
15 6 5 2 2 0 1 0 1 0 0 0 1 0
12 16,5 9 12 6 17,5 10.5 10 6 12 11 29 11 36
Buccal mucosa Hard palate Lip Generalized Anterosuperior Tongue dorsum Lip mucosa and soft palate Lip Tongue dorsum Tongue dorsum Buccal mucosa Buccal mucosa Ventral tongue Generalized
64 25 6 Not applicable 3 2 2 2 1 1 1 1 1 Not applicable
Pediatr Blood Cancer DOI 10.1002/pbc
1026
Cavalcanti et al.
TABLE II. Prevalence of Traumatic Lesions in Non-HSCT-Treated Patients With Fanconi Anaemia Traumatic lesion Cheek biting Tongue biting Lip biting Frictional keratosis
Percentage of patients (n) 20% (28) 9% (12) 4% (6) 8% (11)
Curitiba, Brazil. March, 2010–April, 2014.
clinically controlled or were not yet in an advanced stage of bone marrow failure. The annual malignant transformation rate of oral leukoplakias in healthy individuals is approximately 2% and patients with FA have a 700-fold higher risk to develop head and neck squamous cell carcinoma than the general population [14–15]. The number of white oral lesions that were not related to direct trauma to the oral mucosa was 12% in this sample. In a clinical setting for the treatment of patients with a presumably higher risk for oral malignant transformation, such as those with FA, the correct identification of oral mucosa alterations, particularly leukoplakia, is an important clinical endpoint and can define specific diagnostic, therapeutic, and proservation strategies. Tekcicek and co-workers [4] did not find leukoplakias or other potentially malignant oral lesions in a sample of 26 patients with FA. Similarly, Ac¸ikgo¨z et al. [5] and Arau´jo et al. [10] did not report oral leukoplakias in samples consisting, respectively, of 33 and 15 patients with FA who were not submitted to HSCT. The differences between the results reported in these previous studies and those reported herein, which identified a prevalence of 12% for leukoplakias in patients with FA, might be explained by the larger sample in the present cohort of patients with FA not subjected to HSCT (n ¼ 138). Also, these numbers could be influenced by the specific oral mucosa lesion-oriented approach of the present study, which could have identified oral lesions more frequently. Carrard et al. [16] observed leukoplakia associated with smoking and drinking habits in approximately 1% of their patients who lacked haematological disorders, and only one of those cases (0.2% of the study population) was observed in the younger group, who ranged from 14 to 29 years of age. Shulman [13] noted, in a population of children comparable in age to that of the present study, but lacking FA, one case (0.01%) of homogeneous leukoplakia and a 0.3% prevalence of frictional white lesions. The oral leukoplakia lesions that were diagnosed in the patients with FA of our study appeared to resemble the lesions that are commonly observed in Dyskeratosis Congenita, a syndrome for which oral leukoplakia is a frequently described characteristic [1,17–18]. Oral biopsies and cytology of these specimens failed to show high grade dysplasia and revealed a common finding of hyperkeratosis and acanthosis with none or non-specific
Pediatr Blood Cancer DOI 10.1002/pbc
pathological inflammatory response. Although the diagnosis of leukoplakia is a difficult and typical exclusion diagnosis, oral white patches can be distinguished in a comprehensive clinical oral examination context. The presence of these lesions is considered a relevant endpoint in screening strategies for oral cancer. The clinical significance of the presence of oral leukoplakias prior to HSCT and the relationship between pre-HSCT leukoplakias and subsequent oral malignant transformation in patients with FA, however, has not been established. Moreover, the prevalence of white hyperkeratotic frictional lesions that was observed in this study reinforces the need to establish this differential diagnosis, especially by non-oralmedicine specialists of the HSCT team, in order to establish appropriate strategies for therapeutics and prognoses. Future investigations should focus on longitudinal research designs of the oral mucosa to identify potentially malignant oral lesions in patients with FA. The present study demonstrates an important prevalence of oral lesions in patients with FA, especially non-traumatic oral white lesions, which could be classified clinically as leukoplakias. Our results suggest that oral leukoplakia could be an underreported feature of the FA syndrome phenotype.
REFERENCES 1. Masserot C, Peffault de Latour R, Rocha V, Leblanc T, Rigolet A, Pascal F, Janin A, Soulier J, Gluckman E, Socie´ G. Head and neck squamous cell carcinoma in 13 patients with Fanconi anemia after hematopoietic stem cell transplantation. Cancer 2008;113:3315–3322. ¨ zkan B. Recurrent aphthous ulcers in Fanconi’s anaemia: A case 2. Otan F, Ac¸ikgo¨z G, Sakallioglu U, O report. Int J Paediat Dent 2004;14:214–217. 3. Pasquini R, Zanis Neto J, Medeiros CR, Bitencourt MA, Bonfim CMS, Moreira VA, Setu´bal DC, Flowers MED, Kupka e, Arau´jo MV. Squamous cell carcinoma of the tongue due to Fanconi’s Anemia after bone marrow transplantation. Rev Bras Hematol Hemoter 2003;25:239–246. 4. Tekcicek M, Tavil B, Cakar A, Pinar A, Unal S, Gumruk F. Oral and dental findings in children with Fanconi anemia. Pediatr Dent 2007;29:248–252. 5. Ac¸ikgo¨z A, Ozden FO, Fisgin T, Ac¸ikgo¨z G, Duru F, Yarali N, Albayrak D. Oral and dental findings in Fanconi’s anemia. Pediatr Hematol Oncol 2005;22:531–539. 6. Alter BP. Diagnosis, genetics, and management of inherited bone marrow failure syndromes. Hematology Am Soc Hematol Educ Program 2007;29–39. 7. Gasparini G, Longobardi G, Boniello R, Di Petrillo A, Pelo S. Fanconi anemia manifesting as a squamous cell carcinoma of the hard palate: A case report. Head & Face Med 2006;2:1–5. 8. Torres-Pereira CC, Stramandinoli-Zanicotti RT, Amena´bar JM, Sassi LM, Galbiatti Pedruzzi PA, Piazzetta CM, Bonfim C. Oral squamous cell carcinoma in two siblings with Fanconi anemia after allogenic bone marrow transplantation. Spec Care Dentist 2013; doi: 10.1111/scd.12058. [Epub ahead of print]. 9. Rosenberg PS, Socie´ G, Alter BP, Gluckman E. Risk of head and neck squamous cell cancer and death in patients with Fanconi anemia who did and did not receive transplants. Blood 2005;105:67–73. 10. de Arau´jo MR, Ribas MO, Koubik ACGA, Mattioli T, de Lima AA, Franc¸a BH. Fanconi’s anemia: Clinical and radiographic oral manifestations. Oral Diseases 2007;13:291–295. 11. Lyko K, Bonfim C, Benelli EM, Torres-Pereira CC, Amena´bar JM. Salivary detection of periodontopathic bacteria in Fanconi’s anemia patients. Anaerobe 2013; Sep 19. pii: S 1075–9964 (13) 00153–4. [Epub ahead of print]. 12. WHO collaborating center for oral precancerous lesions. Definition of leukoplakia and related lesions. An aid to studies on oral precancer. Oral Surg Oral Med Oral Pathol 1978;4:518–539. 13. Shulman JD. Prevalence of oral mucosal lesions in children and youths in the USA. Int J Paediatr Dent 2005;15:89–97. 14. Van der Waal I. Potentially malignant disorders of the oral and oropharyngeal mucosa; terminology, classification and present concepts of management. Oral Oncol 2009;45:317–323. 15. Alter BP. Fanconı´’s anemia, transplantation, and cancer. Pediatric Transplantation 2005;9:81–86. 16. Carrard VC, Haas AH, Rados PV, Filho M, Oppermann R, Albandar J, Susin C. Prevalence and risk indicators of oral mucosal lesions in an urban population from South Brazil. Oral Diseases 2011;17: 171–179. 17. Atkinson JC, Harvey KE, Domingo DL, Trujillo MI, Guadagnini JP, Gollins S, Giri N, Hart TC, Alter BP. Oral and dental phenotype of dyskeratosis congenital. Oral Disease 2008;14:419–427. 18. Handley TP, McCaul JA, Ogden GR. Dyskeratosis congenita - Review article. Oral Oncol 2006;42: 331–336.
