- Email: [email protected]
Slaked lime and betel nut cancer in Papua New Guinea
577
SLVL is confirmed, the role of other aetiological factors, especially viruses, in lymphomagenesis should be
TABLE I-SITE OF ORAL CANCER ACCORDING TO WHICH SIDE LIME IS APPLIED
investigated. We thank ProfD. Catovsky for reviewing morphology; ProfD. Mason and colleagues for advice on lymphocyte phenotyping; the protein reference laboratory, Queen Mary’s Hospital, Roehampton; and Dr T. Rabbitts and Prof Y. Tsulimoto for the probes. 1. B. is a Wellcome Research Fellow and T. R. a Wellcome University Award Lecturer.
REFERENCES 1. Melo JV, Robinson DSF, Gregory C, Catovsky D. Splenic B cell lymphoma with "villous" lymphocytes in the peripheral blood: a disorder distinct from hairy cell leukaemia. Leukaemia 1987; 1: 294-99. 2. Bates I, Bedu-Addo G, Bevan D, Rutherford TR. Use of immunoglobulin gene rearrangements to show clonal lymphoproliferanon in hyper-reactive malarial splenomegaly. Lancet
1991; 337: 505-07. 3. Bates I, Bedu-Addo G, Rutherford TR. Extracting, storing and transporting whole blood DNA under tropical conditions. J Clin Pathol 1991; 44: 605-06. 4. Bennett JM, Catovsky D, Caniel M-T, et al. Proposals for the classification of chronic (mature) B and T lymphoid leukaemias. J Clin Pathol 1989; 42: 567-84. 5. Raffeld M, Jaffe ES. bcl-1, t(11;14), and mantle-cell derived lymphomas. Blood 1991; 78: 259-63. 6. Annotation. The role of bcl-2 gene in lymphoma. Br J Haematol 1990; 75: 449-53. 7. Sonnet J, Michaux JL, Hekster C. Incidence and forms of leukaemia among the Congolese Bantus. Trop Geogr Med 1966; 18: 272-86. 8. Spiriano P, Barosi G, Invenizzi R, et al. Splenomegalic immunocytoma with circulating hairy cells. Haematologica 1986; 71: 25-33.
ADDRESSES: Division of Haematology, St George’s Hospital Medical School, Cranmer Terrace, London SW17 ORE, UK (I. Bates, MB, T. Rutherford, PhD, D. H. Bevan, MRCPath); and Komfo Anokye Teaching Hospital, Kumasi, Ghana (G. Bedu-Addo, MB) Correspondence to Dr Imelda Bates.
Slaked lime and betel nut cancer in Papua New Guinea
The side on which lime is applied differs significantly
cell carcinomas involve the corner of the mouth; this is an unusual site and suggests a link with the addition of slaked lime to the areca nut in the mouth. The application of lime is the only element of the chewing process that is localised to this area. The site specificity of the cancer and exposure to lime suggest a possible cause for this tumour and a strategy for its prevention. - To investigate the relation between lime and oral cancer in Papua New Guinea, we studied the site of lime application and tumour development in a prospective series of 169 cases of oral cancer compared with results reported in an identically mapped western series.3 In a separate field study of normal Papua New Guinean adults, intraoral pH was monitored before and after the addition of lime during betel quid chewing to provide evidence that pH is sufficient for reactive oxygen species generation. From 1985 to 1987, 169 patients who presented with newly
diagnosed oral squamous cell carcinomas in seven provincial hospitals in Papua New Guinea were examined. Tumours of the vermilion of the lips and the tonsils were not included. The distribution of tumours is shown in the figure. Data on betel chewing habits were gathered from patients by a standardised interview in hospital. Patients were also asked to demonstrate how they usually applied lime to the betel quid and, in particular, where it was introduced to the mouth; their response was classified as left or right comer, midline, or a combination.
Mean age of both sexes was 50 years. Site distributions similar and are shown combined. Most tumours were distributed from the corner of the mouth, linearly along the buccal mucosa and the lateral border of the anterior tongue. Few were found in the floor of the mouth (figure, upper). The main feature is that over half of the tumours were in the buccal mucosa and 61% of these involved the corner of the mouth, including 23% that were limited to the corner of the mouth alone (more common in males). Of 86 patients with a left-sided tumour, 76% commonly added lime on the left and 62% did so only on this side. Of those patients with right-sided tumours, 79 % added lime to the right side and 70% did so to this side only (table i). The site of tumours and the side of lime application were strongly correlated (X2 56-73, df = 3; p < 0-0001).
were
Oral squamous cell
is the most common Guinea. We have New Papua malignant found that oral cancer in this region is concentrated at the corner of the mouth and cheek, by striking contrast with western populations, and corresponds precisely with the site of application of lime in 77% of 169 cases. Powdered slaked lime applied to the chewed Areca nut with Piper betle inflorescence at the corner of the mouth causes the mean pH to rise to 10, at which reactive oxygen species are generated from betel quid ingredients in vitro. Reactive oxygen species, together with sustained lime-induced cell proliferation, suggest a possible mechanism of carcinogenesis for this tumour. cancer
tumour in
=
TABLE
II-pH CHANGES AFTER CHEWING
BETEL QUID
Lancet 1992; 340: 577-78.
Oral squamous cell carcinoma is found throughout Papua New Guinea, India, and South East Asia. In Papua New Guinea, epidemiological evidence suggests that this condition is linked with chewing betel quid,’ which never includes tobacco. Moreover, the betel nut (Areca catechu) and the lime are added separately, thus facilitating examination of their individual effects. Typically, squamous
was measured by indicator stnps (Universalmdikator pH 0-14, Merck, Darmstadt, Germany) When a reading was equivocal between two whole numbers, the mid-point was recorded. Intra-oral pH. before chewing was also noted The subject then chewed the areca nut and added slaked lime by using the betel pepper pH of the quid was measured at 1 min and 5 min
pH
578
associated with exposure to tobacco in both Papua New Guineas and the USA,6 suggesting that the difference in localisation of the tumours must be because of other factors, such as lime and alcohol. The most obvious explanation for the site distribution in Papua New Guinea is contact with lime. We believe that, together with exposure to tobacco smoke, lime contributes to oral carcinogenesis by two mechanisms. First, lime causes continued and rapid cell turnover by killing cells, thus increasing the likelihood of heritable mutations, and of their being transmitted to daughter cells before complete DNA repair.7 Second, lime and areca nut polyphenols generate reactive oxygen species in vitro; hydrogen peroxide would diffuse into cells and produce O2 and OH. These free radicals can damage DNA,8 and chewers of betel quid have evidence of chromosomal change.8 In addition, lime causes ulceration at the site of its application, exposing basal stem cells to the mutagenic effects of lime and tobacco smoke. We found that with chewing, the pH rise above the threshold required for generation of reactive oxygen species9 was shortlived. Thus, the carcinogenic effects of lime may be limited to the site of its initial (high pH) contact with mucosa and the ingredients of betel quid. If free radicals and proliferation are both critical components of the lime-cancer mechanism, modification of lime may be a valuable public health measure. For instance, almost total quenching of freeradical release could be achieved in vitro by increasing the magnesium content of lime.9 If the calcium hydroxide content in lime, and thus the pH, was lowered, free-radical generation would be reduced9 together with the tissue damage that leads to rapid cell proliferation. Our data strongly suggest the need to field test a modified form of lime. If effective, this modified lime could offer a new and inexpensive method to prevent the most common cancer in Papua New Guinea. This work was assisted by The Western Regional Office of the World Health Organisation. We thank our Papua New Guinea Institute of Medical Research and Department of Health colleagues, especially Dr M. Alpers and Dr D. Paissat, Ms C. Howes for the illustrations, and Dr C. Moore and the American Journal of Surgery for permission to use their figure.
Distribution of oral squamous cell carcinoma by anatomical site in Papua New Guinea. The oral mucosa was divided into 25 regions of equal surface area, each approximately 9 cm2, and tumour site was plotted by locating the centre of each lesion. The sites grouped as corner of mouth, buccal, tongue, floor of mouth, and upper jaw/palate differed significantly between Papua New Guinea (=9046, df=4, p
A field study to examine lime, betel quid, and oral pH was undertaken in 1989. 31 adult betel quid chewers with no evidence of oral malignant disease were examined in two villages, Aupik and Kinbangwa, in the Maprik District of East Sepik Province, which is an area where betel quid chewing and oral cancer are common. Changes in pH during betel quid chewing were rapid and substantial (table II). Before chewing, mean pH was 6-8. 1 min after adding lime, mean pH had risen to 99; after 5 min, mean pH fell to 8.2 as the lime became diluted and buffered by saliva. In both Papua New Guinea and the USA, 70% of oral cancers are found on 20% of the mucosa, but dominant sites differ between the two countries. In the USA (figure, lower)3 and other western countries, tumours predominate in a crescentic area on the floor of the mouth. Oral cancer is
REFERENCES 1. Henderson BE, Aiken GH. Cancer in Papua New Guinea. Natl Cancer Inst Monogr 1979; 53: 67-72. 2. Cooke RA. Verrucous carcinoma of the oral mucosa in Papua New Guinea. Cancer 1969; 24: 397-402. 3. Moore C, Catlin D. Anatomic origins and locations of oral cancer. Am J Surg 1967; 114: 510-13. 4. Langdon JD. Epidemiology and aetiology. In: Henk JM, Langdon JD, eds. Malignant tumours of the oral cavity. London: Edward Arnold, 1985: 3-4. 5. Scrimgeour EM, Jolley D. Trends in tobacco consumption and incidences of associated neoplasms in Papua New Guinea. BMJ 1983; 286: 1414-16. 6. Rothman K, Keller A. The effect of joint exposure to alcohol and tobacco on risk of cancer of the mouth and pharynx. J Chronic Dis 1972; 25: 711-16. 7. Cohen SM, Ellwein LB. Cell proliferation and carcinogenesis. Science
1990; 249: 1007-11. 8. Stich HF, Anders F. The involvement of reactive oxygen species in oral cancers of betel quid/tobacco chewers. Mutation Res 1989; 214: 47-61. 9. Nair UJ, Friesen M, Richard I, MacLennan R, Thomas S, Bartsch H. Effect of lime composition on the formation of reactive oxygen species from the areca nut extract in vitro. Carcinogenesis 1990; 11: 2145-48.
ADDRESS: Queensland Institute of Medical Research, 300 Herston Road, Brisbane, Australia 4029 (S. J. Thomas, FDSRCS, Prof R. MacLennan, FRACP). Correspondence to Mr S. J. Thomas
SLVL is confirmed, the role of other aetiological factors, especially viruses, in lymphomagenesis should be
TABLE I-SITE OF ORAL CANCER ACCORDING TO WHICH SIDE LIME IS APPLIED
investigated. We thank ProfD. Catovsky for reviewing morphology; ProfD. Mason and colleagues for advice on lymphocyte phenotyping; the protein reference laboratory, Queen Mary’s Hospital, Roehampton; and Dr T. Rabbitts and Prof Y. Tsulimoto for the probes. 1. B. is a Wellcome Research Fellow and T. R. a Wellcome University Award Lecturer.
REFERENCES 1. Melo JV, Robinson DSF, Gregory C, Catovsky D. Splenic B cell lymphoma with "villous" lymphocytes in the peripheral blood: a disorder distinct from hairy cell leukaemia. Leukaemia 1987; 1: 294-99. 2. Bates I, Bedu-Addo G, Bevan D, Rutherford TR. Use of immunoglobulin gene rearrangements to show clonal lymphoproliferanon in hyper-reactive malarial splenomegaly. Lancet
1991; 337: 505-07. 3. Bates I, Bedu-Addo G, Rutherford TR. Extracting, storing and transporting whole blood DNA under tropical conditions. J Clin Pathol 1991; 44: 605-06. 4. Bennett JM, Catovsky D, Caniel M-T, et al. Proposals for the classification of chronic (mature) B and T lymphoid leukaemias. J Clin Pathol 1989; 42: 567-84. 5. Raffeld M, Jaffe ES. bcl-1, t(11;14), and mantle-cell derived lymphomas. Blood 1991; 78: 259-63. 6. Annotation. The role of bcl-2 gene in lymphoma. Br J Haematol 1990; 75: 449-53. 7. Sonnet J, Michaux JL, Hekster C. Incidence and forms of leukaemia among the Congolese Bantus. Trop Geogr Med 1966; 18: 272-86. 8. Spiriano P, Barosi G, Invenizzi R, et al. Splenomegalic immunocytoma with circulating hairy cells. Haematologica 1986; 71: 25-33.
ADDRESSES: Division of Haematology, St George’s Hospital Medical School, Cranmer Terrace, London SW17 ORE, UK (I. Bates, MB, T. Rutherford, PhD, D. H. Bevan, MRCPath); and Komfo Anokye Teaching Hospital, Kumasi, Ghana (G. Bedu-Addo, MB) Correspondence to Dr Imelda Bates.
Slaked lime and betel nut cancer in Papua New Guinea
The side on which lime is applied differs significantly
cell carcinomas involve the corner of the mouth; this is an unusual site and suggests a link with the addition of slaked lime to the areca nut in the mouth. The application of lime is the only element of the chewing process that is localised to this area. The site specificity of the cancer and exposure to lime suggest a possible cause for this tumour and a strategy for its prevention. - To investigate the relation between lime and oral cancer in Papua New Guinea, we studied the site of lime application and tumour development in a prospective series of 169 cases of oral cancer compared with results reported in an identically mapped western series.3 In a separate field study of normal Papua New Guinean adults, intraoral pH was monitored before and after the addition of lime during betel quid chewing to provide evidence that pH is sufficient for reactive oxygen species generation. From 1985 to 1987, 169 patients who presented with newly
diagnosed oral squamous cell carcinomas in seven provincial hospitals in Papua New Guinea were examined. Tumours of the vermilion of the lips and the tonsils were not included. The distribution of tumours is shown in the figure. Data on betel chewing habits were gathered from patients by a standardised interview in hospital. Patients were also asked to demonstrate how they usually applied lime to the betel quid and, in particular, where it was introduced to the mouth; their response was classified as left or right comer, midline, or a combination.
Mean age of both sexes was 50 years. Site distributions similar and are shown combined. Most tumours were distributed from the corner of the mouth, linearly along the buccal mucosa and the lateral border of the anterior tongue. Few were found in the floor of the mouth (figure, upper). The main feature is that over half of the tumours were in the buccal mucosa and 61% of these involved the corner of the mouth, including 23% that were limited to the corner of the mouth alone (more common in males). Of 86 patients with a left-sided tumour, 76% commonly added lime on the left and 62% did so only on this side. Of those patients with right-sided tumours, 79 % added lime to the right side and 70% did so to this side only (table i). The site of tumours and the side of lime application were strongly correlated (X2 56-73, df = 3; p < 0-0001).
were
Oral squamous cell
is the most common Guinea. We have New Papua malignant found that oral cancer in this region is concentrated at the corner of the mouth and cheek, by striking contrast with western populations, and corresponds precisely with the site of application of lime in 77% of 169 cases. Powdered slaked lime applied to the chewed Areca nut with Piper betle inflorescence at the corner of the mouth causes the mean pH to rise to 10, at which reactive oxygen species are generated from betel quid ingredients in vitro. Reactive oxygen species, together with sustained lime-induced cell proliferation, suggest a possible mechanism of carcinogenesis for this tumour. cancer
tumour in
=
TABLE
II-pH CHANGES AFTER CHEWING
BETEL QUID
Lancet 1992; 340: 577-78.
Oral squamous cell carcinoma is found throughout Papua New Guinea, India, and South East Asia. In Papua New Guinea, epidemiological evidence suggests that this condition is linked with chewing betel quid,’ which never includes tobacco. Moreover, the betel nut (Areca catechu) and the lime are added separately, thus facilitating examination of their individual effects. Typically, squamous
was measured by indicator stnps (Universalmdikator pH 0-14, Merck, Darmstadt, Germany) When a reading was equivocal between two whole numbers, the mid-point was recorded. Intra-oral pH. before chewing was also noted The subject then chewed the areca nut and added slaked lime by using the betel pepper pH of the quid was measured at 1 min and 5 min
pH
578
associated with exposure to tobacco in both Papua New Guineas and the USA,6 suggesting that the difference in localisation of the tumours must be because of other factors, such as lime and alcohol. The most obvious explanation for the site distribution in Papua New Guinea is contact with lime. We believe that, together with exposure to tobacco smoke, lime contributes to oral carcinogenesis by two mechanisms. First, lime causes continued and rapid cell turnover by killing cells, thus increasing the likelihood of heritable mutations, and of their being transmitted to daughter cells before complete DNA repair.7 Second, lime and areca nut polyphenols generate reactive oxygen species in vitro; hydrogen peroxide would diffuse into cells and produce O2 and OH. These free radicals can damage DNA,8 and chewers of betel quid have evidence of chromosomal change.8 In addition, lime causes ulceration at the site of its application, exposing basal stem cells to the mutagenic effects of lime and tobacco smoke. We found that with chewing, the pH rise above the threshold required for generation of reactive oxygen species9 was shortlived. Thus, the carcinogenic effects of lime may be limited to the site of its initial (high pH) contact with mucosa and the ingredients of betel quid. If free radicals and proliferation are both critical components of the lime-cancer mechanism, modification of lime may be a valuable public health measure. For instance, almost total quenching of freeradical release could be achieved in vitro by increasing the magnesium content of lime.9 If the calcium hydroxide content in lime, and thus the pH, was lowered, free-radical generation would be reduced9 together with the tissue damage that leads to rapid cell proliferation. Our data strongly suggest the need to field test a modified form of lime. If effective, this modified lime could offer a new and inexpensive method to prevent the most common cancer in Papua New Guinea. This work was assisted by The Western Regional Office of the World Health Organisation. We thank our Papua New Guinea Institute of Medical Research and Department of Health colleagues, especially Dr M. Alpers and Dr D. Paissat, Ms C. Howes for the illustrations, and Dr C. Moore and the American Journal of Surgery for permission to use their figure.
Distribution of oral squamous cell carcinoma by anatomical site in Papua New Guinea. The oral mucosa was divided into 25 regions of equal surface area, each approximately 9 cm2, and tumour site was plotted by locating the centre of each lesion. The sites grouped as corner of mouth, buccal, tongue, floor of mouth, and upper jaw/palate differed significantly between Papua New Guinea (=9046, df=4, p
A field study to examine lime, betel quid, and oral pH was undertaken in 1989. 31 adult betel quid chewers with no evidence of oral malignant disease were examined in two villages, Aupik and Kinbangwa, in the Maprik District of East Sepik Province, which is an area where betel quid chewing and oral cancer are common. Changes in pH during betel quid chewing were rapid and substantial (table II). Before chewing, mean pH was 6-8. 1 min after adding lime, mean pH had risen to 99; after 5 min, mean pH fell to 8.2 as the lime became diluted and buffered by saliva. In both Papua New Guinea and the USA, 70% of oral cancers are found on 20% of the mucosa, but dominant sites differ between the two countries. In the USA (figure, lower)3 and other western countries, tumours predominate in a crescentic area on the floor of the mouth. Oral cancer is
REFERENCES 1. Henderson BE, Aiken GH. Cancer in Papua New Guinea. Natl Cancer Inst Monogr 1979; 53: 67-72. 2. Cooke RA. Verrucous carcinoma of the oral mucosa in Papua New Guinea. Cancer 1969; 24: 397-402. 3. Moore C, Catlin D. Anatomic origins and locations of oral cancer. Am J Surg 1967; 114: 510-13. 4. Langdon JD. Epidemiology and aetiology. In: Henk JM, Langdon JD, eds. Malignant tumours of the oral cavity. London: Edward Arnold, 1985: 3-4. 5. Scrimgeour EM, Jolley D. Trends in tobacco consumption and incidences of associated neoplasms in Papua New Guinea. BMJ 1983; 286: 1414-16. 6. Rothman K, Keller A. The effect of joint exposure to alcohol and tobacco on risk of cancer of the mouth and pharynx. J Chronic Dis 1972; 25: 711-16. 7. Cohen SM, Ellwein LB. Cell proliferation and carcinogenesis. Science
1990; 249: 1007-11. 8. Stich HF, Anders F. The involvement of reactive oxygen species in oral cancers of betel quid/tobacco chewers. Mutation Res 1989; 214: 47-61. 9. Nair UJ, Friesen M, Richard I, MacLennan R, Thomas S, Bartsch H. Effect of lime composition on the formation of reactive oxygen species from the areca nut extract in vitro. Carcinogenesis 1990; 11: 2145-48.
ADDRESS: Queensland Institute of Medical Research, 300 Herston Road, Brisbane, Australia 4029 (S. J. Thomas, FDSRCS, Prof R. MacLennan, FRACP). Correspondence to Mr S. J. Thomas