Epidemiologi Kanker Nasofaring (KNF) dan Epstein-Barr Virus (EBV)

Epidemiologi Kanker Nasofaring (KNF) dan Epstein-Barr virus (EBV) Demak L. Tobing R.S. Kanker Dharmais

KNF dan EBV • Ciri-ciri – Rasial/Etnik – Variasi Geografik – Multifaktor etiologi : • Lingkungan • Virus • Faktor resiko genetik

• Tujuan : – Highlight Epidemiologi KNF – Pertanyaan yang belum terjawab – Penelitian terhadap pertanyaan yang belum terjawab

Epidemiologi Diskriptif Overview : • Di Dunia merupakan kanker yang jarang • Populasi tertentu : endemik • Th. 2002 : – angka kejadian : 80.000 – Kematian : > 50.000 – No 23 kasus baru kanker (Parkin DM dkk, 2002)

• Sebaliknya, di Hong Kong – Kasus baru kanker No 4 • KNF : – Lapisan epitel nasofaring – Klasifikasi (WHO) : Tipe histologik • Keratinizing squamous cell carcinoma (tipe I) • Nonkeratinizing carcinoma : – Differentiated (tipe II) – Undifferentiated (tipe III)

• high-incidence area – KNF tipe III ( > 95% ) – KNF tipe II (5%) • low-incidence area – KNF tipe I (predominant) – Etiologi berbeda dari tipe II dan III Zong YS dkk, 1983 ; Yu MC dkk, 1996 ; Vaughan TL dkk, 1996

• Variasi geografik – Nasofaring : KNF • Pada umumnya angka kejadian berdasarkan usia (Laki-laki dan Wanita) – < 1 per 100.000 tahun orang • Angka kejadian meningkat pada populasi Cantonese (Cina sebelah selatan termasuk Hon Kong)

• intermediate rate – Suku asli di Asia Tenggara – Arctic – Afrika Utara – Timur Tengah

Tabel 1. Angka kejadian KNF berdasarkan usia pada populasi Daerah dan populasi

Tahun

China and East Asia China, Hong Kong 1993-1997 China, Taiwan 1997 China, Shanghai 1993-1997 China, Tianjin 1993-1997 China, Beijing 1993-1997 Japan, Osaka Prefecture 1993-1997 Korea, Seoul 1993-1997 Southeast Asia Singapore, Chinese 1998-2002 Singapore, Malay 1998-2002 Singapore, Indian 1998-2002 Malaysia, Sarawak Bidayuh (native) 1996-1998 Malaysia, Sarawak Chinese 1996-1998 Malaysia, Sarawak Malay 1996-1998 Viet Nam, Hanoi 1993-1997 Viet Nam, Ho Chi Minh City 1995-1998 Thailand, Bangkok 1995-1997 Philippines, Manila 1993-1997 Arctic Canada, Northwest Territories 1983-1997 Greenland, native 1992-2002 United States, Alaska native 1992-2002 Middle East/North Africa Algeria, Algiers 1993-1997 Israel, Jews born in Africa or Asia 1993-1997 Israel, non-Jews 1993-1997 Kuwait, Kuwaitis 1994-1997 Kuwait, non-Kuwaitis 1994-1997 North America Canada 1993-1997 United States, Whitek 1998-2002 United States, Blackk 1998-2002 United States, Hawaii Chinese 1993-1997 United States, Hawaii Filipino 1993-1997 United States, Hawaii native 1993-1997 United States, Los Angeles Chinese 1993-1997 United States, Los Angeles Filipino 1993-1997

Angka kejadian (per 100.000 tahun orang) Laki-laki Wanita

21.4 8.9 4.2 1.7 1.0 0.5 1.0

8.3 3.4 1.5 0.5 0.6 0.1 0.3

12.5 5.7 1.5

4.2 2.0 0.1

31.5 12.0 7.8 10.4 4.8 4.5 7.2

11.8 4.1 1.9 4.6 1.7 1.6 2.5

9.2 12.7 7.8

6.0 9.2 2.4

2.7 1.4 1.0 2.6 0.5

1.3 1.9 0.5 0.9 0.4

0.8 0.4 0.8 10.7 3.5 3.6

0.3 0.2 0.3 3.8 1.5 0.9

7.6

2.4

3.7

1.6

• Distribusi Jenis Kelamin dan usia – Laki-laki 2 – 3 x > Wanita – Daerah Low-risk population • Usia ↗, angka kejadian meningkat

– Daerah high-risk population – Puncak pada usia 50 – 59 th, kmd menurun

Low-risk population

Age-specific incidence rates of NPC among White males and females in the United States, 1992 to 2003 (Devi BC et al, 2004)

High-risk population

Age-specific incidence rates of NPC among males and females in Hong Kong, 1980 to 1999 (Lee AW et al, 2003)

• Paparan dengan agen karsinogenik (?) pada usia muda • Sebaliknya – Angka kejadian rendah (usia tua dan dewasa muda) • Asia Tenggara • Timur Tengah • USA – Agen karcinogenik (? umum)

Pola Rasial/Etnik • geographic regions – high- or low-incidence areas, • Distribusi Rasial/Etnik tidak sama • Di Provinsi Cina bagian Tenggara : – Guangdong : >20 per 100,000 tahun-orang pada pria. – Angka pada penduduk berbahasa Cantonese menunjukkan 2 x > dibandingkan yang berbahasa Hakka, Hokkien, dan Chiu Chau . Li CC et al 1985

Sebaliknya • Selangor Malaysia, – Chinese residents • Tertinggi adalah Cantonese, • intermediate – Khek, • Terendah – Hokkien dan Teochiu Armstrong RW et al, 1979

• the United States, angka tertinggi dan selanjutnya 1. Chinese Americans 2. Filipino Americans 3. Japanese Americans, 4. Blacks, 5. Hispanics 6. Whites Burt RD et al, 1992

Asia Tenggara – Variasi : rasial dan campuran dengan Cina Selatan • low incidence – Singapore Indians (tidak bercampur dengan orang Cina) • Higher incidence – Thai, – Macaonese, • Melayu yang menikah dengan keturunan Cina Ho HC, 1976.

Ho Chi Minh City – Hanoi banyak etnik keturunan Cina

Japan and China, – Cina Utara tinggi – Japan rendah •

Nguyen MQ et al, 1998 ; Ho HC et al, 1976; Sawaki S et al, 1976 ; Parkin DM et al, 2002.

Penelitian Migrant • Orang dari high- atau intermediate-risk area migrasi ke negara lower-risk, resiko KNF tetap tinggi • Orang Cina Selatan tinggal di Singapur, Malaysia dan Jepang, angka KNF berbeda dengan Orang Cina Selatan asli Parkin DM, 2002 ; Armstrong RW, 1979 ; Sawaki S, 1976

Tetap tinggi ( berasal dari High-risk area) • Orang Afrika Utara bermigrasi ke Israel. (28). Angka kejadian tinggi meskipun tinggal di Israel • Orang Cina di USA : 10 – 20 x lb tinggi dibandingkan orang kulit putih dan hitam Tabel 1

• Angka Kejadian – rendah pd Chinese migrants ke • United Kingdom • Australia • Lama tinggal di negeri Barat – Meningkat • White males lahir di Cina atau Filipina dibandingkan yang lahir di USA Warnakulasuriya KA et al 1999; McCredie M et al, 1999; Buell P et al.1974; Buell P, 1973

• French origin males lahir di North Africa, dibandingkan dengan yang lahir di southern France

• Penurunan nyata bila Chinese migrasi ke Barat (overestimated) – Laporan tidak memperhitungkan campuran high and low-risk migrants pada populasi asal. Jeannel D et al, 1993

Sebab – cancer registries generally do not record data on ethnic subgroup, rates in Chinese ethnic subgroups cannot be accurately estimated. – traditional Asian lifestyle (berhubungan dengan peningkatan KNF) – individuals who migrate overseas : inherently lower-risk group.

Angka kejadian KNF pada migran tidak dapat secara langsung dibandingkan dengan yang dari asal negrinya.

Secular Trends. • Bukti sejarah Cina, Mesir (42) dan Iran (43), – KNF bukan modern environmental hazards – genetic and/or stable environmental risk factors (berabad-abad) Ho HC et al, 1976 ; Wells C, 1963 ; Wells C, 1940

• Berdasarkan modern cancer registry data, angka kejadian KNF tetap tinggi di Asia Tenggara • Penurunan angka kejadian KNF di Hong Kong sejak th 1970 an Parkin DM et al, 2002 ; Lee AW et al, 2003 ; Muir C et al, 1987 ; Waterhouse J et al,1982 ; Parkin DM et al, 1992 ; Parkin DM et al, 1997

• Perubahan ekonomi penduduk – Taiwan sejak 1980s (48), Singapore Chinese sejak 1990s (1, 44-47, 49). Hong Kong sejak pertengahan th 1940 Muir C et al, 1987 ; Waterhouse J et al, 1982 ; Parkin DM et, 1992 dan 1997

• Sebaliknya, angka kejadian meningkat – Singapore Malays antara 1968 and 1997, – Tetap tinggi pada laki-laki di Cangwu county dan menetap atau sedikit meningkat di Southeastern China antara 1978/1983 dan 2002. Wang H et al, 2006 ; Sun LM et al, 2005

Faktor Resiko • Epstein Barr virus (EBV) – Laten, 90% populasi dunia – Hong Kong • 80% anak-anak usia 6 th, usia 10 th serokoversi 100% (55) – Infeksi subklinik ----- berbagai keganasan termasuk KNF

– Transmisi • Saliva • Negara berkembang terjadi pada usia dini –Kepadatan penduduk –Higienik kurang – Hidup di Limfosit B, epitel nasofaring dan orofaring Rickinson AB et al, 2001; Kangro HO et al, 1994 ; IARC, 1997 ; Mueller NE et al, 1996

• KNF ----EBV – Sejak th 1996 (60) – Express antibody (1970 confirmed) meningkat pada KNF dibandingkan kontrol (61) – Antibodi (62-74) • IgG dan IgA (EBV VCA, EBV EA) • IgG (EBV EBNA 1 dan 2) • IgA (EBV VCA p18 dan EBNA1) • Antibodi thd EBV-specific DNAse

• Antibodi IgA (peningkatan)(76-84) – Mendahului pertumbuhan tumor – Tumor burden – Remission – Recurrence

• IgA EBV VCA – Screening (high-risk population) (85-90) kombinasi dengan antibodi anti-EBV DNAse (73, 91)

• Circulating cell-free EBV DNA – Pada KNF > kontrol (92-95) – Korelasi dengan Stage dan prognosis (92-97) – Prospective studies : predisease level (belum)

• Further : – EBV DNA – EBV RNA – Gene product dalam sel tumor

• International pattern KNF – Distribusi EBV strain – Prototipe B95.8 EBV strain – LMP1 – variasi • amino terminal – Loss of a XhoI restriction site (southern and nothern Chinese, Malays, Alaska dan US) • Carboxyl terminus (Chinese NPC) – 33 bp repeat element – Insersi : 15 bp pada the third repeat element – Delesi : 30 bp pada carboxyl terminus

• Variasi LMP1 menyebabkan KNF lebih agresif ? • Variant (deleted) = peningkatan resiko KNF ? • LMP1 variant mempengaruhi immune selection ? (reduced CTL response) Well-designed epidemiologic studies of risk associations with EBV variants

Pengumpulan bukti-bukti bahwa peran EBV sebagai penyebab KNF (56) ; • early-life infection, tipikal pada high-incidence areas (55, 135) ----- critical. • EBV sendiri tidak cukup menyebabkan KNF, karena sebagian besar orang dewasa di dunia telah terinfeksi EBV. • a small proportion of individuals develop NPC.

• Bagaimana ? – environmental – Faktor genetik Juga berkontribusi pada resiko KNF !

Salt-Preserved Fish dan makanan lain • Konsumsi salt-preserved fish, – Penelitian pada populasi Cina – Resiko relatif KNF bila makan ikan asin tiap minggu dibandingkan yang tidak atau jarang mengkonsumsi : 1.4 sampai 3.2/100.000 th orang – Konsumsi tiap hari : 1.8 sampai 7.5 /100.000 th orang (136-141).

• Preserved food lain – Daging – Telur – Buah – sayur

Tobacco, Other Smoke, and Alcohol • The majority of case control studies examining cigarette smoking and risk of NPC in a variety of populations reported an increased risk of 2to 6- fold (9, 39, 40, 73, 142, 172-181) • some studies found no association (24, 38, 74, 137, 141, 148, 154, 183-186).

• The discrepancy in findings may be due in part to differences in study design and/or exposure assessment • several of the studies reporting a positive association were conducted in low- or intermediate-incidence populations (9, 142, 173, 175-178, 180).

• U.S. study – An estimated two thirds of type I NPC was attributable to smoking, but risk of type II or III NPC was not associated with smoking (9) – the declining prevalence of smoking (187) may explain the recent decreasing trend in the incidence of type I NPC in the United States (52).

– Some researchers have suggested that the high incidence of NPC in southern Chinese and North Africans is caused by smoke from wood fires in chimneyless homes (151, 168, 189). ( five times) – Studies examining burning incense or antimosquito coils have been similarly equivocal, with two studies finding up to a 6-fold excess risk of NPC with use of antimosquito coils (177, 185)

– Alcohol consumption also seems not to be associated with NPC risk, because most (35, 38, 39, 73, 74, 141, 148, 154, 172, 173, 180, 183-185), but not all (9, 139, 175), casecontrol studies were negative. – Inconsistent findings may be due to differences in study characteristics, as well as chance or confounding.

Herbal Medicines – Tradisional – 2 sampai 4 kali resiko KNF – Aspek lain ?! – induce viral lytic antigen expression by activating EBV in vitro (194-197)

• Herbal drugs yang tinggi dan titer anti EBV EBNA (193) – suggesting a direct proliferative effect of herbal medicines on EBV-transformed cells

Occupational Exposures • Occupational exposure to fumes, smokes, dusts, or chemicals overall was associated witha 2- to 6-fold higher risk of NPC in some but not all studies (73, 154, 174, 177, 184) • exposure to formaldehyde is supported by experimental observations in rodents (201, 202), but epidemiologic evidence in humans is limited, especially for endemic types II and III.

• Three case-control studies observed a 2- to 4fold excess risk of NPC (177, 199, 203), and a U.S. study found an increased risk of type I but not type II or III NPC (204), • exposure to wood solvents and preservatives, such as chlorophenols, may also be involved (179, 181, 231)

Familial Clustering • Familial aggregation of NPC has been widely documented in high-incidence (190, 250-253), intermediate-incidence (254-257), and lowincidence populations(258-267). • result from shared genetic susceptibility, shared environmental risk factors, or both • the case of NPC, genes and environmental exposures likely play a combined role

– a complex segregation analysis of familial NPC in southern China (268), multiple genetic and environmental factors, rather than a single major usceptibility gene, seemed most likely to explain the observed pattern of inheritance. – In epidemiologic studies, the excess risk was generally 4- to 10-fold among individuals with a first-degree relative with NPC, compared with those without a family history (73, 137, 141, 174, 180, 269-274).

Human Leukocyte Antigen Genes • Genes conferring susceptibility to NPC • encode proteins required for the presentation of foreign antigens, including viral peptides, to the immune system for targeted lysis

Proposed causal model of endemic (types II and III) NPC

• Because virtually all NPC tumors contain EBV, individuals who inherit HLA alleles with a reduced ability to present EBV antigens may have an increased risk of developing NPC • whereas individuals with HLA alleles that present EBV efficiently may have a lower risk (276, 277).

• Some HLA alleles have been consistently associated with NPC risk. • In southern Chinese and other Asian populations – HLA-A2-B46 (252, 277-284) and B17 (281, 282, 285-287) were generally associated with a 2- to 3-fold increase in NPC risk.

• In contrast, 30% to 50% lower risk of NPC was found in association with HLA-A11 in both Chinese and Whites (277, 281-283, 287, 288), B13 in Chinese (279, 282), and A2 in Whites (288, 289).

A meta-analysis of studies in southern Chinese populations – the combined evidence suggested a positive association of NPC risk with HLA-A2, B14, and B46, – and an inverse association with HLA-A11, B13, and B22 (290).

• Reported associations between NPC risk and other HLA genes, including class II alleles, must be interpreted with caution due to the probability of chance findings based on multiple comparisons.

Other Genetic Variation • Several genetic polymorphisms and chromosomal abnormalities have been identified by epidemiology studies searching for NPC susceptibility loci • A few studies examined genetic variation in genes involved in metabolism of nitrosamines, tobacco, and other contaminants.

• Polymorphisms in – cytochrome P450 2E1 (CYP2E1). (293-295) – CYP2A6 (296) – the absence of glutathione S-transferase M1 (GSTM1) (97-299) and/or GSTT1 (298) were

• associated with 2- to 5-fold increased risk of NPC

• In Taiwan, a variant of CYP2E1 was evenly distributed between familial and nonfamilial NPC cases (270), with no association between NPC risk and genetic polymorphisms in CYP1A1, GSTM1, GSTT1, GSTP1, or Nacetyltransferase 2 (NAT2) (300).

• Among Cantonese subjects, no association was found with genetic variation in CYP2A13 (301). • In Thailand (302) and China (303), polymorphisms in the polymeric immunoglobulin receptor (PIGR), a cell surface receptor proposed to mediate EBV entry into the nasal epithelium, were associated with increased risk of NPC

• Genetic changes – studies of loss of heterozygosity in NPC tumors detected a high frequency of allelic loss, especially on chromosomes 3p, 9p, 11q, 13q, and 14q (305315) – A recent meta-analysis of comparative genomic hybridization results revealed several genomic ‘‘hotspots’’ where chromosomal losses and gains have consistently been detected in NPC tumors (316)

• In addition, tumor-suppressor genes, such as – Ras association domain family 1A (RASSF1A) (317321), – cyclin-dependent kinase inhibitor 2A (CDKN2A, p16/INK4A) (318-320, 322), – and immunoglobulin superfamily member 4 (IGSF4, TSLC1) (321, 323, 324)

may frequently be inactivated in NPC tumors by promoter methylation

Jakarta Minimum Cancer Incidence (Coverage 70% ) 79 Hospitals. 2 Private Clinics, 90 Pathology Laboratories, 44 Municipals Primary health Care (as a coordinator of 301 Primary Health Care in District area).

Top 10 Malignancy in Dharmais NCC in Male 2005-2007

Top 10 Malignancy in Dharmais NCC in Female 2005-2007

13.75

Bronchus and Lung

12.95

Nasopharynx 10.06

Colorectum

9.57

Lymph Nodes 7.47

Leukemia 6.23

Liver 3.89

Oral Cavity

40.25

Breast 17.96

Cervix Uteri Ovary

5.64

Colorectum

3.75

Thyroid Gland

3.54

Lymph Nodes

3.26

Leukemia

3.05

Prostate Gland

2.99

Nasopharynx

2.87

Skin

2.84

Bronchus and Lung

2.85

Soft Tissue

2.74

Corpus Uteri

2.49

0.00

2.00

4.00

6.00

8.00 10.00 12.00 14.00

percent

0.00

10.00

20.00

30.00

percent

40.00

50.00