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

China and East Asia

China, Hong Kong 1993-1997 21.4 8.3
China, Taiwan 1997 8.9 3.4
China, Shanghai 1993-1997 4.2 1.5
China, Tianjin 1993-1997 1.7 0.5
China, Beijing 1993-1997 1.0 0.6
Japan, Osaka Prefecture 1993-1997 0.5 0.1
Korea, Seoul 1993-1997 1.0 0.3
Southeast Asia
Singapore, Chinese 1998-2002 12.5 4.2
Singapore, Malay 1998-2002 5.7 2.0
Singapore, Indian 1998-2002 1.5 0.1
Malaysia, Sarawak Bidayuh (native)
1996-1998 31.5 11.8
Malaysia, Sarawak Chinese 1996-1998 12.0 4.1
Malaysia, Sarawak Malay 1996-1998 7.8 1.9
Viet Nam, Hanoi 1993-1997 10.4 4.6
Viet Nam, Ho Chi Minh City 1995-1998 4.8 1.7
Thailand, Bangkok 1995-1997 4.5 1.6
Philippines, Manila 1993-1997 7.2 2.5
Arctic
Canada, Northwest Territories 1983-1997 9.2 6.0
Greenland, native 1992-2002 12.7 9.2
United States, Alaska native 1992-2002 7.8 2.4
Middle East/North Africa
Algeria, Algiers 1993-1997 2.7 1.3
Israel, Jews born in Africa or Asia 1993-1997 1.4 1.9
Israel, non-Jews 1993-1997 1.0 0.5
Kuwait, Kuwaitis 1994-1997 2.6 0.9
Kuwait, non-Kuwaitis 1994-1997 0.5 0.4
North America
Canada 1993-1997 0.8 0.3
United States, Whitek 1998-2002 0.4 0.2
United States, Blackk 1998-2002 0.8 0.3
United States, Hawaii Chinese 1993-1997 10.7 3.8
United States, Hawaii Filipino 1993-1997 3.5 1.5
United States, Hawaii native 1993-1997 3.6 0.9
United States, Los Angeles Chinese
1993-1997 7.6 2.4
United States, Los Angeles Filipino
1993-1997 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 2-
to 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), case-

control 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 4-
fold 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 low-
incidence 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 N-
acetyltransferase 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 (305-
315)

– 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) (317-
321),

– 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 Top 10 Malignancy in Dharmais NCC in
in Male 2005-2007 Female 2005-2007

Bronchus and Lung 13.75 Breast 40.25

Nasopharynx 12.95 Cervix Uteri 17.96

Colorectum 10.06 Ovary 5.64

Lymph Nodes 9.57 Colorectum 3.75

Leukemia 7.47 Thyroid Gland 3.54

Liver 6.23 Lymph Nodes 3.26

Oral Cavity 3.89 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 0.00 10.00 20.00 30.00 40.00 50.00

percent percent