NASOPHARYNGEAL CARCINOMA (NPC) J. H. C. Ho Medical and Health Department Institute of Radiology, Queen Elizabeth Hospital, Kowloon, Hong Kong
I. Introduction . . . . 11. Histogenesis . . . . 111. Etiology . . . . . A. Early Cases . . . B. Genetic Factors . . C. Environmental Factors IV. Conclusion . . . . References
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Nasopharyngeal carcinoma (NPC) has recently attracted worldwide interest because a high titer of antibodies to Epstein-Barr virus (EBV), which is suspected to have oncogenic properties, has been found with unusual frequency among patients with this neoplasm compared with controls from the general population and also with patients with head and neck tumors other than NPC (de Schryver et al., 1969; W. Henle et al., 1970). It is of interest also that immune responses by the host against tumor-associated antigens have been shown in a number of neoplasms including NPC (Klein, 1970). This neoplasm is rare among most groups of people, but Chinese, particularly those originating from the southern province of Kwangtung, have a very high risk of developing the disease. Lilly (1966) has shown that in inbred strains of mice the incidence of lymphomas and leukemias is linked to a genetically determined susceptibility to tumor induction by oncogenic viruses. The discovery of an association between a virus infection and NPC which has a predilection for an ethnic group has, therefore, stimulated much interest in the nature of the association, which may shed some light on the tantalizing question whether viruses, which are now known to give rise to a variety of tumors in certain mammals and birds, also cause cancer in man. It is the purpose of this chapter to review the etiology of NPC. It. Histogenesis
Many types of nasopharyngeal cancers have been found, but carcinoma is by far the predominant type in people of all races. I n China 57
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and Southeast Asia, where the incidence is exceptionally high, a t leaat 99% of the malignant neoplasms have been reported to be carcinomas (Liang, 1964; Yeh, 1967; Shanmugaratnam and Muir, 1967). In Australia, Scott and Atkinson (1967) detected essentially no difference in the histopathological distribution of nasopharyngeal cancers among Caucasian and Chinese patients. In their series of 213 histologically proven cases of malignant neoplasms, 202, or approximately 95% of them, are carcinomas. I n America, where the incidence of nasopharyngeal cancers is low, the ratio of carcinoma to sarcoma is between 8 : l and 9 : l (Fletcher and Million, 1965; Vaeth, 1960). I n England, also a lowincidence area, the ratio of carcinoma (epithelioma including lymphoepithelioma) to sarcoma is 3.5:l in a series of 208 cases with known histology reported by Lederman (1961). Also in Kenya, Africa, carcinoma is the predominant neoplasm (Clifford, 1965). Table I shows the histological types of neoplasms arising primarily in the nasopharynx of 1606 cases diagnosed a t Queen Mary Hospital, Hong Kong, during the 5-year period 1959-1963. More than one case of reticulum cell sarcoma was diagnosed initially, but later development showed all of them, except one, to be undifferentiated squamous carcinoma. It is anticipated that, if electron microscopy is used routinely, there will be a reduction in the frequency of nasopharyngeal lymphoreticular neoplasms being diagnosed, a t least in Chinese patients. Svoboda et al. (1967) have shown by electron microscopy that the undifferentiated carcinomas, including the so-called lymphoepithelioma, often show evidences indicative of their squamous origin. Although similar evidences-desmosomes and cytoplasmic filamentous inclusionsare occasionally encountered in malignant lymphoma and chordoma (Friedman, 1967), the mere fact that most nasopharyngeal carcinomas
TABLE I HISTOLOQICAL TYPESOF NASOPHARYNQEAL CANCERS DIAQNOSED AT QUEENMARYHOSPITAL (1959-1963) No. of Carcinomas (squamous, undifferentiated and anaplastic) Malignant melanoma Reticulum cell sarcoma Not histologidly confirmed
From Ho (1972), by permission from the editor.
1571 2 1 32
% 98 2
NABOPHARYNGEAL CARCINOMA (NPC)
contain more than one histological type of malignant cells in the same tumor and that typical squamous features are not uncommonly found in sections among predominantly undifferentiated carcinoma cells has led to the belief, which is now generally held, that the undifferentiated carcinoma including lymphoepithelioma are histogenetically variants of squamous carcinoma, the predominant neoplasm in the nasopharynx. It is in patients with this neoplasm, and not others, arising in the nasopharynx that an association with EB virus infection has been discovered, and also it is this cancer that has a predilection for people of Chinese descent. Ali (1967) in his study based on the histological examination of nasopharyngeal mucous membranes obtained at 100 medicolegal autopsies from apparently healthy individuals between ages of 10 and 80, found that under normal conditions only 60% of the total nasopharyngeal epitheIia1 surface was lined by stratified squamous epithelium and that the proportion of squamous epithelium in the nasopharynx appeared to be constant after the first decade of life. Liang et al. (1962) proposed, “Squamous metaplasia would be a prerequisite for the formation of different types of nasopharyngeal carcinoma.” This hypothesis is based on their finding that among 54 cases of malignancy (including precancerous change, carcinoma in situ, and early invasive carcinoma) arising from the nasopharyngeal mucosa, 27, or 50%, arose from the squamous epithelium of the mucosa, and that at the frequent site of carcinomatous origin, i.e., the superior two-thirds of the nasopharynx, the mucosa was normally lined by cylindrical cell epithelium. Further, in their histological examination of 300 complete nasopharyngeal mucosa specimens of cadavers above the age of 15 years, Liang et al. found that 129 specimens showed multiple small foci of squamous metaplasia. They, therefore, held squamous metaplasia to be of great significance in the histogenesis of NPC. On the other hand, they stated in the same paper that, with the exception of cylindrical cell carcinoma which arose from the surface cylindrical cell epithelium of the nasopharyngeal mucosa (including the lining of the crypts), all types of nasopharyngeal carcinoma (including squamous cell carcinoma) could arise either from the cylindrical cell epithelium or from the squamous cell epithelium. This finding was confirmed by Ch’en (1964a) from a study of 90 biopsies of the nasopharyngeal mucosa which showed malignant change. In another study Ch’en (1964b) found that anaplasia could start from a single cell or from a group of cells in the undifferentiated basal layer of the mucosal epithelium, or in the middle layer already beginning to differentiate, or in the well-differentiated superficial layer. Shanmugaratnam and Muir (1967) also found that all forms of nasopharyngeal carcinoma, both
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classical squamous cell carcinomas and undifferentiated carcinomas, might arise from squamous, transitional, or respiratory epithelium. Experience in Hong Kong is in agreement (Ho, 1972). It would appear, therefore, that carcinoma could start de novo without the cells first undergoing squamous metaplasia. Multicentricity of foci of carcinomatous change is not uncommonly seen in Hong Kong cases. Occasionally a new carcinoma may even appear on the opposite side of the nasopharynx from one to a few years after a course of radiotherapy which appeared to have caused the original tumor to disappear. These are unlikely to be recurrences of tumors too small to be noticed during the initial examination, because the smaller the tumor the greater is the chance of its being eradicated or controlled, and in the radiation treatment of NPC the whole nasopharynx is as a rule given the same high dose. Such new carcinomas raise a very important question: If radiotherapy had no prophylactic effect on the process of carcinomatous transformation in these cases, did it play any part in causing or accelerating the transformation, since radiation is known to be carcinogenic? The short interval between irradiation and the development of an apparently new carcinoma does not exclude such a possibility since it is not unlikely that other parts of the nasopharyngeal mucosa might already be primed by the time the first carcinoma was treated or already in the late stage of carcinomatous transformationprecancerous stage, in which case the interval can be very short. A similar example is to be found in the radiation treatment of carcinoma of the buccal mucosa. A new carcinoma may develop in the originally normal looking buccal mucosa on the opposite side, which already had received a good dose of radiation when the first tumor was treated. That a radical course of radiation treatment has little or no prophylactic effect on cells at a certain phase of carcinomatous transformation, a t least in some cases, is beyond doubt. It is, however, of importance to ascertain whether it has any promoting effect on the malignant change. Animal experiments designed to study the effect of radiation on cells at different stages of malignant transformation might help in producing an answer. 111. Etiology
A. EARLY CAB= It is not known whether NPC is largely a product of our environment within the last one and a half centuries or has afflicted man since antiquity, as has been claimed by Clifford (19701, who thinks that the oldest pathological specimens of NPC at present known were derived from
NASOPHARYNGEAL CARCINOMA (NPC)
inhabitants of Northeast Africa and the Middle East from the period 3500-3000 B.c., on the basis largely of the works of Wells (1963, 19641, Krogman (1940), Smith and Dawson (1924), and Derry (1909). The most important evidence is supposed to be found in the works of the first three, but close scrutiny of these works reveals considerable doubt that they are indicative of NPC, and not of other diseases. Wells (1964) stated that only 3 or 4 cases of indubitable carcinoma have been recognized among the tens of thousands of ancient Egyptian mummies and skeletons that have been examined, and that hardly a score of such cancers have been identified from all the cemeteries of the pre-Renaissance world. He thought that several of this very small number appeared to be of nasopharyngeal origin. Through the courtesy of Dr. J. C. Trevor, Director of the Duckworth Laboratory, and the kind cooperation of Professor J. Mitchell and Mr. J. A. Fairfax Fozzard of the University of Cambridge, the author had the opportunity to examine radiographs and photographs of probably the most important specimen, a skull (No. 236) kept a t the Duckworth Laboratory. This specimen shows only destruction of the posterior part of the left maxillary alveolus forming the floor of the left maxillary sinus, the adjacent part of the hard palate and pterygoid laminae, with antemortem loss of the 2nd and 3rd molars. These findings are shown in Figs. 1 and 2. The destruction is indicative rather of carcinoma or myeloma of the maxillary alveolus or of the floor of the maxillary sinus than of NPC, as the destroyed parts are situated in front of the nasopharynx, whereas the bones immediately overlying the nasopharyngeal cavity, which are the ones most commonly involved, were spared. Furthermore, the multiple circular holes in the tables of the cranial vault unaccompanied by any evidence of sclerotic bony reaction around them are far more typical of myelomatosis than NPC metastases. A “strongly probable one” according to Wells (1964) was from Tepe Hissar, Iran, ca. 3000 B.C. (Krogman, 1940). The specimen referred to is 33-23-36, the skull of a male of Mediterranean type from Hissar 11. It shows extensive destruction of the left facial bones-maxilla, palatine, and zygoma. There is an extension of the destruction to the floor of the left orbit. The left maxillary sinus is completely obliterated; the floor of the left nasal fossa is penetrated, and the penetration extends to the right of the midline. All upper teeth on the left side and the right central incisor are missing. The mandible is, however, intact, a fact which, according to Krogman, testifies against injury being the cause. He stated: “It may be conjectured whether the condition is primarily due to sinus infection, brought about by dental disease.” There was no description of destruction of bone in the immediate vicinity of the naso-
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Fro. 1. Photograph of skull specimen No. 236. Dotted line indicates the nasopharyngeal boundaries on the right side (R). Destruction of bone is limited to the floor of the left maxillary sinus and adjacent hard palate and pterygoid laminae.
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FIG.2. Superoinferior X-ray projection of skull specimen No. 236. Dotted line indicates the nasopharyngeal boundaries on the right side (R).Site of lesion is snowed.
pharynx. There are, therefore, no grounds to interpret from these findings that the primary condition could be nasopharyngeal carcinoma. Wells (1964) thought that one of the Romano-Egyptian cases described by Smith and Dawson (1924) was another example of carcinoma of nasopharyngeal origin. The case referred to was reported to be a male
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pre-Christian Nubian (ca. fourth to sixth century, A.D.) with extensive destruction of the base of skull from the cribiform plate to the basiocciput almost reaching the foramen magnum. The site and appearance of the destruction are consistent with a diagnosis of either carcinoma of the sphenoid sinus or nasopharyngeal carcinoma. It is, however, difficult and sometimes impossible to differentiate between the two even in examining patients. Judging from the evidence presently available, we are still far from sure whether nasopharyngeal carcinoma had afflicted human inhabitants of Northeast Africa and the Middle East some 5000 years ago. Since NPC is a prevalent disease in China, and in the province of Kwangtung has even earned the name of “Kwangtung tumor,” it would be pertinent to search old Chinese medical writings for reference to the disease. In a book of 50 volumes called, “Aetiology and Symptomatology of Various Diseases” written by CHOU Uen Fung or CHOU Yuan Fang ( # $ $), a royal physician of the Sui Dynasty (A.D. 589-617), there is a description of various types of superficial tumorous swellings. Only in “shu-lu,” or rat tumor, was there a description of the disease appearing in the neck with its root in the lungs. Jung and Yu (1963) found it impossible to determine whether all, some, or none of the cases of “lo li” (glandular enlargement of the neck) were carcinomatous metastases rather than tuberculosis or other diseases. In The Encyclopaedia of Chinese Medical Terms edited by Wu (1921) a disease, called “shih ying” or (‘shih jung” disease, meaning, respectively, loss of nutrition is described as belonging to one of the four fatal diseases and has the following clinical picture: Masses appear in front of and behind the ear and in the neck. They are stony hard, immobile, neither hot nor cold to the touch and painless at first. As they grow in sire pain gradually appears and fungation sets in. The discharge is sero-sanyineous but not pussy. Ultimately, a crater lined with necrotic tissue is formed. By this time pain becomes intense. Brisk bleeding from the ulcer soon occurs and the patient may die of haemorrhage after 1 or more bleeding episodes or of gradual loss of nutrition.
There is no doubt from this description that the masses are metastatic, not tuberculous, lymph nodes, and that they are most likely caused by a primary carcinoma in the nasopharynx. No mention is made in this encyclopedia as to when this disease was first reported in Chinese medical writings. Now that the name of the disease is known, the task of searching for such information is made easier. It is hoped that workers in mainland China and Taiwan, where one can get access to old Chinese medical writings, will do some work in this direction.
NASOPHARYNGEAL CARCINOMA ( N P C )
B. GENETICFACTORS 1. Sex Incidence In most countries the male to female incidence ratio is over 2:1, but in Sweden it is below 2:l. The crude and age-standardized annual incidence rates of nasopharyngeal carcinoma (with all other neoplasms of the nasopharynx excluded) for different parts of the world where such figures are available are given in Table I1 for comparison. TABLE I1 SEX INCIDENCE RATIOOF NABOPHARYNOEAL CARCINOMA Crude rates per 100,000 Population HongKong (Chinese) Singapore (Chinese) Sweden
Age-standardized rates per 100,OOO
2. Racial Susceptibility Nasopharyngeal carcinoma is rare in most parts of the world except in China and many parts of Southeast Asia inhabited largely by people of mongoloid stock who have had close relationship with Chinese for many centuries dating back to the early Ming dynasty in the 14th century. Although Japanese and Koreans are also mongoloid people and have had an even longer period of association with Chinese, incidence among the Japanese is rare (Miyaji, 1967), and probably this applies also to the Koreans (Clifford, 1970). Although the frequency of the disease is highest among people of Chinese descent both in and outside China, in China itself there is a drop in frequency from south to north according to the relative frequency expressed as percentages of all malignant tumors diagnosed by biopsies reported by major hospitals and medical schools in certain cities and provinces. This is illustrated in Table I11 and Fig. 3. The difference in frequency in different parts of China could be due to geographic reasons or to ethnic differences. It is, therefore, important to determine whether Chinese originating in different parts of China and living in the same locality have any significant differences in susceptibility. Hong Kong is not the ideal place for such a study because of the
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TABLE 111: RELATIVE FREQUENCY OF NABOPIIARYNGEAL CARCINOMA I N CHINESE MAINLAND AND TAIWAN ESTIMATED AS PERCENT OF ALL MALIQNANT TUMORS DIAGNOSED BY BIOPSY Percent of all cancers by biopsy
56.9 of 3010 3 1 . l o f 672
17.4 of 4O26 10.0of 748
16.2 of 1010 23.2 of 5436 7 . 3 of 8332 6 . 7 o f 879
4 . 7 of 1068 6 . 2 of 8636
Place South Canton (Kwangtung province) Kwangei province Central Fukien province Taiwan Shanghai (Kiangeu province) Sian (Shensi province) North Tsinan (Shangtung province) Tientein (Hopei province) Peking
5 . 1 of 2738 7 . 9 of 1562 4 . 0 of 5137
From Ho (1972), by permission from the editor.
constant influx of refugees. However, this influx became insignificant after 1962. The incidence rates by place of origin for Chinese males and females domiciled in Hong Kong in 1969 are given in Tables IV and V. Excluded in the analysis are patients who came from outside Hong
FIG.3. Map of China.
NASOPHARYNQEAL CARCINOMA (NPC)
INCIDENCE RATES OF &INESE
Place of origin
Hong Kong Canton, M a w , and adjacent places Sze Yap area Chiu Chau area Elsewhere in Kwangtung and Kwangsi Elsewhere in China outside Kwangtung or Kwangsi
TABLE IV NASOPHARYNQEAL CARCINOMA FOR HONQKONQ &LEB BY PLACE OF ORIQIN, 1969 Population 1966 byNo. of c e n s u ~ ~ CBBB~C
Crude rate per100,OOO
355,650 214,410 115,440
68 26 28
19.11 12.12 24.25
,, Barnett (1966). b Include an unknown number of non-full-blood Chinese. c Include only cases seen at Medical and Health Department Institute of Radiology. All full-blooded Chin-.
Kong for medical consultation or treatment. The rates for people of Chiu Chau origin of both sexes are significantly lower than those for people who claim origin from other parts of Kwangtung with Hong Kong excluded ( P < 0.01). The people from Chiu Chau are ethnically more TABLE V INCIDENCE RATESOF NASOPHARYNOEAL CARCINOMA FOR HONQKONQ CHINESE FEMALES BY PLACE OF ORIGIN, 1969
Place of origin
Hong Kong Canton, M a w and adjacent p l a w Sze Yap area Chiu Chau area Elsewhere in Kwangtung and Kwangsi Elsewhere in China outside Kwangtung or Kwangsi
Population 1966 bycensus0
No. of cases0
Crude rate per 100,OOO
Agestandardized rate per 1 0 0 , ~
347,210 184,230 103,240
23 3 9
6.62 1.62 8.71
7.40 2.17 10.29
Barnett (1966). Include an unknown number of non-full-blood and Chinese. 0 Include only cases seen at Medical and Health Department Institute of Radiology. d All full-blooded Chinese. 0
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closely related to the people from Fukien than those from other parts of Kwangtung. The rates for people originating from parts of China outside Kwangtung and Kwangsi are significantly lower than those for people from Kwangtung and Kwangsi with Chiu Chau and Hong Kong excluded ( P < 0.01 for males and P = 0.025 for females). Hong Kong was a part of Kwangtung until it was ceded to Great Britain in 1841. These findings are in general agreement with those obtained in an earlier study on the incidence of nasopharyngeal cancer in the Chinese population of Hong Kong in 1961 (Ho, 1967a) and also with those reported by Mekie and Lawley (1954) on the Chinese population in Singapore. They found that the Teochews (people from Chiu Chau) and the Hokkienese (people from Fukien province) had lower frequencies of nasopharyngeal cancer than the Cantonese, Kheks, and people from Hainan Island. The Kheks are people scattered in different parts of China, but the majority of them are from Kwangtung. Muir and Shanmugaratnam (1967) have shown that in multi-racial Singapore the age-adjusted minimum incidence rates for the 12-year period 1950-1961 were the highest for Chinese and lowest for Indians and Pakistanis, those for Malays being in between. This finding is confirmed by Shanmugaratnam (1970) in a later analysis of the incidence rates based on histologically diagnosed cases only for Chinese, Malays, and Indians in Singapore for the 5-year period 1960-1964. The crude rates per 100,000 per annum for the 3 groups are, respectively, 13.3, 3.2, and 0.4, and the corresponding age-standardized rates 20.2, 5.8, and 0.2 for males. For Chinese and Malay females the crude rates are 6.4 and 0.9, and the age-standardized rates 9.0 and 2.0, respectively, there being no cases among Indians. Singapore, unlike Hong Kong, has relatively few immigrants. Chinese living there have been found to have risks according to their places of origin in China similar to those in Hong Kong. Furthermore, Indians who are normally of low risk and living in Singapore among Chinese and Malays do not share their high risk of developing the disease. It would appear, therefore, that it is the ethnic factor, rather than the geographic locality of domicile, which determines the risk. 3. Eject of Distant Migration on People of High Risk
Chinese in Hong Kong or Singapore constitute the majority of the local population and have, therefore, retained largely the customs and ways of life of their ancestors. Chinese in Australia, Hawaii, and California are in the minority and because of the vast distance between these places and the Orient they are likely to retain less. This applies especially to those born in their countries of adoption.
NASOPHARY NGEAL CARCINOMA ( N P C )
I n Australia, Scott and Atkinson (1967) found little difference in the risk of suffering from the disease whether a person of Chinese descent is born in Australia or outside. On the other hand, Worth and Valentine (1967) reported incidence rates for the population over the age of 14 years of Chinese descent to be 35.1 per 100,000 for males born in China and Hong Kong and 10.2 for those born in Australia. For females they are, respectively, 29.1 and 11.1. The corresponding crude rates for those of all ages are, respectively, 31.6 and 7.1 for males and 19.2 and 7.8 for females. Their report was based on an analysis of a series of 15 Chinese cases during a 10-year period 1953-1963. However, they pointed out that of the 11 China-born male cases, it was possible only to ascertain that five had been in Australia more than 5 years when diagnosed, one had been in Australia only 1 month, and the duration of residence was unknown for the other five. If these six were not immigrants but patients who went to Australia from Southeast Asia for treatment or other purposes and excluded from the list then the rate for Chinese males over 14 would be only 16.0 which is only 57% higher than the corresponding rate for non-Australian-born Chinese males. In such a small series a difference of this magnitude is without significance. In a place like Sydney, where all the case material was obtained, it is not at all unusual for Chinese from Southeast Asia traveling there during the 1953-1963 period to seek treatment because of the inadequate radiotherapy facilities in their place of domicile at the time. I n Hawaii, Quisenberry and Reimann-Jasinski (1967) analyzed a series of 14 cases of Chinese descent reported in the Hawaii Tumor Registry during 1960-1962; they found rates for 9 subjects born in the United States including Hawaii to be 6 times higher than for subjects born elsewhere. An annual rate of nasopharyngeal cancer of 54.2 per 100,000 for all ages and both sexes combined for Chinese other than those born in the United States including Hawaii is about 3.5 times higher than the corresponding rate of 15.2 per 100,000 and over 3 times the age-standardized rate of 17.2 for the mean total population of Hong Kong during the 5-year period 1965-1969 with patients from elsewhere excluded. This makes one wonder whether this group might have included Chinese patients who went to Hawaii for medical purposes. An alternative explanation is that Chinese by migrating to Hawaii had become more susceptible to the disease whereas the local-born Hawaiians of Chinese descent were no more susceptible than the Chinese in Hong Kong-a most unlikely explanation. I n the State of California, Zippin et al. (1962) investigated the place of birth of 31 Chinese males reported to the California Tumor Registry during a 16-year period 1942-1957; they found the ratio of observed-to-
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expected ( O / E ) number of cases by age group to be more than 8 times higher in Chinese under the age of 55 born outside United States than in those born inside. No difference was found between the two groups over 55. They stated that a difference in coverage might exist between Chinese born in the United States and those born outside, but they did not mention whether cases in the latter group might have included patients who went to California from the Far East specifically for treatment. These patients are likely to be in the younger age group because the older patients are less fit as well as less willing to make the trip. If such patients were unknowingly included, the O/E ratio would be unnaturally high. In addition, two assumptions were made in the calculation of the O / E ratio. One is that the age-sex-specific rates of New York State applied equally well to each of the age-sex-race-nativity-specific groups in California. This is not valid because the incidence rate for Chinese males reaches a peak at the age period of 50-54, after which the rate declines sharply (Fig. 5) whereas for Caucasian males the peak is reached one to two decades later. The second assumption is that the. age-distribution of the United States-born and foreign-born Chinese populations in California according to the 1950 census constitute the mean age-distributions for the two groups during 1943-1957. This is not necessarily valid. Finally, as the authors themselves have rightly emphasized, caution must be exercised in the interpretation of results based on numbers so small as those in some categories of their series. Buell (1965) , on the other hand, studied the California mortality records of deaths from cancer of the nasopharynx in 67 men and 13 women of Chinese descent during the 14 years from 1949 through 1962. The number of cases analyzed is again small and spread over a long period. He found that the risk of nasopharyngeal cancer in the local-born Chinese is considerably higher than in the white population, but lower t,han that in the immigrant Chinese. The factor of increase is about 20fold for both men and women of Chinese descent born in the United States, and 30- to 40-fold for the men and women born in China. Buell further stated that the Chinese immigrants to California have carried with them as much, if not more, risk of cancer of the nasopharynx as the immigrants to Singapore. While a lower incidence among the United States-born Chinese would support an environmental hypothesis, both Zippin et al. (1962) and Buell were of the opinion that it did not rule out a genetic etiology. It could be the result of a genetic-environmental interaction or a selection against a genotype as a cause of a reduction in the filial generation. Buell feels that there is no doubt that the immigrant generation had a lower fertility than their fathers, for, even as late as 1950, the ratio of
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single adult men to single women was 2:l and several decades earlier the ratio was several times higher. He finds evidence that marriage was often postponed, as revealed by the disparity in the parental age on some birth certificates of Chinese, a paternal age of 40 or 50 and a maternal age of 20 or 30 being not infrequent. Also according to Buell, about 28% of the nasopharyngeal cancer cases were reported to have died unmarried, and some married men were separated from their wives for long intervals, partly due to the Extension Acts of 1882 and 1924 (Lee, 1960). I n conclusion, it could be said that we are still left in doubt whether distant migration has altered the risk of Chinese born in their country of adoption, but the risk of those born in their place of origin appears to be unaffected. Further studies are called for.
4. Risk in People of Part-Chinese Ancestry Ho (196713)reported a crude average annual incidence rate estimated to between 20.0 and 26.7 per 100,000 during 195S1963 among Hong Kong “Macaonese,” a term which had been used by the Macao Government until a few years ago to describe “local” Portuguese as distinct from “continental” Portuguese. Macao has been colonized by Portugal for over 4 centuries, and the “Macaonese” are largely products of intermarriage between the two races, but all of them are Catholics by religion. Many of them have migrated to Hong Kong. In fact, the great majority of the people of Portuguese nationality in Hong Kong are “Macaonese.” According to a communication dated August 15, 1966 from the Commissioner of Registration of the Hong Kong Government, the number of persons resident in Hong Kong of Portuguese nationality who had registered with his department for Hong Kong Identity Cards comprised of 833 males and 735 females over the age of 6, and of 117 males and 121 females between the ages of 6 and 17 years. Those below the age of 6 were not registered, and it is not possible to ascertain the number of those who have adopted British nationality, and have not registered as Portuguese. Those registered as Portuguese included, on the other hand, a small proportion of “continental” Portuguese. With the help of some of the members of their community, it has been estimated that the total Portuguese population in Hong Kong was between 3000 and 4000 a t the time of the study. Even taking the lower estimate of 20.0 per 100,000, the crude incidence rate is unusually high, being higher than the highest of the crude rates for the various ethnic groups of Chinese in Hong Kong, e.g., 13.2 for the people originating from the Sze Yap area (Ho, 1967a). There was probably an underestimation of the “Macaonese” population accounting for its unusually high incidence,
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but there could be no doubt that it was much higher than that for the other non-Chinese ethnic groups in Hong Kong, because among the 53,230 persons classified as non-Chinese in the 1961 census there were five cases of nasopharyngeal carcinoma diagnosed during the 5-year period 1959-1963-four of them “Macaonese,” and one a Malay. There was not a single case among the rest, which include Europeans in the British civil service and armed forces and the foreign business community, Gurkhas in the Gurkha Infantry Brigade, Indians, Pakistanis, and other minority racial groups. I n fact, the author in over 20 years’ practice as a radiotherapist in Hong Kong has seen only one case of NPC among European Caucasians and none among the Gurkhas, Indians, and Pakistanis, although their total number far exceeds that of Macaonese in the population. In Thailand, Garnjana-Goochorn and Chantarakul (1967) engaged in a prospective survey of 1000 consecutive cancer patients in the Tumour Clinic of the Siriraj Hospital in Dhonburi with the intention of finding the relative frequencies of nasopharyngeal cancer among the three racial groups-Chinese, Chinese of part-Thai ancestry, and Thais. Out of the 1000 cases, there were 170 Chinese, 195 Chinese of mixed descent, 628 Thais, and 7 of other nationalities. Nasopharyngeal cancer was found in 27 Chinese (15.9%),20 Chinese of mixed descent (10.3%), and 29 Thais (4.6%). From this study they estimated the ratio of relative frequencies in the 3 groups to be respectively 3.4:2.2:1.0, and believed that this estimation was as near the correct proportion as they could get in Thailand. They further reported that nasopharyngeal cancer constituted 3.5% of all malignant neoplasms diagnosed a t Siriraj Hospital during a 6-year (1957-1962) period. Thais are mongoloid people, mostly Buddhists, but Portuguese are Caucasian Catholics. Yet in both, the products of intermarriage with Chinese appear to inherit at least a part of the high risk of their Chinese ancestors. 5. Familial Aggregations
Reports on familial aggregations of cases of nasopharyngeal carcinoma in literature are scarce. Pang (1959) records finding two pairs of related cases, mother-son and sister-brother combinations, in a series of 34 consecutive cases of nasopharyngeal cancer, including 27 Chinese, in Hawaii. Buell (1965) found one pair, mother-son combination, in his study of 80 certificates of death due to nasopharyngeal cancer in California. Ho (1967b) found 15 instances of familial aggregations in two separate series of 1180 cases of nasopharyngeal carcinoma. I n eight instances two brothers in the family had the disease, in one instance
NASOPHARYNGEAL CARCINOMA (NPC)
three brothers, in two instances a pair of brother and sister, in one instance the son and his father, one nephew and aunt, one sister and her brother, and finally in one instance a female patient had a family aggregation of cases extending over three successive generations. A pedigree study, retrospective and prospective, of this family is shown in Fig. 4. The family was originally from Canton, but generation I1 had settled in Hong Kong. Nos. 3 and 4 of this generation, the two younger brothers of the paternal grandfather of the propositus, died of a disease with a clinical history highly suggestive of NPC, e.g., nasal bleeding, regurgitation of food through the nose, and loss of voice. These are the only symptoms recalled by I11 (No. 1) and related by members of generation IV. When a Chinese of Canton origin dies of a disease with these symptoms, it is most likely NPC with involvement of the last four cranial nerves. The father of the propositus was a proven case of NPC; he was treated at Queen Mary Hospital by the late Professor K. K. Digby, who advised him to go to Shanghai for radiotherapy as there was no such facility in Hong Kong at that time. He died at the age of 38, leaving a wife with seven children and a concubine with three children. There has been no contact between the wife and the concubine, who live separately, since his death. However, it is known from hearsay that all 3 children by the concubine are now over 40 and none suffer from NPC, whereas six of the seven children by the wife had developed the disease verified by biopsy. The wife is still alive a t 78 and well. 1
1. 2. 1 2 8 dx50
D D D dead
4. 5. 6O 7. eo go ion 4x28 dx42 dx35 dx34 %W" W W " "AW" D D A3R AW D AW a l i v e & w e l l A3R a l i v e without recurrence
t age at death 7
no d a t a
dx age at diagnosis
I'not v e r i f i e d
FIQ. 4. Pedigree study of a family with aggregation of NPC cases extending over three successive generations. From Ho (1972), by permission from the editor.
J . H. C. H O
Pedigree studies of Chinese patients in Hong Kong are handicapped by the fact that many of them have lost contact with some or even all of their kinfolk as a result of wars, rebellions, and revolutions which have ravaged China over the last several decades. Some patients do not know the causes of death of relatives because of inadequate diagnostic service. Others were adopted when very young and know nothing about their relatives. Under the assumption that these handicaps probably apply equally to family studies of NPC patients and of patients suffering from other cancers (OC) in a large series, a study has been carried out a t the Medical and Health Department Institute of Radiology, Hong Kong, in 1969 to determine whether close blood-linked relatives of NPC patients have a higher risk of developing NPC than those of patients suffering from other cancers. The results of this study are given in Tables VI and VII. The source of data in the study consists mainly of medical records; these are, as a rule, inadequate for genetic studies, as clinicians are usually more concerned with medical diagnosis and treatment than with obtaining a detailed family history of diseases. T o minimize this inadequacy the medical staff has been requested to inquire for family histories of NPC in both groups of patients. Positive questions were asked in order to counterbalance the memory bias of patients who tend to remember relatives suffering from a disease similar to their own better than those suffering from other diseases. In doubtful cases, the patients were recalled for further questioning by the author. A greater risk of getting NPC is found in relatives of NPC patients than in relatives of patients suffering from other cancers. It is interesting to note that 3 TABLE VI FREQUENCY OF FAMILY HISTORYOF NPC IN PATIENTS WITH NPC AND IN THOSE WITH OTHER CANCERS (OC) DIAGNOSED AT THE MEDICALAND HEALTHDEPARTMENT INSTITUTE OF RADIOLOGY, H O N Q HONG,1969 Cancer
Families with history
Families with no history
14 X’ = 14.77785 ( P < 0.001) t
1072 1086 = 3.864234 (P= 0.00011)
From Ho (1972),by permission from the editor. Of the 12 families, 3 are “boat” people. b Seventy-two were excluded because a family history wm unobtainable, unreliable, or not obtained. In this group, 515 c a m were excluded, 230 for the above reasons and 285 because the cancers are sex-determined, e.g., gynecological, penile, etc.
NAsOPHARY NGEAL CARCINOMA (NPC)
TABLE VII FAMILIAL AQOREQATIONB OF NP CARCINOMA Families 1
2 3 4 5
PATIENTS SEEN IN 1969
Daughter (II/2M 4F) and father Son (V/2M 3F) and mother.
1 Female paternal 1st cousin
Son (IV/4M mother
+ 5F) and
2 Siters (I and II/6M
2 Paternal 1st cousins: Male (III/3M 2F) and M OM)
Son (V/4M father
+ 3F) and
Daughter (IV/lM 5F) and fathero Son (only child) and father
Mother (II/lM daughter
+ 3F) and
Total = 7
Male (V/3M 2F) and brother (11) and brother (11
Male (only child) and his half-brother by same father; latter’s halfbrother by same mother was well
Brother (?/4M 1F) and 1 brother Total = 7
From Ho (1972), by permission from the editor. 0 D iagnosis was based on typical history only. (II/2M 4F) means propositus is the second child (11) of a family of two sons and four daughters.
of the 12 NPC families with aggregations of cases are “boat” people, a very small group of people who have a tendency to marry within their group and have been living in boats, junks, and sampans for centuries until recently when some of them have settled ashore and intermarried with land dwellers. The marine population of Hong Kong, according to the 1966 By-Census (Barnett, 1966), constitutes only 2.76% of the total population and consists largely of “boat” people. Table VII shows the directions of aggregation in the 12 families. If we accept the two unverified cases with only hearsay typical clinical histories (mother of propositus No. 2, and father of propositus No. 8) as positive cases, then the incidence of aggregations in this series is as
J. H. C. H O
great in the vertical as in the horizontal direction. From sheer numbers at risk, one would expect the aggregation in the horizontal direction to be greater than in the vertical. It is also more likely for a patient to know of or remember diseases suffered by relatives belonging to the same generation than by those in earlier generations. Diagnostic facilities were also poorer in the early days. Duration at risk is on the side of the older generations but not to a great extent, as the risk of getting NPC declines after the fifth decade in Chinese except in recent years, when a second but lower peak has become increasingly apparent in the seventh decade. It would appear in the present and past studies that if there were vertical transmissions in NPC they are not sex-linked. The random nature of the aggregations is indicative of a multifactorial etiology, and if genes are involved they are likely to be polygenic. 6. Nasopharyngeal Carcinoma in Twins No report of nasopharyngeal carcinoma occurring in twins has been found in the literature. Of some 6000 cases of nasopharyngeal carcinoma diagnosed at the Queen Mary and Queen Elizabeth Hospitals, where the Medical and Health Department Institute of Radiology is based, during a 20-year period 1951-1970 there was only one verified instance of NPC occurring in a pair of twins, probably dizygotic, of Sze Yap origin. One member, who died of NPC, was a patient of the Institute. The other, who migrated to Canada over 10 years ago, received radiotherapy in Canada for NPC 8 years after the death of his twin brother a t the age of 41, 1.5 years after the clinical onset of his disease. There are an elder and a younger brother and three younger sisters. None of them or their parents are known to have suffered from the same disease. The eldest brother is alive and well. Nothing more is known about the others. A twin birth occurs in about every 100 deliveries among Chinese in Hong Kong. At Tsan Yuk Maternity Hospital there were 673 twin deliveries during the 10-year period 1959-1968. Of these the nature of the twinning is recorded in the case of only 631. Three hundred and fifty (55.6%) of them are biovular and 281 (44.4%) are uniovular (Chun and Lee, 1970).
7 . ABO Blood Group Distribution If a genetic etiology is suspected, it is a call for more data, not for immediate speculations. So far only the ABO group distribution in NPC cases and normal controls have been investigated (Ho, 196713; Clifford, 1970). Clifford, comparing the ABO blood group distributions in 233 Kenyan patients with nasopharyngeal carcinoma and in controls, found a significance level of 3% in the comparison A/O and considers this to
NASOPHARYNGEAL CARCINOMA (NPC)
TABLE VIII ABO BLOODGROUPDISTRIBUTION IN PATIENTS WITH NASOPHAF~YNGEAL CARCINOMA AND CONTROL^ Population (all Chinese)
NPC patients: males NPC patients: females Total Percentage Controls (Grimmo and Lee, 1961) Controls (Tong el al., 1963) Total Percentage
291 99 390 39% 258 5,747 6,005 41.6%
197 69 266 26.6% 181 3,650 3,831 26.5%
205 69 274 27.4% 180 3,515 3,695 25.6%
57 13 70 7% 51 856 907 6.3%
Total 750 250
1,OOO 100% 670 13,768 14,438
From Ho (1972), by permission from the editor. For A/O comparison: t = 0.82093 ( P = 0.41); for B/O comparison: t = 1.62801
(P = 0.104).
be highly suggestive that, in Kenya, group-A persons are “protected” or a t less risk of nasopharyngeal carcinoma and that persons with other blood groups are consequently relatively a t greater risk. He feels that there seems to be an inherited susceptibility to, or protection against, nasopharyngeal carcinoma in some Kenyan Africans. I n Hong Kong a study of the ABO blood group distribution in loo0 consecutive Chinese patients with nasopharyngeal carcinoma failed to reveal any significant difference in the distribution in this group when compared with normal controls in the A/O or BJO comparison. The results are given in Table VIII. Shanmugaratnam (1970) also failed to find any significant difference between NPC cases and controls in Singapore. The distributions of ABO blood groups in Chinese in different parts of China, Singapore, Sumatra, New York City, and Hong Kong are given in Table IX for comparison. There is no great difference in the distributions between those reported by Grimmo and Lee (1961) and Tong et al. (1963) for Chinese in Hong Kong and those reported by Dormanns (1929) and Allen and Scott (1947) for Chinese in Canton and in Singapore, respectively. A very high incidence of the disease is found in all three places. I n the Yangtse River region, Hunan, Hupeh, and Kiangsu, where the relative frequency is lower (Hu and Yang, 1959), there is a definite excess of A group over B, but then in Peking, where the relative frequency is lowest, it is just the reverse. It would appear, therefore, that if certain genes are associated with a greater susceptibility to nasopharyngeal carcinoma in Chinese they are unlikely to be associated with the ones which determine the possession of blood
J . H. C. H O
TABLE IX ABO BLOODGROUPDISTRIBUTIONB AMONG CHINEBE OUTSIDEOF HONGKONQ" AND AMONG CHINESEIN HONGKONG Percentage Place China Yangtge River Hunan Hupeh Kiangsu Kwangtung Canton Canton Peking Peking Hong Kong Singapore Sumatra (East coast) New York City
29.5 1096 42.9 Yang (1925)" 93 43.01 31.18 Yang (1928)" 197 42.13 32.49 Yang (1928)" Yang (1928)" 228 52.63 21.05 196 40.82 32.65 Yang (1928)" 992 45.87 22.78 Dormanns (1929) 101 45.54 29.70 Alley and Boyd (1943)" 1000 30.70 25.10 Liu and Wang (1920)" 427 65.34 4.68 Hung and Steffan (1928)" 670 38.51 27.02 Grimmo and Lee (1961) Tong el al. (1963) 13788 41.74 26.51 Allen and Scott (1947) 624 43.11 24.04 592 40.20 25.00 Bias and Verhoef (1924)O
19.7 7.9 19.35 6.45 17.26 8.12 15.79 10.53 18.37 8.16 25.20 6.15 18.81 5.94 34.20 10.00 19.67 10.30 26.86 7.61 25.53 6.22 27.72 5.13 27.33 7.26
Levine and Wong (1943)"
150 30.00 34.00
From Ho (1972), by permission from the editor. Cited in Mourant and Domaniewska-Sobczak, 1958.
group A, B, or 0 substance. A study of the HLA pattern in Southern Chinese and non-Chinese living in Singapore will soon be conducted. 8. Physical Anthropology
There have been regrettably few attempts to survey the physical characteristics of patients with nasopharyngeal carcinoma for comparison with unaffected subjects matched for ethnic origin, sex, and age. Walsh (1967) concluded from his study that to date no single physical characteristic has been found that is common to the population of those countries with a high incidence of the disease and absent from others. He emphasized, however, that this does not mean that the possibility has been exhausted of finding a unique multifactorial set of characteristics in those populations with high risk, and that many more surveys must be undertaken and submitted to computer analysis.
C. ENVIRONMENTAL FACTORS 1. External Factors a. Inhalants. Dobson (1924) postulated that the high incidence of the disease in Chinese was related to the poorly ventilated houses in
NASOPHARYNGEAL CARCINOMA (NPC)
which they lived and inhaled much of the domestic smoke from burning grass, wood, tobacco, candles, incense (joss sticks), kerosene, and peanut oil lamps. Then Clifford and Beecher (1964) proposed that the inhalation of smoke from burning wood from exotic trees (eucalyptus and wattle) and indigenous acacias in ill-ventilated huts for several hours a day over a period of years may have some bearing on the distribution and incidence of the disease in Kenya, especially when significant quantities of carcinogenic substances, such as benzopyrene and benzanthracene, have been found in the soot taken from the roof of the huts of 46 patients with nasopharyngeal cancer on analysis by Hoffman and Wynder at the Sloane-Kettering Institute, New York. On the other hand, Booth et al. (1968) found similar living conditions among the one million and more people living in the Highlands of Australian New Guinea, but nasopharyngeal carcinoma is a rarity among them. It might be argued that the smoke in the two cases contains different substances, but then the crude annual incidence rates of nasopharyngeal carcinoma for most Kenyan tribes are below 0.5 per 1OO,OOO, and even among the Nandi tribe, which has the highest rate, the rate was only 0.94 (Clifford, 1967), which is only slightly higher than for the Swedes, who live in well-ventilated houses. Furthermore, Ho (1967a) found the incidence rates for the marine population in general and the “boat” people in particular, who live and spend most of their lives in sampans and junks and cook their food in open air, to be significantly higher than that for the land dwellers in Hong Kong. It would appear, therefore, unlikely that domestic smoke plays a significant role in the genesis of nasopharyngeal carcinoma, and certainly it cannot account for the high incidence in Hong Kong Chinese. Opium has also been suspected since it was first introduced into China in the early part of the nineteenth century through Canton, the capital of Kwangtung province. Digby (1951) observed that many Chinese who developed nasopharyngeal cancer were not opium smokers, and Polunin (1967) quotes a personal communication to him by Leong (1964) who estimates that he has seen about 5000 Chinese opiumsmoking men in Singapore, following them up for a period of a year each. Their average age was 48 years, and they had smoked opium for about 20 years, but he did not find a single case of nasopharyngeal cancer among them. Shanmugaratnam and Higginson (1967) found 87% of 63 Chinese male patients with nasopharyngeal carcinoma never smoked opium as against 84% of matched controls. In a retrospective survey of the records of 685 patients with nasopharyngeal carcinoma diagnosed during the 2-year period 1962 and 1963 a t the Medical and Health Department Institute of Radiology, Hong Kong, only four patients admitted to having smoked opium. There may have been some underrecording, but it is unlikely to be more than slight. I n a later study
J. H. C. H O
in 1969 there were 6 cases of opium addiction and three of heroin among 471 cases of nasopharyngeal carcinoma. None of the rest indicated that they had smoked opium at any time. In contrast there were four cases of opium addiction and 2 of heroin among 173 cases of bronchial carcinoma, and 11 cases of opium addiction among 47 cases of laryngeal carcinoma. There is, therefore, no evidence to suggest that opium plays a part in the causation of the high incidence of the disease in Chinese. Oriental incense or joss sticks are burnt not only in Chinese Buddhist and Taoist temples but also on a small scale in many Chinese homes in Hong Kong, China, Southeast Asia, and the United States. Those used in Hong Kong are made from sawdust from sandal-wood imported from Hainan Island and other parts of Kwangtung, Indonesia, India, and Australia in factories in Macao and Hong Kong. During the IO-year period 19551964, and average of 71.4 tons of joss sticks were exported or reexported from Hong Kong to the United States per year according to the Hong Kong Department of Commerce and Industry. Sturton e t al. (1966) found a difference (significant a t the 5% level) between incense burning and nonincense burning for male cases under 50 years of age and for male cases as a whole, but not for those over the age of 50, when a group of 29 male NPC cases was compared with a group of 38 male cases of other cancers. There was, however, no significant difference in the female patients of the two groups. Perhaps, the latter finding is more important than the former, because it is the females, not the males, who attend to the burning of joss sticks in Chinese homes. Furthermore, the incense smoke hypothesis is not in keeping with the finding by Ho (1967a,b) that NPC is rare among Buddhist monks, nuns, and Taoist temple attendants, who spend much of their time in incense-laden atmosphere. In fact, among over 3500 cases of nasopharyngeal carcinoma diagnosed a t the Medical and Health Department Institute of Radiology during the ll-year period 195&1966, there were only one Buddhist nun and one Taoist temple keeper. According to Sturton et a,?. (1966) there were 2000 temples and shrines in the city of Hangchow in central China and about 10,000 monks and a smaller number of Taoist monks or priests in a population of about 800,000 in that city before the institution of the present Chinese Government. Sturton (1965), in his work as a doctor and radiologist from 1921 to 1952 in Hangchow, did not observe any higher incidence of nasopharyngeal cancer than one would find in a large general hospital in England. The apparently high incidence of nasopharyngeal carcinoma in Macaonese who are traditionally Catholics and do not burn joss sticks in their homes or go to Buddhist or Taoist temples for worship, the relatively high incidence in Malays in Southeast Asia, who are traditionally Muslims and do not burn joss sticks, and the
NASOPHARYNGEAL CARCINOMA ( N P C )
high incidence in the “boat” people of Hong Kong, who are less exposed to the smoke from burning joss sticks by virtue of their living in open boats than the land dwellers, are other contradicting evidences. It is, liowever, not possible to draw any conclusion at this stage that, because nasopharyngeal carcinoma appears to be rare in Buddhist monks, nuns, and Taoist temple attendants, joss sticks may have a protective action against the risk of getting the disease. These people belong to a small occupational group and the actual incidence of nasopharyngeal carcinoma in them has yet to be determined. Of the other inhalants, mention must be made of antimosquito coils which have been in common use in Chinese homes in China for many years and in Hong Kong until recent years, when urban areas have been rid of mosquitoes. The coils are still being used in some rural homes. Shanmugaratnam and Higginson (1967) did not find any significant difference between a group of 100 patients with nasopharyngeal carcinoma and a group of matched controls of the same number in their use of antimosquito coils in Singapore. Neither did they find any significant difference between the two groups in their use of cigarettes, pipe tobacco, snuff, and Chinese medicinal balms, oils, drops, and powders for inhalation or intranasal applications. The use of tobacco among Chinese is not as prevalent as among people of western nations, and the introduction of its use as a social habit in China occurred only within this century. Consequently, it could not have been responsible for the high frequency of the disease in China which most probably have existed for a longer period. b. Ingestants. We must not look for carcinogenic inhalants in the environment only of people a t high risk. It has been shown by Druckrey et al. (1964a) that compounds of the nitrosamine group can act systematically and are organ specific. They have further shown that a single dose of such a carcinogen can initiate a train of events which will culminate in cancer development after a long latent period without a further dose (Druckrey et al., 1964b). Bonser (1967) suggests that nitrosamine is not itself carcinogenic, but has to be converted enzymatically to an active carcinogenic metabolite. The enzymes capable of effecting such a conversion are different for different nitrosamines, so that the location of specific enzymes determines the site of the cancer. Nitrosamines are formed when nitrates are used as food additives or preservatives. Fish preserved in salt containing nitrate has been for many years a common and favorite item of food among most Chinese, rich or poor, in or outside China in Southeast Asia or the United States. This is also true for Macaonese in Hong Kong and Macao and to a less extent the Malays in Malaysia. Shanmugaratnam and Higginson (1967) noted
J. H. C. H O
no significant difference in food habits between a group of 100 male patients with nasopharyngeal cancer and a group of matched normal controls. The frequency of use of rice, and a variety of other foodstuffs, including salted and dried food, was approximately the same in the two groups. They pointed out, however, that their negative findings are not conclusive. Further epidemiological studies aa well as investigation into their carcinogenic properties are called for. It is more important to determine whether Chinese who never eat salted fish or food have the same risk of getting the disease as those who do than to compare the frequencies of eating such food between nasopharyngeal cases and matched controls. c. Nasopharyngeal Carcinoma Occurring in Both Marital Partners. During the 14-year period 1956-1969 only two verified instances of the disease occurring in both the husband and the wife of a family are found among 5070 cases diagnosed at the Institute of Radiology, Hong Kong. The husband in the first instance developed symptoms of the disease a t the age 39, just over 6 years after marriage, and the wife a t the age of 36 about 10% years after marriage. Both of them are Catholic, have no family history of nasopharyngeal cancer, and lived together in Hong Kong after their marriage. The husband in the second instance developed symptoms a t the age of 52, and the wife a t the age of 40. Neither of them had a family history of the disease. The exact time of their marriage is not known, but the number of years between marriage and symptomatic onset cannot have been less than 13 years in the case of the wife and 18 years in the case of the husband, judging from the age of their only surviving daughter. The length of stay in Hong Kong before onset was 14 years in the case of the wife and 20 years in the case of the husband. Both have since died, and their daughter is untraced. This incidence must be considered as minimal, because after the death of a spouse the surviving one-might return to China or migrate elsewhere or would not return to the Institute which had failed to cure his or her spouse of the disease to seek treatment. There could not be many such cases because there are few places available for treatment, and the Institute is the only place in Hong Kong where the poor can get free treatment as well as social welfare benefits. Among the 5070 cases, about 200 are patients who came from China or Southeast Asia specifically for treatment, after which they returned to their homes. Of the 121 who came from Southeast Asia during the period 1964-1969, many are, however, still in contact with the Institute. Nasopharyngeal carcinoma is a prevalent disease. Even allowing for some probable underrecording, one cannot but be impressed by the infrequency of such occurrences. It would appear, therefore, that those environmental factors,
NASOPHARYNGEAL CARCINOMA (NPC)
which affect husband and wife alike and are found in most homes, are of little etiological importance, at least during adult life. d. Occupation and Socioeconomic Level. In Singapore, Shanmugaratnam and Higginson (1967) found a wide range of occupations to be represented in both nasopharyngeal cancer and control groups in a retrospective survey, and Polunin (1967) found a lack of a clear-cut association between ways of living and nasopharyngeal cancer. I n Hong Kong, the carcinoma does not appear to occur more frequently in any particular occupation, as in the case of Singapore. In the highly competitive Hong Kong society, where much free enterprise exists, there is a definite possibility that someone who came originally from a poor family could become rich later in life, and vice versa. It is more important to study the early part of the life of a subject in a survey, than the later part. There are in Hong Kong, however, sufficient cases of nasopharyngeal carcinoma who are known to belong to the upper, middle, and lower socioeconomic levels throughout their preceding lives to justify the impression that a higher or lower risk is not associated with any socioeconomic level. Andrews and Michaels (1968a,b) reported three cases of nasopharyngeal carcinoma in Canadian bush pilots, a very small occupational group. One is of French extraction, one is Finnish, and one English, and they had been on their jobs for 10, 28, and 25 years, respectively. Such flying in unpressurieed aircraft subjects the pilots to very frequent and rapid air pressure changes which are likely to produce “otitic barotrauma,” which is thought to be a precursor of nasopharyngeal carcinoma. All three were cigarette smokers. It was thought that cigarette smoke and other potentially carcinogenic substances may be specifically directed to the nasopharyngeal area as a result of pressure changes. It was also pointed out that there was a greater speed of pressure changes experienced by these pilots than that experienced by divers. There was, however, no subsequent report of another case in these pilots or in other groups of airmen working under similar conditions of barometric change, e.g., crop-duster, air taxi, and helicopter pilots. There must be many such airmen all over the world, although the climatic conditions under which they work may not be similar to those for the Canadian bush pilots. For example, the Canadian air in winter is very cold and dry (Lancet Annotations, 1968). Although coincidence cannot be ruled out, the finding of three cases in so small an occupational group certainly deserves further investigation. 2. Internal Factors a. Malnutrition and Vitamin Deficiency. Contrary to the findings by Clifford (1965) in Kenyans, a good nutritional state without clinical
J. H. C. HO
evidence of vitamin A or B group deficiency is the rule rather than the exception in Hong Kong patients except in the terminal stage of the disease. Many of them also gave no history of malnutrition or chronic ill health during childhood. b. Hormonal Factors. Kenyans with nasopharyngeal carcinoma had significantly lower plasma levels of dehydroepiandrosterone sulfate (DS) as compared with the control group, but plasma levels of androsterone sulfate (AS) in both groups were similar (Wang et al., 1969; Clifford, 1970). In Singapore, similar low levels of DS and AS were noted in Chinese patients with nasopharyngeal carcinoma, but studies on the plasma levels of DS, AS, cortisol, and transcortin in apparently normal male subjects from racial groups with high (Chinese), intermediate (Malays), and low (Indians) incidence of the disease revealed no differences (Wang et al., 1969). Plasma estrogens were, however, not measured in the studies carried out in Kenya or Singapore. c. Chronic Infection of the Upper Respiratory Passage and Vasomotor Rhinitis. Although nasal sinus infection is a common complication of established nasopharyngeal carcinoma, only a minority of the patients in Hong Kong gave a past history of chronic upper respiratory infection or vasomotor rhinitis. Vasomotor rhinitis may be common in Chinese, but it is certainly very rare as an antecedent disease in nasopharyngeal carcinoma as seen in Hong Kong. d. Virus. If a virus is involved in the causation of nasopharyngeal carcinoma it has to be one which is ubiquitous to explain the regular high incidence of the disease in Chinese living in widely scattered parts of the world. Furthermore, to explain why Indians, who live in similar environments in Singapore as Chinese and Malays, have a much lower risk of the disease than the other two racial groups, the virus has to be one to which Chinese and, to a lesser extent, Malays are more susceptible than Indians, or, alternatively, one which functions together with other cocarcinogenic or carcinogenic factors, which are peculiar to or selectively affect Chinese and Malays. So far, only an immunological relationship between Epstein-Barr virus (EBV) , a member of the herpes group, and nasopharyngeal carcinoma has been found. Old et al. (1966) found in the sera of nasopharyngeal carcinoma (NPC) patients precipitating antibodies similar to those present in Burkitt’s lymphoma (BL) sera. De Schryver et a2. (1969) found in the sera from African and Chinese postnasal (same as nasopharyngeal) carcinoma an unusual frequency of high titer of membrane reactive antibodies (Anti-MA) when EBV-carrying permanent lymphoblastoid cell lines derived from Burkitt’s lymphoma and infectious mononucleosis (IM) were used as
NASOPHARYNGEAL CARCINOMA (NPC)
target cells. Much lower frequencies were found in control sera from African healthy individuals and patients with neoplastic diseases other than NPC and nonneoplastic diseases, and from Indian donors with buccal, oro- and hypopharyngeal carcinomas. W. Henle et al. (1970) found that 100% of the sera from East African and Chinese patients with NPC had antibodies against E B viral capsid antigens (VCA) and that 84% of them had high titer ( 2 1:160) with a geometric mean titer (GMT) of 1:340, whereas only 10% of the controls from the general population, unmatched for sex and age, and 14% of the patients with head and neck tumors other than N P C showed high titer, with a G M T of 1 : l O and 1:41, respectively. They further found that when the NPC patients from Hong Kong were grouped according to the stage of the disease, presumed to correlate with the tumor burden, the incidence of high titers increased successively from 45% in stage I to ultimately 100% in stage V. The GMT also rose correspondingly from 1:103 in stage I to 1:788 in the stage V. G. Henle and Henle (1972) detected antibodies to early EBV-induced antigens (EA) in infectious mononucleosis, Burkitt’s lymphoma, and nasopharyngeal carcinoma. Whereas in infectious mononucleosis the antibodies to EA disappear usually within 6 months, in Burkitt’s lymphoma and nasopharyngeal carcinoma they usually persist and are frequently found at high titers. EpsteinBarr virus is ubiquitous on a worldwide basis, but no tumor has been induced to date by EBV-carrying materials in laboratory primates. There are, however, some observed effects of EBV infection in vitro which are consistent with-but by no means proof of-an oncogenic potential for the virus. There is a possible analogy with the herpes virus producing malignant proliferation of lymphoid cells in Marek’s disease of fowls, but the virus has not yet been recovered from disrupted cells, although it can spread from lymphoma cells to kidney cells when they are ruptured. I n nasopharyngeal carcinoma, herpes-type viral particles, similar to the EBV particles observed in cultures from B L and IM, have been observed in some of the degenerating lymphoblastoid cells derived from cultures of biopsy specimens from Hong Kong (de-The et al., 1969, 1970). A new human virus, unassignable to any known morphological group, has been observed in cultures of a nasopharyngeal carcinoma from Kenya (Epstein, 1972). This virus was found only in suspension cultures of lymphoblastoid cells released from the original monolayer after 105 days in vitro. Since nasopharyngeal carcinoma is of epithelial, not of lymphoreticular origin, EBV or a similar virus may play no role in the etiology of the disease. If this is so, an explanation has to be found for its close immunological association with EBV, which
J . H. C. HO
is not found in carcinomas arising elsewhere in the head and neck including other parts of the Waldeyer’s ring and tumors other than carcinoma arising in the nasopharynx. If, on the other hand, nasopharyngeal carcinoma provides only a favorable medium for the multiplication of this virus, we should find among the NPC patients a proportion of HTV-negative persons, reflecting the HTV-negative portion of the general population. Furthermore, if the virus were merely a passenger, then why other tumors, such as leukemias, lymphomas, Hodgkin’s disease, reticulum cell sarcoma, and multiple myelomas should not offer similarly favorable habitats. Unfortunately, the increase in anti-EBV titers with the advancement of the disease does not differentiate between a passenger role and a causal relationship. T o determine whether EBV or a similar herpes-type virus plays a role in the genesis of NPC, it is essential to study first the natural history of the virus in man, its prevalence in populations of high and low risks for NPC in different as well as the same parts of the world, its mode of spread, etc. Such a study has already commenced in Southeast Asia, Japan, and France. Then a prospective seroepidemiological study may be called for in an attempt to establish the type of association, causal or noncausal, direct or indirect, which exists between the suspected virus and NPC. As separate exercises, it is of great importance to obtain long-term cultures of the epithelioid cells derived from NPC for investigating the possible presence of herpes-type viral particles or their indicators in such cells, and also look for them in peripheral lymphocytes. 3. Pattern of Age Distribution
Figure 5 gives the age distributions of nasopharyngeal carcinoma in Chinese men in Hong Kong and Singapore and the male population of Sweden for comparison. There is much similarity in the Hong Kong and Singapore patterns, both of which show a rapid, almost uninterrupted and fairly regular increase in incidence after 20-24 years of age, two decades earlier than in Sweden and also earlier than most other epithelial cancers. The incidence then declines after 50-54 in both places, again two decades earlier than that in Sweden. This would suggest that the disease in Hong Kong and Singapore Chinese was not due to continued exposure to an external carcinogen throughout life, as is postulated for most of the common epithelial cancers, or, alternatively, that the susceptibility to the carcinogen is influenced by an internal factor, possibly hormonal in nature, which is responsible for the rapid increase in incidence soon after adolescence and the decrease after 50-54 years of age. Doll (1970) in a personal communication to the author commented that the Hong Kong nasopharyngeal carcinoma pattern is very similar to that
NASOPHARYNGEAL CARCINOMA (NPC)
FIG.5. Male age-specific incidence rates of nasopharynge41 carcinoma for Sweden and for Chinese in Hong Kong and Singapore. Only transitional cell, squamous, and undifferentiated carcinomas are included for Sweden. K e y : -per 100,OOO (Hong Kong), 2019 cases (1965-9) ; --- per 2 million (Sweden), 202 cases (195% 65); . . . . per 100,ooO (Singapore), 839 cases (1950-81). From H o (19721, by permission from the editor.
of cancer of the uterine body and suggested that the possibility of hormonal factors contributing to both should be borne in mind. Figure 6 shows the age incidence curves for nasopharyngeal carcinoma in the two sexes in Hong Kong, where 98.7% of the population are of Chinese descent (Barnett, 1966), and Fig. 7 shows the curves in Sweden. In both places the curves for the two sexes differ only in height but not greatly in shape; the Swedish curves, however, differ significantly both in height and shape from the corresponding ones for Hong Kong. I n Sweden the curves reveal a pattern similar to that for bronchial carcinoma in cigarette smokers and most of the common epithelial cancers.
FIQ.6. Age-specific incidence rates of nasopharyngeal carcinoma by sex in Hong Kong, 1960-1964 and 1% ! 51-969. Patients from elsewhere are excluded from the calculation. K e y : 19604 , male, 1492 cases; 1965-9 ---, male, 2019 cases; I-.... , female, 672 cases; 1966-9 -. .-, female, 887 cases.
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F I ~ 7. . Age-specific incidence rates of nasopharyngeal carcinoma (transitional cell, squamous, and undifferentiated) in Sweden by sex, 1959-1965. K e y : - male, 202 caaes; female, 129 caaes. -.a-
The predominant cancer arising in the nasopharynx of people of different races is a carcinoma of the squamous type showing, in the majority of cases, poor differentiation or absence of differentiation. It is this tumor which shows a predilection for people of Chinese descent, especially those from the southern provinces, and an immunological relationship with EBV ar a similar virus. Chinese migrants in different parts of the world appear to have as much risk of the disease as Chinese inside China including Hong Kong, but whether the risk for people of Chinese descent born and raised in their countries of adoption is altered is not clear. Results of previous studies are far from conclusive. People of part-Chinese ancestry tend to share partly the high risk of their Chinese ancestors. Close blood-linked relatives of nasopharyngeal carcinoma patients have been found to have a higher risk of the disease than those of patients with other cancers, and the aggregation of nasopharyngeal carcinoma appears to be a t least as frequent in the vertical direction as in the horizontal. These are all highly suggestive, but not necessarily, the result of gene action. They may be the result of certain social customs, dietary habits, family recipes for treating minor ailments, etc., passed down to subsequent generations and shared by members of the same generation. We should, therefore, look for environmental factors likely to affect all ethnic groups of high risk. That such factors are also common in people of low risk does not necessarily exclude the possibility of a causative role played by these factors, because they may act together with other factors, especially genetic, which are present only in people of high risk, but their rarity or absence would suggest that they
NASOPHARYNGEAL CARCINOMA (NPC)
may be of etiological importance. Of the environmental factors, fish and probably eggs preserved in salt, which may be a source of carcinogenic or cocarcinogenic nitrosamines acting specifically on the nasopharynx of people with a genetically determined susceptibility, are traditionally common and favorite items in the diet of Chinese, especially those from Kwangtung, whether in China, Hong Kong, Southeast Asia, Australia, or the United States. The Chinese salted fish is always steamed or fried. In Japan, a low incidence area, a different kind of salted fish is often eaten, but it is always baked over a hot iron grill instead. The Chinese salted fish and eggs and the herpes-type virus which has an immunological relationship with nasopharyngeal carcinoma well deserve a thorough investigation. Chinese incense or joss sticks by virtue of the fact that they are commonly used by people of high risk should also be investigated as a possible etiological factor, although evidence so far obtained is all negative. There are still many unknown factors and missing links. All we can say a t present is that the etiology of nasopharyngeal carcinoma is most likely to be multifactorial, and that if a genetic factor were involved it is certain to be polygenic, not sex-linked or related to the ABO blood-group, at least in Chinese. There is an old saying: “A pinch of salt is worth a pound of precept.” What is needed now are more data, not speculation. ACKNOWLEDGMENTS The author is grateful to Dr. the Hon. Gerald Choa, Director of the Medical and Health Services of Hong Kong, for his permission to publish this paper; to Dr. J. K. Craig for helpful information; to Dr. C. C. Lin for histological diagnosis; to the medical staff of the Medical and Health Department Institute of Radiology for their care in obtaining family histories of the cases; to Mr. C. M. Lam for statistical assistance; to Mr. R. Abessor for preparing Figs. 3-7; to Mrs. P. Liu for careful secretarial assistance; to Messrs. K. Fung and H. K . Tam for collection of data, and Messrs. K. W. Leung and A. Lam for photographic assistance. The author is also indebted to the Swedish Cancer Registry and Professor Nils Ringertz, Scientific Surveyor of the Registry, for generous cooperation in supplying Swedish data; to Professor J. Mitchell, F. R. S., and Mr. J. A. Fairfax Fossard of Cambridge University for supplying photographs and radiographs of skull No. 238 kept at Duckworth Laboratory, Cambridge, and to Mr. J. C. Trevor, Director of the Laboratory, for the facilities afforded; to Professor R. Doll of Oxford University for helpful advice; to Professor K. Shanmugaratnam for supplying Singapore data; and finally to Dr. L. Atkinson for helpful information regarding conditions in Australian New Guinea.
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