959 cense, wood or coal
THE LANCET Some
Progress with Nasopharyngeal Carcinoma NASOPHARYNGEAL carcinoma
continues to attract considerable attention, and the massive proceedings of a recent international symposiuml are of wide interest. The histopathological classification of N.P.C. is still disputed. The forthcoming W.H.O. recommendations propose 3 categories-keratinising squamous carcinoma, non-keratinising carcinoma and undifferentiated carcinoma-but there is much to be said for the view that these are to a large extent histological variants of an essentially homogeneous group of tumours. A generally accepted nomenclature is, however, essential to settle issues such as the relationship between histopathology and different risk populations, different age-groups, HLA profiles, and Epstein-Barr virus (both genome and serology). On a more experimental level, N.P.C. has been successfully transplanted into athymic nude mice, with metastases to regional lymph-nodes. Tumours resembling N.P.C., apparently spontaneous, have been described in various strains of dog, and these may prove to be useful animal models. The clinical-stage classification of N.P.C. remains confused and a new scheme has been proposed which is expected to run for a trial period of 5 years. Meanwhile, more detailed clinical studies have defined an interesting subgroup of N.P.C. patients living in an intermediate-risk area, Tunisia. In the high-risk regions of South-East Asia, children are not commonly affected and an additional feature of the Tunisian cases was the occurrence of a paraneoplastic syndrome in about 14% of cases, consisting of hypertrophic pulmonary osteoarthropathy, clubbing, and gynxcomastia in association with mediastinal or pulmonary metastases. It is important to establish whether other intermediate-risk areas such as Uganda, Kenya, and Sudan show a similar double-peak incidence. Exogenous carcinogens which may be implicated remain elusive. There is no convincing evidence that inhaled industrial substances known to affect the upper respiratory and digestive tracts, such as nickel, isopropyl oils, and wood dust, are associated with N.P.C., nor is the tumour strongly linked with
(N.P.c.)
any particular occupation. Carcinogens which may be inhaled in domestic, rather than industrial, contexts have been sought out in high-risk and intermediate-risk areas-from materials such as in1. de
Thé, G , Ito, trol
Y.
(editors) Nasopharyngeal Carcinoma: etiology and conno. 20. International Agency for
IARC Scientific Publications Research on Cancer, Lyon, 1978.
cooking fires and anti-mosquito coils-but the evidence is conflicting. The possible role of ingested carcinogens, in the form of salted fish, provides an attractive alternative. Cantonese salted fish is a traditional food of the southern Chinese and it is one of the first solid foods given to children. It contains dimethylnitrosamine (D.M.N.A.) which has induced malignant tumours of the upper respiratory tract in rats. A small number of rats maintained on a diet containing salted fish have now developed locally infiltrating carcinomas of the nasal and paranasal regions after 1 to 2 years, but interpretation is difficult. Levels of D.M.N.A. in salted fish, estimated by combined gas chromatography and high-resolution mass spectrometry, were variable and were not strikingly higher than those in some cured meat eaten in Europe. Levels of non-volatile nitrosamines in the fish are not known. Other carcinogens may be formed during cooking, or in vivo in the stomach. And whatever the nature of the carcinogen, it presumably has to show some subsequent organotropism for the nasopharynx. of a human tumour associated with distinctive HLA patterns. Mainly for the high-risk southern Chinese, an association between N.P.c. and an increased incidence of HLA-A2 and B-sin 2 is confirmed with respect to initial susceptibility and to survival after diagnosis. Increased risk also seems to be associated with BW17, and decreased risk with All. Preliminary results have now been recorded on the distribution of certain genetically controlled erythrocyte enzymes and serum protein systems in Chinese cases of N.P.C.-for instance, glucose 6-phosphate dehydrogenase, red-cell acid phosphatase, and transferrin. This is an interesting line of inquiry, but more information is needed from other ethnic groups in high, intermediate, and low risk regions in other parts of the world. The distribution of several Epstein-Barr virusdetermined antibodies in N.P.c. is well recorded, particularly among the southern Chinese populations of Hong Kong and Singapore. Seroepidemiological surveys have now been extended to Tunisia, East Africa, France, and the United States: despite variations in antibody titres, an overall association between E.B. virus and N.P.c. has been clearly established, irrespective of ethnic groups and degrees of risk. Whether E.B. virus is passenger or driver in N.P.C. is not conclusively settled, but most investigators regard the virus as one of the ætiological agents. Attention has lately been paid to the IgG, IgM, and IgA components of antibodies to E.B. viral capsid and early antigens (V.C.A., E.A.), and a high frequency and often high titre of E.B.virus-associated serum-IgA has been found in N.P.c. This distinctive and unexplained feature is N.P.c.
likely
to
remains the
be
most
particularly
convincing example
useful in
monitoring
the
960
and Malaysia.’ A paper by DAVIDSON and PARRy,8 from Zaria in the north of Nigeria, now describes a painstaking clinical study of 224 women with peripartum cardiac failure (P.P.C.F.) admitted during a 3 year period, and followed up for 2-5 years (a remarkable achievement in this setting). The peak time for presentation at hospital was four weeks after delivery: only 4 patients were admitted before delivery. The signs were those of gross congestive cardiac-failure and transient hypertension. Where these women differed from those described from other countries, however, was in the degree of fluid retention and its response to treatment. In the space of two weeks there was a mean weight loss of 12.3 kg (29% of the minimum weight) associated with disappearance of the signs of heart-failure and a fall in blood-pressure. Furthermore, only 19% had a recurrence of heart-failure after subsequent pregnancies, and only 10 patients had an episode of heart-failure unrelated to pregnancy. In 82% the heart size was normal after one year. This contrasts with the generally poor prognosis of patients with postpartum cardiac failure previously
of the disease and the effects of treatment, and perhaps in refining prognosis. Upward inflection of E.B.-virus IgA antibody titres may occur months before recurrent or metastatic disease shows itself clinically. E.B.-virus IgA serum antibodies may also be useful in familial studies of
course
inviting speculation about possible links between hypothetical disease susceptibility gene(s) and genes that influence the IgA antibody response. Secretory IgA specific for E.B. virus has been found in throat washings from cases of N.P.C., but it is unclear whether E.B.v. secretory IgA is synthesised before or after tumour development. Work on the E.B. viral genome in N.P.C. is still hampered by the absence of permanent N.P.C. cell lines: N.P.C. cells usually stop growing in vitro after a few weeks. The viral genome has been detected most consistently in cells from anaplastic N.P.C., and its distribution in other histological types of N.P.C. is at present uncertain. One outstanding question relates to the mode of entry of E.B. virus into the tumour cells. Do N.P.c. cells carry E.B.virus receptors, hitherto found only on B lymphocytes, on their cell surfaces? Is there direct contact between E.B. virus genome-containing lymphocytes and adjacent tumour cells, either by cell bridges or by heterokaryon formation, perhaps under the influence of local indigenous myxoviruses? N.P.C.,
reported. Why should the condition be so common in the Zazzau Emirate and surrounding areas settled by
Postpartum Fluid Retention PREGNANCY and labour are good tests of cardiac performance, so it is a great surprise when a woman who has given birth to her child without any problems suddenly goes into heart-failure. In European countries such an event is so rare that the puerperal onset may seem no more than fortuitous, and the concept of a specific form of postpartum cardiac disease has been received with scepticism.1,2 In New Orleans, however, HULL and his colleagues’reported 80 cases of this condition which they named "postpartal heart-failure": response to treatment was slow and mortality was high-more than a quarter died within six months. MEADOWS,s who extended these observations, has been largely responsible for the assertion that there is a form of cardiomyopathy which is peculiar to the postpartum period. Three-quarters of HULL’S patients, and most of those reported subsequently, were Black Americans. Small numbers of cases have now been identified in most countries, but the’ condition seems to be relatively common in Korea6; ,
1. Brown, A. K.,
the Hausa Bakwai? Its incidence is related geographically to the traditional Hausa postpartum practices: for at least forty days after delivery the mother spends 18 hours or more each day lying on a mud bed heated by a fire. The ambient temperature frequently rises to 40 °C (relative humidity more than 60%), and the skin temperature may reach 42 °C. At the same time the women increase their sodium intake to about 450 mmol/day by adding Lake Chad salt to their diet. Postpartum heating is customary in Korea, Malaysia, and other parts of the world, but not amongst the Black Americans described by HULL. The underlying mechanism of P.P.C.F. has been debated in the correspondence columns of this journal.9-11 The universally rapid improvement with treatment and the lack of further episodes of heartfailure in the majority argue against cardiomyopathy, including the "myocardial slippage" postulated by DAVIDSON and PARRY. BROCKINGTON 12 suggested that hypertension was the cause; but the observed rise in blood-pressure is insufficient and, anyway, the features of right-ventricular failure precede those of pulmonary oedema. Many of these observations support SANDERSON’S hypothesis9 that fluid retention is of primary importance. The Hausa hot bed could interfere with the normal control mechanism for excreting excess sodium and
Doukas, N., Riding, W D., Jones, E. W. Br. Heart J. 1967,
29, 387. 2. Benchimol, A. B., Carneiro, R. D., Schlesinger, P. ibid. 1959, 21, 89. 3. Hull, E., Hafkesbring, E. New Orleans med surg. J. 1936-7, 89, 550. 4. Hull, E., Hidden, E.Sth.med J. 1938, 31, 265. 5. Meadows, W. R., Circulation, 1957, 15, 903. 6. Choi, T. R., Lee, K. J., Lee, Y. C. Korean J. intern. Med. 1972, 15, 41.
7. Chen, P. C. Y. Med. J. Malaysia, 1976, 31, 8. Davidson, N. McD., Parry, E. H., O. Q., Jl. 9. Sanderson, J. E., Lancet, 1977, ii, 1159. 10 Sanderson, J. E. ibid. p. 145. 11. Davidson, N. McD. ibid.
93. Med. 1978, 47, 431.
12. Brockington,I. F. Am. J. Cardiol. 1971, 27, 650.
THE LANCET Some
Progress with Nasopharyngeal Carcinoma NASOPHARYNGEAL carcinoma
continues to attract considerable attention, and the massive proceedings of a recent international symposiuml are of wide interest. The histopathological classification of N.P.C. is still disputed. The forthcoming W.H.O. recommendations propose 3 categories-keratinising squamous carcinoma, non-keratinising carcinoma and undifferentiated carcinoma-but there is much to be said for the view that these are to a large extent histological variants of an essentially homogeneous group of tumours. A generally accepted nomenclature is, however, essential to settle issues such as the relationship between histopathology and different risk populations, different age-groups, HLA profiles, and Epstein-Barr virus (both genome and serology). On a more experimental level, N.P.C. has been successfully transplanted into athymic nude mice, with metastases to regional lymph-nodes. Tumours resembling N.P.C., apparently spontaneous, have been described in various strains of dog, and these may prove to be useful animal models. The clinical-stage classification of N.P.C. remains confused and a new scheme has been proposed which is expected to run for a trial period of 5 years. Meanwhile, more detailed clinical studies have defined an interesting subgroup of N.P.C. patients living in an intermediate-risk area, Tunisia. In the high-risk regions of South-East Asia, children are not commonly affected and an additional feature of the Tunisian cases was the occurrence of a paraneoplastic syndrome in about 14% of cases, consisting of hypertrophic pulmonary osteoarthropathy, clubbing, and gynxcomastia in association with mediastinal or pulmonary metastases. It is important to establish whether other intermediate-risk areas such as Uganda, Kenya, and Sudan show a similar double-peak incidence. Exogenous carcinogens which may be implicated remain elusive. There is no convincing evidence that inhaled industrial substances known to affect the upper respiratory and digestive tracts, such as nickel, isopropyl oils, and wood dust, are associated with N.P.C., nor is the tumour strongly linked with
(N.P.c.)
any particular occupation. Carcinogens which may be inhaled in domestic, rather than industrial, contexts have been sought out in high-risk and intermediate-risk areas-from materials such as in1. de
Thé, G , Ito, trol
Y.
(editors) Nasopharyngeal Carcinoma: etiology and conno. 20. International Agency for
IARC Scientific Publications Research on Cancer, Lyon, 1978.
cooking fires and anti-mosquito coils-but the evidence is conflicting. The possible role of ingested carcinogens, in the form of salted fish, provides an attractive alternative. Cantonese salted fish is a traditional food of the southern Chinese and it is one of the first solid foods given to children. It contains dimethylnitrosamine (D.M.N.A.) which has induced malignant tumours of the upper respiratory tract in rats. A small number of rats maintained on a diet containing salted fish have now developed locally infiltrating carcinomas of the nasal and paranasal regions after 1 to 2 years, but interpretation is difficult. Levels of D.M.N.A. in salted fish, estimated by combined gas chromatography and high-resolution mass spectrometry, were variable and were not strikingly higher than those in some cured meat eaten in Europe. Levels of non-volatile nitrosamines in the fish are not known. Other carcinogens may be formed during cooking, or in vivo in the stomach. And whatever the nature of the carcinogen, it presumably has to show some subsequent organotropism for the nasopharynx. of a human tumour associated with distinctive HLA patterns. Mainly for the high-risk southern Chinese, an association between N.P.c. and an increased incidence of HLA-A2 and B-sin 2 is confirmed with respect to initial susceptibility and to survival after diagnosis. Increased risk also seems to be associated with BW17, and decreased risk with All. Preliminary results have now been recorded on the distribution of certain genetically controlled erythrocyte enzymes and serum protein systems in Chinese cases of N.P.C.-for instance, glucose 6-phosphate dehydrogenase, red-cell acid phosphatase, and transferrin. This is an interesting line of inquiry, but more information is needed from other ethnic groups in high, intermediate, and low risk regions in other parts of the world. The distribution of several Epstein-Barr virusdetermined antibodies in N.P.c. is well recorded, particularly among the southern Chinese populations of Hong Kong and Singapore. Seroepidemiological surveys have now been extended to Tunisia, East Africa, France, and the United States: despite variations in antibody titres, an overall association between E.B. virus and N.P.c. has been clearly established, irrespective of ethnic groups and degrees of risk. Whether E.B. virus is passenger or driver in N.P.C. is not conclusively settled, but most investigators regard the virus as one of the ætiological agents. Attention has lately been paid to the IgG, IgM, and IgA components of antibodies to E.B. viral capsid and early antigens (V.C.A., E.A.), and a high frequency and often high titre of E.B.virus-associated serum-IgA has been found in N.P.c. This distinctive and unexplained feature is N.P.c.
likely
to
remains the
be
most
particularly
convincing example
useful in
monitoring
the
960
and Malaysia.’ A paper by DAVIDSON and PARRy,8 from Zaria in the north of Nigeria, now describes a painstaking clinical study of 224 women with peripartum cardiac failure (P.P.C.F.) admitted during a 3 year period, and followed up for 2-5 years (a remarkable achievement in this setting). The peak time for presentation at hospital was four weeks after delivery: only 4 patients were admitted before delivery. The signs were those of gross congestive cardiac-failure and transient hypertension. Where these women differed from those described from other countries, however, was in the degree of fluid retention and its response to treatment. In the space of two weeks there was a mean weight loss of 12.3 kg (29% of the minimum weight) associated with disappearance of the signs of heart-failure and a fall in blood-pressure. Furthermore, only 19% had a recurrence of heart-failure after subsequent pregnancies, and only 10 patients had an episode of heart-failure unrelated to pregnancy. In 82% the heart size was normal after one year. This contrasts with the generally poor prognosis of patients with postpartum cardiac failure previously
of the disease and the effects of treatment, and perhaps in refining prognosis. Upward inflection of E.B.-virus IgA antibody titres may occur months before recurrent or metastatic disease shows itself clinically. E.B.-virus IgA serum antibodies may also be useful in familial studies of
course
inviting speculation about possible links between hypothetical disease susceptibility gene(s) and genes that influence the IgA antibody response. Secretory IgA specific for E.B. virus has been found in throat washings from cases of N.P.C., but it is unclear whether E.B.v. secretory IgA is synthesised before or after tumour development. Work on the E.B. viral genome in N.P.C. is still hampered by the absence of permanent N.P.C. cell lines: N.P.C. cells usually stop growing in vitro after a few weeks. The viral genome has been detected most consistently in cells from anaplastic N.P.C., and its distribution in other histological types of N.P.C. is at present uncertain. One outstanding question relates to the mode of entry of E.B. virus into the tumour cells. Do N.P.c. cells carry E.B.virus receptors, hitherto found only on B lymphocytes, on their cell surfaces? Is there direct contact between E.B. virus genome-containing lymphocytes and adjacent tumour cells, either by cell bridges or by heterokaryon formation, perhaps under the influence of local indigenous myxoviruses? N.P.C.,
reported. Why should the condition be so common in the Zazzau Emirate and surrounding areas settled by
Postpartum Fluid Retention PREGNANCY and labour are good tests of cardiac performance, so it is a great surprise when a woman who has given birth to her child without any problems suddenly goes into heart-failure. In European countries such an event is so rare that the puerperal onset may seem no more than fortuitous, and the concept of a specific form of postpartum cardiac disease has been received with scepticism.1,2 In New Orleans, however, HULL and his colleagues’reported 80 cases of this condition which they named "postpartal heart-failure": response to treatment was slow and mortality was high-more than a quarter died within six months. MEADOWS,s who extended these observations, has been largely responsible for the assertion that there is a form of cardiomyopathy which is peculiar to the postpartum period. Three-quarters of HULL’S patients, and most of those reported subsequently, were Black Americans. Small numbers of cases have now been identified in most countries, but the’ condition seems to be relatively common in Korea6; ,
1. Brown, A. K.,
the Hausa Bakwai? Its incidence is related geographically to the traditional Hausa postpartum practices: for at least forty days after delivery the mother spends 18 hours or more each day lying on a mud bed heated by a fire. The ambient temperature frequently rises to 40 °C (relative humidity more than 60%), and the skin temperature may reach 42 °C. At the same time the women increase their sodium intake to about 450 mmol/day by adding Lake Chad salt to their diet. Postpartum heating is customary in Korea, Malaysia, and other parts of the world, but not amongst the Black Americans described by HULL. The underlying mechanism of P.P.C.F. has been debated in the correspondence columns of this journal.9-11 The universally rapid improvement with treatment and the lack of further episodes of heartfailure in the majority argue against cardiomyopathy, including the "myocardial slippage" postulated by DAVIDSON and PARRY. BROCKINGTON 12 suggested that hypertension was the cause; but the observed rise in blood-pressure is insufficient and, anyway, the features of right-ventricular failure precede those of pulmonary oedema. Many of these observations support SANDERSON’S hypothesis9 that fluid retention is of primary importance. The Hausa hot bed could interfere with the normal control mechanism for excreting excess sodium and
Doukas, N., Riding, W D., Jones, E. W. Br. Heart J. 1967,
29, 387. 2. Benchimol, A. B., Carneiro, R. D., Schlesinger, P. ibid. 1959, 21, 89. 3. Hull, E., Hafkesbring, E. New Orleans med surg. J. 1936-7, 89, 550. 4. Hull, E., Hidden, E.Sth.med J. 1938, 31, 265. 5. Meadows, W. R., Circulation, 1957, 15, 903. 6. Choi, T. R., Lee, K. J., Lee, Y. C. Korean J. intern. Med. 1972, 15, 41.
7. Chen, P. C. Y. Med. J. Malaysia, 1976, 31, 8. Davidson, N. McD., Parry, E. H., O. Q., Jl. 9. Sanderson, J. E., Lancet, 1977, ii, 1159. 10 Sanderson, J. E. ibid. p. 145. 11. Davidson, N. McD. ibid.
93. Med. 1978, 47, 431.
12. Brockington,I. F. Am. J. Cardiol. 1971, 27, 650.
