APRlL 33 34
35. 36 37.
38 39. 40
ULLMANX. U (1973) Mycobacrerrum ulceram in B European Paper presented to Conference on .Mycohacteriem ulceram Middlesex Hospital, London, July 5 -6th. TOLHURIT, J C., BCCKIF,G. and W E L L l N t i r i l N , N. A. M. (1959) The experimental infection of calves with M . ulceruns. J. Hyg. (Lund.1 67, 47. UGWIIABLRULI GROCP (1969): BCG vaccination against Mycohocrrrium uleerans infection (Buruli ulcer), Lancet 1. 111. Fchhfn, F. and L t a m . R. H. (19521: Studies on Mvvcohacrerlum ulceranb. 1. Serological relationship usith other mycobacteria. Aurr. J. exp. Biol. med. Sci. 30, 1. FISHER,S. (1951)’ Antigenic relationships of erythrocyte absorbable reactions of some mycobacteria. Ausl. J . rxp. R i d med S i i 29, I FESNER. F (1952) Studies on Mvcohocrerrum ulceram 11. Cross reactivity in guinea pigs sensitized with Mi.cohotrrrium ulreronr, Ausr J F X ~ Bid . med. Sci. 30, 11. LLACH.R H. and FENSER.F. (1954). Studies on M ulcvrani and :+I. bolner. 111. Growth in the semi-synthetic culture media of Dubos and drug sensitivity in wfro and in vivo. Ausr. J . e.xp. B i d med. Sci. 32, 835 LINNIIS.F and N O R D ~ A ~ .N(1952): , A new rype of pathogenic mycobacterium. N o d Med 47, 681 GRAXGI.J. M. (1973). A possible key test for hfycubacierium ulcerans based o n an amino-acid utilisation test Paper presented to Conference on Mycohucrerium ulcerans. Middlesex Hospital. London. July 5-6th FEXNER, F. (1956): The pathogenic behaviour of Mqcohaclerrum ulccrans, and Mycoboelrrium halnei in the mouse and the developing chick embryo. Amer. Rev. Tuberc. 73, 650 BOI.I.IGER.A,. FORBES. 8. R V and KIRKIAND. W B. (1950): Transnimion oia recently isolated mycobacterium t o phalangers (Trrchosurw vulprculu), Ausr. J . Sci. 12, (4). 146
49. 50. 51
P E X N I N ~A~ TH.O11957) ~ . in Feldman and Karlson 11957) iU>mbactrriurn ulcerans infections Response to chcmotherapy In mice. Amrr. Reu. Tubrrc 75. 266. FFLOMAX, W. H and KARLSO%. A G (1957). Myrobocrer!wn ulcerans infections. Response lo chemotherapy in mice. A m u R r t . Tuherc 75. 266 Li 3s. H F and RFES, R J . W (19b41 ‘Treatment of Mycohacterial skin ulcers in Cganda with a riminophenazine derivative (8663). Lrincri 1.247 REVILL, W. D. L (1967): Treatment of Mjeohocrerum ulcerom infection. Paper presented to Conference on Mgcohorrermm ulcerons, Middlesex Hospital. London, July 5-6th. , R ~ ~ I LW. L .D. L., PIKE.M. C , MORKOW,R H. and A T ~ ~ J.G (19731 A controlled trial of trealment of ,Mycohacrerium ulcerons infection with Clofazimine, Lancer 2, 873. M ~ L ~ N EF. Y .and JOHNSON. B. A. (1950): Supplemcntdr). repolt of a ca.% of chronic ulceration of the foot due to a new pathogenic mycohelxe. Med. rrop. 30, :499. bacterium (MacCalluml, Ann. SOC. FFNNER.F. (1953): Two recently discovered mycobacter~awhich cause skin ulceration in man (M.ulcerans and M . habieii. VI. Internal. Cnngr. Microbiol., Rome. IV, 395 FIN~FR F.. (1957). Homologous and heterologous immunity in Infections of mice with Mycubacfrrium ulcerons and Wycohocterrum balm!, Amer. 1.Tuherc. 76, 79. RADFlinl>. A. J. (1973): The nomenclature of mycobacteriuni ulcerans infections, Trans. roy Soc. rrop Wed. Hyg. 67, ( 6 ) . 885. Ann Rep of the Health and Medical Services of the State of Queensland, 1973-74, p 79.
Aust N Z J Med (1975) 5, pp 169-170 __ _ _ I _ -
Comment CARCINOEMBRYONIC ANTIGEN (CEA): T E N YEARS‘ PERSPECTIVE
The case report by Professor Naim and his colleagues (December issue, page 531) reminds us again of the expectation that the immunology laboratory may yield diagnostic and therapeutic tools for the management of persons with cancer. The first such diagnostic test to become widely available has been the radioimmunoassay for carcinoembryonic antigen (GEA) in peripheral blood. CEA is a glycoprotein which was found in association with carcinoma of the colon as well as normal fetal gastrointestinal tissue ten years ago by Gold and Freedman’. While elevated levels of CEA in blood were first reported to be found exclusively in the blood of persons with carcinoma of the colon’, wider clinical testing showed that CEA was detectable in association with a variety of other cancers including stomach, pancreas, liver, breast and lungss. Several radioimmunoassays are now in use throughout the world for the detection of CEA in blood. The most widely available is that developed by Hansen6 which employs perchloric acid extraction of plasma to eliminate glycoproteins which crossreact with CEA, and zirconyl phosphate gel to precipitate the CEA-anti CEA complexes. The cut-off point for a “positive” test with this method, as well as with the Farr technique developed in Gold’s laborat o y 2 , is 2.5 ng/ml. The direct double antibody microradioimmunoassay developed at the Walter and Eliza Hall Institute is performed on whole serum without perchloric
acid extraction and gives a “positive” result at 5 ng/m13. The Todd assay which has been used extensively in clinical studies at the Chester Beatty Institute also is a direct assay, that is, perchloric acid extraction is not employed, and a “positive” result with this assay is 12.5 ng/ml or higher4. It is clear that the clinician should know the method which his laboratory employs as well as the arbitrary level chosen to designate an abnormal value. When CEA levels in serum or plasma are compared with the extent of spread of cancer, it is found that CEA elevation is infrequently detected when the cancer is at an early curable stage. A collaborative North American study’ which employed the Hansen technique for detection of CEA in persons with well documented carcinoma of colon showed “positive” tests in 18% of persons staged as Dukes A (localized to bowel wall) and 79% staged as Dukes C2 (widely metastatic). Similar results have been described by others ’. Persons with no clinically detectable cancer, but with inflammatory disease of the same organs in which CEAassociated cancers are found, may have elevated blood CEA levels. These diseases include ulcerative colitis’, pancreatitisg, hepatic cirrhosisg, chronic bronchitis and emphysema4, as well as chronic heavy smoking’“. It is apparent that interpretation by the physician of a positive test for CEA is made difficult for several reasons. Many of the non-cancerous diseases which are associated with an elevated level of CEA in blood are conditions which carry an associated increased risk to cancer, e.g. heavy
smoking. Moreover, many of these same conditions. e.g. ulcerative colitis, are difficult to distinguish from cancer at an early treatable stage. In addition. the CEA values found in these non-cancerous conditions are generally at the lower “positive” range. levels which. when found with cancer, often are associated with a localized surgically curable tumor, However, while it is true that a higher level of CEA makes the diagnosis of cancer more likely, the higher level also suggests the presence of metastases. While this is helpful prognostically. it is generally irrelevant to curative therapy. What then are the current clinical applications for testing for CEA in peripheral blood? I . Corroboration of clinical suspicion of cancer. There are selected situations when the clinician suspects cancer, has not found it by conventional techniques, and must decide whether further studies are justified. Provided that the physician takes into consideration the numerous nonmalignant conditions with which CEA is associated. a positive test for CEA in this setting suggests that further evaluation of the patient is probably justified. Examples include: the patient with quiescent ulcerative colitis in whom the test remains persistently positive: the former heavy smoker who continues to give a positive test for CEA (in the absence of chronic lung disease); the elderly patient with iron-deficiency anaemia, the result of whose barium enema is equivocal and who might otherwise not be subjected to the discomfort and risk of further investigations. It must be re-emphasized, of course, that a negative test,for CEA does not exclude the possibility of the presence of cancer. 2. Screening for cancer in selected populations. Mass screening for cancer with the blood test for CEA is probably not justified at this time. Collaborative studies’’ by the Walter and Eliza Hall Institute in Melbourne and the Busselton Population Studies Group in Busselton, Western Australia, of a well defined population showed a prevalence of 4.5% for a positive test for CEA in elderly persons. In the subsequent four years, 11% of those with a positive test died of cancer-most of whom had metastatic diseae at the time of testing. In addition, another 5% were found to have occult cancer four and one-half years after testing when examined radiographically. Nevertheless, this “false positive” rate of some 84%- attributable to heavy smoking, benign gastrointestinal disorders and perhaps advancing age itself-dictates that simple screening for cancer by means of CEA alone is not justified at this time. On the other hand, there remain populations at increased risk to cancer-for example, uranium workers who are prone to the development of carcinoma of the lung‘*-in whom CEA testing probably is justified. Further studies may identify other such populations at high risk in whom screening may be fruitful. 3 . Post-resection follow-up. Return, within 2 weeks of tumor surgery, of an elevated CEA level to the “normal” range suggests the possibility of a successful resection. However, a cure is not established unless the level remains in this range.13 Unfortunately, if CEA in blood returns to an elevated level post-operatively, the tumor usually is widespread and surgical intervention, at least in gastrointestinal tumors, rarely will be curative. Generally, therefore, return of CEA elevation after surgery is valuable as a prognostic sign rather than a guide to definitive therapy. In our limited experience with carcinoma of the colon, reappearance of CEA has occurred about six to eight months before clinical symptoms of recurrence (Stevens, D. P. and Mackay, I. R.,unpublished).
4. Chemotherapy and radiation. Most data suggest that while the blood level of CEA roughly reflects tumor mass remaining following radiation or ~hemotherapy’~. CEA in blood does not appear to make a very useful contribution to therapy in these instances. 5. CEA in body fluids. Interesting possibilities for increased diagnostic sensitivity have been raised by demonstration of CEA in gastric juice (Stevens, D. P. and Mackay, I. R.,unpublished), urine”, and stool1b. Testing of these fluids entails special laboratory methods but the increased sensitivity of testing fluids which directly bathe the tumor offers the likelihood of earlier diagnosis of CEA-related tumors. Further studies are required before wide clinical application of these methods will be justified. In summary. the initial enthusiasm for CEA as a “blood test for cancer” has given way to scepticism engendered by the many non-cancerous conditions with which CEA has been associated. Nevertheless, it appears that wider experience with assays For CEA is leading to a perspective somewhere between these two extremes, and to the acceptance of this test as a clinically applicable adjunct in the diagnosis and management of persons with cancer.
David P. Stevens. Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland. Ohio. U.S.A. References I
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