Definitions and terminology in cancer (tumour)etiologyAn analysis aiming at proposals for a current internationallystandardized terminology *

ERICH HECKER 1

In an attempt to overcome the confusion that exists in the terminology of cancer(tumour) etiology, the author has analysed the current situation andproposed terms which,he hopes, will stimulate international discussion and lead eventually to an agreed standardterminology.

In the course of its development, every field ofscience passes at least once through a period ofconfusion, as a result of the discrepant use ofterminology. At present in cancer (tumour) etiology,such confusion is considerable because some of thekey terms describing the generation of neoplasiaare being used with divergent and even with oppositemeanings. This situation calls for clarification; aclearly defined and generally accepted system ofterminology in cancer (tumour) etiology is essentialfor a more efficient worldwide collaboration inresearch and teaching as well as in documentation,environmental hygiene, and legislation.During recent years, considerable progress has

been made in understanding the contributions ofcausative agents, of patterns of exposure, and ofthe host or target tissue to the etiology of cancers(tumours). This permits in-depth analysis of themeaning of some of the key terms used in this

*The Committee on International Collaborative Activ--ijies (CICA) of the International Union against Cancer(UICC) has decided to attempt to provide an internationallystandardized terminology in cancer (tumour) etiology, incooperation with the International Agency for Researchon Cancer (IARC) and the World Health Organization(WHO). In order to encourage international discussion,CICA requested one of its members, the author, to formulateand publish under his responsibility the present analysisand proposals.

Readers who might care to comment on these proposalsby letter are requested to direct their remarks to the Office ofthe UICC, 3 rue Conseil-General, 1205 Geneva, Switzerlandwithin six months of the appearance of this article.

1 Director, Institut fur Biochemie am Deutschen Krebs-forschungszentrum, im Neuenheimer Feld 280, D-6900Heidelberg, Federal Republic of Germany.

field, to provide a sound background as well as astarting point and a stimulus for the developmentof a proposed concise system of descriptive termi-nology.Such a system has to be purely descriptive and

should be as simple and flexible as possible. Itsdevelopment must not be delayed until mechanisticdetails of the generation of neoplasia have beenexplored. It will be shown that the system requiredcan be based upon well-defined terms that describereproducible (experimental) facts and that termsinvolving hypothetical interpretations can be ex-cluded. In most cases it is considered preferableto clarify and, if necessary, to redefine existingterms rather than to seek to replace them bynew ones.An informal trial to define a limited number of

terms used in cancer (tumour) etiology was made in1971 by a group of temporary advisors to WHO.aA glossary of the definitions of terms proposed

in this paper is given in the Annex.

BASIC CONSIDERATIONS

CarcinogenesisFor " generation of neoplasia ", the term "carcino-

genesis" may be preferred to " tumorigenesis "," oncogenesis ", or " blastomogenesis ".

" Carcinogenesis " (from Latin " carcinus ", thecrab, and " genere ", to make, to create) is generally

a Unpublished document WHO/OH/72.1 1.

3485 1 - BULL. WORLD HEALTH ORGAN., Vol. 54, 1976

E. HECKER

understood to involve all phases of the generationof neoplasia, including in particular the invasivephase. The terms " tumorigenesis ", " oncogenesis",or " blastomogenesis " do not necessarily includethe invasive phase. Also, " carcinogenesis" is themost adequate term to use in connexion with themore complex (multifactorial) patterns of exposure

of the host or target tissue to causative agents.If " carcinogenesis " is accepted as the standard

term to be used to describe the generation ofneoplasia in the broadest possible sense, it will benecessary to state by definition and to agree byconvention that it is meant to involve also thegeneration of, for example, sarcomata and leukaemia.Such a generalization of the more specific meaningattributed to the term " carcinogenesis " in patho-histology appears to be more acceptable than theintroduction of a new term (see also 12, 16).

Fundamental variables of carcinogenesis

The complexity of any process of carcino-genesis requires that the contributions of some

fundamental variables be distinguished clearly.These are: causative agents, patterns of exposure,

and host or target tissue predisposition.One of the main reasons for the present confusion

in terminology in cancer etiology is that frequentlyin carcinogenesis a clear-cut distinction betweencausative agents, patterns of exposure, and hostor target tissue predisposition is not or cannot bemade. In such cases, detailed analysis of the factualinformation available or carefully devised further(experimental) studies should help to clarify thesituation (see Carcinogenic factors and unspecifiedcarcinogenesis, p. 7).

Causative agents. Carcinogenesis is the result ofexposure(s) of the host to causative agents ofexogenous or endogenous origin and of a physical,chemical, or viral nature. By definition and conven-

tion, the term " carcinogen " may be used for suchagents if their origin, nature, and identity are

unequivocally clarified. Carcinogens can inducecarcinogenesis in one or more tissues of the hostand they exhibit " tissue specificity ".The general term " carcinogen " may be specified

with respect to the kind of carcinogenic processcaused (see Solitary carcinogenesis, p. 4, Syn-carcinogenesis, p. 4, and Carcinogenic factors andunspecified carcinogenesis, p. 7). For the sake ofconsistency, terms such as tumorigen, oncogen, andblastomogen should not be used (see also under

Carcinogenesis above and ref. 16). The term " tissuespecificity" is proposed in preference to the term" organotropy " because within a certain organof the host, carcinogenesis may be induced in amore specialized target tissue.According to present knowledge, the majority

of all known carcinogens of a physical, chemical,or viral nature are of exogenous origin (see, forexample, 16, 22). Carcinogens of endogenous originmay be of either chemical or viral nature. Examplesof some well-known carcinogens are given in Table 1.

Pattern of exposure. Carcinogenesis may be theresult of unifactorial or multifactorial exposureof the host or target tissue to carcinogens. Themultiplicity of possible patterns of exposure of thehost or target tissue according to kind(s), number(s),and sequence(s) of carcinogens may be calledcollectively " carcinogenic processes ". By definitionand convention, any carcinogenic process is initiatedby exposure of the host or target tissue to a " solitary(or to an " incomplete ") carcinogen ". A survey ofknown classes of carcinogenic processes is givenin Table 2.

It is proposed that the term " carcinogenic pro-cess" be used in a purely descriptive (i.e., toxico-logical) sense at the level of the organism, withoutimplications at the cellular and molecular levels.To investigate the latter aspects of carcinogenesis,certain carcinogenic processes in certain targettissues may be more useful experimental modelsystems than others.

Host or target tissue predisposition. Dispositionof the host or target tissue may contribute to itsneoplastic response. Such disposition may be eitherinborn (genetically determined) or acquired. Ineither case, by definition, such disposition existsprior to the start of any carcinogenic process.Therefore, it may be called " host or target tissuepredisposition ".Any exposure of the host or target tissue to

predisposing, noncarcinogenic agents prior toexposure to a solitary carcinogen is a conditioningexposure of normal cells. Exposure of the host ortarget tissue to per se non-carcinogenic agents (e.g.,cocarcinogens, see below) after exposure to asolitary carcinogen involves what may be calledneoplasiogenically altered cells and is thereforebasically different from any conditioning exposure.The opposite of host or target tissue predispositionis resistance of the host or target tissue (see below,anticarcinogenesis).

2

DEFINITIONS AND TERMINOLOGY IN CANCER (TUMOUR) ETIOLOGY

Table 1. Examples of carcinogens: solitary carcinogens and cocarcinogens

Origin of Nature of Sources Identity of carcinogenscarcinogens carcinogens of carcinogens solitary carcinogens cocarcinogens

exogenous physical sun, X-ray UV-light, X-rays, products of unknownapparatus, nuclear nuclear fissionfission

chemical chemical raw asbestos, talcum, chromate, iron oxide, phenols, alipha-materials or aromatic hydrocarbons and tic hydrocarbons, detergentsproducts amines, nitrosamines and

nitrosamides, chloromethylmethyl ether, vinyl chloride,plastic film

pharmaceuticals isoniazid, alkylating cyto- dithranol, immunosuppres-statics, diethyl stilbestrol sants

food additives and dimethylaminoazobenzene, ethanol, certain autoxidationcontaminants DDT, nitrosamines and products of unsaturated

nitrosamides fatty acids

fungal and higher aflatoxins, pyrrolizidine limonene, phorbol andplant products alkaloids, cycasin similar diterpenes and their

esters, cyclopropenoicfatty acids

viral biological informational macromolecules Shope papilloma andenvironment fibroma virus

endogenous chemical anabolic and 3-hydroxyanthranilic acid estrogens, androgens, bilecatabolic metabolism acids

viral cell particles with informational macromolecules helper virus (?)latent virus

Table 2. Survey of carcinogenic processes: solitary carcinogenesis and syncarcinogenesis

Pattern of exposure Carcinogenic processesof host or target tissue

Solitary carcinogenesis

Exposure of host or target tissue to one carcinogen

UNIFACTORIAL Causative agent: solitary carcinogen, specific event(s) of solitary carcinogenconsidered irreversible but not lethal

Host or target tissue predisposition: inborn or acquired

Syncarcinogenesis

Exposure of the host or target tissue to more than one carcinogen

Pluricarcinogenesis Cocarcinogenesis

MULTIFACTORIAL Causative agents: Subcarcinogenic dose(s) Causative agents: Subcarcinogenicof one or more solitary (or one or more dose(s) of one or more solitary (or one orincomplete) carcinogen(s) simultaneously more incomplete) carcinogen(s) simul-with or followed by at least one other taneously with or followed by co-solitary carcinogen; specific event(s) of carcinogen; specific event(s) of solitaryboth solitary carcinogens considered (or incomplete) carcinogen consideredirreversible irreversible, specific event(s) of cocar-

cinogen considered reversible

Host or target tissue predisposition: Host or target tissue predisposition:inborn or acquired inborn or acquired

3

4 E. HECKER

Some examples of host or target tissue predisposi-tion have been assembled in Table 3.

Table 3. Examples of inborn or acquired host or targettissue predisposition

Congenital genetic defect predisposing to the development of skincancer following exposure to sunlight (xeroderma pigmentosum)

Partial hepatectomy prior to exposure to a hepatocarcinogen

Exposure to certain per se non-carcinogenic agents, such as cocar-cinogens (see Table 1), prior to exposure to solitary carcinogens

Etiologically undefined non-carcinogenic - influences " such asirritation, wound healing, age, sex, diet, and strain prior toexposure to solitary carcinogens

TERMS FOR SPECIFIC CARCINOGENIC FACTORS AND

PROCESSES

Solitary carcinogenesis

Carcinogenesis may be the result of single orrepeated (chronic) exposure of the host or targettissue to a single carcinogen; such exposure isunifactorial. It is proposed that the carcinogeninvolved be called a " solitary carcinogen " and thecorresponding process " solitary carcinogenesis"(Tables 1 and 2).

After the etiology of certain occupational cancershad become obvious, primarily by clinical observa-tion, solitary carcinogenesis by exogenous physical(28), chemical (42), and viral factors (33) wasdemonstrated experimentally. Subsequent exper-imental investigations revealed the tissue specificityof solitary carcinogens; the wide spectrum ofsolitary carcinogens known today covers specificityfor practically any tissue (36).

In solitary carcinogenesis, the carcinogenic re-sponse of the host or target tissue as identifiedqualitatively by well established histological meansis measured quantitatively by the following criteria:(1) the latent period; a (2) the cancer (or tumour)rate; b and (3) the cancer (or tumour) yield,c or bya combination of these criteria. The specific carcino-genic effect(s) of a solitary carcinogen is considered

a The time elapsing before cancers (tumours) appear.b The number of individuals carrying at least one cancer

(tumour).c The number of cancers (tumours) per individual.

irreversible. Chronic exposure of the host to asolitary carcinogen results in a cumulation of itsspecific carcinogenic effects to cause cancer of thetissue(s) involved (summation hypothesis, see 14).Apart from its specific carcinogenic - effect(s), asolitary carcinogen may cause non-specific epi-phenomena in the host or target tissue(s) due, forexample, to toxicity.

It is preferable to use the term " solitary carcino-gen" (22, 23), referring to the carcinogenic processinvolved, rather than terms such as " carcinogen "," procarcinogen ", " complete carcinogen ", or " fullcarcinogen ". The term " carcinogen " would notbe specific enough because it also covers cocarci-nogens. The other (composite) terms listed aboveare already associated with special meanings:" procarcinogen " refers to the metabolism ofcarcinogens and is used to indicate that the solitarycarcinogen in question requires metabolic activation(to a " proximate " or an " ultimate" carcinogen).The terms " complete carcinogen " or " full carci-nogen " are used to differentiate certain carcinogens(i.e., solitary carcinogens) from " incomplete car-cinogens ".Of all the possible processes of carcinogenesis,

solitary carcinogenesis is the least complex. In theetiology of human cancer, solitary carcinogens areconsidered as first order carcinogenic risk factors(22, 23). As an experimental model, solitary car-cinogenesis may be used to investigate the etiologyof human cancer and the biology and biochemistryof cancer cells.

Syncarcinogenesis and anticarcinogenesis

In most instances, carcinogenesis may resultfrom exposure of the host or target tissue to morethan one carcinogen, i.e., exposure is multifactorial.More specifically, neoplasia may arise because ofan augmentational or synergistic action of sub-carcinogenic doses of two or more carcinogens. Thecorresponding processes may be termed "syn-carcinogenesis ". The origin (exogenous or endo-genous) and nature (physical, chemical, or viral) ofthe synergistically acting carcinogens is unimportant,as also is their number.

In processes of syncarcinogenesis, it is particu-larly important to distinguish clearly the carcino-gens and processes involved from host or targettissue predisposition. For example, in viral car-cinogenesis, if the generation of neoplasia is adirect consequence of an acute infection of thehost, the virus clearly is an exogenous carcinogen

DEFINITIONS AND TERMINOLOGY IN CANCER (TUMOUR) ETIOLOGY

(see Table 1). If, alternatively, the generation ofneoplasia is due to the activation of an integratedviral genome (oncogen hypothesis (26), protovirushypothesis (38)), by convention such a genomemay be considered an endogenous solitary carcinogenor an " incomplete carcinogen " (22). The activationof such a genome or provirus by an additional car-cinogen (of exogenous or endogenous origin and ofphysical, chemical, or viral nature) leading to neo-plasia would consequently be classified as a processof syncarcinogenesis (see Table 1). Clearly, in thiscase, predisposition of the host or target tissue willhave to be considered with the (early) infection bythe virus leading to the incorporation of the viralgenome.The term syncarcinogenesis was proposed in 1949

(1, see also 2) and redefined in 1972 (22, see also 23).The preposition " syn- " is used in the broadestpossible sense excluding, however, any conditioningexposure of the host or target tissue. Also, it doesnot imply any specific mode of pharmacologicalaction (additive versus multiplicative). The Greekprefix " syn- " means the opposite of " anti- ".Exposure of the host or target tissue to a solitary

carcinogen followed by one or more agents mayresult not only in an augmentation of the carcino-genic response (" syncarcinogenesis ") but also inits inhibition (" anticarcinogenesis "), (for a reviewsee 17). Such inhibition is caused by interferenceof the inhibitor (anticarcinogen) with an ongoingprocess of carcinogenesis and may result in alengthening of the latent period, in a reductionof the cancer (or tumour) rates and yields, or in acombination of all three of these criteria.

In anticarcinogenesis, as in syncarcinogenesis,resistance of the host or target tissue is to be dis-tinguished from inhibition due to interference withan ongoing carcinogenic process. Resistance may beinborn or acquired by conditioning of the host ortarget tissue, e.g., by stimulation of its immunesurveillance to protect against cancer virus infectionor by prior adrenalectomy protecting against butteryellow hepatocarcinogenesis. Conditioning treat-ments to acquire resistance may be a means ofcancer prophylaxis. Inhibition by interference withan ongoing carcinogenic process is the basis ofcancer therapy.Owing to the large number of carcinogens

already known (Table 1), theoretically an almostinfinite number of multifactorial patterns of exposureof the host or target tissue and hence of processes ofsyncarcinogenesis may be visualized. In the following

sections, some prototype processes of syncarcino-genesis will be analysed.

Pluricarcinogenesis

Carcinogenesis by simultaneous or sequentialexposure of the host or target tissue to subcar-cinogenic dose(s) of solitary (or to " incomplete ")carcinogen(s) followed by subcarcinogenic doses ofat least one other solitary carcinogen may be called"pluricarcinogenesis " (Table 2).

Carcinogenesis through activation of the latentgenome of a tumour virus by a solitary carcinogen,whatever its origin, nature, and identity, may beclassified as pluricarcinogenesis and the latent viralgenome considered an " incomplete carcinogen ".Such a process of pluricarcinogenesis correspondsto the type of cocarcinogenesis in which the hostor target tissue is exposed to an " incompletechemical carcinogen" at first, followed by exposureto a cocarcinogen.

Experimental investigations into the biology ofpluricarcinogenesis and its possible role in theetiology of human tumours have been initiated inrecent years (e.g., physical, 15; chemical, 27, 29, 36;viral, 32). The role of incomplete carcinogens (ofany origin, nature, and identity) as well as that ofsingle and/or multiple tissue specificity of thesolitary (or incomplete) carcinogens involved re-quires clarification (see, for example, 29).

In pluricarcinogenesis, the response of the hostor target tissue as identified qualitatively by theusual histological means may be measured quanti-tatively by the latent period of the cancer (ortumour), by the cancer (or tumour) rate, by thecancer (or tumour) yield, or by a combination ofthese criteria. Pluricarcinogenesis is the consequenceof the assumed irreversibility of the specific carcino-genic effect(s) caused by the solitary or incompletecarcinogens involved.The term pluricarcinogenesis was proposed in

1972 (22, see also 23) in an attempt to subdivide thesynergistic processes of carcinogenesis according tothe kind, number, and sequence of the carcinogensinvolved (see Table 2). " Pluri- " is an abbreviationof the Latin " pluries ", meaning several. Clearly, itwould be meaningless to use the term " pluri-carcinogen ".

In environmental hygiene, the possibility ofpluricarcinogenesis is of the utmost practicalrelevance (12). However, as an experimental modelfor mechanistic investigations at the cellular andmolecular levels it is obviously impractical; it super-

5

6 E. HECKER

imposes the specific cellular and molecular carcino-genic effects evoked by the carcinogens involved.Even for just one solitary carcinogen these effectsare unknown as yet (22, 23).

Cocarcinogenesis

Carcinogenesis by simultaneous or sequentialexposure of the host or target tissue to subcarcino-genic dose(s) of solitary (or to " incomplete ")carcinogen(s) followed by at least one other causa-tive, but non-initiating, agent may be called cocar-cinogenesis. The latter agent of unequivocallyidentified origin (exogenous or endogenous), nature(physical, chemical, or viral), and identity is called a" cocarcinogen " (Tables 1 and 2).

" Incomplete carcinogens " do not cause neoplasiain a certain tissue even on repeated application,although a single dose of them may be capable ofinitiating that same tissue, e.g., urethane in the skinof mice. An " incomplete carcinogen " for onetissue might be a solitary carcinogen for anothertissue (urethane for mouse lung). It is proposed,therefore, to maintain the term " incompletecarcinogen " and consider " solitary carcinogen"as the alternative (see also Pluricarcinogenesis).The basic elements of cocarcinogenesis were

established in the now classical experiments withmouse skin; after exposure to sub-threshold dosesof carcinogenic aromatic hydrocarbons as solitarycarcinogens, the skin irritant croton oil was usedas a cocarcinogen (3, 8, 30). Later, it was establishedthat the active principles of croton oil are estersof the polyfunctional tetracyclic diterpene phor-bol, such as 12-0-tetradecanoylphorbol-13-acetate(TPA) a (20, 21, 24, 39). With cocarcinogenic dosesof the order of magnitude of hormone doses, thephorbol esters are the most active exogenouscocarcinogens presently known (19, 20). Othercocarcinogens of exogenous and endogenous origin(see Table 1), including viruses, have been identifiedin experiments with hosts other than mice and intarget tissues other than skin (7, 32, 35). The roleof tissue specificity of the solitary (or incomplete)carcinogens and of the cocarcinogens involved incocarcinogenesis remains to be investigated further.The term "cocarcinogenesis " has sometimes

been used to include also conditioning exposure(s)

a Some authors prefer the name phorbol-myristate-acetate (PMA). Boutwell (11) rightly proposed ending thisconfusing duality. The reasons for using the systematicname 12-0-tetradecanoylphorbol-13-acetate (TPA) havebeen detailed elsewhere (23).

prior to the start of the process of carcinogenesis(e.g., 6, 7) as defined above. Such usage is at variancewith the more restricted meaning attributed to it atfirst by Shear (37), and also with the definition ofsyncarcinogenesis (1, see also 2). It also has thedisadvantage of mixing what, because of heuristicreasons, might be kept separate (i.e., carcinogensand carcinogenic processes) from host or target tissuepredisposition. Etymologically and literally, " co- "has the same meaning as " syn- "; it is an abbrevia-tion of Latin " cum ", meaning " together with ".Most probably, the inherent identical meaningsof these prefixes have contributed much to theambivalent usage of the term cocarcinogenesis,causing much of the present terminological confu-sion. To overcome this situation it is proposed thatthe term cocarcinogenesis be reserved and redefinedas above and according to its original meaning(22, 23).

In cocarcinogenesis, the response of the host ortarget tissue as identified qualitatively by wellestablished histological means is measured quantita-tively by the latent period of cancers (or tumours),by the cancer (or tumour) rate, by the cancer (ortumour) yield, or by a combination of these. The(specific) biological effect(s) caused by cocarcinogensis considered to be reversible (5, 10, 18, 20, 22, 23).Cocarcinogenesis is the consequence of the syner-gism of the assumed irreversible specific carcinogeniceffect(s) caused by exposure to a subcarcinogenicdose of a solitary carcinogen (or to an incompletecarcinogen) and of the assumed reversible biologicaleffects caused by subsequent exposure to a cocar-cinogen. Apart from its specific cocarcinogeniceffect(s), a cocarcinogen may cause non-specificepiphenomena in the host or target tissue(s) owing,for example, to toxicity.

It is important to note that reversible biologicaleffects can also cumulate by summation (14).Hence, cumulation of the underlying biologicaleffect(s) may not be misinterpreted as indicatingirreversibility (22). The detection of a definitetumorigenic and even a weak carcinogenic activityin croton oil and the phorbol esters (19, 20) causedsome investigators to question the existence of adefined cocarcinogenic activity (for a review see22; see also 13). Indeed, if merely the end resultof pluricarcinogenesis versus cocarcinogenesis isconsidered (i.e., generation of neoplasia), a quali-tative difference in the biological activities ofsolitary carcinogens and cocarcinogens mightappear not to exist. Clearly, such a point of view

DEFINITIONS AND TERMINOLOGY IN CANCER (TUMOUR) ETIOLOGY

does not differentiate between the diverse biologicalqualities of action of the carcinogens involved.Such differentiation, however, will affect andimprove benefit/risk evaluations preceding preventivelegislation.

That cocarcinogens may play a role in the etiologyof human tumours is suggested by clinical observa-tions (reviews in 1, 2). Also, epidemiological evidenceas to the etiological role of cocarcinogens in certainoccupational cancers has been reported (e.g., 9) andverified experimentally by a number of investigators(review in 34; see also 37). Within the last decade,the existence of a wide variety of cocarcinogensin the plant kingdom has become apparent. Com-pared to solitary carcinogens, they may be consideredas second order carcinogenic risk factors (22, 23).The still increasing number of cocarcinogens callsfor careful investigation of their contributionto the etiology of human cancer and for the adoptionof adequate preventive measures in environmentalhygiene. Such measures must seek to preventexposure not only to solitary (or incomplete)carcinogens but also to cocarcinogens (22, 25, 31,32, 40).

Studies of cocarcinogenesis make it possible toresolve the complexity of cellular and molecularevents comprising carcinogenesis in defined stages.Such stages may be investigated separately toanalyse the mechanism of carcinogenesis at themolecular level (7, 11, 20, 21, 24).

In mechanistic investigations of this kind, for the(submanifestational) exposure to the solitary carci-nogen (or to the incomplete carcinogen) the term" initiation ", and for the exposure to the cocar-cinogen the term " promotion " may be used,respectively.

Carcinogenic factors and unspecified carcinogenesisFor causative agents for which the origin, nature,

and identity is not clarified unequivocally, the term" carcinogenic factor " may be used.

If in any specific case of carcinogenesis the numberand/or sequence of exposure to the carcinogens orcarcinogenic factors involved have not been clarifiedunequivocally, the carcinogenic process may beclassified preliminarily as " unspecified carcino-genesis ".

If, for example, it were established that " hormone-induced cancers " were being generated by a unifac-torial process, the process would be considered assolitary carcinogenesis and consequently the hormoneas a solitary carcinogen. If, however, such cancers

were the result of the synergistic action of, forexample, a virus (perhaps already present in thetarget tissue) and of a hormone, such a process wouldbe considered as syncarcinogenesis, still leaving forclarification the possibilities of either pluri- orcocarcinogenesis classifying the hormone alterna-tively as a solitary carcinogen or as a cocarcinogen(see also 22).

CONCLUSIONS

In cancer etiology, generation of neoplasia in thebroadest possible sense may be described by theterm " carcinogenesis ". The term " carcinogen "may be used to cover the causative agents involvedin carcinogenesis if these are identified unequivocally.The multiplicity of possible exposures of the hostor target tissue, according to kind(s), number(s), andsequence(s) of carcinogens, may be called " car-cinogenic processes ". Together with " host or targettissue predisposition ", carcinogens and carcinogenicprocesses are considered fundamental variables ofcarcinogenesis.A carcinogenic process evoked by unifactorial

exposure of the host or target tissue is specified as" solitary carcinogenesis ". The carcinogenic factorinvolved is a " solitary carcinogen ".

Carcinogenic processes evoked by multifactorialexposure of the host or target tissue are collectivelycalled " syncarcinogenesis ". In cancer etiology,exposure to even a subcarcinogenic dose of asolitary carcinogen, or to an incomplete carcinogen,may cause cancer if the biological effects caused bythe initial exposure, no matter how much later inlife, are augmented by exposure to subcarcinogenicdoses of another solitary carcinogen (" pluri-carcinogenesis ") or to a cocarcinogen (" cocarcino-genesis ").

In the etiology of cancer in man, solitary carcino-gens and cocarcinogens may be considered first-and second-order carcinogenic risk factors, respec-tively. Their distinction may contribute considerablyto more differentiated evaluations of benefit versusrisk. Detailed knowledge in this field constitutes thescientific foundation of cancer prevention by environ-mental hygiene. In experimental cancer research,certain carcinogenic processes verified in appropriatehosts or target tissues may be used as experimentalmodel systems to elucidate the biology and bio-chemistry of the cancer cell and of carcinogenesis.Such elucidations are a prerequisite for the develop-ment of causal therapies of cancer.

7

8 E. HECKER

ACKNOWLEDGEMENTS

The present analysis and proposals were stimulated by informal discussions between the author and membersof the UICC Committee of Quantitative Carcinogenesis (Chairman: P. Shubik), the Feasibility Committee of theIARC (Chairman: J. Higginson) in November 1968 (Kingston, Jamaica), and the Committee of International Colla-borative Activities (CICA) of the UICC, and reached its present form by many discussions with individual cancerresearch workers, e.g., during the 2nd Meeting of the European Association for Cancer Research in October, 1973(Heidelberg), the XIth International Cancer Congress in September, 1974 (Florence), and the Third InternationalSymposium on Detection and Prevention of Cancer in April 1976 (New York). In seeking wide distribution of thispaper within the scientific community of cancer research and the encouragement of international discussion, theauthor gratefully acknowledges the cooperation of the editors of International journal of cancer, Zeitschrift fur Krebs-forschung und klinische Onkologie, Gann, Bulletin of the World Health Organization, and Journal of the National CancerInstitute.

RI2SUMt

DEFINITIONS ET TERMINOLOGIE RELATIVES A L'ETIOLOGIE DES CANCERS (TUMEURS).

ANALYSE ET PROPOSITIONS EN VUE D UNE TERMINOLOGIE INTERNATIONALE NORMALISEE ACTUELLE

Pour tenter de remedier a la confusion qui r&gne dansla terminologie relative a l'etiologie des cancers (tumeurs),I'auteur a analyse la situation actuelle et propose destermes qui, il l'espere, susciteront un debat internationalet permettront de decider en fin de compte d'une ter-minologie normalisee.

Les lecteurs desireux de faire connaitre leurs remarquesau sujet de ces propositions sont pries d'adresser leurslettres a l'Union internationale contre le Cancer, 3, rueConseil-General, 1205 Geneve, Suisse, dans un delai desix mois apres la parution du present article.

REFERENCES

1. BAUER, K. H. tOber Syn- und Anticarcinogenese.Klin. Wochenschr., 27: 118 (1949).

2. BAUER, K. H. Das Krebsproblem, 2. Auflage. Berlin-Gottingen-Heidelberg, Springer-Verlag, 1963.

3. BERENBLUM, I. The cocarcinogenic action of crotonresin. Cancer Res., 1: 44 (1941).

4. BERENBLUM, I. The mechanism of carcinogenesis.A study of the significance of cocarcinogenic actionand related phenomena. Cancer Res., 1: 807 (1941).

5. BERENBLUM, I. The two-stage mechanism of car-cinogenesis as an analytical tool. In: Emmelot,P. & Miuhlbock, O., ed. Cellular control mechanismand cancer. Amsterdam-London-New York, Elsevier,1964, p. 259.

6. BERENBLUM, I. A re-evaluation of the concept ofcocarcinogenesis. Progr. exp. Tumor Res., 11: 21(1969).

7. BERENBLUM, I. Carcinogenesis as a biologicalproblem. In: Neuberger, A. & Tatum, E. L., ed.Frontiers of biology. Amsterdam-Oxford, NorthHolland, and New York, Elsevier, 1974, vol. 34.

8. BERENBLUM, I. & SHUBIK, P. A new quantitativeapproach to the study of the stages of chemicalcarcinogenesis in the mouse's skin. Brit. J. Cancer,1: 383 (1947).

9. BINGHAM, E. & HORTON, A. W. Environmentalcarcinogenesis: experimental observations related

to occupational cancer. In: Montagna, W. &Dobson, R. L., ed. Advances in biology of the skin.Oxford, Pergamon Press, 1966, vol. 7, p. 183.

10. BOUTWELL, R. K. Some biological aspects of skincarcinogenesis. Progr. exp. Tumor Res., 4: 207 (1964).

11. BOUTWELL, R. K. The function and mechanismof promoters of carcinogenesis. Crit. Rev. Toxicol.,2: 419 (1974).

12. CAIRNS, J. The cancer problem. Scientific Americani,233: 64 (1975).

13. CHOUROULINKOV, I. & LAZAR, P. Actions cancero-gene et cocancerogene du 12-O-tetradecanoyl-phorbol-13-acetate (TPA) sur la peau de souris.C. R. Acad. Sci. (Paris), Serie D, 278: 3027 (1974).

14. DRUCKREY, H. & KJPFMtLLER, K. Dosis undWirkung. Aulendorf/Wiurtt, Cantor, 1949.

15. EMMETT, E. A. Ultraviolet radiation as a cause ofskin tumors. Crit. Rev. Toxicol. 2: 211 (1973).

16. EPSTEIN, S. S. Environmental determinants ofhuman cancer. Cancer Res., 34, 2425-2435 (1974).

17. FALK, H. L. Anticarcinogenesis-an alternative.Progr. exp. Tumor Res., 14: 105 (1971).

18. GRAFFI, A. Experimente und Betrachtungen zurNatur und Ursache des Krebses. Sitzungsber. dtsch.Akad. Wiss. Berlin, Ki. Med., No. 2, pp. 1-44 (1964).

19. HECKER, E. Die cocarcinogene Wirkung der Phorbol-ester. In: Holzer, H. & Holldorf, A. W., ed. Mole-

DEFINITIONS AND TERMINOLOGY IN CANCER (TUMOUR) ETIOLOGY 9

kulare Biologie des malignen Wachstums. Berlin-Heidelberg-New York, Springer, 1966, p. 105.

20. HECKER, E. Cocarcinogenic principles from the seedoil of Croton tiglium and from other Euphorbiaceae.Cancer Res., 28: 2338 (1968).

21. HECKER, E. Isolation and characterization of thecocarcinogenic principles from croton oil. In:Busch, H., ed. Methods in cancer research. NewYork-London, Academic Press, vol. 6, 1971, p. 439.

22. HECKER, E. Aktuelle Probleme der Krebsentstehung.Krebsforsch., 78: 99 (1972).

23. HECKER, E. Cocarcinogens and cocarcinogenesis(with a note on synergistic processes in carcino-genesis). In: Grundmann, E., ed. Handbuch derallgemeinen Pathologie. Berlin-Heidelberg, Springer,1975, vol. VI/6, p. 651.

24. HECKER, E. & SCHMDT, R. Phorbolesters-theirritants and cocarcinogens of Croton tiglium L.Prog. Chem. organ. nat. Prod., 31: 377 (1974).

25. HORTON, A. W. & CHRISTIAN, F. M. Cocarcinogenicversus incomplete carcinogenic activity amongaromatic hydrocarbons: contrast between chryseneand benzo(b)triphenylene. J. nat. Cancer Inst., 53:1017 (1974).

26. HUEBNER, R. J. & TODARO, G. J. Oncogens of RNAtumor viruses as determinants of cancer. Proc. nat.Acad. Sci., 64: 1087 (1969).

27. LIHA6EV, A. J. (Combined effect of carcinogenicsubstances). Vopr. Onkol., 14: 114 (1968) (Russian).

28. MARIE, P. ET AL. Contribution A 1'etude du develop-pement des tumeurs malignes sur les ulceres deRoentgen, tumeur maligne developpee sur une radio-dermite experimentale chez le rat blanc. Bull. Ass.fran9. Cancer, 3: 404 (1910).

29. MOHR, U. Pluricarcinogenesis. In: Abstracts of the2nd Meeting of the European Association for CancerResearch, Heidelberg, 2-5 October, 1973, p. 4.

30. MOTTRAM, J. C. A developing factor in experimentalblastogenesis. J. Pathol. Bacteriol, 56: 181 (1944).

31. NARISAWA, T. ET AL. Promoting effect of bile acidson colon carcinogenesis after intrarectal instillationof N-methyl-N-nitro-N-nitrosoguanidine in rats.J. nat. Cancer Inst. 53: 1093 (1974).

32. ROE, F. J. C. Carcinogenesis and sanity. FoodCosmet. Toxicol., 6: 485 (1968).

33. Rous, P. A transmissible avian neoplasm (sarcomaof the common fowl). J. exp. Med., 12: 696 (1910).

34. SALAMAN, M. H. Cocarcinogenesis. Brit. med. Bull.,14: 116 (1958).

35. SALAMAN, M. H. & ROE, F. J. C. Cocarcinogenesis.Brit. med. Bull., 20: 139 (1964).

36. SCHMXHL, D. Entstehung, Wachstum und Chemothe-rapie maligner Tumoren, 2nd ed. Aulendorf/Wuirtt,Cantor, 1970.

37. SHEAR, M. J. Studies in carcinogenesis, V. Methylderivatives of 1:2-benzanthracene. Am. J. Cancer,33: 499 (1938).

38. TEMIN, H. M. The protovirus hypothesis: specula-tions on the significance of RNA-directed DNAsynthesis for normal development and for carcino-genesis. J. nat. Cancer Inst., 46(2): III (1971).

39. VAN DUUREN, B. L. Tumor-promoting agents intwo-stage carcinogenesis. Prog. exp. Tumor Res.,11: 31 (1969).

40. VAN DUUREN, B. L. ET AL. Cocarcinogenesis studieson mouse skin and inhibition of tumor induction.J. nat. Cancer Inst., 46: 1039 (1971).

41. VAN DUUREN, B. L. ET AL. Cocarcinogenic agentsin tobacco carcinogenesis. J. nat. Cancer Inst., 51:703 (1973).

42. YAMAGIWA, K. & ISCHIKAWA, K. Ober die atypischeEpithelwucherung. Gann, 8: 11 (1974). See: Collectedpapers on artificial production of cancer by Prof.K. Yamagiwa. Tokyo, Maruzen Co., 1965, pp. 1-9.

Annex

GLOSSARY OF THE MAIN TERMS AS PROPOSED AND DEFINED OR REDEFINED IN THETEXT, IN ALPHABETICAL ORDER

Carcinogenesis is the generation of benign and malig-nant neoplasia in the broadest possible sense, includingthe generation of sarcomata and leukaemia.

Carcinogens are agents causing the generation ofneoplasia whose origin, nature, and identity are un-equivocally clarified. Carcinogens may exhibit tissuespecificity.

Carcinogenic factors are agents causing the generationof neoplasia whose origin, nature, and identity are notunequivocally clarified.

Carcinogenic processes are all patterns of exposureof the host or target tissue to carcinogens and carcino-genic factors. By definition, carcinogenic processesare started by exposure of the host or target tissue to asolitary (or an incomplete) carcinogen.

Cocarcinogenesis is one of the prototype processesof syncarcinogenesis resulting from simultaneous orsequential exposure of the host or target tissue tosubcarcinogenic dose(s) of solitary (or to incomplete)carcinogen(s) followed by at least one unequivocally

10 E. HECKER

identified causative, but non-initiating, agent. Thelatter agent is called a cocarcinogen and may exhibittissue specificity.Host or target tissue predisposition may be inborn or

acquired and exists prior to the initiation of any car-cinogenic process.

Pluricarcinogenesis is one of the prototype processesof syncarcinogenesis resulting from the simultaneous orsequential exposure of the host or target tissue to sub-carcinogenic dose(s) of solitary (or incomplete) car-cinogen(s), followed by subcarcinogenic doses of at leastone other solitary carcinogen.

Solitary carcinogenesis is the process of carcinogenesisresulting from unifactorial exposure to the host or targettissue to a single carcinogen. Such a carcinogen is calleda solitary carcinogen.

Syncarcinogenesis covers all processes of carcinogenesisresulting from multifactorial exposure of the host ortarget tissue to solitary (or incomplete) carcinogen(s)simultaneously with or followed by other carcinogens.

Unspecified carcinogenesis comprises all patterns ofexposure of the host or target tissue for which thenumber and sequence of carcinogens or carcinogenicfactors has not been unequivocally clarified.