Dr. Bernard Ackerman argues that precancers do not exist as lesions separable from cancers. He observes that terms associated with precancers, such as “dysplasia” and “cancer precursor,” have never been adequately defined. Dr. Ackerman’s criticisms should inspire efforts to develop a robust terminology for the precancers. It seems unproductive to dismiss a promising area of pathology because the semantics are disappointing.
Dr. Ackerman asserts that the most important morphological feature of the precancers—absence of invasion—cannot be reliably determined by histological evaluation. In biology, entities that develop through stages are not easily distinguishable at their transitions (eg, the precise morphological cutoff when a promyelocyte becomes a myelocyte). Our inability to determine the first moment of invasion should not discourage us from recognizing that invasive lesions are preceded by noninvasive lesions.
Finally, Dr. Ackerman indicates that Richard Sutton, Jr. was correct when he wrote, “The acorn is Quercus just as is the oak tree; the fertilized ovum in a human uterus is Homo sapiens; the 1-mm circular, scaling intra-epidermal macule is cancer as appropriately as the stinking ulcer that destroys the malar bone and orbit.” Yes, an acorn is the same organism as the oak tree, but acorns do exist and can be studied as the biological precursor of the oak tree. When the acorn is destroyed, the oak tree never grows. The human embryo may be a homo sapiens, but the embryonic stage precedes the fetal stage in human development and has enhanced our understanding of organogenesis. Likewise, precancers are part of the neoplastic process and may hold the key to carcinogenesis and cancer treatment.
In our article Classifying the Precancers: A Metadata Approach,1 we acknowledged conceptual problems related to the precancers:
During carcinogenesis, morphologically identifiable lesions occur that precede the development of invasive cancer. These lesions are called precancers, premalignancies, preneoplastic lesions, incipient cancers, intraepithelial neoplasias, and preinvasive cancers. The plethora of terms reflects the difficulty of choosing a canonical class term for the precancerous lesions. Currently, the term intraepithelial neoplasia seems to enjoy wide usage among the community of pathologists, but this term has limitations:
Not all epithelial precancers are intraepithelial. Most of the mucosal dysplasias have a well-defined territory bounded by the junction between the epithelium and the underlying stroma. But not all premalignant epithelial lesions can be identified by the presence of atypical cell populations delimited by a basement membrane. Dysplastic lesions of the liver, kidney, thyroid and adrenal are not delimited by a basement membrane.
Not all precancers are epithelial. Intratubular germ cell neoplasms of testis, myelodysplasias, and non-autonomous lymphomas are examples of non-epithelial precancers.
Not all intraepithelial neoplasms are precancers. Neoplasms that are intraepithelial but that are not precancers include: seborrheic keratoses, intraepidermal nevi, common warts and most so-called benign epithelial tumors.
Likewise, the term pre-invasive cancer raises an existential question. Use of the term “pre-invasive cancer” implies that precancers have attained the biological properties of a cancer. This assumption may not be true. Precancers may lack constitutive properties of cancer or may have certain attributes that are absent in cancers. At this point, there is insufficient knowledge to conclude that precancers are types of cancer. In this article, the authors use the term precancers because this term conveys only the defining features: occurrence prior to cancers, and existence as an identifiable lesion.
When considering all the possible classes of precancers, it is worth noting that:
Not all precancers are neoplastic. A diffusely hyperplastic lesion with no known neoplastic properties, but with a frequent association with cancer arising from the hyperplastic tissue, would be considered a precancer. Examples include diffuse atypical endometrial hyperplasia, AIDS-associated lymphoid hyperplasia, helicobacter-associated gastric MALT hyperplasia, diffuse gastric intestinal metaplasia, etc.
Precancers need not progress to cancer and often have a high rate of regression. The low-risk of progression to cancer suggests a strategy for treatment based on enhancing the intrinsic regression rate of precancers. However, when a precancer progresses, cancer is the obligate outcome (i.e. precancers never progress into types of lesions other than cancer). This biological property allows us to infer that agents that induce precancers are carcinogens.
The different kinds of precancers may vary in every biologic feature except those specified in their definition (identifiable lesions that precede the development of cancer). Since precancers, by definition, are the morphologic lesions that precede cancers, one can expect precancers to occur in a somewhat younger population than the population of people who have cancers.
After the first NCI-sponsored precancer classification meeting, we developed a draft classification comprising 6 general classes, 568 concepts, and 4700 terms.1,2 In our article we described, in considerable detail, the deficits of the draft classification and the need to have open community involvement to develop a mature product. The current draft classification can be viewed at http://www.biomedcentral.com/content/supplementary/1472-6947-3-8-S1.htm.
Cancer trialists have seized on precancers as important targets for new therapeutic agents.3 In a recent editorial, Dr. Gary Kelloff provided a clear explanation of the value of precancers as surrogate endpoints in cancer prevention trials. 4 None of this anticipated work will be fruitful if pathologists have inadequate terminology, idiosyncratic diagnostic criteria, and an uninformed biological framework for evaluating these lesions. We expect the next several years will see a serious effort to develop a classification of the precancers, and urge pathologists to contribute to the success of this worthy undertaking.
Jules J. Berman, PhD, MD
Donald E. Henson, MD
References
1. Berman JJ, Henson
DE. Classifying the precancers: A metadata approach. BMC Med Infom Decis Mak
2003;3:8.
2. Henson
DE, Albores Saavedra J, Berman JJ, et al. Meeting Summary: A molecular
classification for precancerous lesions. Report of an Early Diagnosis Research
Network working group, February 1–2, 2001 2001. Available at
http://www3.cancer.gov/prevention/cbrg/molclass.html.
3. O’Shaughnessy
JA, Kelloff GJ, Gordon GB, et al. Recommendations of the American Association
for Cancer Research task force on the treatment and prevention of
intraepithelial neoplasia. Treatment and prevention of intraepithelial
neoplasia: An important target for accelerated new agent development. Clin
Cancer Res 2002;8:314-346.
4. Kelloff GJ, O'Shaughnessy
JA, Gordon GB, et al. Counterpoint: Because some surrogate end point
biomarkers measure the neoplastic process they will have high utility in the
development of cancer chemopreventive agents against sporadic cancers. Cancer
Epidemiol Biomarkers Prev 2003;12:593-596.