Precancer: The Beginning and the End of Cancer (© 2010)

Jules J. Berman and Donald E. Henson
The Precancers: Waiting for a Classification
Human Pathology, 34:833-834, 2003


Precancers are the morphologically identifiable lesions
that precede invasive cancers. In theory, the identification
and elimination of cancer precursors would
lead to the eradication of most human cancers, justifying
an assertion that precancers are the most important
lesions in modern man.1

Pathologists and cytologists have leveraged the pathology
of precancer to achieve the most dramatic reduction
in cancer deaths attributable to medical intervention.
Americans often forget that cancer of the
uterine cervix is the leading cause of cancer deaths in
women in many developing countries.2,3 The relatively
low number of cervical cancer deaths in the United
States is the result of a 70% reduction in age-adjusted
mortality after the introduction of organized Pap smear
screening.4-6 No effort aimed at treating invasive cancers
has provided an equivalent reduction in cancer
deaths.

Recently, precancer has enjoyed renewed attention
from the American Association for Cancer Research
(AACR), which created a multidisciplinary task
force on the treatment and prevention of intraepithelial
neoplasia (IEN). In February 2002, the task force
published its recommendations, which included “focusing
on established precancers as the target for new
agent development because of the close association
between dysplasia and invasive cancer and because a
convincing reduction in IEN burden provides patient
benefit by reducing cancer risk and/or by decreasing
the need for invasive interventions.”7

Precancers have been a subject of research interest
for decades. Many will remember the enthusiasm in the
1960s and 1970s for experimental precancer models. A
classical description of the progression of precancer to
cancer was described by the late Leslie Foulds, who died
while nearing completion of his multivolume work on
neoplastic progression.8 Given the decades-long history
of precancer research, why is there renewed interest in
precancers at this moment?

A major stimulus for precancer research has come
from the Food and Drug Administration’s Modernization
Act of 1997 (FDAMA).9 The FDAMA contains
provisions for “surrogate endpoints” in drug evaluation
when the endpoints seem clinically useful. This opens
the door to using precancers in several surrogate roles.
Foods or drugs that cause precancers to regress are
likely to reduce the incidence of cancer, whereas substances
that increase the incidence of precancers are
likely to increase the incidence of cancers that develop
from those precancers.

The FDAMA seems to provide some relief from the
creeping fear that neither the drug companies nor the
National Cancer Institute (NCI) nor society has the
resources or the patience to conduct randomized clinical
trials for all of the promising new anticancer drugs,
particularly if the endpoints are remote (eg, incidence
or survival).10 One of the most interesting biological
features of precancers is regression.11 The prevalence
of precancers in the population is much higher than
the incidence of cancers that arise from these lesions
(eg, colon adenomas, actinic keratoses, squamous intraepithelial
lesions of the cervix). Precancers may be
amenable to treatment with agents that enhance the
natural tendency of regression. It may take less time to
determine whether a COX-2 inhibitor reduces the
number of colon adenomas than to determine whether
the same inhibitor reduces the number of colon cancer
deaths.

Clinically, the different precancers have a broad
range of importance. Some, such as colon adenomas
and atypical nevi, can be effectively excised. Others,
such as multifocal oral dysplastic leukoplakia, markedly
dysplastic Barrett’s esophagus, and refractory anemia
with excess blasts, may pose frightening clinical dilemmas.
Cancer drug trials for the more serious precancers
are just as important for the affected patients as clinical
trials are for invasive cancers.

Another reason for the renewed focus on precancers
is the new imaging technology that has the potential
to reach the cellular level. Recent advances in endoscope-
coupled microscopy may allow identification
of precancers in deep-seated viscera.12

A third stimulus for renewed interest comes from
the bioinformatics community. Various high-through-
put methods are now available for characterizing normal
tissues, precancers, and cancers by their molecular
profiles. This is the major goal of the NCI’s Cancer
Genome Anatomy Project.13 These studies require welldesigned
protocols using pathology-annotated lesions
logically integrated into vast data libraries. For this to
occur, the scientific community is waiting for a classification
of precancerous lesions that can be used consistently
by the pathology community.

In 2001, an NCI-sponsored workshop urged the
development of a well-characterized and practical classification
for the precancers.14 Subsequently, we published
a comprehensive listing and draft classification
of the precancers.15 The draft precancer classification
contains 4700 precancer terms, with 568 distinct precancer
concepts and 6 precancer classes: (1) acquired
microscopic precancers, (2) acquired large lesions with
microscopic atypia, (3) precursor lesions occurring
with inherited hyperplastic syndromes that progress to
cancer, (4) acquired diffuse hyperplasias and diffuse
metaplasias, (5) currently unclassified entities, and (6)
superclass and modifiers. The precancer list contains
both epithelial and nonepithelial precancerous lesions.
Modern classifications serve as informatics devices
capable of linking, integrating, and retrieving information
contained in diverse biological datasets.16 We used
a novel approach to disease classification, annotating
precancer terms and classes with metadata (ie, data that
describe the data). Metadata annotations are a critical
part of the data, because the annotations can link data
from different databases, aiding the discovery of new
knowledge relevant to precancers.17

We anticipate that the first-draft classification of
the precancers will serve as a scaffold for molecular
annotation. Over the past decade, pathologists may
have noticed an increase in the number and variety of
biopsy specimens submitted to rule out precancerous
lesions. These small specimens will have enormous importance
to the practice of pathology and to cancer
research. Pathologists should be actively engaged in
efforts to describe and understand these lesions, and
are invited to offer modifications or contributions to
the draft precancer classification.

JULES J. BERMAN, PHD, MD
Cancer Diagnosis Program
National Cancer Institute
Rockville, MD

DONALD E. HENSON, MD
Department of Pathology and the Office of Cancer
Prevention and Control
The George Washington University Cancer Institute
Washington, DC

REFERENCES

1. Seidman JD, Berman JJ: Premalignant non-epithelial lesions:
A biological classification. Mod Pathol 6:544-554, 1993

2. Wabinga HR: Pattern of cancer in Mbarara, Uganda. East Afr
Med J 79:193-197, 2002

3. Nze-Nguema F, Sankaranarayanan R, Barthelemy M, et al:
Cancer in Gabon, 1984–1993: A pathology registry–based relative
frequency study. Bull Cancer 83:693-696, 1996

4. Palatianos GM, Cintron JR, Narula T, et al: Father of modern
cytology. A 30-year commemorative. J Fla Med Assoc 79:837-
838, 1992

5. Bergstrom R, Sparen P, Adami HO: Trends in cancer of the
cervix uteri in Sweden following cytological screening. Br J Cancer
81:159-166, 1999

6. Anttila A, Pukkala E, Soderman B, et al: Effect of organised
screening on cervical cancer incidence and mortality in Finland,
1963–1995: Recent increase in cervical cancer incidence. Int J Cancer
83:59-65, 1999

7. 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 88:314-
346, 2002

8. Foulds L: Neoplastic Development. New York, Academic
Press, 1969

9. Food and Drug Administration’s Modernization Act. http://
www.fda.gov/cder/guidance/105-115.htm

10. NCI Deputy Barker hits FDA, calls for new incentives for
pharmaceutical industry. Cancer Lett 29: 1-12, 2003

11. Berman JJ, Moore GW: The role of cell death in the growth
of preneoplastic lesions: A Monte Carlo simulation model. Cell Prolif
25:549-557, 1992

12. Sokolov K, Follen M, Aaron J, et al: Real-time vital optical
imaging of precancer using anti-epidermal growth factor receptor
antibodies conjugated to gold nanoparticles. Cancer Res 63:1999-
2004, 2003

13. The Cancer Genome Anatomy Project. http://cgap.nci.nih.
gov/

14. 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. http://www3.cancer.gov/prevention/cbrg/
molclass.html

15. Berman JJ, Henson DE: Classifying the precancers: A metadata
approach. BMC Med Inform Decis Making 3:8, 2003

16. Mayr E: The Growth of Biological Thought: Diversity, Evolution
and Inheritance. Cambridge, MA, Belknap Press, 1982

17. Dodds D, Watt A, Birbeck M, et al: Professional XML Meta
Data. Birmingham, AL, Wrox, 2001

This editorial is the opinion of the authors and does not represent
policy of the National Cancer Institute or of George Washington
University.