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Precursors to Malignant Melanoma

National Institutes of Health
Consensus Development Conference Statement
October 24-26, 1983

Conference artwork, abstract shapes representing cells, almost floral like, with question marks surrounding.

This statement is more than five years old and is provided solely for historical purposes. Due to the cumulative nature of medical research, new knowledge has inevitably accumulated in this subject area in the time since the statement was initially prepared. Thus some of the material is likely to be out of date, and at worst simply wrong. For reliable, current information on this and other health topics, we recommend consulting the National Institutes of Health's MedlinePlus http://www.nlm.nih.gov/medlineplus/.

This statement was originally published as: Precursors to Malignant Melanoma. NIH Consens Statement 1983 Oct 24-26;4(9):1-14.

For making bibliographic reference to the statement in the electronic form displayed here, it is recommended that the following format be used: Precursors to Malignant Melanoma. NIH Consens Statement Online 1983 Oct 24-26 [cited year month day];4(9):1-14.

Introduction and Conclusions

Introduction

The incidence of melanoma and the number of deaths from it are increasing in many areas of the world. There is evidence that early recognition and surgical removal of melanoma makes this a highly curable cancer. In recent years, medical scientists have become aware of a possible association between certain preexisting pigmented skin lesions and cutaneous melanoma. This interest has developed from identification of two suspected precursors to cutaneous melanoma: (1) acquired abnormal moles known as dysplastic nevi, present both in the general population and in certain melanoma-prone families, and (2) certain congenital nevi. Identification and appropriate management of such precursors could significantly reduce the incidence of and mortality from melanoma.

In an effort to resolve some of the questions surrounding these issues, the National Institutes of Health convened a
Consensus Development Conference on Precursors to Malignant Melanoma on October 24-26, 1983. After a day and a half of presentation by experts of data on these two types of lesions and their potential for becoming cancerous, a consensus panel including representatives of dermatology, pathology, oncology, family medicine, immunology, epidemiology, and the general public considered the scientific evidence and agreed on answers to the following key questions:

  1. Can dysplastic nevi and congenital nevi be defined clinically and histologically?
  2. Are these nevi precursors to melanoma? What are the prevalence, natural history, and determinants of these precursors?
  3. What is appropriate management of patients with dysplastic nevi and congenital nevi regarding: diagnosis, treatment, followup, familial screening, and education?
  4. What directions should be taken for future research on precursor lesions to melanoma?

 

Conclusions

This conference highlighted an important advance in our understanding of melanoma through the identification of a familial syndrome in which multiple dysplastic nevi are associated with development of melanomas. The investigation of patients with this syndrome affords an opportunity not only to advance our knowledge of the biology of melanoma but also to aid the identification of treatable precursor lesions and early melanomas. The result may be a reduction in mortality in these patients.

The consensus panel found that melanoma may arise de novo as well as in association with preexisting melanocytic nevi. The panel also agreed that the dysplastic nevus, a distinctive lesion both clinically and histologically, has been identified in this context, particularly in melanoma-prone families. Dysplastic nevi are both markers and precursors for familial melanoma. Melanoma may develop also in congenital nevi, especially when the lesion is larger than 20 cm.

Strategies for treatment and followup should be formulated individually, on the basis of the risk of melanoma to each patient. Patients with dysplastic nevi and a family history of melanoma should be followed frequently, with documentation of lesions and excision of changing nevi. The relatives of patients with melanoma should be examined for dysplastic nevi and melanoma in view of the familial aggregation of both lesions. Patients with congenital nevi should be followed periodically for changes. Need for education in examination of lesions by patients, relatives, and health professionals is emphasized.

The paucity of existing information on precursors of melanoma coupled with its increasing incidence indicate a continuing need for research.  

Can Dysplastic Nevi and Congenital Nevi Be Defined Clinically and Histologically?

Dysplastic Nevi

Dysplastic nevi are acquired pigmented lesions of the skin whose clinical and histologic definitions are evolving. They differ from common, acquired pigmented nevi in several respects and some cannot be clinically distinguished from melanoma. They were first recognized because of their unusual appearance and increased frequency in certain families. The features of dysplastic nevi that occur in affected families do not differ from those of sporadic lesions.

Typical dysplastic nevi measure 5 to 12 mm in diameter and tend to be larger than common nevi. Dysplastic nevi have both macular and papular components and have borders that usually are irregular and frequently are ill-defined. Their color is variegated, ranging from tan to dark brown on a pink background. Dysplastic nevi may appear anywhere on the body, especially on the trunk. Their frequent occurrence on covered areas, such as buttocks, breast, and scalp, represents a distribution different from that of common nevi. Young adults reportedly have an average of 25 common nevi, but an individual with dysplastic nevi may have more than 100 lesions. Although common nevi usually have appeared by young adult life, dysplastic nevi usually begin to appear in adolescence and continue to appear even after the age of 35.

The accurate diagnosis of dysplastic nevus depends upon histologic confirmation. Typical histopathologic features are superimposed on those of a junctional or compound nevus and include

  1. Basilar melanocytic hyperplasia with elongation of rete ridges.
  2. Cytologic atypia with enlarged hyperchromatic melanocytic nuclei, often present but not essential for the diagnosis.
  3. Melanocytes, spindle-shaped and arranged horizontally, or occasionally epithelioid, aggregating in nests of variable size and fusing with adjacent rete ridges to produce bridging.
  4. Lamellar and concentric dermal fibroplasia.
  5. Lymphocytes in patchy or diffuse superficial dermal infiltrate.

 

These changes may appear focally in any given lesion and may not be evident unless multiple histopathologic sections are studied. These microscopic findings of dysplastic nevus are distinct from those of malignant melanoma in situ.

Congenital Nevi

A congenital nevus is a melanocytic nevus that is present at birth. Some lesions first become apparent during infancy, and when they do, it is assumed that preexisting nevus cells were present. This assumption is based on clinical, histopathological, and biological data. Not all pigmented lesions present at birth represent melanocytic nevi.

Congenital nevi have been divided into three groups according to size in infancy:

  1. Small (less than 1.5 cm in diameter).
  2. Medium (1.5 to 20 cm in diameter).
  3. Large (greater than 20 cm in diameter).

 

It is recognized that nevi thus classified by size occupy different proportions of the body surface at different ages. The sizes of the lesions have different implications for diagnosis, treatment, and prognosis.

Large congenital nevi vary greatly in size. Some occupy a major portion of the body surface and are called giant congenital nevi, bathing trunk nevi, or garment nevi. Clinical features of these lesions are easily recognized and consist of:

  1. Grossly irregular surface.
  2. Increased pigmentation, with varying shades of brown.
  3. Hypertrichosis.

 

These features are present variably within a given lesion and from patient to patient. Although present at birth, the full extent of the large congenital nevus may not become evident until later in infancy.

Medium-sized lesions share the above clinical features and are almost always easily identified as congenital nevi. They are usually apparent at birth but, again, some appear in infancy.

Small congenital nevi may not be recognized as such if the lesions are not apparent at birth. Clinical features may not differ from those of acquired melanocytic nevi because these smaller lesions may have a smooth surface, have more uniform pigmentation, and lack hair.

The classic microscopic description of congenital nevi includes nevus cells in the following locations:

  1. The lower two-thirds of the dermis, occasionally extending into the subcutis.
  2. Between collagen bundles distributed as single cells, or cells in single-file, or both.
  3. In the lower two-thirds of the reticular dermis or subcutis, associated with the appendages, nerves, and vessels.

 

Some congenital nevi do not have these microscopic features. Large congenital nevi usually do in some areas, but elsewhere they may be indistinguishable from acquired nevi. Medium-sized congenital nevi may or may not show the classic microscopic features. Small congenital nevi often do not show the classic microscopic features and thus may be indistinguishable from acquired nevi. On occasion, the classic microscopic picture of congenital nevus may be seen in an acquired nevus.  

Are These Nevi Precursors to Melanoma? What Are the Prevalence, Natural History, and Determinants of These Precursors?

Melanomas may arise de novo or in association with preexisting melanocytic nevi. These preexisting lesions include dysplastic nevi, congenital nevi, and common acquired nevi.

Dysplastic Nevi

Evidence suggests that melanomas can arise directly from dysplastic nevi. Because the reported prevalence of individuals with dysplastic nevi is in the range of 2 to 8 percent, the impact of dysplastic nevi on the incidence of melanoma may be considerable.

Dysplastic nevi can be inherited or may be sporadic. Familial dysplastic nevi can be inherited as an autosomal dominant trait. Sporadic lesions are those occurring with no dysplastic nevi detected in family members. The presence of multiple dysplastic nevi in two or more family members has been termed the "dysplastic nevus syndrome."

Among caucasians in the United States, the lifetime risk of developing cutaneous melanoma is about 0.6 percent or 1 in 150; the risk is about one-tenth of this among black Americans. Among patients with dysplastic nevi, who constitute a heterogeneous group, the overall lifetime risk has been estimated at 10 percent. The risk is greater for those having one relative with melanoma than for those with no such relative.

The lifetime risk of melanoma may approach 100 percent for those people with dysplastic nevi who are from melanoma-prone families, i.e., families with two or more first-degree relatives having cutaneous melanomas. Melanomas in people from these families may arise within the dysplastic nevi or de novo in ostensibly normal skin.

Congenital Nevi

Congenital nevi occur in approximately 1 percent of all newborns. Most of these nevi are small, as defined above.

The lifetime risk of melanoma in patients with large congenital nevi has been estimated to be 5 to 20 percent. It is unclear to what extent melanoma develops in smaller congenital nevi; the incidence has been reported to be increased, but the magnitude of that increase is not well established.  

What Is Appropriate Management of Patients With "Dysplastic" Nevi and Congenital Nevi Regarding: Diagnosis, Treatment, Followup, Familial Screening, and Education?

Dysplastic Nevi

The formulation of an effective management strategy for patients with dysplastic nevi depends upon their classification in one of two groups:

  1. Dysplastic nevi with a family history of melanoma.
  2. Dysplastic nevi without a family history of melanoma.

 

This classification requires an accurate family history and evaluation of first-degree relatives.

Diagnosis

A patient who is suspected of having one or more dysplastic nevi should have the entire integument examined closely in good light. This should include a careful examination of the scalp and eyes. At least one of the more atypical-appearing dysplastic nevi should be subjected to excisional biopsy. The family history should be obtained with special attention given to such items as "moles," "skin conditions," "skin cancer," and melanoma.

Familial Screening

If the family history suggests melanoma, an effort should be made to examine all first-degree relatives. If a melanoma is found in any of these family members, all blood relatives should be examined to determine the extent of the risk of melanoma in the kindred.

Treatment and Followup

In patients with dysplastic nevi and any family history of melanoma, the indication for excising additional dysplastic nevi is the suspicion of early melanoma. In such lesions, the decision will be influenced by variation in color, size of the lesion relative to the patient's other nevi, or progression. Followup should be conducted every 3 to 6 months. In this and all instances where close followup of dysplastic nevi is indicated, photography may be helpful to document the appearance of lesions.

In patients with dysplastic nevi and no family history of melanoma, the risk of melanoma is uncertain. Extant lesions should be followed for evidence of progression.

Education

All patients with dysplastic nevi should be educated about their need for followup. They should be taught self-examination to detect changes in existing nevi and the emergence of new nevi. Finally, as with other people at risk for melanoma, they would be prudent to avoid excessive sun exposure and use sun screens.

Congenital Nevi

The management of congenital nevi depends primarily on their size and the perceived risk of development of melanoma. Large congenital nevi are rare, and their management is complex. The management of patients with large congenital nevi should be individualized to accommodate such factors as technical difficulty and cosmetic consequences of surgical removal as well as the risk of melanoma. Because of the unknown magnitude of the increased incidence of melanoma arising in other congenital nevi, a conservative management is recommended. The lesions should be periodically documented, measured, and observed for alterations of size, shape, color, and topography.

There are insufficient data at present to recommend prophylactic excision of all congenital nevi. Patients with congenital nevi should be examined periodically, initially by their parents, and then be taught self-examination. If an alteration in the nevus is detected, it should be evaluated by a physician and biopsied, if appropriate.  

What Directions Should Be Taken for Future Research on Precursor Lesions to Melanoma?

The paucity of existing information on precursors of melanoma coupled with the increasing incidence of melanoma suggests a need for more research. Epidemiological, clinical, and laboratory studies are required of populations known to be at increased risk for melanoma as well as of general populations.

Prospective studies are needed to collect data aimed at:

  1. Determining patterns of inheritance in melanoma.
  2. Improving the accuracy and reproducibility of diagnosis.
  3. Establishing the incidence and prevalence of melanoma associated with each specific precursor lesion.
  4. Describing the natural history of these precursors.
  5. Identifying other potential risk factors for melanoma.
  6. Quantifying the incidence, if any, of excess nonmelanocytic neoplasms in these patients.

 

Pilot studies should be initiated to evaluate the feasibility of and methodology for large-scale prospective studies. The feasibility and effectiveness of proposed interventions also should be determined.

Laboratory studies should be directed toward understanding how pigment cells in precursor lesions undergo transformation. Research efforts might include:

  1. The application of techniques in cell and organ cultures to characterize the pigment cells from various types of nevi.
  2. A search for specific markers of normal and transformed melanocytes.
  3. Identification of possible oncogenes for melanoma.
  4. An attempt to understand how melanocytes interact with both humoral and cellular immunologic processes.
  5. Studies of systemic abnormalities in patients with dysplastic nevus syndrome.

Consensus Development Panel

Ruth K. Freinkel, M.D.
(Chairperson)
Professor of Dermatology
Northwestern University Medical School
Chicago, Illinois
Gary W. Cage, M.D.
Practice of Dermatology
Bethesda, Maryland
William A. Caro, M.D.
Professor of Clinical Dermatology
Northwestern University Medical School
Chicago, Illinois
D. Martin Carter, M.D., Ph.D.
Professor and Senior Physician
The Rockefeller University
New York, New York
Philip Cole, M.D., Dr.P.H.
Professor of Epidemiology
University of Alabama, Birmingham
Birmingham, Alabama
Robert C. Elston, Ph.D.
Professor and Head
Department of Biometry
Louisiana State University Medical Center
New Orleans, Louisiana
Robert G. Freeman, M.D.
Clinical Professor
Department of Pathology and Dermatology
University of Texas Health Sciences Center at Dallas
Dallas, Texas
Hank C. George, FALU
Manager of Medical Services
Northwestern Mutual Life
Milwaukee, Wisconsin
Aaron B. Lerner, M.D., Ph.D.
Professor and Chairman
Department of Dermatology
Yale University School of Medicine
New Haven, Connecticut
Daniel K. Onion, M.D., M.P.H.
Deputy Director
Maine-Dartmouth Family Practice Residency
Augusta, Maine
Irene Pollin, M.S.W., L.C.S.W.
Private Practice
Chairman, Advisory Council
Medical Crisis Counseling Program
University of Maryland School of Social Work and Community Planning
Chevy Chase, Maryland
Thomas T. Provost, M.D.
Professor and Chairman
Department of Dermatology
Johns Hopkins University School of Medicine
Baltimore, Maryland
Maria L. Turner, M.D.
Associate Professor of Dermatology
George Washington University Medical School
Washington, D.C.
William C. Wood, M.D.
Director
Massachusetts General Hospital Cancer Center
Boston, Massachusetts

Speakers

A. Bernard Ackerman, M.D.
"Abstract for NIH
Consensus Development Conference on Precursors to Malignant Melanoma: Additional Questions"
Professor of Dermatology and Pathology
Director of Dermatopathology
New York University School of Medicine
New York, New York
Bruce Armstrong, M.B., B.S., Dr. Phil.
"Precursors to Malignant Melanoma: Considerations Regarding Future Epidemiological Research"
Director
Research Unit in Epidemiology
University Department of Medicine
Queen Elizabeth II Medical Center
Nedlands
AUSTRALIA
Wallace H. Clark, Jr., M.D.
"Clinical and Histologic Features of Dysplastic Nevi"
Research Professor of Dermatology and Pathology
University of Pennsylvania
Philadelphia, Pennsylvania
Ken Cooke, M.B., Ch.B., Ph.D.
"Epidemiological Considerations Regarding Precursors to Malignant Melanoma"
Department of Preventive and Social Medicine
University of Otago Medical School
Dunedin
NEW ZEALAND
David E. Elder, M.B., Ch.B., F.R.C.P.A.
"Nonfamilial Precursors to Melanoma"
Assistant Professor of Pathology
University of Pennsylvania
Department of Pathology
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania
William L. Epstein, M.D.
"Clinical Characteristics and Management of Dysplastic Nevi"
Professor and Chairman
Department of Dermatology
University of California, San Francisco
San Francisco, California
Thomas B. Fitzpatrick, M.D., Ph.D.
"Melanoma: Historical Overview and Trends"
Professor and Chairman
Department of Dermatology
Harvard Medical School
Chief of Dermatology Service
Massachusetts General Hospital
Boston, Massachusetts
Lynn From, M.D., F.R.C.P.(C)
"Congenital Nevi and Malignant Melanoma"
Pathologist-in-Chief
Assistant Professor
University of Toronto
Women's College Hospital
Toronto, Ontario
CANADA
Mark H. Greene, M.D.
"Precursors to Hereditary Melanoma: The Dysplastic Nevus Syndrome"
Senior Clinical Epidemiologist
Family Studies Section
National Cancer Institute
National Institutes of Health
Bethesda, Maryland
DuPont Guerry, IV, M.D.
"Melanoma Precursors: Followup, Family Screening, and Public Education"
Associate Professor of Medicine
Medical Director
University of Pennsylvania
Pigmented Lesion Clinic
Cancer Center
Department of Medicine
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania
John T. Headington, M.D.
"The Dysplastic Nevus"
Professor of Pathology and Dermatology
University of Michigan
Ann Arbor, Michigan
Alfred W. Kopf, M.D.
"The Dilemma of Congenital Nevocytic Nevi"
Clinical Professor of Dermatology
New York University School of Medicine
New York, New York
Kenneth H. Kraemer, M.D.
"Dysplastic Nevi-Melanoma Risk Assessment: Clinical and Laboratory Considerations"
Research Scientist
Laboratory of Molecular Carcinogenesis
National Cancer Institute
National Institutes of Health
Bethesda, Maryland
Henry T. Lynch, M.D.
"The Relationship Between Familial and Sporadic Precursors to Malignant Melanoma"
Professor and Chairman
Department of Preventive Medicine
Professor of Medicine
Creighton University
Omaha, Nebraska
Martin C. Mihm, Jr., M.D.
"The Clinical and Histopatholic Features and Future of the Dysplastic Nevus and Future Research Aspects"
Professor of Pathology
Harvard Medical School
Dermpath Unit
Massachusetts General Hospital
Boston, Massachusetts
Arthur R. Rhodes, M.D.
"The Causal Association Between Congenital Nevomelanocytic Nevi and Cutaneous Melanoma"
Assistant Professor of Dermatology
Harvard Medical School
Chief, Division of Dermatology
The Children's Hospital
Boston, Massachusetts
Richard W. Sagebiel, M.D.
"Re-examination of Relationships of Dysplastic (Disordered) Nevi to Malignant Melanoma and to Benign Melanocytic Nevi"
Professor of Pathology
Department of Pathology
University of California Medical School
San Francisco, California
Arthur J. Sober, M.D.
"Management of Dysplastic Nevi: Procedure of the Pigmented Lesion Clinic at the Massachusetts General Hospital"
Associate Professor of Dermatology
Harvard Medical School
Massachusetts General Hospital
Boston, Massachusetts

Planning Committee

Rosemary Yancik, Ph.D. (Chairperson)
Special Assistant for Program and Liaison Activities
Division of Resources, Centers, and Community Activities
National Cancer Institute
National Institutes of Health
Bethesda, Maryland
Ruth K. Freinkel, M.D.
Professor of Dermatology
Department of Dermatology
Northwestern University Medical School
Chicago, Illinois
Mark H. Greene, M.D.
Senior Clinical Epidemiologist
Family Studies Section
Division of Cancer Cause and Prevention
National Cancer Institute
National Institutes of Health
Bethesda, Maryland
John T. Headington, M.D.
Professor of Pathology and Dermatology
University of Michigan Medical School
Ann Arbor, Michigan
Stephen I. Katz, M.D.
Chief, Dermatology Branch
Division of Cancer Biology and Diagnosis
National Cancer Institute
National Institutes of Health
Bethesda, Maryland
Martin C. Mihm, Jr., M.D.
Professor of Pathology
Harvard Medical School
Dermpath Unit
Massachusetts General Hospital
Boston, Massachusetts
Fitzhugh Mullan, M.D.
Chief Medical Officer
Office of Medical Applications of Research
Office of the Director
National Institutes of Health
Bethesda, Maryland
Elliott H. Stonehill, Ph.D.
Assistant Director
National Cancer Institute
Office of Medical Applications for Cancer Research (OMACR)
National Institutes of Health
Bethesda, Maryland
Jerome W. Yates, M.D.
Associate Director
Centers and Community Oncology Program
Division of Resources, Centers, and Community Activities
National Cancer Institute
National Institutes of Health
Bethesda, Maryland

Conference Sponsors

National Cancer Institute
Vincent T. DeVita, Jr., M.D.
Director
Office of Medical Applications of Research
J. Richard Crout, M.D.
Director

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