Case 7-2004 — A 48-Year-Old Woman with Multiple Pigmented Lesions and a Personal and Family History of Melanoma
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《新英格兰医药杂志》
Presentation of Case
A 48-year-old woman was evaluated in the clinic because of multiple pigmented skin lesions and a personal and family history of melanoma.
When the patient was 30 years old, a superficial spreading melanoma, 0.34 mm in thickness and Clark level II, was found on the middle lower back. A chest radiograph showed no evidence of metastatic disease. The lesion was excised with a wide margin at another hospital and did not recur. When she was 32 years old, the patient came to the Pigmented Lesion Clinic at this hospital for evaluation as a patient at high risk for melanoma. She performed routine self-examinations of her skin, and physicians at the center examined her every six months. Over the ensuing 11 years, many pigmented lesions were removed; most were benign nevi, but several had features of dysplastic nevi.
At a routine visit when the patient was 43 years old, a papule, 2.5 mm in diameter with a dark center and irregular borders, was observed on the posterior surface of the left arm. Examination of a biopsy specimen obtained at another hospital suggested that the lesion was a superficial spreading melanoma, 0.45 mm in thickness and Clark level III or IV. On review of the slides at this hospital, a diagnosis of borderline spindle- and epithelioid-cell (Spitz) melanocytic tumor was made. The lesion was excised and did not recur. During the ensuing years the patient was lost to follow-up.
At the age of 48 years, the patient returned to the Pigmented Lesion Clinic. Her sister, her father, three paternal aunts, and one paternal uncle had all died from melanoma (Figure 1). She had three healthy children. She worked indoors but had had moderate recreational exposure to the sun in the past. She stated that she used a sunscreen when outdoors.
Figure 1. The Patient's Pedigree.
Yellow symbols indicate family members with melanoma, blue symbols family members without melanoma, circles female family members, squares male family members, and symbols with slashes deceased family members. The numbers below the symbols indicate the ages at which melanoma first developed. The arrow indicates the proband.
On physical examination in the clinic, she was observed to have a fair complexion, with more than 50 evenly dark, oval-to-round, pigmented macules, each less than 5 mm in diameter, as well as minimally elevated plaques. There were scattered freckles in sun-exposed areas, interpreted as a sign of mild-to-moderate sun exposure. The remainder of the physical examination revealed no abnormalities.
Pathological Discussion
Dr. Artur Zembowicz: Sixteen biopsy specimens of pigmented lesions from this patient that were obtained at another facility were reviewed at this hospital at various times. Of the 14 lesions that were junctional or dermal, 2 had histologic features typically associated with dysplastic nevi (Figure 2). Dysplastic nevi differ from typical acquired nevi in both their architectural and cytologic features. They are characterized by the presence of junctional nests (irregular nests of melanocytes at the dermoepidermal junction) extending laterally beyond the dermal component (a phenomenon known as a "shoulder"), fibroplasia of the papillary dermis with a patchy lymphocytic infiltrate, bridging of adjacent rete ridges by nests of melanocytes, and atypia of the melanocytes (known as lentiginous or epithelioid cytologic atypia). They have less severe cytologic atypia than do melanomas and have no superficial pagetoid spread, mitotic activity, or effacement of the dermoepidermal junction (all of which are features of melanoma).
Figure 2. Specimen of a Dysplastic Compound Nevus from the Patient's Back (Hematoxylin and Eosin, x100).
Features include junctional nests extending beyond dermal component as a lateral "shoulder," papillary dermal fibroplasia, bridging of adjacent rete ridges by junctional nests, and mild-to-moderate cytologic atypia of cells at the dermoepidermal junction, known as lentiginous cytologic atypia.
The diagnosis of superficial spreading melanoma was confirmed for the lesion that had been removed when the patient was 29 years old. The biopsy specimen of the lesion found on the arm when the patient was 43 was submitted to us for review, with a presumptive diagnosis of superficial spreading melanoma. It has many histologic features of a spindle- and epithelioid-cell (Spitz) nevus, including symmetry, sharp circumscription, and a mixture of spindle and epithelioid cells with ample amphophilic, glassy cytoplasm and large nuclei (Figure 3). However, the degree of cytologic atypia and pleomorphism exceeds that seen in the majority of Spitz nevi; in particular, some cells have a granular chromatin-staining pattern and eosinophilic macronuclei — findings that, when taken out of the context of the entire lesion, would be compatible with melanoma. Thus, the lesion was interpreted as a borderline melanocytic Spitz tumor with severe atypia, with uncertain biologic potential.
Figure 3. Specimen of a Lesion from the Posterior Surface of the Patient's Left Arm (Hematoxylin and Eosin).
At low magnification (Panel A, x40), the lesion appears to consist of a compound, well-circumscribed, wedge-shaped, symmetric melanocytic proliferation with an irregular pigmentation pattern. A patchy lymphocytic infiltrate is present at the periphery of the lesion. Higher magnification (Panel B, x200) shows oval-to-elongated junctional nests with a fascicular arrangement of cells resembling the "school of fish" pattern often seen in Spitz nevi. There is no upward migration of melanocytic nests ("pagetoid spread"). The cells vary in size. They have epithelioid and spindled shapes with abundant glassy, amphophilic cytoplasm. The nuclei are large and round to oval, with marked variations in size, shape, and chromatin-staining pattern. The nucleoli contain prominent eosinophilic macronucleoli and cytoplasmic pseudoinclusions. Some of the nuclei have bizarre shapes. Mitotic activity was not observed in multiple tissue sections examined.
Differential Diagnosis
Dr. Hensin Tsao: Our patient has multiple generalized, pigmented lesions and a personal and family history of melanoma. Conditions such as hers can be broadly classified according to the type of pigmented lesion and the degree of association with cutaneous melanoma.
Inherited Disorders Associated with Pigmented Lesions
Several inherited disorders are associated with pigmented skin lesions (Table 1). Although many of these syndromes are associated with developmental abnormalities or extracutaneous cancers, none of them have been linked to an increased risk of melanoma. They are therefore unlikely to represent the diagnosis in this case.
Table 1. Some Inherited Disorders Associated with Pigmented Skin Lesions.
Pigmented Lesions and Cutaneous Melanoma
Two disorders are characterized by multiple pigmented lesions and cutaneous melanoma: xeroderma pigmentosum and the familial atypical mole–melanoma (FAMM) syndrome. In xeroderma pigmentosum, defects in the repair of ultraviolet-radiation–induced DNA damage lead to the formation of thousands of sun-induced lentigines that carpet the skin and cause an increase in the risk of cutaneous melanoma by a factor of 600 to 8000.1,2 Patients with this disorder typically present within the first few years of life, and their first skin cancer usually develops before the age of 10 years. Our patient has multiple dysplastic melanocytic nevi rather than lentigines and an onset of melanocytic tumors in adulthood, and she does not have basal-cell or cutaneous squamous-cell carcinomas — skin cancers that commonly occur in xeroderma pigmentosum.
Familial Atypical Mole–Melanoma Syndrome
The literature is replete with terms that describe the association between multiple dysplastic nevi and melanoma. They include the B-K mole,3 familial atypical multiple mole–melanoma (FAMMM),4 dysplastic nevus,5 FAMM syndrome,6 and classic atypical-mole syndromes.7
Two findings unify these syndromes: first, the presence of atypical moles that have border and color variability on clinical examination and architectural disorder and cytologic atypia on histopathological assessment, giving rise to a diagnosis of dysplastic nevus; and second, a familial predisposition to cutaneous melanoma. From the earliest descriptions,3,4 it has been clear that there is considerable variability in the mole phenotype among kindreds and even among individual members of the same family.
Kraemer et al. separated the dysplastic-nevus phenotype from the melanoma phenotype and classified these kindreds into four types in an attempt to codify the phenotype and define the risk of melanoma (Table 2).8 However, assignment of families to a category required that all family members be examined. Furthermore, it is unclear how to account for differences in mole density within a family: some members have hundreds of moles, whereas others may have only a few or none. Most physicians would recognize the FAMM syndrome if a person presented, as our patient has, with large numbers of clinically atypical moles, pathologically proven dysplastic nevi, and a strong personal or family history of melanoma. However, the diagnosis would be less apparent in a person who had only a few atypical moles and reported a remote history of melanoma in the family.
Table 2. Classification of Kindreds with the Dysplastic-Nevus Syndrome.
A useful step is to move away from these syndromic labels and to consider the two essential features of our patient's history — atypical moles and melanoma — separately. The atypical-mole phenotype is usually described as a continuous, quantitative trait based on the number of lesions. In contrast, melanoma, like most cancers, is considered a dichotomous characteristic — that is, it is either present or absent, although highly susceptible persons may have multiple melanomas. Because our ability to understand complex, or quantitative, traits in molecular terms is limited, a full genetic explanation of the FAMM syndrome is still unavailable. However, important advances in our understanding of the melanoma component of the disorder have been made in the past decade.
Atypical Moles
Benign moles are characterized by symmetry, uniform pigmentation, and regular, sharp borders; atypical moles are defined by the absence of one or more of these features (Figure 4). The clinical distinction between atypical and benign moles is often difficult to make. Nevertheless, several population-based studies have found that up to 20 percent of healthy persons have at least 1 atypical mole9,10,11,12,13 and that 40 to 50 percent of persons with melanoma have at least 1 atypical mole, with a small fraction having more than 10 such lesions. Case–control studies of healthy persons and those with melanoma have revealed a direct relationship between the number of atypical moles and the risk of melanoma.9,10,11,12,13 In one study, the presence of a single, clinically identifiable, atypical mole increased the risk of cutaneous melanoma by a factor of 2.2.9
Figure 4. Benign and Atypical Moles in Other Patients.
The clinical appearance of benign and atypical moles may be difficult to correlate with the histologic pattern. Panel A shows a uniformly pigmented plaque with relatively sharp borders and symmetric features; on histologic examination, its features were typical of a junctional nevus. Panel B shows an atypical mole with irregular borders and focal pigmentation; this lesion was found to be a benign compound nevus. Panel C shows an irregularly shaped atypical mole with slight accentuation of pigment at the periphery; it was a lentiginous compound dysplastic nevus with moderate atypia. Panel D shows a relatively uniform, pink plaque with slightly irregular but sharply circumscribed borders; this lesion was a lentiginous compound dysplastic nevus with severe atypia. (Photographs courtesy of Dr. Richard A. Johnson.)
Some members of kindreds with the FAMM syndrome have hundreds of atypical moles whereas others, including those with melanoma, have few or no atypical moles. There are no specific physical or histologic features that distinguish sporadic atypical moles from those that arise in the familial setting. Furthermore, unlike pigmented lesions that emerge early, such as café au lait macules in neurofibromatosis, atypical moles in the FAMM syndrome develop over decades, and mole counts are thus time-dependent and potentially subject to environmental influences, such as sun exposure. For these reasons, clear-cut criteria to define the atypical-mole phenotype remain elusive.
Familial Melanoma
About 10 percent of patients with cutaneous melanoma report a family history of melanoma. Family history alone confers a twofold risk of development of the cancer.14 Familial melanomas can be divided into three groups: sporadic melanomas that cluster in families, familial melanomas that result from low-risk alleles, and familial melanomas that develop because of high-risk, highly penetrant alleles; this final group I will designate hereditary melanoma. In areas where melanoma is endemic, such as Australia, the occurrence of multiple sporadic cases of melanoma in a single family is not uncommon, because all members of the family share the risk factor of sun exposure. In these families, the trait can be scattered across the pedigree rather than involving one side of the family preferentially.
Low-risk alleles and environmental exposure may combine to increase the risk of melanoma in the general population and the density of melanoma in susceptible families. One such gene is the melanocortin 1 receptor gene (MC1R). Sequence variants in MC1R presumably compromise the response of melanocytes to melanocyte-stimulating hormone and, consequently, its ability to synthesize brown eumelanin. Persons with these variants have enhanced sun sensitivity, and their risk for the development of melanoma is two to four times that in persons without MC1R variants.15,16,17
True hereditary melanoma is rare (probably accounting for less than 1 percent of all melanomas). It is associated with high-risk, highly penetrant predisposing alleles and is characterized by a unilateral pattern of melanoma transmission within pedigrees, an early age at onset, and multiple primary tumors in individual persons. Our patient's pedigree (Figure 1) shows an impressive collection of seven melanomas, all on the paternal side of the family and all of which developed about 20 years before the typical mean age for the development of sporadic melanoma. The personal and familial history of melanoma points to a diagnosis of hereditary cancer; to me, this aspect of her disease, rather than the presence of atypical moles, is the real driving force behind her clinical diagnosis. Thus, my clinical diagnosis in this case is hereditary melanoma.
Genetic Basis of Hereditary Melanoma
Recent advances in genetics have enhanced our understanding of hereditary melanoma and can help to understand the diagnosis in our patient. Mutations in two genes — CDKN2A and CDK4 — are known to be involved in hereditary melanoma. Recently, linkage analysis of another group of melanoma-prone kindreds has led to the description of a possible candidate gene on chromosome 1p22.18
CDKN2A (Figure 5) was originally isolated in partial form as p16, a cell-cycle regulator that is frequently deleted and mutated in various cancer cell lines, especially melanoma cell lines.20 Demonstration of its role in hereditary melanoma came with the identification of germ-line CDKN2A mutations in melanoma-prone families that show evidence of linkage to markers on chromosome 9p21.21 At this time, CDKN2A is the gene most frequently identified as mutated in familial melanoma.
Figure 5. CDKN2A Structure and Function.
The CDKN2A gene is composed of four exons: 1, 1, 2, and 3 (Panel A). The p16 protein is a splice product of exons 1, 2, and 3 (green product), whereas p14ARF is a splice product of exons 1, 2, and 3 (yellow product). The p16 protein is an inhibitor of CDK4, which otherwise binds cyclin D and phosphorylates the retinoblastoma protein (pRB); in turn, phosphorylated pRB releases E2F transcription factors that promote the G1-to-S transition and the proliferation of melanocytes (brown cells). The p14ARF protein is an inhibitor of MDM2, which otherwise accelerates the destruction of p53. Loss of p53 denotes cell cycle checkpoint and disrupts the cell's ability to undergo apoptosis (gray cell). The loss of CDKN2A thus contributes to tumorigenesis by compromising both the pRB pathway and the p53 pathway. Phosphate groups are shown as red spheres. The current patient's p16 mutation is a 159 G-to-C transversion (asterisk) in exon 2 (Panel B). The p16 protein is 156 amino acids in length (Panel C); the contributions from exons 1, 2, and 3 are shown. The protein has four ankyrin domains (shown as alternating yellow and tan fragments). The blue lines represent the positions of mutations reported for kindreds with hereditary melanoma, and the height of each blue line represents the relative number of reported families with the given mutation.19 Many mutations occur in the second and third ankyrin repeats, which make critical contact points with CDK4. The mutation in the patient in the current case is shown as a red sphere at amino acid position 53; the mutation and its effect on p16 (Met53Ile) and p14ARF (Asp68His) are shown in the bottom half of the panel, where single-letter codes are used to designate amino acids.
The gene is small but complex. The p16 protein, which is a product of three exons (1, 2, and 3), prevents cyclin-dependent protein kinase 4/6 (CDK4/6) from phosphorylating to the retinoblastoma protein (pRB). Loss of p16 results in hyperphosphorylation of pRB, which in turn compels pRB to release its inhibitory grip on members of the E2F family of transcription factors. These transcription factors are then free to promote the transition from the G1 phase of the cell cycle to the S phase by inducing the requisite S-phase genes.
An alternative exon, 1, can be spliced to exon 2 to form p14ARF (where ARF denotes alternative reading frame). This arrangement allows two messenger RNA transcripts with a shared sequence to be translated in different reading frames, thus generating completely different proteins. The p14ARF inhibits the oncoprotein MDM2, which accelerates the destruction of p53. Loss of p14ARF thus decreases p53 levels by enhancing MDM2-mediated destabilization of p53. Thus, inactivation of a single locus affects two of the major pathways in cancer biology: the pRB pathway and the p53 pathway.
Most mutations of CDKN2A occur in exons 1 and 2 (Figure 5); to date, no deleterious mutations in exon 3 have been reported, although a recurrent intronic mutation 105 bp before exon 3 has been described.22 The frequency of the mutation starts at about 0.01 percent in the general population and increases to about 40 percent in some series of kindreds with hereditary melanoma, especially if they include families that have evidence of linkage to markers on chromosome 9p21. Among families within the Boston area for which we have determined the genotype, the prevalence of CDKN2A mutations is less than 10 percent among kindreds with two affected members and about 40 percent among kindreds, like our patient's family, with four or more affected members; these estimates are similar to those published by the Melanoma Genetics Consortium.23
Several melanoma-prone families have mutations in the p16-binding region of CDK4 that render the protein kinase resistant to p16 inhibition. These two events appear to be genetically reciprocal but phenotypically similar. A few families have also been shown to harbor mutations of CDKN2A exon 1, with the result that p14ARF is selectively disrupted; some of these families appear to be at increased risk for neural tumors.
On the basis of recent data from the Melanoma Genetics Consortium, the penetrance of CDKN2A mutations in the United States is estimated to be 0.5 by the age of 50 years and 0.76 by the age of 80 years.24 The geographic location appears to modify the penetrance: in areas with a higher population incidence of melanoma, such as Australia, the penetrance is higher. This variation suggests that penetrance may be influenced by sun exposure or that there may be differences in the effects of various mutations or modifier genes prevalent in geographically defined ethnic groups. With the identification of other, lower-risk modifier genes, such as MC1R, accurate risk assessment based on genotypic information is likely to become increasingly complex.16 In a mutation-positive family, a noncarrier's risk of melanoma is presumed to be lower than the risk in a carrier, but it is not known whether the noncarrier's risk is as low as the local population rate.
The relationship between CDKN2A and the atypical-mole phenotype is less clear. Kindreds with familial malignant melanoma typically have more members with atypical moles than members with melanoma.3 Hussussian et al. found that within nine families with mutations linked to chromosome 9p21, 33 of 36 persons with melanoma had CDKN2A mutations, and 10 of 33 persons with only dysplastic nevi had mutations.21 Thus, mutations clearly segregate with melanoma but not with atypical moles. It is likely that other genes contribute to the atypical-mole phenotype.
Because of the wide range of penetrance, the possibility of additional high-risk and low-risk genes, and the uncertain medical benefit of the genetic information, the Melanoma Genetics Consortium does not currently recommend testing for CDKN2A mutations outside of defined research protocols.23,25 Our patient declined to participate in our melanoma-genetics research protocol but wanted to pursue formal genetic testing through a commercial laboratory. We referred her to our genetic counselor, who will now discuss the general approach to the management of hereditary cancer and its application to this case.
Genetic Counseling and the Role of Genetic Testing
Ms. Kristin Baker Niendorf: Genetic counseling pertaining to the risk of hereditary cancer consists of educating the patient to permit him or her to make informed decisions. Our patient was first given basic information about the causes of cancer, including melanoma, and the principles of genetics and inheritance. A detailed pedigree was constructed, and the patient was told that there was an increased risk of a hereditary melanoma syndrome in her family. With this background, we discussed the advantages and disadvantages of clinical genetic testing for CDKN2A mutations.
The patient was counseled about the limited value of clinical testing for CDKN2A mutations with respect to her own care, since she should continue melanoma-prevention and melanoma-screening measures regardless of the results. We also discussed the potential emotional effects, both positive and negative, including effects on family and other social relationships. The patient suggested that the genetic information might influence family members to participate in melanoma screening and believed that this would be a possible benefit. We addressed the potential effect of genetic testing on health insurance and employment. At this time, there is little documented use by health insurance underwriters of the results of genetic testing for predisposition to hereditary cancer syndromes.26
We also discussed the potential results of testing, including the following points: first, the absence of any CDKN2A sequence variants does not rule out a hereditary predisposition to melanoma, since other genes may be involved; second, even if a deleterious mutation were detected, predicting the onset and severity of disease in an individual carrier of the mutation is not possible; and third, it can be difficult in some cases to determine whether a detected mutation in CDKN2A is deleterious. After discussion of these issues, the patient still elected to proceed with genetic testing.
Dr. Tsao: Since p16 is a small gene, most laboratories perform direct sequencing of its exons. Our patient indeed had a G-to-C transversion, altering the canonical methionine to an isoleucine at position 53 (Figure 5). Since this mutation occurs in the second exon, the p14ARF sequence of amino acids is also altered, with the replacement of an aspartate by a histidine. We believe that the Met53Ile alteration is a bona fide disease-causing mutation, since it has been reported to be a recurrent founder mutation worldwide and is known to disrupt binding between p16 and CDK4 in functional assays.27
Discussion of Management
There are currently no specific guidelines for the care of carriers of CDKN2A mutations beyond those that are recommended for persons with the FAMM syndrome — that is, routine mole surveillance, strict avoidance of excessive exposure to sunlight, and use of sunscreens. Dr. Sober, would you discuss the possible role of genetic testing in the care of this patient and of patients like her in the future?
Dr. Arthur J. Sober: Genetic testing is well established for risk assessment with respect to certain medical disorders for which interventions can prevent disease or its complications.28 The role of genetic testing in melanoma is much less clear. Although the Melanoma Genetics Consortium has recommended against genetic testing as a clinical practice at this time,23,25 patients may request the test from their practitioners, since it is commercially available.
The question for the clinician is as follows: Would knowing whether a person has a genetic abnormality that confers an increased risk of melanoma affect the care of either that person or his or her family? On the basis of currently available information, I would consider recommending genetic testing to carefully chosen patients with melanoma who have two or more family members with cutaneous melanoma29,30 or to those who have had more than two primary melanomas, even if their family history is not known.27 Appropriate genetic counseling is a prerequisite in either situation. If a genetic abnormality is identified, it might prompt an increase in the frequency of cutaneous surveillance for melanoma or lower the threshold for removal rather than clinical follow-up of a borderline suspicious clinical lesion. Thus, identifying persons with mutations provides an opportunity to tailor surveillance and prevention practices. Since the patient in the current case has already had a melanoma, all preventive efforts would be aimed at reducing the risk of another highly invasive melanoma. This is particularly important because patients with CDKN2A mutations may be at greater risk than the general population of patients with melanoma for multiple primary melanomas.
Dr. Tsao: Dr. Zembowicz, as a pathologist, would you lower your threshold for diagnosing a melanoma in a patient with a known germ-line CDKN2A mutation? More specifically, would you now be more likely to consider the possibility of a Spitzoid melanoma in our patient rather than an atypical Spitz tumor?
Dr. Zembowicz: I would not. It is important to distinguish between the well-established effect of the germ-line mutation in CDKN2A on this patient's increased lifetime risk of melanoma and its implications for the classification of her pigmented lesions. The prevalence and prognostic significance of CDKN2A mutations in Spitz tumors are unknown. To use the genetic information, we would have to compare the clinical behavior of atypical Spitz tumors associated with germ-line CDKN2A mutations with the behavior of those not associated with such mutations. Until more data are available, we have to rely on morphologic criteria.
Dr. Tsao: Before genetic testing, the patient and her children had been lost to follow-up, despite our recommendations for strict surveillance. Currently, the patient has returned to a routine schedule of at least two skin checks per year. Two of her children, who are both less than 20 years of age, have been examined, and both of them have clinically atypical moles. However, since the atypical-mole phenotype is so variable even within a family, the phenotype alone does not allow us to predict their carrier status with any accuracy.31 Thus, both children are enrolled in rigorous surveillance programs at this hospital. As we learn more about the CDKN2A gene and its penetrance, we may be able to inform the children with more accuracy of their individual, rather than collective, risks.
A Physician: Is the patient's surviving sibling going to be tested?
Dr. Tsao: We do not approach siblings directly. We have left it up to the patient to share her genetic information, as she sees fit, with her family. We have counseled her about the risks to various members of her family.
Diagnosis
Hereditary melanoma with a deleterious CDKN2A mutation.
Source Information
From the Wellman Center for Photomedicine (H.T.), the Pigmented Lesion Clinic and the Department of Dermatology (H.T., A.J.S.), the Center for Cancer Risk Analysis (H.T., K.B.N.), and the Dermatopathology Unit, Department of Pathology (A.Z.), Massachusetts General Hospital; and the Departments of Dermatology (H.T., A.J.S.) and Pathology (A.Z.), Harvard Medical School.
References
Kraemer KH, Lee MM, Scotto J. Xeroderma pigmentosum: cutaneous, ocular, and neurologic abnormalities in 830 published cases. Arch Dermatol 1987;123:241-250.
Kraemer KH, Lee MM, Andrews AD, Lambert WC. The role of sunlight and DNA repair in melanoma and nonmelanoma skin cancer: the xeroderma pigmentosum paradigm. Arch Dermatol 1994;130:1018-1021.
Clark WH Jr, Reimer RR, Greene M, Ainsworth AM, Mastrangelo MJ. Origin of familial malignant melanomas from heritable melanocytic lesions: `the B-K mole syndrome.' Arch Dermatol 1978;114:723-728.
Lynch HT, Frichot BC III, Lynch JF. Familial atypical multiple mole-melanoma syndrome. J Med Genet 1978;15:352-356.
Elder DE, Green MH, Guerry D IV, Kraemer KH, Clark WH Jr. The dysplastic nevus syndrome: our definition. Am J Dermatopathol 1982;4:455-460.
NIH Consensus Development Panel on Early Melanoma. Diagnosis and treatment of early melanoma. JAMA 1992;268:1314-1319.
Kopf AW, Friedman RJ, Rigel DS. Atypical mole syndrome. J Am Acad Dermatol 1990;22:117-118.
Kraemer KH, Greene MH, Tarone R, Elder DE, Clark WH Jr, Guerry D IV. Dysplastic naevi and cutaneous melanoma risk. Lancet 1983;2:1076-1077.
Tucker MA, Halpern A, Holly EA, et al. Clinically recognized dysplastic nevi: a central risk factor for cutaneous melanoma. JAMA 1997;277:1439-1444.
Garbe C, Kruger S, Stadler R, Guggenmoos-Holzmann I, Orfanos CE. Markers and relative risk in a German population for developing malignant melanoma. Int J Dermatol 1989;28:517-523.
Garbe C, Buttner P, Weiss J, et al. Risk factors for developing cutaneous melanoma and criteria for identifying persons at risk: multicenter case-control study of the Central Malignant Melanoma Registry of the German Dermatological Society. J Invest Dermatol 1994;102:695-699.
Grob JJ, Gouvernet J, Aymar D, et al. Count of benign melanocytic nevi as a major indicator of risk for nonfamilial nodular and superficial spreading melanoma. Cancer 1990;66:387-395.
Halpern AC, Guerry D IV, Elder DE, et al. Dysplastic nevi as risk markers of sporadic (nonfamilial) melanoma: a case-control study. Arch Dermatol 1991;127:995-999.
Ford D, Bliss JM, Swerdlow AJ, et al. Risk of cutaneous melanoma associated with a family history of the disease. Int J Cancer 1995;62:377-381.
Kennedy C, ter Huurne J, Berkhout M, et al. Melanocortin 1 receptor (MC1R) gene variants are associated with an increased risk for cutaneous melanoma which is largely independent of skin type and hair color. J Invest Dermatol 2001;117:294-300.
Box NF, Duffy DL, Chen W, et al. MC1R genotype modifies risk of melanoma in families segregating CDKN2A mutations. Am J Hum Genet 2001;69:765-773.
Valverde P, Healy E, Sikkink S, et al. The Asp84Glu variant of the melanocortin 1 receptor (MC1R) is associated with melanoma. Hum Mol Genet 1996;5:1663-1666.
Gillanders E, Hank Juo SH, Holland EA, et al. Localization of a novel melanoma susceptibility locus to 1p22. Am J Hum Genet 2003;73:301-313.
Piepkorn M. Melanoma genetics: an update with focus on the CDKN2A(p16)/ARF tumor suppressors. J Am Acad Dermatol 2000;42:705-726.
Kamb A, Gruis NA, Weaver-Feldhaus J, et al. A cell cycle regulator potentially involved in genesis of many tumor types. Science 1994;264:436-440.
Hussussian CJ, Struewing JP, Goldstein AM, et al. Germline p16 mutations in familial melanoma. Nat Genet 1994;8:15-21.
Harland M, Mistry S, Bishop DT, Bishop JA. A deep intronic mutation in CDKN2A is associated with disease in a subset of melanoma pedigrees. Hum Mol Genet 2001;10:2679-2686.
Kefford RF, Newton Bishop JA, Bergman W, Tucker MA. Counseling and DNA testing for individuals perceived to be genetically predisposed to melanoma: a consensus statement of the Melanoma Genetics Consortium. J Clin Oncol 1999;17:3245-3251.
Bishop DT, Demenais F, Goldstein AM, et al. Geographical variation in the penetrance of CDKN2A mutations for melanoma. J Natl Cancer Inst 2002;94:894-903.
Kefford R, Bishop JN, Tucker M, et al. Genetic testing for melanoma. Lancet Oncol 2002;3:653-654.
Hall MA, Rich SS. Laws restricting health insurers' use of genetic information: impact on genetic discrimination. Am J Hum Genet 2000;66:293-307.
Monzon J, Liu L, Brill H, et al. CDKN2A mutations in multiple primary melanomas. N Engl J Med 1998;338:879-887.
Burke W. Genetic testing. N Engl J Med 2002;347:1867-1875.
Goldstein AM, Tucker MA. Screening for CDKN2A mutations in hereditary melanoma. J Natl Cancer Inst 1997;89:676-678.
Holland EA, Schmid H, Kefford RF, Mann GJ. CDKN2A (P16(INK4a)) and CDK4 mutation analysis in 131 Australian melanoma probands: effect of family history and multiple primary melanomas. Genes Chromosomes Cancer 1999;25:339-348.
Wachsmuth RC, Gaut RM, Barrett JH, et al. Heritability and gene-environment interactions for melanocytic nevus density examined in a U.K. adolescent twin study. J Invest Dermatol 2001;117:348-352.
Related Letters:
Case 7-2004: Hereditary Melanoma and Pancreatic Cancer
Koopmann J., Goggins M., Hruban R. H., Tsao H., Sober A. J., Niendorf K. B.(Hensin Tsao, M.D., Ph.D.,)
A 48-year-old woman was evaluated in the clinic because of multiple pigmented skin lesions and a personal and family history of melanoma.
When the patient was 30 years old, a superficial spreading melanoma, 0.34 mm in thickness and Clark level II, was found on the middle lower back. A chest radiograph showed no evidence of metastatic disease. The lesion was excised with a wide margin at another hospital and did not recur. When she was 32 years old, the patient came to the Pigmented Lesion Clinic at this hospital for evaluation as a patient at high risk for melanoma. She performed routine self-examinations of her skin, and physicians at the center examined her every six months. Over the ensuing 11 years, many pigmented lesions were removed; most were benign nevi, but several had features of dysplastic nevi.
At a routine visit when the patient was 43 years old, a papule, 2.5 mm in diameter with a dark center and irregular borders, was observed on the posterior surface of the left arm. Examination of a biopsy specimen obtained at another hospital suggested that the lesion was a superficial spreading melanoma, 0.45 mm in thickness and Clark level III or IV. On review of the slides at this hospital, a diagnosis of borderline spindle- and epithelioid-cell (Spitz) melanocytic tumor was made. The lesion was excised and did not recur. During the ensuing years the patient was lost to follow-up.
At the age of 48 years, the patient returned to the Pigmented Lesion Clinic. Her sister, her father, three paternal aunts, and one paternal uncle had all died from melanoma (Figure 1). She had three healthy children. She worked indoors but had had moderate recreational exposure to the sun in the past. She stated that she used a sunscreen when outdoors.
Figure 1. The Patient's Pedigree.
Yellow symbols indicate family members with melanoma, blue symbols family members without melanoma, circles female family members, squares male family members, and symbols with slashes deceased family members. The numbers below the symbols indicate the ages at which melanoma first developed. The arrow indicates the proband.
On physical examination in the clinic, she was observed to have a fair complexion, with more than 50 evenly dark, oval-to-round, pigmented macules, each less than 5 mm in diameter, as well as minimally elevated plaques. There were scattered freckles in sun-exposed areas, interpreted as a sign of mild-to-moderate sun exposure. The remainder of the physical examination revealed no abnormalities.
Pathological Discussion
Dr. Artur Zembowicz: Sixteen biopsy specimens of pigmented lesions from this patient that were obtained at another facility were reviewed at this hospital at various times. Of the 14 lesions that were junctional or dermal, 2 had histologic features typically associated with dysplastic nevi (Figure 2). Dysplastic nevi differ from typical acquired nevi in both their architectural and cytologic features. They are characterized by the presence of junctional nests (irregular nests of melanocytes at the dermoepidermal junction) extending laterally beyond the dermal component (a phenomenon known as a "shoulder"), fibroplasia of the papillary dermis with a patchy lymphocytic infiltrate, bridging of adjacent rete ridges by nests of melanocytes, and atypia of the melanocytes (known as lentiginous or epithelioid cytologic atypia). They have less severe cytologic atypia than do melanomas and have no superficial pagetoid spread, mitotic activity, or effacement of the dermoepidermal junction (all of which are features of melanoma).
Figure 2. Specimen of a Dysplastic Compound Nevus from the Patient's Back (Hematoxylin and Eosin, x100).
Features include junctional nests extending beyond dermal component as a lateral "shoulder," papillary dermal fibroplasia, bridging of adjacent rete ridges by junctional nests, and mild-to-moderate cytologic atypia of cells at the dermoepidermal junction, known as lentiginous cytologic atypia.
The diagnosis of superficial spreading melanoma was confirmed for the lesion that had been removed when the patient was 29 years old. The biopsy specimen of the lesion found on the arm when the patient was 43 was submitted to us for review, with a presumptive diagnosis of superficial spreading melanoma. It has many histologic features of a spindle- and epithelioid-cell (Spitz) nevus, including symmetry, sharp circumscription, and a mixture of spindle and epithelioid cells with ample amphophilic, glassy cytoplasm and large nuclei (Figure 3). However, the degree of cytologic atypia and pleomorphism exceeds that seen in the majority of Spitz nevi; in particular, some cells have a granular chromatin-staining pattern and eosinophilic macronuclei — findings that, when taken out of the context of the entire lesion, would be compatible with melanoma. Thus, the lesion was interpreted as a borderline melanocytic Spitz tumor with severe atypia, with uncertain biologic potential.
Figure 3. Specimen of a Lesion from the Posterior Surface of the Patient's Left Arm (Hematoxylin and Eosin).
At low magnification (Panel A, x40), the lesion appears to consist of a compound, well-circumscribed, wedge-shaped, symmetric melanocytic proliferation with an irregular pigmentation pattern. A patchy lymphocytic infiltrate is present at the periphery of the lesion. Higher magnification (Panel B, x200) shows oval-to-elongated junctional nests with a fascicular arrangement of cells resembling the "school of fish" pattern often seen in Spitz nevi. There is no upward migration of melanocytic nests ("pagetoid spread"). The cells vary in size. They have epithelioid and spindled shapes with abundant glassy, amphophilic cytoplasm. The nuclei are large and round to oval, with marked variations in size, shape, and chromatin-staining pattern. The nucleoli contain prominent eosinophilic macronucleoli and cytoplasmic pseudoinclusions. Some of the nuclei have bizarre shapes. Mitotic activity was not observed in multiple tissue sections examined.
Differential Diagnosis
Dr. Hensin Tsao: Our patient has multiple generalized, pigmented lesions and a personal and family history of melanoma. Conditions such as hers can be broadly classified according to the type of pigmented lesion and the degree of association with cutaneous melanoma.
Inherited Disorders Associated with Pigmented Lesions
Several inherited disorders are associated with pigmented skin lesions (Table 1). Although many of these syndromes are associated with developmental abnormalities or extracutaneous cancers, none of them have been linked to an increased risk of melanoma. They are therefore unlikely to represent the diagnosis in this case.
Table 1. Some Inherited Disorders Associated with Pigmented Skin Lesions.
Pigmented Lesions and Cutaneous Melanoma
Two disorders are characterized by multiple pigmented lesions and cutaneous melanoma: xeroderma pigmentosum and the familial atypical mole–melanoma (FAMM) syndrome. In xeroderma pigmentosum, defects in the repair of ultraviolet-radiation–induced DNA damage lead to the formation of thousands of sun-induced lentigines that carpet the skin and cause an increase in the risk of cutaneous melanoma by a factor of 600 to 8000.1,2 Patients with this disorder typically present within the first few years of life, and their first skin cancer usually develops before the age of 10 years. Our patient has multiple dysplastic melanocytic nevi rather than lentigines and an onset of melanocytic tumors in adulthood, and she does not have basal-cell or cutaneous squamous-cell carcinomas — skin cancers that commonly occur in xeroderma pigmentosum.
Familial Atypical Mole–Melanoma Syndrome
The literature is replete with terms that describe the association between multiple dysplastic nevi and melanoma. They include the B-K mole,3 familial atypical multiple mole–melanoma (FAMMM),4 dysplastic nevus,5 FAMM syndrome,6 and classic atypical-mole syndromes.7
Two findings unify these syndromes: first, the presence of atypical moles that have border and color variability on clinical examination and architectural disorder and cytologic atypia on histopathological assessment, giving rise to a diagnosis of dysplastic nevus; and second, a familial predisposition to cutaneous melanoma. From the earliest descriptions,3,4 it has been clear that there is considerable variability in the mole phenotype among kindreds and even among individual members of the same family.
Kraemer et al. separated the dysplastic-nevus phenotype from the melanoma phenotype and classified these kindreds into four types in an attempt to codify the phenotype and define the risk of melanoma (Table 2).8 However, assignment of families to a category required that all family members be examined. Furthermore, it is unclear how to account for differences in mole density within a family: some members have hundreds of moles, whereas others may have only a few or none. Most physicians would recognize the FAMM syndrome if a person presented, as our patient has, with large numbers of clinically atypical moles, pathologically proven dysplastic nevi, and a strong personal or family history of melanoma. However, the diagnosis would be less apparent in a person who had only a few atypical moles and reported a remote history of melanoma in the family.
Table 2. Classification of Kindreds with the Dysplastic-Nevus Syndrome.
A useful step is to move away from these syndromic labels and to consider the two essential features of our patient's history — atypical moles and melanoma — separately. The atypical-mole phenotype is usually described as a continuous, quantitative trait based on the number of lesions. In contrast, melanoma, like most cancers, is considered a dichotomous characteristic — that is, it is either present or absent, although highly susceptible persons may have multiple melanomas. Because our ability to understand complex, or quantitative, traits in molecular terms is limited, a full genetic explanation of the FAMM syndrome is still unavailable. However, important advances in our understanding of the melanoma component of the disorder have been made in the past decade.
Atypical Moles
Benign moles are characterized by symmetry, uniform pigmentation, and regular, sharp borders; atypical moles are defined by the absence of one or more of these features (Figure 4). The clinical distinction between atypical and benign moles is often difficult to make. Nevertheless, several population-based studies have found that up to 20 percent of healthy persons have at least 1 atypical mole9,10,11,12,13 and that 40 to 50 percent of persons with melanoma have at least 1 atypical mole, with a small fraction having more than 10 such lesions. Case–control studies of healthy persons and those with melanoma have revealed a direct relationship between the number of atypical moles and the risk of melanoma.9,10,11,12,13 In one study, the presence of a single, clinically identifiable, atypical mole increased the risk of cutaneous melanoma by a factor of 2.2.9
Figure 4. Benign and Atypical Moles in Other Patients.
The clinical appearance of benign and atypical moles may be difficult to correlate with the histologic pattern. Panel A shows a uniformly pigmented plaque with relatively sharp borders and symmetric features; on histologic examination, its features were typical of a junctional nevus. Panel B shows an atypical mole with irregular borders and focal pigmentation; this lesion was found to be a benign compound nevus. Panel C shows an irregularly shaped atypical mole with slight accentuation of pigment at the periphery; it was a lentiginous compound dysplastic nevus with moderate atypia. Panel D shows a relatively uniform, pink plaque with slightly irregular but sharply circumscribed borders; this lesion was a lentiginous compound dysplastic nevus with severe atypia. (Photographs courtesy of Dr. Richard A. Johnson.)
Some members of kindreds with the FAMM syndrome have hundreds of atypical moles whereas others, including those with melanoma, have few or no atypical moles. There are no specific physical or histologic features that distinguish sporadic atypical moles from those that arise in the familial setting. Furthermore, unlike pigmented lesions that emerge early, such as café au lait macules in neurofibromatosis, atypical moles in the FAMM syndrome develop over decades, and mole counts are thus time-dependent and potentially subject to environmental influences, such as sun exposure. For these reasons, clear-cut criteria to define the atypical-mole phenotype remain elusive.
Familial Melanoma
About 10 percent of patients with cutaneous melanoma report a family history of melanoma. Family history alone confers a twofold risk of development of the cancer.14 Familial melanomas can be divided into three groups: sporadic melanomas that cluster in families, familial melanomas that result from low-risk alleles, and familial melanomas that develop because of high-risk, highly penetrant alleles; this final group I will designate hereditary melanoma. In areas where melanoma is endemic, such as Australia, the occurrence of multiple sporadic cases of melanoma in a single family is not uncommon, because all members of the family share the risk factor of sun exposure. In these families, the trait can be scattered across the pedigree rather than involving one side of the family preferentially.
Low-risk alleles and environmental exposure may combine to increase the risk of melanoma in the general population and the density of melanoma in susceptible families. One such gene is the melanocortin 1 receptor gene (MC1R). Sequence variants in MC1R presumably compromise the response of melanocytes to melanocyte-stimulating hormone and, consequently, its ability to synthesize brown eumelanin. Persons with these variants have enhanced sun sensitivity, and their risk for the development of melanoma is two to four times that in persons without MC1R variants.15,16,17
True hereditary melanoma is rare (probably accounting for less than 1 percent of all melanomas). It is associated with high-risk, highly penetrant predisposing alleles and is characterized by a unilateral pattern of melanoma transmission within pedigrees, an early age at onset, and multiple primary tumors in individual persons. Our patient's pedigree (Figure 1) shows an impressive collection of seven melanomas, all on the paternal side of the family and all of which developed about 20 years before the typical mean age for the development of sporadic melanoma. The personal and familial history of melanoma points to a diagnosis of hereditary cancer; to me, this aspect of her disease, rather than the presence of atypical moles, is the real driving force behind her clinical diagnosis. Thus, my clinical diagnosis in this case is hereditary melanoma.
Genetic Basis of Hereditary Melanoma
Recent advances in genetics have enhanced our understanding of hereditary melanoma and can help to understand the diagnosis in our patient. Mutations in two genes — CDKN2A and CDK4 — are known to be involved in hereditary melanoma. Recently, linkage analysis of another group of melanoma-prone kindreds has led to the description of a possible candidate gene on chromosome 1p22.18
CDKN2A (Figure 5) was originally isolated in partial form as p16, a cell-cycle regulator that is frequently deleted and mutated in various cancer cell lines, especially melanoma cell lines.20 Demonstration of its role in hereditary melanoma came with the identification of germ-line CDKN2A mutations in melanoma-prone families that show evidence of linkage to markers on chromosome 9p21.21 At this time, CDKN2A is the gene most frequently identified as mutated in familial melanoma.
Figure 5. CDKN2A Structure and Function.
The CDKN2A gene is composed of four exons: 1, 1, 2, and 3 (Panel A). The p16 protein is a splice product of exons 1, 2, and 3 (green product), whereas p14ARF is a splice product of exons 1, 2, and 3 (yellow product). The p16 protein is an inhibitor of CDK4, which otherwise binds cyclin D and phosphorylates the retinoblastoma protein (pRB); in turn, phosphorylated pRB releases E2F transcription factors that promote the G1-to-S transition and the proliferation of melanocytes (brown cells). The p14ARF protein is an inhibitor of MDM2, which otherwise accelerates the destruction of p53. Loss of p53 denotes cell cycle checkpoint and disrupts the cell's ability to undergo apoptosis (gray cell). The loss of CDKN2A thus contributes to tumorigenesis by compromising both the pRB pathway and the p53 pathway. Phosphate groups are shown as red spheres. The current patient's p16 mutation is a 159 G-to-C transversion (asterisk) in exon 2 (Panel B). The p16 protein is 156 amino acids in length (Panel C); the contributions from exons 1, 2, and 3 are shown. The protein has four ankyrin domains (shown as alternating yellow and tan fragments). The blue lines represent the positions of mutations reported for kindreds with hereditary melanoma, and the height of each blue line represents the relative number of reported families with the given mutation.19 Many mutations occur in the second and third ankyrin repeats, which make critical contact points with CDK4. The mutation in the patient in the current case is shown as a red sphere at amino acid position 53; the mutation and its effect on p16 (Met53Ile) and p14ARF (Asp68His) are shown in the bottom half of the panel, where single-letter codes are used to designate amino acids.
The gene is small but complex. The p16 protein, which is a product of three exons (1, 2, and 3), prevents cyclin-dependent protein kinase 4/6 (CDK4/6) from phosphorylating to the retinoblastoma protein (pRB). Loss of p16 results in hyperphosphorylation of pRB, which in turn compels pRB to release its inhibitory grip on members of the E2F family of transcription factors. These transcription factors are then free to promote the transition from the G1 phase of the cell cycle to the S phase by inducing the requisite S-phase genes.
An alternative exon, 1, can be spliced to exon 2 to form p14ARF (where ARF denotes alternative reading frame). This arrangement allows two messenger RNA transcripts with a shared sequence to be translated in different reading frames, thus generating completely different proteins. The p14ARF inhibits the oncoprotein MDM2, which accelerates the destruction of p53. Loss of p14ARF thus decreases p53 levels by enhancing MDM2-mediated destabilization of p53. Thus, inactivation of a single locus affects two of the major pathways in cancer biology: the pRB pathway and the p53 pathway.
Most mutations of CDKN2A occur in exons 1 and 2 (Figure 5); to date, no deleterious mutations in exon 3 have been reported, although a recurrent intronic mutation 105 bp before exon 3 has been described.22 The frequency of the mutation starts at about 0.01 percent in the general population and increases to about 40 percent in some series of kindreds with hereditary melanoma, especially if they include families that have evidence of linkage to markers on chromosome 9p21. Among families within the Boston area for which we have determined the genotype, the prevalence of CDKN2A mutations is less than 10 percent among kindreds with two affected members and about 40 percent among kindreds, like our patient's family, with four or more affected members; these estimates are similar to those published by the Melanoma Genetics Consortium.23
Several melanoma-prone families have mutations in the p16-binding region of CDK4 that render the protein kinase resistant to p16 inhibition. These two events appear to be genetically reciprocal but phenotypically similar. A few families have also been shown to harbor mutations of CDKN2A exon 1, with the result that p14ARF is selectively disrupted; some of these families appear to be at increased risk for neural tumors.
On the basis of recent data from the Melanoma Genetics Consortium, the penetrance of CDKN2A mutations in the United States is estimated to be 0.5 by the age of 50 years and 0.76 by the age of 80 years.24 The geographic location appears to modify the penetrance: in areas with a higher population incidence of melanoma, such as Australia, the penetrance is higher. This variation suggests that penetrance may be influenced by sun exposure or that there may be differences in the effects of various mutations or modifier genes prevalent in geographically defined ethnic groups. With the identification of other, lower-risk modifier genes, such as MC1R, accurate risk assessment based on genotypic information is likely to become increasingly complex.16 In a mutation-positive family, a noncarrier's risk of melanoma is presumed to be lower than the risk in a carrier, but it is not known whether the noncarrier's risk is as low as the local population rate.
The relationship between CDKN2A and the atypical-mole phenotype is less clear. Kindreds with familial malignant melanoma typically have more members with atypical moles than members with melanoma.3 Hussussian et al. found that within nine families with mutations linked to chromosome 9p21, 33 of 36 persons with melanoma had CDKN2A mutations, and 10 of 33 persons with only dysplastic nevi had mutations.21 Thus, mutations clearly segregate with melanoma but not with atypical moles. It is likely that other genes contribute to the atypical-mole phenotype.
Because of the wide range of penetrance, the possibility of additional high-risk and low-risk genes, and the uncertain medical benefit of the genetic information, the Melanoma Genetics Consortium does not currently recommend testing for CDKN2A mutations outside of defined research protocols.23,25 Our patient declined to participate in our melanoma-genetics research protocol but wanted to pursue formal genetic testing through a commercial laboratory. We referred her to our genetic counselor, who will now discuss the general approach to the management of hereditary cancer and its application to this case.
Genetic Counseling and the Role of Genetic Testing
Ms. Kristin Baker Niendorf: Genetic counseling pertaining to the risk of hereditary cancer consists of educating the patient to permit him or her to make informed decisions. Our patient was first given basic information about the causes of cancer, including melanoma, and the principles of genetics and inheritance. A detailed pedigree was constructed, and the patient was told that there was an increased risk of a hereditary melanoma syndrome in her family. With this background, we discussed the advantages and disadvantages of clinical genetic testing for CDKN2A mutations.
The patient was counseled about the limited value of clinical testing for CDKN2A mutations with respect to her own care, since she should continue melanoma-prevention and melanoma-screening measures regardless of the results. We also discussed the potential emotional effects, both positive and negative, including effects on family and other social relationships. The patient suggested that the genetic information might influence family members to participate in melanoma screening and believed that this would be a possible benefit. We addressed the potential effect of genetic testing on health insurance and employment. At this time, there is little documented use by health insurance underwriters of the results of genetic testing for predisposition to hereditary cancer syndromes.26
We also discussed the potential results of testing, including the following points: first, the absence of any CDKN2A sequence variants does not rule out a hereditary predisposition to melanoma, since other genes may be involved; second, even if a deleterious mutation were detected, predicting the onset and severity of disease in an individual carrier of the mutation is not possible; and third, it can be difficult in some cases to determine whether a detected mutation in CDKN2A is deleterious. After discussion of these issues, the patient still elected to proceed with genetic testing.
Dr. Tsao: Since p16 is a small gene, most laboratories perform direct sequencing of its exons. Our patient indeed had a G-to-C transversion, altering the canonical methionine to an isoleucine at position 53 (Figure 5). Since this mutation occurs in the second exon, the p14ARF sequence of amino acids is also altered, with the replacement of an aspartate by a histidine. We believe that the Met53Ile alteration is a bona fide disease-causing mutation, since it has been reported to be a recurrent founder mutation worldwide and is known to disrupt binding between p16 and CDK4 in functional assays.27
Discussion of Management
There are currently no specific guidelines for the care of carriers of CDKN2A mutations beyond those that are recommended for persons with the FAMM syndrome — that is, routine mole surveillance, strict avoidance of excessive exposure to sunlight, and use of sunscreens. Dr. Sober, would you discuss the possible role of genetic testing in the care of this patient and of patients like her in the future?
Dr. Arthur J. Sober: Genetic testing is well established for risk assessment with respect to certain medical disorders for which interventions can prevent disease or its complications.28 The role of genetic testing in melanoma is much less clear. Although the Melanoma Genetics Consortium has recommended against genetic testing as a clinical practice at this time,23,25 patients may request the test from their practitioners, since it is commercially available.
The question for the clinician is as follows: Would knowing whether a person has a genetic abnormality that confers an increased risk of melanoma affect the care of either that person or his or her family? On the basis of currently available information, I would consider recommending genetic testing to carefully chosen patients with melanoma who have two or more family members with cutaneous melanoma29,30 or to those who have had more than two primary melanomas, even if their family history is not known.27 Appropriate genetic counseling is a prerequisite in either situation. If a genetic abnormality is identified, it might prompt an increase in the frequency of cutaneous surveillance for melanoma or lower the threshold for removal rather than clinical follow-up of a borderline suspicious clinical lesion. Thus, identifying persons with mutations provides an opportunity to tailor surveillance and prevention practices. Since the patient in the current case has already had a melanoma, all preventive efforts would be aimed at reducing the risk of another highly invasive melanoma. This is particularly important because patients with CDKN2A mutations may be at greater risk than the general population of patients with melanoma for multiple primary melanomas.
Dr. Tsao: Dr. Zembowicz, as a pathologist, would you lower your threshold for diagnosing a melanoma in a patient with a known germ-line CDKN2A mutation? More specifically, would you now be more likely to consider the possibility of a Spitzoid melanoma in our patient rather than an atypical Spitz tumor?
Dr. Zembowicz: I would not. It is important to distinguish between the well-established effect of the germ-line mutation in CDKN2A on this patient's increased lifetime risk of melanoma and its implications for the classification of her pigmented lesions. The prevalence and prognostic significance of CDKN2A mutations in Spitz tumors are unknown. To use the genetic information, we would have to compare the clinical behavior of atypical Spitz tumors associated with germ-line CDKN2A mutations with the behavior of those not associated with such mutations. Until more data are available, we have to rely on morphologic criteria.
Dr. Tsao: Before genetic testing, the patient and her children had been lost to follow-up, despite our recommendations for strict surveillance. Currently, the patient has returned to a routine schedule of at least two skin checks per year. Two of her children, who are both less than 20 years of age, have been examined, and both of them have clinically atypical moles. However, since the atypical-mole phenotype is so variable even within a family, the phenotype alone does not allow us to predict their carrier status with any accuracy.31 Thus, both children are enrolled in rigorous surveillance programs at this hospital. As we learn more about the CDKN2A gene and its penetrance, we may be able to inform the children with more accuracy of their individual, rather than collective, risks.
A Physician: Is the patient's surviving sibling going to be tested?
Dr. Tsao: We do not approach siblings directly. We have left it up to the patient to share her genetic information, as she sees fit, with her family. We have counseled her about the risks to various members of her family.
Diagnosis
Hereditary melanoma with a deleterious CDKN2A mutation.
Source Information
From the Wellman Center for Photomedicine (H.T.), the Pigmented Lesion Clinic and the Department of Dermatology (H.T., A.J.S.), the Center for Cancer Risk Analysis (H.T., K.B.N.), and the Dermatopathology Unit, Department of Pathology (A.Z.), Massachusetts General Hospital; and the Departments of Dermatology (H.T., A.J.S.) and Pathology (A.Z.), Harvard Medical School.
References
Kraemer KH, Lee MM, Scotto J. Xeroderma pigmentosum: cutaneous, ocular, and neurologic abnormalities in 830 published cases. Arch Dermatol 1987;123:241-250.
Kraemer KH, Lee MM, Andrews AD, Lambert WC. The role of sunlight and DNA repair in melanoma and nonmelanoma skin cancer: the xeroderma pigmentosum paradigm. Arch Dermatol 1994;130:1018-1021.
Clark WH Jr, Reimer RR, Greene M, Ainsworth AM, Mastrangelo MJ. Origin of familial malignant melanomas from heritable melanocytic lesions: `the B-K mole syndrome.' Arch Dermatol 1978;114:723-728.
Lynch HT, Frichot BC III, Lynch JF. Familial atypical multiple mole-melanoma syndrome. J Med Genet 1978;15:352-356.
Elder DE, Green MH, Guerry D IV, Kraemer KH, Clark WH Jr. The dysplastic nevus syndrome: our definition. Am J Dermatopathol 1982;4:455-460.
NIH Consensus Development Panel on Early Melanoma. Diagnosis and treatment of early melanoma. JAMA 1992;268:1314-1319.
Kopf AW, Friedman RJ, Rigel DS. Atypical mole syndrome. J Am Acad Dermatol 1990;22:117-118.
Kraemer KH, Greene MH, Tarone R, Elder DE, Clark WH Jr, Guerry D IV. Dysplastic naevi and cutaneous melanoma risk. Lancet 1983;2:1076-1077.
Tucker MA, Halpern A, Holly EA, et al. Clinically recognized dysplastic nevi: a central risk factor for cutaneous melanoma. JAMA 1997;277:1439-1444.
Garbe C, Kruger S, Stadler R, Guggenmoos-Holzmann I, Orfanos CE. Markers and relative risk in a German population for developing malignant melanoma. Int J Dermatol 1989;28:517-523.
Garbe C, Buttner P, Weiss J, et al. Risk factors for developing cutaneous melanoma and criteria for identifying persons at risk: multicenter case-control study of the Central Malignant Melanoma Registry of the German Dermatological Society. J Invest Dermatol 1994;102:695-699.
Grob JJ, Gouvernet J, Aymar D, et al. Count of benign melanocytic nevi as a major indicator of risk for nonfamilial nodular and superficial spreading melanoma. Cancer 1990;66:387-395.
Halpern AC, Guerry D IV, Elder DE, et al. Dysplastic nevi as risk markers of sporadic (nonfamilial) melanoma: a case-control study. Arch Dermatol 1991;127:995-999.
Ford D, Bliss JM, Swerdlow AJ, et al. Risk of cutaneous melanoma associated with a family history of the disease. Int J Cancer 1995;62:377-381.
Kennedy C, ter Huurne J, Berkhout M, et al. Melanocortin 1 receptor (MC1R) gene variants are associated with an increased risk for cutaneous melanoma which is largely independent of skin type and hair color. J Invest Dermatol 2001;117:294-300.
Box NF, Duffy DL, Chen W, et al. MC1R genotype modifies risk of melanoma in families segregating CDKN2A mutations. Am J Hum Genet 2001;69:765-773.
Valverde P, Healy E, Sikkink S, et al. The Asp84Glu variant of the melanocortin 1 receptor (MC1R) is associated with melanoma. Hum Mol Genet 1996;5:1663-1666.
Gillanders E, Hank Juo SH, Holland EA, et al. Localization of a novel melanoma susceptibility locus to 1p22. Am J Hum Genet 2003;73:301-313.
Piepkorn M. Melanoma genetics: an update with focus on the CDKN2A(p16)/ARF tumor suppressors. J Am Acad Dermatol 2000;42:705-726.
Kamb A, Gruis NA, Weaver-Feldhaus J, et al. A cell cycle regulator potentially involved in genesis of many tumor types. Science 1994;264:436-440.
Hussussian CJ, Struewing JP, Goldstein AM, et al. Germline p16 mutations in familial melanoma. Nat Genet 1994;8:15-21.
Harland M, Mistry S, Bishop DT, Bishop JA. A deep intronic mutation in CDKN2A is associated with disease in a subset of melanoma pedigrees. Hum Mol Genet 2001;10:2679-2686.
Kefford RF, Newton Bishop JA, Bergman W, Tucker MA. Counseling and DNA testing for individuals perceived to be genetically predisposed to melanoma: a consensus statement of the Melanoma Genetics Consortium. J Clin Oncol 1999;17:3245-3251.
Bishop DT, Demenais F, Goldstein AM, et al. Geographical variation in the penetrance of CDKN2A mutations for melanoma. J Natl Cancer Inst 2002;94:894-903.
Kefford R, Bishop JN, Tucker M, et al. Genetic testing for melanoma. Lancet Oncol 2002;3:653-654.
Hall MA, Rich SS. Laws restricting health insurers' use of genetic information: impact on genetic discrimination. Am J Hum Genet 2000;66:293-307.
Monzon J, Liu L, Brill H, et al. CDKN2A mutations in multiple primary melanomas. N Engl J Med 1998;338:879-887.
Burke W. Genetic testing. N Engl J Med 2002;347:1867-1875.
Goldstein AM, Tucker MA. Screening for CDKN2A mutations in hereditary melanoma. J Natl Cancer Inst 1997;89:676-678.
Holland EA, Schmid H, Kefford RF, Mann GJ. CDKN2A (P16(INK4a)) and CDK4 mutation analysis in 131 Australian melanoma probands: effect of family history and multiple primary melanomas. Genes Chromosomes Cancer 1999;25:339-348.
Wachsmuth RC, Gaut RM, Barrett JH, et al. Heritability and gene-environment interactions for melanocytic nevus density examined in a U.K. adolescent twin study. J Invest Dermatol 2001;117:348-352.
Related Letters:
Case 7-2004: Hereditary Melanoma and Pancreatic Cancer
Koopmann J., Goggins M., Hruban R. H., Tsao H., Sober A. J., Niendorf K. B.(Hensin Tsao, M.D., Ph.D.,)