Are You Confident of the Diagnosis?
An overview of nevi
Melanocytic nevi (typically shortened to “nevi”) are benign neoplasms of melanocytes found within the skin and are commonly referred to as “moles.” Nevi commonly first occur in childhood, although some nevi may be present at birth (so-called “congenital nevi”). Nevi commonly continue to develop into early adulthood, with many patients having changing mole patterns in their teens and early 20s. The development of new ordinary nevi tends to slow down as the patient continues to age, although new nevi may continue to develop into the 40s and beyond.
Nevi are almost universally found in the adult population, with the average Caucasian adult having between 15 and 40 nevi that are at least 2 mm in diameter (Figure 1). Non-Caucasians on average have fewer nevi than Caucasians do. A classic common acquired nevus (also called “common nevus”) is typically less than 5 mm in greatest diameter, round, symmetric, and fairly well-circumscribed in its clinical appearance, with an even brown pigmentation, although the intensity of pigmentation can vary enormously from tan to almost black.
Some nevi may appear amelanotic on clinical examination, with those nevi appearing red rather than brown, with no evident pigmentation. Nevi may be either macular or papular, depending on the placement of melanocytes within the skin, with papular lesions having more melanocytes in the dermis than macular lesions.
Nevi that have irregular features are commonly termed “dysplastic nevi” or “atypical nevi” (Figures 2-7). The use of the term “dysplastic nevus” is confusing and controversial, since the term is used to describe both lesions with an atypical clinical appearance on the skin as well as those with an atypical appearance microscopically; these are two overlapping but not identical groups. It has been suggested that the term “dysplastic nevus” be avoided entirely, with the term “atypical nevus” used for clinically atypical lesions, and the term “nevus with architectural disorder and cytologic atypia” be used for nevi with microscopic dysplasia, although the term “dysplastic nevus” (also named a “Clark’s nevus”) is still widespread to describe both types of lesions.
Clinically dysplastic nevi
There is no widely accepted definition for clinically dysplastic nevi, although all definitions share the principle that these lesions are atypical in their appearance in comparison to an “ordinary” common acquired nevus. At the University of Pennsylvania, the center where the first author practices, the following criteria for clinical dysplasia are used:
The lesion must be at least 5 mm in greatest diameter
The lesion must have some variation in the color of the lesion and some irregularity of the border of the lesion (either the lesion is not completely round, or the lesion’s border is not very sharp, with some “fuzziness” to the edge, making it difficult to tell exactly where the lesion ends
There must be at least a portion of the lesion that is macular.
However, other places use different criteria, with a different size cutoff used, or in some cases, not used at all.
In addition to the above criteria, clinically dysplastic nevi may vary from “ordinary” common acquired nevi in other ways. Dysplastic nevi are often more ovoid than round. In addition, the lesion may have portions that are papular and portions that are macular. One such pattern is the so-called “fried egg” appearance, in which the central portion of a dysplastic nevus is raised with a peripheral macular component. Patients who have dysplastic nevi commonly have an increased number of common acquired nevi as well.
The differential diagnosis for nevi and dysplastic nevi clinically includes other pigmented lesions of the skin, such as seborrheic keratoses, lentigenes, and pigmented basal cell carcinomas, as well as melanoma. Dermoscopy may be helpful in determining lineage as well as diagnosis. The definitive determination of the diagnosis can only be made by microscopic examination, which often means that the lesion must be biopsied.
Microscopically dysplastic nevi
The defining features for microscopically dysplastic nevi are quite different; some correlate to clinical features, but some do not. Not all clinically atypical nevi will demonstrate architectural disorder and cytologic atypia microscopically, and vice versa. Microscopically, dysplastic nevi (DN) may be compound or junctional melanocytic proliferations (Figures 8-10). As with the definition of a clinically dysplastic nevus, the criteria for making the diagnosis of a nevus with microscopic dysplasia will vary depending on the institution. At MD Anderson Cancer Center, the home institution for the last two authors of this manuscript, the designation of a microscopically dysplastic nevus includes the following criteria:
An absolute requirement for the presence of a host response to the atypical melanocytic proliferation, consisting of two components: an inflammatory infiltrate and a fibrotic response. The inflammatory infiltrate is comprised of a variable lymphohistiocytic infiltrate in the superficial dermis accompanied by pigmented macrophages. This is associated with fibroplasia in the papillary dermis, which is typically accentuated around the sides and tips of the rete ridges.
The histologic designation of “dysplasia” in melanocytic lesions requires the presence of both architectural disorder as well as random cytologic atypia of melanocytes. At MD Anderson Cancer Center, architectural atypia is evaluated based upon the following six parameters: circumscription (whether the junctional proliferation ends in a distinct nest or as an indistinct proliferation of single cells towards the periphery of the lesion), cohesiveness of nests, confluence (whether there is fusion among adjacent rete in greater than 50% of the lesion), symmetry of the lesion and/or the associated host response, the presence of upward pagetoid migration (suprabasal melanocytes), and a proliferation of single cell melanocytes predominating over nests. The cytologic atypia present in DN is classically described as “random” rather than uniform and includes such changes as cytoplasmic and nuclear enlargement, nuclear pleomorphism with anisochromatism, and the presence of a variably conspicuous nucleolus. Cytologic atypia is assessed by comparing the nuclear size of the melanocytes along the dermal-epidermal junction to that of the adjacent keratinocytes.
A microscopically dysplastic nevus may be either junctional or compound. In general, a junctional DN consists of a proliferation of a variable combination of single and nested melanocytes along the dermal-epidermal junction with a host response, architectural typia and cytologic atypia as defined above. A compound DN additionally contains a dermal proliferation of nested melanocytes which exhibit maturation, defined as a progressive dispersion as single melanocytes among collagen fibers with a concomitant diminution of cell size with descent into the dermis. In addition, a compound DN typically exhibits a junctional proliferation of melanocytes extending laterally beyond the dermal nests of melanocytes (“shouldering”) .
Microscopically dysplastic nevi are commonly graded according to a three-tiered scheme—as mild, moderate and severe—as a function of the degree of cytologic and architectural atypia. Some dermatopathologists prefer a single grade that incorporates the degree of cytologic and architectural atypia together, while others prefer to grade each of these qualities separately.
The use of immunohistochemistry when evaluating melanocytic lesions has emerged as a useful ancillary test when the designation of benign versus malignant (ie, between DN and melanoma) is not readily apparent on histopathologic grounds alone. The standard panel of antibodies deployed for these types of lesions includes HMB-45 (anti-gp100), anti-MART1 and anti-MIB1 (anti-Ki-67). HMB-45 and MART1 antibodies highlight the extent of the intraepidermal melanocytic proliferation: the degree of single cells and the upward pagetoid migration in the epidermis.
HMB-45 has particular utility as a reflection of the quality of the dermal maturation sequence, since melanocytes in a nevus typically demonstrate a progressive diminution of reactivity with antibodies for HMB-45 with descent into the dermis (this mirrors the morphological maturation sequence described above). In contrast, melanomas lack maturation in their dermal component and as such, exhibit patchy reactivity with antibodies for HMB-45. Finally, the proliferative index is assessed by MIB-1.
Nevi (banal or DN) typically exhibit less than 1% to 5 % labeling with MIB1 (anti-Ki-67) and reactive cells should be confined to the superficial dermis (ie, diminished proliferative index with descent into the dermis). In contrast, melanomas exhibit a much higher proliferative rate with MIB1, and the pattern of reactivity is heterogeneous and patchy—occurring randomly within the dermal component. At MD Anderson Cancer Center, a double immunohistochemical study (a combination of antibodies for MART-1 and Ki-67) is employed to improve the ability to discriminate the proliferative index in melanocytes specifically. This is particularly useful in melanocytic lesions containing a pronounced infiltration of background lymphocytes.
Who is at Risk for Developing this Disease?
Almost all adults will have at least one melanocytic nevus somewhere in on the skin. The number of common acquired nevi appears to be related both to genetic aspects (with some families being more “moley” than others; an increased mole count is also seen in fairer patients and those with lighter eye or hair color) and to sun exposure, with a greater number of ordinary nevi found in patients with a more extensive history of sun exposure. It has been estimated that 55% – 60% of the variation between two different people in terms of the number of moles present on their skin is due to genetic makeup, with the remainder of the difference coming from environmental factors.
In addition to being more common in patients with a more extensive sun exposure history, common acquired nevi are found in increased numbers on areas of the body that are classically sun-exposed. So-called “double-covered” areas, such as the buttocks, where one typically wears two layers of clothing, usually have fewer ordinary nevi than areas of the body that are classically sun-exposed.
In contrast, clinically dysplastic nevi do not appear to have as strong a relationship to sun exposure as common acquired nevi do, with a higher proportion of dysplastic nevi being found in double-covered areas than one would see with common acquired nevi. However, dyplastic nevi probably still have a relationship to sun exposure, particularly intermittent sun exposure, with dysplastic nevi found with greatest frequency on the trunk as compared to the extremities or head and neck.
Estimates of the proportion of the population that has at least one clinically dysplastic nevus vary from 5% to 25% depending on the definition and the population, with 10% being a commonly used figure for the adult Caucasian population in the United States.
What is the Cause of the Disease?
Nevi are normal growths that are found almost universally in adults. However, around 80% of benign nevi have a mutation in BRAF, a member of the Raf kinase family of serine/threonine-specific protein kinases. The typical mutation is a single-base substitution from thymine to adenine at nucleotide 1799, with a resultant substitution of valine for glutamic acid at codon 600 (V600E). That about 80% of nevi have BRAF mutations, a higher proportion than the 60% seen in melanomas, makes it clear that BRAF mutations are not the only important step in the pathogenesis of melanoma. The exact relationship of BRAF mutation to melanoma development is still unclear.
Mutations in NRAS (neuroblastoma RAS) have also been found in dysplastic nevi as well as melanoma. Mutations in the CDKN2A (cyclin-dependent kinase inhibitor 2A) gene may be seen in some patients with large numbers of nevi and a family history of melanoma. The CDKN2A gene encodes p16, a tumor suppressor protein that plays a role in cell cycle regulation.
Systemic Implications and Complications
The terms “dysplastic nevus syndrome” or “atypical mole syndrome” have been used by some authors. As with the term “dysplastic nevus” itself, the criteria for the syndrome vary depending upon the author, but involves a patient who has at least one clinically dysplastic nevus and, depending upon the author, potentially an increased number of ordinary nevi or multiple dysplastic nevi. The term “familial atypical multiple mole melanoma syndrome (FAMMM)” is also used by some authors to describe a patient with atypical mole syndrome and a family history of melanoma.
Having an increased number of ordinary nevi is a risk factor for melanoma, with those having 16- 40 nevi having an increased risk of 1.7-fold over those with 0 -15 nevi, and those with over 100 nevi having an increased risk of 7-fold. A single clinically dysplastic nevus increases the odds of melanoma about two-fold, with higher odds with more lesions. Having 5 or more dysplastic nevi increases the risk about 6-fold.
Although having clinically dysplastic nevi is a risk factor for the development of melanoma, it is unclear whether the dysplastic nevi themselves are at increased risk for becoming melanoma, or if the dysplastic nevi are merely a marker for inheritance of a high-risk genetic profile. The data on the relationship between melanoma and a precursor dysplastic nevus is very unclear, partially because the diagnosis of melanoma can only be made on microscopic examination when the lesion is removed, at which point the melanoma may have eradicated a potential precursor lesion, making it difficult to determine whether the melanoma arose de novo or from a precursor.
Nevi and dysplastic nevi are benign lesions and do not necessarily need to be removed if the diagnosis of a benign lesion is evident on clinical examination. There is generally little indication for all of a patient’s stable nevi to be removed wholesale. However, if the diagnosis is in question and there is consideration that a lesion may not be a nevus but in fact a melanoma, a biopsy would assist in establishing the diagnosis.
If a biopsy were to be performed of a melanocytic lesion, it would be generally preferable for an excisional biopsy to be done, attempting to remove the entire lesion, rather than a sampling biopsy. An evaluation of asymmetry and other architectural features may be important in making an accurate diagnosis of a melanocytic lesion, and such an evaluation is not always possible with a sampling biopsy. That being said, a sampling biopsy is sometimes performed in certain circumstances, such as with a large lesion in a cosmetically sensitive area where there is low suspicion for the lesion being melanocytic.
As was mentioned previously, many centers grade the level of atypia in microscopically dysplastic nevi into different categories such as mild/moderate/severe cytologic atypia. At many such centers, it is common for the treatment options of a dysplastic nevus to vary depending upon the level of atypia. with a general trend towards looking for a higher level of assurance that the lesion has been completely removed with higher levels of atypia. However, there are no randomized control trials examining the natural history of nevi with specific levels of microscopic dysplasia, nor are there trials examining outcomes in patients who have had or who have not had complete removal of dysplastic nevi. At our center, for a lesion with moderate or severe levels of dysplasia, we would typically recommend any clinical residuum be surgically removed, but that protocol is not followed universally.
Optimal Therapeutic Approach for this Disease
Optimally, patients need to be followed for any changes for melanoma, by clinical examination, photography, digital imaging, and biopsies of suspicious lesions. Sun precautions and self-examinations are crucial. To date, topical treatments with retinoids have not been very effective. Other techniques, such as laser surgery, are not recommended as they may not completely remove nevi.
Patients with an increased number of common acquired nevi or with dysplastic nevi are at increased risk of melanoma compared to the average person. Many would recommend that such a patient have a full skin examination at least annually by a physician, in addition to monthly self examination at home, although there are no randomized control trials establishing that this recommendation has any clinical impact in the number or characteristics of melanomas detected.
Unusual Clinical Scenarios to Consider in Patient Management
Patients with an increased number of common acquired nevi or who have dysplastic nevi who have other risk factors for melanoma may need closer follow-up.
What is the Evidence?
Elder, DE, Goldman, LI, Goldman, SC, Greene, MH, Clark, WH. “Dysplastic nevus syndrome: a phenotypic association of sporadic cutaneous melanoma”. Cancer.. vol. 46. 1980. pp. 1787-94. (The original report of dysplastic nevus syndrome.)
Gandini, S, Sera, F, Cattaruzza, MS, Pasquini, P, Abeni, D, Boyle, P. “Meta-analysis of risk factors for cutaneous melanoma: I. Common and atypical nevi”. Eur J Cancer. vol. 41. 2005. pp. 28-44. (An overview of the studies examining whether common or atypical nevi are risk factors for melanoma.)
Metcalf, JS, Maize, JC. “Clark's nevus”. Semin Cutan Med Surg Mar. vol. 18. 1999. pp. 43-6. (An overview of dysplastic nevi.)
Prieto, VG, Shea, CR. “Use of immunohistochemistry in melanocytic lesions”. J Cutan Pathol Nov. vol. 35. 2008. pp. 1-10. (A discussion of how immunohistochemical techniques can be of benefit when attempting to make microscopic diagnoses for melanocytic lesions.)
Rudolph, P, Schubert, C, Schubert, B, Parwaresch, R. “Proliferation marker Ki-S5 as a diagnostic tool in melanocytic lesions”. J Am Acad Dermatol Aug. vol. 37. 1997. pp. 169-78. (How the use of proliferation markers can be helpful in microscopic diagnosis.)
Shea, CR, Vollmer, RT, Prieto, VG. “Correlating architectural disorder and cytologic atypia in Clark (dysplastic) melanocytic nevi”. Hum Pathol May. vol. 30. 1999. pp. 500-5. (How cytologic atypia and architectural disorder come into play in the microscopic diagnosis of dysplastic nevi.)
Thomas, NE. “BRAF Somatic mutations in malignant melanoma and melanocytic naevi”. Melanoma Res. vol. 16. 2006. pp. 97-103. (An overview of BRAF mutations in melanoma and nevi.)
Torres-Cabala, CA, Plaza, JA, Diwan, AH, Prieto, VG. “Severe architectural disorder is a potential pitfall in the diagnosis of small melanocytic lesions”. J Cutan Pathol. vol. 37. 2010. pp. 860-5. (How to be careful about the use of architectural disorder when making microscopic diagnoses of melanocytic lesions.)
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