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Lentiginous melanoma.

The histopathologic recognition of early cutaneous melanoma is to a large extent based on the presence of an atypical lentiginous proliferation of melanocytes along the dermoepidermal junction. This may occur in atrophic sun-damaged skin, such as that seen in lentigo maligna, or in addition to prominent pagetoid spread, as seen in superficial spreading melanoma. In acral sites, there may be a lentiginous proliferation of atypical melanocytes without much pagetoid spread and preservation of the epidermal pattern. Mixed patterns of intraepidermal melanocytic proliferation occur in some melanomas, and there are melanomas that cannot be easily classified into the traditional groupings of lentigo maligna, superficial spreading, or acral lentiginous types. We coined the term lentiginous melanoma to describe what we believed to be a subset of melanomas, usually present in older adults, but also found in middle-aged persons, and in limited biopsies histologically bearing superficial resemblance to lentiginous nevus or atypical (dysplastic) lentiginous nevus of the elderly. (1-3) Similar clinicopathologic findings were noted in a subsequent article by Davis and Zembowicz. (4) Awareness of this entity, together with examination of the entire lesion, will aid in achieving the correct diagnosis.

CLINICAL FINDINGS

Lentiginous melanomas tend to occur in middle-aged and older individuals, with a slight female preponderance. Lesions typically occur on the trunk, head and neck, and proximal upper extremity; if left untreated, they will persist and progress to invasive melanoma over a protracted period of time. In our original description, (1) we presented a series of 16 patients (7 men and 9 women) whose ages ranged from 43 to 90 years, with a mean of 62.9 years. Lesions were located on the trunk (n = 7), head and neck (n = 6), and upper extremity (n = 3). In a subsequent article, Davis and Zembowicz (4) reported similar findings in 5 patients (2 men and 3 women) whose ages ranged from 24 to 66 years (mean, 47.8 years), with lesions occurring on the shoulder, back, upper extremity, and lower extremity (N = 2). In both studies, the investigators were prompted to study this unusual form of melanocytic neoplasm because in the index cases in these studies, the lesions on initial biopsy had a banal appearance resembling lentiginous nevi or lentigo. However, over time, the lesions persisted and progressively enlarged, resulting in complete excision. Remarkably, in Davis and Zembowicz's index case,4 the lesion was present clinically in 1988 and biopsies were performed in 1992, 1995, 1999, and 2004 before complete excision.

This case illustrated the point that evolution of lentiginous melanoma in situ to invasive melanoma is a slow process. All patients in both studies were well and disease-free following definitive surgery.

Ferrara et al (5) recently reported 4 additional cases of lentiginous melanoma occurring in even younger patients, with ages ranging from 26 to 40 years (mean, 32.5 years). In their study, the lesions were followed up by dermoscopy for an extended period of time (ranging from 12 to 31 months) before excision. Interestingly, comparison of the dermatoscopy images at the baseline and at the time of excision showed very little structural change in pigment network and no significant increase in size. These findings further confirm the slow rate of growth of lentiginous melanoma and indicate that the malignant potential of lentiginous melanoma is on par with that of lentigo maligna.

Weedon, (6) who seems to consider lentiginous melanoma as synonymous with atypical lentiginous junctional dysplastic nevus (of the elderly) (see discussion below), reported, in a letter, his personal experience with more than 100 cases and stated that this entity has "a propensity for the shoulders/upper back/deltoid region of the elderly," but it also occurs in younger individuals, especially on the lower legs of females. Weedon also mentioned that this lesion has propensity for local recurrence if incompletely excised. His remarks are consistent with our experience.

HISTOPATHOLOGIC FINDINGS

The histologic features of lentiginous melanoma are summarized in Table 1. Lentiginous melanomas are characterized by a lentiginous proliferation of melanocytes at the dermoepidermal junction, with focal pagetoid spread and occasional nest formation. The melanocytes are disposed as single cells and as small nests with areas of confluent growth occurring over broad areas of the dermoepidermal junction (Figures 1, a and b, and 2, a). There is retention of the retiform epidermis. Papillary dermal fibrosis is absent or only slight, and lamellar fibroplasias or concentric eosinophilic fibrosis, typical of a dysplastic nevus, is absent. In sharp contrast to lentigo maligna, there is only limited or no solar elastosis. Focal pagetoid spread of single melanocytes (but not melanocytic nests) is usually present, but this may not be a prominent finding. Cytologically, the melanocytes demonstrate mild to moderate atypia, manifested by enlarged nuclei with thickened nuclear membranes and prominent nucleoli (Figure 1, c). The nuclei approximate the size of adjacent keratinocyte nuclei; however, marked cellular pleomorphism and anaplasia of melanocytes are not present. Many of the melanocytes may have abundant gray cytoplasm with melanin pigment and the dominant cell type is epithelioid, with only rare scattered spindled melanocytes present. Cytologic features differentiate lentiginous melanoma from other established variants of melanoma. In lentigo maligna, the most frequent cell type is a spindled hyperchromatic melanocyte with scant cytoplasm. In superficial spreading or nodular melanoma, epithelioid cells show severe degree of epithelioid cell atypia. Extension of the melanocytic proliferation down adnexal structures may be present, albeit rarely.

Histologic recognition of lentiginous melanomas in small biopsies may be challenging. Awareness of the size of the lesion is diagnostically important. The true nature of these lesions is more readily apparent in completely excised specimens, as the lesions exhibit a very broad melanocytic proliferation (Figures 2, a and b). The excised melanocytic lesions are usually greater than 1 cm, with the broadest lesion measuring 2.5 cm. Dermal invasion, demonstrating Clark anatomic level II invasion, may be present in 2 of the cases in the original series (1) and in 1 of the cases reported by Davis and Zembowicz. (4) The Breslow thickness ranged from 0.4 to 0.8 mm. (1,4) Dermal mitoses, a dominant dermal nodule, or ulceration was not present in any of the cases in both studies.

[FIGURE 1 OMITTED]

[FIGURE 2a OMITTED]

IMMUNOHISTOCHEMISTRY

Immunohistochemical studies may be helpful in highlighting the extent of the melanocytic proliferation. In the original series, (1) Mart-1 and Mitf highlighted the broad nature of the melanocytic proliferation, and pagetoid spread was also more readily identifiable (Figure 3, a through c).

DISTINCTION FROM OTHER MELANOCYTIC PROLIFERATIONS

The unique clinical and histologic features discussed above and summarized in Table 2 suggest that lentiginous melanoma represents a distinct clinicopathologic entity from a common lentiginous nevus, dysplastic nevus, superficial spreading melanoma, and lentigo maligna. Lentiginous melanomas differ from lentiginous and dysplastic nevi by their ability to attain large size, by the presence of confluent growth of atypical melanocytes spanning the entire lesion, and by pagetoid spread. Lentiginous melanomas do not show architectural alterations of the dermoepidermal junction, such as lamellar fibroplasia typical of dysplastic nevi. Some of the features seen in lentiginous melanoma overlap with those seen in melanomas with a lentiginous junctional proliferation (lentigo maligna, acral lentiginous, and mucosal lentiginous types). (7-9) In contrast to acral and mucosal lentiginous melanoma, lentiginous melanomas are located on the head and neck and the trunk and arms, show preservation of the retiform epidermis, and consist of less cytologically atypical cells. The absence of prominent solar elastosis, epithelioid rather than spindle cell morphology, and preservation of the retiform epidermis are the key histologic features distinguishing lentiginous melanoma from lentigo maligna.

[FIGURE 2b OMITTED]

Atypical lentiginous melanocytic proliferations in elderly patients continue to pose a diagnostic dilemma, with lesions variably categorized as dysplastic nevus, atypical junctional nevus, melanoma in situ (early or evolving), and premalignant melanosis. (8) In a study by Blessing, (10) melanocytic lesions studied in older individuals were a distinct category of lesions with overlapping histologic features of a solar lentigo and atypical melanocytic proliferation. The lesions showed a continuous spectrum from lesions resembling senile lentigo with patchy junctional activity to lesions with a superimposed atypical lentiginous, melanocytic proliferation, bordering on malignant melanoma in situ. The term pigmented lentiginous nevus with atypia was used for lesions bordering on in situ melanoma.

Kossard et al (2) described similar lesions, which they termed lentiginous dysplastic nevus of the elderly. The lesions presented clinically as isolated macules with predominant site distribution on the trunk and limbs. The lesions demonstrated an irregular rete ridge system, with nests and single melanocytes irregularly distributed within the retiform epidermis. Focal confluent growth of melanocytes was present in the suprapapillary plates, and focal atypia, characterized by larger irregular hyperchromatic nuclei, was present. Lesions were commonly associated with transition to malignant melanoma in situ, typically as lentigo maligna. (10) These studies highlight the challenges in correctly classifying atypical lentiginous melanocytic proliferations. Weedon (6) recently summarized his experience with lentiginous junctional nevus (of the elderly). He pointed out the overlapping clinical and histologic features between the 2 entities and it is his belief that they are analogous. Weedon "reluctantly" accepts the term melanoma for these lesions. As indicated in his letter, Weedon's criteria for inclusion are essentially the same as what we have previously described, except that he does not make mention of the lesion size. However, Weedon does acknowledge the propensity of the lesions to recur if incompletely excised, which supports our pragmatic approach to advocate complete removal of lesions showing features of lentiginous melanoma.

[FIGURE 3 OMITTED]

MOLECULAR FINDINGS

Recently, fluorescence in situ hybridization (FISH) has shown some utility as a diagnostic aid in melanocytic lesions with conflicting histopathological findings. (11) Utilizing a FISH assay that may be helpful in diagnosing melanoma, Newman et al (12) demonstrated that 16 of 19 lentiginous melanomas (84%) showed copy number changes in one of four targeted chromosomal loci to meet FISH criteria for melanoma. In the FISH assay targeting loci RREB1 (6p25), MYB (6q23), CCND1 (11q13), and CEP (centromere of chromosome 6), 15 of 16 positive cases demonstrated aberrations in chromosome 6 and one case showed gains in 11q13 (CCND1) in their control group of 17 lentiginous nevi, FISH evaluation was negative. These molecular findings further support the classification of lentiginous melanoma as a variant or subtype of melanoma.

MANAGEMENT IMPLICATIONS

It must be noted that lentiginous melanoma is rare. In our original series, (1) 16 cases of lentiginous melanoma were obtained from a melanoma database during a 4-year period, which included more than 2000 melanomas. Our experience indicates that lentiginous melanoma comprises a small subset of melanoma and should not be overdiagnosed. This is especially true for small-diameter lesions that may have some of the histologic criteria of lentiginous melanoma but clinically and histologically are small and appear completely excised. We do not believe that such lesions should be reported as lentiginous melanoma. Conversely, in limited biopsies, in which features consistent with lentiginous melanoma are present and the lesion extends to the edges, we recommend deferring the final diagnosis until after examination of the reexcision. Only if a broad continuous lentiginous proliferation of atypical melanocytes is present should the diagnosis of lentiginous melanoma be rendered. This approach will avoid overdiagnosing melanoma in small lentiginous nevi with atypia and avert "an epidemic" of lentiginous melanoma. These small-diameter lentiginous nevi with atypia may represent precursor lesions to lentiginous melanomas; molecular alterations in these lesions may in the future help us resolve this issue.

CONCLUSION

Lentiginous melanoma is a rare subset of slowly progressing, radial growth phase melanoma characterized by lentiginous proliferation of moderately atypical epithelioid melanocytes showing focal pagetoid spread and nesting, associated with little architectural changes at the dermoepidermal junction. Given the clinicopathologic findings of broad lesions that persist and progress slowly if untreated, the biologic potential of lentiginous melanoma appears to be similar to that of lentigo maligna. If left untreated, these lesions have the potential to eventually invade into the dermis. Histologic recognition of lentigi nous melanoma and its differentiation from other atypical lentiginous melanocytic proliferations, especially atypical lentiginous nevus (of the elderly) and de novo intraepidermal melanocytic epithelioid cell dysplasia in small biopsies, is very challenging. Yet, awareness of histologic features of lentiginous melanoma is essential to assure appropriate therapy for lesions that have potential for progression to invasive melanoma.

Many thanks to Artur Zembowicz, MD, PhD, for his insightful comments and review of the manuscript.

References

(1.) King R, Page RN, Googe PB, et al. Lentiginous melanoma: a histologic pattern of melanoma to be distinguished from lentiginous nevus. Mod Pathol. 2005;18(10):1397-1401.

(2.) Kossard S, Commens C, Symons M, et al. Lentinginous dysplastic naevi in the elderly: a potential precursor for malignant melanoma. Australas J Dermatol. 1991;32(1):27-37.

(3.) Kossard S. Atypical lentiginous junctional naevi of the elderly and melanoma. Australas J Dermatol. 2002;43(2):93-101.

(4.) Davis T, Zembowicz A. Histological evolution of lentiginous melanoma: a report of five new cases. J Cutan Pathol. 2007;34(4):296-300.

(5.) Ferrara G, Zalaudek I, Argenziano G. Lentiginous melanoma: a distinctive clinicopathological entity. Histopathology. 2008;52(4):523-525.

(6.) Weedon D. Lentiginous melanoma. J Cutan Pathol. 2009;36(11):1232.

(7.) Clark WH Jr, Elder DE, Van Horn M. The biologic forms of malignant melanoma. Hum Pathol. 1986;17(5):443-450.

(8.) McGovern VJ, Cochran AJ, Van der Esch EP, Little JH, MacLennan R. The classification of malignant melanoma, its histological reporting and registration: a revision of the 1972 Sydney classification. Pathology. 1986;18(1):12-21.

(9.) Weedon D. Skin Pathology. 3rd ed. London, England: Churchill Livingstone; 2002.

(10.) Blessing K. Benign atypical naevi: diagnostic difficulties and continued controversy [review]. Histopathology. 1999;34(3):189-198.

(11.) Gerami P, Jewell SS, Morrison LE, et al. Fluorescence in situ hybridization (FISH) as an ancillary diagnostic tool in the diagnosis of melanoma. Am J Surg Pathol. 2009;33(8):1146-1156.

(12.) Newman MD, Mirzabeigi M, Gerami P. Chromosomal copy number changes supporting the classification of lentiginous junctional melanoma of the elderly as a subtype of melanoma. Mod Pathol. 2009;22(9):1258-1262.

Roy King, MD

Accepted for publication April 13, 2010.

From the University of Tennessee, Knoxville Dermatopathology Laboratory, Knoxville, Tennessee.

The author has no relevant financial interest in the products or companies described in this article.

Reprints: Roy King, MD, University of Tennessee, Knoxville Dermatopathology Laboratory, 315 Erin Dr, Knoxville, TN 37919 (e-mail: royelisa@tds.net or rking@labpath.com).
Table 1. Histologic Criteria for Lentiginous Melanoma

1. Broad proliferation of small nests and single cells at the
dermoepidermal junction with areas of confluent growth

2. Preservation of the retiform epidermis

3. Mild to moderate melanocytic atypia with nuclear size
equal to keratinocyte nuclei

4. Single-cell pagetoid spread

5. Lack of significant solar elastosis

Table 2. Salient Histologic Features of Lentiginous
Melanocytic Lesions

 Lentiginous
 Melanoma

Size (usually), mm >10
Normal pattern rete rides Always
Dermal fibrosis Rare (mild)
Solar elastosis Rare
Lentiginous proliferation Always
Pagetoid spread Usually
Nests Often
Epithelioid atypia Always (mild to
 moderate)
Spindle atypia Never

 Lentiginous Dysplastic
 Nevus Nevus

Size (usually), mm <5 >5
Normal pattern rete rides Often Rare
Dermal fibrosis Sometimes (mild) Always
Solar elastosis Sometimes Often
Lentiginous proliferation Always Usually
Pagetoid spread Never Never
Nests Always Always
Epithelioid atypia No Always (but
 variable)
Spindle atypia Never Often

 Superficial Lentigo
 Spreading Maligna
 Melanoma

Size (usually), mm [much greater than] 10 [much greater
 than] 10

Normal pattern rete rides Never Sometimes
Dermal fibrosis Always Sometimes
Solar elastosis Often Always
Lentiginous proliferation Often Always
Pagetoid spread Always Sometimes
Nests Often Rare
Epithelioid atypia Always severe Rare

Spindle atypia Rare Always
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Author:King, Roy
Publication:Archives of Pathology & Laboratory Medicine
Date:Mar 1, 2011
Words:2584
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