Section 1 -

The Freckles and Lentigines Neil Crowson, MD Cynthia M. Magro, MD Martin C. Mihm, Jr., MD

Freckles and lentigines are not classified with precancerous melanocytic proliferations. However, their importance to the surgical pathologist is twofold: first, they can be mistaken for precancrous melanoses. Second, in the context of lentiginosis syndromes, they may be a clue to a systemic disease capable of generating non-melanocytic cancers. In consequence, we will address them briefly. Freckles (Ephelides) Clinical Features Freckles are light brown macules typically less than 2.0 mm in diameter seen in light-skinned individuals on sun-exposed areas. Pigmentation is uniform, becoming more obvious after sun exposure and being inconspicuous during the winter months (Rhodes et al, 1991). Lesions appear during childhood and tend to persist into adulthood; some manifest an autosomal dominant pattern of inheritance. Although they may become clinically inapparent in the elderly, even then they remain visible with Wood lamp examination (Barnhill, 1995). Histopathology A freckle represents a focus of increased melanization of the epidermis due to increased melanin production, with hyperpigmentation of basal layer keratinocytes unaccompanied by elongated retia or increased numbers of melanocytes. Differential Diagnosis The differential diagnosis of the freckle encompasses the café au lait spot, the melanotic macule of Albright, and the lentigo simplex. Distinction of freckles from café au lait spot depends on the identification of giant melanosomes in the latter. The melanotic macule of Albright may be indistinguishable (Barnhill, 1995). Lentigo simplex shows elongated retia with variable melanocytic hyperplasia. An identical histology but with a distinctly different clinical appearance is seen with reticulate pigmentation of the neck (Itin and Lautenschlager, 1998), reticulate pigmentary anomaly of the flexures (Dowling–Degos disease) (Oriba et al., 1991) and reticulate acropigmentation of Kitamura (Erel et al., 1993) with which it overlaps, and the Naegli–Franschetti–Jaddasohn syndrome, which combines reticulate pigmentation of the trunk and limbs with anomalies of eccrine and nail structures (Itin et al., 1993). References Barnhill, RL. Pathology of melanocytic nevi and malignant melanoma. Boston: Butterworth-Heinemann, 1995 Erel A, Guter MA, Edali N. Reticulate acropigmentation of Kitamura: two case reports. Int J Dermatol 32 (10): 726–727, 1993 Oct Itin PH, Lautenschlager S, Meyer R et al. Natural history of the Naegeli–Franceschetti–Jadassohn syndrome and further delineation of its clinical manifestations. J Am Acad Dermatol 28(6): 942–950, 1993 Jun Oriba HA, Lo JS, Dijkstra JWE, Bergfeld WF. Reticulate nonmelanocytic hyperpigmentation anomaly. A probable variant of Dowling Degos disease. Int J Dermatol 1991;30:39-42. Rhodes AR , Albert LS, Barnhill RL, Weinstock MA. Sun-induced freckles in children and young adults. A correlation of clinical and histopathologic features. Cancer 1991;67: 1990–2001. Lentigines: Lentigo Simplex and the Lentiginoses A lentigo is a pigmented macule less than 1.0 cm in diameter and classically 1.0–5.0 mm in diameter. There are clinical variants of lentigines, and several genodermatoses are associated with multiple lentigines, the so-called lentiginosis syndromes. Clinical Features Classically, the lentigo simplex arises in childhood as one of a number of lesions occurring anywhere on the body without a relationship to sun exposure (Rahman and Bahwan, 1996). The lesions are nonpalpable tan, brown, or dark macules that do not exceed 4.0 mm in diameter, except at certain sites such as the genitalia, palms, soles, and mucous membranes, where they may be larger. Some patients manifest disseminated lentigines with a lesional morphology similar to that of lentigo simplex. These may be seen as isolated cutaneous lesions (Crowson et al, 2001) or may be associated with other systemic manifestations (Rahman and Bahwan, 1996). Patients with multiple lentigines in whom no extracutaneous lesions are found should receive genetic counseling, as patients with such systemic lentiginosis syndromes as LAMB syndrome may have family members whose only manifestation is that of multiple cutaneous lentigines. Physical deformities with these syndromes may affect the cardiac, musculoskeletal, neurologic, reproductive, gastrointestinal, auditory, and respiratory systems. The cardiovascular system is the most consistently affected. Various anomalies have been categorized into different syndromes, the best characterized being Carney syndrome and the LEOPARD syndrome. The latter is an acronym which stands for Lentigines, ECG abnormalities, Ocular hypertelorism/obstructive cardiomyopathy, Pulmonary valve stenosis, Abnormalities of genitalia in males, Retardation of growth, and Deafness (Crowson et al, 2001). Carney complex encompasses multiple neoplasms including myxomas at various sites, endocrine tumors, epithelioid blue nevus, melanotic schwannoma, and lentiginosis. The genetic defect in Carney syndrome has been localized to chromosome 2 (2p16) (Stratakis et al., 1996) or the long arm of chromosome 17 (17q2) (Casey et al., 1998), whereas in Peutz–Jeghers syndrome, the genetic defect has been localized to distal 19p (Chrousos and Stratakis, 1998). The term Bannayan–Riley–Ruvalcaba syndrome has been coined to embrace the clinically overlapping features of three entities, all of which combine penile and vulvar lentigines with a variety of syringomata, trichilemmomata, subcutaneous vascular malformations and lipomata, juvenile polyposis coli, and central nervous system abnormalities (Fargnoli et al., 1996). A defect on chromosome 10q23 is said to link this syndrome to juvenile polyposis coli and Cowden disease (Zigman et al., 1997). The diffuse pattern of lentigines may appear at birth or arise during childhood or early adulthood (Uhle and Norvell, 1988). The pattern of inheritance for many of these syndromes is autosomal dominant (Stratakis, 2000). Histopathology The histology comprises hyperpigmentation with elongated retia that are either thin or, at times, club shaped. There is a variable, albeit usually slight, increase in melanocytes. The hypermelanosis is not confined to the basal layer but is seen throughout the epidermis and in the cornified layer. Melanophages and a sparse chronic inflammatory infiltrate may be seen. Some lesions show concentric eosinophilic fibrosis around the tips of retia and fused retia, architectural features characteristically associated with the dysplastic nevus. On occasion, clustered melanocytes may be seen at tips of retia, a finding that suggests that some simple lentigos mature into junctional nevi. Giant melanosomes may be observed and do not necessarily imply a café au lait spot, neurofibromatosis, or melanocytic dysplasia. There is some variation in the light microscopic findings in those lentigines associated with systemic disorders. In the LEOPARD syndrome, a histology similar to that of lentigo simplex is described; increased melanin pigment is seen within the epidermis and melanocytes are increased in number. Unlike lentigo simplex, melanocytes may be distributed in the upper epidermis and may form micronests (Mosher, 1987). These histologic findings are similar to those of Moynahan syndrome. With respect to Peutz–Jeghers syndrome, there may be no accompanying increase in melanocytes, and large melanosomes may be seen within keratinocytes at all levels of the epidermis. In LAMB syndrome, melanocytes may assume an exaggerated dendritic morphology. In NAME syndrome, elongation of retia is not observed; nevi are an important component. References Arnsmeier SL, Paller AS. Pigmentary anomalies in the multiple lentigines syndrome: Is it distinct from LEOPARD syndrome? Pediatr Dermatol 1996;13: 100–104. Casey M, Mah C, Merliss AD et al. Identification of a novel genetic locus for familial cardiac myxoma and Carney complex. Circulation 1998;98: 2560–2566. Chrousos GP, Stratakis CA. Carney complex and the familial lentiginosis syndromes: link to inherited neoplasia and developmental disorders, and genetic loci. J Intern Med 1998;243:573-8. Crowson AN, Magro CM, Mihm MC, Jr. The freckles and lentigines. In: Crowson AN, Magro CM, Mihm MC, Jr. The melanocytic proliferations : a comprehensive textbook of pigmented lesions. New York : John Wiley and sons, 2001:49-72. Fargnoli MC, Orlow SJ, Semel-Concepcion J, Bolognia JL. Clinicopathologic findings in the Bannayan–Riley–Ruvalcaba syndrome. Arch Dermatol 1996;132: 1214–1218. Rahman SB, Bhawan J. Lentigo. Int J Dermatol 1996;35: 229–239. Stratakis CA , Carney JA, Lin JP et al. Carney complex, a familial neoplasia and lentiginosis syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2. J Clin Invest 1996;97:699–705. Stratakis CA. Genetics of Carney complex and related familial lentiginoses, and other multiple tumor syndromes. Front Biosci 2000;5:D353-366. Zigman AF, Lavine JE, Jones MC, Boland CR, Caruthers M. Localization of the Bannayan–Riley–Ruvalcaba syndrome gene to chromosome 10q23. Gastroenterology 1997;113:1433–1437. Mucosal Lentigines Labial Melanotic Macule Clinical Features The labial melanotic macule classically occurs on the lower lip, although lesions can occur anywhere in the oropharynx (Shapiro and Zegarelli, 1971). It is a benign lesion; no tendency to malignant transformation has been reported (Gupta et al., 1997). Histology Epithelial hyperplasia accompanied by parakeratosis, slightly increased numbers of melanocytes which often manifest a dendritic morphology, basilar epithelial pigmentation, and subepithelial melanophages are characteristic. Genital Lentigines Clinical Features In men presenting on the glans penis, corona, sulcus, and penile shaft or in women anywhere on genital mucosa, genital lentigines vary from tan to dark brown and are up to 15.0 mm in diameter. Lesions tend to darken and increase in size with sun exposure or with PUVA therapy. They may appear during pregnancy and in the postpartum period, at times localizing to episiotomy sites. Histology In males epithelial hyperplasia with elongation of retia, basal layer hyperpigmentation, increased numbers of melanocytes, usually with prominent dendritic processes, and subepithelial melanophages are characteristic. Vulvar lentigines show similar features. Lymphoid infiltrates accompanied by stromal fibroplasia, and telangiectasia may be observed and are not features that imply dysplasia. Cytologic atypia is lacking. Case 1 : Vulvar Melanosis Clinical features Vulvar melanosis is often characterized by multiple, intensely pigmented, irregular macules (Rudolph 1990; Kanj et al., 1992; Estrada and Kaufman, 1993) but may present as a macule several centimeters in diameter. If there are any irregularities in pigmentation, several biopsies may be warranted to exclude the possibility of radial growth phase melanoma. Penile melanosis has a similar morphology and can be seen on the glans penis, the penile shaft or the scrotum. With regards to the clinical differential diagnosis, besides malignant melanoma, which is obviously a major concern (Barnhill et al., 1990), there is a report in the literature of Dowling–Degos disease, a form of diffuse pigmentation, in which the manifestations were confined exclusively to the genitalia (Milde et al., 1992). Pigmented Bowen's disease and patch-type bowenoid papulosis are other neoplastic conditions which can mimic genital melanosis. We recently encountered an example of pigmented Paget's disease on the perineum of an elderly man; at an ultrastructural level, the intra-epidermal carcinoma cells contained compound melanosomes evidently derived from dendritic "nurse" melanocytes. These exceptional lesions are reported in the vulva as well (Chiba et al., 2000). The genital lentigines thus raise clinical consideration in respect not only to malignant melanoma, but to other melanoma mimics as well and, as they cannot usually be separated on clinical grounds, a biopsy is almost always warranted (Maize, 1988). Histology Vulvar melanosis histomorphologically resembles vulvar lentigo but, unlike vulvar lentigo, does not usually demonstrate elongation of the retia. Acanthosis may be seen, however (Jih et al., 1999), and there is thus histologic overlap between vulvar lentiginosis and melanosis (Kanj et al., 1992), as exists between penile melanosis and lentiginosis (Breathnach et al., 1992). Nests of melanocytes are not observed. There is uniform hypermelanosis and, although there may be a slight melanocytic hyperplasia, melanocytic atypia should not be observed; its presence indicates atypical genital melanocytic hyperplasia/atypical genital melanosis, and imply a precursor to melanoma (Kerley et al., 1991). A similar phenomenon reported on plantar surfaces is termed atypical melanosis in those lesions showing only a slightly atypical lentiginous melanocytic hyperplasia and premalignant plantar melanosis in those lesions showing greater atypia (Nogita et al., 1994). Acral Lentigines Acral lentigines from of the palms and soles of persons of African extraction, comprise 1.0- to 5.0-mm circumscribed pigmented macules (Rahman and Bahwan, 1996). Elongated retia, hypermelanosis, and a single-cell proliferation of dendritic melanocytes lacking cytologic features of atypia confined to the basal layer of the epidermis characterize the acral lentigo. References Breathnach AS , Balus L, Amantea A. Penile lentiginosis. An ultrastructural study. Pigment Cell Res 5(6): 404-413, 1992 Dec Chiba H, Kazama T, Takenouchi T et al. Two cases of vulval pigmented extramammary Paget's disease: histochemical and immunohistochemical studies. Br J Dermatol 142(6): 1190-1194, 2000 Jun Estrada R, Kaufman R. Benign vulvar melanosis. J Reprod Med 38(1): 5–8, 1993 Jan Gupta G, Williams RE, Mackie RM. The labial melanotic macule: a review of 79 cases. Br J Dermatol 136(5): 772–775, 1997 May Jih DM, Elder DE, Elenitsas R. A histopathologic evaluation of vulvar melanosis. Arch Dermatol 135: 857-8, 1999 Jul Kanj LF, Rubeiz NG, Mroueh AM, Kibbi AG. Vulvar melanosis and lentiginosis: a case report. J Am Acad Dermatol 27(5 Pt 1): 777–778, 1992 Nov Kerley SW, Blute ML, Keeney GL. Multifocal malignant melanoma arising in vesicovaginal melanosis. Arch Pathol Lab Med 115(9): 950–952, 1991 Sep Maize JC. Mucosal melanosis. Dermatol Clin 6(2): 283-293, 1988 Apr Milde P, Goerz G, Plewig G. [Dowling–Degos disease with exclusively genital manifestations]. Hautarzt 43(6): 369–372, 1992 Jun Rudolph RI. Vulvar melanosis. J Am Acad Dermatol 23(5 Pt 2): 982–984, 1990 Nov Shapiro L, Zegarelli DJ. The solitary labial lentigo. A clinicopathologic study of twenty cases. Oral Surg Oral Med Oral Pathol 31(1): 87–92, 1971 Jan Actinic (Solar) Lentigo Actinic lentigines present as multiple tan to brown macules on sun-damaged skin appearing as early as the second decade of life. There is a predilection for the face, the dorsa of the hands, and other sun-exposed sites. These lesions are nearly ubiquitous in elderly Caucasians. The margins may be smooth or irregular, and the size characteristically is between 1.0 and 10.0 mm in diameter. Occasional lesions form confluent, larger patches or even plaques. The surface may show fine wrinkles, and the pigment pattern can be variegated. The histology lentigo depends on the state of evolution at the time of biopsy. Initially, the epidermis manifests a slight increase in basal layer melanocytes that show features of photoactivation comprising increased cell size with preservation of the nuclear-to-cytoplasmic ratios and prominent dendritic cell processes. The hypermelanosis is most conspicuous in the basal layer and extends into the midportion of the stratum Malpighii. Solar elastosis is often difficult to identify from scanning magnification in incipient or early lesions. Progressively, over an elastotic stroma, the retia begin to elongate and manifest angulation. Often, they show irregular shapes, some with a footlike form that, when densely pigmented, has been likened to the blade of a hockey stick wrapped in black tape. There may be some architectural disarray of the epidermis, with slight keratinocytic atypia, raising diagnostic consideration of a superficial pigmented actinic keratosis, the distinction from which may be difficult. However, the stratum corneum appears either orthokeratotic or hyperkeratotic rather than parakeratotic as in an actinic keratosis. Of course, the two lesions may co-exist and/or a lesion may manifest overlapping features with both a superficial pigmented actinic keratosis and a solar lentigo. Evolution into a pigmented reticulated seborrheic keratosis and/or a benign lichenoid keratosis often eventuates. Differential Diagnosis The differential diagnosis includes the superficial pigmented actinic keratosis, the large cell acanthoma, the "ink spot" lentigo, and lentigo maligna. The large cell acanthoma is a variant of actinic lentigo in which keratinocytes in the lower half of the retia show expanded cytoplasms and larger nuclei (Roewert and Ackerman, 1992) and in which the DNA content is increased (DNA index = 1.28–1.5 vs. 1.0) (Rabinowitz and Inghirami, 1992). The so-called "ink spot" lentigo is characterized clinically by a black reticulated appearance and histologically by prominent epidermal melanization, often with transepithelial elimination of pigment to the cornified layer (Bolognia, 1992). Characteristically, the tips of the retia show dense pigmentation. When fusing of rete tips occurs, there is dense pigmentation of the interrete bridge. The important challenge is that presented by lentigo maligna. In lesions of actinic/solar lentigo, chronic photoactivation can lead to a proliferation of plump, somewhat atypical melanocytes with hyperchromatic nuclei. The criteria for diagnosis are: The dominant lesion is actinic lentigo. Nesting and upward migration of melanocytes into the upper spinous and granular layers are not observed. The pattern of melanocytic hyperplasia is of low to moderate density with no areas of confluent lentiginous growth of melanocytes. Retia are usually hyperplastic in actinic lentigo; no areas of retiform effacement with concomitant subjacent regressive stromal alterations are seen. The exception to this rule is the incipient actinic lentigo, which shows minimal or no acanthosis and a retiform pattern that is usually cognate to that of normal skin. Because lentigo maligna may co-exist with or colonize lesions of actinic lentigo, we recommend follow-up of all such cases and, especially if the clinical impression is one of lentigo maligna, we may recommend further biopsies and even occasionally complete excision. References Bolognia JL. Reticulated black solar lentigo ('ink spot' lentigo). Arch Dermatol 1992;128:934–940. Rabinowitz AD, Inghirami G. Large-cell acanthoma. A distinctive keratosis. Am J Dermatopathol 1992;14:136–138. Roewert HJ, Ackerman AB. Large-cell acanthoma is a solar lentigo. Am J Dermatopathol 1992;14:122–132.