and Victor G. Prieto2

Division of Dermatopathology, Miraca Life Sciences, Dallas, TX, USA

MD Anderson Cancer Center, University of Texas, Houston, TX, USA



Clinical Features

Ephelides (freckles) are common, uniformly pigmented, multiple macules (1–5 mm in size) mainly limited to body regions above the waist. These macules are more numerous on sun-exposed areas (face, shoulders, and upper back) and usually fade and become smaller in the winter season. Ephelides appear early in childhood and partly disappear with age and are closely related to pigmentary host characteristics such as fair skin and/or red hair. Only rarely ephelides are seen in individuals with dark skin. Ephelides may manifest an autosomal dominant pattern of inheritance (appearing in sequential generations). High levels of freckling may indicate a raised susceptibility to the development of melanoma. In contrast to solar lentigines, ephelides are not strongly associated with age [14]. There is a strong relation between variants in the gene encoding the melanocortin-1 receptor (MC1R) and ephelides in childhood suggesting the MC1R gene is the major ephelide gene [5].


The epidermis appears normal in structure. The basal cells in the affected areas are more heavily pigmented with melanin than those in the surrounding skin, and there is usually sharp delimitation of the abnormal from the normal areas. There are normal and sometimes decreased numbers of melanocytes within epidermis; however, the melanosomes in those cells are larger than those in the surrounding skin and can sometimes be seen with the microscope as dark, large, intracytoplasmic granules (macromelanosomes). The adnexal structures are not involved. By electron microscopy studies, the melanocytes contain enlarged spherical granular melanosomes as opposed to the striated ellipsoid forms seen in normal skin [3, 6, 7] (Fig. 1.1a–c).


Fig. 1.1
Ephelides. Note the pigmented basal keratinocytes and the decreased number of melanocytes within epidermis (a). Higher magnification showing melanocytes with rare melanosomes (b). Observe the lack of melanocytes (c)

Differential Diagnosis

The clinical differential diagnosis of ephelides includes lentigo simplex and café au lait spot. The diagnosis of café au lait spot will rely on the identification of giant melanosomes and mild increased number of melanocytes. Lentigo simplex (as explained in detail below) will show elongated rete ridges with hyperpigmentation of basal keratinocytes (some authors accept also mild increased in numbers of melanocytes) (Fig. 1.1a–c).

Lentigo Simplex

Clinical Features

Lentigo simplex is a very common, benign, pigmented lesion that can be found anywhere on the body surface and is preferentially observed in young people, although it may occur at any age. They usually appear early in life and are typically not associated with sun exposure. Clinically, lesions present as non-palpable, relatively symmetric, uniform, homogeneous, light-brown to black macules, on the trunk, extremities, genitals, and mucosa surfaces, usually measuring less than 5 mm in size (in certain anatomic sites such as the palms, soles, genitalia, and mucosal membranes, they can be larger). It is rare for a lentigo simplex to be asymmetrical or to have irregular borders. Lentigo simplex may occur as single or multiple lesions. It has been proposed that lentigo simplex may evolve into a lentiginous/junctional melanocytic nevus when melanocytes start proliferating and aggregating to form small nests in the junctional zone. On the other hand, a recent study has shown that absence of BRAF, FGFR3, and PIK3CA mutations can clearly differentiate lentigo simplex from melanocytic nevi and solar lentigo. These results furthermore indicate that lentigo simplex has a distinct yet unknown genetic basis, which does not necessarily exclude the proposed lentigo-nevus sequence [8].

In some instances, multiple lentigines are associated with rare genetic disorders. These include LEOPARD syndrome (lentigines, EKG changes, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, growth retardation, and deafness), Carney complex (lentigines, atrial myxoma, mucocutaneous myxoma, and nevi), Peutz-Jeghers syndrome (oral and perioral lentigines, multiple gastrointestinal polyps, and visceral tumors), xeroderma pigmentosum (lentigines on sun-exposed skin and multiple skin cancers), and Cronkhite-Canada syndrome (buccal, facial, and palmoplantar lentigines, alopecia, nail dystrophy, and intestinal polyps).


Lentigo simplex shows mild elongation of the epidermal rete ridges with variable basal cell hyperpigmentation. The elongated rete ridges are either thin or club shaped. Some authors accept that there may be an increased number of single melanocytes in the basal layer devoid of cytologic atypia. In some cases there are giant melanosomes as in lentigines. Papillary dermis is often fibrotic; however, in contrast with dysplastic rarely is there concentric and lamellar fibroplasia. Also in the papillary dermis, there may be a subtle lymphohistiocytic infiltrate with scattered melanophages. While the majority of lentigo simplex are stable, some may develop junctional nests and melanocytes may descent into papillary dermis. Thus, lentigos and junctional nevi may coexist and can be designated as lentiginous junctional nevus (jentigo) [911]. Because of that apparent capacity to progress , lentigo simplex is being conceived by some authors as embryonic junctional melanocytic nevi , and that such distinction is arbitrary (Fig. 1.2a–c).


Fig. 1.2
Lentigo simplex. The lesion shows elongation of rete ridges and pigmented keratinocytes with absence of solar damage (a). The pigment varies within epidermis and can be prominent in some cases (b). An early transition into an early junctional nevus (jentigo) (c)

Differential Diagnosis

Lentigo simplex is often biopsied to rule out melanoma in situ, especially if the lesion is located in the head and neck of an older individual. In most cases, this differential diagnosis is straightforward. However, in some instances, lentigo simplex may display isolated melanocytes at and above the basal layer. This represents a rare occurrence, and its distinction with melanoma in situ can be problematic if the specimen is small and the complete architecture of the lesion cannot be evaluated. Lentigo simplex located in special sites (such as umbilical, genital, and axillary areas) can also show irregular distribution of the pigment. Close attention to the cytology of the cells is very important to make a distinction from melanoma, as these melanocytes do not differ from those seen in the basal layer of the epidermis, and cytologically they have small nuclei with compact chromatin and scant cytoplasm. Upwardly scattered melanocytes can also be seen in cases of lentigo simplex that have been traumatized. The presence of parakeratosis, spongiosis, extravasated red blood cells, dyskeratotic keratinocytes, and the melanin pigment above the suprabasal layer is a hint that a lesion has been traumatized. The presence of melanocytes with vesicular nuclei and abundant cytoplasm along with signs of solar damage, pagetoid spread of melanocytes, irregular distribution of melanin pigment in epidermis and dermis, and a dense lichenoid inflammatory infiltrate in superficial dermis (especially underneath the area of the lesion) raises the possibility of melanoma in situ. A diagnostic hallmark of melanoma in situ (especially lentigo maligna) is the extension of neoplastic melanocytes down the adnexal epithelial structures , a phenomenon not seen in lentigo simplex (Fig. 1.2a–c).

Actinic Lentigo (Pigmented Early Actinic Keratosis, Solar Lentigo)

Clinical Features

Actinic lentigines are common, macular, hyperpigmented lesions that range in size from a few millimeters to more than a centimeter in diameter. They tend to be multiple with individual lesions gradually increasing in size to larger macules or patches. Synonyms for this condition include solar lentigo, liver spots, age spots, and sun spots. Most commonly it appears on the face, upper extremities, dorsa of the hands, and upper part of the trunk. The incidence increases with age, affecting more than 90 % of white persons older than 50 years of age; however, they are now seen in younger patients likely because of their common exposure to sun and the use of artificial sources of UV light. Clinically, the lesions are usually small, slightly scaly, tan brown, macules, or thin papules on sun-damaged skin. In some cases the color may range from yellow tan to black and many lesions eventually coalesce to form larger patches. These enlarged solar lentigines correspond to evolution into standard actinic keratosis or seborrheic keratosis and may simulate clinically melanoma in situ [2, 12].


The lesions tend to have elongated rete ridges and a proliferation of pigmented basaloid cells, which form buds and strands (bulb-like). Overlying epidermis shows hyper/compact keratosis indicating an abnormal pattern of keratinocytic maturation. In some cases, the rete ridges form large fingerlike projections in a reticulated pattern; however, in lesions from the face, the rete ridge hyperplasia is less prominent and almost absent [13]. Melanocytes can be mildly increased in number, do not have a confluent pattern, and are not cytologically atypical. In rare cases, melanocytes can be seen above the basal cell layer. There are melanophages (secondary to pigment incontinence) in superficial dermis. Solar elastosis is invariably present.

Solar lentigines may progress to standard seborrheic keratosis, thus showing progressive elongation and interanastomosis of rete ridges and horn pseudocysts. At any point in the evolution of a solar lentigo into a seborrheic keratosis, there may be a dense lichenoid inflammatory response along with an interface vacuolar damage of the dermal epidermal junction, known as benign lichenoid keratosis . Actinic lentigo may also undergo regression and it will also show lichenoid changes. In some other cases, there may be progressive architectural disarray of the epidermis with increased cytologic atypia, i.e., standard actinic keratosis. In cases in which there is severe actinic damage, it is not unusual to observe the coexistence of pigmented actinic keratosis and solar lentigo (Fig. 1.3a–c).


Fig 1.3
Solar lentigo. Elongated and pigmented rete ridges with prominent solar elastosis (a). High power showing pigmented retes and the lack of melanocytes (b)

Differential Diagnosis

In some cases, one may notice enlarged and cytologically atypical isolated melanocytes in the basal layer of the epidermis in an otherwise standard solar lentigo. This phenomenon is usually seen when there is severe solar damage. These melanocytes slightly vary in size and shape and may have enlarged and irregularly shaped vesicular nuclei with abundant cytoplasm. Therefore, at times it can be quite difficult to distinguish sun-damaged intraepidermal melanocytic hyperplasia in a solar lentigo versus incipient melanoma in situ (lentigo maligna type), particularly in small biopsies of a larger lesion. Both disorders will show an increased number of cytologically atypical melanocytes in the basal layer of epidermis. A useful feature to make a distinction would be to identify the presence of junctional nests, which will favor a melanocytic lesion (in this case melanoma in situ). Also, if there are solitary melanocytes in a confluent pattern of growth replacing the basal layer of epidermis and with periadnexal distribution, this is indicative of melanoma in situ (see also below in melanoma in situ, lentigo maligna type). If the dominant lesion is a solar lentigo, and there is low density of melanocytes at the basal layer, no lentiginous growth, and no melanocytic nests or pagetoid spread of melanocytes, these features will be in favor of sun-damaged intraepidermal melanocytic hyperplasia in a solar lentigo. Nonetheless, in certain cases it will be impossible to unequivocally separate the two by light microscopy in small samples, thus needing additional biopsies to establish the correct diagnosis.


Fig 1.4
Solar lentigo with subtle intraepidermal melanocytic hyperplasia. Note the focal intraepidermal melanocytic hyperplasia most compatible with chronic sun damage


Fig 1.5
Solar lentigo with early progression to seborrheic keratosis. The lesion shows elongated rete with acanthosis in the background of solar damage (a). The retes are elongated and have pigmented keratinocytes in the basal layer. Prominent solar elastosis is present (b)


Fig 1.6
Solar lentigo with early junctional nevus (“jentigo”). This lesion shows classic features of a solar lentigo along with superimposed melanocytes forming small nests in the junction (a). High power showing fusion of the rete along with rare melanocytes within epidermis (“jentigo”) (b). The presence of these nests represents early transformation into a junctional nevus


Fig 1.7
Solar lentigo with early junctional nevus. Another example with slight higher density of intraepidermal melanocytes and forming small nests (a). Higher magnification showing the rare and banal-appearing nests (b)

Ink-Spot Lentigo

Clinical Features

Ink-spot lentigo (reticulated solar lentigo of the back) is a variant of solar lentigo. It affects fair-skinned individuals and usually presents on a background of solar-damaged skin as a solitary, reticulated, black macule with a wiry, markedly irregular outline (reminiscent of an ink spot). The distribution is limited to sun-exposed areas of the body, usually on the upper back. Most commonly, it presents as one ink-spot lentigo among an extensive number of solar lentigines. Ink-spot lentigines can initially suggest melanoma because of their dark color and irregular borders [17].


Ink-spot lentigines are also similar to solar lentigines. However, the rete ridges appear less blunted and more tortuous (elongated and clubbed); there is epidermal hyperplasia with marked basal, suprabasal, and corneal cell hyperpigmentation. Melanocytes may be normal or mildly increased in number , but without cytologic atypia. The superficial dermis has melanophages.


Fig 1.8
Ink-spot lentigo. Small lesion with pigmented epidermis and melanophages in dermis (a). Note the lentiginous hyperplasia of the epidermis and marked skipping hyperpigmentation of the basal layer (b). There is minimal increase in the number of melanocytes along with scattered melanophages in dermis (c). The papillary plates are less pigmented than the tips of rete ridges

Large Cell Acanthoma

Large cell acanthoma is a pigmented, epidermal lesion that shares clinical and histopathologic features with solar lentigo and actinic keratosis . Some authors consider large cell acanthomas to be an evolutionary phase of solar lentigo to a reticulated seborrheic keratosis or established pigmented actinic keratosis, in which the keratinocytes show uniform enlargement, but the clinical appearance and the biologic potential are the same as conventional solar lentigo. The clinical presentation of the large cell acanthoma is primarily that of a large, flat, slightly scaly, tan macule on sun-damaged skin, i.e., indistinguishable clinically from a solar lentigo [14, 15]. There is a verrucous variant [16].


Large cell acanthoma shows keratinocytes that are uniformly enlarged without a significant increase in the nuclear to cytoplasmic ratio. Some cases may show a slight increased number of melanocytes. These changes can be confused with squamous cell carcinoma in situ, but the uniformity of the keratinocytes and the lack of other cytologic features allow a precise identification. As opposed to solar lentigo , there is no elongation of rete ridges.


Fig. 1.9
Large cell acanthoma. The lesion is composed of large uniform pigmented keratinocytes (a). High power shows lack of elongated retes and the uniform pigmented keratinocytes (b). Note the large keratinocytes (c)

Melanotic Macules

Clinical Features

Benign melanotic macules can be considered as the mucosal counterpart of lentigos. They present clinically as flat, smooth-bordered, well-defined pigmented lesions. Many variants can be included in this category including oral (labial) melanotic macule, genital melanotic macule, melanosis of the areola, melanosis of acral sites, and melanotic macules of the nail bed. They may be solitary of multiple, occasionally associated with complex syndromes.

Oral/labial melanotic macules : More commonly seen in the inferior lip; however, they can also be seen in the palate and tongue. When they present on the lip, the lower vermilion border is the most commonly affected area, although they can be seen anywhere in the oral mucosa [1719]. Oral and labial melanotic macules appear to be more common in patients infected with the human immunodeficiency virus [19, 20]. Multiple lesions can be seen in genetic syndromes including Hunziker-Laugier syndrome, Albright syndrome, neurofibromatosis, and familial polyposis syndrome [21].

Genital melanotic macules : Rare pigmented lesions, more commonly seen on the penis and vulva [22]. In the vulva they are more commonly located in the labia minora but also can be seen in the labia majora, introitus, and perineum. In the vulva they are usually multiple and can be large in size (up to 5 cm in diameter). On the penis, melanotic macules are usually located on the shaft. Lesions can also occur on the glans, and in this location they tend to be more irregular and larger in size. Lesions can also be seen in the scrotum. Melanotic macules on genital areas are clinically indistinguishable from melanoma in situ; however, lesion stability maintained after the phase of initial growth will favor benign over malignant.

Acral melanotic macules : On the volar surface of palms and soles of African American individuals. These lesions tend to be larger and multiple, although usually less than 5 mm in diameter.

Nail bed melanotic macules : Regular, delineated, and elongated pigmented stripes also known as melanonychia striata . Nail bed melanotic macules are the most common cause of melanonychia striata; however, melanomas, nevi, postinflammatory hyperpigmentation, and some complex syndromes can also cause melanonychia striata. Nail bed melanotic macules are usually multiple and randomly distributed as opposed to subungual melanoma which occurs on the thumb or great toe in most cases (90 %).

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Sep 27, 2017 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Lentigines
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