Normal skin, microscopic
The normal histologic appearance of the skin is shown. At the left is the epidermis. A thin layer of keratin (▲) overlies this epidermis. This keratinized layer is thicker on the palms and soles and over areas of the body surface where the skin is persistently rubbed or irritated. Beneath the epidermis (♦) is the dermis (∗) containing connective tissue with collagen and elastic fibers. A hair follicle (■) can be seen at the center with surrounding sebaceous glands (+). Associated with the hair follicle is a small bundle of smooth muscle (□) known as the arrector pili, which can cause the hair to “stand on end” and dimple the skin to form “goose bumps” when exposed to a cold (or stressful) environment.
Normal skin, microscopic
At high magnification, the skin has an overlying acellular keratin layer called the stratum corneum (▲) that continually desquamates. Beneath this is the nearly indistinguishable thin, darker red stratum lucidum (▼). The outer layer of epidermal cells has prominent purplish cytoplasmic granules and is called the stratum granulosum (♦). Below this is the thickest layer, the stratum spinosum (■), with polyhedral cells that have prominent intercellular bridges. A basal layer (+) of cells rests on a basement membrane. In this case, there is also prominent brown melanin pigmentation in the basal region. The upper papillary dermis (□) has small capillary blood vessels (×) that play a role in temperature regulation.
Vitiligo, gross
Irregular areas of hypopigmentation (♦) of the skin are shown here on the hand. This is a localized form of hypopigmentation (as contrasted with the diffuse form known as oculocutaneous albinism ). Many localized cases are idiopathic, although sometimes a systemic disease may be present. Microscopically, melanocytes are absent in the areas of vitiligo. The degree of skin pigmentation is related to melanocyte activity through the enzyme tyrosinase, and stimulated by ultraviolet light exposure, with formation of pigmented melanin granules, which are passed off to adjacent keratinocytes by long melanocyte cytoplasmic processes.
Freckles, gross
Ephelis is a fancy word for a freckle, a localized area of hyperpigmentation that can occur in some fair-skinned individuals, particularly those with red hair. The onset occurs in childhood, and the extent is related to the amount of sun exposure. Microscopically, the number of melanocytes in the skin is normal, but there is focally increased melanin production from each melanocyte. There is no increased risk for malignancy from an ephelis. The cosmetic industry benefits from them.
Age spots, gross
Seen on the hand are age spots or “liver” spots, termed senile lentigines (▲), which are common on areas of sun-exposed skin of older individuals. Perhaps 90% of fair skinned persons older than 70 years have one or more age spots. They are flat lesions with irregular borders, can be pinpoint to 1 cm in size, and are often multiple. They have no significance by themselves except for their cosmetic appearance. Once they appear, they do not change in response to sun exposure. However, they may form in response to a lifetime of sun exposure and may be a marker for skin cancer risk.
Lentigo senilis, microscopic
The microscopic appearance of lentigo senilis, commonly known as an age or “liver” spot, is shown. The rete ridges (∗) of the epidermis are elongated and appear club-shaped or tortuous. Melanocytes are increased in number along the basal layer of the epidermis, and melanophages (▲) filled with brown melanin granules appear in the paler pink lower papillary dermis, just above the darker pink reticular dermis. This process is localized and benign, with no malignant potential. Lentigo simplex is similar but often begins in childhood, may occur anywhere on skin, and is not related to sun exposure.
Tattoo, gross
Tattooing is a practice that is thousands of years old. In many human cultural groups, tattoos have great significance. Rituals can have usefulness for social groups, as long as no one gets hurt. The pigment in tattoos is transferred into the dermis with a needle, so there can be a risk for infection from the tattooing procedure. The tattoo itself over time tends to lose sharpness and intensity of color. Removal of a tattoo can be difficult; a laser light can be used to vaporize the pigment granules beneath the epidermis, but this is a laborious, time-consuming process. Removal at a later date is more likely to be undertaken when the blood ethanol level was high at the time of the tattooing procedure, or social relationships, or cultural values have changed.
Tattoo, microscopic
Tattoo pigment appears here as black granules (▲) deposited deep within the dermis (right panel) so removing or changing a tattoo is difficult. Over time, the pigment can be taken up into dermal macrophages, which can either concentrate it or redistribute it, blurring the pattern, particularly on intricate designs. Granulomatous inflammation or hypertrophic scarring may occur. Different tattoo pigments account for different colors. Some pigments, such as those creating a green color, can impart photosensitivity with inflammation (▲) (left panel) . Red, green, yellow, or blue pigments may cause an allergic reaction.
Melanocytic nevi, gross
Note the discrete brown lesions (▲) on the skin of the anterior chest. A melanocytic nevus is a small, brown, flat (macular) to slightly raised (papular) lesion with sharp borders that is quite common in light-skinned individuals. Such lesions are commonly called moles . These nevi are usually less than 0.6 cm in diameter, and they tend to grow very slowly and retain the same uniform degree of pigmentation and same sharp outlines, so that they seem hardly to change over time. These nevi are benign, with no risk for subsequent malignancy, but they must be distinguished from more aggressive pigmented lesions.
Melanocytic nevi, gross
The left panel shows a halo nevus, so called because the central pigmented area is surrounded by a lighter zone (▲), caused by an immune response to nevus cells. Nevi can show considerable variation in appearance: flat to raised, and pale to darkly pigmented. Most are small, well-circumscribed lesions that hardly seem to change at all, or change very slowly over time. The right panel shows a larger, flat, pigmented nevus on the upper back that can be termed a café au lait spot .
Congenital nevus, gross
Nevi are congenital if present from birth, many having arisen from an embryonic somatic mutation, remain relatively unchanged, and microscopically extend into the deep dermis. Small (<1.5 cm) congenital nevi can be found in approximately 1% to 2% of newborns. The lesion is usually raised, dark to medium brown, with a sharp border (as shown) and smooth or papillomatous surface. Multiple and large congenital nevi carry an increased risk for development of malignant melanoma.
Congenital nevus, microscopic
The microscopic features shown here include nevus cells (▲) extending to deep dermal appendages, neurovascular structures, and subcutaneous fat, with infiltration of nevus cells among collagen bundles, and a subepidermal region with few nevus cells. Though the lower border is indistinct, the cells are small and quite uniform; the lesion shown is benign. Abnormalities in postzygotic somatic NRAS and BRAF mutations may be present. Acquired nevi appearing later in life usually do not involve deeper structures.
Junctional nevus, microscopic
This is the early stage of a junctional, or nevocellular, nevus. It is termed a junctional nevus because there are nevus cells in nests (∗) within the lower epidermis. As nests of cells continue to “drop off” (▲) into the upper dermis, the lesion could then be termed a compound nevus . In contrast to a melanoma, there is no significant atypia of these nevus cells and no adjacent dermal inflammation. In addition, there is a maturation effect so that the nevus cells in the lower epidermis tend to be larger, with pigment, whereas the cells that extend deeper into the dermis are smaller, with little or no pigment. This microscopic maturation with differentiation to smaller cells helps distinguish this lesion from a malignant melanoma.
Intradermal nevus, microscopic
This lesion is termed an intradermal nevus because the nevus cells (melanocytes that are transformed to rounded cells that proliferate as aggregates or nests [∗]) are found solely within the dermis, although close to (▲) the overlying epidermis. This is considered to be a later stage of a junctional (nevocellular) nevus in which the connection of the nevus cells to the epidermis has been lost. The benign nature of the nevus cells is confirmed by their regular, small, uniform appearance. The cells form small aggregates in nests and cords, which are not encapsulated and may interdigitate with adnexal structures. The nevus cells have clear cytoplasm and small round blue nuclei without prominent nucleoli or mitoses.
Spitz nevus, microscopic
Spitz nevi are more common in children, appear red like a hemangioma, and are generally larger than other forms of nevi. They are composed of spindled or epithelioid melanocytes or both, as shown here. The melanocytes display uniform features and cytoplasm is abundant and varies from eosinophilic to slightly basophilic. Nested melanocytes (▲) have fairly uniform cytologic features. There is a gradual transition from larger nests of melanocytes in the superficial dermis to smaller melanocytes in smaller nests, to dispersed aggregates, and single units within the deep dermal component, often appearing adjacent to adnexa (◄). The visible skin lesion has a symmetrical profile and circumscribed margins.
Blue nevus, microscopic
The nevus shown has uniform highly dendritic spindle cells with abundant melanin (►), giving them their grossly blue-black appearance. This color may suggest melanoma, but the blue nevus has regular borders and more uniform pigmentation, and tends to grow slowly. The nevus cells extend into the dermis, but not as nests. They are most common in Asian populations, arising in teenage years, and affecting 3% to 5% of adults, and twice as many women as men.
Dysplastic nevus, microscopic
This atypical melanocytic hyperplasia is “in between” a clearly benign melanocytic nevus and a malignant melanoma. There are an increased number of melanocytes, some with atypical features such as enlarged, irregular nuclei at the dermal-epidermal junction (▲). They are generally larger than 0.5 cm and display an irregular pigment distribution. The autosomal dominant dysplastic nevus syndrome (or familial melanoma syndrome) has many such lesions with an increased risk for eventual development of malignant melanoma, though most lesions act benignly. A CDNK2 gene mutation leads to production of an abnormal p16/INK4A cyclin-dependent kinase inhibitor. Activating mutations in the NRAS and BRAF genes can be present.
Malignant melanoma, gross
This pigmented lesion has been excised with a wide margin. Although this lesion is only about 1 cm in size, it illustrates “ABCDEs” and shows A symmetry, irregular B orders, variable pigmentation C olor, larger D iameter, and E volution with changing appearance—all worrisome signs. Increasing diameter and rapid evolution of the appearance are also suspicious for malignancy. Melanomas begin with a radial growth phase, but over time start a vertical growth phase, invading down into the dermis and developing the potential for metastases to lymph nodes and distant sites. Larger lesions are more likely to have invaded deeper. Sun exposure (UV radiation) leads to an increased risk for malignant melanoma.
Malignant melanoma, microscopic
This neoplasm is composed of large polygonal cells (or spindle cells in some other cases) that have very pleomorphic nuclei that contain prominent nucleoli. The neoplasm in the right panel is producing abundant brown intracytoplasmic melanin pigment (▼). Melanoma cells can make variable amounts of pigment, even within the same lesion (leading to the characteristic variability in color, which helps distinguish it from a benign nevus). Some melanomas may make so little pigment that grossly and microscopically they appear “amelanotic” (left panel) .
Malignant melanoma, microscopic
This Fontana-Masson silver stain shows fine black dusting of melanin pigment within the cytoplasm of the neoplastic cells of this malignant melanoma. Familial and sporadic malignant melanomas can have the CDKN2A ( p16/INK4A ) gene mutation, a cyclin-dependent kinase inhibitor. Mutations in the BRAF and NRAS genes are also seen. Polymorphisms of the melanocortin 1 receptor gene may underlie skin tone with sensitivity to UV radiation and cancer risk. A sixth of melanomas may have an inherited genetic basis with autosomal dominant pattern and variable penetrance.
Malignant melanoma, microscopic
Nests of neoplastic cells have infiltrated downward as part of the ominous vertical growth phase. There was development of a grossly apparent raised nodule by this lesion. The nests here contain abundant brown melanin pigment. An inflammatory reaction of lymphocytes surrounds some tumor nests. This immunologic response is rarely effective on its own in controlling the growth. Thickness, mitotic rate, and ulceration are prognostic indicators. A T1 stage with depth of invasion < 1 mm has a better prognosis. Suspicious pigmented skin lesions should be completely excised.
Seborrheic keratosis, gross
Shown are examples of very common lesions of older individuals—seborrheic keratoses. These warty lesions are usually distributed over the skin of the face, neck, and upper trunk. They develop into rough-surfaced, coin-like plaques that vary from a few millimeters in size to several centimeters. They slowly enlarge over time. They are usually brown, but the amount of pigmentation can vary from one lesion to the next. On close inspection of a lesion, keratin appears to erupt out of small pores on the surfaces.
Seborrheic keratosis (SK), gross
This SK has an appearance as though it had just been pasted or “stuck on” the skin, as seen here in cross-section of an excised lesion. The brownish nodular, rough-surfaced lesion extends above the level of the underlying tan epidermis, with yellow subcutaneous adipose tissue below. In some cases, SKs can have a downward growth phase, termed inverted follicular keratoses . SKs enlarge slowly over time and are usually asymptomatic. Their unsightliness is their only real consequence. A larger lesion might become irritated and itch or bleed from rubbing on clothing or scratching. They are never malignant.
Seborrheic keratosis (SK), microscopic
This SK is formed of benign-appearing, well-differentiated squamous epithelium, and the lesion extends above the level of the surrounding epidermis (▼) seen on the left, giving it the raised appearance as though it were “stuck on” to the skin surface. Broad bands of normal-appearing epidermal cells have large keratin-filled “horn cysts” (□) within them. When irritated by scratching or rubbing, they can enlarge from inflammation with swelling and secondary infection. Activating mutations in the fibroblast growth factor receptor-3 gene may drive their growth.
Acanthosis nigricans, microscopic
These hyperpigmented lesions occur most commonly in areas of flexure, such as at the elbow, axilla, neck, or groin. Their hyperpigmentation is due to increased melanin granules within the epidermal basal layer. Seen here is epidermal downward papillomatosis with overlying hyperkeratosis (∗) and patchy hyperpigmentation (▲) of the basal cell layer. Most cases occur in childhood and are the result of either an autosomal dominant condition or a manifestation of obesity or an endocrinopathy. The appearance of acanthosis nigricans in adults may presage signs and symptoms of an underlying malignancy such as gastric adenocarcinoma.
Fibroepithelial polyp, gross
Two examples of skin tags, each about 0.6 cm long, are shown. These are also termed soft fibromas or acrochordons . They appear as papules or bag-like pedunculated growths connected by a narrow pedicle to the skin of the neck, trunk, or extremities. They are covered by epidermis and composed centrally of a loose overgrowth of connective tissue from the reticular dermis. They can be a nuisance when they appear at the belt line or axillary line, where rubbing and irritation can occur. Similar to hemangiomas and nevi, they may become more numerous during pregnancy.
Epithelial cyst, microscopic
An epithelial cyst (also known as a wen, or sebaceous cyst ) is palpably fluctuant and freely movable. It becomes filled with soft keratinaceous debris. A wen forms when there is down-growth of the overlying epidermis or epithelium of a hair follicle into the underlying dermis. There is continued desquamation of keratin into the center of the expanding cyst (∗). These lesions are common. Larger cysts may become traumatized and rupture, inducing a surrounding inflammatory reaction with swelling that can include acute, chronic, and granulomatous elements.
Epithelial cyst, microscopic
This epithelial cyst was excised from beneath the skin surface, with a rim of dermal connective tissue (♦) on the right. These cysts appear most frequently on the face, scalp, neck, and trunk. They range from 1 to 5 cm in size. They have a wall of epidermis that desquamates the keratin seen here as laminated acellular pink material (■) on the left, which forms the soft cyst contents that give it the fluctuant, movable characteristics that lead to the clinical description sebaceous cyst . Cyst rupture can lead to marked foreign-body inflammation. The lack of a granular cell layer in this example is most characteristic of the variant known as a pilar cyst beneath the scalp.
Actinic keratosis, gross
The irregular, tan to red, plaque-like lesions (◄) with a rough surface seen here on sun-exposed skin may enlarge over time. These lesions are usually <1 cm. This is a potentially premalignant lesion that can give rise to squamous cell carcinoma (SCC) in situ, which can evolve into an invasive squamous carcinoma. It is common for patients to have more than one such lesion in sun-exposed areas of skin. If such a lesion appears on the lips, it is termed actinic cheilitis . Because SCCs often arise in areas of actinic keratosis, removal of these lesions, or topical chemotherapy (imiquimod or 5-FU), is recommended.
Actinic change, microscopic
Extensive, prolonged exposure to sunlight with ultraviolet (UV) radiation, and particularly in light-skinned persons, leads to homogenization of the dermal collagen and elastic fibers, seen here as the pale blue connective tissue (■) in the dermis. The overlying epidermis is atrophic, consistent with aging. The loss of connective tissue integrity, particularly the elastic fibers, increases visible skin aging features such as wrinkles. More sun exposure with UVA rays (there are 500 times more of them than UVB) leads to more wrinkling. UVB rays penetrate less, tend to cause sunburn, and create a greater risk for skin cancer.
Actinic change, microscopic
Actinic damage from increased skin exposure to ultraviolet light in sunlight is shown here. There is parakeratosis (♦) along with keratinocyte atypia (■) limited to the lower epidermal layers. The damaged collagen and elastic fibers appear as homogeneous pale-blue areas (∗) in the dermis, termed solar elastosis . With more extensive solar damage, there can be dermal inflammation (□). Fair-skinned individuals are at greater risk for development of this condition. The actinic damage is cumulative and nonreversible. The loss of dermal connective tissue resiliency with elastic fibers contributes to skin aging with wrinkling.
Squamous carcinoma in situ, microscopic
This actinic keratosis has marked overlying hyperkeratosis with a dense layer of dark pink keratin (∗). Sometimes the hyperkeratosis is so pronounced that there is formation of a “cutaneous horn” of projecting keratin from the lesion. Actinic keratoses are predisposed to progress to squamous cell carcinomas (SCCs). Note the epithelial atypia (♦) here involving the full thickness of the epidermis, without penetrating the basement membrane (◄), which qualifies this lesion as a SCC in situ.
Squamous cell carcinoma in situ, microscopic
Because this malignant neoplasm does not extend below the basement membrane (▲), this carcinoma is termed carcinoma in situ . This condition is sometimes called Bowen disease . Note the normal skin (♦) on the right adjacent to the thicker carcinoma (∗) on the left with more cellular pleomorphism and hyperchromatism. There is also extensive solar elastosis (■), marked by the pale-blue homogeneous appearance of the underlying dermal collagen, a result of chronic sun damage. Loss of normal TP53 tumor suppressor gene function in such lesions is common; RAS mutations may also be present. The cells of these neoplasms are often aneuploid.
Squamous cell carcinoma (SCC), gross
This small nodule (►) on the scalp is centrally ulcerated. Such small skin tumors are often noticed by the patient before reaching a larger size, and smaller, more localized lesions are less likely to have invaded far or metastasized. This explains the high “cure” rate for nonmelanoma skin cancers. SCCs of the skin are related to the amount of past sun exposure; UVB rays create the greatest risk. The surrounding skin may show actinic keratoses (premalignant actinic change from sun damage). Human papillomavirus infection may play a role in development of some of these cancers, particularly with immunosuppression (chemotherapy or allogeneic transplantation).
Squamous cell carcinoma (SCC), gross
This is a large ulcerated SCC (▼) on the dorsum of the hand, and there was a history of both sun exposure and carcinogen exposure. Besides sun exposure, risk factors for SCC of skin include exposure to carcinogens such as tars (polycyclic hydrocarbons), chronic ulcers, burn scars, arsenic poisoning, and radiation exposure. The rare autosomal recessive disorder xeroderma pigmentosum is related to defects in nucleotide excision and repair genes so that pyrimidine dimers formed in cellular DNA from ultraviolet light exposure lead to a 2000-fold increased risk for SCCs, which can arise even in childhood.
Squamous cell carcinoma, microscopic
This well-differentiated carcinoma has large polygonal cells with extensive pink keratinization forming a mass lesion. It is nodular and infiltrates downward as tongues and nests of cells (▲) into the underlying dermis. Compare with non-cancerous squamous epithelium (▼) at the upper right. In spite of the increasing size of these carcinomas, even when ignored and untreated, they typically remain localized for years, but enlarge, ulcerate and potentially metastasize.
Keratoacanthoma (KA), gross
This low-grade skin malignancy thought to arise in pilosebaceous units has an unusual course. It can grow rapidly over weeks to months, reaching a size of 1 cm to several centimeters, suggesting a more aggressive behavior. This period of rapid growth is followed by stabilization, then regression in a year, leaving a residual scar. KAs are most often seen on sun-exposed skin in men older than 50 years, often on the face. Grossly, the lesion seen here appears as a symmetric dome-shaped nodule with a central keratin-filled crater.
Keratoacanthoma (KA), microscopic
This endophytic crater-like lesion has a proliferation of well-differentiated squamous epithelium extending downward in tongues and nests (▲) into the dermis, but remains well demarcated without extensive invasion. The large cells have prominent glassy pink cytoplasm and minimal atypia. Abundant keratin production results in the central collection of keratinaceous material (▼) that erupts outward. KA resembles a well-differentiated squamous cell carcinoma (SCC) but the course and biology are different. HRAS mutations, as well as cyclin D1 overexpression coupled with functional p16 are more frequent in KA than in SCC.
Basal cell carcinoma (BCC), gross
This large carcinoma of the lower lip has a pearly pink papular border (◄) and an ulcerated center. These lesions rarely metastasize, but they are slowly growing and progressively infiltrative over time (a “rodent ulcer” that keeps eating away at normal tissues). Leaving them to get larger just makes the plastic surgeon’s job that much harder, with more disability to the patient, so early detection and excision are essential to reduce morbidity. Most BCCs occur on the head and neck area of adults. There is an increased risk for development of BCC with prolonged sun exposure, specifically with more damaging UVB rays.
Basal cell carcinoma (BCC), microscopic
BCC and squamous cell carcinoma are the most common skin malignancies. Note here the densely packed dark-blue cells (■) expanding in a nodular growth pattern beneath the thin overlying epidermis (►). A BCC can grow quite large and invade surrounding tissues, but it virtually never metastasizes. BCCs around the eye present a challenge to the surgeon to remove while retaining enough tissue for functional closure of the eyelid. It is best to detect them early and excise them when they are small. Most BCCs have mutations in PTCH , a tumor suppressor gene producing a protein receptor for sonic hedgehog signaling pathway, as does the rare basal cell nevus syndrome.
Basal cell carcinoma (BCC), microscopic
The cells of a BCC are dark blue and oblong with scant cytoplasm, resembling the cells along the basal layer of normal epidermis. These cells are arranged into nests or trabeculae that infiltrate downward into the dermis. A nest of tumor often has a palisaded arrangement of cells (▲) around its periphery. These tumor cell nests have an intervening fibrous stroma with variable inflammatory cell component. Nests of basaloid cells dropping off into the upper dermis are shown here. These neoplasms can often be multifocal in areas of chronic sun exposure. They also occur frequently in patients with xeroderma pigmentosum and in patients with immunosuppression.
Xanthoma, gross
Xanthomas are collections of lipid-laden (foamy) histiocytes (macrophages) within the dermis, producing a grossly visible yellowish nodule or plaque. This little yellow plaque (▼) on the upper eyelid seen here on a patient (who did not have any blood lipid abnormality) is called a xanthelasma . In contrast, eruptive xanthomas may appear both on skin and in soft tissues of patients who have familial or acquired forms of hyperlipidemia. Xanthomas tend to increase or decrease in proportion to blood lipid levels.
Xanthoma, microscopic
Numerous foamy macrophages (histiocytes) with a pale appearance to their cytoplasm are seen here within the dermis, below a normal epidermis. This foamy appearance of the cells results from extensive lipid deposition, incorporating cholesterol, phospholipids, and triglycerides, contained within the macrophage cytoplasm. These lesions are benign and a cosmetic issue for most persons, but their appearance suggests a possible underlying disorder of lipid metabolism.
Hemangioma, gross
This red nodular lesion is benign, with sharp borders, and composed of proliferations of small blood vessels. This “juvenile” hemangioma was not apparent at birth but grew rapidly in the first few months of infancy; it will gradually involute over the next 5 to 10 years. However, many small hemangiomas are slow growing and seemingly never change. They can range in color from blue to reddish blue to purple to bright red. They average a few millimeters to several centimeters in size, although some congenital lesions (typically cavernous hemangiomas) can be more extensive (“port wine stain”). Lesions present from birth may be hamartomas rather than true neoplasms.
Hemangioma, microscopic
A reddish “mole” that is small, round, and raised may represent a hemangioma, seen here to be composed of vascular spaces within the upper dermis. These small vascular channels, which may vary in size and shape, are lined by flattened endothelial cells (▲). These lesions often appear to change slowly, if at all, over time and seem to have been present as long as the patient can remember. In the capillary hemangioma shown, most of the vascular spaces are small, and the intervening loose connective tissue stroma may contain larger arterioles or venules. In contrast, a cavernous hemangioma has large, dilated vascular spaces that may extend into the underlying adipose tissue.
Pyogenic granuloma, microscopic
Also known as a lobular capillary hemangioma, this lesion can grossly resemble a hemangioma, but it is characteristically rapidly growing, arising and then receding within weeks to months, rather than persisting for years unchanging. It may develop during pregnancy, then disappear after delivery. Local inflammation or irritation may result in formation of a nodule of granulation tissue (∗) with prominent capillaries (□), as seen here. Around the capillaries are inflammatory cell infiltrates. The lesion often ulcerates. Similar lesions can appear on the gingiva.
