Seborrheic keratoses are the most common benign tumor in older individuals. Seborrheic keratoses have a variety of clinical appearances, as seen in the images below, and they develop from the proliferation of epidermal cells. No specific etiologic factors have been identified.
View Image | Sharply circumscribed elevated seborrheic keratoses. |
View Image | Closer view of multiple seborrheic keratoses in an autosomally dominant mode of inheritance. |
View Image | Seborrheic keratosis showing lackluster surface and appearance of being stuck on the skin surface. |
See Mole or Melanoma? Test Yourself With These Suspicious Lesions, a Critical Images slideshow, to help identify various skin lesions.
Seborrheic keratoses are thought to result from a clonal expansion of a mutated epidermal keratinocyte.[1] Seborrheic keratoses exhibit histologic evidence of proliferation. Increased cell replication has been demonstrated in seborrheic keratoses with bromodeoxyuridine incorporation studies and immunohistochemistry for proliferation-associated antigens.
Reticulated seborrheic keratoses are usually found on sun-exposed skin, and the reticulated type of seborrheic keratoses may develop from solar lentigines.
Epidermal growth factors and their receptors have been studied in the development of seborrheic keratoses.[2, 3, 4] No difference was observed in the expression of immunoreactive growth hormone receptors in keratinocytes from normal epidermis and keratinocytes from seborrheic keratoses. The expression of BCL2, an apoptosis-suppressing oncogene, is low in seborrheic keratosis in contrast to the high values in basal cell and squamous cell carcinoma.[5] No increase is observed in the sonic hedgehog signal transducers patched (ptc) and smoothened (smo) messenger RNA (mRNA) in seborrheic keratosis over normal skin.[6]
A high frequency of mutations in the gene encoding the tyrosine kinase receptor FGFR3 (fibroblast growth factor receptor 3) has been found in certain types of seborrheic keratoses. This was the first clue into the genetic basis for the pathogenesis of seborrheic keratoses. FGFR3 belongs to a class of transmembrane tyrosine kinase receptors involved in signal transduction to regulate cell growth, differentiation, and migration, as well as wound healing and angiogenesis. Upon ligand binding, FGFR3 dimerizes, which, in turn, induces phosphorylation of the kinase domain. Activating mutations in FGFR3 have been found in approximately 40% of hyperkeratotic seborrheic keratoses, 40% of acanthotic seborrheic keratoses, and 85% of adenoid seborrheic keratoses.[7, 8, 9]
More than 80% of seborrheic keratoses have at least one mutation, and 45% have more than one mutation in an oncogene such as FGFR3, PIK3CA, KRAS, and EGFR.[10] The most frequently mutated genes in seborrheic keratoses are FGFR3 (found in 71% or sporadic seborrheic keratosis) and the p110 catalytic subunit of phosphatidylinositol 3 kinase (PI3K) (found in 50% of sporadic seborrheic keratoses).[11] Seborrheic keratoses have a higher proliferative rate than normal keratinocytes, and apoptosis is suppressed in seborrheic keratoses compared with healthy skin.[12, 13] Both of these proteins effect the activity of Akt kinase. The activation of Akt kinase enhances the survival of cells by blocking the p53 pathway and the FOXO-mediated proapoptotic cascade.[14] Thus, the signaling kinase Akt is critical in preventing seborrheic keratosis cells from undergoing programmed cell death. When Akt is inhibited, seborrheic keratosis cells quickly die through apoptosis.[15]
Seborrheic keratoses have a varying degree of pigmentation. In pigmented seborrheic keratoses, the proliferating keratinocytes trigger the activation of neighboring melanocytes by secreting melanocyte-stimulating cytokines. Endothelin-1 has dual stimulatory effects on DNA synthesis and melanization of human melanocytes and has been implicated as playing a part in the hyperpigmentation observed in seborrheic keratoses.[16] Immunohistochemically, the keratinocytes of seborrheic keratoses express low molecular weight keratin but often exhibit a partial lack of the high molecular weight forms of keratin.
Seborrheic keratoses are thought to result from a clonal expansion of a mutated epidermal keratinocyte.[1] (see Pathophysiology). Some cases are inherited through an autosomal dominant mode of inheritance. Sunlight seems to play a role in the development of some seborrheic keratoses.[17] Evidence indicates that at least some seborrheic keratoses have a clonal nature. Activating mutations in the gene encoding the tyrosine kinase receptor FGFR3 have been found in 85% of adenoid seborrheic keratoses. This is discussed in Pathophysiology section.
United States
Seborrheic keratoses are the most common benign tumor in older individuals. The frequency appears to increase with age. In 1963, Tindall and Smith examined a population of individuals older than 64 years in North Carolina and found that 88% of the people had at least one seborrheic keratosis.[18] In this study, 38% of the white women, 54% of the white men, and 61% of the black men and women were found to have 10 or more seborrheic keratoses. In 1965, Young examined 222 residents of the Orthodox Jewish Home for the Aged in New York and found that 29.3% of the men and 37.9% of the women had seborrheic keratosis.
International
In 2000, Memon et al found in a British population younger than 40 years that 8.3% of the males and 16.7% of the females had at least one seborrheic keratosis.[19] In an Australian population, 23.5% of individuals aged 15-30 years were found to have at least one seborrheic keratosis, with no significant differences between the sexes. In another Australian study of 100 people composed of hospital staff and nondermatologic day patients, 12% of people aged 15-25 years (n = 34), 79% of people aged 26-50 years (n = 24), 100% of people aged 51-75 years (n = 25), and 100% of people older than 75 years (n = 17) had seborrheic keratoses. The median number of seborrheic keratoses per person was 6 in the group aged 15-25 years, 5 in the group aged 26-50 years, 23 in the group aged 51-75 years, and 69 in those older than 75 years.
Seborrheic keratoses are less common in populations with dark skin compared to those having white skin; however, black individuals develop a variant of seborrheic keratoses termed dermatosis papulosa nigra. These lesions affect the face, especially the upper cheeks and lateral orbital areas. They are small, pedunculated, and heavily pigmented with a minimal keratotic element. The onset of these lesions generally is earlier than that of ordinary seborrheic keratoses.
No sex difference is apparent in the frequency of occurrence of seborrheic keratoses.
Seborrheic keratoses are the most common benign tumor in older individuals. They appear to increase with age. Seborrheic keratoses have also been found to occur in younger individuals.
Seborrheic keratoses are benign, but secondary tumors and Bowen disease (squamous cell carcinoma in situ) or malignant melanoma may occasionally arise within the lesion. Seborrheic keratoses can also catch on clothing and become irritated. They can itch, grow, and bleed. Scratching seborrheic keratoses or trying to pick them off the skin can result in a secondary infection.
People sometimes have many seborrheic keratoses, and they may obscure the detection of a dysplastic nevus or malignant melanoma.
The lesions generally do not resolve and usually grow larger and thicker with time.
Patients often have heard that they need to have a changing mole examined, and the appearance of seborrheic keratoses prompts them to seek medical care. This provides an excellent opportunity for a complete skin examination to search for skin cancer and a discussion on using sunscreens for both the patient and their family.
Patients can generally be reassured that the lesions are benign and do not need to be removed unless they are changing or become irritated.
Continued follow-up is important. Patients who see a doctor and who are assured that these lesions are benign may not pay attention to newly appearing lesions that continue to develop over time. One of the newly appearing lesions may not be a seborrheic keratosis but, in fact, a malignant tumor.
For patient education resources, visit the Skin Conditions and Beauty Center and Cancer Center. Also, see the patient education article Skin Cancer.
Seborrheic keratoses usually are asymptomatic, but they can be an annoyance. Lesions can itch and rub or catch on clothing, thereby becoming inflamed.
Lesions often are unattractive and serve as negative psychological connotations—daily reminders of aging.[20, 21]
Patients are sometimes concerned that these enlarging lesions are malignant. Sometimes a person may have many seborrheic keratoses and not notice a dysplastic nevus or a malignant melanoma that develops among the seborrheic keratoses. A significant danger can arise if a person does not detect a malignant melanoma at an early stage.
Although lesions may resolve on occasion, spontaneous resolution does not ordinarily occur.
The sign of Leser-Trélat is the association of multiple eruptive seborrheic keratoses with internal malignancy. Most commonly, the sign is observed with adenocarcinoma, especially of the gastrointestinal tract; however, an eruption of seborrheic keratoses may develop after an inflammatory dermatosis (eg, eczema,[22] severe sunburn). In this latter case, no associated malignancy is expected.
Seborrheic keratoses usually begin with the appearance of one or more sharply defined, light brown, flat macules. The lesions may be sparse or numerous.
As they initially grow, they develop a velvety to finely verrucous surface, followed by an uneven warty surface with multiple plugged follicles and a dull or lackluster appearance.
They typically have an appearance of being stuck on the skin surface.
The color of the lesions can vary from pale brown with pink tones to dark brown or black.
Their natural history includes slow enlargement with increasing thickness and the gradual development of new lesions.
A familial trait exists for the development of multiple seborrheic keratoses in about half of the patients, with an autosomal dominant mode of inheritance.
Seborrheic keratoses can occur on almost any site of the body, with the exception of the palms and soles and mucous membranes. In an Australian study of the site of distribution of 3067 seborrheic keratoses, 54.7% were found on the trunk, 15.2% on the hands, 11.4% on the face and neck, 8.5% on the arms, 2.6% on the upper leg, 6% on the lower leg, and 1.6% on the feet. In this study, the prevalence of seborrheic keratosis was higher on sun-exposed areas compared with nonexposed areas when surface area was taken into account.[23]
Initially one or more sharply defined, light brown, flat lesions develop with a velvety to finely verrucous surface. They arise on normal skin. Their initial size is usually less than 1 cm, but the lesions can grow to several centimeters or more. With time, the lesions become thicker and have an appearance of being stuck on the skin surface.
View Image | Seborrheic keratosis showing lackluster surface and appearance of being stuck on the skin surface. |
View Image | This is an autosomal dominant form of multiple seborrheic keratoses. This man's daughter is developing a similar distribution and quantity of seborrhe.... |
View Image | The back of this same patient as in the image above with multiple seborrheic keratoses. His face had a similar number of seborrheic keratoses. |
Fully developed seborrheic keratoses often are deeply pigmented and do not reflect light.
Many lesions show keratotic plugging of the surface.
Some lesions are covered by an adherent greasy-appearing scale and are raised above the surface of the skin. Seborrheic keratoses can feel soft and greasy.
The shape is round to oval, and multiple lesions may be aligned in the direction of skin folds.
The smallest lesions are placed around follicular orifices, especially on the trunk.
Most seborrheic keratoses have fewer hairs than the surrounding skin.
Sometimes the lesions can grow large, with individual seborrheic keratoses reaching many centimeters in size.
Epiluminescent surface microscopic examination of seborrheic keratoses reveals globulelike structures. The globule like structures in seborrheic keratoses are due to intraepidermal horn cysts filled with cornified cells containing melanin. They resemble the brown globules observed in melanocytic neoplasms, which are due to nests of melanocytes at the dermoepidermal junction.
Irritation can cause swelling and sometimes bleeding, oozing, and crusting and a deepening of the color due to inflammation.
Seborrheic keratoses may become red-brown in color when they become inflamed.
Variants include the following:
Seborrheic keratoses are an annoyance. Lesions can itch and rub or catch on clothing, thereby becoming inflamed.
Lesions often are unattractive and have negative psychological connotations—daily reminders of aging.
Patients are sometimes concerned that these enlarging lesions are malignant. Sometimes a person that has many seborrheic keratoses may not notice a dysplastic nevus or a malignant melanoma that develops among the seborrheic keratoses. A significant danger can arise if a person fails to detect a malignant melanoma at an early stage.
No laboratory tests are needed unless the sudden appearance of multiple pruritic seborrheic keratoses occurs, which is known as the Leser-Trélat sign. This has been associated with the development of adenocarcinoma of the gastrointestinal tract,[27] lymphoma, Sézary syndrome, and acute leukemia.
No imaging studies are needed, unless the sudden appearance of multiple pruritic seborrheic keratoses occurs (known as the Leser-Trélat sign).
The shave biopsy provides histologic material for accurate diagnosis and removes the lesion in a cosmetically acceptable manner at the same time. After a shave biopsy is obtained, a curette can be used to smooth and remove any remaining keratotic material.
These lesions are raised above the skin surface, and they show a papillomatous epithelial proliferation containing horn cysts without any tendency toward malignancy. The proliferating cells are epidermal and have a basaloid appearance. The number of epidermal basal cells is greatly increased. The acanthotic pattern (see the images below) is the most frequent, in which a thick layer of basal cells is observed interspersed with pseudo-horny cysts. Invaginations to form keratin-filled pseudocysts are present. Some of these cells contain melanin.
View Image | Acanthotic type of seborrheic keratosis. |
View Image | Higher-power view of the cells in an acanthotic seborrheic keratosis. |
Hyperkeratotic seborrheic keratoses, shown in the images below, have pronounced hyperkeratosis and papillomatosis with less acanthosis. When papillomatosis is particularly prominent, the histology resembles acrokeratosis verruciformis of Hopf. The epidermis is largely composed of squamous cells interspersed with aggregates of basaloid cells.
View Image | Hyperkeratotic type of seborrheic keratosis. |
View Image | Seborrheic keratoses projecting above the level of the epidermis. Cysts represent sections of hyperkeratotic follicles. |
The reticulated or adenoid type (shown in the images below) of seborrheic keratoses contains numerous thin tracts of basaloid epidermal cells that are branched and interwoven. They have less epidermal thickening, and horn pseudocysts usually are less prominent in reticulated seborrheic keratoses. Marked hyperpigmentation is often present, and they have some histologic similarity to lentigo senilis.
View Image | Reticulated (or adenoid) type of seborrheic keratosis. |
View Image | This is a reticulated (or adenoid) seborrheic keratosis with abundant pigment. |
An acantholytic type with acantholysis also occurs and is particularly prominent in the squamous eddies of irritated seborrheic keratosis. Irritated seborrheic keratoses show a change from the basaloid keratinocytes observed in the acanthotic type, which are more mature squamous cells, to cells that are sometimes associated with mild nuclear atypia. The keratinocytes are arranged in swirls or whorls known as squamous eddies. Spindling of keratinocytes is common. Inflammatory cells are often observed intermingled with the proliferated epidermal cells, shown in the image below.
View Image | Seborrheic keratosis with inflammation in the dermis. |
View Image | This seborrheic keratosis was a pedunculated lesion in an axillary fold. Clinically, it had some resemblance to a skin tag. |
The clonal seborrheic keratoses show well-demarcated nests of basaloid or larger squamous cells within an acanthotic seborrheic keratoses. Melanoacanthoma is a deeply pigmented seborrheic keratosis in which an acanthotic proliferation of large dendritic melanocytes is identified. It probably represents a concomitant proliferation or activation of the dendritic melanocytes and epidermal cells. Lichenoid seborrheic keratosis is an inflammatory variant. In one study of 108 seborrheic keratoses, 66% were acanthotic, 25% were hyperkeratotic, and 9% had a reticulated (adenoid) pattern. In this study, 5.5% (6/108) of the specimens contained squamous cell carcinoma and 4 of these appeared to develop within the central portion of the lesion. Also, 4 of the 6 malignancies developed in the reticulated type of seborrheic keratoses.
In irritated seborrheic keratoses, pronounced squamous metaplasia can occur, which may be misdiagnosed as basosquamous carcinoma. This phenomenon is not due to human papillomavirus.[28] Human papillomavirus can be identified in the seborrheic keratoses of patients with epidermodysplasia verruciformis and in seborrheic keratosis–like lesions exhibiting bowenoid changes. These probably should be considered as condylomata rather than as true seborrheic keratoses.[29, 30]
The histologic differential diagnosis of seborrheic keratoses includes verruca vulgaris, fibroepithelial polyp, condyloma acuminatum, acanthosis nigricans, epidermal nevus, confluent and reticulated papillomatosis of Gougerot and Carteaud, hidroacanthoma simplex,[31] acrokeratosis verruciformis of Hopf, lentigo senilis, and tumor of the follicular infundibulum.
Acanthotic seborrheic keratoses may be confused with eccrine poromas, but no ductular differentiation is observed in seborrheic keratosis. Hidroacanthoma simplex can be distinguished from clonal seborrheic keratosis by the presence of ductal and cystic spaces histologically and by a lower density of Langerhans cells and fewer melanin granules in the intraepidermal nests. Verruca vulgaris can usually be differentiated from seborrheic keratoses because verruca vulgaris usually displays keratohyalin granule clumping, perinuclear vacuolization, and ectatic vessels within the papillary dermal tips.
Ammonium lactate and alpha hydroxy acids have been reported to reduce the height of seborrheic keratoses.[32, 33] Superficial lesions can be treated by carefully applying pure trichloroacetic acid and repeating if the full thickness is not removed on the first treatment.
Topical treatment with tazarotene cream 0.1% applied twice daily for 16 weeks caused clinical improvement in seborrheic keratoses in 7 of 15 patients.[34]
In 2017, the US Food and Drug Administration (FDA) approved a concentrated hydrogen peroxide 40% solution (Eskata) for adults with raised seborrheic keratosis. The solution is available within an applicator pen and is administered in a medical office setting by a healthcare professional.[35]
A drug that inhibits the activity of Akt kinase is currently under development and may cause seborrheic keratoses to self-destruct.[15]
A variety of techniques may be used to treat seborrheic keratoses. They include cryotherapy with carbon dioxide (dry ice) or liquid nitrogen, electrodesiccation, electrodesiccation and curettage, curettage alone, shave biopsy or excision using a scalpel, or a laser or dermabrasion surgery. Some of these techniques destroy the lesion without providing a specimen for histopathologic diagnosis.
The shave biopsy provides histologic material for accurate diagnosis and removes the lesion in a cosmetically acceptable manner at the same time. After a shave biopsy is obtained, a curette can be employed to smooth and remove any remaining keratotic material. Generally, this is the author's preferred method of removal.
If a biopsy is not desired, light electrodesiccation facilitates a sharp curettage.
Freezing seborrheic keratoses with dry ice or liquid nitrogen avoids the need for surgical excision; however, complications of freezing include pigmentary changes and on occasion, scarring.
Curettage in conjunction with liquid nitrogen generally gives better results than liquid nitrogen alone.
Application of 70% glycolic acid for 3-5 minutes prior to curetting also is effective.
No consultations are needed, unless the sudden appearance of multiple pruritic seborrheic keratoses occurs (known as the Leser-Trélat sign).
Follow-up for patients with multiple seborrheic keratoses is important because malignant tumors can develop elsewhere on the body (or rarely within a seborrheic keratosis). New seborrheic keratoses develop as people age. Patients who see a doctor and who are assured that these lesions are benign may not pay attention to newly appearing lesions that continue to develop over time. One of the newly appearing lesions may not be a seborrheic keratosis but, in fact, a malignant tumor.
No ongoing medical therapy is needed unless topical therapy has been employed to treat the lesions. A concentrated solution (40%) of hydrogen peroxide was approved by the FDA in 2017 for in office application to patients with raised seborrheic keratoses. Ammonium lactate and alpha-hydroxy acids have been reported to reduce the height of seborrheic keratoses.
Clinical Context: The exact mechanism is unknown. The 40% topical solution is designed to penetrate into the seborrheic keratosis lesion and cause oxidative damage, which can ultimately result in the sloughing of the seborrheic keratosis cells. It is indicated for in-office topical application by a healthcare professional for patients with raised seborrheic keratosis.
Clinical Context: Ammonium lactate lotion contains lactic acid, an alpha-hydroxy acid that has keratolytic action, thus facilitating release of corneocytes. It is available in 12% and 5% strength; 12% strength may cause irritation on the face. It causes disadhesion of corneocytes. Lactic acid is a racemic mixture of 2-hydroxypropanoic acid and is one of the most effective naturally occurring humectants in the skin.
Clinical Context: Trichloroacetic acid cauterizes skin, keratin, and other tissues. Although it is caustic, it causes less local irritation and systemic toxicity than do others in the same class. Treatment of individual seborrheic keratosis with up to 100% trichloroacetic acid can be used to destroy the lesions; however, clinical experience and judgment must be used because scarring may result in inexperienced hands. This treatment must be considered a form of surgery.
Keratolytic agents cause cornified epithelium to swell, soften, macerate, and then desquamate.