Seborrheic Keratosis of the Eyelid

Key Points at a Glance

Key Points of This Disease

• Seborrheic keratosis is the most common benign eyelid tumor in middle-aged and elderly people, also called verruca senilis.
• It causes raised lesions due to age-related thickening and horizontal proliferation of the epidermis, but does not become malignant.
• Among benign eyelid tumors, it accounts for 14% by pathological diagnosis, making it the second most common.
• Color varies from light brown to black, with well-defined borders and a soft, friable surface.
• Differentiation from basal cell carcinoma and malignant melanoma is important; histopathological examination is essential for definitive diagnosis.
• Treatment is usually excision of the tumor along with the epidermis or cryotherapy. Recurrence may occur if resection is marginal.
• If multiple lesions appear rapidly (Leser-Trélat sign), consider the possibility of internal malignancy.

1. What is seborrheic keratosis of the eyelid?

Seborrheic keratosis is the most common benign eyelid tumor in middle-aged and elderly people, also called verruca senilis. It causes raised lesions due to age-related thickening or horizontal proliferation of the epidermis, and tends to enlarge over several years. An important feature is that it does not become malignant.

Epidemiology

• Among benign eyelid tumors, it accounts for 14% (9/64 eyes) by pathological diagnosis, making it the second most common tumor.
• It is considered an age-related change commonly seen in middle-aged and elderly people (mainly after the 50s).
• It is also one of the most common benign tumors on the skin of the whole body, and about 80% of people over 50 have some form of seborrheic keratosis ¹⁾.
• Ultraviolet exposure is known as an exacerbating factor ¹⁾.
• On the eyelid, it commonly occurs on the skin side from the eyelashes.
• Familial occurrence has also been reported¹⁾.

Q Can seborrheic keratosis become cancerous?

A

Seborrheic keratosis is a benign tumor that does not become malignant, and it will not turn into cancer even if left untreated. However, because it can clinically resemble basal cell carcinoma or malignant melanoma, histopathological examination is recommended for a definitive diagnosis. Particularly in cases of rapid growth or when the surface is hard with central ulceration, malignancy must be ruled out.

2. Main Symptoms and Clinical Findings

Close-up photograph of seborrheic keratosis showing a well-demarcated brown verrucous elevation

Assafn. Seborrheic keratosis closup. Wikimedia Commons. 2024. Source ID: commons/Seborrheic_keratosis_closup.jpg. License: CC BY-SA 4.0.

Close-up image of seborrheic keratosis showing a well-demarcated brown to yellowish-brown elevated verrucous lesion with a rough papillary surface, giving a “stuck-on” appearance. This corresponds to the clinical findings of well-defined border, verrucous surface, and elevation discussed in section “2. Main Symptoms and Clinical Findings”.

Subjective Symptoms

It is often asymptomatic. The main subjective symptoms are listed below.

• Cosmetic concerns: Brown or black elevated lesions on the eyelid are often noticed as an aesthetic issue.
• Foreign body sensation: Rarely, when the tumor becomes large, mild foreign body sensation may be reported.
• Tearing and irritation: When occurring at the eyelash margin, irritative symptoms may appear.

Clinical Findings

• Predilection site: Commonly occurs on the skin side of the eyelashes. It can also occur on the skin surface away from the eyelid margin.
• Color: Varies from light brown to black, and color changes may be present within the same lesion.
• Shape and surface characteristics: Well-demarcated. The surface may be rough and irregular due to keratinization, or glossy like a mulberry. Hyperkeratosis may cause papillary elevation.
• Hardness: The surface of the tumor is soft and fragile. This is an important distinguishing feature from basal cell carcinoma (which is hard).
• Size: Varies from a few mm to over 1 cm. It enlarges over a period of years.

Dermoscopic Findings

Observation with a dermoscope is useful as a diagnostic aid, and the following findings are characteristic ²⁾.

• Cerebriform pattern: The surface exhibits brain-like grooves and ridges.
• Milia-like cysts: Observed as white to yellowish-white round dots.
• Comedo-like openings: Observed as brown to black round openings.

If multiple of these findings are present, seborrheic keratosis is highly likely.

Q How to distinguish from basal cell carcinoma?

A

For clinical differentiation, seborrheic keratosis is characterized by “well-defined borders, soft and fragile surface, and absence of central ulceration or depression.” In contrast, basal cell carcinoma shows findings such as “central ulceration, depression, pearly luster, vascular proliferation (telangiectasia), and hardness.” Cerebriform patterns and milia-like cysts on dermoscopy are characteristic of seborrheic keratosis, but differentiation may be difficult in pigmented lesions. Pathological examination is essential for a definitive diagnosis.

3. Causes and Risk Factors

Multiple factors are involved in the development of seborrheic keratosis.

• Aging: The most significant risk factor. It is based on thickening and increased proliferation of epidermal cells with aging.
• Ultraviolet exposure: Sun exposure is involved in the onset and exacerbation ¹⁾. The eyelids are areas easily affected by sunlight.
• Genetic factors: Familial occurrence has been reported, suggesting the involvement of genetic predisposition ¹⁾.
• FGFR3 gene mutation: FGFR3 (fibroblast growth factor receptor 3) gene mutations have been reported in some seborrheic keratoses, and it has been confirmed that mutations are present even at the stage of flat lesions³⁾.
• PIK3CA mutation: Similar to FGFR3, it is involved in the activation of proliferative signaling pathways³⁾.

When to See a Doctor

When a brown or black raised lesion appears on the eyelid, the most common cause is benign seborrheic keratosis, but it may be necessary to differentiate it from malignant tumors. In particular, please see an ophthalmologist promptly in the following cases:

• The lesion is rapidly enlarging
• Accompanied by ulceration or bleeding
• Multiple lesions appear in a short period (suspicion of Leser-Trélat sign)
• The surface is hard and the borders are indistinct

Leser-Trélat Sign

When seborrheic keratoses appear rapidly and in large numbers over a short period, it is called the Leser-Trélat sign, which may indicate a paraneoplastic syndrome associated with internal malignancy⁴⁾. Associated malignancies include gastrointestinal cancers (gastric cancer, colorectal cancer), lung cancer, breast cancer, and lymphoma. However, since seborrheic keratoses also increase with age in healthy individuals, caution is needed only in cases of rapid and multiple appearance.

4. Diagnosis and Examination Methods

Clinical Diagnosis

In elderly patients, it is often clinically diagnosable as a well-demarcated brown to black verrucous raised lesion. However, because there are malignant tumors with similar appearance, pathological examination is always necessary for a definitive diagnosis.

Dermoscopic findings (cerebriform pattern, pseudocysts, pseudocomedones) are useful as diagnostic aids and contribute to improved accuracy in differentiating benign from malignant lesions²⁾.

Q What is a dermoscope?

A

A dermoscope (dermatoscope) is a non-invasive diagnostic aid that uses a specialized lens to magnify pigmented skin lesions. By using polarized light or immersion fluids (such as alcohol or gel), it eliminates surface light reflection and allows detailed observation of pigment structures from the epidermis to the superficial dermis. It is useful for identifying characteristic findings of seborrheic keratosis (gyriform pattern, pseudocysts, pseudocomedones) and improves differentiation from malignant melanoma and basal cell carcinoma.

Histopathological Examination

The definitive diagnosis of seborrheic keratosis is made by histopathological examination. The following findings are characteristic:

• Acanthosis and proliferation of spinous cells¹⁾
• Pseudohorn cysts: Cystic structures containing keratin material are a pathological hallmark¹⁾
• Proliferation of a mixture of basaloid cells and squamous epithelial cells
• Absence of nuclear atypia or infiltrative growth pattern distinguishes it from malignant diseases

All excised specimens must be submitted for pathological examination to confirm the exclusion of malignancy.

Differential Diagnosis

Differential Disease	Key Differentiating Features
Basal cell carcinoma	Central ulceration/depression, vascular proliferation, firm surface, pearly luster
Malignant melanoma	Pigment heterogeneity, rapid enlargement, irregular shape, ABCDE rule
Eyelid nevus (mole)	Present since childhood, flat and soft
Actinic keratosis	Precancerous lesion, red and rough surface, prone to crusting
Pigmented basal cell carcinoma	Pigmentation, pearly luster, vascular proliferation
Verruca vulgaris	Common in young people, HPV infection, cauliflower-like surface

5. Standard Treatment

If there are no cosmetic or functional issues, observation is possible. Treatment is performed when there is a tendency to enlarge, when differentiation from malignancy is necessary, or when the patient desires treatment.

Surgical Excision

This is the first-line treatment. The tumor is excised along with the epidermis, serving both for definitive diagnosis and treatment.

• Ensuring safety margins: Excision at the very edge of the tumor border may lead to recurrence. Excise with sufficient safety margins.
• Management in elderly patients: Elderly patients often have excess skin, so simple closure is possible in many cases.
• Lesions involving eyelashes: If the eyelashes are involved in the tumor, manage the eyelid margin with open treatment.
• Resected specimen: Must be sent for pathological examination to confirm the presence of malignant components.

Cryotherapy

Indicated for small to medium-sized lesions. Cryotherapy using liquid nitrogen can be performed on an outpatient basis and is minimally invasive, but the recurrence rate is slightly higher than that of excision. A disadvantage is that a definitive pathological diagnosis cannot be obtained.

Laser therapy

• CO2 laser vaporization: An excellent option for cosmetic outcomes, with minimal thermal damage to surrounding tissue ⁵⁾. However, vaporized tissue is difficult to evaluate pathologically, so it is contraindicated when malignancy cannot be ruled out.
• Erbium YAG laser: Allows precise vaporization with good cosmetic results ⁵⁾.

Electrocoagulation

An option that can be performed on an outpatient basis for small lesions ¹⁾. The tumor is cauterized by electrocoagulation under local anesthesia.

Treatment options overview

Treatment	Indication	Advantages	Disadvantages
Excision with epidermis	All cases (definitive diagnosis and treatment)	Pathological confirmation and margin control possible	Surgical invasiveness (under local anesthesia)
Cryocoagulation	Small to medium lesions	Minimally invasive, outpatient procedure	Risk of recurrence, no pathological evaluation possible
CO2 laser vaporization	Cases prioritizing cosmetic outcome	Precise, minimally invasive	Pathological evaluation difficult
Erbium YAG laser	Cases prioritizing cosmetic outcome	Precise vaporization, good cosmetic results	Pathological evaluation difficult
Electrocoagulation	Small lesions	Outpatient procedure	Pathological evaluation difficult due to thermal damage

Precautions in treatment

• If cryocoagulation or laser treatment is performed without a clear differentiation from malignant tumors, the diagnosis and treatment of malignant tumors may be delayed.
• Resection exactly at the tumor margin can cause recurrence, so ensuring an adequate safety margin is important.
• Resected specimens must always be submitted for pathological examination to rule out the presence of malignant components.

Q Can it be left untreated?

A

Seborrheic keratosis does not become malignant, so observation is an option if there are no cosmetic or functional problems. However, if clinical differentiation from basal cell carcinoma or malignant melanoma is difficult, or if rapid growth, color change, or ulceration is observed, biopsy or resection is recommended to rule out malignancy. Even if left untreated for a long time, regular observation is important, and if any changes occur, consultation with an ophthalmologist should not be neglected.

6. Pathophysiology and detailed pathogenesis

Seborrheic keratosis is a raised lesion caused by thickening and horizontal proliferation of the epidermis, and is considered a type of age-related change.

Histological features

• Hyperkeratosis and acanthosis: Thickening of the entire epidermis and hyperkeratosis occur ¹⁾.
• Pseudohorn cysts: Cyst-like structures containing keratinous material. This is a characteristic pathological finding, corresponding to “pseudocysts” on dermoscopy ¹⁾.
• Mixture of basaloid cells and squamous cells: The tumor contains both in varying proportions, and there are several histological types such as acanthotic, adenoid, and inflamed types.
• The absence of nuclear atypia and invasive patterns is important for differentiation from malignant tumors.

Molecular mechanisms

• FGFR3 (fibroblast growth factor receptor 3) gene mutations: Mutations are already present at the flat lesion stage and are associated with age and site ³⁾. FGFR3 mutations activate cell proliferation signals and contribute to excessive proliferation of epidermal cells.
• PIK3CA mutation: Involved in activation of the PI3K/Akt/mTOR pathway and may coexist with FGFR3 mutation³⁾.
• These somatic mutations are understood as mutations that accumulate with age and cause increased proliferation through a pathway different from malignant transformation.

Mechanism of Leser-Trélat sign

The association with internal malignancy in cases of rapid multiple onset is thought to be due to overproduction of tumor-derived transforming growth factor alpha (TGF-α) and insulin-like growth factor (IGF), which promote epidermal cell proliferation⁴⁾. It is understood as a type of paraneoplastic syndrome.

7. Latest research and future prospects

For patients: Please read

The following content is currently at the research stage or under clinical trial and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Topical hydrogen peroxide therapy

Topical hydrogen peroxide 40% (Eskata®) has been approved by the FDA for seborrheic keratosis on the trunk and extremities⁶⁾. In phase 3 trials, the treatment group had a significantly higher endpoint achievement rate. Application to the eyelids is currently limited due to effects on the cornea and conjunctiva, and dedicated trials are expected in the future.

AI-assisted dermoscopic diagnosis

AI-assisted diagnostic systems for dermoscopic images have been developed, and improved accuracy in differentiating benign from malignant lesions has been reported⁷⁾. Especially for flat pigmented lesions on the face, studies are accumulating showing discrimination accuracy comparable to that of experts. Application to the eyelids is also a future challenge.

Significance of Leser-Trélat sign as a biomarker

Early identification of Leser-Trélat sign in cases of rapid multiple onset of seborrheic keratosis may lead to early detection of internal malignancy⁴⁾. Since the timing and pattern of the sign vary depending on the type of malignancy, development of systematic screening protocols is underway.

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8. References

1. Hafner C, Vogt T. Seborrheic keratosis. J Dtsch Dermatol Ges. 2008;6(8):664-677.
2. Braun RP, Rabinovitz HS, Oliviero M, et al. Dermoscopy of pigmented skin lesions. J Am Acad Dermatol. 2005;52(1):109-121.
3. Hafner C, Hartmann A, van Oers JM, et al. FGFR3 mutations in seborrheic keratoses are already present in flat lesions and associated with age and localization. Mod Pathol. 2007;20(8):895-903.
4. Schwartz RA. Sign of Leser-Trélat. J Am Acad Dermatol. 1996;35(1):88-95.
5. Wollina U. Erbium-YAG laser therapy — analysis of more than 1,200 treatments. Glob Dermatol. 2016;3(2):223-227.
6. Baumann LS, Blauvelt A, Draelos ZD, et al. Safety and efficacy of hydrogen peroxide topical solution, 40% (w/w), in patients with seborrheic keratoses. Dermatol Surg. 2018;44(11):1439-1446.
7. Tschandl P, Rosendahl C, Kittler H. Dermatoscopy of flat pigmented facial lesions. J Eur Acad Dermatol Venereol. 2015;29(1):120-127.