Dermatology

Seborrheic Keratosis (verruca senilis, senile wart, verruca seborrhoica, seborrheic wart, basal cell acanthoma, basal cell papilloma, benign acanthokeratoma)

Are You Confident of the Diagnosis?

Seborrheic keratosis (SK) is a very frequent benign epithelial skin tumor. It usually is asymptomatic, but occasionally itching, bleeding, pain, redness and crusting is observed after trauma or irritation. In most cases patients will ask for removal of SK due to aesthetic reasons.

  • Characteristic findings on physical examination

SK can be found anywhere on the body with the exception of palms, soles and mucous membranes. However, this lesion has been reported on the conjunctiva. The back, chest, head and neck represent the most commonly affected areas. In intertriginous areas pedunculated SK may they occur. SK can present as single lesions but usually occur disseminated in larger numbers (Figure 1), with sometimes 100 or more lesions. In some cases, the multiple SK on the back are arranged according to a “Christmas tree” pattern.

Figure 1.

SKs are sharply demarcated, round or oval-shaped tumors (Figure 2). Their diameter ranges from a few millimeters to several centimeters. The average size is 0.5 to 1cm. The color of the lesions varies from yellow and brown to black. SK are typically elevated over the skin surface and have a “stuck on” appearance. Their surface can be smooth, uneven, dull, punched-out or verrucous. SK often show keratotic plugs and horn cysts with concentrically attached keratin. Inflammation around the margin of SK is referred to as Meyerson phenomenon.

Figure 2.

In most cases, the diagnosis of SK can be made by their typical clinical appearance. In doubtful cases, dermatoscopy can be helpful. SK are characterized by the following dermatoscopic features:

- horn cysts or pseudocysts (visible as yellow spots)

- pseudofollicular openings

- gyrus sulcus pattern

- opaque yellow-brown or gray-brown color

- possibly streak-like densities, which are not clearly demarcated in contrast to melanocytic lesions

- superficial serpiginous vascular structures

  • Expected results of diagnostic studies

If malignancy cannot be excluded, histologic assessment is recommended. SK show histologically a varying degree of acanthosis, papillomatosis, hyperkeratosis and hyperpigmentation. Horn cysts and horn pseudocysts are often observed. There are several histologic subtypes. Acanthotic SK is the most frequent subtype. Hyperkeratotic and adenoid SK are also major subtypes. Acanthotic SK with marked hyperpigmentation are also called melanoacanthoma.

Other histologic subtypes include clonal SK (showing the Borst-Jadassohn phenomenon), bowenoid SK, and irritated SK. The last is presumably identical with the inverted follicular keratosis and shows squamous eddies.

  • Diagnosis confirmation

In most cases the diagnosis of SK can be made easily by their typical clinical appearance. Sometimes other tumors such as basal cell carcinoma, Bowen disease, actinic keratosis, viral wart, condyloma acuminatum or adnexal tumors have to be distinguished. Pigmented variants may be confused with melanocytic tumors or pigmented basal cell carcinoma. Flat SK may resemble verruca plana juvenilis or solar lentigo. In fact, the latter may be a precursor lesion of SK.

Dermatoscopy is helpful for differential diagnosis. In doubtful cases and to exclude malignant tumors, a biopsy or complete removal of the lesion with histologic evaluation is strongly recommended.

Who is at Risk for Developing this Disease?

The incidence of SK rises with age. According to several epidemiologic studies, SK can be found in 50% to 100% of patients aged 50 or older. A British study found SK in 82% of men and 62% of women over age 70. The prevalence of SK among younger people is lower. However, SK can already be found in young people aged 15 to 30 years. An Australian study reported a prevalence of SK of 24% in this group.

While age is a well-known independent risk factor for SK, the role of UV light is discussed controversially. Some studies report that the cumulative UV light lifetime exposure increases the risk for developing SK, whereas others could not find a significant correlation. In many patients, the SK are found at sun-protected body sites such as intertriginous areas, suggesting that additional risk factors independent from UV light are relevant as well. Increased incidence of SK and early appearance of numerous SK among family members have been reported. This indicates that a genetic predisposition to SK might exist as well.

What is the Cause of the Disease?

SKs are benign clonal tumors. In the last years it has become evident that somatic mutations are associated with SK. These point mutations mainly affect the FGFR3 (fibroblast factor growth factor 3) and PIK3CA (alpha catalytic subunit of the phosphatidylinositol 3-kinase) genes and lead to activation of the RAS/MAPK and PI3K/AKT signaling pathways. Interestingly, the same FGFR3 and PIK3CA mutations have been identified in malignant tumors and are thought to be oncogenic, albeit SK bear no malignant potential.

In germline, the identical FGFR3 mutations cause severe skeletal dysplasia syndromes such as thanatophoric dysplasia. In a comprehensive study, 70% of SK revealed FGFR3 mutations and 50% PIK3CA mutations. Many lesions had both an FGFR3 and PIK3CA mutation simultaneously. Furthermore, activating mutations in KRAS, HRAS, AKT and EGFR genes have been found, but at a lower frequency than FGFR3 and PIK3CA.

In contrast to many malignant tumors, SK are genetically stable and show no chromosomal imbalances. In familial SK, the same mutational spectrum has been found in the lesions as in sporadic SK, suggesting the existence of yet unknown susceptibility genes. Until now, the detection of these oncogenic mutations in SK has no practical clinical consequences for the prognosis or treatment of SK.

Systemic Implications and Complications

In rare cases and especially in elderly people, SK may show a sudden appearance and the growth of numerous lesions in association with a malignant tumor of internal organs. This has been referred to as Leser-Trelat syndrome. About one-third of these patients have concomitant acanthosis nigricans, and nearly half of the patients report pruritus.

The most frequent underlying malignancies are adenocarcinomas of the stomach and colon, but other malignant tumors may be found as well. Disappearance of the multiple SK after successful therapy of the cancer has been reported, as well as reappearance after tumor relapse. In general, the Leser-Trelat syndrome is observed in advanced stages of the cancer and therefore has an unfavorable prognosis with a median survival of 11 months.

It is assumed that this rare paraneoplastic syndrome is caused by soluble growth factors secreted by the tumor. In all cases with a sudden appearance of numerous SK a Leser-Trelat syndrome should be taken into account and cancer of internal organs should be excluded.

Treatment Options

Curettage with a sharp spoon or ring curette

Shave excision with a scalpel/blade

Ablative laser such as CO2 or erbium YAG

Cryotherapy

Optimal Therapeutic Approach for this Disease

As SKs are benign epidermal tumors, no treatment is usually necessary. In rare cases, mechanical irritation of the lesions may cause itching, bleeding and inflammation. Another indication for removal is to exclude malignancy. However, in most cases SK are removed due to cosmetic reasons, because they can be very disfiguring due to their size, color and multiple occurrences.

Surgical treatment represents the standard therapy. After local anesthesia, curettage of the SK with a sharp spoon or a ring curette followed by antiseptical treatment of the wound bed is the method of choice. Alternatively, shave excision with a scalpel or a blade is possible as well. Cryotherapy is also reported in the literature. Flat SK may require only 5 to 10 seconds of spray cooling, while thicker lesions may need a longer treatment or a second application. SK can be also removed by electrodessication.

Several lasers have been used successfully, including ablative lasers such as CO2 or erbium YAG. It is important to note that in all cases with an equivocal dignity the chosen method should provide material for histologic evaluation.

The treatment of patients with large numbers of SKs remains challenging. Surgical removal is still the method of choice, although this approach is limited in patients with 100 and more SKs. Unfortunately, topical or systemic drug therapies with vitamin D analogues, tazarotene or imiquimod have not become accepted due to their limited effectiveness and the observed side effects.

Patient Management

Because SK bear no malignant potential, there is no need for a special patient management. Incidental cases of SK and squamous cell carcinoma or basal cell carcinoma have been reported, but these cases are very rare and it is not clear whether the malignant tumor arose from the SK or both lesions represent simply collision tumors. SK may recur if the removal was insufficient (for example at the margins of a site of former curettage or shave excision). However, it is unknown how often this happens and which of the different methods cause the lowest recurrence rate.

Patients with Leser-Trelat syndrome should be monitored because recurrence of multiple SK after successful tumor therapy may indicate a relapse of the disease.

Unusual Clinical Scenarios to Consider in Patient Management

Verrucous melanomas may easily mimic seborrheic keratoses and must be carefully considered in the differential diagnosis. If there is any uncertainty as to the diagnosis of SK either on a clinical or dermatoscopic basis, a biopsy should be performed.

What is the Evidence?

Duque, MI, Jordan, JR, Fleischer, AB, Williford, PM, Feldman, SR, Teuschler, H. "Frequency of seborrheic keratosis biopsies in the United States: a benchmark of skin lesion care quality and cost effectiveness". Dermatol Surg. vol. 29. 2003. pp. 796-801.

(This study reports on the costs and quality of care in the treatment of SK in the United States.)

Gill, D, Dorevitch, A, Marks, R. "The prevalence of seborrheic keratoses in people aged 15 to 30 years: is the term senile keratosis redundant". Arch Dermatol. vol. 136. 2000. pp. 759-62.

(This study reports a considerably high prevalence of SK in young patients.)

Hafner, C, Toll, A, Fernandez-Casado, A, Earl, J, Marques, M, Acquadro, F. "Multiple oncogenic mutations and clonal relationship in spatially distinct benign human epidermal tumors". Proc Natl Acad Sci U S A. vol. 107. 2010. pp. 20780-5.

(This study identified a high rate of oncogenic mutations (FGFR3, PIK3CA, RAS, etc.) in SK in the absence of senescence, genetic instability and malignancy. Some SK in patients wth multifocal lesions appear to be clonally related despite their spatial distance.)

Hafner, C, Vogt, T. "Seborrheic keratosis". J Dtsch Dermatol Ges. vol. 6. 2008. pp. 664-77.

(A review article on SK.)

Hafner, C, Vogt, T, Landthaler, M, Musebeck, J. "Somatic FGFR3 and PIK3CA mutations are present in familial seborrhoeic keratoses". Br J Dermatol. vol. 159. 2008. pp. 214-7.

(SK in patients with early familial occurrence reveal the same mutational spectrum as sporadic SK.)

Hallermann, C, Gunawan, B, Bertsch, HP. "No chromosomal imbalances in seborrheic keratoses detectable by comparative genomic hybridization". J Invest Dermatol. vol. 123. 2004. pp. 1204-5.

(This study reports that SK are genetically stable as indicated by CGH analysis.)

Logie, A, Dunois-Larde, C, Rosty, C, Levrel, O, Blanche, M, Ribeiro, A. "Activating mutations of the tyrosine kinase receptor FGFR3 are associated with benign skin tumors in mice and humans". Hum Mol Genet. vol. 14. 2005. pp. 1153-60.

(This study identified FGFR3 mutations in SK for the first time. The functional relevance of the mutations were shown in a transgenic mouse model.)

Nakamura, H, Hirota, S, Adachi, S, Ozaki, K, Asada, H, Kitamura, Y. "Clonal nature of seborrheic keratosis demonstrated by using the polymorphism of the human androgen receptor locus as a marker". J Invest Dermatol. vol. 116. 2001. pp. 506-10.

(This study demonstrates that SK are clonal tumors using X-chromosome inactivation analysis.)

Neel, VA, Todorova, K, Wang, J, Kwon, E, Kang, M, Liu, Q, Gray, N, Lee, SW, Mandinova, A. "Sustained Akt Activity Is Required to Maintain Cell Viability in Seborrheic Keratosis, a Benign Epithelial Tumor". J Invest Dermatol. vol. 136. 2016 Mar. pp. 696-705.

(A basic science study investigating the underlying molecular mechanisms important for SKs and potential new therapeutic targets)

Squillace, L, Cappello, M, Longo, C, Moscarella, E, Alfano, R, Argenziano, G. "Unusual Dermoscopic Patterns of Seborrheic Keratosis". Dermatology. 2016 Jan 27.

(A retrospective study looking at the demoscopic patterns found in SKs)

Yeatman, JM, Kilkenny, M, Marks, R. "The prevalence of seborrhoeic keratoses in an Australian population: does exposure to sunlight play a part in their frequency". Br J Dermatol. vol. 137. 1997. pp. 411-4.

(This epidemiologic study indicates that the prevalence of SK is influenced by the UV light exposure.)

**The original source for this chapter was Dr. Christian Hafner. The chapter was revised for this program by Dr. Michael Gober.**

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