Background

This is a common benign skin tumor usually appearing in mid-adult life, occurring on nearly every surface of the body with the exception of the palms and soles. They are gray to black raised lesions with a characteristic "stuck on" appearance. This allows for easy removal by a shave biopsy or laser treatment.

OUTLINE

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
The prevalence of seborrhoeic keratoses in an Australian population: does exposure to sunlight play a part in their frequency? Yeatman JM, Kilkenny M, Marks R. University of Melbourne, Department of Medicine (Dermatology), St Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia.	Br J Dermatol 1997 Sep;137(3):411-4 Abstract quote Although seborrhoeic keratoses (SKs) appear to be very common, there are very few studies reporting details of age-specific prevalence, distribution or possible cause. We report details on the frequency, nature and distribution of SKs in 100 Australian adults in the age groups 15-25, 26-50, 51-75 and those aged more than 75 years. There was an increase in prevalence of SKs from 12% of 15-25 year olds to 100% of those aged more than 50 years. The median number of lesions in those with them also increased with age from six per person in 15-25 year olds to 69 per person in those aged more than 75 years. There was no difference in prevalence or numbers of lesions/person between males and females. SKs on exposed areas were more often flat and more than 3 mm in diameter than those on the non-exposed areas. There was a higher prevalence of SKs on the exposed areas than non-exposed areas when taking into account the surface area. The data in this study demonstrate an increased frequency of SKs compared with those reported from the United Kingdom recently and from Australasia in the past, a phenomenon paralleling the changing frequency of skin cancer in these populations. This fact, plus the finding that SKs were more common as a function of skin surface area on the exposed areas of the body, suggests that sunlight may play a part in their development in those people who are predisposed to develop them.
The prevalence of seborrheic keratoses in people aged 15 to 30 years: is the term senile keratosis redundant? Gill D, Dorevitch A, Marks R. The University of Melbourne, Department of Medicine, Victoria, Australia.	Arch Dermatol 2000 Jun;136(6):759-62 Abstract quote BACKGROUND: Seborrheic keratoses (SKs) are common skin lesions that have been shown to occur with increasing age, although the age of onset is not well recorded. OBJECTIVE: To determine the prevalence, nature, and distribution of SKs in young people. METHODS: One hundred seventy people aged 15 to 30 years were given a total body examination during which the presence, number, site, and size of SKs were recorded. Biopsy specimens were taken from the first 22 people who had lesions clinically diagnosed as SKs. Data on age, skin type, eye color, and hair color were recorded for all respondents. RESULTS: Forty (23.5%) of 170 respondents had at least one SK, with no significant difference between the sexes. There was an increase in prevalence with age from 15.7% in 15- to 19-year-olds to 32.3% in those aged 25 to 30 years. The size of the SKs also increased with age. A total of 77.5% of SKs were found on the trunk and 22.5% on the limbs, head, and neck. There was no correlation between SKs and any particular hair and eye color or skin type. CONCLUSIONS: These findings confirm that SKs are common lesions in young Australians, appearing in a substantial proportion of people younger than 30 years. The term senile keratosis is no longer appropriate for these lesions.

 

DISEASE ASSOCIATIONS	CHARACTERIZATION
Seborrheic keratoses: appearance in course of exfoliative erythroderma and regression associated with histologic mononuclear cell inflammation. Berman A, Winkelmann RK.	Arch Dermatol 1982 Aug;118(8):615-8 Abstract quote We observed a patient in whom large numbers of seborrheic keratoses developed in the course of a generalized dermatitis that progressed into an exfoliative erythroderma. A renal mass was finally discovered and was surgically excised. On microscopic examination, the kidney tumor proved to be a benign fibrous-walled, multilocular cyst. After removal of the renal cyst, the erythroderma and exfoliation subsided. A few months later, the seborrheic keratoses were noted to have become smaller, flatter, and fewer in number. Microscopic examination of five such involuting lesions showed, in each instance, mononuclear cell infiltration of the seborrheic keratoses. Our findings confirm earlier reports that seborrheic keratosis-like lesions developing during the course of widespread inflammatory cutaneous disorders may regress after control of the dermatosis and suggest that mononuclear cell inflammation may be the mechanism by which regression of these lesions is accomplished.
Herpesvirus Infection of Seborrheic Keratoses Paul B. Googe, M.D.; Roy King, M.D.	Am J Dermatopathol 2001;23:146-148 Abstract quote We present three examples of patients with seborrheic keratoses complicated by necrotizing herpesvirus infection. Two patients had localized cutaneous herpetic infections, and the third patient had a generalized cutaneous herpesvirus infection. Two of the lesions were thought to be squamous cell carcinoma. The third was clinically identified as inflamed seborrheic keratosis. Herpesvirus infection was not clinically suspected in two of the patients. The histologic changes were similar in all cases. Epidermal proliferation was accompanied by hyperkeratosis and pseudo horn cyst formation. Extensive keratinocyte necrosis was present along with balloon degeneration of keratinocytes, herpetic viral inclusions, and multinucleated giant cells. Viral lesions of molluscum contagiosum and human papillomavirus have been observed in benign skin proliferations. Nevertheless, we were unable to find descriptions of herpesvirus involvement in seborrheic keratosis in a Medline search. Necrotic seborrheic keratoses should be carefully examined for the possibility of herpesvirus infection, a condition that may be improved by prompt medical intervention as demonstrated in one of our cases.
Transient eruptive seborrheic keratoses associated with erythrodermic psoriasis and erythrodermic drug eruption: Report of two cases Scott L. Flugman, MD Steve A. McClain, MD Richard A. F. Clark, MD Stony Brook, New York	J Am Acad Dermatol 2001;45:S212-4 Abstract quote The appearance of multiple seborrheic keratoses in association with underlying internal malignancy (known as the sign of Leser-Trelat) has generated much discussion and debate in the literature. However, comparatively few case reports exist that examine the appearance of multiple seborrheic keratoses associated with exfoliative erythroderma without underlying malignancy. We report 2 cases in which multiple, biopsy-proven seborrheic keratoses appeared in conjunction with erythrodermic skin eruptions. The underlying diseases in these 2 patients included psoriasis and an eczematous drug eruption; in both cases the erythroderma resolved with appropriate treatment. After resolution of the erythroderma, the newly developed seborrheic keratoses proceeded to involute and gradually fall off. Neither of the patients exhibited any evidence of internal malignancy. These cases represent the first reports of psoriasis and drug eruption as causes of erythroderma-induced transient eruptive seborrheic keratoses. Clinical and pathologic findings are consistent with previous descriptions of this entity.

 

PATHOGENESIS	CHARACTERIZATION
APOPTOSIS
Comparison of benign keratoses using p53, bcl-1, and bcl-2. Ko CJ, Shintaku P, Binder SW. Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA.	J Cutan Pathol. 2005 May;32(5):356-9. Abstract quote   While cell-cycle markers have been used to differentiate benign vs. malignant lesions and to classify malignant lesions, benign keratoses have not been well studied using such markers. We hypothesized that inflammation or irritation of benign keratoses may be related to a shift in the cell cycle. We compared the immunohistochemical staining patterns of 10 seborrheic keratoses (SKs), 10 inflamed seborrheic keratoses (iSKs), and 10 inverted follicular keratoses (IFKs) using antibodies to p53, bcl-1, and bcl-2. Staining with antibodies to p53 was slightly increased in IFKs compared with iSKs or non-inflamed seborrheic keratoses. Bcl-1 staining was similar in all lesions. A population of bcl-2-positive dendritic cells was seen within the epidermal portion of IFKs. Keratinocyte bcl-2 staining was significantly higher in SKs compared with the other two keratoses. Bcl-2 may be increased in SKs as an anti-apoptotic mechanism.
Apoptosis in the areas of squamous differentiation of irritated seborrheic keratosis. Pesce C, Scalora S. Universita di Genova, DISTBIMO, Centro di Anatomia Patologica, Italy.	J Cutan Pathol 2000 Mar;27(3):121-3 Abstract quote Seborrheic keratosis (SK) consists of a localized proliferation of basaloid keratinocytes, often accompanied by hyperkeratosis and hyperpigmentation. In irritated SK, these features are associated with areas of squamous differentiation with larger keratinocytes and squamous cell eddies. This work is concerned with the evaluation of apoptosis, as demonstrated by the TUNEL method, in the different varieties of SK. Apoptosis was highly expressed in the areas of squamous differentiation of irritated SK, but only mildly increased in the other varieties of SK. These data support the hypothesis that apoptosis has a role in the squamous differentiation of irritated SK. In consideration also of previous data showing that irritated SK is associated with downregulation of EGF-R expression and 125I-EGF binding, we postulate that the morphologic features of irritated SK could correspond to an involution phase of the disease, characterized by altered cell balance with inadequate cell renewal and increased cell loss.
CLONALITY
Clonal nature of seborrheic keratosis demonstrated by using the polymorphism of the human androgen receptor locus as a marker. Nakamura H, Hirota S, Adachi S, Ozaki K, Asada H, Kitamura Y. Department of Pathology, Osaka University Medical School, Osaka, Japan.	J Invest Dermatol 2001 Apr;116(4):506-10 Abstract quote We evaluated the clonality of seborrheic keratoses using a polymorphism due to the random inactivation of one of two X chromosomes in females. Thirty-eight seborrheic keratoses obtained from the skin of females with polymorphism of the human androgen receptor (HUMARA) locus were examined by a fluorescent polymerase chain reaction procedure, which allowed accurate measurement of the peak intensities of each HUMARA allele. The epithelial portion of seborrheic keratosis and normal control epidermis adjacent to the seborrheic keratosis were removed by laser capture microdissection. As biopsied specimens of seborrheic keratoses contained small amounts of normal epidermis, the effect of digestion by a restriction enzyme (HhaI) recognizing the nonmethylated active sites was compared between seborrheic keratoses and normal control epidermis in only five seborrheic keratosis cases. Disappearance or significant reduction in intensity of one of two HUMARA alleles was observed after HhaI digestion in seborrheic keratoses, but not in the normal control epidermis. Although the skewing of the polymorphism was not corrected by the normal control epidermis in the remaining 33 seborrheic keratosis cases, one of two HUMARA peaks practically disappeared after HhaI digestion in 20 of 33 seborrheic keratosis cases. In total, 25 of 38 seborrheic keratoses were considered to be monoclonal. The histologic type of seborrheic keratoses did not affect clonality.
HUMAN PAPILLOMAVIRUS
Immunophenotypic and viral (human papillomavirus) correlates of vulvar seborrheic keratosis. Bai H, Cviko A, Granter S, Yuan L, Betensky RA, Crum CP.	Hum Pathol. 2003 Jun;34(6):559-64. Abstract quote Human papillomavirus (HPV) infections of the genital mucosa classically present as warts (condylomata) and are traditionally defined by the presence of viral cytopathic effect (koilocytosis). In recent years, HPV has been detected in vulvar epithelial changes lacking koilocytosis, including squamous papillomas and lesions closely resembling seborrheic keratosis (SK). The purpose of this study was to determine the frequency and type of HPV associated with vulvar SK (VSK) and to compare expression of biomarkers (p16, Mib-1, and cyclin E) in these lesions. Sixty-seven biopsy specimens, including 25 VSKs, 10 nondiagnostic vulvar acanthoses, 12 fibroepithelial polyps (FEPs), and 20 nongenital cutaneous SKs (CSKs), were studied. Biopsy specimens were typed for HPV by polymerase chain reaction and immunostained with Mib-1, cyclin E, and p16(INK4) antibodies. Eighteen of 25 VSKs (72%), 0 of 10 nondiagnostic vulvar acanthuses (0%; P = 0.0001), 2 of 12 FEPs (16.7%; P = 0.004), and 3 of 20 CSKs (15%; P = 0.0002) scored HPV positive. Increased Mib-1 staining was significantly more common in VSKs than in other vulvar lesions, but not in CSKs; increased p16 and cyclin E staining was not more common. VSKs are morphologically and immunophenotypically similar to CSKs but distinct by their association with HPV. Unlike the cervix, p16 and cyclin E will not consistently distinguish VSKs from HPV-negative lesions due to underexpression in low-risk HPV infections (p16) and less-restricted expression in vulvar lesions (cyclin E). Whether CSKs are associated with other forms of HPV infection remains to be determined.
Seborrheic keratoses of black patients with epidermodysplasia verruciformis contain human papillomavirus DNA. Jacyk WK, Dreyer L, de Villiers EM. Department of Dermatology, University of Pretoria, Republic of South Africa.	Am J Dermatopathol 1993 Feb;15(1):1-6 Abstract quote Epidermodysplasia verruciformis (EV) is a rare disease characterized by a generalized cutaneous infection with human papillomaviruses (HPVs) and a propensity for transformation of the lesions to squamous cell carcinomas on sun-exposed areas of the skin. Black-skinned patients with EV have a much lower incidence of skin cancer. Nine of 32 black African patients with EV presented deeply pigmented, flat or slightly raised lesions, located mostly in sun-exposed areas, that clinically had been diagnosed as seborrheic keratoses. Seborrheic keratoses are otherwise very rare in black Africans. Histology of these lesions disclosed seborrheic keratoses, lesions with seborrheic keratosis, and EV changes in the same biopsy specimens and seborrheic keratoses with features of bowenoid dysplasia. Reverse blot hybridization indicated the presence of DNA related to the HPV-5 group of papillomaviruses in seborrheic keratoses in three patients. Subsequent Southern blot analysis revealed a DNA that was related but not identical to any of the papillomaviruses in this HPV-5 group. The fourth lesion studied a few years earlier contained HPV-5c. The question arises whether a different type of HPV is responsible for development of these tumors in black patients with EV.
Absence of human papillomavirus dna in nongenital seborrheic keratosis. Lee ES, Whang MR, Kang WH. Department of Dermatology, Ajou University School of Medicine, Suwon, Korea.	J Korean Med Sci 2001 Oct;16(5):619-22 Abstract quote Seborrheic keratosis (SK) is a benign epidermal tumor of unknown etiology. Because of its wart-like morphology, human papillomavirus (HPV) has been suggested as a possible causative agent. Viral involvement, however, has not been confirmed yet despite extensive research. The aim of this study was to evaluate the presence of HPV 6/11, 31, 33 DNA in nongenital SK. We analyzed 40 biopsy specimens taken from patients with nongenital SK using in situ polymerase chain reaction (PCR) and PCR with tissue extracts. The SK specimens (n=4J Invest Dermatol 2001 Apr;116(4):506-10 Related Articles, Books, LinkOut Clonal nature of seborrheic keratosis demonstrated by using the polymorphism of the human androgen receptor locus as a marker. Nakamura H, Hirota S, Adachi S, Ozaki K, Asada H, Kitamura Y. Department of Pathology, Osaka University Medical School, Osaka, Japan. We evaluated the clonality of seborrheic keratoses using a polymorphism due to the random inactivation of one of two X chromosomes in females. Thirty-eight seborrheic keratoses obtained from the skin of females with polymorphism of the human androgen receptor (HUMARA) locus were examined by a fluorescent polymerase chain reaction procedure, which allowed accurate measurement of the peak intensities of each HUMARA allele. The epithelial portion of seborrheic keratosis and normal control epidermis adjacent to the seborrheic keratosis were removed by laser capture microdissection. As biopsied specimens of seborrheic keratoses contained small amounts of normal epidermis, the effect of digestion by a restriction enzyme (HhaI) recognizing the nonmethylated active sites was compared between seborrheic keratoses and normal control epidermis in only five seborrheic keratosis cases. Disappearance or significant reduction in intensity of one of two HUMARA alleles was observed after HhaI digestion in seborrheic keratoses, but not in the normal control epidermis. Although the skewing of the polymorphism was not corrected by the normal control epidermis in the remaining 33 seborrheic keratosis cases, one of two HUMARA peaks practically disappeared after HhaI digestion in 20 of 33 seborrheic keratosis cases. In total, 25 of 38 seborrheic keratoses were considered to be monoclonal. The histologic type of seborrheic keratoses did not affect clonality.0), analyzed by in situ PCR, were negative for all HPV probes tested (types 6/11, 31, 33). Control slides (condyloma acuminatum, n=3) were positive for type 6/11, 31, and 33 HPV probes tested. Melasma samples (n=4), the negative controls, were consistently negative. No HPV DNA band was detected by PCR with the tissue extracts from paraffin-embedded SK samples, while condyloma acuminatum, the positive controls, showed DNA bands of the correct molecular weights. Our results show that HPV type 6/11, 31, and 33 cannot be recognized as causative agents for nongenital SK, which is in contrast to the previous studies. Further studies are required to reveal the presence of other types (more than 90) of HPV DNA.

 

LABORATORY/ RADIOLOGIC	CHARACTERIZATION
DERMOSCOPY
Dermoscopy of pigmented seborrheic keratosis: a morphological study. Braun RP, Rabinovitz HS, Krischer J, Kreusch J, Oliviero M, Naldi L, Kopf AW, Saurat JH. Pigmented Skin Lesion Clinic, Department of Dermatology, University Hospital Geneva, 24, rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland.	Arch Dermatol 2002 Dec;138(12):1556-60 Abstract quote OBJECTIVES: To describe morphological features of seborrheic keratosis as seen by dermoscopy and to investigate their prevalence. DESIGN: Prospective cohort study using macrophotography and dermoscopy for the documentation of seborrheic keratosis. SETTINGS: Seborrheic keratoses were prospectively collected in 2 sites: a private practice in Plantation, Fla (site 1), and the Department of Dermatology at the University Hospital Geneva in Switzerland (site 2). PATIENTS: A total of 203 pigmented seborrheic keratoses (from 192 patients) with complete documentation were collected (111 from site 1 and 93 from site 2). INTERVENTIONS: Screening for new morphological features of seborrheic keratosis and evaluation of all lesions for the prevalence of these criteria. MAIN OUTCOME MEASURES: Identification of new morphological criteria and evaluation of frequency. RESULTS: A total of 15 morphological dermoscopic criteria were identified. Standard criteria such as milialike cysts and comedolike openings were found in a high number of cases (135 and 144, respectively). We found network and networklike structures to be present in 94 lesions (46%). Using standard diagnostic criteria for seborrheic keratosis, 30 lesions would not have been diagnosed as such. CONCLUSIONS: The classic dermoscopic criteria for seborrheic keratosis (milialike cysts and comedolike openings) have a high prevalence but the use of additional dermoscopic criteria such as fissures, hairpin blood vessels, sharp demarcation, and moth-eaten borders improves the diagnostic accuracy. The proper identification of pigment network and networklike structures is important for the correct diagnosis.

 

CLINICAL VARIANTS/GROSS APPEARANCE	CHARACTERIZATION
SIGN OF LESER-TRELAT
Hereditary onset of multiple seborrheic keratoses: a variant of Leser Trelat sign? Yamamoto T, Yokoyama A. Department of Dermatology, Tsuchiura Kyodo General Hospital, Ibaraki, Japan.	J Dermatol 1996 Mar;23(3):191-5 Abstract quote A 79-year-old man in a cancer-prone family developed disseminated seborrheic keratoses over his trunk and extremities over a few decades without rapid increase. His son, mother, and one of his brothers, who died of gastric cancer, also had numerous seborrheic keratoses for a long time. He had a biliary tract cancer. Histologic examination showed hyperproliferation of basaloid cells branching downwards, as if induced by surrounding stroma. No decrease of the number of seborrheic keratoses after surgical operation has been observed. Examination for the localization of epidermal growth factor receptor (EGF-R) and HER-2/neu oncoprotein by immunohistochemistry revealed positive staining on the epithelial strands branching downwards on the specimens of seborrheic keratoses. A different pattern of expression was demonstrated in normal seborrheic keratosis. These findings suggest that some unidentified growth factors may be involved in the induction of visceral and/or cutaneous neoplasms in this family.
The sign of Leser-Trelat: a paraneoplastic cutaneous syndrome that facilitates early diagnosis of occult cancer. Vielhauer V, Herzinger T, Korting HC. Medizinische Poliklinik, Ludwig-Maximilians-Universitat Munchen, Pettenkoferstr 8a, D-80336 Munchen, Germany.	Eur J Med Res 2000 Dec 29;5(12):512-6 Abstract quote The sign of Leser-Trelat has been described as a rare cutaneous marker of internal malignancy. We report a patient presenting with the sign of Leser-Trelat, in whom a limited diagnostic workup for an associated malignancy lead to the early diagnosis of asymptomatic renal cell carcinoma and curative tumor nephrectomy. A review on this and other cutaneous paraneoplastic syndromes is given. Since they may be the only presenting sign of an occult cancer, patients with these syndromes should undergo a diagnostic screening program for malignant disease.
The sign of Leser-Trelat in a case of adenocarcinoma of the lung. Heaphy MR Jr, Millns JL, Schroeter AL. Department of Dermatology, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA.	J Am Acad Dermatol 2000 Aug;43(2 Pt 2):386-90 Abstract quote This is what we believe to be the first report of the sign of Leser-Trelat in association with occult adenocarcinoma of the lung. The sign of Leser-Trelat is proposed as a sign of possible occult malignancy, despite various suggestions to the contrary. Also, it is suggested that a tumor-produced humoral factor (eg, transforming growth factor-alpha [TGF-alpha]) could be responsible for both the acute eruption of the monomorphous seborrheic keratoses and the nearly concomitant development of acanthosis nigricans, which occurred in our case. The possible distinction between a hyperplastic and a neoplastic origin of various types of seborrheic keratosis is discussed in relation to this hypothetical humoral factor. In addition, we suggest a refinement of the definition of the sign of Leser-Trelat and discuss the use of "sign of Leser-Trelat" and "syndrome of Leser-Trelat" in relation to physical findings. All patients with the sign of Leser-Trelat should undergo a thorough evaluation for occult malignancy.
Sign of Leser-Trelat associated with adenocarcinoma of the rectum. Ginarte M, Sanchez-Aguilar D, Toribio J. Department of Dermatology, Complejo Hospitalario Universitario, Faculty of Medicine, Santiago de Compostela, Spain.	Eur J Dermatol 2001 May-Jun;11(3):251-3 Abstract quote The acute onset and/or rapid increase in size and number of multiple seborrheic keratoses associated with internal malignancy is called sign of Leser-Trelat. Although some authors reject its existence, there are more than 80 well-documented case reports in the literature. Here, we report a 75-year-old man who presented with abrupt appearance of multiple seborrheic keratoses without any suspicious symptom of cancer. The screening for malignant neoplasms let us detect a rectal adenocarcinoma that was in a curative stage. This case-report illustrates a true sign of Leser-Trelat, and proves that these patients must be appropriately investigated for underlying malignancy.
OTHER
Multiple familial seborrheic keratoses. Rongioletti F, Corbella L, Rebora A. Department of Dermatology, University of Genova, Italy.	Dermatologica 1988;176(1):43-5 Abstract quote The early occurrence of seborrheic keratoses is described in 3 members of a family. The autosomal dominant transmission of seborrheic keratoses in this family provides further evidence for a genetic (polygenic) predisposition to seborrheic keratoses.
A case of seborrheic keratosis distributed along skin cleavage lines. Li X, Zhu W. Department of Dermatology, First Affiliated Hospital of Nanjing Medical University, P.R. China.	J Dermatol 1998 Apr;25(4):272-4 Abstract quote A 65-year-old woman with seborrheic keratosis following skin cleavage lines is reported. The mostly brownish-yellow lesions were located on the back. The round, oval, spindle, comet, and slightly raised papules varied from 1 mm to 2 cm in diameter. The distribution of lesions was unusual; they tended to follow skin cleavage lines on her lower back and waist. The arrangement of lesions was streamlined. The skin biopsy specimen revealed hyperkeratosis, acanthosis, and papillomatosis. The acanthosis was caused by proliferation of squamous and basaloid cells.

 

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL	May be endo- or exophytic with basaloid cells admixed with squamous cells. Scattered horn pseudocysts, squamous eddies, and flattened base is characteristic.
Squamous eddies in irritated seborrheic keratosis. Ihm CW. From the Department of Dermatology, Chonbuk University Hospital and Institute for Medical Sciences, Chonju, South Korea.	Am J Dermatopathol. 2007 Feb;29(1):28-31. Abstract quote Seborrheic keratosis is related to the intraepidermal hair follicle in its morphogenesis. Squamous eddies in irritated seborrheic keratosis (ISK) are known to develop by focal maturation of basaloid cells, but the significance of squamous eddies is not understood. The purpose of this study was to elucidate the nature of squamous eddies in ISK. Serial sections of paraffin blocks of 20 cases of ISK were examined. We tracked each squamous eddy through the serial sections to observe the different shapes and positions of the same squamous eddy. In 4 cases, squamous eddies revealed hair shafts at their centers in different sections. In 14 cases, squamous eddies contained acrotrichial canals. In 13 cases, squamous eddies were connected to keratotic invaginations we thought to be follicular infundibula. Eighteen of the 20 cases of ISK showed at least 1 of the morphological features of intraepidermal hair follicle structures. We have found that the squamous eddies of ISK are anatomically related to acrotrichia.
The diagnostic yield of histologic examination of seborrheic keratoses. Eads TJ, Hood AF, Chuang TY, Faust HB, Farmer ER. Department of Dermatology, Indiana University School of Medicine, Indianapolis, USA.	Arch Dermatol 1997 Nov;133(11):1417-20 Abstract quote OBJECTIVE: To examine the diagnostic yield in submitting clinically diagnosed seborrheic keratoses for routine microscopic examination. DESIGN: Retrospective examination of preoperative and postoperative diagnoses based on information provided by the clinician on the laboratory worksheet and the subsequent histopathologic diagnosis. SETTING: A regional nonhospital-based dermatopathology laboratory with specimens submitted by physicians (dermatologists and nondermatologists) practicing in a 4-state midwestern region of the United States. PATIENT MATERIAL: A total of 5592 cutaneous pathology reports were reviewed. Specimens submitted with a preoperative clinical diagnosis of seborrheic keratosis, with or without a modifier, were examined. A comparison group with the clinical diagnosis of melanocytic nevus was reviewed. MAIN OUTCOME MEASUREMENT: Preoperative clinical diagnoses were compared with the microscopic diagnoses. RESULTS: Of 577 specimens clinically diagnosed and submitted as seborrheic keratoses, 37 (6.4%) were histologically diagnosed as malignant tumors. The rate of malignant tumors increased when clinical information suggested findings beyond the classic clinical presentation, such as irritation, or when a malignant tumor was considered in the differential diagnosis. Two lesions that histologically proved to be melanomas were in this group. Comparison of the seborrheic keratosis group with the nevus group showed that seborrheic keratoses were more likely to be malignant tumors than were melanocytic nevi. Clinically diagnosed seborrheic keratoses submitted by dermatologists were more likely than clinically diagnosed melanocytic nevi to be melanomas. CONCLUSIONS: Our data suggest that there were differences in the rate of malignant tumors between dermatologists and nondermatologists and that clinically diagnosed, surgically removed seborrheic keratoses are more likely than clinically diagnosed, surgically removed melanocytic nevi to be malignant tumors.
VARIANTS	Well described variants include a acanthotic or solid type, reticulated or adenoid type, papillomatous or hyperkeratotic, and irritated.
BASAL CLEAR CELLS
Seborrheic keratosis with basal clear cells: a distinctive microscopic mimic of melanoma in situ. Neuhaus IM, LeBoit PE, McCalmont TM. Department of Dermatology, University of California, San Francisco, California, USA.	J Am Acad Dermatol. 2006 Jan;54(1):132-5. Abstract quote   BACKGROUND: We observed seborrheic keratoses with many basilar clear cells, creating a microscopic pattern that mimicked a seborrheic keratosis involved by melanoma in situ. OBJECTIVE: We sought to report a series of these seborrheic keratoses and the immunohistochemical stains used to reach a proper diagnosis. METHODS: We reviewed 9 cases of seborrheic keratosis that had a distinctive pattern of basal clear cells with ample cytoplasm. All cases were evaluated by conventional microscopy, and Melan-A, S-100, and high molecular weight keratin 903 immunostains. RESULTS: The basal clear cells failed to react with Melan-A and S-100 protein antisera. In contrast, these cells labeled with an antikeratin antibody in all cases. In all, 7/9 (78%) showed immunopositivity only at the peripheries of cells, creating a pattern that could be mistaken for a negative stain if not examined at high magnification. LIMITATIONS: This is a retrospective review of cases limited to a large referral dermatopathology service. CONCLUSIONS: We describe a previously uncharacterized pattern of seborrheic keratosis that can microscopically mimic melanoma in situ. Careful conventional microscopy coupled with a panel of immunostains can allow the proper diagnosis to be reached.
DESMOPLASTIC
Desmoplastic seborrheic keratosis. King R, Page RN, Googe PB.	Am J Dermatopathol. 2003 Jun;25(3):210-4 Abstract quote Eleven cases of seborrheic keratoses with desmoplastic stroma and associated nests and cords of squamous epithelium simulating infiltrating carcinoma are presented. There were 7 males and 4 females ranging in age from 44 to 88 years (mean = 62). Eight cases were on the head and neck, one each on the lower and upper extremity, and one on the pubic area. Clinical diagnoses included seborrheic keratosis, squamous and basal cell carcinoma, and dermal nevus. Histologically, the lesions were characterized by exophytic growth pattern of basaloid and squamous cells, without cytologic atypia, and well-demarcated peripheral borders, typical for that seen in seborrheic keratoses. Squamous eddy formation with parakeratosis and spongiosis was present in all cases. Located within the body of the lesions were irregular nests and cords of squamous cells extending into the surrounding dermis with associated fibroblastic dermal proliferation trapping the epithelial nests, simulating invasive carcinoma. Immunohistochemically, the epithelial nests were cytokeratin positive and HPV negative, and the dermal stromal cells were vimentin positive and factor XIIIa, cytokeratin, and CD34 negative. Adjacent changes of carcinoma, trichilemmoma, verruca, or other adnexal neoplasm were not identified. Seborrheic keratoses may demonstrate desmoplastic changes analogous to that seen in desmoplastic trichilemmomas. Awareness of these changes in seborrheic keratosis will avoid misdiagnosis and excessive therapy.
INFLAMMATORY
Inflammatory seborrheic keratoses with mononuclear cell infiltration. Berman A, Winkelmann RK.	J Cutan Pathol 1978 Dec;5(6):353-60 Abstract quote Inflammation in inflammatory seborrheic keratoses was found to be composed of mononuclear cells, particularly lymphocytes. Accumulations of mononuclear cells in the papillary and subpapillary dermis frequently showed no tendency to infiltrate the epithelium. However, dramatic interaction of the seborrheic keratosis and the inflammatory process also was common . The lymphocytic exocytosis into the epithelium followed two basic patterns: eczematous, characterized by intercellular and intracellular edema, microvesicle formation, and epithelial necrosis; and lichenoid, in which a bandlike infiltrate attacked the dermoepidermal junction and hyaline bodies occurred in the infiltrated epithelium and in the dermis. Epithelial changes consisted of necrosis of epithelial cells and related parakeratosis; squamous eddies were occasionally found. Inflammatory cell infiltration in seborrheic keratoses possibly represents a process other than irritation, and we propose that mononuclear cell infiltration in seborrheic keratoses may be related to an involutionary process.
Histologic changes in seborrheic keratoses after rubbing. Berman A, Winkelmann RK.	J Cutan Pathol 1980 Feb;7(1):32-8 Abstract quote Seborrheic keratoses in five patients were rubbed and biopsied at varying intervals after injury. Microscopic examination revealed acute and chronic patterns of histologic change. Hemorrhage, hyalinization of dermal papillae, and necrosis of epithelial tips were conspicuous early changes. Specimens taken more than 48 h after rubbing showed a spectrum of changes which included: loss of epithelial mass, expansion and interconnection of keratin cysts, thinning of the epithelium, proliferation of epithelial strands from the residual epithelium, increase in size of epithelial cells, and evidence of hair follicle relationships including trichostasis spinulosa and, in one specimen, hair germ proliferation. Dermal lymphocytic infiltration was variable and only rarely involved the epithelium. These observations demonstrate a patterned response of the seborrheic keratosis to trauma, and also indicate a relationship between seborrheic keratosis and the hair follicle.
MELANOACANTHOMA
Oral Melanoacanthoma: A Report of 10 Cases, Review of the Literature, and Immunohistochemical Analysis for HMB-45 Reactivity. Fornatora ML, Reich RF, Haber S, Solomon F, Freedman PD.	Am J Dermatopathol 2003 Feb;25(1):12-5 Abstract quote Oral melanoacanthoma (MA) is rare reactive mucosal lesion that, like cutaneous MA, demonstrates hyperplasia of spinous keratinocytes and melanocytes. Unlike MA of the skin, oral MA is unrelated to seborrheic keratosis. This series adds 10 cases to the limited number of previous reports of oral MA. The clinicopathologic features of the cases in this series are generally consistent with those previously reported in the literature; that is, although documented in various intraoral locations in patients of differing ethnicity, oral melanoacanthoma most often presents as an enlarging flat or slightly raised area of hyperpigmentation on the buccal mucosa of adult black women. The current series provides evidence of occurrence over a wider age range (5-77 years) than previously reported. Additionally, the reactivity of oral melanoacanthoma to HMB-45 was investigated. Strong HMB-45 reactivity was present in all cases, thus demonstrating its limited utility in distinguishing oral MA from malignant melanoma.
TRICHILEMMAL
Trichilemmal keratinization in seborrheic keratoses. Masuda M, Kimura S.	J Cutan Pathol 1984 Feb;11(1):12-7 Abstract quote In 33 of 112 seborrheic keratoses reviewed histologically, a keratinization process was observed, which was identical with or showed marked similarity to, trichilemmal keratinization (TK). This type of keratinization took place more frequently in lesions which were pruritic and in those located on the extremities. Histologically, the change was observed in the bottoms of pseudocysts and crypts, in areas showing evidence of inflammation, such as exocytosis, spongiosis and squamous eddy or whorl formation. No relationship was found between the presence of TK or TK-like keratinization and the various histologic types of seborrheic keratoses. It is concluded that a process which can not be distinguished from TK microscopically may occur frequently in seborrheic keratoses as a result of inflammation.
Nonmelanoma skin cancers in association with seborrheic keratoses. Clinicopathologic correlations. Maize JC, Snider RL. Department of Dermatology, Medical University of South Carolina, Charleston 29425-0001, USA.	Dermatol Surg 1995 Nov;21(11):960-2 Abstract quote BACKGROUND. Seborrheic keratoses (SKs) can be seen in association with cancers. OBJECTIVE. Our study was designed to demonstrate the occurrence of concomitant SKs and nonmelanoma skin cancers, as well as to correlate their histological types and clinical locations. The study was not intended to be an epidemiologic survey. METHODS. We prospectively collected 108 completely excised SKs, examined them microscopically, categorized them, and correlated the clinical site, histological type, and determined the incidence of concomitant malignancy. RESULTS. Of the 108 SKs studied, 71 were acanthotic, 27 hyperkeratotic, and 10 reticulated. The incidence of associated nonmelanoma cancers was 4.6%. All malignancies were squamous cell carcinomas and were on sun-exposed skin. Three of the five malignancies arose in conjunction with reticulated SKs. CONCLUSIONS. The incidence of nonmelanoma skin cancer in association with SKs may be greater than previously reported, particularly in SKs situated on photo damaged skin and of the reticulated type. SKs that have undergone recent growth or other clinical change should be biopsied and all SKs that are removed should be examined histologically.
Malignant melanoma arising in a seborrheic keratosis. Zabel RJ, Vinson RP, McCollough ML. Department of Medicine, William Beaumont Army Medical Center, El Paso, TX 79920-5001, USA.	J Am Acad Dermatol 2000 May;42(5 Pt 1):831-3 Abstract quote We report a case of malignant melanoma associated with seborrheic keratosis. This has been reported rarely in the literature, with disagreement regarding whether it is coincidental or whether malignant transformation occurs. Because seborrheic keratoses are common and association with malignant melanoma is very rare, we conclude that the association is coincidental. However, because of the association of other malignancies, a biopsy of any suspect or changing seborrheic keratosis is essential.
SEBACEOMA
Sebaceoma arising in association with seborrheic keratosis. Betti R, Inselvini E, Vergani R, Moneghini L, Crosti C. Clinica Dermatologica IV, Universita degli Studi di Milano, Ospedale San Paolo, Milano, Italy.	Am J Dermatopathol 2001 Feb;23(1):58-61 Abstract quote We report a case of a 60-year-old woman with a 4-year history of an asymptomatic plaque on her left cheek. The lesion was composed of two distinct adjacent and continuous parts comprising a lateral yellowish flat portion and a medial reddish nodular portion. Histologic examination revealed that the plaque was composed of two different adjacent tumors. The lateral portion of the plaque had the aspect of a seborrheic keratosis (SK) with hyperkeratosis and acanthosis with irregular proliferation of apparently benign basaloid and squamous keratinocytes and small horn pseudocysts. The medial portion showed a dermal tumor made up of differently sized lobules composed of immature sebocytes mixed with single or clustered mature sebaceous cells. Sebaceous ductal differentiation was visible. We made the diagnosis of SK associated with sebaceoma. The association of an SK with a benign neoplasm with sebaceous differentiation is rare. It may only be a coincidence, but a role for the preexisting SK cannot be ruled out.

 

SPECIAL STAINS/ IMMUNOHISTO- CHEMISTRY	CHARACTERIZATION
An immunohistochemical and histochemical study of cytokeratin, involucrin and transglutaminase in seborrhoeic keratosis. Broekaert D, Leigh IM, Lane EB, Van Muijen GN, Ramaekers FC, De Bersaques J, Coucke P. Laboratory of Physiological Chemistry, Faculty of Medicine, University of Ghent, Belgium.	Arch Dermatol Res 1993;285(8):482-90 Abstract quote The mode of differentiation of seborrhoeic keratoses was investigated by immunohistochemical staining using cytokeratin (CK) polypeptide-specific monoclonal antibodies and an antibody specific for the particulate form of epidermal transglutaminase (ETgase), and by applying an anti-human involucrin serum. The role played by (E)Tgase was further evaluated using an activity assay based on the covalent attachment of monodansylcadaverine. Samples of uninvolved epidermis served as reference tissue. CK reactivities suggested that seborrhoeic keratoses is a hyperproliferative disease with an epidermal CK composition. CK5 and CK14 were prominent markers of basal and basaloid keratinocytes, whereas a decrease in staining occurred in advanced maturation stages and areas of terminal keratinization. In contrast, CK1 and CK10 were prominent markers of suprabasaloid differentiation stages and produced complementary stainings to those of CK5 and 14. Generally, CK10 staining was more impressive than CK1 staining and seemed to start before CK1 staining. In contrast to CK10 staining, cornified areas lost CK1 reactivity. These staining patterns were similar to those observed in uninvolved reference tissues. The epidermal CK subset was further supplemented with the 'hyperproliferative' CK6 and 16 which occur sequentially. Positive staining for CK6 was noted from basal and proximal basaloid cells onwards, whereas distal basaloid cells additionally showed CK16 staining. The presence of other non-epidermal CK polypeptides could not be shown. The competence for other differentiation markers belonging to the group of (E)Tgase and cornifying cell membranes also evolved with a typical epidermal pattern. (E)Tgase activity was restricted to advanced and terminal stages of keratinization and was dual in nature, i.e. a diffuse cytoplasmic staining occurred together with a prominent staining of cornifying cell membranes.(SPE
ELECTRON MICROSCOPY
Melanosome macrocomplex: an ultrastructural component of patterned and nonpatterned seborrheic keratoses. Shelley WB, Shelley ED, Burmeister V.	J Am Acad Dermatol 1987 Jan;16(1 Pt 1):124-8 Abstract quote An ultrastructural study of five seborrheic keratoses arising in a symmetrical, patterned distribution following the lines of cleavage on the backs of two patients showed the presence of melanosome macrocomplexes 2 to 5 microns in size. Identical findings were seen in fifteen pigmented seborrheic keratoses randomly distributed on the skin of five patients. The membrane-bound macrocomplexes were clusters of closely packed, discrete melanosomes. Present in melanocytes, keratinocytes, Langerhans cells, and dermal macrophages, they were considered to result from sequestration of melanosomes in cell phagosomes. No homogeneous inclusions typical of melanin macroglobules ("giant melanosomes") were found in any of the specimens, supporting the view that neither patterned nor nonpatterned seborrheic keratoses are nevoid in nature.

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
HIDROACANTHOMA SIMPLEX
Pigmented malignant hidroacanthoma simplex mimicking irritated seborrheic keratosis. Lee JY, Lin MH. Department of Dermatology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.	J Cutan Pathol. 2006 Oct;33(10):705-8. Abstract quote Pigmented variant of malignant hidroacanthoma simplex (PMHS) is very rare. We are aware of only two reported cases, all arising in pigmented hidroacanthoma simplex (HS). We report the third case of PMHS arising in a pigmented HS. A 71-year-old-woman presented with a well-demarcated pigmented hyperkeratotic tumor on the right knee resembling irritated seborrheic keratosis. Histopathologic examination of the excised tumor revealed intraepidermal proliferation of atypical polygonal poroid cells forming large, sharply demarcated nests with colonization of dendritic melanocytes. In addition, there were focal changes of a benign pigmented HS and syringofibroadenoma. The key diagnostic features of ductal structures and intracytoplasmic lumina were highlighted by carcinoembryonic antigen and epithelial membrane antigen immunostaining. PMHS should be differentiated from irritated seborrheic keratosis, melanoacanthoma, Bowen's disease and malignant melanoma both clinically and pathologically.
Differentiation of hidroacanthoma simplex from clonal seborrheic keratosis--an immunohistochemical study. Liu HN, Chang YT, Chen CC. Department of Dermatology, Veterans General Hospital-Taipei and National Yang-Ming University, Taiwan, ROC	Am J Dermatopathol. 2004 Jun;26(3):188-93. Abstract quote   Hidroacanthoma simplex (HS) is an uncommon poroid neoplasm confined within the epidermis. The clinical features of HS are not distinctive and histopathologically HS may be confused with clonal seborrheic keratosis (CSK) if cystic or ductal structure is not present. The purpose of our study was to differentiate HS from CSK by the immunohistochemical expressions of various cytokeratins, CEA, CD1a, and S-100 protein, as well as by the degrees of deposition of melanins and glycogen. Four cases of HS and seven cases of CSK were included in the research. In contrast with CSK, HS showed a very low density of Langerhans cells (19.9 +/- 7.7 versus 3.1 +/- 1.0 CD1a (+) cells/mm, P = 0.027) and sparse melanin deposition in the nests. However, HS could not be set apart from CSK by the expressions of cytokeratins. The nests of both HS and CSK showed very similar patterns of cytokeratin expression and seemed to be mainly composed of basaloid cells with focal differentiation toward epidermal suprabasal cells.

Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

Horn pseudocysts -Intraepidermal cysts and invaginations of keratin.

Leser-Trelat sign-Sudden increase in the number and size of seborrheic keratoses associated with an internal cancer. This association has recently been questioned. The most comon cancer is a gastrointestinal tract adenocarcinoma.

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