KIT mutations and CD117 overexpression are markers of better progression-free survival in vulvar melanomas.

BACKGROUND: Few studies have addressed prognostic markers and none has correlated molecular status and prognosis in vulvar melanomas. OBJECTIVES: To evaluate the clinicopathological features of 95 cases of vulvar melanoma. METHODS: p53, CD117, Ki-67, neurofibromin, brafv600e and nrasq61r immunostains, and molecular analyses by either targeted next-generation or direct sequencing, were performed on available archival materials. RESULTS: Molecular testing detected mutations in KIT (44%), BRAF (25%), NF1 (22%), TP53 (17%), NRAS (9%) and TERT promoter (9%). Co-mutation of KIT and NF1 and of KIT and NRAS were identified in two and one cases, respectively. KIT mutations were significantly associated with better progression-free survival in univariate analyses. In multivariate analyses CD117 expression was significantly associated with better progression-free survival. Tumour thickness was significantly associated with worse progression-free and overall survival, and perineural invasion significantly correlated with reduced melanoma-specific survival and reduced overall survival. Cases were from multiple centres and only a subset of samples was available for molecular testing. CONCLUSIONS: KIT mutations and CD117 overexpression are markers of better progression-free survival. In addition to its prognostic value, molecular testing may identify cases that might respond to targeted agents or immunotherapeutic approaches.

Dual role of SIRT1 in UVB-induced skin tumorigenesis.

The protein deacetylase SIRT1 regulates various pathways in metabolism, aging and cancer. However, the role of SIRT1 in skin cancer remains unclear. Here, using mice with targeted deletions of SIRT1 in their epidermis in both resistant B6 and sensitive SKH1 hairless backgrounds, we show that the role of SIRT1 in skin cancer development induced by ultraviolet B (UVB) radiation is dependent on its gene dose. Keratinocyte-specific heterozygous deletion of SIRT1 promotes UVB-induced skin tumorigenesis, whereas homozygous deletion of SIRT1 suppresses skin tumor development but sensitizes the B6 mice to chronic solar injury. In mouse skin, SIRT1 is haploinsufficient for UVB-induced DNA damage repair and expression of xeroderma pigmentosum C (XPC), a protein critical for repairing UVB-induced DNA damage. As compared with normal human skin, downregulation of SIRT1 is in parallel with downregulation of XPC in human cutaneous squamous cell carcinoma at both the protein and mRNA levels. In contrast, homozygous SIRT1 deletion in mouse skin augments p53 acetylation and expression of its transcriptional target Noxa, and sensitizes the epidermis to UVB-induced apoptosis in vivo, while heterozygous SIRT1 deletion has no such effect. The gene dosage-dependent function of SIRT1 in DNA repair and cell survival is consistent with the dual roles of SIRT1 in UVB-induced skin tumorigenesis. Our results reveal the gene dosage-dependent in vivo functions of SIRT1 in skin tumorigenesis and may shed light on the role of SIRT1 in epithelial cancer induced by DNA damage.

Eruptive cutaneous squamous cell carcinoma and psoriasis: response to cetuximab.

Cutaneous squamous cell carcinomas (CSCCs) comprise 20-30% of nonmelanoma skin cancers (NMSCs), and continue to increase in incidence. We report a case of a patient with severe psoriasis who had recurrent and eruptive CSCCs on her leg, which were successfully treated with cetuximab and radiotherapy. The patient had successful long-term clearance of her skin tumours, with the additional finding of resolution of psoriasis while on cetuximab therapy.

UVB-induced ERK/AKT-dependent PTEN suppression promotes survival of epidermal keratinocytes.

Ultraviolet (UV) radiation in sunlight is the major environmental cause of skin cancer. PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a proven critical tumor suppressor. We report here that UVB downregulates PTEN in primary human keratinocytes, human HaCaT keratinocytes and mouse skin. As compared with normal skin, PTEN levels are reduced in human actinic keratosis, a precancerous skin lesion caused by solar UV. PTEN downregulation is mediated by two mechanisms: (1) PTEN is cleaved by active caspase in apoptotic cells in which AKT activation is reduced; and (2) PTEN transcription is suppressed in surviving cells, and this suppression is independent of caspase activation and occurs in parallel with increased ERK and AKT activation. We report here that the combination of ERK and AKT activation is crucial for PTEN suppression in surviving cells following UVB irradiation. AKT activation is higher in UVB-irradiated surviving cells as compared with unirradiated cells. The ERK and AKT pathways are involved in sustaining PTEN suppression in UVB-exposed cells. Increasing PTEN expression enhances apoptosis of keratinocytes in response to UVB irradiation. Our findings indicate that (1) UVB radiation suppresses PTEN expression in keratinocytes; and (2) the ERK/AKT/PTEN axis may form a positive feedback loop following UVB irradiation. Our identification of PTEN as a critical molecular target of UVB provides new insights into the pathogenesis of skin cancer.

Dysplastic naevi with moderate to severe histological dysplasia: a risk factor for melanoma.

BACKGROUND: The risk of malignant melanoma associated with histologically dysplastic naevi (HDN) has not been defined. While clinically atypical naevi appear to confer an independent risk of melanoma, no study has evaluated the extent to which HDN are predictive of melanoma. OBJECTIVES: To estimate the risk of melanoma associated with HDN. Secondarily, the risk associated with number of naevi and large naevi is estimated. METHODS: We enrolled 80 patients with newly diagnosed melanoma along with 80 spousal controls. After obtaining information on melanoma risk factors and performing a complete cutaneous examination, the most clinically atypical naevus was biopsied in both cases and controls. Histological dysplasia was then assessed independently by 13 dermatopathologists (0, no dysplasia; 1, mild dysplasia; 2, moderate dysplasia; 3, severe dysplasia). The dermatopathologists were blinded as to whether the naevi were from melanoma subjects or controls. Multivariate analyses were performed to determine if there was an independent association between the degree of histological dysplasia in naevi and a personal history of melanoma. RESULTS: In persons with naevi receiving an average score of > 1 (i.e. naevi considered to have greater than mild histological dysplasia), there was an increased risk of melanoma [odds ratio (OR) 2.60, 95% confidence interval (CI) 0.99-6.86] which persisted after adjustment for confounders (OR 3.99, 95% CI 1.02-15.71). Very few dermatopathologists reliably graded naevi of subjects with melanoma as being more dysplastic than naevi of control subjects. Among the entire group, the interobserver reliability associated with grading histological dysplasia in naevi was poor (weighted kappa 0.28). CONCLUSIONS: HDN do appear to confer an independent risk of melanoma. However, this result may add more to our biological understanding of melanoma risk than to clinical assessment of risk, because HDN assessed by a single pathologist generally cannot be used to assess risk of melanoma. Future studies should be directed at establishing reproducible, predictive criteria for grading naevi.

Eccrine mucinous metaplasia associated with an apocrine cystadenoma.

Mucinous metaplasia occurs uncommonly in cutaneous pathology, usually at specialized anatomic locations (genitalia, palms, and soles) and within restricted pathologic contexts (inflammation and trauma). Here, we report a unique case of eccrine mucinous metaplasia associated with an apocrine cystadenoma. A 13-year-old girl had an asymptomatic, 4-mm nodule on the chest. Histopathology demonstrated a typical apocrine cystadenoma in the upper and middle dermis. Adjacent to this lesion was a cluster of coiled eccrine secretory glands, of which the inner layer was almost entirely replaced by benign-appearing cells containing abundant, non-sulfated acid mucopolysaccharides. At 10 months' follow up, there was no recurrence. Our case demonstrates that, very uncommonly, mucinous metaplasia may be associated with a pathogenetically separate, adjacent proliferative adenomatous lesion, in this instance, an apocrine cystadenoma.

CD34 expression in desmoplastic melanoma.

BACKGROUND: Primary and metastatic malignant melanoma can simulate various soft tissue tumors, including dermatofibrosarcoma protuberans (DFSP). Expression of CD34, a marker characteristic of DFSP, as well as other spindle cell tumors, has not been previously documented in malignant melanoma. METHODS: We present here an unusual case of metastatic malignant melanoma with a strong histologic resemblance to DFSP and also CD34 expression. RESULTS: The patient, a 72-year-old man with a history of an invasive malignant melanoma of the skin of the right lower abdomen, presented with a right axillary mass. Histologic sections revealed intersecting fascicles of spindle cells with nuclear pleomorphism and numerous mitotic figures, diffusely infiltrating the adipose tissue in a pattern closely simulating that seen in DFSP. In other foci, epithelioid neoplastic cells with abundant cytoplasm, prominent nucleoli, nuclear pseudoinclusions, and focal cytoplasmic melanin pigment were seen. The neoplastic spindle cells were strongly labeled by two anti-CD34 monoclonal antibodies. Some of the spindle cells and the majority of the epithelioid neoplastic cells expressed S-100 protein and focally tyrosinase. The tumor cells were negative for HMB-45 and MART-1. Melanosomes were not identified by electron microscopy. CONCLUSION: This case demonstrates the potential of melanoma to simulate DFSP closely, on both morphologic and immunohistochemical grounds, and confirms the utility of employing a broad panel of immunohistochemical reagents in problematic cases.

A comparative clinical and histologic study of hair transplantation using Er:YAG, Er:YAG/CO2, and standard punch techniques.

BACKGROUND: This study compares the effects of Er:YAG laser alone, Er:YAG/CO2 laser at 5 W (low power), Er:YAG/CO2 at 10 W (high power), and standard punch techniques in 10 men with androgenetic alopecia. OBJECTIVE: To study the clinical and histologic features of hair transplantation with recipient graft defects created by a new hybrid Er:YAG and CO2 laser. METHODS: Ten male patients (mean age 34 y) with Norwood IV-VI androgenetic alopecia had hair replacement surgery with the recipient sites divided into four quadrants comparing cold stell, erbium, combined erbium low-power CO2, and combined erbium high-power CO2 technologies. Hair growth, intraoperative procedure, lateral thermal damage, and patient satisfaction were compared, utilizing each of the four stated technologies. RESULTS: The addition of CO2 laser at both low and high power settings resulted in improved hemostasis when compared with standard punch or Er:YAG laser alone. The mean hair counts were similar for the Er:YAG laser, Er:YAG/CO2 (5 W) laser, and standard punch at both 3 and 6 months after treatment. Lateral thermal damage was not significantly increased by the addition of low-power CO2 to Er:YAG. The addition of high-power CO2 (10 W) laser resulted in slightly lower mean hair counts at 3 months, but significantly decreased at 6 months (P =.05). Also, high-power CO2 laser caused significantly increased lateral damage. There were no detectable differences in hsp70 expression among the groups. CONCLUSION: The addition of 5 W CO2 laser to Er:YAG laser results in better hemostasis than Er:YAG laser alone, while not significantly diminishing mean hair counts or inducing increased lateral thermal damage.

Primary chondroid melanoma.

BACKGROUND: Malignant melanoma is notorious for the wide range of histologic patterns it can assume, among the least frequent of which is chondroid melamona. METHODS: Two cases of primary chondroid melanoma of the distal lower extremity were studied. Tissue for light microscopy was fixed in formalin, embedded in paraffin, and processed routinely. In one case, transmission electron microscopy and immunohistochemical evaluation were performed. RESULTS: Both cases exhibited melanoma in-situ, a conventional (non-chondroid) invasive component, and areas of chondroid differentiation, as confirmed by strongly positive staining with Alcian blue at pH 2.5 and Safranin O. Immunohistochemically, one case expressed S-100 protein and vimentin, and did not express gp100 (HMB-45), tyrosinase, MART-1, the Mel-5 antigen, the NKI/C3 antigen, CD45Ro, cytokeratin, or desmin. Electron microscopy of the chondroid component revealed occasional tumor cells with rare, membrane-bound, electron-dense organelles; the extracellular compartment showed amorphous ground substance consistent with cartilaginous differentiation. CONCLUSIONS: Chondroid change in the absence of osteogenic differentiation is extremely rare in malignant melanoma. Melanoma should be considered in the differential diagnosis of primary cutaneous neoplasms exhibiting cartilaginous differentiation.

Recurrent melanocytic nevus: a histologic and immunohistochemical evaluation.

BACKGROUND: Recurrent melanocytic lesions may histologically resemble malignant melanoma. METHODS: We evaluated the original nevi (ON) and recurrent nevi (RN) of 15 patients by routine histology and immunohistochemistry (IHC), examining expression of S-100 protein, gp100 (with HMB-45), MART-1, tyrosinase, and the Ki-67 proliferation marker. RESULTS: Compared with ON, RN had a dermal scar, a significantly greater number of melanophages, and a greater extent of cellular atypia including prominent nucleoli and larger cell size. Architecturally, RN showed significantly less symmetry than ON; however, the percentage of junctional cohesive nests, the presence of suprabasal spread, and the degree of confluence were similar between ON and RN. Both ON and RN showed a decrease in expression of gp100 and tyrosinase with increasing depth ("maturation gradient") and low proliferative activity in both the junctional (4.6% for ON vs. 4.13% for RN) and the dermal components (0.93% for ON vs. 1.45% for RN). CONCLUSIONS: RN exhibit a dermal scar, a greater number of melanophages, cytologic atypia, and asymmetry than ON, features that may raise concern about the possibility of malignant melanoma. However, the area with the irregular architectural pattern is restricted to the epidermis and dermis immediately above the scar. In addition, IHC helps to distinguish RN from malignant melanoma; specifically, RN demonstrate an immunohistochemical "maturation pattern" (with HMB-45 and anti-tyrosinase) and a low proliferative index (with Ki-67).

Clinical and pathophysiologic correlates of 1064-nm Nd:Yag laser treatment of reticular veins and venulectasias.

BACKGROUND: The goal of sclerotherapy, laser therapy, and intense pulsed-light therapy is to produce long-term, cosmetically significant elimination of disfiguring leg veins. This study examines the histologic and clinical effects of using a 1064-nm Nd:YAG laser system on lower extremity vessels. DESIGN: A single treatment using the following parameters: wavelength, 1064 nm (multiple synchronized pulsing); spot size, 6 mm; pulse duration, 14 milliseconds (single pulse); and fluence, 130 J/cm(2). SETTING: Private dermatology practice. PATIENTS: Thirteen women (mean age, 38.5 years) with blue venulectasia, 0.5 to 1.5 mm in diameter (class 2), and reticular veins, 1.5 to 3.0 mm in diameter (class 3), on the thighs. MAIN OUTCOME MEASURES: Examination of treated and untreated areas by 2 masked observers using macrophotography (1, 2, 3, and 6 months after treatment), Doppler, and optical chromatographic changes. Findings from three 2-mm punch biopsies from treated (immediately and 4 weeks after treatment) and untreated sites. Routine histologic examination; special stains (for elastic and connective tissue and for mucopolysaccharides); and immunohistochemical analysis for expression of the heat shock protein hsp70, tie2 (an endothelial cell-specific receptor tyrosine kinase), and transforming growth factors beta1 and beta2. RESULTS: Eight patients (62%) manifested 75% to 100% clearing of treated vessel surface area. Treated areas revealed perivascular hemorrhage, thrombi, fragmentation and homogenization of elastic fibers, and eosinophilia of vessel walls. Expression of hsp70 and transforming growth factor beta was increased in treated vessels. CONCLUSIONS: Our data confirm the effectiveness of 1064-nm Nd:YAG laser treatment in clearing dilated lower extremity veins, probably by heat-induced vessel damage and subsequent fibrosis. Maintenance of clearing was achieved for up to 6 months. However, the presence of recanalized thrombi in some of the specimens suggests the potential for long-term vessel reappearance.

Reassessment of lymphocytic atypia in the diagnosis of mycosis fungoides.

The manifestations of mycosis fungoides in its early stage may mimic clinically and histologically those of many benign inflammatory dermatoses. Therefore, the diagnosis of mycosis fungoides remains a major challenge for dermatologists and dermatopathologists. For many years, it has been proposed that atypical lymphocytes within the epidermis constitute one of the diagnostic features in mycosis fungoides. Presence of dermal atypical lymphocytes remains controversial as a diagnostic criterion. We reassessed the feasibility of applying lymphocytic atypia within epidermis and dermis as diagnostic criteria discriminating between mycosis fungoides and spongiotic dermatitis. Thirty cases of mycosis fungoides and 30 cases of spongiotic dermatitis were retrieved from archival hematoxylin and eosin-stained histologic sections. Punch biopsy sections were examined by light microscopy; epidermal and dermal lymphocytes were photographed at 1000x (oil immersion). A total of 92 ektachrome slides (35 mM) were developed, coded, and ordered randomly. For each slide, cells were interpreted as typical or atypical lymphocytes by seven pathologists. Atypical epidermal lymphocytes were judged to be present in 9 +/- 2 out of 16 (56%) cases of mycosis fungoides photographed as compared with 8 +/- 3 out of 16 (50%) in spongiotic dermatitis. Dermal lymphocytic atypia was thought to be present in 14 +/- 6 out of 30 (47%) patients with mycosis fungoides. Thirteen +/- 6 out of 30 (43%) patients with non-mycosis fungoides also displayed dermal lymphocytic atypia. No statistical significance was observed in these comparisons (t test, P >.05). Furthermore, atypia of lymphocytes was deemed to be present in 41, 38, 59, 70, 23, 47, and 40 out of 92 slides examined by the investigators, suggesting that observer variation is a very significant factor in our present study. We conclude that it is not possible to distinguish mycosis fungoides from spongiotic dermatitis merely based on lymphocytic atypia within epidermis or dermis.

Basal cell carcinoma originating from a nevus sebaceus on the scalp of a 7-year-old boy.

Basal cell carcinoma (BCC) occurs rarely in children and is most often associated with an underlying condition that predisposes patients to the development of malignancy. There have been numerous reports of BCC developing after puberty in nevus sebaceus; however, such occurrences have rarely been described in children. We report a 7-year-old boy with BCC forming in a nevus sebaceus.

Malignant melanoma with paradoxical maturation.

Typically, melanocytic nevi "mature" (i.e., exhibit a morphologic shift to smaller or spindle cells with progressive depth in the dermis). In contrast, most malignant melanomas (conventional MMs) lack maturation, and are composed of large pleomorphic cells throughout. The authors describe a series of melanomas with paradoxical maturation mimicking the pattern of nevi. Seventeen primary invasive melanomas with paradoxical maturation (IMPs), two epidermotropic metastatic melanomas with maturation (EMMMs), 13 compound nevi (CN), and 14 conventional MMs without apparent maturation were analyzed by histologic, cytomorphometric, and immunohistochemical techniques. With increasing dermal depth, both CN and IMPs had smaller nuclear and cellular areas, and decreased expression of Ki-67, glycoprotein (gp)100 (with HMB-45), and tyrosinase. IMPs had significant differences from conventional MMs; namely, smaller nuclear and cytoplasmic areas (deep), and decreased expression of Ki-67 (superficial and deep), gp100 (deep), and tyrosinase (deep). IMPs also had notable differences from CN: namely, larger nuclear and cellular areas, more confluence, more mitotic figures, increased Ki-67 and gp100 expression in both the superficial and deep portions, and more melanin (deep). The two EMMMs exhibited histologic and immunohistochemical features similar to the primary IMPs. IMP, because of its mimicry of nevus, can present a diagnostic hazard. The authors propose histologic, morphometric, and immunohistochemical criteria that facilitate recognition and accurate diagnosis of this unusual variant of melanoma.

Increased incidence of trisomy 8 in acute myeloid leukemia with skin infiltration (leukemia cutis).

Anecdotal literature reports and the authors' own observations suggest an association between chromosome 8 aneuploidy and leukemia cutis. The authors investigated this potential association by using fluorescence in situ hybridization (FISH) directly on skin infiltrates in a series of 11 patients with acute monocytic leukemia (AML). Seven of the 11 patients were aneuploid for chromosome 8 by FISH which was confirmed by dual color hybridization. Six of these seven patients were AML-M4 or M5 and one was M1. The majority of the cases with leukemia cutis expressed CD4 (90% of cases), CD14 (60%), and/or CD56 (50%) in bone marrow leukemic cells. The data show the utility of examination of skin infiltrates by FISH for the detection of trisomy 8 in leukemia cutis. They also suggest the importance of trisomy 8 as a factor in predisposition to skin infiltration in AML.

Long-term photoepilation using a broad-spectrum intense pulsed light source.

BACKGROUND: The goal of laser or flashlamp photoepilation is to produce long-term, cosmetically significant hair removal. We document the long-term efficacy achieved with an intense pulsed light source for photoepilation. DESIGN: Prospective study comparing long-term results of single vs multiple treatments, and effects of anatomic site and skin type on efficacy of photoepilation with a device emitting broad-spectrum, noncoherent (nonlaser) radiation from 550- to 1200-nm wavelengths, in macropulses divided into 2 to 5 minipulses. SETTING: Private dermatology practice. PATIENTS: Thirty-four patients (8 men, 26 women) with hirsutism. INTERVENTIONS: Parameters for the study were wavelength of 615 to 695 nm, pulse duration of 2.6 to 3.3 milliseconds, fluence of 34 to 42 J/cm(2), 10 x 45-mm exposure field, and application of 1 degrees C cooling gel. MAIN OUTCOME MEASURES: Hair removal efficiency, calculated as percentage ratio of the number of hairs present compared with baseline counts, and patient satisfaction questionnaire completed at last follow-up. RESULTS: The mean hair removal efficiency achieved was 76% after a mean of 3.7 treatments. More than 94% of the sites reached mean hair removal efficiency values greater than 50%. Hair removal efficiency was not significantly related to skin type, hair color, anatomic site, or number of treatments. Side effects were mild and reversible and occurred in a minority of patients (hyperpigmentation in 3 and superficial crusting in 2). CONCLUSIONS: Our data document the long-term clinical efficacy of intense pulsed light source-induced hair removal in light and dark skin phenotypes. Maximal photoepilation was achieved from the initial 1 to 3 treatments; only a small added benefit was seen after more treatments.

Experimental photoimmunotherapy of hepatic metastases of colorectal cancer with a 17.1A chlorin(e6) immunoconjugate.

Photoimmunotherapy (using a monoclonal antibody-targeted photosensitizer and red light) may be a strategy to overcome the limitations inherent in photodynamic therapy of liver tumors. The aims of this study were (a) to test the efficacy of selective treatment of hepatic metastases of colorectal cancer in an orthotopic murine xenograft using the murine monoclonal antibody 17.1A conjugated to the photosensitizer chlorin(e6), and (b) to compare the tumor response after the same light dose was delivered at two different fluence rates. Based on previous biodistribution studies that had shown that the photoimmunoconjugate with a polyanionic charge had both a higher absolute tumor chlorin(e6) content and a greater tumor:normal liver ratio than those obtained with a photoimmunoconjugate bearing a polycationic charge, mice were treated 3 h after i.v. injection of the polyanionic 17.1A chlorin(e6) conjugate or unconjugated photosensitizer. Red light was delivered into the liver tumor by an interstitial fiber, and tumor response end points were total tumor weight in the short term and survival in the long term. There was a highly significant reduction (<20% of controls; P = 0.0035) in the weight of the tumors in the mice treated with photoimmunotherapy, and the median survival increased from 62.5 to 102 days (P = 0.015). Photodynamic therapy with free chlorin(e6) produced a smaller decrease in tumor weight and a smaller extension of survival, neither of which were statistically significant. A comparison of photoimmunotherapy with 10 J of light delivered at 30 or 300 mW showed that the higher fluence rate prolonged survival significantly more than the lower fluence rate. This may have been because the high fluence rate gave a contribution of laser-induced hyperthermia to the photodamage. Correlation studies showed that the amount of normal liver remaining at necropsy correlated best with survival. Photoimmunotherapy shows efficacy in destroying liver tumors, and future studies should maximize selectivity to minimize the destruction of normal liver.

Keratotic melanocytic nevus: a clinicopathologic and immunohistochemical study.

BACKGROUND: Epidermal hyperplasia in melanocytic nevi is a common but little-investigated phenomenon. METHODS: We prospectively examined all melanocytic nevi diagnosed in our department over an 8-month period, for the criteria of keratotic melanocytic nevus (KMN), namely the presence of marked epidermal hyperplasia with or without horn pseudocyst formation, hyperkeratosis, and papillomatosis. In addition to routine histologic review, we studied 12 representative cases with immunohistochemistry to examine expression of Ki-67, epidermal growth factor receptor (EGFR), Bcl-2, and Bax. RESULTS: From a total of 1,527 melanocytic nevi, 95 were KMN (prevalence 6%). The average age was 34 years, with a male:female ratio of 1:2. The predominant location was the trunk (76%), followed by head and neck (20%), and extremities (4%). Clinical diagnoses were atypical nevus (44%), nevus not otherwise specified (43%), and others including seborrheic keratosis, acrochordon, and basal cell carcinoma. Two KMN were junctional, 44 compound, and 49 intradermal. Twenty-three KMN (24%) had histologic features suggesting congenital onset, and 15 (16%) had mild to moderate dysplastic features. Two cases demonstrated induction of sebaceous glands. Significantly increased Ki-67 expression was detected in the hyperplastic epidermis, particularly in deeper areas related to keratinous cysts and hair follicles. Bcl-2 and Bax (anti- and pro-apoptosis proteins, respectively) and EGFR were expressed similarly in both normal and hyperplastic epidermis overlying the KMN. CONCLUSIONS: KMN are commonly biopsied skin lesions, mostly located on the trunk. Many such lesions are clinically considered atypical, in contrast to their benign histologic appearance. The epidermal hyperplasia on top of KMN demonstrates increased cellular proliferation, in the context of adequately regulated apoptosis and EGFR expression. The cellular proliferation seems to commence in hair follicles.