Detection of mucosal human papilloma virus DNA in bowenoid papulosis, Bowen's disease and squamous cell carcinoma of the skin

Human papilloma virus (HPV) is known to be an etiologic agent for benign warts of the skin. Recently, HPV have been detected in malignant skin and mucosal diseases suggesting that HPV infection can induce malignant skin tumors. In the present study, we examined the presence of mucosal HPV DNA in normal tissue, Bowen's disease (BD), Bowenoid papulosis (BP) and squamous cell carcinoma (SCC) of the skin. We detected the HPV DNA with polymerase chain reactions, and identified the type by DNA sequencing. In the results, we detected HPV DNA in none of the 17 normal controls, two of the three BP (66.7%), one of the 21 BD (4.8%), and six of the 26 SCC of the skin samples (23.0%). The occurrence rates of HPV in BP and SCC were significantly elevated compared to that of normal controls (P < 0.01 and P < 0.01, respectively). In addition, the occurrence rate of HPV in BP was significantly elevated compared to that of BD (P < 0.05). The reproducibility was confirmed with a polymerase chain reaction (PCR) with another primer pair. Of the two cases of BP with positive HPV DNA, one case showed HPV 31 and the other case HPV 16. The case of BD with positive HPV DNA showed HPV 31. Of the six cases of SCC with positive HPV DNA, one case showed HPV 16, another case HPV 34, and the other four cases HPV 31. These results showed that mucosal HPV, including HPV 31 and 16, could be detected in SSC of the skin. Mucosal HPV, not only the epidermodysplasia verruciformis type, appear to induce malignant skin tumors.     

Squamous cell carcinoma of the penis in a man with a human papilloma virus 31 infection

We report a 51-year-old man with squamous cell carcinoma (SCC) on his penis. He was surgically treated for his phimosis when he was 20 years old. He presented with an indurated nodule on the tip of his penis. The tumor was treated with partial penectomy and standard inguinal lymphadenectomy. Histological examination revealed that the tumor was a well-differentiated type of SCC. A polymerase chain reaction was performed to detect human papilloma virus (HPV) DNA. The result revealed the presence of HPV in the SCC. The results of sequencing analysis showed that the DNA was HPV 31.     

Increased expression of an epidermal stem cell marker, cytokeratin 19, in cutaneous squamous cell carcinoma

Background Cytokeratin 19 (CK19) has been considered to be a putative marker for epidermal stem cells in the hair follicle bulge. Cumulative reports have shown that epidermal stem cells play an important role in skin carcinogenesis. However, to date there has been no report on the clinical alteration of the stem cells in squamous cell carcinoma (SCC). Objectives To investigate alteration of the stem cells and proliferating cells and to assess their relationship and potential contribution to SCC. Methods Thirty paraffin‐embedded neoplastic skin lesions, consisting of 10 cases each of actinic keratosis (AK), Bowen disease (BD) and SCC, were examined immunohistologically for CK19 and Ki‐67. Results Positive reactivity for CK19 was seen in 30% of AK, 50% of BD and 80% of SCC lesions. There was significantly higher expression levels of CK19 in SCC than in AK and BD (P < 0·05). In addition, BD lesions harboured a significantly higher number of CK19‐positive cells than did AK lesions (P < 0·05). There were significant differences in Ki‐67 labelling indices between AK and BD and between AK and SCC (P < 0·001), but not between BD and SCC (P > 0·05). Furthermore, a serial section comparison study showed that there was a minor population of cells co‐expressing CK19 and Ki‐67 in a subset of the tumour cells of SCC samples. The percentage of CK19+ cells significantly correlated with that of Ki67+ cells in all examined neoplastic skin lesions. Conclusions These results suggest that CK19 expression may be associated with the retention of stem cell characteristics or a state that is uncommitted to terminal squamous differentiation.     

Multiple‐digit periungual Bowen's disease: a novel treatment approach with radiotherapy

Multiple periungual Bowen disease [BD; also known as squamous cell carcinoma (SCC) in situ] is rare. The pathogenesis of the disease is linked to human papilloma virus, and in some instances to chronic immunosuppression. The usual management of periungual BD is by local excision, Mohs micrographic surgery or distal phalanx amputation. Our patient was offered radiotherapy in the hope of maximizing residual function and minimizing morbidity from treatment. A good response was seen at 2 months post‐radiotherapy, but this was followed by relapses at 4 and 6 months post‐radiotherapy. Persistent anonychia resulted in improved access to the involved skin, making topical therapy possible. Radiotherapy can be a valuable management approach for periungual SCC/BD in locations where amputation could result in substantial disability.     

Tight junction-associated proteins (occludin, ZO-1, claudin-1, claudin-4) in squamous cell carcinoma and Bowen's disease

BACKGROUND: The epidermis, which is a typical stratified epithelium, has tight junctions (TJs) in the granular layer, as do simple epithelia. So far, abnormalities of TJs and involvement of claudin-1 have been reported in tumours of simple epithelia. OBJECTIVES: To examine the expression of TJ-associated proteins (occludin, ZO-1, claudin-1 and claudin-4) in normal human epidermis and in malignant disorders of keratinization. METHODS: Expression of the proteins in normal human epidermis, five cases of squamous cell carcinoma (SCC) of the skin and five cases of Bowen's disease (BD) was examined by immunofluorescence staining. RESULTS: In normal human epidermis, occludin, ZO-1 and claudin-4 were expressed at the cell-cell borders in the granular layer specifically or dominantly, whereas claudin-1 was expressed in the whole epithelium. In SCC, occludin, ZO-1, claudin-1 and claudin-4 were strongly expressed in tumour cells with keratinization such as cancer pearls. Claudin-1 was heterogeneously expressed in unkeratinized tumour cells, whereas expression of occludin, ZO-1 and claudin-4 was decreased or absent. In BD, aberrant expression of occludin, ZO-1, claudin-1 and claudin-4 was observed at the cell-cell borders in addition to their expression patterns observed in normal epidermis. CONCLUSIONS: Expression of occludin, ZO-1 and claudin-4 is associated with keratinization in SCC and BD. However, the heterogeneous expression of claudin-1 in SCC is not determined only by keratinization.     

Analysis of αv integrin protein expression in human eyelid and periorbital squamous cell carcinomas

Background: Alpha v integrins are receptors for many extracellular matrix (ECM) protein ligands, including latent transforming growth factor betas (TGFβs). Various studies in mice have shown that ablation of genes encoding αv integrin or TGFβ signaling pathway components leads to spontaneous squamous cell carcinomas (SCCs) in the conjunctiva and periocular skin. Here, we have analyzed patterns of αv integrin protein expression and TGFβ signaling in human eyelid and periorbital SCC samples. Methods: An anti‐αv integrin antibody was used to immunostain 19 eyelid and periorbital SCC samples. Additionally, tissue lysates from resected normal eyelid and SCC samples were analyzed by immunoblotting for αv integrin protein. Tumor sections were also immunostained with an antibody directed against Smad2, an intracellular signaling protein that is phosphorylated by TGFβ receptors. Results: Alpha v integrin protein was highly expressed in the invasive and less‐differentiated components of human SCCs. Lower levels of αv integrin protein were detected in more differentiated components of tumors, as well as in SCC in situ. Patterns of phosphorylated Smad2 immunoreactivity correlated with levels αv integrin expression. Conclusions: Alpha v integrin was expressed at robust levels in tumor cells representing less differentiated, more invasive components of SCC; by contrast, well‐differentiated cells as well as SCC in situ expressed low levels of αv integrin protein. Hsu A, Esmaeli B, Hayek B, Hossain MG, Shinder R, Lazar AJ, McCarty JH. Analysis of αv integrin protein expression in human eyelid and periorbital squamous cell carcinomas.     

Livin和Smac在鲍恩病及皮肤鳞状细胞癌中的表达

目的：确定Livin和Smac在鲍恩病（BD）及皮肤鳞状细胞癌（SCC）中的表达和意义.方法：应用免疫组化SP法检测35例BD和32例SCC中Livin和Smac的表达,分析二者表达的相关性.结果：Livin表达：BD组高于BD癌旁组织（P〈0.001）;BD癌旁组织高于正常对照组（P〈0.05）.SCC组高于SCC癌旁组织（P〈0.001）;SCC癌旁组织高于正常对照组（P〈0.05）.SCC组高于BD组（P〈0.05）.Smac表达：BD组低于BD癌旁组织（P〈0.01）;BD癌旁组织低于正常对照组（P〈0.05）;SCC组低于SCC癌旁组织（P〈0.001）;SCC癌旁组织低于正常对照组（P〈0.05）;SCC组低于BD组（P〈0.05）.Livin和Smac在BD中表达无相关性（P〉0.05）,在SCC中表达呈负相关（P〈0.05）.结论：Livin的过表达和Smac的低表达可能在BD和SCC的发生、发展中起一定作用.     

Pseudocarcinomatous hyperplasia mimicking squamous cell carcinoma in a case of CD56‐positive cytotoxic T‐cell lymphoma

We present the case of an 84‐year‐old patient with a cutaneous CD56 positive cytotoxic T‐cell lymphoma associated with substantial pseudocarcinomatous hyperplasia mimicking squamous cell carcinoma (SCC). The patient presented with a 7‐month history of several progressive, ulcerated plaques on his right forearm. An initial biopsy showed changes consistent with a diagnosis of SCC for which the patient underwent surgical treatment. Several months later, the patient developed recurrent ulcerated plaques on the right forearm of which several biopsies were performed. The biopsies repeatedly showed marked pseudocarcinomatous hyperplasia resembling SCC. Deeper punch biopsies, however, showed a dense superficial and deep infiltrate of markedly atypical lymphocytes. Immunohistochemical analysis revealed strong positive staining for CD3, CD8, CD56 with negative stains for CD30 and Epstein‐Barr virus‐encoded small non‐polyadenylated RNAs (EBER). Staining for beta F1 and gamma‐delta T‐cell receptor (γδ TCR) were both negative. This constellation was most consistent with a diagnosis of cutaneous peripheral T‐cell lymphoma, unspecified in association with marked pseudocarcinomatous hyperplasia. Our case adds cutaneous peripheral T‐cell lymphoma, unspecified to the list of conditions associated with pseudocarcinomatous hyperplasia (PCH) and illustrates once again the potential pitfalls of distinguishing marked pseudocarcinomatous hyperplasia from SCC.     

Anogenital warts in children: Analysis of a cohort of 34 prepubertal children

Anogenital warts are caused by infection with the human papillomavirus. We reviewed the clinical data of 34 children younger than 13 with anogenital warts referred to the department of dermatovenereology of a tertiary care hospital. Suspicion of sexual abuse was raised in 11 (32.4%). Human papilloma virus testing and genotyping was performed in 19 (55.9%) children, and human papilloma virus type 16 was found in 4, which raises the question regarding what type of follow‐up is required for children infected with high‐risk oncogenic HPV types. Although the diagnosis of anogenital warts in children raises concerns regarding sexual abuse, our study supports that pediatric anogenital warts can be associated with nonsexual transmission.     

Keratoacanthoma and other types of squamous cell carcinoma with crateriform architecture: Classification and identification

The terminology and classification of keratoacanthoma (KA) and other types of squamous cell carcinoma (SCC) with crateriform architecture have not been clarified. The study evaluated the clinicopathological features of 41 nodular (exo‐endophytic) SCC lesions with a central keratin‐filled crater, including KA (well‐developed stage). The lesions were histopathologically classified into six categories: (i) KA (well‐developed stage) (27 lesions); (ii) KA‐like SCC (three lesions); (iii) KA with malignant transformation (three lesions); (iv) infundibular SCC (crateriform) (four lesions); (v) crateriform SCC arisen from actinic keratosis (three lesions); and (vi) crateriform Bowen's disease (one lesion). The true characteristics of KA‐like SCC remain unresolved, but there are three possibilities, namely, that it is one step in the evolution of KA, it is a borderline lesion between KA and invasive SCC, or it is one form of “KA with malignant transformation”. KA, KA‐like SCC, KA with malignant transformation and infundibular SCC (crater form) are considered to be hair follicle‐related neoplasms. In contrast, crateriform SCC arisen from actinic keratosis and crateriform Bowen's disease are SCC, which are not related either to the hair follicles or KA. From an etiological standpoint, the presented lesions in these six categories are considered to be mixed up due to the similarity of crateriform architecture between the various types of lesions. However, the information provided in this report is intended to help physicians to make an accurate differential diagnosis of these conditions in clinical practice. The present study provides an opportunity to standardize the terminology for KA and related neoplasms.     

Case of Merkel cell carcinoma with squamous cell carcinoma possibly arising in chronic radiodermatitis of the hand

We report a case of Merkel cell carcinoma (MCC) on the dorsal aspect of the right middle finger associated with multiple squamous cell carcinomas (SCC) possibly arising in chronic radiation dermatitis of the hand of an 80‐year‐old surgeon. In spite of resection of the primary lesion and right axillary lymph nodes, he died of the tumor 5 months after the first visit. Cutaneous and lymph node lesions of MCC were negative for Merkel cell polyoma virus (MCPyV) by immunostaining using monoclonal antibody (CM2B4) and anti‐large T antigen of MCPyV polyclonal antibody, and real‐time polymerase chain reaction. Several differences in clinicopathological findings have been found between MCPyV‐positive cases and negative ones. Several authors have reported that MCPyV‐negative cases have a worse prognosis than MCPyV‐positive ones. Furthermore, in cases of MCC associated with SCC, most tumors have been reported to be MCPyV‐negative. We should pay more attention to the relationship between the carcinogenesis of MCC and ionizing irradiation.     

T‐cadherin loss induces an invasive phenotype in human keratinocytes and squamous cell carcinoma (SCC) cells in vitro and is associated with malignant transformation of cutaneous SCC in vivo

Background Cadherins play important roles in controlling keratinocyte growth, differentiation and survival. Atypical glycosylphosphatidylinositol‐anchored T‐cadherin (T‐cad) is highly expressed in the basal keratinocyte layer of skin. The role of T‐cad in keratinocyte biology and pathology is unclear. Objectives To define the role of T‐cad in the pathogenesis of cutaneous squamous cell carcinoma (SCC) through gain‐of‐function and loss‐of‐function studies in vitro and through examination of T‐cad expression patterns in human cutaneous SCC specimens in relation to histological classification of degree of tumour differentiation. Methods In vitro studies employed lentiviral‐mediated overexpression/silencing of T‐cad in normal human keratinocyte (HaCaT) and SCC (A431) cell lines, monolayer and multicellular spheroid culture models, cell morphology analyses and assays of random motility and invasion. Immunohistochemistry was performed on skin specimens from patients with actinic keratosis, Bowen disease or SCC. Results In vitro, silencing of T‐cad induced a morphologically elongated and disorganized cell phenotype, increased random motility and markedly enhanced invasive potential. Overexpression of T‐cad induced a morphologically spread and compact cell phenotype and blunted invasive potential. In vivo, regional loss of T‐cad expression was more frequent and prominent in SCC classified as moderately‐to‐poorly differentiated than in SCC classified as well differentiated. However, in both categories aberrant and/or absence of T‐cad expression was associated with histological features of a potentially more malignant and invasive phenotype of cutaneous SCC. Conclusions T‐cad is a controlling determinant of SCC phenotype and invasive behaviour and its loss is associated with the process of malignant transformation from noninvasive to invasive SCC.     

Cutaneous lip tumours treated with Mohs micrographic surgery: clinical features and surgical outcome

BACKGROUND: The Australian Mohs micrographic surgery (MMS) database was initiated in 1993 by the Skin and Cancer Foundation Australia (SCFA) with the aim of collecting prospective data, and involved all Mohs surgeons in the country. OBJECTIVES: To present a large series of patients with cutaneous lip tumours treated with MMS in Australia between 1993 and 2002. METHODS: This prospective multicentre case series included all patients with cutaneous lip tumours who were monitored by the SCFA. The main outcome measures were patient demographics, reason for referral, duration of tumour, site, preoperative tumour size and postoperative defect size, recurrences prior to MMS, histological subtypes, perineural invasion and 5-year recurrence after MMS. RESULTS: There were 581 patients (66.1% women and 33.9% men, P < 0.0001) with a mean +/- SD age of 58 +/- 15 years. The upper lip was the most common site involved (81.1%). Basal cell carcinoma (BCC) was diagnosed in 82.3%, squamous cell carcinoma (SCC) in 16.5%, Bowen's disease (BD) in 0.7% and microcystic adnexal carcinoma (MAC) in 0.5% of cases. BCC was more common on the upper lip and in women, whereas SCC was more common on the lower lip and in men (P < 0.0001). Most upper lip tumours occurred in women (75.4%), whereas most lower lip tumours occurred in men (73.6%). SCC was associated with a larger tumour and postoperative defect size compared with the other tumours. The 5-year recurrence for BCC was 3.0%, and there were no cases of recurrence for SCC, BD or MAC. CONCLUSIONS: BCC was the most common cutaneous lip tumour managed by MMS, and was significantly more common on the upper lip and in women. The low 5-year recurrence rate emphasizes the importance of margin-controlled excision.     

Experimental studies on the antiviral agent famciclovir in Behçet''s disease symptoms in ICR mice

Background Chronic oral aphthae, recurrent genital ulcers and uveitis are the three main manifestations of Behçet's disease (BD). The aetiopathogenesis of BD is still obscure, but herpes simplex virus (HSV) is one of the possible causal factors. Various kinds of drugs, including immunosuppressants and aciclovir have been used in treatment, but effectiveness is variable. Objectives To demonstrate the efficacy of famciclovir, an antiviral compound that acts against HSV, varicella‐zoster virus and hepatitis B virus, in a murine model of BD. Methods Using the HSV‐induced BD mouse model, famciclovir was administered variously before and after inoculation or from the day of lesion occurrence, with appropriate controls. Ulceration of the mouth and genital skin and eye involvement were monitored. In addition, spleen cytokine expression was measured by polymerase chain reaction. Results Pretreatment and concurrent treatment did not affect the occurrence of BD, but treatment from the appearance of lesions was effective in improving BD and preventing recurrence. After famciclovir, interleukin 2 expression correlated with the recurrence of BD symptoms. Conclusions This model suggests the possible role of immune response to viral infection in the development and activation of BD. The study provides a rationale for clinical trials of famciclovir in the human form of BD.     

Sind Mutationen der Proteinkinase B (PKB/AKT) bei der Entstehung und Progression von Hauttumoren beteiligt?

Summary: During the last years it became evident that PKB/AKT plays an important role in oncogenic transformation. The gene has been found to be overexpressed in certain human tumors and a viral fusion protein gains transforming capacity. For physiological activation of PKB/AKT its recruitment to the plasma membrane is mandatory; this shift from cytoplasm to the membrane is achieved by the N‐terminal PH‐domain. Full‐length PKB/AKT recruited to the cell membrane becomes phosphorylated on T 308 and S 473, after which the protein is fully active. The analysis of a panel of human skin tumors, including basal cell carcinomas, squamous cell carcinomas and melanomas, for mutations of the PH‐domain and the phosphorylation sites at codons 308 and 473 did not reveal any mutations. It can be concluded that in human skin tumors including melanomas as well as basal cell carcinomas PKB activation by mutation of the activation‐associated phosphorylation sites at codons T 308 or S 473 or of the PH domain does not contribute to carcinogenesis.     

Caveolin-1、Met蛋白在日光性角化病、鲍温病和皮肤鳞状细胞癌中的表达

目的：检测Caveolin-1、Met蛋白在肿瘤边缘正常皮肤、日光性角化病、鲍温病和皮肤鳞状细胞癌组织中的表达情况。方法：通过免疫组化SP法，对肿瘤边缘正常皮肤、日光性角化病(Actinic keratosis，AK)、鲍温病(Bowen's Disease，BD)、皮肤鳞状细胞癌(cutaneous squamous cell carcinoma，cSCC)标本中Caveolin-1、Met进行检测。结果：Caveolin-1在正常皮肤、AK、BD、SCC中阳性率依次为16.7%、36.8%、52.9%、78.9%，四组间采用Kruskal-wallis H秩和检验，差异具有统计学意义(P<0.05)。Met在正常皮肤、AK、BD、SCC中阳性率依次为8.3%、26.3%、58.8%、84.2%，四组间采用Kruskal-wallis H秩和检验，P<0.05，差异具有统计学意义。在cSCC组中，Caveolin-1、Met阳性表达之间呈现正相关(r=0.484,P=0.036)。结论：Caveolin-1、Met在AK、BD和cSCC细胞中表达强度与恶性程度相关，且Caveolin-1、Met可能在cSCC发生、发展中具有协同作用。     

CXCR7 expression correlates with tumor depth in cutaneous squamous cell carcinoma skin lesions and promotes tumor cell survival through ERK activation

The chemokine receptor CXCR7 has been demonstrated to be involved in the development of certain cancers, but its role in cutaneous squamous cell carcinoma (SCC) has not been previously investigated. We seek to determine whether CXCR7 is expressed in human cutaneous SCC skin lesions and SCC cell lines. In addition, we evaluate whether CXCR7 plays a role in SCC cell proliferation, survival and migration and which signalling pathways are involved. Using quantitative RT‐PCR to analyse the mRNA expression of 19 different chemokine receptors, we found that CXCR7 was much more highly expressed compared to other chemokine receptors in cutaneous SCC cell lines (HSC‐1 and HSC‐5). On immunohistochemical staining, CXCR7 was found to be expressed in 70% (28 of 40) of human cutaneous SCC tissue specimens, and its expression correlated with tumor depth >4 mm and cancer stage ≥II. CXCR7 but not CXCR4 protein was expressed on the surface of HSC‐1 and HSC‐5 cells by flow cytometry. Activation of the CXCR7 receptor by CXCL12 promoted survival of HSC‐1 and HSC‐5 cells through the ERK pathway, but had no significant effect on cell proliferation or migration. In summary, our findings indicate that CXCR7 is frequently expressed in cutaneous SCC skin lesions and its expression correlates with tumor depth and cancer stage. CXCR7 is the predominant chemokine receptor expressed in SCC cell lines, and activation of CXCR7 by CXCL12 promotes survival of SCC cells through the ERK pathway. These findings provide new insights into the significance of CXCR7 in the pathophysiology of SCC.     

Detection of human papilloma virus in normal skin and in superficial and nodular basal cell carcinomas in immunocompetent subjects

Background Human papilloma virus (HPV) is increasingly recognized as an important human carcinogen but its role in the aetiopathogenesis of basal cell carcinoma (BCC) in immunocompetent individuals is unclear. Objective A prospective case–control study was designed to compare the prevalence of HPV in BCC and normal skin samples from immunocompetent subjects and to assess the influence of different clinical features on the risk of cutaneous HPV. Methods A total of 142 samples from 70 BCC cases (superficial BCC 38 and nodular BCC 32) and 72 controls were analysed by a degenerated nested PCR technique. Clinical data were recorded and risk factors for HPV infection were assessed by multivariate analysis. Results There were 31 HPV DNA‐positive samples. HPV was detected more frequently in cases (25.7%) than in controls (18.1%) and in nodular (31.3%) than in superficial (21.1%) BCC lesions but differences were not statistically significant. Older age (OR 1.5; 95% CI: 1.02–1.09) and actinic keratosis (OR 2.62; 95% CI 1.15–5.96) were the only significant factors associated to the presence of HPV. Risk of HPV positivity was also higher in blond‐haired subjects, fair/pale skin colour, history of sunburn, solar lentigines and seborrheic keratosis but the differences were not significant. Both in cases and controls, β ‐types were the most frequent. Conclusions HPV does not seem to play a fundamental role in the aetiopathogenesis of either nodular or superficial BCC. The presence of HPV appears to be more related to actinic damage and possibly to an alteration of the barrier function associated with ageing.     

Acquired Epidermodysplasia Verruciformis in a Child with the Human Immunodeficiency Virus

Epidermodysplasia verruciformis (EDV) is a rare genodermatosis characterized by susceptibility to human papilloma virus (HPV) infection. An acquired form of EDV has been described in the setting of immunosuppression, including in patients with the human immunodeficiency virus (HIV). We present the case of an HIV‐positive, adopted Haitian boy who presented with EDV. Few cases of chidren with HIV and acquired EDV have been reported and are likely underrecognized.     

Angiotropism in recurrent cutaneous squamous cell carcinoma: Implications for regional tumor recurrence and extravascular migratory spread

Extravascular migratory metastasis is a form of cancer metastasis in which tumor cells spread by tracking along the abluminal aspect of vessel walls without breaking the vascular endothelial lining or intraluminal invasion. This phenomenon has been extensively described in melanoma and is being increasingly recognized in other neoplasms. Various modalities of treatment, including radiation‐, chemo‐, targeted‐, and immune‐ therapies may potentially induce angiotropic behavior in neoplastic cells. Although there is a risk for tumor recurrence and metastasis, angiotropism may be under‐recognized and is rarely reported. Here, we report a case of recurrent poorly‐differentiated acantholytic squamous cell carcinoma of the scalp with extensive perineural invasion, previously treated with multiple therapies. There was multifocal extravascular cuffing of neoplastic cells around and focally involving the walls of small to medium‐caliber blood vessels within and surrounding the tumor, without obvious tumor intravasation. In addition, small subtle nests of neoplastic keratinocytes were noted along the abluminal aspect of a large‐caliber deep dermal blood vessel in an en‐face margin, away from the main tumor mass. Such involvement can be difficult to identify; and thus, may be missed particularly during intra‐operative frozen section evaluation, leading to false‐negative margins and is therefore, a diagnostic pitfall.