Non‐invasive management of non‐melanoma skin cancer in patients with cancer predisposition genodermatosis: a role for confocal microscopy and photodynamic therapy

Background Patients with genodermatosis such as Gorlin syndrome (GS) and Xeroderma pigmentosum (XP) require a close follow‐up for early diagnosis and treatment of skin cancer. We aimed to evaluate the efficacy of methyl‐aminolevulinate (MAL) photodynamic therapy (PDT) in basal cell carcinomas (BCCs) from patients with GS and XP, and to determine the utility of reflectance confocal microscopy (RCM) in the diagnosis and the evaluation of therapeutic response. Patients and methods We included four patients with GS and two siblings with XP. Single or multiple lesions in localized areas were treated with 1–3 cycles of MAL PDT. RCM was performed before and 3 months after the treatment in target lesions in all the patients. Patients were followed up for 3 years. Results In XP patients, we treated 13 pigmented BCCs on the face. All the lesions responded to the treatment and six lesions showed a complete clinical clearing. In GS patients, facial or trunk areas with multiple BCCs were treated (up to 200). Complete clinical remission was obtained in 25–67% of the lesions. Some nodular and pigmented lesions failed to achieve a complete remission. RCM could identify already described confocal features for BCC. Tumour remissions could be assessed by this technique. Conclusions Methyl‐aminolevulinate PDT may be useful for the treatment of superficial BCC in GS and XP. In some nodular lesions, PDT may complement surgery reducing tumour size. RCM may be regarded in the future as a complementary technique in BCC for the diagnosis and post‐treatment assessment to non‐invasive therapeutic modalities.     

Delayed diagnosis of Gorlin's syndrome in a renal transplant recipient

A 35-year-old woman was referred to the dedicated dermatology clinic for RTR. She underwent her first renal transplant at 18 years of age due to chronic renal failure following reflux nephropathy of the single right kidney (left kidney agenesis). She has since then had two further transplants. During clinical examination she was noted to have at least 16 basal cell carcinomas (BCC) and there are records in the case notes of 10 BCC having being excised and confirmed histologically in the past. By contrast, she had only had two squamous cell carcinomas (SCC) excised. She was also noted to have distinctive facial features, a kyphoscoliosis and palmar pits, and a diagnosis of Gorlin's (naevoid BCC) syndrome (GS) was made. Although immunosuppression may have contributed to the multiplicity of her BCC, the contrasting very small number of SCC is unusual in an organ transplant recipient and this alerted the authors to the diagnosis of GS.     

Characteristics of multiple basal cell carcinomas: The first study on Japanese patients

Basal cell carcinoma (BCC), the most frequent skin cancer, has been increasing in incidence. However, the characteristics of multiple BCC have not been clarified in Japan. Therefore, we conducted a retrospective study to elucidate the features of multiple BCC compared with solitary BCC. The study population consisted of 327 patients with histopathologically proven BCC who were referred to the Department of Dermatology in Tottori University Hospital between November 2006 and April 2016. Of the 327 patients, 304 (93.0%) had solitary BCC and 23 (7.0%) had multiple BCC. The mean age of the patients with solitary BCC was 74.7 years (range, 31–102) and that of patients with multiple BCC was 79.3 years (range, 63–91). There was a significant difference in mean age between the two groups (P = 0.01). Approximately four‐fifths of the BCC were located on the head or neck in the total study population. In the group of patients with multiple BCC, the incidence of lesions on the head and neck was lower and that on the trunk was higher than those in patients with solitary BCC. There was a significant difference in the tumor site between the two groups (P < 0.0001). With respect to tumor histopathology, the ratio of superficial BCC was significantly higher in the group of patients with multiple BCC than in the group of patients with solitary BCC (P < 0.0001). In conclusion, we demonstrated that older age, truncal location and superficial histopathological type of tumor are features of multiple BCC in Japanese subjects.     

Síndrome del nevo basocelular: experiencia en un hospital pediátrico

Nevoid basal cell carcinoma (BCC) syndrome, or Gorlin syndrome, is a rare autosomal dominant disorder associated with mutations in the patched 1 gene, PTCH1. It is characterized by the presence of multiple BCCs in association with disorders affecting the bones, the skin, the eyes, and the nervous system.We describe 6 cases of nevoid BCC syndrome evaluated in our department. Palmoplantar pitting was observed in all 6 patients, multiple BCCs in 5 patients (83%), skeletal anomalies in 3 patients (50%), and odontogenic keratocysts in 1 patient (17%).We would like to stress the importance of early diagnosis and treatment in nevoid BCC syndrome and the need for continuous, long-term follow-up by a multidisciplinary team.     

Basal cell nevus syndrome: clinical and molecular review and case report

Basal cell nevus syndrome (BCNS), also referred to as nevoid basal cell carcinoma syndrome or Gorlin–Goltz syndrome, was first described by Gorlin and Goltz in 1960 as an autosomal dominant disorder characterized by the early appearance of multiple basal cell carcinomas (BCCs), keratocysts of the jaw, ectopic calcifications, palmar and plantar pits, and anomalies of the ocular, skeletal, and reproductive systems. The genesis of this cancer's etiology in relation to BCNS was unclear until a few years ago when molecular analysis studies suggested a relationship between BCC and the loss‐of‐function mutations of the patched gene (PTCH) found on chromosome arm 9q. PTCH inhibits signaling by the membrane protein Smoothened (Smo), and this inhibition is relieved by binding sonic hedgehog (SHH) to PTCH. We describe a patient with multiple BCCs associated with x‐ray anomalies of BCNS and review the basis of the SHH signaling pathway and clinical aspects of BCNS.     

Treatment of Gorlin syndrome (nevoid basal cell carcinoma syndrome) with methylaminolevulinate photodynamic therapy in seven patients,including two children: interest of tumescent anesthesia for pain control in children

Objective To report our experience of methylaminolevulinate photodynamic therapy (MAL‐PDT) in the treatment of multiple basal cell carcinoma (BCC) in adults and children with Gorlin syndrome (GS). Design Report of cases. Setting University of Montpellier, Department of Dermatology. Patients Seven Gorlin patients (41 superficial or nodular carcinomas), including two children. Interventions Prior superficial curettage for superficial BBCs or debulking for nodular BCCs was systematically performed. Methylaminolevulinic acid was applied topically to lesions 3 h before illumination with 635 nm red light for 10 min (37 J/cm²). To prevent treatment discomfort, analgesics and/or cooling by sprayed water were most often provided, and occasionally 1% lidocaine local anesthesia. A ropivacaine‐lidocaine tumescent anesthesia was performed on the youngest patient. Main outcome measures The initial response rate; tolerance, particularly in children; cosmetic outcome. Results Overall clearance in patients was 60% after one session of MAL‐PDT and 78% after three sessions. Resolution of the lesions was accompanied by an excellent cosmetic outcome in all patients. Treatments were well tolerated in adults with moderate pain sensation during illumination. In a child, tumescent anesthesia assured excellent tolerance in all treatment stages. Conclusion We add our experience to previous articles that consider PDT as an interesting option in the treatment of GS. To our knowledge, this study is the first report of MAL‐PDT in GS children using tumescent anesthesia. Specific guidelines for adult and pediatric patients remain to be established.     

Lichen planopilaris after imiquimod 5% cream for multiple BCC in basal cell naevus syndrome

Basal cell naevus syndrome is an inherited autosomal dominant genetic disorder characterised by multiple basal cell carcinomas (BCC), skeletal, neurological and opthalmological abnormalities. The treatment of choice of the often multiple and large BCC consists of a combined approach including surgery, liquid nitrogen and other topical treatment modalities. Imiquimod 5% cream is an immune–response‐modifying drug with antiviral and anti‐tumour activity. Recent reports have associated the immune‐stimulant properties of imiquimod with the exacerbation of several autoimmune skin diseases, such as eczema, psoriasis, vitiligo and lichenoid dermatitis. Here we report a patient with basal cell naevus syndrome who developed a lichen planopilaris on the same site of the scalp, which had been previously treated with two cycles of imiquimod for multiple BCC.     

Three difficult cases: the challenge of autoimmunity,immunodeficiency and recurrent infections in patients with Good syndrome

Good syndrome (GS) is a rare, adult‐acquired primary combined immunodeficiency syndrome arising in the context of previous or current thymoma. Patients with GS frequently develop recurrent sinopulmonary infections and are also at high risk of autoimmune manifestations, including skin conditions such as lichen planus. We report three middle‐aged patients with GS complicated by multiple autoimmune and infectious manifestations. The combination of immunodeficiency, autoimmunity and recurrent infections seen in patients with GS continues to present a management challenge, particularly in patients with oral mucosal disease and recurrent candidiasis. Clinicians should be prompted to investigate an underlying immunodeficiency in patients with multiple autoimmune conditions and recurrent sinopulmonary infections.     

Segmental basal cell naevus syndrome caused by an activating mutation in smoothened

Aberrant sonic hedgehog signalling, mostly due to PTCH1 mutations, has been shown to play a central role in the pathogenesis of basal cell carcinoma (BCC), as well as in basal cell naevus syndrome (BCNS). Mutations in smoothened (SMO) encoding a receptor for sonic hedgehog have been reported in sporadic BCCs but not in BCNS. We report a case with multiple BCCs, pits and comedones in a segmental distribution over the upper part of the body, along with other findings compatible with BCNS. Histopathologically, there were different types of BCC. A heterozygous mutation (c.1234C>T, p.L412F) in SMO was detected in three BCCs but not in peripheral blood lymphocytes or the uninvolved skin. These were compatible with the type 1 mosaic form of BCNS. The p.L412F mutation was found experimentally to result in increased SMO transactivating activity, and the patient responded to vismodegib therapy. Activating mutations in SMO may cause BCNS. The identification of a gain‐of‐function mutation in SMO causing a type 1 mosaic form of BCNS further expands our understanding of the pathogenesis of BCC, with implications for the treatment of these tumours, whether sporadic or inherited.     

Vitamin D‐binding protein polymorphisms are not associated with development of (multiple) basal cell carcinomas

Abstract: Vitamin D‐binding protein (VDBP) single nucleotide polymorphisms (SNP) may affect skin carcinogenesis. The objective was to test the association between two functional VDBP SNPs and the susceptibility to (multiple) basal cell carcinomas (BCCs). Of the 7983 participants, 5790 (72.5%) and 5823 (72.9%) participants were genotyped for rs7041 and rs4588, respectively, and three haplotypes (Gc1s, Gc2 and Gc1f) were analysed. Two hundred and thirty‐three persons developed a BCC of whom 122 (52.4%) developed multiple BCCs during a mean follow‐up of 11.6 years. The VDBP genotype was not associated with (multiple) BCC development using Cox proportional hazards and Andersen‐Gill analyses, respectively. Stratifying age groups demonstrated that in the youngest age‐group, the A/T variant of rs7041 was associated with BCC development [adjusted hazard ratio (HR) = 1.88 (95%CI 1.10–3.20)], while homozygote Gc1s carriers had a significantly lower BCC risk [adjusted HR = 0.53 (95%CI 0.31–0.91)]. In conclusion, the VDBP polymorphisms were not associated with susceptibility to (multiple) BCCs, but age–gene interactions were observed.     

PTCH1 gene haplotype association with basal cell carcinoma after transplantation

Background Basal cell carcinoma (BCC) is 10 times more frequent in organ transplant recipients (OTRs) than in the general population. Factors in OTRs conferring increased susceptibility to BCC include ultraviolet radiation exposure, immunosuppression, viral infections such as human papillomavirus, phototype and genetic predisposition. The PTCH1 gene is a negative regulator of the hedgehog pathway, that provides mitogenic signals to basal cells in skin. PTCH1 gene mutations cause naevoid BCC syndrome, and contribute to the development of sporadic BCC and other types of cancers. Associations have been reported between PTCH1 polymorphisms and BCC susceptibility in nontransplanted individuals. Objectives To search for novel common polymorphisms in the proximal 5′ regulatory region upstream of PTCH1 gene exon 1B, and to investigate the possible association of PTCH1 polymorphisms and haplotypes with BCC risk after organ transplantation. Methods Three PTCH1 single nucleotide polymorphisms (rs2297086, rs2066836 and rs357564) were analysed by restriction fragment length polymorphism analysis in 161 northern Italian OTRs (56 BCC cases and 105 controls). Two regions of the PTCH1 gene promoter were screened by heteroduplex analysis in 30 cases and 30 controls. Results Single locus analysis showed no significant association. Haplotype T₁₆₈₆–T₃₉₄₄ appeared to confer a significantly higher risk for BCC development (odds ratio 2·98, 95% confidence interval 2·55–3·48; P = 0·001). Two novel rare polymorphisms were identified at positions 176 and 179 of the 5′UTR. Two novel alleles of the ‐4 (CGG)_n microsatellite were identified. No association of this microsatellite with BCC was observed. Conclusions Haplotypes containing T₁₆₈₆–T₃₉₄₄ alleles were shown to be associated with an increased BCC risk in our study population. These data appear to be of great interest for further investigations in a larger group of transplant individuals. Our results do not support the hypothesis that common polymorphisms in the proximal 5′ regulatory region of the PTCH1 gene could represent an important risk factor for BCC after organ transplantation.     

Correlation between the dermatoscopic and histopathological features of pigmented basal cell carcinoma

Background Dermatoscopy has a great value in the diagnosis of pigmented basal cell carcinoma (BCC), which is a clinical variant of BCC. The precise definitions of histopathological correlates of dermatoscopic features observed in pigmented BCC have not been established yet. Objective The present study aimed to investigate the correlation between the dermatoscopic features of pigmented BCC and their histopathological counterparts to provide clear histopathological definitions of each dermatoscopic feature. Methods In this case series that comprised a methodological component, after the orientation of dermatoscopic features was determined by placing sutures in the lesions, the histopathological counterparts of each were examined and definitions were made accordingly. Results Although the most common histopathological subtype of BCC is the solid type, the most common histopathological subtype observed in the pigmented BCC lesions in the present study was the superficial multifocal type (72.5%). Blue‐whitish veil was observed in 57.5% (n = 23) of the lesions, a percentage higher than that reported in the literature. In addition to confirming the previously histopathologically defined dermatoscopic features of pigmented BCC, we identified three histopathologically undefined features of pigmented BCC that are spoke‐wheel areas, large blue‐grey ovoid nests and multiple blue‐grey globules. Conclusion Dermatoscopy facilitates prediction of the corresponding histopathological findings in pigmented BCC, based on specific dermatoscopic features.     

High discordance between punch biopsy and excision in establishing basal cell carcinoma subtype: analysis of 500 cases

Background Basal cell carcinoma (BCC) is the most frequently occurring cancer in humans. Worldwide incidences rise about 10% each year, increasing the burden on dermatologists, general practitioners and pathologists as well as increasing costs for the health care system. Increasingly non‐surgical treatment options are used in the treatment of BCC, without histological confirmation of BCC subtype, potentially resulting in under‐treatment. Objective We evaluated the diagnostic accuracy of a punch biopsy for the BCC histological subytpe in a primary BCC and the prevalence of biopsy‐based under‐diagnosis of aggressive subtypes. Accuracy of a punch biopsy was defined as concordance of the diagnosis of subtype of BCC at punch biopsy and excision. Methods A retrospective chart‐review was performed of primary BCC, which were proven by punch biopsy and subsequently treated by excision. The first 100 consecutive BCCs per year during the years 2004–2009 were included, yielding a total of 500 evaluated BCCs. Results The overall accuracy of punch biopsy for BCC subtype at excision was 69%, in single‐type BCC 83% (n = 343) and in mixed‐type BCC 37% (n = 157). Accuracy varied substantially according to BCC subtype, being highest in the superficial subtype (84%) and subsequently in infiltrative (69%), nodular (63%) and micronodular subtype (38%). In 11% of all cases, an unsuspected more aggressive subtype was present. Conclusion Punch biopsy has a high accuracy in single‐type BCCs and a considerably lower accuracy in mixed‐type BCCs for establishing BCC subtype compared to excision. The presence of an unsuspected aggressive subtype could explain therapy failure of non‐surgical treatments like imiquimod or photodynamic therapy.     

Increased immunoreactivity of membrane type-1 matrix metalloproteinase (MT1-MMP) and β-catenin in high-risk basal cell carcinoma

Background Although various immunohistological markers have been investigated to assess the aggressive characteristics of basal cell carcinoma (BCC), the role of membrane type‐1 matrix metalloproteinase (MT1‐MMP) has not been well established. Objectives To clarify the precise role of MT1‐MMP in BCC, MT1‐MMP expression was studied in various histological subtypes of BCC. Materials and methods High‐risk subtypes of BCC were compared by assessing the expression of β‐catenin and MT1‐MMP. The tissue microarray technique was used for immunohistochemical staining. Fifty‐eight samples were divided into six subtypes (10 nodular, 12 mixed, nine infiltrative, eight morphoeiform, 10 micro‐nodular and nine basosquamous). Overall, the 10 nodular BCC samples were classified as low‐risk BCC and the remaining 48 samples were classified as high‐risk BCCs. Results β‐Catenin immunoreactivity was increased in the high‐risk BCCs compared with the low‐risk (nodular) BCC (P < 0·001). Nuclear β‐catenin immunoreactivity was increased at the invading front of mixed BCC tumour islands compared with the upper portion of the lesion (P < 0·01). For the mixed BCC (P < 0·01), infiltrative BCC (P < 0·001), morphoeiform BCC (P < 0·001), micronodular BCC (P < 0·001) and basosquamous (P < 0·001) carcinoma, β‐catenin immunoreactivity was increased at the invading front compared with nodular BCC. MT1‐MMP immunoreactivity was increased in the high‐risk BCCs compared with the low‐risk (nodular) BCC (P < 0·01). The membranous MT1‐MMP immunoreactivity was increased at the invading front of mixed BCC tumour islands compared with the upper portion of the lesions (P < 0·01). For the mixed (P < 0·01), infiltrative (P < 0·05), morphoeiform (P < 0·05), micronodular (P > 0·05) and basosquamous (P < 0·05) BCC, MT1‐MMP immunoreactivity was also increased at the invading front compared with nodular BCC. Conclusions The results of this study suggest that MT1‐MMP might be a novel marker for high‐risk BCC. In addition, expression of both β‐catenin and MT1‐MMP was increased in high‐risk BCC tumour cells, indicating that these two proteins may play an important role in locally invasive and highly destructive growth behaviour of high‐risk BCCs.     

Is occupational solar ultraviolet irradiation a relevant risk factor for basal cell carcinoma? A systematic review and meta‐analysis of the epidemiological literature

Summary Background The most important risk factor for basal cell carcinoma (BCC) is ultraviolet (UV) radiation. It is reasonable to assume that outdoor workers with a long history of work‐related UV exposure are at increased risk of developing BCC. Objectives To analyse systematically the epidemiological literature concerning the evidence of an association between occupational UV exposure and BCC risk in outdoor workers. Methods Systematic literature review of cohort studies and case–control studies providing data on occupational UV exposure and BCC occurrence. PubMed (up to 28 January 2011) was searched, supplemented by hand searching and consultation of experts in the field. The association between occupational UV exposure and BCC risk is presented as odds ratios (ORs). A random‐effects meta‐analysis and sensitivity analysis including meta‐regression on study‐specific covariates were performed. Results Twenty‐four relevant epidemiological studies (five cohort studies, 19 case–control studies) were identified. Twenty‐three studies reported sufficient data to be included in the meta‐analysis. The pooled OR for the association between outdoor work and BCC risk was 1·43 (95% confidence interval 1·23–1·66; P = 0·0001). Studies adjusting for sex (P < 0·0001) and individual nonoccupational UV exposure (P = 0·014) showed a significantly stronger association of occupational UV exposure and BCC risk. Meta‐regression revealed a significant inverse relationship between occupational UV radiation exposure and BCC risk with latitude (P = 0·015). Conclusions Published epidemiological literature indicates that outdoor workers are at significantly increased risk for BCC. This finding is highly relevant for health policy to stimulate the implementation of effective prevention strategies.     

Early‐onset acral basal cell carcinomas in Gorlin syndrome

Two patients are reported in whom early‐onset, distal papules with a histopathological diagnosis of basal cell carcinoma were the first manifestation of Gorlin syndrome (GS). These lesions showed no progression and remained stable through follow‐up. Two different PTCH1 gene mutations were detected in the two patients, and thus a phenotype–genotype correlation of this manifestation of GS was not possible.     

Micronodular basal cell carcinoma: A distinct subtype? Relationship with nodular and infiltrative basal cell carcinomas

Micronodular basal cell carcinoma (BCC) may be more difficult to eradicate and prone to recurrence than nodular subtype. The aim of the study was to compare anatomical and histological characteristics of the basal cell carcinomas subtypes and the relationship of the micronodular BCC with other subtypes. Primary BCCs (n = 3074) were classified as superficial, nodular, micronodular, morpheic/infiltrative. The location was head/neck, limbs, chest/abdomen, back or genitals. Fifty‐one micronodular BCCs were matched randomly with nodular and infiltrative cases, by age, sex, and tumor site. A modified Clark level was used to classify the tumor depth. Micronodular, nodular and infiltrative BCC were prevalently located in the head/neck (P < 0.0001), while superficial in the other regions (P < 0.0001). The Clark level was comparable between micronodular and infiltrative BCC, while nodular BCC showed a more superficial level than micronodular (P < 0.001) and infiltrative (P < 0.001) BCC. No nodular BCC had level IV and only 37.3% level III, while 92% of both micronodular and infiltrative BCC were level III or IV. The percentage of level IV was 11.8% and 25.5% in micronodular and infiltrative BCC, respectively. In the mid‐face/periauricular region, 95.5% of micronodular and 100% of infiltrative cases of were level III or IV, compared to 50% of nodular BCC (P < 0.001). The Clark level of nodular subtype was higher for BCC of mid‐face/periauricular than other regions (P < 0.05). It can be concluded that micronodular BCC shows intermediate characteristics compared with nodular and infiltrative subtypes but appears to have a specific individuality making it a distinct subtype.     

Genetic skin diseases predisposing to basal cell carcinoma

Basal cell carcinoma (BCC) is the commonest cancer in humans. Predisposing factors reflect common genetic variations and environmental influences in most cases. However, an underlying Mendelian disorder should be suspected in a specific subset of patients, namely those with multiple, early onset lesions. Some specific conditions, including Gorlin, Bazex-Dupré-Christol and Rombo syndromes, and Xeroderma Pigmentosum, show BCC as a prominent feature. In addition, BCC may represent a relatively common, although less specific, finding in many other genodermatoses. These include disorders of DNA replication/repair functions (Bloom, Werner, Rothmund-Thomson and Muir-Torre syndromes), genodermatoses affecting the folliculo-sebaceus unit (Brooke-Spiegler, Sch?pf-Schulz-Passarge and Cowden syndromes), immune response (cartilage-hair hypoplasia and epidermodysplasia verruciformis) and melanin biosynthesis (oculocutaneous albinism and Hermansky-Pudlak syndrome), and some epidermal nevus syndromes. Further conditions occasionally associated with BCCs exist, but the significance of the association remains to be proven.     

Dermoscopic features of small size pigmented basal cell carcinomas

Dermoscopic images of histologically proven pigmented basal cell carcinomas (BCC) were retrospectively assessed to compare the dermoscopic features of BCC of 3 mm or less in diameter (n = 6) with BCC of 4–6 mm in diameter (n = 11). All lesions lacked the presence of a pigment network. BCC with a diameter of 3 mm or less had fewer positive dermoscopic features compared with the 4–6 mm in diameter BCC. Multiple blue‐gray globules and large blue‐gray ovoid nests were frequently present. Dermoscopy is a useful tool for early diagnosis of pigmented BCC, even when they are small.     

BAX protein is not expressed by basal cell carcinomas

BAX and related proteins encoded by the BCL2 gene family are involved in the regulation of apoptosis. BAX is an apoptosis-promoting protein. The slow growth of basal cell carcinoma (BCC) has so far been explained by a high apoptotic activity. We investigated immunohistochemically 27 BCCs for expression of the apoptosis-promoting BAX protein. BCC did not express detectable amounts of BAX immunohistochemically. The results indicate that apoptosis in BCC does not involve BAX protein. We propose that the apoptotic pathway in BCC is regulated by either less common members of the BCL2 gene family or bypasses the regulation of the BCL2 gene family.