Current Perspectives on the Role of Matrix Metalloproteinases in the Pathogenesis of Basal Cell Carcinoma.

Basal cell carcinoma (BCC) is the most common skin malignancy, which rarely metastasizes but has a great ability to infiltrate and invade the surrounding tissues. One of the molecular players involved in the metastatic process are matrix metalloproteinases (MMPs). MMPs are enzymes that can degrade various components of the extracellular matrix. In the skin, the expression of MMPs is increased in response to various stimuli, including ultraviolet (UV) radiation, one of the main factors involved in the development of BCC. By modulating various processes that are linked to tumor growth, such as invasion and angiogenesis, MMPs have been associated with UV-related carcinogenesis. The sources of MMPs are multiple, as they can be released by both neoplastic and tumor microenvironment cells. Inhibiting the action of MMPs could be a useful therapeutic option in BCC management. In this review that reunites the latest advances in this domain, we discuss the role of MMPs in the pathogenesis and evolution of BCC, as molecules involved in tumor aggressiveness and risk of recurrence, in order to offer a fresh and updated perspective on this field.

Basal Cell Carcinoma Arising over a Venous Malformation of the Forehead Communicating with the Endocranial Veins.

INTRODUCTION: An increasing number of skin cancer arising over vascular anomaly has been reported in literature. In such cases, the oncologic radicality required to threat skin malignancies may be in contrast with the safety needed when dealing with vascular malformation. As a result, treatment of this association may be insidious and treacherous and imposes a sound knowledge and carefulness. MATERIALS AND METHODS: The authors report on a case of a 77-years-old woman affected by a basal cell carcinoma (BCC) arising over a vascular malformation of forehead. Preoperative radiological imaging revealed an underlying venous malformation (VM) communicating with intracranial district. Patient underwent sclerotherapy of the VM with gelified ethanol in order to reduce potentially fatal bleeding during surgery and, on the other hand, any leakage of the sclerosant in the intracranial veins. Excision of the BCC was then performed without complications. RESULTS: Neither intra-operative nor post-operative complications were observed. Current 3-years follow-up shows no recurrence of BCC whilst the residual VM is stable and clinically silent. CONCLUSIONS: Mechanisms leading to the onset of skin cancers over venous malformations are still unclear. However, association between these 2 conditions may be underestimated with possible catastrophic consequences. Thorough knowledge of vascular malformations and a multidisciplinary approach is of the uttermost importance when dealing with such clinical challenges.

Optical coherence angiography for pre-treatment assessment and treatment monitoring following photodynamic therapy: a basal cell carcinoma patient study.

Microvascular networks of human basal cell carcinomas (BCC) and surrounding skin were assessed with optical coherence angiography (OCA) in conjunction with photodynamic therapy (PDT). OCA images were collected and analyzed in 31 lesions pre-treatment, and immediately/24 hours/3-12 months post-treatment. Pre-treatment OCA enabled differentiation between prevalent subtypes of BCC (nodular and superficial) and nodular-with-necrotic-core BCC subtypes with a diagnostic accuracy of 78%; this can facilitate more accurate biopsy reducing sampling error and better therapy regimen selection. Post-treatment OCA images at 24 hours were 98% predictive of eventual outcome. Additional findings highlight the importance of pre-treatment necrotic core, vascular metrics associated with hypertrophic scar formation, and early microvascular changes necessary in both tumorous and peri-tumorous regions to ensure treatment success.

Extended Central Artery Perforator Propeller Flap for Large Nasal Defects.

Various local flaps have been defined for small skin defects of the nose. However, the repair of large nasal defects is only possible with flaps allowing a large tissue transfer, such as a free flap, forehead flap, and nasolabial flap. In this study, large nasal defects were reconstructed with extended central artery perforator propeller (CAPP) flaps in an attempt to describe a single-stage procedure as an alternative technique to the median forehead flap. Thirteen large nasal skin defects, including dorsum and nasal sidewall and/or dome, were repaired with a CAPP flap between January 2015 and March 2018. A total of 13 patients aged 19 to 92 years were included. The mean follow-up period was 14.9 months. Pathological diagnoses were basal cell carcinoma in 5 patients, squamous cell carcinoma in 6 patients, and trauma in 2 patients. Defect size ranged between 3 × 3 and 4 × 5 cm. Flap size ranged between 3 × 7 and 5 × 10 cm. No major complications including total flap failure, hematoma, or infection were observed. However, a partial flap necrosis occurred in 1 patient. In 3 patients, scar revision surgery was performed at the postoperative period. In conclusion, CAPP flap use is a safe and reliable option to repair large nasal defects. This flap is able to cover large nasal defects including dorsal, dome, and nasal sidewall defects in a single-stage procedure. Requiring no pedicle separation, this flap is an alternative option to the conventional median forehead flap.

Automatic skin lesion area determination of basal cell carcinoma using optical coherence tomography angiography and a skeletonization approach: Preliminary results.

Cutaneous blood flow plays a key role in numerous physiological and pathological processes and has significant potential to be used as a biomarker to diagnose skin diseases such as basal cell carcinoma (BCC). The determination of the lesion area and vascular parameters within it, such as vessel density, is essential for diagnosis, surgical treatment and follow-up procedures. Here, an automatic skin lesion area determination algorithm based on optical coherence tomography angiography (OCTA) images is presented for the first time. The blood vessels are segmented within the OCTA images and then skeletonized. Subsequently, the skeleton is searched over the volume and numerous quantitative vascular parameters are calculated. The vascular density is then used to segment the lesion area. The algorithm is tested on both nodular and superficial BCC, and comparing with dermatological and histological results, the proposed method provides an accurate, non-invasive, quantitative and automatic tool for BCC lesion area determination.

Vascular Patterns in Cutaneous Ulcerated Basal Cell Carcinoma: A Retrospective Blinded Study Including Dermoscopy.

The aim of this retrospective study was to determine the type and prevalence of vascular patterns in the ulcerated and non-ulcerated portions of histologically proven basal cell carcinomas (BCCs) and correlate them with other dermoscopic and clinical features, including the clinically supposed diagnosis. Three authors retrospectively collected 156 clinical and 156 dermoscopic digital images of ulcerated BCCs (histologically confirmed); each image was blindly evaluated by 2 other authors, who did not know the histological diagnosis. Seventeen lesions were completely ulcerated, while 139 lesions presented ulcerated and non-ulcerated portions. Correct clinical diagnosis was associated with the type of lesion, in particular 90.6% of partially ulcerated lesions were correctly diagnosed with clinical-dermoscopic examination, compared with 11.8% of totally ulcerated lesions (χ2 = 64.00, p = 0.000). Presence of arborizing pattern in the ulcerated portion was associated with a correct diagnosis (Fisher's exact test, p = 0.015). Correct diagnosis was also associated with absence of dotted pattern in the non-ulcerated area (χ2 = 16.18, p = 0.000); the absence of hairpin (χ2 = 6.08, p = 0.000) and glomerular patterns were associated with correct diagnosis in the ulcerated areas (χ2 = 18.64, p = 0.000). In case of completely ulcerated BCC the clinician lacks the means to correctly identify the correct nature of the lesion, and is driven towards an incorrect diagnostic conclusion.

Dermoscopic Features of Basal Cell Carcinoma on the Lower Limbs: A Chameleon!

BACKGROUND: Lower limbs represent an uncommon location for basal cell carcinoma (BCC) and only few reports have described dermoscopic features of BCC in this body site. Since BCCs of the lower limbs frequently display nonclassic BCC dermoscopic criteria, they can simulate other benign or malignant lesions. OBJECTIVE: Our aim was to describe the dermoscopic features of BCC located on lower limbs and to define which criteria were more associated with their benign- or malignant-looking appearance. METHODS: We conducted a retrospective study enrolling consecutive patients with histologically confirmed BCCs of the lower limbs. Lesions were classified in 7 categories according to the clinical and dermoscopic global appearance. Clear BCC, squamous cell carcinoma (SCC) or Bowen disease-like, Kaposi disease-like, melanoma-like, and aspecific pattern were considered malignant-looking lesions; however, seborrheic keratosis-like and dermatofibroma-like were considered benign-looking. To define which dermoscopic criteria were independently associated with benign- or malignant-looking appearance, we conducted a multivariate logistic regression analysis. RESULTS: A total of 81 BCCs were enrolled: 18 (22%) were benign-looking lesions (of which 11 were seborrheic keratosis-like and 7 dermatofibroma-like) and 63 (78%) were malignant-looking BCCs (of which 24 were clear-cut BCCs, 23 SCC-like, 2 Kaposi disease-like, 9 melanoma-like, and 5 had aspecific pattern). Multivariate regression analysis showed that erosions/ulceration and vessels were independently associated with malignant-looking appearance. The most represented vessels were glomerular and polymorphic, which are more frequently encountered in SCC, together with ulceration. CONCLUSION: BCC of the lower legs frequently simulates other benign or malignant lesions, with SCC being the main differential diagnosis.

Speckle-variance optical coherence tomography: a novel approach to skin cancer characterization using vascular patterns.

Non-invasive imaging devices are currently being utilized in research and clinical settings to help visualize, characterize, anddiagnose cancers of the skin. Speckle-variance optical coherence tomography (svOCT) is one such technology that offers considerable promise for non-invasive, real time detection of skin cancers given its added ability to show changes in microvasculature. We present four early lesions of the face namely sebaceous hyperplasia, basal cell skin cancer, pigmented actinic keratosis, and malignant melanoma in situ that each display different important identification markers on svOCT. Up until now, svOCT has mainly been evaluated for lesion diagnosis using transversal (vertical) sections. Our preliminary svOCT findings use dynamic en face (horizontal) visualization to differentiate lesions based on their specific vascular organizations. These observed patterns further elucidate the potential of this imaging device to become a powerful tool in patient disease assessment.

Assessment of VEGF and EGFR in the study of angiogenesis of eyelid carcinomas.

A tumor represents an abnormal tissue growth that can arise from any ocular structure, such as eyelids, muscles or the optic nerve. At the eyelids, there are two main tumor types: basal cell carcinoma and squamous cell carcinoma. Angiogenesis plays a crucial role in growth, invasion and metastasis processes of any tumor. It is well known the fact that without new vessels formation tumors cannot exceed 1-2 mm diameter. Immunohistochemical analysis has been performed on 43 cases of primary carcinomas of the eyelid, diagnosed between 2010 and 2014 in the Laboratory of Pathological Anatomy of the University Emergency County Hospital of Craiova, Romania. Biological material was represented by surgical resection samples, coming from the Clinic of Ophthalmology the anteriorly named Hospital. Within the immunohistochemical study, we have evaluated epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) expression in a group of 43 cutaneous carcinomas of the eyelid, depending on the type and differentiation grade of the tumor. Of the 43 samples, 23 came from patients with eyelid basal cell carcinoma and 20 came from patients with eyelid squamous cell carcinoma. In our study, EGFR and VEGF immunoexpression was superior for squamous cell carcinomas, compared to basal cell carcinomas, fact that was statistically significant. Regarding squamous cell carcinomas, the immunoexpression of these two markers was superior in moderate÷poor differentiated forms, compared to well differentiated forms, fact that was statistically significant. The markers used in this study were found to be associated with the acquisition of aggression and angiogenic phenotypes by analyzed carcinomas.

Increasing demonstration of angiogenic markers in skin neoplastic lesions.

BACKGROUND: Skin cancer represents the most common worldwide malignancy. Angiogenesis is an important factor in tumor growth and metastasis. Given these facts, the purpose of the current study was to compare the levels of angiogenic proteins in the context of the most common malignant and premalignant skin lesions. METHODS: Immunohistochemistry of CD31, HIF1A, VEGFR1 and VEGFR2 was performed in basal cell carcinoma (BCC), actinic keratosis (AK) and squamous cell carcinoma of the skin (SCCS). RESULTS: SCCS presented with increased levels of HIF1A, VEGFR1 and VEGFR2 in comparison to AK. In addition, SCCS also demonstrated increased levels of HIF1A to BCCLR or BCCHR. BCC presented with more vessels than AK. However, no correlation was observed among CD31, HIF1A, VEGFR1 and VEGFR2. CONCLUSIONS: SCCS presented with higher levels of HIF1A, VEGFR1 and VEGFR2, while BCC demonstrated an increased number of vessels in relation to AK. These data suggest that antiangiogenic therapy might be useful for skin cancer treatment.

Usefulness of confocal microscopy in distinguishing between basal cell carcinoma and intradermal melanocytic nevus on the face.

The clinical distinction between basal cell carcinoma (BCC) and intradermal melanocytic nevus lesions on the face can be difficult, particularly in young patients or patients with multiple nevi. Dermoscopy is a useful tool for analyzing characteristic dermoscopic features of BCC, such as cartwheel structures, maple leaf-like areas, blue-gray nests and dots, and ulceration. It also reveals arborizing telangiectatic vessels and prominent curved vessels, which are typical of BCC, and comma vessels, which are typical of intradermal melanocytic nevi. It is, however, not always easy to distinguish between these 2 conditions, even when dermoscopy is used. We describe 2 facial lesions that posed a clinical and dermoscopic challenge in two 38-year-old patients; confocal microscopy showed separation between tumor nests and stroma and polarized nuclei, which are confocal microscopy features of basal cell carcinoma.

What is the impact of tumour size on dermoscopic diagnosis of BCC?

BACKGROUND: The effect of size on diagnostic performance of dermoscopy in basal cell carcinomas (BCCs) is yet to be determined. OBJECTIVES: To investigate the differences in dermoscopic features between small- and large-sized BCCs. METHODS: A total of 151 BCCs consecutively collected during a 2-year period were analysed. These tumours were evaluated for the presence of various dermoscopic features (colours, structures and vessels) using the contact polarized dermoscopy. Differences in proportions were evaluated by means of chi-squared test and Fisher's exact test, when appropriate. RESULTS: In all, 62 (41.1%) small (≤ 1 cm) and 89 (58.9%) large (>1 cm) BCCs were included. Arborizing vessels, short fine telangiectasias (SFT) and multiple small erosions were significantly (P < 0.05) more frequent in the group of large BCCs. Further analysis of the effect of size on dermoscopic features within the specific groups, nodular, superficial and ulcerated, found significant difference only in the group of nodular BCCs. Structureless hypopigmentation was significantly (P < 0.05) more frequent in the group of large nodular BCCs in comparison with the small ones. CONCLUSIONS: Despite determined differences in vascular features and multiple erosions between the small and large BCCs, the results of further investigation within the specific groups indicate that dermoscopy is reliable for the diagnosis of BCC regardless of its size.

Expression of vascular endothelial growth factor and microvascular density assessment in different histotypes of basal cell carcinoma.

PURPOSE: In this study, we investigated the expression of vascular endothelial growth factor (VEGF) and tumor microvascular density (MVD) in different histotypes of basal cell skin carcinoma (BCC). METHODS: We used a total 101 histological archival specimens, including superficial, nodular, cystic, keratinocytic, adenoid infiltrative types and cases of metatypical BCC. Routine hematoxylin/eosin (H&E) and immunohistochemical ABC method with NOT AE1/AE3, anti VEGF anti CD34 antibodies were used. VEGF expression in tumor cells was studied in relation to the BCC histotype and demographic characteristics. For statistical analysis ANOVA (F test), Student's t-test, and Karl Pearson coefficient were used. RESULTS: VEGF expression was significantly lower in the superficial histotype compared to all other types of BCC. No significant difference in VEGF expression between infiltrative, metatypical, adenoid and nodular types was found, but the highest expression of VEGF was seen in the infiltrative and metatypical types. Significantly higher MVD was found in infiltrative, adenoid, metatypical and nodular types. CONCLUSION: Our results suggest that the angiogenic potential of BCC correlated with tumor histotype, and histological growth pattern BCC enable distinction of the patients with increased risk of recurrence and / or metastasis.

Statistical evaluation of dermoscopic features in basal cell carcinomas.

BACKGROUND: Early detection of basal cell carcinoma (BCC) is of crucial importance, as serious morbidity may result from undiagnosed tumor. OBJECTIVE: To evaluate diagnostic significance (specificity, sensitivity, positive and negative predictive value) of dermoscopic features in BCCs. METHODS: A prospective observational study was conducted using contact polarized dermoscopy to evaluate the presence of various dermoscopic features. Images were evaluated for a range of dermoscopic colors, structures, and vessels. SETTING: Specialized University Clinic. PATIENTS: A sample of 151 histopathologically verified BCCs was collected from 116 patients (64 males and 52 females). The populations included predominantly Caucasian individuals. MAIN OUTCOME MEASURES: The sensitivity, specificity, positive and negative predictive values of the various dermoscopic features seen in BCCs were calculated according to standard formulas. RESULTS: The highest diagnostic value (specificity [Sp] = 100%, positive predictive value [PPV] = 100%) for BCC had spoke-wheel areas, short fine telangiectasias, white rosette, annular hypopigmentation, multiple erosions, and ulceration. Arborizing vessels (Sp = 96%, PPV = 98%) and microvessels (Sp = 93%, PPV = 97%) had significant diagnostic value for BCC. Annular distribution of telangiectatic vessels (Sp = 96%), translucency (Sp = 93%), and multiple blue-gray globules (Sp = 89%) had the same PPV of 95% for BCCs. Other dermoscopic features of this study are not strongly associated with the diagnosis of BCC. CONCLUSION: Dermoscopic features relevant for diagnosis of BCC have different diagnostic "weight." Clinicians should have known the sensitivity and specificity of each relevant feature before they can make an accurate dermoscopic diagnosis of BCC.

Dermoscopic features in different morphologic types of basal cell carcinoma.

BACKGROUND: Many different phenotypic presentations of basal cell carcinoma (BCC) are possible. OBJECTIVE: This study aims to highlight the similarities and differences in dermoscopic features between different morphologic types of BCC. METHODS: A prospective observational study was performed using contact polarized dermoscopy to evaluate the presence of various dermoscopic features. Images were evaluated for a range of dermoscopic colors, structures, and vessels. Features were compared according to the histopathologic subtype. RESULTS: Of the 151 BCCs, 39.7% were nodular, 37.7% superficial, 13.9% ulcerated, 3.97% pigmented, 2.65% morpheaform, and 1.99% infiltrative BCCs. The dermoscopic features that showed a highly significant difference (p < .001) in distribution between various histologic groups were large blue-gray ovoid nests, leaf-like areas, arborizing vessels, short fine telangiectasias, annular distribution of telangiectatic vessels, structureless hypopigmentation, annular hypopigmentation, translucency, multiple erosions, and ulceration. A significant difference (p < .05) between evaluated groups was found in structureless hyperpigmentation, arborizing microvessels, milky red background, and pigment network. CONCLUSION: The results of the study indicate that the combination of relevant dermoscopic features in different morphologic types of BCC depends on the thickness of the tumor, and not on its histologic nature. In addition, dermoscopy was shown to be not particularly useful in identifying which BCCs are more aggressive.

The -1154 G/A VEGF gene polymorphism is associated with the incidence of basal cell carcinoma in patients from northern Poland.

Vascular endothelial growth factor (VEGF) is believed to play a crucial role in neoplastic angiogenesis. Although the genetic background of basal cell carcinoma (BCC) has been analyzed in some papers, the mechanism of BCC pathogenesis is not fully understood. To the best of our knowledge, VEGF gene polymorphisms have not yet been explored. The aim of the study was to asses the frequency of three polymorphisms in the VEGF gene (-1154 G/A, -460 T/C and +405 G/C) in patients of Polish origin with BCC and control group. In addition, VEGF serum levels of patients with BCC and controls were measured. The study involved 180 patients (96 women, 84 men) with BCC and a mean age of 68.9 ± 11.8, and 215 healthy age- and sex-matched volunteers. The VEGF polymorphisms at positions -1154 and +405 were analyzed using the amplification refractory mutation system polymerase chain reaction method. To assess the VEGF gene polymorphism at position -460, we used the polymerase chain reaction restriction fragment length polymorphism method. Serum levels of VEGF protein were measured using the ELISA test. The presence of the G allele (GA or GG) in the -1154 VEGF polymorphism was associated with an increased risk of BCC development (OR = 7.28, p < 0.0001). Furthermore, the carriers of the AA genotype in -1154 VEGF polymorphism showed significantly reduced risks of BCC (OR = 0.14, p < 0.0001). It was also shown that the GTC haplotype of VEGF predisposes to BCC development (OR = 1.69, p = 0.013), while the presence of the ATG haplotype significantly reduces this risk (OR = 0.17, p = 0.00001). We have found significantly increased VEGF serum levels among BCC patients, in comparison with the healthy controls (mean 596.7 ± 393.5 pg/ml; range 60.1-931.4 vs. 255.9 ± 174.6 pg/ml; range 42.2-553.0 pg/ml; p < 0.0004). The serum levels of VEGF significantly correlated with tumor size: r = 0.41, p < 0.0001. Our results testify to the importance of -1154 G/A VEGF gene polymorphisms in altering the risk of BCC among the population from northern Poland.

Ultrasonographic staging of cutaneous malignant tumors: an ultrasonographic depth index.

The objective of this paper is to assess the role of conventional and high-frequency ultrasound in the evaluation of the depth of cutaneous skin cancer. The study was performed on 46 subjects, divided into 3 categories, according to their skin pathology [basal cell carcinoma (BCC), 18 subjects; superficial spreading melanoma (SSM), 8 subjects; nodular melanoma (NM), 20 subjects]. Conventional and high-frequency ultrasonographic measurements were performed in order to assess the thickness of the tumors and the vascularization degree. We compared the mean values of the tumoral thickness obtained by using ultrasound (ultrasonographic depth index) with the histological depth index, obtained after performing histological sections stained with hematoxylin-eosin, and specific monoclonal antibodies in case of pigmented tumors. We established a correlation index between the histological and ultrasonographic values of the tumoral thickness. We found a strong correlation between the ultrasonographic index (measured by high-frequency sonography) and the histological index for nodular BCC (correlation of 98.4 %), NM subjects (correlation of 98.4 %), and SSM subjects (correlation of 99.4 %). An increase of the blood supply was noticed in nodular lesions only. Ultrasonography allows a very accurate assessment of skin cancer. The ultrasonographic depth index can be considered an objective, non-invasive marker for cutaneous tumors, comparable to the histological one, with a very good sensitivity (98-99 %).