Vascular patterns in basal cell carcinoma: Dermoscopic, confocal and histopathological perspectives

Basal cell carcinoma (BCC) is the most prevalent skin cancer in the Caucasian population. A variety of different phenotypic presentations of BCC are possible. Although BCCs rarely metastasize, these tumors commonly destroy underlying tissues and should therefore be treated promptly. As vascular formation and angiogenesis are indicators of tumor development and progression, the presence of blood vessels, their morphology and architecture are important markers in skin lesions, providing critical information towards pathogenesis and diagnosis. BCC commonly lacks pigmentation, therefore it is important to emphasize the usefulness of vascular feature detection, recognition, quantification and interpretation. To answer the question of whether vascular patterns observed on dermoscopy, reflectance confocal microscopy (RCM) and histopathology might reflect the biologic behavior of BCCs, we undertook this review article. Several studies have sought, by various means, to identify vascular features associated with the more aggressive BCC phenotypes. Dermoscopic vascular pattern assessment can facilitate diagnostic discrimination between BCC subtypes, more aggressive BCCs displaying less or no pink coloration and a relative absence of central tumor vessels. RCM, a novel, non-invasive imaging technique, allows for the quantification of blood vessel size, density, and flow intensity in BCCs. BCCs are distinguished on RCM chiefly by vessels that branch and intertwine between neoplastic aggregates, a pattern strongly reflecting tumor neo-angiogenesis. The analysis of these vascular morphological and distribution patterns can provide further support in the diagnosis, assessment, or monitoring of BCCs. Histopathology shows significantly higher microvessel densities in the peritumoral stroma of BCCs, when compared to normal skin or benign tumors. This angiogenic response in the stroma is associated with local aggressiveness, therefore the quantification of peritumoralmicrovessels may further assist with tumor evaluation. How dermoscopy and RCM vascular patterns in BCC correlate with histopathological subtype and thus help in discriminating aggressive subtypes definitely deserves further investigation.

[1]  A META-ANALYSIS OF THE LITERATURE , 2017 .

[2]  S. Menzies Dermoscopy of pigmented basal cell carcinoma. , 2002, Clinics in dermatology.

[3]  M. Popadić Dermoscopic Features in Different Morphologic Types of Basal Cell Carcinoma , 2014, Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.].

[4]  C. Vachon,et al.  Incidence of basal cell and squamous cell carcinomas in a population younger than 40 years. , 2005, JAMA.

[5]  J. Winer,et al.  Expression of vascular endothelial growth factor does not promote transformation but confers a growth advantage in vivo to Chinese hamster ovary cells. , 1993, The Journal of clinical investigation.

[6]  Josef Smolle,et al.  Sensitivity and specificity of confocal laser‐scanning microscopy for in vivo diagnosis of malignant skin tumors , 2006, Cancer.

[7]  V. de Giorgi,et al.  Dermoscopy, confocal laser microscopy, and hi‐tech evaluation of vascular skin lesions: diagnostic and therapeutic perspectives , 2012, Dermatologic therapy.

[8]  C. Cernea,et al.  Angiogenesis and skin carcinomas with skull base invasion: a case–control study , 2004, Head & neck.

[9]  D. Hui,et al.  The vascular features of psoriatic skin: imaging using in vivo confocal laser scanning microscopy , 2013, Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging.

[10]  A. Eisen,et al.  Matrix metalloproteinases in blood vessel development in human fetal skin and in cutaneous tumors. , 1995, The Journal of investigative dermatology.

[11]  M. Popadić Dermoscopy of aggressive basal cell carcinomas. , 2015, Indian journal of dermatology, venereology and leprology.

[12]  D. Boda,et al.  In vivo reflectance confocal microscopy of basal cell carcinoma with cystic degeneration. , 2014, Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie.

[13]  A. Crowson,et al.  Basal cell carcinoma: biology, morphology and clinical implications , 2006, Modern Pathology.

[14]  D. Kuijpers,et al.  Basal Cell Carcinoma , 2002, American journal of clinical dermatology.

[15]  J. Kreusch,et al.  How to diagnose nonpigmented skin tumors: a review of vascular structures seen with dermoscopy: part II. Nonmelanocytic skin tumors. , 2010, Journal of the American Academy of Dermatology.

[16]  Thilo Gambichler,et al.  Investigation of basal cell carcionoma by confocal laser scanning microscopy in vivo , 2002 .

[17]  Jürgen Kreusch,et al.  Auflichtmikroskopische Charakterisierung von Gefäßmustern in Hauttumoren , 1996, Der Hautarzt.

[18]  A. Srivastava,et al.  The prognostic significance of tumor vascularity in intermediate-thickness (0.76-4.0 mm thick) skin melanoma. A quantitative histologic study. , 1988, The American journal of pathology.

[19]  A. Harris,et al.  Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicator of node metastases and survival in breast cancer , 1992, The Lancet.

[20]  R. Benamouzig,et al.  Microvessel density and VEGF expression are prognostic factors in colorectal cancer. Meta-analysis of the literature , 2005, British Journal of Cancer.

[21]  J. Malvehy,et al.  Semiology and Pattern Analysis in Nonmelanocytic Lesions , 2012 .

[22]  O. Franco,et al.  Cancer associated fibroblasts in cancer pathogenesis. , 2010, Seminars in cell & developmental biology.

[23]  J. Folkman What is the evidence that tumors are angiogenesis dependent? , 1990, Journal of the National Cancer Institute.

[24]  D. Spandidos,et al.  Variations in the expression of TIMP1, TIMP2 and TIMP3 in cutaneous melanoma with regression and their possible function as prognostic predictors , 2016, Oncology letters.

[25]  J. Malvehy,et al.  Dermoscopic criteria and basal cell carcinoma. , 2012, Giornale italiano di dermatologia e venereologia : organo ufficiale, Societa italiana di dermatologia e sifilografia.

[26]  P. Velasco,et al.  Dermatological aspects of angiogenesis , 2002, The British journal of dermatology.

[27]  D. Boda,et al.  In vivo imaging techniques for psoriatic lesions. , 2014, Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie.

[28]  D. Boda,et al.  Evaluation through in vivo reflectance confocal microscopy of the cutaneous neurogenic inflammatory reaction induced by capsaicin in human subjects. , 2012, Journal of biomedical optics.

[29]  M. Lupu,et al.  THE USE OF IN VIVO REFLECTANCE CONFOCAL MICROSCOPY AND DERMOSCOPY IN THE PREOPERATIVE DETERMINATION OF BASAL CELL CARCINOMA HISTOPATHOLOGICAL SUBTYPES , 2022 .

[30]  J. Folkman,et al.  Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma. , 1991, The New England journal of medicine.

[31]  J. Folkman Angiogenesis in cancer, vascular, rheumatoid and other disease , 1995, Nature Medicine.

[32]  Beibei Cheng,et al.  Automatic detection of basal cell carcinoma using telangiectasia analysis in dermoscopy skin lesion images , 2011, Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging.

[33]  R. Adams,et al.  Mechanotransduction, PROX1, and FOXC2 cooperate to control connexin37 and calcineurin during lymphatic-valve formation. , 2012, Developmental cell.

[34]  F. Aslani,et al.  ANGIOGENESIS ASSESSMENT IN BASAL CELL CARCINOMA , 2001 .

[35]  N. Weidner Intratumor microvessel density as a prognostic factor in cancer. , 1995, The American journal of pathology.

[36]  A. Srivastava,et al.  Neovascularization in human cutaneous melanoma: a quantitative morphological and Doppler ultrasound study. , 1986, European journal of cancer & clinical oncology.

[37]  W Blumenfeld,et al.  Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. , 1993, The American journal of pathology.

[38]  E. Guevara-Gutiérrez,et al.  Correlation of dermoscopic findings with histopathologic variants of basal cell carcinoma , 2013, International journal of dermatology.

[39]  I. Zalaudek,et al.  Dermoscopy patterns of fibroepithelioma of pinkus. , 2006, Archives of dermatology.

[40]  Giuseppe Argenziano,et al.  Dermatoscopy of basal cell carcinoma: morphologic variability of global and local features and accuracy of diagnosis. , 2010, Journal of the American Academy of Dermatology.

[41]  Giuseppe Argenziano,et al.  The dermatoscopic universe of basal cell carcinoma , 2014, Dermatology practical & conceptual.

[42]  A. Foss,et al.  Differences in the vascular patterns of basal and squamous cell skin carcinomas explain their differences in clinical behaviour , 2003, The Journal of pathology.

[43]  A. Foss,et al.  Endothelial Cells of Tumor Vessels: Abnormal but not Absent , 2004, Cancer and Metastasis Reviews.

[44]  Melody A Swartz,et al.  Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling. , 2007, Cancer cell.

[45]  M. Neagu,et al.  The role of confocal microscopy in the dermato–oncology practice , 2011, Journal of medicine and life.

[46]  P. Carmeliet,et al.  Angiogenesis in cancer and other diseases , 2000, Nature.

[47]  T. Grunt,et al.  The vascular pattern of basal cell tumors: light microscopy and scanning electron microscopic study on vascular corrosion casts. , 1985, Microvascular research.

[48]  Rachel E Neale,et al.  Basal cell carcinoma on the trunk is associated with excessive sun exposure. , 2007, Journal of the American Academy of Dermatology.

[49]  D. Spandidos,et al.  Neuroendocrine factors: The missing link in non-melanoma skin cancer , 2017, Oncology reports.

[50]  D. Boda,et al.  Assessment of dermal papillary and microvascular parameters in psoriasis vulgaris using in vivo reflectance confocal microscopy , 2017, Experimental and therapeutic medicine.

[51]  M. Neagu,et al.  Real-Time Investigation of Skin Blood Flow Changes Induced by Topical Capsaicin. , 2017, Acta dermatovenerologica Croatica : ADC.

[52]  A. Marghoob,et al.  Dermoscopic Features of Basal Cell Carcinomas: Differences in Appearance Under Non‐Polarized and Polarized Light , 2012, Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.].

[53]  P. Brennan,et al.  Expression of vascular endothelial growth factor in basal cell carcinoma and cutaneous squamous cell carcinoma of the head and neck , 2002, Journal of cutaneous pathology.

[54]  A. Docea,et al.  Reflectance confocal microscopy and dermoscopy for in vivo, non-invasive skin imaging of superficial basal cell carcinoma , 2016, Oncology letters.

[55]  R Bicknell,et al.  Relationship of endothelial cell proliferation to tumor vascularity in human breast cancer. , 1993, Cancer research.

[56]  Karen Glanz,et al.  A randomized trial of tailored skin cancer prevention messages for adults: Project SCAPE. , 2010, American journal of public health.

[57]  I. Zalaudek,et al.  Dermoscopy of Superficial Basal Cell Carcinoma , 2005, Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.].

[58]  K Wolff,et al.  Statistical evaluation of epiluminescence microscopy criteria in the differential diagnosis of malignant melanoma and pigmented basal cell carcinoma , 1997, Melanoma research.

[59]  A. Lee,et al.  Microvessel quantitation and prognosis in invasive breast carcinoma. , 1992, Human pathology.

[60]  Alberto Mantovani,et al.  Inflammation and cancer: back to Virchow? , 2001, The Lancet.

[61]  P. Amerio,et al.  Microvessel density and VEGF expression seems to correlate with invasiveness of basal cell carcinoma. , 2011, European journal of dermatology : EJD.

[62]  A. Lindenmayer,et al.  Endothelial cell markers CD31, CD34, and BNH9 antibody to H- and Y-antigens--evaluation of their specificity and sensitivity in the diagnosis of vascular tumors and comparison with von Willebrand factor. , 1994, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[63]  Sung-Jan Lin,et al.  Cyclooxygenase-2 overexpression in human basal cell carcinoma cell line increases antiapoptosis, angiogenesis, and tumorigenesis. , 2006, The Journal of investigative dermatology.

[64]  H. von Domarus,et al.  Metastatic basal cell carcinoma , 1984 .

[65]  R. Pawankar,et al.  Mast Cells in Basal Cell Carcinoma Express VEGF, IL-8 and RANTES , 2003, International Archives of Allergy and Immunology.

[66]  A. Marghoob,et al.  In vivo reflectance confocal microscopy imaging of melanocytic skin lesions: consensus terminology glossary and illustrative images. , 2007, Journal of the American Academy of Dermatology.

[67]  R. Hofmann-Wellenhof,et al.  The vasculature of nonmelanocytic skin tumors in reflectance confocal microscopy: vascular features of basal cell carcinoma. , 2010, Archives of dermatology.

[68]  M. Lupu,et al.  DERMATOSCOPIC PATTERN VARIABILITY IN BASAL CELL CARCINOMA – IMPLICATIONS IN DIAGNOSIS, PREOPERATIVE ASSESSMENT, AND TUMOR MANAGEMENT , 2018 .

[69]  B. Lebe,et al.  Evaluation of dermoscopic and histopathologic features and their correlations in pigmented basal cell carcinomas , 2006, Journal of the European Academy of Dermatology and Venereology : JEADV.

[70]  G. de Rosa,et al.  The prognostic significance of tumor angiogenesis in nonaggressive and aggressive basal cell carcinoma of the human skin. , 1996, Human pathology.

[71]  D. Ioannides,et al.  Dermoscopic features in the diagnosis of different types of basal cell carcinoma: a prospective analysis. , 2012, Hippokratia.

[72]  Patrick Nicolas,et al.  Microvessel density as a prognostic factor in women with breast cancer: a systematic review of the literature and meta-analysis. , 2004, Cancer research.

[73]  Melody A Swartz,et al.  Interstitial flow differentially stimulates blood and lymphatic endothelial cell morphogenesis in vitro. , 2004, Microvascular research.

[74]  You-Sun Kim,et al.  Expression of Basic Fibroblast Growth Factor, Vascular Endothelial Growth Factor, and Thrombospondin‐1 Related to Microvessel Density in Nonaggressive and Aggressive Basal Cell Carcinomas , 2003, The Journal of dermatology.

[75]  B. Akkaya,et al.  Prognostic Value of Ki‐67, CD31 and Epidermal Growth Factor Receptor Expression in Basal Cell Carcinoma , 2003, The Journal of dermatology.

[76]  E. Bröcker,et al.  Blood Vessel Density in Basal Cell Carcinomas and Benign Trichogenic Tumors as a Marker for Differential Diagnosis in Dermatopathology , 2010, Journal of skin cancer.

[77]  P. Incel,et al.  Vascular patterns of nonpigmented tumoral skin lesions: confocal perspectives , 2015, Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging.

[78]  Michael Bailey,et al.  Dermatoscopy aids in the diagnosis of the solitary red scaly patch or plaque-features distinguishing superficial basal cell carcinoma, intraepidermal carcinoma, and psoriasis. , 2008, Journal of the American Academy of Dermatology.

[79]  Serena Lembo,et al.  Dermoscopic patterns of superficial basal cell carcinoma , 2008, International journal of dermatology.

[80]  Mirjana Janićijević-Petrović,et al.  Expression of vascular endothelial growth factor and microvascular density assessment in different histotypes of basal cell carcinoma. , 2014, Journal of B.U.ON. : official journal of the Balkan Union of Oncology.

[81]  D. Jukic,et al.  Metastatic basal cell carcinoma: four case reports, review of literature, and immunohistochemical evaluation. , 2009, Archives of pathology & laboratory medicine.

[82]  A. Méjean,et al.  Inhibiteurs de l’angiogenèse : revues de l’apport thérapeutique du sorafenib, du sunitinib et du bevacizumab dans le cancer du rein métastatique , 2010 .

[83]  M. Neagu,et al.  Immunomics in Skin Cancer - Improvement in Diagnosis, Prognosis and Therapy Monitoring , 2013, Current proteomics.

[84]  J. Folkman Tumor angiogenesis: therapeutic implications. , 1971, The New England journal of medicine.

[85]  S. Menzies,et al.  Surface microscopy of pigmented basal cell carcinoma. , 2000, Archives of dermatology.

[86]  G. Yancopoulos,et al.  Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. , 1999, Science.

[87]  M. Popadić Statistical Evaluation of Dermoscopic Features in Basal Cell Carcinomas , 2014, Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.].

[88]  M C Mihm,et al.  Angiogenesis and tumor progression of melanoma. Quantification of vascularity in melanocytic nevi and cutaneous malignant melanoma. , 1992, Laboratory investigation; a journal of technical methods and pathology.

[89]  S. González,et al.  Evaluation of Bowen disease by in vivo reflectance confocal microscopy , 2011, The British journal of dermatology.

[90]  A. Marghoob,et al.  The significance of reflectance confocal microscopy in the assessment of solitary pink skin lesions. , 2009, Journal of the American Academy of Dermatology.

[91]  D. Hanahan,et al.  Induction of angiogenesis during the transition from hyperplasia to neoplasia , 1989, Nature.

[92]  H. Dvorak,et al.  Pathogenesis of tumor stroma generation: a critical role for leaky blood vessels and fibrin deposition. , 1989, Biochimica et biophysica acta.

[93]  Peter Carmeliet,et al.  Angiogenesis in life, disease and medicine , 2005, Nature.

[94]  G. Mikhail Metastatic basal cell carcinoma. , 1978, The Journal of dermatologic surgery and oncology.

[95]  S. González,et al.  In vivo reflectance confocal microscopy for early diagnosis of nonmelanoma skin cancer. , 2012, Actas dermo-sifiliograficas.

[96]  M. Ravaioli,et al.  Apoptosis and Microvessel Density in Gastric Cancer: Correlation with Tumor Stage and Prognosis , 2009, The American surgeon.

[97]  G. Fontanini,et al.  CD34 microvessel density and VEGF expression in basal and squamous cell carcinoma. , 2003, Pathology, research and practice.

[98]  S. Youn,et al.  Characteristics of subjective recognition and computer‐aided image analysis of facial erythematous skin diseases: a cornerstone of automated diagnosis , 2014, The British journal of dermatology.

[99]  M. Lupu,et al.  Non-invasive imaging of actinic cheilitis and squamous cell carcinoma of the lip , 2018, Molecular and clinical oncology.

[100]  Josep Malvehy,et al.  Dermoscopy of benign and malignant neoplasms in the pediatric population. , 2010, Seminars in cutaneous medicine and surgery.

[101]  S. Seidenari,et al.  High magnification digital dermoscopy of basal cell carcinoma: a single-centre study on 400 cases. , 2014, Acta dermato-venereologica.

[102]  F. Kuonen,et al.  Non-Melanoma Skin Cancers of the Fronto-Temporal Area Preferentially Localize in the Proximity of Arterial Blood Vessels , 2017, Dermatology.

[103]  Z. Naraghi,et al.  Angiogenesis Evaluation in Cutaneous Basal Cell Carcinoma and Squamous Cell Carcinoma , 2006 .

[104]  E. Tschachler,et al.  Differences in tumor microvessel density between squamous cell carcinomas and basal cell carcinomas may relate to their different biologic behavior , 1997, Journal of cutaneous pathology.

[105]  R Hofmann-Wellenhof,et al.  Dermoscopy of Bowen's disease , 2004, The British journal of dermatology.

[106]  A. Marghoob,et al.  Nonmelanocytic Lesions Defying the Two‐Step Dermoscopy Algorithm , 2006, Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.].

[107]  B. Calenic,et al.  Gene Expression and Proteome Analysis as Sources of Biomarkers in Basal Cell Carcinoma , 2016, Disease markers.

[108]  Jürgen Bauer,et al.  Diagnosis of cutaneous tumors with in vivo confocal laser scanning microscopy , 2010, Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG.

[109]  Juergen Kreusch,et al.  Vascular patterns in skin tumors. , 2002, Clinics in dermatology.

[110]  Lars Holmgren,et al.  Dormancy of micrometastases: Balanced proliferation and apoptosis in the presence of angiogenesis suppression , 1995, Nature Medicine.

[111]  A. Stanton,et al.  Comparison of the microvasculature of basal cell carcinoma and actinic keratosis using intravital microscopy and immunohistochemistry , 2003, The British journal of dermatology.

[112]  D. Bonamonte,et al.  Vascular Patterns in Cutaneous Ulcerated Basal Cell Carcinoma: A Retrospective Blinded Study Including Dermoscopy. , 2017, Acta dermato-venereologica.

[113]  D. Powe,et al.  The tumour stroma of oral squamous cell carcinomas show increased vascularity compared with adjacent host tissue. , 1997, British Journal of Cancer.

[114]  J. Folkman,et al.  Angiogenic factors. , 1987, Science.

[115]  S. González,et al.  Real-time, in vivo confocal reflectance microscopy of basal cell carcinoma. , 2002, Journal of the American Academy of Dermatology.

[116]  Gianluca Petrillo,et al.  Vascular structures in skin tumors: a dermoscopy study. , 2004, Archives of dermatology.

[117]  Donald E Ingber,et al.  Mechanotransduction of fluid stresses governs 3D cell migration , 2014, Proceedings of the National Academy of Sciences.

[118]  J. Breau,et al.  Microvessel density and VEGF expression are prognostic factors in colorectal cancer. Meta-analysis of the literature , 2005 .

[119]  J. Pyne,et al.  Aggressive basal cell carcinoma: dermatoscopy vascular features as clues to the diagnosis , 2012, Dermatology practical & conceptual.

[120]  R. Hofmann-Wellenhof,et al.  Vascular architecture of melanocytic skin tumors. A quantitative immunohistochemical study using automated image analysis. , 1989, Pathology, research and practice.

[121]  Z. Jane Wang,et al.  Automatic detection of basal cell carcinoma using vascular-extracted features from dermoscopy images , 2016, 2016 IEEE Canadian Conference on Electrical and Computer Engineering (CCECE).

[122]  M. Oliviero,et al.  Dermoscopic differentiation of a superficial basal cell carcinoma and squamous cell carcinoma in situ. , 2006, Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.].

[123]  Tarl W. Prow,et al.  Automated Detection of Actinic Keratoses in Clinical Photographs , 2015, PloS one.

[124]  N. Agnantis,et al.  Expression of vascular endothelial growth factor (VEGF) and association with microvessel density in small-cell and non-small-cell lung carcinomas. , 2004, Histology and histopathology.

[125]  E. Bauer,et al.  Basal cell carcinoma and collagenase. , 1986, The Journal of dermatologic surgery and oncology.

[126]  K. Peris,et al.  Vascular patterns in basal cell carcinoma , 2011, Journal of the European Academy of Dermatology and Venereology : JEADV.

[127]  Salvador González,et al.  Clinical Applicability of in vivo Reflectance Confocal Microscopy for the Diagnosis of Actinic Keratoses , 2008, Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.].

[128]  M. Heckmann,et al.  Frequency of facial basal cell carcinoma does not correlate with site-specific UV exposure. , 2002, Archives of dermatology.