Tumor vascularization and clinicopathologic parameters as prognostic factors in merkel cell carcinoma.

PURPOSE: Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine tumor of the skin with an increasing incidence. The clinical course is variable and reliable prognostic factors are scarce. Tumor angiogenesis has been shown to have prognostic impact in different types of cancer. The aim of our study was to determine potential prognostic factors, including tumor vascularization, for clinical outcome of MCC. METHODS: The medical records of 46 patients with MCC diagnosed between 1997 and 2010 were analyzed retrospectively. Tissue samples were immune-stained for the lymphatic endothelial vessel marker podoplanin/D2-40 and the panvascular marker CD31. These immunostained sections were analyzed using computer-assisted morphometric image analyses. Aside from the parameters of tumor vascularization, clinicopathologic features were investigated, and progression-free survival (PFS) and tumor-specific survival (TSS) were assessed. Univariate and multivariate analyses were performed to determine prognostic factors. RESULTS: Male sex of the MCC patients and a high cross-sectional whole vessel area (WVA) in relation to the entire tumor area as determined on CD31-stained tumor sections were found to be negative prognostic factors for PFS in a univariate and multivariate regression analysis. Ulceration of the primary tumor was significantly associated with both impaired PFS and TSS. CONCLUSIONS: Our results indicate a high prognostic impact of tumor vascularization on the clinical outcome of MCC patients. Male sex and ulceration of the primary MCC were identified as independent unfavorable prognostic markers for the clinical outcome. As an outlook, MCC patients with increased angiogenesis might be identified and subjected to a targeted anti-angiogenic treatment.

Increased angiogenesis and VEGF expression correlates with disease severity in prurigo patients.

BACKGROUND: Vascular endothelial growth factor-A (VEGF-A) is known as the major skin angiogenesis factor and can be produced by various resident skin cells including keratinocytes. OBJECTIVES: To identify and characterize the role of VEGF-A in the pathogenesis of prurigo. METHODS: Expression of VEGF, VEGFR2, CD-31, and D2-40 was analyzed in the skin of eleven prurigo patients and seven healthy controls by immunohistochemistry. RESULTS: VEGF immunoreactivity (IR) was markedly increased in the epidermis, dermis and subcutis of prurigo patients, whereas expression of the main receptor for VEGF-A in the skin, VEGFR2, was comparable to that of healthy controls. The increased VEGF expression in the skin was associated with a marked increase in the number (12.8 ± 2.1 vs 5.6 ± 0.5, P < 0.05) but not in the size of blood vessels, as assessed by staining of the endothelial cell marker CD31. This increase in small blood vessels correlated closely with increases in the epidermal thickness in prurigo lesions. The number of lymphatic vessels as assessed by D2-40 staining was found to be similar in prurigo patients and healthy controls. CONCLUSIONS: Based on these findings, we speculate that the observed profound vascular remodelling in prurigo might contribute to the pathogenesis of prurigo and the corresponding clinical symptoms and that targeting of VEGF may present a novel therapeutic strategy in the treatment of prurigo patients.

Sentinel lymph node biopsy and risk factors for predicting metastasis in cutaneous squamous cell carcinoma.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is a common cancer capable of metastasis. Sentinel lymph node biopsy (SLNB) may be a valuable adjunct for patients with cSCC at high risk for metastasis. However, data on risk factors for metastasis and results of SLNB from patients with cSCC are limited. OBJECTIVES: To evaluate risk factors for metastasis in patients with cSCC in a large cohort study with long-term follow-up and to determine the value of SLNB. METHODS: We retrospectively analysed all records of patients who underwent excision of cSCC between January 2005 and August 2009 at a tertiary referral centre. In total, 143 patients were included in the cohort, including 17 patients with SLNB and a follow-up time of ≥ 24 months. RESULTS: Tumour thickness > 4 mm and recurrent cSCC were strongly associated with metastatic disease. All metastases in this cohort occurred within 24 months of follow-up. SLNB showed a low sensitivity with regard to the development of metastasis. Six of 17 patients developed metastatic disease despite a negative SLNB. CONCLUSIONS: Patients with risk factors (cSCC with a tumour thickness > 4 mm or recurrent disease) may develop metastases within the first 2 years despite a negative SLNB. Therefore these patients should be closely monitored during the follow-up. Based on our data SLNB does not provide diagnostic value for patients with cSCC.

Non-invasive diagnosis and monitoring of actinic cheilitis with reflectance confocal microscopy.

BACKGROUND: Actinic cheilitis (AC) represents the equivalent of actinic keratosis on the lip. Various treatment modalities are available and the efficacy of diclofenac in hyaluronic acid has recently been described. Reflectance confocal microscopy (RCM) is a non-invasive imaging technique which has recently been applied for the diagnosis of actinic keratoses. Herein, we describe the applicability of RCM for the diagnosis of AC and for monitoring of treatment response of AC to diclofenac in hyaluronic acid. METHODS: Ten Caucasian patients with clinical suspicion for AC were included in this study. To obtain a non-invasive diagnosis, RCM was performed at baseline, followed by biopsy and respective confocal-histopathological correlation. Six patients with a histological diagnosis of AC were treated with diclofenac in hyaluronic acid, whereby monitoring was performed by RCM. RESULTS: Reflectance confocal microscopy was able to correctly identify 6/7 cases of AC and 3/3 cases of benign lesions. The most important RCM criteria for diagnosis of AC were cellular atypia at the stratum spinosum and granulosum with atypical honeycomb pattern. One patient with AC was misclassified as inflammatory cheilitis by RCM as it showed marked inflammatory response and lacked clear signs of cellular atypia on RCM imaging. Following topical treatment with diclofenac gel, 5/6 patients (83%) showed a good treatment response with regression of dysplasia on consecutive RCM examination. CONCLUSIONS: Reflectance confocal microscopy is a promising tool for the non-invasive diagnosis and monitoring of actinic cheilitis. However, marked inflammation represents a potential diagnostic pitfall. In this regard, biopsy should be performed in doubtful cases.

[Human papillomavirus-associated warts in organ transplant recipients. Incidence, risk factors, management]. / Humane Papillomvirus-assoziierte Warzen bei organtransplantierten Patienten. Inzidenz, Risikofaktoren, Management.

Human papillomaviruses infect the squamous epithelia of the skin and cause warts, and are occasionally found in squamous cell carcinomas. Since cell-mediated immunity plays a crucial role in the control of HPV-infections, organ transplant recipients, unable to mount an adequate T-helper 1 cell-mediated immune surveillance, frequently develop widespread and resistant induced warts. Skin tumors, especially squamous cell carcinomas, are the most common post-transplantation neoplasm. Warts, actinic keratoses and invasive squamous cell carcinomas are known to develop at the same time in the areas. The role of HPV in the development of invasive squamous cell carcinoma under immunosuppression, remains to be elucidated in respect to common risk factors and increased numbers of warts potentially identifying patients at increased risk for carcinoma. We prospectively studied 1690 organ transplant recipients in the dermatology clinic at the Charité University Hospital in Berlin, to evaluate risk factors being involved in the development of HPV-induced warts and to assess a potential association of with the development of non-melanoma skin cancers in this population. The cumulative incidence of warts steadily increased throughout the post-transplant years. The presence of more than 10 verrucae was associated with the development of actinic keratoses, invasive squamous cell carcinoma and basal cell carcinoma. This study shows clear evidence that certain risk factors of skin carcinogenesis in organ transplant recipient such as increased age at transplantation, a high dose of immunosuppression related to a specific type of graft and use of azathioprine or cyclosporine are strongly associated with an increased incidence of warts. Furthermore, HPV-induced verrucae vulgares could be used as a potential predictor for the development of coincidental non melanoma skin cancer in organ transplant recipients and therefore could serve as an early identification marker of skin cancer high-risk patients. The challenging management of warts in organ transplantation patients is reviewed.

Comparison of UV-induced skin changes in sun-exposed vs. sun-protected skin- preliminary evaluation by reflectance confocal microscopy.

BACKGROUND: UV radiation (UVR) represents the main risk factor for skin cancer. Sunscreens are commonly used to prevent acute and chronic effects of UVR. The efficacy of sunscreens is currently determined by measurement of minimal erythema dose. Reflectance confocal microscopy represents a non-invasive imaging technique that allows the in- vivo characterization of the skin at near histological resolution. OBJECTIVE: The aim of this study was to compare standardized clinical and histological features of UV-exposure with morphological changes detected by RCM. RESULTS: RCM allowed the detection of morphological changes induced by UV including spongiosis, sunburn cells, micro-vesicles and blood vessel dilatation. The appearance of sunburn cells and micro-vesicles was depending on the dose of UV-B and on the individual susceptibility of the study participants. CONCLUSION: RCM seems to be beneficial for the non-invasive evaluation of dynamic changes following acute UV exposure. Similar to histopathology RCM allows the characterization of sunburn cells and micro-vesicle formation as a sign for acute photo damage. RCM may therefore be used for classification of sunburn reaction and to test the efficacy of sunscreens on a cellular level.

Epidemiology and aetiology of basal cell carcinoma.

Basal cell carcinoma (BCC) is a malignant epithelial neoplasm of the skin preferentially affecting male caucasians and is rarely observed in patients with more intense skin pigmentation. A characteristic feature of BCCs are their extremely low risk to metastasize. Epidemiological data indicate that the overall incidence is increasing worldwide significantly by about 3-10% per annum.(1-3) Based on the increasing incidence of this usually not life-threatening tumour BCC appears to develop into a growing public health problem. This review elucidates the risk factors for the development and for the progression of BCC leading to an improved understanding of this tumour.

Dermatological aspects of angiogenesis.

Neovascularization is vital for the growth of tumours, providing a lifeline for sustenance and waste disposal. Tumour vessels can grow by sprouting, intussusception or by incorporating bone marrow-derived endothelial precursor cells into growing vessels. Recent advances in vascular biology have identified some key factors that control vascular growth, and have led to the hypothesis that in normal tissues vascular quiescence is maintained by the dominant influence of endogenous angiogenesis inhibitors over angiogenic stimuli. In contrast, increased secretion of angiogenic factors and the down-regulation of endogenous angiogenesis inhibitors induce tumour angiogenesis. Vascular quiescence in the skin seems to be primarily maintained by a balance between the endogenous angiogenesis inhibitors thrombospondin 1 and thrombospondin 2 and the potent proangiogenic factor vascular endothelial growth factor A. Inhibiting tumour growth by controlling angiogenesis is an intriguing approach with great potential for the treatment of vascular tumours such as haemangioma, Kaposi's sarcoma and solid cutaneous tumours such as squamous cell carcinoma, melanoma and basal cell carcinoma. In this review, the role of angiogenesis and more recent topics such as lymphangiogenesis in cutaneous tumour growth, invasion and metastasis will be discussed.

The angiogenesis inhibitor vasostatin does not impair wound healing at tumor-inhibiting doses.

Inhibition of tumor angiogenesis represents a promising new approach for the treatment of human cancers. It has remained unclear, however, whether inhibition of tumor angiogenesis may also result in impaired wound healing, a process thought to be angiogenesis dependent. To determine the effects of the angiogenesis inhibitor vasostatin, a 180 amino acid calreticulin fragment, on wound healing at tumor inhibiting doses, full-thickness wounds were generated on the back of nude mice that were also injected intradermally with CA46 Burkitt lymphoma cells. Mice were treated with daily injections of vasostatin or vehicle control at a site between the wounds and the transplanted tumor cells over 14 d. Vasostatin potently inhibited tumor growth and significantly reduced tumor angiogenesis, as measured by computer-assisted image analysis of CD31-stained tumor sections. Moreover, vasostatin treatment resulted in an increased fraction of mature tumor-associated blood vessels. In contrast, no impairment of wound healing was observed in vasostatin-treated mice, despite a significantly reduced vascularity of the wound granulation tissue. Our results reveal a different sensitivity of malignant tumor growth and physiologic wound healing to inhibition of angiogenesis, and they suggest that therapeutic inhibition of tumor angiogenesis may be achieved without impairment of tissue repair.