High level of TILs is an independent predictor of negative sentinel lymph node in women but not in men.

Factors that are most associated with positive lymph node status in melanoma are Breslow thickness and ulceration. However, there are other factors that have been little explored and could help in the identification of "at risk patients" harbouring occult metastasis. The objective of this study was to determine whether intensity of tumour-infiltrating lymphocytes (TILs) in a cohort study (N = 4133) is an independent predictor of sentinel lymph node (SLN) status in patients with primary cutaneous melanoma. Of the patients with cutaneous melanoma who resulted negative for nodal metastasis, 50.7% had moderate/marked TILs versus 27.7% among those patients who resulted positive for nodal metastasis. In the multivariate analysis, controlling for sex, age, mitotic rate, ulceration and Breslow, high levels of TILs in primary invasive melanoma was associated with a lower risk of developing SLN metastasis (OR 0.46; 95% CI 0.23-0.95, p = 0.037). When the analysis was stratified by sex, the protective effect of moderate/marked TIL remained only for women (OR 0.30; 95% CI 0.10-0.93, p = 0.037) but not for men (OR 0.51; 95% CI 0.19-1.34, p = 0.172). Other independent predictors of negative lymph node were low Breslow thickness (≤ 2.0 mm) and low mitotic rate. Besides predicting a negative lymph node response, TILs were also associated with a decreased risk of 10-year mortality among females with positive lymph node. Our findings suggest that high level of TILs is an independent predictor of negative SLN status among women. Further research is warranted to confirm our findings.

Ultrasonography of Skin Changes in Legs with Chronic Venous Disease.

BACKGROUND: In daily practice, ultrasonography (US) is used only to designate the location and pattern of venous lesions. Skin US is not performed between routine venous investigations. METHODS: Skin morphology is evaluated by the same probes used for routine Duplex evaluation of superficial veins. US findings from evident skin lesions are comparatively evaluated with those from the surrounding apparently normal skin and from the contralateral leg. RESULTS: Inflammation and dermal edema can be found in the apparently normal skin of C2 legs. Swollen legs show thickening of the subcutaneous layer as a result of diffuse soaking or anechoic cavities, with or without dermal edema. Chronic hypodermitis is characterized by inflammatory edema in initial phases, and by liposclerosis in advanced cases. Recrudescence of inflammation provokes focal rarefactions of the subcutaneous layer, possibly related to ulcer opening. CONCLUSION: In legs with venous disorders, sonography refines clinical evaluation of the skin and may reveal changes not highlighted by inspection. Some of these changes could require further investigation because they have not yet been explained or described. Skin sonography should improve knowledge of the natural history of skin changes, as well as contribute to a better grading of venous diseases severity In particular, US evidence of cutaneous and subcutaneous changes in C2 legs should be considered to stratify the treatment in C2 legs, by identifying those in which varicose veins are not simply a cosmetic problem.

Cartilaginous metaplasia of varicose veins: a case report.

Cartilaginous metaplasia of superficial veins was found in a 64-year-old woman who underwent surgery for varicose veins. At operation, some varicose veins of the medial thigh were semi-rigid and fibroelastic to the touch. Histology revealed that half the lumen was occupied by chondroid tissue. The other half was obliterated by fibrous tissue, typical of post-thrombotic involution. Possible causes of cartilaginous metaplasia are briefly discussed.

Skin iron deposition characterises lipodermatosclerosis and leg ulcer.

BACKGROUND: It is commonly reported that chronic venous disease (CVD) increases the skin iron content in which the excess is stored as haemosiderin. Despite increasing interest in the role of haemosiderin in venous ulceration, no study has systematically evaluated the occurrence of iron overload in the limbs of patients with CVD. PURPOSE: To evaluate skin haemosiderin deposition in relation to the presence and severity of skin changes in CVD legs designated according to the clinical, etiologic, anatomic and pathophysiologic (CEAP) classification. METHODS: A total of 85 skin biopsies were taken from the medial aspect of 49 limbs with CVD of CEAP clinical stages C2, C3, C4 and C6. The content of ferric ions was assessed by Perl's Prussian Blue (PPB) stain. RESULTS: No haemosiderin deposition was found in normal skin of C2, C3 and C4A legs, in less severe regions of pigmentation and in some parts of more severely affected limbs. Haemosiderin was always present in lipodermatosclerotic skin and ulcers. Occasionally, haemosiderin was found in the apparently normal perilesional skin of C4b and C6 legs. The regenerating dermis at the base of healing ulcers showed none or light haemosiderin deposition. CONCLUSION: Iron overload is not present in the less severe stages of skin damage due to CVD but lipodermatosclerosis and leg ulcers are always accompanied by haemosiderin deposition. In fact, no severe skin changes occur in CVD legs until iron overload occurs. Our results are in agreement with previous reports suggesting that a genetic inability to counteract skin iron overload is present in these patients. A more detailed analysis of disordered iron metabolism should be undertaken in CVD patients.

Inflammation in venous disease.

Chronic venous disease (CVD), mainly due to venous reflux or, sometimes, to venous outflow obstruction, produces a microcirculatory overload leading to the impairment of venous drainage. Venous drainage depends primarily on a major hemodynamic parameter called trans-mural pressure (TMP). TMP is increased in patients affected by CVD, leading to impaired tissue drainage, and, consequently, facilitating the beginning of the inflammatory cascade. Increased TMP determines red blood cell extravasation and either dermal hemosiderin deposits or iron laden-phagocytes. Iron deposits are readily visible in the legs of all patients affected by severe CVD. Local iron overload could generate free radicals or activate a proteolytic hyperactivity of metalloproteinases (MMPs) and/or downregulate tissue inhibitors of MMPs. These negative effects are particularly evident in carriers of the common HFE gene's mutations C282Y and H63D, because intracellular iron deposits of mutated macrophages have less stability than those of the wild type, inducing a significant oxidative stress. It has been demonstrated that such genetic variants increase the risk of ulcers and advance the age of ulcer onset, respectively. The iron-dependent vision of inflammation in CVD paves the way to new therapeutic strategies including the deliberate induction of iron deficiency as a treatment modality for non-healing and/or recurrent venous leg ulcers. The inflammatory cascade in CVD shares several aspects with that activated in the course of multiple sclerosis, an inflammatory and neurodegenerative disease of unknown origin in which the impairment of cerebral venous outflow mechanisms has been recently demonstrated.

The nature of skin pigmentations in chronic venous insufficiency: a preliminary report.

BACKGROUND: Chronic Venous Insufficiency (CVI) provokes skin pigmentation commonly seen in the gaiter region of the leg. The exact nature and pathogenesis of this are poorly understood. OBJECTIVE: To evaluate the presence of melanin and haemosiderin in histological sections of the skin of limbs with primary varicose veins. METHODS: Histological investigations were performed in 49 biopsies from pigmented and non-pigmented skin of limbs with varicose veins and control limbs. RESULTS: All samples from pigmented skin showed a higher content of melanin than controls. In contrast, haemosiderin was found in only a few biopsies taken from the more severely pigmented skin in areas of lipodermatosclerosis. Erythrocyte diapedesis was observed only where an intense inflammatory process was also present. CONCLUSIONS: Our findings suggest that in the initial phases of skin changes due to venous disease, pigmentation is attributable to melanin. Haemosiderin seems to play a role in the evolution of skin changes toward lipodermatosclerosis and ulceration. Erythrocyte diapedesis is likely to occur only during acute phases of the inflammatory process. Further investigations are needed to explain the cause and the exact cellular and molecular mechanisms responsible for hypermelanisation occurring in early phases of skin changes in CVI.

[Duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs: UIP consensus document - Parte II: anatomy]. / Investigação eco-doppler das veias dos membros inferiores na doenca venosa cronica: Documento de Consenso da UIP - Parte II: anatomia.

OBJECTIVES: Duplex ultrasound investigation has become the reference standard in assessing the morphology and haemodynamics of the lower limb veins. The project described in this paper was an initiative of the Union Internationale de Phlébologie (UIP), The aim was to obtain a consensus of international experts on the methodology to be used for assessment of anatomy of superficial and perforating veins in the lower limb by ultrasound imaging. DESIGN: Consensus conference leading to a consensus document. METHODS: The authors performed a systematic review of the published literature on duplex anatomy of the superficial and perforating veins of the lower limbs; afterwards they invited a group of experts from a wide range of countries to participate in this project. Electronic submissions from the authors and the experts (text and images) were made available to all participants via the UIP website. The authors prepared a draft document for discussion at the UIP Chapter meeting held in San Diego, USA in August 2003. Following this meeting a revised manuscript was circulated to all participants and further comments were received by the authors and included in subsequent versions of the manuscript. Eventually all participants agreed the final version of the paper. RESULTS: The experts have made detailed recommendations concerning the methods to be used for duplex ultrasound examination as well as the interpretation of images and measurements obtained. This document provides a detailed methodology for complete ultrasound assessment of the anatomy of the superficial and perforating veins in the lower limbs. CONCLUSIONS: The authors and a large group of experts have agreed a methodology for the investigation of the lower limbs venous system by duplex ultrasonography, with specific reference to the anatomy of the main superficial veins and perforators of the lower limbs in healthy and varicose subjects.

Duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs--UIP consensus document. Part II. Anatomy.

BACKGROUND: Duplex ultrasound investigation has become the reference standard in assessing the morphology and haemodynamics of the lower limb veins. The project described in this paper was an initiative of the Union Internationale de Phlébologie (UIP). The aim was to obtain a consensus of international experts on the methodology to be used for assessment of anatomy of superficial and perforating veins in the lower limb by ultrasound imaging. METHODS: The authors performed a systematic review of the published literature on duplex anatomy of the superficial and perforating veins of the lower limbs; afterwards they invited a group of experts from a wide range of countries to participate in this project. Electronic submissions from the authors and the experts (text and images) were made available to all participants via the UIP website. The authors prepared a draft document for discussion at the UIP Chapter meeting held in San Diego, USA in August 2003. Following this meeting a revised manuscript was circulated to all participants and further comments were received by the authors and included in subsequent versions of the manuscript. Eventually, all participants agreed the final version of the paper. RESULTS: The experts have made detailed recommendations concerning the methods to be used for duplex ultrasound examination as well as the interpretation of images and measurements obtained. This document provides a detailed methodology for complete ultrasound assessment of the anatomy of the superficial and perforating veins in the lower limbs. CONCLUSIONS: The authors and a large group of experts have agreed a methodology for the investigation of the lower limbs venous system by duplex ultrasonography, with specific reference to the anatomy of the main superficial veins and perforators of the lower limbs in healthy and varicose subjects.

Sentinel lymph node biopsy for high risk cutaneous squamous cell carcinoma: case series and review of the literature.

AIMS: Cutaneous squamous cell carcinoma (SCC) is the second most common skin cancer. The metastatic potential is generally low. However, there are subgroups of patients at higher risk, for whom sentinel lymph node biopsy (SLNB) might be useful. SLNB might allow the timely inclusion of high risk patients in more aggressive treatment protocols, sparing at the same time node-negative patients the morbidity of potentially unnecessary therapy. Our aim was to introduce the concept of SLNB for patients with high risk cutaneous SCC. PATIENTS AND METHODS: We examined a consecutive series of high risk cutaneous SCC patients undergoing SLNB at our large dermatological hospital, and performed a literature review and pooled analysis of all published cases of SLNB for cutaneous SCC. RESULTS: Among the 22 clinically node-negative patients undergoing SLNB at our hospital, one patient (4.5%) showed a histologically positive sentinel node and developed recurrences during follow-up. Sentinel node-negative patients showed no metastases at a median follow-up of 17 months (range: 6-64). The incidence of positive sentinel nodes in previous reports ranged between 12.5% and 44.4%. Pooling together patients from the present and previous studies (total 83 patients), we calculated an Odds Ratio of 2.76 (95% CI 1.2-6.5; p=0.02) of finding positive sentinel nodes for an increase in tumor size from <2 cm to 2.1-3 cm to >3 cm. CONCLUSIONS: Our case series and the pooled analysis support the concept that SLNB can be performed for high risk cutaneous SCC. Prospective multicenter studies are needed to examine the role, utility and cost-effectiveness of SLNB for this population.

Valves in small veins and venules.

It is commonly believed that valves are absent in veins smaller than two millimetres in diameter. Consequently, current investigations on the pathophysiology of chronic venous disease (CVD) consider and evaluate only the valvular competence of large veins. The authors review literature from their own collections as well as from medical database searches to assess the functional relevance of these valves. Microscopic venous valves (MVVs) were first described in 1934 in the human digits and have subsequently been demonstrated in other parts of the human body as well as in many tissues and organs of animals. Their location and arrangement suggests that MVVs prevent blood reflux in small sized veins and restrict flow from postcapillary venules back into the capillary bed. This haemodynamic role of MVVs is strongly supported by the clinical finding that grafting skin rich in MVVs results in long-lasting healing leg ulcers attributable to CVD. The huge body of knowledge available concerning MVVs urges us to correct textbooks of anatomy. Studies on the pathophysiology of CVI should acknowledge that the valvular "chain" is not limited to large veins, but extends down to the venular level where MVVs play an important role in venous haemodynamics.

Duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs--UIP consensus document. Part II. Anatomy.

OBJECTIVES: Duplex ultrasound investigation has become the reference standard in assessing the morphology and haemodynamics of the lower limb veins. The project described in this paper was an initiative of the Union Internationale de Phlébologie (UIP), The aim was to obtain a consensus of international experts on the methodology to be used for assessment of anatomy of superficial and perforating veins in the lower limb by ultrasound imaging. DESIGN: Consensus conference leading to a consensus document. METHODS: The authors performed a systematic review of the published literature on duplex anatomy of the superficial and perforating veins of the lower limbs; afterwards they invited a group of experts from a wide range of countries to participate in this project. Electronic submissions from the authors and the experts (text and images) were made available to all participants via the UIP website. The authors prepared a draft document for discussion at the UIP Chapter meeting held in San Diego, USA in August 2003. Following this meeting a revised manuscript was circulated to all participants and further comments were received by the authors and included in subsequent versions of the manuscript. Eventually, all participants agreed the final version of the paper. RESULTS: The experts have made detailed recommendations concerning the methods to be used for duplex ultrasound examination as well as the interpretation of images and measurements obtained. This document provides a detailed methodology for complete ultrasound assessment of the anatomy of the superficial and perforating veins in the lower limbs. CONCLUSIONS: The authors and a large group of experts have agreed a methodology for the investigation of the lower limbs venous system by duplex ultrasonography, with specific reference to the anatomy of the main superficial veins and perforators of the lower limbs in healthy and varicose subjects.

The "interfascial" veins of the lower limbs.

The veins of the lower limb are commonly divided in deep and superficial ones according to their position with respect to the Muscular Fascia (MF). Anatomical textbooks affirm that all superficial veins are thin walled vessels that run in a yielding layer of fat. Accordingly, no differences between saphenous Veins (SVs) and their tributaries (TVs) are reported by physiologists and pathophysiologists. On the contrary, the SVs do not correspond to the classic anatomic, physiologic and clinical descriptions of the "superficial" veins. In fact, the SVs: 1) are not superficial because they course between the SF and the MF; 2) they are not thin vessels, being their wall thick and rich in muscular cells; 3) they actively contribute to the complex mechanisms of venous return from the lower limbs; and finally, 4) they are quite resistant to hypertension and usually afflicted with limited varicose changes. As a consequence, the SVs should not be longer considered "real" superficial veins and the venous bed of the lower limb would be better represented by a three-layered model.

Segmental hypoplasia of the great saphenous vein and varicose disease.

OBJECTIVES: Primitive narrowing of great saphenous vein segments (saphenous hypoplasia) has been described in healthy limbs. The aim of the present study was to detect great saphenous vein segmental hypoplasia in limbs with varicose veins and to evaluate the local anatomical and haemodynamic patterns. MATERIALS AND METHODS: The incidence of saphenous hypoplasia and the local haemodynamic rearrangement were evaluated by duplex ultrasonography in 676 normal limbs and in 320 limbs with varicose veins. RESULTS: Segmental hypoplasia was demonstrated in 84 normal limbs and in 79 limbs with saphenous reflux. In the latter, the retrograde flow leaves the GSV at the proximal end of the hypoplastic segment to feed tributary veins. CONCLUSIONS: Saphenous hypoplasia occurs in varicose limbs more frequently than in healthy ones (p= >0.001). It greatly influences the path of the reflux and the anatomy of the varicose veins. GSV segmental hypoplasia can be detected preoperatively by duplex ultrasonography. Its occurrence may influence surgical management for two main reasons: in about 68% of varicose limbs with segmental hypoplasia, the distal GSV is competent. If the distal GSV is varicose, its size and flow direction is normalised by treating the accessory vein that bypasses the hypoplastic segment.