Josep Palou

Tumour lymphangiogenesis is a possible predictor of sentinel lymph node status in cutaneous melanoma: a case–control study

Background: Cutaneous melanoma spreads preferentially through the lymphatic route and sentinel lymph node (SLN) status is regarded as the most important predictor of survival. Aims: To evaluate whether tumour lymphangiogenesis and the expression of vascular endothelial growth factor C (VEGF-C) is related to the risk of SLN metastasis and to clinical outcome in a case–control series of patients with melanoma. Methods: Forty five invasive melanoma specimens (15 cases and 30 matched controls) were investigated by immunostaining for the lymphatic endothelial marker D2-40 and for VEGF-C. Lymphangiogenesis was measured using computer assisted morphometric analysis. Results: Peritumorous lymphatic vessels were more numerous, had larger average size, and greater relative area than intratumorous lymphatics. The number and area of peritumorous and intratumorous lymphatics was significantly higher in melanomas associated with SLN metastasis than in non-metastatic melanomas. No significant difference in VEGF-C expression by neoplastic cells was shown between metastatic and non-metastatic melanomas. Using logistic regression analysis, intratumorous lymphatic vessel (LV) area was the most significant predictor of SLN metastasis (p = 0.04). Using multivariate analysis, peritumorous LV density was an independent variable affecting overall survival, whereas the intratumorous LV area approached significance (p = 0.07). Conclusions: This study provides evidence that the presence of high peritumorous and intratumorous lymphatic microvessel density is associated with SLN metastasis and shorter survival. The intratumorous lymphatic vessel area is the most significant factor predicting SLN metastasis. The tumour associated lymphatic network constitutes a potential criterion in the selection of high risk patients for complementary treatment and a new target for antimelanoma therapeutic strategies.

Development of a two-step method for the diagnosis of melanoma by reflectance confocal microscopy

BACKGROUND Reflectance confocal microscopy (RCM) has been shown to improve accuracy in the differentiation of nevus from melanoma, but only a few studies have evaluated both melanocytic lesions (ML) and non-ML. OBJECTIVE We sought to develop an algorithm for the in vivo diagnosis of skin tumors by RCM. METHODS In 143 patients we evaluated 154 skin tumors (100 melanocytic, 54 nonmelanocytic) by RCM before their excision. We analyzed RCM features on stored images and performed univariate and multivariate analyses to determine the association of RCM features with tumor types. RESULTS Four confocal features differentiated ML from non-ML: cobblestone pattern of epidermal layers, pagetoid spread, mesh appearance of the dermoepidermal junction, and the presence of dermal nests. Within ML, the presence of roundish suprabasal cells and atypical nucleated cells in the dermis was associated with melanoma, and the presence of edged papillae and typical basal cells was associated with nevi. Based on the correlation of RCM features with dermatoscopy and histology, we developed a two-step algorithm for the diagnosis of skin tumors by RCM. LIMITATIONS This is a preliminary study, and the results must be validated in further studies with a larger number of cases. CONCLUSION RCM appears to be helpful in improving the presurgical diagnosis of difficult skin tumors.

In Vivo Microscopic Features of Nodular Melanomas Dermoscopy, Confocal Microscopy, and Histopathologic Correlates

OBJECTIVE To characterize nodular melanoma (NM) using dermoscopy, in vivo reflectance-mode confocal microscopy, and histopathologic analysis. DESIGN Consecutive pure NMs and superficial spreading melanomas (SSMs) with nodular or blue areas were studied using dermoscopy and confocal microscopy, and a correlation with histopathologic findings was performed. MATERIALS Ten NMs, 10 SSMs with a nodular area, and 10 SSMs with a blue palpable but not yet nodular area. MAIN OUTCOME MEASURE Confocal differences within the nodular component between pure NMs and SSMs with a nodular area, hypothesizing different biological behaviors. RESULTS Whereas NMs had predominantly nonspecific global dermoscopic patterns, SSMs exhibited a multicomponent pattern and higher dermoscopic scores. Globules, blue-white veil, atypical vessels, and structureless areas were frequent in NMs and in nodular areas from SSMs. At confocal microscopy, NMs exhibited few pagetoid cells within a typical epidermal architecture in the superficial layers in most cases, differing from SSMs frequently characterized by epidermal disarrangement and pagetoid infiltration. At the dermoepidermal junction, dermal papillae were rarely seen in nodular areas both from NMs and from SSMs, frequently substituted by nonaggregated atypical cells distributed in sheetlike structures. In the upper dermis, all groups exhibited plump bright cells, dense dishomogeneous cell clusters, and atypical nucleated cells, whereas cerebriform clusters were characteristic of NMs. Conclusion Distinctive dermoscopic and confocal features seen in NMs compared with SSMs are helpful in making the diagnosis and suggest different biological behavior.

Impact of in vivo reflectance confocal microscopy on the number needed to treat melanoma in doubtful lesions

The number needed to treat (NNT) ratio is an effective method for measuring accuracy in melanoma detection. Dermoscopy reduces the number of false positives and subsequently unnecessary excisions. In vivo reflectance confocal microscopy (RCM) is a noninvasive technique that allows examination of the skin with cellular resolution.

New Dermoscopic Pattern in Actinic Keratosis and Related Conditions

T HE LESIONS SHOWN IN THIS ARTICLE ARE from the upper lip of an 85-year-old woman (Figure 1, inset), the malar of a 67-year-old man (Figure 2, inset), and the forehead of a 56-year-old man (Figure 3, inset). They correspond to actinic keratosis (AK) (case 1), lichenoid AK (case 2), and squamous cell carcinoma that developed on an AK (case 3). Polarized contact dermoscopy of all 3 lesions revealed a pattern called a rosette sign (Figures 1-3, arrows), a term coined by Lester Cowell, MD, and is characterized by 4 white points arranged as a 4-leaf clover (Figure 4) mainly localized inside the follicular openings. Histologically, the rosette sign may correspond to changes of orthokeratosis and parakeratosis (flag sign) (Figure 5 [case shown in Figure 3]). It is occasionally seen in AK and related conditions and could help in their diagnosis. It does not appear in nonpolarized contact dermoscopic images and may therefore represent a tissue and polarized light phenomenon.

Sézary Syndrome and Related Variants of Classic Cutaneous T-cell Lymphoma. A Descriptive and Prognostic Clinicopathologic Study of 29 Cases*

Large series of patients with Sézary syndrome (SS), the leukemic variant of cutaneous T-cell lymphoma (CTCL), have been reported infrequently because of its low incidence. Here we recorded several clinical, histopathological and immunophenotypical features of 29 cases of leukemic CTCL patients from four Dermatology Departments of Catalonia, Spain, and analyzed their prognostic value. Clinical data included sex, age, delay of SS diagnosis, previous diagnosis of lymphoma, B-symptoms, type of skin lesions, peripheral adenopathy, histologic evaluation of lymph node biopsy, visceral involvement, percentage of circulating Sézary cells, serum LDH and beta-2-microglobulin levels, first treatment and response, disease-free interval, further therapies and survival. Histopathological data examined were epidermotropism, depth and thickness of the infiltrate, cell size, adnexal involvement, presence of granuloma, eosinophils and plasma cells, mitotic rate. The percentage of CD45Ro, CD43, CD20, CD30 and CD8 positive dermal cells were also recorded. Survival showed a mean actuarial risk of 57% at 3 years and 38% at 5 years, with a median survival of 48 months. Analysis of actuarial survival demonstrated as following as features linked with a bad prognosis: fast evolution of the disease (from symptoms onset up to diagnosis) (p =0.0274) raised levels of serum lactate dehydrogenase (p =0.0379) and beta-2-microglobulin (p =0.0151), the latter being the most important prognostic factor. In conclusion although SS had been traditionally considered as a low-grade lymphoma, the present study agrees with the recent classification rating SS as an aggressive type of CTCL with a poor prognosis. Our results show that some simple clinical and blood test data can be useful as prognostic indicators in this disease.

Early Stages of Melanoma on the Limbs of High-risk Patients: Clinical, Dermoscopic, Reflectance Confocal Microscopy and Histopathological Characterization for Improved Recognition

Early stages of 36 melanomas on limbs were morphologically characterised. Most occurred in high-risk patients (multiple and/or familial melanoma) attending a referral unit for melanoma and pigmented lesions. None of the tumours was clinically suspicious for melanoma (mean diameter of 4.3 mm). The tumours were classified into four dermoscopic groups: (i) prominent network (n = 16); (ii) delicate network (n = 5); (iii) hypo-pigmentation with dotted vessels (n = 10); and (iv) diffuse light pigmentation with perifollicular pigmentation (n = 5). Confocal microscopy performed in 12 cases allowed the identification of atypical, single cells within epidermal layers. Histopathology showed marked large atypical cells in a pagetoid spreading pattern in most cases. Significant associations were detected between the third dermoscopic group and naevoid histological appearance and delay in detection, and between the fourth group and lentigo-maligna-like features. Dermoscopy allowed an increase in the suspicious threshold in these difficult melanomas in high-risk patients and enabled the subclassification of early melanomas on the limbs, with a correct confocal and histopathological correlation. Although the biological behaviour of these incipient tumours remains uncertain, the most appropriate treatment seems to be recognition and proper excision.

Mid-arm Sentinel Lymph Nodes Showing Surprising Drainage From a Malignant Melanoma in the Forearm

A 51-year-old man with a malignant melanoma in his left forearm was studied to detect the sentinel lymph node and to assess the possibility of micrometastases in regional lymph nodes. Lymphoscintigraphy demonstrated two sentinel lymph nodes in the midarm. Two other nodes in the same location as well as in the left axilla were also observed. The exact location of the sentinel lymph nodes was identified with a gamma-ray detector. At the time of surgery, blue dye was injected around the primary lesion and the two sentinel lymph nodes on the inner side of the left arm were resected. Both lymph nodes were pigmented black. The histopathologic study demonstrated metastases from malignant melanoma in both nodes. This case reflects the main role of lymphoscintigraphy in identifying draining lymph nodes in unusual locations as observed in this patient.

Treatment of patients with progressive unresectable metastatic melanoma with a heterologous polyvalent melanoma whole cell vaccine

Unresectable metastatic melanoma has no elective treatment. Neither chemotherapy, intravenous IL‐2 nor biochemotherapy clearly improves the overall survival. Recent assays with therapeutic vaccines have been recently yielded promising results. Here, we describe the application, clinical tolerance and antitumoural activity of a heterologous polyvalent melanoma whole cell vaccine in patients with metastatic melanoma. Twenty‐eight AJCC stage III/IV melanoma patients with progressive unresectable metastatic disease were treated with our heterologous polyvalent melanoma whole cell vaccine between July 1, 1998 and July 1, 2002. All patients had already been unsuccessfully treated with high doses of IFN‐α2 and/or polychemotherapy and/or biochemotherapy and/or perfusion of extremities, or could not receive other treatments due to their age or underlying illness. Twenty‐three were assessable. The vaccine was constituted by 10 melanoma cell lines, derived from primary, lymph node and metastatic melanomas. Prior to intradermal inoculation, the cells were irradiated and mixed with BCG, and 50% were treated with DNFB. After a median follow‐up of 19 months, 26% of patients responded: 3 CR (18, 16+, and 26+ months), 2 PR (8 and 22 months) and 1 MR (36+ months). The median survival of the whole group was 20.2 months. None of the 28 patients initially included in the study presented significant toxicity. This vaccination program had specific antitumoural activity in advanced metastatic melanoma patients and was well tolerated. The clinical responses and the median survival of our group of patients, together with the low toxicity of our polyvalent vaccine, suggest that this approach could be applied to earlier metastatic melanoma patients.

PRIMARY LOCALIZED CUTANEOUS AMYLOIDOSIS AND FAMILIAL MEDULLARY THYROID CARCINOMA

We have studied a family with an autosomai dominant Inheritance of primary localized cutaneous amyloidosis (PLCA) and familial medullary thyroid carcinoma (MTC). Ten family members were screened for multiple endocrine neoplasia (MEN) 2; five were found to have MTC and two had C‐cell hyperplasia. None had evidence of phaeochromocytoma or parathyroid abnormalities. Five of these seven patients presented characteristic inter‐scapular hyperpigmented lesions, showing dermal amylold deposits In two of the four patients In which a biopsy was performed. The data are analysed In the light of two recent reports of MEN 2A associated with Identical lesions. We conclude that PLCA should be sought in MTC patients, even If no other endocrinopathies are present. This may be Informative of the familial character of MTC in Index cases and also of the tumour gene status in family members who are being screened