Role of obesity on the thickness of primary cutaneous melanoma.

BACKGROUND: Thick primary cutaneous melanoma (PCM) is associated with older age, male sex, being single, a low educational level, self-detection and general practice detection, nodular melanoma (NM) and acral lentiginous melanoma (ALM) types; and are found in the head-neck and lower limb locations. Obesity plays a direct role on melanoma tumour growth, as it has been shown in animal models, but its role in the thickness of PCM remains unknown. OBJECTIVES: We investigated the impact of obesity on the thickness of invasive PCM. METHODS: A cross-sectional study was performed in a prospective cohort for which we collected several clinical and histological data already known to be associated with thick PCM and the Body Mass Index from new cases of invasive PCM which were referred to the dermatology department in Valence. RESULTS: Four hundred and twenty-seven patients were studied. In an univariate analysis, thick PCM was associated with low educational level, obesity, identification by the patient or the general practitioner (GP), location on the cephalic extremity, in a non-visible area of the body, the NM and ALM type, and an ulceration. In a multivariate analysis, NM, ulceration, topography of the melanoma and identification of the melanoma by the patient or GP were significantly associated with thick melanoma. When including only clinical features in the model, low educational level, mode of melanoma identification and obesity were significantly associated with a risk of thick melanoma. CONCLUSIONS: Obesity is a clinical independent risk factor of thick PCM. For health policies, governments should pay greater attention to detect melanoma in obese patients. Our results encourage the basic research on tumoural growth mechanisms due to obesity in melanoma.

[Recurrent pyoderma gangrenosum-like ulcers induced by oral anticoagulants]. / Ulcérations récidivantes à type de pyoderma grangrenosum induites par les antivitamines K.

BACKGROUND: Other than the classic skin necrosis induced by oral anticoagulants (OAC) in patients with protein C and S deficiencies, other types of OAC induced-skin ulcers are little known. Herein, we describe an original case of recurrent pyoderma gangrenosum (PG)-like ulcers induced by OAC. PATIENTS AND METHODS: A 70-year-old female heart-transplant recipient presented deep, hyperalgesic and quickly-spreading necrotic ulceration of the right leg 6 weeks after starting oral anticoagulant therapy with fluindione. Histological analysis revealed dermal infiltrate containing polynuclear neutrophils, which accords with the histopathological diagnosis of leukocytoclastic vasculitis or PG. Infectious, autoimmune and thrombophilic causes were ruled out. Fluindione was withdrawn and the ulcer healed completely within a month. Six months later, right leg ulceration recurred two weeks after the patient resumed fluindione but healed within 1 month of discontinuation of the drug. An OAC from another chemical family (warfarin) was then introduced, with further recurrence of ulceration after 2 weeks of treatment. DISCUSSION: The chronology of events and the negativity of aetiological explorations allowed a diagnosis to be made of OAC-induced skin ulcer, a rare complication of which the pathophysiology is unclear. This is the first case of PG-like ulcers induced by OAC.

[Pachydermatodactyly associated with plantar pachydermy]. / Pachydermodactylie associée à une pachydermie plantaire.

INTRODUCTION: Pachydermodactyly is a superficial fibromatosis located on the proximal portion of fingers'phalanges and interphalangeal joints. Several types of this disease have been described depending on topography, etiology and pathological associations. We report a typical observation of pachydermodactyly associated with a plantar pachydermy. CASE-REPORT: A 19 year-old man was followed for a psychotic disease, associated with mental retardation. On clinical examination, he showed a typical pachydermodactyly, predominantly located on the second, third and fourth fingers of both hands, associated with recent acrocyanosis. A pachydermic aspect was also observed on the external part of the feet sole. Histopathological analysis was identical on digital and plantar lesions with collagen swelling. These lesions extended into the subcutaneous fat only in the feet. DISCUSSION: This observation is compatible with the most classical form of pachydermodactyly which involves several fingers of both hands, usually in men. Furthermore, the association with a psychiatric disorder and the notion of repeated traumatisms have been frequently reported in the literature. However, acrocyanosis and the important disability observed in our case are unusual. Association with plantar pachydermy has never been reported. The identical histological aspect on finger and feet sole suggests that pachydermatodactyly should be integrated in framework of acral pachydermy.

[Photo-induced sarcoidosis]. / Sarcoïdose photodéclenchée.

INTRODUCTION: Among the multiple forms of clinically atypical cutaneous sarcoidosis, lesions limited to light-exposed areas are rare. We describe a fourth observation. CASE REPORT: A phototype V 51-year-old woman, born in Tunisia presented with papular erythema on the face. Treatment with topical steroids did not result in any improvement. Biopsy specimen revealed a non caseating granuloma according with sarcoidosis. Assessment for systemic sarcoidosis was negative. Phototesting showed no abnormalities. The patient was successfully treated with chloroquine. DISCUSSION: Only three similar observations are reported in the literature. The role of light exposure despite the negative phototesting seems to be real. The tallying of these four observations permits one to isolate photo-induced sarcoidosis as a single entity.

[Sub-total hereditary leukonychia, histopathological and electron microscopy study of "milky" nails]. / Leuconychie héréditaire subtotale. Etude histopathologique et ultrastructure des ongles "laiteux".

INTRODUCTION: Leuconychia is the most common of ungueal discoloration or dyschromia. The hereditary form, sub-total or total, is very rare. We report the observation of a family in which thirteen members, distributed over four generations, presented a partial or subtotal leukonychia of all nails. On the basis of this observation and histopathological analysis of the propositus nail, we discuss the different hypotheses proposed to account for white nails. OBSERVATION: A 45 year-old man without previous medical history, showed partial or sub-total leukonychia of his twenty nails. Clinical examination revealed soft nails with slow growth. Discoloration or dyschromia was associated with koilonychia on the fingers without other cutaneous or visceral abnormalities. A longitudinal biopsy of the whole ungueal apparatus of the large toe was performed. Histopathological analysis showed parakeratosis and an abnormal granular layer thickened on the proximal and ventral womb. These abnormalities were responsible for heterogeneous HES coloration, lamellar and dissociated aspect of the nail plates. Electron microscopy revealed dissociated keratin bundles and the existence of intracytoplasmic clear vacuoles probably of lipid origin. This aspect was observed on the proximal part of the dorsal tablet and disappeared in the distal portion of the nail. DISCUSSION: According to Newton's theorem, a surface appears white when it reflects all the radiation of visible light. This mechanism can be proposed to explain leukonychia. On histological level, parakeratosis and dissociation of the keratin bundles may play a role in the modification of the solar light reflection by ungueal plates. In our case, parakeratosis and disorganization of keratin bundles were present in the white part of the nail, but also in the distal, pinkish crescent (distal dorsal plate). Electron microscopy analysis showed clear vacuoles located in the white part of the nail, whereas they were not seen in the distal part. These observations confirm the probable participation of parakeratosis and keratin abnormalities in this pathology but also suggest an important role of lipid vacuoles. Therefore, some white nails may in fact be "milky" nails. Finally, disorganization of the keratin bundles observed, was also reported in other genodermatosis e.g.: epidermolysis bullosa simplex. In this latter pathology, some hard keratin genes mutations (K5 and K14) have been demonstrated. According to these results, a genetic study is on going in this family in order to search for a mutation in one of the hard keratin genes.

Lymphomatoid papulosis: a localized form with acral pustular involvement.

We report a localized form of lymphomatoid papulosis (LyP) presenting as pustular papules of the hands. The histopathology revealed a moderate inflammatory infiltrate composed of atypical pleomorphic large lymphocytes with atypical mitosis and large nuclei. Epidermotropism could be observed. These atypical cells expressed CD4 and CD30. Laboratory examinations and bone marrow explorations remained negative. The clinical presentation of this case of LyP is unusual. Only histopathological features allowed to diagnose LyP. The knowledge that LyP may be associated with neoplasia or lymphoma underlines the need for a long-term follow-up of these patients.

Interleukin 15 skews monocyte differentiation into dendritic cells with features of Langerhans cells.

Langerhans cells (LCs) represent a subset of immature dendritic cells (DCs) specifically localized in the epidermis and other mucosal epithelia. As surrounding keratinocytes can produce interleukin (IL)-15, a cytokine that utilizes IL-2Rgamma chain, we analyzed whether IL-15 could skew monocyte differentiation into LCs. Monocytes cultured for 6 d with granulocyte/macrophage colony-stimulating factor (GM-CSF) and IL-15 differentiate into CD1a(+)HLA-DR(+)CD14(-)DCs (IL15-DCs). Agents such as lipopolysaccharide (LPS), tumor necrosis factor (TNF)alpha, and CD40L induce maturation of IL15-DCs to CD83(+), DC-LAMP(+) cells. IL15-DCs are potent antigen-presenting cells able to induce the primary (mixed lymphocyte reaction [MLR]) and secondary (recall responses to flu-matrix peptide) immune responses. As opposed to cultures made with GM-CSF/IL-4 (IL4-DCs), a proportion of IL15-DCs expresses LC markers: E-Cadherin, Langerin, and CC chemokine receptor (CCR)6. Accordingly, IL15-DCs, but not IL4-DCs, migrate in response to macrophage inflammatory protein (MIP)-3alpha/CCL20. However, IL15-DCs cannot be qualified as "genuine" Langerhans cells because, despite the presence of the 43-kD Langerin, they do not express bona fide Birbeck granules. Thus, our results demonstrate a novel pathway in monocyte differentiation into dendritic cells.

Cross-priming of naive CD8 T cells against melanoma antigens using dendritic cells loaded with killed allogeneic melanoma cells.

The goal of tumor immunotherapy is to elicit immune responses against autologous tumors. It would be highly desirable that such responses include multiple T cell clones against multiple tumor antigens. This could be obtained using the antigen presenting capacity of dendritic cells (DCs) and cross-priming. That is, one could load the DC with tumor lines of any human histocompatibility leukocyte antigen (HLA) type to elicit T cell responses against the autologous tumor. In this study, we show that human DCs derived from monocytes and loaded with killed melanoma cells prime naive CD45RA(+)CD27(+)CD8(+) T cells against the four shared melanoma antigens: MAGE-3, gp100, tyrosinase, and MART-1. HLA-A201(+) naive T cells primed by DCs loaded with HLA-A201(-) melanoma cells are able to kill several HLA-A201(+) melanoma targets. Cytotoxic T lymphocyte priming towards melanoma antigens is also obtained with cells from metastatic melanoma patients. This demonstration of cross-priming against shared tumor antigens builds the basis for using allogeneic tumor cell lines to deliver tumor antigens to DCs for vaccination protocols.

A new Mr 55,000 surface protein implicated in melanoma progression: association with a metastatic phenotype.

Emergence of the invasive phenotype is a key event in the progression of human melanoma from benign proliferative lesions to malignant lesions. Recently we successfully selected in vivo from a poorly metastatic M4Beu. human melanoma cell line two variants (7GP and T1P26) that generate a higher frequency of spontaneous metastases to the lungs into immune-suppressed neonatal rats. Both cell lines showed no significant differences in the integrin profile of the subunits analyzed except for beta3, which was reduced to a background level in metastatic variants. To investigate how these variant sublines of human melanomas manage to sustain growth in the absence of alpha(v)beta3, a subtractive immunization approach was used to elicit host antibody response against cell surface proteins expressed on metastatic variants. In this study, a new monoclonal antibody (MoAb), LY1, that is highly specific for the 7GP and T1P26 variants, was isolated. LY1 identifies a membrane protein of Mr 55,000 on melanoma variants with epitopes that were resistant to sugar-cleaving enzymes. Immunostaining cells from variants by LY1 showed that staining is distributed to the cell periphery with high labeling intensity at the cell-to-cell contact points. This MoAb significantly inhibited invasion of metastatic variants through a reconstituted basement membrane (Matrigel) in vitro. Moreover, tumor growth of melanoma variants was dramatically affected in vivo with this MoAb. In vitro studies indicate that the LY1 MoAb does not inhibit chemotactic migration of the metastatic variants, the adhesion of tumor cells to vitronectin, collagen IV, fibronectin, and laminin, or cell proliferation. Expression of this antigen is high in human striated muscle, heart, spleen, brain, and lung and absent in kidney, liver, and pancreas. Using 59 fixed, paraffin-embedded archival tissues of human melanomas and nevi, LY1-reactive cells were not observed in melanocytes, nevi, or radial growth phase primary melanomas. In sharp contrast, LY1 selectively stained melanocytes derived from the vertical growth phase of many primary melanomas and metastatic melanomas. These results provide evidence that the Mr 55,000 protein expressed by selected variants with increased metastatic properties in vivo plays a functionally important role in determining metastasis. This molecule may represent a new metastatic risk marker in human melanoma and may be of biological importance in the identification of fatal metastatic subpopulations that have acquired competence for metastasis production.

The study of cutaneous melanomas in Camargue-type gray-skinned horses (1): clinical-pathological characterization.

The clinical and pathological characteristics of cutaneous melanomas occurring in Camargue-type gray-skinned horses are reported. Examination of 83 tumor-bearing horses revealed that the tumors occurred most frequently underneath the tail (93.9%) and at high rates in the peri-anal region (43.0%), the lips (33.0%), and the eyelids (24.0%), but rarely in the vulva (3.8%). Tumorous lesions were characterized by the presence of either hemispheric nodules or large infiltrated plaques, or their combinations. Microscopic examination indicated that tumorous lesions were composed mostly of melanocytes and numerous melanophages and that component cells manifested a remarkable cellular atypia with anisocytosis and anisokarinosis. Pathological examination of lesions corresponding to earlier stages of the tumors disclosed that tumor formation and its related melanogenesis occurred in close topographical association with apocrine sweat glands, but not at the dermal-epidermal junction. Larger nodules of the tumors were often composed of a concentric deposition of cell layers, each being separated by dermal components from the epidermis. Because of the absence of their tropism toward the epidermis and their multiloculation, horse melanomas are considered to be different in their pathological characteristics from human melanomas.

The study of cutaneous melanomas in Camargue-type gray-skinned horses (2): epidemiological survey.

An epidemiological survey was made on cutaneous melanomas occurring in Camargue-type, gray-skinned horses in southern France. The population investigated was composed of 264 horses, which were selected from the Camargue horse stud registry and were allowed to be examined by the owners. The presence of tumors was inspected macroscopically according to the standardized protocols of veterinary medicine specialists, and some tumors were subjected to macroscopic histopathological examination. The results indicated that: 1) the prevalence of melanomas in the overall population was 31.4%; 2) the odds ratio was obtained for an age class of 5-9 years, in which most melanomas were presumed to occur; 3) the incidence of melanomas was significantly correlated with age, giving a prevalence of 67% at ages > 15 years; 4) the size and number of tumorous lesions were significantly related to age; 5) little correlation was observed between melanoma incidence and gender; and 6) the most frequently occurring body site of these tumors was underneath the tail. Because of their frequent occurrence in shaded body regions, sun exposure was not likely to be a risk factor for melanoma formation in these horses. In view of the slightly darker skin pigmentation in these horses at younger ages, the unique characteristics of their melanocytes may be associated with melanoma formation.

Cytoplasmic accumulation of peanut agglutinin-binding glycoconjugates in the cells of primary melanoma correlates with clinical outcome.

In an experimental model, human melanoma cell lines enriched for cells that express the glycoconjugate B-D galactose N-acetyl-D-galactosamine, which reacts with the peanut agglutinin lectin (PNA), are associated with an increase in the frequency of metastases. We previously showed that this glycoconjugate is expressed on the cells of some primary melanomas in humans and that such cells are found selectively in melanomas with a high risk for developing metastases and causing death. Using fixed archival tissues from 99 primary melanomas and lectin histochemistry, we found 65 tumors that contained melanoma cells that were PNA-positive. PNA-reactive cells were not identified in normal melanocytes or in the nevocytes of 24 nevi. PNA-reactive material accumulates adjacent to the nucleus in the area of the Golgi apparatus, initially as a tiny dot, but later in quantities sufficient to displace and indent the nucleus, producing a signet ring cell-like appearance. Tumor cells containing PNA-reactive material were associated with more evolved, deeper, and thicker tumors. Two melanomas up to Clark level II were PNA positive (20%), compared with 60% of level III, 76% of level IV, and 100% of level V. Five of 13 tumors less than 0.76 mm thick (39%) were positive, compared with 50% of tumors 0.76 to 1.49 mm thick, 64% of tumors 1.5 to 2.99 mm thick, and 85% of tumors 3 mm thick or thicker. PNA-reactivity was negatively correlated with disease-free survival (PNA-negative, 49.2+/-23 months; PNA-positive grade 1, 41.6+/-26 months and PNA-positive grade 2, 24.4+/-23 months), survival rate 5 years after initial treatment (PNA-negative, 84.8%; PNA-positive grade 1, 63.8%; and PNA-positive grade 2, 31.3%) and disease-free survival at 5 years after initial treatment (PNA-negative, 69.7%; PNA-positive grade 1, 53.2%; and PNA-positive grade 2, 25%).

[Solitary schwannoma of the balanopreputial sulcus]. / Schwannome solitaire du sillon balano-préputial.

INTRODUCTION: Solitary schwannoma is usually located in the head area and the limbs. We report a case of benign solitary schwannoma of the retroglandular sulcus of the glans penis. CASE REPORT: A 64-year-old man had developed over the past year an asymptomatic nodule arising from the retroglandular sulcus of the glans penis. The nodule was removed surgically and histopathological study showed benign schwannoma. There was no association with neurofibromatosis or schwannomatosis. DISCUSSION: Benign solitary schwannoma of the penis is rare. It is most often located on the dorsal shaft of the penis in a young adult. Surgical excision is required. Malignant schwannoma of the penis is very rarely reported.

Generalized granuloma annulare and hepatitis B vaccination.

As hepatitis B vaccination is becoming generalized in Europe, cutaneous adverse events are being more frequently reported in the literature. We report the first case of generalized granuloma annulare following hepatitis B immunization. A 51-year-old woman presented a generalized granuloma annulare one month after the one-year booster injection of the hepatitis B vaccine. The lesions resolved with sulfone therapy. We observed an identical recurrence three weeks after the five-year booster.