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The development of immune checkpoint inhibitors (monoclonal antibodies targeting PD-1/PD-L1 or CTLA-4) represents a significant advance in the treatment of multiple cancers. Given their particular mechanism of action, which involves triggering CD4+/CD8+ T-cell activation and proliferation, they are associated with a specific safety profile. Their adverse events are primarily immune-related, and can affect practically all organs. In this context, dermatological toxicity is the most common, though it mostly remains mild to moderate and does not require discontinuation of treatment. More than a third of patients are faced with cutaneous adverse events, usually in the form of a maculopapular rash, pruritus or vitiligo (only in patients treated for melanoma). Much more specific dermatologic disorders, however, may occur such as lichenoid reactions, induced psoriasis, sarcoidosis, auto-immune diseases (bullous pemphigoid, dermatomyositis, alopecia areata), acne-like rash, xerostomia, etc. Rigorous dermatological evaluation is thus mandatory in the case of atypical, persistent/recurrent or severe lesions. In this article, we review the incidence and spectrum of dermatologic adverse events reported with immune checkpoint inhibitors. Finally, a management algorithm is proposed.

Introduction The management of metastatic cutaneous melanoma is changing, marked by innovative therapies. However, their respective use and place in the therapeutic strategy continue to be debated by healthcare professionals. Objective The French national cancer institute has led a national clinical practice guideline project since 2008. It has carried out a review of these modalities of treatment and established recommendations. Methods The clinical practice guidelines development process is based on systematic literature review and critical appraisal by experts. The recommendations are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines are reviewed by independent practitioners in cancer care delivery. Results This article presents the results of bibliographic search, the conclusions of the literature and the recommendations concerning locoregional treatments of brain metastases for patients with metastatic cutaneous melanoma.

Introduction la mise a disposition recente de nouvelles molecules pour le traitement du melanome cutane metastatique avec un benefice significatif sur la survie des patients souleve aupres des professionnels de sante des interrogations quant a leur utilisation et place dans la strategie therapeutique.

Chronic HSV infection is a cause of chronic perineal ulcerations. We report a case of a chronic and refractory HSV infection revealing chronic lymphoid leukaemia.An 85-year-old woman with an 8-month history of chronic perineal ulcerations was referred to our dermatology department. She had no previous medical history of herpes infection. Skin biopsies ruled out carcinoma but were consistent with HSV infection. A local swab was positive for HSV2. Treatment with valaciclovir and intravenous acyclovir (ACV) at the recommended doses was ineffective. Laboratory tests revealed type-B chronic lymphoid leukaemia. Molecular biology studies confirmed the presence of ACV-resistant HSV via decreased thymidine kinase activity (stop codon: M183stop). Foscarnet was administered for a period of 3 weeks with almost complete healing of the ulcerations. Treatment was stopped prematurely due to acute renal insufficiency and the remaining lesions were treated using imiquimod cream. Valaciclovir was prescribed to prevent further episodes. The condition recurred a mere 11 months later.The prevalence of ACV-resistant HSV is 0.32 % in immunocompetent patients and 3.5 % in immunocompromised patients. Insufficient dosing regimens or prolonged treatment with TK inhibitors result in the local selection of pre-existing mutant HSV viruses. Foscarnet, a DNA polymerase inhibitor, is the treatment of choice in HSV-resistant infections. ACV-resistant HSV is less virulent and replicates less, with reactivations being mainly due to wild-type HSV latent in the neural ganglia. Valaciclovir can be used as a preventive treatment. To our knowledge, this is the first case of ACV-resistant HSV infection revealing chronic lymphoid leukaemia.Chronic perineal ulcerations can be the first manifestation of immunodeficiency seen for example with haematological diseases. In the event of clinical resistance of an HSV infection to recommended thymidine kinase inhibitor regimens, the use of foscarnet should be considered.

Most post transplantation lymphoproliferative disorders (PTLDs) are Epstein-Barr virus (EBV) associated B cell proliferations. We report a case of aggressive anaplastic large cell lymphoma expressing the anaplastic lymphoma kinase (ALK) protein in a 58 year old man who had previously undergone liver transplantation. A definite diagnosis was not possible on histopathological examination. Immunostaining clearly showed a predominant population of small irregular lymphocytes, admixed with large cells strongly positive for CD30, epithelial membrane antigen, and the ALK protein. Neoplastic cells were of the T/cytotoxic phenotype. In situ hybridisation with EBV encoded early RNA probes showed only a few scattered positive non-neoplastic small lymphocytes. Polymerase chain reaction analysis of immunoglobulin and T cell receptor rearrangements was negative. The NPM–ALK fusion transcript associated with the t(2;5) translocation was detected by reverse transcription polymerase chain reaction. A review of the literature revealed 76 cases of T cell PTLD, showing a broad spectrum of morphological features and clinical behaviour. Most of these cases were EBV negative (61 of 76) and occurred after renal transplantation (48 of 76). To our knowledge, this is the first case of ALK positive lymphoma occurring in the setting of organ transplantation. This observation stresses the need for accurate immunostaining for diagnosing this rare, apparently aggressive, lymphoma in immunosuppressed patients.

We report a case of Sweet's syndrome associated with retinoic acid syndrome in a patient with acute promyelocytic leukemia treated with all- trans retinoic acid (ATRA). Sweet's syndrome appeared on day 6 of ATRA therapy for promyelocytic leukemia. It was associated with a mild retinoic acid syndrome, an inflammatory syndrome occurring in 25% of patients treated with ATRA and characterized by features of capillary leakage with systemic inflammatory signs. The ATRA therapy was discontinued for 11 days and treatment with corticosteroids improved the systemic and cutaneous signs. Only 11 cases of Sweet's syndrome associated with ATRA have been previously reported in the literature, involving only the skin in eight cases, the skin and muscles in two cases, and the lung, kidney, fascia, and muscles in one case. Sweet's syndrome was followed by retinoic acid syndrome in one of these cases. The previously reported cases are reviewed, and the mechanisms of Sweet's and retinoic acid syndromes and the link between them are discussed.

The management of metastatic cutaneous melanoma is changing, marked by innovative therapies. However, their respective use and place in the therapeutic strategy continue to be debated by healthcare professionals.The French national cancer institute has led a national clinical practice guideline project since 2008. It has carried out a review of these modalities of treatment and established recommendations.The clinical practice guidelines development process is based on systematic literature review and critical appraisal by experts. The recommendations are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines are reviewed by independent practitioners in cancer care delivery.This article presents the results of bibliographic search, the conclusions of the literature and the recommendations concerning locoregional treatments of brain metastases for patients with metastatic cutaneous melanoma.

Recent years have seen the emergence of new molecules for the treatment of patients with metastatic cutaneous melanoma, with significant benefits in terms of survival and the opening of new therapeutic perspectives. In addition, many techniques are currently being developed for locoregional treatment of metastatic sites. Management of metastatic melanoma is thus fast-changing and is marked by innovative therapeutic approaches. However, the availability of these new treatments has prompted debate among healthcare professionals concerning their use and their place in therapeutic strategy.Since 2008, the French National Cancer Institute (INCa) has been leading a project to define and diffuse national clinical practice guidelines. It has performed a review of these treatment methods, which it aims to circulate, and it is seeking to develop recommendations in order to allow nationwide implementation of innovative approaches while promoting good use thereof.The clinical practice guidelines development process is based on systematic literature review and critical appraisal by experts within a multidisciplinary working group, with feedback from specialists in cancer care delivery. The recommendations are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines are reviewed by independent practitioners in cancer care delivery.This article presents the national recommendations for first- and second-line systemic treatment and for locoregional treatment of metastatic sites in patients presenting metastatic cutaneous melanoma.

Recent developments and therapeutic use of selective BRAF inhibitors (e.g. dabrafenib and vemurafenib) have significantly improved overall survival and disease-free survival of patients with BRAF V600 mutation-positive metastatic melanoma. Despite their survival benefits, small-molecule inhibitors of BRAF are associated with significant and sometimes severe treatment-related dermatological toxicity. The most common adverse skin reactions include photosensitivity, induced malignant lesions of the skin such as keratoacanthomas, squamous cell carcinoma and new primary melanomas, as well as keratinocyte proliferation and differentiation dysfunctions that can manifest as skin papillomas, hand-foot skin reaction, keratosis pilaris-like rash, acantholytic dyskeratosis and cysts of the milia type. In this article, we describe the clinical and histological features of the cutaneous manifestations induced by vemurafenib and dabrafenib on the basis of our clinical experience and a literature review. The crucial role of dermatologists in patient management is also highlighted.

Hailey-Hailey disease (HHD) is a rare hereditary disease in which the genetic defect is characterized by mutation in the ATP2C1 gene coding for a transmembrane calcium pump. It is generally considered a non-immunologic acantholytic dermatosis in which direct and indirect immunofluorescence studies are negative, unlike in autoimmune pemphigus.We describe a case of HHD associated with antidesmoglein antibodies in a 53-year-old woman. The clinical symptoms and histology were typical of HHD. Antidesmoglein antibody tests were positive on several occasions and a difference was found between the two types of Elisa test performed (positive with the MBL kit, negative with the Euroimmun kit).The positive result for desmoglein antibodies could be due to unmasking of antigens by the mechanism of acantholysis. The specificity of the main desmoglein Elisa tests also requires discussion.

This is the third report of an association between T-cell cutaneous lymphoma (mycosis fungoides) and primary hyperparathyroidism (adenoma). Some studies support the concept that hyperparathyroidism may have promotional activity for the development of certain malignant tumors. A high risk for successive or concurrent neoplasms has been reported in patients with parathyroid adenomas. Primary hyperparathyroidism in a neoplastic context may be underreported. Patients with tumor-associated hypercalcemia should be evaluated for the possibility of primary hyperparathyroidism.

Joint clinical and pathological review meeting exists in most academic dermatology departments.The primary objective of the study was to assess the impact of the joint clinical and pathological review meeting in dermatology on patient care.Prospective descriptive study over 6 months (May to October 2008) on all clinical cases of dermatology reviewed at the joint clinical and pathological review meeting in our University Hospital.A total of 139 cases were reviewed during the 6-month period. In 97 cases (69.8%), the joint clinical and pathological review meeting had a positive impact on final diagnosis and/or on patient management. For 27 cases, a consensus diagnosis different from the initial proposal was established. In 21 cases, the joint clinical and pathological review meeting led to additional investigations or therapeutic proposals. The impact of the joint clinical and pathological review meeting was highest for inflammatory skin diseases.The joint clinical and pathological review meeting is a useful procedure to improve diagnostic accuracy in difficult cases.

Types of subepidermal autoimmune bullous dermatosis (AIBD) are classified by anatomoclinical picture and target antigen. A new entity has recently been identified: anti-p200 pemphigoid.An 82-year-old man consulted for a profuse pruritic bullous eruption refractory to the standard treatments for bullous pemphigoid (BP). Direct immunofluorescence examination of a skin biopsy revealed linear deposits of IgG and of C3 at the dermal-epidermal junction, but Elisa screening for circulating anti-BP180 and anti-BP230 antibodies was negative. Indirect immunofluorescence (IIF) testing of cleaved skin revealed a deposit of IgG4 antibodies on the dermal side. Immunoblotting was negative for a dermal extract but showed an antibody directed against a 200-kD epidermal antigen. A diagnosis of anti-p200 pemphigoid was eventually made and the patient was successfully treated with dapsone.The diagnosis of anti-p200 pemphigoid was made in this case in spite of discrepancy between the IIF and immunoblotting results, and despite the fact that the target antigen in this disease is considered as being restricted to dermal sites. Anti-p200 pemphigoid usually begins in the second part of life and differs from standard bullous pemphigoid in terms of more frequent mucous membrane and cephalic involvement, as well as a greater degree of miliary scarring. This disease appears more prominent in males and is associated with psoriasis in around one third of cases. Autoantibodies recognize laminin gamma-1, an extra-desmosomal protein that contributes to dermal-epidermal adhesion.This recently described disease as probably under-diagnosed in France. It should be considered in atypical presentations of bullous disease. Diagnosis is confirmed by immunoblotting detection of autoantibodies directed against a 200-kD antigen normally present in the extract. Dapsone appears to be the most effective treatment.

Skin manifestations associated with myelodysplastic syndrome (MDS) may reveal bone marrow transformation into acute myeloid leukaemia.The objective of this study was to assess the prevalence of skin manifestations associated with MDS. In addition, we evaluated the risk of acute myeloid leukaemia transformation associated with skin manifestations.We studied a cohort of 157 patients with primary MDS followed up prospectively for a median of 44 months. Skin lesions were prospectively assessed as part of medical examination every 6 months by a board certified dermatologist. Survival analyses were performed to assess the association between the presence of skin lesions and the risk of acute myeloid leukaemia.Fifteen patients (9.55%) experienced skin lesions previously reported as associated with MDS. These were neutrophilic dermatosis (7, 4.46%), specific lesions (5, 3.18%), cutaneous vasculitis (2, 1.27%) and Behçet disease (1, 0.63%). Survival analysis showed that the risk of transformation into acute myeloid leukaemia was slightly but not significantly increased in patients with skin lesions as compared with patients without skin lesions with a relative risk of 2.08 (95% CI 0.92-4.67).The prevalence of skin lesions, mostly neutrophilic dermatosis and specific lesions, is relatively high in patients with MDS. There is a trend for a higher risk of transformation into acute myeloid leukaemia in patients with skin lesions.

scleromyxoedema is characterized by dermal mucin deposition associated with a monoclonal gammopathy. This is a rare disease, mostly reported as isolated cases. There is limited data regarding the course and prognosis of the disease. The aim of this study was to determine the clinical characteristics and course of scleromyxoedema.this was a retrospective study in patients from five French university hospitals between 1987 and 2007. Data were collected using a standardized questionnaire. The inclusion criteria were based on the disease diagnosis criteria proposed by Rongioletti and Rebora: (1) generalized, papular and sclerodermiform skin eruption, (2) mucin deposition in the dermis, fibroblastic proliferation and skin fibrosis, (3) presence of a monoclonal gammopathy, (4) absence of thyroid disease.eight patients were included. The mean age at disease onset was 51.5 years (range: 35-67). The mean time from primary symptoms and diagnosis was 41.6 months (range: 4-120). Seven patients had extra-cutaneous involvement: four with peripheral neuropathy and three with interstitial pneumonia. The mean follow-up time was 9 years. Four patients improved: two experienced partial remission and two complete remission. Complete remission was obtained under treatment with dexamethasone (one patient) and thalidomide (one patient). One patient presented a myeloma and one patient presented encephalopathy leading to death.our study shows the frequency of extra-cutaneous involvement and shows that complete remission occurs in some patients.

Regression has been proposed as a potential marker of dissemination in thin melanomas. Previous studies have shown conflicting results.To determine if regression in melanoma is associated with an increased risk of sentinel lymph node (SLN) metastasis.A cohort analysis was conducted. Data on all patients were collected on a standardized case report form during 10 years. A total of 397 consecutive patients with melanoma who underwent a SLN biopsy were analysed. All cases of melanoma and SLN biopsies were examined by the same two pathologists. Differences between melanomas with and without SLN metastasis were compared using Fisher's exact test or the two-sample t-test and the chi(2) test. Multivariable logistic regression was used to adjust for possible confounding factors.We analysed 397 patients (411 melanomas) who underwent a SLN biopsy. The median Breslow index was 1.8 mm (interquartile range 1.1-3). Regression was observed in 23% (n = 94). SLN metastases were observed in 26% (n = 106). The frequency of SLN metastasis was 16% in melanomas with regression and 29% without regression (P = 0.012). The adjusted odds ratio (OR) for regressive melanoma was 0.9 [95% confidence interval (CI) 0.4-1.9; P = 0.777]. The risk of SLN metastasis was increased in melanoma cases with a Breslow index from 1.5 to2.0 mm (adjusted OR 3.1; 95% CI 1.4-7.1; P = 0.006) andor= 2.0 mm (adjusted OR 3.5; 95% CI 1.7-7.4; P = 0.001) and ulceration of the melanoma (adjusted OR 1.8; 95% CI 1.1-3.2; P = 0.03).Regression is not an independent predictor of the risk of SLN metastasis in melanoma.

While many cases of DRESS reaction to minocycline have been described, few of these involve doxycycline.A 59-year-old woman of African origin was repatriated after a journey to Ghana for hyperthermia with infiltrated maculopapular exanthema, facial oedema (no mucosal involvement) and polyadenopathy. Laboratory tests revealed hypereosinophilia, hepatic cytolysis and mononucleosis syndrome. Cutaneous histology was non-specific. The patient had been taking doxycycline as antimalarial prophylaxis for three weeks before the onset of symptoms. DRESS to doxycycline was diagnosed. Patch-tests with doxycycline three months later proved negative. The patient's HLA phenotype was A3/A30 and B39/B42.An intrinsic causal relationship with doxycycline was likely in this case (I3). Although patch-test sensitivity and specificity with doxycycline remains unknown in DRESS exploration, a negative result does not necessarily rule out the diagnosis. A number of cases of DRESS to doxycycline have been described recently, possibly as a result of more frequent prescription (malarial prophylaxis, acne). Subjects of African ethnicity or having specific HLA phenotypes are at higher risk of developing drug hypersensitivity.This patient is the third case of DRESS to doxycycline described in the literature. The originality of this case lies in the allergological investigation using patch-tests and HLA determination.

A clinical picture of hypodermitis in the lumbar region may reveal an abscess arising from infection due to pyonephrosis. We report a case below.A 58 year-old woman consulted for an area of inflammation in the left lumbar region that had been present for two months. The area of inflammation appeared two days after physiotherapy sessions prescribed for lower back pain. Laboratory examinations revealed inflammation associated with moderate renal failure. A skin biopsy sample taken from around the inflamed area showed septal hypodermitis. Ultrasound examination revealed a pocket of liquid measuring 7 x 2 x 2 cm; Proteus mirabilis was isolated following ultrasound-guided needle aspiration,. Magnetic resonance imaging (MRI) and uroscan revealed pyonephrosis with suffusion into the hypodermis and left lumbar fossa.This was a case of bacterial hypodermitis with abscesses secondary to pyonephrosis. Pyonephrosis may be transferred to the skin, causing fistulas and subcutaneous pus collection. In such rare and potentially misleading clinical settings, the diagnosis can be established by imaging.

Malignant melanoma in children is a rare and poorly understood pathology. We report a case of nodular melanoma that developed on congenital naevus in a 6-month-old infant. The histological results revealed a nodular melanoma on a congenital naevus measuring 6.625 mm in tumour thickness according to Breslow. The infant was treated by broad resection without adjuvant treatment. Follow up is 43 months without metastasis. Malignant melanoma is a rare pathology: 1-4% of all melanomas occur before the age of 20 and 0.3-0.4% of those are before puberty. The risk of degeneration of a congenital naevus into a melanoma is approximately 0.7%. Surgical exeresis must be broad. Up to now, no complementary treatment has proven to be effective. Pre-operative examination for sentinel lymph nodes by lymphography can be of interest although such an examination is difficult in children. The prognosis would appear to be similar to that of malignant melanoma in adults with a high mortality. This is therefore an argument in favour of early treatment and prolonged follow up of children with malignant melanoma.

Localized scleroderma or morphea usually appears as flat or depressed lesions.We report 3 cases of morphea with atypical appearance, alternating pigmented and depigmented patches with nodules or sclerous bands, occurring in adult men.The occurrence of nodular elements on generalized or localized scleroderma, although rare, was first reported in the literature by Addisson in 1884. These nodules usually appear during evolution. These scleroderma are then described as being keloidal or nodular. We report 3 cases of nodules on localized scleroderma which appeared at the beginning of the dermatosis and where the scleroderma had a similar unusual irregularly pigmented appearance.

A B-cell lymphoma, restricted to the skin, developed in a 58-year-old man receiving methotrexate for non-rheumatoid peripheral arthritis, with the simultaneous occurrence of a cytolytic hepatitis and carcinoma of the lung. Two weeks after methotrexate was stopped, both the skin tumour and the hepatitis disappeared spontaneously, with no recurrence during a 12-month follow-up period. Immunoglobulin gene rearrangement was shown by polymerase chain reaction (PCR) but in situ hybridization failed to reveal neoplastic cells positive for Epstein-Barr virus (EBV).

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase, the normal role of which remains to be completely elucidated. Although work carried out in mammals suggests a function in neural development, results from studies in Drosophila indicate an additional role in visceral muscle differentiation. The aberrant expression of full-length ALK receptor proteins has been reported in neuroblastomas and glioblastomas, while the occurrence of ALK fusion proteins in anaplastic large cell lymphoma (ALCL) has resulted in the identification of the new tumor entity, ALK-positive ALCL. ALK represents one of few examples of a receptor tyrosine kinase implicated in oncogenesis in both haematopoietic and non-haematopoietic tumors, given that ALK fusions also occur in the mesenchymal tumor known as inflammatory myofibroblastic tumor (IMT). The study of ALK fusion proteins, besides demonstrating their importance in tumor development, has also raised the possibility of new therapeutic treatments for patients with ALK-positive malignancies.

We report four cases of subcorneal pustular dermatosis or Sneddon-Wilkinson disease. Clinical and histological lesions and immunofluorescence data were presented. This disease is classified among neutrophilic dermatitis.All of four patients presented with clinical and histological lesions compatible with the diagnosis of Sneddon-Wilkinson disease. Indeed, direct and indirect immuno-testing were negative. We noted an association with a benign IgA monoclonal gammapathy in one case and with a seronegative polyarthritis in one other case. Three patients correctly responded to dapsone. One of them after transient improvement was resistant to dapsone and then dramatically responded to etretinate.Subcorneal pustular dermatosis is a chronic disease, rarely described in literature. It's a pustular eruption, involving the trunck, axillae and inguinal holds. It's often associated with monoclonal gammapathy, particulary IgA. Its nosological situation is still contested, especially with IgA pemphigus sharing with it the association with IgA monoclonal gammapathy and the same efficacy of dapsone. We discuss relationships between both diseases.

Neurotropic melanoma is a particular anatomopathological form corresponding to dermal proliferation of desmoplastic cells of neuroid differentiation. We report a new case of neurotropic melanoma revealed by facial neuralgia.A 64 year-old man presented in 1996 with a lentigo maligna on the right cheek treated by complete excision. After 2 years of medical supervision, a pigmented lesion recurred leading to new surgical treatment. The histological examination of the total lesion showed intra-epidermal atypical melanocyte proliferation without dermal invasion. In 1999, right trigeminal neuralgia occurred without associated cutaneous change. Cranial MRI revealed an infiltration of the right trigeminal nerve. Endo-buccal surgery disclosed a black swelling of the trigeminal nerve. Histological examination and immunohistochemistry revealed a desmoplastic melanoma.Neurotropic melanoma with nerve invasion by malignant cells presenting as a trigeminal neuralgia is rare. Our case report underlined the depth of the neurotropic melanoma and the initial existence of a lentigo maligna without associated "neurotropic" melanoma.

In a previous study, we showed that the high level of protein tyrosine phosphorylation present in lymphomas containing an anaplastic lymphoma kinase (ALK) can be demonstrated in routinely processed paraffin tissue sections using immunolabelling techniques. In the present study we investigated whether oncogenic tyrosine kinase activation also occurs in other categories of lymphoma by staining 145 cases of lymphoma covering those tumours with a range of different subtypes including those with morphological similarity to ALK-positive anaplastic large cell lymphoma (ALCL). Twelve cases of the borderline malignant disorder lymphomatoid papulosis were also studied. Twenty seven of the 28 cases of ALK-positive ALCL showed the extensive cytoplasmic labelling for phosphotyrosine in the neoplastic cells. The remaining case containing moesin-ALK exhibited membrane-associated phosphotyrosine expression. There was no nuclear phosphotyrosine labelling in any of the ALK-positive ALCL, even though ALK was present within the cell nuclei in 23 of the tumours. Variable degrees of phosphotyrosine labelling, usually membrane-restricted, were observed in 7/40 cases of ALK-negative ALCL, 9/29 cases of diffuse large B-cell lymphoma, 3/6 cases of mediastinal B-cell lymphoma, 2/7 cases of Hodgkin's lymphoma, 3/6 cases of peripheral T-cell lymphomas unspecified, 4/6 cases of B-cell chronic lymphocytic leukaemia, 2/6 cases of follicular lymphomas and 2/12 cases of lymphomatoid papulosis studied. However none of these phosphotyrosine-positive cases showed the strong cytoplasmic labelling comparable to that seen in ALK-positive lymphoma. We conclude that activation of a tyrosine kinase is probably not a major oncogenic event in lymphomas other than ALK-positive ALCL.

Paraneoplastic pemphigus is an autoimmune mucocutaneous disease usually associated with neoplasia as lymphoid proliferations. We report the original case of a patient who had developed a mycosis fongoide preceded by a paraneoplastic pemphigus. To our knowledge, this association has never been reported before. Cutaneous manifestations of mycosis fongoide as pigmentary change are known. This mycosis fongoide was particular in its progressive cutaneous hyperpigmentation.A 70-year-old male patient developed a mycosis fongoide with CD30 positive cells in the dermis several months after the diagnosis of a paraneoplastic pemphigus. Simultaneously, a cutaneous hyperpigmentation was predominantly noticed on photo-exposed areas, which improved after chemotherapy.Paraneoplastic pemphigus may precede the cancer, as is shown by our present case. This paraneoplastic pemphigus is singular because of the lack of oral erosions, patient's prolonged survival and its association with a mycosis fongoide. The diagnosis of mycosis fongoide with CD30 + cells was finally established together with its relationship to the cutaneous hyperpigmentation. Indeed, a few cases of pigmentary changes in mycosis fongoide have already been reported. The pathogenesis is still unknown, but the role of mast cell and stem cell factor in hyperpigmented mycosis fongoide has been proposed.

We report panniculitis revealing alpha-1 antitrypsin deficiency in 3 patients with different Pi phenotypes. The first patient, a 16-year-old woman, had inflammatory skin lesions on the abdomen for 6 months. The lesions regressed spontaneously. Serum alph-1 antitrypsin level was normal but the Pi phenotype was MS. The second case was observed in a 56-year-old man who developed erythematous subcutaneous nodules on the abdomen, legs and buttocks in a trauma context. Serum alpha-1 antitrypsin was very low and the Pi phenotype was ZZ. The third patient was a 40-year-old woman who presented red swelling nodules on the legs. Her serum alpha-1 antitrypsin level was at the lower limit of normal and the Pi phenotype was MZ. Alpha-1 antitrypsin deficiency is an autosomic codominant inherited disorder characterized by inefficient or non-functional serum alpha-1 antitrypsin. The principal clinical manifestations are panlobular emphysema and cirrhoses. About 30 cases of panniculitis have been reported in the literature. In patients presenting panniculitis, we suggest studying the Pi phenotype to determine functional deficiency even if the serum level of alpha-1 antitrypsin is normal.

This report describes a case of anaplastic large cell lymphoma with the canonical t(2;5)(p23;q35) translocation in association with duplication of the short arm of the non-translocated chromosome 2, as demonstrated by two colour fluorescence in situ hybridisation. Because the tumour cells were tetraploid, these abnormalities were in duplicate, with four copies of the full length ALK gene and two copies of the t(2;5)(p23;q35) translocation. Despite multiple copies of the normal ALK gene, immunohistochemical, reverse transcriptase polymerase chain reaction, and western blot analysis demonstrated that only the fusion gene NPM/ALK was expressed and that normal ALK genes remained silent. Although based on a single case, these data indicate that structural rather than numerical abnormalities of the ALK gene are implicated in the pathogenesis of anaplastic large cell lymphomas.

There is controversy in the literature as to whether anaplastic large-cell lymphoma of B-cell phenotype is related to the t(2;5)-positive T- or 'null' cell lymphoma of the same morphology. We report a study of 24 lymphomas with morphological features of anaplastic large-cell lymphoma which expressed one or more B-cell markers and lacked T-lineage markers. Clinical features were more in keeping with large B-cell lymphoma than with classical t(2;5)-positive anaplastic large-cell lymphoma, and immunostaining for anaplastic lymphoma kinase (ALK) protein provided no evidence for the (2;5) translocation (or one of its variants). The staining patterns for CD20 and CD79 were typical of diffuse large B-cell lymphoma, CD30 expression was variable, and most cases (15/22) lacked epithelial membrane antigen (EMA). These findings support the view that 'B-cell anaplastic large-cell lymphoma' is unrelated to t(2;5)-positive (ALK-positive) lymphoma, and that it represents a morphological pattern occasionally encountered among diffuse large B-cell lymphomas. By the same reasoning, most tumours diagnosed as 'ALK-negative anaplastic large-cell lymphoma of T-cell or null phenotype' probably belong to the spectrum of peripheral T-cell lymphomas.

Brooke-Spiegler syndrome is an association of multiple trichoepitheliomas and cylindromas, sometimes accompanied by other adnexal tumors.A 44-year-old woman with trichoepitheliomas involving the naso-genal and mental areas associated with cylindromas and spiradenomas on the forehead and pretragal regions creating a turban effect. Other complete or diassociated syndromes were found in family members. No neoplastic tumor was identified.Brooke-Spiegler syndrome is an hereditary disease with autosomal dominant transmission. Both benign and malignant neoplasias can be associated. The concomitant existence of different tumors could be helpful in understanding the pathophysiology. There is some debate about the exact origin of the trichoepitheliomas, cylindromas and spiradenomas. Several single-cause theories have been put forward but remain to be confirmed as the genetic anomalies identified for trichoepitheliomas and cylindromas map to different sites. Patients with Brooke-Spiegler syndrome should be explored for malignant neoplasia. A family study is indicated.

We report an unusual case of cutaneous CD30-positive lymphoma with pilar tropism and circulating Sezary cells which had a rapidly fatal course.A 78-year-old man presented erythematous infiltration of the face, a pruriginous eruption on the trunk and proximal portions of the limbs with small erythematopurpuric follicular papulae, and node enlargement in the inguinal and axillary areas. The rest of the clinical examination was normal. Circulating Sezary cells were found in significant numbers on two different blood smears. Histologic and immunohistochemistry examination of a skin biopsy evidenced medium to large sized lymphoid cell infiltration in a perifollicular localization. A few small cells penetrated the pilar apparatus. There was no follicular mucinosis. The tumoral cells expressed CD2, CD3, CD4 and 75 p. 100 were positive for CD30. Node aspiration showed lymphomatous cells and CD3+ and CD30+ lymphomatous infiltration was found on marrow smears. A T clone was evidenced both in blood and bone marrow leading to the diagnosis of pilotropic CD30-positive lymphoma. Chlorambucil and prednisone were given. The patient died 5 months later.The cytology findings suggest medium to large cell pleomorphic lymphoma. The circulating Sezary cells, the pilotropic eruption, and the rapidly fatal outcome suggest transformation of a Sezary syndrome into CD30-positive large cell lymphoma which has been described in fungoid mycosis.

We report four cases of a rare subtype of CD30-positive anaplastic large cell lymphoma (ALCL) with a predominant small cell component (small cell variant of ALCL) presenting with a leukaemic feature. Lymph node biopsy showed malignant cells of varying size with a predominant population of small to medium-sized malignant cells associated with large anaplastic cells strongly positive for CD30 and epithelial membrane antigen (EMA). Both large and small cells were reactive with antibody ALK1, which recognizes the chimaeric NPM-ALK protein associated with the t(2;5)(p23;q35). All patients presented with hyperleucocytosis with atypical small lymphocytes. Bone marrow involvement was detected on both aspirate and bone marrow trephine where scattered malignant cells were only demonstrated by immunostaining for CD30 and ALK protein. Atypical cells in peripheral blood, lymph node and skin biopsies showed a T or null cell phenotype. Cytogenetic analysis of blood, bone marrow and/or lymph node revealed the t(2:5)(p23;q35) characteristic of ALCL. The patients responded to chemotherapy but showed early relapse without abnormal cells in peripheral blood. This report shows that the small cell variant of ALCL may have a leukaemic presentation with peripheral blood involvement by atypical lymphocytes and provides evidence that, in the small cell variant of ALCL, the small cell component is a part of the malignant clone.

A case of pure non-epidermotropic cutaneous lymphoma in a human immunodeficiency virus-infected patient is reported following a viral opportunistic infection [cytomegalovirus (CMV) hepatitis]. The lymphoid infiltrate was Epstein-Barr virus and CMV negative with a CD30-positive T-cell phenotype. Molecular analysis demonstrated T cell receptor gene rearrangement, but a non-aggressive disease course was noted supporting a cautious therapeutic approach in this case.

The (2;5)(p23;q35) lymphoma-associated chromosomal translocation creates a novel fusion gene that incorporates parts of the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase and nucleophosmin genes. We report here that the product of this fusion gene accumulates within the nucleoli of neoplastic cells, and that previous reports of a predominantly cytoplasmic localization for the protein represent a tissue-processing artifact. However, nucleolar accumulation of nucleophosmin-ALK may not be necessary for its oncogenic action, because an ALK protein expressed in a lymphoma carrying a variant (1;2) chromosomal translocation did not accumulate in nucleoli. Furthermore, an engineered hybrid TPR-ALK protein can transform rodent fibroblasts and produce lymphomas in mice while remaining confined to the cytoplasm. We propose that the transforming action of ALK may not be reliant on its nucleolar localization, a hypothesis that may have implications for studies of other proteins involved in oncogenesis that are relocalized after the creation of fusion genes.

Analysis of IgH and TcR-gamma genes using consensus primers identifying junctional regions of rearranged genes by polymerase chain reaction (PCR) was performed on tissues involved by Hodgkin's disease (HD) in 90 cases and was correlated with the immunophenotype of Hodgkin and Reed-Sternberg (HRS) cells and the presence of Epstein-Barr virus (EBV) within these cells. Clonal IgH gene rearrangements were found in 1/5 cases of lymphocyte predominance (LP) subtype and none was positive for EBV. In 85 cases of classic HD, no IgH or TcR-gamma gene rearrangements were found in 51 (60 per cent) cases. A similar percentage, but not the same cases, were of null (non-B, non-T) phenotype. Of 30 cases where a B phenotype was assigned to HRS cells, nine had IgH gene rearrangements, three had TcR-gamma gene rearrangements, and two had both genes rearranged. None of the five cases assigned to T phenotype of HRS cells showed rearrangement of TcR-gamma genes, but two cases showed rearranged IgH genes. Among 41 cases of null phenotype, ten had IgH gene rearrangements, five had TcR-gamma gene rearrangements, and three cases had both genes rearranged. Whereas EBV was detectable in HRS cells in 17/43 classic HD cases of assigned B phenotype, EBV was also detectable in 2/5 cases of assigned T phenotype and in 21 cases with the null phenotype. Furthermore, there was no correlation of EBV with the presence or lack or IgH or TCR-gamma gene rearrangements. Of the remainder, half (30 per cent) expressed antigens associated with lymphocytes without an appropriate genotype. The results confirm lymphocyte-lineage committed cells at the origin of HRS cells in 40 per cent of cases. Any hypothesis of a non-lymphocytic origin of HRS cells will require the inducibility of CD30 on candidate precursors and the methodology for probing genetic events in such cells to be addressed.

The t(2;5)(p23;q35) translocation, associated with anaplastic large-cell lymphoma (ALCL), results in the production of the nucleolar protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) protein. This report describes an immunocytochemical study of the distribution of ALK and NPM-ALK proteins using a new monoclonal antibody, ALK1, that recognizes a formalin resistant epitope in both the 80-kD NPM-ALK chimeric and the 200-kD normal human ALK proteins. Cytoplasmic and nuclear labeling was seen in the t(2;5)+ SU-DHL-1 and Karpas 299 cell lines. Normal ALK protein expression was restricted to the central nervous system (in scattered neurons, glial cells, and endothelial cells). Two hundred and thirty-nine cases of lymphoma and 80 nonhematopoietic tumors were immunostained. Antibody ALK1 labeled 53.4% (39 of 73 cases) of CD30+ ALCL. A case of ALCL with a t(1;2) translocation was ALK1+. Three cases of CD30- ALCL with prominent nucleoli showed a unique pattern of coarse granular cytoplasmic labeling. All other tumors, including Hodgkin's disease and lymphomatoid papulosis, were ALK1-. These results indicate that reliable immunostaining of routine biopsy material for NPM-ALK and ALK proteins is feasible. Such analysis is of diagnostic importance, especially because t(2;5)+ ALCL cases have a good prognosis with appropriate treatment.

Recently, Suster and Wong added a distinctive entity to the large nomenclature of sweat gland carcinomas. This tumor is equivalent to the polymorphous low-grade adenocarcinoma of minor salivary glands. It is characterized by its variegated architecture and its relatively indolent behaviour. The authors report here a new case of this neoplasm. The morphological and immunohistochemical criteria and the differential diagnosis are reported.

A B-cell lymphoma, restricted to the skin, developed in a 58-year-old man receiving methotrexate for non-rheumatoid peripheral arthritis, with the simultaneous occurrence of a cytolytic hepatitis and carcinoma of the lung. Two weeks after methotrexate was stopped, both the skin tumour and the hepatitis disappeared spontaneously, with no recurrence during a 12-month follow-up period. Immunoglobulin gene rearrangement was shown by polymerase chain reaction (PCR) but in situ hybridization failed to reveal neoplastic cells positive for Epstein-Barr virus (EBV).

AIMS: (1) To assess the clonality of tumour cells in two patients with mycosis fungoides who subsequently developed Hodgkin9s disease; and (2) to determine whether there is a clonal relation between these two disorders. METHODS: Cutaneous tissue samples involved by mycosis fungoides and lymph nodes involved by Hodgkin9s disease from both patients were investigated by immunohistochemistry and the polymerase chain reaction. RESULTS: Mycosis fungoides tumour cells in both patients expressed multiple T cell associated antigens; Reed-Sternberg (RS) cells had the null phenotype. T cell receptor gamma chain genes were clonally rearranged in mycosis fungoides cells but not in RS cells, including variants, in both patients. In the patient with intermediate transformation to large cell lymphoma, immunoglobulin heavy chain genes were rearranged in the cutaneous tumour, but not in the lymph node involved by Hodgkin9s disease. CONCLUSION: The divergent antigen expression and gene rearrangements observed in these two patients strongly suggest that Hodgkin9s disease and mycosis fungoides are not derived from a single tumour cell clone.

Objectifs Les tumeurs de Spitz sont des tumeurs frequentes et le plus souvent benignes de l’enfant. Il existe neanmoins des formes atypiques a potentiel metastatique pour lesquelles le diagnostic differentiel avec un melanome malin est delicat. A partir de notre serie personnelle et apres une revue de la litterature, nous proposons une mise au point sur le sujet. Methodes Il s’agit d’une etude retrospective d’avril 1989 a septembre 2007 portant sur 44 enfants operes a l’Hopital des Enfants de Toulouse de tumeur de Spitz. A partir du dossier clinique et des comptes-rendus anatomopathologiques, nous avons etudie les donnees demographiques, les indications operatoires, les types histologiques. Le recul post-operatoire moyen est de 6,7 ans. Resultats 44 enfants ont ete operes, 19 filles et 25 garcons âges en moyenne de 6,9 ans au moment de la chirurgie. Les 44 tumeurs de Spitz se repartissaient comme suit : tete et cou 54,5 %, membre pelvien 22,7 %, membre thoracique 18,2 % tronc et abdomen 4,6 %. Dans 88,6 % des cas il s’agissait d’une tumeur de Spitz typique et dans 11,4 % des cas d’une tumeur de Spitz atypique. Aucun « melanome spitzoide » et aucune lesion metastatique n’ont ete retrouves. Conclusion La terminologie « naevus de Spitz » doit etre abandonnee et il faut parler de tumeur de Spitz « typique », « atypique » ou de melanome. La prise en charge therapeutique de ces tumeurs reste difficile car actuellement il n’existe pas de consensus. Elle necessite des anatomopathologistes confirmes. Les tumeurs de Spitz doivent faire l’objet d’une surveillance clinique reguliere. En cas d’atypies cliniques ou d’evolutivite, la lesion doit etre retiree dans sa totalite avec une marge d’au moins 1 cm.