The dysplastic nevus. Separate entity, melanoma precursor or diagnostic dilemma?

Today, 20 years after Clark and Elder postulated their tumor progression model of melanocytic lesions from common nevi to melanoma, there are still controversies surrounding this subject. Despite modem molecular biological developments, a consensus about the question, if the dysplastic nevus should be considered as a separate entity, melanoma precursor or just represent a diagnostic dilemma, still seems to be impossible. In addition, since the term melanocytic dysplasia is not precisely defined with regard to all diagnostic methods (clinical morphology, dermatoscopy, dermatopathology, molecular biology), there is considerable confusion. The question remains if a quite arbitrary classification of melanocytic lesions such as dysplastic nevus is useful at all. In daily practice, dermatologists should be aware of the fact that each suspicious melanocytic lesion could represent an early malignant neoplasia, regardless whether it is formally named dysplastic nevus or initial malignant melanoma. We conclude that solid dermatological experience plus novel tools of documentation represent the key factor to minimize patients' risk.     

How,and from which cell sources,do nevi really develop?

Melanocytic neoplasms are a diverse group of benign and malignant tumors with variable clinical features. While some models still promote the epidermal melanocyte as the origin of melanocytic neoplasms, clinical findings are inconsistent with this theory for the majority of tumors. Despite advances in naevus and melanoma biology, the location and differentiation status of the cell of origin remains undefined. Germ line genetics, biological state and cellular location of the mutated cell, as well as local environmental factors all likely play a role in the development of melanocytic neoplasms. Herein, we will review potential models for melanocytic neoplasia and discuss research challenges and opportunities.     

Correlation between dermoscopic and histopathological diagnoses of atypical nevi in a dermatology outpatient clinic of the Medical School of S?o José do Rio Preto,SP, Brazil

BACKGROUND

The incidence of cutaneous melanoma is increasing worldwide. Since it is an aggressive neoplasm, it is difficult to treat in advanced stages; early diagnosis is important to heal the patient. Melanocytic nevi are benign pigmented skin lesions while atypical nevi are associated with the risk of developing melanoma because they have a different histological pattern than common nevi. Thus, the clinical diagnosis of pigmented lesions is of great importance to differentiate benign, atypical and malignant lesions. Dermoscopy appeared as an auxiliary test in vivo, playing an important role in the diagnosis of pigmented lesions, because it allows the visualization of structures located below the stratum corneum. It shows a new morphological dimension of these lesions to the dermatologist and allows greater diagnostic accuracy. However, histopathology is considered the gold standard for the diagnosis.

OBJECTIVES

To establish the sensitivity and specificity of dermoscopy in the diagnosis of pigmented lesions suspected of malignancy (atypical nevi), comparing both the dermatoscopic with the histopathological diagnosis, at the Dermatology Service of the outpatient clinic of Hospital de Base, São José do Rio Preto, SP.

METHODS

Analysis of melanocytic nevi by dermoscopy and subsequent biopsy on suspicion of atypia or if the patient so desires, for subsequent histopathological diagnosis.

RESULTS

Sensitivity: 93%. Specificity: 42%.

CONCLUSIONS

Dermoscopy is a highly sensitive method for the diagnosis of atypical melanocytic nevi. Despite the low specificity with many false positive diagnoses, the method is effective for scanning lesions with suspected features of malignancy.     

Ichthyosis follicularis with congenital atrichia, nail dystrophy and palmoplantar keratoderma. Variant of IFAP syndrome or a new entity?

A 23-year-old man was seen for dry, rough skin and alopecia present since birth. There was no history of impaired sweating, photophobia, or lacrimation. Examination revealed generalized cutaneous thorn-like projections with nonscarring alopecia, twenty-nail dystrophy, and palmoplantar keratoderma.     

Solar keratoses: Photodynamic therapy,cryotherapy, 5-fluorouracil,imiquimod, diclofenac,or what? Facts and controversies

Actinic keratosis is a common dermatologic condition that may regress, remain stable, or progress to squamous cell carcinoma. Some question whether all actinic keratoses should be routinely treated, whereas others contend that the unpredictable natural history of this disease necessitates treatment to prevent malignant transformation. Available treatments include photodynamic therapy, cryotherapy, 5-fluorouracil, imiquimod, and diclofenac. Each of these options has its advantages and disadvantages, although they all have a place in the management of actinic keratosis. An overview of these treatment modalities is presented, as are the controversies surrounding the treatment of actinic keratosis.     

Dysplastic naevi: To shave,or not to shave? A retrospective study of the use of the shave biopsy technique in the initial management of dysplastic naevi

The management of dysplastic naevi is a controversial subject. This study sought to assess the usefulness of the shave biopsy technique in the initial management of dysplastic naevi, and to demonstrate the advantages over the punch biopsy technique. We report a retrospective observational study of histopathology specimens examined in one histopathology practice over a 14-month period. Patients who had a clinical diagnosis of 'dysplastic naevus', which had initially been biopsied using either a shave or punch biopsy, and then followed up with a full-thickness elliptical excision, were included in the study. Histopathological concordance between the shave and punch biopsy specimens and their respective follow-up elliptical excisions was compared. We found that 21 of 22 (95.5%) shave biopsies were concordant with their respective excision specimens, and that 29 of 41 (70.7%) punch biopsies were concordant with their respective elliptical excision specimens. Of the shave biopsy specimens reviewed, 66% showed that the dysplastic naevi were completely excised with the initial biopsy, compared with 21.2% of the punch biopsy specimens. These findings confirm that shave biopsies provide accurate diagnostic information in the assessment of dysplastic naevi. Shave biopsies enable the entire lesion to be submitted for histopathological assessment, improving the chances of an accurate diagnosis.     

Melanoma—Time to fast or time to feast? An interplay between PPARs,metabolism and immunity

Development and progression of melanoma can be accelerated by intensification of particular metabolic pathways, such as aerobic glycolysis and avid amino acid catabolism, and is accompanied by aberrant immune responses within the tumor microenvironment. Contrary to other cancer types, melanoma reveals some unique tissue-specific features, such as melanogenesis, which is intertwined with metabolism. Nuclear peroxisome proliferator-activated receptors (PPARs) take part in regulation of systemic and cellular metabolism, inflammation and melanogenesis. They appear as a focal regulatory point for these three distinct processes by occupying the intersection among AMP-dependent protein kinase (AMPK), mammalian target of rapamycin (mTOR) and PPAR gamma coactivator 1-alpha (PGC-1α) signalling pathways. When deregulated, they may accelerate melanoma malignant growth. Presenting the contribution of PPARα and PPARγ in melanoma biology, we attempt to ask how two contrasting metabolic states: obesity and fasting, can change progression of the disease and possible outcome of the treatment. This short essay is aimed to provoke a discussion about some practical implications for melanoma prevention and treatment, especially: how metabolic manipulation may be exploited to overcome immunosuppression and support immune checkpoint blockade efficacy.     

Isotretinoin: dose,duration and relapse. What does 30 years of usage tell us?

With 30 years of clinical use, it is appropriate to review the use of isotretinoin. We now understand that retinoids influence cellular growth, differentiation, morphogenesis and apoptosis, inhibit tumour promotion and malignant cell growth, exert immuno‐modulatory actions and alter cellular cohesiveness. This has expanded the indications of isotretinoin from just acne and rosacea to a wide range of inflammatory and malignant skin disorders. While the standard dose of 0.5 to 1 mg/kg per day for 4 months to a cumulative dose of 120–140 mg/kg per day has served us well in the management of acne vulgaris, there is emerging evidence that much lower dosages (as low as 5 mg/day) are just as effective but have significantly fewer adverse effects. Relapse of acne vulgaris continues to be a problem but we are beginning to recognise that this is related less to the cumulative dose and more to the length of sebaceous gland suppression. Other factors important for relapse include a macrocomedonal pattern of acne, smoking and age, both younger (under 14 years) and older (over 25 years). After 30 years of use, we now understand why isotretinoin is such an effective drug. Not only does it clear acne in almost all patients, long‐term remission can be achieved in 70–80% of patients with a single course. Important changes in the use of isotretinoin include using a lower daily dose for a longer period of time. New indications continue to emerge, particularly as a potential treatment for both intrinsic and extrinsic (photo) aging. Teratogenicity however, remains a very significant concern.     

What’s new in atopic eczema? An analysis of systematic reviews published in 2007 and 2008. Part 1. Definitions,causes and consequences of eczema

This review summarizes clinically important findings from nine systematic reviews indexed in bibliographical databases between August 2007 and August 2008, dealing with the definitions, causes and consequences of atopic eczema (AE). One review of diagnostic criteria found that out of 10 sets of criteria, only the UK refinement of the Hanifin and Rajka criteria have been adequately tested (in 19 studies). Another review of 20 named outcome measures found that only three [SCORing Atopic Dermatitis (SCORAD), the Eczema Area and Severity Index (EASI) and the Patient Oriented Eczema Measure (POEM)] had been tested and found to perform adequately. In terms of risk factors for developing disease, a review found that birth by caesarean section increased the risk of asthma and hay fever but not eczema in offspring. A review of cohort studies also found evidence that adverse psychological factors in early life predispose to more atopic disease and a worse prognosis. Another review found that filaggrin gene mutations were a consistently strong risk factor for AE, with a person carrying one of these mutations being over three times more likely to exhibit eczema. It has been suggested that eczema might protect against some forms of cancer, and a detailed systematic review of brain cancers that included 53 233 participants from eight case–control and cohort studies found that having atopic disease was associated with a 39% reduction in glioma risk, a finding that was also present for just those with AE (odds ratio 0.69, 95% CI 0.58–0.82). A further review of case–control and cohort studies failed to find any association between keeping furry pets at birth and subsequent risk of eczema, although pet fur might still exacerbate established disease. In terms of disease consequences, a review found that eczema was the commonest cause of chronic sleep loss in young people, affected the whole family. A review of four economic studies from the US found that the annual cost of AE in the States was as high as $3.8 billion when indirect costs are included.     

A Collodion Baby with Facial Dysmorphism,Limb Anomalies,Pachygyria and Genital Hypoplasia: A Mild Form of Neu-Laxova Syndrome or a New Entity?

Neu-Laxova syndrome is a rare, lethal, autosomal recessive disorder characterized by intrauterine growth retardation, central nervous system anomalies, skin findings, such as ichthyosis, edema, collodion baby and harlequin fetus, facial dysmorphic features, limb anomalies and genital hypoplasia. Although it is generally a lethal condition, cases of such patients who lived beyond 6 months and 10 months of age have been reported. Here, we describe an 8-year-old boy who was born with collodion membrane, facial dysmorphic features, limb anomalies, genital hypoplasia and pachygyria. He had no major health problems over the course of 8 years of follow-up, except for mild mental/motor retardation, ichthyosis, facial dysmorphic features and limb anomalies. Based on these features, we suggest that because Neu-Laxova syndrome represents a heterogeneous phenotype, our case may be a milder variant of this syndrome or a new genetic entity.     

A Pruritic Linear Urticarial Rash,Fever, and Systemic Inflammatory Disease in Five Adolescents: Adult‐Onset Still Disease or Systemic Juvenile Idiopathic Arthritis sine Arthritis?

The characteristic rash of systemic juvenile idiopathic arthritis is a transient erythematous eruption associated with a quotidian spiking fever. Usually asymptomatic, it can be pruritic, with dermatographism at sites of scratching or pressure. An illness similar to this entity in adults is designated adult-onset Still disease. The relationship between the pediatric and adult disease is uncertain and differences in case definition have evolved. Specifically, a sustained arthritis for at least 6 weeks is required for a diagnosis of systemic juvenile idiopathic arthritis, whereas transient arthritis and arthralgia are accepted criteria in adult-onset Still disease. We describe five patients less than 16 years of age who presented with an acute illness characterized by fever and a distinctive skin eruption. Intense pruritus and linear erythematous lesions flared with a spiking fever, usually in the late afternoon and evening. Periorbital edema/erythema and nonlinear urticarial lesions were also seen. Two children had splinter hemorrhages of the nail beds and one girl developed a fixed, scaling, pigmented, linear eruption. Severe malaise, myalgia, arthralgia, and leukocytosis were present in every patient. Other systemic manifestations included sore throat, transient arthritis, abdominal pain, lymphadenopathy, hepatomegaly, splenomegaly, hyperferritinemia, and hepatic dysfunction. No patient had a sustained arthritis. The course of the disease was variable. One patient, diagnosed with macrophage activation syndrome, recovered on oral naproxen. Two patients responded to systemic corticosteroid therapy. One girl developed status epilepticus and died from aspiration and asphyxia. A boy with severe hepatitis developed renal failure and thrombotic thrombocytopenic purpura and was treated with plasmapheresis, dialysis, and systemic corticosteroids; he had recurrent episodes of rash and fever into adult life. These children did not fulfill the case definition of systemic juvenile idiopathic arthritis because they lacked a persistent arthritis. Adolescent and adult patients with the same clinical and laboratory findings are described under the rubric of adult-onset Still disease. Recognition of the distinctive urticarial skin eruption and spiking fever is important in the diagnosis of a disease with severe morbidity and potentially life-threatening complications.