Neglected tropical infectiology, lichen planus of the nails, pathogenesis of skin cancers
Dr Christian Derancourt
An FMC (Formation Médicale Continue or Continuing Medical Education) session was devoted to neglected tropical infectiology, a clear departure from the main topics covered at the AAD. The session took the form of a quiz followed by clarifications and it was clear that the audience was highly knowledgeable; the participants who were questioned at random did not make a single diagnostic error... A few points attracted my attention:
- the significance of post-streptococci complications in scabies in developing countries. The fact that the IACS, International Alliance for the Control of Scabies (website: www.controlscabies.org) exists proves the significance of scabies as a public health issue in these countries.
- the three diagnoses to be considered first of all in the case of a diffuse and itchy eruption in children, in "low-income" tropical countries: scabies, generalised dermatophytosis, and for South America "infective dermatitis" linked to HTLV-1, notably when it affects the scalp and side of the neck (which could resemble profuse seborrhoeic dermatitis).
- the great variability in the clinical presentation of cutaneous leishmaniasis: psoriasiform - which can be easily mistaken - and verrucose forms were presented to us.
- onchocerciasis which must be considered when there are one or more onchocercoma, but also intense pruritus, coalescent confetti-like depigmentation on the front of the legs (probably secondary to pruritus) and distended skin associated with hyperkeratosis...
For one specific case, poster 2374 demonstrated the potential benefit of micrographic Mohs surgery in the treatment of subcutaneous phaeohyphomycosis. The patient, aged 92 and an active farmer, presented damage to his right knee following repeated trauma whilst repairing farm machinery. Hypodermic plaques produced a flow of bloody serum when pressed. The diagnosis was confirmed by an anatomopathological examination (punch biopsy) and cultivation (identification of Fonsecaea pedrosoi). After discussion, the therapeutic option using Mohs surgery was selected and the evaluation of the margins was satisfactory. After one year, no relapse was observed. The authors explained that surgery, when it is technically possible, remains the first indication for this condition in immunocompetent patients, but that relapse may occur. Due to the lack of clear guidelines on surgical treatment, this therapeutic option is particularly interesting.
Dr Rémi Maghia
Assessment of lichen planus of the nails
Antonella Tosti, an international expert on the pathology of the scalp and nails, who relocated from Bologna to Miami, gave us a remarkable review of lichen planus (LP) of the nails. There are five clinical forms: being familiar with them does not only allow for diagnosis, but also understanding of the nature of the treatment proposed depending on the form.
1/"Typical" matrix LP
Characterised by onychorrhexis (longitudinal fissuring), thinning of the nail plate, occasional pterygium unguis (which is a destruction of the matrix), and lump erythema of the lunula.
2/Nail bed LP: moderate subungual hyperkeratosis, usually associated with matrix LP.
3/Trachyonychia: clinically identical to trachyonychia linked to other causes. Nails appear to have been sanded with sandpaper. Benign clinical course.
4/Yellow nail syndrome-like modifications
Thick, yellow toenails
5/Idiopathic atrophy of the nails
Rapid development, many or all nails, begins in youth Bullous or erosive LP of the nails Extremely rare, painful erosions, affecting one or two toenails, anatomopathological diagnosis, resulting in scars.
Three forms do not require treatment:
- Pterygium unguis and idiopathic atrophy of the nails: as these two forms are not reversible.
- Trachyonychia as it is a benign condition.
The four forms to be treated are: "typical" matrix LP, nail bed LP, yellow nail syndrome-like modifications, and bullous or erosive LP of the nails. They are treated with corticosteroids on a systemic or intralesional basis, depending on the number of nails affected. Intralesional protocol; triamcinolone acetonide: from 0.1 to 0.5 ml/nail, every two months. The injection site is in the matrix or the nail bed depending on type of damage. Systemic corticoids: triamcinolone acetonide 0.5 mg/kg/day for 3 to 4 months, then a gradual reduction.
Prof Frédéric Caux
The physiopathological mechanisms which cause skin cancers were brilliantly presented in a plenary session by Paul Khavari from the University of Stanford in California. The ultraviolet rays which induce genome mutations result in the alteration of significant biological mechanisms such as cellular division and differentiation. Recent studies have shown that UV-induced mutations are present in large numbers, even in healthy skin. Knowledge of the signalling pathways involved in basal cell carcinoma (Patched/Sonic hedgehog pathway) and in melanoma (RAS/MAPK pathway) has led to the development of new treatments for these tumours, which inhibit these pathways such as vismodegib, vemurafenib, dabrafenib, etc. On the other hand, the mechanisms responsible for the development of the squamous cell carcinoma are less well known. NGS sequencing of 300 tumours highlighted gene mutations in the Notch signalling pathway (NOTCH1, 2, 3, SPEN). The Notch pathway is involved in normal cell differentiation and its inactivation leads to cellular differentiation. A second significant factor is a disruption of genomic integrity with aneuploidy and chromosome recombinations. This aneuploidy relates to mutations in the KNSTRM gene which codes for a kinetochore protein, the kinetochore being a group of molecules that allow chromosomes to attach to the microtubules during cell division. Mutations of p53, which is considered to be the protector of genomes, are also very common in pre-cancerous lesions (actinic keratosis) and in squamous-cell carcinomas. Additional mutations in proteins in the RAS-MAPK pathway, which is involved in cell division, are also necessary to induce the appearance of tumours. Overall, it is the gradual accumulation of mutations, notably UV-induced, in many genes that lead to the development of squamous-cell carcinomas.
As for actinic keratosis, a poster (P3087) showed a phase 1/2 trial of a new form of ingenol mebutate (Picato) developed to improve the heat stability of the molecule and to allow for use over a larger surface area (an entire bald scalp). Two different concentrations of this product both allowed for an 80% reduction in the number of keratoses at 8 weeks, at the expense of a local inflammatory reaction. Another poster (P3134) showed the very preliminary results of a VDA-1102 molecule which reduces the number of actinic keratoses and squamous cell carcinomas in an animal model. The interesting aspect is that in terms of efficacy this molecule seems comparable to Picato and that its action mechanism is unique. In fact, this molecule reduces glycolysis by the competitive inhibition of the interaction between hexokinase 2 and the VDAC1 mitochondrial channel. Stay tuned!