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Reports written by Dr. Silvina Maldonado (Dermatologist, Argentina) and Dr. Josefina Marco Bonnet (Dermatologist, France)
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Speakers: Dr. Ana Mordoh, Dr. Leonel Fierro, Dr. Francisco Bravo, Dr. Mario Marini, Dr. Miguel Martinez, Dr. Susana Puig, Dr. Raul Cabrara, Dr. Nelson Lobos and Dr. Carlos Silva
Report written by Dr. Silvina Maldonado
Dr Ana Mordoh discussed genetic alterations in melanoma.
After reviewing the different types of genetic alterations (point mutations, indels, simplifications, deletions, gene misorderings, translocations), she mentioned that they are generally somatic, with 5% germinal alterations (familial melanoma). Some 94% of MMs have an altered RTK/RAS pathway (MAP kinases). As for the genetic classification of MM, she focused on BRAF, RAS, NF1 and TRIPLE WILD TYPE. The first three correspond to the MAP kinase pathway: BRAF, which is “druggable” with oncogene inhibitors, and “undruggable” RAS and NF1, the latter of which is insufficient to promote malignant tumour growth (playing only an accompanying role). TRIPLE WILD TYPE melanomas lack the signature of UV damage – these are the acral lentiginous / mucosal MMs with strong lymphocyte infiltration. In practical terms, patients with Intermittent Sun Damage (ISD), for which 30% of melanomas originate from a pre-existing naevus or melanocytes with BRAF mutations, are less than 55 years old, with many naevi located on the trunk and extremities, with BRAF predominance and low mutational load (TMB). In contrast, melanomas in patients with Chronic Sun Damage (CSD) originate from basal melanocytes or the follicular epithelium; these patients are less than 55 years old, with elastosis, actinic keratosis, few naevi on the head and neck or back of the hands, and high TMB, and are NRAS, NF1, KIT, BRAF.
Dr Leonel Fierro reviewed melanoma classifications from a clinical perspective, and among the varieties, he discussed amelanotic spitzoid (favourable course in patients under 10 years of age) and mucosal melanomas (pagetoid, lentiginous or mixed patterns), as well as the malignant blue naevus type, which emerges from a cellular blue naevus or naevus of Ota and develops in the dermis and SCT without affecting the epidermis. With regard to special considerations for MM, he discussed MM in pregnancy (2.8 to 8.5% per 100,000, after neck and breast cancer); he presented an algorithm for surgical treatment (JDDG 2016 Jun; 14(6):585-93), but while he emphasised that pregnancy is not an indication for delaying treatment of MM, he also insisted on the importance of a multidisciplinary Bioethics Committee to make decisions in cases of metastasis. The rate of metastasis to the foetus is 25%, and the prognosis depends as always on the stage of disease progression. As for synchronous MM (multiple primary MM), it occurs when the diagnosis is made within the first 3 months of tumour development and there is a CDKN2A alteration in 8.3–15% of cases, with two age peaks: from 15–39 and from 65–79 years of age, mainly in the extremities, with a history of dysplastic naevi, family history of MM in first-degree relatives, light phototype. MM in children is rare, may be transplacental, via transformation of CMNs, associated with genetic conditions or on top of a pre-existing naevus.
Dr Francisco Bravo reported on uncommon clinicopathological varieties.
Desmoplastic MM (4%), mostly in men older than 60, head and neck, non-specific clinical appearance, 60% amelanotic, de novo or associated with lentigo maligna, generally thick, but oddly enough less aggressive, better prognosis for pure type than mixed type. Primary dermal MM (0.8%), histologically indistinguishable from MTS, low metastatic potential, 80-100% survival at average Breslow thickness of 3 mm. Minimal deviation MM is equivalent to the vertical growth phase of MM but with no cytological atopy. Polypoid MM is a variant of nodular MM, not necessarily pigmented. May present in the upper respiratory tract, oesophagus, rectum, vagina, biliary tract, with no fixed genetic pattern, highly aggressive and generally in younger people aged 20 to 39. Verrucous MM (3%) often leads to diagnostic errors, in the legs and cheeks in young women and very aggressive if not in situ. Pigmented epithelioid melanocytoma (previously known as animal-type) has a low recurrence rate, low lymph node dissemination and systemic dissemination. 1/3 of cases are congenital or from childhood. Mucosal MM (1%) is frequently diagnosed late. Naevoid MM in young people, proximal areas of extremities and trunk, with frankly malignant behaviour. Large nested MM, generally in the sixth decade of life. Amelanotic MM: difficult to diagnose. Follicular MM, simulates itchiness in photoexposed areas. Rhinophymatous MM, difficult to diagnose. Wiesner naevus (BAPoma) is not an MM, but generally a syndrome marker with susceptibility to different types of cancer. Finally, Dr Bravo concluded his presentation with an extremely rare bilateral acral lentiginous melanoma with simultaneous presentation.
Dr Mario Marini presented recent changes to the T (TNM) and its utility in requests for studies and treatments.
He discussed the T’s importance in distinguishing clinicopathological variants of the primary tumour, physiopathology, and molecular studies. He noted that currently, only Breslow and ulceration remain in use for staging purposes (the other indices are optional, but must be reported if present in quantity). He mentioned the creation of subcategory T1b (between 0.8 and 1 mm) in determining whether or not to request a sentinel lymph node (SLN) study, based on the percentage of positive SLNs to avoid unnecessary biopsies. It should be considered in cases of T1a with ulceration, T1b with or without ulceration, and T1a with risk factors (young, high history index, lymphovascular invasion, >75% of HP regression or neurotropic type). This points to the importance of performing complementary studies according to staging, only in cases of advanced tumours and positive SLNs. Ultrasound is very useful for non-palpable lymph nodes and does not replace SLN. It should be requested if the patient meets the criteria for an SLN biopsy and does not have it done, if the SLN was not possible or was technically unsuccessful and when lymphadenectomy is not performed in the context of a positive SLN. At present, its use in Stage IV is being discussed in cases where lymphadenectomy or ultrasound monitoring is performed.
Later, Dr Miguel Martinez talked about when to request imaging and lab studies and which ones to request.
In the diagnostic process, we must base our decisions on clinical observations, HP and potentially the emerging FISH molecular profile for diagnosis of ambiguous melanocytic lesions.
In the prognostic process, for initial staging and treatment planning, SLN biopsy is used after ultrasound of the lymphatic basin.
In the monitoring process, for diagnosis of recurrence or dissemination, in cases where it is determined that there is no additional benefit in low stages (up to IIA); in IIB and IIIA, IIC and IIIB, a cranial, thoracic and abdominal CT scan (and neck if indicated) should be requested, and in the latter two stages, PET-CT is an option, not examining the CNS without symptoms. In IIIC and IIID, CT scan of the entire body or PET-CT and brain NMR. If MTS is suspected or symptoms are present: PET, LDH and NMR.
Dr Susana Puig discussed women with a history of melanoma (pregnancy, replacement therapy, etc.). She noted that the prognosis for MM does not change significantly during pregnancy and that this is the tumour that is most likely to metastasise to the placenta and potentially to the foetus, but that the development of both of these depends on the clinical stage of the disease. Regarding the risks of immunotherapy during pregnancy with PD1 inhibitors (nivolumab), there are some successful cases even though there is a risk of miscarriage up until week 14, and an increased risk in the second and third trimesters of foetal death, premature birth and infant mortality. Always analyse the placenta to assess the risk to the child. Regarding HRT, despite the fact that MM has estrogen receptors that can act as a stimulus to its growth and invasion, some studies have shown improved survival in women and that this therapy is safe.
Dr Raul Cabrara talked about risk prediction in melanoma and the utility of molecular studies. He noted that there are 20 genes associated with MM, some of them very frequent but low-risk and others which are rare but with moderate or high risk. For predicting the risk of hereditary MM, doctors can use INVITAE, preferably as a blood test but also via saliva, buccal smear, or DNA; for clinical risk of recurrence, MTS in melanomas treated via surgery, targeted therapy or immunotherapy, MELAGENIX can be used for biopsies, or SKYLINE (in development at the Mayo Clinic) or SIGNATERA as blood tests. They must be used with caution as they are currently being studied in anticipation of more precise information allowing for their universal use.
Dr Nelson Lobos discussed surgical management of primary melanoma, placing a particular emphasis on fusiform excision or deep shave biopsies whenever possible with a minimal margin and for diagnosis with subsequent treatment measures; in the longitudinal direction in the extremities and otherwise following Langer lines, either with primary closure or healing by secondary intention; and in certain situations, multiple incision biopsies (on the face, with large lesion areas or low suspicion of MM). Margin extension is based on the Breslow depth (NCCN 02/2022). For special cases like subungual MM, there is no evidence that amputation yields even a modest increase in survival, and for lentigo maligna, first-line surgical treatment with monitoring of margins (wide excision, staged square or Mohs techniques if large in size, poorly defined or with microinvasion). Do not use electrosurgery.
To conclude the session, Dr Carlos Silva discussed the treatment of advanced melanoma: 2021 results.
He presented a broad review of studies in which it was shown that a combination of BRAF and MEK inhibitors yields greater survival than use of either individually or placebo, except for Wild-Type BRAF for which equivalent results were observed with use of a combined regimen or nivolumab alone. In any case, there is no level I evidence (randomised phase III trials) to decide which treatment is the most appropriate for MM with BRAF mutations. Either choice is appropriate since they are based on evidence from clinical trials. There is no difference in overall survival. Targeted therapy is more effective in its response but more toxic (except nivolumab + ipilimumab), and requires ongoing treatment. It is still a matter of discussion whether to start early post-surgery therapy in Stage III, or to operate and provide treatment later when Stage IV is reached.
Speakers: Dr. Jose M. Mascaro and Dr. Arnaldo Aldama
Report written by Dr. Silvina Maldonado
For the specific topic, New developments in blistering diseases, Dr Jose M. Mascaro discussed managing pemphigus vulgaris (PV) for the general dermatologist.
Diagnosis is based on clinical signs, compatible HP, detection of IG (+/-C3) in intercellular spaces (ICSs) via IFD and of autoantibodies in the serum (IgG autoantibodies against ICS via IFI/ against Dsg3 (+/-Dsg1) via ELISA or other techniques). For treatment, two steps should be considered: the first aims to induce remission to achieve control of the disease and then consolidation, and the second aims to maintain remission. To accomplish this, rituximab (RTX) is considered to be the first- line treatment, for use in mild PV (<5% of body surface, does not affect ingestion of food, PDAI<15),
either alone (2 infusions of 1 g) or in combination with prednisone at lower doses than those that were used a few years ago (0.5 to 1 mg/kg/day with gradual reduction leading to suspension in 3-4 months). Prednisone 0.5-1.5mg/kg/day is also used alone or in combination with azathioprine, mycophenolate mofetil/mycophenolic acid. For moderate to severe PV, with difficulties ingesting food or >5% body surface and PDAI >15, rituximab is indicated at 2 infusions of 1g combined with prednisone 1mg/kg/day with gradual reduction leading to suspension in 6 months, and if this is contraindicated, the corticosteroid can be combined with AZT or MMF. If the disease is well controlled at 3-4 weeks, continue at the same dose and at 6 months, if complete remission (CR) has been achieved, rituximab is indicated at 500mg or 1 g if it was severe or if high levels of anti-Dsg antibodies persist at 3 months. If CR is not achieved, 2 infusions of 1 g of rituximab at 12 and 18 months, RTX 500mg in patients with CR if they continue to be positive for anti-Dsg antibodies. If the case is not under control at 3-4 weeks and the patient had already received prednisone and RTX, increase corticosteroid to 1.5mg/kg/day or IV pulses. If they had only received prednisone, increase dose and add RTX or immunosuppressants. First-line treatment with RTX increases the 5-year CR rate relative to second- and third-line use. It is worth noting that guidelines have not yet been established to avoid relapses, and proposals include systematic use at 6, 12 and 18 months (EADV Guidelines 202), retreatment with a large number of cycles, or personalised treatment based on biomarker evolution (anti-Dsg antibodies, CD20 lymphocytes, T cells).
To conclude the day, Dr Arnaldo Aldama discussed the long-term management of pemphigus foliaceus with cortisone-sparing agents. Corticosteroids can be used in oral or parenteral form, in a bolus, intralesionally and even topically, with daily or divided dose schedules or with alternating doses, at the lowest possible dose and in combination with other drugs to reduce their dosage and maintain remission. Options include AZT, MMF, RTX and potentially DAPS and cyclosporine. In severe cases, Ig 2-3g/kg on 4-5 days each month, plasmapheresis or immunoadsorption (eliminates 80% of circulating antibodies, in monthly cycles of 4-5 days, but only available to a small number of doctors). As topical treatments: clobetasol, topical ATB, tacrolimus. It is also recommended to take environmental, dietary and photoprotection factors into account.
Speakers: Dr. Graciela Guzman, Dr. Natalia Hernandez, Dr. Lucie Puell, Dr. Ida Duarte, Dr. Ana M. Gimenez and Dr. Juan Pedro Russo
Report written by Dr. Silvina Maldonado
Dr Graciela Guzman said that there are probably no new allergens, except perhaps substitutions by more allergenic molecules, since there is a lot we don’t know about nanotechnology and its toxicity. These allergens are found in everyday items for personal, work-related and recreational use, in medical equipment/implants, and recently we have especially seen allergens associated with personal protective items. In terms of sensitisation to metals, there seems to be a genetic predisposition with alterations to the filaggrin complex. Nickel is the number one allergen, often co-occurring with cobalt and chromium as well as palladium (combined in alloys for dental procedures). In addition to its presence in metals, it is found in diet due to pots that release it, but it also occurs in almonds, nuts, oats and cacao. It is highly prevalent in women – face, neck and hands. It is followed by perfumes and cosmetics (oxidised fragrances): magnolia officinalis, linalool and limonene, methyl glucose dioleate, and carbomers, but as the “allergen of the year”, she mentioned glycolipid and alykl glucosides, which are present e.g. in a commercial product, Tacrolimus (ELIDEL). In cheilitis, perineal dermatitis and stomatitis, the role of mint, cinnamal, anethole, propolis and metals. Dexpantelol (B5) in moisturisers and cosmetics. In stomas, N-butyl monoester of polymethyl vinyl as well as isobornyl acrylate in glucose monitors.
Dr Natalia Hernandez presented a 5-year project in which 64.7% of patients had positive tests on the European standard series, with reactions caused by nickel, fragrance mix I, Peru balsam, fragrance mix II, and methylisothiazolinone (the latter is present in the “slimes” that children play with). She presented clinical cases in which the substances triggered contact dermatitis in different parts of the body, and in which it was not always easy to determine the mechanism by which the contactant produced the reaction. She noted the frequency of allergen positivity in atopic patients and the impact on their quality of life.
Dr Lucie Puell discussed patterns for guiding clinical suspicion: bilateral patchiness, which affects the forehead, cheekbones and chin; airborne, in which the neck is added but the nose is spared; and photoallergic, in which the nose is affected in addition to all of the above. Of the 1800 children and adolescents who were studied, about 70% were female, most with reactions on the face and hands. Reactions were noted on the face for wool alcohols, nickel, and potassium dichromate, and on the hands for nickel/cobalt/potassium dichromate and wool alcohols, in order of frequency. In another study in adults, the frequency was very high on the hands and less on the face/rest of the body, with nickel, cobalt, fragrance mix and chromium being the most commonly involved. She also emphasised the importance of ruling out associated pathologies and two forms together like the occupational and non-occupational airborne forms. Healthcare personnel have been affected by rubber accelerators in elastic bands on masks, formaldehyde, and adhesives like dibromodicyanobutane.
Dr Ida Duarte talked about metallic implants, especially trauma implants since those are the ones for which the most data are available, but also extending the discussion to other types (gynaecological
implants, pacemakers, intravascular and dental implants), and to the dilemma as to whether the failure of an implant is due to a hypersensitivity reaction or vice versa… These reactions manifest as erythema, eczema, oedema and/or joint pain, and present 2 months to 2 years after surgery, with greater frequency in women. The Major Criteria are: onset of chronic dermatitis weeks to months after implantation, positive contact tests for implant components, and complete resolution after implant extraction. The Minor Criteria are: treatment-resistant dermatitis, systemic ACD (allergic contact dermatitis) reaction, ACD physiopathology, and a positive lymphocyte transformation test for metal.
She noted that the sensitisers are nickel (20% sensitisation), chromium (10%) and cobalt (10%), and that these are found in almost all metal alloys:
Other components: methacrylate, benzoyl peroxide, N,N-dimethyl 4 toluidine (accelerator), gentamicin and hydroquinone. Familiarity with these factors is essential in determining the approach to be taken. A study was conducted with 72 patients in which pre-surgical tests were performed only if they had a prior history of allergy to metals (31 tested and 21 positive results, for whom a prosthesis was selected in accordance with the results); the other 41 were tested for post-surgical symptoms and only 10 were positive, of whom 6 had the implant removed with subsequent improvement; the remaining 4 refused. It’s very important to make clear that the pre-operative test indicates a current allergen and does not predict a future allergy, and that a positive post-operative test does not necessarily indicate that the ACD is responsible for the implant’s failure. If it is not possible to remove the implant, systemic corticosteroids are indicated for 21 days; in many cases, adaptive biological immune tolerance is achieved in this time.
Dr Ana M. Gimenez discussed the difficulty often encountered in objectively verifying the cause of ACD, since the standard tests often do not include the components that emerge from detailed questioning of the patient, and presented clinical cases in which a bit of detective work revealed the source of the reaction. Among others, she presented a case in which the difumarate found in the desiccant packets located in sofas and footwear from China triggered an epidemic in Europe, which led to a request for trade restrictions. Another interesting case was positive 2,4-dichlorophenol, found in bikinis, which caused urticaria reactions. She mentioned the reactions following administration of Moderna and Pfizer vaccines (mRNA), especially “covid arm”, which yield negative results for patch tests but positive results in intradermal reaction tests for polyethylene glycol. In conclusion, she presented the case of Myolastan (tetrazepam), which had to be taken off the market following severe illness among machine maintenance staff due to aerial suspension of the product.
Dr Juan Pedro Russo presented the consequences of the use of PPE (personal protective equipment) and recommended identifying areas of increased pressure if pain or non-blanching rash appears in order to avoid pressure lesions; removing after 4 hours; applying a moisturiser or silicone-based cream an hour before; and in case of a non-blanching rash, applying a hydrocolloid bandage. To avoid aggravating rosacea: skin cleansing, barrier restoration using non-sensitising products without fragrances or preservatives, examination and treatment of vascular reactivity, and examination of inflammatory response. Also for dermatitis of the hands, avoid very hot water, opt for glycerine-rich hand sanitisers, emollient-rich and preservative-free moisturisers, and vinyl/nitrite gloves.
