Акценти от 4-ти ден

Dr Lise BOUSSEMART

Dermatologist, Rennes University Hospital, France

The last day began with a session on rare skin tumours (dermatofibrosarcoma, leiomyosarcoma, sebaceous carcinoma, Merkel cell carcinoma, etc.), which are too often diagnosed at a late stage, after clinical and/or histological evidence of metastasisation. Unfortunately, these diagnostic delays are determinant of prognosis.

Dermatologists are well aware that not every flesh-coloured tumour is a lipoma or cyst and that excision must always be accompanied by systematic histological analysis. Other types of physicians may be less well informed. It is untenable to prescribe a months-long course of antibiotics for “ulcerated cysts”, without biopsy. In cases of histological doubt, immunohistochemistry and genetic analysis can be helpful.

For example, Philippe Saiag reminded us that CD34 labelling and factor XIIIa and stromelysin-3 staining, as well as a typical genetic anomaly involving the translocation of chromosomes 17 and 22, can be used as diagnostic markers for Darier-Ferrand dermatofibrosarcoma (dermatofibrosarcoma protuberans or “DFSP”). The chimeric protein resulting from the fusion of the COL1A1 gene and the PDGF gene abnormally activates the PDGF receptors (PDGFR), thus triggering mitosis. A rarer fusion, with the same functional consequences, has recently been described between the COL6A3 and PDGFD genes (particularly in cases involving DFSP of the breast). These histogenetic characteristics provide diagnostic certainty when clinical presentation remains relatively non-specific (i.e. infiltrated papulo-nodular lesions, flesh colour, slow growth, occurrence in young adults).

Slow Mohs micrographic surgery, permitting histologic analysis of the tumour margins, should be used to treat DFSP, and the 3 cm excision margins of yesteryear should be reduced to 1 cm. The good news: the most recent data shows that, with early diagnosis and proper surgical treatment, the risk of local recurrence does not exceed 2%. In cases of inoperable DFSP, imatinib therapy is indicated, with proven efficacy but frequent relapse. Radiation and chemotherapy are contraindicated. In the event of rapid growth, fibrosarcomatous transformation must be suspected, and imaging should be used to identify a metastatic extension. This is the only indication for 3 cm surgical margins. Celeste Lebbé later discussed Merkel cell carcinoma and Kaposi sarcoma, which both have the distinction of being viro-induced. However, while patients with Kaposi sarcoma are HHV-8 positive and do not necessarily require treatment in the absence of symptoms, those with Merkel cell carcinoma (often fatal) can be Merkel cell polyomavirus negative (20% of cases in Europe, 71% of cases in Australia!). These cases are often associated with a higher UV-induced tumour mutational burden. Whether through the recognition of viral antigens or UV-induced neoepitopes, Merkel cell carcinoma has a high immunogenic potential.

The latest development in metastatic Merkel cell carcinoma is, of course, anti PD-1 or PD-L1 immunotherapy, which has demonstrated sustained efficacy. Such treatment is a significant improvement compared to the platinum-etoposide (salt-based) chemotherapy used until now. Thus, avelumab, an anti-PD-L1 antibody, is the first immune checkpoint inhibitor to have received a European MA for this indication in 2017. Nevertheless, as long as it is operable, Merkel cell carcinoma is treated surgically (1 to 2 cm margins according to EADO/EORTC recommendations, using the sentinel lymph node dissection technique) in tandem with adjuvant radiotherapy. The last plenary session again emphasised the futility of systematic lymph node dissection for sentinel node-positive patients. In the past, these dissections were systematically recommended, although there are no proven benefits. It has now been shown that this procedure has no impact on survival rates. It should be noted that the speaker, Daniel Coit, is a surgeon himself and acknowledges that some of his colleagues are opposed to no longer performing a complete lymphadenectomy on sentinel node-positive patients. He believes that this resistance may be related to the procedure itself, which is easier than effectuating close monitoring over the years, and that it is not easy to admit that this long-prevalent technique is unnecessary. Nevertheless, in his New York cohort of more than 380 patients who did not undergo systematic sentinel-node positive dissection (taking into account that dissection is sometimes necessary in cases involving clinical relapse and that such patients present with a significantly higher number of metastases than is typically the case for those undergoing immediate “sentinel-node positive dissection”), the patients operated on due to recurrence have better melanoma survival rates than those who were operated on immediately.

Next, an original presentation by a South African dermatologist (Dagmar Whitaker from Cape Town) highlighted the problem of skin cancer in dark-skinned patients (phototypes V and VI). She emphasised that dark phototypes do not guarantee 100% protection against skin cancers, even UV-induced types. Dark phototypes basically provide a level of protection equivalent to an SPF 15 sunscreen. Late diagnosis is also common, since the clinical manifestations of skin cancer on dark skin (such as hyperpigmentation or depigmentation) may be completely different from those on lighter skin (e.g. erythema). Given South Africa’s dark-skinned population, differential diagnosis is needed to distinguish advanced mycosis fungoides from leprosy. While Kaposi sarcoma lesions are typically described as purplish in colour, they often look hyperpigmented or black in HIV-positive patients. Cutaneous squamous cell carcinoma is often a complication of lupus, AIDS, burn scars, chronic HPV infection, etc.

The epidemiological register of new melanoma cases recorded in Namibia (2,000,000 inhabitants, reliable register) shows an incidence of 1 to 2 cases per 100,000 inhabitants/year in the “black” population as opposed to 40-70 cases per 100,000 inhabitants/year in the “white” population (an incidence comparable to Australia). Melanoma, especially (metastatic) plantar melanoma, is often diagnosed late in dark-skinned individuals. The disease is also common in patients with albinism and xeroderma pigmentosum. Dagmar Whitaker bemoaned the fact that, while two-thirds of the world’s population is dark skinned, most clinical trials are conducted on populations having light phototypes. The last few presentations were dedicated to the future. Caroline Robert and Antoni Ribas envisioned the melanoma landscape in 50 years, once the metastatic stage has been eradicated thanks to:

• very early diagnosis, facilitated by artificial intelligence
• immediate adjuvant treatment with a personalised vaccine via pan-DNA/RNA tumour analysis following excision
• subclinical detection by assaying highly sensitive and specific blood/urinary tumour markers (i.e. DNA and RNA tumour viruses)
• long-term, systemic neo-adjuvant treatment to effectively treat recurrences. This treatment would be adapted to each patient, using anti-PD-1 alone in pre-identified responders, and by other means in potentially resistant patients. Such combinations are foreseeable in the future, by coupling anti-PD-1 and TLR9 agonists (for intra-tumoural injection), PAK4 inhibitors (i.e. p21-activated kinase 4, a new resistance biomarker identified by Antoni Ribas) or Wnt/β-catenin inhibitors, activated by PAK4.

The EADO Congress ended on this pleasantly optimistic note. I thank you for reading our summaries thus far and hope you enjoyed them. I know that I’m returning to Rennes with lots of ideas, motivation and newly acquired knowledge!