Lentigo maligna melanoma, a clinicopathological and grenz rays management study

Lentigo maligna (LM), a neoplastic proliferation of skin melanocytes, is the in situ form of lentigo maligna melanoma (LMM) and it was first described in 1892 by a british surgeon Sir Jonathan Hutchinson. LM and LMM are melanoma types occurring in chronic sun exposed skin (head and neck) affecting mainly elderly patients. To this date no precursor lesion has been attributed to LM/LMM and it hypothesizes that they begin from an intraepidermal atypical melanocytic proliferation. Clinically, it presents as a slow growing diffuse irregular pigmented macula, usually consisting in a large lesion by the time of the diagnosis which hinders the conventional surgical treatment. Due to their large size, blurred margins, and location, LM/LMM have higher recurrence rate compared to other cutaneous melanoma types, resulting in several surgical interventions.

In the last decade, the treatment of advanced melanoma showed a significant improvement of overall patient survival with the use of target therapy and immunotherapy. However, patients can relapse, develop therapy resistance or life threatening side effects, which leads to the search of therapeutic options to overcome treatment failure.

The aim of this thesis is to enhance knowledge about precursor lesions, clinicopathological features of lentigo maligna, analyze treatment outcome with radiotherapy/Grenz Rays, and investigate other treatments to overcome therapy resistance in advanced melanoma.

In Study I we investigate the frequency of nevus associated lentigo maligna and lentigo maligna melanoma (NALMM) and its relationship with clinicopathological features usually related to melanomas occurring in low cumulative solar damaged skin (CSD). Our results demonstrate a higher frequency of NALMM (20%) compared to previous studies. We also detected in this group, high representation of females, thus a significant association between NALMM with multiple nevi and dysplastic nevi. Additionally, if patients in NALMM group developed another melanoma, they presented an increased risk that the second melanoma was also of nevus associated type. These paradigmatic findings could suggest that LM/LMM may also originate from a nevus like other types of melanomas.

In Study II we assess the effectiveness and safety of Grenz Rays (GR) treatment for LM and LMM after a period of 10-12 years. We also evaluate the cosmetical outcome and side effects related to radiotherapy dosage between distinct treatment groups. With a cure rate of 97% we can conclude that GR treatment is an effective, safe, long-lasting option for patients that are not suitable for surgery or for tumors (LM/LMM) that clear histopathological margins are difficult to achieve. We also observed that hyperpigmentation was associated with higher doses of GR.

With Study III we explore an alternative to enhance p53 tumor suppressor function while inhibiting the oncogenic insulin-like growth factor receptor (IGF1R) responsible for MAPK pathway activations. Working with a system biased toward β-arrestin2, we promote the translocation of MDM2 (p53 inhibitor) from nucleus to cytosol, with subsequent increase of p53 levels and decrease of IGF1R expression. Additionally, we tested this biased system in in vitro 3D models and in vivo (zebrafish embryos) in combination therapy with a chemotherapeutic drug dacarbazine showing a synergic effect and resulting in reduction of tumor size and metastasis. We conclude that disequilibrating the β-arr1/2 system towards β-arr2 on the IGF1R/MDM2/p53 axis is a promising strategy to reduce melanoma therapy resistance and improve treatment response to chemotherapy.

In summary, the objective of this thesis it to increase knowledge about the origin of LM/LMM and investigate other treatment options for localized and disseminated disease.

List of scientific papers

I. Drakensjö IRT, Hedblad M-A, Colón E, Girnita A. Nevus-associated lentigo maligna and lentigo maligna melanoma, clinicopathological features. Acta Derm Venereol. 2024; 104: 18381.
https://doi.org/10.2340/actadv.v104.18381

II. Drakensjö IRT, Rosen E, Frohm Nilsson M, Girnita A. Ten-year Follow-up Study of Grenz Ray Treatment for Lentigo Maligna and Early Lentigo Maligna Melanoma. Acta Derm Venereol. 2020 6;100(17):1-5.
https://doi.org/10.2340/00015555-3631

III. Cismas S, Pasca S, Crudden C, Trocoli Drakensjo I, Suleymanova N, Zhang S, Gebhard B, Song D, Neo S, Shibano T, Smith TJ, Calin GA, Girnita A, Girnita L. Competing Engagement of β-arrestin Isoforms Balances IGF1R/p53 Signaling and Controls Melanoma Cell Chemotherapeutic Responsiveness. Mol Cancer Res.
https://doi.org/10.1158/1541-7786.MCR-22-0871