Malignant melanoma of the leg – challenges. A case report

Introduction

Cutaneous melanoma originates from abnormal melanocytes situated within the basal layer of the epidermis. These melanocytes play a crucial role in producing melanin, a substance that absorbs potentially harmful ultraviolet (UV) radiation. If left unaddressed, UV radiation can harm integumentary cells by directly damaging individual DNA strands. While the body typically employs specific DNA repair mechanisms to address UV-induced DNA damage, errors arising from genetic factors or environmental influences within this repair complex may contribute to the development of an invasive melanoma⁽¹⁾.

Several driver gene mutations exist in melanoma, notably in BRAF, NRAS, NF1, and KIT. These mutations collectively trigger the activation of the mitogen-activated protein kinase (MAPK) pathway, inducing unregulated proliferation of the tumor⁽²⁾. In a clinical context, BRAF stands out as the most significant among these driver genes. This is due to the fact that BRAF/MEK inhibitors can be employed as a treatment for BRAF-mutated melanoma^(3,4).

Nodular melanoma represents approximately 5% of cases, characterized by robust vertical invasion without radial growth. The amelanotic form is a rare variant, lacking pigmentation. Acral melanoma is an aggressive subtype with a poor prognosis, accounting for 2-3% of all new melanoma cases⁽⁵⁾. From a histopathological perspective, this subtype exhibits a low mutational burden and does not manifest mutations induced by UV radiation, which are commonly observed in other types of melanoma⁽⁶⁾.

Contemporary systemic therapy has markedly enhanced overall survival and progression-free survival in the management of the disease. The approval of first- and second-generation checkpoint blockade inhibitors has notably improved the outcomes for these patients. Long-term follow-up analysis reveals a median survival approaching six years with the combined use of CTLA4 and PD1 blockade⁽⁷⁾. Additionally, the phase III trial COMBI-d compared the combination of dabrafenib and trametinib with dabrafenib alone. The results showed that the combination reduced the risk of death by 29% compared to monotherapy, with a three-year overall survival of 44% versus 32%^(8,9).

Case report

A 55-year-old patient was diagnosed in 2011 with nodular malignant melanoma on the inner side of the left calf. At that time, a complete resection of the lesion was performed, revealing Clark level III invasion, with a Breslow thickness of 0.75-1.50 mm, accompanied by mitoses, pigmentation, and ulceration. A sentinel lymph node biopsy was conducted, and of the six sentinel nodes examined, none showed tumor invasion. Consequently, it was decided to initiate periodic clinical and imaging monitoring.

In 2022, the patient presented to the surgical service with a new lesion of approximately 6 cm, located 5 cm away from the surgical site. A surgical intervention was performed, involving wide excision, leaving a skin defect of 6/5 cm. The histopathological result confirmed the recurrence, indicating a nodular achromic malignant melanoma with invasion into the hypodermis (Clark level V, Breslow level >4 mm), without ulceration, and with a deep resection margin showing tumor invasion into the hypodermis.

The lesion exhibited a rapid evolution and, at that time, the only surgical solution was the partial amputation of the lower limb. CT and PET-CT scans were performed, revealing tumor recurrence in the metabolically active left calf, along with metabolically active left inguinal-femoral lymph nodes at various degrees, possibly suggesting an oncological origin. Additionally, a test to identify the status of the BRAF gene was conducted, revealing the BRAF V600E mutation.

It was decided to initiate immunotherapy as the initial stage following surgical reevaluation. From January 2023, systemic therapy was initiated, administering four cycles of nivolumab + ipilimumab. A complete CT scan was performed, showing stable disease, and the decision was made to continue with nivolumab monotherapy. After only one administration of nivolumab, the patient showed mild local disease progression. After the fifth administration, the patient experienced severe fatigue, and blood tests indicated dyselectrolytemia-hyponatremia. Thyroid hormones and cortisol were measured, revealing hypothyroidism and hypocorticism.

An endocrinology consultation was requested, which diagnosed panhypopituitarism, and corticosteroid therapy was initiated, followed by thyroid replacement therapy. Consequently, the systemic therapy with PD-1 inhibitors was definitively discontinued, and substitution therapy was continued. During this period, there was local disease progression, accompanied by ulceration and infection, necessitating antibiotic therapy and debridement.

Given the mutant BRAF status, it was decided to initiate systemic therapy with BRAF/MEK inhibitors, resulting in a favorable local evolution marked by a dimensional reduction of the tumor, but with the preservation of an ulcerative area. In August 2023, a surgical intervention was performed, involving the wide excision of the recurrent lesion on the left calf and the excision of a subcutaneous nodule. This time, the patient presented with malignant melanoma of the cellular subtype with fusiform cells, acral type, as indicated by the immunohistochemical result. The decision was made to continue systemic therapy with BRAF/MEK inhibitors, leading to the regression of the inguinal lymph nodes and no further local clinical progression.

Discussion

The BRAF-positive malignant melanoma presents two significant treatment directions – targeted therapy with BRAF/MEK inhibitors and immunotherapy with checkpoint inhibitors. The sequencing of these treatments plays an important role, and the DREAMseq and SECOMBIT studies have demonstrated a survival benefit in favor of administering immunotherapy in the first stage, followed by targeted therapy with BRAF/MEK inhibitors in the second sequence. In the DREAMseq study, a two-year overall survival rate of 72% was observed compared to 51%, while in the SECOMBIT study, a two-year overall survival rate of 73% versus 65% was reported^(10,11).

In the presented case, the patient developed resistance to immunotherapy. This resistance to immunotherapy is classified into primary resistance and secondary resistance. Primary resistance or intrinsic resistance represents the clinical situation where there is no response to immunotherapy⁽¹²⁾. One form of primary resistance is represented by hyperprogression⁽¹³⁾. Current research indicates that the amplification of the murine double minute (MDM) 2/4 gene, mutations in the epidermal growth factor receptor (EGFR) gene, and the chromosome 11 region 13 are linked to the onset of hyperprogressive disease (HPD)^(13-15).

Inhibitors targeting programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) can enhance the expression of interferon g (IFN-g) and trigger the activation of the JAK-STAT signaling pathway. This activation, in turn, induces the expression of IFN regulatory factor 8 (IRF8). The attachment of IRF8 to the MDM2 promoter facilitates its expression, potentially resulting in hyperprogressive disease⁽¹³⁾.

Acquired resistance denotes a clinical scenario where a tumor initially responds well to immunotherapy, but later experiences a relapse or progression following a period of treatment⁽¹²⁾. The mechanisms linked to resistance against immunotherapy can be classified into intrinsic factors that originate within cancer cells to hinder immune recognition and extrinsic factors within the tumor microenvironment. These extrinsic factors encompass stromal and immune cells, along with abnormal blood vessels. Apart from these significant causes, the impact of various external host factors must not be overlooked in the context of immunotherapy resistance. These factors encompass the age, gender and overall health status of patients, as well as various aspects of their lifestyle⁽¹⁶⁾.

The intrinsic factors that can lead to resistance are: 1) loss of neoantigen or lack of antigen mutations, or mutations in IFN signaling; 2) abnormalities in antigen processing; 3) aberrant signaling due to genetic mutations, such as MAPK, PI3, Wnt/b catenin, and interferon JAK1,2/STAT pathways; 4) abnormalities in antigen presentation due to the loss of MHC-1 expression, nonclassical MHC-I expression, or b2 microglobulin mutations; 5) expression or exocytosis of immune checkpoint proteins, such as PD-L1; 6) secretion of metabolites by cancer cells, such as adenosine, hydroxy cholesterol, which lead to the modulation of the tumor microenvironment; 7) epigenetic reprogramming of cancer cells; 8) resistance to apoptosis by the aberrant expression of intrinsic and extrinsic apoptotic proteins. The extrinsic factors are represented by: tumor-infiltrating lymphocytes (TILs), chemokines, tumor vascularization, metabolic products, and tumor-associated macrophages⁽¹⁶⁾.

Throughout the treatment with immune checkpoint inhibitors (PD-1/CTLA4 inhibitors), immune and non-immune adverse reactions may occur. In the CHECKMATE 067 study, immune reactions of any grade with increased frequency were: colitis (25%), rash (23%), and hepatitis (14%). Additionally, endocrinopathies had an increased frequency, hypophysitis representing 8%, hypothyroidism – 2%, and adrenal insufficiency – 4%⁽¹⁷⁾.

Conclusions

Systemic treatment for malignant melanoma has shown improvement in recent decades. Combined therapies, such as PD-1/CTLA4 inhibitors (nivolumab and ipilimumab) and BRAF/MEK inhibitors (dabrafenib/trametinib, encorafenib/binimetinib, vemurafenib/cobimetinib), were the first to demonstrate increased survival compared to monotherapy.

However, adverse reactions can occur in different degrees of severity, and clinical and biological monitoring of the patient is crucial to detect an immune adverse reaction at the onset.

The case presented in this paper is notable for the challenges that emerged during the treatment. Additionally, we wish to emphasize the effectiveness of new systemic therapies, the importance of their sequencing, and complementing, where necessary, with a surgical stage.   
 

Corresponding author: Daniela-Luminiţa Zob E-mail: danielazob@yahoo.com

Conflict of interest: none declared.

Financial support: none declared.

This work is permanently accessible online free of charge and published under the CC-BY licence.