Vol 18, No 6 (2022)
Guidelines / Expert consensus
Published online: 2022-11-09

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Expert recommendations on diagnostic-therapeutic management of melanoma patients

Piotr Rutkowski1, Piotr J. Wysocki23, Katarzyna Kozak1, Anna Nasierowska-Guttmejer45, Arkadiusz Jeziorski6, Wojciech M. Wysocki7, Ewa Kalinka8, Tomasz Świtaj1, Grażyna Kamińska-Winciorek9, Anna M. Czarnecka1, Hanna Koseła-Paterczyk1, Bożena Cybulska-Stopa10, Piotr Wiśniewski11, Anna Szumera-Ciećkiewicz1112, Marcin Zdzienicki1, Marek Ziobro10, Jacek Fijuth13, Andrzej Kawecki14, Andrzej Tysarowski11, Bożena Romanowska-Dixon15, Anna Markiewicz15, Marek Dedecjus16, Tomasz Kubiatowski17, Kamil Dolecki18, Hanna Tchórzewska-Korba19, Lidia Rudnicka20, Witold Owczarek21, Maciej Krzakowski22
Oncol Clin Pract 2022;18(6):357-392.

Abstract

Not available

GUIDELINES FOR DIAGNOSTIC AND THERAPEUTIC MANAGEMENT

Expert recommendations on diagnostic--therapeutic management of melanoma patients

Team of authors:Piotr Rutkowski1Piotr J. Wysocki23Katarzyna Kozak1Anna Nasierowska-Guttmejer45Arkadiusz Jeziorski6Wojciech M. Wysocki7Ewa Kalinka8Tomasz Świtaj1Grażyna Kamińska-Winciorek9Anna M. Czarnecka1Hanna Koseła-Paterczyk1Bożena Cybulska-Stopa10Piotr Wiśniewski11Anna Szumera-Ciećkiewicz1112Marcin Zdzienicki1Marek Ziobro10Jacek Fijuth13Andrzej Kawecki14Andrzej Tysarowski11Bożena Romanowska-Dixon15Anna Markiewicz15Marek Dedecjus16Tomasz Kubiatowski17Kamil Dolecki18Hanna Tchórzewska-Korba19Lidia Rudnicka20Witold Owczarek21Maciej Krzakowski22
1Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw
2Department of Clinical Oncology, University Hospital in Krakow
3Clinic and Department of Oncology, Jagiellonian University — Collegium Medicum, Krakow
4Department of Pathomorphology, Central Clinical Hospital of the Ministry of Interior and Administration, Warsaw
5Lazarski University, Warsaw
6Department of Oncological Surgery, Medical University of Lodz, II Ward of Oncological Surgery, N. Copernicus Provincial Multidisciplinary Centre of Oncology and Traumatology, Lodz
7Department of Surgery, Faculty of Medicine and Health Sciences, Andrzej Frycz-Modrzewski Krakow University, Krakow
8Department of Oncology, Polish Mother’s Memorial Hospital Research Institute, Lodz
9Clinic of Bone Marrow Transplantation and Hematology-Oncology, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Branch in Gliwice
10Department of Clinical Oncology, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Branch in Krakow
11Department of Pathology and Laboratory Diagnostics, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw
12Department of Hematological Diagnostics, Institute of Hematology and Transfusion Medicine in Warsaw
13Department of Radiotherapy, Medical University of Lodz, Lodz
14Department of Head and Neck Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw
15Department of Ophthalmology and Ophthalmic Oncology, Jagiellonian University — Collegium Medicum, Krakow
16Department of Endocrine Oncology and Nuclear Medicine, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw
17Warmian-Masurian Cancer Center of The Ministry of The Interior and Administration’s Hospital, Department of Oncology and Immunohematology with the Day Center of Cancer Therapy, Olsztyn
18The Polish Sarcoma and Melanoma Patients Association “Sarcoma”
19Department of Rehabilitation, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw
20Warsaw Medical University, Infant Jesus Teaching Hospital, Warsaw
21Military Institute of Medicine, Central Clinical Hospital of the Ministry of National Defense, Warsaw
22Department of Lung and Chest Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw

Table of Contents

Methodology 359

Part I. Skin and mucosal melanoma 359

Summary 359

Diagnostics 359

Staging 359

Treatment for stage IIII melanoma (resectable) 360

Treatment of stage III (inoperable) and stage IV 360

Follow-up after treatment 360

Epidemiology and etiology 360

Diagnostics 361

Differential diagnosis 362

Dermoscopy (dermatoscopy) 362

Histopathological diagnosis excisional biopsy of the primary skin lesion (microstaging I) 362

Histopathological diagnosis 363

Molecular diagnostics 364

Staging and prognostic factors 365

Clinical staging 365

Prognostic factors 365

Primary melanoma 365

Metastasis in regional lymph nodes (stage III) 365

Metastases in distant organs (stage IV) 365

Treatment 368

Principles of primary lesion treatment and surgical evaluation of regional lymph nodes 368

Surgical treatment after excisional biopsy 368

Sentinel node biopsy (microstaging II) 368

Radiotherapy 370

Treatment of metastases in regional lymph nodes 370

Treatment after positive sentinel lymph node 370

Treatment in the presence of metastases in clinically detected regional lymph nodes 370

Satellite lesions, in-transit metastases, and local recurrence 371

Melanomas located within the mucous membranes 372

Adjuvant therapy 372

Immunotherapy 373

Interferon alfa-2b 373

Ipilimumab 374

Nivolumab 374

Pembrolizumab 374

Other immunological drugs 374

Molecularly targeted therapy 374

Dabrafenib with trametinib 374

Adjuvant radiotherapy 374

Treatment of metastatic patients 375

Chemotherapy 375

Immunotherapy 375

Anti-CTLA-4 antibodies (ipilimumab) 375

Anti-PD-1 antibodies (nivolumab and pembrolizumab) 377

Anti-PD-1 antibodies with anti-CTLA-4 antibodies (nivolumab with ipilimumab) 378

Molecularly targeted therapy 378

BRAF/MEK inhibitors 378

KIT kinase inhibitors 379

Sequencing of systemic therapy 379

Combination therapy 379

Rehabilitation 379

Physiotherapy of patients with post-treatment lymphedema 379

Follow-up after treatment 381

Conclusions 381

Part II. Ocular melanoma 383

Uveal melanoma 383

Epidemiology and etiology 383

Staging and prognostic factors 383

Signs and symptoms 383

Diagnostic tests 383

Differential diagnostics 386

Remarks 386

Treatment 386

Conservative 386

Radical surgery 387

Treatment in the generalized stage 387

Follow-up and treatment of local complications 387

Conjunctival melanoma 387

Conflict of interest 388

References 388

According to the authors and editors, this report contains the best justified principles of diagnostic and therapeutic procedures prepared on the basis of the scientific value of evidence and recommendations. These principles should always be interpreted in the context of an individual clinical situation. The recommendations do not always correspond to the current reimbursement rules in Poland. In case of doubt, current possibilities for reimbursement of individual procedures should be determined.

The quality of scientific evidence

I Evidence from at least one large randomized controlled clinical trial (RCT) of high methodological quality (low risk of bias) or meta-analysis of properly designed RCTs without significant heterogeneity

II Small RCTs or large RCTs with risk of bias (lower methodological quality) or a meta-analysis of such studies or RCTs with significant heterogeneity

III Prospective cohort studies

IV Retrospective cohort studies or case-control studies

V Uncontrolled studies, case reports, expert opinions

2. Strength of recommendations

1 — Recommendation based on high-quality evidence on which unanimity has been achieved or a high level of expert team consensus

2A Recommendation based on lower-quality evidence on which unanimity has been reached or a high level of expert team consensus

2B Recommendation based on lower-quality evidence on which moderate expert consensus has been achived

Methodology

Review of all phase II and III clinical trials available in PubMed and published between 1990 and 2021 and containing the term “melanoma” and current recommendations of the European Society Medical Oncology (ESMO), American Society of Clinical Oncology (ASCO), National Comprehensive Cancer Network (NCCN), and the Polish Society of Clinical Oncology (PTOK).

Part I.

Skin and mucosal melanoma

Summary

Diagnostics
  • Dermatoscopic examination (dermoscopy) is recommended for the assessment of skin lesions, especially before their planned excision.
  • In the case of skin lesions, an excisional biopsy should be performed (in most cases under local anesthesia), with a minimal surgical margin of 12 mm (III, 2A).
  • The elements of microscopic histopathological reporting of primary cutaneous lesions should obligatorily include (1) infiltration thickness in mm according to Breslow in mm, (2) presence or absence of ulceration, (3) number of division figures per 1 mm2 (mitotic index), (4) pT staging, (5) growth phase, (6) presence or absence of microscopic satellite foci, (7) peripheral and deep surgical margin (assessment of radicality of surgical procedure).
  • Molecular testing for the presence of BRAF gene mutations is mandatory in patients with stage III (operable and non-operable) and IV (I, 1) and recommended for stage IIC.
Staging
  • Physical examination with a careful assessment of the entire skin (especially the assessment of other suspected pigmented lesions, satellite or in-transit nodules, regional lymph nodes, and possible distant metastases).
  • In higher stages, it is recommended to perform an ultrasound examination (US) and computed tomography (CT), and/or positron emission tomography (PET) for proper staging.
Treatment for stage IIII melanoma (resectable)
  • Radical excision of the scar after excisional biopsy of the primary lesion is recommended in all patients with appropriate resection margins (melanoma in situ 5 mm, melanoma with Breslow thickness2 mm 1 cm, melanoma with Breslow thickness > 2 mm2 cm) (I, 1).
  • Sentinel lymph node biopsy (SLNB) is recommended in the case of infiltration with Breslow thickness0.8 mm or (micro) ulceration on melanoma surface, regardless of Breslow thickness (pT1bT4b) (I, 1).
  • Sentinel lymph node biopsy should be performed simultaneously with radical excision of the scar after melanoma excisional biopsy.
  • Lymphadenectomy in the case of positive sentinel lymph node biopsy is not routinely recommended (I, 2A).
  • Lymphadenectomy is indicated in the presence of metastatic melanoma in clinically detected lymph nodes (II, 2A).
  • Systemic adjuvant therapy with immunotherapy (anti-PD-1: nivolumab or pembrolizumab) or targeted therapy (dabrafenib/trametinib, in the presence of BRAF gene mutation) is indicated in all patients with stage III after metastases resection or after resection of stage IV lesions (nivolumab) (I, 1).
  • Radiotherapy as adjuvant treatment is not recommended (II, 1).
Treatment of stage III (inoperable) and stage IV
  • For patients with metastatic disease, enrollment in clinical trials is the most appropriate treatment.
  • Systemic treatment of patients with BRAF V600 mutation includes BRAF inhibitor (in combination with MEK inhibitor) and, regardless of BRAF mutation status, immunotherapy anti-PD-1 (nivolumab or pembrolizumab), anti-CTLA-4 (ipilimumab) antibodies in monotherapy or in combination (nivolumab with ipilimumab) (I, 1).
  • The optimal treatment sequence (especially in the presence of BRAF mutation) has not been definitely established yet.
  • The use of combination therapy with BRAF and MEK inhibitors is associated with a high response rate (approximately 70%) and quick symptom resolution, while treatment with anti-PD-1 antibodies results in a lower response rate; however, responses are mostly long-term and persist even after discontinuation of therapy.
Follow-up after treatment
  • Patient education regarding skin and lymph node self-examination.
  • Medical history and physical examination, including a comprehensive skin assessment, especially the area of scar after resected melanoma and regional lymph nodes (every 36 months for the first 23 years, then every 312 months up to 5 years, and once a year after 5 years) (II, 2A).
  • Ultrasound examination of regional lymph nodes every 46 months if a positive sentinel lymph node is detected without lymphadenectomy and if sentinel lymph node biopsy was not performed in the case of skin melanomaspT1b (every 4 months for the first 2 years, then every 6 months for the next 3 years, up to 5 years inclusive).
  • In asymptomatic patients after 5 years of follow-up, imaging examinations are not recommended.
  • The frequency and type of examinations, as well as the duration of the observation, should depend on individual risk of disease recurrence (II, 2A).

Epidemiology and etiology

Melanomas are malignant neoplasms originating from neuroectodermal melanocytic cells. In Poland, melanomas are relatively rare the standardized incidence rate is about 6 per 100 000, which corresponds to about 3 800 cases per year in recent years (about 1800 in men and about 2000 in women). However, melanomas are neoplasms with the largest incidence growth rate, i.e. increase of newly diagnosed cases. In Poland, in the years 19802010, the number of cases increased almost threefold. The median age of onset is similar for both sexes and is approximately 50 years. Standardized mortality rates are around 2.1 per 100 000 in men and 1.4 per 100 000 in women, accounting for an estimated 700 and 710 deaths from melanoma among men and women, respectively, in recent years [1–3].

The following are considered to be the most important factors of the increased melanoma risk: (1) high exposure to ultraviolet (UV) radiation, both natural (sun rays, especially sunburn in childhood and young age) and artificial (e.g. tanning beds, solariums), (2) constant mechanical or chemical irritation, (3) low skin pigment and (4) genetic predisposition, e.g. familial atypical mole syndrome (FAMS) (III, 2A). Protection against excessive UV radiation represents the most important element of melanoma primary prevention (III, 2A).

In over 90% of cases, melanomas develop in the skin. However, melanocytes are also found in locations other than skin (epithelium of respiratory tract, digestive tract, and genitourinary mucous membranes, as well as uvea and meninges), which may lead to primary melanoma development also in these locations.

Mucosal melanomas are very rare neoplasms and account for up to 1% of all melanomas (several dozen cases are recorded annually in Poland). They mainly develop as tumors of head and neck (nasopharynx), gastrointestinal tract (most often in the anal area), and the genital area (mainly vulva and vagina) [4]. Melanomas of the mucous membrane are a condition which most commonly affects older patients (mean age of onset is about 70 years), although primary oral mucosal melanoma often occurs at an earlier age [5, 6]. Mucosal melanoma is more common in women than in men, mainly due to the development of the disease in the genital area. It is estimated that 20% of mucosal melanomas are multifocal [7], compared with less than 5% of skin melanomas [8]. About 40% of mucosal melanomas are colorless (amelanotic) while in the skin they occur in less than 10% of cases. Mucosal melanomas are characterized by an aggressive clinical course and poor prognosis. Most patients eventually develop distant metastases despite radical surgery. The 5-year survival rate in mucosal melanoma is only 25% [9].

In about 3% of cases [10] melanoma cells are found in the lymph nodes or other organs the primary melanoma lesion cannot be determined and this is the so-called melanoma with an unknown primary (MUP) (T0). MUPs should be treated as cutaneous melanomas. At diagnosis, in approximately 80% of patients, skin melanoma is a local lesion, while the regional and metastatic stage is diagnosed primarily in approximately 15% and 5% of patients, respectively. The 5-year survival rates in early melanoma are 7095%, and 3070%, 2040%, in regional and metastatic stage, respectively, despite using modern systemic treatment.

Advances in adjuvant and palliative treatment are still unsatisfactory in patients with metastatic cutaneous melanoma, and, therefore, melanoma should be detected at the earliest possible stage of the disease. Due to the localization, early identification of the primary lesion (microstaging I excisional biopsy of the primary lesion) and regional lymph nodes metastases (microstaging II sentinel lymph node biopsy) enable cutaneous melanoma radical treatment.

The primary and obligatory rule should be multidisciplinary team (MDT) management of melanoma patients. Team members should be experienced in the diagnosis and treatment of melanomas. Above all this roule should be applied to patients with stage III and IV melanomas [11, 12].

Diagnostics

Skin melanoma may be suspected when skin lesions develop de novo or on the basis of a pigmented nevus. The medical history should include questions about the condition of the skin, i.e. any changes in the existing skin moles, the appearance of new pigment spots and accompanying symptoms (e.g. pruritus), and factors increasing the risk of skin melanoma (e.g. sunburn, use of self-tanning beds solarium, family history of melanomas and previous immunosuppressive treatment, or human immunodeficiency virus [HIV] infection). It should be emphasized that in more than 60% of melanomas diagnosed during clinical assessment, medical history is unrevealing.

Table 1. ABCDE Rule allowing for the initial identification of some melanomas based on clinical examination without the use of additional diagnostic methods

ABCDE System

A (asymmetry) melanoma is asymmetrical according to each axis of the lesion, unlike benign moles, which are usually round or oval, additionally presenting irregular shape with protrusions called islands

B (borders) uneven and notched

C (color) variety of colors (from different shades of brown to black, steely) with uneven pigment distribution, frequently with spot deposits (especially visible in dermatoscopy)

D (diameter) higher than 5 mm or dynamics of morpho­logical changes in the tumor

E (elevation or evolution) elevation of surface above the level of surrounding epidermis. Thin melanomas (thickness 1 mm according to the Breslow scale) make it impossible to palpate protuberance compared to normal skin surrounding the lesion; more important than elevation of primary lesion is extension or evolution

Clinical symptoms are sometimes grouped into systems to facilitate diagnosis (Tab. 1). The best known is the American clinical system ABCDE, currently used mainly for educational purposes, as it allows identifying only part of melanomas, mainly superficially spreading melanomas, and significant part of advanced melanomas. It cannot be used as a screening diagnostic tool in clinical practice. The ABCDE clinical system does not allow for proper classification of about 50% of melanomas (especially early melanomas < 5 mm in diameter, nodular melanomas, usually without color heterogeneity or border irregularity, as well as nonpigmented [amelanotic] melanomas and scalp lesions) [1].

However, the most important element allowing early diagnosis of melanoma is a comprehensive skin examination (IV, 2A). Thin melanomas (with Breslow thickness < 1 mm) are usually detected during a physical examination, but very rarely by the patient or family members. Thorough skin examination should be performed, if possible, during every outpatient visit or hospitalization. The principle is to assess full-body skin in good lighting, including difficult-to-reach areas (head, acral area hands and feet, interdigital spaces, genitals and anal region, and mucous membranes).

Differential diagnosis

Medical conditions to be considered during differential diagnosis of early and locally advanced skin melanoma are presented in Table 2.

Table 2. Clinical differential diagnosis of cutaneous melanoma

Early skin melanoma

Melanocytic naevus, including junctional melanocytic naevus and compound melanocytic naevus

Blue naevus

Simple lentigo

Actinic/solar keratosis

Superficial basal cell carcinoma

Spitz naevus

Tattoo

Locally advanced melanoma

Seborrhoieic keraratosis/wart

— Dermatofibroma/fibrous histiocytoma

— Keratoacanthoma

— Pigmented basal cel carcinoma

— Hemangioma

— Venous extravasation

— Pyogenic granuloma/lobular capillary hemangioma

— Pigmentosus ebaceous cyst

— Kaposi sarcoma

— Glomus tumor

— Other appendicular tumors, particularly pigmentosus

— Onychomycosis

— Subungual or subcorneal hematoma

Dermoscopy (dermatoscopy)

The recommended test used in the initial, quick, and non-invasive diagnosis is dermoscopy (dermatoscopy) (II, A) [13, 14]. The examination consists of a visual assessment of all lesions on the patient’s skin using a hand-held dermatoscope with either polarized or non-polarized light with immersion at 10-fold magnification [13, 14]. Dermoscopy improves diagnostic sensitivity by about 30%. The simplest principle of dermoscopic evaluation (the so-called Argenziano three-point checklist of dermoscopy) is based on the clinical suspicion of melanoma if two of the following three criteria are met: 1) asymmetric distribution of dermoscopic structures within the lesion, 2) atypical pigment network (APN), 3) blue-white veil. The sensitivity and specificity of this diagnostic method reach 96.3% and 94.2%, respectively. Other methods of dermoscopic analysis, including the ABCD dermoscopic method, pattern analysis, seven-point scale, Menzies method, or CASH (color, architecture, symmetry, homogeneity) algorithm, are characterized by comparable sensitivity with slightly greater specificity. It should be emphasized that these dermoscopic evaluation systems do not apply to lesions in “special locations” involving the skin of the face and acral region palms and soles, and on the nail plate, on mucous membranes of the mouth and genitals. In such cases, it is necessary to use dermoscopic algorithms, developed separately based on characteristic features and dermoscopic patterns for the above specific locations. In the case of syndrome of atypical moles, it may be a useful practice to collect photographic documentation of selected lesions or the entire surface of the skin (total body photography) and to compare the photos taken and the observed skin lesions at successive time intervals. Some systems perform an automated comparison of dermoscopic images at successive time intervals, but they are not widely used due to technological limitations.

Initial dermoscopic diagnosis can be verified with reflectance confocal microscopy (RCM) as part of specialist dermatological advice. In justified cases, when an excisional biopsy is not possible (e.g. suspected melanoma in the area of extensive birthmarks in young children), it is possible to perform dermoscopy-guided biopsy and histopathological examination.

Histopathological diagnosis excisional biopsy of the primary skin lesion (microstaging I)

Excisional biopsy of the primary skin lesion, clinically suspected of being malignant melanoma, is the procedure of choice as it provides microscopic confirmation of melanoma diagnosis and makes it possible to obtain information about the most important prognostic factors, which are used for further treatment planning (microstaging) (III, 2A) [1, 12, 15]. There are no indications for „prophylactic” excision of birthmarks that do not raise suspicion of skin melanoma.

Figure 1. (According to W. Ruka) Recommended direction of the cut during the excisional biopsy. Spindle-shaped excision of the suspected pigmentary lesion should be made collaterally to the regional lymph vessel (toward the nearest draining lymph node/lymph vessel confluence), in the majority of cases enabling a primary suture of the wound

Excisional biopsy is a simple surgical procedure and is often possible to run outpatient. Excision of a suspected skin lesion is performed under local infiltration anesthesia with a lateral margin of 13 mm of unchanged skin. Apart from the entire thickness of the skin, the surgical preparation also contains a superficial layer of fatty tissue; the fascia is not cut out, and the wound is closed with a primary suture. The skin incision should be in line with the long axis of the body (Fig. 1), only facial skin should be cut in line with aesthetic lines. Transverse cuts (in the limb localization) should never be performed, as in case of reoperation, they result in a very bad cosmetic effect and are considered an error for oncological reasons.

The results of fine-needle or core-needle aspiration biopsy and incisional (section) or shave biopsy do not provide reliable information regarding primary melanoma in accordance with the requirements of the American Joint Cancer Committee/Union Internationale Contre le Cancer (AJCC/UICC) system, and these methods should not be used.

In the case of very large and ulcerated lesions, the sampling procedure can use imprint cytology, consisting in pressing the glass slide against the tumor surface and sending the collected material for cytological examination, a fine-needle or core-needle biopsy, as well as incisional biopsy (with taking a section from the lesion).

Histopathological diagnosis

Pathological examination of the material obtained by excision of the primary lesion consists of macro- and microscopic examination with the specification of mandatory and conditionally tested features, which should be included in a standardized histopathological report.

  1. Macroscopic examination
  1. Size of removed skin fragment with the lesion (3 dimensions).
  2. Lesion size (2 dimensions).
  3. Color (uniform, non-uniform).
  4. Lesion border (regular, irregular).
  5. Nodule (present, absent).
  6. Margin (lateral, depth).

2. Microscopic examination of the skin with the lesion.

Compulsory microscopic features:

  1. Histopathological diagnosis according to the World Health Organization (WHO) 2018 histopathological classification of melanocytic tumors and the ICD-O code.
  2. Breslow thickness in millimeters, measured from the granular layer of epidermis or ulcer bottom to the deepest infiltrating melanocyte nests.
  3. pT staging according to the 8th edition of AJCC/UICC 2017 pTNM classification [16].
  4. Presence or absence of a full-thickness ulcer resulting from melanoma cell penetration into the epidermis, other than a mechanical ulcer, and its extent determined by the diameter or percentage of affected skin area over the tumor.
  5. Number of division figures per 1 mm2 (only in the vertical component, measured in the fields with the highest mitotic activity, the so-called hot spots).
  6. Growth phases (horizontal [radial] intra-epidermal, in situ and sagittal [vertical], always invasive cutaneous).
  7. Presence or absence of microscopic satellite foci (foci from melanocytes over 0.05 mm in diameter at a distance of more than 0.3 mm and up to 2 cm from the invasive component of the primary melanoma feature N).
  8. Peripheral margin (from in situ and invasive component) and in the depth.

Features conditionally determined in the histopathological report:

  1. Regression degree.
  2. Clark infiltration depth (level I, II, III, IV, V).
  3. Cell type (epithelioid, fusiform, small, pleomorphic, other).
  4. Presence and intensity of tumor-infiltrating lymphocytes (TILs) assessed only in the vertical component: absent, moderately abundant TILs non-brisk, abundant TILs brisk.
  5. Presence or absence of lymphatic and blood vessels infiltration.
  6. Presence or absence of nerve trunks infiltration.
  7. Presence of nevus.

In selected cases, to confirm clinically occult metastases in sentinel lymph nodes and distant metastases, the differential diagnosis between benign and malignant melanocytic lesions should encompass immunohistochemical tests with antibody panel including HMB45, Melan A, p16, SOX-10, and Ki-67.

The WHO Classification of Skin Tumours, the 4th Edition 2018, distinguishes the following types of melanoma [17]:

  • melanocytic tumors in intermittently sun-exposed skin;
    • superficial spreading melanoma, low-CSD melanoma;
  • melanocytic tumors in chronically sun-exposed skin;
    • lentigo maligna melanoma,
    • desmoplastic melanoma;
  • Spitz melanoma;
  • acral melanoma;
  • mucosal melanomas: genital, oral, sinonasal;
    • mucosal lentiginous melanoma,
    • mucosal nodular melanoma;
  • melanoma arising in blue nevus;
  • melanoma arising in giant congenital nevus;
  • ocular melanocytic tumors;
    • uveal melanoma: epithelioid cell melanoma, spindle cell melanoma type A, spindle cell melanoma type B,
    • conjunctival melanoma;
  • nodular melanoma;
  • nevoid melanoma;
  • metastatic melanoma.

Assessment of PD-L1 receptor expression, reported as a percentage of tumor positive cells, may be useful in patients with stage III or IV (I, 2B), although its clinical application is currently very limited [10].

Molecular diagnostics

Performing BRAF gene mutations testing (in formalin-fixed paraffin-embedded [FFPE] tissue specimens) is obligatory in patients with stage III (operable and inoperable) and stage IV (I, 1) melanoma [10] and recommended in stage IIC. However, mutation testing is not recommended in patients with stage I and IIAIIB primary melanomas [10]. In the absence of BRAF gene mutation, NRAS and KIT genes mutations testing (II, 2B) should be considered [10]. There is no need for additional sampling from metastases to verify the presence of molecular abnormalities. Genetic testing should be performed in centers subject to quality control (QC). Laboratories should have two alternative methods to identify BRAF gene mutations at codon 600. The most commonly used tests are based on the qPCR method, which allows identifying the most common mutations in a relatively short time and with high sensitivity. The second method of BRAF gene mutation testing should allow for precise verification of codon 600 mutation type; in such cases, direct Sanger sequencing is used. It enables the identification of all variants occurring in exon 15 of BRAF gene (codon 600 region), including p.(Val600Glu), c. 1799T>A V600E; as well as p.(Val600Glu), c.1799_1800delinsAA, V600E2; p.(Val600Lys), c.1798_1799GT>AA, V600K; p.(Val600Asp), c.1799_1800delinsAC, V600D; p.(Val600Asp), c.1799_1800delinsAT, V600D2; p.(Val600Gly), c.1799T>G, V600G; p.Val600Arg, c.1798_1799GT>AG, V600R; and p.Val600Met, c.1798G>A, V600M. This is of particular importance, considering that particular variants translate into different activities of BRAF protein kinase. For this reason, Sanger sequencing is also commonly used as a verification analysis after mutation detection using a qPCR-based assay. In general, qPCR tests do not distinguish between and not determine exactly which nucleotide (and consequently) amino acid is found in BRAF. It should be also mentioned that, unlike sequencing, qPCR testing is also dedicated to the identification of only selected V600 variants (not all). Therefore, in the case of using the qPCR test, which was dedicated to the identification of only selected V600 variants (not all) and BRAF mutation-negative status, it is recommended to perform direct sequencing to verify the result, especially when the clinical manifestation supports the presence of BRAF gene mutation.

An alternative to tissue sampling for BRAF mutation testing can be circulating tumor DNA (ctDNA) analysis. DNA secreted by cancer cells and slowly circulating in the patient’s bloodstream can be obtained using dedicated blood sampling and collection kits, and this is the so-called liquid biopsy. Molecular biology techniques used to determine the V600 mutation in ctDNA must be characterized by high analytical sensitivity (dedicated qPCR and ddPCR kits). It should be emphasized, however, that ctDNA can be used to test BRAF mutation only when the tissue material is unavailable or is undiagnostic due to low quality [18, 19].

It is recommended to perform the diagnostics of mutations occurring in the promoter of TERT and HRAS genes to correctly classify melanocytic lesions of the spitzoid type, with particular emphasis on differentiation from melanoma in this group of melanocytic lesions [20, 21].

It is currently known that certain melanoma subtypes are associated with specific mutations: mutations in BRAF, CDKN2A, NRAS, and TP53 genes skin melanomas; in NF1 and KIT genes acral melanomas; in SF3B1 genes mucosal melanomas; in GNAQ, GNA11 genes melanomas originating in the cellular blue nevus and the organ of sight [22].

In a small percentage of primary lesions, where the morphology and immunohistochemical testing do not allow for an unambiguous determination of the nosological status (entities belonging to the category of melanocytic lesions with an uncertain malignancy potential, sometimes also referred to as borderline lesions), it is possible to use molecular biology techniques to refine the diagnosis. According to the current recommendations in Europe and worldwide, the following tests can be used for this purpose: immunohistochemical staining, gene expression profiling (GEP), fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH), or next-generation sequencing (NGS).

Staging and prognostic factors

Clinical staging

The current TNM (tumor-node-metastasis) classification system for the clinical and pathological staging of skin melanoma comes from a revision presented in 2017 (Tab. 3) (II, 2A) [16].

The basis for the diagnosis of skin melanomas is the histopathological examination of the entire surgically resected pigmentary lesion. No other procedure, except excisional biopsy (the so-called microstaging I), allows for the correct diagnosis (III, 2A).

After a histopathological diagnosis of cutaneous melanoma is achieved, treatment should be initiated according to the stage (see below).

First of all, a thorough physical examination should be performed, including examination of the full-body skin (presence of other suspicious pigmented, satellite, and/or in-transit lesions), lymph nodes assessment, and examination for the presence of possible distant metastases. Imaging tests are not routinely required in low-stage primary lesion (pT1a) melanomas. However, in higher stages of T (T1bpT4b), it is advisable to perform an ultrasound examination (US) of the regional lymph nodes before removing the scar with sentinel node biopsy. If there are any suspicious changes in the ultrasound examination, a biopsy with histological evaluation should always be performed. If there are no clinical symptoms, imaging tests such as chest, abdominal, pelvic computed tomography (CT) with contrast, positron emission tomography (PET-CT), and magnetic resonance imaging (MRI) of the brain are not recommended, although they may be considered at higher stages (pT3b and higher) (III, 2B) [10]. In the case of clinical metastases in inguinal lymph nodes, pelvic-abdominal CT or MRI with contrast is indicated.

In patients with lymph nodes or skin metastases of melanoma of unknown primary melanoma (UPM), it is necessary to carefully search for a possible primary tumor (especially on the scalp, mucous membranes) and to obtain detailed medical history (e.g. regarding previous lesions treated with ablative methods as part of aesthetic medicine or dermatosurgery). In such a clinical situation, it is advisable to perform additional imaging examinations (brain MRI, CT with contrast, or PET-CT of neck, chest, abdomen, and pelvis) (IV, 2B).

Laboratory tests are not routinely performed while, in stage IV, lactate dehydrogenase (LDH) level is measured.

Prognostic factors

Identification of clinical and pathomorphological prognostic factors aims at understanding the biology of the neoplasm and facilitating the planning of appropriate treatment for a given patient, taking into account the risk of disease recurrence and the probability of survival after treatment.

Primary melanoma

The most important prognostic factors in patients with non-metastatic skin melanomas include Breslow thickness and the presence of (micro) ulceration of the primary lesion. The prognostic significance of the number of infiltrated lymph nodes and microsatellites as a component of feature N was also found. These factors were used in the development of the TNM classification, version 8 (Tab. 3) [12, 15, 16, 23].

Table 3. 2017 TNM AJCC/UICC melanoma staging

A. TNM System Categories

Feature T

Tumor Breslow thickness [mm]

(Micro-) ulceration

Tis (melanoma in situ)

Not applicable

Not applicable

Tx: Primary tumor thickness cannot be assessed (e.g. diagnosis by curettage)

Not applicable

Not applicable

T0: No evidence of primary tumor (e.g. unknown primary or completely regressed melanoma)

Not applicable

Not applicable

T1

T1a

T1b

≤ 1.0

< 0.8

< 0.8

0.81.0

Unknown or unspecified

Without ulceration

With ulceration

With or without ulceration

T2

T2a

T2b

> 1.02.0

> 1.02.0

> 1.02.0

Unknown or undefined

Without ulceration

With ulceration

T3

T3a

T3b

> 2.04.0

> 2.04.0

> 2.04.0

Unknown or undefined

Without ulceration

With ulceration

T4

T4a

T4b

> 4.0

> 4.0

> 4.0

Unknown or undefined

Without ulceration

With ulceration

Feature N

Number of regional lymph nodes with metastases

Presence of in-transit, satellite, and/or microsatellite metastases

Nx

Regional nodes not assessed (e.g. SLN biopsy not performed, regional nodes previously removed for another reason)

Exception: When there are no clinically detected regional metastases in a pT1 cM0 melanoma, assign cN0 instead of pNX

No

N0

No regional metastases detected

No

N1

1 tumor-involved node or in-transit, satellite, and/or microsatellite metastases with no tumor-involved nodes

N1a

1 clinically occult (i.e. detected by SLNB)

No

N1b

1 clinically detected

No

N1c

No regional lymph node disease

Yes

N2

2 or 3 tumor-involved nodes or in-transit, satellite, and/or microsatellite metastases with 1 tumor-involved node

N2a

2 or 3 clinically occult (i.e. detected by SLNB)

No

N2b

2 or 3, at least 1 of which was clinically detected

No

N2c

1 clinically occult or clinically detected

Yes

N3

4 tumor-involved nodes or in-transit, satellite, and/or microsatellite metastases with2 tumor-involved nodes, or any number of matted nodes without or with in-transit, satellite, and/or microsatellite metastases

N3a

4 clinically occult (i.e. detected by SLNB)

No

N3b

≥ 4, at least 1 of which was clinically detected, or presence of any number of matted nodes

No

N3c

2 clinically occult or clinically detected and/or presence of any number of matted nodes

Yes

Feature M

Location of metastases

LDH serum activity

M0

No distant metastases

M1a

Distant metastasis to skin, soft tissue including muscles, and/or nonregional lymph node

Not recorded or unspecified

M1a (0)

Not elevated

M1a (1)

Elevated

M1b

Distant metastasis to lung with or without M1a sites of disease

Not recorded or unspecified

M1b (0)

Not elevated

M1b (1)

Elevated

M1c

Distant metastasis to non-CNS visceral sites with or without M1a or M1b sites of disease

Not recorded or unspecified

M1c (0)

Not elevated

M1c (1)

Elevated

M1d

Distant metastasis to CNS with or without M1a, M1b, or M1c sites of disease

Not recorded or unspecified

M1d (0)

Not elevated

M1d (1)

Elevated

Clinical stages *

Pathological stages**

T

N

M

T

N

M

0

Tis

N0

M0

Tis

N0

M0

IA

T1a

N0

M0

T1a

T1b

N0

N0

M0

M0

IB

T1b

T2a

N0

N0

M0

M0

T2a

N0

M0

IIA

T2b

T3a

N0

N0

M0

M0

T2b

T3a

N0

N0

M0

M0

IIB

T3b

T4a

N0

N0

M0

M0

T3b

T4a

N0

N0

M0

M0

IIC

T4b

N0

M0

T4b

N0

M0

III***

Any T

N1

N2

N3

M0

IIIA

T1a/b–T2a

N1a

N2a

M0

M0

IIIB

T0

T1a/b-T2a

T2b/T3a

N1b/N1c

N1b/c lub N2b

N1aN2b

M0

M0

M0

IIIC

T0

T1aT3a

T3b/T4a

T4b

N2b, N2c

N3b lub N3c

N2c lub N3a/b/c

Każdy N ≥ N1

N1a–N2c

M0

M0

M0

M0

IIID

T4b

N3a/b/c

M0

IV

Any T

Any N

AnyM1

Any T

Any N

AnyM1

*Micro/satellitosis — tumor or nodular infiltration (macro- or microscopically) up to 2 cm from the primary lesion of skin melanoma; in-transit — metastases in the skin or subcutaneous tissue more than 2 cm from the primary lesion of skin melanoma to the level of the nearest regional lymph nodes; LDH — lactate dehydrogenase; SLB — sentinel lymph node biopsy

B. Stages category

*Clinical staging includes primary microstaging and clinical/radiological/histopathological assessment of the presence of metastases. For this reason, in principle, it can only be used after complete excision of the primary skin melanoma (excisional biopsy) and assessment of the presence of metastases in the surrounding lymph nodes and distant organs;

**Pathological staging includes primary microstructure and pathological evaluation of lymph nodes within regional runoff: after sentinel lymph node biopsy or radical lymphadenectomy (except for stages 0 and IA -pTis/pT1 cN0 cM0, where no surgery is performed on regional lymph nodes);

***There are no stage III subgroups in clinical staging

Metastasis in regional lymph nodes (stage III)

The presence of metastases in regional lymph nodes is the most important factor determining the prognosis in patients with skin melanomas. In the case of metastases, the most important factor is the number of metastatic regional lymph nodes. The type of metastasis is also an important factor patients with clinically occult lymph nodes (neoplastic lesions detected during microscopic examination in a non-enlarged and clinically occult lymph node collected during sentinel nodes biopsy) have a better prognosis than patients with clinically detected lymph nodes (tumor lesions diagnosed in the microscopic examination of regional lymph nodes that are detected during physical examination or visible on imaging tests). An additional factor with a significant negative impact on the prognosis in patients with lymph node metastases is the presence of tumor infiltration beyond the lymph node capsule.

Metastases in distant organs (stage IV)

The most important prognostic factors in patients with extra-regional metastases are the location of the metastases and LDH level. Patients with central nervous system (CNS) metastases have the worst prognosis in this group.

Treatment

Principles of primary lesion treatment and surgical evaluation of regional lymph nodes
Surgical treatment after excisional biopsy

Surgery is the treatment of choice in patients with melanoma (I, 1). After an excisional biopsy of suspicious pigmented lesion when the cutaneous melanoma is diagnosed, a decision should be made on a possible radical excision of the scar with appropriate margins and a sentinel lymph node biopsy (Fig. 2).

Radical treatment of the primary melanoma covers radical excision of scar after the excisional biopsy of the primary lesion.

Based on the results of six randomized multicenter studies, extensive (i.e., with margin3 cm) excision of was abandoned in favor of narrower margins of healthy tissues resected. The following margins during radical excision of primary melanoma lesions are currently recommended (excision of scar after excisional biopsy of the primary lesion): melanoma in situ 5 mm margin, melanoma with Breslow thickness2 mm 1 cm, melanoma with Breslow thickness > 2 mm 2 cm (Tab. 4) (I, 1).

Using a margin greater than 2 cm reduces the local recurrence rate but does not improve long-term survival. A scar after excisional biopsy of melanoma with Breslow thickness of2 mm should be removed without the superficial fascia; however, for a scar after biopsy of melanoma with a thicker infiltration and appropriate margin at the bottom, the fascia may be also removed. These rules do not apply to melanoma localized on facial skin, where there is no fascia, and resection margins may be narrower. Some anatomical locations may require smaller margins of radical resection of primary melanoma; however, in the case of invasive melanomas, a minimum margin of 1 cm should be pursued. In the case of subungual localization of melanomas, the distal phalanx should be amputated.

Sentinel node biopsy (microstaging II)

The following patients are eligible for a sentinel lymph node biopsy (I, 1) [1, 12, 24, 25]:

  • after excisional biopsy with a diagnosis of skin melanoma confirmed by histopathological examination, but not after wide excision of the primary lesion;
  • with Breslow infiltration thickness0.8 mm or with (micro) ulceration on melanoma surface, regardless of the thickness (melanoma with the primary lesion classified as pT1b-T4b according to the TNM AJCC/UICC 2017 classification); according to the data of the American Society of Surgical Oncology (SSO), the American Society of Clinical Oncology (ASCO), and the European Society of Medical Oncology (ESMO) [26], a sentinel lymph node biopsy may be considered for melanomas with Breslow thickness 0.81.0 mm in the pT1b stage with additional unfavorable prognostic factors, such as, for example, the mitotic index1/mm2) (II, 2A);
  • without clinical signs of metastases in regional lymph nodes and distant organs.

Sentinel node biopsy is an essential method of assessing the presence of micrometastases in the lymph nodes [23].

Figure 2. Algorithm for diagnosis and therapy in cutaneous melanoma; FNB fine needle aspiration biopsy; TNM tumor-node-metastases stage classification

When performing a sentinel lymph node biopsy, preoperative lymphoscintigraphy and intraoperative lymphoscintigraphy combined with staining should be used. A sentinel node biopsy should be performed after excisional biopsy, simultaneously with radical resection of the scar. The available data do not indicate a negative prognostic impact of the sentinel lymph node biopsy performed 6 weeks after resection of the primary lesion (III, B). The accuracy of the method depends on the cooperation of nuclear medicine specialists, surgeons, and pathologists. Sentinel lymph node biopsy is a „minimally invasive” diagnostic method due to low early and late postoperative complications rates.

All lymph nodes found should undergo pathological examination. It is sufficient to collect one section from the lymph nodes containing overt clinical melanoma metastases (macroscopically visible metastatic deposits). In cases of sentinel lymph nodes examination, aimed at confirmation or exclusion of clinically occult melanoma metastases, serial sections of the entire lymph node should be performed with slices every 24 mm and an immunohistochemical examination of melanoma-specific markers such as HMB45, Melan-A, S-100, and SOX-X. The histopathological report describing this material should include 1) the number of lymph nodes found, 2) the number of lymph nodes containing metastases, 3) the size and location of the largest metastatic site, 4) the presence (or absence) of the spread of metastasis beyond the nodal capsule, and 5) the presence of tumor cell embolism in the vessels.

Table 4. Summary of recommendations of the National Comprehensive Cancer Network (NCCN) v. 1.2021, the European Organization for Research and Treatment of Cancer (EORTC) and the European Society of Medical Oncology (ESMO) regarding the final margin of radical resection of primary skin melanoma depending on its thickness according to the Breslow scale

Melanoma thickness (according to the Breslow scale)

Recommended clinical margin

In situ

0.5 cm

≤ 2.0 mm

1 cm

> 2.0 mm

2 cm

The results of the prospective Multicenter Selective Lymphadenectomy Trial 1 (MSLT-1) indicate that sentinel lymph node biopsy in melanoma patients allows identifying the groups of patients at high risk of neoplastic spreading, helps proper staging, provides excellent regional control, and allows for the qualification of patients for clinical trials according to the same criteria [24]. In the MSLT-1 study, no improvement in relapse-free survival and overall survival in the full study population subjected to sentinel lymph node biopsy was shown compared to the group with follow-up alone. However, in the subgroup of patients with current lymph node metastases, 10-year survival was significantly better in patients who underwent immediate lymphadenectomy in the case of diagnosed sentinel lymph node metastasis compared to patients who underwent such treatment later due to the detection of clinically detected metastases (62.1% vs. 41.5%; p = 0.006) [24].

Radiotherapy

Independent RTH with a radical (non-palliative) intention can only be used in the case of an extensive lentigo malign melanoma (LMM) type lesion.

Palliative radiotherapy can be used in inselected indications as in the case of primary or metastatic lesions that do not respond to systemic treatment.

Treatment of metastases in regional lymph nodes
Treatment after positive sentinel lymph node

After histopathological confirmation of melanoma metastases in sentinel lymph nodes:

  1. the patient can be left under close observation provided that ultrasound examinations of the lymphatic drainage are performed every 34 months (the preferred approach) or,
  2. radical lymphadenectomy, the so-called completion lymph node dissection (CLND), may be considered because, in the remaining lymph nodes (non-sentinel lymph node), melanoma metastases are found using routine histopathological methods in about 20% of patients [27] (especially with the size of micrometastases > 1 mm).

The results of two published randomized clinical trials (RCTs) [28, 29], one of which had insufficient statistical power [29], showed no improvement in melanoma-dependent overall survival in patients undergoing CLND [28] and in distant-metastasis-free survival [29], but disease-free survival was longer in patients undergoing CLND (fewer relapses in the nodal area). At the same time, the basic prognostic significance of sentinel lymph node biopsy was confirmed in these studies (I, 1). It should also be noted that the stage after CLND changed only in about 6% of patients. Currently, CLND is performed in clinical practice only in patients with a very high risk of metastases in non-sentinel lymph nodes, such as large size of the sentinel lymph node metastasis, metastases in more than 2 sentinel lymph nodes, or extra-capsular infiltration of the sentinel lymph node [25, 30].

Before deciding on major local surgery, staging must include high-resolution imaging techniques such as PET-CT, CT, or MRI to rule out distant metastases (III, 2A).

Treatment in the presence of metastases in clinically detected regional lymph nodes

Clinically detected metastases in regional lymph nodes are lesions detected by physical examination or imaging studies (in the 7th edition of the AJCC classification, this feature was referred to as macroscopically visible lymph node metastases). If melanoma metastasis in clinically detected regional lymph nodes is confirmed by fine-needle aspiration biopsy or by histopathological examination, lymphadenectomy should be performed in the area of regional lymphatic drainage.

When qualifying patients for lymphadenectomy, clinical examination and imaging tests should be used. Detailed imaging examinations using PET-CT, CT (especially of the pelvis when metastases in the iliac or obturator lymph nodes are suspected), or MRI should be performed to exclude the presence of distant metastases. Imaging examination to exclude brain metastases is always performed in the case of clinical symptoms and stage IIIC.

Patients with skin melanomas with metastases in regional lymph nodes constitute a group with a very different prognosis (5-year survival rate of 1570%). Prospective clinical trials have not confirmed the benefits of elective lymphadenectomy in patients without clinical evidence of melanoma metastases in the lymph nodes. Currently, lymphadenectomy in patients with skin melanomas is performed only when metastases are found in tissue sampled by fine-needle biopsy (and surgical biopsy in special cases) from enlarged and clinically suspicious lymph nodes or, in some cases, after confirmation of the presence of metastasis in sentinel lymph nodes in clinically unsuspected lymphatic drainage region (microstaging II see above) [1, 24, 31] (Fig. 3).

Figure 3. Skin melanoma stage III (metastases detected clinically or in imaging tests)

Therapeutic lymphadenectomy

The extent of the therapeutic lymphadenectomy in cutaneous melanomas is as follows (III, 2A):

  • in axillary dissection, all lymph nodes should be removed in accordance with the anatomical definition (3 groups of lymph nodes together with surrounding fascia: lower level paramammary and subscapular lymph nodes, middle level middle axillary lymph nodes, upper level axillary and subclavian vein lymph nodes);
  • in inguinal dissection, the lymph nodes in the inguinofemoral area, lying below the inguinal ligament in the femoral triangle, along with fascia of thigh muscles, femoral lymph nodes along the external iliac vessels (possibly also internal and common), and the obturator lymph nodes in the case of diagnosed metastases in sentinel nodes), lymphadenectomy should be limited only to inguinal lymph node;
  • in cervical dissection, modified operations can be performed that meet the requirement of maximal radicality, with the removal of neck structures containing superficial (anterior and posterior) and deep lymph nodes en bloc, limited from the back by the deep cervical fascia, and from the front by platysma muscle.

In some cases, it is necessary to perform a lymphadenectomy in the popliteal or elbow fossa.

In the case of isolated metastases of melanoma with an unknown primary, the same principles of surgical and systemic treatment are applied [32].

Satellite lesions, in-transit metastases, and local recurrence

The terms satellitosis (microscopic and macroscopic), in-transit metastasis, and local recurrence are a continuum and represent different forms of the same pathological phenomenon. Satellitosis is defined as neoplastic infiltration or nodules (macro- or microscopic) in the skin or subcutaneous tissue within 2 cm of the primary melanoma, while in-transit metastases are neoplastic lesions in the skin or subcutaneous tissue more than 2 cm from the primary skin melanoma to the level of the nearest regional lymph runoff. Local recurrence, on the other hand, which often occurs even after very wide resection of the primary lesion) usually represents the spread of melanomas through the surrounding lymphatic vessels; microsatellites become macrosatellites and then may transform into in-transit metastases. For this reason, in most studies the mentioned forms of recurrent melanoma are analyzed together and show a similar prognosis (10-year survival rate of 2030%).

Surgery is the primary method of local treatment of local recurrence and in-transit metastases. Decision whether to operate should be individualised and surgeons should consider the number, size, and location of lesions, as well as the clinical course (III, 2A). In the case of in-transit metastases, surgical treatment involves resection of countable lesions (< 10) with a microscopic margin free of melanoma infiltration (macroscopically it may be narrow). After resection, the patient should be qualified for systemic adjuvant treatment (II, B). In the case of single recurrent lesions, another sentinel lymph node biopsy may be considered. Resection should not be performed in the case of spread of in-transit skin melanomas. In multiple/unresectable lesions, local treatment methods (ablation, radiotherapy, cryotherapy), intratumoral immunotherapy (talimogen laherparepvec T-VEC, PV-10 or interleukin 22 — not reimbursed) or local treatment (imiquimod not registered for this indication), electrochemotherapy (procedure reimbursed in Poland) (II, 2A), or systemic treatment may be considered. In the case of extensive, multiple lesions located on the limb, the preferred method is hyperthermic isolated limb perfusion (HILP), most often with melphalan, which can only be used in centers with appropriate equipment and experienced team (individual reimbursement decisions); the inability to use HILP is an indication for systemic treatment [1, 12, 15, 31, 33, 34].

Melanomas located within the mucous membranes

The clinical stage of mucosal melanoma is defined depending on the location of the primary lesion. However, the simplified staging system originally developed for head and neck melanomas can be used in all mucosal melanomas [35]. It consists of three stages:

  • stage I locally advanced tumor;
  • stage II regional lymph nodes involvement;
  • stage III distant metastases.

Regardless of the primary location, the primary treatment is radical surgical resection within healthy tissue margins (IV, 2A); recommended surgical margins have not been identified [36].

Melanomas of head and neck mucous membranes are very rare neoplasms with an aggressive course and poor prognosis. In 7080% of cases, they develop in the nasal cavity and paranasal sinuses, and the oral cavity in the majority of remaining cases. It should be noted that the disease stage (TNM) is defined differently than in cutaneous melanomas (Tab. 5) [37]. Data on the treatment of mucosal melanomas located in mucous membranes of the head and neck region are limited. Surgery is the treatment of choice in stages T3, N0-1, and T4a, N0-1. For stage T4b, surgery is not recommended, and management should be led by multidisciplinary teams. In the case of involvement of the cervical lymph nodes, the recommended treatment is cervical lymphadenectomy followed by radiotherapy. Postoperative radiotherapy of the primary focus improves locoregional disease control and is recommended in most cases [38]. In melanomas located in the area of the anus/rectum, there was no benefit from abdominoperineal resection if local resection was possible (III, 2A) [36, 39–42]. Radical abdominoperineal resection (APR) with resection of the rectum may be justified in the following clinical situations:

Table 5. The American Joint Committee on Cancer (AJCC) TNM Staging System for Mucosal Melanoma of the Head and Neck (8th ed., 2017)

Primary tumor (T)

T3

Tumors limited to the mucosa and immediately underlying soft tissue, regardless of thickness or greatest dimension; for example: polypoid nasal disease, pigmented or nonpigmented lesions of the oral cavity, pharynx, or larynx

T4

Moderately advanced or very advanced

T4a

Moderately advanced disease

Tumor involving deep soft tissue, cartilage, bone, or overlying skin

T4b

Very advanced disease

Tumor involvingthe the brain, dura, skull base, lower cranial nerves (IX, X, XI, XII), masticator space, carotid artery, prevertebral space, or mediastinal structures

Regional lymph nodes (N)

Nx

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastases

N1

Regional lymph node metastases present

Distant metastases (M)

M0

No distant metastases

M1

Distant metastases present

  • if wide local resection would result in impairment of anal function;
  • if mesenteric lymph nodes are involved (without metastases in other organs);
  • if it is impossible to perform resection with an R0 margin without performing a rectal resection;
  • in the case of emergency surgery if the pathological examination reveals R1 margins or local recurrence.

Complementary radiotherapy is used on general principles in the case of non-radical resection revealed in microscopic evaluation [43]. In some locations, like anal or vulvar melanomas, sentinel lymph node biopsy is recommended (III, 2B).

Adjuvant therapy

Adjuvant therapy after surgical treatment is currently the standard of care. The primary and obligatory rule should be multidisciplinary team management with members having experience in the diagnosis and treatment of melanomas.

Adjuvant systemic therapy can be used after positive sentinel lymph node biopsy without the need for adjuvant lymphadenectomy. Treatment is available in Poland under the current B.59 drug program. The most important studies on the adjuvant treatment in melanoma patients at high risk of recurrence are summarized in the Table 6.

Currently registered agents for systemic (one-year) adjuvant treatment in clinical practice in patients after radical resection of stage III metastases (lymph node or in-transit metastases/satellitosis) include dabrafenib with trametinib (only patients with BRAF mutation), pembrolizumab and nivolumab (the latter also after metastasectomy in stage IV). The published results of clinical trials show an improvement in relapse-free survival, both as a result of adjuvant immunotherapy with immune checkpoint inhibitors and combined therapy with BRAF and MEK inhibitors (only in patients with a BRAF gene mutation) (I, 1).

Table 6. Summary of the most important studies on adjuvant therapy in melanoma patients at high risk of recurrence

Study

COMBI-AD

dabrafenib + trametinib vs. placebo

Checkmate 238

nivolumab vs. ipilimumab

EORTC 1325/Keynote 054

pembrolizumab vs. placebo

Author

Long 2017

Hauschild 2018

Weber 2017

Ascierto 2020

Eggermont 2018

Eggermont 2020

Study population

IIIA (> 1 mm), IIIB, IIIC

IIIB, IIIC, IV

IIIA (> 1 mm), IIIB, IIIC

BRAF gene mutations

100%

41%/43%

44%/43%

RFS

67% vs. 44% (2-year);

HR 0.47

58% vs. 39% (3-year)

54% vs. 38% (4-year);

HR 0.49

52% vs. 36% (5-year);

66% vs. 53% (18-month);

HR 0.66

62.6% vs. 50.2% (24-month);

HR 0.65

58% vs. 45% (36-month)

52% vs. 41% (48-month);

HR 0.68

HR 0.57%; 18-month difference

18.2%: 71.4% vs. 53.2%

36-month difference 20%

64% vs. 44%

OS

91% vs. 83% (2-year)

86% vs. 77% (3-year);

HR 0.57

78% vs. 77% (4-year)

NA

NA — not available; OS — overall survival; RFS — relapse-free survival

Radiotherapy as an adjuvant treatment can only be considered in individual cases and is not recommended as standard of care (II, 1).

There are ongoing studies on the use of systemic preoperative (neoadjuvant) treatment in patients with melanomas with clinical locoregional metastases.

Immunotherapy
Interferon alfa-2b

Based on a positive result from one of three Eastern Cooperative Oncology Group (ECOG) studies ECOG 1684, high-dose interferon alfa-2b (IFN-­ -alfa-2b) has been approved in the US and European Union for the treatment of patients with stage IIB-III melanoma, while in low doses only in Europe for stage II patients [44, 45]. The basis for registration was statistically significant prolongation of overall survival during approx. 7 years of follow-up, which was not confirmed in long-term observation (12 years). The results of the studies show a reproducible (10 out of 17 evaluated studies) improvement in disease-free survival, with recent meta-analyses showing a statistically significant reduction in the relative risk of relapse by 1718% after adjuvant therapy with IFN alfa-2b. The evidence for the overall survival improvement is much weaker and comes mainly from meta-analyses, and points to an im- provement in 5-year overall survival by approx. 35% in the entire group of patients. Due to the controversial importance of adjuvant therapy with IFN alfa-2b in patients with intermediate and high-risk melanomas and its toxicity, the use of the drug should be individualized (II, 2B). The results of meta-analyses indicate that benefits of adjuvant IFN alfa-2b therapy may be observed in patients with ulcerated primary melanoma, especially in the subgroup with micrometastases (in the sentinel lymph node but without macrometastases of clinically enlarged lymph nodes) (I, 2B) [46, 47]. Interferon is not reimbursed in Poland as an adjuvant treatment and is less effective than other drugs currently used in adjuvant treatment.

Ipilimumab

In the United States, ipilimumab (anti-CTLA-4 antibody) is approved for adjuvant treatment of melanoma patients after lymphadenectomy due to regional lymph nodes metastases. A randomized study [48] showed a statistically significant improvement of relapse-free and overall survival after the use of ipilimumab, albeit at the cost of high toxicity of this therapy (II, 2B) [49]. Ipilimumab is not registered for adjuvant treatment in Poland.

Nivolumab

Nivolumab (anti-PD-1 antibody) showed a 10% improvement in relapse-free survival after one year compared to ipilimumab with less toxicity (I, 1) in a randomized clinical trial in patients with stage IIIB, IIIC, and stage IV (metastatic). It is currently registered and reimbursed for this indication [48]. Updated data, after longer follow-up, confirm the efficacy of one year adjuvant nivolumab treatment, regardless of the PD-L1 expression level and BRAF mutation status in relation to RFS (HR 0.66) and DMFS (HR 0.76) [50]. The 3-year relapse-free survival rate was 58% and was over 10% better than for ipilimumab. The results of the 4-year observations are similar.

Pembrolizumab

The results of the Keynote-054/EORTC 1325 study with 1019 patients also showed a reduction in the risk of disease recurrence (HR for RFS 0.57) and DMFS after one-year adjuvant treatment with pembrolizumab compared to placebo in the higher-risk group with stage III resectable disease (stage IIIA with micrometastases > 1 mm, IIIB and IIIC) (I, 1) [51, 52]. The RFS rate after 3.5 years of follow-up was 59.8% in the pembrolizumab group compared with 41.4% for the placebo group [53]. Pembrolizumab is associated with longer recurrence-free survival than placebo with 5-year rate of recurrence-free survival of 55.4%, hazard ratio for recurrence or death of 0.61 as well as 5-year rate of distant metastasis-free survival, of 60.6% and hazard ratio for distant metastasis or death of 0.62 [54].

Pembrolizumab as adjuvant therapy for up to approximately 1 year in stage IIB or IIC melanoma significantly improved relapse-free survival and it is currently approved in this indication, but not reimbursed in Poland (II, 2A) [55].

Other immunological drugs

Other methods of immunotherapy (e.g. interleukin 2), anti-melanoma vaccines, or cytotoxic drugs are of no use in adjuvant postoperative therapy.

Molecularly targeted therapy
Dabrafenib with trametinib

The use of one-year adjuvant treatment with dabrafenib with trametinib in patients with stage III, BRAF-positive, high-risk melanoma (stage IIIA with metastasis > 1 mm, IIIB/III C) showed an improvement in relapse-free and overall survival compared to placebo (I, 1) [56, 57]. Updated data from a 4-year follow-up confirm the benefit of treatment with dabrafenib and trametinib (RFS: 54%; HR: 0.49; DFS: 67%; HR: 0.53) [57]. In addition, a model was also presented to evaluate the percentage of additionally cured patients after the adjuvant treatment (cure rate), which accounts for as much as 17%. After 5-year follow-up, the percentage of patients without relapse was 52% in the group treated with dabrafenib with trametinib compared to 36% in the placebo group [58].

Adjuvant radiotherapy

In selected cases, after surgical treatment of high-risk melanomas, supplementary radiotherapy (RTH) is recommended the dosing regimen includes hypofractionation of 38 Gy/fraction or conventional fractionation depending on the location. Indications for adjuvant RTH after primary tumor resection include the diagnosis of desmoplastic melanoma resected with narrow margins, presence of „positive” surgical margins (especially after resection of local recurrence), the presence of satellite foci, and increased neurotropism.

In the case of resection of local recurrence and lymphadenectomy due to metastases in regional lymph nodes, indications for supplementary RTH may include the presence of extracapsular lymph node infiltration, involvement of4 lymph nodes (stage IIIC), diameter of the metastasis > 3 cm, detection of metastases in cervical lymph nodes (2 or more metastatic lymph nodes or metastasis of at least 2 cm), recurrence after resection [59, 60]. The results of the only completed randomized study, which assessed the value of adjuvant RTH (48 Gy in 20 fractions) after lymphadenectomy in patients at high risk of recurrence, confirmed the improvement of local control after irradiation, without affecting overall survival and increasing long-term locoregional complications and deterioration of patients’ quality of life. This means that the use of adjuvant RTH should be limited (II, 2A) [61]. Adjuvant RTH after CLND should not be used.

Treatment of metastatic patients

The results of treatment of stage IV skin melanomas are still unsatisfactory. Currently, median overall survival exceeds 1224 months, but 5-year survival is chieved by approx. 2040% of patients.

The factors of significant prognostic importance in patients with stage IV melanoma are the performance status [performance status (PS) according to the Eastern Cooperative Oncology Group (ECOG) scale], LDH activity, and location of metastatic lesions. If the patient is eligible for surgical treatment or systemic treatment in stage IV, the disease stage should be assessed with imaging (CT with contrast or PET-CT of the chest, abdominal cavity, and pelvis; brain MRI with contrast) [1].

In the case of secondary lesions on the skin, in soft tissues, or extra-regional lymph nodes (M1a; better prognosis), the possibility of surgical resection should always be considered the same should be done in the case of isolated (although not necessarily single) metastases to parenchymal organs, and then a decision regarding patient qualification for adjuvant treatment with nivolumab should be made (I, 1). In the case of metastatic lesions that cannot be resected, the choice of treatment depends on the presence of metastases in the central nervous system, which requires, first of all, consideration (the decision depends on the location and number of lesions) of neurosurgical treatment and/or irradiation of the central nervous system (usually stereotaxic or radiosurgery [62]) to delay the onset of bleeding or neurological disorders. Irradiation of CNS lesions may also be part of combination therapy during immunotherapy (preferred) or BRAF protein-targeted therapy (II, 2B). There is no indication for whole brain radiotherapy (WBRT) as adjuvant treatment after local treatment of melanoma metastases in CNS, as it does not improve outcomes. Detailed recommendations for the management of melanoma CNS metastases have been published [63].

In palliative care, RTH is also used in patients with metastases in soft tissues (for ulceration and pain) and bones (for pain control).

Progress in the treatment of metastatic melanoma, with low efficacy of classic cytotoxic drugs, is associated with 1) non-specific immunotherapy with anti-CTLA4 (ipilimumab) or anti-PD1 (nivolumab, pembrolizumab) monoclonal antibodies inhibiting systemic immunosuppressive mechanisms to induce antitumor response (activation of T lymphocytes) and 2) targeted therapy with serine-threonine kinase inhibitors (dabrafenib with trametinib, vemurafenib with cobimetinib or encorafenib with binimetinib) (I, A). Treatment with the above-mentioned drugs is reimbursed in Poland under the B.59 drug reimbursment program. Systemic treatment should be performed in centers that provide full range of therapeutic options [64]. The qualification of patients with metastatic melanoma for prospective clinical trials should still be considered (Fig. 4, Tab. 7).

Chemotherapy

Dacarbazine is the only cytotoxic drug registered in disseminated melanoma, and its effectiveness is limited (the objective response rate is 15%, median response duration is 4 months) [1]. The only approved regimen of dacarbazine use is the administration of the drug for 5 consecutive days at a daily dose of 200 mg/m2; the possibility of a 1-day use of the drug at a higher dose (8501000 mg/m2 every 3 weeks) has not been formally approved, although it is a useful treatment in clinical practice. Paclitaxel alone or in combination with carboplatin does not substantially prolong response duration to second-line treatment. Randomized studies did not confirm the greater efficacy of multidrug chemoregimens using dacarbazine in combination with cisplatin, vinca alkaloids (e.g. vinblastine), and nitrosourea derivatives (e.g. carmustine), and tamoxifen.

Figure 4. General algorythm of systemic treatment in patients with advanced stage IV or unresectable stage III melanomas; CNS central nervous system; iBRAF BRAF inhibitor; iMEK MEK inhibitor; LDH lactate dehydrogenase

Immunotherapy
Anti-CTLA-4 antibodies (ipilimumab)

Ipilimumab has been approved for the treatment of patients with disseminated melanomas and compared to gp100 peptide vaccine in second-line showed a statistically significant increase in median overall survival (difference of about 3.5 months) without a significant impact on the progression-free survival [65, 66]. The kinetics and response duration for ipilimumab are different than in classic chemotherapy the benefit of treatment is observed only after 34 months, which limits its use to patients with advanced melanoma with minimal symptoms, good performance status and slow disease course, and (due to safety profile) without accompanying autoimmune diseases. Due to the late occurrence of objective responses, a conclusive assessment of the effectiveness of ipilimumab should be made 12 weeks after the treatment commencement, especially considering the possibility of paradoxical progression (pseudoprogression) related to infiltration of tumors by immunologically active cells in the early stage of therapy. To objectively assess the response to ipilimumab treatment, the use of immune response criteria is indicated [65–67].

Table 7. Treatment options in patients with relapse to the stage of unresectable disease after adjuvant treatment

Adjuvant treatment

First-line treatment of metastatic disease when disease relapse occurs during or < 6 months after completion of adjuvant therapy

First-line treatment of metastatic disease when disease relapse occurs > 6 months after completion of adjuvant therapy

BRAF gene mutations

BRAF WT (wild type)

BRAF gene mutations

BRAF WT (wild type)

Anti-PD-1

Anti-BRAF / MEK

Ipilimumab + nivolumab

Ipilimumab

Ipilimumab + nivolumab

Ipilimumab

Anti-BRAF/MEK

Ipilimumab + nivolumab

Anti-PD-1

Ipilimumab

Ipilimumab + nivolumab

Anti-PD-1

Ipilimumab

Anti-BRAF/MEK

Anti-PD-1

Ipilimumab + nivolumab

Ipilimumab + nivolumab

Anti-PD-1

Anti-BRAF/MEK

Ipilimumab

The predictors of response to ipilimumab treatment have not been established yet. The recommended dose in monotherapy is 3 mg/kg body weight administered intravenously every 3 weeks, for a total of 4 doses (I, 1). The objective response rate after treatment with ipilimumab is low (approx. 10%), long-term benefits are achieved by a limited number of patients (2025%), but they are associated with long-term survival (the longest follow-up is 10 years). The concerns connected with ipilimumab therapy are side effects related to autoimmune reactions (side effects in stages IIIIV occur in about 2025% of patients). The most common immune-related adverse events (irAE) are skin lesions, colitis (most often manifested by diarrhea), hepatotoxicity, and endocrine disorders (including hypopituitarism and thyroid gland insufficiency). In the case of significant symptoms worsening, glucocorticosteroids (prednisone at a dose of 12 mg/kg b.w./ /day or equivalent) should be administered immediately with further treatment in cooperation with a reference center. Appropriate management algorithms are available [66] and should be rigorously applied from the onset of the first symptoms suggesting immune-related toxicity. Treatment with ipilimumab should be carried out only in centers with highest levels of specialized care offering comprehensive diagnostic and therapeutic procedures. It is not justified to undertake the above-mentioned treatment in centers without full management capabilities. Ipilimumab monotherapy is not currently used in the first-line treatment of patients with advanced melanoma.

In the light of the current research results, ipilimumab monotherapy is not the basic type of immunotherapy in patients with advanced melanomas, as it gives worse outcomes than anti-PD-1 antibodies, with a worse safety profile. Treatment should be initiated with anti-PD-1 antibodies (nivolumab or pembrolizumab) in monotherapy or in combination with anti-CTLA-4 (I, 1).

Anti-PD-1 antibodies (nivolumab and pembrolizumab)

Currently, immunotherapy in cutaneous melanomas is mainly based on the use of PD-1 immune checkpoint blockade in monotherapy (nivolumab at a stable dose of 240 mg every 2 weeks or 480 mg every 4 weeks or pembrolizumab at a dose of 200 mg every 3 weeks or 400 mg every 6 weeks) (I, 1) [68–71] or in combination with anti-CTLA-4 antibodies (I, B) [72]. In clinical practice, these agents, in monotherapy or in combination with ipilimumab, showed long-term clinical benefits in some patients with advanced melanomas and significant response rates (up to 50%), with 1-year survival rates of 7080%. The use of nivolumab or pembrolizumab is associated with a 2-year survival rate of 5060% (median survival exceeds 2 years, the 3-year survival rate is approx. 45%), with acceptable toxicity (approx. 15% in stage III/IV, i.e. significantly less than for ipilimumab), although the most severe symptoms also relate to immune-related side effects. Studies have confirmed that pembrolizumab is more effective in terms of overall survival and progression-free survival compared to ipilimumab in first-line treatment and compared to chemotherapy after failure of previous therapy [68–70].

In a clinical study, treatment with the anti-PD-1 antibody, pembrolizumab, was used for up to 2 years. In the group of 104 patients who completed the 2-year treatment, 102 patients (98%) were still alive, and the 9-month progression-free survival rate was 91% (i.e. in the majority of patients disease control is maintained after discontinuation of active treatment). Based on the available literature data, discontinuation of immunotherapy with anti-PD1 antibody may now be considered in patients who maintain objective response (CR, PR)/ /clinical benefit (II, 2B) [73].

Anti-PD-1 antibodies with anti-CTLA-4 antibodies (nivolumab with ipilimumab)

The results of a clinical trial comparing the efficacy of nivolumab monotherapy, ipilimumab monotherapy, and a combination of both drugs showed that nivolumab was more effective than ipilimumab (median progression-free survival was 6.9 months versus 2.9 months, respectively). However, the most effective therapy (compared to ipilimumab) was a combination of these drugs (median progression-free survival 11.5 months) [73] (I, 1), although the study assumptions did not include a formal comparison of treatment results with the combination of nivolumab and ipilimumab and nivolumab monotherapy. The results of combined treatment with ipilimumab and nivolumab were better in patients with a BRAF gene mutation [74], and the 5-year overall survival rate in the combination arm was 52% (i.e. median OS exceeded 60 months) compared to 44% for nivolumab monotherapy [75]. Adverse events, grade IIIIV according to the Common Terminology Criteria for Adverse Events (CTCAE), were observed significantly more often in the arm receiving combination therapy (56.5%), while in the arms with nivolumab and ipilimumab, it was 19% and 27%, respectively. Combined immunotherapy, rather than anti-PD1 monotherapy, may be the preferred option in patients with good performance status with poorer prognostic factors (including BRAF mutation, high LDH activity, mucosal melanomas [76–78] and asymptomatic CNS metastases) (II, 2A) [79, 80].

Molecularly targeted therapy
BRAF/MEK inhibitors

Mutations in the RAS/RAF/MEK/ERK pathway of MAP kinase (MAPK) are found in approx. 75% of skin melanomas. The dominant mechanism leading to RAS/RAF/MAPK pathway overactivity in skin melanoma is an activating mutation of the gene coding BRAF kinase, and somatic mutations of BRAF gene are actually detected in 5070% of skin melanomas arising in places not exposed to long-term sunlight. The results of a pivotal phase III trial with vemurafenib in the first-line treatment in patients with BRAF V600 mutations published in 2011 showed both responses to treatment in 48% of patients treated with BRAF inhibitor (iBRAF) versus 5% in patients receiving dacarbazine, and statistically significant improvement in progression-free survival (difference of approx. 5 months) and overall survival (difference approx. 3 months) [81].

Vemurafenib has been approved for the treatment of patients with advanced melanomas with a BRAF mutation (detection of this mutation is possible in Polish centers using a validated PCR test) (I, A). Although most patients eventually develop resistance to treatment (median progression-free survival is 67 months), the results of phase IIIII studies showed median overall survival in patients with metastatic melanoma of 1316 months, which is statistically significantly higher than previously observed in this group of patients. Vemurafenib is characterized by significant skin toxicity (hypersensitivity to UV radiation), hepatotoxicity typical for kinase inhibitors, and leads to the development of secondary neoplasms (skin cancer or keratoacanthoma in almost 20% of patients). Secondary skin cancers may develop as early as a few weeks after starting vemurafenib therapy. Their diagnosis is an indication for local treatment but does not require drug discontinuation. Adverse events often require a reduction of the vemurafenib dose. In 2012, the therapeutic efficacy of another BRAF inhibitor dabrafenib (with efficacy comparable to vemurafenib, but with a different toxicity profile including lower skin toxicity and a higher frequency of fever) was confirmed. Median PFS was 6.7 months for dabrafenib vs. 2.9 months for dacarbazine, and median overall survival reported in 2013 for dabrafenib was 18.2 months (I, 1) [82]. A phase III clinical trial also confirmed the efficacy of the MEK inhibitor (iMEK) trametinib in the treatment of patients with metastatic melanomas with BRAF gene mutations (I, 2B) [83].

The efficacy of MEK inhibitors was also observed in patients with NRAS mutations (II, 2B) [84].

The results of recent studies (COMBI-d, COMBI-v, coBRIM, and COLUMBUS) have shown that in patients with metastatic melanomas with BRAF gene mutations, the use of a combination of BRAF and MEK inhibitors (dabrafenib with trametinib, vemurafenib with cobimetinib, or encorafenib with binimetinib) is more beneficial than monotherapy with BRAF inhibitor allone, improving the quality of life without increasing toxicity and with improving the quality of life (I, 1) [85–91]. Median overall survival due to treatment with these agents is extended to approx. 2333 months, with median progression-free survival of approx. 1214 months [91–93]. The best overall survival is obtained in patients with normal LDH activity and metastases in fewer than 3 organs.

All drug combinations are currently available in Poland in the first or subsequent treatment lines for patients with advanced melanomas with confirmed presence of BRAF V600 mutation and reimbursed within the B.59 drug program. These drugs also have a beneficial effect in patients with stable and/or asymptomatic brain metastases.

A new option of targeted therapy is reintroduction of combination therapy with BRAF and MEK inhibitors after their early discontinuation due to disease progression. A phase II study showed that 8 out of 25 patients (32%) achieved partial remission of the disease after reintroduction of treatment with dabrafenib and trametinib, and further 40% of patients achieved stabilization with the median progression-free survival of 4.9 months [94]. During the 2017 ASCO Annual Meeting, an analysis of 116 patients with advanced melanoma receiving BRAF inhibitor and BRAF ± MEK inhibitor therapy after a treatment interruption (related to the indication for next line treatment after progression during previous therapy) was presented. The median duration of this therapy used for the first time was 9.4 months and 7.7 months after rechallenge of targeted therapy. The response rate after rechallenge of treatment with BRAF ± MEK inhibitors was 43%: complete responses 3%, partial responses 39%, and disease stabilization 24% and disease progression 30%, no data 4%. Median overall survival from rechallenge was 9.8 months (III, 2A) [95, 96].

KIT kinase inhibitors

In rare cases of patients with melanomas with KIT mutations, the activity of KIT kinase inhibitors has been observed; KIT kinase inhibitors are not reimbursed for this indication (II, B) [97].

Sequencing of systemic therapy

There is no definitive data on the optimal sequence of immunotherapy and targeted therapy in patients with BRAF-mutant melanomas. It should be noted that the activity of BRAF inhibitors is preserved after prior immunotherapy, and the effectiveness of immunotherapy (anti-PD-1) occurs after prior treatment with BRAF inhibitors (Fig. 3) [98]. The recent trials indicate that long-term effects in BRAF-mutated melanoma patients is achieved when first-line line therapy is a combination of nivolumab and ipilimumab. There is also a lack of significant data regarding the preferred systemic treatment in the case of inoperable relapse or metastatic spread after previous adjuvant therapy (Tab. 4 summarizes the ESMO consensus recommendations for this clinical situation) (IV, 2B) [99]. Since BRAF inhibitors (+ MEK inhibitors) treatment in patients with advanced BRAF-mutant melanomas result in rapid tumor response and control in most patients, with limited responce duration associated with activation of resistance mechanisms, these agents should be considered as the treatment of choice in patients who are symptomatic and have significant disease dynamics and/or large tumor burden.

Combination therapy

In 2020, the results of the phase III IMspire150 study were published, in which patients with advanced melanoma (unresectable stage IIIC/IV) with BRAF gene mutations were randomly assigned to first-line treatment with triple combination of atezolizumab (anti-PD-L1 immunotherapy), vemurafenib, and cobimetinib or placebo, vemurafenib, and cobimetinib (the control group). The study found a clinically and statistically significant improvement in investigator-assessed PFS in the atezolizumab group compared to placebo (15.1 vs. 10.6 months; HR 0.78; 95% CI 0.630.97; p= 0.0249) [100]. Response duration was also significantly longer in the atezolizumab arm (21 months) compared to the control arm (12.6 months) (II, 2B). The triple combination seems to be an interesting option, although the long-term results may be comparable to the combination of ipilimumab with nivolumab. Currently, its role is not defined, and it is approved only in the United States.

Inhibitor LAG-3 (relatlimab) in combination with nivolumab improved significantly progression-free survival as compared to anti-PD-1 monotherapy in patients with previously untreated metastatic or unresectable melanoma [II, 2A] [101] this combination is approved but not reimbursed in Poland.

Rehabilitation

Patients treated for melanoma after axillary or inguinal lymph nodes resection may experience ipsilateral limb lymphoedema. Edema is less likely after the sentinel lymph node biopsy.

Lymphoedema is an excessive accumulation of protein-rich fluid in the intercellular spaces. This leads to chronic inflammation, fibrosis and periarticular changes, and emotional changes due to chronic, progressive dysfunction (Tab. 9). According to the published data, the rate of development of lower limb edema after biopsy of inguinal sentinel lymph nodes ranges from 7.6 to 35.1%, and after lymphadenectomy from 48.8 to 82.5%. The upper limb edema rate after axillary lymphadenectomy ranges from 4.4 to 14.6% [102].

Table 8. Recommended follow-up evaluations in patients with skin melanoma

Melanoma stage

Test

Frequency

Early melanomas after excision of primary lesion without metastases in lymph nodes (stages IAIIA)

Medical history and physical examination, including full-body skin surface, area of scar after melanoma excision and regional lymph nodes

Chest X-ray optionally

US of regional lymph nodes when sentinel lymph node biopsy not done in melanomaspT1b

No indications for routinely performed imaging and laboratory tests

Additional examinations (CT with contrast or PET-CT of the chest, abdominal cavity, pelvis ± neck and MRI of CNS or other) always in case of clinical symptoms

Patient education including risk factors and self-monitoring (assessment of the skin and lymph nodes)

Every 612 months during first 5 years, then yearly if clinically indicated (control is possible outside specialized center)

Locally advanced melanomas after excision of primary lesion without metastases in lymph nodes (stages IIBIIC)

Medical history and physical examination, including full-body skin surface, area of scar after melanoma excision and regional lymph nodes

Chest X-ray, abdominal US optionally

US of regional lymph nodes when sentinel lymph node biopsy not done in melanomaspT1b

Imaging tests (CT with contrast or PET-CT of the chest, abdominal cavity, pelvis and neck and MRI of CNS) should be considered every 312 months for the first 2 years, then every 612 months for the next 3 years. There are no indications for routine imaging after 35 years.

No indications for routinely laboratory tests

Additional examinations (CT with contrast or PET-CT of the chest, abdominal cavity, pelvis ± neck and MRI of CNS or others) always in case of clinical symptoms. In patients with melanomas IIBIIC CT could be performed every 612 months, and brain MRI optionally yearly during first 23 years

Patient education including risk factors and self-monitoring (assessment of the skin and lymph nodes)

Every 36 months during first 23 years, then every 612 months until 5 years, and then yearly after 5 years if clinically indicated

After excision of metastases in local lymph nodes or local recurrence/satellite lesion/in-transit metastasis (stages IIIAIIID) or follow-up after sentinel lymph node metastasis without complementary lymphadenectomy

Medical history and physical examination, including full-body skin surface, area of scar after melanoma excision and regional lymph nodes

Chest X-ray optionally

Nodal basin US for regional lymph node assessment every 46 months in the case of positive sentinel lymph node without lymphadenectomy

Imaging tests (CT with contrast or PET-CT of the chest, abdominal cavity, pelvis ± neck and MRI of CNS) should be considered every 312 months for the first 2 years, then every 612 months for the next 3 years, especially in stage IIIC/IIID. There are no indications for routine imaging after 35 years

No indications for routinely laboratory tests

Additional examinations (CT with contrast or PET-CT of the chest, abdominal cavity, pelvis ± neck and MRI of CNS or others) always in case of clinical symptoms. In patients with melanomas IIBIIC CT could be performed every 612 months, and brain MRI optionally yearly during first 23 years

Patient education including risk factors and self-monitoring (assessment of the skin and lymph nodes)

Every 34 months during first ٢ years, every ٣٦ months during subsequent ٣ years, and yearly after ٥ years if clinically indicated

After treatment of distant metastases (stage IV)

Assessment of metastatic lesions in imaging tests (CT with contrast or PET-CT of the chest, abdominal cavity, pelvis ± neck and MRI of CNS or others) depending on location. Lactate dehydrogenase serum level

Follow-up visit schedule individualized for every patient

CNS — central nervous system; CT — computed tomography; LDH — lactate dehydrogenase; MRI — magnetic resonance imaging; US — ultrasound examination

Physiotherapy of patients with post-treatment lymphedema [103]

Patients with secondary edema have a reduced quality of life (EORTC QLQ C30 studies). In the group of patients after lymph nodes resection, prevention of edema should be applied: patients with a high probability of edema should be provided with compression sleeves of the 1st degree of compression (ipsilateral upper limb) and compression hosiery of the 1st2nd degree of compression to prevent swelling of the lower limb (they should be used for at least 6 months after surgery).

Physical examination of lymphoedema consists of line measurements, water displacement/perometer tests, and palpation to determine swelling degree and consistency. The fold test should be applied, and the Stemmer sign should be considered.

Table 9. Stages of lymphoedema

Stage

Clinical manifestations

Conservative therapy

I (implicit)

Lymph transport volume decreased

Swelling not visible

Subjective, negative patient’s feelings

Limb elevation

Self-massage

Prophylactically compression sleeve or hosiery of the 1st degree of compression

II

Accumulation of protein-rich fluid

Visible, soft swelling

Limb elevation

Self-massage

Physical activity

Prophylactically compression sleeve or hosiery of the 1st degree of compression

III

Accumulation of protein-rich fluid

Hard swelling

The onset of fibrosis

Comprehensive decongestion therapy

Compression products (compression sleeve or hosiery)

IV

Accumulation of protein-rich fluid

Hard swelling

Fibrosis

Skin changes (mycoses, eczema)

Comprehensive decongestion therapy

Compression products (compression sleeve or hosiery)

If secondary edema occurs, patients should be referred to specialized centers conducting the rehabilitation of patients with secondary lymphoedema. Such procedures include comprehensive decongestant therapy (lymphatic drainage with compression, kinesitherapy, mechanical pneumatic massage, and other procedures dedicated to this group of patients). After therapy is completed, it is recommended to put on a sleeve or hosiery to support the effects of anti-edema therapy. Compression materials supporting the effects of anti-edema therapy should be tailored to the degree of edema (size, volume of the affected limb). Currently, custom-made sleeves and hosieries are partially reimbursed by the National Health Fund (NFZ) [104].

Study results show that it is very important to inform patients treated for melanoma with sentinel lymph node biopsy or lymphadenectomy about the possibility of secondary lymphoedema and preventive measures. One of the elements of prophylaxis is also physical activity [105, 106].

Follow-up after treatment

The frequency and type of examinations, as well as the duration of the observation period, should depend on the individual risk of disease recurrence (which depends on the initial disease stage) (II, 2A), but one should remember about the possibility of relapse after more than 10 years from the initial treatment [107, 108] (Tab. 5).

The risk of recurrence is highest in the first 3 years after treatment; therefore, recommended follow-up schedules include intensified control during this period, mainly to detect possible loco-regional recurrence, which potentially gives a chance of radical surgical treatment. The basis of post-treatment follow-up is the evaluation of scars following primary excision and lymphadenectomy. Particular care must be taken in assessing the regional lymph nodes (possible in-transit spreading). For the assessment of regional lymph nodes, an ultrasound examination is also recommended in addition to the physical examination. As a large proportion of loco-regional recurrences can be detected by the patient (even > 60%), patient awareness should be raised about the importance of self-examination of the area after resected primary melanoma and regional lymphatic drainage. There are premises that in patients with early-stage melanoma, less intensive control regimens do not adversely affect survival.

Imaging tests are not justified during observation of asymptomatic patients in stages IAIIA; they can be considered for the first 23 years (e.g. CT scan) in asymptomatic patients with stages IIBIIIC (taking into account the recent emergence of new effective drugs for the treatment of disseminated melanomas (IV, 2B), as earlier data showed a minimal gain of up to 2 months in relation to the expected survival benefit from intensive schedules of imaging studies). In turn, in patients with clinical symptoms suggesting the presence of distant metastases (liver enzyme elevation, bone pain, neurological symptoms, cough, and weakness), detailed imaging diagnostics, including CT, MRI, PET-CT, and bone scintigraphy, should be performed.

During follow-up examinations, it is necessary to examine full-body skin (not only the area where cancer previously developed), due to the statistically greater chance of developing a second independent melanoma lesion or other skin cancer.

Additional information for patients is available, among others, on the websites of scientific societies (e.g. www.akademiaczerniaka.pl).

Conclusions

A biopsy that excludes atypical and suspicious pigmented lesions, which may be early melanomas, is of fundamental importance in the diagnosis and determination of the most important prognostic factors (microstaging I). Early diagnosis and resection of melanoma not only improves the prognosis but also gives a chance of recovery in nearly 90% of patients. Typically, pigmented lesions of up to 2 cm in the transverse axis can be removed on an outpatient basis as part of a resection that meets the definition of excisional biopsy. The next steps of the procedure include qualification of patients for radical resection of the scar after excisional biopsy with appropriate margins of 0.52 cm depending on Breslow thickness and the performance of a sentinel lymph node biopsy (stagepT1b). In the case of clinically detected metastases in regional lymph nodes, radical lymphadenectomy is the treatment of choice. It is recommended to qualify patients with high-risk skin melanomas to systemic adjuvant therapy (nivolumab, pembrolizumab, dabrafenib with trametinib). The algorithms of diagnostic and therapeutic management in patients with skin melanomas are presented in Figures 24.

The presence of distant metastases is still associated with a poor prognosis. In patients with metastatic disease, enrollment in a clinical trial is the most appropriate approach. In patients with generalized disease or associated with a high risk of disease recurrence (stage III), it is recommended to test BRAF gene status.

Long-term survival is concerning in stage IV patients who underwent resection of single metastatic lesions. In systemic treatment primarily in the first line in patients with the presence of BRAF V600 mutations, BRAF inhibitor (in combination with MEK inhibitor) is used and, regardless of BRAF mutation status, immunotherapy with anti-PD-1 antibodies (nivolumab or pembrolizumab), ipilimumab (anti-CTLA4 antibody alone or in combination with anti-PD-1). The optimal treatment sequence (especially in the presence of a BRAF gene mutation) is currently not defined. The use of combined therapy with BRAF and MEK inhibitors is associated with a high response rate (approx. 70%) and a rapid relief of disease symptoms, while treatment with anti-PD-1 antibodies results in lower response rates, but they are mostly long-lasting and persist also after treatment discontinuation.

Part II

Ocular melanoma

Uveal melanoma

Epidemiology and etiology

Uveal melanoma is the most common primary intraocular malignant neoplasm in adults. It is significantly different from conjunctival, mucous, and skin melanoma [109]. According to the 2018 National Cancer Registry (NCR) data, ocular neoplasms (C69) account for 0.3% of all neoplastic diseases in Poland (523 cases), and most of them are uveal melanomas. Mortality from this malignant tumor was 0.1% (121 deaths) [110]. The prevalence varies by ethnic group and latitude. The incidence is highest among Caucasians (98% of all patients) and at higher latitudes. In Mediterranean countries, 2 new cases per 1 million inhabitants per year are reported, while in Scandinavian countries it is 811/1 million inhabitants. In the United States of America, on average, 4.3 new cases occur per 1 million inhabitants per year [111–114].

Children rarely suffer from this type of cancer, and their prognosis is significantly better (5-year and 10-year survival rates are 97% and 92%, respectively) [115, 116].

Melanoma develops from the melanocytes of the uveal layer, affecting particular areas of the uveal layer with different frequencies. About 46% of ocular melanomas are found in the iris, 69% in the ciliary body, and most often in the choroid (8590%) [117–119].

Table 10. Primary tumor — T feature

All uveal melanomas

TX

Primary tumor cannot be assessed

T0

No primary tumor

Iris

T1

Tumor limited to the iris

T1a

Tumor limited to the iris, not more than 3 clock hours in size

T1b

Tumor limited to the iris, extending more than 3 clock hours

T1c

Tumor limited to the iris with secondary glaucoma

T2

Tumor of the iris involving the ciliary body and/or the choroid

T2a

Tumor of the iris involving the ciliary body and/or the choroid with secondary glaucoma

T3

Tumor of the iris involving the ciliary body and/or the choroid with scleral infiltration

T3a

Tumor of the iris involving the ciliary body and/or the choroid with scleral infiltration and secondary glaucoma

T4

Melanoma with extraocular infiltration

T4a

Extraocular infiltration of iris melanoma with greatest diameter5 mm

T4b

Extraocular infiltration of iris melanoma with greatest diameter > 5 mm

Ciliary body and choroid

T1

Tumor of the first size category

T1a

Tumor of the first size category without involvement of the ciliary body and retrobulbar infiltration

T1b

Tumor of the first size category with involvement of the ciliary body

T1c

Tumor of the first size category without involvement of the ciliary body, but with a retrobulbar infiltrate with the largest diameter5 mm

T1d

Tumor of the first size category with involvement of the ciliary body and with the largest retrobulbar infiltrate of the largest diameter5 mm

T2

Tumor of the second size category

T2a

Tumor of the second size category without involvement of the ciliary body and retrobulbar infiltration

T2b

Tumor of the second size category with involvement of the ciliary body

T2c

Tumor of the second size category without involvement of the ciliary body, but with a retrobulbar infiltrate with the largest diameter5 mm

T2d

Tumor of the second size category with involvement of the ciliary body and with retrobulbar infiltration with the largest diameter5 mm

T3

Tumor of the third size category

T3a

Tumor of the third size category without involvement of the ciliary body and retrobulbar infiltration

T3b

Tumor of the third size category with involvement of the ciliary body

T3c

Tumor of the third size category without involvement of the ciliary body, but with a retrobulbar infiltrate with the largest diameter5 mm

T3d

Tumor of the third size category with involvement of the ciliary body and with retrobulbar infiltration with the largest diameter5 mm

T4

Tumor of the fourth size category

T4a

Tumor of the fourth size category without involvement of the ciliary body and retrobulbar infiltration

T4b

Tumor of the fourth size category with involvement of the ciliary body

T4c

Tumor of the fourth size category without involvement of the ciliary body, but with a retrobulbar infiltrate with the largest diameter5 mm

T4d

Tumor of the fourth size category with involvement of the ciliary body and with retrobulbar infiltrate with the largest diameter5 mm

T4e

Tumor of any category with retrobulbar infiltration with the largest diameter > 5 mm

aIn order to determine the T feature in ciliary body and choroidal melanoma, it is necessary to first classify the tumor into the appropriate size category based on height and the largest tumor base diameter (Tab. 11)

Staging and prognostic factors

The prognosis of uveal melanoma depends on many factors. One of them is the size of the primary tumor (the largest diameter of the base and height). Larger tumors are associated with worse survival. Increasing the tumor height by 1 mm increases the risk of metastasis by 5% within 10 years. Based on the assessment of thickness (height), tumors were divided into 3 groups: the small (03 mm), medium (medium; 3.18.0 mm), and large (> 8 mm) groups. Five-, 10- and 20-year mortality in particular groups was 6%, 12%, and 20%, respectively, then 14%, 26%, and 37%, and in the last group 35%, 49%, and 67% [120, 121]. Another factor adversely affecting the prognosis is the involvement of the ciliary body. In these cases, 33% of patients metastasize during the 10-year follow-up, as opposed to 7% when the neoplasm covers the iris or up to 25% for the choroid [119, 120]. Other factors that worsen the prognosis and are associated with a greater tendency to metastasize are the following histopathological features: epithelial type melanoma, deep infiltration of eyeball wall (sclera), presence of extraocular infiltrates, high mitotic index, optic nerve infiltration, own vascularization of the tumor with a tendency to form arches branches, closed loops and vascular networks, as well as inflammatory tumor infiltration (especially by T lymphocytes and macrophages) [119, 122–124].

Genetic disorders such as monosomy 3, multiple copies of 1q, 6p, and 8q, loss of 1p, 6q, and 8p, and mutations in the BAP1, GNAQ, and GNA11 genes are associated with a high risk of metastases. In contrast, mutations in the EIF1AX gene are associated with a good prognosis [119, 125].

Local control after the treatment of uveal melanoma is very high (8698%) and is achieved through using various conservative treatment methods, such as brachytherapy, proton therapy, transpupillary thermotherapy (TTT), tumor endo- or exoresection, and their different combinations. In very large tumors, i.e. with a base diameter greater than 20 mm or a height greater than 12 mm, and if the tumor extensively affects the optic nerve, the best treatment is still enucleation (see below) [126]. A big problem in this disease is still high mortality of approx. 50% due to generalized dissemination, with no effective treatment in such cases. In over 90% of cases, the metastases are located in the liver despite good effects of local treatment. This is due to the tendency of uveal melanoma to metastasize in the early stages of its development (formation of micrometastases) and the presence of cancer cells in the vascular bed prior to treatment [119, 127].

The AJCC TNM classification, developed by the American Joint Committee on Cancer, is used for staging and prognosis assessment of uveal melanoma. It takes into account the size of the largest tumor base, its thickness (height), involvement of the ciliary body, presence, and size of extraocular infiltration and presence of metastases [128] (Tab. 1014). Involvement of the surrounding lymph nodes in uveal melanoma is extremely rare. To assess the risk of metastasis, the above-mentioned genetic testing should also be considered, including first of all, monosomy 3 and the BAP1 gene mutation [119] (III, 2B).

Table 11. Regional lymph nodes — N feature

Nx

Regional lymph nodes cannot be assessed*

N0

No metastases in regional lymph nodes

N1

Metastases in regional lymph nodes or separate orbital neoplastic deposits

N1a

Metastases in one or more regional lymph nodes

N1b

Separate orbital neoplastic deposits without continuity with the eyeball, no metastases in regional lymph nodes

*Regional lymph nodes include preauricular, submandibular, and cervical lymph nodes

Table 12. Distant metastases M feature

M0

No distant metastases

M1

Distant metastases present

M1a

Diameter of largest distant metastasis3 cm

M1b

Diameter of the largest metastasis 3.18.0 cm

M1c

Diameter of the largest metastasis > 8 cm

Table 13. Melanoma staging

Stage

Feature T

Feature N

Feature M

I

T1a

N0

M0

IIA

T1bd

N0

M0

T2a

N0

M0

IIB

T2b

N0

M0

T3a

N0

M0

IIIA

T2cd

N0

M0

T3bc

N0

M0

T4a

N0

M0

IIIB

T3d

N0

M0

T4bc

N0

M0

IIIC

T4de

N0

M0

IV

Any T

N1

M0

Any T

Any N

Any M1 ac

Prefixes: y — preoperative radiotherapy or chemotherapy; r — tumor recurrence

Table 14. Histological grading G feature

GX

Histological grade cannot be assessed

G1

Spindle cell melanoma (> 90% of spindle cells)

G2

Mixed cell melanoma (> 10% epithelial cells and < 90% spindle cells)

G3

Epithelial cell melanoma (> 90% of epithelial cells)

Signs and symptoms

About one-third of patients with uveal melanoma are asymptomatic, and if any symptoms occur, they are uncharacteristic. Patients most often report decreased visual acuity and visual field disturbances. Pain may also occur due to elevated intraocular pressure, as well as a veil in front of the eye or image distortion [129].

Figure 5. Classification of ciliary body and uveal melanoma based on thickness and size of the primary tumor (mm)
Diagnostic tests
  1. Ophthalmological examination of the anterior segment of the eyeball in a slit lamp (III, 2A).
  2. Eye fundus examination after pupil dilation (preferably indirect ophthalmoscopy) (III, 2A).
  3. Ultrasound examination (III, 2A):
  1. ultrabiomicroscopy ultrasound examination of the anterior segment of the eyeball, ciliary body, and the front part of the choroid;
  2. ultrasonography of the posterior segment of the eyeball (detection of a mushroom-shaped tumor is a typical feature of uveal melanoma).

4. Optical coherence tomography (OCT) (III, 2A).

5. Taking a photo of the observed lesion to determine any progression (III, 2A).

6. Gonioscopy when it is suspected that the lesion is occupying or reaching filtration angle (III, 2A).

7. Diaphanoscopy or transillumination (reveal tumor base) (III, 2A).

8. Additional examinations (performed in case of diagnostic doubts) (III, 2B):

  1. fluorescein angiography (FA),
  2. indocyanine green angiography (ICGA),
  3. computed tomography of orbits,
  4. magnetic resonance imaging of orbits, autofluorescence [130].

9. Tumor biopsy remains controversial due to the increased risk of dissemination and the high rate of false-negative results [131] (III, 2A) [132] (NCCN Guidelines. Uveal Melanoma. Version 3.2020).

Differential diagnostics

Uveal melanoma is most often differentiated from metastatic tumors of a different location and with pigmented nevi. It is very important to distinguish the atypical, pigmented nevus from small melanoma (TFSOM rule developed by Shields et al.) [133] (III, A).

Less frequently, the differential diagnosis includes choroidal hemangioma (limited or diffuse), intraocular lymphoma, retinal hemangioma, osteoblastoma, retinochoroidal calcification, astrocytoma, and age-related macular degeneration (AMD), especially the wet (exudative) form [130, 134].

Remarks

The greatest tumor diameter and thickness (height) are used to define the size category (Tab. 10, Fig. 5). The determination of pT is required for ciliary and choroidal melanomas but is only feasible if the primary treatment was enucleation of the eyeball. In these situations, a proper technique is essential to visualize the greatest tumor base diameter and thickness (height) in the removed eyeballs. For this purpose, the eyeball should be X-rayed with a strong light source to map the shadow of the tumor on the sclera and determine its position in relation to the optic nerve.

The eyeball should be cut so that the cross-sectional plane contains the greatest tumor base diameter, rests on the shadow, and passes through the center of the disc, as well as the optic nerve.

In the past, in the clinical assessment of tumor dimensions, the greatest base diameter was expressed in multiples of the optic disc diameter (dd) (averagely 1 DD = 1.5 mm), and tumor thickness (height) in diopters (averagely 3 diopters = 1 mm). Currently, the standard is to determine the size of intraocular tumor parameters in millimeters based on measurements performed in an ultrasound examination (determination of T feature). It should be noted that most patients with uveal melanoma are treated conservatively, so ultrasonography remains the only method to assess tumor size.

Treatment

Local treatments for uveal melanoma can be divided into two main types.

Conservative

Conservative treatment to preserve the eyeball and even, in some cases, useful visual acuity. This type of therapy includes:

  1. Radiotherapy in the form of (III, 2A):
  1. Brachytherapy (most frequently used) with the use of various radioactive elements, which allows for very good local tumor control of 9598% [135, 136]. The isotopes of ruthenium-106 (Ru-106) and iodine-125 (I-125) are commonly used. Palladium (Pd-103) and iridium (Ir-192) are used much less frequently due to the short half-life and very high costs of therapy. Ru-106 is effective in treating tumors up to 5 mm in height, or up to 6 mm in height, but in combination with transpupillary thermotherapy (TTT). I-125 is used to treat tumors of thickness ranging from 5 mm to 1012 mm. An important factor determining the use of applicators is also tumor base, which should not exceed the diameter of the applicator and may not exceed 18 mm, which allows for a safe margin [137]. The dose at the tumor top should not be less than 70 Gy, and for I-125 preferably around 82.5 Gy [137–141].
  2. Proton radiotherapy a positive local result is obtained in 9598% of cases. The therapy uses a collimated beam of protons or helium nuclei. Irradiation is performed for 4 consecutive days with a total dose of 60 Gy at the tumor top (4 × 15 Gy) [142].
  3. Stereotactic radiotherapy

2. Local, sparing surgical treatment (III, 2A)

  1. Local resection:
  • Exoresection is used to treat lesions located in the iris, ciliary body, or the anterior choroid. The tumor is removed under the scleral flap in combination with brachytherapy.
  • Endoresection can be performed after prior radiotherapy. The tumor is removed during pars plana vitrectomy (PPV) [143–145].

3. Laser treatment

  1. Transpupillary thermotherapy (TTT) is intended for the treatment of small melanomas. Most often used with brachytherapy, especially in the parathyroid tumor localization, it is the so-called sandwich therapy (III, 2B).
  2. Photodynamic therapy experimental and controversial therapy with the use of a photosensitizing dye (verteporfin) for the treatment of amelanotic, small melanomas [146, 147] (IV, C).
Radical surgery
  1. Enucleation, i.e. removal of the eyeball. Recommended when the tumor thickness and base diameter are over 12 mm and over 20 mm, respectively, and when the tumor infiltrates the optic nerve or there is secondary glaucoma [126] (III, 2A).

It is recommended to implant an orbital implant tight after after enucleation provided that there are no signs of extraocular infiltration, and prosthesis of the orbit is performed up to 14 days after the surgery.

  1. Exenteration, i.e. evisceration of the orbit is indicated in the case of massive extraocular infiltration.
Treatment in the generalized stage

Treatment of generalized uveal melanoma allows extending the survival by a few months, especially if it is possible to use local treatment methods for liver metastases [148]. Surgical resection (if single lesions are present, which is rare), chemoembolization/radioembolization or thermoablation of liver metastases, and systemic treatment are used [119, 149] (III, A). In clinical trials, attempts are made to use therapies affecting the PKC-MAPK pathway, modifying epigenetic mechanisms (e.g. Vorinostat) or immune checkpoints inhibitors (small effects were observed in phase II studies mainly with the combination of nivolumab and ipilimumab) [150, 151]. These studies have so far failed to show positive results [119, 152], except for the data on the use of tebentafusp (IMCgp100), a novel bispecific molecule targeting T cells in the presence of HLA-002, which was compared to historical data (phase II study [153] median OS 16.8 months) and an active comparator (phase III study 1-year OS rate 73% vs. 58%, HR 0.51) this drug is registered in the European Union, but not reimbursed in Poland [154].

Follow-up and treatment of local complications

After treatment of uveal melanoma, the patient should undergo ophthalmological examination every 36 months in the first 2 years, and every 612 months in the following years. The examination should aim to detect a potential local recurrence or complications after therapy. After conservative treatment, it should include at least visual acuity, intraocular pressure measurement, slit-lamp anterior segment examination, and eye fundus examination after pupil dilation, US, photography, and OCT. In turn, after the enucleation, the orbit should be examined (after removal of the epiprosthesis, the orbit should be inspected and palpated), and control MRI examinations of the orbits should be performed every 612 months [155, 156] (III, A).

As a result of the applied conservative treatment, there is a risk of complications in the form of cataracts, secondary glaucoma, iris neovascularization, retinopathy (with maculopathy), and neuropathy. All these complications should be treated, but what is even more important, they should be prevented. The best method of treating retinopathy, maculopathy, and post-radiation neuropathy, as well as iris neovascularization, are intravitreal injections or injections into the anterior chamber of anti-VEGF agents or steroids. In the case of anti-VEGF agents, it is recommended to initially administer 3 injections with an interval of 12 months (depending on the type of drug), and then depending on the clinical picture [157, 158] (III, A).

After ophthalmic treatment, the patient should remain under control to monitor and treat any metastases. For this purpose, it is recommended to perform magnetic resonance imaging, possibly computed tomography or ultrasound of the abdominal cavity every 312 months, and liver tests every 36 months (monitoring towards liver metastases). Chest X-ray is recommended every 12 months [156, 159] (III, A).

Conjunctival melanoma

Conjunctival melanoma is a very rare neoplasm, which accounts for 0.25% of all melanomas and 5% of ocular melanomas. In recent years, a significant increase in the incidence of this type of cancer has been observed [160, 161]. Molecular aspects of the development of conjunctival melanoma include mutations in BRAF and NRAS genes, which are completely different from those reported in uveal melanoma [1] (III, 2A).

The vast majority, i.e. 74%, of melanomas, develop upon primary acquired melanosis (PAM), 7% from a nevus, and 19% de novo [160, 162] (III, 2A).

Local recurrence takes place in 3050% of patients within 5 years [163].

Metastasis occurs in approximately 2030% of patients over 10-year follow-up [160]. Factors associated with a worse prognosis include tumor localization outside the conjunctiva, multinodular type of growth, rapid growth, tumor thickness > 2 mm, recurrence, incomplete resection, and failure to apply adjuvant therapy after resection [160, 164] (III, 2A).

The mainstay of treatment is surgical tumor resection after prior closure of nutrient vessels, with a macroscopically preserved margin of healthy tissue, the size of which remains undefined [160, 164] (III, 2A). Some recommend the use of cryotherapy in sites after resection and swabs with absolute alcohol [160, 165] (IIIB). In very advanced cases, enucleation and exenteration are considered [160, 166, 167] (III, 2A).

The adjuvant treatment includes:

  1. Local chemotherapy:
  1. Mitomycin C, which is administered to the conjunctival sac two weeks after surgery [160, 168–173] not reimbursed use, with very limited clinical data (IV, 2B)
  2. Interferon alfa-2b [160, 174, 175] (IV, 2B)

2. Radiotherapy:

  1. EBRT
  2. Local brachytherapy.

Sentinel lymph node biopsy should be considered, however, bearing in mind that distant metastases occur in 50% of cases, without the presence of neoplastic cells in the surrounding lymph nodes [160, 176, 177] (III, 2B).

Therapeutical options in patients with metastatic conjunctival melanoma include the same treatments as for advanced cutaneous melanoma [160] (III, 2A).

After the treatment of conjunctival melanoma, the patient should remain under constant oncological and ophthalmological monitoring (photographic documentation of the local condition is important every time; it is recommended to check the conjunctiva after turning the eyelids outwards).

Conflict of interest

P. Rutkowski received fees for lectures and participation in Advisory Boards from Novartis, BMS, MSD, Pierre Fabre, Merck, Sanofi, Amgen, Blueprint Medicines. E. Kalinka and A. Czarnecka received fees for lectures and clinical trials from BMS, MSD, Roche. Andrzej Kawecki received fees from the following companies: BMS: fees for lectures and participation in Advisory Board, conducting clinical trials; MSD: fees for lecture and participation in Advisory Board; Merck: fees for lecture and participation in Advisory Board, Sanofi: fees for participation in Advisory Board. M. Ziobro received fees for lectures and participation in Advisory Boards from Novartis, BMS, MSD, Pierre Fabre, Merck, Amgen, Roche, Pfizer. B. Cybulska-Stopa received fees for lectures and participation in Advisory Boards from Novartis, BMS, MSD, Pierre Fabre.

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Key words: melanoma, diagnosis, therapy, immunotherapy, anti-PD-1, anti-CTLA-4, BRAF, MEK, sentinel lymph node biopsy