Melanomas

Early detection of cutaneous melanoma depends on careful observation of moles and pigmented skin lesions. Clinical signs that should not be overlooked include:

• Variations in pigmentation within the same lesion
• Differences in shape and symmetry
• Irregular or poorly defined borders
• Any change in a lesion over time

ABCDE Rule

To facilitate recognition, the ABCDE rule is commonly used:

• A – Asymmetry: one half of the lesion differs from the other
• B – Borders: irregular, jagged, or poorly defined edges
• C – Color: presence of multiple shades within the same lesion
• D – Diameter: greater than 6 mm or progressively increasing
• E – Evolution: changes in size, shape, or color over time

“Ugly Duckling” Sign

An additional useful criterion is the “ugly duckling” rule: a mole that appears different from the others on the body—darker, atypical, or morphologically unusual—should always be considered suspicious and evaluated.

Limitations of the ABCDE Rule

It is important to note that the ABCDE rule may not identify all melanomas. It is less effective for:

• Small lesions
• Amelanotic melanomas (without pigment)
• Certain aggressive variants, particularly nodular melanoma

Nodular melanoma accounts for approximately 10–30% of cases and is characterized by rapid vertical growth. It often appears as a firm, dome-shaped nodule with relatively regular borders and uniform color, which may allow it to escape early detection using ABCDE criteria.

Alternative Criteria for Nodular Melanoma

For nodular melanoma, alternative diagnostic criteria are used:

• EFG rule:
  • E – Elevated (raised)
  • F – Firm (hard consistency)
  • G – Growing (rapid enlargement)
• 3C rule:
  • Color irregularity
  • Contour irregularity
  • Change over time

Clinical Importance

Early diagnosis is particularly critical, especially in older individuals, due to the aggressive behavior of some melanoma subtypes. Continuous self-monitoring of the skin and prompt dermatological evaluation of suspicious lesions remain the most effective strategies for early detection.

Self-Examination of the Skin

Skin self-examination, performed by the patient independently or with the help of a family member (or using mirrors), is a highly useful tool for the early detection of cutaneous melanoma and is considered an important element in prevention and early diagnosis.

How to Perform Self-Examination Correctly

• Perform the examination regularly, ideally after a bath or shower when the skin is clean and dry
• Use a well-lit room with a full-length mirror and a handheld mirror for hard-to-see areas
• Become familiar with the location, appearance, and characteristics of existing moles, birthmarks, and skin spots
• Check for any changes in size, shape, texture, or color compared with previous observations
• Pay attention to any non-healing lesion or ulceration
• Examine the entire body systematically, without omitting any area

Step-by-Step Body Examination

• Inspect the front and back of the body, raising the arms to check the armpits
• Bend the elbows and carefully examine the forearms, palms, fingernails, and the backs of the arms, repeating on both sides
• Examine the legs front, back, and sides, including the area between the buttocks and around the genital region
• Sit down to carefully inspect the feet, including soles, nails, and spaces between toes
• Carefully examine the face, neck, ears, and scalp
  • Use a comb or hairdryer to part the hair
  • When possible, ask for assistance, as the scalp is difficult to inspect alone

Regular self-examination helps identify suspicious lesions early and should always be complemented by periodic dermatological evaluation, especially in individuals at higher risk.

Today, melanoma diagnosis relies not only on clinical examination but also on advanced diagnostic tools that have significantly improved the detection of subtle lesions, including those that do not clearly present the classic ABCDE features.

Dermoscopy (also called epiluminescence microscopy) is a non-invasive and painless examination. Using a specialized handheld device or digital imaging system, the clinician can examine structures beneath the skin surface that are not visible to the naked eye. This allows a more precise evaluation of:

• Pigment distribution within the lesion
• Structural patterns of the mole
• Features suggestive of malignancy or atypia

Based on these observations, the specialist can determine whether the lesion is benign, suspicious, or requires further intervention, such as follow-up monitoring or excision.

Dermoscopy is particularly valuable for the early detection of pigmented lesions with malignant potential, especially in cases where clinical appearance alone is insufficient for diagnosis.

If any unusual change is observed during self-examination, it is essential to promptly consult a general practitioner or dermatologist. Early evaluation remains the most important step for achieving early diagnosis and more effective treatment outcomes.

When a skin lesion is suspected of being a melanoma, the first diagnostic step is an excisional biopsy. This is a minor surgical procedure that involves the complete removal of the lesion, together with a small margin of approximately 2 mm of surrounding healthy skin and underlying subcutaneous tissue.

This approach allows for an accurate histopathological examination, which is essential to define key prognostic factors and to plan the subsequent therapeutic strategy.

After the biopsy, surgical treatment of the primary melanoma is completed through a wider excision, with margins determined according to the tumor thickness (Breslow depth) observed under the microscope.

Sentinel Lymph Node: A Key Step

A fundamental aspect in melanoma management is the evaluation of the sentinel lymph node, which is the first lymph node receiving lymphatic drainage from the tumor site.

This minimally invasive procedure allows clinicians to determine whether tumor cells have begun to spread, identifying patients with non-palpable lymph node metastases who may require further surgical treatment, such as complete lymph node dissection.

The risk of lymph node involvement is strongly correlated with tumor thickness and mitotic activity:

• < 1 mm thickness: lymph node involvement is rare
• 1.5–4 mm thickness: risk of metastasis is approximately 25%
• > 4 mm thickness: risk may reach up to 60%

Indications for Sentinel Lymph Node Biopsy (SLNB)

• Intermediate-thickness melanomas (1–4 mm): indicated due to a metastasis risk of approximately 10–20%
• Thick melanomas (> 4 mm): indicated, with risk exceeding 30–40%
• Thin melanomas (< 1 mm): not routinely indicated, but may be considered in the presence of specific clinical or histological risk factors

This step is essential for accurate staging and for guiding further therapeutic decisions in melanoma management.

To determine the stage of melanoma and select the most appropriate treatment, physicians integrate multiple sources of information:

• Clinical data: obtained from physical examination and imaging studies such as X-rays, CT scans, and MRI
• Pathological data: derived from biopsy analysis, which provides detailed information on tumor characteristics and spread

Key Pathological Factors in Staging

• Tumor thickness: Tumor thickness measures the depth of melanoma invasion within the skin. The Breslow thickness, currently the standard method, is more accurate than the older Clark level system and represents a major prognostic indicator. In general, greater thickness is associated with a higher risk of spread to lymph nodes or distant organs.
• Ulceration: Ulceration refers to the loss of the superficial epidermal layer covering the melanoma. Although not always visible clinically, it is identified microscopically. Its presence is associated with a worse prognosis and a higher likelihood of disease dissemination.
• Lymph node metastasis: Lymph node involvement is classified as:
  • Micrometastases: not detectable on physical examination and identified through sentinel lymph node biopsy
  • Macrometastases: clinically or visually detectable, confirmed through histological examination
• Distant metastasis: Melanoma can spread to distant sites:
  • Metastases to skin, subcutaneous tissue, or distant lymph nodes are generally associated with a relatively better prognosis
  • Metastases to internal organs or vital structures indicate more advanced disease and a poorer prognosis

These parameters together define the stage of melanoma and are essential for guiding prognosis and treatment decisions.

Surgery is the primary treatment for most melanomas and, in many cases, the only treatment required. It also plays an important role in lymph node staging and in the management of selected cases of advanced melanoma.

Wide Local Excision

Wide local excision is performed to remove any residual cancer cells that may remain after the initial biopsy. It represents the standard treatment for melanoma in situ, stage I and II melanoma, and for many cases of stage III disease.

During the procedure, the surgeon removes:

• The area containing the melanoma, including the biopsy scar
• A surrounding margin of healthy skin and subcutaneous tissue (the surgical margin)

The width of the surgical margin is determined by the Breslow thickness of the melanoma, reflecting the depth of tumor invasion into the skin.

The objective is to achieve complete tumor removal while minimizing the risk of local recurrence.

Sentinel Lymph Node Biopsy (SLNB) with Lymphatic Mapping

Sentinel lymph node biopsy is an essential staging procedure used to determine whether melanoma has spread to the lymphatic system.

The sentinel lymph node is the first lymph node that receives lymphatic drainage from the primary tumor site and is therefore the most likely location for early lymph node metastasis.

The procedure includes lymphatic mapping, which helps identify the sentinel node accurately. To achieve this, a blue dye and/or a radioactive tracer is injected near the tumor site. These substances travel through the lymphatic vessels, allowing the surgeon to locate and remove the sentinel lymph node with minimal surgical disruption.

Wide local excision and sentinel lymph node biopsy are complementary procedures that provide crucial information for staging and treatment planning.

Lymph Node Dissection

In selected patients with confirmed lymph node involvement, surgery may be performed to remove all lymph nodes affected by melanoma within the involved nodal basin.

The indication for lymph node dissection is determined on an individual basis, taking into account the extent of nodal disease and the overall treatment strategy.

Molecularly targeted therapies act selectively against cancer cells by targeting specific genetic mutations that drive melanoma growth, while minimizing damage to healthy tissues. Identifying the mutation present in the tumor is essential because it determines eligibility for these treatments.

The most common mutations include:

• BRAF mutation, found in approximately 50% of melanomas. Patients with this mutation may be treated with a combination of BRAF inhibitors and MEK inhibitors. Combining these agents has been shown to improve treatment effectiveness, reduce certain side effects, and delay the development of resistance by melanoma cells.
• c-KIT mutation, found in approximately 1-3% of melanomas, particularly in mucosal melanomas and melanomas arising on the face, hands, and feet. These patients may benefit from targeted oral therapies such as imatinib.

Targeted therapies can be used both in patients with metastatic melanoma and in patients with high-risk melanoma following surgery to reduce the risk of recurrence. In the adjuvant setting, treatment is generally administered for one year.

Recent studies have also shown that, in selected situations, the use of immunotherapy before surgery (neoadjuvant therapy) may further reduce the risk of recurrence.

Side Effects

Side effects vary among individuals but are generally manageable with supportive care. Common adverse effects include:

• Joint and muscle pain
• Fatigue
• Skin redness and itching
• Dry skin
• Photosensitivity, requiring careful sun protection through high-SPF sunscreen and protective clothing
• Development of skin lesions such as keratoses or keratoacanthomas and, less commonly, squamous cell carcinoma, which can usually be managed with surgical removal
• Fever related to treatment, often controlled with temporary interruption of therapy and antipyretic medications

Careful monitoring and appropriate supportive measures help manage side effects effectively while allowing patients to obtain the maximum benefit from targeted therapy.

Immunotherapy, also known as biological therapy or biotherapy, uses the body’s natural immune defenses to recognize and destroy melanoma cells. This is achieved through drugs called monoclonal antibodies, which enhance the immune system’s ability to target cancer.

Ipilimumab

Ipilimumab is a monoclonal antibody that blocks CTLA-4, a protein that normally acts as a brake on the immune system.

A useful analogy is to think of the immune system as a car:

• The accelerator stimulates the immune response.
• The steering wheel directs the response toward cancer cells.
• The brake, represented by CTLA-4, slows immune activity to prevent damage to healthy tissues.

Melanoma can exploit this brake to evade immune attack. By blocking CTLA-4, ipilimumab releases this inhibition and allows immune cells to respond more effectively against tumor cells.

Ipilimumab is administered intravenously in the day-hospital setting, typically for four cycles at three-week intervals.

PD-1 Inhibitors

Drugs that block the PD-1 receptor, such as nivolumab and pembrolizumab, have demonstrated greater efficacy than ipilimumab in many patients, including some who do not respond to anti-CTLA-4 therapy.

PD-1 is another important immune checkpoint that melanoma cells can exploit to suppress immune activity. By inhibiting this pathway, these drugs restore the immune system’s ability to recognize and attack cancer cells.

More recently, additional immune checkpoint inhibitors have been developed. One example is relatlimab, an anti-LAG-3 antibody that can be combined with nivolumab to further enhance antitumor immune responses in selected patients.

Combination Immunotherapy

Clinical studies have shown that combining anti-CTLA-4 and anti-PD-1 therapies can produce higher response rates and improved clinical outcomes compared with either treatment alone.

However, combination therapy is associated with a greater risk of adverse events and therefore requires careful patient selection and monitoring.

Use in Melanoma Treatment

Immunotherapy can be used effectively in:

• Metastatic melanoma
• High-risk melanoma after surgery (adjuvant therapy) to reduce the risk of recurrence

In the adjuvant setting, treatment is generally administered for one year.

Recent evidence also suggests that, in selected patients, neoadjuvant immunotherapy administered before surgery may further reduce the risk of recurrence and improve long-term outcomes.

Side Effects of Immunotherapy

Immunotherapy can trigger immune-related adverse events because it stimulates the immune system to become more active.

The most common side effects include:

• Skin redness and itching
• Colitis
• Diarrhea
• Elevated liver enzymes (transaminases)
• Reduced or altered function of endocrine glands, particularly the thyroid and pituitary glands

Most immune-related adverse events can be effectively managed with corticosteroids or other immunosuppressive medications that reduce excessive immune activation.

Patients experiencing symptoms suggestive of treatment-related toxicity should contact their oncology care team promptly so that appropriate evaluation and treatment can be initiated as early as possible.

The treatment of melanoma, as with many other cancers, may involve a combination of therapeutic approaches, including surgery, radiation therapy, and systemic treatments. Treatment planning is carried out within a Multidisciplinary Pathology Group, ensuring a personalized strategy tailored to each patient’s clinical situation.

Radiation therapy uses high-energy radiation (X-rays) to damage the DNA of cancer cells, preventing their growth and promoting cell death.

In melanoma, radiotherapy is used primarily in advanced stages of the disease, including:

• Controlling the growth of tumor lesions that are no longer responding to systemic treatments (oligoprogression)
• Treating symptomatic metastatic lesions, particularly those causing pain
• Reducing the risk of functional impairment when tumors involve critical structures such as the bones or brain

The Radiation Therapy Pathway

The radiotherapy process consists of three main phases:

Initial Consultation: The radiation oncologist evaluates the patient’s condition, determines whether radiotherapy is indicated, and identifies the most appropriate treatment approach.

Treatment Planning: The radiation oncologist and medical physicist work together to define the treatment area precisely and calculate the optimal radiation dose, maximizing effectiveness while minimizing exposure to surrounding healthy tissues.

Treatment Delivery: Radiotherapy sessions are administered by radiation therapists under the supervision of the radiation oncology team, according to the individualized treatment plan.

Throughout the entire treatment pathway, physicians, nurses, and allied healthcare professionals provide continuous information, support, and assistance to help patients manage therapy safely and effectively.

All cancer treatments are associated with side effects that can affect the patient’s quality of life to varying degrees. Treatments for acute leukemia may also cause significant physical and psychological effects, which can impact daily functioning and overall well-being.

At the Canciolo Cancer Institute, attention to the patient’s quality of life remains a priority throughout the entire treatment pathway. The physicians and nurses of the Multidisciplinary Team provide ongoing support to help manage side effects, including nutritional counseling, psychological support, and pain management therapy.

The impact of cancer also extends to the psychological sphere. A cancer diagnosis is often a traumatic event that affects all aspects of a person’s life and may generate anxiety, fear, anger, and depression.

At the Canciolo Cancer Institute, alongside advanced medical therapies, the care pathway always includes specialized psycho-oncological support, helping patients cope not only with treatment but also with the delicate phases of physical and psychological recovery.

Patients may also participate in psychological support groups, where they can share experiences with others who are facing or have faced a similar condition.

To ensure timely support and provide prompt answers to questions or concerns, the Candiolo Cancer Institute offers a dedicated assistance service for all patients.

From Monday through Friday, between 8:00 a.m. and 5:00 p.m., patients can contact the Oncology Day Hospital Secretariat at +39 011 993 3775 to request an urgent consultation.

Patients are promptly connected with their specialist physician, ensuring rapid access to expert advice, clear information, and immediate support when needed.

Cancer patients often have complex needs that extend beyond the treatment of the disease itself and require comprehensive, multidisciplinary care.

At the Candiolo Cancer Institute, patients who need additional support have access to specialists from a range of disciplines, ensuring personalized management of cancer-related symptoms and associated conditions. Services may include nutritional counseling, physical rehabilitation, pain management, and support for other medical needs that may arise during the course of treatment and recovery.

The goal is to improve quality of life, promote overall well-being, and provide comprehensive care tailored to each patient’s individual needs.

The Social Work Service at the Candiolo Cancer Institute provides information, guidance, and support to patients and their families regarding access to community services and the welfare and social security benefits available under current legislation.

During dedicated consultations, social workers assist with matters such as disability recognition, access to aids and prosthetic devices, employment-related benefits and leave, and other social support services.

The service is available on Wednesdays and Fridays from 9:00 a.m. to 1:00 p.m. and can be contacted at +39 011 993 3059.

Thanks to the large number of cases treated each year, the Candiolo Cancer Institute is a national reference center for the care of this disease. This extensive experience allows us to manage even the most complex cases, always using a personalized approach, tailored to the clinical and individual profile of each patient.

Establishing a treatment plan always begins with an accurate and timely diagnosis. Patients have access to state-of-the-art imaging technologies, such as ultrasound, contrast-enhanced CT, MRI, and cholangio-RM, which are critical for accurately assessing the extent of the tumor.

Advanced laboratory tests, including molecular analyses, are also available to help define biological features of the disease and guide treatment choices.

When appropriate, surgeries are performed using minimally invasive, laparoscopic or robotic techniques. These approaches involve the use of camera-equipped instruments introduced into the abdomen through small incisions, thus reducing surgical trauma. Benefits to the patient include shorter hospital stay times, faster recovery, and lower risk of complications compared with traditional open surgery.

As an IRCCS (Scientific Institute for Research, Hospitalization, and Healthcare), the Candiolo Cancer Institute combines clinical care with a strong focus on scientific research. Patients can be considered for participation in active clinical trials, offering access to innovative therapies not yet available in standard practice. This integration of care and research is a distinctive strength that translates into tangible benefits for patients.

The Interdisciplinary Care Group (GIC or MDT) supports the patient at every stage: from diagnosis, through treatment, to follow-up. Special attention is paid to nutritional support, psychological health and reintegration into daily life. The organization of checkups, examinations, and treatment is designed to ensure continuity, serenity, and a humane, caring approach to each patient’s needs.