Melanomas

Early detection of cutaneous melanoma relies oncareful observation of moles and other pigmented skin lesions. Signs not to be overlooked include:

• uneven color variations;

• Differences in shape and symmetry;

• Irregular or jagged edges;

• Changes in the appearance of the mole over time.

To simplify recognition, theABCDE teaching rule is used:

• A – Asymmetry: half of the mole is not the same as the other;

• B – Edges: irregular, jagged or ill-defined;

• C – Color: presence of different shades in the same mole;

• D – Size: greater than 6 mm or increasing;

• E – Evolution: rapid changes in shape, color or size.

Another useful criterion is the “ugly duckling” rule: a mole that looks different from others on the body, darker or unusual, always deserves attention.

However, it is important to know that the ABCDE rule does not always succeed in detecting smaller melanomas, those without pigment (amelanotic) or some special forms such as nodular melanoma. The latter accounts for about 10-30% of all melanomas, grows rapidly in depth, and often presents as a compact nodule with regular borders and uniform color: because of these very characteristics it can escape ABCDE.

Therefore, in nodular melanoma the evaluation criteria are different and are summarized in two acronyms:

• EFG: Elevated (raised), Firm (hard to the touch), Growing (fast growing);

• 3C: Irregular Color, Irregular Contour (edge), Change (change over time).

Early diagnosis is critical, especially in older people, because this form has more aggressive behavior. Regular skin monitoring and a dermatologic examination when suspected remains the safest strategy for early diagnosis.

Skin self-examination, performed by the patient alone, with the help of family members or using two mirrors, is a very useful tool: it allows early detection of most melanomas and is considered a true predictor.

How to properly perform self-examination:

• Carry it out periodically, preferably after bathing or showering, when the skin is clean;

• Choose a well-lit room with a full-length mirror, and keep a portable mirror available;

• learn where congenital ‘birthmarks’, moles, and spots are located, what they look like, and what their consistency is;

• Check carefully if a mole is different in size, shape, texture, or color from the previous time or if there is an ulcer that does not heal;

• Scrutinize themselves carefully from head to toe, not neglecting a single square inch of skin;

• Look in the mirror at the front and back and lift the arms to examine the armpits as well;

• Bend the elbow and look closely at the fingernail, palm, forearm (including the back) and arm. Repeat on the other arm;

• Examine the legs at the front, back, and sides. Also look between the buttocks and around the genitals;

• Sit down and carefully examine the feet, including nails, soles, and spaces between toes;

• Carefully scrutinize face, neck, ears and scalp. Shake out the hair with a comb or hair dryer, or even better ask for help from a family member or friend as it is not easy to examine the scalp alone.

Today, the diagnosis of melanoma uses not only clinical examination but also innovative tools that have opened new perspectives, particularly for subtle melanomas and for forms that do not clearly show the classic clinical parameters of ABCDE.

Epiluminescence microscopy, also known as dermoscopy, is a simple, noninvasive and painless examination. Using a special camera or magnifying eyepiece, the specialist can observe the pigment distribution within the lesion, assess its characteristics, and determine whether it is a risk lesion. Based on the result, it can then indicate the most appropriate course of treatment.

Dermoscopy is also particularly useful for early detection of pigmented lesions that are more likely to develop into melanoma.

If you notice anything unusual on your skin during a personal checkup, it is essential to contact your primary care physician or a specialist without hesitation: early evaluation is the first step toward early diagnosis and thus more effective treatments.

When a skin lesion is considered suspicious for melanoma, the first step is excisional biopsy. This is a small operation that involves complete removal of the lesion along with a margin of about 2 millimeters of healthy skin and underlying subcutaneous tissue. This makes it possible to obtain an accurate histopathological diagnosis, which is essential for defining all prognostic parameters and planning the subsequent therapeutic strategy.

After biopsy, surgical treatment of primary melanoma is completed by widening the excision, the margin of which depends on the thickness of the lesion observed under the microscope.

Sentinel lymph node: an essential step

Another crucial moment in the management of melanoma is the search for the sentinel lymph node, which is the first lymph node that receives lymph from the tumor area.
This minimally invasive procedure makes it possible to assess whether cancer cells have begun to spread and to detect early patients with nonpalpable lymph node metastases who may need a complete lymph node dissection.

The risk of lymph node involvement is closely related to the thickness of the melanoma and the presence of mitosis:

• With a thickness of less than 1 mm, lymph node involvement is rare;

• between 1.5 and 4 mm, the probability of lymph node metastasis is around 25%;

• Beyond 4 mm, it can be up to 60%.

When sentinel lymph node biopsy (BLS) is indicated

• In intermediate-thickness melanomas (1-4 mm), where the probability of metastasis is 10-20%;

• In thick melanomas (> 4 mm), with a risk of more than 30-40%;

• In thin melanomas (< 1 mm), BLS is not routinely indicated, but can be discussed with the patient in the presence of particular clinical or histologic risk factors.

To determine the stage of melanoma and then plan the most appropriate treatment, physicians collect and integrate different types of information:

• clinical: derived from physical and instrumental examinations (e.g., X-rays, CT scans, MRIs);

• pathological: come from biopsies, which allow analysis of tumor depth (Breslow thickness, Clark level), presence of ulceration, growth rate (mitotic count), and possible involvement of lymph nodes or other organs.

The main factors considered in staging

• Tumor thickness: measures how deeply the melanoma has penetrated the skin. Breslow thickness, now the standard, is more accurate than the old Clark level method and is a key indicator of prognosis: the greater the thickness, the higher the risk of spread to lymph nodes or other organs;

• ulceration: occurs when the superficial skin layer (epidermis) covering the melanoma is not intact. This is not a wound visible to the naked eye, but a mark observable only under a microscope. The presence of ulceration increases the likelihood of disease spread;

• Lymph node metastasis: can be of two types:

  • Micrometastases: not visible to the naked eye, identified by sentinel lymph node biopsy;

  • Macrometastases: detectable by touch during examination or visible to the naked eye by the surgeon or pathologist. In both cases, the diagnosis is confirmed by biopsy;

• Distant metastasis sites: melanoma can spread to areas far from the initial site. If metastases affect the skin, subcutaneous tissue, or distant lymph nodes, the prognosis is generally better than when they affect vital organs or other internal tissues.

Surgery is the first step in the treatment of most melanomas and, in many cases, the only one necessary. It is also used during lymph node biopsy and in the treatment of advanced melanomas.

Wide local excision

Wide local excision is used to remove any possible cancer cells remaining after biopsy. This is the standard procedure for melanomas in situ, stage I and II, and in most stage III cases.

During the surgery, the surgeon removes the part of the skin affected by the tumor, including the biopsy site, and takes an area of surrounding skin and subcutaneous tissue, called the surgical margin, to make sure all cancer cells are removed. The width of the margin depends on the thickness of the primary tumor, that is, how deeply the melanoma has penetrated the skin.

Sentinel lymph node biopsy (SLNB) with lymphatic mapping

Sentinel lymph node biopsy is critical to assess whether the melanoma has spread to the lymph nodes. The sentinel lymph node is the first lymph node to receive drainage from the area affected by the tumor and is therefore the most likely to contain cancer cells.

The procedure includes lymphatic mapping, which guides the surgeon in visually identifying the lymph node to be removed. To do this, a blue dye, often combined with a small amount of radioactive substance, is injected into the skin near the tumor. This allows the surgeon to precisely locate the sentinel lymph node, minimizing the invasiveness of the surgery.

Wide local excision and sentinel lymph node biopsy are complementary procedures that allow accurate planning of the subsequent course of treatment, increasing the likelihood of complete healing.

Lymph node dissection

In some patients in whom melanoma cells are already evident at the lymph node level, surgery aimed at removing all lymph nodes already affected by melanoma may be indicated.

These drugs act selectively on cancer cells, recognizing specific genetic mutations underlying melanoma, without harming healthy cells. Identifying the mutation present in the tumor is critical because it determines the response to therapy. The most common mutations are:

• BRAF, present in about half of melanomas. Patients with this mutation can receive BRAF inhibitors in combination with MEK inhibitors. The combination of the two drugs has been shown to be more effective, with fewer side effects and a slowdown in the development of resistance by cancer cells;

• c-KIT, present in about 1-3% of melanomas, especially those of the mucous membranes, face, hands and feet. These cases may benefit from targeted tablet drugs such as imatinib.

These molecularly targeted drugs can be used effectively in both metastatic patients and operated patients with high-risk melanoma to reduce the risk of recurrence. In the latter case, therapy is limited to one year. Recent studies have also shown how in some particular situations the use of immunotherapy before the surgical stage can further reduce the risk of recurrence.

Side effects

Side effects vary from person to person, but are generally manageable with supportive medications. The most common include joint pain and fatigue, skin redness and itching, skin dryness, photosensitivity (it is important to protect oneself from sunlight, even indirectly by using high-protection creams and opaque clothing, skin formations such as keratoses or keratoacanthomas, sometimes even squamous cell carcinoma, which must be surgically removed but have a benign course, fever due to the action of the drugs, generally resolvable with temporary withdrawal of therapy (2-3 days) and antipyretics.

These controls and precautions allow side effects to be effectively managed, ensuring that the patient receives maximum benefit from the targeted therapy.

Immunotherapy, also known as biological therapy or biotherapy, harnesses the body’s natural defenses to fight melanoma. This is done through drugs called monoclonal antibodies, which act on the immune system to make it more effective against cancer cells.

Ipilimumab

Ipilimumab is a monoclonal antibody that blocks the CTLA-4 protein, a natural brake on the immune system. To understand how it works, we can compare the immune system to a car. Accelerator stimulates the immune response, steering directs the response against cancer cells, and brake, represented by CTLA-4, limits the speed to avoid damage to healthy tissues. Melanoma exploits this brake to escape the immune system. Ipilimumab “removes the brake,” allowing the immune system to act more rapidly against cancer cells.
Administration is intravenous, in day hospital, for 4 cycles at 3-week intervals.

PD-1 inhibitors

Drugs that block the PD-1 receptor ((Nivolumab or Pembrolizumab) have shown greater efficacy than Ipilimumab, even in patients who do not respond to the latter. PD-1 represents another powerful brake on the immune response that cancer cells exploit to survive. Recently, the use of other drugs that act by boosting the immune system, such as the anti-LAG3 Relatlimab in combination with Nivolumab, has also been shown to be an effective strategy in treating patients with melanoma.

Drug combinations

Recent studies have shown that the combination of anti-CTLA-4 and anti-PD-1 offers greater clinical efficacy than the use of the individual drugs. However, this strategy may cause more frequent and more serious adverse events.

These immunotherapy drugs can be used effectively in both metastatic patients and operated patients with high-risk melanoma to reduce the risk of recurrence. In the latter case, therapy is limited to one year. Recent studies have also shown how in some particular situations the use of immunotherapy before the surgical stage can further reduce the risk of recurrence.

Side effects of immunotherapy

The Most frequent side effects caused by immunotherapy are redness and itching, colitis, diarrhea, increased transaminases, impaired or reduced function of endocrine glands (especially thyroid and pituitary). These side effects are treated with cortisone or other drugs that block excessive activation of the immune system. It is important, in case of side effects, to immediately contact the referring treating team (oncology physicians, nurses) to immediately start the indicated therapy (usually cortisone-based).

The treatment of melanoma, as with many other cancer diseases, can combine several therapeutic strategies: surgery, radiation therapy, and other systemic therapies. Planning for these interventions takes place within the Multidisciplinary Pathology Group, ensuring individualized pathways tailored to each patient’s needs.

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

In melanoma, radiotherapy is mainly indicated in advanced disease, for example:

• To control the growth of tumor lesions that no longer respond to systemic treatments (oligoprogression);

• To treat symptomatic secondary injuries, such as pain;

• to limit the risk of functional damage in delicate areas of the body, such as bones or brain.

The radiation therapy pathway has three main phases:

1. Initial consultation: the radiation oncologist assesses the need for treatment and identifies the most appropriate strategy;

2. planning: the radiation therapist, together with the medical physicist, precisely defines the doses and the area to be treated;

3. Treatment execution: the medical radiology technician administers the sessions under the supervision of the radiation oncologist.

Throughout the journey, physicians, nurses and ancillary staff are available to the patient to provide information, support and ongoing assistance.

All cancer treatments involve side effects that impact the patient’s quality of life more or less severely.

The physicians and nurses on the multidisciplinary team are available to provide the patient with all the support he or she needs to manage the various side effects he or she will face both in the course of treatment and in resuming normal activities.

Physiotherapists for functional recovery, nutritionists for nutrition support, palliative physicians for pain control, and psychologists assist the patient in the course of treatment, rehabilitation, and follow-up.

The impact of cancer in a person’s life also affects the psychological sphere: in fact, falling ill with cancer is always a traumatic event that affects all dimensions of the person and can generate anxiety, fear, anger, depression.

In our institute, alongside cutting-edge therapies, the treatment and care pathway always includes a qualified psycho-oncological support that helps the patient cope positively not only with treatment but also with the delicate phase of physical and psychological recovery.

It is also possible to participate in psychological support groups to engage with other people who have gone through or are going through the same experience.

To ensure timely and direct support and receive timely answers to concerns and questions, a dedicated support service is in place at the Candiolo Institute for all patients.

From Monday to Friday, from 8 a.m. to 5 p.m., you can contact the secretariat of the oncology day hospital at 011.993.3775, reporting the need for urgent consultation.

The patient will be quickly put in touch with his or her medical specialist, to receive clear answers and immediate support.

The cancer patient is a person with complex needs that requires multidisciplinary support not only for the cancer disease, but also for all related issues.

At the Candiolo Institute, patients who need or require it have access to specialists in different areas to receive nutritional support, physical therapy, pain therapy and management of other associated conditions.

The Social Service Department of the Candiolo Institute conducts information and orientation interviews to patients and their families on how to access services in the area and how to obtain welfare and social security benefits provided by law (disability, benefits for aids and prostheses, work leave, etc.).

The service operates on Wednesdays and Fridays from 9 a.m. to 1 p.m. (phone: 011 9933059).

With the conclusion of the course of treatment, the follow-up period begins during which, through a series of examinations and visits, the side effects of the therapies performed and their effectiveness are monitored and the patient’s functional recovery is assessed.

Follow-up examinations are especially important to intercept any recurrence early so that appropriate therapy can be intervened. For the patient, they are also a valuable opportunity for dialogue with their medical specialist.

It is the same specialist doctor who schedules follow-up visits, in which the patient’s health condition is assessed and the required test reports are viewed.

Checkups are carried out at scheduled intervals for the duration of 5-10 years.

They have a shorter cadence at first (three to six months), then gradually thin out over time.

Due to the high number of cases treated each year, the Candiolo Institute is a national reference for taking care of esophageal cancer. Our experience enables us to deal with even the most complex situations, always with a personalized approach built on the clinical and personal profile of each patient.

Establishing the treatment plan always starts with an accurate and timely diagnosis. Patients have access to state-of-the-art imaging technologies that allow accurate assessment of the extent of the disease.

In addition, the Institute offers advanced and sophisticated laboratory investigations, including molecular and genomic analyses, which are critical for identifying biological features of cancer and guiding therapeutic decisions.

When indicated, surgery is performed with minimally invasive techniques (laparoscopic or thoracoscopic), which reduce operative trauma, promote faster recovery, and improve postoperative quality of life. Every treatment choice is defined within the GIC, ensuring a consistent and integrated approach.

As an IRCCS, the Candiolo Institute combines clinical practice with a strong vocation for scientific research. Patients can be evaluated for inclusion in active clinical trials, which provide a real opportunity to access innovative therapies not yet available in standard practice. Collaboration between care and research is a distinctive value that translates into concrete opportunities for the patient.

The Interdisciplinary Care Group takes care of the person at every stage: from diagnosis to treatment to follow-up, with attention to nutritional support, psychological health, and reintegration into daily life. The organization of checkups, examinations and treatment is designed to ensure continuity and serenity, always valuing the human dimension of care.