Melanoma

I. What every physician needs to know.

Melanoma is a malignant tumor of melanocytes which are normally found in the basal layer of the epidermis. Unlike other skin cancers which appear mostly in sun-exposed areas, melanoma can occur anywhere on the body including the mucous membranes. Melanoma is primarily a skin cancer of adults and is mainly characterized by visible changes of the skin as discussed below.

II. Diagnostic Confirmation: Are you sure your patient has Melanoma?

As in cases of other skin cancers, melanoma is diagnosed by a careful history, clinical examination, and diagnostic histopathology.

The popular “ABCDE” mnemonic – standing for Asymmetry, Border irregularity, multiple Colors, larger Diameter, and/or Evolving size, shape, or color of the skin lesion – is a common screening tool used during both history and physical evaluation. This is also a helpful tool for patients to understand when performing their own self exams.

Melanoma is most commonly found on the back in men and on the legs in women; however, a thorough examination of the total skin surface is needed for early detection. Often, bright light, magnification, and/or dermoscopy are used during physical examinations.

As it is difficult to diagnose melanoma based on history and physical examination alone, skin biopsy and histopathology is the gold standard to diagnose melanoma.

A. History Part I: Pattern Recognition:

Typically, patients present with a concerning lesion, mole, or pigmented region of skin. Patient complaints often include recent changes in shape, color, size, or sensation of the skin lesion.

The various clinical presentations of melanoma include rapid change in the size of a new or pre-existing skin lesion, appearance of different shades of colors in a mole and irregularity in the shape of a rapidly growing skin lesion. Many patients also complain of bleeding or itching of the lesion. Additionally, growth of a new lesion next to or within an existing mole or the appearance of asymmetric mole-like lesions can be quite common in the history of a melanoma lesion.

In rare cases, melanoma lesions may be clinically apigmented, known as amelanotic melanoma. At times, melanoma can appear as a raised or ulcerated skin lesion on the palmar, plantar, or subungual surfaces. The majority of melanomas arise de novo, but melanoma may also arise within a pre-existing nevus.

B. History Part 2: Prevalence:

More than 75,000 new cases of melanoma are diagnosed annually in the United States. Melanoma is the sixth most common cancer in the United States. The underlying etiology of melanoma is not always known; however, genetic abnormalities and environmental triggers have been implicated as predisposing factors. Individuals with atypical moles, high levels of exposure to sunlight or ultraviolet light, a family history of melanoma and/or increased number of moles are at a higher risk for developing melanoma. Close to 10% of melanomas are familial. Individuals of Caucasian decent, red or blond hair, or light eye color are also at a higher risk for developing melanoma.

C. History Part 3: Competing diagnoses that can mimic Melanoma.

It may be difficult to clinically distinguish early melanoma from benign pigmented lesions. Clinical examination should be followed up with an assessment of risk factors and histopathology to avoid misdiagnosis. In more complex cases, diagnosis should be made in concert with dermatologist and dermatopathologist.

It is important to distinguish melanoma from:

Angiokeratoma (red to blue, hyperkeratotic lesion of capillaries).
Dysplastic nevi (non-uniform, pink to brown moles with irregular borders).
Angioma (red to purple benign growth of blood vessels).
Lentigo (evenly pigmented, symmetrical, tan to dark brown spot on the sun exposed skin).
Pigmented actinic keratosis (rough, scaly lesion caused by sun exposure).
Pigmented basal cell carcinoma (irregularly pigmented, pearly papule).
Seborrheic keratosis (yellow to brown, round to oval benign growths).
Traumatized or irritated nevus.
Traumatic hematoma (may closely resemble melanoma but usually resolves in 1-2 weeks).

Melanoma can be differentiated from all of the skin pathologies mentioned above by history, physical examination, skin biopsy and histopathology.

D. Physical Examination Findings.

A total body skin examination (TBSE) is important in the early detection of melanoma. If suspicious skin lesion is found during TBSE, physicians should look for features such as border irregularity, asymmetry, inflammation, color variegations, atypical enlargements, bleeding or crusting.

Physical examination findings which should increase the suspicious of melanoma and need to be biopsied include:

Asymmetry of the skin lesion when one half of the region is different from the other half.
Uneven, blurred, notched edges or border irregularity of the skin lesion.
Unevenness in color of a lesion, especially shades of brown, black.
Diameter of the mole is greater than 6 mm.
Evolving: Change in color, size, or shape over time.

E. What diagnostic tests should be performed?

There are no physical examination findings which can confirm the diagnosis of melanoma. Diagnosis of melanoma is developed on the combination of clinical findings and histopathology.

Dermoscopy or other skin magnification may be utilized as a part of skin examination. Dermoscopy may be especially useful when assessing hypopigmented or amelanotic melanomas. If there is clinical concern for melanoma on skin exam, a biopsy specimen should be obtained.

The preferred procedure is an excisional biopsy where the entire lesion, along with a small margin of tissue that is not visibly part of the tumor, is removed. With this biopsy technique, the histopathology is most likely able to confirm the diagnosis as well as provide information about the involvement of margins/staging of the tumor.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Melanoma is primarily diagnosed by clinical examination and histopathology. However, due to the similarities to non-cancerous benign lesions and diversity in cytomorphology, diagnosis can be difficult. To aide in the histopathologic diagnosis, immunohistochemistry markers such as MART-1, S-100, HMB-45, vimentin, Mib1, and tyrosinase may be used to better define the lesion histopathologically. In addition, fluorescent in situ hybridization (FISH), comparative genomic hybridization, or gene expression profiling may be used for further testing of equivocal lesions.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

No imaging studies are needed to establish the diagnosis, but are commonly used to stage the cancer. Based on the histologic depth of the tumor, sentinel lymph node mapping and lymphoscintigraphy are performed to further stage the tumor. In other cases, chest X-Rays, computed tomography scan (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), are needed to stage the cancer.

In patients with bone pains and suspicious of metastasis, bone scintigraphy may be obtained. MRI is considered superior to bone scintigraphy to evaluate the involvement of bone marrow.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

III. Default Management.

Once diagnosis is confirmed, management of melanoma should be planned on an individual basis. Treatment varies based on the stage and location of the cancer and on patient’s underlying comorbid conditions. Treatment and management decisions of melanoma should be made in consultation with hematology/oncology and dermatology experts.

Melanoma is divided into five different stages. Stage 0 is limited to the epidermis without invasion of surrounding tissue (melanoma in situ). Stage I and II melanomas are all node-negative with varying depths of invasion. Stage I consists of a tumor less than 2 mm thick with no ulceration or less than 1 mm with ulceration. Stage II consists of a tumor greater than 1 mm with ulceration or greater than 2 mm without ulceration. Stage III includes involvement of lymph nodes, presence of matted lymph nodes, cancer in lymph vessels, and/or the formation of additional small tumors within 2 cm of the primary tumor. Stage IV consists of the cancer spreading to other organs and progressively throughout the body.

Early diagnosis is critical because melanomas are aggressive neoplasms, capable of spreading to any organ of the body. The depth of invasion, known as the Breslow depth, has been shown to be the greatest risk factor for metastasis in melanoma.

Treatment options for melanoma include surgical, medical and physical modalities. At all stages of melanoma, surgery is primarily used to remove the cancerous tumor. Surgical therapies include wide local excision with a minimum of 1 cm margins, sentinel lymph node biopsy, lymphadenectomy, metastatectomy, and limb perfusion. Typically, systemic medical treatments including chemotherapy and immunotherapy become necessary in some cases of Stage II and in almost all cases of Stage III and Stage IV. In special cases, topical therapy with imiquimod, local ablation, intralesional injection with BCG or interferon, or external beam radiation may be used. The proper treatment plan should be established on a patient by patient basis after dermatological, oncological, and pathological evaluations.

A. Immediate management.

Although immediate treatment is not necessary in most cases, high stage melanomas with spread to vital organs may need emergent management. Melanoma has a high propensity of metastasis to the central nervous system. In these patients, immediate supportive management may be needed depending on presenting symptoms (seizures, stroke, etc.) before treatment is initiated.

B. Physical Examination Tips to Guide Management.

There are no physical examination findings of the lesion to assess appropriateness of management, though the physical location of a melanoma may be important in the surgical management of a patient.

A detailed description of chemotherapy and immunotherapy is beyond the scope of this chapter. However, we will explain the common side effects of medications that a hospitalist may encounter during treatment.

Close attention should be given to the patients hearing ability. Also pulmonary and neurological system should be examined regularly as melanoma treatment can affect these organ systems. Patients may also present with extreme fatigue (associated with chemotherapy induced anemia), opportunistic infections (leucopenia), and bleeding (thrombocytopenia).

Commonly used immunotherapeutic agents include interferon alpha, Ipilimumab, and interkeuin-2 (IL-2). These agents can cause weakness, gastroenteritis, and flu-like symptoms and should be kept in mind. Immunotherapy tends to have relatively fewer side effects compared to chemotherapy.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Complete metabolic panel (CMP) should be closely monitored to evaluate for nephrotoxicity once chemotherapy (cisplatin) is initiated. Pulmonary Function Tests can be used to observe pulmonary toxicity associated with carmustine (usually before and after completion of the treatment). Electromyogram (EMG) may need to be ordered in certain cases.

At times, treatment of metastatic widespread melanoma is associated with tumor lysis syndrome and should be monitored by series of blood tests once chemotherapy is initiated.

Usual side effects of chemotherapeutic agents such as pancytopenia, bleeding and severe anemia can also occur after initiation of treatment and should be followed by series of blood counts. How often blood and neutrophil count should be monitored is not known and varies from patient to patient.

D. Long-term management.

After initial treatment, a long term plan is formulated based on stage of the cancer and the patient’s condition. Patient should be followed closely for cancer recurrence and also for side effects of treatment. Depending on thickness of melanoma and stage of cancer, patients should undergo scheduled physical exams on regular basis.

Melanoma can recur near the original site of the tumor. Typically, the treatment for relapses is similar to original treatment but performing a sentinel lymph node biopsy is usually necessary in these cases. Variations from original treatment plan may be considered based on location, thickness, and spread of the new tumor.

Attention should also be given to patient’s social issues and psychiatric outcomes associated with malignancy and its treatment.

E. Common Pitfalls and Side-Effects of Management.

Melanoma can be clinically misdiagnosed as a benign lesion. When in doubt, a biopsy specimen should be obtained.

If local lymph nodes were not removed during original treatment, lymphadenitis may also present. This can be treated by a combination of lymph node dissection, adjuvant therapy (interferon), and/or radiation therapy.

The commonly used chemotherapeutic agents are Paclitaxel (associated with severe allergic reaction), Dacarbazine (chemical phlebitis), Cisplatin (ototoxicity and nephrotoxicity), Carmustine (pulmonary toxicity), Temozolomide (GI side effects), Vinblastine (hair loss), Tamoxifen (lymphedema), and Vindesine (peripheral neuropathy). Like any other chemotherapeutic agents, all agents can cause pancytopenia.

Interleukin-2 can have severe side effects due to its toxicity such as irregular heart rhythm, fever, pulmonary edema, and, rarely, death. For these reasons, its usage is restricted to those with normal heart and lung function who are otherwise in good health.

Ipilimumab can be associated with diarrhea, colitis, hepatitis, inflammation of the skin, and inflammation of the endocrine organs. However, some of these effects can be reduced if Ipilimumab is paired with other drugs such as dacarbazine.

IV. Management with Co-Morbidities.

Treatment of Melanoma may need adjustment in patients with following medical comorbidities.

A. Renal Insufficiency.

Use of Cisplatin should be restricted. Interferon alpha should not be used in combination with ribavirin in patients with reduced kidney function.

B. Liver Insufficiency.

Dosage of paclitaxel, carmustine and vindesine may need to be adjusted in accordance to hepatic impairment.