Lentigo Maligna Melanoma

Synonyms and related keywords: Hutchinson's melanotic freckle, Hutchinson melanotic freckle, skin cancer, freckle cancer, cutaneous melanoma, skin melanoma, cutaneous neoplasm, skin neoplasm, lentigo maligna, UV light exposure, ultraviolet light exposure, UV radiation exposure, ultraviolet radiation exposure, melanocytic nevus, melanocytic nevi


INTRODUCTION

Background: The overall incidence of cutaneous melanoma is increasing faster than that of any other neoplasm. In 2006, an estimated 62,200 patients will have melanoma, and 7,900 will die of the disease (Jemal, 2006). The annual lifetime risk of an American developing invasive melanoma was estimated as 1 in 71 in 2005.

Lentigo maligna melanoma is one of the 4 main subtypes of invasive melanoma and represents 5-15% of cases. The other types are superficial spreading (70%), nodular (10-15%), and acral lentiginous melanoma (5%) (Liu, 2003).

Sir John Hutchinson first described lentigo maligna in 1890; the disease continues to be called Hutchinson melanotic freckle on occasion. The Hutchinson melanotic freckle was originally thought to be infectious because of its slow yet progressive growth. The lesion has subsequently been characterized as malignant lentigo of elderly people, junctional nevus, and melanoma in situ. Most authors currently refer to it as lentigo maligna when it is confined to the epidermis and lentigo maligna melanoma when it violates the dermis.

Pathophysiology: Many authors consider lentigo maligna to be a preinvasive lesion induced by long-term cumulative ultraviolet injury. Conceptually, the term melanoma is used when atypical melanocytes invade the rich vascular and lymphatic networks of the dermis, thereby establishing metastatic potential.

Most malignant melanoma arise as superficial tumors confined to the epidermis, which is often known as horizontal growth. At some point there is a stepwise accumulation of genetic abnormalities leading to proliferation and progression to the vertical growth phase leading to dermal and deeper involvement and subsequently nodal metastases.

Frequency:

• In the US: The incidence of lentigo maligna is greatest in Hawaii, intermediate in the central and southern states, and lowest in the northern states.

• Internationally: The incidence of melanoma is highest in Australia, where lentigo maligna can be found at an annual rate of 1.3 cases per 100,000 population (Holman, 1980).

Mortality/Morbidity: Melanoma is second only to adult leukemia in years of potential life lost in young adults. The disease is responsible for death in a disproportionately high number of young and middle-aged adults.

Lentigo maligna melanoma has mortality rate similar to that of other melanoma types if depth of the tumor is taken into account.

About 10% of melanomas are familial. A first-degree relative has an 8-12 times increased risk of melanoma. The major gene resides on chromosome arm 9p and encodes a tumor suppressor gene called CDKN2A or MTS1. The second gene that has been noted in melanoma prone families is CDK4 and germline mutations have been identified in this group.

Race: Melanoma is the most frequent cancer in white women aged 25-29 years and the second most frequent (after breast cancer) in white women aged 24-30 years with fair skin.

Sex: A slight female preponderance is seen among patients with lentigo maligna.

Age: Patients with lentigo maligna tend to be older than those with superficial spreading malignant melanoma or nodular melanoma.

• Generally, patients with lentigo maligna are older than 40 years, with a mean age of 65 years.

• The peak incidence occurs in the seventh to eighth decades of life.

• Lentigo maligna and lentigo maligna melanoma have higher occupational exposure and lower recreational sun exposure.

CLINICAL

History: The risk of lentigo maligna melanoma increases as the number of years of residence in sunnier climates (eg, southern United States) increases, and risk increases with increased hours of exposure to sunlight, increased amount of actinic damage, and a history of nonmelanoma skin cancer.

• Associations have been reported with the following:

• Basal cell carcinoma

• Light skin color (especially people who have red hair)

• History of severe sunburn

• Porphyria cutanea tarda

• Werner syndrome

• Tyrosine-positive oculocutaneous albinism

• Xeroderma pigmentosa

• Lentigo maligna most commonly affects the sun-exposed skin of the head and neck, with a predilection for the nose and cheek. In fact, in Australia, the lesions occur more commonly on the right side (driver's side) of the head and neck in men and on the left side (passenger's side) in women. According to the Australian road traffic database, most Australian drivers are men, and most passengers in the front seat are women.

• Suspect the possibility of melanoma if a patient reports a new pigmented lesion or changes in an existing mole. About 50% of melanomas can arise from normal skin with no preexisting lesions.

Physical: Patients with melanoma need a complete and thorough physical examination, especially with focus on skin and lymph nodes. Review of systems should focus on symptoms pertaining to metastatic disease. Melanoma usually metastasizes to lungs, liver, and brain.

The most frequent findings suggesting early melanoma are changes in size or color of a new pigmented lesion or an existing mole. Lentigo maligna most commonly affects the sun-exposed skin of the head and neck, with a predilection for the nose and cheek. Less common sites include the arm, leg, and trunk. The conjunctivae and oral mucosa may become involved when a cutaneous lentigo maligna spreads onto mucosal surfaces. Signs suggestive of a more locally advanced lesion include elevation, burning, itching, pain, or bleeding.

• The simple ABCDE rule of melanoma helps patients as well as physicians to suspect and make an early diagnosis.

• A - Asymmetry
• B - Border irregularity

• C - Color variegation

• D - Diameter greater than 6 mm (tip of pencil head), although melanoma can occur in lesions less than 6 mm

• E - Enlargement

• Lentigo maligna, the precursor lesion, has been likened to a stain on the skin. The lesion typically is tan-brown, with differing shades throughout.

• Lentigo maligna can be present for long periods (5-15 y) before invasion occurs, although rapid progression within months has been described. The percentage of lentigo maligna that progress to lentigo maligna melanoma remains unknown, but estimates of the lifetime risk of developing lentigo maligna melanoma in patients diagnosed with lentigo maligna at age 45 years appears to be 5%. The risk for progression to lentigo maligna melanoma appears to be proportional to the size of the lesion of lentigo maligna
  (Weinstock, 1987).

• Distinguishing lentigo maligna from its invasive counterpart on a clinical basis continues to present diagnostic dilemmas, especially in patients who had prior therapeutic interventions like cryotherapy. It is important to have a low threshold for biopsy of pigmented facial lesions.

• In one series of 85 excised lesions with a clinical diagnosis of lentigo maligna, more than 50% had invasive lentigo maligna melanoma.

• A strong correlation exists between patients who report finding a nodule and diagnosis of melanoma. Although palpability usually indicates dermal invasion, clinical examination may be unreliable in early invasive lentigo maligna melanoma (lesions less than 1 mm).

• Assess the total number of all types of moles. More than 50 nevi 2 mm in diameter or larger indicate increased risk.

• Search for dysplastic (clinically atypical) melanocytic nevi. Irregular pigment patterns, such as variegation, central dark areas, or halos of pigment, may indicate the presence of dysplasia. Atypical nevi tend to be larger than common acquired neomelanocytic nevi, which rarely exceed 5 mm.

• Search for congenital melanocytic nevi. People with very large or giant congenital nevi have an increased lifetime risk (>6%) of developing melanoma. Intermediate sized (>0.5 cm), raised, pigmented lesions, with or without hair, that do not have the features of clinically atypical nevi have an uncertain but elevated risk for development of melanoma.

Causes:

• Ultraviolet radiation exposure: For people who live in Australia, risk increases as the number of years spent in Australia increases, and risk increases with increased hours of exposure to sunlight, with the amount of actinic damage, and with history of nonmelanoma skin cancer.

• Increased number of melanocytic nevi, including large or giant congenital nevi

• Fair skin

• History of severe sunburn

• Occupational risk

DIFFERENTIALS

Other Problems to be Considered:

Solar lentigo
Pigmented actinic keratosis
Seborrheic keratosis
Common acquired nevi
Dysplastic nevi

WORKUP

Lab Studies:

• Patients with low risk melanomas, less than 1 mm thick, routinely do not need laboratory studies. Most centers order liver function tests and lactose dehydrogenase (LDH) as part of the initial laboratory evaluation.

Imaging Studies:

• Chest radiograph is done by most institutions in patients with low-risk disease.

• A PET scan, staging CT scans, or MRI can be performed for patients with node positive disease or symptoms suggestive of metastasis, to determine extent of disease.

Other Tests:

• Dermoscopy is a newer tool available to help the dermatologist distinguish benign from malignant lesions. It is a hand held instrument that magnifies the skin lesion ten times to enable more accurate diagnosis.

Procedures:

• Skin biopsy

• Ideal biopsy of lesions should include full thickness skin extending to the subcutaneous fat.

• Avoid superficial skin biopsy by shaving, scissors excision, or curettage because these techniques do not allow for assessment of tumor thickness, which is important for prognostication and treatment planning.

• A better choice would be excisional biopsy with a narrow margin of normal-appearing skin, which usually can be performed on lesions unless the result would be disfiguring, in which case incisional biopsy is considered reasonable. Incisional biopsy is also indicated for lesions that are too large for complete excision.

• The type of biopsy does not influence patient survival or rate of metastasis. Previous concerns that incision into a melanoma promotes its dissemination have been allayed. The excisional biopsy specimen may be obtained by elliptical excision, saucerization, or punch biopsy, if the lesion is small enough. The specimen should include a portion of subcutaneous fat to ensure that accurate microstaging can be determined.

• Lymph node biopsy

• Sentinel lymph node biopsy is done to assess regional lymph node involvement and to decide on adjuvant therapy. It is indicated in all melanoma patients except Stage 0 or Stage 1A, that is, patients with a lesion less than 1 mm.

• If metastasis is present, a full nodal dissection is done to fully stage the disease.

Staging: Lentigo maligna is melanoma in situ.

Lentigo maligna melanoma is melanoma.

The American Joint Committee on Cancer (AJCC) 2002 Tumor, Node, Metastases (TNM) staging for melanoma uses tumor size, rather than invasion, and ulceration to stage the tumor.

• Tumor staging is as follows (for the stages below, a indicates without ulceration, and b indicates with ulceration):

• Tx - Primary tumor cannot be assessed (eg, regressed primary)

• Tis - Melanoma in situ

• T1 - Less than 1 mm

• T2 - 1.01-2.0 mm

• T3 - 2.01-4.0 mm

• T4 - Greater than 4.0 mm

• Nodal staging is as follows (for the stages below, a indicates micrometastasis [clinically occult], and b indicates macrometastasis [clinically apparent]):

• N - Nodal involvement
• N1 – One node
• N2 - 2-3 nodes
• N3 - 4 nodes or more

• M indicates metastasis.

TREATMENT

Medical Care: Various nonsurgical modalities are available to patients in whom surgical therapy is not feasible.

• Cryotherapy is not standard but is often used in patients who are not candidates for surgery.

• Temperatures of -4°C to -7°C selectively destroy melanocytes while preserving keratinocytes in skin and mucosal epithelia.

• The first report of cryotherapy for lentigo maligna was published in 1975.
• Most authors discourage cryotherapy for lentigo maligna because focal lentigo maligna melanoma cannot be detected clinically.
• Risks include hypopigmentation, infection, scarring, inability to detect invasive melanoma, and failure to treat periadnexal involvement.

• Radiation therapy

• Miescher first described radiation therapy in treatment of lentigo maligna in 1954. Others have employed similar techniques with varying results.

  Like cryotherapy, radiation therapy may miss focal lentigo maligna melanoma

• Topical Imiquimod 5% cream has recently been described in many studies to be effective, especially in patients who are not surgical candidates. Imiquimod is an immune response modifier that is offering encouraging results, but further studies are needed to identify ideal treatment protocols.

Surgical Care: Lentigo maligna is treated with definitive surgical therapy. The actual margins of atypia usually extend beyond the clinically apparent margin; total removal may be difficult. National Comprehensive Cancer Network (NCCN) practice guidelines for melanoma in 2006 are as follows (tumor thickness, recommended clinical margin):

• Tumor in situ, margin 0.5 cm
• Tumor less than 1 mm, margin 1 cm
• Tumor 1-2 mm, margin 1-2 cm
• Tumor 2-4 mm, margin 2 cm
• Tumor >4 mm, margin at least 2 cm

But a study by Agarwal and colleagues in 2002 suggests that 5 mm margins are not sufficient in lentigo maligna, given that only 42% of tumors were cleared after a 5 mm excision in this study.

• Standard excisions have a recurrence rate of 8-20%. Mohs surgery and staged excision may offer better control and lower recurrence rates (4-5%)(Stevenson, 2005; Mckenna, 2006).

• Nonsurgical therapies such as cryosurgery, radiotherapy, electrodissection, curettage laser surgery, and topical medications have a recurrence rate of 20-100% at 5 years.

Consultations: Melanoma should be managed by a multidisciplinary team
that includes a dermatologist, surgeon, and medical oncologist.

MEDICATION

In the presence of nodal disease, multiple chemotherapy and immunotherapy drugs have been tested. High-dose alpha-interferon remains the standard adjuvant option, especially with stage III cancer, in which it results in a 9-month increase in disease-free survival and a 1-year increase in overall survival. In the presence of metastases, the options include high-dose interleukin-2, dacarbazine, and temozolomide.

Vaccines have been tested in various studies, but none have lead to any significant survival advantage. GM-CSF has been found to prolong time to progression compared to historical
control in both node-positive and metastatic stage of the disease.

Drug Category: Biological response modulators -- These agents have antiviral, antitumor, and immunomodulatory actions. They are used as adjuvant treatment.

Drug Name	Interferon alfa-2b (Intron A) -- Immunotherapy that has been found to improve disease-free survival in most studies but has only been found to improve survival in 2 studies (Eastern Cooperative Oncology Group [ECOG] 1684 and 1694). The drug is quite toxic and patients are often not able to take the whole year of adjuvant treatment.
Adult Dose	20 million U/m2 IV for 5 consecutive d/wk for 4 wk; then 10 million U/m2 SC 3 times/wk for 48 wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; patients who have anaphylactic sensitivity to mouse immunoglobulin (IgG), egg protein, or neomycin; autoimmune hepatitis
Interactions	Potential risk of renal failure when administered concurrently with interleukin-2; theophylline may increase toxicity by reducing clearance; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Depression and suicidal ideation may be side effects of treatment; infrequently, severe or fatal GI hemorrhage reported in association with alpha interferon therapy; prior to initiation of therapy, perform tests to quantitate peripheral blood hemoglobin, platelets, granulocytes, hairy cell, and bone marrow hairy cells; monitor periodically (eg, monthly) during treatment to determine response to treatment; if patient does not respond within 6 mo, discontinue treatment; if response occurs, continue treatment until no further improvement observed; not known whether continued treatment after that time is beneficial

Drug Name	Aldesleukin (Proleukin) -- Activates T cells and amplifies their responses. Enhances natural killer cells' antitumor activity. Affects tumor growth by activating lymphoid cells in vivo, without affecting tumor proliferation directly.
Adult Dose	600,000-720,000 IU/kg IV q8h for up to 5 d or per protocol
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; caution in patients with preexisting cardiac, pulmonary, CNS, hepatic, or renal impairment
Interactions	Corticosteroids may decrease antitumor effect; NSAIDs increase capillary leak syndrome; potentiates effects of antihypertensive medications
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May cause sepsislike syndrome due to "capillary leak;" other toxicities are flulike syndrome, fever, chills, fatigue, infection, myelosuppression, hepatic toxicity, neurological and neuropsychiatric findings, hypotension, erythema, rash, urticaria, and alteration in thyroid function (including hyperthyroidism and hypothyroidism); high-dose IL-2 has been associated with treatment-related deaths

Drug Category: Antineoplastic agents -- These agents inhibit cell growth and proliferation.

Drug Name	Temozolomide (Temodar) -- Oral alkylating agent converted to MTIC at physiologic pH; 100% bioavailable; approximately 35% crosses the blood-brain barrier. Indicated for glioblastoma multiforme combined with radiotherapy. Significant overall survival was demonstrated in patients treated with temozolomide and radiation, compared with radiotherapy alone.
Adult Dose	Adjust dose according to nadir neutrophil and platelet counts from previous cycle and at time of initiating next cycle Concomitant phase: 75 mg/m2/d PO for 42-49 d with concomitant radiotherapy Maintenance cycle 1:150 mg/m2/d PO for 5 d followed by 23 d without treatment; initiated 4 wk following concomitant phase completion Maintenance cycles 2-6:200 mg/m2/d PO for 5 d; escalate dose from phase 1 only if blood count stable
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity to temozolomide or DTIC, since each drug is metabolized to MTIC
Interactions	None reported
Pregnancy	D - Unsafe in pregnancy
Precautions	Causes bone marrow suppression resulting in thrombocytopenia, anemia, and leukopenia (check blood counts weekly during concomitant phase, then at day 1 and 21 of each cycle); common adverse effects include nausea, vomiting, and alopecia; it is not known if the drug is excreted in breast milk and because of potential serious adverse effects in infants, breastfeeding should be discontinued; PCP prophylaxis required during concomitant phase, continue if lymphocytopenia develops

Drug Name	Dacarbazine (DTIC-Dome) -- Cell-cycle phase-nonspecific antineoplastic alkylating agent. Metabolized by cytochrome P450 system to alkylating form. Inhibits DNA replication, RNA transcription, protein synthesis, and nucleic acid function by substituting an alkyl group for a hydrogen ion in various organic compounds, forming covalent linkages with sulfhydryl groups.
Adult Dose	2-4.5 mg/kg/d IV for 10 d; may repeat in 4 k Alternatively, 250 mg/m2/d IV for 5 d; may repeat in 3 wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in patients with bone marrow suppression, renal and/or hepatic impairment; avoid extravasation

FOLLOW-UP

Further Outpatient Care:

• Follow-up consists of examination of the skin, the primary site, and the regional nodal basin.

• The National Cancer Institute recommends follow-up every 6 months for the first 2 years after surgical therapy in patients without atypical moles and without a family history of melanoma. If the patient is disease-free at 2 years, conduct yearly follow-up visits.

• For patients with atypical moles or a positive family history, follow up every 3-6 months.

• Base the decision to extend the interval after 2 years on the stability and characteristics of the atypical moles.

Deterrence/Prevention:

• Avoidance of sun exposure and use of sunscreen is highly recommended.

Prognosis:

• The overall prognosis is good for patients with localized melanoma and no nodal or distant metastases. An overall 5-year survival rate of 79% has been reported for patients with stage I or stage II lesions.

• In patients with regional nodal disease (ie, stage III), the 3 dominant prognostic variables are the number of nodal metastases, the patient's age, and ulceration in the primary tumor.

• Numerous studies have shown that the number of nodes with metastases has significant prognostic value in patients with stage III disease. Patients with 1 positive node fared the best; 40% remained alive at 10 years. Those with 2-4 positive nodes had an intermediate 10-year survival rate of 26%. Patients with 5 or more positive nodes had the lowest 10-year survival rate, at 15%.

• In both men and women with stage III melanoma, patients older than 50 years tend to do worse. In studies evaluating tumor ulceration as a prognostic factor in lentigo maligna melanoma, the 3-year survival rate for patients with an ulcerated primary tumor was 20%, compared with 35% for those with nonulcerated primary lesions.

• Patients with stage IV melanoma generally have a poor prognosis. From the time the metastasis is diagnosed, the median survival is 6-7.5 months, with a 5-year survival rate of approximately 6%.

Patient Education:

• Education plays an integral role in the follow-up care of patients with melanoma.

• Instruct patients on self-examination for new and locoregional recurrences. Teach them to recognize the classic characteristics of cutaneous melanoma in friends and family. In addition, during every follow-up visit, counsel patients to avoid excess sun exposure, to use sunblock liberally, and to wear protective clothing.

• For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education articles Skin Cancer and Skin Biopsy.

MISCELLANEOUS

Medical/Legal Pitfalls:

• Failure to diagnose, which is often the case of skin lesions that were initially thought to be benign without a biopsy

• Failure to provide adequate follow-up care

• Melanoma should be managed by a multidisciplinary team.

• The team should include a dermatologist, surgeon, medical oncologist, and other allied health workers.