January 17, 2007

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


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.


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.


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.

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.



Other Problems to be Considered:

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


Lab Studies:

Imaging Studies:

Other Tests:


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.


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

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):

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.

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


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 Dose20 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 DoseNot established
ContraindicationsDocumented hypersensitivity; patients who have anaphylactic sensitivity to mouse immunoglobulin (IgG), egg protein, or neomycin; autoimmune hepatitis
InteractionsPotential 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.
PrecautionsDepression 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 Dose600,000-720,000 IU/kg IV q8h for up to 5 d or per protocol
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; caution in patients with preexisting cardiac, pulmonary, CNS, hepatic, or renal impairment
InteractionsCorticosteroids 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.
PrecautionsMay 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 DoseAdjust 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 DoseNot established
ContraindicationsDocumented hypersensitivity to temozolomide or DTIC, since each drug is metabolized to MTIC
InteractionsNone reported
Pregnancy D - Unsafe in pregnancy
PrecautionsCauses 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 Dose2-4.5 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 DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsNone reported
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsCaution in patients with bone marrow suppression, renal and/or hepatic impairment; avoid extravasation


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