MALIGNANT MELANOMA

MALIGNANT MELANOMA Introduction -Melanoma is a tumor that develops as a result of the malignant transformation of melanocytes. -Melanocytes  cells are derived from the neural crest. -Melanomas usually occur on the skin but can arise in other locations where neural crest cells migrate, such as in the gastrointestinal tract, eye or brain. -Melanoma predominantly is an adult disease with a peak incidence in the 4th decade and no sex prevalence. A patient's risk of developing a second primary melanoma after diagnosis of the first one is 3-5%. Incidence -The incidence is estimated to be rising rapidly by almost 6% per year. Morbidity and Mortality -Early diagnosis and treatment before metastasis most important in management. While only 5% of skin cancers are melanomas, about two-thirds of all deaths from skin cancer are due to melanomas Etiology/risk factors 1.Family history Positive family history in 5-10% of patients With at least one affected relative, 2.2-fold higher risk 2.Personal characteristics -Blue eyes, fair and/or red hair, pale complexion -Skin reaction to sunlight - Easily sunburned -Freckling 3.Benign and/or dysplastic melanocytic nevi - Number rather than size has better correlation 4.Immunosuppressive states - Transplant patients, hematologic malignancies 5.Sun exposure during adolescence Ø  High UV-B radiation Ø  Low latitude Ø  Number of blistering sunburns 6.Atypical mole syndrome (formerly termed B-K mole syndrome, dysplastic nevus syndrome, familial atypical multiple mole melanoma) Pathophysiology Benign melanocytic nevi are markers of melanoma risk rather than direct precursors; however, dysplastic nevi are believed to degenerate over time into melanoma. Lentigo maligna is believed to be a pre-invasive precursor of lentigo maligna melanoma, and at least 5% progress to malignancy Clinical presentation Patients usually present with skin lesions that have changed in size, color, contour, or configuration. The acronym "ABCDE" is the hallmark of international public awareness campaigns and may be used to remember the physical characteristics suggestive of malignancy. ABCDE stands for A-Asymmetry of shape B-Border irregular C-Color variations (especially red, white, and blue tones in a brown or black lesion) or deepening of pigmentation D-Diameter greater than 6 mm(size),or recent increase in size E-Elevated surface, erosions or ulcerations, bleeding ,crusting Other symptoms of the lessions Ø  Itching, pain,ulcerate, Bleed, Develop satellites Biopsy -Perform biopsy on all lesions suggestive of melanoma in the thickest part. -If the resection will not result in a disfiguring defect, excisional biopsy with a 2-cm skin margin and extending to the subcutaneous tissue is suggested for lesions less than 1.5 cm in diameter. -If the lesion is large or located in an anatomic area where skin removal would cause disfigurement, an incisional biopsy may be performed. -A full-thickness core punch biopsy in the most raised or irregular area is suggested with the understanding that this area may not be the thickest area. Skin anatomy The skin is composed of multiple layers. The epidermis is the most superficial layer, and it contains keratinocytes in various stages of development. Melanocytes are located in the deepest layer of the epidermis. A basement membrane separates the epidermis from the underlying dermis, which is divided into 2 zones, papillary dermis and reticular dermis. Subcutaneous tissue is deep to the reticular dermis. Histological classification Four major types of melanomas exist based on growth pattern. 1.        Superficial spreading melanoma 2.        Nodular melanoma 3.        Lentigo maligna melanoma 4.        Acral lentiginous melanoma Other more unusual types include mucosal lentiginous melanoma, desmoplastic melanoma, and verrucous melanoma. 1.Superficial spreading melanoma Commonest up to 70% of melanomas in white population. Histologically Ø  Appear singly or in nests along the dermal-epidermal junction Ø   May migrate into the stratum granulosum or stratum corneum Ø   These cells can invade the papillary dermis with an inflammatory lymphocytic infiltrate. Clinically Ø  Usually arise in a preexisting dysplastic nevus. Ø  Typically, this lesion changes slowly over several months to years. Ø  They are usually flat but may become irregular and elevated in later stages. Ø  The lesions average 2 cm in diameter with variegated colors and peripheral notches and/or indentations. 2,Nodular melanoma They comprise approximately 15-30% of melanoma Histology Ø  Characterized by extensive vertical growth into the dermis with a minimal radial component. Clinical Ø  These tumors typically are blue-black but may lack pigment in some circumstances. Ø  They are known to arise without a preexisting lesion. May develop at the site of a preexisting nevus and rapidly becomes a palpable, elevated, firm nodule Breslow classification -Thickness of lesion Stage  1Thickness of 0.75 mm or less Stage 2 Thickness of 0.76-1.50 mm Stage 3 Thickness of 1.51-4.00 mm Stage 4 Thickness greater than 4.00 mm Clark classification Level I - Involves only epidermis (in situ melanoma); no invasion Level II - Invades papillary dermis Level III – Papillary-reticular dermis interface Level  IV - Invades reticular dermis Level V - Invades into subcutaneous tissue TNM classification Primary tumor (pT) pTX - Primary tumor cannot be assessed pT0 - No evidence of primary tumor pTis - Melanoma in situ (Clark level [CL] I) pT1 - Tumor 0.75 mm or less in thickness; invades papillary dermis (CL II) pT2 - Tumor 0.76-1.50 mm in thickness and/or invades to papillary-reticular dermal interface (CL III) pT3 - Tumor 1.51-4.00 mm in thickness and/or invades reticular dermis (CL IV)    pT3a - Tumor 1.51-3.00 mm in thickness    pT3b - Tumor 3.01-4.00 mm in thickness pT4 - Tumor greater than 4.00 mm in thickness and/or invades subcutaneous tissue (CL V) and/or satellite(s) within 2 cm of the primary tumor pT4a - Tumor greater than 4.00 mm in thickness and/or invades subcutaneous tissue pT4b - Satellite(s) within 2 cm of primary tumor Regional lymph nodes (N) NX - Regional lymph nodes cannot be assessed N0 - No regional lymph node metastasis N1 - Metastasis 3 cm or less in greatest dimension in any regional lymph node N2 - Metastasis more than 3 cm in greatest dimension in any regional lymph node(s) and/or in-transit metastasis N2a - Metastasis more than 3 cm in greatest dimension in any regional lymph node(s) N2b - In-transit metastasis N2c - Both N2a and N2b Distant metastasis (M) MX - Distant metastasis cannot be assessed M0 - No distant metastasis M1 - Distant metastasis M1a - Metastasis in skin or subcutaneous tissue or lymph node(s) beyond the regional lymph nodes M1b - Visceral metastasis.  Stage III -Wide local excision of the primary tumor with 2-cm margins remains the first-line therapy. -. Skin grafting or other tissue-transfer technique may be necessary to close the defect. -Perform regional lymph node dissection, since a stage III melanoma represents nodal disease. - If the nodal status is unknown, consider a sentinel lymph node biopsy to determine if the disease is stage I, II, or III. -As in stage II disease, a higher rate of treatment failure exists with wide local excision alone in this group compared to stages 0 and I. Many clinical trials currently are exploring similar options as adjuvant therapy. Stage IV Advanced metastatic melanoma usually is refractory to standard therapy; thus, consider these patients for clinical trials. Some treatments have reported various objective responses, although they usually are short lived. Dacarbazine (DTIC) and the nitrosoureas, carmustine (BCNU) and lomustine (CCNU), produced a 20% objective response rate. Response rates for interferon alfa and interleukin-2 range from 8-22% and 10-20%, respectively. Currently, other studies in progress are comparing other cytotoxic and biologic drug regimens. Prognosis 1)       Size of the tumor and the depth of invasion. Small tumors with minimal invasion (< 0.7 mm) are usually curable by wide local excision. 2)       The prognosis is usually favorable in lentigo maligna melanoma and in superficial spreading melanomas without deep invasion. Most nodular melanomas, particularly if ulcerated and associated with deep invasion, have a poor prognosis. 3)       Lesions of the extremities have a more favorable prognosis than those of the trunk, and 4)       women with malignant melanoma have better survival statistics at 5 and 10 years than men.

Ø  Location in areas of constant trauma or irritation ,lower limb or the back. Pigmented Lesions -The appearance of a new pigmented nevus should arouse suspicion of melanoma. -About one-third of all melanomas arise from pigmented nevi. -Since the average white adult has 15-20 nevi, a clear idea of the indications for biopsy or excision should be developed. Recognition and early excision of atypical pigmented lesions are potentially lifesaving, since surgery is the only effective treatment. Benign /common naevi Junctional nevi -Are usually small, circumscribed, light brown or black, flat or only slightly elevated, and rarely contain hair. They are found on all areas f the body, and moles of the mucous membranes, genitalia, soles, and palms are usually of this type. -The nevus cells are located in the epidermis and at the dermal-epidermal junction. Intradermal nevi  -Range from small spots to extensive areas covering much of the body. -Have variable shape and surface configuration, are usually brown or black, and often are slightly elevated. -Nevus cells are confined to the dermis, and the lesions are basically benign. Compound nevi have both junctional and intradermal elements. Blue nevi -Are circumscribed, flat or dome-shaped, bluish-black lesions, usually on the hands, face, or arms. -Although benign, they may closely resemble nodular melanoma and require diagnostic excisional biopsy. Premalignant lesions Dysplastic nevi Are larger (5-12 mm) than common nevi. -They have macular and papular components, are variegated in color (tan-brown) on a pink base, and have indistinct, irregular edges. -Unlike common nevi, dysplastic nevi are most prevalent on covered body areas, though they can appear anywhere. Any suspicious lesions should be excised. An accurate family history should be obtained in such cases, and first-degree relatives should be examined. Congenital nevi -Occur in about 1% of newborns, and most lesions are small. -Along with dysplastic nevi, these lesions are now classified as precursors of melanoma. -Lifetime risk of melanoma developing in large congenital nevi (> 20 cm) is 5-20%, with some increased risk in smaller lesions as well. -Prophylactic excision is cosmetically prohibitive in many cases, and these lesions must be carefully monitored for suspicious change. Other pigmented lesions, including basal cell carcinomas, seborrheic keratoses, and actinic keratoses, occasionally resemble melanoma and require biopsy for diagnosis. 3..Lentigo maligna melanoma -4-10% of melanomas. Show dermal and epidermal changes from sun exposure. Clinical. Ø  Larger than 3 cm Ø  Flat, tan, and begin as small, freckle-like lesions. Ø  They occur in sun-exposed areas (eg, face and neck of older individuals). Ø  Marked notching of the borders is present. -Lentigo maligna melanoma usually arises within a Hutchinson freckle (lentigo maligna). The histologic appearance Ø  Irregularly shaped hyperchromatic cells that form spindle-shaped nests. Ø  The epidermis is atrophic Ø  The dermis contains solar elastosis with chronic inflammatory infiltrates. 5.Acral lentiginous melanoma This tumor comprises 2-8% of melanomas in whites and 35-60% of melanomas in dark-skinned people. Histology Ø  Occur in dermal-epidermal junction with microinvasion into the papillary dermis. Ø  The cells have increased melanin granule production, which fills their dendritic extensions. Clinical Ø  Occur on the palms of the hands, beneath the nailbeds, and on the soles of the feet. Ø  They may appear as flat, tan, or brown stains with irregular borders on the palms and soles Ø  Subungual lesions can be brown or black, with ulcerations in later stages. No correlation with a worse prognosis is demonstrated for these lesions when tumor thickness is considered. 6.Desmoplastic melanoma -These lesions account for approximately 1% of melanoma cases; they are fairly rare. - They demonstrate a tendency for perineural invasion, especially in the head and neck.  -They have a propensity for higher local recurrence rates but lower regional metastasis rates. Classification and staging Two classification schemes have been developed, based on either: 1.The vertical thickness of the lesion in millimeters (Breslow classification) 2. The anatomic level of invasion of the layers of skin (Clarks staging) Breslow classification scheme is used almost exclusively now since it more accurately predicts future tumor behavior. The TNM (tumor, node, metastasis) system is used for clinical staging Management Surgical therapy-wide margin excision. If the lesion has not spread beyond the primary site, it is potentially curable. Stage I For a T1 lesion, 1-cm excision margins are adequate, but lesions greater than 1 mm require 2-cm margins. Studies demonstrate no improvement in recurrence or survival rates with larger margins of resection. Attempt primary closure and perform skin grafting or flap closure if necessary. For lesions with a depth greater than 1 mm, many recommend sentinel lymph node biopsy at the time of wide local excision (see "Stage II," below). Stage II Perform a 2-cm surgical resection on stage II lesions. No recurrence or survival advantage exists when 2-cm margins are compared to wider margins (4-6 cm). Smaller resection decreases the need for skin grafting and inpatient hospital stay. -Perform a complete therapeutic lymphadenectomy on patients with suspected lymph node metastases based on physical examination. This consists of excision of all lymph nodes in the affected regional lymph node basin. -Consider sentinel lymph node biopsy if no clinically positive nodes are present. Using blue dye and/or radioisotope injected at the site of the primary melanoma, the first-echelon node can be identified within the regional lymph node basin. Send this sentinel node to the pathologist for analysis using routine stains, immunohistochemistry, and even polymerase chain reaction in some centers. -If the sentinel node is positive, then predictive importance exists of regional lymph node metastases; perform a complete lymph node dissection. -The correlation is based on the thickness of the primary tumor. If the sentinel lymph node is negative, a 99% chance exists that all others are negative. This procedure is becoming the standard of care for tumors greater than 1 mm in depth. -Hyperthermic arterial limb perfusion with melphalan for extremity melanomas has been studied as an adjuvant therapy. One study found it to be beneficial in that it produced higher response rates and overall survival rates than those for surgery alone. Other studies do not demonstrate benefit. -Adjuvant chemotherapy and/or biological therapy also are under clinical evaluation. One study demonstrated that high-dose interferon alfa-2b resulted in prolonged relapse-free survival and overall survival compared to no adjuvant therapy. A follow-up study by the same group demonstrated in preliminary results that high-dose interferon offered patients a relapse-free survival benefit over patients who did not receive adjuvant treatment but not over those who received low-dose interferon. -Neither high-dose nor low-dose interferon had a significant overall survival advantage compared to observation alone. High-dose interferon can be associated with significant toxic side effects (ie, liver toxicity), and some patients require dose reduction since it may not be well tolerated.