1.

Definition Cutaneous malignant melanoma is a potentially lethal tumor arising from melanocytes. The essential pathological feature is cytologically malignant cells invading the dermis and epidermis, laterally atypical mitosis.

1b.

Clinico-Histological classification of malignant melanoma Cutaneous malignant melanoma can be classified into five different categories on the basis of histopathology. 1) Superficial Spreading Melanoma The most common, superficial spreading melanomas generally arise from preexisting nevi and undergo a radial growth phase that evolves slowly over a period of time from months to years. They are usually small (i.e., < 2cm) but can be quite large if present for many years. 2) Nodular Melanoma They may begin in previously uninvolved skin or can arise in a preexisting nevus. These frequently grow relatively rapidly over months. 3) Acral-Lentiginous Melanoma Acral-lentiginous melanomas form a high proportion of malignant melanomas seen in Blacks and Orientals. These arise on palms and soles. Pigmentation of the proximal nail fold (Hutchinson sign) is strongly suggestive of subungual melanoma. These are common in tropical Asia.

4) Lentigo Maligna Melanoma Lentigo maligna melanoma almost always occur on sun-exposed skin, and especially on the face in elderly patients. These tumors grow slowly and usually arise from a preexisting solar lentigo or lentigo maligna. Lentigo maligna melanoma may behave similarly to superficial spreading melanoma in that there is frequently an irregular, notched border, asymmetry, and variegated pigment deposition.

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5) Other rarer histologic variants Malignant melanoma tumors are seen that do not fit the classic types. Desmoplastic melanomas Balloon-cell malignant melanoma Amelanotic melanomas 2. Risk factors : Ask history to detect risk factors of developing melanoma (1) (2) (3) (4) Personal history/ family history of melanoma Sun sensitivity light skin types bear an increase risk of melanoma History of acute and intermittent sun exposure/ sunburning in childhood and adolescence One or more large or irregular atypical pigmented lesions -Dysplastic moles and lentigo maligna are 2 pigmented lesions that are potential precursors of melanoma (> 50 moles) Immunosuppression Congenital moles For giant congenital naevi, the lifetime risk of progression to malignant melanoma is estimated at 4-8%. For small and medium congenital naevi, the risk is unknown Sites : soles of feet

(5) (6)

(7)

APPROACH : 1) History : Past medical history including congenital melanocytic nevi and other neoplastic diseases Neoplasia distribution: Head and neck / trunk / upper limbs / lower limbs/finger, subungual, palms/soles Melanoma malignum at the site of preexisting melanocytic nevi Family history of skin cancer Melanocytic nevi in the family Work in the open air Intensive sunburns

2)

Physical examination :

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Preamble: For MOs and Registrars , pertinent to perform biopsies on atypical moles, dysplastic moles, lumps on giant moles, pigmented nodules, nodules on toes, soles of feet to rule out melanoma. a) b) To record location of lesion, size, thickness. Note appearance of lesion (ABCD) i) ii) iii) iv) v) c) e) f) g) g) h) i) Aysmmetry Border irregularity Color variegation - gray to blue-black, brown, red Diameter Elevation or erosion

Inspect and palpate around lesion and over lymphatic drainage area for satellites and/or in-transit metastases Palpate regional lymph nodes for clinical presence of metastases Examine cutaneous surface for other melanomas, congenital and/or atypical nevi Examine pigmentation of nailfold and nail plate Number of common melanocytic nevi: head & neck, trunk, upper limbs, lower limbs Number of atypical melanocytic nevi : head & neck, trunk, upper limbs, lower limbs Freckles

Skin type: Fair (type I, II) Dark (type III, IV)

The ABCD system for early recognition of suspicious pigmented lesion both patient and physicians.

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Asymmetry in shape, color, or appearance of mole Appearance of new pigmented lesions Borders that are notched, irregular in shape, or both Bleeding of moles Colour of mole is variable or contains blue, gray, white, pink, or red Change in shape, size, or color of mole Concern about a skin lesion Diameter exceeds 6 mm in any direction

Summary of Risk Factors/history and clinical : 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Number of nevi (50) Size Site : buttocks, dorsum of feet, scalp Colour variations Sun exposure Genetic, immunologic, environmental Irregular lateral margins Familial dysplastic nevi Congenital nevi BK mole variety in size, colour, outline, trunk, limbs

Investigations : Diagnostic investigations are necessary in the diagnosis, staging and prognosis of melanoma

1) Biopsy and histopathology

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As management and prognosis is dependent on primary tumour thickness, a total excisional biopsy is advocated. A punch biopsy may be performed on the thickest and darkest and ulcerated lesions, if lesion is large. The biopsy is sent to an experienced expert/dermatopathologist for reading. A complete histology report should include the diagnosis and a micrometer measurement (thickness of the lesion in millimeters measured from the top of the granular cell layer to the deepest point of tunour invasion ) and the status of the margins.

2) Other investigations to evaluate extent of spread Biochemistry and hematologic studies - FBC, LFT, LD, serum lactate dehydrogenase level Radiographic tests - chest X-ray, computed tomographic scan /or MRI scan (for Stage III) Sentinel node biopsy is needed in Stage III, where trials are on, giving vaccines or high dose Interferon

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Table 1. Melanoma TNM Classification

T classification T1 T2 T3 T4

Thickness 1.0 mm 1.01 2.0 mm 2.01 4.0 mm > 4.0 mm

Ulceration Status a : without ulceration and level II/III b : with ulceration or level IV/V a: without ulceration b : with ulceration a : without ulceration b : with ulceration a : without ulceration b : with ulceration

N classification N1 N2

No. of Metastatic Nodes 1 node 2 3 nodes

Nodal Metastatic Mass a : micrometastasis* b : macrometastatis+ a : micrometastasis* b : macrometastatis+ c : in transit met(s)/satellite(s) without metastatic nodes

N3

4 or more metastatic nodes, or matted nodes, or in transit met(s)/satellites(s) with metastatic node(s)

M classification M1a

Site Distant skin, subcutaneous, or nodal mets Lung metastases All other visceral metastases Any distant metastasis

Serum Lactate Dehydrogenase Normal

M1b M1c

Normal Normal

Elevated

*Micrometastases are diagnosed after sentinel or elective

lymphadenectomy.

+Macrometastases are defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or when nodal metastasis exhibits gross extracapsular extension.

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Table 2. Stage Groupings For Cutaneous Melanoma

Clinical Staging* (X-ray) T 0 IA IB Tis T1a T1b T2a IIA T2b T3a IIIB T3b T4a IIC III# T4b Any T N N0 N0 N0 N0 N0 N0 N0 N0 N0 N1 N2 N3 IIIA M M0 M0 M0 M0 M0 M0 M0 M0 M0 M0

Pathologic Staging+ (Biopsy of LN) T Tis T1a T1b T2a T2b T3a T3b T4a T4b N N0 N0 N0 N0 N0 N0 N0 N0 N0 M M0 M0 M0 M0 M0 M0 M0 M0 M0

T1-4a T1-4a

N1a N2a N1a N2a N1b N2b N2b N2c N1b N2b N3 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 Any M1

IIIB

T1-4b T1-4b T1-4a T1-4a T1-4a T1-4a/b

IIIC

T1-4b T1-4b Any T

IV

Any T

Any N

Any M1

Any T

*Clinical staging includes microstaging of the primary melanoma and clinical/radiologic evaluation
for metastases. By convention, it should be used after complete excision of the primary melanoma with clinical assessment for regional and distant metastases.

+Pathologic staging includes microstaging of the primary melanoma and pathologic information
about the regional lymph nodes after partial or complete lymphadenectomy. Pathologic stage 0 or stage 1A patients are the exception; they do not require pathologic evaluation of their lymph nodes. #There are no stage III subgroups for clinical staging. Ref : J. Clinical Oncol 19 : 3635-48-2001. American Society of Clinical Oncology.

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Indicators of survival rate in melanoma Breslows thickness is the most important factor in predicting survival

Risk category IA IB IIA IIB IIC 3. Treatment 1) For in-situ lesions:

Melanoma thickness, mm 1 mm 1 mm 1 2mm 2 4 mm >4

5 year survival, % 95% 90% 77% 50% 45%

a) Surgery (Refer to SGH/NUH for staging and surgery.)

is the treatment of choice for primary melanomas and for operable metastases. Complete excision with an adequate margin of round tissue in depth and laterally is the basis.

The current recommended surgical margins are as follows.

Tumor thickness (mm)

Recommended surgical margin (cm) 0.5 1 2 2 2

In situ 1 1 to 2 2 to 4 >4

Mohs microscopic surgery may be used as a tissue saving technique on the face.

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2) Management of patients with pathological involvement of regional lymph node a) Lymph node dissection ii) Elective regional lymph node dissection ( ERLND ) -- the role is still controversial, not indicated for early melanoma < 1 mm thick. iii) Therapeutic lymph node dissection -- recommended when there are clinically suspected regional lymph node enlargement, adjuvant interferon therapy can be considered. iv) Sentinel Lymph Node Biopsy and excision of Micrometastasis Examination of regional lymph node by Sentinel Node biopsy : The lymphatic mapping by cutaneous lympho scientigraphy is performed to evaluate the pathway of lymphatic drainage from the primary melanoma and to identify nodel basins at risk for metastatic carcinoma. (This is not available in Singapore). The intravenous blue dye, and lately, gamma probe guided lymph node biopsy are recommended. These radio-labelled lymph nodes are excised and termed Sentinel lymph node. This helps in a more accurate staging, identifying clinically significant micrometastasis. However, unless surgery is performed to remove all metastasis, this method would influence survival and prognosis. (Ref: JID 2000, 114: 637-642)

4)

Management of advanced disease a) Chemotherapy For Stage III melanomas -- Dacarbazine ( DITC ) is currently regarded as the most effective agent. Other cytotoxic agents eg. nitrosoureas, carmustine (BCNU), tamoxifen, bleomycin, vindesine and cisplatin have some efficacy in disseminated melanomas. Adjuvant chemotherapy -- results disappointing. b) Radiotherapy For radiosensitive lentigo maligna in the elderly, and for treatment of metastases (eg bone) or local recurrence.

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c)

Others Immunotherapy, high dose interferon, vaccine under investigation. Stage III melanoma : Resection and Melacine (vaccine) + Inf-2 Vs Inf2- Stage III, Stage IV melanoma Cancer Vax - polyvalent melanoma vaccine + BCG

5)

Follow-up evaluation and education a) Patients are examined prospectively for recurrent or metastatic disease. For first year : 3 monthly review : to do a) physical examination b) routine blood investigations c) ultrasound examination of regional lymph node bases and of the abdomen d) CXR yearly e) computed tomography } for patients with findings, f) magnetic reasonance imaging } suggestion of metastatic melanoma For second year : 6 monthly review : to do (a) to (f) above After third year, for rest of their life : To repeat (a) to (f) on yearly basis. b) Patient education Patients, especially those with a high risk of developing malignant melanoma, should be taught self-examination and photoprotection. Psychiatric counselling.

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