Malignant melanoma

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1. A rise from skin, mucosa, retina and the leptomeninges Def: Malignant proliferation of melanocytes

2. Epidemiology A pp. 5% of skin malignancy ( 75 per cent of skin malignancy related deaths), MM accounts for 3% of all malignancy worldwide , M ost common cancer in young adults (20–39 years) , 5% of all patients with MM will develop a second primary melanoma, 7% MMs present as occult metastases from an unknown primary Increasing incidence over the years and equal in both sexes

3. Risk factors: Hx of exposure to sunlight: Intense intermittent exposure Significant adult exposure ( associated with sunburn below 10) Geographical location (Australia and New Zealand) Skin Factors: Xeroderma pigmentosum ( RR = 1000) Past medical or family history of MM with dysplastic naevi Previous melanoma (RR= 8 4) Multiple benign or atypical naevi Dysplastic naevi (10% lifetime risk) Red hair (RR= 3) Tendency to freckle Immunosuppression Giant congenital pigmented naevus Albinism Genetic predisposition (CDKN2A gene)

4. Pathophysiology UV exposure is the major causal factor for developing MM Cumulative exposure favours the development of lentigo maligna melanoma (LMM), W hereas ‘flash fry’ exposure , typical of rapidly acquired holiday tans – favours the other morphological variants

5. Diagnosis History Change in size, shape and color Redness Itchy Tender Bleeding Crusting Ulceration Examination : ABCDEs criteria Glasgow 7 point Criteria

6. ABCDEs Criteria A - Asymmetry B - Border irregularity/bleeding C - Color Variation D - Diameter (>6mm) E - Elevation

7. Glasgow 7 point Criteria Major Features: Change in size Irregular shape Irregular color Minor features: Inflammation Oozing Change in sensation

8. Microscopic finding : Nevus nevus cells are arranged in nests. nuclei of nevus cells are uniform and rounded in contour and contain inconspicuous nucleoli. the cells contain melanin pigment. little or no mitotic activity.

9. Microscopy: Melanoma melanoma cells are pleomorphic and have hyperchromatic nuclei with prominent nucleoli. melanin pigment is present as fine granules. frequent mitosis.

10. 4 common variants of MM Superficial spreading melanoma Nodular melanoma Lentigo maligna melanoma Acral lentiginous melanoma

11. 1. Superficial spreading melanoma Most common type (70%) Most likely to arise in a pre-existing naevus , after several years of slow change Followed by rapid growth in the preceding months before presentation Typically it is a d arker pigmented area in a junctional naevus Nodularity within superficial spreading melanoma heralds the onset of the vertical growth phase

12. 2. Nodular melanoma Accounts 15% of all MMs male > female , arise typically de novo in skin More aggressive Shorter clinical onset Presenting i n middle age and usually on the trunk, head or neck A ppear as blue/black papules, 1–2 cm in diameter T hey lack the horizontal growth phase, tend to be sharply demarcated

13. 3. Lentigo maligna melanoma Previously k /a Hutchison’s melanotic freckle Slow growing, varigated brown macule (a lentigo ) , on face, neck or hands of the elderly P ositively correlated with prolonged, intense sun exposure Women > men (5-10%) In situ melanoma in this variant is called lentigo maligna L ess metastatic potential than other variants as they take longer to enter a vertical growth phase

14. 4. Acral lentiginous melanoma Affects the soles of feet and palms of hands Rare in white-skinned individuals More common in the Afro-Caribbean, Hispanic and Asian populations (35–60%) Usually presents as a flat, irregular macule in later life Twenty-five per cent are amelanotic m ay mimic a fungal infection or pyogenic granuloma MM under the finger nail is usually SSM rather than ALM

15. For finger or toe nail lesions , vital to biopsy the nail matrix rather than just the pigment on the nail plate Feature of s ubungual melanoma - Hutchinson’s sign positive ( nail fold pigmentation which then widens progressively to produce a triangular pigmented macule with associated nail dystrophy) The differential diagnosis is ‘benign racial melanonychia ’, which produces a linear dark streak under a nail in a dark-skinned individual

16. Fig: Acral lentiginous melanoma on the sole of the foot Fig: Subungual melanoma – superficial spreading melanoma. Fig: Benign racial melanonychia

17. Miscellaneous Types • Amelanotic melanoma (often arising in the GI tract and presenting with obstruction, intussusception or as a metastasis from an unknown primary ) • Desmoplastic – mostly found on the head and neck region , has a propensity for perineural infiltration and often recurs locally if not widely excised . May be amelanotic clinically

18. Investigations Guidelines for staging are controversial O ffering sentinel node biopsy to patients with clinical stage II disease is prudent I nvestigations for stage III disease should be directed to individual clinical presentation

19. Management focuses on: Prolonging survival Eliminating the cancer Shrinking or stopping the growth of known metastases Controlling symptomatic or risky sites of disease Providing comfort “Depending upon where and how big the metastases are, treatment may involve drug treatments, surgery, and/or radiation therapy ”

20. For Primary: Surgery is the main treatment Handley’s wide local excision ( WLE): wide excision with clearance of margin as well as depth. If primary area is wide, then amputation with one joint above is done . 3. In fingers and toes, disarticulation is required.

21. Regional lymph nodes For biopsy positive nodal disease : block dissection of the regional lymph nodes to remove all the lymph nodes in that regional basin

22. Drug treatments 3 main categories : Immunotherapy – Drugs that stimulate or unleash your immune system to attack and kill the cancer cells 2. Targeted therapy – Drugs that inhibit specific enzymes or molecules important to the cancer cells 3. Chemotherapy – Drugs that stop or slow the growth of cancer cells by interfering with their ability to divide or reproduce themselves

23. Immunotherapy ( nivolumab  [ Opdivo ],  pembrolizumab  [ Keytruda ],  ipilimumab  [ Yervoy ]), which have largely replaced high-dose interleukin-2 (IL-2). These have important benefits for some patients, although each can cause significant side effects. Anti-PD-1 checkpoint inhibitors  — The anti-PD-1 checkpoint inhibitors ( nivolumab ,  pembrolizumab ) unleash the body’s immune system so that it can be able reject the melanoma. Nivolumab is given once every two weeks, while pembrolizumab is given once every three weeks.

24. Targeted therapy Three drugs,  vemurafenib  ( Zelboraf ),  dabrafenib  ( Taflinar ), and  trametinib  ( Mekinist ) block this protein or the pathway it stimulates and cause tumors with this specific mutation in  BRAF  to shrink. Generally, dabrafenib is given in combination with trametinib , as the two agents together have been shown to be more effective and no more toxic than single-agent dabrafenib or vemurafenib .

25. Chemotherapy   dacarbazine  or  temozolomide  to stop or slow the growth of cancer cells by interfering with the ability of cancer cells to divide or reproduce. S/E on highly growing cells. Chemotherapy is less effective than immunotherapy or targeted therapy, and it generally is not used as the initial treatment for patients with advanced disease.

26. Prognosis Very aggressive tumor The higher the mitotic index, the poorer the prognosis of the primary tumor. Once regional nodes are involved clinically, 70–85% of patients will have occult distant metastases . Ageing, Females and Extremities melanoma  better prognosis

27. References Bailey and Love’s Short Practice of Surgery; 26 th Edition SRB’s manual of surgery; 5 th edition Robbin’s Basis of pathology; 9 th edition

28. Summary Definition Epidemiology Risk factors Diagnosis Types of melanoma Investigations Management Prognosis The end