Malignant Melanoma.pptx

Lecture notes for medical students

1. Tips on using my ppt. You can freely download, edit, modify and put your name etc. Don’t be concerned about number of slides. Half the slides are blanks except for the title. First show the blank slides (eg. Aetiology ) > Ask students what they already know about ethology of today's topic. > Then show next slide which enumerates aetiologies. At the end rerun the show – show blank> ask questions > show next slide. This will be an ACTIVE LEARNING SESSION x three revisions. Good for self study also. See notes for bibliography.

2. Malignant Melanoma

3. Malignant Melanoma Malignant Melanoma refers to the malignant lesion arising from the melanoblasts, which are the precursors of the melanocytes arising form the neural crest cells. As a result, melanoma can occur at different sites like skin, meninges, eyes and upper esophagus , where the neural cells migrate during the fetal life.

4. Introduction

5. Introduction Skin is the most common site, representing 4-5% of all the skin malignancies. It is the 5 th most common cancer in men and 6 th most common in female . Malignant melanoma is a relatively uncommon malignancy in India with an incidence of less than 0.5 per 100000 population. It is the most lethal of all skin malignancies.

6. The cells may not contain melanin at all times, thereby known as Amelanotic lesions . Malignant melanoma may arise: In a pre-existing pigmented nevus (90%cases), whether in a junctional nevus, compound nevus or in a Hutchinson’s Lentigo. De novo in apparently normal skin.

7. Etiology / Risk Factors Age : its rare before the puberty. Average of presentation is in late 40’s . Gender: Males > Females. Lower limbs are more commonly involved in females. Females tend to have a better prognosis. Race: Whites are more prone for malignant melanomas, especially those exposed more to sunlight. Caucasians are also commonly affected than Asians. The White to Black ratio is approx. 20:1 Exposure to sunlight (UV rays). (freckling, inability to tan, propensity for sunburns) Abnormalities in chromosomes 1, 6 and 9 have also been noted. Xeroderma pigmentosa . Repeated trauma Pregancy Steroid hormones intake Family h/o melanoma. Common sites of involvement are: Palms, Soles and external genitalia. It may also be found beneath the nail, known as Subungal melanomas.

8. Etiology / Risk Factors

9. Etiology / Risk Factors 10. The possibility of malignant melanoma is greatly elevated in: Preexisting mole changing colour, size and shape, itching and bleeding. Dysplastic nevi in familial melanoma, More than 50nevi, 2mm or greater in diameter. 11. The incidence of cutaneous melanoma is moderately increased when : One family member is diagnosed with melanoma Previous h/o melanoma in the individual Sporadic dysplastic nevi are detected Congenital nevus/nevi are present.

10. Molecular Biology As many as 70% melanomas harbour somatic mutations or deletions affecting the CDKN2A locus on chromosome 9p21

11. CLINICAL TYPES

12. CLINICAL TYPES T hin if they are 1mm or less in depth ; Moderate if they are 1-4mm in depth Thick if they are >4mm in depth .

13. Histological TYPES

14. Histological TYPES Melanoma is classified into 5types: Lentigo malignant melanoma Superficial spreading melanoma Acral lentignous melanoma Nodular melanoma Mucosal lentignous melanoma

15. Lentigo Malignant Melanoma

16. Lentigo Malignant Melanoma Seen in older individuals Age: 6 th – 8 th decades Predominantly composed of spindle shaped malignant cells. Pagetoid cells are not seen. Presents as a thin melanoma. Associated with a better prognosis. Sites: sun exposed skin mainly face. Microscopy: solar elastosis

17. Superficial Spreading Melanoma

18. Superficial Spreading Melanoma Commonest type Can occur anywhere in the body. Pagetoid cells are present that have both juncitonal activity and upward growth resulting in the bulging of the epidermis. Characterised by hyperplastic epidermis. Poor prognosis than Lentigo Malignant Melanoma.

19. Acral Lentignous Melanoma

20. Acral Lentignous Melanoma More common in Blacks. Sites: palms, soles and in sub- ungal positions Has features of both Superficial spreading melanoma and Lentigno Malignant Melanoma. It is devoid of Pagetoid cells. There is marked junctional proliferation with large atypical melanocytes with long dendritic processes. Mucus membrane presentation is most commonly seen in vulva. Poor prognosis especially with mucus involvement. It is the commonest melanoma in Japan.

21. Nodular Melanoma

22. Nodular Melanoma It is the most malignant form of melanoma. Mainly occurs in younger individuals. Can occur anywhere on the body. Presents as a convex palpable lesion. Characterised by growth in vertical direction. It has uniform pigmentation and well circumscribed borders. Ulceration occurs early.

23. Mucosal Lentignous Melanoma Develops from the mucosal epithelium that lines the respiratory, genitourinary and gastrointestinal tracts. Sites: conjunctiva, oral cavity, esophagus , vagina, female urethra, penis and anus. Commonly in elderly population. Poor prognosis than cutaneous melanoma

24. Staging

25. Staging According to the LEVEL OF INVASION: (CLARKE’s) Level I : (in-situ) tumor cells are above the basement membrane Level II : tumor extension into the papillary dermis. Level III: tumor extends into the interface between the papillary and reticular dermis‘. Level IV: tumor extends into the reticular dermis Level V: tumor extends into the subcutaneous fat. According to the LEVEL OF THICKNESS: (BRESLOW’s) Stage I : thickness <0.75mm Stage II: thickness 0.76-1.50mm Stage III: thickness 1.51-3.00mm Stage IV: thickness >3mm Stage I is known as Thin Melanoma and has a good prognosis Stage IV: Thick Melanoma, 10yr mortality is approximately 70%

26. CLINICAL STAGING Stage I : refers to primary tumor only. Stage II: refers to primary tumor along with presence of satellites/ in- transit lesions or regional lymph nodal enlargement. Stage II A: refers to satellite/ in-transit lesions only. Stage II B : refers to lymph nodal involvement. Stage III: refers to metastasis to distant sites.

27. TNM Staging T staging Tx : primary tumor cannot be assessed T0 : No evidence of primary tumor. Tis: Tumor in-situ T1: Melanoma 1mm or less in thickness T2: Melanoma 1.01 – 2mm T3: Melanoma 2.01 – 4mm T4: Melanomas > 4mm N staging NX : regional lymph nodes cannot be assessed N0 : no regional lymph nodes detected N1: 1 node positive. a: micrometastasis b: macrometastasis N2: 2-3 nodes a: microemetastasis b: macrometastasis c: in-transit mets / satellites without metastatic nodes. N3: >4nodes or matted nodes or in-transit/satellite with metastatic nodes. M classification M1a: distant skin, subcutaneous or nodal mets M1b: Lung metastasis M1c: Any other distant metastasis

28. TNM Staging Stage 0 - Tis , N0, M0 Stage IA - T1a, N0, M0 Stage IB - T1b, N0, M0; T2b, N0, M0 Stage IIA - T2b, N0, M0; T3a, N0, M0 Stage IIB - T3b, N0, M0; T4a, N0, M0 Stage IIC - T4b, N0, M0 Stage III - Any T, N 1-3, M0 Stage IIIA - pT1-4a, N1a, M0; pT1-4a, N2a, M0 Stage IIIB - pT1-4b, N1a, M0; pT1-4b, N2a, M0; pT1-4a, N1b, M0; pT1-4a, N2b, M0; pT1-4a/b, N2c, M0 Stage IIIC - pT1-4b, N1b, M0; pT1-4b, N2b, M0; any T, N3, M0 Stage IV - Any T, Any N, M1

29. Spread Local extension: initial spread is by contiguity and continuity. Malignant melanoma has a tendency to form satellite skin nodules. Lymphatic spread: it is the commonest route of spread , reaching the regional lymph nodes by permeation and embolization. It is a/w poor prognosis . By the time regional lymph nodes are involved, 70-80% of patients will have developed distant mets . Hematogenous : it’s a late event. Can spread to skin, liver, lungs, bones and brains. However, lungs and liver are the most common sites. Melanoma is predilected for brain tissue probably due to its similar embryology.

30. CLINICAL FEATURES

31. CLINICAL FEATURES Rapid growth of a long standing mole. Darker pigmentation, increased vascularity. Ulceration of the overlying skin epithelium. Gradual Invasion of the tumor cells into the surrounding skin to produce a ‘halo’ which indicates malignancy. Regional lymph nodal enlargement. Malignant melanoma is not painful but it itches often. Symptoms: c/o lymph nodal enlargement, weight loss, dyspnoea or jaundice. Occular melanomas are most non-cutaneous melanomas.

32. Diagnosis & Investigations

33. Diagnosis & Investigations Classic appearance: A : Asymmetry B : border irregularity C : color variation D : diameter greater than 6mm. Symptoms of bleeding, itching, ulceration and pain usually connote vertical growth and are hallmarks of a late diagnosis Recommendation: An excision biopsy with narrow (2mm) margins of the lesion. Incision for the biopsy should be in the context of the future need for wider re-excision. for sites like face, palms or soles, a full thickness wedge biopsy through the most representative and deepest part with a 2mm rim of normal skin is recommended.

34. Investigations

35. Investigations CXR, MRI brain USG CT scan PET-CT best for identifying the primary (when it is occult) and other sites of melanoma.

36. Treatment

37. Treatment Surgical resection is the mainstay of treatment. Surgery (e.g., wide local excision with SLNB, ELND, or both) is the definitive treatment for early-stage melanoma. Medical management is reserved for adjuvant therapy of patients with advanced melanoma. The role of chemotherapy, radiotherapy, immunotherapy and biochemotherapy is evolving. Management of Primary lesions: Wide local excision with margin being dictated by the thickness of the melanoma. Deep fascia is not involved in the specimen. Subungal melanomas are treated by amputation at the level of the metatarsophalangeal joint. Moh’s microsurgery is an option for Lentigo maligna (melanoma in situ) Post surgery, patients with Ib or stage II melanoma could either receive interferon alpha or be observed. Radiotheraphy is for patients for whom negative margins could not be achieved( Head and Neck melanomas), patients with recurrent resected melanoma or with desmoplastic melanoma with close margins.

38. Management of Regional Lymph nodes

39. Management of Regional Lymph nodes Historically, in an No situation, following surgical excision of the primary, regional lymph nodes were observed and dissected if appeared on follow-up (therapeutic lymph node dissection) or dissected immediately (elective lymph node dissection) Sentinel node biopsy is indicated in all patients with primary 1mm or thicker. It is also indicated in lesions <1mm thick with ulceration; mitosis rate of > 1 per sq.m , they have vertical growth phase, are of Clarke’s level Iv or more, positive third dimension after an excision biospy , etc. Adjuvant radiation may be considered if 3 or more nodes have metastasis , nodes larger than 3cm or with macroscopic extracapsular disease. In the neck, radiation is indicated even if nodes are >2cm and if more nodes have metastasis. After completion of surgery and radiation (if required), all patients with node positive disease could either be observed or given interferon alfa .

40. Metastatic disease In-transit mets : complete surgical excision if fesible . Regional chemotheraphy is effective if melanoma is isolated to the extremity. Melphalan is most commonly used. Intralesional BCG or interferon, or topical imiquimod (for dermal lesions) are immunomodulators that have been tried. Local ablation with cryotherapy or laser, radiation therapy and systemic chemotherapy. Have also been tried. If patient achieves acomplete response, then high dose interferon of r1yr (or pegylated Inteferon alfa 2b for 5years) may be administered. 2. Distant metastasis : depends whether the lesion is limited or disseminated (unresectable). Surgery can be considered after a short period of systemic chemotherapy for patients with solitary or limited distant metastasis. Patient with disseminated disease are managed by systemic therapy, clinical trial or best supportive care.

41. Systemic therapy Iplimumab : a monoclonal antibody directed to the terminal checkpoint receptor termed as ‘cytotoxic T lymphocyte antigen 4 ( CTLA-4 ). Vemurafenib :specific inhibitor of signalling by mutated BRAF Imatinib : a tyrosine kinase inhibitor for patients who demonstrate the c-KIT mutation. Chemotherapeutic agents: Dacarbazine , Temozolomide , Paclitaxel with or without Carboplatin. Biochemotherapy: combination of chemotherapy and biological agents like interleukin 2 or interleukin alfa , is under investigation.

42. Recent Updates Pembrolizumab : recently FDA approved for unresectable or metastatic melanoma and disease progression after treatment with ipilimumab and BRAF inhibitor. Temozolomide (currently used as the first-line drug for melanoma by most oncologists)

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