Malignant melanoma

malignant melanoma

1. Malignant Melanoma By : Dr. Amit Kumar Choudhary

2. INTRODUCTION Malignant transformation of the melanocyte , the cell responsible for the production of the pigment melanin . Precursor melanocytes arise in the neural crest and, as the fetus develops, migrate to multiple areas in the body including the skin , meninges , mucous membranes, upper esophagus, and eyes. 91.2% cutaneous 5.3% ocular 1.3% mucosal 2.2% unknown primary site

3. cutaneous melanoma a carcinogen-induced cancer with a high mutational load, dependenton a particular oncogenic signaling pathway, the mitogen -activated protein kinase (MAPK) pathway BRAF (50%) or NRAS (20%) mutations M ucosal or uveal melanoma BRAF mutations (5% to 20%) KIT mutations (5% to 10 %) Uveal melanomas have mutations in the alpha subunits of G-protein–coupled receptors GNAQ and GNA11

4. MOLECULAR BIOLOGY OF MELANOMA Melanomahas significantly have more sequence variations per megabase of DNA. For example, melanomas have 15 times more mutations per megabase of DNA than colorectal cancer and 4 times more than lung cancer. mutations are cytosine to thymine (C>T) substitutions, typical of UV radiation– induced thymine dimmers M utations in BRAF, NRAS, and cKit .

5. Driver Mutations in Melanoma D ependent upon driver oncogenic mutations in the MAPK pathway,with additional genetic alterations in other pathways leading to uncontrolled cell growth and avoidance of apoptosis activating mutations in the receptor tyrosine kinase KIT (2% to 3%), the G-protein neuroblastoma RAS viral oncogene homolog (NRAS) (15% to 20%), and the serine- threonine kinase BRAF (40% to 50 %). Uveal melanomas have a driver mutations in GNAQ and GNA11, which are the alpha subunits of G-protein–coupled receptors

6. Progression of Melanocytes to Cutaneous Melanoma

7. EPIDEMIOLOGY Malignant melanoma is the sixth most common cancer in US cancer diagnosis . This amounts to 4% of new cancer diagnoses and 1.5% of cancer deaths . Currently, 1 in 49 men and women will be diagnosed with melanoma of the skin during their lifetime. Its incidence is second only to breast cancer for women from birth to age 39 years. Overall 5-year survival rates for melanoma - 82% in the late 1970s (1975 to 1977) to - 91 % in the more recent era (2002 to 2006).

8. Highest per capita incidence of melanoma worldwide is in Australia In nonwhite populations, there is a much higher proportion of melanomas in acral ( subungual , palmar , plantar) and mucosal locations. Ocular and nonacral cutaneous melanomas are 50- to 200-fold more likely in white populations. Gender ratio at diagnosis- 2:1 -male :female , but it depends on the age group.

9. ANATOMIC DISTRIBUTION Most common sites in males are on the back and in the head and neck regions. Women , the most common sites are in the lower extremities, commonly below the knee.

10. ETIOLOGY AND RISK FACTORS Ultraviolet Light Exposure

11. UV light exposure as a major etiologic factor in the development of melanoma . UVC radiation is generally absorbed by the ozone layer. UVB radiation (290 to 320 nm) is associated with sunburn and induction of tanning by melanin pigment production and has etiologic role in melanoma. UVA radiation (320 to 400 nm ),associated with chronic sun damage changes.

12. Physical Traits B lond or red hair, G reen or blue eyes , P resence of multiple (>100) melanocytic nevi, and five or more atypical nevi. A prior diagnosis of melanoma is associated with an eight-fold increased risk of developing a secondary melanoma .

13. Familial Predisposition 5 % of melanomas occur in high-risk families Autosomal dominant inheritance with incomplete penetrance . The most frequent and highest penetrance melanoma susceptibility gene is a germline mutation in CDKN2A , a tumor suppressor gene. germline mutation in cyclin -dependent kinase 4 Other common risk factors include dysplastic nevus syndrome, xeroderma pigmentosum , a family history of melanoma even without the known genetic traits Li- Fraumeni syndrome, germline mutations in p53

14. DIAGNOSIS OF PRIMARY MELANOMA

15. Characteristics of Primary Melanoma Mnemonic ABCD asymmetry , border irregularity, color variation, and diameter >6 mm M elanomas classically are distinguished by their pigmentation . Melanomas may have shades of brown, black, blue,red , and white . “Ugly duckling” sign : A lesion that stands out as different from the patient’s other nevi should be evaluated.

16. S ymptoms of bleeding, itching, pain, and ulceration - hallmarks of a late diagnosis Biopsy F ull-thickness biopsy of the entire lesion, with a narrow (1 to 2 mm) margin of grossly normal skin . This allows assessment of the architecture of the lesion, which is critical for differentiation of melanoma from Spitz nevus ,

17. Melanoma Subtypes: Histologic Growth Patterns Superficial Spreading Melanoma Nodular Melanoma Acral Lentiginous Melanoma Lentigo Maligna Melanoma Lentiginous Melanoma Desmoplastic Melanoma

18. Superficial Spreading Melanoma Most common type 70% of primary cutaneous melanomas It is typical for the trunk and extremities Pagetoid growth of atypical melanocytes in the epidermis. Commonly associated with sun exposure

19. Nodular Melanoma Nodular melanomas lack an RGP, May be nonpigmented Commonly are diagnosed when relatively thick,nodular melanomas are in VGP worst prognosis 20% of cutaneous melanomas.

20. Acral Lentiginous Melanoma ALMs account for <5% of melanomas. Site- Acral sites ( subungual , palmar , plantar) and on mucosal surfaces( anorectal , nasopharyngeal, female genital tract). Independent of UV light exposure. More common in African, Asian, and Hispanic populations than in fair-skinned whites. Prolonged RGP before vertical growth Subungual lesions can be detected by linear pigment streaks arising from the base of the nail.

21. Lentigo Maligna Melanoma Older individuals Chronically sun-damaged skin Commonly on the face shades of brown or black 10% to 20% of melanomas 47% of melanomas of the head and neck Extensive RGP that extends for many years before developing invasion. When melanoma is just in situ, this RGP portion is called lentigo maligna or Hutchinson freckle, as opposed to LMM. LMMs are commonly diagnosed as thin lesions

22. Lentiginous Melanoma Its features include diameter ≥1 cm, elongated and irregular rete ridges confluent melanocytic nests and single cells over a broad area of the dermal/epidermal junction, focal pagetoid spread, cytologic atypia , and possible focal dermal fibrosis.

23. Desmoplastic Melanoma Uncommon form of melanoma, Histologically manifest by dermal melanocytes in a dense stromal response. Usually nonpigmented and usually have lost the melanin production pathway. They usually stain negative for MART-1/ MelanA , gp100 , and tyrosinase , stain for S100. Most commonly in the head and neck

24. Prognostic Factors for Primary Melanomas The best predictor of metastatic risk is the depth of invasion, measured with an ocular micrometer, from the granular layer of the skin to the base of the primary lesion. Other prognostic factor include age, angiolymphatic invasion,mitotic rate, gender, and body site .

25. Depth of Invasion Breslow thickness is the depth of invasion measured from the granular layer of the epidermis to the base of the lesion.

26. AJCC T1 lesions are <1 mm thick T2 lesions are 1 to 2 mm thick, T3 lesions are 2 to 4 mm thick, T4 lesions are >4 mm thick . Clark level level I - melanomas are melanomas in situ, limited to the epidermis or dermal/epidermal junction. level II - melanomas invade into the superficial (papillary) dermis, and these are usually RGP lesions. level III - melanomas fill the papillary dermis. level IV - melanomas invade into the deep (reticular) dermis and have significant metastatic risk. level V - melanomas are uncommon and contain invasion into the subcutaneous fat

27. Ulceration Important negative prognostic feature T1a , T2a , T3a , and T4a melanomas are nonulcerated , and T1b , T2b , T3b , and T4b melanomas are ulcerated.

28. Patient Gender and Skin Location Incidence of melanoma men women But in adolescents and young adults it is more common in women. Prognosis is better for women than men. Extremities is better than that for patients with truncal or head-and-neck melanomas There is a greater risk of lymph node metastasis in young patients at the time of SNBx,especially for patients younger than age 35 years, but the melanoma-associated mortality risk increases with age for all thickness ranges.

29. Growth Pattern Overall, nodular melanomas have the worst prognosis, associated with their diagnosis at a thicker stage. Lesser risk is associated with ALM, superficial spreading melanoma, and LMM, in that order, all associated with decreasing average Breslow thickness. The VGP component appears to be the component of melanoma that determines metastatic risk

30. Mitotic Rate Identified as a negative prognostic feature, especially with six or more mitoses per square millimeter. Other Prognostic Factors Angiolymphatic invasion microscopic satellites

31. MANAGEMENT OF A NEWLY DIAGNOSED CUTANEOUS MELANOMA (STAGE I–II)

32. Complete history and physical examination Biopsy should be done for any suspicious lesions and with a very low threshold for biopsy. NCCN Clinical Practice Guidelines in Oncology (NCCN GuidelinesR ) melanoma in situ , No staging radiographs or blood work low-risk thin melanomas (stage IA) recommend imaging “only to evaluate specific signs or symptoms.” Clinical stage I–II, no other imaging is recommended. Stage III melanoma chest radiograph (CXR), computed tomography (CT) scans, or positron emission tomography (PET)/CT scans, magnetic resonance imaging (MRI) of the brain,

33. Wide Local Excision

34. SURGICAL STAGING OF REGIONAL NODES Melanoma may metastasize by lymphatic or hematogenous routes. Usually, lymphatic dissemination presents earlier than hematogenous dissemination. The finding of lymphatic metastases is associated with a higher risk of systemic disease

35. Intraoperative lymphatic mapping and sentinel lymph node biopsy Vital blue dye ( isosulfan blue) intradermally , The first node(s) into which these lymphatics empty. Lymphoscintigraphy has been coupled with the blue dye injection to support identification of the sentinel node(s), using handheld probes for detection of γ radiation emitted by technetium-99 ( 99Tc ) up to 1 mCi of 99Tc ) and intraoperative intradermal injection of isosulfan blue dye (up to 1 ml) a few minutes prior to the incision. Lymphatic mapping and SNBx using both blue dye and radiocolloid increases sentinel lymph node identification rates to 99% compared with 87% with blue dye .

36. Rate of positive nodes increases with increasing tumor thickness, as would be expected, from <5% for the thin melanomas that undergo SNBx (e.g., T1b lesions) to approximately 40% for thick melanomas

37. Immunohistochemical detection of isolated melanoma cells in a sentinel node when stained for the melanoma marker S100.

38. MANAGEMENT

39. Clinically Localized Melanoma Melanoma In Situ (Clinical TISN0M0, Stage 0) Confined to the epidermis and epidermal/dermal junction Wide excision-Definitive management involves re-excision with a margin of 5 mm. if cosmetically acceptable, obtain a margin of as much as 1 cm, especially if the original biopsy was incomplete. SNBx is not indicated. No adjuvant therapy is needed if the margins are widely clear. Clinical Follow-Up After Surgical Treatment- annual basis

40. Thin Primary Melanoma (Clinical T1A) Melanoma <0.76 mm thick. approximately a 5% risk of subsequent metastasis. AJCC- Melanomas are those <1 mm thick, with less than one mitosis per square millimeter, and without ulceration. stage IA melanomas have a 5-year survival rate of 94%. Wide excision with a 1-cm margin (including skin and all underlying subcutaneous tissue, to the deep muscle fascia) Annual follow-up for many years is recommended rather than frequent follow-up in the first few years.

41. Clinical T2A, T2B Melanomas Melanomas 1 to 2 mm thick, with or without ulceration. Wide excision with a 1- to 2-cm margin and SNBx . SNBx Positive , then subsequent management should follow recommendations given later for stage IIIA melanoma ( T2a with positive SNBx involving one to three nodes) or stage IIIB melanoma ( T2b with positive SNBx involving one to three nodes). Negative , then the patient is considered to have been pathologically staged as T2aN0M0 (stage IB) or T2bN0M0 (stage IIA), and no additional surgical management is required and no adjuvant systemic therapy is indicated.

42. T3A Melanomas (Clinical Stage IIA) Melanomas 2 to 4 mm thick, without ulceration, and in the absence of metastases, these are clinical stage IIA lesions. Definitive management includes wide excision with a 2-cm margin and SNBx . SNBx Negative , then no additional surgical or systemic therapy is indicated . Positive , then management for stage IIIA melanoma should be followed.

43. Clinical T3B Melanomas (Clinical Stage IIB) Melanomas 2 to 4 mm thick with ulceration represent T3b lesions and thus are clinical stage IIB melanomas. Management is wide excision with a 2-cm margin and an SNBx . SNBx Negative, the summary stage is IIB ( T3bN0M0 ). patients, no additional surgical therapy is needed. HDI and pegylated -interferon therapies

44. Thick Melanomas (T4A, T4B, Greater than 4 mm Thick) Metastasis and mortality in the range of 50% over 5 to 10 years. Ulceration increases this risk T4a melanomas are clinical stage IIB, T4b melanomas are clinical stage IIC. Definitive management includes wide excision with at least a 2-cm margin plus SNBx SNBx Positive- CLND Negative- adjuvant interferon

45. SPECIAL CONSIDERATIONS Primary Melanomas of the Head and Neck Large- diameter lentigo maligna on the face that is not amenable to surgical resection because of cosmetic results or comorbid patient conditions superficial or Grenz X-rays with local control rates reported above 90%. imiquimod ointment Desmoplastic melanoma , Adequate margins.If that is not possible, postoperative adjuvant radiation should be considered with 2- to 3-cm margins around the resected lesion.

46. REGIONALLY METASTATIC MELANOMA (STAGE III) Regional metastases are defined as follows: ■ Local recurrence is best defined as recurrence of melanoma in the scar from the original excision or at the edge of the skin graft ■ Satellites metastases recurrences that are separate from the scar but within 2 to 5 cm of it are considered satellite metastases ■ Regional recurrences beyond 5 cm of the scar but proximal to regional nodes are considered in-transit metastases ■ Regional node metastases are typically in a draining nodal basin that is near the lesion.

47. Management of Local Recurrence Local recurrence is common after a primary lesion is inadequately excised. very poor prognosis. Local recurrences were associated with 9% to 11% overall 5-year survival rate, as compared with 86% for those without local recurrence. Management- re-resection of entire scar down to the level of fascia, Excision with a 1- to 2-cm margin.

48. Management of Satellite and In-Transit Metastases Negative prognostic feature, with clinical outcomes similar to those observed for patients with palpable nodal metastases. Excision with SNBx . Radiation therapy Intralesional therapy with interferon-α, interleukin(IL)-2, bacillus Calmette -Guerin (BCG), oncolytic replication competent virus injections and dyes like Rose Bengal diphencyprone , imiquimod , Systemic treatments anti– cytotoxic T-lymphocyte antigen (CTLA4), anti–programmed death 1 PD-1 anti-PD-L1 antibodies, BRAF and other targeted inhibitors

49. Isolated Limb Perfusion and Infusion Patients with extensive regional recurrences in an extremity melphalan or isolated limb infusion.

50. ADJUVANT SYSTEMIC THERAPY (STAGES IIB, IIC, and III) Adjuvant Interferon Therapy (1) HDI-α for 1 month followed by 1 year of intermediate dosing, (2) interferon- α at an intermediate dose administered for 1 or 2 years, (3) interferon-α at a low dose administered for 1 or 3 years, or (4) pegylated interferon administered for a target period of 5 years High-Dose Interferon-𝛂2B Induction phase intravenous infusion, 20 million U/ m2 , for 5 consecutive days every 7 days for 4 weeks . Maintenance phase For the subsequent 48 weeks, 10 million U/ m2 were administered by subcutaneous injection on alternate days for a total of three doses every 7 days Pegylated Interferon-𝛂

51. Biochemotherapy Biochemotherapy consisting of Dacarbazine 800 mg/ m2 on day 1, cisplatin 20 mg/ m2 on days 1 to 4; Vinblastine 1.2 mg/ m2 on days 1 to 4; IL-2 9 MU/ m2 per day continuous intravenous administration on days 1 to 4; interferon 5 MU/ m2 per day subcutaneously on days 1 to 4, 8, 10, and 12; and granulocyte– colony-stimulating fator 5 ug /kg per day subcutaneously on days 7 to 16

52. Cytotoxic T-Lymphocyte Antigen 4 and PD-1 Blockade Ipilimumab is a fully human immunoglobulin G1 monoclonal antibody that blocks CTLA4 lambrolizumab anti-PD-1 IgG4 monoclonal antibody MK-3475

53. THANKS