Malignant Melanoma

Malignant melanoma Recent Advances in the diagnosis and management

1. Malignant melanoma Diagnosis and management –recent advances Moderator : PROF.Dr.V.BALAKRISHNAN,H.O.D Presentor:Dr.S.SIVA SANKAR

2. Malignant Melanoma Melanoma is a cancer of melanocytes and can, therefore, arise in skin, mucosa, retina and the leptomeninges.

3. EPIDEMIOLOGY Cutaneous melanoma is caused by exposure to UVR. Its rise in incidence reflects increased recreational activity in the sun It accounts for less than 5% of skin malignancy (and 1.6% of all malignancy worldwide), it is responsible for over 75% of skin malignancy-related deaths. It is the commonest cancer in young adults (20–39 years) and the most likely cause of cancer-related death.

4. Clinical features Only 10–20% of MM form in pre-existing naevi , with the remainder arising de novo in previously normally pigmented skin. The most likely naevi to form MM are atypical naevi , atypical junctional lenitiginous naevi (usually facial) and giant pigmented congenital naevi .

5. Macroscopic features in naevi suggestive of malignant melanoma ● Change in size (diameter more than 6 mm ) ● Shape ● Colour ● Thickness (elevation/nodularity or ulceration) ● Satellite lesions (pigment spreading into surrounding area) ● Tingling/itching /serosanguinous discharge (usually late signs)

6. Satellite lesion

7. Head and neck—25% Trunk—25% Lower limb—25% Upper limb—11% Other sites—14% Other sites: Eyes (iris, ciliary body, choroids), muco cutaneous junction (anorectal region, genitalia), head and neck (meninges, oropharynx, nasopharynx, paranasal sinuses)

8. Classifications Breslow’s classification Based on thickness of invasion measured by optical micrometer—most important prognostic indicator until nodal spread I: Less than 0.75 mm II: Between 0.76 to 1.5 mm III: 1.51 mm to 4 mm IV: More than 4 mm

9. Clark’s levels Level 1: Only in epidermis Level 2: Extension into papillary dermis Level 3: Filling of papillary dermis completely Level 4: Extension into reticular dermis Level 5: Extension into subcutaneous tissue

10. There are four common macroscopic variants of MM Superficial spreading melanoma (SSM) 70% Nodular melanoma (NM) 12 - 25% Lentigo maligna melanoma (LMM) 7 -15% Acral lentigious melanoma (ALM) 5%

11. Miscellaneous Amelanotic melanoma Desmoplastic melanoma

12. Superficial spreading melanoma (SSM) This is the most common presentation (70%), usually arising in a pre-existent naevus after several years of slow change, followed by rapid growth in the preceding months before presentation . Nodularity within SSM heralds the onset of the vertical growth phase.

13. Nodular melanoma (NM) Nodular melanoma accounts for 15% of all MM More aggressive than SSM Arise de novo in skin and are more common in men than women They typically appear as blue/black papules They lack the horizontal growth phase, so they tend to be sharply demarcated. Up to 5% are amelanotic.

14. Lentigo maligna melanoma LMM previously known as Hutchinson’s melanotic freckle. This variant presents as a slow-growing, variegated brown macule on the face, neck or hands of the elderly. They are positively correlated with prolonged, intense sun exposure, affecting women more than men. They account for between 5% and 10% of MM.

15. Acral lentigious melanoma (ALM) ALM affects the soles of feet and palms of hands presents as a flat, irregular macule. 25% are amelanotic and may mimic a fungal infection or pyogenic granuloma.

16. subungual melanoma Hutchinson’s sign: nail fold pigmentation that 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. Malignancy is unlikely if the nail fold is uninvolved

17. MM under the finger nail are usually SSM rather than ALM. For finger or toe nail lesions it is vital to biopsy the nail matrix, rather than just the pigment on the nail plate.

18. Contrary to the Western countries, in India the more common varieties seen of Melanoma are : Amelanotic, Acral lentiginous and Desmoplastic They usually have no relation to UV exposure and occur often on unexposed body areas.

19. Amelanotic melanoma may present as a flesh- coloured , skin lesion as a metastasis from an unknown skin primary; or, in the gastrointestinal tract, with obstruction or intussusception.

20. Desmoplastic melanoma is mostly found on the head and neck region. It has a propensity for perineural infiltration and often recurs locally if not widely excised. It may be amelanotic clinically.

21. MANAGEMENT -RECENT TRENDS Malignant Melanoma management has undergone a paradigm change due to better understanding of its genetics, histopathology, behavior and discovery of various immuno modulators and target therapies.

22. Staging & Prognosis 1. Clarks level of tumour invasion is NO more a part of the AJCC TNM staging. 2. Histopathology plays a crucial role in TNM staging with tumour thickness, ulceration, mitosis rate. 3. Breslow’s tumour thickness in mm from histopathology forms the main basis for staging. 4. The other important staging factors are Ulceration and Mitotic Rate. 5. Mitotic rate >1/mm2 and presence of ulceration has poorer prognosis.

23. Diagnosis 1. Excision biopsy with 1-2mm margins is the gold standard for staging. 2. Partial biopsy techniques like incisional biopsy, punch biopsy and shave biopsies may lead to inaccurate staging and possible effect on subsequent surgical treatment. 3. Full thickness incisional biopsy may sometimes be indicated in large lesions due to practical reasons but shave biopsies should be avoided as they fail to provide the information about tumour thickness necessary for proper staging. However the type of biopsy has not been shown to alter survival or recurrence.

24. 4. Physical Examination must pay attention to other suspicious lesions, tumour satellite lesions, in-transit metastases, draining lymphnodes and systemic metastases. 5. T1 lesions ( ≤1mm) are considered low risk melanomas and need no further investigations. Sentinel lymph node biopsy (SLNB).

25. Other Investigations . FNAC of lymph node. US abdomen to look for liver secondaries (usually huge hepatomegaly occurs). Chest X-ray to look for secondaries in lung (“cannon ball” appearance). HRCT of chest is ideal

26. Relevant other methods depending on site and spread, e.g. CT scan of head, chest, abdomen, pelvis. Urine for melanuria signifies advanced disease. Tumour markers—LDH; Melan – A; S 100; tyrosinase; HMB 45 are the tumour markers used. MRI of the area; PET scan to detect the spread—in seleted patients only.

27. B-RAF mutation in a proto-oncogene responsible for making a protein B-raf has been associated with poor prognosis but has also lend itself to target therapy improving outcomes. Human melanoma black 45 (HMB 45) is a monoclonal antibody against specific antigen (Pmel 17) present in melanocytic tumours. HMB 45 has got 92% sensitivity.

28. Surgical Excision & Lymphnode Management Frozen sections are unreliable for checking accuracy of resected margins as it fails to differentiate between normal melanocytes and melanoma cells. Whenever possible Excision biopsy should be done with minimal margins for staging and further excision margins can be decided on the basis of Breslow thickness.

29. Melanomas with 1-2mm thickness the largest possible margin should be taken as per guideline but a balance has to be struck between oncological safety and resulting deformity more so in the case of the face where usually 1cm margins are preferred over 2cm. Margins higher than 2cm have not been shown to give any advantage.

30. Sentinel Lymph Node Biopsy(SLND) SLND is only a staging procedure for N0 neck to check the draining lymphnode basin for occult micro-metastases. SLND does not improve overall survival but has been shown to improve 10yr disease free survival rates in intermediate thickness melanomas(1-4mm) and should be done in all these cases. The risk of occult lymphnode involvement in intermediate thickness melanomas is 20-40%. There is also evidence that SNLD has advantage in thin melanomas >0.75mm especially when associated with high risk factors like ulceration and high mitotic rates.

31. FNAC is indicated for all palpable nodes in the regional draining basin and CLND usually performed in all palpable node patients or positive SNLD N0 is accompanied by a high complication rates especially lymphedema.

32. Reconstruction strategies As surgical excisions are becoming ‘less radical’, reconstruction techniques using split or full thickness skin grafts and flaps are being used to do functional salvage of limbs and appendages. Reconstruction also allows for extensive resections in big tumours improving disease free survival rates and also allows early adjuvant therapies due to accelerated healing of surgical sites.

33. Reconstructive techniques allow generous excision margins and good functional rehabilitation. Incomplete margins of excision should be treated with Re-Excision with 1-2cms margins. Surgical approach in many situations like Ear melanomas and Limb melanomas is becoming ‘less radical’ and more function preserving.

34. Facial melanomas post wide local resections are reconstructed with a wide variety of advancement, transposition or pedicled flaps

35. Ear Melanomas are increasingly being treated with perichondrium preserving techniques and skin grafting where there is no invasion into the perichondrium. In cases with such invasions wedge resection and reconstructive flap techniques like Antia -Buch advancement flaps give excellent aesthetic results without compromising on tumour clearance.

36. Subungual and limb melanomas are also not being subjected to amputations any more in most cases barring a huge tumour burden or very aggressive disease based on its physical or histopatholgical features. Heel melanomas are dealt with wide local excisions and Microvascular free flap transfer reconstructions allowing normal ambulation and weightbearing in these patients.

37. Adjuvant Therapies 1. No conclusive evidence has shown overall survival benefits of adjuvant therapies like Elective Lymph Node Dissection (ELND), Isolated limb perfusion, Radiotherapy or Chemotherapy in advanced melanomas. 2. Surgical Excision of distant metastases if possible with minimal complications should be the preferred palliative treatment. May have survival benefits in some cases. 3. Radiotherapy plays a role in local control, pain alleviation and palliation in brain metastases, bone, soft tissue and nerve compressions.

38. Radiotherapy combined with gene target therapy or immune-modulating agents is under trials and showing promising results. However B-RAF inhibitor gene therapy agents are radio- sensitisers and can cause increase radiation toxicity. With such patients stereotactic radiotherapy can be done instead of whole brain irradiation to decrease radiation induced complications.

39. Systemic Therapies for Advanced Malignant Melanomas 1. Gene target therapy with monoclonal antibodies 2. Immunomodulating agents

40. Gene target therapy with monoclonal antibodies Vemurafenib against genetic mutations of B-RAF Dabrafenib N-RAS genes. Thus all advanced melanomas should now be subjected to genetic testing with immunohistochemistry. 40% Melanoma patients show B-RAF mutations.

41. B-RAF inhibitors and MEK (Mitogen-activated-extracellular signal regulated kinase) inhibitors can support first line therapies in patients with High tumour burden, Brain metastases, Elevated LDH levels, Inflammatory syndrome Bone marrow involvement Pre-existing auto-immune disorders like Crohn’s Syndrome, Rheumatoid arthritis, Wegner’s granulomatosis etc. which form a contraindication for immunomodulatory agent administration.

42. Immunomodulating agents are showing a huge promise in the rest majority 60% of advanced melanoma patients who do not show genetic mutations in histopathology Anti-CTLA4 (cytotoxic T lymphocyte associated antigen-4) antibody Ipilimulab has shown survival benefits even in stage IV disease. Anti-PDI (programmed death-I) antibodies Pembrolizumab & Nivolumab have shown promising survival benefits in advanced melanomas. Combination of Ipilimulab and Nivolumab in recent trials such as CHECKMATE 067 trial is showing wonderful results. Many patients on immune modulatory agents will develop vitil i go white patches but these are considered as a marker of good response.

43. Chemotherapy Indications: Secondaries in lungs, liver, bones. b. After surgery for melanoma. Drugs are: a. DTIC: Diethyl triamine iminocarboxamide . Melphalan (Phenyl alanine mustard) Carboplatin, vindesine . CVD regime—is cisplatin, vinblastine and dacarbazine.

44. PROGNOSIS The Breslow thickness of the primary tumour offers the best correlation with survival in stage I disease. The higher the mitotic index, the poorer is the prognosis of the primary tumour . This has greater significance than the presence or absence of ulceration. The presence of lymph node metastases is the single most important prognostic index in melanoma, outweighing both tumour and host factors. The number of affected nodes and the presence of extranodal extension are also significant out- come predictors. Once regional nodes are clinically involved, 70–85% of patients will have occult distant metastases.

45. Followup 90% melanomas recurrence happens in the first 5yrs of resection and hence the frequency of follow-up has to be 3-6monthly. If feasible 10yr follow-up is recommended as melanomas can recur or metastasize late. In thin melanomas no imaging is required In thicker melanomas ultrasound for lymph node basin should be done as it is safe and relatively inexpensive. Abdominal, chest imaging and PET-CT Scan may be required for follow up in advanced melanomas (Stage IIC and above) S-100 protein is a tumour marker that can denote disease relapse especially relevant in advanced melanomas.