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

11. 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%

12. Miscellaneous
• Amelanotic melanoma
• Desmoplastic melanoma

13. 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.

15. 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.

17. 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.

19. 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.

21. 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

22. • 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.

23. 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.

24. • 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.

25. • 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.

26. 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.

27. 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.

30. 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.

31. • 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).

32. 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

33. • 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.

34. • 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.

35. 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.

37. • 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.

38. 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.

39. • 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.

40. 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.

41. • 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.

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

44. • 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.

46. • 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.

49. 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.

50. • 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.

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

52. • 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.

53. 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.

54. • 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 vitiligo white
patches but these are considered as a marker of good response.

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

56. 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.

57. 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.