Malignant melanoma - Incidence, Risk factors, Pathobiology, Clinicopatholgical classification, Clinical presentation, management (NCCN & AJCC) and recent updates.

1. Dr Anand Bhandary Panambur
Surgical Resident.
Dept. of Gen. Surgery,
AJIMS&RC, Mangalore, India
February, 2019

2. • Malignant melanoma refers to a malignant lesion originating in the melanocytes.
• Precursors of melanocytes arise in the neural crest.
• These tumors primarily arise from melanocytes at the epidermal-dermal junction but may also
originate from mucosal surfaces of the oropharynx, nasopharynx, eyes, proximal esophagus,
anorectum, and female genitalia.

3. • Melanoma accounts for 1-3% of all
malignancies.
• Melanoma represents 2% of all skin cancers,
but causes 75% of skin cancer deaths.
• The world’s highest incidence of melanoma is in
Australia and New Zealand (more than twice as
high as in North America).
• About 132,000 new cases of melanoma are
diagnosed worldwide each year, according to
the World Health Organization.

4. Malignant melanoma may arise —
(i) In a pre-existing pigmented naevus (90%), either in
(i) a junctional naevus,
(ii) compound naevus or
(iii) in a Hutchinson's Lentigo (Lentigo maligna subtype of melanoma in situ).
(ii) De novo in apparently normal skin (10%).

5. RISK FACTORS:
• A well-known environmental risk factor is exposure to solar UV radiation. It was recently
reported that greater than 10 tanning bed sessions by adolescents and young adults increased
their relative risk of developing melanoma by twofold.
• Caucasians have at least 20 times the melanoma incidence of African Americans and five times
the melanoma incidence of American Hispanics.
• The incidence of melanoma increases with age.
• The incidence of melanoma is 1.7-fold higher for women than men before 49 years of age.
• Over age 70, the incidence of melanoma is 2.4-fold higher for men than women.
• Man’s lifetime risk of melanoma development is approximately 1.5 times greater than a
woman’s risk.

6. UVA radiation (320-400 nm)-
• Penetrates deeper into the dermis.
• Responsible for sun induced changes in dermal connective tissue and loss of
elasticity (wrinkles, signs of aging)
• UVB (290-320 nm)- causes sunburn
– increased melanin production in skin
Both are carcinogens.

7. Non-environmental risk factors:
• Personal history of melanoma, which is associated with a 10-fold increase in risk.
• Individuals with dysplastic nevi have a 10% overall lifetime risk of melanoma, with tumors
arising from pre-existing nevi or de novo.
• Dysplastic nevus syndrome (B-K mole syndrome) has an autosomal dominant transmission
with high penetrance and is associated with a nearly 100% lifetime risk in being diagnosed with
cutaneous melanoma.
• Congenital nevi increase risk for melanoma proportionally with size. giant congenital nevi are
associated with a 5% to 8% lifetime risk.
• Five to ten percent of cutaneous melanomas occur in patients with a family history of
melanoma, and these individuals have an earlier age of disease onset, commonly express
dysplastic nevi, and more commonly have more than one primary lesion.

8. • Approximately 8% to 12% of melanomas occur in individuals with a genetic predisposition.
• Melanoma development is strongly associated with the p16/CDK4,6/Rb and p14ARF/HMD2/p53
tumor suppressor pathways and the RAFMEK- ERK and PI3K-Akt oncogenic pathways.
• Cyclin-dependent kinase inhibitor 2A (CDKN2A) is the most commonly identified mutation in
suspected familial melanoma.
• Deletions or rearrangements of chromosomes 10 and 8p are also well documented in
cutaneous melanoma.

9. Persons with ≥50 nevi, all of which are >2 mm in diameter, have 5 to 17
times the melanoma risk of persons with fewer nevi.
Individuals who tend to develop freckles also have an increased risk of
melanoma.

10. • Male sex
• Age >60yrs
• Phenotype predisposition:
• Atypical mole/ dysplastic nevus pattern
• Increased mole count(particularly large nevi)
• Tendency to sun burn
• Red hair-blue eyes
• Fitzpatrick skin type 1
• Tanning bed use
• Residence in sunnier climate/ latitude
nearer to equator.
• Actinic keratosis
• Xeroderma pigmentosum
• Immunosuppression :
• Solid organ transplantation.
• HCT
• HIV/AIDS
• F/H of cutaneous melanoma, pancreatic cancer, astrocytoma, uveal melanoma, mesothelioma

11. Clark’s concept - Two phases of growth:
• Initial radial growth phase occurs horizontally.
• later vertical growth phase occurs with invasion.
Radial Growth Phase-
• Tumor cells proliferate at the dermal-epidermal junction.
• Tumor expands radially
• Lesions are confined to epidermis, may have superficial involvement of dermis
Vertical Growth Phase-
• Lesion invades deeper into dermis,
• Development of palpable nodule – *Nodular type of melanoma

13. Clinical Presentation.
Melanoma most commonly manifests as cutaneous disease, and clinical characteristics include
• Asymmetric outline,
• Changing irregular Borders,
• Color variations,
• Diameter greater than 6 mm, and
• Elevation.
Other key clinical characteristics include a pigmented
lesion that has enlarged, ulcerated, or bled.
Amelanotic lesions appear as raised pink, purple,
or normal-colored skin papules and are often
diagnosed late.

14. Asymmetric outline

15. Changing irregular Borders

16. Color variations

17. Diameter greater than 6 mm

19. Macroscopic features in naevi suggestive of malignant melanoma
• Change in size
• Shape
• Color
• Thickness (elevation/nodularity or ulceration)
• Satellite lesions (pigment spreading into surrounding area)
• Tingling/itching /serosanguinous discharge (usually late signs)

21. CLARK’S LEVEL
(Level of invasion)

22. 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.
• It has more radial growth and better prognosis.
• In men, common in back; in women in leg.

23. Nodular melanoma (NM): (More aggressive)
• Nodular melanoma accounts for 15% of all MM and tends to be more aggressive than SSM,
with a shorter clinical onset.
• These lesions often arise de novo in skin and are more common in men than women, often
presenting in middle age and usually on the trunk, head or neck.
• They typically appear as blue/black papules, 1–2 cm in diameter, and because they lack the
horizontal growth phase, they tend to be sharply demarcated.
• Up to 5% are amelanotic.
• Common in mucosa and mucocutaneous junction.
• uniform; nodular; more vertical growth;
• nodal spread is common;
• poor prognosis.

24. Nodular melanoma

25. Lentigo maligna melanoma: Less common, least malignant.
• LMM was previously also 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.
• LMM are thought to have less metastatic potential
than other variants as they take longer to enter a
vertical growth phase.
• Nonetheless, when they have entered the vertical
growth phase their metastatic potential is the same
as any other melanoma.

26. Acral lentiginous melanoma (ALM) poor prognosis, least common.
• ALM affects the soles of feet and palms of hands.
• It is rare in white-skinned individuals (2–8% of MM) but more common in the Afro-
Caribbean, Hispanic and Asian population (35–60%).
• It usually presents as a flat, irregular macule in later life.
• More vertical growth phase.
• 25% are amelanotic and may mimic
a fungal infection or pyogenic granuloma.

27. Amelanotic melanoma:
• This is the worst type.
• Because of the undifferentiation, tumour cells loose their
capacity to synthesize melanin.
• It presents as rapidly progressive pinkish fleshy tumour.
• It may mimic soft tissue sarcoma.
• It needs markers like S100, HMB45 for diagnosis.
Desmoplastic melanoma
• high affinity for perineural invasion;
• is common in head and neck with higher recurrence rate.
• It is amelanotic melanoma with thicker lesion carrying poor prognosis due to neural invasion.

28. Subungual melanoma
• 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.
• A classical feature of a subungual melanoma is Hutchinson’s sign:
nail fold pigmentation that widens progressively to
produce a triangular pigmented macule with associated
nail dystrophy.
• Malignancy is unlikely if the nail fold is uninvolved

30. TNM Staging
NCCN Guidelines 1.2019

32. • In-transit metastases : defined as intralymphatic tumor in skin or subcutaneous tissue >
2cm from the primary tumor but not beyond the nearest regional lymph node basin.
• Microsatellite- defined as presence of tumor nests greater than 0.05mm in diameter, in the
reticular dermis, panniculus or vessels beneath the principal invasive tumor but separated
from it by atleast 0.3mm of normal tissue on the section in which the Breslow measurement
was taken.
• Intralymphatic metastases : characterized as clinically or pathologically detectable satellite
metastases (visible or microscopic cutaneous and/or subcutaneous metastases occurring
within 2cm of the primary melanoma).
Patients with palpable Lymph nodes as well as those
with in-transit disease or microsatellites are clinical stage III.

35. STAGING:
• Stage 0 – (melanoma-in-situ) or stage 1A or 1B with thickness 0.75mm or less, regardless of
other features. (ulceration, mitotic rate)
• Stage 1A with thickness 0.76mm to 1mm with no ulceration and mitotic rate – 0/mm2
• Stage 1B with thickness 0.76 to 1mm with ulceration and mitotic rate more than or equal to
1/mm2 or stage 1B / stage II with thickness 1mm thick, any features (with or w/out ulceration
and any mitotic rate) and clinically negative nodes.
• Stage III with clinically detected (palpable) +ve nodes, microscopic satellitosis and/or in-transit
disease.
• Stage IV – distant metastatic disease.
NCCN Guidelines 1.2019

38. NCCN Guidelines 1.2019

39. NCCN Guidelines 1.2019

41. NCCN Guidelines 1.2019

42. NCCN Guidelines 1.2019

43. NCCN Guidelines 1.2019

44. NCCN Guidelines 1.2019

45. Common sites of distant metastasis in melanoma patients are, in order of decreasing frequency, skin and
subcutaneous tissues (40%), lungs (12% to 36%), liver, and brain.

47. • Pembrolizumab : IgG4 isotype antibody that blocks a protective mechanism of cancer cells and
thereby allows the immune system to destroy them. It targets the programmed cell death 1 (PD-1)
receptor of lymphocytes.
• Nivolumab : human IgG4 anti-PD-1 monoclonal antibody
• Trametinib is a MEK ( mitogen-activated protein kinase kinase ) inhibitor
• Dabrafenib/ Vemurafenib - B-RAF (Rapidly Accelerated Fibrosarcoma) Inhibitor.

48. • Ipilimumab - A recombinant human immunoglobulin (Ig) G1 monoclonal antibody directed
against the human T-cell receptor cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), with
immune checkpoint inhibitory and antineoplastic activities. Ipilimumab binds to CTLA4
expressed on T-cells and inhibits the CTLA4-mediated downregulation of T-cell activation.
• Imiquimod is a topically-applied aminoquinoline immune modulator that induces interferon
production. An immune response modifier (IRM), imiquimod stimulates cytokine production,
especially interferon production, and exhibits antitumor activity, particularly against cutaneous
cancers. Imiquimod's proapoptotic activity appears to be related to Bcl-2 overexpression in
susceptible tumor cells.

49. Principles of biopsy of a suspicious pigmented lesion.
Excisional biopsy (elliptical, punch or saucerization/ deep shave) with 1 to 3 mm margins preferred.
Orientation of elliptical/ fusiform excisional biopsy should be planned with definitive WLE in mind.
(Ex longitudinally and parallel to the underlying lymphatics on the extremities.)
Full thickness incisional or punch biopsy of clinically thickest
portion of lesion acceptable, in certain anatomic areas
(palm/sole, face, ear) or for very large lesions.
Repeat narrow – margin excisional biopsy is recommended if an
initial partial biopsy is inadequate for diagnosis or microstaging
but should not be performed if the intial specimen meets criteria
for SLN staging

54. • Routine SLN biopsy is not recommended for patients with thin melanomas that are T1a
(nonulcerated lesions < 0.8 mm in Breslow thickness).
• SLN biopsy may be considered for thin melanomas that are T1b (0.8 to 1.0 mm Breslow
thickness or < 0.8 mm Breslow thickness with ulceration) after a thorough discussion with the
patient of the potential benefits and risk of harms associated with the procedure.
• SLN biopsy is recommended for patients with intermediate-thickness melanomas (T2 or T3;
Breslow thickness of > 1.0 to 4.0 mm).
• SLN biopsy may be recommended for patients with thick melanomas (T4; > 4.0 mm in Breslow
thickness), after a discussion of the potential benefits and risks of harm.
• In the case of a positive SLN biopsy, CLND or careful observation are options for patients with
low-risk micrometastatic disease, with due consideration of clinicopathological factors.
• For higher-risk patients, careful observation may be considered only after a thorough discussion
with patients about the potential risks and benefits of foregoing CLND.
Sentinel Lymph node Biopsy

55. Who Needs SLNB?
Primary tumor criteria
• >/= 0.8mm Breslow thickness
• <0.8mm
• Clark’s >III
• Ulceration
• Mitoses >/= 1/mm2
• Unknown thickness
• Shave biopsy
• Distorted pathology
• Ambiguous diagnosis of melanocytic lesion

60. Preoperative lymphoscintigraphy

65. Isolated limb infusion.

69. Principles of RT
Primary disease – adjuvant therapy in selected pts with DESMOPLASTIC MELANOMA wit
narrow margins, locally recurrent disease or extensive neutrotropism.
Regional disease
• LDH < 1.5x x upper limit of normal +
• Gross nodal Extracapsular extension and / or
• Parotid : >/= involved node, any size of involvement.
• Cervical >/= 2 involved nodes and /or >/=3cm tumor within a node.
• Axillary >/=2 involved nodes and /or >/=4cm tumor within a node.
• Inguinal >/=3 involved nodes and /or >/=4cm tumor within a node.
Palliative
• Unresectable nodal/ satellite or in-transit disease
Metastatic disease.

70. Metastatic Melanoma of Unknown Primary Site
Approximately 1% to 8% of patients with melanoma present with metastatic disease from melanoma of
unknown primary (MUP) site.
The most common presentation is in the axillary lymph node basin (>50%).
The next most common presentation site is the cervical lymph node basin.
Various reasons have been proposed for the phenomenon of MUP site.
• An unrecognized melanoma, a treated melanoma that had been initially misdiagnosed, a
spontaneously regressed melanoma, and malignant transformation of a melanocyte that had
travelled to a metastatic location.
In order for metastatic melanoma to be classified as MUP site, the histologic diagnosis must be
confirmed, previous biopsies and/or excisions, if any, should be evaluated for a possible diagnosis of
melanoma, and less common primary sites for melanoma should be thoroughly evaluated.
If the metastatic lesion is to a lymph node basin, the drainage areas of that basin should be rigorously
examined.

71. • Furthermore, patients should undergo staging evaluation with CT of the chest, abdomen,
and pelvis (also including neck CT if anatomically appropriate), and MRI of the brain.
• Given their survival profile, such patients with nodal disease should be staged as stage III
and treated similar to stage III patients with a known primary melanoma.

72. Follow-up:
Early melanomas ((e.g. ≤1-mm tumor thickness, nonulcerated, lymph-node negative) -
Every 6 months for 2 yrs. then annually.
Advanced Melanomas (thicker or ulcerated melanomas and those with positive lymph
nodes ) – Every 3-6 months for 3yrs. , every 4-12 months for 2 yrs. and then
annually.

74. Polyvalent melanoma vaccine (Canvaxin)
Univariate and multivariate analyses of these data have demonstrated the prognostic
significance of this allogeneic whole-cell preparation as a postoperative adjuvant
treatment for patients with stage III and IV melanoma. The vaccine has also been shown
promising results after resection of stage II melanoma and in patients with regional in-
transit disease.

77. References:
• Bailey & Love's short practice of surgery. 27th ed.
• Schwartz principles of surgery 10th ed.
• NCCN guidelines – 1.12019
• MD Anderson Surgical Oncology 6th edition.
• AJCC Cancer Staging Manual 8th Edition.