breslow and clarks staging, sentinel lymph node biopsy, adjuvant therapy, histopathological types,

1. Malignant Melanoma
Clinical Features
Pathology
and
Management
Dr SD Sanyal
Lt Col VP Singh
Cl Spl Surg & Surg Oncologist

2. Melanocytes & Melanoma
• Melanoma is a neoplastic disorder produced by malignant transformation
of the normal melanocyte
• Melanocytes are cells responsible for the production of the pigment
melanin
• During the first trimester of fetal life, precursor melanocytes arise in the
neural crest
• As the fetus develops, these cells migrate to areas including the skin,
meninges, mucous membranes, upper esophagus, and eyes
• In each of these locations, melanocytes have demonstrated a potential
for malignant transformation
• The site most commonly associated with melanocytic transformation is
the skin, where melanocytes reside at the dermal/epidermal junction.

3. • Melanocytes are
located in the Stratum
Basale and produce
melanin

4. Pathogenesis
Melanocyte
melanocytic atypia
atypical melanocytic hyperplasia
radial growth phase melanoma
vertical growth phase melanoma
metastatic melanoma

6. Epidemiology & Incidence
• 4% new cancer diagnosis and 1.5% deaths
• Life time risk:
- 1:1500 1:56(W)/1:39(M)
• Higher incidence amongst whites
• Highest per capita incidence amongst
Australians
• Median age for diagnosis is 58 yrs

8. Causes of Melanoma
• 90% linked to UV radiation (Sun exposure)
- UVB radiation
• 8% are due to chromosomal abnormalities
- p16/CDK4
- CDK6
- p14/p53
- CDKN2a
• 2% are unknown

9. Risk Factors
• Family history of melanoma
• Dysplastic nevi (noncancerous, but unusual - looking moles)
• Previous melanoma
• Many nevi (ordinary moles): more than 50
• Severe, blistering sunburns
• Freckling tendency
• Fair skin
• Excessive use of tanning beds
• Genetic predisposition
• Estrogen

10. Signs and symptoms of melanoma
• Melanoma can appear suddenly as a:
- new mole
- develops slowly in or near an existing mole
• Men:
- found between the shoulders and hips
- the head and neck area
• Women:
- lower legs
- between the shoulders
- hips.
• May also appear:
- underneath fingernails & toenails
- on the palms or soles

12. ABCDE of melanoma
• A is for Asymmetry:
– One half of a mole or birthmark does not match the other.
• B is for Border:
– The edges are irregular, ragged, notched, or blurred.
• C is for Color:
– The color is not the same all over
– may include shades of brown or black, or sometimes with
patches of pink, red, white, or blue.
• D is for Diameter:
– The spot is > 6 mm across
• E is for Evolving:
– The mole is changing in size, shape, or color.

13. Histomorphological types
• Superficial Spreading Melanoma
• Nodular Melanoma
• Lentigo Maligna Melanoma
• Acral Lentiginous Melanoma
• Amelanotic Melanoma/ Desmoplastic

14. Superficial Spreading Melanoma
– Most common histologic
type (70%)
– Appear as a flat,
pigmented lesion
growing in the radial
pattern
– Most commonly
associated with sun
exposure
– Sparing of acral sites

15. Nodular Melanoma
– Second most common
type (20%)
– Vertical growth pattern
– Worst prognosis based
on a higher average
tumor thickness
– Lack RGP

16. Lentigo Maligna Melanoma
– Sun-damaged skin
– Flat, darkly pigmented
lesion with irregular
borders and a history of
slow development
– Older individuals
– Extensive RGP
– In situ: Hutchison’s
freckle

17. Acral Lentiginous Melanoma
• Subungual areas and
the glabrous skin of the
palms and soles
• Seen in blacks and
hispanics
• Prolonged RGP
• Confused with
haematomas & chronic
fungal infections

18. • Amelanotic Melanoma/Desmoplastic
– Uncommon
– Difficult to diagnose
– Lacks pigmentation
– Negative for MART/Melan-A
gp-100 & tyrosinase
– Positive for S-100

19. Stage (Clark’s level or Breslow Depth)

20. Clark Classification (Level of Invasion)
• Level I: Lesions involving only the epidermis (in
situ melanoma); not an invasive lesion.
• Level II: Invasion of the papillary dermis but does
not reach the papillary-reticular dermal interface.
• Level III: Invasion fills and expands the papillary
dermis but does not penetrate the reticular
dermis.
• Level IV: Invasion into the reticular dermis but
not into the subcutaneous tissue.
• Level V: Invasion through the reticular dermis
into the subcutaneous tissue.

21. Breslow level of invasion
• Current stage system is based on depth of
invasion
• Measured using ocular micrometer
• Breslows level of :
- < 1mm
- 1 to 4mm
- > 4 mm
used for TNM staging

22. Staging

27. Management

28. Prognostic markers
• Depth of invasion
• Ulceration
• Females < Males
• Head & Neck+ Mucosal>Trunk>Extremities
• Greater risk of LN metastasis in <35 yrs
• Mitotic rate> 6/sq mm
• Angio-lymphatic invasion
• Microscopic satellites

29. Imaging & Laboratory Tests
• Metastatic workup done for stage III onwards
• Chest X Ray
• CT Chest and Abdomen
• PET CT
• MRI brain
• LDH
• Biopsy

30. Management
• Early stages:
– Wide local excision
• More advanced:
– Wide local excision plus sentinel node biopsy,
– Based on the pathology
• Lymphadnectomy
• observation
• interferon
• Metastatic:
– Clinical trial
– Radiation and systemic therapy

31. Preliminary Work Up

32. Stage 0 & IA

33. Stage IB & II

34. Stage III

35. Stage III (In Transit)

36. Stage IV

37. Persistant disease/ True local scar
recurrence

38. Nodal recurrence

39. Follow Up

40. Principles of biopsy
• Excisional bx with 1-3mm margins preferred
• Incisional/ punch full thickness bx of the lesion
over palm, sole, digit, face, ear or for large
lesions
• Shave biopsy may interfere with assessment
of Breslow’s thickness

41. Principles of Pathology
• Elements to be reported:
- Breslow’s depth
- Ulceration
- Mitosis
- Clark’s level
- Peripheral and deep margin status
• ADA recommendations:
- Location
- Regression
- Tumour infiltrating lymphocytes
- VGP
- Angiolymphatic invasion
- Neurotropism
- Histologic subtype
- Pure desmoplasia

42. Wide Excision
• Trunk and proximal extremities:
• - WLE should involve measuring the appropriate
margin (usually 1-2cm) around the entire scar from the
bx/visible edge of residual melanoma and extending
the incision to make an ellipse that is approximately
three times as long as it is wide
• Direction of the scar:
- longitudinal on the extremities, occasionally with
some modification at joints
- along skin lines on the trunk and neck
- upper back  transversely

43. Wide Excision
• Excision should include:
- All skin and subcutaneous tissue to the
deep fascia, but not including the fascia
- When a major cutaneous nerve runs
along the deep fascia to innervate distal
cutaneous structures, it is appropriate to
preserve that nerve

46. SLND & Lymphatic mapping
• Concept and method for sentinel node originally
developed by Cabanas for management of penile
carcinomas
• Initial experience with lymphatic mapping and
sentinel node biopsy for melanoma was the work
of Morton et al. at the John Wayne Cancer
Institute
• They injected a vital blue dye (isosulfan blue)
intra-dermally and found that this stained the
draining lymphatics & the first node(s) into which
these lymphatics empty.

48. SLND & Lymphatic mapping
• Lymphoscintigraphy has been coupled with the blue
dye injection to support identification of the sentinel
node(s), using hand held probes for detection of 'Y
radiation emitted by technetium-99( 99Tc )
• Most surgical oncologists performing sentinel node
biopsy use a combination of radionuclide injection
several hours preoperatively ( in the nuclear medicine
suite, 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
• The sentinel node ( s ) should be both blue and
radioactive ( " hot " )

49. SLN biopsy using TC99

50. SLND & Lymphatic mapping
• Typical results o f SNBx reveal that the rate of
positive nodes increases with increasing
tumour thickness
• The overall rate of positive SNB in most series
(typically for melanomas > 1 mm) is in the
range of 15 % to 25 %
• False-negative SNB in experienced hands +
radiocolloid + handheld gamma probe +/-
blue dye = 1.9 % to 4 %

51. SLND & Lymphatic mapping
• Lymphatic mapping and SNBx:
- all cutaneous sites
- may also be useful for melanomas of mucous
membranes
• A challenging area for SNBx is the head and neck
• Melanomas of the scalp and of the face may drain to
parotid nodes or periparotid nodes for which sentinel
node biopsy is more complex, technically challenging
and associated with greater morbidity
• False-negative sentinel node biopsies are more
common than in trunk and extremity melanomas

52. Patient selection for SLND/Bx
• Depth > 1mm or < 1mm with positive deep
margins
• Mitotic rate > 1
• Pure desmoplastic melanomas

53. Principles of LN dissection
- Levels I, II & III of Axillary Lymph Nodes to be removed
- No added survival benefit in ELND

54. In-transit disease (local disease in
lymphatics)
• 5 to 8% of melanoma patients with a high-risk primary
melanoma (>1.5 mm)
• Hyperthermic regional perfusion
• Melphalan is the chemotherapeutic agent used
• Melphalan heated to 41.5°C/106.7°F and perfused for
60 to 90 minutes
• High response rate > 50%
• Complications
– neutropenia
– amputation
– death
• TNF- alpha /Interferon-alfa + melphalan regression rate
= 90%

55. Principles of Adjuvant therapy
-May be considered from Stage IB onwards
- Agents:

56. Targeted therapies
• BRAF Inhibitor
– PLX4032 (vemurafenib)
• KIT Inhibitor
– Imantinib mesylate

57. Immunotherapy
• Interlukin IL-2 and Interferon in high doses
• BCG
• Monoclonal antibodies
– Ipilmumab
• Tumour vaccine
– Polyvalent melanoma vaccine (Canvaxin)
– Allogenic melanoma cell lysate (Melacin)
– Detoxified endotoxin/myco bacterial cell wall skeleton
(DETOX)
– Gp 100 DNA vaccine
– GM-CSF 2nd generation oncolytic herpes virus vaccine

58. Principles of RT

59. Prevention & Screening
• Protection from sun exposure:
- Building > Clothing > Sun screens
• Self examination
• Consultation of Dermatologist

61. Biopsy
Small and accessible lesions
– Excision with 1 cm margins in suspicious lesions
Large lesions
– Incisional or punch biopsy ?
Shave biopsy discouraged