Malignant Melanoma Clinical Features

Pathology and

Management

Dr SD Sanyal Lt Col VP Singh

Cl Spl Surg & Surg Oncologist

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.

• Melanocytes are located in the Stratum Basale and produce melanin

Pathogenesis Melanocyte

melanocytic atypia

atypical melanocytic hyperplasia

radial growth phase melanoma

vertical growth phase melanoma

metastatic melanoma

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

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

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

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

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.

Histomorphological types

• Superficial Spreading Melanoma• Nodular Melanoma• Lentigo Maligna Melanoma• Acral Lentiginous Melanoma• Amelanotic Melanoma/ Desmoplastic

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

Nodular Melanoma

– Second most common type (20%)

– Vertical growth pattern– Worst prognosis based

on a higher average tumor thickness

– Lack RGP

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

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

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

Stage (Clark’s level or Breslow Depth)

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.

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

Staging

Management

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

Imaging & Laboratory Tests

• Metastatic workup done for stage III onwards• Chest X Ray• CT Chest and Abdomen• PET CT• MRI brain• LDH• Biopsy

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

Preliminary Work Up

Stage 0 & IA

Stage IB & II

Stage III

Stage III (In Transit)

Stage IV

Persistant disease/ True local scar recurrence

Nodal recurrence

Follow Up

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

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

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

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

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.

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 " )

SLN biopsy using TC99

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 %

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

Patient selection for SLND/Bx

• Depth > 1mm or < 1mm with positive deep margins

• Mitotic rate > 1• Pure desmoplastic melanomas

Principles of LN dissection

- Levels I, II & III of Axillary Lymph Nodes to be removed

- No added survival benefit in ELND

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%

Principles of Adjuvant therapy

-May be considered from Stage IB onwards- Agents:

Targeted therapies

• BRAF Inhibitor– PLX4032 (vemurafenib)

• KIT Inhibitor– Imantinib mesylate

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

Principles of RT

Prevention & Screening

• Protection from sun exposure:- Building > Clothing > Sun screens

• Self examination • Consultation of Dermatologist

Thank You

Biopsy

Small and accessible lesions– Excision with 1 cm margins in suspicious lesions

Large lesions– Incisional or punch biopsy ?

Shave biopsy discouraged