A brief information on Malignant Melanoma

1. Dr Harsh R Shah
DNB Surgery Resident,
SNDH.

2. Malignant Melanoma
 Malignant Melanoma refers to the malignant lesion arising from the
melanoblasts, which are the precursors of the melanocytes arising form
the neural crest cells. As a result, melanoma can occur at different sites
like skin, meninges, eyes and upper esophagus, where the neural cells
migrate during the fetal life.
 Skin is the most common site, representing 4-5% of all the skin
malignancies.
 It is the 5th most common cancer in men and 6th most common in female.
 Malignant melanoma is a relatively uncommon malignancy in India with
an incidence of less than 0.5 per 100000 population. It is the most lethal of
all skin malignancies.

3.  All melanomas originate from the melanoblasts in the dermo-epidermal
junction, but the cells may not contain melanin at all times, thereby
known as Amelanotic lesions.
 Malignant melanoma may arise:
1. In a pre-existing pigmented nevus (90%cases), whether in a junctional
nevus, compound nevus or in a Hutchinson’s Lentigo.
2.De novo in apparently normal skin.

4. Etiology / Risk Factors
1. Age: its rare before the puberty. Average of presentation is in late 40’s.
2. Gender: Males > Females. Lower limbs are more commonly involved in females. Females tend to
have a better prognosis.
3. Race: Whites are more prone for malignant melanomas, especially those exposed more to
sunlight. Caucasians are also commonly affected than Asians. The White to Black ratio is approx.
20:1
4. Exposure to sunlight (UV rays). (freckling, inability to tan, propensity for sunburns)
5. Abnormalities in chromosomes 1, 6 and 9 have also been noted. Xeroderma pigmentosa.
6. Repeated trauma can lead to a nevus formation which may later turn to malignant melanoma
7. Pregancy state is associated with increased risk to malignant melanoma.
8. Steroid hormones intake can also lead to it.
9. Family h/o melanoma.
10.Common sites of involvement are: Palms, Soles and external genitalia. It may also be found
beneath the nail, known as Subungal melanomas.

5. 10. The possibility of malignant melanoma is greatly elevated in:
a.Preexisting mole changing colour, size and shape, itching and bleeding.
b.Dysplastic nevi in familiar melanoma,
c. More than 50nevi, 2mm or greater in diameter.
11. The incidence of cutaneous melanoma is moderately increased when:
a.One family member is diagnosed with melanoma
b.Previous h/o melanoma in the individual
c. Sporadic dysplastic nevi are detected
d.Congenital nevus/nevi are present.

6.  Elevated risk factor for cutaneous melanoma include: immunosuppression,
sun sensitivity and h/o acute severe blistering, sunburns and Freckling
Molecular Biology:
- Typical melanomas represent senescent lesions that may be irreversibly
growth arrested. Thereby melanomas may alternatively emerg from
normal melanocytes via alternate pathways.
- As many as 70% melanomas harbour somatic mutations or deletions
affecting the CDKN2A locus on chromosome 9p21

7. Pathology
 Microscopically there occurs:
a. Increase in the junctional activity with hypertrophy of cells.
b.Increase in nucleus to cytoplasm ratio, enlarged nucleolus, hyperchromatism
and mitosis
c. Cytoplasm is often vacuolated with few melanin granules to mimic Paget’s cells.
These changes extend through out the epidermis.
 Invasion of the vacuolated cells into the epidermis: malignant potential of the
nevus.
 Invasion of dermis is indicated by the presence of the circular or polyhydral cells
with abundant spongiocytopalsm and fine granular granules.
 Early stage of lymphatic spread is indicated by formation of small clusters of
tumor cells in the sub-epidermal lymphatics.

8.  Fully developed melanoma is characterised by large tumor cells in the
dermis often showing alveolar arrangement with groups separated by a
fine stroma.
 The transition from normal melanocyte to metastatic melanoma involves
several histologic intermediate stages including:
Melanocytic atypia Atypical melanocytoic hyperplasia Radial
growth phase melanoma Vertical growth phase melanoma
Metastatic melanoma.

9. TYPES
Clinically, lesions are classified as thin if they are 1mm or less in depth;
moderate if they are 1-4mm in depth; and thick if they are >4mm in depth.
Histologically, melanoma is classified into 5types:
1. Lentigo malignant melanoma
2.Superficial spreading melanoma
3. Acral lentignous melanoma
4.Nodular melanoma
5.Mucosal lentignous melanoma

10. Lentigo Malignant Melanoma
 Seen in older individuals
 Age: 6th – 8th decades
 Predominantly composed of spindle shaped malignant cells. Pagetoid
cells are not seen.
 Presents as a thin melanoma.
 Associated with a better prognosis.
 Sites: sun exposed skin mainly face.
 Microscopy: solar elastosis

12. Superficial Spreading Melanoma
 Commonest type
 Can occur anywhere in the body.
 Pagetoid cells are present that have both juncitonal activity and upward
growth resulting in the bulging of the epidermis.
 Characterised by hyperplastic epidermis.
 Poor prognosis than Lentigo Malignant Melanoma.

14. Acral Lentignous Melanoma
 More common in Blacks.
 Sites: palms, soles and in sub-ungal positions
 Has features of both Superficial spreading melanoma and Lentigno
Malignant Melanoma.
 It is devoid of Pagetoid cells. There is marked junctional proliferation with
large atypical melanocytes with long dendritic processes.
 Mucus membrane presentation is most commonly seen in vulva.
 Poor prognosis especially with mucus involvement.
 It is the commonest melanoma in Japan.

16. Nodular Melanoma
 It is the most malignant form of melanoma.
 Mainly occurs in younger individuals.
 Can occur anywhere on the body.
 Presents as a convex palpable lesion.
 Characterised by growth in vertical direction.
 It has uniform pigmentation and well circumscribed borders. Ulceration
occurs early.

17. Mucosal Lentignous Melanoma
 Develops from the mucosal epithelium that lines the respiratory,
genitourinary and gastrointestinal tracts.
 Sites: conjunctiva, oral cavity, esophagus, vagina, female urethra, penis
and anus.
 Commonly in elderly population.
 Poor prognosis than cutaneous melanoma

18. Staging
 According to the LEVEL OF
INVASION: (CLARKE’s)
Level I : (in-situ) tumor cells are above
the basement membrane
Level II : tumor extension into the
papillary dermis.
Level III: tumor extends into the
interface between the papillary and
reticular dermis‘.
Level IV: tumor extends into the
reticular dermis
Level V: tumor extends into the
subcutaneous fat.
 According to the LEVEL OF
THICKNESS: (BRESLOW’s)
Stage I : thickness <0.75mm
Stage II: thickness 0.76-1.50mm
Stage III: thickness 1.51-3.00mm
Stage IV: thickness >3mm
 Stage I is known as Thin Melanoma
and has a good prognosis
 Stage IV: Thick Melanoma, 10yr
mortality is approximately 70%

19. CLINICAL STAGING
Stage I : refers to primary tumor only.
Stage II: refers to primary tumor along with presence of satellites/ in-
transit lesions or regional lymph nodal enlargement.
Stage II A: refers to satellite/ in-transit lesions only.
Stage II B : refers to lymph nodal involvement.
Stage III: refers to metastasis to distant sites.

20. spread
A.Local extension: initial spread is by contiguity and continuity. Malignant
melanoma has a tendency to form satellite skin nodules.
B.Lymphatic spread: it is the commonest route of spread, reaching the
regional lymph nodes by permeation and embolization. It is a/w poor
prognosis. By the time regional lymph nodes are involved, 70-80% of
patients will have developed distant mets.
C.Hematogenous: it’s a late event. Can spread to skin, liver, lungs, bones
and brains. However, lungs and liver are the most common sites.
Melanoma is predilected for brain tissue probably due to its similar
embryology.

21. CARDINAL FEATURES
 Features:
1. Rapid growth of a long standing mole.
2. Darker pigmentation, increased vascularity.
3. Ulceration of the overlying skin epithelium.
4. Gradual Invasion of the tumor cells into the surrounding skin to produce a ‘halo’
which indicates malignancy.
5. Regional lymph nodal enlargement.
 Malignant melanoma is not painful bit it itches often.
 Symptoms: c/o lymph nodal enlargement, weight loss, dyspnoea or jaundice.
 Occular melanomas are most non-cutaneous melanomas.

23. Diagnosis & Investigations
 Classic appearance:
A : Asymmetry
B : border irregularity
C : color variation
D : diameter greater than 6mm.
 Symptoms of bleeding, itching, ulceration and pain usually connote vertical
growth and are hallmarks of a late diagnosis
 Recommendation: An excision biopsy with narrow (2mm) margins of the
lesion. Incision for the biopsy should be in the context of the future need for
wider re-excision. for sites like face, palms or soles, a full thickness wedge biopsy
through the most representative and deepest part with a 2mm rim of normal
skin is recommended.

24.  CBC, Alkaline phosphatase levels, Liver function tests, Sr proteins, Serum
LDH.
 CXR, MRI brain (in stage IV melanoma), USG (best for lymph nodal
involvement), CT scan (depending upon the location and for stage IV
melanoma.
 PET-CT best for identifying the primary (when it is occult) and other sites
of melanoma.

25. TNM Staging
T staging
Tx: primary tumor cannot be
assessed
T0 : No evidence of primary
tumor.
Tis: Tumor in-situ
T1: Melanoma 1mm or less in
thickness
T2: Melanoma 1.01 – 2mm
T3: Melanoma 2.01 – 4mm
T4: Melanomas > 4mm
N staging
NX : regional lymph nodes
cannot be assessed
N0 : no regional lymph nodes
detected
N1: 1 node positive.
a: micrometastasis
b: macrometastasis
N2: 2-3 nodes
a: microemetastasis
b: macrometastasis
c: in-transit mets/ satellites
without metastatic nodes.
N3: >4nodes or matted nodes or
in-transit/satellite with
metastatic nodes.
M classification
M1a: distant skin, subcutaneous
or nodal mets
M1b: Lung metastasis
M1c: Any distant metastasis

26. AJCC groupings based on TNM classification
are as follows:
 Stage 0 - Tis, N0, M0
 Stage IA - T1a, N0, M0
 Stage IB - T1b, N0, M0; T2b, N0, M0
 Stage IIA - T2b, N0, M0; T3a, N0, M0
 Stage IIB - T3b, N0, M0; T4a, N0, M0
 Stage IIC - T4b, N0, M0
 Stage III - Any T, N 1-3, M0
 Stage IIIA - pT1-4a, N1a, M0; pT1-4a, N2a, M0
 Stage IIIB - pT1-4b, N1a, M0; pT1-4b, N2a, M0; pT1-4a, N1b, M0; pT1-4a, N2b, M0; pT1-
4a/b, N2c, M0
 Stage IIIC - pT1-4b, N1b, M0; pT1-4b, N2b, M0; any T, N3, M0
 Stage IV - Any T, Any N, Any M

27. Treatment
Surgical resection is the mainstay of treatment. Surgery (e.g., wide local excision with SLNB,
ELND, or both) is the definitive treatment for early-stage melanoma. Medical management is
reserved for adjuvant therapy of patients with advanced melanoma. The role of chemotherapy,
radiotherapy, immunotherapy and biochemotherapy is evolving.
 Management of Primary lesions:
1. Wide local excision with margin being dictated by the thickness of the melanoma. Deep fascia is
not involved in the specimen.
2. Subungal melanomas are treated by amputation at the level of the metatarsophalangeal joint.
3. Moh’s microsurgery is an option for Lentigo maligna (melanoma in situ)
4. Post surgery, patients with Ib or stage II melanoma could either receive interferon alpha or be
observed.
5. Radiotheraphy is for patients for whom negative margins could not be achieved( Head and
Neck melanomas), patients with recurrent resected melanoma or with desmoplastic melanoma
with close margins.

28.  Management of Regional Lymph nodes:
1. Historically, in an No situation, following surgical excision of the primary, regional
lymph nodes were observed and dissected if appeared on follow-up (therapeutic lymph
node dissection) or dissected immediately (elective lymph node dissection)
2. Sentinel node biopsy is indicated in all patients with primary 1mm or thicker. It is also
indicated in lesions <1mm thick with ulceration; mitosis rate of > 1 persq.m, they have
vertical growth phase, are of Clarke’s level Iv or more, positive third dimension after an
excision biospy, etc.
3. Adjuvant radiation may be considered if 3 or more nodes have metastasis , nodes larger
than 3cm or with macroscopic extracapsular disease. In the neck, radiation is indicated
even if nodes are >2cm and if more nodes have metastasis.
4. After completion of surgery and radiation (if required), all patients with node positive
disease could either be observed or given interferon alfa.

29. Metastatic disease:
1. in-transit mets: complete surgical excision if fesible. Regional chemotheraphy is
effective if melanoma is isolated to the extremity. Melphalan is most commonly used.
Intralesional BCG or interferon, or topical imiquimod (for dermal lesions) are
immunomodulators that have been tried. Local ablation with cryotherapy or laser,
radiation therapy and systemic chemotherapy. Have also been tried.
If patient achieves acomplete response, then high dose interferon of r1yr (or
pegylated Inteferon alfa 2b for 5years) may be administered.
2. Distant metastasis: depends whether the lesion is limited or disseminated
(unresectable). Surgery can be considered after a short period of systemic chemotherapy
for patients with solitary or limited distant metastasis. Patient with disseminated disease
are managed by systemic therapy, clinical trial or best supportive care.

30. Systemic therapy:
1. Iplimumab : a monoclonal antibody directed to the terminal checkpoint
receptor termed as ‘cytotoxic T lymphocyte antigen 4 ( CTLA-4).
2.Vemurafenib :specific inhibitor of signalling by mutated BRAF
3. Imatinib: a tyrosine kinase inhibitor for patients who demonstrate the c-
KIT mutation.
4.Chemotherapeutic agents: Dacarbazine, Temozolomide, Paclitaxel with or
without Carboplatin.
Biochemotherapy: combination of chemotherapy and biological agents
like interleukin 2 or interleukin alfa, is under investigation.

31. Recent Updates
 Pembrolizumab: recently FDA approved for unresectable or metastatic
melanoma and disease progression after treatment with ipilimumab and
BRAF inhibitor.
 Temozolomide (currently used as the first-line drug for melanoma by
most oncologists)

32. -John Diamond.
Thank You……