Malignant melanoma is a cancer or neoplasma of the melanocyte cells which develops from melanocytes.
The annual incidence of malignant melanoma is 10 per 100,000 inhabitants. In Australia there is the highest incidence of melanoma in the world, 57 per 100,000 inhabitants. In Israel there is also an increased incidence of malignant melanoma, 40 per 100,000 inhabitants. In the US in 2014 are expected to be diagnosed 76,100 cases of cutaneous melanoma. The incidence of melanoma increases by 5-7% annually, only lower annual growth of lung cancer in women. Lifetime risk of developing melanoma in 1935 was 1/1500, the risk to life in 2000 was estimated at 1/75. Although malignant melanoma justified only 5% of skin cancers it is responsible for three times more deaths each year than non-melanoma skin cancers. ASCO estimates that in 2014 the US will die by 9700 people malignant melanoma. Melanoma can occur at any age, but the average age at diagnosis is 57 years and 75% of patients aged <70 years. Melanoma is the most common malignancy in women aged 25-29 years and justify more than 7,000 deaths annually.
In Romania the estimated incidence for 2000 was 8.91 per 100,000 population and mortality of 2.46 per 100,000 inhabitants.
1. Malignant melanoma previous
2. Family history of melanoma
3. Dysplastic nevus syndrome (BK mole syndrome)
4. Increased number of benign nevi> 5 nevi with a diameter> 5 mm or> 50 nevi with diameters> 2 mm
5. Skin phenotype: white skin, blond or red hair, blue eyes, freckled
6. The tendency to burn instead of tan
7. History of blistering sunburn in childhood
8. Excessive exposure to sun
9. Large congenital nevi (> 20 mm in diameter)
10. Multiple congenital nevi (> 5% of body surface)
11. Immunosuppressed patients
Clinical-pathological classification of malignant melanoma extraocular
1. Malignant melanoma with superficial dissemination 70%
2. Nodular malignant melanoma 10-15% (malignant melanoma amelanocytic)
1. Malignant melanoma pigmented (lentigo malignant) 10-15%
4. Acrally pigmented malignant melanoma 2-8%
-Periangular malignant melanoma
Signs and symptoms:
Amendments to a preexisting lesions (nevus) as regards color, width or thickness increase, itching, soreness, bleeding.
Multiple primary melanoma occurs in 4-5%.
Relapses skin into the subcutaneous tissue and lymph nodes are the most common (59%).
Metastasis in the order of frequency of appearance: in the lung, liver, intestine, brain, adrenal, kidney, and bone.
Tumor biopsy for lesions less than 2cm excisional biopsy is recommended that fully includes removing the lesion with a small margin of normal skin (1-2mm).
For lesions larger than 2 cm is recommended which should include incisional biopsy of the lesion center, subcutaneous fat and normal skin.
Principles of pathology:
– Biopsy should be read by a pathologist experienced in skin lesions
– The minimum elements that should include a histopathological bulletin are in mm Breslow tumor thickness, histological ulceration (presence or absence), mitotic rate dermal / mm, Clark level for lesions> 1 mm, the peripheral edges and deep biopsy (negative or Positive)
– Microsatelitosis: is defined as the presence of a tumor larger networks of 0.05 mm in diameter reticular dermis, fat or blood vessels tassel below the main invasive tumors but separated from it by at least 0.3 mm normal tissue. Microscopic satellites commonly associated with regional lymph node metastases than the thickness of the tumor.
– Location tumor
– Tumor regression
– Vertical growth phase
– Angiolymphatic invasion
– Sub histologically
– Desmoplasia – pure or mixed (associated with fusiform cells or epithelioid cells)
Screening consists of historical and whole body examination in daylight. For the general population over the age of 20 years recommended a skin exam to 3 years, and at-risk populations clinical examination is recommended annually.
Prevention is by avoiding sun exposure between the hours of 1000 and 1600, the use of protective substances, protective clothing, self-examination, atypical nevi excision in patients with personal history of melanoma.
The diagnosis is confirmed by histopathological examination. Histopathological examination should include width ulceration, Clark level, Breslow depth of invasion, mitotic index, vascular and lymphatic invasion.
Breslow thickness of the primary tumor is a prognostic parameter. Tumor thickness was measured from the granular layer of the epidermis to the deepest melanocytic cells. The likelihood of metastasis when tumor thickness greater than 1,75-2mm.
pT1- tumor ≤ 0.75 mm in thickness
pT2- tumor> 0.75 mm but ≤ 1.5 mm in thickness
pT3- tumor> 4 mm but ≤ 1.5 mm in thickness
pT4 – tumors> 4 mm in thickness
Based on the depth of local invasion considers the risk of local recurrence and metastasis away:
v melanoma with depth of invasion <1 mm: the risk of local recurrence and metastasis distance is less than 5%
v malignant melanoma invasion depth of between 1 mm -4mm has a high risk of metastasis to regional metastases to 40% and less than 20%
v malignant melanoma invasion depth> 4mm has a likelihood of regional metastases and metastases to 60% from 70%
Clark level of invasion
q Clark Level I: the lesion is located in the epidermis, without invading the basement membrane.
q Clark Level II: basal membrane damage exceeded invade the papillary dermis.
q Clark Level III papillary dermis lesion invades interface / reticular dermis.
q Clark Level IV: lesion invades the reticular dermis.
q Clark Level V: lesion invades the underlying subcutaneous fat.
– Table no. AJCC staging malignant melanoma 1 (2010)
Primary Tumor (T)
pTx- primary tumor cannot be assessed
pT0- no evidence of primary tumor
pTis- in situ melanoma, Clark level (malignant noninvasive, atypical melanocytic hyperplasia, severe melanocytic dysplasia)
pT1 – tumor ≤ 1 mm in thickness and invades the papillary dermis (Clark level II)
a. without ulceration; b. With ulceration
pT2 – Tumor> 1 mm but <2 mm in thickness and / or invades the papillary dermis interface / reticular dermis (Clark level III)
a. without ulceration; b. with ulceration
pT3 – Tumor> 2 mm ≤ 4 mm in thickness and / or invades the reticular dermis (Clark level IV)
pT3a – without ulceration
pT3b – with ulceration
pT4 – tumors> 4 mm in thickness and / or satellite tumors at a distance <2 cm of the primary tumor
pT4a – without ulceration
pT4b – with ulceration
Regional lymph nodes (N)
Nx – regional lymph nodes cannot be assessed
N0- no regional lymph node metastasis
N1- metastasis in a single lymph node
a.micrometastases (clinically occult)
b. macrometastases (clinically apparent)
N2 – metastases in lymph 2-3 lymph nodes
N2c.-transit metastases, lymph node metastases without satellites
Metastasis in transit involving the skin or the subcutaneous tissue more than 2 cm from the primary tumor, but does not exceed the regional lymph nodes.
N3 4 or more lymph nodes or lymph nodes block the transit or satellite metastases in lymph node metastasis
Distant metastasis (M)
MX distant metastasis can ot be assessed
M0 – no distant metastases
M1a – metastatic cutaneous or subcutaneous tissue or lymph nodes beyond the regional lymph nodes, normal LDH
M1b- visceral metastases, normal LDH
M1c- All types of visceral metastases or distant but increased LDH
Stg.0 N0 M0 pTis
Stg.IA N0 M0 pT1a
Stg.IB pT1b, N0 M0 pT2a
Stg.IIA pT2b, N0 M0 pT3a
Stg.IIB pT3b, N0 M0 pT4
Stg.III any T N1-3 M0
Stg IIIA pT1-4a N1A-N2a M0
Stg IIIB pT1-4b N1A-N2a M0
pT1-4a N1b-M0 N2b
any M0 T N2c
Stg.IV Any T Any N M1
For staging it is recommended:
· History, clinical examination,
· Blood count, biochemical tests of renal, hepatic, LDH,
· Chest x-ray, bone scans, liver and brain (only in case of suspicion of metastases)
· C. T. lung, liver, brain only in case of suspicion of metastatic disease or stg.II and III,
· Lymphoscintigraphy for sentinel node detection
Histological and immunohistochemical examination.
· Cranial MRI is recommended in patients with distant metastases to detect asymptomatic metastatic disease. In patients without metastases is recommended only in case of symptoms.
· Ultrasound is the best imaging test to diagnose lymph node invasion
· PET / CT (FDG) are the best imaging study to detect other metastatic locations. It is recommended in patients with lymph node metastases, transit or satellite metastases in patients with advanced metastatic disease or to detect other remote locations disease.
Lactic dehydrogenase (LDH) is a tumor marker for liver or lung metastatic disease. LDH is increased in several diseases including malignancies. Although the specificity and sensitivity of this test is to show that low LDH is a predictive factor for poor prognosis. LDH is considered part in melanoma staging system.
Level S-100 β polypeptide Patients positive for this marker have a lower survival than patients negative 2.7 times.
Stg.I and II
a) pT1 and pT2 <1mm. Indicate wide surgical excision and follow-up
b) pT2> 1 mm and pT3. Wide surgical excision is recommended, lymphoscintigraphy or injection of dye around the tumor to detect sentinel lymph node biopsy followed by sentinel lymph node:
1) negative sentinel lymph node. Indicate tracking.
2) positive sentinel lymph node. It is recommended lymph node dissection and sentinel lymph node positive if recommended, clinical trial, observational or adjunctive therapy: Interferon α
c) pT4. The indicated treatment is surgical excision of sentinel node biopsy plus range. If the node is positive, recommend clinical trial, observational or adjunctive therapy with Interferon. Stg.III
a) clinically palpable lymph nodes. Node dissection is recommended therapy.
If lymph nodes are positive recommended clinical trial, observational or adjunctive therapy with Interferon
If the lymph nodes are negative, recommend posttherapeutic tracking.
b) transit metastases (75% occur in the legs)
a) small lesions in limited numbers indicate surgical resection followed by adjuvant therapy with Interferon
b) for patients with multiple metastases in transit states therapeutic options are:
– Isolated hyperthermic perfusion (420C) member in therapy with melphalan
– Or radiation therapy in combination with interferon α, IL-2 or vaccine.
1) Skin metastases surgical excision is recommended followed by chemotherapy, IL-2, interferon or vaccine.
2) pulmonary metastases
a) In patients with extrapulmonary disease-tumor doubling time of greater than 60 days (measured by serial chest X-rays), indicate surgical resection followed by therapy with Interferon, IL-2 and vaccine.
b) patients with unresectable shown chemotherapy associated immunotherapy (interferon, IL-2 vaccine)
3) gastrointestinal metastases. It is recommended for palliative resection surgery (in case of obstruction, perforation or bleeding) associated with interferon, IL-2 or vaccine.
4) liver metastases. Indicate chemotherapy, immunotherapy.
5) adrenal metastases. The recommended treatment is surgical resection associated with chemotherapy and immunotherapy.
6) Bone metastases. Indicate radiotherapy associated with chemotherapy and immunotherapy.
7) Brain metastasis. It is recommended cranial radiotherapy 30Gy in 10 fractions associated with chemotherapy (temozolomide).
Wide surgical excision is the only effective therapy for primary malignant melanoma. Tumor-free resection margins are recommended to be:
– 0.5 cm for melanoma in situ,
– 1 cm for invasion depth <1 mm,
– 2 cm in depth of 2 mm invasion
– 2-4 cm for invasion in greater depth 4mm.
Selective lymphadenectomy is recommended in patients with primary tumors with invasion depth> 1 mm.
For locations on the trunk, head and neck lymph drainage is unpredictable where lymphoscintigraphy is recommended.
The injection of the radionuclide (Tc99) around the primary tumor radionuclide is captured by macrophages and then after 2 hours node node is highlighted by scintigraphy. The intraoperative gamma camera detected the radioactive point. Sentinel node biopsies are performed and if positive node dissection is done.
The sentinel node can be identified by injecting blue bluish patent.
Node biopsy was split into 10 slices 8-10 mm of which 4 are stained with HE, 2 for S-100.1 for HMB-45. Antigens S-100 and HMB-45 are differentiation antigens associated with melanoma. They are useful in the diagnosis of melanoma amelanocytic and undifferentiated tumors.
In patients who underwent sentinel node biopsy and it was positive, node dissection was performed. Of these only 24% -33% had lymph invaded. Sentinel lymph node positivity was between 15% -26% and was based on the depth of invasion of the primary tumor.
At a depth of invasion> 2mm, 18% had positive sentinel node and to an invasion> 3mm, 17% had positive sentinel node.
Node dissection therapy is indicated in patients who have clinically palpable lymph nodes.
Isolated limb infusion is indicated in patients with metastatic melanoma of the extremities in transit or satellite lesions inoperable. It was developed as a therapeutic modality limb salvage locoregional chemotherapy drugs issuing very large systemic doses cannot be tolerated. To lower limbs cannulated external iliac artery and vein and axillary vessels for upper limb. Melphalan agent is used under hyperthermia (temperature of 380 to 410C). The duration of therapy was between 45 ‘and 120’.
Patients with invasion depth pT3b, pT4a), damage in transit (pT4b), invasion of regional lymph nodes (N1, N2) are at risk of relapse and death by 60% at 5 years. Adjuvant therapy is indicated to these two groups of patients:
1)., PT3b pT4a and pT4b
2) . regional lymph nodes invasion (N)
As adjunctive therapy is recommended:
1. Interferon α
a) High doses of interferon α for 1 year.
Induction phase: to receive 20 MU / m2 iv day 5-7 days / week for 4 weeks.
In the maintenance phase: administering 10mIU / m2 sc 3x / week for 48 weeks. It produced 40% improvement in disease free survival at 5 years and 25% improvement in overall survival at 5 years.
2. Peginterferon alpha 2b -6mg / kg / week, sc, 8 doses, and then 3 mg / kg / week sc for 5 years
Treatment of metastatic disease
A. clinical trials are preferred
1. Ipilimumab 3 mg / kg IV in 90 min; 21 days in 4 doses
3 mg/kg IV
IV 3 weeks in IV 100 mL NS in 1 hour and 30 minutes, using 0.22 micron filter in line.
Repeat 3 weeks, 4 cycles
If the disease is stable for more than three months, there is complete or partial response, it is considered repetition of the treatment (reinduction) progression;
4 more cycles in 3 weeks.
Ipilimumab is an antibody directed against the antigen CTLA-4 (cytotoxic T antigen lymphocyte -4). Ipilimumab stimulates T cells and is associated with adverse immune reactions especially in patients with autoimmune diseases to 60% of patients. Diarrhea was the most common adverse effect immune
Targeted therapy against mutant BRAF
Almost half of patients with melanoma have a mutation activated BRAF kinase intracellular signaling. Vemurafenib is a specific inhibitor of signaling through the mutant BRAF gene
2. vemurafenib 960 mg PO every 12 hours for V600E BRAF mutation patients (not recommended in patients with melanoma with BRAF wild type.
Vemurafenib was associated with overall survival and disease free survival improved. The response rate around 53% and the median survival was 15.9 months. Skin complications were frequently associated with this agent: 18% of cutaneous squamous cell carcinoma patients developed or keratocarcinoma, 12% had grade 2 SI3 photosensitivity reactions. Arthralgia occurred in 21% of patients treated with venurafenib.
3. Dabrafenib 150 mg PO x 2 / day (V600E BRAF mutation for patients; not recommended in patients with melanoma with BRAF wild type)
150 mg X 2 / day (12 hours)
One cycle is equal to 4 weeks. It is administered until disease progression or unacceptable toxicity.
Dabrafenib is a BRAF inhibitor and is recommended in patients with metastatic malignant melanoma with BRAF V600E mutation. Side effects were the most common of skin toxicity, fever, arthralgias and headache. Compared with vemurafenib, dabrafenib was associated with fewer squamous skin carcinoma or keratocarcinomas (6%), fever in 11%.
4. Trametinib 2 mg PO / day (V600E BRAF mutation for patients with or V600K); not recommended in patients who have previously received BRAF inhibitors).
Trametinibe is an oral small molecule inhibitor of MEK1 and MEK2 are downstream of the BRAF gene in the pathway of signal transduction. It is recommended in patients with metastatic malignant melanoma with BRAF V600E mutations in the gene or V600K. Trametinib improved disease free survival and survival at 6 months. The most common side effects were rash, diarrhea and peripheral swelling. No adverse reactions associated with skin.
NS IV in 500 -1000 mL or G 5% in 1-2 hours
200 mg / m2 / day on days 1-5
NS IV in 500 -1000 mL or G 5% in 1-2 hours
Repeat 21 days up to 4 cycles of disease progression or intolerable side effects
6. Temozolomide 150 mg / m2 PO on days 1-5;
Repeat in 28 days; It may increase the dose to 200 mg / m2 on days 1-5 PO
200 mg/m2/day, days 1-5
PO, at bedtime
Repeat 28 days, maximum 8 cycles.
Discontinue treatment in clinical or radiological progression.
For patients who have received prior chemotherapy for metastatic malignant melanoma begins with a dose of 150 mg / m2 / day and subsequently increase if well tolerated
7. Interleukin-2.6 million U / kg IV every 8 hours (maximum of 14 doses); Pause 9 days. Repeat for 14 doses (up to 28 doses per cycle).
1. Dacarbazine, Caremustine cisplatin
220 mg/m2/day, days 1-3
IV in 500 -1000 mL NS or G 5% in 1-2 hours
25 mg/m2/day, days 1-3
IV in 100 – 250 mL* NS in 20 – 30 min
150 mg/m2 day 1
if Cisplatin dose is of ≤60 mg use 100 mL NS if the dose of cisplatin> 60 mg 250ml NS
Repeat cycle with dacarbazine and cisplatin in 21 days; repeat the cycle with carmustine to 42 days
d) interferon, dacarbazine, dabrafenib
Interferon alpha-2b (15 million IU / m2 IV on days 1-5, 8-12 and 15-19 as induction then 10 million IU / m2 SC 3x / week after induction Terp
Dacarbazine 200 mg / m2 IV on days 22-26
Dabrafenib 150 mg PO x 2 / day
e) plus Trametinib Dabrafenib
PO Trametinib 2 mg / day plus
Dabrafenib 150 mg PO x 2 / day
unresectable or metastatic melanoma for BRAF V600E mutation or V600K
Pembrolizumab 2 mg / kg IV 21 days until the disease progresses or unacceptable toxicity occurs. Unresectable or metastatic melanoma indicated for progressive disease following ipilimumab and BRAF inhibitor and V600 BRAF mutation if he
Radiation therapy is recommended in patients with unresectable metastatic lymph nodes after resection of nodal relapse in patients with multiple lymph node metastases (> 10 positive nodes) or extracapsular extension. In palliative treatment is recommended in transit metastases, cutaneous metastases, brain, bone. The doses used were 20 Gy in 5 fractions, or 30 Gy in 10 fractions.
The most important prognostic factors are tumor microstaging (tumor thickness and level) and the absence or presence of lymph node metastases.
1. Clark level of invasion
Clark level of invasion of survival at 5 years
Level I 100%
Level II 85%
Level III 65%
Level IV 50%
15% level V
2. Breslow depth of invasion
The depth of invasion of survival at 5 years
Melanoma in situ 100%
<0.75 mm 97-98%
0.75-1.5 mm ≥ 90%
1.5 to 3 mm 75%
> 3 mm 55%
3. tumor ulceration is a poor prognostic factor.
4. Lymph node invasion and invaded unfavorable influence on survival:
Survival positive nodes to 3 years
1 ganglion 40%
2-4 nodes 26%
≥ 5 lymph 15%
5-year survival rates of:
90% for stage I,
45% -77% for stage II,
27% -70% for stage III,
6% -10% for stage IV.
Tracking patients is made by history, clinical examination every 3 months for the first 2 years and 6 months- anually the next 3 years. After five years clinical skin examination is recommended annually.
For stg IA-IIA are recommended:
History and physical examination every 3 months in the first 2 years, 6 months next 3 years and annually over the next 5 years.