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Slide 1-

Controversies in Melanoma Prof Ravi Kant, Dr Ajay Yadav, Dr Vivek Gupta, Dr Vishal Gupta, Ms Tanmya Stuti Ravi
Slide 2-

2 Controversies in Melanoma Biology Detection-Computer, USG, RT-PCR Staging- AJCC 2000 +Prognosis SLN Biopsy + ELND Surgical margins Adjuvant treatment + Vaccines Summary
Slide 3-

3 Biology of melanoma development and progression
Slide 4-

4 Biology of melanoma Melanocytes → Nevus → Dysplastic nevus → Radial growth phase → Vertical growth phase → Metastases.
Slide 5-

5 Melanoma & Nevi Class I = Precursor Class II = Intermediate Class III = VGP tumorigenic VGP = vertical growth phase
Slide 6-

6 Cell cycle regulation in melanoma
Slide 7-

7 Expression of defined molecules in melanoma cell
Slide 8-

8 Express adhesions receptors, Integrins, Adherine, and cellular adhesions molecules
Slide 9-

9 melanoma cells express N-adherine instead of E-adherine. E-adherine allows melanocytes to adhere to keratinocytes, while melanoma cells can not adhere to keratinocytes
Slide 10-

10
Slide 11-

11 B- catenin pathway
Slide 12-

12 Biology- what is new? PTEN pathway = phosphatase and tensin deleted on chromosome 10 → IGF-1 → Akt / PKB (Oncogene)+PtdIns(3,4)P2→ P13 kinase →growth factor + adhesion receptor (integrin)
Slide 13-

13 Biology – what is new? Ras pathway →Grb2/Sos →ras →Raf →MEK 1,2 →MAPK 1.2 →TCF/SRF/Elk-1 →Proliferation As apoptosis is blocked by depriving Bad & Caspase-9 from p13 kinase Apoptosis turned into growth
Slide 14-

Naevi
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15 Nevus Proliferative lesion of melanocytes Scattered along basal layer Acquired - mostly congenital
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16 Naevi : types Lentigo Flat Junctional Compound – slightly elevated Intradermal – papillomatous
Slide 17-

17 Naevi: Lentigo simplex-1 Pigmented macule, <5mm, jet black color In infants & children Melanocytic proliferation along basal layer
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18 Naevi: Lentigo simplex-2 Abundant melanocytes along basal layer Associated with Peutz-Jegher syndrome P-J syndrome = hamartomatous polypes in GIT +naevi in oral & buccal mucosa
Slide 19-

19 Naevi: Junctional Next stage after lentigo Macular lesions, < 7mm Less deeply pigmented than lentigo Homogenous brown black areas Melanocytic proliferation along basal layer Highest malignant potential
Slide 20-

20 Naevi: Compound Next stage of maturation of junctional naevi In children & adolescent Pale brown & papular Junctional + dermal component
Slide 21-

21 Naevi: Intradermal Last stage in maturation Mostly after 30 years of age Flesh colored papule with little pigment Melanocytes confined to dermis only
Slide 22-

22 Blue naevi Benign melanocytic naevi Slate blue color Two types : common & cellular
Slide 23-

23 Common Blue naevi Mostly in scalp & dorsum of hand, feet Dermal collection of spindle melanocytes F > M , max. in 4th decade
Slide 24-

24 Blue naevi: Cellular type Uncommon F > M > 50% in sacrococcygeal area& buttock < 1% under go malignancy Rx : simple excision
Slide 25-

25 Nevus Common Atypical Congenital Spitz Familial
Slide 26-

26 Malignant Melanoma Arises from transformed melanocytes of epidermis Accounts for almost all deaths from skin cancer 4 fold increase in incidence in Australia
Slide 27-

27 Melanoma : Risk Factors-1 Congenital naevi >5% BSA, 1000X Previous melanoma Family history 5 naevi > 5mm (Common nevi) 50 naevi > 2mm (Common nevi)
Slide 28-

28 Melanoma : Risk Factors-2 Dysplastic nevi, Atypical= 2X for single; 12X for >10 Family history Atypical =37-148X Dysplatic naevi syndrome
Slide 29-

29 Melanoma : Risk factors-3 White race, Red hair, Blond hair, Blue eyes Poor tanning ability, Sunburns during childhood Albinism
Slide 30-

30 Melanoma : Risk factors-4 Freckles Equatorial latitude Xeroderma pigmentosa Psoralen sunscreen Tanning salons Junctional naevi
Slide 31-

31 Melanoma : Risk factors-5 Spitz Nevi= benign except when >10 y age +ulceration >1cm Involve subcut fat Mitotic activity >6/mm2
Slide 32-

32 Melanoma : Risk factors-6 Familial syndromes B-K nevus syndromes Atypical nevus CDKN2A mutation CDK4 mutation
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33 DD Pigmented Basal cell CA Seborrheic keratitis Solar lentigines Atypical nevi
Slide 34-

34 MM: Clinical features Lentigo maligna : Hutchinson's freckle (7-15%) Superficial spreading : most common (60-70%) Nodular : 12-25% Acral lentiginous Amelanotic
Slide 35-

35 1. Superficial spreading Melanoma Most common type 70% Occur any where on skin except hands & feet Usually > 5 mm , flat Variegated color pattern Irregular edge with areas of regression Long radial growth phase
Slide 36-

36 2. Nodular Melanoma Most malignant Younger age group Any part of the body raised and always palpable with sharp irregular border Blue, black or gray color Lack of radial growth phase
Slide 37-

37 2. Nodular Melanoma Second most common 15-30 % Rapid onset ♂>♀
Slide 38-

38 3. Lentigo maligna Melanoma Hutchinsons melanotic freckle Least common type 5% Most commonly on face of elderly Begins as irregularly pigmented ,flat, brown macule quite large at the time of diagnosis late invasive growth phase Good prognosis
Slide 39-

39 4. Acral lentiginous Uncommon 1-3% Palm, sole, heel & subungual More common in dark skin persons Subungual –common in big toe or thumb Poor prognosis , 29%@20Y 70% ulcerate, 74% >1.5 mm
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40 4. Acral lentiginous-risk factor >50 y age >3mm width, variegated border Extension of pigment in to nail bed/ nail fold Dark complexioned patient
Slide 41-

41 5. Amelanotic Melanoma Desmoplastic, 1.7% H&N Pink, reveal some pigment on close inspection; Stain+ with S-100 Worse prognosis Often present with regional lymph nodes metastases
Slide 42-

42 5. Amelanotic Melanoma Locally aggressive Known for local recurrences Stain ► S-100
Slide 43-

43 MM : spread Local extension Blood stream : lung, liver, brain, skin Lymphatic : embolisation, permeation satellite nodule in-transit nodule
Slide 44-

44 Controversies in Melanoma Biology Detection-Computer, USG, RT-PCR Staging- AJCC 2000 +Prognosis SLN Biopsy + ELND Surgical margins Adjuvant treatment + Vaccines Summary
Slide 45-

45 MM : Diagnosis Signs of transformation of mole in to MM Major Change in size, shape, color Minor Inflammation, itching Crusting or bleeding > 5mm diameter
Slide 46-

46 MM: Diagnosis A : Asymmetry B : irregular border C : color variegation D : diameter > 5 mm E : enlargement or evolution
Slide 47-

47 Detection- Vision A = asymmetry B = border irregularity C = color variegation D =diameter > 6mm E = elevation, enlargement, evolutionary changes F= any funny change
Slide 48-

48 Detection- Vision Change in size Change in shape Change in Color Inflammation Crusting / bleeding Sensory change > 7mm in size enlargement
Slide 49-

49 Detection- Digital Vision Epiluminescence microscopy Dermatoscopy Surface microscopy Incident light microscopy Can see the dermis, epidermo-dermal junction
Slide 50-

50 Epiluminescence microscopy -ominous signs Melanin pigment network Black dots Globules Streaks Radial streaming Blue-white milky veils Pseudopods Pseudo network Structure less area Melanin reticulum Epidermo-dermal junction Multiple brown dots
Slide 51-

51 Epiluminescence microscopy -good signs Axial symmetry of pigmentation Presence of one color only Sensitivity 92% Specificity 71%
Slide 52-

52 Detection-digital vision Computer based Dermatoscopy Spectrophotometric image analysis Reflectance spectroscopy Computer aided image analysis Topodermatographic USG, MR and OCT = in vivo histology Virtual histology
Slide 53-

53 USG for Regional LN 7.5-20 mhZ for LN : 20-100 for Virtual USG B scan-LN Vassallo index<2 (Long:Trans) Hypoechoic central area Color Doppler-peripheral perfusion USG Guided FNAC +RT-PCR Tyro USG guided anchor wire for mets
Slide 54-

54 Screening Dermatologist or non-Dermatologists?
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55 Screening Dermatologist sensitivity 89% - 97% positive predictive value - 17-75% specificity - 97%
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56 PET vs CT
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57 FDG PET >CT regional and mediastinum lymph nodes abdominal visceral and soft tissue metastasis
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58 Lung mets 87 vs 70 % CT>PET
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59 MRI for brain
Slide 60-

60 A single whole body PET scan could replace all other imaging modalities in melanoma. PET
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61 Cost Limited availability Lack of sufficient data Limitations of PET
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62 Controversies in Melanoma Biology Detection-Computer, USG, RT-PCR Staging- AJCC 2000 + Prognosis SLN Biopsy + ELND Surgical margins Adjuvant treatment + Vaccines Summary
Slide 63-

63 Prognostic factors Tumor thickness = Breslow Vs Level of invasion = Clark level
Slide 64-

64 Thickness vs. Level 54 multivariate analysis of prognostic factors using data from 48 papers Vollmer
Slide 65-

65 Thickness vs. Level Tumor thickness significant in 42 of 54 studies Vollmer
Slide 66-

66 Thickness vs. Level Level of invasion important prognostic factor in only 8 of 48 Studies Vollmer
Slide 67-

67 Thickness vs. Level Tumor thickness 1 , 2, & 4 mm Best for survival data Adopted in 2002 AJCC Buttner Buzaid
Slide 68-

68 Thickness vs. Level- conclusion Clark level of invasion is a minor prognostic factor cutoffs of tumor thickness such as 1mm, 2mm and 4mm provide better prognostic information 2002 AJCC staging of melanoma
Slide 69-

69 Ulceration: prognostic significance Significant prognostic factor Vollmer - multivariate analysis in 7 of 11 studies
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70 Ulceration: prognostic significance strongest predictors of outcome Balch - meta-analysis that included 15,798 patients with localized melanoma
Slide 71-

71 Ulceration: prognostic significance Ulceration has the most significant impact on survival. Buzaid : influence of ulceration according to the tumor thickness
Slide 72-

72 Ulceration Acantholysis Shows autocrine and paracrine pathways are active Adverse prognosis
Slide 73-

73 Ulceration: prognostic significance Independent prognostic factor Included in AJCC 2002 staging Upstage patients compared with those having tumor of same thickness
Slide 74-

74 Satellites vs. In-transit metastases In transit and satellite metastases common manifestations of intralymphatic metastasis associated with poor prognosis
Slide 75-

75 Satellites vs. In-transit metastases prognosis of patient with satellites is usually worse than that of patient with in-transit or nodal metastasis (stage III) Buzaid J Clin Oncol 1997 Haffner Br J Cancer 1992 Cascinelli J Surg Oncol 1986
Slide 76-

76 Satellites vs. In-transit metastases Satellites = pT4b (1997)  N2c / N3 (2002) Stage II  stage III
Slide 77-

77 Lymph node size vs. number-Prognostic value Size not a significant prognostic factor even after stratification according to cutoff size Drepper Cancer 1993 Buzaid J Clin Oncol 1995
Slide 78-

78 Lymph node size vs. number-Prognostic value Number of LN most consistent prognostic factor by multivariate analysis Buzaid J Clin Oncol 1997
Slide 79-

79
Slide 80-

80 Lymph node number-Prognostic value number of positive nodes has replaced size of lymph node mass Current 2002 AJCC staging system.
Slide 81-

81 Lymph node number-Prognostic value N1 = 1 LN N2 = 2 or 3 LNs N3 =  4 LNs AJCC 2002 staging
Slide 82-

82 Prognostic Value of Biochemical & serologic markers Significant prognostic factor in melanoma LDH S-100-B melanoma inhibitory activity serum markers
Slide 83-

83 Prognostic Value of Biochemical & serologic markers After logistic regression analysis, LDH is found to be the only statistically significant marker for progressive disease and the most relevant overall parameter
Slide 84-

84 Prognostic Value of Biochemical & serologic markers AJCC staging 2002 includes LDH Distant metastases + elevated serum LDH = M1c category Two or more reports = > 24 hrs apart.
Slide 85-

85 Prognostic Markers-1 Micro stage Breslow 1,2,4 Clark levels Ulceration Mitotic figures Inflammatory regression Micro satellites Vertical growth fraction Tumor infiltrating lymphocytes Molecular markers Micro staging approaches
Slide 86-

86 Prognostic Markers-2 S phase fraction Mitotic index Ulceration RT-PCR + Tyrosinase or MelanA or MART1 m rna Integrins: β3 subunit of vitronectin-receptor for Vertical growth phase Β1integrin for LN mets
Slide 87-

87 Prognostic Markers-3 MMP-2 ↑=☼ VEGF ↑=☼ Mitf= Microphtalmia transcription factor ↑=☺ CD 40 + =☼ CD 40 L+ CD 40 = worse prognosis
Slide 88-

88 Prognostic Markers-4 Mutation in Codon 12 or 61 of N-ras = ☼ = ↓ OS Mutation in Codon 18 of N-ras exon 1 = ☺ (No mets) Transcription factor = Activator Protein-2=AP-2 Regulates gene in cell cycle and growth control ↓ AP-2= ↓ p21= ↓ RFS & ↓OS
Slide 89-

89 MM : prognostic factors Depth of invasion (BRESLOW) Ulceration High mitotic rate Anatomic location Histologic type Lymphoid & dendritic cell infiltration regression
Slide 90-

90 Depth of invasion in mm: Breslow I  1 II 1-2 III 2-4 IV >4
Slide 91-

91 Depth of invasion : Clark I : superficial to basement membrane II : papillary dermis III : papillary/reticular dermis junction IV : reticular dermis V : subcutaneous fat
Slide 92-

92 Controversies in Melanoma Biology Detection-Computer, USG, RT-PCR Staging- AJCC 2000 +Prognosis SLN Biopsy + ELND Surgical margins Adjuvant treatment + Vaccines Summary
Slide 93-

93 Elective LN dissection Persistent area of controversy Micro metastases in Clinically N-= 14% -20%
Slide 94-

94 Arguments for Elective LN dissection retrospective + prospective studies Goldsmith Memorial hospital 1552 patients 5 yr survival 78% vs. 68%
Slide 95-

95 Melanoma Inter-group Trial 1996 700 patients Prospective study Significantly improved survival rates with ELND in a subgroup = <60 years, non-ulcerated 1-4 mm Balch : Ann Surg 1996
Slide 96-

96 Balch Cancer 1979
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97 Survival advantage ? Positive nodes after ELND 16% Slingluff Ann Surg 1994
Slide 98-

98 Elective LN dissection: no benefit
Slide 99-

99 Elective LN dissection: benefit
Slide 100-

100 ELND or Sentinel LN biopsy ?
Slide 101-

101 Sentinel Lymph Node Biopsy Sensible approach In view of low occult metastasis - 12-15% ; It allows upto 85% of patients with melanoma to be spared a formal lymph node dissection, thus avoiding complication associated with that procedure
Slide 102-

102 SLN biopsy 100% sensitive 97% specific Pu Plast Reconstruct Surg 1999
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103 No decrease in survival compared with patients undergoing ELND Therapeutically equivalent but prognostically more accurate than ELND Essner Ann Surg Oncol 1999
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104 SLN Indications: 5-10% risk of mets to Node Candidate for High dose interferon alfa-2b Melanoma < 1mm thickness but Clarke level III or ↑ (10% risk of recurrence)
Slide 105-

105 Primary tumors between 1mm and 4mm thickness up to 45% incidence of occult nodal metastases
Slide 106-

106 SLN: Contraindication-1 < 1 mm thickness melanoma (< 2% N or M) > 4mm thickness melanoma, Clinically N- (as 60-70% N & occult M 70%)
Slide 107-

107 SLN: Contraindication-2 FNAC + LN Prior wide excision of primary
Slide 108-

108 SLN Micromets: Significance Gershenwald 1999 J Clin Oncol +SLN= 23% rec rate; 16% death rate - SLN=9% recurrence rate, 35% death Clary 2001, Ann Surg 233:250-258 +SLN=40% recurrence, 58%DFS@3y -SLN=14% recurrence, 75%DFS@3y
Slide 109-

109 SLN Micromets: Significance Short term DFS ↑ : HE-, IH-, RT PCR+ Short term DFS ↓ : HE-, IH-, RT PCR+
Slide 110-

110 SLN
Slide 111-

111 Blue dye for SLN Patent blue V & Isosulfan blue Anaphylaxis in 3 / 406 cases Incidence with Isosulfan blue =1% Prepared for anaphylaxis treatment
Slide 112-

112 Blue dye for SLN 2-5 ml of 1% Isosulfan blue into the dermis (not sub cut) around the intact tumor + Exercise+ 5-15 minutes wait Clears from SLN within 45 minutes
Slide 113-

113 Isotope Tc 99m labeled sulfur colloid 100 μm filtered Tc 99m labeled sulfur colloid- even better 99m Tc DTPA mannosyl-dextran → affinity for lymph node; avoid distal lymph node imaging 3 hours prior injection, intradermally around the tumor
Slide 114-

114 Isotope Allows dissection down to the LN without need to create flaps Keep hand held array at an angle= avoid “Shine Through” If ↑ 3:1 resection bed : background ratio = search more SLN
Slide 115-

115 SLN H/E stain Immunohistochemistry to S-100 protein, HMB-45 antigen, RT-PCR Tyrosinase, Mel A 14% are HE – and + by IH 20-30% are HE-, IH- but RT-PCR+ Cell culture technique
Slide 116-

116 Controversies in Melanoma Biology Detection-Computer, USG, RT-PCR Staging- AJCC 2000 +Prognosis SLN Biopsy + ELND Surgical margins Adjuvant treatment + Vaccines Summary
Slide 117-

117 In situ 5 mm <2mm 1cm >2mm 2cm Sober AJ : J Am Acad Dermatol 2001 Current recommendations for surgical margins: primary cutaneous melanoma : thickness based decision
Slide 118-

118 Diameter, Location & Surgical Margins : Zitelli 1997
Slide 119-

119 Surgical margins No significant difference in survival for excision margin 2 cm or 4 cm for tumor between 1mm and 4mm Balch Ann Surg 1993
Slide 120-

120 Tumor thickness =1-2 mm Margin 1cm or 3cm OS same Margin: WHO Melanoma group
Slide 121-

121 No significant difference in survival for margins 2 or 5 cm for tumors between 0.6 mm to 2mm Swedish melanoma group. Cancer 1998 Margin 2 or 5 cm
Slide 122-

122 Mohs Micrographically controlled Surgery In situ fixation- earlier by ZnO Now micrography-sectioned and inked and oriented=mapped
Slide 123-

123 Controversies in Melanoma Biology Detection-Computer, USG, RT-PCR Staging- AJCC 2000 +Prognosis SLN Biopsy + ELND Surgical margins Adjuvant treatment + Vaccines Summary
Slide 124-

124 No Role of prophylactic (adjuvant) Isolated Limb Perfusion
Slide 125-

125 EORTC WHO North American Perfusion Group No improvement in survival Isolated Limb Perfusion
Slide 126-

126 Therapeutic isolated limb perfusion Better DFS No significant change in OS Hafstrom J Clin Oncol 1991
Slide 127-

127 Who are candidates for ILP?
Slide 128-

128 Therapeutic Patients with in transit disease confined to a limb, with no signs of distant metastases at presentation.
Slide 129-

129 Drugs for ILP DTIC + Others Melphalan +others TNF ά Interferon
Slide 130-

130 Palliative Bulky regional disease with limited systemic metastases
Slide 131-

131 identified by prognostic factors or identified by sentinel lymph node biopsy. Clark : J Natl Cancer Inst 1989 Adjuvant Indications: ↑risk for metastatic disease
Slide 132-

132 High risk melanoma: Interferon Thickness >4mm Mitotic index Location Gender Ulceration +SLN AP-2 index
Slide 133-

133 Interferon 2b √ US FDA for high risk melanoma ↓Recurrence Interferon alpha2b ▲DFS , ▲ OS by EOCG HDI 1684, EOCG1690 and French LDI Grob 2000- in selected cases
Slide 134-

134 high dose interferon alpha 2b tamoxifen, cisplatin, and Vindesine GM CSF Levamisole. Adjuvant ?
Slide 135-

135 TNF Interleukin-2 Biochemotherapy Cytokines Ab3 Peptide based vaccines MAGE tumor specific shared ag Adjuvant ?
Slide 136-

136 What are New Options Biochemotherapy DTIC or temozolomide+Nitrosureas Interferon = antiproliferative and immunomodulatory Interleukin-2 =Immunostimulatory cytokine ►NK cells
Slide 137-

137 Vaccines Vaccines-ganglioside GM2 MAGE Tumor specific antigens Ab3 a cytokine Antibody based vaccines HLA based Cell based vaccines Peptide vaccines Recombinant viruses
Slide 138-

138 Controversies in Melanoma Biology Detection-Computer, USG, RT-PCR Staging- AJCC 2000 +Prognosis SLN Biopsy + ELND Treatment margins Adjuvant treatment + Vaccines Summary
Slide 139-

139 Major changes in AJCC classification in 2002 -1 √ Thickness X not levels √ Ulceration √ Number of LN X size of LN √ LDH
Slide 140-

140 Major changes in AJCC classification in 2002-2 √ Upstaging with ulceration √ Merge micro satellite & in-transit mets into stage III √ Include SLN into staging
Slide 141-

141 Major changes Ultrasound of LN RT-PCR Tyrosinase of SLN 1→ 106–109 Detect 1 cancer cell out of 106 – 109 normal cells Thin margins Adjuvant interferon +/-
Slide 142-

142 In situ 5 mm <2mm 1cm >2mm 2cm Sober AJ : J Am Acad Dermatol 2001 Current recommendations for surgical margins: primary cutaneous melanoma
Slide 143-

143 Summary No role of wide margins No role of ELND No role of Prophylactic ILP Role of SLN Interferon alpha2b ▲DFS , ▲ OS → EOCG HDI 1684, EOCG1690 & French LDI Grob 2000- in selected cases
Slide 144-

144 Summary Rx Primary surgical Surgical principles Complete surgical excision Minimum margin 1.0 cm Maximum margin 2.0 cm Do not excise beyond deep fascia
Slide 145-

145 MM :– management of lymph nodes Biopsy : FNAC preferred Elective dissection : for Clinically involved nodes, Satellitosis, Lymphatic invasion
Slide 146-

146 Sentinel lymph node biopsy Detects micrometastasis in lymph nodes Inrtadermal injection of radioactive colloid around lesion Lymph node identified by gamma probe
Slide 147-

147 Sentinel lymph node biopsy Intraoperative identification by using patent blue dye Identify patients appropriate for elective dissection Identify patients among high risk for adjuvant interferon.
Slide 148-

148 Thank You