Malignant Melanoma Diagnosis & Treatment (2018_10_02 00_06_35 Utc).docx

Malignant Melanoma: Qs: 2016 (part of essay Q) - Write short notes on malignant melanoma 2015 (part of essay Q) - Write short notes on sentinel node mapping in Melanoma 2014 (SAQ) - Describe the role and use of sentinel lymph node biopsy in malignant melanoma 2013 (SAQ) - Write short notes on Breslow thickness in Melanoma 2012 (part of essay Q) - Write short notes on clinical signs in Malignant Melanoma 2011 (part of essay Q) - Write short notes on sentinel node biopsy in Melanoma ________________________________________________________________________________________________________________________________________________ Epi:  F>M, 1.5:1  3% of all cancers, 1% of all cancer deaths!  Increasing in incidence ________________________________________________________________________________________________________________________________________________ Features: ABCDE A= asymmetry B= borders (irregular) C = colour (non-uniform) D= diameter (>6mm) E= evolving/elevated These are part of a campaign to raise awareness about Melanoma. ________________________________________________________________________________________________________________________________________________ RFs: 

Sunlight/UV exposure: o Sunburn. o Intense exposure in early years. o Use of tanning beds (WHO “Group 1” carcinogen – 75% increase in melanoma risk).  ^ age  Fair skinned (low Fitzpatrick skin type) & blonde/red hair/blue eyes. o Fitzpatrick skin type I-VI : amount of melanin pigment in skin. Determined by constitutional colour and result of UV exposure.  High number of common naevi/dysplastic naevi (precursors) o note: <10% melanomas develop from a pre-existing nevus  Positive family history: o Melanocortin-1 receptor. o CDKN2A ---> Familial atypical multiple mole melanoma (FAMMM) syndrome o CDK4. o MCR1R.  Previous melanoma (x10 risk increase).  Immunosuppression.  Previous RT.  Xeroderma Pigmentosum: Autosomal Recessive genetic disorder of DNA repair (can't repair damage from UV light)  Albinism. _________________________________________________________________________________________________________________________________________________ Classification: 1. Superficial spreading (80%)  irregular borders and colour variation  commonest in Caucasians  grows slowly and metastasizes late ---> better prognosis 2. Lentigo Maligna Melanoma  elderly patients  occurs on face or scalp 3. Acral Lentiginous  Asians/blacks  Palms, soles, subungual (Hutchinson's sign +ve - melanonychia) 4. Nodular Melanoma  All sites  Younger people, new lesion

5.

 Invades deeply and metatasizes early --> poor prognosis Amelanotic  Atypical appearance - delayed diagnosis

________________________________________________________________________________________________________________________________________________ Diagnosis & Staging:  ABCDE + Seven point checklist: One major / 3 minor. o Major features:  Change in: Colour / size / shape. o Minor features:  Inflammation.  Bleeding/crusting.  Sensory change.  Lesion >/= 7mm in diameter. 

Complete excisional biopsy necessary to determine level and thickness. o NOT PUNCH BX --> don't want to breach --> spread

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Melanoma usually arises in epidermis and spreads out before vertical growth pattern. o Breslow: From stratum granulosum down to maximum tumor depth.  (More helpful for prognosis vs Clark.)  T1: <0.76mm.  T2: 0.76 – 1.5mm  T3: 1.51 – 4mm.  T4: >4mm. o Clark Level: (not really used anymore)  I: Only epidermis.  II: Part of upper dermis.  III: All of upper dermis.  IV: Lower dermis.  V: Subcutaneous tissue.

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SLNB: Early LN & systemic blood borne mets ---> liver and eye o Rationale:  Accurate staging – allows a more rationale F/U strategy.  Prognostic indicator: FYS for patients with nodal micrometastases is 67% & with macrometastases is 43%. (useful for stage II and above).  Better locoregional control:  Complication rates of SLNB vs. lymphadenectomy: 4.6% vs. 23.2%.  By identifying micromets (through SLNB) patients are less likely to require RT to the nodal basin & thus a lower chance of lypmhoedema.  Impacts adjuvant therapy:  Accurate nodal staging important in order to offer patients enrolment in clinical trials.  Marginal benefit of IFN. o To date there is no definitive evidence that SLNB, followed by lymphadenectomy for +ve nodes, confers survival benefit. o MSLT-1:  WLE + SLNB (with CLND - complete lymph node dissection if +ve) vs. observation (with TLND for clinically node +ve).  F/U for 5 years.  No difference in OS.  Incidence of lymphoedema was less in the immediate vs. delayed CLND.  Subgroup analysis in SLN+ve patients:  Better FYS in SLNB+ve + CLND vs. those who had TLND - therapeutic lymph node dissection (72% vs. 52%). o In patients with an intermediate thickness melanoma, therefore may be of benefit to have a CLND in this group. o But no survival benefit if <1mm or >4mm.  Results from MSLT-1 have validated SNB as a minimally invasive diagnostic & staging procedure.  Can assess the regional nodes in primary melanoma with 95-95% accuracy.  Identifies the 15-20% of patients with nodal mets that are candidates for immediate lymphadenectomy.  Identifies the 80-85% who don’t have mets and don’t need dissection. o MSLT-2:

SLN+ve to CLND vs. SLN+ve to US observation (can pick up mets as small as 4mm in the regional nodes).  CLND is standard for a patient with a +ve SLNB, however MSLT-1 data showed that 88% of patients with a single tumor-containing sentinel node will have no additional nodal metastases on CLND (in accordance with theory of sequential metastases) – Incubator hypothesis:  Primary melanoma sends immunosuppressive factors to the sentinel node, these signals foster a nodal microenvironment that favors the growth of tumor cells, which subsequently spread to nonsentinel nodes and then to distant sites (sequential).  MSLT-1 also suggests that if nodal metastases are limited to one or two sentinel nodes then SNB might be therapeutic as well as diagnostic – MSLT-2 was designed to examine this possibility.  Primary outcome is melanoma-specific survival. o Technique: 1. Intradermal injection of a radiotracer around the melanoma lesion. 2. Intradermal injection of blue dye at site of lesion. 3. Massage of lesion for 4-5 minutes to facilitate drainage. 4. Use of gamma-probe to identify hot-spots. 5. Incise over hot spit. 6. Visually search for blue nodes. 7. Removal of any nodes with significant radiotracer activity. 8. Send nodes to pathology. 9. After this continue with WLE of primary lesion – close with a primary closure, split-thickness skin graft or flap closure. o Pathology:  Immunohistochemistry:  S-11: 95% sensitive.  HMB-45: 90% sensitive.  MAGE-1.  CLND H&E:  Misses 12% of positive nodes.  Mutational analysis: done if SNB+ve  BRAF V600.  CKIT. o Imaging:  SLN-ve, depth <2mm: Not recommended.  >2mm depth: CT –TAP for 3-6 months.  SLN+ve: CT-TAP/MRI brain/PET.  Metastatic/recurrent disease: PET-CT. _________________________________________________________________________________________________________________________________________________ 

Treatment:  Surgical: o Excise (typically elliptically) with a margin:  <1mm depth: 1cm margin.  1-4mm: 2cm margin.  >4mm: 3cm margin. o May need a graft depending on size of lesion o Distant metastases:  Potential role for isolated metastectomy.  Adjuvant therapy: o Indications:  SLN+ve.  In-transit / satellite metastases.  Metastatic disease.  Recurrent disease.  Unknown primary melanoma. o CTX:  Novilumab (preferred) - targets PD1  Ipilimumab (antibody to CTLA-4).  Pembrolizumab - targets PD1 ligand  Dabrafenib / Varumafenib (if BRAF V600+ve).  IFN-2a (one year improved DFS but no OS).  IL-2 (recurrence).  MEK-I: Tremetinib. o RT:  Indications:

 Gross residual disease.  Extracapsular nodal extension.  >3 nodes involved.  LN >3cm.  CLND not possible after a +ve SLNB.  Metastatic disease. _________________________________________________________________________________________________________________________________________________ F/U: 5 years for all  Every 4 months for first 2 years  then minimum 6/12 "Bespoke f/u"- examine lesion and relevant lymph node basin _________________________________________________________________________________________________________________________________________________ Prognosis:  Depends on: o Thickness. o Nodal status. o Metastases.  Poor prognostic indicators: male (more tumours on trunk vs females), ^ mitoses, satellite lesions, ulceration  Prognosis: (FYS) o Localised disease: 90%. o Regional metastases: 10-13%. o Distant metastases: 2-5%. _________________________________________________________________________________________________________________________________________________ ___________________________________________________A BIT ON SCCs AND BCCs________________________________________________________________ 1.

Squamous Cell Carcinomas  

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 2.

Def: ulcerated lesion typically on sun-exposed areas with hard raised everted edges Causes: o Sun exposure o May arise in chronic ulcers --> Marjolin's ulcer o Xeroderma pigmentosa Evolves: solar/actinic keratoses --> Bowen's --> SCC o Actinic keratoses:  irregular crusty warty lesios  Pre-malignant (approx 1% p/year transformation rate)  Rx: Cautery, Cryo, 5FU, Imiquimod, Photodynamic phototherapy o Bowen's disease:  Red/brown scaly plaques  SCC in situ  Rx: as for AKs Metastases are rare

Basal Cell Carcinomas    

Commonest cancer Def: pearly nodule typically on sun exposed areas with telangiectactic edge, may ulcerate o above line from tragus to angle of mouth Low grade but locally invasive Rx: excision (Mohs), cryo/radio may be used