CHAPTER 07 : SKIN Flashcards
What is a neoplasm?
What is a malignant neoplasm?
What is a harmartoma?
A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and which persists in the same excessive manner after cessation of the stimulus which evoked the change.
A malignant neoplasm is one that invades surrounding tissues and has a propensity to metastasise.
Hamartoma = a developmental anomaly resulting in the formation of a mass composed of tissues normally present in the locality of the mass, but of improper proportion and distribution with dominance of one type of tissue
What is the aetiology of neoplasms?
Initiation = change in the genome of the cell Promotion = change made permanent by cellular division (initiators and promoters include UV and ionising radiation, chemical carcinogens, viruses) Progression = further cell division to form an invasive tumour.
Inappropriate activation of proto-oncogenes to become oncogenes – these proto-oncogenes encode growth factors, growth factor receptors or transcription factors
Inactivation of other cellular genes – tumour suppresser gene mutation:
o P53 tumour suppressor gene is mutated in the majority of human cancers
What is a BCC?
BCC is a malignant tumour of cells derived from the basal layer of epidermis
A malignant tumour of cells derived from pluripotential cells of the epidermis or outer root sheath of hair follicles
most common skin tumour in Caucasians (lifetime risk 23-39% of Whites in US)
What are the risk factors for BCC?
HOST FACTORS
Genetic, skin type, precursors, immunological
ENVIRONMENT
UV, radiation, chemicals
Name the Fitzpatrick skin types
Type 1 → White skin never tans – always burns
Type 2 → Pale skin - burns on exposure – usually burns
Type 3 → Light skin which will tan – may burn
Type 4 → Mediterranean complexion – rarely burns
Type 5 → Indian Complexion – rarely burns
Type 6 → Black skin – rarely (?never) burns
What aetiological factors are associated with BCC?
UVB actinic damage chronic wounds (Marjolin's ulcer) Chemicals - polycyclic aromatic hydrocarbons, arsenicals, nitrogen mustard Immunosuppression - 50-100x risk Malignant transformation of Sebaceous naevus of Jadassohn 10-15% transform into BCC, trichoblastoma and adnexal hamartomas Rhinophyma - 10% have underlying BCC
What genetic diseases are associated with BCC?
Gorlin’s syndrome (basal cell naevus syn)
- AD
- assocd with palmar pits frontoparietal bossing, overdeveloped supraorbital ridges, odontogenic keratocysts of jaw, sebaceous cyst, abnormal ribs and vertebrae, dural calcification (falx cerebra), high arched palate, learning difficulties
Xeroderma pigmentosum
- AR
- primary deficiency of endonuclease enzyme
- unable to repair UV damaged DNA
Albinism
What is a high risk BCC?
- Poorly defined margin
- Recurrent disease
- > 6mm diameter mask area
- > 10mm diameter cheeks, forehead, scalp, neck
- > 20 mm diameter trunk and extremities
- Morphoeic, sclerosing, infiltrative, micronodular
- Immunosuppressed
- Perineural involvement
What are the histological types of BCC?
1. Localised Nodular 50% Nodulocystic Micronodular Pigmented 2. Superficial / Multifocal 10% 3. Infiltrative Morpheaform (=sclerosing/fibrosing) 2% undefined (10%) Basosquamous
What are the clinical features of BCC?
85% H&N danger areas - periorbital, ear, nl fold pinkish pearly nodules, rolled edges, telangectasia, central ulcer, may be pigmented longstanding tumours invade deep 200+ recorded cases of mets
Histology - atypical cells arranged in palisades and well organised surrounding stroma
What is the treatment for BCC?
Telfer's paper 2008? SURGICAL EXCISION excision margins 2-5mm 3mm = 85% clearance 4mm = 95% Morphoiec 15mm = 95% clearance
30-40% incomplete margins recur
residual tumour found in 45-54% re-excision of incompletely excised lesions
embryonic fusion line areas more prone to deep invasion - medial canthus, EAM, alar base
Recurrence rates 4.5%
Other Rx (cure rate)
EFUDIX
DXT 92%
CRYOTHERAPY
CURETTAGE AND CAUTERY 75%, up to 95% for selected small tumours
PDT - aminolevulinic acid cream = sensitiser
tumour cells convert this to photoactive porphyrins
6hrs later - laser / red light - destroys tumour cells
painful, only Rx tumours
MOHS MICROGRAPHIC 99%
(INTRALESIONAL INTERFERON / BCG)
When is Moh’s micrographic surgery indicated? (US)
areas with high recurrence rate poorly delineated / arising within scar tissue >2cm / aggressive malignant features morphoeic / sclerosing BCC impt areas to preserve uninvolved tissue eg eyelid SCC w perineural invasion microcystic adnexal ca DFSP desmoplastic MM recurrent BCC
How is Moh’s surgery performed?
- debulk tumour
- saucer shaped disk of tissue is excised, oriented, mapped, sectioned and placed on slides for microscopic examination (H&E stain)
- remaining tumour is removed only from the mapped site
What topical therapies are there for non-melanoma skin cancers?
Imiquimod (Aldara)
Imiquimod - Aldara (3x/wk for 4 wks)
- activates host immunity against tumour cells, leading to anti-tumour cytotoxic T cell response
- immuno-enhancing drug
- toll-like receptors on macrophages, Langerhans cells and dendritic cells are activated and upregulates Th1 lymphocyte mediated immune response, releasing cytokines that are tumorcidal
- 5% licensed for biopsy-confirmed superficial BCC >2cm diameter
- curettage then imiquimod may improve its efficacy
- metanalysis showed higher efficacy for Rx of AK and BCC (89-93% treated)
Side effects - local
erythema, erosion, ulceration, dyschromia (hyper hypopigmentation). (systemic - rare flu-like symptoms)
AK - 5 days/wks 4wks
BCC - 5 days/wks 6wks
5 - Fluoruracil (Efudix)
Diclofenac (Solaraze)
5-FU (BCC bd for 3wks, Bowen’s 5 days/wk for 3wks)
incorporated into RNA and inhibits DNA formation by covalent bonding
This blocks thymidylate synthase, DNA and protein synthesis is halted leading to necrosis
Side effects - erythema, erosion, ulceration, delayed wound healing esp lower limbs elderly
Diclofenac - Solaraze
3% diclofenac with hyaluronic acid
inhibit COX2, may inhibit neoplastic cell proliferation by inducing apoptosis
What other treatments are there for NMSCs?
5FU and Imiquimod 75-80% for superficial BCCs
Radiotherapy 96%
- Fractionated, 10 sessions over 2wks
- Very good results esp lower eyelids (globe protected with lead shield)
Photodynamic therapy 82%
- involves use of light source to activate a compound (photosensitizer) within malignant cells.
- Compound then transfers energy to molecular oxygen and destroys tumour cells.
ALA - aminolevulinate
MAL - methyl-ALA
Electrodessication and Curettage 70% (80-90% in appropriately selected pts)
Cryotherapy
- reported up to 96% efficacy
Laser
Moh’s micrographic surgery 99%
Chemical Peels - for precancerous conditions
- iatrogenic creation of cutaneous wound, chemical escharotic that damages the epidermal and dermal layers for therapeutic purposes and allow collagen remodelling and reepithelialisation
Intralesional methotrexate, interferon, 5FU, bleomycin
How does radiotherapy for NMSCs work?
Indications
Elderly pt not fit for surgery
Cosmetically sensitive areas eyelids, canthi nose, ears, lips
Young pts more likely to suffer effects of radiotherapy induced skin cancers later in Iife
Relatively painless,
superficial XR or electrons fractionated over 10 sessions in 2wks
Side effects - erythema, soreness, ulcerate, crust, pale atrophic, patchy, telangectasia on skin in longterm
How is PDT administered?
5 aminolaevulinate cream
Methyl-aminolaevulinate cream
Applied to lesions and cover with occlusive dressing for 4hrs
Dysplastic cells preferentially take this up and an excess of intracellular protoporphyrins result, which is an endogenous photosensitiser
Red light is shone and this activates the protoporphyrins
Highly reactive free radicals are produced and this leads to cell death
What is SCC?
Malignant tumours of cells originating from stratum spinosum of epidermis
occurs in skin w
- AK, keratin horn, leukoplakia, Bowen’s, chronic wound
Histo - dysplstic epidermal keratinocytes extend down through bm into dermis (invasion)
well, mod, poorly differentiated
Poor prognosis if
- depth of invasion
- vascular invasion
- perineural invasion
- lymphocytic infiltration
What are the different types of SCC?
Verrucous
ulcerative
variants
spindle cell
verrucous ca
keratoacanthoma
little prospective evidence of excision margins
usu b/t 5mm - 1cm depending on site
What is the commonly quoted paper for SCC and what are the recommended excision margins?
Multiprofessional guidelines for the management of the patient with primary cutaneous squamous cell carcinoma. Brit J Dermatol 2002
High risk
Location - ear, lip, nose, eyelids, scalp
Diameter - 2cm+ are twice as likely to recur locally and 3x more likely to metastasise than smaller tumours
Depth of invasion - 4mm+ (45% incidence of mets)
Histological differentiation - poorly differentiated and perineural involvement
Host immunosuppression
Low risk = 4mm
High risk = 6mm
What is malignant melanoma?
malignant tumour of epidermal melanocytes
with invasion into dermis
How is MM classified?
SNALAD
Superficial spreading (60%)
Nodular (30%)
Lentigo maligna melanoma (7%)
Acral lentiginous (2-8%) (Subungal - Hutchinson’s sign)
Amelanotic (1-3%)
Desmoplastic (spindle cell, neurotropic) (<1%)
What is Spitz naevus?
juvenile melanoma
histologically looks like melanoma
but clinically looks benign, treated as benign
What is the epidemiology of melanoma?
<5% of skin cancer cases 75%-90% of all skin cancer mortalities UK 6/100,000 Commonest cancer of young adults Lifetime risk 0.5% F:M 2:1
Tell me about the mutation of BRAF oncogene.
- Mutations in the BRAF gene allow for BRAF to signal independently of upstream cues,
and results in overactive downstream signaling. - This leads to excessive cell proliferation and survival, independent of growth factors
Oncogenic BRAF has been implicated in: ~50% of melanoma tumors ~40% of papillary thyroid tumors ~30% of serous ovarian tumors ~10% of colorectal tumors ~10% of prostate tumors
Vemurafenib is an orally available, selective BRAF (V-raf murine sarcoma viral oncogene homolog B1) inhibitor for patients with unresectable or metastatic melanoma that tests positive for the BRAF V600E mutation
What is the aetiology of melanoma?
Risk factors PPARENTS Premalignant lesions (giant CMN, acquired MN, dysplastic naevi, lentigo maligna) Previous melanoma (3-5% of 2nd) Age Race Economic status (higher 3x risk) atypical Naevus syndrome (>100 atypicals) Fitzpatrick Type skin 1&2 Sunburn
What genetic factors predispose to MM?
FHx (5-12% have +ve FHx)
1st degree relative 1.8 RR
BRAF proto-oncogene mutation (assoc w papillary thyroid ca, colorectal ca, non-small cell lung ca, leukaemia
tumour suppressor genes, oncogenes CDKN2A gene mutation (regulates cell cycle during G1 checkpoint)
dysplastic naevus syndrome (Familial atypical multiple mole melanoma FAMMM
xeroderma pigmentosum
Pigmented lesion: ?melanoma, what are the differential diagnoses?
Acquired melanocytic naevus, dysplastic
dermal melanocytoses
pigmented BCC, basal cell papilloma, blue naevus, AK
pyogenic granuloma (amelanotic), SCC
How is MM diagnosed?
Glasgow 7-point checklist (Mackie)
Major (SSC - Size, Shape, Colour)
1 Change in size
2 Irregular shape (esp. SSM and LMM not nodular)
3 Irregular colour
Minor (DISC diameter, Inflammation, sensory, crusting /bleeding)
4 Over 7mm
5 Inflammation
6 Oozing
7 Altered sensation/itch
Any major or any 3 minor = suspicious - biopsy whole lesion with 2mm margin
American ABCD System: A = asymmetry B = border irregular C = colour more than 1 D = diameter over 6mm E = elevation (late feature) Plaster on mole = bad sign
WHAT IS THE MINIMUM DATASET FOR MM REPORTING?
Specimen (site)
Specimen type (excision, incisional (etc)
Gross description (size, max diameter, nodule, border, pigmentation)
Histology (LM, SS, nod, AL, desmoplastic, neurotropic, other)
Growth phase (insitu, invasive, radial, vertical)
Breslow thickness mm Clark level ulceration lymphatic / blood vessel invasion perineural invasion regression microsatellites co-existent naevus mitotic rate tumour infiltrating lymphocytes
Excision margins
deep and peripheral
Pathological staging TNM
What tumour markers are there for MM?
check
H&E staining - older, more crude
newer
FISH - fluorescent in situ hybridisation
genomic hybridisation
Tyrosinase (PCR)
S-100 – detects progression
TA-90 – risk of mets
HLA-DQB1*0301 – experimental, identifies metastasis prone pts
How is Breslow depth measured?
How is Clarks level measured?
from granular layer to deepest melanoma cell Clark 1969 I epidermis II into papillary III all papillary IV invasion of reticular V invasion of sc fat
what is the 5 year survival rate according to stage?
Stage Ia: 95%, Ib: 90%
Stage IIa: 80%, IIb: 65%, IIc: 45%
Stage IIIa: 65%, IIIb: 50%, IIIc: 25%
Stage IV: 8%
How is tumour thickness classified?
TX - Primary tumor cannot be assessed (shave biopsy, regressed primary)
Tis - Melanoma in situ
T1 - ≤1.0 mm (a: without ulceration, b: with ulceration)
T2 - 1.01-2.0 mm (a: without ulceration, b: with ulceration)
T3 - 2.01-4.0 mm (a: without ulceration, b: with ulceration)
T4 - < 4.0 mm (a: without ulceration, b: with ulceration)
What is the N and M classification of melanoma?
N classification is as follows:
N1 - 1 lymph node; a: micrometastasis (clinically occult), b: macrometastasis (clinically apparent)
N2 - 2-3 lymph nodes; a: micrometastasis, b: macrometastasis, c: in transit met(s), satellite(s), without metastatic lymph nodes (N2a: 2-3 nodes positive for micrometastasis; N2b: 2-3 nodes positive for macrometastasis; N2c: In transit met(s) or satellite(s) without metastatic nodes)
N3 - 4 or more metastatic nodes or matted nodes or in-transit metastases or satellite(s) with metastatic node(s)
Note that micrometastases are diagnosed after elective or sentinel lymphadenectomy. Macrometastases are defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or when nodal metastasis exhibits gross extracapsular extension.
M classification is as follows:
M1a - Distant skin, subcutaneous, or nodal metastases, normal lactate dehydrogenase (LDH) level
M1b - Lung metastases, normal LDH level
M1c - All other visceral metastases or any distant metastases with an elevated LDH level
How is MM staged?
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
What is the evidence of excision margins for primary melanoma excision?
*1.0-cm margin for primary melanomas less than 1.0 mm in thickness.
(Diagnosis and treatment of early melanoma. NIH Con- sensus Development Conference. January 27–29, 1992. Consensus statement/NIH Consensus Development Conference 1992)
*1.0-cm margin may also be effective for lesions up to 2 mm in thickness.
Veronesi U, Cascinelli N, Adamus J, et al. Thin stage I primary cutaneous malignant melanoma: comparison of excision with margins of 1 or 3 cm. N Engl J Med. 1988
*1.0 - 2.0 cm margins are commonly used for lesions between 2 and 4 mm in thickness.
*2.0-cm margin may be most appropriate for melanomas 4 mm or more in thickness.
Balch CM, Urist MM, Karakousis CP, et al. Efficacy of 2cm surgical margins for intermediate-thickness melanomas (1–4 mm): Results of a multi-institutional randomized surgical trial. Ann Surg. 1993
Heaton KM, Sussman JJ, Gershenwald JE, et al. Surgical margins and prognostic factors in patients with thick (>4 mm) primary melanoma. Ann Surg Oncol. 1998
*Margins greater than 2.0 cm do not appear to contribute significantly either to survival or local control
Heaton (as above)
McKinnon JG, Starritt EC, Scolyer RA, et al. Histopathologic excision margin affects local recurrence rate: analysis of 2681 patients with melanomas < or =2 mm thick. Ann Surg. 2005
Evidence for melanoma excision margins
WHO Trial - Veronesi et al (NEJM 1988) - Thin MM
For melanomas less than 2 mm there was no difference in survival between 1 and 3 cm excision however 3 patients with 1cm excisions had local recurrence vs. none with wider excision.
Balch et al (Ann Surg 1993) - Intermediate to Thick
For intermediate thickness melanomas 1-4 mm there was no difference between 2 and 4 cm excision margins.
Karakousis (Ann Surg Oncol) also found that 2 cm margins were as effective as 4 cm in local
control of intermediate thickness (1-4 mm) melanoma
UK melanoma study group/BAPS trial (Meiron Thomas 2004) - Thick MM
1cm v 3 cm in 2mm or thicker MM
1 cm margin is assoc with greater risk of local recurrent but NO different in overall survival at 60 months.
Heaton et al. (Ann Surg oncol 1998) found that there was no difference between excisional margins of < 2 cm and > 2 cm in thick lesions but this was a retrospective study.
What is the evidence for excision margins?
WHO trial (Veronesi 1988)
- thin MM 2mm
- 1cm vs 3cm excision margins
- 1cm: greater risk of local recurrence
- no survival benefit at 60mths
Heaton (1998) retrospective
- thick lesions
- no diff b/t 2cm excision margins
Gillgren Scandinavian study 2011 Lancet
- 936pts
- > 2mm (Clinical stage IIA-C)
- 2 cm vs 4cm excision margins
- There was no significant difference in overall survival (65% in both groups; P = .69) or recurrence-free survival (56% in both groups; P = .82) between the 2 approaches at 5 years
What evidence is there for ELND for stage II?
Veronesi WHO trials (1998) - no survival benefit
The sentinel node biopsy debate in MM
SNB only investigation that upstages from II-III or clinically palpable nodes MSLT-1 trial (Morton et al 2006) - 1.2 - 3.5mm - SLNB vs watch and wait - provides prognostic indicator - SLNB +ve proceed to CLND - 6% survival benefit
What investigations are there for stage II disease?
SLNB if offered
CXR
CT
liver USS
What is the clinical staging and 5 year survival of MM?
clinical staging
0 Tis
IA T1a 95
IB T1b or T2a 90
IIA T2b or T3a 80
IIB T3b or T4a 65
IIC T4b 45
III Any T, N+, No M (clinical)
IIIA no ulceration N1a or 2a 65
IIIB ulcerated N1a or b 50
no ulceration N1b/2b/2c
IIIC ulcerated N1b/2b/2c 25
ulc / no ulc N3
IV Any M 8%
What is the management of Stage III melanoma?
IIIa - SLNB positive microscopic disease
IIIb - clinically palpable macroscopic disease
IIIc - intransit mets
Pts with clinical stage III and pathological IIIB are given high dose interferon in most units
MSLT 2 trial - looking at +ve SLNB - immediate CLND or watch and wait.
Veronesi WHO - 2 prospective trials showed no benefit
Balch (1996) and Cascinelli (1998) found benefit in immediate CLND
What is the manangement of Stage IV melanoma?
Chemotherapy - 15% response Immunomodulatory agents (high dose interferon, cisplatin, IL2) - marginal effect on survival Radiotherapy (local, cerebral mets) ANTI CTLA4 AB TRIALS Tremelimumab IgG2 & Ipilimumab
What treatment is there for Stage IV MM?
- Immunotherapy
- Ipilimumab
- Interleukin-2 (IL-2) - Signal transduction inhibitors
- Vemurafenib (for patients who test positive for the BRAF V600 mutation). - Chemotherapy
- Palliative local therapy
Merkel cell tumour
tumours of mechanoreceptors of neural crest origin
worst prognosis of all skin lesions
50% H&N, elderly
resembles oat cell ca of lung (CXR to rule out lung primary)
locally aggressive, metastasise
Rx - WLE and DXT
Adenoid cystic carcinoma
Malignant tumour of eccrine glands mainly scalp
ACC usu in salivary, lacrimal and mucous glands of URT
Rx WLE, not DXT sensitive
