Cutaneous Carcinomas. Cutaneous Carcinoma. Background Cutaneous Cancer. Most common malignancy in world

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1 Cutaneous Carcinomas Otolaryngology-Head and Neck Surgery Most common malignancy in world Ivan El-Sayed, MD, FACS Director Center for Minimally Invasive Skull Base Surgery. Head and Neck Nanomedicine Laboratory. Advanced Skin Cancer of the Head and Neck Update changes in trends, staging, and management of SCC/BCC 2 Background Cutaneous Cancer Cutaneous Carcinoma 82 Types of skin cancer Melanoma Nonmelanoma skin ca (NMSC) Merkel cell Epidermal layer (SCC and BCC) Deeper layers (dermis and adnexal structures) Range of Prognosis Highly aggressive, metastatic (Merkel Cell) Locally destructive (BCCA) 3.5 million BCC/SCC new cases/ year in US in about 2 million patients. Most are BCC More new cases than breast, prostate, lung, colon combined About 3,000 deaths per year Incidence increasing for years Ozone depletion Lifestyle Detection? 1

2 Nonmelanoma Skin Cancer Etiology BCCA and SCCA Developing 1 Skin Cancer increases risk of developing another cancer Increases risk second skin cancer 35% at 3 yrs 50% at 5 yrs UVB (Sunlight) Chemical exposure hydrocarbons, pesticides Ionizing radiation Tobacco Arsenic (in well water) Chronic Skin conditions Impaired Cell Immunity Genetic Diseases HPV 5 6 Two mechanisms of action of UV Carcinogenesis? Impaired Immunity DNA mutations Induced immunosuppression Disease Related Lymphoma Leukemia Autoimmune Epidermodysplasia verruciform UVB( nm) is 10,000 time more mutagenic than UVA( nm) Favors generation of suppressor over helper immune pathways Mostly T cell depletion (CD4+ T cells) Associated with skin cancer 8 2

3 Impaired Immunity Organ Transplant Drug Related Cyclosporin, azathioprin, tacrolimus Varies with transplant type Incidence increases with time after transplant 10% at 10 years 40% at 20 years Why vary with transplant type? Heart transplant requires more immunosuppression Renal transplant performed in older patients Less time to develop skin ca SCC is predominant cancer Highly aggressive tumors 9 10 Organ Transplant Increased risk of NMSC Onset of cancer at a younger age More aggressive tumors with increased morbidity and mortality Some patients develop multiple tumors Increased risk of developing NMSC Population-based Standard Incidence Ratios of Skin Cancer in Transplant Patients Skin Cancer SCC SCC of lip BCC Melanoma Kaposi s Sarcoma Scandinavian population-based registries Jensen JAAD 1999;40:17 Hartevelt Transplantation 1990;49:506; Lindelof BJD 2000;143;513 Increased Incidence in Transplant Patients 65 to 250 fold 20 fold 10 fold 1.6 to 3.4 fold 84 fold 3

4 More aggressive tumors with increased morbidity and mortality Tumors are more aggressive than in non-transplant patients Cincinnati Transplant Tumor Registry 5.2% of individuals with skin cancer died of their tumors More died from SCC than melanoma Risk Factors for Skin Cancer with Organ Transplant Increased General Population Increasing age Fair skin, light hair, light eyes Sun exposure Transplant Population History of previous skin cancer 50% risk of 2nd cancer >70% risk of 2nd skin cancer Precursors lesions? SCCA Actinic Keratosis Bowen s Disease (CIS) BCCA No precursors BCCA Types Nodular Ulcerative most common Superficial Least aggressive Pigmented Morhpeaform (sclerosing) aggressive insidious growth Basosquamous-features of SCCA Image Wikipedia Bowen s Disease

5 High Risk Features for SCCA High Risk Lesions: Aggressive Biologic Behavior SCCA Histology Thickness in mm Depth in Clark s level Perineural involvement Size >2cm Etiology Immune status Anatomic site Current Opinion in Otolaryngology & Head & Neck Surgery: April Volume 19 - Issue 2 - p Anatomic Site Factors Associated with Metastases Higher Rate Recurrence and Lymphatic Met Ear Lip Direct invasion parotid (>50% metastatic) High Rate Recurrence Nasolabial crease Periorbital Preauricular The H Zone of the face along embryonic fusion planes SCC arising in scar, ulcer, burn Large neglected tumors Hx of ionizing radiation, PUVA therapy, arsenic ingestion or immunosuppression

6 Mortality From SCCA Who dies from NMSC? BCCA Rare Pts refused treatment SCCA Is 2 nd most common cause after melanoma Most common if lymphatic spread (>50%) Not hx of refused treatment Elderly Suppressed immune system HIV Organ Transplant Refused Treatment Upset about a positive margin in medial canthus 20 years prior. America Cancer Society Fact Sheet Treatment: Early Stage Cryotherapy (Actinic Keratosis) Electrocautery and Curretage (<.5cm) Surgical Excision Moh s H zone lesion (high risk) Recurrent, indistinct boarders, cosmetically important areas, aggressive histologies, priorly radiated, immunosuppressed, basal nevus Diffuse Treatments : 5FU, chemical/laser peel Surgical Excision (Moh s, WLE) Wide Local Excision When Moh s no longer adequate Recurrent lesions Radiation

7 Radiation therapy IS effective for BCC/SCC but not often used as primary treatment 95% cure rate small lesions 80% cure rate for large lesions (w high risk features) Radiation is generally reserved for High risk SCC/BCC Poor surgical candidates Recurrence after surgery Manage nodal disease prophylactically Drawbacks to Radiotherapy Lack of histological margins Subepithelial spread can be several cm RT Avoided in poorly defined lesion Side effects/scarring with radiation can be significant Significant commitment and access to an skilled radiotherapist can be an issue Recurrence of NMSC after RT may be more aggressive Chemotherapy Hedgehog signaling is normally active in embryonic development (GDC-0499) SCC BCC Topical 5 FU Topical Chemoprevention retinoids 5 FU Imiquimod Intravascular Vismodegib (erivedge) FDA 2012 In BCC Activation of Smoothened (SMO) protein or functional loss of PTCH in >90 % of BCC Erivedge inhibits SMO vismodegib Cl N O HN Cl O S O 27 Teh et al., Cancer Res 2005: 28 7

8 Hedgehog Inhibitor Phase I trial 15 patients with advanced disease 13 had clinical response Overall response rate = 60% 2 had complete response 4 had stable disease 9 months Vismodegib in locally advanced BCC Baseline Week 8 Week 20 FDA approved 2012 (Trial carried out in part at UCSF) Von Hoff 2009 NEJM Phase 1 trial Slide Courtesy Sarah Arron, UCSF Department of Dermatology Week 16: no BCC on biopsy Vismodegib Sekuklic et al NEJM 2012 Updates Indications When and where to use inappropriate for surgery not firmly established Signifcant responses Generally well tolerated 50% discontinued Duration of Adverse events response? ( 9.5mo 25% serious progression free survival ) 100% mild Cost $7500/mo x 10mo Changes in Staging System Surgical Management of T4 recalcitrant lesions

9 Changes in AJCC Staging Advanced Cutaneous Skin Cancer T1 T2 T3 T4 <2cm with less than 2 high risk features >2cm or any size with 2 HR features Invades maxilla, mandible, orbit, t bone invades skeleton or perineural invasion skull base Changes in AJCC Unresectable Advanced N1 single node 3cm or less N2a-c same as head and neck N3 >6cm 33 T Staging Extradermal Invasion 6 th Edition 7 th Edition 6 th ed 7 th ed T:1:</=2cm T2:2-5cm T1: Same T2: >2cm Used to determine T4 Eliminated Lack of data T3:>5cm Lack of evidence to support 5cm threshold 9

10 Histopathologic Grade Anatomic Site 6 th Edition 7 th Edition 6 th ed 7 th ed Not included Now included Degree of differentiation reported as risk factor Not used for T or final stage Added as high risk feature 38 Cranial or facial bone involvement Invasion skull base or axial skeleton 6 th ed 7 th ed 6th ed 7 th ed Included as T4, invasion of extradermal structure T3: invasion maxilla, mandible, orbit, T bone Correlates w HN Ca staging Included as T4 T4 redefined as tumor involving skull base or axial skeleton Or perinueral skull base invasion 10

11 N staging Distant Metastases 6 th ed N0 Absence node N1 Presence node 7 th ed N0-N3 based on size and number of mets Congruent with HN Staging Data shows decreased survival with size and # nodes No Change High Risk Lesions: Patient Approach Resectable? Radiotherapy? Medical Therapy? Recall T4 Lesions Invades skeleton or perineural invasion skull base Direct Extension through skull Patient compliance? Perineural skull base V1,2,3 Facial nerve Auriculotemporal nerve

12 Therapeutic Interventions of T4 Considerations Radiation? Consider wide local excision If + margins, can they be reirradiated? Reduce immunosuppression/ adequate HIV meds Medical therapy?: Hedge hog inhibitor for BCC Massive lesions Failed Radiation Prior surgeries Immunosuppressed High Met rate Invading critical structures Invading unresectable intracranial sites Considerations Massive lesions Size by itself is not a determinant Are socially isolating Impetus to treat if even for palliation How big defect to close? Failed Radiation Prior surgeries Immunosuppressed High Met rate Invading critical structures Invading unresectable intracranial sites Considerations Massive lesions Failed Radiation How much radiation was given? Where was radiation given (is there a field miss?) If you resect, can more be given to critical sites? Prior surgeries Immunosuppressed High Met rate Invading critical structures Invading unresectable intracranial sites

13 Considerations Considerations Massive lesions Failed Radiation Prior surgeries Were they inadequate? Do they impede flap reconstruction? Immunosuppressed High Met rate Invading critical structures Invading unresectable intracranial sites Massive lesions Failed Radiation Prior surgeries Immunosuppressed HIV? Are they on adequate meds yet? Organ Tx: can meds be decreased? High Met rate Invading critical structures Invading unresectable intracranial sites Considerations Massive lesions Failed Radiation Prior surgeries Immunosuppressed High Met rate Image and address nodal basin Invading critical structures Invading unresectable intracranial sites Considerations Massive lesions Failed Radiation Prior surgeries Immunosuppressed High Met rate Invading critical structures Orbit, nose, ear, Facial nerve Invading unresectable intracranial sites

14 Considerations Case: Recurrent BCC Massive lesions Failed Radiation Prior surgeries Immunosuppressed High Met rate Invading critical structures Invading unresectable intracranial sites Cavernous sinus? Dura- where? All prior scar must be included in resection Wide Local Excision Perineural invasion leads to cav sinus 46 yo HIV+ male Rec SCC Maxilla and Orbit to Cav L Cav Sinus Involved

15 Stable at 7 years after Total maxillectomy, Orbit Exent, RT SCC Multiple Prior Resections Rectus flap stable Cav sinus stable Moh s x 3 over 2 years 1 Course of RT Rec Lesion 4 months in nonhealing ulcer Wide Local Excision with margins on skin Gross Tumor on Sagittal Sinus discovered intraopertively MRI, MRV Image guidance Tumor on Sag Sinus (Blue ink marks sinus)

16 Preoperative Assesment MRV Tumor on Sagital sinus Tumor Debrided by neurosurgeon. Plan for re irradiation protocol of residual yo renal transplant patient, WLE re-irradiation 7,000cGy, Erbitux. Local control Ultimately passed away from metastatic SCC. 8 years post Tp in 2002 developed SCC r forehead treated with WLEx developed a recurrence, txed with MMS and 5600cGy second recurrence treated with MMS, noted muscular and perineural invasion of supraorbital nerve- reexcision x2,

17 SCCA Preoperative CSF Leak 7 yr hx rec scc Multiple mohs Treated WLE and Local Advancement flaps Underlying hematologic disorder, hypercoagulable 1 yr hx painful lesion CSF evident Necrosed advancement flap, taken back for free flap excellent result Post Op: Some Successes 55yo renal tx recipient Rec SCCA scalp invading dura with dural resection Scalp and Skull Lesions Limited data available for outcomes Several small series Reconstruction Free tissue transfer common (lat, scapular, RFFF) Defect bone,dura >10cm % complication rate Wound infection assoc with implant Shonka et al Laryngoscope

18 Tips for Advanced disease Conclusion 1) Get negative margins on skin and bone 2)Reirradiate residual margins when possibleoften can, many cases of radiation failure are associated with field miss 3) Calvarial implants are associated with infection in about 20% of cases Advanced Skin Cancer require multidisciplinary care Skilled facility Evaluate reirradiation Consider resection of unresectable lesions for local control and possible long term control Optimize patient status (immunesuppression?) 4)Evaluate neck for metastases in high risk lesion