CURRENT ISSUES IN TRANSPLANT DERMATOLOGY

CURRENT ISSUES IN TRANSPLANT DERMATOLOGY

NO CONFLICTS OF INTEREST TO DISCLOSE

SOLID ORGAN TRANSPLANTATION: 2015 As of April 10, 2015.. 123,319 patients waiting for an organ transplant 2,557 performed this year 1,257 donors 21 patients die each day waiting for a transplant Herrick twins 1st kidney transplant Boston, 1954

Breast cancer RECOMMENDED WAIT-TIMES TYPE OF CANCER RECOMMENDATION (years) >5 (>2 for early disease) Colorectal cancer >5 (>2 for Dukes Stage A or B1) Uterine cervical cancer Renal cell carcinoma/wilm s tumor Bladder cancer >2 Kaposi s sarcoma >2 Lung cancer >2 Testicular cancer >2 Thyroid cancer >2 Prostate cancer Leukemia/lymphoma >2 (>5 for more advanced cervical cancer) >2 (>5 for large cancers; no wait for incidental tumor <5cm) >2 (possibly less for localized disease) >2 (limited data) Adapted from: Kasiske BL, et al. The Evaluation of Renal Transplant Candidates: Clinical Practice Guidelines. Am J Transpl 2001; 1: Suppl 2

WHAT ARE THE CURRENT GUIDELINES? The high recurrence rate of non-melanoma skin cancers occurs irrespective of the time of removal of the lesions before renal transplantation. Nevertheless, the majority of patients with recurrence of non-melanoma skin cancers have been treated less than 2 years before transplantation. A waiting period of 2 years may eliminate some recurrent skin cancers although the impact of this intervention is not established. Kasiske BL, et al. The Evaluation of Renal Transplant Candidates: Clinical Practice Guidelines. Am J Transpl 2001; 1: Suppl 2

SKIN CANCER IN ORGAN TRANSPLANT RECIPIENTS SKIN CANCER Squamous cell carcinoma Squamous cell carcinoma of the lip Basal cell carcinoma Melanoma Kaposi sarcoma INCREASE IN INCIDENCE 65-fold 20-fold 10-fold Threefold 84-fold Actinic Keratoses (precancers) 250-fold Table modified from: Zwald FO, Brown M. Skin Cancers in solid organ transplant recipients. JAAD. Aug 2011. 253-261

SCC: THE MOST COMMON SKIN CANCER IN ORGAN TRANSPLANT RECIPIENTS Squamous Cell and Basal Cell Carcinoma account for 95% of skin cancers in transplant patients 75% occur in photo-distributed areas SCCs are more aggressive in transplant patients Risk of metastases of SCC in transplant patients is 8-13% Compared to 0.5-5% in the general population If you have a skin cancer before transplant, you have nearly 100% chance of getting another after transplant Zwald FO, Brown M. Skin cancers in solid organ transplant recipients. JAAD. Aug 2011

WHAT CONSTITUTES A HIGH-RISK SCC? 2010: AJCC CUTANEOUS SCC STAGING, 7 TH EDITION Clinical Features Large size >2cm Special sites Ear Lip Scalp, temple Over parotid gland Multiple SCCs Rapidly growing lesions In-transit metastases Recurrence Pathologic Features >2mm thickness Clark level 4mm (invasion of reticular dermis) Perineural invasion Poorly or undifferentiated Deep invasion National Cancer Institute; 7 th edition AJCC staging for cutaneous SCC. 2010 O Reilly et al. Skin Cancer in solid organ transplant patients: advances in therapy and management- Part II. JAAD Aug 2011.

CLINICAL IMPLICATIONS OF HIGH-RISK SCC SQUAMOUS CELL CARCINOMA Local Recurrence Local Metastases Distant Metastases Disease-Specific Death 5% 5% 1% 1% RATE OF METASTASES MAY EXCEED 20% IN SELECTED HIGH-RISK FEATURES OVERALL SURVIVAL DECLINES TO BETWEEN 46% and 70% AT 5 YEARS

ARE ALL HIGH-RISK FEATURES EQUAL IN RATE OF METASTASES AND SURVIVAL? Prospective analysis, N=615 Increased tumor thickness Immunosuppression Localization to the ear Increased horizontal size 4% developed metastases 73% within first year none after 4years Retrospective study, N=6160 Perineural invasion Anatomic site cheek, lip, ear Maximum clinical diameter Poor histological differentiation 44% developed metastases within first year average interval to metastases = 26 months Brantsch KD et al. Analysis of risk factors determining prognosis of cutaneous squamous cell carcinoma: A prospective study. Lancet Aug 2008 Brougham N, Dennett ER, Cameron R, Tan ST. The incidence of metastasis From cutaneous squamous cell carcinoma and the impact of its risk factors. J Surg Oncol Dec 2012

SURVIVAL OUTCOMES IN HIGH-RISK SCC Recurrent Disease Deep Invasion Perineural Invasion Lesion Size Lympho-Vascular Invasion Inflammation Nodal Involvement Kyrgidis A, et al. Cutaneous Squamous Cell Carcinoma (SCC) of the Head and Neck: Risk Factors of Overall and Recurrence-Free Survival. European Journal of Cancer 2010 Clayman GL, et al. Mortality Risk from Squamous Cell Skin Cancer. J Clin Oncol 2005 Rowe, DE, et al. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection.jaad 1992.

SCC STAGING + PROGNOSIS/SURVIVAL DATA = WAIT PERIOD GUIDELINES AJCC 7 TH ED STAGING SYSTEM STAGE T N M 0 In-situ N0 M0 I T1 N0 MO II T2 N0 M0 III T3 N0/1 M0 T1/2 N1 M0 IV T1/2/3 N2 M0 ANY T N3 M0 T4 ANY N M0 ANY T ANY N M1 BWH STAGING SYSTEM ALTERNATIVE T T0 T1 T2a T2b T3 DEFINITION In-situ 0 risk factors 1-2 risk factors 3 risk factors 4 risk factors -orbony invasion Risk factors: Tumor diameter >2 cm or greater, poorly differentiated histologic characteristics, perineural invasion, and tumor invasion beyond the subcutaneous fat (excluding bone invasion) T1: Tumor 2 cm in greatest dimension with <2 high-risk features T2: Tumor >2 cm in greatest dimension with or without one additional high-risk feature, or any size with 2 high-risk features

HIGH-RISK SCC WITH LOCAL METASTASES High-risk SCC metastasizes to parotid/cervical lymph nodes incidence 5%, up to 21% in immunocompromised Risk factors: Recurrent lesions, lymphovascular invasion, inflammation, poor histologic differentiation, invasion into the subcutaneous tissues, PNI, and larger size Predictors of poor outcome: Single-modality treatment, increasing node size, multiple nodes, positive nodal margins, extra-capsular spread, immunosuppression Frank Netter Veness MJ, et al. Surgery and adjuvant radiotherapy in patients with cutaneous head and neck squamous cell carcinoma metastatic to lymph nodes; combined treatment should be considered best practice. Laryngoscope 2005 Ch ng S, et al. Parotid and Cervical Nodal Status Predict Prognosis for Patients With Head and Neck Metastatic Cutaneous Squamous Cell Carcinoma. J Surg Oncol 2008 Moore BA, et al. Lymph Note Metastases from Cutaneous Squamous Cell Carcinoma of the Head and Neck. Laryngoscope 2005 O Brien CJ, et al. Significance of clinical stage, extent of surgery, and pathologic findings in metastatic cutaneous squamous carcinoma of the parotid gland. Head and Neck 2002

LOW-RISK NODAL DISEASE: DOES THIS EXIST? Definition O Brien of cutaneous Clinical Staging squamous System cell for carcinoma Metastatic nodal Cutaneous (N) staging Squamous for 7th Cell edition of Carcinoma American Joint of the Committee Parotid and/or on Cancer Neck NX Parotid Regional lymph node cannot be assessed N0 P0 No regional No lymph clinical node disease metastasis in the parotid N1 P1 Metastasis Metastatic in single ipsilateral node up lymph to 3cm node in diameter N2 P2 Metastasis Metastatic in single ipsilateral node >3cm lymph and node, up to >3 6cm in but diameter not >6 cm or in multiple greatest dimension; nodes or in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension; or in bilateral or contralateral lymph nodes, none >6 cm in greatest P3 Metastatic node >6cm in diameter or disease involving facial dimension nerve or skull base N2a Metastasis in single ipsilateral lymph node, >3 cm but not >6 cm in greatest dimension Neck N2 Metastasis in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension N0 Single lymph node measuring 3cm b N2c N1 Single lymph node measuring >3cm or multiple lymph nodes Metastasis in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension measuring 3cm N3 Metastasis in lymph node, >6 cm in greatest dimension N2 Multiple lymph nodes measuring>3cm O Brien CJ, et al. Significance of clinical stage, extent of surgery, and pathologic findings in metastatic cutaneous squamous carcinoma of the parotid gland. Head and Neck 2002

Forest VI, et al. N1S3: A Revised Staging System for Head and Neck Cutaneous Squamous Cell Carcinoma with Lymph Node Metastases. Cancer 2010 LOW-RISK NODAL DISEASE: SEARCHING FOR A DEFINITION N1S3 Staging System Stage I II III Single lymph node measuring 3cm Single lymph node measuring >3cm or multiple lymph nodes measuring 3cm Multiple lymph nodes measuring >3cm

CONSIDERATIONS INDIVIDUAL: Organ to be transplanted Patients who are recipients of a living-related renal or liver allograft Patient s inherent predisposition to further skin cancer development FUTURE DEVELOPMENTS: Sentinel lymph node biopsy

References: Veness MJ, Palme CE, Morgan GJ. High-Risk Cutaneous Squamous Cell Carcinoma of the Head and Neck: Results from 266 Treated Patients with Metastatic Lymph Node Disease. Cancer. 2006;106(11):2389-2396.doi:10.1002/cncr.2198 Jambusaria-Pahlajani A, Kanetsky PA, Karia PS, et al. Evaluation of AJCC Tumor Staging for Cutaneous Squamous Cell Carcinoma and a Proposed Alternative Tumor Staging System. JAMA Dermatol. 2013;149(4):402-410.doi:10.1001/jamadermatol.2013.2456 Brantsch AD, Meisner C, Schönfisch B et al. Analysis of risk factors determing prognosis of cutaneous squamous cell carcinoma: a prospective study. Lancet. 2008;9:713-720.doi:10.1016/s1470-2045(08)70178-5 Clayman GL, Lee JJ, Holsinger FC, et al. Mortality Risk from Squamous Cell Skin Cancer. J Clin Oncol. 2005; 23(4):759-765.doi:10.1200/jco.2005.02.155 Kyrgidis A, Tzellos TG, Kechagias N, et al. Cutaneous squamous cell carcinoma (SCC) of the head of neck: Risk factors of overall and recurrence-free survival. European Journal of Cancer. 2010;46:1563-1572.doi:10.1016/j.ejca.2010.02.046 Brougham N, Dennett ER, Cameron R, Tan ST. The Incidence of Metastasis From Cutaneous Squamous Cell Carcinoma and the Impact of its Risk Factors. J Surg Oncol. 2012;106:811-815.doi:10.1002/jso.23155 Veness MJ, Morgan GJ, Palme CE, Gebski V. Surgery and Adjuvant Radiotherapy in Patients with Cutaneous Head and Neck Squamous Cell Carcinoma Metastatic to the Lymph Nodes: Combined Treatment Should be Considered Best Practice. Laryngoscope. 2005;115:870-875.doi:10.1097/01.mlg.0000158349.64337.ed Andruchow JL, Veness MJ, Morgan GJ, et al. Implications for Clinical Staging of Metastatic Cutaneous Squamous Carcinoma of the Head and Neck Based on a Multicenter Study of Treatment Outcomes. Cancer. 2006;106(5):1078-1083.doi:10.1002/cncr.21698 Palme CE, O Brien CJ, Veness MJ, et al. Extend of Parotid Disease Influences Outcome on Patients With Metastatic Cutaneous Squamous Cell Carcinoma. Arch Otolaryngol Head Neck Surg. 2003;129:750-753. Ch ng S, Maitra A, Allison RS, et al. Parotid and Cervical Nodal Status Predict Prognosis for Patients With Head and Neck Metastatic Cutaneous Squamous Cell Carcinoma. J Surg Oncol. 2008;98:101-105.doi:10.1002/jso.21092 Southwell KE, Chaplin JM, Eisenberg RL, et al. Effect of Immunocompromise on Metastatic Cutaneous Squamous Cell Carcinoma in the Parotid and Neck. Head and Neck. 2006;28:244-248.doi:10.1002/hed.20321 Ebrahimi A, Clark JR, Ahmadi N, et al. Prognostic significance of disease-free interval in head and neck cutaneous squamous cell carcinoma with nodal metastases. Head and Neck. 2012;00:1-6.doi:10.1002/hed23096 Forest VI, Clark JJ, Veness MJ, Milross C. N1S3: A Revised Staging System for Head and Neck Cutaneous Squamous Cell Carcinoma with Lymph Node Metastases. Cancer. 2010;116:1298-304.doi:10.1002/cncr.24855 Moore BA, Weber RS, Prieto V, et al. Lymph Note Metastases from Cutaneous Squamous Cell Carcinoma of the Head and Neck. Laryngoscope 2005;115:1561-1567.doi:10.1097/01.mlg.0000173202.56739.9f Ebrahimi A, Clark JR, Lorincz BB, et al. Metastatic Head and Neck Cutaneous Squamous Cell CarcinomaL Defining a Low-Risk Patient. Head and Neck. 2012;34:365-370.doi:10.1002/hed.21743 O Brien CJ, et al. Significance of clinical stage, extent of surgery, and pathologic findings in metastatic cutaneous squamous carcinoma of the parotid gland. Head and Neck 2002

INTERNATIONAL TRANSPLANT SKIN CANCER COLLABORATIVE @ITSCC_org