SKIN CANCERS AFTER SOLID ORGAN TRANSPLANTATION: Clinicopathological features J. Kanitakis Dept. of Dermatology Ed. Herriot Hospital Lyon, France
CUTANEOUS COMPLICATIONS AFTER SOLID ORGAN TRANSPLANTATION Due to the long-term immunosuppression: Side-effects of immunosuppressive drugs Infections (viral, fungal, bacterial) Tumors Incidence increasing due to the longer survival of Organ Transplant Recipients (OTR)
CANCER RISK AFTER SOLID ORGAN TX Mild increase: colon, lung, prostate, stomach Moderate increase: testis, urinary bladder, melanoma, leukemia, liver, gynecologic ca. High increase: Non-melanoma skin cancers, Kaposi s sarcoma, lymphomas
SKIN CANCERS: THE COMMONEST POST-Tx MALIGNANCIES (75%) Keratinocytic neoplasms (NMSC): Actinic keratoses, Bowen s disease, Squamous & Basal cell carcinomas (>90% of skin cancers): incidence X65-150 vs ethnic- and age-matched populations Kaposi s sarcoma (incidence X85-500) Melanomas (incidence X8-10) Lymphomas Merkel cell carcinoma Other (atypical fibroxanthoma, various sarcomas, sweat-gland ca., ) Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med 2003;348:1681-91
AK/SCC: mainly on sunexposed sites Skin types II-III
ACTINIC (PREMALIGNANT/SOLAR) KERATOSES ( in situ SCC) usually mutiple (field cancerization)
AK & SCC POST- Tx
ACT. KERATOSIS & SCC : CLINICAL CONTINUUM AK+SCC Flat lesions : KA Infiltrated lesions:scc
ACTINIC (PREMALIGNANT) KERATOSES - Keratinocytic intraepidermal neoplasia (I-III) - Rate of transformation of AK to SCC debated (KA = in situ squamous cell carcinoma?) Lower epidermis (I) Whole epidermis (III)
AK/SCC: HISTOPATHOLOGICAL CONTINUUM
BOWEN S DISEASE (= in situ SCC) PROGRESSION TO INVASIVE (BOWENOID) SCC
Association AK/SCC Progression of AK into invasive SCC
POST-TX CUTANEOUS SQUAMOUS CELL CARCINOMAS Commonest post-tx malignancy (incidence X65-150 vs controls) Delay of development: 8 yrs post-tx - shorter in patients grafted > age 40 yrs Cumulative incidence increases exponentially with time post-tx: 40-60% of OTR 20 yrs post-graft in Western Europe 30-50% of OTR with SCC have also BCC or other skin malignancies SCC:BCC ratio usually reversed vs controls (4:1 vs 1:5) Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med 2003; 348: 1681-91
POST-TX CUTANEOUS SQUAMOUS CELL CARCINOMAS Often multiple - associated with other NMSC (keratotic skin lesions/warts, AK, Bowen s disease, BCC) May be clinically misleading ( biopsy warranted) Sun-exposed areas: dorsum of hands in young OTR (Tx <40 yrs), head/neck in older OTR (Tx >40 yrs) May be aggressive/fatal: recurrences 13%, metastasis 5-8% Worse prognosis: multiple tumors, cephalic location (ear+), older age at Tx, poor histologic differentiation, invasion of deep tissues (nerves, cartilage, )
POST-TX CUTANEOUS SQUAMOUS CELL CARCINOMAS > 80% of OTR develop secondary NMSC within 5 yrs after 1st SCC SCC predictive of internal cancers (18.6% of OTR with SCC) Euvrard S, Kanitakis J, Decullier E et al. Subsequent skin cancers in kidney and heart transplant recipients after the first squamous cell carcinoma. Transplantation 2006; 81: 1093
Pourcentage de patients développant de nouvelles tumeurs après le 1 er CSC 100 90 80 70 60 50 40 30 20 10 0 88 100 86 77 67 67 51 40 1 an 2 ans 3 ans 5 ans Rein CĻur
Nombre moyen cumulé de nouvelles tumeurs par patient après le 1 er CSC 10 9 8 7 6 5 4 3 2 1 0 9,73 6,56 4,85 4,6 3,39 2,04 2,61 2,9 1 an 2 ans 3 ans 5 ans Rein CĻur
SCC: predictive of visceral cancers In the general population: skin SCC is the most predictive tumor of 2ry cancer SIR: 2,3 OTR with SCC: > 20% of kidney recipients & 30 % of heart recipients develp 2ry malignancies within 5 years (Harzallah K et al) Dong C & Hemminki K. Int J Cancer 2001 Harzallah K et al. WTC Boston 2006 Euvrard S et al. Transplantation 2006
Aggressive SCC in OTR
SCC in OTR often have a misleading clinical aspect (KA- or wart-like)
Well-differentiated/acantholytic SCC Undifferentiated/spindle cell SCC
Moderately differentiated SCC
SCC: histologic features of aggressiveness Deep invasion (cartilage, bone) Perineural invasion
Hoyo E, Kanitakis J, Euvrard S, et al. Proliferation characteristics of cutaneous squamous cell carcinomas developing in organ graft recipients. Arch Dermatol 1993; 129: 324-7 - No statistically significant difference in AgNOR between post-tx and control SCC (6.5±1.5 vs 6.7±1.1) - Inflammatory infiltrate lower in post-tx SCC (2 vs 3.17) Post-Tx SCC Control SCC
Kanitakis J, Narvaez D, Euvrard S, et al. Proliferation markers Ki67 and PCNA in cutaneous squamous cell carcinomas: lack of prognostic value. Br J Dermatol 1997; 136: 643-4 14 aggressive 28 nonaggressive SCC from OTR
New proliferation/tranformation markers in post-tx skin malignancies p16 p63
BASAL CELL CARCINOMAS IN OTR Less frequent than SCC (ratio 1:3) but RRX10 vs controls Male predominance (4.8:1 vs 1.3:1 in controls) Seem to be relatively more frequent after liver (vs kidney/heart) Tx Develop on sun-protected sites in 37% of cases (vs 29% in controls) Superficial BCC more common vs controls (33% vs 14%) Course usually uneventful after appropriate trt Kanitakis J et al. Basal cell carcinomas in organ transplant recipients. Clinicopathologic study of 176 cases. Arch Dermatol 2003;139:1133-7
Basal Cell Carcinomas in OTR Forehead Axilla
Basal Cell Carcinomas: localisation (%) Post-TX BCC (n:176) Control BCC (n:153) Scalp 1.7 2 Face 58.9 63 Neck 2.3 6 Head/Neck 62.9 71 Trunk 25 16.5 Upper limbs 5.7 2.3 Lower limbs 6.3 5.3 Genitalia 0.6 0 Extracephalic 37.1 29* *p<0.02 Kanitakis J et al. Arch Dermatol 2003;139:1133-7
Basal Cell Carcinomas: histologic subtypes Nodular Superficial Sclerodermiform
Post-Tx Basal Cell Carcinomas Arch Dermatol 2003;139:1133-7 Post-Tx BCC (n:176) Control BCC (n:153) Thickness (mm) 1.2±1.1 1.3±.9 a Ulceration 56.6% 43.8% a Histological subtype (%) Superficial Sclerodermiform 33.6 3.1 14.4 b 7.8 a: ns b: p<0.001 Nodular/other 63.2 77.8 Peritumor infiltrate (%) 1 absent/weak 28.6 13.7 b 2 moderate 43.5 40.5 3 dense 27.9 45.7 Perineural invasion (%) 0 1.3 a
Cancer Res 2005; 65: 1755-60 Immuno-FISH in a BCC from a female OTR (XX) grafted with a male kidney (XY) mab to pan-keratin + probes for chr. X/Y+
High frequency and diversity of cutaneous appendageal tumors in organ transplant recipients Harwood C et al. J Am Acad Dermatol 2003; 48: 401-8 3% of OTR have adnexal tumors Malignant tumors overrepresented in OTR vs controls (43% vs 4%) Sebaceous tumors overrepresented in OTR vs controls (30% vs 6%) Sebaceous carcinoma
POST-TRANSPLANT SKIN CARCINOMAS: PATHOGENESIS (I) Multiple co-carcinogenic factors: 1. UV light +++ : predominance on sun-exposed sites of fairskinned OTR, incidence increase with latitude, characteristic UV-induced p53 mutations 2. Immunosuppressive treatment ++ (duration/depth): CD4 counts lower in OTR with SCC, higher incidence in heart vs kidney TR - Specific pro/anticancer effect of immunosup-pressants: calcineurin Inhibitors (CsA, FK506) mtor inhibitors (sirolimus/everolimus) Transplantation 2004;77:1777 Drugs 2007; 67: 1167-98
POST-TRANSPLANT SKIN CARCINOMAS: PATHOGENESIS (II) 3. β-hpv infection + : 5, 8, 38, multiple «benign» & oncogenic types contained in SCC/AK & BCC 4. Genetic factors ± (HLA homozygosity, polymorphisms in glutathion-s-transferase, IL-10, vit. D rec, p53) 5. Length of pre-tx dialysis, tobacco smoking, alcohol (?) Giampieri & Storey Br J Cancer 2004 Schaper & Pfister Cancer Res 2005 Karagas et al. J Natl Cancer Inst 2006 Ulrich et al Am J Transplant (in press)
Ultraviolet light Immunosuppressive treatments Genetic Factors skin type P53 arginine-arginine genotype? Glutathione S-transferase M1, P1? IL-10 gene aging smoking p53 mutations decrease of Langerhans cell density Local immunodeficiency HPV Skin Carcinoma Systemic immunodeficiency Pre-Tx dialysis Suggested mechanisms of skin carcinogenesis in transplant patients
NMSC management Local trt Adjuvant Systemic Superficial lesions AK, Bowen s disease, BCC Nodular lesions SCC, BCC Cryotherapy, electrodessication, laser, Imiquimod 5FU, PDT local retinoids Excision - - Multiple SCC Excision - Retinoids, IST, switch to mtor inh Agressive SCC Excision - Retinoids, IST, switch to mtor inh Local recurrences Excision - - - Metastatic SCC Lymph node disection X-ray trt retinoids? Chemotherapy EGF-R inhibitors?
Aza 50 + CyA 100 MMF 500 + CyA 50 + Everolimus 1.5 Heart transplant patient 6 months later
POST-Tx SKIN CARCINOMAS: PREVENTION Adequate patient education for sun-protection (clothing measures, sunscreens) (www.scopnetwork.org, www.itscc.org) Regular dermatologic surveillance - early detection & ablation of (pre)malignant lesions Chemoprevention (local/systemic retinoids) Use of mtor inhibitors (sirolimus, everolimus)
POST-TRANSPLANT KAPOSI S SARCOMA Incidence X85-400 vs controls 0.5-5.3% of all OTR according to the country More frequent after liver vs kidney or heart Tx OTR of Mediterranean, Jewish, Arab, African or Caribean ancestry Mean delay of onset: 13 months post-tx - earlier age (43 yrs) vs classic KS Mucocutaneous lesions in 60-90% of OTR-KS, only visceral lesions in 10-15% of OTR-KS (GI tract, lung, lymph nodes)