SKIN CANCERS AFTER SOLID ORGAN TRANSPLANTATION: Clinicopathological features. J. Kanitakis. Dept. of Dermatology Ed. Herriot Hospital Lyon, France

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1 SKIN CANCERS AFTER SOLID ORGAN TRANSPLANTATION: Clinicopathological features J. Kanitakis Dept. of Dermatology Ed. Herriot Hospital Lyon, France

2 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)

3 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

4 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 X 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:

5 AK/SCC: mainly on sunexposed sites Skin types II-III

6 ACTINIC (PREMALIGNANT/SOLAR) KERATOSES ( in situ SCC) usually mutiple (field cancerization)

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8 AK & SCC POST- Tx

9 ACT. KERATOSIS & SCC : CLINICAL CONTINUUM AK+SCC Flat lesions : KA Infiltrated lesions:scc

10 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)

11 AK/SCC: HISTOPATHOLOGICAL CONTINUUM

12 BOWEN S DISEASE (= in situ SCC) PROGRESSION TO INVASIVE (BOWENOID) SCC

13 Association AK/SCC Progression of AK into invasive SCC

14 POST-TX CUTANEOUS SQUAMOUS CELL CARCINOMAS Commonest post-tx malignancy (incidence X 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:

15 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, )

16 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

17 Pourcentage de patients développant de nouvelles tumeurs après le 1 er CSC an 2 ans 3 ans 5 ans Rein CĻur

18 Nombre moyen cumulé de nouvelles tumeurs par patient après le 1 er CSC ,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

19 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

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21 Aggressive SCC in OTR

22 SCC in OTR often have a misleading clinical aspect (KA- or wart-like)

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27 Well-differentiated/acantholytic SCC Undifferentiated/spindle cell SCC

28 Moderately differentiated SCC

29 SCC: histologic features of aggressiveness Deep invasion (cartilage, bone) Perineural invasion

30 Hoyo E, Kanitakis J, Euvrard S, et al. Proliferation characteristics of cutaneous squamous cell carcinomas developing in organ graft recipients. Arch Dermatol 1993; 129: 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

31 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: aggressive 28 nonaggressive SCC from OTR

32 New proliferation/tranformation markers in post-tx skin malignancies p16 p63

33 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

34 Basal Cell Carcinomas in OTR Forehead Axilla

35 Basal Cell Carcinomas: localisation (%) Post-TX BCC (n:176) Control BCC (n:153) Scalp Face Neck Head/Neck Trunk Upper limbs Lower limbs Genitalia Extracephalic * *p<0.02 Kanitakis J et al. Arch Dermatol 2003;139:1133-7

36 Basal Cell Carcinomas: histologic subtypes Nodular Superficial Sclerodermiform

37 Post-Tx Basal Cell Carcinomas Arch Dermatol 2003;139: Post-Tx BCC (n:176) Control BCC (n:153) Thickness (mm) 1.2± ±.9 a Ulceration 56.6% 43.8% a Histological subtype (%) Superficial Sclerodermiform b 7.8 a: ns b: p<0.001 Nodular/other Peritumor infiltrate (%) 1 absent/weak b 2 moderate dense Perineural invasion (%) a

38 Cancer Res 2005; 65: 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+

39 High frequency and diversity of cutaneous appendageal tumors in organ transplant recipients Harwood C et al. J Am Acad Dermatol 2003; 48: % 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

40 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:

41 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)

42 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

43 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?

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45 Aza 50 + CyA 100 MMF CyA 50 + Everolimus 1.5 Heart transplant patient 6 months later

46 POST-Tx SKIN CARCINOMAS: PREVENTION Adequate patient education for sun-protection (clothing measures, sunscreens) ( Regular dermatologic surveillance - early detection & ablation of (pre)malignant lesions Chemoprevention (local/systemic retinoids) Use of mtor inhibitors (sirolimus, everolimus)

47 POST-TRANSPLANT KAPOSI S SARCOMA Incidence X vs controls % 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)