iatrogenic immunosuppression and cutaneous … immunosuppression and cutaneous malignancy jerry d....

©2015 MFMER | slide-1

©2011 MFMER |

slide-1

Iatrogenic Immunosuppression and Cutaneous Malignancy

Jerry D. Brewer, MD, MS, FAAD brewer.jerry@mayo.edu Professor of Dermatology Chair Division of Dermatologic Surgery Department of Dermatology Mayo Clinic / Mayo Clinic College of Medicine

AAD March 6, 2017

©2015 MFMER | slide-2

©2011 MFMER |

slide-2

Disclosures

• None

©2015 MFMER | slide-3

The Dermatology Foundation has supported & advanced my career.

©2015 MFMER | slide-4

Objectives

• Iatrogenic Immunosuppression and Malignancy • Introduction • Pathogenesis • Epidemiology • Outcomes • Risk Factors • Conclusions

©2015 MFMER | slide-5

I have seen bad outcomes in iatrogenically immunosuppressed patients with skin cancer in my practice…

©2011 MFMER | slide-5

1. Frequently 2. Fairly regularly 3. Rarely 4. Never

©2015 MFMER | slide-6

Introduction

©2015 MFMER | slide-7

Skin Cancer • Most common human malignancy • Over 5 million NMSC per year in US • Increased incidence and risk in immunosuppressed

• Solid organ transplantation • NHL/CLL

Rogers HW, Weinstock MA, Feldman SR, Coldiron BM. Incidence estimate of nonmelanoma skin cancer (keratinocyte carcinomas) in the US population, 2012. JAMA Dermatol 2015;

151(10):1081-1086.

©2015 MFMER | slide-8

©2015 MFMER | slide-9

Original Biopsy

©2015 MFMER | slide-10

Organ Transplantation

©2015 MFMER | slide-11

Organ Transplantation

• Final defect size • 8.1x5.5cm

©2015 MFMER | slide-12

US Organ Transplants in 2015

HeartRenalLiverKidney-PancreasLungPancreasIntestineHeart-Lung

Total 30,973

> 250,000 Recipients Alive

©2015 MFMER | slide-13

Transplants per year

©2015 MFMER | slide-14

What would increase the number of transplant patients? Increasing the rate of donation

• Iran has legalized the sale of human organs • Social acceptance of deceased and living donation • Opt-out rather than opt-in policies

• Spain and Ireland • Much higher donation rates

©2015 MFMER | slide-15

©2015 MFMER | slide-16

©2015 MFMER | slide-17

©2015 MFMER | slide-18

Pathogenesis

©2015 MFMER | slide-19

Skin Cancer in Immunosuppressed Patients • Multiple theories

• Decreased immune surveillance • Direct carcinogenesis from medications • Increased infections

• Human papilloma virus • Merkel Cell Polyomavirus

©2015 MFMER | slide-20

©2015 MFMER | slide-21

Epidemiology

©2015 MFMER | slide-22

Risk for developing skin cancer in transplant recipients

• Basal Cell Carcinoma --10X

• Squamous Cell Carcinoma -- 65-250X

• Merkel Cell Carcinoma -- 20X

• Kaposi’s Sarcoma -- 84X

• Melanoma -- 2-8X

©2015 MFMER | slide-23

Characteristics of Skin Cancer in OTRs

• Age • Duration of immunosuppression • Intensity of immunosuppression • Ultraviolet exposure • HPV infection • Type I-III skin • CD4 lymphocytopenia

• Older = more • Longer = more • Stronger = more • More = more • Present = more • Present = more • Lower = more

©2015 MFMER | slide-24

73 year old outdoorsman s/p cardiac transplant 1993

0

20

40

60

80

100

120

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002

©2015 MFMER | slide-25

Outcomes

©2015 MFMER | slide-26

BCC and SCC

©2015 MFMER | slide-27

©2015 MFMER | slide-28

Case

SCC – young in years, old in experience

©2015 MFMER | slide-29

History • Pleasant 30 year old female • History of ulcerative colitis • Developed pulmonary fibrosis

• Due to UC treatment regimen

©2015 MFMER | slide-30

History • Pulmonary fibrosis

• Progressed to bronchiolitis obliterans • Bilateral living related lobar transplant

• 10/15/99 • Bronchiolitis obliterans progressed

• First transplant failed • Double lung transplant

• 2/2006

©2015 MFMER | slide-31

Non-melanoma skin cancer • Every visit

• At least 10-20 biopsies • Most superficially invasive SCC • Around 20-30 HAK’s • Around 30-40 AKs

• Deep aggressive SCC requiring Mohs every 8-12 weeks

©2015 MFMER | slide-32

©2015 MFMER | slide-33

©2015 MFMER | slide-34

©2015 MFMER | slide-35

©2015 MFMER | slide-36

©2015 MFMER | slide-37

©2015 MFMER | slide-38

©2015 MFMER | slide-39

Tumor Burden

©2015 MFMER | slide-40

Outcome • Capecitabine stopped

• Antibody mediated rejection of lungs • Bowel perforation following surveillance colonoscopy • Recurrence of Aspergillus pneumonia

• Tumor rebound • Recurrent aggressive SCC left neck/scalp • Pulmonary nocardia infection • Pulmonary mycobacterium avium complex infection

©2015 MFMER | slide-41

Outcome • Cholangiocarcinoma • Metastases

• Lung, bone, and multiple soft tissues • Deceased

• Aug 15, 2014

©2015 MFMER | slide-42

Lessons Learned • The higher level of immunosuppression

• The bigger the cutaneous challenge! • Age sometimes not a factor • Aggressive treatment promptly is key! • Systemic treatment options sometimes helpful • Very humbling!

©2015 MFMER | slide-43

Incidence of and Risk Factors for Skin Cancer following Cardiac Transplantation

Brewer JD, Colegio O, Phillips PK, Roenigk RK, Jacobs MA, Van de Beek D, Dierkhising RA, Kremers WK, McGregor C, Otley CC. Incidence of and Risk Factors for Skin Cancer after Cardiac Transplantation. Arch Dermatol. 2009;145(12): 1391-1396.

©2015 MFMER | slide-44

Mortality Years post transplantation Cumulative incidence of death

5 yrs 18.4% (95% CI 13.6%-23.0%)

10 yrs 37.9% (95% CI 30.5%-44.5%)

15 yrs 63.5% (95% CI 51.5%-72.5%)

18 yrs 78.7% (95% CI 57.7%-89.3%)

* The majority of death was due to heart failure

©2015 MFMER | slide-45

Mortality • Mortality due to skin cancer

• Only 1 person died due to skin cancer • Melanoma

• 8.6 years post transplantation

©2015 MFMER | slide-46

Melanoma

©2015 MFMER | slide-47

Melanoma in OTRs • MM prior to transplant

• 62 cases of MM in 60 patients • MM after transplant

• 703 cases of MM in 633 patients

Brewer JD, Christenson LJ, Weaver AL, Dapprich DC, Weenig RH, Lim KK, Walsh JS, Otley CC, Cherikh W, Buell JF, Woodle SE, Arpey C, Patton PR. Malignant Melanoma in Solid Organ Transplant Recipients: collection of database cases and

comparison with SEER data for outcome analysis. Arch Dermatol 2011; 147(7):790-796.

©2015 MFMER | slide-48

Overall Survival 3 year Overall Survival

Breslow Depth (mm) MM post OTR SEER

Data p value

< 0.75 88.2% 96.7% <0.001

0.76-1.50 80.8% 93.3% <0.001

1.51-3.0 51.2% 87.4% <0.001

> 3.0 55.3% 76.2% 0.007

Brewer JD, Christenson LJ, Weaver AL, Dapprich DC, Weenig RH, Lim KK, Walsh JS, Otley CC, Cherikh W, Buell JF, Woodle SE, Arpey C, Patton PR. Malignant Melanoma in Solid Organ Transplant Recipients: collection of database cases and

comparison with SEER data for outcome analysis. Arch Dermatol 2011; 147(7):790-796.

©2015 MFMER | slide-49

MM Specific Survival 3 year MM Specific Survival

(95% CI)

Breslow Depth (mm) MM post OTR SEER Data p value

< 0.75 97.8% 98.8% 0.70

0.76-1.50 89.4% 96.6% 0.07

1.51-3.0 73.2% 91.0% 0.002

> 3.0 73.9% 81.0% 0.31

Brewer JD, Christenson LJ, Weaver AL, Dapprich DC, Weenig RH, Lim KK, Walsh JS, Otley CC, Cherikh W, Buell JF, Woodle SE, Arpey C, Patton PR. Malignant Melanoma in Solid Organ Transplant Recipients: collection of database cases and

comparison with SEER data for outcome analysis. Arch Dermatol 2011; 147(7):790-796.

©2015 MFMER | slide-50

MM prior to Transplantation • 60 patients with MM prior to Transplant

• 2 metastases • 1 to LN’s (1 month post MM diagnosis) • 1 to lungs (14.8 years post MM diagnosis)

• No recurrences

Brewer JD, Christenson LJ, Weaver AL, Dapprich DC, Weenig RH, Lim KK, Walsh JS, Otley CC, Cherikh W, Buell JF, Woodle SE, Arpey C, Patton PR. Malignant Melanoma in Solid Organ Transplant Recipients: collection of database cases and

comparison with SEER data for outcome analysis. Arch Dermatol 2011; 147(7):790-796.

©2015 MFMER | slide-51

Conclusions MM in OTRs • Overall survival is worse in OTRs with MM regardless of

Breslow thickness • MM cause specific survival appears to be worse in thicker

MMs • Recurrence of MM is no higher in OTRs with a prior history

of MM

©2015 MFMER | slide-52

Risk Factors

©2015 MFMER | slide-53

Common Risk Factors for Skin Cancer in Transplant Patients • Increasing incidence with increasing age

• Hereditary

• Fair Skin, blond or red hair

• Blue, green or gray eyes

• Celtic background • History of previous NMSC • HPV • Sun exposure

SUN EXPOSURE

©2015 MFMER | slide-54

Kim NN, Boone SL, Ortiz S, Mallett K, Stapleton J, Turrisi R et al. Squamous cell carcinoma in solid organ transplant recipients: influences on perception of risk and optimal time to provide education. Arch Dermatol 2009;145:1196-7.

©2015 MFMER | slide-55

Dermatologic Surgery Volume 40, Issue 2, pages 93-100, 19 DEC 2013 DOI: 10.1111/dsu.12399 http://onlinelibrary.wiley.com/doi/10.1111/dsu.12399/full#dsu12399-fig-0001

©2015 MFMER | slide-56

The Empty Vessel Concept Does Knowledge Equal Behavior?

©2011 MFMER | slide-56

©2015 MFMER | slide-57

Conclusions

©2015 MFMER | slide-58

How to Unlock the Puzzle?... • Immune system • Behavioral factors • Other things that affects carcinogenesis

©2015 MFMER | slide-59

Summary What We Don’t Know

• Immunosuppressed patients with skin cancer • What is the underlying association • Does education and prevention effect outcomes • What predicts bad behavior

©2015 MFMER | slide-60

Future Direction and Research

• Pathogenic mechanisms • Genetic associations

• Optimal management • Formal recommendations needed

• Adjuvant therapy for high risk tumors • Educational strategies

• Effects on outcome

©2015 MFMER | slide-61

What Physicians Need to Know about Skin Cancer in Immunosuppressed Patients • Skin cancer can ruin a life • Skin cancer can take a life • Prevention must come early

• EARLY = CURE • Less immunosuppression = less cancer • Dermatologic surgeons and dermatologists should want to work

with other specialties • Expert help is available (www.ITSCC.org)

©2015 MFMER | slide-62

www.itscc.org