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Rejecting preconceived notions of squamous cell carcinomas in patients experiencing transplant rejections

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By Warren R. Heymann, MD
Aug. 21, 2019
Vol. 1, No. 24

heymann-warren-95px.jpgDermatologists are keenly aware of immunosuppression’s profound biologic effects. Whether by disease or iatrogenic means, clinical vigilance is mandated because of an elevated risk of malignancy, infection, or inflammatory dermatoses. 

In a study of 177 organ transplant recipients (OTR) in Brazil, the mean age of the study was 52 years, while the mean age of transplantation was 42.7 years. The kidney was the most common organ transplanted (72%). Skin lesions were found in 147 patients (83%). Cutaneous infections were seen in 106 patients (60%). Warts (30%) had the highest incidence. Superficial mycoses occurred in 16% of OTR, mostly onychomycosis. Actinic keratosis (AK) occurred in 31% of patients and cutaneous tumors in 56%. Squamous cell carcinoma (SCC) was the most common tumor type affecting 36% of OTR (n = 64), with invasive SCC predominating over in situ SCC, whereas basal cell carcinoma (BCC) accounted for 17% of the tumors. Inflammatory complications predominantly due to transplantation medications (acne, alopecia, hypertrichosis, and gingival overgrowth) were observed in 17.5% of patients. (1)

This commentary focuses on solid organ transplantation (SOT) patients, with an emphasis on squamous cell carcinomas in the context of organ transplant rejection. As the number of transplant recipients escalates, dermatologists will increasingly confront this problem. 

Squamous cell carcinomas (SCCs) are the most frequent skin cancers in the transplant population. In a population-basedRejecting preconceived notions of squamous cell carcinomas

cohort study of 10,649 organ transplant recipients, Garrett et al reported that the incidence ratio for posttransplant skin cancer overall was 1,437 per 100,000 person-years. The specific subtype rates for squamous cell carcinoma, malignant melanoma, and Merkel cell carcinoma were 812, 75, and 2 per 100,000 person-years, respectively. (2) Other risk factors for nonmelanoma skin cancers in the transplant population include an older age at transplantation, a pretransplant history of skin cancer, and Fitzpatrick skin types I and II. (3) Lanz et al have demonstrated that anatomical site (face and scalp > upper extremities), tumor diameter (median 18 mm), tumor depth (median 6.2 mm) and perineural invasion are important factors determining aggressive behavior (defined by nodal or distant metastasis or death by local progression of primary tumors) of SCCs. (4) 

The management of SCC in transplant recipients may be a daunting proposition, often necessitating a multidisciplinary approach (dermatologists, oncologists, plastic surgeons, radiation oncologists, social workers, etc.). Prevention strategies include sun protection and avoidance, topical chemotherapy (5-fluorouracil, imiquimod, etc.), photodynamic therapy, and systemic chemoprevention (acetretin, nicotinamide, and capecitabine). (5) Human papillomavirus vaccine may be a useful modality, an example being a 50-year-old female renal transplant recipient with acquired epidermodysplasia verruciformis that only resolved after the recombinant vaccine to HPV (types 6, 11, 16, and 18) was given following, and in concert with, topical imiquimod and tretinoin, and oral acitretin. (6)

My primary motivation in writing this commentary was based on an intriguing article by Puza et al, who investigated whether there is a relationship between transplant rejection and cutaneous SCCs (cSCC). In total, 1,684 patients were identified from the Duke Enterprise Data Unified Content Explorer who had undergone a renal transplant at Duke over a 20-year period. Of the renal transplant recipients, 126 (7.5%) experienced an episode of rejection and 46 (4.0%) developed a cSCC after transplant. The incidence of cSCC was significantly greater in the rejection group, with 8.7% of patients developing cSCC compared with 2.2% in the no-rejection group (P < 0.001). Median lag time to cSCC was shorter in the rejection group (2.5 years; age 0.4-9.0 years) than the non-rejection group (4.2 years; range 1.3-20.4 years) (P < 0.03). The authors concluded that transplant rejection is associated with both a higher incidence and an accelerated time course for the development of cSCC following renal transplantation. They advised that close dermatological surveillance should be considered following an episode of rejection in this patient population. (7)

Honestly, I was surprised by these results. The authors themselves considered these findings counterintuitive — those patients having transplant rejection demonstrated functioning immunity allowing tumor immunosurveillance — clearly, that was not the case in this study. Presumably, the increased immunosuppression needed to treat the episodes of rejection trumped any potentially helpful anti-carcinogenic mechanism.

There is dearth of literature addressing cSCC in transplantation rejection. In DeRosa et al, a history of allograft rejection was not associated with an increased risk of skin cancer. (3)

Rejection hurts — in love, profession, or organ transplantation. For transplant recipients undergoing rejection, more studies are needed to determine if aggressive cSCCs are truly more frequent and/or aggressive in this population. Regardless, aggressiveness should be the dermatologist’s mantra for the prevention of SCCs by performing careful examinations to recognize and biopsy any suspicious lesions. 

Point to remember: Reject any notion of going lightly on skin cancer surveillance for transplant recipients with a history of organ rejection. 

Our Expert’s Viewpoint
Christopher Miller, MD
Director, Penn Dermatology Oncology Center
Associate Professor of Dermatology
Hospital of the University of Pennsylvania

This study by Puza et al. concludes that kidney transplant rejection increases the risk for cutaneous squamous cell cancer (cSCC), but this conclusion should be interpreted with caution for two reasons. First, the study cohort is too small to make reliable conclusions. The study included only 11 patients who developed cSCC after an episode of rejection. Second, conflicting data from other small cohorts of heart and lung transplant recipients indicate that rejection does not increase the risk for skin cancer (DeRose N et al.  JAMA Dermatol 2019). As we await further studies to resolve this issue, the bottom line remains the same: organ transplant recipients require close surveillance for skin cancer, regardless of their rejection history.

1. Oliveira WRP, Tirico MCCP, Souza AAV, Codarin FP, et al. Skin lesions in organ transplant recipients: A study of 177 consecutive Brazilian patients. Int J Dermatol 2019; 58: 440-448. 
2. Garrett GL, Blanc PD, Boscardin J, Lloyd AA, Ahmed RL, et al. Incidence of and risk factors for skin cancer in organ transplant recipients in the United States. JAMA Dermatol 2017; 153: 296-303.
3. DeRosa N, Paddon VL, Liu Z, Glanville AR, Parsi K. Nonmelanoma skin cancer frequency and risk factors in Australian heart and lung transplant recipients. JAMA Dermatol 2019; Mar 13 [Epub ahead of print]
4. Lanz J, Bavnick JNB, Westhuis M, Quint KD, et al. Aggressive squamous cell carcinoma in organ transplant recipients. JAMA Dermatol 2019; 155: 66-71. 
5. Collins L, Quinn A, Stasko T. Skin cancer and immunosuppression. Dermatol Clin 2019; 37: 83-94. 

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