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Who Needs a Skin Exam? Skin Cancers in Allogeneic Hematopoietic Stem Cell Transplant Recipients in the Contemporary Era

  • Adèle de Masson
    Correspondence
    Correspondence: Adele de Masson, Department of Dermatology, Paris 7 University, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75 010 Paris, France.
    Affiliations
    Department of Dermatology, Assistance Publique–Hôpitaux de Paris Hôpital Saint-Louis, Skin Research Center, Institut National de la Santé et de la Recherche Médicale U976 and University Paris 7, Paris, France
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  • Jean-David Bouaziz
    Affiliations
    Department of Dermatology, Assistance Publique–Hôpitaux de Paris Hôpital Saint-Louis, Skin Research Center, Institut National de la Santé et de la Recherche Médicale U976 and University Paris 7, Paris, France
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  • Gérard Socié
    Affiliations
    Hematology/Transplantation, Assistance Publique–Hôpitaux de Paris Hôpital Saint Louis, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1160 and University Paris 7, Paris, France
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      Allogeneic hematopoietic stem cell transplantation provides a graft-versus-malignancy effect and long-term remissions in high-risk hematological malignancies. Reduced-intensity conditioning regimens have been developed, transplantation has become safer, and the number of long-term transplantation survivors is expected to rise. Wu et al. (2018) report the increased incidence and risk factors of skin cancer in 1994 transplant recipients followed in the last 25 years.

      Abbreviations:

      BCC (basal cell carcinoma), CI (confidence interval), CLL (chronic lymphocytic leukemia), GVHD (graft-versus-host disease), HCT (hematopoietic stem cell transplantation), SCC (squamous cell carcinoma), SIR (standardized incidence ratio), SOT (solid organ transplant)
      • Skin cancer risk is increased in allogeneic hematopoietic stem cell transplant recipients.
      • Reduced-intensity conditioning regimens are increasingly used and these may be a risk factor.
      • Allogeneic hematopoietic stem cell transplantation is a rapidly evolving field and new transplant types are being developed.
      Fifty years after the first successful allogeneic hematopoietic stem cell transplantation (HCT), HCT has provided long-lasting remissions in several previously incurable malignant and nonmalignant hematological disorders. HCT offers cures for inherited bone marrow failure syndromes and acquired aplastic anemia. By inducing a graft-versus-malignancy effect, HCT also provides durable disease control in myeloid and lymphoid hematological malignancies. With the development of non-myeloablative and reduced-intensity conditioning regimens, HCT is now offered to a growing number of elderly or medically impaired patients. Most solid-organ (e.g., kidney, heart, liver) transplant (SOT) recipients require lifelong immunosuppressive drugs to prevent graft rejection. However, development of immune tolerance allows the tapering and withdrawal of immunosuppressive drugs within the first year after allogeneic HCT in the absence of graft-versus-host disease (GVHD). GVHD occurs in roughly half of HCT recipients and remains a major cause of morbidity and death in this population. Allogeneic HCT survivors have an increased risk of malignancy (
      • Curtis R.E.
      • Rowlings P.A.
      • Deeg H.J.
      • Shriner D.A.
      • Socié G.
      • Travis L.B.
      • et al.
      Solid cancers after bone marrow transplantation.
      ). Post-transplantation malignancies in these patients include B-cell (often associated with the presence of Epstein-Barr virus) and T-cell post-transplantation lymphoma disease, myelodysplastic syndromes and acute leukemia, and solid tumors. Squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and melanoma are UV-induced skin cancers. While BCC is more common than SCC in the general population, this ratio is completely reversed in SOT recipients, highlighting the extraordinary risk for SCC development in these immunocompromised patients. T cells are believed to play an important role in the control of SCC (
      • Clark R.A.
      • Huang S.J.
      • Murphy G.F.
      • Mollet I.G.
      • Hijnen D.
      • Muthukuru M.
      • et al.
      Human squamous cell carcinomas evade the immune response by down-regulation of vascular E-selectin and recruitment of regulatory T cells.
      ). In this issue of the Journal of Investigative Dermatology,
      • Wu P.A.
      • Stern R.S.
      • Huang V.
      • Liu K.X.
      • Chen C.
      • Tzachanis D.
      • et al.
      Reduced intensity conditioning regimens, prior chronic lymphocytic leukemia, and graft versus host disease are associated with higher rates of skin cancer following allogeneic hematopoietic stem cell transplantation.
      report on the incidence and risk factors of skin cancer after allogeneic HCT in the modern era.
      The risk of solid organ cancer in allogeneic HCT recipients has been studied for decades. Almost 30 years ago,
      • Witherspoon R.P.
      • Fisher L.D.
      • Schoch G.
      • Martin P.
      • Sullivan K.M.
      • Sanders J.
      • et al.
      Secondary cancers after bone marrow transplantation for leukemia or aplastic anemia.
      studied 2,246 patients who received transplants in Seattle and observed 35 new malignancies, including 3 cases of melanoma and 3 SCCs. Tumors were diagnosed at a median time of 1 year after transplantation (
      • Witherspoon R.P.
      • Fisher L.D.
      • Schoch G.
      • Martin P.
      • Sullivan K.M.
      • Sanders J.
      • et al.
      Secondary cancers after bone marrow transplantation for leukemia or aplastic anemia.
      ). The use of antithymocyte globulin, anti-CD3 antibody, or total body irradiation as a treatment of acute GVHD was significantly associated with the occurrence of solid organ cancer.
      • Bhatia S.
      • Ramsay N.K.
      • Steinbuch M.
      • Dusenbery K.E.
      • Shapiro R.S.
      • Weisdorf D.J.
      • et al.
      Malignant neoplasms following bone marrow transplantation.
      undertook an analysis of 2,150 recipients of HCT at the University of Minnesota between 1974 and 1995. Fifteen patients developed solid tumors (8 in 1,400 allogeneic and 7 in 750 autologous transplant recipients), including 3 cases of melanoma (standardized incidence ratio [SIR] = 10.3, 95% confidence interval [CI], 1.9–25), 1 SCC, and 3 cases of BCC. Total body irradiation was the major risk factor for solid organ cancer (
      • Bhatia S.
      • Ramsay N.K.
      • Steinbuch M.
      • Dusenbery K.E.
      • Shapiro R.S.
      • Weisdorf D.J.
      • et al.
      Malignant neoplasms following bone marrow transplantation.
      ).
      • Curtis R.E.
      • Rowlings P.A.
      • Deeg H.J.
      • Shriner D.A.
      • Socié G.
      • Travis L.B.
      • et al.
      Solid cancers after bone marrow transplantation.
      studied 19,229 patients who received HCT between 1964 and 1992 at 235 centers and found a significantly elevated risk for skin melanoma (SIR = 5.0, 95% CI, 2.5–8.9). Melanoma development was associated with high-dose total body irradiation, and SCC was associated with chronic GVHD and male sex.
      Risk factors for BCC and SCC were determined in a retrospective cohort study of 4,810 patients who received allogeneic HCT between 1969 and 2003 and survived for at least 100 days (
      • Leisenring W.
      • Friedman D.L.
      • Flowers M.E.D.
      • Schwartz J.L.
      • Deeg H.J.
      Nonmelanoma skin and mucosal cancers after hematopoietic cell transplantation.
      ). Among these allogeneic HCT recipients, 237 developed at least one skin or mucosal cancer (BCC, n = 158; SCC, n = 95). Twenty-year cumulative incidences of BCC and SCC were 6.5% and 3.4%, respectively. Total-body irradiation was a significant risk factor for BCC, most strongly among patients younger than 18 years old at HCT. Light-skinned patients had an increased risk of BCC. Acute GVHD increased the risk of SCC, whereas chronic GVHD increased the risk of both BCC and SCC.
      In a more recent study published in 2009 on 28,874 allogeneic transplant recipients, there were 189 observed cases of solid malignancies, including 18 cases of invasive skin SCC. Significantly elevated risks were also observed for tumors of the oral cavity (observed to expected ratio = 7.0), and for melanoma of the skin (observed to expected ratio = 3.5), among others. Chronic GVHD and male sex were the main determinants for risk of SCC of the skin. Interestingly, in this largest series ever published, the risk of skin melanoma was increased, not only by irradiation, but also in patients who were transplanted with T-cell–depleted grafts (
      • Rizzo J.D.
      • Curtis R.E.
      • Socié G.
      • Sobocinski K.A.
      • Gilbert E.
      • Landgren O.
      • et al.
      Solid cancers after allogeneic hematopoietic cell transplantation.
      ).
      In this issue of the Journal of Investigative Dermatology,
      • Wu P.A.
      • Stern R.S.
      • Huang V.
      • Liu K.X.
      • Chen C.
      • Tzachanis D.
      • et al.
      Reduced intensity conditioning regimens, prior chronic lymphocytic leukemia, and graft versus host disease are associated with higher rates of skin cancer following allogeneic hematopoietic stem cell transplantation.
      studied 1,974 adults who received HCT at Beth Israel Deaconess Medical Center and Dana Farber Cancer Institute between 1995 and 2013 for hematologic malignancies, with a median follow-up of 3 years. The risk for SCC (incidence rate ratio = 9.8; 95% CI = 7.7–12.3), BCC (incidence rate ratio = 2.5; 95% CI = 1.9–3.2) and melanoma (SIR = 3.3; 95% CI = 1.7–5.9) was elevated. The 10-year cumulative incidence estimates of SCC and BCC were 5.5% and 3.8%, and these were higher than in the previously published study by
      • Leisenring W.
      • Friedman D.L.
      • Flowers M.E.D.
      • Schwartz J.L.
      • Deeg H.J.
      Nonmelanoma skin and mucosal cancers after hematopoietic cell transplantation.
      . In multivariable models, risk factors for SCC were increased age (P < 0.0001), chronic lymphocytic leukemia (CLL) (P = 0.02), and chronic GVHD (P = 0.0002). Risk factors for BCC were CLL (P = 0.003), reduced-intensity conditioning (P = 0.02), acute GVHD (P = 0.03), and chronic GVHD (P = 0.003). Novel risk factors in this contemporary cohort included prior CLL for SCC and BCC, and reduced-intensity conditioning for BCC (Figure 1). Of note, the inversed SCC/BCC ratio observed in the study by
      • Wu P.A.
      • Stern R.S.
      • Huang V.
      • Liu K.X.
      • Chen C.
      • Tzachanis D.
      • et al.
      Reduced intensity conditioning regimens, prior chronic lymphocytic leukemia, and graft versus host disease are associated with higher rates of skin cancer following allogeneic hematopoietic stem cell transplantation.
      is similar to what had been described in SOT recipients.
      Figure thumbnail gr1
      Figure 1Summary of the risk factors of skin squamous cell carcinoma and basal cell carcinoma after allogeneic hematopoietic stem cell transplantation. Factors associated with the occurrence of basal cell carcinoma or squamous cell carcinoma in multivariable analysis in the study by
      • Wu P.A.
      • Stern R.S.
      • Huang V.
      • Liu K.X.
      • Chen C.
      • Tzachanis D.
      • et al.
      Reduced intensity conditioning regimens, prior chronic lymphocytic leukemia, and graft versus host disease are associated with higher rates of skin cancer following allogeneic hematopoietic stem cell transplantation.
      . Total body irradiation has been associated with an increased risk of skin cancer in previous studies, but is associated with a reduced risk of basal cell carcinoma in the study by
      • Wu P.A.
      • Stern R.S.
      • Huang V.
      • Liu K.X.
      • Chen C.
      • Tzachanis D.
      • et al.
      Reduced intensity conditioning regimens, prior chronic lymphocytic leukemia, and graft versus host disease are associated with higher rates of skin cancer following allogeneic hematopoietic stem cell transplantation.
      . BCC, basal cell carcinoma; CLL, chronic lymphocytic leukemia; GVHD, graft-versus-host disease; TBI, total body irradiation; RIC, reduced-intensity conditioning; SCC, squamous cell carcinoma.
      This increased risk of skin cancer after allogeneic HCT has to be put in perspective with the risk of cutaneous malignancies in SOT recipients. Do we need to screen allogeneic HCT recipients as carefully as SOT recipients for skin cancer? The risk of skin cancer is higher in SOT recipients than in the general population, 65-fold for SCC and 3-fold for melanoma (
      • Moloney F.J.
      • Comber H.
      • O’Lorcain P.
      • O’Kelly P.
      • Conlon P.J.
      • Murphy G.M.
      A population-based study of skin cancer incidence and prevalence in renal transplant recipients.
      ). In a recent multicenter retrospective cohort study of 10,649 adult recipients of a primary transplant across the United States, the incidence of overall skin cancer was 1,437 per 100,000 person-years. Most cancers were SCC, which had the highest incidence rate at 1,355 per 100,000 person-years. By comparison, the general adult population age-adjusted incidence rate of SCC was 38 per 100,000 (
      • Garrett G.L.
      • Blanc P.D.
      • Boscardin J.
      • Lloyd A.A.
      • Ahmed R.L.
      • Anthony T.
      • et al.
      Incidence of and risk factors for skin cancer in organ transplant recipients in the United States.
      ).
      The age-adjusted incidence of SCCs, BCCs, and melanoma in allogeneic HCT recipients in the study by
      • Wu P.A.
      • Stern R.S.
      • Huang V.
      • Liu K.X.
      • Chen C.
      • Tzachanis D.
      • et al.
      Reduced intensity conditioning regimens, prior chronic lymphocytic leukemia, and graft versus host disease are associated with higher rates of skin cancer following allogeneic hematopoietic stem cell transplantation.
      was 1,000, 692, and 141, respectively, per 100,000 person-years.
      These data suggest that the risk of skin cancer in allogeneic HCT recipients may be comparable to that of SOT recipients, and justifies the systematic, lifelong screening of this population for skin cancer, especially in patients with chronic GVHD. The risk of mucosal SCC must not be forgotten in these patients.
      As in SOT recipients, avoidance of excessive sun exposure and self-screening should be encouraged after allogeneic HCT. There is also the question of the immunosuppressive drugs to be used for the prevention and treatment of GVHD in patients at high risk for skin cancer. Calcineurin inhibitors and azathioprine have been linked to the development of skin neoplasms in SOT recipients. Results from clinical trials in SOT suggest that mTOR inhibitors, on the other hand, could reduce the risk of skin cancer in this population. The use of azathioprine has also been associated with SCC after allogeneic HCT, particularly when combined with cyclosporine and steroids for chronic GVHD (
      • Curtis R.E.
      • Metayer C.
      • Rizzo J.D.
      • Socié G.
      • Sobocinski K.A.
      • Flowers M.E.
      • et al.
      Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: an international case-control study.
      ). Although azathioprine is no longer commonly used, it should be noted that mycophenolate mofetil, which shares a similar mode of cellular action with azathioprine, is now widely used in this setting. More studies are also needed to determine the role of human papillomavirus infection in post-allogeneic HCT SCC and the potential utility of human papillomavirus vaccination in the prevention of SCC in these patients. Finally, the continuous progress made in the field of allogeneic HCT, with the development of new reduced-intensity conditioning regimens (associated with an increased risk of BCC in the present study) and, more recently, the growing use of haploidentical transplantation, warrants further evaluation of the long-term effects in these patients. In particular, reduced-intensity conditioning regimens are usually delivered to older or medically impaired patients. BCC is often a disease of older age. Thus, whether reduced-intensity conditioning per se is a risk factor for BCC warrants confirmatory studies.
      Close collaborations between dermatologists and hemato-oncologists for lifelong surveillance of this high-risk population are needed more than ever.

      Conflict of Interests

      The authors state no conflict of interests.

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