Bone Marrow Transplantation, (1999) 23, 1197–1199 1999 Stockton Press All rights reserved 0268–3369/99 $12.00 http://www.stockton-press.co.uk/bmt Case report Anaplastic squamous cell carcinoma (SCC) in a patient with chronic cutaneous graft-versus-host disease (GVHD) B Gmeinhart1, W Hinterberger2, HT Greinix3, W Rabitsch3, R Kirnbauer1, E Reiter3 and B Volc-Platzer1 1Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology and 3Bone Marrow Transplantation Unit, Department of Internal Medicine I, University of Vienna Medical School, Vienna; 22nd Department of Internal Medicine, Donauspital, Vienna, Austria Summary: faces occur progressively 10–15 years thereafter.1–3 The largest cohort study on nearly 20 000 allogeneic BM recipi- We describe an allogeneic bone marrow (BM) recipient ents showed the cumulative incidence for secondary solid who developed aggressive, metastasizing squamous cell tumors to be 6.7%. cancer (SCC) of the skin, and discuss possible risk fac- tors in the development of this secondary solid tumor. The patient had been treated with cyclosporine (CsA), Case report methyl-prednisolone and thalidomide for 3 years because of extensive de novo chronic cutaneous GVHD SCC was diagnosed in a previously healthy 26-year-old occurring 1 year after BMT. Ten years after BMT a Caucasian male patient in January 1985 who subsequently locally invasive and metastasizing SCC occurred on the received 8 units of packed red blood cells and 4 units of patient’s neck, and diagnosis was confirmed by H&E platelets. Five months later, after conditioning with 200 mg histopathology and cytokeratin-immunohistochemistry. Cy/kg body weight (b.w.) over 4 days and TBI of 3 Gy, Analysis of genomic DNA did not reveal p53 mutations he received 2.7 ϫ 108 nucleated cells (NC)/kg b.w. from his nor were HPV sequences detectable. Risk factors HLA class I and II identical brother. Methotrexate (MTX) included conditioning for BMT with total body according to the Seattle protocol was used as GVHD irradiation (TBI) and cyclophosphamide (Cy), immuno- prophylaxis. Neutrophil counts of more than 0.5 ϫ 109/l suppressive treatment for GVHD, and extensive and 1 ϫ 109/l were reached on days ϩ35 and ϩ53, respect- exposure to UV radiation before and after BMT. ively, after BMT. Unsupported platelets Ͼ20 ϫ 109/l, hem- Despite surgery and adjuvant chemotherapy with 5- atocrit Ͼ30% and reticulocytes Ͼ20 000/ml without the fluorouracil (5-FU) the patient died 1 year after the need for further transfusion were reached on days ϩ24 and diagnosis of SCC. ϩ12, respectively. Donor cell engraftment was documented Keywords: secondary malignancy; squamous cell carci- by the presence of donor ABO blood group. Because of noma; GVHD; immunosuppression poor marrow function MTX was stopped on day ϩ39. The patient showed no signs of acute GVHD and was dis- charged on day ϩ49 post BMT. One year after BMT, he developed de novo onset chronic With numbers of BM transplants from related and unrelated cutaneous GVHD with lichenoid lesions on the lips and oral donors increasing recently the frequency of secondary neo- mucosa. We initiated systemic immunosuppression with 1.5 plasms which impair long-term outcome and survival of mg prednisolone/kg b.w./day and CsA 5 mg/kg b.w./day. the BM recipients has also been increasing. The risk of Despite systemic immunosuppression, the cutaneous developing secondary cancer after allogeneic BMT has lesions progressed into chronic scleroderma-like GVHD been reported to be increased 6.69- to 11-fold over that of involving the neck, upper trunk, and upper and lower 1,2 an age-matched population. Whereas lymphoproliferative extremities with thickening of the dermis and contractures cancers, myelodysplastic syndrome, acute leukemia and of the joints, within 10 months. In addition to prednisolone non-Hodgkin’s lymphoma predominate in the first years 25 mg alternate day (a.d.) and CsA 2.5 mg/kg b.w. daily after BMT, solid cancers including neoplasms of the central thalidomide was started (4) at 100 mg/day, and the daily nervous system, bone, inner organs, skin and mucosal sur- dose was increased to 300 mg within 4 weeks. Three months after initiation of thalidomide treatment the sclero- derma-like lesions appeared softer, and joint contractures Correspondence: Dr B Volc-Platzer, Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, University of Vienna were less disabling. No further progression of chronic Medical School, Wa¨hringer Gu¨rtel 18–20, A-1090 Vienna, Austria GVHD was noted. Received 2 September 1998; accepted 28 December 1998 While he was on combined immunosuppressive therapy Secondary skin cancer and GVHD B Gmeinhart et al 1198 Figure 3 Chronic cutaneous GVHD of the skin with atrophy, dyspig- mentation and teleangectasia, and ulcerated SCC with elevated borders, Figure 1 Chronic cutaneous GVHD of the skin with scleroderma-like 10 ϫ 14 cm in size, on the right shoulder (1996, 11 years after BMT). thickening and a trophic ulcer on the right ankle (1987, approximately 2 years after BMT). painless plaque with ulceration on his right shoulder. This and thalidomide, multiple, well-defined, non-painful ulcers lesion was interpreted by the patient as a trophic ulcer simi- with slightly elevated margins developed within the sclero- lar to those he had developed on his legs several years dermatous lesions on the lower legs (Figure 1). Histologic before. Upon referral to our clinic a flat, non-painful ulcer, examination of a skin biopsy revealed ulceration with 10 ϫ 14 cm in size, with markedly elevated borders (Figure necrosis, granulation and excessive fibrosis (Figure 2) but 3) was seen within an area of chronic cutaneous GVHD no evidence of malignant transformation. Local treatment (epidermal atrophy, dyspigmentation and fibrosis/sclerosis), included clostridiopeptidase A (iruxolum) and topical ster- highly suggestive of skin cancer. Histologic examination oids on an a.d. basis. Immunosuppression with CsA 2.5 and immunohistochemistry with the pan-cytokeratin marker mg/kg b.w. daily, prednisolone 75 mg a.d. and thalidomide AE1/AE3 confirmed the diagnosis of SCC with malignant 200/100 mg a.d. was continued. After 20 months the leg epithelial cells containing multiple mitoses (Figure 4). One ulcers were completely healed. Thalidomide therapy was biopsy specimen was studied for the presence of human tapered off after 2 years of therapy in May 1989. Predniso- papilloma virus (HPV). Polymerase chain reaction (PCR) lone and CsA were stopped 9 months later, 3 years after was conducted on the purified DNA using one set of con- initiation of systemic immunosuppressive therapy. sensus primers from the E1 open reading frame of HPV.5 In October 1995 the patient noticed a small, reddish, However, no HPV fragments could be generated from the patient’s sample. In addition, no mutation in the p53 gene Figure 2 H & E histopathology of the chronic GVHD-associated ulcer: granulation tissue with newly formed capillaries, epithelial hyperplasia with regular epithelial cells on top of a fibrotic connective tissue. Perile- Figure 4 H&E histopathology of the tumor: malignant epithelial cells sional and paralesional infiltration of inflammatory mononuclear cells. with multiple atypical and irregular nuclei infiltrating the dermis. Secondary skin cancer and GVHD B Gmeinhart et al 1199 was detected by single-strand conformation polymorphism ple of our patient by a one-step PCR does not exclude HPV (SSCP) analysis.6 infection having contributed to the tumor development as Four weeks after surgery local tumor cell infiltration of a ‘hit and run’ mechanism with loss of the oncogenic virus the M. trapezius and the clavicula had developed. The clav- sequences in the fully developed tumor as has been icula and parts of the M. trapezius were removed before described in an animal cocarcinogenesis model.12 reconstruction of the defect with a flap patch derived from The excess risk of transplanted male patients developing the M. latissimus dorsi. By then, cervical and axillary SCC of the skin and the buccal cavity is unexplained.3 The lymph nodes were infiltrated with a rapidly growing tumor. male H-Y antigen is a minor histocompatibility antigen Local irradiation and chemotherapy with 5-fluorouracil, which is presented to immunocompetent female donor T 450 mg/m2, was initiated. The patient died 1 year after the lymphocytes in association with particular host class-I diagnosis of SCC of the skin from widespread metastatic alloantigen polymorphisms. Therefore, the somewhat disease. increased incidence of GVHD following transplantation of female-derived BM into male recipients is an additional risk factor for the development of SCC over male sex Discussion per se. Based on the knowledge that the risk of developing sec- Skin and mucosal neoplasms account for approximately ondary cutaneous neoplasms increases after allogeneic one-third of all secondary tumors after BMT, with SCC BMT, patients require regular life-long dermatologic fol- representing the majority of cases at about 50%.3 Similarly, low-up examinations but should also be alerted to carry out a significant incidence of skin cancer has been documented self-observation. in solid organ transplant recipients with a 20-fold increased risk for developing SCC in kidney and heart transplant recipients.7 Skin tumors behave more aggressively in these References patients than in immunocompetent individuals and have a higher risk of metastasis.7 It was not until this year that 1 Witherspoon RP, Fischer LD, Schoch G et al. Secondary can- chronic GVHD without treatment was shown to be linked cers after bone marrow transplantation for leukemia or aplastic 3 anemia. New Engl J Med 1989; 321: 784–789. with a higher risk of SCC of the skin and buccal cavity. 2 Bhatia S, Ramsay N, Steinbuch M et al. Malignant neoplasms Irradiation and immunosuppressive drugs are used for following bone marrow transplantation.