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Vol. 100 No 1 ORAL AND MAXILLOFACIAL PATHOLOGY July 2005 Editor: Alan R. Gould Squamous cell carcinoma of the oral cavity associated with graft versus host disease: Report of a case and review of the literature Federica Demarosi, DDS, MD,a Davide Soligo, MD,b Giovanni Lodi, DDS, PhD,c Laura Moneghini, MD,d Andrea Sardella, MD,e and Antonio Carrassi, MD,f Milan, Italy UNIVERSITY OF MILAN Allogenic peripheral stem cell transplantation (HSCT), a procedure that is widely used in the treatment of a large number of malignant and nonmalignant hematological diseases, is still associated with a wide range of complications, one of the most important of which is graft-versus-host disease (GVHD). The patients undergoing allogeneic HSCT are at high risk of developing secondary neoplasms, particularly leukemias and lymphomas. Solid tumors are less frequent, but their incidence seems to be higher in the patients who develop GVHD; the most frequent solid tumors are squamous cell carcinomas. We

here describe the clinical course and histopathologic aspects of a squamous cell carcinoma arising on GVHD-induced oral lesions in a 53-year-old woman with non-Hodgkin’s lymphoma undergoing allogeneic HSCT. Immediately after the transplantation, the patient developed GVHD involving the gastroenteric tract, skin, joints, and oral cavity, which was treated with cyclosporin, prednisone, azathioprine, colchicine, and photophereses. In addition to the sporadic reports of similar pictures published in the literature (16 cases of squamous cell carcinoma owing to oral GVHD in patients undergoing allogeneic HSCT), our case underlines the susceptibility of HSCT patients with oral GVHD to carcinoma of the oral cavity. All patients treated with allogeneic HSCT (particularly those who have developed GVHD) should therefore undergo a careful examination of the oral mucosa and be closely followed up over the long term with the aim of identifying the onset of secondary tumors as early as possible.

(Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;100:63-9) Allogenic hematopoietic stem cell transplantation (HSCT) is an increasingly effective treatment for leukemia and several other malignant and nonmalignant diseases.1,2 However, significant complications are associated with this procedure, including the development of graft-versus-host disease (GVHD) and secondary neoplasms. GVHD is a multisystem immunologic reaction resulting from grafting immunocompetent cells a Assistant researcher, Unit of Oral Pathology and Medicine, School of Dentistry. b Associate Professor, Bone Marrow Transplant Center, IRCCS Ospedale Maggiore. c Researcher, Unit of Oral Pathology and Medicine, School of Dentistry. d Consultant, Department of Pathology, Ospedale San Paolo. e Associate Professor, Unit of Oral Pathology and Medicine, School of Dentistry. f Professor, Unit of Oral Pathology and Medicine, School of Dentistry. Received for publication Jun 15, 2004; returned for revision Sep 15, 2004;

accepted for publication Dec 6, 2004. 1079-2104/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved doi:10.1016/jtripleo200412008 from one person to an immunodeficient host.3 The disease develops as transplanted immunocompetent donor T lymphocytes attack various recipient tissues because of differences in major and minor histocompatibility antigens.1 By definition, acute GVHD (aGVHD) develops within 100 days after HSCT, whereas chronic GVHD (cGVHD) develops after 100 days.3 cGVHD develops in 25% to 40% of long-term survivors after HSCT.3,4 The clinical manifestations of cGVHD most often affect skin, liver, gastrointestinal tract, lungs, and eyes, and 80% or more of these patients have oral involvement. The oral lesions includes atrophy, erythema, lichenoid lesions, xerostomia, and oral pain1,3 Treatment for this condition requires prolonged immunosuppression which can presumably contribute to the development of secondary cancers.1,5 Almost all secondary malignancies after

HSCT, such as lymphoma or leukemia, arise in hematopoietic tissue. Secondary solid tumors are less common, but the incidence appears to increase over time. Squamous carcinomas are the most common solid tumor.1,5,6 63 OOOOE July 2005 64 Demarosi et al Fig 1. Chronic GVHD lichenoid lesions of the right buccal mucosa (January 2000, 14 months after HSCT) Fig 2. Patient’s palate showing a large sharply demarcated red lesion, with a finely papillary surface (November 2002, 4 years after HSCT). Previous studies have shown that HSCT recipients have a slight but significant risk of secondary neoplasm, with the reported incidence being 4- to 7-fold that of the general population.7,8 This incidence is more than 10-fold for cancer of the oral cavity, esophagus, or thyroid gland.9 The largest cohort study on nearly 20,000 allogeneic HSCT recipients showed the cumulative prevalence for secondary solid tumors to be 2.2% at 10 years and 67% at 15 years after transplantation2 In this report

we describe a patient with cGVHD who developed oral carcinoma. The clinical course is described and the literature regarding any recent evidence of the development of solid tumors following HSCT is reviewed. CASE REPORT A 53-year-old white woman presented with a history of follicular non-Hodgkin’s lymphoma (NHL), diagnosed in 1990. She was treated with several courses of chemotherapy and finally enrolled for an allogeneic bone marrow transplantation from her HLA-identical sister. She was first seen at the Oral Pathology and Medicine Unit in November 1998 for preeallogeneic HSCT oral evaluation. At that time, radiological status was normal and no oral mucosa changes, carious lesions, or periodontal alterations were present; she received only a professional oral hygiene. She had never OOOOE Volume 100, Number 1 Demarosi et al 65 Fig 3. Histology of GVHD showing lymphocytic infiltration, degenerate changes of basal cell layer, intracellular edema of epithelial cells, and

ortokeratotic stratified squamous epithelium (253, H&E). Fig 4. Intraoral view of buccal maxilla gingiva showing ulcerated tumor (March 2003, 4 years and 5 months after HSCT) smoked and did not use alcohol. Conditioning regimen included etoposide (30 mg/kg/day 3 2 days), cyclophosphamide (60 mg/Kg/day 3 2 days), and total body irradiation (333 cGy in 3 fractions). GVHD prophylaxis consisted of cyclosporine A (3 mg/kg) and short-course methotrexate. The transplant was complicated by the onset of severe cGVHD at 5 months after the transplant. Clinical findings included mild liver dysfunction and gatrointestinal tract involvement, severe scleroatrophic melanodermic skin lesions of the arms, legs, and trunk, joint pain, and mucosal involvement (vaginal and ocular). The patient was treated with several combinations of immunosuppressive drugs, including cyclosporine A, corticosteroids, azathioprine, mycophenolic acid, and photopheresis, with a partial response. The patient was seen at

the Oral Pathology and Medicine Unit in May 1999 for the first post-allogeneic HSCT oral evaluation. At that time she had no oral mucosal lesions and she needed some restorative and prosthetic treatments. Following this visit the patient was seen at our clinic on a weekly basis from May to November 1999 to perform restorative and prosthetic cure. During this period, no lesion was observed in her oral mucosa. In January 2000, an oral clinical examination revealed bilateral red and white lichenoid-type lesions of the buccal mucosa (Fig 1), and a plaque-like lesion on the dorsum of the tongue. The gingiva was severely erythematous and inflamed, but not ulcerated. Hyposalivation was evident and the saliva was very thick and mucinous. At that time, a clinical diagnosis OOOOE July 2005 66 Demarosi et al Fig 5. Histologic section showing invasive squamous cell carcinoma (103, H&E) of oral cGVHD was made but a biopsy was refused by the patient. The patient was then seen on a monthly

basis until October 2000 and then every 3 months. The patient did not complain of oral symptoms and no topical therapy was started. She was then treated with a combination of cyclosporine A (250 mg/qd) and prednisolone (50 mg/qd). In November 2002 the patient complained of soreness and discomfort in the left maxilla gingiva and palate. A large sharply demarcated erythematous patch with a finely papillary texture covered most of the left palate with extension to the buccal upper gingiva (Fig 2). Erythematous and lichenoid lesions were still present on her right and left buccal mucosa. The impression was that this may have represented an unusual expression of human papillomavirus infection, but the possibility of epithelial dysplasia was also considered. Two incisional biopsies, on the left palate and on the left buccal gingiva, were performed and the specimens showed acute and chronic lichenoid changes (Fig 3). Basal cells showed vacuolization and satellitosis and lymphocytes were

present in the upper levels of the epithelium. The epithelium exhibited a papillary surface morphology with intracellular and intercellular edema of epithelial cells and loss of the normal maturation sequence. Lesions were evaluated by means of in situ PCR using probes for herpes simplex virus types I and II. All these test were negative. Candida hyphae were not detected by PAS staining. The clinical diagnosis of GVHD was confirmed. The patient was treated with a topical corticosteroid ointment and chlorhexidine rinses Concurrently she was treated with azathioprine (100 mg/qd) and photophereses (2 monthly). She was checked a month later and reported continuing discomfort of her palate despite the use of the steroid. On examination, the palate lesion also covered an area of the right palate, and the buccal surface of the left maxilla gingiva. A second biopsy was performed and the specimens (2 from the palate and 1 from the buccal gingiva) showed essentially identical features as the

first biopsy. In March 2003, the patient presented to the follow-up with an eroded mass, 1 3 2 cm in size, involving the buccal gingiva of the left maxilla (Fig 4). Microscopic examination of the gingiva showed a papillary surface of the epithelium with severe dysplasia and invasive squamous cell carcinoma. Moreover, the specimens showed acute and chronic lichenoid inflammation, inter- and intracellular edema of epithelial cells consistent with GVHD (Fig 5). The patient was referred to the Oral Maxillofacial Unit to perform an adequate treatment. DISCUSSION Previous studies have shown that HSCT recipients are at significantly higher risk for developing secondary cancers than the general population.8,10-13 A strong relationship was found between patient age at the time of transplantation and risk of cancer. The risk reaches its peak among children who have undergone transplantation when they are 10 years old, and it is higher for those who are 10 to 29 years old at the time of

transplantation than for those who are 30 years or older.2 Lymphoproliferative cancers, myelodysplastic syndromes, acute leukemias, and non-Hodgkin’s lymphomas predominate early post-HSCT period, while solid tumors occur later.2,7,14 Skin and mucosal neoplasms account for approximately one-third of all secondary solid tumors in HSCT patients, with squamous cell carcinoma representing 50% of these cases.2 In addition to the current case, our review of the literature revealed 16 cases of oral squamous cell carcinoma that developed in patients with allogeneic HSCT (Table I). OOOOE Volume 100, Number 1 Demarosi et al 67 Table I. Oral cancer in HSCT patients Reference 1 Abdelsayed et al, 2002 Bradford et al,24 1990 Flowers et al,25 1992 Lishner et al,17 1990 Lowsky et al,10 1994 Millen et al,15 1997 Otsubo et al,6 1997 Socie et al,20 1991 Zhang et al,26 2002 Current case Gender Age at diagnosis (years) Location Oral cGVHD Interval between HSCT and oral cancer (years) Reason

for HSCT M M F F F M F F F F M M M M M M F 24 14 53 20 14 41 31 27 18 20 24 12 6 35 47 54 53 buccal mucosa tongue tongue tongue tongue buccal mucosa tongue mouth buccal mucosa gingiva mouth lip tongue tongue ower lip lower lip gingiva yes no yes yes no yes yes yes yes yes yes yes no yes yes yes yes 2 8 9 [10 [10 6 [10 6 9 4 NS NS NS 8 7 5 5 ALL ALL FA FA FA AA AA AA FA AA AA AA FA CML CML AML NHL ALL, acute lymphoblastic/lymphocytic leukemia; FA, Fanconi’s anemia; AA, aplastic anemia; CML, chronic myelogenous leukemia; AML, acute myelogenous leukemia; NS, not stated. Potential risk factors associated with the development of secondary cancers after HSCT have been well described. They include GVHD, treatment of the primary malignancy with either radiotherapy or chemotherapy or their combination, transplantation conditioning regimen, antigenic stimulation from histocompatibility differences between recipient and donor, immunosuppressive GVHD prophylaxis, interaction of any of

these factors with genetic predisposition, and other factors such as viruses and gender.2,6,7,13 Chronic GVHD, with its chronic inflammation of the skin and mucosa, has been long suspected to be a potential risk factor for the development of cutaneous and mucosal cancers.2,10,15,16 Several authors have observed the development of solid malignancies at anatomic sites initially involved with cGVHD-related inflammatory processes.1 Lishner et al showed a moderate association between cGVHD and the development of skin cancers.17 In our case, although histopathologic examination of the oral lesions was not initially performed, the buccal mucosa and gingival exhibited erythematous and lichenoid lesions consistent with oral involvement by GVHD. Subsequently, carcinoma evolved in the gingival mucosa. As shown in Table I, almost all documented cases of oral squamous cell carcinoma (SCC) in HSCT patients with GVHD developed from oral mucosa affected by the disease; the time between the diagnosis

of cGVHD and the diagnosis of carcinoma ranged from 2 to more than 10 years. In our case, the patient developed SCC 5 years after HSCT and almost 3 years after the onset of oral cGVHD. Irradiation and immunosuppressive drugs are used for conditioning and for prophylactic treatment of GVHD. Carcinogenesis caused by ionizing radiation has been well studied in healthy animals and in humans.9 Many authors have strongly suggested that irradiation is a major risk factor for post-transplant malignancies.14 The risk of cancer developing in patients who underwent irradiation before HSCT is up to 18.4 times higher than the risk for those who did not undergo irradiation.2 Consistent with this observation, an increased incidence of cancer has been observed in dogs given irradiation before transplant compared to dogs not receiving irradiation.18 Bathia described total body radiation as an independent risk factor for solid tumors.7 Witherspoon described total body irradiation as a risk factor for

malignant neoplasm after marrow transplantation, but the relative risk was lower than that of immunosuppressive treatment with antithymocyte globulin and monoclonal T-cell antibodies.8,19 The strongest effect of irradiation was found by Socié in patients with aplastic anemia. Among patients who underwent marrow transplantation, solid tumors were more frequent in male patients treated with radiation for conditioning. In that study, 7 solid tumors were reported, of which 5 were located in the head and neck region.20,21 Treatment of GVHD with cyclosporine, azathioprine, and thalidomide significantly increased the risk for malignant neoplasms.9 Azathioprine and cyclosporine have been reported to be associated with an increased risk for secondary neoplasms in solid organ transplant recipients and, also, azathioprine appears to promote/ facilitate secondary neoplasms when used as treatment OOOOE July 2005 68 Demarosi et al for cGVHD.14 In contrast to azathioprine, cyclosporine is not

mutagenic but rather induces phenotypic changes, including invasiveness of nontransformed cells, by a cell-autonomous mechanism. Cyclosporine can promote cancer progression by a direct cellular effect that is independent of its effect on the host’s immune cells.22 An increased risk for cutaneous and mucosal neoplasms was reported by Lishner et al, who found these tumors in patients who had cGVHD and prolonged immunosuppressive treatment.17 Thus, immunosuppression using cyclosporine and azathioprine may have contributed significantly to the development of squamous cell carcinoma in our patient. It is very likely that several factors in combination produce secondary malignant neoplasms. Radiation and chemotherapy can cause genetic damage, and immunosuppression exerts a cocarcinogenic effect that favors the outgrowth of malignant cells.9 Our patients received radiation, chemotherapy, and prolonged immunosuppressive therapy. In addition, infectious agents leading to host cell

transformation may be considered. Oncogenic viruses such as human papillomaviruses (HPV) may contribute to squamous cell carcinoma of the skin and buccal mucosa after HSCT.2 Smoking, alcohol, male gender, and older age are considered the most important risk factors of oral cancer. Our patient had none of these; therefore, these risk factors may not be relevant in HSCT patients. Oral lichen planus (OLP) is a relatively common condition of the oral mucosa of unknown etiology that is clinically and histologically identical to cGVHD. In both diseases the immune system plays a primary role in the pathogenesis. On the basis of the evidence from the literature, OLP is considered by the majority of authors to be a condition with a small but significant malignant potential.23 Because of such similarities between cGVHD and OLP, a common malignant potential based on the same mechanisms can be suspected. In conclusion, transplant recipients should be followed indefinitely to detect early oral

cancer and precursor lesions, and they should avoid exposure to carcinogens which may increase the risk of solid cancers. Moreover, the current case and similar sporadic case reports found in the literature highlight the apparent susceptibility of patients with cGVHD to the development of oral cancer. Therefore, it is recommended that thorough evaluation of the oral mucosa and close follow-up be offered to all patients treated with bone marrow transplantation and particularly to those who develop cGVHD. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. REFERENCES 1. Abdelsayed RA, Sumner T, Allen CM, Treadway A, Ness GM, Penza SL. Oral precancerous and malignant lesions associated 21. with graft-versus-host disease: report of 2 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;93:75-80. Curtis RE, Rowlings PA, Deeg HJ, Shriner DA, Socie G, Travis LB, et al. Solid cancers after bone marrow transplantation N Engl J Med 1997;336:897-904. Eggleston

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Thongprasom K. Current controversies in oral lichen planus: report of an international consensus meeting. Part 2 Clinical management and malignant transformation. Oral Surg Oral Med Oral Patol Oral Radiol Endod 2005;100:40-51. Bradford CR, Hoffman HT, Wolf GT, Carey TE, Baker SR, McClatchey KD. Squamous carcinoma of the head and neck in organ transplant recipients: possible role of oncogenic viruses. Laryngoscope 1990;100:190-4. Flowers ME, Doney KC, Storb R, Deeg HJ, Sanders JE, Sullivan KM, et al. Marrow transplantation for Fanconi anemia with or Demarosi et al 69 without leukemic transformation: an update of the Seattle experience. Bone Marrow Transplant 1992;9:167-73 26. Zhang L, Epstein JB, Poh CF, Berean K, Lam WL, Zhang X, et al. Comparison of HPV infection, p53 mutation and allelic losses in posttransplant and nonposttransplant oral squamous cell carcinomas. J Oral Pathol Med 2002;31:134-41 Reprint requests: Federica Demarosi Unità di Patologia e Medicina Orale Dipartimento

di Medicina, Chirurgia e Odontoiatria Via Beldiletto 1 20142 Milano Italy federica.demarosi@unimiit