Oral precancerous and malignant lesions associated with graft-versus-host disease: Report of 2 cases

Oral precancerous and malignant lesions associated with graft-versus-host disease: Report of 2 cases Rafik A. Abdelsayed, DDS, MS,a Ty Sumner, DMD,b Carl M. Allen, DDS, MSD,c Antwan Treadway, DMD,d Gregory M. Ness, DDS,e and Sam L. Penza, MD,f Augusta, Ga, and Columbus, Ohio MEDICAL COLLEGE OF GEORGIA AND THE OHIO STATE UNIVERSITY

The development of secondary malignancies has been recognized as a potential iatrogenic complication in patients who have graft-versus-host disease secondary to bone marrow transplantation. Lymphohematopoietic cancer is most frequent, although solid malignancies have also been reported. We describe 2 patients with graft-versus-host disease who developed oral precancerous and malignant lesions. The first patient, a 24-year-old white man, had erythroplakia of the buccal mucosa that proved to be carcinoma in situ histopathologically. The second patient, a 14-year-old Hispanic boy, developed synchronous cutaneous and lingual squamous cell carcinomas. The current cases and similar sporadic case reports found in the literature highlight the susceptibility of patients with graft-versus-host disease 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 graft-versus-host disease. (Oral Surg Oral Med Oral Pathol

Oral Radiol Endod 2002;93:75-80)

Allogeneic bone marrow transplantation (BMT) has been used increasingly throughout the world as a therapeutic modality in recent years for patients diagnosed with various lymphoreticular malignancies, as well as hematologic and metabolic disorders.1 Pre-BMT conditioning regimens typically make use of high-dose chemotherapy, with or without total body irradiation, to destroy abnormal or malignant cells.2 Graft-versushost disease (GVHD) is a common complication in patients who are treated with allogeneic BMT. The disease develops as transplanted immunocompetent donor T lymphocytes attack various recipient tissues because of differences in major and minor histocom-

Case 2 in this article was presented at the annual meeting of the American Academy of Oral and Maxillofacial Pathology, Chicago, April 27-May 2, 2001. aAssociate Professor, Oral Biology and Maxillofacial Pathology, School of Dentistry, Medical College of Georgia, Augusta. bChief Resident, Oral and Maxillofacial Surgery, School of Dentistry, Medical College of Georgia, Augusta. cProfessor and Director, Oral and Maxillofacial Pathology, College of Dentistry, The Ohio State University, Columbus. dAssistant Professor, Oral and Maxillofacial Surgery, Medical College of Georgia, Augusta. eAssociate Professor–Clinical, Oral and Maxillofacial Surgery, College of Dentistry, The Ohio State University, Columbus. fAssociate Professor–Clinical, Division of Hematology/Oncology, Department of Internal Medicine, College of Medicine and Public Health, The Ohio State University, Columbus. Received for publication Jul 20, 2001; returned for revision Aug 7, 2001; accepted for publication Aug 14, 2001. Copyright © 2002 by Mosby, Inc. 1079-2104/2002/$35.00 + 0 7/14/119736 doi:10.1067/moe.2002.119736

patibility antigens.3,4 After BMT, recipients receive prolonged immunosuppressive therapy in an attempt to prevent this rejection.2 The clinical manifestations of GVHD most often affect the skin, liver, gastrointestinal tract, lung, and eye. Oral involvement is seen as lichenoid mucositis and xerostomia.1,5 The development of secondary malignancies has been recognized as a potentially serious complication after cytotoxic therapy and BMT.2,6-9 The most common secondary malignancies include occurrence of leukemia in donor-derived cells, Hodgkin’s and non-Hodgkin’s lymphoma, and granulocytic sarcoma.2 Rarely reported is the development of nonlymphohematopoietic solid malignancies such as squamous cell carcinoma (SCC), melanoma, glioblastoma, and sarcoma.2,10 Carcinomas have been reported in the skin, liver, lung, parotid gland, and—infrequently—the oral mucosa.11-19 The purpose of this article was to present 2 patients with GVHD, one of whom developed carcinoma in situ of the buccal mucosa and the other, synchronous SCCs of the skin and tongue. CASE REPORTS

Case 1 A 23-year-old white man was referred by his dermatologist and his hematologist/oncologist for evaluation of oral lesions in November 1999. The patient’s medical history was significant for matched, unrelated BMT in June 1998 as treatment for acute lymphoblastic leukemia. Full-body irradiation therapy had been a component of his conditioning regimen before transplantation. A skin biopsy had been performed recently; however, this was equivocal for features of GVHD. It was thought that the oral mucosal status could provide additional information.

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Fig 1. A, The patient in case 1 has a large, sharply demarcated red lesion, with a finely papillary surface, involving the left buccal mucosa. B, Photomicrograph of case 1 showing atrophic mucosal epithelium that exhibits a papillary surface morphology with drop-shaped rete ridges and loss of the normal maturation sequence (hematoxylin and eosin, original magnification ×200). C, Photomicrograph of case 1 showing carcinoma in situ characterized by increased nuclear/cytoplasmic ratios, nuclear hyperchromatism, pleomorphism, and loss of the intercellular polarization (hematoxylin and eosin, original magnification ×400).

Initial examination showed lichenoid striae of the right and left posterior buccal mucosae, as well as the mandibular and maxillary facial gingivae. The striae were interspersed with patches of erythema. At that time a clinical diagnosis of

lichenoid mucositis consistent with oral GVHD was made and the patient was scheduled for a biopsy. Unfortunately, he failed to keep that appointment. Approximately 1 year later the patient returned,

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Fig 2. A, The patient in case 2 has a rough, scaly lesion in the occipital area of the scalp affected by hypopigmentation and hyperpigmentation and alopecia. B, A shave biopsy of the scalp lesion in patient 2 showing severe hyperparakeratosis and atypical epidermal proliferation (hematoxylin and eosin, original magnification ×40). C, Photomicrograph of the scalp lesion in patient 2 showing superficial invasion of the dermis with neoplastic islands of epithelial cells exhibiting nuclear hyperchromatism and pleomorphism (hematoxylin and eosin, original magnification ×400).

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Fig 3. A, The patient in case 2 has a verrucous white lesion involving the left lateral border of the tongue. B, A whole-mount section of the tongue lesion in patient 2 showing an exophytic proliferation of papillary neoplastic keratinized stratified squamous epithelium (hematoxylin and eosin, original magnification ×20). C, Photomicrograph of the tongue lesion in patient 2 showing keratinized and nonkeratinized neoplastic islands of epithelial cells (hematoxylin and eosin, original magnification ×100). D, Photomicrograph of the tongue lesion in patient 2 showing superficial invasion of the connective tissue by neoplastic islands of epithelial cells exhibiting pleomorphism, nuclear hyperchromatism, and occasional mitotic figures (hematoxylin and eosin, original magnification ×200).

complaining of an irritated feeling of his left buccal mucosa. A large, sharply demarcated area of an erythematous patch with a finely papillary texture covered most of the left buccal mucosa (Fig 1, A). No other lesions were noted. The impression was that this may have represented an unusual expression of human papillomavirus infection, but the possibility of epithelial dysplasia was also entertained. Biopsy specimens from the anterior and posterior areas of the lesion showed essentially identical features. The epithelium exhibited a papillary surface morphology with dropshaped rete ridges and pronounced disruption of the normal maturation pattern, consistent with carcinoma in situ (Fig 1, B and C). The lesion was evaluated by means of in situ polymerase chain reaction using probes for human papillomavirus and Epstein-Barr virus. All of the results from these tests were negative for viral DNA. Laser ablation of the lesion was subsequently performed, and healing was uneventful. Initially the buccal mucosa appeared normal; however, a follow-up examination 5 months after surgical excision revealed recurrence of the erythroplakic process on the left posterior buccal mucosa. A second

biopsy showed dysplastic surface epithelium, although the degree of dysplasia was in the mild-to-moderate range in the area sampled. Re-excision of this lesion with periodic reevaluation of the patient’s oral mucosa was planned.

Case 2 In 1988, when this patient was 2 years of age, he was diagnosed with acute lymphocytic leukemia, treated initially with radiation and chemotherapy. In 1991, at 5 years of age, the patient received allogeneic BMT from an HLA-matched sibling. Within several months the patient developed clinical manifestations consistent with GVHD. These included severe bronchiectasis with pneumonia and restrictive lung disease, numerous hypopigmented and hyperpigmented areas on skin, alopecia, and gastrointestinal tract involvement of unspecified nature. In 1997, at 11 years of age, the patient was evaluated for cardiac problems, diagnosed as purulent pericarditis. At this time, the patient was reported to be underweight and underdeveloped. This was thought to be secondary to the effect of radiation on the cranioaxial skeleton, which may have caused impairment of skeletal growth and hypopituitarism.

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Table I. Oral carcinoma in situ/SCC in GVHD Reference

Patient age (y) at diagnosis and sex

Location

Diagnosis

Interval between BMT/ GVHD and oral lesion

Lishner et al11 (1990) Bradford et al18 (1990) Socie et al15 (1991) Socie et al15 (1991) Socie et al15 (1991) Flowers et al19 (1992) Otsubo et al16 (1997) Millen et al17 (1997)

41/M 29/F 29/M 12/M 20/M ?/F 20/F 18/F

Buccal mucosa Tongue Oral cavity Tongue Lip Tongue Gingiva Buccal mucosa

SCC, M-PD SCC, WD EC EC EC SCC SCC, WD SCC, M-WD

6 years 9 years 5 years 6 years 8 years NS 4 years 9 years

Current case 1 Current case 2

24/M 14/M

Buccal mucosa Tongue

Carcinoma in situ Papillary SCC, WD

2 years 8 years

Follow-up data D/GVHD D/GVHD NS NS NS D/GVHD A/F-D D/UD (autopsy was not obtained) A/W D/GVHD

Reason for BMT AA FA AA FA AA FA AA FA LL LL

SCC, Squamous cell carcinoma; GVHD, graft-versus-host disease BMT, bone marrow transplantation; M-PD, moderately to poorly differentiated; D/GVHD, died of graft-versus-host disease; AA, aplastic anemia; M, male; F, female; WD, well differentiated; FA, Fanconi’s anemia; EC, epidermoid carcinoma; NS, not stated; A/F-D, alive and free of disease; M-WD, moderately well differentiated; D/UD, died of undetermined disease; A/W, alive and well; LL, lymphoblastic/lymphocytic leukemia.

In March 2000, the 14-year-old patient presented to the dermatology clinic with a rough, scaly lesion of the right preauricular skin. This was diagnosed histopathologically as SCC. Five months later, the patient returned to the dermatology and oral surgery clinics with a rough, scaly lesion, approximately 1.0 cm in diameter, on the right posterior occipital area of the scalp (Fig 2, A) and a verrucous white lesion on the left lateral border of the tongue (Fig 3, A). A shave biopsy specimen of the scalp lesion showed severe hyperparakeratosis with atypical epidermal proliferation and superficial invasion of the dermis, with neoplastic islands of epithelial cells exhibiting nuclear hyperchromatism and pleomorphism (Fig 2, B and C ) . A diagnosis of well-differentiated SCC was made. Microscopic examination of the tongue lesion showed an exophytic papillary neoplastic proliferation of keratinized stratified squamous epithelium (Fig 3, B) that invaded the superficial connective tissue. The neoplastic epithelium was composed of keratinized and nonkeratinized islands of epithelial cells exhibiting nuclear hyperchromatism, pleomorphism, and occasional abnormal mitotic figures (Fig 3, C and D). A diagnosis of well-differentiated papillary SCC was made. Tissue sections examined by means of in situ hybridization with DNA probes for human papillomavirus genotypes 6,11; 16,18; and 31,33,51 were nonreactive. The patient was treated with wide surgical excision of both the cutaneous and the lingual mucosal lesions. Evaluation of the patient at that time revealed no regional or distant metastasis. In December 2000, the patient died from severe pulmonary complications secondary to GVHD.

DISCUSSION Secondary lymphohematopoietic malignancies developing after BMT are well documented. In addition, the occurrence of synchronous and metachronous solid tumors, including carcinomas, after BMT has infrequently been reported at various anatomic sites. The carcinomas include cutaneous SCC,11,12 hepatocellular carcinoma,13 mucoepidermoid carcinoma of

the lung and parotid gland, 14,15 and oral mucosal SCC.11,15-19 Several authors have observed the development of solid malignancies at anatomic sites initially involved with GVHD-related inflammatory processes. Cutaneous SCC and melanoma have evolved in GVHD-affected skin.11 Pulmonary mucoepidermoid carcinoma reportedly affected an area of the lung that previously had been diagnosed with GVHD-related restrictive lung disease, 5 years after withdrawal of the patient’s immunosuppressive therapy.14 Although rare, this phenomenon has also been reported by Otsubo et al16 in a patient with GVHD who developed gingival SCC in a location previously involved with lichenoid mucositis. In our case 1, although histopathologic examination was not initially performed, the buccal mucosa exhibited lichenoid mucositis consistent with oral involvement by GVHD. Subsequently, carcinoma in situ evolved in the left buccal mucosa. Although the lesion in our case 2 may have developed as de novo papillary SCC, the possibility that it had developed from a preexisting lichenoid mucositis could not be completely excluded. In addition to the current 2 cases, a review of the literature revealed 8 cases of SCCs that developed in patients with allogeneic BMT and GVHD (Table I), with 4 females and 6 males being affected. Their ages at time of diagnosis of carcinoma ranged from 12 to 41 years, with a mean of 26.5 years. In 9 of these 10 documented cases, the time between the diagnosis of GVHD and the diagnosis of carcinoma was reported as ranging from 4 to 9 years, with a mean of 7.5 years. The tongue was the most frequent site of involvement, found in 4 of 10 cases. The buccal mucosa was involved in 3 cases and the gingiva and lip, one case each.

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The lesions that developed in our patients represent the full spectrum of oral cancer, with its dysplastic and invasive phases, apparently developing secondary to GVHD. Neither of the patients was a tobacco or alcohol user. In situ hybridization with DNA probes for human papillomavirus was performed in both cases, and no virus was detected in either. This finding is similar to that reported by Lishner et al.11 Although the pathobiologic mechanism is not fully understood, several investigators have speculated regarding the risk factors involved in the development of solid primary cancer in patients with GVHD. Various theories include individual genetic predisposition to develop second primary malignant tumors,9,20 sequelae of treatment with cytotoxic medications,9 immunosuppressive therapy,20-22 and total-body irradiation.23 The absence of the common etiologic factors for oral cancer in the development of the current cases and the presence of synchronous carcinomas of the skin and tongue in case 2, as well as in other reported cases, suggest that oral cancer in patients with GVHD may have aggressive biologic potential with increased tendency for recurrence and development of new lesions. In summary, the presentation of the current cases, in addition to the sporadic case reports found in the literature, highlights the susceptibility of patients with GVHD to the development of secondary malignancies, including oral cancer. With the increasing use of BMT and the expanding population of surviving cohorts, the prevalence of such malignancies, including solid cutaneous and mucosal tumors, may be expected to rise in this group of patients. Therefore, it is recommended that regular and thorough evaluation of the oral mucosa be offered to all patients with BMT and GVHD.

8. Deeg HJ, Socie G, Schoch G, Henry-Amar M, Witherspoon RP, Devergie A, et al. Malignancies after marrow transplantation for aplastic anemia and Fanconi anemia: a joint Seattle and Paris analysis of results in 700 patients. Blood 1996;87:386-92. 9. Witherspoon RP, Fisher LD, Schoch G, Martin P, Sullivan KM, Sanders J, et al. Secondary cancers after bone marrow transplantation for leukemia or aplastic anemia. N Engl J Med 1989;321:784-9. 10. Deeg HJ, Storb R, Thomas ED. Bone marrow transplantation: a review of delayed complications. Br J Haematol 1984;57:185-208. 11. Lishner M, Patterson B, Kandel R, Fyles G, Curtis JE, Meharchand J, et al. Cutaneous and mucosal neoplasms in bone marrow transplant recipients. Cancer 1990;65:473-6. 12. Gmeinhart B, Hinterberger W, Greinix HT, Rabitsch W, Kirnbauer R, Reiter E, et al. Anaplastic squamous cell carcinoma (SCC) in a patient with chronic cutaneous graft-versus-host disease (GVHD). Bone Marrow Transplant 1999;23:1197-9. 13. Merhav HJ, Landau M, Gat A, Gazit E, Baratz M, Bialy-Golan A, et al. Graft versus host disease in a liver transplant patient with hepatitis B and hepatocellular carcinoma. Transplant Proc 1999;31:1890-1. 14. Sanchez J, Serrano J, Gomez P, Roman J, Cosano A, Torres A. Bronchial mucoepidermoid carcinoma after allogeneic bone marrow transplantation. J Clin Pathol 1997;50:969-70. 15. Socie G, Henry-Amar M, Cosset JM, Devergie A, Girinsky T, Gluckman E. Increased incidence of solid malignant tumors after bone marrow transplantation for severe aplastic anemia. Blood 1991;78:277-9. 16. Otsubo H, Yokoe H, Miya T, Atsuta F, Miura N, Tanzawa H, et al. Gingival squamous cell carcinoma in a patient with chronic graft-versus-host disease. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;84:171-4. 17. Millen FJ, Rainey MG, Hows JM, Burton PA, Irvine GH, Swirsky D. Oral squamous cell carcinoma after allogeneic bone marrow transplantation for Fanconi anaemia. Br J Haematol 1997;99:410-4. 18. 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. 19. Flowers ME, Doney KC, Storb R, Deeg HJ, Sanders JE, Sullivan KM, et al. Marrow transplantation for Fanconi anemia with or without leukemic transformation: an update of the Seattle experience. Bone Marrow Transplant 1992;9:167-73. 20. Lowsky R, Lipton J, Fyles G, Minden M, Meharchand J, Tejpar I, et al. Secondary malignancies after bone marrow transplantation in adults. J Clin Oncol 1994;12:2187-92. 21. Epstein JB, Reece DE. Topical cyclosporin A for treatment of oral chronic graft-versus-host disease. Bone Marrow Transplant 1994;13:81-6. 22. Storb R, Deeg HJ, Whitehead J, Appelbaum F, Beatty P, Bensinger W, et al. Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med 1986;314:729-35. 23. Deeg HJ, Witherspoon RP. Risk factors for the development of secondary malignancies after marrow transplantation. Hematol Oncol Clin North Am 1993;7:417-29.

REFERENCES 1. Storb R, Thomas ED. Allogeneic bone-marrow transplantation. Immunol Rev 1983;71:77-102. 2. Deeg HJ, Sanders J, Martin P, Fefer A, Neiman P, Singer J, et al. Secondary malignancies after marrow transplantation. Exp Hematol 1984;12:660-6. 3. Neville BW, Damm DD, Allen CM, Bouquot JE. Oral and maxillofacial pathology. 1st ed. Philadelphia: W.B. Saunders; 1995. p. 577-8. 4. Lum LG, Seigneuret MC, Storb RF, Witherspoon RP, Thomas ED. In vitro regulation of immunoglobulin synthesis after marrow transplantation. I. T-cell and B-cell deficiencies in patients with and without chronic graft-versus-host disease. Blood 1981;58:431-9. 5. Sullivan KM. Acute and chronic graft-versus-host disease in man. Int J Cell Cloning 1986;4(suppl 1):42-93. 6. Boice JD. Cancer following medical irradiation. Cancer 1981;47(5 Suppl):1081-90. 7. Hawkins MM, Draper GJ, Kingston JE. Incidence of second primary tumours among childhood cancer survivors. Br J Cancer 1987;56:339-47.

Reprint requests: Rafik A. Abdelsayed, DDS, MS Associate Professor Oral Biology and Maxillofacial Pathology School of Dentistry Medical College of Georgia 1120 15th St Augusta, GA 30912 [email protected]