ReportofaCase June-HoByun,DDS,PhD,*Bong-WookPark,DDS,PhD,†Jong-RyoulKim,DDS,PhD,‡Gyeong-WonLee,MD,§andJeong-HeeLee,MD¶ SquamousCellCarcinomaoftheTongueAfterBoneMarrowTransplantandGraft-Versus-HostDisease:ACaseReportandReviewoftheLiterature

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J Oral Maxillofac Surg 66:144-147, 2008

Squamous Cell Carcinoma of the Tongue After Bone Marrow Transplant and Graft-

Versus-Host Disease: A Case Report and Review of the Literature

June-Ho Byun, DDS, PhD, Bong-Wook Park, DDS, PhD,†*

Jong-Ryoul Kim, DDS, PhD,‡ Gyeong-Won Lee, MD,§ and Jeong-Hee Lee, MD¶

Allogenic bone marrow transplantation (BMT) is a cur- ative therapy for malignant and nonmalignant lympho- hematopoietic diseases and other disorders. However, the development of secondary malignancies is an impor- tant complication among transplantation survivors.

¹

Pa- tients who have undergone BMT have a 2- to 8-fold higher risk of developing these cancers than the general population.

^1,2

After BMT, the most common secondary malignancies, such as lymphoma or leukemia, arise in hematopoietic tissue. Moreover, these hematologic sec- ondary malignancies develop relatively early during the post-transplantation period. However, though uncom- mon, secondary solid tumors, like squamous cell carci- noma (SCC), are also associated with BMT, and their incidences appear to increase with time.

^2,3

Potential risk factors associated with the develop- ment of secondary cancers after BMT have been well described and include chronic graft-versus-host dis- ease (GVHD), prolonged immunosuppressive ther- apy, pretransplantation radiation and chemotherapy, antigen stimulation arising from histocompatibility differences between recipient and donor, and other factors such as oncogenic virus infection.

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In this report, we describe a young patient with SCC of the tongue associated with chronic oral GVHD and human papillomavirus (HPV) infection after allo- genic BMT.

Report of a Case

A 17-year-old woman was referred by her hematologist/

oncologist for the evaluation of a tongue lesion in August 2005. She had been diagnosed as having chronic myeloid leukemia in April 2000 and received allogenic BMT in De- cember 2000. The conditioning regimen included busulfan and cyclophosphamide, with cyclosporine and prednisolone as GVHD prophylaxis. Six months after transplantation, chronic GVHD involving the oral cavity, skin, liver, eyes, and the lungs occurred, and required treatment with cyclosporine and prednisolone. Her clinical course was characterized by recurrent episodes of oral mucositis and xerostomia.

Five years later, the patient presented at follow-up with an ulcerative lesion, 1 ⫻ 2 cm in size, involving the left lateral border of the tongue, among areas of mild mucositis (Fig 1). A biopsy of the lesion showed it to be a squamous cell carcinoma. The metastatic work-up was negative, and the tumor was classified as T2N0M0, stage II. In September 2005, she underwent ipsilateral supraomohyoid neck dis- section and partial glossectomy with reconstruction using a cervical myocutaneous regional flap. Histopathologic examination of the surgical specimen showed a moderately differentiated SCC with epithelial koilocytosis (Figs 2,3). No metastasis was found in cervical lymph nodes. The biopsy specimen was also evaluated by polymerase chain reaction (PCR) using probes for HPV and Epstein-Barr virus (EBV), and HPV-16 DNA was detected in the excised lesion (Fig 4).

*Assistant Professor, Department of Oral and Maxillofacial Sur- gery, College of Medicine and Institute of Health Sciences, Gyeo- ngsang National University, Jinju, Korea.

†Assistant Professor, Department of Oral and Maxillofacial Sur- gery, College of Medicine and Institute of Health Sciences, Gyeo- ngsang National University, Jinju, Korea.

‡Professor, Department of Oral & Maxillofacial Surgery, College of Dentistry, Pusan National University, Busan, Korea.

§Instructor, Department of Internal Medicine, College of Medi- cine and Institute of Health Sciences, Gyeongsang National Univer- sity, Jinju, Korea.

¶Assistant Professor, Department of Pathology, College of Med- icine and Institute of Health Sciences, Gyeongsang National Uni- versity, Jinju, Korea.

Address correspondence and reprint requests to Dr Park: De- partment of Oral & Maxillofacial Surgery, College of Medicine and Institute of Health Science, Gyeongsang National University, Chi- lam-dong 90, Jinju-city, Gyeongnam, 660-702, Republic of Korea;

e-mail: parkbw@gsnu.ac.kr

doi:10.1016/j.joms.2006.11.011

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The patient had been followed up for 5 months without any evidence of recurrence or metastasis (Fig 5).

Discussion

Previous studies have shown that solid cancer oc- currence is a later complication in BMT recipients.

^2,3

Skin and mucosal neoplasm account for approxi- mately one third of all secondary solid tumors in BMT patients, and squamous cell carcinoma accounts for 50% of these cases.

²

Chronic GVHD is regarded as a major risk factor of secondary solid tumors in BMT patients.

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Chronic GVHD is accompanied by chronic inflammation, and

this is followed by the orchestration of the inflamma- tory cells involved to form a tumor microenvironment that facilitates the initial steps of carcinogenesis, or alternatively, these inflammatory cells may be co- opted by neoplastic cells during tumor progression.

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Prolonged immunosuppressive therapy is also a sig- nificant risk factor for SCC of skin and oral cavity in transplant recipients.

^3,7

In a large cohort study, long- term chronic GVHD therapy with azathioprine, par- ticularly when combined with cyclosporine and ste- roids, was identified as a major risk factor of SCC development.

³

Azathioprine, when used as treatment for chronic GVHD, appears to facilitate the develop-

FIGURE 1. Preoperative intraoral view. The ulcerative lesion was showed in the left lateral border of the tongue.

Byun et al. Squamous Cell Carcinoma of the Tongue. J Oral Maxillofac Surg 2008.

FIGURE 2. Histologic section showing a moderately differentiated squamous cell carcinoma (hematoxylin and eosin, original magnification x100).

FIGURE 3. Histopathologic examination showed features of koilocy- tosis in the epithelial surface adjacent to the neoplasm (arrows) (hema- toxylin and eosin, original magnification x200).

FIGURE 4. Human papillomavirus-16 DNA was detected in the tongue lesion by PCR (NC, negative control; PC, positive control; M, 100 bp ladder; CC, current case).

BYUN ET AL

145

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ment of secondary neoplasm, and cyclosporine may promote cancer progression via a direct cellular effect that is quite independent of its effect on the host’s immune cells.

⁷

Many investigators strongly suggest that patients who have undergone radiation-based pretransplantation conditioning have an increased

risk of cancer development.

^1-3,5,7

In fact, the risk of cancer in transplant recipients that underwent irradi- ation has been reported to be elevated 18.4-fold.

²

Moreover, oncogenic viruses, such as HPV and EBV, appear to play an etiologic role in many post-trans- plant solid cancers.

^2,4,8-10

A large cohort study found that HPV-16 was the most common type among HPV- positive oral and genital cancers,

⁴

and Hermann et al

¹⁰

reported a case of oral SCC coinfected with HPV-18 and EBV.

In addition to the present case, a review of the literature showed 20 other oral SCC cases that devel- oped in patients who had undergone allogenic BMT (Table 1). The tongue was the most commonly af- fected site (11 cases), and the great majority of cases (18 cases) had chronic GVHD, which was being treated mostly with cyclosporine, prednisolone, and azathioprine. Reasons for BMT (including the present case) were leukemia (8 cases), aplastic anemia (6 cases), Fanconi’s anemia (6 cases), and non-Hodgkin’s lymphoma (1 case). However, several studies have reported that SCC develops in Fanconi’s anemia pa- tients before the administration of any treatment for anemia.

^16,17

In this context, it remains unanswered as to whether carcinoma is caused by BMT factors, the nature of Fanconi’s anemia, or by both.

¹⁷

In the pre-

FIGURE 5. Five months postoperatively, the lateral border of the tongue was reconstructed using a cervical myocutaneous regional flap.

Table 1. ORAL SQUAMOUS CELL CARCINOMAS IN BONE MARROW TRANSPLANTATION PATIENTS

Reference

Age at Diagnosis

(yrs/gender) Location

Oral Chronic

GVHD

Interval Between BMT

and Oral Cancer (yrs)

Medication for Chronic GVHD

Oncogenic Virus Detection

Reason for BMT

Lishner et al,¹¹1990 41/M Buccal mucosa Yes 6 P, A Negative AA

Bradford et al,⁹1990 29/F Tongue Yes 10 Steroids HPV A

Socie et al,¹²1991 29/M Oral cavity Yes 5 Cs NA AA

20/M Lip Yes 8 MTX NA AA

12/M Tongue No 6 Cs NA FA

Flowers et al,¹³1992 30/F Tongue Yes 10 P, A NA FA

25/F Tongue No 12 None NA FA

Lowsky et al,¹⁴1994 31/F Tongue Yes 11 Cy, Cs, P, A NA AA

27/F Mouth Yes 6 P, A NA AA

Otsubo et al,¹⁵1997 20/F Gingival Yes 4 Cs, P NA AA

Millen et al,¹⁶1997 18/F Buccal mucosa Yes 9 Cs, A NA FA

Jansisyanont et al,¹⁷2000 24/F Tongue Yes 15 None NA FA

Abdelsayed et al,¹⁸2002 24/M Buccal mucosa Yes 2 NA Negative ALL

14/M Tongue Yes 8 NA Negative ALL

Zhang et al,⁸2002 35/M Tongue Yes 8 None Negative CML

47/M Lower lip Yes 7 Cs, P HPV18 CML

54/M Lower lip Yes 5 None HPV16, 18 AML

Szeto et al,⁵2004 45/M Tongue Yes 6 Steroid, Thal, A Negative AML

50/M Tongue Yes 2 Steroid, Thal, A Negative AML

Demarosi et al,⁷2005 53/F Gingiva Yes 5 Cs, P Negative NHL

Current case 17/F Tongue Yes 5 Cs, P HPV16 CML

Abbreviations: P, prednisolone; A, azathioprine; Cy, cyclophosphamide; Cs, cyclosporine; MTX, methotrexate; Thal, thalidomide; NA, not available; HPV, human papillomavirus; AA, aplastic anemia; FA, Fanconi’s anemia; ALL, acute lymphoblastic/lymphocytic leukemia; AML, acute myeloid leukemia, CML, chronic myeloid leukemia; NHL, non-Hodgkin’s lymphoma.

Byun et al. Squamous Cell Carcinoma of the Tongue. J Oral Maxillofac Surg 2008.

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viously mentioned 21 cases of oral SCCs after BMT, oncogenic virus infection was evaluated in 11 cases (including the present case), HPV was detected in 4 cases, but no EBV-positive case has been reported to date.

Our patient did not undergo pretransplant radia- tion, and chronic GVHD developed 6 months after BMT. Moreover, chronic oral mucositis had persisted in an intermittent manner until the tongue SCC oc- curred. Histopathologically, the tumor showed fea- tures of koilocytosis throughout the epithelial surface adjacent to neoplasm, which concurs with another report that presented histological features of koilocy- tosis, hyperkeratosis, and parakeratosis, considered pathognomonic of papillomavirus infection.

⁹

In the present case, HPV-16 DNA was detected by PCR, and the tumor histological features were characteristic of epithelial koilocytosis. HPV-16 is the most common form of HPV among HPV-positive oral and genital cancers. In the present case, chronic inflammation due to chronic GVHD, prolonged immunosuppres- sive therapy, and HPV infection are suspected to be causally associated with the development of tongue SCC. We recommend that BMT recipients should be closely followed to ensure the early detection of oral cancer, particularly in those with a chronic GVHD and/or HPV infection.

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