Case report

In June 2007, a 26-year-old woman was referred following the appearance of an exophytic asymptomatic lesion located on the right side of her tongue. Her medical history revealed that she had undergone HSCT in March 1990 at the age of 9 years to treat beta thalassemia major. She received cyclosporine A and corticosteroids for 6 months for postransplant prophylaxis against GvHD. No information on pre-transplant therapy was available. In September 1990, 6 months after HSCT, bilateral lichenoid lesions appeared on the buccal mucosa, compatible with chronic GvHD. The lesions were symptomatic and she received treatment with local corticosteroids and antimycotic drugs for 2 years. In June 1991, hepatitis C (HCV), a common complication in multitransfused patients, was diagnosed and the patient was treated with interferon for 6 months. History-taking failed to disclose smoking or alcohol intake.

Intraoral examination showed an exophytic lesion on the right side of the tongue with a macroscopic appearance of OSCC. White verrucous lesions were present on the other side of the tongue ( Fig. 1 ) and erythematous and lichenoid lesions on her right and left buccal mucosa. Three incisional biopsies were performed on the right side of the tongue, the left side of the tongue and the left buccal mucosa. The first specimen of the tongue confirmed the diagnosis of OSCC. Immunohistochemistry failed to reveal evidence of human papilloma virus (HPV) infection or p16 ^INK4A protein staining. The specimen from the left side of the tongue showed histological features of marked hyperkeratosis with no signs of dysplasia. The third specimen taken from the left buccal mucosa showed histological features of GvHD. Basal cells showed vacuolisation and lymphocytes were present in upper levels of the epithelium. No signs of dysplasia were present. The clinical diagnosis of GvHD was histologically confirmed. The patient underwent surgical excision of the tumour in accordance with standard treatment practice. The resected surgical specimen was margin-free from neoplastic cells. An elective neck dissection did not show any positive lymph node. Final staging of the tumour was pT3N0M0.

Exophytic lesion on the right side of the tongue; white verrucous lesions were present on the other side of the tongue.

In October 2007, a follow-up examination detected an ulcerated lesion of the anterior region of the floor of the mouth. The lesion was asymptomatic and local trauma was excluded. The lesion had no spatial relationship with the site of the OSCC removed 4 months previously. The biopsy specimen of the lesion confirmed the diagnosis of OSCC. Immunohistochemistry failed to reveal evidence of HPV infection or p16 ^INK4A protein staining. Radical surgical excision was performed. The final staging of this second tumour was pT2N0M0.

The patient is now being followed-up and 2 years after the first surgical resection is alive and free of neoplastic disease.

Discussion

HSCT patients have a significantly higher risk of developing secondary cancers than the general population with a more than 10-fold higher incidence of cancer of the oral cavity, oesophagus and thyroid glands . The risk reaches its peak in children who are 10 years old at the time of transplantation, and remains high in those who are 10–29 years old, while it decreases in those who are older than 30 years .

The present case differs from other studies reported in the literature. This is the first report of OSCC in a patient treated for beta thalassemia. The risk of solid cancer was reported to be higher in patients with a primary diagnosis of acute and chronic leukaemia , while other studies found higher risks for patients with a primary diagnosis of aplastic anaemia and Fanconi anaemia . The time elapsing between HSCT and the development of OSCC was longer than expected. According to the current literature data the development of secondary solid tumours peaks between 8 and 9 years after HSCT . The patient developed two OSCCs in the space of a few months. There is only one other literature report of a similar condition by A dbelsayed et al. They described a patient treated with HSCT at 5 years of age for acute lymphocytic leukaemia who developed synchronous cutaneous and lingual squamous cell carcinomas 9 years later .

Several authors have investigated the risk factors involved in the development of secondary neoplasia in HSCT. New malignancies are widely held to be related to the pre-transplant cytotoxic therapy with chemotherapeutic agents or irradiation . The only study investigating this aspect failed to find any relation between cytotoxic therapy and the risk of solid cancer .

Known risk factors for the general population, such as smoking, alcohol consumption and older age are not relevant in HSCT recipients. Chronic GvHD (cGvHD), with its chronic mucosal and cutaneous inflammation, has long been suspected to be a potential risk factor for secondary malignancies after HSCT. Several authors have detected OSCCs in patients with extensive cGvHD . A gingival OSCC in a location of previous lichenoid mucositis was reported by O tsubo et al. and by A dbelsayed et al. who described two patients developing OSCCs, one of them arising in the buccal mucosa that previously exhibited cGvHD . Evidence of the relation between cGvHD and cancer has also been reported in other anatomic sites: cutaneous SCC and melanoma have evolved over GvHD-affected skin , while pulmonary mucoepidermoid carcinoma has affected areas of the lung previously diagnosed with GvHD-related lung disease .

Oral cGvHD is characterized by lesions clinically and histologically identical to oral lichen planus, a relatively common disorder of the oral cavity with a small but significant malignant potential. Both diseases have the same pathogenesis involving T-lymphocytes that chronically attack the oral epithelium. The long-term immunologic damage to the mucosa by T-cells has been implicated in predisposing this tissue to malignant transformation.

HSCT recipients have to take immunosuppressive drugs for long periods to prevent or treat cGvHD, and many authors have emphasized the relationship between prolonged immunosuppressive therapy and the development of solid malignancies . The interactions between chronic inflammation and therapy-induced immunosuppression are not fully understood, but immunosuppression in a field of chronic inflammation, as in cGvHD, may interfere with tissue repair, thereby enhancing the risk for tumour evolution. The ‘field change’ of the oral mucosa due to chronic oral GvHD may also be responsible for the close temporal association between the two tumoural manifestations. It might be speculated that the activated inflammatory cells and cytokine network, which act to promote squamous tumourigenesis, may in the same manner, influence clonal spreading and thus support the process of field cancerisation in this chronic inflammatory disorder.

In conclusion, young HSCT patients with cGvHD may be at high risk of developing OSCC, even a very long time after HSCT. The recognized association between oral GvHD and OSCC should alert physicians to follow-up these patients more closely and to biopsy any suspicious lesions. Strategies to prevent cGvHD should be linked to the development of more effective and less carcinogenic treatments for patients with symptomatic GvHD.