Title: Oral malignancy after prolonged GvHD of the oropharynx
Submitted by Mette D. Hazenberg, MD, PhD, Haematologist, Amsterdam University Medical Center (UMC), Amsterdam, The Netherlands.
The patient is a 71 year-old female, who received a reduced intensity conditioning (RIC) allogeneic hematopoietic progenitor cell transplantation (HCT) 8 years ago because of a very poor risk acute myeloid leukemia (AML). The donor was a 10/10 matched unrelated donor and conditioning therapy consisted of fludarabine and total body irradiation in combination with anti-thymocyte globulin, cyclosporin and mycophenolic acid as graft versus host disease (GvHD) prophylaxis.
The transplantation was complicated by CMV reactivation for which she was treated with valganciclovir, and acute GvHD (grade 1 stadium I) that was limited to the skin and responded well to topical steroid therapy. After stopping mycophenolic acid, during the time when cyclosporine was tapered, she developed chronic GvHD of the skin, oropharynx, liver and esophagus. With cyclosporin back at therapeutic levels and with the addition of ursodeoxycholic acid and dexamethasone oral rinses a temporal improvement was achieved.
However, in the 8 years flowing the transplantation, chronic GvHD remained active, in particular of the oropharyngeal cavity and the skin with frequent exacerbations when immunosuppressants were tapered. A more or less stable situation was reached under combinational therapy of cyclosporine and low-dose prednisolone (10 mg) in combination with dexamethasone oral rinses and local tacrolimus ointment (Protopic) for labial sclerosis. Prolonged local and systemic immunosuppression came however at a toll. Over the years the patient had many local and systemic infections, including herpes simplex virus type I infection and fungal infection (caused by Candida albicans) of the oral cavity.
At one of the routine consultations at the oral GvHD clinic of our hospital, a white lesion was noted on the lower right buccal mucosa. Pathologic examination of a biopsy revealed hyperkeratosis and no signs of a malignancy. Repeated biopsy 6 months later again showed hyper- and perakeratosis, consistent with the clinical diagnosis of leukoplakia. However, a third biopsy, now 1 year after the initial presentation of the white lesion, demonstrated a well differentiated squamous cell carcinoma. She underwent marginal mandibula resection with reconstructive surgery and regional lymph node resection. Examination of the resected materials confirmed UICC pT1N0 squamous cell carcinoma.
Which of the following is true?
A: Oral leukoplakia is a pre-malignant condition
B: Allogeneic HCT recipients should be evaluated for oral malignancies at least once a year
C: The risk for oral malignancy is 20-40 times higher than in the general population 10 years after allogeneic HCT
D: All of the above
Expert perspective by Alexa M.G.A. Laheij, PhD, dentist at Academic Center for Dentistry Amsterdam (ACTA) and Amsterdam UMC, Amsterdam, The Netherlands:
Chronic GvHD of the oral cavity is a common complication of allogeneic HCT. Symptoms can range from very mild to severe and can have a large impact on the quality of life of patients. The patient described above was diagnosed with mucosal GvHD of the oral cavity based on the occurrence of lichenoid lesions consisting of white striae in a reticular pattern on the buccal mucosa. The presence of these lichenoid lesions is sufficient for the diagnosis of oral mucosal chronic GvHD and a biopsy for confirmation is not necessary. Other signs and symptoms of oral mucosal chronic GvHD are mucosal erythema and ulceration, usually on the buccal mucosa and tongue. When asymptomatic, oral mucosal chronic GvHD needs no treatment. In addition to the oral mucosa, chronic GVHD may also affect the salivary glands and the peri-oral soft tissues leading to fibrosis, although the latter is rare.
In many ways the clinical case of this patient is typical for oral GvHD. With systemic therapy, GvHD of the liver, skin and upper gastro-intestinal tract was treated successfully, however, oral GvHD related clinical symptoms did not respond sufficiently and topical therapy was needed for her to be able to achieve sufficient calory intake and prevent weight loss. When systemic immunosuppressants were tapered, oral GvHD flared. In the end a combination of systemic (cyclosporine, low-dose prednisolone) and local (dexamethasone rinses) therapy was needed to maintain a stable situation with mild to absent pain and sufficient quality of life. Another typical aspect of her clinical story is that she developed other features of oral GvHD, despite receiving systemic immunosuppressants. Approximately one year after oral mucosal GvHD diagnosis she developed xerostomia (dry mouth) due to hyposalivation and two years later she developed soft tissue fibrosis leading to stiffening and limitations of opening of the mouth. As indicated above, oral GvHD therapy was complicated by local infections such as herpes simplex virus type I infection of the oral cavity and oral candidiasis.
Management of this typical and complicated case of oral GvHD is a team effort, and the patient was frequently evaluated by a dentist specialized in oral GVHD and an oral hygienist. Specific attention was focused on oral hygiene, opportunistic infections and the prevention of caries, of which the patients was at increased risk due to hyposalivation.
At these visits, the oral cavity was carefully evaluated for the presence of (pre-)malignant lesions, as allogeneic HCT recipients are at risk to develop oral malignancies, in particular squamous cell carcinoma (SCC). This risk is 7-16 times higher than in the general population, increases every year post-transplant to a stunning 20-40 times 10 years after allogeneic HCT, and is the highest in patients with chronic oral GvHD. It is therefore recommended to screen allogeneic HCT patients yearly, and even more frequently for those with germline DNA repair mutations or chronic oral GvHD, and to council patients to avoid other risk factors (smoking, vaping, alcohol, sun exposure etc). Human papilloma virus infection (HPV) vaccination can be considered to reduce the risk of oral SCC, although this is not proven.
Oral leukoplakia is a pre-malignant condition, and careful follow-up is needed. In the clinical case presented here, SCC developed from oral leukoplakia within one year, but it can take many more years. Importantly, SCC can develop at multiple sites at the same time, SCC can recur after treatment, and new primary SCC can develop. Lifelong follow-up with detailed evaluation of the oral cavity is therefore necessary in all allogeneic HCT recipients.
For further reading we recommend:
1. Oral Chronic Graft-versus-Host Disease and Oral Health after Allogeneic Hematopoietic Cell Transplantation — What the Care Team Needs to Know. Laheij AMGA et al, Transplantation and Cellular Therapy (2024) 30: s548-s558. DOI: 10.1016/j.jtct.2024.07.006
2. MASCC/ISOO Clinical Practice Statement: The risk of secondary oral cancer following hematopoietic cell transplantation. Raber-Durlacher JE et al, Supportive Care in Cancer (2024) 32: 545. DOI: 10.1007/s00520-024-08685-y
Correct answer - D
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