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Oral Complications of Chemotherapy and Head/Neck Radiation (PDQ®)

Health Professional Version
Last Modified: 04/10/2014

Graft-versus-Host Disease

Patients who have received allogeneic or matched unrelated transplants are at risk of developing graft-versus-host disease (GVHD).[1,2] A related condition referred to as pseudo-GVHD is occasionally reported in autologous hematopoietic stem cell transplant recipients. GVHD can affect oral tissues and often mimics naturally occurring autoimmune diseases such as erosive lichen planus, pemphigus, scleroderma, and Sjögren syndrome. Oral GVHD has also been linked to oral precancerous and malignant lesions.[3]

Acute GVHD can occur as early as 2 to 3 weeks posttransplant; mucosal erythema and erosion/ulceration are typical manifestations. Chronic oral GVHD changes can be recognized as early as day 70 posttransplant.[4] The pattern and types of lesions seen in acute GVHD are also seen in chronic GVHD, but manifestations can also include raised white hyperkeratotic plaques and striae and persistent reduced salivary function. Oral symptoms of oral GVHD include xerostomia and increased sensitivity and pain with spices, alcohols, and flavoring agents (especially mint flavors in toothpaste and oral care products). Patients may also suffer from odynophagia and dysphagia due to gastrointestinal involvement.[5] All of these symptoms of GVHD may lead to weight loss and malnutrition.[6]

Biopsy of oral mucosa, including both surface epithelium and minor labial salivary glands, may be of value in establishing a final diagnosis.[7,8] Presence of a lymphocytic infiltrate (grade I) with epithelial cell necrosis (grade II) provides the diagnostic basis for oral GVHD. As clinical criteria for recognition of oral signs and symptoms of GVHD have become more established, dependance on the oral biopsy to diagnose oral involvement has lessened. In cases of equivocal examination findings, the biopsy can improve the recognition of oral involvement.

Topical management of mucosal lesions may include steroids, azathioprine, and/or oral psoralen and ultraviolet A (PUVA) therapy (refer to the list on Management of Oral GVHD).[4,9] While topical cyclosporin has been suggested as therapeutically beneficial, its effectiveness is less predictable than that of other treatments—which, when coupled with increased cost of care, usually decreases its utility. The use of FK506 and mycophenolate mofetil to topically treat oral GVHD remains anecdotal and of uncertain efficacy. Systemic therapy (e.g., prednisone, budesonide, cyclosporine, mycophenolate mofetil, and other immunosuppressive agents) is routinely necessary, primarily to treat the condition. Topical treatment can be used to specifically manage oral sensitivity and help heal ulcerations. Patients with clinically significant xerostomia may benefit from pilocarpine (5 mg 3 or 4 times a day) or cevimeline (10 mg 4 times a day) if native salivary gland function remains partially intact.

Submucosal and/or dermal fibrosis can occur in persistent cases of chronic GVHD. This scleroderma-like complication can be subtle and appear as slight mucosal or skin tightness, or it can progress to skin thickening and fibrosis. Intraoral submucosal fibrotic bands have been noted to significantly restrict the oral opening. Successful management of GVHD with systemic therapy will usually see resolution and/or significant resolution of this problem. However, in rare instances, surgical or chemical techniques to disrupt fibrotic bands can be required to improve the oral opening.

Management of Oral GVHD

  • Topical steroids:
    • Rinses: dexamethasone elixir (Decadron 0.1 mg/mL).
    • Gels, creams:
      • fluocinonide (Fluonex)
      • clobetasol (Temovate)
      • halobetasol (Ultravate)
      • betamethasone (Celestone)
    • Powders: beclomethasone (Beclovent) (inhalers applied to mucosa).

  • Other topical immunosuppressants:
    • azathioprine rinse (Imuran; 5–10 mg/mL)
    • cyclosporin (Neoral)

  • Antifungals (when concomitant oral fungal infection is documented):
    • Topical preparations:
      • nystatin (Mycostatin)
      • clotrimazole (Mycelex)
      • amphotericin solution (Amphocin; in the United States, this is compounded)
    • Systemic agents:
      • fluconazole (Diflucan)
      • itraconazole (Sporanox)

  • PUVA.

  • Sialogogues:
    • cevimeline (Evoxac)
    • pilocarpine (Salagen)
    • bethanechol

  • Topical anesthetics:
    • lidocaine (Xylocaine)
    • dyclonine (Dyclone)
    • diphenhydramine (Benadryl)
    • doxepin (Zonalon)

  • Dental caries prevention:
    • Oral hygiene (dental plaque removal)
    • Fluorides:
      • Adult patients: brush-on products, rinses, home-use trays
      • Pediatric patients: brush-on gel (if patient can dependably expectorate the fluoride gel after application)

       [Note: If drinking water does not contain enough fluoride to prevent tooth decay, oral fluoride (e.g., drops or vitamins) should be provided to children younger than 12 years.]

    • Remineralizing solution (calcium phosphate ± fluoride preparations)

References
  1. Schubert MM, Sullivan KM: Recognition, incidence, and management of oral graft-versus-host disease. NCI Monogr (9): 135-43, 1990.  [PUBMED Abstract]

  2. Demarosi F, Bez C, Sardella A, et al.: Oral involvement in chronic graft-vs-host disease following allogenic bone marrow transplantation. Arch Dermatol 138 (6): 842-3, 2002.  [PUBMED Abstract]

  3. Abdelsayed RA, Sumner T, Allen CM, et al.: Oral precancerous and malignant lesions associated with graft-versus-host disease: report of 2 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 93 (1): 75-80, 2002.  [PUBMED Abstract]

  4. Schubert MM, Peterson DE: Oral complications of hematopoietic cell transplantation. In: Appelbaum FR, Forman SJ, Negrin RS, et al., eds.: Thomas' Hematopoietic Cell Transplantation: Stem Cell Transplantation. 4th ed. Oxford, UK: Wiley-Blackwell, 2009, pp 1589-1607. 

  5. Schima W, Pokieser P, Forstinger C, et al.: Videofluoroscopy of the pharynx and esophagus in chronic graft-versus-host disease. Abdom Imaging 19 (3): 191-4, 1994 May-Jun.  [PUBMED Abstract]

  6. Jacobsohn DA, Margolis J, Doherty J, et al.: Weight loss and malnutrition in patients with chronic graft-versus-host disease. Bone Marrow Transplant 29 (3): 231-6, 2002.  [PUBMED Abstract]

  7. Loughran TP Jr, Sullivan K, Morton T, et al.: Value of day 100 screening studies for predicting the development of chronic graft-versus-host disease after allogeneic bone marrow transplantation. Blood 76 (1): 228-34, 1990.  [PUBMED Abstract]

  8. Yamada H, Chihara J, Hamada K, et al.: Immunohistology of skin and oral biopsies in graft-versus-host disease after bone marrow transplantation and cytokine therapy. J Allergy Clin Immunol 100 (6 Pt 2): S73-6, 1997.  [PUBMED Abstract]

  9. Epstein JB, Nantel S, Sheoltch SM: Topical azathioprine in the combined treatment of chronic oral graft-versus-host disease. Bone Marrow Transplant 25 (6): 683-7, 2000.  [PUBMED Abstract]