Abstract
Objective
Patients on immunosuppressant therapy after transplantation have an increased risk of developing cutaneous squamous cell carcinomas. The risk of developing solid tumors of the upper aerodigestive tract in this population has been less defined. We present five patients that subsequently developed oral squamous cell carcinoma after transplantation.
Study design
Retrospective chart review and literature review.
Results
Three bone marrow and two heart transplant patients were subsequently diagnosed with oral (oral cavity or oropharynx) carcinoma. The timing of diagnosis of oral cancer after transplant ranged from 18 months to 17 years post-transplantation.
Conclusions
Patients with a history of transplantation should be routinely assessed for the potential development of oral neoplastic lesions. Oral squamous cell carcinoma in transplant patients can be more aggressive and clinically mistaken for chronic graft versus host disease. It is therefore reasonable to consider early biopsy in these patients to guide the need for intervention.
1
Introduction
The increased risk of developing a cutaneous squamous cell carcinoma (SCC) after transplantation has been well documented. The risk of developing upper aerodigestive tract malignancies in this population is less well defined. The long-term impact of immunosuppressant drugs on transplant patients has yet to be fully elucidated .
Complicating the diagnosis of an oral cancer in this population is the confusing appearance of chronic graft-versus-host disease (GVHD). GVHD is a result of donor CD4 + and CD8 + T cells mounting an immunologic attack on the immunocompromised host cell. This phenomenon occurs most often after stem cell transplantation, but may also present after solid organ transplantation. Most commonly GVHD affects the skin, oral cavity, liver, and gastrointestinal tract. It may occur within 100 days of transplant (acute) or after 100 days from transplant (chronic). The oral presentation of chronic GVHD, seen in up to 90% of patients after stem cell transplant, typically involves the development of mucosal-based lesions, trismus and salivary dysfunction. The accelerated development of dental caries in patients with chronic GVHD is also a common finding .
The clinical presentation of oral SCC in the transplant patient can vary from the traditional appearance seen in immunocompetent patients or can appear similar to the ulcerative patches reminiscent of treatment-related stomatitis. Definitive evaluation can be difficult as these lesions can be mistaken for GVHD (see Figs. 1 and 2 ), bacterial, or viral-mediated etiologies, and may therefore lead to a delay in consultation for biopsy. Of the solid tumors that develop in the head and neck after transplantation, the oral cavity and thyroid are the most common sites for secondary development, and routine screening of this population for these malignancies is not commonly performed.
3
Results
Five patients were identified in our chart review. Three patients had undergone allogeneic bone marrow transplants and two had undergone orthotropic cardiac transplantation. The average patient age at the time of diagnosis of oral cancer was 56 years. The timing of the development of oral cancer in our series ranged widely and was established 18 months to 17 years post-transplantation. Specific attributes of the patients are listed in Table 1 .
| Age/Sex | Yrs post-Txp & Type | Primary site | Immunosuppressive medications | Time length prior to dx | Tumor stage | Smoking history |
|---|---|---|---|---|---|---|
| 67/female | 14, BMT | Oral tongue | Rituximab, prednisone | 10 months | T4aN2bM0 | Nonsmoker |
| 49/female | 17, BMT | Oral tongue | CellCept, prednisone | 9 months | T1N0M0 | 10 pack/yrs |
| 64/male | 11, Heart | Oral tongue | CellCept, Rapamune | 4 months | T2N0M0 | 50 pack/yrs |
| 43/male | 1.5, Heart | Tonsil | Cyclosporine, CellCept | 1 month | T3N2bM0 | 15 pack/yrs |
| 57/male | 2, BMT | Oral tongue | Cyclosporine, prednisone, Rituximab | 12 months | Multiple T1 and T2N0 | nonsmoker |
The response to therapy varied within the group. One patient required only transoral resection for a T1 lesion that was associated with a depth of invasion of less than 2 mm. Two patients required surgical resection of the primary lesion with ipsilateral neck dissection and adjuvant radiation therapy. One patient had a multicentric presentation of tumor on the oral tongue and floor of mouth without significant depth of invasion or lymph node spread. One patient was diagnosed with lung and brain metastases within 1 month of diagnosis of his primary lesion and later died.
4
Discussion
The primary risk factors for post-transplantation secondary cancers include initial treatment with radiotherapy and/or chemotherapy (increasing risk 18 fold), human papilloma virus (HPV) infection, smoking, alcohol use, male gender, and old age . In patients with chronic GVHD who develop SCC, the risk factors are slightly different in that a history of tobacco and alcohol use is often absent and these patients tend to be younger .
GVHD occurs when donor CD4 + and CD8 + T cells recognize recipient HLA antigens as foreign. This can occur despite subtle HLA differences and vigorous HLA matching between donor and recipient. Although GVHD occurs most commonly secondary to stem cell transplants, it can also occur after solid organ transplantation. GVHD occurs in three phases. In the first stage there is recipient tissue damage usually due to induction chemotherapy or radiation therapy. This leads to the release of antigenic material, which is recognized in the second stage by donor T cells. In the third ‘effector’ phase, donor cells coordinate apoptosis of host cells, most commonly in the skin, liver, and gastrointestinal tract. Acute GVHD develops in anywhere from 25 to 50% of allogeneic stem cell transplant patients . Often it is difficult to distinguish between mucositis secondary to induction chemotherapy or true acute GVHD. The timing (greater than 3 weeks after transplantation) and location of the lesions (e.g. involvement the hard palate) help define attributes indicating acute GVHD. Chronic GVHD has been reported in 30–70% of stem cell transplant patients with oral lesions present in 45–90% of those presentations . These lacy, reticulated white plaques resembling lichen planus can occur on the tongue, buccal mucosa, lips, and palate, and may be associated with xerostomia and odynophagia. These lesions are generally treated initially with topical corticosteroids and anesthetics, while encouraging good oral hygiene. Lesions that persist despite conservative initial management warrant biopsy ( Figs. 1 and 2 ) .
