Abstract

Allogeneic hemopoietic stem cell transplantation (HSCT) has been considered a curative treatment option for many hematological and non-hematological disorders. Despite the use of advanced methods of tissue typing and new therapies, graft versus host disease (GVHD) remains a major obstacle. Secondary malignancies are also among the most serious long-term complications after HSCT including leukemia, lymphomas, and to a lesser extent, solid tumors. The most commonly observed solid tumor is squamous cell carcinoma (SCC). We report two cases of SCC of the lower lip diagnosed several years after HSCT. Both cases were complicated with GVHD prior to the development of SCC and had a successful outcome with minimal surgical intervention.

Secondary malignancies are observed more frequently after HSCT compared with the general population.¹ Use of newer therapies and supportive care has improved the number of survivors experiencing more late effects secondary to graft-versus-host disease (GVHD) and autoimmunity. Exposure to chemoradiation before and during transplant along with the occurrence of GVHD carries the highest risk for developing secondary malignancies.² Although the majority are hematological malignancies like leukemias and lymphomas, other malignancies involving the oral cavity, skin, and gut are not uncommon. Squamous cell carcinoma (SCC) is the most common form of solid tumors originating in different sites. A large, international case-control study showed that the strongest risk factors for SCC were the severity of chronic GVHD and the duration of immunosuppressive therapy.³ We present two cases of SCC affecting the lower lip diagnosed several years after allogeneic HSCT. Both patients had extensive chronic GVHD.

Case

Case 1
A 25-year-old male diagnosed with chronic myelogenous leukemia (CML) in May 1995 underwent allogeneic HSCT from a fully human leucocyte antigen (HLA)-matched sibling five months after diagnosis. He received busulphan and cyclophosphamide for conditioning. Short-course methotrexate and cyclosporine A (CSA) were used for GVHD prophylaxis. There were no signs of GVHD by day 120 and CSA was tapered over the following three months. Ten months after the transplant, he had lichenoid lesions in the oral mucosa, which were diagnosed with mucosal biopsy as chronic GVHD. He was treated with CSA and prednisone. Immune suppression was tapered gradually and discontinued after several months.

Thirty-three months posttransplantation he had an exacerbation of GVHD. CSA and prednisone were resumed and mycophenolate mofetil (MMF) 2 g daily in two divided doses was added. Forty-two months after transplantation, MMF was replaced with tacrolimus due to poor control of GVHD. Two months later, he presented with a nodule in the right lower lip, measuring 1.5×1.5 cm, and skin-colored with a verrucous surface. Biopsy showed grade I squamous cell carcinoma (SCC), 1 cm wide and 0.2 cm deep without invasion of vessels or muscles (Figure 1a-d) that was treated by wide local excision. Tacrolimus was continued for another 3 years for GVHD control. Follow-up after 10 years showed no relapse or development of new lesions.

Case 2
A 42-year-old man diagnosed with multiple myeloma was treated with melphalan and prednisone over 6 months. Subsequently, he underwent allogeneic HSCT stem cell from a full HLA-matched sibling donor using cyclophosphamide and total body irradiation (TBI) for conditioning. As GVHD prophylaxis, he received short-course methotrexate and cyclosporine. He developed acute GVHD of the skin and gut after three months. He was treated with methylprednisone and CSA. About five months after transplant, he had lichenoid lesions on the oral mucosa and generalized scleroderma-like changes in the skin. Skin and oral biopsies confirmed the diagnosis chronic GVHD. He was treated with CSA and prednisone. Additional GVHD treatments including MMF and sirolimus were required to control GVHD exacerbations at different time points and he remained on immunosuppressive therapy 10 years after transplantation. Ten years post transplant he developed a 4×3 cm colored skin nodule on the lower lip (Figure 2). The diagnosis of SCC was confirmed by biopsy (Figure 3). The lesion was surgically removed by elliptical excision.

Discussion

HSCT is a known risk factor for SCC. We reviewed the literature for SCC involving the lips after SCT (Table 2). Hasegawa et al⁴ reported 31 patients who developed secondary malignancies out of 557 patients who underwent HSCT. Of these 31 patients, 7 had SCC of the oral cavity. Two patients had acute myeloid leukemia (AML), one had non-Hodgkin lymphoma (NHL), three patients had aplastic anemia (AA) and one patient had multiple myeloma (MM). Six had acute GVHD and all had chronic GVHD and out of seven, six were males. They developed secondary cancers at the average of 8.8 years from the transplant date with an average follow up of 1.33 years after secondary malignancies. Three of them died while the other four were still alive at the time of reporting.

Lishner et al² also reported a 34-year-old male with hepatitis B virus and aplastic anemia who had SCT after conditioning with cyclophosphamide and TBI. He then developed GVHD, which was treated with prednisone and azathioprine. Five years later, he developed a shallow ulcer on the lower lip. One year later it became a tumor with a large ulcer extending to the right buccal and vestibular mucosa and adjacent gingiva. The patient underwent radical surgical resection and reconstruction of the jaw, but died later because of severe infections. Bhatia et al¹ also reported six patients with SCC of the oral cavity, out of 2129 patients who underwent HSCT due to hematological malignancies. The specific location was not mentioned, but three of them were raised from salivary glands. The median age at transplant was 25.7 years; 5 were male and SCC developed 4.7 to 11.7 years after SCT. They all had GVHD. Witherspoon et al³ reported two cases of oral cavity SCC, among 2246 patients who underwent HSCT and had acute GVHD.

Jansisyanont et al⁷ reported a woman with SCC of the dorsum of the tongue 15 years after SCT for Fanconi anemia. The tumor was partially resected, but recurred six months after surgery. Millen et al⁸ reported a case of SCC in the buccal mucosa nine years after SCT for Fanconi anemia. The patient received GVHD prophylaxis with low-dose cyclophosphamide and TBI with oropharyngeal shielding, and developed acute GVHD of the skin and gut followed by chronic cutaneous and hepatic GVHD. The tumor was surgically resected but recurred in the right parotid gland one month later, which was treated with radiotherapy. He died three months post-operatively.

Zhang et al9 reported three cases of oral cavity SCC. The first was a case of SCC of the tongue eight years post-transplant for CML. He developed GVHD one year after transplant, involving the skin, gastrointestinal tract and oral mucosa. He was treated with topical steroids. The patient underwent hemiglossectomy, bilateral neck dissection and post-operative radiotherapy. There was no recurrence two years after treatment. The patient had a history of occasional alcohol drinking but no history of smoking. The second case was carcinoma in situ (CIS) of the lower labial mucosa seven years after SCT for CML. He developed oral GVHD and was treated with topical corticosteroids. The tumor was totally excised with no further follow up reported. The patient had a history of heavy smoking. The third case was CIS of the lower lip five years after SCT for AML. Three months after transplant, the patient developed mild oral GVHD and was treated with corticosteroid mouth rinse. The tumor was surgically excised with a wide margin and there was no recurrence 13 months after excision. The patient had no history of smoking or alcohol consumption. Abdelsayed et al6 reported a male patient who developed CIS of buccal mucosa two years after SCT and GVHD. The total number of reported cases of SCC involving the oral mucosa is ten, with three in the lower lip (Table 3). The reported cases of SCC after SCT mostly developed in male patients, as in our reported cases. Most of them had chronic GVHD involving the skin and the oral mucosa.The tumor developed after a mean of 5 years posttransplant. In our two cases the tumor developed after 4 and 10 years, respectively.

Although many aspects of the development of malignant tumors are still incompletely understood, conditions have been identified under which malignancies develop at a higher frequency. These include, for example, actinic exposure of the skin and the mutagenic effect of ultraviolet light, genetic disorders that are associated with chromosome fragility, defect of repair enzymes, or cellular immune defects. A higher incidence of malignancies has also been observed in patients receiving immunosuppressive therapy or after exposure to ionizing radiation.10,11 Certain viruses, such as Epstein-Barr virus, which is used in the laboratory to immortalize cell lines, can transform cells in vivo, which then may show uncontrolled growth and evolve into malignacies.12

We conclude that GVHD might be a risk factor for SCC of the oral mucosa, which apparently occurs more often in male patients who have undergone HSCT earlier in life. However, further study and a review of a larger cohort of patients in a large registry is required to confirm this conclusion.

References

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