Oral mucositis is often observed with graft-versus-host disease (GVHD); however, the occurrence of oral granuloma is rare. The rapid increase in granulomatous lesions should be distinguished from malignant tumors in patients with GVHD because malignant diseases can develop in those patients. This case is the youngest pediatric patient with granuloma associated with GVHD.

The patient was a 1-year and 5-mo-old girl who presented to our department for the management of oral nodules. At the age of 5 mo, she was diagnosed with primary immunodeficiency disease, cord blood transplant was performed at 11 mo and bone marrow transplant at 1 year of age. After transplantation, GVHD and oral mucositis developed, and tacrolimus was administered. Interestingly, nodules appeared on the lower lip and buccal mucosa, which spontaneously disappeared. Then, a new nodule appeared on the left lateral border of the tongue. Resection was performed and the histopathological diagnosis was granuloma. The origin of these nodules were considered to be the fibroblasts activated under inflammation caused by GVHD because the calcineurin inhibitor tacrolimus acted on their proliferation.

It is very important to distinguish oral granulomatous lesions from malignancies if GVHD is present at the base and if immunosuppressive agents and steroids are being administered.

Although hematopoietic stem cell transplantation can be used to treat and prevent complications caused by primary immunodeficiency disease (PID), graft-versus-host disease (GVHD) can complicate recovery. Oral lesions are frequently observed in association with GVHD, typical findings include lichen planus-like mucosal changes, damage to the salivary glands, and trismus due to sclerosis. However, the occurrence of oral granuloma with GVHD is rare. Here, we report the case of a pediatric patient who developed GVHD after bone marrow transplantation (BMT) for PID and subsequently developed granuloma in the oral mucosa.

The final diagnosis of the presented case was granuloma of the tongue caused by calcineurin inhibitor used for the treatment of oral GVHD.

After the excision, follow-up was performed without additional treatment.

There was no recurrence of the lesion up to 1 year and 5 mo after the excision (Figure 5). However, the patient subsequently died due to an infection associated with PID.

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Figure 5 We observed no recurrence of the lesion at 1 year and 5 mo after the procedure.

GVHD associated with hematopoietic stem cell transplantation can be classified as acute or chronic. In this patient, GVHD developed 21 d after BMT and as such was diagnosed as acute GVHD. After several rounds of gastrointestinal symptoms, the diagnosis transitioned to chronic GVHD.

Typical oral lesions associated with GVHD include mucosal lichenoid changes, damage to the salivary glands, and trismus secondary to sclerosis[1]. In this patient, oral mucositis mainly comprised granulomatous nodules.

Woo et al[2] reported on non-gingival soft tissue granulomatous lesions in patients who developed GVHD after BMT. The features are as follows: (1) A non-gingival soft tissue nodule that exhibits rapid growth, raising malignancy concerns; (2) The presence of a certain degree of oral chronic GVHD in the tissues around the nodule; and (3) The presence of a certain degree of systemic GVHD, for which the patient was being treated with cyclosporin A (CsA)[2].

Among the explanations for these observations, when oral mucositis is caused by GVHD, the fibroblasts of the oral mucosa are activated, and lesions can result from the actions of CsA, which has a proliferative impact on fibroblasts[2,3].

In the present case, granulomatous nodules were detected in the non-gingival oral mucosa within a short time after the onset of GVHD. Initially, nodules were identified on the lower lip and left buccal mucosa; however, they spontaneously disappeared. Later, a nodule emerged at the left tongue border and was surgically removed. Prior to the appearance of these nodules, exacerbation of oral GVHD was observed.

In this case, FK506 was administered in an attempt to prevent and later treat GVHD instead of CsA. FK506 is a calcineurin inhibitor with a similar mechanism of action as CsA. CsA promotes fibroblast proliferation and collagen and glycosaminoglycan synthesis and likewise suppresses their degradation, resulting in connective tissue growth[4].

To our knowledge, 15 cases of transplant-related calcineurin inhibitor-induced oral inflammatory nodules with chronic and oral GVHD have been reported[5-7] (Table 1). The age at transplant was between 11 mo and 50 years, and the present case was the youngest. There were 12 cases where CsA was used as a calcineurin inhibitor and 3 cases where FK506 was used.

On the other hand, Terasawa et al[8] reported the case of a patient with GVHD with a nodule on the lower lip associated with CMV infection. In this case, we examined the nodule that tested negative for CMV. However, it is possible that CMV was involved in generating the earlier lesions that spontaneously disappeared. In Table 1, only four cases, including our case, checked for CMV. Therefore, it is necessary to consider CMV infection when examining the presence of granulomatous nodules with GVHD.

Based on our findings, our conclusion is that the tongue granuloma reported in this patient is most likely the result of fibroblast activation during recovery from oral GVHD exacerbated by the proliferative actions of the calcineurin inhibitor FK506.

Patients with GVHD have a high risk of developing secondary tumors typically within 5 to 10 years following BMT[9]. Furthermore, immunosuppressive agents and steroids administered prophylactically are also risk factors of secondary cancers. Therefore, it is necessary to follow-up with patients who develop GVHD to detect any malignancies as early as possible.

We experienced a rare case of granuloma on the tongue of a pediatric patient with GVHD. The differential diseases include malignant tumor and CMV infection. However, these diseases do not have unique clinical features and can only be differentiated via histopathological examination and quantitative deoxyribonucleic acid testing of the diseased tissue. In particular, if GVHD is present at the base and if immunosuppressive agents and steroids are being administered, it is extremely important to distinguish it from malignant tumors.

The authors would like to thank Dr. Mari Tanaka from the Department of Pediatrics, Tokyo Medical and Dental University, for her kind of this case.