A case of tongue carcinoma associated with chronic graft-versus-host disease after allogeneic haematopoietic stem cell transplantation.
ABSTRACT Graft-versus-host disease (GVHD) can occur at various sites, including the oral mucosa, where it is associated with a high risk of head and neck cancer. We report the case of a 46-year-old woman with tongue cancer that developed following Hodgkin's lymphoma and chronic GVHD, and we discuss the possible causes of cancer development.
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ABSTRACT: Long-term survivors of hematopoietic stem cell transplantation are recognized as a risk group for malignization. Malignant oral neoplasms are increasingly being reported in the literature as a consequence of lesions of chronic graft-versus-host disease, and prolonged multidrug treatment to control its manifestations. This report describes a 43-year-old patient who, after allogeneic bone marrow transplantation, developed an oral squamous cell carcinoma secondary to the use of azathioprine, cyclosporine, prednisone, and tacrolimus, associated with multiorgan chronic graft-versus-host disease involving the oral mucosa, skin, eyes, and liver. This report aims to discuss the possible role of immunosuppressant therapy for chronic graft-versus-host disease on the development of oral squamous cell carcinoma, and the relevance of a close oral follow-up of patients to detect dysplastic or malignant alterations at an early stage.Revista Brasileira de Hematologia e Hemoterapia 01/2014; 36(1):65-8.
Australian Dental Journal 2010; 55: 200–202
A case of tongue carcinoma associated with chronic
graft-versus-host disease after allogeneic haematopoietic
stem cell transplantation
K Noguchi,* M Nakase,* M Inui,* S Nakamura,* K Okumura,* T Tagawa*
*Department of Oral and Maxillofacial Surgery, Division of Reparative and Regenerative Medicine, Institute of Medical Science, Mie University
Graduate School of Medicine, Japan.
Graft-versus-host disease (GVHD) can occur at various sites, including the oral mucosa, where it is associated with a high
risk of head and neck cancer. We report the case of a 46-year-old woman with tongue cancer that developed following
Hodgkin’s lymphoma and chronic GVHD, and we discuss the possible causes of cancer development.
Keywords: Graft-versus-host disease, haematopoietic stem cell, tongue cancer.
Abbreviations and acronyms: GVHD = graft-versus-host disease; HSCT = haematopoietic stem cell transplantation.
(Accepted for publication 21 June 2009.)
Allogeneic haematopoietic stem cell transplantation
(HSCT) is frequently performed in patients with blood
disorders. Graft-versus-host disease (GVHD) often
occurs following HSCT and is classified as acute if it
develops within 100 days of transplantation, or chronic
if it develops later. Symptoms of chronic GVHD can
occur at various sites, including the skin, liver and oral
mucosa, and it is associated with high risks of delayed
liver and head and neck cancer.1,2In this study, we
report a case of tongue cancer that developed in a
patient with Hodgkin’s lymphoma who underwent
HSCT and subsequently developed chronic GVHD.
The patient was a 46-year-old woman who was referred
by the Division of Haematology of a general hospital
due to tongue pain. Seven years earlier, the patient had
received radiotherapy and chemotherapy for Hodgkin’s
lymphoma in the right axilla at the Division of
Haematology at the same hospital. This led to remis-
sion, but the lymphoma recurred in the left side of the
neck 2 years later and the patient underwent chemo-
therapy followed by HSCT, with her sister as the donor.
The patient developed chronic GVHD and was treated
with prednisolone and cyclosporine. After the onset of
GVHD, flare and erosion in the oral mucosa appeared
and disappeared repeatedly. The patient noted white
spots on the right margin of her tongue several months
before her first visit to our hospital. These findings were
considered to be GVHD lesions and were followed up
by the Division of Haematology. However, the lesions
gradually expanded and caused pain. Biopsy was
performed at the Division of Otorhinolaryngology,
but a definite diagnosis was not established and the
patient was referred to our hospital.
The patient was of average physical size and good
nutritional status, and had no remarkable bodily
features. Her facial appearance was symmetrical. Oral
examination revealed a soft, elastic ulcer with a slightly
blurred margin (15 · 14 mm) at the right margin of the
tongue. The surface of the ulcer was uneven and
partially white, and the marginal tissue was slightly
indurate with pressure pain (Fig 1). There were no
abnormal findings in the regional lymph nodes. A
tentative diagnosis of tongue cancer was made. The
tongue mass was removed, together with 5 mm of
marginal tissue, under general anaesthesia 10 days after
the first consultation. Frozen sections of the excised
tissue showed invasive growth of an atypical stratified
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Australian Dental Journal
The official journal of the Australian Dental Association
squamous epithelium from the mucosal epithelium to
the lower layers, and some cornified cell invasion with
nuclear division (Fig 2). On the basis of these findings,
the patient was diagnosed with well-differentiated
squamous cell carcinoma (T1N0M0; stage I). Post-
operative magnetic resonance imaging and positron
emission tomography were performed. There were no
findings indicative of lymph node metastasis or cancer
development⁄metastasis in other organs. No tumour
cells were found in the margins of the excised tissue.
The postoperative outcome was good and there was no
recurrence or metastasis at 1 year and 6 months after
Patients who have undergone HSCT are reported to
have a 4 to 7-fold risk of developing a second primary
cancer compared with other cancer patients.3,4The
tendency increases with time: 0.4% in the first 5
postoperative years, 3.5% in 10 years, and 12.8% in
15 years.5Lymphoma and myelodysplastic syndromes
account for the majority of cancers in the earlier period
(several years after transplantation), whereas solid
carcinomas, including skin, liver and oral cancers tend
to develop at a later stage.6,7The frequency of oral
cancer among secondary cancers ranges from 3.4 to
13.2% in different studies.4,5,8,9This variation could be
due to differences in the use of radiotherapy for the
primary disease, anti-tumour and immunosuppressive
agents, and chronic GVHD. Radiotherapy is a strong
risk factor for cancer development, and patients
pretreated with total body irradiation before HSCT
have an 18.4-fold risk of developing cancer, compared
suppressive agents for the prevention or treatment of
GVHD after HSCT is also thought to encourage cancer
development due to reduced immunocompetence for
tumour suppression, an increase in infection with
oncogenic viruses, and a direct proliferative effect on
cancer cells. These agents have been associated with a
13.8-fold risk of oral cancer development.10The
reported incidence of chronic GVHD in patients after
HSCT ranges from 25% to 40%1,2and oral lesions are
observed in 80% of patients with chronic GVHD.1The
major pathology is a lichen planus-like lesion that is
sometimes associated with oral dryness and mucosal
pain. Almost all patients with oral cancer after HSCT
have GVHD11and develop cancer 2–10 years after the
onset of GVHD. Long-term, chronic stimulation of
the oral mucosal epithelium in GVHD could provide
a potential carcinogenic mechanism.7,10,12The oral
symptoms after HSCT are summarized in Table 1.
In the current case, chronic oral lesions were present
for approximately 4 years, and the persistence of severe
GVHD symptoms may have led to a graft-versus-
lymphoma effect due to transplantation during a non-
remission phase. This could explain why the GVHD
lesions in the tongue turned cancerous. In addition,
cyclosporine, which was used for the treatment of
GVHD in our patient, is known to stimulate carcinoma
Fig 1. Ulcer in the right margin of the tongue.
Fig 2. Well-differentiatedsquamouscellcarcinomawithkeratinization.
Table 1. Summary of chronic GVHD of the oral
mucosa and subsequent cancer development
Oral manifestations occurring in 80% of patients with chronic
oral lichenoid lesion
Oral cancer occurs in 3.4% to 13.2% of patients with secondary
cancers following chronic GVHD
Risk factorradiotherapy after HSCT
2–10 years after onset of
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Carcinoma of the tongue and graft-versus-host disease
induction and growth. The incidence of oral cancer as a
secondary cancer after HCST is relatively low, but it has
been suggested that patients with oral mucosal lesions
associated with chronic GVHD have an increased risk of
cancer. Therefore, it is important to follow up such
patients in cooperation with the division in charge of
transplantation, and to instruct patients to avoid
common risk factors for oral cancer, such as smoking
and drinking. Our patient continued to receive cyclo-
sporine and GVHD lesions persisted over a small area of
the oral mucosa. She continued to receive follow-up
care, with careful attention to the possibility of relapses,
such as lymph node metastasis and the onset of multiple
cancers in the oral cavity or other organs.
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A. Squamous cell carcinoma of the oral cavity associated with
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Address for correspondence:
Dr M Inui
Department of Oral and Maxillofacial Surgery
Graduate School of Medicine
Tsu City 514-8507
ª 2010 Australian Dental Association
K Noguchi et al.