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CASE REPORT

Eben L. Rosenthal, MD, Section Editor

SQUAMOUS CELL CARCINOMA OF THE BUCCAL MUCOSAIN A YOUNG ADULT WITH HISTORY OF ALLOGENEICBONE MARROW TRANSPLANTATION FORCHILDHOOD ACUTE LEUKEMIA

Kei Tomihara, DDS, PhD,1

Hironari Dehari, DDS, PhD,1

Akira Yamaguchi, DDS, PhD,1

Masato Abe, DDS, PhD, 1 Akihiro Miyazaki, DDS, PhD, 1 Kenji Nakamori, DDS, PhD, 1

Masato Hareyama, MD, PhD, 2 Hiroyoshi Hiratsuka, DDS, PhD 1

1 Department of Oral Surgery, Sapporo Medical University, Sapporo, Japan. E-mail: tokei@sapmed.ac.jp2 Department of Radiology, Sapporo Medical University, Sapporo, Japan

Accepted 5 June 2008 Published online 28 October 2008 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hed.20931

Abstract: Background . Secondary cancers are severe com-plications in patients who have had allogeneic bone marrow

transplantation for childhood leukemia. We describe here a caseof squamous cell carcinoma (SCC) of the buccal mucosa in ayoung adult patient who had had allogeneic bone marrow trans-plantation for childhood acute leukemia.

Methods and Results . The primary tumorwas treated with inter-stitial brachytherapy, and lymph node metastasis was treated bysupraomohyoid neck dissection. The patient had a history of acutelymphoblastic leukemia (ALL) at 11 years of age and had receivedan allogeneic bone marrow transplant from a female donor. Furtherinvestigation of the tissue specimens by uorescent in situ hybrid-ization (FISH) revealed that an XX chromosome pattern was domi-nantin thetumorregion, and this suggested that donor-derivedcellsmightaffect carcinogenesis in the recipient.

Conclusions . This case presents an incidence of secondaryoral cancer associated with allogeneic bone marrow transplanta-

tion. VVC

2008 Wiley Periodicals, Inc. Head Neck 31: 565568,2009

Keywords: secondary cancer; squamous cell carcinoma; allo-geneic bone marrow transplantation; uorescent in situ hybridi-zation (FISH); donor-derived cell

O ral squamous cell carcinomas (SCCs) are rareamong children and young adults. However,

recent studies revealed that several cases of oralSCC in children and young adults were inciden-ces of secondary cancer associated with trans-plantation for leukemia and other malignantdiseases. 1 Despite its benets, transplantationfor childhood acute leukemia is controversialbecause of the risk of secondary malignancies.Secondary malignancies are serious complica-tions in patients who have received bone mar-row transplantation or hematopoietic stem celltransplantation for childhood acute leukemia. 2,3

In comparison with secondary hematologicalmalignancies, such as posttransplant lympho-proliferative disorders, secondary solid cancersoccurring after transplantation are not fre-quent, but, nevertheless, an increasing num-ber of cases, including oral SCC, have beenreported. Chronic graft-versus-host disease(GVHD) following transplantation has beensuggested to be strongly associated with anincreased risk of oral SCC. 1

Correspondence to: H. Hiratsuka

VVC 2008 Wiley Periodicals, Inc.

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Here, we describe a case of SCC of the buccalmucosa in a young adult patient who hadreceived an allogeneic bone marrow transplantfor childhood acute leukemia, and we discussthe clinical characteristics and the origin of thesecondary cancer with reference to the relevantliterature.

CASE REPORT

A 24-year-old man was referred to the Depart-ment of Oral Surgery, Sapporo Medical University

Hospital, in March 2007. He was seen with thechief complaint of an exophytic painless lesion of the left buccal mucosa (Figure 1). The lesion hadbeen present for about 3 months and had gradu-ally increased in size. First, he consulted thedepartment of oral surgery of a local hospital, anda biopsy was performed. The histopathologicalexamination revealed a well-differentiated SCC(Figure 2). At the rst visit to our department, thelesion measured 2.2 cm 3 1.6 cm and was poste-rior to the corner of the mouth. The surface mu-cosa of the lesion was ulcerated. No regionallymph nodes could be palpated. Because a surgicalresection had the possibility of causing the loss of the corner of the mouth, radiotherapy was chosen,and the patient was treated with interstitialbrachytherapy of 67.5 Gy. After 4 months, metas-tasis was detected in the ipsilateral submandibu-lar lymph node, and supraomohyoid neck dissec-tion was performed. The patient is now underfollow-up with no recurrence or metastasis.

In this case, we conducted further investiga-tions on the nature of the lesion, because thepatient had experienced chronic GVHD for a longtime after the bone marrow transplantation. Thepatient had a history of acute lymphoblastic leu-kemia (ALL) when he was 11 years old and hadreceived total body irradiation and an allogeneicbone marrow transplant from a female donor. Wesuspected that the lesion was associated with theallogeneic bone marrow transplant, so we exam-ined the nature of the lesion by evaluating the sexchromosome pattern by FISH. The overall fre-quency of an XX chromosome pattern was 88.6 %in the tumor region (Figure 3), but in the adjacentnormal region the XY chromosome pattern was81.5 % (Figure 4). These results strongly suggestthat the lesion originated from the bone marrow-derived cells of the donor.

DISCUSSION

This is the rst report to demonstrate secondaryoral cancer developed from donor-derived cells. Itis well recognized that secondary malignanciesare complications of chemotherapy or combinedtreatment in patients with Hodgkins disease ornon-Hodgkins lymphoma. 4 Several studies alsohave indicated a higher incidence of secondarymalignancies after hematopoietic stem-cell trans-plantation or high-dose chemo/radiotherapy inchildhood acute leukemia. In a large cohort studyof 9720 children treated for ALL, the risk of secondary malignancies increased to 2.5 % at

15 years, based on 10 new leukemias and lympho-mas, 24 neoplasms of the central nervous systemin patients who had undergone cranial irradiation

FIGURE 1. Intraoral photograph showing ulcerated lesion ofthe left buccal mucosa.

FIGURE 2. Hematoxylin-eosinstained section from the primarylesion in the left buccal mucosa showing invasive squamouscell carcinoma (original magnication 3 200).

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before transplantation, and 9 other solid tumors. 5

In another study on secondary malignancies afterbone marrow transplantation for childhood acuteleukemia, the risk of secondary malignanciesamong patients who had received allogeneic trans-plants increased over time to 11 % at 15 years and

was highest for children who had undergonetransplantation when they were younger than10 years. 6

The tumor types of secondary malignanciesoccurring after transplantation were reportedspecically for posttransplant lymphoprolifera-tive disorders, oral SCCs, salivary glands carcino-mas, brain tumors, thyroid tumors, malignantmelanomas, and others. 4 Brain and thyroidtumors accounted for more than one half of allsolid tumors occurring after transplantation. 6

Oral SCC is one of the most common solid cancersoccurring after transplantation. Demarosi et alreported a case of oral SCC in an adult patientwith non-Hodgkins lymphoma who had receivedan allogeneic hematopoietic stem cell transplant,and they reviewed 16 cases of oral SCC in patientswith Fanconis anemia, aplastic anemia, acutelymphoblastic/lymphocytic leukemia, chronic my-elogenous leukemia, and acute myelogenous leu-kemia who had received allogeneic hematopoietic

stem cell transplants. 1 According to that report,almost all patients had chronic GVHD that devel-oped from the oral mucosa and were diagnosedwith oral SCC within 2 to more than 10 years aftertransplantation. In general, posttransplant lym-phoproliferative disorders were diagnosed within2 to 4 months after transplantation, whereas solidtumors were observed after 1 to 5 years. 6

Various factors, including cytotoxic therapy,irradiation, genetic predisposition, immuno-deciency, immunosuppressive therapy againstchronic GVHD with cyclosporine and severalother agents, viral infections, and transformationduring a tissue repair process in a chronic diseaselesion, have been suggested to be associated withthe development of secondary malignancies aftertransplantation. 4

In addition to chronic GVHD, male sex is also asignicant risk factor for oral SCC, but not forbrain tumors. 3,7 According to current studies,transformation of the tissue stem cells is believedto associated with development of epithelial can-cers, and according to this concept, such cellsbecome cancer stem cells. 8,9 Several reports havealso shown possible mechanisms for developmentof cancer in the oral mucosa. 10,11 Braakhuis et al 12

reviewed the role of genetic alterations in the pro-

FIGURE 3. In the tumor cell-inltrated region, 88.6 % of thecells contained double X (green) chromosomes, and 11.4 % ofthe cells containing a single X and a single Y (red) chromo-some.

FIGURE 4. In the adjacent muscularis mucosae region, 18.5 %of the cells contained double X (green) chromosomes, and81.5 % of the cells contained a single X and a single Y (red)chromosome.

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gression from a normal oral epithelial cell to anoral cancer cell. On the other hand, circulating he-matopoietic stem cells have been shown to fusewith several other cell types, 13 and Costea et al 14

hypothesized that the genetic instability and an-euploidy caused by fusion between a hematopoi-etic cell and an oral epithelial cell was very likelyassociated with the origin of cancer stem cells inoral SCC, although direct evidence for such a pro-cess in the development of oral SCC is lacking.Furthermore, in vivo animal experiments haveshown that carcinomasof the stomach can developfrom transplanted bone marrow cells from a do-nor. In that study, a FISH analysis demonstratedthe presence of the Y chromosome in carcinomacells of the stomach of female mice transplantedwith bone marrow from male mice. 15 In our case, aFISH analysis demonstrated a dominant XX chro-mosome pattern in the tumor region, and this sug-gested that donor-derived bone marrow cellsmight affect carcinogenesis in the recipient.

In conclusion, several studies have shown thatlong-term survivors of bone marrow transplanta-tion or hematopoietic stem cell transplantationare at risk for secondary malignancies, includingoral SCC. Hence, patients should be followed upclosely for a long time.

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