lable at ScienceDirect

Journal of Cranio-Maxillo-Facial Surgery 42 (2014) e301ee304

Contents lists avai

Journal of Cranio-Maxillo-Facial Surgery

journal homepage: www.jcmfs.com

Case report

Ameloblastoma with varied sites of metastasis: Report of two casesand literature review

Yi Lin, Jian-feng He*, Zhi-yong Li, Jian-hua LiuDepartment of Oral and Maxillofacial Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, #79 Qingchun Road, Hangzhou 310003,Zhejiang, PR China

a r t i c l e i n f o

Article history:Paper received 23 June 2013Accepted 8 October 2013

Keywords:AmeloblastomaMetastasesHistopathology

* Corresponding author. Tel.: þ86 571 87236893; faE-mail address: lydabao@126.com (J.-f. He).

1010-5182/$ e see front matter � 2013 European Asshttp://dx.doi.org/10.1016/j.jcms.2013.10.010

a b s t r a c t

Objective: We report two rare cases of lung metastasis from maxillary ameloblastoma, in order to reviewits risk and analyse the types of metastases that can present with this disease.Methods: A 40-year-old male with multiple recurrences and a 46-year-old female, who had undergonesuccessful surgical treatment of a maxillary ameloblastoma, presented with metastatic lesions. Theprimary tumour and metastases were benign in both patients. We reviewed and analysed 20 cases of thesame condition reported in recent years.Results: Our initial treatment for the primary maxillary lesion was performed more than 10 years beforethe pulmonary lesions presented. Due to the aggressive nature of this tumour, metastases in the lungsand cervical lymph nodes (male patient) were confirmed.Conclusion: These cases presented a diagnostic challenge due to the multiple and varied sites of recur-rence, which indicate the natural behaviour of this tumour. Different routes of metastasis can occur,including implanting, haematogenous, and lymphatic spread. CT-guided percutaneous transthoracic lungbiopsy is an important method to confirm metastatic ameloblastoma.

� 2013 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rightsreserved.

1. Introduction

Ameloblastoma is a benign tumour of odontogenic epithelialorigin, which accounts for approximately 1% of all mandibular tu-mours and cysts (Adebayo et al., 2011). It is a locally invasivetumour with the tendency to recur. Although histologically benignand clinically slow growing, ameloblastoma may metastasize toregional lymph nodes and distant sites (Eckardt et al., 2009;Dissanayake et al., 2011).

In the WHO classification system of 2005, a clear distinctionbetween ameloblastoma, malignant ameloblastoma, and amelo-blastic carcinomawasmade. Malignant ameloblastoma differs fromameloblastoma because of the presence of distant metastasis;although both share the same benign histology. Ameloblastic car-cinoma has combined histologic features of ameloblastoma, withcytologic atypia and with or without metastasis (Sciubba et al.,2005). Successful treatment for malignant ameloblastoma re-mains elusive. We report two cases of maxillary ameloblastomawith varied sites of metastasis.

x: þ86 571 87236395.

ociation for Cranio-Maxillo-Facial

2. Case reports

2.1. Case 1

A 40-year-old male consulted his stomatologist because of twobony hard lumps in the left maxillary alveolar bone in October1996. An extended resection of left maxilla was performed, with ahistologic diagnosis of ameloblastoma. Subsequently, he experi-enced multiple frequent recurrences during the 10-year follow-upperiod (February 1999eMarch 2009). Pathological features ofrecurrent lesions were consistent with ameloblastoma, withtumour nests comprising stellate cells and peripheral palisading.

In August 2009, computer tomography (CT) confirmed multiplespherical lesions in both lungs without calcification. The largestlesion (3.1 cm) was located in the right hilum (Fig. 1). CT-guidedpercutaneous transthoracic lung biopsy was performed. Micro-scopic evaluation showed primarily ameloblastoma (Fig. 2). InNovember 2011, multiple metastatic lymph nodes in the left neckand superior mediastinumwith second rib destruction were foundon CT (Fig. 3). Although the patient refused lymph node biopsy atthat point, the imaging characteristics and clinical presentationwere consistent with malignant ameloblastomawith metastases tomultiple lymph nodes.

Surgery. Published by Elsevier Ltd. All rights reserved.

Fig. 1. Computed tomography shows metastatic nodules in both lungs. Fig. 3. Computed tomography shows metastatic lymph nodes in the superior medi-astinum with destruction of the second rib (arrow).

Y. Lin et al. / Journal of Cranio-Maxillo-Facial Surgery 42 (2014) e301ee304e302

2.2. Case 2

A 46-year-old female underwent extended resection of the rightmaxilla. 15 years later, in 2011, multiple nodules in both lungs werefound on routine chest X-ray. Thoracic CT (Fig. 4) and CT-guidedpercutaneous transthoracic lung biopsy (Fig. 5) confirmed meta-static ameloblastoma. Second opinion consultation at the Univer-sity of California, Los Angeles concurred with the diagnosis.

3. Discussion

Ameloblastoma is a histologically benign, but locally invasivetumour with a high likelihood of recurrence, but rarely metasta-sizing. The incidence of malignancy/metastasis in relation toameloblastoma has been reported as 2%, but more realistically is far

Fig. 2. The lung metastasis is similar to the primary tumour, demonstrating islands ofepitheliumwith prominent basaloid and columnar peripheral cells and evidence of cellstreaming (H&E, �100).

less (Houston et al., 1993). Many cases of metastasis of amelo-blastomas are linked to multiple operations or recurrences (Luoet al., 2012), and furthermore, it is reported that malignant trans-formation was observed in patient with multiple recurrences (Linet al., 2013). Most reported cases of metastatic ameloblastomasuggest haematogenous or lymphatic spread (Houston et al., 1993).Another unusual mechanism (aspiration of tumour cells from theprimary lesion during surgery) was described by Vorzimer andPerla in 1932, which may contribute to pulmonary, lymphatic, orhaematogenous spread (Vorzimer and Perla, 1932). This hypothesiswas supported by the presence of tumour in the bronchi andbronchioles. Nonetheless, diffusely scattered metastatic lesions inboth lungs and in the surrounding vasculature is more likely theresult of haematogenous spread (Henderson et al., 1999).

The most common site of metastases in ameloblastoma is thelung, followed by cervical lymph nodes, brain, and bone (Eliassonet al., 1989). We analysed 20 cases in addition to our two casesreported in the global literature from 1999 to 2013 (Table 1). We

Fig. 4. Computed tomography shows metastatic nodules in both lungs.

Fig. 5. Lung specimen shows metastatic ameloblastoma (H&E, �400).

Y. Lin et al. / Journal of Cranio-Maxillo-Facial Surgery 42 (2014) e301ee304 e303

found the most frequent site of metastasis to be the lungs (72.7%),especially the patients undergoing multiple operations (80%).Because of this high incidence of lung metastasis, the risk ofintraoperative implantation via endotracheal tube aspiration

Table 1Patient demographics: 22 cases of malignant ameloblastoma.

Author/yearreported

Primarysite

Site ofmetastasis

Number ofsurgeries

Firstmetastasis(years)

Henderson et al.(1999)

Mandible Lungs Multiple 33

Onerci et al.(2001)

Maxilla Lungs Multiple 12

Ciment and Ciment(2002)

Mandible Lungs 1 29

Campbell et al.(2003)

Mandible Lungs 1 19

Zarbo et al.(2003)

Maxilla Iliac Multiple 15

Hayakawa et al.(2004)

Mandible Lungs, kidney 1 3

Hasim et al.(2007)

Mandible Lungs Multiple 18

Gilijamse et al.(2007)

Mandible Cervicallymph nodes

Multiple 13

Cardoso et al.(2009)

Mandible Cervicallymph nodes

1 Primarydiagnosis

Reid-Nicholson et al.(2009)

Mandible Cervicallymph nodes

1 Primarydiagnosis

Senra et al.(2008)

Mandible Lungs 1 7

Papaioannou et al.(2009)

Mandible Lungs Multiple 27

Devenney-Cakir et al.(2010)

Mandible Lungs, skull 1 4

Dissanayake et al.(2011)

Mandible Cervicallymph nodes

1 23

Amzerin et al.(2011)

Mandible Lungs Multiple 5

Lai and Wang(2011)

Maxilla Lungs Multiple 6

Golubovi�c et al.(2012)

Mandible Cervicallymph nodes

0 Primarydiagnosis

Luo et al.(2012)

Mandible Lungs 1 29

Berger et al.(2012)

Maxilla Lungs 1 7

Lin et al. 2013 Maxilla Lungs Multiple 8Present case 1 Maxilla Lungs, cervical

lymph nodesMultiple 13

Present case 2 Maxilla Lungs 1 15

cannot be ignored. It is impossible to determine whether surgeryfor multiple recurrences increase the risk for pulmonarymetastasis.

Metastases to other regions such as the skull, iliac nodes, kidney,and liver are even rarer. The most clinically significant cases are thetwo with cervical lymph node enlargement prior to surgery, with apathologic diagnosis of ameloblastoma; these cases affirm theability of ameloblastoma to spread via the lymphatics.

Although the longest reported survival after pulmonarymetastasis is 37 years (Hasim et al., 2007), the prognosis formetastatic ameloblastoma is still poor. In 1981, Laughlin reviewed43 patients with documented cases of metastatic ameloblastoma:the disease-free interval from first diagnosis to the appearance ofmetastasis was 9 years; the median survival time after metasta-ses was 2 years (Laughlin, 1989). In 1993, Sheppard (Sheppardet al., 1993) reported the time from initial diagnosis to pulmo-nary metastases to range from 0.3 to 31 years. The mean disease-free interval for pulmonary metastasis is 14.37 years and forcervical lymph node metastasis is 12.96 years. This indicates thatcervical metastasis may precede lung metastasis (Duffey et al.,1995). In our study, the mean disease-free interval from diag-nosis of tumour to distant metastasis is 13 years. Thus, devel-opment of metastases is relatively slow, and long term follow-upis recommended for patients with ameloblastoma (Adebayo et al.,2011).

Since aggressive surgery is the only effective treatment for pri-mary ameloblastoma, this therapy is often applied to metastaticdisease (Sheppard et al., 1993). If preoperative tissue diagnosis isdesired, transbronchial biopsy can be performed. Neck dissection isrecommended for patients with lymph node metastases. Radio-therapy and chemotherapy are reserved for the palliative settingand for inoperable tumours (Laughlin, 1989). Platinum-based reg-imens are considered to be first line treatment as far as chemo-therapy is concerned (Amzerin et al., 2011). Campbell reported apatient who received cyclophosphamide (50 mg t.i.d.), withaccompanying decrease in size of the left lung lesion (Campbellet al., 2003). Nonetheless, the effect of these chemotherapy regi-mens is of limited value in the treatment of malignantameloblastoma.

4. Conclusion

From these findings, it is important to note that multiple op-erations or recurrences are the risk factors for ameloblastomametastasis; meanwhile, patients without multiple recurrences ofameloblastoma still have the potential to develop metastatic le-sions. In order to detect metastases as early as possible, the post-operative review should be regular and for life, especially in pa-tients with a history of relapse, as distant metastasis can occurafter a long time. For the diagnosis of metastases, CT-guidedpercutaneous transthoracic lung biopsy and lymph node biopsyare useful methods to confirm metastatic ameloblastoma. Thetreatment of ameloblastoma metastasis requires further researchand practice.

Conflict of interestNone.

Acknowledgements

This work was supported by grants from the National NaturalScience Foundation of China (No. 81001213) and the ZhejiangProvincial Science and Technology Plan (No. 2012C33010).

Y. Lin et al. / Journal of Cranio-Maxillo-Facial Surgery 42 (2014) e301ee304e304

References

Adebayo ET, Fomete B, Adekeye EO: Delayed soft tissue recurrence after treatmentof ameloblastoma in a black African: case report and review of the literature.J Craniomaxillofac Surg 39: 615e618, 2011

Amzerin M, Fadoukhair Z, Belbaraka R, Iraqui M, Boutayeb S, M’rabti H, et al:Metastatic ameloblastoma responding to combination chemotherapy: casereport and review of the literature. J Med Case Rep 5: 491, 2011

Berger AJ, Son J, Desai NK: Malignant ameloblastoma: concurrent presentation ofprimary and distant disease and review of the literature. J Oral Maxillofac Surg70: 2316e2326, 2012

Campbell D, Jeffrey RR, Wallis F, Hulks G, Kerr KM: Metastatic pulmonary amelo-blastoma. An unusual case. Br J Oral Maxillofac Surg 41: 194e196, 2003

Cardoso A, Lazow SK, Solomon MP, Berger JR, Rock A: Metastatic ameloblastoma tothe cervical lymph nodes: a case report and review of literature. J Oral Max-illofac Surg 67: 1163e1166, 2009

Ciment LM, Ciment AJ: Malignant ameloblastoma metastatic to the lungs 29 yearsafter primary resection: a case report. Chest 121: 1359e1361, 2002

Devenney-Cakir B, Dunfee B, Subramaniam R, Sundararajan D, Mehra P, Spiegel J,et al: Ameloblastic carcinoma of the mandible with metastasis to the skull andlung: advanced imaging appearance including computed tomography, mag-netic resonance imaging and positron emission tomography computed to-mography. Dentomaxillofac Radiol 39: 449e453, 2010

Dissanayake RK, Jayasooriya PR, Siriwardena DJ, Tilakaratne WM: Review ofmetastasizing (malignant) ameloblastoma (METAM): pattern of metastasis andtreatment. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 111: 734e741,2011

Duffey DC, Bailet JW, Newman A: Ameloblastoma of the mandible with cervicallymph node metastasis. Am J Otolaryngol 16: 66e73, 1995

Eckardt AM, Kokemüller H, Flemming P, Schultze A: Recurrence ameloblastomafollowing osseous reconstruction-a review of twenty years. J CraniomaxillofacSurg 37: 36e41, 2009

Eliasson AH, Moser 3rd RJ, Tenholder MF: Diagnosis and treatment of metastaticameloblastoma. South Med J 82: 1165e1168, 1989

Gilijamse M, Leemans CR, Winters HA, Schulten EA, van der Waal I: Metastasizingameloblastoma. Int J Oral Maxillofac Surg 36: 462e464, 2007

Golubovi�c M, Petrovi�c M, Jelovac DB, Nenezi�c DU, Antunovi�c M: Malignant ame-loblastoma metastasis to the neckeradiological and pathohistological dilemma.Vojnosanit Pregl 69: 444e448, 2012

Hasim FW, Poon CC, Smith AC: Prolonged survival with confirmed metastaticpulmonary ameloblastoma. Int J Oral Maxillofac Surg 36: 953e955, 2007

Hayakawa K, Hayashi E, Aoyagi T, Hata M, Kuramoto C, Tonogi M, et al: Metastaticmalignant ameloblastoma of the kidneys. Int J Urol 11: 424e426, 2004

Henderson JM, Sonnet JR, Schlesinger C, Ord RA: Pulmonary metastasis of amelo-blastoma: case report and review of the literature. Oral Surg Oral Med OralPathol Oral Radiol Endod 88: 170e176, 1999

Houston G, Davenport W, Keaton W, Harris S: Malignant (metastatic) amelo-blastoma: report of a case. J Oral Maxillofac Surg 51: 1152e1157, 1993

Lai H, Wang J: Benign metastasizing ameloblastoma or malignant ameloblastoma.J Craniofac Surg 22: 995e997, 2011

Laughlin EH: Metastasizing ameloblastoma. Cancer 64: 776e780, 1989Lin Z, Chen F, Wang T, Hu Q, Sun G: The variability and complexity of amelo-

blastoma: carcinoma ex ameloblastoma or primary ameloblastic carcinoma.J Craniomaxillofac Surg 41: 190e193, 2013

Luo DY, Feng CJ, Guo JB: Pulmonary metastases from an ameloblastoma: case reportand review of the literature. J Craniomaxillofac Surg 40: e470ee474, 2012

Onerci M, Yilmaz T, Do�gan R, Sungur A: Pulmonary metastasectomy in the treat-ment of recurrent ameloblastoma of the maxilla and mandible: a case report.Eur Arch Otorhinolaryngol 258: 25e27, 2001

Papaioannou M, Manika K, Tsaoussis B, Cheva A, Sichletidis L, Kioumis J: Amelo-blastoma of the mandible with pulmonary metastases 45 years after initialdiagnosis. Respirology 14: 1208e1211, 2009

Reid-Nicholson M, Teague D, White B, Ramalingam P, Abdelsayed R: Fine needleaspiration findings in malignant ameloblastoma: a case report and differentialdiagnosis. Diagn Cytopathol 37: 586e591, 2009

Senra GS, Pereira AC, Murilo dos Santos L, Carvalho YR, Brandão AA: Malignantameloblastoma metastasis to the lung: a case report. Oral Surg Oral Med OralPathol Oral Radiol Endod 105: e42e46, 2008

Sciubba JJ, Eversole LR, Slootweg PJ: Odontogenic/ameloblastic carcinomas. In:Barnes L, Eveson JW, Reichart P, Sidransky D (eds), World Health Organizationclassification of tumours, pathology and genetics of head and neck tumours.Lyon: International Agency for Research on Cancer, 287e288, 2005

Sheppard BC, Temeck BK, Taubenberger JK, Pass HI: Pulmonary metastatic diseasein ameloblastoma. Chest 104: 1933e1935, 1993

Vorzimer J, Perla D: An instance of adamantinoma of the jaw with metastases to theright lung. Am J Pathol 8: 445e454, 1932

Zarbo RJ, Marunick MT, Johns R: Malignant ameloblastoma, spindle cell variant.Arch Pathol Lab Med 127: 352e355, 2003