Metastasizing Ameloblastoma - a perennial pathological enigma? Report of a case and review of literature.

Journal of Cranio-Maxillo-Facial Surgery xxx (2013) 1e8

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Case report

Metastasizing Ameloblastoma e A perennial pathological enigma? Report of a case and review of literature Gifrina Jayaraj*, Herald Justin Sherlin, Pratibha Ramani, Priya Premkumar, Anuja Natesan, Abilasha Ramasubramanian, Nithya Jagannathan Department of Oral and Maxillofacial Pathology, Saveetha Dental College and Hospitals, 162, P.H. Road, Velappanchavadi, Chennai, India

a r t i c l e i n f o

a b s t r a c t

Article history: Paper received 4 August 2013 Accepted 4 November 2013

The Ameloblastoma is a slow growing locally invasive odontogenic epithelial neoplasm with a high recurrence rate and a low tendency to metastasize. Metastasis in Ameloblastoma was first described by Simmons and Emura in the 1920s. Slootweg and Muller proposed the term Malignant Ameloblastoma to describe a well-differentiated ameloblastoma that metastasizes but maintains the characteristic cytologic features of the original tumour and the term Ameloblastic Carcinoma to an ameloblastoma with malignant cytological features. About 2% of ameloblastomas undergo metastasis. So far there have only been two cases of Metastasizing Ameloblastoma reported from the Indian Subcontinent. We present the case of a 22-year-old male Indian patient, who presented with a diffuse swelling in the left posterior mandible. Radiographs revealed a multilocular radiolucency in the left mandible. On histopathological examination, the lesion was diagnosed as follicular ameloblastoma. Four years later the patient presented with a swelling in the left submandibular region. Histological examination revealed metastatic ameloblastoma within the cervical lymph node. Ó 2013 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

Keywords: Ameloblastoma Metastases Malignant Ameloblastoma

1. Introduction It is over 85 years since Emura (1923) and Simmons (1928) independently reported metastasis in ameloblastoma. It remains a rare entity that is poorly understood. Metastases represent the completion of a complex succession of cell biological events (Valastyan and Weinberg, 2011). Even in carcinomas, metastasis is said to be a highly inefficient process. This being the case, the phenomenon of metastasis in a benign odontogenic neoplasm like ameloblastoma has intrigued both the pathologists and the surgeons over the years. Ameloblastoma is a slow growing locally invasive odontogenic epithelial neoplasm with a high recurrence rate and a low propensity to metastasize (Gardner et al., 2005). Slootweg and Muller (1984) proposed the term Malignant Ameloblastoma to describe a well-differentiated ameloblastoma that metastasizes but maintains the characteristic cytologic features of the original tumour and the term Ameloblastic Carcinoma to an ameloblastoma with malignant cytological features. Metastasizing Ameloblastoma (METAM) is an ameloblastoma that metastasizes in spite of a benign histologic appearance (Sciubba * Corresponding author. Tel.: þ91 9952096111; fax: þ91 044 23781666. E-mail address: [email protected] (G. Jayaraj).

et al., 2005). About 2% of ameloblastomas undergo metastases (Verneuil et al., 2002). The precise sequence of events in the metastatic cascade of Metastasizing Ameloblastoma (METAM) remains elusive. This is because METAM is a rare entity that is not much studied. Ameloblastomas are reported to be more common in dark skinned people and in developing nations (Reichart et al., 1995). There were only two cases (Pradhan et al., 1989; Bansal et al., 2012) of METAM reported from the Indian Subcontinent. This article intends to report a case of Malignant Ameloblastoma with cervical lymph node metastasis along with a review of literature. 2. Case report In 2008, a 19-year-old Indian male presented with a swelling in the left side of the lower jaw present for 2 months. Clinical examination revealed a diffuse swelling in the left posterior side of mandible, measuring 4 cm 4 cm in size, with obliteration of the buccal vestibule and displacement of 38 (Fig. 1). The swelling was non-tender. Mucosa over the swelling appeared normal. There were no palpable lymph nodes in the cervical region. A review of other systems did not reveal any significant findings and haematological findings were within normal limits. A panoramic radiograph revealed a multilocular radiolucency in 36, 37, 38 region extending into the ascending ramus (Fig. 2). Root

1010-5182/$ e see front matter Ó 2013 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jcms.2013.11.009

Please cite this article in press as: Jayaraj G, et al., Metastasizing Ameloblastoma e A perennial pathological enigma? Report of a case and review of literature, Journal of Cranio-Maxillo-Facial Surgery (2013), http://dx.doi.org/10.1016/j.jcms.2013.11.009

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G. Jayaraj et al. / Journal of Cranio-Maxillo-Facial Surgery xxx (2013) 1e8

Fig. 3. Year 2008: 3D-CT surface-rendered image showing a destructive lesion in the left mandible.

Fig. 1. Year 2008: Clinical picture of the primary tumour. Presence of a diffuse extraoral swelling in the left posterior mandible.

resorption was seen in relation to 38. 3D-CT surface-rendered images indicated destruction of the buccal and lingual cortex of the left mandible involving the ascending ramus (Fig. 3). An incisional biopsy was done and the specimen was sent for histopathological

Fig. 2. Year 2008: Radiograph showing multilocular radiolucency in 36, 37 region extending into the ascending ramus.

examination. Histopathology revealed odontogenic epithelium arranged in the form of large follicles with peripheral tall columnar cells exhibiting reversal of polarity resembling ameloblasts. The central cells were loosely arranged resembling stellate reticulum with areas of extensive cystic degeneration. The supporting connective tissue stroma showed moderate vascularity, moderate chronic inflammatory cell infiltrate and peripheral bone. The histopathological diagnosis was follicular ameloblastoma (Fig. 4). Under general anaesthesia a hemimandibulectomy of the left side was performed. The histopathology of the excisional biopsy specimen was consistent with the findings of the incisional biopsy report. Two years later the patient underwent microvascular reconstruction of the mandible. In 2012, the patient re-presented with a swelling in the left side of the neck (Submandibular region) which had been present for 6 months. Clinical examination revealed a non-tender, fluctuant swelling in the left submandibular region of around 5 10 cm in size. The overlying skin was normal in appearance and the swelling was not fixed to the underlying structures (Fig. 5). Aspiration yielded a

Fig. 4. Year 2008: Photomicrograph of the primary tumour showing odontogenic epithelium arranged in the form of follicles lined by peripheral tall columnar cells with palisaded, hyperchromatic nucleus exhibiting reversal of polarity and central stellate reticulum like cells (H&E, 10).



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Fig. 7. Year 2012: CT scan showing a mass in the left submandibular region.

Fig. 5. Year 2012: Presence of a swelling in the left submandibular region.

straw coloured fluid. The patient denied having cough, shortness of breath, weight loss, haemoptysis or bone pain. A review of the patient’s other systems did not reveal any significant findings. Maxillary and mandibular radiographs showed no evidence of local recurrence (Fig. 6). Computed tomography showed a 10 cm 5 cm mass in the left submandibular region (Fig. 7). Subsequently, the mass was excised under general anaesthesia (Fig. 8) and sent for histopathological examination which revealed odontogenic epithelium arranged in the form of numerous follicles lined by peripheral

Fig. 6. Year 2012: Panoramic radiograph showing no evidence of local recurrence in the mandible or maxilla.

tall columnar cells with palisaded, hyperchromatic nucleus exhibiting reversal of polarity and central loosely arranged stellate reticulum like cells. There was evidence of cystic degeneration in many of the follicles. These findings were suggestive of the features of follicular ameloblastoma. There was evidence of lymph node architecture with primary and secondary follicles in the periphery of the lesion (Figs. 9aec and 10). Correlating with the past clinical history, a histopathological diagnosis of Metastasizing Ameloblastoma was made. The patient was advised a full body scan to rule out metastases in other areas. There was no evidence of metastases in any other parts of the body. The patient remains under follow up. 3. Discussion On reviewing the world literature, there has been considerable overlap between the cases reported as Metastasizing Ameloblastoma. Some are true Metastasizing Ameloblastoma satisfying the WHO criteria while others show features of Ameloblastic

Fig. 8. Year 2012: Intraoperative view of the mass in the cervical region.


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Fig. 9. aec Year 2012: Photomicrograph of the excisional specimen showing follicles of ameloblastoma within the cervical lymph node (H&E, 10).

carcinoma. Our search using the terms “Metastasizing Ameloblastoma”, “Malignant Ameloblastoma”, yielded 108 case reports, out of which only 42 cases were consistent with the diagnosis of Metastasizing Ameloblastoma (Table 1). METAM with cervical lymph node metastases were present in 9 cases (Table 2). Malignant Ameloblastoma is defined as a histologically benignappearing ameloblastoma with metastasis (Verneuil et al., 2002). Though ameloblastomas are more common in dark skinned people and in developing countries (Reichart et al., 1995), metastases occur in only 2% of the tumours (Reichart et al., 1995) making METAM a

Fig. 10. Photomicrograph showing follicles lined by peripheral tall columnar cells with hyperchromatic, palisaded nuclei exhibiting reversal of polarity (H&E, 40).

rarity. Our department archives contains a total of 94 cases of ameloblastoma between 2003 and 2013, yet this is our first case of METAM. There are only two more cases (Pradhan et al., 1989; Bansal et al., 2012) consistent with the diagnosis of METAM reported from the Indian Subcontinent. These figures indicate the rarity of this tumour. Previous studies indicate that METAM are more common in the mandible (Emura, 1923; Simmons, 1928; Verneuil et al., 2002; Sciubba et al., 2005). Our patient also presented with the primary tumour in the mandible. The mandible:maxilla ratio from the various reported studies are 4.2:1 (Van Dam et al., 2010), 7.6:1 (Laughlin, 1989) 4.1:1 (Henderson et al., 1999) and show no gender predilection. The average age of the patients with METAM ranges between 5 and 74 years (Reichart and Philipsen, 2004). Our patient was 19 years of age when the primary tumour was diagnosed. He developed metastasis at the age of 23. The number of years between the diagnosis of the primary tumour and metastases varies between 0 and 15 years (Reichart and Philipsen, 2004). In this case, the time lapse was 4 years. The most common sites of metastasis are the lungs (Vorzimer and Perla, 1932; Tsukada et al., 1965; Pennisi et al., 1966; Luo et al., 2012), followed by cervical lymph nodes (Emura, 1923; Simmons, 1928). Other less common sites of metastases include vertebrae (Takahashi et al., 1985; Nguyen, 2005) brain (Laughlin, 1989; White and Patterson, 1986), kidneys (Levine et al., 1981) and even the heart (Zwahlen and Grätz, 2002). The metastatic tumour retains the same histological subtype of the primary tumour and behaves in the same persistent manner as the primary tumour. In the present case, the histology of the metastatic tumour was similar to the primary ameloblastoma, with the odontogenic epithelium arranged in the form of follicles. The peripheral layer consisted of tall columnar cells with palisaded, hyperchromatic nuclei and reversal of polarity. The cells in the centre were loosely



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Table 1 List of reported cases consistent with a diagnosis of Metastasizing Ameloblastoma. Author (year reported)

Sex

Age (yr)

Primary site

Site of metastasis

Years from first metastases.

Emura (1923) Simmons (1928) Vorzimer and Perla (1932) Lee et al. (1959) Tsukada et al. (1965) Pennisi et al. (1966) Hoke and Harrelson (1967) Suzuki et al. (1970) Spiessl and Prein (1972) Eda et al. (1972)

M F M F F M F

18 22 17 18 28 8 46

Mandible Mandible Mandible Mandible Mandible Mandible Mandible

M ?

32 ?

Mandible Mandible

2 15 9 8 31 27 18 24 U U

Buff et al. (1980) Jephcote (1981) Kunze et al. (1985) Takahashi et al. (1985) White and Patterson (1986); Laughlin (1989) Cranin et al. (1987) Inoue et al. (1988) Houston et al. (1993) Newman et al. (1995) Ameerally et al. (1996) Weir et al. (1998) Henderson et al. (1999) Onerci et al. (2001) Zwahlen and Grätz (2002) Ciment and Ciment (2002) Verneuil et al. (2002) Campbell et al. (2003) Hayakawa et al. (2004) Nguyen (2005) Gilijamse et al. (2007) Hasim et al. (2007) Senra et al. (2008) Cardoso et al. (2009) Dao et al. (2009) Van Dam et al. (2010)

M F M F M F F M F M F F M M M M M M M M F F F M F F M M M M F M

6 31 40 62 37 14 67 19 49 16 8 15 37 38 26 70 27 33 42 12 39 19 24 41 26 59 42 42 24 56 40 25

Mandible Mandible Mandible Mandible Mandible Mandible Maxilla Mandible Mandible Mandible Mandible Mandible Mandible Maxilla Mandible Mandible Mandible Mandible Mandible Mandible Mandible Mandible Mandible Mandible Mandible Mandible Mandible Mandible Mandible Maxilla Mandible Mandible

Cervical lymph nodes Cervical lymph nodes Lungs Pleura Lung Lung Cervical spine Lung Lung Bilateral lungs, thoracic vertebrae, submandibular lymph node Lungs Lungs Lungs Cervical vertebrae Lungs, brain, skin Lungs Lungs Cervical lymph node Lung Lungs Lungs Lungs Lungs Lung, skull base, myocardium Lungs Lymph node (at time of diagnosis) Lungs Lung, kidneys Thoracic vertebrae (at the time of diagnosis) Cervical lymph nodes Lungs Lung Cervical lymph node Right submandibular lymph node Lungs Lungs Lungs Lungs Lungs Lung Cervical lymph nodes Lungs

Ricard et al. (2010) Amzerin et al. (2011) Berger et al. (2012) Bansal et al. (2012) Luo et al. (2012)

15 16 5 38 10 36 U 17 U 7 35 33 12 9 29 0 19 2 0 14 18 8 3 12 33 7 10 U 5 0 0 29

U e unknown.

arranged resembling the stellate reticulum. Most of the follicles showed areas of cystic degeneration similar to the primary tumour. The presence of straw coloured fluid on aspiration might have been due to these cystic changes. Though histological subtype does not determine metastasis (Kunze et al., 1985), there is only one case (Eda et al., 1972) of follicular ameloblastoma with cervical lymph node metastases that has been reported apart from the present case. The histological subtype of the other reported cases with cervical lymph node metastases were plexiform ameloblastoma (Houston et al., 1993; Gilijamse et al., 2007; Cardoso et al., 2009; Dao et al., 2009), with one report of Granular cell ameloblastoma (Bansal et al., 2012). Along with the cases reported by Houston et al. (1993), Cardoso et al. (2009), our patient also presented with a metastatic lymph node with no episodes of local recurrence. In these cases the patients presented with metastasis after 17 years and 3 years respectively. In our case, the patient had developed metastasis after 4 years. Nodal metastasis in ameloblastoma was first reported by Emura (1923) and distant metastases by Vorzimer and Perla (1932). The exact reason for metastases is not known. A large primary tumour, delay in treatment, repeated surgery, multiple recurrences, mandibular site, radiation therapy and chemotherapy are all the suggested risk factors associated with metastases (Laughlin, 1989; Houston et al., 1993; Henderson et al., 1999). There are numerous

theories proposed for the metastasis of ameloblastoma. These include spread by haematogenous route, lymphatics and aspiration (Houston et al., 1993; Dao et al., 2009). Vorzimer and Perla (1932) proposed the theory of aspiration based on the following features observed in their case i) extension of primary tumour into the antrum impinging the nasopharynx, ii) the presence of secondary tumour only in the right lung which is the most common site for lodgement of aspired contents. Buff et al. (1980) proposed aspiration of tumour particles liberated during surgery, when the cough reflex is suppressed under anaesthesia. This hypothesis is not favoured much as bilateral lung metastases is observed in most of the cases. A lymphatic spread of ameloblastomas is also proposed (Laughlin, 1989) especially in the case of cervical lymph node metastasis (Emura, 1923), but lymphatic dissemination appears to be an uncommon way by which tumour cells from malignant ameloblastoma are spread. Eisenberg (1993) proposed the theory of heterotropia to explain the occurrence of ameloblastomas in cervical lymph nodes. According to this theory, odontogenic nests of epithelium that are entrapped within the cervical lymph nodes undergo neoplastic transformation resulting in the development of ameloblastoma within the cervical lymph node. Then, the ameloblastoma would represent a second primary rather than a metastasis. However Van Dam et al. (2010) argue that if the theory of


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Table 2 List of cases of METAM with cervical lymph node metastasis. Author (year reported)

Sex

Age at the time of diagnosis of primary tumour (yr)

Primary site

Histology of primary tumour

Site of metastasis

Years from first metastases.

No of recurrences

Emura (1923) Simmons (1928) Eda et al. (1972)

M F F

18 22 44

Mandible Mandible Left maxilla

Unknown Unknown Follicular

2 15 10

Unknown Unknown 6

Houston et al. (1993) Verneuil et al. (2002)

M M

19 70

Left mandible Mandible

17 0

0 Unknown

Gilijamse et al. (2007) Cardoso et al. (2009) Dao et al. (2009) Bansal et al. (2012)

M F M F

12 24 41 40

Mandible Mandible Mandible Mandible

Cervical lymph nodes Cervical lymph node Right submandibular lymph node Cervical lymph nodes

14 3 12 0

2 0 0 0

Current case

M

19

Mandible

Plexiform Multiphasic histologic Pattern Plexiform Plexiform Plexiform Granular cell ameloblastoma Follicular

Cervical lymph nodes Cervical lymph nodes Bilateral lungs, thoracic vertebrae, submandibular lymph node Cervical lymph node Lymph node (at time of diagnosis)

4

0

heterotropia was true, one would expect to see more reports of METAM in patients without a history of previous jaw ameloblastoma which is usually not the case. A word of caution here is that the primary local extension of ameloblastomas should not be mistaken for metastases. This might be the scenario in some of the reported cases where there is a lymph node involvement at the time of diagnosis (Verneuil et al., 2002; Bansal et al., 2012). In the present case, the lymph node represents a metastasis and not an extension of the primary ameloblastoma as there were no palpable lymph nodes or radiographic evidence of metastasis at the time of diagnosis of the primary tumour. Moreover, there was no evidence of local recurrence and a time lapse of 4 years was present from the time of diagnosis of the primary tumour and metastasis. The widely accepted theory is the haematogenous spread of tumour cells. The presence of tumour cells in blood vessel (Hanamura, 1931; Azumi et al., 1981) supports the theory that the metastatic spread of malignant ameloblastoma takes place by the blood stream. The metastatic spread in the present case might also be explained by this theory. Though our patient did not have any local recurrence he had been under surgery twice. Our patient underwent microvascular surgery for mandibular reconstruction. This might have resulted in the dissemination of tumour cells through the blood stream. Although, haematogenous dissemination is a better explanation of tumour spread to distant organs, we identify a few pitfalls in this theory: i) How does a benign odontogenic neoplasm like ameloblastoma extravasate into the blood stream? One of the theories is the dissemination of tumour cells during repeated surgical procedures secondary to multiple recurrences. ii) If this is the case, why does not the Keratocystic odontogenic tumour (KCOT) with a recurrence rate of 3e60% (Shear, 1992) undergo metastasis? Despite the fragile lining, satellite cysts, multiple recurrences and its association with Nevoid Basal Cell Carcinoma Syndrome, a KCOT does not undergo metastases. Moreover, not all cases of METAM are associated with multiple recurrences (Houston et al., 1993; Cardoso et al., 2009) (like the present case). iii) A large quantity of circulating tumour cells are present in the blood stream of a majority of carcinoma patients (Nagrath et al., 2007). Of these cells,

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