Ameloblastic carcinoma of the maxilla: case report and review of the literature

Ameloblastic carcinoma of the maxilla: case report and review of the literature Adil Benlyazid, MD,a Magali Lacroix-Triki, MD,b Richard Aziza, MD,c Anne Gomez-Brouchet, MD,b Maryalis Guichard, MD,a and Jérôme Sarini, MD,a Toulouse, France INSTITUT CLAUDIUS REGAUD

Material and methods. A case of ameloblastic carcinoma of the maxilla arising in a 90-year-old patient is presented along with a review of 65 other cases of the international literature. Results. The median age was 44 years with a predominance of men (42/66). The maxilla was concerned in almost one third of cases (21/66). Twenty patients died of disease after a median time of 60 months. Fifteen patients died with metastatic spread in the lung, brain, or bones; the others were due to a local recurrence. The specific survival rate was 68.7% at 5 years. Conclusion. Ameloblastic carcinoma is a rare entity of odontogenic tumors that exhibits malignant histologic features in the primary site. Specific mortality, estimated at 31.3% at 5 years, was generally due to a metastatic spread. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;104:e17-e24)

Odontogenic malignancies are rare lesions arising from dental embryogenic residues. Odontogenic carcinomas have been designated by a variety of terms, including malignant ameloblastoma, ameloblastic carcinoma (AC), metastatic ameloblastoma, or primary intra-alveolar epidermoid carcinoma. The World Health Organization (WHO) published in 1972 a classification of odontogenic malignant tumours (Table I).1 Since Elzay’s2 and Slootweg and Muller’s3 classifications (Tables II and III), many authors have distinguished ameloblastic carcinoma from malignant ameloblastoma.4-6 Malignant ameloblastomas represent tumors that metastasize while both primary and metastatic lesions retain their benign histological appearance. The term ameloblastic carcinoma was introduced by Elzay.2 In the last update of the WHO classification, published in 2005 (Table IV),7 it is defined as a rare odontogenic malignancy that combines the histological features of ameloblastoma with cytological atypia, even in the absence of metastases. It may develop de novo (primary type) or by malignant transformation of an a

Assistant Professor, Department of Head and Neck Surgery, Institut Claudius Regaud. b Assistant Professor, Department of Pathology, Institut Claudius Regaud. c Assistant Professor, Department of Radiology, Institut Claudius Regaud. Received for publication Sept 13, 2006; returned for revision May 15, 2007; accepted for publication May 17, 2007. 1079-2104/$ - see front matter © 2007 Mosby, Inc. All rights reserved. doi:10.1016/j.tripleo.2007.05.026

ameloblastoma (secondary type) with a distinction between carcinoma ex intraosseus ameloblastoma and carcinoma ex peripheral ameloblastoma. CASE REPORT A 90-year-old man consulted his stomatologist with a maxillary soft tissue growth (Fig. 1). This lesion was biopsied and the first histological diagnosis was invasive squamous cell carcinoma. The patient was referred to our institution. He denied any significant contributing factors such as alcohol or tobacco. His medical history revealed a Parkinson disease. He did not develop any trismus and had no associated pain, paresthesia, weight loss or other constitutional symptoms. Physical examination of this edentulous patient showed an exophytic and ulcerating lesion adjacent to the left alveolar ridge of the maxilla, posterior to the molar area, involving the left retromolar pad, measuring approximately 35 ⫻ 15 mm. Extraoral clinical and neurological examinations did not reveal any abnormality. Trigeminal nerve fonction was intact. No lymph node enlargement was noticed. Magnetic resonance imaging (MRI) showed a low T1weighted signal intensity, a high T2-weighted signal intensity and a homogeneous gadolinium contrasting of the lesion, which was associated with a lysis of the maxillary tuberosity and the floor of the maxillary sinus (Fig. 2). The lesion was bulging in the infratemporal fossa, pushing back the medial pterygoid muscle without invading it. The chest radiograph showed no abnormality. The patient underwent a partial left maxillectomy along the Lefort 1 plane from the premolar region to the maxillary tuberosity including resection of the left pterygoid process and curettage of the mucous membrane of the maxillary sinus. Definitive histological report described an ameloblastic carcinoma involving the sinusal part of the neoplasm, featuring a tumoral proliferation ulcerating the mucosa, arranged in an ameloblastic follicular and plexiform pattern. This pattern

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Table I. World Health Organization classification of odontogenic carcinomas—19721 Odontogenic carcinomas (A) Malignant ameloblastoma (B) Primary intraosseous carcinoma (C) Other carcinoma arising from odontogenic epithelium including those arising from odontogenic cysts

Table II. Elzay’s classification—19822 Primary intraosseous carcinoma Type 1: Arising ex-odontogenic cyst Type 2: Arising ex-ameloblastoma (A) Well differentiated: malignant ameloblastoma (B) Poorly differentiated: ameloblastic carcinoma Type 3: Arising de novo (A) Nonkeratinizing (B) Keratinizing

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Table IV. World Health Organization classification of odontogenic carcinomas—20057 Metastasizing (malignant) ameloblastoma Ameloblastic carcinoma - primary type - secondary type (dedifferentiated) intraosseus - seondary type (dediffenrentiated) peripheral Primary intraosseus squamous cell carcinoma - solid type - derived from keratocystic odontogenic tumor - derived from odontogenic cysts Clear cell odontogenic carcinoma Ghost cell odontogenic carcinoma

Table III. Slootweg and Muller’s classification— 19843 Type 1 Primary intraosseous carcinoma ex-odontogenic cyst Type 2 (A) Malignant ameloblastoma (B) Ameloblastic carcinoma, arising de novo, ex-ameloblastoma or ex-odontogenic cyst Type 3 Primary intraosseous carcinoma arising de novo (A) Nonkeratinizing (B) Keratinizing

was characterized by islands, nests, and anastomosing strands of odontogenic cells within a collagenous stroma. The tumor cell nests showed peripheral palisading of columnar cells with a vacuolated cytoplasm and reverse polarized nuclei, displaced away from basement membrane (Fig. 3). The clearer central cells, inconspicuous in the plexiform areas, were loosely arranged in a pattern reminiscent of stellate reticulum (Fig. 3, A). In some areas, the epithelial component exhibited cytologic malignancy characterized by a nuclear pleomorphism, increased nucleus-to-cytoplasm ratio, hyperchromatic nuclei, and high mitotic rate with a count of 8 mitotic figures per 10 high-power fields (Fig. 3, B and C). The high proliferation level was confirmed by immunohistochemistry as shown by the MIB1/Ki67 index (Fig. 3, D). Focal areas of keratinizing metaplasia were present. The tumor deeply infiltrated the maxillary bone, invading and filling the inferior portion of the maxillary sinus. A curettage of the maxillary sinus was performed and showed a 25-mm-wide tumoral involvement. The margins were reported to be free of tumor. Based on the age of the patient, the complete removal and the absence of evidence of radiosensitivity of this tumor type, postoperative radiotherapy was not initiated. The patient left hospital with a surgical obturator. During follow-up, no local or lymphatic recurrence occured. Computed tomography (CT) scans of the chest and the head and neck area were normal 1 year after the first treatment. General

Fig. 1. View of the ameloblastic carcinoma blast in the oral cavity: exophytic and ulcerating lesion (a) adjacent to the left alveolar ridge of the maxilla (b), posterior to the molar area, involving the left retromolar pad (c), measuring approximately 35 ⫻ 15 mm.

condition gradually worsened. The patient died 25 months after surgery from complication of a gastrostomy procedure without any evidence of recurrent carcinoma.

ANALYSIS OF THE LITERATURE Since Elzay’s2 review and classification of primary intraosseous carcinoma (odontogenic carcinoma), others have reported ameloblastic carcinoma as a separate entity. Slootweg and Muller,3 in 1984, reported 2 cases of ameloblastic carcinoma and reviewed cases in the literature reported as malignant ameloblastomas as far back as 1927. In this paper, we review published cases of ameloblastic carcinomas, including those mentioned by Slootweg and Muller. Sixty-six cases were identified to collect some significant statistical data. These cases are summarized in Table V.3-6,8-42 However, we could only bring out a general trend because of the short follow-up for many cases (26 of them had a

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Fig. 2. MRI of the tumor. A, T1-weighted spin echo sequence (axial view). B, T2-weighted spin echo sequence (axial view). C, T1-weighted spin echo sequence with fat saturation and gadolinium enhancement (axial view). D, T1-weighted spin echo sequence with fat saturation and gadolinium enhancement (coronal view). Unilocular mass involving the pterygo-palatine fossa, measuring 28 mm in its greater size. The tumor shows a low T1 signal intensity (A), a high T2 signal intensity (B) and a homogeneous enhancement with gadolinium (C and D). The white mark (*) indicates the bony invasion of the trabecular space of the posterior maxilla (maxillary tuberosity). The white arrows in panel A show the medial and lateral cortical bone of the maxilla. tb, trabecular bone; ac, ameloblastic carcinoma; mm, masseter muscle; mpm, medial pterygoid muscle; ms, maxillary sinus; it, inferior turbinate; mt, middle turbinate.

follow-up less than 2 years). In addition, the largest published series4 did not provide information on the clinical course of the described cases. The median age of patients was 44 years but this tumor occurs in a wide range of age groups. Breakdown according to age group is presented in Fig. 4. There were 42 men for 24 women (sex ratio ⫽ 1.75/1). The mandible was involved more frequently than the maxilla (45/21) (ratio: 2.14/1). Among the 20 patients mentioned as having died of disease, 15 had a distant metastatic condition. The lung is the site most frequently affected by metastasis, involving 14 of the 20 cases reported as metastatic. Our

additional patient died without any symptom of his carcinoma. After excluding the cases with missing follow-up, the 5-year specific survival rate was 67.8% (Fig. 5). DISCUSSION Clinical features The clinical presentation of ameloblastic carcinoma is variable, such as a cystic lesion with benign clinical features or a large tissue mass with ulceration, bone resorption, and tooth mobility. Swelling, pain, and rapid growth are the most common presenting symptoms.

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Fig. 3. Ameloblastic carcinoma. A, Conventional ameloblastoma area showing typical follicular pattern (hematoxylin and eosin, ⫻ 100). B, Transition zone between a follicular pattern ameloblastoma (bottom) and a dedifferentiated area (upper half) (hematoxylin and eosin, ⫻200). C, Dedifferentiated (carcinoma) area with crowded epithelial cells, nuclear pleomorphism, and mitotic activity (arrowheads) (hematoxylin and eosin, ⫻400). D, MIB1/Ki67 immunostain showing marked proliferation activity in the dedifferentiated zone (left side) compared to the ameloblastoma area (right side) (MIB1 immunostain, ⫻200).

Ameloblastic carcinoma does not seem to show any age group predilection, but in this review, it appears more frequently in men (2/3 of cases) and involves more often the mandible (2/3 of cases) Radiologic features The radiographic appearance of the amelobastic carcinomas described in the literature is generally consistent with that of ameloblastomas, except perhaps the presence of some focal radiopacities, apparently reflecting dystrophic calcifications. These radiologic features, reported by Corio et al.4 in 1987, are not specific to ameloblastic carcinomas, and can be found also in the desmoplastic variant of conventional ameloblastomas. The wide variety of histological appearance of ameloblastomas generates some complexity in the conventional radiographies, CT and MRI. Simultaneous presence of mixed solid and cystic patterns lead many authors to recommend MRI as the best imaging method to assess these lesions.43-45 The solid portions tend to demonstrate intermediate signal intensity on T1 weighted image, high signal intensity on T2 weighted image, and enhancement with gadolinium. The cystic component exhibits a homogeneous intermediate signal intensity on T1 weighted image and homogeneous high signal intensity on T2 weighted image, without enhancement with gadolinium. The mural nodule or thick wall can be detected in the lesion.43

The signs of osseous destruction are found in amelobastic carcinomas as well as in ameloblastomas. These lytic phenomena may be assessed by CT imaging as well as MRI, or both.23 Differential diagnosis The discovery of a carcinoma centrally within the jaws may represent a complex problem: ●

● ●

●

●

One must exclude other differential diagnoses like metastasis or invasion of bone by tumor from adjacent soft tissue or paranasal sinus.9 The metastases in the jaws from visceral neoplasms must be ruled out.4,25 Primary intra-alveolar epidermoid carcinoma must be considered in the differential diagnosis of ameloblastic carcinoma. However, it is possible that this tumor may represent simply a less-differentiated, usually nonkeratinizing form of ameloblastic carcinoma, both lesions being derived from odontogenic remnants.4 The so-called kerato-ameloblastoma is a rare variant of ameloblastoma that contains prominent keratinizing cysts that may distract the pathologist from the otherwise ameloblastomatous feature.4 The acanthomatous ameloblastoma exhibits varying degrees of squamous metaplasia and even keratinization of the stellate reticulum portion of the tumor

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Table V. Review of the published cases of ameloblastic carcinoma of the jaws No.

Year

Author

Ref

Age

Loc

Sex

Follow-up, mo

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62

1927 1932 1948 1952 1957 1957 1957 1957 1958 1968 1969 1971 1971 1972 1972 1974 1974 1975 1977 1979 1980 1981 1981 1984 1984 1986 1986 1987 1987 1987 1987 1987 1987 1987 1987 1988 1989 1990 1991 1991 1992 1992 1995 1996 1998 1998 1998 1998 1998 1998 1998 2000 2002 2002 2002 2003 2003 2003 2003 2003 2003 2004

Risak Spring Grimes Wunderer Meyer Schneider Schneider Schneider Villa Carr Sugimura Dahlgren Herceg Eda Ikemura Byrne Jacob Gall Hoeltje Krempien Daramola Azumi Madiedo Slootweg Slootweg Andersen Nadimi Corio Corio Corio Corio Corio Corio Corio Corio Dorner Mac Clatchey Lee Bruce Nagai Gandy Gandy Lolachi Ingram Fisch Ponsot Infante-Cossio Infante-Cossio Infante-Cossio Lau Lau Simko Cox Mosqueda Mosqueda Sastre Avon Datta Dhir Oginni Oginni Oginni Carinci

[3] [3] [3] [3] [3] [3] [3] [3] [42] [14] [41] [17] [27] [22] [28] [12] [3] [24] [3] [31] [18] [10] [35] [3] [3] [8] [37] [4] [4] [4] [4] [4] [4] [4] [4] [21] [5] [33] [11] [6] [25] [25] [34] [30] [23] [29] [29] [29] [32] [32] [40] [16] [36] [36] [39] [9] [19] [20] [38] [38] [38] [13]

34 5 46 35 39 39 38 62 17 21 29 41 9 44 48 46 44 35 4 5,5 20 23 49 23 75 77 15 33 20 23 67 15 84 46 17 84 77 56 57 50 32 20 82 83 70 69 77 64 23 73 64 25 25 72 40 68 22 72 65 23 61 81

Mand Mand Max Mand Mand Mand Mand Mand Mand Mand Mand Mand Mand Max Mand Mand Mand Mand Mand Max Max Mand Max Mand Mand Max Max Mand Mand Mand Mand Max Mand Mand Mand Mand Max Max Mand Mand Mand Mand Max Max Mand Max Max Max Mand Mand Mand Mand Mand Mand Max Max Mand Max Mand Mand Max Mand

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

0 168 120 0 108 0 0 0 0 132 144 144 121 121 72 18 48 108 36 144 0 5 60 540 12 0 0 8 0 0 0 0 0 12 12 16 24 0 8 11 42 48 0 24 120 60 7 36 60 24 28 30 48 2 24 24 48 20 84 6 15 24

Metastasis Bone Lung

Multiple Bone Lung Multiple Multiple Lung Bone Lung Lung Lung Lung Multiple

Lung

Lung

Brain

Lung

Bone

DOD Alive DOD Alive Alive DOD Alive Alive Alive Alive DOD DOD DOD DOD DOD DOD Alive DOD Alive DOD Alive Alive Alive DOD DOD DOD Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive DOD Alive Alive DOD Alive Alive Alive Alive Alive Alive Alive DOD Alive Alive Alive DOD Alive Alive Alive Alive Alive DOD Alive DOD Alive Alive Alive

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Table V. Continued No.

Year

63 64 65 66

2004 2004 2004 2006

Author Cizmecy Goldenberg Goldenberg Benlyazid

Ref

Age

Loc

Sex

Follow-up, mo

[15] [26] [26]

44 60 72 90

Mand Mand Max Max

F F M M

24 60 24 25

Metastasis Brain

DOD Alive DOD Alive DOD

Mand, mandible; Max, maxilla; M, male; F, female; DOD, dead of disease; DWD, dead without disease.

14 12 10 8 6

(n)

4 2 0

0 to 9

10 to 19

20 to 29

30 to 39

40 to 49

50 to 59

60 to 69

70 to 79

> 80

Age group (Years)

Fig. 4. Breakdown according to age group.

islands; however, peripheral palisading is maintained and no cytologic features of malignancy are found.4,25 The squamous odontogenic tumor may also be mistaken for ameloblastic carcinoma.46 It is composed of islands of squamous epithelium that lack stellate reticulumlike zones and peripheral palisading. In addition, microcystic changes and dystrophic calcifications are occasionally seen in this lesion. However, the epithelium of the squamous odontogenic tumor lacks any cytologic evidence of malignancy.4 An additional consideration in the differential diagnosis is the squamous cell carcinoma arising in the lining of an odontogenic cyst.25,47 Histologically, this tumor tends to more closely resemble oral squamous cell carcinoma than what is described for ameloblastic carcinoma.4 Our case was initially diagnosed as squamous cell carcinoma out of our institution. The biopsy concerned a small part of the tumor, probably in the component exhibiting epithelial malignancy. We could not compare our findings in the surgical specimen with the initial biopsy.

Clinical course and treatment The clinical course is reported as typically aggressive, with extensive local destruction and distant metastatic spread. This criterion seems to be the major factor of prognosis, with preferentially a hematogenic spreading way. However, metastatic lymph nodes have been described. In addition, this relatively high risk of distant metastasis contrasts with the behavior of squamous cell carcinomas that spread rather by the lymphatic way. The most involved site of metastasis is the lung, but brain or bony locations have been reported. These tumors are also prone to numerous recurrences that justify a long follow-up. Wide local excision is the treatment of choice. Some authors advocate 2- or 3-cm bony margins by the mean of an en bloc removal.9,19 Cervical lymph node dissection should be considered when there is obvious lymphadenopathy. Radiotherapy and chemotherapy seem to be of limited value; however, these methods need to be considered when there is a locally advanced or metastatic disease not amenable to surgical resection. Apart from the radiosensitivity of these tumors, which is not

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Fig. 5. Kaplan-Meier survival estimate.

well documented, the use of radiotherapy has its traditional risks of osseous complications, which are osteonecrosis and induced-sarcoma. Ramadas et al.48 found cisplatin, adriamycin, and cyclophosphamide of benefit in malignant ameloblastoma metastasizing in the lung. Close periodic reassessment with a long period of follow-up (at least 10 years) is mandatory. CONCLUSION Ameloblastic carcinoma is a rare entity of odontogenic tumors that exhibits malignant histologic features in the primary or metastasis. Its histological characterization is difficult and needs the exclusion of many differential diagnoses. Its specific mortality, found after this review of 31.3% at 5 years, is certainly underestimated because of the lack of follow-up for many cases published. Death is generally a result of metastatic spread, which concerned almost one third of the published cases. These tumors need to be removed with wide margins to avoid local recurrences that frequently occur because of a minimal extent of the surgical treatment. Neck node involvement is not well documented and the mechanism of the metastatic spreading seems to follow a hematogenic pathway. Thus, if there is no evidence of lymphatic metastasis, it is not recommended to perform a systematic neck dissection. It is not possible to conclude about the interest of adjuvant therapies like radiotherapy and chemotherapy that seem of limited value. The prognosis is dominated by the possibility of local recurrences even after a long relapse, and distant metastases. Metastases generally occur in the lung but also in the bones and the brain. A systematic assessment of the chest by periodic imaging is recommended.

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