Ameloblastic carcinoma: Report of an aggressive case with multiple bony metastases☆

Case report 

A 22-year-old white man presented to his dental practitioner in June 1993 with discomfort in the area of his right mandibular second and third molar teeth. After removal of the teeth, an abnormal tissue was detected in the extraction socket. He was then referred to Roswell Park Cancer Institute for further management. Physical examination revealed a healing mandibular extraction socket. There was a diffuse, nontender swelling of the buccal sulcus of the mandible adjacent to the second and third molar extraction site. There were no other mucosal or bony abnormalities of the oral cavity. Examination of the neck revealed no lymphadenopathy.

Radiographic examination was performed by Ortho-Pan-Tomogram, which revealed a lobulated radiolucent lesion centered at the left angle of the mandible. The lesion extended from the ascending ramus to the mandibular first premolar tooth, with radio-opaque margins. The associated teeth showed no resorption of their roots. A biopsy of the lesion was done through the previous extraction site. Histopathological examination of the biopsy was consistent with ameloblastoma.

In September 1993, the patient underwent resection of the lesion. Intraoperatively, the tumor infiltrated through both the buccal and lingual cortex of the mandible invading the overlying masseter and internal pterygoid muscles. The surgical resection included a right modified radical neck dissection, hemimandibulectomy up to the parasymphseal region, and total parotidectomy with preservation of the facial nerve. The surgical defect was reconstructed with a fibula osteocutaneous free flap.

Pathology 

The resected tumor measured 3 × 3 × 3.5 cm and grossly encircled the mid aspect of the submitted portion of mandible. On cut section the tumor was well demarcated with a firm, homogenous, ivory-white appearance. Grossly it extended into and involved the entire cross-section of the mandible without clear demarcation of the bone.

On histologic examination, the neoplasm was comprised of nests, angulated clusters, and cords of cohesive poorly differentiated malignant small round cells with a basaloid appearance. The cells displayed small hyperchromatic nuclei without nucleoli and scant cytoplasm with indistinct cytoplasmic borders. Mitoses were frequent. In several larger nests the central cells were discohesive, but no stellate reticulum or squamous metaplasia was identified. No glandular or rosette formation was present. The periphery of the nests showed cuboidal cells with focal areas of reversed polarization suggestive of preameloblast (Fig 1).

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Fig. 1. (A) Ameloblastic carcinoma. Tumor grows in angulated nests and clusters with peripheral polarization of nuclei (short arrow) and discohesion of cells within the center of the tumor nests (long arrow). (B) Higher magnification showing small tumor cells with basaloid features (arrow).

The intervening stroma showed areas of dense fibrosis accompanied by marked stromal desmoplastic reaction. The tumor extensively invaded the mandibular bone and was in close proximity to reactive bone. There was no evidence of bone formation by the tumor. The tumor displayed perineural invasion and extended to the anterior margin of resection via the inferior alveolar canal. A parafacial and 4 right level II cervical lymph nodes were all negative for tumor.

Immunohistochemical stains showed strongimmunoreactivity for cytokeratins (AE1/AE3 and Cam 5.2) and vimentin. Stains for muscle specific actin, desmin, S100, neurofilament, chromogranin, neuron specific enolase, synaptophysin, LCA, and myeloperoxidase were negative. The tumor cells also showed granular PAS positivity, which was diastase sensitive, consistent with the presence of glycogen.

Electron microscopy revealed rare tight cell junctions consistent with an epithelial origin. Glycogen and abundant mitochondria were present. No neurosecretory granules were identified (Fig 2).

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Fig. 2. Electron microscopy. Tumor cells show part of a junctional complex (J), numerous granules of glycogen (g) and mitochondria (M).

Clinical follow-up 

Because of the presence of a positive anterior margin, the patient was returned to the operating room, and further resection of the mandible was performed. The surgical defect was reconstructed with a calvarial bone and tongue flap. He received a total dose of 6,000 cGy of postoperative radiation therapy to the primary site and the neck. This was completed in January 1994.

Two months after completing radiotherapy, the patient developed right shoulder discomfort. Radiographic examination revealed a lytic lesion of the humeral head. Further investigation by bone scan revealed areas of increased uptake in the right humeral head and right hip. He underwent biopsy of the right humerus and bone marrow aspiration. The biopsy of the humeral lesion was positive for metastatic ameloblastic carcinoma, similar in morphology to the mandibular primary. The bone marrow biopsy was negative. The metastatic lesion was treated with radiotherapy to the site and chemotherapy consisting of cisplatinum, Adriamycin, methotrexate, and leucovorin.

A repeat bone scan in October 1994 revealed a good response of the right proximal humeral lesion to therapy but also showed widespread metastases to the spine and long bones. Bone scan showed evidence of metastases to left humerus, midthoracic spine, multiple ribs, bilateral femoral heads, and the skull (Fig 3).

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Fig. 3. Bone scan revealing multiple bone metastases.

The patient was treated with radiotherapy for the symptomatic spinal metastases, and he received a second cycle of chemotherapy with only partial response.

Two years after the initial diagnosis, the patient developed metastases to the liver and retroperitoneal nodes. He was treated for symptomatic relief by multiple courses of radiotherapy and chemotherapy. Eventually, he became refractory to chemotherapy and died 4 years after the initial diagnosis. No postmortem examination was performed.

Discussion 

The typical intraosseous ameloblastoma is a low-grade malignancy, which has the tendency to infiltrate cancellous bone without causing bone resorption. Although the clinical course is characterized by local recurrences, rarely do these tumors metastasize and are generally considered benign. Of a total of 126 patients treated at the Mayo Clinic, only 15 died as a result of the tumor.8 Death from ameloblastoma is usually seen in cases with uncontrolled local growth and involvement of vital structures. As a result, location of the tumor in the ascending ramus and the posterior maxilla are the most dangerous because of the close proximity to vital structures of the orbit, pterygomaxillary fossa, and the cranium.9

Rarely, a typical ameloblastoma develops distant metastases and is then classified as a malignant ameloblastoma. This term is reserved for those lesions that despite a seemingly innocuous histology give rise to metastatic growth. This occurs in only about 1% to 5% of cases,10 a rare event in an already rare neoplasm. Only 60 of these cases have been reported in the medical literature between 1923 and 1994.11 Although the typical ameloblastoma has several morphologic appearances, none of these is predictive of biologic behavior and the stimulus for metastatic potential is unknown. Multiple local recurrences, repeated surgical procedures, and radiotherapy or chemotherapy frequently precede metastases from ameloblastoma.12 It has been postulated that dissemination may result from increased malignant behavior stimulated by multiple recurrences or that the repeated surgical procedures required for the treatment of these recurrences causes implantation of tumor cells into blood vessels or lymphatic channels. Kunze et al13 studied 25 cases of malignant ameloblastoma and noted that 80% of metastasis were composed of either a pure or mixed plexiform cell type but that the cytological and morphologic features were not different from the typical ameloblastoma. Laughlin14 reviewed 42 previously published cases of malignant ameloblastoma and reported an additional case. He noted that 75% of metastases were in the chest, including the lungs, pleura, and hilar lymph and that the disease-free interval between the initial diagnosis and the appearance of metastases was 9 years. However, once metastases occurred, the median survival was 2 years.

Although the prognostic significance of the presence of obvious mitotic activity in an otherwise typical ameloblastoma is unknown, their mere presence is not an indication of malignancy.9 Kim et al15 evaluated the proliferative activity in 38 ameloblastomas, 1 recurrent case of ameloblastoma, and 1 ameloblastic carcinoma by immnunohistochemical analysis of proliferating cell nuclear antigen. Although the typical cases of ameloblastoma showed no significant difference in proliferative activity, irrespective of subtype, the case of recurrent ameloblastoma showed significant increase in immunoreactivity, both in the primary and recurrent specimens. The ameloblastic carcinoma showed the highest degree of proliferative activity. Although future studies are needed, this study15 suggests that the degree of proliferation may be indicative of biologic behavior in ameloblastoma.

Carcinomas associated with ameloblastoma have had several terminologies within the medical literature, thus posing a problem in accurately separating malignant ameloblastoma from ameloblastic carcinoma. Several authors have attempted to make a distinction between these 2 entities because ameloblastic carcinomas are clinically more aggressive.16 These definitions have included a well-differentiated ameloblastoma with histologically malignant epithelial component17; a tumor with histologic evidence of malignancy and features of ameloblastoma and concomitant squamous cell carcinoma18; a tumor with combined features of an ameloblastoma with less differentiated areas7; and any ameloblastoma with histologic evidence of malignancy in the primary tumor or the recurrent tumor, irrespective of whether the tumor has metastasized.16 Using the proposed criteria by Slootweg and Muller,7 Nagai et al19 reviewed the literature and reclassified 69 reported cases into 46 ameloblastic carcinomas and 23 malignant ameloblastoma, indicating that the incidence of ameloblastic carcinoma may be twice that of malignant ameloblastoma.

Using the definition of the presence of obvious histologic malignancy regardless of the presence of metastases, Corio et al16 described 8 cases of ameloblastic carcinomas in which the mean age of the patients was 30.1 years; 7 of the 8 cases presented in the mandible, and the most common presenting sign was swelling. Although these cases were described as locally aggressive with bone destruction and extension to the floor of mouth and other adjacent soft tissue, there is no follow-up clinical information and no mention of disease specific patient survival.16

The case described in this report meets the morphologic criteria for ameloblastic carcinoma with the presence of pleomorphic hyperchromatic cells with frequent atypical mitotic figures and the presence of perineural invasion. This lesion presented as discomfort in the right posterior mandible of a 22-year-old white man, clinically similar to the reported cases. The resected tumor showed destruction of the lingual and buccal cortex with infiltration of the adjacent soft tissue, including the overlying masseter and the internal pterygoid muscles. Although there was no clinical or pathologic evidence of metastases at the time of presentation, the patient developed bone metastasis 9 months after his initial presentation despite local radiotherapy. This was followed by aggressive widespread dissemination, despite radiotherapy and chemotherapy, and the patient died 4 years after the initial diagnosis.

Mathew et al20 recently described 5 cases (3 primary mandibular tumors and 2 cases of metastases) in which ameloblastoma was diagnosed by fine-needle aspiration cytology. The smears were hypercellular and occasionally showed tissue fragments of basaloid cells with peripheral palisading. A distinct, 2-cell population was seen, consisting of small, hyperchromatic, basaloid-type cells, and scattered larger cells with more open chromatin. They concluded that, in the right clinical setting and with proper radiological evidence, the cytological features of primary and metastatic ameloblastoma are unique and are sufficient for an accurate diagnosis and follow-up of patients with a history of ameloblastoma.

The diagnosis and extent of these odontogenic tumors are facilitated by both a panorex roentgenogram and computerized axial tomography. Radiographically, they appear as osteolytic processes, exhibiting a unilocular or multilocular appearance. Screening for metastatic disease is advisable, especially in recurrent cases of typical ameloblastoma, malignant ameloblastoma, and ameloblastic carcinoma.

Surgical resection is the treatment of choice. En bloc removal of the mandible or maxilla with 1 to 2 cm of normal bone margin is the safest surgical approach to ensure disease-free survival. This method has resulted in local recurrence rates of less than 15%.

Although generally considered radioresistant,21 there is no well-documented evidence concerning the true radioresponsiveness of these tumors. Atkinson et al22 retrospectively reviewed 10 patients with ameloblastoma treated with megavoltage irradiation at the Princess Margaret Hospital. Seven cases were treated with radiation alone, and 6 (86%) responded initially. Only 1 patient subsequently recurred and was successfully salvaged surgically. Three patients were treated with combined radiation therapy and surgery. They concluded that ameloblastoma is not an inherently radioresistant tumor and that properly applied megavoltage irradiation has a useful role in the management of ameloblastoma. In particular, they concluded that primary radiation should be considered whenever a full-surgical excision was technically difficult because of local invasion or inappropriate because of medical factors. Recommended treatment dosages are between 3,000 cGy and 5,000 cGy. However, an area of concern is that of complications of radiation therapy consisting of osteonecrosis and the theoretical, although rare, danger of postirradiation sarcoma or carcinoma, especially in young patients.21

Chemotherapy as primary treatment does not appear indicated. Results of such treatment for nonmetastatic disease have been poor.23 However, in the setting of metastatic disease, Ramadas et al24 found the use of cisplatin, adriamycin, and cyclophosphamide to be beneficial.

We believe that adequate surgical resection is currently the most appropriate modality for the treatment of ameloblastic carcinoma with radiotherapy being used for metastatic disease not amenable to surgical resection.25