Background
Ameloblastoma is a rare odontogenic epithelial tumor that represents only approximately 1 % of all jaw tumors, but it is the second-most common odontogenic tumor. Although it is always considered a benign odontogenic tumor, ameloblastoma is slow growing, locally aggressive, and has a high propensity for local recurrence if not removed completely. Some authors tend to regard it as a potentially malignant tumor [
1,
2], but metastasis is rare. However, a histologically benign-appearing ameloblastoma can metastasize to local lymph nodes or other distant organs, such as the brain, lung, skin, etc. Over a decade can pass before metastatic tumors are observed after the resection of the primary tumor [
3,
4]. Histologic appearance alone cannot indicate late metastasis. Because of its complex behavior, ameloblastoma continues to be a subject of intense interest and some controversy.
The WHO classification of odontogenous tumors (2005) currently defines malignant ameloblastoma (MA) as “an ameloblastoma that metastasizes in spite of a benign histological appearance.” Ameloblastoma with cytological atypia is defined as ameloblastic carcinoma even if metastasis is absent. Thus, MA is defined as a retrospective diagnosis that can only be made when metastasis occurs. In many cases, MA not only maintains the histological characteristics of the parent tumor but also continues to display similarly indolent clinical behavior. However, the histological features of MA of the lung are seldom discussed in the literature. Because of the low frequency of MA and its unclear clinical history, physicians should avoid misdiagnosing MA as other primary or metastatic tumors of the lung.
Case Presentation
Patients and samples
This study included 3 patients from the Department of Pathology, Fudan University Shanghai Cancer Center, who were diagnosed between 2010 and 2014. Patient 1 was an inpatient of our hospital, and patients 2 and 3 were accepted for consultation. The clinical information and gross features were collected from the referring hospitals and the case files of our hospital. Formalin-fixed paraffin-embedded tissue blocks or unstained slides for the consultation cases were reprocessed for hematoxylin-eosin staining and immunohistochemistry. Slides of one of the local recurrences of patient 2’s mandible tumor were also available. Follow-up information was available in all three cases.
Immunohistochemistry
Immunohistochemistry was performed on three pulmonary MAs and one mandible ameloblastoma. Cytokeratin (dilution 1:150, Dako, clone AE1/AE3), EMA (dilution 1:100, Dako, clone E29), CK7 (dilution 1:200, Dako, clone OV-TL12/30), p63 (dilution 1:50, Dako, clone 4A4), TTF-1 (dilution 1:100, Leica, clone SPT24), SP-A (dilution 1:50, LongIsland, PE10), CK5/6 (dilution 1:200, Dako, D5/16 B4), CK10/13 (dilution 1:100, Dako, DE-K13), and vimentin (dilution 1:1000, clone V9, Dako) were all used a Ventana Benchmark XT autostainer (Ventana Medical Systems Inc., Tucson, AZ, USA). Appropriate positive and negative controls were included.
Discussion
Previous studies have reported MA as “malignant”, “metastatic”, “metastasizing”, “ameloblastoma with metastasis”, etc. and have lacked uniform diagnostic criteria. Metastasis occurring from “adamantinoma of the jaw” was also included in this group. MA has been reported as a heterogeneous clinico-pathological entity that consists of ameloblastomas with different histological and clinical behaviors—from very aggressive to highly indolent. Because cytological atypia are not excluded from the early diagnostic criteria for MA, many reported cases of MA may be malignant entities other than MA [
5,
6]. More than 100 cases of so-called MA have been reported since the first report in 1923 by Emura [
7]. The valid identification of MA remains a problem.
However, the current WHO classification of odontogenic carcinomas clearly distinguishes between MA and ameloblastomatic carcinoma using the typical well-differentiated cellular features of MA [
8]. According to the new definition, MA is less documented in literature. By reviewing 98 cases of MA reported in the literature, Van Dam et al. identified only 24 valid cases of MA based on the printed histological pictures and identified 3 additional cases [
1,
6]. They found that MA can be isolated to a more homogenous clinical pathological entity with special clinical behavior based on histological criteria. They proposed that if aggressive clinic behavior is observed, such as rapid growth and widespread metastasis, ameloblastic carcinoma or other carcinomas should be suspected. We reported another 3 cases of pulmonary MA that were diagnosed using the WHO criteria, similarly to Van Dam.
MA most frequently metastasizes to the lung at a rate of approximately 75-88 % of metastases, and this rate does not differ by gender [
1,
6,
7]. Approximately 80 % of the primary sites of pulmonary MA are located in the mandible, and the remaining cases are maxillary. Pulmonary MA commonly develops via hematogenous and lymphatic routes. In addition, a few metastases are assumed to have occurred due to aspiration, because the tumor grew within the bronchi and bronchioli. This assumption is further sustained because such tumors are often located in the right lung [
9]. The disease-free interval of MA is usually quite long—ranging from 2 months to 45 years (mean, 14-18 years) [
4,
3]. Interestingly, despite many local recurrences and widespread metastatic tumors, many pulmonary MA cases show indolent clinical behavior with long survival times. Longevity is also possible [
10,
11]. Moreover, patients have died of causes other than MA metastasis in some vital cases [
12]. Surgical excision is the only treatment option, because both radiotherapy and chemotherapy are ineffective. In cases of multiple pulmonary metastases, such as our patients, a wider excision has not been shown to be helpful.
The histological features of pulmonary MA have been insufficiently discussed in the literature. Henderson et al. noted that a metastasizing tumor in the lung was more cellular than the primary tumor [
13]. Their histological pictures showed many glandular structures. The same morphology was also noted in a micrograph provided by Mantin O et al. [
14]. Chou YH et al. indicated an interesting interstitial growth pattern of the MA cells in the lung [
15]. We also observed this distinctive finding in all 3 of our cases. In case 2, the locally recurrent mandibular tumor was a solid/multicystic ameloblastoma with a follicular growth pattern. The nests consisted of a stellate reticulum with peripheral palisading basal cells and local squamous metaplasia separated by fibrous stroma. The pulmonary metastatic tumor of patient 2 was more cellular, with many glandular/papillary structures that did not appear in the primary tumor. Among these structures, nests of spindle/ovoid cells with peripheral palisading basal cells and local squamous metaplasia that resembled acanthomatous ameloblastoma were observed. The primary tumors of patients 1 and 3 were not available, but the metastatic tumors also presented similar histological features. The immunochemical staining results identified the ameloblastoma elements among the alveoli of the lung.
In our series, these cases were all initially thought to either clinically or pathologically represent a primary lung tumor, especially the two patients without a clear clinical history. After biopsy, the biphasic morphology initially confounded the preliminary diagnosis. The differential diagnosis included sclerosing hemangioma, adenoma and metastatic lesions, such as adenocarcinoma. We immunohistochemically stained one locally recurrent (patient 2) and 3 metastatic tumors in all three cases. In all tumors, the epithelial components were positive for cytokeratins. Particularly, the nests of spindle/ovoid cells in both the primary and metastatic tumors were CK5/6+, CK10/13+ and p63+, which indicated squamous differentiation. Only the pulmonary metastastic lesions were CK7+, TTF1+ and PE10+, which highlighted the glandular/papillary structures composed of hyperplastic alveolar epithelial cells that may have been stimulated by the non-destructive growth of the ameloblastoma. This non-destructive pattern may at least in part explain the indolent clinical behavior of pulmonary MA, because the metastatic tumor exists in the lung as an interstitial growth for a long time. However, more case observations are needed to support this hypothesis. Furthermore, the two types of hyperplastic cells and this unique growth pattern are important clues for the diagnosis of pulmonary MA.
Because of the limited collection of valid MA cases, the definite histopathological and clinical features of pulmonary MA remain to be clarified. Will metastatic tumors develop different histological patterns? If dedifferentiation occurs in a metastatic tumor [
2,
16], should it still be identified as MA? To our knowledge, certain benign tumors, such as leiomyoma, can also metastasize to the lung [
17]. Further investigations that focus both on the histopathology and clinical behavior as well as the molecular mechanisms of MA are mandatory to elucidate the mysterious nature of this tumor.
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Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
RB carried out the immunohistochemical staining, collected the clinincal and follow-up information and drafted the paper. XX diagnosed the cases, designed the study and revised the paper. LS and XZ diagnosed the cases. All authors read and approved the final manuscript.