Metastasis to an odontogenic cyst: case report and review of literature

INTRODUCTION

Metastatic disease to the maxillofacial region is rare and represents almost 1% of all oral malignancies.^1,2 The prevalence is increased among individuals between the fourth and sixth decades. Among women, the most common primary sources for metastatic disease are the breast, reproductive organs, kidney and colon while among men, the most common primary sites are the lung, kidney, liver and prostate.³

The most commonly affected site of metastasis to the jawbones is the mandibular molar area. The most common reported symptoms are pain, swelling, paresthesia, spontaneous bleeding and teeth mobility; however, metastasis to the jaws can also be asymptomatic. Radiographic features are varied; nonetheless, ill-defined osteolytic lesions are the most common radiographic finding.^3-6

Odontogenic cysts include a range of osteolytic lesions of the jawbones that can be classified as either developmental, inflammatory or even neoplastic. Most developmental cysts are thought to be derived from remnants of odontogenic epithelium. For example, dentigerous cysts are generally classified as developmental cysts and are thought to arise from the epithelial lining of the follicle of an unerupted tooth and are more common in the pediatric population. In contrast, inflammatory cysts are more common in adults and usually have an infectious origin. In these instances, a chronic endodontic or periodontal infection initiates an inflammatory response leading to the formation of a benign cyst. A residual cyst is a subtype of inflammatory odontogenic cyst that persists after removal of the causative tooth.^7-10

Some benign odontogenic cysts, such as odontogenic keratocysts, display biological and clinical features more akin to neoplasia. Several investigators regard odontogenic keratocysts as cystic neoplasms rather that cysts, although this opinion is still actively debated to this day.^10-13

Metastases and odontogenic cysts may occur simultaneously in the same patient. However, the occurrence of a metastatic nidus within a benign odontogenic cyst is exceedingly rare.^14-16

CASE REPORT

A 61-year-old Caucasian woman was referred to an oral and maxillofacial surgeon for the evaluation of an asymptomatic radiolucent lesion in the left mandible. The patient reported fatigue and nocturnal diaphoresis but did not have any weight loss. The patient denied having any orofacial pain or paresthesia.

Her medical history was otherwise non-contributive. She had stopped smoking 3 years prior to the consultation and had an average alcohol intake of 3 drinks per day.

Physical examination was unremarkable. Cranial nerve and intraoral examinations were within normal limits.

A panoramic radiograph (Figure 1) revealed a large, well-defined and corticated unilocular radiolucency in the left premolar mandibular region. The epicenter of this radiolucency was likely associated with a missing second premolar. The lesion extended anteriorly and crossed the midline.

A cone-beam computed tomography (CBCT) scan of the mandible (Figure 2) showed expansion and thinning of the cortical bone surrounding the lesion. There was no perforation of the cortical plates, nor any dental resorption. Based on these findings, a preliminary diagnosis of benign odontogenic cyst was favored, such as a residual cyst or an odontogenic keratocyst. However, because of systemic symptoms, malignancy could not be entirely ruled out.

An incisional biopsy was performed. Histological examination revealed fragments of a fibrocollagenous capsule lined by non-keratinizing stratified squamous epithelium (Figure 3 A), consistent with a benign odontogenic cyst.

Scale bar=20 µm.

However, in one area of the capsule, a cluster of atypical ductal structures was noted, consistent with metastatic adenocarcinoma (Figure 3 B). These structures stained positively for thyroid transcription factor-1 (TTF-1) and cytokeratin 7 (CK7), suggesting either a thyroidal or pulmonary origin (Figure 3 C-D).

Subsequent advanced imagery and lung biopsy revealed a primary pulmonary adenocarcinoma in the pulmonary lingula (Figure 4). Alas, the patient died 12 months after the initial diagnosis.

DISCUSSION

Odontogenic cysts are benign lesions that may, on rare instances, undergo malignant transformation. There have been numerous reports of primary squamous cell carcinoma arising from a benign odontogenic cyst.^17,18 By contrast, metastatic disease within a pre-existing benign odontogenic cyst is exceedingly rare.^14-16

Lung cancer is the most prevalent malignancy among men and the third most common among women worldwide, after breast and colorectal cancer. It is also the main cause of death from cancer among men and the second among women. Men experience nearly a two-fold increase in both incidence and mortality rate compared to women.^19,20 For lung metastases to the jaws, Gultekin et al.²¹ reported a men to women ratio of (3.9:1) in a review of the literature.

Adenocarcinoma is the most common subtype of lung cancer, representing more than 40% of all pulmonary malignancies.^22-24 This tumor typically stains positively with pancytokeratin AE1/AE3, CK7, TTF-1 and Napsin A while it is typically negative for cytokeratin 20 (CK20) and paired box 8 (PAX8).^25-27

In the present case, the mandibular nidus was the first evidence of pulmonary adenocarcinoma. Hirshberg et al³, in their analysis of 673 cases of metastases to the oral cavity, found that in approximately 23% of cases, oral metastases were the first sign of disease. Metastases to the jaws display a wide range of clinical and radiographic features and may mimic benign lesions and odontogenic infections.²⁵

To our knowledge, the present case is the fourth report of metastatic disease arising within a benign odontogenic cyst in the English literature, and the first case of pulmonary metastasis within a pre-existing odontogenic cyst. ^14-16 Clinical features of previously reported cases of metastasis within odontogenic cysts are detailed in Table 1. In two of these cases, paresthesia was reported, while the third was associated with pain. Benign odontogenic cysts are seldom associated with systemic signs or symptoms, unless secondarily infected.²⁸ Therefore, in presence of benign radiographic features accompanied with paresthesia or systemic symptoms, the possibility of a superimposed malignancy must be considered.

Dahl and Terakado et al also reported cases of metastases to the jaws presenting as periapical radiolucencies.^29,30 However, histologic evidence of pre-existing odontogenic lesions is lacking; it is impossible to state whether the radiolucencies were purely metastatic or if they arose within odontogenic lesions. Incidentally, cases of metastastic disease presenting as periapical lesions have been widely reported.^31-33

In our case, aside from the wall of the residual cyst, there was no other detectable metastatic implant in the jawbones. Even though this may be a simple coincidence, there might be some underlying mechanism for this occurrence. In the context of inflammatory odontogenic cysts, it is possible that a cascade of pro-inflammatory cytokines and byproducts of osteolysis at the periphery of the lesion may facilitate chemotaxis and proliferation of metastatic cells in the previously diseased bone. Chemoattracting factors produced during natural bone turnover may recruit circulating cancer cells. Examples of these chemoattractants are C-X-C Motif Chemokine ligand 12 (CXCL12), Osteopontin (OPN), receptor activator of nuclear factor κ-B Ligand (RANKL) and bone morphogenic proteins (BMPs) secreted by osteoblasts.^34,35 Once the metastatic cells acquire adaptive traits to grow in their new microenvironment, a vicious cycle of paracrine and autocrine signaling is established among cancer cells, osteoblasts and osteoclasts, thereby maintaining the metastatic colonization in bone tissue.^36,37 Growth factors such as transforming growth factor beta (TGF-β) and insulin-like growth factors (IGF) may play a key role in the survival of cancer cells in these conditions.³⁸ In addition, the reactive formation of leaky neocapillaries associated with inflammatory lesions, often present around inflamed odontogenic cysts, may further increase the likelihood of a metastatic implant via hematogenous routes.^16,39,40

CONCLUSION

Metastatic disease to the jaws may present with a wide variety of clinical and radiographic features. On rare instances, it may be masked by a superimposed benign condition, thereby posing a diagnostic challenge to the clinician. This case illustrates the necessity for thorough examination of any tissue submitted during routine jaw surgery, even in presence of asymptomatic and seemingly benign odontogenic cysts.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

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