Indian Journal of Cancer Medknow Publications on behalf of Indian Cancer Society ISSN: 0019-509X EISSN: 1998-4774 Vol. 48, Num. 2, 2011, pp. 234-239

Indian Journal of Cancer, Vol. 48, No. 2, April-June, 2011, pp. 234-239

Original Article

Metastatic tumors to the jaw bones: Retrospective analysis from an Indian tertiary referral center

SS Muttagi, P Chaturvedi, A D«SQ»Cruz, S Kane, D Chaukar, P Pai, B Singh, P Pawar

Head and Neck Department, Tata Memorial Hospital, E. B. Marg, Parel, Mumbai - 400 012, India

Correspondence Address:S S Muttagi Head and Neck Department, Tata Memorial Hospital, E. B. Marg, Parel, Mumbai - 400 012 India siddu7376@gmail.com

Code Number: cn11056

DOI: 10.4103/0019-509X.82894

Abstract

Keywords: Jaw bones, metastasis, maxilla, mandible

Introduction

Involvement of the jaw bones by malignant tumors is most often due to direct extension of the disease either from the oral cavity or from the surrounding tissues. However, in the diagnostic work up for malignant tumors of the oral and maxillofacial region, it is necessary to consider the possibility of both primary tumors and metastatic tumors, although the latter has very low incidence compared to the rest of the skeletal metastasis. The estimated incidence of metastasis from primary elsewhere to oral and maxillofacial region ranges from 1 to 3%. ^[1],[2],[3]

Although no particular malignancy seems to favor spread to the oral cavity, some primary tumors are found more often than others, depending on the age and sex of the subjects. Also, due to variation in the incidence of the primary site of the tumor across different parts of the globe, there are variations in the occurrence of the metastatic tumors to the jaw bones, as reported by several studies. ^{[3],[4],[5],[6]}

Being a tertiary referral center, we get an average of 2082 oral primary cancers per year [Table - 1] and majority of them are squamous cell carcinoma due to high prevalence of major risk factors like tobacco (chewing and smoking), alcohol, betel nut/quid chewing, etc. Of these cases, approximately 40% directly involve the jaw bones. With this study, we primarily intend to estimate the incidence of metastatic tumors involving jaw bones in our center and retrospectively analyze the data of our cases in comparison with the available literature.

Materials and Methods

The data of patients with oral cancers were reviewed retrospectively from 2000 to 2005. Only the cases with distant metastasis involving the jaw bones were considered and the details of these patients were obtained from the case records. The details included were: demographic characteristics, site of primary tumors, history of previous treatment, presenting complaint, histopathology, jaw bone involved, time between first presentation and development of metastasis, clinical findings, treatment and prognosis. Only the cases with complete information on the primary site, biopsy, immunohistochemistry and clinico-radiological findings of jaw bone involvement were considered for the study. The data were tabulated, analyzed and compared with the available literature.

Results

There were 37 patients whose records showed that they were the cases of metastatic tumors involving the jaw bone. Of these, eight cases were not considered for the study because three of them were cases of multiple myeloma involving maxillofacial skeleton, two were cases of malignant melanoma involving naso-maxillary region and three cases were non-Hodgkin′s lymphomas. Ten cases were excluded from the study in view of insufficient data confirming metastatic jaw bone tumors. Thus, there were only 19 cases of confirmed metastatic tumors involving the jaw bone, which were analyzed.

The age ranged from 4 months to 69 years. The patients were categorized into three groups based on age and sex: children-adolescent group, adult females and adult males. The age of patients in the children-adolescent group ranged from 4 months to 16 years, with mean age of 5.95 years [Table - 2]. There were four cases of adult males with mean age of 60.5 years (range 53-69 years) [Table - 3]. There were 11 female cases with mean age of 45.6 years (range 53-69 years) as shown in [Table - 4]. The M:F ratio in children-adolescent group was equal, whereas for adults the M: F ratio was 4:11.

Most of the metastatic tumors were of epithelial origin. The primary site varied with age. In the 1st decade, the common primary sites were adrenal gland and brain. In the 2nd decade, bone was the common primary site. In later decades in females, breast was the commonest primary site followed by thyroid. In male patients, there was no predilection of occurrence of metastasis to jaw bones from a particular primary site.

Mandible was the commonest jaw bone in this series; 14/19 cases had metastasis in the mandible. Metastasis to the maxilla was seen in 5/19 cases. Metastasis to the mandible was commonly seen from 4th decade onward, whereas maxilla was the site of metastatic deposit in younger age, occurring in the first three decades of life.

In the mandible, body region (area between parasymphysis and angle of the mandible) was the commonest site involved by metastasis in 6/14 cases, followed by the angle of mandible (4/14 cases) and middle one-third mandible (3/14 cases). There was the involvement of ascending ramus to a variable extent in patients with metastatic disease involving angle of mandible. In one case, entire half of the mandible was involved. There was no correlation with age, type of tumor, and location. In the maxilla, the metastases were from neuroblastoma, osteosarcoma and renal cell carcinoma. The latter presented in older age. There was no definitive common site of metastasis in maxilla. However, variable portions of maxilla were involved and the involvement of maxillary alveolus was invariably present. In one case of metastatic osteogenic sarcoma, there was destruction of adjacent bones: zygoma and a portion of sphenoid.

Nine out of 19 were known cases of previous malignant disease and were treated for the same. They presented with metastatic deposit involving jaw bones during routine follow-up. Ten out of 19 cases were referred to our center and had multiple distant metastases that were detected on work up. Therefore, in these cases, the time between diagnosis of primary tumor and detection of metastatic disease was not known. It was interesting to note that in five of these cases, jaw bone was the first site of metastasis detected on initial presentation [Table - 5]. This group included two cases of thyroid carcinoma, one case of hepatocellular carcinoma, one case of adrenal neuroblastoma and a case of medulloblastoma. In the next four cases, metastasis to jaw bones was secondary to other sites. The mean time between detection of primary tumor and diagnosis of metastasis was 42.7 months.

The commonest finding in these patients was an expansile lesion resulting in gross facial asymmetry with associated symptoms of which pain and paresthesia were common. Large fungating masses with gross destruction of soft tissue and bone were seen in 5 out of 19 cases and bleeding from the lesion was the presenting complaint in them, in addition to gross facial asymmetry, pain and paresthesia. Metastasis from breast (two cases), liver, lung and endometrium presented with large fungating masses involving mandible. It was seen that patients with metastasis involving ascending ramus of mandible and masticatory musculature invariably presented with trismus (four cases). The lesions involving maxilla presented with variable degree of gross facial asymmetry. The metastatic lesions from neuroblastoma and osteogenic sarcoma presented as expansile lesions of upper alveolus with comparatively less soft tissue involvement, whereas the metastasis from renal cell carcinoma presented as an ulceroproliferative growth with soft tissue involvement.

In 6 out of 19 cases, only symptomatic treatment was possible. Palliative treatment was given to 6 out of 19 cases. The role of surgery was confined to resection of symptomatic lesions for improvement in the quality of life. Palliative chemotherapy was limited to the patients with good general condition. The role of radiotherapy was limited to palliation. This mainly included alleviation of pain associated with bone metastasis.

The information on follow-up was available in 15 out of 19 cases. Ten out of 15 cases had follow-up of less than 6 months, six of which were dead due to disease and four were dead due to unknown causes. These included primaries from breast (three cases), lung, liver, endometrium, kidney, thyroid (two cases) and bone (one case). The metastasis from primaries in the brain and adrenals had an average follow-up for 19 months with controlled disease status. The patients who had only jaw metastasis from the primary in thyroid region (two cases) are under regular follow-up after radiotherapy for an average of 3.2 years with controlled status.

Discussion

Metastasis is a consequence of complex biological cascade that begins with detachment of tumor cells from the primary tumor, spreading into the tissues, invading the lymphovascular structures followed by their survival in the circulation. ^[5],[7] The microvasculature of the target organ provides room for the lodgment of metastatic tumor cells, from where they can extravasate, invade and proliferate within this target tissue. Angiogenesis is mandatory for the tumor cell load beyond 2-3 mm for adequate supply of oxygen and nutrients. ^[8]

Recent studies on the mechanism by which cancers metastasize to bone have shown that cancer cells alter the physiologic balance between bone resorption and bone formation. Breast cancer metastases are frequently osteolytic and this has been attributed to overexpression of osteoclast inducing factors such as Parathyroid Hormone Related Protein (PTHrP), interleukin (IL)-8 and IL-11. ^{[9],[10],[11]} Predominantly, osteoblastic metastasis is mediated by osteoblast promoting factors like bone morphogenetic proteins (BMPs), Wnt family ligands, endothelin-1 and platelet-derived growth factor (PDGF). Furthermore, the release of matrix embedded growth factors like insulin-like growth factor (IGF) and transforming growth factor-β (TGF-β) upon osteolysis promotes the induction of osteoclast promoting factors. ^[9],[10]

Although several cases of metastatic tumors to the jaw bones have been reported from different parts of the world, this is the first reported case series from an Indian tertiary referral center. In comparison to the western literature, the commonest primary sites in our study were breast and thyroid. This was because we had more of female patients in our series. The reported incidence of bone metastasis from breast cancer is 20-40%, and bone is the second most common site for metastasis from differentiated thyroid cancers. ^[7] It has been shown that 13.37% of breast cancer and 3.85% of thyroid cancers metastasize to the mandible. ^[7],[12] On the contrary, a study from Japan has shown that female sex is associated with the highest number of metastasis to the jaw bones from choriocarcinoma instead of breast or thyroid cancers. ^[3] In accordance with other studies, female predilection was present in this study in view of breast and thyroid being the commonest sites of primary tumors that have shown a tendency to metastasize to the jaw bones rather than soft tissues of the oral cavity.

Studies have shown that most of the metastatic jaw tumors occur in 5th, 6th or 7th decades; in our series, they were found to occur at an earlier age, between 3rd and 7th decades. ^{[5],[7],[13],[14]} In the younger age group (first to second decade of life), the metastasis was found to occur from adrenal neuroblastoma, medulloblastoma and osteogenic sarcoma. This shows that age and sex can give a clue to the possible primary site of a tumor that can metastasize to the jaw bones. In males, cancers of liver and lung have been shown to be the most common primary tumors that metastasize to jaw bones. We had one case each of primary lung and liver cancer in our series. Compared to female cases, there was a lack of predominant primary site causing metastasis to the jaw bones in males.

Reports from different parts of the world show a variable incidence of metastasis to the jaw bone from different primary sites, ranging from one to four cases per year. ^[4],[6],[7] In our study, although we encounter the highest number of primary oral cancer in a year, the incidence of metastasis to jaw bones was approximately four cases per year (19 cases in 5 years). However, it is important to note that majority of the jaw bone metastasis have a high tendency to go undetected. Majority of the cases either have micrometastasis or in view of poor prognosis and terminal stage of the disease, lose follow-up or are dead before presenting to a clinician. Also, the frequency of micrometastasis in histological sections has been found to be higher than that observed by radiologic methods. ^[15] In the mandible, microscopic deposits of metastatic tumor cells were found in 16% of autopsied carcinoma cases. ^[16] Detection of micrometastasis in such cases would increase the number of reported cases with metastatic tumor in the jaw bones. Earlier, radiographic skeletal survey was commonly used for metastatic work up and jaw bones were not included in the survey. ^[5] This has also contributed to the jaw bone metastases that go undetected. With the advent of Fluorodeoxyglucose Positron emission tomography (FDG-PET) scan, the detection of cases with metastatic disease has improved although FDG-PET cannot detect micrometastasis. However, FDG-PET has been shown to be more sensitive than bone scintigraphy in detection of bone metastasis, especially when the metastasis is osteolytic rather than sclerotic. ^[17],[18] In our series, FDG-PET was an important modality in the detection of metastatic disease.

Oral metastatic mucosal lesions have been described in the literature and are less frequenty known to occur compared to bony lesions. ^{[4],[7],[19],[20],[21]} It appears that bone involvement precedes soft tissue involvement in metastatic tumors of the jaw bones. Metastasis to the jaw bones occurs due to hematogenous route of the spread of malignant tumor and this requires the presence of hematopoietically active bone marrow well connected with sinusoidal vascular spaces at the site of deposition of malignant cells. ^[22],[23] The posterior mandible and focal osteoporotic bone marrow defects in the edentulous mandible have been shown to be the hematopoietically active sites that may attract metastatic tumor cells. ^[16],[24] Vascular changes associated with inflammatory process have been thought to be responsible for oral metastasis. Studies have shown that chronic trauma to the oral tissues favors metastatic spread of malignant tumors to the oral cavity. ^[25] In another study, it was found that in 55 cases, tooth extraction preceded the discovery of the metastasis. ^[26] Thus, the role of trauma to the oral mucosa, especially from ill-fitting denture, sharp tooth or restorations, poor oral hygiene and tooth extraction trauma, in the causation of oral metastasis needs further investigation.

Studies have shown that about 30% of oral metastases have been found to be the first sign of metastatic process. ^[7],[27] In contrast, in our series, 26% of the cases had jaw bones as the first site of metastasis, which was similar with the results of a Korean study. ^[4] It has been proposed that valveless vertebral system of venous plexus that is contributed by caval and azygous venous system is responsible for the increased distribution of axial skeletal and head and neck metastasis, bypassing filtration through the lungs. ^[28],[29] On the contrary, although there is no large case series reported on metastatic jaw bone tumors in children and adolescent age group, in the younger age group maxilla can be a common site of deposition of the disease due to higher vascularity and hematopoietically active bone marrow.

In general, metastasis to the jaw bones is associated with metastasis to several other sites and carries a grave prognosis. The time between detection of primary to the diagnosis of metastasis was 42.7 months in our series. Sixty-six percent (10/15 cases) of the patients were dead before the first 6 months of detection of jaw metastasis.

The longest follow-up (average 3.2 years) was seen in two cases with only jaw bone metastases from differentiated thyroid primary tumor. In view of only jaw bone metastasis, total thyroidectomy and segmental resection of metastatic tumor was done, followed by radioiodine therapy. One patient with adrenal neuroblastoma and one with medulloblastoma had an average follow-up of 19 months. They were diagnosed to have a recurrence later for which further treatment was given.

Conclusions

Metastasis to jaw bone, although rare, is a possible cause of jaw swelling. Age and sex can provide important clue to possible location of primary lesion. There are variations in the predominant primary sites across the globe, giving rise to jaw metastases. We get approximately four cases in a year with metastatic disease manifesting in the jaw bones. Metastasis to jaw bone is associated with poor prognosis, with the majority of patients dying within 6 months of diagnosis. Resectable sole metastasis to jaw bone from differentiated thyroid primary is associated with comparatively better prognosis.

References

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