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J Am Dent Assoc, Vol 137, No 12, 1667-1672. © 2006 American Dental Association

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A retrospective study of 114 cases

	ABSTRACT

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Background. Malignancies involving the bones are metastatic tumors more commonly than primary tumors. In this retrospective study, the authors review metastatic disease in the jaws.

Methods. The authors retrieved cases of metastatic disease in the jaws over a 45-year period from the pathology archives at the University of Michigan School of Dentistry, Ann Arbor, and Indiana University School of Dentistry, Indianapolis.

Results. The authors conducted a retrospective analysis of 114 cases of metastatic disease in the jaws and found that approximately 60 percent of subjects had no history of malignancy. The sex distribution was equivalent. Mandibular predilection was more prominent in females than in males. Metastases from the breast were significantly greater than those from the lung and prostate (P .05), the second and third most frequent sites, respectively. Women exhibited twice as many jaw metastases as did men 31 to 40 years of age and significantly fewer metastases than did men 71 to 80 years of age (P .05).

Conclusion. In the majority of cases, subjects had an undiagnosed primary cancer at the time the metastatic jaw disease presented. The most common site of origin of the primary cancer was the breast, when primary sites were considered independent of sex.

Clinical Implications. Patients with metastatic disease in the jaws may have innocuous dental symptoms, such as pulpal or periodontal pain; therefore, clinicians will play a significant role in diagnosing the life-threatening disease.

Key Words: Maxilla; mandible; carcinoma; breast; prostate; lung

Malignancies involving the bones are metastatic tumors more commonly than primary tumors.¹ The bones most frequently involved with metastatic disease are the vertebrae, ribs, pelvis and skull.¹ In contrast, the occurrence of metastasis from distant primary malignancies to the jaws is considered a rare disease.² These metastatic lesions (or tumors) usually are carcinomas rather than sarcomas, which is consistent with malignancies of epithelial origin accounting for more than 80 percent of all primary cancers, regardless of tumor site.² In this article, we report the findings of a retrospective analysis of 114 previously unreported cases of metastatic disease in the jaws from the pathology archives of the University of Michigan School of Dentistry, Ann Arbor, and Indiana University School of Dentistry, Indianapolis.

	SUBJECTS AND METHODS

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We retrieved records of cases diagnosed as metastatic disease in the jaws over a 45-year interval (1958–2003) from the pathology archives of the University of Michigan School of Dentistry, Ann Arbor, and Indiana University School of Dentistry, Indianapolis. The data collected from these cases included sex, age, clinical signs and symptoms, location and primary tumor diagnosis, as well as radiographic appearance if available. At the time of each subject’s diagnosis, the pathologist contacted the subject’s clinician, and, if a history of primary disease was indicated or was lacking, the pathologist noted it on the biopsy record. If the primary tumor site was available, the pathologist also recorded it.

We retrieved 114 cases of metastatic disease to the jaws from the archives. We obtained appropriate approval and waiver of consent from the Institutional Review Board of the Medical School, University of Michigan, Ann Arbor, and IUPUI/Clarian Institutional Review Board, Indiana University, Indianapolis, before initiating this study.

We used the McNemar test to compare metastases from the breasts with those from the lungs, male reproductive system (which includes the prostate) or colorectal region. We used the Fisher exact test for all other statistical comparisons.

	RESULTS

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After we reviewed 114 cases of metastatic jaw tumors, we found 71 reported symptoms, with the most common symptom being pain (35 cases), followed by paresthesia (19 cases), swelling (11 cases), bleeding (five cases) and temporo-mandibular joint problems (one case). The most common primary tumor site was the breast (29 cases, 25.4 percent), regardless of sex (Table 1). The number of metastatic lesions from the breast was significantly greater than those from the lung (15 cases, 13.2 percent) (P .05), the male reproductive system (11 cases, 9.6 percent) (P .05) or the colorectal region (eight cases, 7.0 percent) (P .001). In 66 cases (57.8 percent), the primary tumor site was unknown at the time of diagnosis (Table 1).

View this table: [in this window] [in a new window]   TABLE 1 Distribution of primary tumor sites*.

 
When we correlated the sites of the primary tumors with the subject’s sex, we found that the breast and lung were the most common primary tumor sites for females and males, respectively (Table 2). In 11 cases, the subject’s sex was not stated. Metastatic lesions from the lung were significantly more common in men than in women (P .002). Men and women had an equivalent number of metastatic lesions from the colorectal region.

View this table: [in this window] [in a new window]   TABLE 2 Site distribution by sex.

 
Mandibular lesions were more common than maxillary lesions in both males (41 and 11, respectively) and females (45 and six, respectively). Overall, 83.5 percent of metastatic jaw lesions occurred in the mandible. When we viewed jaw predilection by sex, we found that mandibular predilection was more prominent in females than in males; 88 percent of metastatic jaw lesions occurred in the mandible in females (a 7.5:1 mandibular to maxillary ratio), and 79 percent of metastatic jaw lesions occurred in the mandible in males (a 3.7:1 mandibular to maxillary ratio). The subject’s sex and jaw distribution were unknown in 11 cases.

We noted a wide age distribution for all subjects. Women exhibited twice as many metastatic jaw lesions as did men 31 to 40 years of age, though this difference was not statistically significant. Men exhibited significantly more metastatic jaw lesions than did women 71 to 80 years of age group (P .05; Figure 1). This disparity was even greater when we combined the 71- to 80-year age group with the 81- to 90-year and 91- to 100-year age groups (P .003). We did not identify any cases of metastatic lesions to the jaws of children or young adults.

View larger version (41K): [in this window] [in a new window]   Figure 1. Age distribution by sex. Men had significantly more metastatic lesions than did women 71 to 80 years of age (*P .05). Women 31 to 40 and 61 to 70 years of age had more metastatic jaw lesions than did men, though these findings were not statistically significant within a specific decade of life.

 
Metastatic disease in the jaws may extend into the overlying soft tissues and appear as a dental or periodontal infection. However, the histologic appearance of metastatic jaw disease often is poorly differentiated, making it challenging to determine the location of the primary lesion.¹ The use of immunohistochemical stains and a thorough medical history can facilitate diagnosis. Figures 2 and 3 show an example of metastatic prostate carcinoma with soft-tissue extension in an 82-year-old man. This lesion appeared as a swelling, with associated purulence in an area of existing dentition. Radiographically, we observed an irregular radiolucent lesion with adjacent radiopacities (Figure 2). On histologic examination, we noted a neoplastic proliferation of cells with large, oval nuclei, prominent nucleoli, scattered atypical mitoses and focal formation of glandular structures (Figures 3A and 3B). These cells extended between trabeculae of viable bone, and we observed small clusters with hyperchro-matic nuclei infiltrating the overlying soft tissue. Between the cell clusters, we noted a distribution of small endothelium-lined vascular channels and erythrocytes. The neoplastic infiltrate was strongly positive for prostate-specific antigen (PSA) and with cytokeratin antibodies (Figures 3C-3F) and negative with CD45 antibodies (Figures 3G-3H). Further consultation with the referring clinician revealed a history of prostatic carcinoma. We diagnosed the lesion as histologi-cally and immunohistochemically consistent with metastatic prostatic adenocarcinoma.

View larger version (30K): [in this window] [in a new window]   Figure 2. Section of a panoramic radiograph showing irregular, mixed radiolucent and radiopaque lesion in the left posterior mandible.

 

View larger version (113K): [in this window] [in a new window]   Figure 3. Hematoxylin and eosin (H&E) and immunohistochemical staining of soft-tissue (A, C, E and G) and intrabony (B, D, F and H) neoplastic infiltrate of lesion shown in Figure 2. Tumor cells were prostate-specific antigen- (PSA) and cytokeratin- (CK) positive but CD45-negative. µm: Micrometers.

 

	DISCUSSION

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People who have metastases to the jaws often have vague or innocuous symptoms that can mimic dental infections. In our study, the most common jaw symptom was pain; pain and pathological fracture have been shown to be indicators of poor prognosis.³ Therefore, dentists should evaluate patients with a history of malignancy who have what appears to be dental-related pain, be it pulpal or periodontal, for the possibility of metastatic disease.

Frequently, patients do not report having a history of cancer at the time of dental treatment or are unaware of having an undiagnosed primary malignancy. After reviewing 114 cases, we found that the primary malignancy was undetected in approximately two-thirds of the cases. This is in contrast to previous studies that have reported that in about one-third to one-fifth of cases the primary cancer is not detected until the oral metastasis is diagnosed.^4–6 For cases in our study, the pathologists signing out the cases contacted clinicians at the time of diagnosis and if a history of primary disease was indicated, this was reflected on the biopsy record. Hence, cases with no history of cancer recorded were not a result of missing information on the biopsy request form.

Lung cancer is the most common cause of cancer death among both men and women^7,8; however, in our study, the most common site of the origin of metastatic jaw tumors was the breast, even when we considered primary sites independent of sex. Perhaps prolonged survival in patients with breast cancer owing to targeted treatment regimens and early detection of recurrent disease^9,10 has facilitated metastasis to distant sites.

In the male subjects in our study, metastasis to the jaws occurred more frequently from the lungs (13.2 percent) than from the prostate (9.6 percent), and most metastasis to the jaws in female subjects were from primary breast malignancies (25.4 percent). In a review of the literature, Hirshberg and colleagues⁶ also reported that the breast and lung were the most common primary sites in women and men, respectively. In contrast, Body¹¹ reported that breast and prostate malignancies were most likely to metastasize to the bone, with approximately 80 percent of all bone metastases arising from primary cancers at these sites. Nishimura and colleagues¹² found the uterus was the most common primary tumor location, with the most common type of cancer being choriocarcinoma, which has a high occurrence rate in the Japanese population. This variation in incidence of primary malignancies may be due to several factors, including geographic influences and genetic mutations, as has been observed with cancers of the gastrointestinal tract.^13,14

The results of our study showed an equivalent sex distribution for metastatic jaw disease, though women exhibited more metastases than did men 31 to 40 years of age, and men exhibited a significantly greater incidence of metastases than did women 71 to 80 years of age (P .05). This most likely is a reflection of the fact that primary breast carcinoma occurs at an earlier age in women, whereas prostate and lung carcinomas occur later in life in men.^15,16

We also found that the location of the lesion was stated on the pathology requisition form by the submitting clinician, though a detailed radiographic description rarely was given. The mandible was the most common site for meta-static lesions. Radiographically, metastatic lesions most often are ill-defined and usually are osteolytic (radiolucent), but they may be osteoblastic (osteosclerotic or radiopaque) or mixed radiopaque and radiolucent lesions.^11,17 The radiographic appearance of the lesions has been attributed to a disruption of the balance between osteo-clastic and osteoblastic activity that occurs during normal bone turnover.^11,17 Tumor type may affect the radiographic appearance of the lesion; prostatic carcinoma metastases are classically osteoblastic (Figure 2), while metastatic breast or renal carcinoma may be osteolytic, osteoblastic or mixed.^11,17

The literature suggests that the jaws are not a common site of metastatic bone disease,^2,5,18 with metastases to the jaws composing less than 1 percent of all metastatic bone lesions.¹⁹ These reports are based on retrospective analyses of symptomatic lesions, but do not take into account the possibility that jaw metastases may be undetected. In fact, radiographic surveys of the jaws are not routine, even at autopsy.² Furthermore, conventional radiographs may not detect meta-static lesions in the jaws.¹ An autopsy study of primary carcinomas at different extraoral sites showed histopathologic evidence of metastatic disease in the mandible, even though no lesions were detected radiographically.¹ Given the vascularity of the jaws, particularly the mandible, and the high bone turnover in this region, a reasonable hypothesis would be that metastases frequently involve the jaws in cases of advanced disease. A prospective screening study in patients with advanced stage malignancies, in which the jaws are imaged routinely by conventional radiographs and bone scintigraphy, would help address this issue.

The radiographic appearance of metastatic disease in the jaws varies from well- to poorly circumscribed radiolucencies; the latter also is known as a "moth-eaten" appearance.¹ Alveolar bone extension may be confused with periodontal disease. Since metastatic carcinomas from the breast and prostate may stimulate bone formation, these metastases may appear as mixed radiopaque and radiolucent lesions.¹ In the metastatic prostate carcinoma case from our study that we discussed, the radiograph showed an irregular radiolucency and radiopacities. Metastatic disease to the jaws may extend into the overlying soft tissues, appearing to be a dental or periodontal infection. Alternatively, metastases may occur directly in the soft tissues, usually the gingiva.¹ Included in the differential diagnosis of metastatic peripheral lesions on the gingiva or alveolar ridge are pyogenic granuloma, peripheral giant cell granuloma and, possibly, ulcerated peripheral ossifying fibroma or fibroma.

The histologic appearance of metastatic jaw disease often is poorly differentiated, making it challenging to determine the location of the primary lesion.¹ Taking a thorough medical history can facilitate a diagnosis, and conducting a screening using a panel of immunohistochemical stains may facilitate a diagnosis. Metastatic breast carcinomas typically are positive for cyto-keratin 7 (CK7), but negative for cytokeratin 20 (CK20), thyroid transcription factor-1 (TTF1) and PSA (Table 3).²⁰ In contrast, metastatic colorectal carcinomas are typically CK20-positive, but CK7-, TTF1- and PSA-negative.^21–23 A metastatic lesion that stains positively for CK7 and TTF1 likely would be from a lung carcinoma,²⁴ whereas metastatic prostate carcinoma would be positive for PSA²⁵ but negative for the other three markers.

View this table: [in this window] [in a new window]   TABLE 3 Antibody positivity of the four most common types of metastatic carcinoma in the jaws.

 
We were unable to determine management of subjects’ care or subjects’ survival in our study because follow-up information was not available; specimens are received from private dental practitioners who often referred the subjects to other clinicians for subsequent treatment. A prospective study linked to management and survival data would help address this issue. In general, survival of patients with advanced disease including metastases is poor, with most patients dying within a year of detection of the bony metastasis.¹

	CONCLUSIONS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Our retrospective analysis of 114 cases is the largest single series of metastatic jaw disease studied. About two-thirds of the cases had an unknown primary malignancy at the time of the presentation of the jaw lesion. The most common site of origin of metastatic jaw tumors was the breast, even when we considered primary sites independent of sex. Patients may have innocuous dental symptoms, such as pain of pulpal or periodontal origin; therefore, all tissue excised from the oral cavity should be submitted for pathological evaluation.

	FOOTNOTES

Dr. Summerlin is an associate professor, Department of Oral Pathology, Medicine and Radiology, Indiana University School of Dentistry, Indianapolis.

Dr. Cordell is a clinical assistant professor, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor.

Dr. Abdelsayed is an associate professor, Oral Biology and Maxillofacial Pathology, Medical College of Georgia, Augusta.

Dr. Tomich is a professor emeritus, Department of Oral Pathology, Medicine and Radiology, Indiana University School of Dentistry, Indianapolis.

The late Dr. Hanks was a professor emeritus, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, and an associate professor emeritus, Department of Pathology, University of Michigan Medical School, Ann Arbor, when this article was written.

Dr. Fear is in private practice, Ann Arbor, Mich.

Dr. Meyrowitz was a dental student, University of Michigan, School of Dentistry, Ann Arbor, when this article was written. He now is a resident, Department of Orthodontics and Pediatric Dentistry, University of Michigan School of Dentistry, Ann Arbor.

The authors thank Dr. Charles J. Kowalski at the University of Michigan, who performed the statistical analyses in this study.

	REFERENCES

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 

1. Neville BW. Oral and maxillofacial pathology. 2nd ed. Philadel-phia: Saunders; 2002:582–7.
   
   
2. Keller EE, Gunderson LL. Bone disease metastatic to the jaws. JADA 1987;115(5):697–701.[Abstract]
   
   
3. Reddi AH, Roodman D, Freeman C, Mohla S. Mechanisms of tumor metastasis to the bone: challenges and opportunities. J Bone Miner Res 2003;18(2):190–4.[Medline]
   
   
4. Zachariades N. Neoplasms metastatic to the mouth, jaws and surrounding tissues. J Craniomaxillofac Surg 1989;17(6):283–90.[Medline]
   
   
5. van der Waal RI, Buter J, van der Waal I. Oral metastases: report of 24 cases. Br J Oral Maxillofac Surg 2003;41(1):3–6.[Medline]
   
   
6. Hirshberg A, Leibovich P, Buchner A. Metastatic tumors to the jawbones: analysis of 390 cases. J Oral Pathol Med 1994;23(8):337–41.[Medline]
   
   
7. Blot WJ, McLaughlin JK. Are women more susceptible to lung cancer? J Natl Cancer Inst 2004;96(11):812–3.[Free Full Text]
   
   
8. Jemal A, Clegg LX, Ward E, et al. Annual report to the nation on the status of cancer, 1975-2001, with a special feature regarding survival. Cancer 2004;101(1):3–27.[Medline]
   
   
9. Immonen-Raiha P, Kauhava L, Parvinen I, et al. Mammographic screening reduces risk of breast carcinoma recurrence. Cancer 2005;103(3):474–82.[Medline]
   
   
10. Galper S, Blood E, Gelman R, et al. Prognosis after local recurrence after conservative surgery and radiation for early-stage breast cancer. Int J Radiat Oncol Biol Phys 2005;61(2):348–57.[Medline]
    
    
11. Body JJ. Rationale for the use of bisphosphonates in osteoblastic and osteolytic bone lesions. Breast 2003;12(supplement 2):S37–S44.[Medline]
    
    
12. Nishimura Y, Yakata H, Kawasaki T, Nakajima T. Metastatic tumours of the mouth and jaws: a review of the Japanese literature. J Maxillofac Surg 1982;10(4):253–8.[Medline]
    
    
13. Hongo M. Review article: Barrett’s oesophagus and carcinoma in Japan. Aliment Pharmacol Ther 2004;20(supplement 8):50–4.
    
    
14. Durno C, Aronson M, Bapat B, Cohen Z, Gallinger S. Family history and molecular features of children, adolescents and young adults with colorectal carcinoma. Gut 2005;54(8):1146–50.[Abstract/Free Full Text]
    
    
15. Lowe FC, Gilbert SM, Kahane H. Evidence of increased prostate cancer detection in men aged 50 to 59: a review of 324,684 biopsies performed between 1995 and 2002. Urology 2003;62(6):1045–9.[Medline]
    
    
16. Jemal A, Thomas A, Murray T, Thun M. Cancer statistics, 2002 (published corrections appear in CA Cancer J Clin 2002;52[2]:119, and CA Cancer J Clin 2002;52[3]:181-2). CA Cancer J Clin 2002; 52(1):23–47.[Abstract/Free Full Text]
    
    
17. Goltzman D. Osteolysis and cancer. J Clin Invest 2001;107(10): 1219–20.[Medline]
    
    
18. Zachariades N, Koumoura F, Vairaktaris E, Mezitis M. Metastatic tumors to the jaws: a report of seven cases. J Oral Max-illofac Surg 1989;47(9):991–6.[Medline]
    
    
19. White SC, Pharoah MJ. Oral radiology: Principles and interpretation. 4th ed. St. Louis: Mosby; 2000:428–30.
    
    
20. O’Connell FP, Wang HH, Odze RD. Utility of immunohistochem-istry in distinguishing primary adenocarcinomas from metastatic breast carcinomas in the gastrointestinal tract. Arch Pathol Lab Med 2005;129(3):338–47.[Medline]
    
    
21. Choi HR, Sturgis EM, Rashid A, et al. Sinonasal adenocarcinoma: evidence for histogenetic divergence of the enteric and nonenteric phenotypes. Hum Pathol 2003;34(11):1101–7.[Medline]
    
    
22. Barbareschi M, Murer B, Colby TV, et al. CDX-2 homeobox gene expression is a reliable marker of colorectal adenocarcinoma metastases to the lungs. Am J Surg Pathol 2003;27(2):141–9.[Medline]
    
    
23. Raspollini MR, Baroni G, Taddei A, Taddei GL. Primary cervical adenocarcinoma with intestinal differentiation and colonic carcinoma metastatic to cervix: an investigation using Cdx-2 and a limited immunohistochemical panel. Arch Pathol Lab Med 2003; 127(12):1586–90.[Medline]
    
    
24. Tot T. The value of cytokeratins 20 and 7 in discriminating metastatic adenocarcinomas from pleural mesotheliomas. Cancer 2001;92(10):2727–32.[Medline]
    
    
25. Cho KR, Epstein JI. Metastatic prostatic carcinoma to supradi-aphragmatic lymph nodes: a clinicopathologic and immunohistochem-ical study. Am J Surg Pathol 1987;11(6):457–63.[Medline]
    
    

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