Vol. 117 No. 3 March 2014
Synchronous antiresorptive osteonecrosis of the jaws and breast cancer metastasis Isadora Luana Flores, DDS, MsC, Alan Roger dos Santos-Silva, DDS, PhD, Ricardo Della Coletta, DDS, PhD, Pablo Agustin Vargas, DDS, PhD, and Márcio Ajudarte Lopes, DDS, PhD State University of Campinas (UNICAMP), Piracicaba, São Paulo, Brazil
Antiresorptive osteonecrosis of the jaws (ARONJ) is a significant and poorly understood oral complication that may affect patients receiving antiresorptive agents, such as intravenous bisphosphonate therapy. There are scarce reports of the coexistence of ARONJ and metastasis at the same jaw site in the English-language literature. In the present case, a 60-year-old white woman was referred for the evaluation of a nonhealing extraction socket. The patient was undergoing treatment with intravenous zoledronic acid to metastatic breast cancer in bone, and her medical history and clinical characteristics led to the diagnosis of ARONJ. Nevertheless, histologic analysis showed a fragment of necrotic bone and bacterial colonies associated with malignant epithelial cells that were confirmed to be metastatic breast adenocarcinoma. This case showed that jaw metastasis can occur at the same time and site of ARONJ, making diagnosis and management challenging. (Oral Surg Oral Med Oral Pathol Oral Radiol 2014;117:e264-e268)
Antiresorptive therapy is commonly established to treat hypercalcemia related to primary bone malignancy or advanced metastatic disease and to treat low bone mass in osteoporosis.1 Intravenous drugs of various classes, including bisphosphonates; the human monoclonal antibody to the receptor activator of nuclear factor k B ligand (denosumab); antiangiogenic drugs such as bevacizumab, cetuximab, panitumumab, and trastuzumab; and the kinase inhibitor sunitinib are antiresorptive drugs that have previously been associated with the oral side effect of osteonecrosis.1,2 Antiresorptive osteonecrosis of the jaws (ARONJ) is a new term that encompasses cases associated with the use of any antiresorptive agents, including bisphosphonates.2 Bisphosphonates are analogs of pyrophosphates that play a crucial role in the management of several medical conditions associated with hypercalcemia and of bone complications in patients with bone metastases and primary malignancies of bone.3,4 Bisphosphonates bind selectively to hydroxyapatite, inhibiting osteoclastic activity.4 Although bisphosphonates provide tremendous benefits, such as decreasing pain and pathologic fracture risks, they may also cause side effects.5,6 For instance, bisphosphonate-related osteonecrosis of the jaws, which was first described by Marx in 2003,7 is a condition defined by an area of exposed necrotic bone in the maxillofacial region lasting more than 8 weeks in a patient exposed to bisphosphonate therapy with no history of head and neck radiotherapy.8,9 Osteonecrosis of the jaws is considered a complication associated with the long-term use of oral and intravenous antiresorptive Piracicaba Dental School, State University of Campinas (UNICAMP). Received for publication Sep 17, 2013; returned for revision Nov 1, 2013; accepted for publication Nov 14, 2013. Ó 2014 Published by Elsevier Inc. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2013.11.495
e264
agents, such as bisphosphonates, and is especially associated with intravenous pamidronate and zoledronic acid.7 These drugs are mainly administered intravenously to control bone metastases of breast cancer, prostate cancer, and multiple myeloma.10 More than 600 cases of ARONJ have been reported in the Englishlanguage literature so far.3,6 Metastasis is a complex biologic process in which tumor cells are able to invade a sequence of biologic barriers11 and proliferate in different sites, including bone. Although jaw metastasis is less frequent when compared with long-bone metastasis, when it occurs it is often associated with advanced breast cancer.12,13 Metastases to the jaws generally indicate the presence of late-stage disease and metastases at other sites. As a consequence, the prognosis is poor and the treatment tends to be palliative.12,13 The investigation of osteonecrotic areas in patients under antiresorptive therapy is recommended to exclude underlying bone pathologies, such as the presence of distant metastasis.8,14-18 Simultaneous ARONJ and jaw metastasis is a rare event, with only 5 previous publications reporting the combination of these conditions (8 cases).4,14,16-18 The aim of the current report is to describe the ninth case in the English-language literature of a patient with ARONJ and hidden jaw distant metastasis due to breast cancer, which was found after microscopic analysis in the osteonecrotic jaw specimens.
CASE PRESENTATION A 60-year-old white woman was referred for the evaluation of a nonhealing socket and exposed necrotic bone after extraction of the upper left second molar 14 months before attending our clinic. Extraoral examination was unremarkable. Intraoral examination found exposed necrotic bone on the left posterior maxilla associated with significant sensitivity, mobility of the upper left first molar (Figure 1), and signs of inflammation in
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CASE REPORT Flores et al. e265 bone exposure. Another curettage of necrotic bone and extraction of the upper second left premolar was performed with the same previous protocol. Although no pain or purulent secretion have been observed, an area of bone exposure is still present. The patient has been under follow-up for 1 year and has been using mouthwash, alcohol-free chlorhexidine gluconate 0.12%, twice daily. She is under continual monitoring by the oncologist, and the association of vinorelbinebased chemotherapy and zoledronic acid weekly in alternated cycles is the current treatment regimen.
Fig. 1. Exposed necrotic bone at the posterior maxilla. the adjacent oral mucosa. Three-dimensional reconstruction achieved with cone beam computed tomography (CBCT) showed rarefaction of bone and thickening of the periodontal ligament space surrounding the upper second left premolar and the upper first left molar (Figure 2). Extensive bone loss was found on the posterior left maxillary region from the second premolar to the left tuberosity, and clouding of the left maxillary sinus suggested soft tissue density (see Figure 2, A). Disruption of lingual cortical bone was found in parasagittal sections of CBCT (see Figure 2, B). Her medical history included breast cancer 16 years earlier. Treatment was partial left mastectomy (quadrantectomy) associated with axillary lymph node dissection. Although no lymph node metastasis was detected, radiotherapy and chemotherapy were performed. Local recurrence occurred after 6 years; the patient underwent another mastectomy, and daily tamoxifen was prescribed. Concomitantly, chest pain was observed, and the bone densitometry suggested bone metastasis in the spinal column. Additional whole-body bone scintigraphy with technetium99m methylene diphosphonate (99mTc-MDP) confirmed metastases to the spinal column and found tumor in the skull, clavicle, scapula, ribs, sternum, thoracic spine, lumbar spine, iliac crest, and acetabulum (Figure 3). Lung metastasis was also present, and intravenous infusion of 4 mg of zoledronic acid (Zometa) every 3 to 4 weeks associated with chemotherapy was the treatment modality established previously during 15 and 8 months, respectively. Although local recurrence was resolved and lung metastases were controlled, new areas of bone metastases were detected. Based on medical history and on clinical and radiologic features, the diagnosis of ARONJ was proposed. Necrotic osseous debridement and extraction of the upper left first molar were performed under prophylactic antibiotic therapy and local anesthesia. Clindamycin, 300 mg 3 times a day, was continued for over 1 week, and the patient returned for subsequent appointments without complaints. Microscopic examination of the surgical specimen found osseous necrotic fragments surrounded by multiple bacterial colonies and ductal structures with malignant neoplastic cells compatible with the diagnosis of breast adenocarcinoma (Figures 4 and 5). Therefore, the histopathology findings were consistent with the presence of metastatic breast cancer infiltrating the jaw simultaneously with ARONJ. After 4 months of followup, the affected area presented total healing; however, the patient complained of local pain. Clinical examination found mobility of the upper left second premolar and a new area of
DISCUSSION Coexistence of ARONJ and metastatic cancer in the same maxillary region was previously described in 5 articles. Bedogni et al.4 were the first to report 2 cases, one of breast cancer and the other of thyroid cancer. Carlson and Basile14 reported 3 cases of multiple myeloma and ARONJ at the same jaw site. Frei et al.16 reported a case in which ARONJ was associated with prostate cancer, and Otto et al.17 reported another case of synchronous metastatic breast cancer and osteonecrosis. Carlson et al.18 recently investigated the incidence of hidden metastasis in 744 sites of ARONJ in a retrospective multicenter study and found metastasis in 19 sites (5.3%) of 16 patients, in which 6 cases were breast cancer. The current case is the ninth report in the English-language literature and was associated with breast cancer. Some malignancies, such as multiple myeloma, breast cancer, and prostate cancer, frequently metastasize to bone, and antiresorptive agents such as intravenous bisphosphonates are recommended as part of the treatment.3,4 The association of long-term intravenous bisphosphonates, chemotherapy, cancer as a comorbidity factor, and oral microbes produce a synergistic effect that increases the chance of triggering ARONJ, particularly when trauma is present.6 In the current case, ARONJ probably was associated with tooth extraction, but the presence of metastatic focus also should be considered when osteonecrosis develops.18 Metastasis from malignant tumors to the oral cavity is rare; it can affect soft tissues or jaws, but osseous involvement is more frequent.16,19 In the present case, the breast adenocarcinoma diagnosis was established only after microscopic evaluation of the necrotic bone fragments. Clinical aspects were strongly suggestive of necrotic bone, and the presence of metastasis was not originally considered. Swelling, intraoral mass, teeth mobility, pain, and paresthesia are the main symptoms reported by patients with jaw metastasis.20 Our patient showed clinical aspects, such as pain and teeth mobility, that can be present both in ARONJ and jaw metastases. It is important to mention that both conditions may exhibit overlapping clinical and radiologic characteristics. CBCT scans of metastatic areas often have a hyperdense and hypodense mixed
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Fig. 2. A, Panoramic reconstruction of cone beam computed tomography showing the bone loss surrounding the upper left second premolar and first molar. Note the extensive bone loss on the left maxillary tuber region and the involvement of the inferior left maxillary sinus through soft tissue density aspect. B, Parasagittal sections found a complete disruption of lingual cortical bone in the upper left second premolar region.
Fig. 3. Bone scintigraphy with technetium-99m methylene diphosphonate, showing the distribution of the metastatic foci.
appearance, leading to a moth-eaten shape, and periodontal ligament involvement could be present.13 Destruction of the trabecular structure of the bone and erosion of the cortical bone are also frequent and suggestive findings of ARONJ in CBCT images.20-22 Some
findings were found in our patient in CBCT images but were not enough to prompt consideration of jaw metastasis. Interestingly, maxilla metastasis was also not detected by 99mTc-MDP, because the sensitivity of bone scintigraphy is limited with regard to diagnosis
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Fig. 4. Fragments of necrotic bone surrounded by nests and cords of epithelial cells infiltrating the stroma of fibrous connective tissue (hematoxylin-eosin, original magnification 20).
Fig. 5. Pancytokeratin immunohistochemistry demonstrating the intense positive cytoplasmic staining of malignant ductal cells (AE1/AE3 stain, 10).
of micrometastasis of jaw, mainly when the lesion is osteolytic (as in our case). Consequently, these cases have a high tendency to have undetected micrometastasis.23 These aspects reinforce the necessity of microscopic analysis of all removed material, including the typical necrotic bone fragments, especially in patients with known history of cancer. The higher bioavailability of the intravenous drugs in the bone matrix when compared with oral bisphosphonates, associated with high concentration of bisphosphonates in the jaws due to higher vascularity and bone turnover than in other parts of the skeleton, should be considered as important in triggering ARONJ.24,25 Interestingly, Lesclous et al.25 have observed persistency of an effective blood supply in the affected site of ARONJ.26 This information argues against the assumption that intravenous bisphosphonates, especially zoledronic acid, could reduce bone angiogenesis.27 These drugs might also induce inflammatory reaction contributing as an important local chemical mediator to the development of ARONJ as well as other pathologies,28 such as jaw metastasis.29,30 Much more needs to be learned about distant metastases in bone. Inflammation, angiogenesis, and cytokine networks may contribute to metastatic processes in the jaws, because these factors may create a host environment suitable for the growth of neoplastic cells.29 Some chemokines, such as stromal cellederived factor 1a (SDF-1a; CXCL12), and their receptors, such as fusin (CXCR4) and chemokine (C-C motif) receptor 7 (CCR7), interleukins 1 and 6, and tumor necrosis factor, have been considered to play a critical role in homing and proliferation of cancer cells at specific metastatic sites.29,30 This microenvironment allows metastatic cells in the bloodstream to potentially colonize traumatized areas in the oral cavity, owing to the affinity for lodging at sites of inflammation (e.g., in the periodontal tissues) in a process called anachoresis.31 Therefore,
the presence of frequent inflammation associated with intravenous bisphosphonates availability can also contribute to survival and proliferation of metastatic cells in the jaws. Additionally, the release of Fas-ligand factor (FasL), a transmembrane protein of the tumor necrosis factor family, by metastatic cancer cells was associated with apoptosis and cell necrosis of the osteoblastic precursor cells, contributing to genesis of osteonecrosis.32 Overexpression of matrix metalloproteinases (MMPs) by cancer cells and risk of osteonecrosis also should be considered, especially when a tooth extraction is performed in the jaws with metastatic focus, because MMPs affect the osseous remodeling process, triggering osteonecrosis.18,33 These aspects contributed to proposed possible reasons for the coexistence of ARONJ and metastasis at the same bony site through molecular mechanisms mediated by cancer cells that contribute to osteonecrosis development. In summary, this case emphasized the necessity of microscopic/histopathologic analysis of all necrotic bone fragments resulting from debridement of clinically diagnosed ARONJ, because they can hide malignancy.
REFERENCES 1. Hellstein JW, Adler RA, Edwards B, et al. Managing the care of patients receiving antiresorptive therapy for prevention and treatment of osteoporosis: executive summary of recommendations from the American Dental Association Council on Scientific Affairs. J Am Dent Assoc. 2011;142:1243-1251. 2. Sivolella S, Lumachi F, Stellini E, Favero L. Denosumab and antiangiogenetic drug-related osteonecrosis of the jaw: an uncommon but potentially severe disease. Anticancer Res. 2013;33:17931797. 3. Ruggiero SL, Fantasia J, Carlson E. Bisphosphonate-related osteonecrosis of the jaw: background and guidelines for diagnosis, staging and management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;102:433-441.
ORAL MEDICINE e268 Flores et al. 4. Bedogni A, Saia G, Ragazzo M, et al. Bisphosphonate-associated osteonecrosis can hide jaw metastases. Bone. 2007;41:942-945. 5. Jagdev SP, Purohit P, Heatley S, Herling C, Coleman RE. Comparison of the effects of intravenous pamidronate and oral clodronate on symptoms and bone resorption in patients with metastatic bone disease. Ann Oncol. 2001;12:1433-1438. 6. Varun B, Sivakumar T, Nair BJ, Joseph AP. Bisphosphonate induced osteonecrosis of jaw in breast cancer patients: a systematic review. J Oral Maxillofac Pathol. 2012;16:210-214. 7. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg. 2003;61:1115-1117. 8. Khosla S, Burr D, Cauley J, et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2007;22:1479-1491. 9. Morag Y, Morag-Hezroni M, Jamadar DA, et al. Bisphosphonaterelated osteonecrosis of the jaw: a pictorial review. Radiographics. 2009;29:1971-1984. 10. Ruggiero SL, Dodson TB, Assael LA, et al. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jawsd2009 update. J Oral Maxillofac Surg. 2009;67:2-12. 11. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70. 12. Ogütcen-Toller M, Metin M, Yildiz L. Metastatic breast carcinoma mimicking periodontal disease on radiographs. J Clin Periodontol. 2002;29:269-271. 13. Orhan K, Bayndr H, Aksoy S, Seker BK, Berberoglu A, Ozan O. Numb chin syndrome as a manifestation of possible breast cancer metastasis around dental implants. Craniofac Surg. 2011;22: 942-945. 14. Carlson ER, Basile JD. The role of surgical resection in the management of bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg. 2009;67:85-95. 15. Pires FR, Miranda A, Cardoso ES, et al. Oral avascular bone necrosis associated with chemotherapy and bisphosphonate therapy. Oral Dis. 2005;11:365-369. 16. Frei M, Bornstein MM, Schaller B, Reichart PA, Weimann R, Iizuka T. Bisphosphonate-related osteonecrosis of the jaw combined with jaw metastasis of prostate adenocarcinoma: report of a case. J Oral Maxillofac Surg. 2010;68:863-867. 17. Otto S, Schuler K, Ihrler S, Ehrenfeld M, Mast G. Osteonecrosis or metastases of the jaw or both? Case report and review of the literature. J Oral Maxillofac Surg. 2010;68:1185-1188. 18. Carlson ER, Fleisher KE, Ruggiero SL. Metastatic cancer identified in osteonecrosis specimens of the jaws in patients receiving intravenous bisphosphonate medications. J Oral Maxillofac Surg. 2013;71:2077-2086. 19. Rodan GA. The development and function of the skeleton and bone metastases. Cancer. 2003;97:726-732. 20. Villa A, Mariani U, Villa F. Oral metastasis of lung cancer: a challenge for the clinician. Oral Maxillofac Surg. 2012;16: 133-135.
OOOO March 2014 21. Wilde F, Heufelder M, Lorenz K, et al. Prevalence of cone beam computed tomography imaging findings according to the clinical stage of bisphosphonate-related osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;114:804-811. 22. Singer SR, Mupparapu M. Plain film and CBCT findings in a case of bisphosphonate-related osteonecrosis of the jaw. Quintessence Int. 2009;40:163-165. 23. Muttagi SS, Chaturvedi P, D’Cruz A, et al. Metastatic tumors to the jaw bones: retrospective analysis from an Indian tertiary referral center. Indian J Cancer. 2011;48:234-239. 24. Hoff AO, Toth BB, Altundag K, et al. Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res. 2008;23: 826-836. 25. Lesclous P, Abi Najm S, Carrel JP, et al. Bisphosphonateassociated osteonecrosis of the jaw: a key role of inflammation? Bone. 2009;45:843-852. 26. Advisory Task Force on Bisphosphonate-Related Ostenonecrosis of the Jaws, American Association of Oral and Maxillofacial Surgeons. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg. 2007;65:369-376. 27. Fournier P, Boissier F, Filleur S, et al. Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res. 2002;62:6538-6544. 28. Aghaloo TL, Kang B, Sung EC, et al. Periodontal disease and bisphosphonates induce osteonecrosis of the jaws in the rat. J Bone Miner Res. 2011;26:1871-1882. 29. Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G. Inflammation and cancer: how hot is the link? Biochem Pharmacol. 2006;72:1605-1621. 30. Müller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001;410:50-56. 31. Stashenko P, Teles R, D’Souza R. Periapical inflammatory responses and their modulation. Crit Rev Oral Biol Med. 1998;9: 498-521. 32. Fromigué O, Kheddoumi N, Lomri A, Marie PJ, Body JJ. Breast cancer cells release factors that induced apoptosis in human bone marrow stromal cells. J Bone Miner Res. 2001;16:1600-1610. 33. Barillé S, Akhoundi C, Collette M, et al. Metalloproteinases in multiple myeloma: production of matrix metalloproteinase-9 (MMP-9), activation of proMMP-2, and induction of MMP-1 by myeloma cells. Blood. 1997;90:1649-1655. Reprint requests: Márcio Ajudarte Lopes Faculdade de Odontologia de Piracicaba - UNICAMP Departamento de Diagnóstico Oral - Semiologia Av. Limeira, 901 CEP 13.414-903 Piracicaba - São Paulo Brazil [email protected]
Synchronous antiresorptive osteonecrosis of the jaws and breast cancer metastasis Isadora Luana Flores, DDS, MsC, Alan Roger dos Santos-Silva, DDS, PhD, Ricardo Della Coletta, DDS, PhD, Pablo Agustin Vargas, DDS, PhD, and Márcio Ajudarte Lopes, DDS, PhD State University of Campinas (UNICAMP), Piracicaba, São Paulo, Brazil
Antiresorptive osteonecrosis of the jaws (ARONJ) is a significant and poorly understood oral complication that may affect patients receiving antiresorptive agents, such as intravenous bisphosphonate therapy. There are scarce reports of the coexistence of ARONJ and metastasis at the same jaw site in the English-language literature. In the present case, a 60-year-old white woman was referred for the evaluation of a nonhealing extraction socket. The patient was undergoing treatment with intravenous zoledronic acid to metastatic breast cancer in bone, and her medical history and clinical characteristics led to the diagnosis of ARONJ. Nevertheless, histologic analysis showed a fragment of necrotic bone and bacterial colonies associated with malignant epithelial cells that were confirmed to be metastatic breast adenocarcinoma. This case showed that jaw metastasis can occur at the same time and site of ARONJ, making diagnosis and management challenging. (Oral Surg Oral Med Oral Pathol Oral Radiol 2014;117:e264-e268)
Antiresorptive therapy is commonly established to treat hypercalcemia related to primary bone malignancy or advanced metastatic disease and to treat low bone mass in osteoporosis.1 Intravenous drugs of various classes, including bisphosphonates; the human monoclonal antibody to the receptor activator of nuclear factor k B ligand (denosumab); antiangiogenic drugs such as bevacizumab, cetuximab, panitumumab, and trastuzumab; and the kinase inhibitor sunitinib are antiresorptive drugs that have previously been associated with the oral side effect of osteonecrosis.1,2 Antiresorptive osteonecrosis of the jaws (ARONJ) is a new term that encompasses cases associated with the use of any antiresorptive agents, including bisphosphonates.2 Bisphosphonates are analogs of pyrophosphates that play a crucial role in the management of several medical conditions associated with hypercalcemia and of bone complications in patients with bone metastases and primary malignancies of bone.3,4 Bisphosphonates bind selectively to hydroxyapatite, inhibiting osteoclastic activity.4 Although bisphosphonates provide tremendous benefits, such as decreasing pain and pathologic fracture risks, they may also cause side effects.5,6 For instance, bisphosphonate-related osteonecrosis of the jaws, which was first described by Marx in 2003,7 is a condition defined by an area of exposed necrotic bone in the maxillofacial region lasting more than 8 weeks in a patient exposed to bisphosphonate therapy with no history of head and neck radiotherapy.8,9 Osteonecrosis of the jaws is considered a complication associated with the long-term use of oral and intravenous antiresorptive Piracicaba Dental School, State University of Campinas (UNICAMP). Received for publication Sep 17, 2013; returned for revision Nov 1, 2013; accepted for publication Nov 14, 2013. Ó 2014 Published by Elsevier Inc. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2013.11.495
e264
agents, such as bisphosphonates, and is especially associated with intravenous pamidronate and zoledronic acid.7 These drugs are mainly administered intravenously to control bone metastases of breast cancer, prostate cancer, and multiple myeloma.10 More than 600 cases of ARONJ have been reported in the Englishlanguage literature so far.3,6 Metastasis is a complex biologic process in which tumor cells are able to invade a sequence of biologic barriers11 and proliferate in different sites, including bone. Although jaw metastasis is less frequent when compared with long-bone metastasis, when it occurs it is often associated with advanced breast cancer.12,13 Metastases to the jaws generally indicate the presence of late-stage disease and metastases at other sites. As a consequence, the prognosis is poor and the treatment tends to be palliative.12,13 The investigation of osteonecrotic areas in patients under antiresorptive therapy is recommended to exclude underlying bone pathologies, such as the presence of distant metastasis.8,14-18 Simultaneous ARONJ and jaw metastasis is a rare event, with only 5 previous publications reporting the combination of these conditions (8 cases).4,14,16-18 The aim of the current report is to describe the ninth case in the English-language literature of a patient with ARONJ and hidden jaw distant metastasis due to breast cancer, which was found after microscopic analysis in the osteonecrotic jaw specimens.
CASE PRESENTATION A 60-year-old white woman was referred for the evaluation of a nonhealing socket and exposed necrotic bone after extraction of the upper left second molar 14 months before attending our clinic. Extraoral examination was unremarkable. Intraoral examination found exposed necrotic bone on the left posterior maxilla associated with significant sensitivity, mobility of the upper left first molar (Figure 1), and signs of inflammation in
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CASE REPORT Flores et al. e265 bone exposure. Another curettage of necrotic bone and extraction of the upper second left premolar was performed with the same previous protocol. Although no pain or purulent secretion have been observed, an area of bone exposure is still present. The patient has been under follow-up for 1 year and has been using mouthwash, alcohol-free chlorhexidine gluconate 0.12%, twice daily. She is under continual monitoring by the oncologist, and the association of vinorelbinebased chemotherapy and zoledronic acid weekly in alternated cycles is the current treatment regimen.
Fig. 1. Exposed necrotic bone at the posterior maxilla. the adjacent oral mucosa. Three-dimensional reconstruction achieved with cone beam computed tomography (CBCT) showed rarefaction of bone and thickening of the periodontal ligament space surrounding the upper second left premolar and the upper first left molar (Figure 2). Extensive bone loss was found on the posterior left maxillary region from the second premolar to the left tuberosity, and clouding of the left maxillary sinus suggested soft tissue density (see Figure 2, A). Disruption of lingual cortical bone was found in parasagittal sections of CBCT (see Figure 2, B). Her medical history included breast cancer 16 years earlier. Treatment was partial left mastectomy (quadrantectomy) associated with axillary lymph node dissection. Although no lymph node metastasis was detected, radiotherapy and chemotherapy were performed. Local recurrence occurred after 6 years; the patient underwent another mastectomy, and daily tamoxifen was prescribed. Concomitantly, chest pain was observed, and the bone densitometry suggested bone metastasis in the spinal column. Additional whole-body bone scintigraphy with technetium99m methylene diphosphonate (99mTc-MDP) confirmed metastases to the spinal column and found tumor in the skull, clavicle, scapula, ribs, sternum, thoracic spine, lumbar spine, iliac crest, and acetabulum (Figure 3). Lung metastasis was also present, and intravenous infusion of 4 mg of zoledronic acid (Zometa) every 3 to 4 weeks associated with chemotherapy was the treatment modality established previously during 15 and 8 months, respectively. Although local recurrence was resolved and lung metastases were controlled, new areas of bone metastases were detected. Based on medical history and on clinical and radiologic features, the diagnosis of ARONJ was proposed. Necrotic osseous debridement and extraction of the upper left first molar were performed under prophylactic antibiotic therapy and local anesthesia. Clindamycin, 300 mg 3 times a day, was continued for over 1 week, and the patient returned for subsequent appointments without complaints. Microscopic examination of the surgical specimen found osseous necrotic fragments surrounded by multiple bacterial colonies and ductal structures with malignant neoplastic cells compatible with the diagnosis of breast adenocarcinoma (Figures 4 and 5). Therefore, the histopathology findings were consistent with the presence of metastatic breast cancer infiltrating the jaw simultaneously with ARONJ. After 4 months of followup, the affected area presented total healing; however, the patient complained of local pain. Clinical examination found mobility of the upper left second premolar and a new area of
DISCUSSION Coexistence of ARONJ and metastatic cancer in the same maxillary region was previously described in 5 articles. Bedogni et al.4 were the first to report 2 cases, one of breast cancer and the other of thyroid cancer. Carlson and Basile14 reported 3 cases of multiple myeloma and ARONJ at the same jaw site. Frei et al.16 reported a case in which ARONJ was associated with prostate cancer, and Otto et al.17 reported another case of synchronous metastatic breast cancer and osteonecrosis. Carlson et al.18 recently investigated the incidence of hidden metastasis in 744 sites of ARONJ in a retrospective multicenter study and found metastasis in 19 sites (5.3%) of 16 patients, in which 6 cases were breast cancer. The current case is the ninth report in the English-language literature and was associated with breast cancer. Some malignancies, such as multiple myeloma, breast cancer, and prostate cancer, frequently metastasize to bone, and antiresorptive agents such as intravenous bisphosphonates are recommended as part of the treatment.3,4 The association of long-term intravenous bisphosphonates, chemotherapy, cancer as a comorbidity factor, and oral microbes produce a synergistic effect that increases the chance of triggering ARONJ, particularly when trauma is present.6 In the current case, ARONJ probably was associated with tooth extraction, but the presence of metastatic focus also should be considered when osteonecrosis develops.18 Metastasis from malignant tumors to the oral cavity is rare; it can affect soft tissues or jaws, but osseous involvement is more frequent.16,19 In the present case, the breast adenocarcinoma diagnosis was established only after microscopic evaluation of the necrotic bone fragments. Clinical aspects were strongly suggestive of necrotic bone, and the presence of metastasis was not originally considered. Swelling, intraoral mass, teeth mobility, pain, and paresthesia are the main symptoms reported by patients with jaw metastasis.20 Our patient showed clinical aspects, such as pain and teeth mobility, that can be present both in ARONJ and jaw metastases. It is important to mention that both conditions may exhibit overlapping clinical and radiologic characteristics. CBCT scans of metastatic areas often have a hyperdense and hypodense mixed
ORAL MEDICINE e266 Flores et al.
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Fig. 2. A, Panoramic reconstruction of cone beam computed tomography showing the bone loss surrounding the upper left second premolar and first molar. Note the extensive bone loss on the left maxillary tuber region and the involvement of the inferior left maxillary sinus through soft tissue density aspect. B, Parasagittal sections found a complete disruption of lingual cortical bone in the upper left second premolar region.
Fig. 3. Bone scintigraphy with technetium-99m methylene diphosphonate, showing the distribution of the metastatic foci.
appearance, leading to a moth-eaten shape, and periodontal ligament involvement could be present.13 Destruction of the trabecular structure of the bone and erosion of the cortical bone are also frequent and suggestive findings of ARONJ in CBCT images.20-22 Some
findings were found in our patient in CBCT images but were not enough to prompt consideration of jaw metastasis. Interestingly, maxilla metastasis was also not detected by 99mTc-MDP, because the sensitivity of bone scintigraphy is limited with regard to diagnosis
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CASE REPORT Flores et al. e267
Fig. 4. Fragments of necrotic bone surrounded by nests and cords of epithelial cells infiltrating the stroma of fibrous connective tissue (hematoxylin-eosin, original magnification 20).
Fig. 5. Pancytokeratin immunohistochemistry demonstrating the intense positive cytoplasmic staining of malignant ductal cells (AE1/AE3 stain, 10).
of micrometastasis of jaw, mainly when the lesion is osteolytic (as in our case). Consequently, these cases have a high tendency to have undetected micrometastasis.23 These aspects reinforce the necessity of microscopic analysis of all removed material, including the typical necrotic bone fragments, especially in patients with known history of cancer. The higher bioavailability of the intravenous drugs in the bone matrix when compared with oral bisphosphonates, associated with high concentration of bisphosphonates in the jaws due to higher vascularity and bone turnover than in other parts of the skeleton, should be considered as important in triggering ARONJ.24,25 Interestingly, Lesclous et al.25 have observed persistency of an effective blood supply in the affected site of ARONJ.26 This information argues against the assumption that intravenous bisphosphonates, especially zoledronic acid, could reduce bone angiogenesis.27 These drugs might also induce inflammatory reaction contributing as an important local chemical mediator to the development of ARONJ as well as other pathologies,28 such as jaw metastasis.29,30 Much more needs to be learned about distant metastases in bone. Inflammation, angiogenesis, and cytokine networks may contribute to metastatic processes in the jaws, because these factors may create a host environment suitable for the growth of neoplastic cells.29 Some chemokines, such as stromal cellederived factor 1a (SDF-1a; CXCL12), and their receptors, such as fusin (CXCR4) and chemokine (C-C motif) receptor 7 (CCR7), interleukins 1 and 6, and tumor necrosis factor, have been considered to play a critical role in homing and proliferation of cancer cells at specific metastatic sites.29,30 This microenvironment allows metastatic cells in the bloodstream to potentially colonize traumatized areas in the oral cavity, owing to the affinity for lodging at sites of inflammation (e.g., in the periodontal tissues) in a process called anachoresis.31 Therefore,
the presence of frequent inflammation associated with intravenous bisphosphonates availability can also contribute to survival and proliferation of metastatic cells in the jaws. Additionally, the release of Fas-ligand factor (FasL), a transmembrane protein of the tumor necrosis factor family, by metastatic cancer cells was associated with apoptosis and cell necrosis of the osteoblastic precursor cells, contributing to genesis of osteonecrosis.32 Overexpression of matrix metalloproteinases (MMPs) by cancer cells and risk of osteonecrosis also should be considered, especially when a tooth extraction is performed in the jaws with metastatic focus, because MMPs affect the osseous remodeling process, triggering osteonecrosis.18,33 These aspects contributed to proposed possible reasons for the coexistence of ARONJ and metastasis at the same bony site through molecular mechanisms mediated by cancer cells that contribute to osteonecrosis development. In summary, this case emphasized the necessity of microscopic/histopathologic analysis of all necrotic bone fragments resulting from debridement of clinically diagnosed ARONJ, because they can hide malignancy.
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