Bisphosphonate-associated osteonecrosis can hide jaw metastases

Bisphosphonate-associated osteonecrosis can hide jaw metastases
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  Bisphosphonate-associated osteonecrosis can hide jaw metastases Alberto Bedogni  a  , Giorgia Saia  b , Mirko Ragazzo  b , Giordana Bettini  a  , Paola Capelli  c ,Emiliano D'Alessandro  d , Pier Francesco Nocini  a  , Lucio Lo Russo  e ,Lorenzo Lo Muzio  e, ⁎ , Stella Blandamura  d a  Section of Oral and Maxillofacial Surgery, University of Verona, Verona, Italy  b Unit of Maxillofacial Surgery, University of Padova, Padova, Italy c  Institute of Pathology, University of Verona, Verona, Italy d Section of Pathological Anatomy, University of Padova, Padova, Italy e  Department of Surgical Sciences, University of Foggia, V.le Pinto, 71100 Foggia, Italy Received 5 April 2007; revised 2 August 2007; accepted 7 August 2007Available online 29 August 2007 Abstract  Background:  Osteonecrosis of the jaw is a well known potential complication of bisphosphonate treatment but its pathogenesis is poorlyunderstood. The current management of patients with bisphosphonate-associated osteonecrosis (BON) is based on  “ expert recommendations ”  andthere is a recognized need of better evidence. We report two cases where BON hid jaw metastases and use them to discuss some limitations of thecurrent recommendations.  Patients:  Two patients undergoing long-term I.V. amino-bisphosphonate treatment for metastatic cancer presented with areas of intraorallyexposed jawbone. Bisphosphonate-associated osteonecrosis was diagnosed on the basis of medical history, clinical and radiological features. Theyunderwent surgical resection of the affected jaw due to unrelenting pain and lack of response to conservative treatments.  Results:  Histological examination of the surgical specimen revealed cancer cells at the margins of the site of osteonecrosis. Our patients did not undergo bone biopsy according to current recommendations, due to lack of clinical and radiological signs suggestive of jaw metastases. Conclusions:  Our findings show that: i) patients with BON may also have jaw metastases; ii) there may not be clinical or imaging hints to this fact and; iii) that a biopsy based on careful selection of the site (with inclusion of necrotic margins) may be needed to reach the correct diagnosis.Further studies should be performed on this topic because of its very important prognostic implications.© 2007 Elsevier Inc. All rights reserved.  Keywords:  Bisphosphonate; Osteonecrosis; Metastasis; Jawbone; Osteomyelitis Introduction Bisphosphonates play a central role in the management of malignancy-associated hypercalcemia and the prevention of  bone complications in patients with bone metastases or multiplemyeloma. Bisphosphonates bind selectively to hydroxyapatiteand accumulate in sites of bone remodeling where they inhibit osteoclastic activity. They also have anti-angiogenic properties both in vitro and in vivo [1].Osteonecrosis of the jaw is a well known potential com- plication of bisphosphonate treatment but its pathogenesis is poorly understood [2 – 7]. The current management of patientswith bisphosphonate-associated osteonecrosis (BON) is basedon  “ expert opinions ” , but there is a recognized need of better evidence [8 – 10].We report two cases where BON hid jaw metastases and usethemtodiscuss somelimitations ofthe currentrecommendations. Cases presentation Clinical case 1 A 65-year-old woman with metastatic breast carcinoma had been treated from 2004 with tamoxifene, steroids and monthly I.V. infusion of zoledronate, with good control of pain and anacceptable quality of life. Bone 41 (2007) 942 – ⁎  Corresponding author. Fax: +39 0881 685809.  E-mail address:  (L. Lo Muzio).8756-3282/$ - see front matter © 2007 Elsevier Inc. All rights reserved.doi:10.1016/j.bone.2007.08.025  She had been edentulous since 2001 and had no history of dental extractions or oral surgery during bisphosphonatetreatment. In September 2005, she reported severe maxillary pain and halitosis.She was then referred to the Department of MaxillofacialSurgery of Verona University, where intraoral examination re-vealed a large area of exposed necrotic bone of the anterior maxilla. Computed tomography (CT) showed a diffuse osteo-sclerotic pattern with sinus formation and anterior bone seques-tration (Fig. 1A). Magnetic resonance imaging (MRI) withgadolinium showed a diffuse osteonecrotic – osteomyelitic process, with unspecific contrast media enhancement (Fig.1B). These clinical and radiological features were compatiblewith a diagnosis of BON. Because of unrelenting pain and lack of response to antibiotic therapy, and after oncological con-sultation, bisphosphonate treatment was suspended. A newtreatment was started, consisting of: 1) 25 sessions of hyper- baric oxygen therapy (HBO); 2) inferior maxillectomy with preservationof thehardpalate (resectionmargins were planned before surgery using CT and MRI) (Fig. 1C); 3) 10-day I.V.cycle of sulbactam-amoxicillin and metronidazole; and; 4) 25 post-surgery HBO sessions.The histological analysis of the specimen revealed, besides anextensive osteomyelitic – osteonecrotic process, metastatic infil-tration of the maxillary bone marrow from breast cancer cells.Importantly, cancer cells were detected in the right maxilla incombination with an osteomyelitic pattern and also found at bothmargins of resection, where bone marrow had no signs of trabecular inflammation or destruction (Fig. 1D). Bone metas-taseswereconfirmedbyimmunohistochemicalstainingwithanti-cytokeratinantibodies(CloneMNF1116,1:200dilution,DAKO).A final diagnosis of maxillary BON and early metastaticlocalization of breast cancer was made. The patient was referredto her oncologist for further evaluation and treatment. At 6 months of follow-up, the patient was free of pain and without clinical and radiological signs of jawbone disease. Clinical case 2 A 57-year-old man with diffusely metastatic thyroid me-dullary carcinoma (MTC) who had been treated with carbo- platin, taxol and epirubicin, was switched to gemcitabineand capecitabine and monthly infusions of bisphosphonates(pamidronate for 5 months and zoledronate for 20 monthsthereafter). Occurrence of severe mandibular pain led the patient to consult his dentist who observed a small area of exposedmandibular bone at the lingual aspect of the left molar regionand a very mobile second molar tooth that was extracted. Boneexposure increased progressively notwithstanding three ses-sions of surgical debridement of the area. The patient was thenreferred to the Department of Maxillofacial Surgery of VeronaUniversity, where in addition to unremitting mandibular pain, Fig. 1. (A) pre-operative axial CTscan showing diffuse osteosclerosis of the maxilla, bone sequestration in its anterior aspect (white arrow), and sinus formation (whitearrow-head). (B) pre-operative MRI (T1-sequence) with gadolinium showing non-specific contrast media enhancement of the maxilla and surrounding soft-tissues.(C) surgical specimen after inferior maxillectomy not including the palate, showing the necrotic bone in the anteriormaxilla (white arrow), and the posteriormargins of  bone resection at the level of the maxillary tuberosities (white arrow-head). (D) histology of the specimen obtained from the right margin of bone resection. Note theinfiltration of breast cancer cells (black arrow-head) within the medullary bone, without signs of necrosis and inflammation of the surrounding bone tissue (black arrow) (Hematoxylin – Eosin stain).943  A. Bedogni et al. / Bone 41 (2007) 942  –  945  facial swelling and trismus were observed. CTshowed increased bone density of the left mandibular body with small lacunae, andextensive periosteal reaction of the inner and outer cortex of theascending ramus (Fig. 2A). MRI showed diffuse osteonecrotic – osteomyelitic changes of the left hemimandible and inflamma-tion of the masseter and pterigoyd muscles (Fig. 2B). Noradiological evidence of jawbone metastases was found and adiagnosis of BON was performed. Because there was noresponse to conservative measures, the patient underwent a left hemimandibulectomy with condylar head preservation andmandibularreconstructionwithtitanium plate(Fig.2C).Marginsof bone resection were planned before surgery using CT andMRI. The management was the same described for clinicalcase 1. Besides the osteomyelitic – osteonecrotic process, thehistological examination of the surgical specimen revealed MTCcells in the left mandibular angle and ascending ramus. Thediagnosis was confirmed by immunohistochemical stainingwithanti-calcitoninantibodies(CloneCAL-3-F5,1:100dilution,DAKO). MTC cellswereorganized in a spotty pattern within theosteomyelitic areas (Fig. 2D) and were fairly distant from theexposed necrotic bone, where no neoplastic cells were found.The anterior margin of bone resection had a normalarchitecture but the posterior margin was infiltrated by cancer cells without trabecular inflammation. The treatment went uncomplicated and the patient was referred to his oncologist for further evaluation and treatment. At 5 months of follow-up, the pain had resolved completely and there was no clinical or radiological evidence of jawbone disease. Discussion This is the first report on the coexistence of BON andmetastatic cancer cells in the same jaw. Our findings suggest that the present recommendations for the diagnostic assessment of patients with BON should be revised.Multiple myeloma, breast cancer and prostate cancer aretumors that frequently metastasize to bone and require bispho-sphonate treatment  [8]. Breast, adrenal, colon – rectum, genitaland thyroid cancers are the most common sources of jawmetastases in women while in men they are lung, prostate,kidney and adrenal tumors [11,12]. Thus, it is not surprising that  BON patients may have jaw metastases. This should always betaken into account because BON and metastases have manyoverlapping clinical and radiological features. Radiologicalfeatures of BON are not specific; in addition, radiologicalfeatures potentially useful in distinguishing osteomyelitis frommetastases are known mainly for the mandible [13,14]. The identification of metastases is especially difficult in the presenceof osteolytic lesions [15]. Moreover, the inflammation associ- ated with cancer may be taken for osteomyelitis [16]. Fig. 2. (A) pre-operative axial CTscan showing the increased medullary bone density of the left hemimandible, and the periosteal reaction of both the outer and inner cortex (white arrow-head). (B) pre-operative MRI (Inversion Recovery sequence) showing the high water content of the medullary bone compartment (white arrow-head) and masticator muscles (black arrows) on the left side, as compared with the opposite normal side. (C) surgical specimen after resection of the left hemimandibleincluding the periosteal envelope.Cross-sectional bonesamples obtainedfor histologicalevaluation: margins of resection(black dotted lines), exposedbone in the oralcavity (black line), areas of diseased bone without intraoral exposure (white dotted lines). (D) histology of the specimen obtained from the ascending ramus of themandible. Note the infiltration of thyroid cancer cells (black arrow-head) within the medullary bone (monoclonal mouse anti-human calcitonin  —  Clone CAL-3-F5,diluted 1:100, DAKO).944  A. Bedogni et al. / Bone 41 (2007) 942  –  945  In the cases reported here, CT and MRI detected theosteomyelitic – osteonecrotic process but not the metastaticinfiltration of the jaw. Conventional imaging techniques suchas radiography, CT and MRI are of little help in the differentialdiagnosis of BON and metastases. There is some evidence that the combined use of sestamibi-scintigraphy and positronemitted tomography may help detect oral osteonecrosis in patients with multiple myeloma, especially for lesions greater than 1 cm [17]. However, this promising approach needs vali- dation on larger samples.The gold-standard for the diagnosis of bone metastases is biopsy. However, the role of biopsy in BON is controversial because any surgical procedure may lead to progression of theunderlying disease [3,7]. Thus, a conservative approach is cur- rently recommend, with biopsy performed only when metasta-ses are suspected [9,17,18].In our patients, clinical and radiological signs of jawbonemetastases were lacking and biopsy was not performed. Patientsunderwent surgical resection because of failure of conservativetreatment for BON. Following current recommendations, our  patients would have not had diagnosis of metastatic infiltrationif they had not required surgery [9,17,18]. The prognostic implications of missing a diagnosis of cancer are clear andsuggest that the current recommendations should be revised.This applies not only to the timing but also to the site of biopsy.As this latter is concerned, the exposed bone is presentlyconsidered the best place to perform biopsy because this limitstrauma to underlying tissues [9]. This approach would have not led to the correct diagnosis in our patients because cancer cellswere present elsewhere in the jaw. Metastatization to theunexposed bone, where inflammation and angiogenesis arehowever present, suggests that the cytokine network may play arole in promoting the  “ homing ”  metastatic cells [19,20].In summary, our report: i) warns about the possibility that  patients with BON may also have jaw metastases, ii) highlightsthat there may not be clinical or imaging peculiar features of this, iii) suggests that a biopsy based on careful selection of thesite (with inclusion of necrotic margins) may be needed to reachthe correct diagnosis. Further studies should be performed onthis topic because of its very important prognostic implications. References [1] Green JR. Antitumor effects of bisphosphonates. Cancer 2003;97:840 – 7.[2] Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avas-cular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg2003;61:1115 – 7.[3] Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases.J Oral Maxillofac Surg 2004;62:527 – 34.[4] Migliorati CA, Schubert MM, Peterson DE, Seneda LM. Bisphosphonate-associated osteonecrosis of mandibular and maxillary bone: an emergingoral complication of supportive cancer therapy. Cancer 2005;104:83 – 93.[5] Bamias A, Kastritis E, Bamia C, Moulopoulos LA, Melakopoulos I, BozasG, et al. Osteonecrosis of the jaw in cancer after treatment with bispho-sphonates: incidence and risk factors. J Clin Oncol 2005;23:8580 – 7.[6] Hellstein JW, Marek CL. Bisphosphonate osteochemonecrosis (bis-phossy jaw): is this phossy jaw of the 21st century? J Oral Maxillofac Surg 2005;63: 682 – 9.[7] Marx RE, Sawatari Y, Fortin M, Broumand V. Bisphosphonate-inducedexposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, rec-ognition, prevention, and treatment. J Oral Maxillofac Surg 2005;63:1567 – 75.[8] Woo SB, Hellstein JW, Kalmar JR. Narrative [corrected] review: bispho-sphonates and osteonecrosis of the jaws. Ann Intern Med 2006;144:753 – 61.[9] Ruggiero S, Gralow J, Marx R, Hoff A, Schubert M, Huryn J, et al.Practical guidelines for the prevention, diagnosis, and treatment of osteo-necrosis of the jaw in patients with cancer. J Oncol Pract 2006;2:7 – 14.[10] Bilezikian JP. Osteonecrosis of the jaw  —  do bisphosphonates pose a risk? N Engl J Med 2006;355:2278 – 81.[11] Hirshberg A, Leibovich P, Buchner A. Metastatic tumors to the jawbones:analysis of 390 cases. J Oral Pathol Med 1994;23:337 – 41.[12] D'Silva NJ, Summerlin DJ, Cordell KG, Abdelsayed RA, Tomich CE,Hanks CT, et al. Metastatic tumors in the jaws: a retrospective study of 114cases. J Am Dent Assoc 2006;137:1667 – 72.[13] Hariya Y, Yuasa K, Nakayama E, Kawazu T, Okamura K, Kanda S. Valueof computed tomography findings in differentiating between intraosseousmalignant tumors and osteomyelitis of the mandible affecting themasticator space. Oral Surg Oral Med Oral Pathol Oral Radiol Endod2003;95:503 – 9.[14] Mignogna MD, Fedele S, Lo Russo L, Ciccarelli R, Lo Muzio L. Case 2.Osteonecrosis of the jaws associated with bisphosphonate therapy. J ClinOncol 2006;24:1475 – 7.[15] Chiandussi S, Biasotto M, Dore F, Cavalli F, Cova MA, Di Lenarda R.Clinical and diagnostic imaging of bisphosphonate-associated osteone-crosis of the jaws. Dentomaxillofac Radiol 2006;35:236 – 43.[16] Pruckmayer M, Glaser C, Nasel C, Lang S, Rasse M, Leitha T. Bonemetastasis with superimposed osteomyelitis in prostate cancer. J Nucl Med1996;37:999 – 1001.[17] Catalano L, Del Vecchio S, Petruzziello F, Fonti R, Salvatore B, MartorelliC, et al. Sestamibi and FDG-PET scans to support diagnosis of jawosteonecrosis. Ann Hematol 2007;86:415 – 23.[18] WeitzmanR,SauterN,EriksenEF,Tarassoff PG,LacernaLV,DiasR, etal.Critical review: updated recommendations for the prevention, diagnosis,and treatment of osteonecrosis of the jaw in cancer patients  —  May 2006.Crit Rev Oncol Hematol 2007 May;62(2):148 – 52. Epub 2007 Mar 1.[19] Lu H, Ouyang W, Huang C. Inflammation, a key event in cancer development. Mol Cancer Res 2006;4:221 – 33.[20] Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G. Inflam-mation and cancer: how hot is the link? Biochem Pharmacol 2006;72:1605 – 21.945  A. Bedogni et al. / Bone 41 (2007) 942  –  945
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