Report of a Case and Review of the Literature Regarding Implant-Related Sarcomas
H. Stan McGuff, DDS, Josefine Heim-Hall, MD, F. Christopher Holsinger, MD, Archie A. Jones, DDS, Daniel S. O’Dell, DDS, MS and Adam C. Hafemeister, BS
Background: The development of malignant neoplasms has been reported as a rare complication of the use of implanted biomaterials. The majority of these cases have been sarcomas related to orthopedic hardware. The authors present the first reported case of a sarcoma arising in association with a dental implant.
Case Description: A 38-year-old woman developed a low-grade chondroblastic osteosarcoma of the right maxilla 11 months after receiving a titanium dental implant. She was treated with systemic chemotherapy and then a maxillary resection. As of this publication, 47 months later, she is alive and disease-free.
Clinical Implications: The use of endosseous implants has been associated with a low risk for the development of cancer. As the use of dental implants continues to expand, dentists need to be aware of this rare but devastating complication.
Key Words: Biomaterials; dental implants; titanium; cancer; osteosarcoma
The use of endosseous dental implants has evolved rapidly in the past several decades and has revolutionized and greatly enhanced the prosthetic rehabilitation of the dentition. Dental implant systems have undergone rigorous in vitro and in vivo testing and have proven to be safe and biocompatible. In 2000, approximately 910,000 dental implants were placed in patients in the United States. The overall success rate for dental implants is more than 90 percent.[3–5] Complications, which are uncommon, include postoperative infection, implant fracture, peri-implantitis, bone loss and failure of osseointegration with loosening of the implant, thus requiring its removal. The development of neoplasia associated with alloplastic implant materials is a rare complication that a number of clinicians and researchers have reported, primarily in the orthopedic literature.[6–30] We report a case of osteosarcoma associated with a maxillary dental implant and review the literature regarding implant-related sarcomas. To date, we are unaware of any other reports of sarcoma associated with a dental implant.
Clinical presentation. A healthy 38-year-old woman sought treatment for pain and swelling of one week’s duration involving the right maxilla in the area of the premolars. Eleven months previously, her periodontist (D.S.O.) had surgically placed a 6.0 x 13– millimeter Replace Select dental implant (Nobel Biocare, Göteborg, Sweden) in the edentulous area of the maxillary right first molar (tooth no. 3); her general dentist subsequently placed a final crown restoration. An oral and maxillofacial surgeon had extracted her first molar two years earlier after endodontic therapy failed. At that time, the surgeon placed Bio-Oss bovine grafting material (Osteohealth, Shirley, N.Y.) in the socket with a CollaTape collagen barrier (Integra LifeSeries, Plainsboro, N.J.). Other than the chief complaint, the patient was in excellent health. Her medical history was significant for mitral valve prolapse. Her medications included a daily aspirin (81 milligrams) and an oral contraceptive. The patient had received ampicillin before undergoing implant placement.
On clinical examination, the periodontist (D.S.O.) detected no dental caries and found the periodontal probing depths to be normal. He found minimal tooth mobility with no evidence of occlusal trauma. The implant was stable. The maxillary right first premolar (tooth no. 5) did not respond to vitality testing.
The periodontist obtained a periapical radiograph, which showed minimal alteration of the osseous trabecular pattern with focal small opacities and widening of the periodontal ligament space on the distal of the second premolar (tooth no. 4) (Figure 1). The preoperative radiograph from one year earlier showed no obvious pathology (Figure 2).
Figure 1. Periapical radiograph made at the time of presentation (Sept. 23, 2004), showing a slightly altered trabecular pattern, small irregular radiopacities and widened periodontal ligament space on the distal aspect of the second premolar.
[in a new window]
Figure 2. Periapical radiograph of the right maxilla made one year before implant placement (Sept. 11, 2003).
The periodontist initially suspected an inflammatory or infectious process. His differential diagnosis included pulpal pathosis, root fracture, peri-implantitis and osteomyelitis. He subsequently prescribed cleocin 150 mg three times daily. However, when the patient showed no clinical response to antimicrobial therapy six days later, the periodontist explored the area surgically. He elevated a mucoperiosteal flap, which revealed perforation of the facial cortex by solid, firm, pink-white tissue. The periodontist performed an incisional biopsy and submitted the tissue for pathological evaluation.
Pathological findings. Sections of the submitted biopsy specimen revealed a malignant neoplasm composed of a dense cellular pleomorphic, hyperchromatic spindle-cell proliferation (Figure 3). The tumor cells formed irregular lacelike trabeculae and solid sheets of osteoid extracellular matrix material. Associated zones of cellular cartilage exhibited atypical chondrocytes with focal multinucleate forms (Figure 4). Numerous mitotic figures were apparent (Figure 5). Localized foci of necrosis were present. An oral and maxillofacial pathologist (H.S.M.) established a diagnosis of chondroblastic osteosarcoma.
Figure 3. Hematoxylin and eosin–stained section of the biopsy specimen showing an osteosarcoma that exhibits a cellular hyper-chromatic spindle-cell proliferation with production of osteoid and chondroid matrix material (magnification x10 ).
Figure 4. Hyperchromatic angulated tumor cells producing pink trabeculated osteoid and adjacent atypical cellular cartilaginous matrix (magnification x40).
Figure 5. Pleomorphic cellular spindled area of the osteosarcoma with numerous mitotic figures and scant interspersed collagen fibers (magnification x60).
Therapy. The periodontist referred the patient to The University of Texas M. D. Anderson Cancer Center for evaluation and treatment. Her initial clinical staging work-up showed no evidence of local, regional or distant metastatic disease. A computed tomographic scan of the head revealed a 2.2 x 2.3 x 1.5-centimeter hyperdense mass of the right maxillary alveolar ridge (Figure 6). The lesion was associated intimately with the dental implant. The tumor infiltrated into the marrow space, eroded the buccal cortex and extended into soft tissue lateral to the maxillary alveolus (Figure 7). The nasal cavity, maxillary sinus, orbit and skull base were not involved.
Figure 6. Computed tomographic scan showing a mixed radiopaque/radiolucent lesion of the right maxilla associated with the dental implant. The tumor has infiltrated the periodontal ligament space of the second premolar.
Figure 7. Computed tomographic scan showing the osteosarcoma eroding the buccal cortex of the maxilla with extension into adjacent soft tissue.
The patient received two initial courses of chemotherapy with doxorubicin and cisplatin. Because the patient developed ototoxicity, the oncologist substituted ifosfamide for cisplatin during two additional rounds of chemotherapy. The patient’s clinical course during chemotherapy was complicated by fever, neutropenia, fatigue, anemia, thrombocytopenia, nausea, vomiting, mucositis, dehydration and stage II chronic kidney disease.
The patient responded favorably to the chemotherapy, with a positron emission tomographic scan showing no detectable residual disease activity and a magnetic resonance imaging scan showing reduction of the maximum tumor dimension to 1.8 cm. A head and neck surgeon (F.C.H.) surgically resected the tumor with a right infrastructure maxillectomy, a partial hard palatectomy and a lateral pterygomaxillary dissection. The surgical margins of resection were negative for tumor. The final pathological stage for the moderately differentiated (low-grade) chondroblastic osteosarcoma was T1 N0 M0, stage IB. Because the patient’s oncologist and head and neck surgeon considered her risk of distant metastasis and local recurrence to be low, they deferred postoperative chemotherapy and local radiation therapy. The patient received a maxillary obturator appliance. Her head and neck surgeon and her medical oncologist have followed her case closely and now, 47 months later, she is alive and disease-free.
Osteosarcoma. Osteosarcoma is a malignant mesenchymal neoplasm in which the tumor cells produce osteoid bone matrix.[31–40] It is the most common form of primary bone cancer.  Osteosarcomas are relatively rare, with an annual incidence of approximately two per 1 million people. There is a peak incidence in adolescence, which represents a period of rapid bone growth. Osteosarcomas also may develop in patients who have pre-existing bone conditions such as Paget disease, fibrous dysplasia and bone infarcts, or in patients who have been exposed to radiation. Men develop osteosarcoma more frequently than do women. Most osteosarcomas arise in the metaphysis of long bones with a predilection for the knee (distal femur, proximal tibia) and the upper arm (proximal humerus). The first symptom for which a patient seeks treatment typically is a painful mass lesion and, occasionally, a pathological fracture. Long-bone osteosarcomas usually are aggressive high-grade malignancies that destroy bone, spread into soft tissue and frequently metastasize to distant sites—most often the lungs. Metastasis tends to occur early in the course of the disease, with many patients having occult or overt distant spread at the time of diagnosis. This accounts for the historically dismal five-year survival rate of about 20 percent, despite radical amputation therapy.
Fortunately, recent advances in treatment have greatly improved survival rates and reduced morbidity. Therapeutic protocols, including presurgical (neoadjuvant) and postsurgical (adjuvant) chemotherapy, have been effective in controlling metastatic disease and in reducing the size of the primary tumor. Radiation therapy also has been effective in controlling local disease. Advanced imaging studies more accurately determine the extent of the disease and allow orthopedic surgeons to perform limb-salvage surgical techniques, which permit many patients to avoid amputation. With these recent advances, the five-year survival rate for patients with long-bone osteosarcomas now approaches 70 percent.
Osteosarcoma of the head and neck is relatively rare, making up less than 10 percent of osteosarcomas in general. Among head and neck sites, the mandible and the maxilla are involved most frequently. The peak incidence for jaw osteosarcoma is in a person’s fourth decade, which is about 10 to 15 years later than for long-bone osteosarcomas. Approximately 60 percent of affected patients are male. The disease affects the mandible almost twice as often as the maxilla.
Patients with osteosarcoma involving the jaws typically exhibit pain, swelling, loose teeth, tooth displacement and paresthesia. Extensive tumors of the maxilla also may cause nasal airway obstruction, nasal drainage, epistaxis and visual disturbances. Jaw osteosarcomas often grow slowly, and clinicians initially can confuse these signs and symptoms with those of common inflammatory and infectious diseases, possibly leading to a delay in diagnosis.
The typical radiographic appearance of osteosarcoma is that of an ill-defined, destructive, “moth-eaten” radiolucency with variable degrees of radiopacity, depending on the amount of calcified matrix produced by the tumor. However, the initial radiographic findings may be quite subtle and nonspecific. The most important early radiographic sign is a localized uniform widening of the periodontal ligament space. This radiographic appearance is caused by the tumor’s spread into the periodontal ligament with resorption of the adjacent alveolar bone. This finding is not specific for osteosarcoma and can be seen in other malignancies involving the jaws, including chondrosarcoma and metastatic carcinoma. Nonneoplastic conditions such as occlusal trauma, orthodontic therapy, pulpal or periapical pathosis and scleroderma also may be associated with widening of the periodontal ligament. However, clinicians always should consider this radiographic finding suggestive of malignancy. Osteosarcomas also may produce radiopaque calcified matrix above the level of the alveolar crest and cause spiking root resorption, resulting in a tapered-pointed root morphology. Occasionally, the clinician may find the classic “sunburst” radiographic pattern caused by radiating spicules of calcified matrix extending from the periosteal surface, especially in occlusal or lateral radiographic projections of the jaw.
Osteosarcoma has a variety of different clinicopathologic types and histologic patterns. The chondroblastic type is the histologic form that most commonly involves the jaws. In comparison with typical long-bone osteosarcomas, jaw osteosarcomas generally are better differentiated, and distant metastasis tends to occur later in the disease course. This explains why survival rates once were considered better for people with jaw osteosarcomas than for people with long-bone osteosarcomas. This no longer is the case, since modern treatment modalities for long-bone osteosarcomas — chemotherapy in particular — have not been equally successful in the treatment of jaw osteosarcomas. Despite the advances in surgical management, the reported five-year survival rate for people with jaw osteosarcomas has remained in the 30 to 50 percent range. Therefore, jaw osteosarcomas represent aggressive malignancies, and mortality most frequently is associated with persistent or recurrent local-regional disease.
The most important prognostic factors for jaw sarcomas are the tumor stage and the oncologic surgeon’s being able to achieve a complete surgical resection with wide negative margins. Consequently, early diagnosis and treatment are essential for patient survival. It is critical that dentists be aware of the subtle clinical presentation and early radiographic signs of osteosarcoma. Dentists always should maintain a high index of suspicion for malignancy and have a low threshold for referring the patient to a specialist or performing a biopsy.
In the case described in this article, when the lesion did not respond to initial antibiotic therapy, the patient’s periodontist promptly performed surgical exploration and an incisional biopsy to establish a definitive diagnosis and allow for timely therapeutic intervention.
Implant-related sarcomas. The development of malignancy in association with implanted orthopedic hardware is a rare but well-known and devastating complication.[6–30] During the last 50 years, researchers have reported approximately 49 sarcomas related to orthopedic hardware in the English-language literature.[6,7] This represents a small number of cases in comparison with the hundreds of thousands of hardware-related orthopedic procedures that clinicians perform annually.[41–42] While most often reported with orthopedic hardware, tumors also have been associated with mechanical heart valves, vascular grafts, sutures, bone wax, surgical sponges and foreign bodies such as bullets and shrapnel.
The use of metallic hardware and other biomaterials for the prosthetic replacement of arthritic joints, repair of skeletal deformities and fracture fixation is routine in the modern practice of orthopedic surgery. These materials have facilitated the relief of human suffering greatly, and they generally are considered to be nontoxic and biocompatible. However, investigators have shown in animal and human studies that many implant materials—such as stainless steel, chromium, cobalt, iron, lead, nickel, manganese, selenium, zinc, beryllium, cadmium, silicon and titanium—have potential oncogenic properties.
Implant-related sarcomas have occurred in patients across a wide age range (11–87 years), with a mean age of 50 years. There does not appear to be a strong sex predilection. The reported interval from implant placement to the development of malignancy has ranged from six months to 30 years, with a mean of nine years. The femur is the bone most often involved, followed by the tibia, pelvis and humerus. This distribution reflects the osseous sites in which orthopedic hardware is placed most often.
Implant-related sarcomas arise in bone or soft tissue contiguous with the implant hardware. Most tumors are high-grade malignancies and have included pleomorphic sarcoma (malignant fibrous histiocytoma), osteosarcoma, Ewing sarcoma, angiosarcoma, fibrosarcoma, malignant peripheral nerve-sheath tumor, synovial sarcoma, epithelioid sarcoma, epithelioid hemangioendothelioma, chondrosarcoma and lymphoma.[6,22–30] There appears to be no correlation between the biomaterial implanted and the histologic type of sarcoma.
Typically, patients initially exhibit symptoms of pain, swelling and stiffness. The clinician may misinterpret these findings as common inflammatory or reactive orthopedic complications, which may lead to a delay in diagnosis and treatment. Imaging studies of implant-related sarcomas show a destructive permeative mass lesion associated with the implant material.
These malignancies tend to pursue an aggressive clinical course, with many patients developing metastatic disease. Mortality is high despite surgical resection, chemotherapy and radiotherapy. The mean survival rate in one series of nine patients was 26 months.
Dental implants. The development of neoplasia in association with dental implants is a rare phenomenon. Squamous cell carcinoma is the malignant neoplasm most commonly reported to involve dental implants.[43–49] In many of these cases, the clinical presentation of the carcinoma was similar to that of peri-implantitis, leading to a potential delay in the clinician’s recognition and diagnosis of the malignancy. A possible role for the implant biomaterials in carcinogenesis has not been definitively demonstrated by researchers, as the majority of these patients have one or more known risk factors for oral squamous cell carcinoma. However, it is well-known that squamous cell carcinomas may arise in sites with persistent inflammation and epithelial turnover, as has been seen in fistula tracts draining chronic osteomyelitis. Another investigator described a single case of implant failure related to the development of a plasmacytoma. This patient had a history of a solitary vertebral plasmacytoma; therefore, it is unlikely that this represented a new implant-induced neoplasm. There also are isolated reports of metastatic breast and lung cancer involving dental implants, which most likely represent coincidental occurrences.[52,53] However, it is possible that the presence of implants may modify the local osseous microenvironment, resulting in conditions favorable to the localization of metastatic disease to peri-implant tissues. We found no other reports of dental implant–related sarcomas in the English-language literature.
The majority of endosseous dental implants consist of titanium, which is considered a highly biocompatible material that will promote bone growth and osseointegration. Most dental implant fixtures are manufactured from commercially pure titanium and various titanium alloys, which may contain variable amounts of iron, oxides, aluminum, vanadium, copper, palladium, niobium, zirconium and molybdenum. Implant superstructure, attachment and restorative elements may consist of various metallic, polymeric and ceramic materials. Implant fixtures also may undergo a variety of surface treatments—such as passivation, anodization and ion implantation—to enhance the surface oxide layer and prevent the release of metallic ions through corrosion. Texturing to increase surface area may be accomplished by plasma spraying, acid etching and blasting with ceramic material. Manufacturers also may coat implants with bioactive materials to enhance osseointegration. The Nobel Biocare Replace Select implant used in this case consisted of commercially pure grade-4 titanium with a nontreated machined threaded surface.
The International Agency for Research on Cancer has classified titanium in Group 3 (meaning that the agent is not classifiable regarding its carcinogenicity to humans),54 and titanium generally is considered to be a safe biomaterial.[54,55] However, in isolated reports, investigators have suggested some potential for titanium to induce neoplasia.[6,56–58]
The development of implant-related sarcomas is associated with direct contact with the implanted material, and tumor induction appears to be mediated by the toxic or mutagenic properties of the implanted material.[6–30] Researchers have demonstrated the dissolution of metallic corrosion products into adjacent peri-implant tissues. Titanium levels can reach up to 300 parts per million in tissues around implants and can produce a clinically visible discoloration. Researchers also have found high levels of titanium in the spleen and lungs of laboratory animals after implant placement. Others demonstrated precursor B-cell proliferation associated with titanium implants in a mouse model. Those investigators believed this phenomenon to be mediated by cytokines released from macrophages or multi-nucleated giant cells that were present at the implant/bone marrow interface. This local disturbance of lymphopoiesis eventually resolved and was not definitively associated with the development of B-cell neoplasia. Several recent animal studies have shown the differential expression of osteopontin, osteocalcin, integrin, apolipoprotein and prolyl 4-hydroxylase genes during bone healing in titanium implant sites in comparison with osteotomy-only control sites.[60–62] Researchers also have demonstrated gene modulation of cultured osteoblasts in vitro on titanium substrates. The results of these studies suggest that titanium induces the selected gene upregulation and that this upregulation plays a role in osseointegration. It is possible that such altered gene expression could be associated with the development of neoplasia.
Additional factors may be involved in implant-related tumor induction. Implanted biomaterials may release trace amounts of residual compounds such as monomers, catalysts, plasticizers and antioxidants that were used during the implant manufacturing process. It is possible that such contaminants could be associated with sarcoma development. Research also has shown that, through a phenomenon known as the Oppenheimer effect, implants of solid materials with a large surface area in soft tissue have induced sarcomas in rodent animal models, even though the material has no inherent toxic or tumorigenic properties.[8,9]
Other contributing or etiologic factors that could have played a role in the development of osteosarcoma in the case reported here include localized osteonecrosis related to implant placement, persistent chronic osteitis and the cumulative low-dose radiation exposure related to multiple radiographic imaging studies of the involved area. Any role played by the osteoconductive graft material placed in the extraction site is undetermined, as we did not find any reports of neoplasia associated with the use of deproteinized bovine bone mineral graft material.
The accumulated clinical and scientific evidence supports the concept that the development of malignancy in relation to the use of implanted biomaterials, while a rare occurrence, is a potential complication of the use of these materials. However, on an individual case basis, it is difficult or impossible to ascribe a definite direct cause-and-effect relationship to the use of an implanted biomaterial and cancer.
Because of the typical clinicopathological presentation of the case we report here and the short interval from implant placement to the development of malignancy, we believe that it is possible that the association of the implant with the development of osteosarcoma may be coincidental.
The fact that implant-related sarcomas have been reported predominantly in the orthopedic literature and have not been associated as frequently with other implanted biomaterials may relate to the large number of hardware-related orthopedic procedures that clinicians perform annually, the use of a wider variety of materials that potentially carry a higher risk and the fact that these orthopedic materials have been used for a longer period.
More research into the oncogenic potential of implanted biomaterials is needed, and as dentists place more dental implants that remain in service for longer periods, dentists need to be aware of and vigilant for this rare and devastating complication.
Dr. McGuff is a professor, Department of Pathology, Graduate School of Biomedical Sciences, and a professor, Department of Otolaryngology, Head and Neck Surgery, School of Medicine, The University of Texas Health Science Center at San Antonio. Address reprint requests to Dr. McGuff at the Department of Pathology, The University of Texas Health Science Center at San Antonio, MSC 7750, 7703 Floyd Curl Drive, San Antonio, Texas 78229-3900, e-mail “email@example.com”.
Dr. Heim-Hall is an associate professor, Department of Pathology, Graduate School of Biomedical Sciences, The University of Texas Health Science Center at San Antonio.
Dr. Holsinger is an assistant professor, Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston.
Dr. Jones is an associate professor, Department of Periodontics, Dental School, The University of Texas Health Science Center at San Antonio.
Dr. O’Dell maintains a private practice in periodontics, Austin, Texas.
Mr. Hafemeister is a fourth-year medical student, The University of Texas Medical School at Houston.
Disclosure. None of the authors reported any disclosures.
 Esquivel-Upshaw J. Dental implants. In: Anusavice KJ, ed. Phillips’ Science of Dental Materials. 11th ed. St. Louis: Saunders; 2003:759–780.
 Ratner BD, Hoffman AS, Scheon FJ, Lemons JE. Biomaterials science: a multidisciplinary endeavor. In: Ratner BD, ed. Biomaterials Science: An Introduction to Materials in Medicine. 2nd ed. Amsterdam, Netherlands: Elsevier Academic Press; 2004:3.
 Lekholm U, Grondahl K, Jemt T. Outcome of oral implant treatment in partially edentulous jaws followed 20 years in clinical function. Clin Implant Dent Relat Res 2006;8(4):178–186.[Medline]
 Romeo E, Chiapasco M, Ghisolfi M, Vogel G. Long-term clinical effectiveness of oral implants in the treatment of partial edentulism: seven-year life table analysis of a prospective study with ITI dental implants system used for single-tooth restorations. Clin Oral Implants Res 2002;13(2):133–143.[Medline]
 Lekholm U, Gunne J, Henry P, et al. Survival of the Brånemark implant in partially edentulous jaws: a 10-year prospective multicenter study. Int J Oral Maxillofac Implants 1999;14(5):639–645.[Medline]
 Keel SB, Jaffe KA, Petur Nielsen G, Rosenberg AE. Orthopaedic implant-related sarcoma: a study of twelve cases. Mod Pathol 2001; 14(10):969–977.[Medline]
 Visuri T, Pulkkinen P, Paavolainen P. Malignant tumors at the site of total hip prosthesis: analytic review of 46 cases. J Arthroplasty 2006;21(3):311–323.[Medline]
 Scheon FJ. Tumorigenesis and biomaterials. In: Ratner BD, ed. Biomaterials Science: An Introduction to Materials in Medicine. 2nd ed. Amsterdam, Netherlands: Elsevier Academic Press; 2004:339–344.
 Kirkpatrick CJ, Alves A, Kohler H, et al. Biomaterial-induced sarcoma: a novel model to study preneoplastic change. Am J Pathol 2000; 156(4):1455–1467.[Abstract/Free Full Text]
 Paavolainen P, Pukkala E, Pulkkinen P, Visuri T. Cancer incidence in Finnish hip replacement patients from 1980 to 1995: a nationwide cohort study involving 31,651 patients. J Arthroplasty 1999;14(3): 272–280.[Medline]
 Case CP, Langkamer VG, Howell RT, et al. Preliminary observations on possible premalignant changes in bone marrow adjacent to worn total hip arthroplasty implants. Clin Orthop Relat Res 1996; (329 suppl):S269–S279.
 Jaffe KA, Morris SG, Lemons JE, Robinson LH. Sarcomas around implants: three cases and a review of the literature. J South Orthop Assoc 1994;3:127–134.
 Jacobs JJ, Rosenbaum DH, Hay RM, Gitelis S, Black J. Early sarcomatous degeneration near a cementless hip replacement. J Bone Joint Surg Br 1992;74(5):740–744.[Medline]
 Jacobs JJ, Skipor AK, Black J, Urban R, Galante JO. Release and excretion of metal in patients who have a total hip-replacement component made of titanium-base alloy. J Bone Joint Surg Am 1991;73(10): 1475–1486.[Abstract/Free Full Text]
 Khurana JS, Rosenberg AE, Kattapuram SV, Fernandez OS, Ehara S. Malignancy supervening on an intramedullary nail. Clin Orthop Relat Res 1991;(267):251–254.
 Ward JJ, Thornbury DD, Lemons JE, Dunham WK. Metal-induced sarcoma: a case report and review of the literature. Clin Orthop Relat Res 1990;(252):299–306.
 Hughes AW, Sherlock DA, Hamblen DL, Reid R. Sarcoma at the site of a single hip screw: a case report. J Bone Joint Surg Br 1987; 69(3):470–472.[Medline]
 Memoli VA, Urban RM, Alroy J, Galante JO. Malignant neoplasms associated with orthopedic implant materials in rats. J Orthop Res 1986;4(3):346–355.[Medline]
 Pedley RB, Meachim G, Williams DF. Tumor induction by implant materials. In: Williams DF, ed. Fundamental Aspects of Biocompatibility. Vol. 2. Boca Raton, Fla.: CRC Press; 1981:175–202.
 Sinibaldi K, Rosen H, Liu SK, DeAngelis M. Tumors associated with metallic implants in animals. Clin Orthop Relat Res 1976;(118): 257–266.
 Sunderman FW Jr. Metal carcinogenesis in experimental animals. Food Cosmet Toxicol 1971;9(1):105–120.[Medline]
 Cole BJ, Schultz E, Smilari TF, Hajdu SI, Krauss ES. Malignant fibrous histiocytoma at the site of a total hip replacement: review of the literature and case report. Skeletal Radiol 1997;26(9):559–563.[Medline]
 Brien WW, Salvati EA, Healey JH, Bansal M, Ghelman B, Betts F. Osteogenic sarcoma arising in the area of a total hip replacement: a case report. J Bone Joint Surg Am 1990;72(7):1097–1099.[Free Full Text]
 Harris WR. Chondrosarcoma complicating total hip arthroplasty in Maffucci’s syndrome. Clin Orthop Relat Res 1990;(260):212–214.
 Lamovec J, Zidar A, Cucek-Plenicar M. Synovial sarcoma associated with total hip replacement: a case report. J Bone Joint Surg Am 1988;70(10):1558–1560.[Free Full Text]
 van der List JJ, van Horn JR, Sloof TJ, ten Cate LN. Malignant epithelioid hemangioendothelioma at the site of a hip prosthesis. Acta Orthop Scand 1988;59(3):328–330.[Medline]
 Weber PC. Epithelioid sarcoma in association with total knee replacement: a case report. J Bone Joint Surg 1986;68(5):824–826.
 Dodion P, Putz P, Amiri-Lamraski MH, Efira A, Martelaere E, Heimann R. Immunoblastic lymphoma at the site of an infected vital-lium bone plate. Histopathology 1982;6(6):807–813.[Medline]
 McDonald I. Malignant lymphoma associated with internal fixation of a fractured tibia. Cancer 1981;48(4):1009–1011.[Medline]
 Tayton KJ. Ewing’s sarcoma at the site of a metal plate. Cancer 1980;45(2):413–415.[Medline]
 Klein MJ, Siegal GP. Osteosarcoma: anatomic and histologic variants. Am J Clin Pathol 2006;125(4):555–581.[Abstract/Free Full Text]
 Unni KK. Osteosarcoma of bone. J Orthop Sci 1998;3(5):287–294.[Medline]
 Smith RB, Apostolakis LW, Karnell LH, et al. National Cancer Data Base report on osteosarcoma of the head and neck. Cancer 2003; 98(8):1670–1680.[Medline]
 Neville BW. Oral and Maxillofacial Pathology. 2nd ed. Philadelphia: W.B. Saunders; 2002:574–577.
 Regezi JA, Sciubba JJ. Oral Pathology: Clinical Pathologic Correlations. 4th ed. St. Louis: Saunders; 2003:321–326.
 Fernandes R, Nikitakis NG, Pazoki A, Ord RA. Osteogenic sarcoma of the jaw: a 10-year experience. J Oral Maxillofac Surg 2007; 65(7):1286–1291.[Medline]
 Karnell LH, Hoffman HT, Smith RB, Robinson RA. Osteosarcoma of the Head and Neck: UIHC Experience Compared to National Data. UIHC Annual Report 1; 2003. “www.uihealthcare.com/depts/cancercenter/patients/2003osteosarcoma.pdf”. Accessed June 26, 2008.
 Pellitteri PK, Ferlito A, Bradley PJ, Shaha AR, Rinaldo A. Management of sarcomas of the head and neck in adults. Oral Oncol 2003; 39(1):2–12.[Medline]
 Mardinger O, Givol N, Talmi YP, Taicher S. Osteosarcoma of the jaw: the Chaim Sheba Medical Center experience. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;91(4):445–451.[Medline]
 Bennett JH, Thomas G, Evans AW, Speight PM. Osteosarcoma of the jaws: a 30-year retrospective review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;90(3):323–332.[Medline]
 Lysaght MJ, O’Loughlin JA. Demographic scope and economic magnitude of contemporary organ replacement therapies. ASAIO J 2000;46(5):515–521.[Medline]
 Mushinski M. Average charges for hip replacement surgeries: United States, 1997. Stat Bull Metrop Insur Co 1999;80(1):32–40.[Medline]
 Abu El-Naaj I, Trost O, Tagger-Green N, et al. Peri-implantitis or squamous cell carcinoma? [in French]. Rev Stomatol Chir Maxillofac 2007;108(5):458–460.[Medline]
 Czerninski R, Kaplan I, Almoznino G, Maly A, Regev E. Oral squamous cell carcinoma around dental implants. Quintessence Int 2006;37(9):707–711.[Medline]
 Shaw R, Sutton D, Brown J, Cawood J. Further malignancy in field change adjacent to osseointegrated implants. Int J Oral Maxillofac Surg 2004;33(4):353–355.[Medline]
 Block MS, Scheufler E. Squamous cell carcinoma appearing as peri-implant bone loss: a case report. J Oral Maxillofac Surg 2001;59(11):1349–1352.[Medline]
 Moxley JE, Stoelinga PJ, Blijdorp PA. Squamous cell carcinoma associated with a mandibular staple implant. J Oral Maxillofac Surg 1997;55(9):1020–1022.[Medline]
 Clapp C, Wheeler JC, Martof AB, Levine PA. Oral squamous cell carcinoma in association with dental osseointegrated implants: an unusual occurrence. Arch Otolaryngol Head Neck Surg 1996;122(12): 1402–1403.[Abstract/Free Full Text]
 Friedman KE, Vernon SE. Squamous cell carcinoma developing in conjunction with a mandibular staple bone plate. J Oral Maxillofac Surg 1983;41(4):265–266.[Medline]
 Saglik Y, Arikan M, Altay M, Yildiz Y. Squamous cell carcinoma arising in chronic osteomyelitis. Int Orthop 2001;25(6):389–391.[Medline]
 Poggio CE. Plasmacytoma of the mandible associated with a dental implant failure: a clinical report. Clin Oral Implants Res 2007;18(4):540–543.[Medline]
 Dib LL, Soares AL, Sandoval RL, Nannmark U. Breast metastasis around dental implants: a case report. Clin Implant Dent Relat Res 2007;9(2):112–115.[Medline]
 Verhoeven JW, Cune MS, van Es RJ. An unusual case of implant failure. Int J Prosthodont 2007;20(1):51–54.[Medline]
 McGregor DB, Baan RA, Partensky C, Rice JM, Wilbourn JD. Evaluation of the carcinogenic risks to humans associated with surgical implants and other foreign bodies: a report of an IARC Monographs Programme Meeting. International Agency for Research on Cancer. Eur J Cancer 2000;36(3):307–313.[Medline]
 Williams DF. Titanium and titanium alloys. In: Williams DF, ed. Fundamental Aspects of Biocompatibility. Vol. 1. Boca Raton, Fla.: CRC Press; 1981:9–44.
 Williams DF. Toxicology of implanted metals. In: Williams DF, ed. Fundamental Aspects of Biocompatibility. Vol. 2. Boca Raton, Fla.: CRC Press; 1981:57.
 Noguera Aguilar JF, Zurita Romero M, Tortajada Collado C, Amengual Antich I, Soro Gosalvez JA, Rial Planas R. Perianastomotic colonic tumors after inclusion of titanium or Lactomer in the anastomotic suture line: an experimental study in rats. Rev Esp Enferm Dig 2000;92(1):36–43.[Medline]
 Yamadori I, Ohsumi S, Taguchi K. Titanium dioxide deposition and adenocarcinoma of the lung. Acta Pathol Jpn 1986;36(5):783–790.[Medline]
 Rahal MD, Delorme D, Branemark PI, Osmond DG. Myelointegration of titanium implants: B lymphopoiesis and hemopoietic cell proliferation in mouse bone marrow exposed to titanium implants. Int J Oral Maxillofac Implants 2000;15(2):175–184.[Medline]
 Ogawa T, Nishimura I. Genes differentially expressed in titanium implant healing. J Dent Res 2006;85(6):566–570.[Abstract/Free Full Text]
 Ogawa T, Nishimura I. Different bone integration profiles of turned and acid-etched implants associated with modulated expression of extracellular matrix genes. Int J Oral Maxillofac Implants 2003; 18(2):200–210.[Medline]
 Ogawa T, Sukotjo C, Nishimura I. Modulated bone matrix-related gene expression is associated with differences in interfacial strength of different implant surface roughness. J Prosthodont 2002;11(4):241–247.[Medline]
 Takeuchi K, Saruwatari L, Nakamura HK, Yang JM, Ogawa T. Enhanced intrinsic biomechanical properties of osteoblastic mineralized tissue on roughened titanium surface. J Biomed Mater Res A 2005;72(3):296–305.[Medline]