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

Abstract

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.[1] In 2000, approximately 910,000 dental implants were placed in patients in the United States.[2] 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.

Case Report

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.

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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.

Discussion

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. [31] Osteosarcomas are relatively rare, with an annual incidence of approximately two per 1 million people.[31] 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,[32] 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.[33]
Osteosarcoma of the head and neck is relatively rare, making up less than 10 percent of osteosarcomas in general.[34] 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.[34] Approximately 60 percent of affected patients are male.[35] The disease affects the mandible almost twice as often as the maxilla.[35]

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.[31] 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.[34] 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.[8]

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.[6]

Implant-related sarcomas have occurred in patients across a wide age range (11–87 years), with a mean age of 50 years.[6] 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.[6] The femur is the bone most often involved, followed by the tibia, pelvis and humerus.[6] 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.[6]

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.[6]

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.[6]

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.[50] Another investigator described a single case of implant failure related to the development of a plasmacytoma.[51] 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.[1] 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.[1] 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.[1] Researchers also have found high levels of titanium in the spleen and lungs of laboratory animals after implant placement.[1] Others demonstrated precursor B-cell proliferation associated with titanium implants in a mouse model.[59] 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.[59] 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.[63] 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.[8] 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.

Conclusion

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.

Footnotes

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 “mcguff@uthscsa.edu”.

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.

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