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Malignant Neoplasia at the site of Total Hip Arthroplasty 

Bryant S. Ho,Michael H. Huo

* Department of Orthopedic Surgery,UT Southwestern Medical Center at Dallas

Address for Correspondence:  

Michael H. Huo, M.D.
Department of Orthopedic Surgery
UT Southwestern Medical Center at Dallas
1801 Inwood Rd.
Dallas, Tx 75390-8883
Email: Michael.Huo@utsouthwestern.eduu
Fax: 214-645-3340


There is a possible relationship between joint replacements and malignancy. We review the current state of metal-on-metal hip implants, the process of metal ion release from the implants, the effect of released metal ions in vivo, the association between neoplasm and metal debris and ions, and the six documented cases of neoplasm around a metal-on-metal total hip replacement. We find no link between released metal ions and the occurrence of neoplasm.

J.Orthopaedics 2008;5(3)e9


metal-on-metal hip implants, metal ion release, metal debris, total hip arthroplasty, total hip replacement, neoplasm, malignancy, cancer.


Total hip arthroplasty (THA) has evolved into one of the most common and cost-effective orthopedic reconstructive procedures with a high long-term success rate. However, due to the dynamic nature of the hip implants and the direct contact with biological tissue, particulate wear and corrosion debris are liberated into the joint space and surrounding tissues 1, 2. The subsequent biological response poses a problem to the durability and long-term efficacy of the hip implants. Metal ions that are released, such as cobalt and chromium, are of importance because of their carcinogenic potential3, 4. Of particular interest are hip implants with metal-on-metal bearings (MOM). There have been several cases of malignant tumors that have developed at the site of such implants. The purpose of this review is to examine if there is any connection between neoplasia and metal ion debris in THA. The following review is organized into six sections: (1) current state of MOM THAs, (2) metal bearing wear and ion release, (3) biology of ions, (4) neoplasia associated with metal debris and ions, (5) reported cases of neoplasia around THA (6) conclusion.

Current State of MOM THA

Metal-on-metal (MOM) bearing coupling was popular in the 1960ís and 1970ís, but was abandoned by US surgeons in favor of metal-on-polyethylene bearings due to concerns over biological reactions and reported high loosening rates. One of the limitations of polyethylene is wear debris generation at the bearing surface. This led to the development of alternative bearing surfaces including the reintroduction of MOM bearings in the late 1980ís5. These newer designs with MOM bearings have been shown to be clinically efficacious and more durable than earlier designs. Dorr et al.6 reported mechanical failure rates (combined rates of revision and loosening) in 56 patients with the Metasul (Zimmer, Warsaw, IN) design from 1991 to 1994. There were 49 patients with primary osteoarthritis, 3 with congenital dysplasia, and 2 each with posttraumatic arthritis and femoral head osteonecrosis. All patients had well functioning hips at an average of 5.2 years of follow-up.

Wear debris and metal ion release are clinical concerns. Jacobs et al.7 reported 3-fold serum concentration increases in titanium and 5-fold increases in chromium at thirty-six months following surgery in 55 patients with MOM THAs compared to control patients without implants. Sauve et al.8 reported 5-fold and 3-fold serum concentration increases for cobalt and chromium, respectively in 310 patients with Ring MOM THAs as long as 30 years after the index surgery. It is of interest to note that in 3 of the patients who underwent revision for aseptic loosening, serum metal concentrations were within normal range.

Meat bearing wear is influenced by several factors: carbon content, manufacturing process, and diametral clearance. Rieker et al.9 reported on analysis of a large collection of retrieved MOM components. These included 608 components from 337 revisions. 172 of these were analyzed for clearance (surface geometry match between the head and the liner). These components were in-vivo from one month to 12 years. They reported several important findings: 1) the mean wear rate in the first year was high (27.8 um/year), 2) the mean wear rate following the second year was low (6.2 um/year), 3) regression analysis showed clearance to be the most important variable correlated with the linear wear rate (p=0.0005). Current laboratory and clinical retrieval data on MOM couplings support the idea that superior wear characteristics are associated with high carbon content, wrought manufacturing, large diameter, and low clearance.

Metal Bearing Wear and Ion Release

Metal ions release can occur by two proposed mechanisms: 1) wear as a function of adhesion, abrasion, or fatigue of the materials resulting in particulate debris, and 2) corrosion of the metal bearing wear resulting in the release of metal ions. Metallic implants have the ability to achieve passivity in-vivo, in which active and passive surfaces between metallic biomaterials and electrolytes exist in contact simultaneously. The protective surface oxide layer on the implants is in a continuous process of partial dissolution and reprecipitation10. Dissolution is favored by contact with proteins and amino acids leading to corrosion. In addition, macrophages that ingest released particles are stimulated by inflammatory mediators such as TNF-α to release reactive oxygen species such as superoxide (O2-) and hydrogen peroxide (H2O2). These products can be metabolized into products such as hypoclorous acid, capable of damaging extracellular matrix components and increasing degradation by proteases11.

High serum and urine metal ion concentrations have been associated with both first and second generation MOM bearings. Jacobs et al.12 found that serum chromium concentration was 9-fold higher and cobalt concentration 3-fold higher in patients with McKee-Farrar THAs than the control patients without implants. Second generation implants showed similar increases in metal ions. Savarino et al.13 reported 4-to-5-fold higher cobalt concentrations and 7-fold higher chromium concentrations in patients with the Metasul THAs than in control patients without implants.

There is concern over metal ion release in the growing population of young and active patients that receive THAs. Heisel et al.14 compared cobalt and chromium levels in patients with MOM THAs as a function of varying levels of activity. They found a 2.7% and 3.0% serum concentration increase in cobalt and chromium, respectively when the patients increased their mean activity by 28% as measured by a 2-dimensional accelerometer worn on the ankle. During treadmill running, mean activity increased by 1621% while serum cobalt and chromium concentrations increased by 3.0% and 0.8%. Based on the accuracy of the tests and the small relative size of serum metal ion changes, the data did not demonstrate statistically significant correlation between activity level and serum metal ions.

Release of metal ions from MOM THAs has clinical significance for child-bearing females. Ziaee et al.15 collected blood from the mother and umbilical cord after five deliveries, four of which involved MOM THAs. The chromium and cobalt levels were an average of 50% lower in the cord than in maternal blood and there was a strong correlation between levels of trace elements in the cord and maternal blood.

Biology of Ions

Metal ion toxicity can occur if the ion binds with a biomolecule. Titanium ions are very active and immediately bind to water or inorganic anions within the tissue. On the other hand, inactive ions such as copper and nickel remain as ions for long durations and have a greater chance of combining with biomolecules to express toxicity10. Trace elements that show similar high-reactive ion binding qualities to titanium, such as zirconium, niobium, and tantalum, hold promise as alloys that could decrease bonds between metal ions and biomolecules. Released ions would instead bind harmlessly to water and inorganic anions in the tissue.

Metal ion toxicity can lead to local tissue inflammation, fibrosis, and necrosis. Mathiesen et al.16 reported extensive periprosthetic tissue necrosis due to metal ion toxicity in 4 of 9 patients with MOM THAs. Metal particles can also be found beyond the periprosthetic tissue to regional lymph nodes, liver, and spleen12, 17, 18. These particles can interfere with osteoblasts and osteoclasts, inducing bone resorption and cause toxicity to macrophages and fibroblasts19, 20.

Several recent studies have documented evidence of hypersensitivity to metal wear particles in patients with painful and failed MOM THAs. Park et al.21 reported a significantly higher prevalence of hypersensitivity to cobalt (p=0.03) in patients with early osteolysis when compared to control patients. The cohort consisted of 169 THAs with second-generation MOM bearings, with ten reported cases of osteolysis. Histiologic analysis of periprosthetic tissue from two patients with osteolysis revealed a perivascular accumulation of CD3-positive T-cells and CD68-positive macrophages. Immunohistochemical analysis demonstrated the presence of bone-resorbing cytokines such as IL-1β and TNF-α. These findings suggest that delayed hypersensitivity in MOM THAs may cause early osteolysis. Milosev et al.22 reported similar evidence of osteolysis from hypersensitivity to metal wear particles. He analyzed a cohort of 591 patients with MOM THAs at a mean of seven years postoperatively and showed a survival rate 91% at ten years (95% confidence interval 0.88 to 0.95). The major cause of failure was aseptic loosening, which occurred in 25 patients. Histological analysis of 17 of the revision THAs showed a hypersensitive reaction in 13 patients (2%), with perivascular infiltration of lymphocytes and aseptic inflammation.

Neoplasia Associated with Metallic Debris and Ions

Metal ions have been linked to increased cancer rates. Visuri et al.23 reported a standardized incidence ratio (rate of occurrence in the cohort compared to the general population) of 3.0 (95% confidence interval 1.1-6.6) for hematopoietic cancers in a cohort of 433 patients with McKee-Farrar MOM THAs. The standardized incidence rate of leukemia was also elevated at 3.2 (95% confidence interval 1.0-7.4).

Current MOM THAs are made of alloy biomaterials consisting of cobalt, chromium, titanium, aluminum, vanadium, and nickel. The carcinogenic potential of cobalt and nickel have been reported in animals. Intramuscular or intrathoracic injections of cobalt metal powder produced fibrosarcomas and rhabdomyosarcomas at the injection sites in mice while intratracheal instillation of nickel metal powder in rats resulted in significant numbers of squamos-cell carcinomas and adenocarcinomas of the lung24. Osteosarcomas and fibrosarcomas have also been found in cats and dogs with stainless-steel metallic composition internal fixation devices25. However, Lewis et al.26 injected CoCrMo or TiAlV wear debris powder into the knee joints in rats. They found no case of neoplasia as a result of this exposure.

The exact mechanisms and association between neoplasia and metallic trace elements remain to be defined. The association of implant loosening and tumors around the implant site in rats suggests that neoplasia resulted from a foreign-body reaction27. This relationship has yet to be established in humans. Macrophages binding to implants result in the generation of reactive oxygen species (ROS)28, 29. ROS can cause alterations in host DNA, most frequently causing guanine-to-thymine transversions30. If these modifications are associated with oncogenes or tumor suppressor genes, then metal ion release can indirectly lead to the pathogenesis of neoplasia. Multiple mutations in the p53 tumor suppressor gene have been reported as guanine-to-thymine transversions31, 32 and oxidative DNA modifications in cancer tissue from ROS have been reported33.

Reported cases of neoplasia

Since 1974, there have been 51 reported cases of malignant tumors at the site of a THA in the English literature. These include 20 cases of malignant fibrous histiocytoma, 10 osteosarcoma, 4 non-Hogkin lymphoma, 3 spindle cell sarcoma, and 2 cases each of pleoemorphic rhabdomyosarcoma, fibrosarcoma, and leiomyosarcoma. Other individual cases were chondrosarcoma, malignant peripheral nerve sheath tumor, synovial sarcoma, multiple myeloma, liposarcoma, adenocarinoma and malignant epithelioid hemangioma. The patients range in age from 39 to 88 years, with a mean age of 66 years. The mean time interval from implantation to the diagnosis of neoplasia was 6.6 years with a range of 0.5 to 20 years. 6 of these occurred around MOM THAs. We will detail these 6 cases.

Penman and Ring34 reported a case of ostesarcoma in a 75-year-old woman with a cobalt-chromium MOM THA. The tumor was discovered 5 years post-operatively on the lateral side of the right femur. There was no history of Pagetís disease or radiotherapy. The authors concluded that metal ion release could have been associated with the development of the tumor.

Swann35 reported a case of malignant fibrous histiocytoma in a 63 year-old man that developed 3.5 years post-operative to a MOM THA. Ryu et al.36 reported a case of soft tissue sarcoma in a 40 year-old man 1.5 years post-operative to a MOM THA. Stephenson et al.37 reported a case of liposarcoma in a 57 year-old man 6 years post-operative to a MOM THA. In all 3 of these cases, the tumors were not in direct contact with the metal implants. Metal content was only measured in the liposarcoma patient and no increased levels were found. This evidence suggested that the tumors were not directly caused by the carcinogenic potential of metal ions or debris from the implants.

Rushford38 reported a case of osteosarcoma in the acetabulum 5 months post-operative to a cobalt-chromium MOM THA in a 54-year-old woman. She had previously developed squamos cell carcinoma in her cervix which was treated successfully with radium insertion and external irradiation. The prosthetic cup was found to be loose and the acetabulum bone quality was abnormal. The authors concluded, based on the greater proportion of bone radiation absorption, that the patientís previous radiotherapy resulted in the subsequent development of osteosarcoma.

Arden and Bywater39 reported a case of fibrosarcoma 2.5 years post-operative to a MOM THA in a 56-year-old patient. The sarcoma was found to arise from the arthroplasty scar and extend down to the pseudo-capsule, but did not involve the femur or pelvis bones. 


There is no conclusive evidence to establish any direct link between metal ion or debris with malignancy around THAs with MOM bearings. It is however critical for these participants to be followed, especially when MOM THAs are being done with greater frequency and in younger patients.

Table 1. Malignant Tumors at the Site of Total Hip Arthroplasty

(click to enlarge)


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This is a peer reviewed paper 

Please cite as : Bryant S. Ho : SMalignant Neoplasia at the site of Total Hip Arthroplasty 

J.Orthopaedics 2008;5(3)e9





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