Just as particles of inhaled carbon and silica are present in regional and distant lymph nodes, it has long been suspected that the particles of wear debris that seem to be the abundant byproduct of total joint prostheses also make their way into the lymphatic system and hence travel to remote sites. But how do we recognize wear debris with certainty? What is the magnitude of this suspected migration, and is it of any clinical importance?
In this issue of The Journal, three studies address migration of orthopaedic wear debris. The article by Benz et al. describes two patients in whom lymph nodes contained polarizable particles that were interpreted as being consistent with polyethylene wear debris. No coexisting metal particles were identified, and neither contralateral lymph nodes nor lymph nodes from patients without a joint implant were analyzed. The authors do not speculate on systemic responses but remind the reader of the potential migration of particles from implants to lymph nodes in the appropriate clinical setting.
In the study by Hicks et al., pelvic lymph nodes that had been obtained for cancer-staging from five patients who had had a total joint arthroplasty were compared with similar lymph nodes from seven patients who had not had an arthroplasty. All available lymph nodes from each patient were studied with light microscopy, and specimens were stained immunohistochemically for markers of macrophage differentiation and activation and for several different cytokines. All ipsilateral lymph nodes from the patients who had had a hip arthroplasty contained prominent macrophages (so-called sinus histiocytosis), along with fragments of refractile, polarizable material, consistent with polyethylene. Particles that looked like metal were also present in nearly all of these nodes. Analysis of adjacent tissue sections showed that macrophages in the region of the apparent debris stained positively for cytokines and markers of cell activation. The apparent metal debris was not characterized further, but lymph nodes contralateral to implants and from patients who did not have a joint implant did not demonstrate sinus histiocytosis, activated macrophages, or polarizable particles. The authors suggest that the inflammatory response to particles in lymph nodes includes macrophage activation and associated cytokine production.
In the third study, Shea et al. examined lymph nodes from patients with (Group 1) and without (Group 2) a prosthetic joint. Particles that were poorly visualized with transmitted light, strongly birefringent under polarized light, within or surrounded by histiocytes, and in the plane of focus of the cells were interpreted as being consistent with the appearance of polyethylene. The authors found such debris in the lymph nodes from twenty-one of the twenty-seven patients who had a total joint implant (Group 1) and from eight of the eighteen patients who did not (Group 2). Six of the eight patients with "false-positive" birefringent debris had had an operation before the dissection of the lymph nodes. Apparently, no additional attempt was made to identify or characterize possible coexisting metal debris in Group 1, and the nature of the polarizable material in Group 2 is unknown. On the basis of these findings, the authors suggest that the use of polarized light alone is insufficient for reliable identification of polyethylene.
So how do we recognize orthopaedic wear debris with absolute certainty or with enough certainty to guide clinical practice? For that matter, how do we make any diagnosis with certainty or with enough certainty to guide clinical practice? We apply tests in the appropriate clinical context. In medicine, no test is perfect, and we use the terms sensitivity and specificity to clarify the most appropriate use of a test. Sensitivity is the prevalence of true-positive results when a test is applied to patients who are known to have the disease, and it is defined as the number of true-positive results divided by the sum of the true-positive and false-negative results5. Specificity describes the prevalence of true-negative results when a test is applied to patients who are at risk for the disease but are known to be free of it, and it is defined as the number of true-negative results divided by the sum of the true-negative and false-positive results5. As a general rule, sensitivity is increased at the expense of specificity, so tests are often combined on the basis of the relative risks of missing a diagnosis (a false-negative result) and those of making an incorrect diagnosis (a false-positive result). For example, when populations are screened for an important disease, a test of high sensitivity but not high specificity is often used. Positive cases are then confirmed with a second test that is of high specificity but not high sensitivity. It is important to recognize that sensitivity and specificity must be determined in the context of the appropriate population of patients. If screening tests are applied to a healthy population, false-positive results will occur. For example, if joint fluid is aspirated, regardless of physical findings, from a consecutive series of patients who have a total joint implant, the high rate of false-positive results on culture may suggest that aspiration of the joint fluid is a poor test for infection1. However, if aspiration and culture of joint fluid is performed only for patients who have a prosthesis and physical findings suggestive of infection, the test appears much more reliable.
It is not possible to determine the sensitivity of birefringence from the study by Shea et al. because the true number of patients who had polyethylene in the lymph nodes is not known. Birefringent material interpreted as being consistent with polyethylene was found in eight of the eighteen patients who did not have a total joint implant but were ill—that is, they had had a lymph node biopsy for another reason. In this population, the authors found the specificity of birefringence to be 10/(10 + 8) = 56 per cent. Thus, as noted by the authors, the criteria listed in this study are in themselves insufficient to allow the recognition of polyethylene with certainty in their series of patients.
This should cause no great surprise. We are commonly exposed to particles that exhibit birefringence under polarized light, and many of these particles make their way into lymph nodes and become phagocytosed by macrophages. Non-fibrous silicates, such as mica, feldspars, and talc, show strong birefringence, are usually colorless, and may exist in the form of small plates or needles within macrophages4. Crystalline silicates, like quartz, can also appear as birefringent small plates or needles, and asbestos fibers may show weak birefringence. We expect to find these inhaled particles predominantly in lung tissue and mediastinal lymph nodes, but despite the pathways so clearly charted in anatomy texts, debris of this type is also sometimes present in cervical, axillary, diaphragmatic, and even abdominal lymph nodes. Silicates and birefringent vegetable fibers can also penetrate the skin during trauma and be transported to lymph nodes, most commonly those of the upper and lower extremities. Barium sulfate is found with some regularity in lymph nodes and appears as weakly birefringent, slightly yellow granules associated with sinus histiocytosis. Other crystalline particles that may be birefringent and widely distributed in tissues include calcium oxalate, calcium pyrophosphate, cystine, sodium urate, and even pigments from protozoa (Plasmodium and Schistosoma)8. Birefringent formalin pigment may be present in histological sections, where, for unknown reasons, it seems to bind most avidly to macrophages. Polymers used in vascular grafts as well as natural fibers may also exhibit strong birefringence, and small fragments of suture and gauze are commonly found at the site of a previous operation as well as in regional lymph nodes. Six of the eight patients who had a "false-positive" result in the study by Shea et al. had had a previous operation. Thus, the biopsy findings must be interpreted in the appropriate clinical context and not simply on the basis of an empirical test such as polarized light microscopy. It is this second level of diagnostic acumen that is missing from the study by Shea et al.
Despite the nature of the control population, I initially suspected that an experienced orthopaedic pathologist could, using light microscopy alone, better interpret the histological slides in the study by Shea et al. The authors kindly made available histological slides prepared from the lymph nodes from seven of their patients who had a "true-positive" finding and from the eight patients who had a "false-positive" finding; all of the nodes contained particles that fulfilled their criteria for having the appearance of polyethylene. I asked a second-year pathology resident to evaluate these slides blindly, to group them on the basis of the presence or absence of orthopaedic wear debris, and to test me in a similar fashion. The pathology resident was unable to improve the specificity reported by Shea et al. When tested blindly, I recognized five of the eight lymph nodes from Group II as containing polarizable material that was not orthopaedic wear debris. The remaining three slides, however, contained material that I incorrectly interpreted as consistent with orthopaedic wear debris, yielding a specificity of 15/(15 + 3) = 83 per cent in this selected group of patients. I have since reviewed these slides again, and I still found the material from the three patients who had a "false-positive" result to be suggestive of orthopaedic wear debris when evaluated with light microscopy. The true nature of the debris in these patients is unknown.
These results suggest that an experienced orthopaedic pathologist can use visual clues to distinguish orthopaedic debris from other birefringent material better than an inexperienced pathologist but cannot do so with certainty in all cases. While the diffuse cytoplasmic birefringence emphasized by Guttmann et al. is very characteristic, it is not specific. Therefore, polarized light microscopy is a useful screening test but should be followed by other observations of increased specificity (confirmatory tests) when definitive identification of polyethylene is necessary. Unfortunately, few other tests currently available provide substantial additional information. The oil-red-O stain10 may be used to identify polyethylene, but it appears to be no more sensitive than polarized light microscopy. Its specificity has not been well defined, but it is known to stain silicone and it probably stains other polymers that may have optical properties similar to polyethylene. Infrared spectroscopy can identify polyethylene with certainty, but current infrared techniques require either relatively large samples or particles suspended in solution. These requirements place limitations on the practical use of infrared at this time, but advances in spectroscopic instrumentation should make infrared microscopy and related methods valuable tools for identifying polymers in tissues in the near future.
Hicks et al. noted that, in some lymph nodes, birefringent debris was accompanied by particles that looked like metal debris. I have also found that particles of probable polyethylene debris are often accompanied by small opaque particles (less than ten micrometers), and I have used energy-dispersive x-ray spectroscopy to confirm that the ionic composition of these particles matches the composition of the suspected implant of origin (or, in some cases, that of a previous implant). Energy-dispersive x-ray spectroscopy and related techniques cannot identify elements with a low atomic number, such as the carbon and hydrogen in polyethylene, but they can be used to exclude silica, barium sulfate, and a few other compounds that could be confused with polyethylene on the basis of their appearance on light microscopy.
Given these limitations, what criteria should be used to identify orthopaedic wear debris in regional and distant sites? When the purpose of the biopsy is to explain adenopathy in a patient who has a total joint implant, particles that impart a diffuse birefringence to the cytoplasm of enlarged histiocytes under polarized light are suggestive but not strictly diagnostic of polyethylene wear debris. Nevertheless, as in the reports by Hicks et al. and by Benz et al., these characteristics alone are usually sufficient for practical patient care. The use of energy-dispersive x-ray spectroscopy or other methods to demonstrate coexisting particles that match the composition of the implant (such as titanium, cobalt-chromium alloy, and carbon fibers) provides additional confidence.
Until more sensitive and more specific tests for the definitive identification of polyethylene become available, it is only possible to speculate on the magnitude of particle migration, the clinical importance of this migration, and the ultimate fate of the debris. It must be recognized that the perceived prevalence of a disease increases with the ability to detect abnormalities associated with it3. Thus, as the ability to detect wear debris increases, it is necessary to guard against the assumption that migration of particles is a new problem, is increasing in prevalence, or demands immediate intervention. It seems likely that some types of debris are ultimately biodegradable, and the over-all excellent results of total joint arthroplasty without important systemic complications provide considerable comfort. However, additional studies are needed to characterize more fully the consequences of the production of debris and of the migration of particles.
Thomas W. Bauer, M.D., Ph.D.