Abstract
Background: Some patients who have a total hip replacement with a
second-generation metal-on-metal articulation have persistent or early
recurrence of preoperative symptoms. Characteristic histological changes in
the periprosthetic tissues suggested the development of an immunological
response. Therefore, in order to determine the relevance of these symptoms, we
performed a study of the clinical data and periprosthetic tissues associated
with endoprostheses with a metal-on metal articulation that had been retrieved
at revision.
Methods: Periprosthetic tissues as well as the clinical data on the
patients were obtained from the first nineteen consecutive revisions performed
at the treating hospitals. At the time of the revision, fourteen patients had
the metal-on-metal articulation exchanged for either an alumina-ceramic or a
metal-on-polyethylene articulation. Five patients received another
second-generation metal-on-metal total joint replacement. Five-micrometer
sections were prepared from the tissue samples, were stained with routine and
immunohistochemical methods, and were examined histologically. Histological
specimens from three groups of patients, two of which were treated with
non-metal-on-metal implants, served as controls.
Results: The majority of patients had persistence of their
preoperative pain or early recurrence of the pain after the original total hip
replacement, and often a pronounced hip joint effusion had developed after the
original replacement. Radiographic follow-up showed the development of
radiolucent lines in five hips and of osteolysis in another seven hips. At the
revision surgery, both the cup and the stem were found to be well fixed in
nine patients. The characteristic histological features were diffuse and
perivascular infiltrates of T and B lymphocytes and plasma cells, high
endothelial venules, massive fibrin exudation, accumulation of macrophages
with droplike inclusions, and infiltrates of eosinophilic granulocytes and
necrosis. Only a few metal particles were detected. Immunohistochemical
analysis demonstrated that the cellular reaction was still active. The
patients who received another second-generation metal-on-metal articulation at
the time of the revision had no decrease in symptoms. In the control group of
tissues obtained at revisions of endoprostheses without cobalt, chromium, or
nickel articulations, there were no similar signs of immune reactions.
Conclusions: These histological findings support the possibility of
a lymphocyte-dominated immunological response. Although the prevalence of this
reaction is low, the persistence or early reappearance of symptoms, including
a marked joint effusion and the development of osteolysis, after primary
implantation may suggest the possibility of such a reaction.
Classic metal-on-metal prostheses made of cobalt-chromium-molybdenum
alloys (McKee-Farrar, Huggler, and Müller types), which were used in the
1960s and 1970s, showed an extremely low rate of wear of the articulating
surfaces, even ten to twenty years after
implantation1-3,
and only a mild foreign-body reaction to the metal
debris3-5.
A second generation of cobalt-chromium-molybdenum-alloy metal-on-metal
bearings for hip endoprostheses were manufactured with improved materials and
methods1,6,7
and were implanted by
Weber8 starting in
1988.
Histological evaluation of the changes in the periprosthetic tissues of a
few patients who had revision of a hip replacement with a second-generation
metal-on-metal articulation suggested a cell-mediated type-IV hypersensitivity
reaction (delayed-type
hypersensitivity9-12).
The changes were characterized by vasculitis with perivascular and intramural
lymphocytic infiltration of the postcapillary venules, swelling of the
vascular endothelium (high endothelial venules), recurrent localized bleeding,
and necrosis. In addition, fibrin exudate and the accumulation of macrophages
with droplike inclusions were frequent
findings13. In
order to determine the relevance of those findings, we reviewed a larger
series of unselected patients who had had a revision of a hip replacement with
a second-generation metal-on-metal articulation.
This investigation was based on tissue obtained from the first
consecutive twenty-four revisions of second-generation metal-on-metal total
hip articulations performed in a group of hospitals. Five patients had a
clinically and bacteriologically proven infection and were excluded. In
fifteen of the remaining nineteen patients, infection was ruled out by
negative preoperative or intraoperative cultures, and none of the nineteen
patients had neutrophilic granulocytes in histological specimens obtained at
surgery.
Sixteen of the nineteen revised joint replacements had a Metasul
articulation (Centerpulse, Winterthur, Switzerland). Two articulations were
distributed by Synthes-Stratec, Ober-dorf, Switzerland, and one, by Plus
Endoprothetik, Rotkreuz, Switzerland.
The tissue samples from seventeen patients were obtained from the joint
capsule, with additional material taken from the acetabular implant-bone
interface in two of them, from the femoral implant-bone interface in two, and
from a bursa in one. In two cases, only material from the acetabulum was
available. The formalin-fixed tissues were decalcified if necessary, and 5 to
10-µm microtome sections were stained with the hematoxylin and eosin,
Giemsa, van Gieson, Prussian blue, and periodic acid-Schiff methods. The
sections were examined histologically under normal light and with polarization
(BX 50; Olympus, Hamburg, Germany).
The amount of metal particles in the tissue was estimated according to a
modified rating
system3
(Table I). The visible metal
particles were characterized by their high density, black color, and bizarre
shape. Their sharp edges light up in polarized light. Lymphocytic infiltration
was assessed by counting the individual cells of a diffuse infiltration and
the number of perivascular agglomerations per field of view
(Table II).
Immunohistochemical analysis was performed to characterize macrophages and
lymphocytes14-23
(Table III). Hematoxylin was
used as a counterstain. Sections of lymph nodes from patients with
tuberculosis and from pharyngeal tonsils with follicular, lymphatic
hyperplasia were stained in the same manner to serve as positive controls.
Specimens from seven patients were overfixed with formalin, and they could not
be further analyzed immunohistochemically.
The patients included ten men and nine women. Their mean age at the time of
the revision was sixty years (range, forty to seventy-six years). The
indication for the primary total hip replacement was degenerative
osteoarthritis in eighteen patients and pseudarthrosis after a femoral neck
fracture in one. The primary metal-on-metal prosthesis had been cemented in
two hips, had been implanted with hybrid fixation (a cemented stem) in one
hip, and had been implanted without any cement in sixteen hips. Two of the
cemented stems (Cases 2 and 3) were made of iron-based alloy S30, and one
(Case 1) was made of Ti-6Al-7Nb alloy. All noncemented stems were made of
Ti-6Al-based alloys, and the metal back of the noncemented cups was pure
titanium. Most of the cups had a polyethylene insert enclosing the
articulating metal surface.
Evaluation of questionnaires and additional inquiries provided a complete
set of clinical data as summarized in the Appendix.
Three groups of patients who had undergone revision of a total hip
replacement served as controls. Existing histological sections from those
patients were examined with light microscopy. No additional material was
available, and no further immunohistochemical analyses were done. Control
group I included eighteen noncemented endoprostheses free of cobalt, chromium,
molybdenum, and nickel. The prostheses consisted of a titanium-alloy stem
(Zweymüller; AlloPro, Baar, Switzerland), an Al2O3
ball head (Biolox; CeramTec, Plochingen, Germany), and an ultra-high molecular
weight polyethylene screw cup (Endler; AlloPro). The revisions were performed
three to sixteen years (average, 10.9 years) after implantation, and they were
due to aseptic loosening of the
cups24. Tissue
samples from three revisions, performed thirty-six, thirty-eight, and seventy
months after the primary implantation, were also available for
immunohistochemical analysis. Control group II included eleven all-cemented
Müller-Charnley prostheses consisting of a curved monobloc
cobalt-chromium-molybdenum femoral component and a polyethylene cup (Protek,
Münsterlingen, Switzerland). These curved stems had loosened aseptically
in the cement mantle after two to sixteen years (average, 9.6 years). A high
degree of polish by metal abrasion was noted on the surfaces of the loosened
stems24. Control
group III comprised fifteen cemented, classic metal-on-metal joint
replacements (McKee-Farrar). Those devices were revised ten months to 23.5
years (average, 8.5 years) after implantation. The histopathological
investigation of the fifteen cases has been previously
reported3, and these
were reinspected.
The majority of the patients had had either persisting or recurrent
pain in the hip and thigh, especially with weight-bearing, early after the
primary implantation of the metal-on-metal articulation. Some also had
symptoms at rest. Other symptoms included a limp (four patients), squeaking
sounds during joint movement (three), and multiple dislocations (two).
Radiographic follow-up of seventeen patients (two patients had no
radiographic follow-up) revealed the development of radiolucent lines in the
proximal part of the femur in five patients, and two of those patients also
had radiolucent lines in the acetabulum. Two patients had osteolysis in the
proximal part of the femur only, and five had osteolysis in the femur and
acetabulum. Only five patients had no major radiographic changes around the
implants.
Revision of the metal-on-metal joint replacement became necessary at an
average of thirty-three months (range, ten to eighty-one months) after the
primary implantation. The indications for revision were increasing pain and
the occurrence of osteolysis.
During the revision surgery, the anchorage of the devices was tested for
stability. In nine hips, both the cup and the stem were still fixed; in four
of them, however, osteolysis was found, primarily in the proximal part of the
femur. In two patients, the cup was fixed but the stem was loose; in two
patients, the stem was fixed but the cup was loose; and in five patients, both
components were completely loose. No information on the fixation of the
components was available for the remaining patient. An extensive joint
effusion was noted in eight patients, and it was often combined with bursa
formation. In five of the eight patients, both the stem and the cup were still
fixed.
The stem was exchanged in ten hips. The acetabular shell and liner were
left in place in one patient, both the shell and the liner were replaced in
eight patients, and only the liner was exchanged in another eight patients. No
information on the stem or acetabular shell was available for two patients. In
twelve patients, an alumina ceramic-on-polyethylene bearing was used to
replace the metal-on-metal articulation. In two patients, a
metal-on-cross-linked polyethylene combination was inserted. Another
cobalt-chromium-molybdenum metal-on-metal articulation was implanted in the
remaining five patients.
In fourteen hips, the revision implants were again fixed without cement.
The type of fixation was changed in three hips: two uncemented stems were
replaced with a cemented stem (hybrid fixation) and one cemented cup was
replaced with an uncemented one (hybrid fixation). In two hips, the stem and
the acetabular shell were left unchanged in situ; one of those prostheses was
completely cemented, and the other had hybrid fixation (cemented stem and
uncemented cup).
At the time of follow-up, one to seven years after revision, the fourteen
patients who had had an exchange of the primary metal-on-metal articulation
with an alumina-on-polyethylene or a metal-on-cross-linked polyethylene
articulation reported total relief of pain. However, hip and thigh pain
persisted in the five patients who had received a second metal-on-metal
articulation. Two of those five patients became free of symptoms after repeat
revision four months and five years after the first revision.
Histological examination of the periprosthetic tissue from all of the
nineteen patients who had had a revision of a metal-on-metal implant showed
only a mild foreign-body reaction to wear particles from the implants.
However, varying numbers of mononuclear and multinuclear macrophages were
found, mainly next to the vessels, in all cases. A few giant cells were also
present in six cases.
Metal particles, visible on light microscopy, were mainly stored in
macrophages. They were very small, measuring from 0.5 to 5 µm in diameter.
The amount of metal particles was rated as "many" (++) or
"abundant" (+++) in five cases and as "excessive"
(++++) in one. The specimens from the other thirteen hips had only a
"few" (+) metal particles
(Table IV). These findings
represent a relatively mild foreign-body reaction. Polyethylene particles were
found in the tissues around one cemented and three uncemented endoprostheses.
Fragments of polymethylmethacrylate were present in one case, and zirconia
contrast medium was found in the tissue around two of the three cemented
implants.
A distinct lymphocytic infiltration, sometimes accompanied by plasma cells,
was observed in the specimens (Table
IV and Fig. 1). In
the inner layer of the neocapsule, the lymphocytes were diffusely distributed
(Fig. 1, A) and were
rated as few (+) in five hips, as many (++) in twelve, and as abundant (+++)
in two. In the intermediate vascular layer, the infiltrates mostly surrounded
postcapillary venules and were also interspersed within the walls of these
venules (Fig. 1, B).
High endothelial venules were identified in seven of the nineteen cases
(Fig. 1, C). The
rating of the perivascular lymphocytic infiltrates revealed few (+) aggregates
in only two hips, many (++) in eight, abundant (+++) in four, and excessive
(++++) in five. Eosinophilic granulocytes of varying density were present in
the tissue from eight patients. Sometimes mast cells were also observed.
A characteristic finding of small droplike inclusions in the cytoplasm of
the macrophages was noted in the tissue from thirteen hips
(Fig. 2). Their size ranged
from the detection limit of 0.5 µm to 15 µm. The inclusions stained
light yellow or greenish with hematoxylin and eosin
(Fig. 2, A), deep blue
with Giemsa stain, and pale blue with Prussian-blue stain
(Fig. 2, B), and they
were positive on periodic acid-Schiff staining
(Fig. 2, C). In
contrast, the inclusions were negative for the CD68 marker
(Fig. 2, D). The
material was not bire-fringent and appeared to be amorphous. On the basis of
the morphological characteristics, this material did not resemble wear debris
from any of the implant materials used.
The tissues often showed an extensive fibrin exudation and areas of
necrosis. In fourteen of the nineteen cases, marked fibrin exudates covered
the surface of the neocapsule, while a cellular lining was lacking. The fibrin
was organized by ingrowing cells and vessels from the underlying tissues,
which resulted in thickening of the capsule. Large necrotic areas were found
in eleven cases. There were also signs of recent or older bleeding, with the
latter characterized by hemosiderin.
Immunohistochemical analysis revealed numerous CD68-positive mononuclear
and multinuclear cells. The subtypes of the CD68-positive macrophages, mature
(25F9-positive) as well as recently invaded (MRP8/MRP14-positive) macrophages,
were regularly present in the tissues. The drop-shaped inclusions in the
cytoplasm were enveloped by a CD68-positive edge
(Fig. 3, A).
The lymphocytic infiltrates, either diffusely distributed or perivascularly
aggregated, consisted of CD20-positive B lymphocytes
(Fig. 3, B) and
CD3-positive T lymphocytes, which outnumbered the B lymphocytes
(Fig. 3, C).
Sometimes, lymph follicles with B lymphocytes were found, and they were often
surrounded by CD3-positive T lymphocytes. The monoclonal antibody Mib-1 showed
that >5% to 10% of the lymphocytes expressed the antigen Ki-67, which is
associated with proliferation (Fig. 3,
D).
Periprosthetic tissues of control group I contained large amounts of
polyethylene wear
particles4. The
foreign-body reaction with extensive phagocytic granulomas, large numbers of
giant cells, and areas of necrosis was much stronger than that in the tissue
surrounding the metal-on-metal implants. Slight fibrin exudation was noted in
four control cases. A single perivascular lymphocytic infiltrate (+) could be
detected in only one case. High endothelial venules were absent (-).
Immunohistochemical analysis, performed in three cases, demonstrated
CD68-positive macrophages containing large amounts of polyethylene particles.
In contrast to the tissues from the hips with the second-generation
metal-on-metal articulation, old macrophages (25F9-positive) were predominant;
only some had recently invaded (MRP8 and MRP14-positive). Very few lymphocytes
could be differentiated as single cells with the use of L26 or CD3, and there
was a lack of signs of activation.
The polished surface of the cemented curved cobalt-chromium-alloy stems
(control group II) had released a large amount of metal debris into the
surrounding tissues, but particles of bone cement, contrast medium, and
polyethylene exceeded the number of metal wear particles. The foreign-body
reaction was dominated by macrophages and foreign-body giant cells containing
the polymer
debris24. A small
number of lymphocytes was present in four of the eleven cases. There were few
(+) diffuse lymphocytic infiltrates in three cases and many (++) in one case.
Few (+) perivascular infiltrates were present in three cases.
In the tissues around the classic metal-on-metal implants (control group
III), the foreign-body reaction to a low number of metal particles was found
to be mild and the histological appearance of the tissues again was dominated
by a reaction to bone cement
debris3. Some
lymphocytic infiltrates were observed in ten of the fifteen cases. There was a
diffuse distribution of a few (+) lymphocytes in five cases, many (++)
lymphocytes in one, and an excessive number (++++) in another. Perivascular
infiltrates were found in the tissues from five hips, two of which had a few
(+) aggregates, two of which had many (++) aggregates, and one of which had
abundant (+++) aggregates. Eosinophils were present in four cases. Thus, in
the tissues surrounding the classic metal-on-metal bearings, signs of a
hypersensitivity reaction were less frequent and of minor intensity compared
with those around the second-generation metal-on-metal articulations.
Pain, osteolysis, and joint effusion typically are not present after
a successful total hip arthroplasty. If pain with weight-bearing or at rest or
radiolucent lines or osteolysis develop over the long term in a patient with
an artificial hip joint, these findings are considered to be nonspecific.
However, our study indicated that, when these problems persist or reappear
soon after a hip replacement with a metal-on-metal articulation and infection
has been excluded, an immunological response should be suspected. This
diagnosis is strongly supported by the development of rapidly increasing
osteolysis and radiolucent lines and the occurrence of a joint effusion.
None of the five patients in this study in whom the revision was done with
a second metal-on-metal articulation had relief of symptoms. Symptoms were
relieved only following revision without an all-metal articulation. This
finding suggests that an immunological response persisted after the first
revision and that the patients had been sensitized to the components of the
all-metal articulation.
The histological examination of the periprosthetic tissue retrieved at the
revision surgery revealed an immunological response. The characteristic
phenomena consisted of diffuse and perivascularly oriented infiltration of
lymphocytes accompanied by plasma cells and sometimes eosinophilic
granulocytes, high endothelial venules, localized bleeding, fibrin exudation,
necrosis, and macrophages with drop-like inclusions. The presence of infection
should be considered if more than a very few neutrophilic granulocytes are
present25.
Findings such as B lymphocytes, plasma cells, and massive fibrin exudation
are not characteristic of a type-IV delayed-type hypersensitivity
reaction9,26-29.
Nevertheless, they support the hypothesis of a relationship between wear of
the all-metal cobalt-chromium articulation and the diagnosis of a
hypersensitivity reaction, which can be described as an aseptic
lymphocyte-dominated vasculitis-associated lesion or as a lymphocyte-dominated
immunological answer (LYDIA).
The majority of the tissue that was examined contained only small amounts
of histologically visible metal wear particles. Correspondingly, the
foreign-body reaction to the metal was relatively mild; sometimes there were
large numbers of phagocytosing macrophages, but there was no substantial
granuloma formation.
Immunohistochemical analysis demonstrated that macrophages that had already
phagocytized foreign material were almost all positive for 25F9 but negative
for MRP8 and MRP14. The relatively high content of freshly recruited MRP8 and
MRP14-positive macrophages suggests chronic inflammation with a continuous
recruitment of inflammatory macrophages from the peripheral blood, as can be
observed in diseases with cell-mediated immune
reactions23. Fibrin
exudation can also be considered to be part of this type of inflammatory
reaction.
Also, the diffuse, perivascular, and intramural lymphocytic aggregates,
composed of CD3-positive T lymphocytes (5% to 10% of which express the
proliferation-associated antigen Ki-67) and of CD20-positive B lymphocytes,
suggest a cell-mediated immune response, in the course of which proliferation
of sensitized T lymphocytes could be induced after a second contact with the
antigen. It is possible that the expression and secretion of pro-inflammatory
cytokines by those reactivated T lymphocytes contribute to the establishment
of a secondary endotheliosis (high endothelial venules) as well as to the
recruitment and activation of monocytes and/or macrophages from the peripheral
blood. These cells then might produce proteases and induce the degradation of
matrix, followed by the disintegration of the
tissue30,31,
and contribute to the development of radiolucent lines and osteolysis despite
the absence of generalized granuloma formation due to excessive particle
release. We speculated that the low but continuous release of metal ions from
the metal-on-metal articulations and their biochemical reactions with the
surrounding tissues, which start immediately after implantation, accelerate or
at least facilitate sensitization and the consequent immunological
response.
The appearance of abundant drop-shaped inclusions in the macrophages is an
unusual finding in periprosthetic tissues and their nature is not yet clear.
The shape, size, and hematoxylin and eosin, Giemsa, and periodic acid-Schiff
staining of these inclusions did not suggest the phagocytosis of particles
from the implants but more likely indicated the phagocytosis of organic
material. Jacobs et al. described an amorphous chromium orthophosphate
hydrate-rich material found both on the devices and in the periprosthetic
tissues as a corrosion product resulting from implant modularity of the head
and neck
junctions32. We
found that, in contrast to the drop-shaped inclusions, these precipitates were
so large that they were incorporated in foreign-body giant cells and could be
recognized on unstained tissue sections by the appearance of their
crystallinity.
In order to find out whether the development of hypersensitivity might be
related to the amount of cobalt and chromium released from the articulating
surfaces, we compared the amount of metal particles seen histologically in the
tissues with the intensity of the lymphocytic infiltrate and found that the
amount of metal wear abraded from the joint was not consistent with that found
in the tissue. In other words, a connection between the immunological response
and the amount of metal contained in the tissue could not be established.
In the control groups, the morphological features of the tissues around the
total hip endoprostheses with components made of cobalt-chromium-molybdenum
alloy were clearly different from those around the prostheses without any
chromium or cobalt. In the latter, there were neither lymphocytic
infiltrations nor changes of the vessels that would indicate a cell-mediated
hypersensitivity. While almost all of the periprosthetic tissues from patients
with components made of cobalt-chromium-molybdenum alloy contained metal
particles, lymphocytic infiltrates were found in only one-third of the cases
with abrasion marks on a cemented cobalt-chromium-molybdenum stem and in
one-half of the cases with a classic metal-on-metal joint. Moreover, the
number of cells within the infiltrates was markedly lower in those two groups
than it was in the group with a second-generation metal-on-metal bearing.
Our findings suggest that lymphocytic infiltration may also occur in the
tissues around other cobalt-chromium-molybdenum-containing implants, as was
demonstrated by Jasty et
al.33. Therefore,
the reaction seen with these second-generation metal-on-metal articulations is
not a new phenomenon. However, at present, we cannot explain the different
intensity of the reaction.
The prevalence of hypersensitivity reactions in patients with an all-metal
joint replacement appears to be low. However, we believe that, despite its low
probability, patients should be informed about the risk of becoming sensitive
to a metal-on-metal articulation. Early intervention may halt the progression
of osteolysis and avoid loosening of the implants. Furthermore, when failure
of an implant with a metal-on-metal articulation is associated with a possible
hypersensitivity reaction, early exchange of the prosthesis with an implant
that has another combination of material for the bearing surfaces is
mandatory.
A table presenting the clinical data on all nineteen patients is available
with the electronic versions of this article, on our web site at
(go to
the article citation and click on "Supplementary Material") and on
our quarterly CD-ROM (call our subscription department, at 781-449-9780, to
order the CD-ROM). ?
Note: The authors acknowledge the cooperation of the orthopaedic
surgeons who provided us with tissue and clinical data: Prof. Dr. Böhler,
Linz, Austria, Prof. Dr. Bösch, Wiener Neustadt, Austria; Dr. Burckhardt,
Olten, Switzerland; Dr. Hersche, Zürich, Switzerland; Dr. Heynen,
Auckland, New Zealand; Dr. Jovanovic, Münsterlingen, Switzerland; Dr.
Köhler, Donauwörth, Germany; Prof. Dr. Landsidl, Wien-Speising,
Austria; Prof. Dr. Lazovic, Oldenburg, Germany; Dr. v. Rothkirch, Hamburg,
Germany; Dr. Sieber, Biel, Switzerland; Dr. Staubli, Luzern, Switzerland; and
Mr. Sunduram, Wappnam, Australia.
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