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Granular Histiocytosis of Pelvic Lymph Nodes following Total Hip Arthroplasty. The Presence of Wear Debris, Cytokine Production, and Immunologically Activated Macrophages*

DAVID G. HICKS, M.D., ALEXANDER R. JUDKINS, B.A., JOSHUA Z. SICKEL, M.D., RANDY N. ROSIER, M.D., J. EDWARD PUZAS, M.D. and REGIS J. O'KEEFE, M.D., ROCHESTER, NEW YORK

Investigation performed at the Departments of Pathology and Orthopaedics, University of Rochester, Rochester

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
Infiltration of regional lymph nodes by macrophages has been demonstrated after total joint arthroplasty. Although lymph nodes regulate the immune response, neither cytokine production nor the degree of immunological activation of cells within these nodes after total joint arthroplasty has been investigated. Pelvic lymph nodes were obtained from five patients who had had a total of eleven arthroplasties in seven hips three to twenty years before a pelvic staging procedure for adenocarcinoma (of the prostate in four patients and of the endometrium in one). All lymph nodes had polyethylene or metal debris as well as effacement of the normal nodal architecture by a histiocytic infiltrate. These changes were bilateral in the patients who had had an arthroplasty of both hips but were present only on the ipsilateral side in the patients who had had an arthroplasty of one hip. Analysis of specimens from pelvic lymph nodes on the side of the involved hip demonstrated intense immunohistochemical staining of histiocytes for the major histocompatibility complex class-II antigen HLA-DR, a marker of histiocyte immune activation. In contrast, staining was absent in specimens from the contralateral lymph nodes as well as in those from seven patients who had had a prostatectomy but not a hip arthroplasty. Immunohistochemical staining for interleukin-1ß, tumor necrosis factor-, and interleukin-6 demonstrated a much greater expression of these cytokines in the involved lymph nodes. CLINICAL RELEVANCE: Additional improvements in total joint replacement will be facilitated by a more thorough understanding of the biological response to the components and materials of implants. While local biological factors leading to failure of prostheses are currently under intense investigation, the mechanisms and importance of regional and systemic immune responses to wear debris require further study.

	Introduction

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While improvements in materials and methods have made total joint arthroplasty a safe and effective procedure, failure of the implant necessitating a revision is still common. The causes of aseptic failure are incompletely understood but appear to be related to the release of wear debris, including metal, polyethylene, and polymethylmethacrylate, into the joint. These particles are shed as a result of mechanical forces and incite an inflammatory response.

Recently, a number of important cytokines have been identified in the synovial membrane surrounding failed total joint prostheses. Macrophages phagocytize polymethylmethacrylate particles of specific size and produce tumor necrosis factor-, an important mediator of the local inflammatory response^13,21,28. Similarly, other studies have demonstrated the stimulation of interleukin-1 synthesis by macrophages in periprosthetic membranes²⁴. These cytokines mediate the inflammatory response and activate osteoclasts, resulting in periprosthetic bone resorption^11,12,22,26.

Several studies have suggested that macrophages containing particles of wear debris are not limited to the local, periprosthetic area. Studies by Walker and Bullough⁴⁵ as well as by Mendes et al.³³ demonstrated wear debris in lymph nodes after the placement of implants, while other studies^2,5,18,20,40 have demonstrated infiltration of the lymph nodes by macrophages after total joint arthroplasty. Recently, Bos et al. found histological evidence of inflammation in regional lymph nodes as well as in the periprosthetic membranes in thirty-two patients who had had a total joint arthroplasty⁹. However, cytokine production by macrophages within regional lymph nodes has not been investigated previously.

While lymph nodes function principally to regulate the immune response, the degree of immunological activation of cells within regional lymph nodes after joint arthroplasty has not been identified. Macrophages play a pivotal role during immunological activation; phagocytized proteins are partially degraded within intracellular vesicles, where they become associated with the major histocompatibility complex class-II molecule HLA-DR¹⁰. This complex is subsequently transported to the cell membrane, where it can interact with CD4+ lymphocytes to activate the immune response^10,23,27. Although CD4+ lymphocytes are tolerant to autologous protein fragments, presentation of foreign protein fragments results in interleukin-2 synthesis, which drives the immunological response^10,29. Thus, macrophages are immunologically activated as antigen-presenting cells when they express HLA-DR^10,27,35,37. Two recent investigations suggested that macrophages in membranes surrounding loose total hip components express HLA-DR^3,4. However, the immunological activation of these cells is uncertain because no control tissue was examined to evaluate the basal level of expression of HLA-DR in unactivated macrophages.

In the current study, histological and immunohistochemical methods were used to investigate macrophage activation and cytokine production in the regional lymph nodes of five patients. All five had previously had a hip replacement and had subsequently had nodal dissection for the staging of adenocarcinoma. Activated macrophages were identified in the nodes by HLA-DR expression. Cytokines involved in the inflammatory response to regionally disseminated wear debris, including tumor necrosis factor-, interleukin-1ß, and interleukin-6, were identified by immunohistochemical localization and were associated with chronic inflammatory changes within the lymph nodes. In contrast, inflammation was absent and there was little or no cytokine or HLA-DR expression in seven control pelvic lymph nodes or in lymph nodes from the contralateral side in two patients who had had a hip arthroplasty.

	Materials and Methods

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Slides were prepared from tissue blocks of pelvic lymph nodes retrieved from the pathology files, at the University of Rochester, of five patients who had had a total joint arthroplasty and had subsequently had a biopsy of nodes for the staging of pelvic cancer. Slides were also prepared from the tissue blocks of pelvic lymph nodes of seven additional patients who had had a staging procedure for pelvic adenocarcinoma but not a hip arthroplasty. No tumor was identified in the lymph nodes in either group of patients. Tissue from all patients was initially fixed in formalin and embedded in paraffin, and four-micrometer sections were prepared for hematoxylin and eosin, histochemical, and immunohistochemical staining.

Histochemical Staining
Periodic acid-Schiff stains, which react with the aldehydes of polysaccharides and glycosaminoglycans, were performed on sections of lymph nodes according to a method described previously³⁰.

Immunohistochemical Methods
Immunohistochemical analysis was performed with the biotin-streptavidin method⁴³, with use of various antibodies (Table I)^{6,7,17,32,41,46}. Endogenous peroxidase activity was consumed with hydrogen peroxide, and the tissue sections were rinsed in phosphate-buffered saline solution. The slides were incubated with the primary antibody overnight at 4 degrees Celsius. (Phosphate-buffered saline solution with 0.5 per cent bovine serum albumin was used as a diluent for the antibodies and was applied alone as the negative control for each antibody.) The secondary antibodies (Vector Laboratories, Burlingame, California), used at 1:200 dilution, were incubated with the sections for thirty minutes. Horseradish peroxidase-streptavidin conjugate (Jackson Immunoresearch Labs, West Grove, Pennsylvania), used at 1:1000 dilution, was applied and allowed to incubate for thirty minutes. The chromagen 3-amino-9-ethylcarbazole (Zymed Laboratories, South San Francisco, California) was then applied to each section. The sections were counterstained with Mayer hematoxylin and then were mounted with permanent aqueous media.

Histological Analysis
The morphological and immunohistochemical features of the lymph nodes were quantified with use of a modification of the system of Mirra et al.³⁶ for the assessment of membranes obtained from failed joint arthroplasties (Table II). Ten to twenty fields were analyzed under medium power for each lymph node. All available nodes (one, two, or three from each side of the pelvis) from each patient were evaluated. Similar histological and immunohistochemical findings were present in multiple lymph nodes from the same side of the pelvis.

	Results

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Clinical Findings
Pelvic lymph nodes from five patients who had had a total of eleven arthroplasties in seven hips were available for review after excision for the staging of a pelvic tumor (Table III). The study group included two patients who had had a bilateral arthroplasty, two patients who had had a primary arthroplasty and had had two revisions each, and one patient who had had a primary arthroplasty without a revision. Lymph nodes were removed from both sides of the pelvis for the staging of prostatic adenocarcinoma (three patients) or endometrial carcinoma (one patient); in the remaining patient, who had carcinoma of the prostate, lymph nodes were obtained from one side of the pelvis. Of the seven primary arthroplasties, two were performed with cement and five, without cement; of the four revision procedures, two were performed with cement and two, without cement. The mean age (and standard deviation) of the four men and one woman was 68.4 ± 5.13 years (range, sixty-two to seventy-five years), and the mean time from the initial procedure to removal of the lymph nodes was 8.8 ± 6.76 years (range, three to twenty years). The arthroplasty preceded the development of the carcinoma in all five patients.

Morphological Findings
Architectural and histological changes were present in the regional pelvic lymph nodes of all five patients (Table III). These changes were bilateral in the patients who had had a bilateral arthroplasty, they were present only on the ipsilateral side in the patients who had had a unilateral arthroplasty, and they were absent in the seven control patients who had had a prostatectomy but no joint replacement.

Effacement of the normal nodal architecture by a histiocytic infiltrate was the most striking and consistent feature and was graded on a scale of 1+ to 4+ (Table II). Under normal conditions, the follicles of pelvic lymph nodes are surrounded by loose connective tissue containing variable numbers of sinus histiocytes (Fig. 1-A). In contrast, nodes from the same side as the hip arthroplasty had a much more intense histiocytic infiltrate, ranging from focal parasinusoidal aggregates of histiocytes to replacement of large portions of cortex and medulla by sheets of histiocytes (Figs. 1-B and Figs. 1-C). In the specimens from three patients, multinucleated histiocytic cells were a prominent feature (Fig. 2-A), and those from one patient had focal areas of necrosis. The specimens from four patients had areas of fibroblastic proliferation associated with the histiocytic infiltrates, and in those from one patient this was a prominent feature (Fig. 2-B).

View larger version (157K): [in this window] [in a new window]   Figs. 1-A, 1-B, and 1-C: Histological sections of lymph nodes from controls and from patients who had had a total hip arthroplasty. Fig. 1-A: Photomicrograph of a specimen from a lymph node, obtained at biopsy from a patient who had had a prostatectomy but not an arthroplasty. There is preservation of the normal nodal architecture with variable amounts of sinus histiocytosis (H). L = lymphoid follicles (hematoxylin and eosin, original magnification x 20).

View larger version (148K): [in this window] [in a new window]   Photomicrograph of a specimen from a lymph node, obtained at biopsy from a patient who had had an arthroplasty. There is extensive histiocytic infiltrate (H) and partial replacement of the normal nodal architecture. L = lymphoid follicles (hematoxylin and eosin, original magnification x 20).

View larger version (126K): [in this window] [in a new window]   Magnification of the same specimen seen in Fig. 1-B, showing cytological detail of infiltrating histiocytes (H), including abundant eosinophilic granular cytoplasm, large reactive-appearing nuclei, and prominent nucleoli. Normal lymphocytes (L) are seen at the top of the image (hematoxylin and eosin, original magnification x 200).

View larger version (131K): [in this window] [in a new window]   Figs. 2-A and 2-B: Histological sections demonstrating histiocytic and fibroblastic changes in lymph nodes after total hip arthroplasty. Fig. 2-A: Photomicrograph of a specimen from an involved lymph node, demonstrating numerous multinucleated histiocytic cells (arrows), the appearance of which is similar to that seen in Fig. 1-C. Multinucleated cells were a prominent feature in the specimens from three patients (hematoxylin and eosin, original magnification x 200).

View larger version (155K): [in this window] [in a new window]   Photomicrograph of a specimen from an involved lymph node, showing fibroblastic proliferation. This was noted in association with the histiocytic infiltrates in the specimens from four patients (hematoxylin and eosin, original magnification x 50).

View larger version (144K): [in this window] [in a new window]   Figs. 3-A and 3-B: Histological sections demonstrating wear debris in lymph nodes after total hip arthroplasty. Fig. 3-A: Photomicrograph made under polarized light, demonstrating histiocytes containing abundant refractile, polarizable debris, consistent with polyethylene fragments (hematoxylin and eosin, original magnification x 200).

View larger version (150K): [in this window] [in a new window]   Photomicrograph of metallic wear debris in sinus histiocytes. This was identified in all but one affected node (hematoxylin and eosin, original magnification x 200).

Histochemical and Immunohistochemical Findings
Immunohistochemical staining for KP-1 (CD-68) and HAM-56 (histiocyte markers) was strongly positive in the cells infiltrating the affected nodes, confirming the identity of these cells as histiocytes (Fig. 4). The periodic acid-Schiff histochemical stain was intensely positive in these cells, similar to the findings in previous reports⁴⁰.

View larger version (121K): [in this window] [in a new window]   Photomicrograph of a specimen from an involved lymph node from a patient who had had a total hip arthroplasty, demonstrating strong immunoreactivity for KP-1 (CD-68, a histiocyte marker) and confirming the identity of these cells as histiocytes. Adjacent lymphocytes have no immunoreactivity (original magnification x 100).

View larger version (149K): [in this window] [in a new window]   Figs. 5-A and 5-B: Photomicrographs of specimens from lymph nodes from a patient who had had a total hip arthroplasty, showing immunohistochemical localization of tumor necrosis factor-. Fig. 5-A: Histiocytes (H) from ipsilateral lymph nodes demonstrated staining for tumor necrosis factor-. Lymphocyte (L) immunoreactivity was also present. The staining demonstrated a coarse, granular pattern in these cells (see Fig. 7-C) (original magnification x 100).

View larger version (133K): [in this window] [in a new window]   Histiocytes (H) from the contralateral lymph nodes had no immunoreactivity with tumor necrosis factor- antibody. L = lymphocytes (original magnification x 100).

View larger version (149K): [in this window] [in a new window]   Figs. 6-A and 6-B: Photomicrographs of specimens from lymph nodes from a patient who had had a total hip arthroplasty, showing the immunohistochemical localization of interleukin-6. Fig. 6-A: Histiocytes (H) from the ipsilateral lymph nodes demonstrated staining for interleukin-6. Lymphocyte (L) immunoreactivity was also present. The staining was diffuse and showed a fine cytoplasmic granularity (see Fig. 7-D) (original magnification x 100).

View larger version (125K): [in this window] [in a new window]   Histiocytes (H) from the contralateral lymph nodes did not demonstrate staining with interleukin-6 antibody. L = lymphocytes (original magnification x 100).

View larger version (148K): [in this window] [in a new window]   Color photomicrographs demonstrating co-localization of metal particles and the immunohistochemical localization of CD-68 (Fig. 7-A), HLA-DR (Fig. 7-B), tumor necrosis factor- (Fig. 7-C), and interleukin-6 (Fig. 7-D). The metal particles are black, and the stain appears red (original magnification x 200).

View larger version (149K): [in this window] [in a new window]   Color photomicrographs demonstrating co-localization of metal particles and the immunohistochemical localization of CD-68 (Fig. 7-A), HLA-DR (Fig. 7-B), tumor necrosis factor- (Fig. 7-C), and interleukin-6 (Fig. 7-D). The metal particles are black, and the stain appears red (original magnification x 200).

View larger version (128K): [in this window] [in a new window]   Figs. 8-A and 8-B: Photomicrographs of specimens from lymph nodes from a patient who had had a total hip arthroplasty, showing immunoreactivity with the LN-3 antibody, which recognizes the major histocompatibility complex class-II antigen HLA-DR. Fig. 8-A: Histiocytes from all ipsilateral lymph nodes demonstrated intense staining for LN-3, consistent with immunological activation of these cells (original magnification x 100).

View larger version (136K): [in this window] [in a new window]   LN-3 staining was absent in histiocytes (H) from the contralateral lymph nodes. B-lymphocytes, which constitutively express HLA-DR, showed scattered positive staining in lymphoid follicles (L) (arrows) (original magnification x 100).

View larger version (145K): [in this window] [in a new window]   Color photomicrographs demonstrating co-localization of metal particles and the immunohistochemical localization of CD-68 (Fig. 7-A), HLA-DR (Fig. 7-B), tumor necrosis factor- (Fig. 7-C), and interleukin-6 (Fig. 7-D). The metal particles are black, and the stain appears red (original magnification x 200).

View larger version (153K): [in this window] [in a new window]   Color photomicrographs demonstrating co-localization of metal particles and the immunohistochemical localization of CD-68 (Fig. 7-A), HLA-DR (Fig. 7-B), tumor necrosis factor- (Fig. 7-C), and interleukin-6 (Fig. 7-D). The metal particles are black, and the stain appears red (original magnification x 200).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
Previous reports have established that sinus histiocytosis occurs in regional lymph nodes after joint arthroplasty^5,18,40. More recently, Albores-Saavedra et al. demonstrated histiocytic effacement of lymph nodes in six of six patients after hip arthroplasty, suggesting that this tissue reaction occurs commonly². As in the present study, only lymph nodes on the ipsilateral side of the pelvis were involved, although those authors did not have clinical data related to the arthroplasty for three of their patients.

The present study further defines the inflammatory and immunological features of this process. Isolated macrophages have been shown to phagocytize both methylmethacrylate and metallic debris with the subsequent stimulation of cytokine production, including tumor necrosis factor-, interleukin-1ß, and interleukin-6^19,21,24. In the present study, histological sections of the nodes demonstrated histiocytic infiltration and replacement of the lymph nodes and strongly positive staining of the macrophages for these cytokines. Furthermore, the histiocytes expressed the class-II antigen HLA-DR, a specific marker of immunologically activated macrophages; this finding has apparently not been reported previously with regard to either lymph nodes or periprosthetic membranes in association with joint arthroplasty.

Thus, the present study demonstrates that macrophages in regional lymph nodes become immunologically activated in response to particles of wear debris and express the major histocompatibility complex class-II antigen HLA-DR. Macrophages initiate the immune response through phagocytosis and presentation of antigens to CD4+ lymphocytes, a process that depends on HLA-DR^{1,10,27,34,37}. Unlike macrophages that phagocytize material without discrimination, CD4+ lymphocytes, or T-helper cells, have the ability to discriminate between autologous and foreign substances and are responsible for activation of the immune system. Under normal conditions, presentation of autologous proteins to CD4+ cells does not result in immune activation, although this does occur in autoimmune disorders such as rheumatoid arthritis²⁹.

HLA-DR molecules are structurally similar to immunoglobulin molecules and become associated with partially degraded proteins within the lysosomal compartment of macrophages and histiocytes²³. This complex is subsequently transported to the cell membrane. The expression of HLA-DR suggests that the phagocytized material may be coated with autologous proteins that can be metabolized and complexed to HLA-DR. More importantly, the presence of HLA-DR indicates that phagocytized particles of wear debris cause a physiological activation of the macrophage immune response. This suggests that cytokine secretion results from normal macrophage function rather than from a non-specific toxic effect. Although this hypothesis requires further study, it raises the possibility that pharmacological agents that alter macrophage function and immune activation may result in decreased cytokine secretion in response to particles of wear debris and therefore may inhibit the loosening process.

Immunologically activated macrophages have an altered metabolism, including increased phagocytosis and motility, as well as increased secretion of inflammatory cytokines, such as interleukin-1ß, interleukin-6, and tumor necrosis factor-³⁵. These cytokines mediate inflammation and act as a chemoattractant and activator of quiescent macrophages, enhance lymphocyte proliferation and differentiation, and stimulate the expression of other inflammatory cytokines and prostaglandin derivatives^{1,13,27,28,39}. Since these cytokines stimulate osteoclastic bone resorption, their presence in periprosthetic membranes may elicit the osteolysis that occurs during loosening of the implant^{8,11,12,22,26}.

Inflammatory changes were present in affected lymph nodes as early as three years after the arthroplasty; the intensity of the response did not appear to be related to the duration for which the implant had been in place, the use of cement, or the type of prosthesis that had been inserted. In the patients who had had a bilateral arthroplasty, nodes on both sides of the pelvis were affected, while in those who had had a unilateral arthroplasty, only nodes on the ipsilateral side were affected. As a control, nodes from an additional seven patients who had had a staging procedure for a pelvic tumor but no arthroplasty were evaluated, and none of these specimens demonstrated inflammatory changes. Particles of wear debris, including polarizable material consistent with polyethylene debris, were present only in affected lymph nodes and were absent in the contralateral lymph nodes and in the control patients.

The presence of metallic or polyethylene debris in all affected nodes suggests that these agents are responsible for activating the inflammatory response. Particles of wear debris generated within the joint capsule may be transported by the lymphatic system to regional lymph nodes. Alternatively, macrophages that have phagocytized particles of wear debris may migrate to regional lymph nodes, although the absence of inflammatory changes in the contralateral lymph nodes suggests that the inflammatory process is limited to regional lymph nodes. Locally, wear debris stimulates an inflammatory reaction, which has been associated with a histiocytic reaction resulting in periprosthetic bone resorption in hips that have had an arthroplasty either with or without cement^15,16,25,31.

Previous studies have shown that intracapsular wear debris accumulates within a year after total hip arthroplasty^9,20. In the present study, the duration that the prosthesis was in place ranged from three to twenty years, and these prostheses were associated with the presence of wear debris within the regional lymph nodes. Although the long-term effect of chronic macrophage activation within inflamed lymph nodes is unknown, chronic activation and hyperplasia of other tissues has been associated with malignant lesions^38,42.

Although two recent investigations^14,44 demonstrated a slight (1.6 and threefold) increase in the risk of lymphatic tumors after total joint arthroplasty, these data have to be interpreted with caution, given the rarity of the tumor and the relatively small number of patients followed in each study. In the larger series (1358 patients), Gillespie et al. found that, if tumors identified during the first two years after the hip replacement were excluded, the arthroplasty was associated with no increase in the prevalence of lymphatic cancer¹⁴. Furthermore, Visuri and Koskenvuo observed no increase in the over-all prevalence of cancer after arthroplasty in their series of 433 patients⁴⁴, while Gillespie et al. found a slight decrease in the first ten years and a slight increase more than ten years after implantation. Thus, despite the many joint arthroplasties performed, there is no clear evidence of an increased risk of a malignant tumor. However, the dissemination of particles of wear debris and the inflammatory changes observed in lymph nodes indicate the need for further investigation with larger numbers of patients.

The local biological factors that contribute to failure of the implant are currently being scrutinized. However, additional studies are needed to elucidate the mechanisms and importance of regional and systemic responses to wear debris. A more thorough understanding of the biological response to the components and materials of prostheses may be expected to lead to further improvements in total joint replacement.

NOTE: The authors thank Saul S. Suster, M.D., and Sarah S. Singal, M.D., for contribution of clinical histories and case material, and Barb Stroyer and Robin Moynes for technical assistance.

	Footnotes

 
*No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. Funds were received in total or partial support of the research or clinical study presented in this article. The funding sources were National Institutes of Health Grants AR28420 (J. E. P.), AR38618 (J. E. P.), and AR38945 (R. N. R.), and an Orthopaedic Research and Educational Foundation Career Development Award (R. J. O'K.).

Departments of Pathology (D. G. H., A. R. J., and J. Z. S.) and Orthopaedics (R. N. R., J. E. P., and R. J. O'K.), University of Rochester Medical Center, P.O. Box 665, Rochester, New York 14642.

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