CASE 1. A forty-nine-year-old woman had a total hip replacement in 1974 for congenital dislocation of the left hip. Revision arthroplasties were performed in 1976, 1981, 1985, and 1992 for aseptic loosening. The most recent revision, in January 1992, was performed for pain in the left hip and loosening of the prosthesis. Considerable loss of periprosthetic bone necessitated reconstruction with use of bulk femoral and acetabular allografts. Gross inspection of the polyethylene acetabular component showed slight wear. However, histological examination of the synovial and periprosthetic tissues revealed abundant shards of polyethylene within the macrophages and within the multinucleated foreign-body giant cells.
In November 1992, the patient had repair of a bilateral inguinal hernia. An enlarged inguinal lymph node, which measured 2.7 by 2.1 by 0.8 centimeter, was encountered during the left herniorrhaphy. The node was excised, and histopathological examination of frozen sections was performed. There was no evidence of an infection or malignant lesion.
CASE 2. A sixty-four-year-old woman had a total knee replacement on the left for rheumatoid arthritis in 1981. The history included tuberculosis, which had been diagnosed in 1968 after the biopsy of a tender erythematous nodule on the scalp.
In 1987, the left lower limb became erythematous and swollen. A biopsy of the skin showed a perivascular mononuclear infiltrate, and the patient was managed with antibiotics for a presumptive cellulitis. Subsequently, inguinal adenopathy developed, and an enlarged inguinal lymph node on the left that measured 3.5 by 2.0 by 0.8 centimeter was excised. Evaluation of the node with light microscopy showed sinus histiocytosis and lymphoid follicular hyperplasia. These changes were believed to reflect chronic lymphadenitis. There was no evidence of granulomas.
In April 1992, the cellulitis of the left limb and the left inguinal adenopathy recurred. A biopsy of an enlarged inguinal lymph node again showed marked follicular hyperplasia and sinus histiocytosis, with polarizable particles within the sinus histiocytes. Subsequently, a fistula draining copious pus developed in the left inguinal region. The infection resolved after treatment with penicillin.
In May 1992, the patient continued to have several enlarged non-tender inguinal nodes and an erythematous, swollen left limb. A computed tomography scan of the pelvis was made to evaluate the extent of the lymphadenopathy. The scan showed an enlarged inguinal node (1.2 by 0.8 centimeter) on the left (Fig. 1). The prosthesis was revised in the fall of 1992, and lysis with cavitation was found in the distal part of the femur and in the proximal part of the tibia. The lysis presumably had been caused by the mediators of inflammation that had been released by the macrophages as they phagocytosed polyethylene wear debris; certain mediators of inflammation (interleukin-1 and prostaglandin E2) are potent stimulators of bone resorption23.
In each patient, the inguinal lymph nodes ipsilateral to the total joint prosthesis were grossly enlarged. Histological examination of tissue sections embedded in paraffin and stained with hematoxylin and eosin revealed reactive changes and sinus histiocytosis (Fig. 2). Follicular lymphoid hyperplasia was moderate in the first patient (Case 1) and extensive in the second patient (Case 2). In both patients, the trabecular and capsular sinuses were dilated with abundant, tightly packed macrophages that contained abundant, granular, eosinophilic cytoplasm (Fig. 3-A and 4-A). Under polarized light, angular shards of intensely birefringent particles were seen throughout the sinuses of the nodes in association with macrophages (Figs. 3-B and 4-B). The birefringence and needle-like morphology of the particles were consistent with polyethylene wear debris (Fig. 5).
Examination of individual cells under high magnification revealed that the polyethylene particles were within the cytoplasm of macrophages. Light microscopy showed no evidence of metal particles within the specimen from either patient. The tissues could not be evaluated for the presence of bone cement because they had been processed in xylene, which dissolves polymethylmethacrylate.
Total joint prostheses produce particulate debris through adhesive, abrasive, and fatigue (delamination) wear processes occurring at the articulating interface between metal and polyethylene, at the junctions of the modular portions of a modular total joint prosthesis, at the interface between the component and the cement, or at the interface between the implant and the bone. Polyethylene, polymethylmethacrylate, and metal particles are all capable of stimulating resorption of periprosthetic bone1,4,11,12,18,20,21,23,27,28. The adverse consequences of loss of periprosthetic bone have focused a great deal of attention on the problems caused by wear particles at the implant-bone interface. Much less attention has been focused on the pathological response to these particles at distant sites in the body.
The tissue response to wear particles is a foreign-body reaction, with varying amounts of macrophages and foreign-body giant cells10,26,28. Synovial macrophages readily engulf particles that are released into the joint space. When the production of particulate debris exceeds the phagocytic capacity of synovial macrophages, excess particles migrate into periprosthetic tissue, where they are ultimately phagocytosed by macrophages that release agents that stimulate the resorption of bone21, or they enter the lymphatic vessels27. There is evidence that macrophages laden with particles can also gain entry into the lymphatics9. Macrophages in the lymph nodes endocytose the free particles that are traveling within the lymphatic system. A steady influx of wear debris causes these macrophages to accumulate within the sinuses of the lymph node3. During a period of several years, macrophages containing particles may become so abundant that they cause dilatation of the nodal sinuses and enlargement of the node. The accumulation of histiocytes or macrophages within the sinuses of lymph nodes is described pathologically as sinus histiocytosis. The histopathological responses to polyethylene particles in lymph nodes and in periprosthetic tissue are comparable. At both sites, macrophages containing polyethylene have abundant, granular, eosinophilic cytoplasm with small central nuclei. Polyethylene particles that are smaller than three micrometers are seen within the individual cells, and larger particles are surrounded by foreign-body giant cells21.
Systemic Migration of Particles Derived from Implants
The literature contains numerous reports of the migration of particles, released from implants, to lymph nodes and to many organs. The spread of particles of silicone elastomer and liquid droplets from breast implants was well documented by Travis et al., who found the translocation of these particles to be due to migration through soft tissues, entry into the lymphatic system, and direct entry into the vascular system. Silicone particles have been found to migrate from breast implants through soft tissue to sites as distant as the groin5. Silicone lymphadenopathy in the axilla is common in patients who have breast implants25. The hematogenous dissemination of silicone to viscera has also been reported as a result of the injection of the material into soft tissue24. As reported in the orthopaedic literature, silicone lymphadenopathy has become a common finding in patients who have a finger-joint prosthesis made of silicone elastomer6,7.
The number of reports documenting the dissemination of particles from a total joint prosthesis into the lymphatic system is increasing, suggesting that this phenomenon may be more common than previously thought. Several studies of animals have documented the lymphatic spread of polyethylene particles to the regional lymph nodes15,26. Bos et al. found evidence from human autopsies that polyethylene, polymethylmethacrylate, and metal particles released from stable total hip replacements had spread to inguinal, para-iliac, and para-aortic lymph nodes as early as 1.5 years after the implantation of the prosthesis. Sinus histiocytosis in association with wear particles of polyethylene has been an incidental finding in lymph nodes biopsied at revision arthroplasty16 and in the staging of prostate2,8 and breast cancer17. Adenopathy related to an implant is not limited to total hip and knee prostheses. O'Connell and Rosenberg recently reported axillary histiocytic lymphadenopathy in association with polyethylene wear particles from a total shoulder replacement.
Kinetics of Migration of Particles from Joints and Bone
The kinetics of migration of particles from joints and osseous sites has been the subject of several investigations. Noble et al. investigated the leakage of particles, labeled with a radioisotope, from intra-articular sites of injection in the knees of rabbits. The particles included human serum albumin, carbonized microspheres, gold colloid, and ferric hydroxide, with sizes ranging from thirty nanometers to tens of micrometers. Approximately 1 per cent of the injected dose of ferric hydroxide (so-called inert) particles, which were less than one micrometer in diameter, migrated from the joint twenty-four hours after injection. The kinetics of migration (the rate of leakage) of particles from the joint space was related to the size of the particles. There was an order-of-magnitude difference in the rates of leakage (2.2 to 0.1 per cent after twenty-four hours) for particles ranging from less than 0.1 to 15.0 micrometers.
In another study, a canine model was used to investigate the spread of cell-sized radioactive microspheres from the distal part of the femur into the lymphatic system, venous drainage, and local tissue19. In that model, microspheres (fifteen micrometers in diameter) were injected into the medullary canal of the femur. The particles entered directly into the venous system within fifteen seconds of injection and were effectively filtered by the lungs, thus preventing dissemination into the arterial system. No migration of the particles from the femur into the lymphatic system was found after four days. However, similar microspheres that had been injected into soft tissue in the distal part of the femur were found in the iliac lymph nodes in two of nine animals after the same period of time. In neither of these animals were particles found in the lungs. A subsequent study13 demonstrated that particles as large as 100 micrometers, injected into the medullary canal of the distal part of the femur, migrated to the lungs within fifteen minutes after the injection. These results suggest that, under certain conditions, particles generated by wear might directly enter the venous system. Most of these particles would be filtered by the lungs, preventing hematogenous spread. Collectively, the investigations indicate that a considerable number of particles can be disseminated to various sites in the body within hours after their generation.
Clinical Implications
Lymphadenopathy secondary to the accumulation of wear particles in sinus macrophages may cause confusion regarding the appropriate diagnosis, especially in patients in whom a malignant lesion is suspected. Shinto et al. reported the case of a nineteen-year-old man who was first seen with pain in the right inguinal region and a palpable mass, measuring three by three centimeters, three years following a total knee replacement on the right after the resection of an osteosarcoma. A lymph node was biopsied because metastatic recurrence of the osteosarcoma was suspected. Histological examination revealed sinus histiocytosis caused by metal particles that had been released from the knee prosthesis. There was no evidence of a malignant lesion.
In the two patients in the present report, polyethylene particles were found in association with adenopathy of the inguinal nodes ipsilateral to the total joint prosthesis. The enlarged inguinal node in the first patient (Case 1) was an incidental finding at herniorrhaphy, and the inguinal adenopathy in the second patient (Case 2) was detected after the patient was first seen with an ipsilateral cellulitis. For both patients, histological examination revealed extensive sinus histiocytosis, with the presence of polyethylene in macrophages and foreign-body giant cells.
One of our patients (Case 2) had a second pathological process contributing to the development of lymphadenopathy. In addition to the sinus histiocytosis, extensive hyperplasia of the lymphoid follicles with abundant active germinal centers was seen. As polyethylene is not immunogenic, the lymphoid hyperplasia was solely a response to the skin infection. Polyethylene particles were not present within lymphoid follicles.
The ultimate fate of particles released from a total joint prosthesis is not known. The findings of a recent report suggest that metallic particles from an orthopaedic prosthesis may pass through the lymphatics and gain a systemic distribution14. Our ongoing study of specimens obtained at autopsy has not yet revealed metal or polyethylene particles distributed in end organs. However, the population sample from which we obtain specimens has been limited.
The clinical sequelae of polyethylene particles in the lymph nodes and other organs is not known. However, the fact that disseminated polyethylene particles cannot be removed focuses attention on investigations of the long-term response of the host to such particles.
NOTE: The authors thank Jerry E. Enis, M.D., for providing information about the patient who had a total knee prosthesis.