Abstract
Background:
Although total hip arthroplasty is one of the most common orthopaedic surgical procedures, it remains unclear whether histopathological examination of the excised femoral head adds to the quality of patient care. We propose that assessment of femoral heads resected during total hip arthroplasty and donated for allograft use may provide a profile of femoral head pathology that benefits total hip arthroplasty patients and bone donors.
Methods:
We retrospectively analyzed the histological findings reported for 6161 femoral heads donated for allograft use between 1993 and 2006. Specimens obtained during total hip arthroplasty and specimens donated at death were reviewed. Follow-up investigations that resulted from abnormal histopathological findings were also reviewed. The Western Australian Cancer Registry was used to determine whether patients with a suspected neoplasm were subsequently diagnosed with such a disease. A retrospective review of the histopathological findings was conducted to evaluate and reclassify all previous observations of abnormalities.
Results:
One hundred and five femoral heads demonstrated abnormal or reactive histopathological features not reported prior to surgery and were rejected for allograft use. A reactive lymphocytic infiltrate, most likely due to osteoarthritis, was the most commonly identified feature (forty-five cases). Other features observed in twenty-seven cases were also most likely due to the presence of severe osteoarthritis. Ten femoral heads demonstrated plasmacytosis, which may have been related to osteoarthritis. Two patients were diagnosed with Paget's disease, and two, with rheumatoid arthritis. Nineteen patients had a suspected neoplasm. Of these nineteen, eight cases of non-Hodgkin's lymphoma or chronic lymphocytic leukemia and one case of myelodysplastic syndrome were confirmed on further investigation. One subsequently confirmed malignancy was detected per 770 femoral heads examined.
Conclusions:
Our findings indicate that, even with a detailed medical history and careful physical examination, clinically important diseases including neoplasms and Paget's disease are observed in patients diagnosed with osteoarthritis prior to total hip arthroplasty. Histological examination plays an integral role in quality assurance in femoral head banking, and it also represents a possible early diagnostic test for bone and bone-marrow-related diseases in patients undergoing total hip arthroplasty.
Total hip arthroplasty is currently one of the most common orthopaedic surgical procedures in Western countries, with the United States reporting more than 220,000 total hip arthroplasties annually1. In Australia, resected femoral heads from total hip arthroplasty are collected for use as allografts. The safety and quality of these allografts are regulated by guidelines established by national and international organizations such as the American Association of Tissue Banks (AATB) guidelines, the European Association of Musculo Skeletal Transplantation (EAMST) guidelines, and the Australian Therapeutic Goods Administration (TGA) Code of Good Manufacturing Practice—Human Blood and Tissues. These guidelines govern donor selection, tissue procurement, tissue processing, microbiological monitoring, tissue sterilization, tissue preservation, and tissue storage.
The development of infectious diseases, including hepatitis and human immunodeficiency virus (HIV), as a result of the transplantation of a contaminated allograft has long been identified as a risk2-7. Recent reports have shown that living cells remain within fresh-frozen allografts8-10; although the potential risk of disease transmission from donor to recipient by these surviving cells is unknown, to our knowledge no cases of tumor transmission resulting from the use of bone allograft have been identified to date11.
The relatively infrequent occurrence of disease transmission from the allograft to the recipient is attributable to the strict screening of donors. A donor is required to undergo serological testing, a medical and social history review, physical examination, and bacteriological culturing of tissue swabs and samples, as well as autopsy in the case of deceased donors, prior to the acceptance of a musculoskeletal donation. Serological tests include those for Treponema pallidum (TPHA), hepatitis B and C, HIV, and human T-lymphotropic virus (HTLV). Screening, including a medical history, excludes donors with other potentially serious transmissible diseases, malignancy, systemic disorders that may compromise the integrity of the bone (e.g., rheumatoid arthritis), or other diseases of unknown etiology. Finally, histopathological examination of a bone chip taken from the retrieved bone as well as of a soft-tissue sample may enable the detection and exclusion of abnormal pathologies that had not been revealed by the review of the donor's medical history. In Western Australia, histopathological examination is performed as part of routine musculoskeletal tissue-banking practice.
Since the femoral heads obtained during total hip arthroplasty do not routinely undergo histopathological examination in Australia, we propose that assessment of bone from resected femoral heads collected for use as allografts will profile the femoral head pathology and may prove beneficial to total hip arthroplasty patients and to bone donors. The current retrospective study was designed to examine the prevalence of findings identified by histopathological screening in 6161 femoral head allografts retrieved over a fourteen-year period in order to determine whether routine histopathological examination should be performed in all tissue-banking procurements and whether such an examination would add to the quality of patient care.
The records associated with all femoral head donations (from both living and deceased donors) in Western Australia between 1993 and 2006 were analyzed retrospectively. These records, including the results of screening tests and histopathological reports, were collected as part of routine tissue-banking practice. Potential donors included patients undergoing total hip arthroplasty who were asked either by the surgeon or through the hospital's admission system to donate the removed femoral head. The donor's signed consent was obtained and was witnessed by a member of the medical staff or other authorized individual. Potential donors also included individuals who had registered with the Australian Organ Donor Register prior to death; further consent in such cases was obtained from the next of kin by a donor coordinator. There was no donation without consent.
The donor and the donated tissue were required to pass several screening tests prior to histopathological examination, including a medical and social history review, serological testing and bacteriological culturing, physical examination, and autopsy in the case of deceased donors. These procedures are explained in more detail in a recent review of tissue banking in Western Australia12.
The femoral head and accompanying bone and soft-tissue specimens were recovered from either the operating room or the mortuary. Recovery of a femur from a deceased donor was performed within twenty-four hours of death by a team consisting of an orthopaedic surgeon and two trained technicians; the recovery was performed only if the body had been refrigerated within six hours after death. A bone chip from the central cancellous bone of the femoral head (up to 2 × 1 × 1 cm in size) and a soft-tissue sample were fixed in 10% buffered formalin solution for at least twenty-four hours. The bone chip was decalcified in 10% ethylenediaminetetraacetic acid (EDTA) according to standard protocols. Each specimen was then processed and embedded in a paraffin block for sectioning.
Initial histopathological assessment was performed on hematoxylin and eosin-stained sections at the time of donation. The pathologist then conducted subsequent investigations if warranted (see Appendix). All lymphoid aggregates were stained for pan-B-cell and pan-T-cell markers (CD20, CD79a, and CD3; Dako, Campbellfield, Australia) to determine clonality. Cases of plasmacytosis were examined with use of immunoglobulin antibodies (Dako) to confirm the presence of a mixture of cell types bearing kappa and lambda light chains. Suspected malignancies were classified with use of a panel of antibodies to markers including CD20, CD79a, CD5, CD10, BCL2, and BCL6 (Dako and Novocastra [Leica Microsystems], North Ryde, Australia). Suspected cases of rheumatoid arthritis were confirmed with use of antibodies to CD20, CD79a, and CD4 markers (Dako and NeoMarkers [Thermo Fisher Scientific], Scoresby, Australia). All immunohistochemical staining protocols used automated antibody incubation, and Dako EnVision+ Kits were used with the DAB+ chromogen for visualization. Additional staining, including Gömöri methenamine silver, Gram, and Ziehl-Neelsen, was performed in specimens in which inflammation and/or granuloma was evident.
Histopathological examination of the bone and soft-tissue sections was performed and reported by several consultant surgical pathologists at PathWest (QEII Medical Centre) or Royal Perth Hospital at the time of total hip arthroplasty. The presence of any histopathological abnormality resulted in rejection of the femoral head, in accordance with the Perth Bone and Tissue Bank protocol. In the event that two or more pathologies were identified, the more clinically important one was recorded as the reason for rejection.
If the histopathological findings suggested the presence of a neoplasm, the orthopaedic surgeon and/or primary care physician was notified and the patient was referred to a consultant hematologist or oncologist for further assessment. We used the Western Australian Cancer Registry to obtain follow-up data through April 2010 for all patients with suspected neoplasms.
The pathology reports for all cases rejected because of histopathological findings at the time of donation were reviewed. In addition, all of the tissue sections were reexamined by pathologists (P.R. and M.H.Z.) experienced in musculoskeletal tissue banking and bone pathology. The results of any immunohistochemical studies, special stains, fine-needle aspiration biopsy, flow cytometry, and polymerase chain reaction (for detection of immunoglobulin lambda and kappa light chain restriction) were also reviewed. All diagnoses were reviewed and reclassified into clear categories by the same two pathologists.
The study was approved by the Human Research Ethics Committee at the University of Western Australia.
Statistical Methods
The Student t test was used to evaluate differences in age between the groups, and the normality assumption was checked. Logistic regression was used to compare the prevalence of abnormal histopathological results in men with that in women, and the odds ratio (with 95% confidence interval [CI]) was calculated. A two-sided p value of <0.05 was considered significant. The prevalence of an abnormal histopathological finding is reported per 1000 femoral heads donated between 1993 and 2006.
Source of Funding
There was no external funding source for this study.
Histopathologically Based Rejection by the Tissue Bank
A total of 7803 femoral heads (3892 from male donors and 3786 from female donors; the sex was not known for the remaining 125 donors) were donated during the period from 1993 to 2006, and 2582 of these were rejected (Fig. 1, A). The donations included 177 cadaveric femoral heads (2.27%; 128 from male donors and forty-three from female donors). The medical and social history screening identified factors that excluded 1642 of the donations from acceptance in the bone bank, and further histopathological examination was not performed on these specimens. The remaining 6161 femoral heads underwent histopathological examination, and 105 were rejected solely on the basis of the reported histopathological findings; only two of these rejections were from cadaveric donors. In all cases, the condition identified by the histopathological examination had not been known prior to resection of the femoral head. The 105 femoral heads rejected on the basis of the histopathological results represented 4.07% of the 2582 rejections and 1.70% of the 6161 donations that underwent histopathological examination. The number of femoral head donations rejected because of histopathological results alone was similar to the number rejected because of microbiological results; greater than the number rejected because of HIV, TPHA, and HTLV; and less than the number rejected because of hepatitis (Table I). The overall risk that a donation would fail the histopathological screening was 17.04 per 1000 donations.
Donors rejected on the basis of the histopathological examination ranged from thirty-five to ninety-three years in age (mean [and standard deviation], 67.46 ± 11.37 years) and included forty-two men and sixty-three women. The recorded age range for all femoral head donations was fourteen to ninety-seven years (mean, 65.75 ± 11.49 years). The mean age of the donors rejected on the basis of the histopathological results was not significantly different from the mean age of all donors. The probability of failing the histopathological screening was 52% greater in female donors than in male donors (odds ratio = 1.52; 95% CI = 1.02 to 2.27; p = 0.04).
Histopathological Features (Figs. 2-A through 2-F)
The most common reason for rejection at the histopathological screening stage was the identification of populations of lymphoid cells within the bone marrow (Fig. 1, B). Reactive lymphocytic infiltrates accounted for 43% (45) of the 105 histopathological rejections (Table II). These cases involved multiple focal lymphoid aggregates, which were either intertrabecular, paratrabecular, or perivascular in distribution, within the marrow space (Fig. 2-A; see Appendix). The lymphoid cells were usually small and were characterized by round to oval nuclei showing condensed chromatin and small nucleoli. Immunohistochemical staining with pan-B-cell (CD20) and pan-T-cell (CD3) markers often identified a mixture of T and B cells. In other cases the aggregates were composed of small, round, mature lymphocytes and a small number of plasma cells. The prevalence of reactive lymphocytic infiltrates was 7.30 per 1000 donations, and 64% (29) of the 45 reactive lymphocytic infiltrates were from female donors (odds ratio = 1.79; 95% CI, 0.96 to 3.34; p = 0.07).
An additional twenty-seven femoral heads were rejected because of various osteochondral disorders and nonspecific changes in myeloid marrow tissue, including granuloma (Fig. 2-F), inflammation, and metabolic disorder (not further classified), that were found during the microscopic examination. Ten donations were rejected because of the presence of plasmacytosis. The pathologists retrospectively reviewed each of these thirty-seven cases during the current study. They confirmed the absence of any histological features of malignancy (see Appendix), and concluded that the histologic features were more consistent with severe osteoarthritis or with a reactive change in the bone marrow associated with osteoarthritis (Table II).
Microscopic findings suggestive of a neoplastic disorder were reported in nineteen femoral heads (from eleven female and eight male donors with a mean age of 69.68 ± 10.62 years); these represented 18% of the 105 histopathological rejections (Fig. 2-B; see Appendix). These findings warranted referral to a consultant hematologist or oncologist for further assessment. Follow-up investigations confirmed eight malignancies, and another patient with a suspected B-cell neoplasm was later diagnosed with myelodysplastic syndrome. Confirmed malignancies included non-Hodgkin's lymphoma and chronic lymphocytic leukemia (Figs. 2-C and 2-D; see Appendix). Three patients who were not diagnosed with a malignancy immediately following the total hip arthroplasty were so diagnosed during the follow-up monitoring, at forty-one, forty-three, and fifty-one months after the histopathological finding (see Appendix). The prevalence of findings that were suggestive or diagnostic of neoplasms was 3.08 per 1000 femoral head donations examined with use of histopathology. One subsequently confirmed malignancy was detected per 770 femoral head donations that were screened with use of histopathology.
Two cases of Paget's disease (Fig. 2-E) and two cases of rheumatoid arthritis were identified during the histopathological examination; these had been either unreported in the medical history obtained during the screening or previously undiagnosed. All four diagnoses were confirmed by further investigations conducted at the time of total hip arthroplasty (see Appendix).
Clinically important diseases, including confirmed neoplasms (eight cases), myelodysplastic syndrome (one case), rheumatoid arthritis (two cases), and Paget's disease (two cases), were identified at a rate of 2.11 per 1000 femoral heads undergoing histopathological examination.
Abnormal or reactive features were found in 1.70% (105) of the 6161 femoral heads in the current study, and these donations were rejected for allograft use. The most common reason for rejection at the time of histopathological screening was the identification of changes that were classified during the retrospective review as representing primarily reactive lymphocytic infiltrates. The retrospective review of the pathological results for the 105 rejected donations also confirmed thirteen cases of clinically important diseases including non-Hodgkin's lymphoma, chronic lymphocytic leukemia, myelodysplastic syndrome, rheumatoid arthritis, and Paget's disease. Thus, a clinically important disease was detected at a rate of 2.11 per 1000 femoral heads undergoing histopathological examination, with one confirmed malignancy per 770 femoral heads examined.
Impact of Histopathological Examination on Tissue Banking
The overall rejection rate of musculoskeletal tissue donations in Western Australia has been reported previously to be 32%12. The high rejection rate reflects the aggressive policy of discarding any specimens that do not satisfy all requirements of the protocol. The histological results were responsible for 4.37% of the total rejections, in 1.38% of the total donors, between 1993 and 200212. The results of the current study revealed similar percentages when only femoral heads (donated from 1993 to 2006) were analyzed.
The current findings are comparable with the histopathological rejection rate of 1.31% previously reported for the South Australian Bone Bank13. Histopathological rejection rates of 3.6% and 7.9% were reported in two other previous studies of bone donations14,15; however, those two studies had a much smaller cohort size (137 and 1146). Similar studies examining the prevalence of discrepant and discordant preoperative diagnoses in primary total hip and total knee arthroplasty revealed additional unanticipated findings on pathological examination in between 0% and 9.5% of cases16-21.
All donated tissues with a reported histopathological “abnormality” were rejected, in accordance with the musculoskeletal tissue banking protocol. Unfortunately, these rejections included cases in which findings of inflammatory infiltration or various osteochondral disorders were reported. A careful retrospective review of these histological findings revealed that these cases were most likely due to the presence of osteoarthritis, and that such donations should not be excluded since osteoarthritic bone is acceptable for allograft use.
The presence of morphologically benign lymphoid aggregates in patients without known lymphoproliferative disease is a common finding. We identified forty-five cases in which reactive lymphocytic infiltrates were present in sufficient size or number to be considered notable and be reported by the pathologists who performed the original examinations in our study. Benign aggregates of lymphoid cells are a common finding in bone marrow, both in bone marrow trephine specimens and in specimens examined during autopsy22. The prevalence of these aggregates increases with age and is higher in women than in men. Marrow lymphoid aggregates may be observed in a wide range of disorders23, including osteoarthritis, but their clinical importance is unclear in the majority of patients. The diagnostic distinction between benign reactive aggregates and marrow involvement by well-differentiated lymphocytic lymphoma and other lymphomas of small-cell morphology (e.g., follicular and mantle zone lymphoma) can be difficult23-25. Nineteen cases with features highly suggestive of a neoplasm were also noted in the current study. Although we are aware of no reports of tumor transmission resulting from bone grafts, there have been many reports of the development of donor-related malignancies following other types of organ donation11,26,27. This difference may be due in part to the immunocompetence of the allograft recipient and in part to the treatment of the bone tissue prior to transplantation (processing, irradiation, and/or freezing, which result in a very low probability of cell survival).
It is important to note that the variety of abnormalities initially reported will reflect variations in the interpretation and reporting style among the individual pathologists—e.g., if occasional lymphoid aggregates are present, some pathologists may report this as an abnormality but others may judge the same aggregates to be too sparse and unimportant to note. The lack of a centralized review involving standard criteria and reporting formats, as well as the use of pathologists unfamiliar with bone tissue banking, may have led to the unnecessary rejection of some femoral head donations. The implementation of standard criteria and reporting formats would be likely to reduce the rejection of femoral heads due to trivial or unimportant findings and to make interpretation of histopathological reports easier for tissue banks.
Given that there is currently no evidence that the neoplasms identified in the current study can be transmitted to the recipient, performing histopathological assessment can only be seen as a means of risk mitigation, especially to those supplying fresh-frozen bone for allograft. However, further studies are required to examine the risk that these abnormalities pose to the allograft recipient.
Benefits of Histopathological Examination for the Total Hip Arthroplasty Patient
The identification of thirteen previously undiagnosed cases of malignancy, rheumatoid arthritis, and Paget's disease highlights the potential benefits of histopathological examination in patients undergoing total hip arthroplasty. It is noteworthy that clinical evidence of malignancy did not appear until up to 4.25 years after the highly suspicious pathological results were reported at the time of the total hip arthroplasty. There have been a few previous reports in which the presence of a neoplasm was suspected on the basis of pathological examination of bone sections, although limited or no follow-up was performed in these cases14,15,20. For instance, one case involving the detection of a previously undiagnosed metastatic mammary carcinoma has been reported28. Although the number of cases of neoplastic disease in the present study was small, the most commonly identified feature was the presence of reactive lymphocytic infiltrates. These benign lymphoid aggregates may be an early indicator of disease, as indicated in a study by Faulkner-Jones et al. in which 22% of patients with morphologically benign lymphoid aggregates were later diagnosed with lymphoproliferative disease29. Likewise, thirteen patients with a suspected low-grade B-cell lymphoma were followed for a median of 7.2 years, and two of the patients developed malignant disease and three continued to require regular monitoring30. Additional studies are required to determine whether patients with low-grade proliferative disorders of the bone marrow require further long-term follow-up and monitoring.
Performing routine histopathological examination in total joint arthroplasty patients takes advantage of the opportunity to screen patients for bone-related malignancies or early indicators of other diseases, but such an examination increases the cost to the health-care system. The fact that histopathological examination revealed an unsuspected malignancy in one in 770 femoral heads in our study presents evidence of the possible economic benefits of histopathological examination during total joint arthroplasty. In comparison, annual mammography has been reported to detect six malignancies per 1904 screened women31, and flexible sigmoidoscopy has been reported to detect five colorectal cancers per 489 people screened32. Although the incidence of bone-related malignancies is lower, the estimated cost of treatment per case is much higher for leukemia and non-Hodgkin's lymphoma (A$51,196 and A$27,620, respectively, in 2000-2001, when A$1.00 equaled approximately US$0.55) than for colorectal cancer and breast cancer (A$18,246 and A$11,897, respectively)33. Furthermore, early detection is paramount since advanced disease requires more aggressive, and more expensive, treatment and since bone and marrow-related malignancies are difficult to effectively treat. Although the results of previous studies to examine the cost-effectiveness of routine histopathological screening have suggested considerable cost savings on a population basis if histopathological examination is not performed during total joint arthroplasty, the effects and costs of missed diagnoses were not addressed16,20. Further studies are required to assess the cost-effectiveness of routine histopathological screening in light of our findings.
Limitations of the Study
Our study had several limitations because of its retrospective nature. Collection of the bone and soft-tissue specimens was not standardized according to size and anatomical site, possibly leading to some missed diagnoses. The results for some cases that received follow-up could not be obtained because of the lengthy period of data collection. Finally, the findings reported in the current retrospective study had already resulted in the unnecessary rejection of osteoarthritic femoral heads. Consequently, although it is clear that occult abnormalities do occur in total hip arthroplasty patients, we suggest that the reported prevalences be interpreted with caution.
Conclusions
Routine pathological examination during total hip arthroplasty could play an important role in the early detection of abnormal bone pathology and could also play a quality assurance role in ensuring the correctness of the diagnosis. Further histopathological studies could potentially provide important information regarding the etiology of pathologic osseous conditions. In addition, histopathological screening during tissue banking allows for quality assurance of the banked tissue, although careful assessment of all allograft rejection criteria is required.
Tables presenting data on the cases of suspected and confirmed neoplasm and Paget's disease and a table describing the criteria associated with the initial histopathological rejections are available with the online version of this article as a data supplement at jbjs.org.
Note: The authors thank Joyleen Winter and Anne Cowie from the Perth Bone and Tissue Bank and Dr. Timothy Threlfall from the Western Australian Cancer Registry for helping with data collection and procurement.
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