Increased cortical density in popliteal lymphadenopathy as a promising radiological sign to help differentiate adverse local tissue reaction from infections in complications following a knee arthroplasty—three case reports

Introduction

Total knee arthroplasty (TKA) is a widely performed surgical procedure that is highly effective in treating advanced osteoarthritis of the knee by reducing pain and improving function (1). Nevertheless, some patients experience suboptimal outcomes after surgery or have implant failures, leading to the need for revision surgery.

Previous studies investigated the failure causes after total knee arthroplasties and differed between early (within the first 2 years after primary TKA) and late revision (thereafter). They found that adverse local tissue reaction (ALTR) and accordingly aseptic loosening as most common causes for late revisions (2). Periprosthetic joint infection (PJI) and instability were the most common revision causes in the early failure groups (3). However, in recent years, infection cases have increased, likely due to the rising number of patients with obesity and diabetes undergoing knee prosthesis procedures (4).

Differentiating between PJI and ATLR is crucial, as the clinical presentations and radiographic findings can overlap between these two entities, yet their treatments are markedly different.

Radiography is integral to pre-operative assessments, postoperative care, and long-term follow-up surveillance. It can reveal normal component alignment, complications such as periprosthetic radiolucency and osteolysis, reactive bone formation, periostitis, and periprosthetic fractures. However, radiography may lack sensitivity to subtle variations in bone mineralization and alignment, potentially obscured by surrounding bone or the prosthesis itself (5).

Computed tomography (CT) can provide additional information, although not all patients with suspected prosthetic complications undergo this imaging modality. CT imaging can unveil changes in surrounding bone not apparent on radiographs, revealing radiographically occult evidence of loosening, osteolysis, fracture, and reactive bone formation. CT can also aid in the detection of lymphadenopathy, a finding that has recently gained significant importance due to its potential role in diagnosing and differentiating complications associated with prosthetic joints. Enlarged lymph nodes of the iliac chain were found to be a significant predictor of PJI (6-8).

Not only do immune cells migrate to the nodes, but the prosthetic wear material can also undergo this migration. The migration of particles is a well-known phenomenon in ALTR, a complex process that has multiple presentations and causes various radiological manifestations such as synovitis, granulomatosis, metallosis, etc. (8) and that involves materials such as metal, cement, and polyethylene. Metallosis involves the local deposition of metal wear debris, leading to gray/black discoloration of the periprosthetic soft tissues.

There are no studies directly associating the presence of popliteal lymphadenopathy (PLN) with complications arising from knee prostheses. However, the cellular and molecular mechanisms responsible for PLN expansion have been investigated preclinically in the contexts of chronic sterile infections, such as rheumatoid arthritis (RA), and PJI. In RA, numerous studies have demonstrated that morphological changes in lymph node architecture are primarily attributed to the accumulation of B lymphocytes within the germinal centers located in the lymph node cortex (9,10). Conversely, in PJI, other studies have shown that morphological alterations are due to the activation of T cells in the paracortex. This process is mediated by dendritic cells migrating from infected tissues to the lymph node to present antigens (11).

The molecular mechanisms underlying these processes cannot be directly investigated through clinical research due to ethical constraints associated with human subject research. Nonetheless, these mechanisms can be indirectly elucidated by examining the architectural changes in lymphadenopathys. At the imaging level, the subcapsular sinus, cortex, and paracortex correspond to the radiological cortex, while the medullary sinus corresponds to the radiologically observed fatty hilum, containing fat and efferent vessels (12).

Two retrospective studies that examined the size of PLNs in patients who underwent MRI, each including more than fifty individuals, revealed a maximum diameter ranging from 0.4 to 0.8 mm (13,14). The results of the studies experiments were similar. Furthermore, the presence of a PLN was reported to be largest in neonates and become smaller with age (13,14). Due to low antigenic stimulation, PLNs undergo replacement of lymphatic parenchyma with fatty tissue (fatty change). The popliteal fossa, having a high fat content, makes it difficult to differentiate the PLN from its surroundings, affecting its visibility on imaging techniques. Additionally, aside from fatty change, PLNs in some cases may be too small to be visible on US, MRI, or CT examinations, resulting in invisibility. This reveals that macroscopic detection of PLN may have high sensitivity for detecting pathology.

To our knowledge, there are no studies that evaluate PLNs in patients with knee prostheses. Based on our experience, we present some cases suggesting that an accurate radiological evaluation of PLNs could play a role in the diagnosis, follow-up, and management of patients who have undergone knee prosthesis surgery. We present this article in accordance with the CARE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-378/rc).

Case presentation

Three representative cases of patients who underwent knee prosthetic replacement due to septic or aseptic complications at our institution are presented. All patients had undergone prior CT scans, and the definitive diagnosis was established through pathological anatomy, delineating the septic or aseptic etiology.

All three patients exhibited symptoms of progressive pain and swelling, beginning between one and seven years after surgery, without presenting fever. Analytical parameters suggestive of infection, including erythrocyte sedimentation rate higher than 30 mm/h and C-reactive protein level >1 mg/dL, remained unaltered in all patients.

Patients underwent knee X-rays and complementary CT scans to detect periprosthetic osteolysis. Preoperative CT images were thoroughly examined in all cases, with a particular focus on the popliteal recess. The presence of PLNs and their number were carefully evaluated, considering intrinsic PLNs features such as low-density hilum, peripheral high-density cortex, and lymph node shape.

Radiological findings, including joint effusion and periprosthetic osteolysis, were observed in all cases. However, the presence of altered PLNs was not a consistent finding in all three cases. In one case, a knee prosthesis infection accompanied by three enlarged PLNs, of normal density, with a more rounded morphology and an absent fatty hilum was observed. Furthermore, imprecise margins of all PLNs and slight adjacent fat trabeculation were noted (Figure 1).

Figure 1 Knee radiograph and knee CT of Patient #1 showing radiological findings suggestive of prosthetic infection. (A) An AP knee radiograph depicting a unicompartmental prosthesis located in the medial compartment of the knee, revealing an area of osteolysis adjacent to the tibial component (arrow). (B) A knee CT scan in bone reconstruction and coronal plane confirming the observed area of osteolysis in the X-ray (arrow). (C,D) Knee CT in soft tissue reconstruction, presented in axial sections, illustrating abundant joint effusion with synovitis (*) and the presence of a PLN (circle). This PLN exhibits signs of infection, characterized by a rounded morphology, an absent fatty hilum, and imprecise margins with slight adjacent fat trabeculation. CT, computed tomography; AP, anteroposterior; PLN, popliteal lymphadenopathy.

A second case involved a knee prosthesis complicated by ALTR and a periprosthetic fracture, showing six PLNs with an increase in cortical density, with preserved fatty hilum, three of them increased in size (Figure 2). Finally, the last case exhibited aseptic loosening with the presence of three PLNs with an increase in cortical density and dense material in the popliteal recess, attributed to the migration of prosthetic debris (cement) (Figure 3). It was possible to verify through serial radiographic controls beforehand that the increase in density in the popliteal recess had been progressively increasing year by year (Figure 4). A detailed table of the characteristics in size, cortical thickness, and cortical density can be found in Appendix 1.

Figure 2 Knee CT of Patient #2 showing a periprosthetic fracture and radiological findings suggestive of metallosis. (A) Coronal CT of the knee in bone reconstruction revealing a femoral periprosthetic spiral fracture (thin arrow) and extensive areas of lysis at the cement-bone interface (thick arrow). (B,C) Axial CT of the knee in soft tissue reconstruction displaying significant joint effusion (*) and the presence of multiple dense PLNs (circles). The increase in density is observed in the cortex of the lymph node, while the fatty hilum remains preserved. CT, computed tomography; PLN, popliteal lymphadenopathy.

Figure 3 Knee radiograph and knee CT of Patient #3 showing radiological findings suggestive of metallosis and migration of cement to the popliteal recess. (A) Lateral knee X-ray revealing a total knee prosthesis with highly dense areas in the popliteal fossa (arrow). (B,C) Axial CT scans of the knee illustrating significant joint effusion (*). Highly dense areas in the popliteal fossa (arrows), which correspond to migrated cement, and dense PLNs (circles). The increase in density of the PLNs is also observed in the cortex of the lymph node, with preservation of the fatty hilum. CT, computed tomography; PLN, popliteal lymphadenopathy.

Figure 4 Progressive lateral knee radiographs of Patient #3 performed annually to evaluate prosthetic loosening demonstrate an increase in the density of the popliteal recess each year (arrows), corresponding to the migration of cement to the popliteal recess. No PLNs are observable in the radiographs. Images (A) and (B) serve as controls to evaluate prosthetic loosening, while (C) has already undergone prosthetic replacement. PLN, popliteal lymphadenopathy.

In one case, the diagnosis of septic loosening was made following the Philadelphia criteria (15) and it was histopathologically confirmed by the presence of abundant synovial proliferation and at least five neutrophils per high-power field (×400) found in at least five separate microscopic fields (Figure 5).

Figure 5 Histologic features from Patient #1, who underwent prosthetic replacement due to clinical suspicion of prosthetic infection. The pathological anatomy confirmed that it was an infectious process. (A) Synovial-like tissue with wear debris reaction (arrow) and numerous neutrophils (circle) indicative of infection (hematoxylin-eosin, 20× magnification). (B) Granulation tissue with numerous neutrophils (circle) indicative of infection (hematoxylin-eosin, 40× magnification).

The other two cases were histopathologically diagnosed with ATLR, characterized by the presence of multinucleated cells and prosthetic debris (16,17) (Figures 6,7).

Figure 6 Histologic features from Patient #2, obtained during the prosthetic replacement performed due to periprosthetic fracture. The pathological anatomy confirmed the presence of a metallosis-type ATLR, with numerous metal particles found within the cytoplasm of macrophages. (A) Synovial-like tissue with metallosis characterized by innumerable particles of metal alloy in the cytoplasm of macrophages (circles) (hematoxylin-eosin, 20× magnification). (B) Connective tissue with macrophages containing metal particles (circles). Note the presence of foreign body giant cells (arrows), indicative of ATLR (hematoxylin-eosin 40× magnification). ATLR, adverse tissue local reaction.

Figure 7 Histologic features from Patient #3, obtained during the prosthetic replacement performed due to prosthetic loosening, which show the abundant presence of migrated material in the popliteal recess, corresponding to the high-density areas observed in the CT scan. Additionally, some macrophages with metal in their cytoplasm can be observed, related to additional changes due to metallosis. (A) Synovium with prosthetic wear debris reaction (hematoxylin-eosin, 10× magnification). (B) Bone cement (*) surrounded by foreign body type giant cells (arrows). Note the presence of macrophages containing metal particles (circles) (hematoxylin-eosin, 40× magnification). CT, computed tomography.

Clinical and radiological features of each patient are described in detail as a supplementary file (Appendix 2). All procedures conducted in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and adhered to the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patients for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Regarding the previously described complications, none of the patients exhibited specific clinical features suggestive of infection, loosening, or ALTR. As indicated in the literature, clinical diagnosis alone is insufficient for detecting PJI (18). According to Shohat et al. (19), fever and erythema are highly specific (96.21% and 94.70%), but their sensitivity is low (40.82% and 42.86%), limiting their utility in diagnostic algorithms. Pain, while highly sensitive (96.6%), is the least specific symptom (5.3%), often overlapping with aseptic failure. This underscores the pivotal role of radiological testing.

The presence of altered PLNs could be observed in our patients who presented with both infection and ALTR. CT scans are valuable for detecting inguinal and/or iliac lymphadenopathy, a significant predictor of hip prosthesis infection (6). Additionally, CT may identify PLNs and their morphologic features. Beyond simply reporting the number of PLNs, it is crucial to conduct a comprehensive assessment of their morphological features. Key characteristics to consider include size, cortical thickness, peripheral high-density cortex, and peripheral fat trabeculation.

We have compared our findings with those from the referenced studies. Musters et al. (14) provided measurements based on the major diameter, whereas Moon et al. (13) focused on the minor diameter. The mean minor diameter observed in our cases was 5.45±2.79 mm, comparable to the findings of Moon et al., who reported a mean of 4.96±2.4 mm in their series of 222 patients. Conversely, the mean major diameter was 9.56±4.16 mm, significantly larger than the results reported by Musters et al., who found a mean of 5.7±0.15 mm in their series of 150 patients.

It is important to note that these studies are not directly comparable due to our limited sample size of three patients. Moreover, Musters et al. indicated that there was no relation between different clinical situations, including inflammation and malignancy, and the presence of PLNs. However, their study had limitations, primarily the small size of the cohorts in the different groups. Our study, conversely, focused specifically on cases that underwent prosthetic knee replacement, rather than a general population as in their study. We noted intrinsic node characteristics such as cortical density and cortical thickness, not just global node size. We consider our cases to be an important preliminary observation that can serve as a starting point for further research on the role of PLNs as promising imaging signs to detect different prosthetic complications.

We also advocate for a more detailed characterization of lymph node morphology and for the establishment of consensus guidelines to determine whether the minor or major diameter should be studied. We recommend the conduct of new studies with larger patient cohorts, taking into account other clinical characteristics such as age, medical antecedents, and surgical antecedents.

In reference to the expansion of the PLN, it was the cortex that increased in size both in cases of ATLR and PJI. Characteristically, at the metal-bone interface, macrophages become activated after phagocytosing a large number of particles, forming giant cells, many of which are unable to move and migrate. This may correspond to areas of periprosthetic osteolysis at that level. However, some of these cells and particles migrate via the lymphatic pathway to local lymph nodes. It is within the cortex of these lymph nodes where complex mechanisms occur in the immune response, involving the activation of T and B cells (20).

Moreover, the cortical area of the PLNs adjacent to the knee prosthesis in cases of ATLR is phenotypically denser than those adjacent to PJIs, that has been correlated with histopathological evidence of metal particles within macrophages in the enlarged lymph nodes. This represents a novel radiological finding that holds significant potential for enhancing the differential diagnosis of complications associated with knee prostheses.

While metal particle migration to the articular synovium is documented (8), to our knowledge, there are no reported cases of lymphatic metallosis reported in imaging techniques. According to our theory, it was the cortex that showed an increased density by CT in the two cases of ATLR because there is where the macrophages stay.

However, material migration, whether through contiguous pathways or via lymphatics or vessels from the prosthesis to the popliteal recess, can result in imaging patterns resembling lymphadenopathy, thereby posing a diagnostic challenge for radiologists.

In conclusion, recognizing the utility of CT in pre-surgical assessments for knee replacement complications, our center now performs more CT scans. X-rays typically cannot detect PLNs, possibly explaining why PLNs had not been previously described as indicative of knee prosthetic complications. Preliminary findings are presented to prompt future population analyses and a more exhaustive study.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: With the arrangement by the Guest Editors and the editorial office, this article has been reviewed by external peers.

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-378/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-378/coif). The special issue “Advances in Diagnostic Musculoskeletal Imaging and Image-guided Therapy” was commissioned by the editorial office without any funding or sponsorship. X.T. served as the unpaid Guest Editor of the issue. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institution and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patients for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Price AJ, Alvand A, Troelsen A, Katz JN, Hooper G, Gray A, Carr A, Beard D. Knee replacement. Lancet 2018;392:1672-82. [Crossref] [PubMed]
2. Khan M, Osman K, Green G, Haddad FS. The epidemiology of failure in total knee arthroplasty: avoiding your next revision. Bone Joint J 2016;98-B:105-12. [Crossref] [PubMed]
3. Fehring TK, Odum S, Griffin WL, Mason JB, Nadaud M. Early failures in total knee arthroplasty. Clin Orthop Relat Res 2001;315-8. [Crossref] [PubMed]
4. O'Toole P, Maltenfort MG, Chen AF, Parvizi J. Projected Increase in Periprosthetic Joint Infections Secondary to Rise in Diabetes and Obesity. J Arthroplasty 2016;31:7-10. [Crossref] [PubMed]
5. Hochman MG, Melenevsky YV, Metter DF, Roberts CC, Bencardino JT, Cassidy RC, Fox MG, Kransdorf MJ, Mintz DN, Shah NA, Small KM, Smith SE, Tynus KM, Weissman BN. ACR Appropriateness Criteria(®) Imaging After Total Knee Arthroplasty. J Am Coll Radiol 2017;14:S421-48. [Crossref] [PubMed]
6. Isern-Kebschull J, Tomas X, García-Díez AI, Morata L, Ríos J, Soriano A. Accuracy of Computed Tomography-Guided Joint Aspiration and Computed Tomography Findings for Prediction of Infected Hip Prosthesis. J Arthroplasty 2019;34:1776-82. [Crossref] [PubMed]
7. Isern-Kebschull J, Tomas X, García-Díez AI, Morata L, Moya I, Ríos J, Soriano A. Value of multidetector computed tomography for the differentiation of delayed aseptic and septic complications after total hip arthroplasty. Skeletal Radiol 2020;49:893-902. [Crossref] [PubMed]
8. Kassarjian A, Isern-Kebschull J, Tomas X. Postoperative Hip MR Imaging. Magn Reson Imaging Clin N Am 2022;30:673-88. [Crossref] [PubMed]
9. Li J, Kuzin I, Moshkani S, Proulx ST, Xing L, Skrombolas D, Dunn R, Sanz I, Schwarz EM, Bottaro A. Expanded CD23(+)/CD21(hi) B cells in inflamed lymph nodes are associated with the onset of inflammatory-erosive arthritis in TNF-transgenic mice and are targets of anti-CD20 therapy. J Immunol 2010;184:6142-50. [Crossref] [PubMed]
10. Kuzin II, Kates SL, Ju Y, Zhang L, Rahimi H, Wojciechowski W, Bernstein SH, Burack R, Schwarz EM, Bottaro A. Increased numbers of CD23(+) CD21(hi) Bin-like B cells in human reactive and rheumatoid arthritis lymph nodes. Eur J Immunol 2016;46:1752-7. [Crossref] [PubMed]
11. Sokhi UK, Xia Y, Sosa B, Turajane K, Nishtala SN, Pannellini T, Bostrom MP, Carli AV, Yang X, Ivashkiv LB. Immune Response to Persistent Staphyloccocus Aureus Periprosthetic Joint Infection in a Mouse Tibial Implant Model. J Bone Miner Res 2022;37:577-94. [Crossref] [PubMed]
12. Uematsu T, Sano M, Homma K. In vitro high-resolution helical CT of small axillary lymph nodes in patients with breast cancer: correlation of CT and histology. AJR Am J Roentgenol 2001;176:1069-74. [Crossref] [PubMed]
13. Moon HJ, Suh JS, Lee SH. Magnetic resonance appearance of normal popliteal lymph nodes: location and relationship of number, fatty change, and size of the lymph nodes with aging. Korean J Radiol Soc 2002;47:665-71.
14. Musters GD, Kleipool RP, Bipat S, Maas M. Features of the popliteal lymph nodes seen on musculoskeletal MRI in a Western population. Skeletal Radiol 2011;40:1041-5. [Crossref] [PubMed]
15. Goswami K, Parvizi J, Maxwell Courtney P. Current Recommendations for the Diagnosis of Acute and Chronic PJI for Hip and Knee-Cell Counts, Alpha-Defensin, Leukocyte Esterase, Next-generation Sequencing. Curr Rev Musculoskelet Med 2018;11:428-38. [Crossref] [PubMed]
16. Tallroth K, Eskola A, Santavirta S, Konttinen YT, Lindholm TS. Aggressive granulomatous lesions after hip arthroplasty. J Bone Joint Surg Br 1989;71:571-5. [Crossref] [PubMed]
17. Slullitel PAI, Brandariz R, Oñativia JI, Farfalli G, Comba F, Piccaluga F, Buttaro M. Aggressive granulomatosis of the hip: a forgotten mode of aseptic failure. Int Orthop 2019;43:1321-8. [Crossref] [PubMed]
18. Parvizi J, Schmidt MG, Goldstein EJC. Periprosthetic Joint Infection. N Engl J Med 2023;388:1439. [Crossref] [PubMed]
19. Shohat N, Goswami K, Tan TL, Henstenburg B, Makar G, Rondon AJ, Parvizi J. Fever and Erythema are Specific Findings in Detecting Infection Following Total Knee Arthroplasty. J Bone Jt Infect 2019;4:92-8. [Crossref] [PubMed]
20. Gretz JE, Anderson AO, Shaw S. Cords, channels, corridors and conduits: critical architectural elements facilitating cell interactions in the lymph node cortex. Immunol Rev 1997;156:11-24. [Crossref] [PubMed]