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Abstract
Even though the average surgical pathologist reviews far more non-neoplastic orthopaedic pathology on a daily basis, most current research focuses on rare tumours and their even less frequent molecular events. Our experiences among consults and focused conferences strongly suggest that there remains a practice gap regarding knowledge and diagnosing specific non-neoplastic orthopaedic conditions. One of the most frequent intraoperative consultations performed in the USA, among both academic and private institutions, relates to revision arthroplasty and the determination of infection in periprosthetic joints. Pathologists play a critical role in this algorithm, helping determine intraoperatively whether patients require antibiotic spacers prior to reimplantation. Many pathology departments have abandoned the examination of arthroplasty specimens because they (and their surgeons) mistakenly believe there is little clinically relevant information to be gained by thorough pathological examination. However, recent literature has challenged this concept, emphasising the importance of distinguishing avascular necrosis (from osteoarthritis/degenerative joint disease with secondary osteonecrosis), subchondral insufficiency fracture, septic arthritis (from so-called ‘sterile’ osteomyelitis/pseudoabscesses), underlying crystalline diseases and incidental/occult neoplasia. Histological evaluation of historically insignificant orthopaedic specimens, such as tenosynovium from carpal tunnel syndrome/trigger finger, is now seen as valuable in early diagnosis of cardiac amyloidosis. Not infrequently, orthopaedic conditions like haemosiderotic synovitis, osteocartilaginous loose bodies or rheumatoid nodules, may histologically mimic bona fide neoplasms, notably diffuse tenosynovial giant cell tumour, synovial chondromatosis and epithelioid sarcoma, respectively. Here is a review of the more common non-neoplastic orthopaedic conditions, those likely to be examined by the practising surgical pathologist, with updates and guidelines for establishing clinically relevant diagnoses.
- ARTHRITIS
- Carpal Tunnel Syndrome
- Morphological and Microscopic Findings
- OSTEOARTHRITIS
- Pathology, Surgical
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- ARTHRITIS
- Carpal Tunnel Syndrome
- Morphological and Microscopic Findings
- OSTEOARTHRITIS
- Pathology, Surgical
Introduction
Age-related fractures are projected to exceed over 3 million in 2025.1 2 The prevalence of degenerative joint disease/osteoarthritis (DJD/OA) worldwide is 7%, affecting almost 500 million people, with over 32 million residing in the USA.3 The Centers for Disease Control and Prevention reports that in the USA alone there are approximately 719 000 total knee arthroplasties and 332 000 total hip arthroplasties (THA) annually, and these numbers do not reflect total shoulder replacements and other similar surgeries in the hands and feet.4 Although the most common reason for THA is DJD/OA, avascular necrosis (AVN) of the femoral head accounts for between 5% and 18% of these surgeries in the USA5 and is the third most common cause for THA in the UK.6 7 Additional non-neoplastic specimens likely to be encountered by the average surgical pathologist include but are not limited to digit and limb amputations, often due to non-healing ulcers, gangrene or osteomyelitis (OM), non-osteochondroma exostoses, entheses, trigger finger and carpal tunnel syndrome biopsies, and loose bodies. If one compares the sum of all the above potential non-neoplastic diseases with that of the incidence of primary bone tumours, one must question why there is not a greater focus in surgical pathology on non-neoplastic musculoskeletal diseases. The American Cancer Society’s estimate for 2023 was that 3970 people in the USA would be diagnosed with a primary bone sarcoma, a number that could be handled by one group of pathologists at a single large institution.8 It is our hope that this review will provide the practising pathologist with updates and helpful diagnostic tools regarding the more commonly encountered non-neoplastic orthopaedic conditions.
Degenerative joint disease/osteoarthritis
DJD/OA is the most common form of joint disease worldwide, accounting for most joint replacements.9 10 Simply put, it is a disease of articular cartilage, characterised by progressive erosion and loss of the articular cartilage surface with secondary changes to the underlying subchondral bone and surrounding soft tissue structures. DJD/OA may be a primary disorder (without a predisposing factor or disease) or occur secondary to other pre-existing conditions, including trauma, inflammation, crystal deposition disease, osteonecrosis and congenital abnormalities. Most arise as a primary condition, possibly related to ageing and overuse, with most patients older than 60 years of age. However, excessive joint use alone does not necessarily lead to DJD/OA, and some have suggested that underutilisation (or joint disuse) may be an even greater risk factor.11 Although any joint may be affected, DJD/OA more frequently involves the knees and hands in women and the hips in men. Clinical symptoms include joint pain, often worse in the morning, stiffness and reduced the range of motion. Patients with secondary DJD/OA report similar symptoms but often present at an earlier age.
Radiologically, in the initial stages of DJD/OA, joint space narrowing, due to articular cartilage loss, is typically observed. With progression and continued loss of articular cartilage, subchondral bone sclerosis and cyst formation may become evident. Osteophytes frequently develop peripherally at the non-weight-bearing areas and may contribute to displacement of the joint space.
Pathological changes parallel what is seen with radiology with the earliest stages involving mainly the articular cartilage, with vertical and horizontal tears/fissures of the superficial cartilage matrix, associated with attempts at repair, ‘cloning’ (discrete nests of chondrocytes) of the adjacent proliferating chondrocytes. With progression, the articular surface is ultimately sloughed, exposing the underlying subchondral bone, which becomes thickened and polished (eburnated) at the load-bearing areas of the joint (figure 1A,B). Below the subchondral bone, the intertrabecular zones become progressively fibrotic, often developing myxoid degeneration and subchondral cyst formation (figure 1C, D). When necrosis develops secondary to severe DJD, it generally is not identified grossly and remains confined to the area of eburnated and sclerotic subchondral bone (figure 1E,F), helping to separate the process from primary AVN (to be discussed in greater detail later). Aggregates of lymphocytes and plasma cells may be present. Rarely, subchondral acute inflammation and even ‘pseudoabscesses’, often associated with cyst formation, mimic an infectious process12 13 (f igure 2A,B). Nevertheless, in the absence of penetrating trauma or hardware involving the affected joint, such findings should not be interpreted as acute OM or septic arthritis and more likely represent a form of non-infectious sterile inflammation. Systemic symptoms of infection and bacteraemia are absent in DJD pseudoabscess. Peripherally, at the non-weight-bearing surface of the joint, osteophytes often develop. Portions of sloughed cartilage and subchondral bone or dislodged osteophytes may remain within the joint space, ultimately forming so-called ‘loose bodies’. In many instances, mild chronic synovitis, papillary synovial hyperplasia or detritic synovitis accompany the changes in the bone and articular cartilage.
Degenerative joint disease/osteoarthritis (DJD/OA): (A) Gross specimen of DJD/OA illustrating an irregular variable cartilage surface, with proliferation and osteophyte formation peripherally and loss of articular cartilage more centrally (eburnation). (B) Early DJD/OA is characterised by chondrocyte cloning, a distinct clustering of chondrocyte proliferation indicative of a response to injury. Similar features also are seen in osteophytes, at the non-weightbearing surfaces. (C) Evolving and early DJD/OA with fibrillation/fissures in the articular cartilage surface. (D) With progression, there is complete loss of the articular surface, with subchondral sclerosis, fibrosis of the intertrabecular zones with myxoid degeneration and subchondral cyst formation. (E) (Low power) and (F) (high power): Severe DJD sometimes is associated with secondary osteonecrosis. In contrast to AVN, the necrotic area is generally not visible grossly and confined to the area of eburnation and sclerotic subchondral bone. AVN, avascular necrosis
Pseudoabscess in DJD/OA: (A) (low power) and (B) (high power): Aggregates of neutrophils and necrotic debris, sometimes surrounded by histiocytes, may mimic infectious osteomyelitis. In the absence of an obvious infection, these foci in routine arthroplasty specimens, especially DJD/OA, have been referred to as pseudoabscesses or ‘sterile’ osteomyelitis. DJD/OA. degenerative joint disease/osteoarthritis.
‘Loose bodies’
As used by surgeons, the term ‘loose body’ incorporates a wide variety of lesions within the joint, technically referring to free-floating tissue without an obvious connection (or blood supply). By far the most common ‘loose body’ are the osteocartilaginous (osteoarticular) loose bodies (OLB) associated with severe DJD/OA.14 15 Grossly and histologically, OLB displays concentric layering (resembling the cut surface of a tree trunk), composed of variable amounts of viable proliferating cartilage (remains alive due to nutrients from synovial fluid) and necrotic bone. Individual proliferating chondrocytes, while often quite cellular and compact, do not exhibit a clustering growth pattern nor significant cytological atypia (figure 3A,B). Quite often, the adjacent synovium, if biopsied, reveals evidence of osteocartilaginous metaplasia.
Loose bodies; Osteocartilaginous loose body (OLB), synovial chondromatosis (SC) and osteochondritis dissecans (OCD): (A, B) Low and high-power magnification view of OLB, demonstrating concentric layering pattern of viable cartilage and necrotic bone. The cartilage does not show cytological atypia or a clustered growth pattern. (C) Lateral plain film of SC, characterised by multiple articular and periarticular nodules with calcifications, also within a popliteal cyst. (D) Low-power view of SC, characterised by nodules of hyaline cartilage surrounded by soft tissue lined by synovium. (E) Individual chondrocytes are arranged in variably small clusters and often show significant cytological atypia. (F) Plain film, OCD in femoral condyle. Fragmented bone and cartilage are still partially attached to the articular surface of the lateral aspect of medial condyle, classic location (red circle). If the process is not halted, the fragment may detach from the joint leaving a crater-shaped, radiolucent defect in the articular surface. (G) OCD: Low-power magnification view of the osteochondral fragment with viable articular cartilage and (H) attached necrotic bone. Note the absence of the distinct layering of OLB or clustering growth pattern of SC.
OLB should be distinguished from the far less common synovial chondromatosis (SC), a benign but locally aggressive hyaline cartilage neoplasm occurring within the synovium, bursa and/or tendon sheaths surrounding joints. Compared with OLB, the ‘loose bodies’ of SC are typically more uniform in size and shape, occur in the absence of DJD/OA and typically involve the large joints of younger patients, between 30 and 50 years of age, with males affected twice as often as females.16 17 We should point out that other smaller joints also may be involved, including the temporomandibular joint18 19; facet joints of the vertebrae20; and hands and feet.21 Radiologically, SC usually presents as multiple, articular and periarticular nodules with varying degrees of calcifications (figure 3C). Erosion of adjacent bony cortex is sometimes observed.22
Histologically, the nodules of SC are mildly to moderately cellular and often at least partially, covered by a synovial lining. Unlike OLB, Individual chondrocytes are arranged in variably small clusters and often show significant cytological atypia (figure 3D,E). Central enchondral ossification is not uncommon, but the typical ‘layering’ observed with OLB is absent. The clustering of the chondrocytes in SC may resemble that seen in DJD, referred to as ‘cloning’. Unlike cloning in DJD, the clustering pattern of chondrocytes in SC is uniformly present through the tissue and the individual chondrocytes exhibit significant atypia. Synovial chondrosarcoma, heralded by prominent myxoid degeneration, loss of the clustered chondrocyte growth pattern, occasional bone permeation and spindling of the tumour cells at the periphery of the nodules, is extraordinarily rare.16 23 24
Up to 50% of SC harbour FN1::ACVR2A gene rearrangements, and IDH1 and IDH2 mutations are absent.25–27 Fusion status does not distinguish SC from synovial chondrosarcoma. Local recurrences occur in up to 20% of patients. The presence of multiple local recurrences occurring within short intervals should raise the suspicion of synovial chondrosarcoma.28
Osteochondritis dissecans (OCD), fragmentation of small focus of subchondral bone, classically affects children and adolescents particularly physically active males. The aetiology of OCD is not fully elucidated with theories proposing repetitive microtrauma, ischaemia, genetic predisposition and defective ossification. The knee (lateral aspect of the medial femoral condyle) is the most common affected joint (75%), and elbow (capitulum), ankle (talus), femoral head, distal tibia and wrist are less frequently involved. In the initial stages, fragmented bone remains in place by the intact overlying articular cartilage. With progression the fragmented bone undergoes necrosis and gets detached from the parent bone. Additionally, as a result of losing support from the underlying bone, the articular cartilage softens leading to further instability of the bone fragment. If the process is not arrested, eventually fragmented bone and cartilage detach from the joint as loose bodies leaving a crater-shaped, radiolucent defect in the articular surface29 30 (figure 3F). Damaged articular surface is prone to early DJD/OA, if left untreated. The morphological features of the arthroscopy specimen vary depending on stage of OCD. Histological findings are typically those of an osteochondral fragment, consisting of articular cartilage with no to variable amounts of attached necrotic bone, without the distinct layering of OLB (figure 3G,H). For all practical purposes, if a pathologist receives a specimen labelled ‘loose body’ in a teenager, especially if associated with the knee, it is an OCD until proven otherwise.
Avascular necrosis
AVN, also known as aseptic necrosis, may occur in any bone, can be traumatic or atraumatic but, especially in the hip, is pathologically defined as subchondral osteonecrosis in the absence of hip dislocation/fracture and infection. Although AVN may occur in other bones, including the proximal humerus and distal femur, it is most commonly seen in the femoral head. New cases of femoral head AVN in the USA range between 10 000 and 20 000 annually, usually affecting patients in their late 30s and early 40s.31 32 Risk factors associated for AVN include trauma, chronic steroid use, autoimmune disease especially systemic lupus erythematous (SLE), decompression sickness (diver’s disease), radiation, alcohol use, organ transplant particularly kidney, sickle cell anaemia, leukaemia and storage diseases such as Gaucher’s disease. The exact mechanism by which these diseases result in blood supply damage and critical ischaemia is unclear.32 Plain films usually show changes with more advanced disease when non-surgical intervention is less likely to be successful. The frog leg lateral view (hips abducted) may display the classic crescent sign, indicative of subchondral structural collapse. This is diagnostic of AVN, but, if not clinically suspected, this view is often not obtained, missing this characteristic finding (figure 4A). MRI tends to be the most sensitive imaging study of AVN, particularly in the early stages, but specific findings depend on the extent of necrosis and chronicity of AVN. A low signal intensity band on T1 and T2-weighted images surrounding the ischaemic bone and a second high signal inner band presumed to represent reactive interface (double-line sign) are often evident. In advanced stages, necrotic bone has a signal similar to fluid and secondary features such as collapse of the femoral head, joint effusion and loss of cartilage are appreciated33 (figure 4B). Nevertheless, clinical and radiological findings are not entirely specific to AVN, and most patients undergoing hip arthroplasty have only plain films, usually not including the frogview, for preoperative imaging and evaluation. Based on large studies from the Cleveland Clinic and Hospital for Special Surgery, between 2.9% and 4.0% of all cases suspected to represent DJD/OA are found to have primary AVN on definitive pathological evaluation.34 35 Most but not all such patients appear to be older and lack obvious risk factors for AVN (idiopathic). Conversely, between 16% and 19% of all patients clinically suspected to have AVN are found to have no evidence of osteonecrosis, instead showing advanced DJD/OA.34 35
Avascular necrosis: (A) Lateral frog leg view X-ray of left hip revealing the classic crescent sign (subchondral fracture/separation), marked by yellow arrows. (B) MRI of right humerus: There is serpiginous T2 hyperintense and hypointense signal of the superomedial humeral head involving a geographic area (yellow arrows). There is collapse of the humeral head with further progression of delamination of the cartilage. (C) Gross specimen, showing detached articular surface and wedge-shaped chalky underlying necrosis. (D) Low-power view, demonstrating articular cartilage detachment, with minimal attached bone, and large necrotic area. Note that the necrosis extends underneath intact (non-detached) articular cartilage as well, an important distinction from DJD/OA with secondary osteonecrosis. (E) Interface of necrotic area (upper left) with early reparative changes and non-necrotic intramedullary bone (lower right). (F) High-power view of avascular necrosis with necrotic marrow (adipocyte tombstones) and bone with empty lacunae. DJD/OA, degenerative joint disease/osteoarthritis.
In classic examples, gross examination reveals lifting/separation of the articular surface from the underlying bone (subchondral fracture), with an underlying wedge-shaped area of chalky yellow discolouration, surrounded by a rim of hyperaemia (figure 4C). Histologically, the overlying cartilage is viable (receives nutrition from the synovial fluid), even when separated, and often has a small attached segment of necrotic bone (dependent on adequate blood flow from an arterial supply). The necrosis is most obvious in the intertrabecular marrow and fat, as the bone trabeculae may still have scattered osteocytes remaining within lacunae. Various degrees of repair and fibrosis are appreciated at the periphery. Importantly, the grossly visible necrotic area extends beyond the subchondral fracture also involving trabecular bone and marrow underlying intact articular cartilage, an important distinction between AVN and DJD/OA with secondary osteonecrosis (figure 4D–F).
Subchondral insufficiency fracture
An important differential diagnosis to consider for both DJD/OA with secondary osteonecrosis and AVN is subchondral insufficiency fracture (SIF). SIF as a concept was introduced in 199636 referring to small fracture/microfractures occurring due to deficient elastic resistance underneath the articular cartilage. Classic clinical setting is elderly women with osteoporosis; however, it may also affect younger adults, particularly active and obese males.37–39 Other risk factors include renal and kidney transplant and SLE. Unlike DJD/OA and AVN, SIF patients report acute onset pain usually as a result of minor injury such as twisting or long walks with heavy bags. Initial plain films are normal, and MRI is the modality of choice for diagnosis of SIF if clinically suspected. Characteristic MRI findings include diffuse oedema and band-like low signal intensity corresponding to a fracture line.40 41 Early diagnosis prior to surgery may allow for native joint sparing and conservative management. SIF typically shows little to no obvious gross changes, other than very focal subchondral hyperaemia. Histological evaluation reveals a superficial articular cartilage fracture and focal ‘microscopic’ necrosis, limited to the area of fracture and superficial subchondral bone, sometimes associated with repair and fracture callus (figure 5A–C). Such small largely microscopic areas of fracture/necrosis should not be confused with primary AVN (always much larger and evident grossly) or DJD/OA with secondary osteonecrosis.42 43 In the experience of the Hospital for Special Surgery, pathological examination noted that SIF accounted for the largest number of discrepant pathological diagnoses for specimens labelled as ‘DJD’ in the hips.23
Subchondral insufficiency fracture: (A) Microfracture in surface cartilage. (B, C) Low-power and high-power magnification view of the underlying bone and marrow showing a linear subchondral area of microscopic necrosis and reparative changes/fracture callus.
Destructive arthropathy of the femoral head
Rapidly progressive/rapidly destructive arthritis represents a rapidly progressive and non-infectious degenerative change, occurring over a short period of time (weeks to months), culminating in femoral head collapse. There is significant overlap with so-called neuropathic joint (Charcot joint); however, underlying mechanisms remain unclear.44–47 The disease occurs mostly in elderly women, involving unilateral or bilateral hip joints with progressive destruction of the joint (within weeks to months).48–50 Radiologically, rapid loss of articular surface with joint space narrowing is characteristic, and collapse of the femoral head may be appreciated. The gross examination is striking, as the articular surface is often completely lost with subchondral bone destruction/collapse, leading to a markedly misshapen femoral head. Osteophytes are not formed due to the short time interval. Additional histological findings, beyond loss of the articular cartilage, include foci of non-geographically distributed osteonecrosis, trabecular fractures and fracture callus/remodelling, necrotic bone fragments surrounded by histiocytic granulomatous inflammation and joint detritus in the intertrabecular spaces. Abundant bony detritus also accumulates in the synovium (detritic synovitis), always an indication of a rapidly destructive arthropathy (figure 6A–C).
Destructive arthropathy of the femoral head: (A, B) Low-power and high-power views show abundant bony detritus accumulating in the synovium, often associated with a significant histiocytic giant cell response (detritic synovitis). (C) The articular surface is sloughed and subchondral sclerosis is limited due to the rapid pace of the joint destruction. Similar detritus, as seen in the synovium, accumulates in intertrabecular spaces associated with multiple foci of necrosis and fracture repair.
Bone infections (OM)
OM, inflammation/infection of the bone, may be challenging to diagnose on biopsy material and difficult to treat and eradicate. Generally, OM can occur due to ‘primary’ haematogenous seeding (predominantly paediatric patients)51 or be ‘secondary’ due to a contiguous infection/inflammation of the adjacent soft tissue or wound (eg, stepping on a nail, long-standing ulcer). Underlying risk factors include diabetes, peripheral vascular disease, penetrating trauma, intravenous drug use, immune suppression and foreign body implants, including heart valves and joint replacements. Patients with chronic renal failure on haemodialysis are at increased risk of OM, most commonly involving the spine and ribs. People who use IV drugs may develop OM in unusual anatomic locations, including the sternoclavicular joints and the symphysis pubis, frequently due to Pseudomonas aeruginosa. Patients with sickle cell anaemia are at increased risk for developing Salmonella OM. The radiologic findings are often not apparent early in the onset but may include ill-defined lucent and permeative areas within the long bone metaphysis (figure 7A). With progression and more extensive intramedullary bone destruction, periosteal reactions occur, sometimes associated with soft tissue extension (abscess), mimicking a primary sarcoma. Occasionally, a portion of necrotic bone (sequestrum) forms a radiodense area within the lytic defect.
Bone infections (osteomyelitis, OM): (A) Plain X-ray of acute OM revealing ill-defined lucent and permeative areas within the distal tibial metaphysis (yellow arrows). Note the open physis indicative of an immature skeleton. (B) Acute OM is characterised by significant neutrophilic inflammation, replacing the bone marrow and associated with bone necrosis and active resorption, with significant osteoclastic activity. (C) With progression and/or absence of adequate therapy, acute OM may progress to chronic OM, with patchy intertrabecular fibrosis, bone remodelling and lymphoplasmacytic inflammation. (D) A case of Mycobacterium tuberculosis OM (Pott disease) with characteristic necrotising granulomatous inflammation (chronic granulomatous OM).
Historically, OM can be classified temporally as acute (within 2 weeks of onset), subacute (within one to several months) and chronic (usually beyond several months).52 Acute haematogenous OM is more common in children, typically affecting the long bone metaphysis.53 54 In addition to localised signs and symptoms such as tenderness, decreased range of motion and joint effusion, childhood haematogenous OM also is characterised by systemic presentations of fever, irritability and malaise. Adult OM is often ‘secondary’, contiguous and due to underlying risk factors.
Definitive diagnosis hinges on positive microbial studies, either blood or bone culture, and histological changes in bone biopsy. Rendering an actual diagnosis of ‘OM’ on histology alone is somewhat controversial. However, we believe that the diagnosis can be rendered provided the following criteria are met: (1) inflammation, (2) bone destruction and/or evidence of damage and remodelling and (3) clinical context (eg, not typically incidental but clinically suspected). In acute OM, neutrophils predominate, associated with bone necrosis and active resorption, with significant osteoclastic activity (figure 7B). As OM progresses, a lymphoplasmacytic and histiocytic infiltrate begins to dominate (chronic OM). In addition, there is marrow fibrosis, indicative of repair/scarring and chronicity. However, such histological changes in chronic and/or resolving OM may be quite non-specific and must be correlated within the clinical context to be diagnostic (figure 7C). Rarely, granulomatous OM is caused by Mycobacterium tuberculosis, atypical mycobacterium complex and fungi (figure 7D). Systemic sarcoidosis involving bones may mimic granulomatous infectious OM. In cases suspected of systemic sarcoidosis, we recommend the following sign-out approach: ‘Granulomatous OM (see comment)’, and in the comment, we would elaborate on sarcoidosis as a likely differential diagnosis particularly if the granulomas are well formed and non-necrotic, lacking any micro-organisms on AFB or GMS special stains.
The treatment of OM usually involves surgical debridement and variably long courses of ntravenous antibiotics.
Periprosthetic joint infection
Total large joint arthroplasty/replacement is one of the most common and successful surgical procedures performed in the USA.35 Failed joint replacements are generally the result of either mechanical wear (aseptic loosening) or periprosthetic joint infection (PJI) (septic loosening). At surgery, this distinction has immediate clinical consequences, as the orthopaedic surgeon must decide, based on all available information, whether to reimplant a new prosthesis in one or two stages, with the latter incorporating an antibiotic delivery device/spacer (figure 8A). In cases of septic loosening, the use of an antibiotic spacer appears to result in an improved clinical outcome.
Periprosthetic joint infection: (A) Depending on the patient and the clinical scenarios, different types of antibiotic spacers (antibiotic delivery devices) may be used, from left to right: Static, dynamic and mould injected (courtesy of Dr Luke Nystrom, Cleveland Clinic Orthopaedic Oncology). (B) (H&E) and (C) (polarised) Polyethylene wear debris, consisting of fine granular to thread-like particles, strongly birefringent, generally observed within histiocytes, some multinucleated, is typically the dominant foreign material seen in aseptic loosening. Asteroid body, not exclusive to sarcoidosis, is seen at the centre, a feature rarely seen as a result of arthroplasty wear debris and granulomatous reactions. (D) Metallic wear debris manifesting as small particles of dark black discolouration, free and within histiocytes. The most likely areas to observe ‘significant’ acute inflammation are in loose granulation tissue-like areas (E) and the tissue at the fibrin interface (periprosthetic interface) (F) Less commonly, significant acute inflammation is seen in more fibrotic areas (G).
Routine histological findings in tissue from large joint revision arthroplasty include abundant mechanical wear debris, notably polyethylene, metal (cobalt-chromium, titanium, zirconium or nickel) and methyl methacrylate. Polyethylene debris is often abundant, consisting of fine granular to thread-like particles, strongly birefringent, generally observed within histiocytes. Larger fragments/shards of polyethylene may be seen in multinucleated giant cells (figure 8B,C). In contrast, methyl methacrylate (cement) is dissolved during processing; only the spaces, usually within giant cells, where the cement once localised, are seen, sometimes accompanied by refractile barium lining these spaces. Metallic debris usually manifests as small particles of dark black discolouration, often within histiocytes (figure 8D). Although chronic inflammation (lymphocytes and plasma cells) may be present, neutrophils should not generally be seen outside of infection. Positive culture is the gold-standard test for diagnosing infection; however, several studies have shown that histological examination of periprosthetic tissues may be highly predictive of PJI. At our institutions, if PJI is suspected intraoperatively, frozen section is requested. In the literature, most agree that at least five neutrophils per high-power field in five separate high-power fields have the best predictive value.55 56 However, this finding should be further correlated with the clinical picture and additional lab studies (ESR: Erythrocyte sedimentation rate, C reactive protein, alpha defensin, microbial cultures). Indeed, ‘positive’ histology represents only a minor criterion for establishing the diagnosis of PJI (table 1).55 The absence of neutrophils at frozen section does not necessarily mean that no infection is present; likewise, the presence of neutrophils does not always imply infection. Other potential causes of a neutrophilic infiltrate include a previously undocumented inflammatory arthritis, crystalline diseases, and fracture.57 It is also worth mentioning that the finding of neutrophils within fibrin should not be considered ‘positive’; only neutrophils localised in extravascular soft tissues should be documented (figure 8E–G). Potential pitfalls include lobulated lymphocytes mimicking neutrophils, failure to recognise bone marrow, and neutrophils localised only to fibrin or solely within vascular spaces (not in extravascular soft tissues) (figure 9A–D).
Summary of scoring-based criteria for periprosthetic joint infection55
Periprosthetic joint infection (PJI) pitfalls: (A) Potential pitfalls include lobulated and twisted lymphocytes mimicking neutrophils. (B) Trilineage haematopoiesis in bone marrow contains neutrophils, which should not be interpreted as ‘positive’. (C) Granulation tissue may be seen at the fibrin interface but, in this case, lacks neutrophils. (D) Neutrophils may be prominent solely within vascular spaces (not in extravascular soft tissues), and this is not indicative of PJI.
Aseptic lymphocytic vasculitis-associated lesion (ALVAL) is an unusual form of periprosthetic joint reaction typically seen in and around metal-on-metal hip replacements and characterised by varying combinations of perivascular lymphoid infiltrates (often with plasma cells), sheets of macrophages, necrosis and intracytoplasmic metal particles. Solid and partially cystic masses may also develop.58 59 However, in our experience, the findings of ALVAL are not necessarily specific and not always seen in the setting of metal-on-metal prostheses. Significant acute inflammation, as defined previously and even in the presence of the ALVAL-like features, favours PJI.
Rheumatoid arthropathy and spondyloarthropathy (seronegative)
Rheumatoid arthritis (RA) is a chronic autoimmune disease that predominantly involves small joints of hands and feet. Common symptoms include swollen, warm and tender joints, joint stiffness, usually worse in the mornings or after periods of inactivity, fatigue, low-grade fever and loss of appetite. With progression, symptoms spread to wrists, knees, hips, ankles, elbows and shoulders, typically bilaterally. Unlike DJD/OA, RA is a systemic disease and may affect other organs including lung, kidney, cardiovascular system, skin and eyes. Within the joints, it starts with synovial inflammation and progresses to joint destruction, bone erosion, loss of articular cartilage, with deformity and further pain. In developed countries, such as the USA, RA affects 0.5%–1% of adults.60 In contrast to DJD/OA that typically affects distal interphalangeal joints, RA involves the proximal interphalangeal and metacarpophalangeal (MP) joints. Plain film, the traditional imaging gold standard for RA, detects bone erosions, joint space narrowing (loss of cartilage) and juxta articular osteoporosis. In advanced cases subluxation and ankylosing may be evident. Currently, MRI and ultrasound are used for detection of early RA visualising soft tissue changes such as synovitis and tenosynovitis.61 While the diagnosis of RA is predominantly clinical, based on the 2010 American College of Rheumatology and the European League Against Rheumatism (ACR/EULAR) diagnostic criteria,62 histological examination of joint tissue plays an important adjunct role. The synovium shows synovial hyperplasia (increased layers of synovium), thickened synovial fronds with fibrosis, increased surface fibrin and fibrinoid necrosis, dense subsynovial lymphoplasmacytic inflammation with aggregates, and, less often, necrobiotic nodules composed of granulomatous inflammation with central fibrinoid necrosis (rheumatoid nodules) (figure 10A–F). When occurring in isolation (eg, soft tissue masses in the distal extremities) and in the absence of a known history of RA, the necrotising palisaded granulomatous inflammation of rheumatoid nodules may mimic epithelioid sarcoma. A pankeratin stain can be useful in such situations, as it is essentially always positive in epithelioid sarcoma and always negative in RA. Loss of INI-1 in epithelioid sarcoma is characteristic of the vast majority (80%–90%) of epithelioid sarcomas, but we would recommend pankeratin as the initial ‘screening’ immunohistochemical stain (figure 10G–I). The inflammatory synovium also expands to cover the bone (pannus), resulting in loss of overlying cartilage, which is dependent on synovial fluid for its nutrition, decreased bone mineral content (osteopenia), and, ultimately, ‘secondary’ DJD/OA, with bone erosions and subchondral cyst formation.
Rheumatoid arthropathy (RA): RA (A–F): (A–C) Necrobiotic rheumatoid nodules surrounded by histocytes with central necrosis and mucinous material. Note the mitotic figure (black circle) in (C). (D) Low-power magnification of thickened synovial fronds expanded by dense lymphoplasmacytic inflammation. (E) High-power magnification of hyperplastic synovium, with multinucleated histocytes and lymphocytes. (F) Pannus formation, ‘invasive synovium’, characterised by destructive growth of synovium at the interface of synovium with articular cartilage/bone, is the irreversible stage of erosive RA arthritis. The pannus grows over the articular cartilage, depriving it of the nutrients received from synovial fluid and leading to secondary DJD/OA. Epithelioid sarcoma (G–J): (G) Necrotising granulomatous-like growth of epithelioid sarcoma, mimicking necrobiotic nodules of RA. (H) Intermediate power view, demonstrating plump spindle to epithelioid cells arranged in ribbons, sheets and cords. The tumour cells are virtually always positive for pan-keratin (I), and most also show loss of INI-1 nuclear expression (not shown).
Seronegative spondyloarthropathies (sPA) are a group of inflammatory rheumatoid-like arthropathies with distinct clinical features involving axial and peripheral joints, enthesitis (tendinopathy, inflammation at the site of tendon attachment) and extra-articular manifestations. There is a close association with HLA-B27. The global prevalence of sPA is estimated to be around 0.5%–1.9%.63 The group classically includes ankylosing spondylitis (AS), psoriatic arthritis, arthritis associated with inflammatory bowel disease (IBD) and reactive arthritis (formerly known as Reiter arthritis, associated with GI or urogenital infections).64 Similar to RA, symptoms improve with activity. The key features distinguishing sPA from RA are the presence of enthesitis and negative serological workup for rheumatoid factor. In any patient, especially among the young with chronic back pain, ankylosing spondylitis should be considered.65 Plain films may not show changes in the early stages, but long-standing cases reveal dramatic changes in spine and sacroiliac joints, including as follows: ‘shiny corner’ (sclerosis at the attachment of annulus fibrosis to the anterior corner of vertebral endplate), ‘bamboo spine’ (calcification of fibrous ring of the intervertebral discs forming marginal syndesmophytes) and ‘squaring’ of vertebral bodies.66 History of predisposing factors (psoriasis, IBD, recent GI/GU infection) should be sought in cases with sudden onset of arthropathy, dactylitis and uveitis. Pathological features may closely resemble RA, especially in cases where peripheral joint involvement is present. Inflammatory serum markers are elevated, and HLA-B27 should be confirmed. As pain management and medical treatments are the mainstay of treatment, surgery is the last resort.
Crystalline deposition disease
Gout (monosodium urate crystals)
Gout has plagued humanity for more than 4500 years, first identified by Egyptians in 2640 BC and later documented by Hippocrates in 5th century BC.67 Population studies reveal a pooled global range of prevalence of <1% to 6.8% and an incidence of 0.58–2.89 per 1000 person-years.68
Gout, caused by persistent chronic hyperuricaemia resulting in deposition of monosodium urate (MSU) crystals in soft tissues and joints, may be due to overproduction from inborn errors of purine metabolism (such as Lesch-Nyhan syndrome), extensive cell turnover (eg, myeloproliferative disorders, tumour lysis syndrome, tissue damage), excess dietary purine (red meat, some seafood) or underexcretion (acquired renal disease, genetic disorders and some diuretics). Regardless of aetiology, the clinical manifestations of gouty arthritis encompass four distinct syndromes—asymptomatic hyperuricaemia, nephrolithiasis, acute gouty arthritis and chronic tophaceous gout; the latter two are of primary concern to the pathologist. The most common clinical manifestation is a painful arthritis, frequently monoarticular and most often afflicting, at least initially, the first metatarsophalangeal joint (the great toe), generally resolving within days to weeks, only to recur later. Repeated attacks over a period of years lead to chronic gout. Tophi, soft tissue masses consisting of urate crystals, are most seen in this ‘chronic’ setting. Radiologic findings tend to be minimal in the early course of the disease, consisting simply of soft tissue swelling. With progression, periarticular soft tissue densities (tophi), accompany bony erosions on both sides of the joints with relatively well-preserved joint spaces, most frequently involving the digits of the hands and feet. Osteopenia, more characteristic of RA, is not observed in gout.
Confirming MSU crystals in synovial fluid aspirate constitutes the gold-standard diagnostic method. However, the histological features of gout vary depending on the stage at which it is diagnosed. At the onset, a mixture of numerous inflammatory cells, including neutrophils, lymphocytes and histiocytes, infiltrates the synovial membranes. Indeed, gout is the common crystal disease associated with acute OM, sometimes an incidental finding in digit amputations. Histologically, gouty tophi appear in aggregates as amorphous, chalky white, acellular material surrounded by a very prominent histiocytic giant cell reaction (figure 11A). Within the feathery amorphous material, diagnostic urate crystals are generally easily observed but the crystals are water soluble and lost during typical H&E-stained slide preparations. Nevertheless, unstained slides allow for easy confirmation, obviating the need for alcohol fixatives. Using compensated polarising microscopy, these crystals usually appear needle-shaped with strong negative birefringence (figure 11B) (ie, yellow when the long axis of crystals is parallel to the axis of compensator and blue when the axis of the crystals are perpendicular).
Crystalline disease: Gout (A, B): (A) Serpiginous amorphous fibrillar material surrounded by a prominent histiocytic (foreign body) giant cell response, leading to granulomatous appearance. (B) Under compensated polarising microscopy, gout uric acid crystals usually appear needle-shaped with strong negative birefringence (yellow when the long axis of crystals is parallel to the axis of compensator and blue when the axis of the crystals are perpendicular). These crystals are generally lost during the H&E staining process but can be seen with polarisation of unstained slides. CPPD/Pseudogout (C–E): (C, D) Distinct aggregates of basophilic to grey-brown material, of amorphous calcium pyrophosphate deposits. In contrast to gout, an intense inflammatory response is not usually present. The crystals are small, rectangular to rhomboid and tend to be uniform, with weakly positive birefringence. (E) Soft tissue chondromas occasionally contain CPPD crystals. Tumoral calcinosis (TC) (F) is associated with large plates of non-polarising basophilic calcifications, often associated with grungy material and an intense histiocytic (foreign body) giant cell reaction. Neither CPPD nor TC is lost with formalin fixation and the subsequent H&E-staining process. CPPD, calcium pyrophosphate dihydrate deposition disease.
Calcium pyrophosphate dihydrate deposition disease (pseudogout)
The clinical features of calcium pyrophosphate dihydrate deposition disease (CPPD) vary considerably, ranging from asymptomatic, incidental joint calcifications (chondrocalcinosis) to an acute arthritis, closely resembling gout (pseudogout). Some forms resemble DJD/OA while others may mimic acute RA. Most patients are middle-aged to older adults; the most common anatomic location is the knee. Other sites, including the wrist and vertebra, may be affected, and multiple joints are frequently involved. Consequently, pathologists may encounter CPPD in a variety of clinical settings, ranging from incidental in herniated intervertebral disc material to total joint replacement specimens for DJD/OA. In our experience,69 CPPD occurs in about 9% of knee arthroplasty specimens, almost always related to DJD, and in 3% of femoral head resections, virtually always involving the joint capsule, synovium, or menisci, and rarely articular cartilage. Radiographic features also are quite variable, ranging from tumour-like deposition of CPPD within joints, including synovial membrane, menisci and articular cartilage, to OA with joint space narrowing and subchondral sclerosis.
The histological hallmark is the presence of deeply basophilic, small and mostly uniform rectangular to rhomboid fragments of calcification deposited in aggregates within articular cartilage, synovial fronds and/or menisci. In contrast to the needle-shaped profiles of urate crystals, the rhomboid CPPD crystals are preserved with routine processing/staining and generally show weak positive birefringence with compensated polarising microscopy. In our experience, acid decalcification sometimes washes away CPPD crystals. Nevertheless, this is not a problem if soft tissue, joint capsule/meniscus, is routinely submitted separately and not decalcified. Paradoxically, the crystals are not typically associated with a significant inflammatory/histiocytic response. Chondroid metaplasia, a feature only rarely seen with tumoral calcinosis (TC), is sometimes present with CPPD, especially in the digits, and soft tissue chondromas occasionally exhibit CPPD (figure 11C–E).
Tumoral calcinosis
TC represents localised deposits of calcium crystals, calcium hydroxyapatite, within soft tissues, often adjacent to joints. When presenting within tendons, the process is sometimes referred to as calcific tendonitis. TC most commonly presents sporadically, possibly resulting from local trauma but also may be due to a metabolic abnormality of calcium and phosphate metabolism. Most patients are within the 2nd–5th decades of life at presentation and painless periarticular, soft tissue swelling, involving one or more joints, is the most frequent complaint. Additionally, patients with chronic renal failure may develop multifocal deposits of calcium hydroxyapatite. Radiologically, TC exhibits multiple, soft tissue calcifications often localised around a joint, frequently affecting the hips, followed by the elbows and shoulders. Pathological examination reveals large nodules and plates of non-birefringent, basophilic calcifications, surrounding by an inflammatory reaction, primarily histiocytes and multinucleated giant cells (figure 11F).
Haemosiderotic synovitis
Haemosiderotic synovitis (HS) is a non-neoplastic synovial proliferation as a result of haemarthrosis with chronic bleeding and reabsorption of the blood products by synoviocytes. Main risk factors include trauma and coagulopathy, either haemophilic or non-haemophilic, and less frequently synovial haemangioma, but it may be seen any time there has been prior surgical intervention, including revision arthroplasy. The knee is the most commonly affected joint, and symptoms include joint effusion, pain and swelling. Histologically, HS is characterised by synovial hyperplasia and haemosiderin deposition in both synovial cells and subsynovial macrophages (figure 12A, B). In MRI diffuse synovial thickening, deposition of haemosiderin and low signal intensity on both T1-weighted and T2-weighted sequences overlap with diffuse tenosynovial giant cell tumour (TGCT).70 Similarly, at the time of synovectomy, to the surgeon, a rusty colour and synovial hyperplasia mimics diffuse TGCT; therefore, it is not uncommon to receive a specimen labelled synovium and not to rule out ‘PVNS’ (pigmented villonodular synovitis, an older term for diffuse TGCT). In contrast to TGCT, HS does not demonstrate expansile/tumefactive growth and nodule formation. Nodules and sheets of subsynovial rounded mononuclear and epithelioid cells, admixed with osteoclast-like giant cells, seen in TGCT, is absent in HS, where haemosiderin deposition is limited mostly to the surface71 72 (figure 12C).
Haemosiderotic synovitis: (A, B) Low-power and high-power views of haemosiderotic synovitis with single layer of synovium accompanied by a fibrotic subsynovium. Haemosiderin deposits are within both synoviocytes and subsynovial histiocytes. In contrast, (C) diffuse tenosynovial giant cell tumour (also known as pigmented villonodular synovitis) is characterised by an expanded synovium largely the result of nodules of histiocytoid cells, often but not always accompanied by osteoclast-type giant cells.
Amyloidosis in carpal tunnel release
Amyloidosis (AL) represents a group of disorders involving protein misfolding which results in aggregates of extracellular deposits of amyloid fibrils, leading eventually to organ dysfunction. The precursor protein defines the amyloid type, and this in turn determines the organs involved. Transthyretin, also known as prealbumin, and immunoglobulin light chain are the two primary proteins that deposit in the myocardium. A significant number of patients with amyloid transthyretin, but less commonly amyloid immunoglobulin light chain, also have deposits in soft tissue structures, which may lead to carpal tunnel syndrome (usually bilateral), trigger finger, spinal stenosis and biceps tendon rupture. Carpal tunnel syndrome often precedes cardiac involvement by 5–10 years. Sperry et al 73 74 sought to determine if cardiac disease existed concomitant to the finding of trigger finger or bilateral carpal tunnel disease. Tenosynovial biopsy was positive via Congo red in about 2% of cases with trigger finger and 10% of cases with bilateral carpal tunnel syndrome, and at least 10% of patients with carpal tunnel syndrome (much less with trigger finger) had significant cardiac AL. Congo red staining of carpal tunnel tenosynovium can be a useful adjunct for screening for early and reversible cardiac AL, especially among males older than 50 years, females older than 60 years, and in the presence of bilateral carpal tunnel symptoms (figure 13A, B). It is important to note that ‘congo-philic’ staining and precipitates may occur in the collagen of carpal tunnel specimens, leading to false positive diagnoses. To confirm positivity, apple-green birefringence visualized by polarizing microscopy must be present. Identification of amyloid deposits in wrist/finger soft tissue has allowed early intervention in the hope of preventing advancing disease. In our institutions, positive Congo red staining in wrist/hand tenosynovium biopsies is reflexed to mass spectrometry for subtyping of amyloid deposits.
Amyloidosis in carpal tunnel release: (A) Congo red special stain revealing amorphous deeply red amyloid deposits. (B) Characteristic apple-green birefringence under polarised light microscopy.
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References
Footnotes
Handling editor Vikram Deshpande.
X @nooshin_dashti, @reith16, @ScottBikeethan
Contributors ND: writing–original draft, writing–review and editing. JR: writing–review and editing. SK: conceptualisation, writing–original draft preparation, supervision. ND: guarantor.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Commissioned; externally peer reviewed.