9 Linden E. Craig1 and Keith G. Thompson2 1University of Tennessee, USA 2Massey University, New Zealand This chapter covers tumors and tumor‐like lesions of synovial (diarthrodial) joints (Box 9.1). Synovial joints are formed by the cavitation of primitive mesenchyme between the bones of the cartilaginous fetal skeleton. The mesenchymal cells that remain and synthesize synovial fluid have classically been termed type B synoviocytes. Ultrastructurally, they contain abundant rough endoplasmic reticulum and free ribosomes, consistent with a synthesis function.1 Immunohistochemically, they are vimentin positive, cytokeratin negative, and CD18 negative (Figure 9.1). Intermingled with these local‐origin mesenchymal cells are type A synoviocytes, which are CD18 positive, indicating bone marrow origin. Type A synoviocytes are also vimentin positive and cytokeratin negative. Ultrastructurally, they contain abundant mitochondria, Golgi vacuoles, lysosomes, phagosomes, vesicles, and surface undulations, consistent with phagocytic and/or dendritic cell function. Type A synoviocytes increase in number with degenerative joint disease (Figure 9.2).2 Figure 9.1 Normal canine synovium (A). There are 1–2 layers of synoviocytes, the majority of which are vimentin positive (B). Approximately half of the synoviocytes are CD18 positive (C), indicating hematopoietic origin; these are the dendritic/phagocytic type A synoviocytes. All synoviocytes are cytokeratin negative (D). Figure 9.2 Hyperplastic and inflamed synovium from a dog with chronic degenerative joint disease. The synoviocytes form a layer 5–7 cells thick, and there are perivascular plasma cells and lymphocytes in the subintima (A). The majority of synoviocytes are vimentin positive (B). There are increased CD18‐positive (type A) cells, especially lining the joint space and sloughed into the synovial fluid (C). All synoviocytes are cytokeratin negative (D). Type A and B synoviocytes are indistinguishable by light microscopy. Together they form a single or double layer without tight junctions, desmosomes, or a basement membrane. This layer completely lines all but the articular cartilage of synovial joints. Type C synoviocytes have also been described in dogs as a potential transitional or stem cell form3; however, given the different origins of the two cell types (local mesenchyme versus bone marrow), it is difficult to explain the existence of a transitional cell type. The most common type of tumor arising from the synovium is histiocytic sarcoma, arising from bone marrow–origin histiocytes (also known as type A synoviocytes) residing in the synovium. Synovial myxoma is the second most common tumor of joints; these may arise from type B (synovial fluid synthesis) synoviocytes, but until a specific marker of type B synoviocytes is identified, this cannot be proven. The synovial membrane is supported by connective tissue (subintima) that varies in composition with the area of the joint. In some areas, the connective tissue is loose and well vascularized and may form villi (areolar synovium). In other areas (typically fat pads), the subintima contains adipocytes (adipose synovium). There are also areas where the synovium rests directly on dense collagen (fibrous synovium).4 The subintima also contains blood vessels, nerves, histiocytes, mast cells, fibroblasts, and undifferentiated mesenchymal cells. Theoretically, a joint neoplasm could arise from any of these cell types. Tendon sheaths and bursae are also lined by synovium and could therefore be affected by similar neoplasms. In addition to synoviocytes and mesenchymal cells of the subintima, tumors can arise from chondrocytes within periarticular fibrocartilage or areas of synovial chondroid metaplasia. Synovial tumors are best characterized in dogs, but likely occur in all species. They typically arise as a solitary lesion in a weight‐bearing joint in a middle‐aged to older animal. Affected animals often have a gradual onset of clinical signs that can mimic degenerative joint disease. Even on clinical and radiographic evaluation, the findings can be difficult to differentiate from the periarticular proliferation associated with degenerative joint disease. Knowing the anatomic location of the lesion, as well as the species and breed affected are helpful, as some lesions have predispositions for certain sites and/or breeds. Radiography will usually indicate whether a tumor is centered on a joint or tendon sheath, whether it contains foci of mineralization, and whether there is any involvement of adjacent bone. Both benign and malignant lesions can be associated with bony lysis around the joint. Magnetic resonance imaging (MRI) is also used to determine the extent of the tumor into surrounding tissues.5 In most cases, histopathology is required to make a definitive diagnosis of joint lesions. In the case of synovial tumors in dogs, immunohistochemistry (IHC) may also be required.6 Cytological examination can identify the process as neoplastic, but identifying the tissue of origin is difficult. Histiocytic tumors can usually be recognized, but there are no cytologic features to be certain a tumor is of type B synoviocyte origin. Both benign and malignant joint tumors can contain inflammatory cells, so their presence does not rule out neoplasia. Historically, synovial cell sarcoma has been reported to be the most common1 or only malignant tumor of joints.2 In the past, most mesenchymal tumors in or near joints were diagnosed as synovial cell sarcoma based on location. However, more recent studies using IHC have shown that multiple types of mesenchymal tumors with very different behaviors occur within and around joints, and in fact, the majority of joint tumors in animals are not synovial cell sarcoma. In humans there is a sarcoma that often occurs near joints, but outside the joint capsule. It was originally named synovial cell sarcoma based on its microscopic appearance which mimics the embryonic synovium. Approximately 20 years ago, a chromosomal translocation between the SYT gene on chromosome 18 and the SSX gene on the X chromosome was discovered in these tumors.3 This genetic translocation has come to define synovial cell sarcoma in humans and has allowed the identification of this tumor in many primary locations far from joints, including kidney, pleura, and heart. It is now known that the cell of origin is not synovial, but a pluripotential mesenchymal stem cell that occurs throughout the body.4 The chimeric protein product of the chromosomal translocation is responsible for the malignant transformation and sometimes drives differentiation into both mesenchymal and epithelial cell types. The tumor in humans is monophasic (spindle cells only) or biphasic (spindle and epithelial cells). Although the epithelial component is cytokeratin positive, IHC is rarely used to identify the tumor in humans, because the molecular test for the genetic translocation is more sensitive and specific. So the name synovial cell sarcoma is now known to be a misnomer in humans for a soft tissue sarcoma that is sometimes biphasic and has a specific genetic translocation. Although a misnomer, the term synovial sarcoma is still used in human pathology for a mesenchymal tumor with this unique chromosomal translocation. Therefore, the identification of cytokeratin‐positive cells within canine sarcomas does not indicate synovial origin,5 as previously published.6 Normal synoviocytes are not cytokeratin positive and the tumor in humans called synovial cell sarcoma is known to not be of synoviocyte origin. In fact, veterinary pathologists have no marker to identify malignant tumors of synoviocyte origin, except those of histiocytic (type A) origin, in which CD18 can be used. If a tumor of type B synoviocytes exists, it would be expected to produce synovial fluid, as the normal type B synoviocytes do. Therefore, the synovial myxoma is the most likely tumor of type B synoviocyte origin. A malignant counterpart has not been identified and even if it exists, we have no way of recognizing it (i.e., no specific marker of type B synoviocyte origin). Looking in animals for a chromosomal translocation similar to that in humans would only identify a mesenchymal tumor not of synovial origin, so there is no reason to look for this molecular anomaly if we are trying to find a sarcoma of synovial origin. Synovial sarcoma in humans is one of many sarcomas that are now identified by molecular means; studies looking for genetic markers of malignancy are currently underway in a variety of canine sarcomas. Synovial cell sarcoma is a rare tumor in animals, if it occurs at all. Although they have been described in a variety of species, the diagnosis is often based on location (joint) and morphology (spindle cell). It cannot be assumed that all mesenchymal tumors that occur in the joint are synovial cell sarcomas. In fact, most tumors occurring within the joint of dogs are histiocytic sarcomas.6 Previous reports of synovial cell sarcomas in dogs did not distinguish between the different types of sarcomas that occur within the joint,7 and likely grouped histiocytic sarcoma, other sarcomas, and benign synovial myxomas together. Reports of synovial cell sarcoma in cats have also been based on location and histologic appearance. In cats, even in cases in which the tumor is diagnosed as histiocytic, the term synovial cell sarcoma has been used.8 Animals diagnosed with synovial cell sarcomas often have a long history of lameness and/or a mass centered on the joint. The classic radiographic finds are changes (lysis and/or proliferation) affecting bones on both sides of the joint. Synovial cell sarcoma in animals is typically described as an infiltrative mass within a joint. The mass is often ill‐defined and infiltrates and effaces the joint lining, sparing the articular cartilage. The tumor can also infiltrate into the adjacent bones and muscles. Synovial cell sarcomas have been reported in most joints. The stifle is the most frequently reported site, but they are also reported in other joints. Synovial cell sarcomas described in animals are typically monophasic spindle cell tumors without any specific distinguishing features. Although cleft‐like spaces, epithelioid cells, and concentric whorls have all been described, these are not specific to synovial cell sarcoma. Cytokeratin staining has been used to identify synovial cell sarcomas in dogs,6 but this was based on the human criteria for a tumor of nonsynoviocyte origin. The cytokeratin‐positive cells are a small minority (usually less than 10%) and they do not differ morphologically from the surrounding spindle cells (Figure 9.3). Since normal synoviocytes do not stain with cytokeratin, the relevance of using cytokeratin positivity to diagnose tumors of synovial origin is questionable. The rationale for using cytokeratin staining to identify synovial cell sarcomas was based on the cytokeratin‐positive epithelioid cells of the biphasic human synovial cell sarcomas. However, since human synovial cell sarcoma is now known to be of nonsynovial origin, this criterion is no longer valid. The significance of cytokeratin staining of some joint tumors is unknown. Cytokeratin staining is rare in other sarcomas, but has been reported in peripheral nerve sheath tumors in dogs.9 Figure 9.3 This tumor from a dog was diagnosed as synovial cell sarcoma based on location (intra‐articular) and the small proportion of neoplastic mesenchymal cells which are positive for cytokeratin by immunohistochemistry (A). Cytokeratin‐positive cells are no longer thought to indicate synovial origin. All the cells are vimentin positive (B) and CD18 negative (C). Biphasic synovial cell sarcomas are rare to nonexistent in animals. The published images of biphasic synovial cell sarcomas in animals show anaplastic or round cell populations without epithelioid features10–12 or longitudinal and cross‐sections of perpendicular bundles of spindle cells mimicking two cell populations.13,14 The authors of this chapter have never seen a biphasic synovial tumor in an animal. The biphasic morphology cannot be used to identify tumors of synovial origin, as the biphasic synovial sarcomas in humans are of nonsynovial origin. Spindle cell tumors in the joint should be diagnosed in the same manner as spindle cell tumors elsewhere, using IHC and cell morphology rather than basing the diagnosis on location. In dogs, the behavior of synovial cell sarcomas has been reported to be highly variable.6,7,14 This is likely a reflection of the many different types of sarcomas that have been identified as synovial cell sarcoma. In one study in which five cases of synovial cell sarcoma were identified by cytokeratin staining, the four dogs with follow‐up information included one dog with radiographic evidence of metastasis and three dogs in which amputation was apparently curative.6 These numbers are obviously small; however, the 25% rate of metastasis is similar to that reported for canine soft tissue sarcomas. Histiocytic sarcoma is a malignancy of dendritic cell origin that may be localized or disseminated. It is described in detail in Chapter 8. In veterinary medicine, this neoplasm is best characterized in dogs. The localized form occurs in the spleen, lymph node, lung, bone, skin, subcutis, brain, and joints. The disseminated form involves multiple sites and may represent a later stage of the localized form. The neoplastic cells express leukocyte surface markers characteristic of dendritic cells, such as CD1, CD11c, and MHC II. Because most leukocyte surface markers are detectable only in frozen tissue, CD18, a formalin‐resistant marker of hematopoietic origin, is used to help diagnose histiocytic sarcoma in formalin‐fixed tissue. Although it is not specific for histiocytic sarcoma, CD18 membrane staining of cells with the appropriate morphology is considered diagnostic.1,2 These tumors likely arise from cells classically termed type A synoviocytes; however, because their appearance and behavior is similar to histiocytic sarcomas arising in other tissues, histiocytic sarcoma is the appropriate diagnosis, rather than histiocytic synovial cell sarcoma. Histiocytic sarcoma is the most commonly occurring tumor within the joints of dogs.3 Rottweilers, golden retrievers, Labrador retrievers, and flat‐coated retrievers are predisposed.4 Bull mastiffs are overrepresented in New Zealand. Although Bernese mountain dogs are predisposed to histiocytic malignancies (25% of all tumors in this breed are histiocytic, and 80% of cases of disseminated histiocytic sarcoma are in Bernese mountain dogs),2 the joints are less often affected than other sites in this breed.3,5 Flat‐coated retrievers, on the other hand, are more likely to develop histiocytic sarcoma in the joint than any other site.6,7 A study comparing the molecular characteristics of histiocytic sarcoma in Bernese mountain dogs and flat‐coated retrievers indicates genetic differences between the breeds may explain site predisposition for each breed.8 Rottweilers are diagnosed at a younger age3 and are more likely to have the disseminated rather than localized form.5 Histiocytic sarcoma has also been reported in the joints of cats,9,10 most commonly affecting the tarsal joint (Figure 9.4A–D), and less commonly the stifle. Figure 9.4 Synovial histiocytic sarcoma in a cat. (A) Multiple tumor lobules surround the tarsal joint, extend along tendon sheaths and infiltrate adjacent skeletal muscles. (B) Highly cellular cytological preparation containing pleomorphic tumor cells. Note the anisokaryosis, prominent nucleoli and frequent binucleate and multinucleate forms. Scattered neutrophils and lymphocytes are present in the background. (C) Histology from the same tumor. Tumor cells vary markedly in size and many have large, hyperchromatic nuclei with prominent nucleoli. Many possess abundant eosinophilic cytoplasm and some contain phagocytosed inflammatory cells. A mitotic figure is present in the lower center. (D) CD18 immunohistochemistry of the tumor showing strong membrane reactivity. Dogs usually present with lameness and a soft tissue swelling around the joint. Sometimes the lameness is of long duration and may be attributed to degenerative joint disease. In the stifle, there may be a cranial drawer sign and/or history of cranial cruciate ligament rupture.11 In one study, over 50% of dogs with histiocytic sarcoma of the stifle had a history of cranial cruciate rupture.3 These tumors occur in affected stifle joints with and without surgical repair, including tibial plateau leveling osteotomy (TPLO).12 This is hypothesized to be due to malignant transformation of dendritic cells within a chronically inflamed synovium.3 One study of 920 European Bernese mountain dogs demonstrated an increased predisposition (odds ratio 5.4) for histiocytic sarcoma in joints with previous joint disease, such as ruptured cranial cruciate ligament, patellar luxation, fragmented medial coronoid process, and trauma.13 Radiographically there is soft tissue swelling, bony lysis, and sometimes bony proliferation on both sides of the affected joint (Figure 9.5). In the stifle, the patella is often displaced by the mass. This malignant tumor cannot be distinguished radiographically from benign joint tumors, such as synovial myxoma, which can also cause bony lysis. Figure 9.5 Synovial histiocytic sarcoma of the elbow joint of dog. There are areas of bony lysis in the distal humerus, proximal radius, and proximal ulna. There is also a pathologic fracture of the distal humerus. (Image courtesy of S. Hecht.) Histiocytic sarcoma is a grossly multilobulated infiltrative tumor that often fills the joint and extends into the surrounding bones and soft tissues (Figure 9.6). The stifle is the most common joint affected, followed by the elbow, shoulder, coxofemoral, carpal, and tarsal joints.3,4 In some cases, the majority of the mass is outside the joint capsule (Figure 9.7). Figure 9.6 Synovial histiocytic sarcoma of the stifle joint of dog. Tumor nodules fill the joint and extend outside the joint capsule. Note lateral fabellotibial suture repair (arrow) and the lack of cruciate ligaments. Prior to the use of immunohistochemical markers for histiocytic lineage, this tumor would have likely been diagnosed as a synovial cell sarcoma. Figure 9.7 Synovial histiocytic sarcoma lateral to the right elbow in a dog. Multiple tumor nodules infiltrate the triceps and anconeus muscles following extension from the synovium of the adjacent elbow joint. Asterisk marks the olecranon. The tumor in cats has a similar gross appearance: a soft, multilobular, pale tan mass which bulges into the joint space, extends along tendon sheaths and infiltrates adjacent muscles and subcutaneous tissues (Figure 9.4A).
Tumors of Joints
Introduction
General considerations
Clinical characteristics
Other considerations
References
MALIGNANT TUMORS
Does synovial cell sarcoma exist in animals?
Synovial cell sarcoma
Clinical findings
Gross findings
Histologic features
Prognosis
References
Histiocytic sarcoma
Incidence
Clinical findings
Gross findings
Cytologic features
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