Non-Neoplastic Orthopaedic Pathology
Section 1 -
Non-Neoplastic Orthopaedic Pathology
Andrew E. Rosenberg, M.D.
Alan L. Schiller, M.D.
The pathology of the musculoskeletal system is complex, as there are many types of diseases that
primarily, or secondarily affect the skeleton. This review will cover the common non-neoplastic and
neoplastic conditions that frequently result in a specimen to be analyzed by surgical pathologists.
In the routine handling of orthopaedic specimens those that contain bone require special handling.
Large pieces of bone should be cut into slabs 0.5-1.0 cm. thick before being fixed in neutral buffered
10% formalin. This allows for proper fixation to be completed within 24 hours. Next, the specimen
should be decalcified in one of the various types of commercially available decalcifying solutions. In
our laboratory we use a mixture of 5% hydrochloric acid and EDTA, which works rapidly and requires
approximately 24 hours for adequate decalcification. Of course this depends on the quantity and type of
bone (cortical or trabecular), as well as its state of mineralization. Following decalcification, the
specimen should be washed and processed routinely. Most bone biopsy specimens should be processed in
Appropriate decalcification does not interfere with antigen preservation and therefore, is not an
obstacle in performing immunohistochemistry. Several carefully controlled studies have shown that the
common weak and strong decalcifying agents do not significantly alter the immunoreactivity of most
diagnostically important antibodies. It has been our experience that any antibody that can be used on
formalin-fixed tissue can also be successfully applied to tissue that has been fixed, decalcified and
paraffin embedded by standard techniques. In fact, over decalcification of tissue usually results in the
loss of fine cellular detail before its antigenicity is destroyed.
The exposure of bone specimens to most decalcifying agents, does, however, modify DNA and RNA so that
the ability to perform flow cytometry and other molecular techniques may be seriously compromised. This
should be taken into consideration when handling a specimen and can be circumvented by not decalcifying a
portion of the specimen or decalcify with formic acid, as it has been shown to minimize the problem.
Artifacts in Orthopaedic Pathology
Some of the more common artifacts in orthopaedic pathology are introduced by inappropriate processing
such as applying excessive pressure to the specimens, allowing insufficient fixation, decalcification or
over decalcification and not removing the bone dust that is generated during sawing. Applying excessive
pressure squeezes and stretches cells making their identification impossible. This is most relevant when
trying to distinguish an inflammatory infiltrate from lymphoma. Incomplete fixation, before
decalcification, allows bubbles of carbon dioxide liberated by the decalcifying acid to become trapped
within the tissue. As a result, structures that simulate signet ring cells or adipocytes are produced.
Insufficient decalcification allows the calcium hydroxyapatite crystals to remain in the bone. This
obscures the underlying architecture of the collagen, which prevents differentiation of lamellar from
woven bone and the identification of cement lines (Paget's disease). Furthermore, mineralized bone is
poorly cut by the microtome and may be shattered or even pop out of the paraffin block. Excessive
decalcification interferes with hematoxylin staining and makes the tissue brittle and also difficult to
cut. Severe over decalcification digests cells, which can produce changes that mimic osteonecrosis.
Sawing bone generates bone dust, which is unavoidably pushed into lacunae and marrow spaces.
Histologically, this too can simulate osteonecrosis, as well as fat necrosis and degenerative diseases.
It is not uncommon for orthopedic surgeons to request a frozen section on a bone tumor biopsy. This
procedure helps determine whether the sample contains diagnostic tissue and if so, may provide enough
information so a definitive procedure can be performed during the same operation. The tissue can be
handled routinely without removing the bone except for thick pieces of cortex. In our frozen section
laboratory we use an inexpensive disposable cutting blade system that allows us to discard blades that
have been nicked or dulled by the bone. Once a diagnosis is rendered or a list of differential
possibilities is generated the specimen can be triaged, if necessary, so that the appropriate studies
such as electron microscopy, immunohistochemistry, flow cytometry, cytogenetics, PCR etc. can be
Arthritis can be defined as inflammation of the joint. It may be a manifestation of a multitude of
diseases, which may or may not have associated pathognomonic histologic findings. Pathologists are
frequently expected to identify the type of arthritis from specimens that range from small fragments of
synovium to entire diarthrodial joints. Final interpretation should include correlation of the clinical
findings and radiographic changes with the microscopic evaluation of the available tissue including the
periarticular soft tissues, articular cartilage and subchondral bone.
The term osteoarthritis, or degenerative joint disease when used without qualifiers, refers to a
relatively well-defined clinicopathologic disorder characterized by joint degeneration. It is one of the
most common types of arthritis and in the common primary form, has an unknown etiology. Although the
term osteoarthritis implicates inflammation in its pathogenesis, morphologically, synovial inflammation
is usually not prominent and is believed to be a secondary phenomenon. In osteoarthritis it is the
articular cartilage and not the synovium that is the primary target of destruction.
In the early stages of OA the stressed chondrocytes begin to proliferate and the composition of the
articular cartilage changes with an increase in the amounts of water and glycosaminoglycans. Chondrocyte
proliferation is evident microscopically by "cloning" of chondrocytes in which the newly formed
chondrocytes are arranged in small groups and clusters. This is followed by vertical and sometimes
horizontal fibrillation and clefting of the cartilage. At this stage, gross exam of the cartilage
reveals a granular surface that is softer than normal (chondromalacia). Continued wear and tear results
in a loss of the matrix proteoglycans that exposes the supportive collagen network and makes it appear
more fibrous. Eventually, full thickness portions of the articular cartilage are sloughed and as the
subchondral bone plate becomes the new articular surface the friction smoothes and burnishes it and gives
it the appearance of polished ivory (bone eburnation). In response to the altered transmission of
mechanical forces through the joint, the subchondral bone and supporting trabeculae are rebuttressed and
form a sclerotic zone. The most superficial layers of the eburnated bone undergo necrosis, presumably
from the heat generated by friction. Frequently small fractures occur in the articular bone surface and
this induces callus formation that is composed of reactive woven bone and fibrocartilage. The latter
protrudes from the articular surface and gives it a knobby appearance. The fracture sites also allow the
synovial fluid to be forced into the subchondral regions and form subchondral cysts. The cysts are lined
by fibrous tissue and can achieve large size.
Osteophytes form just peripheral to the articular surface. They are composed of a cap of fibro or
hyaline cartilage that gradually undergoes enchondral ossification and forms a base of trabecular bone.
The osteophytes can develop into large lip-like excrescence or flat plates that overgrow the articular
surface in an attempt to renew it.
The synovium usually shows alterations that are minor in comparison to the destruction of the
articular surface. The synovium may become congested, edematous or fibrotic and occasionally it may
develop a villous architecture. Fragmentation of the articular surface produces free pieces of cartilage
and bone that may become embedded within the synovium and form loose bodies. In severe disease a fibrous
pannus develops. Uncommonly, the synovium may be infiltrated by a dense lymphoplasmacytic infiltrate
that simulates the changes in rheumatoid arthritis.
Rheumatoid Arthritis (RA)
Rheumatoid arthritis is a multifaceted immunologic disease that is characterized by chronic symmetric
polyarthritis. It primarily affects the synovium causing potentially severe secondary changes in the
periarticular soft tissues, articular cartilage and subchondral bone.
The characteristic synovial changes in untreated rheumatoid arthritis include hypertrophy and
hyperplasia of the synovial lining cells, a dense lymphoplasmacytic infiltrate with the formation of
lymphoid follicles and germinal centers within the subsynovial connective tissue, a fibrinous exudate
that may develop into "rice bodies" or undergo organization on the synovial surface and uncommonly,
palisading granulomas. These changes expand the synovium and produce prominent villous folds. In active
disease the fibrinous exudate may be rich in neutrophils, however, they usually do not infiltrate the
synovium proper. When this does occur it may be difficult to exclude infection. In treated RA, the
inflammatory infiltrate may be sparse and consist mainly of histiocytes.
Eventually the inflamed synovium may adhere to and cover the articular surface forming a pannus. (L.
piece of cloth). The pannus interferes with the diffusion of nutrients from the synovial fluid into the
articular cartilage and in combination with degradative enzymes released by the inflammatory cells the
chondrocytes die, and the cartilaginous surface of the joints is destroyed. Similarly, the inflamed
synovium can destroy periarticular structures such as joint capsules, tendons and ligaments or erode into
bone at the synovium insertion site. When the bone is eroded the marrow is replaced by fibrous tissue
that may contain chronic inflammatory cells and thereby simulate an infectious osteomyelitis.
The end stage joint shows massive destruction of the articular surfaces with obliteration of the joint
space and bony or fibrous ankylosis of the opposing subchondral bones. There is relatively little bony
reaction with regards to subchondral sclerosis and osteophyte formation.
Based strictly on morphology, and not clinical findings, lab data nor distribution of joint
involvement, it is not possible to reliably distinguish the histologic changes associated with rheumatoid
arthritis from those that are manifestations of other collagen vascular diseases. In fact, the synovial
pannus, which is considered the hallmark of rheumatoid arthritis, can be present in non-inflammatory
settings such as posttraumatic arthritis and severe osteoarthritis.
Osteonecrosis (Avascular Necrosis)
Osteonecrosis (ON) or avascular necrosis refers to a wedge shaped bone infarct that occurs adjacent to
the articular surfaces or apophyses. ON is associated with many conditions including fractures,
corticosteroid administration, alcohol abuse, sickle cell anemia, Gaucher's disease, Caisson's disease,
pregnancy, etc. In many cases there is no underlying etiology. Although it is generally accepted that
the necrosis follows interference with blood flow, its pathogenesis in most situations is not
Most specimens removed for ON are done late in the course of the disease; therefore, the morphological
changes are well developed. The center of the infarct consists of necrotic trabecular bone that is
characterized by empty lacunae. The marrow is also necrotic and the liberation of the lipids by the dead
adipocytes can lead to the formation of calcium soaps and dystrophic calcification. A peripheral rim of
reactive fibrovascular tissue surrounds the zone of necrosis. This collar of reparative tissue grows
into the area of necrosis and provides access for osteoclasts and macrophages to remove the dead bone and
clear away the nonviable marrow. Also, the fibrovascular tissue is a reservoir for mesenchymal cells
that have the capacity to differentiate into osteoblasts. The osteoblasts deposit viable woven and
lamellar bone on the surfaces of dead trabeculae. This process of viable bone replacing dead bone is
known as creeping substitution. Because of the change in transmission of the mechanical forces the
uninvolved bone immediately surrounding the infarct is also buttressed and this forms a sclerotic rim,
which separates the infarct from the uninvolved bone. In neighboring, but uninvolved regions, the bone
becomes osteoporotic because of the hyperemia and disuse secondary to pain.
Initially, the articular cartilage overlying the infarct remains viable because it is nourished by
synovial fluid. The underlying dead subchondral bone no longer undergoes normal remodeling therefore,
the trabeculae develop fatigue microfractures. Over time, there is significant collapse of the dead bone
that causes the articular cartilage to become detached and fragmented. The change in the shape and
contour of the articular surface results in secondary osteoarthritis and destruction of the joint.
Synovial Reaction to Joint Prostheses
Large Joint Detritic Synovitis
Large joint arthroplasty is one of the commonest elective orthopedic surgical procedures performed
today. Over 140,000 total hip arthroplasties, 103,000 revisions and 30,000 partial hip replacements were
performed in the United States in 1996 (0.7% of the U.S. population). Complications are few, however as
arthroplasties have been performed on younger and more physically active patients, an increased incidence
of aseptic loosening of the prostheses has occurred. This is because the materials used in large joint
reconstruction; i.e., high density polyethylene (lines articular surface of acetabulum or tibial plateau,
metal alloys (proximal femur and articular surface of femoral head and articular surface of femoral
condyles, and barium impregnated methyl methacrylate (bone cement used to anchor components to bone),
although highly durable and relatively inert, do have a tendency to undergo mechanical failure over time,
particularly with excessive use. In vivo, this mechanical failure is usually manifested by progressive
fragmentation of the components. This occurs at the interface between moving parts of the artificial
joint, or between host tissue and prosthetic material. The net result is that microscopic fragments of
the prosthetic components are sloughed into the joint cavity where they elicit an inflammatory reaction.
This is usually accompanied by osteolysis or resorption of the involved bones producing clinical
loosening of the prosthetic joint components. The cardinal symptom of loosened prostheses is progressive
"Detritic synovitis" is the descriptive term applied to the constellation of changes seen in the
synovium and soft tissue that surrounds these loose large joint arthroplasties. The most commonly
involved joints are the hips and knees. Detritic synovitis presents as red/tan nodular thickening of the
synovium. In a minority of cases the synovium may be black due to the extensive deposition of metal
debris and this has been termed 'metallosis'. In detritic synovitis particles of synthetic material
within the synovium elicit an intense histiocytic and foreign body giant cell reaction. The histiocytes
are oval and rounded and have abundant eosinophilic foamy to granular cytoplasm. Nuclei are central,
round and lack nucleoli. Mitoses are not seen. Three types of foreign material are recognizable.
Methyl methacrylate (bone cement) is dissolved in tissue processing by xylene. In vivo it elicits a
foreign body giant cell reaction and in tissue sections these cells surround large oval and rounded
defects, which appear empty, but often contain fine crystals of refractile, weakly polarizing barium
granules, which is mixed in the methylmethacrylate so its extent can be assessed radiographically. Small
fibers and fragments of polyethylene are also found within foreign body giant cells. These are typically
small, except in the knee joint where they tend to be large. The smaller fibers may be overlooked
without examining slides under polarized light. Larger pieces of polyethylene appear translucent or have
a subtle green/yellow hue with conventional H&E stains. The metal debris is the most inconspicuous
and therefore most easily overlooked of the foreign material. Although the metal particles rarely exceed
50 microns, most pieces measure less than 1 micron and are evenly dispersed as single black fragments or
particles within the cytoplasm of histiocytes. Additional histologic findings include papillary
fibrocartilaginous metaplasia of the synovial surface, sheets of coagulative necrosis without
inflammation, aggregates of hemosiderin-laden macrophages, and in a minority of cases reactive
myofibroblastic proliferation that resemble nodular/proliferative fasciitis. The presence of stromal
infiltrates of neutrophils is strongly correlated with bacterial infection surrounding the prosthesis.
It is worth noting that particles of metal, polyethylene, and the typical histiocytic reaction that
accompanies them, can also be found in regional lymph nodes. These lymph nodes are often enlarged and
may be suspicious for involvement by a malignant tumor. This can result in confusion at the time of
staging procedures performed during treatment of pelvic malignancies, usually prostatectomy in males and
hysterectomy and/or oophorectomy in females. We have also seen this finding in axillary nodes that are
being biopsied as sentinel nodes in the setting of breast cancer and melanoma of the upper extremity.
Detritic synovitis occurs on the background of loose large joint prostheses, and hence its management
revolves around reconstruction of the affected joint. This is frequently troublesome because of the
severe localized osteoporosis that usually accompanies loosening of the
Sarcoma arising in association with a metallic prosthesis or hardware is uncommon, but a well
recognized complication. The material used in these prosthesis is generally considered to be nontoxic,
however some of the constituents have been shown to be potentially carcinogenic in animal studies. To
date fewer than 40 cases have been reported in the literature. These sarcomas are of different types but
are usually osteosarcoma or malignant fibrous histiocytoma, although a variety of other sarcomas have
also been reported. In a recent study by Keel et al. on 12 cases the patients ranged in age from 18 to
85 (mean 55) and the time interval between the placement or hardware and diagnosis of sarcoma ranged from
2.5 to 33 (mean 11) years. The patients complained of pain, swelling, or loosening of hardware and were
found to have a destructive bone or soft tissue mass radiographically. Of 8 patients with follow-up, 5
died of disease. Although the possibility of a sarcoma arising in association with an implant is very
small, it should be considered when pain or other new findings develop in patients with metallic
orthopedic hardware. One should, however also be aware that destructive tumoral reaction ("tumoral
detritic synovitis") can also occur.
Small Joint Detritic Synovitis
The prostheses used to replace damaged small synovial joints such as those in the hands and feet are
different from the ones used for large joint arthroplasty. Small joint prostheses are composed of
silicone polymers. Silicone (dimethyl siloxane) is comprised of carbon, oxygen, hydrogen and silica.
Depending on the length of polymer chain and the degree of cross-linking between individual chains,
silicone may have properties of a liquid, gel or solid. The solid silicone prostheses, which are often
referred to by their proprietary name as "silastic prostheses" have been extensively used for small joint
reconstruction and like their large joint counterparts, have for the most part, been extremely successful
in alleviating pain and dysfunction. Unfortunately, as with large joint arthroplasties a minority of
patients encounter problems due to mechanical failure of the components, particularly in those joints
subjected to greater degrees of stress and activity, such as the thumb and hallux. The abraded silicone
particles are capable of eliciting an inflammatory reaction that differs somewhat from large joint
detritic synovitis. Particle size is important and those measuring 0.001-1.5 mm3 elicited a
histiocytic and foreign body giant cell reaction while large ones do not. Silicone particles can enter
the lymphatic system and be deposited in lymph nodes resulting in lymphadenopathy.
Small joint detritic synovitis produces a nodular thickening of synovial membrane similar to its
large joint counterpart. Blackening of the membrane does not occur since metal alloys are not a part of
these prostheses. Microscopically, the subsynovial space is expanded by a histiocytic and multinucleated
giant cell infiltrate that surrounds small fragments of yellow-green lobulated foreign material (the
fragmented solid phase silicone). This material predominantly occurs within the cytoplasm of mononuclear
histiocytes, synovial cells and multinucleated giant cells, however small pieces may be found in an
entirely extracellular location. Solid silicone is refractile but not birefringent and hence is not
visible when viewed with polarized light. Neutrophils are not typically found unless there is a
coexistent bacterial infection. Other changes in the synovial membrane include scattered lymphocytes and
plasma cells, strands of fibrosis and embedded shards of bone. The latter probably arises from the
adjacent bones, which may also contain large amounts of silicone particles. In a minority of cases the
intraosseous silicone elicits intense osteoclastic resorptive activity that may produce radiographically
and surgically detectable cystic defects. Silicone synovitis is managed by thorough curettage and
reconstruction of the affected joint if possible.
Gaucher's disease is defined as a genetic, multisystem, lipid, lysosomal, storage disease
characterized by the abnormal catabolism and storage of the sphingolipid glucosylceramide. It is the
most common of the genetic lysosomal storage diseases affecting 1 in 50,000-100,00 live births and is
inherited in an autosomal recessive fashion or acquired through a spontaneous mutation. Patients with
Gaucher's disease have a deficiency in the enzyme glucocerebrosidase. The substrate of the enzyme,
glucosylceramide, accumulates in the lysosomes of macrophages in affected patients, where it is stored in
a specific architectural arrangement. Glucosylceramide, a normal cell membrane component, is generated
in macrophages as they degrade effete cells during the process of routine cell turnover. The lysosomes,
distended with their contents, engorge the cytoplasm of the macrophages and cause it to have a
characteristic fibrillar (likened to wrinkled cigarette paper) appearance.
The genetic code for glucocerebrosidase is located in chromosome 1,q21. In Gaucher's patients, over
150 different mutations, including point mutations, crossovers and recombinations have been identified in
this chromosomal region. Some of the mutations are more common than others, some are associated with
certain subtypes of the disease and some are found in specific patient populations. For example, the
N370S mutation is particularly frequent in Ashkenazi Jews where it occurs in approximately 1 in 855
births and produces the type 1 variant.
Gaucher's disease has been divided into three clinical types based on whether they are neuronopathic
or non-neuronopathic, the age of the patient at onset of symptoms and the rate of disease progression.
The type 1 variant is the most common and presents during childhood or adulthood and is most common in
Ashkenazi Jews. The signs and symptoms are variable and are usually related to splenomegaly,
hepatomegaly, hematologic abnormalities, and problems with the pulmonary system as well as the skeletal
The splenomegaly can be massive and the accompanying hypersplenism results in pancytopenia and very
low platelet counts, which may cause serious bleeding abnormalities.
The skeletal complications are numerous and can be extremely disabling; they fall into
different types, which are each related to their pathophysiology. The failure of bone modeling is caused
by osteoclast dysfunction and manifests as the Erlenmayer flask deformity of long bones. Osteoporosis of
varying degrees of severity is related to diminished osteoblastic activity. Local lytic lesions produced
by mass-like aggregates of Gaucher cells can be complicated by pathologic fracture. Bone infarcts, which
are common in these patients, are of uncertain etiology and may involve the medullary cavity of the
diaphysis, metaphysis, or the subchondral regions adjacent to joints (avascular necrosis). Most of the
infarcts are clinically silent, but some can be extremely painful producing the so-called Gaucher's
crisis. Lastly, Gaucher's patients have a diminished capacity to fight infection, especially that caused
by bacteria; therefore they are prone to the development of osteomyelitis.
Histologically, Gaucher cells are about 2 to 6 times the diameter of a normal macrophage, contain
round or oval vesicular nuclei and abundant fibrillar eosinophilic cytoplasm. The fibrillar cytoplasm is
caused by the presence of numerous lysosomes that are filled with glucocerebroside stored as striated
helical structures in which there is specific arrangement of the different side chains of the
glucocerebroside molecule. In bone tissue the Gaucher cells are most numerous in the hematopoietic
marrow, where they are arranged in solid sheets, clusters or individual large cells that displace the
The cellular mechanisms underlying the multisystem organ dysfunction produced by Gaucher cells is
currently being elucidated. Recent evidence suggests that once the macrophages ingest and store the
glucocerebroside, they become activated and produce a variety of different cytokines that in turn results
in organ dysfunction.
Aside from supportive care, there are four broad categories of treatment for Gaucher's patients.
These include enzyme replacement, organ (bone marrow) or cell (macrophage) transplantation, reducing the
production of glucocerebroside and lastly, gene therapy. The effectiveness of theses various treatments
continually improve as advances in their respective technologies are achieved.
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