MUSCULOSKELTAL SYSTEM PART-2
ARTHRITIS
Osteoarthritis (Degenerative joint disease) is the most common joint disorder. It is
a frequent consequence of aging and is an important cause of physical disability in
individuals over the age of 65. The fundamental feature of osteoarthritis is
degeneration of the articular cartilage.
In most cases, osteoarthritis appears insidiously with age and without apparent
initiating cause (primary osteoarthritis). When osteoarthritis manifests in youth, there
is typically some predisposing condition, such as previous traumatic injury,
developmental deformity, or marked obesity. In these settings the disease is called
secondary osteoarthritis. Gender has some influence; knees and hands are more
commonly affected in women, whereas hips are more commonly affected in men.
Pathological features
Early changes include proliferation with disorganization of the chondrocytes in the
superficial part of the articular cartilage with subsequent reduction of elasticity.
As the superficial part of the cartilage are degraded vertical and horizontal
fibrillation and cracking of the matrix occur.
Eventually, full-thickness portions of the cartilage are lost, and the subchondral
bone plate is exposed. Friction smooths and polishes the exposed bone
(eburnation).
Small fractures displace pieces of cartilage and subchondral bone into the joint,
forming loose bodies (joint mice). The fracture gaps are filled with synovial fluid
to form eventually fibrous walled cysts.
Mushroom-shaped osteophytes (bony outgrowths) develop at the margins of the
articular surface that may have mechanical effect on adjacent structures e.g.,
nerves.
In severe disease, a fibrous synovial pannus covers the peripheral portions of the
articular surface.
Pathogenesis
Regardless of the inciting stimulus (wear & tear of aging, estrogens in females, and
genetic susceptibility), early osteoarthritis is marked by degenerating cartilage
containing more water and less proteoglycan. The collagen network is also
diminished, presumably as a result of decreased local synthesis and increased
breakdown; chondrocyte apoptosis is increased.
Overall, cartilage tensile strength and resilience are reduced. In response to these
degenerative changes, chondrocytes in the deeper layers proliferate and attempt to
"repair" the damage by synthesizing new collagen and proteoglycans. Although
these reparative changes are initially able to keep pace, matrix changes and
chondrocyte loss eventually predominate.
Gout
This is a disorder caused by the tissue accumulation of excessive amounts of uric
acid, an end product of purine metabolism. It is marked by recurrent episodes of acute
arthritis, sometimes accompanied by the formation of large crystalline aggregates
called tophi & chronic joint deformity. All of these are the result of precipitation of
monosodium urate crystals from supersaturated body fluids. Not all individuals with
hyperuricemia develop gout; this indicates that influences besides hyperuricemia
contribute to the pathogenesis. Gout is traditionally divided into primary (90%) and
secondary forms (10%). Primary gout designates cases in whom the basic cause is
unknown or when it is due to an inborn metabolic defect that causes hyperuricemia. In
secondary gout the cause of the hyperuricemia is known.
Pathologic features
The major morphologic manifestations of gout are
1. Acute arthritis
2. Chronic tophaceous arthritis
3. Tophi in various sites, and
4. Gouty nephropathy
In gouty Acute arthritis in addition to features of acute inflammation needle shape
monosodium urate crystals are frequently found in the cytoplasm of the neutrophils as
well as in small clusters in the synovium.
In Chronic tophaceous arthritis: visible deposits seen in the synovium that becomes
hyperplastic, fibrotic, and thickened by inflammatory cells, forming a pannus that
destroys the underlying cartilage, and may erode subjacent bone. In severe cases,
fibrous or bony ankylosis occurs, resulting in loss of joint function.
Tophi are the pathognomonic hallmarks of gout.
Tophi can appear in the articular cartilage, periarticular ligaments, tendons, and
soft tissues, including the ear lobes. Superficial tophi can lead to large ulcerations
of the overlying skin.
Microscopically, they are formed by large aggregations of urate crystals
surrounded by an intense inflammatory reaction of lymphocytes, macrophages, and
foreign-body giant cells, attempting to engulf the masses of crystals.
Gouty nephropathy
This refers to the renal complications associated with urate deposition including
medullary tophi, intratubular precipitations and renal calculi. Secondary
complications such as pyelonephritis can occur, especially when there is urinary
obstruction.
Pathogenesis
Although the cause of excessive uric acid biosynthesis in primary gout is unknown
in most cases, rare patients have identifiable enzymatic defects or deficiencies that
are associated with excess production of uric acid.
In secondary gout, hyperuricemia can be caused by increased urate production
(e.g., rapid cell lysis during chemotherapy for lymphoma or leukemia) or
decreased excretion (chronic renal failure), or both. Reduced renal excretion may
also be caused by drugs such as thiazide diuretics, because of their effects on uric
acid tubular transport.
Whatever the cause, increased levels of uric acid in the blood and other body fluids
(e.g., synovium) lead to the precipitation of monosodium urate crystals. The
precipitated crystals are chemotactic to neutrophils & macrophages through
activation of complement components C3a and C5a fragments. This leads to a
local accumulation of neutrophils and macrophages in the joints and synovial
membranes to phagocytize the crystals. The activated neutrophils liberate
destructive lysosomal enzymes. Macrophages participate in joint injury by
secreting a variety of proinflammatory mediators such as IL-1, IL-6, and TNF.
While intensifying the inflammatory response, these cytokines can also directly
activate synovial cells and cartilage cells to release proteases (e.g., collagenases)
that cause tissue injury.
Repeated bouts of acute arthritis, however, can lead to the permanent damage seen
in chronic tophaceous arthritis.
Pseudogout (chondrocalcinosis) (Calcium pyrophosphate crystal deposition
disease). Pseudogout typically first occurs in the age 50 years or older. It involves
enzymes that lead to accumulation and eventual crystallization of pyrophosphate with
calcium. The pathology in pseudogout involves the recruitment and activation of
inflammatory cells, and is reminiscent of gout. The knees, followed by the wrists,
elbows, shoulders, and ankles, are most commonly affected. Approximately 50% of
patients experience significant joint damage.
Infectious Arthritis:
can cause rapid joint destruction and permanent deformities. Microorganisms can
lodge in joints during hematogenous dissemination, by direct inoculation or by
contiguous spread from osteomyelitis or a soft tissue abscess.
Suppurative Arthritis is a subtype of infectious arthritis in which the bacteria seed the
joint during episodes of bacteremia. Haemophilus influenzae predominates in children
under age 2 years, S. aureus is the main causative agent in older children and adults,
and gonococcus is prevalent during late adolescence and young adulthood. There is
sudden onset of pain, redness, and swelling of the joint with fever, leukocytosis, and
elevated ESR. In 90% of nongonococcal suppurative arthritis, the infection involves
only a single joint-usually the knee. Joint aspiration is typically purulent, and allows
identification of the causal agent.
JOINT TUMORS AND TUMOR-LIKE LESIONS
Ganglion and Synovial Cysts
A ganglion is a small (<1.5 cm) cyst located near a joint capsule or tendon sheath; the
wrist is an especially common site. It is firm to fluctuant pea-sized nodules. Because
they arise by cystic degeneration of connective tissue they are grossly translucent and
microscopically lack a true cell lining. They are usually asymptomatic.
Synovial cyst occurs due to herniation of synovium through a joint capsule or massive
enlargement of a bursa. A good example is the Baker cyst that occurs in the popliteal
fossa.
Pigmented Villonodular Tenosynovitis (PVNS) & Giant-Cell Tumor (GCT) of
Tendon Sheath
These are closely related benign neoplasms of synovium. PVNS tends to involve
joints diffusely, whereas GCT usually occurs as a single tendon sheath nodule.
Grossly, both lesions are red-brown to orange-yellow. In PVNS the joint synovium is
diffusely converted into red-brown finger-like projections, and nodules. In contrast,
GCT is well circumscribed and contained. Microscopically, Tumor cells in both
lesions resemble synoviocytes. In PVNS they spread along the surface and infiltrate
the subsynovial compartment. In GCT the cells grow in a solid nodular aggregate.
Other typical findings include hemosiderin deposits, foamy macrophages, &
multinucleated giant cells. PVNS usually affects the knee (80% of cases). Patients
typically complain of pain, locking, and recurrent swelling. In contrast, GCT
manifests as a solitary, slowly growing mass frequently involving wrist and finger
tendon sheaths. GCT is the most common soft tissue tumor of the hand.
SKELETAL MUSCLES
Diseases that affect skeletal muscle can involve any portion of the motor unit; these
include
1. Disorders of the motor neuron or axon (neurogenic atrophy)
2. Abnormalities of the neuromuscular junction (e.g. myasthenia gravis)
2. Disorders of the skeletal muscle itself (myopathies)
Muscle Atrophy is a non-specific response in a variety of muscle disorders. It is
characterized by abnormally small myofibers; the type of fibers affected by the
atrophy, their distribution in the muscle, and their specific morphology help identify
the etiology of the atrophic changes.
Neurogenic Atrophy is due to lack of normal enervation. The loss of a single neuron
will affect all muscle fibers in a motor unit, so that the atrophy tends to be scattered
over the field. It is characterized by involvement of both fiber types, and by clustering
of myofiers into small groups.
Muscular Dystrophy
The muscular dystrophies are “a heterogeneous group of inherited disorders, often
presenting in childhood, characterized by progressive degeneration of muscle fibers
leading to muscle weakness and wasting.” In advanced cases muscle fibers are
replaced by fibrofatty tissue. This histologic feature distinguishes dystrophies from
myopathies, which also present with muscle weakness.
Example on this group are:
1.
X-Linked Muscular Dystrophy: Duchenne Muscular Dystrophy (DMD)
.:
This X-linked inherited disease is the most common & the most severe form
of muscular dystrophy. It becomes clinically evident by age 5, with
progressive weakness leading to wheelchair dependence by age 10 to 12 years,
and death by the early 20s. The same gene is involved in a related but milder
form designated Becker muscular dystrophy. DMD is caused by abnormalities
in the dystrophin gene located on the short arm of the X chromosome. In
affected families, females are carriers; they are clinically asymptomatic.Boys
with DMD show delayed walking.
2. Myotonic Dystrophy: The cardinal neuromuscular symptom in myotonic
dystrophy is myotonia, which is a sustained involuntary contraction of a group
of muscles. Patients often complain of "stiffness" and have difficulty in
releasing their grip, for instance, after a handshake. Myotonic dystrophy is
inherited as an autosomal dominant trait that is associated with a CTG
trinucleotide repeat expansion on chromosome 19 that affects the mRNA for
the myotonia-protein kinase. The disease often presents in late childhood with
gait abnormalities.
Diseases of the Neuromuscular Junction
Myasthenia Gravis is “an autoimmune disorder of the neuromuscular junction
characterized by muscle weakness.” The disease can present at any age and has a
predilection for women. Thymic hyperplasia is found in 65% and a thymoma in 15%
of patients. Circulating antibodies to the skeletal muscle acetylcholine receptors
(AChRs) are present in nearly all patients, associated with a decrease in the number of
AChRs.
Pathogenesis
In most cases, the autoantibodies against the AChR lead to loss of functional
AChRs at the neuromuscular junction either by (1) increasing degradation of the
receptors, and/or (2) blocking the binding of acetylcholine (ACh) to its receptor.
The link between autoimmunity to AChRs and the thymic abnormalities is unclear.
Nevertheless, most patients show improvement after thymectomy.
Typically, weakness is first noticed in the extraocular muscles as evidenced by
drooping eyelids (ptosis) and double vision (diplopia). The generalized muscle
weakness can fluctuate dramatically, with alterations occurring over the course of
days, hours, or even minutes. Sensory and autonomic functions are not affected.
Respiratory impairment was a major cause of mortality in the past.
Lambert-Eaton
Myasthenic
Syndrome
characteristically
develops
as
a
paraneoplastic process, most commonly in the setting of small-cell carcinoma of the
lung; it can also occur in the absence of malignancy. Although individuals with this
syndrome also present with muscle weakness
Skeletal Muscle Tumors
Rhabdomyosarcoma
Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood and
adolescence, usually appearing before age 20. They occur most commonly in the head
and neck or genitourinary tract.
Chromosomal translocations are found in most cases; the more common t(2;13)
translocation (gene that controls skeletal muscle differentiation & development)
Gross features
Tumors arising near the mucosal surfaces of the bladder or vagina, can present as
soft, gelatinous, grapelike masses, designated sarcoma botryoides.
In other cases they are deceptively demarcated or infiltrative grayish-white to
brownish masses.
Microscopical features
Rhabdomyosarcoma is histologically subclassified into the embryonal, alveolar,
and pleomorphic variants.
The rhabdomyoblast is the diagnostic cell in all types; it exhibits granular
eosinophilic cytoplasm, and may be round or elongated; the latter are known as
tadpole or strap cells and may contain cross-striations visible by light microscopy.
Skeletal muscel differentiation can be demonstrated by immunohistochemistry and
electron microscopy.
Rhabdomyosarcomas are aggressive neoplasms. Location and the histologic variant of
the tumor influence survival; embryonal, pleomorphic, and alveolar variants have
progressively worsening prognoses. The malignancy is curable in almost two-thirds of
children, but adults do much more poorly.
SOFT TISSUE TUMORS
Fatty Tumors
1. Lipomas are benign tumors of fat, and are the most common soft tissue tumors of
adulthood. Most lipomas are solitary lesions. Lipomas can be subclassified based on
their histologic features (e.g., conventional, myolipoma, spindle cell, myelolipoma,
pleomorphic, angiolipoma). Most lipomas are mobile, slowly enlarging, painless
masses. They are usually seen in adults age 40+; associated with obesity; there are no
gender differences. They are rare in children. Multiple lipomas are more common in
women. Pathological features: Conventional lipomas (the most common subtype)
are soft, yellow, well-encapsulated masses They can vary considerably in size.
Microscopically, they consist of mature fat cells with no pleomorphism.
2. Liposarcoma is a malignant neoplasm of adipocytes. These tumors occur most
commonly in the 40 to 60 years of age & mostly in the deep soft tissues or in visceral
sites. The prognosis of liposarcomas is greatly influenced by the histologic subtype;
well-differentiated and myxoid variants tend to grow in a fairly indolent fashion and
have a more favorable outlook than do the more aggressive round cell and
pleomorphic variants, which tend to recur after excision and metastasize to lungs. A
t(12;16) chromosomal translocation is associated with myxoid liposarcomas.
Pathological features:
Usually they are relatively well-circumscribed large masses.
Several different histologic subtypes are recognized, including two low-grade
variants, the well-differentiated liposarcoma and the myxoid liposarcoma, the
latter characterized by abundant, mucoid extracellular matrix.
Some well-differentiated lesions can be difficult to distinguish histologically from
lipomas, whereas very poorly differentiated tumors can resemble various other
high-grade malignancies.
In most cases, cells indicative of fatty differentiation are present. Such cells are
known as lipoblasts; they recapitulate fetal fat cells with cytoplasmic lipid
vacuoles that scallop the nucleus.
Fibrous Tumors and Tumor-Like Lesions
Reactive Proliferations
1. Nodular Fasciitis is a self-limited, reactive fibroblastic proliferation that typically
occurs in adults on the volar aspect of the forearm. Patients characteristically present
with a several-week history of a solitary, rapidly growing mass. Preceding trauma is
noted in up to 15% of cases.
2. Myositis Ossifican is distinguished from other fibroblastic proliferations by the
presence of metaplastic bone. It usually develops in the proximal muscles of the
extremities in athletic adolescents and young adults after trauma. The involved area is
initially swollen and painful, eventually evolving into a painless, hard, well-
demarcated mass. It is vital to distinguish the lesion from extra-skeletal osteosarcoma.
3. Fibromatoses are a group of fibroblastic proliferations distinguished by their
tendency to grow in an infiltrative fashion and, in many cases, to recur after surgical
removal. Although some lesions are locally aggressive, they do not metastasize. The
fibromatoses are divided into two major clinicopathologic groups: superficial(eg
palmar fibromatosis (Dupuytren contracture) and penile fibromatosis (Peyronie
disease)) and deep (include the so-called desmoid tumors that arise in the abdominal
wall & muscles of the trunk and extremities)
Fibrosarcoma:
is a malignant neoplasm composed of fibroblasts. Most occur in adults, typically in
the deep tissues of the thigh and retroperitoneal area. As with other sarcomas,
fibrosarcomas often recur locally after excision (>50% of cases) and can metastasize
hematogenously (>25% of cases), usually to the lungs.
Pathological features:
These unecapsulated, infiltrative sarcomas show frequently areas of hemorrhage and
necrosis. Microscopically, the low-grade tumors may closely resemble fibromatosis;
less differentiated examples show densely packed spindled cells growing in a
herringbone fashion, there are frequent mitoses, and necrosis.
Fibrohistiocytic Tumors
These are composed of a mixture of fibroblasts and phagocytic, lipid-laden cells
resembling activated macrophages. The neoplastic cells are most likely fibroblasts.
Nevertheless, a significant number of such tumors actually derive from other
mesenchymal cell types. Thus, the term fibrohistiocytic, especially in regard to the
malignant variants, should be considered descriptive and not necessarily referring to a
specific cellular origin. These tumors are divided into benign, of intermediate
malignant potential, frankly malignant.
1. Benign Fibrous Histiocytoma (Dermatofibroma) are relatively common benign
lesions in adults presenting as small (<1 cm) mobile nodules in the dermis or
subcutaneous tissue. Microscopically, the lesion consists of bland, interlacing spindle
cells admixed with foamy, lipid-rich histiocyte-like cells.
2. Malignant Fibrous Histiocytoma (MFH) is a term rather loosely applied to a
variety of soft tissue sarcomas characterized by considerable cytologic pleomorphism,
the presence of bizarre multinucleate cells, and storiform architecture. Despite the
name, the phenotype of many such tumors is fibroblastic and not histiocytic. MFH
exhibiting fibroblastic differentiation are usually large (5-20 cm), gray-white
unencapsulated masses that often appear deceptively circumscribed. They usually
arise in the musculature of the proximal extremities or in the retroperitoneum. Most of
these tumors are extremely aggressive, recur unless widely excised, and have a
metastatic rate of 30% to 50%.
Smooth Muscle Tumors
1. Leiomyomas are common, well-circumscribed neoplasms that can arise from
smooth muscle cells anywhere in the body, but are encountered most commonly in the
uterus.
2. Leiomyosarcomas (15% of soft tissue sarcomas). They occur in adults, more
commonly females. Deep soft tissues of the extremities and retroperitoneum are
common sites. Microscopically, they show spindle cells with cigar-shaped nuclei
arranged in interweaving fascicles.Superficial leiomyosarcomas are usually small and
have a good prognosis, whereas retroperitoneal tumors are large, cannot be entirely
excised, and cause death by both local extension and metastatic spread.
Synovial Sarcoma (10% of all soft tissue sarcomas)
The cell of origin is unclear and is most certainly not a synoviocyte. Reflecting a non-
joint origin, 90% of synovial sarcomas are not intra-articular but rather paraarticular.
They are typically seen in the 20-40 years of age. Most develop in deep soft tissues
around the large joints of the extremities, especially around the knee. Most synovial
sarcomas show a characteristic t(X;18) translocation, which relates to prognosis.
Microscopically, synovial sarcomas may be biphasic or monophasic. Classic biphasic
synovial sarcoma exhibits differentiation of tumor cells into both epithelial-like cells
and spindle cells. Common metastatic sites are lung, bone, and regional lymph nodes.
Only 10% to 30% live for more than 10 years.