Musculoskeletal System Chapter Notes | Pathology - NEET PG PDF Download

Introduction

Bones are a kind of connective tissue made up of cells called osteoclasts and osteoblasts, along with a framework of minerals and proteins. The framework has a hard part made of minerals like calcium and phosphate, and a soft part made mostly of a protein called collagen (about 90–95%). This soft part also has other proteins that help cells stick together and send signals, such as osteopontin, fibronectin, and thrombospondin. There are also proteins that bind calcium, like osteocalcin, and substances called proteoglycans, such as biglycan and decorin.

The hard part of the bone is first laid down around the collagen fibres and fills the spaces between them. This creates a strong material that can handle stress.

Osteoblasts are cells that make and release the organic part of the bone. They come from a type of cell called mesenchymal cells. When an osteoblast creates a matrix that becomes mineralized, it transforms into an osteocyte. The process of mineralization is carefully regulated and depends on the action of a protein called alkaline phosphatase from osteoblasts. This protein likely works by breaking down substances that prevent mineralization. A protein called core-binding factor A1 (CBFA1, also known as Runx2) controls the production of important proteins in osteoblasts, such as osterix, osteopontin, bone sialoprotein, type I collagen, osteocalcin, and RANK ligand. The expression of Runx2 is partly controlled by bone morphogenic proteins (BMPs).

Osteoclasts are the cells responsible for breaking down bone. A protein called macrophage colony-stimulating factor (M-CSF) is crucial in this process, helping to fuse osteoclast precursor cells into active osteoclasts. RANK ligand, found on osteoblast progenitors and stromal fibroblasts, binds to the RANK receptor on osteoclast progenitors, promoting their differentiation and activation. Alternatively, a soluble decoy receptor called osteoprotegerin can bind to RANK ligand and prevent osteoclast differentiation. Various growth factors and cytokines, including interleukins 1, 6, and 11, TNF, and interferon-gamma, influence osteoclast differentiation and function.

Remodeling of bone

The basic multicellular unit (BMU), consisting of groups of osteoclasts and osteoblasts, is responsible for the cycle of bone remodeling. In cortical bone, BMUs create tunnels through the tissue, while in cancellous bone, they travel across the trabecular surface. Bone remodeling begins with the contraction of lining cells and the recruitment of osteoclast precursors. These precursors combine to form multinucleated, active osteoclasts that aid in bone resorption. Osteoclasts adhere to the bone and remove it through acidification (with protons secreted by type II carbonic anhydrase) and proteolytic digestion (by cathepsin K). As the BMU advances, osteoclasts leave the resorption site, and osteoblasts arrive to cover the area and initiate new bone formation by secreting osteoid, which eventually becomes mineralized bone. Once the osteoid is mineralized, osteoblasts flatten out and form a layer of lining cells over the new bone. Bone remodeling occurs along the lines of force created by mechanical stress.

Biochemical markers of bone resorption

• Amino and carboxy terminal crosslinking telopeptide of bone collagen
• Pyridinoline

Cleidocranial dysplasia is a condition that affects bone development and is caused by mutations that deactivate the Runx2 gene. Two important substances, parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D, play a role in maintaining mineral balance by activating receptors on osteoblasts.

Concept

Most hormones that influence osteoclast function do not act directly on these cells. Instead, they affect the signaling of M-CSF and RANK ligand in osteoblasts. Both PTH and 1,25(OH)2D increase the number and activity of osteoclasts, while estrogen reduces both through this indirect mechanism. Calcitonin, however, directly inhibits osteoclast function by binding to its receptor on these cells. Tetracycline is a marker of bone growth in human biopsies. It is absorbed into bone and binds to newly formed bone at the bone/osteoid interface, producing a linear fluorescence. This method, known as tetracycline labeling, helps measure the amount of bone growth over a period of about 21 days. In double tetracycline labeling, a second dose is given 11–14 days after the first, allowing measurement of the bone formed in that interval by the distance between the two fluorescent labels.

Paget's Disease: Characteristics of Bone

• Paget's disease is characterized by a mosaic pattern of lamellar bone when observed under a microscope. This indicates a disorganized but thickened bone structure.

Osteoblastoma

• Osteoblastoma is different from osteoid osteoma in its frequency of occurrence in the spine.
• The pain associated with osteoblastoma is dull and achy, and it does not respond to salicylates, which are a type of pain reliever.
• Osteoblastoma does not cause a significant bony reaction, meaning there is not much visible change in the surrounding bone.

Biomarkers

• Free lysyl-pyridinoline
• Tartarate-resistant acid phosphatase (TRAP)
• Hydroxyproline (Note: This marker is not very specific)
• Bone-specific alkaline phosphatase
• Procollagen type IC and IN propeptide
• Osteocalcin
• Alkaline phosphatase (Note: This marker is also not very specific)

Paget's Disease (Osteitis Deformans)

Paget's disease, also known as osteitis deformans, is a condition that affects the bones in a complex manner. It involves a process where there is intense breakdown of bone followed by rapid rebuilding, resulting in an overall increase in bone mass. The disease progresses through three distinct stages:

• Initial Osteolytic Stage: This is the first stage where there is significant bone destruction.
• Mixed Osteoclastic-Osteoblastic Stage: In this stage, both bone resorption by osteoclasts and bone formation by osteoblasts occur.
• Burnt-Out Quiescent Osteosclerotic Stage: This is the final stage where the disease becomes quiescent, and there is a predominance of sclerotic (hard) bone.

Paget's disease usually begins after the age of 40 and can affect anyone, but it is more common in older adults and certain ethnic groups. There is a suspected link to slow viral infections caused by paramyxovirus.

Monostotic vs. Polyostotic Paget's Disease

In about 15% of cases, Paget's disease affects a single bone (monostotic), which can include bones such as the:

• Tibia
• Ilium
• Femur
• Skull
• Vertebra
• Humerus

In the remaining cases, multiple bones (polyostotic) are involved, including the:

• Pelvis
• Spine
• Skull

Up to 80% of cases affect the axial skeleton or proximal femur.

X-ray Findings

On X-rays, bones affected by Paget's disease appear enlarged, with thickened cortices (the outer layer of bone) and spongy bone. There is also an increase in serum alkaline phosphatase levels and higher urinary excretion of hydroxyproline, which are indicators of increased bone turnover.

Symptoms and Complications

The most common symptom of Paget's disease is pain. Overgrowth of facial bones can lead to a condition known as leontiasis ossea, and weakened bones may cause issues at the base of the skull, a condition called platybasia.

Under a microscope, the defining feature of Paget's disease is a mosaic pattern of lamellar bone. This pattern is created by prominent cement lines that connect unevenly arranged units of bone, resulting in weak bones that are prone to fractures.

Complications from Paget's disease can include:

• Arteriovenous Shunts: Formation of arteriovenous shunts within the bone marrow, leading to high output cardiac failure.
• Increased Risk of Sarcomas: Higher risk of developing sarcomas such as osteosarcoma and chondrosarcoma.
• Secondary Osteoarthritis: Development of secondary osteoarthritis due to joint involvement.
• Chalk-Stick Type Fractures: Fractures resembling chalk-stick fractures due to the abnormal bone structure.

Benign Tumors of the Bone

Osteoma

• Subperiosteal osteomas are non-cancerous growths that primarily impact the skull and facial bones.
• These tumors are usually found as single instances and are most common in middle-aged adults.
• However, in certain cases, such as individuals with Gardner’s syndrome, multiple osteomas can occur.

Osteoid Osteoma and Osteoblastoma

• Osteoid osteoma and osteoblastoma are benign bone tumors that have similar microscopic characteristics but differ in size, origin, and symptoms.
• Osteoid osteoma.
  • Size: Less than 2 cm.
  • Typically seen in: Teenagers and young adults.
  • Common locations: Femur or tibia, usually on the cortex.
  • Symptoms: Pain, often occurring at night and significantly relieved by aspirin.
• Histology.
  • Central nidus of osteoid surrounded by a dense sclerotic rim of reactive cortical bone.
  • X-rays: Show a central radiolucency encircled by a sclerotic rim.

Osteochondroma (Exostosis)

• Osteochondroma, also known as exostosis, is a benign bone growth characterized by a cartilage cap.
• This growth originates from the epiphyseal growth plate and is commonly observed in adolescent males.
• Symptoms.
  • Firm, solitary growth at the ends of long bones.
  • Pain and deformity may occur, but some cases are asymptomatic.
• Malignant Potential. Rarely, osteochondromas can undergo malignant transformation.
• Multiple Hereditary Exostosis. Genetic Condition. Involves the occurrence of multiple osteochondromas due to a genetic predisposition.
• EXT Gene Inactivation. Both copies of the EXT gene in growth plate chondrocytes are inactivated during the development of osteochondromas.
• Age of Onset. These tumors typically become noticeable during childhood.

Chondroma

• Chondromas are benign tumors composed of hyaline cartilage, usually found in bones that develop from cartilage.
• They can be categorized into enchondromas and subperiosteal or juxtacorticalchondromas:
  • Enchondroma. Originates from within the bone (intramedullary).
  • Subperiosteal or juxtacortical. Arises from the surface of the bone.
• Enchondromas are the most common type of cartilage tumor within bones, often found in the short tubular bones of the hands and feet.
• They consist of well-defined nodules of benign hyaline cartilage. The centre can calcify while the edges might undergo enchondral ossification.
• The unmineralised cartilage nodules create distinct oval lucencies, surrounded by a thin rim of denser bone (known as the O ring sign).

Patients with Ollier’s disease may experience malignant transformation to chondrosarcoma. Those with Maffuci’s syndrome are at a higher risk of ovarian cancer and brain gliomas.

• Ollier’s disease. Characterised by multiple enchondromas (enchondromatosis).
• Maffuci’s syndrome. Involves soft tissue hemangiomas along with enchondromatosis.

Malignant Tumours of the Bone

Osteosarcoma

• Osteosarcoma is the most prevalent type of primary malignant bone tumour.
• Approximately 75% of cases occur in individuals under the age of 20.
• There is another peak of occurrence in the elderly, often associated with conditions such as Paget disease, bone infarcts, and prior irradiation.
• Osteosarcoma is more common in males, particularly those with familial retinoblastoma.
• Patients typically experience localized pain and swelling.
• The tumour usually develops in the metaphysis of long bones, especially around the knee.
• Grossly, the tumour appears as a large, firm white-tan mass with areas of necrosis and bleeding.
• Microscopically, it features anaplastic cells that produce osteoid and bone.
• The tumour often breaches the cortex and lifts the periosteum, leading to reactive periosteal bone formation.
• The triangular shadow seen between the cortex and lifted periosteum in radiographic images is known as Codman’s triangle.

Chondrosarcoma

• Chondrosarcoma comprises a group of tumours that produce neoplastic cartilage.
• Similar to chondromas, chondrosarcomas can be classified as intramedullary or juxtacortical.
• Chondrosarcoma is the second most common malignant matrix-producing bone tumour, following osteosarcoma.
• Histologically, chondrosarcoma consists of malignant hyaline and myxoid cartilage, with possible spotty calcifications and central necrosis leading to cystic spaces.
• These tumours can vary in cell density and appearance, with malignant cartilage invading the marrow space and surrounding existing bone trabeculae.
• Chondrosarcomas typically arise in central skeletal regions such as the pelvis, shoulder, and ribs.
• Unlike chondromas, chondrosarcomas rarely affect the distal extremities.
• The clear cell variant of chondrosarcoma often originates from the epiphysis of long bones.

Osteoclastoma or Giant Cell Tumour of Bone

• Other giant cell lesions include:
  • Brown tumour seen in hyperparathyroidism
  • Giant cell reparative granuloma
  • Chondroblastoma
  • Pigmented villonodular synovitis
• This malignant tumour contains multinucleated giant cells mixed with stromal cells.
• More common in females, most frequently affecting those aged 20-40 years.
• It involves the epiphysis of long bones, particularly around the knee.
• Microscopically, it shows osteoclast-like giant cells (with over 100 nuclei) among mononuclear stromal cells.
• Most tumours are solitary.
• Radiographically, they appear large, lytic, and eccentric, eroding the subchondral bone plate.
• The overlying cortex is often destroyed, causing a bulging soft tissue mass with a thin shell of reactive bone, giving a soap bubble appearance.
• These tumours have a high recurrence rate after removal.

Ewing’s Sarcoma and Primitive Neuroectodermal Tumour (PNET)

• Ewing sarcoma and PNET are primary malignant small round cell tumours of bone and soft tissue.
• Although similar, they are distinct based on specific diagnostic criteria and neural differentiation.
• Tumours showing neural differentiation are referred to as PNETs, while undifferentiated tumours are called Ewing’s sarcoma.
• Ewing’s sarcoma has the youngest average age at diagnosis, with around 80% of patients under 20 years old.
• Boys are slightly more affected than girls.
• The classic translocation associated with Ewing’s sarcoma is t(11;22)(q24;q12), with the most common fusion gene (EWS-FLI1) acting as a dominant oncogene driving cell growth.
• The presence of p30/32, a product of the mic-2 gene, marks Ewing’s sarcoma.
• These tumours generally arise in the diaphysis of long bones, particularly the femur and flat bones of the pelvis.
• The tumour consists of sheets of uniform small round cells, slightly larger than lymphocytes, often with clear cytoplasm due to high glycogen content.
• They may form Homer-Wright rosettes, indicative of neural differentiation.
• Patients present with painful enlarging masses that are often tender, warm, and swollen, along with systemic signs like fever, increased ESR, anaemia, and leukocytosis, resembling an infection.
• X-rays reveal characteristic periosteal reactions, showing layers of reactive bone in an ‘onion-skin’ pattern.

Note: The most prevalent type of skeletal malignancy is metastatic tumors.

Soft Tissue Tumors

Synovial Sarcoma

• Synovial sarcomas account for approximately 10% of all soft tissue sarcomas.
• Less than 10% of these tumors occur within joints.
• They primarily affect the lower limbs, with a particular focus on areas near the knee and thigh.
• Biphasic synovial sarcoma is characterized by the presence of two distinct types of tumor cells: epithelial-like cells and spindle cells.
• In some cases, calcified deposits may be observed, aiding in diagnosis through imaging techniques.
• Diagnostic tests reveal that these tumor cells exhibit positive reactions for keratin and epithelial membrane antigen, helping to differentiate them from most other sarcomas.
• Many synovial sarcomas harbor a specific chromosomal alteration, t(X;18), leading to the formation of SYT-SSX1 or -SSX2 fusion genes. This chromosomal alteration is associated with a poor prognosis.

Architectural Patterns in Soft Tissue Tumors

• Tumor Type
• Fascicles of eosinophilic spindle cells crossing at right angles
• Smooth muscle
• Short fascicles of spindle cells radiating from a central point, resembling spokes on a wheel—storiform
• Fibrohistiocytic
• Nuclei arranged in columns —palisading
• Schwann cell
• Herringbone
• Fibrosarcoma
• A combination of spindle cell fascicles and clusters of epithelioid cells—biphasic
• Synovial sarcoma

Inflammatory Myopathies

Inflammatory myopathies represent the most significant group of treatable acquired causes of muscle weakness. This category encompasses conditions characterized by muscle inflammation and damage, leading to weakness and dysfunction. The three primary types of inflammatory myopathies are: polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM). Each of these conditions has distinct clinical features, diagnostic criteria, and treatment approaches.

Criteria for Diagnosis of Inflammatory Myopathies

• Myopathic muscle weakness: Muscle weakness is a key feature in all three conditions. In polymyositis, weakness is present, while in dermatomyositis, it typically has a slow onset with early involvement of distal muscles and frequent falls. Inclusion body myositis also presents with muscle weakness.
• Electromyographic findings: Electromyography (EMG) in polymyositis shows myopathic changes with mixed potentials. Dermatomyositis and inclusion body myositis also exhibit myopathic changes, but with specific differences in findings.
• Muscle enzymes: Muscle enzyme levels are elevated in both polymyositis (up to 50-fold) and dermatomyositis (up to 10-fold) or may be normal. Inclusion body myositis also shows elevated or normal muscle enzymes.
• Muscle biopsy findings: Muscle biopsy is crucial for diagnosis. Polymyositis shows primary inflammation with the CD8/MHC-I complex and no vacuoles. Dermatomyositis exhibits perifascicular, perimysial, or perivascular infiltrates and perifascicular atrophy. Inclusion body myositis shows primary inflammation with the CD8/MHC-I complex, vacuolated fibers with amyloid deposits, cytochrome c oxidase–negative fibers, and signs of chronic myopathy.
• Rash or calcinosis: Dermatomyositis is characterized by the presence of a rash, while polymyositis and inclusion body myositis do not have this feature.

Muscular Dystrophies

Muscular dystrophies encompass a diverse range of inherited disorders that typically manifest in childhood and are characterized by progressive muscle weakness and atrophy. The most prevalent forms are X-linked conditions known as Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). DMD is more common and severe than BMD.

Both DMD and BMD arise from mutations in a gene responsible for producing dystrophin, a crucial protein. Dystrophin, along with the dystrophin-associated protein complex, forms a vital link between the muscle cell's internal structure and the surrounding connective tissue. This connection is essential for transmitting the force generated by muscle contractions to the connective tissue. In the absence of dystrophin, muscle cells begin to degenerate.

Histopathological Features:

• DMD: Characterized by the complete lack of functional dystrophin.
• BMD: Involves reduced production of an altered form of dystrophin.
• Common histopathological abnormalities in both DMD and BMD include:
• Variation in muscle fiber size due to the presence of both small and enlarged fibers.
• Increased internalized nuclei within muscle fibers.
• Degeneration, necrosis, and breakdown of muscle fibers.
• Regeneration of muscle fibers following injury.
• Proliferation of endomysial connective tissue.

In DMD, there is often an abundance of enlarged, rounded, hyaline fibers lacking typical cross-striations, believed to be hypercontracted fibers. This phenomenon is less common in BMD. As the disease progresses, muscle tissue may be extensively replaced by fat and connective tissue. Cardiac complications, such as interstitial fibrosis, particularly in the subendocardial layers, are also observed in DMD.

Clinical Features:

• DMD: Boys with DMD appear normal at birth and achieve early motor milestones. However, they may experience delays in walking, with initial weakness in pelvic girdle muscles followed by involvement of shoulder girdle muscles. This progression leads to the characteristic Gower’s sign, where children use their hands to assist in standing up. Calf muscles may exhibit pseudohypertrophy, initially due to increased muscle fiber size and later because of fat and connective tissue replacement. Cognitive impairment may also be present. Elevated serum creatine kinase levels are common in early childhood but decrease as muscle mass declines. Fatalities often result from respiratory failure, lung infections, and cardiac issues.
• BMD: Symptoms in BMD typically emerge later than in DMD, often during childhood or adolescence, with a more gradual and variable progression. Cardiac complications are frequently observed in BMD patients.