Sample Chapter Pathology for Dental Students, 1e by Khanna To Order Call SMS at +91 8527622422
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  • 1. chapter chapter 16 Musculoskeletal System Bone Bone is the basic unit of human skeletal system. It provides framework for and bears the weight of body, protects vital organs, supports mechanical movement, and hosts hematopoietic cells. Bones can be classified based on their location, size, and structure. Location: Based on location, bones can be classified as follows: Axial skeleton: Bones of skull, vertebral column, sternum, and ribs Appendicular skeleton: Bones of pectoral girdle, pelvic girdle, and limbs Size: Based on size, bones can be classified as follows: Long bone: Tubular in shape, with a hollow shaft and two ends, e.g., bones Must know of the limbs Osteomyelitis Short bone: Cuboidal in shape, located only in foot (tarsal bones) and wrist (carpal bones) Metabolic Bone Diseases Regions: A long bone can be divided into several regions (Figure 16.1): Bone Tumors Epiphysis: In long bones, the epiphysis is the region between growth plate • Osteosarcoma and expanded end of bone, covered by articular cartilage. Metaphysis: The metaphysis is junctional region between the growth plate • Ewings Sarcoma and diaphysis. • Giant Cell Tumor Diaphysis: The diaphysis is shaft of long bones, located in the region between metaphyses, and composed mainly of compact cortical bone. Fibrous Dysplasia Medullary canal contains marrow and a small amount of trabecular bone. Aneurysmal Bone Cyst Physis (epiphyseal plate, growth plate): The physis is the region that separates the epiphysis from the metaphysis. It is the zone of endochondral ossification in an actively growing bone or the epiphyseal scar in a fully grown bone. Blood supply: Bone has a rich vascular supply, receiving 10%–20% of the cardiac output. The blood supply varies with different types of bones, but blood vessels are especially rich in areas that contain red bone marrow. Long bones: Diaphyseal nutrient artery Metaphyseal and epiphyseal arteries Periosteal arterioles: Several of these vessels supply the outer layers of cortical bone.Chapter-16.indd 325 13/12/12 4:04 PM
  • 2. 326 Section B | Systemic Pathology Spongy cavities. It consists mainly of Haversian systems or second- bone ary osteons. Spongy bone (trabecular bone, cancellous bone): Spongy bone is so named because it is sponge like with numerous Epiphysis cavities. It is located within the medullary cavity and con- sists of extensively connected bony trabeculae that form 16 Epiphyseal plate a sponge-like network. Mature trabecular bone exhibits lamellae and osteocytes between the lamellae. Inactive os- teocytes are also present on the bone surface with a flat- Musculoskeletal System Compact tened shape. bone Based on matrix arrangement, bone tissue can be classified as follows (Figure 16.2a & b): Diaphysis Lamellar bone: Lamellar bone is a mature bone with colla- gen fibers that are arranged in lamellae. In contrast to spongy bone, in which lamellae are arranged parallel to each other, in compact bone, the lamellae are concentrically organized around a vascular canal termed a Haversian canal. Woven bone: Woven bone is an immature bone in which Metaphysis collagen fibers are arranged in irregular random arrays, and contain smaller amounts of mineral substance and a higher Secondary proportion of osteocytes than lamellar bone. Woven bone ossification is temporary and is eventually converted to lamellar bone; center this type of bone is also a pathologic tissue in adults, except at few places, such as areas near sutures of the flat bones of Figure 16.1: Parts of a long bone. the skull, tooth sockets, and insertion site of some tendons. Based on developmental origin, bones can be classified as follows: Large irregular bones, short bones, and flat bones: These Intramembranous bone: Intramembranous bone develops bones receive a superficial blood supply from the periosteum from direct transformation of condensed mesenchyme. and the remaining from large nutrient arteries that penetrate Flat bones are formed in this way. directly into medullary bone. The two systems anastomose Intracartilaginous bone: Intracartilaginous bone forms freely. by replacing a reformed cartilage model. Long bones are formed in this way. Types of Bone Tissue Microscopic Structure of Bone Based on texture of cross sections, bone tissue can be clas- sified as follows: Bone cells Compact bone (dense bone, cortical bone): Compact bone Osteoblasts: Pluripotent stem cells can differentiate along is ivory like and dense in texture, without any spaces or many cell lines, e.g., osteoblasts, chondroblasts, bone mar- Periosteum Haversian system Cement lines Trabeculae Osteoclasts Osteoblast Lacuna Haversian Canaliculi with osteocyte canal Figure 16.2: (a) Structure of lamellar bone, (b) structure of woven bone.Chapter-16.indd 326 13/12/12 4:04 PM
  • 3. Musculoskeletal System 327 row fibroblasts etc. These stem cells give rise to osteopro- When stimulated by RANKL, RANK signaling activates the genitor cells committed to the osteoblastic lineage, which transcription factor NF-kB that is required for the generation then give rise to osteoblasts. Osteoblasts are located along and survival of osteoclasts. Because OPG and RANKL oppose the surface of bone or osteoid, and are responsible for syn- each other, either bone formation or resorption can be favored thesizing organic components of bone matrix, including by tipping the RANKL: OPG ratio in one way or the other. type I collagen, proteoglycans, and glycoproteins. Osteo- blasts also synthesize the enzyme alkaline phosphatase, 16 Osteomyelitis which is locally needed for mineralization of osteoid. They have receptors for various regulatory hormones, e.g., para- Musculoskeletal System Infection of the bone (osteo) and marrow (myelo) by bacteria, thormone, estrogen, leptons etc. Each active osteoblast has viruses, or fungi is labeled osteomyelitis. eccentrically located nuclei with a conspicuous nucleolus Classification: and a perinuclear halo, resembling a plasma cell. However, the osteoblast does not exhibit clock-face or cartwheel-like Pyogenic (bacterial) osteomyelitis chromatin pattern that is seen in a plasma cell. An inactive Mycobacterial osteomyelitis osteoblast has a flattened shape with low alkaline phos- Syphilitic osteomyelitis phatase activity. Osteoblasts do not divide. They give rise to osteocytes, remain as osteoblasts, or return to the state Pyogenic (Bacterial) Osteomyelitis of osteoprogenitor cells from which they derived. Pyogenic osteomyelitis most frequently targets children and Osteocytes: An osteoblast becomes an osteocyte when young adults. the cell is encased by osteoid matrix that it synthesizes by itself. Lacunae and canaliculi form around the osteocyte Modes of spread: Hematogenous, extension from contiguous and its cytoplasmic processes, respectively. site of infection, e.g., cellulitis and direct implantation. Osteoclasts: Osteoclasts are thought to be derived from Common causative organisms: Staphylococcus aureus is monocyte–macrophage system and are responsible for bone implicated in 80%–90% cases (it expresses receptors for bone resorption. They are multinucleated cells rich in lysosomes matrix components such as collagen, and therefore facilitates the that contain tartrate-resistant acid phosphatase (TRAP) attachment of the organism to bone). Other causative organisms which act on the mineral substrate. They demonstrate include E. coli, Pseudomonas, Klebsiella, Haemophilus influenzae, cytoplasmic processes and are found in resorption craters and Salmonella. Mixed infections are also seen. known as Howship’s lacunae located along the endosteal Predisposing factors: surface of cortical bone and trabecular bone. Osteoclasts are much more efficient at bone resorption than osteoblasts Location of infection is influenced by vascular circulation. The are at bone deposition, but at the same time, have a much most frequent sites are areas of rapid growth (distal femur, proxi- shorter life span than the latter. Osteoclasts are rarely mal tibia, proximal humerus, and distal radius). seen in routine histologic sections of normal bone. An The slowing or sludging of blood flow, as the vessels make increased number of osteoclasts is characteristic of diseases sharp angles at the metaphysis, predisposes the vessels to with increased bone turnover. thrombosis and the bone itself to localized necrosis and bac- Bone matrix: The bone matrix has two components: organic terial seeding. In the presence of bacterial infection elsewhere, and inorganic. The organic component is primarily composed a site of thrombosis acts as a nidus for bacterial growth and of Type I collagen (95%) and amorphous glycosaminoglycans, development of osteomyelitis. phospholipids, proteins such as osteocalcin, osteopontin, os- Trauma is an important predisposing factor for osteomyelitis teonectin etc. The inorganic matrix is mainly comprised of because it aids in venostasis and thrombosis. calcium hydroxyapatite. To begin with, the inorganic matrix is Stages of infection: laid down as unmineralized osteoid. Osteoblasts then secrete Acute (develops over days and weeks) alkaline phosphatase, which cleaves the phosphate groups and Chronic (develops over weeks to months; may persist for acts as foci for calcium and phosphate deposition. years) Several pathways regulate bone homeostasis. One such pathway involves three factors: Sequence of events in osteomyelitis: Transmembrane receptor RANK (receptor activator for NF-kB) Localization of bacteria RANK ligand (RANKL) expressed on osteoblasts and mar- row stromal cells Osteoprotegrin (OPG)—a decoy receptor made by osteo- Bacteria induce an acute inflammatory reaction and cell death blasts, and can bind RANKL and short circuit its interaction Influx of “neutrophils” (neutrophils with RANK. enzymatically destroy bone)Chapter-16.indd 327 13/12/12 4:04 PM
  • 4. 328 Section B | Systemic Pathology Continuing exudation raises the tissue pressure Relieved by compromise of vessels; the only potential space available, consequently leading to ischemia Transmission of infection via Haversian system to periosteum 16 Subperiosteal abscess formation Musculoskeletal System Lifting of the periosteum, which further impairs blood supply Devitalization of bone resulting in sequestrum or dead bone formation (Figure 16.3a) Figure 16.3b: Section of chronic osteomyelitis showing fragments of dead bone surrounded by chronic non-specific inflammation and foreign body giant cells (H&E; 200×). Rupture of periosteum and formation of a draining sinus Chronic osteomyelitis (Figure 16.3b) is frequently the result with proliferative periostitis and periostitis ossificans. Garre’s of inadequate antibiotic treatment or incomplete surgical osteomyelitis has a characteristic radiographic picture showing debridement, and is characterized by extensive reactive woven new periosteal proliferation located in successive layers to the or lamellar bone formation in the periosteum (involucrum). condensed cortical bone. Brodie’s abscess is a small devascularized osteomyelitic focus Complications: in the cortex, which becomes encapsulated and surrounded by dense sclerotic reactive bone. Draining sinus tract Suppurative arthritis Sclerosing osteomyelitis of Garre is a specific type of chronic Pathological fracture osteomyelitis that primarily affects children and adolescents, Secondary ankylosis (fibrosis and fusion of joint) and is typically seen in the jaw. It is also known as chronic Endocarditis nonsuppurative sclerosing osteomyelitis, chronic osteomyelitis Squamous cell carcinoma with a chronic nonhealing ulcer (Marjolin’s ulcer) Clinical features: Fever, leukocytosis, and throbbing pain over the affected region (Ewing’s sarcoma is a close clinical differential due to similar presentation). X-ray: Usually shows a lytic focus surrounded by sclerosis. Tuberculous Osteomyelitis 1%–3% cases of pulmonary and extrapulmonary tuberculosis present with osseous involvement. Tuberculous osteomyelitis usually affects adolescents and adults, and presents mostly as a solitary lesion; may be multifocal in AIDS. Modes of spread: Hematogenous, direct extension, and lymphatic Common sites: Spine (lumbar and thoracic), knee, and hip Clinical features: Pain, fever, and weight loss Complications: Psoas abscess Pathological fracture Neurological deficit and paraplegia due to extension of disease Figure 16.3a: Sequestrum or dead bone showing irregular surface process into dural space with resultant pressure on the cord and ragged margins. Tuberculous arthritisChapter-16.indd 328 13/12/12 4:04 PM
  • 5. Musculoskeletal System 329 Sinus tract formation Table 16.1: Classification of primary tumors involving bones Ankylosis Histological Benign Malignant types Syphilitic Osteomyelitis Hematopoietic – • Myeloma (40%) • Malignant lymphoma In skeletal syphilis, bone involvement is rare, as disease is readily Chondrogenic • Osteochondroma • Chondrosarcoma diagnosed and treated before this stage. It may be: (22%) • Chondroma • Dedifferentiated Congenital: Bone involvement starts in fifth month of • Chondromyxoid chondrosarcoma 16 fibroma • Mesenchymal chond- gestation; manifests with osteochondritis and periostitis rosarcoma Musculoskeletal System as spirochetes tend to localize in areas of active enchondral Osteogenic (20%) • Osteoid osteoma Osteosarcoma ossification (osteochondritis) and the periosteum (periostitis). • Osteoblastoma Acquired: Bone involvement is seen in tertiary stage. Unknown origin • Giant cell tumor (10%) • Unicameral bone cyst Generally involves skull and long tubular bones, e.g., tibia • Aneurysmal bone cyst (“Saber shin”: massive reactive periosteal bone deposition on Fibrogenic • Metaphyseal fibrous Fibrosarcoma medial and anterior surface of tibia). defect (fibroma) • Nonossifying fibroma Morphology: Syphilitic lesions show a granulomatous reaction • Fibrous histiocytoma around necrotic bone with numerous plasma cells. • Desmoplastic fibroma Notochordal Benign notochordal Chordoma tumor Primary Bone Tumors Neuroectodermal Ewing’s sarcoma Salient features of primary bone tumors Aneurysmal bone cyst They are predominantly seen in the first three decades of life, Metaphyseal lesions centered in the cortex: during the ages of greatest skeletal growth activity. Nonossifying fibroma (NOF) Benign tumors are by far more common than malignant Osteoid osteoma ones. The most common benign tumors are osteochondroma, Metaphyseal exostosis: fibro-osseous lesions, and enchondroma. Osteochondroma Some primary bone tumors are labeled as potentially malig- Diaphyseal intramedullary lesions: nant tumors as they show local aggression but only rarely me- Ewing’s sarcoma tastasize, e.g., giant cell tumor of bone. Lymphoma Among primary malignant neoplasms, osteosarcoma and multiple myeloma have the highest incidence, followed by Ewing’s chondrosarcoma and Ewing’s sarcoma. sarcoma The commonest sites for primary bone tumors, both benign Ada- mantinoma and malignant, are in distal femur and proximal tibia, which are the bones with highest growth rate. Fibrous Osteoid dysplasia Primary bone tumors have very typical radiographic appear- osteoma ances, and a clinico-radiological correlation is a must for cor- rect histopathological diagnosis. Enchondroma Chondromyxoid Classification of primary tumors involving bones have been fibroma given in Table 16.1. Distribution of bone tumors in long bones (Figure 16.4): Osteo- Osteo- sarcoma Epiphyseal lesions: chondroma Chondroblastoma Giant cell tumor Aneurysmal Metaphyseal intramedullary lesions: bone cyst Epiphyseal Osteosarcoma plate Giant Chondrosarcoma cell Fibrosarcoma tumor Osteoblastoma Enchondroma Chondroblastoma Fibrous dysplasia Simple bone cyst Figure 16.4: Distribution of bone tumors in long bones.Chapter-16.indd 329 13/12/12 4:04 PM
  • 6. 330 Section B | Systemic Pathology Myeloma Presents with intense pain, which increases during night and Fibrous dysplasia is relieved by aspirin (pain is thought to be due to excessive Enchondroma PGE2 production by proliferating osteoblasts). Diaphyseal lesions centered in the cortex: Also observed in most cases is localized swelling and tender- Adamantinoma ness. Osteoid osteoma X-ray: Shows a central nidus smaller than 1.5 cm that is 16 surrounded by sclerotic bone. The nidus may be difficult to see Gross and Microscopic Features of the on plain X-ray. CT is modality of choice to identify the nidus. Common Bone-Forming Tumors Musculoskeletal System Bone scan always demonstrates intense focal uptake. The lesion Bone-forming tumors are neoplasms, in which neoplastic cells can occur only in the cortex, in both the cortex and medulla, produce bones. or only the medulla. The four diagnostic features include (1) a well-defined round-or-oval lesion, (2) i.e., less than 2 cm in Classification: diameter, (3) has a homogeneous dense center, and (4) a 1–2- Benign mm peripheral radiolucent zone. The radiologic differential Osteoma includes osteoblastoma, osteomyelitis, arthritis, stress fracture, Osteoid osteoma and enostosis. Osteoblastoma Malignant: Osteogenic sarcoma Gross morphology: Appears as a well-defined round-to-oval mass of gritty tissue of less than 2 cm in size. Benign Tumors Microscopy (Figure 16.5): There is a distinct demarcation between nidus and reactive bone. The central nidus is comprised of Osteoma randomly interconnecting trabeculae of woven bone prominently Skeletal distribution: Involves flat bones of skull, face, and rimmed by osteoblasts. Stroma surrounding tumor bone consists paranasal sinuses (especially frontal and ethmoid). of loose connective tissue with many dilated–congested capillaries. Clinical features: The nidus is enveloped by sclerotic bone. Osteomas are often incidental and asymptomatic findings; Treatment and prognosis: Osteoid osteoma usually resolves they occur in middle age, and are solitary and slow growing. without treatment over a period of time. If the patient does May lead to cosmetic deformity, obstruction of sinus cavity, not wish to endure the pain and prolonged use of nonsteroidal or impingement on brain and eye. anti-inflammatory medications, surgical removal, or percutaneous Gross morphology: ablation of the nidus can be undertaken. Osteomas are mostly sessile, round-to-oval, and bosselated. They are seen projecting from subperiosteal/endosteal surface of cortex. Multiple osteomas may present with intestinal polyposis and Surrounding soft tissue tumors (Gardner syndrome). Nidus stroma Microscopy: They are composed of compact, lamellar bone that is deposited in a cortical pattern with Haversian-like systems. Rarely they may contain a component of trabecular bone in which the intertrabecular spaces are filled with marrow material. Treatment and prognosis: Simple excision is the treatment of choice for symptomatic lesions. The lesion does not recur after surgical excision and is not associated with malignant change. Osteoid Osteoma Skeletal distribution: Long bones (femur and tibia) Usually intracortical; less frequently arises from the medul- Figure 16.5: Section from osteoid osteoma showing a nidus lary cavity comprised of randomly interconnecting trabeculae of woven bone prominently rimmed by osteoblasts and surrounding stroma Clinical features: consisting of loose connective tissue with many dilated–congested It is common in the age group of 10–30 years. capillaries (H&E; 200×).Chapter-16.indd 330 13/12/12 4:04 PM
  • 7. Musculoskeletal System 331 Osteoblastoma Environmental contribution: Radiation, thorotrast, and therapeutic irradiation are all implicated. Children Skeletal distribution: treated with alkylating agents have an increased risk of Osteoblastoma is a solitary, benign, bone-forming tumor that oc- osteosarcoma. curs in the spine and long bones of young adults. Commonly in- volved sites include vertebrae, tibia, femur, humerus, and pelvis. It is usually metaphyseal in location, and may be intracortical Classification or intramedullary in origin. 1. Based on affected age and presence of pre-existing bone 16 Clinical features: Osteoblastoma and osteoid osteoma are pathology: Musculoskeletal System histologically very similar, yet these two tumors are very different Primary (arise de novo): Common in the age group be- in their presentation, localization, radiographic appearance, tween 10 and 25 years. treatment, and potential for recurrence. Osteoblastoma can be Secondary (secondary to pre-existing bone pathology): differentiated from the latter based on the following features: Occurs in older patients (more than 40 years), and con- stitutes about 6%–10% of all osteosarcomas. Conditions It is larger than 2 cm (also called giant osteoid osteoma). predisposing to secondary osteosarcoma: It occurs in an older age group. Paget’s disease Usually does not cause localized night pain and, when pain Exposure to radiation occurs, is not relieved by NSAIDs. Chemotherapy (alkylating agents) Does not present with an intense bony reaction unlike osteoid Bone lesions like fibrous dysplasia, osteochondroma, osteoma. enchondroma, and bone infarcts. Preferentially involves posterior elements of vertebrae, spine, 2. Based on skeletal distribution/anatomical site: femur, and bones of the foot. Intramedullary: Conventional osteosarcoma (the most An associated soft tissue mass may be seen in about 25% of common type) is invariably intramedullary and metaph- patients. yseal (zone of maximum bone growth) in origin. Long Gross morphology: On gross examination, osteoblastomas are bones like lower end of femur, upper end of tibia, and up- red-to-tan in color with hemorrhagic areas. The compact tissue per end of humerus are involved in that order of frequency. is granular, friable, and gritty. Intracortical Surface Microscopy: The lesion is comprised of calcified osteoid growing 3. Based on morphology: within a highly vascularized connective tissue and surrounded About 85% of osteosarcoma cases are of the “conven- by minimal sclerosis. The vascular stroma is characterized by tional intramedullary” type, and the other 15% con- pleomorphic spindle cells. The tumor cells differentiate into sists of several other subtypes, including telangiectatic, osteoblasts, which make varying amounts of osteoid and low-grade intramedullary, and small cell, as well as, the woven bone. Cartilage production is a very rare finding in an surface subtypes parosteal, periosteal, and high-grade osteoblastoma, and should raise suspicion of osteosarcoma. surface osteosarcoma. Treatment and prognosis: Surgical resection by curettage, Conventional intramedullary osteosarcoma can be fur- intralesional excision, or en bloc excision are all treatment options ther subdivided into the following subtypes: depending on site. Osteoblastic (shows a large amount of osteoid and bony trabeculae) Malignant Tumor (Osteogenic Sarcoma) Chondroblastic (malignant cartilage forms nearly 90% of the tumor) Osteogenic sarcoma is a malignant mesenchymal tumor in Fibroblastic (comprised of a large spindle cell/fibro- which neoplastic cells directly lay down bone matrix (osteoid). blastic component) It is the most common primary malignant bone tumor, excluding Surface osteosarcomas can be further subdivided into myeloma and lymphoma. the following subtypes: Juxtacortical (parosteal) osteosarcoma Pathogenesis − Affects old age Genetic contribution: Mutations in tumor suppressor genes, − Is a slow-growing, low-grade tumor with a good e.g., P53 or RB1 are commonly associated. Germline muta- prognosis. tions in P53 gene induces multiple carcinomas and sarcomas − It is classically located on the posterior aspect of (Li-Fraumeni syndrome). Patients with hereditary retinoblas- lower femur, where it typically presents as a large tomas have a markedly increased risk of developing osteosar- lobulated mass encircling the bone. coma. Abnormalities in CDK4, P16, INK4A, cyclin D1, and Periosteal osteosarcoma MDM2 are also implicated in nonhereditary osteosarcomas. − Grows on the surface of long bonesChapter-16.indd 331 13/12/12 4:04 PM
  • 8. 332 Section B | Systemic Pathology − Is usually limited to the cortex − Has a prominent cartilaginous component − Behaves more aggressively than a parosteal osteosarcoma, but less aggressively as compared to a high-grade surface variant Osteosarcoma of jaw 16 − Affects older age − Involves mandible and alveolar ridges of maxilla − Has a prominent chondroblastic component Musculoskeletal System − Has a relatively good prognosis Osteosarcoma in Paget’s disease − It is usually multicentric. − Pelvis, humerus, and femur bones are involved in that order of frequency. − Has a poor prognosis. Clinical Features Osteosarcomas present as painful, progressively enlarging masses with a large soft-tissue component, sometimes associated with a pathological fracture. Levels of serum alkaline phosphatase are raised. X-ray Figure 16.6a: Bulky, gritty, and gray–white tumor, containing areas of hemorrhage and necrosis and showing destruction of cortex. On radiographs, conventional osteosarcoma is seen as a meta- physeal, large, permeative, destructive, mixed sclerotic, and lytic lesion. Bone formation within the tumor is characteristic of osteosarcoma, and is usually visible on the X-rays. Tumor breaks through the cortex, results in reactive periosteal bone formation, and lifts the periosteum. The triangular shadow between cortex and raised periosteum is radiographically called “Codman’s triangle.” The periosteal reaction is laid down to the surface of the bone, and this is labeled as “sunray appearance.” Morphology Gross (Figure 16.6a) Bulky, gritty, and gray–white tumor, often containing areas of hemorrhage and necrosis Destruction of cortex and soft tissue extension are common Penetration of epiphyseal plate/entry into joint is infrequent Microscopy: Diagnostic features (Figure 16.6b): Malignant Lace like osteoid Frankly sarcomatous stroma comprised of large atypical spin- stromal cells dle-shaped cells with bizarre tumor giant cells and mitoses. Figure 16.6b: Sarcomatous stroma comprised of large atypical Direct formation of tumor osteoid. In H&E sections, osteoid spindle-shaped cells showing direct formation of tumor osteoid, is seen as an eosinophilic, glassy, homogenous material, pro- seen as eosinophilic, glassy, homogenous material (H&E; duced by neoplastic cells and arranged in a thin anastomosing 400×). lace-like pattern. Besides osteoid, chondroblastic and fibroblastic elements may be present. In the presence of abundant malignant cartilage, Diagnosis tumor qualifies as a chondroblastic variant of osteosarcoma. Imaging Spontaneous necrosis and vascular invasion are frequently FNAC seen. Open biopsyChapter-16.indd 332 13/12/12 4:04 PM
  • 9. Musculoskeletal System 333 Metastasis Lungs, other bones, pleura, and heart are common sites of metastasis. Regional lymph nodes are rarely involved. Prognosis 16 Long-term survival rate is 60%–70% (with chemotherapy and limb salvage therapy). Musculoskeletal System Clinicopathological Features of Common Cartilage-Forming Tumors Cartilaginous neoplasms of bone are characterized by formation Figure 16.7a: X ray showing a lobulated cartilaginous exostosis of hyaline or myxoid cartilage. arising from upper femur (arrow). Classification: Fibrous Trabecular Benign layer bone Osteochondroma Chondroma Chondroblastoma Chondromyxoid fibroma Malignant: Chondrosarcoma Benign Tumors Osteochondroma (Exostosis) Osteochondroma is a benign bony outgrowth attached to the underlying bone. It is capped by hyaline cartilage. It is the most frequent benign bone tumor. Multiple osteochondromas occur in the setting of multiple hereditary exostoses, which is associated with inactivation of EXT gene and is autosomal dominant in Cartilage inheritance. Solitary osteochondromas are thought to arise due cap to displacement of lateral portion of the growth plate. Figure 16.7b: Osteochondroma comprised of outermost fibrous Skeletal distribution: Most commonly, it arises from the layer, followed by a cartilage cap, underlying which mature tra- metaphysis of lower femur, upper tibia, and upper humerus. becular and cortical bone can be seen (H&E; 100×). Clinical features: Solitary osteochondromas are diagnosed in later life as com- Cross section through the lesion demonstrates mature trabe- pared to multiple osteochondroma, which is usually present cular and cortical bone. in childhood. The cortex of stalk appears to merge with cortex of host bone. Osteochondromas may be asymptomatic or present with pain and deformity; they sometimes cause interference with func- Complications: tion of regional tendons and blood vessels. Bursitis (development of bursa around head of a long-stand- ing osteochondroma) X-ray (Figure 16.7a): They are metaphyseal in origin and grow Formation of osteocartilaginous loose bodies in a direction opposite to adjacent joint. Development of secondary chondrosarcoma (incidence of Gross morphology: Osteochondromas may be sessile or development of secondary chondrosarcoma in solitary os- pedunculated, mushroom shaped, with an average size of 4–10 cm. teochondroma is 1%–2% and is as high as 10% in multiple Microscopy (Figure 16.7b): lesions). The outermost layer is a fibrous membrane, continuous with the periosteum of the adjacent bone. Chondroma Under the fibrous membrane is cartilage cap (which is formed Chondroma is the most common intraosseous cartilaginous by mature hyaline cartilage). tumor. Based on location, it may be classified as intramedul-Chapter-16.indd 333 13/12/12 4:04 PM
  • 10. 334 Section B | Systemic Pathology lary (also known as enchondroma) and subperiosteal or jux- tacortical. It may be solitary or multiple. Multiple enchondromas can manifest as Ollier’s disease (a rare, nonhereditary disorder characterized by multifocal proliferation of dysplastic cartilage, also known as enchondromatosis) or as Maffucci syndrome 16 (multiple enchondromas and soft-tissue hemangiomas). The risk of malignant transformation, usually to chondrosar- coma, is very high (20%–30%) in multiple enchondromas. Musculoskeletal System Chondromas mainly occur in bones that develop from enchondral ossification (they are thought to develop from rests of growth plate cartilage that proliferate and enlarge). Most lesions are asymptomatic (detected incidentally); may occasionally manifest with pain or cause pathological fracture. X-ray: Plain radiograph shows an intramedullary zone of stippled Figure 16.9: Chondroblastoma comprised of closely packed and ring-shaped calcifications. Enchondroma characteristically clusters of embryonic chondroblasts (polyhedral cells with a sharply-defined cell membrane, and lobulated nuclei showing involves the acral skeleton (small bones of the hands and feet) longitudinal grooves) (H&E; 200×). and the long bones (such as femur, humerus, tibia, fibula, radius, and ulna). In the long bones, the tumor is found in metaphyses and proximal/distal diaphyses. It is intramedullary in location and commonly involves the Gross morphology: They are usually smaller than 3 cm, gray– epiphyseal ends of femur, humerus, and tibia, and small bones blue, and translucent. of hands and feet. Presents with pain, restricted mobility, and joint effusion (be- Microscopy (Figure 16.8): cause of proximity to the joint). Sections show well-circumscribed nodules of hyaline cartilage. X-ray: Typical radiological presentation is that of a well-defined Chondrocytes in the lacunae are cytologically benign. lytic lesion surrounded by sclerosis. Spotty calcification is common. Cartilage in periphery of nodules undergoes enchondral Cysts are present about 20% of the time, and both MRI and CT ossification and the center frequently calcifies and dies. can define fluid levels. Chondroblastoma Gross morphology: On gross examination, chondroblastoma has a lobulated, round form, and is made up of friable, soft, Clinical features: grayish-pink tissue that may be gritty. Chondroblastoma is a rare tumor seen in children and adoles- Microscopy (Figure 16.9): cents with open growth plates; most commonly in males less than 20 years. Chondroblastoma is extremely cellular and is comprised of closely packed clusters of tumor cells. The basic tumor cell is an embryonic chondroblast, a poly- hedral cell with a sharply-defined cell membrane, and lobu- lated nuclei showing longitudinal grooves (coffee-bean appearance), without sufficient differentiation to produce intercellular chondroid. Mitoses and necrosis are frequently observed. Scant amount of lace-like hyaline matrix may be laid down, which calcifies to produce a characteristic chicken-wire cal- cification. Scattered osteoclastic giant cells may be seen. Treatment: Curettage or surgical excision is the treatment of choice. Due to the risk of recurrence and associated functional loss, the initial curettage should be as meticulous as necessary to ensure complete removal of the lesion. Figure 16.8: Section from an enchondroma showing well-cir- cumscribed nodules of hyaline cartilage with cytologically benign Prognosis: It is locally invasive; rarely metastasizes to lungs; chondrocytes (H&E; 100×). recurrences are common.Chapter-16.indd 334 13/12/12 4:04 PM
  • 11. Musculoskeletal System 335 Chondromyxoid Fibroma (CMF) chondrosarcoma arises from benign cartilage defects such as osteochondroma or enchondroma. Chondrosarcoma can also Clinical features: Affects young adults and presents with localized be classified as intramedullary, which generally arises from dull aching pain and swelling in the affected region. an enchondroma, and surface which arises from a pre-existing X-ray: Seen as a large, lobulated, sharply-defined, eccentric osteochondroma. Chondrosarcoma can also be classified based on: lytic lesion, surrounded by a rim of sclerosis in the metaphysis Topography of long bones. Conventional intramedullary (central) chondrosarcoma 16 Gross: − Arises from medullary cavity of long bones, pelvis, Musculoskeletal System Average size is 3–8 cm. costochondral junction of ribs, and shoulders Cut surface is solid, glistening, and tan–gray. − X-ray shows a lytic lesion with blotchy calcification (Figure 16.11a) Microscopy (Figure 16.10): − Causes fusiform thickening of shaft and perforation of The predominant features of CMF are the zonal architecture cortex and lobular pattern. − May arise de novo (80%–90%) or in a pre-existing Hypocellular lobules of poorly formed hyaline cartilage and osteochondroma (10%–20%) myxoid tissue are separated by fibrous septae. Juxtacortical (peripheral) chondrosarcoma: Arises in the Nodules of cartilage are found in between fibromyxoid areas. shaft of a long bone. The chondrocytes in myxoid areas are plump-to-spindled in Morphology shape and have indistinct cell borders. Conventional (which is further subtyped as hyaline or Varying degree of cytological atypia may be seen. myxoid) Small foci of calcification may be observed. Clear cell Treatment and prognosis: Treatment of CMF is en bloc excision. Dedifferentiated Recurrences after curettage are common. Mesenchymal Signs of malignancy in an osteochondroma: Malignant Tumors Rapid growth; size more than 8 cm Chondrosarcoma Cartilaginous cap more than 3-cm thick Chondrosarcoma is a malignant mesenchymal tumor that produces X-ray showing irregular margins of the cartilage cap cartilage matrix. There are several subtypes of chondrosarcoma, Morphology of chondrosarcoma: which vary in terms of location, appearance, treatment, and Gross: prognosis. On gross examination, chondrosarcoma is a gray–white, lob- Classification: Primary chondrosarcoma is very uncommon, ulated, bulky, translucent mass with a gelatinous consistency. arises centrally in the bone, and is found in children. Secondary Erosion/destruction of cortex is frequent. Calcification and ossification may be seen. Figure 16.10: Hypocellular lobules of poorly formed hyaline cartilage and myxoid tissue separated by fibrous septae; the chondrocytes in the myxoid areas appear plump-to-spindled with Figure 16.11a: X ray pelvic region showing a large lytic lesion indistinct cell borders (H&E; 100×). with blotchy calcification suggesting a chondrosarcoma.Chapter-16.indd 335 13/12/12 4:04 PM
  • 12. 336 Section B | Systemic Pathology 16 Musculoskeletal System Figure 16.11b: Section from a chondrosarcoma showing cartilaginous lobules comprised by atypical chondrocytes (H&E; 200×). Figure 16.12a: Radiograph showing a lytic, expansile, epiphyseal Microscopy (Figure 16.11b): lesion in the femur without any sclerosis or periosteal reaction. The cortex shows thinning and destruction. Histologically, chondrosarcoma is comprised of invasive lob- ules of anaplastic cartilage. It is differentiated from benign cartilaginous tumors based on presence of two or more cells per lacuna, binucleated cells, enlarged plump, and hyperchro- matic nuclei and nuclear pleomorphism. Abundant mitoses and enchondral ossification is seen (to be differentiated from osteosarcoma in which the osteogenesis is directly from malignant mesenchymal cells). Chondrosarcoma is classified into Grades I, II, and III, based on cellularity, pleomorphism, mitoses, and necrosis. Prognostic factors: Size more than 10 cm is associated with bad prognosis. Tumor–X-ray correlation is a must (more radiolucent the tu- mor, higher the grade, and worse the prognosis). Treatment and prognosis: Treatment of chondrosarcoma is wide surgical excision. There is a very limited role for chemotherapy or radiation. Figure 16.12b: Tan-to-light brown epiphyseal tumor showing abundant hemorrhage and necrosis. Giant Cell Tumor (GCT or Osteoclastoma) Clinical features: GCT is the most common tumor of epiphyses Microscopy (Figure 16.12c): in skeletally mature individuals with closed growth plates. It often shows metaphyseal extension. Common sites include lower end GCT has two components: of femur, upper end of tibia, and lower end of radius. Stromal cells: Uniform oval mononuclear cells with indis- tinct cell membrane, which grow in a syncytial pattern. X-ray (Figure 16.12a): Radiographs show a lytic, expansile, Giant cells: Large giant cells with 20–30 (up to 100) nuclei epiphyseal lesion without any peripheral sclerosis or periosteal arranged toward the center. reaction. There is thinning and destruction of cortex with frequent Stromal cells are the basic neoplastic element and their num- extension into intermuscular septae and joint space. ber correlates with clinical evolution of this tumor. Gross (Figure 16.12b): The tumor is variable sized, solid, and All GCTs should be regarded as potentially malignant tan-to-light brown with fibrous trabeculae. Hemorrhage and (approximately 4% give rise to distant metastasis). necrosis are common. Focal deposition of osteoid or bone may be seen.Chapter-16.indd 336 13/12/12 4:04 PM
  • 13. Musculoskeletal System 337 Stromal cells They are located in the diaphysis or metaphysis, and arise from the medullary canal. Pain, tenderness, and swelling accompanied by fever, leukocy- tosis, and elevated ESR, are the presenting features of Ewing’s sarcoma (mimics chronic osteomyelitis). It may present as a soft-tissue neoplasm without involvement of underlying bone (extraskeletal Ewing’s). 16 X-ray: Reactive periosteal bone is laid in layers parallel to cortex Musculoskeletal System (“onion-skin” appearance). Microscopy (Figure 16.13): Biopsy shows a highly cellular, infiltrative neoplasm consist- ing of sheets of tightly packed, round cells with very scant cytoplasm (“round blue cell tumor”). These are divided into irregular nests/lobules by fibrovascular septae. Giant cells The tumor cells appear to be of two distinct types: the larger round cells with a high nuclear/cytoplasmic ratio, fine chro- Figure 16.12c: GCT of bone comprised of uniform oval mono- matin pattern and occasional small, inconspicuous nucleoli, nuclear cells that grow in a syncytial pattern (stromal element) and the smaller and darker cells with eosinophilic cytoplasm and large giant cells with up to 100 nuclei arranged toward the and hyperchromatic, “shrunken” nuclei. The latter are actually center (H&E; 200×). degenerated cells, a typical finding in Ewings sarcoma. The cells have ill-defined cytoplasmic borders with small amounts of vacuolated-to-clear cytoplasm attributed to the Features differentiating GCT of bone from other giant cell- presence of cytoplasmic glycogen that gives a granular posi- containing lesions: tivity with PAS stain (Figure 16.14). Giant cells in other giant cell-containing lesions have fewer nuclei. Necrosis is prominent but tumor giant cells are rare. Filigree There is a uniform distribution of giant cells in GCT of bone, pattern (bicellular stands of tumor cells separated by fine vas- unlike other giant cell lesions wherein giant cells are focally cular stroma) is sometimes observed. This pattern has been aggregated. found to be associated with a low survival rate. Other giant cell lesions of bone: Metaphyseal fibrous defect Nonossifying fibroma Chondromyxoid fibroma Chondroblastoma Eosinophilic granuloma Solitary bone cyst Osteitis fibrosa cystica Aneurysmal bone cyst Osteoid osteoma Osteoblastoma Tumors of Neuroectodermal Origin Tumors of neuroectodermal origin include Ewing’s sarcoma and primitive neuroectodermal tumor (PNET). Clinical features: Affect children and young adults (peak incidence between 5 and 20 years); they are rare after 30 years. Present as a lytic lesion in long bones; most common skeletal Figure 16.13: Section from Ewing’s sarcoma showing a cellular, sites include femur, tibia, and humerus, and also pelvis and infiltrative neoplasm consisting of sheets of round cells with ribs (Askin tumor of the chest). Associated soft tissue mass is scant cytoplasm arranged in irregular nests/lobules separated by a common finding. fibrovascular septae (H&E; 400×).Chapter-16.indd 337 13/12/12 4:04 PM
  • 14. 338 Section B | Systemic Pathology PAS positive granules Wilms’ tumor, neuroblastoma, and rhabdomyosarcoma are the main sources of bony metastases in children. Metastasis is usually multifocal and has a predilection for the hematopoietic marrow sites in the axial skeleton (vertebrae, pelvis, ribs, and cranium) and proximal long bones. Metasta- ses to long bones distal to the elbows and knees and the small 16 bones of the hands and feet are rare. Occasionally, metastases may appear as solitary lesions (particularly true for lung, kid- ney, and thyroid cancer). Musculoskeletal System Carcinoma of prostate, breast, and carcinoid tumor gives rise to pure osteoblastic metastasis. Pure lytic metastasis is seen in carcinoma of kidney, lungs, Figure 16.14: Ewing’s sarcoma cells showing a granular positivity GIT, and malignant melanoma. with PAS stain due to presence of cytoplasmic glycogen. At places, tumor cells form pseudorosettes (Homer–Wright rosettes). Perivascular rosetting (rosetting around blood ves- Cystic Lesions of Bone sels) is also common. Rosetting is more commonly seen in Solitary (Simple, Unicameral) Bone Cyst PNET and indicates neural differentiation. The morphologi- cal spectrum of neuroectodermal tumors thus varies from un- Unicameral bone cysts (UBC) are metaphyseal lesions that differentiated Ewing’s to a differentiated PNET. consist of a fluid-filled cavity lined by a thin membrane. They have an unknown pathogenesis Cytogenetics: They are most commonly seen in children aged 5–20 years, 95% cases show reciprocal translocation 11:22 (q24:q12). and may occasionally persist into adulthood. This translocation is common to Ewing’s sarcoma and PNET. Common location is the upper end of humerus and femur; Fusion of EWS gene with FLI-1/ERG gene leads to produc- most UBCs are asymptomatic and come to notice when a tion of chimeric transcription factors that result in abnormal pathological fracture occurs. Some are discovered as inciden- cell proliferation. tal findings. Treatment and prognosis: Radiologically the lesion appears as a well-defined osteolytic Hematogenous metastasis to lungs, liver, bones, and brain area with a thin sclerotic margin. The cyst may expand the leads to an early spread. bone, causing thinning of overlying cortex. There is no pe- Disease stage at diagnosis (including tumor volume) is the riosteal reaction visible unless there has been a previous frac- main prognostic factor for patients with ES/PNET; use of ture. A fragment of cortex that has fallen into a dependent combined chemotherapy and radiotherapy improves clinical position inside the cyst is known as the “fallen-leaf ” or “fall- outcome. en-fragment” sign. PNET has worse prognosis as compared to Ewing’s, despite Gross pathology: UBC is generally unilocular with a smooth neural differentiation. inner lining; it is filled with yellow- or amber-colored fluid. Microscopy: Pathways of Spread of Tumors to Bone Cyst wall consists of thin collagenous tissue having scattered osteoclastic giant cells and newly formed reactive bony tra- Direct beculae. Lymphatic or hematogenous Fracture may alter the appearance with secondary hemorrhage, Intraspinal seeding hemosiderin deposits, and macrophages in the cyst wall. Metastatic Bone Tumors Aneurysmal Bone Cyst (ABC) Metastatic cancers are the most frequent malignant tumors ABC is an expanding osteolytic lesion filled with blood found in bone. They are by far more common than primary bone (aneurysm means dilatation). tumors, and are characterized by the following features: It is common in young patients under 30 years of age and 80% metastasis to bone comes from breast, lungs, prostate, most frequently involves the metaphysis of long bones or the and kidney. vertebral column.Chapter-16.indd 338 13/12/12 4:04 PM
  • 15. Musculoskeletal System 339 Its pathogenesis is not clear. It probably arises from persistent Metabolic and Endocrine alteration in the local hemodynamics. Diseases of Bone X-ray: Shows a characteristic ballooned-out, expansile lesion underneath the periosteum. Osteoporosis (Osteopenia) Clinical features: ABC enlarges over a period of years to produce It is a clinical syndrome common in elderly and postmeno- pain, tenderness, and pathological fracture. pausal women, characterized by a quantitative reduction of 16 Gross pathology (Figure 16.15a): The lesion consists of a large bone tissue mass with normal levels of serum calcium, inor- ganic phosphorus, and alkaline phosphatase. Musculoskeletal System hemorrhagic mass covered over by thinned-out reactive bone. Osteoporosis may be asymptomatic or may manifest with a Microscopy: fragile skeleton associated with increased risk of fractures, The cyst consists of blood-filled aneurysmal spaces of variable and consequent pain and deformity. Particularly common are size, some of which are endothelium lined (Figure 16.15b). chronic backache and fractures of distal radius, femoral neck, The spaces are separated by connective tissue septae, which and vertebral bodies. may contain osteoid tissue. Numerous osteoclast-like multinucleate giant cells are seen. Predisposing factors: The condition has to be distinguished histologically from gi- Genetic factors: 60%–80% variation in bone density is ant cell tumor and telangiectatic osteosarcoma. genetically determined and implicated genes include RANKL, OPG, and RANK, which are the key regulators of osteoclasts. Sex: Females appear to have a greater predisposition to os- teoporosis. The reduction of estrogen levels at menopause is one of the strongest risk factors for developing osteoporosis. Women may also experience a drop in estrogen during certain cancer treatments. Men experience a gradual reduction in tes- tosterone levels as they age. Some treatments for prostate can- cer reduce testosterone levels in men. Lowered sex hormone levels tend to weaken bone. Ageing: Osteoporosis is more common in the aged (senile os- teoporosis) and this is attributed to decreased replicative and biosynthetic activity of osteoprogenitor cells and osteoblasts associated with ageing. Figure 16.15a: Gross picture of an ABC showing a large pha- Reduced physical activity: People who spend a lot of time sit- langeal hemorrhagic mass covered over by thinned-out reactive ting have a higher risk of osteoporosis than their more-active bone. counterparts. Starvation: People who have anorexia are at higher risk of osteoporosis. Low food intake can reduce the amount of cal- cium ingested. Intake of systemic steroids, anticonvulsants, and heparin: Long-term use of corticosteroid medications, such as predni- sone, and other medications interfere with the bone-rebuild- ing process. Radiology: Radiological evidence of osteoporosis becomes apparent after more than 30% of bone mass is lost. Pathology: Osteoporotic trabeculae are thinned out with loss of their in- terconnections. Figure 16.15b: Section from ABC comprised of blood filled cystic Cortex is thinned out by subperiosteal and endosteal resorp- spaces separated by connective tissue septae, which contain tion. osteoid and numerous osteoclast-like multinucleate giant cells Haversian system appears widened; sometimes so much that (H&E; 100×). the cortex mimics cancellous bone.Chapter-16.indd 339 13/12/12 4:04 PM
  • 16. 340 Section B | Systemic Pathology Hyperparathyroidism patients on long-term dialysis. It is more common in children. Clinical symptoms of bone disease in advanced renal failure Hyperparathyroidism may be: appear in less than 10% of the patients. Radiological and Primary: Due to autonomous hyperplasia or a neoplastic histological changes are observed in fairly large proportion growth (usually an adenoma) of parathyroids. of cases. Secondary: This type is usually secondary to a prolonged state Pathogenesis: of hypocalcemia. 16 Chronic renal failure Manifestations: Musculoskeletal System Severe hyperparathyroidism of primary or secondary (chronic renal failure) type Impaired renal • Decreased conversion of excretion of phosphate vitamin D metabolite Oversecretion of parathyroid hormone 25 hydroxy cholecalciferol to its active form 1,25 dihydroxycholecalciferol Increased osteoclastic resorption of bone • Reduced intestinal absorption of calcium Susceptibility to fractures, skeletal deformities and joint pains Dysfunction as a result of deranged weight bearing Hyperphosphatemia and hypocalcemia Osteitis fibrosa cystica Note: The bony changes are known to disappear after cure of Increased parathormone and resultant osteoclastic activity primary hyperparathyroidism (removal of functioning adenoma). Biochemical abnormalities: Include excessive parathyroid Metabolic acidosis (result of decreased renal function) hormone, hypercalcemia, hypophosphatemia, and hypercal- ciuria. X-ray: Major lesions of renal osteodystrophy Cortical bone is affected more severely than cancellous bone, Manifestations: focal areas of erosion of cortical bone (subperiosteal resorp- Osteomalacia in adults and rickets in children tion) are frequently seen along the radial surface of phalanges Secondary hyperparathyroidism and osteitis fibrosa cystica of index and middle fingers. Osteosclerosis (enhanced bone density in the upper and lower Loss of lamina dura at roots of teeth may also be observed. margins of vertebrae) Pathology: Pathological features include: Metastatic calcification in medium-sized blood vessels, periar- ticular tissue, myocardium, eyes, lungs, and gastric mucosa Minor degree of generalized bone rarefaction to prominent areas of bone destruction (lytic lesion) with cyst formation. Dialysis-related metabolic bone disease: Long-term dialysis Increased number of bizarre osteoclasts at the surface of moth- employing an aluminum-containing solution is a major cause of eaten trabeculae and cortex. metabolic bone lesions (aluminum interferes with deposition Replacement of bone and bone marrow by fibrosis. of calcium hydroxyapatite in bone and results in osteomalacia, In cancellous bone, osteoclasts tunnel in and dissect along secondary hyperparathyroidism, and osteitis fibrosa cystica). In the length of trabeculae to create the appearance of railroad such cases, accumulation of ␤2-microglobulin amyloid causes tracks (dissecting osteitis). dialysis-related amyloidosis. Microfractures and microhemorrhages occur in the marrow cavity, and induce an influx of macrophages and repair tissue. This leads to formation of masses of reactive tissue called "Brown Paget’s Disease of Bone (Osteitis Deformans) tumors" (highly vascular tissue with abundant hemosiderin), First described by Sir James Paget in 1877, Paget’s disease of which may undergo cystic degeneration when it is labeled bone is an osteolytic and osteosclerotic bone disease of uncertain osteitis fibrosa cystica or von Recklinghausen disease of bone. etiology. It may involve one (monostotic) or more bones (polyostotic), Renal Osteodystrophy and affects predominantly males over the age of 50 years. Renal osteodystrophy encompasses a number of skeletal Paget’s disease is thought to be a form of slow virus infection abnormalities appearing in patients of chronic renal failure or caused by a paramyxovirus (which has been detected in osteo-Chapter-16.indd 340 13/12/12 4:04 PM
  • 17. Musculoskeletal System 341 clasts). The virus-infested osteoclasts release IL-6 and induce Bones most often affected, in descending order of frequen- osteoclastic recruitment leading to resorption. cy, are ribs, craniofacial bones (especially maxilla), femur, Clinical features: tibia, and humerus. The condition generally remains asymptomatic, and is dis- Monostotic Paget’s disease most frequently involves tibia, pel- covered incidentally, but infrequently may produce tumor- vis, femur, skull, and vertebrae. like enlargement of the affected bone. Order of involvement in polyostotic Paget’s disease is verte- Polyostotic fibrous dysplasia brae, pelvis, femur, skull, sacrum, and tibia. 16 This form of fibrous dysplasia comprises 25% of all patients Monostotic form of the disease may remain asymptomatic; le- and affects several bones. Musculoskeletal System sion is discovered incidentally on radiological examination. It has an earlier onset than the monostotic form. Polyostotic form, however, is more widespread and may pro- Most frequently affected bones are craniofacial bones, ribs, duce pain, fractures, skeletal deformities, bone overgrowth vertebrae, and long bones of the limbs. (leontiasis ossea or overgrowth of the craniofacial skeleton), Spontaneous fractures and skeletal deformities are com- and, occasionally, sarcomatous transformation. mon in the childhood polyostotic form of the disease. It may also manifest with platybasia (flattening of the base Albright syndrome of skull due to weakened bone), chalk-stick type of fractures It is also called McCune–Albright syndrome, and is a form in the long bones, or severe secondary osteoarthritis with of polyostotic fibrous dysplasia associated with endocrine marked elevation of serum alkaline phosphatase and normal- dysfunction. to-high serum calcium level. It accounts for less than 5% of all cases and is more com- Pathology: Three sequential stages are identified in Paget’s disease: mon in females. Initial osteolytic stage: This stage is characterized by the areas Albright syndrome is characterized by polyostotic bone of osteoclastic resorption produced by increased number of lesions, skin pigmentation (café-au-lait macular spots), osteoclasts. sexual precocity, and infrequently other endocrinopathies. Mixed osteolytic–osteoblastic stage: Imbalance between os- Pathology: teoblasts laying down new bone and osteoclastic resorption Gross: so that mineralization of the newly laid matrix lags behind, Lesions appear as sharply demarcated localized defects mea- resulting in development of a characteristic mosaic pattern of suring 2–5 cm in diameter. osteoid seams or cement lines. Thin, smooth, overlying cortex with cut section of the lesion Quiescent osteosclerotic stage: After many years, excessive bone showing replacement of normal cancellous bone of the mar- formation results so that the bone becomes more compact row cavity by gritty, gray–pink, rubbery soft tissue, which may and dense, producing osteosclerosis. However, newly formed have areas of hemorrhage, myxoid, and cystic degeneration. bone is poorly mineralized, soft, and susceptible to fractures. Radiologically, this stage produces characteristic cotton-wool Histology (Figure 16.16): appearance of the affected bone. Characteristic benign-looking fibroblastic tissue is arranged in a loose, whorled pattern in which irregular and curved trabeculae of woven (nonlamellar) bone are laid down. Fibro-Osseous Lesions of Bone Fibro-osseous lesions of bone include: Fibrous Dysplasia This is a benign condition, possibly of developmental origin, characterized by the presence of localized area of replacement of bone by fibroconnective tissue with a characteristic whorled pattern, containing trabeculae of woven bone. Radiologically, the typical focus of fibrous dysplasia is well demarcated and has a ground-glass appearance. Fibrous dysplasia is classified into three types: Monostotic fibrous dysplasia Monostotic fibrous dysplasia affects a solitary bone and is Figure 16.16: Section from FD comprised of benign-looking the most common type of fibrous dysplasia, comprising fibroblastic tissue arranged in a loose, whorled pattern within about 70% of all cases. which irregular and curved trabeculae of woven (nonlamellar) Most patients are between 20 and 30 years of age. bone are laid down (H&E; 100×).Chapter-16.indd 341 13/12/12 4:04 PM
  • 18. 342 Section B | Systemic Pathology Numerous osteoclasts are noted in relation to the bony tra- Joints beculae. Rarely, secondary malignant change can ensue, most often os- Functions of joints: teogenic sarcoma. Enable movement and provide mechanical support Solid joints provide structural integrity Fibrous Cortical Defect (Metaphyseal Fibrous Cavitated joints are lined by synovial cells and aid in movement 16 Defect, Nonossifying Fibroma) Synovial lining: Type A cells: Macrophage like; synthesize hyaluronic acid Musculoskeletal System Occurs in the metaphyseal cortex of long bones (most commonly tibia or femur) of children. It is generally solitary, but may be Type B cells: Fibroblast like; produce various proteins multiple and bilaterally symmetrical. Articular cartilage helps in: X-ray: Presents as an eccentric lesion in the metaphysis with a Friction-free movement in joints. sharply delimited border. Spreading the load evenly in weight-bearing joints, so that the un- derlying bones absorb shock and weight without being crushed. Pathogenesis: Pathogenesis is not known. According to some authors it arises from some developmental defects involving the epiphyseal plate, whereas, others believe it has a histiocytic origin Osteoarthritis (based on close morphological resemblance to fibrohistiocytic Osteoarthritis is a degenerative joint disease characterized by tumors). age-dependent progressive erosion of articular cartilage. Clinical features: It is usually asymptomatic and discovered It is more common in females than in males. accidentally on routine X-ray. Osteoarthritis may be primary or secondary (secondary osteoarthritis may occur following congenital hip dislocation, Pathology: trauma, fracture, obesity, severe mechanical stress, and diabetes). Gross: It primarily targets weight-bearing joints, e.g., hip, knee, distal Fibrous cortical defect (metaphyseal fibrous defect) is generally interphalangeal joints of hands, and lower lumbar vertebrae. a small lesion, less than 4 cm in diameter, granular, and brown. Larger lesion (5–10 cm) is referred to as nonossifying fibroma. Clinical Features Microscopy (Figure 16.17): Osteoarthritis is asymptomatic or may manifest with: Deep aching pain with movement of joints along with stiffness. Sections show cellular masses of fibrous tissue showing sto- Limitation of movement with crepitations (crackling sound). riform pattern interspersed with numerous multinucleate Bone eburnation (when cartilaginous protection is reduced, osteoclast-like giant cells. subchondral bone may be exposed and damaged, with regrowth Focal areas showing hemosiderin-laden macrophages and leading to a proliferation of ivory-like, dense, reactive bone in foam cells are commonly encountered. central areas of cartilage loss, a process called eburnation). Small fractures in articular bones. Atrophy of regional muscles and laxity of ligaments (conse- quent to decreased movement because of the pain). Hard, bony, painless enlargements called Heberden’s nodes at the base of distal interphalangeal joint of the fingers and Bouchard’s nodes on the proximal interphalangeal joints (due to degenerative changes in the interphalangeal joints). Osteophytes (due to reactive bone formation at the margins of the joints). Osteophytes in spine may cause compression of cervical and lumbar nerve roots causing pain, muscle spasms, and neurological deficit. Pathogenesis Release of IL-1 and TNF from chondrocytes Figure 16.17: Section from NOF showing cellular masses of Activation of catabolic metalloproteinases fibrous tissue arranged in a storiform pattern (H&E; 200x). (collagenase and stromelysin)Chapter-16.indd 342 13/12/12 4:04 PM
  • 19. Musculoskeletal System 343 Secondary amyloidosis Sjögren’s syndrome Destruction of articular cartilage matrix Iatrogenic effects of therapy (fibrillation and erosion of cartilage surface) Release of proteoglycan/collagen Pathogenesis fragments into the synovial fluid Pathogenesis of RA has been depicted in Flowchart 16.1. Exposed subchondral bone becomes new articular Rheumatoid factor (RF): Local stimulation of B cells produces 16 surface and begins to resemble “ivory” IgM autoantibodies directed against the Fc receptor for IgG. Musculoskeletal System Note: There is no specific laboratory test for osteoarthritis, no means of preventing primary osteoarthritis, and no definite Morphology methods for arresting its progression. Synovial hyperplasia (multilayering of synovial cells) Infiltration of synovium by dense perivascular inflammatory Rheumatoid Arthritis (RA) cells (B cells, CD4+ T cells, at places forming lymphoid ag- Rheumatoid arthritis (RA) is a chronic, nonsuppurative, gregates, plasma cells, and macrophages) autoimmune disease. Genetic susceptibility (HLA-DR4) Clinical Features (MHC class II) Occurs between 40 and 70 years of age, and is female pre- Antigenic stimulation dominant. (Infectious agent, e.g., EBV) It is an insidious onset, multisystem disease, which involves three or more joints. CD4+ T cells Commonly affected joints include metacarpophalangeal and proximal interphalangeal joints of hands, along with larger joints like wrists, elbows, ankles, and knees, which show sym- Cytokines metric involvement. (TNF-␣, IF-␥, and IL-1) Morning stiffness lasting longer than 1 hour before improve- ment is a classical feature (unlike osteoarthritis in which the pain and stiffness gets worse with progressive use of the joint Activate during the day). Advanced disease in the hands and wrists produces ulnar de- viation of the fingers (Swan neck deformity) leading to laxity of the soft tissues. B cells Endothelial cells Macrophages Carpal tunnel syndrome (compression of median nerve) is commonly seen. Also seen are general malaise, weakness, fever of unknown origin, Anti-IgG antibody Release of adhesion • Cytokines weight loss, myalgias, and inflammation of tendons and bursae. (Rheumatoid factor) molecules • Proteases Extra-articular Manifestations of RA Formation of immune complexes, pannus Subcutaneous (rheumatoid) nodules, which occur on exten- sor surface of limbs, occiput, and sacrum Cardiac involvement (carditis) Activation of complement system Medium-to-small vessel vasculitis seen in patients with severe Phagocytosis of immune erosive disease complexes (ragocytes) Skin ulceration, gangrene, and obliterative endarteritis (asso- ciated with high titers of RA) Inflammatory damage to synovium, small vessels, collagen, and Peripheral neuropathy destruction of cartilage, bone, fibrosis, and ankylosis Pulmonary involvement: Pleuritis, intrapulmonary nodules, interstitial fibrosis (Caplan’s syndrome–restrictive lung disease with rheumatoid nodules and coal worker’s pneumoconiosis) Joint deformity Hepatitis Ocular involvement: scleritis, episcleritis, and dryness of the eye Flowchart 16.1: Pathogenesis of rheumatoid arthritis.Chapter-16.indd 343 13/12/12 4:04 PM
  • 20. 344 Section B | Systemic Pathology Increased vascularity due to vasodilation and telangiectasia Tuberculous Arthritis Deposition of fibrin in synovium and accumulation of neu- trophils in synovial fluid Tuberculous arthritis is a chronic progressive monoarticular Osteoclastic activity in underlying bone arthritis, which mainly affects the weight-bearing joints, e.g., Pannus formation (Pannus is a combination of neovascular- hips, knees, and ankles. Systemic symptoms may or may not be ization, inflammation, and fibrinoid deposits, which progres- present. 16 sively destroys the underlying cartilage and subchondral bone). Crystallopathies X-ray: Musculoskeletal System Articular crystal deposits include: Joint effusion Juxta-articular osteopenia with bone erosions Endogenous crystals: Monosodium urate (MSU), calcium Narrowing of joint spaces due to loss of articular cartilage pyrophosphate dihydrate, and calcium phosphate Exogenous crystals: Corticosteroids, talc, polyethylene, and Diagnosis of RA silicone Four of the following should be present for the diagnosis of RA: Gouty Arthritis Morning stiffness of >1 hour for at least 6 weeks Arthritis and soft tissue swelling of >3 joints, present for at Gouty arthritis is a male dominant disease, characterized by least 6 weeks hyperuricemia with plasma urate level more than 7 mg/dl Arthritis of hand joints, present for at least 6 weeks (upper limit of solubility of MSU in serum at 37°C and blood Symmetric arthritis, present for at least 6 weeks pH). Subcutaneous nodules in specific places It involves the metatarsophalangeal joints followed by ankles Rheumatoid factor above the 95th percentile and knees; wrists may be affected later. Radiological changes suggestive of joint erosion Typically manifestions include: Recurrent attacks of acute arthritis and deposits of MSU tophi (meaning porous stones) in soft tissue. Juvenile Rheumatoid Arthritis Renal disease affecting interstitium and blood vessels (uric Juvenile rheumatoid arthritis is a chronic inflammatory condition acid nephrolithiasis). that begins in patients under 16 years of age. Types: Must be present for a minimum duration of 6 weeks. Metabolic gout (10% cases): Due to disorder in metabolism More common in girls than boys. of uric acid (a product of purine metabolism) leading to its Abrupt onset of spiking fever, transient skin rash, hepatosple- overproduction. nomegaly, and serositis. Renal gout (90% cases): Due to reduced renal excretion of Affects knees, wrists, elbows, and ankles (large joints affected uric acid. May be secondary to diabetes mellitus, leukemia, more than small joints) diuretic therapy, treatment of disseminated cancer, and drugs RA negative, rheumatoid nodules negative, and ANA positive like aspirin, pyrazinamide, nicotinic acid, ethambutol, and Potential extra-articular manifestations: pericarditis, myo- ethanol. carditis, pulmonary fibrosis, glomerulonephritis, and uveitis Infectious Arthritis Pathogenesis Infectious arthritis is arthritis secondary to infection with any Interaction of MSU crystals with microbial pathogen. mononuclear phagocytes and neutrophils May be secondary to hematogenous spread, osteomyelitis, and complications of intra-articular infection or surgery. Stimulates the MSU crystals lyse Is potentially serious and can lead to permanent deformities. production of IL-1 neutrophils Common causative organisms are gonococci, meningococci, pneumococci, staphylococci, streptococci, H. influenza, and Gram-negative bacilli. Neutrophils release Presents with sudden onset of pain, swollen joints with re- lysosomal enzymes stricted mobility, fever, leukocytosis, and increased ESR. and free radicals Commonly involved joints include knees, hips, shoulders, Inflammatory reaction elbows, and wrists. Predisposing conditions: Immune deficiency, debilitating ill- X-ray: Juxta-articular bone erosion by crystal deposits with loss ness, joint trauma, and intravenous drug abuse. of joint space.Chapter-16.indd 344 13/12/12 4:04 PM
  • 21. Musculoskeletal System 345 Pathology sarco- and myo- both refer to muscle). The nucleus contains genetic material of the muscle cell. The sarcolemma is the name Acute gout: given to the plasma membrane of the muscle cell. The cytosol is Predominantly a disease of lower extremities; most com- the cytoplasm of the muscle cell. monly affecting the great toe The sarcoplasmic reticulum is the endoplasmic reticulum Triggered by precipitation of needle-shaped crystals of of the muscle cell. There are sac-like regions of the sarcoplasmic MSU from serum or synovial fluid, which leads to intense- reticulum known as terminal cisternae. The terminal cisternae act 16 ly painful joint effusion containing crystals, polymorphs, as calcium-storage sites. The calcium ions stored in the terminal and macrophages, lasting for hours to week. cisternae are essential in muscle contraction. A myofibril is a Musculoskeletal System Chronic gout: cylindrical bundle of contractile proteins found within the muscle Presence of tophi, which usually develop after approxi- cell. Myofibrils are composed of individual contractile proteins mately 10 years of disease. called myofilaments. These myofilaments are generally divided Tophi represent deposits of MSU that occur in tissue most into thick and thin myofilaments. The thin myofilaments are commonly in and around the affected joints. composed mainly of a protein known as actin. Actin filaments are Sections through a tophus exhibit an exuberant granu- anchored into the Z line of a sarcomere. The thick myofilaments lomatous reaction complete with foreign body multinucle- are composed mainly of the protein myosin. ated giant cells surrounding a central core of amorphous It is the orderly overlapping of the actin and myosin filaments MSU crystals. that give cardiac and skeletal muscle their striated appearance Pseudogout (light and dark bands). Characterized by deposits of calcium pyrophosphate dihy- Each muscle is supplied by a motor nerve originating from drate crystal deposition in joint cavities. neurons in the spinal cord or brain stem. Sporadic (idiopathic), hereditary, or secondary Knee involved in more than 50% cases Human skeletal muscle contains two major types of fibers: Patients more than 50 years of age Type I are slow twitch fibers (red muscle) that are rich in mito- Rhomboid crystals deposit in articular cartilage (chondro- chondria and oxidative enzymes, and have a great capacity for calcinosis) long, sustained contraction without fatigue, (e.g., soleus muscle). May be asymptomatic or manifest as acute/subacute or Type II are fast twitch fibers (white muscle) that are poor in chronic arthritis mitochondria, use both oxidative metabolism and anaerobic glycolysis, and are quicker to fatigue (e.g., biceps muscle). Reactions of muscle fibers: Muscle Segmental necrosis (only a portion of myocyte is destroyed, un- Muscle terminology: dergoes myophagocytosis, and gets replaced by collagen and fat) Myofiber or myocyte: a muscle cell Vacuolization, alteration in structural proteins, and accumu- Sarcolemma: the plasma membrane of a muscle cell lation of intracytoplasmic deposits Sarcoplasm: the cytoplasm of the muscle cell Regeneration Sarcoplasmic reticulum: the endoplasmic reticulum of a Hypertrophy muscle cell Sarcosome: the mitochondria of a muscle cell Classification of the Disorders of Muscle Sarcomere: the contractile or functional unit of muscle The entire muscle is surrounded by connective tissue called the Muscle disorders include: epimysium and is made up of smaller bundles known as fascicles. Muscle weakness secondary to diseases involving motor Fascicles are actually bundles of individual muscle cells (myofibers neuron pathways, neuromuscular synapse (e.g., myasthenia or myocytes). Each of these bundles is surrounded by a connective gravis) tissue sheath called the perimysium. Each muscle cell is surrounded Neurogenic atrophy occurs when a motor neuron or its axon by a connective tissue sheath known as the endomysium. This degenerates, leading to atrophy of both Type I and Type II sheath is very important in physiology of muscle contraction fibers. because it electrically insulates the individual muscle cells from Muscular dystrophy (MD) is an inherited progressive pri- each other. At ends of the muscle, all of connective tissue sheaths mary muscle disease that most commonly presents in early (epimysium, perimysium, and endomysium) converge to form a childhood. tendon, which will connect the muscle to its attachment site. Congenital myopathies are rare, primary, nonprogressive Each muscle fiber (muscle cell) contains all of organelles that muscle diseases that present at birth with poor muscle tone we find in other cell types. Although these organelles are the [e.g., central core disease, Nemaline (rod) myopathy]. same as in other cells, they are given special names (the prefixes Polymyositis and dermatomyositisChapter-16.indd 345 13/12/12 4:04 PM
  • 22. 346 Section B | Systemic Pathology Muscular Dystrophies Degeneration, necrosis, and phagocytosis of muscle fibers Regeneration of muscle fibers and proliferation of endomysial Muscular dystrophies include: connective tissue. DMD cases also show enlarged, rounded X-linked inheritance: Duchenne and Becker hyaline fibers with loss of cross striations (hypercontracted Autosomal recessive: Limb girdle fibers); a finding rare in BMD. Autosomal dominant: Fascioscapulohumeral and oculopha- ryngeal Laboratory Findings 16 Duchenne Muscular Dystrophy (DMD) Antenatal diagnosis of dystrophin defect using recombinant Musculoskeletal System DNA technology. Most severe and common type of dystrophy. Serum CK (creatinine kinase) levels decline as muscle tissue is X-linked inheritance; females are carriers. progressively replaced by fat and fibrous tissue. Presents with progressive muscle weakness and wasting, which manifests by 5 years. Myasthenia Gravis Paralysis and death by second to third decade. Weakness begins in the pelvic girdle muscles, and then shoul- Autoimmune disease characterized by reduction in acetylcholine der girdle is affected. receptors due to presence of an autoantibody against them. Characterized by a positive Gowers’ maneuver (requiring the Acetylcholine receptor antibody accelerates degradation of assistance of upper extremities to stand up) and pseudohyper- the receptor aided by complement activation and blocks re- trophy (enlargement of calf muscles with weakness). ceptor function. May affect cardiac muscle resulting in arrhythmias and heart May be associated with thymic hyperplasia as well as thymomas. failure. Ptosis and diplopia are the most common initial presenta- May be associated with intellectual impairment. tions. Death results from respiratory insufficiency, pulmonary in- Histopathology is not diagnostic; Type II fiber atrophy may fection, and cardiac failure. be observed in late stage. Pathogenesis: Treatment includes anticholinesterase drugs, thymectomy, immunosuppression, and plasmapheresis. Abnormalities in a gene encoding dystrophin located in the Xp21 region. Deletion (most common), point mutation also seen. Dystrophin and dystrophin-associated protein complex an- Self Assessment chors actin to membrane glycoprotein; absence of dystrophin causes transfer of the force of contraction to connective tissue 1. Write briefly on the clinicopathological features of: and myocyte degeneration. Pyogenic osteomyeli s Tuberculous osteomyeli s Becker Muscular Dystrophy (BMD) Classifica on of bone tumors Osteogenic sarcoma Less common, less severe. Osteochondroma BMD patients have mutations in dystrophin gene resulting Chondrosarcoma in decreased amount of dystrophin, usually of abnormal mo- Giant cell tumor lecular weight. Ewing’s sarcoma Cys c lesions of bone Morphology of Dystrophic Muscle Brown’s tumor Most histopathological abnormalities are common to DMD and Fibrous dysplasia BMD, and include: Rheumatoid arthri s Gout Variation in fiber size (presence of both small and large fibers) with fiber splitting 2. Differen ate between: Increased number of internalized nuclei (normally less than Osteogenic sarcoma and Ewing’s sarcoma 3% are internalized) Osteogenic sarcoma and giant cell tumor of boneChapter-16.indd 346 13/12/12 4:04 PM