Bones, Joints, and Soft Tissue Tumors PDF

SURGICAL PATHOLOGY M.01 Bones, Joints, and Soft Tissue Tumors Dr. Espiritu | September 17, 2024 OUTLINE B. BONE COMPOSITION I. BONES.............................

SURGICAL PATHOLOGY M.01 Bones, Joints, and Soft Tissue Tumors Dr. Espiritu | September 17, 2024 OUTLINE B. BONE COMPOSITION I. BONES........................................................................ 1 A. Function of the Bones.......................................... 1 B. Bone Composition............................................... 1 C. Types of Bone Based on Shape............................. 2 D. Cellular Components of Bone.............................. 3 II. DEVELOPMENT (READING ASSIGNMENT)................... 3 III. CONGENITAL AND DEVELOPMENTAL DISORDERS..... 4 A. Introduction........................................................ 4 B. Dwarfism............................................................ 4 C. Osteogenesis Imperfecta.................................... 4 Fig. 2. Composition of the Bones D. Osteopetrosis..................................................... 5 Ø Made up of: IV. METABOLIC DISEASES OF BONES............................... 6 o Organic component A. Introduction......................................................... 6 o Inorganic component B. Osteoporosis and Osteopenia............................... 6 Ø Organic Component: Osteoid (35%) V. Checkpoint................................................................ 7 o Unmineralized, organic portion of the VI. References................................................................ 7 bone matrix that forms prior to the Extracellular maturation of bone tissue I. BONES Component o Composition: (Bone Type I collagen A. FUNCTION OF THE BONES Matrix) Glycosaminoglycans Other proteins: osteopontin (osteocalcin) § Produced by osteoblasts § It contributes to the regulation of bone formation, mineralization, and Ca homeostasis § It can be used for diagnostic purposes as a specific marker for osteoblast activity Ø Inorganic Component: Minerals (65%) o Hydroxyapatite crystals [Ca10(PO4)6(OH)2] Responsible for bone hardness Repository for calcium (99%) and phosphorus (85%) in the body 2 Types of Bone Matrix Woven Bone Lamellar Bone Fig. 1. Functions of the bone Ø Adult bones: o Total number: 206 o 12% of the body weight Ø Functions: o Mechanical support Fig. 3. Woven Bone Fig. 4. Lamellar Bone o Transmission Immature or primary form Mature bone o Protection of internal organs o Mineral homeostasis (calcium & phosphate) bone o Hematopoietic organ during post-natal life Produced rapidly during fetal Produced slowly during the o Facilitation of movement: development and in response repair of fractures to injury Transmit the force of muscle contraction Random, disorganized Parallel arrangement of The bone will act as a lever while the joints will arrangement of collagen collagen fibers form the pivot point fibers (haphazard arrangement) BASTIAN, TRILLANA, ASAYTUNO, RAPOSAS SURGICAL PATHOLOGY Page 1 of 10  SURGICAL PATHOLOGY M.01 Bones, Joints, and Soft Tissue Tumors Dr. Espiritu | September 17, 2024 Woven Bone Lamellar Bone Weaker or less mechanical Stronger strength Found in the early stages of Replaces woven bone as fracture healing, in the growth remodelling occurs, making plates, and in certain up the structure of adult pathologic conditions such as compact and cancellous in bone tumors or bone osteomyelitis Presence of this bone in adult is always abnormal, but not a specific finding 2 Bones under Lamellar Bone Spongy Bone (Cancellous Compact Bone (Cortical Bone) Bone) Long Fig. 6. Long Bone Ø Parous, honeycomb-like Ø Dense and solid structure Ø Highly organized Made up of: Ø Made up of trabeculae Ø Layered structure Ø Cortex (outer) (thin, branching bone o Made up of compact bone plates) Ø Medulla (inner) The spaces between the Made up of cylindrical units o Made up of cancellous or spongy bone trabeculae are filled with bone called osteons or haversian Ø In between of thin bone trabeculae: marrow can marrow, typically red marrow systems, which provide be found for hematopoiesis strength o Fatty marrow (white) Primarily in the interior of Found on the outer surface of o Hematopoietic marrow (red) bones, such as the ends of bones, providing rigidity and Parts: long bones (epiphyses), inside strength Ø Epiphysis – ends of the long bones the vertebrae, and in flat bones Ø Diaphysis – long portion in the center of the (e.g., ribs, pelvis) bone C. TYPES OF BONE BASED ON SHAPE Ø Long Ø Short Ø Flat Ø Irregular Ø Sesamoid Short Fig. 7. Short bone Ø Roughly equal entities Ø Carpal bone: o Equal thickness giving it a cube-like shape o Majority is made up of spongy or cancellous bone o Thin lining of compact bone Fig 5. Types of Bones Flat Fig. 8. Flat bone Ø Thin, flattened and somewhat curved Ø Consist of two parallel layers of compact bone with spongy bone (diploe) in between Ø Functions: o Protect internal organs § E.g., ribs, scapula o Serve as a surface for muscle attachment BASTIAN, TRILLANA, ASAYTUNO, RAPOSAS SURGICAL PATHOLOGY Page 2 of 10  SURGICAL PATHOLOGY M.01 Bones, Joints, and Soft Tissue Tumors Dr. Espiritu | September 17, 2024 D. CELLULAR COMPONENTS Ø Can be found in the substance of fully formed bone (lamellar bone) Ø Occupies the lacuna (chamber) o Contains the bone Ø Functions: o Mechanosensors and orchestrators of the bone remodeling process § Calcium and phosphate regulation § Mechanotransduction Ø Most abundant type of cells in mature bone tissue Ø Long-lived: it can survive as long as the Fig. 9. Cellular components of bones lacuna that they occupy exists Osteoblasts Fig. 10. Osteoblast in an immature bone; Yellow – unmineralized part or osteoid Fig. 13. Osteoclasts at the periphery with multinucleation Ø Arise from osteogenic stem cells Ø Seen surrounding the osteoid Osteoclasts Ø Specialized macrophages Ø Functions: Ø Multinucleation o Synthesize, transport, and assemble Ø Bone resorption matrix Ø Functions: o Regulate mineralization o Degrade bone: § To initiate bone remodeling § Mediate bone loss in pathologic condition by increasing resorptive activity Ø Derived from myeloid monocyte lineage that will circulate in the blood after they formed in the bone marrow Ø Matrix metalloproteases: o Bone remodeling o Very strong that it can dissolved inorganic and organic bone Fig.11. Diagram of bone remodelling components II. DEVELOPMENT (READING ASSIGNMENT) Osteocytes Ø Most bones that form during embryogenesis develop from a cartilage mold via endochondral ossification Ø The cartilage mold (anlagen) is synthesized by mesenchymal precursor cells Ø A central medullary canal within the anlagen is created by chondroblasts at approximately 8 weeks of gestation Ø Simultaneously, osteoblasts begin to deposit the cortex beneath the nascent periosteum of the midshaft (diaphysis) o This forms a primary center of ossification resulting in Fig. 12. Example of Lamellar Bone; Lower portion are radial bone growth the osteocytes that can be seen as long cytoplasmic processes that will be imbedded in the bony Ø At the longitudinal ends (epiphysis), endochondral canaliculi which will maintain the viability of the ossification forms secondary centers of ossification osteocytes by providing nutrients and bone product. BASTIAN, TRILLANA, ASAYTUNO, RAPOSAS SURGICAL PATHOLOGY Page 3 of 10  SURGICAL PATHOLOGY M.01 Bones, Joints, and Soft Tissue Tumors Dr. Espiritu | September 17, 2024 Ø Eventually, plates of cartilage anlage become entrapped Ø Expressed in the growth between the expanding centers of ossification forming plate proliferating zone physes or growth plates (Fig. 26.3) Ø Via Frizzled and LRP5/6 Ø Chondrocytes within the growth plates undergo sequential Wnt Growth Factors receptors, activate β- proliferation, hypertrophy, and apoptosis catenin to promote Ø Matrix mineralizes during apoptosis and is invaded by chondrocyte proliferation capillaries, providing the nutrients for activation of and maturation osteoblasts and osteoid synthesis Ø A transcription factor Ø Most calcified cartilage matrix is ultimately resorbed leaving expressed by proliferating, only strut-shaped remnants that serve as scaffolding for but not hypertrophic, SOX9 bone deposits known as primary spongiosa, the earliest chondrocytes bone trabeculae (see Fig. 26.3) Ø Essential for differentiation o Over time, this process produces longitudinal bone of chondrocyte precursors growth Ø A transcription factor Ø Flat bones (e.g., cranium) are formed by intramembranous expressed in early ossification, in which a dense layer of mesenchyme is hypertrophic chondrocytes directly ossified by osteoblasts without a cartilage and immature anlagen RUNX2 mesenchymal cells Ø Bones enlarge by deposition of new bone on a preexisting Ø Controls terminal surface, a process called appositional growth chondrocyte and osteoblast differentiation Ø Secreted by a variety of mesenchymal cells Ø FGFs (most notably FGF-3) Fibroblast Growth act on hypertrophic Factors (FGFs) chondrocytes to inhibit proliferation and promote differentiation Ø Members of the TGF-β family Ø Expressed at various stages of chondrocyte Bone Morphogenic development Proteins (BMPs) Ø Have diverse effects on chondrocyte proliferation and hypertrophy at the growth plate III. CONGENITAL AND DEVELOPMENTAL DISORDERS A. INTRODUCTION Ø Two umbrella terms: o Dysostoses Ø Local and systemic factors that regulate bone development o Dysplasia include the following: Ø Defects in formation of cartilage anlage Ø Induces and maintains that gives rise to bone Growth Hormone (GH) Ø Clinically observed as abnormality in the chondrocyte proliferation Ø Acts on proliferating shape and number of bones Thyroid Hormone chondrocytes to induce Ø Examples: hypertrophy Dysostoses o Polydactyly or supernumerary Ø Secreted locally by bone formation: formation of prehypertrophic extra digits chondrocytes o Aplasia: absence of digits Indian Hedgehog (Ihh) Ø Coordinates chondrocyte o Syndactyly: fusion of bones that proliferation and should normally separate differentiation with Ø Abnormalities of bone development or osteoblast proliferation remodeling Ø Produced by perichondrial o Bone is formed but does not grow stromal cells and early or is not maintained normally Dysplasias Parathyroid Hormone- proliferating chondrocytes Ø Due to genetic mutations that affect Related Protein (PTHrP) Ø Activates the PTH receptor bone-forming cells to maintain chondrocyte Ø Example: proliferation o Achondroplasia: dwarfism BASTIAN, TRILLANA, ASAYTUNO, RAPOSAS SURGICAL PATHOLOGY Page 4 of 10  SURGICAL PATHOLOGY M.01 Bones, Joints, and Soft Tissue Tumors Dr. Espiritu | September 17, 2024 B. DWARFISM Ø Most common congenital dysplasia, although not lethal Ø Characterized by congenital short stature Ø Autosomal dominant disorder resulting to diminished elongation of long bones Fig. 16. Meet Christopher Alvarez, in his mid- to o Gain-of-function mutation late twenties, diagnosed with thanatophoric dysplasia. He is a college graduate and a that activates the fibroblast journalist – the exception to norm of early growth factor 3 (FGF-3) death. Ø Manifestations: o Shortened proximal QUICK REVIEW! extremities Dwarfism Thanatophoric Dysplasia o Normal trunk length Ø MC congenital dysplasia Ø MC lethal form of dwarfism o Enlarged head and a bulging Ø Not lethal forehead Ø Autosomal dominant Achondroplasia o Depression at the root of the Gain-of-function mutation in FGFR-3 leads to… nose Ø Shortened proximal Ø ­ FGFR-3 signaling → more extremities severe phenotype Ø Normal trunk length Ø Shortening of the limbs Ø Enlarged head and a bulging Ø Frontal bossing forehead Ø Macrocephaly Ø Depression at the root of the Ø Small chest cavity → nose respiratory insufficiency C. OSTEOGENESIS IMPERFECTA Ø The most common inherited disorder of connective tissue Ø Aka: brittle bone disease Ø Autosomal dominant disorder Ø Mutation in genes that encode for alpha-1 or alpha-2 chain Fig. 14. Achondroplasia features. of type 1 collagen o Review: bony matrix is mainly made up of type 1 Ø Most common lethal form of collagen dwarfism o A mutation can down-regulate bone matrix Ø Gain-of-function mutation in FGF-3 formation causing reduced bone formation and has a different pathway when skeletal fragility compared to achondroplasia Ø Affects the following: o Increased FGFR-3 signaling o Bone: underdeveloped ligaments which results in a more severe o Teeth: dentinogenesis imperfecta (DI) phenotype § Abnormal dentin formation Ø Most patients die at birth or soon after § Causes opalescent brown teeth Ø Manifestations: o Eyes: blue sclera o Shortening of the limbs § A thin scleral layer leading to blue o Frontal bossing coloration o Macrocephaly Thanatophoric o Small chest cavity Dysplasia ▪ Leads to respiratory insufficiency Fig. 17. Clinical features of Osteogenesis Imperfecta. Fig. 15. Thanatophoric Dysplasia Features. BASTIAN, TRILLANA, ASAYTUNO, RAPOSAS SURGICAL PATHOLOGY Page 5 of 10  SURGICAL PATHOLOGY M.01 Bones, Joints, and Soft Tissue Tumors Dr. Espiritu | September 17, 2024 Table 2. Subtypes of osteogenesis imperfecta (larger at the end) Fig. 18. X-ray findings of healthy bone vs. Infantile osteopetrosis. No medullary canal. MEMORIZE! D. OSTEOPETROSIS/MARBLE BONE DISEASE/ ALBERS SCHONBERG DISEASE Ø Group of disorders characterized by excessive bone formation due to defective osteoclast function and reduced bone resorption Ø Leads to a diffuse symmetric skeletal sclerosis Fig. 19. Erlenmeyer flask deformity seen in osteopetrosis. Ø Reduced bone resorption o Yields excessive bones but brittle, thus fractured easily, comparable to a piece of chalk Ø Morphology: o No medullary canal due to absence of osteoclast o End of long bones are bulbous: Erlenmeyer flask deformity Not pathognomonic for osteopetrosis § Seen also in diseases that Fig. 20. Other diseases that present with Erlenmeyer Flask Deformity. cause widening of meta diaphysis especially in distal femur o Small neural foramina o Persistent primary spongiosa Fills the medullary cavity No room for hematopoiesis No formation of mature trabeculae Woven bone rather than lamellar bone in fills the medullary cavity because there is no formation of mature trabeculae → brittle bone Fig. 21. Section of proximal tibial diaphysis from a fetus with osteopetrosis. The cortex (1) is present, but the medullary cavity (2) is Anemia occurs due to obliterated filled with primary spongiosa, which replaces the hematopoietic bone marrow elements. Table 2. Classification of Osteopetrosis (larger at the end) Fig. 22. Bone marrow biopsy. A: Enlarged and thickened bone trabeculae encroaching marrow spaces forming mosaic pattern. B: Pronounced narrowing of bone marrow spaces with hypocellular bone marrow. C: Presence of cartilaginous islands. BASTIAN, TRILLANA, ASAYTUNO, RAPOSAS SURGICAL PATHOLOGY Page 6 of 10  SURGICAL PATHOLOGY M.01 Bones, Joints, and Soft Tissue Tumors Dr. Espiritu | September 17, 2024 IV. METABOLIC DISEASES OF BONE cause increased bone A. INTRODUCTION resorption Ø Systemic condition that results in reduced bone strength, Ø Smoking and tobacco use altered mineralization or composition of the bone o Associated with increased bone Ø Metabolic abnormalities may result to skeletal defects of loss different types Ø Excessive alcohol absorption o Impair calcium absorption B. OSTEOPOROSIS AND OSTEOPENIA Ø Reduced peak bone mass Ø Osteoporosis: Ø Genetic factors o Clinically significant decrease in bone mass o Decreased vitamin D receptors, (osteopenia) estrogen receptors, mutations o Most associated with aging and post- in collagen chains menopausal hormonal changes in women o Leads to increased fracture risk Ø Histologically, the bone appears normal but of decreased Osteopenia Ø Osteopenia is a term used to describe quantity Vs. decreased in bone mass Ø Post-menopausal osteoporosis: increased osteoclastic Osteoporosis Ø Osteoporosis is a form of osteopenia activity primarily affecting trabecular bone Ø Hence, osteoporosis is an osteopenia severe enough to Ø Senile osteoporosis: predominantly affects cortical bones increase the risk of fracture Ø Achieved during adulthood Ø Level is influenced by: Peak Bone o Heredity Mass o Physical activity o Diet o Hormonal state Ø Aging o Senile osteoporosis o Slow bone formation leading to an overall decrease in bone mass o Osteoblast activity decreases or stays the same with age o Osteoclast activity increases with age o Imbalance occurs where more bone is broken down than what Fig. 23. Osteoporosis: bones are thinner compared to normal trabecular is formed and cortical bone o Osteoblast activity and synthetic activity is reduced Ø Reduced physical activity o Mechanical forces stimulate bone remodeling (i.e., sedentary lifestyle) Risk Factors Ø Reduced dietary intake of calcium and vitamin D o Impaired bone mineralization o Includes overall poor nutrition, especially in the elderly Ø Decreased levels of hormones o Sharp decline in estrogen levels in women accelerate bone resorption and reduces Fig. 24. Markedly thinned out trabecular (black line) and cortical (blue line) bone density bone o Androgen deficiency in men causes low testosterone can Ø Results in bone structures inadequate for weight bearing also lead to decreased bone o Fractures commonly occur: mass but effect is slower as § Especially compression fractures of compared to women the vertebrae that cause spinal Ø Medications deformity o Prolonged use of § Most typically kyphosis and shortened glucocorticoids since they stature inhibit osteoblast activity and BASTIAN, TRILLANA, ASAYTUNO, RAPOSAS SURGICAL PATHOLOGY Page 7 of 10  SURGICAL PATHOLOGY M.01 Bones, Joints, and Soft Tissue Tumors Dr. Espiritu | September 17, 2024 V. CHECKPOINT! A. COL1A1 1. A 29-year-old woman, G3, P2, gives birth to an infant B. EXT following an uncomplicated pregnancy. The infant’s C. FGFR3 height is below the fifth percentile. On physical D. FBN1 examination, the infant’s torso and head size are E. HGPRT normal, but the extremities are short. The forehead F. RB appears prominent. Radiographs show short, slightly 4. A 17-year-old primigravida gives birth prematurely to bowed long bones, but no osteopenia. The other two an infant small for gestational age. The infant has children in the family are of normal height. The affected immediate respiratory distress. Newborn examination child has no difficulty with activities of daily living after shows limb shortening, frontal skull bossing, and small modifications are made in the home and school for thorax. A radiograph shows normal bone density short stature, and later becomes a physician. Which of without fractures. What is the most likely diagnosis? the following conditions is likely to be present in this A. Achondroplasia child? B. Congenital syphilis A. Achondroplasia C. Osteogenesis imperfecta B. Hurler syndrome D. Rickets C. Osteogenesis imperfecta E. Thanatophoric dysplasia D. Rickets 5. A 2-year-old child has a history of multiple bone E. Scurvy fractures with minor trauma. On examination he has F. Thanatophoric dysplasia hepatosplenomegaly and palsies involving cranial 2. A 14-year-old girl who was normal at birth now has nerves II, VII, and VIII. Laboratory studies show bilateral hearing loss. Audiometry indicates bilateral pancytopenia. Radiographs reveal diffusely and mixed conductive and sensorineural hearing loss. CT symmetrically sclerotic bones with poorly formed scan of the head shows maldevelopment of both metaphyses. Molecular analysis of his bone reveals a middle ears with deficient ossification. Further history defect in production of carbonic anhydrase to indicates that her dentist has tried various whiteners to solubilize hydroxyapatite crystal. He is treated with diminish the yellow-brown color of her teeth, which hematopoietic stem cell transplantation. Which of the have a slight bell-shaped appearance. The optometrist following cells in his bones was most likely functionally noted that her sclerae have a peculiar steel-gray color, deficient and replaced following transplantation? and her vision is 20/40. At age 30 years, she falls and A. Chondroblast fractures the left femur. A radiograph shows that the B. Chondrocyte femur is osteopenic. Bone densitometry reveals C. Osteoblast osteopenia of all measured sites. Which of the D. Osteoclast following molecular mechanisms is most likely to E. Osteocyte produce these findings? 6. A 77-year-old woman trips on the carpet in her home A. Deficient hypoxanthine-guanine and falls to the floor. She immediately has marked pain phosphoribosyltransferase (HGPRT) activity in the right hip. On physical examination, there is B. Diminished osteoprotegerin binding to shortening of the right leg with external rotation and macrophage RANK receptor marked pain with any movement. A radiograph shows C. Failure of type I collagen formation by a right femoral neck fracture. The fracture is repaired. osteoblasts Six months later, a dual-energy x-ray absorptiometry D. Fibroblast growth factor receptor 3 inhibition of (DEXA) scan of the patient’s left hip and lumbar cartilage proliferation vertebrae shows bone mineral density 2 standard E. Increased interleukin-6 production by deviations below the young adult reference range. osteoblasts Which of the following cellular processes contributes F. Reduced number of vitamin D receptors most to development of her findings? 3. A 23-year-old primigravida notes decreased fetal A. Decreased secretion of interleukin-6 by movement, and a screening ultrasound at 18 weeks’ monocytes gestation shows decreased fetal size. A stillborn is B. Increased sensitivity of osteocytes to delivered at 25 weeks’ gestation. At autopsy, a parathyroid hormone radiograph shows marked osteopenia and multiple C. Insensitivity of bone matrix to 1,25- bone fractures. Mutational analysis of fetal cells is dihydroxycholecalciferol most likely to show an abnormality involving which of D. Mutation in the fibroblast growth factor receptor the following genes? 3 gene BASTIAN, TRILLANA, ASAYTUNO, RAPOSAS SURGICAL PATHOLOGY Page 8 of 10  SURGICAL PATHOLOGY M.01 Bones, Joints, and Soft Tissue Tumors Dr. Espiritu | September 17, 2024 E. Increased osteoclast activity F. Synthesis of chemically abnormal osteoid matrix 7. A 35-year-old woman with active lupus nephritis falls forward and lands on her left hand. She has immediate pain. On examination there is crepitus at the wrist. A radiograph shows radial and navicular fractures along with marked osteopenia. Which of the following medications most likely contributed to the fracture? A. Hydrocortisone B. Ibuprofen C. Lisinopril D. Losartan E. Methotrexate 8. An epidemiologic study of postmenopausal women is performed. The subjects undergo periodic examination by dual-energy x-ray absorptiometry (DEXA) scan performed on the hip and lumbar vertebrae to evaluate bone mineral density over the next 10 years. They respond to a survey regarding their past and present use of drugs, diet, activity levels, history of bone fractures, and medical conditions. A cohort of the subjects is identified whose bone mineral density is closest to that of the young adult reference range and in whom no bone fractures have occurred. Which of the following strategies is most likely to be supported by the study data to provide the best overall long-term reduction in risk of fracture in postmenopausal women? A. Increasing bone mass with exercise during young adulthood B. Limited alcohol use, and avoidance of the use of tobacco C. Initiation of estrogen replacement therapy after a fracture D. Supplementation of the diet with calcium and vitamin D after menopause E. Use corticosteroid therapy for inflammatory conditions A 8. A 7. E 6. D 5. E 4. A 3. C 2. A 1. VI. REFERENCES Ø Dr. Espiritu’s discussion Ø Trans 2025 BASTIAN, TRILLANA, ASAYTUNO, RAPOSAS SURGICAL PATHOLOGY Page 9 of 10  SURGICAL PATHOLOGY M.01 Bones, Joints, and Soft Tissue Tumors Dr. Espiritu | September 17, 2024 BASTIAN, TRILLANA, ASAYTUNO, RAPOSAS SURGICAL PATHOLOGY Page 10 of 10  SURGICAL PATHOLOGY M.02 Bones, Joints, and Soft Tissue Tumors Dr. Espiritu | September 18, 2024 OUTLINE B. HYPERPARATHYROIDISM I. METABOLIC DISEASES OF BONE (CONTINUATION)...... 1 Ø Excess production of parathyroid hormone leads to increased osteoclast activity, bone resorption, and A. Rickets and Osteomalacia................................... 1 osteopenia B. Hyperparathyroidism.......................................... 1 C. Paget’s Disease.................................................. 1 Primary Hyperparathyroidism II. FRACTURES................................................................ 2 Ø Causes generalized osteoporosis by mobilizing III. AVASCULAR NECROSIS............................................... 3 calcium from bone and increasing urinary phosphate IV. OSTEOMYELITIS......................................................... 4 excretion A. Pyogenic Osteomyelitis....................................... 4 Ø Hypercalcemia and hypophosphatemia: when bone is destroyed, calcium is released B. Tuberculous Osteomyelitis.................................. 5 Ø Bone loss predisposes microfractures that elicit a V. NEOPLASTIC BONE-FORMING TUMORS..................... 6 vascular and macrophage rich repair response A. Osteoid Osteoma and Osteoblastoma................. 6 B. Osteosarcoma.................................................... 6 VI. Checkpoint................................................................ 7 VII. References................................................................ 9 I. METABOLIC DISEASES OF BONE (CONTINUATION) A. RICKETS AND OSTEOMALACIA Ø Deficiency in vitamin D causes hypocalcemia, resulting in defective bone formation Ø Vitamin D deficiency = impaired calcium and phosphate absorption Figure 4. Brown Tumor Rickets: Children Osteomalacia: Adults Ø Skeletal manifestation: forms masses of reactive tissues known as “brown tumors” Description o As an effect of bone resorption, this will Ø Interferes with the Ø Bone formed during cause hemorrhage, increased vascularity deposition in the remodeling is under- and deposition of hemosiderin growth plates mineralized, resulting o Non-neoplastic lesion in a predisposition to fractures Ø Growth plates are not involved anymore Clinical Manifestations Ø Delayed growth Ø Fractures Ø Bowing of the legs Ø Deformities (genu varum) Ø Bone pain Ø Thickening of the Ø Muscle weakness wrists and ankles Ø Waddling gait Ø Skeletal deformities (pigeon chest, skull deformities) Ø Muscle weakness Ø Bone pain Figure 5. Dissecting osteitis (resembles train tracks) Ø Decreased number of osteoclasts: dissects the bony trabecula forming dissecting osteitis C. PAGET’S DISEASE Description Ø Formation of increased but disordered and structurally unsound bone Ø Abnormal bone architecture caused by increases in both osteoblastic and osteoclastic activity Ø Spine, pelvis, calvarium of the skull, femur and tibia Ø Unknown etiology, but viral etiology is suggested due to intranuclear inclusion in the osteoclasts = PARAMYXOVIRUS (but not yet proven) Figure 3. Bowing of the legs (genu varum) in rickets MORADILLO, RAGOJOS, QUEZON, RAPOSAS SURGICAL PATHOLOGY Page 1 of 9  SURGICAL PATHOLOGY M.02 Bones, Joints, and Soft Tissue Tumors Dr. Espiritu | September 18, 2024 Clinical Manifestation Fracture Occurs when a joint dislocates and one of Ø Involves multiple bones dislocation the bones of the joint fractures Ø Axial skeleton or proximal femur is involved in majority of Bone partially fractures on one side, does Greenstick cases not break completely, because the rest of fracture Ø Asymptomatic, discovered as an accidental the bone cannot bend radiographic finding Hairline fractures A thin, partial fracture of the bone Ø Less often pain caused by fractures Impacted A piece of the bone may impact another Ø Marked increase in serum ALP and normal serum fracture bone calcium and phosphorus Intra-articular Fracture extends into the surface of a joint o Increased ALP is an indication of an fractures osteoblastic activity Longitudinal Extends along the length of the bone Morphologic Phases fracture Osteolytic phase Osteoclastic resorption predominates Oblique fracture Opposite to the bone’s long axis Mixed osteoblastic New bone formation leads to a Pathological When an underlying condition weakens and osteolytic characteristic mosaic pattern fractures the bone and causes a fracture phase Spiral fracture On part of the bone twists during a break Late Bone density is increased; trabeculae Repeated stress and strain can fractur a (osteosclerotic) are thick, and mosaic pattern is Stress fracture bone phase prominent Transverse Straight break across the bone Complications fracture Ø Bone pain resulting from fractures: although bone is thick, it lacks strength; fractures can lead to deformity Healing of Fractures Ø High-output cardiac failure can result from multiple Ø Break in the bone → hematoma formation → activation of functional arteriovenous shunts within highly vascular coagulation cascade → formation of organized hematoma early lesions Ø Healing quality: Ø Hearing loss is caused by narrowing of auditory foramen o Near-perfect union in children and young or direct involvement of bones of the middle ear adults Ø Osteosarcoma in approximately 1% of all individuals o In older adults, other bone disorders with Paget’s disease (osteoporosis, osteomalacia) may complicate healing Ø Factors affecting healing: o Inadequate immobilization can cause delayed union or nonunion, leading to pseudoarthrosis (false joint) o Infection, malnutrition, and skeletal dysplasia also interfere with healing Ø Fractures have to be immobilized o Inadequate immobilization = result in delayed healing o Complications: false joint Sequence of fracture healing Initial stage Blood vessel rupture forms a hematoma Figure 6. Mosaic pattern of Paget’s disease of the bone (fracture): that fills the injury site Provides a fibrin mesh, attracting II. FRACTURES Clot function inflammatory cells, fibroblasts, and Ø Full or partial break in the continuity of bone tissues capillaries, forming granulation tissue Ø Fractures can occur in any bone in the body PDGF, TGF-β, FGF, and others activate Growth factor osteoprogenitor cells, stimulating release Different ways bones can fracture osteoclastic and osteoblastic activity Break to bone that doesn’t damage Soft tissue Forms initially, providing some anchorage Closed fracture surrounding tissue or tear through the callus but not enough structural support for skin (procallus) weight-bearing Damages surrounding tissue and Within 2 weeks, osteoprogenitor cells Compound Bony callus penetrates skin (more serious because of deposit woven bone, transforming the fracture formation the risk of infection) procallus into a bony callus for stabilization Muscle or ligament pulls on bone Mesenchymal cells can become Avulsion fracture fracturing it Chondrocyte chondrocytes, producing fibrocartilage and Comminuted Impact shatters bone into many pieces differentiation hyaline cartilage, which undergoes fracture endochondral ossification Compression or Generally occurs in the spongy bone in crush fracture the spine MORADILLO, RAGOJOS, QUEZON, RAPOSAS SURGICAL PATHOLOGY Page 2 of 9  SURGICAL PATHOLOGY M.02 Bones, Joints, and Soft Tissue Tumors Dr. Espiritu | September 18, 2024 Newly deposited bone connects the fracture o Pregnancy Bone bridging ends, allowing increased stiffness and o Radiation therapy strength for weight-bearing o Sickle cell crisis Excess fibrous tissue, cartilage, and woven o Tumors Callus bone are resorbed, recreating lamellar bone o Dysbarism (e.g., decompression sickness) maturation and restoring the medullary cavity Figure 7. When bone necroses, there will be collapse (a) of the head of the bone leading to degradation (b) of cartilage leading to avascular necrosis Ø One of the common areas where avascular necrosis occurs is in the femur Ø Necrosis happens because of the presence of an obstruction or an interruption in the blood vessels supplying the head and neck of the bone involved o Mostly, the affected portion will be the head and the neck o The end result of the obstruction in the blood supply is necrosis Figure 6. Healing Fractures. Begins with an organizing hematoma. Within 2 weeks, the tow ends of the bone are bridged by a fibrin meshwork in which osteoclasts, osteoblasts and chondrocytes differentiate from precursors. These cells produce cartilage and bone matrix which with adequate immobilization, remodels into normal lamellar bone Figure 8. Gross picture of avascular necrosis: Femoral head with a subchondral, wedge-shaped pale area of osteonecrosis (white arrow); III. AVASCULAR NECROSIS Intact cartilage (pink arrow) Ø Infarction of the bone and the marrow Ø AKA osteonecrosis Ø It is usually in the medulla because, in the cortex, there is o Relatively a common condition a collateral blood supply that can limit the extent of o Mostly limited to the medullary cavity, but necrosis sometimes can involve both the medulla and Ø If the infarct is subchondral, the overlying cartilage is going cortex to be intact Ø Causes: Ø Avascular necrosis is only derived on the bone o Fractures and corticosteroid administration (the o The cartilage is still intact since it gets nutrients two most common causes) derived from the synovial fluid o Alcohol abuse o Bisphosphonate therapy o Connective tissue disease o Chronic pancreatitis o Gaucher disease MORADILLO, RAGOJOS, QUEZON, RAPOSAS SURGICAL PATHOLOGY Page 3 of 9  SURGICAL PATHOLOGY M.02 Bones, Joints, and Soft Tissue Tumors Dr. Espiritu | September 18, 2024 Clinical Course and Complications Ø In the acute stage, pyogenic osteomyelitis may resolve with antibiotic therapy Ø Osteonecrosis: o The disorder may compress vasculature and produce pyogenic exudate (pus containing a lot of netrophilic infiltrates), resulting in ischemic necrosis of bone and marrow; o Necrotic bone (known as the sequestrum) § Acts as a foreign body and as a locus for persistent infection Ø Subperiosteal dissection by pyogenic exudate may further impair blood supply: o Pyogenic exudate – can insinuate itself in between the outer portion of the bone and the periosteum Figure 9. Histologic features of avascular necrosis of the bone: → impairment of the blood supply Dead bone (a) surrounded by necrotic adipocytes (b) Ø Sinus formation: o Pus can rupture into surrounding tissues and form Ø One of the common areas where avascular necrosis occurs sinuses draining through skin is in the femur o A sleeve of new bone formation (involucrum) may Ø Dead bone (A) – characterized by the presence of empty surround the infected necrotic area which may be lacunae localized by a surrounding wall of granulation Ø Since the bone marrow is also involved, the adipocytes in tissue (Brodie abscess) the bone marrow will also appear necrotic (B) IV. OSTEOMYELITIS Ø Inflammation of the bone and the marrow Ø Almost always secondary to infection due to progressive inflammatory reaction and apposition of new bone A. PYOGENIC OSTEOMYELITIS Ø Pyogenic osteomyelitis is an acute pyogenic infection of bone Ø Most often initially involved (most common sites): o Metaphysis o Distal end of the femur o Proximal end of the tibia o Proximal end of the humerus Ø Most often caused by S. aureus (80% - 90% of cases) Figure 10. Initial stage of Osteomyelitis: Brodie Abscess. Presence of o Express cell proteins that can bind to the bone neutrophil infiltrates and cells debris. matrix and facilitate adherence to the bone Ø Gram-negative bacilli (less common causes) are frequently B. TUBERCULOUS OSTEOMYELITIS isolated in individuals with genitourinary tract infections Ø This disorder is secondary to tuberculous infection located and in intravenous drug users: elsewhere o E. coli Ø A cell-mediated type IV hypersensitivity reaction as it o Pseudomonas forms caseating granulomas leading to collapse in bone o Klebsiella Ø It characteristically occurs in: Ø Salmonella osteomyelitis: o Vertebrae (Pott’s disease) o Commonly isolated in individuals with sickle cell § Vertebral collapse can lead to spinal deformity disease § Because the infection is characterized by a Ø Mixed bacterial infection can occur as: progressive inflammatory destruction and o A direct spread apposition of new bone o Inoculation of 2 organisms during surgery o Hip o In patients with open fractures o Long bones, especially the femur and tibia Ø Group B strep/Escherichia/Haemophilus: newborns o Bones of the hands and feet MORADILLO, RAGOJOS, QUEZON, RAPOSAS SURGICAL PATHOLOGY Page 4 of 9  SURGICAL PATHOLOGY M.02 Bones, Joints, and Soft Tissue Tumors Dr. Espiritu | September 18, 2024 Figure 11. Diagrammatic representation of a patient with Pott’s disease Ø Involvement of the vertebra can cause: o Back pain o Neurological deficits o Progressive kyphosis of the lower thoracic and Figure 14. Langhan’s multinucleated giant cell (red arrow) in the boney lumbar spin tissue. Granuloma (black arrow); lamellar bone (yellow arrow) o Abscesses that can lead to the development of soft tissue mass → neurological manifestations Ø Diagnosis of osteomyelitis requires: o The most definitive: determining the organisms via biopsy and cultures o Careful assessment of radiographs and MRI Ø Treatment is often a combination of: o Culture-directed antibiotics o Surgical debridement of nonviable tissue V. NEOPLASTIC BONE-FORMING TUMORS A. OSTEOID OSTEOMA AND OSTEOBLASTOMA Ø More common Ø Based on cell type Ø Tumors that produce unmineralized osteoid or mineralized woven bone Ø Benign bone-producing tumors Ø Have similar basic histologic features Figure 12. Patient with Pott’s disease showing kyphosis. o However, the differences will be in: ▪ Size ▪ Site of origin ▪ Symptoms of the patient Ø Under the microscope, no basic difference in osteoid osteoma and osteoblastoma Ø In order to arrive at the diagnosis of whether it is osteoid osteoma versus osteoblastoma, one needs to do clinical correlation and evaluation Ø Benign: osteoid osteoma, osteoblastoma Ø Malignant: osteosarcoma Table 2. Clinical differences between osteoid osteoma and osteoblastoma OSTEOID OSTEOMA OSTEOBLASTOMA 2 cm Figure 13. Tuberculous osteomyelitis Caseation necrosis. (red arrow): Younger age group Usually affects 10-30 y/o epithelioid cells. (black arrows): Langhan’s cells. Appendicular skeleton Posterior spine o 50% involving the cortex of (lamina and pedicles) the femur and tibia Severe nocturnal pain Painful caused by prostaglandin E2 o Prostaglandin E2 Do not induce reactive synthesis from cortical bone proliferating osteoblasts MORADILLO, RAGOJOS, QUEZON, RAPOSAS SURGICAL PATHOLOGY Page 5 of 9  SURGICAL PATHOLOGY M.02 Bones, Joints, and Soft Tissue Tumors Dr. Espiritu | September 18, 2024 OSTEOID OSTEOMA OSTEOBLASTOMA B. OSTEOSARCOMA Relieved by aspirin and Unresponsive to aspirin and Ø The most common primary malignant tumor of bone NSAIDs NSAIDs Ø Accounts for 20% of bone malignancies Treatment: radio-frequency Treatment: curettage or en- ablation bloc excision Epidemiology Associated with thick rim of Ø Bimodal age distribution: cortical bone that is visible o 75% occurs before 20 years of age radiographically o First peak of incidence occurs in young adulthood o There is a smaller second peak that will occur among older adults where there is a possible predisposing condition such as Paget’s disease, bone infarcts, and prior radiation o If it has a predisposing condition, it is called a “secondary osteosarcoma” Ø Men are affected slightly more often than women (1.6:1) Figure 15.