Download Pathology Exam 1 – Review Sheet Lecture 1 – Histology of Bone

Pathology Exam 1 – Review Sheet
Lecture 1 – Histology of Bone and Cartilage
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Embedding and Sectioning requires decalcification prior to fixation
Cartilage
- Is a tough, flexible form of CT with an ECM composed of high
concentrations of GAGs & proteoglycans which interact with collagen and
elastic fibers
 Chondrocytes (cells) imbedded in the extensive ECM in cavities =
lacunae
 Avascular, nutrients must diffuse from perichondrium (external layer
of dense CT) through matrix to chondrocytes
- The firm consistency of cartilage ECM -> allows the tissue to bear
mechanical stresses
- Shock absorbing and sliding regions within joints with smooth lubricated
surface
- Development and growth of long bones
- Three major forms of cartilage (ground substance consisting of
chrondroitin sulfate)
1. Hyaline cartilage
2. Fibrocartilage
3. Elastic cartilage
Hyaline Cartilage
- The hardest, and most abundant
- Contains few collagen type II fibers – visible only by EM
- Articular cartilage, tracheal rings, ribs and nose
Fibrocartilage
- More pliable than hyaline (comb of hyaline and dense CT)
- Contains a dense matrix of type 1 collagen fibers visible with light
microscopy – as well as type II collagen fibers
- Found in – intervertebral discs, meniscus
Elastic Cartilage
- Most pliable form
- Interlacing elastic fibers in addition to type II collagen
- External ear, epiglottis, larynx
Cartilage growth
- Appositional growth, at the surface, just beneath the perichondrium
 Perichondrial fibroblasts give rise to chondroblasts -> differentiate
into chondrocytes
- Interstitial growth, reconversion of lacunae bound chondrocytes to
chondroblasts, with synthesis of new cartilage (limited by avascular
nature of cartilage)
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Bone
- A specialized CT dedicated to support and protection of the body
- Serves as a reservoir of calcium, phosphate and other ions
- Specialized CT composed of calcified ECM – the Bone Matrix
 Highly ordered type 1 collagen fibers (Strength), proteoglycans,
glycoproteins, minerals – primarily calcium hydroxyapatite (rigidity)
- Three major cell types
1. Osteocytes – cavities (lacunae), between bone matrix layers
(lamellae), with cytoplasmic processes extending into canaliculi
between lamellae
2. Osteoblasts – synthesize the organic components (glycoproteins,
mucopolysaccharides, type 1 collagen
3. Osteoclasts – Multinucleated, giant cells involved in the resorption
and remodeling of bone
- General Structure
 Cortex/compact bone – outer solid region (80% bone mass, contains
lamellae)
 Spongy/Cancellous bone – found in epiphyses and peripheral to the
medullary cavity - blood cell progenitors and adipose, crossed by
spicules called trabeculae
 Lined on both their internal and external surfaces by layers of CT
containing osteogenic cells, endosteum and periosteum
Periosteum
- Outer layer = dense CT
- The inner region contains osteoblasts and mesenchymal stem cells, the
osteoprogenitor cells, which can differentiate into osteoblasts
Endosteum
- The thin endosteum covers the trabeculae of bone matrix that project into
the marrow cavities
Osteoblasts
- Synthesize and secrete the organic components of the bone matrix
(osteoid)
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Located at the surface of bone matrix, cuboidal to columnar shape and
basophilic cytoplasm when active, more flattened shape, less basophilic
cytoplasm when inactive
- Inactive osteoblasts represent most of the flattened lining cells of the
endosteum and periosteum
Osteocytes
- Develop from osteoblasts that have been surrounded by calcified bone
matrix
- Located in lacunae
- Cells cytoplasmic processes are found in canaliculi
Osteoclasts
- Large, motile cells, multiple nuclei, involved in matrix resorption during
bone growth and remodeling
 Digest bone matrix (collagenase), other enzymes, pumped proteins
that create an acid environment
 “Howship’s lacunae” – indentations in bone due to resportion
Cortical/ Compact Bone
- Composed of lamellae (layers) of calcified matrix arranged concentrically
around Haversion canals, which transmit nerves and blood vessels
 Lamellae delimited by lacunae
 Lacunae connected by canaliculi
- This Haversion system, or osteon, allows for nutrition and oxygen to reach
osteocytes
Spongy/ Cancellous Bone
- The loose network of bone trabeculae containing spaces for marrow and
other CT’s
Osteogenesis
- Occurs by one of two processes by which osteoid is deposited
1. Intramembranous Ossification
2. Endochondral Ossification
Intramembranous Ossification
- Osteoblasts differentiate directly from mesenchyme and begin secreting
osteoid
- Osteoid is ossified to become lamellar bone
- Seen in the formation of flat bones (frontal and parietal bones of the
skull)
Endochondral Ossification
- Seen in formation of long and short bones
- A hyaline cartilage model – replaced by bone
1. Proliferation and hypertrophication of cartilage cells
2. Calcification of cartilage, cells below the perichondrium differentiate
into osteoprogenitor cells -> differentiate into osteoblasts (thin bone
collar)
3. Primary ossification centers form in the diaphysis
4. Secondary ossification centers form in the epiphysis
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5. Bone replaces cartilage, except the articular cartilage and epiphyseal
plate
6. Epiphyseal plates ossify – cartilage remains at articular surfaces
Bone Reformation
- The combined activities of osteoblasts and osteoclasts allows for bone
formation, remodeling
- As bone contains osteoprogenitor cells, it has an excellent capacity for
repair
Joints
- Areas where adjacent bones are capped and held together firmly by CT’s
Synovial Joints
- A dense CT capsule encloses a sealed joint cavity containing clear,
viscous, synovial fluid
- The joint cavity partially lined by synovial membrane  secretes the
synovial fluid  derived from blood plasma with a high concentration of
hyluronan
- The synovial membrane contains
 Capillaries – provide the plasma component of the synovial fluid
 Fibroblastic (type B) synoviocytes – produce hyaluronon to the
plasma
 Macrophage like (type A) synoviocytes
Articular Cartilage
- Provides a smooth surface for articulation
- Surface lacks a perichondrium
Intervertebral Disks
- Located between adjacent vertebrae
- The outer annulus fibrosis is composed of fibrocartilage
- The inner nucleus pulposis contains gel like material derived from the
notochord
Lecture 3 – Neoplasia I
 Neoplasia
- Clonal mass of cells the growth of which is uncoordinated with the
surrounding normal tissues, and persists in the absence of inciting
stimulus
- Genetically – monoclonal proliferations – with autonomous growth
related to somatic mutations
- Composed of parenchymal cells and stroma
 Host is induced to supply a stroma for the cells angiogenic factors
 Tumor
- Swelling
- Mass due to a neoplasm
 Neoplasia vs. Adaptation
- A neoplasm is a tissue overgrowth which is independent of the
restrictions governing the remainder of the body
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Adaptive responses (hyperplasia, metaplasia) – persist for only as long as
there is a corresponding environmental stimus
- Neoplasms differ from adaptive as they serve no useful purpose to the
organism
Dysplasia
- Sometimes if an injurious stimulant persists, the orderly arrangement of
the cells in hyperplasia and/or metaplasia is disturbed, and/or the
normal maturation of the cells is interrupted
- Can regress, especially if the inciting cause is removed
- Can become marked – carcinoma in situ (CIS) – a preinvasive stage of
CA
Benign vs. Malignant Tumors
- Based on a judgment of the tumor’s potential clinical behavior
- Benign
 Microscopic and/or gross characteristics considered to be relatively
innocent
 Remain localized, amenable to local surgical removal
- Malignant
 Cancers
 Will invade and destroy adjacent structures
 Spread to distant sites to cause death
Nomenclature of Benign Tumor
- Benign tumors look like their parent tissue, designated by attaching the
suffix – oma to the cell type from which the tumor arises
- Fibroma, Chondroma, epithelia – adenomas but with finger like fronds –
papillomas
Polyp
- When a neoplasm benign or malignant, produces a macroscopically
visible projection above a mucosal surface and projects
Nomenclature of Malignant Tumor
- Arising in “solid mesenchymal tissues” – derivatives are called sarcomas
- Malignant neoplasms of epithelial cells – carcinomas
 Glandular pattern – adenocarcinomas
 Squamous cells – squamous cell carcinomas
 Poorly or undifferentiated carcinoma
Characteristics of Benign and Malignant Tumors
- There are four features by which benign and malignant tumors can be
distinguished
1. Differentiation and anaplasia
2. Rate of growth
3. Local invasion
4. Metastasis
Differentiation and Anaplasia
- Characteristics seen only in the parenchymial cells that are the
transformed elements of neoplasms
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Benign neoplasms are characterized of well differentiated cells that
closely resemble their normal counterparts – lipoma
- Malignant neoplasms are characterized by a wide range of differentiation,
from well, to moderate, to poorly differentiated
- Malignant neoplasms composed of undifferentiated cells – anaplastic
 Lack of differentiation
 Nuclear pleomorphism (variations of size and shape)
 Hyperchromatic (Darkly stained) nuclei
 Numerous and/or atypical mitoses
Rate of Growth
- Generally; benign slow, cancers fast, spreading locally, metastasizing and
causing death
- The rate of growth of malignant tumors – usually inversely related to
their level of differentiation
Local Invasion
- A benign neoplasm remains localized at its site of origin
- No capacity to infiltrate or metastasize to distant sites
- Most are circumscribed, often with a surrounding fibrous capsule
- Cancers grow by progressive infiltration, destruction and penetration of
the surrounding tissues
Metastasis
- Secondary implants of tumor that are discontinuous with the primary
tumor – located in remote tissues
- Malignancies disseminated by
1. Seeding within body cavities: cystadenocarcinomas – metastasis
within the peritoneum
2. Lymphatic spread: natural pathways of local lymphatic drainage
3. Hematogenous spread
Lecture 4 – Neoplasia II
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Mechanisms of Invasion and Metastasis
- Two phases
1. Invasion of the ECM
2. Vascular dissemination, homing of tumor cells, and colonization
- Steps in the invasion of ECM
1. “Loosening up” of cell-cell interaction, involving Cadherins
2. Local degradation of the basement membrane and ECM –with type IV
collagenase
3. Changes in attachment of tumor cells to newly cleaved ECM proteins
4. Migration/Locomotion of tumor cells through the basement
membrane
- Vascular dissemination and homing of tumor cells
 In the circulation tumor cells may adhere to other tumor cells, as well
as blood cells, including platelets
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 Adhesion at a distant site is accomplished with adhesion molecule like
integrins (hemidesmosomes) and laminin receptors
 Extravasation involves proteolytic enzymes
 At a new site, tumor cells proliferate and develop a blood supply
Local Effects
- The erosive and destructive growth of cancers, or the expansile pressure
of a benign tumor on any surface can cause ulcerations, secondary
infections, and bleeding
- Can cause obstruction of a lumen
- External compression of ducts
- Effusion
Paraneoplastic Syndrome
- Sx complexes in CA patients that cannot be explained by local invasion,
metastasis, or by elaboration of hormones of the tumor’s native tissue
- Fall into five groups
1. Endocrine
2. Hematologic
3. Osteoarticular
4. Cutaneous
5. Neurologic
- Endocrinopathies
 As the tumor cells are not of endocrine origin, they exhibit “ectopic
hormone production”
 Cushing syndrome – tumor cells produce corticotropin, resulting in
ACTH release from the pituitary, resulting release of corticosteroids
from the adrenal cortex
Most common
 Hypercalcemia – can be due to bony metastases, or to tumor
production of parathyroid hormone related protein (PTHrP)
- Neuromyopathic PN Syndromes
 Multiple forms, peripheral neuropathies, myasthenic syndrome
similar to myatsthenia gravis
 Causes may be immune related
- Dermatologic Disorders
 Acanthosis nigricans – gray-black patches of hyperkeratosis of the
axilla and other flexural areas
- Hypertrophic Osteoarthropathy
 Periosteal new bone formation, arthritis of adjacent joints and
clubbing of digits
- Vascular and Hematologic Manifestations
 Migratory thrombophlebitis (Trousseau syndrome) – carcinoma of
the pancreas or lung
 Acute disseminated IV coagulation (DIC) – acute promyelocytic
leukemia
Tumor Grading and Staging
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Grading and staging – used to judge the prognosis
Grading – degree of differentiation of the tumor cells, on the number of
mitoses or architectural features
- Staging – based on the size of the primary tumor, the extent of spread to
regional lymph nodes, and the presence or absence of distant metastases
TNM System
- T: Primary tumor
- N: Regional lymph node
- M: Metastasis
Laboratory Dx of CA
- Clinical tumor markers
- Biochemical molecules, proteins, secreted by known cell types, and
analyzed for in a pt’s serum or urine
- PSA, carcinoembryonic Ag (CEA), alpha fetoprotein (AFP), HCG,
monoclonal Ig’s
PSA
- Prostate CA
- When elevated
- May be elevated in benign hypertrophy
CEA
- Carcinomas of colon, pancreas, stomach and breast
AFP
- Hepatocellular carcinoma, germ cell tumors
All of these tests lack both the sensitivity & specificity necessary for the early
detection of CA’s
Useful for recurrences after excision
Immunohistochemistry – Laboratory Dx
- Immunoperoxidase
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Epithelial cells contain the intermediate filament cytokeratin, while
vimentin is present in CT cells of mesenchymal origin. Chromogranin and
synaptophysin are present in tumors of neuroendocrine origin
- IHC
 Categorization of undifferentiated malignant tumors
 Determination of the site of origin of metastatic tumors
Flow Cytometry
- Usually WBC’s or lymphocytes
Lecture 5 – Neoplasia III
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Carcinogens
- Agent known or suspected to participate in the causation of tumors
- The ultimate site of action – DNA
- Mutagenic
- Three classes
1. Chemicals
2. Radiant energy
3. Microbial agents
Chemical Carcinogenesis
- Initiation – results from exposure of cells to carcinogenic agent - causes
permanent DNA damage
- Promotion – induce tumors in initiated cells, but cannot produce tumors
by themselves - not directly on the DNA, reversible
Chemical carcinogens (initiators) are divided into
1. Direct-acting agents; no metabolic conversion to become carcinogenic
2. Indirect-acting agents; require metabolic conversion to become an
ultimate carcinogen
Direct Carcinogens
- Includes CA chemotherapeutic agents – alkylating
Indirect Carcinogens
- Includes the polycyclic hydrocarbons, present in fossil fuels, produced
from animal fats during the broiling of meats, benzopyrene formed in the
combustion of tobacco, and implicated as a cause of lung CA
- While metabolic activation is required for conversion into ultimate
carcinogens, other metabolic pathways may lead to inactivation
(detoxification) of the carcinogen
- Cytochrome p450 oxidase
Carcinogens permanently alter DNA
- Any gene may be a target – but oncogens and tumor suppressor genes are
especially important (RAS and p53)
- Afloxtoxin B1 – naturally occurring agent – Aspergillus
- High correlation between the dietary levels of this food contaminant and
the incidence of hepatocellular carcinoma in parts of Africa and the far
East
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Additional chemical carcinogens
 Vinyl chloride, arsenic, nickel, chromium, insecticides, polychlorinated
biphenyls
 Nitrites – food preservatives, nitrosylate amines in food – Nitrosamine
(suspected carcinogen)
- Promoters stimulate the proliferation and clonal expansion of mutated
cells
 Inducers; viruses, dietary factors, other chemical and hormonal
influences
 Undergo additional mutations, eventually developing into a malignant
tumor
Radiation Carcinogenesis
- UV Radiation
 UV-B
 Increased risk of squamous cell, basal cell carcinoma
 Possibly melanoma of the skin
 Formation of pyrimidine dimers in DNA
- Ionizing Radiation
 Electromagnetic (Xrays, gamma) and particulate (alpha, beta, protons
and neutrons)
 Hierarchy of vulnerability of tissues
 Myeloid leukemias, breast, lung, salivary glands
Microbial Carcinogenesis
- Oncogenic RNA Viruses
 Human T Cell Leukemia Virus Type 1 (HTLV-1)
 Form of T cell leukemia/lymphoma
 Tropism for CD4+ T cells – targets for neoplastic transformation
 Infection requires transmission of infected T cells via sexual
intercourse, blood products or breast feeding
 Stimulation mediated by Tax
 Tax stimulates proliferation of T cells via activation of a transcription
factor – pro-survival/anti-apoptotic gene
- Oncogenic DNA Viruses
 HPV
 EBV
 HBV
 Kaposi Sarcoma Virus (Human Herpesvirus 8)
HPV
- 70 distinct types
- Some types; 1,2,4 and 7; benign squamous warts
- Genital warts – 6 and 11
- High risk HPV’s *** 16 and 18 – squamous cell carcinoma of the cervix
and anogenital region
- At least 20% oropharyngeal CA’s related with HPV
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The oncogenic potential of HPV related to the products of two viral genes
E6 and E7
EBV
- Member of the herpes family of virus
- The African form of Burkitt Lymphoma
- B-cell lymphomas in immunosuppressed individuals
- A subset of Hodgkins lymphoma
- Nasopharyngeal carcinoma
- Burkitt lymphoma is a neoplasm of B lymphocytes – most common
childhood tumor in central Africa and New Guinea
- EBV infects B lymphocytes
 Uses the complement receptor CD21 to attach to and infect B cells
 Latent
 Proliferation can increase the probability of translocations especially
t(8:14) – activates c-MYC oncogenes
HBV
- Epidemiologic studies strongly suggest a close association between HBV
and liver CA
HCV
- a RNA virus also associated with hepatocellular carcinoma
HHV8
- Kaposi Sarcoma
- 90%
H Pylori
- Cause of peptic ulcers
- Genesis of both gastric adenocarcinomas and gastric lymphomas
- Increased epithelial proliferation in a background of chronic
inflammation
Lecture 6 – Neoplasia IV
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The Molecular Basis of Cancer
- Fundamental Principles
 Nonlethal genetic damage (mutations) lies at the heart of
carcinogenesis
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 Action of the environmental agents (chemicals, radiation, viruses,
inherited in the germ line, spontaneous mutation also occurs)
 Tumor formed by the clonal expansion of a single precursor cell that
has incurred genetic damage – tumors are monoclonal
 Four classes of normal regulatory genes
1. The growth promoting proto-oncogenes
2. The growth inhibiting tumor suppressor genes
3. Genes that regulate apoptosis
4. Genes involved in DNA repair
 Carcinogenesis is a multistep process resulting from multiple
mutations
Activation of Growth Promoting Oncogens
- Normal Growth
i.
GF binds receptor
ii.
GF-R activated -> activation of signal transducing proteins at inner
aspect of PM
iii.
Transduction of signal across the cytosol to the nucleus by second
messengers or a cascade of transduction molecules
iv.
Induction and activation of nuclear regulatory factors that initiate
DNA transcription
v.
Entry and progression of the cell into the cell cycle
Proto-oncogenes
- Participate in cellular functions related to growth and proliferation
- Proteins encoded may function as GF’s or their receptors, signal
transducers, transcription factors or cell cycle proteins
Oncogenes
- Produced by mutations in proto-oncogenes
- Encode oncoproteins – serve functions similar to their normal
counterparts
- Have the ability to promote cell growth in the absence of growthpromoting signals
- Products often; 1. Devoid of internal regulatory elements, 2. Does not
depend on GF’s or other external signals
- Oncogenes put proto-oncogenes into “overdrive”
- Several with GF-Receptors: constitutively activated by various
mechanisms, including point mutations, gene rearrangements and
overexpression
1. Tyrosine Kinase domain
 Transmembrane protein domain
 Undergo constitutive dimerization and activation without
binding of GF
 Deliver continuous mitogenic signals to the cell -> proliferation
2. RET Proto-oncogene
 A receptor tyrosine kinase
 Point mutations
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 Associated with dominantly inherited Multiple Endocrine
Neoplasia (MEN) type IIa and IIb
3. ERBB2 (HER-2/NEU) Proto-oncogene
 EGF family
 Overexpressed via gene amplification in some breast CA’s and
other adenocarcinomas
Oncogenes – Signal Transducing Proteins
- RAS family of GTP binding proteins
- Point mutations of RAS family genes – HRAS, KRAS, NRAS – the single
most common abnormality
- Approx. 90% pancreatic adenocarcinomas, 50% colon, endometrial and
thyroid CA’s and 30% of lung CA’s and myeloid leukemias -> RAS
mutations
RAS Activation
- Activated when phosphorylated to a GTP-bound state
- Once activated, recruits RAF -> stimulates the MAP-kinase pathway
- Transmit growth-promoting signals to the nucleus
- MUTATED RAS protein -> permanently activated (due to its inability to
hydrolyze GTP) -> uncontrollable cell growth
Oncogenes – Nonreceptor Tyrosine Kinase Proto Oncogenes
- Normally function in signal transduction pathways that regulate cell
growth
- Chromosomal translocations -> create fusion genes encoding
constitutively active tyrosine kinases
- In CML and some ALL’s -> translocation of 9 to 22 – t(9:22) where it fuses
with the BCR gene
Transcription Factors
- Contains specific AA sequences that allow them to bind DNA
- Growth autonomy may occur as a consequence of mutations of genes that
regulate
- The MYC oncogene – most closely associated with human tumors
MYC Oncogene
- Translocation of the C-MYC gene t(8:14) – results in dysregulation of MYC
expression in Burkitt’s lymphoma
Tumor Suppressor Genes
- The products of tumor suppressor genes “apply breaks” to cell
proliferation, and so their inactivation can lead to unregulated cell growth
- Growth inhibitory signals originate outside the cell and use receptors,
signal transducers, and nuclear transcription regulators to accomplish
their effects
- The protein products of tumor suppressor genes may function as
i.
Cell surface receptors
ii.
Signal transduction molecules
iii.
Transcription factors
iv.
Cell cycle inhibitors
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Regulators of cellular responses to DNA damage
Cell Cycle Regulation
- The orderly progression of the cells through the phases of the cell cycle is
orchestrated by cyclin-dependent kinases (CKDs) which are activated
by cyclins
- CDK-inhibitors – p16, p21 -> exert negative control on the cell cycle
- Cell Cycle Checkpoints
 Main checkpoints are G1/S and G2/M
 Defects in checkpoints are a major cause of genetic instability in CA
cells
RB
- First and prototypic tumor suppressor gene discovered
- Discovered by studying the rare disease Retinoblastoma
- “Two hit hypothesis of oncogenesis” – sporadic vs familial
- Retinoblastoma develops when a cell becomes homozygous for the
mutant allele
- The product of the RB gene is a RB protein – nuclear phosphoprotein;
plays a key role in regulating the cell cycle
 Exists in an active hypophosphorylated state in quiescent cells and an
active hyperphosphorylated state in the G1/S transition
- Germline loss or mutations – predispose to the occurrence of
retinoblastoma
- Mutations in other genes that control RB phosphorylation (p16) are seen
in other CA’s
- Transforming proteins of several oncogenic DNA viruses – HPV, can act
by neutralizing RB
P53
- Located on chromosome 17
- About 50% of human CA’s contain this gene
- Homozygous loss of p53 occurs in virtually every type of CA
- Inactivating mutations are usually acquired in somatic cells (not inherited
in the germ line)
- Less common; individuals inherit one mutant p53 allele – rare at risk of
the second allele mutation
 These people have Li-Fraumeni syndrome
 25 fold greater risk of developing a malignant tumor
- “molecular policeman” – prevents the propagation of genetically damaged
cells
- p53 itself is a transcription factor
- Its mechanisms include
i.
Activating a temporary cell cycle arrest (quiescence)
ii.
Induction of permanent cell cycle arrest (senescence)
iii.
Triggering apoptosis
P16
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Mutations or silencing of the p16 gene have been detected in bladder,
head and neck tumors, ALL and cholangiocarcinomas
Evasion of Apoptosis
- FasL pathway (CD95 receptor pathway)
- Mitochondrial apopototic pathway
 Tumor cells evade cell death by reducing CD 95 levels
 Inactivating death induced signaling complex by FLICE protein
 Reduce egress of cytochrome c from mitochondrion as a result of upregulation of BCL2
 Loss of p53
 Loss of apoptotic peptidase activating factor 1 (APAF1)
 Upregulation of inhibitors of apoptosis (IAP)
BCL 2
- The best established anti-apoptosis mechanism of malignancies
- 85% follicular type B cell lymphomas have a t(14:18)  brings the IgH
gene on chromosome 14 next to the BCL 2 gene on chromosome 18 –
resulting in overexpression of BCL2 protein
Lecture 7 – Histology of the Muscular System
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Four basic tissue types
1. Muscle
2. Epithelium
3. CT
4. Nervous tissue
Muscle tissue is composed of cells that maximize the cellular property of
contractility
Mesodermal origin, differentiate with cell lengthening, and synthesis of the
myofibrillar proteins actin and myosin
Three types of muscle tissue
1. Skeletal
2. Cardiac
3. Smooth
Skeletal Muscle
- Or striated muscle
- Consists of muscle fibers which are long, cylindrical, multinucleated
- Embryonic development: mesenchymal myoblasts fuse forming
myotubues with multiple nuclei
- Myotubes differentiate to form striated muscle fibers
- Nuclei are located just below the sarcolemma
- Longitudinally sectioned muscle fibers show cross striation of alternating
light and dark bands
 Dark bands – A bands
 Light bands – I bands
 I bands are bisected by a dark line, the Z disc
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 Sarcomere extends from Z disc to Z disc
- The sarcoplasm (skeletal muscle cytoplasm) contains primarily long
cylindrical filament bundles myofibrils – running parallel to the long
access of the fiber
- A and I banding pattern – due to the regular arrangement of thick and
thin myofilaments, myosin and F-actin respectively
- Sarcoplasm also contains abundant SER and Mitochondria
- Thin layers of collagen rich CT organize muscle fibers
- The Epimysium – external sheath of dense CT surroundsd the entire
muscle
- Perimysium – thin CT layer surrounding each bundle of muscle fibers,
termed fascicle
- Within fascicles – very thin layer of reticular fibers and fibroblasts the
endomysium
Tendons
- Attach muscle to bone
- Composed of dense regular CT
- Composed of parallel (type 1) collagen fibers – allowing for extreme
tensile strength
- Fibroblasts located between thick collagen fibers
- Minimal vascularization
Muscle Fiber Types
- Skeletal muscle cells are highly adapted for the work of contraction
- Mitochondria provide energy in the form of ATP and other
phosphorylated compounds emerging from the aerobic metabolism of
FA’s
- Glycogen is also available in the cytoplasm
- Fibers of a given skeletal muscle – grouped physiologically into three
types (functional)
1. Red (aerobic) fibers – small, with high myoglobin content and rich
blood supply, for slow but sustained contractions
2. White (anaerobic) fibers – large, with low myoglobin content, and
minimal blood supply, for rapid contractions, but easily fatigue
3. Intermediate fibers
Innervation of Skeletal Muscle
- Innervation of muscle is essential – muscle fiber will die if destroyed
- The motor unit is a motor axon and all of the fibers that it innervates
 Allows several fibers to act in unison
 Nerve bundle branches to innervate several fibers at motor end plates
- Sensory nerves provide information about muscle tension
 Feedback system components: muscle tone, allows for proprioception
 Nerve endings are located within the tendon and at the muscle spindle
Ligaments
- Yellow elastic tissue
- Connect bones within a joint
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- Composed of parallel bundles of collagen and elastic fibers
Smooth Muscle
- Smooth muscle is specialized for slow, steady contraction, controlled by a
variety of involuntary mechanisms
- Cells are small, “cigar shaped” with a central nucleus
- Cells;
 Communicate via gap or nexus junctions
 More capable of regeneration than skeletal muscle cells
- Located as cell layers in walls of hollow organs of the digestive,
respiratory, urogenital and circulatory systems
- Fibers are elongated, tapering and nonstriated cells – each enclosed by a
thin basal lamina and a fine network of reticular fibers, the endomysium
- The bundles of thin and thick actin and myosin myofilaments crisscross
obliquely through the cell, and attach to dense bodies located near the
sarcolemma
Lecture 9 – Introduction to Pathology of Bones
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Classification of Bone Diseases
- Skeletal dysplasias (skeletal malformations)
 Achondroplasias – disproportionate, short stature, short limbs,
normal trunk lengths
 Osteopetrosis (inhibited osteoclastic activity)
 Osteogenesis imperfect (inadequate osteoblastic activity)
- Bone metabolic disease (disturbances of bone remodeling)
 Osteoporosis (estrogen deficiency leads to increased osteoclastic
activity)
 Osteomalacia (normal osteoblastic activity but DEFECTIVE
MINERALIZTION which results in exaggeration of the osteoid seams
 Paget disease (greatly accelerated remodeling process)
- Bone Infection (osteomyelitis)
- Bone tumors
Osteomyelitis
- Denotes inflammation of bone and marrow
- Commonly implies a corresponding infection of the bone
- All types of organisms – viruses, parasites, fungi, bacteria can produce
osteomyelitis
- Pyogenic and mycobacteria – most common
Pyogenic Osteomyelitis
- Pus-producing osteomyelitis – almost always caused by bacteria
- Organisms reach the bone by
1. Hematogenous spread
2. Extension from a contiguous site
3. Direct implantation
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In healthy children – most cases are hematogenous in origin and develop
in the long bones, with initiating bacteremia stemming from seemingly
trivial injury to the mucosa or skin
- In adults – most often occurs as a complication of open Fx’s surgical
procedures and DM infections of the feet
- Staphylococcus aureus is responsible for 80-90%
 express receptors for bone matrix components such as collagen,
facilitating adherence to bone
- E. coli, Pseudomonas, Klebsiella – frequently isolated from individual swith
G.U tract infections, or who are IV drug abusers
- Mixed bacterial infections are seen in the setting of direct spread, or
inoculation of organisms during surgery or open Fx’s
- In the neonatal period, H. influenza and group B streptococci are frequent
pathogens
- Individuals with sickle cell – predisposed to Salmonella infection
- The location of the infection within a bone – influenced by the osseous
vascular circulation – varies with age
 Neonate – metaphyseal vessels penetrate the growth plate; frequent
infection of the metaphysis, epiphysis or both
 Children – localization of microorganisms in the metaphysis is typical
 After growth plate closure – The metaphyseal vessels reunite with
their epiphyseal counterparts and provide a route for bacteria to seed
the epiphyses, and subchondral regions in the adult
Morphogoly of Pyogenic Osteomyelitis
- Depends on the stage (acute, subacute, chronic)
- Depends on the location
- The entrapped bone undergoes necrosis within 48 hours
 Dead bone – sequestrum
 Inflammation can spread within the shaft of the bone and may reach
the periosteum
 Children especially, subperiosteal abscesses may form
 Rupture of the periosteum can lead to a soft tissue abscess and
eventual draining sinus
- In infants, uncommonly in adults, epiphyseal infection spreads through
the articular surface
 Produce septic or suppurative arthritis
 May result in permanent damage to the articular cartilage
- After the first week, chronic inflammatory cells become more numerous
– release cytokines which stimulate osteoclastic bone resoprtion,
ingrowth of fibrous tissue, and the deposition of reactive bone at the
periphery
 When newly deposited bone forms a sleeve of living tissue around the
segment of devitalized infected bone – involucrum
Clinical Course of PO
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Dx is strongly suggested by the radiographic characteristics – focus on
bone destruction surrounded by a zone of sclerosis
- Many untreated cases; blood cultures positive, but biopsy and bone
cultures are required to identify the pathogen in most instances
- Combination of Abx and surgical drainage usually curative
- 5-25% cases fail to resolve and persist as chronic infections
Tuberculous Osteomyelitis
- A resurgence of tuberculous osteomyelitis is occurring in developed
countries
- Attributed to the influx of immigrants from countries where TB is
endemic and the greater number of immunosuppressed people
- Approx. 1-3% of individuals with Pulmonary or Extrapulmonary TB have
osseous infection
- Organissm – usually blood borne – originate from a focus of active
visceral disease
- Spine, knees and hips – most common sites
- Tends to be more destructive and resistant to control than PO
- Pott Disease (in the spine)