MUSCLE

Skeletal Muscle
Function Movement/Maintenance of posture
- Contractions are voluntary
Joint stabilization
- Attach to bone
Heat generation
- Shivering thermogenesis
Structure Endomysium - surrounds each muscle fiber (myocytes)
Fascicle - surrounds and separates the muscles
Perimysium - surrounds the fascicles
Epimysium - surrounds the muscle as a whole
(Epimysium, endomysium, and fascicles are connective tissues
Cells Muscle fibers/myocytes
Large, long, cylindrical
Multi-nucleated
Nuclei at periphery
Striated
Sarcomere Unit of contraction (actin and myosin)
Length varies from 2 to 3 micrometers, approximately
Each sarcomere can shorten by about 30%
Z line, A band (thick filament), I band (includes the Z line), thin filament
(space around the Z line in the I band)
Slide theory: calcium attaches to troponin/tropomyosin; they roll away, exposing the
active site on actin
Development of Myoblasts differentiate into myotubes (fusion: multinuclear cells)
Muscle Cells Satellite cells remain behind as stem cell population at the periphery of the muscle
cell (fiber)

Duchenne muscular dystrophy: caused by a mutation in the dystrophin gene, located

on the human X chromosome, affected around 1/3600 males
Fiber Types Fast Muscle (white): Used occasionally
- Glycolytic metabolism (anaerobic), low mitochondria; produce lactic acid (e.g.
type IIb fiber)
Slow Muscle (red): Used often
- Oxidative metabolism (aerobic), high mitochondria (e.g. type I or IIa fiber)
Amount of stain is proportional to the density of mitochondria in the muscle
- Type I fiber: dark, many mitochondria, aerobic
- Type II fiber: light, few mitochondria, anaerobic
Cardiac Muscle
Heart Highly resistant to fatigue; Slow twitch; Coordinated contraction
Cardiomyocytes: High mitochondria density (appx 40% of cell volume)
Oxidative Metabolism: fatty-acid oxidation (mitochondrial OXPHOS)
Fragile to ischemia/hypoxia
Cardiomyocytes
Slow

Cardiomyocytes: Branched, produced a continuous 3D network

Connected to each Mono- or bi-nucleated (mostly mono)
other Interconnected via intercalated discs - 3 Components:
1. Fascia Adherentes - a ribbon-like structure that stabilizes cells (vertical zones)
2. Gap Junction - mainly lateral-facing zones
• Tubes that connect adjacent cells via hydrophilic channels, which allow material
to pass from one cell to the next without having to pass thru the plasma
membranes of the cells (Ca2+, cAMP, ATP, etc.)
3. Desmosome - mainly lateral-facing zones
• A small, circular, dense area within the intercellular bridge that forms the site of
adhesion between cells

Smooth Muscle
Function Involuntary contraction
Can be stimulated by stretching or hormones
Contractions are slow, sustained, and resistant to fatigue
Major locations: Inside the eye (iris), walls of vessels, respiratory tubes, digestive tubes,
reproductive organs
Histology Small in diameter and spindle-shaped
Mono-nucleated
Nuclei in center
Can be connected via gap junctions (coordinated contraction)
Focal Densities Attachment junctions of actin and myosin filaments
Cell shape is changed by contraction
BONE AND CARTILAGE
Bones: 206 bones in adult humans (270 at birth)
Function and Structure
Mechanical Support - Movement/maintenance of posture; Protection against damage
Synthesis sites of blood cells - Hematopoiesis (bone marrow, i.e. medullary cavity)
Metabolism/Homeostasis - Minerals (calcium, phosphate), Fat (marrow adipocytes), Acid-base balance
Bone (ECM) matrix Compact Bone: (cortical/dense) Spongy Bone: (trabecular/cancellous)
- Type I collagen - Hard outer layer - 20% of total bone mass
- Mineral in the form of calcium hydroxyapatite (HA) - Accounts for 80% of bone mass - Nearly 10x the SA of compact bone, providing blood
crystals (~65%) [HA: Ca5(PO4)3(OH)] Lamellae - concentric layers in an osteon and air
HA crystals serve as a source of Ca and P Circumferential lamellae - layers in compact bone

Bone Cells
Osteocytes - Responsible for
maintaining the matrix
and responding to
mechanical stress
- Derived from
osteoblasts
Osteoblasts - Divide & synthesize
bone matrix
- Mono-nucleated
Osteoclasts - Responsible for
degrading bone matrix
- Multi-nucleated,
derived from bone
marrow precursors

Osteoporosis -Imbalance of osteoblasts and osteoclasts

-In remodeling, bone removal is equaled by bone formation
-With advancing age and/or change in hormonal status, bone removal exceeds bone formation resulting in osteoporosis
Osteoclast Formation, Function, and Survival
-Activation: RANKL binds to RANK on pre-fusion osteoclast, becomes multinucleated osteoclast, then activated osteoclast = bone resorption
-Inhibition: Denosumab binds to RANKL (blocking its interaction with RANK), osteoclast formation/function/survival is inhibited = bone respiration is inhibited

Bone Growth
Endochondral Ossification 1. Hyaline cartilage formation
(long bones) 2. Emergence of primary ossification
center (replacement of cartilage by
osteoblasts)
3. Emergence of secondary ossification
center (epiphyseal growth plate)
4. Completion of bone growth
Intramembraneous Ossification Direct mineralization of primitive
(flat bones -e.g. the skull vault healing of mesenchymal tissues
bone fractures) 1. Development of center of ossification
(osteoblasts at periphery)
2. Formation of trabeculae
3. Osteocytes deposit mineral salts
(calcification)
4. Development of periosteum, spongy
bone, and compact bone tissue

CARTILAGE Hyaline Cartilage: firm Fibrocartilage: firm Elastic Cartilage: flexible

E.g. joint E.g. meniscus E.g. outer ear
- Support and reinforcement - Absorb shock (matrix similar but less - Maintains the shape of a structure while
- Firm, glassy, smooth firm than that in hyaline cartilage allowing great flexibility
- Principally collagen type II and - Collagen type I (very rich) and II - Yellow, opaque (aka yellow cartilage)
proteoglycans - Bundle of collagen - Collagen type II & elastic fibers
Major location: Embryonic skeleton, ends
of long bones, costal cartilages of the ribs, Major location: Intervertebral discs, Major location:
cartilages of the nose, etc. meniscus Outer ear, larynx, epiglottis
1. Appositional Growth: New surface
layers of matrix are added to the pre-
existing matrix by proliferation of
chondrocytes. Majority of cell growth.
2. Interstitial Growth: Increase in
internal mass of cartilage by
chondrocytes (proliferation of
chondrocytes and production of
ECM). In mature cartilage, cell
turnover rate is low but active in
childhood.
NEOPLASIA AND CANCER BIOLOGY

Epidemiology of Cancer
Second leading cause of death in US; 1/4 deaths in US due to cancer
1.6 million new cancer cases in 2011 (.77 million females, .82 million males) - and almost 600k deaths
Most common for women - breast; men - prostate; both - lung (smoking)
Risk increases with age, but some cancers have characteristic distribution

Non-Neoplastic Growth Disturbances

Choristoma Ectopic focus of mature tissue found at an abnormal location Islands of pancreatic tissue in the intestinal wall; foci of grey
matter in white matter of brain
Hamartoma Focal growth of cells/tissue elements occurring where such elements are normally present Congenital nevi in the skin; bile duct hamartoma of liver
Why not neoplasm? Choristomata and hamartomata are congenital lesions whose growth parallels that of the body as a whole
Hyperplasia Cellular proliferation in an organ/tissue, resulting in an increased number of cells while Mammary glands in pregnancy (progesterone-dependent);
generally preserving normal tissue architecture; occurs only in cells capable of mitotic division lymph nodes in infection; fibrous tissue in tissue repair
Hypertrophy Increase in size of individual cells, which may result in enlargement of the organ but preserves Myocardium in hypertension
normal architecture
Metaplasia Process in which fully-differentiated cells of one type are replaced by fully differentiated cells Squamous metaplasia in respiratory epithelium of smokers;
of another type; usually seen in epithelia in response to chronic irritation glandular metaplasia in the esophagus due to gastric reflux
Dysplasia Proliferation of epithelial cells which show some cytological features of malignancy and
distort the epithelial organization to some degree, but which differentiate fully by the time they
reach the upper layers of epithelium and do invade the BM
Why not neoplasm? Stimulus-dependent and typically cease when the stimulus is withdrawn

Important Generalizations About Neoplastic Growth

- Carcinomas (90%) are much more common than sarcomas (10%)
- Leukemias and lymphomas are most common forms of sarcoma, and together they account for 8% of cancer incidence and mortality. Most other types of sarcoma are very rare.
- Benign neoplasia is usually not a precursor of cancer: most benign neoplasms are no more likely to become malignant than the adjacent normal tissue
- Important exceptions: certain types of nevi (moles) and colonic adenomas
Neoplastic Nomenclature Gross Features Microscopic features Examples
Growth
Neoplasm Abnormal tissue mass whose growth exceeds and is uncoordinated with that of adjacent normal tissue and growth persists after cessation of the provoking stimuli
Benign “-oma” Expansile (compress Architecture: well-circumscribed, encapsulated, Adenomatous polyp
- Adenoma adjacent tissue), small, and expansile growth
(glandular) encapsulated, well- Cytologic: close resemblance to its normal
- Squamous differentiated, slow rate of counterpart and usually diploid
papilloma (e.g. wart) growth (years), non-invasive,
an never metastasize

Malignant “carnicoma” - Rapid growth (drays to Architecture: infiltrative, invasive, necrosis, and Invasive Colonic
epithelial tissues months), large infiltrative, destruction of normal architecture Adenocarcinoma
- Adenocarcinoma invasive, necrosis, Cytologic: discohesion, pleomorphism (various
(glands) hemorrhage, and metastasis changes in size/shape), anaplasia (poor
- Squamous Spread of malignant tumors: differenation), loss of polarity, increase in
carcinoma progressive infiltration, nucleus/cytoplasm, hyperchromasia (increased
“sarcoma” - invasion, and destruction of chromatin content), irregularly granular
nonepithelial tissues adjacent normal tissue chromatin, prominent nucleoli (increased rRNA
synthesis), tumor giant cells, and increased or
abnormal mitoses

Invasion Carcinoma-in-situ Invasive Carcinoma

Mechanism: Involves surrounding No invasion

Degradation of ECM by tissues Extends beyond the
collagenases, plasmin, Limited to epithelial cells basement membrane
and other proteolytic
enzymes
 Metastasis - process by which malignant cells migrate (usually thru blood or lymphatic system) from site of origin of the neoplasm to other
sites in the body, where they resume growth and form new malignant lesions (i.e. metastases)
Pathway of Spread Examples Mechanism Grading and Staging Diagnosis

Seeding of body cavities and Tumor cells adhere to and
surfaces invade BM and pass thru
ECM by degrading its
E.g. gallbladder and pancreatic components which consists
carcinomas of collagen, laminin,
proteoglycans, and
fibronection
Grading - based on degree of
differentiation of tumor cells and
the number of mitoses
Low grade = typically well-
differentiated
High grade = poorly
differentiated (anaplastic)
Reliable diagnosis of cancer
absolutely requires microscopic
evaluation of the lesion via a
biopsy - known as the tissue
diagnosis, and is generally
rendered by a pathologist

Intravasation and form

tumor embolus
Lymphatic Spread Staging - side of primary lesion, Diagnostic Features of
Most common pathway for the initial Adhere to vascular BM its extent of spread to regional Malignancy:
dissemination of carcinomas; lymph nodes, and absence or 1. Metastasis
however, sarcomas can also spread Extravasation presence of blood-borne 2. Invasion of adjacent normal
by this route. metastasis (TNM system or tissue
Form metastatic deposit Tumor Nodes Metastasis) 3. Loss of normal tissue
E.g. breast, colon, and lung architecture
carcinomas 

However, when cytologic
features of malignancy are
Hematogenous Spread present, a diagnosis can be made
Invasion into venous vessels leading by examning individual cells that
to distant metastases have been scraped or sloughed by
a tissue (e.g. Pap smear for
E.g. sarcomas, renal cell carcinoma, cervical cancer or fine needle
hepatocellular carcinoma (hepatoma), aspiration)
follicular carcinoma of the thyroid,
choriocarcinoma (germ cell tumor),
and osteogenic sarcoma

Tumor Progression
- Tendency of neoplastic cells to evolve over time by changing their biological behavior (e.g. rapid growth and metastasis) and phenotype (e.g. increased anaplasia)
- Most tissues are thought to contain a subpopulation of stem cells that retain the ability to replication
• Mitotic division of stem cells in normal tissues gives rise to two classes of cells: those committed to terminal differentiation and new stem cells that replenish the replicative
pool
- Mutations in Two Categories of Genes:
• Promote cell proliferation or survival (e.g. GF receptors, intracellular signaling molecules, cell-cycle regulatory proteins)
• Others inhibit cell growth, promote cell death (apoptosis), invasion, or other aspects of the neoplastic phenotype
- Mutations occur due to genetic instability of these neoplastic cells, which are more prone to mutate than normal cells
- Progression dependent upon 2 factors:
• Natural selection - evolution of amore malignant clone over time due to a selective growth advantage
• Genetic instability - malignant cells are more prone to mutate and accumulate additional genetic defects
Causes of Cancer

Chemical Carcinogenesis - multistep process involving a sequence of initiation (mutation)

carcinogens followed by promotion (proliferation) - 2 step model
Initiators: Promoters:
- Direct-acting chemical carcinogens (mutagens that cause cancer directly by - Cause cellular proliferation of mutated (initiated cells)
modifying DNA) - Proliferation of a mutated cell may lead to accumulation of additional
- Indirect-acting chemical carcinogens (procarcinogens) (require metabolic mutations
conversion to form active carcinogens)
Physical UV Radiation Ionizing Radiation
carcinogens/ - UVB sunlight is the most carcinogenic - X-rays, gamma rays, alpha and beta particles, protons, and neutrons
ionizing - Produces pyrimidine dimers in DNA leading to transcription errors and - Cells in S and G2/mitosis of the cell cycle are most sensitive
radiation mutations of proto-oncogens and tumor suppressor genes - Causes cross-linking and chain breaks in nucleic acids
- Increased risk of skin cancer - Atomic bomb - leukemias, thyroid cancer, other
- Xeroderma pigmentosum - autosomal recessive inherited defect in DNA - Uranium miners - lung cancer
repair
Viruses RNA oncogenic viruses DNA oncogenic viruses
- Human T-cell leukemia virus (HTLV-1) - adult T-cell leukemia/lymphoma - Hepatitis B virus causes hepatocellular carcinoma
- Hepatitis C - hepatocellular carcinoma - Epstein-Barr virus (EBV) - Burkitt lymphoma, B-cell lymphomas in
immunosuppressed patients and nasopharyngeal carcinoma
- HPV - benign squamous papillomas (warts), cervical cancer
- Kaposi sarcoma-associated herpesvirus (HHV8) - Kaposi sarcoma
Inflammation Barrett esophagus - esophageal adenocarcinoma
and cancer
Familial gene Familial polyposis coli
alterations
ENVIRONMENTAL PATHOLOGY

Occupational Hazards

Pneumoconiosis Definition: lung disease secondary to inhalation of dusts, fumes, or vapors

Variables:
- Concentration of pollutant in the air
- Size and shape - 5 microns in diameter or less in order to reach the alveolar sacs
- Chemical nature and solubility
- Duration of exposure
Types: Simple/uncomplicated stage: macule composed of dust-containing macrophages in a mesh of reticulin
Coal-worker’s Complications: “progressive massive fibrosis,” increased incidence of TB, chronic bronchitis, and emphysema
Pneumoconiosis
Silicosis - Chronic, nodular, densely, fibrosing pneumoconiosis due to the inhalation of silica particles
- Acellular fibrosis nodules affecting the upper zones of lungs that contain polariscopic
birefringent particles of silica and silicates
Eventually, end stage will be honey comb lung
- Simple stage: collagenous nodules
- Complicated stage: > 2 cm mass composed of dense collagenous and pigmented infiltration
with obiterative endarteritis
- Complications include: superimposed rheumatoid arthritis (Caplan’s syndrome) or other
autoimmune diseases, chronicc bronchitis, emphysema, cor pulmonale, and pulmonary TB
Abestosis Formation of asbestos bodies
Diffuse interstitial fibrosis: affecting the lower lobes due to the inhalation of asbestos fibers
(family of fibrous silicates)
Progressive massive fibrosis
- Gross: small, firm, dark brown lungs; primarily affects lower lobes resulting in a “honey
comb” lung
- Microscopy: discrete foci of fibrosis of walls of respiratory bronchioles with asbestosis bodies
Pleural effusions
Pleural plaques
- Gross: vary from gray-white to nodular ivory white; posterolateral thorax and dome of
diaphragm
- Microscopy: acellular basket-weave collagen
Bronchogenic carcinoma (adenocarcinoma)
Malignant mesothelioma
- Gross: often encasing and arising from pleura; occasionally arising from the peritoneal cavity
- Microscopy: biphasic - epithelial and mesenchymal components

Smoking
Environmental Tobacco Smoke (ETC): composed of mainstream smoke exhaled by the smoker and side stream smoke (main component of environmental tobacco smoke)
emitted from the burning tobacco between puffs. Greatest amount of smoke from a lit cigarette is side stream smoke. ETS is classified as a known human lung carcinogen.
- Leading cause of preventable premature death
- No change in heavy smokers in US, but smoking is declining today
Smoking-Related Conditions and Diseases
Cardiovascular Disease Assoc. Cancers Pulmonary Dis. Prenatal and Pediatric Conditions Female-Related Path
- 1/5 of deaths attributed to cardiovascular Mouth Pneumonia - Increases miscarriages - More young women than men smoke
disease is due to smoking Pharynx Influenza - Decreased birth weight by 200 gm - Lung cancer caused more deaths than
- Coronary artery disease, stoke, sudden Larynx Chronic bronchitis - 33% increase in stillbirths and early breast in 1993
cardiac death, myocardial infart, peripheral Lung Emphysema neonatal deaths - Smoke and oral contraceptives greatly
vascular disease, aortic aneurysm Esophagus Chronic airway - Reduction in growth and educational increases the risk of dying due to
- Pathogenesis: damage vascular Stomach obstruction achievement cardiovascular disease than women who do
endothelium - promotes atherosclerosis; Pancreas - Increased risk of lower respiratory not smoke or use oral contraceptives
coronary artery vasco-occlusive factors - Uterine cervix tract infections (bronchitis and - Greater risk for:
platelet aggregation, vasomotor activity, Kidney pneumonia) in children - Post-menopausal osteoporosis - smoke
and prothrombogenic; CO leads to Ureter - Increased prevalence of fluid in the has an anti estrogen effect
increased plasma viscosity and fibrinogen Urinary bladder middle ear - Reduced fertility
levels - smoking is a major risk factor for Leukemia (14% - More asthma - Spontaneous abortion
coronary vasospasm of US leukemias) Other: - Subarachnoid hemorrhage is 6x - Increased incidence of abruptio
Increase risk for more common in young smokers placentae, placenta previa, bleeding
eye cataracts during pregnancy
- Stroke

Adverse Drug Reactions (ADRs) - Any response to a drug that is noxious and unintended and that occurs at dosage used in man for prophylaxis, diagnosis, or treatment
Importance Types of ADRs ADR Patterns Specific Agents

- 5% of hospital Side effects Blood dycrasias Aspirin

admissions - e.g. streptomycin
- 5-10% of pts ototoxicity
show signs of Extension effects
ADR’s during - e.g. excessive rxn to
hospital stay moderate dose of insulin
- Many are from Drug interaction
OTC meds - e.g. potentiation of
barbiturates by dilantin
Idiosyncratic reaction
- e.g. bone marrow
suppression by cyclosporin
Hypersensitivity
- e.g. penicillin treatment
resulting in anaphylactic
shock
- Agents: chloramphenicol, sulfonamides,
quinidine
- Effects: Agranulocytosis, aplastic anemia,
hemolytic anemia, thrombocytopenia
Skin and Mucosal Reactions
- Agents: ampicillin, penicillin, heparin,
librium
- Effects: urticaria, bullous, or exfoliative
eruptions
Hepatic Reactions
- Agents: acetaminophen, antineoplastics,
isoniazid
- Effects: range from mild cholestatic jaundice
to massive necrosis
Renal Reactions
- Agents: antineoplastics, cephalosporins,
gentamicin, diuretics
- Effects: range from transient hematuria to
renal failure and remia
Hypersensitivity rxns, eczematous or desquamative rashes, angioedema,
urticaria, asthma, anaphylaxis, hemorrhage, gastric mucosa irritation;
decreased platelet aggregation (blocks clycooxygenase in prostacyclin
and thromboxane synthesis)
Barbiturates
Accounts for ~75% of suicidal deaths via therapeutic agents; as little of 3
gm of short-acting or 5 gm of long-acting may be fatal; CNS depressant -
systemic hypoxia
Estrogens
2-3x increased risk of endometrial cancer with high dose of exogenous
estrogen
Leads to vaginal adenosis and clear cell adenocarcinoma in offspring and
testicular tumors in male offspring
Increase in breast cancer (e.g. hormonal replacement therapy)
5x risk of thrombosis with oral contraceptive pills - primarily in smokers
less than 35 y.o. with long termm usage; synthetic estrogens stimulate the
synthesis of clotting factor sby the liver and cigarette smoke injures
endothelial cells promoting thrombogenesis - also increase risk of
developing liver adenoma
Non-Therapeutic Agents
Ethyl Alcohol
- Acute alcohol intoxation related to
blood EtOH levels - dependent on
intake/degradation; depressed
medullary centers leads to respiratory
arrest
- Chronic alcoholism:
- Liver - fatty change, Mallory-hyaline
bodies, cirrhosis
- Pancreas - acute and chronic
pancreatitis
- Myopathies - cardiomyopathy and
skeletal muscle involvement
- CNS - Wernicke-Korsakoff’s
syndrome (Wernicke’s
encephalopathy - acute syndrome of
confusion, abnormal eye movements,
cerebellar dysfunction; Korsakoff’s
psychosis - chronic memory disorder
affect recent and remote membrane)
secondary to thiamin deficiency
- Testes - atrophy
Methyl Alcohol Carbon Monoxide
- Poisonings - 5% in automobile exhaust
uncommon despite - Nonirritating, colorless,
presence in solvents, tasteless, odorless gas
sterno, and anti- - 200x affinity of O2 for
freeze; as little as 20 hemoglobin
mL may be fatal - Carboxyhemoglobin - stable
- Methyl alcohol - - Acute intoxication: cherry
formaldehyde and red (skin and mucous
formic acid - destroys membranes) intoxication
retina receptors - leading to anoxic
blindness encephalopathy
- Antidote: intravenous - Chronic intoxication: occurs
ethyl alcohol when Hgb is 30% saturation;
fatal when 60-70% saturated
- induces CNS depression
Lead (Pb) (plumbism) Mercury
- Primarily affects infants and children - Acute manifestations:
- Clinical symptomatology: mental stomach and colon
retardation, somnolence, convulsions, erosions; kidneys
encephalopathy (acute tubular necrosis
- Deposited/stored in epiphyseal region of ATN)
growing bone with slow release - Chronic
- Inhibits Hgb syntehsis resulting in manifestations: chronic
basophilic stippling of RBCs (clumping gastritis, “lead line”
of rRNA and mRNA), hemolytic anemia, similar to that seen in
and microcytic and hypo chromatic lead poisoning; CNS
anemia (focal cerebral atrophy
- Deposition at the gingivodental junction - mad as a hatter)
causing a pigmented line or “lead line”
- CNS: myelin degernation, myopathy of
active muscle groups (first write and
fingers)
- Renal: proximal tubular damage (acute
tubular necrosis)
- Diagnosis: serum lead and FEP (free
RBC protoporphyrin) levels

Drug Addiction
Psycho-depressants Opiates Cocaine Psychostimulants and hallucinogens
Primarily barbiturates Heroin - sudden death due to: - Lethal cardiac arythmias and LSD (lysergic acid diethylamide)
(CNS depressants - Overdose myocardial infection - Acutely mydriasis
leading to hypoxia) - Pulmonary complications (including - Cerebral infarction and - Hyperthermia; Tachycardia; Elevated BP
edema, septic embolism, lung abscess, intracranial hemorrhage - Increased alternates (central sympathomimetic stiulation)
and foreign body granulomas - Rhabdomyolysis - Adverse effects include psychosis (bad trip) leading to self-injury/
secondary to talc and other - Chronic manifestations include suicide and flashbacks that are more common in heavy users
substances) perforation of the nasal septum,
- Infections (infective endocartitis, viral decreased lung diffusion Marijuana
hepatitis, AIDS, skin abscesses, and capacity, and dilated -Distorts sensory perception and impairs motor coordination
cellulitis) cardiomyopathy -6x increase in schizophrenia
- Kidney diseases (including -Lungs (laryngitis, pharyngitis, bronchitis, asthma)
amyloidosis and focal segmental -Induce angina in a person with coronary heart disease
glomerulosclerosis) -May induce chromosomal damage in somatic and germ cells

Environmental and Occupational Carcinogens

Coke Oven Emissions Naphthalene Vinyl Chloride
Aromatic hydrocarbons (benzo pyrene) Chemical synthesizers, dye makers, rubber workers Affects chemical synthesizers, rubber workers, produces
- Pulmonary and renal carcinomas - Affects bladder (transitional cell carcinoma) angiosarcoma of the liver
SKIN -
General Function:
- Protection
- UV, virus infection, mechanical
- Sensory Reception
- Touch, pressure, pain
- Thermoregulation
- Sweating, insulation, vasoconstriction
- Metabolic Function
- Energy storage, vitamin D production

EPIDERMIS
Keratinocytes Melanocytes
Produce keratin filaments - Exist in skin, eyes, hair
(1k-2k melanocytes/mm^3)
- Melanogenesis - activated by
UV-B light
- Melanin is synthesized in
melanosomes, which are
transferred to the
keratinocytes
- Melanosomes are
responsible for color and
photo protection
- Light-skinned: smaller and
clustered melanosomes
- Darker-skinned: larger and
dispersed melanosomes
Melanosomes
- Organelle for synthesis,
storage, and transport of
malling
- Tyrosinase - rate limited
oxidase that is required for
melanin production (e.g.
blackening of sliced potatoes)
- Maturation from
premelanosome to
melanosome - tyrosinase is
activated at Stage III and IV of
melanosomes and initiates
melanin synthesis by
catalyzing the oxidation of Tyr
to DOPA
Langerhans Cells
- Dendritic cells: antigen-
processing and presenting cells
(APCs) - present antigen to T-
cells (exist in all layers of the
epidermis)
- Roles in pathogen/virus
infection, rejection in skin
allografts, protective against
epidermal tumors
- Chemical carcinogens,
immunosuppressive agents, and
excessing UV-B light reduce the
number of Langerhans cells
Merkel Cells
- Mechanosensory cells
(touch cells) in vertebrate
skin that have synaptic
contacts with
somatosensory nerve
fibers
- Express touch receptors
and contain
neuroendocrine granules
(dense core granules)
Epidermal Issues
Dry Skin Vitiligo Mutations in Melanoma Langerhans Cell Histiocytosis
- Filaggrin is a kertohyalin granule - Symmetrical areas of depigmentation of - 5th most common cancer in men and - When Langerhans’s cells get overly
- Mutations in Filaggrin gene lead to the skin occur, often on the hands, fingers, women in the US excited, they will overproduce
ichthyosis vulgarism (severe dry and face - Overall, melanomas have more mutations cytokines and cause localized damage
skin) - Keratinocytes are not affected than any other type of cancer - E.g. 13-m.o. boy with recurrent upper
- Due to an autoimmune destruction of - Targetable mutations can be identified in respiratory infections, persistent fevers,
melanocytes and is associated with other ~70% of patients with cutaneous and chronic rash. Skin biopsy showed
autoimmune diseases (e.g. type I diabetes) melanoma (e.g. mutations in BRAF) histolytic infiltration positive for CD1A

DERMIS
Hair Follicle
- Hair is a specialization of
the epidermis
- Hair follicles produce long,
thin cylindrical structure
(hair shafts), composed
largely of keratin produced
by living keratinocytes at
hair follicles (hair itself is
dead)
- Pigmentation in hair comes
from melanocytes
Sebaceous Gland
- Exocrine glands in the skin
that secrete an oily or waxy
matter, sebum, to lubricate
and waterproof the skin and
hair of mammals
- All parts of the skin except
the palms of the hands and
soles of the feet in humans
- Acne is usually attributable to
overactive sebaceous glands
Fordyce Spot
- Visible sebaceous glands
- Not associated with any
disease/illness, nor are they
infectious, but rather they
represent a natural
occurrence on the body
Eccrine Sweat Gland
- Small, tubular structures of the - Histologically similar to eccrine
skin that produce and secrete
sweat (largely water and NaCl,
but can secrete
immunoglobulins and
antimicrobial peptides)
- Innervated by the sympathetic
NS and adrenergic fibers
- Composed of a straight and
spiral duct (2 cell layer) and a
coiled gland (mono layer)
Apocrine Gland
sweat glands
- Larger glands that secrete into an
adjacent hair follicle via a duct
- Secrete sweat and oily compounds
(e.g. pheromone)
- In humans, apocrine glands are
found in limited locations (axillae,
areola/nipples, ear canal, eyelids,
etc.) (widely distributed over the
body in non-primate mammals)
SUBCUTIS
Largely composed of fibroblasts, adipocytes, and immune cells (e.g. macrophages)
Contains the glandular part of some sweat glands and hair bulbs
Thermoregulation (insulation and vasodilation/vasoconstriction
Energy storage

Fat
- Subcutaneous Fat (apple-shaped body) - Higher risk
• Reduced insulin sensitivity
• Pro-inflammatory
• High CV risk
- Visceral Fat (pear-shaped body) - Lower risk
• Lower inflammation
• Low CV risk
- Fat mass is largely determined by adipocyte size (can expand
10x)
- Adipocyte number is determined in childhood
• Number increases in childhood and adolescence
• Levels off and remains constant in in adulthood in both lean
and obese individuals
- Major weight loss by bariatric surgery results in a significant
decrease in cell volume
• However, fails to reduce adipocyte cell number 1-2 yr post-
surgery
SOFT TISSUES OF THE ORAL CAVITY

- Oral cavity and vermilion of lips are surfaced by a protective mucous membrane
(mucosa) which contains sensory receptors, such as taste buds of the tongue
- Oral epithelium is supposed by a thin delicate lamina propr. and a subjacent dense
collagenous submucosa
- Within the submucosa of the oral cavity, there are hundreds of small accessory
salivary glands (minor salivary glands), predominantly of thee mucous type
- Sebaceous glands (without associated hair) are also often seen in the submucosa =
fordyce granules

- In the attached gingiva and hard palate, the epithelium has well developed rete - Submucosa inserts into skeletal muscle, providing flexibility
ridges (pegs) to counteract frictional and shear forces
- Other areas of the mouth are surfaced by thinner parakeratinzed or non- - No granular cell layer or lucidum layer in the oral cavity
keratinized epithelium with less well developed rate ridges - Most keratinized layer has nuclei (parakeratin)


Functional Types of Oral Mucosa

Lining Mucosa Non-keratinized Vermilion of Lips

or lightly Dry, stratified squamous non-keratinized epithelium
keratinized Distinguished by a red border known as vermilion border - jxjn between
(lips, soft palate, oral mucosa and skin of lips, becoming modified keratinized epithelium
cheeks, floor of Epithelium is thin and blood vessels are near the surface of the papillary
mouth, and layer
ventral tongue) Color is derived from a highly vascularized dermis and the presence of
eleidin (transparant protein)
No sweat glands or sebaceous glands

Buccal Mucosa
Same histology as the lips; however, submucosa contains fat cells an mixed
glands (seromucous) located within and between the muscle fibers

Masticatory Highly Features

Mucosa keratinized Well developed deep rete ridges
(attached Dense supporting collagen
gingiva, hard Function
palate) Histologic features support ability to resist forces associated with
mastication
Attached gingiva has similar features for the same reason

Gingiva
(AKA marginal epithelium)
Covers the coronal part of the alveolar process, passes over the crest of the
alveolar bone and interdental septa and encircles the necks of teeth
Attached gingiva is well-keratinized whereas gingival sulcus is non-
keratized
Sulcus side - thin epithelium and inflammatory cells
Specialized (e.g. dorsum of 3 Prominent Features:
Mucosa tongue) - Highly keratinized epithelium
- Prominent rete ridges
- Highly muscular
Lingual Papillae
Filiform Papillae Thin, long papillae "V"-shaped
cones and are the most numerous.
These papillae are mechanical and
do not contain taste buds. Highly
keratinized.
Colonized by bacteria

Fungiform Papillae Resemble mushrooms and contain

taste buds located anterior-dorsal
surface, as well as at the sides of
the tongue.

Myoepithelial Cells
Circumvallate Arranged in a circular-shaped row Usually associated with glandular epithelium,
Papillae just in front of the sulcus express smooth muscle actin and thus can
terminalis of the tongue. They contract and help expel contents of exocrine
contain taste buds are associated glands
with ducts of Von Ebner's glands.
Tonsils
-Collection of lymphoid tissue
Foliate Papillae Ridges and grooves towards the -Lingual tonsils, palatine tonsils, and
posterior part of the tongue found adenoids make up Waldezyers Ring, which
on lateral margins and contain guards entrance to GI and respiratory tract
taste buds.

Mucous Acini Serous Acini Mixed

Sublingual salivary gland Parotid salivary gland Submandibular salivary gland
Basal orientation of nuclei Serous demilunes
PATHOLOGY OF SKIN Macule <1 cm flat area of discoloration without change in texture

Diagnostic Tests: skin scrapings, Woods lamp examination, skin biopsy Patch >1 cm flat area of discoloration without change in texture

Skin Neoplasms Papule <1 cm, elevated, palpable skin lesion

- Carcinomas = malignancies with epithelial differentiation Plaque >1 cm, elevated, palpable skin lesion
- Sarcomas = malignancies with mesenchymal differentiation
- Names are determined by the cell toward which microscopic differentiation is observed Nodule Rounded skin lesion of roughly equal diameter and depth
- Exceptions: Vesicle Intracutaneous, fluid-filled space, <1 cm in diameter
- Keratoses = benign neoplasms with epithelial differentiation
- Adnexal neoplasms and cysts, which are sometimes classified with regard to the structure rather than the Bulla Intracutaneous, fluid-filled space, >1 cm in diameter
cell
- Melanocytic nevi = benign neoplasms of melanocytes Pustule Intracutaneous, pus-filled space, often within a hair follicle

Benign and pre-invasive neoplasms with epidermal differentiation (keratoses)

Verruca Vularis - Warts - proliferation induced by HPV DNA (therefore, hyperplasia) but considered neoplasms
(common wart) - Rough, scaly papules
and Condyloma - Any age, occur with increased frequency in immunocompromised pts
(genital wart) - Marked thickenings of epidermis, often in a papillated configuration
- Clumping of keratin filaments in the cytoplasm and wrinkled nuclear outline are characteristic viropathic alterations
- HPV: different types are associated with specific types of lesions, some are oncogenic (leading to squamous cell carcinoma)
- Treated by destructive modalities
Seborrheic - Greasy, brown, scaly growth
Keratosis (SK) - Common in older patients
- Not induced by HPV
- No biological significance, completely benign
-
Solar Keratosis - Extremely common, typically in older adults (50% of light skinned)
(AK) - Scaly, papular lesion on sun-damaged skin
- Cumulative UV radiation is the primary factor in lesion development
- Represent squamous cell carcinoma at an embryonic stage
- Foci of abnormal keratinocytes, alternating with normal keratinocytes, within the epidermis
- Unstable lesions that can progress to form invasive carcinoma (risk is <10%, but important
to have them treated)
Malignant neoplasms with epithelial differentiation (carcinomas)
Basal Cell - Most common skin cancer
Carcinoma - Most common type of human malignancy (500k diagnoses annually)
- Clinical morph ranges from thin reddish papillose to densely indurated, ulcerated plaques
- Prototypical BCC: pearly, translucent, telangiectactic papule
- Risk of developing BCC is proportional to one’s cumulative UV exposure and inversely
proportional to one’s degree of skin pigmentation
- Histologically, “basloid” cells, display peripheral palisading and adjacent mutinous storm
- Morbidity due to relentless local growth, with invasion of contiguous structures
- Metastasis are rare
Squamous - 2nd most common type of skin cancer (100k diagnoses annually)
Cell - Development of butaneuos SCC is primarily related to cumulative UV radiation exposure,
Carcinoma also other risk factors: persistent chronic inflammation or radiation injury
- Microscopically, clusters of abnormal (malignant) keratinocytes that invade the dermis;
irregular, hyperhcromatic nuclei; cytoplasms show evidence of keratinization
- More aggressive malignancy than BCC
- Risk of metastasis still low (SCC of lip has higher risk of metastasis)
Notes About - Tanning (UVA) and burning (UVB) cause AKs, BCCs, SCCs, and melanomas (in old) &
Solar Damage wrinkles (in young)
- Receive majority of lifetime UV dosage during childhood and adolescence

Select benign neoplasms with mesenchymal differentiation

Hemangioma - Most are cherry and pyogenic; can develop at any age
- “Pyogenic granuloma” (PG - misnomer) - lesions known as lobular capillary hemangioma;
ulcerated, reddish papule, history of recent bleeding; usually on hand or foot
- Vascular proliferation that occasionally develops at the site of an injury
- Microscopically, aggregations of thin-walled blood vessels

Dermatofibroma - Most common neoplasm of fibrocystic lineage

- Typically presents as a firm papule or nodule on the extremity
- Sometimes develop at sites of trauma, but lesions persist
- Hyperpigmented
- Microscopically, nodular proliferation of spindled and dendritic cells, usually between markedly
thickened collagen bundles
- Believed to actively secrete cytokines or GFs that induce hyperplasia and hyper pigmentation of
the overlying epidermis
Melanoma
- Most important cutaneous malignant neoplasm (most lethal)
- Incidence is increasing, but may be due to diagnostic measures
- Suspicious lesions can be recognized by their large size, asymmetry, irregular borders, and irregular coloration
- Changes in long-standing pigmented lesions or new lesions late in life are suspicious and should be biopsied
- Incidence: diagnosis increasing rapidly but mortality only slightly increased
- Epidemiology: increased risk for light-skin, large numbers of melanocytic nevi and/or dysplastic nevi are also risk
factors
- Stage I (confined to skin) - 5 yr survival rate >80%
- Stage II (regional lymph node metastases) - 5 year survival rate <50%
- Stage III (systemic) - fatal within a few months or years
- Biologic response modifiers may change the poor prognosis of metastic melanoma (not chemo/radiation)
- Melanoma in Situ - has not infiltrated the underlying dermis, completely curable if removed
- Most important prognostic indicator: thickness of primary neoplasm = micro stage measurement (aka
Breslow’s levels)
- Women have a better prognosis
- Best prognosis occurs in extremity lesions, then trunk, and head/neck are least favorable
- Surgical Therapy: conservative but total excision, evaluation, re-excision is then recommend

Melanocytic Nevi - Epidermal, vascular, and connective tissue nevi can all occur as “birthmarks”
- Some melanocytic nevi are congenital; most are acquired benign neoplasms
- Most congenital and acquired are composed of clusters of bland, uniform cells with rounded or oval
nuclei
- Other variants: halo nevi, blue nevi, Spitz’s nevi, and dysplastic nevi
- Mixtures can occur too
Acquired Melanocytic - Evolve from “junctional” pattern (flat clinical lesions, with melanocytes in nests at the dermal/
Nevi epidermal jxn)
- Progress to “compound” pattern (slightly elevated, papular lesions with clusters of melanocytes both at
the jxn and in the superficial dermis
- Continue to progress to “intradermal” pattern (elevated or polyploid clinical lesions with clusters of
melanocytes only in the dermis
- Increase in number thru childhood and early adulthood
- Peak in the fourth decade of life
- Involute throughout later adulthood
- All are small, symmetrical, and evenly colored
Congenital - Present at birth or become evident in early childhood
Melanocytic Nevi - Larger than acquired ones (>1.5 cm)
- Giant congenital nevi involve skin of an entire extremity or body region
- Low risk of developing melanoma from it
- Show same histologic pattern as acquired, but lesions are larger and extend
more deeply into the dermis
Clark’s or Dysplastic - First characterized in families that had inherited genetic defect leading to
Nevi increased incidence of melanomas
- Later found to be a type of melanocytic nevus that is quite common in normal
individuals
- Distinctive histologic appearance and an atypical clinical appearance
8 Protypical Patterns of Inflammatory Skin Disease
Spongiotic - Fluid between keratinocytes (widened intercellular spaces)
Dermatitis (Eczema) - Fluid has a weepy, oozing clinical appearance
- Prototypical form: poison oak deramtitis, variant of allergic contact dermatitis (ACD)
- ACD - type iV hypersensitivity rxn to an exogenous allergen that contacts the skin
- First phase - allergen (hapten) is bound and presented by Langerhans cells (antigen-presenting) in presence of
HLA
- Second phage - T-helper cells bind the antigenic complex, triggering a cytokine cascade
- Most common reason people seek dermatologic care
Psoriasiform - Thickening of the epidermis
Dermatitis - 2% of Americans
- Chronic, scaley, treatment-resistant rash; inherited, but genetic expression is variable
- Erythrodermia - life-threatening, diffuse involvement
- Primarily affects the skin, but can show systemic manifestations: oligoarticular, deforming arthritis
- Epidermis is hyperplastic; proliferation driven by a chronic inflammatory rxn
- Bacterial infections can be a triggering or exacerbating factor
- Histologically, thickening of epidermis, vascular dilation of superficial vessels, and overlying crust of
neutrophils
Vesiculobullous - Pathological separation of adjacent tissues, most commonly at the level of the epidermis/dermis
Dermatitis - Prototypical disorder: Bullous pemphigoid (BP) - primarily affects older pts, usually has an indolent course,
(blistering disorders) prognosis is favorable unless disease is extensive; immune-merited disease (autoimmune)
- Histologically, sub epidermal cleft, numerous eosinophils in blister cavity and in adjacent dermis
- Antibodies react with a unique protein (BP antigen) in BM, trigger complement cascade, inflammatory run then
damages BM leading to blistering

Inferface Dermatitis - Inflammatory rxn focused on the basal layer of the epidermis
- Prototypes: erythema multiforme (EM) and lichen planus (LP)
- EM - flat red lesions, often develop dusky centers (target appearance); lesions are often acral but can involve
mucous membranes and process may generalize; acute and episodic rxn, 2-3 wks before resolving
- Toxic epidermal necrolysis (TEN or Stevens-Johnson Syndrome) - when generalization occurs, may be life
threatening due to metabolic imbalance, puts admitted to burn unit for care
- Histologically, vacuolization of the basal layer of the epidermis with necrosis of single keratinocytes, individual
keratinocytes are “bumped off” by a cell-mediated immune response - rxn triggered by herpes virus (e.g. cold
sore)
- LP - puritic, pylogonal, purplish papules, often acral in distribution, papules can last weeks to months; also the
result of a cell-mediated immune rxn against keratinocytes but triggering rxns are not understood
- Both can be treated with topical and systemic corticosteroids
Vasculitis - Inflammation of blood vessels
- Inflammation could be neutrophilic or lymphocytic, and vessels large or small
- Prototype: allergic vasculitis or small vessel leukocytoclastic vasculitis (LCV)
- LCV - hemorrhagic papules; necrosis of dermal capillary walls by a neutrophilic infiltrate; fibrin, RBCs, and nuclear debris surround the damaged
vessels; e.g. of Type III hypersensitivity rxn
- Viscera may be involved
- Neutrophilic vasculitis in larger vessels - nodular rather than papular skin lesions, greater systemic involvement
8 Protypical Patterns of Inflammatory Skin Disease
Granulomatous - Inflammatory infiltrates rich in macrophages
Dermatitis - Firm nodular lesions
- Prototype: sarcoidosis - “naked tubercles” (clusters of macrophages)
- Cutaneous infections often show a mixture of macrophages and neutrophils (suppurative and granulomatous)
Folliculitis - “Zit”
- Inflamed hair follicles
- Prototypes: suppurative (bacterial) folliculitis and acne vulgaris
- Suppurative folliculitis: caused by staphylococci, red papule and pustules which are itchy, oral antibiotics
although some scalp folliculitis is resistant
- Histologically, follicle filled and surrounded by a mixture of inflammatory cells (lots of neutrophils)
- Acne vulgaris - 2 fundamental pathogenic processes: follicles keratinize abnormally and then have a tendency to
get clogged (i.e. comedo formation) and then are subsequently prone to becoming inflamed
- Abnormal keratinization is treated using vitamin A derivatives known as retinoids (Retin-A as an anti-wrinkle
cream and Accutane systemically - teratogenic)
Panniculitis - Inflammation of subcutaneous fat - lobules of adipocytes separated and supported by fibrous septa
- Inflammatory rxns are divided into lobular panniculitis and septal panniculitis based on the zone in which the inflammation predominates
- Prototype: erythema nodosum (EN, type of septal panniculitis) - red, indurated, warm, deep nodules and plaques on lower extremities
- Histologically, granulomatous inflammation in a septal distribution