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General pathology is the study of mechanisms of disease, with
emphasis on etiology and pathogenesis.
Systematic pathology is the study of diseases as they occur
within particular organ systems it involves:
Etiology
Pathogenesis
Epidemiology
Macro and microscopic appearance
Specific diagnostic features
Natural history and
Sequelae
Clinical pathology is often referred to as laboratory medicine
and includes a number of diagnostic disciplines. 4
Pathology provides the basis for understanding:
The mechanisms of disease
The classification of diseases
The diagnosis of diseases
The basis of treatment
Monitoring the progress of disease
Determining prognosis
Understanding complications
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Basic Concepts
Cellular and tissue growth is a normal component of normal
physiology
Cellular events:
Leucocyte transmigration
Phagocytosis
Marc Imhotep Cray, M.D. Widmaier, EP. Vander’s Human Physiology : The Mechanisms of Body Function. 13th Ed. McGraw-Hill, 2014. 25
Light micrograph of a human blood smear
Marc Imhotep Cray, M.D. Widmaier, EP. Vander’s Human Physiology : The Mechanisms of Body Function. 13th Ed. McGraw-Hill, 2014. 26
Cells of Inflammation
Leukocytes (WBCs) are major cellular participants in
inflammation and include
Neutrophils
T and B lymphocytes
Monocytes-macrophages
Eosinophils
Mast cells and basophils
Each cell type has specific functions but they overlap and
change as inflammation progresses
Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: LLW, 2012.
Marc Imhotep Cray, M.D. 28
Effector functions of neutrophils
Marc Imhotep Cray, M.D. Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. 29
Baltimore: LLW, 2012.
Cells of inflammation: morphology & function (2)
Endothelial cell
Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: LLW, 2012.
Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: LLW, 2012.
Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: LLW, 2012.
Marc Imhotep Cray, M.D. Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. 33
Baltimore: LLW, 2012.
More cells of inflammation: morphology
and function (6)
Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed.
Marc Imhotep Cray, M.D. 34
Baltimore: LLW, 2012.
Acute inflammation cont’d.
Densely packed (PMNs) with
multilobed nuclei (arrows)
3. Transmigration and
accumulation of neutrophils
Vasodilation
Slowing of circulation
Lymphocytes (double-
headed arrow), plasma cells
(arrows) and a few
macrophages (arrowheads)
are present
Margination, rolling,
activation and adhesion
Transmigration (diapedesis)
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Leukocyte Extravasation & Phagocytosis:
Animation
Widmaier, EP. Vander’s Human Physiology : The Mechanisms of Body Function. 13th Ed. McGraw-Hill, 2014. 48
Chemical Mediators of Inflammation
Tissue injury stimulates production
of inflammatory mediators in
plasma & release into circulation
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Chemical Mediators of Inflammation (2)
Chemicals that are released from damaged tissues
and inflammatory cells orchestrates inflammatory
process
e.g. histamine, prostaglandins, leukotrienes & TNF-α
followed by
Widmaier, EP. Vander’s Human Physiology : The Mechanisms of Body Function. 13th Ed. McGraw-Hill, 2014.
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Phagocytosis & intracellular destruction of a microbe (2)
Abbas AK, Lichtman AH, Pillai S. Cellular And Molecular Immunology. Saunders-Elsevier, 2015.
Marc Imhotep Cray, M.D. 57
Phagocytosis illustrated
Scanning electron microscope (SEM) images of a single neutrophil
and macrophage (LR) engulfing bacterium.
Le T and Bhushan V. Microbiology. In: First Aid for the USMLE Step 1 2016. McGraw-Hill, 2016.
Marc Imhotep Cray, M.D. Abbas AK, Lichtman AH, Pillai S. Cellular And Molecular Immunology. Saunders-Elsevier, 2015. 68
Types of Adaptive Immune Responses
There are two types of adaptive immune responses, called humoral
immunity and cell-mediated immunity mediated by different
components of the immune system and function to eliminate different types
of microbes
Humoral immunity is mediated by molecules in blood and mucosal secretions, called
antibodies produced by cells called B lymphocytes (also called B cells)
o Antibodies recognize microbial antigens, neutralize infectivity of microbes, and
target microbes for elimination by various effector mechanisms
Marc Imhotep Cray, M.D. Abbas AK, Lichtman AH, Pillai S. Cellular And Molecular Immunology. Saunders-Elsevier, 2015. 71
Active immunity and Passive immunity
Active immunity= Protective immunity against a microbe is
usually induced by host’s response to microbe
The form of immunity that is induced by exposure to a foreign antigen
is called active immunity b/c immunized individual plays an active role
in responding to antigen
Marc Imhotep Cray, M.D. Abbas AK, Lichtman AH, Pillai S. Cellular And Molecular Immunology. Saunders-Elsevier, 2015. 74
Autoimmune diseases
Autoimmune diseases occur when immune system
attacks ‘self’ cells and tissues
this is referred to as a breakdown of “immune
tolerance”
This leads to inflammation and tissue damage,
which may be
o highly localized (e.g. type 1 diabetes mellitus) or
o generalized (e.g. systemic lupus erythematosus)
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Neoplasia
Neoplasia means “new growth” and indicates presence of
cells or tissues showing evidence of abnormally controlled
or disordered growth
Benign vs Malignant
Benign neoplasms expand locally but do not invade
adjacent tissues or spread to distant sites, while
Malignant neoplasms (cancers) invade adjacent tissues
and spread to distant sites
Marc Imhotep Cray, M.D. 84
Neoplasia (2)
Preneoplastic and neoplastic cellular changes
Neoplasia Uncontrolled, clonal proliferation of cells
Can be benign or malignant
Dysplasia Disordered, non-neoplastic cell growth
Used only with epithelial cells
Mild dysplasia is usually reversible
Severe dysplasia usually progresses to carcinoma in situ
Differentiation degree to which a malignant tumor resembles its tissue of
origin
Well-differentiated tumors closely resemble their tissue of origin
poorly differentiated look almost nothing like their tissue of origin
Anaplasia Complete lack of differentiation of cells in a malignant neoplasm
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Neoplasia (3)
Genetic and environmental factors influence development of
neoplasia
Most germline (i.e. inherited and present in all cells)
genetic influences on neoplasm development are
polygenic in nature, while
A minority of neoplasms occur in association with a clearly
defined inherited defect in a single gene (monogenic)
Features such as
tumor type
grade (histological assessment of aggressiveness)
size and
presence of lymph node metastases
are most commonly assessed features used to predict biological behavior
of malignant neoplasms (See Grading & Staging, slides # 74 & 75.) 90
Neoplasia (8)
Most cancers (>90%) arise from "epithelial" tissues,
such as inside lining of colon, breast, lung or prostate
These are referred to as carcinomas and usually
affect older people
Contrastly, sarcomas are tumors that arise from
"mesenchymal" tissues such as bone, muscle,
connective tissue, cartilage and fat
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Bronchogenic carcinoma, gross
The large carcinoma ( ) in the upper lobe is
arising in a lung with centriacinar
emphysema, suggesting cigarette smoking as
the risk factor
There are patchy infiltrates in lower lobe
representing pneumonia, likely from central
airway obstruction by this large mass
There is inferior congestion, likely
exacerbated by heart failure
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Neoplasia (10) Breast cancer
Breast cancer is second most common malignancy in women
(only exceeded by lung cancer in populations where cigarette
smoking is common)
Almost all breast cancers are carcinomas
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Neoplasia (11) Colorectal cancer
Colorectal cancer is one of three most common cancers in
Western populations
it is likely that environmental factors, including Western diet with low
roughage, contribute to this
Almost all colorectal cancers are carcinomas
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Neoplasia (12) Prostatic cancer
Prostatic cancer is increasing in incidence among middle-aged
and elderly men although this may partly reflect increased
detection of disease in its early stages in screening programs
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Neoplasia (13)
Certain neoplasms occur primarily in childhood
e.g. neuroblastoma and nephroblastoma
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Atherosclerosis
Atherosclerosis is a very common disease process occurring
within arteries, especially large elastic arteries and their
major branches
Earliest lesions comprise ‘fatty streaks’ within arterial
intima
Established atherosclerotic plaques comprise a “cap” of
fibrous tissue beneath which are pools of fat, foamy
macrophages and smooth muscle cells
Dystrophic calcification is common in older lesions
Plaque surface may ulcerate (plaque rupture) leading to
a thrombus that coats plaque acute vascular occlusion
See: Atherosclerosis and Thrombosis Illustrated Notes - Offline
Marc Imhotep Cray, M.D. Online version 136
Arteriosclerosis
Arteriosclerosis is a general term for several
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Atherosclerosis:
pathogenic progression
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Pathobiology of Atherosclerosis
(pathogenesis)
When excess cholesterol deposits on cells and on
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Cerebrovascular disease
Apart from ischemic heart disease, atherosclerosis
also commonly affects carotid and intracranial
arteries leading to cerebrovascular disease (e.g.
strokes [CVA], vascular dementia) while
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Thrombosis
Thrombosis occurs after activation of clotting cascade
and is a vital physiological mechanism for limiting
blood loss when hemorrhage occurs
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Embolism
An embolism occurs when an embolus migrates from
one part of body and causes a blockage of a distant
blood vessel
embolus can be made up of materials other than a
thrombus, for example
o Air
o Amniotic fluid
o Fat or
o Tumor tissue
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Valvular Heart Disease
The mitral and aortic valves are valves most commonly
affected by degenerative disease in adults
Stenosis or incompetence of these valves may lead to
cardiac failure and (apart from mitral stenosis) left
ventricular cardiac hypertrophy
aortic stenosis is a not uncommon cause of sudden death
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Viral Myocarditis and Cardiomyopathy
Unusual conditions of myocardium such as viral myocarditis
and cardiomyopathy (e.g. hypertrophic cardiomyopathy) are
important causes of sudden death in young adults
Obstructive hypertrophic cardiomyopathy (subset) asymmetric
septal hypertrophy and systolic anterior motion of mitral valve,
outflow obstruction, dyspnea, possible syncope
In hypertrophic cardiomyopathy diastolic dysfunction ensues
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Cardiac failure
Cardiac failure occurs when heart is unable to eject blood
sufficiently effectively during systole
Common causes of heart failure include
ischemic heart disease N.B. Under conditions of poor tissue
cardiac valvular disease perfusion, there will be more anaerobic
hypertensive heart disease glycolysis and more acidosis in cells
chronic lung disease throughout the body. The blood lactate
rises in this condition.
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Hypertension
Hypertension is common, often asymptomatic and has many
causes including
Stress
Obesity
Renal artery stenosis and
Hormonal defects such as Cushing’s syndrome and Conn’s
syndrome
Chronic hypertension is characterized by an imbalance in
sodium and water homeostasis
Untreated hypertension can lead to accelerated
atherosclerosis and to end-organ damage, including
hypertensive nephropathy, hypertensive heart disease and
intracerebral hemorrhage
Marc Imhotep Cray, M.D. 170
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Respiratory System
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Pneumonia
Pneumonia means inflammation within lung
and most commonly occurs as a result of an
infection
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Tuberculosis
Tuberculosis affects millions of individuals worldwide and most
commonly occurs in developing countries
There is a strong association between tuberculosis and HIV
infection particularly in Africa
Tuberculosis is caused by Mycobacterium tuberculosis
bacterium and is classically associated w extensive tissue
necrosis and granulomatous inflammation
TB Infection may be localized (e.g. to lung) or widespread
latter is commonly fatal
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Chronic obstructive pulmonary disease (COPD)
COPD is characterized by presence of
emphysema (lung tissue destruction) and
chronic bronchitis (excess bronchial mucus and airway wall
thickening)
in variable proportions
There is a strong association with cigarette smoking
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Asthma
Asthma is a reversible obstructive pulmonary airway defect
associated with bronchial smooth muscle hypersensitivity
and excess bronchial mucus production
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Restrictive Lung Disease (RLD)
Diseases that make lung tissue stiffer result in
restrictive lung disease:
lungs are unable to expand fully and total lung
capacity (TLC) is reduced
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Gastrointestinal System
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Barrett esophagus
Chronic GERD (gastroesophageal reflux disease) with
esophageal mucosal injury can lead to metaplasia
of normal esophageal squamous mucosa into gastric-
type columnar mucosa, but with intestinal-type
goblet cells= known as Barrett esophagus
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Peptic ulcer disease (PUD)
PUD is common in Western populations and involves
mucosal ulceration within stomach and duodenum
Drake RL, et al. Gray’s Atlas Of Anatomy, 2nd Ed. Churchill Livingstone, 2015.
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Abdominal contents in situ and in relation
to alimentary system
Moore
Marc KL, Dalley
Imhotep Cray,AF, Agur A. MOORE Clinically Oriented Anatomy, 7th ed. LLW,
M.D. 223
2014.
Malabsorption
Malabsorption of nutrients from food may be
caused by
pancreatic exocrine insufficiency (e.g. chronic
pancreatitis) or
a specific or generalized defect w/i luminal GIT
o Specific defects include pernicious anemia [damage to
intrinsic factor (IF)] producing parietal cells w/i
specialized gastric mucosa)
o generalized defects include post-infectious diarrhea
(damage to small intestinal microvillous brush border)
Complications include
acute and chronic cholecystitis
obstructive jaundice and
acute pancreatitis
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Acute & Chronic Pancreatitis
Acute pancreatitis is a potentially life-threatening
condition that most commonly occurs secondary to
alcohol abuse and/or gallstones
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Diabetes Mellitus: Type 1 vs Type 2
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Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations
of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012. 243
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Cirrhosis and portal hypertension
Cirrhosis diffuse bridging fibrosis and
regenerative nodules disrupt normal architecture of
liver
increase risk for hepatocellular carcinoma (HCC)
Etiologies include alcohol (60–70% of cases in
US), nonalcoholic steatohepatitis, chronic viral
hepatitis, autoimmune hepatitis, biliary disease,
genetic / metabolic disorders
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Renal System
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Urinary tract infections
UTIs are much more common in females than males
and usually occur secondary to infection with fecal
bacteria such as Escherichia coli
Infections commonly involve bladder (causing cystitis)
but may also involve kidneys (causing pyelonephritis)
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Glomerulonephritis
Glomerulonephritis means inflammation centered on
glomeruli remainder of nephron may show secondary
changes
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Nervous System
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Increased intracranial pressure (ICP)
Raised ICP may occur secondary to intracranial
hemorrhage (usually acute onset) or as a result of a
space-occupying lesion such as a neoplasm (usually
gradual onset)
Early effects include cranial nerve compression (e.g. third
nerve compression leading to pupillary dilatation)
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Strokes (CVA)
CVA present clinically as sudden neurological defects
and may be caused by
intracranial hemorrhage (e.g. subarachnoid or
intracranial hemorrhage) or
cerebral infarction (usually secondary to thrombotic or
embolic occlusion of a carotid or intracranial artery)
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Vascular (multi-infarct) dementia, gross
Multiple vascular events, including embolic
arterial occlusion, atherosclerosis with
vascular narrowing and thrombosis, and
hypertensive arteriolar sclerosis may lead
to focal but additive loss of cerebral tissue
Cumulative effect of multiple small areas of
infarction ( ) may result in clinical findings
equivalent to AD along with focal neurologic
deficits or gait disturbances
Vascular dementia marked by loss of
higher mental function in a stepwise, not
continuous, fashion
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Musculoskeletal System
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Osteoporosis & Osteomalacia
Osteoporosis is loss of bone matrix (density) and most
commonly occurs in postmenopausal women
hormone replacement therapy is an important
prophylaxis against its development
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Osteoarthritis
Osteoarthritis is a wear-and-tear condition most
commonly affecting major weight-bearing joints and
characterized by erosion of articular cartilage and
osteophyte formation
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Rheumatoid arthritis (RA)
Rheumatoid arthritis is a multisystem disorder
comprising a symmetrical inflammatory polyarthritis
together w extra-articular manifestations including
pulmonary fibrosis and subcutaneous nodules
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Endocrine System
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Endocrine hormones pathologies
Endocrine hormones are key factors in regulation of
metabolism, and correct regulation of their production is
essential
Excess endocrine hormone production results in conditions
such as
Cushing’s syndrome (excess glucocorticosteroids)
Conn’s syndrome (excess mineralocorticoids)
Graves’ disease (excess thyroid hormone) and
Acromegaly (excess growth hormone)
Insufficient endocrine hormone production results in
conditions such as
Addison’s disease (insufficient corticosteroids) and
Hypothyroidism
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Practice Q&A
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Question 1
A 45-year-old man has had a fever and dry cough for 3 days, and
now has difficulty breathing and a cough productive of sputum. On
physical examination his temperature is 38.5 C. Diffuse rales are
auscultated over lower lung fields. A chest radiograph shows a
right pleural effusion. A right thoracentesis is performed. The fluid
obtained has a cloudy appearance with a cell count showing
15.500 leukocytes per microliter, 98% of which are neutrophils.
Which of the following terms best describes his pleural process?
A Serous inflammation
B Purulent inflammation
C Fibrinous inflammation
D Chronic inflammation
EMarcGranulomatous
Imhotep Cray, M.D. inflammation 294
Answer 1
(A) Incorrect. A transudate in a serous effusion has few cells.
(B) CORRECT. The neutrophils suggest an acute process; the fluid is
characteristic for an exudate. Such a large amount of purulent
exudate in the pleural space can be termed an empyema.
(C) Incorrect. Fibrin can often accompany acute inflammatory
processes, but a process with so many neutrophils is best
characterized as a purulent exudate.
(D) Incorrect. Chronic inflammation has a preponderance of
mononuclear cells, not neutrophils.
(E) Incorrect. A granulomatous response is characterized by
mononuclear cells.
A T1 N1 M0
B T1 N0 M1
C T2 N1 M0
D T3 N0 M0
E T4 N1 M1 298
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Answer 3
(A) Incorrect. This classification is for a small primary cancer with
nodal metastases but no distant metastases.
(B) Incorrect. This classification is for a small primary cancer with no
lymph node metastases but with distant metastases.
(C) Incorrect. This classification is for a larger primary cancer with
nodal metastases but no distant metastases.
(D) Incorrect. This classification is for a larger primary cancer with
no metastases to either lymph nodes or to distant sites.
(E) CORRECT. She has a large invasive (high T) primary tumor mass
with axillary node (N > 0) and lung metastases (M1).
A Unlikely to be malignant
B Arising from epithelium
C May spread via lymphatics and bloodstream
D Has an in situ component
E Well-differentiated and localized
A Epithelial dysplasia
B Cytoplasmic fatty metamorphosis
C Nuclear pyknosis
D Atrophy
E Anaerobic glycolysis
F Autophagocytosis
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Answer 8
(A) Incorrect. Although dysplasia can be a premalignant condition,
it is still reversible.
(B) Incorrect. Fatty change is potentially a reversible condition.
(C) CORRECT. The hypotension leads to diminished tissue perfusion
with ischemic injury. Nuclear chromatin clumping is reversible, but
nuclear pyknosis is not.
(D) Incorrect. 'Downsizing' of the cell in atrophy is reversible.
(E) Incorrect. A lack of sufficient oxygen may lead to anaerobic
metabolism, but this can be temporary until the hypoxia is relieved.
(F) Incorrect. The cell 'downsizes' with autophagocytosis of
cytoplasmic organelles, via its own lysosomes, but the cell does not
die.
Marc Imhotep Cray, M.D. 309
Question 9
A 73-year-old man suffers a "stroke." On physical examination he
cannot move his right arm. A cerebral angiogram demonstrates
occlusion of the left middle cerebral artery. An echocardiogram
reveals a thrombus within a dilated left atrium. Which of the
following is the most likely pathologic alteration from this event that
has occurred in his brain?
A Physiologic atrophy
B Breast trauma
C Lactation
D Radiation injury
E Hypoxic injury
Marc Imhotep Cray, M.D. 312
Answer 10
(A) Incorrect. At age 30 she is premenopausal.
(B) CORRECT. Fat necrosis is seen with trauma to the breast, and
her lawyer will make good use of that documentation. The pattern
of multiple injuries of differing ages at different sites suggests
abuse.
(C) Incorrect. Lactation leads to a physiologic hyperplasia of the
breast with increase in lobules.
(D) Incorrect. A variety of vascular and parenchymal changes can
occur with radiation injury.
(E) Incorrect. The breast is not a site for hypoxic injury.
See next slide for links to tools and resources for further study. 314
Tools & resources for further study :
eNotes:
IVMS General Pathology Lecture Notes.pdf
Images:
IVMS-Gross Pathology, Histopathology, Microbiology and Radiography High
Yield Image Plates.pdf
Atlas:
Klatt EC. Robbins and Cotran Atlas of Pathology 3rd Ed. Elsevier-Saunders,
2015.
WebPath Website:
http://www-medlib.med.utah.edu/WebPath/webpath.html
Textbooks:
Kumar V and Abbas AK. Robbins and Cotran Pathologic Basis of Disease 8th
ed. Philadelphia: Saunders, 2014.
Rubin
Marc R Cray,
Imhotep andM.D.
Strayer DS Eds. Baltimore: Lippincott Williams & Wilkins, 2012. 315