ABOUT MYSELF

I completed my MBBS from SRMC & RI Porur Chennai in 1993. Thereafter I

have completed my Diploma in Clinical Pathology from MMC Chennai, which
has given me a deeper understanding of the Basic sciences. Further to this I did
my Post graduate MD in Pathology from PGIBMS Taramani Chennai. I have also
passed the National Boards in Pathology earning my DNB.
Though not actively working as a Pathologist at present, nevertheless, due to
my strong academic grounding in the Basic Sciences I decided to compile
answers to previous years TN Dr MGR University Questions in order to make
the preparation easier for students who find it difficult to assimilate huge
quantities of subject matter in the short time available.
In this offering I have endeavored to give the answers as clearly as possible and
in a point wise manner to make reading easier. Illustrations have also been
given. Extensive reference has been made to standard textbooks.
I sincerely hope that medical students benefit from this effort covering
Pharmacology, Microbiology and Pathology.
Lastly students are encouraged to give their constructive feedback and help
improve the content matter and correct mistakes that are bound to creep in,
despite my best efforts to avoid them.
Lakshmi Venkataraman
([email protected])

Copyright Dr Lakshmi Venkataraman - 2015

ACKNOWLEDGEMENT
I wish to thank my mother Dr Sankari Venkataraman, a Prof of Physiology
(Retd), for going through my answers patiently and helping me to improve
upon the contents especially in Physiology with her numerous valuable
suggestions and inputs.
My children put up with me spending more time at the Computer than with
them and bore me out patiently for the last few months. Thank you for your
patience.
I should mention here my husbands valuable advice and suggestions for
managing the documents properly while they were getting ready. I also wish to
thank his office team for helping to put the book on the web with suitable
modifications.

DEDICATION
This work is dedicated to all medical students

Copyright Dr Lakshmi Venkataraman 2015

Table of Contents
PATHOLOGY I FEBRUARY 2015 ...................................................................................................... 4
I. Elaborate on: .......................................................................................................................... 4
II. Write notes on: ..................................................................................................................... 5
III. Short answers on: ................................................................................................................ 9
PATHOLOGY I AUGUST 2015 ....................................................................................................... 12
I. Elaborate .............................................................................................................................. 12
II. Write notes on .................................................................................................................... 14
III. Short answers on ............................................................................................................... 18
PATHOLOGY II FEBRUARY 2015 ................................................................................................... 20
I. Elaborate on ......................................................................................................................... 20
II. Write notes on: ................................................................................................................... 22
III. Short answers on: .............................................................................................................. 25
PATHOLOGY II AUGUST 2015 ...................................................................................................... 28
Elaborate on............................................................................................................................ 28
II. Write notes on .................................................................................................................... 30
III. Short answers on ............................................................................................................... 33
BIBLIOGRAPHY ............................................................................................................................ 35

PATHOLOGY I FEBRUARY 2015

I. Elaborate on:
1. Classify Hemolytic Anemias. Write in detail about the pathogenesis, blood picture and clinical
features of beta Thalassemia major.
Hemolytic anemias are defined as those anemias which result form an increase in the rate of red cell
destruction.
In hemolytic disorders, red cells are destroyed prematurely, usually in a random fashion. If the red
blood cell life span is only moderately shortened, the patient will usually have little, if any, anemia
because the bone marrow is capable of increasing the rate of new red blood cell production by 4-8
times.
Based on the site of hemolysis, hemolytic anemias can be classified as Intracorpuscular versus
Extracorpuscular Defects
Intracorpuscular defects
These are intrinsic to the red blood cell. They are usually inherited, and generally (but not always)
the abnormality is observable in the peripheral blood smear.
Extracorpuscular defects
refer to problems in the environment of the red blood cell, not in the red blood cell itself.
Extracorpuscular hemolysis is usually acquired and is often but not always discernible in the form
of morphologic abnormalities in the peripheral blood smear.

Laboratory findings Common to hemolytic anemias

The major criteria for the laboratory diagnosis of hemolytic anemia are reticulocytosis and
an increase in serum level of unconjugated bilirubin.
Serum level of lactic dehydrogenase (LDH) is elevated.
Serum haptoglobin level is decreased.
The peripheral blood smear often but not invariably shows morphologic changes in the red blood
cells compatible with hemolysis.
THALASSEMIA MAJOR
Thalassemias are a heterogeneous group of genetic disorders which result from a reduced rate of
synthesis of or globin chains in the Hemoglobin molecule.
Pathogenesis
Complete (0 0) or almost complete (0 +) failure of -globin chain synthesis resulting from
4

inheritance from each parent of one of over 400 different point mutations or deletions in the globin gene or its controlling sequences.
There is a severe imbalance of : -chains with precipitation of the excess -chains in erythroblasts
leading to ineffective erythropoiesis, severe anaemia and extramedullary haemopoiesis.
Clinical features
Anaemia presents at the age of 36 months when the switch from - to -chain synthesis normally
occurs. Milder cases present later (up to the age of 4 years).
Failure to thrive, intercurrent infection, pallor, mild jaundice (due to hemolysis).
Enlargement of the liver and spleen (extramedullary hematopoiesis), expansion of the bones
resulting from bone marrow hyperplasia especially of the skull with bossing and a hair-on-end
appearance on X-ray; thalassaemic facies, caused by expansion of skull and facial bones.
Features of iron overload as a result of blood transfusions and increased iron absorption include
melanin pigmentation, growth/ endocrine defects, e.g. diabetes mellitus, hypothyroidism,
hypoparathyroidism, failure of sexual development, cardiac failure or arrhythmia, liver abnormality.
Blood picture
Severe anaemia (Hb 2060 g/L) with reduced mean corpuscular volume and mean corpuscular
haemoglobin.
Blood film shows hypochromic, microcytic cells, target cells, erythroblasts and, often, myelocytes.
Bone marrow is hypercellular with erythroid hyperplasia.

High performance liquid chromatography or haemoglobin electrophoresis can be used to measure

the concentration of the different haemoglobins present in red cells. No Hb A is detected in 0 0
patients.
DNA analysis reveals the specific mutations or deletions.

II. Write notes on:

1. Growth factors
Healing involves an orderly sequence of events which includes regeneration and migration of
specialized cells, angiogenesis, proliferation of fibroblasts and related cells, matrix protein synthesis
and finally cessation of these processes.
These processes, at least in part, are mediated by a series of low molecular weight polypeptides
referred to as growth factors.
These growth factors have the capacity to stimulate cell division and proliferation. Some of the
factors, known to play a role in the healing process, are briefly discussed below.
Sources of Growth Factors:
Following injury, growth factors may be derived from a number of sources such as:
1. Platelets, activated after endothelial damage,
2. Damaged epithelial cells,
3. Circulating serum growth factors,
4. Macrophages, or
5. Lymphocytes recruited to the area of injury

The healing process ceases when lost tissue has been replaced.
The mechanisms regulating this process are not fully understood. TGF- acts as a growth inhibitor
for both epithelial and endothelial cells and regulates their regeneration.
Applied aspect
A major activity of growth factors is to stimulate the function of growth control genes, many of
which are called proto-oncogenes because mutations in them lead to unrestrained cell proliferation
characteristic of cancer (oncogenesis)
1. Mutations and amplifications in the Receptor for EGF namely EGFR-1 have been detected in
cancers of the lung, head and neck, and breast, glioblastomas, and other cancers.
Nowadays the mutated growth factor receptor is being targeted in the treatment of cancer by
means of Monoclonal antibodies that bind to and inactivate it.
2. The receptor for Hepatocyte growth factor (HGF), namely c-MET, is often highly expressed or
mutated in human tumors, especially in renal and thyroid papillary carcinomas.
Several HGF and c-MET inhibitors are presently being evaluated in cancer therapy clinical trials.
3. Loss of TGF- receptors frequently occurs in human tumors, providing a proliferative advantage to
tumor cells; on the contrary its overexpression leads to excessive fibrosis and hypertrophic scars. Its
overexpression has also been documented in Systemic sclerosis and Marfans syndrome.
2. Transplant rejection
Antigens encoded by the MHC on chromosome 6 are critical immunogenic molecules that can
stimulate rejection of transplanted tissues.
Thus, optimal graft survival occurs when recipient and donor are closely matched with regard to
histocompatibility antigens.
Transplant rejection reactions are usually categorized as hyperacute, acute and chronic
rejection, based on the clinical tempo of the response and pathophysiologic mechanisms involved.
However, in practice, the features of each overlap, creating ambiguity in diagnosis.
Categorization of transplant rejection is also complicated by the toxicity of immunosuppressive
drugs employed to control rejection reactions.
a) Hyperacute rejection
(i) Occurs within minutes of transplantation
(ii) Mediated by preformed antidonor antibodies present in the recipients circulation (e.g., ABO
incompatibility)
(iii) Antigens in the endothelium of the transplanted organ are recognized by the preformed
antibodies (IgM and IgG) capable of complement activation, resulting in thrombosis and fibrinoid
necrosis and followed by ischemic necrosis of the transplanted organ.
b) Acute rejection
(i) Occurs within days or months after the transplantation or at any time after the withdrawal of
6

immunosuppressive therapy.
(ii) Mediated by both humoral (antibody-mediated) and cellular (T cellmediated) mechanisms.
(iii) Vasculitis is a prominent feature. It is mediated by antidonor antibodies that attack the vessel
wall, with subsequent thrombosis and thickening of the arterioles. Vascular changes cause an
ischemia of the transplanted organ.
(iv) Interstitial accumulation of lymphocytes is a prominent feature. It is associated with
parenchymal cell injury (e.g., tubular epithelium of kidneys or myocytes in the heart).
c) Chronic rejection
(i) Caused predominantly by vascular changes (intimal fibrosis) accompanied by ischemia and loss of
parenchymal cells.
(ii) Gradual and progressive decline in transplanted organ function over a period of months and
years.
3. Cystic fibrosis.
Cystic fibrosis (CF) is an autosomal recessive disorder that affects epithelial cell ion transport and
causes abnormal fluid secretion in exocrine glands, as well as in respiratory, gastrointestinal, and
reproductive mucosa.
Indeed, abnormally viscid mucous secretions that block the airways and the pancreatic ducts are
responsible for the two most important clinical manifestations: recurrent and chronic pulmonary
infections and pancreatic insufficiency.
Molecular pathogenesis
It is an example of a Channelopathy; a channelopathy is caused by the dysfunction of a specific
ion channel in cell membranes.
Cystic fibrosis involves inherited mutations in the genes encoding proteins involved in
transmembrane ionic flow of exocrine secretions.
In normal epithelia, the transport of chloride ions across the cell membrane occurs through
transmembrane proteins such as CFTR that form chloride channels.
Mutations in the CFTR gene render the epithelial membranes relatively impermeable to chloride
ions with consequent effects that lead to the clinical picture of CF.
CFTR also regulates other ion channels and cellular processes.
CFTR association with the epithelial sodium channel (ENaC) is necessary to reabsorb luminal
chloride ions and augment sodium reabsorption
Therefore, in the sweat ducts, loss of CFTR function leads to decreased reabsorption of sodium
chloride and production of hypertonic (salty) sweat which forms the basis for the SWEAT
CHLORIDE TEST.
PATHOPHYSIOLOGICAL BASIS OF LUNG AND INTESTINAL AFFECTATION IN CF
In contrast with that in the sweat glands, CFTR in the respiratory and intestinal epithelium forms
one of the most important avenues for active luminal secretion of chloride.
CFTR mutations result in loss or reduction of luminal chloride secretion.
Active luminal sodium absorption through ENaCs also is increased, and both of these ion changes
increase passive water reabsorption from the lumen, lowering the water content of the surface
fluid layer coating mucosal cells.
The respiratory and intestinal complications in CF result from an isotonic but low-volume surface
fluid layer.
In the lungs, this dehydration leads to defective mucociliary action and the accumulation of
concentrated, viscid secretions that obstruct the air passages and predispose to recurrent
pulmonary infections.
Genetic and Environmental Modifiers of the disease
(i) Reduced expression of mannose-binding lectin 2 (involved in microbial opsonization) confers an
increased risk of end-stage lung disease;
(ii) polymorphisms that influence transforming growth factor- expression (a direct inhibitor of
CFTR function) also exacerbate the pulmonary phenotype.
7

(iii) The nature of secondary pulmonary infections (e.g., Pseudomonas), with more or less mucoid
polysaccharide biofilm production, also impact subsequent inflammation and lung destruction.
4. Hodgkin Lymphoma
HL is a form of lymphoma arising in a single node or chain of nodes and spreading characteristically
to the anatomically contiguous nodes.
It is characterized morphologically by the presence of neoplastic giant cells, ReedSternberg (RS)
cells, which induce the accumulation of reactive lymphocytes, histiocytes, and granulocytes.
The neoplastic cells comprise a minor fraction (1%5%) of the total tumor cell mass.
HL is one of the most common forms of malignancy in young adults, with an average age at diagnosis
of 32 years.
The disease is curable in most cases.
Five subtypes of HL are recognized. The first four are grouped into the so-called classical HL,
whereas the last form (lymphocyte predominance) is considered to be a separate entity:
HL, nodular sclerosis type (65%75% of cases)
HL, mixed cellularity type (20%25% of cases)
HL, lymphocyte rich (rare)
HL, lymphocyte depletion type (a rare and somewhat controversial form of disease)
HL, lymphocyte predominance type (6%)
PATHOGENESIS
The origin of RS cells remained mysterious through the 19th and most of the 20th centuries but was
finally solved by molecular studies performed on single microdissected RS cells.
These showed that every RS cell from any given case possessed the same immunoglobulin gene
rearrangements. In addition these studies revealed that the rearranged immunoglobulin genes had
undergone somatic hypermutation.
As a result, it is now agreed that Hodgkin lymphoma is a neoplasm arising from germinal center B
cells.

III. Short answers on:

1. Dystrophic calcification
Pathologic calcification is the abnormal tissue deposition of calcium salts, together with smaller
amounts of iron, magnesium, and other mineral salts.
There are two forms of pathologic calcification, namely dystrophic and metastatic.
Dystrophic calcification
This occurs in previously damaged tissue, such as areas of old trauma, tuberculous lesions,
scarred heart valves, & atherosclerotic lesions.
Deposition ultimately involves precipitation of a crystalline calcium phosphate similar to bone
hydroxyapatite:
Pathogenesis
The calcification evolves in the following manner
Initiation (nucleation) occurs extracellularly or intracellularly.
9

Extracellular initiation occurs on membrane-bound vesicles from dead or dying cells that
concentrate calcium due to their content of charged phospholipids;
membrane-bound phosphatases then generate phosphates that form calcium-phosphate
complexes;
the cycle of calcium and phosphate binding is repeated, eventually producing a deposit.
Initiation of intracellular calcification occurs in mitochondria of dead or dying cells.
Propagation of crystal formation depends on the concentration of calcium and phosphates, the
presence of inhibitors, and structural components of the extracellular matrix.
Morphology.
Histologically, with the usual hematoxylin and eosin stain, calcium salts have a basophilic,
amorphous granular, sometimes clumped appearance. They can be intracellular, extracellular, or in
both locations.
In the course of time, heterotopic bone may be formed in the focus of calcification. On occasion
single necrotic cells may constitute seed crystals that become encrusted by the mineral deposits.
2. Gauchers cell
Gaucher disease is an autosomal recessive disease characterized by mutations in the gene for
glucocerebrosidase.
Glucosylceramide (cerebroside) is derived from the degradation of glycosphingolipids, which are
abundant in the plasma membranes of neurons and blood cells.
Cerebroside is cleaved to glucose and free ceramide by the action of glucocerebrosidase.
Deficiency of this enzyme results in the accumulation of cerebroside in lysosomes of phagocytic
cells throughout the body.
Macrophages engorged with stored lipid (Gaucher cells) can be seen in the spleen, liver, lymph
nodes, and bone marrow.
Morphology
Affected cells (i.e., Gaucher cells) are distended with periodic acidSchiff (PAS)-positive material with
a fibrillary appearance resembling crumpled tissue paper (composed of elongated lysosomes
containing stored lipid in bilayer stacks).
3. Arthus reaction
There are 2 types of Immune complex mediated Hypersensitivity.
1. Local Arthus reaction
2. Systemic immune complex deposition
Local Arthus reaction
Arthus reaction is typically elicited in the skin by injecting an Antigen in the perivascular space of
an immunised animal and immune complexes form locally.
The antigen diffusing into the vessel wall encounters the antibody entering the vessel wall from
the circulation.
Antigen and antibody meeting in the vessel wall form immune complexes, which activate the
complement system.
Activated complement forms chemotactic fragments that attract neutrophils, thus causing an
inflammation in the vessel wall.
In the clinical setting, immune complexes are formed in the vessels in Polyarteritis nodosa. This is
the equivalent of the experimental Arthus phenomenon.
4. Chloroma
AML most commonly presents with signs of fatigue, fever, and spontaneous mucosal (gingival and
urinary tract) and cutaneous bleeding (petechiae and ecchymoses).
Uncommonly, patients present with localized masses composed of myeloblasts in the absence of
marrow or peripheral blood involvement (referred to as myeloblastomas, granulocytic sarcomas, or
chloromas).
Without systemic treatment, these typically progress to typical AML.
5. Vitamin C deficiency
10

Vitamin C deficiency is now most common in elderly people and in chronic alcoholics, whose diet is
often lacking in fresh fruit and vegetables.
The vitamin (ascorbic acid) is essential principally for collagen synthesis: it is necessary for the
production of chondroitin sulphate and hydroxyproline from proline.
Minor deficiency may be responsible for lassitude and an unusual susceptibility to bruising.
Severe deficiency causes scurvy, a condition characterised by swollen, bleeding gums, hyperkeratosis
of hair follicles, and petechial skin haemorrhages.
Pathogenesis of bleeding and poor wound healing in Scurvy
The most clearly established function of vitamin C is the activation of prolyl and lysyl hydroxylases
from inactive precursors, allowing for hydroxylation of procollagen.
Inadequately hydroxylated procollagen cannot acquire a stable helical configuration or be
adequately cross-linked, so it is poorly secreted from the fibroblasts.
Those molecules that are secreted lack tensile strength, are more soluble, and are more vulnerable
to enzymatic degradation.
Collagen, which normally has the highest content of hydroxyproline, is most affected, particularly
in blood vessels, accounting for the predisposition to hemorrhages in scurvy.

11

PATHOLOGY I AUGUST 2015

I. Elaborate
1. Define Neoplasia. Write in detail about the molecular basis of cancers. Add a note on
Oncogenes and their mode of activation.
Definition
Neoplasia means new growth. British pathologist Sir Rupert Willis defined it as follows:
A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with
that of normal tissues and persists in the same excessive manner after cessation of the stimuli that
evoke the change.
In contrast to normal cells, the growth of neoplastic cells is
(i) Autonomous - The growth of neoplastic cells is independent of growth factors and regulatory
mechanisms operating inside the normal tissues.
(ii) Excessive - This excess may be evident in the size of the outgrowths and the duration of the
proliferation.
(iii) Disorganized - The structures formed by tumor cells differ from normal tissues and do not fit into
the general organization scheme of the normal body.
The Molecular basis of carcinogenesis includes
1) Non-lethal genetic damage lies at the heart of carcinogenesis.
Such genetic damage (mutation) may be acquired by the action of environmental agents such
as chemicals, radiation or viruses or it may be inherited in the germ line.
2) The three classes of normal regulatory genes involved in Neoplastic transformation are:
i) The growth promoting proto-oncogenes
Activation of proto-oncogenes to oncogenes leads to uncontrolled cell proliferation and neoplastic
transformation. Proto oncogenes are activated by
Point mutation
Chromosomal rearrangements (translocation and deletions)
Gene amplification
Insertional mutagenesis when a viral genome incorporates into host DNA eg EBV
Examples of normal proto oncogene and its activated counterpart c-oncogene

ii) Cancer suppressor genes (anti-oncogenes)

Its physiologic role is to regulate cell growth however, the inactivation of cancer suppressor genes is
the key event in cancer genesis
Examples of tumour suppressor genes include Rb, P53, APC, Ras and NF-1&2 genes
iii) Genes that regulate apoptosis
Genes that prevent or induce programmed cell death are also important variables in the cancer
development.
These genes include bcl-2 that inhibits apoptosis whereas, others such as bax, Bad, and bcl-5 favour
programmed cell death.
Genes that regulate apoptosis may be dominant as are proto-oncogenes or may behave as cancer
suppressor genes (recessive in nature)
iv) Genes that regulate DNA repair
Inability to DNA repair can predispose to mutations in the genome and hence, to neoplastic
transformations.
12

Eg Xeroderma pigmentosum
Molecular basis of Multistep carcinogenesis
Neoplastic transformation is a multistep process both morphologically and at the molecular level.
A single alteration is not sufficient to cause malignancy as illustrated below.

ONCOGENES AND THEIR ACTIVATION

Oncogenes are cancer-inducing genes derived from normal cellular genes called protooncogenes.
Human oncogenes, named cellular oncogenes (c-oncogenes), are homologous to viral oncogenes (voncogenes), known for some time to cause cancer in animals.
All these genes are involved in cell proliferation and differentiation and are classified on the basis of
their function into four groups. These functional groups and the representative protooncogenes and
c-oncogenes are listed below.

Mode of activation
Protooncogenes can be transformed into oncogenes through four basic mechanisms:
1. Point mutation
A single base substitution in the DNA chain results in a miscoded protein. Point mutation of the ras
oncogene is found in approximately 30% of common human cancers, such as carcinoma of the lung,
large intestine, and pancreas.
2. Gene amplification
This lesion is associated with an increased number of copies of a protooncogene. The best example
is amplification of c-myc in neuroblastomas. The more c-myc is amplified, the more malignant are
these childhood tumors.
3. Chromosomal rearrangements
Translocations and deletions of parts of chromosomes lead to a juxtaposition of genes that are
normally not in close proximity to one another. These rearrangements form new gene complexes, in
which one gene acts as the promoter for the other. For example, translocation of the c-myc gene
(normally located on chromosome 8) onto chromosome 14 positions this protooncogene next to the
immunoglobulin heavy chain gene. The immunoglobulin gene is activated in B lymphocytes and acts
as a promoter for the c-myc gene. This chromosomal rearrangement is the basis of malignant
transformation of lymphocytes in Burkitt lymphoma.
4. Insertional mutagenesis
13

This form of oncogene activation occurs because of an insertion of a viral gene into the mammalian
DNA, resulting in genetic dysregulation. The best example of such an event may be found in
hepatitis virus Binfected human liver cells.

II. Write notes on

1. Pathogenesis of shock.
Shock is the final common pathway for several potentially lethal clinical events, including severe
hemorrhage, extensive trauma or burns, large myocardial infarction, massive pulmonary embolism,
and microbial sepsis.
Shock is characterized by systemic hypotension due either to reduced cardiac output or to reduced
effective circulating blood volume.
The consequences are impaired tissue perfusion and cellular hypoxia. At the outset the cellular
injury is reversible; however, prolonged shock eventually leads to irreversible tissue injury that often
proves fatal.
The causes of shock fall into three general categories
Cardiogenic shock results from low cardiac output due to myocardial pump failure. This can be
due to intrinsic myocardial damage (infarction), ventricular arrhythmias, extrinsic compression
(cardiac tamponade, or outflow obstruction (e.g., pulmonary embolism).
Hypovolemic shock results from low cardiac output due to the loss of blood or plasma volume,
such as can occur with massive hemorrhage or fluid loss from severe burns.
Septic shock results from vasodilation and peripheral pooling of blood as part of a systemic
immune reaction to bacterial or fungal infection. Its complex pathogenesis is discussed below
PATHOGENESIS OF SEPTIC SHOCK
It is now established that septic shock can be caused by localized infection even without
spread into the bloodstream.
Most cases of septic shock are now caused by Gram-positive bacteria, followed by Gram-negative
bacteria and fungi.
Morbidity and mortality in sepsis are consequences of tissue hypoperfusion and multi-organ
dysfunction despite initially preserved or even increased cardiac output.
This is due to systemic vasodilation accompanied by widespread endothelial cell (EC) activation and
injury, leading to a hypercoagulable state and DIC.
There are also systemic metabolic changes that suppress normal cellular function.
The pathogenesis of sepsis is a combination of direct microbial injury and activation, and host
inflammatory responses
A. Inflammatory mediators:
Microbial cell wall components activate leukocytes and EC via toll-like receptors and other receptors
of innate immunity. Activation triggers release of inflammatory cytokines, prostaglandins, reactive
oxygen species, and platelet activating factor.
Coagulation and complement cascades are also directly activated, which can, in turn, drive
additional inflammatory responses.
B. Endothelial cell activation and injury:
EC activation leads to an adhesive, procoagulant EC phenotype with markedly increased thrombotic
and bleeding tendencies (DIC in up to 50% of cases), as well as vasodilation and increased
permeability.
The production of other endothelial anticoagulant factors, such as tissue factor pathway inhibitor,
thrombomodulin, and protein C, is also diminished.
Acting in concert, these effects promote the systemic deposition of fibrin-rich thrombi in small
vessels, thus exacerbating tissue hypoperfusion.
In full-blown disseminated intravascular coagulation (DIC), there is also consumption of clotting
factors and platelets, leading to concomitant hemorrhage.
14

The loosened EC junctions become leaky, resulting in the accumulation of protein-rich exudates and
edema throughout the body.
Expression of vasoactive inflammatory mediators together with increased NO production, leads to
systemic relaxation of vascular smooth muscle, producing hypotension and further reductions in
tissue perfusion.

C. Metabolic abnormalities:
Insulin resistance and hyperglycemia are characteristic of the septic state, attributable to
inflammatory cytokines and the early production of stress-induced hormones such as glucagon,
growth hormone, and cortisol. With time, adrenal insufficiency may supervene.
D. Immune suppression:
The hyperinflammatory state initiated by sepsis can activate potent counter-regulatory
immunosuppressive mechanisms.
E. Organ dysfunction:
Hypotension, edema, and small vessel thrombosis all reduce oxygen and nutrient delivery to tissues;
the cellular metabolism in various tissues is also deranged due to insulin resistance.
Myocardial contractility may be directly impacted, and endothelial damage underlies the
development of acute respiratory distress syndrome.
2. Amyloidosis.
Amyloid is a proteinaceous substance deposited between cells in various tissues and organs in a
variety of clinical settings.
The name derives from its starchlike staining properties (PAS [periodic acid schiff] positive).
It appears amorphous, eosinophilic, hyaline extracellular substance is seen under the microscope.
Amyloids are chemically diverse.
15

 Amyloids have typical physical properties. All amyloids, irrespective of their biochemical
composition, form nonbranching long fibrils (7.510 mm). By electron diffraction, they are arranged
into -pleated sheets.
As amyloid accumulates, it produces pressure atrophy of adjacent parenchyma.

The proteins that form amyloid fall into two general categories:
(1) normal proteins that have an inherent tendency to fold improperly, associate to form fibrils, and
do so when they are produced in increased amounts and
(2) mutant proteins that are prone to misfolding and subsequent aggregation.
Of the many biochemically distinct forms of amyloid proteins that have been identified, three are
most common:
a) Amyloid light chain (AL):
Immunoglobulin light chains derived from plasma cells; lambda light chain amyloid occurs more
often than kappa;
Associated with plasma cell tumors (e.g., multiple myeloma).
b) Amyloid-associated (AA):
A non-immunoglobulin protein derived from a larger serum precursor called serum amyloid
associated (SAA) protein synthesized by hepatocytes as part of the acute phase response;
AA amyloid is associated with chronic inflammatory states.
c) -Amyloid (A):
Forms the core of cerebral plaques and deposits within cerebral vessel walls in Alzheimer disease;
it derives from a transmembrane amyloid precursor protein
AMYLOIDOSIS
Amyloidosis is a group of diseases characterized by a deposition of amyloid in various organs.
The deposition of amyloid may occur as a primary Amyloidosis (e.g., in multiple myeloma) or in a
secondary Amyloidosis during the course of chronic inflammatory or other diseases.
The disease may be limited (localized) to a single organ, or it may be systemic.
Some forms may be hereditary.
MORPHOLOGY
The most severely affected organs in systemic amyloidosis
1. Kidneys
Both kidneys are enlarged, pale, and waxy. Glomerular mesangial, interstitial, and vascular wall
depositions of amyloid are found.
2. Spleen
Splenomegaly presents with either nodular (follicular) depositions (sago spleen) or map like (red
pulp) depositions (lardaceous spleen).
3. Liver
Hepatomegaly, extracellular amyloid with pressure atrophy of hepatocytes.
4. Small blood vessels
Many organs show vascular deposits of amyloid, and, accordingly, the diagnosis may be made by
biopsy of tissue from the fat pad, gingiva, or rectum.
5. Heart
May be involved in any form of systemic amyloidosis. It is also the major organ involved in senile
systemic amyloidosis. The heart may be enlarged and firm, but more often it shows no significant
changes on gross inspection. Histologically the deposits begin as focal subendocardial accumulations
and within the myocardium between the muscle fibers.
6. Other organs
Amyloidosis of other organs is generally encountered in systemic disease. The adrenals, thyroid, and
pituitary are common sites of involvement. The gastrointestinal tract may be involved at any level,
from the oral cavity (gingiva, tongue) to the anus.
DIAGNOSIS
1. The diagnosis of amyloidosis depends on the histologic demonstration of amyloid deposits in
16

tissues.
2. The most common sites biopsied are the kidney, when renal manifestations are present, or rectal
or gingival tissues in patients suspected of having systemic amyloidosis.
The histologic diagnosis of amyloid is based on its staining characteristics. The most commonly used
staining technique uses the dye Congo red, which under ordinary light imparts a pink or red color to
amyloid deposits. Under polarized light, the Congo-red stained amyloid shows a green birefringence.
Confirmation can be obtained by electron microscopy where -pleated sheet arrangement of the
fibrils is seen.
3. Examination of abdominal fat aspirates stained with Congo red can also be used for the diagnosis
of systemic amyloidosis. The test is quite specific, but its sensitivity is low.
4. In suspected cases of immunocyte-associated amyloidosis, serum and urine protein
electrophoresis and immunoelectrophoresis should be performed. Bone marrow aspirates in such
cases often show monoclonal plasmacytosis, even in the absence of overt multiple myeloma.
5. Scintigraphy with radiolabeled serum amyloid P (SAP) component is a rapid and specific test,
since SAP binds to the amyloid deposits and reveals their presence. It also gives a measure of the
extent of amyloidosis and can be used to follow patients undergoing treatment.
3. Megaloblastic Anemia.
Megaloblastic anemias are characterized by impaired DNA synthesis and distinctive morphologic
changes of affected RBC precursors and their descendants in the blood and bone marrow.
It is a disease of older age, most commonly diagnosed in the fifth to eighth decade of life.
Two main types are:
Pernicious anemia, the major form of vitamin B12 deficiency anemia
Folate deficiency anemia
A deficiency of vitamin B12 and folic acid or impairment in their use results in defective nuclear
maturation due to deranged or inadequate synthesis of DNA.

4. Myelofibrosis
In this myeloproliferative disorder, marrow fibrosis supervenes early in the disease course, often
after a brief period of granulocytosis and thrombocytosis.
As hematopoiesis shifts from the fibrotic marrow to the spleen, liver, and lymph nodes, extreme
splenomegaly and hepatomegaly develop.
The extramedullary hematopoiesis at these sites is disordered and ineffective, resulting in anemia
and thrombocytopenia.
Neutropenia also may occur but tends to be mild.
Pathogenesis
17

Primary defect is within the haemopoietic stem cell; fibrosis results from a reactive non-neoplastic
proliferation of marrow stromal cells.
Molecular pathogenesis
Activating JAK2 mutations are present in 50% to 60% of cases and activating MPL mutations in 1%
to 5%.
The marrow fibrosis and obliteration may be secondary to release of fibrogenic factors from
neoplastic megakaryocytes; platelet-derived growth factor and transforming growth factor- (TGF) are both implicated.
Laboratory features
Normochromic normocytic anaemia. This may be severe.
Leucocytosis and thrombocytosis occur early, and later leucopenia and thrombocytopenia
Blood film: red cell poikilocytosis with teardrop forms, circulating red cell and white cell precursors
(leucoerythroblastic picture).
Serum lactic dehydrogenase is raised, in distinction to PRV or ET.
Liver function tests are often abnormal because of extramedullary haemopoiesis.
Bone marrow aspiration is usually unsuccessful (dry tap); the trephine biopsy shows increased
cellularity, increased megakaryocytes and fibrosis
Both liver and spleen show foci of extramedullary hematopoiesis.
JAK-2 mutations are seen in 50% cases
Clinical features
Age usually >60 years.
Massive splenomegaly may lead to left hypochondrial pain.
Nonspecific symptoms (e.g., fatigue, weight loss, and night sweats) result from increased
metabolism associated with the expanded mass of hematopoietic cells. Owing to high cell turnover,
hyperuricemia and secondary gout can complicate the picture.
Prognosis
Variable; mean survival 3-5 years.
Cause of death is often due to intercurrent infections, bleeding or transformation to AML.

III. Short answers on

1. Acute phase reactants.
Measurement of a number of specific proteins gives useful information in the diagnosis and
management of disease
Characteristic changes in the concentration of certain plasma proteins are seen following surgery
or trauma, or during infection or tumour growth. The proteins involved are called acute phase
reactants.
These acute phase proteins may be used to monitor progress of the condition or its treatment.
Acute-phase reactants that increase in plasma are C-reactive protein, a1-antitrypsin, ceruloplasmin,
fibrinogen, serum amyloid associated (SAA)protein, and some others.
There are sensitive biochemical tests that measure the concentration of C-reactive protein in blood.
These tests can be used instead of the standard ESR.
2. LE cell.
In tissues, nuclei of damaged cells react with ANAs, lose their chromatin pattern, and become
homogeneous, to produce so-called LE bodies or hematoxylin bodies.
Related to this phenomenon is the LE cell, which is readily seen when blood is agitated in vitro to
damage the cell and expose its nucleus.
The LE cell is any phagocytic leukocyte (blood neutrophil or macrophage) that has engulfed the
denatured nucleus of an injured cell.
The demonstration of LE cells in vitro was used in the past as a test for SLE. With new techniques for

18

detection of ANAs, however, this test is now largely of historical interest. Sometimes, LE cells are
found in pericardial or pleural effusions in patients.
3. Chronic granulomatous disease.
Deficiency of NADPH oxidase is the basic defect in children suffering from chronic granulomatous
disease.
In this disease, the leukocytes cannot generate superoxide, which impairs the oxygen-dependent
killing of bacteria.
Oxygen-independent killing of bacteria is especially important in such people suffering from
congenital deficiency of NADPH oxidase (chronic granulomatous disease) or myeloperoxidase
deficiency.
These children are especially sensitive to infection with catalase-positive microbes such as
Staphylococcus aureus. Catalase-negative streptococci are less dangerous.
These bacteria produce peroxide that is used by the leukocytes to generate hypochloric acid and to
kill the pathogens. Deficiency of myeloperoxidase is characterized by an inability of leukocytes to
produce H2O2 and hypochloric acid.
Affected children are prone to fungal infections.
4. Langerhans cell histiocytosis.
Langerhans cells are the antigen presenting cells found in the epidermis.
Langerhans cell histiocytosis (Histiocytosis X) is a disease principally of smokers, characterised by
the proliferation of Langerhans cells forming nodular infiltrates.
The proliferating Langerhans cells have abundant, often vacuolated cytoplasm and vesicular
nuclei containing linear grooves or folds.
Dermal infiltrates are composed of cells that have the immunohistochemical and ultrastructural
features of epidermal Langerhans cells as follows.
The presence of Birbeck granules in the cytoplasm is characteristic. Birbeck granules are
pentalaminar tubules, often with a dilated terminal end producing a tennis racketlike appearance,
which contain the protein langerin.
In addition, the tumor cells also typically express HLA-DR, S-100, and CD1a.
A primary form of the disease occurs in children younger than 2 years of age and is known as
LettererSiwe disease.
5. Name four Monoclonal Gammopathies.
Multiple myeloma
Waldenstrms macroglobulinemia
Heavy chain disease
Primary or immunocyte associated amyloidosis
Monoclonal gammopathy of undetermined significance

19

PATHOLOGY II FEBRUARY 2015

I. Elaborate on
1. Define Diabetes Mellitus. What are the types? Describe the Pathophysiology, morphology and
complications of Diabetes Mellitus.
Definition
Diabetes mellitus is a complex metabolic disturbance characterized by hyperglycemia due to insulin
deficiency or tissue resistance to the action of insulin.
Diabetes may be classified as Primary and Secondary.
Primary diabetes has no obvious cause.
It accounts for 95% of all cases.
Two clinical types are recognized: type 1 (insulin dependent) and type 2 (non-insulin dependent).
Secondary diabetes (5%) is caused by underlying disease
Destructive lesions of the pancreas (e.g., chronic pancreatitis)
Endocrine diseases (e.g., Cushing syndrome, glucagonoma syndrome, and acromegaly)
Drugs (e.g., diuretics such as thiazides)
Genetic syndromes (e.g., Turner syndrome and Down syndrome)
PATHOPHYSIOLOGY
A. Type I - IDDM
The pathogenesis of type 1 diabetes involves the interplay of genetic and environmental factors.
Genetic factors
Of these, the principal susceptibility locus for type 1 diabetes resides in the chromosomal region
that encodes the class II MHC molecules on 6p21 (HLA-D).
Between 90% and 95% of white patients with type 1 diabetes have HLA-DR3, or DR4, or both, in
contrast with about 40% of normal subjects, and 40% to 50% of patients are DR3/DR4
heterozygotes, in contrast with 5% of normal subjects.
Environmental factors
Evidence suggests that environmental factors, especially infections, may be involved in type 1
diabetes.
It has been proposed that certain viruses (mumps, rubella, and coxsackie B viruses, in particular)
may be an initiating trigger, perhaps because some viral antigens are antigenically similar to beta cell
antigens (molecular mimicry), leading to bystander damage to the islets during the bodys immune
response.
Immune mechanisms have been implicated in the pathogenesis of type 1 diabetes.
It is assumed that the cytotoxic T cells destroy the islets of Langerhans, thus causing an absolute
deficiency of insulin.
Type 1 diabetes is associated with a number of autoimmune diseases.
These patients also have antibodies to insulin and beta cells of the islets.
B. Type II NIDDM
Type 2 diabetes is a prototypical complex multifactorial disease.
Environmental factors, such as a sedentary life style and dietary habits play a role.
Genetic factors are also involved in the pathogenesis, as evidenced by the disease concordance rate
of 35% to 60% in monozygotic twins; however there is no association with MHC molecules.
Type 2 diabetes is caused by a combination of peripheral insulin resistance and inadequate
compensatory responses by pancreatic -cells (relative insulin deficiency).
MORPHOLOGY
Pancreas: Findings are variable.
Type 1: Islet number and size are reduced and a lymphocytic infiltrate (insulitis) may be present.
Type 2: Subtle reduction in islet cell mass may be accompanied by amyloid deposition, occasionally
effacing the islets.
20

 Diabetic macrovascular disease is manifested as accelerated atherosclerosis in the aorta and

large and medium-sized arteries; hyaline arteriolosclerosis is more prevalent and severe.
Diabetic microangiopathy is reflected by diffuse basement membrane thickening, most evident in
the capillaries of the skin, skeletal muscle, retina, renal glomeruli, and renal medulla.
Such capillaries are more leaky than normal to plasma proteins.
Basement membrane thickening can also affect nonvascular structures (e.g., renal tubules, Bowman
capsule, peripheral nerves, and placenta).
The microangiopathy underlies the development of diabetic nephropathy, retinopathy, and some
forms of neuropathy.
Diabetic nephropathy involving the glomerulus includes
(i) diffuse basement membrane thickening,
(ii) mesangial sclerosis consists of diffuse increase in mesangial matrix,
(iii) nodular glomerulosclerosis (Kimmelstiel-Wilson lesion) The glomerular lesions take the form of
ovoid or spherical, often laminated, nodules of matrix situated in the periphery of the glomerulus.
(iv) exudative lesions.
(v) Vascular effects include renal artery atherosclerosis and arteriolosclerosis with hypertension.
(vi) There is increased incidence of infections, including pyelonephritis and sometimes necrotizing
papillitis.
Diabetic retinopathy
The retinal vasculopathy of diabetes mellitus can be classified into background (preproliferative)
diabetic retinopathy and proliferative diabetic retinopathy.
Background retinopathy is characterised by microaneurysms; proliferative retinopathy involves
neovascularisation or formation of new vessels that breach the internal limiting membrane of the
retina.
Diabetic neuropathy is a combination of direct neural injury as well as microvascular ischemia
COMPLICATIONS OF DIABETES
The most important complications of this disorder are:
Atherosclerosis
Arterial hypertension
Diabetic nephropathy
Diabetic retinopathy
Peripheral neuropathy
Cataracts
PATHOGENESIS
At least three distinct metabolic pathways have been implicated in the deleterious effects of
persistent hyperglycemia on peripheral tissues, namely
(i) Formation of Advanced Glycation End Products.
Advanced glycation end products (AGEs) are formed as a result of nonenzymatic reactions between
intracellular glucose-derived substances with the amino groups of both intracellular and extracellular
proteins. The natural rate of AGE formation is greatly accelerated in the presence of hyperglycemia.
This cross-linking decreases protein removal while enhancing protein deposition. AGE-modified
matrix components also trap nonglycated plasma or interstitial proteins.
In large vessels, trapping of LDL, for example, retards its efflux from the vessel wall and enhances
the deposition of cholesterol in the intima, thus accelerating atherogenesis.
In capillaries, including those of renal glomeruli, plasma proteins such as albumin bind to the
glycated basement membrane, accounting in part for the basement membrane thickening that is
characteristic of diabetic microangiopathy.
(ii) Activation of Protein kinase C
Activation of intracellular protein kinase C (PKC) by Ca2+ ions and the second messenger diacyl
glycerol (DAG) is an important signal transduction pathway in many cellular systems. Intracellular
hyperglycemia stimulates the de novo synthesis of DAG from glycolytic intermediates, and hence
21

causes activation of PKC.

Some effects of AGEs and activated PKC overlap, and both contribute to the long-term
complications of diabetic microangiopathy.
(iii) Disturbances in Polyol pathways
In some tissues that do not require insulin for glucose transport (e.g., nerves, lenses, kidneys, blood
vessels), persistent hyperglycemia in the extracellular milieu leads to an increase in intracellular
glucose.
This excess glucose is metabolized by the enzyme aldose reductase to sorbitol, a polyol, and
eventually to fructose, in a reaction that uses NADPH (the reduced form of nicotinamide
dinucleotide phosphate) as a cofactor.
NADPH is also required by the enzyme glutathione reductase in a reaction that regenerates reduced
glutathione (GSH). GSH is one of the important antioxidant mechanisms in the cell, and any
reduction in GSH increases cellular susceptibility to oxidative stress.

II. Write notes on:

1. Biliary Cirrhosis
A disorder of bile ducts progressing to cirrhosis.
The 3 major disorders of bile ducts include
(i) Primary biliary cirrhosis
(ii) Secondary biliary cirrhosis
(iii) Primary sclerosing cholangitis
We shall discuss primary and secondary biliary cirrhosis here.
Primary biliary cirrhosis is an autoimmune disease. Cirrhosis develops because of autoimmune
destruction of intrahepatic bile ducts and fibrous repair of these lesions.
Secondary biliary cirrhosis develops in response to chronic bile duct obstruction. Biliary stasis leads
to the destruction of bile ducts and fibrous repair, which ultimately subdivides the liver into small
nodules typical of cirrhosis.

2. Pathogenesis of essential hypertension

22

Hypertension represents an elevation in systolic and/or diastolic blood pressure.

Essential hypertension is characterized by a chronic elevation in blood pressure that occurs without
evidence of other disease (Idiopathic), and secondary hypertension by an elevation of blood
pressure that results from some other disorder, such as kidney disease.
Pathogenesis
1. The pathogenesis of essential hypertension is thought to reside with the kidney and
a) its role regulating vascular volume through salt and water elimination;
Reduced renal sodium excretion in the presence of normal arterial pressure may be a key initiating
event in essential hypertension and, indeed, a final common pathway for the pathogenesis of
hypertension.
Decreased sodium excretion may lead sequentially to an increase in fluid volume, increased cardiac
output, and peripheral vasoconstriction, thereby elevating blood pressure.
b) the renin-angiotensin-aldosterone system through its effects on blood vessel tone, regulation of
renal blood ow, and salt metabolism;
c) and the sympathetic nervous system, which regulates the tone of the resistance vessels.
Vasoconstrictive influences, such as factors that induce vasoconstriction or stimuli that cause
structural changes in the vessel wall, can lead to an increase in peripheral resistance and may also
play a role in primary hypertension. Moreover, chronic or repeated vasoconstrictive influences could
cause thickening and rigidity of the involved vessels.
The medications that are used in the treatment of hypertension exert their effects through one or
more of these regulatory mechanisms.
2. Although single gene disorders in the above pathways are rare causes of hypertension, it is
apparent that subtle variations in their activity might influence blood pressure in the broader
population:
Mutations in enzymes that influence aldosterone synthesis (11b-hydroxylase, 17a-hydroxylase)
lead to increased aldosterone production
Mutations in the renal epithelial Na+ channel protein lead to increased sodium resorption (Liddle
syndrome).
3. Environmental factors can modify the impact of genetic determinants.
Stress, obesity, smoking, physical inactivity, and heavy consumption of salt have all been implicated
as exogenous factors in hypertension.
Indeed, evidence linking the level of dietary sodium intake with the prevalence of hypertension in
different population groups is particularly impressive. Moreover, in both essential and secondary
hypertension, heavy sodium intake augments the condition.
To summarize, essential hypertension is a complex, multifactorial disorder.
Although single gene disorders can be responsible for hypertension in rare cases, it is unlikely that
such mutations are a major cause of essential hypertension. It is more likely that essential
hypertension results from interactions of mutations or polymorphisms at several loci that influence
blood pressure, with a variety of environmental factors (e.g. stress, salt intake).
3. Polycystic kidney disease.
Two forms of Polycystic kidney disease (PCKD) are known to occur.

23

4. Gall stones
Also referred to as Cholelithiasis
There are 2 basic types of gallstones, each having a distinct pathogenesis.
Pathogenesis:
Bile formation in the liver:
Cholesterol is insoluble in water. When secreted by hepatocytes into the bile, it is held in solution by
the combined action of bile acids and lecithin and is carried in the form of mixed lipid micelles. If bile
has too much cholesterol or is decient in bile acids, it becomes supersaturated in cholesterol. Bile
from people who have cholesterol gallstones contains more cholesterol and fewer bile salts as it
leaves the liver than bile of normal persons.
The supersaturated cholesterol precipitates as solid crystals to form stones (lithogenic bile).
Local factors in the gallbladder: Bile in the gallbladder from patients with gallstones crystallizes
more easily than normal. Pronucleating biliary proteins and hypersecretion of gallbladder mucus
accelerate cholesterol precipitation from gallbladder bile.
Gallbladder motility: Impaired gallbladder motor function leads to bile stasis and permits biliary
sludge to form. This sludge progresses to macroscopic stones.
Pigment stones form in the setting of increased unconjugated bilirubin (most commonly due to
chronic hemolytic conditions) and precipitation of calcium bilirubin salts. In underdeveloped
countries, pigmented stones are often formed because biliary infections (e.g., with Escherichia coli,
Ascaris lumbricoides, or Opisthorchis sinensis) promote bilirubin glucuronide deconjugation

24

Morphology
Cholesterol stones arise exclusively in the gallbladder, and are classically hard and pale yellow;
bilirubin salts can impart a black color. When composed predominantly of cholesterol, they are
radiolucent; calcium carbonate deposition in 10% to 20% of stones is sufficient to render them
radiopaque. Single stones are ovoid; multiple stones tend to be faceted.
Pigmented stones can be black (sterile gallbladder bile) or brown (with infection); both are soft
and usually multiple, and 50% to 75% of pigmented stones are radiopaque.
Clinical Features
Roughly 70% to 80% of gallstone patients are asymptomatic throughout life;
Symptoms include spasmodic, colicky pain due to passing stones in the bile ducts (smaller stones
cause symptoms more commonly than do large stones).
Associated gallbladder inflammation (cholecystitis) generates right upper abdominal pain.
Clear mucinous secretions in an obstructed gallbladder distend the gallbladder (mucocele).
There is also increased risk for gallbladder carcinoma.

III. Short answers on:

1. Good pasture syndrome
This pulmonaryrenal disease is caused by antibodies that react with type IV collagen in the
glomerular and pulmonary vascular basement membranes.
It is characterized by the simultaneous appearance of proliferative, usually rapidly progressive
glomerulonephritis and necrotizing hemorrhagic interstitial pneumonitis.
25

Immunofluorescence staining shows linear staining pattern of the basement membranes.

Both the lung hemorrhage and the glomerulonephritis improve with intensive plasma exchange.
Otherwise, the prognosis is unfavorable.
2. Aschoff body
The Aschoff body is the characteristic granulomatous lesion of rheumatic myocarditis, developing
several weeks after symptoms begin.
This structure initially consists of a perivascular focus of swollen eosinophilic collagen surrounded by
lymphocytes, plasma cells and macrophages.
With time, the Aschoff body assumes a granulomatous appearance, with a central brinoid focus
associated with a perimeter of lymphocytes, plasma cells, macrophages and giant cells. Eventually,
the Aschoff body is replaced by a nodule of scar tissue.
3. Cervical Intraepithelial Neoplasia
Precancerous cervical epithelial histologic changes are classified as low-grade or high-grade
squamous intraepithelial lesions (LSIL and HSIL, respectively).
More than 80% of LSIL and 100% of HSIL lesions are associated with high-risk HPV; HPV 16 is the
most common type associated with both.
LSIL show only mild dysplasia, involving the more basal layers of the epithelium. While associated
with productive HPV infection, there is no significant alteration of the host cell cycle. Approximately
60% of LSIL spontaneously regress within 2 years, while another 30% persist over that period; only
10% progress to HSIL, and LSIL does not proceed directly to invasive carcinoma.
It is therefore not treated like a premalignant lesion.
HSIL exhibit moderate to severe dysplasia and involve progressively more of the epithelial
thickness; this category also includes carcinoma in situ.
There is further HPV-driven deregulation of the cell cycle, with increased proliferation, decreased
epithelial maturation, and diminished viral replication.
Approximately 30% of HSIL will regress over 2 years, 60% will persist, and 10% will progress to
carcinoma within a 2-10 year period.
Early detection of cervical dysplasia
Cervical precancerous lesions are associated with abnormalities in cytologic preparations (Pap
smears) that can be detected long before any abnormality is visible on gross inspection.
Early detection of dysplastic changes is the rationale for the Papanicolaou (Pap) test, in which cells
are scraped from the transformation zone and examined microscopically. To date, the Pap smear
remains the most successful cancer screening test ever developed
The recently introduced quadrivalent HPV vaccine for types 6, 11, 16, and 18 is very effective in
preventing HPV infections, which is expected to greatly lower the frequency of genital warts and
cervical cancers associated with these HPV serotypes.
Despite its efficacy, the vaccine does not supplant the need for routine cervical cancer screeningmany at-risk women are already infected, and the vaccine protects against only some of the
serotypes.
4. Henoch Schonlein Purpura
This is a systemic hypersensitivity response due to immune complex deposition and characterized
by purpuric rash, abdominal pain, polyarthralgia, and acute glomerulonephritis.
It can occur at any age but typically presents in children between the ages of 3 and 8 years; findings
include purpuric skin lesions (due to a vasculitis), abdominal symptoms (e.g., pain, vomiting,
bleeding), arthralgia, and GN with a combination of hematuria, nephritic syndrome, and/or
nephrotic syndrome.
Morphology of glomerular lesions
Glomerular lesions vary from focal mesangial proliferation to crescentic GN but are always
associated with mesangial IgA deposition.
Although the course is variable, the overall prognosis is usually excellent; recurrent hematuria can
persist for years.
26

5. Cartilage forming bone tumors

Cartilage tumors account for the majority of primary bone tumors and are characterized by the
formation of hyaline or myxoid cartilage; fibrocartilage and elastic cartilage are rare components. As
in most types of bone tumors, benign cartilage tumors are much more common than malignant
ones.

27

PATHOLOGY II AUGUST 2015

Elaborate on
1. 50 years / Male admitted in emergency care with chest pain, profuse sweating and Rapid pulse.
What is your diagnosis? Describe the Etiopathogenesis, Morphology and Complications of the
above mentioned disease.
The clinical picture is suggestive of acute myocardial infarction.
Myocardial infarction (MI) is myocyte cell death caused by vascular occlusion.
A. RISK FACTORS

B. ETIOPATHOGENESIS
Most myocardial infarcts are caused by Coronary artery occlusion by thrombus on preexisting
atherosclerotic plaque.
MIs are due most commonly to intraplaque hemorrhage, plaque erosion, or plaque rupture with
superimposed thrombosis.
In 10% of cases, vascular occlusion is a consequence of vasospasm or embolization in the coronary
circulation or due to smaller vessel obstruction (e.g., vasculitis, amyloidosis, sickle cell disease, etc.).
SUBENDOCARDIAL INFARCT
A subendocardial infarct affects the inner one third to one half of the left ventricle.
It may arise within the territory of one of the major epicardial coronary arteries or it may be
circumferential, involving subendocardial distributions of multiple coronary arteries.
Subendocardial infarction generally results from hypoperfusion of the heart.
It may be due to atherosclerosis in a specic coronary artery, or it may develop in disorders that
limit myocardial blood ow globally, such as aortic stenosis, hemorrhagic shock or hypoperfusion
during cardiopulmonary bypass.
Most subendocardial infarcts do not arise as a consequence of occlusive coronary thrombi, although
small particles of plateletbrin thrombus may be seen in the epicardial coronary artery that
supplies the region of infarction.
Thus for circumferential subendocardial infarction caused by global hypoperfusion of the
myocardium, coronary artery stenosis need not be present.
Because necrosis is limited to the inner layers of the heart, complications arising in transmural
infarcts (e.g., pericarditis and ventricular rupture) do not follow subendocardial infarction.
TRANSMURAL INFARCT
A transmural infarct involves the full left ventricular wall thickness, usually after occlusion of a
coronary artery by atherosclerotic thrombus.
As a result, transmural infarcts typically conform to the distribution of one of the three major
coronary arteries.
Right coronary artery: Occlusion of the proximal portion of this vessel results in an infarct of the
posterior basal region of the left ventricle and the posterior third to half of the interventricular
septum (inferior infarct).
LAD coronary artery: Blockage of this artery produces an infarct of the apical, anterior and
anteroseptal walls of the left ventricle.
Left circumex coronary artery: Obstruction of this vessel is the least common cause of
myocardial infarction and leads to an infarct of the lateral wall of the left ventricle.
Myocardial infarction does not occur instantaneously.
28

Rather, it rst develops in the subendocardium and progresses as a wavefront of necrosis from
subendocardium to subepicardium over the course of several hours.
Transient coronary occlusion may cause only subendocardial necrosis, whereas persistent occlusion
eventually leads to transmural necrosis.
The goal of acute coronary interventions (pharmacologic or mechanical thrombolysis) is to interrupt
this wavefront and limit myocardial necrosis.
Subendocardial vs transmural infarct

In chronic cardiac hypoperfusion, extensive collateral circulation, which preferentially supplies the
outer or subepicardial layer, often limits an infarct to subendocardial myocardium.
However, in fatal cases of acute myocardial infarction, transmural infarcts are more common than
those restricted to the subendocardium.
Infarcts involve the left ventricle much more commonly and extensively than the right ventricle.
This difference may be partly explained by the greater workload imposed on the left ventricle by
systemic vascular resistance and the greater thickness of the left ventricular wall.
Right ventricular hypertrophy (e.g., in pulmonary hypertension) increases the incidence of right
ventricular infarction.
C. MORPHOLOGY
Macroscopic Characteristics of Myocardial Infarcts
The early stages of myocardial infarction have been characterized most thoroughly in experimental
animals.
Within 10 seconds after ligation of a coronary artery, the affected myocardium becomes cyanotic
and, rather than contracting, bulges outward during systole. If the obstruction is promptly relieved,
myocardial contractions resume and no anatomic damage ensues, although contractility may be
depressed in the postischemic tissue for many hours (stunned myocardium) as a result of the
deleterious effects of reactive oxygen species formed upon reperfusion of acutely ischemic
myocardium.
This reversible stage continues for 20 to 30 minutes of total ischemia, beyond which time damaged
myocytes progressively die.
THE FIRST 24 HOURS: Electron microscopy is required to discern the earliest morphologic features
of ischemic injury.
Reversibly injured myocytes show subtle changes of sarcoplasmic edema, mild mitochondrial
swelling and loss of glycogen (the ultrastructural correlates of stunned myocardium).
After 30 to 60 minutes of ischemia, when myocyte injury has become irreversible, mitochondria are
greatly swollen with disorganized cristae and amorphous matrix densities
The nucleus shows clumping and margination of chromatin and the sarcolemma is focally disrupted.

29

II. Write notes on

1. Crescentic Glomerulonephritis
Crescentic or Rapidly progressive glomerulonephritis (RPGN) is characterized clinically by a rapid,
progressive renal decline. RPGN is divided into three broad groups based on immunologic findings;
in each group, diseases can be associated with known disorders,
although roughly 50% are idiopathic.

Pathogenesis
Type I RPGN (20% of RPGN) is an anti-GBM disease characterized by linear IgG (and C3) GBM
deposits. In some cases, the anti-GBM antibodies cross-react with pulmonary alveolar basement
30

membranes to produce pulmonary hemorrhages (Goodpasture syndrome). The reason for

autoantibody formation is unknown, although a high prevalence of certain HLA haplotypes suggests
a genetic predilection; solvent exposures or virus infections have been implicated as the inciting
trigger in susceptible hosts.
Type II RPGN (25% of RPGN) is an immune complexmediated disease. It can be a complication of
any of the immune complex nephritides, including postinfectious GN.
Immunofluorescence shows characteristic granular staining; besides crescent formation, there is
often glomerular cellular proliferation.
Type III RPGN (pauci-immune type) (more than 50% of RPGN) is characterized by the absence of
anti-GBM antibodies or immune complexes.
Instead, patients typically have circulating antineutrophil cytoplasmic antibody (ANCA), associated
with a systemic vasculitis.
In idiopathic cases, more than 90% of patients have elevated ANCA titers. It is not yet clear that
the ANCAs are causal in any of the type III RPGN.

A, Focal and segmental necrotizing glomerulonephritis. RPGN typically begins by causing focal and segmental necrosis
(Nec) of glomerular capillary loops, associated with a localized inflammatory exudate. The inflammatory cells and fibrin
cross through the defect of the basement membrane into the urinary space (US). B, Crescentic glomerulonephritis.
Exudate in the urinary space evolves into a crescent (Cr), which compresses the collapsed glomerular capillaries (cap).

Morphology
RPGN histology is characterized by focal glomerular capillary necrosis and distinctive crescents
formed by parietal cell proliferation and inflammatory cell migration into Bowman space. With time,
crescents can undergo sclerosis.
Immunofluorescence reveals linear staining in anti-GBM disease, granular deposits in immune
complex disease, and little to no staining for pauci-immune disease.
EM in RPGN classically exhibits distinct ruptures in the GBM; subepithelial electron-dense deposits
can also occur in type II disease.
Clinical Course
All forms of RPGN typically present with hematuria, red cell casts, moderate proteinuria, and
variable hypertension and edema.
In Goodpasture syndrome, the course may be dominated by recurrent hemoptysis.
Serum analyses for anti-GBM, antinuclear antibodies, and ANCA are diagnostically helpful.
Renal involvement is usually progressive over the course of a few weeks, culminating in severe
oliguria.
2. H. Pylori gastritis.
Gastritis is an inflammation of the mucosa of the stomach. It is a common disease that may occur in
an acute or a chronic form.
Morphologically, acute gastritis typically presents with shallow erosions of the mucosa (erosive
gastritis).
Chronic gastritis may be erosive or nonerosive.
Chronic nonerosive gastritis is inflammation of the mucosa of the stomach that may be caused by
immunologic mechanisms, infection, and prolonged ingestion of drugs or alcohol or cigarette
smoking.
Several clinicopathologic forms of chronic gastritis are recognized:
Chronic type A gastritis (autoimmune gastritis)
31

Chronic type B gastritis (Helicobacter pylori gastritis).

H. pylori infection is a risk factor for peptic ulcer disease, gastric adenocarcinoma, and gastric
lymphoma.
Hypertrophic gastritis (Menetrier disease; in this rare form of gastritis, the gastric mucosa has giant
folds.)

Morphology
In early stages of the disease, it is possible to distinguish type A from type B gastritis histologically,
but in advanced stages, such a distinction is not always possible.
(i) In the early stages of autoimmune gastritis, the mucosa of the fundus and body is infiltrated with
lymphocytes and plasma cells.
(ii) Acute stages of H. pylori infection are associated with infiltrates of neutrophils in the glands and
the lamina propria.
(iii) H. pylori can be seen in the gastric glands, mostly in the pyloric antrum.
(iv) As the diseases progress, both forms of chronic gastritis are accompanied by:
Atrophy of gastric glands
Intestinal metaplasia
Lymphocytic follicles in the atrophic mucosa
In this advanced stage of the disease, it is difficult to find H. pylori, which does not survive in the
metaplastic intestinal glands.
Reliable histopathologic distinction of type A from type B chronic gastritis becomes impossible in the
diseases later stages.
Clinical Features
H. pylori can be diagnosed by antibody serologic test, urea breath test, bacterial culture, direct
bacterial visualization in gastric biopsy, or DNA-based tests.
3. Sex cord stromal tumors of ovary.
These tumors account for 10% of all ovarian tumors.
They occur at any age and commonly secrete steroid hormones.
These ovarian neoplasms are derived from the ovarian stroma, which in turn is derived from the
sex cords of the embryonic gonad.
Because the undifferentiated gonadal mesenchyme eventually produces structures of specific cell
type in both male (Sertoli and Leydig) and female (granulosa and theca) gonads, tumors resembling
all of these cell types can be identified in the ovary
Moreover, because some of these cells normally secrete estrogens (granulosa and theca cells) or
androgens (Leydig cells), their corresponding tumors may be either feminizing (granulosatheca cell
tumors) or masculinizing (Leydig cell tumors).
The most important sex cord stromal tumors are as follows

32

Prognosis of sex cord tumors

Most sex cord tumors are benign. Approximately 25% of all granulosa cell tumors are prone
to recur or metastasize during the 10-year period after diagnosis and are considered low-grade
malignant. Highly malignant tumors of this type are extremely rare. SertoliLeydig cell tumors also
may be occasionally malignant.
4. Diabetic Microangiopathy.
The important morphologic changes in Diabetes mellitus are related to the many late systemic
complications of diabetes. In individuals with tight control of diabetes, the onset might be delayed.
In most patients, however, morphologic changes are likely to be found in arteries (macrovascular
disease), basement membranes of small vessels (microangiopathy), kidneys (diabetic nephropathy),
retina (retinopathy), nerves (neuropathy), and other tissues. These changes are seen in both type 1
and type 2 diabetes.

III. Short answers on

1. Takayasu arteritis.
(i) Also known as giant cell aortitis or pulseless disease
(ii) Most often affects young adult women (<40 years) of East Asian descent
(iii) Affects aortic arch (30%) and its branches but also other parts of the aorta and even the
pulmonary artery; affected vessels have a thickened wall and narrowed lumen.
(iv) Histologically presents as granulomatous giant cell arteritis, similar to temporal arteritis
(v) Symptoms of ischemiavisual and neurologic symptoms and the absence of pulse.
(vi) Pulmonary hypertension may be present because of the involvement of pulmonary artery
(vii) Clinically the course may be variablerapid downhill course, 1 or 2 years, or slowly progressive
33

course
2. Zollinger Ellison syndrome
(i) Gastrin-secreting tumor (80% in the pancreas, 15% in the duodenum, and 5% in other sites)
(ii) Presence of Hypergastrinemia (demonstrable in blood)
(iii) Peptic ulcers, solitary or multiple. Diagnosis of ZollingerEllison syndrome is suspected if ulcers
are:
multiple
Unusual site (e.g., jejunum and Meckel diverticulum)
Resistant to standard ulcer therapy
Occur in the setting of multiple endocrine neoplasia
3. Familial Adenomatous Polyposis syndrome.
(i) It is an autosomal dominant hereditary tumor syndrome.
(ii) It is linked to deletion of the tumor suppressor gene called adenomatous polyposis coli (APC) on
chromosome region 5q21.
(iii) The colon contains numerous (>100) tubular adenomas.
(iv) Tumors are not present at birth but appear in childhood and become clinically evident in the
second decade of life
(v) Adenocarcinoma develops in all patients. By age 40 years, cancer is found in 100% of patients.
(vi) Prophylactic colectomy must be performed in midlife.
4. Pagets disease of breast.
(i) Paget disease of the breast is a term used for infiltrating ductal carcinomas involving the
epidermis of the nipple and the areola.
(ii) It can be recognized clinically as a reddened, moist, or scaly skin lesion resembling eczema.
(iii) Histologically, the epidermis appears infiltrated with large mucopolysaccharide-filled tumor
cells, which are most prominent in the basal portion of the epidermis. Tumor cells may form small
groups and extend to the surface, causing ulceration, often with superimposed infection.
(iv) The prognosis of Paget disease of the breast depends on the extent of the underlying infiltrating
ductal carcinoma.
5. Glioblastoma Multiforme.
(i) It is the most common glioma (60% of all gliomas), accounting for 15% of all intracranial tumors
(including metastases). It is a Grade IV astrocytoma.
(ii) The peak incidence in the 45- to 60-year-old age group, but it may occur in children, teenagers,
and very old people as well.
(iii) It may begin as a highly malignant glioblastoma multiforme (primary glioblastoma multiforme),
or it may develop from the progression of diffuse astrocytoma with early and frequent p53
mutations (secondary glioblastoma multiforme).
(iv) There is invasive growth; it may extend to the other side of the brain (bilateral butterfly
lesions seen by CT scan or at autopsy). It may be multifocal.
(v) Marked macroscopic and microscopic pleomorphism (note that it is called multiforme). Gross
examination shows areas of necrosis, hemorrhage, cystic change etc.
(vi) Microscopically, the diagnosis is made by recognizing the variegated pattern rather than a
specific anaplastic cell. Typically tumors show anaplasia, pleomorphism, necrosis, numerous
mitosis, and vascular-endothelial (glomeruloid) proliferation.
(vii) It has an extremely bad prognosis. Mean survival is 1 year, and only 1% of all patients survive 3
years.

34

BIBLIOGRAPHY
1. Robbins and Cotran Pathologic Basis of Disease, Eighth edition
2. Pocket Companion to Robbins and Cotran Pathologic Basis of Disease
Eighth edition
3. Underwoods Pathology, A Clinical approach, Sixth Edition
4. Robbins Basic Pathology, Ninth Edition
5. Rubins Pathology, Sixth edition
6. Dacie and Lewis, Practical Hematology, Eleventh edition
7. Concise Guide to Hematology, Schmaier and Lazarus
8. Hematology Lecture Notes, EPHTI

35