1

4. F A B classification of leukemia.
Leukemias
Definition: Group of malignant diseases arising from hematopoietic cells;
1. Etiology:
1. Herditory:
a. Hodgkins disease is 99% more in identical twins
b. Leukemias more common in same families
2. Genetic disorders: Inherited genetic factors with genomic instability:eg:
a. Fanconi anemia
b. Ataxia telangiectasia
c. Down syndrome
2

d. Wiscott Aldrich syndrome
3. Viral infection:
a. Human T cell Leukemia Virus-1(HTLV): T cell leukemia
b. Ebstein Bar virus: lymphoma
c. Herpes virus-8: Kaposis sarcoma
d. Hepatitis C: lymphoma
e. HIV: B-cell and Burkitts lymphomas
f. Helecobacter pylori: lymphoma of stomach
4. Environmental agents:
a. Ionizing radiation: Leukemias
b. Drugs:
i. Phenytoin: lekemias and lymphomas
ii. Cancer chemotherapy-leukemia
c. Gluten sensitivity: intestinal lymphoma
d. HIV: B cell lymphomas
5. Immune deficiency:
a. Congenital or acquired immune deficiency: leukemia and lymphoma
6. Iatrogenic Factors:
a. Radiotherapy- leukemia
2. Pathogenesis:
1. Malignant transformation of a single clone of cells belonging to lymphoid or myeloid series
due to a genetic damage to DNA; this is followed by proliferation of affected clone
2. Chromosomal translocation: eg: Philedelphia Chromosome t(9;22) in CML
3. Maturation defect: i.e failure to mature beyond myeloblast or lymphoblast;
4. Myelosupression: bone marrow is suppressed by the excessive cancer cells
5. Infiltration: bone marrow and liver, spleen, lymphnodes and CNS are infiltrated by leukemic
cells

Classification
Types of classification:
1. Historical classification
2. French American British classification (FAB)
3. WHO classification

I. Historical classification:



1. Leukemias: Acute in the sense the disease progresses rapidy and blast cells predominate in
blood smear; chronic in which disease progresses slowly and blast cells are not seen in early
smears
3

a. Acute myeloblastic leukemia (AML)
b. Acute lymphoblastic leukemia(ALL)
c. Chronic myeloid(myelocytic) leukemia(CML)
d. Chronic lymphocytic leukemia(CLL)
2. Lymphomas:
a. Hodgkin
b. Non Hodgkin
II. Present major classification:
1. Lymphoid neoplasm: arise from precursors of lymphocytes:
2. Myeloid neoplasm: arise from hematopoietic stem cells that give rise to:
3. Histiocytic neoplasms

FAB Classification:


1. WHO Classification of Lymphoid neoplasms:
1. Acute lymphoblastic leukemia, ALL
a. Precursor B cell neoplasm( blast cells):
i. Precursor B Lymphoblastic leukemia/lymphoma
b. Peripheral B cell neoplasm (mature cells):
i. Chronic lymphocytic leukemia (CLL)
ii. Follicular lymphomas
iii. Hairy cell leukemia
iv. Burkits lymphoma etc
c. Plasma cell neoplasms:
1. Plasmocytoma/Plasma cell myeloma
d. Precursor T cell neoplasm( blast cells): (Acute lymphoblastic leukemia, ALL)
i. Precursor T Lymphoblastic leukemia/lymphoma
ii. Peripheral T cell and NK cell neoplasm (mature cells):
iii. Adult T cell leukemia/lymphoma
iv. NK/T cell lymphoma
v. NK cell leukemia etc
e. Hodgkin lymphoma (Reed Sternberg cells + ve):
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i. Classical:
1. Nodular sclerosis
2. Mixed cellularity
3. Lymphocyte rich
4. Lymphocyte depletion
ii. Lymphocyte predominance
2. WHO classification of Classification of Myeloid neoplasm: 5 groups:
1. Myeloproliferative diseases
2. Myelodysplastic / Myeloproliferative diseases
3. Myelodysplastic syndromes (MDS)
4. Acute myeloid leukemia
5. Acute biphenotypic leukemia

1. Myeloproliferative diseases:
1. Chronic myeloid leukemia
2. Chronic neutrophilic leukemia
3. Chronic eosinophilic leukemia
4. Chronic idiopathic myelofibrosis
5. Polycythemia veera
6. Essential thrombocytosis
7. Chronic myeloproliferative diseases
2. Myelodysplastic / Myeloproliferative diseases:
1. Chronic myelomonocytic leukemia
3. Myelodysplastic syndromes (MDS):
1. Refractory anemia
2. Refractory anemia with sideroblasts
3. Refractory anemia with excess blasts
4. Myelodysplastic syndrome unclassified
4. Acute myeloid leukemia:
1. AML with recurrent cytogenetic abnormalities
2. AML with multilineage dysplasia
3. AML with MDS
4. AML, not otherwise classified:
a. AML minimally differentiated
b. AML without differentiation
c. AML with maturation
d. Acute monoblastic and monocytic leukemia
e. Acute erythroid leukemia
f. acute megakaryocytic leukemia
g. acute basophilic leukemia
h. Acute panmyelosis with myelofibrosis
i. Myeloid sarcoma
5. Acute biphenotypic leukemia

5

Blood and bone marrow pictures:
1. Acute lymphoblastic leukemia ALL: peak incidence at 2-5 years of age, and another peak in old
age
1. Blood and Peripheral smear:
a. Changes in WBC:
i. Total count may be very high 50-100x10or less than 10,000/microL
ii. Lymphoblasts:
1. Are seen in large no. (Convent party appearance)
2. The cells are round and small,
3. Cytoplasm is scanty and homogeneous;
4. Granules are absent;
5. Nucleus one or two nucleoli.
6. The cells are PAS/Sudan Black negative; acid phosphatase positive;
7. Some Markers:
a. CD 19 positive in B cell type
b. CD 7 positive in T cell type
iii. RBC: normochromic and normocytic anemia
iv. Platelets: thrombocytopenia
2. Bone marrow changes in ALL:
1. Lymphoblasts:
a. Are seen in large no. Counts more than 20% (WHO) and 30% (FAB) are diagnostic of ALL
b. Lymphoblasts are large cells; contain large round or indended nucleus; stippled with
nuclear chromatin; nuclear membrane is dense; nucleoli 1-2 are seen; cytoplasm is
scanty; it is basophilic and without granules;
c. Lymphoblasts are TdT and adenosine deaminase positive;
2. Erythropoietic series:reduced in no; megaloblasts and ring sideroblasts may be seen.
3. Megakaryocytes are reduced or absent.
4. Cytogenetics :
a. Aneuploidy in 75%
b. Philadelphia chromosome in 15%
5. Cell markers seen ALL:
a. Leukocyte common antigen
b. Positive sheep erythrocyte rosette test in B cell types

2. Acute Myeloblastic (myelogenous; myeloid) Leukemia (AML): median age 50 years; may
rarely occur in childhood.
1. Blood Picture:
a. Total Leukocyte count is raised; occasionally normal
b. Plenty of blast cells:
i. Blast cells are large in size
ii. Round or oval nucleus nearly filling the cell
iii. Abundant granular cytoplasm
iv. Auer rods are seen sometimes which are abnormal derivatives of primary
azurophilic granules
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v. Nuclear chromatin is delicate
vi. Nucleoli 3-5
vii. Cytochemistry:
1. Peroxidase and sudan black positive
2. Phosphatase negative
viii. Markers:
1. CD 19 negative
2. CD 7 Negative
3. CD 13 and 33 positive
c. Polymorphs and few lymphocytes are seen
d. RBC: normochromic normocytic anemia
e. Platelets: severe thrombocytopenia
2. Bone Marrow:
a. Maroow is hypercellular; occasionally hypocellular
b. Myeloblasts are predominant; > 20%(WHO) or > 30% FAB is diagnostic of ALL
c. Immature granulocytes, erythroblasts, megaloblastic erythroblasts and sideroblasts are
seen
d. Plasma cells and monocytes are moderately elevated
e. Megakaryocytes are reduced or absent
f. Cytogenetics:
i. Presence of cells with aneuploidy; translocation or inversions
ii. Philadelphia chromosome in 3% cases
g. Cytochemistry:
i. Myeloperoxidase, sudan black, PAS are positive in M6 cells
ii. Non specific esterase positive in M4 and M5
iii. Acid phosphatase positive in M4 and M5
h. Biochemistry:
i. Serum muramidase elevated in M4 and M5
ii. Serum uric acid elevated in general

3. Chronic lymphocytic (lymphatic)leukemia (CLL):over 50 years of age with male
preponderance; hepatosplenomegaly, lymphadenopathy and anemia
a. Blood picture:
i. Normochromic and normocytic anemia; mild reticulocytosis; 20% coombs have
positive hemolytic anemia
ii. Absolute neutrophil count is within normal range; granulocytopenia in advanced
stage
iii. Marked leukocytosis(50,000-200,000/l)
iv. 90% of leukocytes is mature small lymphocytes; degerated lymphocytes are
called smudge or basket cells
v. Platelets is normal or moderately reduced
b. Bone marrow:
i. Increased lymphocyte count
ii. Reduced myeloid precursors
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iii. Reduced erythroid precursors
c. Other tests:
i. Lymph node: Replacement of lymphnode with diffuse small lymphocytes
ii. Erythrocyte rosette test: positive with mouse RBCs
iii. Markers: CD5 is positive for immunoglobulins
iv. Coombs +ve in 20%
4. Chronic Myeloid (myelocytic) leukemia (CML): peak in 3-4 decades of life; juvenile form in
children; anemia, weight loss, bleeding, priapism, lymphadenopathy and splenomegaly.
a. Blood: 3 phases: chronic, accelerated and blast crisis phases
i. RBC: Normocytic normochromic anemia
ii. WBC:
1. General: Marked leukocytosis: 200 000/L; myelocites present
2. Chronic Phase:
a. Myeloblast <10%
b. Basophils > 10%
3. Accelerated phase:
a. Increasing anemia
b. Blasts 10-20%
c. Low platelet count
4. Blast crisis:
a. Blasts > 20%
iii. Platelet: normal or raised in the cases
b. Bone marrow:
i. Hypercellular marrow
ii. Myeloid predominance
iii. Increased myeloid erythroid ratio
iv. Myelocytes predominance
v. Erythropoiesis: reduction in erythropoietic series
vi. Megakaryocytes: more and smaller
vii. Cytogenetics:
1. Philedelphia chromosome in 90 to 95%; it is reciprocal translocation of
long arm of 22 and long arm of chromosome 9
viii. Cytochemistry:
1. Neutrophil alkaline phosphatase is reduced; increased in leukaemoid
reaction
ix. Other findings:
1. Serum B 12 elevated
2. Serum uric acid elevated

S.N: Philadiphia chromosome:
The Philadelphia chromosome is made when the Abl gene on chromosome 9 is mistakenly
transferred to chromosome 22 and attaches to the Bcr gene. This creates a new fusion gene
called Bcr-Abl which leads to leukemic process.

8



S.N: Leukemoid reaction:
The term leukemoid reaction describes an elevated white blood cell count, that is a
physiologic response to stress or infection (as opposed to a primary blood malignancy, such as
leukemia)
Leukemoid reaction may be myeloid (more common) or lymphoid
Causes:
1. Infections:
Staphylococcal pneumonia
Meningitis
Diphtheria
Any sepsis
Endocarditis
Septic abortion
2. Toxins:
Eclampsia
Mercury poisoning
Burns
3. Malignancy:
Multiple myeloma
Myelofibrosis
Hodgkin
CLL
4. Severe Hemorrhage and hemolysis
Lab:
1. Myleloid luekemoid reaction:
Leukocytosis upto 100,000/L
Blasts < 5%
Toxic granulation or Dohle bodies in Neutrophils in infections
Philadelphia chromosome negative
No organ infiltrations
2. Lymphoid leukemoid reaction:
Infections:
Pertusis
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Infectious mononucleolus
Cytomegalo virus
Chickenpox
Measles
Tuberculosis
Lab:
Leukocyte count upto 100,000/L
Mostly mature lymphocytes
Mimics CLL
Difference between leukaemoid reaction and leukemia
S.No Leukaemoid reaction Leukemia
1 The infection leading to leukemoid
reaction will be present
Splenomegaly, lymphadenopathy and bleeding
tendency are evident
2 Leukocyte count upto 100,000/L

Leukocyte count often more than 100,000/L

3 Immature cells are less Immature cells are more
4 WBC may show toxic granulation due to
infection
Absent
5 Anemia is less More
6 Bone marrow: less hypercelluar More hypercellular
7 Autopsy: no organ infiltration of blasts Present in liver, spleen, CNS etc



4. A 35 years, old man was admitted with history of painless cervical and axillary
lymphadenopathy. He had history of loss of weight, fever and night sweating and was found to
have cutaneous anergy. No hepatosplenomegaly.
a) What is your most probable diagnosis?
b) Give the classification of the condition.
c) Describe the morphology of any two types.
Lymphomas
1. These are malignant neoplasm derived from lymphocytes, usually in lymph nodes but also in
other organs or in soft tissue.
Unlike the leukemia the tumor cells do not appear in the blood in detectable numbers
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2. TYPES OF LYMPHOMAS:
The lymphomas are broadly grouped into two types:
A. Non-Hodgkins lymphomas (60%)
B. Hodgkins lymphoma (also known as Hodgkin's disease) (40%)
3. Cells of origin:
The non- Hodgkins lymphomas are derived from either B or T lymphocytes. The cell of origin in
Hodgkins lymphoma is now known to be of B-cell origin

Hodgkins disease
1. Neoplasm (lymphoma) arising from lymph node with secondary involvement of extra nodal sites
2. Age 15-35 yrs with male preponderance; another peak at 5th decade
3. Symptoms include
painless swelling of the lymph nodes in the neck, armpits, or groin
fever and chills
night sweats
weight loss
loss of appetite
itchy skin
nodes are painful after alcohol consumption
4. Classifications:
1. Conventional:
a. Non Hodgkin- heterogynous group
b. Hodgkin (Reed Sternberg cell +ve)
2. Rye classification:
1. Lymphocyte predominant type
2. Nodular sclerosis
3. Mixed cellularity
4. Lymphocyte depletion type
3. Modified WHO classification:
1. Classic Hodgkin Disease:
a. Lymphocyte predominant type
b. Nodular sclerosis
c. Mixed cellularity
d. Lymphocyte depletion type
2. Nodular lymphocyte predominant Hodgkin disease
6. Reed-Sternberg cell:
1. These are neoplastic cells of HD
2. <5% of the total tumor cell mass.
3. Most Reed-Sternberg cells are of B-cell origin, derived from lymph node germinal centers but
no longer able to express antibodies.
4. Types of RS cells:
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a. Classic RS: large cell with bilobed nucleus in mirror image pattern; each nucleus
contains a prominent nucleolus with clear halo around it giving a owl eye
appearance
b. Lacunar type: smaller; pericellular space is seen; present in nodular sclerosis
c. Polyploid type: large and lobulated pop corn like nucleus; seen in lymphocyte
predominance
d. Pleomorphic: atypical nuclei and pleomorphic; seen in lymphocyte depletion
5. Origin: they arise from B cells;
6. Markers are CD 15 and CD 30
7. Gross appearance HD node:
a. Cervical, supraclavicular, axillary nodes are commonly involved.
b. Initially nodes are discrete, but later become matted due to surrounding infiltration.
c. C.S: grey white and fish flesh like; nodular due to scarring in nodular sclerosis; spots
of necrosis in mixed cellularity and lymphocyte predominance.
8. Microscopic (morphology):
I. Classic HD:
a. Lymphocyte predominant type:
i. Proliferation of small lymphocytes mixed with histiocytes
1. Nodular form: large nodules seen
2. Diffuse form: no nodular pattern seen
ii. RS cells few in no
d. Nodular sclerosis: show
i. Bands of collagen: fibrous tissue in variable amount
ii. Lacunar type RS cells with peri cellular halo
iii. Nodules between fibrous tissue contain lymphocytes, histiocytes,
eosinophils, Neutrophils, and plasma cells
e. Mixed cellularity type:
i. Lymph nodes are replaced by mixture of apparently normal cells:
lymphocytes, histiocytes, eosinophils, Neutrophils, and plasma cells
ii. Areas of fibrosis and necrosis may be seen
f. Lymphocyte depletion type:
i. Diffuse fibrotic variant: entire node is replaced by fibrous tissue appearing as
fibrillar hyaline material; few lymphocytes, atypical lymphocytes,
pleomorphic RS cells are present.
ii. Reticular variant: more cellular; few lymphocytes, large no. of atypical
histiocytes and few typical RS cells are seen.
II. Nodular-lymphocyte predominant type:
I. Newly described
II. Nodular appearance
III. Small lymphocytes predominance
IV. Few RS cells
V. CD 45 positive
VI. Chronic relapsing course
VII. May transform into large B cell NHL
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Non Hodgkin Lymphomas:
The types of NHL represent different stages in lymphocyte differentiation
85% are of B cell origin, the rest are T cell or null cell
Classification of NHL
1. Low grade (indolent)
o Long life expectancy if left untreated
o 85-90% present at stage III or IV disease
o Incurable
Types:
1. Small lymphocytic (similar to chronic lymphocytic leukaemia)
This lymphoma is slow growing and composed of small round lymphocytes with scant
cytoplasm and very few mitoses. They almost all of B-cell origin and express pan B-cell
markers, such as CD20, as well as CD5 and CD23. In time they may transform to more
aggressive forms of large cell lymphoma
2. Follicular lymphomas-
Further subdivided on the basis of the relative numbers small cleaved and large non-
cleaved cells in the follicles, into (a) small cleaved, (b) mixed or (c) large
2. Intermediate
Diffuse lymphomas- again subdivided on the same basis as the follicular lymphomas
into (a) small cleaved cell, (b) mixed or (c) large cell
3. High grade (aggressive)
o Life expectancy in weeks if not treated
o Potentially curable
o Types:
Lymphoblastic
Burkitts lymphom

Burkitt's lymphoma (BL) (Short notes)
Is a cancer of the lymphatic system (in particular, B lymphocytes).
Highly aggressive lymphoma
Usually found in extranodal sites or presenting as an acute leukaemia.
> 90% are E-B virus positive
EBV has trophism for B cells; considered as causative factor for Burkitts lymphoma
Currently Burkitt's lymphoma can be divided into three main clinical variants; By morphology, it
is almost impossible to differentiate these three clinical variants:
o The African endemic,
o The sporadic and
o The immunodeficiency-associated variants.
1. The endemic variant:
o Occurs in equatorial Africa.
o Disease characteristically involves the jaw or other facial bone
2. The sporadic type:
o Jaw is less commonly involved, comparing with the endemic variant. Ileo-cecal region is
the common site of involvement.
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3. Immunodeficiency-associated Burkitt lymphoma:
o Is usually associated with HIV infection or occurs in the setting of post-transplant
patients who are taking immunosuppressive drugs.
o Actually, Burkitt lymphoma can be the initial manifestation of AIDS.
Morphology
Consists of sheets of monotonous population of medium size lymphoid cells with high
proliferative activity and apoptotic activity.
The "starry sky" appearance seen under low power is due to scattered macrophages containing
dead body of apoptotic tumour cells.
Multiple myeloma (Myeloma)






1. It is malignancy of plasma cells; monoclonal proliferation of B-cells
2. peek incidence 50-60 years; more in males
3. Aetiology:
1. Radiation
2. Occupational exposure to petroleum products
3. Chromosomal deletions and translocations; Abnormalities are commonly found on
chromosome 13 and chromosome 11,
4. Oncogenes: MYC and RAS
4. Pathogenesis:
1. Multiple myeloma cells adhere to the stromal cells in the bone marrow; inhibit
osteoblastic activity.
2. Adhesion of the multiple myeloma cells stimulates production of interleukin-6, a growth
factor required for survival of the multiple myeloma cells.
3. Interleukin-6 stimulates increased osteoclastic activity
4. This results in bone lesions (lytic lesions), osteoporosis, and hypercalcemia
5. Multiple myeloma cells produce excessive monoclonal proteins - M proteins, which are
classified as heavy amino acid chains and light amino acid chains.
6. The M protein level is referred to as the M-spike in immune electrophoresis. In multiple
myeloma patients the M protein is most commonly Ig.G or IgA.
7. The light amino acid chains are of two types: kappa and lambda. Kappa is twice as
prevalent as lambda. When detected in the urine the light chain fragments are called
14

Bence-Jones proteins. They are followed as an indicator of disease activity and
progression.
5. Morphology: osseous and extra osseous lesions
1. It begins in bone marrow in 95% cases
2. Multiple bones are involved- skull, spine and pelvis
3. Normal marrow is replaced by reddish grey gelatinous tissue
4. In X-ray punched out appearance is characteristic
5. bone marrow aspiration may be a dry tap; biopsy required
6. Bone marrow:
1. Hyper cellular
2. >10% are myeloma cells: similar to plasma cells but vary in size; nuclus is
eccentric; unlike normal plasma cell its nuclear chromatin does not show car-
wheel pattern
3. Nucleoli are present
4. Cytoplasm is abundant with perinuclear halo; vacuolation and Russel bodies
containing antibodies
5. Variants of plasma cells:
Flame cells: red cytoplasm
Mott cells: contain grapelike cytoplasmic droplets


Plasma cell Myeloma cell: eccentric nucleus with halo; no cart weel



Normal Protein electrophoresis Myeloma- M spike in Gamma region
2. Extra osseous:
1. Atypical plasma cells in blood
2. Anaemia
3. Hyperviscocity of blood
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4. Nephrosis due to Bence-Jones proteinuria
5. Polyneuropathy
6. Pathologic fractures of bones
7. Systemic amyloidosis myeloma proteins
8. Hepato splenomegaly due to myeloma cells
Bence Jones Protein:
1. Multiple myeloma cells produce excessive monoclonal proteins - M proteins, which are
classified as heavy amino acid chains and light amino acid chains
2. The light amino acid chains are of two types: kappa and lambda. Kappa is twice as prevalent as
lambda. When detected in the urine the light chain fragments are called Bence-Jones proteins
3. Light chains (molecular weight 22,000 d) are polypeptides synthesized by plasma cells and
assembled with heavy chains to form the various classes of immunoglobulins, for example,
immunoglobulin G (IgG), immunoglobulin M (IgM), and immunoglobulin A (IgA).
4. Plasma cells normally produce a slight excess of light chains that are either excreted or
catabolized by the kidney
5. 1% of myeloma are nonsecretory: no Bence-Jones proteins in urine
6. Kappa light chains usually exist as monomers (22,000 d) and are therefore small enough to be
filtered through the glomerulus, but they may exist as dimers. Lambda light chains usually exist
as dimers (44,000 d) and, therefore, are less likely to be filtered and appear in urine.
7. Light-chain proteins appear in urine in high concentration either when the production of light-
chain proteins is markedly increased or when the ability of the proximal tubules to reabsorb all
the filtered protein is exceeded.
8. Since mostly excreted in urine they are not present in detectable amount in blood except in
renal failure.
9. They on heating precipitate at 40-60 C and redissolve at higher temperature
10. Causes:
1. Multiple myeloma
2. Plasmacytoma
3. Waldenstrom macroglobulinemia
11. Tests:
1. 5 ml of urine is mixed with 2-3 drops of acetic acid and heated in a water bath; at 40-
60C there will be cloudiness and precipitation; on further heating over 70C the
precipitate dissolves and reappear when cooling below 60 C
2. Serum electrophoresis demonstrates M-band
Multiple myeloma affecting kidney:
1. Tumour invasion: ureteric obstruction and renal hypertension
2. Hypercalcemia
3. Hyperurecemia
4. Amyloidosis
5. BJ proteinuria
6. Glomerular disease
Myeloma kidney (cast nephropathy)
1. Myueloma kidney is one of the several renal dysfunctions due to light chain proteinuria
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2. Light chains bind with Tamm-Horsfall mucoprotein, which is secreted by tubular cells in
ascending loop of Henle, forming casts
3. Light chains can precipitate in the tubules, leading to obstructing, dense, intratubular casts in
the distal and collecting tubules that may initiate a giant cell reaction
4. Multinucleated giant cells surround the casts which produces nephropathy
5. Light chain proteins also have direct toxic effect on renal epithelial cells
6. It may also be deposited in basement membrane to produce glomerulopathy

LABORATORY INVESTIGATION OF SUSPECTED MYELOMA
1. Diagnostic triad:
1. myeloma cells >10% in bone marrow
2. Lytic lesions in bones
3. M proteins in serum and urine
2. Serum proteins:
1. Rise in total serum proteins due to paraproteinemia (M proteins or abnormal
immunoglobulin e.g. Bence Jones proteins)
2. Normal IgG, IgA, IgM and albumin levels are low
3. Serum electrophoresis:
1. Spike produced by M proteins; in the region of IgG in 50%; IgA in 25%
2. Another 20 have only light chains in serum
3. No M-bands in non secretary myeloma(1%)


4. Serum viscocity:
Hyperviscocity in myeloma
The normal reference range is 1.4-1.8 Centipoises ; >5 in myeloma
Rouleaux formation is often present with increased serum viscosity.
5. Hypercalcemia
6. Hyperurecemia
3. Urine: Bence Jones proteins are present in urine; >6 gms/dL
4. Bone marrow:
1. Hyper cellular
2. >10% are myeloma cells: similar to plasma cells but vary in size; nuclus is
eccentric; unlike normal plasma cell its nuclear chromatin does not show car-
wheel pattern
3. Nucleoli are present
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4. Cytoplasm is abundant with perinuclear halo; vacuolation and Russel bodies
which contain antibodies
5. Variants of plasma cells:
Flame cells: red cytoplasm
Mott cells: contain grapelike cytoplasmic droplets


1. Polycystic kidney disease: PKD(short notes)
1. Renal parenchyma is converted into cysts of varying sizes
2. Two types:
1. Adult type: autosomal dominant (ADPKD)
2. Infantile type: autosomal recessive (ARPKD)
3. Adult type:
1. Incidence 1 in 400 to 1000
2. PKD gene is located is in chromosome 16 and rarely in 4
3. Bilateral and diffuse
4. Symptoms appear in 30-50 years of age
5. Morphology:
1. Bilaterally enlarged; lobulated; may weigh up to 4 kg
2. Cut surface show cysts in different size; contain straw yellow to reddish brown
material
3. Renal pelvis is distorted by cysts; do not communicate with each other( contrast
to hydronephrosis)
6. Histology:
1. Cysts are parts of nephrons
2. Epithelial lining of cysts are that tubules
3. Parts of glomerulus could be recognized among the cysts
4. Intervening normal renal parenchyma may be seen
5. Acquired inflammation due to pyelonephritis, nephrosclerosis etc may be seen


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7. Clinical:
1. Manifest in 30-50 years of age
2. Presents as hematuria and renal pain
3. Hypertension is common
4. Associated cystic changes in liver, panctreas and spleen etc may be present
5. Berry aneurysm of circle of Willis present in 15%
6. Acquired infections may further damage the kidney
2. Infantile type:
1. Autosomal recessive
2. 1 in 20,000 incidence
3. Mutation in chromosome 6-6p-21
4. Bilateral
5. Manifest at birth and renal failure in early childhood
6. Morphology:
1. Bilateral enlargement
2. Smooth surface and shape not distorted
3. Cut surface: small cysts extend radially to cortex; mostly normal parenchyma; pelvis and
ureters normal
7. Histology:
1. Total no of nephrons are normal
2. Sponge like cysts develop from collecting tubules and show cylindrical and secular
dilatation lined by cuboidal or columnar epithelium
3. Many glomeruli undergo cystic dilatation


8. Clinical:
1. Gross enlargement may interfere normal delivery
2. Renal failure occurs early
3. Associated cystic disease in liver may lead to congenital fibrosis, portal hypertension
and splenomegaly
4. Severely affected infants are often born with pulmonary hypoplasia and suffer from respiratory
compromise

Glomerulonephritis

19





Glomerulonephritis (Bright disease; nephritic syndrome)
1. Definition:
Renal diseases in which an immunologic mechanism triggers inflammation and proliferation of
glomerular tissue that can result in damage to the basement membrane, mesangium, or
capillary endothelium.
2. Classification:
1. Primary:
1. Acute:
1. Post streptococcal
2. Non streptococcal
2. Rapidly progressive
3. Minimal change disease
4. Membranous
5. Membrano proliferative
6. Focal proliferative
7. Focal segmental glomerulosclerosis
8. IgA nephropathy
9. Chronic GN
2. Secondary:
1. SLE
2. Diabetic nephropathy
3. Amyloid nephropathy
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4. Polyarteritis nodosa
5. Wageners granulomatosis
6. Goodpasture syndrome
7. Henoch-Schonlein purpura
8. Systemic infection: Bacterial endocarditis; Falciform malaria etc
9. Idiopathic mixed cryoglobulinemia
3. Hereditary nephritis:
1. Alports syndrome
2. Fabrys disease
3. Nail-patella syndrome
3. Etiopathogenesis of post streptococcal glomerulonephritis (PSGN):
1. Glomeruli consists of: endothelium, epithelium,mesangium and basement membrane(GBM)
2. Acute glomerulonephritis follows infection with certain strains of group A beta-hemolytic
streptococci (GABS). The ones that produce a clear zone of hemolysis around the colony are
called beta hemolytic streptococci;
3. GABS contain M, T and R proteins. Of these, the M protein is the nephritogenic antigen. It is
located in the bacterial cell wall
4. Among the M types, commonly identified nephritogenic strains are 12,4,1
5. It follows mostly skin infection but can also occur after throat infection with nephritogenic
strains
6. Evidence:
1. Low serum complement (C3) levels in the acute phase
2. High serum levels of antibodies to streptococcal antigens
3. Electron microscopy reveals lumpy-bumpy deposits on glomerular membrane and in
mesangium
7. Immune-mediated renal injury is a result of renal deposition of circulating immune complexes or
due to their in-situ formation or both
8. Glomerular inflammation follows which leads to complement (C3) activation by classic or more
probably alternate pathway
9. The immune complexes are deposited in the glomerulus produce structural and functional
changes by destruction of basement membrane and accumulation of inflammatory cells
Pathology:
1. Morphology:
1. Kidneys enlarge symmetrically
2. Petichial hemorrhages on the cortical surface give flea-bitten appearance
2. Light microscopy:
1. Glomeruli:
Enlarged and hypercellular glomeruli
Proliferation of mesangial, endothelial and occasionally epithelial cells
Infiltration of polymorphs and sometimes monocytes
2. Tubule:
Deposition of fibrin in tubular lumen and mesangium
RBCs in tubular lumen
3. Interstitium:
21

Edema and leukocytic infiltration in renal interstitium
4. Vessels:
No changes in blood vessels

3. Clinical:
1. Age incidence is 5-12 years
2. Symptoms develop 1-2 week following streptococcal infection
3. Oliguria and smoky urine
4. Edema is the most frequent manifesting symptom
5. Gross hematuria occurs at onset
6. Hypertension is the third cardinal feature
7. Salt and water retention
8. Complications:
1. CCF
2. Hypertensive encephalopathy
3. Acute renal failure
4. Progressive glomerulonephritis
9. Prognosis:
1. Complete recovery if there are no complications
4. Lab Diagnosis:
Urine
1. Urine output most is often reduced
2. proteinuria
3. Hematuria
4. Polymorphonuclear leukocytes and renal epithelial cells
5. Hyaline and/or cellular casts are almost always present.
6. RBC casts have been found in 60-85%
Streptococcal infection
1. Cultures from either the pharynx or skin may be positive
2. ASO, AH, anti-DNase B are positive
3. An ASO titter of 250 U or higher is highly suggestive of recent streptococcal infection.
Complement
1. The concentration of C3 has been found to be decreased in more than 90% of patients
Renal
1. The elevation in the serum concentrations of creatinine and BUN is usually modest,
although some patients may have severe azotemia (Blood urea nitrogen) at onset.
2. The electrolyte profile is usually normal;
3. Hyperkalemia and metabolic acidosis are in patients with significant renal functional
impairment. The same applies to hyperphosphatemia.
Blood
1. A mild anemia (normocytic, normochromic) is
2. WBC and platelet counts are usually normal, although an occasional patient exhibits a
leukocytosis; rarely, a mild thrombocytopenia may be present.

22


Short notes:

1. Definition:
Primary glomerular diseases are disorders in which the kidneys are the only or predominant
organ involved
2. Examples of Primary glomerular disease:
1. Post streptococcal GN
2. Cresentric GN
3. Membranous glomerulopathy
4. Focal segmental glomerulosclerosis
5. Memranoproliferative GN
6. IgA nephropathy
7. Chronic GN
3. Classification of types of glomerular disease:
1. Antibody mediated : Three forms of antibody mediated injuries:
1. In situ immune complex deposition:
1. Fixed or in situ : Intrinsic glomerular antigens
2. Planted: Antigens planted within the glomerulus
2. Circulating antigen antibody complexes:
1. Endogenous:
a. DNA, tumor antigens
2. Exogenous:
Infectious products
3. Cytotoxic antibodies
2. Cell mediated
3. Alternate complement pathway

Normal Post streptococcal

23






Membranous




4. In situ Immune complex disease
1. Fixed or in situ immune complex: Anti GBM antibody induced nephritis: two
experimental models:
i. Masugi model;
24

a. Antibodies are formed against antigens which are normal components of
GBM
b. Diffuse linear pattern of immune complex deposition along GBM
c. 5% of Nephritis belong to this model
d. Eg: Good pasture syndrome
ii. Heymann model:
a. Antibodies react with antigens in the basal surface of visceral epithelial cells
b. This is followed by complement activation
c. Immune complexes are formed and deposited along the sub epithelial
aspect of basement membrane in a granular pattern
d. Eg: membranous glomerulonephritis
2. Planted antigen antibody complex:
i. Bacterial, viral and parasitic products and other such antigens may get deposited in
glomerulus
ii. Antibodies bind to these antigens and induce complement activation leading to
immune complex formation and glomerular inflammation.
iii. Eg. Post streptococcal GN
3. Circulating antigen antibody complexes:
i. Endogenous: eg: SLE
i. Antigen from host tissue form antibody complexes and then get trapped in
glomeruli
ii. Complements are activated
iii. Glomerular injury occurs
iv. Eg: nephritis in SLE
ii. Exogenous:
i. Antigens are formed against infections like streptococci, Hepatitis B,
Treponema, Plasmodium etc
ii. Trapped in glomeruli followed by inflammation
iii. Eg: Nephritis associated with streptococci, Hepatitis B, Treponema,
Plasmodium etc
4. Cytotoxic antibodies:
i. Glomerular cells themselves may act as antigens
ii. Antibodies develop and immune complexes are formed
iii. Injury is caused by cytotoxic mechanism
5. Cell mediated injury:
iv. T cells get sensitized and together with activated macrophages can cause
glomerular injury
v. Cytokines and other mediators from T cells are responsible for this cytotoxic injury
vi. Example: pauci-immune glomerulonephritis
6. Alternate complement pathway:
1. The normal complement system consists of the classic and alternative pathways. The
classic pathway is activated by the interaction of C1 with an antigen-antibody complex.
This interaction results in the formation of C4b2a, which is the classic pathway C3b
25

convertase. The alternative pathway utilizes C3 and factors B and D to form the
alternative pathway convertase C3b,Bb.
2. Mainly Complement- 3 contributes to this type of injury
3. Immune complexes are found in the mesangium and subendothelial spaces, and they
trigger complement activation and the release of cytokines and chemokines. The release
of inflammatory mediators causes an influx of inflammatory cells and leads to mesangial
and endothelial cell proliferation.
4. Example : Memranoproliferative glomerulonephritis
7. Mediators of glomerular injury:
5. Cells:
1. Neutrophils and monocytes: release proteases which cause GBM degradation;
2. Macrophages and T lymphocytes and NK cells: produce variety of lymphokines
and other mediators
3. Platelets: release eicosanoids and growth factors
4. Mesangial cells: release cytokines, chemokines, eicosanoids and growth factors
etc
6. Soluble mediators:
1. Formation of C5b-C9 causes cell lysis
2. Interleukin-1 and TNF produce leukocyte adhesion and other effects
3. Fibrin leaks into Bowmans space and induce crescent formation
4. Plasminogen activator inhibitors induce thrombosis and fibrosis
8. Glomerular localization of antigen antibody complexes:
1. Immune complexes get deposited in mesangium, subenotheilal space, sub epithelial space
2. The deposits may be granular or diffuse linear pattern
3. Localization depends on molecular charge:
1. anionic : sub endothelial
2. cationic: sub epithelial
3. neutral: mesangium
9. The injury process due to antigen antibody complexes:
1. There are histologic and functional changes
2. Histologic:
1. Histologic changes may be diffuse, global or segmental or masangial
2. Leukocytic infiltration at the site and hypercellularity
3. Proliferation of measangial and epithelial cells
4. Formation of crescent
5. Basement membrane thickening
6. Hyalinization and sclerosis
10 . Functional changes:
1. Proteinuria
2. Hematuria
3. Renal failure


Short notes:
26


Synonym: rapidly progressive glomerulonephritis:
1. Definition:
1. A syndrome of severe glomerular injury
2. Does not denote any specific etiology
3. Rapid and progressive loss of renal function
4. Classic histology is presence of crescents in most glomeruli;
2. Classification:
1. Group I:
1. Anti GBM antibody induced glomerulonephritis
2. Linear deposits of Ig.G and C3 in GBM
3. In some similar lesions in lungs (Good pasture syndrome)
2. Group II:
1. Immune complex mediated disease
2. Granular pattern of immune complex deposits
3. Eg. Post infectious, SLE, IgA, Henoch-Schonlein nephropathies
3. Group III:
1. Pauci immune type
2. No immune complex or anti GBM antibody deposits
3. Antineutrophil cytoplsamic or perinuclear antibodies are present in serum
4. Mostly idiopathic
5. Probably a manifestation of small vessel vasculitis limited to glomerulus
3. Pathology:
1. Kidneys are enlarged, pale with petichiae
2. Crescents are present in Bowman capsule; they are formed by proliferation of parietal
cells, monocytes, macrophages, Neutrophils and lymphocytes in a fibrin meshwork;

3. Rupure of GBM and passage of proteins, inflammatory cells into Bowmans space which
form crescents.

4. Clinical:
1. Hematuria
27

2. Hypertension and edema
3. Hemoptysis in Good-pasture syndrome
4. Presence of serum anti-GBM, antinuclear, ANCA antibodies depending on the type
5. Plasma exchange, steroids, cytotoxic agents may help in recovery.




1. Definition: It is a membranous glomerulopathy with diffuse thickening of glomerular capillary
wall, immune complex deposits along the sub epithelial side of GBM
1. Massive proteinuria >3.5 gm/day
2. Hypoalbuminemia < 3 gm/dL
3. Edema
4. Hyperlipidemia and lipiduria
2. Age: 6-8 years
3. Etiology and Classification:
1. Idiopathic
2. Drug induced: gold, NSAID
3. Malignancy: Hodgkin, Ca Lung, colon and melanoma
4. SLE
5. Infections: Hepatitis B,C, syphilis, malaria etc
6. Autoimmune : thyroiditis
4. Pathogenesis:
1. Immune complex mediated
2. Idiopathic form: the in situ antigen is an unidentified antigen due to a genetic
susceptibility
3. C5b-C9 complex induce mesangial and epithelial cells to liberate proteases and oxidants
which cause capillary wall injury and increased protein leakage.
4. No circulating immune complex
5. In secondary forms specific antigens could be identified
5. Pathology:
1. Kidneys are enlarged and pale
2. Glomeruli:
1. Diffuse thickening of capillary wall
2. Thickening of GBM
3. No cellular proliferation
3. Tubule:
1. Normal
4. Interstitium:
1. Fine Fibrosis and scanty inflammatory cells
5. Vessels:
28

1. Hypertensive changes in late stage
6. Electron microscopy:
1. Immune complex deposits in subepithelial location
2. GBM appear as spikes between deposits
7. Immunoflorescence:
1. Granular deposits of immune complex (IgG+C)
6. Complications:
1. Hypertension
2. End stage renal disease and renal failure
3. Azotemia
4. Renal vein thrombosis


1. In 1919, Good pasture described a syndrome characterized by hemoptysis, alveolar hemorrhage
and necrosis, and proliferative glomerulonephritis in a patient during an influenza epidemic.
Autopsy revealed that the patient had a vasculitis
2. Definition:
Is a triad of diffuse pulmonary hemorrhage (as seen in the images below),
glomerulonephritis, and circulating anti glomerular basement membrane (anti-GBM)
antibodies.
3. It is a type I of crescentric glomerulonephritis
4. It is a immune complex disease due to anti GBM antibodies which also cross react with
pulmonary alveolar basement membrane producing both pulmonary and renal lesions
5. The antigen called Goodpasture antigen is a component of alpha 3 chain of collagen type IV
6. Pathology:
a. Kidneys are enlarged, pale with petichiae
b. Crescents are present in Bowman capsule; they are formed by proliferation of parietal
cells, monocytes, macrophages, Neutrophils and lymphocytes in a fibrin meshwork;

c. Rupture of GBM and passage of proteins, inflammatory cells into Bowmans space which
form crescents.
d. Diffuse linear pattern of immune complex deposition along GBM


1. It is a tubulo interstitial diseasae resulting from repeated attacks of inflammation and scarring.
2. Etiopathogenesis: two types
a. Reflux nephropathy
b. Obstructive pyelonephritis
3. Reflux nephropathy:
29

a. Congenital absence or shortening of intravesical portion of ureter leading to reflux
during micturition as the valvular mechanism is lost
b. Urine reflux into ureter and pelvis
c. One or both kidneys are damaged with scarring
d. Urinary infection is also common
4. Obstructive pyelonephritis:
a. Obstruction can occur at variable levels( eg. Pelvi ureteric junction or posterior urethral
valve or renal calculi)
b. Unilateral or bilateral
c. Infections superimpose obstruction
d. Inflammations lead to chronic pyelonephritis
5. Morphology:
a. Gross:
i. Kidneys are irregularly scarred
ii. Small and contracted
iii. Capsule is adherent with scars
iv. If bilateral the involvement is asymmetrical as opposed to chronic
glomerulonephritis which is symmetrical
v. The diseased cortex is dilated, blunted, and deformed.
vi. The overlying cortex is represented by scar which show U shaped depressions
on the cortical surface
vii. Pelvis is dilated
b. Microscopic:
i. Interstitium:
1. Chronic inflammation is seen
2. Varying degrees of inflammation in the cortex and medulla
3. Neutrophilic infiltrations
4. Pus casts in the tubules
5. Xanthogranulomatous pyelonephritis occurs in proteus infections
6. Fibrotic changes in cortex, medulla and calyx
7.
ii. Tubules:
1. Tubules show atrophy, hypertrophy and dilatations
2. Dilated tubules are filled with colloid casts (throidization)
iii. Glomerulus:
1. Periglomerular fibrosis may be present
2. Focal segmental glomerulosclerosis may be seen
iv. Blood vessels:
1. Show obliterative endarteritis
2. Secondary changes may occur due to hypertension
v. Pelvi calyceal system:
1. Pelis and calyx are dilated
2. Walls show chronic inflammation with lymphoid follicles
3. Epithelium undergoes squamous metaplasia
30











Haematopathology
Anemia:
1. Definition:
a. Defined as a reduction below normal limits of the total circulating red cell mass (or)
b. Hg% > 2 standard deviations below the mean for age, sex and race
c. Characterized by:
i. Reduced HB%
ii. Reduced PCV
iii. Reduced RBC count
iv. Anaemia is a sign of an underlying pathology (it is not a diagnosis)
2. Classification:
a. Blood loss:
i. Acute: Trauma
ii. Chronic: peptic ulcer; haemorrhoids, Menorraghia
b. Hemolytic:
i. Intrinsic: (within RBC)
1. Hereditary
a. RBC Memrane disorders:
i. Spherocytosis
ii. Increase in membrane lecithin
b. RBC Enzyme disorders:
i. Pyruvate kinase deficiency
ii. Hexokinase deficiency
iii. G6P Deficiency
31

iv. Glutathione synthetase deficiency
c. Hemoglobin disorders:
i. Reduced Globin: Thalassemias
ii. Abnormal globins: Sickle cell; unstable hemoglobins
2. Acquired:
a. Membrane defect: paroxysmal nocturnal hemoglobinuria
ii. Extrinsic: (outside RBC)
1. Antibody mediated:
a. Isohemagglutinins:
i. Transfusion reaction
ii. ABO incompatibility
iii. Rh incompatibility
b. Autoantibodies:
i. Idiopathic
ii. Drug induced- eg. penicillin
iii. SLE
iv. Neoplasms
v. Mycoplasma infection- paroxysmal cold hemoglobinuria
2. Mechanical trauma:
a. MIcroangiopathic:
i. Thrombotic thrombocytopenic purpura
ii. Disseminated intra vascular coagulation
b. Cardiac:
i. Prosthetic valve replacement
3. Infections:
a. Malaria
b. Hook worm
4. Chemical injury:
a. Lead poisoning
5. Sequestration:
a. Hypersplenism
c. Impaired production:
i. Defect ion proliferation and maturation of stem cells:
1. Aplastic anemia
2. Pure red cell anemia
3. Renal failure ( erythropoietin deficiency)
4. Endocrine ( Hypothyroidism)
ii. Defect ion proliferation and maturation of erythroblasts:
1. Defect in DNA synthesis:
a. B12 deficiency
b. Folic acid deficiency
2. Defect in Hb synthesis:
a. Iron deficiency
d. Unknown or multiple mechanism:
32

i. Sideroblastic anemia
ii. Chronic infections: osteomyelitis; lung abscess
iii. Chronic inflammation: Rheumatoid arthritis
iv. Marrow infiltration: Myelophthisic anemia
3. Morphologic classification:
a. Microcytic hypochromic
b. Normocytic normographic
c. Machrocytic normochromic


a. Hemolytic:
i. Intrinsic: (within RBC)
1. Hereditary
a. RBC Memrane disorders:
i. Spherocytosis
ii. Increase in membrane lecithin
b. RBC Enzyme disorders:
i. Pyruvate kinase deficiency
ii. Hexokinase deficiency
iii. G6PD Deficiency
iv. Glutathione synthetase deficiency
c. Hemoglobin disorders:
i. Reduced Globin: Thalassemias
ii. Abnormal globins: Sickle cell; unstable hemoglobins
2. Acquired:
a. Membrane defect: paroxysmal nocturnal hemoglobinuria
ii. Extrinsic: (outside RBC)
1. Antibody mediated:
a. Isohemagglutinins:
i. Transfusion reaction
ii. ABO incompatibility
iii. Rh incompatibility
b. Autoantibodies:
i. Idiopathic
ii. Drug induced- eg. penicillin
iii. SLE
iv. Neoplasms
v. Mycoplasma infection- paroxysmal cold hemoglobinuria
2. Mechanical trauma:
33

a. MIcroangiopathic:
i. Thrombotic thrombocytopenic purpura
ii. Disseminated intra vascular coagulation
b. Cardiac:
i. Prosthetic valve replacement
3. Infections:
a. Malaria
b. Hook worm
4. Chemical injury:
a. Lead poisoning
5. Sequestration:
a. Hypersplenism

Hemolytic anemias:
1. Hereditory Spherocytosis:
a. Inherited disorder of red cell membrane
b. Autosomal dominat; autosomal recessive
c. Mutation of red cell ankyrin, a-spectrin, band-3 etc with abnormal protein complex
responsible for stability to RBC;
d. Membrane instability leads to loss of fragments of membrane in circulation of blood and
the RBC adopts a spherical shape which is a microcyte;
e. Spheroidal shape ands reduced membrane plasticity leads to sluggish movement within
the spleen
f. Spleen captures spherocytes which are phagocytosed by RE cells;
g. Splenectomy prevents hemolysis
h. Morphology:
i. Spherocytes are smaller, hyperchromic, lacking central pallor
ii. Marrow hyperplasia
iii. Reticulocytosis
iv. Hemosiderosis
v. Mild jaundice
vi. Gall stones due Hb pigments
vii. Splenomegaly
2. G6PD:
a. It is an X-linked recessive trait; males are affected while female are carriers
b. G6PD A- and G6PD mediteranian variants are the most common defective enzymes
c. Glucose 6 phosphate dehydrogenase in RBC reduces NADP to NADPH; NADPH is
essential for reducing glutathione; reduced glutathione is essential for neutralizing
H2O2 and other oxidant radicals.
d. Absence of G6PD leads to accumulation of oxidant radicals within RBCs and RBC
metabolism is deranged leading to formation of Heinz bodies which damage the
membrane and lead to haemolysis
e. Spleen tries to remove Heinz bodies and the the remaining part of RBC appear as bite
cells
34

f. The oxidant stress is produced by liberating free radical by leukocytes during infections
like viral hepatitis, pneumonia, typhoid etc
g. Drugs like primaquine, chloroquine, sulphonamides also induce oxidant stress
h. Young RBCs are resistant to oxidant stress and recovery is due to attainment of
increased young RBC population
3. Sickle cell disease:
a. Intorduction:
i. It is a hereditary hemoglobinopathy; autosomal recessive
ii. Sickle cells are resistant to malarial infection- a factor for increased S gene
concentration in malaria endemic places
iii. Normal Hb consists of:
1. Hb A ( 2 alpha and 2 beta chains)
2. Hb A 2 ( 2 alpha and 2 delta)
3. Hb F ( 2 alpha and 2 gamma)
iv. Sickle cell Hb defect:
1. In Beta chain at 6 th position there is substitution of valine for glutamic
acid- HbS
v. When deoxygenated HbS undergo polymerization and RBC aquires the shape of
a sickle
vi. Sickle cells undergo membrane changes: allow more K and H2O efflux; they
become dehydrated and sticky.
vii. Sickling and stickiness cause vascular occlusion- eg. Bones and penis
viii. Sickle cell disease occurs in 3 states:
1. Homozygous: severe disease
2. Heterozygous: carrier state; disease may manifest in severe hypoxia
3. Double heterozygous: HbS is associated with HbC or thalassaemia traite
b. Clinical feautures:
i. Anemia: there is severe anemia due to hemoplysis
ii. Vaso occlusive diseases:
1. Bones, lungs, penis, liver, spleen etc are involved
2. Bone pain and priapism (persistant erection of penis) are common
3. Dactylitis of hands and bones called hand foot syndrome
4. Acute chest syndrome in which lung inflammation leads to pulmonary
dysfunction
5. CNS: seizures can occur
6. Ulcres over legs
iii. Hyperbilrubinemia: mild haemolytic jaundice ( indirect bilirubinnemia)
iv. Acute Crisis events:
a. Sequestration crisis: Sickele cells trapped in spleen lead to
splenomegaly, hypovolemia, and shock
b. Aplastic crisis: transient bone marrow failure due to parvovirus
B19 infection of RBC progenitor cells; there is severe anemia
c. Vasoocclusive crisis: acute chest syndrome, priapism, seizures
and stroke
35

v. Chronic hypoxia: this leads to stunted growth, developmental retardation and
damage to renal medulla leading to dehydration
1. Impaired splenic function leads to infection by capsulate organisms
Pneumococcal and H.influenza produce septicemis and meningitis
vi. Pulmonary hypertension is a complication of chronic intravascular hemolysis
c. Morphology:
i. Hyperplstic bone marrow;
ii. Extra medullary erythropiesis in liver and spleen
iii. Splenomegaly:
1. Congestion of red pulp
2. Sickle cells in splenic cords
3. Thrombosis, infarction and fibrosis in spleen
4. Spleen becomes fibrotic and small- autosplenectomy
iv. Vascular occlusions seen in lungs, kidney, bones
v. Pigment gall stones
d. Lab Diagnosis:
i. Sickle cells in peripheral smear; target cells and RBC with Howell-Jolly bodies
ii. Sickling test:
1. Test I:
Patiens blood is mixed with metabisulfite which consumes oxygen
and anoxia induces sickling of RBCs
2. Test II:
a. A freshly prepared sodium dithionate and disodium hydrogem
phosphate are mixed with 2:3 proportion
b. 5 drops of this mixture is taken on glass slide
c. A drop of patients blood is added
d. The specimen is covered by cover slip and sealed with Vaseline
e. The slide is examined under microscope for sickling, periodically
over 24 hours
f. A control is used for comparison
iii. Hb electrophoresis demonstrates HbS
iv. Prenatal diagnosis is done by DNA analysis from amniocentesis
e. Treatment:
i. Hydroxyurrea:
1. Causes increase in HbF which prevents polymerization
2. Acts as anti inflammatory agent by suppressing leukocytosis and
inflammation
3. Increases red cell volume and HbS concentration is lowered
4. It gets oxidised to form Nitric oxide
ii. Nitric Oxide:
1. Nitric oxide is a potent vasodilator and inhibit platelet aggregation
2. Nitric oxide therapy
3.
iii. Antibiotic prophylaxis against sepsis
36

iv. Vaccination against H.inf and pneumococci
v. RBC transfusion
vi. Adequate hydration
vii. Stem cell transplantation

Thalassemias: (Mediteranian anemia)
1. Unlike hemoglobinopathies which are qualitative defects, thallasemias are quantitative defects
of globin chain synthesis
2. It is an autosomal recessive disease with a spectrum manifestations
3. The defective genes are either in alpha ( Chr 11) or beta (Chr 16) chains
4. There are 4 major types of globins labelled as alpha (), beta (), gamma (), and delta (). The
dominant haemoglobin in adults (haemoglobin A) is composed of 2 alpha and 2 beta chains.
Thalassemia refers to a spectrum of diseases characterized by reduced or absent production of
one or more globin chains.
5. Relative excess of beta chains due to impaired production of alpha globin results in less stable
chains. This leads to the clinical disease known as alpha thalassemia. Similarly, impaired
production of beta globin chains manifests with a more severe disease known as beta
thalassemia.
6. Classification:
a. -thalassemia:
i. Major (Cooleys anemia): is homozygous; alpha chains are reduced; HbA is less;
severe anemia
ii. Trait: heterozygous; clinically normal
iii. Hb Barts hydrops fetalis: all four alpha chains are suppressed; Hb consist only of
4 chains called HbBarts; severe intrauterine hemolysis and fetal death
iv. HbH disease: deletion of 3 alpha chains leads to HbH(4) disease; severe
hemolysis
b. B-thalassemia:
i. Major: homozygous; Beta chains are less; alpha chains are in excess; HbF is
more; severe anemia due to hemolysis
ii. Trait: mild symptoms
7. - Thalassemia:
a. Reduced synthesis of globin chains; and globin chains are synthesized more
leading to excess production of HbH (4) and Hb Barts (4)
37

b. Silent carrier: asymptomatic carriers; one chain gene is deleted
c. Trait: 2 chain genes are deleted; asymptomatic
d. HbH: deletion of 3 chain genes; HbH(4) is in excess; HbH has severe affinity for O2
and tissue hypoxia and severe anemia
e. Hydrops fetalis: all 4 chain genes are deleted; Hb Barts are more; in utero tissue
hypoxia and anemia lead to hydrops and fetal death
8. -Thalassemia:
a. Disease due to Impaired synthesis of chains & excess synthesis of chains
b. Molecular lesions:
i. 0: complete absence of chains
ii. +: partial synthesis of chains
c. Types of mutations:
i. Transcription defect: promoter sequence is defective
ii. Translation defect: defect coding sequence with creation of stop codons
iii. Splicing defect: mutation affect splice junctions and normal splicing does not
occur
d. Mechanism of anemia:
i. Deficiency of chains and decreased Hb A : produce hypochromic microcytic
red cells
ii. Excessive chain synthesis produce soluble inclusions within RBC and a
membrane damage results leading to apoptosis and further destruction in
spleen
iii. Ineffective erythropoiesis
iv. Increased erythropoietin produce medullary and extra medullary hyperplasia of
hematopoietic tissue
v. Excessive iron absorption from gut leading to hemochromtosis
e. Clinical syndromes:
i. Thalassemia major:
homozygous; absence of chains; severe hemolysis; severe anemia
requiring repeated transfusions;
ii. Thalassemia minor:
heterozygous; partial absence of chains; mild microcytic anemia; no
symptoms
iii. Thalassemia intermedia:
Genetically heterozygous but more severe than Thalassemia minor
f. Morphology:
i. Thalassemia major
1. Genotypes are +/ +; 0/0; o/+
2. Anemia from 6-9 months; Hb F protects young infants;
3. Hb 3-6 gm/dL
4. Smear:
a. anisocytosis, poikilocytosis, microcytosis, hypochromia
b. target cells, basophilic stifling, fragmented red cells
c. Reti count is elevated
38

d. Normoblasts with poor hemoglobinzation
5. HbF is markedly elevated as it does not require chains
6. HbA2 may be normal or high or low
7. Increase in marrow of facial bones gives malar prominence and wide
separation teeth
8. Hemosiderisis and hemochomotosis in several organs
9. Growth retardation
10. Hepato splenomegaly
ii. Thalassemia minor:
1. More common than major
2. Heterozygous and carriers of the defective genes
3. Mild anemia: hyochromic, microcytic, target cells, basophilic stifling
4. Mild hyperplasia of marrow
5. HbA2 is increased as it contains and and no chains
6. HbF is normal or slightly increased



Megaloblastic anemia:
1. Definition:
It is a type of anemia due to impaired DNA synthesis; maturation of nucleus is delayed while
cytoplasm increase normally leading to megaloblasts in bone marrow and macrocytes in
peripheral smear.
2. Biochemical basis:
a. Folate and B12 are essential for synthesis of thymidine one of 4 bases of DNA;
b. B12 is essential cofactor for methionine synthase which converts homocysteine to
methionine.
c. In the same reaction N- methyl FH4 is converted to tetra hydro folic acid (FH4)
d. In B12 deficiency FH4 is trapped as N- methyl FH4
e. FH4 is crucial for convertion of deoxyurine monophosphate to deoxythymidine
monophosphate which is the immediate precursor of DNA
3. Etiologic classification:
a. B12 deficiency:
i. Inadequate in take: vegetarians and exclusive breast feeding
ii. Malbsorption:
1. intrinsic factor deficiency
2. Tropical sprue
3. Regional ileitis
4. Fish tapeworm infestation
iii. Increased demand:
1. Pregnancy
39

2. Hyperthyroidism
3. cancer
b. Folate deficiency:
i. Inadequate intake: alcoholism, old age
ii. Malabsorption:
1. Tropical sprue
2. Regional ileitis
iii. Excess demand:
1. Pregnancy, lactation, infancy
2. Malignancy,
3. TB
4. Rheumatoid arthritis
c. Other causes:
i. DHF reductase inhibitors: methotrxate
ii. Unknown: Di Guglielmos syndrome
4. B12 deficiency anaemia: Pernicious anaemia:
a. Causes:
i. Inadequate in take: vegetarians and exclusive breast feeding
ii. Malbsorption:
1. intrinsic factor deficiency
2. Tropical sprue
3. Regional ileitis
4. Fish tapeworm infestation
iii. Increased demand:
1. Pregnancy
2. Hyperthyroidism
3. Cancer
b. Metabolism:
i. Microorganism is the primary source of Vit.B12
ii. Human derive it only from animal food products
iii. Daily requirement is 2-3 mg
iv. Absorption require intrinsic factor from gastric fundus
v. Absorption is mainly from ileum
vi. 1% absorption occurs in alternate pathway which does not require intrinsic
factor
c. Incidence: common in 5
th
to 8
th
decades 0f life;
d. Pathogenesis:
i. Initaial event in pernicious anemia is autoimmune destruction of gastric mucosa
ii. Type I and II antibodies prevents binding of B12 to intrinci factor and to ileual
mucosa
e. Morphology:
i. Alimentary tarct:
1. Toungue is glassy
40

2. Stomach shows atrophy; epithelium has more goblets cells and is called
intestinalization
3. Some cells show megaloblastic changes
4. CNS:
a. Degeneration of myelin in dorasal and lateral tracts
b. Some degeneration in posterior ganglio and dorasal and latral
roots- subacute combined degeration
f. Lab diagnosis:
g. B12:
i. Blood picture:
1. Hb% is decreased
2. Red Cells:
a. Macrocytosis
b. Anisocytosis
c. Poikilocytosis
d. Macroovalocytes
e. Basophilic stipling
f. Occasional normoblasts
3. Reticulocytes: low or normal
4. Values:
a. MCV and MCH are elevated
b. Normal or reduced MCHC
c. Leukocytes: reduced in no and hypersegmented polymorphs
d. Occasional myelocytes
e. Platelets: reduced and some bizarre forms
ii. Bone Marrow:
1. Hypercellular with decreased myeloid-erythroid ratio
2. Megaloblasts:
a. Abnormal, large, nucleated erythroid precursor;
b. Less mature nucleus but more cytoplasmic material- nuclear
cytoplsmic asynchrony
c. Nuclei are large, fine reticulum, lighther staining
d. Some cells may show mitosis
e. Degenerated erythroid precursors may be seen
3. Giant metamyelocytes and band cells may be seen
4. Megakaryocytes are normal in no; occasional cell with hypersegmented
nucleus
5. Prussian blue staining may show increase in iron granules in erythroid
precursors
6. Chromosomes may show breaks
iii. Biochemistry:
1. Unconjugated bilirubin is raised due to ineffective eryhtropoiesis
2. Serum iron and ferritin are normal or elevated
iv. Special tests:
41

1. Serum B12 assay: microbiological and radioassay
2. Schilling test:
A Schilling test may be given in two parts. Part one measures the
amount of vitamin B12 passed in urine after a known amount of the
vitamin tagged with a radioactive substance is swallowed. If the
intestines absorb vitamin B12 normally, a certain amount of the vitamin
(up to 25% of the amount swallowed) will be passed in the urine. If the
intestines cannot absorb the vitamin normally, very little or no vitamin
B12 will be present in the urine.
A Schilling test with abnormal results (no vitamin B12 in the urine) may
be repeated after giving an oral dose of intrinsic factor and radioactive
B12. This is called part two of the test, and it tells whether the vitamin
deficiency is caused by a lack of intrinsic factor or from a problem with
the intestines.
Folic acid deficiency:
1. Sources: green vegetables, fruits, animal proteins; heating may reduce folic acid content
of food
2. Lab investications:
v. Normal serum level is 6-18 ng/ml
vi. Urinary excretion of FIGLU (formiminoglutamic acid): addition of oral histidine
increases urinary excretion of FIGLU in folate deficiency
vii. Serum folate assay:
1. Microbiological assay
2. Radiassay
viii. Red cell folate assay: RBC contain 20-50 times more folate; decrease in folate
deficiency.





42



Iron Deficiency Anemia:
1. Definition of anemia:
a. Defined as a reduction below normal limits of the total circulating red cell mass (or)
b. Hg% > 2 standard deviations below the mean for age, sex and race
c. Characterized by:
iii. Reduced HB%
iv. Reduced PCV
v. Reduced RBC count
vi. Anemia is a sign of an underlying pathology (it is not a diagnosis)
2. Metabolism:
a. No regulated pathway for iron metabolism
b. 1-2 mg lost by shedding mucosal and skin epithelial cells
c. 20% of heme iron in animal source and 1-2% non heme iron from vegetable sources are
absorbed
d. VitC enhances absorption
e. Both nonheme iron and heme iron have 6 coordinating bonds; however, 4 of the bonds
in heme bind pyrroles, making them unavailable for chelation by other compounds.
Therefore, ascorbic acid chelates nonheme iron to enhance absorption but has no effect
upon heme iron. Many dietary components, such as phytates, phosphates, oxalates, and
tannates, bind nonheme iron to decrease nonheme iron absorption. They do not affect
heme. This explains why heme is so effectively absorbed with foods containing these
chelators. Iron hemoglobin structure.
f. Total Iron content of men 6gm and women 2 gm; 80% in haemoglobin, myoglobin and
iron containing enzymes as functional iron and rest in ferritin and hemisiderin as storage
iron.
3. Etiology of anemia:
a. Iron requirement is 7-10 mg for men and 7-20 mg in women per day
b. 10% - 15% is absorbed out of daily requirement i.e 1 mg is absorbed everyday
c. Deficiency occurs due to :
i. Dietary lack
ii. Impaired absorption
iii. Increased requirement
iv. Chronic blood loss
d. Dietary lack:
i. Infants take only milk which has less iron; breast milk contains .3mg/L
ii. Iron in cows milk has poor bioavailabilty
43

iii. Cereals have iron ; non introduction of weaning food also leads to iron deficnecy
after 6 months of age
iv. Adults:
1. Not consuming iron rich food
2. Taking tea, coffee which contain iron chelators
3. Consuming large quantity of milk in the place of iron rich food
4. Faddism
e. Impaired absorption:
i. Tropical sprue
ii. Steatorrhea
iii. Chronic diarrhoea
iv. Gastrectomy
f. Increased requirement:
i. Infants and children
ii. Adolescents
iii. Premenopausal women
iv. Repeated pregnancies
g. Chronic blood loss:
i. Peptic ulcer
ii. Haemorrhoids
iii. Cancer GIT
iv. Hookworm
v. Dysmenorrhea
vi. Renal tumors
4. Morphology:
a. Bone marrow:
i. Moderate increase in erythroid precursors(more normoblasts)
ii. Disappearance of stainable iron from mononuclear phagocytic cells in the bone
marrow by Prussian blue staining
b. Peripheral smear:
i. Small red cells (microcytes) and pale(hypochromic)
ii. The zone of pallor in RBC is enlarged to give pessary sign
iii. Poikilocytes containing small elongated cells are present
5. Lab tests:
a. Haemoglobin is reduced
b. Hematocrit (PCV) is lowered
c. Serum iron and ferritin are low
d. Total plasma iron binding capacity is high
e. Reduction in transferring Saturation below 15%
f. Serum level of hepcidin is low
g. Free erythrocyte protoporphyrin is elevated

Aplastic anemia:
44

1. Definition: a syndrome of marrow failure associated with pancytopenia which includes anemia,
neutropenia and thrombocytopenia.
2. Classification:
a. Acquired:
i. Idiopathic:
1. Primary stem cell defect
2. Immune mediated
ii. Chemical agents:
1. Dose related:
a. Alkylating agents
b. Antimetabolites
c. Benzene
d. Chloremphenicol
e. Inorganic arsenicals
2. Idiosyncratic:
a. chloramphenicol
b. phenylbutazone
c. organic arsenicals
d. chlorpromazine
e. DDT
iii. Physical agents:
1. Irradiation
iv. Viral infections:
1. Hepatitis
2. CMV
3. EB virus
4. Herpes
v. Miscelaneous:
1. Drugs and chemicals
b. Inherited:
i. Fanconi anemia
3. Pathogenesis:
a. Not fully understood
b. Two suggested mechanisms:
i. Immune suppression of marrow :
The causal agent antigenically alter the stem cell followed by activation of T
cells; cytokines and TNF prevent normal stem cell growth.
ii. Intrinsic abnormality of stem cells:
Insult to marrow causes genetic damage to stem cells leading to aplstic
anemia
4. Morphology:
i. Bone marrow preferably from Marrow biopsy:
1. Hypocellular marrow
2. Devoid of hematopietic cells
45

3. Only fat cells, plasma cells and lymphocytes are seen
ii. Blood smear:
1. Normocytic normochromic rbc
2. Reticulocytopenia
5. Clinical findings:
i. Any age either sex
ii. Anemia: pallor and fatique
iii. Thrombocytopenia: petichiae and echymosis
iv. Granulocytopenia: persistant or recurrent infections
v. No splenomegaly
6. Treatment:
a. Withdrwl of affending agent
b. Bone marrow transplant
7. Prognosis: unpredictable

Shortnotes:

1. Reticulocytes are immature red blood cells, typically composing about 1% of the red cells in the
human body.
2. Reticulocytes develop and mature in the red bone marrow and then circulate for about a day in
the blood stream before developing into mature red blood cells.
3. Like mature red blood cells, reticulocytes do not have a cell nucleus. They are called
reticulocytes because of a reticular (mesh-like) network of ribosomal RNA that becomes visible
under a microscope with certain stains such as new methylene blue.
4. Reticulocyte production index:
a. The idea of the RPI is an index of erythropoietic activity of bone marrow
b. RPI should increase in response to any loss of red blood cells.
c. If reticulocyte production is not raised in response to anemia, then the anemia may be
due to an acute cause with insufficient time to compensate, or there is a defect with red
blood cell production in the bone marrow.
d. Marrow defects include nutritional deficiencies (i.e. iron, folate, or B12) or insufficient
erythropoietin, the stimulus for red blood cell production.
e. Reticulocytopenia, or "aplastic crisis", is the term for an abnormal decrease of
reticulocytes in the body
f. Reticount is increased following hemorrhage and following anemia treatment with iron



46



1. It results from passage of IgG from mother to fetus
2. IgG develop due to:
a. Rh sensitization:
Rh ve Mother sensitized by fetal Rh +ve RBC by feto maternal transfusion that occurs
during pregnancy and labour
More than 60 antigens in RBC
Rh factor is one
Rh factor has many antigens:
D, C,E, Kell, Kidd, K, M, Duffy
90 % Rh disease due to D antigen
C&E 10%
1 ml of fetal blood can produce adequate sensitization
Ig M and IgG antibodies are produced
Ig G crosses placenta into fetal circulation
Adheres to fetal RBC
Produce haemolysis by compliment activation
Increasing severity by successive pregnancies
ABO incompatibility will reduce severity of Rh incompatibility
b. ABO incompatibilty:
When mother is one blood group of a,b,O group and the baby is different group
A1 more antigenic; o group mother and A1 group fetus
O - A1 severe incompatibility due to Ig.G
ABO in 20 % pregnancies
Among them 20 % develop icterus
Overall incidence is 1-2 %
First pregnancy can be affected
Less jaundice but anemia may be significant
< 10% MAY GO FOR EXCHANGE TRANSFUSION
3. The blood group incompatibility produce hemolysis and unconjugated hyperbilirubinemia in NB
4. High levels exceeding 20 mg/dL may produce kernictreus
5. Phototherapy and exchange transfusions are the treatments









47




























48



7. F A B classification of leukemia.

Leukemias
Group of malignant diseases arising from hematopoietic cells;
1. Etiology:
7. Herditory:
a. Hodgkins disease is 99% more in identical twins
b. Leukemias more common in same families
8. Genetic disorders: Inherited genetic factors with genomic instability:eg:
a. Fanconi anemia
b. Ataxia telangiectasia
c. Down syndrome
d. Wiscott Aldrich syndrome
9. Viral infection:
a. Human T cell Leukemia Virus-1(HTLV): T cell leukemia
b. Ebstein Bar virus: lymphoma
c. Herpes virus-8: Kaposis sarcoma
d. Hepatitis C: lymphoma
e. HIV: B-cell and Burkitts lymphomas
f. Helecobacter pylori: lymphoma of stomach
10. Environmental agents:
a. Ionizing radiation: Leukemias
b. Drugs:
i. Phenytoin: lekemias and lymphomas
ii. Cancer chemotherapy-leukemia
c. Gluten sensitivity: intestinal lymphoma
d. HIV: B cell lymphomas
11. Immune deficiency:
a. Congenital or acquired immune deficiency: leukemia and lymphoma
12. Iatrogenic Factors:
a. Radiotherapy- leukemia
2. Pathogenesis:
49

6. Malignant transformation of a single clone of cells belonging to lymphoid or myeloid series
due to a genetic damage to DNA; this is followed by proliferation of affected clone
7. Chromosomal translocation: eg: Philedelphia Chromosome t(9;22) in CML
8. Maturation defect: i.e failure to mature beyond myeloblast or lymphoblast;
9. Myelosupression: bone marrow is suppressed by the excessive cancer cells
10. Infiltration: bone marrow and liver, spleen, lymphnodes and CNS are infiltrated by leukemic
cells

Classification
Types of classification:
4. Historical classification
5. French American British classification (FAB)
6. WHO classification

I. Historical classification:




3. Leukemias: Acute in the sense the disease progresses rapidy and blast cells predominate in
blood smear; chronic in which disease progresses slowly and blast cells are not seen in early
smears
a. Acute myeloblastic leukemia (AML)
b. Acute lymphoblastic leukemia(ALL)
c. Chronic myeloid(myelocytic) leukemia(CML)
d. Chronic lymphocytic leukemia(CLL)
4. Lymphomas:
a. Hodgkin
b. Non Hodgkin
II. Present major classification:
4. Lymphoid neoplasm: arise from precursors of lymphocytes:
5. Myeloid neoplasm: arise from hematopoietic stem cells that give rise to:
6. Histiocytic neoplasms

50

FAB Classification:



1. WHO Classification of Lymphoid neoplasms:
2. Acute lymphoblastic leukemia, ALL
a. Precursor B cell neoplasm( blast cells):
i. Precursor B Lymphoblastic leukemia/lymphoma
b. Peripheral B cell neoplasm (mature cells):
i. Chronic lymphocytic leukemia (CLL)
ii. Follicular lymphomas
iii. Hairy cell leukemia
iv. Burkits lymphoma etc
c. Plasma cell neoplasms:
1. Plasmocytoma/Plasma cell myeloma
d. Precursor T cell neoplasm( blast cells): (Acute lymphoblastic leukemia, ALL)
i. Precursor T Lymphoblastic leukemia/lymphoma
ii. Peripheral T cell and NK cell neoplasm (mature cells):
iii. Adult T cell leukemia/lymphoma
iv. NK/T cell lymphoma
v. NK cell leukemia etc
e. Hodgkin lymphoma (Reed Sternberg cells + ve):
i. Classical:
1. Nodular sclerosis
2. Mixed cellularity
3. Lymphocyte rich
4. Lymphocyte depletion
ii. Lymphocyte predominance
2. WHO classification of Classification of Myeloid neoplasm: 5 groups:
6. Myeloproliferative diseases
7. Myelodysplastic / Myeloproliferative diseases
8. Myelodysplastic syndromes (MDS)
9. Acute myeloid leukemia
51

10. Acute biphenotypic leukemia

1. Myeloproliferative diseases:
8. Chronic myeloid leukemia
9. Chronic neutrophilic leukemia
10. Chronic eosinophilic leukemia
11. Chronic idiopathic myelofibrosis
12. Polycythemia veera
13. Essential thrombocytosis
14. Chronic myeloproliferative diseases
2. Myelodysplastic / Myeloproliferative diseases:
1. Chronic myelomonocytic leukemia
3. Myelodysplastic syndromes (MDS):
5. Refractory anemia
6. Refractory anemia with sideroblasts
7. Refractory anemia with excess blasts
8. Myelodysplastic syndrome unclassified
4. Acute myeloid leukemia:
6. AML with recurrent cytogenetic abnormalities
7. AML with multilineage dysplasia
8. AML with MDS
9. AML, not otherwise classified:
a. AML minimally differentiated
b. AML without differentiation
c. AML with maturation
d. Acute monoblastic and monocytic leukemia
e. Acute erythroid leukemia
f. acute megakaryocytic leukemia
g. acute basophilic leukemia
h. Acute panmyelosis with myelofibrosis
i. Myeloid sarcoma
10. Acute biphenotypic leukemia


Blood and bone marrow pictures:
1. Acute lymphoblastic leukemia ALL: peak incidence at 2-5 years of age, and another peak in old
age
2. Blood and Peripheral smear:
a. Changes in WBC:
i. Total count may be very high 50-100x10or less than 10,000/microL
ii. Lymphoblasts:
1. Are seen in large no. (Convent party appearance)
2. The cells are round and small,
3. Cytoplasm is scanty and homogeneous;
52

4. Granules are absent;
5. Nucleus one or two nucleoli.
6. The cells are PAS/Sudan Black negative; acid phosphatase positive;
7. Some Markers:
a. CD 19 positive in B cell type
b. CD 7 positive in T cell type
iii. RBC: normochromic and normocytic anemia
iv. Platelets: thrombocytopenia
3. Bone marrow changes in ALL:
6. Lymphoblasts:
a. Are seen in large no. Counts more than 20% (WHO) and 30% (FAB) are diagnostic of ALL
b. Lymphoblasts are large cells; contain large round or indended nucleus; stippled with
nuclear chromatin; nuclear membrane is dense; nucleoli 1-2 are seen; cytoplasm is
scanty; it is basophilic and without granules;
c. Lymphoblasts are TdT and adenosine deaminase positive;
7. Erythropoietic series:reduced in no; megaloblasts and ring sideroblasts may be seen.
8. Megakaryocytes are reduced or absent.
9. Cytogenetics :
a. Aneuploidy in 75%
b. Philadelphia chromosome in 15%
10. Cell markers seen ALL:
a. Leukocyte common antigen
b. Positive sheep erythrocyte rosette test in B cell types

2. Acute Myeloblastic (myelogenous; myeloid) Leukemia (AML): median age 50 years; may
rarely occur in childhood.
5. Blood Picture:
a. Total Leukocyte count is raised; occasionally normal
b. Plenty of blast cells:
i. Blast cells are large in size
ii. Round or oval nucleus nearly filling the cell
iii. Abundant granular cytoplasm
iv. Auer rods are seen sometimes which are abnormal derivatives of primary
azurophilic granules
v. Nuclear chromatin is delicate
vi. Nucleoli 3-5
vii. Cytochemistry:
1. Peroxidase and sudan black positive
2. Phosphatase negative
viii. Markers:
1. CD 19 negative
2. CD 7 Negative
3. CD 13 and 33 positive
c. Polymorphs and few lymphocytes are seen
53

d. RBC: normochromic normocytic anemia
e. Platelets: severe thrombocytopenia
6. Bone Marrow:
a. Maroow is hypercellular; occasionally hypocellular
b. Myeloblasts are predominant; > 20%(WHO) or > 30% FAB is diagnostic of ALL
c. Immature granulocytes, erythroblasts, megaloblastic erythroblasts and sideroblasts are
seen
d. Plasma cells and monocytes are moderately elevated
e. Megakaryocytes are reduced or absent
f. Cytogenetics:
i. Presence of cells with aneuploidy; translocation or inversions
ii. Philadelphia chromosome in 3% cases
g. Cytochemistry:
i. Myeloperoxidase, sudan black, PAS are positive in M6 cells
ii. Non specific esterase positive in M4 and M5
iii. Acid phosphatase positive in M4 and M5
h. Biochemistry:
i. Serum muramidase elevated in M4 and M5
ii. Serum uric acid elevated in general

7. Chronic lymphocytic (lymphatic)leukemia (CLL):over 50 years of age with male
preponderance; hepatosplenomegaly, lymphadenopathy and anemia
a. Blood picture:
i. Normochromic and normocytic anemia; mild reticulocytosis; 20% coombs have
positive hemolytic anemia
ii. Absolute neutrophil count is within normal range; granulocytopenia in advanced
stage
iii. Marked leukocytosis(50,000-200,000/l)
iv. 90% of leukocytes is mature small lymphocytes; degerated lymphocytes are
called smudge or basket cells
v. Platelets is normal or moderately reduced
b. Bone marrow:
i. Increased lymphocyte count
ii. Reduced myeloid precursors
iii. Reduced erythroid precursors
c. Other tests:
i. Lymph node: Replacement of lymphnode with diffuse small lymphocytes
ii. Erythrocyte rosette test: positive with mouse RBCs
iii. Markers: CD5 is positive for immunoglobulins
iv. Coombs +ve in 20%
v.
8. Chronic Myeloid (myelocytic) leukemia (CML): peak in 3-4 decades of life; juvenile form in
children; anemia, weight loss, bleeding, priapism, lymphadenopathy and splenomegaly.
a. Blood: 3 phases: chronic, accelerated and blast crisis phases
54

i. RBC: Normocytic normochromic anemia
ii. WBC:
1. General: Marked leukocytosis: 200 000/L; myelocites present
2. Chronic Phase:
a. Myeloblast <10%
b. Basophils > 10%
3. Accelerated phase:
a. Increasing anemia
b. Blasts 10-20%
c. Low platelet count
4. Blast crisis:
a. Blasts > 20%
iii. Platelet: normal or raised in the cases
b. Bone marrow:
i. Hypercellular marrow
ii. Myeloid predominance
iii. Increased myeloid erythroid ratio
iv. Myelocytes predominance
v. Erythropoiesis: reduction in erythropoietic series
vi. Megakaryocytes: more and smaller
vii. Cytogenetics:
1. Philedelphia chromosome in 90 to 95%; it is reciprocal translocation of
long arm of 22 and long arm of chromosome 9
viii. Cytochemistry:
1. Neutrophil alkaline phosphatase is reduced; increased in leukaemoid
reaction
ix. Other findings:
1. Serum B 12 elevated
2. Serum uric acid elevated


S.N: Philadiphia chromosome:
The Philadelphia chromosome is made when the Abl gene on chromosome 9 is mistakenly
transferred to chromosome 22 and attaches to the Bcr gene. This creates a new fusion gene
called Bcr-Abl which leads to leukemic process.

55



S.N: Leukemoid reaction:
The term leukemoid reaction describes an elevated white blood cell count, that is a
physiologic response to stress or infection (as opposed to a primary blood malignancy, such as
leukemia)
Leukemoid reaction may be myeloid (more common) or lymphoid
Causes:
1. Infections:
Staphylococcal pneumonia
Meningitis
Diphtheria
Any sepsis
Endocarditis
Septic abortion
2. Toxins:
Eclampsia
Mercury poisoning
Burns
3. Malignancy:
Multiple myeloma
Myelofibrosis
Hodgkin
CLL
4. Severe Hemorrhage and hemolysis
Lab:
1. Myleloid luekemoid reaction:
Leukocytosis upto 100,000/L
Blasts < 5%
Toxic granulation or Dohle bodies in Neutrophils in infections
Philadelphia chromosome negative
No organ infiltrations
2. Lymphoid leukemoid reaction:
Infections:
Pertusis
56

Infectious mononucleolus
Cytomegalo virus
Chickenpox
Measles
Tuberculosis
Lab:
Leukocyte count upto 100,000/L
Mostly mature lymphocytes
Mimics CLL
Difference between leukaemoid reaction and leukemia
S.No Leukaemoid reaction Leukemia
1 The infection leading to leukemoid
reaction will be present
Splenomegaly, lymphadenopathy and bleeding
tendency are evident
2 Leukocyte count upto 100,000/L

Leukocyte count often more than 100,000/L

3 Immature cells are less Immature cells are more
4 WBC may show toxic granulation due to
infection
Absent
5 Anemia is less More
6 Bone marrow: less hypercelluar More hypercellular
7 Autopsy: no organ infiltration of blasts Present in liver, spleen, CNS etc












57


2. A 35 years, old man was admitted with history of painless cervical
and axillary lymphadenopathy. He had history of loss of weight,
fever and night sweating and was found to have cutaneous anergy.
No hepatosplenomegaly.
a) What is your most probable diagnosis?
b) Give the classification of the condition.
c) Describe the morphology of any two types.
Lymphomas
1. These are malignant neoplasm derived from lymphocytes, usually in lymph nodes but also in
other organs or in soft tissue.
Unlike the leukemia the tumor cells do not appear in the blood in detectable numbers
2. TYPES OF LYMPHOMAS:
The lymphomas are broadly grouped into two types:
A. Non-Hodgkins lymphomas (60%)
B. Hodgkins lymphoma (also known as Hodgkin's disease) (40%)
3. Cells of origin:
The non- Hodgkins lymphomas are derived from either B or T lymphocytes. The cell of origin in
Hodgkins lymphoma is now known to be of B-cell origin

Hodgkins disease
1. Neoplasm (lymphoma) arising from lymph node with secondary involvement of extra nodal sites
2. Age 15-35 yrs with male preponderance; another peak at 5th decade
3. Symptoms include
painless swelling of the lymph nodes in the neck, armpits, or groin
fever and chills
night sweats
weight loss
loss of appetite
itchy skin
nodes are painful after alcohol consumption
4. Classifications:
4. Conventional:
a. Non Hodgkin- heterogynous group
b. Hodgkin (Reed Sternberg cell +ve)
5. Rye classification:
5. Lymphocyte predominant type
6. Nodular sclerosis
7. Mixed cellularity
58

8. Lymphocyte depletion type
6. Modified WHO classification:
3. Classic Hodgkin Disease:
a. Lymphocyte predominant type
b. Nodular sclerosis
c. Mixed cellularity
d. Lymphocyte depletion type
4. Nodular lymphocyte predominant Hodgkin disease
6. Reed-Sternberg cell:
7. These are neoplastic cells of HD
8. <5% of the total tumor cell mass.
9. Most Reed-Sternberg cells are of B-cell origin, derived from lymph node germinal centers but
no longer able to express antibodies.
10. Types of RS cells:
a. Classic RS: large cell with bilobed nucleus in mirror image pattern; each nucleus
contains a prominent nucleolus with clear halo around it giving a owl eye
appearance
b. Lacunar type: smaller; pericellular space is seen; present in nodular sclerosis
c. Polyploid type: large and lobulated pop corn like nucleus; seen in lymphocyte
predominance
d. Pleomorphic: atypical nuclei and pleomorphic; seen in lymphocyte depletion
11. Origin: they arise from B cells;
12. Markers are CD 15 and CD 30
7. Gross appearance HD node:
a. Cervical, supraclavicular, axillary nodes are commonly involved.
b. Initially nodes are discrete, but later become matted due to surrounding infiltration.
c. C.S: grey white and fish flesh like; nodular due to scarring in nodular sclerosis; spots
of necrosis in mixed cellularity and lymphocyte predominance.
8. Microscopic (morphology):
I. Classic HD:
b. Lymphocyte predominant type:
i. Proliferation of small lymphocytes mixed with histiocytes
1. Nodular form: large nodules seen
2. Diffuse form: no nodular pattern seen
ii. RS cells few in no
d. Nodular sclerosis: show
i. Bands of collagen: fibrous tissue in variable amount
ii. Lacunar type RS cells with peri cellular halo
iii. Nodules between fibrous tissue contain lymphocytes, histiocytes,
eosinophils, Neutrophils, and plasma cells
e. Mixed cellularity type:
i. Lymph nodes are replaced by mixture of apparently normal cells:
lymphocytes, histiocytes, eosinophils, Neutrophils, and plasma cells
ii. Areas of fibrosis and necrosis may be seen
59

f. Lymphocyte depletion type:
i. Diffuse fibrotic variant: entire node is replaced by fibrous tissue appearing as
fibrillar hyaline material; few lymphocytes, atypical lymphocytes,
pleomorphic RS cells are present.
ii. Reticular variant: more cellular; few lymphocytes, large no. of atypical
histiocytes and few typical RS cells are seen.
II. Nodular-lymphocyte predominant type:
I. Newly described
II. Nodular appearance
III. Small lymphocytes predominance
IV. Few RS cells
V. CD 45 positive
VI. Chronic relapsing course
VII. May transform into large B cell NHL

Non Hodgkin Lymphomas:
The types of NHL represent different stages in lymphocyte differentiation
85% are of B cell origin, the rest are T cell or null cell
Classification of NHL
4. Low grade (indolent)
o Long life expectancy if left untreated
o 85-90% present at stage III or IV disease
o Incurable
Types:
1. Small lymphocytic (similar to chronic lymphocytic leukaemia)
This lymphoma is slow growing and composed of small round lymphocytes with scant
cytoplasm and very few mitoses. They almost all of B-cell origin and express pan B-cell
markers, such as CD20, as well as CD5 and CD23. In time they may transform to more
aggressive forms of large cell lymphoma
2. Follicular lymphomas-
Further subdivided on the basis of the relative numbers small cleaved and large non-
cleaved cells in the follicles, into (a) small cleaved, (b) mixed or (c) large
5. Intermediate
Diffuse lymphomas- again subdivided on the same basis as the follicular lymphomas
into (a) small cleaved cell, (b) mixed or (c) large cell
6. High grade (aggressive)
o Life expectancy in weeks if not treated
o Potentially curable
o Types:
Lymphoblastic
Burkitts lymphoma:
Burkitt's lymphoma (BL) (Short notes)
Is a cancer of the lymphatic system (in particular, B lymphocytes).
Highly aggressive lymphoma
60

Usually found in extranodal sites or presenting as an acute leukaemia.
> 90% are E-B virus positive
EBV has trophism for B cells; considered as causative factor for Burkitts lymphoma
Currently Burkitt's lymphoma can be divided into three main clinical variants; By morphology, it
is almost impossible to differentiate these three clinical variants:
o The African endemic,
o The sporadic and
o The immunodeficiency-associated variants.
4. The endemic variant:
o Occurs in equatorial Africa.
o Disease characteristically involves the jaw or other facial bone
5. The sporadic type:
o Jaw is less commonly involved, comparing with the endemic variant. Ileo-cecal region is
the common site of involvement.
6. Immunodeficiency-associated Burkitt lymphoma:
o Is usually associated with HIV infection or occurs in the setting of post-transplant
patients who are taking immunosuppressive drugs.
o Actually, Burkitt lymphoma can be the initial manifestation of AIDS.
Morphology
Consists of sheets of monotonous population of medium size lymphoid cells with high
proliferative activity and apoptotic activity.
The "starry sky" appearance seen under low power is due to scattered macrophages containing
dead body of apoptotic tumour cells.
Multiple myeloma (Myeloma)






5. It is malignancy of plasma cells; monoclonal proliferation of B-cells
6. peek incidence 50-60 years; more in males
7. Aetiology:
1. Radiation
2. Occupational exposure to petroleum products
3. Chromosomal deletions and translocations; Abnormalities are commonly found on
chromosome 13 and chromosome 11,
4. Oncogenes: MYC and RAS
61

Pathogenesis:
1. Multiple myeloma cells adhere to the stromal cells in the bone marrow; inhibit
osteoblastic activity.
2. Adhesion of the multiple myeloma cells stimulates production of interleukin-6, a growth
factor required for survival of the multiple myeloma cells.
3. Interleukin-6 stimulates increased osteoclastic activity
4. This results in bone lesions (lytic lesions), osteoporosis, and hypercalcemia
5. Multiple myeloma cells produce excessive monoclonal proteins - M proteins, which are
classified as heavy amino acid chains and light amino acid chains.
6. The M protein level is referred to as the M-spike in immune electrophoresis. In multiple
myeloma patients the M protein is most commonly Ig.G or IgA.
7. The light amino acid chains are of two types: kappa and lambda. Kappa is twice as
prevalent as lambda. When detected in the urine the light chain fragments are called
Bence-Jones proteins. They are followed as an indicator of disease activity and
progression.
Morphology: osseous and extra osseous lesions
2. It begins in bone marrow in 95% cases
3. Multiple bones are involved- skull, spine and pelvis
4. Normal marrow is replaced by reddish grey gelatinous tissue
5. In X-ray punched out appearance is characteristic
6. bone marrow aspiration may be a dry tap; biopsy required
7. Bone marrow:
1. Hyper cellular
2. >10% are myeloma cells: similar to plasma cells but vary in size; nuclus is
eccentric; unlike normal plasma cell its nuclear chromatin does not show car-
wheel pattern
3. Nucleoli are present
4. Cytoplasm is abundant with perinuclear halo; vacuolation and Russel bodies
containing antibodies
5. Variants of plasma cells:
Flame cells: red cytoplasm
Mott cells: contain grapelike cytoplasmic droplets


Plasma cell Myeloma cell: eccentric nucleus with halo; no cart
weel
62


Normal Protein electrophoresis
Myeloma- M spike in Gamma region
8. Extra osseous:
1. Atypical plasma cells in blood
2. Anaemia
3. Hyperviscocity of blood
4. Nephrosis due to Bence-Jones proteinuria
5. Polyneuropathy
6. Pathologic fractures of bones
7. Systemic amyloidosis myeloma proteins
8. Hepato splenomegaly due to myeloma cells

Bence Jones Protein:
12. Multiple myeloma cells produce excessive monoclonal proteins - M proteins, which are
classified as heavy amino acid chains and light amino acid chains
13. The light amino acid chains are of two types: kappa and lambda. Kappa is twice as prevalent as
lambda. When detected in the urine the light chain fragments are called Bence-Jones proteins
14. Light chains (molecular weight 22,000 d) are polypeptides synthesized by plasma cells and
assembled with heavy chains to form the various classes of immunoglobulins, for example,
immunoglobulin G (IgG), immunoglobulin M (IgM), and immunoglobulin A (IgA).
15. Plasma cells normally produce a slight excess of light chains that are either excreted or
catabolized by the kidney
16. 1% of myeloma are nonsecretory: no Bence-Jones proteins in urine
17. Kappa light chains usually exist as monomers (22,000 d) and are therefore small enough to be
filtered through the glomerulus, but they may exist as dimers. Lambda light chains usually exist
as dimers (44,000 d) and, therefore, are less likely to be filtered and appear in urine.
18. Light-chain proteins appear in urine in high concentration either when the production of light-
chain proteins is markedly increased or when the ability of the proximal tubules to reabsorb all
the filtered protein is exceeded.
63

19. Since mostly excreted in urine they are not present in detectable amount in blood except in
renal failure.
20. They on heating precipitate at 40-60 C and redissolve at higher temperature
21. Causes:
1. Multiple myeloma
2. Plasmacytoma
3. Waldenstrom macroglobulinemia
22. Tests:
1. 5 ml of urine is mixed with 2-3 drops of acetic acid and heated in a water bath; at 40-
60C there will be cloudiness and precipitation; on further heating over 70C the
precipitate dissolves and reappear when cooling below 60 C
2. Serum electrophoresis demonstrates M-band
Multiple myeloma affecting kidney:
1. Tumour invasion: ureteric obstruction and renal hypertension
2. Hypercalcemia
3. Hyperurecemia
4. Amyloidosis
5. BJ proteinuria
6. Glomerular disease
Myeloma kidney (cast nephropathy)
7. Myueloma kidney is one of the several renal dysfunctions due to light chain proteinuria
8. Light chains bind with Tamm-Horsfall mucoprotein, which is secreted by tubular cells in
ascending loop of Henle, forming casts
9. Light chains can precipitate in the tubules, leading to obstructing, dense, intratubular casts in
the distal and collecting tubules that may initiate a giant cell reaction
10. Multinucleated giant cells surround the casts which produces nephropathy
11. Light chain proteins also have direct toxic effect on renal epithelial cells
12. It may also be deposited in basement membrane to produce glomerulopathy

LABORATORY INVESTIGATION OF SUSPECTED MYELOMA
5. Diagnostic triad:
1. myeloma cells >10% in bone marrow
2. Lytic lesions in bones
3. M proteins in serum and urine
6. Serum proteins:
1. Rise in total serum proteins due to paraproteinemia (M proteins or abnormal
immunoglobulin e.g. Bence Jones proteins)
2. Normal IgG, IgA, IgM and albumin levels are low
3. Serum electrophoresis:
1. Spike produced by M proteins; in the region of IgG in 50%; IgA in 25%
2. Another 20 have only light chains in serum
3. No M-bands in non secretary myeloma(1%)

64


4. Serum viscocity:
Hyperviscocity in myeloma
The normal reference range is 1.4-1.8 Centipoises ; >5 in myeloma
Rouleaux formation is often present with increased serum viscosity.
5. Hypercalcemia
6. Hyperurecemia
7. Urine: Bence Jones proteins are present in urine; >6 gms/dL
8. Bone marrow:
1. Hyper cellular
2. >10% are myeloma cells: similar to plasma cells but vary in size; nuclus is
eccentric; unlike normal plasma cell its nuclear chromatin does not show car-
wheel pattern
3. Nucleoli are present
4. Cytoplasm is abundant with perinuclear halo; vacuolation and Russel bodies
which contain antibodies
5. Variants of plasma cells:
Flame cells: red cytoplasm
Mott cells: contain grapelike cytoplasmic droplets


1. Polycystic kidney disease: PKD(short notes)
4. Renal parenchyma is converted into cysts of varying sizes
5. Two types:
1. Adult type: autosomal dominant (ADPKD)
2. Infantile type: autosomal recessive (ARPKD)
6. Adult type:
1. Incidence 1 in 400 to 1000
2. PKD gene is located is in chromosome 16 and rarely in 4
3. Bilateral and diffuse
4. Symptoms appear in 30-50 years of age
5. Morphology:
65

1. Bilaterally enlarged; lobulated; may weigh up to 4 kg
2. Cut surface show cysts in different size; contain straw yellow to reddish brown
material
3. Renal pelvis is distorted by cysts; do not communicate with each other( contrast
to hydronephrosis)
6. Histology:
1. Cysts are parts of nephrons
2. Epithelial lining of cysts are that tubules
3. Parts of glomerulus could be recognized among the cysts
4. Intervening normal renal parenchyma may be seen
5. Acquired inflammation due to pyelonephritis, nephrosclerosis etc may be seen


7. Clinical:
1. Manifest in 30-50 years of age
2. Presents as hematuria and renal pain
3. Hypertension is common
4. Associated cystic changes in liver, panctreas and spleen etc may be present
5. Berry aneurysm of circle of Willis present in 15%
6. Acquired infections may further damage the kidney
2. Infantile type:
9. Autosomal recessive
10. 1 in 20,000 incidence
11. Mutation in chromosome 6-6p-21
12. Bilateral
13. Manifest at birth and renal failure in early childhood
14. Morphology:
1. Bilateral enlargement
2. Smooth surface and shape not distorted
3. Cut surface: small cysts extend radially to cortex; mostly normal parenchyma; pelvis and
ureters normal
15. Histology:
1. Total no of nephrons are normal
2. Sponge like cysts develop from collecting tubules and show cylindrical and secular
dilatation lined by cuboidal or columnar epithelium
66

3. Many glomeruli undergo cystic dilatation


16. Clinical:
1. Gross enlargement may interfere normal delivery
2. Renal failure occurs early
3. Associated cystic disease in liver may lead to congenital fibrosis, portal hypertension
and splenomegaly
4. Severely affected infants are often born with pulmonary hypoplasia and suffer from respiratory
compromise

Glomerulonephritis





67

Glomerulonephritis (Bright disease; nephritic syndrome)
1. Definition:
Renal diseases in which an immunologic mechanism triggers inflammation and proliferation of
glomerular tissue that can result in damage to the basement membrane, mesangium, or
capillary endothelium.
2. Classification:
1. Primary:
10. Acute:
1. Post streptococcal
2. Non streptococcal
11. Rapidly progressive
12. Minimal change disease
13. Membranous
14. Membrano proliferative
15. Focal proliferative
16. Focal segmental glomerulosclerosis
17. IgA nephropathy
18. Chronic GN
2. Secondary:
10. SLE
11. Diabetic nephropathy
12. Amyloid nephropathy
13. Polyarteritis nodosa
14. Wageners granulomatosis
15. Goodpasture syndrome
16. Henoch-Schonlein purpura
17. Systemic infection: Bacterial endocarditis; Falciform malaria etc
18. Idiopathic mixed cryoglobulinemia
4. Hereditary nephritis:
1. Alports syndrome
2. Fabrys disease
3. Nail-patella syndrome
3. Etiopathogenesis of post streptococcal glomerulonephritis (PSGN):
10. Glomeruli consists of: endothelium, epithelium,mesangium and basement membrane(GBM)
11. Acute glomerulonephritis follows infection with certain strains of group A beta-hemolytic
streptococci (GABS). The ones that produce a clear zone of hemolysis around the colony are
called beta hemolytic streptococci;
12. GABS contain M, T and R proteins. Of these, the M protein is the nephritogenic antigen. It is
located in the bacterial cell wall
13. Among the M types, commonly identified nephritogenic strains are 12,4,1
14. It follows mostly skin infection but can also occur after throat infection with nephritogenic
strains
15. Evidence:
1. Low serum complement (C3) levels in the acute phase
68

2. High serum levels of antibodies to streptococcal antigens
3. Electron microscopy reveals lumpy-bumpy deposits on glomerular membrane and in
mesangium
16. Immune-mediated renal injury is a result of renal deposition of circulating immune complexes or
due to their in-situ formation or both
17. Glomerular inflammation follows which leads to complement (C3) activation by classic or more
probably alternate pathway
18. The immune complexes are deposited in the glomerulus produce structural and functional
changes by destruction of basement membrane and accumulation of inflammatory cells
Pathology:
5. Morphology:
1. Kidneys enlarge symmetrically
2. Petichial hemorrhages on the cortical surface give flea-bitten appearance
6. Light microscopy:
1. Glomeruli:
Enlarged and hypercellular glomeruli
Proliferation of mesangial, endothelial and occasionally epithelial cells
Infiltration of polymorphs and sometimes monocytes
2. Tubule:
Deposition of fibrin in tubular lumen and mesangium
RBCs in tubular lumen
3. Interstitium:
Edema and leukocytic infiltration in renal interstitium
4. Vessels:
No changes in blood vessels

7. Clinical:
1. Age incidence is 5-12 years
2. Symptoms develop 1-2 week following streptococcal infection
3. Oliguria and smoky urine
4. Edema is the most frequent manifesting symptom
5. Gross hematuria occurs at onset
6. Hypertension is the third cardinal feature
7. Salt and water retention
8. Complications:
1. CCF
2. Hypertensive encephalopathy
3. Acute renal failure
4. Progressive glomerulonephritis
9. Prognosis:
1. Complete recovery if there are no complications
8. Lab Diagnosis:
Urine
1. Urine output most is often reduced
69

2. proteinuria
3. Hematuria
4. Polymorphonuclear leukocytes and renal epithelial cells
5. Hyaline and/or cellular casts are almost always present.
6. RBC casts have been found in 60-85%
Streptococcal infection
4. Cultures from either the pharynx or skin may be positive
5. ASO, AH, anti-DNase B are positive
6. An ASO titter of 250 U or higher is highly suggestive of recent streptococcal infection.
Complement
2. The concentration of C3 has been found to be decreased in more than 90% of patients
Renal
4. The elevation in the serum concentrations of creatinine and BUN is usually modest,
although some patients may have severe azotemia (Blood urea nitrogen) at onset.
5. The electrolyte profile is usually normal;
6. Hyperkalemia and metabolic acidosis are in patients with significant renal functional
impairment. The same applies to hyperphosphatemia.
Blood
3. A mild anemia (normocytic, normochromic) is
4. WBC and platelet counts are usually normal, although an occasional patient exhibits a
leukocytosis; rarely, a mild thrombocytopenia may be present.


Short notes:

4. Definition:
Primary glomerular diseases are disorders in which the kidneys are the only or predominant
organ involved
5. Examples of Primary glomerular disease:
1. Post streptococcal GN
2. Cresentric GN
3. Membranous glomerulopathy
4. Focal segmental glomerulosclerosis
5. Memranoproliferative GN
6. IgA nephropathy
7. Chronic GN
6. Classification of types of glomerular disease:
1. Antibody mediated : Three forms of antibody mediated injuries:
1. In situ immune complex deposition:
1. Fixed or in situ : Intrinsic glomerular antigens
70

2. Planted: Antigens planted within the glomerulus
2. Circulating antigen antibody complexes:
1. Endogenous:
b. DNA, tumor antigens
2. Exogenous:
Infectious products
3. Cytotoxic antibodies
2. Cell mediated
3. Alternate complement pathway

Normal Post streptococcal






Membranous

71




4. In situ Immune complex disease
5. Fixed or in situ immune complex: Anti GBM antibody induced nephritis: two
experimental models:
iii. Masugi model;
a. Antibodies are formed against antigens which are normal components of
GBM
b. Diffuse linear pattern of immune complex deposition along GBM
c. 5% of Nephritis belong to this model
d. Eg: Good pasture syndrome
iv. Heymann model:
a. Antibodies react with antigens in the basal surface of visceral epithelial cells
b. This is followed by complement activation
c. Immune complexes are formed and deposited along the sub epithelial
aspect of basement membrane in a granular pattern
d. Eg: membranous glomerulonephritis
6. Planted antigen antibody complex:
i. Bacterial, viral and parasitic products and other such antigens may get deposited in
glomerulus
ii. Antibodies bind to these antigens and induce complement activation leading to
immune complex formation and glomerular inflammation.
iii. Eg. Post streptococcal GN
7. Circulating antigen antibody complexes:
i. Endogenous: eg: SLE
i. Antigen from host tissue form antibody complexes and then get trapped in
glomeruli
ii. Complements are activated
iii. Glomerular injury occurs
iv. Eg: nephritis in SLE
ii. Exogenous:
i. Antigens are formed against infections like streptococci, Hepatitis B,
Treponema, Plasmodium etc
ii. Trapped in glomeruli followed by inflammation
72

iii. Eg: Nephritis associated with streptococci, Hepatitis B, Treponema,
Plasmodium etc
8. Cytotoxic antibodies:
i. Glomerular cells themselves may act as antigens
ii. Antibodies develop and immune complexes are formed
iii. Injury is caused by cytotoxic mechanism
5. Cell mediated injury:
iv. T cells get sensitized and together with activated macrophages can cause
glomerular injury
v. Cytokines and other mediators from T cells are responsible for this cytotoxic injury
vi. Example: pauci-immune glomerulonephritis
6. Alternate complement pathway:
7. The normal complement system consists of the classic and alternative pathways. The
classic pathway is activated by the interaction of C1 with an antigen-antibody complex.
This interaction results in the formation of C4b2a, which is the classic pathway C3b
convertase. The alternative pathway utilizes C3 and factors B and D to form the
alternative pathway convertase C3b,Bb.
8. Mainly Complement- 3 contributes to this type of injury
9. Immune complexes are found in the mesangium and subendothelial spaces, and they
trigger complement activation and the release of cytokines and chemokines. The release
of inflammatory mediators causes an influx of inflammatory cells and leads to mesangial
and endothelial cell proliferation.
10. Example : Memranoproliferative glomerulonephritis
7. Mediators of glomerular injury:
11. Cells:
1. Neutrophils and monocytes: release proteases which cause GBM degradation;
2. Macrophages and T lymphocytes and NK cells: produce variety of lymphokines
and other mediators
3. Platelets: release eicosanoids and growth factors
4. Mesangial cells: release cytokines, chemokines, eicosanoids and growth factors
etc
12. Soluble mediators:
1. Formation of C5b-C9 causes cell lysis
2. Interleukin-1 and TNF produce leukocyte adhesion and other effects
3. Fibrin leaks into Bowmans space and induce crescent formation
4. Plasminogen activator inhibitors induce thrombosis and fibrosis
8. Glomerular localization of antigen antibody complexes:
4. Immune complexes get deposited in mesangium, subenotheilal space, sub epithelial space
5. The deposits may be granular or diffuse linear pattern
6. Localization depends on molecular charge:
1. anionic : sub endothelial
2. cationic: sub epithelial
3. neutral: mesangium
9. The injury process due to antigen antibody complexes:
73

3. There are histologic and functional changes
4. Histologic:
1. Histologic changes may be diffuse, global or segmental or masangial
2. Leukocytic infiltration at the site and hypercellularity
3. Proliferation of measangial and epithelial cells
4. Formation of crescent
5. Basement membrane thickening
6. Hyalinization and sclerosis
10 . Functional changes:
4. Proteinuria
5. Hematuria
6. Renal failure


Short notes:

Synonym: rapidly progressive glomerulonephritis:
5. Definition:
1. A syndrome of severe glomerular injury
2. Does not denote any specific etiology
3. Rapid and progressive loss of renal function
4. Classic histology is presence of crescents in most glomeruli;
6. Classification:
1. Group I:
1. Anti GBM antibody induced glomerulonephritis
2. Linear deposits of Ig.G and C3 in GBM
3. In some similar lesions in lungs (Good pasture syndrome)
2. Group II:
1. Immune complex mediated disease
2. Granular pattern of immune complex deposits
3. Eg. Post infectious, SLE, IgA, Henoch-Schonlein nephropathies
3. Group III:
1. Pauci immune type
2. No immune complex or anti GBM antibody deposits
3. Antineutrophil cytoplsamic or perinuclear antibodies are present in serum
4. Mostly idiopathic
5. Probably a manifestation of small vessel vasculitis limited to glomerulus
7. Pathology:
1. Kidneys are enlarged, pale with petichiae
2. Crescents are present in Bowman capsule; they are formed by proliferation of parietal
cells, monocytes, macrophages, Neutrophils and lymphocytes in a fibrin meshwork;

74

3. Rupure of GBM and passage of proteins, inflammatory cells into Bowmans space which
form crescents.

8. Clinical:
1. Hematuria
2. Hypertension and edema
3. Hemoptysis in Good-pasture syndrome
4. Presence of serum anti-GBM, antinuclear, ANCA antibodies depending on the type
5. Plasma exchange, steroids, cytotoxic agents may help in recovery.




7. Definition: It is a membranous glomerulopathy with diffuse thickening of glomerular capillary
wall, immune complex deposits along the sub epithelial side of GBM
1. Massive proteinuria >3.5 gm/day
2. Hypoalbuminemia < 3 gm/dL
3. Edema
4. Hyperlipidemia and lipiduria
8. Age: 6-8 years
9. Etiology and Classification:
1. Idiopathic
2. Drug induced: gold, NSAID
3. Malignancy: Hodgkin, Ca Lung, colon and melanoma
4. SLE
5. Infections: Hepatitis B,C, syphilis, malaria etc
6. Autoimmune : thyroiditis
10. Pathogenesis:
1. Immune complex mediated
75

2. Idiopathic form: the in situ antigen is an unidentified antigen due to a genetic
susceptibility
3. C5b-C9 complex induce mesangial and epithelial cells to liberate proteases and oxidants
which cause capillary wall injury and increased protein leakage.
4. No circulating immune complex
5. In secondary forms specific antigens could be identified
11. Pathology:
1. Kidneys are enlarged and pale
2. Glomeruli:
1. Diffuse thickening of capillary wall
2. Thickening of GBM
3. No cellular proliferation
3. Tubule:
1. Normal
4. Interstitium:
1. Fine Fibrosis and scanty inflammatory cells
5. Vessels:
1. Hypertensive changes in late stage
6. Electron microscopy:
1. Immune complex deposits in subepithelial location
2. GBM appear as spikes between deposits
7. Immunoflorescence:
1. Granular deposits of immune complex (IgG+C)
12. Complications:
1. Hypertension
2. End stage renal disease and renal failure
3. Azotemia
4. Renal vein thrombosis


7. In 1919, Good pasture described a syndrome characterized by hemoptysis, alveolar hemorrhage
and necrosis, and proliferative glomerulonephritis in a patient during an influenza epidemic.
Autopsy revealed that the patient had a vasculitis
8. Definition:
Is a triad of diffuse pulmonary hemorrhage (as seen in the images below),
glomerulonephritis, and circulating anti glomerular basement membrane (anti-GBM)
antibodies.
9. It is a type I of crescentric glomerulonephritis
10. It is a immune complex disease due to anti GBM antibodies which also cross react with
pulmonary alveolar basement membrane producing both pulmonary and renal lesions
11. The antigen called Goodpasture antigen is a component of alpha 3 chain of collagen type IV
12. Pathology:
a. Kidneys are enlarged, pale with petichiae
76

b. Crescents are present in Bowman capsule; they are formed by proliferation of parietal
cells, monocytes, macrophages, Neutrophils and lymphocytes in a fibrin meshwork;

c. Rupture of GBM and passage of proteins, inflammatory cells into Bowmans space which
form crescents.
d. Diffuse linear pattern of immune complex deposition along GBM


6. It is a tubulo interstitial diseasae resulting from repeated attacks of inflammation and scarring.
7. Etiopathogenesis: two types
a. Reflux nephropathy
b. Obstructive pyelonephritis
8. Reflux nephropathy:
a. Congenital absence or shortening of intravesical portion of ureter leading to reflux
during micturition as the valvular mechanism is lost
b. Urine reflux into ureter and pelvis
c. One or both kidneys are damaged with scarring
d. Urinary infection is also common
9. Obstructive pyelonephritis:
a. Obstruction can occur at variable levels( eg. Pelvi ureteric junction or posterior urethral
valve or renal calculi)
b. Unilateral or bilateral
c. Infections superimpose obstruction
d. Inflammations lead to chronic pyelonephritis
10. Morphology:
a. Gross:
i. Kidneys are irregularly scarred
ii. Small and contracted
iii. Capsule is adherent with scars
iv. If bilateral the involvement is asymmetrical as opposed to chronic
glomerulonephritis which is symmetrical
v. The diseased cortex is dilated, blunted, and deformed.
vi. The overlying cortex is represented by scar which show U shaped depressions
on the cortical surface
vii. Pelvis is dilated
b. Microscopic:
i. Interstitium:
1. Chronic inflammation is seen
2. Varying degrees of inflammation in the cortex and medulla
3. Neutrophilic infiltrations
4. Pus casts in the tubules
77

5. Xanthogranulomatous pyelonephritis occurs in proteus infections
6. Fibrotic changes in cortex, medulla and calyx
7.
ii. Tubules:
1. Tubules show atrophy, hypertrophy and dilatations
2. Dilated tubules are filled with colloid casts (throidization)
iii. Glomerulus:
1. Periglomerular fibrosis may be present
2. Focal segmental glomerulosclerosis may be seen
iv. Blood vessels:
1. Show obliterative endarteritis
2. Secondary changes may occur due to hypertension
v. Pelvi calyceal system:
1. Pelis and calyx are dilated
2. Walls show chronic inflammation with lymphoid follicles
3. Epithelium undergoes squamous metaplasia





Short notes:

1. Definition: it is an acute suppurative inflammation of the kidney caused by pyogenic bacteria
2. Etiopathogenesis:
a. Mostly ascending infection from lower UTI with E.coli (90%), Enterobacter, Klebsiella,
Psuedomonas and Proteus
b. Haematogenous from sites of infection
3. Ascending infection:
Female:
i. Fecal contamination of urethral orifice in female
ii. Short urethra
iii. Bacterial adherence to mucosa due to hormonal influence
78

iv. Prostatic secretion is antibacterial and is lacking in female
v. Urethral trauma during sexual intercourse (honeymoon pyelitis)
vi. Aggravating factors:
1. Diabetes
2. Pregnancy
3. Urinary obstruction due to calculi etc
4. Bladder catheterization
vii. In bladder they produce asymptomatic bacteria; on ascending up to renal cortex
pyelonephritis is produced;
viii. Reflux mechanism is not involved as in chronic pyelonephritis
4. Haematogenous infection:
a. Infants
b. Malignancy with immunoincompetence
5. Morphology:
a. Gross:
i. Enlarged and swollen kidneys; bulge on section
ii. Cut surface show small pockets of pus with hemorrhagic rim mainly in cortex
b. Microscopy:
i. Acute inflammation of interstitium with large no of polys
ii. Destruction of tubules
iii. Abscess in renal parenchyma
iv. Glomerulus and renal vessels not much affected due to their resistance to
infection
6. Clinical:
a. Acute onset of chills with fever
b. Loin pain
c. Dysuria
d. Frequency of micturition
7. Lab: Urine
a. Bacturia
b. Pus cells
c. Pus cell casts
8. Complications:
a. Papillary necrosis
b. Pyonephrosis(bag of pus in kidney)
c. Perinephric abscess(due to local spread)

Short notes:

1. Urinary casts are cylindrical structures produced by the kidney and present in the urine in
certain disease states.
2. They form in the distal convoluted tubule and collecting ducts of nephrons, then dislodge and
pass into the urine, where they can be detected by microscopy.
79

3. They form via precipitation of Tamm-Horsfall mucoprotein which is secreted by renal tubule
cells, and sometimes also by albumin in conditions of proteinuria.
4. Cast formation is pronounced in environments favoring protein denaturation and precipitation
(low flow, concentrated salts, low pH). Tamm-Horsfall protein is particularly susceptible to
precipitation in these conditions.
5. The Tamm-Horsfall protein is a glycoprotein isolated from normal urine by Tamm and Horsfall
in the early fifties. This protein is excreted by the thick ascending branch of the loop of Henle
and the first part of the distal tubules. Normal daily excreted quantity ranges from 25 to 50 mg.
This protein is the major fraction of the uromucoprotein.
6. Casts are elements of the urinary sediment, formed by the polymerisation of the Tamm-Horsfall
fibrils, taking the shape of the site of its formation (casting). Casts are formed, after the loop, in
the late section of the distal tubules and the early section of the collecting tubes. The formation
site is the nephron's section where the dilution is maximal.
7. As mentioned earlier, fibril's formation is inhibited by a low ionic strenght, and the precipitation
is promoted by the addition of albumin.
8. Types of casts:
1. Hyaline casts
a. The most common type of cast, hyaline casts are solidified Tamm-Horsfall mucoprotein
secreted from the tubular epithelial cells of individual nephrons.
b. Low urine flow, concentrated urine, or an acidic environment can contribute to the
formation of hyaline casts, and, as such, they may be seen in normal individuals in
dehydration or vigorous exercise.
c. Hyaline casts are cylindrical and clear, with a low refractive index, so that they can easily
be missed on cursory review under brightfield microscopy, or in an aged sample where
dissolution has occurred. On the other hand, phase contrast microscopy leads to easier
identification.
d. Given the ubiquitous presence of Tamm-Horsfall protein, other cast types are formed
via the inclusion or adhesion of other elements to the hyaline base.
2. Granular casts
a. The second-most common type of cast, granular casts can result either from the
breakdown of cellular casts or the inclusion of aggregates of plasma proteins (e.g.,
albumin) or immunoglobulin light chains.
3. Waxy casts
a. waxy casts suggest the very low urine flow associated with severe, longstanding kidney
disease such as renal failure. It is seen in Chronic Renal Failure.
4. Fatty casts
a. Formed by the breakdown of lipid-rich epithelial cells, these are hyaline casts with fat
globule inclusions, yellowish-tan in color. They can be present in various disorders,
including nephrotic syndrome, diabetic or lupus nephropathy.
5. Cellular casts
a. Red blood cell casts
i. The presence of red blood cells within the cast is always pathological, and is
strongly indicative of glomerular damage, which can occur in glomerulonephritis
from various causes or vasculitis, including Wegener's granulomatosis, systemic
80

lupus erythematosus, post-streptococcal glomerulonephritis or Goodpastures
syndrome.
b. White blood cell casts
i. Indicative of inflammation or infection, the presence of white blood cells within
or upon casts strongly suggests pyelonephritis, a direct infection of the kidney.
c. Epithelial cell casts
i. This cast is formed by inclusion or adhesion of desquamated epithelial cells of
the tubule lining. Cells can adhere in random order or in sheets and are
distinguished by large, round nuclei and a lower amount of cytoplasm.




81

Legend: A: Hyaline cast; B: Fatty cast; C: Hyaline to finely granular cast; D: Cellular cast;
E: Cellular to coarsely granular cast; F: Coarsely granular cast; G: Finely granular cast; H:
Granular to waxy cast, I: Waxy cast.




Short notes:

Synonym:
Chronic glomerulonephritis:
End stage renal disease:
1. Chronic glomerulonephritis represents the end-stage of all glomerulonephritis with unfavorable
evolution. This general (glomerular, vascular and interstitial) affection constitutes the "end stage
kidney". In most cases, it is associated with systemic hypertension.
2. Causes:There are a number of different forms of glomerulonephritis, including:
1. acute glomerulonephritis,
2. membranoproliferative glomerulonephritis,
3. rapidly progressive glomerulonephritis,
4. idiopathic membranous glomerulonephritis, and
5. IgA nephropathy, any of which can progress to chronic glomerulonephritis.
6. Systemic hypertension
3. Morphology:
1. Gross: Kidneys are symmetrically contracted,and have diffusely granular cortical
surfaces.
2. C.S: the cortex is thinned; peripelvic fat is increased;
3. Microscopic:
i. Glomeruli: reduced in no.; mostly converted into hyalinized tufts
ii. Tubules: atrophy of tubules; tubular cells show hyaline deposits
iii. Interstitium: show fine fibrosis and chronic inflammatory cells
iv. Vessels: in hypertension, the vessels show arteriolar sclerosis
4. Patients on dialysis: show acquired cystic disease, adenomas, calcification of tufts.
Short notes:

1. Definition: destruction of tubular epithelial cells leading to acute renal failure.
2. Commonest cause of renal failure
3. Pathogenesis: two types:
1. Ischemic; & Toxic
2. Tubular epithelium is highly susceptible for ischemic or toxic agents
3. Arteriolar vasoconstriction and toxins produce necrosis of tubules and the debris causes
obstruction to urinary outflow
82

4. Increased intratubular pressure produce damage to basement membrane and rupture of
tubules
5. Leakage of fluid from tubules produce interstitial edema
6. This further compress tubules and arterioles leading on to a vicious cycle.
7. The events end up in acute renal failure reduced GFR and olguria
4. Ischemic ATN: synonyms: lower nephron nephrosis; shock kidney
1. More common- 80%
2. Due to hypotension from:
1. Burns
2. Hemorrhage
3. Crush injuries
4. Mismatched blood transfusion
5. Black water fever
3. Morphology:
1. Gross: kidneys are enlarged and swollen
2. C.S: pale cortex and dark medulla
3. Microscopy:
a. Glomeruli are not affected
b. Interstitium show edema
c. Tubules:
Dilatation
Focal necrosis
Flattened epithelium
Lumen contains eosinophilic hyaline and hemoglobin casts
Disruption of tubular basement membrane
4. Prognosis: depends on underlying cause; usually worse
5. Toxic ATN: upper nephron nephrosis
1. Etiology:
1. Poisons: Mercuric chloride, carbon tetrachloride, mushroom poison, insecticides
2. Heavy metals: lead, mercury, arsenic, phosphorus and gold
3. Drugs: sulfonamides, gentamycin, halothane, salicylates
4. Radiographic contrasts
2. Morphology:
1. Gross: kidneys are enlarged and swollen
2. C.S: pale cortex and dark medulla
3. Microscopy:
a. Glomeruli are not affected
b. Interstitium show edema
c. Tubules:
Diffuse and not focal involvement
Proximal tubules are necrotic and desquamated and calcified
Tubular basement membrane is intact
Flat and thin epithelial regeneration may be seen
4. Prognosis:
83

5. Relatively good
Short notes:

Nephrolithiasis or urolithiasis
1. Incidence 2%; 20-30 years of age;
2. Types:
1. Calcium stones:
1. 75% commoner
2. Calium oxalate, phosphate or mixed
3. Etiology:
a. Mostly idiopathic
b. Hyperparathyroidism
c. Renal hypercalciuria
4. Pathogenesis:
a. Imbalance between calcium ions and factors inhibiting precipitation
b. An epithelial debris forms a nidus around which Ca is deposited
5. Morphology:
a. Stones are small, ovoid, hard, granular rough surface
2. Mixed stones:
1. M,ade of magnesium ammonium- calcium phosphate called struvite stones
2. Etiology: fallow infection like proteus( not with E.coli)
3. Morphology:
a. Yellow-white
b. Soft and friable
c. Irregular
d. Stag horn stone: the stone takes the shape of renal pelvis
3. Uric acid:
1. Radiolucent
2. Formed in Gout and Leukemias due to hyperuricosuria
3. Salicylates and probenacid also produce uricosuria
4. Acidc pH and low urinary volume are favourable for the stone formation
5. Stones are yellow brown , multiple and smooth and hard, C.S show lamination
4. Cystine stones:
1. Associated with cystinuria
2. Exces cystine in urine form crystals and then stones
3. Stones are small, rounded, smooth and multiple; yellow and waxy.
5. Others: Xanthine stones occur in hereditary xanthinuria

S.N:
1. Leading cause of renal morbidity
2. 40% of diabetics develop end stage kidney disease
3. Diabetes affects:
a. Glomerulus:
84

i. Non nephrotic proteinuria
ii. Nephrotic syndrome
iii. Chronic renal failure
b. Renal arterioles:
i. Hyalinizing arteriolar sclerosis
4. Proteinuria:12-22 years after diabetes; initially microalbuminemia occurs followed by nephrotic
type proteinuria;
5. Pathogenesis:
a. It is described as diabetic microangiopathy
b. Glycosylation end products leads to thickening of GBM and increased mesangial matrix
c. Hemodynamic changes i.e increased GFR, increased glomerular capillary pressure,
glomerular hypertrophy lead to glomerulosclerosis
d. Sequence of changes:
Hyperglycemia glomerular hyperperfusion renal hyperperfusion deposition of
protein in measngium glomerulosclerosis renal failure
6. Morphology:
a. GBM: increased thickening is the basic pathology
b. Measngium: proliferation of mesangial cells and increase in mesangial matrix
c. Diffuse Glomerulosclerosis:
i. Capsular cap: eosinophilic hyaline thickening of the parietal layer Bowmans
capsule
ii. Fibrin cap: eosinophilic material on the walls of lobular capillary vessels
d. Nodular Glomerulosclerosis:
i. Occurs in juvenile diabetes
ii. Nodular lesions appear in glomeruli which contain lipid and fibrin
iii. Nodules compress glomerular capillaries which ultimately lead to contracted
kidney
e. Vascular lesions:
i. Atherosclerosis of renal arteries
ii. Arterioscelrosis of afferent and efferent arterioles
iii. They produc renal ischemia
f. Pyelonephritis:
i. Bacterial infections lead to papillary necrosis leading to pyelonephritis (acute
and chronic)
g. Tubular lesions:
i. Glycogen deposits in the epithelial cells of proximal convoluted tubules
ii. They are called Armanni-Ebstein lesions

S.N: Analgesic nephropathy.
1. Analgesic nephropathy is injury to the kidney caused by analgesic medications such as aspirin,
phenacetin, and NSAID. The term usually refers to damage induced by excessive use of
combinations of these medications, especially combinations that include phenacetin
2. There is a predominant involvement of tubules and interstitium
3. Pathology:
85

a. Acute or chronic
b. There is Interstitial edema with leukocytic infiltration
c. Focal tubular necrosis
d. In chronic form there will be fibrosis and tubular atrophy

S.N: Haemolytic uremic syndrome.(Thrombotic micro angiopathy)
1. It belongs to group called thrombotic microangiopathy
2. There is thrombosis in the capillaries and arterioles through the body
3. Triad:
a. Microangiopathic hemolytic anemia
b. Thrombocytopenia
c. Renal failure
4. Classification:
a. Childhood HUS:
i. Due to bacterial dysentery and its toxic effect on capillary endothelium
b. Adult HUS:
i. Infection
ii. Antiphospholipid antibodies
iii. Pregnancy complication
iv. Oral contraceptive
v. Radiation
vi. Immunosupressive drugs
5. Pathogenesis:
a. Classic Childhood HUS:
i. Follows E.coli and shigella infection
ii. Toxin acts on endothelium of microvascular system:
1. Endothelial lysis
2. Leukocyte adhesion
3. Increased thrombosis
4. Vasoconstriction
6. Morphology:
1. Diffuse cotrtical necrosis
2. Endothelial and sub endothelial swelling swelling in glomeruli
3. Measngiolysis
4. Thrombus occlusion of afferent arterioles

Pathology: short notes

1. Definition: the rate of sedimentation of red blood cells per hour
2. Estimation:
86

a. Wintrobes and Landsbergs method: ESR is measured on undiluted blood in a
haematocrit tube
b. Westerngrens method: measured on venous blood diluted with 1 volume of 3.8%
sodium citrate and 4 volume of blood
c. Modified methods:
i. Zeta sedimentation ratio
ii. Micro ESR method
3. Normal ESR:
a. Westerngrens method: 10mm/hour for men; 20 mm/hour women; ESR increases
normally with age
4. Factors influencing ESR:
a. Specific gravity of plasma
b. Rouleaux formation of RBCs
c. No of red cells
d. Plasma viscosity
e. Prior IV fluids
5. Roleaux formation depends on:
a. Fibrinogen
b. Alpha 2 globulin and gamma gloubulin
c. Glycoprotein
6. Conditions of elevated ESR:
a. Infections: TB, Kala Azar,most chronic infections
b. Inflammation: Rheumatoid arthritis, Rheumatic fever, other connective tissue disorders
c. Neoplasm: Multiple myeloma, lymphoma, paraproteinemias
d. Miscellaneous: aplastic anemia, autoimmune disorders, anemia
7. Conditions of low ESR:
a. Ploycythemia
b. Sickle cell anemia
1. Turner syndrome:
1. Pathophysiology:
a. It is a monsomy (45, X0) due to loss of one X chromosome in paternal meiotic division
b. Turner syndrome is also caused by the absence of one set of genes from the short arm
of one X chromosome
c. In addition to monosomy X, a similar clinical picture is found with a individuals with X0-
XX mosaic karyotypes.
2. The frequency is approximately 1 in 2000 live-born female infants .

As many as 15% of
spontaneous abortions have a 45,X karyotype.
3. Features:
a. Short stature
b. A high arched palate suggests the diagnosis. Patients may have dental crowding or
malocclusion.
c. Ovarian failure
d. Lymphedema may be present at any age
87

4. Turner syndrome may be prenatally diagnosed by amniocentesis or chorionic villous sampling.
2. Down syndrome:
1. In 1866, Down described clinical characteristics of the syndrome that now bears his name.
2. It is caused by trisomy in chromosome 21
3. The frequency is about 1 case in 800 live births.
4. Causes of trisomy:
a. Non dysjunction of one chromosome during maternal meiosis to form egg
b. Mother is a translocation carrier in which translocation of long arm occurs between 14
and 21 chromosomes; she remains normal due to balanced translocation and the
offspring inherits the trisomy syndrome
c. Advanced maternal age is the important factor for trisomy 21
5. Features:
a. Mangoloid slant of palpebral fissure
b. Simian crease in palms
c. Sandle cleft between 1&2 toes
d. CHD often endocardial cushion defect
e. Proneness for leukemia
f. Association: deafness and hypothyroidism
g. Accident proneness
h. Love for music and cooperation with mother in household work are interesting faetures
6. Prognsosis:
a. Mostly aborted
b. Dath from 1 year to 50 years
Kleinfelters syndrome:
1. It is a trisomy affecting sex chromosomes; It is defined classically by a 47,XXY karyotype with
variants that demonstrate additional X and Y chromosomes.
2. Affected person is a genotypically a male with abnormal feautures
3. 80% are have 47 xxy while others are mosaics
4. Approximately 1 in 500-1,000 males is born with an extra sex chromosome
5. The 47,XXY karyotype of Klinefelter syndrome spontaneously arises when paired X
chromosomes fail to separate (nondisjunction in stage I or II of meiosis, during oogenesis or
spermatogenesis). Maternal and paternal meiotic nondisjunction each account for
approximately 50% of Klinefelter syndrome cases
6. Infertility, tyeasticular dysgenesis and gynecomastia are the 2 most common symptoms that
lead to diagnosis in patients with Klinefelter syndrome.
7. Other symptoms include fatigue, weakness, erectile dysfunction, osteoporosis, language
impairment, academic difficulty, subnormal libido, poor self-esteem, and behavioral problems.
Von Willebrand disease:
1. Hereditary coagulation disorder due to qualitative and quantitative defect in von
Willebrand factor which is Factor VIII and vWF complex
2. vWF gene is located in Chromosome 12 while factor VIII gene is in X chromosome
88

3. vWF is synthesised in endothelial cells, megakaryocytes and platelets while Factor VIII is
synthesised in Liver
4. vWF facilitates adhesion of platelets; Factor VIII activates Factor X in coagulation cascade
5. vWF and Factor VIII circulate and function as single unit for clotting mechanism: factor X
actvation and platelet adhesion;
6. Clinical types:
a. Type I: common variety; 50% vWF activity; synthesis of vWF is normal but release is
inhibited
b. Type II: less common; normal vWF but functionally defective
c. Type III: rare form; most severe; vWF is absent.
7. Manifestations:
a. Spontaneous bleeding from mucous membranes
b. Excessive bleeding from wounds
8. Lab findings:
a. Bleeding time is prolonged
b. Normal platelet count
c. Reduced plasma vWF
d. Platelet adhesion using ristocetin is defective
e. Reduced Factor VIII
9. Treatment:
a. Cryoprecipitate or factor VIII concentrate

Meningioma:
1. The tumour arises from capcell layers of arachnoid
2. 20% of intracranial tumours
3. Common sites:
a. More common:
i. latreral cerebral convexities
ii. midline along falx cerebri
iii. olfactory grove
b. less common:
i. cerebral ventricles
ii. foramen magnum
iii. cerebello pontine angle
iv. spinal cord
4. Usually solitary; multiple in patients of neurofirmatosis
5. Age : 2-6 decade; slight female preponderance
6. They are benign tumours; melignant meningioma can occur rarely
7. Morphology:
a. Circumscribed solid spherical mass-1 to 10 cm
b. Attached to dura but not invasive
c. C.s: firm and fibrous; occasional calcification
d. Microscopy: 5 types
89

i. Meningtheliomatous: polygonal cells; central nucleus with abundant
cytoplasm;irregular lobulation by collagenous stroma
ii. Fibrous meningioma: tumour cells form parallel bundles
iii. Transitional meningioma:cells with syncytial and fibroblastic features; cells in
whorled pattern
iv. Angioblastic meningioma: resemble in hemangioblastoma
v. Anaplastic : malignant variety

1. It is a type of reversible cell injury
2. It is due to derangement of plasma membrane
3. Cellular swelling is the first manifestation of almost all forms of injury to cells. It is a difficult
morphologic change to appreciate with the light microscope; it may be more apparent at the
level of the whole organ.
4. Morphology:
a. When it affects many cells in an organ, it causes some pallor, increased turgor, and
increase in weight of the organ.
b. On microscopic examination, small clear vacuolesmay be seen within the cytoplasm;
these represent distended and pinched-off segments of the endoplasmic reticulum. This
pattern of nonlethal injury is sometimes called hydropic change or vacuolar
degeneration.
c. Swelling of cells is reversible.
d. The ultrastructural changes of reversible cell injury include:
1. plasma membrane alterations
blebbing
blunting
distortion of microvilli
creation of myelin figures
loosening of intercellular attachments
mitochondrial changes
2. mitochondrial swelling
mitochondrial rarefaction
appearance of small phospholipid-rich amorphous densities
3. dilation of the endoplasmic reticulum
detachment
disaggregation of polysomes nuclear alterations
disaggregation of granular and fibrillar elements




1. definition:
90

a. Embolism is the process of partial or complete obstruction of some part of CVS by any
mass carried in the circulation
b. Liquid embolism are due to fat globules, amniotic fluid, and bone marrow
2. Fat embolism:
a. Obstruction of arteriole or capillaries by fat globules
b. Causes:
1. Trauma of bones: fractures and orthopaedic surgeries
2. Trauma of soft tissue injury: crush injury of muscles and pelvic tissue injury in
purperium
3. Burns
4. Diabetes mellitus
5. Fatty liver
6. Pancreatitis
7. Sickle cell anemia
8. Fat or oil introduced in the body
c. Pathogenesis: Theories:
1. Mechanical: Mechanical injury to fat tissues and entering venous circulation
2. Emulsion instability: Aggregation of plasma lipids due to disturbances in
emulcification
3. Intravascular coagulation: In stress some factor actvates DIVC and aggregation
of fat emboli
4. Toxic injury: free fatty acids injure capillaries and lead to pulmonary edema
3. Amniotic fluid embolism:
a. Pathogenesis:
1. Mechanism not clear
2. May enter through tears in the myometrium and endocervix
3. Omniotic fluid may eneter uterine sinusoids during vigorous contractions
b. Morphology:
1. Haemorrhages and oedema in lungs; amniotic fluid traces in pulmonary
90microcirculation
2. Changes of ARDS
3. Dilatation of Rt heart
c. Causes of death:
1. Hypoxia
2. Anaphylaxis
3. DIC
4. Haemorrhage due to thrombocytopenia

1. Autosomal recessive lipid storage disorder characterized by accumulation of sphingomyelin and
cholesterol due to deficiency of sphincomyelinase.
2. Type A: more common; infancy; hepeato splenomegaly; lymphadenopathy, mental retardation;
cherry red spot in macula of retina
3. TypeB: later childhood; progressive hepato splenomegaly; cirrhosis; lung infiltration
91

4. Microscopy:
a. Lysosomal deposits of sphingomyelin and cholesterol
b. The pathologic hallmark in Niemann-Pick disease types A and B is characteristic lipid-
laden foam cell, often termed the Niemann-Pick cell, on bone marrow examination.
c. These cells, which can be readily distinguished from Gaucher cells by histologic and
histochemical characteristics, are histologically similar to cells found Wolman disease,
cholesterol ester storage disease, lipoprotein lipase deficiency, and, in some patients,
G
M1
gangliosidosis type 2.
Myelodysplastic syndrome:
1. Definition: group of haematopoietic clonal stem cell disorders having . All are characterized by a
hypercellular or hypocellular marrow with impaired morphology and maturation (dysmyelopoiesis) and
peripheral blood cytopenias, resulting from ineffective blood cell production.
2. All 3 cell lineages in myeloid hematopoiesis can be involved, including erythrocytic, granulocytic, and
megakaryocytic cell lines.
3. FAB classification:
a. Refractory anemia: Anemia without blasts in blood; marrow shows <5% blasts
b. Refractory anemia with ringed sideroblast : marrow shows >15% ringed sideroblasts
c. Refractory anemia with excess blasts:
d. Chronic myelomonocytic leukemia
e. Refractory anemia with excess blasts in transformation
4. Etiology;:
a. Idiopathic
b. Radiation exposure
c. Benzene carcinogen
d. Secondary MDS follow cancer therapy
e. Fanconi anemia
5. Pathophysiology : Chromosomal defects: trisomies, translocations and deletions are seen;
Mutation in N-RAS oncogene
6. Age: 6
th
decade; male preponderance;
7. Clinical: Anemia, fever, wt loss, splenomegaly in 20%
8. Lab:
a. Blood: cytopenia of 2 or more cell lines-pancytopenia
b. Macrocytic or dimorphic anemia
c. Hyposegmented and hypogranular Neutrophils
d. Myeloblasts may be seen
e. Thrombocytopenia and large platelets
9. Marrow:
a. Hypo or hyper cellular
b. Ring sideroblasts
c. Hyposegmented and hypogranular myeloid precursors
d. Reduced magakaryocytes

Disseminated Intravascular Coagulation (DIC) (consumptive coagulopathy)
1. Thrombohaemorrhagic disorder occurring as a secondary complication of a systemic disease
92

2. Causes:
a. Massive tissue injury:
i. abruption placentae
ii. amniotic fluid embolism
iii. Retained dead foetus
iv. Crush injuries
v. Surgery
vi. Malignancy
b. Infections:
i. Endotoxicemia
ii. Gram negative sepsis
iii. Viral infections
iv. Malaria
v. Aspergellosis
c. Epithelial damage:
i. Aortic aneurysm
ii. Haemolytic uremic syndrome
iii. Burns
iv. Acute glomerulonephritis
d. Miscelaneous:
i. Snake venom
ii. Shock
iii. Intravascular haemolysis
iv. Heat stroke
3. Pathogenesis:
a. Activation of coagulation by releasing tissue factors following tissue injury
b. Endothelial damage in microcirculation followed by platelet adhesion
c. Consumption of coagulation factors during extensive coagulation
d. Fibrinolysis - a secondary event
4. Clinical:
a. Organ (kidney, brain etc) damage due thrombotic ischemia
b. Haemolytic anemia
c. Thrombotic manifestations
5. Lab:
a. Platelet count is low
b. Smear : schistocytes and fragmented red cells
c. Prolonged prothrombin, thrombin and partial thromboplastin times
d. Low plasma fibrinogen
e. Fibrin degradation products are elevated

93





1. Fibronectin is adhesive Glycoprotein called CAM or cell adhesion molecules, one of the
components of extra cellular matrix (ECM)
2. They are located in cell membrane where they function as receptors for hemotypic and
heterotypic interaction between cells
3. Fibronectin is a large protein that binds to many molecules like collagen, fibrin, proteoglycons
and cell surface receptors.
4. 2 typpes: tissue fibronectin formed by fibroblasts and plasma fibronectins synthesised in liver
5. Tissue fibronectins forms fibrils that helps in wound healing
6. Plasma Fibronectin binds to fibrin forms a provisional clot that fills a gap created by a wound
7. Tissue fibronectins are responsible for the primitive matrix found in fetus
8. Fetal fibronectin is detectable in vaginal secretions of pregnant women and its estimation helps
in detecting preterm delivery; From weeks 22 to 35 in your pregnancy, there should be very
little fFN detectable.


1. A lab test for the diagnosis of SLE
2. Principle:
a. antinuclear antibodies (ANA) cannot penetrate the intact cells and need to be exposed
for ANA to bind.
b. ANA and cell nucleus binding form a mass called LE Body.
c. Phagocytic leukocyte engulfs LE body and becomes an LE cell
d. Formation of LE cell can be demonstrated in vitro as follows:
e. Blood sample is traumatised to liberate leukocyte nucleus which get exposed to ANA in
the same sample; LE body is formed and leukocyte phagocytes it to form LE cell
3. LE Cell: LE body is engulfed by a neutrophil and occupies the cell space pushing the nucleus to
the margin as a rim. This cell is called LE cell and if it hapeens with monocyte it is called a Tart
cell.

94


4. LE cell is positive in 70% of SLE and also rheumatoid arthritis, lupoid hjepatitis, penicillin
sensitivity etc
Free radicals:
1. Cells generate energy by reducing molecular oxygen to water. During this process small quantities of
partially reduced reactive oxygen forms are produced as an unavoidable by product of mitochondrial
respiration
2. Free radicals are called reactive oxygen species
3. Free radicals can damage lipids, proteins and nucleic acids.
4. Cells radical scavenging system and imbalance between radical production and scavenging would result in
oxidfative stress
5. Production:
a. Ultra violet and Xrays hydrolyse water induce O and OH free radicals
b. Ccl4 can generate ccl3
c. In cellular respiration the following radicals are produced:
i. Superoxide
ii. Hydrogen peroxide
iii. Hydroxyl ion
iv. Nitric oxide
d. In inflammation polymorph produce superoxide ions
e. Intrcellular oxidase enzymes like xanthine oxidase also produce superoxide radicals
f. Intracellular iron and copper catalyse free radical formation as in Fenton reaction
g. Nitric oxide is a free radical generated by endothelial cells, macrophages, neurons etc
6. Effects of free radicals:
a. Cell membrane damage by peroxidation membrane lipid
b. Free radicals promote oxidation of amino acid side chains leading to protein fragmentation
c. They react with DNA and produce breaks leading to cell aging and malignant transformation
7. Scavenging free radicals:
a. Spontaneous decay into stable ions
b. Vit.A, E, C and glutathione are antoxidants that block or inactivate free radicals
c. Metallo proteins like transferring, ferritin, lactoferrin and ceruloplasmin bind iron and copper
preventing them from catalyzing the formation of free radicals
d. Catalase, superoxide dismutase, glutathione peroxidise are enzymes that break down hydrogen
peroxide and superoxide radicals


1. The Rye classification of Hodgkins Disease was developed at the International Symposium in
Rye, NY in 1965(4).
95

2. Rye classification divides Hodgkin disease as follows:
a. Lymphocyte predominance- best prognosis
b. Nodular sclerosis- good pronsis
c. Mixed cellularity-fair prognosis
d. Lymphocyte depletion- poor prognosis
3. Value:
a. It is widely used because of its simplicity, and its clinical and prognostic value
b. It provides prognostically useful histologcal features which help in determining therapy


1. Mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean
corpuscular hemoglobin concentration (MCHC) were first introduced by Wintrobe in 1929 to
define the size (MCV) and hemoglobin content (MCH, MCHC) of red blood cells. Termed red
cell indices, these values are useful in elucidating the etiology of anemias. Red cell indices
can be calculated if the values of hemoglobin, hematocrit (packed cell volume), and red
blood cell count are known.
2. Variation in the size of red cells (anisocytosis) can be quantified and expressed as red cell
distribution width (RDW) or as red cell morphology index.
3. MCV defines the size of the red blood cells and is expressed as femtoliters (10
15
; fl) or as
cubic microns (m
3
).
4. MCH quantifies the amount of hemoglobin per red blood cell.
5. MCHC indicates the amount of hemoglobin per unit volume. In contrast to MCH, MCHC
correlates the hemoglobin content with the volume of the cell. It is expressed as g/dl of red
blood cells or as a percentage value.
6. RDW represents the coefficient of variation of the red blood cell volume distribution (size)
and is expressed as a percentage.
7. Red cell indices MCV, MCH and MCHC are calculated from hemoglobin, hematocrit, and red blood
cell count as follows:

a. MCV = PCV in L / L of blood
RBC count / L of Blood
b. MCH = ____Hb / L__________
RBC count / L of Blood
c. MCHC = _____Hb / dL______
PCV in L / L of blood
d. RDW = ( standard deviation of MCV mean MCV) 100

8. Normal values:
1. Hb%: Male: 13.8 to 17.2 gm/dL; Female: 12.1 to 15.1 gm/dL
2. RBC Count: Male: 4.7 to 6.1 million cells/mcL; Female: 4.2 to 5.4 million cells/mcL
3. MCV: 80 to 100 femtoliter(fl)
4. MCH: 27 to 31 picograms/cell
5. MCHC: 32 to 36 grams/dl
6. packed cell volume (PCV): 48% for men and 38% for women.
7. RDW : The normal value for RDW is 13 1.5%.
96


Automatic tissue processor:
1. It is tool for studying histopathology specimens
2. It has 12 1 separate stages completing the process in 18 hours
3. Steps:
a. 10 % formalin fixation
b. Ascending grades of alcohol to dehydration
c. Xylene/ toluene/ chloroform for clearing
d. Paraffin impregnation
4. The tissue blocks are sectioned using microtome and studied under microscope after staining

Henoch Schonlein purpura.
1. A self limiting hypersensitivity vasculitis in children and young adults
2. Circulating immune complexes are deposited in vessel walls containing Ig A, C3 and fibrin
3. In some cases presecence of properdin suggests activation of alternate pathway
4. Causes
a. The etiology of Henoch-Schnlein purpura is unknown.
b. About 50% of patients have a preceding upper respiratory illness (URI).
c. Multiple infectious agents as well as drugs, foods, and insect bites may trigger Henoch-
Schnlein purpura.
d. Antistreptolysin O titers are raised in 20-50% of patients.
5. The most common symptoms of Henoch-Schnlein purpura include the following:
a. Rash (95-100%), especially involving the legs, may not be present on initial presentation
b. Subcutaneous edema (20-50%)
c. Abdominal pain and vomiting (85%)
d. Joint pain (60-80%), especially involving the knees and ankles
e. Scrotal edema (2-35%)
f. Bloody stools
6. Lab:
a. Urinalysis: Hematuria and/or proteinuria are present in 10-20% of patients.
b. Platelet count and coagulation studies: Platelet count is usually in the reference range
but may be elevated; the platelet count should not be low in Henoch-Schnlein purpura.
A normal platelet count rules out idiopathic thrombocytopenic purpura (ITP). A normal
platelet count and normal coagulation studies (ie, PT, aPTT, fibrin split products) rule out
thrombotic thrombocytopenic purpura (TTP).
F.N.A.C.
1. Fine needle aspiration cytology is a minimal invasive diagnostic cytology
2. Almost all organs are accessible for this study
3. It is used for diagnosis of palpable lesions:
a. Breast mass
b. Lymph nodes
c. Thyroid tissue
97

d. Salivary tumours
e. Abdominal mass
f. Testis
g. Prostate
h. Bone and joints
i. Orbit
4. Advantages:
a. Quick and less painful
b. No hospitalization, anaesthesia are required
c. Multiple attempts are possible
d. Cost effective
5. Procedure :
a. Large bore needle with syringe
b. Skin cleaned and mass fixed by fingers
c. Sample tissue is aspirated
d. Aspirate is spread on a glass slide
e. After air drying it is fixed with ethanol
f. Stained by Papanicolaou or H&E stain
6. Uses:
a. HPE
b. Microbiological exam
c. Flow cytometry
d. Immunocytology
7. Side effects:
a. Hematoma
b. Infection
c. Pneumothorax
d. Tumour dissemination

Virchows triad:
1. The pathogenesis of thrombus depends on 3 factors called Virchows triad:
a. Endothelial injury
b. Stasis or turbulent blood flow
c. Hypercoagulability
2. Endothelial injury:
a. Intact epithelium has:
i. Thrombus inhibitory factor
ii. Heparin like substance
iii. Thrombomodulin
iv. Platelet inhibitors
v. Tissue plasminogen activator
b. Prothrombotic factors:
i. Thromboplastin
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ii. Von Willebrand factor
iii. Inhibitor of plasminogen activator
c. Endothelial injury occurs in :
i. Myocardial infarction
ii. Atherosclerosis
iii. Hypertension
iv. Arteritis
v. Diabetes mellitus
vi. hypercholesterolemia
vii. endotoxins
viii. smoking
d. Platelets in endothelial injury:
i. Platelet adhesion
ii. Release of platelet granules alpha and dense bodies containing factors that
activate coagulation cascade
iii. Secondary platelet aggregation due to ADP from platelet dense granules
e. Activation of intrinsic and extrinsic pathways of coagulation
3. Alteration of Blood flow:
In turbulence and stasis the normal axial flow of blood is disturbed.the platelets undergo
margination and pavemnting that facilitate thrombus formation.
4. Hypercoagulability:
a. Causes of hypercoagulability:
i. Advancing age,
ii. smoking,
iii. oral contraceptives,
iv. obesity
b. Effects of hypercoagulability:
i. Increase in coagulation factors:
1. Fibrinogen
2. Prothrombin
3. Fcatiors: VIIa, VIIIa, Xa
ii. Increase in platelets
iii. Increase in coagulation inhibitors
1. Antithrombin III
2. Fibrin split products


1. First reported in 1963 by Wermer, multiple endocrine neoplasia (MEN) syndromes consist of
rare, autosomal dominant mutations in genes that regulate cell growth.
2. Current classification recognizes type 1 MEN and type 2 MEN, with subcategories type 2A
MEN (Sipple syndrome) and type 2B MEN
3. The MENIN gene responsible for type 1 MEN is located on chromosome 11 and produces a
tumor suppressor protein called menin. The MENIN gene is ubiquitously expressed and is
99

localized to the nucleus of cells. The former term "amine precursor uptake and
decarboxylation (APUD) system" is obsolete. Neuroendocrine tumors can derive
from various tissues
4. The gene responsible for type 2 MEN is a proto-oncogene called RET
5. Type 1 MEN:
a. hyperfunctioning tumors in all 4 parathyroid glands, pancreatic islets (eg,
gastrinoma, insulinoma, glucagonoma, vasoactive intestinal peptide tumor
[VIPoma], pancreatic polypeptideproducing tumor [PPoma]), and the anterior
pituitary (eg, prolactinoma, somatotropinoma, corticotropinoma, nonfunctioning
tumors).
b. Other associated tumors include lipomas, angiofibromas, or those located in the
adrenal gland cortex (rarely, in the adrenal medulla).
6. Type 2A MEN:
a. medullary thyroid carcinoma (MTC), pheochromocytoma (about 50% of cases), and
hyperparathyroidism caused by parathyroid gland hyperplasia (about 20% of cases).
7. Type 2B MEN is defined by medullary thyroid cancer and pheochromocytoma. Associated
abnormalities include mucosal neuromas, medullated corneal nerve fibers, and marfanoid
habitus.
8. Mixed syndrome:
a. Consists of endocrine plus other tumors
b. Eg: von Lippel-Lindau syndrome
c. Neurofibromatosis with MEN syndrome
Pannus:
1. Rheumatoid arthritis is a chronic multisystem disease of unknown cause
2. Prominent feature is inflammatory arthritis of peripheral joints
3. Histologically there is diffuse proliferative synovitis with formation of pannus
4. Fluid and immune system cells accumulate in the synovium to produce a pannus, a growth
composed of thickened synovial tissue.
5. Microscopy:
a. Diffuse proliferative synovitis
b. Numerous folds of large villi of synovium
c. Thickening of synovial membrane due to edema, congestion and syniviocyte layers
d. Synovial infiltration of lymphocytes, plasma cells and macrophages
e. Fibrinoid necrosis and fibrin deposition
6. The pannus progressively destroys articular cartilage and bone
7. Further damage leads to bony ankylosis and rupture of tendons

100















Short notes:

1. Definition: it is an acute suppurative inflammation of the kidney caused by pyogenic bacteria
2. Etiopathogenesis:
a. Mostly ascending infection from lower UTI with E.coli (90%), Enterobacter, Klebsiella,
Psuedomonas and Proteus
b. Haematogenous from sites of infection
3. Ascending infection:
Female:
i. Fecal contamination of urethral orifice in female
ii. Short urethra
iii. Bacterial adherence to mucosa due to hormonal influence
iv. Prostatic secretion is antibacterial and is lacking in female
v. Urethral trauma during sexual intercourse (honeymoon pyelitis)
vi. Aggravating factors:
101

1. Diabetes
2. Pregnancy
3. Urinary obstruction due to calculi etc
4. Bladder catheterization
vii. In bladder they produce asymptomatic bacteria; on ascending up to renal cortex
pyelonephritis is produced;
viii. Reflux mechanism is not involved as in chronic pyelonephritis
4. Haematogenous infection:
a. Infants
b. Malignancy with immunoincompetence
5. Morphology:
a. Gross:
i. Enlarged and swollen kidneys; bulge on section
ii. Cut surface show small pockets of pus with hemorrhagic rim mainly in cortex
b. Microscopy:
i. Acute inflammation of interstitium with large no of polys
ii. Destruction of tubules
iii. Abscess in renal parenchyma
iv. Glomerulus and renal vessels not much affected due to their resistance to
infection
6. Clinical:
a. Acute onset of chills with fever
b. Loin pain
c. Dysuria
d. Frequency of micturition
7. Lab: Urine
a. Bacturia
b. Pus cells
c. Pus cell casts
8. Complications:
a. Papillary necrosis
b. Pyonephrosis(bag of pus in kidney)
c. Perinephric abscess(due to local spread)

Short notes:

1. Urinary casts are cylindrical structures produced by the kidney and present in the urine in
certain disease states.
2. They form in the distal convoluted tubule and collecting ducts of nephrons, then dislodge and
pass into the urine, where they can be detected by microscopy.
3. They form via precipitation of Tamm-Horsfall mucoprotein which is secreted by renal tubule
cells, and sometimes also by albumin in conditions of proteinuria.
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4. Cast formation is pronounced in environments favoring protein denaturation and precipitation
(low flow, concentrated salts, low pH). Tamm-Horsfall protein is particularly susceptible to
precipitation in these conditions.
5. The Tamm-Horsfall protein is a glycoprotein isolated from normal urine by Tamm and Horsfall
in the early fifties. This protein is excreted by the thick ascending branch of the loop of Henle
and the first part of the distal tubules. Normal daily excreted quantity ranges from 25 to 50 mg.
This protein is the major fraction of the uromucoprotein.
6. Casts are elements of the urinary sediment, formed by the polymerisation of the Tamm-Horsfall
fibrils, taking the shape of the site of its formation (casting). Casts are formed, after the loop, in
the late section of the distal tubules and the early section of the collecting tubes. The formation
site is the nephron's section where the dilution is maximal.
7. As mentioned earlier, fibril's formation is inhibited by a low ionic strenght, and the precipitation
is promoted by the addition of albumin.
8. Types of casts:
6. Hyaline casts
a. The most common type of cast, hyaline casts are solidified Tamm-Horsfall mucoprotein
secreted from the tubular epithelial cells of individual nephrons.
b. Low urine flow, concentrated urine, or an acidic environment can contribute to the
formation of hyaline casts, and, as such, they may be seen in normal individuals in
dehydration or vigorous exercise.
c. Hyaline casts are cylindrical and clear, with a low refractive index, so that they can easily
be missed on cursory review under brightfield microscopy, or in an aged sample where
dissolution has occurred. On the other hand, phase contrast microscopy leads to easier
identification.
d. Given the ubiquitous presence of Tamm-Horsfall protein, other cast types are formed
via the inclusion or adhesion of other elements to the hyaline base.
7. Granular casts
a. The second-most common type of cast, granular casts can result either from the
breakdown of cellular casts or the inclusion of aggregates of plasma proteins (e.g.,
albumin) or immunoglobulin light chains.
8. Waxy casts
a. waxy casts suggest the very low urine flow associated with severe, longstanding kidney
disease such as renal failure. It is seen in Chronic Renal Failure.
9. Fatty casts
a. Formed by the breakdown of lipid-rich epithelial cells, these are hyaline casts with fat
globule inclusions, yellowish-tan in color. They can be present in various disorders,
including nephrotic syndrome, diabetic or lupus nephropathy.
10. Cellular casts
a. Red blood cell casts
i. The presence of red blood cells within the cast is always pathological, and is
strongly indicative of glomerular damage, which can occur in glomerulonephritis
from various causes or vasculitis, including Wegener's granulomatosis, systemic
lupus erythematosus, post-streptococcal glomerulonephritis or Goodpastures
syndrome.
103

b. White blood cell casts
i. Indicative of inflammation or infection, the presence of white blood cells within
or upon casts strongly suggests pyelonephritis, a direct infection of the kidney.
c. Epithelial cell casts
i. This cast is formed by inclusion or adhesion of desquamated epithelial cells of
the tubule lining. Cells can adhere in random order or in sheets and are
distinguished by large, round nuclei and a lower amount of cytoplasm.




Legend: A: Hyaline cast; B: Fatty cast; C: Hyaline to finely granular cast; D: Cellular cast;
E: Cellular to coarsely granular cast; F: Coarsely granular cast; G: Finely granular cast; H:
Granular to waxy cast, I: Waxy cast.
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Short notes:

Synonym:
Chronic glomerulonephritis:
End stage renal disease:
1. Chronic glomerulonephritis represents the end-stage of all glomerulonephritis with unfavorable
evolution. This general (glomerular, vascular and interstitial) affection constitutes the "end stage
kidney". In most cases, it is associated with systemic hypertension.
2. Causes:There are a number of different forms of glomerulonephritis, including:
1. acute glomerulonephritis,
2. membranoproliferative glomerulonephritis,
3. rapidly progressive glomerulonephritis,
4. idiopathic membranous glomerulonephritis, and
5. IgA nephropathy, any of which can progress to chronic glomerulonephritis.
6. Systemic hypertension
3. Morphology:
1. Gross: Kidneys are symmetrically contracted,and have diffusely granular cortical
surfaces.
2. C.S: the cortex is thinned; peripelvic fat is increased;
3. Microscopic:
i. Glomeruli: reduced in no.; mostly converted into hyalinized tufts
ii. Tubules: atrophy of tubules; tubular cells show hyaline deposits
iii. Interstitium: show fine fibrosis and chronic inflammatory cells
iv. Vessels: in hypertension, the vessels show arteriolar sclerosis
4. Patients on dialysis: show acquired cystic disease, adenomas, calcification of tufts.
Short notes:

1. Definition: destruction of tubular epithelial cells leading to acute renal failure.
2. Commonest cause of renal failure
3. Pathogenesis: two types:
1. Ischemic; & Toxic
2. Tubular epithelium is highly susceptible for ischemic or toxic agents
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3. Arteriolar vasoconstriction and toxins produce necrosis of tubules and the debris causes
obstruction to urinary outflow
4. Increased intratubular pressure produce damage to basement membrane and rupture of
tubules
5. Leakage of fluid from tubules produce interstitial edema
6. This further compress tubules and arterioles leading on to a vicious cycle.
7. The events end up in acute renal failure reduced GFR and olguria
4. Ischemic ATN: synonyms: lower nephron nephrosis; shock kidney
1. More common- 80%
2. Due to hypotension from:
1. Burns
2. Hemorrhage
3. Crush injuries
4. Mismatched blood transfusion
5. Black water fever
3. Morphology:
1. Gross: kidneys are enlarged and swollen
2. C.S: pale cortex and dark medulla
3. Microscopy:
a. Glomeruli are not affected
b. Interstitium show edema
c. Tubules:
Dilatation
Focal necrosis
Flattened epithelium
Lumen contains eosinophilic hyaline and hemoglobin casts
Disruption of tubular basement membrane
4. Prognosis: depends on underlying cause; usually worse
5. Toxic ATN: upper nephron nephrosis
1. Etiology:
1. Poisons: Mercuric chloride, carbon tetrachloride, mushroom poison, insecticides
2. Heavy metals: lead, mercury, arsenic, phosphorus and gold
3. Drugs: sulfonamides, gentamycin, halothane, salicylates
4. Radiographic contrasts
2. Morphology:
1. Gross: kidneys are enlarged and swollen
2. C.S: pale cortex and dark medulla
3. Microscopy:
a. Glomeruli are not affected
b. Interstitium show edema
c. Tubules:
Diffuse and not focal involvement
Proximal tubules are necrotic and desquamated and calcified
Tubular basement membrane is intact
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Flat and thin epithelial regeneration may be seen
4. Prognosis:
5. Relatively good
Short notes:

Nephrolithiasis or urolithiasis
1. Incidence 2%; 20-30 years of age;
2. Types:
1. Calcium stones:
1. 75% commoner
2. Calium oxalate, phosphate or mixed
3. Etiology:
a. Mostly idiopathic
b. Hyperparathyroidism
c. Renal hypercalciuria
4. Pathogenesis:
a. Imbalance between calcium ions and factors inhibiting precipitation
b. An epithelial debris forms a nidus around which Ca is deposited
5. Morphology:
a. Stones are small, ovoid, hard, granular rough surface
2. Mixed stones:
1. M,ade of magnesium ammonium- calcium phosphate called struvite stones
2. Etiology: fallow infection like proteus( not with E.coli)
3. Morphology:
a. Yellow-white
b. Soft and friable
c. Irregular
d. Stag horn stone: the stone takes the shape of renal pelvis
3. Uric acid:
1. Radiolucent
2. Formed in Gout and Leukemias due to hyperuricosuria
3. Salicylates and probenacid also produce uricosuria
4. Acidc pH and low urinary volume are favourable for the stone formation
5. Stones are yellow brown , multiple and smooth and hard, C.S show lamination
4. Cystine stones:
1. Associated with cystinuria
2. Exces cystine in urine form crystals and then stones
3. Stones are small, rounded, smooth and multiple; yellow and waxy.
5. Others: Xanthine stones occur in hereditary xanthinuria

S.N:
1. Leading cause of renal morbidity
2. 40% of diabetics develop end stage kidney disease
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3. Diabetes affects:
a. Glomerulus:
i. Non nephrotic proteinuria
ii. Nephrotic syndrome
iii. Chronic renal failure
b. Renal arterioles:
i. Hyalinizing arteriolar sclerosis
4. Proteinuria:12-22 years after diabetes; initially microalbuminemia occurs followed by nephrotic
type proteinuria;
5. Pathogenesis:
a. It is described as diabetic microangiopathy
b. Glycosylation end products leads to thickening of GBM and increased mesangial matrix
c. Hemodynamic changes i.e increased GFR, increased glomerular capillary pressure,
glomerular hypertrophy lead to glomerulosclerosis
d. Sequence of changes:
Hyperglycemia glomerular hyperperfusion renal hyperperfusion deposition of
protein in measngium glomerulosclerosis renal failure
6. Morphology:
a. GBM: increased thickening is the basic pathology
b. Measngium: proliferation of mesangial cells and increase in mesangial matrix
c. Diffuse Glomerulosclerosis:
i. Capsular cap: eosinophilic hyaline thickening of the parietal layer Bowmans
capsule
ii. Fibrin cap: eosinophilic material on the walls of lobular capillary vessels
d. Nodular Glomerulosclerosis:
i. Occurs in juvenile diabetes
ii. Nodular lesions appear in glomeruli which contain lipid and fibrin
iii. Nodules compress glomerular capillaries which ultimately lead to contracted
kidney
e. Vascular lesions:
i. Atherosclerosis of renal arteries
ii. Arterioscelrosis of afferent and efferent arterioles
iii. They produc renal ischemia
f. Pyelonephritis:
i. Bacterial infections lead to papillary necrosis leading to pyelonephritis (acute
and chronic)
g. Tubular lesions:
i. Glycogen deposits in the epithelial cells of proximal convoluted tubules
ii. They are called Armanni-Ebstein lesions

S.N: Analgesic nephropathy.
1. Analgesic nephropathy is injury to the kidney caused by analgesic medications such as aspirin,
phenacetin, and NSAID. The term usually refers to damage induced by excessive use of
combinations of these medications, especially combinations that include phenacetin
108

2. There is a predominant involvement of tubules and interstitium
3. Pathology:
a. Acute or chronic
b. There is Interstitial edema with leukocytic infiltration
c. Focal tubular necrosis
d. In chronic form there will be fibrosis and tubular atrophy

S.N: Haemolytic uremic syndrome.(Thrombotic micro angiopathy)
7. It belongs to group called thrombotic microangiopathy
8. There is thrombosis in the capillaries and arterioles through the body
9. Triad:
a. Microangiopathic hemolytic anemia
b. Thrombocytopenia
c. Renal failure
10. Classification:
a. Childhood HUS:
i. Due to bacterial dysentery and its toxic effect on capillary endothelium
b. Adult HUS:
i. Infection
ii. Antiphospholipid antibodies
iii. Pregnancy complication
iv. Oral contraceptive
v. Radiation
vi. Immunosupressive drugs
11. Pathogenesis:
a. Classic Childhood HUS:
i. Follows E.coli and shigella infection
ii. Toxin acts on endothelium of microvascular system:
1. Endothelial lysis
2. Leukocyte adhesion
3. Increased thrombosis
4. Vasoconstriction
12. Morphology:
1. Diffuse cotrtical necrosis
2. Endothelial and sub endothelial swelling swelling in glomeruli
3. Measngiolysis
4. Thrombus occlusion of afferent arterioles

Pathology: short notes

1. Definition: the rate of sedimentation of red blood cells per hour
109

2. Estimation:
a. Wintrobes and Landsbergs method: ESR is measured on undiluted blood in a
haematocrit tube
b. Westerngrens method: measured on venous blood diluted with 1 volume of 3.8%
sodium citrate and 4 volume of blood
c. Modified methods:
i. Zeta sedimentation ratio
ii. Micro ESR method
3. Normal ESR:
a. Westerngrens method: 10mm/hour for men; 20 mm/hour women; ESR increases
normally with age
4. Factors influencing ESR:
a. Specific gravity of plasma
b. Rouleaux formation of RBCs
c. No of red cells
d. Plasma viscosity
e. Prior IV fluids
5. Roleaux formation depends on:
a. Fibrinogen
b. Alpha 2 globulin and gamma gloubulin
c. Glycoprotein
6. Conditions of elevated ESR:
a. Infections: TB, Kala Azar,most chronic infections
b. Inflammation: Rheumatoid arthritis, Rheumatic fever, other connective tissue disorders
c. Neoplasm: Multiple myeloma, lymphoma, paraproteinemias
d. Miscellaneous: aplastic anemia, autoimmune disorders, anemia
7. Conditions of low ESR:
a. Ploycythemia
b. Sickle cell anemia
1. Turner syndrome:
1. Pathophysiology:
a. It is a monsomy (45, X0) due to loss of one X chromosome in paternal meiotic division
b. Turner syndrome is also caused by the absence of one set of genes from the short arm
of one X chromosome
c. In addition to monosomy X, a similar clinical picture is found with a individuals with X0-
XX mosaic karyotypes.
2. The frequency is approximately 1 in 2000 live-born female infants .

As many as 15% of
spontaneous abortions have a 45,X karyotype.
3. Features:
a. Short stature
b. A high arched palate suggests the diagnosis. Patients may have dental crowding or
malocclusion.
c. Ovarian failure
110

d. Lymphedema may be present at any age
4. Turner syndrome may be prenatally diagnosed by amniocentesis or chorionic villous sampling.
2. Down syndrome:
1. In 1866, Down described clinical characteristics of the syndrome that now bears his name.
2. It is caused by trisomy in chromosome 21
3. The frequency is about 1 case in 800 live births.
4. Causes of trisomy:
a. Non dysjunction of one chromosome during maternal meiosis to form egg
b. Mother is a translocation carrier in which translocation of long arm occurs between 14
and 21 chromosomes; she remains normal due to balanced translocation and the
offspring inherits the trisomy syndrome
c. Advanced maternal age is the important factor for trisomy 21
5. Features:
a. Mangoloid slant of palpebral fissure
b. Simian crease in palms
c. Sandle cleft between 1&2 toes
d. CHD often endocardial cushion defect
e. Proneness for leukemia
f. Association: deafness and hypothyroidism
g. Accident proneness
h. Love for music and cooperation with mother in household work are interesting faetures
6. Prognsosis:
a. Mostly aborted
b. Dath from 1 year to 50 years
Kleinfelters syndrome:
1. It is a trisomy affecting sex chromosomes; It is defined classically by a 47,XXY karyotype with
variants that demonstrate additional X and Y chromosomes.
2. Affected person is a genotypically a male with abnormal feautures
3. 80% are have 47 xxy while others are mosaics
4. Approximately 1 in 500-1,000 males is born with an extra sex chromosome
5. The 47,XXY karyotype of Klinefelter syndrome spontaneously arises when paired X
chromosomes fail to separate (nondisjunction in stage I or II of meiosis, during oogenesis or
spermatogenesis). Maternal and paternal meiotic nondisjunction each account for
approximately 50% of Klinefelter syndrome cases
6. Infertility, tyeasticular dysgenesis and gynecomastia are the 2 most common symptoms that
lead to diagnosis in patients with Klinefelter syndrome.
7. Other symptoms include fatigue, weakness, erectile dysfunction, osteoporosis, language
impairment, academic difficulty, subnormal libido, poor self-esteem, and behavioral problems.
Von Willebrand disease:
1. Hereditary coagulation disorder due to qualitative and quantitative defect in von
Willebrand factor which is Factor VIII and vWF complex
111

2. vWF gene is located in Chromosome 12 while factor VIII gene is in X chromosome
3. vWF is synthesised in endothelial cells, megakaryocytes and platelets while Factor VIII is
synthesised in Liver
4. vWF facilitates adhesion of platelets; Factor VIII activates Factor X in coagulation cascade
5. vWF and Factor VIII circulate and function as single unit for clotting mechanism: factor X
actvation and platelet adhesion;
6. Clinical types:
a. Type I: common variety; 50% vWF activity; synthesis of vWF is normal but release is
inhibited
b. Type II: less common; normal vWF but functionally defective
c. Type III: rare form; most severe; vWF is absent.
7. Manifestations:
a. Spontaneous bleeding from mucous membranes
b. Excessive bleeding from wounds
8. Lab findings:
a. Bleeding time is prolonged
b. Normal platelet count
c. Reduced plasma vWF
d. Platelet adhesion using ristocetin is defective
e. Reduced Factor VIII
9. Treatment:
a. Cryoprecipitate or factor VIII concentrate

Meningioma:
1. The tumour arises from capcell layers of arachnoid
2. 20% of intracranial tumours
3. Common sites:
a. More common:
i. latreral cerebral convexities
ii. midline along falx cerebri
iii. olfactory grove
b. less common:
i. cerebral ventricles
ii. foramen magnum
iii. cerebello pontine angle
iv. spinal cord
4. Usually solitary; multiple in patients of neurofirmatosis
5. Age : 2-6 decade; slight female preponderance
6. They are benign tumours; melignant meningioma can occur rarely
7. Morphology:
a. Circumscribed solid spherical mass-1 to 10 cm
b. Attached to dura but not invasive
c. C.s: firm and fibrous; occasional calcification
d. Microscopy: 5 types
112

i. Meningtheliomatous: polygonal cells; central nucleus with abundant
cytoplasm;irregular lobulation by collagenous stroma
ii. Fibrous meningioma: tumour cells form parallel bundles
iii. Transitional meningioma:cells with syncytial and fibroblastic features; cells in
whorled pattern
iv. Angioblastic meningioma: resemble in hemangioblastoma
v. Anaplastic : malignant variety

1. It is a type of reversible cell injury
2. It is due to derangement of plasma membrane
3. Cellular swelling is the first manifestation of almost all forms of injury to cells. It is a difficult
morphologic change to appreciate with the light microscope; it may be more apparent at the
level of the whole organ.
4. Morphology:
a. When it affects many cells in an organ, it causes some pallor, increased turgor, and
increase in weight of the organ.
b. On microscopic examination, small clear vacuolesmay be seen within the cytoplasm;
these represent distended and pinched-off segments of the endoplasmic reticulum. This
pattern of nonlethal injury is sometimes called hydropic change or vacuolar
degeneration.
c. Swelling of cells is reversible.
d. The ultrastructural changes of reversible cell injury include:
1. plasma membrane alterations
blebbing
blunting
distortion of microvilli
creation of myelin figures
loosening of intercellular attachments
mitochondrial changes
2. mitochondrial swelling
mitochondrial rarefaction
appearance of small phospholipid-rich amorphous densities
3. dilation of the endoplasmic reticulum
detachment
disaggregation of polysomes nuclear alterations
disaggregation of granular and fibrillar elements




1. definition:
113

a. Embolism is the process of partial or complete obstruction of some part of CVS by any
mass carried in the circulation
b. Liquid embolism are due to fat globules, amniotic fluid, and bone marrow
2. Fat embolism:
a. Obstruction of arteriole or capillaries by fat globules
b. Causes:
1. Trauma of bones: fractures and orthopaedic surgeries
2. Trauma of soft tissue injury: crush injury of muscles and pelvic tissue injury in
purperium
3. Burns
4. Diabetes mellitus
5. Fatty liver
6. Pancreatitis
7. Sickle cell anemia
8. Fat or oil introduced in the body
c. Pathogenesis: Theories:
1. Mechanical: Mechanical injury to fat tissues and entering venous circulation
2. Emulsion instability: Aggregation of plasma lipids due to disturbances in
emulcification
3. Intravascular coagulation: In stress some factor actvates DIVC and aggregation
of fat emboli
4. Toxic injury: free fatty acids injure capillaries and lead to pulmonary edema
3. Amniotic fluid embolism:
a. Pathogenesis:
1. Mechanism not clear
2. May enter through tears in the myometrium and endocervix
3. Omniotic fluid may eneter uterine sinusoids during vigorous contractions
b. Morphology:
1. Haemorrhages and oedema in lungs; amniotic fluid traces in pulmonary
113microcirculation
2. Changes of ARDS
3. Dilatation of Rt heart
c. Causes of death:
1. Hypoxia
2. Anaphylaxis
3. DIC
4. Haemorrhage due to thrombocytopenia

1. Autosomal recessive lipid storage disorder characterized by accumulation of sphingomyelin and
cholesterol due to deficiency of sphincomyelinase.
2. Type A: more common; infancy; hepeato splenomegaly; lymphadenopathy, mental retardation;
cherry red spot in macula of retina
3. TypeB: later childhood; progressive hepato splenomegaly; cirrhosis; lung infiltration
114

4. Microscopy:
a. Lysosomal deposits of sphingomyelin and cholesterol
b. The pathologic hallmark in Niemann-Pick disease types A and B is characteristic lipid-
laden foam cell, often termed the Niemann-Pick cell, on bone marrow examination.
c. These cells, which can be readily distinguished from Gaucher cells by histologic and
histochemical characteristics, are histologically similar to cells found Wolman disease,
cholesterol ester storage disease, lipoprotein lipase deficiency, and, in some patients,
G
M1
gangliosidosis type 2.
Myelodysplastic syndrome:
1. Definition: group of haematopoietic clonal stem cell disorders having . All are characterized by a
hypercellular or hypocellular marrow with impaired morphology and maturation (dysmyelopoiesis) and
peripheral blood cytopenias, resulting from ineffective blood cell production.
2. All 3 cell lineages in myeloid hematopoiesis can be involved, including erythrocytic, granulocytic, and
megakaryocytic cell lines.
3. FAB classification:
a. Refractory anemia: Anemia without blasts in blood; marrow shows <5% blasts
b. Refractory anemia with ringed sideroblast : marrow shows >15% ringed sideroblasts
c. Refractory anemia with excess blasts:
d. Chronic myelomonocytic leukemia
e. Refractory anemia with excess blasts in transformation
4. Etiology;:
a. Idiopathic
b. Radiation exposure
c. Benzene carcinogen
d. Secondary MDS follow cancer therapy
e. Fanconi anemia
5. Pathophysiology : Chromosomal defects: trisomies, translocations and deletions are seen;
Mutation in N-RAS oncogene
6. Age: 6
th
decade; male preponderance;
7. Clinical: Anemia, fever, wt loss, splenomegaly in 20%
8. Lab:
a. Blood: cytopenia of 2 or more cell lines-pancytopenia
b. Macrocytic or dimorphic anemia
c. Hyposegmented and hypogranular Neutrophils
d. Myeloblasts may be seen
e. Thrombocytopenia and large platelets
9. Marrow:
a. Hypo or hyper cellular
b. Ring sideroblasts
c. Hyposegmented and hypogranular myeloid precursors
d. Reduced magakaryocytes

Disseminated Intravascular Coagulation (DIC) (consumptive coagulopathy)
1. Thrombohaemorrhagic disorder occurring as a secondary complication of a systemic disease
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2. Causes:
a. Massive tissue injury:
i. abruption placentae
ii. amniotic fluid embolism
iii. Retained dead foetus
iv. Crush injuries
v. Surgery
vi. Malignancy
b. Infections:
i. Endotoxicemia
ii. Gram negative sepsis
iii. Viral infections
iv. Malaria
v. Aspergellosis
c. Epithelial damage:
i. Aortic aneurysm
ii. Haemolytic uremic syndrome
iii. Burns
iv. Acute glomerulonephritis
d. Miscelaneous:
i. Snake venom
ii. Shock
iii. Intravascular haemolysis
iv. Heat stroke
3. Pathogenesis:
a. Activation of coagulation by releasing tissue factors following tissue injury
b. Endothelial damage in microcirculation followed by platelet adhesion
c. Consumption of coagulation factors during extensive coagulation
d. Fibrinolysis - a secondary event
4. Clinical:
a. Organ (kidney, brain etc) damage due thrombotic ischemia
b. Haemolytic anemia
c. Thrombotic manifestations
5. Lab:
a. Platelet count is low
b. Smear : schistocytes and fragmented red cells
c. Prolonged prothrombin, thrombin and partial thromboplastin times
d. Low plasma fibrinogen
e. Fibrin degradation products are elevated

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1. Fibronectin is adhesive Glycoprotein called CAM or cell adhesion molecules, one of the
components of extra cellular matrix (ECM)
2. They are located in cell membrane where they function as receptors for hemotypic and
heterotypic interaction between cells
3. Fibronectin is a large protein that binds to many molecules like collagen, fibrin, proteoglycons
and cell surface receptors.
4. 2 typpes: tissue fibronectin formed by fibroblasts and plasma fibronectins synthesised in liver
5. Tissue fibronectins forms fibrils that helps in wound healing
6. Plasma Fibronectin binds to fibrin forms a provisional clot that fills a gap created by a wound
7. Tissue fibronectins are responsible for the primitive matrix found in fetus
8. Fetal fibronectin is detectable in vaginal secretions of pregnant women and its estimation helps
in detecting preterm delivery; From weeks 22 to 35 in your pregnancy, there should be very
little fFN detectable.


1. A lab test for the diagnosis of SLE
2. Principle:
a. antinuclear antibodies (ANA) cannot penetrate the intact cells and need to be exposed
for ANA to bind.
b. ANA and cell nucleus binding form a mass called LE Body.
c. Phagocytic leukocyte engulfs LE body and becomes an LE cell
d. Formation of LE cell can be demonstrated in vitro as follows:
e. Blood sample is traumatised to liberate leukocyte nucleus which get exposed to ANA in
the same sample; LE body is formed and leukocyte phagocytes it to form LE cell
3. LE Cell: LE body is engulfed by a neutrophil and occupies the cell space pushing the nucleus to
the margin as a rim. This cell is called LE cell and if it hapeens with monocyte it is called a Tart
cell.

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4. LE cell is positive in 70% of SLE and also rheumatoid arthritis, lupoid hjepatitis, penicillin
sensitivity etc
Free radicals:
1. Cells generate energy by reducing molecular oxygen to water. During this process small quantities of
partially reduced reactive oxygen forms are produced as an unavoidable by product of mitochondrial
respiration
2. Free radicals are called reactive oxygen species
3. Free radicals can damage lipids, proteins and nucleic acids.
4. Cells radical scavenging system and imbalance between radical production and scavenging would result in
oxidfative stress
5. Production:
a. Ultra violet and Xrays hydrolyse water induce O and OH free radicals
b. Ccl4 can generate ccl3
c. In cellular respiration the following radicals are produced:
i. Superoxide
ii. Hydrogen peroxide
iii. Hydroxyl ion
iv. Nitric oxide
d. In inflammation polymorph produce superoxide ions
e. Intrcellular oxidase enzymes like xanthine oxidase also produce superoxide radicals
f. Intracellular iron and copper catalyse free radical formation as in Fenton reaction
g. Nitric oxide is a free radical generated by endothelial cells, macrophages, neurons etc
6. Effects of free radicals:
a. Cell membrane damage by peroxidation membrane lipid
b. Free radicals promote oxidation of amino acid side chains leading to protein fragmentation
c. They react with DNA and produce breaks leading to cell aging and malignant transformation
7. Scavenging free radicals:
a. Spontaneous decay into stable ions
b. Vit.A, E, C and glutathione are antoxidants that block or inactivate free radicals
c. Metallo proteins like transferring, ferritin, lactoferrin and ceruloplasmin bind iron and copper
preventing them from catalyzing the formation of free radicals
d. Catalase, superoxide dismutase, glutathione peroxidise are enzymes that break down hydrogen
peroxide and superoxide radicals


1. The Rye classification of Hodgkins Disease was developed at the International Symposium in
Rye, NY in 1965(4).
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2. Rye classification divides Hodgkin disease as follows:
a. Lymphocyte predominance- best prognosis
b. Nodular sclerosis- good pronsis
c. Mixed cellularity-fair prognosis
d. Lymphocyte depletion- poor prognosis
3. Value:
a. It is widely used because of its simplicity, and its clinical and prognostic value
b. It provides prognostically useful histologcal features which help in determining therapy


1. Mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean
corpuscular hemoglobin concentration (MCHC) were first introduced by Wintrobe in 1929 to
define the size (MCV) and hemoglobin content (MCH, MCHC) of red blood cells. Termed red
cell indices, these values are useful in elucidating the etiology of anemias. Red cell indices
can be calculated if the values of hemoglobin, hematocrit (packed cell volume), and red
blood cell count are known.
2. Variation in the size of red cells (anisocytosis) can be quantified and expressed as red cell
distribution width (RDW) or as red cell morphology index.
3. MCV defines the size of the red blood cells and is expressed as femtoliters (10
15
; fl) or as
cubic microns (m
3
).
4. MCH quantifies the amount of hemoglobin per red blood cell.
5. MCHC indicates the amount of hemoglobin per unit volume. In contrast to MCH, MCHC
correlates the hemoglobin content with the volume of the cell. It is expressed as g/dl of red
blood cells or as a percentage value.
6. RDW represents the coefficient of variation of the red blood cell volume distribution (size)
and is expressed as a percentage.
7. Red cell indices MCV, MCH and MCHC are calculated from hemoglobin, hematocrit, and red blood
cell count as follows:

a. MCV = PCV in L / L of blood
RBC count / L of Blood
b. MCH = ____Hb / L__________
RBC count / L of Blood
c. MCHC = _____Hb / dL______
PCV in L / L of blood
d. RDW = ( standard deviation of MCV mean MCV) 100

8. Normal values:
8. Hb%: Male: 13.8 to 17.2 gm/dL; Female: 12.1 to 15.1 gm/dL
9. RBC Count: Male: 4.7 to 6.1 million cells/mcL; Female: 4.2 to 5.4 million cells/mcL
10. MCV: 80 to 100 femtoliter(fl)
11. MCH: 27 to 31 picograms/cell
12. MCHC: 32 to 36 grams/dl
13. packed cell volume (PCV): 48% for men and 38% for women.
14. RDW : The normal value for RDW is 13 1.5%.
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Automatic tissue processor:
1. It is tool for studying histopathology specimens
2. It has 12 1 separate stages completing the process in 18 hours
3. Steps:
a. 10 % formalin fixation
b. Ascending grades of alcohol to dehydration
c. Xylene/ toluene/ chloroform for clearing
d. Paraffin impregnation
4. The tissue blocks are sectioned using microtome and studied under microscope after staining

Henoch Schonlein purpura.
1. A self limiting hypersensitivity vasculitis in children and young adults
2. Circulating immune complexes are deposited in vessel walls containing Ig A, C3 and fibrin
3. In some cases presecence of properdin suggests activation of alternate pathway
4. Causes
a. The etiology of Henoch-Schnlein purpura is unknown.
b. About 50% of patients have a preceding upper respiratory illness (URI).
c. Multiple infectious agents as well as drugs, foods, and insect bites may trigger Henoch-
Schnlein purpura.
d. Antistreptolysin O titers are raised in 20-50% of patients.
5. The most common symptoms of Henoch-Schnlein purpura include the following:
a. Rash (95-100%), especially involving the legs, may not be present on initial presentation
b. Subcutaneous edema (20-50%)
c. Abdominal pain and vomiting (85%)
d. Joint pain (60-80%), especially involving the knees and ankles
e. Scrotal edema (2-35%)
f. Bloody stools
6. Lab:
a. Urinalysis: Hematuria and/or proteinuria are present in 10-20% of patients.
b. Platelet count and coagulation studies: Platelet count is usually in the reference range
but may be elevated; the platelet count should not be low in Henoch-Schnlein purpura.
A normal platelet count rules out idiopathic thrombocytopenic purpura (ITP). A normal
platelet count and normal coagulation studies (ie, PT, aPTT, fibrin split products) rule out
thrombotic thrombocytopenic purpura (TTP).
F.N.A.C.
1. Fine needle aspiration cytology is a minimal invasive diagnostic cytology
2. Almost all organs are accessible for this study
3. It is used for diagnosis of palpable lesions:
a. Breast mass
b. Lymph nodes
c. Thyroid tissue
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d. Salivary tumours
e. Abdominal mass
f. Testis
g. Prostate
h. Bone and joints
i. Orbit
4. Advantages:
a. Quick and less painful
b. No hospitalization, anaesthesia are required
c. Multiple attempts are possible
d. Cost effective
5. Procedure :
a. Large bore needle with syringe
b. Skin cleaned and mass fixed by fingers
c. Sample tissue is aspirated
d. Aspirate is spread on a glass slide
e. After air drying it is fixed with ethanol
f. Stained by Papanicolaou or H&E stain
6. Uses:
a. HPE
b. Microbiological exam
c. Flow cytometry
d. Immunocytology
7. Side effects:
a. Hematoma
b. Infection
c. Pneumothorax
d. Tumour dissemination

Virchows triad:
1. The pathogenesis of thrombus depends on 3 factors called Virchows triad:
a. Endothelial injury
b. Stasis or turbulent blood flow
c. Hypercoagulability
2. Endothelial injury:
a. Intact epithelium has:
i. Thrombus inhibitory factor
ii. Heparin like substance
iii. Thrombomodulin
iv. Platelet inhibitors
v. Tissue plasminogen activator
b. Prothrombotic factors:
i. Thromboplastin
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ii. Von Willebrand factor
iii. Inhibitor of plasminogen activator
c. Endothelial injury occurs in :
i. Myocardial infarction
ii. Atherosclerosis
iii. Hypertension
iv. Arteritis
v. Diabetes mellitus
vi. hypercholesterolemia
vii. endotoxins
viii. smoking
d. Platelets in endothelial injury:
i. Platelet adhesion
ii. Release of platelet granules alpha and dense bodies containing factors that
activate coagulation cascade
iii. Secondary platelet aggregation due to ADP from platelet dense granules
e. Activation of intrinsic and extrinsic pathways of coagulation
3. Alteration of Blood flow:
In turbulence and stasis the normal axial flow of blood is disturbed.the platelets undergo
margination and pavemnting that facilitate thrombus formation.
4. Hypercoagulability:
a. Causes of hypercoagulability:
i. Advancing age,
ii. smoking,
iii. oral contraceptives,
iv. obesity
b. Effects of hypercoagulability:
i. Increase in coagulation factors:
1. Fibrinogen
2. Prothrombin
3. Fcatiors: VIIa, VIIIa, Xa
ii. Increase in platelets
iii. Increase in coagulation inhibitors
1. Antithrombin III
2. Fibrin split products


1. First reported in 1963 by Wermer, multiple endocrine neoplasia (MEN) syndromes consist of
rare, autosomal dominant mutations in genes that regulate cell growth.
2. Current classification recognizes type 1 MEN and type 2 MEN, with subcategories type 2A
MEN (Sipple syndrome) and type 2B MEN
3. The MENIN gene responsible for type 1 MEN is located on chromosome 11 and produces a
tumor suppressor protein called menin. The MENIN gene is ubiquitously expressed and is
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localized to the nucleus of cells. The former term "amine precursor uptake and
decarboxylation (APUD) system" is obsolete. Neuroendocrine tumors can derive
from various tissues
4. The gene responsible for type 2 MEN is a proto-oncogene called RET
5. Type 1 MEN:
a. hyperfunctioning tumors in all 4 parathyroid glands, pancreatic islets (eg,
gastrinoma, insulinoma, glucagonoma, vasoactive intestinal peptide tumor
[VIPoma], pancreatic polypeptideproducing tumor [PPoma]), and the anterior
pituitary (eg, prolactinoma, somatotropinoma, corticotropinoma, nonfunctioning
tumors).
b. Other associated tumors include lipomas, angiofibromas, or those located in the
adrenal gland cortex (rarely, in the adrenal medulla).
6. Type 2A MEN:
a. medullary thyroid carcinoma (MTC), pheochromocytoma (about 50% of cases), and
hyperparathyroidism caused by parathyroid gland hyperplasia (about 20% of cases).
7. Type 2B MEN is defined by medullary thyroid cancer and pheochromocytoma. Associated
abnormalities include mucosal neuromas, medullated corneal nerve fibers, and marfanoid
habitus.
8. Mixed syndrome:
a. Consists of endocrine plus other tumors
b. Eg: von Lippel-Lindau syndrome
c. Neurofibromatosis with MEN syndrome


Pannus:
1. Rheumatoid arthritis is a chronic multisystem disease of unknown cause
2. Prominent feature is inflammatory arthritis of peripheral joints
3. Histologically there is diffuse proliferative synovitis with formation of pannus
4. Fluid and immune system cells accumulate in the synovium to produce a pannus, a growth
composed of thickened synovial tissue.
5. Microscopy:
a. Diffuse proliferative synovitis
b. Numerous folds of large villi of synovium
c. Thickening of synovial membrane due to edema, congestion and syniviocyte layers
d. Synovial infiltration of lymphocytes, plasma cells and macrophages
e. Fibrinoid necrosis and fibrin deposition
6. The pannus progressively destroys articular cartilage and bone
7. Further damage leads to bony ankylosis and rupture of tendons

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