Dr.

Hassan Abdelrahman Soliman

New Edition 2024

By: Dr. Hassan A. Soliman
01001592680 Royal Med - 2027
01020172375
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 Dr. Hassan Abdelrahman Soliman

Cellular Adaptation
Def: New, altered steady state intermediate between normal unstressed cells
& injured overstressed cells.
Reversible changes in the no, size, phenotype, metabolic activity or function of cells
in response to changes in their environment.

I- Physiological Adaptation: The cells response to normal stimulation

As hormones, endogenous chemical substance
Or ↑ demand of mechanical stress.
E.g.: ▪ Enlargement of uterus & breasts by pregnancy & lactation.
▪ Enlargement of bones & muscles by heavy exercise.

II- Pathological Adaptation: The cells response to abnormal pathological stimuli

which are non lethal.
Adaptive Changes:
1- Hyperplasia
Increase in the size of an organ or tissue dt ↑ in No. of constituent parenchymal cells.

► In cell population capable of replication.

► Stops after removal of stimuli. ► If persist stimuli  may lead to cancer.

* Physiological: "serve useful function"

- Hormonal: ♀breast & uterus "endometrium" during puberty & pregnancy.
- Compensatory: hepatocytes after partial hepatectomy,
To ↑ its functional demands.
* Pathological:
- Hormonal: 1- hyperestrinism  endometrium enlargement.
2- ↑ androgens & estrogen  senile prostatic hyperplasia.

2- Hypertrophy
Increase in size of an organ or tissue dt enlargement of size of individual cells
without ↑ in no. of cells.

►Usually in organs with restricted mitosis & proliferation as cardiac - skeletal muscle.
► Caused by: ↑ functional demand – hormonal stimuli – Growth factors.
► Aim: to achieve homeostasis in response to increase work load.

* Physiological:
- Pregnant uterus "myometrium" - Athletics muscle.
* Pathological: (Adaptive)
- Cardiac muscle in chronic hypertension - Stomach in pyloric stenosis.
N.B.: 1&2 are closely related & both may act together to overall ↑ of organ size.
E.g.: pregnant uterus.
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 Dr. Hassan Abdelrahman Soliman

Drawbacks of hypertrophy:
* If the stress persist  functionally significant cell injury.
* A limit is reached beyond which the enlargement of muscles can’t longer
compensate for increase work load  degenerative changes
e.g. fragmentation & loss of myofibrillar contractile elements  muscle failure.

Causes of limitation of adaptation:

1- Vasculature to supply adequate blood to enlarged muscle.
2- Mitochondria to supply adequate ATP.
3- Biosynthetic machinery to provide sufficient contractile protein & other
cytoskeletal elements.

3- Atrophy
Reduction of the size of an organ after reaching its normal adult size
Dt ↓ Both No. &/or size of cells.
► Cells still surviving.
► Associated with fibrosis.
► Associated with diminished function of the tissue.

* Physiological:
- Ovary & breast after menopause.
- Senile atrophy of geriatrics in heart.
- Involution: A form of physiological atrophy.
It's return back to normal size after hyperplasia or hypertrophy.
If removal of causative stimuli & return back of equilibrium.
E.g.: Uterus after labour.

* Pathological: (Localized or Generalized)

- Ischemic atrophy: dt ↓ of blood supply. E.g. atherosclerosis
- Pressure atrophy: dt continuous  on a tissue  ↓ blood supply
"amyloidosis – benign tumour".
- Neuropathic atrophy: dt loss of motor nerve supplying of a muscle.
"Poliomyelitis"
- Disuse: decreased work load e.g. "immobilized limb"
- Starvation: "generalized atrophy".

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 Dr. Hassan Abdelrahman Soliman

4- Metaplasia
A reversible change or replacement of adult cell type (epithelial or mesenchymal)
by another adult cell of the same tissue.

i.e.: replacement of more sensitive cells to stress by more resistance cells

able to with stand it "adaptive substitution".

Types: A- Epithelial Squamous Metaplasia:

** Transformation of sensitive epithelial cell types to resistant sq. epithelium.
** Mech: Genetic re-programming of stem cells to differentiate along a new
pathway rather than phenotypic change of already differentiated cells

►Cause: chronic irritation.

►Advantage: New cells more ability to survive.
►Dis-advantage: Less performing the functions & loss the imp. protective mech.
►Complication: If stimulus persist  cancer transformation, e.g.: Sq.C.C.

- Transitional epithelium of urinary bladder, ureter, renal pelvis in stones & Bilhariziasis.
- Columnar epithelium of gall bladder in cases of stones & inflammation.
- Pseudo stratified ciliated columnar respiratory epithelium in smoking or ↓↓ vit A.
- Uterine endocervical glandular epithelium in chronic irritating conditions (HPV)

B- Epithelial Columnar Metaplasia:

- Stratified squamous epithelium of lower 1/3 esophagus  columnar mucous sec
in case of GERD “Barrett's esophagus”

C- Mesenchymal Cell Metaplasia:

** Mech: Undifferentiated mesenchymal cells in connective tissue.
- Fibroblast  osteo or chondro-blast in foci of fracture, to produce bone or cartilage.
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 Dr. Hassan Abdelrahman Soliman

Growth Abnormalities
Hypoplasia:
↓ in size of an organ dt incomplete development in embryonic or fetal life.
E.g.: kidney & uterus.
Aplasia:
Failure of development of an organ, so, proper form & functions aren't acquired.
E.g.: Bone marrow.
Agenesis: Complete absence of an organ or part of an organ.
E.g.: Solitary kidney.
Dysplasia:
Def: Disorderly proliferation of cells (non-neoplastic) describing:
loss in the uniformity of individual cells & their architectural orientation.

Causes: Chronic irritation  chronic inflammation  ↑exposure to growth

factors  ↑ proliferation  loss of normal orientation & polarity.

Changes: - Pleomorphism.
- Hyper-chromatism.
- Abundant mitoses.
- Loss of normal orientation. (Loss of polarity).

Site: commonly epithelial cells especially in the cervix uteri.

Degrees: Mild - Moderate - Marked.
Fate: * Mild & Moderate  reversible after removal of the cause.
* Marked & whole thickness  pre-invasive neoplasm.
"Carcinoma in situ"

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 Dr. Hassan Abdelrahman Soliman

Neoplasia
= New growth
Tumor: Any swelling or mass (neoplastic, non-neoplastic) as in inflammation, haematoma.
But in practice Neoplasm = Tumor = oma.
Cancer: Common term of malignant neoplasms.
Oncology: the science studying neoplasms.

Neoplasm:
Abnormal new growth of cells independent on normal growth stimuli.
Characterized by:
1- Purposeless "not beneficial & may be harmful"
2- Persist even after cessation of the stimuli, "irreversible".
3- Autonomous i.e. continuous, auto regulated.
4- Uncoordinated growth with the surroundings = can grow even in mal-nutrition.
5- Evoked by known or unknown stimuli.
6- Disturbed proliferation, differentiation & organization.
7- Loss of regulation of mitosis & cell maturation.
8- Loss of specialized function, tissue morphology & characteristics.

Components:
A- Parenchymal neoplastic cell "proliferating tumour cells"
B- Supportive stroma "Connective tissue, blood vessels, lymphatic"

Classifications:
1- According to clinical behavior (Benign, Malignant).
2- According to cell of origin “histo-genetically”:
- Epithelial "surface- glandular"
- Mesenchymal
- Germ cells "totipotential cells"

Characteristics:
1- Pattern of growth
* Benign  expansile
* Malignant  infiltrative

2- Capsulation & Plane of Cleavage

* A zone of dense fibrous tissue around a neoplasm.
* Caused by pressure atrophy of the surrounding tissue by growing neoplastic cells.
* Benign tumours mostly capsulated with few exceptions, even so,
a plane of cleavage is always present.
* Absent in malignant tumours dt invasion & infiltration to the surrounding.
Q: Enumerate benign tumours without capsule?? (5)
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3- Rate of growth
* Benign  Slowly, over period of years "mostly".
* Malignant  Rapidly locally
distant metastasis
Host factors influence growth rate:
1- Hormones if hormonally dependant cells "breast, ovary, uterus, prostate, …
2- Blood supply: ↑ supply  ↑rate of growth.
♠ Tumor cells secrete their own angiogenesis factors.
♠ without supply the solid tumors can't grow beyond 2-3mm diameter.
3- Unknown factors.
4- Differentiation
* Def: is the extent of morphological & functional resemblance of tumor cells
to their normal original cells "counterpart".
* Benign  resemble the original cells "well differentiated"
= tumour cells are very closely to normal
& mitosis is very scanty in no. & normal in configuration.
* Malignant  with wide range of differentiation:
Well differentiated  completely undifferentiated.

Anaplasia (Atypia): "De-differentiation"

Loss of structural & functional differentiation of normal cells.
"Anaplasia is Marker of cancers"
♠ Malignant tumors formed by undifferentiated cells called Anaplastic tumors
Characterized by group of microscopic features seen in malignant cells:
1- Nuclear & cellular pleomorphism:
Wide variation in shape & size of cells & nuclei.
2- Hyperchromatism:
- Darkly stained nuclei - Prominent nucleoli
3- Disturbed nucleo-cytoplasmic ratio: (n: 1:4 or 1:6)
↑ to reach 1 : 1 = enlargement of nucleus.
4- Abundant mitosis:
↑ proliferative activity & abnormal atypical figures
"tripolar, quadripolar, multipolar spindles".
5- Tumor giant cells:
Cellular enlargement with large polypoid nucleus or multiple nuclei.
6- Loss of polarity:
Loss of tissue architecture, lack of recognizable patterns of orientation bt them

► Well diff tumors retain the function of normal cells.

As production of hormones (Endocrinal glands) or keratin (St. Sq. epith)
► ↑ anaplasia of malignant cells  ↑ structural & functional deviation from normal
cells  loss of tissue architecture  ↑degree of spread  ↑ bad prognosis
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 Dr. Hassan Abdelrahman Soliman

5- Recurrent after excision

* Benign  Not recur, except if inadequate removal.
* Malignant  commonly recur dt no capsule, infiltrative growth.

6- Fate & Prognosis

* Benign: not fatal except:
1- in vital area as brain, heart
2- Disturbed function as hormone secreting tumors "adenomas".
* Malignant: usually fatal.

7- Angiogenesis
Def: Formation of new vessels from pre-existing vasculature
caused by endothelial growth factors secreted by tumor cells.
Role: 1- ↑ rate of growth in primary site.
2- responsible for haematogenous spread & metastasis.
Quantity & Quality: Benign  Few no. of well developed vessels
Malignant  ↑ no. of poorly developed.

8- Metastasis
Def: Tumour implants discontinuous with the primary tumor in remote tissues.
* Benign  Never.
* Malignant  all show metastasis with few exceptions as B.C.C of skin.
"Metastasis is Marker of cancers"

Benign Malignant
1- Mode of growth Expansion Invasion
2- Rate of growth Slow Rapid
3- Capsulation Usually encapsulated Not
4- Plane of cleavage Present Absent
5- Recurrence No recurrence if complete R Usually recurrence
6- Fate Not fatal unless in vital site Usually fatal
7- Metastasis Never Occur in far tissues
8- Differentiation Well = resemble origin Not close
9- Histology:
Uniform in size, shape, Variable in size & shape
Cells
arrangement with loss of polarity
Nuclei Normochromic Hyperchromatic
Mitosis Few or absent Many, abnormal
N/C ratio Normal (1:4  1:6) Increased (1:1)
Blood vessels Well formed Badly formed

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 Dr. Hassan Abdelrahman Soliman

Mechanism of Invasion & Metastasis:

- Complex process, series of steps.
- Done only by certain sub clones have the genetic program to complete all steps.
"heterogenous metastatic potential"
- The process can be interrupted at any stage by host or tumour selected factors.

A- Invasion of extra cellular matrix: (Basement membrane – interstitial C.T)

1- Detachment of tumour cells from cell mass.
2- Attachment of tumour cells to matrix.
3- Degradation of extra cellular matrix substance.
4- Migration via degraded matrix.

B- Vascular dissemination & homing of tumor cells:

1- Invasion of vessel wall "blood-lymphatic"
Circulate as emboli singly or by aggregation or adhesion with platelets or WBC's.
2- Attachment to specific organ endothelium.
3- Degradation of vascular basement membrane.
4- Enter into the new tissue "homing".
5- Development of its own blood supply.
6- Proliferation  Secondary growth  Mass.

Factors determining site of secondary growth

1- Vascular & lymphatic drainage of primary tumor.
2- Interaction of tumour cells with organ specific receptor
dt it may express adhesion molecules. "Organ tropism". E.g.:
* Prostatic carcinoma  Bone.
* Bronchogenic carcinoma  Brain & Adrenals.
* Neuroblastoma  Liver & Bone.
3- Microenvironments of organ or site:
E.g.: ↑↑ protease inhibitors  resist tumour penetration
Tumor chemo-attractants  recruit tumour cells.

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 Dr. Hassan Abdelrahman Soliman

Spread of Malignant Tumors

1- Direct spread  surrounding structures.
2- Lymphatic spread:
* Most commonly & early for carcinomas with few exceptions.
* Along lymph vessels.
* Site: daring LN  enlarge & replaced by malignant cells.
* Mech.: a- Lymphatic Permeation:
* In small lymphatics.
* Malignant cells grow side by side in the lumen till regional LN.
b- Lymphatic Embolization:
* In medium & large lymphatics.
* Small masses of malignant cells carried as emboli in lymph current.

3- Haematogenous spread:
* Most commonly in sarcomas.
* Along blood vessels V > A dt - Small - Thin walled
- Badly formed - Easily penetrated.
* Neoplastic cells reach the blood via:
a- Lymphatics & thoracic duct.
b- Lymphatics around the walls of veins.
c- Direct invasion of blood vessels mostly in rich supplied organs
or extensive motility, that squeezes tumour cells into capillaries.
(Tongue & Stomach)
* Site:
According the anatomical distribution of circulation "veins" E.g.:
- Portal circulation PV  liver
- Systemic circulation  lungs  via heart  any organ
- Proximal to Para vertebral plexus "thyroid, prostate" vertebral column.
► commonest sites: Lungs - Liver - Bone - Brain.
* Some carcinomas invade the veins:
- Renal C.C.  renal vein "snake like fashion"  IVC  Rt heart  lung.
- H.C.C.  invade portal & hepatic radicals  grow within  main veins.
- Chorio-caecinoma  wide spread to lungs.
- Malignant melanoma.

4- Natural Passages: As bronchi, ureters, fallopian tubes.

5- Trans-coelomic spread: Via serous cavities "P.P.P."
E.g.: Cancer stomach  ovary "Krunkenberg's tumour".
6- Inoculation:
Implantation of malignant cells in surgical wound during surgical removal
of malignant tumours.
7- Peri-neural Lymphatics: Along nerves.
E.g.: prostate & salivary glands.
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 Dr. Hassan Abdelrahman Soliman

* Grading (Pathological Term)

A system for assessment of malignant tumors according degree of differentiation.
- Based on (1) cytological differentiation of tumour cells.
(2) No. of mitosis.
- ↑ grading  ↓ differentiation  ↑ aggressiveness & level of malignancy.
- Classification grads: I, II, III, IV in order of increasing anaplasia.

* Staging (Clinical Term)

A system for assessment of malignant tumors according degree of spread in the body.
- According to size of tumor & methods of its spread.
- Obtained by: 1- Clinical examination.
2- Radiological (CT - MRI) examination.
3- Surgical exploration.
- ↑ Stage  late tumor  bad prognosis. Staging has greater clinical
value than grading
- Methods: Stages O to IV
TNM system
T: extent of primary tumour in tissues "size & local spread" T0, T1, T2, T3, T4
N: degree of LN involvement N0, N1, N2, N3
M: presence of distant metastases M0, M1

Special Forms of Neoplasia

Carcinoma in situ "Stage 0 carcinoma"
(Pre-invasive, Intraepithelial carcinoma)
Malignant changes in epithelial cells
with cytologic criteria of malignancy "sever dysplasia & anaplasia ………..."
But without invasion of basement membrane.
► E.g.: carcinoma in situ of cervix "remains years then invasion".
► Prognosis: Good.

Occult carcinoma
Carcinoma which manifest itself primarily by metastasis
dt the original tumor is not sufficiently large to produce symptoms.
E.g.: - Prostatic carcinoma. - Pancrease "body & tail".
- Thyroid carcinoma "papillary". - Nasopharyngeal carcinoma.
- Maxillary antrum. - Apex of the lung.
- Fundus of the stomach. - Ceacoum.
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 Dr. Hassan Abdelrahman Soliman

Locally Malignant Tumors

Are malignant tumors which invade & destruct locally but do not giving distant metastases.
Dt: have no metastatic sub-clones able to invasion.
E.g.: - Adamantinoma of jaw.
- Basal cell carcinoma.
- Carcinoid tumor of appendix.
- Cranio-pharyngioma.
- Gaint cell tumour of the bone. "Osteoclastoma".

Teratoma
A Tumor arising from totipotential germ cells which have the ability to
differentiate to any of 3 germ lines, so can give rise any tissue of the body.
"ectoderm mesoderm endoderm"
  
Skin, nerve, teeth F, B,C&,M GIT, glands

Sites: normally T.P cells present in

1- Gonads "testis & ovary".
2- Midline of the body "sacro-cocsogyeal, retroperitoneal, mediastinal,
base of the skull or pineal body".
Types:
1- Mature: all the parts are mature = well differentiated.
2- Mature with Malignant: mature tissues & undergo malignant changes.
3- Immature: the parts are less well differentiated or immature.

Mixed Tumors
Tumors showing mixed tissue components "epithelial & mesenchymal".
* Derived from: 1- divergent differentiation of the stem cell. (In the past)
2- epithelial or myoepithelial cells or both.

* Components  epithelial
 Stroma: fibromyxoid, fat, cartilage, tooth.
E.g.: mixed tumor of salivary gland. "Pleomorphic Adenoma"

♦ Hamartoma: "not a neoplasm"

Mal-formative lesion, where the tissues components of the part are arranged
haphazardly "in disorganized manure".
* Non capsulated mass
* Present at birth  manifest later on.
* Sites: Lung - kidney.
* E.g.: hamartomatous nodule of the lung containing islands of cartilage, bronchi
& blood vessels.
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Epithelial Tumors
I- Benign
1- Papilloma:
Def: Benign tumor of surface covering epithelium "internal or external".
Gross: Finger-like processes which may be:
- Simple
- Compound with thick short branches
- Villous with thin long filaments
- Sessile or pedunculated.
Microscopically:
- Covering: proliferative epithelium. "Achanthosis, Parakeratoaia, Keratosis"
- Core: connective tissue "blood vv, lymphatic, nerves"
E.g.: Squamous cell papilloma of skin, tongue, mouth, larynx, …..

2- Adenoma:
Def: Benign tumor of glandular epithelium "endocrine & exocrine".
Types:
a- Functioning: "endocrine" ↑ Production of secreting hormone.
E.g. thyroid, pituitary & suprarenal glands.
b- Non-functioning "exocrine" No ↑ in secretions.
E.g.: breast, salivary, sweat, lacrimal glands & intestine.

Microscopically:
1- Simple adenoma: Acini separated by connective tissue stroma.
E.g.: - adenoma of kidney
- adenoma of endocrinal glands.

2- Fibro adenoma: Glandular tissue & fibrous tissue are present together.
E.g.: glandular epithelium of the Breast.
Have 2 forms:
A- Peri-canalicular:
Proliferated dense fibrous tissue stroma, large in amount, surrounding:
Round or oval, variable sized, multiple acini lined by single or multiple layers
of cuboidal epithelium with intact basement membrane.
B- Intra-canalicular:
Proliferated loose myxomatous connective tissue stroma compressing:
the acini  collapse of their lumina. "Slit like irregular clefts"
Lined by more than one layer of cuboidal epithelial cells.

N.B.: Both patterns present in same tumour, with predominance of one of them.
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3- Cystadenoma: "Ovary"
A- Mucinous:
Cystic tumour of multiple loculi containing mucous with smooth surface
lined by tall columnar mucous secreting cells, with basal nuclei.
B- Papillary serous cystadenoma:
Cystic tumour, multilocular with papillary projections lined
by cuboidal epithelium & contains serous fluid.

4- Adenomatous polyp:
The tumor glandular epithelium project above the surface
of mucous membrane  pedicle dt traction of the viscus.
E.g.: - adenomatous polyp of stomach, colon or rectum

3- Nevus:
Def: Benign tumor of melanocytes.
Gross: pigmented & slightly elevated above surface of the skin.
Microscopic: aggregation of nevus cells in nests, from the dermo-epidermal
junction into dermis & their nuclei are uniform & rounded.

Classification of Tumours
Origin Benign Malignant
I- Tumours of epithelial origin:
St. Sq. epithelium Squamous cell papilloma Squamous cell carcinoma
Glandular epithelium Adenoma Adenocarcinomma
Melanocytes Nevus Malignant Melanoma
II- Tumours of mesenchymal origin:
Fibrous tissue Fibroma Fibrosarcoma
Fat tissue Lipoma Liposarcoma
Muscle Myomma Myosarcoma
Cartilage Chondroma Chondrosarcoma
Bone Osteoma Osteosarcoma
Blood vessels Haemangioma Angiosarcoma
Lymph vessels Lymphangioma Lymphangiosarcoma
Lymphoid Tissue -------- Lymphoma
Haemopoietic cells -------- Leukaemia
Neurofibroma
Nerve cells Neurofibrosarcoma
Schwannoma
Fibro-histio-cytic B. fibrous histiocytoma M. fibrous histiocytoma
III- Tumours from totipotential cells (Germ cells):
Mature Teratoma Immature Teratoma
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II- Malignant "Carcinomas"

Def:
Types:
Characteristics:
1- Arising from surface epithelium:
DD (1)Squamous C Carcinoma (2)Basal Cell Carcinoma
Locally malignant tumour arising
Malignant tumour arising from all
from basal layer of epidermis of
layers of st. sq. epi, especially
Def skin & skin appendages.
Prickel cell layers
"dermo-epidermal junction"
1-Skin "face-extremities" 1- Face "middle third" 
2-Mucous membranes "tongue, anal eyelids, nose, cheeks
lips, larynx, vagina, esophagus" & angle of the mouth.
Sites
3-On top Squamous metaplasia 2- Forehead
"U.B- G.B-bronchi" 3- Scalp
Predisposing Irritating conditions – Black race Sun light – White, fair people
Small hard nodule Firm nodule or papule
 
Gross Typical malignant ulcer slowly ↑in size & ulcerate
which increase in size gradually Rodent malignant ulcer
No.: Single Single
U
Size: Large Smaller
L
Edges: Raised – everted dt Raised, beaded & rolled in dt
C
Base: Hard&fixed to underlying structure Indurated, fixed
E
Floor: Necrotic material Necrotic material
R
Outline: Irregular Less irregularity
Regional LN  infiltrated
LN No LN affection
enlarged - hard – discrete
* Irregular masses of cells called * Irregular dermal masses
cell nests or epithelial pearls, with geographic appearance
Invading deep underlying tissue formed of malignant
composed of : basal cells (basaloid):
1- Outer layer: columnar epithelial 1-outer layer: tall columnar cells
cells showing pleomorphism & "palisading manner" with basal
Microscope hyperchromatism of nuclei dark nuclei.
2- Intermediate layer: polygonal. 2- Inner layer: rounded polygonal
3- Inter layer: keratinized flat cells, with dark hyper-chromatic
epithelial cells. nuclei.
* Fibrous tissue stroma "blood vv- * Fibrous stroma in between
lymphatic" in between nests. containing chronic inflam cells.
Spread Direct – Blood – Lymphatic Local only. No metastasis.
Grading of S.C.C: according to the number of cell nests:
I- > 75 % cell nest  slowly growing, differentiated, radio-resistant
II- 50 – 75 % cell nests
III- 25 – 50 % cell nests
IV- < 25 % cell nests  rapidly growing, undifferentiated, radio-sensitive.
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 Dr. Hassan Abdelrahman Soliman

(3)Malignant Melanoma
Def: Malignant tumour from epidermal melanocytes.
Incidence:
- Most aggressive malignant cutaneous tumours.
- De novo or on top of nevus.
- With sun exposure & common in white persons.

Sites: * Skin (any Where)

- Head - Neck - Hands - Sole of foot
* Eye:
- Retina - Choroid - Iris

Gross: Mass:
* Size: variable.
* Pigmented.
* Bleeds easily on touch.

Microscopically:
* At demo-epidermal junction  invading down toward dermis.
* Tumour cells: = Malignant nevus cells
- Variable in size
- Variable in shape
- Large hyper chromatic nuclei
- Melanin pigment in cells & stroma.
* Stroma: very rich by blood vessels.

Spread:
- Early by blood  liver, lung. "Exception"
- Lymphatics  regional LN.

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 Dr. Hassan Abdelrahman Soliman

2- Arising from Glandular Epithelium:

Adenocarcinoma
Def: Malignant tumour of glandular epithelium.
Sites:
- Mucosa of stomach, colon, G.B
- Breast, liver, pancreases, kidney, LN.
- Ovary, endometrim, thyroid ….

Gross:
* In hollow organs:
1- Fungating or polypoid mass (Exophytic):
As cauliflower mass bulging in the lumen.

2- Ulcerating:  Typical malignant ulcer.

3- Diffuse infiltrating (Annular - Endophytic):

Infiltrates whole thickness of wall  diffuse thickening of wall
 segment narrowing of lumen.

* In Solid organs  non encapsulated mass infiltrate surroundings

& may forming malignant ulcer.

Microscopically:
1- Well differentiated: malignant epithelium arranged in the form of acini (glandular)
2- Moderately differentiated.
3- Poorly differentiated: Groups of malignant cells separated by fibrous tissue.
Cell > fibrous = encephaloid "soft-brain like"
Cell < fibrous = scirrhous "hard"
N.B.:
Mucoid carcinoma: adenocarcinoma characterized by excessive mucus secretion.
Gross  Jelly like, semi translucent appearance.
Microscopic:
Foamy cells with central nuclei

Signet ring appearance with eccentric
Crescent like hyper-chromatic nuclei
& clear cytoplasm

Rupture

Mucin pools

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 Dr. Hassan Abdelrahman Soliman

Connective Tissue Tumour

I- Benign
1- Fibroma:
Def: benign tumour of fibrous tissue.
Sites: Subcutaneous tissue Fascia Tendon sheaths
Fibrous stroma of ovary, breast & kidney. Inter muscular septa
Gross: - Rounded, oval mass - Slowly growing
- Encapsulated - Soft or hard according collagen content.
Microscopically: interlacing bundles of: * Fibrocytes. * Collagen fibers.

2- Lipoma:
Def: benign tumour of adult fat cells.
Sites: - Subcutaneous fat "neck, shoulder, back" - Retroperitoneal & mesentric fat.
Gross:
Colour: Yellow. Shape: rounded, oval mass.
Size: Variable. Capsule: thin delicate fibrous.
Cut surface: yellow, lobulated. Touch: greasy. Consistency: soft
Microscopic:
- Group of mature fat cells.
- Separated by thin fibro vascular stroma.
- Cells: clear vacuolated cytoplasm with eccentric nuclei.

3- Leiomyoma:
Def: benign tumor of smooth muscle fibers.
Sites: - Uterus + mixed with fibrous tissue "fibromyoma".
- Intestine - Stomach - Oesophagus.
Gross: Number: Single or multiple.
Site: Submucosal - Subserosal - Intramural.
Shape: rounded mass
Consistency: firm
Capsule: false capsule. "compressed the surrounding tissue"
Cut section: whorly appearance "white fibrous tissue & red myomatous tissue"
Microscopic: Interlacing bundles of:
- Smooth muscle cells "plump cells, rod shaped nuclei"
- Fibroblasts "slender cells, elongated tapering nuclei"

4- Osteoma:
Def: benign tumor of the bone.
Types: Compact (ivory): skull bones. Hard rounded sessile mass with a smooth surface.
Osteoid osteoma: ends of long bones.

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 Dr. Hassan Abdelrahman Soliman

5- Chondroma:
Def: benign tumor of cartilage.
Sites: - Short bones "hands & feet" - Flat bones as ribs & sternum.
Gross:
- Encapsulated mass
- Septa  lobules
- Cut surface: bluish gray & semi translucent.
Microscopic:
- Lobules separated by thin fibrous septa rich in blood vessels.
- Chondrocytes variable size & shape & irregular arranged in lacune.
- Faint blue homogenous chondroid matrix.

6- Hemangioma:
Def: benign tumour of blood vessels at birth or in early life.
Sites: Skin, lips, tongue, liver, bone, brain.
Types: - Capillary - Cavernous
Gross:
- Circumscribed - Un-capsulated tumour.
- Slightly raised above surface. - Red to blue in colour.
Microscopic:
- Closely packed cap. usually filled with blood but may be empty.
- Separated by scant C.T stroma.
Or
- Large vascular spaces filled with blood engorged or clotted.
- Lined by flattened endothelial cells.
- Separated by thick fibrous tissue septa.

7- Neurofibroma – Schwannoma:
Def: benign tumor of nerve sheath.
* Neurofibroma from epi & endoneurium
* Schwannoma from schwan cells surrounding the axons.
Sites:
- 8th cranial nerve. "commonest" - Peripheral nerves.

II- Malignant Tumours

"Sarcomas" Sarc = Flesh
Def: malignant tumors of mesenchymal origin.
Classifications:
*Differentiated: (( Low grad ))
- Fibro sarcoma - Lipo-sarcoma
- Chondro sarcoma - Osteo-sarcoma
- Rhabdomyo-sarcoma - Angiosarcoma
* Undifferentiated: (( High grad )) Complete anaplasia
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 Dr. Hassan Abdelrahman Soliman

Cancer
Genetic hypothesis of cancer:
1- The 1ry genetic defect occurs in a single progenitor cell & is not repaired.
((Stage of Initiation))
2- Promotion of initiated cells by exposure to some agents  stimulate
uncontrolled proliferation. ((Stage of Promotion & Clonal expansion))
3- Accumulation of 2ry genetic changes. ((Tumour progression))
♠ Cancer is a genetic disease at somatic cell level affecting single
progenitor cell  clonal expansion  cancer.

Pathogenesis: Genetic damage or mutations are dt:

(1) Acquired "environmental agents".
Or (2) Inherited mutations in the germ cell line.

Etiology: Carcinogenic agents

I- Chemical Carcinogens:
♣ Their effects to produce neoplasms divided into 3 sequential stages:
1- Initiation: induction of mutations in the genome of cells
 Permanent alteration in DNA structure "Not repaired".
"Alone is not sufficient for tumour formation"
2- Promotion: start the tumour process & proliferation of initiated (mutated) cells.
as hormones “estrogen” - drugs - GFs - Phenols - sweeteners.
"Alone is not carcinogenic, not mutagenic"
3- Progression: occurrence & accumulation of more mutations.
 phenotypic features of cancer (morphologically & biochemically).
They may be:
1- Direct acting:
- Not require any metabolic conversion or activation to become carcinogenic.
- As anticancer drugs (alkylating agents)  lymphoma, leukemia, bladder cancer.
2- Indirect acting = Pro-carcinogens:
- Become carcinogens after metabolic activation & conversion within the body
In the liver by mono-oxygenases of cytochrome P-450 in the ER.
♦ Polycyclic aromatic hydrocarbons
"tobacco, soot, tar, minerals oil, smoked food"  lung & skin cancer.
♦ Azo dyes & aromatic amines "rubber industries"  bladder cancer, HCC.
♦ Asbestos & silica  lung cancer & mesothelioma.
♦ Aflatoxin B "fungs Asergillus flavus"  hepatocellular carcinoma.
♦ Estrogen hormone  endometrial & breast carcinoma.
♦ Arsenicals  skin cancer.
♦ Vinyl chloride  liver angio-sarcoma.
♦ Nitrosamines & nitrosamides  stomach cancer.
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 Dr. Hassan Abdelrahman Soliman

II- Physical & Radiation carcinogens:

♣ Causing mutations with long period of latency (10-20Y)
♣ Radiation damage the nuclear DNA by:
- Directly alter cellular DNA.
- Formation of reactive free radicals or pyrimidine dimers in DNA,
- Enhance the effect of other carcinogens (co-carcinogens).

1- Ultraviolet rays "Sun, UV lamps":

E.g. Skin cancers "SqCC, BCC & MM" or leukaemia.

2- Ionizing radiation (particular): Higher dose  ↑↑ risk

"X-ray, α, β, γ rays, radioactive isotopes, protons, neutrons"
♦ Miners of radioactive elements  lung cancer.
♦ Survivors of atomic bomb, Chernobyl leakage  leukemia.
♦ Therapeutic radiation of neck  thyroid, breast cancer.

3- Electromagnetic radiations "power cables, cellphones, microwaves":

Long term use (probable risk)  brain tumors.

III- Biological carcinogens & Viral oncogenesis:

♣ Viral DNA or RNA in host cells may lead to:
- Induction of mutations.
- Activation growth promoting pathways or inhibit tumor suppressor pathways.
- Alter host cells enter cell cycle  autonomous growth.
E.g.:
1- Human T-cell leukemia virus type1 (HTLV-1) Leukemia & lymphoma.
2- Human papilloma virus  Squamous cell carcinoma of skin, cervix, anal canal.
3- EBV  Hodgkin, Burkitt's lymphoma & nasopharyngeal cancer.
4- Hepatitis B  hepatocellular carcinoma.

♣ Bacteria:
- Prolonged Helicobacter pylori infection  gastric carcinoma & lymphoma.

♣ Parasites:
- Schistosoma haematobium  UB sq. carcinoma.
- Liver flukes “Clonorchis sinensis”  cholangio-carcinoma.

♣ Fungi:
- Aspergillus flavus  HCC
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 Dr. Hassan Abdelrahman Soliman

Host Response against Tumour

“Tumour Immunology”
Body’s immune system can recognize tumour cells as non self  try to destroy it.

Tumour Antigens:
♦ Recognized by host immune cells CD8+ T cells
1- Onco-protein from mutated oncogenes as RAS.
2- Proteins of mutated TSG as p53.
3- Over expressed cellular proteins as HER2/ neu in breast cancer.

Anti tumour immune responses:

1- Cell mediated mech: (main mech) By CD8 + T cell , NKC & macrophages.

2- Humoral mech: Targeted Ab in some types of lymphoma.

Immuno-therapy:
1- Cellular immunotherapy: infusion of tumour specific cytotoxic T cells.
2- Cytokine therapy: IL2 , Interferon α
3- Monoclonal Ab therapy.

Clinical Effects of Tumors on Host

I- Local effects:
1- Compression or pressure on surrounding  pain, cosmetic problem, function loss.
e.g.: pituitary adenoma  serious endocrinopathy.
2- Mechanical obstruction as intestinal obstruction.
3- Tissue destruction, infiltration & replacement  loss of function.
4- Infarction, ulceration, hemorrhage.

II- Systemic effects:

Anemia
Causes:
1- Chronic blood loss e.g. GIT, UT neoplasm  iron ↓ anemia.
2- Poor nutrition e.g. oral, esophageal cancers.
3- ↓ Production RBC's e.g. metastasis in bone marrow.

Effect:  weakness & fatigue.

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 Dr. Hassan Abdelrahman Soliman

Malnutrition & Cachexia

Cachexia: state of general muscle weakness, wasting & loss of body fat.
= emaciation + anorexia + muscle wasting.
Causes:
1- Loss of appetite as in H&N or UGIT cancers
2- Nausea & vomiting dt radio or chemo therapy.
3- Tumour substance inhibits absorption & produce diarrhea as TNF-α
4- Novel proteoglycans  break down of skeletal muscle proteins
 detected in patient's urine.
5- Necrosis of tissues, infections, anxiety, pain, insomnia all may play a role.

Infections
Causes: 1- Obstructive neoplasms.
E.g.: BGC  bronchial obstruction  bronchiectasis or pneumonia.
2- ↓ host immunity.
Fever
Causes:
Secretion of cytokines & pyrogens e.g.: Hodgkin’s lymphoma, osteosarcoma

Tumor Lysis Syndrome

1- Extensive destruction of large no. of rapidly proliferating cells.
2- ↑ uric acid, potassium, phosphate & ↓ Ca in blood  acidosis & renal failure.
As in Lymphomas or after chemotherapy

Paraneoplastic Syndrome
Are complex manifestations developing in advanced cancer cases
Not dt direct spread
Not dt metastasis of the tumour
Not dt usual hormonal secretion by the tissue of origin of the tumour

1- Ectopic hormonal production (most imp cause)

E.g.: Lung cancer (small cc) ACTH or like sub.  Cushing's syndrome.
Lung cancer (sq.cc)  parathormone like sub.  hypercalcaemia.
H.C.C  Insulin  Hypoglycemia.

2- Neuromyopathy, osseous, hematologic & renal effects.

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 Dr. Hassan Abdelrahman Soliman

Laboratory Diagnosis of Cancer

1- Histologic methods: "most important"

More helpful when:
a- Available clinical data.
b- Proper preservation & sampling.

Using:
* Paraffin embedding technique: (2-5 days)
Tissue is fixed by formalin 10%  Washed by alcohol  embedding in
paraffin wax  Paraffin blocks  Sectioned by microtome (3-5 micron)
 stained by haematoxylin & eosin (H&E).

* Frozen section: (15min)

Fresh unfixed tissue  cooling -25C  sectioned  stained.

2- Cytologic methods:
a- Fine needle aspiration (FNAC):
Of cells & fluids from palpable tumours to be smeared, stained & examined.
E.g.: Breast, thyroid, LN, ……

b- Exfoliate Cytology":
Of sheded off tumour cells in to body cavities or on mucous membranes.
E.g.: cancer cervix, cancer stomach, bronchi & UB.

3- Immuno-histo-chemistry:
♠ Detection of all products or surface markers (Ags) by specific monoclonal Ab
♠ Which revealed by using fluorescent or chemical reactions.
♠ The Ag-Ab complex is visible by chromogen.
♠ Reaction is the most specific & sensitive.
♠ used in:
- Determine origin of tumour.
- Prognostic markers.
- Predict response to treatment.

E.g.: Desmin is a specific markers

for Muscular neoplasms.

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 Dr. Hassan Abdelrahman Soliman

4- Flow Cytometry:
♠ Measurement of the DNA content of tumour cells.
♠ The DNA content is related to the prognosis of the tumour.

5- Tumour Markers:
♠ Tumour- derived associated molecules which can detected in blood.
# Roles:
(1) Adjuvant in diagnosis "Not in 1ry diagnosis".
(2) Progression of the tumor = follow up.
(3) Evaluate treatment.
(4) Detect presence of metastasis.
(5) Localization of 1ry site of metastasing tumor.
(6) Occurrence of recurrences.
E.g.:
a- Alpha-fetoprotein (α FP):
Normally, produced by fetal yolk sac & embryonic liver cells.
But, never in adults.
So, if ↑↑  liver & testicular cancer.

b- Prostatic specific antigen (PSA)

if ↑↑  Prostatic carcinoma.
Help in diagnosis of early cases.

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 Dr. Hassan Abdelrahman Soliman

Epidemiology of Cancer
Incidence: 18 million new case / year
Developed: Lung > breast > prostate > colorectal.
Developing: Liver > cervix > oral cavity > oesophegous.

♂: Lung > prostate > colon > UB.

♀: Breast > lung > colon > corpus uterine.

Q. Commonest cancers causing death? 20% of all deaths are cancer related
♂: Lung > Prostate > Colon > Pancreas > NHL
♀: Lung > Breast > Colon > Pancreas > Ovary.

Epidemiological Factors In Neoplasia

Predisposing Epidemiologic Factors
(Endogenous host + Exogenous environmental)

1- Familial & Genetic factors:

* Relatives of cancer patients  3X higher risk for cancer than normal persons.
* Familial cancers  at early age, multiple sites & in 2 or more 1st degree relatives.
* Genetic cancers  5% of all cancers.

Cancer Features
AD
Familial retinoblastoma
40% familial
AD
Familial polyposis coli Adenomas seen at birth or in early age
100% colon cancer at age 50ys
Multiple endocrine neoplasia (MEN) Tumours in several endocrine organs
AD
Neurofibromatosis
50% of cases have multiple NF
Von Recklinghausen’s Dis
& pigmented café au lait spots
♀ relatives of a case are 2-6X more risk
Breast cancer
Mutation of BRCA-1 & BRCA-2
Down’s  ↑ risk of leukemia
Congenital chromosomal syndromes Klinefelter  ↑ risk of male breast cancer
& extra gonadal germ cell tumours.
Defect in DNR repair genes.
DNA chromosomal Instability
Extreme sensitivity to UV rays
Xeroderma pigmentosa
Development of skin cancer in early age < 20Y
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 Dr. Hassan Abdelrahman Soliman

2- Racial & Geographical Factors:

♦ Egyptians  cancer bladder.
♦ Japanese  cancer stomach (5X Americans)
♦ White Europeans & Americans  prostate, lung, breast, liver, colorectal & liver.
♦ Black Africans  Skin, penis, cervix, liver.
♦ South east Asians - Chinese  nasopharyngeal carcinoma.

3- Environmental & Cultural Factors:

* Habits: Alcohol  cancer liver, oropharynx, larynx, esophagous.
Smoking (The single most imp factor)
 cancer lung, oral cavity, phaynx, larynx, esoph, stomach, …

* Industrial: Asbestos  cancer lung.

Arsenic  skin cancer
Vinyl chloride  liver angio-sarcoma.
Naphthylamine, Benzene.

* Diet: food additives, ↓ vit A, ↑ animal fats, ↓ fibers  colon cancers.

4- Age: The most significant risk factor for cancer.

↑ risk with Age Dt ▪ alteration of host cells
▪ accumulation of mutations dt long exposure to carcinogens
▪ ↓ Immunologic defenses

► Some tumors have 2 peaks of incidence (Bimodal) as acute leukemia.

"Tumours common in children <15 y"??

♦ Acute leukemias ♦ Lymphomas
♦ Nephroblastoma"Wilms' tumour" ♦ Neuroblastoma
♦ Retinoblastoma ♦ Hepatoblastoma
♦ Teratoma ♦ Ewing’s sarcoma
♦ Rhabdomyosarcoma

5- Sex:
The difference in incidence are related to:
specific sex hormones & anatomical variations.

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 Dr. Hassan Abdelrahman Soliman

Chronic Non-Neoplastic (Pre-malignant) conditions

= Clinical conditions are associated with ↑ risk of cancer

1- Inflammatory & hyperplastic conditions:

♦ Cirrhosis  HCC
♦ Chronic atrophic gastritis  stomach cancer.
♦ Chronic ulcerative colitis  colon cancer.
♦ Old burn scar  Sq. C.C. (Marjolin’s ulcer).
♦ Chronic bronchitis in heavy smokers  BGC
♦ Chronic irritation by jagged teeth or ill fitting denture  oral cancers.
♦ H. pylori infection  gastric cancer & lymphoma
♦ HPV  oral & cervical cancers.

2- Dysplastic changes & carcinoma in situ:

♦ Leukoplakia in oral or genital mucosa  Squamous cell carcinoma.
♦ Dysplastic cervical proliferations (CIN)  cervical carcinomas.
♦ Bronchial dysplasia.
♦ Bowen’s disease of the skin.
♦ Barrett’s oesophagous.
♦ Intra lobular & intra ductal breast carcinoma

3- Benign tumors: commonly not turn malignant

♦ Multiple adenomas of the colon  colorectal adenocarcinoma.
♦ Neurofibromas  sarcoma.

Hormonal Factors

♦ Estrogen ↑  breast & endometrial carcinomas.

♦ OCP  breast cancer & liver adenoma.
♦ Steroids  liver tumors B & M.
♦ Androgens  prostatic carcinoma.

So, ► Prostatic carcinoma usually respond to estrogen therapy.

► Breast cancer may regress after oophorectomy, pituitary removal
or androgens intake.

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