Chapter 5

DISORDERS OF GROWTH
AND NEOPLASIA 3

Dr Miran Atif Elkordy

Mechanism of spread of malignant
tumors
Invasion of Extracellular Matrix (ECM)
Vascular Dissemination and Homing of
Tumor Cells
Mechanism of spread of malignant
tumors
Invasion of Extracellular Matrix (ECM):
1-Loss of cellular cohesion:
Normal cells are glued together by molecules
called cadherins. Tumor cells lose the normal
cadherin expression, allowing them to detach
(loosening up).
2-Attachment of tumor cells (through
receptors) to matrix components:
mainly to laminin of basement membrane and
fibronectin of the interstitial tissue. Attachment to
ECM promotes the next steps.
Mechanism of spread of malignant
tumors
3- Degradation of the ECM:
 by proteolytic enzymes secreted by the tumor
cells or by stimulated host cells (fibroblasts &
macrophages).
 Several enzymes are released as:
 Type IV collagenase (causing lysis of basement
membranes)
 Cathepsin D (causing degradation of interstitium).
 Degradation of ECM is very important for the
tumor cells to create passageways for their
migration.
Mechanism of spread of malignant
tumors
4-Migration (mobility) of tumor cells
by pseudopodia
This is mediated by tumor-derived
cytokines (mobility factors) such as
“autocrine mobility factor”.
The process may be helped by acquiring
negative charges on surface of tumor cells
causing their repulsion and loss of contact
inhibition.
Mechanism of spread of malignant
tumors
Vascular Dissemination and Homing of
Tumor Cells:
1. Tumor cell mobility allows cells to come in
contact with blood vessels.
2. Tumor cells can penetrate lymphatics,
capillaries & venules, but rarely arterioles
(thick-walled).
3. Once the tumor cells cross the vascular
basement membranes, they reach circulation
as tumor emboli.
Mechanism of spread of malignant
tumors
Fate of tumor emboli:
a)Most tumor emboli are destroyed by immune
mechanisms.
b)The surviving tumor cells adhere to platelets.
This affords them some protection from antitumor
immune cells.
c) Finally, the surviving tumor cell emboli get
impacted in small vessels, where they adhere to
the endothelium, cross the basement membrane &
settle in the new site (homing). In their new sites,
tumor cells proliferate forming metastatic deposits
(metastasis, secondary tumors).
Mechanism of spread of malignant
tumors
Fate of tumor emboli:
Some tumors show organ tropism.
 prostatic carcinoma prefer spreads to bone,
 bronchogenic carcinomas tend to involve
the adrenals and the brain
 neuroblastomas spread to the liver and
bones.
Such organ tropism may be related to
expression of adhesion molecules whose
ligands are expressed by endothelial cells
Mechanism of spread of malignant
tumors
NEOPLASIA
Classification of Tumors
According to their behavior:
◦ Benign Tumors.
◦ Malignant Tumors.
◦ Intermediate Tumors.
According to cell of origin (Histogenetic
Classification):
◦ Epithelial tumors.
◦ Mesenchymal tumors.
◦ Tumors arising from lymphoid and hematopoietic organs
◦ Others.
Intermediate Tumors (Locally
Malignant Tumors).
Some malignant tumors are locally invasive and
destructive but rarely give rise to metastases
(previously termed locally malignant tumors).
Such tumors usually grow slowly, can recur after
surgical excision, but have a better prognosis than
malignant tumors that metastasize.
Examples:
1) Basal cell carcinoma of the skin
2) Giant cell tumor of bone (osteoclastoma)
3) Some neuroendocrine tumors as carcinoid
tumor.
Benign Epithelial Tumors
Benign epithelial tumors:
1. Surface: Papilloma
◦ Squamous Cell papilloma
◦ Transitional Cell Papilloma (Villous
Papilloma
◦ Columnar Cell Papilloma
2. Glandular: Adenoma
◦ Exocrine or endocrine glands
◦ Mucosal glands
 Benign Epithelial Tumors
Papilloma:
Definition:
◦ benign surface
epithelial tumor
◦ Forms microscopic
or macroscopic
finger-like fronds
Benign Epithelial Tumors
Microscopic Picture:
 They have a branching
fibrovascular core
 covered by proliferated
epithelium.
Papillomas are rarely
endophytic pushing the
basement membrane and grow
inwards, compressing the
subepithelial tissues without
invasion, thus called inverted
papilloma (inverted papillomas
of urinary bladder & nose).
Benign Epithelial Tumors
Papilloma:
Papillomas are classified according to type
of epithelium into:
1. Squamous Cell Papilloma
2. Transitional Cell Papilloma (Villous
Papilloma)
3. Columnar Cell Papilloma
Benign Epithelial Tumors
1- Squamous Cell
Papilloma:
Definition & origin:
A benign tumor of stratified
squamous epithelium.
Sites:
 Skin, lip, tongue, oral mucosa,
pharynx, larynx, oesophagus,
cervix, vagina & anal canal.
Gross Picture:
• Sessile or pedunculated.
• With progressive growth, 
complex papillary pattern.
Benign Epithelial Tumors
1- Squamous Cell
Papilloma:
Microscopic Picture:
Connective tissue cores
 covered by thick stratified
squamous epithelium with
acanthosis (increased
prickle cell layers) and
hyperkeratosis.
Complications: May rarely
change into squamous cell
carcinoma.
Benign Epithelial Tumors
2- Transitional Cell
Papilloma (Villous
Papilloma):
Definition & origin:
benign tumor arising
from urothelium
(transitional
epithelium of
urinary tract).
It is strongly pre-
malignant.
Benign Epithelial Tumors
3- Columnar Cell
Papilloma
These are papillomas
arising from columnar
epithelium
e.g. duct papilloma
arising from the
epithelium of major
ducts, e.g. of breast or
pancreas
Benign Epithelial Tumors
Adenoma:
Definition and origin:
A benign tumor arising from glandular
epithelium (acini and /or small ducts).
Sites:
Exocrine or endocrine glands (breast,
salivary glands, pancreas, thyroid)
Mucosal glands: e.g. GIT & endometrium
(mucosal adenoma, adenomatous polyp)
Benign Epithelial Tumors
1- Adenoma of
endocrine or exocrine
glands:
Gross Picture:
a capsulated
globular or ovoid mass.
Cut section may be solid,
cystic or cystic with small
projecting papillae.
Benign Epithelial Tumors
Microscopic Picture:
(Several Patterns):
1- Simple adenoma:
proliferated acini
separated by delicate
stroma.
Example: pancreatic,
adenoma.
Benign Epithelial Tumors
2- Fibroadenoma:
Consists of
glandular & wide
stromal
proliferations.
Breast is the main
site.
 Benign Epithelial Tumors
3- Cystadenoma: secretions
are retained leading to
cystic dilatation of the
proliferated acini. Example:
ovarian cystadenoma.
4- Papillary Cystadenoma:
It is a cystadenoma in
which the epithelial lining
proliferates forming
papillae. Example: papillary
cystadenoma of the ovary.
Benign Epithelial Tumors
Complications of adenomas:
Adenoma of endocrine glands may function
e.g. thyroid adenoma may cause
thyrotoxicosis.
Malignant change (adenocarcinoma).
Benign Epithelial Tumors
2- Adenomas of
Mucosal Glands:
Gross Picture:
 Adenomas of mucosal
glands such as the
colon may project on
the surface of mucosa
into the colonic lumen
and is called a polyp.
 A polyp may be
sessile or
Benign Epithelial Tumors
2- Adenomas of
Mucosal Glands:
Microscopic Picture:
 Covered by columnar
epithelium
 and the core contains
proliferated glands, so it is
called adenomatous polyp.
 Some adenomas of the
colon may acquire a
papillary architecture and
are called villous adenoma
Malignant Epithelial Tumors
CARCINOMAS
Surface epithelium:
◦ Squamous cell
carcinoma.
◦ Basal cell carcinoma.
◦ Transitional cell
carcinoma.
Glandular
epithelium:
◦ Adenocarcinoma
Squamous Cell Carcinoma
Definition & Origin:
A malignant tumor of stratified squamous epithelium.
Sites:
Skin
Squamous mucous membranes : lip, tongue, mouth,
pharynx, larynx, oesophagus, cervix, vagina & anal
canal.
Other mucous membranes on top of squamous
metaplasia e.g. SCC of urinary bladder due to
bilharziasis
Predisposing factors:
Prolonged exposure to sun.
Chemical carcinogens
Squamous Cell Carcinoma
Gross Picture:
ln surfaces, the tumor pattern may be:
Fungating polypoid pattern.
Ulcerative type.
Infiltrative pattern
Squamous Cell Carcinoma
Microscopic Picture:
The dermis or submucosa
is infiltrated by
malignant epithelial cells
In the form of cell nests
replicate the normal
epidermis (the periphery
shows basal cell
differentiation, followed
by prickle cells &
granular cells with the
center showing whorly
keratin pearls).
Squamous Cell Carcinoma
Microscopic Picture:
Well differentiated neoplasms will form
cell nests.
Less differentiated neoplasms, will form
fewer cell nests
Anaplastic carcinoma (undifferentiated), no
cell nests may be detected.
Squamous Cell Carcinoma
Broder’s grading of Squamous Cell
Carcinoma:
Grade I: 75-100% of the tumor consists of
cell nests.
Grade II: 50-75% cell nests.
Grade III: 25-50% cell nests.
Grade IV: 0-25% cell nests.
Spread:
Local, lymphatic and late by blood.
Adenocarcinoma
Definition and origin:
malignant tumors from
glandular epithelium
either of:
 The mucosal surfaces (as
gastrointestinal mucosa,
endometrium or
endocervix).
 Glandular organs
(endocrine or exocrine
glands as prostate, ovary,
mammary gland, salivary
Adenocarcinoma
Gross Picture:
 ln mucous surfaces, the tumor pattern may be:
Fungating polypoid pattern.
Ulcerative type.
Infiltrative pattern
 ln endocrine and exocrine glands
irregular infiltrative growth.
1-Adenocarcinoma
Microscopic types:
Well differentiated
Adenocarcinoma:
 Tumour is formed of malignant
acini.
 They are irregular with no
definite basement membranes.
 Their lumens are irregular.
 The cells show malignant features
 They exist in abnormal sites
( submucosa, musculosa or
serosa) due to infiltration.
 1-Adenocarcinoma
Well differentiated Adenocarcinoma:
 may be cystically dilated
(cystadenocarcinoma) if the malignant
cell secretions are retained.
 Some malignant cells in these tumors
may show papillary proliferations
(papillary adenocarcinoma or papillary
cystadenocarcinoma).
- Less differentiated
adenocarcinomas:
- show less degrees of acinar
differentiation.
2-Mucin secreting carcinomas:
 Mucinous
adenocarcinoma
(mucoid or colloid
Carcinoma):
This is an adenocarcinoma
with abundant extracellular
mucin secretion
 Signet ring cell
carcinoma: The
malignant cells show
intracytoplasmic mucin
that pushes the nuclei
eccentrically. NO ACINI
3-Carcinoma simplex
(undifferentiated
carcinoma, spheroidal
cell carcinoma):
• These are malignant
tumors of glandular
origin that neither
exhibit acinar
differentiation nor
secrete mucin.
• Malignant cells form
solid groups
Adenocarcinoma
Sites:
Most common in breast
Less common in other glandular sites
mainly GIT.
Spread:
Local, lymphatic and late by blood