Lecture 13 neoplasia

Prof.Dr.
Khalil Hassan Zenad
Aljeboori
Copyrights©2017lAliraqiaUniversitylDentistrylPathologylProf.Dr.KhalilHassanZenadAljeboori.
NEOPLASIA (TUMORS)
Lecture 13

Characters of cancer cells (malignant cells): anaplastic cells.
1.Pleomorphic variation in size and shape of cells and nuclei.
2.Abnormal nuclear morphology hyper chromic, high nuclear cytoplasm ratio, variation in nuclear
shape and abnormal clumping and distribution of chromatin and large prominent nucleoli.
3.Frequent mitosis and thick irregular cell membrane.
4.Loss of polarity i.e. cells growth in disorganized fashion.
5.Other change tumor giant cells abnormal large cells with single huge pleomorphic nuclei or other
with two or more nuclei.
6.Ischemic malignant tumor mass is a poor prognosis indicate rapid aggressive tumor.
All tumor masses have stroma formed from connective tissue and blood vessels. Stroma or
desmoplasia give to tumor mass blood supply and mechanical support.
Tumor cells release substances that stimulate endothelial cells to form new blood vessels within tumor
and endothelial cells release growth factors enhance tumor growth.
Abnormal tissue proliferation which exceeds that of normal tissue and under no control of body.
Tumor initiating cell or stem cell:
tumor cellular mass originated from single cell referred as stem cell.

• Benign: general lythe name of tumors was suffix oma to the cell of origin for example fibrous
tissue-fibroma, cartilage_ chondroma, osteoid tissue osteoma. For glandular epithelium Adenoma
and non-glandular epithelium such as of skin, papilloma, and larynx, transitional cell Papilloma for
urinary bladder epithelium.
• Malignant tumor (cancer): similar to benign tumor nomenclature but certain addition sarcoma
for tumor initiated from mesenchymal tissue example fibrosarcoma for fibrous tissue, liposarcoma
for fatty tissue, leiomyosarcoma for smooth muscles, rhabdomyosarcoma for striated muscle fibers
(heart, skeletal muscles) carcinoma- malignant neoplasm that arises from epithelial cells.
Carcinoma with microscopic glandular growth adenocarcinoma, carcinoma with recognizable
squamous epithelium such as skin, esophagus, and uterine cervix termed squamous cell carcinoma.
Undifferentiated (anaplastic) malignant tumor refer to cancer of composed undifferentiated
(anaplastic) cells. Some tumor cells showed divergent differentiation such as mixed tumor of
salivary gland have epithelial, myoepithelial, bone, cartilage, (derived from myoepithelial cells)
mixed tumors called also a pleomorphic adenoma.
Nomenclature of neoplasms:

Lymphoma, leukemia derived from hemopoietic cells. Teratoma composed of different neoplastic cell
types of various germ layer example skin, hair (ectodermal layer), muscle, fat (mesodermal) and gut
epithelia (endodermal) sometime tooth, brain tissue, and bronchial structure seen. Teratoma mostly
common in ovary, because of skin, hair, follicle, and sebaceous gland is present in ovary teratoma so
called dermoid cyst.
Other tumor originated from testicular germ cell called seminoma. As for from hepatocytes hepatoma
and hepato cellular carcinoma.
• Choriostoma (hetrotopia or ectopia):
Presence of normal tissue in abnormal location example pancreatic tissue in the wall of esophagus or
stomach or small intestine or adrenal gland in sub renal capsule location. It form nodules or masses
but not tumor.
• Hamartoma :aberrant differentiation produce mass of disorganized mature specialized tissue
example lung hamartoma contain island of cartilage, blood vessels, bronchial type structures and
lymphoid tissue all these tissue present in the lung but disorganized fashion.

Malignant of tumor differ from benign by the following:
1. Malignant transformation of the target cells.
2. Growth rate, growth limit, mode of growth.
3. Local invasion, infiltration
4. Distant metastasis
5. Malignant tumor cell were anaplastic
6. Associated with more mitotic figures
7. Frequent tissue destruction
8. Recurrent after removal
9. Scanty stroma, no capsule
10. Hyperchromatic, pleomorphic cell nuclei
11. More nucleoli.
Biology of tumor growth:

Associated with certain microscopical features used to differentiate benign
from malignant.
Differentiation:
Extent to which neoplastic cells resemble comparable normal cells so divided to according
degree of differentiation.
1. Very well differentiated tumor
2. well differentiated tumor
3. moderately differentiated tumor
4. poorly differentiated tumor.
5. Undifferentiated (anaplastic) tumor.
1. Malignant transformation:

• Well differentiated tumor composed of cells example thyroid carcinoma- have
normal appearing follicles, squamous cell carcinoma contain cell resemble epithelium.
• Poorly differentiated tumor: composed of cells barely resemble the normal cells
of origin. I.e. some resemblance occur focally in tumor parts.
• Moderately differentiated tumor: occupy a morphological position between
well differentiated and poorly differentiated.
• Undifferentiated (anaplastic) tumor: complete lack of differentiation, the tumor
cells have primitive appearance not be assigned to any of normal mature cells.

having features of malignancy, disordered growth encountered in squamous epith of skin,
cervix and bronchial mucosa. Dysplasia have changes include pleomorphism,
hyperchromatic, large nuclei, and abundant mitotic figures. Dysplasia graded into mild,
moderate and severe.
When Dysplasia involve all thickness of epithelia is considered pre invasive neoplasm
referred as carcinoma in situ. Once tumor cells move beyond the normal confines through
breaching the limiting basement membrane the tumor considered invasive carcinoma.
Dysplastic changes are found in foci adjacent invasive carcinoma, in long time smoking
dysplasia of epith. Of bronchi precedes appearance of the cancer. Mild to moderate
dysplastic changes that do not involve entire thickness of epithelia may be reversible with
the removal of inciting cause the epithelia revert to normal i.e. dysplasia does not progress
to cancer. Severe dysplasia more serious is associated with invasive carcinoma.
Dysplasia:

Determined by three main factors
1. Length of cell cycle
2. Size of replicative pool=mean part of tumor made up of dividing cells
3. The rate of which cell leave the growing tumor.
Tumor growth fraction a size of replicative pool to total size of tumor. So large growth
fraction of tumor indicate tumor growth rapidly than small growth fraction.
As tumor grow cells leave the tumor pool by:
1. Shedding.
2. Necrosis.
3. Apoptosis.
4. Differentiation.
5. Reversion to Go.
2. Growth rates of tumor cells:

Leukemia, lymphoma and small cell undifferentiated carcinoma have high
growth fraction whereas colon and breast cancer have low growth
fraction. Also the growth fraction has effect on susceptibility of cancer to
chemotherapy. Correlate inversely with their level of differentiation i.e.
malignant tumor grow rapidly than benign and poorly differentiated
tumor grow rapidly than well differentiated also some factor affect
growth rate such as hormonal stimulation, blood supply, example during
pregnancy uterine leiomyoma increased in size but at menopause the
tumor atrophy or replaced by collagen indicate effect of steroid hormones
on tumors.
Some tumor grow slowly for years but suddenly increase in size of tumor
and cause death this occur due to sub clone of aggressive transformed
cells this termed dedifferentiation.

3. Local invasion: benign tumors remain confined to the site of origin
without have ability to invade locally or metastasize to distant sites
in contrast malignant tumor are invasive and penetrate and destroy
the underlying tissue i.e. no capsule surrounded so in surgery remove
the margin of normal tissue surrounding the tumor.
4. Metastasis: in the only definite criteria of malignancy (benign tumor
do not metastasize), all malignant tumor metastasize except glioma of
CNS and basal cell carcinoma of skin (both not metastasize). In general
cancer metastasize are more rapidly growing and of large size.

Direct seeding of body cavity (periton) for ovarian tumor, tumor of appendix
fill periton, other cavities involved pleural, and pericardia, subarachnoid.
Lymphatic spread: most common pathway for carcinoma metastases but
sarcoma may use this route. Example breast carcinoma metastasize to axillary
lymph node, lung carcinoma to hilar, trachea bronchial and mediastinal lymph
nodes.
Hematological spread: typical for sarcoma but also seen with carcinoma, veins
have thin wall so easily penetrated by malignant cells, then tumor cell follow
the venous flow and to liver, lung are more frequently by metastases through
portal area drainage flow to liver to vena cava and lung. Carcinoma of
thyroid and prostate metastasize to adjacent paravertebral plexus of vein of
vertebral bone.
Pathway of spread:

Precancerous condition:
Ulcerative colitis
Atrophic gastritis
Viral B,C hepatitis
Cutaneous actinic keratosis
Leukoplakia of oral cavity
Host against cancer-tumor immunology:
Immune system try emerging malignant cells and destroy them this is referred
immune surveillance, during increase frequency of tumor in immunodeficient
state either congenital immunodeficient or acquired immunodeficient like in
Aids increase incidence of tumor such as lymphoma, Kaposi sarcoma.

1- Cytotoxic T cell, these CD8+ protective against viral associated neoplasm (EBV, papilloma virus), also
some cytotoxic T cell have receptor for 1gG; specific type antibody dependent cell cytotoxicity(ADCC)
2- Natural killer cells NK cells lymphocytes destroy tumor cells without sensitization, it is first line of
defense after activation by IL2 and IL15 NK cell lyse tumor cells.
3- Macrophages: exhibit cytotoxicity against tumor cell; it collaborate with NK cells for antitumor
reactivity, interferon gamm (INF-) secreted by sensitized T cells and N killer cells activate macrophages
to kill tumor cells by production reactive oxygen species.
Tumor cells escape or evade the immune response by:
1- Selective over growth of Ag negative tumor cells
2- Loss of expression of MHC molecules (HLA-I), so CD8 T cell still inactive.
3- Lack of costimulation T cell need two signal for sensitization against cancer cells one by MHC-1 class,
Ag molecules and other costimulatory molecule, failure to express the later molecules by tumor cell
prevent sensitization and enhance apoptosis to T cells
4- Immune suppression by tumor growth factor B.
5- Ag masking of tumor cells Ag either masked or hidden from immune system
6- Killing cytotoxic T cell by hepatocellular carcinoma, melanoma cell tumor.
Cellular effector mechanism against the tumor

1.Local progration : when tumor enlarged destroy remaining surrounded
tissue tumor of GIT cause obstruction carcinoma of esophagus, pyloric
region, of pancreas bile duct cause jaundice, sometime peristaltic
movement of intestine with tumor cause intussusceptions.
2.Functional hormonal activity some benign tumor produce hormonal
activity more than the malignant some non endocrine tumors produce
hormone or hormone like substances
3.Bleeding and secondary infection
4.Acute presentation occur when perforation of stomach, intestine, rupture
of tumor itself example ovarian tumor.
5.Cancer cachexia, weakness, anemia, anorexia.
Effect of tumor on the host:

A. Endoerinopathy: cancer cells of non-endocrine origin give hormone abnormal (ectopic
hormones) production such as:
 Cushing syndrome due to which ACTH or ACTH like peptides it is associated with small cell
carcinoma of lung.
 Inappropriate ADH secretion is associated with small cell carcinoma of lung.
 Hypercalcemia with increase secretion of parathyroid hormone it occur in association with
carcinoma of lung, breast, kidney, ovary.
 Hypoglycemia due to increase of insulin like substances in fibrosarcoma and hepatocellular
carcinoma.
 Polycythemia: due to increase secretion of erythropoietin with renal cell carcinoma
hepatocellular carcinoma.
B.Neuromyopathy peripheral neuropathy with myasthenia gravis like syndrome occur in
association with small cell carcinoma of lung.
C.Dermatopathies:
1.Acanthosisnigricans- gray black patches of skin due to secretion of epidermal growth
factor as in lung and uterine carcinoma.
2.Dermatomyositis.
6. Paraneoplastic syndromes: include:

D. Hypertrophic osteoarthopathy, clubbing of finger occur with bronchial
carcinoma.
E. Vascular and hematologic changes
1.Migratory thrombophlebitis with pancreatic and lung carcinoma
2.Disseminated intravascular coagulation with leukemia, prostatic
carcinoma
3.Small vegetation form on valves due to tumor emboli of mucinous
adenocarcinoma
4.Erythrocytosis due to erythropoietin produced by renal cell carcinoma and
hepatocellular carcinoma.
5.Autoimmune hemolytic anemia seen with leukemia and lymphoma.
6.Other effect such as fever, nephrotic syndrome, and amyloidosis occur
with renal cell carcinoma, multiple myeloma.

Grading and staging reflect the level of aggressiveness of various neoplasms
Grading=differentiation
Grade, number of mitosis, absence or presence of necrotic ischemia these
features are interrelated. Cancer grading 1to4 G1 (differentiated) G2
moderately differentiated G3 for poorly differentiated, G4 for
undifferentiated so the grading of cancer is of less clinical value than staging.
Staging:
The staging of tumor based on
1. The size of tumor
2. Spread to regional lymph node
3. Presence or absence of blood born metastasis
Grading and staging:

The UICC referred as TNM system;
T= primary tumor
N= regional lymph node
M= metastasis
With increase in size the primary cancer described T1 to T4 some T refer depth of invasion not
the size as in GIT carcinoma TIS indicate carcinoma in situ.
No- no nodal involvement whereas N1to N3 involvement of increase number of lymph
nodes.
Mo= No distant metastasis where as M1 or M2 presence of blood born metastasis
Example breast carcinoma 3cm in maximal dimension with axillary lymph node metastasis
node would be T2N1.
Staging of neoplasms is great important for predicting prognosis and selection best form of
therapy. Although staging value more than grading clinically but both generally correlated
i.e. High grade present at high stage and low grade present at low stage.
Two major staging system are currently used union international center
cancer and American joint committee (UICC and AJC respectively

Substance released by cancer cell into blood or substances created by
body in response to cancer, they include cell surface Ag, cytoplasmic
proteins, enzymes and hormones it is specific to a particular neoplasms.
It is useful for:
1. Support diagnosis of cancer.
2. To determine response to therapy.
3. To indicate recurrence during follow up period.
Tumor markers

Some of tumor markers can detected immunohistochemically.
Among tumor markers:
Carcinoembryonic Ag (CEA). Complex glycoprotein present indicator for different neoplasm as colorectal,
pancreatic, breast carcinoma.
1.-fetoprotein (AFP):
Indicator for hepatocellular carcinoma, germ cell tumor of testis or ovary.
2. Prostatic specific Ag (PSA):
Indicator for prostatic carcinoma but other disorders such as hyperplasia of prostate, prostatitis raise PSA
also
3. Ca-125 glycoprotein expressed during fetal development indicator for ovarian cancer, pancreatic. In
certain cases high level of ca-125 in pregnancy, endometriosis and liver failure.
4. Ca-15-3: it is important in crease carcinoma as an indicator, also for lung cancer ovary cancer and liver
carcinoma ca 15-3 with cea important for lung cancer identification, where asca 15-3 with ca-125 important
for breast cancer.
5. HCG- human chorionic gonadotropin important for testicular tumor.
6. Immunoglobulin important in multiple myelom
7. Free DNA markers:
TP 53, APC, RAS mutant in colon cancer in (stool, serum)
TP 53, RAS mutant in lung cancer in (sputum, serum)
TP 53 mutant inurin. Bladder cancer.

Chemical carcinogen:
A.Direct chemical carcinogen: these require no metabolic conversion to become carcinogenic, such
as alkylating agents this chemotherapeutic drugs for leukemia, lymphoma although it is used as
therapeutic for some disorders (rheumatic arthritis) but is use of caution because it is carcinogenic.
B. Indirect Chemical carcinogen: require metabolic conversion to become carcinogen.
1.Polycyclic hydrocabone example benzopyrene present in tobacco in cigarette smoking, also
produced from animal fat during broiling meats in which the active molecules epoxide combine with
DNA or RNA of the cells.
2. Aromatic amines and azo dyes: B-nephthaline with bladder cancer in workers of aniline dye
and rubber to damage DNA require enzyme cytochrome p_450 dependent monooxygenase.
3. Aflatoxin B1 produced by aspergillus that grow in stored grains and nuts and this toxin
associated with hepatocellular carcinoma.
4. Vinyl choride, arsenic, nickel, chromium and insecticides all potential carcinogen.
5. Nitrites as in food preservative cause nitrosylation of amines group contained in food. The
nitrosoamine is formed and to be carcinogenic.
Carcinogenesis:

All are mutagenic contain the reactive group combine with DNA, RNA.
Oncogene and tumor suppressor such as RAS and p 53 are important target
for chemical carcinogens. Some chemical carcinogens (aflatoxin) cause
mutation in p53 gene that establish that aflatoxin is carcinogen.
Some chemical carcinogen activity augmented by subsequent
administration of promoters such as hormone, phenol, drugs. Promoters are
not mutagenic but induce cell proliferation i.e use initiators may cause
mutation activation of oncogene subsequent application of promoters lead
clonal expansion of initiated mutated cells so cancer develop.
Mechanism of action of chemical carcinogen:

Radiation source of (UV-ray of sunlight, X- ray, nuclear fission radionuclides)
are carcinogen. Survivors of automic bombs dropped on Heroshima and
Nagasaki have leukemia as well as thyroid, breast, cancer, accident at
chernobyl associated with high cancer in surrounding area in (USSR),
therapeutic irradiation of head and neck give incidence of papillary thyroid
carcinoma, the irradiation cause mutagenic effect, chromosome breakage,
translocation, point mutation and DNA damage.
UV light of sun cause melanoma, squamous cell carcinoma, basal cell
carcinoma.
UV light damage DNA by forming pyrimidine dimmers, this DNA damage
repair by nucleotide excision pathway. Patient with xerodermapigmentosum
have defect in nucleotide excision pathway. For this reason skin cancer
increased.
• Radiation carcinogenesis

Oncogenic RNA viruses:
Human T cell leukemia virus_1 (HTLV_1) is a retrovirus associated with
human T cell leukemia, lymphoma. Similar to human immune deficiency
virus (HIV) it has receptor on CD4 and induce neoplastic transformation of
human infection, transmission of infected T cells required sexual inter
course, blood products and breast feeding. (HTL-V-1) does not contain
viral oncogene, but encode viral protein Tax, after a latent period of
infection develop lymphoma, leukemia in adult.
• Microbial carcinogenesis:

It is associated with human cancer;
1.Papilloma (wart) caused by (HPV 1,2,4,7)
2.Squamous cell carcinoma of cervix and anogenital
region caused by (HPV 16,18)
3.Oropharyngeal carcinoma with HPV
4.Genital wart with (HPV 6, 1) infection with HPV
associated with RAS gene mutation lead to cancer.
Oncogenic DNA viruses:
Human Papilloma virus

The implicated in the following cancer:
1.Burkitt lymphoma_ B cell tumor.
2.B_ cell lymphoma in Aids, B_ cell tumor.
3.Hodgkin’s lymphoma B_ cell tumor.
4.Nasopharyngeal carcinoma.
EBV use complement receptor, CD21 to attach to B cells, then B cells proliferation. One of EBV encoded
gene LMP_1 as oncogene promote B cell proliferation and prevent apoptosis by activating BCL2.
Another EBV encoded gene EBNA-2 gene including cyclin D.
In immunologically normal individual EBV drive B cell proliferation is controlled a self-limited
infectious monocleosis. But evation immune response_ a key for EBV oncogenesis. In region when
malaria is present and depress immune response i.e. in endemic area of burkitt lymphoma allowing B
cell proliferation and burkitt lymphoma although LMP-1 oncogene recognized by immune cells, other
mutation such as t (8:14) cause lymphoma by translocation, also this tumor activate MYC oncogene as
a substitution for LMP-1 signaling allowing tumor cells to evade immune response and regulate LMP-1.
Epstein_ Barr virus (EBV)

Most of hepatocellular carcinoma due to HBV or HCV. But HBV and HCV
genomes do not encode any viral encoprotein. The dominant effect seem
to be immunologically mediated chronic inflammation with hepatocytes
death lead to Regeneration.
Exposure to genotoxic agents cause genomic damage.
Activation of NF_KB pathway in hepatocytes caused by mediator derived
from activated immune cells these NF_KB in hepatocytes block apoptosis
and enhance liver cellular proliferation. Both HBV and HCV contain
proteins (HBX) within their genomes directly promote development of
cancer.
Hepatitis B-cell viruses:

Helicobacter pylori:
First bacteria associated with gastric carcinoma and gastric lymphoma. There is initial
development of chronic gastritis, gastric atrophy and intestinal metaplasia, dysplasia and
gastric epith carcinoma. H.pylori genome contain gene implicated in oncogenesis like HBV,
HCV. H.pylori contain cytotoxin associated A gene (cag_A) cause gastric epithelial
proliferation.
H.pylori, also associated with gastric lymphoma during activation of T cells which enhance
B cell proliferation due to mutation growth regulatory gene so eradication of H.pylori cure
the lymphoma by remove T cells activation.
Schistosoma (Bilharzia) :
associated with bladder carcinoma due chronic inflammatory response by parasite, it’s
excreta, parasitic components ova, cause inflammatory damage in tissue of bladder epith,
the mutation and cancer development either transitional or squamous cell carcinoma.

Lecture 13 neoplasia

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Lecture 13 neoplasia

Similar to Lecture 13 neoplasia (20)

More from Green-book

More from Green-book (20)

Recently uploaded

Recently uploaded (20)

Lecture 13 neoplasia