Download lec#17

Neoplasia
lecture3
Dr Heyam Awad
FRCPath
2016
Topics to be covered
• Dysplasia and carcinoma in situ
• Cancer stem cells
• Epidemiology of neoplasia
Dysplasia and carcinoma in situ
• Dysplasia = from Greek word
Bad or
difficult
Formation
or division
dysplasia
• Disordered but non-neoplastic proliferation.
• Loss of uniformity of individual cells and in their architectural
orientation
• Expansion of immature cells
• Seen mainly in epithelial lesions
Disorganized proliferation= polarity lost =
arrangement disturbed
Dysplasia/ microscopically
• Loss of orientation
• Pleomorphis
• Large cells
• Hyperchromatic nuclei
• More mitoses than normal
• Mitosis in an abnormal location ( normal location is at the basal layers
of epithelium… abnormal: mitosis seen in more superficial layers)
Dysplasia. Note the intact basement
membrane (no invasion)
Dysplasia in glandular epithelium
Dysplasia divided to mild, moderate and severe
according to extent of involvement and degree of
nuclear abnormality
• Although non neoplastic, dysplastic cells can accumulate mutations
and transform to malignant lesions.. But not always and not
commonly.
Carcinoma in situ
• Means= severe dysplasia involving the whole thickness of the
epithelium
Carcinoma in situ
• Carcinoma in situ is considered a pre-invasive stage of cancer
Dysplasia, behavior
• Non- neoplastic
• Dysplastic foci usually seen adjacent to areas of malignant
transformation and can predict malignant transformation.
• They are precursors of malignancy.
• However, mild and moderate dysplasia Can regress if initial insult
removed
• The presence of dysplasia preceding cancer is utilized clinically for
screening purposes
• Cervical cancer in the majority of cases originates from dysplasia…
screening for dysplasia by cervical smear (pap smear) helps to detect
these precancerous lesions and treatment to prevent cancer can be
offered.
• Colon cancer can occur in patients with inflammatory bowel disease..
Again dysplasia preceded invasive cancer… surveillance helps
detecting these precancerous lesions.
Cancer stem cells
• Cancer cells keep growing and proliferating . They are immortal and
with limitless proliferative capacity.
• So: they must contain cells with stem-like properties.
Stem cells are immortal
Cancer stem cell hypothesis
• It is thought that only a special subset of cells within a tumor has the
capacity for self renewal (act as stem cells)
• This means that a cancer mass is composed of two types of cells: the
“differentiated “ cells that have limited self renewal capacity and stem
cells that are immortal and can divide asymmetrically and keep the
tumor mass immortal.
• SO :TUMOR MASS IS IMMORTAL BUT NOT EVERY TUMOR CELL IS
IMMORTAL.
Cancer stem cells
• Cancer stem cells are essential for tumor persistence… so elimination
of these stem cells is important to cure patients
• If cancer stem cells not eliminated… tumor is immortal… no cure
Problem with cancer stem cells
• They resist therapy.
• Why? 1. Because of their low rate of cell division . Note: the available
chemotherapy targets highly dividing cells
•
2. because they produce factors that make them resistant to
chemo.. Like MDR 1= multiple drug resistance 1
MDR1
• MDR1 gene encodes a glycoprotein that makes cells resist drugs by
several mechanisms, including efflux of the drug and decreased
uptake of the drug by the cells…
• So as if MDR1 is swiping away the drug from the cancer cells.
• MDR1 is expressed in cancer stem cells making them resistant to
chemotherapy.
Why we are failing to cure cancer
• Probably because of the stem cells…
• Chemotherapy kills the proliferating mass of tumor leaving the cancer
stem cells that can proliferate and cause recurrence and metastasis
Origin of cancer stem cells
• Can arise from normal tissue stem cells or from differentiated cells
transforming to stem cells with ability of self renewal.
• Note: do not mix normal tissue stem cells with cancer stem
cells…they mean different things!!!!
• There is evidence that cancer stem cells can originate from tissue
stem cells or from differentiated cells
• Example: chronic myelogeous leukemia (CML) originates from
hematopoietic stem cells, whereas acute myeloid leukemia are
derived from differentiated myeloid precursors
• Cancer epidemiology
USA 2010
Cancer incidence/USA 2013
Notes
• In USA .. The leading cause of cancer death in both sexes is lung
cancer
• In USA the most common cancer in women is breast cancer and in
men is prostate cancer
NOTES
• In men.. Cancer death rates increased in the last decades.. But now
started to decline
• In women: overall death rate decreased slightly.. Due to decline in
cervical cancer, colon and stomach
• Lung cancer in women is increased
Jordan
• National cancer registry
• According to 2013 stats the most common cancer among Jordanian
males is colorectal cancer followed by lung cancer
• According to 2013 stats, the most common cancer among Jordanian
females is breast followed by colorectal cancer.
Cancer in Jordan
Five year survival
• Five-year absolute survival rates describe the percentage of patients
alive five years after the disease is diagnosed.
Geographic and environmental factors
• Environmental factors are the predominant cause of cancer
• Geographic variations in cancer incidence are due to different life
styles and to environmental factors
• When people move from one geographic area to another, subsequent
generations acquire the same risk of cancer development as original
population.
• Table 5-2 ,page 171 about occupational cancer.. Have a look please.
Cancer and age
• In general , frequency of cancer increases with age.
• Why: accumulation of mutation takes time! And immunity declines
with aging.
• However, cancer occurs in children. It is responsible for 10% of all
deaths in children younger than 15 years.
• Most common childhood tumors: leukemias, lymphomas, CNS tumors
and soft tissue and bone sarcomas.
heredity
• Some cancers have inherited predisposition., but still the majority of
these need environmental factors to develop cancer
• Only 5-10% of cancers are inherited
• This inheritance is usually indirect and its effect is subtle
Autosomal dominant cancer syndromes
• Single gene mutations
• Typically linked to inheritance of a cancer suppressor gene.
• E:g Retinoblastoma.. More will be discussed later
Autosomal recessive syndromes
• Usually the problem in DNA repair genes
• Example: xeroderma pigmentosum… more later!
Familial cancers of uncertain inheritance
• All common cancer types can occur in familial forms with unclear
pattern of inheritance
• Familial cancers are characterized by: early age, arise in 2 or more
close relatives of the index case, can be multiple and bilateral
• Familial cancers are not associated with a specific phenotype. Colon
cancer can be sporadic, autosomal dominant inheritance ( associated
with polyps) or familial with no previous polyps
• Predisposition to cancer in these familial cases is probably dominant
but incomplete penetrance or multifactorial inheritance cannot be
excluded
• Genotype may affect the likelihood of developing environmentally
induced cancer
• Polymorphism in drug metabolizing enzymes affect lung cancer
development among smokers
• Genome wide association studies GWAS in lung cancer found variants
in a nicotine acid receptor being associated with lung cancer…. These
variants were associated with number of cigarettes smoked, so they
indirectly increase lung cancer risk by increasing nicotine addiction
Acquired pre-neoplastic syndromes
• = preneoplastic or precancerous lesions
• These increase the likelihood of cancer but the majority do not
progress to cancer
• They are important for screening
• Also if removed.. Can help decreasing cancer incidence
• They contain genetic mutations found in the cancer arises from them
Examples of preneoplastic lesions
• Squamous metaplasia and dysplasia of bronchial mucosa in smokers
• Endometrial hyperplasia and dysplasia
• Leukoplakia
• Colonic adenomas
Are benign tumors precancerous
• In general no
• Some have more risk than other, colonic adenomas have increased
risk of malignant transformation and risk depending on degree of
dysplasia ( high grade dysplasia carries more risk of malignant
transformation than low grade dysplasia)