Pathology - Neoplasia 1-2-3 Flashcards
definition of a Lesion
Modification of tissue or organ due to an injury or disease process, often resulting in impairment of normal function
Is a tumor a neoplasm?
Yes
Is a mass, lump, a neoplasm?
No, its an aggregation of quantity of solid tissue
Definition of a Nodule
small rounded mass
Definition of a polyp
Any lesion or mass of tissue protuding from normal surface level, usually in lumen of a hallow organ
definition of a papilla (microscopic term)
finger-like projection consisting of surface epithelium over core of connective tissue (villus style)
Definition of a cancer
Any malignant neoplasm
definition of oncology
study of neoplasms, malignancies (or a medical specialty)
Examples of non-neoplastic growths
- Malformations
- Repair, if excessive healing
- hypertrophy
- hyperplasia
- metaplasia
Definition of a choristoma
a malformation, synonym of ectobic tissue
Definition of hyperplasia
increase in cell numer in response to a stimulus, can be physiological or pathological
When/how does hyperplasia occurs
in occurs in cells with the capacity to divide, mediated by hormones or growth factors
Examples of hyperplasia
- Hyperplasia of epithelial cells in the female breast during pregnancy
- Hyperplasia of hepatocytes to regenerate liver parenchyma after partial resection
- Prostatic hyperplasia in older males from androgens
- Endometrial hyperplasia in postmenopausal women receiving estrogens
Why is hyperplasia not neoplasia
- Cells are genotypically and phenotypically normal
- The organ involved is usually (but not always) diffusely enlarged, i.e., does not form a localized mass
- The hyperplasia generally ends when the stimulus ends, i.e., is generally reversible
In what case hyperplasia may be a precursor of neoplasia, example
endometrial hyperplasia may become endometrial carcinoma
Definition of metaplasia
replacement of one type of normall adult cell/tissue by another normal tissue.
It happens in epithelial tissues often mediated by inflammation
Examples of metaplasia
- squamous metaplasia in bronchial epithelium due to smoking
definition of a neoplasm
A new (neo) growth or formation (plasma). A pathological disturbance of growth characterized by an excessive and unceasing proliferation of cells. Independant of normal regulatory control.
From what arise neoplasms and cancers
from DNA-related alterations passed to progeny cells (i.e. heritable), with added epigenetic changes
How are neoplasms classified?
- organ or precise site
- histological type
- additional subtyping includes immunohistochemical, molecular, and genetic features
how do we call a malignant neoplasm on a squamous epithelium?
squamous cell carcinoma
malignant neoplasm on melanocytes
melanoma
malignant neoplasm in germ cells
dysgerminoma
benign melanocytes neoplasm
nevus
benign germ cells neoplasm
benign cystic teratoma
benign epithelial neoplasm
squamous papilloma
malignant fibroblasts neoplasm
fibrosarcoma
general name for malignant mesenchymal (solid tissue) neoplasm
Sarcoma
malignant adipocytes neoplasm
liposarcoma
malignant lymphoid cell neoplasm
lymphoma
malignant hematopoietic cells neoplasm
leukemia
malignant smooth muscle cells neoplasm
leiomyosarcoma
neoplasms are composed of:
- the abnormal neoplastic cells with variable degrees of differentiation
- a non-neoplastic stroma of connective tissue, inflammatory cells and blood vessels
name a liquid neoplasm
leukemia
macroscopy of a neoplasm
- Mass, swelling, diffuse enlargement.
- Circumscribed, to invasive and metastasizing (usually irregular shape)
- Often pale or white
Secondary changes: ulceration, bleeding, necrosis
- Invade, damage and destroy surrounding tissues, cause fractures…
malignant glandular neoplasm
adenocarcinoma
microscopic morphology of a neoplasm
abnormal cytology i.e. of individual cells or cellular atypia or pleomorphism: abnormal variation in cell size, shape, color, compared with normal ones in same tissue
possible change in the nucleus of a neoplasm
hyperchromasia, increased size and nucleo/cytoplasmic ratio, increased and abnormal mitoses (e.g., tripolar), more prominent nuclei
possible change in the cytoplasm of a neoplasm
tells us differentiation of cell type - loss of normal features, increased basophilia (more RNA)
how different is the histology of a neoplasm ?
Abnormal histoly because of dysorganization of the cells
- loss of architecture, polarization
-abnormal pattern, arrangement of the cells - invasion into surrounding tissues
what functional characteristics of the tissue of origin does a neoplasm retain?
- cytoplasmic substances : keratin, mucin, bile
- endocrine: production of hormones
- innapropriate (ectopic) hormone secretion by non-endocrine neoplasms (e.g. with lung carcinoma)
Benign vs Malignant in terms of systemic effects
benign does not have a systemic effetcs, and malignant yes. potential for metastases
Is a malignant neoplasm encapsulated?
No, but benign yes.
benign glandular neoplasm
adenoma
local symptoms/signs of a benign neoplasm
obstruction, pressure, pain
complications of a benign neoplasm
bleeding, necrosis, ulceration, perforation. potential for malgnant transformation in some
2 main characteristics of malignant neoplasms
- invasion : the ability to infiltrate and destroy surrounding tissues
- metastatic potential : the ability to develop secondary foci (or metastases) of tumor growth at a distance from the primary tumor
How to make a diagnosis of malignancy?
- clinical assessment
- Macroscopic findings: imaging, pathologic assessment, and especially
- microscopic evaluation (biopsy): marked cellular atypia, loss of architecture, invasion of surrounding tissues
what is the suffix for neoplasm
“oma”
name some caveats concerning benign and malignant neoplasm
- Tumors of borderline or
intermediate malignancy - Continuum between benign and malignant neoplasms
- Special case of CNS neoplasms (can kill even if benign by increased intracranial pressure)
incidence of sarcomas vs carcinomas
carcinomas: more common
Sarcomas: less common
etiology of carcinomas vs sarcomas
carcninomas: Generally known: environmental, viral
Sarcomas: viral, unknown
Metastatic spread carcinomas vs sarcomas
carcinoma: lymphatics, then hematogenous
sarcomas: hematogenous
Macroscopy difference carcinoma vs sarcomas
carcinoma: variably hard
Sarcoma: fleshy, firm
Histological difference carcinoma vs sarcoma
carcinoma: from islands of cells separated by stroma
Sarcoma: sheets of spindle cells admixed with stroma between cells
Histochemestry difference carcinoma vs sarcoma
carcinoma: epithelial e.g. mucin
Sarcoma: mesenchymal, e.g. fat
immuno-histochemistry carcinoma vs sarcomas
carcinoma: Keratins
Sarcoma: vimentin, muscle actin (?)
5 phases of biology of malignant neoplasm
- Transformation
- Growth - proliferation of transformed cells
- Diversification/clonal expansion of neoplastic cells
- local invasion
- Distant metastases
What is transformation in the biology of malignancy?
process whereby normal cells become neoplastic or cancerous (carcinogenesis = oncogenesis=tumorigenesis)
When/how does tranformation occurs in the biology of malignancy
occurs by the accumulation of genetic alterations and epigenetic changes so the cells can escape permanently from normal growth regulatory mechanism
on what depends on how fast neoplastic cells double?
on the proliferation rate
main cause of carcinoma of the cervix
HPV
sequence of development of carcinoma of the cervix
normal -> dysplasia (or CIN I-II) -> carcinoma in-situ (or CIN III) -> invasive squamous cell carcinoma
CIN: Cervical intraepithelial neoplasia
What are CIS
Carcinoma in situ : cells that are genotypically and phenotypically cancerous cells that remain localized to their tissue of origin, usually an epithelium
why do we say that CIN are pre-malignant or pre-cancerous?
- No invasion (yet) through the basement membrane (BM)
- Because no lymphatics/blood vessels above BM, cannot metastasize
But it is NOT a benign neoplasm
5 types of CIN and their associated intra epithelial grade
Condyloma = CIN I = LSIL
Mild dysplasie CIn I - LSIL
Moderate dysplasia = CIN II - HSIL
Severe dysplasia = CIN III - HSIL
CIS = CIN III = HSIL
Other squamous/squamoid epithelia
- Vaginal intraepithelial neoplasia, VIN
- Skin, oral cavity, bronchus, laryns
- urothelium (lining renal pelvis, ureters, bladder)
What means “grading”
determination of degree of differentiation of a malignant neoplasm
What is “differentiation”?
degree of resemblance to the normal/parent tissue
What is de-differentiation?
loss of the ressemblance with normal tissue
Anaplasia?
complete de-differentiation i.e. no resemblance to normal/parent tissue
What means “low grade”
grade 1 = well differentiated = closest resemblance to parent tissue = better prognosis
Squamous cell carcinoma grading
what is meant by ‘‘levels of heterogeneity”
different histological types in one site - same histological type in different sites and subpopulations of cells in one neoplasm
4 stages of the mechanism of invasion of CIS into underlying stroma to invasive carcinoma
routes of metastases (3)
- lymphatic vessels to lymph nodes
- blood vessels (hematogenous)
- Transcoelomic (seeding via body cavities)
Difference between staging and grading of malignant neoplasms?
- staging is the determination of the size and extent of spread of a malignant neoplasm - has prognostic and therapeutic implication
What is the TNM system?
-Primary tumor size, characteristics (T)
- presence or absence of lymph node metastases (N)
- Presence or absence of distant metastases (M)
primary tool used for staging
- resected surgical specimen (pathology) but also imaging, labs, etc.
Tools to diagnose and stage neoplasms (6)
- clinical (history, physical ex)
- radiological/imaging
- clinical laboratory (biochem, hemato)
- tumor markers
- Pathologic / tissue diagnosis (sytopatho, biopsy, histopatho)
- Ancillary pathologic diagnosis techniques
Examples of ancillary pathologic diagnosis techniques
- immunohistochemistry :
Diagnosis of histological type of malignancy
Typing of lymphoma/leukemia (B, T-cell types…)
Prognostic and predictive markers, e.g., estrogen, progesterone receptors - Flow cytometry
Mostly for immunophenotyping of lymphomas/leukemias - Molecular/cytogenetic analyses
Clonality of B or T-cell lymphomas
Chromosomal alterations (mutations, deletions…)
Prognostic and predictive indicator
4 possible goals of therapy of neoplasms
- curative
- debulking
- adjuvant, neo-adjuvant
- Palliative
possible therapies of neoplasms
- surgery
- radiation therapy
- chemotherapy
- immunotherapy
- targeted molecular therapies
difference between prognostic and predictive factors
prognostic factors: determine outcome (chances of survival, 5-year survival rate)
Predictive factors: determine responsiveness of a neoplasm to a drug
(like the presence of certain proteins determines potential response to a drug)
heritable factors account for higher proportion of some cancers, which one?
40% prostate
35% colo-rectum
25% breast
what percentage of cancers are due to environmental, potentially avoidable causes?
80-90%
Exogenous etiologies of cancer
- chemical carcinogens
- physical agents (radiation, uv)
- biological agents (viruses, HPV, bacteria)
Endogenous etiologies of cancer
- Heredity
- gender and hormones
- altered immunity (age, immunosupressant drug, AIDS)
Principle causes of human cancer
25% tobacco
25% diet
20% sexual behaviour, infection
tobacco has a strong association with cancer of:
lung, mouth, pharynx, larynx, esophagus, pancreas, urothelium (kidney, bladder)
what is the relative risk (RR) of a regular smoker vs passive smokers
regular RR 20
passive RR 1.15-1.2
What is a direct-acting carcinogen
a chemical carcinogen that doesn’t need metabolic conversion
What is a indirect-acting carcinogen
require metabolic conversion to mutagenic carcinogens
what is a promotor in chemical carcinogenesis
not mutagenic, increase proliferation, including of cells with DNA mutations, favoring tumor growth (e.g., phorbol esters, hormones, alcohol…)
how are classified carcinogens ?
in 3 groups
1. carcinogenic to human
2. probably/possibly carcinogenic
3. not classifiable as carcinogenic
examples of medicinal drugs that are carcinogens
- anti-cancer drugs
- hormones like estrogens
- immunosuppressants like cyclosporine
examples of physical carcinogens
- radiation : ionizinf x and beta rays, alpha beta particles (nuclear)
- UV
- elctromafnitic field (possibly carcinogenic) leukemia in children
mechanism of UV as a carcinogen
formation of pyrimidine dimers, damaging DNA and overwhelming DNA repair mechanisms
Mechanism of radiation as carcinogen
damage to chromosomes, translocations, mutations…
link between chronic infections and cancer (may be)
Indirect via inflammation, cell damage and regeneration with ensuing proliferation (cf. promoters…) that allow the expression of new mutations
Is HIV a direct or indirect carcinogen?
indirect - acts by its immunosuppressive effects
Examples of direct carcinogen caused by an infection
HPV, EBV, HBV
are bacteria/parasite a direct or indirect carcinogen?
indirectly, by cell damage, inflammation, cytokines
difference between initiators and promoters
initiators (either direct or indirect acting, damaging DNA),
and promoters (increasing proliferation)
characteristics of normal stem cells
- Undifferentiated, capable of self-renewal
- Asymmetrical replication
One daughter cell differentiates → mature cell - Other daughter cell remainsan undifferentiated stem cell
two main types of stem cells
- embyonic, unlimited potential
- adult stem cells
possible use of stemm cell in regenerative medecine
- Hematopoietic stem cells can be purified based on cell surface markers and used in stem cell transplantation to treat leukemias, lymphomas and some solid tumors
- Embryonic stem cells used for in vitro fertilization
characteristics of cancer stem cells
- Capable of self-renewal, as normal stem cells
- Potentially arise from transformation of
Normal stem cells or Differentiated tissue cells - Must be eliminated to cure a cancer, but are resistant to therapy
Why are cancer stem cells resistant to therapy
- Low rate of replication, so less amenable to chemotherapeutic drugs that target rapidly dividing cells
- Express factors such as multiple drug resistance 1 (MDR-1) that counter the effects of drugs
to what can lead a molecular alterations of a cell ?
can be responsible for :
- transformation of a normal to a neoplastic cell,
- for its proliferation,
- continued growth,
- diversification and evasion of normal controlling mechanisms (e.g., apoptosis)
how do you call multiple molecular alterations of a cell
multistep carcinogenesis
most molecular alterations involve ___
DNA
Driver vs Passenger (in mutation)
Driver: alter function of cancer genes, with direct control, clustered
Passenger: random, do not affect behavior, but may provide a selective advantage e.g., after therapy…
hallmarks of cancer (resume card, high yield)
- self-sufficiency in growth : unrestricted proliferation without external stimuli
- insensitivity to growth inhibitory stimuli
- altered cell metabolism
- evasion of apoptosis
- unlimited replicative potential
- sustained angiogenesis (required in most0
- invasion and metastasis
- evasion of immune surevillance
- Defects in DNA repair : genomic instability, facilitating mutations in protooncogenes and tumor supressor genes
Primary effects of gene alterations in cancer:
- unrestricted proliferation without external stimuli, medicated by oncogenes, conferring self/sufficiency in growth signals
- insentivity to growth inhibitory stimuli : tumor suppressor genes, also resulting in unrestricted proliferation
- Defects in DNA repair genes: genomic instability, thereby facilitating mutations in proto-oncogenes and tumor suppressor genes
Secondary gene alterations in cancer
- Altered cellular metabolism
- Evasion of cell death by apoptosis mediated by alterations intumor supressor genes or anti-apoptotic genes
- Unlimited replicative potential: activation of telomerases (e.g., by mutated tumor suppressor genes )
- Sustained angiogenesis required in most
- Ability to invade and metastasize
why do we need to know all the molecular stuff in oncology?
Because treatment will be designed according to what characteristic of cell alteration we face
e.g. cell sustaining proliferative signaling -> EGFR inhibitors
what are oncogenes
- are derevied from proto-oncogenes (normal genes involved in proliferation)
- promote autonomous growth of cancer cells
example of an oncogenes that present as a growth factor
platelet-derived growth factor (PDGF) secreted by glioblastomas and is a receptor on cell surface → autocrine loop (self stimulation)
- cancer cells can make own growth factors to stimulate their own surface receptors, i.e., an autocrine loop (≠ normal paracrine loop)
What can be oncogenes (5) ?
- growth factor oncogene
- growth factor receptors
- signal transducing proteins
- nuclear transcription factors
- cycling and CDKs
common oncogene that act as nuclear transcription factor
MYC, leads to Burkitt lymphoma
What is the cell cycle?
the process a cell goes through to divide and make new cells
How can cyclins and CDKs cause cancer?
mutations make cyclin or CDK overactive. it causes the cell to keep going through the cell cycle without stopping. This means the cancer cells keep dividing and growing uncontrollably.
which gene is the guardian of the genome?
TP53
What does wild P53 protein
- Arrests cell cycle in late G1 via CDK inhibitor p21
- Assists in DNA repair
- Apoptosis if DNA cannot be repaired
- Angiogenesis inhibitor via thrombospondin-1
What does a MUTATED P53?
Genetic, Li-Fraumeni syndrome, SAs, leukemias, breast and adrenal cortical CAs
Somatic, homozygous, in breast, lung, colon CAs
