Neoplasia. Pathophysiology of tumors and cancer. The following pictures and descriptions were found at: www-medlib.med.utah.edu/WebPath/NEOHTML. Cells normally differentiate, grow, mature and divide.
Pathophysiology of tumors and cancer
These are regulated processes, balanced in a healthy system such that cell birth is nearly equal to cell death
1. Signaling by biochemicals released from one cell that interact with other cells
growth factors or cytokines
2. Other external factors , such as contact inhibition
genes and chromosomal factors - telomeres
braking proteins – Rb proteins
A tumor cell’s growth is divisionautonomous – independent of controls
Neoplasm – a type of tumor – group of neoplasic cells
Study of tumors is oncology from Greek for tumor
Benign: grow slowly
low mitotic rate
not invasive; well-defined borders
remain localized; do not metastasize
Any increase in tissue size is not necessarily neoplasia. Here is an example of left ventricular cardiac hypertrophy in which there has been an increase in the size of the myocardial fibers in response to an increased pressure load from hypertension. With hypertrophy, the cells increase in size, but the cells do not increase in number. Except for being larger, the cells are normal in appearance. Alterations in cell growth can be physiologic (normal responses to stimuli) or pathologic. These alterations of cell growth are potentially reversible and include:
Hypertrophy: an increase in cell size. Increase in skeletal muscle fiber size is a physiologic response to exercise, but the cardiac hypertrophy shown above is a pathologic response to abnormally elevated blood pressure.
Hyperplasia: an increase in the number of cells. Postpartum breast lobules undergo hyperplasia for lactation, but endometrial hyperplasia in a postmenopausal woman is abnormal.
The large fronds of endometrium seen in this uterus opened to reveal the endometrial cavity are a result of hyperplasia. This resulted from increased estrogen. With hyperplasia, there is an increase in cell numbers to produce an increase in tissue size. However, the cells are normal in appearance. Sometimes hyperplasias can be "atypical" and the cells not completely normal. Such conditions can be premalignant.
The first step toward neoplasia is cellular transformation. Here, there is metaplasia of normal respiratory laryngeal epithelium on the right to squamous epithelium on the left in response to chronic irritation of smoking. The two forms of cellular transformation that are potentially reversible, but may be steps toward a neoplasm, are:
Metaplasia: the exchange of normal epithelium for another type of epithelium. Metaplasia is reversible when the stimulus for it is taken away.
Dysplasia: a disordered growth and maturation of an epithelium, which is still reversible if the factors driving it are eliminated.
This is the next step toward neoplasia. Here, there is normal cervical squamous epithelium at the left, but dysplastic squamous epithelium at the right. Dysplasia is a disorderly growth of epithelium, but still confined to the epithelium. Dysplasia is still reversible.
Of course, neoplasms can be benign as well as malignant, though it is not always easy to tell how a neoplasm will act. Here is a benign lipoma on the serosal surface of the small intestine. It has the characteristics of a benign neoplasm: it is well circumscribed, slow growing, and resembles the tissue of origin (fat).
At low power magnification, a lipoma of the small intestine is seen to be well demarcated from the mucosa at the lower center-right. This neoplasm is so well-differentiated that, except for its appearance as a localized mass, it is impossible to tell from normal adipose tissue.
Remember that the most common neoplasm is a benign nevus (pigmented mole) of the skin, and most people have several, as seen here over the skin of the chest. As a general rule, benign neoplasms do not give rise to malignant neoplasms.
Malignant – cancer – from Latin for crab (pigmented mole) of the skin, and most people have several, as seen here over the skin of the chest. As a general rule, benign neoplasms do not give rise to malignant neoplasms.
autonomy and anaplasia
Grow rapidly ; high mitotic index, poorly differentiated; do not have a capsule; invade surrounding structures; can metastasize from the primary to a secondary site (metastasis).
Some epithelia are accessible enough, such as the cervix, that cancer screening can be done by sampling some of the cells and sending them to the laboratory. Here is a cervical Pap smear in which dysplastic cells are present that have much larger and darker nuclei than the normal squamous cells with small nuclei and large amounts of cytoplasm.
When the entire epithelium is dysplastic and no normal epithelial cells are left, then the process is beyond dysplasia and is now neoplasia. If the basement membrane is still intact, as shown here, then the process is called "carcinoma in situ" because the carcinoma is still confined to the epithelium.
This is a neoplasm. Neoplasia is uncontrolled new growth. Note the mass of abnormal tissue on the surface of the cervix. The term "tumor" is often used synonymously with neoplasm, but a "tumor" can mean any mass effect, whether it is inflammatory, hemodynamic, or neoplastic in origin. Once a neoplasm has started, it is not reversible.
This is the microscopic appearance of neoplasia, or uncontrolled new growth. Here, the neoplasm is infiltrating into the underlying cervical stroma.
This gastric adenocarcinoma is positive for cytokeratin by immunoperoxidase. This is a typical staining reaction for carcinomas and helps to distinguish carcinomas from sarcomas and lymphomas. Immunoperoxidase staining is helpful to determine the cell type of a neoplasm when the degree of differentiation, or morphology alone, does not allow an exact classification.
Here is a small hepatic adenoma, an uncommon benign neoplasm, but one that shows how well-demarcated an benign neoplasm is. It also illustrates how function of the normal tissue is maintained, because the adenoma is making bile pigment, giving it a green color.
In contrast, this hepatocellular carcinoma is not as well circumscribed (note the infiltration of tumor off to the lower right) nor as uniform in consistency. It is also arising in a cirrhotic (nodular) liver.
Malignant neoplasms are also characterized by the tendency to invade surrounding tissues. Here, a lung cancer is seen to be spreading along the bronchi into the surrounding lung.
This is an example of metastases to the liver. Note that the tan-white masses are multiple and irregularly sized. A primary neoplasm is more likely to be a solitary mass. Metastasis is the best indication that a neoplasm is malignant.
Here are three abnormal mitoses. Mitoses by themselves are not indicators of malignancy. However, abnormal mitoses are highly indicative of malignancy. The marked pleomorphism and hyperchromatism of surrounding cells also favors malignancy.
Nomenclature – In General : not indicators of malignancy. However, abnormal mitoses are highly indicative of malignancy. The marked pleomorphism and hyperchromatism of surrounding cells also favors malignancy.
Tissue of origin + “-oma” indicates a benign tumor
Malignant tumors – use embryonic origin of tissue not indicators of malignancy. However, abnormal mitoses are highly indicative of malignancy. The marked pleomorphism and hyperchromatism of surrounding cells also favors malignancy.
Carcinomas come from ectoderm and
Endoderm - epithelial and glandular tissue
Sarcomas arise from mesoderm
connective tissue, muscle, nerve and endothelial tissues
Autonomy – proliferate in the absence of external growth signals
increase in growth factor receptors
post-receptor signal cascade inside the cell stuck in the “on” position
Overcome antigrowth signals: cancer:
contact with basement membrane, other cells
inactivation of tumor suppressor genes
or activation of the cyclindependent kinases that drive the cell
Prevention of apoptosis
in non-mutant state called
stimulate cell growth and replication
when turned “on” by mutation cause uncontrolled growth
Tumor suppressor genes cancer:
negatively regulate proliferation - antioncogenes
want these to remain intact
takes two “hits” to remove both genes
Gene silencing cancer:
regions of genes normally turned off
can spread without mutation and turn off tumor suppressor genes
drugs that demethylate DNA may turn genes back on
Loss of caretaker genes cancer:
angiogenic factors or vascular endothelial growth factor (VEGF)
possible source of new therapies
decreased cell-to-cell adhesion
secretions of proteases
ability to grow in new locations
to be passed down, mutations must occur in germ cells
inherited mutations almost always in tumor suppressor genes (table 9-6)
these individuals are targets for cancer screening
Viral causes of cancer: cancer:
viruses assoc. with about 15 % of cancers world wide – us. Cervix or liver
hepatitis B or C in chronic form
Human papilloma virus
spread through sexual contact
HPV integrates into DNA and uses viral oncogenes
Epstein-Barr and Kaposi sarcoma cancer:
both herpes viruses
Human T cell leukemia-lymphoma virus
blood transfusions, needles, sex and breast feeding
infections may be asymptomatic
may have high incidence, but low #’s of cancer
cofactors increase the risk of cancer
Bacterial causes of Cancer cancer:
Helicobacter pylori infects >1/2 world’s population
assoc. with B cell lymphomas of the stomach
treatment with antibiotics can cause regression of lymphoma
Tumors arise in MALT -MALTomas
Gene-Environment Interactions: cancer:
Exposure to environmental agents can cause increased risk of cancer
cancer in lab animals – carcinogens
Comparisons of populations
genetics vs. lifestyle
“Genetics loads the gun; the environment pulls the trigger.” director of Nat’l Institute of Environmental Health & Safety
Diagnosis: trigger.” director of Nat’l Institute of Environmental Health & Safety
screening procedures and blood tests:
substances on plasma membranes
in blood, spinal fluid or urine
hormones, genes antigens or antibodies
Markers can be used: trigger.” director of Nat’l Institute of Environmental Health & Safety
to screen and identify individuals at high risk
to help diagnose the specific type of tumor
to follow the course of the cancer
Stages of cancer spread: trigger.” director of Nat’l Institute of Environmental Health & Safety
Stage 1 – confined to site of origin
Stage 2- cancer is locally invasive
Stage 3 – cancer has spread to regional structures
Stage 4- cancer has spread to distant sites
TNM system: trigger.” director of Nat’l Institute of Environmental Health & Safety
presence of distant metastasis
Staging may influence choice of treatment
A metastasis grows when: trigger.” director of Nat’l Institute of Environmental Health & Safety
vascular network is developed
host defenses are evaded
a compatible environment is available
Branches of peripheral nerve are invaded by nests of malignant cells. This is often why pain associated with cancers is unrelenting.
loss of muscle function
Cachexia – wasting
malignancy in blood forming organs
Leukopenia and thrombocytopenia
tumor invasion of bone marrow
chemotherapy or radiation
kill tumor without damage to surrounding tissues
tumor must be accessible
method of choice
can remove entire tumor
adjuvant chemotherapy or radiation palliation
Nonspecific enhancement of the immune system – interferons or interleukins
protect against recurrence
eliminates cancer cells only
T- cell based or antibody responses
chemo and radiation suppress bone marrow
decrease in red blood cells, white blood cells and platelets
Hair and skin:
skin breakdown and dryness
also due to damage of hypothalamus and/or pituitary
sperm or embryo bank