Neoplasia (Chapter 6)

Neoplasm

A cellular growth that no longer responds to normal genetic controls; cell continues to reproduce, without need for them, deprives other cells of nutrition

Characteristics of each tumor depends on:

neoplasms may consist of atypical or immature cells; type of cell the tumor arises from and unique structure and growth pattern

Tumor

swelling that can be caused by number of conditions; used to define a mass of cells that arises because of overgrowth (“new growth”)

Cancer

Greek word for “crab” from “karkinoma” which is another name for malignant tumor

Neoplasms distinguished by:

Cell characteristics, rate of growth, manner of growth, capacity to invade and metastasize to other parts of the body, potential for causing death

Cell characteristics

the appearance and behavior of cells

Rate of growth

how fast cells multiply and increase in size

Manner of growth

the pattern by which tumor expands and develops

Capacity to invade and metastasize to other parts of the body

the ability of cells to spread into nearby tissues and distant parts

Potential for causing death

likelihood that the disease can become life-threatening

Benign characteristics

well-differentiated that resemble cells of tissue origin, usually progressive and slow and may come to a standstill/regress, grows by expansion without invading surround tissue (encapsulated), does not spread by metastasis

Malignant characteristics

undifferentiated with anaplasia and atypical structure that often bears little resemblance to origin; variable and depends on level of differentiation (more undifferentiated = more rapid rate of growth), grows by invasion sending out processes that infiltrate the surrounding tissues; gains access to blood and lymph channels to metastasize to other areas of the body

Examples of benign tumors

lipoma, leiomyoma, papilloma

Examples of malignant tumors

carcinoma, sarcoma, lymphomas

Lipoma

benign tumor of fat tissue

Leiomyoma

benign tumor of smooth muscle

Papilloma

benign tumor of epithelial tissue

Carcinomas

malignant epithelial tumors (e.g. adenocarcinoma arise in ducts or glands)

Sarcomas

malignant connective tissue tumors

Lymphomas

cancers of lymphatic tissue

Cancer is characterized by

uncontrolled cell proliferation

Clonal proliferation or expansion occurs

Cancer cell progeny can accumulate faster than nonmutant neighbors

due to mutation cell acquires characteristics that allow it to have selective advantage over its neighbors (ex: increased growth rate or decreased apoptosis)

Angiogenesis

mutant cells secrete growth factors & stimulate the development of new capillaries in the tumor

Malignant transformation

is the process during which a normal cell becomes a cancer cell

Multiple mutations are required before cancer can devleop

Mutation is alteration in DNA-sequence affecting expression or function of a gene; gene amplification is repeated duplication of chromosome: 10s or 100s of gene copies made

Chromosome translocation

large changes in chromosome structure; piece of one chromosome is translocated to another chromosome

Cancer-associated genes classified categories:

proto-oncogenes, oncogenes, tumor-suppressor genes

Proto-oncogenes

normal nonmutant genes that code for normal cellular growth

Oncogenes

mutated proto-oncogenes that promote excessive cell growth

Tumor-suppressor genes

prevent uncontrolled cell growth and help maintain genomic stability (referred to as anti-oncogenes)

3 key genetic mechanisms that paly a role in human carcinogenesis

Activation of oncogenes, inactivation of tumor suppressor genes, defects in DNA repair genes

Activation of oncogenes

mutations of proto-oncogenes can convert them into oncogenes, promoting uncontrolled cell growth and proliferation

Inactivation of tumor suppressor genes

loss or alteration of tumor suppressor genes removes important controls on cell division, DNA repair, and apoptosis

Defects in DNA repair genes

mutations in genes responsible for repairing DNA damage allow additional mutations to accumulate, increasing cancer risk

Examples of chromosomal translocations associated with cancers

Burkitt lymphoma & chronic myelogenous leukemia (CML)

Burkitt lymphoma

the myc proto-oncogene which encodes a growth signal protein, is translocated from its normal position on chromosome 8 to chromosome 14

chronic myelogenous leukemia (CML)

involving chromosomes 9 and 22 results in formation of an abnormal fusion protein, a hybrid oncogenic protein (bcr-abl) that promotes cell proliferation

Carcinogenesis

process by which carcinogenic (cancer-causing) agents cause normal cells to become cancer cells

Multistep mechanism that can be divided into 3 stages

Initiation, promotion, progression

Initiation

exposure of cells to a carcinogenic agent causes alterations in DNA, affecting genes that regulate cell growth, DNA repair, or apoptosis

Promotion

allows growth and proliferation of cells triggered by multiple growth factors and chemicals - reversible if the promoter substance is removed

Progression

is the process when tumor cells acquire malignant phenotypic changes (become malignant and aggressive)

Risk factors predisposing to cancer:

heredity, hormonal factors, immunologic mechanisms, environmental agents (chemicals, radiation, cancer-causing viruses)

Heredity

genetic predisposition is identified in 50 types of cancer (BRCA ½ genes = genetic susceptibility to breast and ovarian cancer)

Carcinogen

an agent capable of causing cancer

Direct-reacting agents

do not require activation in the body to become carcinogenic and can bind directly to DNA and cause mutations

Indirect-reacting agents (procarcinogens or initiators)

become active only after metabolic conversion; the activated metabolite binds to DNA causing mutations

Difference between carcinogen & promoter - carcinogen

produces genetic mutations that can transform a normal cell into an initiated cell (cigarette smoke directly associated with lung and laryngeal cancer)

Difference between carcinogen & promoter - promoter

does not cause mutations but encourages the growth and division of previously mutated cells (inflammation caused by H. pylori increase the risk of gastric cancer

Oncoviruses

several viruses have been associated with human cancer: oncogenic viruses insert their genetic material into a host cell

Oncoviruses - 4 DNA viruses that have been identified in human cancers

Human papillomavirus (HPV), Epstein-Barr virus (EBV), Kaposi sarcoma herpesvirus (KSHV or HHV8), Hepatitis B (HBV)

2 types of clinical manifestations of cancer

local effects & systemic effects

Local effects

cancer disrupts tissue integrity; compress and erode blood vessels causing ulceration, necrosis, and bleeding; infiltrate and destroy normal tissues, leading to inflammation and pain

Systemic effects

commonly seen in advanced stages; cancer cachexia

Cancer cachexia

a syndrome characterized by progressive weight loss, loss of skeletal muscle and fat, weakness, anorexia

Common local effects of tumors include:

pain (may be absent until very late stages), obstruction (tumor compresses a duct or passageway), tissue necrosis and ulceration (may lead to bleeding or infection around the tumor)

Common systemic manifestations include:

weight loss (due to increased demands from tumor cells on the body), anemia (due to blood loss at tumor site), severe fatigue (due to inflammatory changes, anemia), effusions (inflammation causes fluid buildup in body cavities)

Paraneoplastic syndrome

not directly related to tumor invasion or metastasis, often caused by ectopic hormone production or immune mechanisms

Examples of paraneoplastic syndrome

Squamous cell carcinoma of the lung can secrete parathyroid hormone, resulting in hypercalcemia

Small cell lung carcinoma can secrete adrenocorticotropic hormone (ACTH), causing Cushing syndrome

Metastasis

is the spread of cancer cells from the site of the original tumor to distant tissues and organs through the body; is a complex process that requires cells to have many new abilities

Invasion

is local spread of cancer; is a prerequisite for metastasis and the first step in the metastatic process; invasion then requires that the cancer attach to specific receptors and survive in the specific environment

Epithelial-mesenchymal transition (EMT)

process in which epithelial cells lose their normal characteristics and acquire mesenchymal features

Process of EMT

Many epithelial-like characteristics (polarity, adhesion); migratory capacity increases (cancer cells secrete protease); resistance to apoptosis increases; dedifferentiation (favors growth in foreign microenvironments and the establishment of metastatic disease)

Migratory capacity increases

cancer cells secrete protease; digest the extracellular matrix and basement membranes; create pathways through which cells can move

Dedifferentiation

cells are able to withstand the physiologic stresses of travel in the blood and lymphatic circulation and survive in a new environment

Major routes by which cancer spreads from its primary site to distant locations

Lymphatic metastasis & hematologic metastasis

Lymphatic metastasis

often the earliest detectable spread in many epithelial cancers

first destination: regional lymph nodes

sentinel lymph node biopsy is important in detecting the cancer spread

ex: breast cancer frequently spreads first to the axillary lymph nodes

Hematologic metastasis

cancer cells spread through the blood, associated with more advanced disease

first destination: organs with rich blood flow (lungs, liver, bone, brain)

ex: osteosarcoma commonly spreads to the lungs via bloodstream; renal cell carcinoma often metastasizes hematologic to the lungs and bones

Stages characteristics

involves the size of the tumor, the degree to which it has invaded, and the extent to the spread

Stage 1

tumor is confined to its organ of origin

Stage 2

tumor is locally invasive

Stage 3

tumor has advanced to regional structures

Stage 4

tumor has spread to distant sites

Tumor (T)

primary tumor; the number equals size of tumor and its local extent

T0

organ free of tumor

Tis

carcinoma in situ (pre-invasive cancer)

T1

lesion <2 cm in size

T2

lesion 2-5 cm

Nodes (N)

lymph node involvement; a higher number means more nodes are involved

N0

no lymph nodes involved

N1

regional lymph nodes involved

N2

more lymph nodes involved

Metastases (M)

extent of distant metastases

M0

no metastases

M1

distant metastases present

Carcinoma in situ (CIS)

is a pre-invasive cancer in which abnormal cells are present only in the epithelium (the layer of tissue where they originated)

CIS characteristics

cells have not crossed the basement membrane or invaded surrounding tissues

no invasion into underlying tissue

considered stage 0 cancer in many organs

if untreated, CIS progresses to invasive carcinoma

Tumor grade

refers to how closely tumor cells resemble the normal tissue from which they arose (degree of differentiation)

Low-grade tumors

well-differentiated, look similar to normal cells, grow and spread more slowly

High-grade tumors

poorly differentiated or undifferentiated, markedly abnormal appearance, higher mitotic activity, tend to behave more aggressively

Tumor markers

substances produced by benign or malignant cells; found in a tumor cell and secreted into body fluids (hormones, enzymes, antigens, antibodies)

Tumor markers are used to…

screen and identify individuals at high risk for cancer; diagnose specific types of tumors; follow the clinical course of cancer

Liver and germ cell tumors (TM)

secrete alpha fetoprotein (AFP) into the blood

Prostate tumors secrete prostate-specific antigen (PSA)

used for screening, risk assessment, evaluation of suspected prostate cancer, and monitoring treatment or recurrence

Ovarian epithelial tumors secrete cancer antigen - 125 (CA-125)

used for monitoring treatment response and detecting recurrence of ovarian cancer; not a good screen test: CA-125 can be elevated in benign conditions

Cancer treatment surgery

is a definitive treatment of cancers that do not spread beyond the limits of surgical excision

Must achieve adequate margins

tumor should be completely removed along with sufficient amount of surrounding healthy tissue; surgeon provides critical staging information

Palliative

performed not to cure a disease, but to relieve symptoms and improve quality of life

Example of palliative treatment

Colostomy - creates an alternative pathway for stool to bypass an obstructing colorectal tumor to relieve bowel obstruction

Mutations of the APC gene

close to 100% lifetime risk of colon cancer; colectomy which is removal of colon