Neoplasms Flashcards
All tumors have two basic components
(1) neoplastic cells that
constitute the tumor parenchyma
(2) reactive stroma made
up of connective tissue, blood vessels, and variable numbers of
cells of the adaptive and innate immune system
classification of tumors and their biological behavior are based
primarily on
parenchymal component, but their growth and
spread are critically dependent on their stroma
desmoplasia
parenchymal cells stimulate the formation of an abundant collagenous stroma
Some desmoplastic tumors—for example, some cancers of the
female breast—are stony hard or scirrhous
Benign Tumors
connective tissue origin a. Arise from the mesoderm b. Examples (1) Lipomas derive from adipose tissue (2) Leiomyomas of the uterus are derived from smooth muscle Unusual tumors that are usually benign
Lipoma Gross/Histo
Gross: Adipose Tissue; well-circumscribed
yellow tumor. Adipose tissue
is connective tissue; therefore
it derives from the mesoderm.
Histology: tumor is composed of benign fat cells with empty spaces
Leiomyomas Gross/Histo
uterus derived from smooth muscle
Gross: The tumor fills the endometrial cavity and distends the uterus. On cross section the benign smooth
muscle tumor has a whorled appearance.
Unusual tumors that are usually
Benign
Mixed tumors
Composed of neoplastic cells that have two different morphologic
patterns, but derive from the same germ cell layer
Not the same as a teratoma
pleomorphic adenoma of the parotid gland
Teratoma
Derive from more than one germ layer—ectoderm, endoderm, and/or
mesoderm (Fig. 9-1 C; Link 9-4); may be benign or malignant
(2) Sites: ovaries (most common site), testes, anterior mediastinum, and pineal gland; tend to have a midline location (pineal gland, anterior mediastinum) or close to the midline (ovaries and testes)
Cystic teratoma
ovary, showing the cystic nature of
the tumor. Hair is present, and
a tooth is visible (arrow). Teratomas can arise from ectoderm, endoderm,
and mesoderm
squamous epithelium (epithelial origin), sebaceous glands (endodermal origin), and cartilage (mesodermal origin)
Malignant tumors (cancer)
- Definition: Characterized by an unregulated proliferation of cells that invade tissue and are
capable of spreading to other sites that are remote from the primary site of origin
What is a Carcinoma?
Derive from epithelial tissue—squamous, glandular, or transitional
epithelium
b. Primary sites for squamous cell carcinoma (SCC) include oropharynx, larynx, upper/ middle esophagus, lung, cervix, penis, and skin. Squamous cell cancers commonly have keratin pearls that stain bright red with a hematoxylin-eosin
Carcinoma Histologic Features
keratin pearls (concentric
layers of eosin-staining keratin
similar to the layers of a pearl).
Squamous cell carcinoma. The many well-differentiated foci of eosinophilic-staining neoplastic cells produce keratin in layers (keratin pearls). Note how squamous epithelium takes up the red eosin stain
Primary sites for adenocarcinoma
a (glandular epithelium) include lung, distal esophagus
to rectum, pancreas, liver, breast, endometrium, ovaries, kidneys, and prostate
Adenocarcinomas commonly have glands with secretions in the lumen
Adenocarcinoma histology
glands lined by neoplastic glandular cells with hyperchromatic and irregular nuclei, and a gland lumen with the material in the lumen. G, Adenocarcinoma.
Irregular glands infiltrate the stroma. The nuclei lining the gland lumens are cuboidal and contain nuclei with hyperchromatic nuclear chromatin.
Glandular cells appear to pile up on each other. Many of the gland lumens contain secretory material (arrow).
Primary sites for transitional cell carcinoma
urinary bladder, ureter, and
renal pelvis
Sarcomas
Derive from connective tissue (mesoderm origin)
b. Approximately 40% of sarcomas are located in the lower extremity.
c. Examples include those that arise from bone (osteosarcoma); and skeletal muscle (rhabdomyosarcoma; see also Link 24-23 A, B)
Osteogenic Sarcoma
The light-colored mass of tumor in the metaphysis abuts the epiphyseal plate and has spread laterally out through the cortex and into the surrounding tissue
Rhabdomyosarcoma
Gross: the tumor has a fleshlike appearance
Histology: the tumor is composed of elongated cells that resemble fibroblasts.
Hamartoma
Nonneoplastic overgrowth of disorganized tissue that is indigenous to a particular site
Examples: bronchial hamartoma (contains cartilage, Peutz-Jeghers (PJ) polyp (contains glandular tissue)
Hamartoma of lung
composed of cartilaginous tissue
Choristoma (heterotopic rest)
a. Definition: Mass of non-neoplastic tissue that is located in a foreign place
b. Examples: pancreatic tissue in the wall of the stomach (Link 9-7), brain tissue in the nasal cavity, functioning thyroid tissue in the liver (Link 9-8)
Heterotopic pancreatic tissue
the stomach wall is composed of pancreatic ducts and rare acini interspersed among smooth
muscle bundles.
Parenchyma
Neoplastic component of a tumor that determines its biological behavior
Stroma
Nonneoplastic supportive tissue of a tumor
b. Most infiltrating carcinomas induce
production of a dense, fibrous stroma (called desmoplasia) that surrounds invading cancer.
Differentiation in benign Tumors
Benign: Usually well-differentiated (resembles the parent tissue) and does not have the capacity to spread to distant sites
Well-differentiated or low-grade malignant cancer
Cancer cells histologically resemble the parent tissue
(Examples: parenchyma showing keratin pearls (characteristic of squamous tissue; or glandular lumens with secretions (characteristic of normal gland lumens with secretions
Poorly differentiated, high-grade, or anaplastic cancer
Do not resemble the parent tissue histologically (e.g., no glands,
keratin)
Moderately well-differentiated (intermediate-grade) cancer
Exhibit histologic features that are between those of low- and high-grade
cancer (i.e., occasional gland-like structures are seen, or areas that look like keratin are present, whereas the rest of the tumor has no characteristics of the tissue of origin)
Cell organelles in malignant versus normal cells
a. Less mitochondria
b. Rough endoplasmic reticulum (RER) is less prominent.
c. Loss of cell-to-cell adhesion molecules (cadherins). Cadherins are a group of
calcium-dependent transmembrane proteins that play an important role in cell-to-cell adhesion. Loss of adhesion allows malignant cells to extend into the surrounding tissue.
Nuclear features when compared to a normal cell
a. Nucleus is larger, has irregular borders, and has more chromatin (hyperchromatic).
b. Nucleolus is larger and has irregular borders.
c. Mitoses have normal and atypical mitotic spindles
Biochemical changes in malignant cells
- Rely on anaerobic glycolysis for energy. Explains why there is more lactic acid produced under hypoxic conditions than one would see in a normal cell
Increased uptake of a glucose analog in malignancy
a. A special test has been developed in which cancer cells take up a glucose analog with positron emission tomography (PET).
b. PET scan is widely used in the diagnosis, staging, and monitoring of therapy of various kinds of cancer.
Do cancer cells have glucose?
Cancer cells do not process glucose as well as normal cells, and store glucose in the form of glycogen within the cytosol.
Some cancers (e.g., prostate cancer) derive energy from β-oxidation of fatty acids rather than anaerobic glycolysis.
The growth rate in benign and malignant tumors
- Benign tumors usually have a slow growth rate.
- Malignant tumors have a variable growth rate.
a. Growth rate correlates with degree of
differentiation of the malignant tumor.
b. Example: Anaplastic (high-grade)
cancers have an increased growth rate,
whereas low-grade cancers tend to
grow more slowly. - Clinically detectable tumor mass must have 30 population doublings to produce 109 cells, which equals 1 g of tissue.
- Malignant cells with an increased growth rate (e.g., acute myelogenous leukemia) are treated
with cell cycle–specific chemotherapy agents.
When malignant cells are killed, other malignant cells quickly enter the cycle, and the cycle repeats itself so that the size of the tumor begins to shrink.
MTX (Methotrexate)
inhibits the synthesis (S) phase of the cell cycle (duplication of
DNA)
Vincristine
inhibits the mitotic (M) phase of the cell cycle
When malignant cells are killed, other malignant cells quickly enter the cycle, and the cycle repeats itself so that the size of the tumor begins to shrink
Monoclonality in benign and malignant tumors
- Nonneoplastic tumors derive from multiple cells (polyclonal).
- Benign and most malignant tumors derived from a single precursor cell
The monoclonal origin of neoplasms
glucose-6-phosphate dehydrogenase (G6PD) isoenzymes A and B in selected neoplasms (e.g., leiomyoma of the uterus). All the neoplastic smooth muscle cells in uterine leiomyomas have either the A or the B G6PD isoenzyme. Nonneoplastic smooth muscle proliferations in the uterus (e.g., pregnant uterus) have some cells with the A isoenzyme and others with the B isoenzyme, indicating their polyclonal origin
Telomerase activity in benign and malignant tumors
a. Definition: Repetitive sequences of nontranscribed DNA located at the ends of chromosomes
b. Prevent end-to-end fusion of chromosomes during normal mitosis and, along with other factors, are important in determining the longevity of a cell
c. Shorten with each round of replication and eventually, when only a few nucleotide bases remain, genome becomes unstable, which produces a signal for apoptosis
Telomerase activity in Malignant and Benign Cells
Benign tumors have normal telomerase activity.
Malignant cells have upregulation of telomerase activity, which prevents the naturally programmed shortening of telomere complexes with cell replication; hence the cell no longer undergoes apoptosis.
Upregulation of decay-accelerating factor (DAF) by malignant cells
- DAF normally degrades C3 convertase and C5 convertase in the classical and alternative complement pathways.
- Upregulation of DAF ensures that degradation of the convertases just mentioned prevents formation of the membrane attack complex (MAC; C5b-9); therefore cancer cells cannot be killed by the MAC
Local invasion and metastasis
Benign tumors: do not invade. Exception is a dermatofibroma, which invades tissue but does not metastasize
Malignant: a. Invade tissue. Invasion is an important criterion for malignancy.
b. Some tissues resist invasion. Examples include mature cartilage and the elastic tissue of arteries.
All malignant tumors require oxygen and nutrients to survive and do so by stimulating angiogenesis within the tumor and its metastatic sites
The sequence of Invasion in lymph nodes and Venules
Clonal expansion growth, diversification, angiogenesis
Metastatic subclone
Adhesion to and invasion of basement
membrane
Passage through extracellular matrix
Intravasation
Interaction with host lymphoid cells
Tumor cell embolus
Adhesion to the basement membrane
Extravasation Metastatic
deposit
Angiogenesis
Growth
Lymphatic spread
(1) Lymphatic spread to regional lymph nodes is the first step for dissemination in
carcinomas. Lymph nodes are the first line of defense against the spread of carcinomas.
(2) Using the model of invasion and metastasis discussed in carcinomas,
the vessel that is invaded is an afferent lymphatic vessel. The tumor emboli enter the sinuses of the regional lymph nodes and invade the parenchymal tissue of the lymph node.
(3) Tumor cells that invade efferent lymphatics send tumor emboli into the thoracic duct, and from there they enter the systemic circulation, where they disperse to capillaries in target organs to form metastatic foci. This is the hematogenous phase of cancer dissemination in carcinomas.
Hematogenous spread
(1) Sarcomas initially invade capillaries and/or venules and directly spread to distant sites without involving the lymph nodes.
(2) Malignant cells entering the portal vein metastasize to the liver (Fig. 9-7 A), whereas those that enter the vena cava metastasize to the lungs.
(3) Both carcinomas and sarcomas have hematogenous dissemination; however,
carcinomas usually invade regional lymph nodes before entering the systemic circulation
Seeding (transcoelomic) spread
(1) Definition: Malignant cells exfoliate from a serosal surface and implant and invade tissue in a body cavity (pleural, pericardial, or peritoneal).
(2) Primary surface-derived ovarian cancers (e.g., serous cystadenocarcinoma) commonly seed the omentum and produce malignant effusions in the peritoneal cavity.
(3) Peripherally located lung cancers (usually adenocarcinomas) commonly seed the parietal and visceral pleurae, causing malignant pleural effusions. A variant of seeding is a medulloblastoma, high-grade cancer arising in the brain that
commonly exfoliates malignant cells into the cerebrospinal fluid and seeds the
brainstem and spinal cord.
Perineural invasion by malignant cells
usually painful
Vertebral column metastasis
(1) Most common metastatic site in bone
(a) Breast cancer is the most common
cancer metastatic to bone.
(b) Prostate cancer is the second most
common cancer metastatic to bone.
(2) Batson paravertebral venous plexus is responsible for the predilection of bone
metastases to the vertebrae.
Osteoblastic metastasis
(1) Malignant cells in metastatic sites secrete cytokines that specifically activate osteoblasts, which initiate reactive bone formation (Fig. 9-7 E).
The second most common cancer producing osteoblastic metastases is breast cancer.
(2) Bone formation in metastatic sites produces radiodensities that are identified in
radiographs
is the most common cancer-producing osteoblastic metastases.
Prostate cancer
elevated, because osteoblasts use this
an enzyme in bone formation.
Serum alkaline phosphatase (ALP)
Osteolytic metastases
Osteolytic metastases produce radiolucencies in bone that are identified in radiographs (Figs. 9-7 F, G).
Clinical findings include pathologic fractures and/or hypercalcemia, if osteolytic lesions are extensive
Pathogenesis of Osteolytic metastases
(a) Malignant cells in metastatic sites
produce chemicals (e.g.,
prostaglandin E2
[PGE2], interleukin [IL]-1) that locally
activate osteoclasts.
(b) Cancers that commonly produce lytic
metastases include lung cancer,
RCCs, and breast cancer.Lymph nodes
(e.g., metastatic breast/lung cancer most common). Lymph nodes are the
most common overall site for metastasis
Lungs
metastatic breast cancer most common cause
Liver
metastatic colorectal cancer most common cause
Bone
metastatic breast cancer most common cause
Brain
metastatic lung cancer most common cause
Second most common cause of death in the United States
Cancer
Causes
a. External factors: Tobacco (#1), alcohol, chemicals, radiation, microbial pathogens
b. Internal factors: Hormones, immune conditions, inherited mutations
c. Geographic and ethnic factors
risk factor for cancer.
Age
Colorectal, lung, and prostate cancer progressively increase in incidence with age, whereas
others reach a peak and begin to decline (e.g., malignant melanoma)
the leading cause of disease-related (noninjury) mortality
among children 1 to 14 years of age
Malignant neoplasms
Top three cancers in children, in decreasing order
leukemia (acute lymphoblastic
leukemia is the most common leukemia), central nervous system (CNS; cerebellar
tumors are the most common), and neuroblastoma (malignant tumor arising from
postganglionic sympathetic neurons).
common cancers in children that are not common in adults
rhabdomyosarcoma (malignancy of skeletal muscle),
Wilms tumor (malignant tumor of the kidney that is derived from the metanephric blastema),
retinoblastoma (malignant tumor in the eye),
osteosarcoma (malignancy of osteoid in bone), and
Ewing sarcoma
(neuroectodermal malignancy of bone).
common in adults but
uncommon in children
Epithelial tumors of organs, such as lung, colon, and breast
Top three noncutaneous cancer sites in men
prostate, lung/
bronchus, and colorectal
Top three noncutaneous cancer sites in women
breast, lung/
bronchus, and colorectal.
Top three sites for gynecologic cancers
ovary, uterine corpus
(endometrium), and cervix
Autosomal dominant cancer
syndrome (Retinoblastoma)
malignancy of the eye, nearly always occurring before age 5. Of all cases of retinoblastoma, 60% are nonhereditary and are usually unilateral, 15% are autosomal dominant and have unilateral retinoblastomas, and 25% are autosomal dominant and have bilateral retinoblastomas.
In the autosomal dominant type, one of the RB1 genes on chromosome 13 is mutated in germ cells.
A second mutation of the RB1 gene on the remaining chromosome 13 (deletion or recombination mutation) must
occur after birth (“two hits”) to produce a unilateral retinoblastoma or a bilateral retinoblastoma.
In the sporadic type of retinoblastoma, the two somatic mutations of the RB1 suppressor gene on chromosome 13
occur in early childhood and produce unilateral retinoblastomas.
In the autosomal dominant type of
retinoblastoma, there is an additional risk for developing second malignancies, which include osteosarcoma
(malignancy of bone; most common), a soft tissue sarcoma (malignancy of connective tissue), or a malignant
melanoma (malignancy of melanocytes).
Familial adenomatous polyposis (Autosomal Dominant)
colorectal cancer from malignant transformation of polyps develops by
age 50 years. There is inactivation of the adenomatous polyposis coli (APC) suppressor gene and an increased
incidence of desmoid tumors (fibromatosis of the anterior abdominal wall)
Li-Fraumeni syndrome (AD)
increased risk for developing brain tumors, sarcomas, leukemias (malignant transformation marrow stem cells), carcinomas (e.g., breast, brain) before age 50. There is a heterozygous
loss-of-function mutation in the suppressor gene encoding p53
Hereditary nonpolyposis colon cancer (Lynch syndrome) (AD)
increased risk for developing colorectal cancers (especially in the proximal colon) without having previous polyps.
It is caused by a germline mutation that inactivates DNA mismatch repair genes, which causes a microsatellite repeat replication error (called microsatellite instability).
Microsatellites are repeated sequences that predispose to replication errors if there are mutations in DNA repair enzymes (e.g., mismatch repair genes).
The microsatellites become unstable
(become longer or shorter) and produce frameshift mutations that inactivate or alter tumor suppressor gene function leading to cancer.
Microsatellite instability is found in the majority of patients with
hereditary nonpolyposis colon cancer
BRCA1 and BRCA2 genes
Inactivation of these genes increases the risk for developing breast cancer
(sometimes bilateral) and ovarian cancer. Because of the very high risk for these cancers, many women with
these mutations elect to have prophylactic bilateral mastectomy and oophorectomy in the absence of a
detectable tumor in these sites
Autosomal recessive syndromes with defects in DNA repair (Xeroderma pigmentosum)
the increased risk at an early age for developing skin cancers (basal cell
carcinoma, squamous cell carcinoma, and malignant melanoma) due to the inability to repair pyridine dimers
produced by exposure to ultraviolet light.
Chromosome instability syndromes (Autosomal recessive syndromes with defects in DNA repair (Xeroderma pigmentosum))
Chromosomes are susceptible to damage by ionizing radiation and drugs. In ataxia telangiectasia, there is an increased risk for developing malignant lymphomas. In Bloom syndrome, there is an increased risk for developing gastrointestinal tumors and malignant lymphoma. In
Fanconi syndrome, there is an increased risk for developing malignant lymphomas, squamous cell carcinoma, and hepatocellular carcinomas.
Familial cancer syndromes
No clearly defined pattern of inheritance; however, certain cancers (e.g., breast, ovary, colon) develop with
increased frequency in families. This syndrome sometimes involves inactivation of the BRCA1 and BRCA2
suppressor genes
Nasopharyngeal carcinoma is causally associated
Epstein-Barr virus (EBV)
SCC of the esophagus
associated with alcohol abuse, smoking, and other
unknown factors.
Japan
Adenocarcinoma of the stomach is causally associated with smoked foods.
Southeast Asia
HCC is causally associated with chronic liver disease such as that
caused by hepatitis B virus (HBV) or hepatitis C virus (HCV). Other associations include cirrhosis of any etiology as well as aflatoxin, a toxin derived from Aspergillus that contaminates improperly stored food crops
Sub-Saharan Africa
Burkitt lymphoma is causally associated with EBV. Kaposi sarcoma
(KS) is causally associated with human herpesvirus 8 (HHV-8)
Actinic (solar) keratosis
Squamous cell carcinoma
Atypical hyperplasia of ductal epithelium of the breast
Adenocarcinoma
Chronic irritation at sinus orifices, third-degree burn scars
Squamous cell carcinoma
Chronic ulcerative colitis
Adenocarcinoma
Complete hydatidiform mole
Choriocarcinoma
Dysplastic nevus
Malignant melanoma
Endometrial hyperplasia
Adenocarcinoma
Glandular metaplasia of esophagus (Barrett’s esophagus)
Adenocarcinoma
Glandular metaplasia of stomach (Helicobacter pylori)
Adenocarcinoma
Myelodysplastic syndrome
Acute leukemia
Regenerative nodules in cirrhosis
Adenocarcinoma
Scar tissue in the lung
Adenocarcinoma
Squamous dysplasia of oropharynx, larynx, bronchus, cervix
Squamous cell carcinoma
Tubular adenoma of the colon
Adenocarcinoma
Vaginal adenosis (diethylstilbestrol exposure)
Adenocarcinoma
Villous adenoma of rectum
Adenocarcinoma
Reducing weight to prevent cancer
(1) More adipose tissue increases aromatase conversion of androgens to estrogen.
(2) Increased levels of estrogen increase the risk for developing endometrial and breast cancer.
Sunscreen protection
Decreases the risk for developing BCC, SCC, and malignant
melanoma of skin
Immunization
HBV immunization. Decreases the risk for developing HCC, due to HBV-induced
cirrhosis
b. Human papillomavirus (HPV) immunization. Immunization against HPV decreases the risk for developing SCC of the cervix and penis
Cervical Papanicolaou (Pap) smears
(1) Pap smears decrease the risk for cervical cancer due to HPV. HPV subtypes
16 and 18 are the most common. This explains why cervical cancer is the least
common gynecologic cancer and the least common gynecologic cancer-causing death.
(2) Pap smears detect dysplasia of the cervical mucosa, the precursor to invasive cervical cancer (Link 9-13). Cervical dysplasia is treated by cervical conization and other interventions
Cytologic features of malignant disease detected by a vaginal Papanicolaou (Pap) smear
Malignant cells have enlarged hyper-chromatic nuclei, in contrast to the small nuclei of normal cell
ABL
Nonreceptor tyrosine kinase activity
Translocation t(9;22); forms a fusion gene (BCR-ABL)
Chronic myelogenous leukemia: chromosome 22 with the translocation is called the Philadelphia chromosome.
ERBB2 (also called
Her-2/Neu)
Receptor synthesis
Amplification or
overexpression
In breast carcinoma, ERBB2 is a marker of aggressiveness (poor prognosis). It is amplified or overexpressed in 25% of breast cancers
C-MYC
Nuclear transcription Translocation t(8;14)
Burkitt lymphoma
N-MYC
Nuclear transcription
Amplification
Neuroblastoma, small cell carcinoma of the lung
RAS
Guanosine. triphosphate
signal transduction Point mutation •
Accounts for 15%–20% of all cancers: pancreatic carcinomas (90%); ≈50% of endometrial, colon, and thyroid cancers; 30% of lung adenocarcinomas and myeloid leukemias; and urinary bladder cancer
RET
Receptor synthesis
Point mutation •
Multiple endocrine neoplasia lla/llb syndromes leukemia
SIS (PBGFB)
Growth factor synthesis Overexpression Osteosarcoma, astrocytoma
APC
Prevents nuclear transcription
(degrades catenin, an activator
of nuclear transcription)
• Inherited mutation (AD): familial polyposis (colorectal carcinoma)
• Somatic mutations: colon and stomach cancer
BRCA1/BRCA2
Regulates DNA repair • Inherited mutation: female breast, ovary carcinomas; carcinoma of the
male breast
NF1
Regulates DNA repair • Inherited mutation: female breast, ovary carcinomas; carcinoma of the
male breast
NF2
Cytoskeletal stability • Inherited mutation (AD): neurofibromatosis type 2: bilateral acoustic neuromas (schwannoma), meningioma
Somatic mutation: schwannoma, meningioma
p53
Inhibits G1 to S phase Repairs DNA, inhibits the BCL2 antiapoptosis gene (initiates apoptosis) • Inherited mutation (AD): Li-Fraumeni syndrome: breast carcinoma, brain tumors, leukemia, sarcomas • Somatic mutation: most human cancers (p53 gene is the most common gene producing cancer)
RB1
Inhibits G1 to S phase • Inherited mutation (AD): retinoblastoma, osteosarcoma
Somatic mutation: retinoblastoma, osteosarcoma, carcinomas of breast,
lung, colon
TGF-b
Inhibits G1 to S phase • Inherited mutation: familial stomach cancer
Somatic mutation: pancreatic and colorectal carcinomas
VHL
Regulates nuclear transcription • Inherited mutation (AD): von Hippel–Lindau syndrome: cerebellar
hemangioblastoma, retinal angioma, renal cell carcinoma (bilateral),
pheochromocytoma (bilateral)
WT1
Regulates nuclear transcription • Inherited mutation (AD): Wilms tumor
Sporadic mutation: Wilms tumor
Mechanism of action of chemical carcinogens
a. Direct-acting carcinogens. Contain electron-deficient atoms that react with electron-rich atoms in DNA (e.g., alkylating agents, nickel).
b. Indirect-acting carcinogens
(1) Require metabolic conversion to a carcinogen before they become active
(2) For example, PAHs from cigarette smoke, smoked meats, or meats cooked at a high temperature over an open flame are metabolized in the liver cytochrome P450 system and converted into DNA-binding epoxides that are carcinogenic.
Sequence of chemical carcinogenesis
Initiation
Promotion
Progression
Aflatoxin (from
Aspergillus)
Ingestion of maize and peanuts grown in hot/humid
climates
Hepatocellular carcinoma in association with
HBV
Alkylating agents
Oncology chemotherapy •
Malignant lymphoma
Arsenic
Herbicides (common in vineyard workers), fungicides, animal dips; metal smelting; intentional/accidental poisoning
Squamous cell carcinoma of skin, lung cancer, liver angiosarcoma (malignancy of blood vessels)
Asbestos
Roofing material (roofers with over 20 years of
experience have had contact with asbestos); insulation
for pipes in ships in shipyards (no longer used for
insulation), old homes; old cars with brake liners
• Bronchogenic carcinoma (most common), pleural
mesothelioma
Azo dyes
Used in paints, printing inks, varnishes, leather products,
carpets, food products
Hepatocellular carcinoma
Benzene
Component of light oil; used in printing industry, dry
cleaning, paint, adhesives and coatings
• Acute leukemia, Hodgkin lymphoma
Beryllium
Used in the space industry (missile fuel and space
vehicles; metal alloys in aerospace appliances and
nuclear reactors)
• Bronchogenic carcinoma
Cadmium
Used in industries where ore is being smelted; electroplating; welders who have welded on cadmium-containing alloys or worked with silver
solders; found in some batteries
• Prostate and lung cancer
Cyclophosphamide
Chemotherapy agent • Transitional cell carcinoma of urinary bladder
Diethylstilbestrol (DES)
Once used to treat women with threatened abortions • Daughters exposed to mothers who took DES
may develop clear cell carcinoma of vagina/cervix
β-Naphthylamine
(aniline dyes) and
aromatic amines
Workers in the rubber, chemical, leather, textile, metal,
and printing industries
Transitional cell carcinoma of urinary bladder
Nickel
Nickel plating, by-product of stainless steel welding, ceramics, batteries, spark plugs
Bronchogenic carcinoma, nasal cavity cancer
Oral contraceptives
Birth control pill •
Breast and cervical cancer; hepatic adenoma
tendency to rupture
Polycyclic
hydrocarbons
Formed when coal, soot (chimney sweeper), wood, gasoline, oil, tobacco, or other organic materials are burned; also formed in food when fish or meats are charbroiled on an open flame
Squamous cell carcinoma: skin (scrotum with soot in chimney sweeper), oral cavity, mid-esophagus, larynx, lung
Adenocarcinoma: distal esophagus, pancreas, kidney
Transitional cell carcinoma: urinary bladder, renal
pelvis
Polyvinyl chloride F
Found in plastic piping material, adhesive plastics,
refrigerant
Liver angiosarcoma
Radon and decay
products
By-product of decay of uranium, hazard in quarries and underground mines
Bronchogenic carcinoma
Silica
Chemical of silicon dioxide, rock quarries, sandblasting •
Bronchogenic carcinoma
Helicobacter pylori
s adenocarcinoma and low-grade malignant lymphoma
of the stomach
Fusobacterium nucleatum
in the early stages of colorectal cancer development
Schistosoma haematobium
Causes SCC of the urinary bladder
Clonorchis sinensis and Opisthorchis viverrini
Cause cholangiocarcinoma of bile ducts
Order of importance of microbial agents causing cancer
viruses > bacteria > parasites
Ionizing radiation-induced cancers
Ionizing radiation–induced cancers
Examples of ionizing radiation–induced cancers
(1) Acute myeloblastic leukemia (AML) and chronic myelogenous leukemia (CML)
(a) Leukemia is the most common overall cancer due to ionizing radiation.
(b) Radiologists and individuals exposed to radiation in nuclear reactors are at
increased risk of developing leukemia.
(2) Papillary thyroid carcinoma
HCV (RNA)
Produces cirrhosis
Hepatocellular carcinoma
HTLV-1 (RNA)
Activates TAX gene, stimulates polyclonal T-cell proliferation, inhibits p53 suppressor gene
T-cell leukemia and lymphoma
EBV (DNA virus)
Promotes polyclonal B-cell proliferation, which increases the
risk for a t(8;14) translocation
Burkitt lymphoma, CNS lymphoma in AIDS, mixed cellularity
Hodgkin lymphoma, nasopharyngeal carcinoma
HBV (DNA)
Activates proto-oncogenes inactivates p53 suppressor gene • Hepatocellular carcinoma
HHV-8 A
Acts via cytokines released from HIV and HSV • Kaposi sarcoma
HPV types 16
and 18
Type 16 (≈50% of cancers): E6 gene product inhibits the p53 suppressor gene
Type 18 (≈10% of cancers): E7 gene product inhibits the RB1 suppressor gene
Squamous cell carcinoma of vulva, vagina, cervix, anus
(associated with anal intercourse), larynx, oropharynx
Host defenses against cancer
- Humoral immunity. Humoral immunity involves antibodies and complements.
- Type IV cell-mediated immunity (CMI)
a. CMI is the most efficient mechanism for killing cancer cells.
b. Cytotoxic CD8 T cells. Recognize altered class I antigens on neoplastic cells and destroy them. - Natural killer (NK) cells. Directly kill malignant cells (type IV hypersensitivity) or use the indirect killing of cells via type II hypersensitivity reactions.
- Macrophages kill cancer cells; however, they are not as effective as cytotoxic T cells and NK
cells.
Grading criteria for cancer
a. Degree of differentiation (e.g., low, intermediate, or high grade [anaplastic])
b. Nuclear features, invasiveness
Staging criteria
Most important prognostic factor for survival
TNM system for staging cancer
(1) TNM progresses from the least to the most important prognostic factor.
(2) T refers to tumor size. A malignant tumor that is ≥2 cm is inherently capable of metastasizing.
(3) N refers to whether lymph nodes are involved.
(4) M refers to extranodal metastases (e.g., liver, lung)
For a carcinoma to reach M
already has passed through N (lymph nodes) and
spread to other organ sites via the bloodstream.
If there are no extranodal metastases, then N
(lymph nodes) is the most
important prognostic factor for survival
Cancer effects on the host
Cachexia Anemia Hemostasis abnormalities Fever in malignancy Paraneoplastic syndromes
Signs and symptoms of malignant tumors
General symptoms: • Cachexia • Loss of well-being Neurologic symptoms Obstruction: • Airways • Digestive tube Respiratory symptoms: • Dyspnea • Pneumonia Splenomegaly Intestinal obstruction Abdominal masses Skin lesions Liver enlargement Ascites Bleeding: • Rectal • Urinary tract • Vaginal Thrombosis
Paraneoplastic syndromes
Distant effects of a tumor that are unrelated to metastasis
b. Epidemiology of paraneoplastic syndromes
(1) Predate the onset of metastasis
(2) Occur in 10% to 15% of cancer patients
(3) Involve multiple organ systems and mimic metastatic disease
(4) Some cancers may ectopically secrete hormones
Acanthosis nigricans
Stomach carcinoma Black, verrucous lesion
Eaton-Lambert syndrome
Small cell carcinoma of lung Myasthenia gravis–like symptoms (e.g., muscle weakness);
antibody directed against calcium channel
Hypertrophic osteoarthropathy
Bronchogenic carcinoma Periosteal reaction of distal phalanx (often associated with clubbing of nail)
Nonbacterial thrombotic endocarditis
Mucus-secreting pancreatic and
colorectal carcinomas
Sterile vegetations on mitral valve
Seborrheic keratosis
Stomach carcinoma Sudden appearance of numerous pigmented seborrheic
keratoses (Leser-Trélat sign)
Superficial migratory thrombophlebitis
Pancreatic carcinoma Release of procoagulants (Trousseau sign)
Nephrotic syndrome
Lung, breast, stomach carcinomas Diffuse membranous glomerulopathy
Hypertrophic osteoarthropathy
clubbing. Note the bulbous swelling of the connective tissue in the terminal phalanxes.
B, Hypertrophic osteoarthropathy of the tibia showing periosteal elevation
of the tibia
Cushing syndrome
Small cell carcinoma of lung, medullary carcinoma of thyroid, pancreatic cancer ACTH
Gynecomastia
Choriocarcinoma (testis), seminoma hCG
Hypercalcemia •
Renal cell carcinoma, primary squamous cell carcinoma of lung, breast
carcinoma, adult T-cell leukemia/lymphoma - PTH-related protein
Malignant lymphomas (contain 1α-hydroxylase) - Calcitriol (vitamin D)
Hypocalcemia
Medullary carcinoma of the thyroid Calcitonin
Hypoglycemia
Hepatocellular carcinoma, ovarian carcinoma, fibrosarcoma Insulin-like factor
Hepatocellular carcinoma,
ovarian carcinoma, fibrosarcoma Insulin-like factor
Secondary polycythemia
Renal cell carcinoma, hepatocellular carcinoma, cerebellar hemangioma Erythropoietin
AFP
Hepatocellular carcinoma, yolk sac tumor (endodermal sinus tumor) of ovary or testis
Bence Jones protein (light chains)
Multiple myeloma, Waldenström macroglobulinemia (represent light chains in urine)
CA 15-3
Breast cancer
CA19-9
Pancreatic, colorectal carcinomas
CA125
Surface-derived ovarian cancer (e.g., serous cystadenocarcinoma; helpful in distinguishing benign
from malignant tumors)
CEA
Colorectal and pancreatic carcinomas (monitor for recurrences); cancers of lung, stomach, heart
LDH
Malignant lymphoma (prognostic factor for response to standard therapy)
Neuron specific enolase
Small cell carcinoma of lung
PSA
Prostate carcinoma (also increased in prostate hyperplasia)
Biological markers of cancer include
hormones, enzymes, oncofetal antigens,
immunoglobulins, and glycoproteins
Cytokeratin stain positive
epithelial tissue origin
Vimentin stain positive
connective tissue origin
CD45 positive
malignant lymphoma
Epithelial Dysplasia commonly leads to the development of__________________ It should be immediately treated by_________________
Carcinomas, Excision
