chapter 7
Intro + mod 1-
• Introduction
• Cancer remains one of the leading causes of death in the United States and a major public health issue worldwide.
• The diagnosis of cancer evokes significant fear despite advances in prevention, early detection, and treatment.
• Oncology is the study of cancer and includes prevention, diagnosis, and treatment.
• Cellular Proliferation
• Cellular proliferation is the generation of new daughter cells from progenitor (parent) cells.
• Meiosis is the process of dividing germ cells, producing oocytes and sperm.
• Mitosis is the division and proliferation of all other nongerm cells.
• Proliferation through mitosis occurs continuously and/or in response to physiologic need.
• Epithelial cells of the skin continuously reproduce to replace cells damaged by the environment.
• Proliferation rates increase during wound healing to replace injured tissue.
• Red blood cells (RBCs) are replaced at the end of their 120-day lifespan.
• RBC proliferation increases exponentially after excessive blood loss to maintain blood volume and tissue oxygenation.
• A regulated balance between cell growth and cell death is required to maintain homeostasis.
• Loss of regulated cell division leads to overproliferation and cellular crowding.
• Differentiation
• Differentiation is the orderly process of cellular maturation that results in achievement of a specific function.
• Regulation of proliferation and differentiation is controlled by genes, growth factors, nutrients, and environmental stimulation.
• A balance between differentiated cells and undifferentiated cells is required to meet physiologic demands.
• Stem cells are highly undifferentiated cells capable of dividing into progenitor cells.
• Stem cells divide into like stem cells and progenitor (parent) cells.
• Progenitor cells continue dividing and further differentiate into daughter cells.
• Daughter cells mature into highly specialized, functional cells.
• Undifferentiated cells possess flexibility and adaptability.
• With each step toward differentiation, flexibility decreases while specialized function increases.
• During extensive blood loss, daughter cells differentiate into RBCs to restore circulating volume.
• Loss of differentiation renders cells incapable of performing designated physiologic functions.
• Altered Cellular Proliferation and Differentiation
• Cancer occurs at the cellular level because of gene malfunction that goes unrepaired.
• Cancer develops when genes controlling cell reproduction, growth, differentiation, and death are altered.
• Altered proliferation permits uncontrolled cell growth.
• Altered differentiation results in loss of specialized function.
• Cancer cells fail to undergo expected cell death.
• Neoplasms are irreversible, deviant cell clusters that grow autonomously.
• Cancer describes highly invasive and destructive neoplasms.
• Neoplastic cells ignore genetic controls regulating proliferation and differentiation.
• Neoplasms may arise from proliferating parenchymal cells (functional tissue) or stromal cells (supportive tissue).
• Rapidly dividing labile cells (e.g., epithelial cells, blood cells) are highly prone to neoplasm formation.
• Permanent cells (e.g., cardiac myocytes, mature neurons, lens cells) are not prone to neoplastic development.
• Carcinogenesis
• Carcinogenesis is the origin and development of cancerous neoplasms.
• Carcinogenesis is heavily influenced by mutations, gene variants, and epigenetic changes.
• Mutations are abnormal changes in the DNA of a gene.
• Two major types of gene mutations influence cancer development:
• Inherited (germ-line) mutations
• Present in the oocyte or sperm before fertilization.
• Account for approximately 5% of cancers.
• Exhibit incomplete penetrance; not all individuals with the mutation develop cancer.
• Individuals inherit one defective gene copy, increasing susceptibility.
• Additional mutations increase cancer risk and earlier onset.
• Present in all cells, including germ cells, and can be transmitted to offspring.
• Acquired (somatic) mutations
• Occur after fertilization.
• Account for approximately 95% of cancers.
• May result from environmental exposures or unknown causes.
• Both gene copies must mutate for loss of regulation.
• Accumulate over time, often manifesting later in life.
• Passed to daughter cells but not to subsequent generations.
• Genetic Mutations and DNA Repair
• DNA is continuously damaged by environmental factors.
• Mutator genes repair DNA and protect genomic integrity.
• Disabling DNA-repair mechanisms allows mutations to persist.
• Unrepaired mutations create genomic instability conducive to neoplastic transformation.
• Multiple gene categories typically require mutation for neoplasia to develop.
• The mutation–transformation–neoplasia sequence is unique to each cancer type and may take years.
• Conceptual sequence of genomic cancer mechanisms:
• Carcinogenic agent → DNA damage
• Failure of DNA repair
• Mutation in cell genes
• Activation of growth-promoting oncogenes
• Inactivation of tumor suppressor genes
• Disruption of apoptosis control
• Unregulated growth and differentiation
• Cancer formation
• Oncogenes
• Oncogenes are mutated genes capable of causing cancer.
• Oncogenes promote unregulated cell growth and may inhibit cell death.
• Germ-line oncogene activation is often incompatible with life.
• Most oncogene activation occurs in somatic cells.
• Oncogenes arise from mutation of protooncogenes, which are normal regulatory genes.
• Protooncogenes may convert into oncogenes by:
1. Point mutation — alteration of a single nucleotide base pair producing abnormal proteins.
2. Translocation — chromosomal breakage and reattachment to another chromosome causing excessive protein production.
3. Gene amplification — accelerated replication of genes leading to overproduction of gene products.
• Translocations are commonly associated with leukemias, lymphomas, and solid tumors.
• Gene amplification correlates with poor prognosis in certain solid tumors.
• Oncogene transformation mechanisms include:
• Encoding growth factors
• Disrupting cell surface receptor signaling
• Altering nuclear proteins regulating cell cycle and apoptosis
• Viral oncogenes insert viral DNA into host genetic material, altering regulation.
• More than 40 human oncogenes have been identified.
• Tumor Suppressor Genes
• Tumor suppressor genes regulate cell division and apoptosis.
• They maintain optimal cell number for homeostasis.
• Mutation inactivates tumor suppressor genes, permitting uncontrolled growth.
• Loss of tumor suppressor function leads to cellular “immortality.”
• These mutations may occur in germ-line or somatic cells.
• TP53 gene
• Located on chromosome 17.
• Opposes cell division in response to DNA damage.
• Delays cell cycle to allow DNA repair.
• Initiates apoptosis if repair fails.
• Deletion or mutation is common in colorectal and other cancers.
• Loss permits replication of damaged DNA.
• Rb gene
• Suppresses tumor proliferation.
• Mutation leads to retinoblastoma.
• Follows dominant inheritance when germ-line.
• Associated with other cancers (osteosarcoma, breast, pancreatic, lung).
• BCL-2 gene
• Inhibits apoptosis.
• Mutation causing persistent activation prevents normal cell death.
• Leads to accumulation of immortal cells.
• Implicated in certain leukemias.
• Genetic testing
• Analyzes DNA for mutations linked to specific cancers.
• Can confirm mutation presence but does not guarantee disease development.
• Emotional and psychological consequences may be significant.
• Gene Variants and Epigenetics
• Gene variants (polymorphisms) are inherited nucleotide differences that are not mutations.
• Single nucleotide polymorphisms may alter gene function modestly.
• Variants may influence hormone levels and cancer susceptibility.
• Variants do not directly cause cancer but may predispose cells to neoplasia.
• Epigenetic changes alter gene expression without DNA sequence mutation.
• Mechanisms include:
• DNA methylation
• Histone modification
• RNA interference
• These processes activate or deactivate genetic material regulating growth and division.
• Genetic mutations, gene variants, and epigenetic changes are necessary but not sufficient alone for invasive cancer.
• Additional host genetic alterations influenced by carcinogens are required.
• Carcinogens
• A carcinogen is a cancer-causing agent.
• Carcinogens initiate or promote tumor formation by interfering with molecular pathways.
• Direct carcinogens modify DNA.
• Indirect carcinogens induce immunosuppression or chronic inflammation.
• Known carcinogenic exposures include:
• Radiation
• Reactive oxygen species
• Hormones
• Tobacco
• Infectious microorganisms
• Chemicals
• Cancer often has a prolonged latent period between initiation and clinical manifestation.
• Radiation
• Ionizing radiation includes gamma rays, x-rays, and ultraviolet rays.
• Produces reactive oxygen species that damage plasma membranes and DNA.
• Can directly kill cells or induce mutations.
• Labile cells are most affected.
• Radiation therapy exploits high proliferative rates of cancer cells.
• Ultraviolet radiation (290–320 nm) induces mutation and cell death.
• Risk depends on exposure duration, burn frequency, and skin tone.
• Hormones
• Certain tumors depend on hormones for growth.
• Tumors of breast, uterus, prostate, and adrenal glands contain hormone receptors.
• Hormones may promote or treat cancer.
• Corticosteroids can kill lymph cells and inhibit mitosis.
• Hormone manipulation (e.g., estrogen blockade with tamoxifen) can inhibit tumor growth.
• Removal of hormone-secreting tissues alters tumor growth dynamics.
• Chemicals
• Carcinogenic chemicals include tobacco, asbestos, benzene, insecticides, and formaldehyde.
• Mechanisms involve free radical formation and interference with cellular proteins and enzymes.
• Enzymes metabolize and inactivate carcinogens.
• Genetic, environmental, and lifestyle factors influence enzyme activity and susceptibility.
• Tobacco
• Cigarette tar contains thousands of carcinogenic substances.
• Smoking causes approximately one in five deaths annually in the United States.
• Smokers die approximately 10 years earlier than nonsmokers.
• Tobacco causes lung cancer and promotes laryngeal, lip, esophageal, and bladder cancers.
• Exhibits dose-dependent risk.
• Microbes
• Viral infections account for approximately 15% of human cancers.
• Human papillomavirus (HPV) is linked to cervical cancer.
• Hepatitis B and C viruses are linked to hepatocellular carcinoma.
• Retroviruses (e.g., HIV) alter gene regulation and suppress immunity.
• Helicobacter pylori is linked to gastric cancer.
• Chronic inflammation supports tumor growth.
• Initiation–Promotion–Progression Theory
• Carcinogenesis requires multiple steps.
• Initiation involves exposure to a carcinogenic agent causing DNA mutation.
• Promotion is expansion and proliferation of mutated cells.
• Promotion depends on continued exposure to the promoting agent.
• Chronic inflammation is a common promoter.
• Progression is acquisition of autonomous growth independent of promoter exposure.
• Cancer does not develop if initiation or promotion occurs alone.
• Promotion before initiation does not result in cancer.
Module 2
The Impact of Cancer on Tissues, Organs, and Organ Systems
• Neoplasms exhibit autonomy and anaplasia.
• Autonomy refers to unregulated proliferation of neoplastic cells.
• Anaplasia refers to loss of cellular differentiation and subsequent loss of cell function.
• The greater the degree of anaplasia, the more aggressive and malignant the tumor.
• Cells with marked anaplasia demonstrate wide variation in size and shape.
• Anaplastic cells show enlarged nuclei and rapid, atypical mitosis.
Figure — Cellular Anaplasia
• Illustration demonstrates cells with variable size and shape.
• Enlarged nuclei and atypical mitotic figures are evident.
• Visual reinforces morphologic correlation between anaplasia and malignancy.
• Instructors test recognition that nuclear enlargement and pleomorphism correlate with tumor aggressiveness.
Additional Characteristics of Neoplasms
• Loss of cell-to-cell communication permits unrestricted tumor growth.
• Increased energy expenditure deprives surrounding normal cells of nutrients.
• Increased motility and decreased cohesion/adhesion facilitate tumor migration.
• Rapid angiogenesis supports nutrient delivery to proliferating tumor cells.
• Tumor cells secrete substances that alter metabolism and degrade adjacent tissues.
• Cancer cells express foreign antigens that may trigger immune responses.
• Normal proliferating cells are sensitive to neighboring cells and cease reproduction once contact is established.
• Neoplastic cells do not respond to inhibitory cell-to-cell contact signals.
• Deviant growth factors promote rapid reproduction and angiogenesis.
• Increased tumor blood flow diverts oxygen and nutrients from neighboring tissues.
• Resultant ischemia and necrosis occur in adjacent normal tissues.
• Tumor-secreted enzymes degrade extracellular matrix, facilitating invasion.
• Neoplastic cells may be eliminated by inflammatory and immune responses.
• Immunodeficiency increases risk for cancer development.
Benign Versus Malignant
• Tumors are classified as benign or malignant based on location and appearance relative to tissue of origin.
• Benign tumors remain localized and resemble the tissue of origin.
• Benign tumors demonstrate proliferation without significant loss of differentiation.
• Large benign tumors may impinge on structures, obstruct vital functions, and cause death.
• Some benign growths (e.g., polyps, skin tags) are tumors but not true neoplasms.
• Malignant tumors are invasive and destructive.
• Malignant tumors proliferate rapidly and metastasize.
• Malignant tumors do not resemble the tissue of origin.
• Malignancies promote ischemia and necrosis due to excessive nutrient consumption.
• Cancer typically refers to malignant neoplasms.
Figure — Benign vs Malignant
• Benign tumor: slow-growing mass without invasion.
• Malignant tumor: aggressive growth with invasion into tissues and vessels.
• Visual emphasizes invasion and vascular penetration as hallmarks of malignancy.
Cancer Spread
Local Spread
• Local spread is proliferation within the tissue of origin.
• Tumor enlargement leads to loss of organ function.
• Obstruction, hemorrhage, and necrosis may result.
• Tumor remains confined in early stages.
• Localized growth carries more favorable prognosis.
Direct Extension
• Direct extension involves tumor invasion into adjacent tissues and organs.
• Penetration of the basement membrane is the first step in epithelial tumors.
• Tumors lacking basement membrane encounter less resistance to invasion.
• Tumor cells adhere to extracellular matrix via adhesion molecules.
• Enzymes are released to dissolve extracellular matrix.
• Tumor cells move into adjacent tissues and repeat degradation and invasion.
• Seeding describes dissemination of tumor cells to secondary sites within cavities.
• Peritoneal and pleural cavities facilitate tumor spread along membranes.
Metastases
• Metastases occur when tumors spread to distant sites via lymphatics or blood.
• Metastatic growth is the lethal component of cancer.
• Distant spread complicates detection and treatment.
Figure — Metastatic Spread
• Demonstrates primary tumor breaching extracellular matrix.
• Shows tumor entry into vascular system.
• Illustrates tumor cell interaction with platelets and host lymphocytes.
• Displays angiogenesis at metastatic site.
• Visual sequence tested as invasion → circulation → extravasation → angiogenesis.
Mechanism of Metastasis
Basement membrane and extracellular matrix degradation.
Entry into blood or lymph circulation.
Exit from circulation and adhesion to distant tissue.
Establishment of angiogenesis at distant site.
• Lymphatic capillaries are thinner and more easily invaded.
• Tumor binds endothelial cells and degrades vessel wall.
• If immune defenses fail, tumor establishes distant proliferation.
• Tumor secretes growth factors to promote angiogenesis at new site.
Organ Tropism
• Organ tropism describes affinity of tumors for specific distant sites.
• Determined by:
1. Favorable environment of target tissue.
2. Adhesion molecule compatibility.
3. Vascular flow patterns.
• Colon tumors commonly metastasize to liver via portal circulation.
• Lung frequently involved due to vena cava transport.
• Breast and prostate tumors often metastasize to bone.
Cancer Nomenclature
• Tumor names often use suffix “-oma.”
• Benign tumors combine tissue prefix + “-oma.”
• Epithelioma (squamous epithelium).
• Papilloma (fingerlike epithelial projections).
• Adenoma (glandular).
• Teratoma (germ cell).
• Osteoma (bone).
• Chondroma (cartilage).
• Malignant epithelial tumors use “carcin” + “-oma” → adenocarcinoma.
• Malignant connective tissue tumors use “sarc” + “-oma” → chondrosarcoma.
• Exceptions include lymphoma, melanoma, leukemia, hepatoma (malignant).
Table — Tumor Nomenclature
• Epithelial: Papilloma → Squamous cell carcinoma; Adenoma → Adenocarcinoma.
• Endothelial: Hemangioma → Hemangiosarcoma; Lymphangioma → Lymphangiosarcoma.
• Connective: Fibroma → Fibrosarcoma; Lipoma → Liposarcoma; Chondroma → Chondrosarcoma; Osteoma → Osteosarcoma.
• Muscle: Leiomyoma → Leiomyosarcoma; Rhabdomyoma → Rhabdomyosarcoma.
• Neural: Glioma → Glioblastoma, astrocytoma, medulloblastoma, oligodendroglioma; Meningioma → Meningeal sarcoma.
• Blood: Myelocytic leukemia; Polycythemia vera; Multiple myeloma; Lymphocytic leukemia or lymphoma.
• Carcinoma in situ describes epithelial carcinoma confined above the basement membrane.
• Tumor remains in original location.
• Often asymptomatic.
• Detection at this stage yields favorable prognosis.
• Once basement membrane is penetrated, metastasis may occur.
Cancer Classifications
Staging
• Staging classifies tumor size, location, lymph node involvement, and spread.
• Higher stage number indicates greater size and spread.
• Guides treatment decisions.
TNM Classification
• T = primary tumor size.
• N = regional lymph node involvement.
• M = distant metastases.
Table — TNM Classification
• TX: Tumor cannot be measured.
• T0: Tumor not found.
• Tis: Carcinoma in situ.
• T1–T4: Increasing size/extent.
• NX: Nodes cannot be measured.
• N0: No nodal involvement.
• N1–N3: Increasing nodal involvement.
• MX: Metastasis cannot be measured.
• M0: No distant metastasis.
• M1: Distant metastasis present.
Tumor Grading
• Grading assesses degree of anaplasia.
• Grade I: Well differentiated.
• Grade II: Moderately differentiated.
• Grade III–IV: Highly undifferentiated.
• Higher grade = greater deviation from tissue of origin.
Cancer Prognosis
• Influenced by tumor type, location, stage, age, overall health, and treatment response.
• Expressed as 5-year survival rate.
• Includes cancer-free, remission, and living-with-cancer individuals.
General Manifestations
Early Manifestations
• Result from inflammatory and immune responses.
• Result from increased metabolic rate.
• Result from local tissue encroachment.
• Result from paraneoplastic syndromes.
Inflammatory and Immune Responses
• Lymphadenopathy due to lymphocyte hyperplasia.
• Supraclavicular nodes act as sentinel nodes.
• Fever due to pyrogen release.
• Anorexia from inflammatory mediators and altered taste.
• Increased metabolic demand leads to weight loss.
Cachexia
• Cachexia is severe wasting syndrome.
• Caused by early satiety and inflammatory mediators such as tumor necrosis factor.
• Tumor necrosis factor suppresses fatty acid mobilization.
• Lipid energy becomes unavailable, promoting tissue wasting.
Figure — Cachexia
• Demonstrates profound tissue wasting in pancreatic carcinoma.
• Reinforces metabolic basis beyond simple appetite loss.
Local Manifestations
• Space-occupying tumor mass.
• Loss of organ function.
• Bleeding, bruising, poor wound healing.
• Bone marrow crowding suppresses RBC and platelet production.
• Anemia and clotting abnormalities occur.
• Palpable masses common in breast, testicle, lymph nodes.
• Compression pain: headache, bone pain, abdominal pain.
• Organ-specific symptoms (e.g., constipation, hemoptysis).
ABCDE Warning Signs of Skin Cancer
• Asymmetry
• Border irregularity
• Color variation
• Diameter >6 mm
• Elevation change
Paraneoplastic Syndromes
• Hormonal, neurologic, hematologic, chemical disturbances.
• Not directly due to invasion or metastasis.
• Ectopic hormone secretion outside endocrine glands.
• Hormones not under feedback control.
• Excess ADH causes water retention, edema, coma.
• Neurologic disturbances from fluid imbalance or vascular compromise.
Diagnostic Tests
• Imaging: x-ray, endoscopy, ultrasound, CT, MRI.
• Biopsy and cytology confirm diagnosis.
• Tumor markers detected in blood, urine, or tissue.
Tumor Markers
• May be produced by tumor or host response.
• PSA elevated in prostate conditions.
• CA 125 elevated in ovarian and other cancers and noncancerous conditions.
• CEA used for colorectal monitoring; elevated in multiple cancers and inflammatory states.
• Not diagnostic alone; trends over time are most informative.
Cancer Treatment
Treatment Goals
Eradication.
Control of growth/spread.
Symptom reduction.
Strategies
• Surgery removes tumor or affected tissue.
• Chemotherapy interrupts tumor growth.
• Radiation damages DNA and prevents replication.
• Biologic response modifiers alter immune response.
• Hormones manipulate tumor growth.
• Bone marrow and stem cell transplantation restore blood cells.
Table — Treatment Strategies
• Surgery: removal; complications include bleeding, infection.
• Chemotherapy: systemic; nausea, hair loss, immunosuppression.
• Radiation: external/internal; skin damage, organ fibrosis.
• Biologic response modifiers: immune modulation; fever, fatigue.
• Hormones: receptor targeting; exaggerated hormone effects.
Palliative Care
• Symptom management without cure.
• Addresses fatigue, nausea, pruritus, diarrhea.
• Provides psychosocial and nutritional support.
Cancer Prevention
• Avoid carcinogens.
• Exercise and balanced diet.
• Vaccination (e.g., hepatitis B).
• Sunscreen and protective clothing.
• Tobacco and alcohol avoidance.
• Prevention linked to lifestyle factors and obesity.
Immunotherapy
• Immune checkpoint inhibitors block inhibitory immune signals.
• Immune modulators enhance immune responses.
• Monoclonal antibodies target specific cancer cells.
• T-cell transfer therapy expands tumor-targeting T cells.
• Treatment vaccines boost immune response against cancer.
Children and Cancer
• Leading disease-related cause of death ages 1–14.
• Most childhood cancers originate from ectodermal and mesodermal germ layers.
• Developmental pliancy influences susceptibility.
• Common types: leukemia, brain tumors, neuroblastoma, Wilms tumor, Hodgkin lymphoma, non-Hodgkin lymphoma, rhabdomyosarcoma, retinoblastoma, osteosarcoma, Ewing sarcoma.
• Often genetic or epigenetic in origin.
• Warning signs: mass, pallor, bruising, pain, limping, fever, headaches, vision changes, rapid weight loss.
• 5-year survival rate exceeds 75%.
module 3
The following clinical models apply knowledge related to altered cellular proliferation and differentiation.
• Common features across tumor types include cellular autonomy and anaplasia.
• Differences in clinical manifestations and diagnosis depend on tumor type and anatomic location.
Lung Cancer
• Lung cancer is the leading cause of cancer deaths worldwide.
• Smoking and environmental toxin exposures are strongly implicated in carcinogenesis.
Pathophysiology
• Lung cancer most often results from environmental toxin exposure combined with genetic susceptibility.
• Active smoking accounts for approximately 90% of cases.
• Most remaining cases are associated with occupational exposures such as asbestos and radon.
• A small percentage have no known environmental trigger.
• Repeated toxin exposure causes DNA damage.
• Mutations commonly occur in the ras family of oncogenes, Rb, p53, and other tumor suppressor genes.
• In adenocarcinoma, ras gene activation contributes to tumor progression.
• Two major categories exist:
Non–Small Cell Lung Cancer (85%)
• Adenocarcinoma is the most common form in the United States.
• Develops in peripheral bronchiolar and alveolar tissue.
• Leads to pleural fibrosis and adhesions.
Figure 7.10 — Adenocarcinoma of the Lung
• Shows tumor in upper right lobe.
• Demonstrates peripheral bronchiolar and alveolar origin.
• Illustrates relationship to pleural structures.
• Tested concept: peripheral origin and pleural involvement.
• Squamous cell carcinoma begins with injury to bronchial columnar epithelium.
• Smoking causes squamous metaplasia.
• Progression: metaplasia → dysplasia → carcinoma in situ → invasive tumor.
• Large cell carcinoma includes tumors that are neither adenocarcinoma nor squamous cell.
• Cells are large and highly anaplastic.
Small Cell Lung Cancer (15%)
• Highly malignant epithelial tumor.
• Grows rapidly and metastasizes early.
• Strongly linked to smoking.
• All forms can penetrate epithelial layers.
• Tumors invade lung tissue, pleural cavity, chest wall, and beyond.
• Large tumors may compress cervical and thoracic nerves.
• Spread occurs via lymphatics and blood.
• Organ tropism includes bone, liver, and brain.
Clinical Manifestations
• Persistent cough.
• Hemoptysis (bloody sputum).
• Chest pain.
• Shortness of breath.
• Symptoms often attributed to smoker’s cough or bronchitis.
• Systemic manifestations and paraneoplastic syndromes may occur.
Diagnostic Criteria
• Physical examination.
• Complete blood count.
• Chest x-ray.
• Bronchoscopy.
• Sputum cytology.
• Tissue biopsy confirms cell type.
Staging
• Stage I: confined to lungs, no lymph nodes.
• Stage II: lung and nearby lymph nodes.
• Stage III: lung and mediastinal lymph nodes.
• Stage IV: spread to both lungs, pleural fluid, or distant organs.
• Most diagnoses occur at stage III or IV.
Treatment
• Based on tumor type (small cell vs non–small cell).
• Small cell:
• More responsive to chemotherapy.
• Often widely disseminated at diagnosis.
• Surgery and radiation rarely improve long-term survival.
• Non–small cell:
• Surgical resection if possible.
• Surgery alone or surgery plus chemotherapy may cure.
• If unresectable, radiation provides local control.
• Five-year survival:
• 49% localized.
• 16% regional.
• 2% distant metastasis.
Colon Cancer
• Most common GI tract cancer.
• Multifactorial origin: genetic, environmental, dietary.
• Increased risk with chronic inflammatory GI conditions.
Pathophysiology
• Primary risk factor: age over 50.
• Risk factors include:
• Family history.
• Smoking.
• Alcohol.
• Chronic inflammatory bowel disease.
• Obesity.
• Physical inactivity.
• High-fat, low-fiber diet.
• Fiber binds carcinogens and increases transit time.
• Bile acids promote tumors in colon.
• Protective nutrients: selenium, vitamins A/C/E, cruciferous vegetables.
• Tumors range from benign polyps to invasive adenocarcinomas.
Classification:
Nonneoplastic polyps.
Neoplastic adenomatous polyps.
Adenocarcinomas.
• Average nine major mutations in cancerous tumors.
• Five to seven mutations needed for malignancy.
Two pathways:
Chromosomal instability (85%).
Replication errors (15%).
• Chromosomal instability includes:
• Aneuploidy.
• Deletions (5q, 18q, 17p).
• KRAS mutation.
• Early event: loss of APC tumor suppressor gene.
• APC mutation leads to adenomatous polyps.
• Additional mutations include DCC and p53 deletion.
• Replication errors involve defective DNA repair with intact chromosomes.
• Transformation begins at base of colonic crypts.
• Mitosis occurs at crypt base.
• Cells migrate upward and normally undergo apoptosis.
• Tumor cells resist apoptosis and accumulate.
Figure 7.11 — Adenomatous Polyp to Adenocarcinoma
• Transformation at crypt base.
• Resistance to apoptosis.
• Formation of adenomatous polyp.
• Progression to adenocarcinoma.
• Tested concept: APC mutation and stepwise mutation model.
Clinical Manifestations
• Often asymptomatic early.
• Occult blood in ascending colon tumors.
• Visible blood in descending/rectal tumors.
• Abdominal pain.
• Bowel obstruction.
• Anemia.
• Change in bowel habits.
• FOBT and guaiac detect occult blood.
Diagnostic Criteria
• Colonoscopy every 10 years beginning at age 50.
• CBC.
• Liver function tests (liver tropism).
• Serum CEA.
• Sigmoidoscopy.
• Biopsy.
• Modified TNM used.
• Staging based on bowel wall penetration.
• Liver common metastatic site.
Table 7.4 — TNM for Colorectal Cancer
• Tumor penetration depth emphasized.
• N and M similar to classic TNM.
Treatment
• Surgical resection.
• Cure in ~50% localized cases.
• Advanced disease treated with combination chemotherapy, biologics, radiation.
• Five-year survival:
• 90.2% localized.
• 71.8% regional.
• 14.3% distant.
Brain Cancer
• Feared due to neurologic disability.
• Common in children (second to leukemia).
• Most brain cancers are metastatic.
• Ionizing radiation increases risk.
Pathophysiology
• 95% include:
• Brain metastases.
• Gliomas.
• Meningiomas.
• Pituitary adenomas.
• Acoustic neuromas.
• Adults: supratentorial tumors.
• Children: infratentorial tumors.
Figure 7.12 — Intracranial Tumor Distribution
• Most arise in cerebral hemispheres.
• Demonstrates supratentorial vs infratentorial distribution.
• Gliomas (astrocytomas) most common primary tumor.
• p53 mutations or 17p13.1 deletion in diffuse astrocytomas.
• 20% well differentiated.
• 40% highly undifferentiated.
• Rarely metastasize outside CNS.
• Prognosis based on anaplasia.
• TNM not used because:
• Location more important than size.
• Historically thought no CNS lymphatics.
• Short survival limits metastasis.
• WHO classification used.
Table 7.5 — WHO CNS Tumor Grading
• Based on morphology, mitotic activity, necrosis, angiogenesis, genetics, molecular markers.
Clinical Manifestations
• Depend on size and location.
• Neurologic deficits.
• Vision changes.
• Weakness or paralysis.
• Cognitive and behavioral changes.
• Increased intracranial pressure → headache, vomiting.
• Seizures.
• Compression of respiratory/cardiac centers → death.
Diagnostic Criteria
• Neurologic examination.
• CT, MRI, radiographs.
• Cerebral angiography.
• PET scan.
• Spectroscopy for metastasis differentiation.
Treatment
• Surgical resection when feasible.
• Radiation therapy.
• Intrathecal chemotherapy for certain tumors.
• Local chemotherapy during surgery.
• Whole brain radiation for metastases.
• Anticonvulsants for seizure management.
Leukemia
• Malignant neoplasm of blood-forming organs.
• Replaces bone marrow with immature blasts.
• Blasts circulate in blood.
• DNA changes from radiation, chemicals, chromosomal abnormalities.
• Classified as acute or chronic.
• Classified as lymphoid or myeloid.
Acute Leukemias
• ALL common in children.
• AML common in adults.
Figure 7.13 — Acute Lymphoblastic Leukemia
• Shows lymphoblasts with irregular nuclei.
• Demonstrates immature blast morphology.
Pathophysiology
• Blasts replace marrow elements.
• Decreased functional WBCs, RBCs, platelets.
• Spread to liver, spleen, lymph nodes.
Clinical Manifestations
• Infections.
• Anemia.
• Bleeding, epistaxis.
• Bone pain.
• CNS infiltration → headache, seizures, coma.
• Hepatosplenomegaly.
• Fever, weight loss.
Diagnostic Criteria
• Blast count >20%.
• Microscopic analysis.
Treatment
• Combination chemotherapy.
• Intrathecal chemotherapy for ALL.
• Induction, intensification, maintenance.
• Goal: remission (<5% blasts).
• ALL 5-year survival >80% children.
• AML remission ~70% adults.
Chronic Leukemias
• CLL and CML common in older adults.
Figure 7.14 — Chronic Lymphocytic Leukemia
• Shows numerous small lymphocytes.
Pathophysiology
• CLL: deletion 13q, p53 loss, trisomy 12.
• CML: 9;22 translocation → Philadelphia chromosome.
• BCR-ABL tyrosine kinase activation.
Clinical Manifestations
• Fatigue.
• Lymphadenopathy.
• Hepatosplenomegaly.
• Infection.
• Weight loss.
• Bone pain.
Diagnostic Criteria
• Elevated WBC.
• Bone marrow biopsy.
• Cytologic analysis for chromosomal abnormalities.
Treatment
• Early CLL often untreated until symptomatic.
• Stem cell transplantation may cure >50%.
• Immediate chemotherapy if WBC >100,000/mm³.
• Splenectomy if massive enlargement.
• Median survival 5–10 years.
Lymphomas
• Malignant lymphocytes forming solid tumors in lymph tissue.
• Classified as Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL).
Hodgkin Lymphoma
• Painless cervical lymphadenopathy.
• Risk factors: EBV, genetics, immunosuppression.
• Peaks at 10–30 years and >50 years.
Pathophysiology
• Presence of Reed-Sternberg cells.
• Derived from B lymphocytes.
Figure 7.15 — Reed-Sternberg Cell
• Large, multinucleated with eosinophilic nucleoli.
• Diagnostic feature of HL.
• Five subtypes listed.
• Organ tropism: lung, liver, bone, bone marrow.
Clinical Manifestations
• Enlarged rubbery nodes.
• Fever.
• Night sweats.
• Weight loss.
• Pruritus.
• Mediastinal mass.
Diagnostic Criteria
• Reed-Sternberg cells present.
• Ann Arbor staging I–IV.
Treatment
• Stage I–II: chemotherapy ± radiation.
• Stage III–IV: combination chemotherapy.
• 5-year survival ~85%.
Non-Hodgkin Lymphoma
• Broad range of B- and T-cell malignancies.
• More common than HL.
• No Reed-Sternberg cells.
• Often noncontiguous node involvement.
Pathophysiology
• Variable mutations.
• 85% B-cell origin.
• Organ tropism: liver, spleen, bone marrow.
Clinical Manifestations
• Painless lymphadenopathy.
• Fever.
• Night sweats.
• Weight loss.
• Infection risk.
Diagnostic Criteria
• Lymph node biopsy.
• CT scans.
• CSF analysis for aggressive types.
Treatment
• Indolent vs aggressive classification.
• Early indolent → radiation.
• Advanced → combination chemotherapy ± stem cell transplant.
• 5-year survival ~60%.
Summary
• Neoplasia results from disordered proliferation and differentiation.
• Mutations in growth-regulating genes drive transformation.
• Carcinogenesis is multistage.
• Carcinogens include radiation, ROS, hormones, tobacco, microbes, chemicals.
• Latent period often prolonged.
• Neoplastic cells are autonomous and anaplastic.
• Spread via lymphatics and blood.
• Metastasis contributes to lethality.
• Treatment includes surgery, chemotherapy, radiation, hormones, immunotherapy.