Concise Exam Notes on Neoplasia

Learning Objectives

• Define neoplasm and differentiate neoplastic growth from normal adaptive changes (atrophy, hypertrophy, hyperplasia).
• Describe the phases of the cell cycle.
• Relate cell differentiation properties to cancer cell clone development and tumor behavior.
• Trace the pathway for hematologic spread of metastatic cancer cells.
• Explain cancerous tissue growth using growth fraction and doubling time concepts.
• Describe cancer-associated genes and cellular/molecular pathways.
• Describe genetic events and epigenetic factors in tumorigenesis.
• State the importance of cancer stem cells, angiogenesis, and cell microenvironment in cancer growth/metastasis.
• Characterize mechanisms of anorexia/cachexia, fatigue/sleep disorders, anemia, and venous thrombosis in cancer patients.
• Define paraneoplastic syndrome, its pathogenesis, and manifestations.
• Compare cancer screening mechanisms.
• Differentiate curative, control, and palliative cancer treatments, considering risks/benefits.
• Cite common cancers affecting infants, children, and adolescents.
• Describe differences between cancers affecting children and adults.
• Discuss potential long-term effects of radiation/chemotherapy on adult survivors of childhood cancer.
• NURSING CONCEPTS: Cellular Regulation

Concepts of Cell Differentiation and Growth

• Cancer: Altered cell differentiation and growth disorder, resulting in neoplasia (“new growth”).
• Neoplasm development: Uncoordinated and autonomous, lacking normal regulatory controls.
• Normal tissue renewal/repair: Involves cell proliferation and differentiation.
  • Proliferation: Adaptive process for new cell growth.
  • Differentiation: Cells become more specialized with each mitotic division.
• Apoptosis: Programmed cell death eliminating senescent/damaged cells.

The Cell Cycle

• Orderly sequence of events for cell duplication and division.
• Genetic information copied, chromosomes aligned for distribution into daughter cells.
• Four phases: G1, S, G2, and M.
  • G1: RNA and protein synthesis, cell growth.
  • S: DNA synthesis, two chromosome sets develop.
  • G2: RNA and protein synthesis continues.
  • M: Nuclear (mitosis) and cytoplasmic division.
• Interphase: G1, S, and G2 phases.
• Continually dividing cells cycle from one mitotic division to the next.
• G0: Resting state when cells leave the cell cycle due to adverse conditions or specialization.
• Cells in G0 may re-enter the cell cycle with signals like nutrients or tissue injury.
• Highly specialized cells (e.g., neurons) may permanently stay in G0.
• Checkpoints: Pauses in the cell cycle to check DNA replication accuracy, allowing defect repair.
• Cyclins: Proteins controlling cell cycle entry/progression, binding to cyclin-dependent kinases (CDKs).
• Kinases: Enzymes that phosphorylate proteins.
• CDKs: Phosphorylate target proteins, expressed continuously but inactive until bound by cyclins.
• Cyclins: Synthesized during specific phases, degraded after task completion.
• G2 to M transition: Critical checkpoint.
• CDK inhibitors (CKIs): Regulate cell cycle checkpoints.
• Manipulation of cyclins, CDKs, and CKIs: Basis for newer cancer drug therapies.

Cell Proliferation

• Process of increasing cell numbers via mitotic cell division.
• Normal tissue: Cell proliferation is regulated to balance cell division with cell death or shedding.
• Two major cell categories:
  • Gametes (haploid): Ovum and sperm, designed for sexual fusion.
  • Somatic cells (diploid): Formed after fusion, comprise the rest of the body.
• Cell types divided into 3 large groups:
  • Well-differentiated neurons and cardiac muscle cells
  • Progenitor/parent cells (blood, skin, liver): Continually divide and replicate.
  • Undifferentiated stem cells: Triggered to enter the cell cycle and produce progenitor cells.

Cell Differentiation

• Process where proliferating cells become specialized.
• Results in fully differentiated adult cells with specific structural, functional, and life expectancy characteristics.
• Regulated by internal processes (gene expression) and external stimuli (neighboring cells, extracellular matrix, maternal circulation, growth factors, cytokines, nutrients).

Understanding the Cell Cycle

• Cell cycle phases: Synthesis (S), Mitosis (M), Gap 1 (G1), Gap 2 (G2) and dormant phase (G0).
  • S phase: DNA synthesis and chromosome replication occurs.
  • M phase: Mitotic spindle forms and cell division with formation of two daughter cells.
  • G1 phase: Cell prepares for DNA replication and mitosis through protein synthesis.
  • G2 phase: Enzymes and other proteins needed for cell division are synthesized.
  • G0 phase: Cell may leave the cell cycle and either remain in a state of inactivity or re-enter the cell cycle at another time.

Checkpoints and Cyclins

• Checkpoints in the cell cycle can arrest it if events haven't completed.
• G1/S checkpoint monitors DNA damage.
• G2/M checkpoint prevents mitosis if DNA replication is incomplete.
• Cyclins are regulated by CKIs, which regulate DNA repair during checkpoints.

Stem Cells

• Remain incompletely differentiated throughout life.
• Reserve cells that remain dormant until cell replacement is needed.
• Properties: Self-renewal (undergo numerous mitotic divisions while maintaining an undifferentiated state) and potency (differentiation potential).
• Types of stem cells relating to potency (differentiation potential):
  • Totipotent: Immature stem cell capable of differentiating into any cell type, or one that can divide until it creates an entire, complete organism.
  • Pluripotent: Can differentiate into the three germ layers of the embryo but cannot develop into an entire organism.
  • Multipotent: Give rise to only a few cell types.
  • Unipotent: Produce only one cell type but retain self-renewal.
• Types of stem cells relating to origin:
  • Embryonic stem cells: Pluripotent cells derived from the inner cell mass of the blastocyst stage of the embryo.
  • Adult stem cells: Reside in specialized microenvironments and have essential roles in homeostasis.
• Cancer stem cells (tumor-initiating cells): Identified in various cancers like breast, prostate, AML.

Characteristics of Benign and Malignant Neoplasms

• Body organs composed of parenchymal (functional) and stromal (supporting) tissue.
• Tumor: Swelling caused by several conditions, including inflammation and trauma and also used to define a mass of cells that arises because of overgrowth.
• Neoplasms classified as benign or malignant.
  • Benign: Well-differentiated cells clustered in a single mass; typically non-fatal unless interfering with vital functions.
  • Malignant: Less well-differentiated; can break loose, enter circulatory/lymphatic systems, and form secondary tumors (metastasize) at other sites.
• Terminology:
  • Tumors usually named by adding the suffix -oma to the parenchymal tissue type from which the growth originated.
  • Carcinoma: Malignant tumor of epithelial tissue.
  • Sarcomas: Malignant tumors of mesenchymal origin.
  • Papillomas: Benign finger-like projections.
  • Polyp: Growth projecting from a mucosal surface.
  • Oncology: Study of tumors and their treatment.

Benign and Malignant Neoplasms Comparison

Benign Neoplasms

• Well-differentiated cells resemble tissue of origin.
• Slow, progressive growth that may come to a standstill or regress.
• Grow by expansion and are localized to their site of origin, lacking the capacity to infiltrate or metastasize.
• Sharp line of demarcation between the benign tumor and the adjacent tissues, facilitates surgical removal.

Malignant Neoplasms

• Invade and destroy nearby tissue, with the potential to cause death.
• Rapid growth rate.
• May compress blood vessels and outgrow their blood supply, causing ischemia and tissue injury.
• Two categories: solid tumors and hematologic cancers.
  • Solid tumors: Initially confined to a specific tissue or organ, spread is termed metastasis.
  • Hematologic cancers: Involve cells normally found in the blood and lymph; disseminated diseases from the beginning.
• Carcinoma in situ: Localized preinvasive lesion.

Cancer Cell Characteristics

• Abnormal and rapid proliferation and loss of differentiation.
• Anaplasia: Loss of cell differentiation.
• Genetic Instability: High frequency of mutations resulting from mutation phenotype.
• Growth Factor Independence: Ability to proliferate without growth factors.
• Cell Density–Dependent Inhibition: Loss of contact inhibition.
• Anchorage Dependence: Cancer cells remain viable and multiply without attachment to other cells and the extracellular matrix.
• Cell-to-Cell Communication: Faulty cell-to-cell communication, interfering with intercellular connections and responsiveness to signals.
• Life Span: Unlimited lifespan (immortal).
• Antigen Expression: Cancer cells express several cell surface molecules or antigens that are immunologically identified as foreign.
• Production of Enzymes, Hormones, and Other Substances: Cancer cells secrete degradative enzymes that enable invasion and metastatic spread or ectopic production of hormones.
• Cytoskeletal Changes: Cancer cells may show cytoskeletal changes and abnormalities that facilitate invasion and metastasis.

Invasion and Metastasis

• Cancer spreads by direct invasion and extension, seeding cancer cells in body cavities, and metastatic spread through the blood or lymph pathways.
• Seeding of cancer cells into body cavities occurs when a tumor sheds cells into these spaces.
• Metastasis: Development of a secondary tumor in a location distant from the primary tumor.
• Metastasis occurs through the lymph channels (i.e., lymphatic spread) and the blood vessels (i.e., hematogenic spread).

Tumor Growth

• Depends on dividing cells, cell cycle duration, and cell loss vs. new cell production.
• Cancer cells do not die on schedule, and growth factors prevent cells from exiting the cycle cell and entering the G0 phase.
• Growth fraction: Ratio of dividing to resting cells.
• Doubling time: Time to double the total mass of cells in a tumor.

Etiology of Cancer

• Genetic and Molecular Basis of Cancer
  • molecular pathogenesis of most cancers is thought to originate with genetic damage or mutation with resultant changes in cell physiology that transform a normally functioning cell into a cancer cell.
  • Epigenetic factors that involve the silencing of a gene or genes may also be involved in the molecular pathogenesis of cancer
  • essential role of cancer stem cells in cancer pathogenesis has been identified.
  • the cellular microenvironment is now recognized as an essential contributor to cancer development, growth, and progression.

Cancer-Associated Genes

• Cancer-associated genes based on whether gene overactivity or underactivity increases the risk for cancer.
  • Proto-oncogenes --> oncogenes
  • Tumor suppressor genes.

Genetic Events Leading to Oncogene Formation

• Chromosomal translocations: gene is translocated from its normal position on chromosome
• Gene amplification: Multiple copies of specific genes may lead to overexpression, with higher-than-normal levels of proteins that increase cell proliferation.

Genetic Events Leading to Loss of Tumor Suppressor Gene Function

• mutation of tumor suppressor genes = unregulated growth.
• TP53 gene - mutations have been associated with lung, breast, and colon cancer.

Epigenetic Mechanisms

• Silencing genes, such as tumor suppressor genes.
• Methylation in the gene's promoter region, a change that prevents transcription and causes gene inactivity.

Molecular and Cellular Pathways

• Defects in DNA repair mechanisms.
• Defects in Growth Factor Signaling Pathways
• Evasion of Apoptosis
• Evasion of Cellular Senescence
• Development of Sustained Angiogenesis
• Invasion and Metastasis

Carcinogenesis

• Initiation: Carcinogenic agents cause cells to become vulnerable to cancer transformation.
• Promotion: Prolific growth of cells triggered by multiple growth factors and chemicals.
• Progression: Tumor cells acquire malignant phenotypic changes that promote invasiveness.

Heredity

• Hereditary predisposition to approximately 50 types of cancer has been observed in families.
• Several cancers exhibit an autosomal dominant inheritance pattern that dramatically increases the risk of developing a tumor

Hormones

• Effect of hormones on cancer of the breasts, ovary, and endometrium in people assigned female at birth and of the prostate and testis in people assigned male at birth. Suggested that it may reside with the ability of hormones to drive the cell division of a malignant phenotype.

Immunologic Mechanisms

• the immune system plays a significant role in resistance against tumor development (immune surveillance hypothesis).
• immunotherapy is a cancer treatment modality designed to heighten the person’s general immune responses to increase tumor destruction

Chemical Carcinogens

• Direct-reacting agents, which do not require activation in the body to become carcinogenic
• Indirect-reacting agents, called procarcinogens or initiators, become active only after metabolic conversion
• Cigarette smoke contains both procarcinogens and promoters.
• Exposure to many chemical carcinogens is associated with lifestyle risk factors, such as smoking, dietary factors, and alcohol consumption.

Radiation

• Sun/UV: Ultraviolet radiation causes skin cancer, and skin cancer develops primarily on skin areas more frequently exposed to sunlight (e.g., the head and neck, arms, hands, and legs).
• Ionizing: increased incidences of leukemia and cancers of the breast, lung, stomach, thyroid, salivary gland, gastrointestinal system, and lymphoid tissues.

Oncogenic Viruses

• Human papillomavirus (HPV): squamous cell carcinoma of the cervix and anogenital region.
• Epstein-Barr virus (EBV): Burkitt lymphoma; nasopharyngeal cancer; B-cell lymphomas in immunosuppressed people, such as those with AIDS; and Hodgkin lymphoma.
• Hepatitis B virus (HBV): Hepatitis B, cirrhosis, and hepatocellular carcinoma.
• human T-cell leukemia virus-1 (HTLV-1): human T-cell leukemia.

Clinical Manifestations

• Tissue Integrity disrupted - bleeding, ulceration and necrosis.
• Systemic Manifestations:
  • Anorexia and Cachexia.
  • Fatigue and Sleep Disorders.
  • Anemia.

Screening, Diagnosis, and Treatment

• Screening: Secondary prevention for early cancer recognition in asymptomatic people.
• Diagnostic Methods: Blood tests for tumor markers, cytologic studies, and tissue biopsy, endoscopic examinations, ultrasonography, x-ray studies, MRI, computed tomography (CT), and positron emission tomography.

Tumor Markers

• Tumor markers are antigens expressed on the surface of tumor cells or substances released from normal cells in response to the presence of the tumor (National Cancer Institute, 2019b).
• Used for screening, establishing prognosis, monitoring treatment and detecting recurrent disease.
• the serum markers that have proved most useful in clinical practice are human chorionic gonadotropin (hCG), CA 125, PSA, α-fetoprotein (AFP), carcinoembryonic antigen (CEA), and cluster of differentiation (CD) blood cell antigens (National Cancer Institute, 2019b).
• Elevated levels of CEA and AFP are found in other noncancerous conditions and depend on tumor size so that neither is useful as an early screening test for cancer.
• Elevated tumor marker levels can indicate a poor prognosis or the need for more aggressive treatment.

Cytologic and Histologic Methods

• Histologic and cytologic studies are laboratory methods used to examine tissues and cells.
• Papanicolaou Test: detects cancer cells in cytologic smear.
• Tissue Biopsy: involves removing a tissue specimen for microscopic study.

Staging and Grading of Tumors

• Basic methods for grading cancerous tumors
  • grading according to the histologic or cellular characteristics of the tumor.
  • staging according to the clinical spread of the disease.
• TNM system: classifies the disease into stages using three tumor components:
  • T stands for the size and local spread of the primary tumor.
  • N refers to the involvement of the regional lymph nodes.
  • M describes the extent of the metastatic involvement.

Cancer Treatment

• Goals: Curative, control, and palliative.
• Modalities: Surgery, radiation therapy, chemotherapy, hormonal therapy, and biotherapy.

Surgery

• Oldest treatment for tumors.
• Used in; diagnosis, staging, tumor removal, and palliation (symptom relief).

Radiation Therapy

• Primary therapy or adjuvant treatment.
• Destroys or damages cancer cells.
• Therapeutic effects of derive from the fact that the rapidly proliferating and poorly differentiated cells of a cancerous tumor are more likely to be injured than are the more slowly proliferating cells of normal tissue.
• Approaches to improving the efficacy of radiation therapy include image-guided radiation therapy (IGRT) and the use of radiosensitizers.

Chemotherapy

• Major systemic treatment for cancer (reaches tumor and distant sits).
• The lethal action at the cellular level by targeting processes that prevent cell growth and replication.
• Classified according to:
  • site and mechanism of action.
  • cell cycle-specific or cell-cycle nonspecific.

Hormonal Therapy

• Disrupts the hormonal environment of cancer cells.
• Tumors responsive to hormonal manipulation; those of the breast, prostate, and endometrium.

Biotherapy

• Use of immunotherapy and biologic response modifiers to change the person’s own immune response to cancer.
• Types:
  • Monoclonal antibodies.
  • Immune inhibitors.
  • Cancer vaccines.
  • Nonspecific immunotherapies
  • Biologic Response Modifiers: Cytokines, which include the interferons and ILs; MoAbs ; and hematopoietic growth factors.

Childhood Cancers

• Cancer is the second most common cause of death among children aged 1 to 14 years in the United States.
• Spectrum of cancers that affect children include the hematopoietic system, nervous system, soft tissues, bone, and kidneys.

Radiation Therapy Late Effects

• long-term effects are influenced by the organs and tissues included in the treatment field, type of radiation administered, daily fractional and cumulative radiation dose, and age at treatment.
• Moderate doses of CRT are also associated with obesity, particularly in patients assigned female at birth (Konończuk et al., 2021).
  -Whole-brain radiation or CRT was the primary method of preventing CNS relapse in children with ALL but now there are better methods available because of side effects from treating the whole brain.

Chemotherapy Late Effects

• Potential late effects of alkylating agents include dose-related gonadal injury.
  Anthracyclines; which are widely used in treating childhood cancers; can result in cardiomyopathy and eventually congestive heart failure (Berkman et al., 2021).
• Itrathecal combination chemotherapy to prevent relapse of ALL in the CNS, which is a sanctuary for ALL cells, is known to cause significant and persistent cognitive impairment in many children.

Pediatric Considerations

• A change in blood cell production is a warning sign of cancer in children, leading to more frequent and severe infections, fatigue, and paleness