Tumor and Neoplasia Notes

Tumor or Neoplasia

  • Tumor or neoplasia is a new growth of tissue that usually forms a mass. A malignant neoplasm is a cancer.
  • Tumor means swelling in Greek.
  • Neoplasia: neo means new and plasia means formation.

Cancer

  • Cancer is uncontrolled division of genetically abnormal cells and their spread into surrounding tissues and distant places.

Pathogenesis of Cancer

  • Cancer results from an interaction between environmental (external) factors and a genetically susceptible host.
  • Normal cells divide as needed and stop, attach to other cells, and stay in place.
  • Normal cells undergo apoptosis when they are no longer needed.
  • Cancer cells lose their ability to stop dividing, attach to other cells, stay where they belong, and die at the proper time.

Differences Between Cancer Cells and Normal Cells

  • Cancer cells are less specialized than normal cells.
  • Cancer cells can ignore apoptotic signals.
  • Cancer cells can influence the normal cells, molecules, and blood vessels surrounding the tumor (microenvironment).
  • Cancer cells can hide from the immune system or use it to survive and grow.

Causes of Cancer - DNA Damage

  • DNA damage, a physical injury to DNA strands, can be caused by:
    • Environmental factors: tobacco, ionizing radiation, UV rays, and viruses.
    • Endogenous causes: Reactive oxygen species (ROS) released during cellular metabolism.
    • Random injury during DNA replication.
  • Protective events after DNA damage include:
    • Arrest of cell division.
    • Activation of DNA repair enzymes.
    • Induction of apoptosis.
  • Unrepaired DNA damage leads to gene Mutation.

DNA Damage

  • Types of DNA damage:

    • Single-strand break
    • Damaged base
    • Double-strand break
    • Intra-strand crosslink
    • Inter-strand crosslink
    • Mismatch

  • DNA Repair Mechanisms

    • Direct reversal
    • Base excision repair
    • Nucleotide excision repair
    • Mismatch repair
    • Double strand break repair
    • Homologous recombination
    • Non-homologous end joining

Gene Mutation

  • A permanent change in DNA that creates an abnormal protein or prevents specific protein formation.
  • Acquired gene mutations:
    • Most common cause of cancer.
    • Occur from damage to a gene in a cell during a person’s life.
    • Cancer that occurs because of acquired mutations is called sporadic cancer.
  • Germline mutations:
    • Less common.
    • Occur in a sperm cell or ova cell.
    • Pass directly from parent to child at conception.
    • Cancer caused by germline mutations is called inherited cancer, accounting for about 5-20% of all cancers.

Gene Mutation Types

  • Substitution
  • Insertion
  • Deletion

Genes Linked to Cancer

  • Tumor suppressor genes:
    • Protective genes that monitor the rate of cell division, repair DNA damage and control apoptosis.
    • Recessive mutations that decrease the function of these genes induce cancer.
  • Oncogenes:
    • Present normally as proto-oncogenes and involved in cell growth.
    • Dominant mutations that increase the function of these genes induce cancer.

Carcinogenic Agents

  • Viral Carcinogenesis:
    • DNA (HPV): Cancer cervix
    • HBV: Hepatocellular carcinoma
    • EBV: Burkitt's lymphoma
    • DNA Herpes virus 8: Kaposi sarcoma
    • HCV: Hepatocellular carcinoma
    • AIDS related cancer: Kaposi sarcoma, Non Hodgkin lymphoma and Cancer cervix
  • Chemical Carcinogenesis:
    • Arsenic, benzene, cadmium, chromium and coal tar: Skin, lung and liver
    • Aflatoxin (product of aspergillus flavis fungus): DNA breaks and hepatocellular carcinoma
    • High fat diet: Colon cancer
    • Tobacco: Lung cancer
    • Alcohol: Liver cancer
    • Estrogen: Endometrial- Breast cancers
    • Androgen: Prostate Cancer
  • Physical Carcinogenesis:
    • Ionizing radiation: Bone, skin or blood cancers
    • Ultraviolet rays: Skin cancer
    • Heat: Cancer lip
    • Inhalation of asbestos: Mesothelioma of the pleura and Lung cancer

Classification of Tumors

  • According to the behavior of the tumor: benign, in situ, malignant, and tumors of unknown behavior.
  • According to the tissue of origin: epithelial tumors and connective tissue tumors.

Microscopic Criteria of Malignant Cells

  1. Undifferentiated cells: anaplastic or atypical
  2. Non uniform cells: pleomorphic.
  3. Dark stained nucleus: hyperchromatic.
  4. Increase nucleus-cytoplasmic (N/C) ratio.
  5. Prominent nucleoli.
  6. Loss of polarity.
  7. Frequent abnormal mitoses.

Differences Between Benign and Malignant Tumors

CharactersBenignMalignant
DifferentiationWell differentiatedLack of differentiation
Growth/InvasionExpansile/CapsulatedInfiltrative/No Capsule
MetastasisNo Metastatic spreadMetastatic
PrognosisGoodBad

Differences Between Carcinoma and Sarcoma

CharacterCarcinomaSarcoma
DefinitionMalignant tumor of epitheliumMalignant tumor of mesenchymal tissue
StructureCells in groups with fibrous stromaIndividual cells in sheets with vascular stroma
ConsistencyFirmSoft and fleshy
SpreadEarly by lymphaticEarly by blood

Methods of Spread of Malignant Tumors

  1. Local Invasion:

    • Mechanism of tumor cell invasion and metastasis:
      • Decrease adherence of tumor cells to each other by inhibition of E-cadherin expression
      • Increase growth factor secretion.
      • Degradation of ECM through secretion of collagenase, cathepsin B and gelatinase.
      • Attachment of malignant cells to ECM component.
      • Failure to synthesize basement membrane.
      • Migration of tumor cells by secretion of motility factor.

  2. Locally Malignant Tumors:

    • Tumors of unknown behavior - borderline - locally aggressive, which spread locally only (no distant spread or metastasis).
    • Examples:
      • Basal cell carcinoma of the skin (rodent ulcer).
      • Adamantinoma of the jaw.
      • Carcinoid tumor of the appendix.
      • Astrocytoma of the brain.
      • Craniopharyngioma of pituitary gland.
      • Giant cell tumor of bone (grade I and II).

  3. Blood Spread:

    • Sarcoma is the commonest tumor spread via blood.
    • Venous spread more common than arterial, forming tumor emboli which stop first in the lung or liver.
    • Carcinomas with early blood spread:
      • Renal cell carcinoma.
      • Hepatocellular carcinoma.
      • Follicular carcinoma of thyroid.
      • Choriocarcinoma of uterus.

  4. Lymphatic Spread:

    • Tumor emboli: Small group of tumor cell spread to regional lymph node
    • Lymphatic permeation: Solid cord of tumor blocks the lymph vessel and leads to retrograde spread: ex Edema of the skin around the nipple (Peau d’orange)
    • Perineurial lymphatic spread: spread via lymphatic vessels near big nerves
    • Carcinoma is the most common tumor spread via lymphatics

  5. Transcoelomic Implantation:

    • Spread of malignant tumors in organs covered by serous membranes, e.g., carcinoma of stomach or colon spreads through the peritoneum to the ovaries forming Krukenberg tumor.

Tumor Angiogenesis

  • Definition: Tumors induce new blood vessels formation.
  • Pathogenesis:
    • A source of blood supply to provide oxygen and other nutrients.
    • Tumor cells secrete vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) that induce capillary growth.
    • Cancer cells stop producing PKG which inhibits angiogenesis.
    • The tumors are able to make their own blood vessels through cancer stem cells.
  • Importance of tumor angiogenesis:
    • Tumor survival and growth.
    • Waste pathway.
    • Increase size of the tumor.
    • Spread and metastasis.
    • New blood vessels may be lined by endothelium and cancer cells helping blood spread.

Cancer Stem Cells (CSCs)

  • Stem cells found within the malignant tumor, having the original characters of normal stem cells.
  • Characters:
    1. Give rise to all cell types found in tumor: Tumorigenic
    2. Self-renewal so they have unlimited proliferative capacity
    3. Minor population in tumor cells so they escape therapy
    4. Resistance to drugs, radiation and cell stress.
    5. Relapse and metastasis
    6. CSCs are targets for specific therapies

Tumors of Epithelium

  • Benign tumors:
    • Papilloma
    • Adenoma
  • Malignant tumors:
    • Carcinoma

Papilloma

  • Definition: A benign tumor arises from surface epithelium, strongly associated with HPV.
  • Gross:
    1. Cauliflower like outward projection.
    2. Slightly elevated or finger like growth.
    3. Simple or branched.
  • Microscopically:
    1. Benign proliferated epithelial cells cover a fibro-vascular core.
    2. The basement membrane is intact.
  • Types:
    1. Squamous cell papilloma: Skin, lip, and tongue.
    2. Columnar cell papilloma:
      • Duct papilloma of the breast: Arises from the epithelium of the main duct near the nipple.
      • Adenomatous polyp: Mixed adenoma/papilloma tumor. Arises from the mucosa of the GIT and gall bladder. A type called villous papilloma is precancerous.
    3. Transitional cell papilloma: Arises mainly from the urothelium of the urinary bladder and ureter.

Adenoma

  • Definition: A benign tumor arises from the secretory or glandular epithelium.
  • Site: thyroid, ovary, breast, GIT, and pituitary.
  • Types and gross picture:
    1. Solid: pituitary adenoma.
    2. Cystic (cystadenoma): ovary and thyroid adenomas.
    3. Mixed with fibrous tissue: breast fibroadenoma.
    4. Adenomatous polyp: glands take polypoid shape: GIT
  • Microscopically: Capsulated and formed of differentiated cells as the original gland.

Carcinoma

  • Definition: A malignant tumor of epithelium.
  • Gross (Naked eye appearance):
    • Fungating or polypoid: outward complex branching cauliflower mass.
    • Infiltrating: transmural growth causing thickening and narrowing.
    • Ulcerative: Malignant ulcer.
  • Characters of malignant ulcer:
    • Large
    • Raised everted edges
    • Fixed hard infiltrating base
    • Necrotic floor
  • Microscopic types (classification) of carcinoma:
    1. Carcinoma arising from surface epithelium:
      • Squamous cell carcinoma.
      • Basal cell carcinoma.
      • Transitional cell carcinoma.
      • Carcinoma in situ (intra epithelial carcinoma)
    2. Carcinoma arising from glandular epithelium:
      • Adenocarcinoma
      • Mucoid carcinoma
    3. Adenosquamous carcinoma
    4. Anaplastic carcinoma
    5. Large cell carcinoma
    6. Small cell carcinoma

Squamous Cell Carcinoma

  • Definition: Malignant tumor arises from the stratified squamous epithelium.
  • Gross: Fungating- Infiltrating- Ulcerative.
  • Microscopically: Dermal infiltration by masses of large pleomorphic polygonal squamous cells. The cells in the central area are replaced by keratin (Epithelial pearl or Cell nest).
  • Sites: skin, lip, tongue, larynx, esophagus, cervix, vagina, vulva, and anal canal.

Basal Cell Carcinoma

  • Definition: Malignant tumor arises from basal cell layer of skin. Locally malignant tumor that destroys surrounding tissue but does not give metastasis.
  • Gross:
    1. Small nodule increases in size and then ulcerate.
    2. The ulcer has eroded edge (Rodent ulcer).
    3. Enlargement of cervical lymph nodes with rodent ulcer is usually due to secondary bacterial infection.
  • Microscopically: Dermal infiltration by masses of hyperchromatic malignant Basal cells. The peripheral cell layers are arranged near each other in a Palisade manner.
  • Sites: sun exposed areas face.

Carcinoma In Situ

  • Pre-invasive carcinoma.
  • Definition: intraepithelial malignant cells with intact basement membrane.
  • Microscopically: malignant changes appear in the epithelial cells before the basement membrane is infiltrated (no stromal invasion).
  • Sites: cervix, breast and bronchi.
  • Carcinoma in situ will not usually form a mass.

Benign Tumors of Connective Tissue

  • Fibroma: Benign tumor of fibrous tissue
  • Lipoma: Benign tumor of fatty tissue
  • Chondroma: Benign tumor of cartilage
  • Osteoma: Benign tumor of bone
  • Leiomyoma: Benign tumor of smooth muscle
  • Rhabdomyoma: Benign tumor of striated or cardiac muscles.
  • Hemangioma: Benign tumor of blood vessels
  • Nevus: Benign tumor of pigmented cells
  • Melanoma: Malignant tumor of pigmented cells

Sarcoma

  • Malignant tumor of mesenchymal tissue

Teratoma

  • Benign tumor of the ovary or testis composed of mature tissue representing at least 2 embryonic layers (ectoderm, mesoderm or endoderm)
  • Ectodermal (most common): squamous epithelium, sebaceous glands, hair follicles, brain tissue
  • Mesodermal (second most common): bone, cartilage, smooth muscle, fibroadipose tissue
  • Endodermal: intestinal or respiratory epithelium, thyroid, salivary gland
  • Origin: Arises from pluripotent stem cells as germ cells and embryonal cells.

Hamartoma

  • Definition: Focal malformation consists of the same tissue elements normally found at that site but they are growing in a disorganized manner.

Para-neoplastic Syndrome

  • Definition: Disorders result from substances produced by the tumor (hormones or cytokines), that are triggered by an altered immune system response to a neoplasm. Occur remotely from the tumor itself.
  • Examples:
    • Cushing syndrome (increase cortisone level) associated with small cell carcinoma of the lung.
    • Hypercalcemia associated with squamous carcinoma of the lung.

Disturbance of Growth

  1. Hyperplasia:

    • Definition: Increase in the number of normal looking cells in a given tissue.

  2. Hypertrophy:

    • Definition: Increase in the size of cells.

  3. Atrophy:

    • Definition: Decrease in size of the organ due to decrease in the size and number of its cells.

  4. Metaplasia:

    • Definition: Change of one type of tissue into another type.

  5. Dysplasia:

    • Definition: Atypical hyperplasia or the appearance of abnormal hyperplastic cells within the epithelium.