Neoplasia Overview

Neoplasia

• A disorder of cell growth triggered by a series of genomic alterations
• Excessive proliferation is independent of and uncontrolled by physiologic growth signals
• Alterations give neoplastic cells a survival and growth advantage
• Alterations affect a single cell and its clonal progeny
• Neoplasms are clonal: neoplastic cells derive from a single mother cell

Neoplasms: Benign and Malignant

• Benign neoplasms stay localized and do not spread/metastasize to other sites
• Benign neoplasms are usually well-circumscribed and non-infiltrative
• Benign neoplasms are possible to remove surgically
• Malignant neoplasms are cancerous
• Malignant neoplasms have invasive growth that destroys adjacent tissues
• Malignant neoplasms can spread to distant sites (metastasize)
• Approximately 30% of tumors first present as metastatic disease
• Treatment for malignant neoplasms is complicated, especially in advanced disease
• Prognosis for malignant neoplasms may be questionable
• Benign neoplasms may behave aggressively, cause significant morbidity, or be fatal
• Cancers may occasionally be quite small and require a high level of clinical skill to suspect and identify

Benign vs. Malignant: Microscopic Features

• Well-differentiated (resembling normal tissue) vs. poorly-differentiated (not resembling normal tissue)
• Typical tissue organization vs. atypical tissue structure
• Rare, normal mitoses vs. frequent, abnormal mitoses
• Histologic features of malignancy include pleomorphism (variable size and shape of cells/nuclei), high nuclear/cytoplasmic ratio of cells, and loss of identifiable differentiation

Neoplasm Nomenclature

• Beginning of the name identifies tissue of origin
• Ending of the name usually means neoplasm
• -oma usually means benign
• -carcinoma and -sarcoma are always malignant

Dysplasia

• Genetically altered cells stay within epithelium
• Basement membrane acts as a barrier between epithelium and connective tissue
• Dysplasia cannot grow aggressively or metastasize
• The patient can be cured by surgical excision
• Dysplasia is a precursor to carcinoma
• Once dysplasia invades through the basement membrane into connective tissue, it becomes carcinoma
• Carcinoma in situ: dysplasia involving full thickness of epithelium but still confined by the basement membrane; the patient can still be cured by complete surgical excision

Teratoma

• A benign tumor containing cells/tissues from more than one tissue type and more than one germ layer
• Nearly all other neoplasms consist of cells of one tissue type
• Originates from germ cells

Hamartoma

• A benign proliferation of cells/ tissues native to the involved site
• Considered a benign, highly differentiated neoplasm

Choristoma

• Benign proliferation of cells/ tissues in a non-native site
• Considered a benign, highly differentiated neoplasm

Cancer Epidemiology

• Cancer is the 2nd leading cause of death in both adults and children
• The leading causes of death in adults are (1) cardiovascular disease, (2) cancer, and (3) chronic respiratory disease
• The leading causes of death in children are (1) accidents, (2) cancer, and (3) congenital defects
• The most common cancers by incidence in adults are (1) breast/prostate, (2) lung, and (3) colorectal cancer
• The most common causes of cancer mortality in adults are (1) lung, (2) breast/prostate, and (3) colorectal cancer
• The most common cancers by incidence in adults are (1) breast/prostate, (2) lung, and (3) colorectal cancer
• The most common causes of cancer mortality in adults are (1) lung, (2) breast/prostate, and (3) colorectal cancer.
• Cardiovascular disease is the leading cause of death in the US and worldwide.
• Cancer is the second leading cause of death in the US and worldwide.
• Lifetime cancer risk: Males - Risk of developing: 40%; Risk of death: 21%
  • Lifetime cancer risk: Females - Risk of developing: 39%; Risk of death: 18%
• Approximately 50% of US cancer diagnoses/deaths are accounted for by the ‘big 4’: Lung, Breast, Prostate, Colorectal
• Some cancers are more aggressive than others

Basal cell carcinoma and Squamous cell carcinoma of skin

• Most common human cancers by far
• BCC: 3-4 million cases per year in US
• SCC: 2-3 million cases per year in US
• Not included in cancer registries or epidemiology statistics
• Indolent and treatable

Cancer Screening:

• Screening seeks to catch dysplasia (precancerous change) before it becomes carcinoma
• Screening seeks to catch carcinoma before clinical symptoms arise
• Purpose of screening is to decrease cancer-specific mortality
• Cancers that do not produce symptoms until late in disease have undergone additional divisions and mutations
• Cancers detected late tend to have a poor prognosis
• Common screening methods:
  • Pap smear - detects cervical dysplasia (CIN) before it becomes carcinoma
  • Mammography - detects in situ breast cancer (e.g., DCIS) before it invades or invasive carcinoma before it becomes clinically palpable
  • Prostate-specific antigen (PSA) and digital rectal exam - detects prostate carcinoma before it spreads
  • Hemoccult test (for occult blood in stool) and colonoscopy - detect colonic adenoma before it becomes colonic carcinoma or carcinoma before it spreads

Cancer and Age

• Most cancers occur over 55 years of age
• Men aged 60-79: main cause of death
• Women aged 40-79: main cause of death
• Explained by:
  • Accumulation of pathogenic genomic alterations in (stem) cells over lifetime
  • Decline in immune system competence
• Cancer accounts for 10% of all childhood deaths
• 80% of childhood cancers are cured
• Most common pediatric cancers are leukemia/lymphoma and brain/CNS tumors

Carcinogenesis

• Carcinogenesis results from the accumulation of complementary genomic alterations
• Genomic (genetic and epigenetic) alterations come from three sources:
  • DNA replication errors during (stem) cell division
    • Approximately 65-70% of mutations in human cancers
    • ~ 3 mutations and an unknown number of epigenetic alterations occur every time a normal human stem cell divides
  • Environmental factors
  • Inherited/hereditary genetic mutations
    • 5-10% of cancers have a hereditary component
• Stem cells in different adult tissue types undergo different numbers of cell divisions
• Strong correlation (0.8) between average number of stem cell divisions per tissue and rate/risk of cancer in that tissue

Environmental Factors

• Remarkable geographic variation in cancer incidence
• Evidence of the role of environmental carcinogens
• Environmental influences appear to be dominant risk factors for many cancers
• Approximately 20-40% of cancers may be preventable

Tobacco

• World’s single greatest preventable cause of death
• Single most important factor contributing to premature death in the US
• Implicated in 80% of 140,000 annual lung cancer deaths
• 4000-7000 due to secondhand smoke
• Also implicated in cancers of:
  • Oral cavity, pharynx, larynx
  • Esophagus
  • Pancreas
  • Colon
  • Bladder

Obesity

• Strongly associated with cancer risk
• 10% of cancer deaths attributed to obesity
• Linked with > 10 cancers
  • Colon
  • Rectum
  • Postmenopausal breast cancer
  • Prostate
• More than two-thirds of Americans are overweight/obese
• 20% of children/adolescents obese

Alcohol

• Contributes to 5% of cancer deaths
• Increased risk of cancers of:
  • Oral cavity, pharynx, larynx
  • Esophagus
  • Liver
  • Colon
  • Breast
• Alcohol and tobacco synergistically increase the risk of cancers in the upper aerodigestive tract

Infectious Agents

• 15% of cancers worldwide are caused by infectious agents
• 30-45% of cancers in the developing world
• Many individuals infected with hepatitis C virus (HCV) may develop hepatocellular (liver) carcinoma.
• Human papillomavirus (HPV)
  • Cause of cervical carcinoma
  • Cause of an increasing fraction of head and neck cancers
  • Oropharynx, in particular
  • Incidence of HPV-positive oropharyngeal cancer has now surpassed the incidence of cervical carcinoma

Reproductive History

• Cumulative exposure to estrogen stimulation increases the risk of breast and endometrial cancer
• ½ the risk of breast cancer if age at first full-term pregnancy < 20 years compared to > 35 years
• Postmenopausal hormone replacement therapy increases the risk of breast cancer

Other Environmental Carcinogens

• In the environment: UV rays, smog
• In the workplace: asbestos
• In diet: grilled meat, fat, alcohol

Acquired Predisposing Conditions

• Chronic inflammation (infectious or non-infectious)
  • Increased cell proliferation to repair damage → increased opportunity for genetic mutations
  • Presence of activated immune cells in inflamed tissue
    • Produced reactive oxygen species are directly genotoxic
• Alcoholism → pancreatitis: increased risk of pancreatic carcinoma
• Inflammatory bowel disease: increased risk of colorectal carcinoma
• Autoimmune diseases, e.g. Sjögren syndrome: increased risk of MALT lymphoma
• Immunodeficiency: Intact immune system, in particular intact T-cell immunity, is critical for normal cell surveillance
  • Deficits in immune function associated with increased cancer risk
    • HIV/AIDS
    • Chronic pharmacologic immunosuppression
    • Kaposi sarcoma: seen in HIV/AIDS
• Precursor lesions:
  • Metaplasia
    • e.g. Barrett’s esophagus
  • Hyperplasia
    • e.g. endometrial hyperplasia
  • Dysplasia
  • Benign neoplasia
    • e.g. colorectal adenoma

Genetics and Cancer

• Nevoid basal cell carcinoma syndrome (NBCCS)