Neoplasia

Rates of growth of tumor cells

Metastasis – pathways of spread, mechanisms

Epidemiology of Cancer

Precancerous conditions

Growth of tumor cells

Rate of growth of a tumor depends on doubling time of tumor cells, fraction of tumor cells that are in the replicative pool, rate at which cells are shed /die and ? level of

differentiation

Pathways of spread

Direct seeding of body cavities and surfaces

Lymphatic spread

Hematogenous spread

Direct seeding

Peritoneal implants of cancer cells (blue arrow)

Malignancy penetrates into natural body cavities like peritoneal, pleural, pericardial, joint space

• Peritoneal deposits in ovarian carcinoma

• Pseudomyxoma peritonei from mucin secreting carcinoma of appendix

• Krukenberg tumor: metastasis from carcinoma of stomach to both ovaries

Krukenberg tumor

Lymphatic spread• Most common pathway for spread of

carcinoma

• Tumor cells enter lymphatics at tumor margin and follow the route of drainage

• Sentinel node - first node in regional lymphatic basin that receives lymph flow from primary tumor is usually involved

• Skip metastases (local lymph nodes are bypassed)

Hematogenous spread

• Typical of sarcomas

• Lungs and liver most commonly affected

Prostatic carcinoma preferentially spreads to boneBronchogenic carcinomas to adrenals and brain Neuroblastomas to the liver and bones.

Skeletal muscles (rich in capillaries) are rarely the site of metastasis

Hallmarks of malignant tumor

• Invasion of extracellular matrix

• Vascular dissemination and homing of tumor cells

INVASION & METASTASIS

Invasion of ECM

1. Detachment of tumor cells from each other

2. Degradation of ECM

3. Attachment to matrix components

4. Migration of tumor cells

Detachment

• Normal cells : adhesion molecules

• Down regulation of E-cadherin in Carcinoma Breast / Colon

• Mutations for gene in catenin

Degradation of ECM

• Proteolytic enzymes secreted by tumor cells themselves or by inducing host cells

• Serine, cysteine and matrix metalloproteinases

• MMP 9, MMP 2 - collagenases

• Metalloproteinase inhibitors levels are reduced

Attachment to matrix

• Tumor cell attachment to laminin and fibronectin

• Increased number of integrin receptors

Migration of tumor cells

• Cleavage products of matrix components

• Growth promoting,

• Angiogenic,

• Chemotactic activities

Vascular dissemination and homing of

tumor cells

• In the circulation - homotypic adhesion - heterotypic adhesion

• Adhesion to endothelium

• Egress through basement membrane

• Chemokines

Organ tropismAdhesion moleculesChemokines

A 66-year-old man has a routine physical examination and a stool sample proves positive for the presence of occult blood. He undergoes colonoscopy and a 5 cm sessile mass is present in the sigmoid colon. Biopsy of the mass yields a diagnosis of adenocarcinoma. A chest x-ray shows multiple 1 to 3 cm nodules in both lungs. Presence of which of the following in the neoplastic cells is most likely to explain the presence of lung nodules? A Vimentin B Leukocyte common antigen C Laminin receptor D Telomerase E DNA topoisomerase II

A 60-year-old man who has a 90 pack year history of cigarette smoking has had a chronic cough for the past 10 years. He has begun to lose weight (3 kg) during the past year. No abnormal findings are noted on physical examination. He has a chest radiograph that reveals a right hilar mass. A sputum cytology shows atypical, hyperchromatic squamous cells. What is the most common initial pathway for metastases from this lesion?A BloodstreamB Pleural cavityC Contiguous spread to chest wallD LymphaticsE Bronchi

Cancer Incidence in the United states by site and sex

Cancer Incidence in the United states

• 2nd most common cause of death, >75% in 55yrs and older

• Lifetime risk : men > women, men 1 in 2, women 1 in 3

• Relative risk: • 23 times higher risk of lung cancer in male smokers v/s non smokers• 2 times greater risk in first degree relative of women with breast cancer

• Cancers in children: • 2nd most common cause of death, (accidents most common)• most common cancer: acute lymphoblastic leukemia( 33%)∼

Geographic and environmental factors

Blacks: greatest risk for cancer and related deaths of any racial group or ethnicity (all cancers except malignant melanoma)

Hispanics and Asians: lower incidence rates for all cancers combined than whites (exceptions are cancers associated with infections - cervix (human papillomavirus), liver (hepatitis B & C), stomach (helicobacter pylori)

Native Americans: Highest incidence and cancer-related deaths due to kidney cancer than all racial and ethnic populations

Worldwide: Melanoma is the most rapidly increasing cancer

China: Nasopharyngeal carcinoma secondary to EBV

Japan: Stomach adenocarcinoma due to smoked foods

Southeast Asia: Hepatocellular carcinoma due to HBV + aflatoxins

Africa: Burkitt's lymphoma due to EBV Kaposi's sarcoma due to HHV-8

Geographic and environmental factors

Agents Human Cancer Site and Type Typical Use or OccurrenceArsenic Lung, skin,

hemangiosarcomaIn alloys, electrical devices, medications,

fungicides, and animal dipsAsbestos Lung, mesothelioma;

gastrointestinal tractIn existing construction, fire-resistant textiles, friction materials, roofing papers, floor tiles

Benzene Leukemia, Hodgkin lymphoma

In light oil, Formerly used as solvent and fumigant

Beryllium Lung Aerospace applications and nuclear reactorsCadmium Prostate In batteries, alloy, metal plating and coatingsChromium Lung Component of metal alloys, paints, pigments

Ethylene oxide Leukemia Ripening agent for fruits/nuts. In rocket propellant, in fumigants, sterilants

Nickel Nose, lung Nickel plating, ferrous alloys, batteriesRadon Lung Serious hazard in quarries and mines

Vinyl chloride Angiosarcoma of liver Refrigerant, Adhesive for plastics

Occupational Cancers

Anything that we do for pleasure is either illegal, immoral, fattening, or even worse can cause “ CANCER ”

51-year-old man worked for 10 years in a factory producing plastic pipes

Weight loss, nausea, and vomiting worsening over the past 5 months

An abdominal CT scan reveals a 12 cm right liver lobe mass, Liver biopsy reveals a neoplasm composed of spindle cells forming irregular vascular channels

Exposure to which of the following substances most likely led to development of this neoplasm?

A BenzeneB RadonC CyclophosphamideD AsbestosE Vinyl chloride

Genetic Predisposition to Cancer

• Autosomal dominant inherited cancer syndromes

• Defective DNA repair syndromes

• Familial Cancers

Is Cancer hereditary ?

Inherited Cancer Syndromes (Autosomal Dominant)

Gene Inherited PredispositionRB Retinoblastomap53 Li-Fraumeni syndrome (multiple tumors)p16INK4A MelanomaAPC Familial adenomatous polyposis/colon cancerNF1, NF2 Neurofibromatosis 1 and 2BRCA1, BRCA2 Breast and ovarian tumorsMEN1, RET Multiple endocrine neoplasia 1 and 2MSH2, MLH1, MSH6 Hereditary nonpolyposis colon cancerPATCH Nevoid basal cell carcinoma syndrome

• tend to arise in specific sites and tissues• associated with a specific marker phenotype

Inherited Autosomal Recessive Syndromes of Defective DNA Repair

Xeroderma pigmentosum - increased risk for skin cancers (basal cell, squamous cell carcinoma) on exposure to ultraviolet light (defective DNA repair)

Chromosome instability syndromes - chromosomes susceptible to damage by ionizing radiation and drugs; predisposition to cancers (e.g., leukemia, lymphoma); disorders include Fanconi anemia, Ataxia telangiectasia, Bloom syndrome

Familial Cancers

• Carcinoma Colon / Breast / Ovary, Brain tumors

– Early age of onset– Tumors in two or more close relatives of index case– Sometimes multiple / bilateral– not associated with specific marker phenotypes– Transmission pattern is not clear (siblings have a relative

risk between 2 and 3)

Non Hereditary predisposing conditions

• Endometrial hyperplasia – Endometrial adenocarcinoma

• Cervical dysplasia – Squamous cell carcinoma of cervix

• Bronchial metaplasia – Squamous cell carcinoma of lung

• Chronic inflammation

• Precancerous conditions

Chronic inflammation and Cancer

• Ulcerative colitis• Crohn disease• H pylori gastritis• Viral hepatitis• Chronic pancreatitis

In 1863 Virchow proposed that cancer develops at sites of chronic inflammation

Precancerous ConditionsPRECURSOR LESION CANCER

Actinic (solar) keratosis Squamous cell carcinomaAtypical hyperplasia of ductal epithelium of breast AdenocarcinomaChronic irritation at sinus orifice, third-degree burn scars Squamous cell carcinomaChronic ulcerative colitis AdenocarcinomaComplete hydatidiform mole ChoriocarcinomaDysplastic nevus Malignant melanomaEndometrial hyperplasia AdenocarcinomaGlandular metaplasia of esophagus (Barrett's esophagus) AdenocarcinomaGlandular metaplasia of stomach (Helicobacter pylori) AdenocarcinomaMyelodysplastic syndrome Acute leukemiaRegenerative nodules in cirrhosis AdenocarcinomaScar tissue in lung AdenocarcinomaSquamous dysplasia of oropharynx, larynx, bronchus, cervix Squamous cell carcinomaTubular adenoma of colon AdenocarcinomaVaginal adenosis (diethylstilbestrol exposure) AdenocarcinomaVillous adenoma of rectum Adenocarcinoma

An epidemiologic study is performed to determine risk factors for development of malignant neoplasms. A statistical analysis of pre-existing medical conditions is done. Some pre-existing conditions are observed to precede development of malignant neoplasms, while others do not. Which of the following conditions is most likely to be statistically unrelated to subsequent malignancy?

A Endometrial atypical hyperplasiaB Chronic alcoholism with hepatic cirrhosisC Cervical squamous dysplasiaD Chronic ulcerative colitisE Uterine leiomyomas

Telomerase / Limitless Replicative Potential “IMMORTAL CELLS”

Summary• The rate of growth of a tumor depends on doubling time, fraction in

replicative pool, rate at which cells are shed/die • Pathways of spread - direct seeding, lymphatic and hematogenous • Metastasis involves invasion of extracellular matrix followed by

vascular dissemination and homing of tumor cells• Incidence of cancer and cancer related deaths – some are more

common in certain populations, occupations and locations• Cancer is hereditary• There are also non-hereditary predisposing conditions• Malignant cells show up-regulation of telomerase activity

Required reading: Robbins Basic Pathology 9E, p169-172, 191-195Recommended reading: Robbins and Cotran Pathologic Basis of Disease 8E, p268-276, 298-300