Oncopathology and Genetic disorders

What is a Tumor

Abnormal growth of cells forming a mass

benign

localized, non-invasive

malignant

cancer, invasive, can spread

tumor types

•Fibroma – fibrous tissue

•Chondroma – cartilage

•Adenoma – glandular tissue (e.g., bowel, thyroid, adrenal)

•Cystadenoma – adenoma forming cysts

•Papilloma – finger-like projections (skin, mucosa)

Polyp – outward-growing mass, often in colon

Carcinomas

arise from epithelial cells (most common)

•Adenocarcinoma → from glandular epithelium
•Squamous cell carcinoma → from squamous epithelium (skin, mucosa)

Sarcomas

arise from mesenchymal/connective tissues

•Fibrosarcoma → fibrous tissue
•Chondrosarcoma → cartilage

Leukaemias & Lymphomas

arise from blood cells

Well-differentiated

resemble normal cells, slower growth

Poorly differentiated / Anaplastic

little resemblance, rapid growth, loss of function

Differentiation in tumors

Benign tumors: always well differentiated

Malignant tumors: range from well differentiated to completely undifferentiated.

Pleomorphism

•Variation in cell size and shape

•Marker of aggressive tumors

Histologic Features of Aggressive Tumors

•Hyperchromatic nuclei (dark-stained)

•↑ Nucleus-to-cytoplasm ratio

•Numerous abnormal mitotic figures

Benign Tumors

•Well-encapsulated, remain at site of origin

•Surrounded by fibrous capsule → clear border

•“Pushing border” → expand but don’t invade

•Easier to remove surgically

Malignant Tumors

•Infiltrate & destroy surrounding tissues

•Break through natural boundaries → spread locally

•Removal requires excision of surrounding tissue

•Makes surgery more complicated

metastasis

•Spread of tumor cells from original site → distant organs

•Forms secondary tumors

•Most important feature distinguishing malignant from benign

Main Routes of Spread in metastasis

Lymphatic spread (common in carcinomas):
•Tumor cells travel via lymphatics → lymph nodes
•Sentinel lymph node = first affected node

Haematogenous spread (carcinomas & sarcomas)
•Via bloodstream → common sites: liver, lungs

•Direct seeding (body cavities)

•Tumor cells implant in cavities (e.g., gastric carcinoma → ovaries)

Causes of Tumors – Risk Factors

•Geographical and environmental factors
Sunlight
Asbestos and other workplace agents
Smoking and alcohol consumption
Viruses (HPV)

•Age
In general, the incidence of cancer increases with age
Some tumours occur at a typical age

•Inheritance - tumour syndromes
Caused by the inherited mutation of one gene
E.g.: Rb – retinoblastoma, p53 – Li-Fraumeny syndrome,
APC – familiar adenomatous polyposis

•Acquired pre-neoplastic disorders
Well-known predisposing factors for tumour formation
E.g.: bronchial epithelial metaplasia and dysplasia, endometrial hyperplasia and dysplasia, colon villous adenoma

Causes of Tumors - Carcinogens

•A carcinogen is any agent that promotes the development of cancer

•Chemical carcinogens

•Sir Percival Pott – scrotum cancers of the chimney-sweepers caused by the soot

•Direct acting agents ->directly damage DNA e.g:alkylating agents

•Pro-carcinogens - Agents requiring metabolic activation eg: aflatoxin

•Irradiation carcinogens

•UV, X-ray, nuclear fission, radionuclides

•Viral and microbial carcinogens

•HPV
High risk: 16,18 – cervical and ano-genital carcinoma, pharyngeal carcinoma

•EBV
Burkitt’s lymphoma, Hodgkin’s lymphoma, nasopharyngeal carcinoma
Endemic in Africa, and sporadic elsewhere

•HBV and HCV
Detectable in 70-80% of HCCs

•Helicobacter pylori
Causes peptic ulcer
Important in the development of gastric adenocarcinomas and MALT lymphoma

Carcinogenesis – How Cancers Develop

•Transformation of normal cells into cancer cells

•Caused by non-lethal genetic damage
Environmental factors: chemicals, radiation
Inherited genetic mutations

Key Gene Targets

•Proto-oncogenes → Oncogenes → promote uncontrolled cell growth

•Tumor suppressor genes → loss removes “brakes” on cell division

•Caretaker genes → DNA repair failure → mutation accumulation

•Apoptosis-regulating genes → impaired cell death → survival of abnormal cells

Antitumor immunity

•Mediated by T cells, NK cells, and APCs recognizing tumor antigens

Immune Surveillance

•Immune system identifies tumor cells as “foreign”

•Destroys them before uncontrolled growth

•Tumor antigens → activate immune response

•Some tumors evade immune detection, allowing progression

Clinical Relevance

•Basis for modern cancer immunotherapy:
Immune checkpoint inhibitors
Cancer vaccines

Hallmarks of cancer

•Self-sufficiency in growth signals – divide without external cues

•Insensitivity to inhibitory signals – ignore “stop” signals

•Altered metabolism – reprogrammed energy use for rapid growth

•Evasion of apoptosis – resist programmed cell death

•Limitless replicative potential – divide indefinitely

•Sustained angiogenesis – form new blood vessels for nutrients & oxygen

•Invasion & metastasis – spread locally and to distant organs

•Evasion of immune surveillance – avoid destruction by immune system

•Anatomical Effects

•Due to size & location
Brain tumor → pressure, obstruction
Bile duct obstruction → jaundice

Functional Effects

•Hormone production by tumors

•Insulinoma → hypoglycemia

•Adrenal adenoma → Cushing’s syndrome

Paraneoplastic Syndromes

•Indirect systemic effects of cancer

•Hypercalcemia (bone breakdown substances)

•Venous thrombosis (↑ clotting tendency)

•Cachexia

•Progressive wasting of fat & muscle

•Symptoms: weakness, anorexia, anemia

•Caused by cytokines disrupting metabolism

Reduces quality of life & complicates treatment

•Grading

•Based on differentiation of tumor cells

•Well-differentiated → resemble normal cells, slower growth

•Poorly differentiated → abnormal cells, faster growth & spread

•Tells us: how aggressive the tumor is likely to be

•Staging

•Based on extent of spread

•Most common: TNM system
T = size of primary tumor
N = lymph node involvement
M = metastasis (distant spread)

•Tells us: prognosis & best treatment options

•Morphologic Methods

•Histopathology: tissue architecture (H&E staining)

•Cytology: study of individual cells

•Biopsy Techniques

•Excisional / Incisional biopsy – tissue removal for diagnosis

•Core biopsy – uses a larger needle to obtain a tissue core

•FNAB (Fine Needle Aspiration Biopsy) – minimally invasive sampling

•Screening Methods

•PAP smear – exfoliative cytology for cervical cancer screening

•Immunohistochemistry (IHC)

•Uses antibodies to detect specific antigens in tumor cells

•Helps identify cell type, origin, prognosis, therapy targets

•Molecular Diagnosis

•Detects genetic alterations (PCR, FISH, NGS)

•Identifies oncogenes, tumor suppressor mutations, predictive markers