Salient Features of Neoplasia

1. Definition

2. Nomenclature

Benign Tumors

• Fibroma, lipoma, chondroma, osteoma (mesenchymal)
• Adenoma (glandular epithelium) - e.g., hepatic adenoma
• Papilloma (surface epithelium) - e.g., squamous papilloma

Malignant Tumors

Exceptions (malignant despite benign-sounding names): lymphoma, melanoma, mesothelioma, seminoma.

Special Tumors

• Mixed tumor: Single clonal progenitor differentiating along more than one lineage. Example: pleomorphic adenoma of parotid (epithelial + myxoid stroma + cartilage/bone).
• Teratoma: Contains tissues from >1 germ cell layer; arises from totipotent germ cells (ovary, testis, midline rests).

3. Key Characteristics: Benign vs. Malignant

4. Differentiation and Anaplasia

• Pleomorphism - variation in cell and nuclear size/shape
• Hyperchromatic nuclei - dark-staining due to excess DNA
• High nuclear-to-cytoplasmic ratio (normal 1:4-6 becomes 1:1)
• Prominent nucleoli ("owl eye" nucleoli)
• Atypical mitoses - tripolar or quadripolar spindles
• Loss of polarity - disorganized architecture
• Tumor giant cells - single cells with one huge nucleus or two large nuclei

5. Local Invasion

• Benign tumors: grow slowly, develop a rim of compressed fibrous tissue (capsule). This makes them discrete, moveable (non-fixed), and surgically resectable by enucleation.
• Malignant tumors: lack well-defined capsules; infiltrate and destroy surrounding normal tissues. Even an apparent capsule must be scrutinized microscopically for tiny tongues of invasion (e.g., follicular carcinoma of thyroid). Surgeons must resect a wide margin of normal tissue; pathologists examine for clean surgical margins.

6. Metastasis

Routes of metastasis:

1. Lymphatic spread - most common route for carcinomas; initial spread to regional lymph nodes (sentinel node concept).
2. Hematogenous spread - preferred by sarcomas; tumor cells enter veins (thin-walled veins more easily than arteries).
   • Liver and lungs are the most common sites (portal drainage → liver; all systemic venous blood → lungs).
   • Renal cell carcinoma, hepatocellular carcinoma, and follicular thyroid carcinoma favor venous invasion.
3. Seeding of body cavities - transcoelomic spread; e.g., ovarian carcinoma seeding the peritoneum.

7. Hallmarks of Cancer (Hanahan & Weinberg)

1. Self-sufficiency in growth signals - constitutive activation of growth factor receptors (e.g., RAS mutations, HER2 amplification) or autocrine production of growth factors.
2. Insensitivity to growth inhibitory signals - loss of tumor suppressor genes:
   • RB: "Governor of the cell cycle" - normally restrains G1→S transition.
   • TP53: "Guardian of the genome" - triggers cell cycle arrest or apoptosis in response to DNA damage.
3. Altered cellular metabolism (Warburg effect) - shift to aerobic glycolysis even in the presence of O₂; fuels biosynthesis. Oncometabolites (e.g., 2-HG from mutant IDH1/2) further drive epigenetic changes.
4. Evasion of cell death (apoptosis) - overexpression of anti-apoptotic BCL2, loss of pro-apoptotic signals.
5. Limitless replicative potential (immortality) - reactivation of telomerase, maintaining telomere length and bypassing replicative senescence.
6. Sustained angiogenesis - tumors >1-2 mm require new blood supply; achieved via VEGF and other angiogenic factors (angiogenic switch).
7. Invasion and metastasis - degradation of ECM (MMPs), epithelial-mesenchymal transition (EMT), vascular intravasation/extravasation.
8. Evasion of immune surveillance - downregulation of MHC-I, expression of immune checkpoint ligands (PD-L1), recruitment of immunosuppressive cells (Tregs, MDSCs).

8. Carcinogenesis: A Multistep Process

• Initiation - irreversible mutation induced by carcinogen
• Promotion - reversible proliferative stimulus
• Progression - additional mutations → increasing malignancy (invasion, metastasis)

Types of genetic lesions:

• Driver mutations - directly contribute to cancer development (tightly clustered in oncogenes/tumor suppressors)
• Passenger mutations - neutral in terms of fitness; far outnumber driver mutations; serve as "mutational fingerprint" (e.g., UV-signature in melanoma)

Key gene categories:

Epigenetic changes:

• Hypermethylation of tumor suppressor promoters (silencing)
• Global DNA hypomethylation (genomic instability)
• Histone modifications

9. Epidemiology and Risk Factors

• Age: Most cancer deaths occur between 55-75 years; rising incidence reflects accumulation of somatic mutations + declining immune surveillance with age.
• Environmental exposures:
  • Tobacco: responsible for ~90% of lung cancer deaths; also mouth, pharynx, larynx, esophagus, pancreas, bladder.
  • Alcohol: carcinogen for oropharynx, larynx, esophagus, breast, liver (acts synergistically with tobacco).
  • Diet/Obesity: increased risk for many cancers.
  • Radiation (UV, ionizing): melanoma, squamous/basal cell carcinoma; leukemia, thyroid.
  • Infectious agents: ~15% of all cancers worldwide (HPV → cervical/oropharyngeal; H. pylori → gastric; HBV/HCV → hepatocellular; EBV → Burkitt/nasopharyngeal; HTLV-1 → T-cell leukemia).
• Geographic variation: reflects environmental differences (e.g., Japanese migrants to USA show intermediate cancer rates that shift toward US rates over generations).

Hereditary cancer syndromes (autosomal dominant):

Autosomal recessive DNA repair defects:

• Xeroderma pigmentosum (nucleotide excision repair), Ataxia-telangiectasia (ATM), Fanconi anemia, Bloom syndrome

10. Clinical Aspects of Neoplasia

Effects of tumors on the host:

1. Location and compression - e.g., a small benign pituitary adenoma causing hypopituitarism; a small meningioma causing serious neurological deficits.
2. Functional activity - hormone-secreting tumors (e.g., beta-cell adenoma → hypoglycemia; adrenal pheochromocytoma → hypertension).
3. Ulceration and bleeding - particularly GI tumors.
4. Infection - in ulcerated masses.
5. Cachexia - progressive wasting; mediated by TNF-α, IL-6, and other cytokines; metabolic derangements outpace nutritional intake.
6. Paraneoplastic syndromes - signs/symptoms not explained by the tumor mass or metastases; caused by ectopic hormone secretion or autoimmune mechanisms (e.g., Cushing syndrome from ACTH-secreting small-cell lung cancer, hypercalcemia from PTHrP, Trousseau sign, cerebellar degeneration).

• Robbins & Kumar Basic Pathology, Chapter 6 (Neoplasia), pp. 187-240