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NEOPLASIA - Comprehensive 2nd Year MBBS Pathology Notes (Robbins)

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1. NEOPLASIA - Definition

• The word "tumor" originally meant swelling from inflammation but is now equated with neoplasm.
• Oncology (Greek oncos = tumor) is the study of tumors.
• All tumors have two components:
  • Parenchyma: the neoplastic cells themselves (determines behavior and classification)
  • Stroma: supportive connective tissue, blood vessels, and immune cells (determines growth and spread)
• When parenchymal cells stimulate abundant collagen production, it is called desmoplasia (e.g., scirrhous carcinoma of the breast).

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2. CLASSIFICATION OF NEOPLASMS

A. Based on Behavior

B. Based on Cell/Tissue of Origin (Nomenclature)

• Mesenchymal benign tumors: cell name + "-oma" (e.g., fibroma, lipoma)
• Malignant mesenchymal: cell name + "-sarcoma"
• Malignant epithelial: "carcinoma" (glandular = adenocarcinoma; squamous = squamous cell carcinoma)
• Some confusing names: lymphoma, melanoma, mesothelioma, and seminoma are all malignant despite benign-sounding names
• Hamartoma: disorganized mass of indigenous cells (e.g., pulmonary hamartoma) - benign
• Choristoma: heterotopic rest of normal cells (e.g., pancreatic tissue in stomach wall)

C. Carcinomas vs. Sarcomas

• Carcinoma: malignant neoplasm of epithelial origin (most common human cancers)
• Sarcoma: malignant neoplasm of mesenchymal origin

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3. BENIGN vs. MALIGNANT NEOPLASMS - Differences

• Pleomorphism (cellular and nuclear)
• Abnormal nuclear morphology (hyperchromatism, coarse chromatin, prominent nucleoli)
• Increased mitotic figures, including atypical (tripolar/quadripolar) mitoses
• Loss of polarity
• Giant cells (tumor giant cells)

"Next to metastasis, invasiveness is the most reliable discriminator of malignant and benign tumors." - Robbins PBD

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4. MALIGNANT NEOPLASMS - Routes / Pathways of Spread (Metastasis)

Routes of Spread:

A. Lymphatic Spread

• Most common route for carcinomas
• Tumor cells invade lymphatic channels and travel to regional lymph nodes, then to distant nodes
• The first lymph node to receive drainage from a primary tumor is the sentinel lymph node - biopsy of this node can determine spread
• Examples:
  • Breast carcinoma → axillary lymph nodes (medial tumors → internal mammary nodes)
  • Carcinoma of the lung → hilar and mediastinal lymph nodes
  • Stomach carcinoma → left supraclavicular node (Virchow's node - Troisier's sign)
  • Prostate carcinoma → pelvic lymph nodes
• "Skip metastasis" can occur - tumor bypasses local nodes to appear in distant nodes

B. Hematogenous (Blood-borne) Spread

• Typical of sarcomas but also many carcinomas
• Tumor cells enter blood vessels (veins more easily than arteries - thinner walls)
• Portal vein drainage → liver (colorectal carcinoma)
• Pulmonary veins → lung (most tumors)
• Vertebral plexus (Batson plexus) → vertebral column (prostate, breast, thyroid, renal, lung - "BPTRL")
• Common sites of hematogenous metastasis: liver, lungs, brain, bone
• Examples:
  • Follicular thyroid carcinoma - hematogenous (not lymphatic) spread
  • Renal cell carcinoma → lungs ("cannonball" metastases on X-ray)
  • Prostate carcinoma → bones (osteoblastic metastases)
  • Breast/lung carcinoma → brain

C. Seeding/Transcoelomic Spread (Spread across Body Cavities)

• Tumor cells penetrate into natural body cavities (peritoneal, pleural, pericardial, subarachnoid)
• Dissemination as free-floating fragments or tumor cells
• Examples:
  • Carcinoma of the stomach or colon → peritoneal cavity → pseudomyxoma peritonei (ovarian/appendicular mucinous tumors)
  • Ovarian carcinoma seeds the peritoneal cavity diffusely
  • Malignant mesothelioma seeds the pleural cavity
  • Krukenberg tumor: gastric or colorectal adenocarcinoma metastasizes to both ovaries via transcoelomic spread; mucin-secreting signet ring cells
  • Brain tumors (e.g., medulloblastoma, ependymoma) spread via cerebrospinal fluid (subarachnoid seeding)

D. Direct (Contiguous) Spread

• Local invasion through tissues to adjacent organs
• Examples:
  • Carcinoma of the rectum invades bladder, uterus
  • Carcinoma of the stomach invades pancreas
  • Carcinoma of the cervix invades rectum, bladder

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5. MODES OF METASTASIS (Summary)

1. Local invasion of the ECM - loss of E-cadherin, activation of MMPs (matrix metalloproteinases) to degrade basement membrane and interstitial matrix
2. Intravasation - entry into blood/lymphatic vessels
3. Survival in circulation - evasion of immune destruction
4. Arrest in distant organ capillary beds
5. Extravasation - exit from vessels at new site
6. Colonization - formation of micrometastasis, then macrometastasis (requires angiogenesis)

• Anatomical (vascular/lymphatic) patterns of drainage
• Expression of adhesion molecules on tumor cells matching ligands in target organs
• Chemokine receptors on tumor cells matching chemokines produced by target organs (e.g., CXCR4 on breast cancer cells; CXCL12 in bone marrow)

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6. TUMOUR MARKERS - Role in Diagnosis

• Screening (limited - low specificity)
• Diagnosis (supportive, not definitive)
• Staging and prognosis
• Monitoring response to therapy
• Detection of recurrence after treatment

Major Tumor Markers:

AFP and CEA are oncofetal antigens - normally expressed in fetal tissue, re-expressed in malignancy.

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7. LABORATORY DIAGNOSIS OF CANCER

Sampling Approaches:

1. Excision (complete removal - small lesions)
2. Incisional biopsy (taking a portion of a large mass)
3. Core needle biopsy (cutting needle - preserves architecture)
4. Fine-needle aspiration (FNA) - small-gauge needle; yields cells for cytology (not histology)
5. Cytologic smears - exfoliated cells (e.g., Pap smear for cervical cancer; sputum cytology; urine cytology; pleural/ascitic fluid)

Testing Modalities:

• Histopathology (routine H&E): gold standard; reveals tissue architecture, differentiation, invasion
• Immunohistochemistry (IHC): identifies protein expression to classify tumor lineage
  • Cytokeratin → carcinoma (epithelial)
  • Vimentin → sarcoma (mesenchymal)
  • LCA (CD45) → lymphoma
  • S-100, HMB-45 → melanoma
  • PSA → prostate carcinoma
  • ER/PR, HER2 → breast carcinoma (prognostic and therapeutic)
• Flow cytometry: immunophenotyping of leukemias and lymphomas using surface markers
• Serum tumor markers: PSA, AFP, CEA, CA-125, beta-hCG (discussed above)
• Molecular profiling (DNA/RNA sequencing, FISH, PCR):
  • Diagnose specific entities (BCR-ABL in CML; t(14;18) in follicular lymphoma)
  • Identify therapeutic targets (EGFR mutation in lung cancer → erlotinib/gefitinib)
  • Detect minimal residual disease (MRD)
  • Identify hereditary cancer predisposition (BRCA1/2)
  • Liquid biopsy: circulating tumor DNA (ctDNA) and circulating tumor cells in blood, urine, stool, sputum

Grading vs. Staging:

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8. TERATOMA

Classification:

1. Mature (Benign) Teratoma

• Most common form, especially in females (dermoid cyst)
• Cystic; lined by squamous epithelium with hair shafts, sebaceous glands, teeth, and cartilage
• Usually found in young adult women
• Karyotype: 46,XX in ovarian teratomas
• Origin: arises from an ovum after the first meiotic division
• Bilateral in 10-15% of cases
• Malignant transformation in ~1% - most commonly to squamous cell carcinoma
• May cause paraneoplastic syndromes (e.g., inflammatory limbic encephalitis)

2. Immature (Malignant) Teratoma

• Contains immature/embryonal tissue - most often immature neuroectodermal tissue (neural tube-like structures)
• Graded I-III based on proportion of immature neuroepithelial elements
• Aggressive; can metastasize
• More common in children and young adults

3. Monodermal (Highly Specialized) Teratoma

• Composed predominantly of one tissue type
• Examples:
  • Struma ovarii: predominantly thyroid tissue; may cause hyperthyroidism
  • Carcinoid tumor of the ovary: neuroendocrine cells; may cause carcinoid syndrome if bilateral/metastatic

• Mature teratoma in children: benign
• Mature teratoma in adults: considered malignant (unlike in females) due to metastatic potential
• Often mixed with other germ cell components

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9. CHEMICAL CARCINOGENESIS

Description:

Steps with Examples:

Step 1: INITIATION

• Exposure to a carcinogen (initiator) in sufficient dose
• Causes permanent, irreversible DNA mutation
• The cell is "initiated" - it carries a heritable genetic change but looks normal
• Single exposure is sufficient; effect is permanent and cumulative
• Example: benzo[a]pyrene (cigarette smoke) → metabolized by cytochrome P-450 to an epoxide → binds guanine → G→T transversion mutation in TP53 or RAS

Step 2: PROMOTION

• Exposure to a promoter (non-carcinogenic by itself)
• Causes proliferation of initiated cells - clonal expansion of mutated cells
• Effect is reversible if promoter is withdrawn (unlike initiation)
• Drives accumulation of further mutations in subclones
• Examples: phorbol esters (TPA/PMA) - promote tumors in mouse skin experiments; estrogen - promotes endometrial and breast cancers; chronic inflammation (IBD, chronic hepatitis, Barrett esophagus)

Step 3: PROGRESSION

• Accumulation of additional mutations
• Gradual acquisition of the malignant phenotype (invasiveness, metastatic ability)
• Subclones emerge through Darwinian selection
• Genomically unstable clones survive and proliferate

Types of Chemical Carcinogens:

• Alkylating agents: β-propiolactone, dimethyl sulfate, diepoxybutane
• Anticancer drugs: cyclophosphamide, chlorambucil, nitrosoureas (cause secondary leukemias)
• Acylating agents: 1-acetyl-imidazole, dimethylcarbamoyl chloride

• Polycyclic aromatic hydrocarbons: benz[a]pyrene (tobacco smoke, barbecued meat) → lung, skin cancer
• Aromatic amines/azo dyes: 2-naphthylamine (β-naphthylamine) → bladder cancer (excreted as glucuronide, cleaved in bladder); dimethylaminoazobenzene (butter yellow) → liver cancer
• Nitrosamines: nitrosamines in smoked meats → stomach cancer
• Natural products:
  • Aflatoxin B1 (Aspergillus flavus on peanuts/grains) → binds guanine, causes G→T mutation in codon 249 of TP53 → hepatocellular carcinoma (especially in HBV-endemic areas)
  • Cycasin, betel nuts
• Others: vinyl chloride → angiosarcoma of the liver; asbestos → mesothelioma, bronchogenic carcinoma; benzene → leukemia; nickel/chromium → lung/nasal sinus carcinoma

Key Molecular Mechanism:

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10. QUICK REFERENCE COMPARISON TABLE

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Exam Tips (2nd Year MBBS):

• Definition of neoplasm (Robbins): disorder of cell growth triggered by mutations, independent of physiologic controls
• Metastasis = only reliable hallmark that distinguishes benign from malignant (some malignant tumors like glioma and BCC rarely metastasize but they are still malignant because they invade)
• Most common route of spread for carcinomas = lymphatic; for sarcomas = hematogenous
• Virchow's node = left supraclavicular node enlarged by gastric carcinoma (Troisier's sign)
• Krukenberg tumor = bilateral ovarian metastases from gastric/colorectal signet-ring cell carcinoma
• AFP = HCC + yolk sac tumor; CEA = colorectal; PSA = prostate; CA-125 = ovary; hCG = choriocarcinoma
• Aflatoxin B1 → codon 249 TP53 mutation → HCC
• Teratoma: contains all 3 germ layers; ovarian = usually benign; testicular adult = malignant
• Initiation is irreversible; promotion is reversibleAll notes are drawn directly from Robbins & Cotran Pathologic Basis of Disease and Robbins & Kumar Basic Pathology. Here is a topic-by-topic summary of what is covered above:

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What's Covered (All Your Topics):

1. Neoplasia - Definition: Disorder of cell growth from mutations giving growth advantage independent of physiologic controls (Robbins PBD, p. 254)
2. Classification: Benign vs. malignant; carcinoma vs. sarcoma; full nomenclature table by tissue of origin; mixed tumors; confusing names (lymphoma, melanoma are malignant)
3. Benign vs. Malignant Neoplasms - Differences: Complete comparison table covering differentiation, anaplasia, growth rate, invasion, capsule, metastasis, nuclear features, necrosis, recurrence, prognosis
4. Routes / Pathways of Spread of Malignant Neoplasms:
   • Lymphatic (carcinomas) - axillary nodes (breast), Virchow's node (stomach)
   • Hematogenous (sarcomas + carcinomas) - liver, lungs, bone, brain; Batson's plexus
   • Transcoelomic/Seeding - peritoneal cavity (ovarian Ca, Krukenberg tumor), CSF (medulloblastoma)
   • Direct/Contiguous spread
5. Modes of Metastasis: Full invasion-metastasis cascade (loss of E-cadherin, MMP activation, intravasation, survival, extravasation, colonization); organ tropism via chemokine receptors
6. Tumor Markers: AFP, CEA, PSA, hCG, CA-125, CA 19-9, CA 15-3, calcitonin, LDH, thyroglobulin - with normal values, associated cancers, clinical uses and limitations
7. Cancer - Laboratory Diagnosis: Biopsy types, histopathology, IHC, flow cytometry, molecular profiling, liquid biopsy, grading vs. staging
8. Teratoma: Definition, origin (totipotential germ cells), three categories (mature/benign, immature/malignant, monodermal), dermoid cyst morphology, struma ovarii, carcinoid; testicular vs. ovarian differences
9. Chemical Carcinogenesis: Initiation (irreversible, DNA mutation) → Promotion (reversible, clonal expansion) → Progression; direct-acting vs. indirect-acting (procarcinogens); key examples: benzo[a]pyrene (lung), aflatoxin B1 (HCC, codon 249 TP53), 2-naphthylamine (bladder), vinyl chloride (angiosarcoma), nitrosamines (stomach)