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NEOPLASIA - Complete MUHS Exam Notes

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1. NEOPLASIA - Definition and Classification

Definition (Robbins)

"A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after cessation of the stimuli which evoked the change." - Willis

• Growth is autonomous (not regulated by normal controls)
• Monoclonal in origin (arises from a single transformed cell)
• Contains two components: parenchyma (neoplastic cells) and stroma (connective tissue + vessels)

Classification of Neoplasms

Nomenclature Table

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2. DIFFERENCES - Benign vs Malignant Neoplasms

Gross Appearance

• Rounded, well-circumscribed
• Usually encapsulated (fibrous capsule)
• Smooth surface
• Homogeneous cut surface
• No necrosis or hemorrhage
• Example: Uterine leiomyoma - "whorled white firm nodule"

• Irregular, ill-defined margins
• No capsule (invades surrounding tissue)
• Irregular surface
• Heterogeneous - areas of necrosis, hemorrhage
• "Crab-like" projections (hence "cancer" from Latin cancer = crab)
• Example: Carcinoma breast - hard, gritty, irregular mass with spiculated margins

Easy-to-Draw Gross Diagram

BENIGN TUMOR                    MALIGNANT TUMOR
    ___________                     ~~~~~~~~~~~
   /           \                   /  Necrosis  \
  |  Homogenous |                 |  /~~~~~~~~\  |
  |  well-defined|                | |Hemorrhage| |
  |   mass      |                 |  \~~~~~~~~/  |
   \___________ /                  \~irregular~/
   [Smooth capsule]               [No capsule, irregular]

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3. ANAPLASTIC TUMOR CELLS - Morphology

Morphological Features of Anaplastic Cells

• Pleomorphism - variation in size and shape of nuclei and cells
• Hyperchromatism - dark-staining nuclei (excess DNA)
• High nuclear:cytoplasmic (N:C) ratio - normally 1:4 to 1:6; in cancer cells approaches 1:1
• Prominent nucleoli - large, often multiple, "owl eye" appearance
• Abnormal mitoses - tripolar, quadripolar spindles; bizarre mitotic figures
• Coarse chromatin - clumped at nuclear membrane

• Loss of polarity (cells no longer arranged in organized fashion)
• Loss of cohesion between cells
• Abundant, often basophilic cytoplasm

• Loss of normal tissue architecture
• Sheets and nests of cells without gland formation
• Tumor giant cells - mononucleate or multinucleate

Histopathology Diagram (Easy to Draw in Exam)

NORMAL EPITHELIUM          ANAPLASTIC CARCINOMA
[ ] [ ] [ ] [ ]            [@@] [@@@] [@]
[ ] [ ] [ ] [ ]            [@@@@@][@][@@@@]
[ ] [ ] [ ] [ ]            [abnormal mitosis*]
                           ----basement membrane----
Regular nuclei,            Irregular, hyperchromatic
organized layers           nuclei, loss of polarity

• @ = large irregular dark nucleus
• • = abnormal mitotic figure (tripolar)

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4. TERATOMA

• Mature teratoma (Dermoid cyst): Benign; most common in ovary; contains hair, teeth, sebaceous material, cartilage, neural tissue
• Immature teratoma: Malignant; contains immature (embryonal) tissues, especially neural elements
• Monodermal teratoma: Specialized; e.g., struma ovarii (all thyroid tissue), carcinoid

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5. ROUTES/PATHWAYS OF SPREAD OF MALIGNANT NEOPLASMS

Modes of Metastasis

1. Direct/Local Invasion (Contiguous Spread)

• Tumor directly invades and destroys adjacent tissues
• Example: Carcinoma cervix invades bladder/rectum; carcinoma breast invades chest wall
• Mechanism: Proteases (MMPs), loss of E-cadherin, pseudopods

2. Lymphatic Spread (Most common for carcinomas)

• Tumor cells enter lymphatic channels and travel to regional lymph nodes
• Forms tumor emboli in lymph nodes
• Sentinel node = first draining lymph node (important in breast/melanoma surgery)
• Example: Carcinoma breast - axillary lymph nodes; carcinoma tongue - submandibular nodes
• Virchow's node = left supraclavicular node; enlarged in gastric carcinoma (Troisier's sign)

3. Hematogenous Spread (Most common for sarcomas)

• Tumor enters blood vessels (veins more than arteries - thinner walls)
• Portal system drains to liver; systemic veins to lungs
• Liver and lungs are most common sites of blood-borne metastases
• Example: Renal cell carcinoma - lung metastases; colon carcinoma - liver metastases; prostate - bone ("osteoblastic" metastases)
• Mechanism: Tumor cells secrete VEGF - angiogenesis - enter vessels - survive in circulation - adhere to endothelium - extravasate - proliferate

4. Transcoelomic (Seeding of Body Cavities)

• Tumor cells shed into peritoneal, pleural, or pericardial cavities
• Example: Ovarian carcinoma seeds peritoneum (pseudomyxoma peritonei); gastric carcinoma seeds peritoneum causing Krukenberg tumor (bilateral ovarian metastasis with signet ring cells)

5. Perineural Spread

• Tumor spreads along nerve sheaths
• Example: Carcinoma prostate, pancreas - perineural invasion
• Explains pain in many cancers

Metastasis - Mechanism (Invasion-Metastasis Cascade)

PRIMARY TUMOR
    |
    v
Invasion of ECM (loss of E-cadherin, ↑ MMPs)
    |
    v
Intravasation into blood/lymph vessels
    |
    v
Survival in circulation (evasion of NK cells)
    |
    v
Arrest in target organ capillaries
    |
    v
Extravasation
    |
    v
Proliferation → METASTATIC DEPOSIT

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6. LABORATORY DIAGNOSIS OF CANCER

A. Histologic and Cytologic Methods

• Most definitive method
• Entire lesion removed and examined
• Used for small accessible lesions

• Part of lesion taken
• Used for large, deep-seated lesions

• Small-bore needle aspirates cells
• Examined as smear on slide
• Rapid, minimally invasive
• Used for breast lump, thyroid, lymph nodes
• Limitation: Cannot assess architecture (only cytology)

• Cells shed naturally examined
• Pap smear - cervical cancer screening
• Sputum cytology - lung cancer
• Urine cytology - bladder cancer
• Pleural/ascitic fluid cytology

• Rapid intraoperative histology (within 30 minutes)
• Used to assess surgical margins during cancer surgery
• Limitation: Inferior morphologic detail

B. Immunohistochemistry (IHC)

• Antibodies against tissue-specific antigens
• Identifies cell lineage of poorly differentiated tumors

C. Flow Cytometry

• Rapid analysis of cell surface proteins, DNA content
• Used for classification of hematopoietic neoplasms
• Detects aneuploidy (abnormal DNA content - marker of malignancy)

D. Tumor Grading and Staging

• Grade 1 (well-differentiated) - low malignancy
• Grade 2 (moderately differentiated)
• Grade 3 (poorly differentiated) - high malignancy
• Grade 4 (undifferentiated/anaplastic)

• T = Primary tumor size (T0-T4)
• N = Regional lymph node involvement (N0-N3)
• M = Distant metastasis (M0-M1)

E. Molecular Diagnosis

• PCR - detects specific translocations (e.g., BCR-ABL in CML, t(9;22))
• FISH - detects gene amplifications (HER2 in breast cancer, MYCN in neuroblastoma)
• DNA sequencing - identifies driver mutations (TP53, KRAS, BRAF)
• Liquid biopsy - circulating tumor DNA (ctDNA) in blood
• Next-generation sequencing (NGS) - comprehensive mutational profiling

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7. TUMOR MARKERS - Role in Diagnosis

Uses of Tumor Markers

1. Screening (limited use - poor sensitivity/specificity)
2. Monitoring response to therapy
3. Detecting recurrence after treatment (most important use)
4. Prognosis

Important Tumor Markers Table

Limitations

• Low sensitivity (cancer may not produce marker)
• Low specificity (benign conditions also elevate markers)
• Best used for monitoring, not primary diagnosis

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8. ONCOGENIC VIRUSES - Enumerate, Cancer Caused by Each

RNA Oncogenic Viruses

DNA Oncogenic Viruses

HPV Mechanism Diagram (from Robbins)

Also: Bacterial Carcinogen

• H. pylori - Gastric adenocarcinoma and MALT lymphoma
• Mechanism: Chronic inflammation, CagA protein disrupts epithelial signaling

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9. CHEMICAL CARCINOGENESIS - Process and Examples

Definition

Two-Stage Process: Initiation and Promotion

Stage 1: INITIATION

• Exposure to initiating agent (carcinogen)
• Causes permanent, irreversible DNA mutation
• Single exposure sufficient
• Cell does not become malignant immediately
• The mutation is heritable (passed to daughter cells)
• Initiated cells = morphologically normal but genetically altered
• Cannot be reversed

Stage 2: PROMOTION

• Promoters act on initiated cells - no inherent carcinogenicity alone
• Cause clonal expansion of initiated mutated cells
• Stimulate cell proliferation, inhibit apoptosis
• Reversible - if promoter stopped, cells may not progress
• Example: Phorbol esters (TPA), chronic inflammation, unopposed estrogen

Progression

• Further mutations in expanding clone
• Acquisition of additional oncogenic alterations
• Eventual emergence of full malignant phenotype

KEY CONCEPTS

• Initiator without promoter = no tumor
• Promoter without initiator = no tumor
• Initiator first, THEN promoter = TUMOR
• Promoter first, THEN initiator = NO tumor (order matters!)

Classification of Chemical Carcinogens

A. Direct-Acting Carcinogens (do not require metabolic activation)

• Already reactive electrophiles
• Generally weak carcinogens
• Examples: β-Propiolactone, Dimethyl sulfate, Alkylating agents (cyclophosphamide, chlorambucil, nitrosoureas)
• Clinical note: Some anticancer drugs (alkylating agents) can cause secondary AML years later

B. Indirect-Acting Carcinogens (Procarcinogens)

• Require metabolic activation by cytochrome P-450 to become ultimate carcinogens
• More common and more potent

Mechanism of Action (MOA)

1. Chemical carcinogen (procarcinogen) enters cell
2. Metabolized by cytochrome P-450 to electrophilic ultimate carcinogen
3. Electrophile reacts with nucleophilic sites on DNA (guanine N-7 most common)
4. Forms DNA adducts
5. If repair fails - permanent mutation in proto-oncogene or tumor suppressor gene
6. Mutated cell = initiated cell
7. Promoters cause clonal expansion
8. Accumulation of additional mutations = cancer

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10. PARANEOPLASTIC SYNDROMES

Definition

• Local or distant spread of the tumor, OR
• Elaboration of hormones appropriate to the tissue of origin

Importance (Exam Point)

1. May be the earliest manifestation of an occult/occult neoplasm
2. May produce significant clinical illness (even lethal)
3. May mimic metastatic disease and confound treatment
4. Occur in ~10% of cancer patients

Classification with Examples (Robbins & Cotran Table 7.11)

A. Endocrinopathies (Ectopic Hormone Production)

B. Nerve and Muscle Syndromes

C. Dermatologic Disorders

D. Osseous/Articular Changes

E. Vascular/Hematologic Changes

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11. TELEPATHOLOGY AND PRECANCEROUS LESIONS

Telepathology

• Digital transmission of pathologic images for remote diagnosis
• Process: Glass slide - scanned to digital format - transmitted via internet - viewed remotely by pathologist
• Types:
  • Static - pre-selected images sent; quick but limited
  • Dynamic (real-time) - remote control of robotic microscope; comprehensive but needs fast network
  • Whole slide imaging (WSI)/Virtual microscopy - entire slide scanned at multiple magnifications; most modern approach
• Uses: Intraoperative frozen section consultation, expert second opinion, rural/underserved areas, digital pathology archives, AI integration

Precancerous Lesions (Precancerous Conditions)

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QUICK EXAM SUMMARY TABLES

Virchow's vs Sentinel Lymph Node

Key Differentials for Exam

• BLESS = Benign: Localized, Encapsulated, Slow-growing, Similar to normal, Seldom kills

• MIDAS = Malignant: Invasive, Differentiation (poor), Abnormal mitoses, Spreads (metastasizes), Survival (poor)

Routes of Spread - Summary

METASTASIS ROUTES
├── 1. Direct/Local invasion (all cancers)
├── 2. Lymphatic (carcinomas > sarcomas)
│         └── Regional LN → distant LN
├── 3. Hematogenous (sarcomas, RCC, HCC)
│         └── Via veins → Liver, Lungs, Brain, Bone
├── 4. Transcoelomic (peritoneal, pleural)
│         └── Ovarian Ca → peritoneum
└── 5. Perineural spread
          └── Prostate Ca, Pancreatic Ca

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Sources

• Robbins, Cotran & Kumar Pathologic Basis of Disease (10th Ed.) - Chapters 7 (Neoplasia), Block 3-4
• Robbins & Kumar Basic Pathology - Chapter 6 (Neoplasia)
• All images: Robbins & Cotran Pathologic Basis of Disease via medical library

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• Define every term asked - neoplasia, metastasis, paraneoplastic syndrome
• Always write a table when comparing benign vs malignant
• Draw the chemical carcinogenesis diagram (initiation-promotion) - easy marks
• For oncogenic viruses - remember virus name, cancer type, and one key protein/mechanism
• Paraneoplastic: Always mention "10% of cancers," give 3-4 clinical examples, explain significance
• Lab diagnosis: Organize as histologic, IHC, molecular, tumor markers - don't mix them up
• Routes of spread: Always give an example for each route