Neoplasm

Definition

"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."

Structure of a Neoplasm

1. Parenchyma - the neoplastic cells themselves. The classification and biologic behavior of a tumor are based primarily on this component.
2. Reactive stroma - supportive connective tissue, blood vessels, and immune cells. Growth and spread are critically dependent on the stroma (it supplies the blood supply).

• Some tumors have scant connective tissue and are soft/fleshy.
• Others stimulate abundant collagen formation (called desmoplasia), making them stony hard (e.g., some breast cancers, called scirrhous tumors).

Classification: Benign vs. Malignant

Benign Tumors

Malignant Tumors ("Cancer")

• Carcinomas - from epithelial cells (e.g., adenocarcinoma, squamous cell carcinoma)
• Sarcomas - from mesenchymal/solid connective tissues (e.g., fibrosarcoma, chondrosarcoma)
• Leukemias/Lymphomas - from blood-forming cells and lymphocytes

Key Molecular Concepts

• Mutations may be from mutagen exposure, spontaneous replication errors, or inheritance.
• Epigenetic changes (altered DNA methylation, histone modification) also play a role.
• Genetic alterations are heritable (passed to daughter cells), so cells with growth advantages outcompete neighbors - a process of Darwinian selection / clonal evolution.
• Individual tumors begin as clonal (progeny of a single mutated cell).

Special Types

• Mixed tumors - contain more than one cell lineage (e.g., pleomorphic adenoma of the salivary gland, with both epithelial and myxoid/cartilaginous components).
• Teratoma - arises from totipotential germ cells; contains cells from more than one germ layer (ectoderm, mesoderm, endoderm), potentially forming bone, hair, teeth, nerve tissue, etc.
• Undifferentiated malignant neoplasm - ~2% of cancers; cells of unknown origin.

Precursor / Pre-neoplastic Changes

• Metaplasia - replacement of one cell type by another
• Dysplasia - disordered but not yet autonomous growth
• These can progress to neoplasia with further mutations.

Tumor: Definition and Classification by Nature

Definition

1. Differentiation and anaplasia
2. Local invasion
3. Metastasis

Classification Based on Nature

1. Benign Tumors

• Well-differentiated - cells closely resemble their normal tissue of origin, both morphologically and functionally
• Slow growth - mitoses are rare and of normal configuration
• Encapsulated - usually surrounded by a fibrous capsule, clearly demarcating them from surrounding tissue
• Non-invasive - pushing borders, not infiltrating
• No metastasis
• Usually not fatal - exceptions occur when located in critical areas (e.g., a benign brain tumor can still be life-threatening due to mass effect)

Benign follicular adenoma of the thyroid. Note the well-differentiated, normal-looking colloid-filled thyroid follicles. (Robbins, Cotran & Kumar)

2. Malignant Tumors (Cancer)

• Variable differentiation - from well-differentiated to poorly differentiated (anaplastic)
• Anaplasia - loss of differentiation; reliable indicator of malignancy. Features include:
  • Pleomorphism - variation in cell size and shape
  • Abnormal nuclear morphology - large, hyperchromatic nuclei; increased nuclear:cytoplasm ratio (approaches 1:1 vs normal 1:4 to 1:6); irregular nuclear shape
  • Abnormal mitoses - atypical, bizarre mitotic figures (tripolar, quadripolar spindles)
  • Loss of polarity - disorganized cell arrangement relative to each other and basement membranes
  • Tumor giant cells - single huge polymorphic nucleus or multiple large hyperchromatic nuclei
• Invasive - infiltrating, irregular borders; destroys adjacent tissue
• Metastasis - spread via lymphatics, blood vessels, or body cavities
• Areas of necrosis - due to rapid growth outpacing vascular supply

Anaplastic tumor showing cellular and nuclear variation in size and shape. The arrow points to a tripolar spindle - an abnormal mitosis. (Robbins, Cotran & Kumar)

3. Borderline / Intermediate Tumors

• Show nuclear abnormalities and mitotic activity exceeding benign tumors but lack frank stromal invasion
• Classic example: borderline epithelial tumors of the ovary (serous borderline tumor / tumor of low malignant potential)
• Behavior is unpredictable - they may recur locally or, rarely, metastasize

Comparison Table: Benign vs. Malignant

Nomenclature Summary by Tissue of Origin

Note on exceptions: Some malignant tumors carry names ending in -oma (misleadingly suggesting benign): lymphoma, melanoma, mesothelioma, and seminoma are all malignant. These exceptions are firmly entrenched in medical terminology.

Genes, Oncogenes, and Tumor Suppressor Genes

1. Definition of a Gene

• Humans have approximately 20,000–25,000 protein-coding genes, located on 23 pairs of chromosomes.
• DNA exists as a double helix held together by complementary base pairing (A-T, G-C).
• Each gene has two copies called alleles - one inherited from each parent.
• Gene expression follows the central dogma: DNA → mRNA (transcription) → Protein (translation).
• Mutations (changes in DNA sequence) can alter gene function - the foundation of cancer biology.

2. Oncogenes

Definition

"Proto-oncogenes encode growth factors, growth factor receptors, signal transducers, transcription factors, or cell cycle components. The corresponding oncogenes encode oncoproteins with functions like their normal counterparts, with the important difference that they are usually constitutively active and thereby relieve cells of their normal dependency on growth factors."

• Robbins, Cotran & Kumar - Pathologic Basis of Disease

How Proto-oncogenes Become Oncogenes

Genetic behavior

• Dominant - only one mutated allele is sufficient to drive oncogenesis (gain-of-function)
• The normal allele cannot compensate for the hyperactive mutant

Types of Oncogene Products (Proto-oncogene categories)

Signal transduction steps involving proto-oncogene products (Emery's Elements of Medical Genetics)

3. Tumor Suppressor Genes (TSGs)

Definition

"The products of most tumor suppressor genes act as negative regulators of cell proliferation, and loss of their function therefore leads to excessive growth. Tumor suppressor proteins control a series of checkpoints that prevent uncontrolled growth."

• Robbins, Cotran & Kumar - Pathologic Basis of Disease

Knudson's "Two-Hit" Hypothesis

• First hit - mutation/deletion of one allele (may be germline/inherited or somatic)
• Second hit - loss or mutation of the remaining normal allele (somatic event)

• Familial cases (e.g., familial retinoblastoma) - inherit one defective allele; only one somatic hit needed → earlier, bilateral tumors
• Sporadic cases - both hits must occur somatically → later, usually unilateral tumors

Mechanisms of TSG Inactivation

Key Tumor Suppressor Genes

p53 and MDM2: In unstressed cells, p53 has a short half-life (~20 min) because MDM2 targets it for destruction. DNA damage activates kinases (e.g., ATM) that release p53 from MDM2, stabilizing it to activate hundreds of target genes that induce cell cycle arrest, senescence, or apoptosis.

4. Key Differences: Oncogenes vs. Tumor Suppressor Genes

Key Concept: Cancer generally requires both mechanisms - oncogene activation to press the accelerator, and tumor suppressor gene inactivation to cut the brakes. This is why carcinogenesis is a multi-step process requiring accumulation of multiple genetic "hits" over time.