Neoplasia: Hallmarks & Progression
Grade vs stage, carcinoma vs sarcoma, and the paraneoplastic classics
Benign vs malignant and tumor nomenclature
Neoplasia. A neoplasm is a clonal proliferation that keeps growing after the initiating stimulus is gone. Hyperplasia, by contrast, is a polyclonal response that regresses when the stimulus is removed.
Benign stays put; malignant invades. Benign tumors are well differentiated, grow slowly with few mitoses, are usually encapsulated and noninvasive, and do not metastasize. Malignant tumors range from well differentiated to anaplastic, grow rapidly with atypical mitoses, invade, and metastasize. Metastasis is the single most definitive sign of malignancy: a bland-looking tumor that has metastasized is malignant.
| Feature | Benign | Malignant |
|---|---|---|
| Differentiation | Well differentiated; resembles tissue of origin | Variable, up to anaplastic |
| Growth | Slow; few, normal mitoses | Rapid; atypical mitoses |
| Borders | Encapsulated, noninvasive | Invasive, poorly demarcated |
| Metastasis | Never | Yes (most definitive sign) |
| Usual name | "-oma" (adenoma, lipoma, papilloma) | Carcinoma or sarcoma |
Carcinoma vs sarcoma. A malignant epithelial tumor is a carcinoma: adenocarcinoma if it forms glands, squamous cell carcinoma if it recapitulates squamous epithelium. A malignant mesenchymal (connective tissue) tumor is a sarcoma, such as liposarcoma or osteosarcoma. Carcinomas are far more common and occur mainly in older adults; several sarcomas (osteosarcoma, Ewing sarcoma, rhabdomyosarcoma) peak in children and adolescents.
| Tissue | Benign | Malignant |
|---|---|---|
| Glandular epithelium | Adenoma | Adenocarcinoma |
| Squamous epithelium | Papilloma | Squamous cell carcinoma |
| Fat | Lipoma | Liposarcoma |
| Bone | Osteoma | Osteosarcoma |
| Smooth muscle | Leiomyoma | Leiomyosarcoma |
| Skeletal muscle | Rhabdomyoma | Rhabdomyosarcoma |
| Blood vessels | Hemangioma | Angiosarcoma |
Look-alike terms. A hamartoma is a disorganized overgrowth of tissue native to the site (e.g., pulmonary hamartoma); a choristoma is normal tissue in an abnormal location (e.g., pancreatic rest in the stomach wall); a teratoma contains tissues from more than one germ layer.
Anaplasia, dysplasia, and carcinoma in situ
Anaplasia. Literally "to form backward": loss of differentiation, dedifferentiating toward primitive cells. It is the cytologic hallmark of malignancy and shows:
- Pleomorphism (variation in cell and nuclear size and shape)
- High nuclear-to-cytoplasmic ratio
- Hyperchromatic nuclei with prominent nucleoli
- Abnormal (atypical) mitoses
- Loss of polarity (disorganized orientation)
Dysplasia. Disordered epithelial growth with cellular atypia and loss of normal maturation. Mild to moderate dysplasia may regress if the stimulus is removed (severe dysplasia often does not), and it often follows chronic injury or metaplasia (e.g., Barrett esophagus, HPV infection of the cervix).
Carcinoma in situ (CIS). Full-thickness atypia with an intact basement membrane. Because lymphatics and vessels lie beneath the basement membrane, CIS cannot yet spread. Examples: cervical CIN 3 and ductal carcinoma in situ of the breast.
Invasive carcinoma. Once cells breach the basement membrane the lesion is invasive; invasion defines malignancy and opens the route to metastasis.
- NormalOrganized, maturing epithelium
- DysplasiaDisordered growth; potentially reversible atypia
- Carcinoma in situFull-thickness atypia; basement membrane intact
- Invasive carcinomaBreaches the basement membrane
- MetastasisDistant spread
Grade, stage, and spread
Grade vs stage. Grade is the degree of differentiation (how abnormal the cells look on histology; e.g., Gleason score in prostate cancer). Stage is the extent of spread: size, nodes, and metastases. Stage has greater prognostic value than grade, so two colon cancers of identical grade can have very different outcomes.
TNM. T = tumor size and local extent, N = regional lymph node involvement, M = distant metastasis. Distant metastasis (M) is the single most important prognostic factor (M > N > T).
Routes of spread. Carcinomas typically spread first through lymphatics to regional nodes (the basis of sentinel node biopsy); sarcomas spread hematogenously. Carcinomas that spread through blood like sarcomas: renal cell carcinoma, hepatocellular carcinoma, follicular thyroid carcinoma, and choriocarcinoma. A third route is seeding of body cavities, classically ovarian carcinoma across the peritoneum. Liver and lung are the most common sites of blood-borne metastases, and in adults metastases outnumber primary tumors in liver, brain, and bone.
- DetachmentLoss of E-cadherin breaks cell-cell adhesion
- AttachmentCells bind laminin in the basement membrane
- DegradationMMPs/collagenases digest type IV collagen
- IntravasationEntry into vessels or lymphatics
- Survival in circulationEvade immune attack and shear stress
- Extravasation and colonizationExit at a distant site and grow
Germline or somatic loss of E-cadherin (CDH1) is characteristic of invasive lobular breast carcinoma and diffuse (signet ring cell) gastric carcinoma, which infiltrate as single, discohesive cells.
Hallmarks of cancer
Hanahan-Weinberg hallmarks. Six acquired capabilities let a clone escape normal controls:
- Self-sufficiency in growth signals: activated oncogenes (e.g., RAS, MYC, HER2)
- Insensitivity to anti-growth signals: loss of tumor suppressors such as RB and p53 at the G1/S checkpoint
- Evasion of apoptosis: e.g., BCL-2 overexpression from t(14;18) in follicular lymphoma
- Limitless replication: telomerase maintains telomeres
- Sustained angiogenesis: VEGF and FGF recruit new vessels
- Tissue invasion and metastasis
Later additions. Immune evasion (e.g., PD-L1 expression engaging PD-1 on T cells, the target of checkpoint inhibitors) and altered metabolism. The Warburg effect is aerobic glycolysis: tumor cells favor glycolysis to lactate even with ample oxygen, which supplies biosynthetic building blocks and underlies FDG-PET imaging. Genomic instability and tumor-promoting inflammation act as enabling characteristics.
Systemic effects: cachexia and paraneoplastic syndromes
Cachexia. Weight loss, muscle wasting, and anorexia caused by a cytokine-mediated catabolic state, not simply by the tumor consuming nutrients. Mediators: TNF-α (originally named cachectin), IL-6, and IFN-γ; IL-1 also contributes.
Paraneoplastic syndromes. Effects of tumor-secreted hormones or cytokines, or of cross-reacting antibodies, rather than of local tumor bulk; they may be the first clue to an occult cancer.
| Syndrome | Mediator | Classic tumor(s) |
|---|---|---|
| SIADH (hyponatremia) | ADH | Small cell lung cancer |
| Cushing syndrome | ACTH | Small cell lung cancer |
| Lambert-Eaton syndrome | Antibodies to presynaptic P/Q-type Ca²⁺ channels | Small cell lung cancer |
| Hypercalcemia | PTHrP | Squamous cell lung, head and neck, renal cell, bladder |
| Hypercalcemia | 1,25-(OH)₂ vitamin D | Lymphoma |
| Polycythemia | Erythropoietin | Renal cell, hepatocellular, hemangioblastoma, pheochromocytoma |
| Myasthenia gravis | Anti-AChR antibodies | Thymoma |
| Anti-NMDA receptor encephalitis | Anti-NMDA receptor antibodies | Ovarian teratoma |
Reading the labs. SIADH from ectopic ADH gives euvolemic hyponatremia with low serum osmolality and inappropriately concentrated urine. PTHrP-driven hypercalcemia comes with a suppressed PTH, because PTHrP is not detected by the PTH assay. In lymphoma, tumor cells express 1α-hydroxylase and convert 25-OH vitamin D to calcitriol.
Skin and clotting clues. Acanthosis nigricans (velvety hyperpigmented plaques) signals gastric adenocarcinoma; a sudden eruption of seborrheic keratoses (sign of Leser-Trélat) signals GI adenocarcinoma; migratory superficial thrombophlebitis (Trousseau syndrome) signals pancreatic adenocarcinoma.
Small cell lung cancer = ADH + ACTH + Lambert-Eaton (proximal weakness that improves with repeated use). Squamous cell lung cancer = PTHrP and hypercalcemia.