• Clinical science

General oncology

Abstract

Oncology is the science of tumors. This learning card explains basic concepts relevant to the development, progression, spread, complications, diagnosis, and management of cancer. Histological analysis helps to determine tumor type and grade, whereas the TNM classification system is used to assess staging. Because it is standardized and used internationally, the TNM classification helps unify oncological research and therapy protocols. Metastasis occurs via different pathways mainly by hematogenous or lymphatic spreading. Therapy can be curative (mostly in early tumor stages) or palliative (mostly later stages). In addition to surgically removing a tumor, it can be beneficial to perform neoadjuvant (before surgery) and/or adjuvant (after surgery) radiation, chemotherapy, or both. Response rates to these forms of treatment are highly variable.

In addition to local effects, such as compression or infiltration of neighboring structures, malignant tumors can also cause systemic complications such as paraneoplastic syndromes and cancer anorexia-cachexia syndrome. See the learning card on paraneoplastic syndromes for more information.

For more details about tumor markers and immunohistochemical markers, see the learning card on tumor markers.

Nomenclature

Terminology

Term Definition
Normal cell
  • Cells without atypia, pleomorphism, or dysplasia
  • Normal nuclear:cytoplasmic ratio
  • Intact cell polarity
Neoplasia
  • Abnormal growth of cells. Can be either malignant or benign.
Tumor
  • Abnormal growth of cells or edema that leads to swelling of tissue
Carcinoma
Sarcoma
  • Malignant cells arise from mesenchyme (e.g., sarcoma botryoides, liposarcoma, leiomyosarcoma)
Dysplasia
  • Presence of pleomorphism: cells of different shape and size
  • Loss of cell orientation
  • Increased nuclear:cytoplasmic ratio
  • No invasion of the basement membrane
Carcinoma in situ (CIS)
Invasive carcinoma
  • Invasion of the basement membrane
  • Factors that promote invasion
    • Metalloproteases (e.g., hydrolases, collagenases)
    • Inactivation of E-cadherins → removal of contacts between neighboring cells
Metastasis
  • Spread of malignant cells to distant organs, tissues (e.g., colorectal cancer spreading to the liver)
    • Lymphatic spread
    • Hematogenous spread

Benign and malignant tumors

Benign tumor Malignant tumor
Differentiation (grading)
  • Well differentiated (low grade)
  • Poorly differentiated (high grade)
Growth
  • Slow with low rate of cell division (low mitotic rate)
  • "Mass effect" with compression of non-tumor tissue
  • Rapid with high rate of cell division (high mitotic rate)
  • Locally destructive and invasive
Macroscopy
  • Well demarcated from surrounding tissue
  • Possible necrosis (e.g., squamous cell carcinoma of the lung)
  • Usually no tumor capsule
  • Infiltration (invasion) into surrounding tissue
  • Bleeding
Microscopy
  • Almost no irregularities of cellular structures
  • Detection and confirmation of cellular atypia
    • Nuclei: enlargement , polymorphism , increased cell count and/or enlarged nucleoli are all signs of increased activity of nuclei, polychromasia
    • Numerous mitotic figures

Metastasis and relapse

Tumor origin

Cell origin Benign tumor Malignant tumor
Epithelial tumors
  • Papilloma
  • Squamous cell carcinoma
  • Adenoma
  • Adenocarcinoma

Mesenchymal tumors

  • Fibroma
  • Fibrosarcoma
  • Liposarcoma
  • Chondroma
  • Blood vessels
  • Hemangioma
  • Hemangiosarcoma
  • Lymphatic vessels
  • Lymphangioma
  • Lymphangiosarcoma
  • Rhabdomyocytes
  • Rhabdomyoma
  • Leiomyocytes
  • Leiomyoma
  • Leiomyosarcoma
  • Mesothelium
  • Neuroectodermal cells
Special variants of mesenchymal tumors
Neuroectodermal tumors
  • Benign glioma
Germ cell tumors
  • Germ cells
Embryonal tumors

References:[1]

General epidemiology (United States)

In 2018, approximately 1.7 million people will be diagnosed with cancer in the United States. Cancer is the 2nd leading cause of death after heart disease. The most common type of cancer in both men and women is skin cancer, with basal cell carcinoma being more common than squamous cell carcinoma and melanoma.

Epidemiology of common cancer types in 2018

The following numbers are an estimation of new cancer cases and their mortality in the United States (excluding skin cancer).

Type Incidence/year in men Incidence/year in women Mortality/year
Breast 2,550 266,120 41,400
Lung and Bronchus 121,680 112,350 154,050
Prostate 164,690 N/A 29,430
Colorectal 75,610 64,640 50,630
Bladder 62,380 18,810 17,240
Kidney 42,680 22,660 14,970
Uterus N/A 63,230 11,350
Pancreas 29,200 26,240 44,330
Thyroid 13,090 40,900 2,060
Non-Hodgkin lymphoma 41,730 32,950 19,910
Leukemia 35,030 25,270 24,370

References:[2]

Carcinogenesis

  • Definition: A multistep process by which normal cells develop and accumulate genetic mutations (inherited or acquired), resulting in a monoclonal expansion of mutated cells that can progress to the development of neoplasia.
  • Process
    1. Initiation: DNA damage
    2. Promotion: DNA damage is passed on
    3. Latency: time between promotion and progression
    4. Progression: The neoplastic cell line proliferates with the acquired DNA damage, leading to malignant transformation.

DNA damage

Key genes involved in carcinogenesis

Properties of malignant cells

  • Uncontrolled cell proliferation
  • Failure to differentiate
  • Failure of normal apoptotic pathways
  • Defective DNA repair pathways
  • Lack of response to external growth inhibiting signals
  • Increased angiogenesis
  • Shift in cellular metabolism (e.g., Warburg effect)

References:[3]

Oncogene

Proto-oncogene Chromosome Gene product Associated malignancies
BRAF
  • 7q34
Serine/threonine kinase
BCR-ABL
  • t(9;22) (q34.1;q11.21)
Tyrosine kinase
JAK2
  • 9p24.1

HER2/neu (c-erbB2)

  • 17q12
Receptor tyrosine kinase
ALK
  • 2p23.2-p23.1
  • Lung adenocarcinoma
RET
  • 10q11.21
c-KIT
  • 4q12
Cytokine receptor
L-myc-1 (MYCL1)
  • 1p34.2
Transcription factors
N-myc (MYCN)
  • 2p24.3
c-myc
  • 8q24.21
KRAS
  • 12p12.1
GTPase
BCL-2
  • 18q21.33

Antiapoptotic molecule
CDK4
  • 12q14.1
Cyclin-dependent kinase
CCND1
  • 11q13.3
Cyclin D protein (regulatory protein of the cell cycle)
ERBB1
  • 7p11.2
Epidermal growth factor receptor
  • Squamous cell carcinoma of the lung

Tumor suppressor genes

  • Definition: A gene that normally controls and suppresses cell proliferation. Loss of function or inactivation leads to an increased risk of developing cancer. Both alleles need to be mutated in order for complete loss of function of the gene.
Gene Chromosome Gene product Associated malignancy
TP53
  • 17p13.1
  • Most human cancers
  • LiFraumeni syndrome
Rb
  • 13q14.2
CDKN2A
  • 9p21.3

APC
  • 5q22.2
  • A protein that prevents unregulated cell proliferation by inhibiting β-catenin synthesis
BRCA1
  • 17q21.31
  • DNA repair protein
BRCA2
  • 13q13.1
  • DNA repair protein
MMR gene family
  • Varies depending on the mutated protein+
DCC
  • 18q21.2

SMAD4 (DPC4)
  • 18q21.2
MEN 1
  • 11q13.1
NF1
  • 17q11.2

NF2
  • 22q12.2

  • Merlin (schwannomin)
TSC1
  • 9q34.13
TSC 2
  • 16p13.3
VHL
  • 3p25.3
WT1
  • 11p13
WT2
  • 11p15.5

Carcinogens

Chemical carcinogens

Substance Occurrence Malignancy
Benzene, Benzol
  • Gasoline
  • Cigarette smoke
Vinyl chloride
Nitrosamines
  • Cured meat, fish, bacon
Aromatic amines (β-Naphthylamine)
  • Rubber
Asbestos
  • Insulation material (formerly used in construction and shipbuilding)
Wood dust
  • Woodworking (e.g., sawing, drilling, sanding)
  • Adenocarcinoma of nose and paranasal sinuses
Ethanol
  • Alcoholic beverages
Alkylating agents
Cigarette smoke
Radon
  • Accumulates in basements, and byproduct of uranium decay
Aflatoxin
  • Stored nuts and grains
Arsenic
  • Contaminated groundwater (esp. in developing countries)
  • Pesticides, herbicides
  • Metal smelting
  • Lung cancer
  • Squamous cell carcinoma
  • Hepatic angiosarcomas

Radiation

Type Occurrence Malignacy
Nonionizing radiation
  • UV-B
  • Skin cancers
Ionizing radiation
  • X-rays
  • Gamma rays

Oncogenic infections

Infective agent Associated malignancies
DNA viruses
EBV
HBV
HHV-8
HPV 16
  • Squamous cell carcinoma of the vulva, vagina, cervix, anus, oropharynx, larynx
HPV 18
RNA viruses
HTLV-1
HCV
Nonviral pathogens
Schistosoma haematobium
Clonorchis sinensis (Chinese liver fluke)
H. pylori

Cancer-Immunity cycle

Grading and staging

Grading (oncology)

  • Definition: Process of classifying tumors based on their histological appearance (degree of differentiation).
  • Indicators of poor differentiation
    • High-proliferation index
    • Presence of nucleoli
    • Giant cells with multiple nuclei
    • Hyperchromasia and heterogenous chromatin distribution
    • Abnormal shape of cell or nucleus (nuclear atypia, enlarged nucleoli)
    • Different cell polarity
    • Different orientation of nuclei belonging to the same group of cells
    • Increase in mitotic figures
  • Anaplasia: loss of morphological features of malignant cells so that resemblance to normal cells of a particular tissue where tumor cell originated from is lost

Grading systems

AJCC grading system

  • Most commonly used grading system for nonhematological malignancies
  • Can be applied to a wide range of tumors
Grading Differentiation of malignant tissue
G1 Well differentiated (low grade)
G2 Moderate differentiation (intermediate grade)
G3 Poor differentiation (high grade)
G4 Undifferentiated / anaplastic (high grade)
GX Differentiation cannot be assessed

Cancer-specific grading systems

Staging (oncology)

  • Definition: Method of determining and classifying a tumor according to its spread throughout the body.
  • Prognosis: Stage of the tumor is typically more important than the grade in determining the prognosis.

Staging systems

  • TNM and AJCC systems are most commonly used

TNM classification

  • T: size or direct extent of the primary tumor
  • N: Involvement of regional lymph nodes
  • M: Presence of distant metastasis
  • L: Lymphatic vessel involvement
    • L0: No invasion into lymphatic vessels
    • L1: Invasion into lymphatic vessels
  • V: Vein involvement
    • V0: No invasion into veins
    • V1: Invasion into veins
  • By adding a "C" to any category, it's possible to express the certainty of the diagnosis
    • C1: Routine procedure (clinical examination, x-ray)
    • C2: Special procedure (e.g. ERCP, CT)
    • C3: Based on biopsy, cytology or surgical exploration
    • C4: Based on surgery and additional histopathological workup
    • C5: Based on autopsy and histopathological workup
  • By adding a prefix to TNM it's possible to indicate additional diagnostic or clinical information
    • cTNM: Staging based on clinical criteria (usually between C1 and 3)
    • pTNM: Histopathological staging (= C4)
    • uTNM: Endosonographic staging
    • aTNM: Autopsy
    • yTNM: Following neoadjuvant therapy
    • rTNM: Relapse

T, N, and M have independent prognostic values. N and M are typically the most important determinants of prognosis.

AJCC staging system

  • Stage 0 (carcinoma-in-situ)
  • Stage I–III: tumor spread into nearby tissues
  • Stage IV: tumor spread to distant parts of the body

Cancer-specific staging systems

Spread determines Stage, and Stage determines Survival more than grade!

Metastasis

Overview

Most carcinomas spread lymphatically. However, renal cell carcinoma, follicular thyroid carcinoma, hepatocellular carcinoma, choriocarcinoma primarily spread hematogenously!

Mechanisms of Metastasis

  • Complex genetic changes are responsible for the selection of tumor subclones that are capable of metastasis.
  • All metastases can be understood as arising from a two-part process: invasion of local extracellular tissue → dissemination and colonization.
  • Invasion of extracellular tissue: loss of cellular adhesions → adhesion to basement membrane → invasion through basement membrane → passage through extracellular tissue
    • Loss of E-cadherin expression is associated with tumor metastatic potential
    • Overproduction of proteases such as collagenase and matrix metalloproteinases degrade the basement membrane and interstitial matrix; Neoplastic cells encounter various chemotactic and angiogenic factors in the newly exposed extracellular matrix.
    • Autocrine signaling via tumor-produced cytokines and paracrine signaling by cleaved matrix components and extracellular growth factors stimulate tumor cell locomotion towards vasculature or lymphatics.
  • Dissemination and colonization: encountering vascular or lympathic routes → evasion of host defenses → implantation with distant tissue
    • Host defenses destroy the majority of circulating cancer cells. Mechanisms to avoid this include tumor cell aggregation, formation of platelet-tumor complexes, and binding of active coagulation factors to form malignant emboli.
    • Disruption of cellular adhesion molecules (laminins, cadherins) enable extravasation at distant tissues. CD44 has been recently implicated in this process.

Common sites for cancer metastasis

Organ with metastasis Primary tumor located in
Liver
Bone
Brain

Generally, tumors in the brain (approximately 50%) and in the bone are most often metastatic rather than primary tumors!

References:[4][5]

Cancer anorexia-cachexia syndrome

  • Definition: A syndrome characterized by progressive wasting of skeletal muscle mass with or without loss of body fat that occurs in patients with advanced cancer.
  • Pathophysiology
  • Clinical features: weight loss, poor appetite, ↓ adipose tissue, muscle wasting, fatigue
  • Diagnosis: no formal diagnostic criteria available, but some features for diagnosis include
  • Treatment
    • Corticosteroids (e.g., prednisolone)
    • Progesterone analogs (e.g., megestrol acetate)
    • Cannabinoids (e.g., dronabinol)
    • Nutritional counseling, parenteral nutrition
  • Prognosis: poor prognostic indicator

References:[6][7][8][9]

Antineoplastic therapy

Definitions

  • Curative therapy: therapy with the intent of curing the disease
  • Palliative therapy: therapy with the intent of relieving symptoms and improving quality of life
  • Neoadjuvant therapy: : chemotherapy and/or radiation before elective surgery (e.g., preoperative radio-/chemotherapy in advanced rectal cancer)
  • Adjuvant: therapy: chemotherapy and/or radiation after surgery (e.g., postoperative chemotherapy in advanced colorectal cancer)

Modalities of antineoplastic therapy

Besides tumor grade and stage, it is important to consider the patient's performance status (Karnofsky score), general well-being, comorbidities, and the patient's wishes when choosing a treatment option.

Treatment evaluation

Assessing resection

Resection margin Definition Examined by
R0
  • Complete removal: Resection margins are macro- and microscopically free of tumor tissue
Pathologist
R1
  • Microscopically visible tumor tissue in resection margins
R2
  • Macroscopically visible tumor tissue remains
    • Size/extent of residual tumor tissue is indicated in operative report
Surgeon

Assessing response

Complete response

(CR)

No clinical or radiological evidence of tumor disease over a certain amount of time (depends on tumor type)

Partial response

(PR)

Decrease in tumor volume by a certain percentage (depends on tumor type)

Stable disease

(SD)/ (NC )

Minimal decrease or increase of all lesions/tumor volume

Progressive disease

(PD)

Increase of all lesions/tumor volume