General oncology

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.

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	Malignant cells arise from epithelium (e.g., squamous cell carcinoma, basal cell carcinoma)
Sarcoma	Malignant cells arise from mesenchyme (e.g., sarcoma botryoides, liposarcoma, leiomyosarcoma)
Hamartoma	A benign mass composed of mature cells that are native to the tissue of origin but have abnormal tissue organization (e.g., Peutz-Jeghers syndrome, pulmonary hamartoma, iris hamartoma). Has a low potential to undergo malignant transformation.
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)	Irreversible dysplasia Involves the entire thickness of the epithelium No invasion of the basement membrane
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	No metastases Relapses are rare	Metastases and relapses are common

Tumor origin

	Cell origin	Benign tumor	Malignant tumor
Epithelial tumors	Squamous epithelium	Papilloma	Squamous cell carcinoma: common types include squamous cell lung cancer, cutaneous SSC, esophageal cancer, pharyngeal cancer, cervical cancer, vulvar and vaginal cancer
	Urothelium		Urothelial cancer (transitional cell carcinoma)
	Glandular-/mucosal epithelium	Adenoma	Adenocarcinoma: common types include lung adenocarcinoma, gastric cancer, colorectal cancer, breast cancer, prostate cancer
	Cuboidal epithelium		Papillary thyroid carcinoma
Mesenchymal tumors	Fibrocytes	Fibroma: can occur almost anywhere in the body; common types include ovarian fibroma, dermatofibroma, nonossifying fibroma	Fibrosarcoma
	Adipocytes	Lipoma	Liposarcoma: most commonly develop in extremities and retroperitoneum
	Chondrocytes	Chondroma	Chondrosarcoma
	Osteoblasts	Osteoblastoma	Osteosarcoma
		Osteoma
	Blood vessels	Hemangioma: e.g.: cherry hemangioma, hepatic hemangioma, infantile hemangioma	Hemangiosarcoma (linked to vinyl chloride toxicity)
	Lymphatic vessels	Lymphangioma	Lymphangiosarcoma
	Rhabdomyocytes (striated muscle cells)	Rhabdomyoma: may be either neoplastic or a hamartoma	Rhabdomyosarcoma
	Leiomyocytes (smooth muscle cells)	Leiomyoma: most common type is uterine leiomyoma	Leiomyosarcoma: can present as a rare neoplasm of the small bowel, the uterus, or the skin.
	Mesothelium	Benign mesothelioma	Malignant mesothelioma
	Meninges	Meningioma	Malignant anaplastic meningioma
	Neuroectodermal cells		Ewing's sarcoma
Special variants of mesenchymal tumors	Hematopoietic cells (e.g., B cells, T cells)		Myelogenous leukemia (AML, CML) Acute lymphoblastic leukemia Multiple myeloma
			Hodgkin lymphoma Non-Hodgkin lymphoma
Neuroectodermal tumors	Glial cells	Benign glioma	Astrocytoma Glioblastoma
	Melanocytes	Nevus	Malignant melanoma
Germ cell tumors	Germ cells	Differentiated teratoma	Malignant teratoma Seminoma
Embryonal tumors	Primitive epithelial cells		Embryonal carcinoma Nephroblastoma (Wilms' tumor) Neuroblastoma Retinoblastoma Hepatoblastoma Choriocarcinoma

References:^[1]

In 2018, approximately 1.7 million people will be diagnosed with cancer in the United States. Cancer is the 2^nd 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 (Sorted by total incidence)	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

• The most common types of cancer in men excluding skin cancer are:
  1. Prostate cancer
  2. Cancer of the lung and bronchus
  3. Colorectal cancer
• The most common cancer in women excluding skin cancer are:
  1. Breast cancer
  2. Cancer of lung and bronchus
  3. Colorectal cancer
• The types of cancer with the highest mortality rate in both men and women are (in descending order):
  1. Cancer of lung and bronchus.
  2. Prostate cancer (men), breast cancer (women)
  3. Colorectal cancer
• The types of cancer that are most common and have the greatest mortality rate in children (< 15 years) are:
  1. Leukemia (ALL, AML)
  2. Brain and spinal cord tumors
  3. Neuroblastoma

References:^[2][3]

• 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

• Mutations: duplication , insertion , deletion , point mutation
  • Consequences: silent mutation, nonsense mutation, missense mutation
• Chromosomal translocation
  • Example: translocation t(9;22) in chronic myeloid leukemia. There is reciprocal translocation resulting in an elongated chromosome 9 (9q+) and truncated chromosome 22 (22q‑), also known as Philadelphia chromosome.
• Amplification: increased gene expression
  • Example: There is overexpression of the HER2/neu gene in several forms of breast cancer.

Key genes involved in carcinogenesis

• (Proto‑)oncogene
  • Mutations of proto-oncogenes → formation of oncogenes
• Tumor suppressor genes
  • Inhibits uncontrolled proliferation
• Apoptosis regulatory genes
  • Loss of regulatory genes (e.g., Bax) leads to cell immortality and increased proliferation.
• Factors that affect key genes involved in carcinogenesis
  • Exposure to risk factors
  • Diet

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:^[4]

Tumor grading

• 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

• Gleason score for prostate cancer
• Nottingham grading system for breast cancer

Tumor staging

• 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
  • Tcis: Carcinoma in situ (no basement membrane penetration - no infiltration of submucosa)
  • T1-4 based on the size and/or extent of the primary tumor
    • T4 refers to infiltration of neighboring organs
• N: Involvement of regional lymph nodes
  • N0: No lymph node involvement
  • N1-3 based on type of tumor and lymph node involvement
• M: Presence of distant metastasis
  • M0: No distant metastasis
  • M1: Presence of distant metastasis
  • Mx: Unknown if distant metastasis is present or not
• 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
  • pTNM: Histopathological staging

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

• Ann-Arbor staging system for Hodgkin lymphoma

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

Overview

• Metastasis: spread of malignant cells to distant organs, tissues (e.g., colorectal cancer spreads to the liver)
  • Lymphatic metastasis
    • Dissemination of malignant cells via lymphatic vessels and lymph nodes
    • Most common route of metastasis for most carcinomas
  • Hematogenous metastasis
    • Dissemination of malignant cells via blood vessels. Venous dissemination is more common than arterial dissemination because the thin wall of veins is easier to invade.
    • Most common route of metastasis for most sarcomas.
  • Seeding (oncology): spillage of malignant cells to neighboring structures → implants at a site adjacent to the primary tumor and subsequent growth
  • Transcoelomic metastasis: spread of malignant cells into body cavities by penetration of surfaces such as the pleura, pericardium, and peritoneum
  • Canalicular metastasis: spread of malignant cells via canalicular system (e.g. bile ducts, lactiferous ducts, urinary tract, and the subarachnoid space)

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

• Brain metastases: appear in the white-gray matter junction as multiple well-circumscribed lesions
• Bone metastasis: usually involve the axial skeleton (e.g., vertebral column, pelvic girdle)
  • Types of bone lesions
    • Lytic: lung, kidney, multiple myeloma
    • Blastic: prostate
    • Mixed: breast
  • For bone metastasis see the learning card on malignant bone tumors.

Organ with metastasis	Primary tumor located in
Liver	Colon Stomach Pancreas
Bone	Prostate Breast Kidney Thyroid Lung Multiple myeloma
Brain	Lung Breast Melanoma Colon Kidney

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

References:^[5][6]

• 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
  • Excess in proinflammatory cytokines (IL-1, IL-6, IFN-γ, and TNF-α) as a result of tumor growth → ↑ basal metabolic rate and catabolism
    • Proteasomal activation and breakdown of myosin in skeletal muscle + loss of adipose tissue
    • Negative nitrogen balance
• Clinical features: weight loss, poor appetite, ↓ adipose tissue, muscle wasting, fatigue
• Diagnosis: no formal diagnostic criteria available, but some features for diagnosis include
  • Weight loss
  • Decreased appetite
  • Loss of subcutaneous fat
  • Muscle wasting (temporal, deltoid, and quadricep regions)
  • Edema (in the ankles, or around the sacrum)
  • Ascites
• Treatment
  • Corticosteroids (e.g., prednisolone)
  • Progesterone analogs (e.g., megestrol acetate)
  • Cannabinoids (e.g., dronabinol)
  • Nutritional counseling, parenteral nutrition
• Prognosis: poor prognostic indicator

References:^{[7][8][9][10]}

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

• Surgery (e.g., hysterectomy, mastectomy, prostatectomy)
• Chemotherapeutic drugs (e.g., BEP regimen in seminoma testicular cancer)
  • Combinations of multiple classes of chemotherapy are often used to treat malignancy
  • Cancers develop resistance by expressing multi-drug resistance protein 1 (also called P-glycoprotein) ^[11]
    • P-glycoproteins are transmembrane ATP-dependent efflux pump proteins that decrease intracellular concentrations of chemotherapeutics.
    • Expressed in adrenocortical carcinoma as well as cancers of the colon, liver, pancreas, kidney, ovary, and breast
• Radiotherapy
• Hormone therapy (e.g. antiandrogens in prostate cancer)
• Biological agents (e.g. CD20 antibodies in non-Hodgkin lymphoma)

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.