General oncology — Medicine Library

Summary

Oncology is the science of tumors. This article explains basic concepts relevant to the development, progression, spread, and diagnosis 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.

Principles of cancer care, paraneoplastic syndromes, and tumor markers are covered in detail in their respective articles.

Nomenclature

Terminology

Basic terminology in oncology
Term	Definition
Normal cell	Cells without atypia, pleomorphism, or dysplasia Normal nuclear:cytoplasmic ratio Intact cell polarity: Epithelial cells have a specific microscopic structure with different lateral, apical, and basal membrane domains.
Neoplasia	Excessive proliferation of cells Neoplasms consist of two components: Parenchyma: neoplastic cells Stroma: connective tissue and blood vessels supporting the parenchyma Monoclonal in origin Can be either malignant or benign
Tumor	Abnormal growth of cells or edema that leads to swelling of tissue Tumor does not necessarily mean neoplasia.
Adenoma	A benign tumor that arises from glandular epithelial cells.
Carcinoma	Malignant cells that arise from epithelium (e.g., squamous cell carcinoma, basal cell carcinoma)
Sarcoma	Malignant cells that 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) Low potential to undergo malignant transformation
Choristoma	Presence of normal tissue at a site where this type of tissue is not normally found (e.g., the presence of gastric tissue in the ileum, as is sometimes seen in Meckel diverticulum)
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 severe 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 → disruption of intercellular adhesions between neighboring cells
Metastasis	Spread of malignant cells to distant organs, tissues (e.g., colorectal cancer spreading to the liver) Lymphatic spread Hematogenous spread

Pap smear showing severe dysplasia Ductal carcinoma in situ Invasive lobular carcinoma of the breast Neoplastic progression Liver metastasis from pancreatic carcinoma Invasive breast carcinoma of no special type (invasive ductal carcinoma) 1/3 Cervical intraepithelial neoplasia (CIN III) Invasive ductal carcinoma of the breast Spectrum of cervical dysplasia

Benign and malignant tumors

Overview of benign and malignant tumors
	Benign tumor	Malignant tumor
Differentiation(grading)	Well-differentiated (low grade)	Poorly differentiated (high grade)
Growth	Slow growth with a low rate of cell division (low mitotic activity) Mass effect with compression of non-tumor tissue	Unpredictable growth, high rate of cell division (high mitotic activity) Suppressed cellular apoptosis Locally destructive and invasive
Macroscopy	Necrosis is rare. Well-demarcated from surrounding tissue	Possible necrosis (e.g., squamous cell carcinoma of the lung) Usually no tumor capsule Infiltration (invasion) of surrounding tissue Bleeding
Microscopy	Almost no irregularities of cellular structures	Detection and confirmation of cellular atypia Nuclei: Enlargement , polymorphism , polychromasia , increased cell count and/or enlarged nucleoli are all signs of increased activity of nuclei. Numerous mitotic figures (increased proliferation of malignant cells with typical and atypical mitoses)
Metastasis and relapse	No metastases Relapses are rare.	Metastases and relapses are common.

Tumor origin

Types of tumors based on cell origin
Type of tumors	Cell origin	Benign tumor	Malignant tumor
Epithelial tumors	Squamous epithelium	Papilloma	Squamous cell carcinoma (e.g., squamous cell lung cancer, cutaneous SCC, esophageal cancer, pharyngeal cancer, cervical cancer, vulvar and vaginal cancer)
	Urothelium	Papilloma	Urothelial cancer (transitional cell carcinoma)
	Glandular/mucosal epithelium	Adenoma	Adenocarcinoma (e.g., 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: ovarian fibroma, dermatofibroma, nonossifying fibroma	Fibrosarcoma
	Adipocytes	Lipoma	Liposarcoma: most commonly develop in extremities and retroperitoneum
	Chondrocytes	Chondroma	Chondrosarcoma
	Osteoblasts	Osteoblastoma	Osteosarcoma
	Osteoblasts	Osteoma	Osteosarcoma
	Blood vessels	Hemangioma (e.g., cherry hemangioma, hepatic hemangioma, infantile hemangioma)	Hemangiosarcoma (linked to vinyl chloride toxicity)
	Lymphatic vessels	Lymphangioma A malformation of the lymphatic system composed of endothelium-lined cysts that contain lymphatic fluid Most commonly manifests as a cluster of clear and/or hemorrhagic vesicles on the skin	Lymphangiosarcoma A rare cutaneous malignancy that can develop in patients with long-standing chronic lymphedema A classic complication of prior radical mastectomy or radiation therapy (Stewart-Treves syndrome) Presents with multiple purple-colored macules and/or papules
	Rhabdomyocytes (striated muscle cells)	Rhabdomyoma: may be either neoplastic or a hamartoma	Rhabdomyosarcoma
	Leiomyocytes (smooth muscle cells)	Leiomyoma: uterine leiomyoma (most common type)	Leiomyosarcoma: a rare neoplasm of the small bowel, the uterus, or the skin
	Mesothelium	Benign mesothelioma	Malignant mesothelioma
	Meninges	Meningioma	Malignant anaplastic meningioma
	Neuroectodermal cells	N/A	Ewing sarcoma
Special variants of mesenchymal tumors	Hematopoietic cells (e.g., B cells, T cells)	N/A	Myelogenous leukemia (AML, CML) Acute lymphoblastic leukemia Multiple myeloma
Special variants of mesenchymal tumors	Hematopoietic cells (e.g., B cells, T cells)	N/A	Lymphomas Hodgkin lymphoma Non-Hodgkin lymphoma
Neuroectodermal tumors	Glial cells	Benign glioma	Astrocytoma Glioblastoma
Neuroectodermal tumors	Melanocytes	Nevus	Malignant melanoma
Germ cell tumors	Germ cells	Differentiated teratoma	Malignant teratoma Seminoma
Embryonal tumors	Primitive epithelial cells	N/A	Embryonal carcinoma Nephroblastoma Neuroblastoma Retinoblastoma Hepatoblastoma A rare childhood tumor of liver precursor tissue Usually diagnosed before the age of 3 years Choriocarcinoma

**Pap smear showing severe dysplasia**
Photomicrograph of squamous cells of the cervix (Papanicolaou stain; very high magnification;)
There is a loosely connected group of abnormal squamous epithelial cells (blue-green cytoplasm). The nuclei are variable in size with a high nuclear-cytoplasmic ratio and there are course clumps of chromatin. The large cell with pink cytoplasm is a normal superficial squamous cell.
These findings are characteristic of severe dysplasia as seen in high-grade squamous intraepithelial lesion (HSIL).

Source: “High-Grade SIL, ThinPrep” by Ed Uthman, Flickr, licensed under CC BY 2.0.

**Ductal carcinoma in situ**
Photomicrograph of a breast tissue biopsy specimen (H&E stain; high magnification)
Intraductal tumor cells (green overlay) with a hyperchromatic nucleus are visible. Calcifications (red overlay) are visible in the lower duct.
These are characteristic histological features of ductal carcinoma in situ.
Click on the Smartzoom button to view the entire specimen through a virtual microscope.

Source: © Smart Zoom, Smart In Media. Image and annotations in digital microscopy: PD Dr. Alberto Perez Bouza

**Invasive lobular carcinoma of the breast**
Photomicrograph of a breast tumor tissue specimen (H&E stain; 40x magnification)
Infiltrating malignant cells can be seen as single cells, narrow chords (examples indicated by green overlay), and characteristic single-file formations (examples indicated by blue overlay). The tumor cells are seen growing between distorted ductuli (D) and lobuli (L), surrounded by conspicuously pale connective tissue. There is no tubule formation of the tumor (as is commonly seen in other types of adenocarcinomas of the breast).
This is the typical appearance of invasive lobular carcinoma of the breast.
Click on the microscope icon (at the top) to view the entire specimen through a virtual microscope.

Source: © Smart Zoom, Smart In Media. Image and annotations in digital microscopy: PD Dr. Alberto Perez Bouza

**Neoplastic progression**
Typical neoplastic disease progression begins with the appearance of dysplastic cells, which have varying nuclei sizes and shapes, and disrupt surrounding tissue architecture. The cells continue to proliferate and become more dysplastic resulting in the formation of carcinoma-in-situ, which is still contained by the basement membrane (BM). Expression of metalloproteases enables the cells to break through the BM and the cancerous cells can then enter the vascular system and metastasize to distant locations. Expression of angiogenic or lymphangiogenic factors promote the recruitment of vessels, thereby facilitating metastasis.

© AMBOSS

**Liver metastasis from pancreatic carcinoma**
Cross section of autopsied human liver
Numerous variably-sized pale or white-tan nodules scattered throughout the liver. The tumor is an adenocarcinoma. One of the most primary sites for metastatic adenocarcinoma is the liver.

Source: "Secondary tumor deposits in the liver from a primary cancer of the pancreas", Haymanj, Wikimedia Commons licensed under Public Domain

**Invasive breast carcinoma of no special type (invasive ductal carcinoma) 1/3**
Photomicrograph of biopsy specimen (H&E stain; low magnification) from a mobile breast lump in 64-year-old female patient
Main image: At low magnification, a dense irregular mass (purple/pink) with poorly circumscribed borders can be seen infiltrating the mature adipose tissue of the breast (white). The mass is composed of disorganized tubular formations of the carcinoma (dark blue/basophilic staining) and surrounding collagenous connective tissue (pink/eosinophilic staining; also known as “desmoplastic stroma”).
Top right inset: very low magnification overview indicating the location of the main image on the specimen

Source: © IMPP

**Cervical intraepithelial neoplasia (CIN III)**
Photomicrograph of cervical tissue (H&E stain; very high magnification;)
There is a loss of epithelial architecture involving more than two-thirds of the epithelium, but the basement membrane is still intact. There is a high nuclear-to-cytoplasmic ratio, overlapping nuclei, and nuclear atypia. Mitotic figures can be seen. Epithelial cells with perinuclear halos are present in the superficial layers; these cells are koilocytes and indicate HPV infection.
These findings are consistent with severe dysplasia and (CIN III), and the changes are irreversible

Source: “Cervical intraepithelial neoplasia (4) CIN3” by KGH, Wikimedia Commons, licensed under CC BY-SA 3.0.

**Invasive ductal carcinoma of the breast**
Photomicrograph of a surgical sample of breast tissue (H&E stain, low magnification)
An area of sclerosis (light purple) is visible in the center of the invasive ductal carcinoma (dark purple).
Click on the Smartzoom button to view the entire specimen through a virtual microscope.

Source: © Smart Zoom, Smart In Media. Image and annotations in digital microscopy: PD Dr. Alberto Perez Bouza

**Spectrum of cervical dysplasia**
Photomicrograph of a cervical biopsy specimen (H&E stain; high magnification)
1. Normal squamous epithelium (N; green overlay): normal nuclear-cytoplasmic ratio, intact cell polarity (epithelial cells have distinct lateral, apical, and basal membrane domains)
2. Mild dysplasia (1; yellow overlay): mild pleomorphism (loss of uniformity in cell size and shape), mild chromatin abnormalities (hyperchromatic), koilocytes (cells with perinuclear halos), dysplasia confined to the basal third of the epithelium
3. Moderate dysplasia (2; blue overlay): loss of cell polarity, moderate nuclear pleomorphism, moderate nuclear chromatin abnormalities, increased normal and abnormal mitosis, dysplasia confined to the basal two-thirds of the epithelium
4. Severe dysplasia (3; red overlay): irreversible high-grade dysplasia, irregular epithelial stratification, involves the entire thickness of the epithelium, clear demarcated basement membrane (no invasion)
Koilocytes in dysplastic cervical epithelium indicate an underlying persistent HPV infection as the cause of dysplasia.

Source: “Spectrum of SIL/Cervical Dysplasia” by Ed Uthman, Flickr, licensed under CC BY 2.0. The supplementary image with overlays of relevant areas was adapted from the image mentioned above (© AMBOSS).

General epidemiology

In 2020, approximately 1.8 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. [1]

Epidemiology of common cancer types in 2020 [2]

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

Epidemiology of most common cancer types
Type	Incidence/year in men	Incidence/year in women	Mortality/year
Breast cancer	2,620	276,480	42,690
Lung and bronchus cancer	116,300	112,520	135,720
Prostate cancer	191,930	N/A	33,330
Colorectal cancer	78,300	69,650	53,200
Bladder cancer	62,100	19,300	17,980
Kidney cancer	45,520	28,230	14,830
Uterine cancer	N/A	65,620	12,590
Pancreatic cancer	30,400	27,200	47,050
Thyroid cancer	12,720	40,170	2,180
Non-Hodgkin lymphoma	42,380	34,860	19,940
Leukemia	35,470	25,060	23,100

The most common types of cancer in men
(excluding skin cancer)

Prostate cancer

Lung and bronchus cancer

Colorectal cancer
The most common cancer in women
(excluding skin cancer)

Breast cancer

Lung and bronchus cancer

Colorectal cancer
The types of cancer with the highest
mortality rate in both men and women (in descending order)

Cancer of lung and bronchus

Prostate cancer (men), breast cancer (women)

Colorectal cancer
The most common types of cancer that have the greatest
mortality rate in children (< 15 years)

Leukemia (ALL, AML)

Brain and spinal cord tumors

Neuroblastoma

Incidence of cancers in the US (2025 estimates) Cancer mortality in the US (2025 estimates)

Carcinogenesis

Overview

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 passed on
3. Latency: the time between promotion and progression
4. Progression: proliferation of the neoplastic cell line with the acquired DNA damage, leading to malignant transformation

Properties of malignant cells

Sustained proliferative signaling: due to mutation of
genes regulating cell division and growth
- (Proto‑)oncogene: See “Proto-oncogene” below.
- Growth factor receptors (e.g., ERBB2, EGFR)
- Signaling molecules (e.g., Ras, B-Raf) [3]
- Transcription factors (e.g., MYC, TP53) [4]
- Cell cycle regulators (e.g., cyclins, CDKs)
Evade growth suppressors
[5]
- Tumor suppressor genes: See “Tumor suppressor genes” below.
- Loss of contact inhibition
  
  Mutated or absent E-cadherin → loss of growth inhibitory signals and contact inhibition of proliferation → excessive cell proliferation
  
  Due to mutations in genes that regulate contact inhibition (e.g., NF2 gene)
Genome instability and mutations
- Mutations: See “Gene mutations” and “Chromosomal translocation” in the “Basics of human genetics” article.
- Gene amplification: increased gene expression (e.g., overexpression of ERBB2 gene in several forms of breast cancer)
Resist
cell death
- Occurs because of mutations in apoptosis regulatory genes
- Loss of regulatory genes (e.g., Bax, TP53, BCL-2) leads to cell immortality and increased proliferation.
Enable replicative immortality: telomerase reactivation → ↑ length of telomeres → ↑ number of possible cell replication cycles
Deregulate cellular energetics:
a shift in cellular metabolism from
glycolysis and
mitochondrial oxidative phosphorylation to glycolysis and preferential lactate generation, regardless of the oxygen supply (Warburg effect)

In differentiated, non-malignant cells, glycolysis converts glucose to pyruvate, which then undergoes mitochondrial oxidative phosphorylation under aerobic conditions, or anaerobic glycolysis to generate lactate under anaerobic conditions.

In malignant cells, the so-called Warburg effect occurs, in which pyruvate is preferentially converted to lactate, regardless of the cellular oxygen supply. This mechanism supplies rapidly dividing malignant cells with the necessary carbon to synthesize cellular structures. [6]
Induce
angiogenesis
[5]
- Angiogenesis helps maintain an adequate supply of oxygen and nutrients to the neoplastic cells.
- Regulated by angiogenic (e.g., VEGF, FGF) and inhibitory factors that are produced by neoplastic or supporting cells
- Occurs as:
  
  Vasculogenesis: de novo formation of blood vessels from bone marrow-derived endothelial cells
  
  Neoangiogenesis: formation of blood vessels from existing blood vessels and capillaries
- Newly formed blood vessels may be dilated or leaky.
Activate invasion and metastasis: See “Metastasis” below.
Avoid immune detection: See “Defense mechanisms of malignant cells” below.
Tumor-promoted inflammation

Cancer hallmarks and treatment options Philadelphia chromosome and pathophysiological consequences Chronic myeloid leukemia: t(9;22)(q34;q11) Philadelphia chromosome

Defense mechanisms of malignant cells [7]

Immune response modification
- ↓ MHC class I expression on malignant cells → inability of cytotoxic T-cells to recognize and mount an immune response against these cells
- Secretion of immunosuppressive molecules (e.g., TGF-β) → enhanced immune tolerance of malignant cells
- Enhanced regulatory T-cell activity → limited immune response
Immune checkpoints
[8]
- Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)
  
  Upregulation of CTLA-4 → promotion of binding to B7 protein (surface receptor on antigen-presenting cells, also called CD80 or CD86) → T-cell inactivation and simultaneous reduction of costimulation by binding of CD28 to B7
  
  CTLA-4 is inhibited by anti-CTLA-4 antibody ipilimumab.
- Programmed death-ligand system
  
  Expression of programmed death-ligand 1 (PD-L1) and PD-L2 on tumor cells surface or environment → binding to programmed cell death protein 1 (PD-1) on T-cells → T-cell dysfunction
  
  PD-L1 and PD-L2 are inhibited by cancer immunotherapy agents atezolizumab, durvalumab, and avelumab.
  
  PD-1 is inhibited by cancer immunotherapy agents nivolumab and pembrolizumab.
Development of resistance to
chemotherapeutic agents
- Expression of multidrug resistance protein 1 (MDR1; also called P-glycoprotein). [9]
- 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

Target of anti-CTLA-4 antibodies Anti-PD-1 antibodies

Etiologic field cancerization [10]

Definition: a collection of factors (e.g., lifestyle, environmental, microbial, genetic) and their interactions that affect tissues and potentially predispose individuals to the development of disease
Pathophysiology: carcinogenic exposure → transformation of normal cells → wide area of premalignant cells at the primary site and adjacent areas
Examples
- Interactions between the immune system, microbiome, and diet influence the development of ulcerative colitis and colorectal cancer.
- Prolonged exposure to tobacco smoke, alcohol consumption, and persistent HPV infection influence the development of head and neck cancer.
- Chronic sun exposure, UV radiation, and genetic predisposition influence the development of skin cancer.
- Exposure to industrial carcinogens, chronic inflammation, and genetic susceptibility influence the development of bladder cancer.

**Cell Cycle and Cancer: Phases, Hallmarks, and Development**
© AMBOSS

**Cancer hallmarks and treatment options**
The hallmarks of cancer development and growth have been highlit in bold type, whereas the treatment options directed against the underlying mechanisms appear in plain type.

© AMBOSS

**Cancer hallmarks**
There are ten hallmarks of cancer acquired by cancer cells during human tumor development.

© AMBOSS

**Philadelphia chromosome and pathophysiological consequences**
© AMBOSS

**Chronic myeloid leukemia: t(9;22)(q34;q11) Philadelphia chromosome**
Karyogram and fluorescence in situ hybridisation (FISH) of a patient with chronic myeloid leukemia
In the karyogram (left image) and enlarged image (above right), the long arms of chromosome 9 and chromosome 22 are both of different size. This difference is caused by a translocation between both chromosomes, which resulted in an elongated chromosome 9 (9q+) and a shortened chromosome 22 (Philadelphia chromosome). The translocation can be also be detected using FISH (right image). A red probe is used to display the break on chromosome 9 (9q34) and a green probe to display the break on chromosome 22 (22q11). The red area reflects the intact chromosome 9; the pure green area the intact chromosome 22. The areas with a red-green signal signify the fusion of chromosome 9 and parts of chromosome 22.

Our great thanks to Dr. Wisplinghoff (Dr. Wisplinghoff's laboratory) for kindly providing this image.

**Anti-PD-1 antibodies**
Anti-PD-1 antibodies remove negative signals and enhance the T cell-mediated killing of cancer cells.

© AMBOSS

**Target of anti-CTLA-4 antibodies**
Anti-CTLA-4 antibodies block the molecule CTLA-4, thereby reducing negative signals that would otherwise prevent T-cell activation.
APC: antigen-presenting cell; MHC: major histocompatibility complex; TCR: T-cell receptor

© AMBOSS

Oncogene

Oncogene: the product of a
gain-of-function mutation in a proto-oncogene which leads to overexpression of signaling proteins and growth factors, and thus, uncontrolled cellular proliferation (e.g., dysplasia, neoplasia)

Only one allele of the proto-oncogene requires damage to form an oncogene.

Often present in cancer cells
Proto-oncogene:
Genes that encode proteins that are important in normal cell division and cell differentiation. Examples include:

Protein kinases, e.g., protein kinase B (PKB)

PKB activates and inhibits various substrates, regulates apoptosis, activates translation and, indirectly, cell division.

PKB is activated by phosphatidylinositide 3-kinase (PI3K).

Ligand-directed transcription factors (intracellular hormone receptors)

GTP-binding proteins

G protein-coupled receptors

Small G-proteins such as Ras

Tyrosine kinase receptors

Growth factors and cytokines

Overview of proto-oncogenes [11]
Proto-oncogene	Chromosome	Gene product	Associated malignancies
BRAF	7q34	Serine/threonine kinase	Melanoma Non-Hodgkin lymphoma Papillary thyroid carcinoma Hairy cell leukemia
BCR-ABL	t(9;22) (q34.1;q11.21), also known as Philadelphia chromosome	Non-receptor tyrosine kinase	CML: t(9;22) ALL
JAK2	9p24.1	Non-receptor tyrosine kinase	Chronic myeloproliferative disorders
ERBB2 (HER2/neu)	17q12	Receptor tyrosine kinase	Breast cancer Gastric cancer
ALK	2p23.2-p23.1		Lung adenocarcinoma
RET	10q11.21		Papillary thyroid cancer Pheochromocytoma MEN 2A and MEN 2B
c-KIT	4q12	Cytokine receptor	Gastrointestinal stromal tumors Mastocytosis
L-myc-1 (MYCL1)	1p34.2	Transcription factors	Lung cancer (SCLC)
N-myc (MYCN)	2p24.3		Neuroblastoma
c-myc	8q24.21		Burkitt lymphoma: t(8;14)
KRAS	12p12.1	GTPase	Colorectal cancer Lung cancer Pancreatic cancer
BCL-2	18q21.33	Antiapoptotic molecule	Follicular lymphoma: t(14;18) Diffuse large B cell lymphoma
CDK4	12q14.1	Cyclin-dependent kinase	Liposarcoma [12] Melanoma [13] Glioblastoma multiforme (GBM)
CCND1	11q13.3	Cyclin D (regulatory protein of the cell cycle)	Mantle cell lymphoma: t(11;14)
ERBB1	7p11.2	Epidermal growth factor receptor	NSCLC

“Adenocarcinoma of Lung Kinase”: Cancer (adenocarcinoma of lung) and the gene product (tyrosine kinase) are associated with ALK mutations.

L-myc is associated with lung cancer and n-myc with neuroblastoma.

c-KIT mutations affect CytoKIne recepTor production.

BCL-2 mutations are associated with diffuse large B-cell lymphoma.

**Protein Kinases: Cell Signaling and Phosphorylation**
© AMBOSS

Tumor suppressor genes

Tumor suppressor gene: a
gene that normally controls and suppresses cell proliferation

Loss of function or inactivation leads to an increased risk of developing cancer.

Both alleles must be mutated in order for complete loss of function of the gene.

Overview of tumor suppressor genes
Gene	Chromosome	Gene product	Associated malignancy
TP53	17p13.1	p53 protein Causes cell apoptosis Activates proapoptotic genes (e.g., BAX) Causes cell cycle arrest at the G1 phase (by activating p21) Inhibits entry in the S phase via inhibition of pRb phosphorylation	Most human cancers Li-Fraumeni syndrome
Rb	13q14.2	Retinoblastoma protein (Rb protein): causes cell cycle arrest at the G1 phase by inhibiting E2F transcription factor	Retinoblastoma Osteosarcoma
CDKN2A	9p21.3	p16 protein, which normally causes cell cycle arrest at the G1 phase	Melanoma Pancreatic cancer Lung cancer
APC gene	5q22.2	A protein that prevents unregulated cell proliferation by inhibiting β-catenin synthesis → inhibition of the β-catenin/Wnt pathway	Familial adenomatous polyposis (associated with colorectal cancer) Sporadic colorectal cancer
PTEN [14]	10q23	Negatively regulates the PI3k/AKT pathway	Breast cancer Prostate cancer Endometrial cancer Cowden syndrome
BRCA1	17q21.31	DNA repair protein	Breast cancer Ovarian cancer Pancreatic cancer
BRCA2	13q13.1	DNA repair protein	Breast cancer Ovarian cancer Pancreatic cancer
MMR gene family	Varies depending on the mutated protein	DNA repair proteins	Lynch syndrome
DCC (Deleted in colorectal cancer)	18q21.2	Transmembrane receptor involved in cell apoptosis	Colorectal cancer
SMAD4 (DPC4) (Deleted in pancreatic cancer)	18q21.2	A DNA binding protein involved in signal transduction from TGF-β receptors	Pancreatic cancer
MEN 1	11q13.1	Menin	MEN 1
NF1	17q11.2	Neurofibromin (Ras GTPase-activating protein)	Neurofibromatosis type 1
NF2	22q12.2	Merlin (schwannomin)	Neurofibromatosis type 2
TSC1 (Tuberous sclerosis complex 1)	9q34.13	Hamartin protein	Tuberous sclerosis
TSC2 (Tuberous sclerosis complex 2)	16p13.3	Tuberin protein	Tuberous sclerosis
VHL	3p25.3	Protein involved in the degradation of hypoxia-inducible factor 1a	Von Hippel Lindau disease
WT1 (Wilms Tumor 1)	11p13	Transcription factor that regulates urogenital development	Nephroblastoma (Wilms tumor)
WT2 (Wilms Tumor 2)	11p15.5	Transcription factor that regulates urogenital development	Nephroblastoma (Wilms tumor)

Mutations of the Rb (retinoblastoma) gene mutations cause Retinoblastomas and bone cancer (osteosarcoma).

PTEN mutation is associated with cancers of the Prostate, breasT, and ENdometrium.

Mutations in MEN 1 affect its gene product: MENin.

Cell cycle regulation

Carcinogens

Chemical carcinogens

Examples of chemical carcinogens
Substance	Sources of exposure	Malignancy
Aflatoxin	Stored nuts and grains (Aspergillus flavus growth)	Hepatocellular carcinoma (HCC)
Alkylating agents	Chemotherapeutic agents (e.g., cyclophosphamide, melphalan, busulfan, carmustine)	Leukemia Lymphoma
Aromatic amines (β-naphthylamine, benzidine)	Tobacco smoke Dyes (occupational exposure in the textile industry) Rubber	Bladder cancer (transitional cell carcinoma)
Arsenic	Contaminated groundwater (esp. in developing countries) Pesticides, herbicides (e.g., vineyard workers) Metal smelting	Lung cancer Squamous cell carcinoma Hepatic angiosarcomas
Asbestos	Insulation material (formerly used in construction and shipbuilding) Asbestos cement (fibrolite), roofing, and siding	Lung cancer (bronchogenic carcinoma) Mesothelioma The risk of developing bronchogenic carcinoma is greater than that of developing mesothelioma.
Benzene, benzol	Gasoline Cigarette smoke	Acute leukemia Non-Hodgkin lymphoma
Beryllium	Occupations that involve beryllium production and processing, esp.: [15][16] Smelting and founding Welding Manufacturing Industrial ceramics Electronics Automotive, aerospace, and defense components Dental supplies and prostheses See also “Beryllium” in “Rare pneumoconioses”.	Lung cancer
Chromium	Significant in workers exposed to: Galvanization (chrome plating) Paint and glass manufacturing Tanning leather Building materials	Lung cancer
Cigarette smoke	First-hand smoke: smoke inhaled by the smoker Second-hand smoke: exhaled smoke that is inhaled by others in the vicinity of the smoker Third-hand smoke: smoke particles that adhere to surfaces in the surroundings of the smoker All three have been proven to be carcinogenic.	Transitional cell carcinoma of the bladder Squamous cell carcinoma (cervix, oropharynx, esophagus, larynx, lung) Small cell lung cancer Pancreatic adenocarcinoma Adenocarcinoma of the esophagus Renal cell carcinoma
Ethanol	Alcoholic beverages	Squamous cell carcinoma of the esophagus Hepatocellular carcinoma (HCC)
Nickel	Occupations that involve mining, smelting, welding, and casting of alloys (e.g., in coins, jewelry)	Lung cancer
Nitrosamines	Cured meats (e.g. bacon) and fish Cold-smoked foods Tobacco [17]	Gastric cancer
Radon	Accumulation in basements Uranium mining (extraction of uranium ore from the ground): miners are exposed to radon gas, which is emitted during natural radioactive decay of uranium ore	Lung cancer: Radon is the second most common cause following exposure to cigarette smoke. [18]
Silica	Occupations that involve cutting, drilling, chipping, or grinding crystalline silica (e.g., quartz) or materials that contain it (e.g., sand, granite), esp.: [19] Sandblasting Glass manufacturing Construction work See also “Etiology” in “Silicosis.”	Lung cancer
Vinyl chloride	Production of polyvinyl chloride (PVC) and PVC-related manufacturing (e.g., of PVC pipes, cables)	Lung cancer Hepatocellular carcinoma Glioblastoma Angiosarcoma
Wood dust	Woodworking (e.g., sawing, drilling, sanding)	Adenocarcinoma of the nose and paranasal sinuses

Radiation

Overview of radiation
Type	Occurrence	Malignancy
Nonionizing radiation	UV-B	Skin cancers
Ionizing radiation	X-rays Gamma rays	Leukemias (especially AML and CML) Papillary thyroid cancer Osteosarcoma Liver angiosarcoma

Oncogenic infections

Infective agent	Associated malignancies
DNA viruses
EBV	Burkitt lymphoma Hodgkin lymphoma Nasopharyngeal carcinoma Oral hairy leukoplakia Primary CNS lymphoma in immunocompromised patients Gastric carcinoma
HBV	Hepatocellular carcinoma
HHV-8	Kaposi sarcoma
HPV 16	E6 gene product inhibits TP53 gene, E7 gene product inhibits RB1 gene Squamous cell carcinoma of the vulva, vagina, cervix, anus, penis, oropharynx, larynx
HPV 18
RNA viruses
HTLV-1	Adult T-cell leukemia
HCV	Hepatocellular carcinoma
Nonviral pathogens
Schistosoma haematobium	Squamous cell carcinoma of the bladder
Clonorchis sinensis (Chinese liver fluke)	Cholangiocarcinoma
H. pylori	Gastric adenocarcinoma MALT lymphoma
Streptococcus bovis	Colorectal cancer

Cancer-Immunity cycle

Grading and staging

Tumor grading

Definition: the process of classifying tumors based on their histological appearance (degree of cell differentiation)
Indicators of poor differentiation
- High-proliferation index
- Presence of nucleoli
- Giant cells with multiple nuclei
- Hyperchromasia and heterogeneous 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
- Usually, higher-grade tumors are more aggressive than lower-grade tumors.

Grading	Differentiation of malignant tissue
G1	Well differentiated (low grade)
G2	Moderately differentiated (intermediate grade)
G3	Poorly differentiated (high grade)
G4	Undifferentiated/anaplastic (high grade)
G_X	Differentiation cannot be assessed.

Cancer-specific grading systems
- Gleason score for prostate cancer
- Nottingham grading system for breast cancer

Gleason grading system Histopathological grades of cervical cancer

Tumor staging [20]

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

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

TNM classification

T stage: size or direct extent of the primary tumor

Tcis: carcinoma in situ (no basement membrane penetration and no infiltration of submucosa)

T1–4 based on the size and/or extent of the primary tumor (T4 refers to the infiltration of neighboring organs)
N stage: involvement of regional lymph nodes

N0: no lymph node involvement

N1–3 based on type of tumor and lymph node involvement
M stage: presence of distant metastasis

M0: no distant metastasis

M1: present distant metastasis

Mx: unknown if distant metastasis present or not
By adding a "C" to any category, it is 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 is 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.

Esophageal cancer

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

Lugano staging system for lymphomas

**Gleason grading system**
The pathological patterns of prostate CA in a biopsy sample are rated numerically according to severity. The scores of the most common and second most common patterns are added to obtain the Gleason score. This score is then used to determine the grade group, which is used for risk stratification.

© AMBOSS

**Histopathological grades of cervical cancer**
LSIL: low-grade squamous intraepithelial neoplasia
HSIL: high-grade squamous intraepithelial neoplasia
CIN: cervical intraepithelial neoplasia

© AMBOSS

**Esophageal cancer**
Cross-section of the esophageal wall showing the stages of infiltration by malignant tumors

© AMBOSS

Metastasis

Definition

Metastasis: the spread of malignant cells to distant organs, tissues (e.g., colorectal cancer spreads to the liver)

Types of metastasis [21]

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 thin vein walls facilitate invasion.
- 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 (e.g., after a biopsy of cancer the cancer cells spill and implant along the biopsy canal)
Transcoelomic metastasis: spread of malignant cells into body cavities by penetration of surfaces such as the pleura, pericardium, and peritoneum (e.g., ovarian cancer spread to the liver via the peritoneal cavity)
Canalicular metastasis: spread of malignant cells via canalicular system (e.g. bile ducts, lactiferous ducts, urinary tract, and the subarachnoid space)
Cavitating pulmonary metastasis
[22]
[23]

Spread of malignant cells that form cavitary lesions in the lungs (e.g., gastrointestinal adenocarcinomas, renal cell carcinoma)

Cavitary lesions are most commonly caused by squamous cell carcinoma (e.g., lung, head, and neck cancer)
Cystic pulmonary metastasis: spread of malignant cells that form cystic lesions (contain a thin wall) in the lungs (e.g., colorectal cancer, soft tissue sarcomas, transitional cell carcinoma) [24][25]

“Four Carcinomas Route Hematogenously”: Follicular thyroid carcinoma, Choriocarcinoma, Renal cell carcinoma, and Hepatocellular carcinoma spread via the blood, compared to most carcinomas which spread lymphatically.

Peritoneal carcinomatosis

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 and dissemination and
colonization.

Invasion of extracellular tissue: loss of adhesion to the 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 lymphatic 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) enables extravasation at distant tissues.

Common sites for cancer metastasis [26]

The target organ for metastasis is usually the first capillary bed encountered by the neoplastic cells during spread.
Certain types of cancer have a tendency to spread to particular organs (organ tropism; e.g., prostate cancer to bone, lung cancer to adrenal glands)

Common origins of cancer metastases
Organ with metastasis	Associated features	Primary tumor location
Liver	Second most common site of metastasis (following regional lymph nodes) Usually distributed throughout the liver parenchyma	Colon Breast Stomach Esophagus Pancreas Lung Kidney
Bone	Most bone tumors result from metastases. Usually involve the axial skeleton (e.g., vertebral column, pelvic girdle) Types of bone lesions Lytic : NSCLC, kidney, multiple myeloma, thyroid Blastic : prostate, SCLC Mixed: breast For more information on bone metastasis, see “Bone metastases.”	Prostate Breast Thyroid Lung Kidney Skin (e.g., melanoma) Lung Multiple myeloma
Brain	Approximately 50% of brain tumors result from metastases. Appear in the white-gray matter junction as multiple well-circumscribed lesions	Lung Breast Skin (e.g., melanoma) Colon Kidney
Lungs	Most commonly multiple pulmonary nodules Usually involves both lungs	Breast Colon Kidney Prostate Bladder Skin (e.g., melanoma) Head and neck

Approximately 50% of brain tumors and most bone tumors are not primary tumors but rather result from metastases.

“Cancers spread progressively to the liver”: Colon, Stomach, and Pancreas cancers metastasize to the liver.

“BLT with a kosher pickle and mayo on the bun”: Breast, Lung, Thyroid, Kidney, Prostate cancers, and Multiple myeloma metastasize to the bone.

Most common routes of metastasis with TNM classification Liver metastases from pancreatic neuroendocrine tumor $Pathologic fracture$ Metastasis in bronchial carcinoma Osteolytic metastasis Cerebral metastases Lung metastases Small pulmonary nodules

**Peritoneal carcinomatosis**
Abdominal ultrasound (longitudinal section)
A heteroechoic nodular mass is seen arising from the peritoneal surface of the anterior abdominal wall (green hatched overlay). The mass is well vascularized, as evident on color Doppler (red and blue areas within the green window).
Anechoic intraperitoneal free fluid, or ascites (light blue overlay), is seen between the mass and the adjacent intestinal loops (white outline).
These findings suggest peritoneal carcinomatosis.

Our great thanks to sono.gallery, a medical ultrasound library by Dr. Daniel Merkel, for providing the images and videos.

**Most common routes of metastasis with TNM classification**
Arrows have been color-coded according to the site of the primary tumor:
Pink: skin cancer
Blue: breast cancer
Green: lung cancer
Orange: pancreatic cancer
Red: colon cancer
Lime: ovarian cancer
The table provides examples of suffixes used to specify the affected organs according to the TNM classification.

© AMBOSS

**Liver metastases from pancreatic neuroendocrine tumor**
Ultrasound liver (oblique plane) of patient with pancreatic neuroendocrine tumor
Several rounded, hyperechoic lesions (green overlay) are seen in the right hepatic lobe.
Liver metastases from a pancreatic neuroendocrine tumor are usually circumscribed and round or oval in shape. They may appear hypoechoic, hyperechoic, or targetoid, and may contain cystic or necrotic areas.

Dashed line: diaphragm

Our great thanks to sono.gallery, a medical ultrasound library by Dr. Daniel Merkel, for providing the images and videos.

**Pathologic fracture**
X-ray right shoulder (AP view; external rotation) of a patient with metastatic renal cell carcinoma
A fracture (dashed lines) traverses a lytic lesion (green overlay) involving the surgical neck of the humerus. The lesion margin is ill-defined (wide zone of transition) and cortical breakthrough is present.

Source: “Pathologische Fraktur des Humerus bei einer Metastase eines Nierenzellkarzinoms.” by Hellerhoff, Wikimedia Commons, licensed under CC BY-SA 3.0. The supplementary image with overlays of relevant areas was adapted from the image mentioned above and licensed under CC BY-SA 3.0.

**Metastasis in bronchial carcinoma**
Bone scintigraphy in a 68-year-old patient with known lung carcinoma (tracer: technetium ⁹⁹m, approximately 3 hours after injection)
Two images of the bony skeleton from a ventral view and two images from a dorsal view are shown (the second in each case with altered thresholds for contrast enhancement).
Zones of increased intensity can be seen in the right femur and one left rib (red arrowheads), which is a highly-suggestive of bone metastases.
Another zone of increased intensity is seen in the metatarsophalangeal joint of the left foot (blue arrowhead), which is most indicative of rhizarthrosis.

Our great thanks to PD Dr. M. Jergas (Center for Diagnostic and Interventional Radiology, St. Elizabeth Hospital, Cologne) for kindly providing this image.

**Osteolytic metastasis**
X-ray femur (AP view) of a patient with bronchogenic carcinoma
A lytic cortical lesion (red overlay) involves the middle third of the femur.
Metastases can be lytic, sclerotic, or mixed-density lesions. Osteolytic lesions are the most common and are usually metastases from carcinomas of the kidney, lung, breast, gastrointestinal tract, or thyroid gland.

Our great thanks to PD Dr. M. Jergas (Center for Diagnostic and Interventional Radiology, St. Elizabeth Hospital, Cologne) for kindly providing this image.

**Cerebral metastases**
CT head (left: without contrast; right: with contrast; axial plane) of patient with breast cancer
Three intraparenchymal masses (left frontal lobe, right frontal lobe, and right parietal lobe) are accompanied by vasogenic edema (green overlay). The lesions (red overlay) are hyperdense and more conspicuous after IV contrast administration.

Source: “Brain Metastasis From Breast Cancer” by Jmarchn, Wikimedia Commons, licensed under CC BY-SA 3.0. The supplementary image with overlays of relevant areas was adapted from the image mentioned above and licensed under CC BY-SA 3.0.

**Small pulmonary nodules**
CT chest (axial plane; lung window) of a patient with lung metastases from colon carcinoma
Multiple small, circumscribed nodules of varying sizes (examples indicated by green overlays) can be seen in both lungs. A few nodules (examples indicated by red overlays) contain small foci of air, which may represent small bronchioles or sites of early cavitation.

Source: “Metastatic colonic adenocarcinoma - CT scan - Case 263” by Yale Rosen, Flickr, licensed under CC BY-SA 2.0. The supplementary image with overlays of relevant areas was adapted from the image mentioned above and licensed under CC BY-SA 2.0.

**Pulmonary nodules**
X-ray chest (PA view) of a patient with lung metastases
Multiple pulmonary nodules with circumscribed margins can be seen in both lungs (examples indicated by green overlays). Differential diagnoses include malignant etiologies (metastatic disease, primary lung cancer, lymphoma) and benign etiologies (infection, embolism, autoimmune disease). An old healed fracture of the right clavicle (white arrow) is also visible.

Source: “The appearance of lung metastasis in patient that was reported” by Ghaemmaghami F, Zarchi MK, Early Onset of Metastatic Gestational Trophoblastic Disease after Full-Term Pregnancy, International Journal of Biomedical Science, licensed under CC BY 2.5. Modifications: removed yellow arrow. The supplementary image with overlays of relevant areas was adapted from the image mentioned above (© AMBOSS).

**Lung metastases**
Photograph of a lung (longitudinal section) autopsied from a patient who died from metastatic prostate cancer
Multiple white nodules of varying sizes can be seen throughout the lung parenchyma, including the visceral surface.

Source: “Metastatic prostatic adenocarcinoma” by Yale Rosen, Flickr, licensed under CC BY-SA 2.0.

Tumor markers

Definition: Substances produced by cancer cells that are found in increased amount in the bloodstream, urine, or body tissues.

The most commonly tested
tumor markers include the following
- Alpha fetoprotein (AFP)
- β-HCG
- Carcinoembryonic antigen (CEA)
- Prostate-specific antigen (PSA)
- Calcitonin
- Alkaline phosphatase
- Placental alkaline phosphatase
- Lactate dehydrogenase
- Neuron specific enolase (NSE)
- CA 19–9
- CA 15–3
- CA 125
- Chromogranin A
- S-100 protein
- β2 microglobulin
- Thyroglobulin
- Monoclonal immunoglobulins

For more details for each tumor marker see the article on tumor markers.

Conditions associated with tumors

Neurocutaneous syndromes associated with neoplasms

Overview of neurocutaneous syndromes associated with neoplasms
Condition	Key features		Neoplasms
Neurofibromatosis type I	Cafe au lait spots	Axillary/inguinal freckling Lisch nodules	Multiple neurofibromas Optic glioma Pheochromocytoma
Neurofibromatosis type II	Cafe au lait spots	Bilateral cataracts	Bilateral vestibular schwannoma Meningioma Ependymoma
Tuberous sclerosis	Ash leaf spots , shagreen patch , adenoma sebaceum Infantile spasms, intellectual disability		Giant cell astrocytoma Cardiac rhabdomyoma Renal angiomyolipoma
von Hippel-Lindau syndrome	Renal and pancreatic cysts		Retinal and CNS hemangioblastoma Bilateral renal cell carcinoma Pheochromocytoma
Sturge-Weber syndrome	Port-wine stain Seizures, intellectual disability		Leptomeningeal angioma
Ataxia telangiectasia	Spider angioma Ocular teleangiectasia, cerebellar ataxia		Lymphoma Leukemia Gastric carcinoma

Gastrointestinal conditions associated with neoplasms

Overview of gastrointestinal conditions associated with neoplasms
Condition		Key features	Neoplasms
Inflammatory bowel disease	Ulcerative colitis	See “Crohn disease and ulcerative colitis” for details.	Cholangiocarcinoma Colorectal cancer
Inflammatory bowel disease	Crohn disease	See “Crohn disease and ulcerative colitis” for details.	Small intestine, colon Non-Hodgkin lymphoma
Plummer-Vinson syndrome		Iron deficiency anemia, postcricoid dysphagia, and upper esophageal webs	Esophageal squamous cell carcinoma
Barrett esophagus		Esophageal squamous epithelium is replaced by columnar epithelium and goblet cells (intestinal metaplasia) due to longterm reflux esophagitis	Esophageal adenocarcinoma
Atrophic gastritis	Autoimmune atrophic gastritis (AIG)	Autoimmune destruction of the parietal cells → achlorhydria → ↑ release of gastrin → hyperplasia of enterochromaffin-like cells → ↑ risk of neuroendocrine tumors	Gastric adenocarcinoma	Gastric neuroendocrine tumors Esophageal squamous cell carcinoma
Atrophic gastritis	Environmental metaplastic atrophic gastritis (EMAG)	Colonization by H. pylori → local destruction of mucosa → ↓ production of mucins and atrophy of the gastric glands → hypergastrinemia and epithelial dysplasia → epithelial metaplasia → ↑ risk of gastric cancers	Gastric adenocarcinoma	Gastric MALT lymphoma
Liver cirrhosis		Chronic damage to the liver, most commonly due to excessive alcohol consumption → hepatic parenchymal necrosis and inflammation → fibrosis and abnormal tissue architecture → ↓ liver function	Hepatocellular carcinoma

Infectious conditions associated with neoplasms

Overview of infectious conditions associated with neoplasms
Condition		Key features	Neoplasms
DNA virus infections	EBV infection	Acute infection: fever, malaise, and fatigue, followed by acute pharyngitis, tonsillitis, lymphadenopathy, and/or splenomegaly lasting up to a month Oncogenic potential; higher risk for immunocompromised individuals (e.g., HIV infection/AIDS)	Burkitt lymphoma Hodgkin lymphoma Nasopharyngeal carcinoma Oral hairy leukoplakia Primary CNS lymphoma in immunocompromised patients Gastric carcinoma
	HBV infection	Acute or chronic inflammation of the liver after an incubation period of 1–6 months Can rarely cause acute liver failure	Hepatocellular carcinoma
	HHV-8 infection	Infects endothelial cells causing malignant, multifocal, highly vascularized tumors	Kaposi sarcoma
	HPV 16	E6 gene product inhibits TP53 gene, E7 gene product inhibits RB1 gene	Squamous cell carcinoma of the vulva, vagina, cervix, anus, penis, oropharynx, larynx
	HPV 18
RNA virus infections	HTLV-1 infection	Has reverse transcriptase Endemic to Japan and the Caribbean	Adult T-cell leukemia HIV: aggressive malignant NHLs
	HIV infection	Acute infection: nonspecific manifestations, including fever, headache, weight loss, lymphadenopathy Advanced infection: esophageal or bronchial candidiasis, pneumocystis pneumonia	Adult T-cell leukemia HIV: aggressive malignant NHLs
	HCV infection	Acute or chronic inflammation of the liver after an incubation period of 2 weeks to 6 months Can rarely cause acute liver failure Often leads to chronic hepatitis	Hepatocellular carcinoma
Nonviral pathogen infections	Schistosoma haematobium	Causes schistosomiasis Endemic to sub-Saharan Africa, the Middle East, and the southern Arabian Peninsula	Squamous cell carcinoma of the bladder
	Clonorchis sinensis (Chinese liver fluke)	Mostly asymptomatic If symptomatic: cholangitis, cholelithiasis, nonspecific symptoms (e.g., abdominal pain, diarrhea, fatigue)	Cholangiocarcinoma
	Streptococcus bovis	Can cause infective endocarditis	Colorectal cancer
	Clostridium septicum	Can cause gas gangrene	Colorectal cancer

Miscellaneous conditions associated with neoplasms

Miscellaneous conditions associated with neoplasms
Condition	Key features	Neoplasms
Down syndrome	Characteristic appearance that includes upward-slanting palpebral fissures and a single transverse palmar crease Organ malformations (e.g., heart defects) Intellectual disability.	ALL
Paget disease of the bone	Increased bone turnover → replacement of normal lamellar bone with weak, woven bone	Osteosarcoma

Paraneoplastic conditions

Overview of paraneoplastic conditions
Condition		Key features		Neoplasms
Neuromuscular	Lambert-Eaton myasthenic syndrome	Anti-VGCC antibodies → proximal muscle weakness and reduced or absent reflexes		Small cell lung cancer
	Myasthenia gravis	Autoantibodies against nicotinic AChRs of neuromuscular endplates → fatigable weakness of skeletal muscles		Thymoma
	Polymyositis	Cell-mediated cytotoxicity against unidentified skeletal muscle antigens	Proximal muscle weakness affecting both sides	Adenocarcinoma (most common) Ovarian cancer
	Dermatomyositis	Antibody-mediated vasculopathy	Proximal muscle weakness affecting both sides	Adenocarcinoma (most common) Ovarian cancer
Neurological	Paraneoplastic encephalomyelitis	Immune reaction against neural antigens	Symptoms of encephalitis (e.g., memory deficits, seizures) and myelitis (e.g., limb paresis)	Small cell lung cancer Anti-NMDA encephalitis: ovarian teratoma
	Paraneoplastic cerebellar degeneration	Immune reaction against neural antigens	Ataxia, vertigo, nystagmus, diplopia	Anti-Yo antibodies: gynecological malignancies Anti-Hu antibodies: small cell lung cancer Anti-Tr antibodies: Hodgkin lymphoma
	Opsoclonus-myoclonus syndrome	Cellular immune reaction against onconeural antigens → opsoclonus, myoclonus		SCLC (in adults) Pediatric cases of neuroblastoma
Endocrine	Cushing syndrome	Ectopically produced ACTH → moon facies, buffalo hump, hirsutism, hyperpigmentation		SCLC
	Syndrome of inappropriate ADH secretion	Ectopically produced ADH → anorexia, nausea, vomiting		SCLC
	Hypercalcemia of malignancy	Various mechanisms → ↑ serum Ca²⁺ → nephrolithiasis, nephrocalcinosis, bone pain, arthralgias, myalgias		Squamous cell carcinomas Hodgkin lymphoma, NHL Multiple myeloma Urogenital cancers
Mucocutaneous	Malignant acanthosis nigricans	Ectopically produced TGF-α and EGF → brown to black, intertriginous and/or nuchal hyperpigmentation and dermal thickening		Gastric adenocarcinoma and other gastrointestinal cancers
	Necrolytic migratory erythema	Multiple areas of centrifugally spreading erythema that develop into develop into painful and pruritic crusty patches with central areas of bronze-colored induration		Glucagonoma
	Paraneoplastic seborrheic keratosis (Leser-Trélat sign)	Activation of epidermal growth factor receptors → multiple, sudden-onset seborrheic keratoses		Solid cancers (especially gastrointestinal adenocarcinoma)
Skeletal	Hypertrophic pulmonary osteoarthropathy (Bamberger-Marie syndrome)	Ectopically produced growth factors (e.g., VEGF, PDG) → clubbing, joint pain, thickening of tubular bones		NSCLC (especially lung adenocarcinoma)
Hematological	Polycythemia	Ectopically produced EPO → hyperviscosity syndrome, plethora, facial flushing		Renal cell carcinoma Pheochromocytoma Hemangioblastoma Leiomyoma
	Pure red cell aplasia	Absence of red cell precursor cells → anemia		Thymoma
	Good syndrome	Hypogammaglobulinemia → immunodeficiency		Thymoma
	Trousseau syndrome (thrombophlebitis migrans)	Hypercoagulability → recurring, migrating clots		Pancreatic cancer
	Nonbacterial thrombotic endocarditis	Deposition of noninfectious thrombi on the heart valves		Adenocarcinomas (e.g., pancreas cancer, colorectal cancer)
Miscellaneous	Neoplastic fever	Cytokine mediated fever, malaise, weight loss		Most cancers
Miscellaneous	Membranous glomerulonephritis	MAC forms on glomerular epithelial cells → edema, hypoalbuminemia, hyperlipidemia		Lung cancer Colon cancer

**Neurofibromatosis type 1**
Multiple light brown macules with irregular borders (café-au-lait spots) are visible on the upper left arm, shoulder, and back.
This presence of multiple café-au-lait spots is highly suggestive of neurofibromatosis type 1.

Source: Courtesy of Dr. Gary M. White, MD

**Lisch nodules**
Right eyes of a father and son
Multiple brown-yellow, well-defined, and partly confluent papules (hamartomas) are visible on the iris.
These lesions are called Lisch nodules and can be seen in the vast majority of individuals with neurofibromatosis I.

Source: © IMPP

**Neurofibromas**
Multiple papules and nodules of varying sizes located on the upper back.
Numerous neurofibromas are pathognomonic of neurofibromatosis type 1 (von Recklinghausen disease).

Source: © IMPP

**Vestibular schwannomas and parasagittal meningioma**
MRI head (T1-weighted; with contrast; A: axial plane; B: coronal plane) of a patient with neurofibromatosis type 2 (NF2)
The bilateral contrast-enhancing cerebellopontine angle masses (green overlay) represent vestibular schwannomas. The parasagittal location of the third intracranial mass (red overlay) suggests that it is a meningioma.
Bilateral vestibular schwannomas are the hallmark feature of NF2. Many patients also develop meningiomas and other tumors of the central nervous system.

Source: “Figure 1. in: Magnetic resonance findings of neurofibromatosis type 2: a case report” by Gabriela Spilberg et al., Cases Journal, licensed under CC BY 2.0. The supplementary image with overlays of relevant areas was adapted from the image mentioned above (© AMBOSS).

**Ash-leaf spots**
Four ellipsoid, hypopigmented macules (ash-leaf spots) are located on the back of the patient (green overlay).
The presence of more than three ash-leaf spots is characteristic of tuberous sclerosis.

Source: Courtesy of Dr. Gary M. White, MD

**Shagreen patch**
Photograph of the back of a patient with tuberous sclerosis complex
A flesh-colored, irregularly shaped, slightly elevated patch can be seen on this patient's lumbosacral region. The fibrotic tissue gives it a bumpy appearance, which is often compared to that of orange peel.

Source: “Figure 1, in: Brain Proteomic Profiling in Intractable Epilepsy Caused by TSC1 Truncating Mutations: A Small Sample Study” by Liu Y-D, Ma M-Y, Hu X-B, Yan H, Zhang Y-K, Yang H-X, Feng J-H, Wang L, Zhang H, Zhang B, Li Q-B, Zhang J-C and Kong Q-X, frontiers in Neurology, licensed under CC BY 4.0. Modifications: image is cropped.

**Adenoma sebaceum in patient with tuberous sclerosis**
Multiple papules, resembling acne, can be seen on this patient's face.
These findings are suggestive of adenoma sebaceum, a cutaneous condition in patients with tuberous sclerosis characterized by the presence of angiofibromas.

Source: “A case of tuberous sclerosis showing facial angiofibromas in characteristic butterfly pattern.” by Herbert L. Fred, MD and Hendrik A. van Dijk, Wikimedia Commons, licensed under CC BY-SA 3.0.

**Large angiomyolipoma associated with tuberous sclerosis**
T2-weighted MRI of the abdomen with gadolinium-based contrast medium, frontal section: large angiomyolipoma of the left kidney (K) associated with tuberous sclerosis (L = liver, S = spleen)

Source: © IMPP

**Hemangioblastomas of the central nervous system in Von-Hippel-Lindau syndrome**
MRI images (contrast-enhanced; T1-weighted) of a patient with Von-Hippel-Lindau syndrome.
Image A (brain; axial view) shows a tumor within the lateral aspect of the right cerebellum. It consists of an enhancing solid component (red overlay) and a larger, hypointense part representing a cystic component (blue overlay).
Image B (brain; sagittal view) shows a contrast-enhancing tumor (green overlay) between medulla oblongata and cerebellum, within the region of the foramen of Magendie/median aperture.
Image C (spine MRI; sagittal view) shows a hyperintense tumor (yellow overlay) within the dorsal/posterior spinal canal at the level of vertebra C5-C6.
Von-Hippel-Lindau syndrome is a hereditary disorder characterised by the development of tumors in multiple parts of the body. This includes hemangioblastomas of the central nervous system, such as in this example. Hemangioblastomas are highly vascular tumours, resulting in the intense enhancement demonstrated on these post contrast images. Peritumoural cysts are common in these tumors, and result from plasma ultrainfiltrate passing through the permeable tumor blood vessels.

Source: “Figure 3. in: Personalized Medicine for Nervous System Manifestations of von Hippel–Lindau Disease” by Victoria Schunemann, Kristin Huntoon, Russell R. Lonser, Frontiers in Surgery Journal, Neurosurgery, licensed under CC BY 4.0. The supplementary image with overlays of relevant areas was adapted from the image mentioned above (© AMBOSS).

**Retinal hemangioblastoma in von Hippel-Lindau disease**
Fundus photography of a left eye
Adjacent nasally to the optic disc, a sharply demarcated orange lesion is visible.
This is the typical appearance of a retinal hemangioblastoma. Approx. 50% of patients with a solitary lesion will have von Hippel-Lindau disease. The vast majority of patients with multiple lesions will have von Hippel-Lindau disease.

Source: “Figure 1B. in: Pathology characteristics of ocular von Hippel-Lindau disease with neovascularization of the iris and cornea: a case report” by Shida Chen, Emily Y Chew & Chi-Chao Chan, Journal of Medical Case Reports, BioMed Central, licensed under CC BY 4.0. Modifications: image cropped & removal of the letter B.

**Port-wine stain (nevus flammeus)**
A sharply demarcated, irregularly configured, erythematous area with a smooth surface on the left side of this 2-month-old infant's face is visible.

Image source of original image: www.paediatrie-in-bildern.de. Created by: Dr. Thomas Rautenstrauch. Modifications to original image: anonymized.

**Ataxia telangiectasia**
Medial angle of the left eye showing severely dilated blood vessels on the conjunctiva (conjunctival telangiectasia).
Conjunctival telangiectasias are a clinical finding of ataxia telangiectasia (Louis-Bar syndrome), a rare neurocutaneous syndrome

Source: "Ataxia-telangiectasia", National Eye Institute, Wikimedia Commons licensed under Public Domain

**Ocular and cerebral manifestations in ataxia teleangiectasia**
Image A: Close-up photograph of the left eye while the patient is looking to the right-top
A significantly dilated vessel of the conjunctiva can be seen (apart from that, the prominent epicanthic fold suggests an asian background of the patient).
Image B: Cranial MRI (T1w, sagittal view)
A remarkable atrophy of the cerebellum can be noted, leading to secondary enlargement of the cerebrospinal fluid system.
When put together, both findings are characteristics of neurocutaneous syndrome ataxia telangiectasia (Louis-Bar syndrome).

Source: “Figure 1: The clinical features of an AT patient” by Zhao Chen, Wei Ye, Zhe Long et al., Plos One, licensed under CC BY 4.0.

References

"Cell Signaling in Cancer". https://www.technologynetworks.com/cancer-research/articles/cell-signaling-in-cancer-313171. [2018-12-17]
Bhagwat AS, Vakoc CR. "Targeting Transcription Factors in Cancer". Trends in Cancer. 1(1). :53-65. (2015)
Mendonsa AM, Na T-Y, Gumbiner BM. "E-cadherin in contact inhibition and cancer". Oncogene. 37(35). :4769-4780. (2018)
Liberti MV, Locasale JW. "The Warburg Effect: How Does it Benefit Cancer Cells?". Trends Biochem Sci. 41(3). :211-218. (2016)
Rabinovich GA, Gabrilovich D, Sotomayor EM. "Immunosuppressive Strategies that are Mediated by Tumor Cells". Annu Rev Immunol. 25(1). :267-296. (2007)
Buchbinder EI, Desai A. "CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition.". Am J Clin Oncol. 39(1). :98-106. (2016)
Flynn SD, Murren JR, Kirby WM, et al. "P-glycoprotein expression and multidrug resistance in adrenocortical carcinoma.". Surgery. 112(6). :981-6. (1992)
Lochhead P, Chan AT, Nishihara R, et al. "Etiologic field effect: reappraisal of the field effect concept in cancer predisposition and progression". Modern Pathology. 28(1). :14-29. (2015)
Cooper R, Harrison A. "The uses and adverse effects of beryllium on health". Indian Journal of Occupational and Environmental Medicine. 13(2). :65. (2009)
"Beryllium Toxicity". https://www.atsdr.cdc.gov/csem/csem.asp?csem=5&po=6
Hecht SS, Hoffmann D. "Tobacco-specific nitrosamines, an important group of carcinogens in tobacco and tobacco smoke". Carcinogenesis. 9(6). :875-884. (1988)
"What Causes Lung Cancer". https://www.lung.org/lung-health-and-diseases/lung-disease-lookup/lung-cancer/learn-about-lung-cancer/what-is-lung-cancer/what-causes-lung-cancer.html. [2017-11-24]
Deslauriers JR, Redlich CA. "Silica Exposure, Silicosis, and the New Occupational Safety and Health Administration Silica Standard. What Pulmonologists Need to Know.". Annals of the American Thoracic Society. 15(12). :1391-1392. (2018)
Cowherd SM. "Tumor Staging and Grading: A Primer". Humana Press. :1-18. (2011). ISBN: 9781603272155
Kumar V, Abbas AK, Aster JC. "Robbins & Cotran Pathologic Basis of Disease". Elsevier Saunders. (2014). ISBN: 9781455726134
Yu X, Wang P, Liang Z. "Cavitary Pulmonary Metastases: CT Features and Their Correlation with the Pathology of the Primary Malignancy". The Chinese-German Journal of Clinical Oncology. 3(1). (2004)
Gunasekaran K, Baskaran B, Rahi MS, Rudolph D, Parekh J. "Cavitating pulmonary metastases from a renal cell carcinoma". Clinics and Practice. 10(1). (2020)
Sagar D, Adeni A. "Unusual cystic lung metastasis". BMJ Case Reports. :bcr-2018-224648. (2018)
Fielli M, Avila F, Saino A, Seimah D, Fernández Casares M. "Diffuse cystic lung disease due to pulmonary metastasis of colorectal carcinoma". Respiratory Medicine Case Reports. 17. :83-85. (2016)
Obenauf AC, Massagué J. "Surviving at a Distance: Organ-Specific Metastasis". Trends in Cancer. 1(1). :76-91. (2015)
Lodish HF, Zipursky HF, Matsudaria HF, et al. "Molecular Cell Biology". Scientific American Library. (2000). ISBN: 0716731363
Assi T, Kattan J, Rassy E, et al. "Targeting CDK4 (cyclin-dependent kinase) amplification in liposarcoma: A comprehensive review". Crit Rev Oncol Hematol. 153. :103029. (2020)
Lee B, McArthur GA. "CDK4 inhibitors an emerging strategy for the treatment of melanoma". Melanoma Management. 2(3). :255-266. (2015)
Coleman WB. "Molecular Pathogenesis of Prostate Cancer". Elsevier. :555-568. (2018). ISBN: 9780128027615
"Skin Cancer". https://web.archive.org/web/20201231013700/https://www.cdc.gov/cancer/skin/statistics/index.htm
"Cancer Stat Facts: Common Cancer Sites". https://seer.cancer.gov/statfacts/html/common.html. [2018-04-01]
Chen C-Y, Peng H-C, Chen Y-Y, Chan C-C, Yu C-J. "Association of environmental heavy metals exposure and lung cancer incidence and prognosis". 11.1 Lung Cancer. (2016)