Neoplasia

Overview Characteristics of neoplasms compared to

normal tissues Types of neoplasms

Benign vs malignant Cellular differentiation

Genetic basis for neoplasia

What is a “neoplasm”? Lay term of “tumor” conveys usual

connotations – ie a new growth or mass Definition revolves around these features:

Monoclonal proliferation of cells with specific mutations

Excessive and unregulated growth of these cells, often at the expense of surrounding normal tissue

Biology of tumor growth

Terms to know about when discussing neoplasia Metastasis - spread of a malignant tumor

from one site to another via blood or lymph Benign – typically refers to those tumors

incapable of metastasis and having a good clinical outcome (prognosis)

Malignant – those tumors capable of invasive growth and/or metastasis, often fatal if not treated effectively

More terms…. Parenchyma – these are the tumor cells

themselves, usually referring to epithelial cells in organs.

Stroma – connective tissue cells that support the parenchymal cells – not actually tumor cells, but are stimulated to grow by the tumor via growth factors, eg angiogenesis

Cellular differentiation Tumors are often “graded” as to how

closely they resemble the normal parent tissue that they are derived from.

Well-differentiated means the cells are very similar in appearance and architectural arrangement to normal tissue of that organ

Normal cervical “Pap smear”

Malignant cervical “Pap smear”

Colonic “adenoma” illustrating a “well-differentiated” neoplasm similar to normal colon mucosa

Differentiation “Poorly-differentiated” refers to tumors

that show only minimal resemblance to the normal parent tissue they are derived from.

“Anaplastic” means the tumor shows no obvious similarity to it’s parent tissue, usually associated with aggressive behavior

So what?????? Differentiation often provides clues as to the

clinical aggressiveness of the tumor Tumors often lose differentiation features over

time as they become more “malignant” and as they acquire more cumulative genetic mutations

Differentiation often predicts responsiveness to certain therapies, eg estrogen receptors and Tamoxifen in breast cancers

Gross (macroscopic) features of two breast neoplasms

Benign – circumscribed, often encapsulated, pushes normal tissue aside

Malignant – infiltrative growth, no capsule, destructive of normal tissues

Classification of neoplasms Epithelial tumors

Benign forms – adenoma , papilloma Malignant forms – carcinoma, eg

adenocarcinoma, squamous cell carcinoma Mesenchymal tumors

Benign forms – fibroma, leiomyoma, Malignant forms – sarcoma, eg fibrosarcoma,

leiomyosarcoma

Classification continued Tumors of lymphocytes are always

malignant – called lymphoma Tumors of melanocytes

Benign – nevus Malignant - melanoma

Microscopic features of tumors Loss of normal architectural arrangement –

Microscopic features of tumors Pleomorphism – variation in size and shape

of cells within the neoplasm

Microscopic features of tumors Mitotic activity - Increased in more

malignant tumors and often abnormal in shape

Precursors of neoplasia Hyperplasia Metaplasia Chronic inflammation dysplasia

Metaplasia, dysplasia, neoplasia Metaplasia – an adaptive

change in differentiation, reversible, no mutations necessary. Eg- change of esophageal

mucosa from squamous to gastric type in the setting of acid reflux (“heartburn”). Better able to withstand the corrosive effects of the acid.

Metaplasia is fertile ground for development of “dysplasia” (disordered growth)

Metaplasia, dysplasia, neoplasia Dysplasia refers to recognizable morphologic changes in

cells that indicate the presence of genetic mutations beginning the development of a neoplasm

Often graded, eg PAP smears for uterine cervical cancer are low and high grade

Causes of Cancer Most cancer arises as the result of somatic

mutations in the genome resulting from: Chance (ie, we don’t know) Environmental factors – chemical, radiation,

viruses Ageing

Inherited cancer syndromes- defect in germline DNA

Environmental carcinogens Chemicals capable of DNA damage Initiators vs Promoters Common denominator is “electrophilic

intermediates” forming adducts with DNA Some are direct acting, others are activated

in the body, usually in the liver by cytochrome P-450 enzymes

Radiation Ionizing radiation – x-rays, gamma rays,

radioactive materials such as Radon gas – all cause a variety of defects to DNA

UV light (non-ionizing) – primarily sun-exposure and T-T dimerization – skin cancers

Common features of viral carcinogenesis Oncogenic viruses typically integrate their

genomes into host cells and enter a period of “latency”

May be of DNA or RNA type DNA viruses include EBV, HPV and

Hepatitis B virus RNA viruses include retroviruses like

HTLV-1 and indirectly HIV

Viral carcinogenesis Human papilloma virus (HPV) prototype

Cause warts Some types have stronger cancer causing

associations, esp 16 and 18 with uterine cervix cancer - Pap smears of cervix can detect precursor lesions of infection – Rx

Viral genes interact with human genes concerned with cell division

How does HPV cause cancer? Gene products of certain sub-type (eg 16

and 18) interfere with normal cellular proteins

Early viral proteins E6 and E7 bind p53 and RB proteins respectively

Other oncogenic viruses Epstein-Barr virus (EBV) associated with

some lymphomas and nasopharyngeal carcinoma

Hepatitis B virus associated with malignant liver tumors