Neoplasia review

NEOPLASIA REVIEWFe A. Bartolome, MD, FPASMAPDepartment of PathologyOur Lady of Fatima University

Nomenclature

Benign tumors

1. Suffix “oma” generally indicates a benign tumor

2. Benign tumors of epithelial origina. Arise from ectoderm or endodermb. Example – tubular adenoma arising

from glands in the colon

3. Benign tumors of connective tissue origin arise from mesoderm• Example – lipoma from adipose

Nomenclature

Benign tumors

4. Tumors that are usually benign

a. Mixed tumors• Neoplastic cells have two different

morphologic patterns but derive from the same germ cell layer

• Example – pleiomorphic adenoma of parotid gland

Nomenclature

Benign tumors

4. Tumors that are usually benign

b. Teratomas • Tumors that derive from more than

one germ cell layer – contain tissue derived from ectoderm, endoderm, and mesoderm

• Sites: ovaries, testes, anterior mediastinum, and pineal gland

Nomenclature

Malignant tumors (cancers)

1. Carcinomasa. Derive from epithelial tissue –

squamous, glandular, transitionalb. Sites of squamous cell carcinoma• Oropharynx, larynx, upper/middle

esophagus, lung, cervix, skinc. Sites of adenocarcinoma• Lung, distal esophagus to rectum,

pancreas, liver, breast, endometrium, ovaries, kidneys, prostate

Nomenclature

Malignant tumors (cancers)

2. Sarcomas

a. Derive from connective tissue

b. Example – osteogenic sarcoma in bone

Nomenclature

Tumor-like Conditions

1.Hamartoma a. Non-neoplastic overgrowth of

disorganized tissue indigenous to a particular site

b. Examples – bronchial hamartoma, Peutz-Jeghers polyp

2.Choristoma (heterotopic rest)a. Non-neoplastic normal tissue in a foreign

locationb. Examples – pancreatic tissue in stomach

wall; gastric mucosa in Meckel diverticulum

Properties

Components of benign & malignant tumors

1.Parenchyma• Neoplastic component that determines the

tumor’s biologic behavior

2.Stroma • Non-neoplastic supportive tissue• Most infiltrating carcinomas induce

production of a dense, fibrous stroma

Properties

Differentiation

1.Benign tumors• Usually well-differentiated – resemble

parent tissue

2.Malignant tumorsa. Well-differentiated or low gradeb. Poorly-differentiated, high grade, or

anaplasticc. Intermediate grade – features between

low- and high-grade cancers

Properties

Nuclear Features

1.Benign tumors• Nuclear:cytoplasmic ratio close to normal• Mitoses with normal mitotic spindles

2.Malignant tumorsa. Nuclear:cytoplasmic ratio increased with

prominent nucleolib. Mitoses have normal and atypical mitotic

spindles

Properties

Growth Rate

1.Benign tumors• Usually with slow growth rate

2.Malignant tumors• Variable growth rate – correlates with

degree of differentiation• Anaplastic cancers with increased growth

rate• 30 doubling times required for a tumor to

be clinically evident equivalent to 109 cells, 1 gram of tissue, volume of 1 ml

Properties

Monoclonality

•Benign and malignant tumors derive from a single precursor cell

•Non-neoplastic proliferations derive from multiple cells (polyclonal)

Properties

Telomerase Activity

1.Telomerase functiona. Preserves length of telomeres (sequences

of non-translated DNA at the ends of chromosomes)

b. Prevents gene loss after multiple cell division

2.Benign tumors with normal telomerase activity

3.Malignant tumors with increased telomerase activity do not lose genetic material after multiple cell division

Properties

Local Invasion• Second most important criterion for

malignancy1.Benign tumors do not invade usually enclosed in a fibrous capsule (except uterine leiomyoma)

2.Malignant tumors invade tissue• Basal cell CA of the skin invade tissue but

do not metastasize

3.Some tissues resist invasion – mature cartilate, elastic tissue in arteries

Properties

Local Invasion

Sequence of invasion by malignant tumors:1.Loss of intercellular adherence• E-cadherin not produced

2.Cell invasion occursa. Cell receptors attach to laminin

(glycoprotein in the basement membrane)b. Cells release type IV collagenase

dissolve BMc. Cell receptors attach to fibronectin in the

ECMd. Cells produce cytokines (stimulate

locomotion) and proteases (dissolve connective tissue)

e. Cells produce factors that stimulate angiogenesis (EGF, bFGF)

Properties

Metastasis

•Benign tumors do not metastasize•Malignant tumors metastasize

Pathways:1. Lymphatic spread to lymph nodes –

usual for carcinomas2. Hematogenous

Usual for sarcomas Cells entering portal vein liver Cells entering vena cava lungs

3. Seeding – malignant cells exfoliate from surface and implant and invade tissue in a body cavity

Properties

Metastasis

•Bone metastases

1. Vertebral column Most common metastatic site in bone Due to Batson paravertebral venous

plexus2. Osteoblastic metastases

Radiodensities seen on radiograph (eg prostate cancer)

Increased serum alk phos reactive bone formation

Properties

Metastasis

•Bone metastases

3. Osteolytic metastases Radiolucencies on radiographs (eg lung

CA) Pathogenesis:

a. Production of substances that activate osteoclasts (e.g. PGE2, IL-1)

b. Production of parathyroid hormone-related protein (e.g. Squamous cell CA in lungs, renal cell CA)

Consequences: pathologic fractures, hyper-calcemia

Properties

Metastasis

•Metastasis often more common than a primary cancer

a. Lymph nodes – metastatic breast and lung CA

b. Lungs – metastatic breast CAc. Liver – metastatic lung CAd. Bone – metastatic breast CAe. Brain – metastatic lung CA

Acquired neoplastic disorders

1. Autosomal dominant cancer syndrome

a. Retinoblastoma – inactivation of RB suppressor gene

b. Familial adenomatous polyposis - inactivation of APC suppressor gene; colorectal cancer by age 50

c. Li-Fraumeni syndrome – inactivation of TP53 suppressor gene

d. Hereditary nonpolyposis colon cancer (Lynch syndrome) – DNA mismatch repair genes

e. Breast & ovarian cancer – BRCA1 and BRCA2 genes


2. Autosomal recessive syndromes with defects in DNA repair

a. Xeroderma pigmentosum – skin cancer due to UVL (basal cell CA, squamous cell CA)

b. Chromosome instability syndromes – damage by ionizing radiation and drugs• Include Fanconi anemia, ataxia

telangiectasia, Bloom syndrome


3. Familial cancer syndromes

• No defined pattern of inheritance

• Cancers (breast, ovary, colon) develop with increased frequency in families

• Sometimes involves BRCA1 and BRCA2 genes

Carcinogenesis

Types of gene mutation

1. Point mutations – most common type

2. Balanced translocations

3. Other mutations• Deletion, gene amplification (multiple

copies of a gene), over-expression (increase in baseline gene activity

Carcinogenesis

Genes involved in cancer

1. Proto-oncogenes

• Involved in normal growth and repair• Protein products include: growth

factors, growth factor receptors, signal transducers, nuclear transcribers

• Mutations cause sustained activity of the genes

Carcinogenesis


2. Suppressor genes (anti-oncogenes)

• Protect against unregulated cell growth• Control G1 to S phase of the cell cycle

and nuclear transcription• Mutations cause unregulated cell

proliferation

Carcinogenesis


3. Anti-apoptosis genes (BCL2 family of genes)

• Protein products prevent cytochrome c from leaving the mitochondria

• Mutation causes increased gene activity (e.g.overexpression) prevents apoptosis (e.g. B-cell follicular lymphoma) Translocation t(14:18) cause over-

expression of BCL2 protein prevent apoptosis of B cells

Carcinogenesis


4. Apoptosis genes

• Regulate programmed cell death• Example – BAX apoptosis gene

a. Activated by TP53 if DNA damage is excessive

b. Protein product inactivates BCL2c. Inactivation of TP53 BAX

inoperative no apoptosis

Carcinogenesis


5. DNA repair genes

• Examples of DNA repaira. Mismatch repair genes – correct

errors in nucleotide pairingb. Nucleotide excision repair – excise

pyrimidine dimers in UVL-damaged skin

• Mutation allows cells with non-lethal damage to proliferate increased risk for cancer

Chemical Carcinogens

1. Polycyclic hydrocarbons in tobacco smoke• Most common group of carcinogens in the

USA

2. Mechanisms:a. Direct-acting carcinogens• With electron-deficient atoms that react

with electron-rich atoms in DNA (e.g. Alkylating agents)

b. Indirect-acting carcinogens• Activated by the liver cytochrome P-450

system (e.g. Polycyclic hydrocarbons)

Chemical Carcinogens

3. Sequence of chemical carcinogenesis

a. Initiation• Irreversible mutation

b. Promotion• Promoters (e.g. Estrogen) stimulate

mutated cells to enter the cell cycle

c. Progressioni. Development of tumor heterogeneityii. Examples – production of cells that

invade or metastasize

Microbial Carcinogenesis

Radiation

1. Ionizing radiation• Hydroxyl free radical injury to DNA• Examples: AML or CML; papillary thyroid

CA; lung, breast or bone cancers• Leukemia – most common cancer due to

ionizing radiation

2. UV light• Formation of pyrimidine dimers distort

DNA• Examples: basal cell CA (most common),

squamous cell CA, malignant melanoma

Host Defense vs. Cancer

1. Humoral immunity – antibodies and complement

2. Type IV cellular immunity• Most efficient mechanism• Cytotoxic CD8 T cells – recognize altered

class I antigens on neoplastic cells and destroy them

3. Natural killer cells – direct and indirect killing via type II hypersensitivity

4. Macrophages – activated by gamma-interferon

Cancer Grading

• Degree of differentiation Low, intermediate, or high

grade

• Nuclear features

• invasiveness

Cancer Staging

• Most important prognostic factor• TNM system

1. Progresses from the least to the most important prognostic factor

2. T – tumor size > 2 cm correlates with metastatic ability

3. N – nodal involvement4. M – extranodal metastases

Cancer Effects on Host

1. Cachexia (wasting disease)

• Irreversible catabolic reaction• Mechanism: tumor necrosis factor-

alphaa. Secreted from host macrophages

and cancer cellsb. Suppresses the appetite centerc. Increases beta-oxidation of fatty

acids


2. Anemia

a. Anemia of chronic diseaseb. Iron deficiency due to GI blood lossc. Macrocytic anemia – due to folate

deficiency from rapid tumor growthd. Myelophthisic anemia• Anemia related to bone metastasis• Immature hematopoietic elements

in peripheral blood Teardrop RBCs indicate myelo-

fibrosis secondary to bone metastasis


3. Hemostasis abnormalities

a. Increased risk for vessel thrombosis• Due to thrombocytosis, increased

synthesis of coagulation factors (fibrinogen, factors V and VIII)

• Release of pro-coagulants from cancer cells (e.g. Pancreatic CA)

b. DIC due to release of tissue thromboplastin from cancer cells


4. Paraneoplastic syndromes

a. Distant effects of a tumor that are unrelated to metastasis – may predate the onset of metastasis

b. Occur in 10-15% of cancer patientsc. Involve multiple organ systems and

mimic metastatic diseased. May involve ectopic secretion of

hormone


Syndrome Associated cancer Comment

Acanthosis nigricans Stomach carcinoma Black verrucoid-appearing lesion

Eaton –Lambert synd. Small cell CA of lung Myasthenia gravis-like symptoms

Hypertrophic osteoarthropathy

Bronchogenic CA Periosteal reaction of distal phalanx

Nonbacterial thrombotic endocarditis

Mucus-secreting pancreatic and colorectal carcinomas

Sterile vegetations on mitral valve

Seborrheic keratosis Stomach carcinoma Sudden appearance of numerous pigmented seborrheic keratoses (Leser-Trelat sign)

Superficial migratory thrombophlebitis

Pancreatic carcinoma Release of pro-coagulants (Trosseau sign)


Disorder Associated cancer Ectopic hormone

Cushing syndrome Small cell CA of lung, medullary thyroid CA

ACTH

Gynecomastia Choriocarcinoma (testis)

hCG

Hypercalcemia Renal cell CA, primary SCCA lung, breast CA

PTH-related protein

Hypocalcemia Medullary thyroid CA Calcitonin

Hypoglycemia Hepatocellular CA Insulin-like factor

Hyponatremia Small cell CA of lung ADH

Secondary polycythemia

Renal cell and hepato-cellular CA

erythropoietin

Tumor Markers

• Biologic markers

• Include hormones, enzymes, oncofetal antigens, glycoproteins

• Identify tumors

• Estimate tumor burden

• Detect recurrence

Tumor Markers

Tumor marker Associated cancer

AFP Hepatocellular CA, yolk sac tumor (endodermal sinus tumor) of ovary or testis

Bence Jones protein

Multiple myeloma, Waldenstrom’s macroglobulinemia (represent light chains in urine)

CA 15-3 Breast carcinoma

CA 19-9 Pancreatic carcinoma

CA 125 Surface-derived ovarian cancer (e.g. Serous cystadenocarcinoma)

CEA Colorectal and pancreatic carcinomas

PSA Prostate carcinoma (also increased in prostate hyperplasia)

Documents

Neoplasia review