Path - Neoplasia 1, 2, 3

What are the number 1 and number 2 leading causes of death in the US?

1 = Heart disease 2 = Cancer

What tumor weight/size is the minimum to be clinically detectable?

1 g (30 doublings)

What tumor weight/size is the maximum compatible with life?

1 kg (40 doublings)

Identify the four steps and mechanisms of invasion

1. Detachment of tumor cells from each other 2. Attachment to matrix component 3. Degradation of ECM 4. Migration of tumor cells

**Carcinomas typically spread through the lymphatic system. Identify the four carinomas that spread hematogenously:

1. Follicular CA of thyroid 2. Choriocarcinoma 3. Renal cell CA 4. Hepatocellular CA Four Carcinomas Route Hematogenously

Identify the four steps in metastatic cascade - the ability to invade and metastasize

1. Invasion of basement membrane 2. movement through ECM 3. vascular dissemination 4. homing

Identify the top three incidence of cancer and cancer related deaths in children age 0-14

1. Leukemia 2. Brain and CNS 3. Neuroblastoma (same order for incidence and mortality)

Identify the various routes of metastasis

1. Seeding of body cavities 2. lymphatic spread 3. hematogenous spread

Identify two way to identify the origin of poorly differentiated and anaplastic carcinoma

1. identify the expression of cell markers unique to certain tissues 2. cytogenetics or molecular diagnosis

What two features can be seen in anaplasia, dysplasia and well-differentiated tumors?

1. loss of cellular polarity 2. Cellular atypia

Identify the two characteristics of metastatic tumors in the liver

1. multiple lesions 2. areas of central umbilication due to ischemia

Compare adenoma, carcinoma and papilloma

Adenoma = benign, epithelial neoplasm of glandular tissue Papilloma = benign, epithelial neoplasm of non-glandular tissue Carinoma = malignant, epithelial neoplasm

Lung cancer most commonly metastasizes to which site?

Adrenal and liver (brain)

Chromosomes breaks at centromeres and sister chromatids move to opposite ends of the cell during which phase of mitosis?

Anaphase

Define: Complete lack of differentiation of cells in a malignant neoplasm.

Anaplasia

The pathology report comes back from your sample of a tumor. It states that the tumor is anaplastic. What does this mean for your patient?

Anaplasia means means that the tumor is poorly differentiated. Anaplasitic tumors are more aggressive and come with a poorer prognosis.

What is the indicator of apoptosis?

Apoptotic body (fragmentation and condensation of nuclear chromatin)

Define: ↓ in tissue mass due to ↓ in size and/or number of cells. Causes include disuse, denervation, loss of blood supply, loss of hormonal stimulation, poor nutrition.

Atrophy

Define: a pathologic term for a structural abnormality in a cell. It is used to describe atypical cells. Seen in only pre-malignant (dysplasia) and malignant tumors (neoplasia)

Atypia

Why does the degree of differentiation depend on the percentage of cells within the cell cycle?

Because cells within the cell cycle cannot differentiate. Therefore the larger proportion of cells in the cell cycle, the lower the percentage of cells will be differentiated and the more likely the tumor is to be poorly-differentiated.

How does differentiation vary in benign vs malignant tumors?

Benign tumors = well differentiated because typically only 1-10% of cells are in the cell cycle. Thus cells/tissues typically resemble normal cells/tissues Malignant tumors = poorly differentiated because 20-80% of cells are in the cell cycle, thus cells and tissues typically do not resemble mature cells/tissues

Patients working in industries involving the manufacture/use of aniline dyes have an increased incidence of which cancer?

Bladder

Prostate cancer most commonly metastasizes to which site?

Bone

Are most of the bone tumors metastatic or primary?

Bone metastasis >> primary bone tumor

Compare carcinomas and sarcomas

Both malignant, but: carcinoma = epithelial cells sarcoma = mesenchymal tissue

A 68-y-o Japanese immigrant presents with fatigue, dyspepsia, and loss of weight. He has a 30 year history of chronic gastritis. Biopsy of stomach mucosa indicates adenocarcinoma. The metastatic potential of cancer cells would be enhanced by upregulation of the following proteins? CD2, CD4, CD8, CD22, CD44

CD44

Which cancers are more susceptible to chemo and radiotherapy? Cancers with rapid growth or cancers with slow growth?

Cancers with rapid growth

What term refers to the spatial difference in shape, structure and function of cells, exhibited by almost all cells, which allows them to carry out specialized functions.

Cell polarity

Ki-67 and PCNA are indicators of what?

Cell proliferation

What is the clinical significance of difference in growth rate of tumors?

Cells within the cell cycle are susceptible to chemo and radiotherapy

Define: normal tissue found in a foreign location

Choristoma

Pancreatic tissue in mucosa of the stomach or intestines is an example of what?

Choristoma

What population has an increased incidence of carcinoma of oropharynx, esophagus, pancreas, bladder and lung?

Cigarette smokers

**Identify the most common primary tumors that metastasize to the liver

Colon >> stomach > pancreas

What is the most important challenge you will face as a pathologist?

Decide whether the tumor is benign vs malignant

Hyperplasia of activated fibroblasts and production of abundant collagen in the stroma leads to what neoplastic process?

Desmoplasia

Linitis plastica in diffuse stomach cancer, breast cancer (invasive ductal carcinoma), prostate cancer and Cholangiocarcinoma are all examples of what neoplastic process?

Desmoplasia (blue = collagen; pink = muscle)

Define: Fibrous tissue formation in response to neoplasm (e.g., linitis plastica in diffuse stomach cancer)

Desmoplasia (often a stoney hard tumor due to the collagen secreted by active fibroblasts)

Define: The degree/extent to which neoplastic parenchymal cells resemble the corresponding normal mature parenchymal cells (tissue of origin), both morphologically and functionally

Differentiation

What factor determines the growth rate of tissues?

Doubling time The shorter, the quicker growth rate

Define: Disordered, non-neoplastic cell growth. Term used only with epithelial cells. Reversible when mild; severe usually progresses to carcinoma in situ

Dysplasia

Benign tumor cells remain attached to each other by adhesion molecules such as...? (In malignant tumors, invasive subclone occurs due to mutation and this molecule is not produced, causing the cohesiveness of tumor cells to be reduced)

E-cadherin

Why do malignant tumors show central necrosis?

Eventually, the tumor outgrows the blood supply, and areas of ischemic necrosis appear the diffusion of nutrients is limited to a diameter of 1-2mm

Which of the following tumors is a benign tumor? melanoma, hepatoma, seminoma, astrocytoma, fibroma

Fibroma

In general, carcinomas spread early to the lymphatics in order to metastasize. What are the exceptions?

Four Carcinomas Route Hematogenously F = Follicular CA of thyroid C = Choriocarcinoma R = Renal cell CA H = Hepatocellular CA

A patient presents with an autosomal dominant genetic disease characterized by the development of benign polyps in the GI tract + hyperpigmented macules. You diagnose this as Peutz-Jeghers syndrome. This is an example of type of tumor/lesion?

Hamartoma

Define: Non-neoplastic tumor-like lesions with disorganized and haphazard growth of tissues normally found at a given site

Hamartoma

Compare the consistency of a mass: Hard. Soft. Rubbery.

Hard = abundant of collagenous stroma: stony hard (desmoplasia or cirrhosis) Soft = stroma scant. Tumor is soft and fleshy Rubbery = between soft status and hard status.

Which route of metastasis is the most common for sarcoma? Seeding of body cavities, lymphatic spread, hematogenous spread

Hematogenous spread

Define: abudant DNA, extremely dark staining

Hyperchromasia

Define: an increase in cell numbers. May be a risk for future malignancy but not considered premalignant

Hyperplasia

Define: increase in size of cells

Hypertrophy

What does a higher percentage of abnormal mitoses tell you about a neoplasm?

It is more likely to be malignant

Which cancer rate is highest in Japan? New Zealand?

Japan = gastric cancer New Zealand = skin

What pair of molecules is important for malignant tumors tight attachment to matrix components?

Laminin receptor/laminin

Colorectal cancer most commonly metastasizes to which site?

Liver

What is the most important criteria to differentiate an EARLY benign vs malignant neoplasm? rate of growth, differentiation, local invasion, metastasis.

Local invasion (metastasis is #2, but may not be present in an early neoplasm)

Which route of metastasis is the most common for carcinoma? Seeding of body cavities, lymphatic spread, hematogenous spread

Lymphatic spread (will eventually spread hematogenous)

Which of lymphoma or leukemia originates from the bone marrow? Which from the lymphoid tissue?

Lymphoma originates in lymphoid tissue Leukemia originates in bone marrow stem cells

What are the top three causes of cancer related death in males and females

Males: 1 = lung, 2 = prostate, 3 = colorectal Females: 1= lung, 2 = breast, 3 = colorectal

What are the top three cancer incidence in males and females

Males: 1 = prostate, 2 = lung, 3 = colorectal Females: 1= breast, 2 = lung, 3 = colorectal (but... skin cancer has highest incidence for both male and female, but we dont count it in epidemiology)

Compare a mature teratoma vs immature teratoma

Mature teratome = benign Immature teratoma aka teratocarcinoma = malignant

Patients exposed to asbestos have an increased incidence of which cancer?

Mesothelioma

Chromosomes line up at the equatorial plane of the cell in which phase of mitosis?

Metaphase

Barrett esophagus is an example of what type of cellular change?

Metaplasia

Define: Replacement of one cell type by another. Usually due to exposure to an irritant, such as gastric acid or cigarette smoke. Reversible if the irritant is removed but may undergo malignant transformation with persistent insult

Metaplasia

Define: Spread of a tumor to sites that are physically discontinous with the primary tumor?

Metastasis

Which cell changes are irreversible? Hyperplasia, hypertrophy, atrophy, neoplasia, dysplasia, metaplasia

Neoplasia (Dysplasia and metaplasia can become irreversible if chronic irritant persists)

Match neoplasia, hyperplasia, and tumors with monoclonal or polyclonal

Neoplasia/tumors are monoclonal Hyperplasia is polyclonal

Define: a monoclonal proliferation of cells that is uncontrolled and excessive. Can be benign or malignant

Neoplasm

Is hyperplasia premalignant?

No

Compare the two types of bone metastasis: osteoblastic vs osteolytic

Osteoblastic: reactive bone formation, increase serum alk phosphatase, dense bone on Xray, prostate cancer is most common Osteolytic: tumor produce PGE2 and osteoclast activating factor (IL-1) activate osteoclasts, hypercalcemia, lucencies on Xray, breast cancer is an example

What effect does decreased P53 have on angiogenesis?

P53 inhibits VEGF and promotes thrombospondin-1 production. Decreased P53 will lead to an increase in VEGF and a decrease in thrombospondin-1, both contributing to an increase in angiogenesis

*A tumor derives its name based on?

Parenchyma

*Which of stroma or parenchyma is composed of monoclonal neoplastic cells?

Parenchyma

Define: variation in size and shape of cells and nuclei

Pleomorphism

Define: club-shaped growth projecting from mucosal surface into lumen of a hollow viscus?

Polyp (Can be benign epithelial tumor = papilloma, or hyperplasia)

Which of the following bone metastasis can cause osteoblastic metastasis? lung, kidney, prostate, thyroid, breast

Prostate (always causes osteoblastic) Breast (can cause both osteoblastic and osteo lytic) all other bone metastases are lytic

Presence of a small (less than 2cm) firm, discreet, non-neoplasic calcification inside the lung is an example of what process?

Pulmonary hamartoma

What is the most common site of metastasis?

Regional lymph node (followed by liver and lung)

Most sarcomas spread hematogenously. Which sarcoma is the exception and invades locally instead of spreading through the blood

Rhabdomyosarcoma

Primary pulmonary cancer, sub-arachnoid cancer, GI cancers and ovarian cancer, all share which route of metastasis? Seeding of body cavities, lymphatic spread, hematogenous spread

Seeding of body cavities

Define: the 1st node in a regional lymphatic system that receives lymph flow from primary tumor

Sentinel lymph node

What type of vessels are susceptible to invasion?

Small venules or capillaries (smooth muscle of arteries prevents penetration)

Which is more important for describing a tumor? Grade or stage

Stage (both have some effect on predicting outcome but staging is more important)

Differentiate the 4 grades of cancer

Stage 1 = well differentiated Stage 2 = moderately differentiated Stage 3 = poorly differentiated Stage 4 = nearly anaplastic

*The growth and spread of a tumor are critically dependent on its?

Stroma

*Which of stroma or parenchyma is composed of connective tissue, blood vessels and immune cells

Stroma

Which of stroma or parenchyma determines the consistency of a mass?

Stroma

As a tumor progress from early (submicroscopic phase) to later stages, how does the percentage of cells in the proliferative pool change?

Submicroscopic phase has a higher percentage of cells in the proliferative phase as tumors progress to later stages, a lower percentage of cells are in the proliferative pool

Differentiate the 3 stages of cancer: T, N and M

T = size of primary tumor N = Nodal involvement M = Distant metastases

A tumor secreting what factors allows it to grow larger than 1-2 mm

TAF (tumor angiogenic factors = HIF, VEGF, bFGF, Ras, myc and decreased P53) which all stimulate proliferation and in-growth of blood vessels, enabling tumor growth to be supported by perfusion

What type of tumor is composed of more than one parenchymal cell type and can be derived from more than one germ layer; but all cells arise from a single clone capable of producing all of these cell types

Teratoma

A 58-y-o woman presents with a lump in her left breast. A 3 cm hard mass is found by physical exam and excisional biopsy indicates breast cancer. The growth of cancer cells would be enhanced by down regulation of the gene for which of the following? VEGF, bFGF, Thrombospondin-1, Ki-67, PCNA

Thrombospondin-1

*Which of the following are anti-angiogenic factors? VEGF, angiostatin, Thrombospondin-1, bFGF, tumstatin, HIF, endostatin

Thrombospondin-1 and all the -statins, angiostatin, tumstatin, endostatin

What is the key difference between sarcomas and carcinomas?

Tissue of origin Sarcoma = mesenchymal cell origin (both have s's) carcinoma = epithelial cell origin

Which type of cancer is most closely associated with tracheal lymph nodes? Axillary lymph nodes?

Tracheal lymph nodes = lung cancer axillary lymph nodes = breast cancer

True or false: Metastasis unequivocally marks a tumor as malignant

True

What is the most important factor determining the rate of growth for tumors?

Tumor angiogenesis

Which cell type is the main secreter of motility factor? Stromal cells or tumor cells?

Tumor cells

Presence of a cell with a single huge polymorphic nucleus or 2 or more nuclei that are hyperchromatic and large are indicative of what?

Tumor giant cells that represent anaplasia

What quality of tumor vessels enhances the ability of tumor metastasis?

Tumor vessels are more leaky and dilated compared to normal vessels. This makes it easier for tumor cells to enter the vessels and spread to other areas of the body.

*Which of the following are pro-angiogenic factors? VEGF, angiostatin, Thrombospondin-1, bFGF, Tumstatin, HIF, endostatin

VEGF, bFGF, HIF

Identify the most common site for bony metastasis?

Vertebral column

Stomach adenocarcinoma most commonly metastasizes to which site?

Virchow's LEFT supraclavicular node

In terms of differentiation. Which tumors that closely resemble their tissue of origin. And which tumors look almost nothing like their tissue of origin.

Well-differentiated closely resemble tissue of origin (less aggressive) Poorly-differentiated look nothing like their tissue of origin (more aggressive)

Tissue demonstrating a nuclei/cytoplasm ratio of 1:1, cellular pleomorphism and nuclear changes can be described as?

cellular atypia

An increased stroma/parenchyma ratio is a sign of what?

desmoplasia

What receptor is expressed on tumor cells binds with fibronectin in the plasma or the tissues and helps the tumor invade (migrate)?

fibronectin receptor

Which of the following are not tumors? hamartoma, hepatoma, fibroma, melanoma, seminoma, chondroma, hematoma, osteoma, lymphoma, astroycytoma, granuloma, choristoma.

hamartoma, hematoma, granuloma and choristoma

*Which of the following tumors are malignant? hamartoma, hepatoma, fibroma, melanoma, seminoma, chondroma, hematoma, osteoma, lymphoma, astroycytoma, granuloma, choristoma.

hepatoma, melanoma, lymphoma, seminoma and astrocytoma

What is the key difference between benign vs malignant neoplasms?

invasion of metastisis Benign tumors = non-invasive, non-metastatic (capsule) Malignant tumors = invasive with metastatic potential. (No capsule)

Melanoma most commonly metastasizes to which site?

liver and lung

Testicular tumors most commonly metastasizes to which site?

local lymph nodes (para-aortic nodes)

Loss of the ability to differentiate epithelial cells by shape and size leading to an inability to tell the top from the bottom of skin describes what process?

loss of cellular polarization seen in dysplasia

**Identify the most common primary tumors that metastasize to the brain

lung > breast > melanoma, colon, kidney (lubmeck)

Breast cancer most commonly metastasizes to which site?

lung and bone

What two organs are most commonly involved in sarcomas spreading through the blood?

lungs and liver (brain also possible)

What is secreted by tumor cells and plays a critical role in migration?

motility factor

How do newly formed endothelial cells stimulate the growth of adjacent tumor cells?

newly formed endothelial cells secrete growth factors such as IGF and PDGF, which stimulate the adjacent tumor cells

Compare the percentage of cells that are able to proliferate (enter cell cycle) in normal tissue vs benign tumor vs malignant tumor

normal tissue = 1% benign tumor = 1-10% malignant tumor = 20-80%

Identify the most common symptom of bone metastasis?

pain

*The biological behavior of a tumor is based primarily on its?

parenchyma

What molecule is produced by tumor cells and leads to the degradation of the ECM?

type IV collagenase (MMP)