Topics A67-71. Neoplasm 4: Epidemiology, Preneoplastic Disorders, Grading/Staging, Tumor Effects, Diagnosis

Question 1

How many people die every year from cancer around the world?

What are the top 3 causes of death worldwide vs in developed countries?

Answer 1

50 million deaths/year from cancer

Worldwide cause of death ranking:
1. Infectious disease
2. Cardiovascular disease
3. Cancer
Developed countries have infectious disease lower on the list, so cancer is #2.

Question 2

What are the top 3 cancers in MEN as in total incidence (morbidity)? What are the top 3 cancers as cause of death (mortality)?

Answer 2

Morbidity:

1. Prostate (25% of total cancers)
2. Lung (15% total)
3. Colorectal (10% total)

Mortality:

1. Lung
2. Prostate
3. Colorectal

Question 3

What are the top 3 cancers in WOMEN as in total incidence (morbidity)? What are the top 3 cancers as cause of death (mortality)?

Answer 3

Morbidity:

1. Breast (25% of total cancers)
2. Lung (15% total)
3. Colorectal (10% total)

Mortality:

1. Lung
2. Breast
3. Colorectal

Question 4

What type of cancer (mentioned in lecture) has been declining in incidence since the early 20th century? Why?

Answer 4

Stomach cancer: mostly due to refrigeration and using less preservatives than were necessary previously (smoked meats etc). Continues to be common in Japan due to eating smoked fish.

Most of the other major cancers increased in incidence until the last 20 years or so, when better diet, screening, and treatment began to help

Question 5

What are the 2 peak ages when cancers are most common?

Answer 5

• Around age 5: due to mutated inherited genes

- Age 60-70: accumulation of somatic mutations begins to form cancers

Question 6

What are the 3 most common childhood cancers?

Answer 6

Leukemias, Neuroblastoma, Ewing sarcoma

(at least according to Matolcsy lecture… but looking it up, Ewing sarcoma is more rare. My histo class ranked them: 1. CNS tumors like medulloblastoma, 2. Solid tumors like in kidneys, 3. Neuroblastoma… but leukemia should still be the most common one. Annoying to not have a consistent answer)

Question 7

Why do some countries have unusually high rates of certain cancers? Can you give any examples?

Answer 7

Not related to genes but environment and habits

India: chewing betel nut related to oral cancers

Africa: Burkitt lymphoma from malaria and EBV

Developing countries in general have higher rates of hepatocellular cancers from endemic Hepatitis B and C

Question 8

What are some environmental factors related to cancer?

5 are listed from lecture, but just remember some examples

Answer 8

1. Alcohol: related to oral, liver, esophageal, breast, bowel
2. Smoking: lung, oral, kidney, urinary bladder, etc
3. Obesity: colorectal cancer
4. HPV: cervical cancer
5. Hepatitis B or C: liver

Question 9

What is preneoplasia?

Answer 9

Precancerous states that may indicate a high likelihood for cancer, hopefully to stop it before it starts.

Essentially it is dysplasia (disordered growth with changes in chromatin, cell morphology, etc.)

Question 10

What does “obligate precancerous state” mean? What are 3 examples of this? (all were mentioned in previous topics)

Answer 10

Person will for sure get cancer due to a hereditary disorder

1. XPA: Xerodema Pigmentosum -> skin cancer
2. Ataxia Teleangiectasia: p53 mutation -> many cancers
3. Familial Adenomatous Polyposis: APC mutation -> colon cancer

Question 11

6 conditions that predispose for a cancerous state:

this is the overview, will elaborate on them after

Answer 11

1. Persistent Regeneration
2. Hyperplasia -> Dysplasia -> Neoplasia
3. Chronic Inflammation
4. Immune deficiency
5. Autoimmunity: mostly B cell proliferation
6. Benign Neoplasms transform into Malignant

Question 12

What are 2 examples of persistent regeneration?

conditions that predispose for a cancerous state

Answer 12

1. Liver Cirrhosis: Necrosis of liver parenchyma, remaining cells proliferate too quickly and may make mistakes, prone to become cancerous
2. Paget’s disease: Osteoclasts overactive, need to rebuild more. Risk for osteosarcoma.

Question 13

What are 2 examples of how hyperplasia may develop into metaplasia, then dysplasia, then neoplasia?
(conditions that predispose for a cancerous state)

Answer 13

1. Bronchus: continuous smoke irritation causes ciliary epithelium hyperplasia
2. Ductal hyperplasia of the breast or endometrial hyperplasia: high estrogen content causes hyperplasia of both, may eventually transform to neoplasia

Question 14

Why is chronic inflammation related to carcinogenesis? Some examples?
(conditions that predispose for a cancerous state)

Answer 14

Inflammatory cells release ROS that not only kill pathogens but can damage DNA. They also release cytokines that induce normal cells to proliferate

Examples: ulcerative colitis and colon cancer, gastritis and stomach cancer, viral hepatitis, etc.

Question 15

What are 2 examples of immunosuppressed states and their cancer relations?
(conditions that predispose for a cancerous state)

Answer 15

1. AIDS: Kaposi sarcoma, glial cell tumors, lymphomas
2. Post-transplant patients are chronically immunosuppressed, often have lymphomas (PTLD = post-transplant-lymphoproliferative-disorders), also skin cancers

Question 16

What are 2 examples of autoimmune diseases that have increased risk for cancer? What type of cancer?
(conditions that predispose for a cancerous state)

Answer 16

1. Hashimoto thyroidits
2. Sjogren syndrome

Both cause B cell proliferation, have risk for B cell lymphomas

Question 17

Benign tumors can transform into malignant, but with variable incidence. Which ones have high, medium, and low incidence?
(conditions that predispose for a cancerous state)

Answer 17

1. High incidence: stomach and colon, up to 50% of cases
2. Medium incidence: Hepatocellular adenoma, about 20% incidence

Low incidence: leiomyoma (of uterus) and hypophysis: almost never

Question 18

Intraepithelial neoplasms: What is the first one that developed a system to classify the likelihood of developing neoplasia based on morphology?

Answer 18

Cervical Intraepithelial Neoplasms: from Papanicolou of the pap smear for Cervical Intraepithelial Neoplasia (CIN)

Cervical cancers appear at squamo-columnar junction. Take sponge and collected desquamated cells (“exfoliative cytology”) then smear and analyze under microscope.

Question 19

What are the 5 classifications of pap smear?

Answer 19

P1: Inactive, normal
P2: Active, normal (P1 and P2 depend on menstrual stage)
P3: Suspicious, maybe normal or not. Should repeat exam.
P4: Dysplasia
P5: Neoplasia

Question 20

What should be done if dysplasia is seen during a Cervical intraepithelial neoplasia (CIN) screening?

Answer 20

Perform a “co-resection” - cut off some of the dysplastic area and analyze it under a microscope. Then you can grade it CIN-I CIN-II or CIN-III depending on how much of the epithelium is replaced by dysplastic basal cells

Question 21

What are the criteria for CIN-I, CIN-II, CIN-III

Answer 21

CIN-I: 1/3 of epithelium replaced by immature basal cells
CIN-II: 2/3 of epithelium replaced by basal cells
CIN-III: Whole epithelium replaced by basal cells

If it gets any deeper than CIN-III, it passes the basement membrane and becomes an invasive carcinoma

Question 22

What are some examples of other neoplasm screening methods that follow similar patterns to the CIN scheme?
(not a detailed question, just be familiar)

Answer 22

Vagina: PIN
Prostate: PIN
Pancreas: PAN (because prostate used the P already)
Breast: DIN (ductal in situ neoplasm)
AML-MDS: acute myeloid leukemia-myelodysplastic syndrome

Question 23

During a physical examination, what is a good sign of precancous states?

Answer 23

Leukoplakia: “white spot” - for example, on mucous membranes

Doesn’t mean neoplastic for sure, just suspicious. Maybe hyperplasia, dysplasia.

Question 24

What is the difference between “grading” and “staging” of tumor classifications?

Answer 24

Grading: based on morphology, degree of dysplasia, increasing order of anaplasia from Grade I to IV. Very subjective

Staging: Based on the size of the primary tumor and its spreading to lymph nodes and metastases.

Question 25

What are the criteria for the T part of the TNM Staging system?

Answer 25

T for Tumor, based on depth/size of tumor. This example is with colon cancer, but it varies by region
T1: Just in mucosa
T2: Disrupts Muscularis Mucosae
T3: Makes it to Lamina Propria
T4: Invades peritoneum

Question 26

What are the criteria for the N part of the TNM Staging system?

Answer 26

N for Nodes (testing lymph node metastases)
N0: No metastases
N1: Has 1 to 3 regional metastases
N2: Spread to more distant or more than 3 lymph nodes
Nx: unknown if there are metastases

Question 27

What are the criteria for the M part of the TNM Staging system?

Answer 27

M for Metastasis
M0: No metastases
M1: Metastasis to a distant organ, beyond regional lymph nodes
Mx: unknown if there are metastases

Question 28

What is Stage I? How long is the 5 year survival rate? What is the treatment?

Answer 28

T1-T2, N0, M0
High survival (93%)
Treatment is surgery

Question 29

What is Stage II? How long is the 5 year survival rate? What is the treatment?

Answer 29

T3-T4, N0, M0
Still high survival (75%)
Treatment is surgery

Question 30

What is Stage III? How long is the 5 year survival rate? What is the treatment?

Answer 30

T1-T4, N1, M0
Modest survival rate, 44%
Treatment is still only surgery

Question 31

What is Stage IV? How long is the 5 year survival rate? What is the treatment?

Answer 31

Any T stage, any N stage, but M1 for sure
Low survival rate (8%)
Treatment is chemotherapy

Question 32

Why is the TNM staging scale not useful for some cancers?

What are 2 examples of those cancers?

Answer 32

TNM works better for solid tumors

1. RAI staging for chronic lymphoid leukemia (CLL), stage the lymph node and organ involvement
2. Ann-Arbor staging: for Hodgkin lymphoma

Question 33

What are 3 damaging local effects that may result from cancer?

Answer 33

1. Perforations may cause bleeding from the vascular structure or necrosis
2. Infection: occurs because cellular barriers are destroyed
3. Compression of organs -> pressure atrophy. Or may compress blood vessel, causing ischemia.

Question 34

What are the 2 important systemic effects of cancers?

Answer 34

Both related to humoral activity of the tumor

1. Cachexia: progressive loss of body fat and lean body mass, with weakness, anorexia, anemia, generalized atrophy.
2. Paraneoplastic syndromes: 10-15% of tumors have variety of symptoms that cannot be explained just by metastases or by hormones that are normal for the tissue origin of the tumor. Humoral activity of the tumor.

Question 35

How can some cancers cause Cushing syndrome? What is this an example of?

Answer 35

Small-cell lung cancers and some pancreas cancers can produce ACTH, which increases cortisol levels.

This is an example of an endocrinopathy paraneoplastic syndrome where you have “ectopic secretions”

Question 36

Besides Cushing syndrome, what are some other endocrinopathies from paraneoplastic syndromes with ectopic hormone secretion?
(4 examples in lecture, just be familiar.. probably Cushing is most important to know)

Answer 36

• Hyperparathyroidism from kidney or lung cancers producing PTH
• Hypoglycemia from sarcomas producing insulin
• “Carcinoid syndrome” - ulcers in stomach because vasoactive amines secreted by lung or pancreatic cancer
• Polycythemia: high RBC count related to overproduction of EPO from hepatocellular or kidney cancer

Question 37

What type of paraneoplastic syndrome can exist in the skin?

Answer 37

Acanthosis nigricans: hyperkeratinized black spots on the skin

Certain tumors like GI and lung cancers make epidermal growth factor, which makes skin undergo hyperplasia.

Question 38

What is the Trousseau phenomenon type of paraneoplastic syndrome?
Why does it occur?

Answer 38

Migratory Thrombophlebitis: thrombosis occurs in various parts of the venous network

Mostly occurs due to cancer cells producing coagulants like mucins

Question 39

Why does DIC occur as a paraneoplastic syndrome?

Answer 39

Disseminated Intravascular Coagulation: again pro-coagulants like mucin are secreted.

Pancreatic cancer or Acute Leukemias may cause DIC

Question 40

What is the Marantic Endocarditis (non-infective) type of paraneoplastic syndrome?

Answer 40

Mitral valve has small precipitates of fibrin and platelets due to hypercoagulable state of advanced cancers
(will be in cardio topics later)

Question 41

What is the Hyperplastic Osteoarthropathy paraneoplastic syndrome?

Answer 41

Clubbing of fingertips, also related to EPO synthesis. Affects joints as well.

Origin is bronchogenic carcinoma.

Question 42

4 morphological / “general” methods of diagnosis for neoplasms:

Answer 42

1. Excision or Biopsy (core biopsy, thick needle aspiration)
2. Smears: Fine Needle Aspiration and Cytologic Smears like Pap
3. Immunocytochemistry
4. Flow Cytometry

Question 43

What is a common type of excision used for rapid evaluation?

Answer 43

Frozen section: can be done within minutes, while person is on operating table. But may not provide enough detail.

Question 44

What is the advantage of Fine Needle Aspiration vs Thick Needle (Core Biopsy)? What are the disadvantages?

Answer 44

Advantages of fine needle: doesn’t leave a cosmetic mark, can go to deep tissues like pancreas

Disadvantages: Just makes a smear of the cells so you don’t get an idea of the tumor architecture or invasion, only see individual cells. Cannot diagnose if it’s metastatic based on fine needle, need biopsy for that.

Question 45

Why are cytologic smears like the pap smear possible from just scraping the surface or fluids near the tissue you want to examine?

Answer 45

Neoplastic cells are less cohesive, they shed into fluids and secretions. These can then be evaluated to see how anaplastic they are.

Question 46

What are some ways that immunocytochemistry is used in neoplasm diagnosis?

Answer 46

• Good for identifying origins of metastatic cancers based on tumor antigens
• Detect estrogen receptors for breast cancer
• Presence of cytokeratin can help diagnose undifferentiated carcinomas from large cell lymphoma

Question 47

When is flow cytometry usually used in cancer diagnosis?

was in the immuno powerpoints

Answer 47

Classifications of leukemia and lymphomas… ratios and prevalence of CD antigens can be indicative of specific lymphomas or leukemias

Question 48

What are 2 examples of lab techniques used for molecular diagnosis of malignancy and prognosis?

Answer 48

1. PCR: may be used to determine if, for example, immunoglobulins are monoclonal vs polyclonal (monoclonal associated with neoplasm)
2. FISH or PCR: detect oncogenes like HER2/NEU (breast cancer) or NMYC (neuroblastoma)

Question 49

What is an example of molecular diagnosis being used to test for hereditary predisposition to cancer?

Answer 49

The BRCA1 (tumor suppressor gene associated with breast cancer) screening test

Question 50

What is an example of how the “minimal residual disease” can be evaluated by molecular diagnostic techniques?
(may not be important to remember for now)

Answer 50

BCR-ABL transcripts analyzed by PCR assay after treatment of chronic myeloid leukemia

(Or PSA, or many other examples)

Question 51

What’s one way that “next-generation” technology be used in tumor molecular diagnostics?

Answer 51

Whole Genome Sequencing: compare genome of neoplasm vs normal cells.

You may see “driver” mutations - ones that drive the cancer, or “passenger” mutations - mutations that don’t have a clear advantage or disadvantage.

Question 52

Examples of 3 tumor markers / tumor antigens used in screening, and why are they only used for screening and not diagnosis?

Answer 52

1. PSA: prostate specific antigen. Good to test recurrence and minimal residual disease
2. CEA: carcinoembryonic antigen. Test for colon, pancreas, stomach, breast cancer. Not specific.
3. Alpha Fetoprotein: hepatocellular carcinoma, teratocarcinoma. Also low specificity.

All are low sensitivity tests, can have many false positives and negatives. However they are easier and less invasive than other procedures. Better for screening and testing recurrence.