Neoplasia Basic Concepts

V.O. Speights, Jr., D.O. Robbins & Cotran Pathologic Basis of Disease 8th Edition 2010 (Big Robbins) Pages 259-330, Chapter 7 All slides from the book have the references to this chapter.

Feb 19, 2013 10 am-noon A TBL session Feb 21, 2013 9-10am

(254) 724-3688 email: vspeights@sw.org

Slides Lectures 1-2 1-120 (TBL Session)

Lecture 3 – 121-end

Learning Objectives After this presentation the students should be able to

Define neoplasia, distinguish the parenchyma from the stroma; know the characteristics and nomenclature of benign and malignant tumors; and know the concepts of differentiation, anaplasia, and grading

Recognize and define the importance of sentinel lymph nodes Know the concept of epidemiology and its importance in assessing cancer risks Understand the importance of BRCA testing and its indications Understand the different pre-neoplastic conditions mentioned in lecture Understand the actions of p53 and oncogenic infectious agents, including RNA viruses,

DNA viruses, helicobacter Understand the various tumor markers Understand the concepts of grading and staging Know the principles of surgical pathology (frozen and permanent sections) as presented

in lecture Understand the importance of cervical dysplasia and atypical nevi as they relate to

cancer risk Know the biologic significance and importance of cervical dysplasia, atypical nevi,

dysplasia in the gastrointestinal tract, hyperplasia and atypia of the breast, and hyperplasia of the prostate as they relate to cancer risks

Be able to recognize appropriate diagnostic workup for the neoplastic and pre-neoplastic conditions mentioned in the lecture, including frozen section, fine needle aspiration, Pap testing, and specialized testing for the types of cancer mentioned in lecture

Understand the concept of multi-step carcinogenesis and the general processes involved in it—see slide 121

Lecture 3 objectives To know the concepts of apoptosis, oncogenes, and tumors suppressors To understand the patterns of colorectal neoplasia To understand the basic sequence and components of carcinogenesis To know the genetic abnormalites and associated cancers in slides 151-156 To understand basic cancer treatments

Multi-step Carcinogenesis

Each cancer results from an accumulation of multiple mutations

Activation of oncogenes (stuck accelerator) and loss of cancer suppressor genes (faulty brake)

Summary Overview of Carcinogenesis Tumors arise from clonal growth of cells that have

incurred mutations in four classes of genes. These genes that regulate cell growth (proto-oncogenes and tumor suppressor genes) and those that regulate apoptosis and DNA repair.

Mutation in no single gene is sufficient to cause cancer. Typically, the phenotypic attributes characteristic of malignancy develop when multiple mutations involving multiple genes accumulate. The stepwise accumulation of mutations and increasing malignance is referred to as tumor progression.

Proto-oncogenes

Become oncogenes when mutated Can lead to development of cancer Encode oncoproteins which endow the cell

with self sufficiency and growth

Apoptosis

Like leaves falling off trees “Programmed  cell  death” A normal phenomenon that eliminates cells which are no

longer needed and maintains a steady number of cell population in tissues

Eliminates cells that are genetically altered or injured beyond repair without elicting a host response

Robbins, 8th Edition page 25

Colorectal cancer as an example of different patterns of Neoplasia Next 7 slides

Need to know etiology/category, molecular defect, clinical presentation and histology—see Table 17-10 p 822

Familial Adenomatous Polyposis (FAP) --Numerous colorectal adenomas as teenagers (at least 100) --Mutation of adenomatous polyposis coli gene (APC) --APC is a tumor suppressor which complexes with B-catenin --Degrades B-catenin, preventing its accumulation in cytoplasm --If APC is mutated, cytoplasmic B-catenin increases, goes into the nucleus and activates cellular proliferation. --FAP is rare but up to 80% of colon cancers/adenomas develop through the APC pathway.

Pathogenesis of colorectal carcinoma (CRC) 80% of sporadic CRC Both copies of APC gene must be

inactivated for adenomas to develop Loss of APC function leads to

accumulation of Beta Catenin Promotes cell proliferation Additional mutations (such as K-ras) Mutation/loss of tumor suppressors (such as p-53)

Dysplastic (adenomatous) polyp also called a tubular adenoma (the name you will see used most often)

All tubular adenomas have at least some dysplastic change (nuclear  enlargement,  hyperchromatism,  stratification).  Don’t  worry about the difference between villous and tubular adenomas

Colorectal carcinoma pathogenesis Fig 17-49, p 823 Adenoma-Carcinoma sequence

Additional slide about the adenoma-carcinoma sequence.

Patterns of Colorectal neoplasia continued Hereditary Nonpolyposis Colorectal Cancer

HNPCC or Lynch syndrome Defects in genes (basically 4 genes) involved in DNA mismatch

repair (spell checkers) Microsatellites are tandem repeats of 1-6 nucleotides In HPNCC errors in microsatellites occur and are not corrected

leading to increasing abnormalities in the genome. Usually right sided neoplasms HPNCC accounts for 2% of colon cancers but up to 15 % of

sporadic colon cancers are associated with microsatellite instability.

Mismatch repair pathway Fig 17-50 p 824

Patterns of Colorectal Neoplasia

1.

2.

3.

4. 5

1. Classic FAP, although it is rare. 2. Rare form of FAP

3. Lynch syndrome. 4 Most common CRC

5.Minority of CRC, MSI testing ordered.

Compare Table 17-10 in Robbins 8th Use this to aid your understanding of the previous slide.

General patterns of neoplasia and its development Next 11 slides

Fig 7-25, p 280

Fig 7-36 p 298

Babak Abbassi

Fig 7-26 p 282

Phosphatase and tensin homologue--PTEN Gene located on chromosome 10 Tumor suppressor Mutated  in  Cowden’s  syndrome --Benign hamartomatous lesions in skin and intestinal tract --Increased risk of breast,thyroid, and endometrial cancer Cowden’s  is  rare  but  PTEN  is  very  commonly  mutated  in  many  cancers

Tumor Progression

Many tumors become larger and more aggressive over time

This is associated with subsequent appearance of sub-population of cells with different phenotypic attributes

Tumors are monoclonal in origin but cells are heterogenous at the time of clinical presentation

Fig 7-24 p 279

Fig 7-38, p 301

A-C. Cells capable of metastasis may be rare variant clones, the majority of the tumor cells (signature) or a combination.

D. Development and establishment of metastatic tumor is influenced by the stroma—angiogenesis, immune reaction etc—seed and soil.

Epithelial to mesenchymal transition (EMT) Carcinoma cells down regulate epithelial markers such as E-cadherin and up

regulate mesenchymal markers such as Vimentin and smooth muscle actin. Promotes a migratory phenotype with resistance to apoptosis and enhanced invasiveness. Seen in breast cancer Robbins p 302

Practical Aspects of Multistep Carcinogenesis Identifies markers for cancer risks, for both

patient and family (abnormal p53) Gives targets to aim at for directed therapy K-ras in colorectal cancer; Epidermal Growth factor Receptor (EGFR) in lung cancer

Genetic changes in specific cancers--next 6 slides Balanced Translocation Common in hematopoietic neoplasms Philadelphia chromosome Seen in chronic myelogenous leukemia Chromosomes 22-9 Shows translocation at least BCR-ABL

Burkitt's lymphoma, 8-14 Follicular B-cell lymphoma, 14-18

Karyotypic Changes in Tumors (cont’d) Deletions

most common in solid, non hematopoietic tumors Gene amplifications

Increased amounts of nuclear material which code for certain molecules

NMYC in neuroblastoma HER-2/neu (also called c-erb-2) in breast

carcinoma, getting attention in gastric cancer

BCR-ABL

ABL translocates from chromosome 9 to 22, fuses with Break-Point Cluster Region Gene forming BCR-ABL

Predicts responses to an inhibitor of BCR-ABL infuson kinase-Gleevec, (Imantinib mesylate) used for Chronic Myelogenous Leukemia (CML) and gastrointestinal stromal tumors

BCR-ABL

ABL proto-oncogene has tyrosine kinase activity normally held in check by regulatory controls

Normally localized in the nucleus Promotes apoptosis in cells with DNA damage When fused, BCR-ABL is retained in the cytoplasm

rather than the nucelous Activates tyrosine kinase Tyrosine kinase inhibitators (TKI) such as Gleevec can be used

for treatment Does not have apoptic activity characteristic of normal ABL

Chemotherapy

Works best on rapidly dividing cells Affects some of the healthy cells in the body that

divide quickly Hair follicles causing baldness Affects cells in the bone marrow, causing fatigue,

increased risk of bleeding, and risk of infection Cells of skin and mouth causing dryness/sores Cells in stomach causing gastrointestinal symptoms

such as nausea and diarrhea

Radiation Treatment

Affects cells that are actively dividing Also affects the cells of normal tissues (need to

strike a balance between destroying cancer cells and sparing normal cells)

Different types of radiation treatment, some of which may require daily visit for several weeks. Need compliant patient Need reliable transportation

Website

www.MyBiopsy.org Maintained by the College of American

Pathologists Readable, practical information for

physicians and patients about many types of cancer

Neoplasia Basic Pathology Questions Robbins, Pages 166-178 & 193-208 1. A 55 year old female presents with a large retroperitoneal mass. The initial

differential diagnosis includes abscess. A laparotomy biopsy is done, revealing a tumor of mesenchymal (fatty) lineage. The tumor consists of varying numbers of lipocytes and is found to be malignant. Which of the following is true of this tumor? it is derived from an epithelial surface it is a chondrosarcoma it has definite malignant stromal elements it would be classified as a choristoma it may show a wide range of parenchymal differentiation

2. A 35-year old female presents with an enlargement of the parotid gland. A Fine Needle Aspiration (FNA) shows epithelial elements with some squamous differentiation and ductal formation. Some fibromyxoid stroma is seen in the background.    Which  is  true  of  this  patient’s  tumor?

a. it contains components from all three of the germ layers (endoderm, ectoderm, and mesoderm)

b. is best classified as a mixed tumor of salivary glands c. almost always shows N-MYC amplification d. it has an irregular invasive border e. it characteristically spreads by seeding the body cavities

Questions  cont’d 3. Which of the following shows the best example of an environmental factor

contributing to cancer risks? a. the incidence of gastric cancer in Japanese vs. Americans vs. children of Japanese

who live in America b. children with retinoblastoma c. the adenoma-carcinoma sequence in adenomatous polyps d. endometrial carcinoma associated with atypical hyperplasia e. cancer developing in chronic ulcerative colitis

4. A 22-year old female presents for a pap test. Liquid based cytology is obtained. Examination  of  the  specimen  shows  some  “atypical”  cells  which  are  submitted  for  further testing. This shows the cells to be positive for human papilloma virus (HPV) types  16  &  18.    The  patient’s  history  is  otherwise  positive  for  the  usual  childhood  diseases and infectious mononucleosis several years ago. Which is true of this patient’s  HPV  infection?

a. it can be diagnosed by polymerase chain reaction (PCR) evidence of BCR-ABL b. it is always associated with genital warts of low malignant potential c. it is associated with Her2/neu overexpression but not amplification d. it shows elevated serum carcinoembryonic antigen e. it stimulates the loss of tumor suppressor genes

Questions  cont’d 5. A long time smoker presents with weakness, shortness of breath and

Cushing’s  syndrome.    A  Fine  Needle  Aspiration  (FNA)  is  done,  and  small  cell carcinoma of the lung is diagnosed. Which of the following does he most likely have?

a. renal cell carcinoma b. Epstein-Barr Virus infection with a lymphoproliferative disorder c. thymoma d. syndrome of inappropriate of antidiuretic hormone (SIADH) e. high levels of erythropoietin

6. A patient presents with an adenomatous polyp showing foci of cancer

(adenocarcinoma) stage I. Which is true about the pathogenesis of this patient’s  cancer?

a. it probably developed due to increased DNA methylation b. it would be associated with increased tumor suppressor activity c. it has a genetic abnormality including a translocation between

chromosomes 14 and 18 d. it has a balanced translocation between chromosomes 9 and 22 e. it shows sustained angiogenesis

Questions  cont’d 7. Question from Laboratory A 41 year old female presents for her physical examination. Her past history is

positive for a benign mixed tumor of the salivary gland which was removed as well as a history of abnormal Pap smear. A Pap test was done, and revealed some abnormal cells; however HPV testing was negative. The patient also had an abnormal  mole  on  her  back  which  was  excised  and  read  as  “dysplastic  nevus”.    Which  of  the  following  is  true  about  this  patient’s  followup? a. she needs estrogen receptor testing done on her pap test b. the salivary gland tumor should have been tested for microsatellite instability (MSI) c. she needs followup for development of other abnormal pigmented lesions d. she needs a cervical biopsy with frozen section e. at her next visit, she needs a traditional pap smear rather than liquid-based pap test

ANSWERS 1. E 2. B 3. A 4. E 5. D 6. E 7. C

Neoplasia Basic Pathology Questions 2007 1. A polyp is removed from the large intestine from a 50 year old male. It

measures approximately 1cm in greatest dimension. It contains some dysplasia. No evidence of definite malignancy is identified. This polyp a. did not bleed because it was benign b. is best called a choristoma c. probably projected above the mucosal surface of the colon d. had a neoplastic stroma e. arose from mesenchymal tissue in the lamina propria

2. A 10cm retro-peritoneal tumor is resected. It is found to be malignant

and derived from lipocytes (fat cells). Many of the nuclei are enlarged and pleomorphic with some tripolar mitotic figures. This tumor a. commonly has ducts and myxoid stroma b. is well differentiated c. is also called a hamartoma d. is derived from more than one germ cell layer e. is usually quite large when discovered

3. A 37 year old female undergoes a hysterectomy. On examination of the uterus, several benign neoplasms are noted in the wall of the uterus. These are composed of smooth muscular tissue. These tumors

a. Are most accurately called leiomyomas b. are not affected by estrogen c. are an example of intraepithelial neoplasia d. usually show ischemic necrosis in their central portion e. typically have an irregular, invasive border

4. A 60 year old smoker is found to have a 1cm lung cancer. Under the microscope, the tumor cells resemble normal squamous epithelial cells, with intercellular bridges and keratin pearls. This tumor

a. is a grade 4 carcinoma b. is diagnosed much less commonly in males than females c. probably has a well-defined border with a smooth capsule d. should have surgical removal with HPV testing e. has the potential to invade into surrounding tissue

5. Which of the following is a well-established association? a. Barrett’s  esophagus  predisposing  to  esophageal  cancer b. prostatic hyperplasia leading to carcinoma of the prostate c. BRCA-2 and familial adenomatosis polyposis d. Human Papilloma Virus types 6 and 11 with invasive cervical cancer e. Human Herpes Virus (HHV) 8 causing squamous carcinoma of the scrotum

ANSWERS 1. C 2. E 3. A 4. E 5. A