Pathology, Lecture 10, Neoplasia
-
Upload
ali-hassan-al-qudsi -
Category
Documents
-
view
603 -
download
10
Transcript of Pathology, Lecture 10, Neoplasia
![Page 1: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/1.jpg)
NEOPLASIA (2010-2011)
Dr.H.M.Zahawi,FRC.Path
![Page 2: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/2.jpg)
OBJECTIVES Definitions of terms used in neoplasia Nomenclature of tumors Characteristics of benign & malignant
tumors Routes of metastasis Epidemiology of CANCER The molecular basis of neoplasia Carcinogenesis Tumor immunity The clinical effects of tumors Tumor grading and staging The laboratory diagnosis of neoplasia
![Page 3: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/3.jpg)
General terms used :
Neoplasm = New growth of cells producing a mass
Benign neoplasm = Limited new growth without invasion or spread
Malignant neoplasm = invasive growth that also spreads Carcinoma : Malignant tumor of epithelial cells Sarcoma : Malignant tumor of connective tissue
cells Lymphoma
![Page 4: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/4.jpg)
Cancer is a general term for all malignant growths of whatever type
Tumor may be used instead of neoplasm but the term is not accurate
Oncology : study of cancer in all its aspects
![Page 5: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/5.jpg)
NEOPLASM :
Abnormal mass of tissue, the growth of which EXCEEDS and is UNCOORDINATED with that of of the normal tissues, and PERSISTS in the same manner even AFTER CESSATION of the stimulus which produced the change
A neoplasm develops from a single transformed cell !!!
![Page 6: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/6.jpg)
Features of transformed cells :
Persistent & useless Uncontrolled growth * Immortal Transplantable
![Page 7: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/7.jpg)
This cell may arise from : Endoderm Mesoderm Ectoderm
Epithelial cells may arise from any of the above Connective tissue is from
mesoderm
![Page 8: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/8.jpg)
Classification of Tumors :
Cell of origin Behavior of tumor : Benign or
malignant Appearance of the tumor:
Solid/cystic Degree of differentiation
![Page 9: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/9.jpg)
Structure of neoplasms : - Parenchymal cell - Stromal ( supporting cell )
Degree & type of stromal cells may contribute to the appearance of tumors
If there is stromal proliferation hardness of the tumor Scirrhous tumor Desmoplasia
e.g.carcinoma of breast, pancreas…..etc
![Page 10: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/10.jpg)
If there is lack of many stromal cells, the tumor may be soft or cystic.
This feature may be included in the name of the tumor..e.g… Cystadenoma of ovary Poorly differentiated
cystadenocarcinoma of ovary Moderately differentiated scirrhous carcinoma of breast
![Page 11: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/11.jpg)
Serous cystadenoma of ovary
![Page 12: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/12.jpg)
Scirrhous Carcinoma of breast
![Page 13: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/13.jpg)
Benign Epithelial tumors :
Adenoma - glandular epithelium tumor often producing a secretion e.g. (mucin) which may be intraepithelial or intraluminal
Papilloma – epithelial tumor forming finger like projections from epithelial surface with a connective tissue core
Polyp – a tumor projecting from the mucosal surface of a hollow organ
![Page 14: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/14.jpg)
Structure of Polyp
![Page 15: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/15.jpg)
Malignant epithelial tumor : Carcinoma
Squamous cell carcinoma e.g. skin,mouth
cervix, bronchus….etc
Adenocarcinoma from glandular origin, e.g.G.I.T.,endometrium,breast, kidney, thyroid…..etc
![Page 16: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/16.jpg)
Connective tissue cell origin :
Benign :Named by tissue of origin with
attachedsuffix – omae.g. fibroma, lipoma, chondroma…etc
Not all endings (– oma) are benign tumors e.g. : granuloma,lymphoma, hamartoma, choristoma…etc
![Page 17: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/17.jpg)
Malignant connective tissue tumors:
SARCOMA : Prefix (origin)+ suffix (sarcoma) e.g. Osteosarcoma, liposarcoma,
angiosarcoma leiomyosarcoma,
rhabdomyosarcoma…
![Page 18: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/18.jpg)
Some tumors are MIXED !!!
![Page 19: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/19.jpg)
Mixed Tumors :
Tumors derived from a single germ cell layer that differentiates into more than one cell type.
e.g. mixed tumor of salivary gland, Fibroadenoma of breast
OR : Teratomas – made of a variety of
parenchymal cell types that derive from more than one germ cell layer formed by totipotent cells that are able to form ectoderm, endoderm & mesoderm
![Page 20: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/20.jpg)
TERATOMA : May be benign or malignant
depending on structure, site, age, sex ….
Contain skin ,sebaceous & mucus glands,hair,cartilage, bone, respiratory epithelium, glial tissue…..etc.
Usual location is ovary or testes
![Page 21: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/21.jpg)
Tumors of primitive fetal origin :
Blastoma : from immature tissue May arise in kidney, liver, retina…etc e.g. Retinoblastoma
The great majority of these tumors are malignant & occur in infants & children
![Page 22: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/22.jpg)
Some tumors have names that do not conform with general rules :
Melanomas arise from nevus cells Seminomas arise from testicular germ
cells Lymphomas arise from lymph nodes Some tumors are named eponymously e.g. Hodgkins disease, Wilm’s
tumor….etc
Note : See table on page 176
![Page 23: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/23.jpg)
Some ‘tumors’ are NOT true neoplasms
Hamartoma : Tumor like malformation in which
there is abnormal mixing of normal
components of the organ ,either in the form of change
in quantity or arrangement of tissue elements.
e.g. Lung Hamartoma.
![Page 24: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/24.jpg)
Choristoma :
Different types of tissue, ectopic to the region.
e.g. Meckle’s Diverticulum, Salivary tissue in LN
Both are present at birth & do not become
malignant .
![Page 25: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/25.jpg)
How do benign & malignant tumors differ?
Differentiation & anaplasia Rate of growth Presence of capsule Local invasion Distant metastases
![Page 26: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/26.jpg)
Benign versus malignant tumors
![Page 27: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/27.jpg)
- This indicates the degree of resemblance of the tumor cell to its cell of origin,
functionally & morphologically. e.g –
Cells of a lipoma may look exactly like normal fat cells.
1- Differentiation:
![Page 28: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/28.jpg)
LIPOMA LIPOSARCOMA
![Page 29: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/29.jpg)
Features of differentiation include : Epithelial cells :
- formation of glands - formation of keratin - formation of secretion…etc
Connective tissue cells : - formation of osteoid - presence of lipoblasts - Striations in tumors of
skeletal muscle….etc
![Page 30: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/30.jpg)
Well formed glandular architecture
![Page 31: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/31.jpg)
![Page 32: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/32.jpg)
No acini ! SIGNET CELLS
![Page 33: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/33.jpg)
- When a tumor cell loses its differentiation
it gradually gains features of DYSPLASIA
It is a process of gradual loss of differentiation
It is an abnormal growth which may precede malignancy
Complete loss of differentiation
ANAPLASIA
![Page 34: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/34.jpg)
Cytological Features of Dysplasia
Increased nuclear size , N/C ratio Variation in nuclear & cell size :
PLEOMORPHISM Loss of differentiating features Increased nuclear DNA content
HYPERCHROMATISM
![Page 35: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/35.jpg)
Features of dysplasia (continued) :-
Nucleoli :Prominent, sometimes multiple
Mitotic figures : Increased Abnormal mitoses: may be present Loss of polarity : in an epithelial
surface
![Page 36: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/36.jpg)
Severe Dysplasia/ Anaplasia
![Page 37: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/37.jpg)
Intraepithelial Neoplasia
Dysplasia involving an epithelial surface
Low grade & High grade High grade dysplasia ,limited by
epithelial basement membrane CARCINOMA IN SITU
![Page 38: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/38.jpg)
Intraepithelial Neoplasia
![Page 39: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/39.jpg)
NOTE :
Not all dysplasias progress to higher grade or carcinoma in situ.
Not all carcinoma in situ progress to invasive CA
Some cases of dysplasia can regress
![Page 40: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/40.jpg)
Rate of growth usually correlates with level of differentiation May be rapid in some benign tumors Some tumors may shrink in size Some malignant tumors may outgrow their blood supply
2- Rate of growth
![Page 41: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/41.jpg)
Some tumor growths are semicontroled :
HORMONE DEPENDENCE : This is through presence of receptors on
surface - Breast CA
- Thyroid CA - Prostatic CA
![Page 42: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/42.jpg)
Benign tumors frequently have a capsule
Malignant tumors progressively invade & destroy surrounding tissue e.g.Breast cancer infiltrating skin Basal cell carcinoma face infiltrating nerve *Second most important feature
distinguishing malignant tumors
3- Local invasion & Encapsulation
![Page 43: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/43.jpg)
Spread of malignant tumors to distant sites not contigious with the main tumor
Most important in diagnosing malignancy
All tumors can potentially metastasize except BASAL CELL CARCINOMA
Metastasis is often proportionate to the size and differentiation of the primary tumor
4- Metastasis :
![Page 44: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/44.jpg)
Routes of metastases :
Lymphatics Blood vessels Seeding within body cavities/ Transcoelomic Spread
![Page 45: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/45.jpg)
1- Lymphatic Spread : More characteristic in Carcinoma Spread follows the anatomical route of
drainage unless skip “metastases” e.g. Breast cancer in left upper upper quadrant Left axillary L.N. In medial quadrant internal mammary chain supraclavicular & infraclavicular Lung Ca - Peribronchial tracheobronchial LNs hilar LNs
![Page 46: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/46.jpg)
IMPORTANT IN SURGICAL RESECTION :
Sentinal Lymph Node : First lymph node in the pathway of a primary tumor. Usually outlined by dye
Not all enlarged L.N.s indicate metastases
e.g. Reactive hyperplasia Histiocytic infiltrate in sinuses
![Page 47: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/47.jpg)
2- Hematogenous spread :
Usually venous first following anatomical drainage : Lung & Liver More characteristic of Sarcoma ,but may in occur in later stages of carcinoma Certain carcinomas invade veins early
RENAL Carcinoma renal vein IVC Hepatocellular Carcinoma Portal &Hepatic
v.
![Page 48: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/48.jpg)
3- Transcoelomic spread:
Within peritoneal or pleural cavity e.g.: CA of upper lobe of lung to lower lobe CA of stomach to ovary CA of ovary tends to spread widely through peritoneal surface CA of colon across peritoneum to S.I.& colon
![Page 49: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/49.jpg)
BENIGN vs MALIGNANT
Anaplastic High mitotic index Rapid growth Infiltrative growth without capsule Invasion Metastases
Well-differentiated Low mitotic index Slow Growth With capsule No invasion No metastases
Summary : Differences between benign & malignant neoplasms
![Page 50: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/50.jpg)
EPIDEMIOLOGY of CANCER
![Page 51: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/51.jpg)
2006 Estimated US Cancer Cases*
*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.Source: American Cancer Society, 2006.
Men720,280
Women679,510
31% Breast
12% Lung & bronchus
11% Colon & rectum
6% Uterine corpus
4% Non-Hodgkin lymphoma
4% Melanoma of skin
3% Thyroid
3% Ovary
2% Urinary bladder
2% Pancreas
22% All Other Sites
Prostate 33%
Lung & bronchus 13%
Colon & rectum 10%
Urinary bladder 6%
Melanoma of skin 5%
Non-Hodgkin4% lymphoma
Kidney 3%
Oral cavity 3%
Leukemia 3%
Pancreas 2%
All Other Sites 18%
![Page 52: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/52.jpg)
2006 Estimated US Cancer Deaths*
Men291,270
Women273,560
26% Lung & bronchus
15% Breast
10% Colon & rectum
6% Pancreas
6% Ovary
4% Leukemia
3% Non-Hodgkin lymphoma
3% Uterine corpus
2% Multiple myeloma
2% Brain/CNS
23% All other sites
Lung & bronchus 31%
Colon & rectum 10%
Prostate 9%
Pancreas 6%
Leukemia 4%
Liver & intrahepatic 4%bile duct
Esophagus 4%
Non-Hodgkin 3% lymphoma
Urinary bladder 3%
Kidney 3%
All other sites 23%
![Page 53: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/53.jpg)
Incidence may be related to ethnic &geographic differences in community :
Nasopharyngeal CA Cervical CA & Cancer of the penis Burkitt Lymphoma Multiple myeloma Chronic lymphocytic leukemia
![Page 54: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/54.jpg)
Genetic polymorphism is responsible for :
Individual predisposition to disease
Individual response to environmental
agents
Individual response to drugs
![Page 55: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/55.jpg)
FACTORS WHICH MAY PLAY A ROLE IN THE INCIDENCE OF CANCER INCLUDE :
![Page 56: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/56.jpg)
1- Geographic location :
Gastric CA -- High in Japan Skin CA------ High in New Zealand Hepatocellular CA --- High in
Africa,China Breast CA ---- High in USA Prostatic CA ---- High in USA Colorectal CA ----High in USA Nasopharyngeal CA--- Far East Burkitt Lymphoma ----- Africa
![Page 57: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/57.jpg)
CANCERS common in JORDAN include :
Lung CA Colorectal CA } MALES Prostate CA
--------------------------------------------- Breast CA Colorectal CA } FEMALES Lung CA
Lymphomas are also common
![Page 58: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/58.jpg)
2- Environment :
Diet Occupation Sunlight Personal habits
![Page 59: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/59.jpg)
3- Age : In general , cancer incidence ≈ AGE However , certain cancers occur more in children
Acute Leukemia Some Lymphoma Some CNS Tumors Bone &soft tissue Sarcomas
![Page 60: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/60.jpg)
4- Heredity : 5-10% of tumors
Inherited Cancer Syndromes : Presence of defined genetic
abnormality, usually AD, often specific phenotype
e.g. APC gene : Familial Adenomatous Polyposis Coli MEN1 & RET genes : MEN syndrome NF1 & NF2 genes : Neurofibromatosis RB gene : Retinoblastoma
![Page 61: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/61.jpg)
Familial cancers : No specific phenotype & multifactorial Family members have higher incidence to common
cancers - CA of COLON
- CA of BREAST - CA of OVARY
Younger age groups, multiple or bilateral, two or more family members are affected.
Some linked to inheritance of mutant genes e.g. BRCA-1 & BRCA-2
![Page 62: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/62.jpg)
AR syndromes of DNA Repair :
Chromosomal & DNA instability Best example :
XERODERMA PIGMENTOSUM
![Page 63: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/63.jpg)
5- Acquired Preneoplastic Syndromes These are associated with increased risk for CA
and most are related to rapid or abnormal cell proliferation .
1- Endometrial Hyperplasia & carcinoma 2- Cervical Dysplasia & Cervical CA Bronchial dysplasia & lung CA 3- Liver Cirrhosis & Hepatocellular
![Page 64: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/64.jpg)
Acquired preneoplastic syndromes (continued)
4- Chronic healing process
5- Ulcerative Colitis & Colorectal CA 6- Villous Adenoma & Colorectal CA7- Leukoplakia & Squamous cell CA
![Page 65: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/65.jpg)
MOLECULAR BASIS OF CANCER
![Page 66: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/66.jpg)
Neoplasms arise from a single clone of cells :
Group of cells produced from a single ancestral cell by repeated cellular replication.
Thus they can be said to form a single "clone".
MONOCLONAL
![Page 67: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/67.jpg)
Principles :
Tumors arise from clonal growth of cells that have developed mutations in four classes of genes :
Growth promoting proto-oncogenes Growth inhibiting tumor suppressor genes Genes regulating apoptosis Genes involved in DNA repair
More than one mutations in above result in abnormal growth of cells
![Page 68: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/68.jpg)
Carcinogenesis is a MULTISTEP PROCESS !
![Page 69: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/69.jpg)
Multistep Carcinogenesis :
![Page 70: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/70.jpg)
Steps in Neoplastic Transformation :
1-Non lethal damage TRANSFORMATION 2-Cell Proliferation : initially Polyclonal MONOCLONAL CELLS
3-Genetic instability of malignant phenotype
cells with diverse features progression of tumor INVASION & METASTASES
![Page 71: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/71.jpg)
Heterozygous X-linked marker:
G6PD isoenzyme. In females
heterozygous for G6PD, normal tissues contain two populations of cells whereas their neoplasms are homozygous for one isoenzyme
Monoclonal proliferation
![Page 72: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/72.jpg)
Clinical Examples :
Chronic myeloid leukemia (CML): Philadelphia Chromosome
(9:22 ) Multiple Myeloma single immuno-
globulin specific for the tumor. T&B cell lymphomas : specific gene
rearrangement
![Page 73: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/73.jpg)
Tumor Progression :
This is the stepwise accumulation of
mutations resulting in increasing features of malignancy.
![Page 74: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/74.jpg)
![Page 75: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/75.jpg)
GENES IN NEOPLASTIC TRANSFORMATION
![Page 76: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/76.jpg)
Genes in Neoplastic Transformation:
![Page 77: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/77.jpg)
Outline of Gene Action :
![Page 78: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/78.jpg)
Proto-oncogenes
Normal genes whose products (Oncoproteins) promote cell growth
Oncogenes are mutant versions of proto-
oncogenes that function autonomously without normal signals
![Page 79: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/79.jpg)
Arise from mutant proto-oncogenes They are dominant genes. They include :
Growth factors Cell surface receptors Signal transduction proteins Nuclear transcription factors Cell cycle proteins Inhibitors of apoptosis
1-Genes coding for growth : Classified by site of action
![Page 80: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/80.jpg)
1-Oncogenes coding Growth Factors
Normal Cell growth is stimulated by GF Platelet derived growth factor (PDGF)
seen in glioblastomas Fibroblast growth factor(FGF)-stomach
CA & melanoma……etc Transforming Growth Factor (TGF-)in
sarcomas Products of other oncogens (e.g.RAS)
may cause over expression of GF
![Page 81: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/81.jpg)
2-Oncogenes coding Growth Factor Receptors
GF integrate with membrane receptors tyrosine kinase activity nucleus
Mutant receptor continuous signals even in the absence of GF…..OR
Normal but overexpressed hypersensitive to GF
Epidermal GF receptor family: ERBB1 in 80% of sq.CA lung ERBB2 ( HER 2 NEU) in 25-30% of
breast & ovarian CA --- Increase = POOR PROGNOSIS
![Page 82: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/82.jpg)
3- Oncogenes in Signal Transduction:
RAS & non receptor ABL RAS action:
GDP GTP proliferation
Mutations in GAPs(NF1):Neurofibromatosis Commonest oncogen mutation Point mutations in codon 12, 13 are present in 30% of cancers, specially CA pancreas
&Colon
Active RAS
GTPase activity by (GAP)
![Page 83: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/83.jpg)
Action of ABL : Non receptor associated tyrosine kinase signal transmission
Normal ABL is located in nucleus where it promotes apoptosis
Chronic myeloid leukemia : Mutation 9:22 translocation BCR- ABL gene This new gene is retained in
cytoplasm where it has tyrosine kinase activity cell proliferation
New action is Proliferation +No Apoptosis
![Page 84: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/84.jpg)
4-Nuclear Transcription Factors : DNA transcription regulated by genes
e.g. MYC*, JUN, FOS….etc. In normal :MYC protein + DNA
Activation of Cyclin Dependant Kinases ( CDK’s)
initiation of cell cycle MYC MYC mutation sustained activation Examples :
Dysregulation of MYC present in Burkitt’s lymphoma (t8:14)
Breast ,colon, lung CA & neuroblastoma
![Page 85: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/85.jpg)
5- Cyclins & Cyclin Dependant – Kinases regulate Cell Cycle phases
Family of proteins that control entry of the cells at specific stages of cell cycle
( D, E, A, B….etc.) Level of a specific cyclin increases at a
specific stage, then decreases rapidly after the cell departs that stage
Function by phosphorylating certain proteins ( e.g.RB protein)
Cyclins bind to CDKs, activating them
![Page 86: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/86.jpg)
G2
(Labile cells)G0
(Stable cells)
(Permenant cells)
G0
G1S
M
CELL CYCLE PHASES
![Page 87: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/87.jpg)
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 5 November 2007 08:09 AM)
© 2007 Elsevier
![Page 88: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/88.jpg)
Two important groups :
- Cyclin D family CDK4 & CDK6 at G1 S phase checkpoint - Cyclin B-CDK1 activate G2 M
transition
![Page 89: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/89.jpg)
Activity of CDK/ Cyclin regulated by CDK inhibitors
Non selective wide inhibition : p21, p27 and p57 Selective effect on cyclinD/CDK4 &
cyclinD/CDK6 : p15, p16, p18, and p19
![Page 90: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/90.jpg)
Cyclin/CDK/RB function
Loss of normal cell cycle control is central to malignant transformation& at least one of the following is
mutated in most human cancers : - Cyclin D - CDK 2, CDK 4, CDK 6 - CDK inhibitors - RB
![Page 91: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/91.jpg)
Mutations that disregulate activity of cyclins & CDKs → cell proliferation
Examples : Cyclin D is overexpressed in breast,
liver, & esophageal cancers Amplification of CDK4 gene present
in melanoma, sarcomas, glioblastoma
![Page 92: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/92.jpg)
Growth inhibitory pathway by: * Regulate cell cycle : Rb gene * Regulate cycle & apoptosis: P 53
* Block GF signals: TGF- * APC regulates -catenin
Cancer suppressor genes are recessive genes which may be lost in familial or sporadic cases.
2- Cancer Suppressor Genes:-
![Page 93: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/93.jpg)
1- RB gene :
First studied in Retinoblastoma: Called RB gene Both copies of gene must be lost for neoplastic transformation to occur This is called loss of heterozygosity
![Page 94: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/94.jpg)
Retinoblastoma :
Autosomal dominant hereditary disease May be sporadic In familial, patients carry one mutation in
their genome No tumor develops unless two alleles in 13q14 become mutant (two hit theory) ↑incidence of bilateral Retinoblastoma
and ↑ osteosarcoma
![Page 95: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/95.jpg)
Inheritance of Retinoblastoma
![Page 96: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/96.jpg)
Mode of action of RB gene:
RB exists in active nonphosphorylated & inactive phosphorylated forms. Active RB binds to transcription factors (E2F) NO TRANSCRIPTION CyclinD/CDK4, and cyclinE/CDK2
phosphorylate RB. Inactive RB releases transcription factor E2F TRANSCRIPTION (G1 S phase ) Many oncogenic DNA viruses may act
similarly by inactivating RB
![Page 97: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/97.jpg)
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 5 November 2007 08:09 AM)
© 2007 Elsevier
![Page 98: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/98.jpg)
2- P 53 70% of tumors show homozygous loss of p53 p53 is a negative regulator of cell cycle,
present in low levels with short half life MDM2 protein which targets it for
destruction Called ‘Guardian of the Genome’ OR
(Policeman) preventing genetically damaged cells from progressing through new cycle.
![Page 99: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/99.jpg)
Mode of activation & action :
P53 senses DNA damage through various sensors e.g. ATM protein
P53 is activated by anoxia, or DNA damage and accumulates in cell with long half life after release of MDM2
Activated p53→ Transcription of CDKI(p21) → cell cycle
arrest at G1 Transcription of GADD45 ( repair gene) p53 is a regulator of apoptosis
![Page 100: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/100.jpg)
More time for repair Normal Failed repair Apoptosis or
Senescence(permanent cell cycle arrest)
Fixed mutation NEOPLASIA
![Page 101: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/101.jpg)
Action of p53
![Page 102: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/102.jpg)
P53 may show the following :
Acquired mutation in many cancers e.g. colon, breast, lung , leukemia…etc Inherited mutation in Li - Fraumeni S. sarcoma, leukemia, breast carcinom and gliomas ….. etc May be blocked by some DNA viruses producing viral induced cancers
![Page 103: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/103.jpg)
3- TGF-
Antiproliferative activity: - regulation of RB pathway at G1 by action on some cyclins & CDKs - blocks GF signals
Mutational inactivation of TGF- components seen in 100% of pancreatic carcinoma & the majority of colonic CA
![Page 104: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/104.jpg)
4- APC gene
Cytoplasmic protein , acts as an adhesion molecule by regulating level of
-catenin in cytoplasm* APC--- -catenin --- E-Cadherin Result intercellular adhesion* Mutant APC -- -catenin nucleus Result stimulates proliferation
![Page 105: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/105.jpg)
Individuals with inherited one mutant allele of APC develop 100s to 1000s of adenomatous polyps in their 2nd.-3rd.decade of life
Additional mutations colonic carcinoma
100% risk in familial polyposis coli 70-80% of sporadic colonic
carcinoma show mutant APC
![Page 106: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/106.jpg)
Mutations in genes involved in programmed
cell death which regulate mitochondrial permeability promoting or suppressing apoptosis.
BAX, BAK promote permeability BCL-2 , BCL-XL inhibit permeability BH3-only protein regulates the ballance
BCL-2 prevents apoptosis, prolonging life. Activated by translocation (18:14) Follicular B cell Lymphoma
3- Evasion of Apoptosis :
![Page 107: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/107.jpg)
These are specialized structures at the end of chromosomes which are shortened after each division and may play a role in determining the life of individual cells. Shortening is prevented by TELOMERASE Active in stem cells, not in somatic cells Majority of cancers telomerase
4-Limitless replication potential(Telomeres)
![Page 108: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/108.jpg)
Repair mutations in other genes Persons with inherited mutations in these genes are at ↑ risk for cancer These include :
1- Nucleotide excision repair genes Damage by U-V light . Defective in Xeroderma Pigmentosum Damage by ionizing radiation Drugs e.g. nitrogen mustard
5- Genomic instability due to defective DNA Repair Genes
![Page 109: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/109.jpg)
Repair genes (continued)
2-Mismatch repair genes : These repair errors in pairing of nucleotides during cell division
e.g. G+T instead of A+T ( HNPCC).(Hereditary Nonpolyposis Colonic Ca.)
![Page 110: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/110.jpg)
Repair genes ( continued) :
3- BRCA -1 & BRCA-2 80% familial breast cancer & ovarian
CA BRCA –2 in breast CA in both sexes, e.g: prostate,ovary, pancreas,
stomach CA
Rarely inactivated in sporadic cases.
![Page 111: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/111.jpg)
Tumors remain small or in situ ( <1-2mm.diameter) without angiogenesis
Angiogenesis ≈ Antiangiogenesis Angiogenic Switch Controlled by hypoxia which induces angiogenic factors by tumor cells Hypoxia-Induced Factor(HIF-1) VEGF RAS mutation VEGF Proteases from tumor or stroma VEGF
6- Development of Sustained Angiogenesis :
![Page 112: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/112.jpg)
Anti- Angiogenesis :
VHL protein can destroy HIF-1 No VEGF so VHL acts as tumor suppressor
Germ line mutation of VHL hereditary renal CA , hemangiomas in CNS……etc
Anti-angiogenic factors : e.g. P53 antiangiogenic thrombospondin Inactivation of P53 angiogenesis - vascular density = Poor prognosis
![Page 113: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/113.jpg)
Tumors may generate clones with different phenotypic features, accumulate mutations, leading to a more aggressive nature e.g.
Non antigenic growth , Increase rate of growth,
Invasion, Metastases …etc Rate of generation of these clones
differs in individual tumors e.g. Osteosarcoma versus Basal Cell Carcinoma
7- Ability to invade & metastasize
![Page 114: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/114.jpg)
Metastatic Pathway:
![Page 115: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/115.jpg)
Metastases occurs in two phases :
![Page 116: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/116.jpg)
1- Invasion :
Loosening of intercellular junctions Attachment Degradation of ECM Migration
2- Vascular dissemination
![Page 117: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/117.jpg)
![Page 118: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/118.jpg)
1- Mechanism of invasion of ECM :
1- Detachment of tumor cells Inactivation of E-Cadherin OR activation of catenin detachment of tumor cells - Loss of function E-Cadherin in many CAs -2- Degradation of ECM by proteases :e.g. Matrix Metalloproteinase (MMPs) Cathepsin D Type IV collagenase
![Page 119: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/119.jpg)
- Result of digestion of ECM Cleavage products of matrix have chemotactic activity for more tumor cells
3- Attachment of tumor cells to matrix components by laminin & integrin receptors to basement membrane & ECM
4- Migration of tumor cells : Tumor derived cytokines e.g. Autocrine motility factor
![Page 120: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/120.jpg)
2- Vascular dissemination : 1- Invasion of the circulation :
Adhesion to endothelium retraction ofendothelium vessel
2- Attack by NK cells, some escape by formation of a thrombus3- Escape from circulation :
Adhesion to endothelium retraction of endothelium escape to tissue
![Page 121: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/121.jpg)
WHAT INFLUENCES SITE OF METASTASES ?
Anatomical Location Complimentary adhesion molecule between tumor cells & target
organs Chemoatractants liberated by
target organs Protease inhibitors present in
certain tissues
![Page 122: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/122.jpg)
Examples of Tropism ( Homing )
Prostatic Carcinoma Bone Lung Carcinoma Adrenals & Brain Neuroblastoma Liver & Bone Less common sites of metastases
include skin,muscle thyroid,breast….etc.
Spleen , Cartilage , Heart are almost never involved by metastatic tumours.
![Page 123: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/123.jpg)
Each cancer must result from accumulation of multiple mutations,
in many genes including those in apoptosis & senescence
EXAMPLE :
Steps in carcinogenesis may be followed genetically & histologically :
![Page 124: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/124.jpg)
![Page 125: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/125.jpg)
Different Gene Lesions :
Point mutation mainly in RAS Balanced translocation mainly in hematopoietic tumors: 9;22 , 8;14 , 14;18
& rare in solid tumors :Ewing Sarcoma Gene amplification :
Neuroblastoma : N-MYC Breast carcinoma : HER2/NEU
![Page 126: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/126.jpg)
Chromosomal deletions: More in nonhematopoietic & solid tumors e.g. Retinoblastoma 13q band14 also several in colorectal CA Chromosomes loss or gain : ( Aneuploidy) Result : Change in structure or quantity of
gene product
![Page 127: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/127.jpg)
![Page 128: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/128.jpg)
Gene Amplification :
![Page 129: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/129.jpg)
CARCINOGENIC AGENTS
![Page 130: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/130.jpg)
Direct Carcinogens - Directly produce damage without
prior metabolic conversion Indirect Carcinogens- (Procarcinogen) Metabolic conversion in liver by cytochrome P-450 dependent mono- oxygenases ultimate carcinogen
- CHEMICAL CARCINOGENS :
![Page 131: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/131.jpg)
Action of chemical carcinogens :
Initiator - Chemical inducing irreversible DNA damage
Promoter -Augment effect of initiator by promoting cell growth e.g. phorbol ester (PTA) activate signal transduction or GF secretion , hormones, saccharine …..etc
No tumor develops unless the promoter is applied AFTER the initiator.
![Page 132: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/132.jpg)
Classes of Chemical Carcinogens :
1- Alkylating Agents : Direct, used in chemotherapy of cancer may induce Leukemia
2- Polycyclic Hydrocarbons : Indirect & very strong e.g.cigarette smoke CA Lung
3- Aromatic Amines & Azo dyes : Rubber & Food Industry e.g.
naphthylamine Bladder CA
![Page 133: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/133.jpg)
Chemical carcinogens ( Continued)
4- Nitrosamines : Endogenous or food preservatives e.g.Gastric & Colon CA…etc.
5- Aflatoxin B1 : Naturally occurring carcinogen present in fungus.
Aspergillus flavus Hepatocellular CA
![Page 134: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/134.jpg)
Mode of action in chemical Carcinogens
Chemical carcinogens contain highly reactive electrophil groups that combine to DNA, RNA, or proteins producing mutations
Genes commonly affected are RAS & P53 May be very specific‘ Signature
Mutation’ Some strong chemicals act as Initiator &
Promoter e.g. polycyclic hydrocarbon
![Page 135: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/135.jpg)
U-V light : - Effect depends on intensity of exposure & quantity of melanin - Production of pyrimidine dimers in DNA MUTATION in RAS , P 53 - Failed repair Skin CA - Skin cancer includes :
Squamous Cell CA Basal Cell CA Melanoma
2- PHYSICAL CARCINOGENS :
![Page 136: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/136.jpg)
Ionizing Radiation: - Explosions Leukemia after 7 yrs.
Latent period Breast,colon, thyroid, lung CA
- Therapeutic exposure Thyroid CA, Leukemia
- Mechanism:Free radical injury Mutations in RAS, RB. P53 Asbestos fiber inhalation : Mesothelioma & Lung CA
![Page 137: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/137.jpg)
A - DNA Viruses :
Benign squamous papilloma (wart) groups 1,2,4 & 7 * Low risk groups (6, 11) Genital Squamous Cell Papilloma * High risk group ( 16, 18 ) Squamous Cell CA in cervix, vulva, perianal & oropharyngeal regions
3- VIRAL CARCINOGENESIS :
1- HPV-Human Papilloma Virus
![Page 138: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/138.jpg)
Mode of Action :
HPV have transforming early genes (E6,E7) inactivate suppressor genes
E6 acts on p53no apoptosis E7 binds to E2F blocks Rb action
& activates cyclins, & inhibit CDKI High risk groups have a stronger
affinity of early genes to E2F Result Cell proliferation
![Page 139: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/139.jpg)
BURKITT’S LYMPHOMA ** B CELL LYMPHOMA HODGKIN’S LYMPHOMA subset NASOPHARYNGEAL CA
----------------------------------------- Post transplant lymphoma CNS Lymphoma in AIDS patients
2- EBV : Ebstein Barr Virus
![Page 140: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/140.jpg)
Mode of action in Burkitt’s Lymphoma :
EBV has LMP1 gene- receptor for B lymphocytes
Induce B cell proliferation Prevents apoptosis by activating BCL2
Controlled POLYCLONAL B proliferation Infectious Mononucleosis
Dysregulation of c- myc by translocation : BURKITT’S Lymphoma (t 8:14) Malaria & Malnutrition may play a role in
immunity ( Lost T cell control ). In endemic cases EBV is identified in tumor cells
![Page 141: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/141.jpg)
In Nasopharyngeal Carcinoma :
LMP 1 is expressed on epithelial cells activating cell proliferation
========================
LMP 1 also activates pro- angiogenic factors
Both in Burkitt Lymphoma & Nasopharyngeal Carcinoma other
environmental factors play a role
![Page 142: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/142.jpg)
Multifactorial oncogenic effect but mainly
Immunologically mediated chronic liver disease Cirrhosis Hepatocellular CA
in 70 -85% Action :* Cell proliferation
mutation * HBV encodes Hbxprot.
growth promoting genes *Hbx binds to p 53 Inactivates suppressor function
(HCV is similar but HCV core Protein)
3-HBV ( Hepatitis B Virus )
![Page 143: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/143.jpg)
B- Oncogenic RNA Viruses :
HTLV-1 induces Leukemia /Lymphoma
Transmitted sexually,blood or milk Mode of action : Virus TAX gene attaches to T cells: Produce cytokines +receptor
autocrine stimulation proliferation Suppresses action of TP53 &CDKI POLYCLONAL MONOCLONAL LEUKEMIA
![Page 144: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/144.jpg)
First described as a cause for peptic ulcer Multifactorial etiology in gastric CA &
gastric lymphoma ( MALT lymphoma ) Immune mediated gastric damage with FR Occurs in only 3% after a long latent
period H.pylori contains (Cag A)genes GF Cell proliferation
Helicobacter pylori in carcinogenesis
![Page 145: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/145.jpg)
Mode of action :
LYMPHOMA : Chronic gastritis mucosal lymphoid
follicles reactive polyclonal B cells monoclonal B cells Malt lymphoma
CARCINOMA : Chronic gastritis atrophy
intestinal metaplasia dysplasia Gastric Carcinoma
![Page 146: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/146.jpg)
CANCERS --ASSOCIATED CARCINOGEN
CA LUNG Smoking CA CERVIX Sexual transmission of HPV CA BLADDER Rubber Industry CA LIVER Aflatoxin & HBV infection CA THYROID Radiation ANGIOSARCOMA of Liver Plastic(PVC) MESOTHELIOMA Asbestos
![Page 147: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/147.jpg)
TUMOR IMMUNOLOGY
![Page 148: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/148.jpg)
What is Immune Surveillance ?
Normal immunity present to protect against development of tumors
Evidence ? When there is no immunity → More
Cancers Patients with congenital immune
deficiency have 200 times risk of cancer & immunosuppressed patients have increased rates of cancers (Lymphoma)
![Page 149: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/149.jpg)
Explanation of failed survailance
This may be lost during tumor progression
There may be acquired immunosuppression produced by oncogenic agents
![Page 150: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/150.jpg)
Anti tumor Host Mechanisms :
1- Sensitized Cytotoxic T lymphocytes 2- Natural Killer cells may kill tumor cells without previous sensitization. 3- Macrophages activated by IFN- may destroy tumor cells
4- Humoral AB mechanisms
![Page 151: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/151.jpg)
Tumor Antigens :
Tumors share MHC with normal cells
Tumor specific & Tumor Associated AGs may be helpful in diagnosis & follow
up of some tumors Therefore, they may act as tumor
markers
![Page 152: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/152.jpg)
Specific & Associated Tumor AG:
1- Products of mutant oncogenes & tumor suppressor genes e.g. RAS protein
2- Mutant proteins induced by chemical and radiation induced tumors
3- Overexpressed normal cellular proteins or aberrantly expressed e.g. :
Tyrosinase in melanoma Cancer Testes Genes : MAGE-1(melanoma..) HER-2 in CA breast
![Page 153: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/153.jpg)
4- Tumor AG produced by oncogenic viruses in HPV & EBV infection
5- Oncofetal AG: Carcinoembryonic AG (CEA) in colon and fetoprotein in liver CA 6- Several mucins: MUC-1 in breast CA and CA-125, CA-19-9 in ovarian CA 7- Cell Type- specific differentiation AG in B lymphomas (CD10&CD20)
![Page 154: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/154.jpg)
Clinical Aspects of Neoplasia
![Page 155: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/155.jpg)
Effects of tumors on body:
Location of tumor is of importance 1- Mass effect by pressing on vital areas e.g.airway, intestine , BV, brain,nerve obstruction, infarction , paralysis…etc 2- Local destruction of epithelial surface or BV ulceration , bleeding , infection
3- Hormonal activity
![Page 156: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/156.jpg)
4 - Cancer Cachexia :
Wasting syndrome characterized by anorexia , loss of body fat & weight,with
marked weakness,anemia & fever.
Reduced food intake but high metabolic rate
Possibly due to release of cytokines by tumor cells & macrophages
![Page 157: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/157.jpg)
5 - Paraneoplastic Syndrome :
Systemic symptoms that can’t be explained by effects of local or distant spread of tumor or hormones appropriate to tumor tissue.
Due to ectopic production of hormones or other factors They may precede the tumor or mimic metastases They occur in about 10%-15% of malignant tumors.
![Page 158: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/158.jpg)
Types of Paraneoplastic Syndromes :
Endocrinopathies e.g hyperglycemia,
hypoglycemia, Cushing’s S…..etc Nerve & Muscle Syndromes e.g
myasthenia gravis Dermatologic disorders Osseous & Articular changes Vascular & hematological changes Nephrotic syndrome
![Page 159: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/159.jpg)
Well Known Examples of Paraneoplastic Syndromes
Small Cell CA lung ACTH , ADH, Bone changes,nervous system disorders
Squamous Cell CA lung & Breast CA Parathormone related &othersHypercalcemia
Pancreatic & lung CA clotting factors Deep vein thrombosis N.B. Hypercalcemia is commonly produced by
lytic bone metastases
![Page 160: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/160.jpg)
examples (continued)
Hepatic & Renal CA Polycythemia Pancreatic, Gastric CA Carcinoid S. Advanced Cancers Nonbacterial thrombotic
endocarditis. Colonic Adenocarcinoma Acanthosis nigricans
![Page 161: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/161.jpg)
Grading & Staging of Tumors :
Must be documented for all malignant tumours : To quantify the aggressiveness of
tumor To outline mode of therapy To compare different modes of
therapy To give an approximate prognosis
![Page 162: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/162.jpg)
Prognosis :
This indicates the final outcome of the disease in terms of 5year or 10 year survival.
This is influenced by : Tumor Type e.g. Lung CA versus
Lip CA Tumor Grade & Stage Host reactions
![Page 163: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/163.jpg)
Grade of tumor: Based on level of differention :
This indicates the degree of resemblance of tumor cells to cell of origin and is always based on microscopic criteria.
Grade I : Well differentiated tumor Grade II :Moderately differentiated
tumor Grade III : Poorly differentiated tumor Grade IV : Anaplastic tumor
![Page 164: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/164.jpg)
STAGE of Tumor :
This indicates the extent of spread of the tumor.
Clinical ,investigative procedures and pathological appearance of tumor have to be used to assess it.
It depends on : * Size of tumor * Regional lymph node involvement * Metastases to distant organs
![Page 165: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/165.jpg)
TNM Staging System :
T : Size and extent of primary tumor(1-4)
N : Presence and extent of lymph node
involvement ( 0-3) M : Presence or absence of distant metastasis ( X0-1) e.g.T1,N1, M0-----------------------------------
![Page 166: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/166.jpg)
Others : American Joint Committee staging system ( AJC) Stage 0-IV
- Duke’s staging for colonic CA - Lymphoma Staging system And many more…….etc Staging is more important than
grading because it affects treatment
![Page 167: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/167.jpg)
CANCER DIAGNOSIS
![Page 168: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/168.jpg)
General Outline :
History & clinical examination Radiographic techniques
i- X rayii- CT scaniii- MRIiv- Ultrasound
Laboratory tests : general & specialized
![Page 169: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/169.jpg)
1- Cytological methods : Study of cells : - Smear - FNA, Brush, Fluid tapping…etc Papanicolaou stain (PAP) often
used. False(+), False (-) - A negative report does not exclude malignancy, repeat - Advise biopsy, even if (+ )
1-Morphological Methods :
![Page 170: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/170.jpg)
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 18 December 2006 10:36 AM)
© 2005 Elsevier
Normal PAP smear of Cervix
![Page 171: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/171.jpg)
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 18 December 2006 10:36 AM)
© 2005 Elsevier
Dysplastic Epithelial Cells (PAP smear)
![Page 172: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/172.jpg)
2- Histological methods :
Biopsy of tissue: Needle & core biopsy , Endoscopic
Biopsy, or open surgical biopsy Frozen Section (Rapid technique) Paraffin Section ( 36-48 hrs. or longer ) H&E, Special histochemical stains e.g. ( PAS, CONGO RED, PERL’s stains) or by IMMUNOHISTOCHEMICAL Methods
![Page 173: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/173.jpg)
3- Immunocytochemistry
Staining by use of monoclonal AB directed against various components in cell may help in diagnosis of undifferentiated cancers or help in identifying source of a metastatic tumor. e.g.
Cytokeratin Carcinoma Common leukocyte antigenLymphoma S 100 Neural tissue, melanocytic lesions Desmin, Vimentin Sarcoma
![Page 174: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/174.jpg)
Undifferentiated Tumor
![Page 175: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/175.jpg)
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 18 December 2006 10:36 AM)
© 2005 Elsevier
Cytokeratin for epithelial cells indicating Carcinoma
![Page 176: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/176.jpg)
Undifferentiated Malignant tumor
![Page 177: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/177.jpg)
Desmin Positive for connective tissue indicating Sarcoma
![Page 178: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/178.jpg)
4-Electron microscopy :
For recognition of desmosomes , or neurosecretory granules….etc. 5- Flow Cytometry : For measuring DNA content , detecting diploid versus aneuploid tumors….etc. Correlates with rate of growth & prognosis Useful in the diagnosis & classification of
Lymphoma & Leukemia
![Page 179: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/179.jpg)
Used to identify tumor associated enzymes, hormones , antigens … etc
These are useful as markers for diagnosis of a tumor OR for assessing the progress of a known tumor
2- Biochemical Assays :
![Page 180: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/180.jpg)
Tumor markers represent biochemical indicators of the presence of a tumor.
Their uses are to : I - Confirm diagnosis. II -Determine the response to treatment . III - Detect early relapse. Present in serum or urine. Many are present in normal & tumor tissue, so they
are not very specific but their level is important.
![Page 181: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/181.jpg)
Types of Tumor Markers
1- Hormones : Human Chorionic Gonadotrophic Hormone ( HCG)
Elevated levels are seen in Pregnancy & Gestational Trophoblastic Disease
Calcitonin useful in diagnosis of some thyroid carcinomas Ectopic hormones in paraneoplastic S.not used
![Page 182: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/182.jpg)
2- Oncofetal Antigens : Carcinoembryonic Antigen ( CEA ) : in fetal tissue & some malignancies – Colorectal CA & Pancreatic CA
Alpha Fetoprotein (AFP) :
Cirrhosis : Elevated Hepatocellular carcinoma : Extremely
high
![Page 183: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/183.jpg)
3- Isoenzymes :
Prostatic Acid Phosphatase ( PAP ) levels seen in Metastatic prostatic CA Useful in : * Staging prostatic CA * Assessment of prognosis * Response to therapy.
![Page 184: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/184.jpg)
4- Specific Proteins : Immunoglobulins secreted in Multiple Myeloma Prostate -specific antigen ( PSA ) : Present in epithelium of prostatic
ducts. * Prostatic hyperplasia &
* in Prostatic CA * Level correlates with Stage of CA
![Page 185: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/185.jpg)
5- Several mucins
MUC-1 in breast CA CA-125 in ovarian CA CA-19-9 in pancreatic & hepatobiliary
CA
![Page 186: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/186.jpg)
Methods used include : PCR (Polymerase Chain Reaction) FISH (Fluorescent In Situ Hybridization)
Used to detect gene rearrangement, translocations, amplifications…etc
BCR-ABL Chronic Myeloid Leukemia Monoclonal proliferation of B or T cells 13q 14 deletion in Retinoblastoma….
3- Molecular Diagnosis :
![Page 187: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/187.jpg)
For prognosis : gene amplification HER- 2 NEU in breast carcinoma N-MYC in neuroblastoma
Detection of residual disease in chronic myeloid leukemia (BCR-ABL) Detection of genes of hereditary cancer e.g BRCA-1 in breast cancer
![Page 188: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/188.jpg)
BE AWARE OF CANCER !!!
![Page 189: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/189.jpg)
EARLY DIAGNOSIS of CANCER :
This is very important as many cancers are curable if they are diagnosed early. Specific symptoms should be followed up e.g. Abnormal bleeding Change of voice Change in a nevus Abnormal lump in breast An ulcer that does not heal……etc.
![Page 190: Pathology, Lecture 10, Neoplasia](https://reader030.fdocuments.in/reader030/viewer/2022020711/5475b59bb4af9fa90a8b5bb1/html5/thumbnails/190.jpg)
Specific procedures : - Self examination of the breast - Mammography - Serial PAP smears for the cervix - Serial sputum cytology in smokers - Serial urine cytology in some cases, e.g. bilharziasis, workers in rubber Screening for genetic mutations in
familial cancers.