neoplasm. neoplasia definitions of terms used in neoplasia nomenclature of tumors characteristics of...

NEOPLASM

NEOPLASIA

• 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

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

• 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

Willis Definition:

• “Neoplasm is an abnormal mass of tissue the growth of which exceeds and is uncoordinated with that of normal tissue and persists in the same excessive manner after cessation of the stimuli which evoked the change”

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 !!!– Clonal – Derived from one individual cell

• Fundamental to the origin of all neoplasms are heritable (genetic) changes that allow excessive and unregulated proliferation that is independent of physiologic growth-regulatory stimuli.

FEATURES OF TRANSFORMED CELL

•Genetically Altered•Autonomous•Uncontrolled growth*•Clonal

ORGANS/TISSUES SMALLER THAN NORMAL

• DEVELOPMENTAL AGENESIS APLASIA HYPOPLASIA ATRESIA

• ACQUIRED ATROPHY

ABNORMAL PATTERNS OF CELL GROWTH / DIFFERENTIATION

• METAPLASIA

• DYSPLASIA

ENDOCERVIX, SQUAMOUS METAPLASIA

G.D. Abrams, University of Michigan Medical School

ENDOCERVIX, SQUAMOUS METAPLASIA

G.D. Abrams, University of Michigan Medical School

SQUAMOUS EPITHELIUM, NORMAL

G.D. Abrams, University of Michigan Medical School

SQUAMOUS EPITHELIUM, MODERATE DYSPLASIA

G.D. Abrams, University of Michigan Medical School

SQUAMOUS EPITHELIUM, SEVERE DYSPLASIA

G.D. Abrams, University of Michigan Medical School

NEOPLASM / “TUMOR”

• MASS (“NEW GROWTH”) – PROLIFERATING CELLS

• AUTONOMOUS• NON-EQUILIBRIUM, UNCOORDINATED

GROWTH• PERSISTENT / IRREVERSIBLE

NEOPLASTIC TRANSFORMATION

• SERIES OF GENETIC EVENTS

• CLONAL CHARACTERISTICS

Benign Tumor: growth by expansion

Malignant Tumor: growth by invasion

Regents of The University of Michigan

BENIGN AND MALIGNANT GROWTH

• BENIGN COHESIVE /EXPANSILE CIRCUMSCRIBED / LOCALIZED

• MALIGNANT POORLY CIRCUMSCRIBED / INVASIVE….METASTASIZING

• This may arise from ===• Ectoderm• Endoderm• Mesoderm

• Epithelial cells may arise from any of the above

• Connective tissue is from mesoderm

Classification of tumors

• Cell of origin• Behavior of tumor: Benign or malignant • Appearance of the tumor: Solid/cystic• Degree of differentiation

CLASSIFICATION

• Benign tumors• Malignant tumors • Mixed tumors• Tetatoma of both benign and

malignant

• Tumors, benign and malignant, have two basic components

• (1) the parenchyma, made up of transformed or neoplastic cells

• The parenchyma of the neoplasm largely determines its biologic behavior, and the component from which the tumor derives its name

• (2) Stroma the supporting, host-derived, non-neoplastic made up of connective tissue, blood vessels, and host-derived inflammatory cells.

• Stroma, it carries the blood supply and provides support for the growth of parenchymal cells.

Structure of Neoplasm

• 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

• Desmoplasia - Collagenous Stroma, e.g.carcinoma of breast, pancreas..etc

• Scirrhous tumor – Stony hardness type of desmoplasia

• Thyroid nodule

• 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 cyst adenocarcinoma of ovary

• Moderately differentiated scirrhous carcinoma of breast

Serous cyst adenoma of ovary

Scirrhous carcinoma of breast Desmoplasia

• Colored mammogram of scirrhous breast cancer

Benign tumors

• Benign tumors are(microscopic and gross characteristics) are

• Innocent• Localized• Cannot spread to other sites• Easy for surgical resection• Survival of the patient is fair.• But in certain tumors it can be serious.

Malignant tumors

• 1.Are cancers, 2 They are not localized 3.They invade, destroy the adjacent structures. 4.Distant metastasis 5. Can cause death

Nomenclature – Benign Tumors

• -oma = benign neoplasm• Microscopic and Macroscopic

classification.• Mesenchymal tumors–Chrondroma: cartilaginous tumor–Fibroma: fibrous tumor–Osteoma: bone tumor

• chondroma.A. Normal cartilage.B. A benign chondroma closely

• Epithelial Tumor–Adenoma: Tumor forming glands–Papilloma: Tumor with finger like

projections–Cystadenoma – Cystic tumor in ovary–Papillary Cystadenoma: Papillary pattern

and cystic tumor forming glands–Polyp: Tumor that projects above a mucosal

surface and into lumen

Papilloma

Adeomatous Polyp

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

epithelia surface with a connective tissue core• Polyp a tumor projecting from the mucosal surface of

a hollow organ

• Adenoma of benign arise in solid organs• Liver, Thyroid and Kidney typically glandular

pattern• Since they are benign they remain discrete

pushing compressing the surrounding tissue and remain localized also they show tissue of origin

Malignant tumors

• Malignant neoplasms arising in mesenchymal tissue or its derivatives are called Sarcomas

• A cancer of fibrous tissue origin is a fibrosarcoma, and a malignant neoplasm composed of chondrocytes is a chondrosarcoma.

• Chondrosarcoma of bone.The tumor is composed of malignant chondrocytes

Nomenclature – Malignant Tumors

• Sarcomas: mesenchymal tumor–chrondrosarcoma: cartilaginous

tumor–fibrosarcomama: fibrous tumor–osteosarcoma: bone tumor

• SARCOMA :

• Prefix (origin)+ suffix (sarcoma) e.g.Osteosarcoma,liposarcoma,angiosarcoma, leiomyosarcoma,rhabdomyosarcoma

• Carcinomas: Epithelial tumors

–ADENOCARCINOMA: Tumor cells resemble glandular pattern–SQUAMOUS CELL CARCINOMA: Tumor cells

resemble stratified squamous differentiation–undifferentiated carcinoma: no differentiation–note: carcinomas can arise from ectoderm,

mesoderm, or endoderm

• Malignant neoplasms of epithelial cell origin are called carcinomas

• Carcinoma : Malignant tumor of epithelial cells (Ectoderm/Endoderm/Mesoderm)

• Sarcoma : Malignant tumor of connective tissue cells (Mesenchymal)

• Lymphoma

• Carcinomas that grow in a glandular pattern are called ADENOCARCINOMAS, and those that produce squamous cells are called squamous cell carcinomas.

• 1. Squamous cell carcinoma • Example-. skin, mouth cervix, bronchus.etc • 2. Adenocarcinoma from glandular origin• Example-.G.I.T., endometrium ,breast, kidney,

thyroid..etc

MIXED TUMOR• Derived from one germ cell layer!

• 1. FIBROADENOMA• IT HAS DUCTAL ELEMENT - ADENOMA• ALSO EMBEDED IN LOOSE FIBROUS TISSUE -

FIBROMA

• 2. TUMOR OF THE SALIVARY GLAND (Most common)• PLEOMORPHIC ADENOMA – (epithelial +myoepithelial + stromal myxoid)

Fibroadenoma

• Fibroadenoma is the most common benign (noncancerous) growth in the breast. If it is diagnosed on needle biopsy and the mammographic finding is consistent with a fibroadenoma, it is typically simply followed, with no additional excision. In some instances it may be removed for cosmetic reasons.

• A patient's age determines the preferred imaging method. In general, ultrasonography (US) is preferred if a palpable mass is found, if a patient is younger than 30 years, or if the patient is not pregnant, Mammography and US are both useful if the patient.

Fibroadenoma breast mammogram

Pleomorphic Adenoma

TERATOMA

• Teratomas originate from totipotential stem cells which contains recognizable mature or immature cells or tissues representative of more than one germ-cell layer and sometimes all three.

BENIGN

•Mature teratoma•Dermoid cyst•Well Differentiated

MALIGNANT

•Immature Teratoma•Terato carcinoma•Poorly Differentiated

• Teratomas originate from totipotential stem cells such as those normally present in the ovary and testis and sometimes abnormally present in sequestered midline embryonic rests

Testicular teratoma

Seminoma testis

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 28 July 2005 03:41 PM)

© 2005 Elsevier

• Aberrant differentiation (not true neoplasms)–Hamartoma: disorganized mass of

tissue whose cell types are indiginous to the site of the lesion, e.g., lung–Choriostoma: ectopic focus of normal

tissue (heterotopia), e.g., pancreas, perhaps endometriosis too

BENIGN SOUNDING DESIGNATIONS• Misnomers–Hepatoma: malignant liver tumor–Melanoma: malignant skin tumor–Seminoma: malignant testicular

tumor–Lymphoma: malignant tumor of

lymphocytes

Hamartoma

• Clinical presentation• Pulmonary hamartomas are usually

asymptomatic and found incidentally when imaging the chest for other reasons. It can occasionally present with haemoptysis, bronchial obstruction and cough (especially endobronchial types) .

Characteristics of Benign & Malignant tumors

Differentiation

• Extent of resemblance to normal parenchymal cells morphologically and functionally

• Benign tumors are generally well differentiated, closely resembling a normal cell

• Malignant tumors can be well differentiated to completely undifferentiated

A. Normal Myometrium, B. Leiomyoma, C. Leiomyosarcoma (Mitotic figures & hyperchromasia)

Anaplasia

• Lack of Differentiation -- Anaplasia

• Malignant neoplasms are poorly differentiated and said to be Anaplastic

• Less mature cells with stem-cell like properties

Anaplasia

• Characteristic Features:-

• 1. Pleomorphism• 2. Abnormal nuclear morphology• 3. Mitoses• 4. Loss of polarity• 5. Other Changes

• 1. Pleomorphism -- Variation in size and shape of cell and nuclei

• 2. Abnormal Nuclear Morphology:-

• Increased chromatin• Dark staining of nuclei – Hyperchromasia• Large and irregular nuclei • Increased nuclear cytoplasmic ratio

Small cell carcinoma of lung - - Hyperchromasia, little cytoplasm, increased nuclear cytoplasm ratio, increased mitoses

• 3. Mitoses:-

• High proliferative activity of parenchymal cells• *Also present in normal tissues undergoing

hyperplasia• Increased mitotic figures with tripolar,

quadripolar, or multipolar spindles

Sarcoma – Atypical mitotic figure present in center field

• 4. Loss of Polarity:-• Anaplastic cells lose normal polarity resulting

in a disorganized fashion

• 5. Other Changes:-• Tumor giant cell formation with polymorphic

nucleus that are hyperchromatic

Soft tissue sarcoma – Giant cells with bizzare nuclei

Dysplasia• Literally means abnormal growth or loss in architectural

orientation

• Malignant transformation is a multistep process• In dysplasia some but not all of the features of malignancy are

present, microscopically

• Dysplasia may develop into malignancy– Uterine cervix– Colon polyps

• Graded as low-grade or high-grade, often prompting different clinical decisions

• Dysplasia may NOT develop into malignancy• HIGH grade dysplasia often classified with CIS

Cervical Dysplasia -- In this example the dysplastic epithelium involves almost the entire thickness of the epithelium. Full thickness dysplasia is referred to as carcinoma in situ.

Cervix - Dysplastic squamous epithelium is observed on the right. Compare to normal squamous epithelium on the left. Dysplasia often precedes carcinoma and is thought of as "pre-malignant" in most cases. Mild dysplasias may be reversible and do not always progress to carcinoma

CERVICAL DYSPLASIA• the nuclear atypia of the dysplatic

cells. Large and immature appearing nuclei, irregular nuclear borders and clumping of the DNA.

Rate of Growth

• Rate of growth of tumor is determined by:

1. Doubling time of tumor cells2. Fraction of tumor cells that are in replicative pool3. Rate at which cells die

*Dividing cells do not complete the cell cycle like normal cells do, therefore cell cycle time can be the same or longer than normal cells!!

• Growth Fraction – Proportion of cells within tumor that are in the proliferative pool– Mostly during the early phase of growth

– Later stages, cells leave the proliferative phase– *By the time tumor is clinically detectable, most cells

are not in the replicative pool

– E.g. Leukemia and Lymphomas – High growth fraction (Excess of cell production over cell loss)

– E.g. Colon and Breast Cancer – Low growth fraction (Small margin between cell production and cell loss)

• How does the growth fraction of tumor cells have an effect on their on their susceptibility to treatment??

• Chemotherapy acts on cells that are in cell cycle• Aggressive tumors E.g. leukemia and certain

lymphomas can be quickly treated with chemo

• Low growth fraction tumors will need to be shifted from the G0 phase into cell cycle by debulking the tumor.

Natural History Of Malignant Tumors

1. Malignant change in the target cell, referred to as transformation

2. Growth of the transformed cells 3. Local invasion4. Distant metastases

Benign vs Malignant Features

Feature Benign Malignant

Rate of growth slow. Mitoses few and normal

Variable. Mitoses more frequent and may be abnormal

Differentiation Well differentiated Some degree of anaplasia

LOCAL INVASION

Cohesive growth. Capsule & BM not breached

Poorly cohesive and

infiltrative!Metastasis Absent May occur

Benign vs Malignant

• Rate of growth– Most benign tumors grow slowly while most

cancers grow fast• Many exceptions

– Rate of growth for malignant tumors correlates with degree of differentiation

– Despite rapid growth, cancers usually take years to become clinically apparent

– Rapid growth may lead to necrosis

Benign vs Malignant

• Local invasion– Benign neoplasm do not have the capacity to

invade – Invasion is a characteristic of malignancy– Benign neoplasm often develop a fibrous capsule

– Malignant tumors lack this demarcation, allowing it to penetrate or invade

– Surgical resection becomes difficult at this point

A lipoma is comprised of mature adipose tissue and is typically encapsulated. A portion of the capsule is present on the left side of the picture.

Malignant tumors are generally not encapsulated and infiltrate tissue stroma. In this example of a malignant mesothelioma, the pleura is widely infiltrated by the malignant process and the tumor extends into adjacent fat. No normal tissue is present in this photograph.

• Carcinoma in situ - Without invasion of the basement membrane

Benign vs Malignant

• Metastasis– Metastases are secondary, remote implants of

tumor– Metastatic spread is the most important hallmark

of malignancy– Cancers differ in their ability to metastasize– Methods of metastasis:

• Seeding – Peritoneal cavity involvement• Lymphatic spread – Normal route of lymphatic drainage• Hematogenous spread – Veins are penetrated easily

due to thin walls

METASTASIS

• A COMPLEX CASCADE OF EVENTS• VIA BLOOD • VIA LYMPH• DIRECT

CANCER CELLS WITHIN BLOOD VESSEL

G.D. Abrams, University of Michigan Medical School

CANCER CELLS WITHIN LYMPHATIC

G.D. Abrams, University of Michigan Medical School

PERITONEUM, CARCINOMATOSIS

Department of Pathology, University of Michigan

PERITONEAL METASTASES

Department of Pathology, University of Michigan

LIVER, METASTASES

Department of Pathology, University of Michigan

LUNG, METASTASES

Department of Pathology, University of Michigan

VERTEBRAE, METASTASES

Department of Pathology, University of Michigan

VERTEBRA, METASTASIS

Department of Pathology, University of Michigan

BRAIN, METASTASIS

Department of Pathology, University of Michigan

LIVER, METASTASES

Department of Pathology, University of Michigan

Epidemiology

Epidemiology

• The study of the relationships of various factors determining the frequency and distribution of diseases in the human community

• Contributes to understanding of risk factors and the origin of cancers

• Smoking – Lung cancer• Fatty diets – Colon cancer

Epidemiology

• Geographic and environmental factors– Breast cancer – Death rates 4-5x higher in US and

Europe than in Japan– Stomach cancer – Death rates 7x higher in Japan

than in the US– Hepatocellular carcinoma – Uncommon in US, one

of the most common and lethal cancers in some African populations

• Most geographic patterns related to environmental exposures

Epidemiology

• Age– Frequency of cancer increases with age with peak

between ages of 55 and 75– Increased accumulation of somatic mutations

• Heredity– 5-10% of cancers

• Acquired preneoplastic disorders– Dysplasia, colonic adenoma