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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