1. NEOPLASM

2. 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

3. 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

4. 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

5. 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”

6. 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

7. 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.

8. FEATURES OF TRANSFORMED CELL
Genetically Altered
Autonomous
Uncontrolled growth*
Clonal

9. ORGANS/TISSUES SMALLER THAN NORMAL
DEVELOPMENTAL
AGENESIS
APLASIA
HYPOPLASIA
ATRESIA
ACQUIRED
ATROPHY

10. ABNORMAL PATTERNS OF CELL GROWTH / DIFFERENTIATION
METAPLASIA
DYSPLASIA

11. ENDOCERVIX, SQUAMOUS METAPLASIA
G.D. Abrams, University of Michigan Medical School

12. ENDOCERVIX, SQUAMOUS METAPLASIA
G.D. Abrams, University of Michigan Medical School

13. SQUAMOUS EPITHELIUM, NORMAL
G.D. Abrams, University of Michigan Medical School

14. SQUAMOUS EPITHELIUM, MODERATE DYSPLASIA
G.D. Abrams, University of Michigan Medical School

15. SQUAMOUS EPITHELIUM, SEVERE DYSPLASIA
G.D. Abrams, University of Michigan Medical School

16. NEOPLASM / “TUMOR” MASS (“NEW GROWTH”) – PROLIFERATING CELLS
AUTONOMOUS
NON-EQUILIBRIUM, UNCOORDINATED GROWTH
PERSISTENT / IRREVERSIBLE

17. NEOPLASTIC TRANSFORMATION
SERIES OF GENETIC EVENTS
CLONAL CHARACTERISTICS

18. Benign Tumor: growth by expansion
Malignant Tumor: growth by invasion
Regents of The University of Michigan

19. BENIGN AND MALIGNANT GROWTH
COHESIVE /EXPANSILE
CIRCUMSCRIBED / LOCALIZED
MALIGNANT
POORLY CIRCUMSCRIBED /
INVASIVE….METASTASIZING

20. This may arise from ===
Ectoderm
Endoderm
Mesoderm
Epithelial cells may arise from any of the above
Connective tissue is from mesoderm

21. Classification of tumors
Cell of origin
Behavior of tumor: Benign or malignant 
Appearance of the tumor: Solid/cystic
Degree of differentiation

22. CLASSIFICATION
Benign tumors
Malignant tumors
Mixed tumors
Tetatoma of both benign and malignant

23. 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

24. (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.

26. 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

27. This infiltrating ductal carcinoma of the breast is definitely infiltrating the surrounding breast. The central white area is very hard and gritty, because the neoplasm is producing a desmoplastic reaction with lots of collagen. This is often called a "scirrhous" appearance. There may also be focal dystrophic calcification giving the cut surface a gritty texture.

29. Thyroid nodule

32. 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 

33. Serous cyst adenoma of ovary

34. Scirrhous carcinoma of breast Desmoplasia

35. Colored mammogram of scirrhous breast cancer

36. 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.

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

38. Nomenclature – Benign Tumors
-oma = benign neoplasm
Microscopic and Macroscopic classification.
Mesenchymal tumors
Chrondroma: cartilaginous tumor
Fibroma: fibrous tumor
Osteoma: bone tumor

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

40. 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

41. Papilloma

42. Adeomatous Polyp

43. 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

44. 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

45. 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.

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

47. Nomenclature – Malignant Tumors
Sarcomas: mesenchymal tumor
chrondrosarcoma: cartilaginous tumor
fibrosarcomama: fibrous tumor
osteosarcoma: bone tumor

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

49. 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

50. 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.

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

52. 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)

53. 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. 

54. A patient's age determines the preferred imaging method
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.

55. Fibroadenoma breast mammogram

57. Pleomorphic Adenoma

58. 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.

59. BENIGN
Mature teratoma
Dermoid cyst
Well Differentiated

60. Poorly Differentiated
MALIGNANT
Immature Teratoma
Terato carcinoma
Poorly Differentiated

61. 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

62. Testicular teratoma
Tumor characteristics: Firm, whitish, ovoid mass with discrete yellow and grey areas.

63. Seminoma testis
The firm whitish areas nearby showed extensive intratubular germ cell neoplasia.

64. Figure 7-4 A, Gross appearance of an opened cystic teratoma of the ovary. Note the presence of hair, sebaceous material, and tooth. You do not need a microscope to appreciate this tumor produces both connective tissue as well as epithelial derived elements.
Remember, pure “epithelial” tumors may evoke a fibrous response, such as breast or pancreas or prostate adenocarcinomas, but the connective tissue us regarded as NON-neoplastic.
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 28 July :41 PM)
© 2005 Elsevier

65. 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
Misnomers are often REDUNDANT, to try to correct the misnomer.

66. BENIGN SOUNDING DESIGNATIONS
Misnomers
Hepatoma: malignant liver tumor
Melanoma: malignant skin tumor
Seminoma: malignant testicular tumor
Lymphoma: malignant tumor of lymphocytes

68. 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) .

69. Characteristics of Benign & Malignant tumors

70. 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

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

72. Anaplasia Lack of Differentiation -- Anaplasia
Malignant neoplasms are poorly differentiated and said to be Anaplastic
Less mature cells with stem-cell like properties

73. Anaplasia Characteristic Features:- 1. Pleomorphism
2. Abnormal nuclear morphology
3. Mitoses
4. Loss of polarity
5. Other Changes

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

75. 2. Abnormal Nuclear Morphology:-
Increased chromatin
Dark staining of nuclei – Hyperchromasia
Large and irregular nuclei
Increased nuclear cytoplasmic ratio

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

77. 3. Mitoses:-
High proliferative activity of parenchymal cells
*Also present in normal tissues undergoing hyperplasia
Increased mitotic figures with tripolar, quadripolar, or multipolar spindles

78. Sarcoma – Atypical mitotic figure present in center field

79. 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

80. Soft tissue sarcoma – Giant cells with bizzare nuclei

81. 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
Do you remember from chapter 1 that DYS- was one of the seven -plasia brothers?

83. 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.

84. Cervix - Dysplastic squamous epithelium is observed on the right
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

85. CERVICAL DYSPLASIA
the nuclear atypia of the dysplatic cells. Large and immature appearing nuclei, irregular nuclear borders and clumping of the DNA.

87. Rate of Growth Rate of growth of tumor is determined by:
1. Doubling time of tumor cells
2. Fraction of tumor cells that are in replicative pool
3. 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!!

88. 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)

89. 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.

90. Natural History Of Malignant Tumors
Malignant change in the target cell, referred to as transformation
Growth of the transformed cells
Local invasion
Distant metastases
Another linear process, such as the epics of inflammation or healing.

91. Benign vs Malignant Features
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
In some tumors, like smooth muscle tumors, counting mitoses may be the main way to differentiate a benign from a malignant process!
“If you want to think od “anaplasia” as DE-differentiation, you can, but remember, differentiation NEVER occurs backwards!
“LOCAL INVASION” is in HUGE ALL CAPS font because it is the single most important differentiating feature.
ALL malignancies can potentially metastasize, but there is at least one common benign condition which is also said to “metastasize”. Can you name it?

92. 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

93. 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

94. 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.

95. 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.

96. Carcinoma in situ - Without invasion of the basement membrane

97. 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

98. METASTASIS
A COMPLEX CASCADE OF EVENTS
VIA BLOOD
VIA LYMPH
DIRECT

99. CANCER CELLS WITHIN BLOOD VESSEL
G.D. Abrams, University of Michigan Medical School

100. CANCER CELLS WITHIN LYMPHATIC
G.D. Abrams, University of Michigan Medical School

101. PERITONEUM, CARCINOMATOSIS
Department of Pathology, University of Michigan

102. PERITONEAL METASTASES
Department of Pathology, University of Michigan

103. LIVER, METASTASES
Department of Pathology, University of Michigan

104. LUNG, METASTASES
Department of Pathology, University of Michigan

105. VERTEBRAE, METASTASES
Department of Pathology, University of Michigan

106. VERTEBRA, METASTASIS
Department of Pathology, University of Michigan

107. BRAIN, METASTASIS
Department of Pathology, University of Michigan

108. LIVER, METASTASES
Department of Pathology, University of Michigan

111. Epidemiology

112. 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

115. 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

116. Epidemiology Age Heredity Acquired preneoplastic disorders
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