from robins pathological basis of disease

1. Neoplasia-I
Dr.Mohamid Afroz Khan

2. Neoplasia
• Cancer is one of the leading causes of death
worldwide.
• Emotional and physical suffering by the
patient.
• Different mortality rate
– Some are curable
– Others are fatal

3. Characteristics of
cancers:
• Genetic disorder caused by DNA
mutations; by environmental insults.
• Epigenetic changes:DNA methylation and
alterations in histone modifications.
• These genetic and epigenetic changes alter
the expression genes that regulate
fundamental cellular processes, such as
growth, survival, and senescence.

4. • These genetic alterations are heritable, being
passed to daughter cells upon cell division .
• Cells harboring these alterations are subject
to darwinian selection
cells bearing mutations that
provide them with growth or survival
advantages outcompeting their neighbours
and thus coming to dominate the population
Conferred on a single cell that gives rise
to the tumor, all tumors are clonal (i.e., the
progeny of one cell). .

5. Hallmarks of cancer:
• The growth of cancers becomes autonomous
and is unregulated by physiologic cues.
• Lack of response to growth inhibitory
signals that control nonneoplastic cellular
proliferations such as hyperplasias.
• Evasion of cell death, allowing cancer cells to
survive under conditions that induce
apoptosis in normal cells.
• limitless replicative potential cancer cells
immortal.
• Development of angiogenesis to sustain the
growth of cancer cells;

6. • Ability to invade local tissues and spread to
distant sites.
• Reprogramming of metabolic pathways—
specifically, a switch to aerobic glycolysis
even when there is abundant oxygen.
• Ability to evade the immune system.

7. Definition of Neoplasia
• “A neoplasm is an abnormal mass of tissue,
the growth of which exceeds and is
uncoordinated with that of the normal tissues
and persists in the same excessive manner
after cessation of the stimuli which evoked the
change”
• Genetic changes
• Autonomous
• Clonal

8. Nomenclature
Benign tumors :
– Will remain localized
– Cannot spread to distant sites
– Generally can be locally excised
– Patient generally survives
- can produce more than localized lumps, they are
responsible for serious disease.

9. Nomenclature
Malignant neoplasms:
– Can invade and destroy adjacent structure
– Can spread to distant sites(metastasize)
– Cause death (if not treated )

10. • All tumors have two basic components:
–Parechyma: made up of neoplastic cells
–Stroma: made up of connective tissue,
blood vessels, and macrophages and
lymphocytes.

11. • The neoplastic cells largely determine a tumor's
behaviour & pathologic consequences.
• Growth and evolution is dependent on their
stroma.
• Adequate stromal blood supply is requisite for
the tumor cells to live and divide.
• The stromal connective tissue provides the
structural framework essential for the growing
cells.

12. • In some tumors, the stromal support is scant
and so the neoplasm is soft & fleshy.
• In other cases the parenchymal cells stimulate
the formation of an abundant collagenous
stroma, referred to as desmoplasia.
• Demoplastic tumors—for example, some
cancers of the female breast—are stony hard
or scirrhous.

13. Nomenclature – Benign Tumors
• -oma = benign neoplasm
• Examples:
-Benign tumor arising in fibrous tissue:
Fibro + oma = Fibroma
-Benign tumor arising in fatty tissue:
Lipo + oma = lipoma
• Epithelial benign tumors are classified on the basis of :
– The cell of origin
– Microscopic pattern
– Macroscopic pattern

14. .
Benign epithelial tumors
Adenoma
• is applied to a benign epithelial neoplasm
derived from glands, although they may or
may not form glandular structures.
Examples
– Respiratory airways: Bronchial adenoma
– Renal epithelium: Renal tubular adenoma
Papillomas
• Benign epithelial neoplasms producing
microscopically or macroscopically visible
finger-like or warty projections from epithelial
surfaces are referred to as papillomas.

15. Benign tumor (adenoma) of the thyroid. Note the normal-
looking (well-differentiated), colloid-filled thyroid follicles

16. .
Benign epithelial tumors
Papillomas
• Benign epithelial neoplasms producing
microscopically or macroscopically visible finger-
like or warty projections from epithelial surfaces
are referred to as papillomas.
Examples
• Squamous epithelium: squamous papilloma
• Large cystic masses, as in the ovary, are referred to as
cystadenomas.
• Some tumors produce papillary patterns that protrude
into cystic spaces and are called papillary cystadenomas.

17. Papilloma

18. Papilloma
Papillary adenoma of colon. Note the fingerlike projections of the
tumor.

19. • Polyp : When a neoplasm, benign or
malignant, produces a macroscopically visible
projection above a mucosal surface and
projects.
• For example, into the gastric or colonic lumen,
it is termed a polyp.

20. Polyp
Colonic polyp. This benign glandular tumor (adenoma) is projecting into the
colonic lumen and is attached to the mucosa by a distinct stalk

21. Nomenclature – Malignant Tumors
• Malignant neoplasms arising in “solid”
mesenchymal tissues or its derivatives are
called sarcomas.
• Cancer of fibrous tissue origin is a
fibrosarcoma.
• Malignant neoplasm composed of
chondrocytes is a chondrosarcoma
• Those arising from the mesenchymal cells of
the blood are called leukemias or lymphomas.

22. • Malignant tumors arising from epithelial origin
:derived from all three germ layers, are called
carcinomas.
• Renal tubular epithelium (mesoderm) is a
carcinoma.
• Arising in the skin (ectoderm) and
• Lining epithelium of the gut (endoderm)

23. Carcinoma subdivided:
• Carcinomas that grow in a glandular
pattern are called adenocarcinomas.
tissue or organ of origin renal cell
adenocarcinoma.
• That produce squamous cells are called
squamous cell carcinomas.
• The tumor shows little or no
differentiation called poorly differentiated or
undifferentiated carcinoma.

24. This view shows the transition from normal squamous
epithelium into invasive carcinoma.

25. A hallmark of well differentiated squamous cell carcinoma is that the
nests of invading cells still attempt to make keratin which then gets
deposited in the center of the nests, resulting in a keratin "pearl".

26. Another characteristic of a well differentiated squamous cell
carcinoma is that it still makes visible intercellular bridges.

27. Adenocarcinoma of colon arising in a case of ulcerative colitis

28. Lymph node with undifferentiated large cell carcinoma of the lung. If these
epithelial tumor cells formed little circular or tubular structures called
“glands”, it might better be termed “adenocarcinoma”. If it showed any
attempt at keratin formation, “pearls”, or intercellular bridges between
tumor cells, it might best be termed “squamous cell” carcinoma.

29. Tumors with mixed differentiation:
• Differentiation of a single neoplastic clone along
two lineages - mixed tumors.
Example -1.Mixed tumor of salivary gland origin.
These tumors contain epithelial components
scattered within a myxoid stroma that contains
islands of cartilage or bone .
All these elements, arise from a single clone
giving rise to epithelial and myoepithelial cells;
thus, these neoplasms is pleomorphic adenoma.
2.Fibroadenoma of the female breast is
common mixed tumor. This benign tumor
contains a mixture of proliferating ductal
elements(adenoma) embedded in a loose
fibrous tissue (fibroma).

30. This mixed tumor of the parotid gland contains epithelial cells forming
ducts and myxoid stroma that resembles cartilage.

31. Teratoma
• Tumor comprised of cells from more than one
germ layer arise from totipotent cells (usually
gonads ) those normally present in the ovary
and testis .
• Such cells differentiate into any of the cell
types found in the adult body & that mimic, in
a helter-skelter fashion, bits of bone,
epithelium, muscle, fat, nerve, and other
tissues- it is a benign (mature) teratoma;
• when less well differentiated, it is an
immature, potentially or overtly, malignant
teratoma.
Examples-ovarian cystic teratoma (dermoid
cyst), which differentiates principally along
ectodermal lines to create a cystic tumor lined
by skin replete with hair, sebaceous glands,
and tooth structures

32. A, Gross appearance of an opened cystic teratoma of the ovary. Note the presence
of hair, sebaceous material, and tooth. B, A microscopic view of a similar tumor
shows skin, sebaceous glands, fat cells, and a tract of neural tissue (arrow).

33. • Aberrant differentiation (not true
neoplasms):
Hamartomas :present as disorganized but benign-
appearing masses composed of cells indigenous to
the particular site.
Example : pulmonary chondroid harmatoma
contains islands of disorganized, but histologically
normal cartilage, bronchi, and vessels.
Choriostoma:congenital anomaly ectopic focus of
normal tissue (heterotopia). Example, a small nodule
of well-developed pancreatic substance found in the
submucosa of the stomach, duodenum, or small
intestine.

34. Tissue of Origin Benign Malignant
COMPOSED OF ONE PARENCHYMAL CELL TYPE
Tumors of Mesenchymal Origin
Connective tissue and derivatives Fibroma Fibrosarcoma
Chondroma Chondrosarcoma
Endothelial and Related Tissues
Blood vessels Hemangioma Angiosarcoma
Lymph vessels Lymphangioma Lymphangiosarcoma
Synovium Synovial sarcoma
Mesothelium Mesothelioma
Brain coverings Meningioma Invasive meningioma
Blood Cells and Related Cells
Hematopoietic cells Leukemias
Lymphoid tissue Lymphomas
Muscle
Smooth Leiomyoma Leiomyosarcoma
Striated Rhabdomyoma Rhabdomyosarcoma

35. Tumors of Epithelial Origin
Stratified squamous Squamous cell papilloma Squamous cell carcinoma
Basal cells of skin or adnexa Basal cell carcinoma
Epithelial lining of glands or ducts Adenoma Adenocarcinoma
Papilloma Papillary carcinomas
Cystadenoma Cystadenocarcinoma
Respiratory passages Bronchial adenoma Bronchogenic carcinoma
Renal epithelium Renal tubular adenoma Renal cell carcinoma
Liver cells Liver cell adenoma Hepatocellular
carcinoma
Urinary tract epithelium
(transitional)
Transitional-cell papilloma Transitional-cell
carcinoma
Placental epithelium Hydatidiform mole Choriocarcinoma
Testicular epithelium (germ cells) Seminoma
Tumors of Melanocytes Nevus Malignant melanoma
MORE THAN ONE NEOPLASTIC CELL TYPE
Salivary glands Pleomorphic adenoma (mixed
tumor of salivary origin)
Malignant mixed tumor of
salivary gland origin
MORE THAN ONE NEOPLASTIC CELL TYPE DERIVED FROM MORE THAN ONE GERM CELL
Totipotential cells in gonads or in
embryonic rests
Mature teratoma, dermoid
cyst
Immature teratoma,
teratocarcinoma

36. Characteristics of Benign and
Malignant Neoplasms
1.Differentiation And Anaplasia
2.Rate of growth
3.Local invasion
4.Distant metastases.

37. Differentiation
• Refers to extent to which neoplastic
parenchymal cells resemble the corresponding
normal parenchymal cells, both
morphologically and functionally.
1.Well differentiated neoplasm
– Resembles mature cells of tissue of origin
2.Poorly diffentiated neoplasm
– Composed of primitive cells with little diffrerentiation
3.Undifferentiated or “anaplastic” tumor

38. • Benign neoplasms are composed of well
differentiated cells that closely resemble
their normal counterparts.
• Mitoses are usually rare
• Ex.
A lipoma is made up of mature fat cells
laden with cytoplasmic lipid vacuoles.
A chondroma is made up of mature
cartilage cells that synthesize their usual
cartilaginous matrix—evidence of
morphologic and functional differentiation.

39. Leiomyoma of the uterus. This benign, well-differentiated tumor contains
interlacing bundles of neoplastic smooth muscle cells that are virtually
identical in appearance to normal smooth muscle cells in the myometrium.

40. Benign tumor (adenoma) of the thyroid. Note the normal-looking (well-
differentiated), colloid-filled thyroid follicles.

41. • Malignant neoplasms are characterized by
a wide range of parenchymal cell
differentiation, from surprisingly well
differentiated to completely undifferentiated.
• The amount of stromal connective tissue
determine the consistency of a neoplasm.
• Certain cancers induce a dense, abundant
fibrous stroma (desmoplasia)- hard, socalled
scirrhous tumors.

42. Malignant tumor (adenocarcinoma) of the colon.Compared with the well-
formed and normal-looking glands characteristic of a benign tumor the
cancerous glands are irregular in shape and size and do not resemble the
normal colonic glands. This tumor is considered differentiated because
gland formation can be seen. The malignant glands have invaded the
muscular layer of the colon.

43. • Malignant neoplasms that are composed of
undifferentiated cells are said to be anaplastic.
• The term anaplasia literally means “back-
ward formation”implying dedifferentiation, or
loss of the structural and functional
differentiation of normal cells.
• However, that most cancers do not represent
“reverse differentiation” of mature normal
cells but, in fact, arise from less mature cells
with “stem-cell-like” properties, such as tissue
stem cells .

44. Anaplasia
• Pleomorphism
– Size
– shape
• Abnormal nuclear morphology
– Hyperchromasia
– High nuclear cytoplasmic ratio
– Coarsely Chromatin ,clumping
– Prominent nucleoli
• Mitoses
– Mitotic rate
– Atypical bizzare mitotic figure –tripolar ,multipolar ,qudripolar spindle
• Loss of polarity -anaplastic cell orientation disturbed

45. Anaplastic tumor of the skeletal muscle (rhabdomyosarcoma). Note the
marked cellular and nuclear pleomorphism, hyperchromatic nuclei, and tumor
giant cells.

46. Anaplastic tumor showing cellular and nuclear variation in size and shape.
The prominent cell in the center field has an abnormal tripolar spindle.

47. Metaplasia
• Is defined as the replacement of one type of cell
with another type.
• Is nearly always found in association with tissue
damage, repair, and regeneration.
• Often the replacing cell type is more suited to a
change in environment.
• For e.g., gastroesophageal reflux damages the
squamous epithelium of the esophagus, leading
to its replacement by glandular (gastric or
intestinal) epithelium,& suited to the acidic
environment.

48. Dysplasia
• Is a term that means disordered growth.
• Dysplasia often occurs in metaplastic
epithelium, but not all metaplastic epithelium
is dysplastic.
• Dysplasia is occure principally in epithelia &
• Is characterized by changes that include a loss
in the uniformity of the individual cells as well
as a loss in their architectural orientation.

49. Dysplasia
• Cells exhibit pleomorphism & contain large
hyperchromatic nuclei with a high nuclear to-
cytoplasmic ratio.
• E.g. in squamous epithelium the usual progressive
maturation of tall cells in the basal layer to flattened
squamous on the surface may be lost and replaced
by a scrambling of dark basal-appearing cells
throughout the epithelium.
• Mitotic figures - more abundant than usual.

50. This epithelium shows severe dysplasia: Note that dysplastic basal cells characterized by
cuboidal shape, high nuclear cytoplasmic ratio, hyperchromatism, mitotic activity, and some
loss of orientation to the basement membrane, occupy the lower two thirds of the surface
rather than just the basal row of cells. More differentiated cells which occupy the outer third,
though still retaining some dysplastic nuclear features have the appearance of maturing
squamous cells rather than basal cells, and eventually become flattened on the surface

51. Dysplasia
• When dysplastic changes are marked & involve the
entire thickness of the epithelium but the lesion
remains confined by the basement membrane,
• It is considered a preinvasive neoplasm and is
referred to as carcinoma in situ
• Once the tumor cells breach the basement
membrane, the tumor is said to be invasive.
• Dysplastic changes are found adjacent to foci of
invasive carcinoma, & in some situations, such as in
long-term cigarette smokers and persons with
Barrett esophagus, severe epithelial dysplasia
frequently antedates the appearance of cancer.
• Does not necessarily progress to cancer. Mild to
moderate changes that do not involve the entire
thickness of epithelium may be reversible.

52. A, Carcinoma in situ. This low-power view shows that the entire thickness of the
epithelium is replaced by atypical dysplastic cells. There is no orderly differentiation of
squamous cells. The basement membrane is intact, and there is no tumor in the
subepithelial stroma. B, A high-power view of another region shows failure of normal
differentiation, marked nuclear and cellular pleomorphism, and numerous mitotic
figures extending toward the surface.

53. RATES OF GROWTH
Growth rate of tumor determine by :
• Doubling time of tumor cells
– Lengthens as tumor grows
– 30 doublings (109 cells) = 1 g
– 10 more doublings (1 kg) = lethal burden
• Fraction of tumor cells in replicative pool
--growth fraction
– May be only 20% even in rapidly growing tumors
• Rate at which tumor cells are shed or lost
– Apoptosis
– Maturation

54. Schematic representation of tumor growth. As the cell population expands, a
progressively higher percentage of tumor cells leaves the replicative pool by
reversion to G0, differentiation, and death.

55. LOCAL INVASION
• Benign tumors grow as cohesive expansile masses that
remain localized to their site of origin and do not have
the capacity to infiltrate, invade, or metastasize to distant
sites.
• All benign tumor they grow and expand slowly, they
usually develop a rim of compressed connective tissue,
sometimes called a fibrous capsule
• Capsul derived -Extracellular matrix due to atrophy of
normal parenchymal cells under the pressure of an
expanding tumor.
• It keeps the benign neoplasm as a discrete, readily
palpable, and easily movable mass .

56. Fibroadenoma of the breast. The tan-colored, encapsulated
small tumor is sharply demarcated from the whiter breast tissue

57. Microscopic view of fibroadenoma of the breast . The fibrous capsule
(right) delimits the tumor from the surrounding tissue.

58. • In malignant tumor the growth of cancers is
accompanied by progressive infiltration, invasion,
and destruction of the surrounding tissue.
• Are poorly demarcated from the surrounding normal
tissue, and a well-defined cleavage plane is lacking.
• Slowly expanding , develop enclosing fibrous capsule
& push along a broad front into adjacent normal
structures.
• Shows rows of cells penetrating the margin and
infiltrating the adjacent structures, a crablike pattern
of growth.

59. Cut section of an invasive ductal carcinoma of the breast. The lesion is
retracted, infiltrating the surrounding breast substance, and would be stony
hard on palpation.

60. The microscopic view of the breast carcinoma. illustrates the invasion of
breast stroma and fat by nests and cords of tumor cells . The absence of
a well-defined capsule should be noted.

61. METASTASIS
• Are tumor implants discontinuous with the
primary tumor.
• The invasiveness of cancers permits them to
penetrate into blood vessels, lymphatics,& body
cavities -spread.
• Exceptions- glial cells tumor in the central
nervous system, called gliomas, & basal cell
carcinomas of the skin. Both are locally invasive
forms of cancer, but they rarely metastasize.

62. METASTASIS
• Pathways of Spread:
(1) Direct seeding of body cavities or surfaces,
(2) lymphatic spread,
(3)Hematogenous spread.

63. Direct seeding of body cavities or surfaces:
• Most often involved is the peritoneal cavity but any other
cavity—pleural, pericardial, subarachnoid, and joint
space—may be affected
• Such seeding is particularly characteristic of carcinomas
arising in the ovaries, all peritoneal surfaces become
coated with a heavy layer of cancerous glaze.
• Mucus-secreting appendiceal carcinomas fill the
peritoneal cavity with a gelatinous neoplastic mass called
as pseudomyxoma peritonei.

64. Colon carcinoma invading pericolonic adipose tissue.

65. Lymphatic Spread:
• Most common pathway for initial dissemination of
carcinoma.
• Lymphatic vessels located at the tumor margins are
apparently sufficient for the lymphatic spread of
tumor cell.
• Pattern of lymph node involvement follows the
natural routes of lymphatic drainage.

66. Axillary lymph node with metastatic breast carcinoma. The
subcapsular sinus (top) is distended with tumor cells. Nests of tumor
cells have also invaded the subcapsular cortex.

67. • A sentinel lymph node- “the first node in a regional
lymphatic basin that receives lymph flow from the
primary tumor.”
• Biopsy of sentinel nodes is used to assess the
presence or absence of metastatic lesions in the
lymph nodes.
• Assessing the future course of the disease and for
selecting suitable therapeutic strategies, such as in
breast carcinoma.

68. Haematogenous Spread
• Is typical of sarcomas but is also seen with carcinomas.
• Arteries, with their thicker walls, are less readily penetrated
than are veins.
• When tumor cells pass through the pulmonary capillary beds,
pulmonary metastases themselves give rise to additional
tumor emboli.
• With venous invasion the blood-borne cells follow the venous
flow draining the site of the neoplasm, & the tumor cells
come to rest in the first capillary bed they encounter.
• Cancers arising in close proximity to the vertebral column
embolize through the paravertebral plexus- e.g. vertebral
metastases of carcinomas of the thyroid and prostate.

69. A liver studded with metastatic cancer.

70. Microscopic view of liver metastasis. A pancreatic
adenocarcinoma has formed a metastatic nodule in the liver.

71. Benign vs Malignant Features
Feature Benign Malignant
Rate of growth Progressive but
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

72. Comparison between a benign tumor of the myometrium
(leiomyoma) and a malignant tumor of the same origin
(leiomyosarcoma).

73. Epidemiology
• Cancer is a disorder of cell growth and behavior,
its ultimate cause at the cellular and subcellular
levels
• Study of cancer patterns - origins of cancer.
Epidemiologic studies have established the
causative link-
- Between smoking and lung cancer,
-Comparison of diet and cancer rates in the
Western world
-Africa has implicated high dietary fat and low
fiber in the development of colon cancer.

74. GEOGRAPHIC AND ENVIRONMENTAL FACTORS
• Sun exposure
– Melanomas 6x incidence New Zealand vs Iceland
– Blacks have low incidence of melanoma
• Smoking and alcohol abuse
• Body mass
– Overweight = 50% increase in cancer
• Environmental vs racial factors
– Japanese immigrants to USA
• Viral exposure
– Human papilloma virus (HPV) and cervical cancer
– Hepatitis B virus (HBV) and liver cancer (Africa)
– Epstein-Barr Virus (EBV) and lymphoma

75. Predisposing Factors for Cancer
• Age
– Most cancers occur in persons ≥ 55 years
– Childhood cancers
• Leukemias & CNS neoplasms
• Bone tumors
• Genetic predispostion
– Familial cancer syndromes
• Early age at onset
• Two or more primary relatives with the cancer
• Multiple or bilateral tumors
– Polymorphisms that metabolize procarcinogens, e.g.,
nitrites
• Nonhereditary predisposing conditions
– Chronic inflammation
– Precancerous conditions
• Chronic ulcerative colitis
• Atrophic gastritis of pernicious anemia
• Leukoplakia of mucous membranes

76. THANK YOU.....