A paraneoplastic syndrome occurs when a neoplasm elaborates a substance that results in an effect that is not directly related to growth, invasion, or metastasis of the tumor itself. Most paraneoplastic syndromes result from elaboration of hormone-like s

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Tumor 2 Pathology and Histology
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A model of neoplastic transformation (Scientific
Truth?)
Mutation in gene A
Mutation in gene B,C, etc.
Increasing chromosomal aneuploidy
However, this is NOT cancer
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Hepatocellular Carcinoma
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THIS IS CANCER Renal Cell Carcinoma
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Metastatic Carcinoma to Liver
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Cancer is NOT one disease
Deaths ?
Incidence ?
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Germ cell layers
Cancers are also classified according to what
germ cell layer they originate.
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Terminology

• Neoplasia new growth
• Tumor swelling caused by inflammation, now
  tumor neoplasm
• Cancer Latin cancer crab, malignant tumors
• Oncology Greek oncos tumor

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Terminology
Neoplasias are classified into two basic types

• Benign mass of proliferating cells not subject
  to normal physicological controls which can
  increase in size but not invade surrounding
  tissue or spread to other parts of the body
• Malignant mass of proliferating cells not
  subject to normal physiological control with
  capacity to extend (invade) adjacent normal
  tissues and to spread (metastasize) to distant
  organ sites

CANCER refers to virtually all malignant
neoplasias
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Mesenchymal connective tissue endothelial
relatedBenign Malignant

• Fibroma
• Lipoma
• Chondroma
• Osteoma
• Hemangioma
• Meningioma

• Fibrosarcoma
• Liposarcoma
• Chondrosarcoma
• Osteogenic sarcoma
• Angiosarcoma
• Invasive meningioma
• Synovial sarcoma
• Mesothelioma

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Epithelial originBenign
Malignant

• Adenoma
• Renal tubular adenoma
• Liver cell adenoma
• Hydatidiform mole

• Squamous cell carcinoma
• Basal cell carcinoma
• Adenocarcinoma
• Renal cell carcinoma
• Hepatocellular carcinoma
• Choriocarcinoma
• Seminoma
• Embryonal carcinoma

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Macroscopic Criteria for Classification
ofBenign Malignant

• Structure typical of tissue of origin
• Encapsulated
• Slow growth
• No metastasis

• Atypical structure
• Locally invasive, infiltrating
• Rapid erratic growth
• Metastasis

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Fibroadenoma
Ductal carcinoma
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Microscopic Criteria for Classification
ofBenign Malignant

• Well differentiated
• Uniform
• NC 14 or 16
• Rare normal mitotic figures
• Normal orientation
• Abundant stroma

• Generally less well differentiated to
  undifferentiated (anaplastic)
• Pleomorphic
• NC 11
• Hyperchromatic
• More mitoses, abnormal bizarre
• Loss of polarity
• Tumor giant cells

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Abnormal mitoses
Pleomorphic, hyperchromatic, multinucleated,
giant, bizarre
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Abnormal mitosis - Here are three abnormal
mitoses. Mitoses by themselves are not indicators
of malignancy. However, abnormal mitoses are
highly indicative of malignancy. The marked
pleomorphism and hyperchromatism of surrounding
cells also favors malignancy.
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Spread of Tumors

• Direct invasion infiltration destruction of
  surrounding tissue
• Metastasis noncontiguous spread to other
  organ/body locations
• Lymphatics carcinomas, lymphatic drainage
• Veins arteries sarcomas, renal cell
  carcinoma, hepatocellular carcinoma
• Implantation open field, ovarian carcinomas,
  appendix pseudomyxoma peritonei

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Staging of Malignant Neoplasms
Stage Definition
Tis/T0 In situ, non-invasive (confined to epithelium)
T1 Small, minimally invasive within primary organ site
T2 Larger, more invasive within the primary organ site
T3 Larger and/or invasive beyond margins of primary organ site
T4 Very large and/or very invasive, spread to adjacent organs
N0 No lymph node involvement
N1 Regional lymph node involvement
N2 Extensive regional lymph node involvement
N3 More distant lymph node involvement
M0 No distant metastases
M1 Distant metastases present
In the diagram above utilizing a lung carcinoma
as an example, the principles of staging are
illustrated
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Grading of Malignant Neoplasms
Grade Definition
I Well differentiated
II Moderately differentiated
III Poorly differentiated
IV Nearly anaplastic
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Neoplasia -

• Uncontrolled new growth by cells that are no
  longer under complete physiologic control
• Irreversible
• May be benign or malignant

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Lipoma - Of course, neoplasms can be benign as
well as malignant, though it is not always easy
to tell how a neoplasm will act. Here is a benign
lipoma on the serosal surface of the small
intestine. It has the characteristics of a benign
neoplasm it is well circumscribed, slow growing,
non-invasive, and closely resembles the tissue of
origin (fat).
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Lipoma - At low power magnification, a lipoma of
the stomach is seen to be well demarcated from
the mucosa at the lower center-right. This
neoplasm is so well-differentiated that, except
for its appearance as a localized mass, it is
impossible to tell from normal adipose tissue.
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Lipoma - Here is the lipoma at high
magnification. This is a good example of how a
benign neoplasm mimics the tissue of origin.
These neoplastic adipocytes are indistinguishable
from normal adipocytes.
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Liposarcoma - This large mass lesion is a
liposarcoma. Common sites are the retroperitoneum
and thigh, and they occur in middle aged to older
adults. This one is yellowish, like adipose
tissue, and is well-differentiated. Though
indolent, it continues growing to reach a large
size, and following excision, it has a tendency
to recur.
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Liposarcoma - This liposarcoma has enough
differentiation to determine the cell of origin
(adipocyte), but there is still significant
pleomorphism of these neoplastic cells
(lipoblasts).
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Liposarcoma - At high magnification, large
bizarre lipoblasts are seen in this liposarcoma.
Sarcomas are best treated surgically, because
most respond poorly to chemotherapy or radiation.
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The first step toward epithelial neoplasia is
cellular transformation
Traditionally, two forms of cellular
transformation have been recognized that are
potentially reversible, but may be steps toward a
neoplasm. These are

• Metaplasia the exchange of normal epithelium for
  another type of epithelium. Metaplasia is
  reversible when the stimulus for it is taken
  away.
• Dysplasia a disordered growth and maturation of
  an epithelium, which is still reversible if the
  factors driving it are eliminated.

However, Hyperplasia an increase in the number
of phenotypically normal cells, may also reflect
an early stage of transformation.
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Metaplasia - The chronic irritation from
cigarette smoke has led to an exchanging of one
type of epithelium (the normal respiratory
epithelium at the right) for another (the more
resilient squamous epithelium at the left). Thus,
there is metaplasia of normal respiratory
laryngeal epithelium to squamous epithelium in
response to chronic irritation of smoking.
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Dysplasia

• disordered growth
• Loss in uniformity of the individual cells
• Loss of architectural orientation
• Pleomorphism
• Hyperchromatic
• Increased mitoses (normal)

Carcinoma in situ

• Dysplastic changes involve entire thickness of
  epithelium
• If left untreated, will progress to invasive
  cancer

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Dysplasia - This is the next step toward
neoplasia. Here, there is normal cervical
squamous epithelium at the left, but dysplastic
squamous epithelium at the right. Dysplasia is a
disorderly growth of epithelium, but still
confined to the epithelium. Dysplasia is still
reversible.
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Dysplasia - When the entire epithelium is
dysplastic and no normal epithelial cells are
present, then the process has gone beyond
dysplasia and is now neoplasia. If the basement
membrane is still intact, as shown here, then the
process is called "carcinoma in situ" because the
carcinoma is still confined to the epithelium.
Neoplastic epithelium is termed carcinoma.
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Carcinoma in situ
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Cervical Cancer neoplastic epithelium has
created a gross mass (tumor) and invaded
underlying tissue.
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Cervical Cancer This is the microscopic
appearance of neoplasia, or uncontrolled new
growth. Here, the neoplasm is infiltrating into
the underlying cervical stroma.
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Squamous Cancer - This is a squamous cell
carcinoma. Note the disorderly growth of the
squamous epithelial cells in these large nests
with pink keratin in the centers. Neoplasms may
retain characteristics of their cell of origin.
Benign neoplasms mimic the cell of origin very
well, but malignant neoplasms less so.
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Adenomatous polyps - Multiple adenomatous polyps
(tubulovillous adenomas) of the cecum are seen
here in a case of familial adenomatous polyposis,
a genetic syndrome in which an abnormal genetic
mutation leads to development of multiple
neoplasms in the colon.
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Differentiation - The concept of differentiation
is demonstrated by this small adenomatous polyp
(tubular adenoma) of the colon. Note the
difference in staining quality between the
epithelial cells of the adenoma at the top and
the normal glandular epithelium of the colonic
mucosa below.
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Adenocarcinoma - micro - The infiltrating glands
of this colonic adenocarcinoma demonstrate less
differentiation than the adenomatous polyp,
although they still resemble glands. In general,
less differentiation of a neoplasm means a
greater likelihood of malignant behavior. This is
the basis for grading. The higher the grade, the
more aggressive the malignant neoplasm. Benign
neoplasms are not graded.
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Prostate Gland - The normal appearance of
prostate is shown at high magnification. Note the
small pink laminated concretion (these are
corpora amylacea) in the gland lumen to the left
of center. Note the infoldings of the columnar
epithelium.
Prostate Gland - This is the gross appearance of
nodular prostatic hyperplasia (benign prostatic
hyperplasia, or BPH). The normal prostate is 3 to
4 cm in cross section, by comparison
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Prostatic Adenocarcinoma - At low magnification,
a needle biopsy of prostate is seen. The biopsy
is filled with back-to-back glands with nuclei
demonstrating hyperchromatism and pleomorphism.
This is adenocarcinoma of prostate.
Prostatic Adenocarcinoma - The gross appearance
of adenocarcinoma of the prostate is shown here
in cross section. The entire prostate is
involved. The yellowish nodules represent larger
foci of carcinoma.
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Lung Cancer - Malignant neoplasms are also
characterized by their tendency to invade
surrounding tissues. Here, the tan tissue of a
lung cancer is seen to be spreading along the
bronchi into the surrounding lung. The dark round
areas are lymph nodes also involved by the
neoplasm.
Tumor Invasion
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Lung Cancer - This is a squamous cell carcinoma
of the lung. It is a bulky mass that extends into
surrounding lung parenchyma.
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Breast Cancer - 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 is also focal
dystrophic calcification leading to the gritty
areas.
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Breast Cancer - At high magnification, the
infiltrating ductal carcinoma of breast has
pleomorphic cells infiltrating through the
stroma. Note the abundant pink collagen bands
from desmoplasia, making the tumor feel firmer
than normal breast tissue on palpation.
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Perineural Invasion - Branches of peripheral
nerve are invaded by nests of malignant cells.
This is termed perineural invasion. This is often
the reason why pain associated with cancers is
unrelenting.
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Metastases

• A primary neoplasm is more likely to appear
  within an organ as a solitary mass.
• The presence of metastases are the best
  indication that a neoplasm is malignant. The
  original clone of cells that developed into a
  neoplasm may not have had the ability to
  metastasize, but continued proliferation of the
  neoplastic cells and acquisition of more genetic
  mutations within the neoplastic cells can give
  them the ability to metastasize.

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Peritoneal Metastases - Neoplasms can spread by
seeding within body cavities such as the pleural
cavity or peritoneal cavity. This pattern of
spread is more typical for carcinomas than other
neoplasms. Note the multitude of small tan tumor
nodules seen over the peritoneal surface of the
mesentery shown here.
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Metastatic Carcinoma within Vessel - Both
lymphatic and hematogenous spread of malignant
neoplasms is possible to distant sites. Here, a
breast carcinoma has spread to a lymphatic within
the lung.
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Metastatic Breast Cancer to Lung Pleura - Here is
microscopic evidence of the spread of a carcinoma
via body cavities. A focus of metastatic breast
carcinoma is present along the pleura overlying
the lung.
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Sarcoma - This large fleshy mass arose in the
retroperitoneum and is an example of a sarcoma.
Sarcomas arise within mesenchymal tissues. This
one happened to be a "malignant fibrous
histiocytoma" which is a wastebasket term for
sarcomas that do not resemble mesenchymal cells
such as striated muscle (rhabdomyosarcoma),
smooth muscle (leiomyosarcoma), fat
(liposarcoma), blood vessels (angiosarcoma), bone
(osteosarcoma), or cartilage (chondrosarcoma).
Sarcomas tend to be big and bad.
Examples of Non Epithelial Cancers
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Sarcoma - Sarcomas tend to have a spindle cell
pattern. Note that some of these neoplastic cells
are much larger than others, and thus very
pleomorphic.
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Osteosarcoma - Here is an osteosarcoma of bone.
The large, bulky mass arises in the cortex of the
bone and extends outward.
Osteosarcoma - The osteosarcoma is composed of
spindle cells. The pink osteoid formation seen
here is consistent with differentiation that
suggests osteosarcoma
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Summary

• There is increasing emphasis from funding
  agencies for investigators performing cancer
  research to demonstrate a Translational
  component between their studies and the clinical
  condition.
• In order to make a VALID linkage between the
  investigators model system and the cancer being
  studied by the basic science investigator, an
  understanding of the histogenesis and
  histopathologic classification of the cancer they
  are studying is essential.