Neoplasia

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.

At high magnification, the normal

cervical squamous

epithelium at the left merges into

the dysplastic squamous

epithelium at the right in which

the cells are more disorderly and

have darker nuclei with more

irregular outlines.

dysplasi

a

Some epithelia are accessible enough, such as the cervix, that cancer

screening can be done by sampling some of the cells and sending them to

the laboratory.

Here is a cervical Pap smear in which dysplastic cells are present that

have much larger and darker nuclei than the normal squamous cells with

small nuclei and large amounts of cytoplasm.

dysplastic cells

normal squamous cells

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.

This is a neoplasm (uncontrolled new growth). Neoplastic cells are no

longer under complete physiologic control. Note the mass of abnormal

tissue on the surface of this cervix. The term "tumor" is often used

synonymously with neoplasm, but a "tumor" can mean any mass effect,

whether it is inflammatory, hemodynamic, or neoplastic in origin. Once a

neoplasm has started, it is not reversible.

This is the microscopic appearance of neoplasia, or uncontrolled new growth.

Here, the neoplasm is infiltrating into the underlying cervical stroma.

Of course, there can be carcinoma in situ in which a full-fledged neoplasm is

present, but has not yet invaded. Over time, neoplasms may acquire

characteristics that make them able to invade tissues, and this distinguishes them

as malignant.

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.

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).

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.

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.

Benign neoplasms can be multiple, as is

shown in this uterus opened anteriorly to

reveal Leiomyomas of varying size, but all

benign and well-circumscribed firm white

masses. Remember that the most common

neoplasm is a benign nevus (pigmented

mole) of the skin, and most people have

several. As a general rule, without

additional transforming influences, benign

neoplasms do not give rise to malignant

neoplasms.

The microscopic

appearance of a

leiomyoma indicates that

the cells do not vary greatly

in size and shape and

closely resemble normal

smooth muscle cells.

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. The genetic abnormalities

present in neoplasms can be inherited

or acquired.

This schwannoma was resected

from a nerve. This neoplasm arises

from the Schwann cells that

myelinate peripheral nerve fibers.

Note the circumscribed nature of

this benign neoplasm. Though

benign, this neoplasm could cause

dysfunction of the nerve by mass

effect.

The schwannoma is seen microscopically to be composed of

spindle cells (like most neoplasms of mesenchymal origin), but the

cells are fairly uniform and there is plenty of pink cytoplasm.

Here is a small, round fibroadenoma

of the breast, a benign neoplasm

most commonly diagnosed in

younger women of reproductive age.

The blue dye was injected during a

radiographic procedure to mark the

location of the neoplasm so the

surgeon could find and remove it.

Remember that the most

common neoplasm is a benign

nevus (pigmented mole) of the

skin, and most people have

several, as seen here over the

skin of the chest. As a general

rule, benign neoplasms do not

give rise to malignant neoplasms

unless a series of transforming

events occur.

Here is a small hepatic

adenoma, an uncommon benign

neoplasm, but one that shows

how well-demarcated a benign

neoplasm is. It also illustrates how

function of the normal tissue can

be maintained, because this

adenoma is making bile pigment,

giving it a green color with

formalin fixation.

In contrast, this hepatocellular

carcinoma is not as well

circumscribed (note the

infiltration of tumor off to the

lower right) nor as uniform in

consistency. It is also arising in

a cirrhotic (nodular) liver.

This renal cell carcinoma demonstrates

distortion and displacement of the renal

parenchyma by the tumor mass in the lower pole

of the kidney. This malignant neoplasm has a

variegated appearance on its cut surface, with

yellow to white to red to brown areas.

This excision of skin demonstrates a malignant melanoma, which is much

larger and more irregular than a benign nevus. From the history provided by

the patient, we know that it grew quickly in size in 3 months. In contrast, a

benign nevus hardly seems to change at all over many years.

This is an example of metastases to the liver. Note that the tan-white masses are

multiple and irregularly sized. Like many large metastatic lesions, there is central

necrosis. 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.

central necrosis

Microscopically, metastatic

adenocarcinoma is seen in a

lymph node here. It is common

for carcinomas to metastasize

to lymph nodes. The first

nodes involved are those

receiving lymphatic drainage

from the site of the primary

neoplasm.

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.

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.

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.

In this small focus of metastatic carcinoma to the epicardium can be

seen a key feature of neoplasms--angiogenesis. Note the proliferation of

many small capillaries adjacent to the neoplastic cells. Neoplasms can

produce factors that promote vascular growth to provide them a vascular

supply and continued uncontrolled growth.

metastatic carcinoma

capillaries

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.

This is a squamous cell

carcinoma of the lung. It is a

bulky mass that extends into

surrounding lung parenchyma.

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.

Microscopically, the infiltrating ductal

carcinoma extends irregularly through

the tissue as cords and nests of

neoplastic cells with intervening

collagen. There is a

purplish microcalcification at the

lower center right. Neoplastic cells are

not as robust or as organized as

normal cells and are more likely to

undergo necrosis. Dystrophic

calcification can occur in these areas.

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.

Microscopically, invading adenocarcinoma can be seen here. Normal

gastric epithelium at the left merges with the carcinoma at the right, and

irregular neoplastic glands infiltrate downward into the submucosa.

Normal gastric epithelium

carcinoma

infiltrate downward

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.

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.

At high magnification, the normal colonic epithelium at the left contrasts with the

atypical epithelium of the adenomatous polyp (tubular adenoma) at the right.

Nuclei are darker and more irregularly sized and closer together in the

adenomatous polyp than in the normal mucosa. However, the overall difference

between them is not great, so this benign neoplasm mimics the normal tissue

quite well and this neoplasm is, therefore, well-differentiated.

It has areas that appear red because it is bleeding, and this led to a

positive occult blood in stool which was the screening method for detection.

Neoplasms may not maintain the structure of normal tissues, so there is

often irregular growth with necrosis and hemorrhage, particularly in larger

and more aggressive neoplasms.

This is the view on colonoscopy of

an adenocarcinoma of the colon.

This is a bulky mass which

spreads over the colonic mucosal

surface.

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.

Immunohistochemical staining is helpful to determine the cell type of a

neoplasm when the degree of differentiation, or morphology alone, does

not allow an exact classification. Traditionally, the tumor cell morphology

on light microscopy has been used to predict tumor behavior and

prognosis. Further developments in molecular biology provide additional

methods to determine tumor cell characteristics that can indicate how the

tumor will act, how it can be treated, and what the prognosis for the

patient may be.

This gastric

adenocarcinoma is

positive for cytokeratin,

with brown-red reaction

product in the neoplastic

cell cytoplasm, with

immunohistochemical

staining. This is a typical

staining reaction for

carcinomas and helps to

distinguish carcinomas

from sarcomas and

lymphomas.

The normal squamous

epithelium at the left merges

into the squamous cell

carcinoma at the right, which

is infiltrating downward. The

neoplastic squamous cells are

still similar to the normal

squamous cells, but are less

orderly. This is a well-

differentiated squamous cell

carcinoma.

Here is a moderately

differentiated squamous cell

carcinoma in which some, but not

all, of the neoplastic cells in nests

have pink cytoplasmic keratin.

In general, neoplasms with less

differentiation are more

aggressive, growing more quickly,

invading, or metastasizing.

At high magnification, this squamous cell carcinoma demonstrates enough

differentiation to tell that the cells are of squamous origin. The cells are pink and

polygonal in shape with intercellular bridges (seen as desmosomes or "tight

junctions" by electron microscopy). However, the neoplastic cells show

pleomorphism, with hyperchromatic nuclei. A mitotic figure is present near the

center.

intercellular bridges

mitotic figure

This neoplasm is so poorly differentiated that it is difficult to tell what

the cell of origin is. It is probably a carcinoma because of the

polygonal nature of the cells. Note that nucleoli are numerous and

large in this neoplasm. Neoplasms with no differentiation are said to

be anaplastic.

Neoplasia in the pediatric age range is not common.

Childhood malignancies are rare, but those that occur often have the

appearance of primitive "small round blue cell tumors" such as the

neuroblastoma seen here.

The pediatric malignancies may include:

Childhood Malignancy Location

Leukemia / lymphoma Blood, marrow, lymph nodes

Neuroblastoma Adrenal, extra-adrenal ganglia

Medulloblastoma Cerebellum

Retinoblastoma Eye

Wilms tumor Kidney

Ewing sarcoma Bone

A mitotic figure is seen here in

the center, surrounded by cells of

a poorly differentiated squamous

cell Ca., with pleomorphic cells

that have minimal pink

keratinization in their cytoplasm.

In general, mitoses are more

likely to be seen in malignant

neoplasms. Remember, though,

that normal cells can be actively

dividing in many tissues of the

body, including skin, bone

marrow, gonads, and

gastrointestinal tract.

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.

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.

Here is a fleshy mass arising in the soft tissues of the lower leg.

The tibia and the fibula are seen in cross section. This neoplasm

proved to be a malignant fibrous histiocytoma. Sarcomas tend to invade

locally, as can be seen here by the ill-defined margins of the mass.

fleshy mass

fibula

tibia

ill-defined margins

Sarcomas tend to have

a spindle cell pattern.

Note that some of these

neoplastic cells are

much larger than others,

and thus very

pleomorphic.

This sarcoma seen at medium

magnification is composed of

pleomorphic cells that vary

markedly in size and shape.

The cell of origin of sarcomas is

often difficult to determine

because of their tendency to be

poorly differentiated or even

anaplastic.

This sarcoma has many

mitoses.

A very large abnormal

mitotic figure is seen at

the right.

This sarcoma is positive for

vimentin by

immunohistochemical staining.

The positive neoplastic cells are

invading into normal large round

pale pink muscle fibers (which are

not staining for vimentin) at the

left. This is a typical

immunohistochemical staining

reaction for sarcomas.

Here is an osteosarcoma of

bone. The large, bulky mass

arises in the cortex of the bone

and extends outward.

The osteosarcoma is

composed of spindle cells.

The pink osteoid formation

seen here is consistent

with differentiation that

suggests osteosarcoma.

osteoid

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.

This liposarcoma has

enough differentiation to

determine the cell of origin

(adipocyte), but there is still

significant pleomorphism

of these neoplastic cells

(lipoblasts).

At high magnification, large bizarre lipoblasts are seen in this

liposarcoma. Sarcomas are best treated surgically, because most

respond poorly to chemotherapy or radiation.

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 substances by the neoplastic cells, but a

variety of effects are possible.

Sometimes the appearance of the paraneoplastic

syndrome may precede diagnosis of the neoplasm and

may give a clue to its presence.

Here is an example of c-erb-B2 (HER2)

positivity of the neoplastic cells in a

breast carcinoma. This oncogene acts

via reduplication of the normal proto-

oncogene hundreds of times, leading to

production of a protein product that

drives unregulated cell growth. This is

detected here by immunohistochemical

staining, with the brown reaction

product concentrated in a

perimembranous pattern around the

neoplastic cells.

This is an example of c-myc positivity

in a carcinoma. This oncogene acts via

DNA transcriptional activation. The

nuclear binding is demonstrated here

by immunohistochemical staining in

which the brown reaction product is

localized to the neoplastic cell nuclei.

This is an example of bcl-2 positivity in a lymphoma. In this

case, the overexpression of this oncogene results in an

inhibition of apoptosis, and increased numbers of lymphocytes.

The immunohistochemical staining shown here highlights these

neoplastic lymphocytes within lymphoid follicles and interfollicular

areas.

Staging and Grading

Staging and grading schema have been devised for malignant

neoplasms, because the stage and/or grade may determine the

treatment and the prognosis. In general, the higher the stage, the larger

a neoplasm is and the farther it has likely spread.

Staging

The most common systems for staging employs the TNM classification.

A "T" score is based upon the size and/or extent of invasion. The "N"

score indicates the extent of lymph node involvement. The "M" score

indicates whether distant metastases are present. Staging forms have

been devised for each organ or site that a malignant neoplasm can

occur, and the criteria are listed on the form. The forms are filled out

using clinical and pathologic criteria and aid in determination of therapy,

estimating the prognosis, and developing statistics useful for determining

outcomes.

In the diagram below utilizing a lung carcinoma as an

example, the principles of staging are illustrated:

Grading

Grading schema are based upon the microscopic

appearance of a neoplasm with H&E staining. In general, a

higher grade means that there is a lesser degree of

differentiation and the worse the biologic behavior of a

malignant neoplasm will be.

A well-differentiated neoplasm is composed of cells that

closely resemble the cell of origin, while poorly

differentiated neoplasms have cells that are difficult to

recognize as to their cell of origin. Grading schema have

been devised for many types of neoplasms, mainly

carcinomas. Most grading systems have three or four

grades (designated with numbers or roman numerals).

In the diagram below utilizing an adenocarcinoma as an

example, the principles of grading are illustrated:

The End of the

laboratory

practice

2016