Neoplasia This is the next step toward neoplasia. Here, there is  - PowerPoint Presentation

Slide1

NeoplasiaSlide2

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.

dysplasia Slide3

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 cellsSlide4

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.Slide5

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.Slide6

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.Slide7

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.Slide8

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.Slide9

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

.Slide10

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.Slide11

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. Slide12

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.Slide13

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.Slide14

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.Slide15

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.Slide16

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 necrosisSlide17

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.Slide18

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.Slide19

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 carcinomacapillariesSlide20

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.Slide21

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.Slide22

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.Slide23

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 downwardSlide24

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.Slide25

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

.Slide26

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.Slide27

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. Slide28

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.Slide29

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. Slide30

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.Slide31

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 figureSlide32

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.Slide33

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.Slide34

The pediatric malignancies may include:

Childhood MalignancyLocation

Leukemia / lymphomaBlood, marrow, lymph nodes

Neuroblastoma

Adrenal, extra-adrenal gangliaMedulloblastomaCerebellumRetinoblastomaEye

Wilms tumorKidney

Ewing sarcomaBoneSlide35

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.Slide36

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.Slide37

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 marginsSlide38

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.Slide39

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.Slide40

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.

osteoidSlide41

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).Slide42

At high magnification

, large bizarre

lipoblasts

are seen in this

liposarcoma. Sarcomas are best treated surgically, because most respond poorly to chemotherapy or radiation.Slide43
Slide44

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.Slide45

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.Slide46

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.Slide47

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.StagingThe 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.Slide48

In the diagram below utilizing a lung carcinoma as an example, the principles of staging are illustrated:Slide49
Slide50

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).Slide51

In the diagram below utilizing an

adenocarcinoma as an example, the principles of grading are illustrated:Slide52
Slide53
Slide54

The End of the laboratory practice

2016