Chapter 7- Neoplasia: Characteristics of Benign & Malignant Neoplasms Flashcards
1
Q
Although an innocent face may mask an ugly nature, in
general, benign and malignant tumors can be distinguished on the basis of differentiation and
anaplasia, rate of growth, local invasion, and metastasis
A
2
Q
What is differentiation?
A
Differentiation refers to the extent to which neoplastic parenchymal cells resemble the
corresponding normal parenchymal cells, both morphologically and functionally.
3
Q
What is anaplasia?
A
- *lack of**
- *differentiation** is called anaplasia
4
Q
In general, benign tumors are well differentiated.
T or F
A
True
5
Q
The neoplastic cell in a benign adipocyte tumor—a lipoma—so closely resembles the
normal cellthatit may be impossible to recognize it as a tumor by microscopic examination of
individual cells.
Only the growth of these cells into a discrete mass discloses the neoplastic
nature of the lesion.
One may get so close to the tree that one loses sight of the forest.
A
6
Q
In welldifferentiated
- *benign tumors**, mitoses are extremely scant in number and **are of normal
configuration. **
T or F
A
T
7
Q
A
FIGURE 7-4 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.
8
Q
A
FIGURE 7-5 Benign tumor (adenoma) of the thyroid. Note the normal-looking (welldifferentiated),
colloid-filled thyroid follicles
9
Q
Malignant neoplasms are characterized by a wide range of parenchymal cell differentiation,
from surprisingly well differentiated ( Fig. 7-6 ) to completely undifferentiated
A
10
Q
Certain welldifferentiated
adenocarcinomas of the thyroid, for example, may form normal-appearing
follicles, and some squamous cell carcinomas contain cells that do not differ cytologically from
normal squamous epithelial cells ( Fig. 7-7 ).
Thus, the morphologic diagnosis of malignancy in
well-differentiated tumors may sometimes be quite difficult.
T or F
A
T
11
Q
What is moderately differentiated?
A
In between the two extremes lie
tumors that are loosely referred to as moderately well differentiated
12
Q
A
FIGURE 7-6 Malignant tumor (adenocarcinoma) of the colon. Note that compared with the
well-formed and normal-looking glands characteristic of a benign tumor (see Fig. 7-5 ), 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.
13
Q
A
FIGURE 7-7 Well-differentiated squamous cell carcinoma of the skin. The tumor cells are strikingly similar to normal squamous epithelial cells, with intercellular bridges and nests of keratin pearls (arrow).
14
Q
Malignant neoplasms that are composed of poorly differentiated cells are said to be _____________
A
anaplastic.
15
Q
What is the hallmark of malignancy?
A
Lack of differentiation, or anaplasia, is considered a hallmark of malignancy
16
Q
What does anaplasis literally means?
A
The term
anaplasia literally means “to form backward,” implying a reversal of differentiation to a more
primitive level.
17
Q
It is believed, however, that most cancers do not represent “reverse
differentiation” of mature normal cellsbut, in fact,arise from less mature cells with “stem-celllike”
properties, such as tissue stem cells ( Chapter 3 ).
T or F
A
T
18
Q
In well-differentiated tumors ( Fig. 7-7 ),
daughter cells derived from these “cancer stem cells” retain the capacity for differentiation,
whereas in poorly differentiated tumors that capacity is lost.
T or F
A
T
19
Q
Lack of differentiation, or anaplasia, is often associated with many other morphologic changes
A
- Pleomorphism
- Abnormal nuclear morphology
- Mitoses
- Loss of polarity
- Other changes
- tumor giant cells
- necrosis.
20
Q
What is pleomorphism?
A
Pleomorphism. Both the cells and the nuclei characteristically display
pleomorphism—variation in size and shape ( Fig. 7-8 ). Thus, cells within the same
tumor are not uniform, but range from large cells, many times larger than their
neighbors, to extremely small and primitive appearing
21
Q
A
FIGURE 7-8 Anaplastic tumor of the skeletal muscle (rhabdomyosarcoma). Note the marked
cellular and nuclear pleomorphism, hyperchromatic nuclei, and tumor giant cells
22
Q
Abnormal nuclear morphology .
A
Characteristically the nuclei contain abundant chromatin and are dark staining (hyperchromatic).
The nuclei are disproportionately large for the
cell,and thenuclear-to-cytoplasm ratio may approach 1 : 1instead of the normal _1 : 4
or 1 : 6._
The nuclear shape is variable and often irregular, and the chromatin is often
coarsely clumpedanddistributed along the nuclear membrane.
Large nucleoli are
usually present in these nuclei.
23
Q
What is the normal nuclear: cytoplasm ?
A
normal 1 : 4
or 1 : 6.
24
Q
Mitoses.
As compared with benign tumors and some well-differentiated malignant
neoplasms, undifferentiated tumors usually possess large numbers of mitoses, reflecting the higher proliferative activity of the parenchymal cells.
T or F
A
T
25
The presence of mitoses,
however, **does not necessarily indicate that a tumor is malignant** or t**hat the tissue is
neoplastic.**
T or F
T
26
Many normal tissues exhibiting rapid turnover, such as **:**
**bone marrow**, have
**numerous mitoses**, and **non-neoplastic proliferations such as hyperplasias contain many
cells in mitosis.**
27
With regards to mitoses, the more important as a morphologic feature of malignancy are
**atypical,**
**bizarre mitotic figures, sometimes producing tripolar**, **quadripolar, or multipolar spindles** (
Fig. 7-9 ).
28
FIGURE 7-9 Anaplastic tumor showing cellular and nuclear variation in size and shape. The
prominent cell in the center field has an abnormal tripolar spindle.
29
What happens in loss of polarity .?
In addition to the cytologic abnormalities, the **orientation of anaplastic**
**cells is markedly disturbed** (i.e., they lose normal polarity).
* *Sheets or large masses** of
* *tumor cells grow in an anarchic, disorganized fashion.**
30
Another feature of anaplasia is the formation of describe tumor giant cell?
tumor giant cells, some
possessing only a **single huge polymorphic nucleus** and others having two or more
large, hyperchromatic nuclei ( Fig. 7-8 ).
These giant cells are not to be confused with
inflammatory Langhans or foreign body giant cells, which are derived from macrophages
and contain many small, normal-appearing nuclei.
31
Although growing tumor cells
obviously require a blood supply, **often the vascular stroma is scant, and in many
anaplastic tumors, large central areas undergo ischemic necrosis.**
**T or F**
T
32
define METAPLASIA.
Metaplasia is **defined as the replacement of one type of cell with another type .**
Metaplasia 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 example,
gastroesophageal reflux damages the squamous epithelium of the esophagus, leading to its
replacement by glandular (gastric or intestinal) epithelium, more suited to the acidic
environment.
33
Define Dysplasia.
Dysplasia is a term that **literally means disordered growth.**
Dysplasia **often occurs**
**in metaplastic epithelium**, but **not all metaplastic epithelium is also dysplastic**.
Dysplasia is
encountered principally in **epithelia**, and it is **characterized by a constellation of changes** that
include a **loss in the uniformity of the individual cells** as well as a **loss in their architectural**
**orientation**.
Dysplastic cells **exhibit considerable pleomorphism** and **often contain large**
**hyperchromatic nucle**i with a **high nuclearto-cytoplasmic ratio.** The architecture of the tissue
may be disorderly.
For example, in **squamous epithelium** the usual progressive maturation of tall
cells in the basal layer to flattened squames on the surface may be lost and **replaced by a
scrambling of dark basal-appearing cells** throughout the epithelium.
**Mitotic figures are more
abundant than usual, a**lthough almost invariably they**have a normal configuration**.
Frequently,
however, the **mitoses appear in abnormal locations within the epithelium**.
For example, in
**dysplastic stratified squamous epithelium,** mitoses are not confined to the basal layers but
instead may appear at all levels, including surface cells.
34
Dysplasia can be into:
* carcinoma in situ
* invasive
35
What is carcinoma in situ?
When **dysplastic changes are marked**
and **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**
36
Once the tumor **cells breach the basement membrane,** the tumor is said to
be\_\_\_\_\_\_\_-
invasive.
37
Dysplastic changes are often found where?
Dysplastic changes are often found **adjacent to foci of invasive carcinoma,** and in
some situations, such as in **long-term cigarette smokers and persons with Barrett esophagus,**
**severe epithelial dysplasia frequently antedates the appearance of cancer**
38
Dysplasia always progress to cancer.
T or F
FALSE
dysplasia
**does not necessarily progress to cancer**
39
When can dysplasia be reversible?
**Mild to moderate changes that do not involve the entire thickness of epithelium may be reversible**, and with **removal of the inciting causes** the
epithelium may revert to normal.
Even carcinoma in situ may take years to become invasive.
40
FIGURE 7-10 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. The basement membrane is not seen in this section.
41
As you might presume, the **better the differentiation of** the **transformed cell,** the **more
completely it retains the functional capabilities** found in its normal counterparts.
T or F
T
Thus**, benign**
**neoplasms and well-differentiated carcinomas of endocrine glands frequently elaborate the
hormones characteristic of their origin.**
Increased levels of these hormones in the blood are
used clinically to detect and follow such tumors.
**Welldifferentiated squamous cell carcinomas** of
the **epidermis elaborate keratin,** just as well-differentiated hepatocellular carcinomas elaborate
bile.
42
**Highly anaplastic undifferentiated cells,** whatever their tissue of origin, **lose their
resemblance to the normal cells from which they have arisen.**
T or F
T
43
In some instances, new and
unanticipated functions emerge.
Some tumors **may elaborate fetal proteins not produced by
comparable cells in the adult.**
**T or F**
T
44
Carcinomas of nonendocrine origin may produce a variety of
hormones.
For example, bronchogenic carcinomas may produce corticotropin, parathyroid-like
hormone, insulin, and glucagon, as well as others.
45
Despite exceptions, the **more rapidly growing
and the more anaplastic a tumor,**the**less likely it will have specialized functional activity.**
T or F
T
The
cells in benign tumors are almost always well differentiated and resemble their normal cells of
origin; the cells in cancer are more or less differentiated, but some derangement of
differentiation is always present.
46
A fundamental issue in tumor biology is to u**nderstand the factors that affect the growth rates** of
**tumors and their influence on clinical outcome and therapeutic responses.**
One can begin the
consideration of tumor cell kinetics by asking the question:
**How long does it take to produce a
clinically overt tumor mass**?
It is a reasonable estimate the original transformed cell
(approximately **10 μm in diameter) must undergo at least 30 population doublings** to produce
10^ 9 cells (weighing approximately 1 gm), which is the smallest clinically detectable mass.
In
contrast, only 10 additional doubling cycles are required to produce a tumor containing 10 ^12
cells (weighing -1kg), which is usually the maximal size compatible with life. These are minimal
estimates, based on the assumption that all descendants of the transformed cell retain the
ability to divide and that there is no loss of cells from the replicative pool. **This concept of tumor
as a “pathologic dynamo” is *_not entirely correct_*, as we discuss subsequently**
***Nevertheless, this
calculation highlights an extremely important concept about tumor growth: By the time a solid
tumor is clinically detected, it has already completed a major portion of its life span. This is a major impediment in the treatment of cancer and*underscores the need to develop diagnostic
markers to detect early cancers.**
47
The **rate of growth of a tumor** is determined by **three main factors**:
* the **doubling time** of tumor cells,
* the **fraction of tumor cells that are in the replicative pool,**
* and th**e rate at which cells are shed or die.**
48
Because cell cycle controls are deranged in most tumors, tumor cells can be
triggered to cycle without the usual restraints.
The dividing cells, however, do not necessarily
complete the cell cycle more rapidly than do normal cells. In reality, total cell cycle time for many
tumors is equal to or longer than that of corresponding normal cells.
**T or F**
**T**
Thus, it can be safely
concluded that growth of tumors is not commonly associated with a shortening of cell cycle time.
49
What is growth fraction?
The proportion of cells within the tumor population that are in the proliferative pool is referred to
as the growth fraction.
50
Clinical and experimental studies suggest that during the early, submicroscopic phase of tumor growth, the vast majority of transformed cells are in the
**proliferative pool** ( Fig. 7-11 ).
As tumors continue to grow, cells leave the proliferative pool in
ever-increasing numbers as a **result of shedding, lack of nutrients, necrosis, apoptosis,
differentiation, and reversion to the nonproliferative phase of the cell cycle (G0).**
Thus, by the
**time a tumor is clinically detectable**, **most cells are not in the replicative pool. Even in some
rapidly growing tumors, the growth fraction is only about 20% or less.**
51
FIGURE 7-11 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.
52
Ultimately the **progressive growth of tumors** and **the rate at which they grow are determined by
an excess of cell production over cell loss**
53
In some tumors, especially those with a relatively
high growth fraction, the **imbalance is large,** resulting in **more rapid growth than in those in**
which cell production exceeds cell loss by only a small margin
54
Give example of cancer with relatively high growth fraction.
Some leukemias and lymphomas
and certain lung cancers (i.e., small-cell carcinoma) have a relatively high growth fraction, and
their clinical course is rapid. By comparison, many common tumors, such as cancers of the colon and breast, have low growth fractions, and cell production exceeds cell loss by only about
10%; they tend to grow at a much slower pace.
55
Give example of cancer with low growth fraction.
By comparison, **many common tumors**, such as **cancers of the colon and breast**, have low growth fractions, and **cell production exceeds cell loss by only about**
**10%;** they tend to grow at a much slower pace.
56
Several important conceptual and practical lessons can be learned from studies of tumor cell
kinetics:
* Fast-growing tumors may have a high cell turnover , implying that rates of both proliferation and apoptosis are high. Obviously if the tumor is to grow, the rate of proliferation must exceed that of cell death.
* The growth fraction of tumor cells has a profound effect on their susceptibility to cancer chemotherapy. Because most anticancer agents act on cells that are in cycle, it is not difficult to imagine that a tumor that contains 5% of all cells in the replicative pool will be
slow growing but relatively refractory to treatment with drugs that kill dividing cells. One
strategy used in the treatment of tumors with low growth fraction (e.g., cancer of colon
and breast) is first to shift tumor cells from G0 into the cell cycle. This can be
accomplished by debulking the tumor with surgery or radiation.
The surviving tumor cells
tend to enter the cell cycle and thus become susceptible to drug therapy. Such
considerations form the basis of combined-modality treatment.
**Some aggressive tumors**
**(such as certain lymphomas and leukemias)** that **contain a large pool of dividing cells**
literally melt away with chemotherapy and may even be cured.
57
We can now return to the question posed earlier:
How long does it take for one transformed cell
to produce a clinically detectable tumor containing 10 ^9 cells?
If **every one of the daughter cell**s
**remained in cell cycle** and **no cells were shed or lost,** we could anticipate the answer to be **90
days**(**30 population doublings**, with a cell cycle time**of 3 days**).
In reality, the **latent period
before which a tumor becomes clinically detectable is unpredictable**but**typically much longer
than 90 days,****as long as many years for most solid**tumors,**emphasizing once again that
human cancers are diagnosed only after they are fairly advanced in their life cycle.**
After they
become clinically detectable, the average volume-doubling time for such common killers as
**cancer of the lung and colon is about 2 to 3 months.** As might be anticipated from the
discussion of the variables that affect growth rate, however, the range of doubling time values is
extremely broad, varying from less than 1 month for some childhood cancers to more than 1
year for certain salivary gland tumors. Cancer is indeed an unpredictable group of disorders.
58
In general, the growth rate of tumors correlates with their **level of differentiation,** and **thus most
malignant tumors****grow more rapidly than do benign lesions.**
There are, however, many
exceptions to such an oversimplification.
Some benign tumors have a higher growth rate than
malignant tumors.
Moreover, the rate of growth of benign as well as malignant neoplasms may
not be constant over time.
59
What factors may affect the tumor's growth?
Factors such as **hormonal stimulation, adequacy of blood supply,**
and unknown influences may affect their growth.
60
For example, **the growth of uterine leiomyomas**
(**benign smooth muscle tumors)** **may change over time** because of **hormonal variations**.
Not
infrequently, repeated clinical examination of women bearing such neoplasms over the span of
decades discloses no significant increase in size.
61
**After menopause the neoplasms may atrophy**
and **may be replaced largely by collagenous, sometimes calcified, tissue.**
T or F
T
62
During pregnancy
**leiomyomas** frequently enter a growth spurt. Such changes reflect the responsiveness of the
tumor cells to circulating levels of steroid hormones, particularly estrogens.
63
Cancers show a
wide range of growth. Some malignant tumors grow **slowly for years and then suddenly increase
in size, explosively disseminating to cause death within a few months of discovery.**
It is possible
that such behavior results from the emergence of an **aggressive subclone of transformed cells.**
At the other extreme are malignant neoplasms that grow more slowly than do benign tumors
and may even enter periods of dormancy lasting for years.
On occasion, cancers decrease in
size and even spontaneously disappear, but such “miracles” are rare enough that they remain
intriguing curiosities.
64
CANCER STEM CELLS AND CANCER CELL LINEAGES
The continued growth and maintenance of many tissues that contain short-lived cells, such as
the formed elements of the blood and the epithelial cells of the gastrointestinal tract and skin, require a resident population of tissue stem cells that are long-lived and capable of selfrenewal.
Tissue stem cells are rare and exist in a niche created by support cells, which produce
paracrine factors that sustain the stem cell. [4]
Recall from Chapter 3 that **tissue stem cells
divide asymmetrically to produce two types of daughter cells**—*those with limited proliferative
potential, which undergo terminal differentiation*and *die, and those that retain stem cell
potential*
65
**CANCER STEM CELLS AND CANCER CELL LINEAGES**
**Cancers are immortal** and **have limitless proliferative** capacity, **indicating that like normal
tissues**,**they also must contain cells with “stemlike” properties**. [5,] [6]
The concept of cancer
stem cells has several important implications.
Most notably, **if cancer stem cells are essential for
tumor persistence,**it follows that these cells must be**eliminated to cure the affected patient**.
It is
hypothesized that like normal stem cells**, cancer stem cells have a high intrinsic resistance to
conventional therapies**,**because of their low rate of cell division and the expression of factors,**
**such as multiple drug resistance-1 (MDR1), that counteract the effects of chemotherapeutic
drugs.**
Thus, the limited success of current therapies may in part be explained by their
failure to kill the malignant stem cells that lie at the root of cancer. Cancer stem cells could arise
from normal tissue stem cells or from more differentiated cells that, as part of the transformation
process, acquire the property of self-renewal.
For example, chronic myelogenous leukemia (CML)
originates from the malignant counterpart of a normal hematopoietic stem cell, whereas certain
acute myeloid leukemias (AMLs) are derived from more differentiated myeloid precursors that
acquire an abnormal capacity for self-renewal. The identification of “leukemia stem cells” has
spurred the search for cancer stem cells in solid tumors. Most such studies have focused on
the identification of tumor-initiating cells (T-ICs), which are defined as cells that allow a human
tumor to grow and maintain itself indefinitely when transplanted into an immunodeficient mouse.
T-ICs have been identified in several human tumors, including breast carcinoma, glioblastoma
multiforme, colon cancer, and AML, [5] [6] [7] [8] in which they constitute 0.1% to 2% of the total
cellularity.
66
More recent studies have shown that in some cancers, **T-ICs ( tumor initiating cancers) are very common,** representing
**25% of the total cellularity**. [9]
Thus some tumors may have a small number of T-ICs that then
**“differentiate” to form the bulk of the tumor**, while **other tumors may be primarily composed of TICs.**
In the future, it will be important to identify the tumorigenic population in each tumor to
direct therapy against tumor stem cells. An emerging theme is that the genes and pathways that
maintain cancer stem cells are the same as those that regulate normal tissue stem cell
homeostasis.
Examples include BMI1, a component of the polycomb chromatin-remodeling
complex that promotes “stem-ness” in both normal hematopoietic and leukemic stem cells; and
the **WNT pathway, a key regulator of normal colonic crypt stem cells that has been implicated in**
the **maintenance of colonic adenocarcinoma** “stem cells.” [9,] [10]
Important remaining
questions revolve around whether T-ICs are an accurate measure of cancer stem cells, if
cancer stem cells remain dependent on the “niche” that supports normal stem cells, and if it will
be possible to selectively target cancer cell “stem-ness” factors
67
**Nearly all 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,** as do
malignant tumors.
T or F
T
68
Because benign tumors **grow and expand slowly**, **they usually develop a rim of compressed connective** tissue, sometimes called a **fibrous capsule,** **which separates them from the host tissue**.
T or F
T
This **capsule is derived largely from the extracellular matrix** of the **native tissue**
**due to atrophy of normal parenchymal cells** under the **pressure of an expanding tumor.**
69
Such
**encapsulation does not prevent tumor growth,** but it **keeps the benign neoplasm as a discrete,
readily palpable, and easily movable mass that ca**n be**surgically enucleated**
**T or F**
T
70
Although a **well-defined cleavage plane exists around most benign tumors,** in some it is
lacking.
Give example
, hemangiomas (neoplasms composed of tangled blood vessels) are often unencapsulated and may appear to permeate the site in which they arise (commonly the dermis of the skin).
71
FIGURE 7-12 Fibroadenoma of the breast. The tan-colored, encapsulated small tumor is
sharply demarcated from the whiter breast tissue.
72
```
FIGURE 7-13 Microscopic view of fibroadenoma of the breast seen in Figure 7-12 . The
fibrous capsule (right) delimits the tumor from the surrounding tissue.
```
73
The **growth of cancers** is accompanied by \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
progressive infiltration, invasion, and destruction of
the surrounding tissue.
74
In general, malignant tumors are\_\_\_\_\_\_\_\_\_\_\_ ( Figs. 7-14 and 7-15 ).
poorly demarcated from the
surrounding normal tissue, and a well-defined cleavage plane is lacking
75
* *Slowly expanding malignant tumors**, however, **may develop an apparently enclosing fibrous**
* *capsule** and **may push along a broad front into adjacent normal structures.**
T or F
T
76
Histologic
examination of such pseudo-encapsulated masses **almost always shows \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_**
rows of cells
* *penetrating the margin** and **infiltrating the adjacent structures, a crablike pattern** of growth that
* *constitutes the popular image of cancer.**
77
FIGURE 7-14 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.
78
FIGURE 7-15 The microscopic view of the breast carcinoma seen in Figure 7-14 illustrates
the invasion of breast stroma and fat by nests and cords of tumor cells (compare with
fibroadenoma shown in Fig. 7-13 ). The absence of a well-defined capsule should be noted.
79
Most malignant tumors are **obviously invasive** and **can be expected to penetrate the wall of the
colon or uterus,**for example,**or fungate through the surface of the skin.**
**They recognize no
normal anatomic boundaries.**
**Such invasiveness makes their surgical resection difficult or impossible,** and **even if the tumor appears well circumscribed it is necessary to remove a
considerable margin** of apparently normal tissues adjacent to the infiltrative neoplasm
80
Next to
the development of metastases, __________ is the **most reliable feature that differentiates
malignant from benign tumors.**
invasiveness
81
What is carcinoma in situ?
We noted earlier that some cancers seem to evolve from a
**preinvasive stage referred** to as **carcinoma in situ**
82
Carcinoma in situ commonly occurs in carcinomas of the
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
skin, breast, and certain other sites and is best illustrated by carcinoma of the uterine cervix
83
What type of cancer display cytologic features of malignancy without invasion of the basement membrane?
**In situ epithelial cancers** display the cytologic features of **malignancy without
invasion of the basement membrane.**
**They may be considered one step removed from invasive cancer**; *with time, most penetrate the basement membrane and invade the subepithelial stroma.*
84
What are metastases?
Metastases are tumor implants **discontinuous with the primary tumor**
85
What unequivocally
**marks a tumor as malignant**.
Metastasis
**because benign neoplasms do not metastasize**
86
The invasiveness
of cancers permits them to :
The invasiveness
of cancers **permits them to penetrate into blood vessels, lymphatics, and body cavities,**
**providing the opportunity for spread**.
87
The invasiveness
of cancers permits them to penetrate into blood vessels, lymphatics, and body cavities,
providing the opportunity for spread.
With few exceptions, **all malignant tumors can
metastasize**. The major exceptions are:
* most malignant neoplasms of the glial cells in the central nervous system, called **gliomas**,
* and **basal cell carcinomas of the skin**
**Both are locally invasive
forms of cancer, but they rarely metastasize. It is evident then that the properties of invasion and metastasis are separable**
88
**In general, the more aggressive,** the **more rapidly growing,** and the **larger the primary
neoplasm,**the**greater the likelihood that it will metastasize or already has metastasized.**
There
are **innumerable exceptions,** however.
* *Small, well-differentiated, slowly growing lesions**
* *sometimes metastasize widely;** conversely, some rapidly **growing, large lesions remain localized**
* *for years.**
Many factors relating to both invader and host are involved.
89
Approximately 30% of newly diagnosed individuals with **solid tumors (excluding skin cancers
other than melanomas)**present with metastases.**Metastatic spread strongly reduces the
possibility of cure; hence, short of prevention of cancer, no achievement would be of greater
benefit to patients than methods to block metastases.**
90
Pathways of Spread
Dissemination of cancers may occur through one of three pathways:
* (1) direct seeding of body cavities or surfaces,
* (2) lymphatic spread,
* and (3) hematogenous spread.
Although direct transplantation of tumor cells, as for example on surgical instruments, may theoretically occur, it is rare and we do not discuss this artificial mode of dissemination further. Each of the three major pathways is described separately.
91
How does the Seeding of Body Cavities and Surfaces as pathway of spread happens?
Seeding of body cavities and surfaces may occur **whenever a malignant neoplasm penetrates
into a natural “open field.”**
92
What is most often involved in the pathway of Seeding of Body Cavities and Surfaces ?
Most often involved is the peritoneal cavity ( Fig. 7-16 ), but any
other cavity—**pleural, pericardial, subarachnoid, and joint space—may be affected**
Such
seeding is particularly **characteristic of carcinomas arising in the ovaries**, when, not infrequently,
all peritoneal surfaces become coated with a heavy layer of cancerous glaze. Remarkably, the
tumor cells may remain confined to the surface of the coated abdominal viscera without
penetrating into the substance
93
What is **pseudomyxoma peritonei?**
Sometimes mucus-secreting appendiceal carcinomas fill the
peritoneal cavity with a gelatinous neoplastic mass referred to as ***pseudomyxoma peritonei.***
94
FIGURE 7-16 Colon carcinoma invading pericolonic adipose tissue.
95
What is the most common pathway for the initial dissemination of
carcinomas , and sarcomas may also use this route?
Transport through lymphatics
96
Tumors **do not contain
functional lymphatics,** but lymphatic vessels located at the tumor margins are apparently
sufficient for the lymphatic spread of tumor cells.
T or F
T
97
The **emphasis on lymphatic spread** for
carcinomas and hematogenous spread for sarcomas is misleading, **because ultimately there
are numerous interconnections between the vascular and the lymphatic systems.**
98
The pattern
of lymph node involvement follows the\_\_\_\_\_\_\_\_\_\_\_\_\_
natural routes of lymphatic drainage.
99
How is the lymphatic spread of breast cancer?
Because
carcinomas of the breast **usually arise in the upper outer quadrants**, they **generally disseminate**
**first to the axillary lymph nodes**.
Cancers of the inner quadrants **drain to the nodes along the** **internal mammary arteries**
Thereafter the **infraclavicular and supraclavicular nodes may**
**become involved**
100
Carcinomas of the lung arising in the major respiratory passages metastasize
first to the\_\_\_\_\_\_\_\_\_\_\_\_\_\_
perihilar tracheobronchial and mediastinal nodes.
101
What is skip metastasis?
Local lymph nodes, however, may
be bypassed—so-called “skip metastasis”—**because of venous-lymphatic anastomoses or
because inflammation or radiation has obliterated lymphatic channels.**
102
FIGURE 7-17 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.
103
In breast cancer, determining the involvement of axillary lymph nodes is very important for
assessing the future course of the disease and for selecting suitable therapeutic strategies.
To
avoid the considerable surgical morbidity associated with a full axillary lymph node dissection,
biopsy of\_\_\_\_\_\_\_\_\_ is often used to assess the presence or absence of metastatic lesions
in the lymph nodes.
sentinel nodes
104
What is a sentinel lymph node?
A sentinel lymph node is defined as “**the first node in a regional lymphatic**
**basin that receives lymph flow from the primary tumor.”** [12]
Sentinel node mapping can be
done by injection of radiolabeled tracers and blue dyes, and the use of frozen section upon the
sentinel lymph node at the time of surgery can guide the surgeon to the appropriate therapy.
Sentinel node biopsy has also been used for detecting the spread of melanomas, colon
cancers, and other tumors.
105
In many cases the **regional nodes** serve as \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
* *effective barriers to further dissemination of the**
* *tumor,** at least for a while.
Conceivably the cells, after arrest within the node, may be destroyed by a tumor-specific immune response. Drainage of tumor cell debris or tumor antigens, or both,
also induces reactive changes within nodes
106
Thus, enlargement of nodes may be caused by :
* (1) the spread and growth of cancer cells or
* (2) reactive hyperplasia ( Chapter 13 ).
Therefore, **nodal enlargement in proximity to a cancer, while it must arouse suspicion,** does not necessarily
mean dissemination of the primary lesion.
107
Give an example of lymphatic spread.
Breast
108
Hematogenous spread is **typical of sarcomas** but is also **seen with carcinomas**.
Arteries, with
their thicker walls, are less readily penetrated than are veins.
109
Arterial spread may occur,
however, **when tumor cells\_\_\_\_\_\_\_\_\_**
pass through the pulmonary capillary beds or pulmonary
arteriovenous shunts or when pulmonary metastases themselves give rise to additional tumor
emboli.
110
In such vascular spread, **several factors influence** the **patterns of distribution of the
metastases.**
With venous invasion the blood-borne cells follow the **venous flow draining the site**
of the neoplasm, and the tumor cells often come to rest in the\_\_\_\_\_\_\_\_\_\_\_
first capillary bed they encounter.
111
Understandably the\_\_\_\_\_\_\_\_\_\_\_ are **most frequently involved in such hematogenous**
dissemination ( Figs. 7-18 and 7-19 )
liver and lungs
because **all portal area drainage flows to the liver and all
caval blood flows to the lungs.**
112
Cancers arising in **close proximity to the vertebral column** often
embolize through the \_\_\_\_\_\_\_\_, and this pathway is **involved in the frequent
vertebral metastases of carcinomas of the thyroid and prostate.**
paravertebral plexus
113
FIGURE 7-18 A liver studded with metastatic cancer.
114
FIGURE 7-19 Microscopic view of liver metastasis. A pancreatic adenocarcinoma has
formed a metastatic nodule in the liver.
115
Certain cancers **have a propensity for invasion of veins** such as:
Renal cell carcinoma
Hepatocellular carcinomas
116
Renal cell carcinoma often invades the
\_\_\_\_\_\_\_\_\_\_\_\_\_\_
branches of the renal vein and then the renal vein itself to grow in a snakelike fashion up the
inferior vena cava, sometimes reaching the right side of the heart.
117
Hepatocellular carcinomas
often penetrate \_\_\_\_\_\_\_\_\_\_\_\_
portal and hepatic radicles to grow within them into the main venous channels.
118
Remarkably, **such intravenous growth** **may not be accompanied by widespread dissemination.**
Histologic evidence of penetration of small vessels at the site of the primary neoplasm is
obviously an **ominous feature**.
Such changes, however, must be viewed guardedly because, for
reasons discussed later, they do not indicate the inevitable development of metastases
119
Many observations suggest that **mere anatomic localization of the neoplasm and natural
pathways of venous drainage do not wholly explain the systemic distributions of metastases.**
For example, breast carcinoma preferentially spreads to bone, bronchogenic carcinomas tend
to involve the adrenals and the brain, and neuroblastomas spread to the liver and bones.
Conversely, skeletal muscles and the spleen, despite the large percentage of blood flow they
receive and the enormous vascular beds present, are rarely the site of secondary deposits.
The probable basis of such tissue-specific homing of tumor cells is discussed later.
120
TABLE 7-2 -- Comparisons between Benign and Malignant Tumors
Differentiation/anaplasia
Benign
* Well differentiated;
* structuresometimes typical of tissue of origin
Malignant
* Some lack of differentiation with anaplasia;
* structure often atypical
121
TABLE 7-2 -- Comparisons between Benign and Malignant Tumors
Rate of growth
Benign
* Usually progressive and slow;
* may come to a standstill or regress;
* mitotic figures rare and normal
Malignant
* Erratic and may be slow to rapid;
* mitotic figures may be numerous
and abnormal
122
TABLE 7-2 -- Comparisons between Benign and Malignant Tumors
Local invasion
Benign
* Usually cohesive expansile welldemarcated
masses that do not invade or infiltrate surrounding
normal tissues
Malignant
* Locally invasive,
* infiltrating surrounding tissue;
* sometimes may be seemingly cohesive and
expansile
123
TABLE 7-2 -- Comparisons between Benign and Malignant Tumors
Metastasis
Benign
* Absent
Malignant
* Frequently present;
* the larger and more undifferentiated the primary,
the more likely are metastases
124
FIGURE 7-20 Comparison between a benign tumor of the myometrium (leiomyoma) and a
malignant tumor of the same origin (leiomyosarcoma).
125
