Malignant Tumors.

The nomenclature of malignant tumors essentially follows the same schema used for benign
neoplasms, with certain additions. Malignant tumors arising in mesenchymal tissue are usually
called sarcomas (Greek sar = fleshy) because they have little connective tissue stroma and so
are fleshy (e.g., fibrosarcoma, liposarcoma, leiomyosarcoma for smooth muscle cancer, and
rhabdomyosarcoma for a cancer that differentiates toward striated muscle). Malignant
neoplasms of epithelial cell origin, derived from any of the three germ layers, are called
carcinomas. Thus, cancer arising in the epidermis of ectodermal origin is a carcinoma, as is a
cancer arising in the mesodermally derived cells of the renal tubules and the endodermally
derived cells of the lining of the gastrointestinal tract. Carcinomas may be further qualified.
One with a glandular growth pattern microscopically is termed an adenocarcinoma, and one
producing recognizable squamous cells arising in any epithelium of the body is termed a
squamous cell carcinoma. It is common practice to specify, when possible, the organ of origin
(e.g., a renal cell adenocarcinoma or bronchogenic squamous cell carcinoma). Not
infrequently, however, a cancer is composed of undifferentiated cells of unknown tissue origin,
and must be designated merely as a poorly differentiated or undifferentiated malignant tumor.

DIFFERENTIATION AND ANAPLASIA

Differentiation refers to the extent to which neoplastic cells resemble comparable normal cells,
both morphologically and functionally; lack of differentiation is called anaplasia.
Well-differentiated tumors are composed of cells resembling the mature normal cells of the
tissue of origin of the neoplasm ( Fig. 7-5 ). Poorly differentiated or undifferentiated tumors
have primitive-appearing, unspecialized cells. In general, benign tumors are well differentiated
( Fig. 7-6 ). The neoplastic cell in a benign smooth muscle tumor—a leiomyoma—so closely
resembles the normal cell that it may be impossible to recognize it as a tumor by microscopic
examination of individual cells. Only the massing of these cells into a nodule discloses the
neoplastic nature of the lesion. One may get so close to the tree that one loses sight of the
forest.

Figure 7-5 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.

Figure 7-6 Benign tumor (adenoma) of the thyroid. Note

the normal-looking (well-differentiated), colloid-filled thyroid
follicles. (Courtesy of Dr. Trace Worrell, University of Texas
Southwestern Medical School, Dallas, TX.)
Malignant neoplasms, in contrast, range from well differentiated to undifferentiated. Malignant
neoplasms composed of undifferentiated cells are said to be anaplastic. Lack of differentiation,
or anaplasia, is considered a hallmark of malignant transformation. Anaplasia literally means
"to form backward," implying a reversion from a high level of differentiation to a lower level.
There is substantial evidence, however, that most cancers do not represent "reverse
differentiation" of mature normal cells but, in fact, arise from stem cells that are present in all
specialized tissues. The well-differentiated cancer ( Fig. 7-7 ) evolves from maturation or
specialization of undifferentiated cells as they proliferate, whereas the undifferentiated
malignant tumor derives from proliferation without complete maturation of the transformed
cells.

Figure 7-7 Malignant tumor (adenocarcinoma) of the

colon. Note that compared with the well-formed and
normal-looking glands characteristic of a benign tumor (see
Fig. 7-6 ), 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. (Courtesy of Dr. Trace Worrell,
University of Texas Southwestern Medical School, Dallas,
TX.)

Lack of differentiation, or anaplasia, is marked by a number of morphologic changes.

• Pleomorphism. Both the cells and the nuclei characteristically display

pleomorphism—variation in size and shape ( Fig. 7-8 ). Cells may be found that are many
times larger than their neighbors, and other cells may be extremely small and primitive
appearing.

• Abnormal nuclear morphology. Characteristically the nuclei contain an abundance of

DNA and are extremely dark staining (hyperchromatic). The nuclei are
disproportionately large for the cell, and the nucleus-to-cytoplasm ratio may approach
1:1 instead of the normal 1:4 or 1:6. The nuclear shape is very variable, and the
chromatin is often coarsely clumped and distributed along the nuclear membrane. Large
nucleoli are usually present in these nuclei.

• 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. The presence of mitoses,
however, does not necessarily indicate that a tumor is malignant or that the tissue is
neoplastic. 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. More important as a morphologic feature of malignant neoplasia are
atypical, bizarre mitotic figures, sometimes producing tripolar, quadripolar, or multipolar
spindles ( Fig. 7-9 ).

• 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.

• Other changes. Another feature of anaplasia is the formation of tumor giant cells, some
possessing only a single huge polymorphic nucleus and others having two or more
nuclei. 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. In the cancer giant cell, the nuclei are hyperchromatic and
large in relation to the cell. 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.

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.

Seeding of Body Cavities and Surfaces.

Seeding of body cavities and surfaces may occur whenever a malignant neoplasm penetrates
into a natural "open field." Most often involved is the peritoneal cavity ( Fig. 7-18 ), 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. Sometimes mucus-secreting appendiceal
carcinomas fill the peritoneal cavity with a gelatinous neoplastic mass referred to as
pseudomyxoma peritonei.

Figure 7-18 Colon carcinoma invading pericolonic adipose

tissue. (Courtesy of Dr. Melissa Upton, University of
Washington, Seattle, WA.)

Lymphatic Spread.

Transport through lymphatics is the most common pathway for the initial dissemination of
carcinomas ( Fig. 7-19 ), and sarcomas may also use this route. Tumors do not contain
functional lymphatics, but lymphatic vessels located at the tumor margins are apparently
sufficient for the lymphatic spread of tumor cells.[11] 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. The pattern
of lymph node involvement follows the natural routes of lymphatic drainage. 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 quadrant may drain through
lymphatics to the nodes within the chest along the internal mammary arteries. Thereafter the
infraclavicular and supraclavicular nodes may become involved. However, breast cancer is
now considered to be a systemic disease even at the time of detection, and treatment is
directed to both local control and the eradication of occult systemic micrometastases. [12]
Carcinomas of the lung arising in the major respiratory passages metastasize first to the
perihilar tracheobronchial and mediastinal nodes. Local lymph nodes, however, may be
bypassed—"skip metastasis"—because of venous-lymphatic anastomoses or because
inflammation or radiation has obliterated lymphatic channels.

Figure 7-19 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. (Courtesy of Dr. Trace Worrell,
University of Texas Southwestern Medical School, Dallas,
TX.)

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.
Usually, lymphatic spread of breast cancers is assessed by performing a full axillary lymph
node dissection. Because this procedure is associated with considerable surgical morbidity,
biopsy of sentinel nodes is often used. A sentinel lymph node is defined as "the first node in a
regional lymphatic basin that receives lymph flow from the primary tumor."[13] Sentinel node
mapping can be done by injection of radiolabeled tracers or blue dyes, but the combination of
these techniques provides the best results. Sentinel node identification has also been used for
detecting the spread of melanomas, colon cancers, and other tumors.[13][14]

In many cases, the regional nodes serve as effective barriers to further dissemination of the
tumor, at least for a time. 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. Thus, enlargement of nodes may be caused by (1)
the spread and growth of cancer cells or (2) reactive hyperplasia ( Chapter 14 ). Therefore,
nodal enlargement in proximity to a cancer does not necessarily mean dissemination of the
primary lesion.

Hematogenous Spread.

Hematogenous spread is typical of sarcomas but is also seen with carcinomas. Arteries, with
their thicker walls, are less readily penetrated than are veins. 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. In such arterial spread, a number of factors condition the patterns of distribution of the
metastases. With venous invasion, the blood-borne cells follow the venous flow draining the
site of the neoplasm. Understandably the liver and lungs are most frequently involved
secondarily in such hematogenous dissemination ( Fig. 7-20 and Fig. 7-21 ). All portal area
drainage flows to the liver, and all caval blood flows to the lungs. Cancers arising in close
proximity to the vertebral column often embolize through the paravertebral plexus, and this
pathway is probably involved in the frequent vertebral metastases of carcinomas of the thyroid
and prostate.

Figure 7-20 A liver

studded with metastatic
cancer.

Figure 7-21 Microscopic view of liver metastasis. A

pancreatic adenocarcinoma has formed a metastatic nodule in
the liver. (Courtesy of Dr. Trace Worrell, University of Texas
Southwestern Medical School, Dallax, TX.)

Table 7-2 -- Comparisons Between Benign and Malignant Tumors

Characteristics Benign Malignant

Some lack of differentiation with

Well differentiated; structure may
Differentiation/anaplasia anaplasia; structure is often
be typical of tissue of origin
atypical

Usually progressive and slow;

Erratic and may be slow to rapid;
may come to a standstill or
Rate of growth mitotic figures may be numerous
regress; mitotic figures are rare
and abnormal
and normal

Usually cohesive and expansile Locally invasive, infiltrating the

well-demarcated masses that do surrounding normal tissues;
Local invasion
not invade or infiltrate surrounding sometimes may be seemingly
normal tissues cohesive and expansile
 Characteristics Benign Malignant

Frequently present; the larger

and more undifferentiated the
Metastasis Absent
primary, the more likely are
metastases

Figure
7-22 Compar
ison between a
benign tumor
of the
myometrium
(leiomyoma)
and a
malignant
tumor of similar
origin
(leiomyosarco
ma

Malignant melanoma of the skin is usually asymptomatic, although itching may be an early
manifestation. The majority of lesions are greater than 10 mm in diameter. The most important
clinical sign of the disease is change in color, size, or shape in a pigmented lesion. Unlike
benign (nondysplastic) nevi, melanomas exhibit striking variations in pigmentation, appearing
in shades of black, brown, red, dark blue, and gray ( Fig. 25-8A ). On occasion, zones of white
or flesh-colored hypopigmentation are also present. The borders of melanomas are not
smooth, round, and uniform, as in nevocellular nevi, but irregular and often "notched." In
summary, the clinical warning signs of melanoma are (1) enlargement of a pre-existing mole,
(2) itching or pain in a pre-existing mole, (3) development of a new pigmented lesion during
adult life, (4) irregularity of the borders of a pigmented lesion, and (5) variegation of color within
a pigmented lesion.

Keratoacanthoma is a rapidly developing neoplasm that clinically and histologically may mimic
well-differentiated squamous cell carcinoma. Often it will heal spontaneously, without
treatment! Men are more often affected than women, and lesions most frequently affect
sun-exposed skin of whites older than age 50 years.[32]

Keratoacanthomas appear clinically as flesh-colored, dome-shaped nodules with a central,

keratin-filled plug, imparting a crater-like topography ( Fig. 25-12A ). Lesions range in size from
1 cm to several centimeters across and have a predilection for facial skin, including the cheeks,
nose, and ears, and the dorsa of the hands.

SQUAMOUS CELL CARCINOMA

Squamous cell carcinoma is the second most common tumor arising on sun-exposed sites in
older people, exceeded only by basal cell carcinoma. Except for lesions on the lower legs,
these tumors have a higher incidence in men than in women. Exposure to sunlight is the major
predisposing factor; others include industrial carcinogens (tars and oils), chronic ulcers and
draining osteomyelitis, old burn scars, ingestion of arsenicals, ionizing radiation, and (in the
oral cavity) tobacco and betel nut chewing.

The most commonly accepted exogenous cause of squamous cell carcinoma is exposure to
UV light with subsequent DNA damage. Individuals who are immunosuppressed as a result of
chemotherapy or organ transplantation, or who have xeroderma pigmentosum ( Chapter 7 ),
are at increased risk for developing neoplasms.[35] A considerable proportion of these are
squamous cell carcinomas. Sunlight, in addition to its effect on DNA, also seems to have a
direct and, at least, a transient immunosuppressive effect on skin by affecting the normal
surveillance function of antigen-presenting Langerhans cells in the epidermis.[36][37] DNA
sequences of certain viruses (e.g., human papillomavirus [HPV] type 36) have been detected
in potential precursors of squamous cell carcinoma, suggesting a role for these agents in the
evolution of certain, but not all,[38] cutaneous epithelial neoplasms. Finally, certain chemical
agents appear to have direct mutagenic effects by producing DNA adducts with subsequent
oncogene activation.[39] (See Molecular Genetics of Skin Cancers for additional details).

Invasive squamous cell carcinomas are usually discovered while they are small and resectable;
less than 5% have metastases to regional nodes, and these lesions are generally deeply
invasive.

Morphology.

Squamous cell carcinomas that have not invaded through the basement membrane of the
dermoepidermal junction (termed in situ carcinoma) appear as sharply defined, red, scaling
plaques. More advanced, invasive lesions are nodular, show variable keratin production
appreciated clinically as hyperkeratosis, and may ulcerate ( Fig. 25-14A ). Well-differentiated
lesions may be indistinguishable from keratoacanthoma. When the oral mucosa is involved, a
zone of white thickening may be seen, an appearance caused by a variety of disorders and
referred to clinically as leukoplakia.

Unlike actinic keratoses, squamous cell carcinoma in situ is characterized by cells with atypical
(enlarged and hyperchromatic) nuclei at all levels of the epidermis. When these cells break
through the basement membrane, the process has become invasive. Invasive squamous cell
carcinoma ( Fig. 25-14B,C ) exhibits variable differentiation, ranging from tumors formed by
polygonal squamous cells, arranged in orderly lobules and exhibiting numerous large zones of
keratinization, to neoplasms formed by highly anaplastic, rounded cells with foci of necrosis
and only abortive, single-cell keratinization (dyskeratosis). These latter tumors may be so
poorly differentiated that electron microscopy for the detection of keratinocyte intercellular
attachment sites (desmosomes) or reaction of tissue with antibodies to keratin or epithelial
membrane-associated antigens may be necessary to definitively establish cell lineage.
BASAL CELL CARCINOMA

Basal cell carcinomas are common, slow-growing tumors that rarely metastasize. They have a
tendency to occur at sites subject to chronic sun exposure and in lightly pigmented people. As
with squamous cell carcinoma, the incidence of basal cell carcinoma rises sharply with
immunosuppression and in patients with inherited defects in DNA repair (e.g., xeroderma
pigmentosum; Chapter 7 ).

These tumors present clinically as pearly papules often containing prominent, dilated
subepidermal blood vessels (telangiectasias) ( Fig. 25-15A ). Some tumors contain melanin
and, thus, appear similar to melanocytic nevi or melanomas. Advanced lesions may ulcerate,
and extensive local invasion of bone or facial sinuses may occur after many years of neglect or
in unusually aggressive tumors, explaining the past designation rodent ulcers. One common
and important variant, the superficial basal cell carcinoma, presents as an erythematous,
occasionally pigmented plaque that may resemble early forms of malignant melanoma.
Careful inspection usually reveals characteristic pearly papules at the periphery of the plaque.

Morphology.

On histologic examination, tumor cells resemble those in the normal basal cell layer of the
epidermis. They arise from the epidermis or follicular epithelium and do not occur on mucosal
surfaces. Two patterns are seen: multifocal growths originating from the epidermis and
extending over several square centimeters or more of skin surface (multifocal superficial type)
and nodular lesions growing downward deeply into the dermis as cords and islands of
variably basophilic cells with hyperchromatic nuclei, embedded in a mucinous matrix, and
often surrounded by many fibroblasts and lymphocytes ( Fig. 25-15B ). The cells forming the
periphery of the tumor cell islands tend to be arranged radially with their long axes in
approximately parallel alignment (palisading). The stroma shrinks away from the epithelial
tumor nests ( Fig. 25-15C ), creating clefts or separation artifacts that assist in differentiating
basal cell carcinomas from certain appendage tumors also characterized by proliferation of
basaloid cells (e.g., trichoepithelioma).

Basal Cell Nevus Syndrome.

This rare, dominantly inherited syndrome[40] is associated with the development of numerous
basal cell carcinomas in early life and with abnormalities of bone, nervous system, eyes, and
reproductive organs. The molecular genetics of this rare yet informative condition are
described below under Molecular Genetics of Skin Cancers.

Leprosy

Leprosy, or Hansen disease, is a slowly progressive infection caused by Mycobacterium

leprae, affecting the skin and peripheral nerves and resulting in disabling deformities. M.
leprae is, for the most part, contained within the skin, but leprosy is likely to be transmitted
from person to person through aerosols from lesions in the upper respiratory tract. Inhaled M.
leprae, like M. tuberculosis, is taken up by alveolar macrophages and disseminates through
the blood, but grows only in relatively cool tissues of the skin and extremities. Despite its low
communicability, leprosy remains endemic among an estimated 10 to 15 million people living
in poor tropical countries.

Pathogenesis.

M. leprae is an acid-fast obligate intracellular organism that grows very poorly in culture but
can be grown in the armadillo. It grows more slowly than other mycobacteria and grows best at
32 掳 to 34 掳 C, the temperature of the human skin and the core temperature of armadillos.
Like M. tuberculosis, M. leprae secretes no toxins, and its virulence is based on properties of
its cell wall. The cell wall is similar enough to that of M. tuberculosis that immunization with
bacille Calmette-Gu 茅 rin confers some protection against M. leprae infection. Cell-mediated
immunity is reflected by delayed type hypersensitivity reactions to dermal injections of a
bacterial extract called lepromin.

Leprosy has two strikingly different patterns of disease. Patients with the less severe form,
tuberculoid leprosy, have dry, scaly skin lesions that lack sensation. They often have large,
asymmetric peripheral nerve involvement. The more severe form of leprosy, lepromatous
leprosy, includes symmetric skin thickening and nodules. This is also called anergic leprosy,
because of the unresponsiveness (anergy) of the host immune system. Cooler areas of skin,
including the earlobes and feet, are more severely affected than warmer areas, such as the
axilla and groin. In lepromatous leprosy, damage to the nervous system comes from
widespread invasion of the mycobacteria into Schwann cells and into endoneural and
perineural macrophages. In advanced cases of lepromatous leprosy, M. leprae is present in
sputum and blood. People can also have intermediate forms of disease, called borderline
leprosy.

The T-helper lymphocyte response to M. leprae determines whether an individual has

tuberculoid or lepromatous leprosy.[109] Patients with tuberculoid leprosy have a T H1 response,
with production of IL-2 and IFN-纬. As with M. tuberculosis, IFN-纬 is critical to mobilizing an
effective host macrophage response. IL-12, which is produced by antigen presenting cells, is
important to the generation of TH1 cells ( Chapter 6 ). Low levels of IL-12 or unresponsiveness
of T cells to this cytokine may reduce the T H1 response, leading to lepromatous leprosy. In
addition to TH1 cells, lymphocytes bearing the 纬/未 T-cell receptor infiltrate the lesions of
leprosy and produce IFN-纬 in patients with tuberculoid leprosy. Patients with lepromatous
leprosy have a defective TH1 response or a dominant TH2 response, with production of IL-4,
IL-5, and IL-10, which may suppress macrophage activation in response to M. leprae. In some
cases, antibodies are produced against M. leprae antigens. Paradoxically, these antibodies
are usually not protective, but they may form immune complexes with free antigens that can
lead to erythema nodosum, vasculitis and glomerulonephritis.

Morphology.

Tuberculoid leprosy begins with localized skin lesions that are at first flat and red but enlarge
and develop irregular shapes with indurated, elevated, hyperpigmented margins and
depressed pale centers (central healing). Neuronal involvement dominates tuberculoid leprosy.
Nerves become enclosed within granulomatous inflammatory reactions and, if small enough
(e.g., the peripheral twigs), are destroyed ( Fig. 8-35 ). Nerve degeneration causes skin
anesthesias and skin and muscle atrophy that render the patient liable to trauma of the
affected parts, with the development of indolent skin ulcers. Contractures, paralyses, and
autoamputation of fingers or toes may ensue. Facial nerve involvement can lead to paralysis of
the eyelids, with keratitis and corneal ulcerations. On microscopic examination, all sites of
involvement disclose granulomatous lesions closely resembling those found in tuberculosis,
and bacilli are almost never found. The presence of granulomas and absence of bacteria
reflect strong T-cell immunity. Because leprosy pursues an extremely slow course, spanning
decades, most patients die with leprosy rather than of it.
 Figure
8-35 聽
Leprosy. A,
Peripheral
nerve. Note
the
inflammator
y cell
infiltrates in
the
endoneural
and
epineural
compartme
nts. B, Cells
within the
endoneuriu
m contain
acid-fast
positive
lepra bacilli.
聽
(Courtesy
of E. P.
Richardson,
Jr. and U.
De
Girolami,
Harvard
Medical
School.)

Lepromatous leprosy involves the skin, peripheral nerves, anterior chamber of the eye,
upper airways (down to the larynx), testes, hands, and feet. The vital organs and central
nervous system are rarely affected, presumably because the core temperature is too high for
growth of M. leprae. Lepromatous lesions contain large aggregates of lipid-laden
macrophages (lepra cells), often filled with masses of acid-fast bacilli (globi; Fig. 8-36 ). The
failure to contain the infection and to form granulomas reflects failure of the T H1 response.
Macular, papular, or nodular lesions form on the face, ears, wrists, elbows, and knees. With
progression, the nodular lesions coalesce to yield a distinctive leonine facies. Most skin
lesions are hypoesthetic or anesthetic. Lesions in the nose may cause persistent inflammation
and bacilli-laden discharge. The peripheral nerves, particularly the ulnar and peroneal nerves
where they approach the skin surface, are symmetrically invaded with mycobacteria, with
minimal inflammation. Loss of sensation and trophic changes in the hands and feet follow the
nerve lesions. Lymph nodes show aggregation of foamy macrophages in the paracortical
(T-cell) areas, with enlargement of germinal centers. In advanced disease, aggregates of
macrophages are also present in the splenic red pulp and the liver. The testes are usually
extensively involved, with destruction of the seminiferous tubules and consequent sterility.

Figure 8-36 聽 Lepromatous leprosy. Acid-fast bacilli ("red

snappers") within macrophages