Pathology (neoplasia1)

• A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after cessation of the stimuli which evoked the change. 
• Genetic changes allow excessive and unregulated proliferation that becomes autonomous (independent of physiologic growth stimuli), although tumors generally remain dependent on the host for their nutrition and blood supply.
• Clonal

• (1) clonal neoplastic cells that constitute their parenchyma
• (2) reactive stroma made up of connective tissue, blood vessels, and variable numbers of macrophages and lymphocytes

• Although the neoplastic cells largely determine a tumor's behavior and pathologic consequences, their growth and evolution is critically dependent on their stroma.
• An adequate stromal blood supply is requisite for the tumor cells to live and divide, and the stromal connective tissue provides the structural framework essential for the growing cells.
• In addition, there is cross-talk between tumor cells and stromal cells that directly influences the growth of tumors.
• In some tumors, the stromal support is scant and so the neoplasm is soft and fleshy.
• In other cases the parenchymal cells stimulate the formation of an abundant collagenous stroma, referred to as desmoplasia.
• Some demoplastic tumors—for example, some cancers of the female breast—are stony hard orscirrhous

parenchymal

Adenoma is applied to a benign epithelial neoplasm derived from glands, although they may or may not form glandular structures

papillomas

Those benign neoplasms that form large cystic masses, as in the ovary, are referred to as cystadenomas

papillary cystadenomas

True

• When a neoplasm, benign or malignant, produces a macroscopically visible projection above a mucosal surface and projects, for example, into the gastric or colonic lumen, it is termed a polyp

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, chondrosarcoma, leiomyosarcoma, and rhabdomyosarcoma)

True

Malignant neoplasms of epithelial cell origin, derived from any of the three germ layers, are called carcinomas

Resemble

• Arise from kidney
• Resemble glands

mixed tumors (mixed tumor of salivary gland origin)

• These tumors contain epithelial components scattered within a myxoid stroma that sometimes contains islands of cartilage or bone.
• All these elements, it is believed, arise from a single clone capable of giving rise to epithelial and myoepithelial cells; thus, the preferred designation of these neoplasms is pleomorphic adenoma.
• The great majority of neoplasms, even mixed tumors, are composed of cells representative of a single germ layer

This mixed tumor of the parotid gland contains epithelial cells forming ducts and myxoid stroma that resembles cartilage.

• 1) Contains recognizable mature or immature cells or tissues representative of more than one germ cell layer and sometimes all three.
• 2) Teratomas originate from totipotential cells such as those normally present in the ovary and testis and sometimes abnormally present insequestered midline embryonic rests.
• 3) When all the component parts are well differentiated, it is abenign (mature) teratoma; when less well differentiated, it is an immature, potentially or overtly, malignant teratoma.
• 4) A particularly common pattern is seen in the ovarian cystic teratoma (dermoid cyst), which differentiates principally along ectodermal lines to create a cystic tumor lined by skin replete with hair, sebaceous glands, and tooth structures

Totipotent cells

Gross appearance of an opened cystic teratoma of the ovary. Note the presence of hair, sebaceous material, and tooth. B, A microscopic view of a similar tumor shows skin, sebaceous glands, fat cells, and a tract of neural tissue (arrow).

• Hamartomas present as disorganized but benign-appearing masses composed of cells indigenous to the particular site.
• They were once thought to be a developmental malformation, unworthy of the -oma designation. For example, pulmonary chondroid harmatoma contains islands of disorganized, but histologically normal cartilage, bronchi, and vessels.
• However, many hamartomas, including pulmonary chondroid hamartoma, have clonal, recurrent translocations involving genes encoding certain chromatin proteins

• This congenital anomaly is better described as a heterotopic rest of cells.
• For example, a small nodule of well-developed and normally organized pancreatic substance may be found in the submucosa of the stomach, duodenum, or small intestine.
• This heterotopic rest may be replete with islets of Langerhans and exocrine glands. Not a neoplasm

True

• Salivary glands: Pleomorphic adenoma (mixed tumor of salivary origin)/ Malignant mixed tumor of salivary gland origin
• Renal anlage: Wilms tumor

differentiation and anaplasia, rate of growth, local invasion, and metastasis.

• Differentiation refers to the extent to which neoplastic parenchymal cells resemble the corresponding normal parenchymal cells, both morphologically and functionally;
• lack of differentiation is called anaplasia.
• In general, benign tumors are well differentiated
• In well-differentiated benign tumors, mitoses are extremely scant in number and are of normal configuration.

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

Benign tumor (adenoma) of the thyroid. Note the normal-looking (well-differentiated), colloid-filled thyroid follicles.

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.

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

• Malignant neoplasms that are composed of poorly differentiated cells are said to be anaplastic.
• Lack of differentiation, or anaplasia, is considered a hallmark of malignancy.
• It is believed,, that most cancers do not represent “reverse differentiation” of mature normal cells but, in fact, arise from less mature cells with “stem-cell-like” properties, such as tissue stem cells.
• In well-differentiated tumors daughter cells derived from these “cancer stem cells” retain the capacity for differentiation, whereas in poorly differentiated tumors that capacity is lost.

• Pleomorphism--> variation in size and shape of cell and nucleus
• Abnormal nuclear morphology
• Mitoses
• Loss of polarity--> the orientation of anaplastic cells is markedly disturbed
• Tumor giant cells
• Necrois

• Nuclei contain abundant chromatin and are dark staining (hyperchromatic)
• The nuclei are disproportionately large for the cell, and the nuclear-to-cytoplasm ratio may approach 1 : 1 instead of the normal 1 : 4 or 1 : 6.
• The nuclear shape is variable and often irregular
• Chromatin is often coarsely clumped and distributed along the nuclear membrane.
• Large nucleoli

False

atypical, bizarre figures, sometimes producing tripolar, quadripolar, or multipolar spindles

• tumor giant cells-->some possessing only a single huge polymorphic nucleus and others having two or more large, hyperchromatic nuclei
• Foreign body GC--> many small, normal-appearing nuclei

• 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.

• 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 nuclei with a high nuclear to-cytoplasmic ratio. The architecture of the tissue may be disorderly

• 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, although 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.
• 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.
• Once the tumor cells breach the basement membrane, the tumor is said to be invasive

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

True

• 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.
• However, dysplasia does not necessarily progress to cancer.
• 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.

the more rapidly growing and the more anaplastic a tumor, the less likely it will have specialized functional activity

• 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.

• The original transformed cell (approximately 10 μm in diameter) must undergo at least 30 population doublings to produce 10⁹ 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 10¹² cells (weighing -1kg), which is usually the maximal size compatible with life.

True

• the doubling time of tumor cells,
• the fraction of tumor cells that are in the replicative pool
• the rate at which cells are shed or die.

• False
• growth of tumors is NOT commonly associated with a shortening of cell cycle time

• Tumors are more likely to enter cycle
• Duration of each cycle is NOT different

The proportion of cells within the tumor population that are in the proliferative pool is referred to as the growth fraction

• During the early, submicroscopic phase of tumor growth, the vast majority of transformed cells are in the proliferative pool
• 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.

Leukemia, lymphoma, Small cell lung cancer

Most solid tumors (CRC, breast)

Fast-growing tumors may have a high cell turnover, implying that rates of both proliferation and apoptosis are high

susceptibility to cancer chemotherapy

Slow/ refractory

• 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.

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

• True
• (but has many exceptions)

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

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

• 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
• 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

cells that allow a human tumor to grow and maintain itself indefinitely when transplanted into an immunodeficient mouse

Wnt pathway

• 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.
• Because they 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.
• 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.
• Such encapsulation does not prevent tumor growth, but it keeps the benign neoplasm as a discrete, readily palpable, and easily movable mass that can be surgically enucleated .
• 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)

Fibroadenoma. The fibrous capsule (right) delimits the tumor from the surrounding tissue

• The growth of cancers is accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue.
• In general, malignant tumors are poorly demarcated from the surrounding normal tissue, and a well-defined cleavage plane is lacking.
• Slowly expanding malignant tumors, however, may develop an apparently enclosing fibrous capsule and may push along a broad front into adjacent normal structures.
• 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

Breast cancer :invasion of breast stroma and fat by nests and cords of tumor cells

Always microinvasions are seen at the margin

invasiveness

In situ

Metastases are tumor implants discontinuous with the primary tumor

Metastasis

Most malignant neoplasms of the glial cells in the CNS, called gliomas, and basal cell carcinomas of the skin. Both are locally invasive forms of cancer, but they rarely metastasize

• True
• With some exceptions

• (1) direct seeding of body cavities or surfaces
• (2) lymphatic spread
• (3) hematogenous spread

peritoneal cavity

Ovarian carcinoma

mucus-secreting appendiceal carcinomas

lymphatics

False

Tumors do not contain functional lymphatics, but lymphatic vessels located at the tumor margins are apparently sufficient for the lymphatic spread of tumor cells

• 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.

Carcinomas of the lung arising in the major respiratory passages metastasize first to the perihilar tracheobronchial and mediastinal nodes

• because of venous-lymphatic anastomoses or
• because inflammation or radiation has obliterated lymphatic channels.

the first node in a regional lymphatic basin that receives lymph flow from the primary tumor

• (1) the spread and growth of cancer cells
• (2) reactive hyperplasia

sarcomas

• Veins
• (arteries have ticker walls)

when tumor cells pass through the pulmonary capillary beds or pulmonary arteriovenous shunts or when pulmonary metastases themselves give rise to additional tumor emboli

• 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.
• Understandably the liver and lungs are most frequently involved in such hematogenous dissemination because 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 involved in the frequent vertebral metastases of carcinomas of the thyroid and prostate

• 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.
• Hepatocellular carcinomas often penetrate portal and hepatic radicles to grow within them into the main venous channels.
• Remarkably, such intravenous growth may not be accompanied by widespread dissemination.

False

• breast carcinoma preferentially spreads to bone
• bronchogenic carcinomas tend to involve the adrenals and the brain
• neuroblastomas spread to the liver and bones

skeletal muscles and the spleen

• Differentiation/anaplasia: Well differentiated; structure sometimes typical of tissue of origin/ Some lack of differentiation with anaplasia; structure often atypical
• Rate of growth: Usually progressive and slow; may come to a standstill or regress; mitotic figures rare and normal/ Erratic and may be slow to rapid; mitotic figures may be numerous and abnormal
• Local invasion: Usually cohesive expansile well-demarcated masses that do not invade or infiltrate surrounding normal tissues/ Locally invasive, infiltrating surrounding tissue; sometimes may be seemingly cohesive and expansile
• Metastasis: Absent/ Frequently present; the larger and more undifferentiated the primary, the more likely are metastases