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What is neoplasm?
- 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.
What are the components of all tumors?
- (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
What is the importance of stroma in a tumor?
- 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
The nomenclature of tumors and their biologic behavior are based primarily on the ..................component
What is an adenoma?
Adenoma is applied to a benign epithelial neoplasm derived from glands, although they may or may not form glandular structures
Benign epithelial neoplasms producing microscopically or macroscopically visible finger-like or warty projections from epithelial surfaces are referred to as .............
What are cystadenoma?
Those benign neoplasms that form large cystic masses, as in the ovary, are referred to as cystadenomas
Some tumors produce papillary patterns that protrude into cystic spaces and are called .................
True or false: A polyp can be benign or malignant
What is a polyp?
- 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
What is sarcoma?
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 or false: carcinomas may arise from any of the three germ cell layers
What is carcinoma?
Malignant neoplasms of epithelial cell origin, derived from any of the three germ layers, are called carcinomas
Squamous cell carcinoma would denote a cancer in which the tumor cells ........stratified squamous epithelium, and adenocarcinoma denotes a lesion in which the neoplastic epithelial ...........glands
What does renal cell adenocarcinoma imply?
- Arise from kidney
- Resemble glands
divergent differentiation of a single neoplastic clone along two lineages creates what are called........
mixed tumors (mixed tumor of salivary gland origin)
What are the features of 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.
What are the features of teratoma?
- 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
Teratoma is derived from..............
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).
What are the features of hamartoma?
- 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
What is choristoma?
- 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 or False: many hamartomas are indeed neoplastic
What are the examples of tumors with MORE THAN ONE NEOPLASTIC CELL TYPE (MIXED TUMORS) USUALLY DERIVED FROM ONE GERM CELL LAYER?
- Salivary glands: Pleomorphic adenoma (mixed tumor of salivary origin)/ Malignant mixed tumor of salivary gland origin
- Renal anlage: Wilms tumor
benign and malignant tumors can be distinguished on the basis of ................................
differentiation and anaplasia, rate of growth, local invasion, and metastasis.
What is differentiation?
- 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
What is anaplasia?
- 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.
What are the morphological features associated with anaplasia?
- Pleomorphism--> variation in size and shape of cell and nucleus
- Abnormal nuclear morphology
- Loss of polarity--> the orientation of anaplastic cells is markedly disturbed
- Tumor giant cells
What are the Abnormal nuclear morphology in anaplasia?
- 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
True or False: high number of mitosis always show malignancy
More important as a morphologic feature of malignancy are mitosis with ........................................
atypical, bizarre figures, sometimes producing tripolar, quadripolar, or multipolar spindles
What is the difference between tumor GC and inflammatory Langhans or foreign body giant cells?
- 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
What is 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.
What is dysplasia?
- 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
What is the example of dysplasia in squamous epithelium?
- 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 or false: dysplasia occurs in metaplastic epithelium
What is the importance of dysplasia?
- 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.
What is the relation of anaplasia to function?
the more rapidly growing and the more anaplastic a tumor, the less likely it will have specialized functional activity
What is true about the differentiation of benign and malignant tumors?
- 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.
What are some facts about tumor growth time?
- 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 or False: By the time a solid tumor is clinically detected, it has already completed a major portion of its life span
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
- the rate at which cells are shed or die.
True or false: growth of tumors is commonly associated with a shortening of cell cycle time
- growth of tumors is NOT commonly associated with a shortening of cell cycle time
What is different between tumor cells and normal cells regarding cell cycle?
- Tumors are more likely to enter cycle
- Duration of each cycle is NOT different
What is growth pool?
The proportion of cells within the tumor population that are in the proliferative pool is referred to as the growth fraction
What is the relation of proliferative pool to life span of the tumor?
- 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.
Which tumors has high growth fractions?
Leukemia, lymphoma, Small cell lung cancer
Which tumors have low growth fractions?
Most solid tumors (CRC, breast)
What is the turn over of fast growing tumor?
Fast-growing tumors may have a high cell turnover, implying that rates of both proliferation and apoptosis are high
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 .........growing but relatively .............to treatment with drugs that kill dividing cells
How can we treat tumors with low growth fraction with chemotherapy?
- 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.
What is the latent period before a cancer become detectable?
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 or False: 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
- (but has many exceptions)
How does tissue Stem cells divide?
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
Why do 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
What is the origin of cancer stem cells?
- 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
What are tumor-initiating cells (T-ICs)?
cells that allow a human tumor to grow and maintain itself indefinitely when transplanted into an immunodeficient mouse
Which gene maintain CRC stem cells stemness?
What are the local features of benign tumors?
- 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
What are the local features of cancers?
- 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
What is the hallmark of pseudocapsules of cancers?
Always microinvasions are seen at the margin
Next to the development of metastases, ............is the most reliable feature that differentiates malignant from benign tumors.
........... epithelial cancers display the cytologic features of malignancy without invasion of the basement membrane.
What are metastasis?
Metastases are tumor implants discontinuous with the primary tumor
..............unequivocally marks a tumor as malignant
What are the exceptions in malignant tumors that do not metastasize?
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 or False: 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
What are the major routes of metastases?
- (1) direct seeding of body cavities or surfaces
- (2) lymphatic spread
- (3) hematogenous spread
What is the serosal surface that is most commonly involved in metastasis?
In ..........all peritoneal surfaces become coated with a heavy layer of cancerous glaze
............................ fill the peritoneal cavity with a gelatinous neoplastic mass referred to as pseudomyxoma peritonei
mucus-secreting appendiceal carcinomas
Transport through ...................is the most common pathway for the initial dissemination of carcinomas
True or False: tumor contains functional lymphatics
How do tumors spread via lymph?
Tumors do not contain functional lymphatics, but lymphatic vessels located at the tumor margins are apparently sufficient for the lymphatic spread of tumor cells
What is the pattern of lymphatic spread in 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.
What is the distribution of lung cancer along lymphatics?
Carcinomas of the lung arising in the major respiratory passages metastasize first to the perihilar tracheobronchial and mediastinal nodes
What is the reason for skip metastasis ?
- because of venous-lymphatic anastomoses or
- because inflammation or radiation has obliterated lymphatic channels.
A sentinel lymph node is defined as ...................
the first node in a regional lymphatic basin that receives lymph flow from the primary tumor
What are the causes of LAP in cancer?
- (1) the spread and growth of cancer cells
- (2) reactive hyperplasia
Hematogenous spread is typical of ...............
Which vessels are more prone to invasion?
- (arteries have ticker walls)
When can a tumor spread via arterial route?
when tumor cells pass through the pulmonary capillary beds or pulmonary arteriovenous shunts or when pulmonary metastases themselves give rise to additional tumor emboli
Which organs are most frequently involved in venous metastasis and how?
- 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.
What are the tumors most commonly metastasize via paravertebral route?
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
What are the cancers with propensity for venous invasion?
- 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.
True or False: Histologic evidence of penetration of small vessels at the site of the primary neoplasm show inevitability of metastasis
What are some examples in which mere anatomic localization of the neoplasm and natural pathways of venous drainage do not wholly explain the systemic distributions of metastases?
- breast carcinoma preferentially spreads to bone
- bronchogenic carcinomas tend to involve the adrenals and the brain
- neuroblastomas spread to the liver and bones
What are the tissues that despite much blood they receive are not involved in metastasis?
skeletal muscles and the spleen
Compare benign and malignant tumors
- 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