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Robbins and Cotran Pathologic Basis of Disease #
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Structured data


Pathology textbook

Table of Contents

Chap 1. The Cell as a Unit of Health and Disease #

Chap 7. Neoplasia #

Cancer is the second leading cause of death in US. First is Cardiovascular disease.

Cancer is not one disease but many disorders with widely different natural histories and responses to treatments. Hodgkin lymphoma are curable, Pancreatic adenocarcinoma are fatal.

Nomenclature #

Neoplasia means "new growth" and a new growth is called a Neoplasm.

Oncology is the study of tumors or neoplasms.

Willis came closest:

"A neoplasm is an adnormal mass of tissue, the growth of which exeeds 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."

In the modern era,

"A neoplasm can be difined as a disorder of cell growth that is triggered by a series of acquired mutations affecting a single cell and its clonal progeny."

All tumors have two basic components:

  1. neoplastic cells that constitute the tumor parenchyma (실질조직)
  2. reactive stroma (반응성 기질) made up of connective tissue, blood vessels, and variable numbers of cells of the adaptive and innate immune system.

The classification of tumors and their biologic behavior are based primarily on the parenchymal component, but their growth and spread are critically dependent on their stroma.

Benign Tumors #

A tumor is said to be benign when its gross and microscopic appearances are considered relatively innocent, implying that it will remain localized, will not spread to other sites, and is amenable to local surgical removal.

In general, benign tumors are designated by attaching the suffic -oma to the name of the cell type from which the tumor originates.

  • fibroma (섬유종): in fibrous tissue
  • chondroma (연골종): cartilaginous tumor
  • adenoma (선종): epithelial neoplasms derived from glands (선)
  • papilloma (유두종): visible fingerlike or warty projections from epithelial surfaces
  • cystadenoma (낭종): in the ovary
  • polyp (용종): into the gastric or colonic lumen.
  • adenomatous polyp (샘종성 폴립): polyp has glandular tissue

(fig. 7-1)

Milignant Tumors #

These are collectively referred to as Cancer. Malignant tumors can invade and destroy adjacent structures and spread to distant sites (metastasize) to cause death.

Some are discovered earyl enough to be excised surgically or are treated succeffully with chemotherapy or radiation, but the designation malignant always raises a red flag. (Greek sar = fleshy)

  • sarcomas (육종): in solid mesenchymal tissues (중간엽조직)
  • leukemias: white blood
  • lymphomas (림프종): tumors of lymphocytes or their precursors
  • carcinomas (암종) : epithelial cell origin, derived from any of the three germ layers
    • squamous cell carcinoma (편평세포암종): the tumor cells resemble stratified squamous epithelium (계층화된 비늘모양의 상피)
    • adenocarcinoma (선암종): lesion in which the neoplastic epithelial cells grow in an glandular pattern

Not infrequently, a cancer is composed of cells of unknown tissue origin, and must be disegnated merely as an undifferentiated malignant tumor.

Mixed Tumors #

In most benign and malignant neoplasms, all of the parenchymal cells closely resemble one another. Infrequently, however, divergent differentiation of a single neoplastic clone creates a mixed tumor, such as the mixed tumor of salivary gland (침샘).

These tumors contain epithelial components scattered within a myxoid stroma (점액성 기질) that may contain islands of cartilage (연골) or bone (fig. 7-2)

  • pleomorphic adenoma (다태성 선종): All of these elements arise from a single clone capable of producing both epithelial and myoepithelial cells
  • teratoma (기형종): contains recognizable mature or immature cells or tissues belonging to more than one germ cell layer - from totipotential germ cells that are normally present in the ovary and testis, embryonic rests
    • ovarian cystic teratoma (fig. 7-3)

(table 7-1)

Characteristics of Benign and Malignant Neoplasms #

In general, benign and malignant tumors can be distinguished on the basis of a number of histologic and anatomic features.

Growth rate is not a very useful discriminator between benignity and malignancy.

Differentiation and Anaplasia #

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 (퇴형 발육).

In general, benign tumors are well differentiated (fig. 7-4, 7-5).

In contrast, while malignant neoplasms exhibit a wide range of parenchymal cell differentiation, most exhibit morphologic alterations that betray their malignant nature (fig. 7-6)

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.

Lack of differentiation, or anaplasia, is often associated with many other morphologic changes.

  • Pleomorphism (다태성): Variation in size and shape. Cells within the same tumor are not uniform, but range from small cells with an undifferentiated appearance, to tumor giant cells.
  • Adnormal nuclear morphology: Nuclei are disproportionately large for the cell, with a nuclear-to-cytoplasm ration that may approach 1:1 instead of the normal 1:4 or 1:6. The shape is variable, irregular, and the chromatin is often coarsely clumped and distributed alog the nuclear membrane, or more darkly stained than normal (hyperchromatic).
  • Mitoses: In undifferentiated tumors, many cells are in mitosis, reflecting the high proliferative activity of the parenchymal cells.
  • Loss of polarity: The orientation of anaplastic cells is markedly disturbed.
  • Other changes: Growing tumor cells oviously require a blood supply, but often the vascular stroma (혈관 기질) is insufficient, and as a result in many rapidly growing malignant tumors develop large central areas of ischemic necrosis (응고괴사).

Benign neoplasms and well-differentiated carcinomas of enocrine glands frequently secrete hormones characteristic of their origin. Incresed levels of these hormones in the blood are used clinically to detect and follow such tumors.

Some tumors express fetal proteins that are not produced by comparable cells in the adult, while others express proteins that are normally only found in other types of adult cells.

Metaplasia is defined as the replacement of one type of cell with another type. It is nearly always found in association with tissue damage, repair, and regeneration. Often the replacing cell type is better suited to some alteration in the local environment.

Dysplasia is a term that literally means "disordered growth." It is encountered principally in epithelia and is characterized by a constellation of changes that include a loss int the uniformity of the individual cells as well as a loss in their architectural orientation.

Dysplastic cells may exhibit considerable pleomorphism and oftern contain large hyperchromatic nuclei with a high nuclear-to-cytoplasmic ration.

When dysplastic changes are marked and involve the full thickness of the epithelium, but the lesion does not penetrate the basement membrane, it is considered a preinvasive neoplasm and is referred to as carcinoma in situ. (fig. 7-10)

Although dysplasia may be a precursor to malignant transformation, it does not always progress to cancer.

While it should be noted that dysplasia often occurs in metaplastic epithelium, not all metaplastic epithelium is dysplastic.

Local Invasion #

The growth of cancers is accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue, whereas nearly all benign tumors grow as cohesive expansile masses that remain localized to their site of origin and lack the capacity to infiltrate, invade, or metastasize to distant sites.

Malignant tumors are, poorly demarcated from the surrounding normal tissue, and a well-defined cleavage plane is lacking (fig. 7-13, 7-14)

Next to the development of metastases, invasiveness is the most reliable feature that differentiates cancers from benign tumors. Most malignant tumors do not recognize normal anatomic boundaries and can be expected to penetrate the wall of the colon or uterus.

Some cancers seem to evolve from a preinvasive stage referred to as carcinoma in situ. This commonly occurs in carcinomas of the skin, breast, and certain other sites and is best illustrated by carcinoma of the uterine cervix (자궁 경관).

Metastasis #

Metastasis is defined by the spread of a tumor to sites that are physically discountinuous with the primary tumor, and unequivocally marks a tumor as mailgnant, as by definition benign neoplasms do not metastasize.

The invasiveness of cancers permits them to penetrate into blood vessels, lymphatics, and body cavities (체강), providing the opportunity for spread.

All malignant tumors can metastasize. But Gliomas (central nervous system) and basal cell carcinomas of the skin can't.

In general, the likelihood of a primary tumor metastasizing correlates with lack of differentiation, aggressive local invasion, rapid growth, and large size.

Approximately 30% of newly diagnosed 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 an effective means to block metastasis.

Blood cancers (the leukemias and lymphomas) are derived from blood-forming cells that normally have the capacity to enter the bloodstream and travel to distant sites; as a result, these are often disseminated at diagnosis and are always taken to be malignant.

Pathways of Spread #

Dissemination of cancers may occur through on of three pathways:

Direct seeding of body cavities or surfaces #

These may occur whenever a malignant neoplasm penetrates into a natural "open field" lacking physical barriers. Most often involved is the peritoneal cavity (복강, fig. 7-15), but any other cavity - pleural (흉막), pericardial (심막), subarachnoid (지주막), and joint spaces - may be affected.

Such seeding is particulrly characteristic of carcinomas arising in the ovaries, which, not infrequently, spread to peritoneal surfaces, which become coated with a heavy cancerous glaze.

Lymphatic spread #

Transport through lymphatics is the most common pathway for the initial dissemination of carcinomas (fig 7-16).

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

The pattern of lymph node involvement follows the natural routes of lymphatic drainage. Because carcinomas of the breast usually arise in the upper outer quadrant, they generally disseminate first to the axillary lymph nodes.

In Breast cancer, determining the involvement of axillary lymph nodes is important for assessing the future course of the disease and for selecting suitable therapeutic strategies.

A sentinel lymph node is defined as "the first node in an regional lymphatic basin that receives lymph flow from the primary tumor."

Sentinel node mapping can be done by injection of radiolabeled tracers or colored dyes, and examination of frozen sections of the sentinel lymph node performed during surgery can guide the surgeon to the approapriate therapy.

Sentinel node examination has also been used for detecting the spread of Melanomas, Colon cancers, and other tumors.

In many cases, the regional nodes serve as effective barriers to further dissemination of the tumor, at least for a while. Conceivably, after arrest within the node the cells 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 the spread and growth of cancer cells or reactive hyperplasia.

Hematogenous spread #

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 vascular spread, several factors influence the patterns of distribution of the metastases. With venous invasion, the bloodborne 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.

The liver and the 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.

Certain cancers have a propensity for invasion of veins. Renal cell carcinoma often invades the branches of the renal vein and then the renal vein itself, from where it may grow in a snakelike fashion up the inferior vena cava, sometimes reaching the right side of the heart.

Histologic evidence of penetration of small vessels at the site of the primary neoplasm is obviously an ominous feature.

(table 7-2)

Characteristics Benign Malignant
Differentiation/anaplasia Well differentiated; structure sometimes typical of tissue of origin Some lack of differentiation (anaplasia); structure often atypical
Rate of growth Usually progressive and slow; may come to a standstill or regress; mitotic figures rare and normal Erratic, may be slow to rapid; mitotic figures may be numerous and abnormal
Local invasion Usally cohesive, expansile, well-demarcated masses that do not invade or infiltrate surrounding normal tissues Locally invasive, infiltrating surrounding tissue; sometimes may be misleadingly cohesive and expansile
Metastasis Absent Frequent; more likely with large undifferentiated primary tumors

Epidemiology of Cancer #

The Global Impact of Cancer #

Environmental Factors #

Age #

Acquired Predisposing Conditions #

Genetic Predisposition and Interactions Between Environmental and Inherited Factors #

Molecular Basis of Cancer: Role of Genetic and Epigenetic Alterations #

Cellular and Molecular Hallmarker of Cancer #

Self-Sufficiency in Growth Signals: Oncogenes #

Proto-oncogenes, Oncogenes, and Oncoproteins #

Insensitivity to Growth Inhibition: Tumor Suppressor Genes #

Whareas Oncogenes drive the prolifereation of cells, the products of most Tumor suppressor genes apply brakes to cell proliferation, and adnormalities in these genes lead to failure of growth inhibition, another fundamental hallmark of carcinogenesis.

The protein products of tumor suppressor genes may function as transcription factors, cell cycle inhibitors, signal transduction molecules, cell surface receptors, and regulators of cellular responses to DNA damage.

Knudson's "two hit" hypothesis of oncogenesis, RB and Retinoblastoma (Fig. 7-28)

(Table 7-7) Selected Tumor Suppressor Genes and Associated Familial Syndromes and Cancers

RB: Governor of Proliferation #

RB, a key negative regulator of the G1/S cell cycle transition, is directly or indirectly inactivated in most human cancer.

The decision of a cell to progress from G1 into S is of great importance, since once a cell enters the S phase it is obligated to complete mitosis. High levels of CDK4/cyclin D, CDK6/cyclin D, and CDK2/cycln E complexes lead to hyperphosphorylation and inhibition of RB, releasing E2F transcription factors that drive the expression of genes that are needed for progression to S phase. (Fig 7-29)

Two questions

  1. Why do patients with germline RB mutations preferentially develop only a few types of cancer?
  2. Why aren't acquired mutations of RB found in all kinds of cancer?

Loss of normal cell cycle control is central to malignant transformation and that at least one of four key regulators of the cell cycle (p16/INK4a, cyclin C, CDK4, RB) is dysregulated in the vast majority of human cancers.

The antiproliferative effect of RB is abrogated in cancers through a variety of mechanisms, including:

  • Loss-of-function mutations affecting RB
  • Gene amplifications of CDK4 and cyclin D genes
  • Loss of cyclin-dependent kinase inhibitors (p16/INK4a)
  • Viral oncoproteins that bind and inhibit RB (E7 protein of HPV)

TP53: Guardian of the Genome #

TP53, a tumor suppressor gene that regulates cell cycle progression, DNA repair, cellular senescence, and apoptosis, is the most frequently mutated gene in human cancer.

It's found in more than 50% of cancers.

Most case 2 alleles mutated, less commonly, individuals inherit one mutated TP53 allele. (Li-Fraumeni syndrome, 25-fold greater chance)

Analogous to RB, many tumors lacking TP53 mutations have instead other mutations affecting proteins that regulate p53 function. (MDM2 stimulate the degration of p53) (Fig. 7-30)

DNA damage is sensed by complexes containing kinases of the ATM/ATR family; these kinases phosphorylate p53, liberating it from inhibitors such as MDM2. Active p53 then upregulates the expression of proteins such as the cyclin-dependent kinase inhipbitor p21, therebry causing cell-cycle arrest at the G1-S checkpoint.

Like RB, p53 is inactivated by viral oncoproteins, such as the E6 protein of HPV.

Other Tumor Suppressor Genes #

(Table 7-7)

APC: Gatekeeper of Colonic Neoplasia #

Adenomatous polyposis coli (APC) is a member of the class tumor suppressors that function by downregulating growth-promoting signaling pathway

APC is a component of the WNT signaling pathway, which has a major role in controlling cell fate, adhesion, and cell polarity during embryonic development. (Fig. 7-31)

E-Cadherin #

beta-catenin binds to the cytoplasmic tail of E-cadherin, a cell surface protein that maintains intercellular adhesiveness.

Germline loss-of-function mutations of E-cadherin gene, known as CDH1, cause familial gastric carcinoma.


CDKNA2 encodes two protein product: the p16/INK4a cyclin-dependent kinase inhibitor, which block CDK4/cyclin D-mediated phosphorylation of RB, thereby reinforcing the RB checkpoint; and p14/ARF, which activates the p53 pathway by inhibiting MDM2 and preventing destruction of p53.

TGF-beta Pathway #

TGF-beta is a potent inhibitor of proliferation. It regulates cellular processes by binding to TGF-beta receptors I and II.

In many forms of cancer these growth-inhibiting effects are impaired by loss-of-function mutation in the TGF-beta signaling pathway.


PTEN (phosphates and tensin homologue) is a membrane-associated phosphates, acts as a tumor suppressor by serving as a brake on the PI3K/AKT arm of the receptor tryosine kinase pathway.

NF1 #
NF2 #
WT1 #
STK11 #

Growth-Promoting Metabolic Alterations: The Warburg Effect #

Even in the presence of ample oxygen, cancer cells demonstrate a distinctive form of cellular metabolism characterized by high levels of glucose uptake and increased conversion of glucose to lactose (fermentation) via the glycolytic pathway.

Evasion of Programmed Cell Death (Apoptosis) #

The sequence of events that lead to Apoptosis by signaling through the death receptor CD95/Fas.

Limitless Replicative Potential: The Stem Cell Like Properties of Cancer Cells #

Angiogenesis #

Invasion and Metastasis #

Invasion and metastasis are the results of complex interactions between cancer cells and normal stroma and are the major causes of cancer-related morbidity and mortality. Hence, they are the subjects of intense scrutiny.

For tumor cells to emerge from a primary mass, enter blood vessels or lymphatics, and produce a secondary growth at a distant site, they must go through a series of steps (Fig. 7-36), each of which is inefficient and subject to a multitude of controls; hence, at any point in the sequence, the breakaway cells may not survive.

The metastatic cascade is divided into two phases

  1. invasion of the extracellular matrix (ECM)
  2. vascular dissemination, homing of tumor cells, and colonization

Subsequently, the molecular genetics of the metastatic cascade, as currently understood, are presented.

Invasion of Extracellular Matrix #

Tissues are organizaed into compartments separated from each other by two types of ECM: basement membrane and interstitial connective tissue.

A carcinoma must first breach the underlying basement membrane, then traverse the interstitial connective tissue, and ultimately gain access to the circulation by penetrating the vascular basement membrane.

This process is repeated in reverse when tumor cell emboli extravasate at a distant site.

Invasion of the ECM initiated the matastatic cascade and is an active process that can be resolved into several steps. (Fig. 7-37)

  • "Loosening up" of tumor cell-tumor cell interactions
  • Degradation of ECM
  • Attachment to novel ECM components
  • Migration and invation of tumor cells

Dissociation of cancer cells from one another is often the result of alterations in intercellular adhesion molecules and is the first step in the process of invasion.

Normal epithelial cells are tightly glued to each other and the ECM by a variety of adhesion molecules. Cell-cell interactions are mediated by the cadherin family of transmembrane glycoproteins.

E-cadherins mediate the homotypic adhesion of epithelial cells. In several epithelial tumors, including adenocarcinomas of the colon, stomach, and breast, E-cadherin function is lost.

Presumably, this reduces the ability of cells to adhere to each other and facilitates their detachment from the primary tumor and their advance into the surrounding tissues.

Degradation of the basement membrane and interstitial connective tissue is the second step in invasion.

Tumor cells may accomplish this by either secreting proteolytic enzymes themselves or by inducing stromal cells (e.g., fibroblasts and inflammatory cells) to elaborate proteases.

Many different families of proteases, such as matrix metalloproteinases (MMPs), cathepsin D, and urokinase plasminogen activator, have been implicated in tumor cell invasion.

MMPs regulate tumor invasion not only by remodeling insoluble components of the basement membrane and interstitial matrix but also by releasing ECM-sequestered growth factors.

Indeed, cleavage products of collagen and proteoglycans also have chemotatic, angiogenic, and growth-promoting effect.

For example, MMP9 is a gelatinase that cleaves type IV collagen of the epithelial and vascular basement membrane and also stimulates release of VEGF from ECM-sequestered pools.

Concurrently, the concentrations of metalloproteinase inhibitors are reduced so that the balance is tilted greatly toward tissue degradation.

The third step in invasion involves changes in attachment of tumor cells to ECM proteins.

Normal epithelial cells have receptors, such as integrins, for basement membrane laminin and collagens that are polarized at their basal surface; these receptors help to maintain the cells in a resting, differentiated state.

Loss of adhesion in normal cells leads to induction of apoptosis, while, not surprisingly, tumor cells are resistant to this form of cell death.

Locomotion is the final step of invasion, propelling tumor cells through the degraded basement membranes and zones of matrix proteolysis.

Migration is a multistep process that involves many families of receptors and signaling proteins that eventually impinge on the actin cytoskeleton.

Cells must attach to the matrix at the leading edge, detach from the matrix at the trailing edge, and contract the action cytoskeleton to ratchet forward.

Proteolytic cleavage liberates growth factors bound to matrix molecules. Stromal cells also produce paracrine effectors of cell motility, such as hepatocyte growth factor/scatter factor, which binds to the receptor tyrosine kinase MET on tumor cells.

The ECM and stromal cells surrounding tumor cells are not a mere static barrier for tumor cells to traverse but instead constitute a varied environment in which reciprocal signaling between tumor cells and stromal cells may either promote or prevent tumorigenesis and/or tumor progression.

Tumor cells reside in a complex and ever-changing milieu composed of ECM, growth factors, fibroblasts, and immune cells, with significant cross-talk among all the components.

Vascular Dissemination and Homing of Tumor Cells #

Once in the circulation, tumor cells are vulnerable to destruction by a variety of mechanisms, including mechanical shear stress, spoptosis stimulated by loss of adhesion, and innate and adaptive immune defenses.

Within the circulation, tumor cells tend to aggregate in clumps. This is favored by homotypic adhesions among tumor cells as well as heterotypic adhesion between tumor cells and blood cells, particulary platelets (Fig. 7-36).

Formation of platelet-tumor aggregates may enhance tumor cell survival and implantability.

Tumor cells may also bind and activate coagulation factors, resulting in the formation of emboli. Arrest and extravasation of tumor emboli at distant sites involves adhesion to the endothelium, followed by egress through the basement membrane.

Of particular interest is the CD44 adhesion molecule, which is expressed on normal T lymphocytes and is used by these cells to migrate to selective sites in lymphoid tissues.

The site at which circulating tumor cells leave the capillaries to form secondary deposits is related to the anatomic location and vascular drainage of the primary tumor and the tropism of particular tumors for specific tissues.

Organ tropism may be related to the following mechanisms:

  • Tumor cells may have adhesion molecules whose ligands are expressed preferentially on the endothelial cells of the target organ.
  • Chemokines have an important role in determining the target tissues for metastasis. For instance, some breast cancer cells express the chemokine receptors CXCR4 and CCR7.
  • In some cases, the target tissue may be a nonpermissive environment - "unfavorable soil", so to speak, for the growth fo tumor seedlings.

Breast cancer cells secrete parathyroid hormone-related protein (PTHRP), which stimulates osteoblasts to make RANK ligand (RANKL). RANKL then activates osteoclasts, which degrade the bone matrix and release growth factors embedded within it, like IGF and TGF-beta.

Molecular Genetics of Metastasis Development #

Several competing theories have been proposed to explain how the metastatic phenotype arises. (Fig. 7-38)

  • The clonal evolution model suggests that as mutations accumulate in genetically unstable cancer cells and the tumor become heterogeneous, a rare subset of tumor cell subclones acquires a pattern of gene expression that is permissive for all steps involved in metastasis.
  • A subset of breast cancers has a metastatic gene expression signatures similar to that found in metastases, although no clinical evidence for metastasis is apparent.
  • combines the two aboves.
  • Capacity for metastasis involves not only properties intrinsic to the cancer cells but also the characteristics of their microenvrioment, such as the components of the stroma, the presence of infiltrating immune cell, and angiogennesis.

At least a dozen genes lost in metastatic lesions have been confirmed to function as "metastatis suppressors", most appear to affect various signaling pathways.

Among candidates for metastasis oncogenes are SNAIL and TWIST, which encode transcription factors whose primary function is to promote epithelial-to-mesenchymal transition(EMT).

In EMT, carcinoma cells downregulate certain epithelial markers (e.g., E-cadherin) and upregulate certain mesenchymal markers (e.g., vimentin and smooth muscle action). These changes are believed to favor the development of a promigratory phenotype that is essential for metastasis.

Loss of E-cadherin expression seems to be a key event in EMT, and SNAIL and TWIST are transcriptional repressors that downregulate E-dadherin expression.

Role of Stromal Elements in Metastasis #

Macrophases in the stroma secrete matrix-degrading proteases, and cleavage of ECM proteins can release latent angiogenic factors and growth factors, such as TGF-beta.

Successful tumor cells must co-opt these and other interactions and use them to promote their growth and invasion, and it follows that these interactions, and the stromal cells themselves, are potential targets in cancer treatment.

Evasion of Host Defense #

Long one of the “holy grails” of oncology, the promise of therapies that enable the host immune system to recognize and destroy cancer cells is finally coming to fruition, largely due to a clearer understanding of the ways by which cancer cells evade the host response.

Paul Ehrlich first conceived the idea that tumor cells can be recognized as “foreign” and eliminated by the immune system. Subsequently, Lewis Thomas and Macfarlane Burnet formalized this concept by coining the term immune surveillance, which implies that a normal function of the immune system is to constantly “scan” the body for emerging malignant cells and destroy them.

This idea has been supported by many observations—the presence of lymphocytic infiltrates around tumors and reactive changes in lymph nodes draining sites of cancer; experimental results, mostly with transplanted tumors; the increased incidence of some cancers in immunodeficient people and mice; the direct demonstration of tumor-specific T cells and antibodies in patients; and most recently and most directly, the response of advanced cancers to therapeutic agents that act by stimulating latent host T-cell responses.

The fact that cancers occur in immunocompetent individuals indicates that immune surveillance is imperfect; however, that some tumors escape such policing does not preclude the possibility that many others were aborted. Assuming that the immune system is capable of recognizing and eliminating nascent cancers, it follows that the tumors that do grow out must be composed of cells that are either invisible to the host immune system or that release factors that actively suppress host immunity.

The term cancer immunoediting has been used to describe the ability of the immune system to shape and mold the immunogenic properties of tumor cells in a fashion that ultimately leads to the darwinian selection of subclones that are best able to avoid immune elimination.

In support of this idea, in the past several years it has become evident that tumors produce a number of factors that promote immune tolerance and immune suppression, and that therapeutic agents that neutralize these factors can lead to tumor regression, even in patients with advanced cancers. These encouraging clinical responses constitute strong evidence that evasion of host immunity is indeed a hallmark of many, if not all, human cancers.

The following section explores some of the important questions about tumor immunity: What is the nature of tumor antigens? What host effector systems recognize tumor cells? How do tumors evade these host mechanisms? And, how can immune reactions against tumors be exploited therapeutically?

Tumor Antigene #

Antitumor Effector Mechanisms #

Immune Surveillance and Escape #

Genome Instability #

Hereditary Nonpolyposis Colon Cancer Syndrome #

Xeroderma Pigmentosum #

Diseases with Defects in DNA Repair by Homologous Recombination #

Cancers Resulting from Mutations Induced by Regulated Genomic Instability: Lymphoid Neoplasms #

Cancer-Enabling Inflammation #

Dysregulation of Cancer-Associated Genes #

Chromosomal Changes #

Chromosomal Translocations #
Deletions #
Gene Amplification #
Chromothrypsis #

Epigenetic Changes #

Noncoding RNAs and Cancer #

Molecular Basis of Multistep Carcinogenesis #

Carcinogenic Agents and Their Cellular Interactions #

Chap 23. The Breast #

  • Lobule
  • Duct
  • Intralobular stroma
  • Interlobular stroma

Disorders of Development #

Clinical Presentations of Breast Disease #

Inflammatory Disorders #

Benign Epithelial Lesions #

Carcinoma of the Breast #

Types of Breast Carcinoma #

Carcinoma in situ refers to a neoplastic proliferation of epithelial cells that is confined to ducts and lobules by the basement membrane.

It's now recognized that these growth patterns are not related to the cell of origin, but rather reflect differences in tumor cell genetics and biology. By current convention, "lobular" refers to invasive carcinomas that are biologically related to LCIS, and "ductal" is used more generally for adenocarcinomas that cannot be classified as a special histologic type.

Carcinoma in Situ #

Ductal Carcinoma in Situ (DCIS) #

DCIS is a malignant clonal proliferation of epithelial cells limited to ducts and lobules by the basement membrane.

Myoepithelial cells are preserved in involved ducts/lobules, although they may be diminished in number. DISC can spread throughout the ductal system and produce extensive lesions involving an entire sector of a breast.

DCIS is almost always dected by mammography. Without screening, fewer than 5% of all carcinomas are detected when in situ, but DCIS comprises 15% to 30% of carcinomas in screened populations (Fig. 23-14).

Most are identified as a result of calcifications associated with secretory material or necrosis; less commonly, periductal fibrosis surrounding DCIS forms a mammographic density or a vaguely palpable mass.

(Fig. 23-17) Morphology

The majority of these invasive cancers occurs in the same quadrant and have a similar grade and expression of ER and HER2 as the asosciated DISC. Tumors with high-grade or extensive DCIS are believed to have a higher risk for progression to invasive carcinoma.

Remarkably, the overall death rate for women with DCIS is lower than that for women in the population as a whole, possibly because mammographic screening is a "marker" for better access to medical care or other socioeconomic factors that are associated with longevity.

Mastectomy is curative in greater than 95% of women. Breast conservation is appropriate for most women but has a slightly higher risk of recurrence - about half of which are DCIS and half invasive carcinoma.

The major risk factors for recurrence are

  1. high nuclear grade and necrosis
  2. extent of disease
  3. positive surgical margins

Postoperative radiation therapy and Tamoxifen also reduce the risk of recurrence.

Luminal Carcinoma in Situ (LCIS) #

LCIS is clonal proliferation of cells within ducts and lobules that grow in a discohesive fasion, usually due to an acquired loss of the tumor suppressive adhesion protein E-cadherin.

The term "lobular" was used to describe this lesion because the cells expend but do not distort involved space and, thus, the underlying lobular architecture is preserved.

LCIS is always an incidental biopsy finding, since it is not associated with calcifications or stromal reactions that produce mammographic desities.

As a result, its incidence (1% to 6% of all carcinomas) did not increased after the introduction of mammographic screening. When both breasts are biopsied, LCIS is bilateral in 20% to 40% of cases, compared with 10% to 20% of cases of DICS.

The cells of atypical lobular hyperplasia, LCIS, and invasive lobular carcinoma are morphologically identical. In most cases, loss of cellular adhesion of normal epithelial cells in the breast and other glandular tissues.

E-cadherin functions as a tumor suppressor protein in such tissues, and may be lost in neoplastic proliferations through a variety of mechanisms, including mutation of the E-cadherin gene (CDH1).

(Fig. 23-19) Morphology

LCIS is a risk factor for invasive carcinoma. Invasive carcionma develops in 25% to 35% of women over 20 to 30 years time, or at a rate of about 1% per year, similar to that observed for untreated DISC.

However, unlike DCIS, the risk is almost as high in the contralateral breast as in the ipsilateral breast.

Invasive carcinomas developing in women after LCIS are three-fold more likely to be lobular carcinoma; however, most are of other morphologies.

Treatment choices include bilateral prophylatic mastectomy, tamoxifen, or, more typically, close clinical follow-up and mammographic screening.

Invasive (Infiltrating) Carcinoma #

Invasive carcinomas can be divied based on molecular and morphologic characteristics into several clinically important subgroups.

Breast carcinomas have a wide variety of morphologic apperances. One third can be classified morphologically into special histologic types, some of which are strongly associated with clinically relevant biologic characteristics.

These breast cancers fall into three major molecular subtypes, each with important associations with clinical features, response to treatment, and outcome. (Fig 23-20, Table 23-3)

  1. ER-positive, HER2-negative
  2. HER2-positive
  3. ER-negative, HER2-negative

ER-positive, HER2-negative (also termed "luminal," 50% to 65% of cancers) is divided into two subgroups based on proliferlation rates.

  1. ER-positive, HER2-negative, low proliferation (40% to 55%):
    • This group of breast cancers makes up the majority of cancers in older women and in men.
    • It's also the most common type detected by mammographic screening and in women treated with menopausal hormon therapy.
    • The gene expression signature of this group of cancers is dominated by genes that are directly regulated by Estrogen receptor.
    • When these carcinomas do metastasize, it is often after a long period of time (over 6 years) and typically to bone.
    • They respond well to hormonal treatment and long survival with metastatic disease is possible, despite the fact that incomplete responses to chemotheraphy are the rule.
  2. ER-positive, HER2-negative, high proliferation (10%):
    • Although these tumors are ER-positive, ER levels may be low and progesterone receptor expression may be low or absent.
    • This is the most common type of carcinoma associated with BRAC2 germline mutations.
    • The mRNA expression pattern is similar to other ER+ cancers, but there is higher expression of genes related to proliferation.
    • These tumors tend to have a much higher burden of chromosomal aberrations that low-grade ER+ tumors. However, unlike low-grade ER+ cancers, about 10% of these carcinomas show a complete response to chemotherapy.

HER2-positive (20%) is the second most mulecular subtype of invasive breast cancer. * About half of these cancers are ER+. When present, ER expression is usually low; progesterone receptor expression is often absent. * These cancers are relatively more common in young women and in non-white women. * More than half (53%) of familial breast cancers in patients with germline TP53 mutations (Li-Fraumeni syndrome) develop carcinomas that are positive for both ER and HER2. * The mRNA profile shows increased expresion of HER2 and flanking genes on the same amplicon, as well as genes related to proliferation. * These cancers characteristically have complex interchromosomal translocations, high-level amplifications of HER2, and a high mutational load. * Identification of cancers belonging to this subtype is achieved through assays of HER2 protein overexpression or HER2 gene amplification. (Fig. 23-21) * Cancers in this group can metastasize when small in size and early in the course, oftern to viscera and brain.

Before the implementation of HER2-targeted therapy, HER2+ cancers were associated with a poor clinical outcome. However, one third or more of these carcinomas respond completely to antibodies that bind and block HER2 activity, and such patients now have an excellent prognosis. The remarkable efficacy of this form of therapy proves the importance of HER2 as an oncogenic "driver".

While the introduction of trastuzumab (Herceptin), a humanized monoclonal antibody that specifically binds and inhibits HER2, markedly improved the outlook for patients with HER2 overexpression cancers, not all HER2+ carcinomas respond and some that do become resistant to treatment.

Multiple mechanisms of primary or acquired resistance have been described. Some tumors express a truncated form of HER2 that lacks the trastuzumab-binding site but retains kinase activity, while others upregulate downstream pathway, such as the PI-3 kinase pathway.

Numerous therapeutic agents are under investigation to improve response and overcome resistance to trastuzumab, including new antibodies that bind different HER2 epitopes; dual tyrosine kinase inhibitors that target both EGFR and HER2; antibody-toxin conjugates (one of which is now approved for use); and inhibitors of downstream signaling components, such as PI-3 kinase and AKT.

ER-negative, HER2-negative tumors ("basal-like" triple negative carcinoma; 15%) * These cancers are more common in young premenopausal women as well as African American and Hispanic women. * The majority of carcinomas arising in women with BRCA1 mutations are of this type. * Due to high proliferation and rapid growth, this type of cancer is particularly likely to present as a palpable mass in the interval between mammographic screenings.

These are the most distinctive group of breast cancers. They share a number of genetic similaties with serous ovarian carcinomas, including the association of familial cancers of both types with germline BRCA mutations.

Neverthless, in some cases features are present that overlap with other molecular subgroups. For example, about 10% of basal-like cancers express ER and about 15% express HER2. Thus, assays for protein expression or gene amplification must be done to determine whether treatment targeting ER or HER2 is indicated.

These cancers can metastasize when small in size, frequently to vercera and to the brain. However, approximately 30% completely respond to chemotherapy and cure may be possible in this chemosensitive subgroup.

Recurrences are generally diagnosed within 5 years of treatment. Local recurrence is common, even after mastectomy. Prolonged survival after distant metastasis is rare.

All types of invasive carcinoma are graded using the Nottingham Histologic Score. Carcinomas are scored for tubule formation, nuclear pleomorphism, and mitotic rate and the points added to divide carcinomas into grade I (well differentiated), grade II (moderately differentiated), and grade III (poorly differentiated) types.

Special Histologic Types of Invasive Carcinoma #

Multiple subtypes of invasive carcinoma are recognized withdistinctive morphologies and relatively unique biologic characteristics.

Lobular carcinoma is the subtype with the clearest association of phenotype and genotype. Most cases show biallelic loss of expression of CDH1. Due to loss of E-cadherin, lobular carcinomas are discohesive and often fail to incite a desmolastic response.

Medullary carcinoma is of great interest due to the finding that many tumors of this type have features that are characteric of BRCA1-associated carcinomas. Among cancers arising in BRCA1 carriers, 13% are of medullary type, and up to 60% have a subset of medullary features.

Although the majority of medullary carcinomas are not associated with germline BRCA1 mutations, hypermethylation of the BRCA1 promoter leading to downregulation of BRCA1 expression is abserved in 67% of these tumors.

Micropaillary carcinoma shows a characteristic pattern of anchorage-independent growth. Although the cells are adherent to each other and express E-cadherin, they lack adhesion to the stroma.

Male Breast Cancer #

In man only 1% of that in women.

Risk factors are similar to those in women and include increasing age, first degree relatives with breast cancer, exposure to exogenous strogens or ionizing radiation, infertility, obesity, prior benign breast disease, and residency in Western countries.

From 3% to 8% of cases are associated with Klinefelter syndrome and decreased testicular function.

From 4% to 14% of cases in males are attributed to germline BRCA2 mutations.

The pathology of male breast cancer is remarkably similar to that of cancers seen in women. However, ER positivity is more common (81%).

Prognostic and Predictive Factors #

The outcome for women with breast cancer depends on the biologic features of the carcinoma (molecular or histologic type) and the extent to which the cancer has spread (stage) at the time of diagnosis.

Many women with breast cancer have a normal life expectancy, whereas others have only a 10% chance of being alive in 5 years. Tumors that present with distant metastasis (<10% of breast cancer cases) or with inflammatory carcinoma (<5%) have particularly poor prognosis.

Stromal Tumor #

Other Malignant Tumors of the Breast #

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