A tumor is considered benign when its gross and microscopic characteristics are relatively innocent, implying that it will remain localized and cannot spread to other sites. A benign tumor is generally composed of well-differentiated cells that resemble their normal counterpart. In general, the addition of the suffix -oma to the cell of origin describes benign tumors; for example, adenoma indicates a benign tumor of epithelial cell origin. Tumors that arise from mesenchymal tissues are designated according to their putative cell of origin (e.g., fibroma, chondroma, lipoma, and leiomyoma). Benign tumors can also be classified on the basis of their macroscopic pattern; for example, papillomas are benign epithelial tumors with certain growth characteristics, such as exophytic or finger-like projections.

The classification of malignant tumors essentially follows that of benign tumors, with some exceptions. Malignant neoplasms arising from epithelial cells are termed carcinomas. Carcinomas are further classified on the basis of the type of epithelium, for example, glandular as adenocarcinoma (Fig. 10.2), squamous as squamous cell carcinoma (Fig. 10.3), and transitional as transitional cell carcinoma. Malignant epithelial tumors that have not extended through the underlying basement membrane are described as in situ carcinoma. Malignant tumors arising from mesenchymal tissue are broadly designated as sarcomas (Fig. 10.4). These are further subclassified on a histogenetic basis according to the normal tissue they resemble or its embryonal counterparts, for example, fibrosarcoma, chondrosarcoma, leiomyosarcoma, and rhabdomyosarcoma.

There are tumors that do not follow any classification scheme, and they have been identified by trivial names, such as seminoma and melanoma. Other tumors carry eponyms, such as Hodgkin’s disease and Ewing’s sarcoma.

Tumors within a single organ or single type of epithelium are further subclassified into different types; each has its own characteristics, prognosis, and response to therapy. Malignant tumors that extend into surrounding tissue without respecting normal tissue boundaries, are capable of invading lymphatics and blood vessels, and can be transported to distant sites. Several salient abnormalities are helpful to the pathologist in making the morphological diagnosis of such tumors, and they are expressed in two ways: First, there are abnormalities that affect individual cells in the form of cytological features and increased mitotic activity. Cytological features of malignancy include cell enlargement, increased ratio of nuclear to cytoplasmic area, pleomorphism (variation in size and shape), clumping of nuclear chromatin, and big nucleoli (Fig. 10.2b). Second, there are abnormalities that affect intercellular relationship, i.e., altered orientation of neoplastic cells and stroma leading to disorganization [3].

Normal cells have an ordered growth pattern and a predicted relationship with their neighboring cells, and that growth pattern is predominantly two-dimensional. Further normal cell division is inhibited by contacts made with other cells; this is the phenomenon of contact inhibition [8]. In contrast, tumor cells exhibit loss of contact inhibition and continue to display a disordered growth pattern.

Another feature that distinguishes normal growth from malignant proliferation is the reduced dependence of the latter on the presence of the known stimulatory and inhibitory growth factors. The diversion from the control of the growth regulatory factors can be explained, in part, by the discovery of biochemical changes within cancer cells resulting from some genetic alterations. Thus, when normal cells are grown in culture, they continue to divide for a limited number of generations and then experience a senescent crisis, in which most cells stop dividing and die and no cells survive to establish permanent cell lines. On the other hand, human tumor cells usually have an unlimited potential for growth and are thus immortalized [9].

This distinctive growth factor independence or autonomy has been attributed to several mechanisms including ability of tumor cells to secrete mitogenic growth factors that have a growth-stimulatory ability on the same cell that has released them [10].

Another characteristic feature of human malignancy is its ability to escape the human immune surveillance pathways. It is known that human tumor cells express on their surfaces novel antigens that are not present on the surfaces of their untransformed progenitors. One type of novel antigen may be common to many different types of malignancy and may be recognized by the natural killer lymphocytes even without specific prior immunization [5]. In other instances, novel antigens specific to a particular type of tumor may be displayed. According to one theory of tumorigenesis, all individuals develop abundant transformed cells over the course of their lives, but most of these cells are recognized and destroyed by one or another module of the host’s immune mechanisms. Support for this theory stems from the observation of the substantial increase in the incidence of malignancy in patients with acquired immune deficiency syndrome, in patients with organ transplants receiving intensive immunosuppressive agents, and in patients with other immune deficiency disorders. It has been proven that tumor cells may escape the host immune system by downregulating the expression of HLA antigens, which normally assist lymphocyte recognition of the target cells.

Tumor cells exhibit a vast array of metabolic differences distinguishing them from their untransformed counterparts. This is illustrated primarily in simplified metabolic activities and by an increased synthesis of material necessary for cell division. Some of the most striking metabolic alterations include the utilization of anaerobic pathways and the increased utilization of glucose transport [11].

Enormous scientific evidence has accumulated over more than half a century to indicate that neoplastic transformation occurs as a direct consequence of alterations to the cell genome.

Four basic approaches have been used to identify genes involved in cancer: (a) the study of cancer-causing viruses, (b) bioassays for cancer genes in tissue culture systems, (c) localization of genes at sites of chromosomal alteration in tumor specimens, and (d) isolation of genes for cancer-predisposing familial syndromes.

It is well known that agents that induce damage of the DNA (mutagens) have potential carcinogenic effects. The DNA found in the nucleus of every living cell encodes the heritable or genetic information necessary to direct the development of that organism from a single fertilized cell to the mature organism. Therefore, the progenitor tumor cells that sustain genetic alterations are said to undergo somatic mutations that promote the multistep process of neoplastic development.

From many studies, it became very clear that some of the information encoding cancerous behavior of the donor cells could be passed to the recipient cells via DNA molecules. It was not until the early 1980s that, with the advent of gene cloning, it was possible to isolate these cellular oncogenes (Table 10.1).

Activation of cellular oncogenes is a complex process that involves a variety of somatic mutational mechanisms. The c-myc oncogene develops its malignant properties through mechanisms that affect the level of expression of its encoded proteins without any associated alteration in its protein structure. Recently, the prognostic significance of c-myc in lymphoma has also been described [15].

On the other hand, a quantitative change in the structure of the encoded proteins may be responsible for oncogene activation. In chronic myelogenous leukemia, for example, the abl gene undergoes fusion with a fully unrelated gene, bcr. The bcr-abl hybrid protein encoded by these fused genes differs substantially in structure and function from the normal abl proto-oncogene protein [16].

It was clear, however, that single oncogenes were not capable of inducing transformation of fully normal cells into totally malignant cells. Instead, the action of a single oncogene usually induces only partial progression to malignancy. Fortunately, this has served as a protective mechanism to prevent the development of cancers in response to single oncogenes that arise through isolated genetic mishaps. Therefore, it appears that each step through which cells pass in the progression from normalcy to malignancy (multistep carcinogenesis) is characterized by a distinct genetic change, often one that creates an oncogene. However, the precise number of the distinct steps for most human tumors is poorly understood.

Nonlethal genetic damage may be acquired by the action of environmental agents, such as chemicals, radiation, or viruses, or it may be inherited in the germ line. The current hypothesis implies that cancer formed as a result of clonal expansion of a single progenitor cell that has incurred the genetic damage (i.e., tumors are monoclonal). This theory has been supported by many studies that revealed clonality in neoplasm that have been assessed readily in women who are heterozygous for polymorphic X-linked markers, such as the enzyme glucose-6-phosphate dehydrogenase or X-linked restriction fragment length polymorphisms or in clonality assessed in lymphoid neoplasm. Mutant alleles of proto-oncogenes are called oncogenes [17, 18].

Three classes of normal regulatory genes—growth-promoting proto-oncogenes; growth-inhibiting cancer suppressor genes (antioncogenes); and genes that regulate programmed cell death, or apoptosis—are the principal targets of genetic damage [1]. They are considered dominant because they transform cells despite the presence of their normal counterpart. In addition to the three classes of genes mentioned earlier, a fourth category of genes, those that regulate repair of damaged DNA, is pertinent in carcinogenesis.

Genes that promote autonomous cell growth in cancer cells are called oncogenes. They are derived by mutations in proto-oncogenes and are characterized by the ability to promote cell growth in the absence of normal growth-promoting signals. Their products, called oncoproteins, resemble the normal products of proto-oncogenes except that oncoproteins are devoid of important regulatory elements, and their production in the transformed cells does not depend on growth factors or other external signals.

All normal cells require stimulation by growth factors to undergo proliferation. Many cancer cells acquire growth self-sufficiency, however, by acquiring the ability to synthesize the same growth factors to which they are responsive. Such is the case with platelet-derived growth factor (PDGF) and transforming growth factor α (TGF-α). Many glioblastomas secrete PDGF, and sarcomas make TGF-α.

There are several oncogenes that encode growth factor. Those oncogenes represent either mutation or overexpression of normal forms of growth factor receptors. Mutant receptor proteins can send continuous mitogenic signals to cells, even in the absence of the growth factor in the environment [1]. Overexpression can render cancer cells hyperresponsive to normal levels of the growth factor, a level that would not normally trigger proliferation. Among the examples of overexpression is the receptor called HER2 (ERBB2), which is present in 30 % of breast cancers and present in variable percentages in other human cancer. Breast cancers which are positive for Her2 are more sensitive to the mitogenic effects of small amounts of growth factors, and a high level of HER2 protein in breast cancer is associated with poor prognosis. The clinical significance of HER2 in breast cancers is clearly evident by the treatment of breast cancer with anti-HER2 antibodies which block the extracellular domain of this receptor [19, 20].

Mutations in genes that encode various components of the signaling pathways are a common process in cancer. These signaling molecules couple growth factor receptors to their nuclear targets. The most important members in this category are RAS and ABL.

Approximately 30 % of all human tumors contain mutated versions of the RAS gene. In some tumors, such as colon and pancreatic cancers, the incidence of RAS mutations is even higher [1]. The activated RAS in turn activates downstream regulators of proliferation, including the RAF-MAP kinase mitogenic cascade, which flood the nucleus with signals for cell proliferation. In chronic myeloid leukemia and certain acute leukemias, this activity is unleashed because the ABL gene is translocated from its normal abode on chromosome 9 to chromosome 22, where it fuses with part of the breakpoint cluster region (BCR) gene. The BCR-ABL hybrid gene has potent tyrosine kinase activity, and it activates several pathways, including the RAS-RAF cascade just described. The crucial role of BCR-ABL in transformation has been confirmed by the dramatic clinical response of patients with chronic myeloid leukemia after therapy with an inhibitor of ABL kinase called STI 571 (Gleevec); this is another example of rational drug design emerging from an understanding of the molecular basis of cancer.

Growth autonomy in neoplasm may occur as a consequence of mutations affecting genes that regulate transcription of DNA such as MYC oncogene that has been localized to the nucleus. The MYC proto-oncogene is expressed in virtually all cells, and the MYC protein is induced rapidly when quiescent cells receive a signal to divide. The MYC protein binds to the DNA, causing transcriptional activation of several growth-related genes, including cyclin-dependent kinases (CDKs), whose product drives cells into the cell cycle. In normal cells, MYC levels decline to near basal level when the cell cycle begins. In contrast, oncogenic versions of the MYC gene are associated with persistent expression or overexpression, contributing to sustained proliferation. The classic example is the dysregulation of the MYC gene resulting from a t(8; 14) translocation that occurs in Burkitt’s lymphoma [1].

While oncogenes play a critical role in tumorigenesis, another group of genes known as tumor suppressors appears to be equally significant. These tumor suppressor genes, as the name implies, function in the normal cells to restrict cellular proliferation. However, tumor suppressor genes are involved in tumorigenesis when they suffer genetic inactivation or loss-of-function mutations, affecting the two redundant copies of these genes and resulting in the elimination of that important barrier to cell growth.

The loss of wild-type tumor suppressor genes such as Rb and p53 is associated with a wide variety of human tumors. Many proto-oncogenes transform in model systems in which the wild-type gene is overexpressed or expressed in the wrong cell type; similarly, overexpression or inappropriate expression of some proto-oncogenes, such as c-myc, is thought to be tumorigenic in some human tissues.

The most commonly mutated tumor suppressor gene in human cancer is p53, with at least 50 % of tumors having abnormal p53 genes [21]. The gene participates in a cell cycle checkpoint signal transduction pathway that causes either a G1 arrest or apoptotic cell death following DNA damage. Loss of p53 function during tumorigenesis can thus result in both inappropriate progressions through the cell cycle after DNA damage and survival of a cell that might otherwise have been destined to die. Another newly discovered tumor suppressor gene is the p16. Since its discovery as a CDKI (cyclin-dependent kinase inhibitor) in 1993, the tumor suppressor p16 has gained widespread importance in tumor biology [22]. The frequent mutations and deletions of p16 in human cancer cell lines first suggested an important role for p16 in carcinogenesis.

APC is another tumor suppressor gene [23] and its loss is common in colon cancer. APC is a cytoplasmic protein whose function in normal cells is to bind another protein called β-catenin and bring about its degradation. β-Catenin is a transcriptional factor, and, if APC function is defective by mutation, accumulated level of β-catenin occurs in the cells, driving cell proliferation. Individuals born with one mutant allele develop hundreds to thousands of adenomatous polyps in the colon during their teens or 20s. If the cells develop a second mutation of the normal inherited gene on the other allele, it leads to development of carcinoma of the colon.

Inherited cancer syndromes include several well-defined cancers in which inheritance of a single mutant gene greatly increases the risk of a person developing a tumor. The predisposition to these tumors shows an autosomal dominant pattern of inheritance. Childhood retinoblastoma is the most striking example of this category.

Familial adenomatous polyposis is the other classic example. For most the development of the clinical features is age dependent, and that development may be early in life, as with hereditary retinoblastoma, or relatively later in life as with colorectal carcinoma.

Almost all the common types of cancers that occur sporadically have been reported to occur in familial forms. Examples include carcinomas of the colon and breast. Inherited susceptibility to breast cancer has been an area of intensive investigation for the past 10 years. Early work focused on identifying modes of transmission, which culminated in the identification of chromosome 17q12–21 as the first human genomic region that harbored an autosomal dominant susceptibility gene for breast cancer (BRCA1) in 1990. BRCA1 was subsequently identified, followed shortly by the identification of BRCA2 [26]. Research has elucidated much about the mutation spectrum and mutation frequency of these genes in specific populations in the past 3 years and is beginning to identify potential functions. Whereas progress in this area has been rapid and much is now known about inherited susceptibility to breast cancer, much more needs to be done to make these discoveries useful in the diagnosis, treatment, and ultimately prevention of breast cancer.

One of the best-studied examples is xeroderma pigmentosum, in which DNA repair is defective. It is a rare autosomal recessive disease characterized by deficiency of endonuclease, the enzyme partly responsible for repair of DNA damage. Children with this disorder develop multiple squamous cell carcinomas [18].