Neoplasia describes a large number of human diseases with extremely diverse characteristics. Therefore, the classification of neoplastic diseases into categories and subcategories is of great value in understanding them, diagnosing them, studying them, and developing treatments for them. Malignant transformation, by definition, results in abnormal cellular behavior. Tumor cells that have retained many of their specialized tissue functions and that are very similar appearing to their normal cellular counterparts are identified as well differentiated. Conversely, tumor cells that have lost much of their functions and that bear little similarity to their normal counterparts are identified as poorly differentiated. Poorly differentiated tumors are sometimes so abnormal that their cell or organ of origin cannot be recognized. However, although poorly differentiated tumor cells may have lost much of their specialized functions, their cellular ancestry can often still be recognized by more primitive characteristics.
The broadest classification of tumors relies on the most fundamental characterization of cell types based on their primitive embryologic origins. During early embryonic development, three cell lineages are established: ectoderm, endoderm, and mesoderm. All subsequent cells, including adult tumors, can be traced to one of these three cellular origins. As such, tumors are broadly classified into the categories of carcinoma if they originate from ectodermal or endodermal tissues or as sarcomas if they originate from mesodermal tissues. Even if completely unrecognizable by morphologic analysis, fundamental differences in the expression of certain proteins, especially intermediate filaments such as keratins and vimentin, will identify the lineage of origin.
Carcinomas are the most common cancer type and include all the common epithelial tissue cancers such as lung, colon, breast, and prostate cancers. Sarcomas arise from mesenchymal cell types, which are predominantly the connective tissues. Malignancies of blood cells, including leukemias and lymphomas, are technically a subtype of sarcomas because they are of mesenchymal origin. However, because of the highly specialized nature of hematologic cell types, they are generally grouped together and considered to be the entity of hematologic neoplasms, which includes leukemias and lymphomas. Further classification of carcinomas and sarcomas is based on the organ of origin. In the growing infant and child, mesenchymal tissues are very active in growth and remodeling, and mesenchymal tumors are common, including tumors of the muscle, cartilage, bone, and blood. In adults, the mesenchymal tissues are not very active, and epithelial tumors are by far the most common, including tumors of the lung, breast, prostate, and colon. Developments in gene expression profiling of tumors have enabled classification of tumors based on characteristic molecular portraits, and further work in this area may result in an entirely new classification of human tumors based on their gene expression profiles.
Epithelial cells are in constant turnover, arising from a basal layer that continually generates new cells. The mature and functional layer of cells performs specialized tissue or organ functions, and with senescence it is eventually sloughed off. Proliferating epithelial cells normally observe anatomic boundaries such as the basement membrane that underlies the basal layer of cells in the epithelium. The potential to divide, migrate, and differentiate is tightly controlled. The stimulus to divide may be autonomous or exogenous as a response to factors from adjacent or distant cells. Inhibitory signals and factors may also be present and serve to function as negative regulators to check uncontrolled growth. The neoplastic phenotype of epithelial cells can be seen as a spectrum from hyperplastic to preinvasive to frankly invasive and metastatic neoplasia, as illustrated in Figure 5–1. Because of their embryonic origins, malignancies of epithelial origin are termed carcinomas. Hyperplasia can be a normal physiologic response in some situations, such as that which occurs in the lining of the uterus in response to estrogens before the ovulatory phase of the menstrual cycle. It may also be a pathologic finding and associated with a predisposition to progress to invasive carcinoma. In such instances of hyperplasia, there are usually accompanying disorders of maturation that may be recognizable by microscopic examination. These changes are termed dysplasia, atypical hyperplasia, or metaplasia depending on the type of epithelium in which they are observed. More aggressive proliferation without the ability to invade through the basement membrane is termed preinvasive carcinoma, or carcinoma in situ. Technically, these cells do not have the capacity to invade the basement membrane and metastasize, although they may over time progress to invasive carcinoma. The term “invasive carcinoma” implies that tissue boundaries, especially the basement membrane, have been breached. Metastatic carcinoma occurs via the lymphatic system to regional lymph nodes and via the bloodstream to distant organs and other tissues. This pattern of metastasis, however, is not unique to epithelial malignancies. Epithelial neoplasms in general have a variable propensity to spread to regional nodes and distant sites. It is assumed that the natural history of most tumors is to follow this pattern of spread over time. The specific genotypic and phenotypic changes necessary to accomplish this spread are not well understood; they may, in some cases, be shared across tumor types, and in other cases they are unique to a given neoplasia. Certain molecular characteristics have been linked to clinical characteristics, although the exact mode of action is not fully understood.
Schematic depiction of phenotypic transition of epithelial cells from hyperplasia to invasive carcinoma.
From a pathophysiologic standpoint, certain structural and functional characteristics must be acquired by malignant cells, as outlined in Table 5–4. An increase in growth rate through several mechanisms has been described for different tumor types. It is known that the proliferative fraction (the percentage of cells in S phase, or actively synthesizing DNA) is elevated, and more so in histologically and clinically aggressive tumors. Changes in the tightly regulated cell cycle machinery have been observed, including abnormal levels of cyclins and other proteins that regulate cyclin-dependent kinases responsible for entry of the cell into S phase. Likewise, alterations of intermediate signaling proteins have been noted that couple external growth factor and hormonal stimuli to proliferation. The ability of cells to migrate and pass through cellular and ECM barriers can be enhanced in tumor cells. This can occur through the activation of proteolytic enzyme cascades from within the tumor cell or by the action of stromal cells that are directed to do so as a result of factors produced by nearby tumor cells. Through similar mechanisms, malignant cells can induce the formation of a microvasculature that is essential to support the continued growth of a tumor colony. Other functions necessary to breach the immune defenses and survive destruction by antitumor drugs can be mediated by the genetic program already possessed in latent form by tumor cells. Examples include modulation of antigens and alterations in drug metabolism or metabolic pathways that are targeted by certain drugs.
Table 5–4Phenotypic changes in the progression of neoplasia. |Favorite Table|Download (.pdf) Table 5–4 Phenotypic changes in the progression of neoplasia.
Abnormalities of cell cycle control
Exaggerated response to hormonal or growth factor stimuli
Lack of response to growth inhibitors or cell contact inhibition
Evasion of immune system
Invasion of tissue and stroma
Attachment to extracellular matrix
Secretion of proteolytic enzymes
Recruitment of stromal cells to produce proteolytic enzymes
Loss of cell cohesion
Ability to gain access to and egress from lymphatics and bloodstream
Establishment of metastatic foci
Ability to recruit vascularization to support growth of primary or metastatic tumor
Altered drug metabolism and drug inactivation
Increased synthesis of targeted enzymes
Enhanced drug efflux
Enhanced DNA damage repair
As described earlier, there is evidence that discrete phenotypic changes that arise from specific genetic alterations account for the progression from hyperplasia to metastatic neoplasia. Moreover, there is an interplay between these genetic changes and the inherent program of gene expression of a given epithelial type. Other highly regulated functions of epithelial cells include active or passive transport of ions or molecules as well as synthesis and secretion of specific proteins. These functions may also be lost, altered, or even enhanced for specific tumor types and likewise can create specific pathophysiologic and clinical entities. Two epithelial neoplasms are discussed in further detail. Colon cancer is an example of an epithelial neoplasm for which precursor lesions have been well studied because we can seek out and biopsy such lesions by colonoscopy. Breast epithelial tissue is responsive to steroid hormones and growth factors that may play a role in the development and behavior of breast cancer.
What factors determine the malignant potential of epithelial versus mesenchymal tumors?
What is the term applied to malignancies of epithelial origin?
What is the spectrum of characteristics of the neoplastic phenotype in epithelial cells?
The model of stepwise genetic alterations in cancer is best illustrated by observations made in colonic lesions representing different stages of progression to malignancy. Certain genetic alterations are found commonly in early-stage adenomas, whereas others tend to occur with significant frequency only after the development of invasive carcinoma. These changes are in keeping with the concept that serial phenotypic changes must occur in a cell for it to exhibit full malignant (invasive and metastatic) properties (Table 5–4). Two principal lines of evidence support the model of stepwise genetic alterations in colon cancer.
The rare familial syndromes associated with predisposition to colon cancer at an early age are now known to result from germline mutations. Familial adenomatous polyposis is the result of a mutation in the APC gene, which encodes a cell adhesion protein that has also been implicated in the control of β-catenin, a potent transcriptional activator. In the tumors that subsequently develop, the remaining allele has been lost. Similarly, hereditary nonpolyposis colorectal cancer is associated with germline mutations in DNA repair genes such as hMSH2 and hMLH1. These genes can also be affected in sporadic cancers.
The carcinogenic effects of factors known to be linked to an increased risk of colon cancer constitute the second line of evidence for a genetic basis for colon cancer. Substances derived from bacterial colonic flora, ingested foods, or endogenous metabolites such as fecapentaenes, 3-ketosteroids, and benzo[α]pyrenes are mutagenic. Levels of these substances can be reduced by low-fat and high-fiber diets, and several epidemiologic studies confirm that such diets reduce the risk of colon cancer. Furthermore, because the risk of sporadic colon cancer in older individuals is mildly elevated in the presence of a positive family history, there may be other inherited genetic abnormalities that interact with environmental factors to cause colon cancer. The sequence of genetic changes may not need to be exact to lead to the development of an invasive cancer, although there is mounting evidence that some genetic lesions tend to develop early, whereas others may develop late in the course of the natural disease. All phenotypic changes cannot be explained by a known genetic abnormality, nor do all identified genetic alterations have a known phenotypic result. However, the stepwise nature of genotypic and phenotypic abnormalities is well established.
The earliest molecular defect in the pathogenesis of colon cancer is the acquisition of somatic mutations in the APC gene in the normal colonic mucosa. This defect causes abnormal regulation of β-catenin, which leads to abnormal cell proliferation and the initial steps in tumor formation. Subsequent defects in the TGF-β signaling pathway inactivate this important growth inhibitory pathway and lead to further tumor mucosal proliferation and the development of small adenomas. Mutational activation of the K-ras gene leads to constitutive activation of an important proliferative signaling pathway, is common at these stages, and further increases the proliferative potential of the adenomatous tumor cells. Deletion or loss of expression of the DCC gene is common in the progression to invasive colon cancers. The DCC protein is a transmembrane protein of the immunoglobulin superfamily and may be a receptor for certain extracellular molecules that guide cell growth and/or apoptosis. Mutational inactivation of p53 is also a commonly observed step in the development of invasive colon cancer, seen in late adenomas and early invasive cancers, and leads to loss of an important cell cycle checkpoint and inability to activate the p53-dependent apoptotic pathways. Identification of genetic abnormalities in the progression of colon cancer to metastatic disease is currently under investigation.
In parallel to these sequential abnormalities in the regulation of cell proliferation, colon cancers also acquire defects in mechanisms that protect genomic stability. These generally involve mutations in mismatch repair genes or genes that prevent chromosomal instability. Mismatch repair genes are a family of genes that are involved in proofreading DNA during replication and include MSH2, MLH1, PMS1, and PMS2. Germline mutations in these genes cause the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. Nonhereditary colon cancers develop genomic instability through defects in the chromosomal instability (CIN) genes. Defects in these genes lead to the gain or loss of large segments or entire chromosomes during replication leading to aneuploidy.
The stepwise acquisition of genetic abnormalities described previously is associated with alterations in the phenotypic behavior of the colonic mucosa. The earliest change in the progression to colon cancer is the increase in cell number (hyperplasia) on the epithelial (luminal) surface. This produces an adenoma, which is characterized by gland-forming cells exhibiting increases in size and cell number but no invasion of surrounding structures (Figure 5–2). Presumably, these changes are due to enhanced proliferation and loss of cell cycle control but before acquisition of the capacity to invade ECM. Additional dysplastic changes such as loss of mucin production and altered cell polarity may be present to a variable degree. Some adenomas may progress to carcinoma in situ and ultimately to invasive carcinoma. An early feature associated with disrupted architecture even before invasion occurs is the development of fragile new vessels or destruction of existing vessels that can cause microscopic bleeding. This can be tested for clinically as a fecal occult blood determination used for screening and early diagnosis of preinvasive and invasive colon cancer. It is not known whether all invasive colon cancers pass through a hyperplastic or preinvasive stage, and there is no information available for epithelial malignancies in general.
Edge of an adenomatous polyp, showing adenomatous change (left), compared with normal mucosal glands (right). Adenomatous change is characterized by increased size and stratification of nuclei and loss of cytoplasmic mucin. Note the arrangement of nuclei of the adenoma perpendicular to the basement membrane (polarity). (Reproduced, with permission, from Chandrasoma P et al. Concise Pathology, 3rd ed. Originally published by Appleton & Lange. Copyright © 1998 by The McGraw-Hill Companies, Inc.)
Further functional changes in the cell and surrounding tissue are also manifested in the preinvasive and invasive stages. Once the basement membrane is penetrated by invasive malignant cells, access can be gained to the regional lymphatics and spread to regional pericolic lymph nodes can occur. Entry of cells into the bloodstream can lead to distant spread in a pattern that reflects venous drainage. Therefore, hematogenous spread from primary colon tumors to the liver is common, whereas rectal tumors usually disseminate to liver, lung, and bone. In addition to anatomic considerations, there may exist specific tropism of malignant cells mediated by surface proteins that cause the cells to preferentially home in on certain organs or sites.
Colonic epithelium is specialized to secrete mucus proteins and to absorb water and electrolytes (Chapter 13). The maintenance of a tight luminal barrier, intracellular charge differences, and the ability to exclude toxins are additional specialized functions. Some of these functions are maintained in the progression to neoplasia and may contribute to a specific phenotype of the malignant cell. One example is the expression of a transporter membrane protein, MDR-1, present on several types of epithelium, including the colon. MDR-1 is known to cause efflux of several compounds out of the cells, presumably as a protective mechanism to exclude toxins. In advanced colon cancer, this protein may contribute to the relative resistance of this and other tumor types to a variety of chemotherapeutic agents that are transported by MDR-1. In some cases, the activation of a latent gene encoding carcinoembryonic antigen (CEA) can result in measurable levels of the CEA protein in the serum of patients with localized or metastatic colon cancer as well as other adenocarcinomas.
What are the two principal lines of evidence in favor of the model of stepwise genetic alterations in colon cancer?
What is an explanation for the frequent appearance of occult blood in stools of patients with even early colon carcinoma?
What are two genes whose products contribute to the classic phenotype of colon carcinomas?
The female breast is a specialized gland that undergoes repeated cycles of growth factor and hormone-induced changes that define the different stages of breast development (fetal, pubertal, menstrual, pregnancy-associated, and lactational growth together with postlactational involution). Deregulation in this complex biology leads to a diverse group of breast diseases inherently connected with growth factor or hormonal signaling. Factors associated with an increased risk of breast cancer development may provide clues to early driving forces. Prolonged usage of high doses of exogenous estrogen is a risk factor that implicates the estrogen signaling pathway. In contrast, reduced exposure to estrogen protects against the development of breast cancer. This has been demonstrated in ovariectomized animal models of breast carcinogenesis and is confirmed by clinical studies demonstrating that women who have undergone oophorectomy at a young age have a significant reduction in their lifetime risk of developing breast cancer. The clinical success of antiestrogen therapies provides proof of principle of the essential role of estrogen signaling in the pathogenesis of breast cancer. Agents that inhibit the production of estrogen or the ability of estrogen to activate the ER are highly effective in the treatment of patients with early or advanced breast cancer, are active in halting disease progression in patients with preinvasive breast cancers, and are also active in the primary prevention of breast cancer in women at risk. However, although the central role of estrogen signaling in the pathogenesis of breast cancer is now well established, the evidence to date does not etiologically implicate genetic abnormalities of the ER or its downstream targets in the development of breast cancer. It appears that ER signaling is a physiological pathway existing in breast epithelial cells whose continued signaling activity is favorable to, or perhaps even necessary for, the oncogenic process. Yet the estrogen signaling pathway is intact in only one half of patients diagnosed with breast cancer; the remaining half appear to have no expression of the ER or activity of the estrogen signaling pathway. This has led some investigators to believe that ER-negative breast cancer is a different disease with an alternative pathophysiology. Most likely, there are common early molecular steps in the development of ER-positive and ER-negative breast cancers; however, at an early or intermediate step, these pathways diverge, leading to the development of breast cancers with distinctly different phenotypes.
The specific signaling pathways that are pathologically or mutationally activated in the progression of breast epithelial cells to preinvasive and invasive cancer are yet undefined. However, the tyrosine kinase growth factor receptors of the human epidermal growth factor receptor (HER) family are prime candidates. Amplification of the HER2 gene and overexpression of the HER2 protein are common in preinvasive and invasive breast cancers. Overexpression of the HER1 gene, also called the EGFR, is also seen with less frequency. The HER3 protein is similarly overexpressed in a majority of breast cancers. Antibodies that target the HER2 receptor have activity in the treatment of breast cancer, further confirming the role of this receptor signaling pathway. The HER family receptors activate a number of downstream signaling pathways, including proliferative pathways, apoptotic pathways, and metabolic pathways. The PI3 kinase protein is frequently mutationally activated in breast cancers enhancing survival and stress response. Inactivating mutations of p53 are also seen frequently in breast cancers and are associated with a worse prognosis.
The loss of genomic stability is also a common event in the pathogenesis of breast cancers. The group of genes involved in the DNA repair mechanism associated with breast cancers was identified in the hereditary breast and ovarian cancer syndromes. Five to 10% of breast cancer cases appear to be associated with an inherited predisposition and linked with predisposition to ovarian cancer. Familial clustering has long been noted in certain kindreds, and this led to the chromosomal localization of putative breast cancer susceptibility genes. This process is termed “linkage analysis,” whereby the characteristic of developing breast cancer can be shown to segregate with certain markers of known chromosomal location. The identification of two discrete genes, BRCA1 and BRCA2, then followed through the use of positional cloning, which describes a variety of strategies to pinpoint a gene over a large segment of the genome without knowledge of the gene’s function but the presumption that mutations in this gene should be seen in susceptible individuals (eg, women with breast cancer in families with breast cancer clustering). Inherited mutations in the BRCA1 and BRCA2 genes appear to be associated with a likelihood of developing breast cancer over a lifetime of up to 80%. Mutations in these genes are also associated with a high incidence of ovarian cancer and can lead to increased incidences of prostate cancer, melanomas, and breast cancer in males. Both of these genes function as tumor suppressor genes such that breast tumors contain both the inherited abnormality in one allele as well as a somatic loss of the remaining allele. Although sporadic (nonfamilial) cases of breast cancer rarely contain BRCA1 mutations, they may have reduced BRCA1 expression or may have abnormalities in other proteins that interact with BRCA1 to perform what appears to be a DNA repair function involving double-strand breaks in DNA. It is likely that other inherited genetic abnormalities will be identified that confer an increased risk of breast cancer. Generally, it will be more difficult to identify those that have only modest penetrance (ie, confer only a slight increase in breast cancer risk). Identifying mutations with high penetrance in individuals allows such individuals to take preventive measures. Identification of mutations with undefined penetrance or risk is less informative until future studies can better define their risk.
The scheme depicted in Figure 5–1 applies to progressive changes toward invasive breast carcinoma, and this full spectrum may be seen in patients who undergo biopsy to evaluate breast masses or mammographic abnormalities. Carcinoma in situ of the breast represents a preinvasive lesion in which enhanced proliferation and malignant cell morphology are observed but no invasion of the basement membrane can be demonstrated. Therefore, lymph nodal or distant metastases cannot occur at this stage, presumably because the invasive phenotype has not yet been acquired. Certain molecular abnormalities can be seen at this stage, including HER2 oncogene amplification and p53 tumor suppressor gene mutations.
Cancer of the breast is almost always due to malignant transformation of the secretory epithelial cells. However, two distinct subtypes are recognized. Cancers arising from the collecting ducts are called ductal carcinomas, whereas those arising from the terminal lobules are called lobular carcinomas. Ductal carcinomas comprise the majority of breast cancers, and lobular carcinomas represent a minority. Both in situ and invasive breast cancers fall into these two common classifications. Ductal and lobular cancers have distinct morphologic characteristics as well as molecular features specific to each subtype. For example, lobular carcinomas have loss of the cell adhesion protein E-cadherin and typically grow in a more diffuse pattern with less formation of dense solid tumors. Consequently, lobular carcinomas are often more difficult to detect radiographically in their primary tumors and even in metastatic sites. Lobular cancers also have less frequent abnormalities of the p53 tumor suppressor protein and only rarely have amplification of the HER2 gene.
Progressive changes in epithelial cell morphology and behavior are seen in lesions that often predate the development of invasive breast cancer. Atypical ductal hyperplasia and atypical lobular hyperplasia are proliferative abnormalities of the breast epithelium, and their presence confers an increased risk of subsequent development of breast cancer. Ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS) are noninvasive carcinomas that are more strongly associated with the concurrent or subsequent development of invasive breast cancer. Although these progressive cellular changes are well described in the progression to breast cancer, it is not clear that these are sequential steps that a clonal population of cells needs to undergo to evolve into invasive breast cancer. Alternatively, these may be various manifestations of a field defect in the breast epithelium, which leads cells to progress along any of several parallel oncogenic pathways. For example, the risk conferred by DCIS is not only of a subsequent invasive ductal cancer but also of an invasive lobular cancer, and the same is true for LCIS. In addition, although close to 50% of DCIS lesions have amplification and overexpression of HER2, only 20% of invasive cancers show this oncogenic molecular abnormality. It remains possible that invasive breast cancer and in situ breast cancer both arise from a common oncogenic pathway that ultimately diverges into separate in situ or invasive endpoints.
The hallmark of invasive breast cancer is the ability of the tumor cells to pass the basement membrane, invade the stroma, and gain access to lymphatic and vascular structures. The spread of tumor cells past the basement membrane to regional lymph nodes and to distant organs is the result of molecular events that are not yet well described. Cell surface proteins involved in adhesion and in degradation of ECM are likely involved. The phenotypic behavior of breast cancer among patients varies greatly, indicating the diverse nature of this disease. Some breast cancers metastasize with high frequency, whereas others rarely do so. Some breast cancers metastasize rapidly, whereas others do so after a long latent period. Some breast cancers preferentially metastasize to bone, whereas others prefer the liver or the lung as metastatic sites and yet others prefer the brain. Specific molecular features must underlie the diverse phenotypes of breast cancer, and indeed breast cancer is likely a compilation of many different disease subsets.
The development of techniques to simultaneously determine the expression of 10,000 or more genes is revolutionizing the way we classify cancers. This technology has already created new paradigms for the classification of breast cancers. At least four overall molecular subtypes of breast cancer are now widely recognized, including the basal subtype, the HER2 overexpressing subtype, and the luminal A and luminal B subtypes. More comprehensive molecular analyses using larger sample sets are identifying even smaller subtypes buried within these subtypes. These molecular subtypes have strong prognostic significance, with the luminal A subtype having the best prognosis and the basal subtype having a particularly poor prognosis. The subtypes are also linked with specific mechanistic characteristics. The luminal subtypes are characterized by the expression of ER-linked genes, and the function of the ER plays an important role in these cancers. The HER2 overexpressing subtypes are linked with the amplification and overexpression of the HER2 oncogene and the consequent downstream signaling events related to it. The basal subtype lacks a unifying molecular attribute, but its hallmark is a significant amount of genomic instability.
In addition to its prognostic significance, the analysis of breast cancers by molecular signatures has predictive value linked with sensitivity to various anticancer treatments. As a consequence, there are many different predictive gene signatures being developed as commercial assays for the analysis of clinical breast cancer samples, providing validated prognostic and predictive scores, enabling more personalized treatment planning for individual patients.
Mesenchymal, Neuroendocrine, & Germ Cell Neoplasia
Mesenchymal, neuroendocrine, and germ cell neoplasms account for a large proportion of the tumors of childhood and young adulthood, ostensibly because these cells are actively dividing and more subject to mutational events. Table 5–5 is a representative list of mesenchymal, neuroendocrine, and germ cell tumors, as well as the embryologic cell groups from which they arise. Owing to the extensive migration and convolution of embryonic cell layers during early development, these tumor types may not evolve in specific anatomic sites. Neuroendocrine tumors (NETs) are derived from cells that migrate throughout the body and have developed specific enzymatic capabilities and accumulation of cytoplasmic proteins that serve a secretory function. As such, they are frequently identified by certain enzymatic markers, in particular, nonspecific esterase. Although they were all originally thought to arise from the neural crest, not all NETs can be traced to the neural crest. Indeed tumors of this classification may not have a common embryonic ancestry. However, this tumor classification has been maintained because of their unique specialized secretory functions. NETs can secrete biologically active peptides and produce specific clinical syndromes because of their secretory activities. Germ cell tumors can arise within the testes or in extragonadal sites through which germ cells migrate during development. Mesenchymal cells, by virtue of their function, are distributed throughout the body, and mesenchymal tumors can arise at any anatomic site.
Table 5–5Neoplasia of mesenchymal, neuroendocrine, and germ cells.
NETs arise from neural crest tissue and, more specifically, from enterochromaffin cells, whose final resting place after embryonic migration is along the submucosal layer of the intestines and pulmonary bronchi. Reflecting this embryonic origin, neuroendocrine cells can at times express the necessary enzymes to produce bioactive amines as well as a variety of small peptide hormones. Only a low-grade NET is classified as a carcinoid tumor (regardless of any hormonal secretion). Cytoplasmic granules typical of neuroendocrine cells are also commonly seen. These features may also be shared by other tumors of neural crest origin. In contrast to epithelial neoplasms, morphologic changes observed with the light microscope do not distinguish between malignant and benign cells. The anatomic distribution of primary NETs is consistent with embryonic development patterns, as listed in Table 5–6. NETs and other mesenchymal neoplasms have similar patterns of tissue invasion followed by local and distant spread to regional lymph nodes and distant organs. The characteristics of increased mitotic count (an indicator of rapid proliferation), nuclear pleomorphism, lymphatic and vascular invasion, and an undifferentiated growth pattern are associated with a higher rate of metastases and a less favorable clinical prognosis.
Table 5–6Neuroendocrine tumor location by site of embryonic origin. |Favorite Table|Download (.pdf) Table 5–6 Neuroendocrine tumor location by site of embryonic origin.
|Foregut ||Midgut ||Hindgut |
|Esophagus ||Jejunum ||Rectum |
|Stomach ||Ileum || |
|Duodenum ||Appendix || |
|Pancreas ||Colon || |
|Gallbladder and bile duct ||Liver || |
|Ampulla of Vater ||Ovary || |
|Larynx ||Testes || |
|Bronchus ||Cervix || |
|Thymus || || |
A frequent site of NET metastasis is the liver. In this setting, especially with midgut NETs, there can be a constellation of symptoms as a consequence of vasoactive substances including serotonin secreted into the blood, referred to as the carcinoid syndrome (Table 5–7). These substances reflect the neuroendocrine origin of NETs and the latent machinery that can be activated inappropriately in the malignant state. Many of these peptides are vasoactive and can cause intermittent flushing as a result of vasodilation. Other symptoms often observed include secretory diarrhea, wheezing, and excessive salivation or lacrimation. Long-term tissue damage can also occur by exposure to these substances and their metabolites. Fibrosis of the pulmonary and tricuspid heart valves, mesenteric fibrosis, and hyperkeratosis of the skin have all been reported in patients with carcinoid syndrome. A urinary marker commonly used to aid in the diagnosis or to monitor patients being treated is a metabolite of serotonin, 5-hydroxyindoleacetic acid (5-HIAA), because the production of serotonin in carcinoid syndrome is also associated with the ability to take up and decarboxylate amine precursors.
Table 5–7Peptides and amines secreted by neuroendocrine tumor cells. |Favorite Table|Download (.pdf) Table 5–7 Peptides and amines secreted by neuroendocrine tumor cells.
Adrenocorticotropic hormone (ACTH)
Melanocyte-stimulating hormone (β-MSH)
Vasoactive intestinal peptide
What are some of the hormones and growth factors to which breast tissue responds?
What are some factors associated with increased risk of breast cancer?
What are the two main subtypes of breast cancer?
To what tissues do breast cancers tend to metastasize and why?
What products produced by neuroendocrine tumors reflect their embryonic origin?
What are some short-term symptoms and long-term complications precipitated by release of excessive amounts of these products?
Testicular Germ Cell Cancer
Testicular cancer arises chiefly from germ cells within the testes. Germ cells are the population of cells that give rise to spermatozoa through meiotic division and can, therefore, theoretically retain the ability to differentiate into any cell type. Some testicular neoplasms arise from remnant tissue outside the testes owing to the midline migration of germ cells that occurs during early embryogenesis. This is followed by the formation of the urogenital ridge and eventually by the aggregation of germ cells in the ovary or testes. As predicted by this pattern of migration, extragonadal testicular germ cell neoplasms are found in the midline axis of the lower cranium, mediastinum, or retroperitoneum. The pluripotent ability of the germ cell (ie, the ability of one cell to give rise to an entire organism) is most evident in benign germ cell tumors such as mature teratomas. These tumors often contain differentiated elements from all three germ cell layers, including teeth and hair in lesions termed dermoid cysts. Malignant teratomas can also exist as a spectrum bridging other germ cell layer–derived neoplasms such as sarcomas and epithelium-derived carcinomas. Malignant testicular cancers may coexist with benign mature teratomas, and the benign component sometimes becomes apparent only after the malignancy has been eradicated with chemotherapy.
Proteins expressed during embryonic or trophoblastic development such as alpha-fetoprotein and human chorionic gonadotropin can be secreted and measured in the serum. Testicular carcinoma follows a lymphatic and hematogenous pattern of spread to regional retroperitoneal nodes and distant organs such as lung, liver, bone, and brain. The exquisite sensitivity of even advanced testicular cancers to radiation and chemotherapy may be a result of the foreign nature of malignant germ cells when present in a mature organism. This foreign nature may create more specific activity of cytotoxic insults and stimulate a more vigorous immune rejection of tumor.
From what cellular elements of the testes does testicular cancer generally arise?
What are some characteristic markers that may be monitored in testicular tumor progression?
The sarcomas consist of a family of mesenchymal neoplasms whose morphologic appearance and anatomic distribution mirror the early mesenchymal elements from which they derive (Table 5–5). They arise in structures composed of the mesenchymal cell type or in locations where remnant cells eventually come to rest in the path of early tissue migration. Several of the less mature sarcomas that resemble more primitive cells are seen in children, because this compartment of cells is usually dividing more rapidly. These sarcomas include rhabdomyosarcoma and osteosarcoma, which are less common in adults. The morphologic appearance of sarcomas does not involve perceptible architectural changes, because cell polarity and gland formation do not occur in normal mature mesenchymal cells such as muscle or cartilage. Nuclear pleomorphism and mitotic rate determine the grade of a tumor; a higher grade correlates with a higher propensity to invade local and distant structures and a poorer survival. Sarcomas also have a tendency to retain the cell appearance and repertoire of expressed proteins of the cell of origin. Bone matrix of calcium and phosphorus can form within osteosarcomas, and calcification of these tumors can be observed on radiography. There is less of a propensity for direct tissue invasion by sarcomas than by epithelial malignancies. However, tissue destruction can result when a sarcoma compresses but does not invade adjacent tissue, leading to the formation of a pseudocapsule. Sarcomas exhibit metastatic dissemination to regional lymph nodes and distant organs, especially the lungs. High-grade histologic features and anatomic location are factors influencing the likelihood and timing of metastases.
Various genetic abnormalities have been detected in sarcomas. Mutations in the p53 tumor suppressor gene are the most commonly detected lesion, although such changes are also seen in epithelial neoplasms. The NF1 tumor suppressor gene was originally identified through a germline mutation of this gene in patients with type 1 neurofibromatosis. This inherited syndrome is characterized by café-au-lait hyperpigmented skin spots and multiple benign neurofibromas (benign tumors of Schwann cells) under the skin and throughout the body. These can degenerate into malignant neurofibrosarcomas (malignant schwannoma). NF1 mutations have since been detected in sporadic sarcomas of different types. Defective or absent activity of the NF1 protein is known to cause enhanced activation of the G protein–signaling pathways. Given the complex set of cellular activities governed by G protein–mediated pathways, the mechanisms by which NF1 abnormalities contribute to the malignant phenotype are not fully understood.
From what two kinds of locations do sarcomas arise?
What kinds of sarcomas are more common in children?
Are sarcomas more or less likely to directly invade tissues compared with epithelial malignancies?
To what sites do sarcomas commonly metastasize?
What is the most common genetic lesion in sarcomas?
What are the characteristics of type 1 neurofibromatosis, and what is a likely molecular basis for the development of neoplasia in this syndrome?
Hematologic neoplasms are malignancies of cells derived from hematopoietic precursors. The true hematopoietic stem cell has the capacity for self-renewal and the ability to give rise to precursors (colony-forming units) that proliferate and terminally differentiate toward one of any lineage (Figure 5–3). Distinct hematologic neoplasms can arise from each of the mature cell types. Many of these arise in the bone marrow, circulate in the bloodstream, and can infiltrate certain organs and tissues. Others may form tumors in lymphoid tissue, particularly lymphomas, which arise from lymphoblasts. The lineage of a hematopoietic cell and the degree of differentiation along that lineage are associated with the cell surface expression of characteristic proteins, many of which are receptors, others are adhesion molecules and proteases, and some are of unknown function. These clusters of differentiation (CD) antigens have become essential diagnostic tools in the management of hematologic neoplasms, and some types of malignancies are defined by characteristic CD expression patterns.
Classification of leukemias according to cell type and lineage. (Redrawn, with permission, from Chandrasoma P et al. Concise Pathology, 3rd ed. Originally published by Appleton & Lange. Copyright © 1998 by The McGraw-Hill Companies, Inc.)
The cellular ultrastructure and machinery of the malignant cell can somewhat resemble that of its cell of origin. A markedly enhanced proliferative rate and arrest of differentiation are the hallmarks of these neoplasms. Examination of the interphase nucleus of cells can sometimes reveal chromosomal abnormalities such as deletions (monosomy), duplications (trisomy), or balanced translocations. Certain types of hematologic neoplasms tend to have stereotypic chromosomal abnormalities. Given their clonal nature, these abnormalities will be evident on all malignant cells. In some cases of chromosomal translocation, a new fusion gene is formed and can result in production of a fusion protein possessing abnormal function compared with the original gene products (Table 5–8). This function usually involves loss of cell cycle control, abnormal signal transduction, or reprogrammed gene expression as a result of an aberrant transcription factor. In contrast to solid tumors, many hematologic malignancies are specifically linked to certain chromosomal translocations; therefore, karyotype studies are essential in the diagnosis of hematologic malignancies. Other genetic changes described in hematologic malignancies include mutations or deletions of the p53, retinoblastoma (Rb), and Wilms tumor (WT1) suppressor genes and activating mutations in the N-ras oncogene. Additional genetic changes can be detected in the clonal evolution of leukemias as disease progresses to a more aggressive form in the patient’s course. This finding lends further support to the theory that neoplasia is the result of stepwise genetic alterations that correspond to the sequential acquisition of additional phenotypic changes that favor abnormal growth, invasion, and resistance to normal host defenses.
Table 5–8Chromosomal translocations of hematologic neoplasms. |Favorite Table|Download (.pdf) Table 5–8 Chromosomal translocations of hematologic neoplasms.
|Neoplasm ||Chromosomal Translocation ||Fusion Gene Resulting from Translocation ||Fusion Protein Function |
|Follicular lymphoma ||t(14;18) ||IgH-bcl-2 ||Inhibitor of apoptosis |
|Mantle cell lymphoma ||t(11;14) ||IgH-bcl-1 ||Cyclin |
|Follicular lymphoma ||t(14;19) ||IgH-bcl-3 ||Transcription repressor |
|Diffuse large-cell lymphoma ||t(3;14) ||IgH/K/L-bcl-6 ||Transcription repressor |
|Burkitt lymphoma ||t(8;14) ||IgH-myc ||Transcription factor |
|Anaplastic large T-/null-cell lymphoma ||t(2;5) ||NPM-ALK ||Tyrosine kinase |
|CML ||t(9;22) ||bcr-abl ||Tyrosine kinase |
|AML M3 ||t(15;17) ||PML-RAR ||Transcription factor |
|AML ||t(8;21) ||AML1 ||Transcription factor |
|T-cell ALL ||t(1;14) ||tal-1-TCR ||Transcription factor |
Malignant lymphomas are a diverse group of cancers derived from the immune system, which result from neoplastic proliferation of B or T lymphocytes. These tumors may arise anywhere in the body, most commonly within lymph nodes but occasionally in other organs in which lymphoid elements reside. One subtype of lymphomas that are composed of mixtures of cell types with a unique biology is called Hodgkin lymphomas, whereas all other types of lymphomas are referred to as non-Hodgkin lymphomas.
Several factors are associated with the development of non-Hodgkin lymphoma. These include congenital or acquired immunodeficiency states such as AIDS or iatrogenic immunosuppression used in organ transplantation. Viruses are associated with the pathogenesis of some types. For example, most cases of Burkitt lymphoma that occur in Africa (endemic form) are associated with Epstein-Barr virus (EBV), whereas Burkitt lymphoma occurring in temperate zones is associated with EBV in only 30% of cases. Human T-cell leukemia/lymphoma virus I (HTLV-I) plays a causative role in the genesis of adult T-cell leukemia/lymphoma, in which the malignant cells contain the integrated virus. Human herpesvirus-8 (HHV-8) has been associated with body cavity–based lymphoma, a rare B-cell lymphoma that occurs predominantly in patients with AIDS. Chronic immune stimulation may be a causal mechanism in the development of lymphomas as well. For example, chronic gastritis secondary to Helicobacter pylori infection may give rise to gastric mucosa-associated lymphoid tissue (MALT) lymphomas. Resolution of gastric MALT lymphoma may occur in the majority of patients with localized disease who are treated with antibiotics effective against H pylori.
The classification of lymphomas has evolved over several decades, as their distinguishing molecular characteristics are better characterized. The latest classification was devised in 2008 by an international group of lymphoma specialists for the World Health Organization. This scheme characterizes non-Hodgkin lymphomas according to their B-cell or T-cell origin using a combination of criteria: clinical and morphologic features, cytogenetics, and immunoreactivity with monoclonal antibodies that recognize B-cell and T-cell antigens, as well as genotypic determination of B-cell and T-cell receptor rearrangements. Additionally, precursor undifferentiated B-cell and T-cell lymphoblastic lymphomas are in a separate class from the more mature B-cell and T-cell lymphomas. Most non-Hodgkin lymphomas originate in B cells and express on their surface CD20, a B-cell marker. Their monoclonal origin can be inferred by characterization of the specific class of light chain that is expressed: Either kappa or lambda B-cell lymphomas are further classified as malignant expansions of cells from the germinal center, mantle zone, or marginal zone of normal lymph nodes. The mature B-cell non-Hodgkin lymphoma classification encompasses more than 20 classes and smaller subtypes within some of these classes.
Somatic gene rearrangements occur normally during B-cell and T-cell differentiation. The genes for variable and constant regions of the immunoglobulin heavy and light chains are discontinuous in the B-cell germline DNA but are combined by somatic rearrangement to produce a functional antibody molecule. The T-cell receptor gene is analogous to the immunoglobulin molecule in that discontinuous segments of this gene also undergo somatic rearrangement early in T-cell development. DNA hybridization by Southern blot analysis permits recognition of a band of electrophoretic mobility that serves as a fingerprint for a monoclonal population of lymphoma cells.
Most non-Hodgkin lymphomas exhibit karyotypic abnormalities. The most prevalent translocations include t(8;14), t(14;18), and t(11;14) (Table 5–8). Each translocation involves the immunoglobulin heavy chain gene locus at chromosome 14q32 with an oncogene. Identification and cloning of the breakpoints have identified 8q24 as c-myc, 18q21 as bcl-2, and 11q13 as bcl-1. The proximity of these oncogenes to the immunoglobulin gene results in deregulation and increased expression of the oncogene product.
Representative subtypes of non-Hodgkin lymphoma include the indolent lymphomas such as follicular lymphoma, marginal zone lymphomas, and the aggressive lymphomas such as mantle cell lymphoma, diffuse large-cell lymphoma, and Burkitt lymphoma.
Follicular lymphomas are low-grade tumors that may be insidious in their presentation. The translocation t(14;18)(q32;q21) is found in more than 90% of follicular lymphomas. The mutation results in overexpression of the bcl-2 protein by these cells. The bcl-2 is an oncogene that codes for a protein that blocks apoptosis when overexpressed. The absence of bcl-2 translocation as assessed by the highly sensitive polymerase chain reaction test may be a marker for complete remission status in patients whose lymphomas harbor this translocation. Spontaneous regression of lymph node size is common in patients with follicular lymphomas. However, this class of lymphoma is not curable with standard chemotherapy; although the patient with follicular lymphoma tends to have an indolent clinical course, transformation to a more aggressive grade of lymphoma occurs in 40–50% of patients by 10 years.
An important subtype of marginal zone lymphomas are the MALT lymphomas, which may originate in the stomach, lungs, skin, parotid gland, thyroid, breasts, and other extranodal sites, where they characteristically align themselves with epithelial cells. A close association has been established between gastric MALT lymphomas and H pylori infection.
Mantle cell lymphoma presents histologically as a monotonous population of small to medium-sized atypical lymphoid cells with a nodular or diffuse pattern that is composed of small lymphoid cells with irregular nuclear outlines. The diagnosis of mantle cell lymphoma is based on morphologic criteria with confirmation by monoclonal antibody staining against cyclin D1 (bcl-1). The t(11;14) translocation seen in the majority of cases of mantle cell lymphoma results in juxtaposition of the PRAD1 gene on chromosome 11 with the immunoglobulin heavy chain gene on chromosome 14. This results in overexpression of the PRAD1 gene product, cyclin D1. Cyclin D1 binds to and activates cyclin-dependent kinases, which are thought to facilitate cell cycle progression through the G1 phase of the cell cycle. This disease occurs more commonly among older males and presents with adenopathy and hepatosplenomegaly. Mantle cell lymphomas are significantly more resistant to treatment with combination chemotherapy than follicular lymphomas and are also incurable.
Diffuse large-cell lymphoma is the most prevalent subtype of non-Hodgkin lymphoma. One-third of presentations involve extranodal sites, particularly the head and neck, stomach, skin, bone, testis, and nervous system. Diffuse large B-cell lymphomas commonly harbor mutations or rearrangements of the BCL6 gene.
Virtually all cases of Burkitt lymphoma are associated with alterations of chromosome 8q24, resulting in overexpression of c-myc, an oncogene that encodes a transcriptional regulator of cell proliferation, differentiation, and apoptosis. Adults presenting with high tumor burdens and elevated serum lactate dehydrogenase have a poor prognosis. Disease with a large tumor burden may be associated with a hypermetabolic syndrome that is triggered by treatment as the tumor undergoes sudden lysis. This syndrome may lead to life-threatening hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia.
Anaplastic large-cell lymphoma is characterized by the proliferation of highly atypical cells that express the CD30 antigen. These tumors usually express a T-cell phenotype and are associated with the chromosomal translocation t(2;5)(p23;q35), resulting in the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion protein. Activation of the ALK receptor tyrosine kinase results in an unregulated mitogenic signal.
Another type of T-cell lymphoma is the adult T-cell leukemia/lymphoma, an aggressive disease associated with HTLV-I infection that is characterized by generalized adenopathy, polyclonal hypergammaglobulinemia, hypercalcemia, and lytic bone lesions.
Finally, Hodgkin lymphoma is distinguished by the presence of the Reed-Sternberg giant cell of B-cell lineage, which is considered the malignant cell type in this neoplasm. The Reed-Sternberg cell constitutes only 1–10% of the total number of cells in pathologic specimens of this disease and is associated with an infiltrate of nonneoplastic inflammatory cells.
Acute & Chronic Leukemias
Leukemias are neoplasms derived from hematopoietic precursors, and depending on the precise step in hematopoiesis that is disrupted by the molecular genetic abnormalities, the cellular expansion can involve cells with features resembling any phase of lymphocytic or myelocytic maturation. Accordingly, leukemias are classified by the lymphocytic or myelocytic lineage of the neoplastic cells as well as the acute or chronic classification that describes the natural time-course of the disease states.
Acute myelogenous leukemia (AML) is a rapidly progressive neoplasm derived from hematopoietic precursors, or myeloid stem cells, that give rise to granulocytes, monocytes, erythrocytes, and platelets. There is increasing evidence that genetic events occurring early in stem cell maturation can lead to leukemia. First, there is a lag time of 5–10 years to the development of leukemia after exposure to known causative agents such as chemotherapy, radiation, and certain solvents. Second, many cases of secondary leukemia evolve out of a prolonged “preleukemic phase” manifested as a myelodysplastic syndrome of hypoproduction with abnormal maturation without actual malignant behavior. Finally, examination of precursor cells at a stage earlier than the malignant expanded clone in a given type of leukemia can reveal genetic abnormalities such as monosomy or trisomy of different chromosomes. In keeping with the general molecular theme of neoplasia, additional genetic changes are seen in the malignant clone compared with the morphologically normal stem cell that developmentally precedes it.
Acute myelocytic leukemias are classified by morphology and cytochemical staining as shown in Table 5–9. Auer rods are crystalline cytoplasmic inclusion bodies characteristic of, though not uniformly seen in, all myeloid leukemias. In contrast to mature myeloid cells, leukemic cells have large immature nuclei with open chromatin and prominent nucleoli. The appearance of the individual types of AML mirrors the cell type from which they derive. M1 leukemias originate from early myeloid precursors with no apparent maturation toward any terminal myeloid cell type. This is apparent in the lack of granules or other features that mark more mature myeloid cells. M3 leukemias are a neoplasm of promyelocytes, precursors of granulocytes, and M3 cells exhibit abundant azurophilic granules that are typical of normal promyelocytes. M4 leukemias arise from myeloid precursors that can differentiate into granulocytes or monocytes, whereas M5 leukemias derive from precursors already committed to the monocyte lineage. Therefore, M4 and M5 cells both contain the characteristic folded nucleus and gray cytoplasm of monocytes, whereas M4 cells contain also granules of a granulocytic cytochemical staining pattern. M6 and M7 leukemias cannot be readily identified on morphologic grounds, but immunostaining for erythrocytic proteins is positive in M6 cells, and staining for platelet glycoproteins is apparent in M7 cells.
Chromosomal deletions, duplications, and balanced translocations had been noted on the leukemic cells of some patients before the introduction of molecular genetic techniques. Cloning of the regions where balanced translocations occur has, in some cases, revealed a preserved translocation site that reproducibly fuses one gene with another, resulting in the production of a new fusion protein. M3 leukemias show a very high frequency of the t(15;17) translocation that juxtaposes the PML gene with the RAR-α gene. RAR-α encodes a retinoic acid steroid hormone receptor, and PML encodes a transcription factor. The fusion protein possesses novel biologic activity that results in enhanced proliferation and a block of differentiation. Interestingly, retinoic acid can induce a temporary remission of M3 leukemia, supporting the importance of the RAR-α–PML fusion protein. Monosomy of chromosome 7 can be seen in leukemias arising out of the preleukemic syndrome of myelodysplasia or in de novo leukemias, and in both cases this finding is associated with a worse clinical prognosis. This monosomy as well as other serial cytogenetic changes can also be seen after relapse of treated leukemia, a situation characterized by a more aggressive course and resistance to therapy.
Table 5–9Classification of acute myelogenous leukemias (AML). |Favorite Table|Download (.pdf) Table 5–9 Classification of acute myelogenous leukemias (AML).
|M1 ||Myeloblasts without differentiation |
|M2 ||Myeloblasts with some degree of differentiation |
|M3 ||Acute promyelocytic leukemia |
|M4 ||Acute myelomonocytic leukemia |
|M5 ||Acute monocytic leukemia |
|M6 ||Erythroleukemia |
|M7 ||Megakaryoblastic leukemia |
As hematopoietic neoplasms, acute leukemias involve the bone marrow and usually manifest abnormal circulating leukemic (blast) cells. Occasionally, extramedullary leukemic infiltrates known as chloromas can be seen in other organs and mucosal surfaces. A marked increase in the number of circulating blasts can sometimes cause vascular obstruction accompanied by hemorrhage and infarction in the cerebral and pulmonary vascular beds. This leukostasis results in symptoms such as strokes, retinal vein occlusion, and pulmonary infarction. In most cases of AML and other leukemias, peripheral blood counts of mature granulocytes, erythrocytes, and platelets are decreased. This is probably due to crowding of the bone marrow by blast cells as well as the elaboration of inhibitory substances by leukemic cells or alteration of the bone marrow stromal microenvironment and cytokine milieu necessary for normal hematopoiesis. Susceptibility to infections as a result of depressed granulocyte number and function and abnormal bleeding as a result of low platelet counts are common problems in patients initially presenting with leukemia.
Chronic myelogenous leukemia (CML) is an indolent leukemia manifested by an increased number of immature granulocytes in the marrow and peripheral circulation. One of the hallmarks of CML is the Philadelphia chromosome, a cytogenetic feature that is due to balanced translocation of chromosomes 9 and 22, resulting in a fusion gene, bcr-abl, that encodes a kinase that phosphorylates several key proteins involved in cell growth and apoptosis. The fusion gene can recreate a CML-like syndrome when introduced into mice. CML eventually transforms into acute leukemia (blast crisis), which is accompanied by further cytogenetic changes and a clinical course similar to that of acute leukemia. Targeted therapies that inhibit the enzymatic function of the bcr-abl kinase by competing with the ATP-binding site, induce remissions in most patients in chronic phases of CML. Furthermore, resistance to these bcr-abl inhibitors can involve amplification of the bcr-abl breakpoint as well as the development (or clonal expansion) of mutations in the ATP-binding pocket of bcr-abl, which prohibit the binding of inhibitors.
Acute lymphocytic leukemia (ALL) is a rapidly progressive neoplasm derived from immature lymphocytes named lymphoblasts, which overtake the bone marrow and sometimes infiltrate other organs. Genetic events are also commonly seen in ALL and are linked with biological outcome and used for prognostication. The morphologic classification of ALL, previously used for many years, is now being revised in favor of classification according to B-cell or T-cell lineage and encompassing the spectrum of cytogenetic abnormalities. The Philadelphia chromosome can also be seen in some cases of ALL, but its biological role may be different than in CML because the targeted therapies that block it are not as effective as they are in CML.
Chronic lymphocytic leukemia (CLL) is a neoplasm of more mature B cells. Because CLL results in increased numbers of lymphocytes in the peripheral blood that may not exhibit morphologic abnormalities, assays of clonality are essential in the diagnosis of CLL. The disease involves expansion of a neoplastic clone, and clonality can be easily assayed by the exclusively expressed antibody light chains normally present in B cells. CLL and the small lymphocytic subtype of non-Hodgkin lymphoma are very similar in pathophysiology and actually represent the same underlying disease, differing mainly in the accumulation of neoplastic cells either in the blood and bone marrow (CLL) or in lymph nodes (small lymphocytic lymphoma).
Systemic Effects of Neoplasia
Many effects of malignancies are mediated not by the tumor cells themselves but by direct and indirect effects, as outlined in Tables 5–10 and 5–11, respectively. Direct effects (Table 5–10) include compression or invasion of vital structures such as blood and lymphatic vessels, nerves, spinal cord or brain, bone, airways, GI tract, and urinary tract. These may cause a typical pain pattern as well as dysfunction of the involved organ and obstruction of a conduit. On occasion, an inflammatory or desmoplastic host response rather than the tumor itself can result in the same effect.
Table 5–10Direct systemic effects of neoplasms. |Favorite Table|Download (.pdf) Table 5–10 Direct systemic effects of neoplasms.
|Effect ||Clinical Syndrome |
|Vessel compression ||Edema, superior vena cava syndrome |
|Vessel invasion and erosion ||Bleeding |
|Lymphatic invasion ||Lymphedema |
|Nerve invasion ||Pain, numbness, dysesthesia |
|Brain metastases ||Weakness, numbness, headache, coordination and gait abnormalities, visual changes |
|Spinal cord compression ||Pain, paralysis, incontinence |
|Bone invasion and destruction ||Pain, fracture |
|Bowel obstruction and perforation ||Nausea, vomiting, pain, ileus |
|Airway obstruction ||Dyspnea, pneumonia, lung volume loss |
|Ureteral obstruction ||Renal failure, urinary infection |
|Liver invasion and metastases ||Hepatic insufficiency |
|Lung and pleural metastases ||Dyspnea, chest pain |
|Bone marrow infiltration ||Pancytopenia, infection, bleeding |
Table 5–11Paraneoplastic syndromes (indirect systemic effects of neoplasms). |Favorite Table|Download (.pdf) Table 5–11 Paraneoplastic syndromes (indirect systemic effects of neoplasms).
|Tumor Type ||Cause of Indirect Effect ||Clinical Syndrome |
|Effects of Hormone or Peptide Secretion |
|Lung ||ACTH ||Cushing syndrome |
|Lung, breast, kidney, others ||PTH or PTH-related protein ||Hypercalcemia |
|Lung ||ADH, ANP ||SIADH, hyponatremia |
|Germ cell, trophoblastic, hepatoblastoma ||Gonadotropins (FSH, LH, βhCG) ||Gynecomastia, precocious puberty |
|Lung, gastric ||Growth hormone ||Acromegaly |
|Neuroendocrine (eg, carcinoid) ||Various vasoactive peptides ||Flushing, wheezing, diarrhea |
|Sarcoma, mesothelioma, insulinoma ||Insulin, insulin-like growth factor ||Hypoglycemia |
|Cutaneous Effects |
|GI ||Unknown ||Acanthosis nigricans (hyperkeratosis and hyperpigmentation in skin folds) |
|GI, lymphoma ||Unknown ||Leser-Trélat (large seborrheic) keratoses |
|Lymphoma, hepatoma, melanoma ||Melanin deposits ||Melanosis (skin darkening) |
|Lymphoma ||Autoantibodies to subepidermal proteins ||Skin bullae (blisters) |
|Myeloid leukemia ||Neutrophilic skin infiltrates ||Sweet syndrome |
|Neurologic Effects |
|Lung, prostate, colorectal, ovarian, cervical, others ||Unknown ||Subacute cerebellar degeneration |
|Lung, testicular, Hodgkin disease ||Unknown ||Limbic encephalitis |
|Lung ||Unknown ||Dementia |
|Lung, others ||Unknown ||Amyotrophic lateral sclerosis |
|Lung, others ||Unknown ||Peripheral sensory or sensorimotor neuropathy |
|Lymphoma ||Unknown, ?autoantibodies ||Ascending radiculopathy (Guillain-Barré syndrome) |
|Lung, GI ||Autoantibodies to voltage-gated Ca2+ channels ||Eaton-Lambert (myasthenia-like) syndrome |
|Hematologic and Coagulopathic Effects |
|Several ||Unknown ||Anemia |
|Adenocarcinomas (especially gastric) ||Unknown ||Microangiopathic hemolytic anemia |
|Several ||Interleukin-1, −3, and hematopoietic growth factors ||Granulocytosis |
|Hodgkin, others ||Eosinophilic hematopoietic growth factors ||Eosinophilia |
|Several ||Unknown ||Thrombocytosis |
|Adenocarcinomas (especially pancreatic), others ||Unknown, ?exposed phospholipids from cell membranes ||Thrombosis |
|Adenocarcinoma (especially prostate) ||Urokinase, other mediators of fibrinolysis ||Disseminated intravascular coagulation |
|Metabolic Effects |
|Various ||Interleukin-1, tumor necrosis factor ||Cachexia, anorexia |
|Lymphoma, others ||Interleukins-1, −6 ||Fever |
|Hematologic neoplasms ||Hypermetabolism/cell breakdown products ||Hyperuricemia, hyperkalemia, hyperphosphatemia |
|Lymphoma, others ||Tumor hypoxia ||Lactic acidosis |
Indirect effects (Table 5–11) are heterogeneous and poorly understood. Likewise, the onset and clinical course are unpredictable. When affecting distant targets uninvolved by tumor, they are collectively termed paraneoplastic syndromes. Some of these effects are stereotypic syndromes resulting from the elaboration of peptide hormones or cytokines with specific biologic activity, as shown in Table 5–11. The peptides secreted by a given neoplasm may reflect the tissue of origin or may be the result of activation of latent genes not normally expressed. Common examples of paraneoplastic phenomena include the syndrome of inappropriate antidiuretic hormone (SIADH), seen most often in small-cell lung cancer. The result of ectopic ADH production is retention of free water and hyponatremia, which can result in altered sensorium, coma, and death. Another peptide secreted in cases of small-cell lung cancer is ACTH, which can lead to Cushing syndrome with excessive adrenocorticosteroids, skin fragility, central redistribution of body fat, proximal myopathy, and other features. Hypercalcemia can be seen in many types of malignancies, and its several causes include secretion of a parathyroid hormone–like peptide as a result of activation of the parathyroid hormone–related protein (PTHrP) gene, as well as the elaboration of local-acting cytokines that increase bone uptake in areas of tumor infiltration of bone.
In some malignancies such as NETs, several active peptides may act in concert to produce a constellation of symptoms and tissue effects. Cytokines such as the interleukins and tumor necrosis factor may be responsible for tumor-related fevers and weight loss. Some paraneoplastic syndromes are associated with the development of autoantibodies as a result of an immune response to tumor-associated antigens or an inappropriate production of antibody, as can be seen in lymphoid neoplasms. Finally, the nucleic acid, cytoplasmic, and membrane products of cell breakdown can result in electrolyte and other metabolic abnormalities as well as coagulopathic disorders, resulting in clotting or bleeding.
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