CANCER, TECHNICAL INFORMATION AND DEFINITIONS

A new growth is a “neoplasm.” Neoplasia literally means “new growth.” The term “tumor” was originally applied to the swelling caused by inflammation.  Neoplasms also may induce swellings, but by long precedent, the non-neoplastic usage of “tumor” has passed into limbo; thus, the term is now equated with neoplasm.  Oncology (Greek “oncos”= tumor) is the study of tumors or neoplasms.  Cancer is the common term for all malignant tumors.  

BENIGN TUMORS           

In general, these are designated by attaching the suffix “-oma” to the cell of origin.  For example, a benign tumor arising from fibroblastic cells is called a fibroma.  A cartilaginous tumor is a chondroma, and a tumor of osteoblasts is an osteoma.  In contrast, nomenclature of benign epithelial tumors is more complex.  They are variously classified, some based on their cells of origin, others on microscopic architecture, and still others on their macroscopic patterns. 

Adenoma is the term applied to the benign epithelial neoplasm that forms glandular patterns as well as to the tumors derived from glands but not necessarily reproducing glandular patterns.  On this basis, a benign epithelial neoplasm that arises from renal tubular cells growing in the form of numerous tightly clustered small glands would be termed an adenoma, as would a heterogeneous mass of adrenal cortical cells growing in no distinctive pattern.  Benign epithelial neoplasms producing microscopically or macroscopically visible finger-like or warty projections from epithelial surfaces are referred to as papillomas.  When a neoplasm, benign or malignant, produces a macroscopically visible projection above the mucosal surface and projects, for example, into the gastric or colonic lumen, it is termed a polyp.  The term polyp preferably  is restricted to benign tumors.  Malignant polyps are better designated polypoid cancers. 

MALIGNANT TUMORS

The nomenclature of malignant tumors essentially follows the same schema used for benign neoplasms, with certain additions.  Malignant tumors  are usually called sarcomas (Greek “sar” = fleshy) because they have little connective tissue stroma and so are fleshy, e.g., fibrosarcoma, liposarcoma, and leiomyosarcoma for smooth muscle cancer and fibromyosarcoma for a cancer that differentiates toward striated muscle.  Malignant neoplasms of epithelial cell origin, derived from any of the three germ layers, are called carcinomas.  Thus cancer arising in the epidermis of ectodermal origin is a carcinoma, as is a cancer arising in the mesodermally derived cells of the renal tubules and the endodermally derived cells of the lining of the gastrointestinal tract.  Carcinomas may be further qualified.  One with a glandular growth pattern microscopically  is termed an adenocarcinoma, and one producing recognizable squamous cells arising in any epithelium of the body would be termed a squamous cell carcinoma.  It is further common practice to specify, when possible, the organ of origin, e.g., a renal cell adenocarcinoma or bronchogenic squamous cell carcinoma.  Not infrequently, however, a cancer is composed of undifferentiated cells and must be designated merely as a poorly differentiated or undifferentiated malignant tumor. 

In most neoplasms, benign and malignant, the parenchymal cells bear a close resemblance to each other, as though all were derived from a single cells, as indeed we know to be the case with most cancers.  Infrequently divergent differentiation of a single line of parenchymal cells creates what are called mixed tumors.  The best example is the mixed tumor of salivary gland origin.  These tumors contain epithelial components scattered within a myxoid stroma that sometimes contains islands of apparent cartilage or even bone.  All these elements, it is believed, arise from epithelial and myoepithelial cells of salivary gland origin; thus the preferred designation of these neoplasms is pleomorphic adenoma.  The teratoma, in contrast, is made up of a variety of parenchymal cell types representative of more than one germ layer, usually all three.  They arise from totipotential cells and so are principally encountered in the gonads but rarely in sequestered primitive cell rests elsewhere.  These totipotential cells differentiate along various germ lines, producing, for example, tissues that can be identified as skin, muscle, fat, gut epithelium, tooth structures, and, indeed, any tissue of the body. 

CHARACTERISTICS OF BENIGN AND MALIGNANT NEOPLASMS

In the great majority of instances, the differentiation of a benign from a malignant tumor can be made morphologically with considerable certainty; sometimes, however, a neoplasm defies catagorization.  Occasionally this prediction is confounded by a marked discrepancy between the morphologic appearance of a tumor and its biologic behavior:  An innocent face may mask an ugly nature.  Such deception or ambiguity, however, is not the rule; in general, there are criteria by which benign and malignant tumors can be differentiated, and they behave accordingly.  These differences can conveniently be discussed under the following headings:  (1)  differentiation and anaplasia,  (2) rate of growth,   (3)  local invasion, and (4)  metastasis.

DIFFERENTIATION AND ANAPLASIA

The terms differentiation and anaplasia apply to the parenchymal cells of neoplasms.  Differentiation refers to the extent to which parenchymal cells resemble comparable normal cells, both morphologically and functionally.  Well-differentiated tumors are thus composed of cells resembling the mature normal cells of the tissue of origin of the neoplasm.  Poorly differentiated or undifferentiated tumors have primitive-appearing, unspecialized cells.  In general, benign tumors are well differentiated. 

Malignant neoplasms, in contrast, range from well differentiated to undifferentiated.  Malignant neoplasms composed of undifferentiated cells are said to be anaplastic.  Indeed, lack of differentiation, or anaplasia, is considered a hallmark of malignant transformation.   Lack of differentiation, or anaplasia, is marked by a number of morphologic and functional changes.  Both the cells and the nuclei characteristically display pleomorphism – variation in size and shape.  Characteristically the nuclei contain an abundance of DNA and are extremely dark staining (hyperchromatic).  The nuclei are disproportionately large for the cell, and the nuclear-cytoplasmic ratio may approach 1:1 instead of the normal 1:4 or 1:6.  The nuclear shape is usually extremely variable, and the chromatin is often coarsely clumped and distributed along the nuclear membrane.  Large nucleoli are usually present in these nuclei. 

As compared with benign tumors and some well-differentiated malignant neoplasms, undifferentiated tumors usually possess large numbers of mitoses, reflecting the higher proliferative activity of the parenchymal cells.  It should be noted, however, that the presence of mitoses does not necessarily indicate that a tumor is malignant or that the tissue is neoplastic.  Many normal tissues exhibiting rapid turnover, such as bone marrow, have numerous mitoses, and non-neoplastic proliferations such as hyperplasias contain many cells in mitosis.  More important are atypical, bizarre mitotic figures sometimes producing tripolar, quadripolar, or multipolar spindles. 

Another feature of anaplasia is the formation of tumor giant cells, some possessing only a single huge polymorphic nucleus, whereas others have two or more nuclei.  These giant cells are not to be confused with inflammatory Langhans or foreign body giant cells, which possess many small, normal-appearing nuclei.  In the cancer giant cell, the nucleus is hyperchromatic and is very large in relation to the cell.  In addition to the cytologic abnormalities described here, the orientation of anaplastic cells is markedly disturbed.  Sheets or large masses of tumor cells grow in an anarchic, disorganized fashion.

Before we leave the subject of differentiation and anaplasia, we should discuss dysplasia, a term used to describe disorderly but non-neoplastic proliferation.   Dysplasia is encountered principally in the epithelia.  It is a loss in the uniformity of the individual cells as well as a loss in their architectural orientation.  Dysplastic cells exhibit considerable pleomorphism (variation in size and shape) and often possess deeply stained (hyperchromatic) nuclei, which are abnormally large for the size of the cell.  Mitotic figures are more abundant than usual, although almost invariably they conform to abnormal locations within the epithelium.  Thus, in dysplastic stratified squamous epithelium, mitoses are not confined to the basal layers and may appear at all levels and even in surface cells.  There is considerable architectural anarchy.  For example, the usual progressive maturation of tall cells in the basal layer to flattened  squames on the surface may be lost and replaced by a disordered scrambling of dark basal-appearing cells.  When dysplastic changes are marked and involve the entire thickness of the epithelium, the lesion is considered a preinvasive neoplasm and is referred to as carcinoma in situ.  Although dysplastic changes are often found adjacent to foci of invasive carcinoma and, in long-term studies of cigarette smokers, epithelial dysplasia almost invariably antedates the appearance of cancer, dysplasia does not necessarily progress to cancer.  Mild to moderate changes that do not involve the entire thickness of epithelium may be reversible, and with removal of the putative inciting causes, the epithelium may revert to normal. 

 RATE OF GROWTH

The generalization can be made that most benign tumors grow slowly over a period of years, whereas most cancers growth rapidly, sometimes at an erratic pace, and eventually spread and kill their hosts.  Some benign tumors have a higher growth rate than malignant tumors.  Moreover, the rate of growth of benign as well as malignant neoplasms may not be constant over time.  Factors such as hormone dependence, adequacy of blood supply, and likely unknown influences may affect their growth. 

In general, the growth rate of tumors correlates with their level of differentiation, and thus most malignant tumors grow more rapidly than do benign lesions.  There is, however, a wide range of behavior.  Some malignant tumors grow slowly for years and then suddenly increase in size virtually under observation, explosively disseminating to cause death within a few months of discovery.  It is believed that such behavior results from the emergence of an aggressive subclone of transformed cells. On occasion, cancers have spontaneously disappeared, but the handful of “miracles” fills only a small volume. 

 LOCAL INVASION

Nearly all benign tumors grow as cohesive expansile masses that remain localized to their site of origin and do not have the capacity to infiltrate, invade, or metastasize to distant sites, as do malignant tumors. 

The growth of cancers is accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue.  In general, they are poorly demarcated from the surrounding normal tissue, and a well-defined cleavage plane is lacking. 

Most malignant tumors are obviously invasive and can be expected to penetrate the wall of the colon, or uterus, for example, or fungate through the surface of the skin.  They recognize no normal anatomic boundaries.  Such invasiveness makes their surgical resection difficult, and even if the tumor appears well circumscribed, it is necessary to remove a considerable margin of apparently normal tissues about the infiltrative neoplasm; this is referred to as “radical surgery.”  Next to the development of metastases, invasiveness is the most reliable feature that differentiates malignant from benign tumors. We noted earlier that some cancers seem to evolve from a preinvasive stage referred to as carcinoma in situ.  This is best illustrated by carcinoma in the uterine cervix. In situ cancers display the cytologic features of malignancy without invasion of the basement membrane.  They may be considered one step removed from invasive cancer, and indeed with time most penetrate the basement membrane and invade the subepithelial stroma.

METASTASIS

Metastases are tumor implants discontinuous with the primary tumor. Metastasis unequivocally marks a tumor as malignant because benign neoplasms do not metastasize.  The invasiveness of cancers permits them to penetrate into blood vessels, lymphatics, and body cavities, providing the opportunity for spread.  With few exceptions, all cancers can metastasize. The major exceptions are most malignant neoplasms of the glial cells in the central nervous system, called gliomas, and basal cell carcinomas of the skin.  Both are highly invasive forms of neoplasia (the latter being known in the older literature as rodent ulcers because of their invasive destructiveness), but they rarely metastasize.  It is evident then that the properties of invasion and metastasis are separable. 

In general, the more aggressive, the more rapidly growing, and the larger the primary neoplasm, the greater the likelihood that it will metastasize or already have metastasized. 

Approximately 30% of newly diagnosed patients with 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 confer greater benefit on patients than methods to prevent distant spread.

 PATHWAYS OF SPREAD

Dissemination of cancers may occur through one of three pathways:  (1)  direct seeding of body cavities or surfaces, (2)  lymphatic spread, and  (3)  hematogenous spread.  Although direct transplantation of tumor cells, as for example on surgical instruments, may theoretically occur, it is rare and, in any event, an artificial mode of dissemination that is not discussed further.  Each of the three major pathways is described separately.

 SEEDING OF BODY CAVITIES AND SURFACES

This may occur whenever a malignant neoplasm penetrates into a natural “open field.”  Most often involved is the peritoneal cavity, but any other cavity – pleural, pericardial, subarachnoid, and joint spaces – may be affected.  Such seeding is particularly characteristic of carcinomas arising in the ovaries, when, not infrequently, all peritoneal surfaces become coated with a heavy layer of cancerous glaze.

 LYMPHATIC SPREAD   

Transport through lymphatics is the most common pathway for the initial dissemination of carcinomas, but it should be remembered that sarcomas may also use this route.  The emphasis on lymphatic spread for carcinomas and hematogenous spread for sarcomas is misleading because ultimately there are numerous interconnections between the vascular and lymphatic systems.  The pattern of lymph node involvement follows the natural routes of drainage.  Because carcinomas of the breast usually arise in the upper outer quadrants, they generally disseminate first to the axillary lymph nodes.  Cancers of the inner quadrant may drain through lymphatics to the nodes within the chest along the internal mammary arteries.  Thereafter the infraclavicular and supraclavicular nodes may become involved.  Carcinomas of the lung arising in the major respiratory passages metastasize first to the perihilar tracheobronchial and mediastinal nodes. Local lymph nodes, however, may be bypassed – “skip metastasis” – because of venous-lymphatic anastomoses or because inflammation or radiation has obliterated channels.  Enlargement of nodes may be caused by (1) the spread and growth of cancer cells or (2) reactive hyperplasia.  It should be noted therefore that nodal enlargement in proximity to a cancer does not necessarily mean dissemination of the primary lesion.

This pathway is typical of sarcomas but is also used by carcinomas. Arteries, with their thicker walls, are less readily penetrated than are veins.  Arterial spread, however, may occur 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 arterial spread, a number of factors (to be discussed) condition the patterns of distribution of the metastases.  With venous invasion, the blood-borne cells follow the venous flow, draining the site of the neoplasm.  Understandably, the liver and lungs are most frequently involved secondarily in such hematogenous dissemination. 

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 to grow in a snake-like fashion up the inferior vena cava, sometimes reaching the right side of the heart.  Hepatocarcinomas often penetrate portal and hepatic radicles to grow within them into the main venous channels. 

 EPIDEMIOLOGY

Because cancer is a disorder of cell growth and behavior, its ultimate cause has to be defined at the cellular and subcellular levels.  Study of cancer patterns in populations, however, can contribute substantially to knowledge about the origins of cancer. For example, the concept that chemicals can cause cancer arose from the astute observations of Sir Percival Pott, who related the increased incidence of scrotal cancer in chimney sweeps to chronic exposure to soot.  Thus major insights into the etiology of cancer can be obtained by epidemiologic studies that relate particular environmental, racial (hereditary?), and cultural influences to the occurrence of malignant neoplasms.