by Robert C. Mellors, M.D., Ph.D.
Biological Characteristics of Benign and Malignant Neoplasms
In general, malignant tumors differ from benign tumors in four biological properties: structure, rate of growth, invasive growth, and disseminated growth by metastasis. Of these characteristics, metastasis is a unique feature of malignant neoplasms, is a major factor in the fatal course of the disease, and is the main deterrant to its successful treatment. Given that fact, whenever possible , it is of paramount clinical importance to diagnose and treat potentially malignant tumors before the progression to metastasis.
Structure of Tumors and Tumor Cells
The gross appearance of neoplasms is highly variable, consistent with the diversity of their origin, size, and biological behavior.
Neoplasms may be firm, hard (scirrhous), or soft, homogeneous or heterogenous in texture, solid or cystic, pale or dark, and discolored by endogenous pigments, hemorrhage, or necrosis. Slowly growing benign tumors often present as an expansive mass that pushes normal tissues aside, are well circumscribed or encapsulated, and are freely movable in relation to adjacent tissues. By contrast, rapidly growing malignant tumors tend to have an indistinct irregular shape, are not encapsulated, and are fixed to adjacent structures by infiltrative growth or disseminated by metastases.
67 Leiomyomas of uterus
Multiple, round, nodular masses distort this uterus (cervix at 6:00 o'clock). Note that the lesions are within the myometrium and are discrete. Some of these leiomyomas are subserosal and some are submucosal.
144 Bronchogenic carcinoma
The tumor arises from the main stem bronchus which has been opened. A relatively small part of the tumor is intrabronchial; from here it invades through the wall and into the adjacent pulmonary parenchyma.
148 Infiltrating duct carcinoma of breast
The tumor occupies the top portion of the specimen. Note the white streaks coursing through the lesion and contrast it with the normal adipose tissue of the breast.
160 Papillary adenocarcinoma of the ovary
The tumor is a multilocular cyst which has been partially opened revealing several other cysts as well as solid masses inside. The latter have a granular surface suggesting papillary fronds. Because of the common presence of cysts within the tumor, this lesion is frequently called "cystadenocarcinoma".
85 Adenomatous polyp of colon
This is an example of tubular adenoma which frequently acquires the shape of a polyp in the colon and is commonly called "adenomatous polyp". Note stalk at the top. A white piece of paper has been placed behind the lesion.
1473 Adenocarcinoma of the colon
The tumor is a flat, sessile polyp with heaped up edges which involves most of the circumference of the colon here shown open. Invasion of the colonic wall is visible on the cut surface above.
1487 Adenocarcinoma and adenomatous polyp of colon
This surgical specimen shows two lesions: at right is an ulcerated, sessile lesion, an adenocarcinoma. Contrast it with the lesion at top left, a round, pedunculated polyp. Microscopically, this is an tubular adenoma (frequently called an adenomatous polyp).
196 Hepatocellular carcinoma and cirrhosis of the liver
A large tumor mass occupies most of the right lobe. Other, satellite nodules are seen. Note the presence of cirrhosis in the less involved left lobe.
81 Normal cervix Note the intact, small os and the uniform, smooth and pink epithelium.
1474 Squamous cell carcinoma of cervix
The tumor extends to the anterior and posterior lips and appears somewhat granular and hemorrhagic. The cervix is surrounding by a narrow vaginal cuff.
4023 Neuroblastoma of adrenal gland
The tumor in this case is grossly larger than the kidney. On section, the tumor is soft and contains dark hemorrhagic areas with pale regions of necrosis and gritty calcification.
4024 Wilms' tumor of kidney
On section, the large roughly spherical tumor mass has a diversity of textures and colors (variegated appearance), with pale "fish flesh" areas of tumor contrasting with residual uninvolved renal parenchyma.
1475 Myxoma of heart
This benign tumor, seen here arising from the usual place, the left side of the atrial septum, is usually a well vascularized, polypoid, gelatinous structure (hence the name, by analogy to the myxoid or gelatinous material of the umbilical cord). The tumor cell derives from primitive mesenchymal cells of the subendocardial stroma. For a long time, this tumor was confused with a mural thrombus and there were doubts about its true neoplastic nature.
1476 Fibroadenoma of breast
This benign neoplasm, composed of both stromal and glandular elements, is sharply circumscribed. In this specimen, the tumor has been split in half and is surrounded by normal breast tissue.
127 Leiomyoma of esophagus
The esophagus is oriented vertically and has been opened to reveal a well circumscribed, white tumor present under the mucosa which has been split open. The whorls on the cut surface are characteristic of this lesion.
48 Fibroadenoma of breast
The lesion, the most common benign tumor of the breast, has been removed without much normal breast tissue around. It is shown after bisection.
46 Myeloid leukemia of spleen
A normal spleen is shown at right. The spleen on the left is greatly enlarged due to infiltration by leukemic cells.
161 Seminoma of testis
The testis has been split open, the spermatic cord is at upper left. The tumor replaces most of the testis and has a white, fleshy appearance. A narrow rim of normal testicular parenchyma surrounds the tumor.
142 Multiple myeloma of lumbar spine
The cancellous bone of the vertebral bodies is focally replaced with a soft, reddish tumor. There are many of these lesions varying in size considerably.
392 Hodgkin's lymphoma, lymph nodes
Several lymph nodes are enlarged, matted together and replaced by soft, fleshy tumor.
232 Pheochromocytoma of adrenal (chromaffin reaction)
The adrenal gland has been resected and opened in half. The right side was treated with a chromate salt and the surface of the tumor changed to a deep mahogany brown color (almost black in the picture) indicating a positive chromaffin reaction due to the presence of cathecholamines. Note a narrow rim of yellow adrenal cortical tissue around the fleshy, focally hemorrhagic tumor.
Histologically, all neoplasms with the possible exception of leukemias are composed of two main parts: tumor cells which comprise the parenchyma or specific component and proliferate to enlarge the tumor; and tumor stroma, a supporting framework consisting of connective tissue and newly formed blood vessels elicited from adjacent tissues. The stromal reaction of some tumors is characterized by overproduction of fibrous stroma (DESMOPLASIA).
Some neoplasms, such as benign tumors and some slowly growing malignant tumors, have a cellular maturity and histological organization similar to normal adult tissues at the site of origin and are said to be structurally differentiated. Whereas, more rapidly growing malignant tumors show a greater degree of structural abnormality and resemble immature embryonal tissues or stem cells capable of proliferative activity. The loss or absence of organizational, structural, and functional differentiation of cells is termed undifferentiation or anaplasia ("backward growth"). Anaplasia is a characteristic property of malignant tumor cells. The grading of a cancer is an estimate of its malignant behavior and is based upon its degree of structural abnormality. In general, the more marked the anaplasia of a tumor, the more malignant is its biological behavior, as shown by tumor recurrence,invasion, and metastasis.
The cytological changes characteristic of malignant tumor cells reflect the degree of anaplasia (undifferentiation) and include: increased structural variations (pleomorphism) in cellular and nuclear size and shape compared to corresponding normal cells; large hyperchromatic nuclei containing a coarse, irregular network of chromatin; increased nuclear to cytoplasmic ratio of mass; tumor giant cells; large nucleoli; increased or bizarre mitotic figures; chromosomal abnormalities; and cytoplasmic changes. No one of these attributes alone is unique to cancer cells.
246 Squamous cell carcinoma in-situ of cervix, Pap smear
Cells exfoliated from a lesion of the cervix display characteristic abnormalities of cancer cells, specially the increased nucleus / cytoplasmic ratio, pleomorphism and hyperchromatism
243 Invasive carcinoma of cervix, Pap smear
These cancer cells are very anaplastic and show marked variation in size. Note the enormous size of the tumor cells which can be appreciated in comparison with neutrophils present in the smear.
128 Invasive carcinoma of bronchus, sputum Pap smear
This single cell from a Pap smears shows increased nuclear / cytoplasmic ratio and keratin rich cytoplasm which appears as orange on the Papanicolaou stain.
1477 Bizarre mitotic figure with multipolar spindle
These abnormal mitoses are seen in anaplastic tumors. From a case of carcinoma of the ovary.
Growth Characteristics of Tumor Cells
The most fundamental properties of tumor cells are relatively autonomous growth and reproduction and, for malignant tumors, invasion and metastasis. Tumor cells proliferate without relation to the needs of the host in which they arise. Tumor cells are self-controlling and have various levels of independence from normal growth control mechanisms.
The normal cell cycle is divisible into four sequential phases that culminate in cell division: the interphase gap (G1), DNA synthesis (S), the gap between the end of DNA synthesis and the beginning of mitosis (G2), and mitosis (M). A fifth interval, G zero, is designated for cells that are no longer in the normal cycle. Some of these cells may be induced to reenter the cycle by appropriate stimuli, and others may never reenter and eventually die.
In the tumor cell cycle, neoplastic cells may undergo successive cycles of mitosis, or leave the cell cycle and enter G zero. Some of the neoplastic cells in the G zero state will die while others remain as dormant or latent tumor cells and may reenter the cycle of cell division with the appropriate stimulus.
Normal cells of the body can be divided into several categories: continually replacing cells (hematopoietic tissue, surface epithelium, some glandular epithelium, male germ line); non-renewing cells with regenerative capacity (liver, kidney, connective tissue, some glandular epithelium); and essentially non-replacing cells (neurons, muscle, female germ line). Relevant to the study of neoplastic growth is the category of "continually replacing cells". For example, hematopoietic precursor cells comprise stem cells that are capable of an indefinite number of divisions and progeny cells that either proliferate or mature to a non-proliferative state ("end cells"). As the cells mature toward the "end cell" state, they lose their proliferative potential and gain characteristics of differentiation. In this context, neoplastic growth can be viewed as a disorder of maturation or differentiation in which many of the tumor cells remain in the replicating pool of undifferentiated stem cells.
The cell growth kinetics of tumor cells and the cell cycle time, from one mitosis to the next, can be measured using radioactive DNA labeling and autoradiography. The cell cycle time of tumor cells varies with cancer type (72-260 hours) and, surprisingly, is often considerably longer than that of normal dividing cells, such as bone marrow precursor cells (18 hours) or colonic crypt epithelial cells (39 hours). The increased frequency of mitosis often seen in malignant tumors is attributed in part to the longer mitotic interval of tumor cells compared to normal cells.
The "growth fraction" of tumor cells (expressed as percent of tumor cells actually proliferating) and the volume "doubling time" of a tumor can be determined. The growth fraction for common types of human cancers varies widely (5-90%). At the same time, the rate of cell loss from the death of cancer cells may be as much as 90%, or more, of tumor cells per unit time. The true measure of tumor growth is thus the excess of tumor cells produced over those lost per unit time, a value that is reflected in the tumor volume "doubling time".
The volume-doubling time of individual tumors varies greatly, depending upon histogenetic type, growth fraction, blood supply, and other factors, and may change over time. In general, malignant tumors usually grow more rapidly than benign tumors, undifferentiated malignant tumors grow faster than well differentiated malignant tumors, and carcinoma metastases in lung grow more rapidly than the primary carcinomas from which they have arisen. The doubling time is an indicator of the biological aggressiveness of human tumors. Growth fractions and doubling times of representative human cancers are given in the table.
Table: Average Growth Fractions and Doubling Times of Human Cancers
A theoretical calculation can be made of the number of tumor cell doublings required for the progression from a single transformed cell of 10 micrometer diameter to a 1 cm diameter (~1 gm) solid tumor that is clinically detectable, for example, by chest x-ray. Thirty doublings would be needed to produce a 1 gm tumor, assuming that all of the tumor cells proliferate and none die or are lost. The doubling time is a critical variable in the latency period, the interval between the initiation and clinical expression, of a tumor. Of course, the actual time of occurrence of a tumor-initiating event is seldom known. At a doubling time of about 60 days, approximately 60 months would be required for the tumor to reach a detectable size of ~1 gm. A tumor size of 10 gm would require only 3.3 additional doublings, but the doubling time of a tumor tends to increase as the tumor enlarges.
The doubling time correlates with the biological aggressiveness of a tumor. In a series of patients with Burkitt's lymphoma, one of the fastest growing human tumors, the clinically determined doubling time of the lymphomas was found to average less than 3 days. By contrast, primary adenocarcinomas of the colon and rectum have an average doubling time of about 600 days.
Clonal Origin and Progression of Tumors
Most human tumors appear to have a clonal origin and to arise either by clonal expansion of a single transformed cell or by clonal selection of transformed cells having a selective growth advantage. The evidence for tumor monoclonality includes: the presence in a variety of tumors of a single form of certain isoenzymes, such as glucose-6-phosphate dehydrogenase; the production by individual myelomas and B-cell lymphomas of only a single molecular type of immunoglobulin heavy and light chains;
and karyotypic similarities, such as the possession of the Philadelphia chromosome by chronic myelogenous leukemia cells.
Despite their apparent clonal origin, tumor cells within the same lesion often display heterogeneity in several biological characteristics. An explanation of this seeming paradox is found in the stem cell model of cancer which postulates that tumor stem cells have the capacity for self renewal and are responsible for the initial and continuing growth of the tumor. The original clone of tumor cells expands and generates a wide range of variant clones. Depending on selective pressures in the tumor's microenvironment, some subclones survive and expand rapidly while other subclones die out.
The evolution of tumor-cell heterogeneity is usually accompanied by the development of more aggressive characteristics, such as an increasing growth rate, invasiveness, and metastasis, and by morphological and biochemical changes in the tumor. This entire process is termed "progression" and has important consequences as regards tumor behavior and response to therapy. Examples of tumor progression include the conversion of a benign to a malignant neoplasm, of a non-invasive (in-situ) to an invasive carcinoma, of a low grade to a highly malignant cancer with a rapid fatal course.
A major factor in progression appears to be that most tumor cells are genetically less stable than normal cells and this instability produces variant clones. Chromosomal abnormalities in number and structure are often seen in tumor cells. These abnormalities include: a gain or loss of chromosomes (aneuploidy); deletion (loss of a segment of a chromosome); inversion ("flip-flop" of two segments of a chromosome); translocation (rearrangement of segments between two chromosomes); and mutation (heritable change in the structure or expression of a gene) ranging from chromosomal change to single base-pair substitution (point mutation).
Molecular genetic mechanisms implicated in tumor progression include: chromosomal rearrangements or mutations that "activate" cell oncogenes (proto-oncogenes); and loss of putative "tumor suppressor" genes.
Precursor Lesions and Carcinoma in Situ
In mucous membrane sites, where repeated clinical observation and tissue or cell sampling are possible, carcinomas are often seen to be preceded by non-invasive lesions. The epithelial cells of these precursor lesions may have atypical features, among them: enlarged nuclei; somewhat disorderly positional arrangement; and greater than normal proliferative activity. This abnormal tissue development in the mucosa of the uterine cervix is commonly termed "dysplasia".
Some of the dysplastic lesions may revert to normal, while others progress over time to develop many cellular features of squamous carcinoma except for tissue invasion. Such an intraepithelial lesion with the cellular features of squamous carcinoma, but remaining confined to the cervical mucosa and not invading through the basement membrane, is termed carcinoma-in-situ.
1478 Squamous cell carcinoma in-situ of cervix
The edge of the lesion is shown: to the left is normal squamous epithelium with its basal cell layer and orderly maturation upwards. Note the normal cells with small nuclei and abundant, clear cytoplasm (due to abundant glycogen content). The right side shows carcinoma in-situ characterized by lack of maturation, altered cell polarity, some nuclear pleomorphism and increased nuclear / cytoplasmic ratio. As is characteristic of carcinoma in-situ, the neoplastic cells are confined to the epithelial layer and have not invaded through the epithelial basement membrane.
138 Squamous cell carcinoma in-situ of cervix
To the right is normal squamous epithelium with its basal cell layer and orderly maturation upwards. The left side shows carcinoma in-situ characterized by lack of maturation, altered cell polarity, nuclear pleomorphism and increased nuclear / cytoplasmic ratio. As is characteristic of carcinoma in-situ, the neoplastic cells are confined to the epithelial layer and have not invaded through the epithelial basement membrane, under which, the submucosal stroma contains chronic inflammatory cells.
379 Squamous cell carcinoma in-situ of bronchus, low power
Normal respiratory epithelium is at right (note columnar cells with cilia) and the tumor is at left. Note that it occupies the mucosa which has been transformed into multiple layers of poorly differentiated epithelial cells with little or no maturation. The bronchial lumen contains numerous exfoliated tumor cells.
378 Squamous cell carcinoma in-situ of bronchus, high power
This is a higher magnification of the previous lesion, with the tumor at left and normal respiratory epithelium at right. The exfoliated tumor cells in the bronchial lumen show many of the cytologic features of malignant cells.
1479 Intraductal carcinoma of breast (also called comedocarcinoma)
The neoplastic proliferation is entirely intraductal. There is no evidence of invasion. Note central necrosis of the tumor.
44 Transitional cell carcinoma in-situ of bladder
The urothelium has been replaced by neoplastic carcinoma cells showing pleomorphic, hyperchromatic nuclei.
Epidemiologic, histologic, and cytologic studies show that there is a spectrum of changes leading from dysplasia to carcinoma-in-situ to invasive carcinoma of the uterine cervix.
Colorectal adenocarcinomas often arise in benign adenomas rather than directly from normal mucosa. Colorectal tumor progression is frequently associated with the mutational activation of an oncogene and the loss of tumor suppressor genes.
It is possible that malignant neoplasms seldom if ever develop from the normal precursor tissue without passing through intervening non-malignant or non-invasive steps.
Invasion and Metastasis of Malignant Tumor Cells
The dual properties of invasion and metastasis distinguish malignant from benign tumor cells. Invasion of normal tissue is a fundamental characteristic of malignant tumor cells and is one of their potentially most dangerous properties. Microscopic invasion of cancer cells commonly occurs beyond the gross boundaries of a primary tumor and in some operative cases may extend beyond the surgical margins of apparently normal tissue. In addition, invasion is a prerequisite for tumor cell metastasis which is the physical separation and dissemination of malignant tumor cells from the tissue of origin to another site by lymphatic, vascular and other routes . The presence or absence of regional and, particularly, distant metastasis is a major factor in determining the prognosis of a malignant neoplasm.
Conceptually, metastasis involves three steps or processes: tumor cell invasion, embolization, and extravasation.
In the process of tissue invasion by an epithelial cancer, tumor cells must traverse the barriers of the basement membrane and the stromal extracellular matrix. The sequence of events includes:
The detachment of cancer cells from the tissue of origin apparently involves many factors, among them: decreased mutual adhesiveness; diminished number of cell junctions; and other alterations in surface membrane structures.
The attachment of tumor cells to certain matrix components, such as the glycoprotein laminin, appears to be a factor in the process of invasion. Some invasive tumor cells have an increased number of laminin receptors on their surfaces. It is possible that increased binding of tumor cells to laminin facilitates their invasiveness.
The active degradation of components of the basement membrane, and subsequently of the stromal extracellular matrix, is required for invasion. The enzymatic breakdown of proteins and proteoglycans is accomplished in various ways. Some invasive tumor cells produce plasminogen activator, a serine protease that splits plasminigen into its proteolytically active form, plasmin, whereas others release type IV collagenase (which can cleave basement membrane collagen), cathepsins, and heparanase. In some tumors, proteolytic enzymes are released in the stroma by "cooperating" host cells, such as macrophages.
The next step in invasion requires active cancer cell locomotion and infiltration into the region where the matrix has been broken down. There, infiltrating cancer cells with the capacity to proliferate produce progeny cells. The processes of matrix degradation and tumor cell locomotion are repeated over and over as tumor cells infiltrate normal tissue and finally invade lymphatic or blood vascular channels.
Tumor Cell Embolization
Even though malignant tumor cells may invade lymphatic or blood vessels and enter the circulation, only an extremely small number of embolized cells are apparently able to establish metastatic lesions. For example, experimental animal studies indicate that less than 0.01% (< 1 in 10,000) of cancer cells entering the blood stream give rise to metastatic tumors. Tumor cell invasion of blood, or lymphatic, vessels is not sufficient by itself to establish metastatic tumor growth. The survival and growth of metastatic cells is not a random process but depends upon the selection of cancer cells possessing specific properties needed for metastatic growth.
Tumor Cell Extravasation
This process involves more than the mere lodging of embolized cancer cells in small vessels, such as capillaries or lymphatics. The sequence of mechanisms includes:
The cancer cell attaches to the endothelial surface, induces endothelial retraction, migrates through the breach, dissects beneath the endothelium, degrades the vascular basement membrane, and migrates out of the vascular compartment to form a metastatic tumor.
Within a primary cancer, there is a marked cellular heterogeneity of metastatic potential. Factors which influence the establishment of tumor metastases include: genetic instability of the tumor cells; enzymatic degradation of basement membrane collagen; ability to withstand rheologic trauma; size of the tumor cell embolus; interaction with cytotoxic T-cells, natural killer cells, and macrophages; entrapment by fibrin or platelets; surface properties (glycoproteins) which may favor the ability of variant tumor cells to reach and colonize specific organs.
Routes of Metastasis
Malignant tumor cells may spread by three major routes: lymphatics, blood vessels, and implantation (seeding) by physical contact between tumor and normal serosal or mucosal surfaces or surgical instrument.
132 Metastatic carcinoma of lung in peritracheal lymph nodes
Several lymph nodes attanched to the trachea and main stem bronchi are enlarged and totally replaced by tumor.
121 Liver metastasis of adenocarcinoma of colon
The liver is almost completely replaced by round tumor metastases with central necrosis and focal hemorrhage.
1481 Bone metastases from bronchogenic carcinoma
Note total or near-total replacement of vertebral bone at top and bottom as well as a round metastasis within the second-from-the top vertebral body.
51 Metastatic carcinoma to vertebrae
Note destruction and collapse of one vertebral body whose bone has been replaced by soft tumor tissue. This osteolytic metastasis has resulted in a so-called compression fracture.
124 Brain metastasis of lung adenocarcinoma
Note metastatic tumor in the temporal lobe at left.
375 Lung metastases of adrenal adenocarcinoma
Most of the lung is replaced by round metastatic deposits. Note that some of the tumor appears to be growing inside blood vessels (center left)
1480 Lymph node metastasis from carcinoma of the breast
This axillary lymph node shows permeation of the subcapsular sinuses by clusters of cancer cells. Note preservation of cortical lymphocytes (germinal centers).Tumor cells are seen within lymphatic channels entering the lymph node (bottom).
1490 Perineural invasion by adenocarcinoma of gall bladder
A nerve is seen at top left. Note tumor (adenocarcinoma) invading the perineural space.
1482 Vascular invasion by bronchogenic carcinoma
Section of lung showing complete obliteration of thin walled vessel (probably a vein) by tumor and thrombus.
60 Lung metastases of adenocarcinoma of colon
The metastatic tumor, composed of rather well differentiated glands, is at left. The compressed pulmonary tissue is at right.
58 Bone metastases of carcinoma of colon
The bone is almost completely replaced by masses of tumor. Note some residual, necrotic bone at 9 and 12 o'clock.
389 Tumor embolus in esophageal blood vessel
A cluster of cancer cells is seen within a small blood vessel in the muscularis.
Carcinomas often metastasize initially to regional lymph nodes and later to lungs, liver, bones, brain, and other organs. Breast carcinomas commonly metastasize first to the adjacent axillary lymph nodes. Bronchogenic carcinomas frequently spread initially to perihilar or mediastinal lymph nodes. Colorectal carcinomas often metastasize first to mesenteric lymph nodes. Carcinomas and sarcomas also often metastasize by hematogeneous routes to lungs, liver, bones, brain, and other sites. Cancer cells reaching venous tributaries of the inferior vena cava flow to the right side of the heart and reach the lungs. Malignant tumor cells entering the portal venous circulation flow to the liver. Cancer cells reaching the paravertebral venous plexus metastasize to vertebrae, pelvis, and skull. Systemic arterial routes carry malignant tumor cells to these and other distant sites.
Spontaneous Regression of Tumors
The spontaneous regression of pathologically confirmed human cancers, including those with metastases, is extremely rare but is documented for some malignant tumors of infancy and childhood and also of adults. Notable in this regard is neuroblastoma of infants and childhood. This tumor originates from neuroblasts of the adrenal medulla and usually has a highly malignant course but, remarkably, in a small proportion of cases regresses by "maturation"/ differentiation to a benign ganglioneuroma or disappears.
Suggestive evidence for a role of the host in the biological control of human cancer includes: the long interval of time often elapsing before in situ carcinoma (of the uterine cervix or other site) becomes invasive; the hormonal dependence of certain cancers (of breast and prostate); the delayed recurrence or late metastasis of cancer after a silent period of one or more decades; and rare instances of the spontaneous regression of cancer and attributable in some cases to the process of differentiation.