Epidemiology of Cancer

• Americans have a one in five chance of dying of cancer.
  
• Lung cancer is the major cause of cancer death in both men and women.
  
• Although breast cancer is 2.5 times more frequent than lung cancer in women, cure rates for breast cancer are much higher than for lung cancer.

Geographic factors:

Incidence and death rates from specific forms of cancer vary around the world. Example:  stomach cancer in Japan.

Environmental factors:

Obesity
Alcohol abuse
Smoking
Asbestos, vinyl chloride, 2-naphthylamine

Age:

Each age group has its own predilection for certain forms of cancer. Cancer accounts for 10% of deaths in children under 15, second only to accidents.

Heredity:

Hereditary forms of cancers can be divided into three categories.

• Inherited cancer syndromes (autosomal dominant) -- Inherited predisposition indicated by strong family history of uncommon cancer
  example:  Familial retinoblastoma, Familial adenomatous polyps of the colon, multiple endocrine neoplasia syndromes
• Familial cancers -- Evident familial clustering of cancer, but role of inherited predisposition may not be clear in an individual case
  example:  breast cancer, ovarian cancer
• Autosomal Recessive Syndromes of Defective DNA Repair
  example:  Xeroderma pigmentosum, ataxia-telangiectasia

Acquired Preneoplastic Disorders:

Regenerative, hyperplastic and dysplastic proliferations are thought to be fertile soil for the development of malignant neoplasm.
    example:  Endometrial hyperplasia, cirrhosis
"Precancerous conditions" are conditions associated with increased risk of malignancy
    example:  chronic atrophic gastritis of pernicious anemia, solar keratosis of the skin and chronic ulcerative colitis

II. CLINICAL FEATURES OF MALIGNANCY

Location and impingement on adjacent structures:

Mediastinal masses can compress the trachea causing respiratory distress.
Colon tumors can cause obstruction.

Functional activity such as hormone synthesis:

Parathyroid tumor may secrete parathyroid hormone resulting in hypercalcemia. Pheochromocytoma can elaborate catecholemines.

Bleeding and secondary infections:

Colon cancer often presents with melena (blood in the stool).

Initiation of acute symptoms caused by rupture or infarction:

Ovarian tumors can experience torsion and present with acute pain and even rupture as the venous drainage becomes blocked before the arterial supply.

Cancer Cachexia:

Cachexia refers to a wasting syndrome consisting of progressive loss of body fat accompanied by profound weakness, anorexia and anemia. The cause of cancer cachexia is not known. Probably results from actions of cytokines produced either by the tumor or by the host in response to tumor.

Paraneoplastic Syndromes:

Refers to symptom complexes in cancer patients that cannot be readily explained. Approximately 10% of patients with advanced malignancies have paraneoplastic syndromes. It is worthwhile to recognize these syndromes as they may represent the earliest manifestation of malignancy in your patient. Some common paraneoplastic syndromes include:

• Cushings syndrome (excessive ACTH or ACTH-like peptides) Lung cancer, Pancreatic cancer
• Hypercalcemia (osteolysis or calcemic humoral substances) Lung cancer
• Neuromyopathic syndromes such as myasthenia gravis (immunologic?) Lung cancer
• Acanthosis nigricans ( ?immunologic) Gastric, Lung, Uterine cancer
• Clubbing of fingers and hypertrophic osteoarthropathy (unknown) Lung cancer
• Trousseau's syndrome (tumor products activate clotting) Pancreas, Lung cancer

III. CYTOLOGIC FEATURES OF MALIGNANCY

Two forms of cytologic specimens:

• Fine needle aspirate (FNA)
• Exfoliative cytology which includes sputum, urine, pleural fluid, pap smears

Malignant Cells:

• Disturbed polarity and loss of cohesiveness: nuclei oriented in different directions and are irregularly spaced. Cells become detached from one another.
• Pleomorphism: variation in size, shape and number of nucleoli.
• Molding of nuclei: nuclei appear pushed into one another or stacked together like a vertebral column.
• Nuclear to cytoplasmic ratio increased.
• Chromatin shows irregular clumping and hyperchromasia.
• Nuclear membrane is irregular with angular bites.
• Abnormal mitoses: may be present (quadripolar, mercedes benz, dispersed).

IV. HISTOLOGIC (ARCHITECTURAL) AND GROSS FEATURES OF MALIGNANCY

Cytology versus Histology in the Diagnosis of Malignancy

The cytologic features of malignancy can be applied to histologic sections. Although fine nuclear detail may be lost by formalin fixation and processing necessary for histologic sections, nuclear features of malignancy should still be discernable. Cohesiveness of cells is more easily evaluated on cytologic material.

Histologic sections provide added information:

• Architecture
• Relationship of cancer cells to normal structures (depth of invasion, etc.)

The Architectural Features of Malignancy

Invasion of the underlying or surrounding tissue: In carcinomas, (epithelial origin) invasion is defined by extension of tumor beyond the basement membrane. In mesenchymal tumors (sarcomas) invasion is defined by an irregular front penetrating the surrounding tissue.

Stromal changes: The change that occurs in the stroma as tumor invades is called desmoplasia. Desmoplasia refers to the stroma composed of connective tissue and blood vessels that surrounds the infiltrating tumor. The spindle shaped cells that make up the desmoplasia are not themselves neoplastic. Desmoplasia is a response to invasion of tissue by malignant tumor cells.

Loss of normal structure: As tumors become less and less differentiated, they resemble the tissue of origin less and less. For example, well differentiated prostatic adenocarcinoma shows small round glandular structures, while poorly differentiated tumors show complicated glandular patterns and sheets of tumor cells.

New structures: Some tumors will create structures such as complicated "cribriform" gland structures (colon, endometrium cancers) or papillary structures (thyroid, bladder cancers) Sarcomas may form "herringbone" arrangements.

Necrosis: Although present in inflammatory and infectious processes, necrosis may also be present in malignancies and often indicates that the tumor has outgrown its blood supply.

Angiogenesis: Because tumors cannot grow without a blood supply, angiogenesis factors are involved in tumor vessel growth.

Inflammation: Tumors often incite inflammation.

Irregular borders: Malignant tumors often have irregular borders due to the progressive infiltration, invasion and destruction of surrounding tissue. In general, they are poorly demarcated from the surrounding tissue and a well-defined cleavage plane is lacking.

Necrosis: Seen on histologic sections, necrosis can also be identified on gross examination of tissues. It is not specific for malignancy, but can be associated with a malignant tumor that has outgrown it's blood supply.

Metastasis: Metastases are tumor implants discontinuous with the primary tumor. With few exceptions (some types of brain and skin tumors), all malignancies can metastasize. With extremely few exceptions, metastasis marks a tumor as malignant because benign tumors do not metastasize.

Metastasis and Pathways of Spread

Seeding of body cavities and surfaces: This occurs when a malignant neoplasm penetrates into a natural "open field" such as peritoneal cavity, pleural space, pericardial cavity, etc. Most common examples, ovarian carcinoma and mucin secreting ovarian and appendiceal carcinomas (pseudomyxoma peritonei).

Lymphatic spread: This is the most common pathway for dissemination of carcinomas (although sarcomas can also use this route). The pattern of lymph node involvement follows the natural routes of drainage.

Hematogenous spread: This pathway is typical of sarcomas. Arteries are more difficult for tumor to penetrate than veins. With venous invasion, the blood-borne cells follow the venous flow draining the site of the tumor. Liver and lungs are frequently involved.

V. GRADING AND STAGING OF TUMORS

GRADE:

The grade of a tumor is based on the degree of differentiation of the tumor cells, the degree of cytologic atypia and the number of mitoses within the tumor.

In general, low grade tumors are well differentiated, have minimal cytologic atypia and low mitotic rates. High grade tumors are poorly differentiated, have marked cytologic atypia and high mitotic rates.

STAGE:

The stage of a tumor is based on the size of the primary tumor, the extent of invasion into surrounding tissue, the spread to regional lymph nodes and the presence or absence of blood-borne metastases. The staging system used here is the American Joint Committee (AJC) on Cancer Staging. The staging scheme varies by tumor site, but all tumors are assigned a "T" stage referring to tumor size, degree of penetration of surrounding tissue; a "N" indicative of presence of lymph node involvement and a "M" which indicates the existence of metastases.

GRADE THE TUMOR!
STAGE THE PATIENT!

Diagnostic Electron Microscopy

Although cytologic and histologic features of malignancy can be appreciated at the ultrastructural level, the main use of diagnostic electron microscopy is involved not with the question of whether a tumor is malignant or not, but with the issue of tumor classification. Cytoplasmic organelles such as melanosomes are indicative of melanocytic lesions such as malignant melanoma, the presence of desmosomes points to an epithelial tumor (carcinoma), and structures such as myosin and actin filaments arranged in "Z" bands are indicative of skeletal muscle differentiation and hence if found in a tumor would suggest a rhabdomyosarcoma. Neurosecretory dense core granules are found in tumors with neuroendocrine differentiation.

Immunocytochemistry (IPEX, Brown Stains)

Antibodies directed against antigens found in specific tumors types can be used to help diagnose poorly differentiated tumors. Tumors which look similar on hematoxylin-eosin stained sections can be differentiated from each other using these "special stains". Examples include using anti-cytokeratin antibodies to distinguish poorly differentiated carcinoma (keratin positive) from a high grade lymphoma (keratin negative). Monoclonal antibody directed against HMB45 is very helpful in the diagnosis of malignant melanoma.

Immunocytochemistry is also used commonly in the diagnosis of lymphomas. Specific antibodies directed against B and T cell markers as well as against kappa and lambda antigens are available.

Another use of immunocytochemical stains is for the detection of molecular changes. Mutations of the p53 gene leads to accumulation of the mutant protein which can be detected using immunocytochemical stains.

Serum Tumor Markers

Tumor markers include cell surface antigens, cytoplasmic proteins, enzymes and hormones which indicate the presence of tumor. Many tumor markers are also used as immunohistochemical stains. A tumor marker is measured in serum or other body fluid in the clinical laboratory, often utilizing immunoassays. The following are several clinically important tumor markers.

Prostate specific antigen (PSA): A serine protease produced by normal as well as neoplastic prostate epithelium. In normal men, only small amounts circulate in the serum. Elevated blood levels are associated with prostatic cancer. Benign conditions such as prostatic hyperplasia can also raise the serum PSA level, but to a lesser degree.

Carcinoembryonic antigen (CEA): A complex glycoprotein that is normally produced in embryonic tissue of the gut, pancreas, and liver. It is elevated in some colorectal and pancreatic neoplasms. Increased serum levels can also sometimes be present in patients with gastric and breast cancers. Non neoplastic causes of increased serum CEA include smoking, alcoholic cirrhosis and ulcerative colitis.

Ca-125: A glycoprotein expressed by coelomic epithelium during fetal development. Increased serum levels can be present in patients with ovarian cancer. Other malignancies such as pancreatic carcinoma may also have increased levels. Non malignant causes of high serum Ca125 include pregnancy, endometriosis and liver failure.

Tumor markers may:

• Suggest/support a diagnosis of malignancy (ie Prostate Specific Antigen PSA)
• Predict relapse (ie Carcinoembryonic antigen CEA)
• Determine the response to therapy (ie CA-125)

Flow Cytometry

Flow cytometry is a technique used to measure individual cell characteristics such as membrane antigens and DNA content of tumor cells. The classification of leukemias and lymphomas is based on cell surface antigens which can be easily identified by flow cytometry. DNA ploidy appears to correlate with prognosis in a variety of tumors. In general, aneuploidy seems to be associated with a poorer prognosis in early-stage breast cancer, bladder, lung, colorectal and prostate cancer.

Molecular Diagnosis of Malignancy

This topic will be covered later. Briefly, molecular techniques such as polymerase chain reaction, the Southern blot analysis of DNA and the Northern blot analysis of RNA are used in tumor diagnosis.