MD2B - Introduction to Oncology - Diagnostic Evaluation, Classification, and Staging

Neha Vapiwala, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: December 22, 2001

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Diagnosis

The primary objectives in a diagnostic evaluation for suspected cancer are determinations of the tissue type, the primary site of malignancy, the extent of disease within the body and the tumor's future recurrence potential. Despite the advent of improved biochemical methods and imaging technology over the years, early detection of cancer remains a key to survival. As a result, the presence of specific signs and symptoms, bothersome enough to lead a patient to seek health care, becomes a crucial determinant, along with thorough evaluation by the physician.

An effective evaluation always begins with a detailed history and physical exam. Assessment of risk factors, family history and exposures are important components of this process, as is a well-performed examination of the often-neglected lymph nodes.

Laboratory data provide information on the functioning of specific organs and metabolic processes that may be affected in cancer patients or altered by subsequent cancer therapy. Analysis of blood, serum, urine and other body fluids for chemical and hematologic values often give nonspecific, nondiagnostic information. However, certain malignancies do have characteristic or highly suggestive findings to aid in diagnosis. Tumor markers are tumor-derived or tumor-associated proteins, antigens, genes or hormones that can also aid in diagnosis, in the measurement of therapeutic response, in locating tumor origin or in determining recurrence. Recently developed advances in laboratory techniques that provide diagnostic and prognostic data include monoclonal antibody production, radioimmunoassay and flow cytometry.

Imaging procedures play a vital role in diagnosis, allowing physicians to ascertain the presence of a mass, localize it for biopsy, characterize tissue, and determine anatomical extent of disease in preparation for subsequent therapy (surgery and radiation therapy, for example). These procedures are selected based on the organ site involved, with preferences based on suitability, cost, efficiency and accuracy of acquired data. Both noninvasive and invasive techniques are discussed below, respectively.

Radiographic studies, or x-rays, permit visualization of internal body structures, and can be site specific, such as mammography. Computerized tomography (CT) can provide a radiographic image of a selected body plane and thus may be particularly helpful in evaluating small calcified or cavitated chest lesions, for example. Computerized tomography is considered one of the most cost-efficient tests in diagnosing and staging malignancies. The administration of contrast may enhance detection in certain cases, such as myelography or gastrointestinal evaluations. Nuclear medicine studies are very sensitive and often detect sites of abnormal metabolic behavior months before radiographic changes occur. Examples include positron emission tomography (PET) scan in brain imaging and radiolabled monoclonal antibodies such as CYT-103 and TAG-72, the latter associated with mucin-producing adenocarcinomas. Ultrasonography is non-radiographic and noninvasive, using high-frequency sound waves to view deep soft-tissue structures. It is often used for detecting ascites, biliary or renal obstruction, or pelvic tumors, and is also useful for guiding biopsies. Magnetic resonance imaging, or MRI, is similar to the CT in that it creates sectional body images. Rather than using ionizing radiation, MRI employs radiofrequency pulses in a magnetic field. It is most applicable for malignant disease in the central nervous system, spine, head and neck and musculoskeletal system, aiding in detection, localization and staging. In fact, MRI with gadolinium enhancement is considered the best diagnostic tool for detection of brain metastases.

Fiber optic examinations (endoscopy, bronchoscopy, sigmoidoscopy) involve the use of fiber optic endoscopes to directly view the interior of a hollow viscus. These examinations may include biopsies depending on the clinical circumstances, organ and instrumentation used. Biopsy methods for accurate histologic or cytologic proof of malignancy are absolutely essential to workup and subsequent management of suspected cancer patients. Fine-needle aspiration (FNA), stereotactic localization with CT or MRI and laparoscopy are primary examples of applying imaging procedures for obtaining tissue specimens.

Classification and Nomenclature

Clarifying definitions is crucial to the discussion of cancer. The term cancer itself is synonymous withmalignant neoplasm and refers to deregulated "new growth" of cells that is capable of metastasis and invasion. A tumor is a swelling or mass of tissue that may be benign or malignant. A primary tumor describes the original site of tumor origin, whereas a secondary or metastatic tumor refers to a lesion that resembles the primary tumor histologically but is in a new, separate location. A second primary lesion refers to the presence of another, different neoplasm in the same patient. This is a rare occurrence, and certain patients are predisposed to the development of second primaries for a variety of reasons, including genetic factors, carcinogenic exposures, or side effects of anticancer treatment itself. Various biological and cytologic factors are used to distinguish between benign and malignant tumors. In general, benign tumors are relatively slow-growing, do not invade adjacent tissues, do not destroy normal tissue or metastasize, and rarely cause death. Under the microscope they are often composed of uniform, well-differentiated cells.

In contrast, malignant tumors feature generally rapid growth, high mitotic rates, invasion of surrounding tissues, lymphatics and blood vessels, and distant metastases. They are often composed of anaplastic cells that are poorly differentiated and have abnormal chromosome numbers.

Specific nomenclature indicates characteristics of the neoplasm. Benign tumors typically end in -oma, (eg. lipoma, glioma) whereas malignant tumors end in either -sarcoma, if derived from connective tissue, or -carcinoma if arising from epithelial tissue. Carcinomas are further classified as adeno- for glandular epithelial tissue and squamous- for squamous epithelial tissue. To further describe histologic appearances, terms such as cystic, follicular, papillary, medullary, exophytic, and polypoid are often added. Exceptions naturally exist, notably melanoma, lymphoma and hepatoma, which are malignant tumors with the -oma suffix. Prefixes such as malignant can further characterize tumors (malignant glioma).

Staging and Grading Classification

Staging is a method of classifying a malignancy by the extent of its spread within the body. It is determined both clinically and histologically. The majority of staging classifications are based on the anatomic extent of disease. The most important goal of staging is to provide data for proper treatment planning, but it also assists with prognosis, treatment evaluation and exchange of information between different treatment centers.

The TNM committee of the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC) devised the TNM staging system as an internationally consistent staging scheme for solid-tumor malignancies. The three categories are quantified and graded to represent progressive size or involvement. The extent of the primary tumor (T) may be measured on the basis of combinations of depth of invasion, surface spread and tumor size. The presence and extent of lymph node metastases (N) is assessed in terms of sizes and locations of involved nodes. Finally, the presence of distant metastases is determined. One should distinguish between a cTNM, based on clinical exam and a pTNM, which relies on surgical findings. Once the TNM numerical values are assigned, the patient is placed into one of four stages (I, II, III, IV), with increasing stage indicating more advanced disease.

Nonsolid malignancies (leukemias, for example) do not conform to this staging scheme because of their inherently disseminated nature. Leukemias are often grouped according to their predominant cell types, while myeloma patients follow a three-stage prognostic system relating "M proteins" to myeloma cell mass.

Not all cancer types fall neatly into TNM classifications. The AJCC and UICC continue to work on developing staging systems for malignancies such as cancers of small intestine and spinal cord, mesothelioma, carcinoid and Kaposi's sarcoma.

Patient Performance Classification

Treatment decisions depend greatly on a patient's functional status as assessed by performance scales. The most commonly used are the Karnofsky Performance Status Scale, which scores from 0% for dead to 100% for no complaints; the Eastern Cooperative Oncology Group (ECOG) scale, which rates from 0 for asymptomatic to 4 if bedridden; and the World Health Organization (WHO) scale, which assigns a 0 to fully active patients and a 4 to the completely disabled.

Grading

Grading is a histopathologic classification comparing cellular anaplasia, differentiation and mitotic activity to assess degree of malignancy of tumor cells for prognosis and treatment.

Two grading systems are often used. One employs descriptive terms such as well-, moderately- or poorly-differentiated, while the second grades numerically, from grade 1 for most differentiated to grade 4 for undifferentiated. In addition, special grading systems can exist and are widely for some tumors. The "Gleason" grading system for prostate cancer is a prime example. Finally, it is important to remember that a tumor grade may not only change with time, but several grades of cells can exist within the same tumor, thus, an adequate biopsy specimen is a must.



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