Staging of cancer

ALSO KNOWN AS: Clinical staging, pathological staging, restaging

DEFINITION: Staging is the process in which the location, extent, and degree of metastasis (spread) of a primary or original cancerous tumor is determined.

Cancers diagnosed or treated: All solid tumor cancer diagnoses are staged similarly. Nonlocalized leukemias are staged in unique ways according to the specific diagnosis. The diagnostic processes to stage a specific case vary according to cancer type and location.

Why performed: Cancer staging is integral to determining overall disease prognosis and influencing treatment modality choices. Stage assessment also plays a vital role in assuring effective communication among the patient’s medical team and accurate disease surveillance and epidemiology efforts.

Patient preparation: Patient preparation varies according to the technique or supporting procedures used to help stage the cancer. These procedures range from physical examination and imaging X-rays, ultrasounds, computed tomography (CT), and magnetic resonance imaging (MRI) scans to laboratory tests, biopsies, and surgical excisions with subsequent pathological examination of the tumor. Any preparation required of these supporting procedures will apply to the process.

Types of staging: There are four different types of cancer staging—clinical staging, pathological staging, post-therapy staging, and restaging. Clinical staging occurs through nonpathological means based on physical examination and imaging technology, such as X-ray, MRI, and CT, as well as immunologic and molecular blood tests to detect and measure cancer markers where applicable.

Pathological staging is accomplished following tissue removal by biopsy, in which surgical tumor excision is assessed as a sound treatment option. The biopsied tissue and removed tumor, surrounding tissue, and nearby lymph nodes are examined microscopically and histologically to determine the type and extent of the cancer from a pathologic perspective. Because treatment considerations and survival statistics are based on the stage of a patient’s cancer, the initial stage assessment remains static throughout the disease regardless of progression and response to treatment.

Post-therapy staging is completed after the patient receives an initial treatment, such as chemotherapy, hormone therapy, or radiation therapy, before surgery or in cases where surgery is not performed. It is assessed using clinical staging guidelines.

Should a patient enter remission but experience a recurrence, restaging is necessary if additional treatment is planned. The restaging process, including clinical and pathological staging, is identical to the original process but is now designated with a lowercase r. For example, a restaged Stage IV grouping is recorded as Stage rIV.

A limited number of classification systems are utilized to maintain terminology consistency. Efforts toward additional interpretive continuity are ongoing. Although the type of cancer dictates which specific categorization is applied, common elements include tumor location, size and number, lymph node involvement, and degree of metastasis (spread). The most prevalent systems include tumor-node-metastasis (TNM) staging (TNM) and overall group staging.

The tumor-node-metastasis (TNM) classification is adapted by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control.

Category T, for tumor, provides information about the original tumor, such as measurement (in millimeters, centimeters) at the site of origin and its degree of invasion into nearby tissues and organs.

• TX: Cannot be measured/evaluated
• T0: No evidence of primary tumor
• Tis: In situ tumor (tumor limited to cell layers of the original site)

Beyond Tis, numerical tumor categorization (T1, T2, T3, T4) offers a relative degree of severity, with higher numbers reflecting a larger tumor or more aggressive invasion. For example, T1 indicates a smaller, least aggressive tumor, while T4 indicates a larger, more aggressive tumor.

The tumor grade is the degree of abnormality (amount of differentiation from normal cells) and is determined pathologically by microscopic analysis. Typically, well-differentiated or low-grade tumors are considered the least aggressive and are associated with the best overall outcomes.

• GX: Cannot be determined
• G1: Tumor cells well differentiated from surrounding tissue
• G2: Tumor cells moderately well differentiated from surrounding tissue
• G3: Tumor cells poorly differentiated from surrounding tissue
• G4: Tumor cells undifferentiated from surrounding tissue

Some cancers, like prostate and central nervous system (CNS), have specific staging criteria. The most common approach to classifying prostate cancer is the Gleason system, which is based on the degree of epithelial change, including size, shape, and pathologic differentiation. The Gleason Score or Sum (GS) represents the sum of the primary and secondary grades of the prostate tumor. Based on a ranking from G2 (least aggressive, best prognosis) to G10 (most aggressive, poorest prognosis), the higher the sum, the more severe the disease. Several similar classification systems are used to grade CNS/brain cancers—the World Health Organization (WHO), Kernohan, or Ringertz. Rather than tumor size, grading is based on tissue differentiation and degree of vascularity and necrosis. Classification is made based on a three- or four-grade system, with the higher number associated with more aggressive cancer.

Category N, for regional lymph nodes, describes the degree to which lymph nodes have been affected by cancer using sentinel node biopsy. The (nearby) sentinel node or nodes are detected by injecting a radioactive or colored dye solution at the tumor site. The indicator solution travels within the lymph system, where circulating cancer cells follow. The area is scanned to detect the presence of the indicator solution in nearby or sentinel lymph nodes. One or more lymph nodes are removed and examined pathologically for the presence of cancer cells. Positive findings typically result in further removal and testing of nearby lymph nodes to determine the extent.

• NX: Cannot be measured/evaluated
• N0: Nearby lymph nodes are clear of cancer

Beyond N0, numerical categorization describes the size, location, and number of lymph nodes affected. The higher the number, the more lymph nodes are involved.

• N1: One to two lymph nodes affected
• N2: Three to six lymph nodes affected
• N3: Seven or more lymph nodes affected

For distant metastasis, the M category describes the degree to which the primary tumor has spread (metastasized) into surrounding tissues or organs.

• MX: Metastasis cannot be measured
• M0: No cancer metastasis detected
• M1: Cancer metastasis detected

Although the TNM metrics are relatively universal, each cancer type has a customized version of this classification system. In some instances, many additional subcategories refine tumor classification and offer additional prognostic information to the provider. In other cases, the staging classification may be simplified using truncated categorization.

Based on the established TNM categories, an overall cancer group stage is determined. Although criteria for stage assignment varies somewhat according to cancer type, the following provides a top-level overview of stage groupings:

• Stage 0: Carcinoma in situ (cancer is limited to the site of origin)

Stages I through III classify cancer, where higher numbers indicate more extensive and aggressive disease. Some cancer types utilize subcategories in staging to provide more specific information about type, behavior, and prognosis.

• Stage IV: Distant metastatic cancer (cancer has spread to another, distant organ)

Special cases include female reproductive cancers, Hodgkin's disease/lymphoma, cancer, and leukemia. Female reproductive cancers are staged according to the International Federation of Gynecologists and Obstetricians (FIGO). Although FIGO staging classification guidelines generally follow the general TNM/group staging approach, many of the female reproductive cancers, including those of the ovary, breast, cervix, and uterus, are subclassified in great detail.

Hodgkin disease and other cancers of the lymphoid system were previously staged using the Ann Arbor classification system. Stages I through IV were defined by the anatomical location of affected lymph nodes. The higher the stage number, the more lymph nodes were affected and the more aggressive the disease. Each stage assignment was subclassified as A (asymptomatic) or B (symptomatic). Though some practitioners still use this classification, the Lugano classification system, based on the Ann Arbor system, is the modern staging preference. Lugano classification incorporates F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) in the initial staging assessment.

Colorectal cancer historically used Dukes’ staging classification, an older system that corresponds closely to group staging. Dukes’ A through D colorectal cancer stages effectively translate to group Stages I through IV. The TNM system has largely replaced it. Additionally, the AJCC recommends a stage grouping method involving the cancer's pathologic stage.

Because leukemia involves the bone marrow and has often affected many organs, including the liver, spleen, and lymph nodes, staging is based primarily on the patient’s survival outlook according to disease progression. Although not all forms of leukemia utilize a formal staging system, each has a dedicated staging classification system. For example, chronic myelogenous leukemia (CML) is classified into three phases (as opposed to stages):

• Chronic: Fewer than 5 percent immature cells in circulation/bone marrow; mildly symptomatic, readily responsive to treatment
• Accelerated: 5 to 30 percent immature cells in circulation/bone marrow; more symptomatic, less responsive to treatment
• Acute/blast phase: Less than 30 percent immature cells in circulation/bone marrow; very aggressive, acute disease

Additional staging classifications, such as Rai (Stages 0-IV; U.S. predominant) and Binet (Stages A, B, and C; European predominant), are used for chronic lymphocytic leukemia (CLL). Still, other systems are applied to different leukemia types, such as the Stage 1 through Stage 3 classification based on the level of anemia and spleen size for hairy cell leukemia (HCL).

In addition to providing information on each cancer case's size, extent, and prognostic status, staging plays a vital role in epidemiology and treatment studies. The National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program and other cancer registries, such as the National Program of Cancer Registries (NPCR), use summary staging classification in their surveillance and epidemiology efforts. For these purposes, all cancers are grouped into one of the following five summary categories:

• In situ: Early-stage cancer, present only in the cell layers where first detected
• Localized: Cancer localized to tissue/organ where first detected; no evidence of metastasis
• Regional: Cancer metastasized to nearby lymph nodes, tissues, organs
• Distant: Cancer metastasized to distant lymph nodes, tissues, organs
• Unknown: Insufficient data available to classify

The data collected are made available to clinical and research professionals so they may better understand and address the cancer burden according to various demographics and metrics, including cancer stage.

Results: Cancer staging is a vital component of the diagnostic process. Accurate stage assessment will guide the medical team in making optimal treatment recommendations for patient care according to prognostic expectations. The classification remains constant throughout the disease because the original stage's epidemiologic value is significant. Restaging occurs only if treatment is planned following a recurrence.

Bibliography

Baatrup, Gunnar, ed. Multidisciplinary Treatment of Colorectal Cancer: Staging, Treatment, Pathology, and Palliation. 2nd ed., Springer, 2021.

"Cancer Staging." American Cancer Society, 18 Feb. 2022, www.cancer.org/cancer/diagnosis-staging/staging.html. Accessed 20 July 2024.

"Cancer Staging." National Cancer Institute, 14 Oct. 2022, www.cancer.gov/about-cancer/diagnosis-staging/staging. Accessed 20 July 2024.

"Cancer Staging System." Cleveland Clinic, 25 Mar. 2022, my.clevelandclinic.org/health/diagnostics/22607-cancer-stages-grades-system." Accessed 20 July 2024.

Olawaiye, Alexander B., et al. "The New (Version 9) American Joint Committee on Cancer Tumor, Node, Metastasis Staging for Cervical Cancer." CA: A Cancer Journal for Clinicians, vol. 71, no. 4, 2021, pp. 287-298. doi.org/10.3322/caac.21663.