The History, Application, and Evolution of Staging in Cancer

January 2024 Vol 15, No 1

Categories:

Cancer Staging
Frederick Greene, MD, FACS
Medical Director, Cancer Data Services
Atrium Health/Levine Cancer Institute, Charlotte, NC

From both a patient and physician standpoint, the discussion of a new cancer diagnosis is both difficult emotionally and necessary to begin devising a plan for treatment and a positive outcome. Following the initial response, many patients will then ask, “Doctor, what is my stage?” While many patients are not familiar with the specifics of cancer staging, more and more patients understand that strategies exist that classify their cancer in order to direct treatment, follow-up, and prediction of outcomes. For patients not attuned to the use of staging classifications, they will hopefully learn about these primarily from their treating physicians and, secondarily, from their nurse navigator, and finally, from information gained through literature, internet, and social media searches. The goal of this article is to serve as an opportunity to learn about one of the most important strategies for classifying adult solid tumors: the T(umor) N(ode) M(etastasis) System.

From both a patient and physician standpoint, the discussion of a new cancer diagnosis is both difficult emotionally and necessary to begin devising a plan for treatment and a positive outcome.

The concept of cancer staging is inherently important to all cancer patients and to all who practice clinical medicine. Staging provides a framework for discussion with patients and coordination of care among physicians who treat malignancy. It is designed to stratify patients into groups that have similar outcomes. To achieve this, a common classification structure and rules that are valid for solid tumors at all cancer sites have been created. The TNM classification was developed by Pierre Denoix, a surgeon working in Paris in the 1940s and 1950s, and is considered an “anatomical” system based on the size or thickness (T) in millimeters or centimeters (eg, breast, lung, liver, thyroid, melanoma) or depth of penetration (eg, stomach, colon, rectum) of the cancer into the wall of an organ, as well as the presence of cancer cells in lymph nodes (N) and other organs throughout the body (M).

Since the mid-1980s, the TNM system has been considered the worldwide strategy for the staging of adult solid malignancy.1 The categorization of tumor features and identification of prognostic groupings are vital for planning clinical trials to assess treatment strategies whether they are surgical-, drug-, or radiation-based. In addition, staging enables meaningful comparison of outcomes across large and diverse populations. Without a staging system, the stratification of most solid tumors would be garbled, and the difficulties in making rational treatment recommendations would only be amplified in the increasingly complex world consisting of many different (multimodal) forms of therapy. The creation of a uniform staging system and recognition of the power of data generated from its application were key to the development of the National Cancer Database (NCDB) in the late 1980s as a major undertaking by the American College of Surgeons Commission on Cancer and the American Cancer Society.2 This national database includes information on approximately 40 million patients and represents 70% of all cancer patients in the United States. The NCDB data are used for clinical research, development of treatment guidelines, and to study outcomes of a large variety of cancers.

Characteristics of the TNM System

Although the TNM classification is an anatomical system, the ability to group TNM categories into “stages” is based on a generalized pattern of biological behavior that governs the progression of tumor growth. A solid tumor first grows locally in overall size and extent. At some sites, such as the colon and rectum, the depth of tumor penetration through the bowel wall is most relevant. At other sites, such as primary breast cancer, tumor diameter determines the T category. Metastases to regional lymph nodes (N category) usually precede systemic (throughout the body) metastasis. Finally, metastases (M category) develop past these nodal basins either into nonregional lymph nodes or into a variety of solid organs (eg, liver, lung, brain).

One of the most important issues for patients is the prognosis of their cancer—what does the future hold? The spread of tumors—regionally and especially systemically—has typically been the most important prognostic factor, but not the only one. A helpful broad definition of a cancer prognostic factor is a variable that can explain some of the differences between certain cancers that are associated with the expected course and outcome. Since individual solid tumors of a given type and stage may be biologically unique, the variability of tumor growth may be the result of multiple prognostic factors operating at the same tumor site and type. In the TNM system, these factors have been recognized as influencing prognosis, but they cannot be expressed in terms of T, N, or M status. Over the past several years these elements have been incorporated as “prognostic” factors. Along with determining the “stage” (combination of T, N, and M) of a cancer, physicians take these prognostic factors into account when recommending treatment of a variety of malignancies.

Application of Prognostic Factors

The American Cancer Society estimates that approximately 1.9 million new cancer cases will be diagnosed in 2023.3 Of these, approximately 1.6 million will be solid tumors occurring in adults and, therefore, suitable for staging using the TNM system. The clinician’s role begins with the selection of appropriate diagnostic tests for a specific site and tumor type. Without knowledge of a specific tumor’s prognostic factors, it would be impossible to choose a proper imaging modality, serum marker, or other clinical assessment that would provide relevant information. Prognostic factors also allow for tailoring an optimal treatment plan for each patient. In the era of multimodal therapy, selection of appropriate preoperative or postoperative chemoradiation is based on knowledge of the “clinical” or “pathological” stage of the cancer. The clinical stage is determined prior to beginning treatment and is based on physical examination, radiological studies, and other tests that can determine the extent of a cancer. The pathological stage is computed after the tumor and lymph nodes have been surgically removed and any other sites of cancer have been biopsied.

The TNM stage is but one prognostic factor that allows for optimal treatment planning. Once treatment has been chosen, these factors also allow for the prediction of outcome for the individual patient. This assessment refines expectations of prognosis and can help determine appropriate follow-up intervals and methods for monitoring patients based on the biologic features of their cancer. These factors are further used to give patients and their caregivers an educational perspective relative to the short-term and long-term outcomes of the malignancy.

Tumor-Related Prognostic Factors

The identification of tumor-related prognostic factors begins with an assessment by the pathologist of the morphology (structure of the tumor), grade, and growth pattern of an individual cancer. Determination of the anatomic extent of the tumor (TNM stage) occurs in 2 phases. The first phase is a clinical assessment (cTNM) based on physical exam and imaging studies. The second phase is the pathological assessment (pTNM) that occurs after surgical resection. Surgical removal has also become more common after radiation, chemotherapy, or both and is termed “neoadjuvant” therapy. The pathologist describes the tumor’s extent based on gross and microscopic features of the removed tumor and lymph nodes. Pathological staging has historically been more precise than clinical staging and has been regarded as more reliable for predicting prognosis. Recently, the inclusion of tumor markers has enhanced the ability of the pathologist to give vital information for clinical decision-making. One example is the use of serum markers in staging of testicular cancer. Although many of these molecular markers are not included in the TNM staging strategy, the future use of genetic as well as molecular markers has great potential. Another dimension of tumor-related factors, but less well defined than pathological factors, is the overall effect that tumors have on individual patients. This is manifest by clinical symptoms and performance status. Prior to beginning cancer treatment, the physician assesses a patient’s ability to perform behaviors necessary for daily activity. These performance scoring systems (Karnofsky index, Eastern Cooperative Oncology Group score, etc) play a role in selecting the safest treatment for an individual patient.

The TNM stage is but one prognostic factor that allows for optimal treatment planning. Once treatment has been chosen, these factors also allow for the prediction of outcome for the individual patient.

One of the inherent difficulties in updating the TNM system is the decision as to what new information to include. In breast cancer alone, consideration of at least 80 prognostic variables was undertaken during the review for the latest edition of the AJCC Cancer Staging Manual.4 Obviously not all of these variables have the same importance. Each has to be judged on the basis of clinical impact and the likelihood of being an independent variable that can stand alone as a prognosticator of outcome. Using breast cancer as an example, the customary and historical prognostic parameters of lymph node status, tumor size, histologic grade, and overall pathological TNM are traditionally strong prognostic factors. More recently it has been appreciated that the steroid receptor status (estrogen receptor, progesterone receptor) and the level of the human epidermal growth factor receptor 2 are important in the assessment of patient outcomes and treatment planning. These factors are now important elements in determining the TNM stage of breast cancer.

TNM staging is in fact our “language of cancer.” To ensure a meaningful dialogue between a patient and his or her physician or navigator, this language must be understood and utilized by both.

Managing Change

The re-evaluation of data is an absolute necessity to assure appropriate, up-to-date staging of any cancer site even though revisions in assigning stage present problems for data registries and for those designing clinical trials that include patients over a significant time period. Cancer outcomes based on stage groups (IIA, IIIC, etc) can only be determined by analyzing registries and robust data sets. Stage information for cancer patients is routinely stored in hospital and state cancer registries. These changes to TNM staging are illustrated by a major change in breast cancer staging introduced in an earlier edition of the AJCC Cancer Staging Manual relating to the assessment of regional lymph nodes. Historically, in this staging strategy, N1 reflects cancer presence in 1 to 3 axillary lymph nodes, while N2 describes patients having 4 to 9 axillary nodes involved. A patient with 10 or more axillary lymph nodes is placed into an N3 category. Supraclavicular (above the collarbone) nodal involvement was designated as M1 (stage IV). Using large data sets, it was recognized that women with supraclavicular nodal involvement had the same outcomes as women with multiple node involvement in the axilla. A consequence of grouping women with supraclavicular nodal involvement into the M1 category was to exclude these patients from clinical trials treating local and regional disease (N1-3) even though they had survival patterns similar to women with advanced local disease. Following these analyses, supraclavicular node-positive patients reverted to the N3 category, placing them in groups defined as having “localized” cancer and are now candidates for clinical trials that are designed for “localized” cancer.

Another example of staging system modification dealing with breast cancer involves the classification of “sentinel” lymph nodes, which has become important in the management of patients with breast cancer. Many women can now avoid a complete axillary nodal removal in favor of identifying the sentinel node, or first node, that indicates cancer spread. A strategy for sentinel node documentation was needed. The notation for a sentinel node is the N designation followed by “(sn).” This indicates that only the sentinel node was reported and that a full axillary dissection was not performed. If the sentinel node is found to be pathologically free of cancer, the proper designation would be N0 (sn).

Staging and Large Data Sets

The NCDB, discussed above, contains appropriate TNM staging information, as well as treatment characteristics, patient demographics, and survival relative to treatment and stage. Data items that enable comparison of populations are continually being modified and supplemented as the importance of new variables emerge. One of the many distinguishing features of the NCDB compared with other oncologic outcomes data registries is the inclusion of specific surgical and pathological details of patient care. These items include the surgical procedure, size of the surgical margin, number of regional lymph nodes obtained, and information related to remaining tumor. In addition, the various treatment modalities and follow-up findings are included.

Staging and Neoadjuvant Therapy

Since the development of the TNM strategy in the late 1940s and 1950s, treatment of cancer has evolved into the use of various cancer therapies that are interwoven into a matrix involving surgical resection, radiation, and chemotherapy. Over the past decade, the concept of preoperative chemoradiation (neoadjuvant) has been applied to a variety of tumors. Currently these cancers are being treated with nonsurgical modalities after initial confirmation of the cancer and careful clinical staging. The incorporation of neoadjuvant therapy is a much more recent innovation than the initial designation of group staging in the TNM system and presents the challenge of incorporating temporal factors into the staging system.

The complete response (CR) to neoadjuvant therapy has also been defined as one of the most important prognostic indicators in tumors amenable to preoperative therapy. A complete pathologic response (pCR) to drug or radiation therapy for carcinomas of the rectum, breast, and head and neck portends a much better outcome than in those patients who do not respond to neoadjuvant therapy. Using proper prefixes to identify the point at which assessments are made, the traditional categories T0, N0, and M0 indicate that there is no obvious tumor remaining after initial chemotherapy, radiation, or use of both modalities.

When creating a new stage grouping, it is important to assure that this designation will be applicable to any site that might be treated with neoadjuvant therapy, and that the designation has prognostic significance in the likelihood of either a clinical CR or pathological CR. Currently these strategies are utilized for breast, rectal, head and neck, pancreatic, and other GI malignancies. There is growing evidence that at some tumor sites, such as anus and rectum, the reliability of clinical determination of CR may be reliable enough to avoid surgical resection.

Educational processes for both patients and clinicians must accompany the introduction of any new staging definitions both to raise awareness of and to assure comprehension of the meanings of staging terms. Patient education is particularly critical to allow meaningful conversations among patients, caregivers, and treating physicians. TNM staging is in fact our “language of cancer.”5 To ensure a meaningful dialogue between a patient and his or her physician or navigator, this language must be understood and utilized by both.


References

  1. Greene FL, Sobin LH. A worldwide approach to the TNM staging system: collaborative efforts of the AJCC and UICC. J Surg Oncol. 2009;99:269-272.
  2. Winchester DP, Stewart AK, Phillips JL, Ward EE. The National Cancer Data Base: past, present, and future. Ann Surg Oncol. 2010;17:4-7.
  3. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73:17-48.
  4. Amin M, Edge S, Greene FL, et al (eds). AJCC Cancer Staging Manual. Eighth Edition. Springer; 2016.
  5. Greene FL, Sobin LH. The TNM system: our language for cancer care. J Surg Oncol. 2002;80:119-120.
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