Cancer staging

Cancer staging is the process of determining the extent to which a cancer has developed by spreading. Contemporary practice is to assign a number from I to IV to a cancer, with I being an isolated cancer and IV being a cancer which has spread to the limit of what the assessment measures. The stage generally takes into account the size of a tumor, whether it has invaded adjacent organs, how many regional (nearby) lymph nodes it has spread to (if any), and whether it has appeared in more distant locations (metastasized).

The most clinically useful staging system is the tumor, node, and metastasis (TNM) staging system developed by the American Joint Committee on Cancer (AJCC) in collaboration with the Union for International Cancer Control (UICC), herein referred to as the AJCC TNM staging system. The AJCC TNM system classifies cancers by the size and extent of the primary tumor (T), involvement of regional lymph nodes (N), and the presence or absence of distant metastases (M), supplemented in recent years by evidence-based prognostic and predictive factors. There is a TNM staging algorithm for cancers of virtually every anatomic site and histology, with the primary exception of pediatric cancers.

TNM staging system

The AJCC and UICC periodically modify the AJCC TNM staging system in response to newly acquired clinical and pathological data and an improved understanding of cancer biology and other factors affecting prognosis. Periodic and, to the extent possible, evidence-based revision is a key feature that makes this staging system the most clinically useful among staging systems and accounts for its widespread use worldwide. However, because changes in staging systems may make it difficult to compare outcomes of patients over time, evidence-based changes to this staging system are made with deliberate care.

In general, the revision cycle for AJCC TNM staging has historically been 5 to 7 years. This approach provides sufficient time for implementation of changes in clinical management and cancer registry operations and for relevant examination and discussion of data supporting changes in staging. Table 1.1 shows the publication year for each version of the AJCC TNM system up through this current AJCC Cancer Staging Manual, 8^th Edition. The AJCC Cancer Staging Manual, 7^th Edition was used for cancer patients diagnosed on or after January 1, 2010. The 8^th Edition published in this manual is effective for cancer patients diagnosed on or after January 1, 2018. The AJCC recognizes that rapidly evolving evidence may necessitate more frequent updates of AJCC TNM staging in the future, and anticipates providing more frequent updates for disease sites as new and validated evidence becomes available. Moreover, the AJCC also recognizes that as clinical cancer care continues to evolve and incorporates factors that are not used to determine stage but that provide key information on specific outcomes and/or expected benefit from specific therapies, new, validated clinical tools will be needed to help clinicians efficiently and accurately use these important data to enhance clinical care (see Anatomic Staging and the Evolving Use of Nonanatomic Factors).

see AJCC Cancer Staging Manual Publishing History

Cancer staging can be divided into a clinical stage and a pathologic stage. In the TNM (Tumor, Node, Metastasis) system, clinical stage and pathologic stage are denoted by a small "c" or "p" before the stage (e.g., cT3N1M0 or pT2N0). This staging system is used for most forms of cancer, except brain tumors and hematological malignancies.

Clinical stage is based on all of the available information obtained before a surgery to remove the tumor. Thus, it may include information about the tumor obtained by physical examination, blood tests, radiologic examination, biopsy, and endoscopy.
Pathologic stage adds additional information gained by examination of the tumor microscopically by a pathologist after it has been surgically removed.

Because they use different criteria, clinical stage and pathologic stage often differ. Pathologic staging is usually considered to be more accurate because it allows direct examination of the tumor in its entirety, contrasted with clinical staging which is limited by the fact that the information is obtained by making indirect observations of a tumor which is still in the body. However, clinical staging and pathologic staging often complement each other. Not every tumor is treated surgically, therefore pathologic staging is not always available. Also, sometimes surgery is preceded by other treatments such as chemotherapy and radiation therapy which shrink the tumor, so the pathologic stage may underestimate the true stage.

Considerations

Correct staging is critical because treatment (particularly the need for pre-operative therapy and/or for adjuvant treatment, the extent of surgery) is generally based on this parameter. Thus, incorrect staging would lead to improper treatment.

For some common cancers the staging process is well-defined. For example, in the cases of breast cancer and prostate cancer, doctors routinely can identify that the cancer is early and that it has low risk of metastasis.^[1] In such cases, medical specialty professional organizations recommend against the use of PET scans, CT scans, or bone scans because research shows that the risk of getting such procedures outweighs the possible benefits.^[1] Some of the problems associated with overtesting include patients receiving invasive procedures, overutilizing medical services, getting unnecessary radiation exposure, and experiencing misdiagnosis.^[1]

The AJCC TNM stage for each cancer type is built by defining the anatomic extent of cancer for the tumor (T), lymph nodes (N), and distant metastases (M), supplemented in some cases with nonanatomic factors. For each of the T, N, and M, there is a set of categories, most often defined by a number (e.g., T1, N2). The description of the anatomic factors is specific for each disease site. These descriptors and the nomenclature for TNM have been developed and refined over many editions of the AJCC Cancer Staging Manual by experts in each disease and by cancer registrars who collect the information, taking into consideration the behavior and natural history of each type of cancer. These elements are then combined, in a fashion set forth for each cancer type, into prognostic stage groups (often called “stage groups”).

Importantly, the term stage should be used only to describe the aggregate information resulting from T, N, and M category designations (i.e., based on T, N, and M classifications) combined with any prognostic factors relevant to the specific disease. The term stage should not be used to describe individual T, N, or M category designations that often are mistakenly referred to as “stage.”

Assigning the T, N, and M categories follows general rules described in the tables in this chapter. These rules apply to all cancer sites, with relatively few exceptions. These exceptions are defined in the relevant disease-specific chapters.

Rules are repeated throughout this chapter to facilitate easy reference based on the topic.

Before delineating the specific rules for T, N, and M categorization and for generating prognostic stage groups, it is important to first delineate the time points, termed classifications, at which staging information is collected and reported.

TNM Staging Classification: Clinical, Pathological, Posttherapy, Recurrence, and Autopsy

Stage may be defined at several time points in the care of the cancer patient. To properly stage a patient’s cancer, it is essential to first determine the time point in a patient’s care. These points in time are termed classifications, and are based on time during the continuum of evaluation and management of the disease. Then, T, N, and M categories are assigned for a particular classification (clinical, pathological, posttherapy, recurrence, and/or autopsy) by using information obtained during the relevant time frame, sometimes also referred to as a staging window. These staging windows are unique to each particular classification and are set forth explicitly in the following tables. The prognostic stage groups then are assigned using the T, N, and M categories, and sometimes also site-specific prognostic and predictive factors.

Among these classifications, the two predominant are clinical classification (i.e., pretreatment) and pathological classification (i.e., after surgical treatment).

Clinical Classification (cTNM)

Clinical stage classification is based on patient history, physical examination, and any imaging done before initiation of treatment. Imaging study information may be used for clinical staging, but clinical stage may be assigned based on whatever information is available. No specific imaging is required to assign a clinical stage for any cancer site. When performed within this framework, biopsy information on regional lymph nodes and/or other sites of metastatic disease may be included in the clinical classification.

Clinical evaluation by physical examination often underestimates the extent of cancer burden at the time of patient presentation. Although imaging is not required to assign clinical stage, clinical imaging has become increasingly important, and for many cancer sites, imaging is essential to stage solid tumors accurately. Imaging allows assessment of the tumor’s size, location, and relationship to normal anatomic structures, as well as the existence of nodal and/or distant metastatic disease. Computed tomography (CT) and magnetic resonance (MR) imaging are the most commonly used imaging modalities, although positron emission tomography (PET; often combined with CT), ultrasound, and plain film radiography also have important roles in various clinical situations. Thus, a new section was added to the disease site chapters to provide context-specific imaging information. To adequately and comprehensively communicate essential information, radiologists should use standardized nomenclature and structured report formats, such as those recommended by the Radiological Society of North America (RSNA) reporting initiative (http://www.rsna.org/Reporting_Initiative.aspx). In addition to providing key information for assigning the T, N, and M categories, clinical imaging is invaluable for guiding biopsies and surgical resections. Later in the course of a patient’s treatment, imaging also often plays an important role in monitoring response to treatment.

Pathological Classification (pTNM)

Pathological stage classification is based on clinical stage information supplemented/modified by operative findings and pathological evaluation of the resected specimens. This classification is applicable when surgery is performed before initiation of adjuvant radiation or systemic therapy.

Posttherapy or Post Neoadjuvant Therapy (ycTNM and ypTNM)

Stage determined after treatment for patients receiving systemic and/or radiation therapy alone or as a component of their initial treatment, or as neoadjuvant therapy before planned surgery, is referred to as posttherapy classification. It also may be referred to as post neoadjuvant therapy classification.

Recurrence or Retreatment (rTNM)

Staging classifications at the time of retreatment for a recurrence or disease progression is referred to as recurrence classification. It also may be referred to as retreatment classification.

Autopsy (aTNM)

Staging classification for cancers identified only at autopsy is referred to as autopsy classification.

Pathologic

Pathologic staging, where a pathologist examines sections of tissue, can be particularly problematic for two specific reasons: visual discretion and random sampling of tissue. "Visual discretion" means being able to identify single cancerous cells intermixed with healthy cells on a slide. Oversight of one cell can mean mistaging and lead to serious, unexpected spread of cancer. "Random sampling" refers to the fact that lymph nodes are cherry-picked from patients and random samples are examined. If cancerous cells present in the lymph node happen not to be present in the slices of tissue viewed, incorrect staging and improper treatment can result.

Current research

New, highly sensitive methods of staging are in development. For example, the mRNA for GCC (guanylyl cyclase c), present only in the luminal aspect of intestinal epithelium, can be identified using molecular screening (RT-PCR) with a high degree of sensitivity and exactitude. Presence of GCC in any other tissue of the body represents colorectal metaplasia. Because of its high sensitivity, RT-PCR screening for GCC greatly reduces underestimation of disease stage. Researchers hope that staging with this level of precision will lead to more appropriate treatment and better prognosis. Furthermore, researchers hope that this same technique can be applied to other tissue-specific proteins.

AJCC Prognostic Stage Groups

For the purposes of tabulation and to analyze the care of patients who generally have a similar prognosis, T, N, and M are grouped into prognostic stage groups, commonly referred to as stage groups. As introduced earlier, a stage group is determined from aggregate information on the primary tumor (T), regional lymph nodes (N), and distant metastases (M), as well as any specified prognostic factors for certain cancer types. Stage groups are based primarily on anatomic information, supplemented by selected prognostic factors in some disease sites. Stage groups are defined for each of the classifications: clinical stage group and pathological stage group.

Systems

Staging systems are specific for each type of cancer (e.g., breast cancer and lung cancer). Some cancers, however, do not have a staging system. Although competing staging systems still exist for some types of cancer, the universally-accepted staging system is that of the UICC, which has the same definitions of individual categories as the AJCC.

Systems of staging may differ between diseases or specific manifestations of a disease.

Blood

Lymphoma: uses Ann Arbor staging
Hodgkin's Disease: follows a scale from I to IV and can be indicated further by an A or B, depending on whether a patient is non-symptomatic or has symptoms such as fevers. It is known as the "Cotswold System" or "Modified Ann Arbor Staging System".^[2]

Solid

For solid tumors, TNM is by far the most commonly used system, but it has been adapted for some conditions.

Breast cancer: In breast cancer classification, staging is usually based on TNM,^[3] but staging in I–IV may be used as well.
Cervical and ovarian cancers: the "FIGO" system has been adopted into the TNM system. For premalignant dysplastic changes, the CIN (cervical intraepithelial neoplasia) grading system is used.^[4]
Colon cancer: originally consisted of four stages: A, B, C, and D (the Dukes staging system). More recently, colon cancer staging is indicated either by the original A-D stages or by TNM.^[5]
Kidney cancer: uses TNM.^[6]
Cancer of the larynx: Uses TNM.^[7]
Liver cancer: Uses TNM.^[8]
Lung cancer: uses TNM.^[9]
Melanoma: TNM used. Also of importance are the "Clark level" and "Breslow depth" which refer to the microscopic depth of tumor invasion ("Microstaging").^[10]
Prostate cancer: TNM almost universally used. ^[11]
Testicular cancer: uses TNM along with a measure of blood serum markers (TNMS).
Non-melanoma skin cancer: uses TNM.
Bladder cancer: uses TNM.^[12]

Overall stage grouping

TNM information in each chapter provides precise criteria and rules for categorizing the T, N, or M of a patient for the relevant classification (e.g., clinical, pathological). This information is used to assign prognostic stage groups based on the assigned T, N, and M categories (with other prognostic factors if required for that specific cancer type).

Elements of TNM tables	Description
Classification	A lower case prefix describes the time point in a patient’s cancer continuum when stage is assigned, including: · c: clinical · p: pathological · yc: post neoadjuvant (radiation or systemic) therapy—clinical · yp: post neoadjuvant (radiation or systemic) therapy—pathological · r: recurrence or retreatment · a: autopsy
Category	T-, N-, and M-specific data are used to assign a cancer site–specific T, N, and M category for a patient at a given classification. Generally, the higher the T, N, or M category, the greater the extent of the disease and generally the worse the prognosis. Note: Exceptions exist in which T-, N-, or M-specific category elements may represent unique characteristics of the cancer but not necessarily worse prognosis. For example, N1c in colon cancer does not represent greater nodal disease burden than N1a or N1b, but rather a unique situation.
Subcategory	Some disease sites have subcategories devised to facilitate reporting of more detailed information and often more specific prognostic information. Examples: · breast cancer: T1mi, T1a, T1b, T1c · breast cancer: N2a, N2b · prostate cancer: M1a, M1b, M1c Note: If there is uncertainty in assigning a subcategory, the patient is assigned to the general category. For example, a breast cancer reported clinically as <2 cm without further specification is assigned T1 and cannot be assigned T1a, T1b, or T1c. If uncertain or incomplete information precludes subcategory assignment, which may result in different stage groups or management paradigms, a subcategory assignment may still be required. In that case, the general category, the physician/managing team categorization, or the lower or less advanced subcategory should be used.
AJCC prognostic stage groups (stage groups)	AJCC prognostic stage groups are assigned based on disease site–specific T, N, and M categories and relevant prognostic factors to group patients with similar prognosis and/or treatment approach. For each cancer type in which prognostic factors are used to assign stage groups, a separate stage group may be assigned based solely on anatomic categories so as to allow stage group comparisons among patients who have and do not have available prognostic factor information.

T, N, M and Prognostic Factor Category Criteria

The three categories—T, N, and M—and the prognostic factors collectively describe, with rare exceptions, the extent of tumor, including local spread, regional nodal involvement, and distant metastasis. It is important to stress that each component (T, N, and M) is referred to as a category. The term stage is used when T, N, and M and cancer site–specific required prognostic factors are combined. The criteria for T, N, and M are defined separately for cancers in different anatomic locations and/or for different histologic types.

This category...	Is defined by...
T	The size and/or contiguous extension of the primary tumor. Note: The roles of the size component and the extent of contiguous spread are specifically defined for each cancer site.
N	Cancer in the regional lymph nodes as defined for each cancer site, including · absence or presence of cancer in regional node(s), and/or · number of positive regional nodes, and/or · involvement of specific regional nodal groups, and/or · size of nodal metastasis or extension through the regional node capsule, and/or · In-transit and satellite metastases, somewhat unique manifestations of nonnodal intralymphatic regional disease, usually found between the primary tumor site and draining nodal basins. Note: For melanoma and Merkel cell carcinoma, nonnodal regional metastasis, such as satellites and in-transit metastases, may be included in the N categorization (see the melanoma and Merkel cell carcinoma chapters for specifics). For colorectal carcinoma, mesenteric tumor deposits without remaining nodal architecture are included in the N category.
M	The absence or presence of distant metastases in sites and/or organs outside the local tumor area and regional nodes as defined for each cancer site. For some cancer sites, the location and volume or burden of distant metastases are included.
Prognostic factors required for stage grouping	The prognostic factors required for stage grouping have such a strong correlation with prognosis that they are included in the AJCC Prognostic Stage Groups table. It is important to collect these factors in cancer registries and databases to measure their impact on prognosis.

Primary Tumor (T) Categories

Primary tumor categories have specific notations to describe the existence, size, or extent of the tumor.

Tumor category...	Is assigned when there is...
TX	No information about the T category for the primary tumor, or it is unknown or cannot be assessed Note: Use of the TX category should be minimized.
T0	No evidence of a primary tumor
Tis	Carcinoma in situ Examples of exceptions include: Tis for in situ melanoma of the skin, germ cell neoplasia in situ for testis, and high-grade dysplasia in colorectal carcinoma.
T1, T2, T3, or T4	Primary invasive tumor, for which a higher category generally means · an increasing size · an increasing local extension, or · both

Regional Lymph Node (N) Categories

Categorizing regional lymph node involvement depends on its existence and extent.

Regional node category...	Is assigned when there is...
NX	No information about the N category for the regional lymph nodes, or it is unknown or cannot be assessed Note: Use of NX should be minimized.
N0	No regional lymph node involvement with cancer and for some disease sites, nonnodal regional disease as noted earlier
N1, N2, or N3	Evidence of regional node(s) containing cancer, with · an increasing number, and/or · regional nodal group involvement, and/or · size of the nodal metastatic cancer deposit, or · non-nodal regional disease as noted earlier for melanoma and Merkel cell carcinoma, and for colorectal carcinoma

Distant Metastasis (M) Categories

The distant metastasis category specifies whether distant metastasis is present.

Distant metastasis category...	Is assigned when there is...
M0	No evidence of distant metastasis
M1	Distant metastasis
Notes: There is no designation of MX. The absence of any clinical history or physical findings suggestive of metastases in a patient who has not undergone any imaging is sufficient to assign the clinical M0 category (cM0). There is no designation of pM0. Biopsy or other pathological information is required to assign the pathological M1 category. Patients with a negative biopsy of a suspected metastatic site are classified as clinical M0 (cM0).

Distant Metastasis: Selected Locations

The M1 category may be specified further according to the location of distant metastases.

Location	Notation
Pulmonary	PUL
Osseous	OSS
Hepatic	HEP
Brain	BRA
Distant lymph nodes	LYM
Bone marrow	MAR
Pleura	PLE
Peritoneum	PER
Adrenal	ADR
Distant skin	SKI
Other	OTH

Unknown Designation: X

The X designation is used if information on a specific T or N category is unknown; such cases usually cannot be assigned a stage. Therefore, TX and NX should be used only if absolutely necessary. Of note, there is no MX category.

Exceptions: TX

Stage may be assigned when the TNM stage group results in Any T or Any N with M1, which includes TX or NX. These are classified as Stage IV. Examples include:

· TX NX M1, or

· TX N3 M1.

Stage may be assigned when the TNM stage group results in Any T or Any N with M0, which includes TX or NX. Examples include:

· TX N1 M0 Stage III in melanoma clinical stage

· T4 NX M0 Stage III in pancreas

MX is Not a Valid M Category

The MX category was eliminated from the AJCC and UICC TNM systems in the AJCC Cancer Staging Manual, 6^th Edition. Unless there is clinical or pathological evidence of distant metastases, the patient is classified as clinical M0 and denoted as cM0. It is not necessary to perform any imaging or invasive studies to categorize a patient as cM0. A history and physical examination are all that is needed to assign cM0. The M category must always be known and reported to assign a stage group.

Pathologists should not report an M category unless appropriate for the specimen evaluated. CAP Cancer Protocols require documentation of distant metastases as pM1 only if present in the specimen(s) provided to the pathologist. If the pathologist does not review and report on a metastatic specimen, or if a biopsy is performed of a possible distant metastasis and the biopsy does not show cancer, then there should be no mention of the M category in the pathology report, or the pathologist should designate the M category as “not applicable.” The term MX should not be used in the pathology report.

The managing physician should stage a patient for whom a biopsy performed for possible distant metastasis does not demonstrate cancer as cM0; there is no pM0 designation. Only the managing physician can assign cM0 after taking into account physical examination, imaging, and other information.

AJCC Prognostic Stage Groups

The purpose of defining and assigning stage groups is to generate a reproducible and easily communicated summary of staging information. The staging tables generally group patients with similar prognoses, usually with a statistically significant separation in outcomes between stage groups. Patients within a stage group generally have similar outcomes, even though their burden of disease may vary. Exceptions to this general stage group convention are noted in each chapter where relevant. For example, to retain an anatomic- and TNM-based staging system in melanoma, some prognostic overlap was allowed between patients with Stage IIC melanoma and those with Stage IIIA melanoma; many patients with Stage IIIA disease have a prognosis more favorable than that of patients with Stage IIC disease.

Stage groups are denoted by Roman numerals from I to IV with increasing extent of disease and generally with worsening overall prognosis. Stage I generally indicates cancers that are smaller or less deeply invasive without regional disease or nodes, Stages II and III define patients with increasing tumor or nodal extent, and Stage IV identifies those who present with distant metastases (M1) at diagnosis.

The term Stage 0 is used to denote carcinoma in situ (or melanoma in situ for melanoma of the skin or germ cell neoplasia in situ for testicular germ cell tumors) and generally is considered to have no metastatic potential. Stage 0 is determined by microscopic examination of the primary tumor. Stage I through Stage IV subgroups are denoted by capital letters—for example, A, B, or C—according to cancer site stage grouping definitions and are used to expand the main groupings to provide more refined prognostic information.

Prognostic Factors Required for Stage Grouping

For some cancer types, in addition to T, N, and M categories, prognostic factors are required to assign a stage group. Examples include tumor grade, age at diagnosis, histologic type, mitotic rate, serum tumor markers, hormone receptors, hereditary factors, prostate-specific antigen, and Gleason score. Specifically, cancer site–specific prognostic factors populate nonanatomic categories and are defined clearly if required for a particular disease site.

These factors generally constitute categories used with the TNM categories to assign prognostic stage groups. In some cases in which factors are used in stage groups, an X category is provided for use by the managing physician if the factor is not available. Generally, in cases in which the factor is absent and X is not provided as an option, the physician’s determination or lowest category (best prognosis) of the factor is used to assign the stage group.

In contrast, cancer registry data collection should record X or unknown if the prognostic factor is not available, and should not use the lowest category. This allows for accurate analysis of the data.

Stage Classifications

Stage classifications are determined according to the point in time of the patient’s care in relation to diagnosis and treatment. The five stage classifications are clinical, pathological, posttherapy/post neoadjuvant therapy, recurrence/retreatment, and autopsy.

Classification	Designation	Details
Clinical	cTNM or TNM	Criteria: used for all patients with cancer identified before treatment It is composed of diagnostic workup information, until first treatment, including: · clinical history and symptoms · physical examination · imaging · endoscopy · biopsy of the primary site · biopsy or excision of a single regional node or sentinel nodes, or sampling of regional nodes, with clinical T · biopsy of distant metastatic site · surgical exploration without resection · other relevant examinations Note: Exceptions exist by site, such as complete excision of primary tumor for melanoma.
Pathological	pTNM	Criteria: used for patients if surgery is the first definitive therapy It is composed of information from: · diagnostic workup from clinical staging combined with · operative findings, and · pathology review of resected surgical specimens
Posttherapy or post neoadjuvant therapy	ycTNM and ypTNM	For purposes of posttherapy or post neoadjuvant therapy, neoadjuvant therapy is defined as systemic and/or radiation therapy given before surgery; primary radiation and/or systemic therapy is treatment given as definitive therapy without surgery. yc The yc classification is used for staging after primary systemic and/or radiation therapy, or after neoadjuvant therapy and before planned surgery Criteria: First therapy is systemic and/or radiation therapy yp The yp classification is used for staging after neoadjuvant therapy and planned post neoadjuvant therapy surgery. Criteria: First therapy is systemic and/or radiation therapy and is followed by surgery.
Recurrence or retreatment	rTNM	This classification is used for assigning stage at time of recurrence or progression until treatment is initiated. Criteria: Disease recurrence after disease-free interval or upon disease progression if further treatment is planned for a cancer that: · recurs after a disease-free interval or · progresses (without a disease-free interval) rc Clinical recurrence staging is assigned as rc. rp Pathological staging information is assigned as rp for the rTNM staging classification. This classification is recorded in addition to and does not replace the original previously assigned clinical (c), pathological (p), and/or posttherapy (yc, yp) stage classifications, and these previously documented classifications are not changed.
Autopsy	aTNM	This classification is used for cancers not previously recognized that are found as an incidental finding at autopsy, and not suspected before death (i.e., this classification does not apply if an autopsy is performed in a patient with a previously diagnosed cancer). Criteria: No cancer suspected prior to death Both clinical and pathological staging information is used to assign aTNM.

Clinical Classification

Classification of T, N, and M during the diagnostic workup time frame is denoted by use of a lower case c prefix: cT, cN, and cM0, cM1 or pM1, or the use of no prefix: T, N, M.

Clinical stage is important to record for all patients because:

· clinical stage is essential for selecting initial therapy, and

· clinical stage is critical for comparison across patient cohorts when some have surgery as a component of initial treatment and others do not.

Clinical stage may be the only stage classification by which comparisons can be made across all patients, because not all patients will undergo surgical treatment before other therapy, and response to treatment varies. Differences in primary therapy make comparing groups of patients difficult if that comparison is based on pathological assessment. For example, it is difficult to compare patients treated with primary surgery with those treated with chemotherapy or radiotherapy without surgery or neoadjuvant therapy.

Time frame: Clinical classification is based on any information gathered about the extent of the cancer from the time of diagnosis until the initiation of primary treatment or the decision for watchful waiting or supportive care, and is based on the shorter of two periods of time:

· within 4 months after diagnosis, or

· the time of cancer progression if the cancer progresses before the end of the 4-month window; data on the extent of the cancer is included only before the date of observed progression

Criteria: All patients with cancer identified before treatment.

Clinical classification is based on:

· clinical history and symptoms

· physical examination

· imaging

· endoscopy or surgical exploration without resection

· biopsy of the primary site, biopsy or excision of a single regional node or sentinel nodes, sampling of regional nodes with clinical T, or biopsy of a distant metastatic site

Clinical classification is based on evidence acquired from the date of diagnosis until initiation of primary treatment. Examples of primary treatment include definitive surgery, radiation therapy, systemic therapy, and neoadjuvant radiation and systemic therapy.

Importantly, clinical stage groups cannot be assigned for some cancer sites if the necessary minimum information to assign a clinical stage group is not available. Although this scenario is quite uncommon, it may occur—for example, if lymph nodes cannot be examined before surgical resection or if a cancer is identified and resected incidentally during surgery for another medical condition.

Component of clinical staging	Details
Assignment of stage by managing physician	Clinical stage is assigned based on a synthesis of clinical data from multiple sources and only by the managing physician, usually a surgical or medical oncologist. As noted earlier, the assignment of clinical stage also may include pathological data from biopsies.
Known or suspected tumor	Tumor must be known or suspected and have a diagnostic workup including at least a history and physical examination to assign a clinical stage. Incidental findings at the time of surgical treatment may not be assigned a clinical stage retrospectively.
Imaging studies	Imaging may be of value and useful, but imaging is not necessary to assign a clinical stage. Guidelines for diagnostic evaluation of individual cancer types are found in these publications: · ACR Appropriateness Criteria® http://www.acr.org/ac · NCCN Guidelines® http://www.nccn.org.
Impact of subsequent information	The clinical stage should not be changed based on: · subsequent information obtained from the pathological examination of resected tissue, or · information obtained after initiation of definitive therapy.

Clinical T (T or cT)

Assessment of the primary tumor is necessary to determine the cT category.

Component of cT	Details
Tumor size and extent	Based on physical examination, imaging, endoscopy, biopsy of the primary site (core through long axis), surgical exploration, or other relevant examinations. The most accurate size should be used, as some methods may overestimate the size. Therefore, the largest size may not be the most accurate and should not be used automatically. Guidance on which imaging technique(s) may be most accurate is discussed in site-specific chapters. Physicians should document the most accurate tumor size used for staging.
Tumor size in millimeters and rounding for T-category assignment	Primary tumor size is the most accurate/largest dimension and is · measured to the nearest whole millimeter, unless a smaller unit is specified in a specific disease site, and · rounded up or down as appropriate for assigning T category: o down when the numerals are between 1 and 4 o up when the numerals are between 5 and 9. Examples: · Tumor measured as 2.2 mm is recorded as 2 mm. · Tumor measured as 1.7 mm is recorded as 2 mm. · Tumor measured as 2.04 cm is recorded as 20 mm and would be grouped with ≤2 cm and not >2 cm. Nonexhaustive exceptions: · Melanoma: primary tumor measured to nearest 0.1 mm · Breast cancer: primary tumor >1.0 mm to 1.4 mm rounded to 2 mm (this avoids assigning the “microinvasion” category to cancer >1.0 mm)
Surgical exploration	Observations made at surgical exploration without resection are used to assign clinical categories. Biopsies of the primary site during surgical exploration without resection of the primary tumor are used for clinical categorization. Exception: This information also may be used for pathological T categorization if the biopsy provides histologic material corresponding to the highest possible T category for the specific cancer type, and if it meets other criteria described in stage group.
Synchronous primary tumors in a single organ: (m) suffix	For multiple tumors in a single organ, T is assigned to the highest T category; the preferred designation is: · m suffix; for example, pT3(m) N0 M0 If the number of tumors is important, an acceptable alternative is: · number of tumors; for example, pT3(4) N0 M0 Note: The (m) suffix applies to multiple invasive cancers. It is not applicable to multiple foci of in situ cancer or a mixed invasive and in situ cancer.
Direct extension into an organ	Direct extension of a primary tumor into a contiguous or adjacent organ is classified as part of the tumor (T) classification and is not classified as metastasis (M). Example: Direct extension into the liver from a primary colon cancer would be in the T category and not in the M category.
Microscopic assessment of highest T category	If microscopic assessment of the primary site or regional tissue establishes the highest T category, it is: · assigned as cT, and · it also may be used for assignment of pT ONLY if there is microscopic confirmation of the highest pN. There must be microscopic confirmation of both the highest T and the highest N in order to assign a pathological stage group without resection of the primary site.
Unknown primary or no evidence of primary tumor	If there is no evidence of a primary tumor, or the site of the primary tumor is unknown, staging may be based on the clinical suspicion of the primary tumor, with the tumor categorized as T0. The rules for staging cancers categorized as T0 are specified in the relevant disease site chapters. Examples of exception: The T0 category is not used for head and neck squamous cancer sites, as such patients with an involved lymph node are staged as unknown primary cancers using the cervical lymph node system (T0 remains a valid category for HPV- and EBV-associated oropharyngeal and nasopharyngeal cancers).
Tis	In situ neoplasia identified during the diagnostic workup on a core or incisional biopsy is assigned cTis.
Any T	Any T includes all T categories except Tis. This includes TX and T0.

Clinical N (N or cN)

Assessment of the regional lymph nodes is necessary to determine the cN category.

Component of cN	Details
Lymph node assessment	Clinical regional lymph node assessment may be performed by physical examination and imaging. Clinical nodal category cN0 may be assigned based solely on physical examination. Imaging to assess regional lymph nodes is not required to assign clinical stage.
Node status not required in rare circumstances	For some cancer sites in which lymph node involvement is rare, patients whose nodal status is not determined to be positive for tumor should be designated as cN0. These circumstances are identified in specific disease chapters for these sites; NX is not listed as a category. Example: Bone and soft tissue sarcoma may use cN0 to assign the clinical stage group, that is, cT1 cN0 cM0.
Microscopic assessment for cN	Microscopic examination of regional nodes during the diagnostic workup is included in the clinical classification as cN. Microscopic examination or assessment may be by: · fine-needle aspiration (FNA), · core biopsy, · incisional biopsy, · excisional biopsy, or · sentinel node biopsy/procedure. This information also is included in the pathological staging if the patient has surgical resection as the first course of therapy. Example: Sentinel node biopsy performed before neoadjuvant therapy in breast cancer is designated as clinical (cN).
Sentinel lymph node	A sentinel lymph node (SLN) is a regional lymph node that receives direct afferent lymphatic drainage from a primary tumor site (e.g., breast, melanoma), and in many solid tumors it represents the regional lymph node(s) most likely to contain metastatic disease, if any are involved. More than one SLN may be present in a regional nodal basin, and some primary tumors (e.g., melanoma) may drain to more than one regional nodal basin. Sentinel nodes are identified by lymphatic mapping as evidenced by nodes that concentrate a colloidal material injected near the primary tumor or in the involved organ (the most commonly used agents for sentinel node biopsy are vital stains such as isosulfan blue and/or radiotracers such as technetium-99 (⁹⁹Tc)-sulfur colloid). In some circumstances, the managing physician also may label regional lymph nodes that are palpably abnormal during surgery as sentinel nodes. Nodes that do not concentrate colloidal material and are resected along with other sentinel nodes are nonsentinel nodes and are considered as part of the sentinel node procedure. Their resection is not coded as a separate nodal procedure or a lymph node dissection.
Sentinel node (sn) and FNA or core biopsy (f)	To distinguish lymph nodes identified during diagnostic evaluation by sentinel node biopsy or FNA or core biopsy from those identified by physical examination and imaging, the following suffixes are used in assigning the clinical N (cN) category: If SLN biopsy is performed as part of the diagnostic workup: · the cN category should have the sn suffix; for example, cN1(sn). If an FNA or a core biopsy is performed on lymph nodes as part of the diagnostic workup: · the cN category should have the f suffix; for example, cN1(f).
Isolated tumor cells (ITCs): use of the (i+) designator	ITCs include single tumor cells or small clusters of cells ≤0.2 mm in greatest diameter, generally without stromal response in the lymph node. Such cells usually are found in the subcapsular nodal sinuses but may be seen within the nodal parenchyma. Because ITCs may represent in-transit tumor cells that are not proliferating within the node, lymph nodes with only ITCs usually are categorized as N0, with some exceptions. They are denoted as N0(i+). The concepts regarding this staging rule continue to evolve, and further study is warranted. In the meantime, the staging rule serves as a guideline for uniformity and consistency in practice in recording information, and clinical judgment by the managing physician prevails. Exception: In melanoma and Merkel cell carcinoma, tumor cell deposits defined here as ITCs are considered positive nodes and are designated as N1 or higher. Note: Cancer site–specific designators have been developed to identify ITCs in nodes. For example, N0(i+) in breast and gynecologic cancers applies to nodes with ITCs only.
Pathological techniques for ITCs or detection of micro-metastasis	ITCs or lymph node micro-metastases may be identified in lymph nodes by hematoxylin and eosin staining or by specialized pathological techniques, such as IHC for cytokeratin proteins for carcinomas. Specialized pathology techniques, such as IHC and molecular techniques, are not recommended for routine examination of lymph nodes. The concepts regarding this staging rule continue to evolve, and further study is warranted.
Nonmorphologic techniques for identifying ITCs: use of the (mol+) designator	Nonmorphologic techniques, including flow cytometry and reverse transcriptase polymerase chain reaction studies, may identify minimal deposits of cancer in lymph nodes. These deposits usually are classified as clinically node negative and are identified with the (mol+) designator: for example, cN0(mol+). The concepts regarding this staging rule continue to evolve, and further study is warranted.
Micro-metastases: use of the mi designator	Lymph node micro-metastases are defined as tumor deposits >0.2 mm but ≤2.0 mm. For certain disease sites, micro-metastases are denoted by using the mi designator: for example, cN1mi. Further studies are needed to determine the significance of micro-metastases across many cancer sites. The concepts regarding this staging rule continue to evolve, and further study is warranted.
Extranodal extension	Extranodal extension (ENE) is defined as the extension of a nodal metastasis through the lymph node capsule into adjacent tissues. ENE is the preferred terminology. It also is termed extranodal spread, extracapsular extension, or extracapsular spread.
Regional node metastasis invading a distant organ is ENE	A regional node extending into a distant structure or organ is categorized as ENE and is not considered distant metastatic disease.
Regional nodes when tumor involves more than one organ or structure	In rare cases in which a tumor involves more than one organ or structure, the regional nodes include the nodes of all involved structures, even if the nodes of the primary site are not involved. Example: If a primary transverse colon cancer invades the stomach, for staging purposes, the gastric regional nodes are considered regional for the transverse colon, even if the regional nodes of the colon are not involved.
Microscopic assessment of regional node is the highest N category	If microscopic assessment of the regional node is the highest N category, it is · assigned as cN, and · also may be used for the assignment of pN ONLY if there is microscopic confirmation of the highest pT. There must be microscopic evidence of both highest T and highest N to assign a pathological stage group without surgical resection of the primary site.
Any N	Any N includes all N categories, including NX and N0.

Clinical M Classification (cM and pM)

Assignment of the M category for clinical classification may be cM0, cM1, or pM1. The M category is based on clinical history, physical examination, any imaging results, and whether there is microscopic confirmation of the distant metastasis during the diagnostic workup. The terms pM0 and MX are NOT valid categories in the TNM system.

Component of clinical M	Details
No distant metastasis	cM0 If there are no symptoms or signs of distant metastasis, M is categorized as clinically M0 (cM0). Evaluation methods include: · history and physical examination · imaging studies Note: Imaging studies may be used in assigning the M category but are not required to assign the cM0 category.
Clinical evidence of distant metastasis	cM1 If there is clinical evidence of distant metastases on physical examination, imaging studies, or invasive procedures, but no microscopic evidence of the presumed distant metastases, M is categorized as clinically M1 (cM1). Examination methods include: · physical examination · imaging (if performed) · exploratory surgery and/or endoscopy (if performed)
Microscopic evidence of distant metastasis	pM1 If there is microscopic evidence of distant metastatic disease, M is categorized as pathological M1 (pM1). Microscopic evidence includes: · cytology from FNA · core biopsy · incisional biopsy · excisional biopsy · resection
Use of pM1 for multiple distant metastases	pM1 In patients who have distant metastases in multiple sites and have a cancer type for which M subcategories distinguish between one or more metastatic sites, microscopic evidence of one of these sites is necessary to assign the higher pM subcategory. In general, metastases to both sides of a paired organ are considered a single metastatic site of involvement (e.g., metastases to both lungs are designated metastasis to one distant site—lung). If clinical evidence of distant metastasis remains in other areas that are not or cannot be microscopically confirmed, cM1 is assigned.
pM1, both clinical and pathological Stage IV	pM1 A patient may be staged as both clinical and pathological Stage IV if: · there is confirmatory microscopic evidence of a distant metastatic site during the diagnostic workup, which is categorized as pM1, and · T and N are categorized only clinically. Example: cT3 cN1 pM1 clinical Stage IV and cT3 cN1 pM1 pathological Stage IV
Circulating tumor cells and disseminated tumor cells: cM0(i+) category	cM0(i+) Patients with: · Circulating tumor cells (CTCs) in blood, or · Disseminated tumor cells (DTCs) in organs and micro-metastasis in bone marrow detected by IHC or molecular techniques are categorized as cM0(i+). The cM0(i+) category denotes the uncertain prognostic significance of these findings. The concepts regarding this staging rule continue to evolve, and further study is warranted.
Clinical suspicion and biopsy does not confirm distant metastatic disease	If there is clinical suspicion for distant metastases and a biopsy or excision does not confirm metastatic cancer, M is categorized as clinically M0 (cM0) or clinically M1 (cM1) based on the evaluation of other possible sites of distant metastatic disease. There is no TNM pM0 designation. Note: pM0 is not a valid category. If clinical evidence of distant metastasis remains in other areas that are not or cannot be confirmed microscopically, cM1 is assigned.
Unknown distant metastasis status	MX does not exist MX is not a valid category and cannot be assigned. Unless there is clinical or pathologic evidence of metastases, M is categorized as clinically negative: cM0.
Direct extension into an organ not M category	Direct extension from the primary tumor or lymph nodes into a contiguous or adjacent organ is not included in the M category but is used in the T and N category assignments as noted earlier. Example: Direct extension of a colon cancer into the liver is categorized as pT4 and cM0.
Definition of metastases timing	Metastases defined during the relevant time frame/staging window are classified as metastases (cM1/pM1) and are considered synchronous with diagnosis of the primary cancer. Metastases detected after the relevant time frame/staging window are not included in the initial staging and generally are considered recurrent cancer.

Pathological Classification

Classification of T, N, and M after surgical treatment is denoted by use of a lowercase p prefix: pT, pN, and cM0, cM1, or pM1.

Time frame: From date of diagnosis through surgical resection in the absence of cancer progression

Criteria: Surgery is first therapy

Pathological classification is based on the:

· clinical stage information (acquired before treatment), and supplemented/modified by

· operative findings, and

· pathological evaluation of the resected specimen(s).

Pathological stage is assigned for patients first treated with surgery. The surgical resection required for assignment of this classification is specified for each disease site, and ranges from resection of the tumor to complete resection of the organ and usually includes resection of at least some of the regional lymph nodes.

The purpose of pathological classification is to provide additional precise and objective data:

· for prognosis and outcomes, and

· to guide subsequent therapy.

Criteria for assigning pathological stage
Component of pathological staging	Details
Assignment of pathological stage by managing physician	Pathological stage is based on a synthesis of clinical and pathological findings and is assigned only by the managing physician, such as a surgical, radiation, or medical oncologist.
Primary tumor surgical resection for pathological staging	The surgical resection criteria in the disease site must be met in order to assign a pathological stage. The extent of primary tumor surgical resection ranges from: · resection of the tumor, up to · complete resection of the organ, and · usually includes resection of at least some regional lymph nodes Note: Surgical resection criteria depend on the cancer site–specific information necessary to determine the need for adjuvant therapy and the patient’s prognosis, including tumor (T) and regional nodes (N).
Basis of pathological staging	Pathological staging encompasses: · clinical staging information · the surgeon’s operative findings · pathological evaluation of the resected specimen(s)
Imaging studies used in assigning pathological stage	Imaging studies performed after surgery are included in the pathological staging if they are within the time frame or staging window.
Unresectable tumor and assignment of pathological stage	If the highest T and N categories or the M1 category of the tumor are confirmed microscopically, even if a primary tumor technically cannot be removed or if it is unreasonable to remove it, the criteria for pathological staging are considered satisfied without total removal of the primary tumor. Note: Microscopic confirmation of the highest T and N does not necessarily require removal of that structure and may entail biopsy or FNA only. Example: Supraclavicular node involvement in inflammatory breast cancer in which inflammatory carcinoma was identified on the core needle breast biopsy and the supraclavicular node involvement is documented by FNA

Pathological T (pT)

The pathological assessment of the primary tumor generally is based on resection of the primary tumor.

Component of pT	Description
Tumor size and extent	Primarily based on size and local extension of the resected specimen The pathologist provides information to assign the pT category based on the specimen received, but this may not be the final pT used for staging assignment. Final pT is assigned by the managing physician and also may include clinical stage information and operative findings.
Tumor size in millimeters and rounding for T-category assignment	Primary tumor size is the most accurate/largest dimension and is: · measured to the nearest whole millimeter, unless a smaller unit is specified in a specific disease site, and · rounded up or down as appropriate for assigning T category: o down when the numerals are between 1 and 4 o up when the numerals are between 5 and 9 Examples: · Tumor measured as 2.2 mm is recorded as 2 mm. · Tumor measured as 1.7 mm is recorded as 2 mm. · Tumor measured as 2.04 cm is recorded as 20 mm, and would be grouped with ≤2 cm and not >2 cm Nonexhaustive exceptions: · Melanoma: primary tumor measured to nearest 0.1 mm · Breast cancer: primary tumor >1.0 mm to 1.4 mm rounded to 2 mm (this avoids assigning the “microinvasion” category to cancer >1.0 mm)
Resection specimen role in pT category	pT category optimally is based on resection of a single specimen. If resected in several partial specimens at the same or separate operative setting, a reasonable estimate of size and extension should be made. The estimate of multiple specimens may be based on the best combination of gross and microscopic findings, and may include reconstruction of the tumor with the assistance of the radiologist and surgeon. See CAP Protocols for tumor-specific recommendations.
Impact on pT category of positive resection margins	The presence of microscopic cancer at the resection margin does not affect the assignment of the pT category, which is assigned based on findings in the resection specimen and at operation. In situations in which the surgeon has left behind grossly identified tumor in performing a noncurative resection, the T category should be based on all available clinical and pathological information.
Pathological tumor size variance based on assessment approach	Tumor size may vary based on whether it is measured on an unfixed or a fixed specimen. Size is often reported on the fixed specimen, and gross impression of tumor size may be adjusted based on microscopic examination. The pathologist should note potential alteration in tumor size caused by fixation if it might affect staging.
Synchronous primary tumors is a single organ: (m) suffix	For multiple tumors in a single organ, T is assigned to the highest T category; the preferred designation is: · m suffix; for example, pT3(m) N0 M0 If the number of tumors is important, an acceptable alternative is: · number of tumors; for example, pT3(4) N0 M0 Note: The (m) suffix applies to multiple invasive cancers. It is not applicable for multiple foci of in situ cancer, or for a mixed invasive and in situ cancer.
Direct extension into regional node	If a primary tumor directly extends into a regional lymph node, it is: · included in the N category as a positive regional lymph node · not included as a criterion for assigning the T category
Tumor nodule in node area not considered in T category	Rounded tumor nodules with smooth-contoured capsules in the regional nodal drainage area generally represent lymph nodes completely replaced with cancer and are classified as lymph nodes, unless there is clear evidence of residual blood vessel wall to justify classification as vascular involvement. They are not considered in the T category.
Direct extension into an organ	Direct extension of a primary tumor into a contiguous or adjacent organ is classified as part of the tumor (T) classification and is not classified as metastasis (M). Example: Direct extension of a primary colon cancer into the liver is categorized as T4 and is not in the M category.
Unresected tumor and highest T category	The pathological T (pT) category may be assigned without tumor resection if: · a biopsy of the primary tumor (cT) is performed and is adequate to evaluate the highest pT category. Other criteria, such as microscopic confirmation of the highest pN, must be met in order to assign pathological staging.
Disease sites have specific rules	Some disease sites have specific rules to guide assignment of pT. Refer to specific disease site chapters for further guidance.
Unknown primary or no evidence of primary tumor	If there is no evidence of a primary tumor, or the site of the primary tumor is unknown, staging may be based on clinical suspicion of the primary tumor, with the tumor categorized as T0. The rules for staging cancers categorized as T0 are specified in the relevant disease site chapters. Examples of exception: The T0 category is not used for head and neck squamous cancer sites, as such patients with an involved lymph node are staged as unknown primary cancers using the system for cervical nodes and unknown primary tumors of the head and neck (T0 remains a valid category for HPV- and EBV-associated oropharyngeal and nasopharyngeal cancers).
Tis and surgical resection criteria	In situ neoplasia identified from a surgical resection, as specified in the disease site pathological criteria, is assigned pTis. In situ neoplasia identified microscopically during the diagnostic workup may be used to assign the pathological stage pTis if the patient had a surgical resection and no residual tumor was identified.
Any T	Any T includes all T categories except Tis. This includes TX and T0.

Pathological N (pN)

Pathological assessment of regional node involvement (pN) is necessary.

Component of pN		Details
Microscopic assessment for pN		Microscopic assessment of a regional node includes: · FNA cytology · Core biopsy · Incisional biopsy · Excisional biopsy · SLN biopsy/procedure · Regional lymph node dissection
Requirements for assigning pN category		To assign a pN category, there must be: · pathological documentation of the presence or absence of cancer in at least one node, and · pathological assessment of the primary tumor (pT), except in cases of an unknown primary (T0) Note: It is not necessary to pathologically confirm the status of the highest N category to assign the pN. If pT is available (resection), then any microscopic evaluation of nodes is classified as pN. For example, assessment of the axillary nodes is sufficient to assign pN for breast cancer, and it is not necessary to microscopically confirm the status of supraclavicular nodes. Many cancer sites have specific recommendations regarding the minimum number of lymph nodes to be removed during lymph node dissection to provide optimal prognostic information. However, pathological categorization (pN) still applies even in cases in which fewer than the recommended number of lymph nodes are resected (e.g., a colon cancer resection specimen with only four pathologically negative lymph nodes is categorized as pN0). FNA and core needle biopsy of a node both satisfy the requirement that at least one regional node be microscopically examined.
Categorize N		pN generally is categorized by disease-specific rules based on: · number and/or · location of positive regional nodes and/or · size of the largest deposit of tumor cells in the node(s)
Size of regional nodal metastasis		Size of regional nodal metastasis generally is specified in disease site chapters and may be based on: · size of metastasis in the node, · size of the lymph node, or · size of the nodal mass, which may be a mass of matted nodes For some disease sites, the size of tumor metastasis within the regional lymph node is a criterion for the N category. If the size of the tumor in the regional nodal metastasis is unknown, the size of the involved lymph node may be used. The size of any mass, from a single node to a conglomerate mass of matted nodes, is used to determine the N category for some disease sites, such as head and neck. Note: Please refer to disease site chapters for specific criteria on assessment of size of regional nodal metastasis.
Direct extension into regional node is N category		If a primary tumor directly extends into a regional lymph node, it is: · included in the N category as a positive regional lymph node · not included as a criterion for assigning the T category
Tumor nodule in node area not considered in T category		Rounded tumor nodules with smooth-contoured capsules in the regional nodal drainage area generally represent lymph nodes completely replaced with cancer and are classified as lymph nodes, unless there is clear evidence of residual blood vessel wall to justify classification as vascular involvement. They are not considered in the T category.
Sentinel node or regional node excision		Microscopic examination of regional nodes without resection of the primary site (during the diagnostic workup) is included in the clinical classification as cN. Microscopic examination of regional nodes with surgical resection of the primary site (surgical treatment) is categorized as pN. Example: Sentinel node biopsy performed at the time of wide re-excision for melanoma (surgical treatment) is pathological (pN).
SLN		An SLN is a regional lymph node that receives direct afferent lymphatic drainage from a primary tumor site (e.g., breast, melanoma), and in many solid tumors represents the regional lymph node(s) most likely to contain metastatic disease, if any are involved. More than one SLN may be present in a regional nodal basin, and some primary tumors (e.g., melanoma) may drain to more than one regional nodal basin. Sentinel nodes are identified by lymphatic mapping, as evidenced by nodes that concentrate a colloidal material injected near the primary tumor or in the involved organ (the most commonly used agents for sentinel node biopsy are vital stains such as isosulfan blue and/or radiotracers such as ⁹⁹Tc-sulfur colloid). In some circumstances, the managing physician also may label regional lymph nodes that are palpably abnormal during surgery as sentinel nodes. Nodes that do not concentrate colloidal material and are resected along with other sentinel nodes are nonsentinel nodes, and are considered part of the sentinel node procedure. Their resection is not coded as a separate nodal procedure or a lymph node dissection.
Sentinel node (sn) and FNA or core biopsy (f)		If SLN biopsy is performed in the absence of complete dissection of the nodal basin: · the N category should have the sn suffix; for example, pN0(sn). If FNA or core biopsy is performed in the absence of a complete dissection of the nodal basin: · the N category should have the f suffix; for example, pN0(f). Note: This distinguishes it from a complete nodal dissection, for which the pN is assigned without the (sn) or (f) suffix.
ITCs: use of the (i+) designator		ITCs include single tumor cells or small clusters of cells ≤0.2 mm in greatest diameter, generally without stromal response in the lymph node. These cells usually are found in the subcapsular nodal sinuses but may be seen within the nodal parenchyma. Because ITCs may represent tumor cells that are in transit that are not proliferating within the node, lymph nodes with only ITCs usually are categorized as N0, with some exceptions. They are denoted as N0(i+). The concepts regarding this staging rule continue to evolve, and further study is warranted. In the meantime, the staging rule serves as a guideline for uniformity and consistency in practice in recording information, and clinical judgment by the managing physician prevails. Exception: In melanoma and Merkel cell carcinoma, ITCs are considered positive nodes and are designated as N1 or higher. Note: There are cancer site–specific designators to identify ITCs in nodes. Example:* N0(i+) in breast and gynecologic cancers applies to nodes with ITCs only.*
Pathological techniques for ITCs or detection of micro-metastasis		ITCs or lymph node micro-metastases may be identified in lymph nodes by hematoxylin and eosin staining or by specialized pathological techniques, such as IHC for cytokeratin proteins for carcinomas. Specialized pathology techniques such as IHC and molecular techniques are not recommended for routine examination of lymph nodes. The concepts regarding this staging rule continue to evolve, and further study is warranted.
Nonmorphologic techniques for identifying ITCs: use of (mol+) designator		If used, nonmorphologic techniques, including flow cytometry and reverse transcriptase polymerase chain reaction studies, may identify minimal deposits of cancer in lymph nodes. These usually are classified as clinically node negative and identified with the (mol+) designator: for example, cN0(mol+). The concepts regarding this staging rule continue to evolve, and further study is warranted.
Micro-metastases: use of mi designator		Lymph node micro-metastases are defined as tumor deposits >0.2 mm but ≤2.0 mm. For certain disease sites, micro-metastases are denoted by using the mi designator: for example, cN1mi. Further studies are needed to determine the significance of micro-metastases across many cancer sites. The concepts regarding this staging rule continue to evolve, and further study is warranted.
Extranodal extension (ENE)		ENE is defined as the extension of a nodal metastasis through the lymph node capsule into adjacent tissues. ENE is the preferred terminology. It is sometimes also termed extranodal spread, extracapsular extension, or extracapsular spread.
Regional node metastasis invading a distant organ is ENE	A regional node extending into a distant structure or organ is categorized as ENE and is not considered distant metastatic disease.
Recommended minimum number of lymph nodes		As noted in previous editions of the AJCC Cancer Staging Manual, as well as this 8^th Edition, several cancer sites contain a recommendation regarding the minimum number of regional nodes to be surgically resected and pathologically analyzed for determination of the N category. These recommendations are offered as metrics for evaluation of quality review of the extent of surgical resection and resultant pathological analysis. These minimum benchmarks should not be construed as unique indicators for additional surgical resection or adjuvant therapy if the recommended nodal count has not been met. In cases in which fewer than the recommended optimal number of lymph nodes are removed, pathological node category (pN) should be assigned and complete pathological staging applied based on whatever number of nodes are reported. A suboptimal node count may lead to further dialogue between the surgeon and pathologist to support the opportunity for further evaluation (e.g., fat clearance techniques) of the node-bearing specimen to assure that a maximum node assessment is reached; however, this is not necessary to assign the pathological node category.
Node status not required in rare circumstances		For some cancer sites in which lymph node involvement is rare, patients whose nodal status is not determined to be positive for tumor should be designated as cN0. These circumstances are identified in specific disease site chapters for these sites; NX may not be listed as a category. The assignment of cN0 will ensure it is not confused with a case in which the nodes were microscopically proven to not contain tumor, that is, pN0. Examples: For bone and soft tissue sarcoma, cN0 may be used to assign the pathological stage group—that is, pT1 cN0 cM0. For melanoma, cN0 may be used to assign a pathological stage group for T1 melanoma.
Regional node invading a distant organ		Tumor involving a regional node and extending into a distant structure or organ is categorized as ENE and is not considered metastatic disease.
Regional nodes when a tumor involves more than one organ or structure		In the rare occurrence in which a tumor involves more than one organ or structure, the regional nodes include those of all involved structures, even if the nodes of the primary site are not involved. Example: If a transverse colon cancer invades the stomach, the gastric regional nodes would be considered regional for the transverse colon, even if the colon regional nodes were not involved.
Unresectable tumor and highest N category		If the primary tumor and/or regional lymph nodes technically cannot be removed or it is clinically not indicated to remove them, the following criteria may be used to assign pathological stage: · microscopically confirmed highest T category, and · microscopically confirmed single node or nodes in the highest N category Note: Microscopic confirmation of the highest T and N categories may use biopsy or FNA only.
Any N		Any N includes all N categories. This includes NX and N0.

Pathological M Categorization (cM and pM)

Any of the M categories (cM0, cM1, or pM1) may be used with pathological stage grouping. The terms pM0 and MX are NOT valid categories in the TNM system.

Component of M for pathological staging	Details
No distant metastasis	cM0 If there are no symptoms or signs of distant metastasis, the case is classified as clinically M0 (cM0). Evaluation includes: · history and physical examination · imaging studies performed Note: Imaging studies are NOT required to assign cM0.
Clinical evidence of distant metastasis	cM1 Patients with clinical evidence of distant metastases by history, physical examination, imaging studies, or invasive procedures, but without microscopic evidence of the presumed distant metastases, are categorized as clinically M1 (cM1). Examination methods include: · physical examination · imaging · exploratory surgery or endoscopy
Microscopic evidence of distant metastasis	pM1 Patients in whom there is microscopic evidence confirming distant metastatic disease are categorized as pathologically M1 (pM1). Microscopic evidence includes: · cytology from FNA · core biopsy · incisional biopsy · excisional biopsy · resection
Use of pM1 if there are multiple distant metastases	pM1 In patients who have distant metastases in multiple sites, and have a cancer type for which M subcategories distinguish between one or more metastatic sites, microscopic evidence of one of these sites is necessary to assign the higher pM subcategory. In general, metastases to both sides of a paired organ are considered a single metastatic site of involvement (e.g., metastases to both lungs are assigned as metastasis to one distant site—lung). If clinical evidence of distant metastasis remains in other areas that are not or cannot be microscopically confirmed, cM1 is assigned.
pM1 may be used for both clinical and pathological Stage IV	pM1 A patient may be staged as both clinical and pathological Stage IV if there is: · confirmatory microscopic evidence of a distant metastatic site during the diagnostic workup, which is categorized as pM1, and · T and N may be categorized only clinically. Example: cT3 cN1 pM1 clinical Stage IV, and cT3 cN1 pM1 pathological Stage IV
Circulating tumor cells and disseminated tumor cells: cM0(i+) category	cM0(i+) Patients with · CTCs, or · DTCs in organs and micro-metastasis in bone marrow, detected by IHC or molecular techniques, are categorized as cM0(i+). The cM0(i+) category denotes the uncertain prognostic significance of these findings. The concepts regarding this staging rule continue to evolve, and further study is warranted.
Clinical suspicion of metastasis, but biopsy does not confirm distant metastatic disease	If there is clinical suspicion of distant metastases and a biopsy or excision does not confirm metastatic cancer, M is classified as clinically M0 (cM0) or clinically M1 (cM1) based on the evaluation of other possible sites of distant metastatic disease. There is no TNM pM0 designation. Note: pM0 is not a valid category If clinical evidence of distant metastasis remains in other areas that are not or cannot be microscopically confirmed, cM1 is assigned.
Unknown distant metastasis status	MX does not exist MX is not a valid category and cannot be assigned. Unless there is clinical or pathologic evidence of metastases, M is categorized as clinically negative: cM0.
No direct extension in M category	Direct extension from the primary tumor or lymph nodes into a contiguous or adjacent organ is not included in the M category but is used in the T and N category assignments as noted earlier. Example: Direct extension of a colon cancer into the liver is categorized as pT4 and cM0.

Posttherapy or Post Neoadjuvant Therapy Classification (yTNM)

For purposes of posttherapy or post neoadjuvant therapy classification, neoadjuvant therapy is defined as systemic and/or radiation therapy given before surgery; primary radiation and/or systemic therapy is treatment given as definitive therapy without surgery.

Classification of T, N, and M after systemic or radiation treatment intended as definitive therapy, or after neoadjuvant therapy followed by surgery, is denoted by use of a lowercase yc or yp prefix, respectively: ycT, ycN, c/pM, and ypT, ypN, c/pM, respectively. The c/pM category may include cM0, cM1, or pM1.

Time frame: After primary systemic and/or radiation therapy without subsequent surgical resection, or after neoadjuvant and before planned surgical resection

Criteria: First therapy is systemic and/or radiation therapy.

y-clinical (yc) classification is based on the:

· clinical history and physical examination and

· any imaging studies, if performed

Note: imaging studies may be considered standard practice, but are NOT required to assign yc categories.

Time frame: The yp classification is used when staging after neoadjuvant therapy and planned post neoadjuvant therapy surgery. The time frame should be such that the post neoadjuvant therapy surgery and staging occur within a period that accommodates disease-specific circumstances, as outlined in the specific chapters and in relevant guidelines.

Criteria: First therapy is systemic and/or radiation therapy followed by surgery.

y-pathological (yp) classification is based on the:

· y-clinical stage information, and supplemented/modified by

· operative findings, and

· pathological evaluation of the resected specimen.

Observed changes between the clinical classification and the posttherapy classification may provide clinicians with information regarding the response to therapy. The clinical extent of response to therapy may guide the scope of planned surgery, and the clinical and pathological extent of response to therapy may provide prognostic information and guide the use of further adjuvant radiation and/or systemic therapy.

Examples of treatments that satisfy the definition of neoadjuvant therapy for a disease site may be found in sources such as the NCCN Guidelines, ASCO guidelines, or other treatment guidelines. Systemic therapy includes chemotherapy, hormone therapy, and immunotherapy. Not all medication given to a patient meets the criteria for neoadjuvant therapy (e.g., a short course, such as a few days of endocrine therapy in breast cancer or prostate cancer that is provided for variable and often unconventional reasons, should not be categorized as neoadjuvant therapy).

The time frame should be such that the post neoadjuvant therapy surgery and staging occur within a period that accommodates disease-specific circumstances, as outlined in the specific chapters and in relevant guidelines.

The post neoadjuvant therapy assessment of the T and N (yTNM) categories uses specific criteria. In contrast, the M category for post neoadjuvant therapy classification remains the same as that assigned in the clinical stage before initiation of neoadjuvant therapy (e.g., if there is a complete clinical response to therapy in a patient previously categorized as cM1, the M1 category is used for final yc and pc staging).

Component of posttherapy staging	Details
Assignment of stage by managing physician	Posttherapy or post neoadjuvant therapy stage is based on a synthesis of clinical and pathological findings and is assigned only by the managing physician, such as a surgical, radiation, or medical oncologist. Pathologists may provide T, N, and M information based on the specimens received to assist the managing physician in assigning the final stage. Radiologists may provide T, N, and M information based on imaging studies to assist the managing physician in assigning the final stage.
Use of yTNM	To use the yTNM classification, the extent of disease is assessed: · after systemic and/or radiation therapy as the primary treatment, and · after surgery when it follows the systemic and/or radiation therapy
Use of y prefix	The y prefix is always combined with either a clinical or pathological prefix, that is, ycTNM or ypTNM.
Time frame in the patient’s care for use of yc and yp	· ycTNM denotes information gathered using clinical classification rules and methods: o after neoadjuvant systemic and/or radiation therapy, and o before surgical resection or if no surgery is performed. · ypTNM denotes information gathered using pathological classification rules and methods: o after neoadjuvant systemic and/or radiation therapy, and o after the surgical resection. Examples: · ycT and ycN with cM or pM · ypT and ypN with cM or pM.
Distant metastasis	The presence of distant metastases is classified by the M status defined during the clinical classification, cM or pM, before initiation of neoadjuvant radiation and/or systemic therapy. Note: Once distant metastasis is identified, that M category designation always remains, even if there no longer is evidence of the metastasis after neoadjuvant therapy. In this situation, the yc and yp stages always maintain the M1 category.
Complete pathological response	If a complete pathological response has occurred and the ypTNM is ypT0 ypN0 cM0, no stage group is assigned. Note: This situation is not classified as Stage 0, because such a designation would denote in situ neoplasia. Nonetheless, the individual T, N, and M categories should be documented as T0, N0, M0. The complete pathological response also may be documented by using the response designation.
Response to neoadjuvant therapy	It is important to record the response to neoadjuvant therapy. Consult disease site chapters for specific systems. For example, some disease sites include “complete,” “partial,” and “no response,” whereas others consist of a numerical scoring system or a “regression score.” If surgery is performed, it is critical to also assign the ypT and ypN for analysis of response to neoadjuvant therapy.
Mucin pools, necrosis, and other reactive changes not included in the assessment of residual cancer	Histologic confirmation of residual cancer requires identification of non-necrotic tumor cells. Mucin pools, necrosis, and other degenerative and reactive changes without viable-appearing tumor cells are insufficient for a diagnosis of residual cancer. Mucin pools and necrotic cells currently play no role in assigning the ypT and ypN.

[null Recurrence or Retreatment Classification (rTNM])

Classification of T, N, and M for recurrence or retreatment is denoted by use of the lowercase r prefix: rcT, rcN, rc/rpM, and rpT, rpN, rc/rpM. The rc/rpM may include rcM0, rcM1, or rpM1.

Time frame: From identification of recurrence or progression until treatment is initiated

Criteria: Disease recurrence after disease-free interval, or disease progression

The recurrence or retreatment classification is assigned if a cancer recurs after an interval during which the patient has been considered cancer-free (disease-free interval), or if the cancer progresses and the patient has never been disease-free (even if no retreatment is planned).

Assessment of recurrence and retreatment follows specific criteria.

Recurrence/retreatment staging assessment criteria
Component of recurrence/retreatment staging	Details
Stage at initial diagnosis is not affected by recurrence	The initially assigned clinical and pathological stages at diagnosis do not change if a cancer recurs or progresses.
Use of r prefix	In staging for recurrence or retreatment, the r prefix is applied.
Information included: r classification	All information available at the time of recurrence or retreatment should be used to determine the rTNM stage, including clinical and pathological information. Important: Biopsy confirmation is not required but is encouraged if clinically feasible. rc The r-clinical (rc) classification is based on: · clinical history and physical examination and · any imaging studies, if performed Note: Imaging studies may be considered standard practice but are NOT required to assign rc categories. rp The r-pathological (rp) classification is based on: · r-clinical stage information, and supplemented/modified by · operative findings, and · pathological evaluation of the resected specimen.

Autopsy Classification (aTNM)

Classification of T, N, and M at autopsy is denoted by use of the lowercase a prefix: aT, aN, aM.

Time frame: At death

Criteria: Incidental finding of cancer at autopsy; cancer not suspected or evident before death (i.e., classification does not apply if autopsy is performed in a patent with a known cancer before death).

Autopsy assessment has specific criteria.

Component of autopsy staging	Details
Diagnosis at autopsy	Cancer must be diagnosed at autopsy. No prior suspicion or evidence of cancer before death.
Information included	All clinical and pathological information is included. It is obtained: · at time of death, and · through postmortem examination.

AJCC Educational Resources

AJCC provides staging resources for the physician to support their care of patients. The AJCC provides webinars, presentations, articles, brochures and other resources all of which can be obtained on the AJCC website.

Registrar

AJCC is dedicated to supporting cancer registrars in the transition to directly assigning AJCC TNM stage.

Please visit the AJCC website for all registrar focused education.

Physician

The AJCC provides resources beneficial to physicians in their use and understanding of the AJCC TNM staging system.

Articles

Articles on the AJCC staging system from various medical journals are available for physicians to better understand the issues.

7th Edition | 8th Edition

Webinars

Webinars on the AJCC staging rules and the most common disease sites have been recorded by the physician expert panels members involved in that disease site.

7th Edition | 8th Edition

AJCC Cancer Staging Manual Publishing History

The publication dates and effective dates for past editions of the AJCC Cancer Staging Manual are:

Edition	Publication Year	Effective Year	Resources
1	1977	1978	AJCC 1^st Ed Cancer Staging Manual
2	1983	1984	AJCC 2^nd Ed Cancer Staging Manual
3	1988	1989	AJCC 3^rd Ed Cancer Staging Manual
4	1992	1993	AJCC 4^th Edition Cancer Staging Manual
5	1997	1998	AJCC 5^th Ed Cancer Staging Manual
6	2002	2003	AJCC 6^th Ed Cancer Staging Manual Part 1 AJCC 6^th Ed Cancer Staging Manual Part 2
7	2009	2010	AJCC 7^th Ed Cancer Staging Manual
8	2016	2018	Purchase Here

References

1 2 3
American Society of Clinical Oncology, "Five Things Physicians and Patients Should Question" (PDF), Choosing Wisely: an initiative of the ABIM Foundation, American Society of Clinical Oncology, archived from the original (PDF) on July 31, 2012, retrieved August 14, 2012 , citing
- Carlson, R. W.; Allred, D. C.; Anderson, B. O.; Burstein, H. J.; Carter, W. B.; Edge, S. B.; Erban, J. K.; Farrar, W. B.; Goldstein, L. J.; Gradishar, W. J.; Hayes, D. F.; Hudis, C. A.; Jahanzeb, M.; Kiel, K.; Ljung, B. M.; Marcom, P. K.; Mayer, I. A.; McCormick, B.; Nabell, L. M.; Pierce, L. J.; Reed, E. C.; Smith, M. L.; Somlo, G.; Theriault, R. L.; Topham, N. S.; Ward, J. H.; Winer, E. P.; Wolff, A. C.; NCCN Breast Cancer Clinical Practice Guidelines Panel (2009). "Breast cancer. Clinical practice guidelines in oncology". Journal of the National Comprehensive Cancer Network : JNCCN. 7 (2): 122–192. PMID 19200416.
- Thompson, I.; Thrasher, J. B.; Aus, G.; Burnett, A. L.; Canby-Hagino, E. D.; Cookson, M. S.; d'Amico, A. V.; Dmochowski, R. R.; Eton, D. T.; Forman, J. D.; Goldenberg, S. L.; Hernandez, J.; Higano, C. S.; Kraus, S. R.; Moul, J. W.; Tangen, C. M.; AUA Prostate Cancer Clinical Guideline Update Panel (2007). "Guideline for the Management of Clinically Localized Prostate Cancer: 2007 Update". The Journal of Urology. 177 (6): 2106–2131. PMID 17509297. doi:10.1016/j.juro.2007.03.003.
↑ "Hodgkin's Disease - Staging". oncologychannel. Retrieved 2010-10-14.
↑ "Breast Cancer Treatment - National Cancer Institute". Cancer.gov. 2010-08-13. Retrieved 2010-10-14.
↑ Eric Lucas (2006-01-31). "FIGO staging of cervical carcinomas". Screening.iarc.fr. Retrieved 2010-10-14.
↑ "Colon Cancer - Staging". oncologychannel. Retrieved 2010-10-14.
↑ "Stages of kidney cancer". Cancerhelp.org.uk. 2010-06-30. Archived from the original on 2009-01-22. Retrieved 2010-10-14.
↑ "The stages of cancer of the larynx". Cancerhelp.org.uk. 2010-07-28. Archived from the original on 2008-12-16. Retrieved 2010-10-14.
↑ "How is liver cancer staged?". Retrieved 2013-06-02.
↑ Imaging in Lung Cancer Staging at eMedicine
↑ "malignant melanoma: staging". Chorus.rad.mcw.edu. Archived from the original on 2010-07-18. Retrieved 2010-10-14.
↑ "NCCN Guidelines for Patients". National Comprehensive Cancer Network. Retrieved 2015-11-01.
↑ "ACS : How Is Bladder Cancer Staged?". Cancer.org. 2010-04-20. Retrieved 2010-10-14.

External links

"Staging: Questions and Answers" at the National Cancer Institute

Overview of tumors, cancer and oncology (C00–D48, 140–239)

Conditions

Benign tumors	Hyperplasia Cyst Pseudocyst Hamartoma
Malignant progression	Dysplasia Carcinoma in situ Cancer Metastasis Primary tumor Sentinel lymph node
Topography	Head/Neck (Oral, Nasopharyngeal) Digestive system Respiratory system Bone Skin Blood Urogenital Nervous system Endocrine system
Histology	Carcinoma Sarcoma Blastoma Papilloma Adenoma
Other	Precancerous condition Paraneoplastic syndrome

Staging/grading

Carcinogenesis

Misc.

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