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The Eighth Edition Lung Cancer Stage Classification
CHAPTER 3
The Eighth Edition Lung Cancer Stage Classification DANIEL J. BOFFA, MD
INTRODUCTION The fundamental purpose of stage classification is to provide a common (global) nomenclature that can be used to communicate the anatomic extent of cancer in a consistent and detailed way. In addition to providing a universal language to describe each oncologic scenario, the staging nomenclature allows patients to be organized according to their anatomic extent of disease, a step that is critical for the estimation of prognosis, the study of treatment effectiveness, and the communication of practice standards. Therefore, the stage classification not only provides the backbone for current lung cancer practice but also represents the pathway for future developments.
DERIVATION OF STAGE CLASSIFICATION The framework for the lung cancer stage classification is the “TNM” system, which designates a separate component to reflect the anatomic extent of disease for the Tumor, Lymph Nodes, and the presence of systemic Metastases. Each component (T, N, M) has a set of categories (e.g., “1a,” “2c,” “3a”), which are defined by specific descriptors of anatomic extent of disease (e.g., size attribute for T indicator, location of lymph node metastases for N indicator, etc.). Prognosis is used as a tool to identify cohorts of patients that seem more alike (coalesced within a stage category) and cohorts that appear to be distinct (belonging to a separate category), with a stepwise progression toward worse prognosis (e.g., “T2” status associated with worse prognosis than “T1”). Finally, the various combinations of categories (i.e., T1N0M0) are organized into stage groups (e.g., I, II, IIIA, etc.) to reflect the anatomic extent of disease status across all three components (TNM). The current lung cancer stage classification (eighth edition) and the prior (seventh) edition were the result of an international collaboration between the
Union Internationale Contre le Cancer (UICC) and American Joint Committee on Cancer (AJCC).1 To inform the eighth edition, an international database was created containing data from 70,967 nonesmall cell lung cancers to 6189 small cell lung cancers diagnosed between 1999 and 2010.2 Compared with the prior edition, the updated database contains more recent data (by 10 years) and more detailed case information, which increased the number of stage descriptors that could be evaluated and validated. The cases were submitted from 35 sources from 16 different countries (5% from North America, 44% from Asia, 49% from Europe, 2% from Australia). This geographic diversity is critical to the global application of the classification, as significant regional differences in prognosis have been noted previously.3 A series of separate analyses were necessary to disentangle regional effects and differences in source data (i.e., registry vs. institutional database) to render a classification system that is broadly applicable.4 Important changes in the eighth edition are listed in Table 3.1. Additional details regarding the stage classification are available in Refs. 1,2,5e9.
INFORMING THE STAGE CLASSIFICATION The stage classification should reflect the best available information at the time the determination was made. The determination should include not only all imaging (CT and PET scanning) and invasive testing details (e.g., mediastinoscopy or ultrasound-guided biopsy of a liver lesion) but also the patient’s history (e.g., rib pain to suggest chest wall invasion, or headaches suggesting brain metastases) and details of the physical examination (i.e., palpable supraclavicular lymph nodes). In the absence of positive findings in at least one source of information for the stage, the patient would be considered “0.” 57
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Diagnosis and Evaluation
TABLE 3.1
Changes in Stage Classification With Eighth Edition Anatomic Attribute
Seventh Edition Descriptor
Eighth Edition Descriptor
T COMPONENT Tumor >1 but 2 cm
T1a
T1b
Tumor >2 but 3 cm
T1b
T1c
Tumor >4 but 5 cm
T2a
T2b
Tumor >5 but 7 cm
T2b
T3
Tumor >7 cm
T3
T4
Tumor invading diaphragm
T3
T4
Tumor invasion into mediastinal pleura
T3
Dropped
Tumor invading <2 cm of carina
T3
T2a
Tumor associated with atelectasis of entire lung
T3
T2a
M1b
M1c
M COMPONENT >1 extrathoracic metastasis CHANGE TO STAGE GROUPS
•
•
T1a, T1b, T1c (N0, M0)
IA
IA1, IA2, IA3
T1a, T1b, T1c, T2a (N1, M0)
IIA
IIB
T3, N2 (M0)
IIIA
IIIB
T3, T4, N3 (M0)
IIIB
IIIC
(T-any, N-any) M1a, M1b
IV
IVA
(T-any, N-any) M1c
IV
IVB
Because all patients will have a history and undergone physical examination, all patients will at least have information for the M component (hence MX is not an allowed designation). However, although an assessment of the M component can be based on symptoms and physical examination alone, usually imaging or other testing is needed to define the T and N components (hence TX and NX are permissible). The amount of information about the stage classification and the reliability thereof can vary. Stage may be defined by clinical assessment alone, by imaging (chest radiograph [CXR], CT, PET, MRI, etc.) or by biopsies. The stage should always be noted based on the available information (e.g., an initial stage defined by clinical assessment and preliminary imaging), even though the stage classification may change as further information becomes available. Once the pretreatment stage evaluation has been completed, a final clinical stage should be noted; this plays a major role in defining a treatment approach for the patient.
•
For areas in which there are multiple sources of information (i.e., a PET scan of mediastinal nodes and a mediastinoscopy), the stage should reflect the information that is most likely to be accurate (i.e., mediastinoscopy assuming as flourodeoxyglucose (FDG)-avid nodes were assessed).
STAGING PREFIXES A series of prefixes added to the stage designation communicate additional details (Table 3.2). • The prefix “c” refers to the “clinical” stage and should reflect all information obtained before the surgical procedure to eliminate the primary tumor. This would include not only noninvasive modalities (CT scan and PET scan) but also invasive staging (endobronchial ultrasound lymph node biopsy or a liver biopsy). Results from biopsies that occurred before surgery to remove tumor (i.e., mediastinoscopy) would be a part of the clinical stage, even though a pathologist would review the material.
CHAPTER 3 The Eighth Edition Lung Cancer Stage Classification
59
TABLE 3.2
Types of Staging Assessments
•
•
Prefix
Name
Definition
c
Clinical
Before initiation of any treatment, using any and all information available (e.g., including mediastinoscopy)
p
Pathologic
After resection, based on pathologic assessment
y
Restaging
After part or all of the treatment has been given
r
Recurrence
Stage at time of a recurrence
a
Autopsy
Stage as determined by autopsy
The prefix “p” denotes the pathologic stage and is informed by all available information after the primary tumor has been removed. The surgical specimen would represent the most accurate information for the stage components that were evaluated (most commonly T and N). The M component is typically not evaluated in the surgical specimen, and the pathologic M component would be informed by the best available clinical stage information. If the zero lymph nodes in a patient were removed during surgery (a practice that is unacceptable as routine but occurs on rare occasion because of extensive scarring), then the patient would be pT1aNx. The “Nx” denotes the fact that no nodes were examined. The prefix “y” indicates that the stage determination is being made after the patient has received some form of nonsurgical therapy (i.e., chemotherapy or radiation) and is combined with “c” or “p” depending on when the determination is being made. For example, a clinical stage III patient (cT3N2M0) treated with chemoradiation would be designated as ycT3N0M0 if restaging imaging revealed the lymph nodes had normalized in response to chemoradiation; if after resection the lymph nodes had truly been rendered free of tumor, the restage would be ypT3N0M0.
Additional Notation The completeness of the tumor removal is communicated by the “R” indicator. R0 refers to complete removal of tumor with negative surgical margins. R1 denotes microscopic residual tumor only, typically at surgical margins, whereas R2 reflects macroscopic (grossly visible) tumor left behind.
TNM COMPONENTS T Component The T component is defined by attributes of the primary tumor (Table 3.3).7 Size plays a prominent role in defining
the T status. Tumors up to 5 cm are stratified at 1 cm intervals within the T1 (3 cm) and T2 (>3 but 5 cm) designations. Size criteria also qualify for the T3 (>5 but 7 cm) and T4 (>7 cm) tumor designations. • For clinically staged tumors, the size of the groundglass (GG) component should be recorded, but the cT category is determined by the maximum dimension of the solid component. Recognizing that slice thickness and window settings can affect measurements; we recommend using lung windows with a slice thickness of 1 mm.4 • For pathologically staged tumors (i.e., surgical specimen), the lepidic or in situ component should be recorded, but size for pT is determined by the maximum diameter of the invasive component.4 The relationship between the tumor and airway also contributes to the T descriptor. Invasion of a main bronchus is a T2a attribute. • In prior classifications, invasion within 2 cm of carina was a T3 attribute, but this is no longer the case. • Atelectasis extending to the hilum is designated as T2a, regardless of whether it involves a lobe or an entire lung. Tumor extension beyond the lung parenchyma is an important T descriptor. Extension into the visceral pleura of primary tumor lobe, hilar fat, or visceral pleura of adjacent lobes (i.e., across fissures) is a T2 attribute. Extension into chest wall, phrenic nerve, and partial or full thickness of pericardium are T3 attributes. Extension into mediastinum (e.g., infiltration into fat, recurrent laryngeal nerve) is a T4 attribute, as is extension into spine, carina, and now diaphragm (this was previously T3). • The T classification of superior sulcus (Pancoast) tumors varies by tumor extension. Tumors that involve only the thoracic nerve roots (i.e., T1, T2) are T3 tumors. Extension into C8 or higher nerve roots, the brachial plexus, subclavian vessels, vertebral bodies, or spinal canal is T4.
TABLE 3.3
Definitions for T, N, M Descriptors T (Primary Tumor) T0 Tis T1
Label No primary tumor Carcinoma in situ (squamous or adenocarcinoma)
Tis
Tumor 3 cm
T1mi
Minimally Invasive adenocarcinoma
T1mi
T1a
Superficial spreading tumor in central airwaysa
T1aSS
T1a
Tumor 1 cm
T1a1
T1b
Tumor >1 but 2 cm
T1b>1e2
T1c
Tumor >2 but 3 cm
T1c>2e3
T2
Tumor >3 but 5 cm or tumor involving: visceral pleurab
T2Visc Pl b
main bronchus (not carina), atelectasis to hilum
T2Centr
T2a
Tumor >3 but 4 cm
T2a>3e4
T2b
Tumor >4 but 5 cm
T2b>4e5
T3
T4
Tumor >5 but 7 cm
T3>5e7
or invading chest wall, pericardium, phrenic nerve
T3Inv
or separate tumor nodule(s) in the same lobe
T3Satell
Tumor >7 cm
T4>7
or tumor invading mediastinum, diaphragm, heart, great vessels,
T4Inv
recurrent laryngeal nerve, carina, trachea, esophagus, spine or tumor nodule(s) in a different ipsilateral lobe
T4Ipsi
Nod
N (REGIONAL LYMPH NODES) N0
No regional node metastasis
N1
Metastasis in ipsilateral pulmonary or hilar nodes
N2
Metastasis in ipsilateral mediastinal/subcarinal nodes
N3
Metastasis in contralateral mediastinal/hilar or supraclavicular nodes
M (DISTANT METASTASIS) M0
No distant metastasis
M1a
Malignant pleural/pericardial effusionc
M1aPl Dissem
or pleural/pericardial nodules or separate tumor nodule(s) in a contralateral lobe
M1aContr Nod
M1b
Single extrathoracic metastasis
M1bSingle
M1c
Multiple extrathoracic metastases (1 or >1 organ)
M1cMulti
TX, NX: T or N status not able to be assessed. a Superficial spreading tumor of any size but confined to the tracheal or bronchial wall. b Such tumors are classified as T2a if 4 cm, T2b if >4 5 cm. c Pleural effusions are excluded that are cytologically negative, nonbloody, transudative, and clinically judged not to be due to cancer. Reproduced with permission from Detterbeck FC, Boffa DJ, Kim AW, Tanoue LT. The eighth edition lung cancer stage classification. Chest. 2017;151(1):193e203.
CHAPTER 3 The Eighth Edition Lung Cancer Stage Classification •
Extension of a tumor into a mediastinal lymph node impacts both T (T4 ¼ invasion into mediastinum) and N parameters (N2 by direct tumor extension).
The T descriptor continues to be affected by the presence of additional tumor nodules. Additional tumor nodules in the same lobe as the dominant primary tumor remain T3, whereas additional tumor nodules in different ipsilateral lobe are T4. • This applies regardless of whether there is involvement of nodal sites or distant (extrathoracic) sites. There are several special situations. A superficial spreading tumor in central airways is classified as T1a, regardless of location. Carcinoma in situ is classified as Tis; note that this now applies to both squamous carcinoma and adenocarcinoma.4 Minimally invasive adenocarcinoma is classified as T1mi. A minimally invasive adenocarcinoma has an invasive component of 5 mm and a size of the lepidic (noninvasive) component of 3 cm.10 (Note that these diagnoses can only be made in resected tumors.)
N Component There are four N categories that are determined by the location of the involved lymph nodes (Table 3.3).7 Fig. 3.1 provides a description and diagram of the lymph node map.11 • Direct extension of the primary tumor into an adjacent node is counted as nodal involvement. • Although not included in the eighth stage classification, the staging committee did note that the number of involved node stations was prognostic for pathologically staged tumors (single vs. multiple N1 or N2 station involvement) but not for clinically staged tumors.7 No difference was seen between multiple N1 stations and a single N2 skip metastasis (no N1 involvement). • The AJCC, UICC, and IASLC recommend that at least six nodes are removed during surgical resection, three from N1 and three from N2 stations (i.e., a representative node from each station) for accurate staging.7
M Component The M categories and descriptors are summarized in Table 3.3. Pleural/pericardial nodules, pleural/pericardial effusion, and contralateral/bilateral pulmonary nodules are classified as M1a. M1b denotes tumors with a single distant (extrathoracic) metastasis. M1c includes tumors with multiple metastases, either multiple metastases in a single organ or multiple metastases in multiple organs.
•
61
The staging committee did not identify any consistent differences with respect to the site of metastasis among tumors with a single distant metastatic focus (i.e., brain vs. adrenal).8
STAGE GROUPS The various combinations of TNM designations are organized into summary stage groupings based on prognosis (Tables 3.4 and 3.5). The derivation of stage groups for the eighth edition included extensive testing in multiple subgroups, adjusted Cox regression analyses, validation set analyses, and considerations regarding practicality and clinical relevance. • Stage I involves T1-T2a, N0, M0 tumors. • Stage II involves either T2b-T3N0M0 tumors or T1-T2N1M0 tumors. • Stage III is divided into three subgroups for the eighth edition. Stage IIIA includes T4N0M0 and T3-4N1M0 tumors as well as T1-T2N2M0 tumors. Stage IIIB tumors are either T3-T4N2M0 or T1-T2N3M0. Stage IIIC involves T3-T4N3M0 tumors. • Stage IV is divided into two subgroups. Stage IVa includes all M1a and M1b tumors, regardless of T or N classification. Stage IVB involves all M1c tumors.
THE IMPACT OF MULTIPLE-STAGE DESCRIPTORS AND THE STAGE DESIGNATION Patients commonly have multiple anatomic attributes that affect the stage designation for the T, N, and M indicators. In general, the patient’s stage designation should reflect the highest staging designation. For instance, if a patient has a small lung cancer (1.9 cm ¼ T1b) and it invades the visceral pleura (visceral pleural invasion ¼ T2), then the patient would be T2. Similarly, if a patient has hilar nodal metastases (N1) and mediastinal nodal metastases (N2), then the patient would be classified as N2. On the other hand, when there is uncertainty about the presence of a marker of a stage category, the rule is to designate the patient with the lower category. One of the novel lines of investigation for the eighth edition of the stage classification was to determine whether multiple “positive” stage attributes conferred a worse prognosis for the “T” indicator. More specifically, the staging committee analyzed the impact of having more than one anatomic attribute that conferred more advanced T status. For example, a tumor can be designated as T3 because of size (5e7 cm), invasion (chest wall invasion), or by being associated with an additional nodule in the same lobe as the primary
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Diagnosis and Evaluation
supraclavicular zone 1 Low cerviacl, supraclavicular, and sternal notch nodes
Superior mediastinal nodes Upper zone 2R Upper paratracheal (right) 2L Upper paratracheal (left) 3a Prevascular 3p Retrotracheal 4R Lower paratracheal (right) 4L Lower paratracheal (left)
Aortic nodes AP zone 5 Subaortic 6 Paraaortic (ascending aorta or phrenic)
Inferior mediastinal nodes Subcarinal zone 7 Subcarinal
Lower zone 8 Paraesophageal (below carina) 9 Pulmonary ligament
N1 nodes 3p
3a
Hilar/interlobar zone 10 Hilar 11 Interlobar
Peripheral zone 12 Lobar 13 Segmental 14 Subsegmental
FIG. 3.1 The IASLC Node Map for Lung Cancer. (Copied with permission from Rusch V, Asamura H,
Watanabe H, et al. The IASLC lung cancer staging project: a proposal for a new international lymph node map in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol. 2009;4(5): 568e577.)
CHAPTER 3 The Eighth Edition Lung Cancer Stage Classification
tumor. However, the presence of more than one positive descriptor did not consistently confer a worse prognosis than a single positive descriptor.9,12
TABLE 3.4
Lung Cancer Stage Grouping (Eighth Edition)
T/M Label
N0
N1
N2
N3
T1
T1a ≤1
IA1
IIB
IIIA
IIIB
T1b >1-2
IA2
IIB
IIIA
IIIB
T1c >2-3
IA3
IIB
IIIA
IIIB
T2a Cent, Yisc Pl
IB
IIB
IIIA
IIIB
T2a >3-4
IB
IIB
IIIA
IIIB
T2b >4-5
IIA
IIB
IIIA
IIIB
T3 >5-7
IIB
IIIA
IIIB
IIIC
T3 Inv
IIB
IIIA
IIIB
IIIC
T3 Satell
IIB
IIIA
IIIB
IIIC
T4 >7
IIIA
IIIA
IIIB
IIIC
T4 Inv
IIIA
IIIA
IIIB
IIIC
T4 Ipsi Nod
IIIA
IIIA
IIIB
IIIC
M1a Contr Nod
IVA
IVA
IVA
IVA
M1a Pl Dissem
IVA
IVA
IVA
IVA
M1b Single
IVA
IVA
IVA
IVA
M1c Multi
IVB
IVB
IVB
IVB
T2
T3
T4
M1
MULTIPLE PULMONARY SITES OF LUNG CANCER Patients with multiple pulmonary sites of lung cancer are seen with increasing frequency. There has been significant variability in how TNM classification has been applied to these tumors.13 The staging committee proposed definitions and a schema for stage classification of such tumors.6,14,15 Four patterns of disease are distinguished (Table 3.6); the clinical presentation, pathologic correlates, and biologic behavior of these suggest specific applications of TNM classification rules. • Patients can present with second primary lung cancers. The demographic characteristics, outcomes, and recurrence patterns for each tumor are similar to those of single “typical” lung cancers according to the stage and histologic type.16 Note that most second primary lung cancers have the same histotype as the first primary, and that there is substantial variability in biomarker patterns (i.e., either different in clearly related metastases or the same in clearly different tumors). Multiple primary lung cancers should each be designated with a separate T, N, and M category for each tumor. • A solid primary lung cancer may have one or more separate solid tumor nodule(s) of the same histologic type (referred to as intrapulmonary metastasis in the pathology community). These tumors should be classified according to the location of the separate nodule relative to the index tumordT3 for a same-lobe, T4 for a different lobe on the same-side (ipsilateral), and M1a for an other-side (contralateral) locationdwith a single N and M category. It is important to recognize that most additional solid
Reproduced with permission from Detterbeck FC, Boffa DJ, Kim AW, Tanoue LT. The eighth edition lung cancer stage classification. Chest. 2017;151(1):193e203.
TABLE 3.5
5-Year Survival (%)
Type
63
IA1
IA2
IA3
IB
IIA
IIB
IIIA
IIIB
IIIC
IVA
IVB
Clinical
92
83
77
68
60
53
36
26
13
10
0
Pathologic
90
85
80
73
65
56
41
24
12
-
-
Average overall survival in the IASLC global database of patients diagnosed during 1999e2010. Reproduced with permission from Detterbeck FC, Boffa DJ, Kim AW, Tanoue LT. The eighth edition lung cancer stage classification. Chest. 2017;151(1):193e203.
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TABLE 3.6
Schematic Summary of Patterns of Disease and TNM Classification of Patients With Lung Cancer With Multiple Pulmonary Sites of Involvement Second Primary Lung Cancer
Multifocal GG/L Nodules
Pneumonic-Type of Adenocarcinoma
Separate Tumor Nodule
Imaging features
Two or more distinct masses with imaging characteristics of lung cancer (e.g., spiculated)
Multiple ground-glass or part-solid nodules
Patchy areas of ground glass and consolidation
Typical lung cancer (e.g., solid, spiculated) with separate solid nodule
Pathologic features
Different histotype or different morphology by comprehensive histologic assessment
Adenocarcinomas with prominent lepidic component (typically varying degrees of AIS, MIA, LPA)
Same histology throughout (most often invasive mucinous adenocarcinoma)
Distinct masses with the same morphology by comprehensive histologic assessment
TNM classification
Separate cTNM and pTNM for each cancer
T based on highest T lesion with (#/m) indicating multiplicity; single N and M
T based on size or T3 if in single lobe, T4 or M1a if in different ipsi- or contralateral lobes; single N and M
Location of separate nodule relative to primary site determines if T3, T4, or M1a; single N and M
Conceptual view
Unrelated tumors
Separate tumors, albeit with similarities
Single tumor, diffuse pulmonary involvement
Single tumor with intrapulmonary metastasis
AIS, adenocarcinoma in situ; GG/L, ground glass/lepidic; LPA, lepidic predominant adenocarcinoma; MIA, minimally invasive adenocarcinoma. Reproduced with permission from Detterbeck F, Nicholson F, Franklin W, et al. The IASLC lung cancer staging project: summary of proposal revisions of the classification of lung cancers with multiple pulmonary sites of involvement in the forthcoming eighth edition of the TNM classification. J Thorac Oncol. 2016;11(5):639e650.
•
•
nodules seen on imaging are not malignant, and that the separate tumor nodule designation should not be used if the additional tumor is thought to be a separate primary lung cancer. Patients may present with multiple lung cancer nodules with prominent ground-glass or lepidic (GG/L) features. This group has different demographic characteristics, excellent outcomes, and infrequent recurrences outside the lung parenchyma.15 These GG/ L tumors should be designated by the T category of the highest T lesion, the number or “m” in parentheses (#/m) to indicate the multiplicity, and a collective N and M category for all. A detailed histologic assessment of such GG/L tumors is not required. A pattern of lung adenocarcinoma exists that appears radiologically similar to pneumonia (the so-called “pneumonic-type” lung cancer). Extrathoracic and nodal involvement is infrequent, but prognosis is distinctly worse than that for patients with multiple distinct GG/L nodules.15 Diffuse pneumonic-type lung cancers are designated by size (or T3) if involving one lobe, T4 if involving multiple sameside lobes, and M1a if involving both lungs with a single N and M category for all areas of involvement.
PRACTICE CONSIDERATIONS Caution: Revisions of Stage Classification The stage classification is revised regularly to reflect advances (e.g., in basic knowledge of the disease, or technical [imaging] advances) that may affect stage determination and survival. However, the revisions of the stage classification are not designed to evaluate the effectiveness of treatment across tumor attributes. Therefore, changes in staging nomenclature should have no immediate bearing on the way patients are treated. More specifically, “stage-specific” treatment recommendations are widely available to facilitate the communication of practice standards within the oncologic community. In the event that a specific oncologic scenario is reclassified to a higher or lower stage, clinicians should not interpret the reclassification to be justification for a change in treatment. The treatment is defined by the outcomes of patients with particular anatomic tumor characteristics, not by the name or stage group to which these anatomic characteristics are assigned. For example, if a patient’s tumor attributes were reclassified from stage II to stage III during a revision, the clinician should not automatically treat the
CHAPTER 3 The Eighth Edition Lung Cancer Stage Classification
65
patient according to preexisting stage III guidelines (which refer to patients with the previous, not the new anatomic descriptors).17
tumors, as described in this chapter, represents the worldwide standard as of January 1, 2018.
Caution: Prognosis
REFERENCES
Although prognosis was the primary determinant of how to coalesce or separate tumors in the stage classification, the survival estimates should not be expected to be overly accurate for any specific patient. This may seem somewhat counterintuitive. However, it must be kept in mind that the survival estimates represent an average of a multitude of variables that impact prognosis. The prognosis varies considerably across the geographic regions and data sources included in the staging database. In addition, patient health, sociodemographic factors (age, race, etc.), the extent and accuracy of the staging evaluation (i.e., whether PET scanning and brain imaging were done and whether abnormal radiographic findings were pathologically confirmed), the type of surgical procedure performed, the use of additional therapies (i.e., chemotherapy and radiation), and a tumor’s mutational status can all impact a patient’s survival. Furthermore, cancer survival changes over time; to this point, there has been a roughly 30% increase in survival in the eighth edition stage database compared with the seventh edition 10 years earlier.18 It is important to note that the observed prognosis of patients in the eighth edition database is that of the patients who were diagnosed between 1999 and 2010; the relevance to the exact prognosis of patients diagnosed today is highly questionable. Therefore, although the differences in survival across staging parameters should be consistent across patients (i.e., discrimination between groups), the actual 5-year mortality (calibration) is likely quite different than what is listed in Table 3.5, which should be kept in mind when counseling patients. Multiple efforts are underway to “personalize” survival estimates for lung cancer patients and will likely take advantage of both clinical and molecular data in the future.
1. Detterbeck FC, Boffa DJ, Kim AW, Tanoue LT. The eighth edition lung cancer stage classification. Chest. 2017; 151(1):193e203. 2. Rami-Porta R, Bolejack V, Giroux DJ, et al. The IASLC lung cancer staging project: the new database to inform the eighth edition of the TNM classification of lung cancer. J Thorac Oncol. 2014;9(11):1618e1624. 3. Detterbeck FC, Boffa DJ, Tanoue LT. The new lung cancer staging system. Chest. 2009;136(1):260e271. 4. Travis WD, Asamura H, Bankier AA, et al. The IASLC lung cancer staging project: proposals for coding T categories for subsolid nodules and assessment of tumor size in part-solid tumors in the forthcoming eighth edition of the TNM classification of lung cancer. J Thorac Oncol. 2016;11(8):1204e1223. 5. Goldstraw P, Chansky K, Crowley J, et al. The IASLC lung cancer staging project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer. J Thorac Oncol. 2016;11(1):39e51. 6. Detterbeck FC, Bolejack V, Arenberg DA, et al. The IASLC lung cancer staging project: background data and proposals for the classification of lung cancer with separate tumor nodules in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol. 2016;11(5): 681e692. 7. Asamura H, Chansky K, Crowley J, et al. The international association for the study of lung cancer lung cancer staging project: proposals for the revision of the N descriptors in the forthcoming 8th edition of the TNM classification for lung cancer. J Thorac Oncol. 2015;10(12):1675e1684. 8. Eberhardt WEE, Mitchell A, Crowley J, et al. The IASLC lung cancer staging project: proposals for the revision of the M descriptors in the forthcoming eighth edition of the TNM classification of lung cancer. J Thorac Oncol. 2015;10(11): 1515e1522. 9. Rami-Porta R, Bolejack V, Crowley J, et al. The IASLC lung cancer staging project: proposals for the revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol. 2015;10(7): 990e1003. 10. Boffa DJ, Hancock JG, Yao X, et al. Now or later: evaluating the importance of chemotherapy timing in resectable stage III (N2) lung cancer in the National Cancer Database. Ann Thorac Surg. 2015;99(1):200e208. 11. Rusch V, Asamura H, Watanabe H, et al. The IASLC lung cancer staging project: a proposal for a new international lymph node map in the forthcoming 7th edition of the TNM classification for lung cancer. J Thorac Oncol. 2009; 4(5):568e577. 12. Detterbeck FC, Nicholson AG, Franklin WA, et al. The IASLC lung cancer staging project: summary of proposals
CONCLUSION Stage classification is a nomenclature to describe the anatomic extent of a malignant tumor. It is a fundamental tool for communication about the tumor in a specific patient at hand, groups of patients in research studies, observed prognosis of past patients with tumors categorized by a particular stage group(s), and the outcomes of particular treatment approaches in past patients with a particular anatomic extent of disease. The eighth edition stage classification of lung
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for revisions of the classification of lung cancers with multiple pulmonary sites of involvement in the forthcoming eighth edition of the TNM classification. J Thorac Oncol. 2016;11(5):639e650. 13. Fonseca A, Detterbeck FC. How many names for a rose: inconsistent classification of multiple foci of lung cancer due to ambiguous rules. Lung Cancer. 2014; 85(1):7e11. 14. Detterbeck FC, Franklin WA, Nicholson AG, et al. The IASLC lung cancer staging project: background data and proposed criteria to distinguish separate primary lung cancers from metastatic foci in patients with two lung tumors in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol. 2016; 11(5):651e665. 15. Detterbeck FC, Marom EM, Arenberg DA, et al. The IASLC lung cancer staging project: background data and proposals for the application of TNM staging rules to lung cancer presenting as multiple nodules with ground glass
or lepidic features or a pneumonic type of involvement in the forthcoming eighth edition of the TNM classification. J Thorac Oncol. 2016;11(5):666e680. 16. Detterbeck F, Arenberg D, Asamura H, et al. The IASLC lung cancer staging project: background data and proposed criteria to distinguish separate primary lung cancers from metastatic foci in patients with two lung tumors in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol. 2016;11(5):651e665. 17. Boffa DJ, Detterbeck FC, Smith EJ, et al. Should the 7th edition of the lung cancer stage classification system change treatment algorithms in non-small cell lung cancer? J Thorac Oncol. 2010;5(11):1779e1783. 18. Detterbeck FC, Chansky K, Groome P, et al. The IASLC lung cancer staging project: methodology and validation used in the development of proposals for revision of the stage classification of NSCLC in the forthcoming (eighth) edition of the TNM classification of lung cancer. J Thorac Oncol. 2016;11(9):1433e1446.
The Eighth Edition Lung Cancer Stage Classification DANIEL J. BOFFA, MD
INTRODUCTION The fundamental purpose of stage classification is to provide a common (global) nomenclature that can be used to communicate the anatomic extent of cancer in a consistent and detailed way. In addition to providing a universal language to describe each oncologic scenario, the staging nomenclature allows patients to be organized according to their anatomic extent of disease, a step that is critical for the estimation of prognosis, the study of treatment effectiveness, and the communication of practice standards. Therefore, the stage classification not only provides the backbone for current lung cancer practice but also represents the pathway for future developments.
DERIVATION OF STAGE CLASSIFICATION The framework for the lung cancer stage classification is the “TNM” system, which designates a separate component to reflect the anatomic extent of disease for the Tumor, Lymph Nodes, and the presence of systemic Metastases. Each component (T, N, M) has a set of categories (e.g., “1a,” “2c,” “3a”), which are defined by specific descriptors of anatomic extent of disease (e.g., size attribute for T indicator, location of lymph node metastases for N indicator, etc.). Prognosis is used as a tool to identify cohorts of patients that seem more alike (coalesced within a stage category) and cohorts that appear to be distinct (belonging to a separate category), with a stepwise progression toward worse prognosis (e.g., “T2” status associated with worse prognosis than “T1”). Finally, the various combinations of categories (i.e., T1N0M0) are organized into stage groups (e.g., I, II, IIIA, etc.) to reflect the anatomic extent of disease status across all three components (TNM). The current lung cancer stage classification (eighth edition) and the prior (seventh) edition were the result of an international collaboration between the
Union Internationale Contre le Cancer (UICC) and American Joint Committee on Cancer (AJCC).1 To inform the eighth edition, an international database was created containing data from 70,967 nonesmall cell lung cancers to 6189 small cell lung cancers diagnosed between 1999 and 2010.2 Compared with the prior edition, the updated database contains more recent data (by 10 years) and more detailed case information, which increased the number of stage descriptors that could be evaluated and validated. The cases were submitted from 35 sources from 16 different countries (5% from North America, 44% from Asia, 49% from Europe, 2% from Australia). This geographic diversity is critical to the global application of the classification, as significant regional differences in prognosis have been noted previously.3 A series of separate analyses were necessary to disentangle regional effects and differences in source data (i.e., registry vs. institutional database) to render a classification system that is broadly applicable.4 Important changes in the eighth edition are listed in Table 3.1. Additional details regarding the stage classification are available in Refs. 1,2,5e9.
INFORMING THE STAGE CLASSIFICATION The stage classification should reflect the best available information at the time the determination was made. The determination should include not only all imaging (CT and PET scanning) and invasive testing details (e.g., mediastinoscopy or ultrasound-guided biopsy of a liver lesion) but also the patient’s history (e.g., rib pain to suggest chest wall invasion, or headaches suggesting brain metastases) and details of the physical examination (i.e., palpable supraclavicular lymph nodes). In the absence of positive findings in at least one source of information for the stage, the patient would be considered “0.” 57
58
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TABLE 3.1
Changes in Stage Classification With Eighth Edition Anatomic Attribute
Seventh Edition Descriptor
Eighth Edition Descriptor
T COMPONENT Tumor >1 but 2 cm
T1a
T1b
Tumor >2 but 3 cm
T1b
T1c
Tumor >4 but 5 cm
T2a
T2b
Tumor >5 but 7 cm
T2b
T3
Tumor >7 cm
T3
T4
Tumor invading diaphragm
T3
T4
Tumor invasion into mediastinal pleura
T3
Dropped
Tumor invading <2 cm of carina
T3
T2a
Tumor associated with atelectasis of entire lung
T3
T2a
M1b
M1c
M COMPONENT >1 extrathoracic metastasis CHANGE TO STAGE GROUPS
•
•
T1a, T1b, T1c (N0, M0)
IA
IA1, IA2, IA3
T1a, T1b, T1c, T2a (N1, M0)
IIA
IIB
T3, N2 (M0)
IIIA
IIIB
T3, T4, N3 (M0)
IIIB
IIIC
(T-any, N-any) M1a, M1b
IV
IVA
(T-any, N-any) M1c
IV
IVB
Because all patients will have a history and undergone physical examination, all patients will at least have information for the M component (hence MX is not an allowed designation). However, although an assessment of the M component can be based on symptoms and physical examination alone, usually imaging or other testing is needed to define the T and N components (hence TX and NX are permissible). The amount of information about the stage classification and the reliability thereof can vary. Stage may be defined by clinical assessment alone, by imaging (chest radiograph [CXR], CT, PET, MRI, etc.) or by biopsies. The stage should always be noted based on the available information (e.g., an initial stage defined by clinical assessment and preliminary imaging), even though the stage classification may change as further information becomes available. Once the pretreatment stage evaluation has been completed, a final clinical stage should be noted; this plays a major role in defining a treatment approach for the patient.
•
For areas in which there are multiple sources of information (i.e., a PET scan of mediastinal nodes and a mediastinoscopy), the stage should reflect the information that is most likely to be accurate (i.e., mediastinoscopy assuming as flourodeoxyglucose (FDG)-avid nodes were assessed).
STAGING PREFIXES A series of prefixes added to the stage designation communicate additional details (Table 3.2). • The prefix “c” refers to the “clinical” stage and should reflect all information obtained before the surgical procedure to eliminate the primary tumor. This would include not only noninvasive modalities (CT scan and PET scan) but also invasive staging (endobronchial ultrasound lymph node biopsy or a liver biopsy). Results from biopsies that occurred before surgery to remove tumor (i.e., mediastinoscopy) would be a part of the clinical stage, even though a pathologist would review the material.
CHAPTER 3 The Eighth Edition Lung Cancer Stage Classification
59
TABLE 3.2
Types of Staging Assessments
•
•
Prefix
Name
Definition
c
Clinical
Before initiation of any treatment, using any and all information available (e.g., including mediastinoscopy)
p
Pathologic
After resection, based on pathologic assessment
y
Restaging
After part or all of the treatment has been given
r
Recurrence
Stage at time of a recurrence
a
Autopsy
Stage as determined by autopsy
The prefix “p” denotes the pathologic stage and is informed by all available information after the primary tumor has been removed. The surgical specimen would represent the most accurate information for the stage components that were evaluated (most commonly T and N). The M component is typically not evaluated in the surgical specimen, and the pathologic M component would be informed by the best available clinical stage information. If the zero lymph nodes in a patient were removed during surgery (a practice that is unacceptable as routine but occurs on rare occasion because of extensive scarring), then the patient would be pT1aNx. The “Nx” denotes the fact that no nodes were examined. The prefix “y” indicates that the stage determination is being made after the patient has received some form of nonsurgical therapy (i.e., chemotherapy or radiation) and is combined with “c” or “p” depending on when the determination is being made. For example, a clinical stage III patient (cT3N2M0) treated with chemoradiation would be designated as ycT3N0M0 if restaging imaging revealed the lymph nodes had normalized in response to chemoradiation; if after resection the lymph nodes had truly been rendered free of tumor, the restage would be ypT3N0M0.
Additional Notation The completeness of the tumor removal is communicated by the “R” indicator. R0 refers to complete removal of tumor with negative surgical margins. R1 denotes microscopic residual tumor only, typically at surgical margins, whereas R2 reflects macroscopic (grossly visible) tumor left behind.
TNM COMPONENTS T Component The T component is defined by attributes of the primary tumor (Table 3.3).7 Size plays a prominent role in defining
the T status. Tumors up to 5 cm are stratified at 1 cm intervals within the T1 (3 cm) and T2 (>3 but 5 cm) designations. Size criteria also qualify for the T3 (>5 but 7 cm) and T4 (>7 cm) tumor designations. • For clinically staged tumors, the size of the groundglass (GG) component should be recorded, but the cT category is determined by the maximum dimension of the solid component. Recognizing that slice thickness and window settings can affect measurements; we recommend using lung windows with a slice thickness of 1 mm.4 • For pathologically staged tumors (i.e., surgical specimen), the lepidic or in situ component should be recorded, but size for pT is determined by the maximum diameter of the invasive component.4 The relationship between the tumor and airway also contributes to the T descriptor. Invasion of a main bronchus is a T2a attribute. • In prior classifications, invasion within 2 cm of carina was a T3 attribute, but this is no longer the case. • Atelectasis extending to the hilum is designated as T2a, regardless of whether it involves a lobe or an entire lung. Tumor extension beyond the lung parenchyma is an important T descriptor. Extension into the visceral pleura of primary tumor lobe, hilar fat, or visceral pleura of adjacent lobes (i.e., across fissures) is a T2 attribute. Extension into chest wall, phrenic nerve, and partial or full thickness of pericardium are T3 attributes. Extension into mediastinum (e.g., infiltration into fat, recurrent laryngeal nerve) is a T4 attribute, as is extension into spine, carina, and now diaphragm (this was previously T3). • The T classification of superior sulcus (Pancoast) tumors varies by tumor extension. Tumors that involve only the thoracic nerve roots (i.e., T1, T2) are T3 tumors. Extension into C8 or higher nerve roots, the brachial plexus, subclavian vessels, vertebral bodies, or spinal canal is T4.
TABLE 3.3
Definitions for T, N, M Descriptors T (Primary Tumor) T0 Tis T1
Label No primary tumor Carcinoma in situ (squamous or adenocarcinoma)
Tis
Tumor 3 cm
T1mi
Minimally Invasive adenocarcinoma
T1mi
T1a
Superficial spreading tumor in central airwaysa
T1aSS
T1a
Tumor 1 cm
T1a1
T1b
Tumor >1 but 2 cm
T1b>1e2
T1c
Tumor >2 but 3 cm
T1c>2e3
T2
Tumor >3 but 5 cm or tumor involving: visceral pleurab
T2Visc Pl b
main bronchus (not carina), atelectasis to hilum
T2Centr
T2a
Tumor >3 but 4 cm
T2a>3e4
T2b
Tumor >4 but 5 cm
T2b>4e5
T3
T4
Tumor >5 but 7 cm
T3>5e7
or invading chest wall, pericardium, phrenic nerve
T3Inv
or separate tumor nodule(s) in the same lobe
T3Satell
Tumor >7 cm
T4>7
or tumor invading mediastinum, diaphragm, heart, great vessels,
T4Inv
recurrent laryngeal nerve, carina, trachea, esophagus, spine or tumor nodule(s) in a different ipsilateral lobe
T4Ipsi
Nod
N (REGIONAL LYMPH NODES) N0
No regional node metastasis
N1
Metastasis in ipsilateral pulmonary or hilar nodes
N2
Metastasis in ipsilateral mediastinal/subcarinal nodes
N3
Metastasis in contralateral mediastinal/hilar or supraclavicular nodes
M (DISTANT METASTASIS) M0
No distant metastasis
M1a
Malignant pleural/pericardial effusionc
M1aPl Dissem
or pleural/pericardial nodules or separate tumor nodule(s) in a contralateral lobe
M1aContr Nod
M1b
Single extrathoracic metastasis
M1bSingle
M1c
Multiple extrathoracic metastases (1 or >1 organ)
M1cMulti
TX, NX: T or N status not able to be assessed. a Superficial spreading tumor of any size but confined to the tracheal or bronchial wall. b Such tumors are classified as T2a if 4 cm, T2b if >4 5 cm. c Pleural effusions are excluded that are cytologically negative, nonbloody, transudative, and clinically judged not to be due to cancer. Reproduced with permission from Detterbeck FC, Boffa DJ, Kim AW, Tanoue LT. The eighth edition lung cancer stage classification. Chest. 2017;151(1):193e203.
CHAPTER 3 The Eighth Edition Lung Cancer Stage Classification •
Extension of a tumor into a mediastinal lymph node impacts both T (T4 ¼ invasion into mediastinum) and N parameters (N2 by direct tumor extension).
The T descriptor continues to be affected by the presence of additional tumor nodules. Additional tumor nodules in the same lobe as the dominant primary tumor remain T3, whereas additional tumor nodules in different ipsilateral lobe are T4. • This applies regardless of whether there is involvement of nodal sites or distant (extrathoracic) sites. There are several special situations. A superficial spreading tumor in central airways is classified as T1a, regardless of location. Carcinoma in situ is classified as Tis; note that this now applies to both squamous carcinoma and adenocarcinoma.4 Minimally invasive adenocarcinoma is classified as T1mi. A minimally invasive adenocarcinoma has an invasive component of 5 mm and a size of the lepidic (noninvasive) component of 3 cm.10 (Note that these diagnoses can only be made in resected tumors.)
N Component There are four N categories that are determined by the location of the involved lymph nodes (Table 3.3).7 Fig. 3.1 provides a description and diagram of the lymph node map.11 • Direct extension of the primary tumor into an adjacent node is counted as nodal involvement. • Although not included in the eighth stage classification, the staging committee did note that the number of involved node stations was prognostic for pathologically staged tumors (single vs. multiple N1 or N2 station involvement) but not for clinically staged tumors.7 No difference was seen between multiple N1 stations and a single N2 skip metastasis (no N1 involvement). • The AJCC, UICC, and IASLC recommend that at least six nodes are removed during surgical resection, three from N1 and three from N2 stations (i.e., a representative node from each station) for accurate staging.7
M Component The M categories and descriptors are summarized in Table 3.3. Pleural/pericardial nodules, pleural/pericardial effusion, and contralateral/bilateral pulmonary nodules are classified as M1a. M1b denotes tumors with a single distant (extrathoracic) metastasis. M1c includes tumors with multiple metastases, either multiple metastases in a single organ or multiple metastases in multiple organs.
•
61
The staging committee did not identify any consistent differences with respect to the site of metastasis among tumors with a single distant metastatic focus (i.e., brain vs. adrenal).8
STAGE GROUPS The various combinations of TNM designations are organized into summary stage groupings based on prognosis (Tables 3.4 and 3.5). The derivation of stage groups for the eighth edition included extensive testing in multiple subgroups, adjusted Cox regression analyses, validation set analyses, and considerations regarding practicality and clinical relevance. • Stage I involves T1-T2a, N0, M0 tumors. • Stage II involves either T2b-T3N0M0 tumors or T1-T2N1M0 tumors. • Stage III is divided into three subgroups for the eighth edition. Stage IIIA includes T4N0M0 and T3-4N1M0 tumors as well as T1-T2N2M0 tumors. Stage IIIB tumors are either T3-T4N2M0 or T1-T2N3M0. Stage IIIC involves T3-T4N3M0 tumors. • Stage IV is divided into two subgroups. Stage IVa includes all M1a and M1b tumors, regardless of T or N classification. Stage IVB involves all M1c tumors.
THE IMPACT OF MULTIPLE-STAGE DESCRIPTORS AND THE STAGE DESIGNATION Patients commonly have multiple anatomic attributes that affect the stage designation for the T, N, and M indicators. In general, the patient’s stage designation should reflect the highest staging designation. For instance, if a patient has a small lung cancer (1.9 cm ¼ T1b) and it invades the visceral pleura (visceral pleural invasion ¼ T2), then the patient would be T2. Similarly, if a patient has hilar nodal metastases (N1) and mediastinal nodal metastases (N2), then the patient would be classified as N2. On the other hand, when there is uncertainty about the presence of a marker of a stage category, the rule is to designate the patient with the lower category. One of the novel lines of investigation for the eighth edition of the stage classification was to determine whether multiple “positive” stage attributes conferred a worse prognosis for the “T” indicator. More specifically, the staging committee analyzed the impact of having more than one anatomic attribute that conferred more advanced T status. For example, a tumor can be designated as T3 because of size (5e7 cm), invasion (chest wall invasion), or by being associated with an additional nodule in the same lobe as the primary
62
SECTION I
Diagnosis and Evaluation
supraclavicular zone 1 Low cerviacl, supraclavicular, and sternal notch nodes
Superior mediastinal nodes Upper zone 2R Upper paratracheal (right) 2L Upper paratracheal (left) 3a Prevascular 3p Retrotracheal 4R Lower paratracheal (right) 4L Lower paratracheal (left)
Aortic nodes AP zone 5 Subaortic 6 Paraaortic (ascending aorta or phrenic)
Inferior mediastinal nodes Subcarinal zone 7 Subcarinal
Lower zone 8 Paraesophageal (below carina) 9 Pulmonary ligament
N1 nodes 3p
3a
Hilar/interlobar zone 10 Hilar 11 Interlobar
Peripheral zone 12 Lobar 13 Segmental 14 Subsegmental
FIG. 3.1 The IASLC Node Map for Lung Cancer. (Copied with permission from Rusch V, Asamura H,
Watanabe H, et al. The IASLC lung cancer staging project: a proposal for a new international lymph node map in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol. 2009;4(5): 568e577.)
CHAPTER 3 The Eighth Edition Lung Cancer Stage Classification
tumor. However, the presence of more than one positive descriptor did not consistently confer a worse prognosis than a single positive descriptor.9,12
TABLE 3.4
Lung Cancer Stage Grouping (Eighth Edition)
T/M Label
N0
N1
N2
N3
T1
T1a ≤1
IA1
IIB
IIIA
IIIB
T1b >1-2
IA2
IIB
IIIA
IIIB
T1c >2-3
IA3
IIB
IIIA
IIIB
T2a Cent, Yisc Pl
IB
IIB
IIIA
IIIB
T2a >3-4
IB
IIB
IIIA
IIIB
T2b >4-5
IIA
IIB
IIIA
IIIB
T3 >5-7
IIB
IIIA
IIIB
IIIC
T3 Inv
IIB
IIIA
IIIB
IIIC
T3 Satell
IIB
IIIA
IIIB
IIIC
T4 >7
IIIA
IIIA
IIIB
IIIC
T4 Inv
IIIA
IIIA
IIIB
IIIC
T4 Ipsi Nod
IIIA
IIIA
IIIB
IIIC
M1a Contr Nod
IVA
IVA
IVA
IVA
M1a Pl Dissem
IVA
IVA
IVA
IVA
M1b Single
IVA
IVA
IVA
IVA
M1c Multi
IVB
IVB
IVB
IVB
T2
T3
T4
M1
MULTIPLE PULMONARY SITES OF LUNG CANCER Patients with multiple pulmonary sites of lung cancer are seen with increasing frequency. There has been significant variability in how TNM classification has been applied to these tumors.13 The staging committee proposed definitions and a schema for stage classification of such tumors.6,14,15 Four patterns of disease are distinguished (Table 3.6); the clinical presentation, pathologic correlates, and biologic behavior of these suggest specific applications of TNM classification rules. • Patients can present with second primary lung cancers. The demographic characteristics, outcomes, and recurrence patterns for each tumor are similar to those of single “typical” lung cancers according to the stage and histologic type.16 Note that most second primary lung cancers have the same histotype as the first primary, and that there is substantial variability in biomarker patterns (i.e., either different in clearly related metastases or the same in clearly different tumors). Multiple primary lung cancers should each be designated with a separate T, N, and M category for each tumor. • A solid primary lung cancer may have one or more separate solid tumor nodule(s) of the same histologic type (referred to as intrapulmonary metastasis in the pathology community). These tumors should be classified according to the location of the separate nodule relative to the index tumordT3 for a same-lobe, T4 for a different lobe on the same-side (ipsilateral), and M1a for an other-side (contralateral) locationdwith a single N and M category. It is important to recognize that most additional solid
Reproduced with permission from Detterbeck FC, Boffa DJ, Kim AW, Tanoue LT. The eighth edition lung cancer stage classification. Chest. 2017;151(1):193e203.
TABLE 3.5
5-Year Survival (%)
Type
63
IA1
IA2
IA3
IB
IIA
IIB
IIIA
IIIB
IIIC
IVA
IVB
Clinical
92
83
77
68
60
53
36
26
13
10
0
Pathologic
90
85
80
73
65
56
41
24
12
-
-
Average overall survival in the IASLC global database of patients diagnosed during 1999e2010. Reproduced with permission from Detterbeck FC, Boffa DJ, Kim AW, Tanoue LT. The eighth edition lung cancer stage classification. Chest. 2017;151(1):193e203.
64
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Diagnosis and Evaluation
TABLE 3.6
Schematic Summary of Patterns of Disease and TNM Classification of Patients With Lung Cancer With Multiple Pulmonary Sites of Involvement Second Primary Lung Cancer
Multifocal GG/L Nodules
Pneumonic-Type of Adenocarcinoma
Separate Tumor Nodule
Imaging features
Two or more distinct masses with imaging characteristics of lung cancer (e.g., spiculated)
Multiple ground-glass or part-solid nodules
Patchy areas of ground glass and consolidation
Typical lung cancer (e.g., solid, spiculated) with separate solid nodule
Pathologic features
Different histotype or different morphology by comprehensive histologic assessment
Adenocarcinomas with prominent lepidic component (typically varying degrees of AIS, MIA, LPA)
Same histology throughout (most often invasive mucinous adenocarcinoma)
Distinct masses with the same morphology by comprehensive histologic assessment
TNM classification
Separate cTNM and pTNM for each cancer
T based on highest T lesion with (#/m) indicating multiplicity; single N and M
T based on size or T3 if in single lobe, T4 or M1a if in different ipsi- or contralateral lobes; single N and M
Location of separate nodule relative to primary site determines if T3, T4, or M1a; single N and M
Conceptual view
Unrelated tumors
Separate tumors, albeit with similarities
Single tumor, diffuse pulmonary involvement
Single tumor with intrapulmonary metastasis
AIS, adenocarcinoma in situ; GG/L, ground glass/lepidic; LPA, lepidic predominant adenocarcinoma; MIA, minimally invasive adenocarcinoma. Reproduced with permission from Detterbeck F, Nicholson F, Franklin W, et al. The IASLC lung cancer staging project: summary of proposal revisions of the classification of lung cancers with multiple pulmonary sites of involvement in the forthcoming eighth edition of the TNM classification. J Thorac Oncol. 2016;11(5):639e650.
•
•
nodules seen on imaging are not malignant, and that the separate tumor nodule designation should not be used if the additional tumor is thought to be a separate primary lung cancer. Patients may present with multiple lung cancer nodules with prominent ground-glass or lepidic (GG/L) features. This group has different demographic characteristics, excellent outcomes, and infrequent recurrences outside the lung parenchyma.15 These GG/ L tumors should be designated by the T category of the highest T lesion, the number or “m” in parentheses (#/m) to indicate the multiplicity, and a collective N and M category for all. A detailed histologic assessment of such GG/L tumors is not required. A pattern of lung adenocarcinoma exists that appears radiologically similar to pneumonia (the so-called “pneumonic-type” lung cancer). Extrathoracic and nodal involvement is infrequent, but prognosis is distinctly worse than that for patients with multiple distinct GG/L nodules.15 Diffuse pneumonic-type lung cancers are designated by size (or T3) if involving one lobe, T4 if involving multiple sameside lobes, and M1a if involving both lungs with a single N and M category for all areas of involvement.
PRACTICE CONSIDERATIONS Caution: Revisions of Stage Classification The stage classification is revised regularly to reflect advances (e.g., in basic knowledge of the disease, or technical [imaging] advances) that may affect stage determination and survival. However, the revisions of the stage classification are not designed to evaluate the effectiveness of treatment across tumor attributes. Therefore, changes in staging nomenclature should have no immediate bearing on the way patients are treated. More specifically, “stage-specific” treatment recommendations are widely available to facilitate the communication of practice standards within the oncologic community. In the event that a specific oncologic scenario is reclassified to a higher or lower stage, clinicians should not interpret the reclassification to be justification for a change in treatment. The treatment is defined by the outcomes of patients with particular anatomic tumor characteristics, not by the name or stage group to which these anatomic characteristics are assigned. For example, if a patient’s tumor attributes were reclassified from stage II to stage III during a revision, the clinician should not automatically treat the
CHAPTER 3 The Eighth Edition Lung Cancer Stage Classification
65
patient according to preexisting stage III guidelines (which refer to patients with the previous, not the new anatomic descriptors).17
tumors, as described in this chapter, represents the worldwide standard as of January 1, 2018.
Caution: Prognosis
REFERENCES
Although prognosis was the primary determinant of how to coalesce or separate tumors in the stage classification, the survival estimates should not be expected to be overly accurate for any specific patient. This may seem somewhat counterintuitive. However, it must be kept in mind that the survival estimates represent an average of a multitude of variables that impact prognosis. The prognosis varies considerably across the geographic regions and data sources included in the staging database. In addition, patient health, sociodemographic factors (age, race, etc.), the extent and accuracy of the staging evaluation (i.e., whether PET scanning and brain imaging were done and whether abnormal radiographic findings were pathologically confirmed), the type of surgical procedure performed, the use of additional therapies (i.e., chemotherapy and radiation), and a tumor’s mutational status can all impact a patient’s survival. Furthermore, cancer survival changes over time; to this point, there has been a roughly 30% increase in survival in the eighth edition stage database compared with the seventh edition 10 years earlier.18 It is important to note that the observed prognosis of patients in the eighth edition database is that of the patients who were diagnosed between 1999 and 2010; the relevance to the exact prognosis of patients diagnosed today is highly questionable. Therefore, although the differences in survival across staging parameters should be consistent across patients (i.e., discrimination between groups), the actual 5-year mortality (calibration) is likely quite different than what is listed in Table 3.5, which should be kept in mind when counseling patients. Multiple efforts are underway to “personalize” survival estimates for lung cancer patients and will likely take advantage of both clinical and molecular data in the future.
1. Detterbeck FC, Boffa DJ, Kim AW, Tanoue LT. The eighth edition lung cancer stage classification. Chest. 2017; 151(1):193e203. 2. Rami-Porta R, Bolejack V, Giroux DJ, et al. The IASLC lung cancer staging project: the new database to inform the eighth edition of the TNM classification of lung cancer. J Thorac Oncol. 2014;9(11):1618e1624. 3. Detterbeck FC, Boffa DJ, Tanoue LT. The new lung cancer staging system. Chest. 2009;136(1):260e271. 4. Travis WD, Asamura H, Bankier AA, et al. The IASLC lung cancer staging project: proposals for coding T categories for subsolid nodules and assessment of tumor size in part-solid tumors in the forthcoming eighth edition of the TNM classification of lung cancer. J Thorac Oncol. 2016;11(8):1204e1223. 5. Goldstraw P, Chansky K, Crowley J, et al. The IASLC lung cancer staging project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer. J Thorac Oncol. 2016;11(1):39e51. 6. Detterbeck FC, Bolejack V, Arenberg DA, et al. The IASLC lung cancer staging project: background data and proposals for the classification of lung cancer with separate tumor nodules in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol. 2016;11(5): 681e692. 7. Asamura H, Chansky K, Crowley J, et al. The international association for the study of lung cancer lung cancer staging project: proposals for the revision of the N descriptors in the forthcoming 8th edition of the TNM classification for lung cancer. J Thorac Oncol. 2015;10(12):1675e1684. 8. Eberhardt WEE, Mitchell A, Crowley J, et al. The IASLC lung cancer staging project: proposals for the revision of the M descriptors in the forthcoming eighth edition of the TNM classification of lung cancer. J Thorac Oncol. 2015;10(11): 1515e1522. 9. Rami-Porta R, Bolejack V, Crowley J, et al. The IASLC lung cancer staging project: proposals for the revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol. 2015;10(7): 990e1003. 10. Boffa DJ, Hancock JG, Yao X, et al. Now or later: evaluating the importance of chemotherapy timing in resectable stage III (N2) lung cancer in the National Cancer Database. Ann Thorac Surg. 2015;99(1):200e208. 11. Rusch V, Asamura H, Watanabe H, et al. The IASLC lung cancer staging project: a proposal for a new international lymph node map in the forthcoming 7th edition of the TNM classification for lung cancer. J Thorac Oncol. 2009; 4(5):568e577. 12. Detterbeck FC, Nicholson AG, Franklin WA, et al. The IASLC lung cancer staging project: summary of proposals
CONCLUSION Stage classification is a nomenclature to describe the anatomic extent of a malignant tumor. It is a fundamental tool for communication about the tumor in a specific patient at hand, groups of patients in research studies, observed prognosis of past patients with tumors categorized by a particular stage group(s), and the outcomes of particular treatment approaches in past patients with a particular anatomic extent of disease. The eighth edition stage classification of lung
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for revisions of the classification of lung cancers with multiple pulmonary sites of involvement in the forthcoming eighth edition of the TNM classification. J Thorac Oncol. 2016;11(5):639e650. 13. Fonseca A, Detterbeck FC. How many names for a rose: inconsistent classification of multiple foci of lung cancer due to ambiguous rules. Lung Cancer. 2014; 85(1):7e11. 14. Detterbeck FC, Franklin WA, Nicholson AG, et al. The IASLC lung cancer staging project: background data and proposed criteria to distinguish separate primary lung cancers from metastatic foci in patients with two lung tumors in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol. 2016; 11(5):651e665. 15. Detterbeck FC, Marom EM, Arenberg DA, et al. The IASLC lung cancer staging project: background data and proposals for the application of TNM staging rules to lung cancer presenting as multiple nodules with ground glass
or lepidic features or a pneumonic type of involvement in the forthcoming eighth edition of the TNM classification. J Thorac Oncol. 2016;11(5):666e680. 16. Detterbeck F, Arenberg D, Asamura H, et al. The IASLC lung cancer staging project: background data and proposed criteria to distinguish separate primary lung cancers from metastatic foci in patients with two lung tumors in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol. 2016;11(5):651e665. 17. Boffa DJ, Detterbeck FC, Smith EJ, et al. Should the 7th edition of the lung cancer stage classification system change treatment algorithms in non-small cell lung cancer? J Thorac Oncol. 2010;5(11):1779e1783. 18. Detterbeck FC, Chansky K, Groome P, et al. The IASLC lung cancer staging project: methodology and validation used in the development of proposals for revision of the stage classification of NSCLC in the forthcoming (eighth) edition of the TNM classification of lung cancer. J Thorac Oncol. 2016;11(9):1433e1446.