Reporting lung cancer pathology specimens. Impact of the anticipated 7th Edition TNM Classification based on recommendations of the IASLC Staging Committee

Authors


W D Travis, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. e-mail: travisw@mskcc.org

Abstract

Led by the International Association for the Study of Lung Cancer (IASLC), there are currently several major international collaborative projects underway that will have a significant impact on the future reporting of lung cancer pathology. In particular, the IASLC Staging Committee has just completed an analysis of >100 000 lung cancer cases, providing the basis for proposed revisions of the current TNM staging classification. The purpose of this review is not to provide a comprehensive document on recommendations for specimen processing, but rather to discuss how the anticipated changes in the 7th edition TNM will impact on specimen processing, specifically looking at tumour size, how to deal with multiple tumours and visceral pleural invasion. TNM staging of carcinoid tumours and small cell carcinoma is also discussed.

Abbreviations:
AJCC

American Joint Committee on Cancer

CT

computed tomography

H&E

haematoxylin and eosin

IASLC

International Association for the Study of Lung Cancer

NSCLC

non-small cell lung cancer

SCLC

small cell carcinoma

SEER

Surveillance Epidemiology and End Results

UICC

International Union Against Cancer

VPI

visceral pleural invasion

Introduction

Historically, lung cancer pathology has been a fairly static field. Due to the recognized poor prognosis for lung cancer patients with little improvement over the past few decades in the 10–15% 5-year survival for patients with non-small cell lung cancer (NSCLC), there has been little excitement about lung cancer pathology. Other than the distinction between NSCLC and small cell carcinoma (SCLC), there did not seem to be much point in further histological subtyping of NSCLC, and the staging system seemed quite adequate. This perception has changed dramatically in the past decade with many significant advances and evolution. Led by the International Association for the Study of Lung Cancer (IASLC), there are currently several major efforts underway that will have a significant impact on lung cancer pathology. The IASLC Staging Committee has just completed an analysis of >100 000 lung cancer cases that provides the basis for revision of the current TNM. However, there are also newly developed projects sponsored by the IASLC that include a Prospective Lung Cancer Staging Project and an International Registry of Neuroendocrine Lung Tumours. In addition, a new International Multidisciplinary Classification of Lung Adenocarcinoma project is underway that will lead to major revisions in lung adenocarcinoma classification. This adenocarcinoma project is sponsored by the IASLC, American Thoracic Society and European Respiratory Society.

In 2009 the 7th edn of the International Union Against Cancer (UICC) and American Joint Committee on Cancer (AJCC) TNM Staging system for lung cancer will be published. Although the final UICC and AJCC TNM Staging documents will not be available until the middle of 2009, a series of white papers have been published by the Staging Committee of the IASLC.1–11 These white papers form the basis of the TNM revisions. These revisions will have an impact on the pathologist’s approach to processing of lung cancer specimens for staging purposes. The focus of this review is to highlight the anticipated changes in TNM staging for lung cancer. However, since the final TNM documents are not published, what is written in this review needs to be confirmed after the official publications are available.

A variety of articles have been written on the topic of pathological processing specimens for lung cancer. Protocols are published by the College of American Pathologists,12 Association for the Directors of Anatomic Pathology13 and the Royal College of Pathologists.14 The purpose of this review is not to provide a comprehensive document on recommendations for specimen processing, but rather to discuss how the anticipated changes in the 7th edn TNM will impact on specimen processing.

Tumour size

A significant change in the 7th edn TNM system will be the addition of new size cut-offs at 2, 5 and 7 cm in addition to the traditional one at 3 cm (Table 1).5,8 The tentative proposed staging categories for each size cut-off are summarized in Table 2. Previous studies have proposed that in addition to 3 cm, cut-offs should be added for T1 tumours at 2 cm 15–18 and for T2 tumours at 5 cm,19,20 and 7 cm.21,22

Table 1.   IASLC Staging Committee-proposed TNM descriptor definitions (final TNM document is pending)†
  1. *Most pleural (and pericardial) effusions with lung cancer are due to tumour. In a few patients, however, multiple cytopathological examinations of pleural (pericardia) fluid are negative for tumour, and the fluid is non-bloody and is not an exudate. Where these elements and clinical judgment dictate that the effusion is not related to the tumour, the effusion should be excluded as a staging element and the patient should be classified as T1, T2, T3 or T4.5

  2. †Reproduced with permission from reference.5 This may not be the final version of TNM, which will not be published until 2009. Please refer to 2009 7th edn AJCC or UICC documents for final staging information.

  3. ‡The uncommon superficial spreading tumour of any size with its invasive component limited to the bronchial wall, which may extend proximally to the main bronchus, is also classified as T1a.

T descriptors
 TXPrimary tumour cannot be assessed, or tumour proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy
 T0No evidence of primary tumour
 TisCarcinoma in situ
 T1Tumour ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e. not in the main bronchus)*
 T1aTumour ≤2 cm in greatest dimension
 T1bTumour >2 cm but ≤3 cm in greatest dimension
 T2Tumour >3 cm but ≤7 cm or tumour with any of the following features (T2 tumours with these features are classified T2A if ≤5 cm)
 T2aTumour >3 cm but ≤5 cm in greatest dimension
 T2bTumour >5 cm but ≤7 cm in greatest dimension
 T3Tumour >7 cm or one that directly invades any of the following: chest wall (including superior sulcus tumours), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium, or tumour in the main bronchus <2 cm distal to the carina‡, but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumour nodule(s) in the same lobe
 T4Tumour of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body, carina, separate tumour nodule(s) in a different ipsilateral lobe
N descriptors
 NXRegional lymph nodes cannot be assessed
 N0No regional lymph node metastases
 N1Metastases in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension
 N2Metastasis in ipsilateral mediastinal and/or subcarinal lymph nodes(s)
 N3Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)
M descriptors
 MXDistant metastasis cannot be assessed
 M0No distant metastasis
 M1Distant metastasis
 M1aSeparate tumour nodule(s) in a contralateral lobe; tumour with pleural nodules or malignant pleural (or pericardial) effusion*
 M1bDistant metastases
Table 2.   IASLC Staging Committee-proposed stage groupings according to T, N and M categories*
6th edn
T/M descriptor
Proposed T/MN0N1N2N3
  1. *Reproduced with permission from reference.5 This may not be the final version of TNM, which will not be published until 2009. Please refer to 2009 7th edn AJCC or UICC documents for final staging information. Changes in bold represent changes from the 6th edition TNM staging classification for specific categories.

T1 (≤2 cm)T1aIAIIAIIIAIIIB
T1(>2–3 cm)T1bIAIIAIIIAIIIB
T2 (≤5 cm)T2aIBIIAIIIAIIIB
T2 (>5–7 cm)T2bIIAIIBIIIAIIIB
T2 (>7 cm)T3IIBIIIAIIIAIIIB
T3 invasion IIBIIIAIIIAIIIB
T4 (same lobe nodules) IIBIIIAIIIAIIIB
T4 (extension)T4IIIAIIIAIIIBIIIB
M1 IIIAIIIAIIIBIIIB
T4 (pleural effusion)M1aIVIVIVIV
M1 (contralateral lung) IVIVIVIV
M1 (distant)M1bIVIVIVIV

Another issue regarding tumour size is whether it should be measured in a fixed or unfixed specimen. According to the UICC and AJCC, tumour size for pT should be recorded from the unfixed tumour specimen.23 This recommendation is supported by a recent paper by Hsu et al. that showed that after formalin fixation, 20% of tumours >3 cm shrank by an average of >1 cm.24 Although this could result in tumours being down staged from T2 to T1, patients with these tumours had a similar 5-year survival to the remaining group of patients with tumours >3 cm that did not shrink.24

Multiple tumours

When lung cancer presents with multiple tumour nodules in the lungs it presents a difficult challenge. First the pathologist must identify the tumours and describe them accurately. Second, the gross or microscopic location of the various tumours in relationship to each other, and in particular the distance from the dominant lesion, needs to be described. Third, the tumours need to be evaluated histologically to determine whether they have similar or different histological features. Finally, a summary statement needs to be made after evaluation of the entire case to determine whether the tumours represent synchronous primaries or intrapulmonary metastases. This will influence how the patient is staged.

One issue is the method by which the multiple tumours are identified. This can happen by radiological methods such as computed tomography (CT), by the surgeon at the time of operation or by the pathologist either grossly or microscopically. When a surgeon is aware that a lung specimen has multiple tumours, it is useful to communicate this information to the pathologist so they can give appropriate attention to each lesion. Pathologists should record the nodule number, size and the relative distance between the lesions, and in particular the distance from the dominant lesion, as well as the relationship to the pleura and bronchial margin. When a pathologist encounters multiple lesions, it may be useful to speak with the surgeon or to review CTs to correlate the pathology with the clinical and/or radiological findings. Because the lung tissue is collapsed in a resected specimen, sometimes pathologists have more difficulty than radiologists or surgeons in identifying small tumours, particularly adenocarcinomas with a predominant component of bronchioloalveolar carcinoma.

Rule no. 5 of the TNM states that when there are ‘multiple simultaneous tumors in a single organ, that the overall stage for the patient should be based on the tumor with the highest T category’.23 This applies to multiple tumours of different histological type. In addition, they recommend that parentheses should be used, i.e. T3(m) or T3(4) to indicate the multiplicity or the number of tumours.23,25 If there are synchronous separate primaries, each tumour should be classified independently. UICC defines a synchronous primary cancer if the second new primary cancer is diagnosed within 2 months of the initial primary cancer.23 This follows criteria set by the National Cancer Institute Surveillance Epidemiology and End Results (SEER) programme.

In the 6th Edition Staging system, multiple same-lobe nodules of similar histology are classified as T4, resulting in designation as Stage IIIB.26,27 In addition, multiple different lobe nodules are regarded as M1 regardless of whether they are ipsilateral or contralateral, resulting in designation as Stage IV. Several studies have indicated that the survival for patients with T4 or M1 status, according to multiple nodules alone, was significantly better than for patients who qualify for one of these stage groupings based on other T or M factors.28,29 The analysis by the IASLC staging committee of data both from the IASLC and the SEER datasets indicated that it is more appropriate to regard separate same-lobe nodules5,8 as T3; separate tumour nodules in a different ipsilateral lobe as T4 and separate tumour nodule(s) in a contralateral lobe as M1a.5,8 These recommendations are summarized in Table 3.

Table 3.   IASLC Staging Committee recommendations for multiple synchronous tumours of similar histology: changes in T and M classification in 7th edn
Location6th edn7th edn
Same lobeT4T3
Ipsilateral different lobeM1T4
Contralateral lungM1M1a

As regards multiple synchronous tumours, there is a discrepancy in the 6th edns between the UICC and AJCC documents. According to the UICC, General Rule No. 5 applies only to ‘grossly recognizable multiple primary simultaneous carcinomas’ and does not apply to multiple separate microscopic foci accompanying a single grossly detected tumour.23 In contrast, the AJCC states that ‘satellite nodules’ defined as additional small tumour nodules in the same lobe as the primary tumour are classified as T4.27 These nodules are in the same lobe as the primary tumour but are anatomically distinct from it. The term satellite nodule refers to tumour nodules identified by imaging studies such as CT or by gross findings at thoracotomy, but not to such nodules detected solely on pathological examination of a resection specimen. Therefore the UICC will accept tumours grossly recognized by a pathologist in addition to at thoracotomy, whereas AJCC will only recognize nodules found by CT or the surgeon. It is to be hoped this discrepancy will be resolved in the 7th edns.

The pathological assessment of multiple tumours to determine whether they are the same or different is a complicated issue. The primary approach is by light microscopy to compare the histological appearance of each tumour. If a tumour is squamous cell, small cell or large cell carcinoma, there is often a relatively uniform histological appearance. If it is an adenocarcinoma, a more detailed approach is needed because of the great amount of histological heterogeneity that occurs. It is not sufficient to regard all adenocarcinomas as being of similar histology. Recently, we proposed a modification of the World Health Organization subclassification of lung adenocarcinoma so that mixed subtype adenocarcinomas are given an estimated percentage for each of the individual subtypes present. This is a useful way to document whether multiple lung adenocarcinomas are morphologically similar or different.30 In the future, molecular tools may be helpful in sorting out this problem, but at the present time there is no definitive molecular assay to be certain if a tumour is a separate primary or a metastasis.

Pleural invasion

Evaluation of the lung cancer gross specimens for visceral pleural invasion (VPI) requires careful assessment of the relationship of the tumour to the overlying pleura. Microscopic assessment is dependent on appropriate histological sections being taken from the area deemed most likely to show invasion. The 7th edn UICC and AJCC has made some new recommendations for evaluation of VPI. According to the current 6th edn, even if a tumour is <30 mm in size, VPI will increase the T staging factor from T1 to T2, resulting in upstaging of a tumour from Stage IA to IB.26,27 However, neither the UICC nor the AJCC provided a precise definition of VPI and neither mentions the elastic layer of the visceral pleura. The UICC TNM Supplement 3rd edn makes reference to ‘invasion of the lamina propria serosae’,31 but does not define this and makes no reference to the elastic layer of the visceral pleura. The elastic layer of the visceral pleura is not specifically mentioned in either the UICC or AJCC documents. The proposal for the 7th edn UICC and AJCC lung cancer staging system recommends a slightly modified version of the Hammar classification of pleural invasion that includes the use of elastic stains (Table 4).32,33

Table 4.   Classification of visceral pleural invasion (VPI)*
  1. *From reference.2

Proposed modification of Hammar Classification of VPI
 PL0Tumour located within the lung parenchyma or only superficially invading in the pleural connective tissue, but not beyond the elastic layer of the visceral pleura
 PL1Tumour invades into the visceral pleura beyond the elastic layer
 PL2Tumour invades to visceral pleural surface
 PL3Tumour invades into the parietal pleura or the chest wall
Correlation between PL and T status
 T1 = PL0
 T2 = PL1 or PL2
 T3 = PL3

Whereas many studies report data on VPI, only a small number use elastic stains and the Hammar or the Japanese Lung Cancer Society classification. Each of these studies has shown prognostic significance for the various levels of VPI in NSCLC.34–38 Three studies demonstrated VPI had significance for survival on multivariate analysis.34–36,38 Earlier studies have suggested VPI had no prognostic significance in small, early-stage NSCLC, but these studies used neither elastic stains nor a classification like that proposed by Hammar.15,39 Ou et al. suggested that VPI carries an increased risk of mortality but that this may depend on tumour size.40 However, since their data were from the California SEER registry data, they could not discriminate between the T factors of VPI, hilar atelectasis or obstructive pneumonitis.40 The proposed prospective IASLC staging database will be required to resolve the relative importance of the various T factors including VPI.

In 1991, Gephardt et al. made a survey of lung cancer surgical pathology reports under the auspices of the College of American Pathologists and found that VPI was addressed in only 65% of cases.41 Although recording of the presence or absence of VPI has probably improved since that time, there are still some lung cancer pathology reports that do not have this information, and many pathologists do not perform elastic stains. Elastic stains are not established as a requirement for assessing in cases where the presence of VPI is indeterminate by examination of haematoxylin and eosin (H&E) sections. Taube et al. recently collected data from members of the American Association of Directors of Anatomic and Surgical Pathology and found that 51% never use elastic stains, 29% use them sometimes and 20% use them routinely.42 Using elastic stains to evaluate 100 NSCLC < 30 mm in size, Taube found VPI in 19% of specimens where VPI failed to be detected on review of only H&E stains.42 This resulted in upstaging of these tumours from Stage IA to Stage IB. With a web-based questionnaire to assess VPI in a set of photomicrographs of the pleura with elastic stains in lung cancer specimens, Butnor et al. found a ‘fair’κ statistic for interobserver agreement with a value of 0.35.43 Most of the survey participants thought that invasion of the elastic layer was necessary for VPI.

The IASLC Staging Committee is recommending that the 7th edn TNM Staging system define VPI as invasion beyond the elastic layer (Table 4).2 This is based on a slight modification of a previous diagram of the pleura proposed by Hammar for classification of VPI.33 A number of publications have validated this proposal.34–38,44 In this classification proposal, tumours that are situated within the subpleural lung parenchyma or that invade superficially into the connective tissue of the pleura without crossing the elastic layer are classified as PL0. A PL1 designation is given if a tumour invades beyond the elastic layer. PL2 is applied if the tumour invades to the visceral pleural surface. Tumours that invade into the parietal pleura are classified as PL3. Tumours that are PL0 should have the T category be assigned based on other features. PL1 or PL2 are regarded as VPI and correspond to T2 descriptors. PL3 indicates invasion of the parietal pleura and corresponds to T3 status. The Px category in the Hammar classification is not included in the new proposal. The only appropriate use for the ‘x’ category is PLx, where the PL category is unknown. A tumour is classified as T2a if it reaches T2 status based on VPI and it is ≤5 cm in size. A tumour is classified as T2b if it is >5 cm but ≤7 cm in size. A T3 designation is given if a tumour is >7 cm.

In cases where the presence of pleural invasion is indeterminate based on evaluation of H&E-stained slides. The 7th edn TNM will recommend elastic stains be used. However, it is not necessary to perform an elastic stain in every lung cancer specimen. In some cases VPI is clearly present based on review of H&E-stained sections and sometimes, by lowering the microscopic condenser, the elastic layer can be seen on H&E. Nevertheless, in a substantial percentage of cases the elastic layer is completely imperceptible on H&E (Figure 1) and only visualized with elastic stains (Figure 2). In order to classify a tumour as PL1, it needs to have invaded beyond this thick elastic layer. The thick elastic layer within the visceral pleura is the one that should be invaded. There is some variation in the anatomy of the elastic layers of the visceral pleura, so it may be situated near the lung parenchyma, near the surface of the pleura or in the middle. In some cases there is a perceptible connective tissue layer between the lung parenchyma and the thick elastic layer; invasion of this connective tissue that falls short of traversing the elastic layer is regarded as PL0. A tumour remains classified as PL0 if tumour cells intermingle with elastic fibres without penetration beyond the elastic layer. In some cases elastic stains are difficult to interpret due to pleural inflammation and/or fibrosis that result in alteration of the elastic layers, often with reduplication. In difficult cases where the visceral pleura elastic layer is not clearly discernable or there is prominent reduplication of the elastic fibres, one has to apply General Rule 4 of the TNM classification and assign the lower category in such circumstances.25

Figure 1.

 The visceral pleura appears to be intact without invasion by the underlying adenocarcinoma on H&E examination. There is fibrous thickening of the pleural surface without any apparent upward growth of tumour into it.

Figure 2.

 The elastic stain demonstrates that there is extensive invasion by tumour beyond the elastic layer. What cannot be appreciated on the H&E in Figure 1 is that tumour has not only invaded the pleura, but has caused invagination of the elastic layer beneath the pleural surface.

Occasionally, a tumour will invade across the interlobar fissure, and the 6th edn UICC TNM classification states ‘a tumour with local invasion of another ipsilateral lobe without tumour on the visceral pleural surface should be classified as T2’.31 This is another topic that has little data to provide clear guidance, and the data have resulted in conflicting recommendations (T2 or T3).45–47

Ipsilateral parietal and/or visceral pleural nodules of tumour that are discontinuous from the main tumour are classified as T4.48 In addition, if tumour involves the parietal pericardium by direct extension it is regarded as T3, but if it involves the visceral pericardium, it is T4.

M factor

On behalf of the IASLC Staging Committee, Postmus et al. recommended that the M1 category be divided into two groups. Distant metastases outside the lung and/or pleura would be classified as M1b. M1a would consist of (i) separate tumour nodule(s) in a contralateral lobe; (ii) tumour with pleural nodules; or (iii) malignant pleural or pericardial effusion.7 The changes between UICC/AJCC 6th and 7th edns are summarized in Table 5.

Table 5.   IASLC Staging Committee recommendations for reclassification of M status
M factor characteristics6th edn7th edn
Malignant pleural or pericardial effusion, pleural nodulesT4M1a
Contralateral lung additional nodules of similar histologyM1M1a
Distant metastasesM1M1b

Benign pleural or pericardial effusions that do not have malignant cells by multiple cytopathological examinations are regarded as not being related to the tumour and are excluded from impacting on stage. These cases are not classified as M1 and are given the appropriate T classification according to the T factor status of the tumour. This is maintained from the 6th edn AJCC/UICC staging system. However, if a pleural or pericardial effusion is documented to have malignant cells, it would be classified as M1a rather than T4, as in the 6th edn.7

Carcinoid tumours

The TNM staging classification has traditionally not been applied to carcinoid tumours. In the 2003 TNM Supplement, the UICC say that TNM staging ‘applies to all types of carcinoma including small cell carcinoma; however it does not apply to carcinoids’.48 Nevertheless, the TNM staging classification has been demonstrated to be useful in numerous publications on typical and atypical carcinoids.26,49–56 For this reason, in the 7th edn, the IASLC Staging Committee has recommended that the TNM be applied to pulmonary carcinoid tumours.2

This analysis was based on 1437 surgically managed pulmonary carcinoids in the National Cancer Institute SEER registry and 513 carcinoids incidentally submitted to the IASLC Lung Cancer Staging Database.2 In this study, we found that all T, N and M categories as defined by the IASLC proposal for the 7th edn of the NSCLC TNM staging system are generally useful for staging of bronchopulmonary carcinoid tumours. Our study showed the combined stage groupings (I versus II versus III/IV) had significant differences in survival, but the subcategories of the stage groupings (IA versus IB and IIA versus IIB) did not. Our analysis revealed two major issues for future clarification, including carcinoids presenting with multiple nodules and the question if the new proposed size cut-offs of 5 and 7 cm are meaningful in carcinoids. The paucity of deaths we observed in patients with multiple carcinoids probably reflects the indolent behaviour of patients with diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. In addition, the relatively small tumour size of pulmonary carcinoids compared with NSCLC suggests it may be difficult to find sufficient cases to perform a rigorous analysis of the impact of size >5 or 7 cm in pulmonary carcinoid tumours. Two major projects are in place that, it is hoped, will address this by the time of preparation of the 8th edn TNM Staging system. One includes the prospective IASLC Staging database and the second is the establishment of an International Registry of Pulmonary Neuroendocrine Tumours.

Small cell carcinoma

The UICC has historically stated that TNM is applicable to all types of carcinoma, including SCLC.57 However, the Veterans Administration Lung Study Group and IASLC systems of ‘limited’ and ‘extensive’ disease are often used.58 Therefore the TNM system is sometimes not considered in the diagnosis and management of SCLC. The IASLC staging committee, led by Shepherd et al., made a comprehensive review of 12 620 SCLCs in the IASLC staging database and recently published data that further support the use of TNM staging for SCLC.10

Acknowledgements

The author would like to acknowledge Professor Peter Goldstraw for his insightful comments and his leadership of the IASLC Staging Project. Gratitude is also extended to all the members of the IASLC Staging Committee and Dr Leslie Sobin for his valuable input.

Ancillary