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New TNM Classification for Lung Cancer. Part II: A review

Dr. Alberto De la Guerra

Dr. Alberto De la Guerra's avatar

Published online: February 07, 2010

Disclosures of potential conflicts of interest and author contributions are found at the end of this article.

BACKGROUND: The American Joint Committee on Cancer and the Union Internationale Contre le Cancer have redefined the criteria for staging lung cancer based on the proposals made by the International Association for the Study of Lung Cancer, which appeared in the recently launched 7th edition of the TNM system. This article evaluates those changes and reviews the literature with particular attention to background information on the areas of controversy. As well, we examine the latest reports appraising the new staging system.

Introduction

The objective of this article is to review the changes in the lung cancer TNM staging system derived from the work of the IASLC. The changes included in the 7th edition of the TNM were based on the largest retrospective database ever accrued for the study of lung cancer. Moreover, for the first time the proposed revisions were internally and externally validated (1).

Because the LCSP database was not purposely designed to study the staging system, some TNM descriptors were not evaluated either because of insufficient number of cases or lack of validation. The following sections in this article discuss the major changes to the ISS of lung cancer and evaluates recent reports validating the new TNM system.

Anatomic extent of the primary tumor (T)

In the AJCC Cancer Staging Manual and UICC TNM Classification of Malignant Tumors the T factor is divided into four descriptors (T1-4) depending on size, site, number, and local extent of the primary tumor: the size and non-size based descriptors.

Size-based T descriptors.

The value of tumor size in NSCLC prognosis is supported by large clinical evidence (2-6). The tumor size threshold of 3 cms was set-up on the 2nd edition of the TNM classification of malignant tumors in 1974 (7), and despite the advances in surgical procedures, adjuvant treatment, and mostly in imaging technology, this measure has remained unchanged for 35 years. Several reports have stressed the need to adopt new cutoff points to subclassify and reclassify the T component to improve its prognostic relevance (8-17).

The 7th edition of the TNM for lung cancer confers more importance to the size-based T descriptors and divides them as exposed earlier in this article. These modifications have been validated by recent studies that showed better survival stratification and prognosis estimation with the new T definitions (18-20).

Two earlier publications that evaluated large databases concluded that tumor size is an independent and major prognostic factor for survival in NSCLC (21, 22), and recent reports using the new TNM system support those conclusions (23,24). Benefits of the modifications are illustrated on table 6a: survival rates exhibit stepwise deterioration as the T factor increases (24, 25); survival rates are improved with the new system due to reclassification (up- and downstaging) of patients when compared to series reporting survival rates with the previous TNM, showed in table 6b (26, 27).

Table 6a. Five year survival by pT classification with the 7th edition.

T component

5-year survival  (%)

 

Kameyama et al (25)

Li et al (24)

T1a

82.6

75.49

T1b

73.3

74.58

T2a

63.5

60.87

T2b

50.1

55.63

T3

40.6

46.15

T4

34.6

NS

NS, not shown.

Table 6b. Five year survival by pT classification with the 6th edition.

T component

5-year survival  (%)

 

Mountain CF (26)

Naruke et al (27)

T1

67

68.9

T2

57

42.5

T3

38

31.9

T4

7 (cT)

18.9

Non–size-based T descriptors.

Pleural dissemination and pericardial effusion.

According to the TNM staging manual, pleural dissemination means the presence of ipsilateral malignant pleural effusion (MPE) or pleural nodules (28). Even so, some authors use the term as a synonym for pleural nodules. Pleural nodules are defined as pleural tumor foci separated from direct pleural invasion by the primary tumor, classified as T4 (28). These pleural tumors must be differentiated from direct tumor invasion to the visceral (T2) or parietal pleura (T3).

In TNM staging, either pleural fluid cytology or clinical judgment are valid to establish the diagnosis of a MPE and consider it as a T4 factor (26). Malignant pericardial effusions are classified according to the same rules. Pleural dissemination and pericardial effusion are T4 descriptors, grouped into stage IIIB in absence of distant metastasis.

The diagnosis of a MPE is a sign of advanced disease, and almost every cancer can involve the pleura (29, 30). However, NSCLC is the most common cause of MPE and entails the worst prognosis (31-33); only a few patients survive beyond 12 months (tables 7a and 7b). Ipsilateral MPE is a locally advanced disease that precludes surgical treatment in lung cancer (34-36). Unlike other malignant effusions, those caused by NSCLC have low sensitive to chemo- and radiotherapy (37-39); therefore patients are considered mainly for palliative therapy (40-43). In a similar way, NSCLC is the most frequent cause of malignant pericardial effusion, which has a grim prognosis too (44-46).

Table 7a. Median survival time for stage IIIB, with and without pleural effusion, and for stage IV disease.

Stage

MST (months)

Sugiura et al (39)

Mott et al (48)

IIIB without PE

15.3

12

IIIB with PE

7.5

2

IV

5.5

4

MST= Median survival time; PE= pleural effusion.

Table 7b. Postoperative survival of patients with different pathologic T4 categories (*).

pT4 Categories

5-year survival  (%)

Osaki et al (36)

Kameyama et al (49)

Satellite nodule (same lobe)

26.7

57.4

Mediastinal invasion

18.2

13.4

Pleural dissemination

0

5.0

(*) Data adapted from references 36 and 49.

The ISC proposal to reclassify pleural dissemination from T4 to the new descriptor M1a is the most anticipated change in the new TNM system after the magnitude of evidence demonstrating that survival rates of patients with stage IIIB due to MPE are no different from those with stage IV disease (35, 36, 39, 47-50). Survival rates are shown in table 8.

Table 8. Postoperative survival rates of NSCLC with malignant pleural effusion (MPE): no significant difference with stage IV disease (*).

Status at thoracotomy

5-year survival  (%)

No pleural effusion

45.4

Non-MPE

42.5

MPE

15.9

Pathologic stage IV

11.2

(*) Data from Naruke et al (35).

The analysis made by the ISC showed that patients with cT4 due to pleural dissemination had a 5-year survival rate of 2% (51, 52). Recent studies corroborated these findings, validating the upstaging of cases with MPE from the T4 descriptor to the new M1a descriptor (53, 54).

Multiple nodules.

The existence of multiple primary cancers (MPC) was initially reported by Warren and Gates in 1932 (55); though, to date accurate diagnosis of MPC is not easy due to a lack of consensus on definition and diagnostic criteria (56). Thanks to advancement in diagnostic modalities the incidence of clinically detected multiple primary lung cancers (MPLCs) has increased (57-59).

In 1975, Martini and Melamed were the first to propose clinical and histopathologic criteria for the differential diagnosis of second lung cancers (60). MPLCs may be synchronous, if detected simultaneously, or metachronous, if tumors are separated in time (61, 62). It is beyond the intention of this article to discuss second lung cancers but rather to discriminate between synchronous nodules for staging purposes.

Synchronous nodules may represent a MPLC (second primary), a metastasis, or an extension from the primary (satellite nodule) (63). Table 9 shows the most accepted definitions of second lung cancers.

In 1989, Deslauriers et al. described intrapulmonary metastasis in patients with NSCLC as satellite nodules, and defined them as “well-circumscribed accessory carcinoma foci clearly separated from the main tumor but with identical histologic characteristics” (64). The 5- year survival rates for patients with satellite nodules were 21.6% compared to 44% for patients without satellite nodules. They concluded that patients with satellite nodules should be classified as stage IIIA.

Table 9. Definitions of second primary, satellite nodules and metastasis (*).

Type

 Definition

Satellite nodule

Same histology

And same lobe as primary cancer

And no systemic metastasis

MPLCs

Same histology, anatomically separated

Tumors in different lobes

And no N2-3 involvement

And no systemic metastasis

Same histology, temporally separated

 =4-yr interval between tumors

And no systemic metastasis from either tumor

Different histology

Or different molecular genetic features

Or arising separately from foci of CIS

Metastasis

Same histology

With multiple systemic metastasis

Same histology, in different lobes

 And presence of N2-3 involvement

Or < 2-yr interval

(*) Data adapted from references 60 and 63.

The concept of satellite nodules was not considered in NSCLC staging system until 1992 by the AJCC and in 1993 by the UICC (65, 66). Prior to this, all nodules were designated M1 disease. The evolution of satellite nodule descriptors is shown in table 10.

Table 10. Evolution of satellite nodule staging in the TNM system (*).

Location

TNM descriptor

4th edn

4th edn supplement

5th - 6th edn

7th edn

Ipsilateral same lobe

M1

T increases by one level

T4

T3

Ipsilateral different lobe

M1

T4

M1

T4

Contralateral lung

M1

M1

M1

M1

(*) Data adapted from references 65 and 66.

The T4 descriptor includes diverse tumors with dissimilar prognosis: invasion of the mediastinum, heart, great vessels, trachea, esophagus, vertebral body, and carina; tumor with a malignant pleural or pericardial effusion, or with satellite tumor nodule(s) within the ipsilateral primary-tumor lobe of the lung (26).

The IASLC lung cancer staging project committee has acknowledged the multiple reports showing better survival for primary tumors with satellite nodules than other T4 tumors (66-75) and has downstaged them accordingly (51, 76). Outcomes of resected lung cancers with satellite nodules are shown in table 7b and table 11.

Table 11. Survival rates of patients with satellite nodules (SN) in various series.

Study (reference)

5-year survival  (%)

SN same lobe

SN different lobe

Any pT4

Rao et al (66)

57

NR (*)

18

Okada et al (70)

29.6

23.4

NS

Oliaro et al (68)

35

33

18

Nagai et al (71)

26.8

22.5

17.6

Strand et al (2)

30

22.9

8

Lee et al (72)

30.3

30.7

16.2

Okumura et al (73)

34

11

34

(*) NR = not reported.

Later studies found that the new T descriptor for satellite nodules proposed by the IASLC reflects better the outcomes of that group of patients, which showed superior survival rates (53, 54, 77). Even though there is a need of prospective trials to validate this finding, now these patients will be considered for surgery (78, 79).

Involvement of regional lymph node (N)

Analysis from the international database of the IASLC showed that current N descriptors provide good survival stratification, and therefore considered appropriate to maintain them without modifications (80). Lung cancer survival rates by pathologic N factor are shown in table 12; note the similarity on survival.

Table 12. Lung cancer survival rates by pathologic N factor. Comparison between 6th and 7th editions of the TNM system.

N factor

5-year survival (%)

6th edition (*)

7th edition (**)

pN0

63.1

56

pN1

42.1

38

pN2

17.4

22

pN3

2.3

6

(*) Data from Naruke et al (35)

(**) Data from Rusch et al (80).

Proposals to subdivide the N factor into 4 zones according to the extent of involvement of regional lymph nodes will not be part of TNM changes in the 7th edition. Although, recent reports showed that the IASLC recommendation to group patients according to nodal zones are appropriate and provide excellent survival stratification (53, 81).

Presence or absence of distant metastases (M)

The analysis of the M component made by the IASLC showed similar 5-year survival for pleural dissemination (6%) and contralateral lung nodules (3%), but worse outcome for distant metastasis (1%). Therefore, the ISC recommended dividing the M factor into M1a and M1b, to differentiate intrathoracic from distant metastasis (52); see table 13. Recent studies found the same differences in survival among these new M categories, validating the proposed changes (53, 54, 82).

A major change in the M component is the elimination of the codes MX and pM0 (except at autopsy). This proposal was not made by the IASLC, but by the AJCC/UICC members. In absence of clinical or pathologic evidence of metastasis, cases should be classified as clinical M0 (cM0). Also, since pathologists normally do not have information about metastasis, the M factor will not appear in pathology staging templates on the 7th edition (83).

Table 13. Survival of M1 subgroups with the new TNM system (*).

M descriptor

Median Overall Survival (months)

5-yr survival (%)

Pleural Dissemination (M1a)

4

2

Contralateral nodule (M1a)

6

4

Distant metastasis (M1b)

3

1

(*) Data adapted from Groome et al (1).

Anatomic stage (Stage grouping)

Lung cancers with similar prognosis are grouped based on the assigned T, N, and M categories. Stage groups are also termed prognostic groups due to correspondence of increasing values with worse prognosis (from stage 0 to stage IV); staging is not relevant for occult carcinoma TXN0M0 (26).

The ISC has not added new subdivisions to the stage grouping (76), but changes to the T and M descriptors led to modifications in TNM subsets and consequently in stage groups, as previously described in this article.

Now staging is less intuitive than before since the designation of groups is more complex due to the new T and M descriptors, but better reflects the differences in prognosis among stages (84). Five-year survival rates according to clinical and pathologic stages between the forthcoming and the current TNM system are shown in table 14.

Table 14. Lung cancer survival rates by clinical and pathologic stages.

Stage

5-year survival  (%)

6th edition (*)

7th edition (**)

cStage

pStage

cStage

pStage

IA

61

67

50

73

IB

38

57

43

58

IIA

34

55

36

46

IIB

24

39

25

36

IIIA

13

23

19

24

IIIB

5

NR

7

9

IV

1

NR

2

13

NR = not reported

(*)  Data adapted from Mountain (26).

(**) Data adapted from Goldstraw et al (76).

The applicability and validity of the new prognostic groups has been confirmed by recent studies (19, 20, 24, 82, 85, 86); their results showed that the new TNM is superior to the current system in predicting prognosis of each stage.

Other changes

Visceral Pleural Invasion (VPI)

The definition of VPI in the existing AJCC-UICC staging documents lacks precision (87-92). As described elsewhere in this article, the IASLC has proposed a new classification of pleural invasion based on Hammar’s classification, which incorporates the use of elastic stains when H&E sections are inconclusive (93).

The IASLC was unable to carry out an analysis of data regarding this topic since there was incomplete pathologic information about VPI, thus the proposal was not validated. However, on behalf of the IASLC Staging Committee, Travis et al. (93) stated that “the goal is to define pleural invasion in a manner that will allow for accurate collection of data regarding this important T factor for future analysis in a prospective database” (page 1386). Meanwhile they advocate keeping the present TNM that classifies a tumor with VPI as T2.

However, the applicability of the new classification for VPI is supported by recent publications (94-96); survival analysis confirmed that VPI defined by the IASLC as tumor extension beyond the elastic layer is valid (see definitions on table 4). Two of these studies also suggested that VPI has impact on survival dependant on tumor size (94, 95). We should wait for larger prospective studies to confirm those findings.

SCLC.

The AJCC-UICC staging system applies to all types of carcinoma (97), but is seldom used for staging SCLC because reliability of the TNM system traditionally hinged on surgery, and less than 5% of patients with SCLC are candidates for operation (98). Thus, SCLC is classified with either the Veterans’ Administration Lung Study Group (VALSG) or the IASLC binary schemes, into limited (LD) and extensive disease (ED); LD corresponds with TNM stages I to IIIB, and ED is equivalent to stage IV (99).

For many decades both two-stage systems had been used interchangeably for SCLC, albeit their staging criteria differ (table 15). Consequently, treatment outcomes may be dissimilar depending on the staging system selected (100, 101). Another problem shows up when we need to compare surgical and medical series staged with different systems: the two-stage scheme employed by oncologists and radiotherapists, and the TNM classification used by surgeons (102, 103). Some authors state that staging SCLC with the TNM system will allow comparing results from surgery with those from chemo and radiotherapy (104-106).

Table 15. SCLC staging systems.

Stage

Staging system (reference)

VALSG (107)

IASLC (99)

LD

Primary tumor and nodal involvement limited to one hemithorax, including ipsilateral supraclavicular lymph nodes. Disease can be encompassed in a single radiation port.

In addition, contralateral mediastinal and  supraclavicular lymph nodes, and ipsilateral pleural effusion. No distant metastasis.

ED

Tumor outside the limits of a single radiation port, including malignant pleural or pericardial effusion and contralateral supraclavicular or cervical lymph nodes.

Any distant metastasis.

LD: limited disease; ED: extensive disease.

Almost 30 years ago, Shields and associates (108) showed the importance of TNM staging in SCLC. Since then, several authors confirmed the prognostic value of the TNM system in this type of tumors (109-117); table 16 shows survival rates of SCLC in different TNM stages.

Table 16. 5-year survival rates for patients with SCLC by pTNM stages.

Study (reference)

Pathologic stage (%)

I

II

III

Rea et al (109)

52.2

30

15.3

Shah et al (118)

57.1

0

55.5

Tsuchiya et al (119)

66

56

13 (IIIA)

Lucchi et al (106)

47.7

14.6

9

Brock et al (103)

58

18

23

Inoue et al (110)

56.1 (IA) - 30 (IB)

57.1 (IIA) - 42.9 (IIB)

--

After a thorough review and survival analysis of 12,620 cases of SCLC from their international database, the IASLC recommended the use of the TNM system for this type of cancer (120); results are shown in table 17.

Table 17. Survival for clinical TNM stage SCLC from the IASLC database (120).

Stage

5-year survival  (%) MST (months)

IA

36

31

IB

31

35

IIA

53

68

IIB

16

17

IIIA

11

13

IIIB

10

12

IV

2

8

MST= Median survival time

Further assessment of the IASLC database confirmed that TNM pathologic staging correlates with survival of resected SCLC, supporting the proposal to use the TNM system for all SCLC cases (121). The applicability of the proposal has been recently validated by Ignatius Ou et al (122): reclassification of 10,660 SCLC patients from the California Cancer Registry according to the new TNM showed improved prognostic significance.

Carcinoid Tumors.

In general, the TNM system is not used to stage carcinoid tumors. However, many authors applied the TNM for carcinoid tumors of the lung and demonstrated its prognostic value (123-127).

The 7th edition of the TNM introduces a new TNM classification: Neuroendocrine Tumors, including pulmonary carcinoids that must be staged as carcinomas. The TNM for neuroendocrine tumors of the lung was introduced following the IASLC proposals (128).

Because the AJCC-UICC staging system was not recommended before for staging carcinoid tumors, there was little information available in the IASLC database to analyze all the TNM descriptors, thus further documentation of these tumors, using the new classification, will allow a more detailed evaluation of prognostic factors.

CONCLUSIONS

Changes included in the 7th edition of the TNM are the result of an analysis of the largest number of lung cancer cases ever accumulated, and comprise the largest validation ever done so far. However, data was not collected purposely to study the lung cancer staging system, which resulted in incomplete information, with the result that many descriptors were not revised (129). This does not reduce the value of the new revision, which remains the best data review so far and is seen as a large step in the right direction.

To overcome the drawbacks of their retrospective project, the IASLC has launched a prospective project to improve upcoming editions of the staging system for lung cancer (130).

As exposed before, recent reports showed the feasibility and superiority of the new system, though we need larger prospective data to validate it.

Conflict of interest statement

No financial conflicts or disclosures to report.

CITE THIS ARTICLE:
Dr. Alberto De la Guerra. New TNM Classification for Lung Cancer. Part II: A review. Doctors Lounge. Available at: https://www.doctorslounge.com/index.php/articles/page/342. Accessed November 22 2017.

References

1. Groome PA, Bolejack V, Crowley JJ, Kennedy C, Krasnik M, Sobin LH, Goldstraw P; IASLC International Staging Committee; Cancer Research and Biostatistics; Observers to the Committee; Participating Institutions. The IASLC Lung Cancer Staging Project: validation of the proposals for revision of the T, N, and M descriptors and consequent stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol 2007; 2 (8): 694-705.

2. Strand TE, Rostad H, Møller B, Norstein J. Survival after resection for primary lung cancer: a population based study of 3211 resected patients. Thorax 2006; 61 (8): 710-715.

3. Suzuki K, Nagai K, Yoshida J, Nishimura M, Takahashi K, Yokose T, Nishiwaki Y. Conventional clinicopathologic prognostic factors in surgically resected nonsmall cell lung carcinoma. A comparison of prognostic factors for each pathologic TNM stage based on multivariate analyses. Cancer 1999; 86 (10): 1976-1984.

4. van Rens MT, de la Rivière AB, Elbers HR, van Den Bosch JM. Prognostic assessment of 2,361 patients who underwent pulmonary resection for non-small cell lung cancer, stage I, II, and IIIA. Chest 2000; 117 (2): 374-379.

5. Hung JJ, Hsu WH, Hsieh CC, Huang BS, Huang MH, Liu JS, Wu YC. Post-recurrence survival in completely resected stage I non-small cell lung cancer with local recurrence. Thorax 2009; 64 (3): 192-196.

6. Casali C, Storelli E, Morandi U. The prognostic impact of tumor size in resected stage I non-small cell lung cancer: evidence for a two thresholds tumor diameters classification. Lung Cancer 2006; 54 (2): 185-191.

7. Mountain CF, Carr DT, Anderson WA. A system for the clinical staging of lung cancer. Am J Roentgenol Radium Ther Nucl Med 1974; 120 (1): 130-138.

8. López-Encuentra A, Duque-Medina JL, Rami-Porta R, de la Cámara AG, Ferrando P; Bronchogenic Carcinoma Co-operative Group of the Spanish Society of Pneumology and Thoracic Surgery. Staging in lung cancer: is 3 cm a prognostic threshold in pathologic stage I non-small cell lung cancer? A multicenter study of 1,020 patients. Chest 2002; 121 (5): 1515-1520.

9. Sakakura N, Mori S, Okuda K, Fukui T, Hatooka S, Shinoda M, Matsuo K, Yatabe Y, Yokoi K, Mitsudomi T. Subcategorization of lung cancer based on tumor size and degree of visceral pleural invasion. Ann Thorac Surg 2008; 86 (4): 1084-1090.

10. Flieder DB, Port JL, Korst RJ, Christos PJ, Levin MA, Becker DE, Altorki NK. Tumor size is a determinant of stage distribution in t1 non-small cell lung cancer. Chest 2005; 128 (4): 2304-2308.

11. Takeda S, Fukai S, Komatsu H, Nemoto E, Nakamura K, Murakami M; Japanese National Chest Hospital Study Group. Impact of large tumor size on survival after resection of pathologically node negative (pN0) non-small cell lung cancer. Ann Thorac Surg 2005; 79 (4): 1142-1146.

12. Gajra A, Newman N, Gamble GP, Abraham NZ, Kohman LJ, Graziano SL. Impact of tumor size on survival in stage IA non-small cell lung cancer: a case for subdividing stage IA disease. Lung Cancer 2003; 42 (1): 51-57.

13. Wisnivesky JP, Yankelevitz D, Henschke CI. The effect of tumor size on curability of stage I non-small cell lung cancers. Chest 2004; 126 (3): 761-765.

14. Lyons G, Quadrelli S, Silva C, Vera K, Iotti A, Venditti J, Chertcoff J, Chimondeguy D. Analysis of survival in 400 surgically resected non-small cell lung carcinomas: towards a redefinition of the T factor. J Thorac Oncol 2008; 3 (9): 989-993.

15. Mery CM, Pappas AN, Burt BM, Bueno R, Linden PA, Sugarbaker DJ, Jaklitsch MT. Diameter of non-small cell lung cancer correlates with long-term survival: implications for T stage. Chest 2005; 128 (5): 3255-3260.

16. Okada M, Nishio W, Sakamoto T, Uchino K, Yuki T, Nakagawa A, Tsubota N. Effect of tumor size on prognosis in patients with non-small cell lung cancer: the role of segmentectomy as a type of lesser resection. J Thorac Cardiovasc Surg 2005; 129 (1): 87-93.

17. Birim O, Kappetein AP, Takkenberg JJ, van Klaveren RJ, Bogers AJ. Survival after pathological stage IA nonsmall cell lung cancer: tumor size matters. Ann Thorac Surg 2005; 79 (4): 1137-1141.

18. Ruffini E, Filosso PL, Bruna MC, Coni F, Cristofori RC, Mossetti C, Solidoro P, Oliaro A. Recommended changes for T and N descriptors proposed by the International Association for the Study of Lung Cancer - Lung Cancer Staging Project: a validation study from a single-centre experience. Eur J Cardiothorac Surg 2009; 36 (6): 1037-1044.

19. Fukui T, Mori S, Hatooka S, Shinoda M, Mitsudomi T. Prognostic evaluation based on a new TNM staging system proposed by the International Association for the Study of Lung Cancer for resected non-small cell lung cancers. J Thorac Cardiovasc Surg 2008; 136 (5): 1343-1348.

20. Kassis ES, Vaporciyan AA, Swisher SG, Correa AM, Bekele BN, Erasmus JJ, Hofstetter WL, Komaki R, Mehran RJ, Moran CA, Pisters KM, Rice DC, Walsh GL, Roth JA. Application of the revised lung cancer staging system (IASLC Staging Project) to a cancer center population. J Thorac Cardiovasc Surg 2009; 138 (2): 412-418.

21. Ignatius Ou SH (Ou SH), Zell JA, Ziogas A, Anton-Culver H. Prognostic significance of the non-size-based AJCC T2 descriptors: visceral pleura invasion, hilar atelectasis, or obstructive pneumonitis in stage IB non-small cell lung cancer is dependent on tumor size. Chest 2008; 133 (3): 662-669.

22. Koike T, Tsuchiya R, Goya T, Sohara Y, Miyaoka E. Prognostic factors in 3315 completely resected cases of clinical stage I non-small cell lung cancer in Japan. J Thorac Oncol 2007; 2 (5): 408-413.

23. Ye C, Masterman JR, Huberman MS, Gangadharan SP, McDonald DC, Kent MS, DeCamp MM. Subdivision of the T1 size descriptor for stage I non-small cell lung cancer has prognostic value: a single institution experience. Chest 2009; 136 (3): 710-715.

24. Li Z, Yu Y, Lu J, Luo Q, Wu C, Liao M, Zheng Y, Ai X, Gu L, Lu S. Analysis of the T descriptors and other prognosis factors in pathologic stage I non-small cell lung cancer in China. J Thorac Oncol 2009; 4 (6): 702-709.

25. Kameyama K, Takahashi M, Ohata K, Igai H, Yamashina A, Matsuoka T, Nakagawa T, Okumura N. Evaluation of the new TNM staging system proposed by the International Association for the Study of Lung Cancer at a single institution. J Thorac Cardiovasc Surg 2009; 137 (5): 1180-1184.

26. Mountain CF. Revisions in the international system for staging lung cancer. Chest 1997; 111 (6): 1710-1717.

27. Naruke T, Tsuchiya R, Kondo H, Asamura H. Prognosis and survival after resection for bronchogenic carcinoma based on the 1997 TNM staging classification: the Japanese experience. Ann Thorac Surg 2001; 71(6): 1759-1764.

28. Sobin LH, Wittekind C eds. Lung and pleural tumours. In: Sobin LH, Wittekind C eds. UICC International Union Against Cancer, TNM classification of malignant tumours, 6th ed. New York: Wiley-Liss, 2002; pp. 97-107.

29. Antony VB, Loddenkemper R, Astoul P, Boutin C, Goldstraw P, Hott J, Rodriguez Panadero F, Sahn SA. Management of malignant pleural effusions. Eur Respir J 2001; 18 (2): 402-419.

30. American Thoracic Society. Management of malignant pleural effusions. Am J Respir Crit Care Med 2000; 162 (5): 1987-2001.

31. Antunes G, Neville E, Duffy J, Ali N; Pleural Diseases Group, Standards of Care Committee, British Thoracic Society. BTS guidelines for the management of malignant pleural effusions. Thorax 2003; 58 (Suppl 2): ii29-ii38.

32. Sahn SA. Pleural diseases related to metastatic malignancies. Eur Respir J 1997; 10 (8): 1907-1913.

33. Heffner JE, Nietert PJ, Barbieri C. Pleural fluid pH as a predictor of survival for patients with malignant pleural effusions. Chest 2000; 117 (1): 79-86.

34. Sawabata N, Matsumura A, Motohiro A, Osaka Y, Gennga K, Fukai S, Mori T; Japanese National Chest Hospital Study group for Lung Cancer. Malignant minor pleural effusion detected on thoracotomy for patients with non-small cell lung cancer: is tumor resection beneficial for prognosis? Ann Thorac Surg 2002; 73 (2): 412-415.

35. Naruke T, Tsuchiya R, Kondo H, Asamura H, Nakayama H. Implications of staging in lung cancer. Chest 1997; 112 (4 Suppl): 242S-248S.

36. Osaki T, Sugio K, Hanagiri T, Takenoyama M, Yamashita T, Sugaya M, Yasuda M, Yasumoto K. Survival and prognostic factors of surgically resected T4 non-small cell lung cancer. Ann Thorac Surg 2003; 75 (6): 1745-1751.

37. Rodriguez Panadero F. Lung cancer and ipsilateral pleural effusion. Ann Oncol 1995; 6 (Suppl 3): S25-S27.

38. Ohta Y, Tanaka Y, Hara T, Oda M, Watanabe S, Shimizu J, Watanabe Y. Clinicopathological and biological assessment of lung cancers with pleural dissemination. Ann Thorac Surg 2000; 69 (4): 1025-1029.

39. Sugiura S, Ando Y, Minami H, Ando M, Sakai S, Shimokata K. Prognostic value of pleural effusion in patients with non-small cell lung cancer. Clin Cancer Res 1997; 3 (1): 47-50.

40. Naito T, Satoh H, Ishikawa H, Yamashita YT, Kamma H, Takahashi H, Ohtsuka M, Hasegawa S. Pleural effusion as a significant prognostic factor in non-small cell lung cancer. Anticancer Res 1997; 17 (6D): 4743-4746.

41. Patel V, Shrager JB. Which patients with stage III non-small cell lung cancer should undergo surgical resection? Oncologist 2005; 10 (5): 335-344.

42. Kvale PA, Selecky PA, Prakash UB; American College of Chest Physicians. Palliative care in lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007; 132 (3 Suppl): 368S-403S.

43. The NCCN Clinical Practice Guidelines in OncologyTM Non-Small Cell Lung Cancer (Version 2.2009). © 2009 National Comprehensive Cancer Network, Inc. Available at: NCCN.org. Accessed: October 25, 2009. To view the most recent and complete version of the NCCN Guidelines, go online to http://www.nccn.org.

44. Maruyama R, Yokoyama H, Seto T, Nagashima S, Kashiwabara K, Araki J, Semba H, Ichinose Y. Catheter drainage followed by the instillation of bleomycin to manage malignant pericardial effusion in non-small cell lung cancer: a multi-institutional phase II trial. J Thorac Oncol 2007; 2 (1): 65-68.

45. Kunitoh H, Tamura T, Shibata T, Imai M, Nishiwaki Y, Nishio M, Yokoyama A, Watanabe K, Noda K, Saijo N; JCOG Lung Cancer Study Group, Tokyo, Japan. A randomised trial of intrapericardial bleomycin for malignant pericardial effusion with lung cancer (JCOG9811). Br J Cancer 2009; 100 (3): 464-469.

46. Kaira K, Takise A, Kobayashi G, Utsugi M, Horie T, Mori T, Imai H, Inazawa M, Mori M. Management of malignant pericardial effusion with instillation of mitomycin C in non-small cell lung cancer. Jpn J Clin Oncol 2005; 35 (2): 57-60.

47. Alon BN, Anson BL. Pleural effusion in patients with non-small cell carcinoma--stage IV and not T4. Lung Cancer 2007; 57 (1): 123.

48. Mott FE, Sharma N, Ashley P. Malignant pleural effusion in non-small cell lung cancer--time for a stage revision? Chest 2001; 119 (1): 317-318.

49. Kameyama K, Huang CL, Liu D, Okamoto T, Hayashi E, Yamamoto Y, Yokomise H. Problems related to TNM staging: patients with stage III non-small cell lung cancer. J Thorac Cardiovasc Surg 2002; 124 (3): 503-510.

50. Leong SS, Rocha Lima CM, Sherman CA, Green MR. The 1997 International Staging System for non-small cell lung cancer: have all the issues been addressed? Chest 1999; 115 (1): 242-248.

51. Rami-Porta R, Ball D, Crowley J, Giroux DJ, Jett J, Travis WD, Tsuboi M, Vallières E, Goldstraw P; International Staging Committee; Cancer Research and Biostatistics; Observers to the Committee; Participating Institutions. The IASLC Lung Cancer Staging Project: proposals for the revision of the T descriptors in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol 2007; 2 (7): 593-602.

52. Postmus PE, Brambilla E, Chansky K, Crowley J, Goldstraw P, Patz EF Jr, Yokomise H; International Association for the Study of Lung Cancer International Staging Committee; Cancer Research and Biostatistics; Observers to the Committee; Participating Institutions. The IASLC Lung Cancer Staging Project: proposals for revision of the M descriptors in the forthcoming (seventh) edition of the TNM classification of lung cancer. J Thorac Oncol 2007; 2 (8): 686-693.

53. Ignatius Ou SH (Ou SH), Zell JA. Validation study of the proposed IASLC staging revisions of the T4 and M non-small cell lung cancer descriptors using data from 23,583 patients in the California Cancer Registry. J Thorac Oncol 2008; 3 (3): 216-227.

54. William WN Jr, Lin HY, Lee JJ, Lippman SM, Roth JA, Kim ES. Revisiting stage IIIB and IV non-small cell lung cancer: analysis of the surveillance, epidemiology, and end results data. Chest 2009; 136 (3): 701-709.

55. Warren S, Gates O. Multiple primary malignant tumors: a survey of the literature and a statistical study. Am J Cancer 1932; 16: 1358-1414.

56. Howe HL (ed). A review of the definition for multiple primary cancers in the United States. Workshop proceedings from December 4-6, 2002, in Princeton, New Jersey. Springfield (IL): North American Association of Central Cancer Registries, May 2003. Downloaded from: http://www.naaccr.org on October 27, 2009.

57. Quadrelli S, Lyons G, Colt H, Chimondeguy D, Silva C. Lung cancer as a second primary malignancy: increasing prevalence and its influence on survival. Ann Surg Oncol 2009; 16 (4): 1033-1038.

58. De Leyn P. Second primaries: M01-01. J Thorac Oncol 2007; 2 (8): S149-S150.

59. Girard N, Ostrovnaya I, Lau C, Park B, Ladanyi M, Finley D, Deshpande C, Rusch V, Orlow I, Travis WD, Pao W, Begg CB. Genomic and mutational profiling to assess clonal relationships between multiple non-small cell lung cancers. Clin Cancer Res 2009; 15 (16): 5184-5190.

60. Martini N, Melamed MR. Multiple primary lung cancers. J Thorac Cardiovasc Surg 1975; 70 (4): 606-612.

61. Facility Oncology Registry Data Standards (FORDS): Revised for 2009. Chicago, Illinois: Commission on Cancer, American College of Surgeons; 2002.

62. Johnson CH, Adamo M (eds.), SEER Program Coding and Staging Manual 2007. National Cancer Institute, NIH Publication number 07-5581, Bethesda, MD 2008 revision. Appendix C - Site-Specific Coding Modules. Part 3 C30.0 -C39.9: pgs 375-526.

63. Shen KR, Meyers BF, Larner JM, Jones DR; American College of Chest Physicians. Special treatment issues in lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007; 132 (3 Suppl): 290S-305S.

64. Deslauriers J, Brisson J, Cartier R, Fournier M, Gagnon D, Piraux M, Beaulieu M. Carcinoma of the lung. Evaluation of satellite nodules as a factor influencing prognosis after resection. J Thorac Cardiovasc Surg 1989; 97 (4): 504-512.

65. Urschel JD, Urschel DM, Anderson TM, Antkowiak JG, Takita H. Prognostic implications of pulmonary satellite nodules: are the 1997 staging revisions appropriate? Lung Cancer 1998; 21 (2): 83-87.

66. Rao J, Sayeed RA, Tomaszek S, Fischer S, Keshavjee S, Darling GE. Prognostic factors in resected satellite-nodule T4 non-small cell lung cancer. Ann Thorac Surg 2007; 84 (3): 934-938.

67. Riquet M, Cazes A, Pfeuty K, Ngabou UD, Foucault C, Dujon A, Banu E. Multiple lung cancers prognosis: what about histology? Ann Thorac Surg 2008; 86 (3): 921-926.

68. Oliaro A, Filosso PL, Cavallo A, Giobbe R, Mossetti C, Lyberis P, Cristofori RC, Ruffini E. The significance of intrapulmonary metastasis in non-small cell lung cancer: upstaging or downstaging? A re-appraisal for the next TNM staging system. Eur J Cardiothorac Surg 2008; 34 (2): 438-443.

69. Trousse D, D'Journo XB, Avaro JP, Doddoli C, Giudicelli R, Fuentes PA, Thomas PA. Multifocal T4 non-small cell lung cancer: a subset with improved prognosis. Eur J Cardiothorac Surg 2008; 33 (1): 99-103.

70. Okada M, Tsubota N, Yoshimura M, Miyamoto Y, Nakai R. Evaluation of TMN classification for lung carcinoma with ipsilateral intrapulmonary metastasis. Ann Thorac Surg 1999; 68 (2): 326-330.

71. Nagai K, Sohara Y, Tsuchiya R, Goya T, Miyaoka E; Japan Lung Cancer Registration Committee. Prognosis of resected non-small cell lung cancer patients with intrapulmonary metastases. J Thorac Oncol 2007; 2 (4): 282-286.

72. Lee JG, Lee CY, Kim DJ, Chung KY, Park IK. Non-small cell lung cancer with ipsilateral pulmonary metastases: prognosis analysis and staging assessment. Eur J Cardiothorac Surg 2008; 33 (3):480-484.

73. Okumura T, Asamura H, Suzuki K, Kondo H, Tsuchiya R. Intrapulmonary metastasis of non-small cell lung cancer: a prognostic assessment. J Thorac Cardiovasc Surg 2001; 122 (1): 24-28.

74. Bryant AS, Pereira SJ, Miller DL, Cerfolio RJ. Satellite pulmonary nodule in the same lobe (T4N0) should not be staged as IIIB non-small cell lung cancer. Ann Thorac Surg 2006; 82 (5): 1808-1813.

75. Port JL, Korst RJ, Lee PC, Kansler AL, Kerem Y, Altorki NK. Surgical resection for multifocal (T4) non-small cell lung cancer: is the T4 designation valid? Ann Thorac Surg 2007; 83 (2): 397-400.

76. Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, Postmus PE, Rusch V, Sobin L; International Association for the Study of Lung Cancer International Staging Committee; Participating Institutions. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol 2007; 2 (8): 706-714.

77. Ruffini E, Filosso PL, Bruna MC, Coni F, Cristofori RC, Mossetti C, Solidoro P, Oliaro A. Recommended changes for T and N descriptors proposed by the International Association for the Study of Lung Cancer - Lung Cancer Staging Project: a validation study from a single-centre experience. Eur J Cardiothorac Surg 2009; 36 (6): 1037-1044.

78. Molina JR. The case of a good satellite: outcomes of resected ipsilateral same-lobe satellite pulmonary nodules. Chest 2009; 136 (3): 660-662.

79. Pennathur A, Lindeman B, Ferson P, Ninan M, Quershi I, Gooding WE, Schuchert M, Christie NA, Landreneau RJ, Luketich JD. Surgical resection is justified in non-small cell lung cancer patients with node negative T4 satellite lesions. Ann Thorac Surg 2009; 87 (3): 893-899.

80. Rusch VW, Crowley J, Giroux DJ, Goldstraw P, Im JG, Tsuboi M, Tsuchiya R, Vansteenkiste J; International Staging Committee; Cancer Research and Biostatistics; Observers to the Committee; Participating Institutions. The IASLC Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol 2007; 2 (7): 603-612.

81. Lee JG, Lee CY, Bae MK, Park IK, Kim DJ, Kim KD, Chung KY. Validity of International Association for the Study Of Lung Cancer proposals for the revision of N descriptors in lung cancer. J Thorac Oncol 2008; 3 (12): 1421-1426.

82. Zell JA, Ignatius Ou SH, Ziogas A, Anton-Culver H. Validation of the proposed International Association for the Study of Lung Cancer non-small cell lung cancer staging system revisions for advanced bronchioloalveolar carcinoma using data from the California Cancer Registry. J Thorac Oncol 2007; 2 (12): 1078-1085.

83. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. eds. Part I. General information on cancer staging and end-results reporting. 1. Purposes and principles of cancer staging. In: Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. eds. AJCC Cancer Staging Manual. 7th ed., 2010, Springer; pp. 3-14.

84. Rami-Porta R, Crowley JJ, Goldstraw P. The revised TNM staging system for lung cancer. Ann Thorac Cardiovasc Surg 2009; 15 (1): 4-9.

85. Uhm J, Hong J, Choi M, Kim K, Han J, Kim J, Shim Y, Kwon O, Ahn J, Ahn M, Park K. External validation of proposals for the revision of the TNM stage groupings by the IASLC lung cancer staging project in Korean non-small cell lung cancer patients. J Clin Oncol (Meeting Abstracts) 2008; 26 (15S): 22140.

86. Suzuki M, Yoshida S, Tamura H, Wada H, Moriya Y, Hoshino H, Shibuya K, Yoshino I. Applicability of the revised International Association for the Study of Lung Cancer staging system to operable non-small-cell lung cancers. Eur J Cardiothorac Surg 2009; 36 (6): 1031-1036.

87. Sakakura N, Mori S, Okuda K, Fukui T, Hatooka S, Shinoda M, Matsuo K, Yatabe Y, Yokoi K, Mitsudomi T. Subcategorization of lung cancer based on tumor size and degree of visceral pleural invasion. Ann Thorac Surg 2008; 86 (4): 1084-1090.

88. Travis WD; IASLC Staging Committee. Reporting lung cancer pathology specimens. Impact of the anticipated 7th Edition TNM classification based on recommendations of the IASLC Staging Committee. Histopathology 2009; 54 (1): 3-11.

89. Shimizu K, Yoshida J, Nagai K, Nishimura M, Yokose T, Ishii G, Nishiwaki Y. Visceral pleural invasion classification in non-small cell lung cancer: a proposal on the basis of outcome assessment. J Thorac Cardiovasc Surg 2004; 127 (6): 1574-1578.

90. Shimizu K, Yoshida J, Nagai K, Nishimura M, Ishii G, Morishita Y, Nishiwaki Y. Visceral pleural invasion is an invasive and aggressive indicator of non-small cell lung cancer J Thorac Cardiovasc Surg 2005; 130 (1): 160-165.

91. Osaki T, Nagashima A, Yoshimatsu T, Yamada S, Yasumoto K. Visceral pleural involvement in nonsmall cell lung cancer: prognostic significance. Ann Thorac Surg 2004; 77 (5): 1769-1773.

92. Satoh Y, Ishikawa Y, Inamura K, Okumura S, Nakagawa K, Tsuchiya E. Classification of parietal pleural invasion at adhesion sites with surgical specimens of lung cancer and implications for prognosis. Virchows Arch 2005; 447 (6): 984-989.

93. Travis WD, Brambilla E, Rami-Porta R, Vallières E, Tsuboi M, Rusch V, Goldstraw P; International Staging Committee. Visceral pleural invasion: pathologic criteria and use of elastic stains: proposal for the 7th edition of the TNM classification for lung cancer. J Thorac Oncol 2008; 3 (12): 1384-1390.

94. Shim HS, Park IK, Lee CY, Chung KY. Prognostic significance of visceral pleural invasion in the forthcoming (seventh) edition of TNM classification for lung cancer. Lung Cancer 2009; 65 (2): 161-165.

95. Yoshida J, Nagai K, Asamura H, Goya T, Koshiishi Y, Sohara Y, Eguchi K, Mori M, Nakanishi Y, Tsuchiya R, Miyaoka E; Japanese Joint Committee for Lung Cancer Registration. Visceral pleura invasion impact on non-small cell lung cancer patient survival: its implications for the forthcoming TNM staging based on a large-scale nation-wide database. J Thorac Oncol 2009; 4 (8): 959-963.

96. Warth A, Muley T, Herpel E, Pfannschmidt J, Hoffmann H, Dienemann H, Schirmacher P, Schnabel PA. A histochemical approach to the diagnosis of visceral pleural infiltration by non-small cell lung cancer. Pathol Oncol Res 2009 Sep 3. [Epub ahead of print].

97. Wittekind C, Greene FL, Henson DE, Hutter RVP, Sobin LH. eds. Lung. In: Wittekind C, Greene FL, Henson DE, Hutter RVP, Sobin LH. eds. UICC International Union Against Cancer, TNM Supplement, a commentary on uniform use. 3rd ed., New York: Wiley-Liss, 2003; pp. 47, 97, 98, 143–149.

98. The NCCN Clinical Practice Guidelines in OncologyTM Small Cell Lung Cancer (Version 2.2009). © 2009 National Comprehensive Cancer Network, Inc. Available at: NCCN.org. Accessed: October 25, 2009. To view the most recent and complete version of the NCCN Guidelines, go online to http://www.nccn.org.

99. Stahel RA, Ginsberg R, Havemann K, Hirsch FR, Ihde DC, Jassem J, Karrer K, Maurer LH, Osterlind K, Van Houtte P. Staging and prognostic factors in small cell lung cancer: A consensus report. Lung Cancer 1989; 5 (4-6): 119-126.

100. Micke P, Faldum A, Metz T, Beeh KM, Bittinger F, Hengstler JG, Buhl R. Staging small cell lung cancer: Veterans Administration Lung Study Group versus International Association for the Study of Lung Cancer—what limits limited disease? Lung Cancer 2002; 37 (3): 271-276.

101. Chandra V, Allen MS, Nichols FC 3rd, Deschamps C, Cassivi SD, Pairolero PC. The role of pulmonary resection in small cell lung cancer. Mayo Clin Proc 2006; 81 (5): 619-624.

102. Veronesi G, Scanagatta P, Leo F, De Pas T, Pelosi G, Catalano G, Gandini S, De Braud F, Spaggiari L. Adjuvant surgery after carboplatin and VP16 in resectable small cell lung cancer. J Thorac Oncol 2007; 2 (2): 131-134.

103. Brock MV, Hooker CM, Syphard JE, Westra W, Xu L, Alberg AJ, Mason D, Baylin SB, Herman JG, Yung RC, Brahmer J, Rudin CM, Ettinger DS, Yang SC. Surgical resection of limited disease small cell lung cancer in the new era of platinum chemotherapy: Its time has come. J Thorac Cardiovasc Surg 2005; 129 (1): 64-72.

104. Leo F, Pastorino U. Surgery in small-cell lung carcinoma. Where is the rationale? Semin Surg Oncol 2003; 21 (3): 176-181.

105. Ginsberg RJ. Small cell lung cancer: how should we treat it? What is it? Ann Thorac Surg 2000; 70 (5): 1453-1454.

106. Lucchi M, Mussi A, Chella A, Janni A, Ribechini A, Menconi GF, Angeletti CA. Surgery in the management of small cell lung cancer. Eur J Cardiothorac Surg 1997; 12 (5): 689-693.

107. Zelen M. Keynote address on biostatistics and data retrieval. Cancer Chemother Rep 3 1973; 4 (2): 31-42.

108. Shields TW, Higgins GA Jr, Matthews MJ, Keehn RJ. Surgical resection in the management of small cell carcinoma of the lung. J Thorac Cardiovasc Surg 1982; 84 (4): 481-488.

109. Rea F, Callegaro D, Favaretto A, Loy M, Paccagnella A, Fantoni U, Festi G, Sartori F. Long term results of surgery and chemotherapy in small cell lung cancer. Eur J Cardiothorac Surg 1998; 14 (4): 398-402.

110. Inoue M, Miyoshi S, Yasumitsu T, Mori T, Iuchi K, Maeda H, Matsuda H. Surgical results for small cell lung cancer based on the new TNM staging system. Thoracic Surgery Study Group of Osaka University, Osaka, Japan. Ann Thorac Surg 2000; 70 (5): 1615-1619.

111. Zimmermann FB, Bamberg M, Molls M, Jeremic B. Limited-disease small-cell lung cancer. Semin Surg Oncol 2003; 21 (3): 156-163.

112. Sakai M, Ishikawa S, Yamamoto T, Onizuka M, Sakakibara Y, Iijima T, Noguchi M. Preoperative TNM evaluation of peripheral clinical stage I small cell lung cancer treated by initial lobectomy with adjuvant chemotherapy. Interact Cardiovasc Thorac Surg 2005; 4 (2): 118-122.

113. Badzio A, Kurowski K, Karnicka-Mlodkowska H, Jassem J. A retrospective comparative study of surgery followed by chemotherapy vs. non-surgical management in limited-disease small cell lung cancer. Eur J Cardiothorac Surg 2004; 26 (1): 183-188.

114. Granetzny A, Boseila A, Wagner W, Krukemeyer G, Vogt U, Hecker E, Koch OM, Klinke F. Surgery in the tri-modality treatment of small cell lung cancer. Stage-dependent survival. Eur J Cardiothorac Surg 2006; 30 (2): 212-226.

115. Bischof M, Debus J, Herfarth K, Muley T, Kappes J, Storz K, Hoffmann H. Surgery and chemotherapy for small cell lung cancer in stages I-II with or without radiotherapy. Strahlenther Onkol 2007; 183 (12): 679-684.

116. Lim E, Belcher E, Yap YK, Nicholson AG, Goldstraw P. The role of surgery in the treatment of limited disease small cell lung cancer: time to reevaluate. J Thorac Oncol 2008; 3 (11): 1267-1271.

117. Hanagiri T, Sugio K, Baba T, Ichiki Y, Yasuda M, Uramoto H, Ohga T, Takenoyama M, Yasumoto K. Results of surgical treatment for patients with small cell lung cancer. J Thorac Oncol 2009; 4 (8): 964-968.

118. Shah SS, Thompson J, Goldstraw P. Results of operation without adjuvant therapy in the treatment of small cell lung cancer. Ann Thorac Surg 1992; 54 (3): 498-501.

119. Tsuchiya R, Suzuki K, Ichinose Y, Watanabe Y, Yasumitsu T, Ishizuka N, Kato H. Phase II trial of postoperative adjuvant cisplatin and etoposide in patients with completely resected stage I-IIIa small cell lung cancer: the Japan Clinical Oncology Lung Cancer Study Group Trial (JCOG9101). J Thorac Cardiovasc Surg 2005; 129 (5): 977-983.

120. Shepherd FA, Crowley J, Van Houtte P, Postmus PE, Carney D, Chansky K, Shaikh Z, Goldstraw P; International Association for the Study of Lung Cancer International Staging Committee and Participating Institutions. The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. J Thorac Oncol 2007; 2 (12): 1067-1077.

121. Vallières E, Shepherd FA, Crowley J, Van Houtte P, Postmus PE, Carney D, Chansky K, Shaikh Z, Goldstraw P; International Association for the Study of Lung Cancer International Staging Committee and Participating Institutions. The IASLC Lung Cancer Staging Project: proposals regarding the relevance of TNM in the pathologic staging of small cell lung cancer in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol 2009; 4 (9): 1049-1059.

122. Ignatius Ou SH, Zell JA. The applicability of the proposed IASLC staging revisions to small cell lung cancer (SCLC) with comparison to the current UICC 6th TNM Edition. J Thorac Oncol 2009; 4 (3): 300-310.

123. Asamura H, Kameya T, Matsuno Y, Noguchi M, Tada H, Ishikawa Y, Yokose T, Jiang SX, Inoue T, Nakagawa K, Tajima K, Nagai K. Neuroendocrine neoplasms of the lung: a prognostic spectrum. J Clin Oncol 2006; 24 (1): 70-76.

124. Cardillo G, Sera F, Di Martino M, Graziano P, Giunti R, Carbone L, Facciolo F, Martelli M. Bronchial carcinoid tumors: nodal status and long-term survival after resection. Ann Thorac Surg 2004; 77 (5): 1781-1785.

125. Bini A, Brandolini J, Cassanelli N, Davoli F, Dolci G, Sellitri F, Stella F. Typical and atypical pulmonary carcinoids: our institutional experience. Interact Cardiovasc Thorac Surg 2008; 7 (3): 415-418.

126. Filosso PL, Rena O, Donati G, Casadio C, Ruffini E, Papalia E, Oliaro A, Maggi G. Bronchial carcinoid tumors: surgical management and long-term outcome. J Thorac Cardiovasc Surg 2002; 123 (2): 303-309.

127. Mezzetti M, Raveglia F, Panigalli T, Giuliani L, Lo Giudice F, Meda S, Conforti S. Assessment of outcomes in typical and atypical carcinoids according to latest WHO classification. Ann Thorac Surg 2003; 76 (6): 1838-1842.

128. Travis WD, Giroux DJ, Chansky K, Crowley J, Asamura H, Brambilla E, Jett J, Kennedy C, Rami-Porta R, Rusch VW, Goldstraw P; International Staging Committee and Participating Institutions. The IASLC Lung Cancer Staging Project: proposals for the inclusion of broncho-pulmonary carcinoid tumors in the forthcoming (seventh) edition of the TNM Classification for Lung Cancer. J Thorac Oncol 2008; 3 (11): 1213-1223.

129. Silvestri GA. A seismic shift in staging. J Thorac Oncol 2007; 2 (8): 682-683.

130. Giroux DJ, Rami-Porta R, Chansky K, Crowley JJ, Groome PA, Postmus PE, Rusch V, Sculier JP, Shepherd FA, Sobin L, Goldstraw P; International Association for the Study of Lung Cancer International Staging Committee. The IASLC Lung Cancer Staging Project: data elements for the prospective project. J Thorac Oncol 2009; 4 (6): 679-683.


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March 01, 2010 03:03 PM

Dear Dr. M. Jagesh Kamath,

I am glad you enjoyed the article; thank you for your kind words.

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March 01, 2010 08:01 AM

Dr. A. De la Guerra, thank you so much for this prompt and comprehensive answer. I learned a lot from your article and your reply. The information you wrote about the diagnostic approach to PE is very useful and your comment to justify excluding the M descriptor from the pathology staging templates is very much appreciated.
Best Regards.


February 28, 2010 05:46 AM

ERRATUM: Re: New TNM Classification for Lung Cancer. Part II: A review. by Dr. A. De la Guerra. Doctors Lounge Website. Available at: http://www.doctorslounge.com/index.php/articles/page/342. Accessed February 27 2010. In the section: Pleural dissemination and pericardial effusion, in the second paragraph, lines 2 and 3, the sentence: “Notice that diagnosis of a MPE can also be made by pleural biopsy, but in such cases disease is listed as M1 - stage IV”, should not be present. Both citologic and pathologic diagnosis of a MPE were considered T4 in the 6th edition of the TNM. The author regrets the error.


February 28, 2010 05:43 AM

Dear Dr. Safaa Mahmoud,

Thank you for your comments.

Your observation about the different forms of pleural involvement and their classification is almost exact, except for separate pleural nodules; they were T4, now M1a, the same as MPE.

On your first question, about the diagnosis and clinical staging of pleural effusions (PE) in patients with NSCLC, these are the rules for classification, word for word, according to the 6th edition of the TNM staging system (1-3):

“Most pleural effusions associated with lung cancer are due to tumor. However, there are a few patients in whom multiple cytopathologic examinations of pleural fluid are negative for tumor. In these cases, the fluid is non-bloody and is not an exudate. When these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging element and the patient should be staged T1, T2, and T3.”

The opposite is also valid, that is to say, when the clinical picture is highly suggestive of MPE, despite a negative fluid cytology. We have to consider that pleural fluid cytology is diagnostic in only 60% of MPE (4, 5). There is evidence that clinical evaluation, including antecedent of cancer and CT characteristics, has a sensitivity of more than 90% in the diagnosis of MPE (6).

Clinical judgment is appropriate to establish the diagnosis of a MPE, when common diagnostic procedures had failed, in patients with microscopic confirmation of lung cancer, that due to the stage of the disease are not considered for treatment with curative intent (surgery with or without adjuvant therapy), and pathologic proof of MPE has no clinical relevance; consider that clinical stage guides initial management; pathologic stage defines prognosis.

If the diagnosis of cancer has not been established yet, or the patient has early stage disease, pathologic confirmation is mandatory. Most accepted approach for the diagnosis of exudative PE is:

• Cytological examination of pleural fluid; if negative repeat.
About 50% of MPE are negative at first thoracentesis (7).

• If second examination of pleural fluid is negative, do a contrast enhanced thoracic CT scanning to evaluate any pleural abnormality and make a decision to carry out a biopsy.
CT sensitivity for malignant pleural dissemination is about 85% (4, 8, 9).

• If thickening or nodularity is found, perform an imaging-guided pleural biopsy.
CT-guided pleural biopsy has almost 100% of sensitivity against 50% of blind biopsy (10, 11).

• If pleural biopsy is negative: do a thoracoscopy.

Your concern about the inconsistency in the statement that “diagnosis of a MPE can also be made by pleural biopsy, but in such cases disease is listed as M1 - stage IV” is absolutely justified. I appreciate very much your observation (and applaud your perspicaciousness). I didn’t notice the mistake; the correct statement must be that both, positive fluid cytology and pleural biopsy are valid to classify the tumor as T4 (according to the 6th edition). I am publishing an erratum right now.

On your commentary regarding the new pathology staging templates, I agree with you. Ideally every member of the multi-disciplinary team dedicated to the management of lung cancer should have the most complete and accurate information of the patient. In practice, communication between clinicians and pathologists is far from optimal.

The reason to exclude the M descriptor from the pathology staging templates is, as you mention, that pathologists usually do not have data about metastasis. The problem is that the pathologic assignment of the presence of metastases (pM1) requires a positive biopsy, consequently pMX does not exist. Pathologic classification of the absence of distant metastases (pM0) can only be made at autopsy. The risk of maintaining the M factor on the pathology staging templates is that if the pathologist does not know the clinical M he may consign a MX and exclude the case from staging.

Thank you again for your interest in the article.


References.

1. Mountain CF. Revisions in the international system for staging lung cancer. Chest 1997; 111 (6): 1710-1717.

2. Sobin LH, Wittekind C eds. Lung and pleural tumours. In: Sobin LH, Wittekind C eds. UICC International Union Against Cancer, TNM classification of malignant tumours, 6th ed. New York: Wiley-Liss, 2002; pp. 97-107.

3. Lung. In: American Joint Committee on Cancer. AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 167-181.

4. Maskell NA, Butland RJ; Pleural Diseases Group, Standards of Care Committee, British Thoracic Society. BTS guidelines for the investigation of a unilateral pleural effusion in adults. Thorax 2003; 58 Suppl 2: ii8-17.

5. Villena Garrido V, Ferrer Sancho J, Hernández Blasco L, de Pablo Gafas A, Pérez Rodríguez E, Rodríguez Panadero F, Romero Candeira S, Salvatierra Velázquez A, Valdés Cuadrado L; Area de Tecnicas y Trasplantes. SEPAR. Diagnosis and treatment of pleural effusion. Arch Bronconeumol 2006; 42 (7): 349-372.

6. Alemán C, Sanchez L, Alegre J, Ruiz E, Vázquez A, Soriano T, Sarrapio J, Teixidor J, Andreu J, Felip E, Armadans L, Fernández De Sevilla T. Differentiating between malignant and idiopathic pleural effusions: the value of diagnostic procedures. QJM 2007; 100 (6): 351-359.

7. Moffett PU, Moffett BK, Laber DA. Diagnosing and managing suspected malignant pleural effusions. J Support Oncol 2009; 7 (4): 143-146.

8. Traill ZC, Davies RJ, Gleeson FV. Thoracic computed tomography in patients with suspected malignant pleural effusions. Clin Radiol 2001; 56 (3): 193-196.

9. Arenas-Jiménez J, Alonso-Charterina S, Sánchez-Payá J, Fernández-Latorre F, Gil-Sánchez S, Lloret-Llorens M. Evaluation of CT findings for diagnosis of pleural effusions. Eur Radiol 2000;10 (4): 681-690.

10. Maskell NA, Gleeson FV, Davies RJ. Standard pleural biopsy versus CT-guided cutting-needle biopsy for diagnosis of malignant disease in pleural effusions: a randomised controlled trial. Lancet 2003; 361 (9366): 1326-1330.

11. Adams RF, Gleeson FV. Percutaneous image-guided cutting-needle biopsy of the pleura in the presence of a suspected malignant effusion. Radiology 2001; 219 (2): 510-514.


February 26, 2010 01:58 PM

Dr. A. De la Guerra, thank you so much for this comprehensive article.  Based on the new staging classifications, pleural involvement in lung cancer would follow one of these forms: direct tumor extension to visceral pleura described as T2, to parietal pleura described as T3; separate pleural nodules described as T4 and malignant pleural effusion (MPE) described as M1a.  Would you please comment on this statement if correctly received: MPE is considered as T4 if diagnosed only by clinical findings, but I find it strange that MPE is considered T4 if diagnosed by cytology but M1a if diagnosed by biopsy. And this how it is stated in the article (In TNM staging, either pleural fluid cytology or clinical judgment are valid to establish the diagnosis of a MPE and consider it as a T4 factor (26). Notice that diagnosis of a MPE can also be made by pleural biopsy, but in such cases disease is listed as M1 - stage IV).

Second as mentioned in your article, (since pathologists normally do not have information about metastasis, the M factor will not appear in pathology staging templates on the 7th edition (83)). We all understand that this information is always missing in the request sent to pathologist but do not you agree that pathologists should insist of getting the request with complete information including metastasis status when available rather than omitting this part at all. Would you kindly comment on this too?
Thank you again for this very comprehensive review, great effort indeed.


February 24, 2010 01:23 AM

Very comprehensive study on the new TNM System.Well done, and neatly presented by Dr.Guerra.Congratulations!