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Extranodal Extension in Metastatic Non-small Cell Lung CancerResponse FREE TO VIEW

Adam M. Bell, MD; Barry R. DeYoung, MD; Jamie Weydert, MD
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Affiliations: University of Iowa Health Care, Iowa City, Iowa,  Department of Surgery,  Department of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan

Correspondence to: Adam M. Bell, MD, University of Iowa, Department of Pathology, 200 Hawkins Dr, Iowa City, IA 52242; e-mail: adam-bell@uiowa.edu



Chest. 2007;132(6):2058-2060. doi:10.1378/chest.07-1852
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Published online

We read with much interest the study of Lee et al (April 2007)1 on the prognostic significance of extranodal extension (ENE) of metastatic non-small cell lung cancer. This is a much needed area of research, and there is strong agreement with the authors’ goal of improving existing pathologic staging standards. However, we feel that the authors’ conclusions could be strengthened by addressing the following concerns:

  1. A reproducible definition of ENE is not provided. Generally considered synonymous with the term extracapsular extension, this term implies the presence of proliferating malignant cells outside the capsule of an involved lymph node. As an example, Fleishmann et al2 in 2005 provided the following definition for ENE: “… perforation of the capsule by tumor tissue with extranodal growth. Histopathologically, extranodal extension must be differentiated from tumor deposits in the pericapsular lymphatics.” The definition of terminology and the application of criteria for assessing ENE should be explicitly listed in the “Materials and Methods” section; the failure to do this results in the inability to reproduce the study/results and could lead to erroneous conclusions based on the current data.

  2. The photomicrograph proffered to depict ENE (Fig 1 in the article1) does not, in our opinion, appear to demonstrate ENE. We interpret the image to depict metastatic tumor within capsule-confined lymph node parenchyma and pericapsular lymphatics, and believe it does not demonstrate unequivocal evidence of ENE.

  3. While we do not dispute that the identification of ENE may be of significant prognostic value, it is our experience that variations in surgical technique may limit the assessment of ENE in some practices. For example, in our academic medical center, specimens from thoracic lymph node biopsies and excisions are often received as partially cauterized and fragmented specimens with variable amounts of attached perinodal soft tissue. Lymph node handling and sectioning methods will need to be expanded to account for these potential limitations if the documentation of ENE is to become the standard of practice.

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

The authors have no conflicts of interest to disclose.

Figure Jump LinkFigure 1. Top: Extranodal tumor extension causing fibrosis in the perinodal adipose tissue outside the vanished LN capsule (hematoxylin-eosin, original × 13.2). Center: Extensive extranodal soft-tissue cancer involvement with desmoplasia was demonstrated on the left side (hematoxylin-eosin, original × 13.2). Bottom: LN architecture was almost effaced by tumor cell nests with extranodal fatty tissue involvement (hematoxylin-eosin, original × 33).Grahic Jump Location
Lee, Y, Wu, C, Kuo, S, et al (2007) Significance of extranodal extension of regional lymph nodes in surgically resected non-small lung cancer.Chest131,993-999. [PubMed] [CrossRef]
 
Fleischmann, A, Thalmann, GN, Markwalder, R, et al Extracapsular extension of pelvic lymph node metastases from urothelial carcinoma of the bladder is an independent prognostic factor.J Clin Oncol2005;23,2358-2365. [PubMed]
 
To the Editor:

The major purpose of our published research1 was to find out the significance of extranodal extension (ENE) of regional lymph nodes (LNs) in surgically resected non-small cell lung cancer. We would like to respond to the comments from Bell et al, as follows:

  1. Our response to the concern about a reproducible definition of ENE is that the terminology and application of criteria for assessing ENE had been explicitly addressed in the “Materials and Methods” section,1as “… (2) extranodal extension, in which cancer cells invaded beyond the capsule of the LN.” Pericapsular lymphatic tumor deposit, whether present or not, was not included in the definition of ENE. The term ENE was used in various cancers and in the literature for many years, and different subclassifications of ENE have been proposed.5

  2. Our response to the concern about the previously shown photomicrography depictingd ENE is that the photomicrograph we proffered in our article1 demonstrated that the metastatic tumor was not only invading through the vanishing LN capsule but was also accompanied by vascular invasion, a frequent phenomenon that was significantly correlated with ENE (p < 0.001) [Table 1 in our article].1 Our specimens of LNs with ENE frequently showed an extensive extranodal tumor area, even replacing LN architecture. We would like to share with the readers more photomicrographs of ENE demonstrating various severities of ENE (Fig 1 ).

  3. Our response to the concern about “variations in surgical technique may limit assessment of ENE in some practices” is that all patients cared for by our team had undergone systemic dissection of LNs. By using surgical clips and scissors during LN dissection, the problem of partially cauterized and fragmented specimens could be avoided. However, if in that case, thoroughly examining fragmented lymph nodes by sectioning at 1- to 2-mm intervals, which was described in the last paragraph of the “Materials and Methods” section,1 carefully processing different cut surfaces,6 and integrating microscopic observations from every field would facilitate ENE evaluation.

References
Lee, YC, Wu, CT, Kuo, SW, et al Significance of extranodal extension of regional lymph nodes in surgically resected non-small cell lung cancer.Chest2007;131,993-999. [PubMed] [CrossRef]
 
Palamba, HW, Rombouts, MC, Ruers, TJM, et al Extranodal extension of axillary metastasis of invasive breast carcinoma as a possible predictor for the total number of positive lymph nodes.Eur J Surg Oncol2001;27,719-722. [PubMed]
 
Katz, A, Strom, EA, Buchholz, TA, et al Locoregional recurrence patterns after mastectomy and doxorubicin-based chemotherapy: implications for postoperative irradiation.J Clin Oncol2000;18,2817-2827. [PubMed]
 
Hofer, MD, Kuefer, R, Huang, W, et al Prognostic factors in lymph node-positive prostate cancer.Urology2006;67,1016-1021. [PubMed]
 
Sanchez-Ortiz, RF, Pettaway, CA The role of lymphadenectomy in penile cancer.Urol Oncol2004;22,236-244. [PubMed]
 
Junker, K Histopathologic evaluation of mediastinal lymph nodes in lung cancer.Lung Cancer2004;45(suppl 2),S79-S83. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Top: Extranodal tumor extension causing fibrosis in the perinodal adipose tissue outside the vanished LN capsule (hematoxylin-eosin, original × 13.2). Center: Extensive extranodal soft-tissue cancer involvement with desmoplasia was demonstrated on the left side (hematoxylin-eosin, original × 13.2). Bottom: LN architecture was almost effaced by tumor cell nests with extranodal fatty tissue involvement (hematoxylin-eosin, original × 33).Grahic Jump Location

Tables

References

Lee, Y, Wu, C, Kuo, S, et al (2007) Significance of extranodal extension of regional lymph nodes in surgically resected non-small lung cancer.Chest131,993-999. [PubMed] [CrossRef]
 
Fleischmann, A, Thalmann, GN, Markwalder, R, et al Extracapsular extension of pelvic lymph node metastases from urothelial carcinoma of the bladder is an independent prognostic factor.J Clin Oncol2005;23,2358-2365. [PubMed]
 
Lee, YC, Wu, CT, Kuo, SW, et al Significance of extranodal extension of regional lymph nodes in surgically resected non-small cell lung cancer.Chest2007;131,993-999. [PubMed] [CrossRef]
 
Palamba, HW, Rombouts, MC, Ruers, TJM, et al Extranodal extension of axillary metastasis of invasive breast carcinoma as a possible predictor for the total number of positive lymph nodes.Eur J Surg Oncol2001;27,719-722. [PubMed]
 
Katz, A, Strom, EA, Buchholz, TA, et al Locoregional recurrence patterns after mastectomy and doxorubicin-based chemotherapy: implications for postoperative irradiation.J Clin Oncol2000;18,2817-2827. [PubMed]
 
Hofer, MD, Kuefer, R, Huang, W, et al Prognostic factors in lymph node-positive prostate cancer.Urology2006;67,1016-1021. [PubMed]
 
Sanchez-Ortiz, RF, Pettaway, CA The role of lymphadenectomy in penile cancer.Urol Oncol2004;22,236-244. [PubMed]
 
Junker, K Histopathologic evaluation of mediastinal lymph nodes in lung cancer.Lung Cancer2004;45(suppl 2),S79-S83. [PubMed]
 
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