- Email: [email protected]
Histopathologic evaluation of mediastinal lymph nodes in lung cancer
Lung Cancer 45 Suppl. 2 (2004) S79–S83
www.elsevier.com/locate/lungcan
Histopathologic evaluation of mediastinal lymph nodes in lung cancer K. Junker Institute of Pathology, Bergmannsheil – University Hospital, B¨ urkle-de-la-Camp-Platz 1, D-44789 Bochum, Germany
KEYWORDS Mediastinal lymph node metastases; histopathologic evaluation; therapy-induced tumour regression; isolated tumour cells; micrometastases; EUS-guided fine-needle aspiration
Summary Regional lymph nodes represent the most frequent metastatic site in lung cancer. During histopathologic assessment of lymph-node involvement, in the presence of gross tumour, one or several H&E-stained sections will suffice to demonstrate the tumour and its possible extranodal extension. In the absence of macroscopically detectable metastatic tumour growth, the entire node should be submitted for microscopic examination and be cut into 3- to 4-mm slices in the longitudinal or transverse plane. If the node is sliced, care should be taken to process different surfaces for microscopic examination. After neoadjuvant therapy, the percentage of therapy-induced necrosis and the still vital tumour tissue in the dissected lymph nodes should be estimated microscopically. EUS-guided fine-needle aspiration with subsequent cytologic examination represents a complementary method in the evaluation of mediastinal lymph-node lesions. The proposed way of histopathologic evaluation of mediastinal lymph nodes tries to reach a high diagnostic yield, and to offer a compromise between theoretical demands and practical feasibility. © 2004 Elsevier Science Ltd.
1. Introduction Treatment of lung cancer, especially of non-smallcell lung cancer, is largely determined by the tumour stage at the time of diagnosis. The tumour stage as given in the TNM classification [1] consists of three decisive parameters: the extension of the primary tumour, the involvement of regional lymph nodes, and the occurrence of distant metastases. The assessment of mediastinal lymph nodes gains special importance in the distinction between * PD Dr. Klaus Junker. Tel.: +49-(234)-302-4850; fax: +49-(234)-302-4819. E-mail: [email protected]
locally limited (stages I/II) and locally advanced stages (stages IIIA/IIIB) of lung cancer. Whereas lymph-node involvement generally represents one of the most important prognostic factors in lung cancer, the survival probability is once again negatively influenced by the metastatic spread to mediastinal lymph-node sites.
2. Lymphatic spread of lung cancer Regional lymph nodes represent by far the most frequent metastatic site in lung cancer. In general, in the course of metastatic spread, first bronchopulmonary and hilar lymph nodes are involved, followed by metastases to mediastinal
0169-5002/$ – see front matter © 2004 Published by Elsevier Ireland Ltd. doi:10.1016/j.lungcan.2004.07.000
S80
Fig. 1. Schematic representation of the lymphatic spread of lung cancer depending on its origin from different lobes of the lung (redrawn after Junker and M¨ uller [2]): (A) right upper lobe and middle lobe; (B) right lower lobe; (C) left upper lobe; (D) left lower lobe.
lymph-node stations. Predominantly, ipsilateral mediastinal spread is observed first. But in primary tumours arising from the left lower lobe of the lungs, a predominant involvement of contralateral mediastinal lymph nodes has to be taken into account, the subcarinal lymph-node stations forming the most frequent metastatic site in the mediastinum, occurring from primaries in all lobes with comparable frequency [2] (Figure 1). A station-by-station involvement of the different mediastinal nodes should not be expected, because lymph-node skipping is a frequent observation in lung cancer, independent of the underlying cause [3].
3. Histopathologic lymph-node assessment In mediastinoscopy as well as in patients treated by surgery, the examination of a higher number of lymph nodes increases the likelihood of proper staging and, in patients with stage-I non-smallcell lung cancer, is even said to affect patients’ outcome, obviously predominantly an effect of stage migration [4]. Another factor that influences correct staging is the extent of macroscopic and microscopic work-up. The first prerequisite is a careful macroscopic inspection of all resected intrapulmonary, hilar, and mediastinal lymph nodes or – in the case of mediastinoscopy – of all dissected tissue. Every detectable node should be submitted for microscopic examination. Concerning further histologic evaluation, a compromise has to be
K. Junker found between theoretical demands and practical feasibility. According to calculations by Wilkinson and Hause [5], the failure to identify a tumour within a lymph node is related to the size of the lymph node, the size of the lesion, the number of stations examined, and the location of the tumour within the node. For example, a lymph node of 5 mm diameter with a randomly distributed 1 mm lesion reveals an only 37% chance of identifying the lesion with a single section through the centre of the node. Wilkinson and Hause argue that the common practice of cutting a node in half and placing both cut surfaces in the cassette for further sectioning would not provide any significant advantage in increasing the percentage success of identifying a nodal lesion. On the other hand, according to their recommendations, cutting a lymph node into four nearly equally thick portions (two quarter sections and one centre section) and proper orientation of these slices in the microtome would significantly improve the success of identification of lymph-node metastases, without requiring complicated stepsectioning techniques (Figure 2). For example, in a lymph node of 8 mm diameter with a 2 mm tumour, this approach reaches a 100% chance of identifying the lesion. But this probability declines rapidly in cases with a less favourable proportion between size of tumour and lymph node. Of course, the calculations mentioned above are only of interest in lymph-node biopsies or lymphnode dissections without macroscopically visible metastatic tumour. In the presence of gross tumour, one or several H&E-stained sections will suffice to demonstrate the tumour and its possible extranodal extension [6]. In the absence of macroscopically detectable metastatic tumour growth, the “Association of Directors of Anatomic and Surgical Pathology” [6] recommends to submit the entire node for microscopic examination and to cut it into 3- to 4-mm slices in the longitudinal or transverse
A
B
C
AA BB CC
Cut
A
A
B
B
C
C
Fig. 2. Orientation of sections of a lymph node in the microtome to achieve maximal sampling surface for microscopic examination (redrawn after Wilkinson and Hause [5]).
Histopathologic evaluation of mediastinal lymph nodes in lung cancer plane. Smaller nodes (less than ~4 mm), which cannot be sliced in this manner, may be submitted in toto. If the node is sliced, care should be taken to process different surfaces for microscopic examination (Figure 2). The examination of several levels of each slice, stained with H&E only, is recommended. Additional immunohistochemical analyses may be useful in selected cases, e.g., staining with neuroendocrine markers like chromogranin, synaptophysin, or CD 56 (neural cell adhesion molecule, NCAM) in the assessment of microfocal lymph-node involvement in small-cell lung cancer. Because of the well-known heterogeneity of lung cancer, the histologic tumour type found in the lymph-node metastases may differ from that seen in the primary tumour as a result of selection of special tumour cell clones during the metastatic process [7]. The comparability of lymph-node dissection or mediastinal staging between different hospitals or different trials depends on a standardized documentation. In all corresponding specimens, the different mediastinal lymph-node levels should therefore be specified, for example, according to the Mountain/Dresler mapping scheme [8]. After mediastinal lymph-node dissection and histologic examination, the lymph-node involvement is reported in the pN descriptor according to the “TNM classification of malignant tumours” [1]. According to the corresponding recommendations the pN0 classification requires the histologic evaluation of at least six lymph nodes. In general, far more lymph nodes are microscopically investigated. The number of morphologically assessed lymph nodes as well as the number of lymph nodes with metastatic involvement should be given in the corresponding report. The presence of extranodal extension or of lymphangitic spread in the mediastinal adipose tissue should also be reported.
4. Isolated tumour cells and micrometastases In the evaluation of mediastinal lymph nodes, isolated (disseminated or circulating) tumour cells have to be separated from micrometastases. Whereas isolated tumour cells can only be detected by additional morphological or non-morphological techniques (e.g., immunocytochemistry, polymerase chain reaction), a micrometastasis represents a metastasis with a maximum diameter of 2 mm. In non-small-cell lung cancers with pN0 lymph-node status, isolated tumour cells could be detected in regional lymph nodes of about 15% of the
S81
patients by means of additional immunocytochemical investigations [9]. However, up to now this is not part of a standard morphological evaluation of mediastinal lymph nodes. In the TNM classification, corresponding results should be given separately [10].
5. Therapy-induced tumour regression – mediastinal downstaging After neoadjuvant therapy, the percentage of therapy-induced necrosis and still vital tumour tissue should be estimated microscopically. For this purpose, a regression grading system can be used, including therapy-induced effects in the primary tumour as well as in regional lymph nodes: Grade I:
no or only spontaneous tumour regression in the sections of the primary lesion and regional lymph nodes; Grade II: morphological evidence of therapy-induced tumour regression with Grade IIa: at least 10% residual tumour cells in the sections of the primary lesion and/or regional lymph nodes presenting more than focal microscopic disease, Grade IIb: less than 10% residual tumour cells in the sections of the primary lesion and/or regional lymph nodes presenting focal microscopic disease; Grade III: complete tumour regression with no evidence of vital tumour tissue in the sections of the primary lesion and regional lymph nodes. This regression grading system proved to be a significant prognostic factor in patients with locally advanced non-small-cell lung cancer and tumour resection after neoadjuvant therapy [11–13]. The morphological changes following neoadjuvant therapy do not show qualitative differences in the area of the primary tumour compared to the corresponding lymph-node metastases. But when comparing the single characteristics of therapy– induced tumour regression, marked quantitative differences could be established, indicating that a pathologic complete response could more often be achieved in the former lymph-node metastases (Junker et al., unpublished data). In resection specimens after neoadjuvant therapy, the comparison between the initial clinical lymph node status (N–classification) and the histopathologic evaluation (ypN–classification) results in the so-called mediastinal downstaging, which may be of prognostic relevance for the further outcome of the patients [14]. But according
S82 to own investigations, the grading of therapy– induced tumour regression, considering therapy– induced effects both in the primary tumour and in corresponding lymph-node metastases, seems to be a more precise method for predicting the outcome of the disease than the exclusive assessment of mediastinal downstaging [11].
K. Junker positron emission tomography (PET) is more accurate than computed tomography in the detection of mediastinal lymph-node metastases. Up to 24% of the PET scans, however, show falsepositive results. The histopathologic evaluation has therefore also been recommended in patients with “tumour-positive” mediastinal lymph nodes on PET scans [25–27].
6. Mediastinoscopy Mediastinoscopy will be performed if suspicious or enlarged lymph nodes are detected on radiographic imaging or in computed tomography. The sensitivity of mediastinoscopy in confirming metastases to accessible mediastinal lymph nodes ranges from 79% to 93% [15–17], the specificity in detecting mediastinal lymph-node metastases being 100%. In non-small-cell lung cancer patients with negative mediastinoscopic findings, N2 disease was still identified at thoracotomy in 14.7% [18]. A negative mediastinoscopic finding does therefore not definitely exclude advanced lung cancer. But it is still standard of care that patients with radiographically enlarged mediastinal lymph nodes may not be excluded from potentially curative surgery without histologic or cytologic confirmation of mediastinal lymph-node lesions. For the future, tumour tissue from mediastinal lymph-node biopsies may also be valuable for the assessment of special targets in molecular therapy.
7. Fine-needle aspiration Fine-needle aspiration with subsequent cytologic examination represents an additional method in the evaluation of mediastinal lymph-node lesions. It is of special value in the assessment of lymph nodes not accessible to mediastinoscopy. Fine-needle aspiration can be guided by endotracheal/endobronchial, or endo-oesophageal ultrasound (EUS), or by computed tomography [19]. Prospective trials on patients with lung cancer have shown a sensitivity and specificity of EUS-guided fine-needle aspiration in detecting mediastinal lymph-node metastases ranging from 82% to 96% and 80% to 100%, respectively [20–24]. Sensitivity and specificity of EUS decrease, however, if fine-needle aspiration is not performed. As in mediastinoscopy, a negative finding in EUS-guided fine-needle aspiration does not definitely exclude the presence of metastatic spread to mediastinal lymph nodes.
8. Positron emission tomography Several prospective trials have demonstrated that
9. Conclusion In summary, the proposed way of histopathologic evaluation of mediastinal lymph nodes in patients with lung cancer tries to offer a compromise between theoretical demands and practical feasibility and to reach a high diagnostic yield without employing step-sectioning techniques. Adjustment according to local requirements may, however, be necessary.
References 1. Sobin LH, Wittekind C. TNM Classification of Malignant Tumours, 6th edition. New-York: Wiley-Liss; 2002. 2. Junker K, M¨ uller KM. Metastasierungsmuster beim Bronchialkarzinom. Z Herz Thorax Gef¨ aßchir. 1989;3:189–94. 3. Junker K, Gumprich T, M¨ uller KM. Diskontinuierliche Lymphknotenmetastasen (“skipping”) bei b¨ osartigen Lungentumoren. Chirurg 1997;68:596–9. 4. Gajra A, Newman N, Gamble GP, et al. Effect of number of lymph nodes sampled on outcome in patients with stage I non-small cell lung cancer. J Clin Oncol 2003;21:1029–34. 5. Wilkinson EJ, Hause L. Probability in lymph node sectioning. Cancer 1974;33:1269–74. 6. Silverberg SG, Connolly JL, Dabbs D, et al. Association of directors of anatomic and surgical pathology. Recommendations for processing and reporting of lymph node specimens submitted for evaluation of metastatic disease. Am J Clin Pathol 2001;115:799–801. 7. WHO. Histological Typing of Lung and Pleural Tumours. 3rd edition. Berlin: Springer, 1999. 8. Mountain CF, Dresler CM. Regional lymph node classification for lung cancer staging. Chest 1997;111:1718–23. 9. Passlick B, Izbicki JR, Kubuschok B, et al. Detection of disseminated lung cancer cells in lymph nodes: impact on staging and prognosis. Ann Thorac Surg 1996;61:177–83. 10. Hermanek P, Hutter RVP, Sobin LH. Classification of isolated tumor cells and micrometastasis. Cancer 1999;86:2668–73. 11. Junker K, Langner K, Klinke F, et al. Grading of tumor regression in non-small cell lung cancer: Morphology and prognosis. Chest 2001;120:1584–91. 12. Thomas M, R¨ ube C, Semik M, et al. Impact of preoperative biomodality induction including twice-daily radiation on tumor regression and survival in stage III non-small-cell lung cancer. J Clin Oncol 1999;17:1185–93. 13. Junker K, Thomas M, Schulmann K, et al. Tumour regression in non-small cell lung cancer following neoadjuvant therapy. Histological assessment. J Cancer Res Clin Oncol 1997;123: 469–77. 14. Choi NC, Carey RW, Daly W, et al. Potential impact on survival of improved tumor downstaging and resection rate by preoperative twice-daily radiation and concurrent
Histopathologic evaluation of mediastinal lymph nodes in lung cancer
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21.
chemotherapy in stage IIIA non-small cell lung cancer. J Clin Oncol 1997;15:712–22. Patterson GA, Ginsberg RJ, Poon PY. A prospective evaluation of magnetic resonance imaging, computed tomography, and mediastinoscopy in the preoperative assessment of mediastinal node status in bronchogenic carcinoma. J Thorac Cardiovasc Surg 1987;94:679–84. Coughlin M, Deslauriers J, Beaulieu M. Role of mediastinoscopy in pretreatment staging of patients with primary lung cancer. Am J Surg 1981;47:251–3. Serna DL, Aryan HE, Chang KJ. An early comparison between endoscopic ultrasound-guided fine-needle aspiration and mediastinoscopy for diagnosis of mediastinal malignancy. Am J Surg 1998;64:1014–8. Jolly PC, Hutchinson CH, Detterbeck F. Routine computed tomography scans, selective mediastinoscopy, and other factors in evaluation of lung cancer. J Thorac Cardiovasc Surg 1991;102:266–71. LeBlanc JK, Espada R, Ergun G. Non-small cell lung cancer staging techniques and endoscopic ultrasound: tissue is still the issue. Chest 2003;123:1718–25. Fritscher-Ravens A, Soehendra N, Schirrow L. Role of transoesophageal endosonography-guided fine-needle aspiration in the diagnosis of lung cancer. Chest 2000;117:339–45. Kondo D, Imaizumi M, Abe T. Endoscopic ultrasound
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examination for mediastinal lymph node metastases of lung cancer. Chest 1990;98:586–93. Giovannini M, Seitz JF, Monges G. Fine-needle aspiration cytology guided by endoscopic ultrasonography: results in 141 patients. Endoscopy 1995;27:171–7. Hawes RH, Gress F, Kesler KA. Endoscopic ultrasound versus computed tomography in the evaluation of the mediastinum in patients with non-small cell lung cancer. Endoscopy 1994; 26:784–7. Gress FG, Savides TJ, Sandler A. Endoscopic ultrasonography, fine-needle aspiration biopsy guided by endoscopic ultrasonography, and computed tomography in the preoperative staging of non-small cell lung cancer: a comparison study. Ann Intern Med 1997;127:604–7. Platz EF, Lowe VJ, Goodman PC. Thoracic nodal staging with PET imaging with 18FDG in patients with bronchogenic carcinoma. Chest 1995;108:1617–21. Steinert HC, Hauser M, Allemann F. Non-small cell lung cancer: nodal staging with FDG PET versus CT with correlative lymph node mapping and sampling. Radiology 1997;202:441–6. Roberts PF, Follette DM, von Haag D. Factors associated with false-positive staging of lung cancer by positron emission tomography. Ann Thorac Surg 2000;70:1154–9.
www.elsevier.com/locate/lungcan
Histopathologic evaluation of mediastinal lymph nodes in lung cancer K. Junker Institute of Pathology, Bergmannsheil – University Hospital, B¨ urkle-de-la-Camp-Platz 1, D-44789 Bochum, Germany
KEYWORDS Mediastinal lymph node metastases; histopathologic evaluation; therapy-induced tumour regression; isolated tumour cells; micrometastases; EUS-guided fine-needle aspiration
Summary Regional lymph nodes represent the most frequent metastatic site in lung cancer. During histopathologic assessment of lymph-node involvement, in the presence of gross tumour, one or several H&E-stained sections will suffice to demonstrate the tumour and its possible extranodal extension. In the absence of macroscopically detectable metastatic tumour growth, the entire node should be submitted for microscopic examination and be cut into 3- to 4-mm slices in the longitudinal or transverse plane. If the node is sliced, care should be taken to process different surfaces for microscopic examination. After neoadjuvant therapy, the percentage of therapy-induced necrosis and the still vital tumour tissue in the dissected lymph nodes should be estimated microscopically. EUS-guided fine-needle aspiration with subsequent cytologic examination represents a complementary method in the evaluation of mediastinal lymph-node lesions. The proposed way of histopathologic evaluation of mediastinal lymph nodes tries to reach a high diagnostic yield, and to offer a compromise between theoretical demands and practical feasibility. © 2004 Elsevier Science Ltd.
1. Introduction Treatment of lung cancer, especially of non-smallcell lung cancer, is largely determined by the tumour stage at the time of diagnosis. The tumour stage as given in the TNM classification [1] consists of three decisive parameters: the extension of the primary tumour, the involvement of regional lymph nodes, and the occurrence of distant metastases. The assessment of mediastinal lymph nodes gains special importance in the distinction between * PD Dr. Klaus Junker. Tel.: +49-(234)-302-4850; fax: +49-(234)-302-4819. E-mail: [email protected]
locally limited (stages I/II) and locally advanced stages (stages IIIA/IIIB) of lung cancer. Whereas lymph-node involvement generally represents one of the most important prognostic factors in lung cancer, the survival probability is once again negatively influenced by the metastatic spread to mediastinal lymph-node sites.
2. Lymphatic spread of lung cancer Regional lymph nodes represent by far the most frequent metastatic site in lung cancer. In general, in the course of metastatic spread, first bronchopulmonary and hilar lymph nodes are involved, followed by metastases to mediastinal
0169-5002/$ – see front matter © 2004 Published by Elsevier Ireland Ltd. doi:10.1016/j.lungcan.2004.07.000
S80
Fig. 1. Schematic representation of the lymphatic spread of lung cancer depending on its origin from different lobes of the lung (redrawn after Junker and M¨ uller [2]): (A) right upper lobe and middle lobe; (B) right lower lobe; (C) left upper lobe; (D) left lower lobe.
lymph-node stations. Predominantly, ipsilateral mediastinal spread is observed first. But in primary tumours arising from the left lower lobe of the lungs, a predominant involvement of contralateral mediastinal lymph nodes has to be taken into account, the subcarinal lymph-node stations forming the most frequent metastatic site in the mediastinum, occurring from primaries in all lobes with comparable frequency [2] (Figure 1). A station-by-station involvement of the different mediastinal nodes should not be expected, because lymph-node skipping is a frequent observation in lung cancer, independent of the underlying cause [3].
3. Histopathologic lymph-node assessment In mediastinoscopy as well as in patients treated by surgery, the examination of a higher number of lymph nodes increases the likelihood of proper staging and, in patients with stage-I non-smallcell lung cancer, is even said to affect patients’ outcome, obviously predominantly an effect of stage migration [4]. Another factor that influences correct staging is the extent of macroscopic and microscopic work-up. The first prerequisite is a careful macroscopic inspection of all resected intrapulmonary, hilar, and mediastinal lymph nodes or – in the case of mediastinoscopy – of all dissected tissue. Every detectable node should be submitted for microscopic examination. Concerning further histologic evaluation, a compromise has to be
K. Junker found between theoretical demands and practical feasibility. According to calculations by Wilkinson and Hause [5], the failure to identify a tumour within a lymph node is related to the size of the lymph node, the size of the lesion, the number of stations examined, and the location of the tumour within the node. For example, a lymph node of 5 mm diameter with a randomly distributed 1 mm lesion reveals an only 37% chance of identifying the lesion with a single section through the centre of the node. Wilkinson and Hause argue that the common practice of cutting a node in half and placing both cut surfaces in the cassette for further sectioning would not provide any significant advantage in increasing the percentage success of identifying a nodal lesion. On the other hand, according to their recommendations, cutting a lymph node into four nearly equally thick portions (two quarter sections and one centre section) and proper orientation of these slices in the microtome would significantly improve the success of identification of lymph-node metastases, without requiring complicated stepsectioning techniques (Figure 2). For example, in a lymph node of 8 mm diameter with a 2 mm tumour, this approach reaches a 100% chance of identifying the lesion. But this probability declines rapidly in cases with a less favourable proportion between size of tumour and lymph node. Of course, the calculations mentioned above are only of interest in lymph-node biopsies or lymphnode dissections without macroscopically visible metastatic tumour. In the presence of gross tumour, one or several H&E-stained sections will suffice to demonstrate the tumour and its possible extranodal extension [6]. In the absence of macroscopically detectable metastatic tumour growth, the “Association of Directors of Anatomic and Surgical Pathology” [6] recommends to submit the entire node for microscopic examination and to cut it into 3- to 4-mm slices in the longitudinal or transverse
A
B
C
AA BB CC
Cut
A
A
B
B
C
C
Fig. 2. Orientation of sections of a lymph node in the microtome to achieve maximal sampling surface for microscopic examination (redrawn after Wilkinson and Hause [5]).
Histopathologic evaluation of mediastinal lymph nodes in lung cancer plane. Smaller nodes (less than ~4 mm), which cannot be sliced in this manner, may be submitted in toto. If the node is sliced, care should be taken to process different surfaces for microscopic examination (Figure 2). The examination of several levels of each slice, stained with H&E only, is recommended. Additional immunohistochemical analyses may be useful in selected cases, e.g., staining with neuroendocrine markers like chromogranin, synaptophysin, or CD 56 (neural cell adhesion molecule, NCAM) in the assessment of microfocal lymph-node involvement in small-cell lung cancer. Because of the well-known heterogeneity of lung cancer, the histologic tumour type found in the lymph-node metastases may differ from that seen in the primary tumour as a result of selection of special tumour cell clones during the metastatic process [7]. The comparability of lymph-node dissection or mediastinal staging between different hospitals or different trials depends on a standardized documentation. In all corresponding specimens, the different mediastinal lymph-node levels should therefore be specified, for example, according to the Mountain/Dresler mapping scheme [8]. After mediastinal lymph-node dissection and histologic examination, the lymph-node involvement is reported in the pN descriptor according to the “TNM classification of malignant tumours” [1]. According to the corresponding recommendations the pN0 classification requires the histologic evaluation of at least six lymph nodes. In general, far more lymph nodes are microscopically investigated. The number of morphologically assessed lymph nodes as well as the number of lymph nodes with metastatic involvement should be given in the corresponding report. The presence of extranodal extension or of lymphangitic spread in the mediastinal adipose tissue should also be reported.
4. Isolated tumour cells and micrometastases In the evaluation of mediastinal lymph nodes, isolated (disseminated or circulating) tumour cells have to be separated from micrometastases. Whereas isolated tumour cells can only be detected by additional morphological or non-morphological techniques (e.g., immunocytochemistry, polymerase chain reaction), a micrometastasis represents a metastasis with a maximum diameter of 2 mm. In non-small-cell lung cancers with pN0 lymph-node status, isolated tumour cells could be detected in regional lymph nodes of about 15% of the
S81
patients by means of additional immunocytochemical investigations [9]. However, up to now this is not part of a standard morphological evaluation of mediastinal lymph nodes. In the TNM classification, corresponding results should be given separately [10].
5. Therapy-induced tumour regression – mediastinal downstaging After neoadjuvant therapy, the percentage of therapy-induced necrosis and still vital tumour tissue should be estimated microscopically. For this purpose, a regression grading system can be used, including therapy-induced effects in the primary tumour as well as in regional lymph nodes: Grade I:
no or only spontaneous tumour regression in the sections of the primary lesion and regional lymph nodes; Grade II: morphological evidence of therapy-induced tumour regression with Grade IIa: at least 10% residual tumour cells in the sections of the primary lesion and/or regional lymph nodes presenting more than focal microscopic disease, Grade IIb: less than 10% residual tumour cells in the sections of the primary lesion and/or regional lymph nodes presenting focal microscopic disease; Grade III: complete tumour regression with no evidence of vital tumour tissue in the sections of the primary lesion and regional lymph nodes. This regression grading system proved to be a significant prognostic factor in patients with locally advanced non-small-cell lung cancer and tumour resection after neoadjuvant therapy [11–13]. The morphological changes following neoadjuvant therapy do not show qualitative differences in the area of the primary tumour compared to the corresponding lymph-node metastases. But when comparing the single characteristics of therapy– induced tumour regression, marked quantitative differences could be established, indicating that a pathologic complete response could more often be achieved in the former lymph-node metastases (Junker et al., unpublished data). In resection specimens after neoadjuvant therapy, the comparison between the initial clinical lymph node status (N–classification) and the histopathologic evaluation (ypN–classification) results in the so-called mediastinal downstaging, which may be of prognostic relevance for the further outcome of the patients [14]. But according
S82 to own investigations, the grading of therapy– induced tumour regression, considering therapy– induced effects both in the primary tumour and in corresponding lymph-node metastases, seems to be a more precise method for predicting the outcome of the disease than the exclusive assessment of mediastinal downstaging [11].
K. Junker positron emission tomography (PET) is more accurate than computed tomography in the detection of mediastinal lymph-node metastases. Up to 24% of the PET scans, however, show falsepositive results. The histopathologic evaluation has therefore also been recommended in patients with “tumour-positive” mediastinal lymph nodes on PET scans [25–27].
6. Mediastinoscopy Mediastinoscopy will be performed if suspicious or enlarged lymph nodes are detected on radiographic imaging or in computed tomography. The sensitivity of mediastinoscopy in confirming metastases to accessible mediastinal lymph nodes ranges from 79% to 93% [15–17], the specificity in detecting mediastinal lymph-node metastases being 100%. In non-small-cell lung cancer patients with negative mediastinoscopic findings, N2 disease was still identified at thoracotomy in 14.7% [18]. A negative mediastinoscopic finding does therefore not definitely exclude advanced lung cancer. But it is still standard of care that patients with radiographically enlarged mediastinal lymph nodes may not be excluded from potentially curative surgery without histologic or cytologic confirmation of mediastinal lymph-node lesions. For the future, tumour tissue from mediastinal lymph-node biopsies may also be valuable for the assessment of special targets in molecular therapy.
7. Fine-needle aspiration Fine-needle aspiration with subsequent cytologic examination represents an additional method in the evaluation of mediastinal lymph-node lesions. It is of special value in the assessment of lymph nodes not accessible to mediastinoscopy. Fine-needle aspiration can be guided by endotracheal/endobronchial, or endo-oesophageal ultrasound (EUS), or by computed tomography [19]. Prospective trials on patients with lung cancer have shown a sensitivity and specificity of EUS-guided fine-needle aspiration in detecting mediastinal lymph-node metastases ranging from 82% to 96% and 80% to 100%, respectively [20–24]. Sensitivity and specificity of EUS decrease, however, if fine-needle aspiration is not performed. As in mediastinoscopy, a negative finding in EUS-guided fine-needle aspiration does not definitely exclude the presence of metastatic spread to mediastinal lymph nodes.
8. Positron emission tomography Several prospective trials have demonstrated that
9. Conclusion In summary, the proposed way of histopathologic evaluation of mediastinal lymph nodes in patients with lung cancer tries to offer a compromise between theoretical demands and practical feasibility and to reach a high diagnostic yield without employing step-sectioning techniques. Adjustment according to local requirements may, however, be necessary.
References 1. Sobin LH, Wittekind C. TNM Classification of Malignant Tumours, 6th edition. New-York: Wiley-Liss; 2002. 2. Junker K, M¨ uller KM. Metastasierungsmuster beim Bronchialkarzinom. Z Herz Thorax Gef¨ aßchir. 1989;3:189–94. 3. Junker K, Gumprich T, M¨ uller KM. Diskontinuierliche Lymphknotenmetastasen (“skipping”) bei b¨ osartigen Lungentumoren. Chirurg 1997;68:596–9. 4. Gajra A, Newman N, Gamble GP, et al. Effect of number of lymph nodes sampled on outcome in patients with stage I non-small cell lung cancer. J Clin Oncol 2003;21:1029–34. 5. Wilkinson EJ, Hause L. Probability in lymph node sectioning. Cancer 1974;33:1269–74. 6. Silverberg SG, Connolly JL, Dabbs D, et al. Association of directors of anatomic and surgical pathology. Recommendations for processing and reporting of lymph node specimens submitted for evaluation of metastatic disease. Am J Clin Pathol 2001;115:799–801. 7. WHO. Histological Typing of Lung and Pleural Tumours. 3rd edition. Berlin: Springer, 1999. 8. Mountain CF, Dresler CM. Regional lymph node classification for lung cancer staging. Chest 1997;111:1718–23. 9. Passlick B, Izbicki JR, Kubuschok B, et al. Detection of disseminated lung cancer cells in lymph nodes: impact on staging and prognosis. Ann Thorac Surg 1996;61:177–83. 10. Hermanek P, Hutter RVP, Sobin LH. Classification of isolated tumor cells and micrometastasis. Cancer 1999;86:2668–73. 11. Junker K, Langner K, Klinke F, et al. Grading of tumor regression in non-small cell lung cancer: Morphology and prognosis. Chest 2001;120:1584–91. 12. Thomas M, R¨ ube C, Semik M, et al. Impact of preoperative biomodality induction including twice-daily radiation on tumor regression and survival in stage III non-small-cell lung cancer. J Clin Oncol 1999;17:1185–93. 13. Junker K, Thomas M, Schulmann K, et al. Tumour regression in non-small cell lung cancer following neoadjuvant therapy. Histological assessment. J Cancer Res Clin Oncol 1997;123: 469–77. 14. Choi NC, Carey RW, Daly W, et al. Potential impact on survival of improved tumor downstaging and resection rate by preoperative twice-daily radiation and concurrent
Histopathologic evaluation of mediastinal lymph nodes in lung cancer
15.
16.
17.
18.
19.
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