Lung Cancer 24

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Introduction

In recent decades, lung cancer has been divided into two main groups: small-cell lung cancers (SCLC) and non-small-cell cancers (NSCLC). The second groupis made upof squamous-, adeno-, and large-cell and giant-cell cancers.

This simple scheme is based on the fact that in the past small-cell cancers were regarded primarily as systemic diseases and therefore largely excluded from surgical treatment. In contrast, non-small-cell cancers, at least in their early stages, were regarded as potentially operable. However, the exact N-status can only be documented by pre-, intra- or postoperative histological examination of the locoregional lymph nodes (N1±3). This principle has so far been accepted as essential to postoperative supportive radiotherapy of the locoregional fields and adjuvant chemotherapeutic regimens. How- ever, the therapeutic regimens yield only limited success. Therefore, improvement of therapeutic modalities for both locoregional and distant metastases will not be possible until we also have more accurate preoperative staging methods. Pre- operative mediastinoscopy has been shown to have only limited success in lymph node staging (Drings 1998). Therefore, more effective radiological or scintigraphic methods would also be very valuable for surgical planning.

Recently, discussion about how to improve surgical treatment in general, and surgical treatment for the early stages of small-cell (oat-cell) cancers in particular, has arisen and intensified throughout the world. In this context, it is clear that a new concept of diagnosis and therapy also needs new synergistic approaches to locoregional lymph node staging.

However, before we analyze the methods and possibilities of N-staging, especially with a view to sentinel lymph node (SLN) detection, the principles of detection and localization of lung primaries should be discussed.

Initial Laboratory Investigations other than Radiodiagnosis and Histo-/Cytological Analysis to Assure Diagnosis and Subtype of Lung Cancer Besides biopsy and cytopathological investigations there are some clinical and serological (paraneo- plastic) signs that can point us in the right direction in the search for lung cancer. In addition to the question of operability and sentinel node detection, these findings can also be helpful in the differential diagnosis between small-cell cancer, which is mostly not operable, and non-small-cell cancer, which can be more closely evaluated from the aspect of operability.

These clinical signs are summarized in Table 1.

Useful Serological Parameters in Confirmation of SCLC

In the attempt to achieve an initial separation between small-cell types (oat-cell, or round-cell subtype) of lung cancer for systemic therapeutic treatment, a serological analysis of neural cell adhesion molecule (NCAM) and neuron-specific enolase (NSE) values can be helpful to confirm small-cell anaplastic cancers or at least to detect this type as a component of the neoplastic lesion. The values obtained in the investigation of 221 cases are listed in Table 2.

Chapter 24

Lung Cancer 24

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Is N0-status Predictable in Cases

with Normal CEA Values and a Tumor Shadow Disappearance Rate of 0.8 or More?

Takamochi et al. (2001) investigated 269 cases of pulmonary adenocarcinoma. They found that normal serum CEA values and tumor shadow disappearance rate (TDR) of0.8 or more on CT investigation were accompanied by a zero N-stage.

The authors reviewed contrast-enhanced CT scans and recorded the maximum dimension of each tumor both on pulmonary (pDmax) and on mediastinal (mDmax) window setting images, the largest dimension perpendicular to the maximum axis on both pulmonary (pDperp) and mediastinal (mDperp) window setting images, and the sizes of all detectable hilar mediastinal lymph nodes. The definition of a new radiological parameter, tumor shadow disappearance rate (TDR), is calculated from the following formula:

TDR 1 mDmax mDperp=pDmax

pDperp :

The conclusion reached by the authors might be helpful in decision making when patients undergo lymph node staging.

Elimination of Peripheral Noncancerous Lesions and Confirmation of Peripheral (Scar) Cancers Primarily unclear results on clinical examination and on imaging investigations sometimes influence the decision on whether a sentinel node search will later be necessary for N-staging.

Such lesions are:

· The unclear ªperipheral round focus,º which makes extirpation and intraoperative histopathological diagnosis necessary (Fig. 1). Before any cancer treatment the round, mostly infracla- vicular, focus must be evaluated:

± Round foci of tuberculosis (formerly known as ªAssmann fociº with dust-like calcifications) must be ruled out (sputum, tuberculin test, search for Simon apical foci, etc.)

± Hamartomas often have a chondroma-like structure with associated glandular broncho- genic structures on X-ray pictures; the chon- Table 1. Clinical signs characteristic for different subtypes

oflung cancer Signs/clinical

diagnosis Hormone

activity/

symptoms

Subtype oflung cancer

Syndrome Ectopically pro- duced hormone activity and symptoms Hyperpara-

thyroidism Parathormone

(hypercalcemia) Squamous cell cancer Cushing syn-

drome ACTH or ACTH-

like substance Small-cell cancer Hypertension,

hypoglycemia, hypokalemia Inappropriate

antidiuretic hormone pro- duction (SIADH)

Blood sodium

low Small cell cancer

Clinical

diagnosis Symptoms

Peripheral

neuropathy Weakness ofdis-

tal extremities All subtypes, quite common in small cell cancer-cases Myopathy Muscular weak-

ness in proximal extremities

All subtypes, quite common in small cell cancer-cases

Table 2.Neural cell adhesion molecule (NCAM) and neuron- specific enolase (NSE), tumor markers ofsmall cell anaplastic bronchial cancer. Values increase with extension ofdis- ease

Marker No. of positive

cases % Value of

measure

NCAM 113/221 51 >20 ll

NSE 75/221 34 >25 ll

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droma-like proliferations often show minimal dust-like calcifications similar to tubercular foci. Intraoperatively these lesions can be identified in frozen sections, and cancer can be ruled out or confirmed.

The group of peripheral lung cancers, some decades ago often confused with residual tuberculosis (ªperipheral scar cancerº) and more frequent at that time than scarring is now, is of special interest:

± Because ± as already mentioned ± not all pulmonary foci of this special category are primary lung cancers.

± Because this category can be analyzed and the diagnosis can be made with the aid of video-assisted thoracoscopic lung biopsy.

± The search for sentinel lymph node(s) (SLN) can easily be carried out intraoperatively, for instance by peritumoral blue dye injection.

However, the real problem is that not all typi- cally located nodules are primary cancerous lesions. In a series investigated by Murasugi et al. (2001), of 81 patients only 44 (55%) had malignancies, which were primary cancers in 28 cases and metastatic lesions in 16.

This splitting into primaries and metastatic cancers demonstrates that the sentinel node concept cannot be applied until after the diagnosis has been confirmed by histopathological and, in some cases, additional immunohistochemical evaluations.

· Early outbreak of a peripheral cancer into the regional soft tissue (e.g., ªPancoast tumorº) (Fig. 2)

± In most cases, this tumor type is highly aggressive. It is characterized by fast progres- Elimination of Peripheral Noncancerous Lesions and Confirmation of Peripheral (Scar) Cancers 303

Fig. 1.Peripheral lung cancer, often observed as round focus.

NB: A clear cancer diagnosis must be made as early as possible. Approximately 20±30% of lung cancers have more or less peripheral localizations. Labeling of SLN by endoscopic or peritumoral injection of marker solution is possible. Radio- logical examination reveals a so-called peripheral round focus. Differential diagnosis must include, in particular: (a) cancer, (b) tuberculosis, (c) hamartoma. Diagnosis can be made by endobronchial biopsy or, if this is not possible, by transthoracic aspiration cytology. When (b) or (c) is suspected, excision should be performed via thoracotomy, fol- lowed by (b) tuberculostatic therapy or (c) no further treatment. In cancer cases a search for the sentinel lymph node (SLN) should be carried out, as should N-staging

Fig. 2.Peripheral lung cancer breaking out into the regional soft tissue parts and facultative cancer infiltration of stellate ganglion; cervical lymph nodes may be already involved.

Therefore, a SLN search by radioimaging is of no value; in addition, even special labeling of SLNs has no value. Break- out type ? Pancoast tumor with Horner symptom complex in later stages, when stellate ganglion has already been infiltrated by cancer. N- and M-staging should be performed, but no isolated SLN search

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sion and, in most cases, high proliferation activity (high S-phase values, high MiB I values, and high rate ofmitoses).

· Multifocal peripheral bronchioloalveolar cancers, partly with massive mucus formation (Fig. 3).

Primary Multicentricity of Lung Cancer:

Compatibility with the SLN Concept?

In lung cancer treatment, in the clinical and radiodiagnostic investigations synchronous multicentricity and back-metastasis to the lungs must be distinguished. It is essential that this is done before mediastinoscopy and/or SLN labeling is started. In this context it must also be emphasized that primary multicentricity does not contraindi-

cate surgical treatment, which can sometimes be curative.

With regard to this point, it must be emphasized that, at least in cases with ipsilateral multicentricity, the surgical treatment is basically not different from lobectomy or pneumectomy procedures in cases with unifocal lung cancers. In cases with bilateral cancer foci, in addition to lobectomy or pneumectomy on the side with more intensive cancer involvement, laser and irradiation therapy ofsmaller foci on the contralateral side are considered and performed, as well as lymphadenectomy.

Because some ofthese multifocal cancer types have low degrees ofmalignancy, the 78.3% 5-year survival rate published by Kawashima (2002) is not too astonishing.

Kawashima et al. collected 33 cases ofmulti- centric carcinomas. The results are listed briefly in Table 3.

Fig. 3.Bronchioloalveolar cancer subtype. Because ofpossible multifocality exact preliminary diagnosis must be made before the SLN search. In bronchioloalveolar cancer there are dissemi- nated cancer foci; this condition is referred to as ªholoblastosisº in older publications and is bilateral in 5±10% of cases. Left: nodal type; right: pneumonia-like tumor growth pattern. Caveat:

without due care acute asphyxia can arise during endoscopy in the case of the mucinous subtype, as a result of mucus aspiration

Table 3.Data recorded in 33 cases with synchronous multicentricity treated by Kawashima et al. (2002) No. of

patients Male Female Mean age/

range Ipsilateral Bilateral involvement

Adeno-Ca Adeno- and other types

Overall 5 year survival

33 20 13 67; 51±79 27 6 12 (36%) 6 (18.2%) 78.3%

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Stage-adapted Diagnostic Strategies Related to the SLN Concept

With regard to the SLN concept and procedures along it, it must be pointed out that

· All noninvasive diagnostic procedures can be helpful before the sentinel node search is started.

· All invasive surgical procedures serving the staging can locally change the lymphatic flow and make the SLN search impossible.

Therefore, we need a very clear-cut diagnostic and staging concept which does not interrupt the normal lymphatic flow and thereby make the SLN search impossible.

The following sequence of evaluations seems to be possible:

· A first stepshould be evaluation by radioimaging (PET, PET plus CT or MRI) plus serological investigations (NCAM, NSE, etc.) in order to rule out inoperable cases.

· A second stepin cases that are not advanced is histo- and/or cytopathological confirmation of cancer in biopsy and/or smear material following endobronchial sampling or transthoracic puncture, etc.

· A last stepbefore operation is mediastinoscopy, the aim being:

± Confirmation of the diagnosis: in this case the sentinel node concept (intraoperative peritumoral blue dye injection) can still be applied, or

± Decision between mediastinal lymph node dissection (MLND) versus systematic node dissection (SS), which influences the lymphatic drainage. In such cases application of the SLN concept can lead to inadequate results.

The different points are analyzed, explained, and discussed in more detail below.

Significance of PET in Staging Lung Cancer Introductory Remarks

There is as yet no uniform system for detecting tumor-free or tumor-infiltrated SLNs in lung cancer with high levels of sensitivity and specificity. It will be easily understood that the development of a plausible and rational basic concept for this tumor type is extremely difficult.

With all this in mind, it is clear that any methods that make it possible to detect cancer-infiltrated lymph nodes already in the presurgical stage would be highly valuable with a view to treatment strategies. In addition, it must be said that preoperative N-staging is performed almost exclusively in NSCLC cases and only rarely in cases of SCLC (Fig. 4).

Significance of PETin Staging Lung Cancer 305

Fig. 4.Lung cancer with hilar and mediastinal lymph node metastases. The cor- onal PET image shows an area of focally increased metabolic activity in the upper lobe of the right lung (P). In addition, there are positive lymph nodes in the right hilar region and in the mediastinum (LN)

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T-staging Supported by FDG-PET

FDG-PET is particularly accurate in detecting malignant pulmonary lesions. Lung cancer shows a high uptake of FDG, whereas background activity in the normal lung and mediastinum is generally low. Numerous studies have demonstrated that FDG-PET is the most accurate noninvasive method of detecting and staging lung cancer. The evaluation of solitary pulmonary nodules was one of the earliest applications of FDG-PET for extracranial tumors. Prospective studies have shown that FDG- PET has both sensitivity and specificity of approximately 90% in the evaluation of solitary pulmonary nodules (Coleman 1999; Marom et al. 2000).

False-positive findings are caused by inflammatory processes, such as tuberculomas, aspergillosis, and coccidioidomycosis. Accordingly, the specificity of FDG-PET tends to be lower in countries where these diseases are endemic.

False-negative findings can be due to several factors: for example the sensitivity of current PET scanners for lesions with a diameter of less than 1 cm is lower than for larger lesions owing to par- tial volume effects. More importantly, some subtypes of malignant tumors, e.g. carcinoids and bronchioloalveolar carcinomas, show only a small amount of FDG accumulation and may give false- negative results despite being greater than 1 cm in diameter (Erasmus et al. 1998; Higashi et al. 1998).

Kalff et al. prospectively studied the impact of FDG-PET on the clinical management of 105 patients with NSCLC (Kalff et al. 2001). Indications for PET were primary staging (n =59), restaging (n=34), and suspected malignancy, subsequently confirmed as NSCLC (n=12). In 27 (26%) of the 105 cases, PET results led to a change from curative to palliative therapy after up-staging of disease extent. PET appropriately down-staged 10 of 16 patients initially scheduled for palliative therapy, al- lowing potentially curative treatment in 4 patients and no treatment in 6 patients. PET influenced the radiation delivered in 22 (65%) of 34 patients who subsequently received radical radiotherapy. Twelve patients considered ªprobably inoperableº on conventional imaging studies were down-staged by PET and underwent potentially curative surgery.

PET missed only 1 primary tumor, which was a 5- mm scar carcinoma.

CT and PET understaged 3 of 20 surgical patients, 2 with N1 lesions (<5 mm) and 1 with un-

recognized atrial involvement, and PET failed to detect 1 small intrapulmonary metastasis that was apparent on CT. No pathological N2 disease was missed by PET. FDG-PET changed or influenced management decisions in 70 patients (67%) with NSCLC: patients were frequently spared unnecessary treatment, and management was more appropriately targeted. However, FDG-PET cannot be seen as a replacement for invasive diagnostic procedures.

N-staging [Search for Cancer-infiltrated SLN(s)]

by FDG-PET

Comparisons with Results of CT

Several studies have evaluated the application of FDG-PET for mediastinal staging of lung cancer.

The criteria for the analysis of mediastinal lymph node involvement varied between studies. Some investigators reported sensitivity and specificity on a patient basis, while others determined the number of mediastinal sites involved, and still others analyzed the number of lymph node regions involved. Nevertheless, in all studies reported so far, FDG-PET was found to be significantly more accurate than CT for mediastinal staging of lung cancer. Vansteenkiste et al. performed a prospective study of 690 lymph node stations from 68 patients with potentially operable NSCLC (Vansteenkiste et al. 1998). CT correctly identified the nodal stage in 40 patients (59%), with understaging in 12 patients and overstaging in 16 patients. PET combined with CT was accurate in 59 patients (87%), with understaging in 5 patients and overstaging in 4 patients.

For detecting locally advanced disease (N2/N3), the sensitivity, specificity, and accuracy for PET combined with CT were 93%, 95%, and 94% respectively, compared with 75%, 63%, and 68% for CT alone. Pieterman et al. prospectively compared the ability of a standard approach including CT, ultrasonography, bone scanning, and, when indicated, needle biopsies with FDG-PET to detect metastases in mediastinal lymph nodes and at distant sites in 102 patients with resectable NSCLC (Pieter- man et al. 2000). The sensitivity and specificity of PET for the detection of mediastinal metastases were 91% and 86%, respectively; the correspond- ing values for CT were 75% and 66%. When the results of PET and CT were adjusted for each other,

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only PET results were positively correlated with the histopathological findings in mediastinal lymph nodes. PET identified distant metastases that had not been found by conventional imaging modalities in 11 of 102 patients. The sensitivity and specificity of PET for the detection of both mediastinal and distant metastatic disease were 95% and 83%, respectively. An important finding in this study was that when FDG-PET was used to identify the stage of disease a different stage was found from that determined by standard methods in 62 patients: a lower stage in 20 and a more advanced stage in 42. Gupta et al. assessed the comparative efficacy of FDG-PET in the evaluation of small (<1 cm), intermediate (1±3 cm), and large (>3 cm) lymph node lesions in 54 patients (Gupta et al. 2000). PET was accurate in 94% of patients in lymph node staging, as opposed to 61% with CT. Overall, the sensitivity, specificity, and accuracy of PET for staging mediastinal lymph nodes (N=168) was 96%, 93%, and 94%, as against 68%, 65%, and 66% with CT. The positive and negative predictive values of PET in detecting mediastinal adenopathy were 86% and 98%, as opposed to 47% and 82%, respectively, with CT. PET was also very reliable and had superior accuracy (95%) in detecting lymph nodes smaller than 1 cm in size.

Farrell et al. used FDG-PET for nodal staging in 84 patients with stage I NSCLC (Farrell et al.

2000). On comparison of stages determined by PET and by histopathological investigation, the disease was found to have been accurately determined by PET in 72 (86%) patients, understaged in 2 (2%), and overstaged in 10 patients (12%).

The overall sensitivity and specificity of PET were 82% and 86%, respectively. For a meta-analysis of FDG-PET and CT for detecting mediastinal nodal metastases in patients with NSCLC, 14 studies involving 514 patients assessed by FDG-PET and 29 studies involving 2226 patients studied with CT were selected. PET was significantly more accurate than CT in the demonstration of nodal metastases.

The mean sensitivity and specificity were 79% and 91%, respectively, for PET and 60% and 77%, respectively, for CT.

Conclusions

Generally, false-positive PET results occur because of inflammatory reactions in lymph nodes (e.g., sarcoidosis). Therefore, it is mandatory that mediastinoscopy is performed for histological confirmation of positive PET results. However, owing to its high sensitivity for mediastinal lymph node involvement, FDG-PET may assist in the selection of surgically curable candidates. Thus, patients with negative PET scans may proceed to surgery without further invasive diagnostic procedures. In addition, whole-body PET studies detect metastatic disease that is not found by conventional imaging modalities and demonstrate that some of the ana- tomical abnormalities shown on CT are benign.

Management has been reported to be changed in upto 41% of patients on the basis of the results of whole-body studies.

Stage Values of PET-CT-MRI Pre-evaluation, Mediastinoscopy and SLN Search in N-staging of NSCLC

Limited Value of Regional Surgical Cancer Clearance Lloyd and Silvestry (2001) have appealed more than once for every effort to be made to carry out accurate investigation of the mediastinal nodes in cases of NSCLC, specifying that CT should be sup- plemented by PET and endoscopic ultrasound so- nography. In addition, for histo- and cytopathological confirmation of the cancer diagnosis transbronchial and/or transcarinal punctures should be carried out.

With further research using the new improved techniques: CT, PET, endoscopic ultrasound sono- graphy, and transbronchial biopsy or fine-needle aspiration cytology (FNAC), widespread improvement in the accuracy of pretreatment staging of NSCLC will be possible.

Quite lately, McManus et al. (2001) published an overview of the pattern- and organ-related frequencies of distant metastases from NSCLC evaluated by prestaging PET investigations in the different stages. The results are shown in Table 4.

Stage Values of PET-CT-MRI Pre-evaluation, Mediastinoscopy and SLN Search in N-staging of NSCLC 307

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Pattern of Distant (Hematogenous) Metastases fromLung Cancer

The pattern summarized for distant metastasis is highly characteristic for lung cancer, and especially for the small-cell (anaplastic, ªoat-cellº) type; but high-grade adenocarcinomas and anaplastic squamous cell cancers also develop metastases in the organs listed (see Fig. 5). After confirmation of the diagnosis oflung cancer by biopsy or cytology and before local SLN labeling, N-staging, and surgical treatment (lobectomy, pneumectomy) the organs listed and the skeleton must be carefully checked by radiodiagnostic imaging to exclude the presence at least of any currently detectable distant metastasis.

Besides the well-known possibility ofmetastatic involvement ofbrain, liver, kidney, and skeleton, the possibility ofso-called endocrine metastasis into the thyroid gland, the adrenals, and the pan- creas must also be considered and should be carefully checked for by means of the radiodiagnostic imaging techniques (Fig. 5).

Confirmation of the Lung Cancer Diagnosis Using Histo- and Cytopathological Principles J Routine Methods

Bronchoscopy, in which minibiopsy specimens are taken from suspicious areas and which can reach bronchi ofthe fourth, or sometimes even the fifth order oframification, and endobronchial cytology (smears) are the main sources ofmaterial for confirmation of the diagnosis of lung cancer. As a rule, this diagnostic principle can also make it possible to discriminate between small-cell and non-small-cell cancer.

Ifthe diagnosis cannot be made by these techniques, there are still further methods that can make it possible: transcarinal lymph node puncture (especially for cancers of the lower lobes) (Fig. 6) and transthoracic FNAC for peripheral lung cancers.

J More Aggressive Diagnostic Principles

In most lung cancer clinics mediastinoscopy is one ofthe methods routinely used in diagnosis. This method is used to confirm a diagnosis of lung cancer on the one hand, and to exclude other malignant diseases, such as lymphomas, thymomas and Hodgkin's disease, on the other. In addition, mediastinoscopy is helpful in lung cancer staging.

Whereas in bilateral lung cancers N1 sites can seldom be reached for biopsy, biopsies of more centrally localized N2 positions can regularly be taken for diagnostic purposes. Contralateral sites (N3) can also be monitored. The histopathological results allow further conclusions on operability and whether a pre- or intraoperative search for sentinel lymph nodes should be made.

After using computer-supported tomography (CT) in a study, Ota et al. (2001) published data on the frequencies with which lung cancers in different localizations (upper lobes, right-sided middle lobe and lower lobes) involve the highest risks for the development ofmetastases. But with regard to the sensitivities ofradioimaging techniques, at least some ofthe sites thought on clinical examination and CT to be cN1 sites are in reality already N2 sites.

Whether or not a case oflung cancer is operable depends on the localization ofthe nodes involved and needs to be assessed individually in each case.

The data on lymphatic spread to the different basins are summarized in Fig. 5.

Table 4.Rates ofdistant metastases from non-small-cell lung cancers (NSCLC) obtained by pre-PET stage No. of

cases withNSCLC

Stage I Stage II Stage III PET detected dis- tantmetas- tasis/es

Ab-domi- nal

Adre-

nals Liver Other Lung Bone

167 39 28 100 24

(19%) 17 7 4 6 10 6

Pre-PET stage

7.5% 18% 24%

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Ifperipheral lung cancer is suspected but the primary diagnosis cannot be made from a transthoracic FNAC, a minithoracotomy near to the pu- tative cancerous region is the last chance ofcon- firming the diagnosis without performing thoracotomy when a reliable histo- or cytopathological diagnosis has not been achieved preoperatively.

As already mentioned, in every case the first diagnostic effort must include subtyping and tumor grading in addition to confirmation of the cancer diagnosis. This is easy to understand, because in small-cell cancers the search for SLNs is only of importance in a very early stage, whereas in non- small-cell cancers reflections on curative treatment, including locoregional cancer clearance, are important in a higher proportion ofcases.

Our own experience is based on the diagnosis ofmore than 15000 cases, ifclinically necessary also ruling out non-lung cancers (e.g. thymoma, lymphoma, Hodgkin's disease, etc.) by means of immunohistochemical markers. We obtained most

ofthe biopsies or cytological smears from the same large center. Our experience underlines the necessity for experienced pathologists and lung clinics to work together to obtain reliable diagnoses.

The results obtained during a very long period ofcooperation clearly demonstrated that histologically, and in some cases also cytologically confirmed diagnoses of lung cancer, including quali- fied subtyping, was absolutely secure, with no mis- interpretations.

It must be borne in mind that this standard was only made possible by constant diagnostic work by the same specialists (pulmonologists, to obtain suitable material for use in diagnosis, and one pathologist who was highly experienced in lung tumor pathology and immunohistochemistry). It is very helpful to have a histo-/cytopathologically based diagnosis available preoperatively. This makes therapy planning and communication with the patients much easier.

Stage Values of PET-CT-MRI Pre-evaluation, Mediastinoscopy and SLN Search in N-staging of NSCLC 309

Fig. 5. Overview ofthe pattern ofmetastasis characteristic

for lung cancers. Distant metastasis: skin (M1) = stage IV. The patients should be checked for operability; approximately 40% ofall cases are operable

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Figure 7 demonstrates the ways available for obtaining specimens (biopsies) or cytological material from lesions in central, intermediary and peripheral locations.

Demonstration of Lung Cancer Diagnosis in Scarce Tissue by FNAC

Whereas in diagnostic efforts a histopathological diagnosis can generally be made easily by using HE, cytokeratin staining, carcinoid markers (chromogranin A), and immunohistochemical lympho-

ma markers (limited only when the biopsies are too small), diagnosis by cytopathology is more limited, because the significant material needed for diagnosis is often scarce, often with only a few smears of different quality available. This means that the possibility of extending the spectrum of immunohistochemical evaluations is limited in many cases.

Figures 8±10 show a series of cytology smears demonstrating the different diagnoses. The next series (Figs. 11±14) shows cytopathological pictures of FNAC smears of small-cell lung cancer (Giemsa and immunohistochemical staining for cytokeratins 8, 18, 19). This nonaggressive (noninvasive) method in connection with other clinical results (imaging investigations) helps to define whether the search for SLNs is indicated and whether the cancer is operable.

Figures 15±17 demonstrate carcinoids with different degrees of differentiation and malignancy as seen on histological investigation (Figs. 15±17).

Exclusion of Primary Mediastinal Neoplastic Lesions in Differential Diagnosis Against

Mediastinal Metastases of Primary Lung Cancers Primary lung cancers can be very small and are primarily not detected by the diagnostic methods described.

The primaries can be masked when cancer-related bronchial stenosis has resulted in retention pneumonia. In such cases, often with small primaries, large mediastinal lymph node metastases may have developed. These can mimic primary mediastinal neoplasms. Therefore, in biopsy specimens obtained by mediastinoscopy, primary mediastinal cancers must be ruled out or definitely confirmed by histopathological investigations.

The most important primary mediastinal cancers are:1) Hodgkin's disease

2) Lymphomas 3) Thymomas

These are illustrated in Figs. 18 and 19.

Fig. 6.Frequencies of cN1 positions of lymph node metastases depending on lobe-related localization of the primary lung cancer

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Exclusion of Primary Mediastinal Neoplastic Lesions in Differential Diagnosis Against Mediastinal Metastases 311

Fig. 7.Combined histo- and cytopathological techniques applied to ensure lung cancer diagnosis. a Endoscopic biopsy techniques plus exfoliative cytology. b Transthoracic aspiration cytology (FNAC). c Transcarinal puncture of bifurcation lymph node(s) in advanced cases. Diagnoses made by investigations including typing by histopathology only in biopsies were secure in 84% of cases, whereas when all histo- and cytopathological techniques are used the diagnoses are secure in 96%

Figs. 8±10.Diagnosis of small cell lung cancers (SCLCs) in primaries and lymph node metastasis

Fig. 8.SCLC: small cancer cell cluster with spindle-shaped nuclei and sparse cytoplasm. In MiB I reaction, in most cases 70±80% of the nuclei are stained, but mitoses hardly detectable

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Fig. 9.SCLC: strongly positive cytoplas- mic reaction with antibodies directed to cytokeratins

Fig. 10.SCLC: FNAC of a suspect lymph node. The very small cancer cell clus- ters with partly spindle-shaped and partly round nuclei together with cytokeratin positivity allow the diagnosis of SCLC. Ultrarapid immunohistochemical reaction can be performed intraoperatively for an immediate decision on operability

Figs. 11±14.Diagnosis of adenocarcinomas with exclusion of carcinoids in FNAC smears

Fig. 11.Adenocarcinomas of the lung (non-small-cell lung cancer; NSCLC):

highly differentiated adenocarcinoma with moderately polymorphous nuclei located eccentrically in the cytoplasm.

A carcinoid character of the lesion must be ruled out using antibodies directed to chromogranin, synaptophy- sin, etc. The antibody MiB I should be used for determination of proliferative activity. SLN search can give a reliable indication of whether or not lesion is operable

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Exclusion of Primary Mediastinal Neoplastic Lesions in Differential Diagnosis Against Mediastinal Metastases 313

Fig. 12.Cytology of moderately differentiated adenocarcinoma (NSCLC). SLN search and intraoperative staging help to clear the question of operability

Fig. 13.Polymorphous cellular lung cancer, with giant cell formation in parts. It is important to exclude metastasis from a polymorphous cellular thyroid cancer or e.g. polymorphous nuclear cancers from other sites (ovary, endometrium:

type II etc.)

Fig. 14.Differentiated carcinoid of the bronchus. Staining with antibodies directed to chromogranin A. SLN search is very valuable as surgery can then be adapted for stage

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Figs. 15±18.Bronchial carcinoid Fig. 15.Differentiated bronchial carcinoid with isomorphic tumor cell nuclei, low rate of mitosis and a tubulo-alveolar growth pattern

Fig. 16.Bronchial carcinoid: positive immunohistochemical reaction with antibodies directed to chromogranin A

Fig. 17.Bronchial carcinoid: silver staining according to Grimelius. Note: Bron- chial carcinoids must be identified at the earliest possible time point by additional special diagnostic methods (immunohistochemical procedures in biopsy and cytopathological material and clinical examinations (5-hydroxy- acetic acid excretion with urine, etc.), because precise diagnosis can influence the radiological imaging (somatostatin receptor imaging for general and N-staging) and operative principles (see also Chapter 27: neuroendocrine tumors)

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Differential Diagnosis of Anaplastic Lung Cancers J How to distinguish the Small-cell Type

of Lung Cancer

In biopsy specimens taken endoscopically from the primaries and in cytological smears of these, in the case of cancers with a low grade of differentiation it is sometimes difficult to discriminate between small-cell lung cancers and low-differentiation adenocarcinomas and squamous cell cancers.

As frequently demonstrated by pathologists, mixed-type cancers with small-cell and squamous- cell differentiation in the same microscopic field can be observed. These difficulties are documented in Fig. 20.

This difficulty in histological and cytological subtyping can be at least one of the important factors in deciding whether a lesion is operable, because the small-cell type has the highest tendency to hematogenous metastatic spread.

As Tables 5 and 6 show, immunohistochemical investigations of different markers helpto differentiate clearly between different round-cell neoplastic lesions of the lung and to exclude metastatic processes of an anaplastic cancer. In our experience anaplastic (low-differentiation) squamous-cell cancer, low-differentiation adenocarcinoma and small-cell anaplastic lung cancer look quite similar and are sometimes difficult to differentiate (see Fig. 20).

315 Exclusion of Primary Mediastinal Neoplastic Lesions in Differential Diagnosis Against Mediastinal Metastases

Fig. 18.Biopsy taken from a patient with Hodgkin's disease, showing typical Sternberg-Reed cells stained with the Ki1 antibody

Fig. 19.This smear shows loosely layered cell populations, some with epithelial character and some with typical lymphocytic features. Further immunohistochemical reaction must be performed to confirm the diagnosis of thymoma

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Significance of Immunohistochemical Lymph Node Analysis for Up-staging and Prognosis

As in the case of other tumor entities (e.g., breast cancer), the question arises of whether immunohistochemical lymph node evaluations contribute to more exact lymph node staging (up-staging) and more adequate application of surgical and adjuvant therapy regimens. This question is of vital interest, especially when preoperative N-staging by mediastinoscopy is carried out.

Recently Gu et al. (2002) analyzed this problem to obtain a more significant overview of the indi- vidual state of lymphatic spread. Their results are briefly summarized in Table 7.

New Approaches Concerning Cancer Cell Proliferation Ramnath et al. (2001) compared the significance of cancer cell nuclei-related minichromosome mainte- nance protein expression (MCM2) with Ki67 expression rate for survival in NSCLC patients.

He found that immunostaining of tumor tissue for MCM2 helps in the prediction of prognosis and that MCM2 seems to be an important independent prog- nostic parameter. Interpretable results were obtained in more than 96% of paraffin-embedded specimens.

Staining of under 25% of the cancer cell nuclei sig- nals a favorable prognosis. In the series of cases investigated 35% belonged to this group.

Lately Fukuse et al. (2000) obtained 5-year survival rates of 66% among pN2-positive cases with low proliferation reflected in PCNA measurements and only 21.5% among cases with high proliferation in PCNA stainings. Analogous results can be obtained using the antibody Ki 67 (MiB I).

Because as a rule similar proliferation activity to that in the primaries is found in lymph node metastases, immunohistochemical measurements in biopsy material from the primaries would allow an approximate estimate of the tendency to locoregional spread.

Tanaka et al. (2000) see mutated p53 activity and higher proliferative activity as an indication for mediastinoscopy in NSCLC even when CT is negative. They base this on their observation that the rate of false-negative results was 24.1% in their series with p53 positivity and above-normal proliferative activity in the biopsy specimen taken from the primary.

Fig. 20. Reflection on differential typing of low-differentiation lung cancer subtypes

Table 5. Differential diagnosis of SCLC against other anaplastic cancers or round cell proliferations

Diagnosis Immunohistochemical

investigations to check the diagnosis

Small cell anaplastic bron-

chial cancer Cytokeratins 8, 18, 19 Pancytokeratin Small cell cancer inter-

mediary type versus bronchus carcinoid

Pancytokeratin only ? small cell cancer Chromogranin A NSE, S100 Protein 5-Hydroxytryptamine ? bronchial carcinoid Differential diagnosis:

plasma-cell granuloma, immune-cell hyperplasia, malignant lymphoma

CD 45, 4KB5, L26, anti- bodies directed to j and k, IgG, IgA, CD43

Metastatic cancer Cytokeratins 7, 8, 18, 19 Estrogen, Progesterone- receptor proteins (breast cancer)

Oncoproteins (e.g. c-erbB1-B3) Suppressor genes (mutated): p53, etc.

(17)

N-level-dependent Survival

Basic Data for Comparison with Results of Future Sentinel Node Detection Programs

Andre et al. (2001) investigated the survival rates of 702 patients treated in the Department of Medi- cine in Villejuif for NSCLC with ipsilateral mediastinal lymph node involvement (N2). The authors analyzed the prognosis of patients with resected N2 NSCLC, with the aim of proposing homoge-

neous patient subgroups. The results obtained are displayed in Table 8.

These data, documenting different subgroups of N2 involvement, are of interest for comparisons of results obtained by treatment in accordance with the SLNconcept, especially with the group devel- oping skip metastasis (see Schinkel et al. 1999).

The benefit 10% of mediastinoscopy with lymph node dissection for intended N-staging has been clearly demonstrated by Oosterhuis et al. (2001).

This limited but far-reaching N-staging procedure is of benefit in supporting the following aims:

N-level-dependent Survival 317

Table 6.Differential diagnosis of the different subtypes of bronchial cancers against other cancers breaking through into or metastasizing to the bronchial system

Most important subtype Differential diagnosis Confirmation of diagnosis:

primary of the lung Exclusion of other cancers

SCLC Non-Hodgkin and Hodgkin

lymphoma Immunohistochemical:

cytokeratin 8, 18, etc. posi- tiveMiB I = mostly high proliferation >80% positive

Non-Hodgkin lymphomas:

CLA

Thymoma B-Cell markers

(CD20=L26, CD22 =4KB5) T-Cell markers

(CD3 =UCHL1, CD43) negative

Hodgkin lymphoma: CD30 negative

Thymoma: see addendum*

NSCLC: squamous cell can-

cer Breakthrough of esophageal

carcinoma Bronchoscopy with biopsy

for confirmation Esophagoscopy for exclusion of esophageal cancer NSCLC: adenotype(s) Metastatic process Immunohistochemical

demonstration of typical cytokeratin pattern:

CK 8, 18, 19, 21

Colon cancer Breast cancer Prostatic cancer, etc.

Exclusion by clinical investigations

* Thymus neoplasms: Subtyping in Type A, AB, B1, B2, B3 and C; lymphocyte poor types A, B3, C

Epithelial differentiated thymomas: Thymic carcinoma (TCA). Invasive thymic neoplasm of epithelial type (TNET) Lymphocyte rich thymomas: Three distinct subpopulations of lymphatic cells (see Li et al. 2004). Analysis of antigen expression pattern: The presence or absence of T-cell associated antigen deletion and the expression of CD10 and CD34 by 4-colour flow cytometry can help differentiate thymoma from T-cell ALL/LBL.

Table 7.Rates of cancer-positive nodes in cases diagnosed as N0 on HE staining, including rates of mutated p53 positivity (LN lymph nodes)

CK+ cells p53+ CK AE1/ AE3 in N0

nodes p53 in N0 nodes CK + p53 in N0

nodes

35/474 LN20/263 LN17/49 patients 10/25 patients 22/49

7.4% 7.6% 34.7% 40% 44.9%

(18)

· Detection of unsuspected N2 involvement.

· Selection of patients for neoadjuvant chemotherapy.

The results of this investigation are summarized in Table 9.

The general clinical value of cervical mediastinoscopy has been recently evaluated by Ebner et al.

(1999). The indications for it have been summarized as follows:

· Staging of NSCLC and SCLC

· Diagnosis of mediastinal masses or lung tumors without previous histological examination

· Restaging after primary chemotherapy

· Assessment of prognosis in patients with bor- derline operability

The results of Ebner's estimates are summarized in Table 10.

N-positive Rates in Relation to T-stage

In 1997, de Leyn et al., investigating 235 cases of NSCLC, estimated that only 50% of patients with enlarged mediastinal lymph nodes were found to

have cancer infiltration of these nodes. However, in contrast to these findings even small nodes can be cancer infiltrated.

No. of

cases Sensi-

tivity Speci-

ficity Accura-

cy Overall positive and negative predictive value 42 76.7% 100% 83.3% 100% and 87%,

respectively

These results published by de Leyn's group are shown in Tables 11 and 12. In spite of these widely known facts, many surgeons believe that a mediastinum seen as normal on CT does not need to be investigated preoperatively.

Table 8.Five-year survival rates of patients with different subtypes of NSCLC (different types of lymph node involvement).

Preoperative chemotherapy was associated with a better prognosis for cases [L1 one level involved, L2 multiple levels involved, c clinical involvement, m minimal involvement with cN2 (P<0.0001)]

Cancers treated with primary surgery mN2L1 mN2L2 cN2L1 cN2L2

n =244 n =78 n =118 n =122

558 34% 11% 8% 3%

Table 9.Value of mediastinoscopy for staging and further decision making in NSCLC cases Consecutive cases (n) Mediastinal node

dissection Unsuspected N2

disease Reduction in no. of unsuspected node involvement by IHC

Benefit from neoadjuvant therapy

183 158 24 (15%) 15?10% 10%

Table 10.Applicability of mediastinoscopy for regional staging in NSCLC No. of cases For staging For diagno-

sis For oper-

ability After chemo-

therapy Sensitivity Specificity Accuracy

224 59.2% 30.6% 5.4% 4.8% 87% 100% 93%

No. of cases Sensitivity Specificity Accuracy Overall positive and negative predictive value

42 76.7% 100% 83.3% 100% and 87%, respectively

Table 11.Basic results: Cancer infiltration, extra nodal infiltrates and infiltration of more than one level

No. of

cases Media-

stinoscopy, nodes positive

Extranodal cancer infiltrates in N2

More than one level involved

235 47 (20%) 21 16

(19)

In the studies conducted by Watanabe et al.

(1999) in 218 stage IIIA-N2 patients, overall survival of 23% was found. The survival rate increased to 30% in those in whom complete resection (R0) was achieved.

In these studies the 5-year survival rates of IIIA-N2 cases depended clearly on the extension of the primaries (Table 13).

It might be possible to increase the relatively high survival rate of 48% in cases with cancers that, while small (<20 mm), were already classed as stage N2 by more complete N-staging involving labeling procedures. In Motta et al.'s (1999) series of patients with stage I (T1N0 to T2N0) disease, the survival rates decreased at the size cut-off point of 3 cm in the primary.

Mediastinoscopy is a valuable preoperative method of excluding or confirming operability and the nature of non-lung-cancer lesions, such as

· Thymoma

· Mediastinal teratoma

· Hodgkin's disease

· Non-Hodgkin lymphoma

and for sentinel node detection and/or N-staging.

The above different tumor entities require different treatment strategies.

Therefore, mediastinoscopy and histopathological examination together are valuable in diagnosis and in planning of therapy in general, and this technique cannot be seen only as a means of lymph node staging in bronchial carcinoma. In the main it is used to clarify the question of operability in advance of an attempt at surgery, and with this also that of N(SLN) staging.

Points leading to the exclusion or confirmation of operability are summarized in Table 14.

Approach to Testing Operabilityof NSCLC

The following scheme gives a rough overview of operability:

· Mediastinoscopy with lymph node investigations.

· Radiodiagnostic techniques including PET, CT are the diagnostic methods that can be applied preoperatively.

· Intraoperatively, N-staging with exact lymph node investigations (frozen sections, cytology, etc.) and ultrarapid immunohistochemistry (see Chapter 17) are the most helpful methods.

Concerning the N-positions of cancer-involved lymph nodes with a view to operability after earlier location of the primary by radioimaging and mediastinoscopy, N3-positions can be confirmed or ruled out.

In the case of lymphatic metastasis to the contralateral side a stage of N3 must be assumed, which corresponds to extensive disease (Fig. 21).

In the case of cancer infiltration of a peribronchial lymph node near to the primary only, the N1-situ- ation (limited disease) seems to be possible (Figs. 22, 23). In the case of lymph node connec- tions of the tracheo-broncho-pulmonary situs exact knowledge is necessary for preoperative (via mediastinoscopy) or intraoperative (frozen section combined with imprint cytology) staging investigations. Positive peribronchial lymph nodes less than 2 cm from the trachea and/or positive nodes of the aortic-pulmonary window as well as positive nodes at the bifurcation of the trachea are critical for ascertaining operability. Preoperative M-staging

Table 12. Rates of positive lymph nodes in N0 cases with different stages (CT)

cT1N0 cT2N0 cT3N0 cT4N0

9.5% 17.7% 31.2% 33.3%

Table 13.Five-year survival rates Cancers <20 mm 21±

30 mm 31±

50 mm >51 mm

48.1% 27.7% 31.2% 16.7%

Table 14.Mediastinoscopy as a routine method of assessing operability

Exclusion of

operability ? Contralateral lymph nodes involved in metastatic process (histology: tumor positive)

? Extranodal cancer infiltration histologically confirmed

? Unresectable superior mediastinal nodes involved (histology or needle biopsy)

Limited chance of operability in other stages than I and II

? In confirmed stage III cases surgical treatment can be put forward as best course in special cases

(20)

for exclusion of distant metastases is obligatory (see Tables 13, 15, 21).

Is There a Role for Routine Mediastinoscopy in Patients with Peripheral T1 Lung Cancers?

Quite a large number of patients with small peripheral lung cancers harbor radiographically occult lymph node involvement. In these cases especially, mediastinoscopy helps in the identifica- tion of patients with regionally advanced disease (mediastinal/precardial nodes positive) prior to resection (Fig. 24). Diagnosis by methods of this kind excludes the search for sentinel nodes, but al- lows the indication for neoadjuvant chemotherapy to be recognized and makes it possible to avoid unnecessary operations (Tahara et al. 2000).

Special Approaches for Obtaining Specimens for Cancer Diagnosis

a) Endoscopic ultrasound-guided transesophageal fine-needle aspiration (EUS-FNA).

b) Transpleural techniques for NSCLC diagnosis.

Ad a) EUS-FNA: Ryan et al. (2001) reported briefly on the methods of lung cancer biopsy. The authors emphasize the possibility of using EUS-FNA biopsy of mediastinal nodes. The sensitivity in the diagnosis of carcinoma in lymph nodes was more than 90% in their own studies, with no complica- tions.

In an earlier study by Gress et al. (1997) EUS- FNA had a specificity of 96% for nodal involvement, compared with 49% for CT.

In addition, Serna et al. (1998) recorded a sensitivity of 86% for EUS-FNA, compared with 100%

for mediastinoscopy, but the authors emphasized that both methods had both a specificity and a positive predictive value of 100%.

Fig. 21.Evaluation of limited [a lymph node involvement on same side as primary only (N1)] and of extensive disease [b lymph node involvement of contralateral nodes (N3)]

(21)

Ad b) The possibility that transpleural techniques for NSCLC diagnosis might involve a dan- ger of relapse and worsening of prognosis has been discussed. Recently Sawabata et al. (2001) published the results obtained in their comparative studies on the frequencies of local and distant re- currence rates after transpleural and transbronchial procedures for NSCLC diagnosis, in which they investigated 45 and 195 cases, respectively.

Neither local nor distant relapse rates showed statistically significant differences. The survival rates were better in the transpleural diagnostic group (P=0.04). The results are summarized in Table 15. The authors concluded from their results that transpleural diagnosis is an appropriate way to diagnose operable lung cancer that is difficult to verify by bronchoscopy, because this method does not affect relapse rates or prognosis.

Fig. 22.Broncho-aortopulmonary situs: preoperative staging should perhaps be performed with a view to ascertaining whether or not the lesion is operable.

Use of mediastinoscopy MRI-Sinerem imaging, PET, etc. might allow clearer planning of any operation

Table 15.Comparison of relapse rates after transpleural and transbronchial diagnosis of lung cancer Transpleural

technique Transbronchial

technique Relapse rate

total Transpleural

transbronchial Transpleural transbronchial distant vs local

Survival transpleural vs transbronchial (%)

n=45 n =194 42 7 35 4/3 vs 20/15 79.4 vs 60.3

(P=0.90)

(22)

Fig. 23.Topography of the situs with lymph node groups (N1±N3 positions) relevant for pre- and intraoperative node staging and decision making on operability. N1 = bronchopulmonary nodes. Overview of the localizations of bronchopulmonary and tracheobron- chial nodes. This scheme is basic to the development of radiological imaging-systems to localize sentinel node(s) and gives preoperatively answers about operability

Fig. 24a,b.Preoperative staging using imaging systems (N1 position see Figs. 21, 23).aEvaluation of the nodes in aortopulmonary ªwindowº (N2);

bmediastinal nodes (N3). Demonstra- tion of the exact localization of the nodes in the ªaortopulmonary windowº

(23)

Skip Metastasis of NSCLC Makes N-staging More Difficult

Sentinel Node Detection Rates in NSCLC and Significance of Skip Metastasis

The numbers of cases in which a search for sentinel nodes has been carried out are mostly low so far.

In Liptay et al.'s (2000) studies there were 45 evaluable cases. The results are summarized in Ta- ble 16. These results demonstrate that a gamma probe-guided SLNsearch also helps to obtain a clear-cut overview for improved locoregional cancer clearance in cases with positive N2 positions.

Does the Rate of Skip Metastasis Hamper Use of the Sentinel Node Concept?

If the rate of skip metastasis is very low, as it is in breast cancer (*3%), the presence of such metas- tases do not prejudice the sentinel node concept.

However, when the rate is much higher, the prac- ticability of using this concept in daily routine is called in question.

In 1999 Schinkel et al. published their data, which are based on 170 cases of NSCLC (stage I: n=15, stage II: n=42, stage IIIa: n =113). The authors found N2 disease in 68 cases, and a rate of 81% with skip metastases. This rate is extremely high, and we did not find other systematic evaluations to this problem.

But against the backdrop of an abundantly developed network of lymphatics along the tracheo- bronchial system and within the mediastinum, it seems inevitable that primary regional lymph nodes will be by-passed. Therefore, the strong UICC concept (Figs. 25±27) is more a working for- mulation and does not correspond with the sentinel node concept in every case.

Comparative Studies of Mediastinal Lymph Node Dissection with Systematic Node Sampling Such studies can be seen as a basis for the later comparisons with the results of sentinel node projects.

Keller et al. (2000) compared mediastinal lymph node dissection (MLND) with systematic sampling (SS). The results are summarized in Table 17. They document that completeness of locoregional cancer clearance depends on the quality of the surgical strategy on the one hand and the side where the cancer is localized and, depending on this, on the different side-related surgical benefits on the other.

In a recently published Chinese study (Wu et al.

2001) of 504 patients with NSCLC treated by lobectomy or pneumectomy, radical lymphadenectomy (RL) and conventional lymphadenectomy (CL) were compared and referred to the different tumor stages.

RL was statistically superior in clinical stage I cases (P<0.014), but not in higher stages (Table 18).

This means that even in stage II cases the possibility of surgical locoregional clearance is already past in many cases and the rate of systemic spread has already increased, limiting the likelihood of survival.

In conclusion, based on these facts, the question arises of whether a sentinel node showing solitary cancer infiltration, but located near the hilus or in the carina region, can be regarded as a N1 site but in an unusual basin deviating from the UICC scheme. Comparison of the survival rate could give some insight in this direction (Table 19).

Keller et al. (2000) compared the results of systematic lymph node sampling (SS) with those of mediastinal lymph node dissection (MLND). In 373 patients the median survival was 57.5 months for those who had undergone complete MLND and 29.2 months for those who had undergone SS (P=0.004). The survival advantage was limited to patients with right-sided lung cancers (66.4 months versus 24.5 months) (P<0.001). The authors emphasize that in their nonrandomized study SS was as efficacious as complete MLND in staging patients Comparative Studies of Mediastinal Lymph Node Dissection with Systematic Node Sampling 323

Table 16.Intraoperative sentinel node search using^99mTc-nanocolloid No. of

cases Mean time labeling^99mTc 63 (23±170) min

SLNidentification rate (%)

SLN positive SLN positive, no other metastases

Inaccurate

SLN detection SLN nodes mediastinal (N2 positive)

45 63 min 37 (82%) 12 (32%) 35/37 (94%) 2 (5%) 8 (22%)

(24)

Figs. 25±27.Overview of N-staging in stages N1±3 of lung cancer (Spiessl et al. 1990/1993)

Fig. 25.Stage N1

Fig. 26.Stage N2

Table 17.Comparison of mediastinal lymph node dissection (MLND) with systematic node sampling (SS), related to side of localization and survival^a

SS MLND N2

total Metastases Median survival (months)

187 40% 60% 186 41% 59% 222 30% 12% 57.5 29.2

P=0.004

aComparison (right vs left side; % survival) Right side Left side

Months Months

66.4 24.5

P=0.001

No. N1 N2

of cases (n)

No. N1 N2

of cases (n)

MLND SS

(25)

with NSCLC. However, complete MLND identified significantly more levels of N2 disease.

Lymph Node Sampling Strategy in NSCLC Cases Systematic lymph node dissection is considered to improve local control at least in early stages (Wu et al. 2001). Naruke et al. (1999) investigated 1815 cases. The lymphatic routes from each lobe were analyzed by examining which nodes had the most likelihood of metastasis or to find out in the case of small tumors which node was the SLNand suitable for video-assisted thoracic surgery (VATS).

Comparative Studies of Mediastinal Lymph Node Dissection with Systematic Node Sampling 325 Fig. 27.Stage N3

Table 18.Survival of patients after radical (RL) and conventional (CL) lymphadenectomy in NSCLC, stage I Total

no. of cases

RL CL No. of

nodes in RL (aver- age)

No. of nodes in CL (aver- age)

Stage I survival in RL group Stage I survival in CL group

320 160 160 9.49 3.63 91.8 86.9 81.4 74.2 88.7 72.5 58.5 52.1

1 3 5 9 1 3 5 9

Table 19. Rates of unexpected N2 disease in lung cancer cases (NSCLC)

Authors No. of

cases SLN Unex-

pected N2 positivity Little et

al. (1999) 9 9 5

Oda et al.

(1998) 10 7

Positive Negative