Although metastasis in regional lymph nodes is one of

Nodal Occult Metastasis in Patients With Peripheral Lung Adenocarcinoma of 2.0 cm or Less in Diameter Jian Wu, MD, Yasuhiko Ohta, MD, Hiroshi Minato, MD, Yoshio Tsunezuka, MD, Makoto Oda, MD, Yoh Watanabe, MD, and Go Watanabe, MD First Department of Surgery and Department of Pathology, Kanazawa University School of Medicine, and Department of Thoracic Surgery, Kanazawa Medical College, Kanazawa, Japan Background. Detection of occult micrometastasis in regional lymph nodes is crucial for diagnosis and selection of appropriate therapy for patients with pn0 nonsmall-cell lung carcinoma. Using immunohistochemical staining, we evaluated the impact of detection of occult micrometastasis on the prevalence and prognosis of patients with lung adenocarcinoma of 2.0 cm or less in diameter. Methods. A total of 103 pn0 disease patients with peripheral lung adenocarcinomas of 2.0 cm or less in diameter were enrolled in this study. We studied 1,438 regional lymph nodes for occult micrometastasis by immunohistochemical staining for cytokeratins. Results. Micrometastasis was detected in 49 lymph nodes (3.4%) of 21 patients (20.4%) but not in patients with localized bronchioloalveolar carcinoma or localized bronchioloalveolar carcinoma with foci of collapse of alveolar structure. The 5-year survival rate (61.9%) of patients with micrometastasis was significantly (p 0.0041) lower than that of patients without micrometastasis (86.3%). Conclusions. There still remains a risk of nodal micrometastasis in patients with primary peripheral lung adenocarcinoma, even if the diameter of the tumor is smaller than 2.0 cm. Selection of patients for limited surgery should be done prudently, taking into consideration the risk of nodal micrometastasis. (Ann Thorac Surg 2001;71:1772 8) 2001 by The Society of Thoracic Surgeons Although metastasis in regional lymph nodes is one of the most important prognostic factors affecting the staging process, only hematoxylin and eosin staining has been performed in routine practice. Recent progress in immunohistochemical staining and genetic methods has made it possible to find obscure or occult metastasis in various distant organs, including lymph nodes, in patients with carcinoma. A number of studies have shown that immunohistochemical methods are far more sensitive for the detection of micrometastasis compared to the conventional hematoxylin and eosin staining method, and they have also shown that the detection of micrometastasis has a predictive value for recurrence [1 4]. In previous studies, the micrometastases in the regional lymph nodes have been detected in 10.2% to 70.5% of lung cancer patients with pn0 disease [5 9]. For early non-small-cell lung cancer patients with a peripheral tumor 2.0 cm or less in diameter, the nodal metastatic rate has been reported to be 15% to 18% [10, 11]. In addition, some studies have shown that the outcomes of patients with early-stage peripheral adenocarcinoma of Accepted for publication Feb 2, 2001. Address reprint requests to Dr Ohta, First Department of Surgery, Kanazawa University School of Medicine, Takara-machi 13-1, Kanazawa 920-8641, Japan; e-mail: yohta@med.kanazawa-u.ac.jp. 2.0 cm or less in diameter were significantly better than those of patients with tumors of 2.1 cm or more in diameter [11, 12]. Recently, a new histologic classification has been proposed for small adenocarcinoma of the lung (tumor maximum diameter 2 cm) [13]. In this classification, small-sized adenocarcinomas are divided into two groups and into six distinctive structural patterns based on tumor growth patterns. One group is cases in which alveolar lining cells have been replaced by tumor cells. This group includes type A (localized bronchioloalveolar carcinoma), type B (localized bronchioloalveolar carcinoma with foci of collapse of alveolar structure), and type C (localized bronchioloalveolar carcinoma with foci of active fibroblastic proliferation). Another group is the nonreplacement type, which includes type D (poorly differentiated adenocarcinoma), type E (tubular adenocarcinoma), and type F (papillary adenocarcinoma with compressive and destructive growth). Some small bronchioloalveolar carcinomas such as Noguchi s type A and type B are regarded as in situ carcinomas, for which limited surgery has been proposed to be effective [14]. However, there have been few studies on the pervasion of nodal micrometastasis in small-sized lung carcinoma. In this study, we assessed the prevalence of nodal micrometastasis in patients with small peripheral lung adenocarcinoma, and we examined the clinical relevance 2001 by The Society of Thoracic Surgeons 0003-4975/01/$20.00 Published by Elsevier Science Inc PII S0003-4975(01)02520-6

Ann Thorac Surg WU ET AL 2001;71:1772 8 NODAL OCCULT METASTASIS WITH PERIPHERAL LUNG ADENOCARCINOMA 1773 of immunohistological patterns to outcomes as well as clinical applications. Patients and Methods Lymph node samples were obtained from 136 patients with primary lung adenocarcinoma in which the tumor size ranged from 0.5 to 2.0 cm in maximum diameter. All of the patients had undergone standard lobectomy or pneumonectomy with standard systematic lymphadenectomy of both hilar and mediastinal lymph nodes, as previously described [15, 16], in Kanazawa University Hospital between January 1981 and December 1996. The hematoxylin and eosin stained sections of both lung tumors and lymph nodes were reviewed, and the pathologic stages and grades of the tumor were determined according to the Japan Lung Cancer Society classification [17]. Among these patients, 30 were diagnosed as being lymph node positive by conventional pathologic examination, and 3 were in stage IB (T2 N0 M0) with visceral pleural involvement; these patients were excluded from the study. The other 103 patients in stage IA (T1 N0 M0) without overt lymph node metastasis were selected as the subjects for further study. Immunohistochemical staining was performed for the detection of occult lymph node micrometastasis. The 103 patients included 43 men and 60 women with a mean age of 62.3 9.8 years (range, 38 to 80 years). The total number of lymph nodes studied was 1,438. According to Noguchi s histologic classification [13], 11 cases were type A, 3 were type B, 61 were type C, 5 were type D, 8 were type E, and 15 were type F. The basic clinical features of the patients are summarized in Table 1. Table 1. Nodal Micrometastasis and Its Association With Clinicopathologic Characteristics of 103 Patients With Primary Lung Adenocarcinoma Smaller Than 2.0 cm in Diameter a Characteristic Total Positive (%) p Value Number of patients 103 21 (20.4) Sex 0.9080 Male 43 9 (20.9) Female 60 12 (20.0) Age (years) 0.4251 62 46 11 (23.9) 62 57 10 (17.5) Differentiated 0.0031 Well 71 11 (15.5) Moderately 23 4 (17.4) Poorly 9 6 (66.7) Noguchi s type 0.0012 A, B 14 0 (00.0) C 61 9 (14.8) D, E, F 28 12 (42.9) Location 0.6426 Right upper lobe 41 7 (17.1) Right middle lobe 11 2 (18.2) Right lower lobe 21 3 (14.3) Left upper lobe 23 7 (30.4) Left lower lobe 7 2 (28.6) Blood vessel invasion 0.4776 Negative 84 16 (19.0) Positive 19 5 (31.3) Lymphatic vessel invasion 0.0183 Negative 75 11 (14.7) Positive 28 10 (35.7) a For all patients, mean age ( SD) was 62.3 9.8 years; for micrometastasis-positive patients, mean age was 61.8 8.3 years. For all patients, mean tumor diameter ( SD) was 15.7 3.6 mm; for micrometastasispositive patients, mean diameter was 15.3 3.7 mm. Immunohistochemical Staining Method Serial sections were collected from formalin-fixed, paraffin-embedded tissue blocks. The labeled Streptavidin- Biotin immunohistochemical staining method (LSAB) was carried out as follows: 4- m-thick sections were baked at 60 C for 1 hour, dried at 37 C for 3 days, then deparaffinized and rehydrated. After being washed in phosphate-buffered saline (PBS) solution, the tissue sections were soaked in citrate buffer (0.01 mol/l, ph 6.0; Wako Pure Chemical Industries, Ltd, Tokyo, Japan) and treated by microwaves (500 W) three times for 5 minutes for antigen retrieval. The slides were cooled at room temperature and washed in PBS solution, and endogenous peroxidase activity was blocked in 3% hydrogen peroxide (Wako Pure Chemical Industries) PBS solution for 15 minutes at room temperature. After the sections had been rinsed under running water for 10 minutes, they were blocked with 2% horse serum albumin (DAKO, Carpinteria, CA) for 10 minutes and incubated with monoclonal mouse antihuman cytokeratin antibody (AE1/AE3; DAKO) (1:50 dilution with PBS solution) at 4 C over night. The slides were then washed three times for 5 minutes each in PBS solution and incubated with a biotinylated secondary antibody (antimouse and antirabbit immunoglobulin G; DAKO) for 20 minutes. After they had been washed in PBS solution, avidin-biotinperoxidase complex (DAKO LSAB 2 Kit; DAKO) was added for another 20 minutes. The color was developed in a solution consisting of 30 mg of 3,3 -diaminobenzidine tetrahydrochloride (Wako Pure Chemical Industries) with 0.03% 150 ml hydrogen peroxide for 3 to 7 minutes. Counterstaining was done with Mayer s hematoxylin (Muto Pure Chemicals, Tokyo, Japan). Sections of primary tumor samples served as positive controls. All of the immunostained slides were assessed independently by two of the authors (J.W. and Y.O.) without any knowledge of clinicopathologic information. Lymph nodes were considered to be positive for occult micrometastasis if they contained any strong immunoreactive epithelial cells in the subcapsular sinus or in the cortex of the lymph node. All of the positively stained cells or groups of the cells were further confirmed as being cytologically atypical epithelial cells (enlarged nuclear size and apparent increased nuclear to cytoplasmic ratio) before being finally designated as micrometastasis of lymph nodes [9]. Cases with discrepant evaluations were evaluated by a third viewer (H.M.).

1774 WU ET AL Ann Thorac Surg NODAL OCCULT METASTASIS WITH PERIPHERAL LUNG ADENOCARCINOMA 2001;71:1772 8 Fig 1. The spread of lymphatic micrometastases in relation to sites of the primary tumor (proposed by the Japan Lung Cancer Society [17]). Bars between the filled circles refer to the same cases. (RLL right lower lobe; RML right middle lobe; RUL right upper lobe; LUL left upper lobe; LLL left lower lobe; open circle single-level metastasis; filled circle multilevel metastasis.) Statistical Analysis Statistical calculations were carried out using StatView software (Abacus Concepts, Berkeley, CA) and JMP Statistical Discovery software (SAS, Cary, NC). The analysis of differences in categorical outcomes was determined by the 2 test or Fisher s exact test and by logistic regression for continuous variables. The actuarial overall survivals were analyzed by the Kaplan-Meier method, and differences in their distributions were evaluated by the logrank test. Cox s proportional hazards models was used for multivariate analysis. A p value of less than 0.05 was defined as being statistically significant. in the opposite hilar area was found in 1 patient. Therefore, the revised stages were IIA in 13 patients, IIIA in 7 patients, and IIIB in 1 patient. The results of immunohistochemical study for micrometastasis are shown in Table 1. The incidence of micrometastasis was significantly higher in the patients with poorly differentiated tumors than in those with welldifferentiated tumors (p 0.0003) or moderately differentiated tumors (p 0.0097). Nodal micrometastasis was not detected in the patients with type A or B tumors in Noguchi s classification. The incidence of nodal micrometastasis was significantly higher in patients with type D, E, or F tumors in Noguchi s classification than in patients with type A or B (p 0.0023) or type C (p 0.0034). In addition, the incidence of nodal micrometastasis tended to be higher in cases of tumors with lymphatic vessel invasion than in cases of tumors without such invasion. The 5-year survival rate of patients without nodal micrometastasis (n 82) was 86.3%, whereas that of patients with nodal micrometastasis (n 21) was only 61.9%. A significant (p 0.0041) difference in survival curves was found between patients with and without nodal micrometastasis (Fig 2). In univariate analysis, male gender (p 0.0012), older age (p 0.0192), and histologically moderately and poorly differentiated tumor (p 0.0123) were significantly associated with poor survival (Table 2). The survival curves of patients with tumors classified according to Noguchi s classification are shown in Figure 3. Survival of patients with type A or B was significantly better than that of patients with type D, E, or F (p 0.0139). Table 3 shows the results of multivariate analysis. Sex, age, and lymph nodal micrometastasis were the characteristics that retained significant independent prognostic impact. We also compared survival of patients with pathologic N1 or N2 disease (n 30) with survival of patients with pn0 disease (n 103), and significant differences in Results In all of the primary tumors, staining of AE1/AE3 (reddish-brown color) was found in the cell cytoplasm and membrane. Micrometastasis was detected in 49 lymph nodes (3.4%) of 21 patients (20.4%). Either a single or small clusters of positive tumor cells were usually found in the subcapsular sinus or vessels. In the nodal micrometastasis positive group, 12 patients died during follow-up (57.1%). Cause of death was local recurrence in 1 patient (8.3%), systemic metastasis in 8 patients (66.7%), and unknown or other diseases in 3 patients (25.0%). In the negative group, 18 patients died (22.0%). Cause of death was local recurrence in 5 patients (27.8%), systemic metastasis in 8 patients (44.4%), and unknown or other diseases in 5 patients (27.8%). In the 21 positive patients, micrometastasis-positive lymph nodes were found at the mediastinum in 5 patients (23.8%), at the hilum in 13 patients (61.9%), and in both areas in 3 patients (14.3%) (Fig 1). Micrometastasis Fig 2. Kaplan-Meier overall survival plots for 103 patients with lung adenocarcinoma of 2 cm in diameter according to the occult lymph nodal micrometastasis. The prognosis of patients with micrometastasis was significantly poorer than that of patients without micrometastasis (p 0.0041).

Ann Thorac Surg WU ET AL 2001;71:1772 8 NODAL OCCULT METASTASIS WITH PERIPHERAL LUNG ADENOCARCINOMA 1775 Table 2. Univariate Analysis of Prognostic Factors Associated With Postoperative Survival in 103 Patients With Primary Lung Adenocarcinoma Smaller Than 2.0 cm in Diameter Variable n 5-Year Hazard Ratio (95% Survival (%) a Confidence Interval) p Value b Sex 3.44 (1.62 7.35) 0.0012 Male 43 69.2 Female 60 89.4 Age (years) 2.54 (1.13 5.70) 0.0192 62 46 93.1 62 57 71.5 Differentiated 2.42 (1.18 4.95) 0.0123 Well 71 85.6 Moderately and poorly 32 71.0 Noguchi s type A, B 14 100 c 3.88 (1.52 3.35) 0.0139 C 61 85.2 D, E, F 28 65.4 Blood vessel invasion 0.56 (0.25 1.26) 0.1534 Negative 84 81.8 Positive 19 78.2 Lymphatic vessel invasion 0.71 (0.33 1.52) 0.3785 Negative 75 81.1 Positive 28 80.9 Lymph nodal micrometastasis 2.78 (1.34 5.77) 0.0041 Negative 82 86.3 Positive 21 61.9 a The survival was calculated by the Kaplan-Meier method. b By means of the log-rank test. c Not significant. survival were found (Fig 4). The survival of patients with pathologic N1 or N2 disease was significantly shorter than that of patients with nodal micrometastasis (p 0.0144). Comment Occult nodal micrometastasis has been defined as a small amount of malignant cells in lymph nodes that apparently cannot be identified by conventional histologic Fig 3. Kaplan-Meier overall survival plots for 103 patients with lung adenocarcinoma of 2 cm in diameter according to Noguchi s classification. The prognosis of patients with type D, E, or F was poorer than that of patients with type A or B (Type A/B versus type C, p 0.0891; type A/B versus type D/E/F, p 0.0139). examinations [5 9]. Although identification of nodal micrometastasis could be expected to serve as a basis for the selection of patients with peripheral small lung carcinoma that would benefit from so-called limited surgery, there is still a paucity of markers for the detection of micrometastasis. In this study, we employed a nodal Table 3. Multivariate Prognostic Factors Analysis of the 103 Patients in Table 2 by Cox s Proportional Hazards Regression Model Variable Hazard Ratio 95% Confidence Interval p Value Sex Female 1 Male 1.66 1.14 2.50 0.0079 Age (years) 62 1 62 1.59 1.05 2.52 0.0283 Differentiated Well 1 Moderately and poorly 1.11 0.75 1.64 0.5994 Noguchi s type A, B 1 C, D, E, F 0.001 0.09 1.01 0.0513 Lymph nodal micrometastasis Negative 1 Positive 1.66 1.11 2.44 0.0141

1776 WU ET AL Ann Thorac Surg NODAL OCCULT METASTASIS WITH PERIPHERAL LUNG ADENOCARCINOMA 2001;71:1772 8 Fig 4. Kaplan-Meier survival plots for all of 133 patients with lung adenocarcinoma of 2 cm in diameter according to the nodal status, including micrometastasis. (A) Patients without metastasis, including micrometastasis (n 82, 61.6%; 5-year survival, 86.3%). (B) Patients with nodal micrometastasis (n 21, 15.8%; 5-year survival, 61.9%). (C) Patients with macroscopic nodal metastasis (n 30, 22.6%; 5-year survival, 31.8%). The differences in prognosis among A, B, and C were significant (A versus B, p 0.0041; A versus C, p 0.0001; B versus C, p 0.0144). immunohistochemical method for cytokeratin fragments to detect micrometastasis. The anticytokeratin antibody used, AE1/AE3, can recognize a wide spectrum of cytokeratin protein fragments [18, 19]. Whereas AE1 reacts with 40k, 50k, and 56.5k keratin classes, AE3 reacts with 46k, 52k, 58k, 65k, 66k, and 67k keratin classes. Therefore, this mixture potentially represents an excellent reagent for detection of keratin proteins expressed in cancer cells [20]. In this study, nodal micrometastasis was detected in 20.4% of patients (21:103), in whom malignant cells had not been found in regional lymph nodes. As for the relation between nodal micrometastasis and tumor differentiation, our results showed that poorly differentiated tumors have a significantly higher rate of micrometastasis than well-differentiated tumors (p 0.0007) or moderately differentiated tumors (p 0.0097). A previous study on small-sized lung adenocarcinoma also showed that the histologic degree of differentiation was significantly associated with lymph node metastasis [21]. In this study, patients with tumors of Noguchi s type A or B had no lymph node micrometastasis, whereas patients with types C, D, E, and F showed a high risk of micrometastasis. As was previously reported [9], lymphatic vessel invasion of primary lung carcinoma was closely associated with nodal micrometastasis in this cohort of patients with small-sized adenocarcinoma. Survival analyses revealed that the outcomes of patients with occult lymph node micrometastasis were significantly worse than those of patients without such micrometastasis. In multivariate analysis, nodal micrometastasis retained independency as a prognostic indicator in patients with lung adenocarcinoma smaller than 2.0 cm in diameter. Our results correspond to those of previous reports in which various other markers, such as Ber-Ep4, CAM-5.2 or p53, also showed poorer prognosis in patients with nodal micrometastasis than in those without nodal micrometastasis [5 9]. The study by Noguchi and colleagues [13] on the pathologic characteristics of small adenocarcinoma of the lung showed that type A or B tumors could be regarded as in situ carcinoma, whereas type C appeared to be an advanced stage of types A and B. Our results confirmed the excellent survival rate of patients with type A or B (5-year survival, 100%), and no lymph node metastasis, including micrometastasis, was found in patients with these two types of tumors. Considering the differences in prognosis according to Noguchi s classification, patients with type A or B tumors might benefit from limited surgery [14] or from video-associated thoracic surgery [22]. On the other hand, standard resection with lymph node dissection would be a reasonable surgical modality for patients with other types of tumor. Koike and colleagues [11] found that, among pathologic T1 N0 cases, the survival of patients with small lung cancer with a diameter of 2.0 cm or less is better than that of other T1 N0 cases. However, our results indicate that there still remains a risk of nodal micrometastasis in patients with peripheral lung adenocarcinoma, even if the diameter of the tumor is smaller than 2.0 cm. Therefore, we recommend that selection of patients for limited resection be done prudently. The application of an immunohistochemical method for the detection of nodal micrometastasis will be useful for clinicians to determine an appropriate follow-up schedule and to expand new clinical trials of adjuvant therapy to potentially benefit patients with lung adenocarcinoma smaller than 2.0 cm in diameter. References 1. Greenson J, Isenhart CE, Rice R, Mojzisik C, Houchens D, Martin EW. 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Chest 1998; 113(Suppl):S6 S12.1st kmm, 2nd kmm INVITED COMMENTARY The article by Wu and associates is a retrospective report of the results of an immunohistochemical (IHC) assessment of patients with early stage non-small cell lung cancer. However, it is really an acknowledgment of the fact that a significant component of patients with perceived early stage disease will recur following surgical therapy alone, verifying the perception that a large percentage of lung cancer patients are under-staged using current techniques. The article examines 103 patients who would historically be considered the most favorable prognostic subset of all patients with non-small cell lung cancer. IHC analysis produced a change in stage in 19.8% of cases. In some, these were dramatic, ie, changes from surgical stage 1A to 3A and 3B. Previous assessments of IHC applications in tumor staging have appropriately included concerns regarding which IHC technique is most appropriate and accurate. Dr Wu s analysis is compelling because they have validated the accuracy of their IHC results with follow-up demonstrating a significant difference in five year survival between patients with micrometastasis (61.9%) compared to those without micrometastasis (86.3%). Their assessments have included the identification of a subset of patients, specifically those with poorly differentiated tumors and lymphatic invasion, which are more likely to demonstrate micrometastasis with IHC. They have also supported the perception that certain subtypes of bronchoalveolar cell cancers (specifically type A and B) have a significantly decreased risk of early lymphatic spread as manifested by a virtual absence of micrometastasis in this group and the identification of 100% 5-year survivorship. This article reinforces the importance of anatomic resection and careful lymph node analysis to obtain appropriate staging information even in individuals presenting with early stage disease. The overall accuracy of any staging approach will still be contingent on the completeness of nodal sampling at mediastinoscopy and thoracotomy, and the acuity of the assessment of the standard H&E slides. In our laboratory, IHC assessment costs approximately $50 per slide, although this would superficially appear to increase the expense of managing these patients, the cost would be considered small if it resulted in improved staging and treatment decisions in 20% of patients initially thought to have early stage disease. This report raises the question as to whether IHC techniques should be applied in all patients undergoing mediastinoscopy. Improving the accuracy of the assessment to differentiate early stage patients from those with 3A and 3B disease prior to thoracotomy would greatly facilitate the decision regarding neoadjuvant therapy in this patient population. Dr Wu s data suggest that the most cost effective approach should direct IHC analysis at all patients with poorly differentiated tumors and lymphatic invasion. The results would also provide additional support to the evolving concept that patients with early stage type A and B bronchoalveolar cell carcinomas may be managed appropriately with nonanatomic resections. How much weight to ultimately give IHC assessment 2001 by The Society of Thoracic Surgeons 0003-4975/01/$20.00 Published by Elsevier Science Inc PII S0003-4975(01)02623-6