Ann Thorac Surg 2004;78:1190-1193
© 2004 The Society of Thoracic Surgeons
Original article: general thoracic
Imprint Cytology for Detecting Metastasis of Lung Cancer in Mediastinal Lymph Nodes
Kenichi Okubo, MDa,*,
Tatsuo Kato, MDb,
Akira Hara, MDc,
Naoki Yoshimi, MDc,d,
Keiichi Takeda, CTe,
Fumihiko Iwao, CTe
a General Thoracic SurgeryGifu National Hospital, Gifu, Japan
b Pulmonary Medicine, Gifu National Hospital, Gifu, Japan
e Laboratory Medicine, Gifu National Hospital, Gifu, Japan
c Department of Tumor Pathology, Gifu University, Gifu, Japan
d Department of Tumor Pathology, University of the Ryukyu, Okinawa, Japan
Accepted for publication April 1, 2004.
* Address reprint requests to Dr Okubo, General Thoracic Surgery, Gifu National Hospital, 5-1-1 Hino-higashi, Gifu 500-8718, Japan
okubo{at}gifu.hosp.go.jp
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Abstract
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BACKGROUND: Lymph node metastasis of lung cancer has been evaluated with histologic examination. We studied the usefulness of cytologic diagnosis for detecting metastasis of lung cancer in mediastinal nodes.
METHODS: Five hundred twelve stations of mediastinal nodes in 157 patients with lung cancer were excised for staging of the disease through mediastinoscopy or thoracoscopy. Among them, 474 stations of mediastinal nodes in 151 patients were examined for metastasis both with imprint cytology and with hematoxylin-eosin histology independently. The final diagnostic decision was made by overall pathologic information, including cytology and histology. The diagnostic accuracies were compared between cytologic and histologic examinations.
RESULTS: Cytologic examination identified 66 positive stations and 2 suspicious stations in 45 patients, whereas histologic examination identified 61 positive stations in 42 patients. The final pathologic diagnosis was 70 positive stations and 1 suspicious station in 45 patients. The sensitivity, accuracy, and negative predictive value of cytologic examination for node metastasis were 95.7%, 99.4%, and 99.3%, respectively, and those of histologic examination were 87.1%, 98.1%, and 97.7%, respectively. On a patient basis the sensitivity, accuracy, and negative predictive value of cytologic examination were 100%, 100%, and 100%, respectively, whereas those of histologic examination were 93.8%, 98.0%, and 97.2%, respectively. An additional 3 patients (2.0%) who had contralateral mediastinal node metastasis diagnosed only with cytology were identified with upstaged disease.
CONCLUSIONS: Imprint cytology for detecting metastasis of lung cancer in mediastinal nodes has high sensitivity and accuracy and is no less useful than histologic examination.
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Introduction
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Currently, induction chemoradiotherapy is applied for locally advanced non–small-cell lung cancers [1, 2]. Diagnosis of mediastinal lymph node involvement is crucial [3], because the therapeutic strategy differs depending on the stage of lung cancer. Preoperative pathologic diagnosis of mediastinal nodes is still necessary in view of the inaccurate evaluation of lymph node metastasis by computed tomographic scan or even by positron emission tomography scanning [4].
Cytodiagnosis is useful for small specimens, the cut surfaces of which cannot be made as a tissue block, and has the advantage of easy preparation. However, few studies have investigated cytologic examination for detecting metastasis of lung cancer in mediastinal lymph nodes. To explore the usefulness of cytodiagnosis in mediastinal node metastasis, we combined imprint cytology with conventional hematoxylin-eosin histology for specimens obtained from lung cancer patients through mediastinoscopy or thoracoscopy.
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Material and Methods
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From April 1997 to July 2003, 512 stations of mediastinal lymph nodes in 157 patients with lung cancer were excised for staging of the disease through mediastinoscopy or thoracoscopy. During the same period 373 patients underwent pulmonary resection for lung cancer, which indicates that approximately 42% of patients with lung cancer underwent staging mediastinal node biopsy. Among them 474 stations of mediastinal nodes in 151 patients were examined both cytologically and histologically. Although 27 stations of negative mediastinal nodes in 9 patients with benign lung diseases suspected of being lung cancer before operation were excised during this period, we excluded them to focus on the staging of true lung cancer. These data were analyzed to evaluate the usefulness of cytologic diagnosis.
The patients were 114 men and 37 women with a mean age of 64.7 years (range, 19 to 78 years). Histology of lung cancer was adenocarcinoma in 78, squamous cell carcinoma in 59, large-cell carcinoma in 7, adenosquamous carcinoma in 4, and small-cell carcinoma in 3. Radiologically identified mediastinal nodes were excised before the thoracotomy for pulmonary resection when node metastasis was suspected, and the therapeutic strategy was decided accordingly. Generally ipsilateral superior mediastinal and subcarinal nodes (with contralateral paratracheal nodes, when identified) were excised through mediastinoscopy. Aortic nodes (subaortic [No. 5] and paraortic [No. 6]) or inferior mediastinal nodes (paraesophageal [No. 8] and pulmonary ligament [No. 9]) were additionally excised through thoracoscopy when the cancer was located on the left or when suspicious nodes were radiologically identified. The excised nodes were defined according to the lung cancer staging of the American Joint Committee for Cancer Staging and End-Results Reporting [5] and the Japan Lung Cancer Society [6].
Each node excised was bisected, and the cut surface was imprinted with a glass slide, followed by 95% ethanol fixation and Papanicolaou stain before microscopic evaluation. When a node station consisted of multiple pieces of excised specimen, each was bisected, and then each cut surface was imprinted with a glass slide. More than 1 glass slide was rarely used because of the amount of specimen. The rest of the specimen used for imprint cytology was fixed with 10% formaldehyde on the basis of each station, followed by paraffin embedding and hematoxylin-eosin staining before histologic evaluation. Cytology was diagnosed as an intraoperative assessment, and histology was later examined independently. The same pathologist made the final diagnosis of node metastasis when discrepancy occurred between cytology and histology. According to the final diagnosis we studied sensitivity (true positive/true positive + false negative), specificity (true negative/true negative + false positive), accuracy (true positive + true negative/true positive + false positive + true negative + false negative), positive predictive value (true positive/true positive + false positive), and negative predictive value (true negative/true negative + false negative) of cytologic and histologic examinations on the bases of node stations and patients.
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Results
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Among 474 node stations in 151 patients, cytologic examination identified 66 positive stations in 45 patients and 2 suspicious stations in 2 patients. Histologic examination identified 61 positive stations in 42 patients. One of 2 suspicious stations in cytology was positive in histology, and the other was negative in histology. The final pathologic diagnosis was 70 positive stations and 1 suspicious station in 45 patients. The diagnosis was cancer positive when either cytologic or histologic examination showed positive results. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of cytologic examination, excluding 2 suspicious nodes, were 95.7%, 100%, 99.4%, 100%, and 99.3%, respectively (Table 1). Those of histologic examination were 87.1%, 100%, 98.1%, 100%, and 97.7%, respectively (Table 2). Typical node station with both cytology- and histology-positive findings and that with cytology-positive/histology-negative findings are shown in Figures 1 and 2.
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Fig 1. (A) Cytologic finding of the ipsilateral lower paratracheal (No. 4R) lymph node showing adenocarcinoma. (Papanicolaou stain, x400.) (B) Histologic finding of the same node showing an adenocarcinoma. (Hematoxylin & eosin stain, x100.)
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Fig 2. Imprint cytology of a subcarinal (No. 7) lymph node showing squamous cell carcinoma. (Papanicolaou stain, x400.) The histologic specimen showed no malignant cells.
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On a patient basis, cytologic examination identified 45 patients with mediastinal node metastasis. Two cytologically suspicious nodes were seen in patients with other positive node stations. Histologic examination identified 42 patients with node metastasis. The final diagnosis was positive in 45 patients, showing that the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of cytologic examination were all 100% (Table 3). Those of histologic examination were 93.3%, 100%, 98.0%, 100%, and 97.2%, respectively (Table 4). Three cytology-negative and histology-positive nodes were seen in 2 patients with other positive stations. Among 9 cytology-positive and histology-negative stations, 3 stations were seen in 3 patients (2.0%) with otherwise negative nodes each. An additional 3 cytology-positive and histology-negative stations were seen in contralateral mediastinal nodes in 3 patients (2.0%) with ipsilateral mediastinal node metastasis. The other 3 stations were seen in 3 patients with other positive nodes. All patients who showed discrepancy between cytologic and histologic examination results are listed in Table 5.
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Comment
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Mediastinal lymph node metastasis is a stage-decisive factor of lung cancer. Patients with N2 stage IIIA non–small-cell lung cancer have shown poor prognosis with primary resection with or without adjuvant therapy [7–9]. Currently multimodality therapy—induction chemoradiotherapy followed by pulmonary resection—is applied for this stage of lung cancer [1, 2]. Given the increased postoperative morbidity after the induction therapy and the prolonged duration of the multimodality therapy, preoperative diagnosis of mediastinal node metastasis should be accurate. Although radiologic diagnosis with computed tomography and positron emission tomography scanning are useful for staging lung cancer, inaccurate staging is frequently encountered [4], and pathologic confirmation is still required.
Endoscopic mediastinal node biopsy and sequential pulmonary resection when the node metastasis is negative would benefit patients. This would reduce the risk of a second operation and also result in elimination of the cost, time, and resources required for a separate procedure. Frozen section is the most commonly practiced method for the intraoperative assessment of mediastinal node metastasis. The sensitivity of mediastinal node metastasis identification with frozen section has been reported as 92% to 99% [10–12]. In theory, imprint cytology should be advantageous over frozen section because it is faster and cheaper, does not waste tissue in the cryostat, and does not introduce frozen artifacts into tissue that may make the permanent histologic diagnosis difficult. In this study we compared the diagnostic accuracy of imprint cytology with that of histology.
In our results cytologic examination showed higher sensitivity, accuracy, and negative predictive value in detecting metastasis in excised specimens than histologic examination did, on both a node-station basis and a patient basis. Specificity and positive predictive value were 100%, because all positive imprint and histology findings were considered to be true-positive results. Our results also compare favorably with those in other studies with frozen section. The discrepancy in cytologic and histologic examinations can be explained by the fact that micrometastasis could be identified in only 1 microscopic view. The reason for the higher sensitivity of cytologic diagnoses in our results might be that more cut surface was examined with imprint cytology because of multiple pieces from each node station with forceps-biopsy. Because excised specimens were examined with cytology first, the possibility that histology would have identified malignant cells without cytology could not be excluded.
Patients who showed a discrepancy in cytologic and histologic examinations are listed in Table 5. Three node stations in 2 patients with cytology-negative and histology-positive findings did not cause staging changes with the positive results, because other positive mediastinal nodes were identified in each patient. However, among 9 node stations in 9 patients with cytology-positive and histology-negative findings, 6 patients were upstaged with the positive results: 3 patients with N0 or N1 (stage I or II) to N2 (stage IIIA) disease and 3 patients with N2 (stage IIIA) to contralateral N3 (stage IIIB) disease [13]. These 6 patients were clinically treated with multimodality therapy for locally advanced lung cancer under the accurate pathologic staging.
Although some reports have shown the usefulness of cytologic diagnosis in evaluating sentinel lymph nodes with breast cancer and melanoma [14–16], only a few have been seen regarding mediastinal nodes with lung cancer [17]. We started intraoperative imprint cytology of mediastinal nodes because of initial poor availability of frozen-section examination in our hospital; however, our results showed high sensitivity and accuracy of cytologic diagnosis in detecting node metastasis. Cytologic diagnosis has an easy preparation and is time saving. Imprint cytology for detecting mediastinal node metastasis of lung cancer is no less useful than histology.
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Abstract
Introduction
