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Autopsy Results After Surgery for Non-Small Cell Lung Cancer
ORIGINAL ARTICLE
AUTOPSY RESULTS OF NSCLC SURGICAL PATIENTS
Autopsy Results After Surgery for Non–Small Cell Lung Cancer NICOLE M. FINKE, MD; MARIE-CHRISTINE AUBRY, MD; HENRY D. TAZELAAR, MD; GREGORY L. AUGHENBAUGH, MD; CHRISTINE M. LOHSE, BS; V. SHANE PANKRATZ, PHD; AND CLAUDE DESCHAMPS, MD OBJECTIVE: To determine the percentage of metastatic and unexpected residual lung cancer at autopsy in patients considered for curative resection of non–small cell lung cancer during a time when computed tomography was available as a preoperative staging tool. MATERIAL AND METHODS: Clinical data and surgical and autopsy slides of all patients who underwent curative resection of non– small cell lung cancer at the Mayo Clinic in Rochester, Minn, between 1985 and 1999 and who underwent autopsy within 30 days of surgery were reviewed retrospectively for the presence of residual or metastatic disease. RESULTS: The study group consisted of 25 men and 7 women, with a mean age of 70 years. A pulmonary metastasis was identified at surgery in 1 patient (3%). Metastases were found in an additional 5 patients (16%) at autopsy, 1 of whom had 2 sites involved. These sites included the liver in 2 and lung, epicardium, adrenal gland, and kidney in 1 each. The average diameter of metastases was 1.6 cm. No factor studied was found to be significantly associated with the presence of unrecognized metastatic disease at autopsy. CONCLUSION: The advent of computed tomography as a staging tool has decreased the percentage of patients with undiagnosed metastatic disease at surgery; however, preoperative understaging in lung cancer remains a problem.
Mayo Clin Proc. 2004;79(11):1409-1414 CT = computed tomography; NSCLC = non–small cell lung cancer
L
ung cancer is the leading cause of death from cancer in both men and women in North America. An estimated 175,000 new cases of non–small cell lung cancer (NSCLC) are diagnosed each year in the United States alone.1 Although surgical resection provides the best hope for cure, only one third of patients are candidates for definitive surgical management.2 In one study, the overall cumulative 5-year survival rate for patients with primary lung cancer managed by resection increased from 23% in 19603 to 54% in 1990.4 This increased survival rate was attributed to more accurate preoperative evaluation and staging of lung cancer. Before the introduction of computed tomography From the Department of Laboratory Medicine and Pathology (N.M.F., M.-C.A., H.D.T.), Department of Radiology (G.L.A.), Division of Biostatistics (C.M.L., V.S.P.), and Division of General Thoracic Surgery (C.D.), Mayo Clinic College of Medicine, Rochester, Minn. Dr Finke is now with the Elmhurst Memorial Hospital, Elmhurst, Ill. Address reprint requests and correspondence to Marie-Christine Aubry, MD, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (e-mail: aubry.mariechristine @mayo.edu). © 2004 Mayo Foundation for Medical Education and Research
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(CT) as a staging tool, one study showed that 49 (24%) of 202 patients who underwent curative resection of lung cancer and died within 30 days postoperatively were found to have unrecognized metastatic disease at autopsy.5 In addition, residual disease at the site of previous resection was found in 24 (12%) of 202 patients.5 The purpose of this study was to determine the percentage of metastatic and unexpected residual lung cancer at autopsy in patients considered for curative resection of NSCLC during a period when CT was available as a preoperative staging tool. MATERIAL AND METHODS Preoperative chest CT with routine evaluation of adrenal glands was introduced for patients undergoing clinical staging of lung cancer at the Mayo Clinic in Rochester, Minn, in the mid-1980s. Therefore, the period chosen for this retrospective study was from 1985 to 1999. This study was approved by the Mayo Foundation Institutional Review Board. Inclusion criteria included patients with a diagnosis of NSCLC who underwent curative surgery and who died within 30 days of the surgery and subsequently underwent an autopsy. Mayo Clinic pathology and surgical databases were searched to identify patients who met these criteria. Medical records were reviewed for age at diagnosis, sex, preoperative work-up, type of surgery, clinical and postsurgical tumor stage, and type of autopsy. Autopsies were either complete with evaluation of all organs or limited to certain organs. All available CTs were reviewed by a chest radiologist (G.L.A.), and, when unavailable, data were collected from radiology reports. Radiological data included extent of CT (limited to chest, chest extending to upper abdomen, and complete abdomen), primary tumor site, size of primary tumor, presence and location of indeterminate pulmonary nodules, adenopathy, and other nodules suggestive of metastatic disease. Hematoxylin-eosin–stained slides from the primary lung tumor and the autopsy specimens were also reviewed. Lung tumors were classified according to the most recent World Health Organization classification.6 Residual disease was defined as tumor present in tissue around the bronchial stump or tumor in mediastinal lymph nodes not sampled at surgery. Synchronous primary lung carcinoma was defined as carcinoma of a different histological sub-
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TABLE 1. Clinical and Pathologic Features of 32 Patients With Non–Small Cell Lung Cancer No. (%) of patients*
Feature Mean age (y) (range) at surgery Sex Male Female Tumor type Squamous cell Adenocarcinoma Large cell Spindle cell Type of surgery Lobectomy Pneumonectomy Wedge resection Preoperative tumor stage Occult IA IB IIA IIB IIIA IIIB Postoperative tumor stage 0cis† IA IB IIA IIB IIIA IIIB IV Autopsy tumor stage IA IB IIA IIB IIIA IIIB IV Autopsy type Complete Chest and abdomen only Chest only Other
70 (46-84) 25 (78) 7 (22) 19 (59) 11 (34) 1 (3) 1 (3) 17 (53) 10 (31) 5 (16) 1 (3) 9 (28) 8 (25) 0 (0) 7 (22) 5 (16) 2 (6) 1 (3) 5 (16) 7 (22) 0 (0) 10 (31) 5 (16) 3 (9) 1 (3) 5 (16) 6 (19) 0 (0) 8 (25) 5 (16) 2 (6) 6 (19) 25 (78) 3 (9) 2 (6) 2 (6)
*Data are number (percentage) of patients unless indicated otherwise. †Carcinoma in situ.
type or, if the same subtype, a tumor with areas of in situ carcinoma that occurred in a different lobe.7 If the second lung tumor did not meet these criteria, it was diagnosed as a T4 or distant metastasis, in accordance with guidelines from the American Joint Committee on Cancer.8 Sites and size of distant metastases were recorded. Staging, clinical and pathologic (postoperative and at autopsy), was determined according to guidelines from the American Joint Committee on Cancer. Differences in the clinical and pathologic variables between patients with and without unrecognized metastatic disease at autopsy were evaluated using the Fisher exact 1410
TABLE 2. Computed Tomographic Findings in 32 Patients With Non–Small Cell Lung Cancer
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No. (%) of patients
Findings Primary tumor site* RUL RML RLL LUL LLL LUL, LLL LUL, RUL Mediastinal adenopathy Indeterminate pulmonary nodules† Findings in other sites Benign renal cysts Splenomegaly Adrenal adenoma Renal and adrenal masses
12 (38) 0 (0) 4 (13) 8 (25) 4 (13) 3 (9) 1 (3) 8 (25) 9 (28) 6 (19) 2 (6) 2 (6) 1 (3)
*The mean size of the primary tumor was 4.0 cm (range, 0.8-12.0 cm). LLL = left lower lobe; LUL = left upper lobe; RLL = right lower lobe; RML = right middle lobe; RUL = right upper lobe. †The mean size of the indeterminate pulmonary nodules was 0.8 cm (range, 0.3-2.0 cm).
test and Wilcoxon rank sum tests. All tests were 2-sided, and P<.05 was considered statistically significant. RESULTS The clinical and pathologic features of the 32 patients are detailed in Table 1. There were 25 men and 7 women, with a mean age of 70 years. A CT scan of the chest was limited to the chest in 9 patients and extended to the upper abdomen (including adrenal glands) in 10. Complete abdominal CT, without contrast, was performed in 16 (50%), including 1 patient who had a scan of the chest that extended to the abdomen. Radiological results are detailed in Table 2. The tumors were mostly located within the upper lobes (75%) and had a mean diameter of 4.0 cm. Indeterminate nodules were identified in 9 patients, and 8 patients had mediastinal adenopathy. Renal and adrenal masses that measured 5.5 and 3.5 cm in diameter, respectively, were identified on the chest CT scan of 1 patient; however, according to the pathology report, their presence was not confirmed at autopsy. Most patients presented with clinical stage I or II disease, and all underwent curative surgery. Patients primarily underwent lobectomy (53%). One patient (3%) underwent concomitant resection of an indeterminate nodule present in a different lobe, representing a pulmonary metastasis. The most common histological type was squamous cell carcinoma (59%), followed by adenocarcinoma (34%). The pathologic stage changed from the clinical stage in 13 patients (41%): the tumors were upstaged in 11 patients (34%) and downstaged in 2 (6%).
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AUTOPSY RESULTS OF NSCLC SURGICAL PATIENTS
TABLE 3. Detailed Features of Patients With Undiagnosed Metastatic Lung Cancer at Autopsy* Patient No./ age (y)/sex
CT chest/ abdomen
Surgical resection
Tumor type
Surgical stage
Autopsy type
Distant metastases (diameter, cm)
1/59/F 2/50/M 3/76/M 4/70/M 5/62/M
Yes/No Yes/No Yes/No Yes/Yes Yes/No
Yes Yes Yes Yes Yes
SCC AC SCC SCC SCC
0cis† IIB IIB IB IIIB
Complete C&A Complete Complete C&A
Opposite lung (0.3) Adrenal gland (3.0) Liver (6 nodules, 0.3-2.5) Liver (1 nodule, 1.5) Epicardium, kidney (1.5)
*AC = adenocarcinoma; C & A = chest and abdomen only; CT = computed tomography; SCC = squamous cell carcinoma. †Carcinoma in situ.
Twenty-five patients (78%) underwent a complete autopsy. No patients were found to have residual locoregional lung tumor at autopsy. Unrecognized metastatic disease was found in 5 patients (16%) (Table 3). The mean age of these 4 men and 1 woman was 63 years. Pathologic staging ranged from stage 0cis (carcinoma in situ) to stage IIIB. Four patients had metastatic disease limited to 1 site, and 1 patient had metastatic disease in 2 locations. Metastatic sites included the liver in 2 and lung, epicardium, adrenal gland (Figure 1), and kidney in 1 each. The average diameter of metastatic foci was 1.6 cm. Imaging results were available for review in 2 patients (patients 1 and 2). Retrospective review of the chest CT scan in patient 1 confirmed the presence of the indeterminate nodules seen preoperatively in the right upper and lower lobes, one of which was identified at autopsy as a distant pulmonary metastasis. Retrospective review of the abdominal portion of the CT scan from patient 2 showed only partial imaging of the left adrenal gland, in which a 3.0-cm-diameter metastasis was identified at autopsy. The patient with the liver metastasis underwent preoperative abdominal CT; the metastasis was not noted on the scan, but it was not a contrast-enhanced study. Of the 8 other patients described as having indeterminate pulmonary nodules on preoperative chest CT, 3 were
found to have a malignancy at autopsy: 2 with pulmonary metastases (including the previously described patient 1) (Figure 2) and 1 with a synchronous primary tumor. The indeterminate nodules in the remaining 5 patients were not commented on in either the surgical or autopsy reports. No clinical or pathologic feature studied was significantly associated with the presence of previously unrecognized metastatic disease at autopsy (Table 4). DISCUSSION The introduction of CT as a preoperative staging tool for lung cancer has slightly reduced the number of patients with unsuspected metastases undergoing surgery for potential cure. Indeed, the percentage of patients with undiagnosed metastases in our study (16%) was lower than that reported previously in a study by Matthews et al (24%).5 However, despite this technologic improvement, a sixth of our patients had undetected metastatic disease, emphasizing the limitations of preoperative work-up. Clinical staging differed from pathologic staging in 41% of our resected lung cancers, similar to findings in other studies.9,10 In one study, the reported sensitivity of CT to distinguish T1 to T2 from T3 to T4 tumors was 62%.11 In
FIGURE 1. Left, Primary adenocarcinoma of the lung. Right, Adrenal metastasis (normal adrenal gland on the right side) with similar histological features (Left and Right, hematoxylin-eosin, original magnification ×100).
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FIGURE 2. Top, Chest computed tomogram shows the presence of a spiculated mass consistent with lung carcinoma (arrowhead) and a small indeterminate nodule (arrow). Middle, Intermediate-magnification photomicrograph of the spiculated mass shows a moderately well-differentiated adenocarcinoma (hematoxylin-eosin, original magnification ×100). Bottom, Intermediate-magnification photomicrograph of the indeterminate nodule from the other lung shows histological features identical to the main mass, therefore representing metastatic disease (hematoxylin-eosin, original magnification ×100).
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other studies, the reported sensitivity of CT to detect invasion of mediastinal structures was low, with false-negative rates of up to 20%.7,11-13 The reported sensitivity and specificity of CT to detect metastases are 63% and 73%, respectively.14 Therefore, CT likely contributes to understaging, and newer tools may be able to improve our ability to detect extensive local disease and metastases. Recent reports on whole-body positron emission tomography with 18fluorodeoxyglucose suggest that this modality might be superior to conventional CT in the preoperative staging of lung cancer.14-18 Use of positron emission tomography has been reported to change clinical management in up to 41% of patients with lung cancer by detecting unsuspected metastases or indicating that abnormalities on CT may not be malignant.15,17 Because of their respective strengths, the use of both modalities could likely enhance the detection of metastases in patients with lung cancer. Nonetheless, as shown in our study, the limitations of chest CT do not account for all cases of understaged lung cancer. Several organs are not evaluated routinely with preoperative CT scanning. In our study, 3 patients (9%) had undetected liver and kidney metastases despite normal laboratory test results, and 1 patient with a liver metastasis had a normal abdominal CT. However, CT in this case was performed without intravenous enhancement; thus, it was a suboptimal examination. Although routine examination of the liver by CT has been recommended by the British Thoracic Society,19 this recommendation is not followed routinely.20 These recommendations derive from studies that suggest a low incidence, ranging from 0% to 4.9%, and a high negative predictive value (>90%) of occult metastases in these organs.21,22 The incidence of such occult metastases in our study was higher and also likely underestimated because almost a fourth of our patients did not undergo a complete autopsy, and, therefore, some organs were not evaluated. In addition, bones other than the vertebral column are not routinely evaluated at autopsy. A recent pilot study found occult cerebral or skeletal metastases in 28% of patients with NSCLC and recommended routine contrast-enhanced magnetic resonance imaging of the brain in patients with operable NSCLC greater than 3 cm in diameter.23 The usefulness of routine bone imaging needs further investigation. The balance between the risk of falsepositive routine test results and cost needs to be determined through larger prospective clinicopathologic studies. Indeterminate nodules identified on preoperative chest CT represented either metastatic or new primary lung cancer in almost half of our patients with these nodules. Although indeterminate pulmonary nodules in general most often represent benign lesions,24 they are more likely to represent metastatic disease or a new lung primary tumor in the presence of known lung cancer. In a study of 72 patients
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AUTOPSY RESULTS OF NSCLC SURGICAL PATIENTS
with a history of lung cancer who underwent video-assisted thoracoscopic surgery for an indeterminate nodule found on CT, the nodules were malignant in 63 patients (88%).25 In our study, stage and histological type were not found to be predictive of occult metastatic disease. This is in contrast to other studies that have shown that, stage for stage, adenocarcinoma and large cell carcinoma have a greater metastatic propensity to metastasize than squamous cell carcinoma.21 Others have also reported an increased percentage of extrathoracic metastases in patients with nodal involvement.26 Although some of our patients did not undergo preoperative CT, none of them had unresectable or metastatic disease at autopsy, and they were not significantly different from patients who did undergo preoperative CT. None of the patients who underwent curative resection were found to have residual locoregional disease at autopsy. This is in contrast to the results of the study by Matthews et al,5 who found that 12% of their patients had residual locoregional disease. This difference in residual locoregional disease may be the result of improved surgical techniques in the 26-year interval between the 2 studies, including more thorough sampling of mediastinal lymph nodes using lymphadenectomy. Our study has limitations. It is retrospective, and therefore an exhaustive radiologic-pathologic correlation of indeterminate nodules or other findings was not possible. Not all the autopsies were complete, and therefore common sites of metastases, such as brain, liver, and adrenal glands, were not evaluated; thus, our results may have underestimated the true presence of disease. Although the number of patients evaluated was relatively small, our study still represents a large autopsy series, and our results emphasize the continued need for improved preoperative techniques to evaluate the extent of local disease and the presence of metastases in patients being considered for lung cancer resection. CONCLUSION The advent of CT as a staging tool has decreased the percentage of patients with undiagnosed metastatic disease at surgery. However, preoperative understaging in lung cancer remains a problem. We thank Dr Jeffrey L. Myers for his editorial comments. REFERENCES 1. Jemal A, Tiwari RC, Murray T, et al, American Cancer Society. Cancer statistics, 2004. CA Cancer J Clin. 2004;54:8-29. 2. Bulzebruck H, Bopp R, Drings P, et al. New aspects in the staging of lung cancer: prospective validation of the International Union Against Cancer TNM classification. Cancer. 1992;70:1102-1110.
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TABLE 4. Comparison of Clinical and Pathologic Features Between Patients With and Without Unrecognized Metastatic Disease at Autopsy No. (%) of patients*
Feature Mean age (y) (range) at surgery Sex Male Female Abdominal computed tomogram Yes No Tumor type Squamous cell Adenocarcinoma Large cell Spindle cell Pathologic tumor stage 0cis† IA IB IIA IIB IIIA IIIB
Without metastatic disease (n=26)
With metastatic disease (n=5)
71 (46-84)
63 (50-76)
20 (77) 6 (23)
4 (80) 1 (20)
15 (58) 11 (42)
1 (20) 4 (80)
15 (58) 9 (35) 1 (4) 1 (4)
4 (80) 1 (20) 0 (0) 0 (0)
0 (0) 5 (19) 6 (23) 0 (0) 8 (31) 5 (19) 2 (8)
1 (20) 0 (0) 1 (20) 0 (0) 2 (40) 0 (0) 1 (20)
P value .12 >.99
.17 .74
.22
*Data are number (percentage) of patients unless indicated otherwise. The patient with the discovered pulmonary metastases at surgery is excluded from the calculation because the metastases were not discovered at autopsy. †Carcinoma in situ.
3. Pearson FG. Lung cancer: the past twenty-five years. Chest. 1986;89(4, suppl):200S-205S. 4. Wada H, Tanaka F, Yanagihara K, et al. Time trends and survival after operations for primary lung cancer from 1976 through 1990. J Thorac Cardiovasc Surg. 1996;112:349-355. 5. Matthews MJ, Kanhouwa S, Pickren J, Robinette D. Frequency of residual and metastatic tumor in patients undergoing curative surgical resection for lung cancer. Cancer Chemother Rep 3. 1973;4:63-67. 6. Travis WD, Colby T, Corrin B, et al. Histological Typing of Lung and Pleural Tumours. 3rd ed. Berlin, Germany: Springer-Verlag; 1999:1-156. International Histological Classification of Tumours. 7. Martini N, Heelan R, Westcott J, et al. Comparative merits of conventional, computed tomographic, and magnetic resonance imaging in assessing mediastinal involvement in surgically confirmed lung carcinoma. J Thorac Cardiovasc Surg. 1985;90:639-648. 8. Fleming ID, American Joint Committee on Cancer, American Cancer Society, American College of Surgeons. AJCC Cancer Staging Manual. 5th ed. Philadelphia, Pa: Lippincott-Raven; 1997:xv, 294. 9. Lahde S, Paivansalo M, Rainio P. CT for predicting the resectability of lung cancer: a prospective study. Acta Radiol. 1991;32:449-454. 10. Lewis JW Jr, Pearlberg JL, Beute GH, et al. Can computed tomography of the chest stage lung cancer? yes and no. Ann Thorac Surg. 1990;49:591595. 11. De Leyn P, Vansteenkiste J, Cuypers P, et al. Role of cervical mediastinoscopy in staging of non-small cell lung cancer without enlarged mediastinal lymph nodes on CT scan. Eur J Cardiothorac Surg. 1997;12:706-712. 12. Quint LE, Glazer GM, Orringer MB. Central lung masses: prediction with CT of need for pneumonectomy versus lobectomy. Radiology. 1987; 165:735-738.
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13. Musset D, Grenier P, Carette MF, et al. Primary lung cancer staging: prospective comparative study of MR imaging with CT. Radiology. 1986;160: 607-611. 14. Valk PE, Pounds TR, Hopkins DM, et al. Staging non-small cell lung cancer by whole-body positron emission tomographic imaging. Ann Thorac Surg. 1995;60:1573-1581. 15. Weder W, Schmid RA, Bruchhaus H, Hillinger S, von Schulthess GK, Steinert HC. Detection of extrathoracic metastases by positron emission tomography in lung cancer. Ann Thorac Surg. 1998;66:886-892. 16. Hustinx R, Paulus P, Jacquet N, Jerusalem G, Bury T, Rigo P. Clinical evaluation of whole-body 18F-fluorodeoxyglucose positron emission tomography in the detection of liver metastases. Ann Oncol. 1998;9:397-401. 17. Lewis P, Griffin S, Marsden P, et al. Whole-body 18F-fluorodeoxyglucose positron emission tomography in preoperative evaluation of lung cancer. Lancet. 1994;344:1265-1266. 18. Marom EM, McAdams HP, Erasmus JJ, et al. Staging non-small cell lung cancer with whole-body PET. Radiology. 1999;212:803-809. 19. British Thoracic Society, Society of Cardiothoracic Surgeons of Great Britain and Ireland Working Party. BTS guidelines: guidelines on the selection of patients with lung cancer for surgery. Thorax. 2001;56:89-108.
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20. American Thoracic Society, European Respiratory Society. Pretreatment evaluation of non-small-cell lung cancer. Am J Respir Crit Care Med. 1997; 156:320-332. 21. Hillers TK, Sauve MD, Guyatt GH. Analysis of published studies on the detection of extrathoracic metastases in patients presumed to have operable non-small cell lung cancer. Thorax. 1994;49:14-19. 22. Silvestri GA, Littenberg B, Colice GL. The clinical evaluation for detecting metastatic lung cancer: a meta-analysis. Am J Respir Crit Care Med. 1995; 152:225-230. 23. Earnest F IV, Ryu JH, Miller GM, et al. Suspected non-small cell lung cancer: incidence of occult brain and skeletal metastases and effectiveness of imaging for detection—pilot study. Radiology. 1999;211:137-145. 24. Suzuki K, Nagai K, Yoshida J, et al. Video-assisted thoracoscopic surgery for small indeterminate pulmonary nodules: indications for preoperative marking. Chest. 1999;115:563-568. 25. Dowling RD, Keenan RJ, Ferson PF, Landreneau RJ. Video-assisted thoracoscopic resection of pulmonary metastases. Ann Thorac Surg. 1993;56: 772-775. 26. Deslauriers J, Gregoire J. Clinical and surgical staging of non-small cell lung cancer. Chest. 2000;117(4, suppl 1):96S-103S.
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AUTOPSY RESULTS OF NSCLC SURGICAL PATIENTS
Autopsy Results After Surgery for Non–Small Cell Lung Cancer NICOLE M. FINKE, MD; MARIE-CHRISTINE AUBRY, MD; HENRY D. TAZELAAR, MD; GREGORY L. AUGHENBAUGH, MD; CHRISTINE M. LOHSE, BS; V. SHANE PANKRATZ, PHD; AND CLAUDE DESCHAMPS, MD OBJECTIVE: To determine the percentage of metastatic and unexpected residual lung cancer at autopsy in patients considered for curative resection of non–small cell lung cancer during a time when computed tomography was available as a preoperative staging tool. MATERIAL AND METHODS: Clinical data and surgical and autopsy slides of all patients who underwent curative resection of non– small cell lung cancer at the Mayo Clinic in Rochester, Minn, between 1985 and 1999 and who underwent autopsy within 30 days of surgery were reviewed retrospectively for the presence of residual or metastatic disease. RESULTS: The study group consisted of 25 men and 7 women, with a mean age of 70 years. A pulmonary metastasis was identified at surgery in 1 patient (3%). Metastases were found in an additional 5 patients (16%) at autopsy, 1 of whom had 2 sites involved. These sites included the liver in 2 and lung, epicardium, adrenal gland, and kidney in 1 each. The average diameter of metastases was 1.6 cm. No factor studied was found to be significantly associated with the presence of unrecognized metastatic disease at autopsy. CONCLUSION: The advent of computed tomography as a staging tool has decreased the percentage of patients with undiagnosed metastatic disease at surgery; however, preoperative understaging in lung cancer remains a problem.
Mayo Clin Proc. 2004;79(11):1409-1414 CT = computed tomography; NSCLC = non–small cell lung cancer
L
ung cancer is the leading cause of death from cancer in both men and women in North America. An estimated 175,000 new cases of non–small cell lung cancer (NSCLC) are diagnosed each year in the United States alone.1 Although surgical resection provides the best hope for cure, only one third of patients are candidates for definitive surgical management.2 In one study, the overall cumulative 5-year survival rate for patients with primary lung cancer managed by resection increased from 23% in 19603 to 54% in 1990.4 This increased survival rate was attributed to more accurate preoperative evaluation and staging of lung cancer. Before the introduction of computed tomography From the Department of Laboratory Medicine and Pathology (N.M.F., M.-C.A., H.D.T.), Department of Radiology (G.L.A.), Division of Biostatistics (C.M.L., V.S.P.), and Division of General Thoracic Surgery (C.D.), Mayo Clinic College of Medicine, Rochester, Minn. Dr Finke is now with the Elmhurst Memorial Hospital, Elmhurst, Ill. Address reprint requests and correspondence to Marie-Christine Aubry, MD, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (e-mail: aubry.mariechristine @mayo.edu). © 2004 Mayo Foundation for Medical Education and Research
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(CT) as a staging tool, one study showed that 49 (24%) of 202 patients who underwent curative resection of lung cancer and died within 30 days postoperatively were found to have unrecognized metastatic disease at autopsy.5 In addition, residual disease at the site of previous resection was found in 24 (12%) of 202 patients.5 The purpose of this study was to determine the percentage of metastatic and unexpected residual lung cancer at autopsy in patients considered for curative resection of NSCLC during a period when CT was available as a preoperative staging tool. MATERIAL AND METHODS Preoperative chest CT with routine evaluation of adrenal glands was introduced for patients undergoing clinical staging of lung cancer at the Mayo Clinic in Rochester, Minn, in the mid-1980s. Therefore, the period chosen for this retrospective study was from 1985 to 1999. This study was approved by the Mayo Foundation Institutional Review Board. Inclusion criteria included patients with a diagnosis of NSCLC who underwent curative surgery and who died within 30 days of the surgery and subsequently underwent an autopsy. Mayo Clinic pathology and surgical databases were searched to identify patients who met these criteria. Medical records were reviewed for age at diagnosis, sex, preoperative work-up, type of surgery, clinical and postsurgical tumor stage, and type of autopsy. Autopsies were either complete with evaluation of all organs or limited to certain organs. All available CTs were reviewed by a chest radiologist (G.L.A.), and, when unavailable, data were collected from radiology reports. Radiological data included extent of CT (limited to chest, chest extending to upper abdomen, and complete abdomen), primary tumor site, size of primary tumor, presence and location of indeterminate pulmonary nodules, adenopathy, and other nodules suggestive of metastatic disease. Hematoxylin-eosin–stained slides from the primary lung tumor and the autopsy specimens were also reviewed. Lung tumors were classified according to the most recent World Health Organization classification.6 Residual disease was defined as tumor present in tissue around the bronchial stump or tumor in mediastinal lymph nodes not sampled at surgery. Synchronous primary lung carcinoma was defined as carcinoma of a different histological sub-
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TABLE 1. Clinical and Pathologic Features of 32 Patients With Non–Small Cell Lung Cancer No. (%) of patients*
Feature Mean age (y) (range) at surgery Sex Male Female Tumor type Squamous cell Adenocarcinoma Large cell Spindle cell Type of surgery Lobectomy Pneumonectomy Wedge resection Preoperative tumor stage Occult IA IB IIA IIB IIIA IIIB Postoperative tumor stage 0cis† IA IB IIA IIB IIIA IIIB IV Autopsy tumor stage IA IB IIA IIB IIIA IIIB IV Autopsy type Complete Chest and abdomen only Chest only Other
70 (46-84) 25 (78) 7 (22) 19 (59) 11 (34) 1 (3) 1 (3) 17 (53) 10 (31) 5 (16) 1 (3) 9 (28) 8 (25) 0 (0) 7 (22) 5 (16) 2 (6) 1 (3) 5 (16) 7 (22) 0 (0) 10 (31) 5 (16) 3 (9) 1 (3) 5 (16) 6 (19) 0 (0) 8 (25) 5 (16) 2 (6) 6 (19) 25 (78) 3 (9) 2 (6) 2 (6)
*Data are number (percentage) of patients unless indicated otherwise. †Carcinoma in situ.
type or, if the same subtype, a tumor with areas of in situ carcinoma that occurred in a different lobe.7 If the second lung tumor did not meet these criteria, it was diagnosed as a T4 or distant metastasis, in accordance with guidelines from the American Joint Committee on Cancer.8 Sites and size of distant metastases were recorded. Staging, clinical and pathologic (postoperative and at autopsy), was determined according to guidelines from the American Joint Committee on Cancer. Differences in the clinical and pathologic variables between patients with and without unrecognized metastatic disease at autopsy were evaluated using the Fisher exact 1410
TABLE 2. Computed Tomographic Findings in 32 Patients With Non–Small Cell Lung Cancer
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No. (%) of patients
Findings Primary tumor site* RUL RML RLL LUL LLL LUL, LLL LUL, RUL Mediastinal adenopathy Indeterminate pulmonary nodules† Findings in other sites Benign renal cysts Splenomegaly Adrenal adenoma Renal and adrenal masses
12 (38) 0 (0) 4 (13) 8 (25) 4 (13) 3 (9) 1 (3) 8 (25) 9 (28) 6 (19) 2 (6) 2 (6) 1 (3)
*The mean size of the primary tumor was 4.0 cm (range, 0.8-12.0 cm). LLL = left lower lobe; LUL = left upper lobe; RLL = right lower lobe; RML = right middle lobe; RUL = right upper lobe. †The mean size of the indeterminate pulmonary nodules was 0.8 cm (range, 0.3-2.0 cm).
test and Wilcoxon rank sum tests. All tests were 2-sided, and P<.05 was considered statistically significant. RESULTS The clinical and pathologic features of the 32 patients are detailed in Table 1. There were 25 men and 7 women, with a mean age of 70 years. A CT scan of the chest was limited to the chest in 9 patients and extended to the upper abdomen (including adrenal glands) in 10. Complete abdominal CT, without contrast, was performed in 16 (50%), including 1 patient who had a scan of the chest that extended to the abdomen. Radiological results are detailed in Table 2. The tumors were mostly located within the upper lobes (75%) and had a mean diameter of 4.0 cm. Indeterminate nodules were identified in 9 patients, and 8 patients had mediastinal adenopathy. Renal and adrenal masses that measured 5.5 and 3.5 cm in diameter, respectively, were identified on the chest CT scan of 1 patient; however, according to the pathology report, their presence was not confirmed at autopsy. Most patients presented with clinical stage I or II disease, and all underwent curative surgery. Patients primarily underwent lobectomy (53%). One patient (3%) underwent concomitant resection of an indeterminate nodule present in a different lobe, representing a pulmonary metastasis. The most common histological type was squamous cell carcinoma (59%), followed by adenocarcinoma (34%). The pathologic stage changed from the clinical stage in 13 patients (41%): the tumors were upstaged in 11 patients (34%) and downstaged in 2 (6%).
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AUTOPSY RESULTS OF NSCLC SURGICAL PATIENTS
TABLE 3. Detailed Features of Patients With Undiagnosed Metastatic Lung Cancer at Autopsy* Patient No./ age (y)/sex
CT chest/ abdomen
Surgical resection
Tumor type
Surgical stage
Autopsy type
Distant metastases (diameter, cm)
1/59/F 2/50/M 3/76/M 4/70/M 5/62/M
Yes/No Yes/No Yes/No Yes/Yes Yes/No
Yes Yes Yes Yes Yes
SCC AC SCC SCC SCC
0cis† IIB IIB IB IIIB
Complete C&A Complete Complete C&A
Opposite lung (0.3) Adrenal gland (3.0) Liver (6 nodules, 0.3-2.5) Liver (1 nodule, 1.5) Epicardium, kidney (1.5)
*AC = adenocarcinoma; C & A = chest and abdomen only; CT = computed tomography; SCC = squamous cell carcinoma. †Carcinoma in situ.
Twenty-five patients (78%) underwent a complete autopsy. No patients were found to have residual locoregional lung tumor at autopsy. Unrecognized metastatic disease was found in 5 patients (16%) (Table 3). The mean age of these 4 men and 1 woman was 63 years. Pathologic staging ranged from stage 0cis (carcinoma in situ) to stage IIIB. Four patients had metastatic disease limited to 1 site, and 1 patient had metastatic disease in 2 locations. Metastatic sites included the liver in 2 and lung, epicardium, adrenal gland (Figure 1), and kidney in 1 each. The average diameter of metastatic foci was 1.6 cm. Imaging results were available for review in 2 patients (patients 1 and 2). Retrospective review of the chest CT scan in patient 1 confirmed the presence of the indeterminate nodules seen preoperatively in the right upper and lower lobes, one of which was identified at autopsy as a distant pulmonary metastasis. Retrospective review of the abdominal portion of the CT scan from patient 2 showed only partial imaging of the left adrenal gland, in which a 3.0-cm-diameter metastasis was identified at autopsy. The patient with the liver metastasis underwent preoperative abdominal CT; the metastasis was not noted on the scan, but it was not a contrast-enhanced study. Of the 8 other patients described as having indeterminate pulmonary nodules on preoperative chest CT, 3 were
found to have a malignancy at autopsy: 2 with pulmonary metastases (including the previously described patient 1) (Figure 2) and 1 with a synchronous primary tumor. The indeterminate nodules in the remaining 5 patients were not commented on in either the surgical or autopsy reports. No clinical or pathologic feature studied was significantly associated with the presence of previously unrecognized metastatic disease at autopsy (Table 4). DISCUSSION The introduction of CT as a preoperative staging tool for lung cancer has slightly reduced the number of patients with unsuspected metastases undergoing surgery for potential cure. Indeed, the percentage of patients with undiagnosed metastases in our study (16%) was lower than that reported previously in a study by Matthews et al (24%).5 However, despite this technologic improvement, a sixth of our patients had undetected metastatic disease, emphasizing the limitations of preoperative work-up. Clinical staging differed from pathologic staging in 41% of our resected lung cancers, similar to findings in other studies.9,10 In one study, the reported sensitivity of CT to distinguish T1 to T2 from T3 to T4 tumors was 62%.11 In
FIGURE 1. Left, Primary adenocarcinoma of the lung. Right, Adrenal metastasis (normal adrenal gland on the right side) with similar histological features (Left and Right, hematoxylin-eosin, original magnification ×100).
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FIGURE 2. Top, Chest computed tomogram shows the presence of a spiculated mass consistent with lung carcinoma (arrowhead) and a small indeterminate nodule (arrow). Middle, Intermediate-magnification photomicrograph of the spiculated mass shows a moderately well-differentiated adenocarcinoma (hematoxylin-eosin, original magnification ×100). Bottom, Intermediate-magnification photomicrograph of the indeterminate nodule from the other lung shows histological features identical to the main mass, therefore representing metastatic disease (hematoxylin-eosin, original magnification ×100).
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other studies, the reported sensitivity of CT to detect invasion of mediastinal structures was low, with false-negative rates of up to 20%.7,11-13 The reported sensitivity and specificity of CT to detect metastases are 63% and 73%, respectively.14 Therefore, CT likely contributes to understaging, and newer tools may be able to improve our ability to detect extensive local disease and metastases. Recent reports on whole-body positron emission tomography with 18fluorodeoxyglucose suggest that this modality might be superior to conventional CT in the preoperative staging of lung cancer.14-18 Use of positron emission tomography has been reported to change clinical management in up to 41% of patients with lung cancer by detecting unsuspected metastases or indicating that abnormalities on CT may not be malignant.15,17 Because of their respective strengths, the use of both modalities could likely enhance the detection of metastases in patients with lung cancer. Nonetheless, as shown in our study, the limitations of chest CT do not account for all cases of understaged lung cancer. Several organs are not evaluated routinely with preoperative CT scanning. In our study, 3 patients (9%) had undetected liver and kidney metastases despite normal laboratory test results, and 1 patient with a liver metastasis had a normal abdominal CT. However, CT in this case was performed without intravenous enhancement; thus, it was a suboptimal examination. Although routine examination of the liver by CT has been recommended by the British Thoracic Society,19 this recommendation is not followed routinely.20 These recommendations derive from studies that suggest a low incidence, ranging from 0% to 4.9%, and a high negative predictive value (>90%) of occult metastases in these organs.21,22 The incidence of such occult metastases in our study was higher and also likely underestimated because almost a fourth of our patients did not undergo a complete autopsy, and, therefore, some organs were not evaluated. In addition, bones other than the vertebral column are not routinely evaluated at autopsy. A recent pilot study found occult cerebral or skeletal metastases in 28% of patients with NSCLC and recommended routine contrast-enhanced magnetic resonance imaging of the brain in patients with operable NSCLC greater than 3 cm in diameter.23 The usefulness of routine bone imaging needs further investigation. The balance between the risk of falsepositive routine test results and cost needs to be determined through larger prospective clinicopathologic studies. Indeterminate nodules identified on preoperative chest CT represented either metastatic or new primary lung cancer in almost half of our patients with these nodules. Although indeterminate pulmonary nodules in general most often represent benign lesions,24 they are more likely to represent metastatic disease or a new lung primary tumor in the presence of known lung cancer. In a study of 72 patients
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AUTOPSY RESULTS OF NSCLC SURGICAL PATIENTS
with a history of lung cancer who underwent video-assisted thoracoscopic surgery for an indeterminate nodule found on CT, the nodules were malignant in 63 patients (88%).25 In our study, stage and histological type were not found to be predictive of occult metastatic disease. This is in contrast to other studies that have shown that, stage for stage, adenocarcinoma and large cell carcinoma have a greater metastatic propensity to metastasize than squamous cell carcinoma.21 Others have also reported an increased percentage of extrathoracic metastases in patients with nodal involvement.26 Although some of our patients did not undergo preoperative CT, none of them had unresectable or metastatic disease at autopsy, and they were not significantly different from patients who did undergo preoperative CT. None of the patients who underwent curative resection were found to have residual locoregional disease at autopsy. This is in contrast to the results of the study by Matthews et al,5 who found that 12% of their patients had residual locoregional disease. This difference in residual locoregional disease may be the result of improved surgical techniques in the 26-year interval between the 2 studies, including more thorough sampling of mediastinal lymph nodes using lymphadenectomy. Our study has limitations. It is retrospective, and therefore an exhaustive radiologic-pathologic correlation of indeterminate nodules or other findings was not possible. Not all the autopsies were complete, and therefore common sites of metastases, such as brain, liver, and adrenal glands, were not evaluated; thus, our results may have underestimated the true presence of disease. Although the number of patients evaluated was relatively small, our study still represents a large autopsy series, and our results emphasize the continued need for improved preoperative techniques to evaluate the extent of local disease and the presence of metastases in patients being considered for lung cancer resection. CONCLUSION The advent of CT as a staging tool has decreased the percentage of patients with undiagnosed metastatic disease at surgery. However, preoperative understaging in lung cancer remains a problem. We thank Dr Jeffrey L. Myers for his editorial comments. REFERENCES 1. Jemal A, Tiwari RC, Murray T, et al, American Cancer Society. Cancer statistics, 2004. CA Cancer J Clin. 2004;54:8-29. 2. Bulzebruck H, Bopp R, Drings P, et al. New aspects in the staging of lung cancer: prospective validation of the International Union Against Cancer TNM classification. Cancer. 1992;70:1102-1110.
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TABLE 4. Comparison of Clinical and Pathologic Features Between Patients With and Without Unrecognized Metastatic Disease at Autopsy No. (%) of patients*
Feature Mean age (y) (range) at surgery Sex Male Female Abdominal computed tomogram Yes No Tumor type Squamous cell Adenocarcinoma Large cell Spindle cell Pathologic tumor stage 0cis† IA IB IIA IIB IIIA IIIB
Without metastatic disease (n=26)
With metastatic disease (n=5)
71 (46-84)
63 (50-76)
20 (77) 6 (23)
4 (80) 1 (20)
15 (58) 11 (42)
1 (20) 4 (80)
15 (58) 9 (35) 1 (4) 1 (4)
4 (80) 1 (20) 0 (0) 0 (0)
0 (0) 5 (19) 6 (23) 0 (0) 8 (31) 5 (19) 2 (8)
1 (20) 0 (0) 1 (20) 0 (0) 2 (40) 0 (0) 1 (20)
P value .12 >.99
.17 .74
.22
*Data are number (percentage) of patients unless indicated otherwise. The patient with the discovered pulmonary metastases at surgery is excluded from the calculation because the metastases were not discovered at autopsy. †Carcinoma in situ.
3. Pearson FG. Lung cancer: the past twenty-five years. Chest. 1986;89(4, suppl):200S-205S. 4. Wada H, Tanaka F, Yanagihara K, et al. Time trends and survival after operations for primary lung cancer from 1976 through 1990. J Thorac Cardiovasc Surg. 1996;112:349-355. 5. Matthews MJ, Kanhouwa S, Pickren J, Robinette D. Frequency of residual and metastatic tumor in patients undergoing curative surgical resection for lung cancer. Cancer Chemother Rep 3. 1973;4:63-67. 6. Travis WD, Colby T, Corrin B, et al. Histological Typing of Lung and Pleural Tumours. 3rd ed. Berlin, Germany: Springer-Verlag; 1999:1-156. International Histological Classification of Tumours. 7. Martini N, Heelan R, Westcott J, et al. Comparative merits of conventional, computed tomographic, and magnetic resonance imaging in assessing mediastinal involvement in surgically confirmed lung carcinoma. J Thorac Cardiovasc Surg. 1985;90:639-648. 8. Fleming ID, American Joint Committee on Cancer, American Cancer Society, American College of Surgeons. AJCC Cancer Staging Manual. 5th ed. Philadelphia, Pa: Lippincott-Raven; 1997:xv, 294. 9. Lahde S, Paivansalo M, Rainio P. CT for predicting the resectability of lung cancer: a prospective study. Acta Radiol. 1991;32:449-454. 10. Lewis JW Jr, Pearlberg JL, Beute GH, et al. Can computed tomography of the chest stage lung cancer? yes and no. Ann Thorac Surg. 1990;49:591595. 11. De Leyn P, Vansteenkiste J, Cuypers P, et al. Role of cervical mediastinoscopy in staging of non-small cell lung cancer without enlarged mediastinal lymph nodes on CT scan. Eur J Cardiothorac Surg. 1997;12:706-712. 12. Quint LE, Glazer GM, Orringer MB. Central lung masses: prediction with CT of need for pneumonectomy versus lobectomy. Radiology. 1987; 165:735-738.
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13. Musset D, Grenier P, Carette MF, et al. Primary lung cancer staging: prospective comparative study of MR imaging with CT. Radiology. 1986;160: 607-611. 14. Valk PE, Pounds TR, Hopkins DM, et al. Staging non-small cell lung cancer by whole-body positron emission tomographic imaging. Ann Thorac Surg. 1995;60:1573-1581. 15. Weder W, Schmid RA, Bruchhaus H, Hillinger S, von Schulthess GK, Steinert HC. Detection of extrathoracic metastases by positron emission tomography in lung cancer. Ann Thorac Surg. 1998;66:886-892. 16. Hustinx R, Paulus P, Jacquet N, Jerusalem G, Bury T, Rigo P. Clinical evaluation of whole-body 18F-fluorodeoxyglucose positron emission tomography in the detection of liver metastases. Ann Oncol. 1998;9:397-401. 17. Lewis P, Griffin S, Marsden P, et al. Whole-body 18F-fluorodeoxyglucose positron emission tomography in preoperative evaluation of lung cancer. Lancet. 1994;344:1265-1266. 18. Marom EM, McAdams HP, Erasmus JJ, et al. Staging non-small cell lung cancer with whole-body PET. Radiology. 1999;212:803-809. 19. British Thoracic Society, Society of Cardiothoracic Surgeons of Great Britain and Ireland Working Party. BTS guidelines: guidelines on the selection of patients with lung cancer for surgery. Thorax. 2001;56:89-108.
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20. American Thoracic Society, European Respiratory Society. Pretreatment evaluation of non-small-cell lung cancer. Am J Respir Crit Care Med. 1997; 156:320-332. 21. Hillers TK, Sauve MD, Guyatt GH. Analysis of published studies on the detection of extrathoracic metastases in patients presumed to have operable non-small cell lung cancer. Thorax. 1994;49:14-19. 22. Silvestri GA, Littenberg B, Colice GL. The clinical evaluation for detecting metastatic lung cancer: a meta-analysis. Am J Respir Crit Care Med. 1995; 152:225-230. 23. Earnest F IV, Ryu JH, Miller GM, et al. Suspected non-small cell lung cancer: incidence of occult brain and skeletal metastases and effectiveness of imaging for detection—pilot study. Radiology. 1999;211:137-145. 24. Suzuki K, Nagai K, Yoshida J, et al. Video-assisted thoracoscopic surgery for small indeterminate pulmonary nodules: indications for preoperative marking. Chest. 1999;115:563-568. 25. Dowling RD, Keenan RJ, Ferson PF, Landreneau RJ. Video-assisted thoracoscopic resection of pulmonary metastases. Ann Thorac Surg. 1993;56: 772-775. 26. Deslauriers J, Gregoire J. Clinical and surgical staging of non-small cell lung cancer. Chest. 2000;117(4, suppl 1):96S-103S.
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