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Ann Thorac Surg 1996;62:246-250
© 1996 The Society of Thoracic Surgeons

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Original Articles: General Thoracic

Distribution of Distant Metastases From Newly Diagnosed Non-Small Cell Lung Cancer

Department of Radiology and Section of Thoracic Surgery, Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan

Accepted for publication February 24, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Background. The purpose of our study was to determine the incidence and locations of M1 disease at presentation in patients with non-small cell lung cancer to help design appropriate preoperative imaging algorithms.

Methods. All patients with non-small cell lung cancer seen between 1991 and 1993 were identified, and records were reviewed. For patients with M1 disease, the sites of distant metastases and the methods of diagnosis were recorded.

Results. Of 348 patients identified, 276 (79%) had M0 disease and 72 (21%) had M1 disease. In 40 of 72 patients (56%), M1 disease was detected via chest or abdominal computed tomography (CT). Brain, bone, liver, and adrenal glands were the most common sites of metastatic disease, in decreasing order. Brain metastases often occurred as an isolated finding, although isolated liver metastases were uncommon.

Conclusions. M1 disease was common at presentation, and was often detectable via chest CT. The incremental yield of abdominal CT over chest CT was very small, and therefore abdominal CT is not an effective method of screening for metastases if chest CT has been performed.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
In patients with non-small cell lung cancer (NSCLC), distant metastatic (M1) disease is generally considered a contraindication to resection of the primary tumor. Knowledge of the sites of metastatic disease and the frequency with which it occurs at presentation can be used to design appropriate algorithms for the preoperative imaging work-up. Based mainly on data from autopsy studies, NSCLC is known to spread to the adrenal glands and liver. However, given the relatively low frequency of this occurrence at presentation, there is controversy over the usefulness of abdominal imaging in diagnosing abdominal spread of disease before thoracotomy [1].

The purpose of our study was to determine (1) the percentage of patients with NSCLC who have M1 disease at presentation and (2) the locations of these distant metastases. Furthermore, we aimed to determine the incremental yield of abdominal computed tomographic (CT) scanning over chest CT scanning in diagnosing M1 disease.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
All patients who presented with newly diagnosed NSCLC between July 1991 and July 1993, and who were treated at some time during the course of their disease at our institution, were retrospectively identified via computerized searches of tumor registry data and review of thoracic surgery records and weekly multidisciplinary thoracic tumor board minutes. Three hundred forty-eight patients were identified who met these selection criteria, and all patient records were reviewed to determine whether the patient had any clinical or imaging evidence of M1 disease at the time of presentation. M1 disease was defined using the criteria of the American Joint Committee on Cancer [2]. In this classification scheme, metastatic disease to peribronchial, hilar, mediastinal, scalene, or supraclavicular lymph nodes is considered regional disease. Involvement of any other lymph nodes is considered M1 disease.

M0 disease was defined in our study as the absence of evidence of distant metastatic disease at presentation based on clinical examination, chest CT scans, and any other available imaging studies, such as abdominal CT or bone scan. Chest CT scans were obtained in all patients unless distant metastases were previously diagnosed by some other means, such as conventional chest radiography or physical examination. Chest CT scans usually extended caudally to include the adrenal glands and the superior portions of the liver. Abdominal CT examinations, including scans from the lung bases to the iliac crests, were routinely obtained in patients discussed at thoracic tumor board and in those referred by the thoracic surgery service; physicians from other services did not usually request abdominal CT. Both chest and abdominal CT studies were performed using state-of-the-art techniques, ie, dynamic scanning during bolus injection of intravenous contrast material. One hundred fifty milliliters of 60% iodinated contrast material was used for a chest study alone, and 200 mL was used for a combined chest and abdominal CT scan. In general, bone scans and head CT scans were obtained only if the patient had signs or symptoms suggestive of metastases to the bone or brain, respectively.

Patient age, sex, histologic tumor type, and type of CT scan obtained (head, chest, abdominal, or a combination of these) were recorded for all patients. In addition, T and N tumor classifications based on the official CT interpretation in the patient's chart were determined. A lymph node was considered abnormal if the report indicated that it was enlarged or if the stated diameter was larger than 1 cm.

For patients with M1 disease, location of the distant metastases, method of detection, (eg, CT, physical examination) and method of proof (eg, biopsy, follow-up) were recorded. Many patients presented to an outside institution and were referred to our institution for treatment; copies of the outside records for some of these patients were incomplete, and therefore not all of the above information could be obtained.

Statistical comparisons of proportions between the M0 and M1 groups and among the various cell types were performed using a ² distribution for 2 x 3 contingency tables and Fisher's exact test for 2 x 2 contingency tables. A p value of less than 0.05 was considered significant.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Two hundred seventy-six of 348 patients (79%) had M0 disease, and 72 of 348 (21%) had presumed or proven M1 disease.

Of the 276 patients in the M0 group, 176 were male and 100 were female. Patients ranged in age from 28 to 91 years (mean, 65 years). Adenocarcinomas and squamous cell carcinomas were equally prevalent (107 cases each). There were 31 large cell, 14 poorly differentiated, eight bronchoalveolar cell, five carcinoid, two adenosquamous, one neuroendocrine, and one adenoid cystic cancer. Twenty-four patients had head CT, 120 patients had chest CT (without abdominal CT), 153 had chest and abdominal CT, and 3 patients had insufficient documentation in the chart to determine whether body CT was performed at presentation. T and N classifications based on CT findings could not be obtained for 10 patients because the body CT report could not be located or the information it contained was insufficient. Breakdown of stage by cell type is given in Table 1. Because of the relatively small number of patients with stage II disease, stages I and II were combined in the table. Of the 266 M0 patients with a classifiable stage using CT, 56 (21%) had T1 N0 disease.

Fourteen percent of all CT stage T1 N0 patients had M1 disease. Fourteen percent of CT stage I patients, 14% of CT stage II patients, 19% of CT stage IIIA patients, and 32% of CT stage IIIB patients had M1 disease. This finding of increasing rate of M1 disease for advancing TN stage on CT scans was seen for both adenocarcinomas and squamous cell carcinomas (p < 0.05), although it was not observed for large cell carcinomas (p > 0.05).

No statistically significant differences were observed between the M0 and the M1 groups for the proportion of adenocarcinomas, squamous cell carcinomas, or large cell carcinomas, or the proportions of stage II or stage IIIA cancers based on CT data (p > 0.05). The M1 group had significantly more stage IIIB cancers than the M0 group (p < 0.003), and the M0 group had significantly more stage I cancers than the M1 group (p < 0.03). Squamous cell carcinomas, adenocarcinomas, and large cell carcinomas were equally likely to have distant metastatic disease (p > 0.05).

The M1 group had a significantly larger proportion of abdominal CT scans as compared with the M0 group (p < 0.001). This was true for patients with all CT stages.

In the majority of patients (40/72 = 56%), M1 disease was detected via body CT. Three of these 40 patients had only chest CT, and the remaining 37 of 40 patients had both chest and abdominal CT. Twenty-eight of these 37 patients with both chest and abdominal CT had metastases that were visible on the chest portion of the CT, eg, metastases to the adrenal glands, bone, or body wall. The remaining 9 of 37 patients had liver metastases without other thoracic or abdominal metastases (2 of these 9 patients had metastases to brain or bone).

In 25 patients, metastases were diagnosed preoperatively by means of head CT or magnetic resonance imaging, in 8 by bone scan, in 6 by conventional radiographs, in 6 by physical examination, in 5 by spine magnetic resonance imaging, and in 1 by myelography. Several patients had metastases detected by more than one of these methods. Multiple lung metastases were diagnosed at operation in 2 patients. In 1 patient, an autopsy performed 12 days after thoracotomy revealed multiple bilateral lung metastases.

Fifty-five of 72 patients (76%) had proof of M1 disease via tissue sampling (39/72), increase in the size of one or more lesions on follow-up imaging (10/72), or positive bone scan (without tissue sampling or follow-up imaging studies) (6/72). Seventeen of 72 patients (24%) had no proof, and a presumptive diagnosis of M1 disease was made based on convincing findings at body CT (9 patients), CT or magnetic resonance imaging of the head or spine (10 patients), or both. Such findings included destructive bone lesions, multiple masses in abdominal organs, and brain or spine masses with imaging features typical of metastatic disease. In cases with equivocal imaging findings and no definitive proof, it was assumed that the finding did not represent metastatic disease.

Distant metastases were most commonly diagnosed in the brain (47%), followed by bone (36%), liver (22%), adrenal glands (15%), body wall (13%), lung (11%), spleen (6%), (nonosseous) spinal canal (3%), and pancreas (1%). Six percent of patients had metastases to abdominal lymph nodes, and 4% had metastases to axillary lymph nodes (one with biopsy proof). Forty-eight patients had metastases isolated to one body part, as follows: brain, 14 patients; bone, 12 patients; liver, 7 patients; adrenal glands, 3 patients; body wall, 3 patients; lung, 6 patients; and abdominal lymph nodes, axillary lymph nodes, and spinal canal, 1 patient each. The remaining 24 patients had multifocal metastases.

The breakdown in frequency of metastatic disease to specific sites according to histology is given in Table 2. Adenocarcinomas more commonly metastasized to the brain as compared with squamous cell carcinomas (p < 0.05), and squamous cell carcinomas more commonly metastasized to axillary lymph nodes as compared with adenocarcinomas (p < 0.05). There was no significant difference between adenocarcinomas and squamous cell carcinomas for the rates of metastases to bone, liver, adrenal glands, body wall, lung, spleen, abdominal lymph nodes, spinal canal, and pancreas (p > 0.1).

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment References

In an autopsy study of 125 men [9], Weiss and Gillick reported that extrathoracic metastases were more common in men with adenocarcinoma compared with men with squamous cell carcinoma. A prospective study by Salvatierra and colleagues [7] similarly found that patients with adenocarcinoma or large cell carcinoma were at a significantly higher risk for extrathoracic metastases compared with patients with squamous cell carcinoma. There was no relationship between the TN stage and the presence of metastases for adenocarcinoma or large cell carcinoma. On the other hand, there was an association between advanced N classification and metastases for squamous cell carcinoma, and none of the stage I squamous cell carcinomas had distant metastases [7]. Although our results also showed a higher proportion of M1 disease in patients with adenocarcinoma or large cell carcinoma (22%) as compared with patients with squamous cell carcinoma (16%), this difference was not statistically significant (p > 0.05). Moreover, in contrast to the study of Salvatierra and colleagues [7], our data showed a trend toward increasing frequency of metastases with increasing TN stage for both adenocarcinomas and squamous cell carcinomas (see Table 1). This trend was not present for large cell carcinomas in our study.

The frequency of proven M1 disease in patients with clinical T1 N0 M0 lesions is reported to range from 0% to 17%, according to several reports in the literature [13–17]. This correlates well with our figure of 14% in patients with T1 N0 stage based on CT findings.

Limitations of our study include the nature of our patient population. Because ours is a tertiary care institution, many of our patients arrive with a known diagnosis of lung cancer and with outside imaging studies. These patients may be sent to our institution for a specific treatment, such as a complex resection or an experimental chemotherapy/radiotherapy protocol. Therefore, it is possible that our patient base does not reflect the overall patient population in the community. In addition, our results may be skewed by the preoperative imaging studies acquired. We generally obtain bone scans and head CT scans only for patients with signs or symptoms of metastases to these body parts. Therefore it is possible that we have overlooked occult metastases to brain or bone. However, our clinical experience in following up such patients suggests that this is a rare occurrence.

Another limitation is the lack of abdominal CT scans on all patients. It is unclear why a significantly larger proportion of the M1 group had abdominal CT scans as compared with the M0 group. This could have reflected physician ordering patterns: patients in the M1 group might have appeared more ill on clinical examination, leading to more extensive imaging. Advanced stage of the tumor on initial chest radiographs probably did not influence the decision to obtain abdominal CT, because the M1 group had proportionally more abdominal CTs than the M0 group for all CT stages (I-IIIB). It is possible that many of the abdominal CTs were obtained in M1 patients after discovery of other evidence of distant metastatic disease, to complete the survey of the body. Alternatively, abdominal CT might have led to detection of more occult metastases, placing more patients in the M1 group. Thus, some of the patients in the M0 group may actually have had occult abdominal metastases that remained undetected because more thorough abdominal imaging was not performed.

Most patients with metastases to bone or brain are symptomatic [7], leading to acquisition of appropriate imaging studies for confirmation of metastatic disease. In contrast, the majority of patients with liver or adrenal gland metastases are asymptomatic and have no routine clinical indicators of hepatic or adrenal gland disease [7]; failure to detect such spread of disease may lead to an unnecessary operation. Therefore, the question arises as to whether it is useful to obtain preoperative imaging studies of the abdomen. An analysis of multiple published studies addressing the detection of extrathoracic metastases in patients with presumed operable NSCLC found that 30 of 632 patients (4.7%) had adrenal gland metastases and 12 of 529 (2.3%) patients had hepatic metastases detected via abdominal CT, ultrasonography, or radionuclide scanning [1].

The liver was the third most common location for metastases in our study (16/72 patients) (after brain and bone), although only 9 of 16 patients had liver metastases without other chest or abdominal CT findings to indicate metastatic disease. Isolated liver metastases (ie, without concurrent spread to brain or bone) occurred in only 7 of 16 patients. If only chest CT had been performed in these 7 patients, it could be speculated that M1 disease may have gone undetected, and these patients might have undergone thoracotomy. However, these 7 patients comprise only 2% of our study population.

In conclusion, our study found that brain, bone, liver, and adrenal glands were the most common sites of metastatic disease from NSCLC at presentation, in that order. Brain metastases commonly occurred as an isolated finding. On the other hand, isolated liver metastases were distinctly uncommon, and most patients with liver metastases had other metastases that were detectable using chest CT. Therefore, the incremental yield of abdominal CT over chest CT is very small, and abdominal CT is not an effective method of screening for patients with metastases if chest CT has been performed.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Address reprint requests to Dr Quint, Department of Radiology, Box 0030, University of Michigan Medical Center, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0030.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Mark D. Iannettoni Richard I. Whyte Mark B. Orringer Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Quint, L. E. Articles by Orringer, M. B. Search for Related Content PubMed PubMed Citation Articles by Quint, L. E. Articles by Orringer, M. B.