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Solitary Pulmonary Nodules in Patients with Extrapulmonary Neoplasms¹

¹ From the Departments of Radiology (L.E.Q., C.H.P.) and Surgery, Section of Thoracic Surgery (M.D.I.), University of Michigan Health Systems, 1500 E Medical Center Dr, Box 0300, Ann Arbor, MI 48109-0030. Received October 6, 1999; revision requested November 5; final revision received February 11, 2000; accepted February 28. Address correspondence to L.E.Q. (e-mail: lequint@umich.edu).

	ABSTRACT

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PURPOSE: To determine the frequency of single lung metastasis, primary lung cancer, and benign lesions in patients with a solitary lung nodule and a primary extrapulmonary neoplasm.

MATERIALS AND METHODS: The authors evaluated the electronic charts of 149 patients with an extrapulmonary malignant neoplasm and a solitary pulmonary nodule. The histologic characteristics of the nodule were correlated with those of the extrapulmonary neoplasm and with patient age and smoking history.

RESULTS: Patients with carcinomas of the head and neck, bladder, breast, cervix, bile ducts, esophagus, ovary, prostate, or stomach were more likely to have primary bronchogenic carcinoma than lung metastasis (ratio, 25:3 for patients with head and neck cancers; 26:8 for patients with other types of cancer combined). Patients with carcinomas of the salivary glands, adrenal gland, colon, parotid gland, kidney, thyroid gland, thymus, or uterus had fairly even odds (ratio, 13:16). Patients with melanoma, sarcoma, or testicular carcinoma were more likely to have a solitary metastasis than a bronchogenic carcinoma (ratio, 23:9). Thirty patients had a benign nodule. There was substantial overlap in age distribution among the patients with benign disease, lung cancer, and metastasis, although no patient younger than 44 years had a lung cancer. Smokers had a 3.5-fold higher chance of developing lung cancer compared with nonsmokers.

CONCLUSION: The likelihood of a primary lung cancer versus a metastasis depends on the histologic characteristics of the extrapulmonary neoplasm and the patient’s smoking history.

Index terms: Lung, CT, 60.281 • Lung, nodule, 60.281 • Lung neoplasms, 60.31, 60.32 • Lung neoplasms, CT, 60.1211 • Lung neoplasms, secondary, 60.33

	INTRODUCTION

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It is not uncommon for a patient who currently has or has previously had extrapulmonary neoplasm to develop a solitary pulmonary nodule. Such a nodule may be detected with chest radiography or computed tomography (CT) performed as part of the work-up or follow-up of the known extrapulmonary malignancy. The determination of the etiology of such a nodule is usually important to direct the appropriate therapy (eg, observation, biopsy, resection, chemotherapy, radiation therapy, or a combined approach). Sometimes it is difficult or impractical to obtain tissue and thus establish a definitive diagnosis. In such cases, it may be helpful to know the likelihood that such a nodule represents a benign lesion, metastasis, or primary bronchogenic carcinoma.

The purpose of our study was to determine, on the basis of the histologic characteristics of the extrapulmonary neoplasm as well as patient age and smoking history, the frequency of single lung metastasis, primary lung cancer, and benign disease in patients with a solitary lung nodule at chest CT and a known primary extrapulmonary neoplasm.

	MATERIALS AND METHODS

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We retrospectively evaluated the electronic patient charts of all the patients seen at our institution between January 1994 and July 1999 in whom a solitary pulmonary nodule at chest CT and an extrapulmonary malignant neoplasm were identified. Patients were identified by means of computerized searches of CT reports in the radiology information system, review of weekly thoracic tumor board notes, and review of operating room log books. Electronic patient charts were examined to determine the histologic characteristics of the primary tumor and the lung nodule and to determine whether the patient had a smoking history. CT had been performed for a variety of reasons, most commonly for cancer follow-up or for further evaluation of an abnormality seen on chest radiographs. CT was performed with a variety of different scanners, both helical and nonhelical, by using section thicknesses of 5.0–10.0 mm. Many of the examinations were performed at outside institutions. The CT reports used to identify the patients in this study were patient care documents; most were dictated by one of the five chest CT specialists (one of which was L.E.Q.) in our department. Institutional review board approval was obtained. The institutional review board did not require us to obtain informed consent for chart review.

The extrapulmonary neoplasm and the lung nodule could be either synchronous or metachronous (ie, the extrapulmonary neoplasm occurred before the lung nodule). For a patient to be included in the study, the CT report had to include mention of a solitary lung nodule at least 5.0 mm in diameter and without definite calcification. Patients with multiple nodules at least 5.0 mm in diameter were excluded from the study. CT scans were reviewed only when the report was ambiguous (eg, when nodule size was not given or when the morphology of the lesion was described as questionably nodular). The presence of other CT findings of disease (eg, mediastinal lymph node enlargement) was noted, although this did not constitute an exclusionary criterion. Patients were included only if a definitive diagnosis could be made for the lung nodule by means of histologic examination or clinical course.

One hundred forty-nine patients met the entry criteria. Ten patients had two extrapulmonary malignancies, and each of these patients was entered into the database twice (once for each primary malignancy). One patient, who had three extrapulmonary malignancies, was entered into the database three times. Thus, there were 161 patient entries. In 150 of the 161 patient entries, the cell type of the nodule was determined by means of core biopsy (n = 12), cytologic biopsy (n = 11), or resection (n = 127). In 10 of the 161 entries, stability of size for at least 2 years (n = 5) or resolution without chemotherapy (n = 5) helped to establish a benign diagnosis. In one of the 161 entries, thin-section CT demonstrated fatty attenuation consistent with a hamartoma.

On the basis of the results of the conventional radiographic study by Cahan et al (1), our study data were analyzed by using the following histologic groupings for the extrapulmonary neoplasms: Group 1 included patients with squamous cell cancers of the head and neck; group 2, patients with lymphoma or leukemia; group 3, patients with carcinomas of the urinary bladder, breast, uterine cervix, biliary tree, esophagus, ovary, prostate, or stomach; group 4, patients with carcinomas of the salivary glands, adrenal gland, colon, parotid gland, kidney, thyroid gland, thymus, or uterus; and group 5, patients with melanoma, sarcoma, or testicular carcinoma.

In patients with squamous cell cancer of the head and neck and a lung nodule showing squamous cell differentiation, it was often difficult to distinguish between a metastasis and a new primary lung cancer on the basis of the histologic findings. According to the method used by Lefor et al (2) for distinguishing primary from metastatic disease, we considered patients in this setting to have a new primary lung cancer if there was no associated anterior cervical lymphadenopathy at physical examination. Conversely, if anterior cervical lymphadenopathy was mentioned in the patient chart, we considered the lung nodule to represent a metastasis.

The percentage of patients with a benign lesion, solitary metastasis, or primary lung cancer was tabulated for each group. The ² test was used to determine the statistical significance of associations between groups (ie, cancer types) and the presence of primary lung cancers, metastases, or benign lesions. The data were analyzed first by using all data entries and second after the elimination of entries obtained from patients with multiple extrapulmonary primary malignancies.

The percentage of patients who smoked was determined for each group, and the average number of pack-years of smoking was calculated. The percentage of patients who smoked was correlated with the percentage of patients with primary lung cancer within each group. The relationship between smoking history and lung cancer was determined for each group (after controlling for group) by using the Cochran-Mantel-Haenszel test. The odds ratio for lung cancer was obtained from a logistic regression of the risk of lung cancer as a function of smoking history after controlling for group.

	RESULTS

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The nodules were 5.0 mm–3.0 cm in diameter. In 10 patients, the CT scans were reviewed to confirm the solitary nature, size, and/or nodular morphology of the lesion. Five of these patients were excluded from further analysis because they had more than one nodule larger than 5.0 mm in diameter.

The patients with primary lung cancers ranged in age from 44 to 96 years, the patients with metastases ranged in age from 21 to 96 years, and the patients with benign lesions ranged in age from 32 to 96 years. There was a substantial overlap in age among the three groups. Although no patient younger than 44 years had a primary lung cancer, the lesions in these patients could still be either benign or malignant (owing to metastatic disease).

The distribution of the number and percentage of patients with metastases versus primary lung cancers or benign lesions (according to histologic group) is shown in Table 1. Of the 33 patients with a primary malignancy of the head and neck (group 1), 25 (76%) had a primary lung cancer, three (9%) had a metastasis, and five (15%) had a benign lesion. Of the 14 patients with lymphoma or leukemia (group 2), eight (57%) had a primary lung cancer and six (43%) had a benign lesion; none of the patients in this group had a metastasis. Of the 45 patients with a carcinoma of the urinary bladder, breast, uterine cervix, biliary tree, esophagus, ovary, prostate, or stomach (group 3), 26 (58%) had a primary lung cancer, eight (18%) had a metastasis, and 11 (24%) had a benign lesion. Of the 31 patients with a carcinoma of the salivary glands, adrenal gland, colon, parotid gland, kidney, thyroid gland, thymus, or uterus (group 4), 13 (42%) had a primary lung cancer, 16 (52%) had a metastasis, and two (6%) had a benign lesion. Of the 38 patients with melanoma, sarcoma, or testicular carcinoma (group 5), nine (24%) had a primary lung cancer, 23 (60%) had a metastasis, and six (16%) had a benign lesion (Table 1).

Twenty-eight of the 33 patients in group 1 (patients with squamous cell carcinoma of the head and neck) had a malignant nodule, and five had a benign nodule (Table 1). Three of the 28 patients with malignant nodules were considered to have metastatic disease. In two of the three patients, the nodule showed an unusual growth pattern that was histologically identical to that of the primary head and neck neoplasm. In one of the three patients, the nodule showed squamous cell cancer and the patient had concomitant cervical lymph node enlargement at physical examination. Twenty-five of the 28 patients with malignant nodules were considered to have primary lung cancers. In nine of the 25 patients, the lung nodule showed a histologic appearance that was distinctly dissimilar to that of the patient’s head and neck neoplasm. In two of the 25 patients, there was invasive squamous cell cancer arising in a bronchus. In 14 of the 25 patients, the nodule showed squamous cell cancer; no concomitant cervical lymph node enlargement was palpable.

In groups 1–3, 16 patients had mediastinal lymph node enlargement; none had a solitary metastasis (Table 2). Thirteen of the 16 patients had a primary lung cancer, and three had a benign nodule. In groups 4 and 5, 10 patients had mediastinal lymph node enlargement. Three of the 10 patients had a solitary pulmonary metastasis (one each had sarcoma, melanoma, and colon cancer), four had a primary lung cancer, and three had a benign lung lesion.

View larger version (14K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Graph shows the correlation between smoking history and frequency of primary lung cancer. There was a statistically significant relationship between smoking history and frequency of lung cancer (P = .002).  = group 1,  = group 2,  = group 3,  = group 4,  = group 5.

	DISCUSSION

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Currently, patients with known primary neoplasms undergo disease staging and follow-up with CT rather than chest radiography. CT enables detection of smaller nodules, and it may depict multiple nodules in patients with only a single nodule evident at conventional radiography (3). Furthermore, indeterminate nodular opacities at conventional radiography may be clearly benign at CT (eg, calcified granulomas or bone islands). Thus, a solitary nodule (without obvious calcification) at CT might have different diagnostic implications than a solitary nodule at conventional radiography.

Despite these potential discrepancies, our study results were similar to those of Cahan et al (1), possibly because most CT nodules larger than 5.0 mm would be detectable at conventional radiography. In both studies, patients with a solitary pulmonary nodule and a history of head and neck cancer were much more likely to have a primary bronchogenic carcinoma than a lung metastasis (ratio, 158:10 in the study by Cahan et al and 25:3 in our study).

Cahan et al (1) found that patients with many other malignancies also were more likely to have a primary lung cancer than a metastasis; corresponding ratios for the other cancers were as follows: urinary bladder, 25:3; breast, 40:23; uterine cervix, 24:4; common bile duct, 1:0; esophagus, 4:0; ovary, 6:3; prostate, 26:0; and stomach, 7:0. In an additional study of patients with breast cancer and a solitary pulmonary nodule at conventional radiography (4), the ratio was 22:18. For all of these types of malignancies combined, our study showed a ratio of 26:8 (ie, approximately 3:1). In the study by Cahan et al (1) and in our study, all malignant solitary nodules in patients with lymphoma or leukemia were lung cancers.

Data from the study by Cahan et al (1) suggest that patients with cancers of the colon, kidney, or uterus have a fairly even chance of demonstrating a primary lung cancer versus a metastasis. Our data are in agreement: The ratio in the group of patients with tumors encompassing these histologic types was 13:16.

For melanomas, bone tumors and soft-tissue sarcomas, and testicular cancers, Cahan et al (1) reported ratios of 7:29, 5:55, and 6:12, respectively. Our data revealed a ratio of 9:23 for these combined malignancies. In other words, patients with these primary malignancies are much more likely to have a solitary metastasis than a primary lung cancer.

The major difference between our findings and those of Cahan et al (1) is in the number and percentage of benign lesions. In the study by Cahan et al, there were only 11 benign lesions in the approximately 800 patients who underwent thoracotomy during a 35-year period because of a lung opacity at chest radiography, compared with 30 benign nodules in our CT study. Undoubtedly, more benign lesions are being detected in the current era, probably because of the ability to identify small nodules with CT. Furthermore, the study by Cahan et al may have been biased toward malignant lesions, because it included only those patients who underwent thoracotomy. Our study, on the other hand, included some patients with clinical and biopsy follow-up.

It is very likely that cigarette smoking is the major etiologic factor leading to the relationship that has been demonstrated between lung cancer and various other cancers. Smoking is a known risk factor not only for lung cancer, but also for some of the extrapulmonary primary neoplasms described in our study, including head and neck, bladder, and esophageal cancers. Therefore, it is not surprising to find a high percentage of lung cancers in patients with these malignancies. Our study results showed good correlation between the percentage of patients who smoked and the percentage of patients with a primary lung cancer, which is suggestive of a causal relationship. (The data point in the Figure for group 2 patients may be an outlier owing to the relatively small number of patients in this group and/or the relatively high average number of pack-years in this group.) It should be noted, however, that most of the patients in our study were smokers, and many of them did not have lung cancer. Conversely, four nonsmokers had lung cancer. Therefore, a positive or negative history of smoking is not definitive for predicting the etiology of a nodule in these patients. Lack of a smoking history, however, makes the diagnosis of lung cancer unlikely.

The presence of other CT abnormalities aside from a solitary pulmonary nodule might sway the interpreting radiologist toward a diagnosis of either metastasis or primary lung cancer, depending on the nature of these abnormalities. For example, a patient with breast cancer and multiple bone and liver lesions, in addition to the pulmonary nodule, might have metastatic breast cancer as the sole diagnosis. Very few of our patients had such definitive findings, however, and, therefore, we did not include those data in this report. Because a fair number of our study patients had mediastinal lymph node enlargement at CT, we analyzed the data based on that finding. Our data showed that, except for the patients in group 5 (patients with melanoma, sarcoma, and testicular carcinoma), the presence of mediastinal lymph node enlargement was strongly suggestive of a primary lung cancer. Presumably, in most patients, the mediastinal lymph node enlargement was due to metastatic lung cancer.

It is possible that an analysis of nodule morphology might have provided important information regarding lesion etiology. For example, smooth margins would theoretically be more indicative of a benign lesion or a metastasis, whereas irregular margins might be suggestive of a new lung cancer. We did not analyze these features, however, because many of the nodules were less than 1.0 cm in diameter. Morphologic analysis of such small lesions is difficult.

One limitation of our study was the relatively small number of patients with each individual type of primary malignancy; this necessitated the grouping of patients and negated the value of the statistical analyses on the basis of individual histologic tumor types. Our grouped data, however, did show differences among the various sets of neoplasms, similar to what has been published on the basis of conventional radiographic lung nodule detection (1).

Another limitation of our study was the lack of definitive proof of metastasis versus primary lung cancer in patients with a primary squamous cell cancer of the head and neck and a lung nodule showing squamous cell cancer. We opted to use the algorithm suggested by Lefor et al (2), in which the presence or absence of palpable anterior cervical lymphadenopathy is considered to be diagnostic of metastatic disease or primary lung cancer, respectively. It should be noted, however, that previous cervical lymph node dissection disrupts the normal lymphatic drainage patterns; in such patients, metastatic disease may not manifest initially in cervical lymph nodes. Therefore, a patient with squamous cell carcinoma of the lung, absence of cervical lymphadenopathy, and a history of previous cervical lymph node dissection might actually have a lung metastasis rather than a primary lung carcinoma. Six patients in our series fit these criteria; therefore, our classification of their nodules as primary bronchogenic carcinomas could have been erroneous. In our clinical experience, however, most patients with a history of head and neck cancer who undergo resection of squamous cell cancer of the lung do not subsequently develop multiple new lung nodules. This supports our conclusion that the lung nodule is usually a primary bronchogenic carcinoma rather than a solitary metastasis.

Our study may have been limited by selection bias, because not all patients with an extrapulmonary primary malignancy were followed up with serial CT examinations by using a set protocol. At our institution, however, almost all oncology patients with a new abnormality at conventional radiography subsequently undergo thoracic CT for further evaluation.

In summary, our study data showed that most patients with an extrapulmonary neoplasm and a solitary pulmonary nodule at chest CT have a primary lung cancer rather than a metastasis or a benign lesion, although the likelihood of a primary lung cancer varies, depending on the histologic characteristics of the extrapulmonary neoplasm. Metastasis is more common than primary lung cancer in patients with melanoma, sarcoma, or testicular carcinoma.

	ACKNOWLEDGMENTS

 
The authors thank Manette London and Lori Zaremba, BSN, for help in identifying the patients to be included in this study. We also acknowledge the assistance of Achamyeleh Gebremariam, MS, and CHOICES (Consortium for Health Outcomes, Innovation and Cost Effectiveness Studies) at the University of Michigan Health System with the statistical analyses.

	FOOTNOTES

 
² Current address: St Joseph Mercy Health System, Ann Arbor, Mich.

Author contributions: Guarantor of integrity of entire study, L.E.Q.; study concepts and design, L.E.Q.; definition of intellectual content, C.H.P., M.D.I., L.E.Q.; literature research, C.H.P., L.E.Q.; clinical studies, L.E.Q., C.H.P.; data acquisition, C.H.P., L.E.Q.; data analysis, C.H.P., M.D.I., L.E.Q.; manuscript preparation, editing, and review, C.H.P., M.D.I., L.E.Q.

	REFERENCES

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 

1. Cahan W, Shah H, Castro E. Benign solitary lung lesions in patients with cancer. Ann Surg 1978; 187:241-244.[Medline]
2. Lefor A, Bredenberg C, Kellman R, Aust J. Multiple malignancies of the lung and head and neck. Arch Surg 1986; 121:265-270.[Abstract/Free Full Text]
3. Peuchot M, Libshitz H. Pulmonary metastatic disease: radiologic-surgical correlation. Radiology 1987; 164:719-722.[Abstract/Free Full Text]
4. Casey J, Stempel B, Scanlon E, Fry W. The solitary pulmonary nodule in the patient with breast cancer. Surgery 1984; 96:801-805.[Medline]

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