Annals of Oncology Advance Access published online on July 17, 2008
Annals of Oncology, doi:10.1093/annonc/mdn421
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The clinical significance of radiologically detected silent pulmonary nodules in early breast cancer
1 Department of Medical Oncology, Imperial College Healthcare NHS Trust, Charing Cross Hospital, London
2 Department of Radiology, Imperial College Healthcare NHS Trust, Charing Cross Hospital, London
3 Department of Respiratory Medicine, Imperial College Healthcare NHS Trust, Charing Cross Hospital, St Mary's Hospital, London
4 Department of Surgery, Imperial College Healthcare NHS Trust, Charing Cross Hospital, London, UK
* Correspondence to: Dr J Stebbing, Department of Medical Oncology, Imperial college, The Hammersmith Hospitals NHS Trust, Charing Cross Hospital, First Floor, E Wing, Fulham Palace Road, London W6 8RF, UK. Tel: +44-208-7468295; Fax: +44-208-8461433; E-mail: j.stebbing{at}imperial.ac.uk
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Abstract |
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Background: Increasing numbers of patients with early cancer undergo routine staging using computerized tomography (CT). Those in whom indeterminate pulmonary nodules are visualized without the presence of other metastatic lesions represent a clinical dilemma regarding their management as early breast cancer or metastatic disease.
Patients and methods: Medical records of breast cancer patients who underwent thoracic CT scans between the years 2002 and 2008 were analyzed. Those with obvious metastatic disease were excluded. Patients were identified via the radiology database by searching for the terms: ‘suspicious lung metastases’ and ‘indeterminate nodules’.
Results: Out of 1578 new patients assessed from 2002 to 2008, we carried out 802 staging CT scans. Thirty-four cases (4.2%) with indeterminate pulmonary nodules were identified. We categorized cases by size and number of nodules. At a median follow-up of 18 months, there were no changes in lesion size in 86% of patients with a solitary nodule <1 cm and 89% with multiple subcentimeter nodules. In contrast, in 100% of cases with pulmonary nodules >1 cm, the nodules had progressed at follow-up (
2, P = 0.004).
Conclusions: Breast cancer cases with subcentimeter indeterminate pulmonary lesions and no evidence of metastases elsewhere are unlikely to represent metastatic disease. Treatment with curative intent or entry into clinical trials should not be excluded.
breast cancer, CT, indeterminate, lung nodule, suspicious
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Breast cancer accounts a third of all cancer cases in British women and represents the second commonest cause of female cancer death in the United Kingdom; between 1983 and 2002, the incidence has increased by 45% [1]. Since the early 1990s there has been an improvement in long-term survival with a 17%–20% increase in survival rates [2–4].
A typical schedule of either neo-adjuvant chemotherapy before surgery or adjuvant chemotherapy, radiotherapy and/or endocrine treatment is offered to minimize the risk of recurrence and improve the overall outcome. We have observed that increasing numbers of patients have attended clinic following routine staging investigations using computerized tomography (CT) scans, with indeterminate pulmonary nodules and no evidence of metastatic disease elsewhere. It is unclear whether such patients should be managed as early breast cancer, using treatments with curative intent, or as metastatic disease.
We therefore wished to investigate the incidence, the characteristics and outcomes of patients with indeterminate or suspicious pulmonary nodules in breast cancer, which have important implications for their therapeutic and psychological management as well as entry and recruitment into clinical trials.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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CT images for all breast cancer patients between January 2002 and January 2008 were identified via the radiology database searching for the following terms: ‘suspicious lung metastases’ and/or ‘indeterminate nodules’ and ‘breast cancer’. In addition, thoracic CT images carried out for patients on the breast cancer database between the years 2002 to 2007 were independently reviewed by a radiologist, to ensure that all relevant cases were identified and that our search terms did not exclude individuals with indeterminate silent lung nodules.
Suspicious pulmonary lesions were identified on CT imaging of the thorax either at initial staging before treatment or at restaging to assess for recurrent disease and disease progression, often as part of clinical trial protocols. Suspicious pulmonary lesions were formally reviewed at the multidisciplinary meeting by a consultant radiologist and then independently reported by the radiology department.
We defined a suspicious indeterminate pulmonary nodule or suspicious lung metastasis as one or more radiologically distinct lesions within the pulmonary parenchyma which were <1.5 cm in size. Because of their size, we did not consider these lesions amenable to fine needle aspiration or biopsy (despite differing protocols at other institutions especially those in the United States).
Data were obtained from the electronic medical records. The following information was collated: date of diagnosis, histological information, date of diagnosis of pulmonary nodules, size and number of pulmonary nodules involved, treatment following diagnosis of pulmonary nodules, dates and results of subsequent CT scans, time to progression and outcome at last follow-up.
Indeterminate pulmonary nodules were considered to be unlikely to be related to breast cancer if there was no radiologic change in size of the lesion after 12 months from the initial CT thorax scan. However, they were monitored for 2 years according to the CT guidelines employed within the radiology department at Imperial Healthcare NHS Trust, London, UK. All patients were scanned with i.v. contrast-enhanced CT using the Siemens Sensation 16 which became available at our institution at the start of this study.
Pulmonary nodules were considered malignant if there was clinical evidence of progression (enlargement) on serial CT imaging of the marker pulmonary nodules. The chi-square (2) test was used to analyze the categorical frequency data; appropriate ethical approval was obtained.
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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From a total of 1578 patients who were assessed by the Breast Cancer unit, 802 underwent thoracic CT scans and of these 65 cases (8.1%) were identified via the radiology database using our search terms. After review of these scans, 34 cases (4.2%) with indeterminate pulmonary nodules were included in this analysis, none of whom had respiratory symptoms. The remaining cases were excluded because the primary findings on the scan were then immediately found to be an infective cause (n = 3), an effusion (n = 6), a normal scan (n = 14), sarcoma of the breast (n = 3) or other metastatic disease (n = 5).
patient characteristics
The 34 cases with indeterminate pulmonary nodules were categorized according to the size of the nodules which revealed eight cases (24%) with nodules >1 cm (1–1.5 cm), seven cases (21%) with a solitary nodule less than a centimeter (<1 cm) and 19 cases (55%) with multiple nodules each smaller than a centimeter in size (<1 cm) (Table 1). The histological data are summarized in Table 1 and revealed that 30 of the 34 (88%) cases were invasive ductal carcinoma, two (6%) were invasive lobular carcinoma, one (3%) case revealed a papillary carcinoma of the breast and a further case (3%) revealed medullary carcinoma. Seventeen cases (50%) were grade 3 carcinomas, 10 cases (29%) were grade 2, two cases (6%) grade 1 and five individuals (15%) did not have recorded histological grades. When stratified according to stage of disease, five cases (15%) had stage I disease, 22 cases (65%) had stage II disease and seven cases (20%) had stage III disease. Further breakdown of the tumor–node–metastasis staging is summarized in Table 1.
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The majority of cases were estrogen/progesterone receptor positive (23 patients, 68%) and 11 cases (32%) were positive for HER2 staining by immunohistochemistry and/or FISH. There were no significant differences between these characteristics and those of the entire cohort. Out of the 34 cases, 29 (85%) were nonsmokers, two (6%) were active smokers and three (9%) were ex-smokers, all having stopped at least 10 years before their oncological diagnosis.
morphology and position of nodules
Individual review of the 34 cases was undertaken to assess the position and characteristics of the lesions. It was noted that in 21 of the 34 cases (62%), the lesions were located peripherally and were abutting a pleural surface and hence described as being pleurally based. Of the remaining 13 cases, two revealed lesions scattered throughout the lungs and in the other eight cases the lesions were positioned in a centrilobular distribution (as previously described by others [5, 6]). The characteristics of the lesions appeared to fall into three categories—rounded, angular or associated with a ‘tree in bud’ appearance. An angular shape is what we used to describe nodules which were not completely round and had a more geographical shape with straight angular edges.
The nodules which were <1 cm in size demonstrated a similar distribution of angular and rounded lesions with 12 cases and 11 cases, respectively. In comparison, all eight cases with nodules >1 cm were found to be rounded in nature. Three cases had lesions associated with plugging of the small airways giving a tree in bud appearance, which are typically associated with infective or inflammatory processes. Peripheral ground-glass opacity is also more commonly associated with an infective etiology (although this was not observed in any of the cases analyzed in this study). Scarring was also noted in five cases and emphysematous changes were seen in three cases. Interestingly, only two cases showed any evidence of calcification associated with the nodules.
Further size classification of the nodules assessed within this study revealed that in 14 cases the lesions identified were <5 mm in size. In 12 cases, the lesions were between 5 and 9 mm in maximum diameter. The eight cases with nodules that were between 1 and 1.5 cm all eventually progressed to metastatic disease.
With regards to the number of nodules in each case, as previously mentioned, there were seven cases with a solitary nodule <1 cm. Among the 13 cases with multiple lesions <1 cm, 11 cases involved less than five nodules, six cases showed between 5 and 10 nodules and two cases were associated with >10 nodules scattered throughout the lungs. Calcified granulomata with a typical appearance was observed in our series but not reported as suspicious and therefore we have not discussed them in the context of this study.
treatment data
Analyses of treatments administered following the discovery of the pulmonary nodules demonstrated that in the group with the solitary nodules <1 cm, three of seven (43%) patients received endocrine treatment. Similarly, in the category with multiple nodules <1 cm, 8 of 19 cases (42%) received endocrine treatment, but in four cases (21%) chemotherapy with adjuvant intent was administered and in two other cases (11%) chemotherapy in the neo-adjuvant setting was administered after the multidisciplinary team discussion. In comparison, in the category with nodules >1 cm, seven of eight cases (88%) of the patients received chemotherapy according to metastatic chemotherapeutic protocols (Table 2).
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outcome data
At follow-up, it was found that there was no change in the size of the lesions in six of seven (86%) of the patients in the category with a solitary nodule <1 cm (Table 3). In the other case, the lesion had regressed at follow-up. In the cases with multiple subcentimeter nodules, again the majority (17 of 19, 89%) had no change on the follow-up scanning. There were two cases with progression at follow-up and in both of these cases there were 5–10 pulmonary nodules. In contrast, in the category (eight cases) with pulmonary nodules >1 cm, all patients had progressed at follow-up: six of these eight cases had other evidence of distant metastases elsewhere and in two of the cases the lung lesions had increased in size more than three-fold. The median follow-up time measured 18 months (range 10–72 months). Comparing the 26 individuals with a nodule or nodules <1 cm with the eight cases with a nodule >1 cm, those with smaller nodules were significantly less likely to have progressive disease during follow-up (
2, P = 0.004).
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Detection of indeterminate pulmonary nodules with breast cancer raises management dilemmas requiring decisions to be made between aggressive early surgical and cytotoxic therapies versus management of metastatic disease. Indeterminate pulmonary lesions may also limit participation in clinical trials. Our study of 34 cases over the last 5 years has shown for the first time that indeterminate pulmonary nodules <1 cm are not likely to represent metastatic disease even in patients with more histologically aggressive primary breast cancers. We recommend therefore that these cases should be managed with standard adjuvant therapy in order to offer the maximal benefit from treatment, with subsequent CT follow-up in (Figure 1). This has broad implications across ‘general oncologic staging’ in presumed early malignancy.
The limitations of this work include the absence of histologic confirmation of lung lesions which would have provided more definitive conclusions than those based on CT observations alone. However, there are well-known ethical issues with biopsy in such cases [7–10], exacerbated when lesions are small and in the lungs with an obvious high risk of complications. Within our median follow-up of 18 months, the systemic therapy (which was variable), may cause tumor stabilization, causing a malignancy to be incorrectly diagnosed as benign. While we initially relied upon radiology reports to undertake this study (akin to the ‘real life’ setting in clinic), we also reviewed all the staging CT scans and found no additional suspicious lung nodules beyond the ones reported.
In published lung cancer screening program CT guidelines and guidelines regarding the detection of small pulmonary nodules [11–13], detected noncalcified nodules <0.5 cm in diameter do not justify immediate diagnostic work-up but only annual repeat screening to determine whether interim growth has occurred. Lesions between the sizes of 0.6 and 0.8 cm should be scanned regularly at 3–6 months, followed by a scan at 9–12 months and 24 months, while lesions >0.8 cm should be followed up by contrast-enhanced dynamic CT scanning at 3, 9 and 24 months [13]. On the basis of the consensus statement of the Society of Thoracic Radiology on screening for lung cancer with helical CT published by Aberle et al. [14] in 2001, indeterminate pulmonary nodules are usually solid, smooth edged and do not show benign calcification, air bronchograms or converging vessels. Typically, they are not spiculated and are of unknown chronicity. Positron emission tomography (PET) scanning with biopsy maybe advisable if lesions are increasing in size. PET scanning is recognized to be of diagnostic benefit in assessing the likelihood of malignancy in solid pulmonary nodules >1.0 cm in diameter and a standardized uptake value >3 is sensitive and specific for cancer [15]. However, if a nodule is subsolid or <1.0 cm in diameter, sensitivity and specificity decline. False positives on PET scanning have been reported in granulomatous and other lung diseases [16].
Other differential diagnoses for indeterminate lung nodules include infective causes such atypical pneumonia, TB, atypical mycobacteria and old chickenpox scarring; noninfective causes may include inflammatory granulomata, rheumatoid nodules and atypical bronchoalveolar hyperplasia. In the baseline survey carried out by the Early Lung Cancer Action Plan (ELCAP), a study designed to screen for lung cancer in former smokers, it was noted that there was a 23% chance of an incidental finding of a lung nodule in the control group [17, 18]. Parenchymal changes have also been reported following high-dose chemotherapy with autologous bone marrow transplantation; potential ground-glass attenuation, nodular or mass-like consolidation abnormalities, which may occur due to drug toxicity, should not be confused with disease progression [19].
The incidence of indeterminate suspicious pulmonary nodules in this study is notably lower than that reported in the screening studies such as the ELCAP study undertaken in North America. This maybe due to a number of factors including the younger age of patients in our study, the otherwise healthier status of the patients before their diagnosis of cancer and the fact that the majority of patients in our study were nonsmokers compared with those in the United States who undergo screening CTs for lung cancer. There is also likely to be a difference in rates of healed granulomatous disease between the United Kingdom and United States, which may contribute to this apparent discrepancy. Further diagnostic investigations can assist in excluding malignancy with indeterminate lung nodules. These tests include fiberoptic bronchoscopy (FOB) and percutaneous transthoracic fine needle aspiration (FNA). FOB has limited usefulness in the diagnosis of small peripheral nodules. However, if the nodules are endobronchial or more in keeping with an infective cause, a transbronchial needle aspiration or bronchial lavage may increase sensitivity. CT-guided percutaneous tranthoracic FNA maybe employed in the diagnosis of small peripheral lung nodules, which are >0.5 cm in diameter.
In an earlier review by Casey et al. [20] in 1984, which examined solitary pulmonary nodules in patients with breast cancer, 52% of patients who underwent a lung biopsy had primary lung cancer, 43% had metastatic disease and 5% had a benign lesion. The high secondary malignancy rates reported in their study are most likely influenced by the limited imaging technology at the time, when nodules would only have been detected on conventional chest radiographs or first-generation CT scans, hence only the largest and most suspicions nodules would have been seen and biopsied. Another study regarding the significance of noncalcified lung nodules in patients with extrapulmonary cancers [21] demonstrated that the incidence of metastatic breast cancer to the lungs within the subset of breast cancer patients that were included was 16%. This finding was based on 10 of the 64 cases analyzed with breast cancer and at least one pulmonary nodule. The size of the pulmonary nodules was not stated in their results but all lesions were of sufficient size to undergo evaluation by biopsy. In comparison, our study looks at only indeterminate pulmonary nodules, which were not amenable to biopsy based on the Imperial College Healthcare NHS Trust protocol in London, UK, and revealed that only 2 of 26 cases with lesions <1 cm progressed and all eight cases with lesions >1 cm subsequently showed clinical evidence of metastatic disease (P = 0.004).
We have used serial CT scanning to monitor patients with indeterminate pulmonary nodules in (Figure 1). This practice has emerged as an alternative to more invasive technique due to technical limitations on the basis of the size of the indeterminate lesions in questions. Serial imaging was also used in the ELCAP and other recent studies [13, 17, 21, 22] and this may account for the lower rate of malignancy compared with earlier reports but also complicates management by the frequent finding of nonspecific abnormalities and false positives such as indeterminate pulmonary nodules (Figure 1). The use of thinner sections and workstation viewing rather than film may contribute to an increasing incident of indeterminate pulmonary lesions reported on routine or staging CT scans. These results should be weighed against the clinical picture when deciding on the management plan. There is no consensus on the management of indeterminate pulmonary nodules. As we illustrate, cases with subcentimeter indeterminate pulmonary lesions are unlikely to represent metastatic disease and more aggressive treatment or entry into clinical trials should not automatically be excluded. We are also using research techniques for the detection of minimal residual disease (including use of plasma DNA fragment size and circulating tumor cells) to help establish whether some of these patients are likely to have relapsed disease at the time of CT scanning (data not shown) and information thus obtained maybe useful in clarifying whether patients have frank metastatic secondaries at the time of presentation.
While this study cannot exclude the fact that breast cancer therapies administered to patients (Table 2) may have ensured that during our follow-up progression was prevented in the lungs, recent retrospective data indicate that aggressive management of patients with an oligometastasis (especially to the bone) and new primary breast cancer is associated with a more favorable outcome [23, 24]. Taken together, we suggest that patients with primary breast lesions and questionable metastases including indeterminate lung nodules should be offered treatment with curative intent.
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We are grateful to Dr Ann Strickland for her help during the grand round presenting these cases. Conflict of interest: none declared.
Received for publication May 28, 2008. Accepted for publication June 10, 2008.
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References |
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