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Table of Contents
ORIGINAL ARTICLE
Year : 2022  |  Volume : 5  |  Issue : 1  |  Page : 59-66

Significance of too-small-to-characterize (TSTC) pulmonary nodules in known extrapulmonary solid tumors: A retrospective observational study


1 Department of Radiodiagnosis and Imaging, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai - 400 012, Maharashtra, India
2 Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai - 400 012, Maharashtra, India
3 Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai - 400 012, Maharashtra, India

Date of Submission19-Sep-2021
Date of Decision20-Feb-2022
Date of Acceptance10-Mar-2022
Date of Web Publication31-Mar-2022

Correspondence Address:
Abhishek Mahajan
M.D., Fellowship In Cancer Imaging, MRes (KCL, London), FRCR (UK), Consultant Radiologist, The Clatterbridge Cancer Centre NHS Foundation Trust, Pembroke Place, Liverpool, L7 8YA
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/crst.crst_228_21

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  Abstract 


Background: Increased use of chest computed tomography (CT) scanning and greater awareness among general radiologists has led to a rise in lung nodule identification. Nodules less than 1 cm in diameter are considered small, and the morphology of such nodules is difficult to characterize.
Objectives: The aim of our study was to determine the significance of pulmonary nodules that are too-small-to-characterize on CT scan in patients with extrapulmonary solid tumors and to determine the characteristics that help in distinguishing malignant from benign pulmonary nodules.
Materials and Methods: We conducted a retrospective observational study in the Department of Radiodiagnosis of the Tata Memorial Hospital, Mumbai, India, and included patients with non-pulmonary solid malignancies who had obtained baseline CT/positron emission tomography (PET) scans between January 2010 and December 2014. Demographic information, site of the primary tumor, and histological diagnosis were recorded. Baseline and follow-up CT images were read by two radiologists. The significance of associated risk factors was analyzed using Pearson's Chi-square test. A multivariable logistic regression model was used.
Results: Our study included 200 patients and 334 nodules, of which 148 (44.3%) nodules were found to be benign and 127 (38%) were malignant. The remaining 59 (17.7%) nodules in 32 patients were indeterminate. Most nodules located at a distance of less than 10 mm from the pleura were benign, whereas more than 2/3rd of the nodules more than 10 mm away from the pleura were malignant (n = 60/94, 63.8% P = 0.0001). The mean size of the 148 benign nodules (5.3 mm) was smaller than that of the 127 malignant nodules (9.2 mm). Nearly 93% of malignant nodules were solid (P = 0.0001). About 83% of malignant nodules were round, while 7 of 10 linear-shaped nodules were either benign or indeterminate (P = 0.006). Among the nodules associated with poorly differentiated primary neoplasms, 63.6% were malignant, 25% were benign, and 11.4% were indeterminate (P = 0.005).
Conclusions: Too-small-to-characterize pulmonary nodules detected on CT are a common clinical problem and are more likely to be benign or indeterminate even in patients with known extrapulmonary neoplasms. Using nodule size, distance from the pleura, and morphological pointers, radiologists can help clinicians decide whether there is a need for biopsy or a short-interval follow-up. We have proposed a Pulmonary Metastases Cancer Imaging and Reporting Data System (PM-CI-RADS).

Keywords: Benign, CT, extra-pulmonary, feeding artery, lung neoplasm, malignant, pulmonary metastasis, pulmonary nodules, TSTC, PMCIRADS


How to cite this article:
Mahajan A, Monachen M, Shukla S, Agarwal U, Sable N, Prabhash K, Rane S, Thakur M. Significance of too-small-to-characterize (TSTC) pulmonary nodules in known extrapulmonary solid tumors: A retrospective observational study. Cancer Res Stat Treat 2022;5:59-66

How to cite this URL:
Mahajan A, Monachen M, Shukla S, Agarwal U, Sable N, Prabhash K, Rane S, Thakur M. Significance of too-small-to-characterize (TSTC) pulmonary nodules in known extrapulmonary solid tumors: A retrospective observational study. Cancer Res Stat Treat [serial online] 2022 [cited 2022 May 21];5:59-66. Available from: https://www.crstonline.com/text.asp?2022/5/1/59/341241






  Introduction Top


Pulmonary nodules are frequently detected on chest computed tomography (CT) scans. An integrated health system report found that the incidence of pulmonary nodules increased steadily from 2006 to 2012, with positive findings on approximately 25%–30% of all chest CT scans suggesting that nodules were identified much more frequently than previously reported.[1] Large studies have demonstrated the prevalence of lung nodules to be between 25% and 51% in healthy adult volunteers and lung cancer screening populations with almost one-fourth of these individuals having 1–6 nodules on a low–dose chest CT.[2],[3] Increased use of chest CT scans and greater awareness among general radiologists has led to this rise in nodule identification. Many of these nodules are of benign etiology, while others turn out to be primary lung cancer or metastases from an extrapulmonary primary neoplasm. The prevalence of pulmonary metastasis in individuals with extrapulmonary malignancies is about 54%.[4]

Lung metastases can occur in many ways: by direct extension, through blood, lymphatics, spread within the pleural space, or via the endobronchial route. Lung nodules are the most common thoracic manifestation of metastasis. In most cases, they are of hematogenous origin. However, lung nodules that are seen on the CT scan in patients with a known primary may represent something other than metastases. Granulomas, focal areas of infection, scarring, and intrapulmonary lymph nodes are all very common and may mimic metastases on the CT scan. These are generally small, measuring a few mm in diameter. Nodules larger than a few mm, particularly when rounded and sharply defined, are more likely to represent metastatic disease. Nodular metastases are usually multiple.

The management of lung nodules detected incidentally has been clearly defined in the literature.[5] The guidelines for the management of solid nodules by the Fleischner Society were published in 2005. Later, in 2013, separate guidelines were issued for sub-solid nodules. The British Thoracic Society guidelines published in August 2015 for the management of pulmonary nodules seen on a CT scan emphasize size assessment based on the volume of the nodule rather than its diameter and supersede the Fleischner Society guidelines in the United Kingdom. However, such well-defined guidelines do not exist for small pulmonary nodules, especially those that are too small to characterize and are detected in patients with known extrapulmonary malignancies.

All CT scans of the thorax should be reconstructed and archived with contiguous thin sections (≤1.5 mm, typically 1.0 mm) to allow the radiologist to precisely characterize and measure small pulmonary nodules.[6] Nodules less than 1 cm in diameter are considered small,[7] and the morphology of such nodules is difficult to characterize. Our study aimed to resolve the diagnostic dilemma that is encountered in clinical practice regarding the next step to be taken when a too-small-to-characterize pulmonary nodule is detected in a patient with a known extrapulmonary neoplasm.


  Materials and Methods Top


General study details

This was a retrospective study conducted between January 2010 and December 2014 in the Department of Radiodiagnosis at the Tata Memorial Hospital, a tertiary care cancer hospital in Mumbai, India. We strictly followed the ethical guidelines established by the Declaration of Helsinki and other guidelines such as Good Clinical Practice Guidelines and those established by the Indian Council of Medical Research (ICMR). The study was conducted after clearance from the Institutional Review Committee (Project number 1845, approved on June 20, 2019, by IEC-II) (Supplementary Appendix 1). A waiver of the requirement to obtain informed consent was obtained from the ethics committee. Given the retrospective nature of the study, it was not registered in a publicly accessible clinical trials registry. No funding was utilized for the study.

Participants

We included treatment-naïve patients with a known extrapulmonary solid tumor malignancy who had obtained a baseline CT/positron emission tomography (PET) scan. We selected the patients who had incidentally detected pulmonary nodules, and whose baseline and follow-up imaging scans were available. The patients were identified using the Picture Archiving Communication System (PACS) and Hospital Information System (HIS) database with complete documentation of both baseline and follow-up CT/PET scans. Eligibility criteria for the study included: treatment-naïve patients with a known primary extrapulmonary solid tumor, with non-calcified too-small-to-characterize pulmonary nodules. We excluded patients with leukemia and lymphoma; patients who had died or who had not been sufficiently followed up (either for 2 years or until a biopsy had been performed), patients with concurrent infections, prior pulmonary granulomatous infection and pulmonary emphysema, patients whose baseline or follow-up imaging was not available in the digital format on PACS, and patients with extrapulmonary primary cancer with known lung metastases who went on to develop new small lung nodules.

Variables

Our primary objective was to determine the significance of too-small-to-characterize pulmonary nodules on CT in patients with extrapulmonary solid tumors. Our secondary objective was to determine the characteristics of pulmonary nodules on CT that could help distinguish between benign and malignant nodules.

Study methodology

Patient's characteristics, including name, age, gender, histopathological diagnosis of primary, stage of disease, ongoing treatment (if any), time from presentation to imaging, and the type of investigation done (CT/PET-CT), were recorded. Both the baseline and the follow-up CT scans were assessed by two radiologists. All CTs were of high-resolution (HRCT chest), done either independently or as part of a CT thorax and abdomen protocol with or without contrast, on either GE Lightspeed 16-slice or Siemens Somatom emotion 16-slice CT scanners with volumetric acquisition and 1-mm-thick slices. We first determined whether any nodule(s) existed. If a nodule(s) was detected and was identifiable on the follow-up CT scan, the following factors were assessed: site (upper/middle/lingular/lower lobe), size (longest diameter), shape (round, oval, linear), margins, distance from the pleura, location (central/peripheral/peri-fissural), morphology (solid, ground glass, mixed), density (Hounsfield units), and SUV (standardized uptake values) on PET-CT. The results of histopathological analysis of nodules were recorded where available. The date of the scan and the interval between the scans were noted. These criteria were analyzed on the baseline CT scan, and the interval change (if any) in these parameters between the initial and follow-up CT was noted. The nodule was considered benign if it regressed without any therapy, or a biopsy proved a non-malignant condition, or if it remained stable for 2 years after the initial CT scan. The nodule was considered malignant if it grew in size or histopathology proved malignancy. The nodule was considered indeterminate if it remained stable in size during a follow-up of less than 2 years, regressed in size with therapy, and/or there was no pathological proof, or was a ground glass nodule(s) that remained stable over 2 years after the initial CT scan. We have proposed a Pulmonary Metastases Cancer Imaging and Reporting Data System (PM-CI-RADS) to standardize reporting of pulmonary nodules in known extrapulmonary solid malignancies [Supplementary appendix 2].

Statistics

Our sample size calculation was based on the assumption that approximately 200 patients would be required to yield valid results based on a similar number of patients in the previously published study by Hanamiya et al.[8] Data were entered into the Statistical Software for the Social Sciences (IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.) and subsequently analyzed. The relationship between nodule character (malignant/benign/indeterminate) and nodule size, shape, margin, morphology, distance from pleura, histology of primary, and differentiation of primary was assessed using Pearson's Chi-square test. A multivariable logistic regression model was used to determine the predictors of malignancy. Nodule morphology and the distance between the nodule and the pleura were included in this model. P < 0.05 was considered statistically significant.


  Results Top


There were 358 treatment-naïve patients with a known extrapulmonary primary solid tumor and small pulmonary nodules, who had baseline CT/PET scans performed between January 2010 and December 2014 (5 years), and the last follow-up scan in December 2016. Of these, 200 patients were enrolled in the study. The average interval between the baseline and follow-up scans was 736 days (~2 years) [Figure 1].
Figure 1: Flowchart showing the method of patient selection for the study

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Out of the total patients, 91 (45.5%) were men and 109 (54.5%) were women. The patients were classified into four groups [Table 1] according to the primary malignancy based on the results of Quint et al.[9] and Khokhar et al.[10] In this classification system, the four groups are based on the previously reported likelihood that their associated primary malignancies metastasize to the lung. Patients in group 1 were thought to have the lowest risk of developing metastatic disease, and those in group 4 were thought to have the highest. This method of grouping is said to allow a better analysis for rare tumor types encountered in small numbers of patients.[10] These studies were based on the earlier work by Cahan et al.,[11] who in 1978 listed the incidence of lung metastases (post-thoracotomy) from various primaries.
Table 1: Type of primary cancer with the absolute number (percentage) of benign/indeterminate/malignant lung nodules

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The groups consisted of Group 1: squamous cell cancers of the head and neck (n = 33); Group 2: carcinomas of the esophagus, pancreas or stomach, breast, uterine cervix, ovary, prostate, urinary bladder (n = 84); Group 3: carcinomas of the salivary glands, parotid gland, thyroid gland, thymus, colon, adrenal gland, kidney, or uterus (n = 42); and Group 4: melanoma, sarcoma, or testicular carcinoma (n = 41).

In total, 200 patients had 334 lung nodules. A single nodule was present in 163 (81.5%) patients, and the rest had multiple nodules. As per our criteria, 148 (44.3%) nodules were benign, and 127 (38%) were malignant. Of the benign nodules, 8 (5.4%) regressed in 4 patients without therapy, while 140 (94.6%) were stable over 2 years of follow-up. Of the malignant nodules, 121 (95.3%) showed an increase in size on follow-up CT scans, and 6 (4.7%) were proven malignant by lung nodule biopsy. The remaining 59 (17.7%) nodules in 32 patients were classified as indeterminate. Of these, 40 (67.7%) nodules remained unchanged in size over a <2-year follow-up, while 19 (32.2%) nodules decreased in size with therapy [Figure 2].
Figure 2: Classification of nodules into benign, indeterminate, and malignant

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Of the 200 patients, 118 (59%) did not have any other (extrapulmonary) distant metastases, while 82 (41%) patients did. In the presence of extrapulmonary metastases, the likelihood of pulmonary metastases is presumed to be higher. Of these 82 patients who had extrapulmonary metastases, the detection of pulmonary metastases in 27 patients resulted in a change in management (from curative intent to palliative chemotherapy).

The relationship between nodule/primary tumor characteristics and the number of benign/indeterminate/malignant lung nodules is summarized in [Table 2]. The mean distance of the nodule from the pleura was 7.7 mm (range: 0–45). The mean distance of benign nodules from the pleura was 6.4 mm (range: 0–33) The mean distance of the 127 malignant nodules from the pleura was 9.7 mm (range: 0–45). Thus, benign nodules were closer to the pleura as compared to malignant nodules (P = 0.0001). Most benign nodules were observed to be less than 10 mm from the pleura, whereas over 2/3rd of the nodules more than 10 mm away from the pleura were malignant (n = 60/94, 63.8% of cases; P = 0.0001). The mean size of the 148 benign nodules (5.3 mm) was smaller than that of 127 malignant nodules (9.2 mm). Furthermore, the size of the malignant nodules increased by a mean of 4.2 mm, while that of the benign nodules decreased by a mean of 1.7 mm. Also, 98% of benign nodules were smaller than 10 mm (P < 0.0001). The shape of 79% of the nodules was round; 82.7% of malignant nodules were round, as were 82.4% of the benign ones. Further, 70% of the linear-shaped nodules were either benign or indeterminate (P < 0.006). Data regarding differentiation of the primary tumor were available for only 106 of 200 patients (53%), corresponding to 133 nodules. Of these, 66.9% of nodules were associated with a well-differentiated primary and 33.1% with a poorly differentiated one. Among the nodules associated with a poorly differentiated primary neoplasm, 63.6% were malignant, 25% were benign, and 11.4% were indeterminate (P = 0.005). Of the 334 nodules, 269, (80.5%) were solid. Almost 93% of malignant nodules were solid, compared to 76.4% of benign nodules and 64.4% of indeterminate nodules (P = 0.0001). The majority of ground-glass nodules (85.4%) were either benign or indeterminate. There was no significant relationship between the type of margin and malignancy; however, 6 out of 7 (85.7%) of spiculated nodules were malignant.
Table 2: Nodule/primary tumor characteristics and the number of benign/indeterminate/malignant lung nodules

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On multivariate analysis [Table 3], a nodule >10 mm from the pleura was four times more likely to be malignant.
Table 3: Multivariate analysis to determine the predictors of malignancy: Distance of the nodule from the pleura

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  Discussion Top


Based on the results of prior studies, it has been established that nodules attached to the pleura or fissures are unlikely to be malignant[12] and that intrapulmonary lymph nodes and old granulomas[13],[14],[15],[16],[17] are usually located in the sub-pleural area. In our study [Table 2], we found that the mean distance of benign nodules from the pleura (6.4 mm) was significantly shorter as compared to that of malignant nodules (9.7 mm, P = 0.0001). Most nodules less than 10 mm from the pleura were benign, whereas more than 2/3rd of the nodules more than 10 mm away from the pleura were malignant (n = 60/94, 63.8% P < 0.0001). On multivariate analysis [Table 3], a nodule >10 mm from the pleura was four times more likely to be malignant. Thus, most of the small (<10 mm) sub-pleural nodules detected on a thin-slice CT scan in our study were either intrapulmonary lymph nodes or inflammatory focal lesions. However, a malignant nodule might occasionally be <10 mm and might be located just below the pleura. Short-interval follow-up CT scans may be recommended for such nodules as a trans-bronchiolar percutaneous lung biopsy often cannot ascertain the pathological nature of small pulmonary nodules.[18] Growth can be demonstrated in most malignant tumors as small as 5 mm on a single repeat CT scan obtained 30 days after the first scan.[19]

Hanamiya et al.[8] observed that the mean size of the 28 malignant nodules (17 mm) was larger than that of 109 benign nodules (6.4 mm, P = 0.0001). Nodules <10 mm were more likely to be benign (n = 105/111, 95% of cases), whereas those measuring ≥10 mm were more likely to be malignant (n = 22/26, 85% of cases; P = 0.0001). Additionally, 30% of ≥5-mm nodules and 85% of ≥10-mm nodules were malignant. In our study [Table 3], the mean size of the 148 benign nodules (5.3 mm) was smaller than that of the 127 malignant nodules (9.2 mm). Almost all (98%) benign nodules were <10 mm (P = 0.0001). Thus, most nodules <10 mm in size and at a distance of <10 mm from the pleura were benign in the present study. This result is consistent with that of prior studies.[8]

Previous clinical studies have shown that malignant nodules are commonly solid.[20],[21],[22] Li et al.[23] showed that out of 108 benign nodules, 54 showed pure ground-glass attenuation, 27 showed mixed solid and ground-glass attenuation, and 27 were solid at low-dose CT. Of all the ground-glass nodules, 92 (85%) resolved within 3 months. Therefore, ground-glass opacities are more likely to be benign.[24] Of the 334 nodules in our study [Table 2], 269 (80.5%) were solid. Nearly 93% of malignant nodules were solid, which was statistically significantly higher compared to 76.4% of benign nodules and 64.4% of indeterminate nodules (P = 0.0001). The majority of ground-glass nodules (85.4%) were either benign or indeterminate. This is consistent with previous literature and reflects the more likely inflammatory nature of ground-glass nodules.[20],[21],[22]

Li et al.[24] reported that benign lesions were more likely to be polygonal-shaped (38%, 46 of 122) than malignant lesions (7%, 1 of 15; P = 0.019). Almost all (98%) the polygonal nodules were benign. The authors suggested that a polygonal shape or a smooth margin were associated with a 98%–100% likelihood of benignity and could be more helpful in differentiating solid benign nodules from malignant nodules than complex shape, an irregular margin, or internal air bronchogram. In our study [Table 2], 79% of the nodules were round; 82.7% of the malignant nodules were round, as were 82.4% of the benign ones. We classified polygonal nodules as either oval or linear, depending on the predominant shape. More than two-thirds (68.3%) of oval nodules were either benign or indeterminate, as were 70% of linear-shaped nodules (P = 0.005). Thus, we found that round nodules could be either malignant or benign, while oval, linear, or polygonal nodules were almost always benign. Siegelman et al.[22] reported that smooth or moderately smooth margins were seen in 61% of 279 benign nodules (including 153 nodules with diffuse calcifications), while irregular shapes with spiculation were seen in 65% of 283 primary malignant tumors. In our study [Table 2], we found no significant relationship between any specific margin type and malignancy; however, 6 out of 7 (85.7%) spiculated nodules were malignant. All of these were metastases from a head/neck primary rather than a second primary lung cancer. The association between spiculated margins and malignancy has been well established in the literature.[25],[26]

Eccles et al.[27] reported that the degree of differentiation was inversely related to the metastatic potential of a particular tumor. Shimada et al.[28] reported that tumor differentiation and vascular invasion significantly affected the prediction of cancer recurrence. Chung et al.[29] found that patients with an undifferentiated squamous cell carcinoma of the lung had more distant metastases than differentiated tumors Ichinose et al.[30] and Sun et al.[31] reported that the histologic grade had significant prognostic value for survival in patients with non–small cell lung cancer. Our study showed that in patients with poorly differentiated primaries, the percentage of malignant nodules (63.6%) was significantly higher than that in well-differentiated primary cancers (38.2%) (P = 0.005), concurring with the literature. Thus, poorly differentiated malignancies were associated with a higher frequency of malignant lung nodules.

Limitations: The time duration between the two scans could not be strictly kept constant for all subjects because of the retrospective nature of this study. Not all patients had a baseline chest radiograph done; Our study had several limitations. thus, that parameter could not be assessed.


  Conclusion Top


Too-small-to-characterize lung nodules detected on CT scans in patients with known primary non-pulmonary solid neoplasms are a common clinical problem. These are more likely to be benign or indeterminate than malignant. Using nodule size, distance from the pleura, and useful morphological pointers, radiologists can help clinicians to decide between an immediate biopsy or a short-interval follow-up. Reporting these nodules using the standardized Pulmonary Metastases Cancer Imaging and Reporting Data System (PM-CI-RADS). Will help streamline assessment and follow-up.

Data sharing statement

Individual participant data will not be shared.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.


  Supplementary Appendix 1: Study protocol Top


Significance of TSTC Pulmonary Nodules In Known Extrapulmonary Malignancies: An audit.

Principal Investigator

Dr. Abhishek Mahajan

Assistant Professor

Department of Radio Diagnosis

Tata Memorial Hospital

TABLE OF CONTENTS



STUDY SUMMARY


  1. Introduction and Rationale: Top


The small nodules detected in patients with malignant neoplasm on initial staging CT pose a major problem in determining the clinical stage and management of these nodules. It is often difficult and impractical to prove the pathological characteristics of such specimens by using a biopsy or resection. Therefore, recognition of the frequency and significance of pulmonary nodules found on CT can help to determine the proper management for these nodules.[1]

Usually, the emergence of PNs during treatment or follow-up leads clinicians to favor the hypothesis that the disease has metastasized to the lungs. In some malignancies, such as colorectal cancer and osteosarcoma, patients with few pulmonary metastases and good control of the primary site are considered for surgical resection.[6] However, most patients thought to have pulmonary metastases are deemed incurable and are assigned to palliative treatment. This assumption directly affects the treatment and prognosis of patients.

Previous studies have reported the frequency and significance of pulmonary nodules detected on CT in patients with extrapulmonary malignant neoplasms.[2–4] These studies were performed with conventional or helical CT using a section thickness of 5–10 mm and included lesions ≥5.0 mm in diameter. Few studies have previously investigated the frequency and characteristics of pulmonary nodules, including those smaller than 5.0 mm, by using thin-section CT in patients with extrapulmonary malignant neoplasms.

The detection of pulmonary nodules with chest CT has increased with the increasing use and the evolution of CT technology. In 1991, Chalmers and Best reported the detection rate of nodules using conventional CT with 10-mm slice thickness to be 13% in patients with extrapulmonary malignant neoplasm and normal chest radiograph.[2] In 1999, Henschke et al. reported the detection rate of one or more non-calcified nodules to be 23% of baseline by CT with a 10-mm slice thickness in the Early Lung Cancer Action Project (ELCAP), a program designed to screen for lung cancer among former smokers.[5]

A 2012 study detected one or more non-calcified nodules in 75% of patients with extrapulmonary malignant neoplasms, which was a higher rate than that described in most previous reports. They concluded that the nodule detection rate on thin-section CT in patients with extrapulmonary malignancy is high and that most of the nodules <10 mm in size and located <10 mm from the pleura were benign, even in patients with primary extrapulmonary malignant neoplasms.[1]

A 2015 study determined that multiple pulmonary nodules (>5 mm) and cavitation were the two characteristics associated with the highest chances of metastatic disease in patients with an extrapulmonary primary neoplasm.[7]

The purpose of this study was to determine the frequency and significance of pulmonary nodules detected on thin-section CT in patients with extrapulmonary malignant neoplasms and to assess whether the characteristics of nodules on CT will help distinguish if they are benign or malignant.


  Aims/Objectives Top


  1. To determine the significance of TSTC pulmonary nodules on CT in patients with extrapulmonary solid tumors.
  2. Do characteristics of pulmonary nodules on CT help distinguish whether the nodules are malignant or benign?



  3. Methods: Top


Retrospective observational study.

3a. Eligibility criteria:

Inclusion criteria

  • Patients with a known primary solid tumor and having noncalcified TSTC pulmonary nodules.


Exclusion criteria

  • Patients with hematological malignancies such as leukemia and lymphoma will be excluded
  • Patients will be excluded if they had died or if there is no sufficient follow-up until either 2 years had passed or until a diagnostic biopsy is performed.
  • Patients with concurrent infectious disease, prior pulmonary granulomatous infection, and pulmonary emphysema will also be excluded.


3b. Ethics:

The study will be conducted after clearance from Scientific Review Committee, The Human Ethics Committee. The study will also be conducted in accordance with the guidelines of the Indian Council of Medical Research 2006.

3c. Study Site:

Tata Memorial Hospital

3d. Study Procedure:

January 2011–December 2015 (5 years) ---- Last follow-up in December 2017 will be considered.

After approval by the ethics committee, the CT images of TSTC pulmonary nodule cases (~500 patients) in known extra-pulmonary primary solid tumors that presented in the above period and meet the inclusion and exclusion criteria will be analyzed.

Using a uniform window width and window level (lung window (window width: 1600 HU; window level: −600 HU) and mediastinal window (window width: 350 HU; window level: 50 HU)) baseline imaging findings will be noted in terms of side, location, distance from pleura, size, margin, shape, morphology, density (as per CRF). Interval chemotherapy will be considered.

For both baseline and follow-up CT, two radiologists will interpret the CT images for whether the nodule exists; if it exists, whether it is the same nodule and its CT morphology will be assessed. If the observers arrive at a decision that the nodule on the follow-up CT is the same one they evaluated on the initial CT, the longest diameter of the nodule and the distance from the nearest pleural surface will be measured.

Baseline CT morphology of the nodule and the interval change of the nodule between initial CT and follow-up CT will be evaluated.

The nodule will be considered benign if

  • It resolves without any therapy
  • Biopsy proves a non-malignant condition
  • It remains stable over 2 years after the initial CT


The nodule will be considered malignant if

  • It grows in size
  • Or histopathology proves a malignant condition (Biopsy procedures will typically include fiberoptic bronchoscopy, percutaneous transthoracic fine-needle aspiration/biopsy (FNA/B), surgical biopsy via video-assisted thoracoscopy (VATS), or thoracotomy.)


The nodule will be considered indeterminate if

  • It remains stable in size during a follow-up of less than 2 years and has no pathological proof


GGO nodules that remain stable over 2 years after the initial CT will also be defined as indeterminate (Lung Adenocarcinoma showing GGO often grows very slowly and sometimes shows no change over a 2-year period.)

3e. Statistical Analysis:

  • The relationship between the nodule size and characteristics and the primary focus will be analyzed using Fisher's exact test.
  • A multivariable logistic regression model will be used to determine the predictors of malignancy.
  • This model includes the number of nodules (single/multiple), age, sex, primary histology, disease stage, nodule size, and CT characteristics.



  References Top


  1. Hanamiya M, Aoki T, Yamashita Y, Kawanami S, Korogi Y. Frequency and significance of pulmonary nodules on thin-section CT in patients with extrapulmonary malignant neoplasms. Eur J Radiol. 2012 Jan; 81(1):152-7. doi: 10.1016/j.ejrad. 2010.08.013. Epub 2010 Sep 15. PubMed PMID: 20828958.
  2. Chalmers N, Best JJ. The significance of pulmonary nodules detected by CT butbnot by chest radiography in tumour staging. Clin Radiol 1991;44(6):410–2.
  3. Quint LE, Park CH, Iannettoni MD. Solitary pulmonary nodules in patients with extrapulmonary neoplasms. Radiology 2000;217(1):257–61.
  4. Khokhar S, Vickers A, Moore MS, Mironov S, Stover DE, Feinstein MB. Significance of non-calcified pulmonary nodules in patients with Extrapulmonary cancers. Thorax 2006;61(4):331–6.
  5. Henschke CI, McCauley DI, Yankelevitz DF, et al. Early lung cancer action project: overall design and findings from baseline screening. Lancet 1999;354(9173):99–105.
  6. Pastorino U, Buyse M, Friedel G, et al; International Registry of Lung Metastases: Long-term results of lung metastasectomy: Prognostic analyses based on 5206 cases. J Thorac Cardiovasc Surg 113:37-49, 1997.
  7. Caparica R, Mak MP, Rocha CH, Velho PH, Viana P, Moura MR, et al. Pulmonary Nodules in Patients With Nonpulmonary Cancer: Not Always Metastases. Journal of Global Oncology. 2016 Feb 3:JGO-2015.






 
  References Top

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Gould MK, Tang T, Liu IL, Lee J, Zheng C, Danforth KN, et al. Recent trends in the identification of incidental pulmonary nodules. Am J Respir Crit Care Med 2015;192:1208-14.  Back to cited text no. 1
    
2.
Lacson R, Prevedello LM, Andriole KP, Gill R, Lenoci-Edwards J, Roy C, et al. Factors associated with radiologists' adherence to Fleischner Society guidelines for management of pulmonary nodules. J Am Coll Radiol 2012;9:468-73.  Back to cited text no. 2
    
3.
Henschke CI, McCauley DI, Yankelevitz DF, Naidich DP, McGuinness G, Miettinen OS, et al. Early lung cancer action project: Overall design and findings from baseline screening. Lancet 1999;354:99-105.  Back to cited text no. 3
    
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Crow J, Slavin G, Kreel L. Pulmonary metastasis: A pathologic and radiologic study. Cancer 1981;47:2595-602.  Back to cited text no. 4
    
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Macmahon H, Naidich DP, Goo JM, Lee KS, Leung AN, Mayo JR, et al. Special report: Guidelines for management of incidental pulmonary nodules detected on CT images: From the Fleischner society 2017. Radiology 2017;284:228-43.  Back to cited text no. 5
    
6.
B. MacMahon H, Naidich DP, Goo JM, Lee KS, Leung AN, Mayo JR. Guidelines for management of incidental pulmonary nodules detected on CT images: From the Fleischner Society 2017. Radiology 2017;284:228-43.  Back to cited text no. 6
    
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    Figures

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