ELSEVIER
Lung Cancer
journal homepage: www.elsevier.com/locate/lungcan
lungcancer
EUS-FNA for the detection of left adrenal metastasis in patients with lung cancer
Olga C.J. Schuurbiersa,*, Kurt G. Tournoye, Hans J. Schoppersª, Bernadette G. Dijkmanª, Henri J.L.M. Timmersb, Lioe-Fee de Geus-Oeic, Johanna M.M. Grefted, Klaus F. Rabef, P.N. Richard Dekhuijzenª, Henricus F.M. van der Heijdenª, Jouke T. Annemaf
a Department of Pulmonology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
b Department of Endocrinology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
” Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
d Department Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
e Department of Pulmonology, Ghent University Hospital, Ghent, Belgium
Department of Pulmonology, Leiden University Medical Centre, Leiden, The Netherlands
ARTICLE INFO
Article history: Received 27 September 2010 Received in revised form 3 December 2010 Accepted 18 December 2010
Keywords:
Lung cancer EUS-FNA Left adrenal metastasis Staging 18FDG-PET-CT Left adrenal gland Ultrasound
SUMMARY
In patients with lung cancer, enlarged or 18Fluoro-deoxyglucose positron emission tomography (18FDG- PET) positive left adrenal glands are suspected for distant metastases and require tissue confirmation for a definitive assessment. The aim of this study was to assess the sensitivity of endoscopic ultrasound- guided fine-needle aspiration (EUS-FNA) for left adrenal metastases in lung cancer patients with a suspect adrenal gland based on imaging.
EUS-FNA findings of patients with (suspected) lung cancer and CT enlarged or 18FDG-PET positive left adrenal glands were retrospectively evaluated. In the absence of metastases at EUS, clinical and radiological follow-up was obtained.
In 85 patients, EUS-FNA demonstrated left adrenal metastases of lung cancer in 53 (62%), benign adrenal tissue in 25 (29%), a metastasis from colon carcinoma in 1 (1%) and a primary adrenocortical carcinoma in 1 (1%) patient. In five patients (5.9%), the aspirates contained non-representative material. EUS outcomes were false negative in two patients. Sensitivity and negative predictive value (NPV) for EUS-FNA of the left adrenal gland were at least 86% (95% CI 74-93%) and 70% (95% CI 50-85%). No complications occurred.
EUS-FNA is a sensitive, safe and minimally invasive technique to provide tissue proof of left adrenal metastases in patients with (suspected) lung cancer and enlarged or 18FDG-PET positive adrenal glands. Therefore, EUS-FNA qualifies as the staging test of choice for patients with lung cancer with suspected left adrenal metastases.
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1. Introduction
Adrenal glands are a predilection site for metastatic spread in patients with lung cancer. Autopsy series have shown a prevalence of adrenal metastases in 35-59% of patients with lung cancer [1,2]. The incidence of adrenal masses in patients with lung cancer varies from 4.1% to 18% [3]. Up to 4-7% of patients with otherwise opera- ble NSCLC present with a unilateral adrenal mass; 40% of these are malignant and present as a solitary site of metastatic spread [4,5]. As the majority (approximately two-thirds) of adrenal masses in patients with non-small cell lung cancer (NSCLC) represent benign adenomas [6], tissue verification of suspected malignant involve- ment is essential.
Computed tomography (CT) or integrated 18FDG-PET-CT are used in standard diagnostic work-up of lung cancer patients and are helpful in the detection of distant metastases [6]. Due to the limited positive predictive value (PPV) of both CT (62%) and 18FDG-PET-CT (81%) for the assessment of left adrenal metastases, tissue proof of malignant involvement is needed [7-9]. Chemical shift MRI [10-12] and CT protocols with unenhanced and delayed enhanced techniques [13,14] seem interesting noninvasive alter- native approaches, but await further validation.
Traditional techniques to obtain tissue of left adrenal glands include percutaneous CT-guided FNA and open or laparoscopic adrenalectomies. These procedures are either invasive and asso- ciated with considerable complications such as pneumothorax and hemorrhage [15-18].
The left adrenal gland can be visualised and real-time sampled from the stomach using endoscopic ultrasound [19]. Trans- esophageal ultrasound guided fine needle aspiration (EUS-FNA) is a safe and minimally invasive alternative for surgical mediasti- nal staging that is incorporated in international guidelines [20,21].
* Corresponding author at: Department of Pulmonary Diseases 454, Radboud Uni- versity Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Tel .: +31 24 361 45 79; fax: +31 24 361 03 24.
E-mail address: o.schuurbiers@long.umcn.nl (O.C.J. Schuurbiers).
Reports about EUS-FNA for the assessment of left adrenal metas- tases in patients with lung cancer are limited, mostly single centre case series and rarely take PET findings into account [19,22-27]. The aim of this multicentre study was to investigate the sensitivity of EUS-FNA in patients with (suspected) lung cancer with a sus- pect left adrenal gland metastasis based on CT and/or 18FDG-PET imaging.
2. Methods
2.1. Patients
Patients who underwent EUS-FNA for the diagnosis and staging of lung cancer and in whom the left adrenal gland had been eval- uated and aspirated between November 2001 and October 2009 were retrospectively identified. Patients with either enlarged left adrenal glands (short axis of the body >10 mm), 18FDG-PET uptake in the left adrenal gland or those in whom the loss of the typical seagull shape was missing were included in the study. Prior to EUS, all patients underwent CT or 18FDG-PET-CT as part of their routine staging procedure. Data on patient demographics and clinical and radiological follow-up were extracted from patient charts. Patients underwent EUS in the Ghent University Hospital, Belgium, the Lei- den University Medical Centre, the Netherlands or the Radboud University Nijmegen Medical Centre, The Netherlands. These cen- tres are referral centres for the diagnosis and staging of lung cancer by endosonography.
2.2. EUS-FNA
EUS-FNA examinations were performed by chest physicians who were specifically trained in EUS for the diagnosis and staging of lung cancer [7,28]. EUS was performed in a standardized way in an outpatient setting under conscious sedation using midazolam. A linear scanning Pentax EG 3870 UTK/34 UX, Olympus/Olympus GF-UCT 140-AL5 echo-endoscope was used in combination with a Hitachi or Aloka ultrasound scanner. The adrenal gland was routinely evaluated from the stomach in all patients prior to the mediastinal evaluation. With colour Doppler the presence of ves- sels in the vicinity of the LAG was evaluated. Sonographically suspect left adrenal glands (defined as short axis of the body >1 cm, presence of hypo-echoic texture in the left adrenal body or absence of normal sea-gull shape) were punctured under real- time ultrasound guidance from the stomach with a 22-gauge needle (Medi-Globe type Sonotip II (GUS-01-27-022), Hancke-Villman needle (Medi-Globe) and Olympus: EZ Shot NA-200H-8022). Fine needle aspirates were in general repeated until - according to rapid on site examination (ROSE) of the obtained aspirates - representa- tive material was obtained (Fig. 1).
2.3. Handling of the EUS aspirates and cytological examination
The aspirated material was processed in the following way: one smear was allowed to dry and stained with Diff-Quik for ROSE by a trained cytotechnician or chest physician to assess specimen adequacy. An additional smear was fixed in alcohol 96% and sub- sequently Papanicolaou-stained in the laboratory. The needle and remainder of the aspirate was rinsed in Unifix (a formaldehyde- based fixative; Klinipath, Duiven, The Netherlands) and processed into a paraffin-embedded cellblock for additional immunocyto- chemical staining using several organ- and tissue-specific markers [29]. Specific cell markers used in this study were among others cytokeratins 7 and 20, vimentin, thyroid transcription factor 1 (TTF- 1), CD56, synaptophysin, chromogranin and p63.
All specimens were examined by a cytopathologist for a defini- tive diagnosis. Final diagnoses were classified as metastasis of
| Mean age (range), year | 65 | (37-86) |
| Gender, no. (%) | ||
| Male | 51 | (60) |
| Female | 34 | (40) |
| Indication for EUS, no. (%) | ||
| Staging of biopsy-proven lung cancer | 45 | (53) |
| Diagnosis and staging of suspected lung cancer | 40 | (47) |
| CT scan characteristics LAG, no. (%) | ||
| Enlargedª | 71 | (84) |
| Normal shape and size | 11 | (13) |
| Mean adrenal diameter of LAG on CT in mm mean (range) | 33 | (5-120) |
| Metabolic activity LAG on PET-scan, no. (%) | ||
| Increasedb | 46 | (54) |
| Not increased | 7 | (8) |
| PET scan not available | 32 | (38) |
Abbreviations: EUS, endoscopic ultrasound; LAG, left adrenal gland; PET, positron emission tomography; CT, computed tomography.
a Loss of normal seagull shape or LAG body short axis >1 cm.
b Increased FDG uptake relative to uptake in the liver.
primary lung cancer, metastasis of malignancy of other primary site, benign adrenal tissue, primary adrenocortical carcinoma or non-representative material.
2.4. FDG-PET metabolic activity scoring
An FDG-PET scan was readily available for revision in a sub- group of 31 patients. The FDG-PET scans were interpreted by an experienced nuclear physician (LFdGO). The FDG-uptake in the left adrenal gland was visually scored as “not suspect” if the metabolic activity in the left adrenal gland was equal to that of the liver and as “suspect” if the metabolic activity was increased above liver background.
2.5. Statistical methods
SPSS software was used for descriptive analyses to summarize patient characteristics and EUS-FNA results. The reference standard for the final diagnosis was a combination of clinical and radiolog- ical follow-up. Missing values regarding follow-up were regarded false negative. Continuous variables were described as means, and dichotomous variables were expressed as simple proportions. The Chi-square test was used for correlating two categorical variables. A p-value <0.05 was considered statistically significant.
3. Results
3.1. Patients
Eighty-five patients (51 men, 34 women; mean age 65 years, range 37-86) were included. Patient characteristics and EUS indi- cations are summarized in Table 1. EUS-FNA was performed for the staging of known lung cancer in 45 patients, and in 40 patients for the diagnosis and staging of suspected lung cancer.
3.2. EUS-FNA results
EUS-FNA provided tissue proof of left adrenal metastases of a primary lung cancer in 53 of 85 patients (62%). Benign adrenal tissue was found in 25 patients (29%), a primary adrenocortical carcinoma in one, a metastasis from colon carcinoma in another patient and not representative material was obtained in five (5.9%) patients (Table 2). The median number of aspirations of the left adrenal gland was 3.0 (range 1-6). No complications occurred. The proportion of left adrenal metastases found by EUS-FNA was com-
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| Diagnosis | LAG enlarged on CTª and/or PET positiveb, no. (%) | LAG enlarged on CTª, no. (%) | LAG PET positiveb, no. (%) | LAG enlarged on CTª and PET positiveb, no. (%) |
|---|---|---|---|---|
| Metastasis of lung cancer | 53(62.4) | 45(63.4) | 31 (67.4) | 25 (73.5) |
| NSCLC | 48 (56.5) | 42(59.2) | 27(58.7) | 22(64.7) |
| Not specified | 27(31.8) | 25(35.2) | 11 (23.9) | 10(29.4) |
| SCC | 6(7.1) | 5(7.0) | 5(15.9) | 4(11.7) |
| AC | 10(11.8) | 8(11.3) | 7(15.2) | 5(14.7) |
| LCC | 5(5.9) | 4(5.6) | 4(8.7) | 3(8.8) |
| SCLC | 5(5.9) | 3(4.2) | 4(8.7) | 3(8.8) |
| Primary adrenocortical carcinoma | 1(1.2) | 1 (1.4) | 1 (2.2) | 1 (2.9) |
| Metastasis of colon carcinoma | 1(1.2) | 1 (1.4) | 0(0.0) | 0(0.0) |
| Benign adrenal tissue | 25(29.4) | 20(28.2) | 11 (23.9) | 6(17.6) |
| Non-diagnostic | 5(5.9) | 4(5.6) | 3(6.5) | 2(5.8) |
| Total | 85 (100) | 71 (100) | 46 (100) | 34 (100) |
Abbreviations: EUS, endoscopic ultrasound; FNA, fine-needle aspiration; LAG, left adrenal gland; CT, computed tomography; PET, positron emission tomography; NSCLC, non-small cell lung carcinoma; SCC, squamous cell carcinoma; AC, adenocarcinoma; LCC, large cell carcinoma; SCLC, small cell lung carcinoma.
a Loss of normal seagull shape or LAG body short axis >1 cm.
b Increased FDG uptake relative to uptake in the liver.
| LAG sizeª | Benign (n=22) | Malignant (n=54) | Not diagnostic (n=5) | Total (n=81) |
|---|---|---|---|---|
| Range | 7-40 | 9-120 | 5-38 | 5-120 |
| Mean ± SD | 22.3±9.4 | 32.4±21.3 | 19.4±13.3 | 28.6±19.1 |
| Median | 22.5 | 27 | 19.0 | 25 |
| ≥30 | 6 | 26 | 1 | 33 |
| <30 | 16 | 28 | 4 | 48 |
Abbreviations: EUS, endoscopic ultrasound; LAG, left adrenal gland.
a LAG body short axis in mm (on EUS or if not available on CT).
parable between patients with enlarged and 18FDG-PET-positive left adrenal glands (63% vs. 67%, respectively).
Out of 81 left adrenal glands of which the diameter on EUS or CT was recorded, 33 had a diameter of 30 mm or more (Table 3). Of those, 26 (79%) were malignant (OR 2.41 (95% CI 0.90-6.42)). On the other hand, 58% (28 out of 48) left adrenal glands with a diameter smaller than 30 mm were found to be malignant.
3.3. Final diagnosis
Follow-up information was available for 23 of 30 patients in whom no left adrenal metastases were found by EUS. Follow- up (12.9 months, range 2.0-40 months) was not suspicious for metastatic malignant disease based on clinical grounds (11 patients) and/or on repeat CT of the left adrenal gland (10 patients). In two patients the left adrenal gland increased in size consid- erable in 3 months after EUS and was considered metastatic. In one of these patients the adrenal metastasis was confirmed with a surgical biopsy. These false negatives were probably due to a sampling error as the cytology specimen showed benign adrenal cells.
Sensitivity and NPV of EUS-FNA for malignant involvement of the left adrenal gland were 86% (95% CI 74-93%) and 70% (95% CI 50-85%). For this calculation we assumed that all 7 patients in whom follow-up was missing were false negative. If all missing val- ues were true negative sensitivity and NPV would reach 96% and 91%.
3.4. Correlation of EUS-FNA results with FDG-uptake
In 32 of 46 patients referred for EUS-FNA of the left adrenal gland based on 18FDG-PET positive results, malignancy of the left adrenal gland was confirmed. In 11 patients EUS-FNA did not find malig- nancy (benign adrenal tissue). When EUS-FNA of the left adrenal gland was considered as a gold standard, any 18FDG uptake had a PPV of 74%.
In the subgroup of patients (n =31) in whom the degree of FDG- uptake by the left adrenal gland was scored by an experienced nuclear physician, correlation of EUS-FNA results with FDG-uptake was significant (Pearson Chi-square value 17.9; p=0.001). In 18FDG-PET negative left adrenal glands, no metastases have been identified by EUS-FNA (Table 4). The vast majority (82%) of left adrenal glands with increased FDG-uptake was found to be malig- nant.
4. Discussion
In this retrospective multicenter study in patients with lung cancer and suspected left adrenal metastases, EUS-FNA provided tissue proof of metastatic spread in 53 of 85 patients (62%). The sensitivity for EUS-FNA of the left adrenal gland was at least 86%. Additionally, EUS-FNA also excluded the presence of left adrenal metastases in 25 patients (29%) with a NPV of at least 70%. These operating characteristics are very conservative and are probably better as patients with missing follow up were regarded false neg-
ative. The PPV of 18FDG-PET for assessment of left adrenal gland metastases in our subgroup with a FDG-PET available for revision was 82% in case of PET positive left adrenal glands. The data con- firm the need for tissue proof of suspected metastatic spread to correctly stage lung cancer patients in order to prevent over stag- ing.
The present study is a multicentre study on EUS-FNA of the left adrenal gland in lung cancer patients that is performed by chest physicians trained in pulmonary oncology and EUS-FNA. EUS-FNA is already an established technique for mediastinal nodal staging [20,21]. The advantage of EUS is that mediastinal nodal staging and assessment of the left adrenal gland can be performed during the same procedure.
Previously, EUS-FNA for the analysis of the left adrenal gland has been reported in six single centre case series of patients with left adrenal metastases [22-27]. Four studies included het- erogeneous populations with a wide variety of EUS indications (not specifically patients with lung cancer) [22,24,25,27]. Further- more, none of these studies particularly took CT-enlargement or PET-positivity of the adrenal masses into account. Among the included patients with known or suspected lung cancer in whom EUS-FNA of the left adrenal gland was performed, 40-68% of EUS-FNA yielded benign adrenal tissue, and adrenal metastases from lung cancer were found in 14-60% of patients [22-25,27]. In the most recently published study, 59 cases of patients with enlarged or 18FDG-PET positive (left) adrenal glands were retro- spectively selected from a pool of 7500 patients referred for EUS [26]. Left adrenal gland metastasis was confirmed in 22 patients (37%). Altered shape of the left adrenal gland on EUS imaging was a significant predictor for malignancy whereas left adrenal gland size (>30 mm) on CT and hypo echoic EUS features were not [26].
In the present study the degree of 18FDG-uptake was interpreted qualitatively, since it was previously reported that additional SUV analysis does not help to further differentiate between malig- nant and benign adrenal lesions, due to a distinct overlap in SUVs between benign and malignant lesions [9]. From the present data it can be concluded that it is relatively save to consider any 18FDG- uptake in the adrenal above physiological accumulation in the liver as “positive or suspicious”. Such criterion results in a PPV of 82% and did not misclassify any of the seven PET-negative cases.
| Interpretation of PET | Final diagnoses of EUS-FNA, no. (%) | |||
|---|---|---|---|---|
| Malignant | Benign | Not-representative | Total | |
| Not suspectª | 0 | 5 | 2 | 7 |
| Suspectb | 18 | 4 | 2 | 24 |
| Total | 18 | 9 | 4 | 31 |
Abbreviations: EUS, endoscopic ultrasound; FNA, fine-needle aspiration; LAG, left adrenal gland; PET, positron emission tomography.
a The metabolic activity of the left adrenal gland was classified as ‘not suspect’ if the uptake was equal to or less than the FDG-uptake in the liver.
b Metabolic activity above liver background.
Previous PET-CT studies that assessed left adrenal gland metas- tases using SUVmax cut-off levels also report PPVs of 81%. However, in these studies histological prove was only available in the minor- ity of cases [7,9].
Whether normal sized 18FDG-PET negative patients should be routinely investigated cannot be answered. One report on a patient with a normal left adrenal gland on CT (and no PET performed) showed an enlarged left adrenal gland on EUS examination and EUS-FNA revealed a left adrenal gland metastasis [30]. Also two cases of malignancy in the left adrenal gland were detected in sub- jects, referred for EUS-FNA as part of mediastinal staging, with normal left adrenal glands on CT [23].
Various limitations apply to this study. Its retrospective design, the absence of surgical verification of the left adrenal gland on those patients in whom EUS did not find malignant involvement and the missing follow-up in several patients. However, we choose a con- servative approach reporting our data classifying missing follow-up as false negative most likely underestimating the value of EUS. The patients included in this study are a subset of a much larger population. A selection bias is present, as the population studied represents a subgroup of lung cancer patients that were referred from other centers for EUS-FNA. It is unknown how many centers base their stage M1b adrenal metastasis on radiologic or nuclear findings only. Left adrenal gland size was only measured by the short axis of the corpus of the left adrenal gland body, loss of the typical “sea-gull shape” was not always specifically mentioned. Whether the short axis of the corpus of the left adrenal gland or the altered shape of the left adrenal gland is predictive of malig- nancy cannot be answered. In the present study only patients with suspected left adrenal glands- and not right adrenal glands were considered. The right adrenal gland should be approached from the duodenum - this is technically more demanding- and only 10 cases have been described [26,27,31].
An important issue when new approaches are validated for clin- ical implementation is to report complications. One case of left adrenal hemorrhage after EUS-FNA has been reported [32]. In con- trast to the reported complication rate for percutaneous adrenal biopsies of 8.4% [16,17], and open adrenalectomies of 34% [18], no complications occurred during or shortly after EUS-FNA pro- cedures in this and previous case series on left adrenal gland EUS-FNA [22-27]. In patients with suspected pheochromocytoma - for instance in patients with an enlarged adrenal gland without a known primary tumour with a predilection for metastatic spread to the adrenal gland - metanephrines in plasma or 24-h urine should be measured to rule out this clinical condition and to prevent a hypertensive crisis. To date, endosonography is implemented for minimally invasive mediastinal staging of lung cancer. An impor- tant advantage of EUS above EBUS (endobronchial ultrasound) is the ability to evaluate the left adrenal glands in addition to staging of the mediastinal nodes.
5. Conclusions
EUS-FNA is a sensitive, safe and minimally invasive technique to provide tissue proof of left adrenal metastases in patients with (suspected) lung cancer and enlarged or PET positive left adrenal glands. Therefore EUS-FNA qualifies as the staging test of choice for patients with lung cancer with suspected left adrenal metastases.
Conflict of interest
The authors declare no potential conflict of interest. No source of funding has been received for this study.
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