A reference standard was not available in 7 of 61 patients (inadequate follow up n=6, death from another cause n=1). EBUS-TBNA identified a malignant etiology in 22 of 27 cases (Table 5). The diagnoses of cancer in 5 patients with false-negative EBUS-TBNA by the gold standard were NSCLC (n=2), SCLC (n=1), metastatic renal cell carcinoma (n=1), and Hodgkin lymphoma (n=1). The patient with Hodgkin lymphoma had mediastinoscopy as a gold standard. The other 4 patients with false-negative EBUS-TBNA for cancer had a CT-guided lung biopsy confirming cancer diagnosis, with a presumptive diagnosis of metastatic mediastinal disease based on follow-up without confirmatory biopsy. In these 5 patients, 7 lymph nodes and 1 mass were biopsied. Only 1 lymph node station contained calcification and EBUS-TBNA sampling showed normal lymphoid tissue.
The sensitivity, specificity, positive predictive value, and negative predictive value of EBUS-TBNA for all cancers (primary lung cancer staging, restaging, and reevaluation after cancer therapy, SCLC, lymphoma, and metastatic cancer) were 81%, 100%, 100%, and 84%, respectively.
Although many studies have identified the utility of EBUS-TBNA, specific reasons for inadequate sampling have often not been clearly identified.3–5,9–14 Lymph node-specific factors that may influence EBUS-TBNA yield include its site, size, echogenicity, and the presence of calcification. EBUS-TBNA is one of many modalities available to sample the mediastinum.1 Thus, it is important to investigate the influence of specific lymph node characteristics that may be identified by prelymph node sampling on the accuracy of EBUS-TBNA and whether another more invasive test, such as mediastinoscopy, may be needed. An earlier study comparing EBUS-TBNA, positron emission tomography, and CT in staging the mediastinum in 102 patients with NSCLC identified 2 false-negative results for EBUS-TBNA.5 Lymph node calcification was deemed the cause of the false-negative test in 1 of these patients. In our recent study of factors influencing the result of EBUS-TBNA in a population of patients presenting to a lung cancer institute, lymph node calcification was thought to contribute to inadequate sampling in 2 patients.20 The geographic location of our 2 centers allowed us an ideal opportunity to assess the influence of calcified lymph nodes on EBUS-TBNA in mediastinal and hilar lymph node sampling. The presence of lymph node calcification was not different between the group undergoing EBUS-TBNA and the control group. The natural history of primary histoplasmosis infection involves lymph node granulomatous inflammation and calcification as a host defense mechanism.21 The majority of patients with evidence of nodal calcifications in an endemic histoplasmosis region have had a histoplasmosis infection that is asymptomatic (99.5%).16 The prevalence of mediastinal and hilar nodal calcification secondary to tuberculous in the region is unknown; however, the yearly incidence of Mycobacterium tuberculosis infection in our area is not high (4.7 cases per 100,000) and the estimated latent tuberculosis prevalence is 4.2%.22 Thus, it is probable that the majority of calcified lymph nodes is secondary to histoplasma infection given the high prevalence of earlier histoplasma infection by skin testing.15 In fact, the presence of a high prevalence of calcified lymph nodes rather than the cause allowed the analysis of EBUS-TBNA in this specific setting.
In this study population, the presence of mediastinal dystrophic calcification did not affect accuracy of EBUS-TBNA in the overall patient population. When EBUS-TBNA was analyzed on a per lymph node rather than per patient basis, the yield of adequate tissue was less in lymph nodes that were calcified (66%) than in those that were not calcified (81%). However, this did not provide evidence to consider them to be different as the 95% CI between the differences did not include 0. It should be noted, however, that this was a fairly small retrospective analysis and thus was not powered to perform any formal statistical hypothesis testing on the primary study outcome. It also should be noted that this is a retrospective analysis and not every calcified lymph node identified on a CT scan was biopsied (not enlarged or not required for biopsy for instance in the staging of NSCLC). The authors admit that in cases with diffuse nodal calcification in which only 1 positive lymph node by on-site evaluation was required (eg, SCLC), a node that was not calcified would have been preferential. Although nodal calcification did not impact the quality of the EBUS image, the authors did attempt to avoid the calcified area of a lymph node when sampling.
However, it is important to note that sampling from a lymph node station containing calcification with EBUS-TBNA identified cancer in 3 patients. Thus, in the radiographic staging of lung cancer in patients with dystrophic lymph node calcification, it is important that cancer treatment is not denied on the basis of lymph node enlargement with or without calcification without definitive lymph node sampling.
The sensitivity of EBUS-TBNA for cancer at our institution was similar to that of other published studies.2–5 Of note, when comparing studies of EBUS-TBNA for cancer, it is important to define the population that is being studied (primary NSCLC staging vs. all cancer patients). In our population, 5 patients had EBUS-TBNA tests that were false negative for cancer and none of these patients had false-negative sampling from calcified lymph nodes. In agreement with our recent study from an academic cancer institute,20 our study has shown decreased adequacy of sampling smaller lymph nodes.
In conclusion, our results give no reason to conclude that EBUS-TBNA is a not a safe and effective method for sampling lymph nodes in a population of patients with a high prevalence of dystrophic calcification, including mediastinal and hilar lymph node calcification. In patients undergoing cancer staging, who have lymphadenopathy deemed radiographically secondary to the residual effects of granulomatous inflammation, such as histoplasmosis, cancer therapy should be based on definitive lymph node sampling.
1. Detterbeck FC, Jantz MA, Wallace M, et al. Invasive mediastinal staging of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007;132(3 suppl):202S–220S.
2. Ernst A, Anantham D, Eberhardt R, et al. Diagnosis of mediastinal adenopathy-real-time endobronchial ultrasound
guided needle aspiration versus mediastinoscopy. J Thorac Oncol. 2008;3:577–582.
3. Herth FJ, Ernst A, Eberhardt R, et al. Endobronchial ultrasound
-guided transbronchial needle aspiration of lymph nodes in the radiologically normal mediastinum. Eur Respir J. 2006;28:910–914.
4. Yasufuku K, Chiyo M, Koh E, et al. Endobronchial ultrasound
guided transbronchial needle aspiration for staging of lung cancer. Lung Cancer. 2005;50:347–354.
5. Yasufuku K, Nakajima T, Motoori K, et al. Comparison of endobronchial ultrasound
, positron emission tomography, and CT for lymph node staging of lung cancer. Chest. 2006;130:710–718.
6. Wallace MB, Pascual JM, Raimondo M, et al. Minimally invasive endoscopic staging of suspected lung cancer. JAMA. 2008;299:540–546.
7. Gu P, Zhao YZ, Jiang LY, et al. Endobronchial ultrasound
-guided transbronchial needle aspiration for staging of lung cancer: a systematic review and meta-analysis. Eur J Cancer. 2009;45:1389–1396.
8. Adams K, Shah PL, Edmonds L, et al. Test performance of endobronchial ultrasound
and transbronchial needle aspiration biopsy for mediastinal staging in patients with lung cancer: systematic review and meta-analysis. Thorax. 2009;64:757–762.
9. Garwood S, Judson MA, Silvestri G, et al. Endobronchial ultrasound
for the diagnosis of pulmonary sarcoidosis
. Chest. 2007;132:1298–1304.
10. Wong M, Yasufuku K, Nakajima T, et al. Endobronchial ultrasound
: new insight for the diagnosis of sarcoidosis
. Eur Respir J. 2007;29:1182–1186.
11. Tremblay A, Stather DR, Maceachern P, et al. A randomized controlled trial of standard versus endobronchial ultrasonography-guided transbronchial needle aspiration in patients with suspected sarcoidosis
. Chest. 2009;136:340–346.
12. Kennedy MP, Jimenez CA, Bruzzi JF, et al. Endobronchial ultrasound
-guided transbronchial needle aspiration in the diagnosis of lymphoma. Thorax. 2008;63:360–365.
13. Yasufuku K, Chiyo M, Sekine Y, et al. Real-time endobronchial ultrasound
-guided transbronchial needle aspiration of mediastinal and hilar lymph nodes. Chest. 2004;126:122–128.
14. Herth FJ, Eberhardt R, Vilmann P, et al. Real-time endobronchial ultrasound
guided transbronchial needle aspiration for sampling mediastinal lymph nodes. Thorax. 2006;61:795–798.
15. Leggiadro RJ, Luedtke GS, Convey A, et al. Prevalence of histoplasmosis
in a midsouthern population. South Med J. 1991;84:1360–1361.
16. Gurney JW, Conces DJ. Pulmonary histoplasmosis
. Radiology. 1996;199:297–306.
17. Shweihat Y SR, Joshi M, Shah H, et al. Endobronchial ultrasound
transbronchial needle aspiration in a geographical region with endemic histoplasmosis
infection. Chest. 2008;134:S13004.
18. Chalaoui J, Gregoire P, Sylvestre J, et al. Pulmonary hyalinizing granuloma: a cause of pulmonary nodules. Radiology. 1984;152:23–26.
19. Colen RR, Nagle JA, Wittram C. Radiologic-pathologic conference of the Massachusetts General Hospital: pulmonary hyalinizing granuloma. AJR Am J Roentgenol. 2007;188:W15–W16.
20. Kennedy MP, Jimenez CA, Morice RC, et al. Factors affecting the diagnostic yield of endobronchial ultrasound
-guided transbronchial needle aspiration. J Bronchol Intervent Pulmonol. 2010;17:202–208.
21. Kauffman CA. Histoplasmosis
: a clinical and laboratory update. Clin Microbiol Rev. 2007;20:115–132.
22. Bennett DE, Courval JM, Onorato I, et al. Prevalence of tuberculosis infection in the United States population: the National Health and Nutrition Examination Survey, 1999 to 2000. Am J Respir Crit Care Med. 2008;177:348–355.