*2.2.2 Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA)*

EBUS-TBNA has been significant in the diagnostic pathway of sarcoidosis and has obviated the need for a TBB (in most cases where mediastinal adenopathy is present) with associated risk of pneumothorax. EBUS-TBNA is a safe minimally invasive option and is the preferred diagnostic procedure before surgical techniques such as mediastinoscopy are considered for sampling mediastinal nodes [25].

Kitamura et al. demonstrated a sensitivity of 87.5% for combined cytological and histological examination [26]. A prospective study by Oki et al. compared the diagnostic yield of EBUS-TBNA and TBLB through a flexible bronchoscope in patients with stage I and II of sarcoidosis [27]. The diagnostic yield was 94% (stage I, 97%; stage II, 88%) and 37% (stage I, 31%; stage II, 50%), respectively; the complications such as pneumothorax and moderate bleeding were noted in patients, who underwent TBLB, albeit one case of pneumothorax and three cases of moderate bleeding among a total of 62 patients were seen.

A randomized controlled trial evaluated the use of endosonographic nodal aspiration against bronchoscopic biopsy, among patients with suspected stage I/II pulmonary sarcoidosis [28]. The diagnostic yield to detect granulomas for endosonography was 80% (95% CI, 73–86%), in comparison to 53% (95% CI, 45–61%) for bronchoscopy cohort (P < 0.001), suggesting a significantly higher diagnostic yield with endosonographic procedures. On the other hand, a randomized controlled trial by Gupta et al. showed that the diagnostic yield in sarcoidosis by conventional TBNA along with endobronchial biopsy (EBB) and TBLB is similar to EBUS-TBNA with TBLB [29].

The diagnostic accuracy of EBUS-TBNA with rapid on-site evaluation (ROSE) was compared to the final cytological assessment and to TBLB and EBB in a prospective study, and it showed that sensitivity for EBUS-TBNA with ROSE was 87.8% (specificity 91%, positive predictive value 97.7%) and concluded that it should be considered as first-line investigation for the evaluation of mediastinal adenopathy [30].

In patients with predominant mediastinal and/or intra-abdominal lymph nodes, which is not amenable for EBUS procedure, endoscopic ultrasound-guided fine aspiration (EUS-FNA) can be a potential option; Michael et al. demonstrated in a retrospective study that [31] EUS-FNA was able to diagnose sarcoidosis in 86% of cases (n = 18 of 21) and was able to rule out recurrence of malignancy in 75% (three out of four cases).

#### *2.2.3 Transbronchial lung cryobiopsy (TBLC)*

Transbronchial lung cryobiopsy is currently being increasingly considered as a diagnostic tool in ILD. The procedure requires general anesthesia and fluoroscopic

**23**

*Current Diagnostic Techniques in Sarcoidosis DOI: http://dx.doi.org/10.5772/intechopen.90692*

**2.3 Ultrasound (US)-guided biopsy**

respectively [34].

diagnostic modality.

lymph node.

mediastinoscopy [38].

*2.4.2 Video-assisted thoracoscopic surgery (VATS)*

**thoracoscopy (VATS)**

*2.4.1 Cervical mediastinoscopy*

guidance for sampling with a cryoprobe [32]. In a retrospective study by Jacob et al., they were able to demonstrate a diagnostic yield of up to 92.6% on a small sample size in the study [33]. The main advantage of TBLC is related to larger biopsy sample in comparison to traditional transbronchial biopsy with associated crushing artifact of the sample. However, TBLC has the limitations related to training and the need for general anesthesia. Moreover, there is a significant risk of complications including pneumothorax and bleeding ranging from 9 to 10% and from 14 to 20%,

Hagmeyer et al. demonstrated that the risk of severe complications can be reduced from 84 to 14% by technical modification of this procedure. Hence, it may

The diagnostic workup for sarcoidosis should include the least invasive investigation at the outset of evaluation; thus, neck ultrasound may provide an ideal modality for that purpose. We have demonstrated that a core biopsy of cervical lymph nodes (ranging from 7 to 14 mm in diameter), with no sonographic appearance of being marked was adequate to make a histological diagnosis of sarcoidosis [36]. In this retrospective analysis, we showed that if there were no suitable cervical lymph node for biopsy, an US evaluation and biopsy of abnormal parotid glands may help establish the diagnosis of sarcoidosis [36]. In view of the ease of this procedure and its cost-effectiveness (approximately £1000/= saving in comparison to EBUS-TBNA per patient in the UK), this could potentially be considered as a first-line investigation if appropriate expertise is available. Hence, it is proposed that the diagnostic algorithm as shown in **Figure 5** for the investigation of mediastinal lymphadenopathy should include US-guided core biopsy of cervical lymph nodes +/− parotid glands if deemed abnormal. We envisage that a prospective multicenter study of wider application of this technique would be desirable to generalize the use of this minimally invasive

prove to be a useful step before consideration of surgical lung biopsy [35].

**2.4 Surgical techniques: cervical mediastinoscopy and video-assisted** 

Cervical mediastinoscopy (CM) is one of the preferred surgical techniques to evaluate mediastinal lymphadenopathy. The procedure helps to obtain samples from paratracheal and subcarinal lymph nodes. Since the advent of EBUS-TBNA, EUS-FNA, and PET-CT, the frequency of mediastinoscopy as a diagnostic procedure has declined significantly. Moreover, it is reserved when the above techniques have been inconclusive or not feasible due to the location of the enlarged

Onat et al. reported the safety of CM and demonstrated that it is a reliable method, in the evaluation of mediastinal lymphadenopathy [37]. In a meta-analysis by Agarwal et al., they reported a diagnostic yield between 82 and 97% for cervical

VATS biopsy should be considered when there is difficulty in establishing the diagnosis with other less invasive options especially if a specific histological diagnosis would help the prognosis or treatment [39]. The diagnostic yield, sensitivity,

#### *Current Diagnostic Techniques in Sarcoidosis DOI: http://dx.doi.org/10.5772/intechopen.90692*

*Sarcoidosis and Granulomatosis - Diagnosis and Management*

Bronchoalveolar lavage findings supportive of sarcoidosis include predominant lymphocytosis on differential cell count analysis along with CD4/CD8 lymphocyte ratio of more than 1. Müller-Quernheim et al. demonstrated that inflammation is compartmentalized in sarcoidosis resulting in lymphocyte abundance in the involved organs [21]. In a study by Prasse et al., patients with sarcoidosis had higher expression of IL2, IFN gamma, and TNF alpha [22]. Furthermore, Tanriverdi et al. showed that high CD4/CD8 ratio, though specific is not a sensitive test for the diagnosis of sarcoidosis, and therefore, it does require clinico-radiological and pathological correlation [23]. BAL lymphocytosis of ≥40% in the appropriate clinical context would support the diagnosis of hypersensitivity pneumonitis or cellular nonspecific interstitial pneumonia (NSIP) over sarcoidosis [24]. However, bronchoalveolar lavage findings in isolation are unlikely to help establish the diagnosis of sarcoidosis.

EBUS-TBNA has been significant in the diagnostic pathway of sarcoidosis and has obviated the need for a TBB (in most cases where mediastinal adenopathy is present) with associated risk of pneumothorax. EBUS-TBNA is a safe minimally invasive option and is the preferred diagnostic procedure before surgical techniques such as mediastinoscopy are considered for sampling mediastinal nodes [25]. Kitamura et al. demonstrated a sensitivity of 87.5% for combined cytological and histological examination [26]. A prospective study by Oki et al. compared the diagnostic yield of EBUS-TBNA and TBLB through a flexible bronchoscope in patients with stage I and II of sarcoidosis [27]. The diagnostic yield was 94% (stage I, 97%; stage II, 88%) and 37% (stage I, 31%; stage II, 50%), respectively; the complications such as pneumothorax and moderate bleeding were noted in patients, who underwent TBLB, albeit one case of pneumothorax and three cases of moder-

A randomized controlled trial evaluated the use of endosonographic nodal aspiration against bronchoscopic biopsy, among patients with suspected stage I/II pulmonary sarcoidosis [28]. The diagnostic yield to detect granulomas for endosonography was 80% (95% CI, 73–86%), in comparison to 53% (95% CI, 45–61%) for bronchoscopy cohort (P < 0.001), suggesting a significantly higher diagnostic yield with endosonographic procedures. On the other hand, a randomized controlled trial by Gupta et al. showed that the diagnostic yield in sarcoidosis by conventional TBNA along with endobronchial biopsy (EBB) and TBLB is similar

The diagnostic accuracy of EBUS-TBNA with rapid on-site evaluation (ROSE) was compared to the final cytological assessment and to TBLB and EBB in a prospective study, and it showed that sensitivity for EBUS-TBNA with ROSE was 87.8% (specificity 91%, positive predictive value 97.7%) and concluded that it should be considered

In patients with predominant mediastinal and/or intra-abdominal lymph nodes,

Transbronchial lung cryobiopsy is currently being increasingly considered as a diagnostic tool in ILD. The procedure requires general anesthesia and fluoroscopic

as first-line investigation for the evaluation of mediastinal adenopathy [30].

which is not amenable for EBUS procedure, endoscopic ultrasound-guided fine aspiration (EUS-FNA) can be a potential option; Michael et al. demonstrated in a retrospective study that [31] EUS-FNA was able to diagnose sarcoidosis in 86% of cases (n = 18 of 21) and was able to rule out recurrence of malignancy in 75% (three

*2.2.2 Endobronchial ultrasound-guided transbronchial needle aspiration* 

ate bleeding among a total of 62 patients were seen.

to EBUS-TBNA with TBLB [29].

*2.2.3 Transbronchial lung cryobiopsy (TBLC)*

*(EBUS-TBNA)*

**22**

out of four cases).

guidance for sampling with a cryoprobe [32]. In a retrospective study by Jacob et al., they were able to demonstrate a diagnostic yield of up to 92.6% on a small sample size in the study [33]. The main advantage of TBLC is related to larger biopsy sample in comparison to traditional transbronchial biopsy with associated crushing artifact of the sample. However, TBLC has the limitations related to training and the need for general anesthesia. Moreover, there is a significant risk of complications including pneumothorax and bleeding ranging from 9 to 10% and from 14 to 20%, respectively [34].

Hagmeyer et al. demonstrated that the risk of severe complications can be reduced from 84 to 14% by technical modification of this procedure. Hence, it may prove to be a useful step before consideration of surgical lung biopsy [35].

#### **2.3 Ultrasound (US)-guided biopsy**

The diagnostic workup for sarcoidosis should include the least invasive investigation at the outset of evaluation; thus, neck ultrasound may provide an ideal modality for that purpose. We have demonstrated that a core biopsy of cervical lymph nodes (ranging from 7 to 14 mm in diameter), with no sonographic appearance of being marked was adequate to make a histological diagnosis of sarcoidosis [36]. In this retrospective analysis, we showed that if there were no suitable cervical lymph node for biopsy, an US evaluation and biopsy of abnormal parotid glands may help establish the diagnosis of sarcoidosis [36]. In view of the ease of this procedure and its cost-effectiveness (approximately £1000/= saving in comparison to EBUS-TBNA per patient in the UK), this could potentially be considered as a first-line investigation if appropriate expertise is available. Hence, it is proposed that the diagnostic algorithm as shown in **Figure 5** for the investigation of mediastinal lymphadenopathy should include US-guided core biopsy of cervical lymph nodes +/− parotid glands if deemed abnormal. We envisage that a prospective multicenter study of wider application of this technique would be desirable to generalize the use of this minimally invasive diagnostic modality.

### **2.4 Surgical techniques: cervical mediastinoscopy and video-assisted thoracoscopy (VATS)**

#### *2.4.1 Cervical mediastinoscopy*

Cervical mediastinoscopy (CM) is one of the preferred surgical techniques to evaluate mediastinal lymphadenopathy. The procedure helps to obtain samples from paratracheal and subcarinal lymph nodes. Since the advent of EBUS-TBNA, EUS-FNA, and PET-CT, the frequency of mediastinoscopy as a diagnostic procedure has declined significantly. Moreover, it is reserved when the above techniques have been inconclusive or not feasible due to the location of the enlarged lymph node.

Onat et al. reported the safety of CM and demonstrated that it is a reliable method, in the evaluation of mediastinal lymphadenopathy [37]. In a meta-analysis by Agarwal et al., they reported a diagnostic yield between 82 and 97% for cervical mediastinoscopy [38].

#### *2.4.2 Video-assisted thoracoscopic surgery (VATS)*

VATS biopsy should be considered when there is difficulty in establishing the diagnosis with other less invasive options especially if a specific histological diagnosis would help the prognosis or treatment [39]. The diagnostic yield, sensitivity,

**Figure 5.**

*Diagnostic approach in suspected pulmonary sarcoidosis. EBUS-TBNA, endobronchial ultrasound-guided transbronchial needle aspiration; TBB, transbronchial biopsy; EBB, endobronchial biopsy; VATS, videoassisted thoracoscopic biopsy [36].*

and specificity of VATS reported in a meta-analysis were 92.7% (87.6–95.8%), 91% (89–92%), and 58% (31–81%), respectively [40]. VATS procedures have the advantage of technically enabling multilobed biopsies in comparison to open lung biopsy [41]. Currently, mini-VATS is also being increasingly considered given the less postoperative complications and decreased length of hospital stay [42, 43]. VATS procedure should be done by experienced thoracic surgeons, as there is a potential need for mini-thoracotomy in 25% of cases, to obtain adequate tissue for diagnosis [44]. Furthermore, there is a mortality rate of approximately 2% at 30 days associated with this surgical procedure as demonstrated by a meta-analysis conducted by Wallis et al. [45].
