Randomized comparison of power Doppler ultrasonography-guided core-needle biopsy with open surgical biopsy for the characterization of lymphadenopathies in patients with suspected lymphoma

In the case of clinical suspicion of lymphoma, the histological examination of lymphadenopathy is essential for defining a correct diagnosis and for developing a proper treatment plan [1]. An open surgical biopsy (OSB) is still the “gold standard,” owing to the large amount of tissue obtained [2]. Preoperative evaluation includes (1) a careful and through physical examination, i.e., palpation of superficial lymph node regions performed by a physician experienced in the management of patients with lymphoma; (2) gray-scale ultrasonography scans (US), i.e., a technology that is readily available in clinical practice and is considered to provide sufficient information for selecting the node to be biopsied [1, 2]; and (3) computed tomography (CT), performed to strengthen the suspicion of lymphoma [2]. However, the possible presence of enlarged reactive or necrotic lymph nodes and/or of nonpalpable but histologically significant malignant lymph nodes may impair the success of an OSB. Another limitation is mostly related to patients whose conditions may be too unstable for undergoing general anesthesia and surgical intervention [3]. Thus, a study that has value to decide the primary interventionist diagnostic tool for suspected lymphoma is a clinically important topic. New mini-invasive approaches to this procedure based on imaging-guided methods are now available.

The introduction of the new generation of ultrasonographic and biopsy needle devices, which already have been proven valuable in the management of patients with lymphoma in our cancer center [4‐8], provides the opportunity to develop effective combined diagnostic strategy. The modern US instruments merge tissue harmonic compound, which generates an image from multiple imaging lines that strike the target from different angles [9], with power Doppler (PD) which allows the study of the angioarchitecture of lymph node tissue [5, 6, 8, 10]. Neoplastic angiogenesis such as vessel proliferation (endothelial cell migration and proliferation) and abnormal vascularization (tube formation with stenosis, occlusion, and/or dilation and/or arteriovenous shunts) is recognized as being critical for B cell lymphoma pathogenesis [11, 12]. Power Doppler ultrasonography (PDUS) equipment detects fine flow signals, mimicking an angiography of microvascular intranodal network. The result is a high-resolution quality examination that allows better detection of both superficial and deep-seated malignant lymphadenopathies compared with results obtained with gray-scale US [13]. Regarding biopsy needle devices, the latest Menghini needles have ultrathin sharpened cannula with trocar stylet and automatic aspiration with tiny battery-powered vacuum [14]. These characteristics make particularly effective the needle devices with large gauge [15]. Under PDUS guidance, the tip of cutting needle can be careful positioning into the most significant target, obtaining histological suction of the core of nodal lesion [14‐16]. Nevertheless, few clear indications for performing such procedure are available. The Lugano classification for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma recommend core-needle biopsy when surgical intervention is not possible and to document relapse [2]. However, the existing guidelines are not evidence based, a uniform program for optimal imaging guidance is lacking, and the characteristics of biopsy needle, i.e., gauge, length, tip configurations, and sampling mechanisms, are still a matter of opinion among experts [1, 14, 16]. Thus, this approach requires validation with randomized studies.

Our trial was intended to test the efficacy of PDUS-guided core-needle cutting biopsy (CNCB) compared with OSB as first-line diagnostic approach for pathologic lymphadenopathies in patients with clinical suspicion of lymphoma. The primary endpoint of the study was the sensitivity for diagnosis of malignancy for each of the two interventionist methods, i.e., percutaneous biopsy by using modified Menghini needle under modern US guidance and standard excisional biopsy. Additional endpoints were times to biopsy, rates of biopsy-related complications, and costs.

Routine biopsy of lymphadenopathies by using core-needle under imaging guidance in patients with suspicion of lymphoma is controversial [1, 2]. Usually, such procedures are reserved for lymph nodes that are accessible only with surgical risk or for critical ill patients, and in case of relapse [2]. Most studies on this issue were retrospective, included an imaging support based on traditional radiological tools (such as gray-scale US and CT, which study mostly morphological characteristics, i.e., the dimensional features of lymph node, not distinguishing between viable tumor and inflammation, necrosis and/or fibrosis), and have tested the role of small (≥18-gauge) needle devices with obsolete configurations [16]. Thus, it is reasonable to investigate a front line diagnostic combination of new generation imaging equipment and technologically refined cutting needle with large gauge [15].

Our randomized study was an examination of two different interventionist approaches, one surgery-driven (standard arm) and the other one hematology-driven (experimental arm), in patients with lymphadenopathies clinically suspected for lymphoma. Traditionally, whole lymph nodes are resected when it is necessary to determine whether a lymphadenopathy is lymphoma or some other conditions, such as metastases of a nonhematological tumor [1, 2]. In our trial, the entire decision making process for biopsy in the standard arm was left to the surgeon’s discretion: the selection of the node to be biopsied was based on physical examination and gray-scale US [17]. In the daily diagnostic service of our surgery unit, as in others [21], power Doppler ultrasonographic technology was limited in its availability for routine clinical practice. In the experimental arm, the selection of the node to be biopsied and biopsy itself were exclusively based on the expertise of hematologists. In fact, the hematological unit kept a modern US equipment available and had it run by experienced operators, who were members of the hematological staff trained in diagnostic PDUS [4, 5]. The goal of the study was to maintain optimal accuracy of the diagnostic work-up of lymphadenopathies, while avoiding psychological and physical pain of an unnecessary surgical intervention.

The primary endpoint in this trial, a greater sensitivity with the experimental approach, was proven being the comparison with standard approach significantly advantageous for PDUS-guided CNCB. The number of cases in which a definite diagnosis of malignancy could not be established at first biopsy was almost 8 times higher on standard tissue specimens than core-needle material. As a consequence, the clinicians recommended a re-biopsy (OSB) significantly more often in the standard group than experimental group, also considering the four patients with inadequate samples randomized in the core-needle group (19 vs. 6 cases, respectively; P = 0.006). Not all lymph nodes may be involved by the main disease entity. There is a risk of removing satellite reactive lymph nodes, thus missing the primary diagnosis of a malignant disease present in another node, which is sometimes deeper seated or even seated in a different anatomic area. An affected lymph node may also undergo necrosis and/or steato-fibrotic changes, which could avert the pathologist from the correct diagnosis. These are all potential sources of inaccuracy in standard excisional biopsy [5]. In our study, PDUS technology accurately selected the most suspected target, imaged all nodal lesion clearly, and simultaneously monitored the entire puncture process (in both superficial and deep-seated regions). The cutting needle had a diameter of 1.6 mm with ultrathinner tip and wall, and powered automatic suction. Although the tissue volume obtained by CNCB was smaller than OSB, the experimental method provided enough tissue for architectural-morphologic pattern assessment, immunohistochemical staining, and/or molecular testing (Figs. 2 and 3) [1].

For all secondary endpoints in this trial, the comparison was significantly disadvantageous for excisional biopsy. Compared with PDUS-guided CNCB, standard approach had significantly more waiting time to allocated interventionist procedure, considerably higher amounts of biopsy-related complications (analgesia required for postoperative pain was about 5-fold higher), and extraordinarily higher costs for the National Healthcare System (performance of one biopsy was 24-fold more expensive with standard approach).

Our study suffers from three major limitations. First, this trial was conducted in one single center. Therefore, studies from other institutions are needed to assess (1) interobserver and interequipment PDUS variability; (2) core-needle specimen quality reproducibility, e.g., tissue harvested, size and preservation; and (3) concordance by pathologists in diagnosing and subtyping lymphoma on core-needle material. Second, a bias error could have been committed due to a more accurate selection of nodal target to be biopsied in the core-needle group leading the study toward a better sensitivity for experimental arm than standard arm. A factor that may have a strong influence to explain such bias is the high specialization (derived from long and extensive experience) [4‐8] of hematology team to identify the right lymph node and to biopsy it, as compared to the surgeons. Finally, the rate of failure with PDUS-guided CNCB was 1.6% (6/376 patients randomly allocated to core-needle biopsy procedure). In four patients (those with inadequate samples), stiffened tissue of nodular sclerosis Hodgkin lymphoma (documented at re-biopsy) which was seated in subclavicular area (a particular hindered region) led to the sampling error of CNCB. For the two false negative results (benign lymphoid hyperplasia), the final diagnosis (at second biopsy) was conclusive for small lymphocytic indolent non-Hodgkin lymphoma, suggesting that in some instances, there is a need of a large amount of lymph node tissue for correct histological assessment.

To the best of our knowledge, this study is the first to compare in a randomized fashion the sensitivity of imaging-guided CNCB and OSB in detecting lymphoma. Under optimal study conditions (avoiding patients with obesity), with modern US equipment and an experienced operator, core-needle biopsy is a reliable and cost-effective diagnostic procedure [22]. Histological patterns of lymphoma are recognizable in core material and are useful in diagnosing and subtyping according to the current WHO classification of tumors of haematopoietic and lymphoid tissues [1, 15]. A 16-gauge cutting needle is recommended, and at least two passes yielding two tissue cores, with total length of 30–60 mm should be taken. CNCB is less traumatic and well tolerated by patients. It should be recommended as first-line procedure, for both superficial and deep-seated lymph nodes, for patients with a suspected lymphoma, and not merely for patients with poor medical condition when surgical intervention is not possible or to document relapse.