|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 22, No 18 (September 15), 2004: pp. 3733-3740 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.02.171 Randomized Comparison of Power Doppler Ultrasound-Directed Excisional Biopsy With Standard Excisional Biopsy for the Characterization of Lymphadenopathies in Patients With Suspected LymphomaFrom the Departments of Clinical and Experimental Medicine, Intestinal Surgery, Histopathology, and Laboratory Medicine, CEINGE-Biotecnologie Avanzate, Federico II University Medical School, Naples, Italy Address reprint requests to Bruno Rotoli, MD, Divisione di Ematologia, II Policlinico, Via S Pansini 5, 80131, Naples, Italy; e-mail: rotoli{at}unina.it
PURPOSE: The sensitivity of lymph node excisional biopsy requires validation. Power Doppler ultrasound (US) helps predict the malignant status of lymphadenopathies. We used power Doppler US to select for biopsy the lymph node most suspected of malignancy. PATIENTS AND METHODS: One hundred fifty-two patients having lymphadenopathies with clinical suspicion of lymphoma were divided into two well-matched groups and randomly assigned to undergo either standard or power Doppler US-directed lymph node excisional biopsy. RESULTS: Histology showed a malignancy in 64% of patients in the standard group (lymphoma, 49 patients; carcinoma, two patients) and in 87% of patients in the US-assisted group (lymphoma, 62 patients; carcinoma, one patient). There were significantly fewer biopsy-related complications in the assisted group than in the standard group. During the follow-up of the patients with lymph nodes reported as being reactive, 14 of 29 patients in the standard group were rebiopsied and were found to have lymphoma (13 patients) or carcinoma at the subsequent lymph node histology, whereas none of the patients in the assisted group (nine patients) required a second biopsy. Thus, biopsy provided false-negative results for malignancy in 21% of patients affected by lymphoma in the standard group and never in the assisted group (P < .01). CONCLUSION: Power Doppler US is an accurate tool for screening lymphadenopathies to be removed by excisional biopsy in patients with suspected lymphoma.
In case of clinical suspicion of lymphoma, a lymph node enlargement requires histologic assessment to define a correct diagnosis and to develop a proper treatment plan. Prebiopsy evaluation of enlarged cervical, supraclavicular, axillary, or inguinal lymph nodes is usually left to physical examination alone; a careful and thorough palpation of superficial lymph node regions, performed by a physician experienced in the management of patients with lymphoma, is considered to provide sufficient information to schedule an excisional biopsy.1 However, the possible presence of enlarged reactive or necrotic lymph nodes and of nonpalpable but histologically significant malignant lymph nodes may impair the success of an excisional biopsy.2,3 New approaches to this procedure based on imaging-assisted methods are now available. Power Doppler ultrasound (US) is a recent imaging technique that is able to accurately define the anatomic site of a lymph node, with its morphologic (including size, shape, and hilar and cortical deformation) and vascular characteristics.4,5 Compared with the standard color Doppler, the properties of power Doppler US are homogeneous noise appearance, less direction and velocity dependence, less temporal variance, improved vessel contrast, and higher sensitivity. Power Doppler US clearly assesses in vivo intranodal angioarchitecture, mimicking angiography, distinguishing arterial and venous vessels, and calculating velocimetric parameters of the vessel flow.4–6 Angiogenesis is recognized as being critical for solid tumor growth, invasion, and metastasis. The various steps of neoplastic angiogenesis, such as basement membrane disruption, endothelial cell migration and proliferation, and tube formation, lead to the development of abnormal vascularization, with stenoses, occlusion, and/or dilation and/or arterovenous shunts.7 The findings of increased endothelial cell and vessel proliferation in bone marrow or enlarged lymph nodes pointed to a possible role of neoangiogenesis in the pathogenesis of multiple myeloma or B-cell lymphomas.8,9 With appropriate and standardized methodology,10 power Doppler US has proven useful to identify malignant lesions because it detects more flow signals than gray-scale and color Doppler US, thus better differentiating between benign and malignant superficial lymphadenopathies.4–6,11,12 We performed a randomized comparison of power Doppler US-directed excisional biopsy with standard excisional biopsy to characterize superficial lymphadenopathies in patients with clinical suspicion of lymphoma.
Study Design and Patient Characteristics During the past 4 years, 152 consecutive subjects (82 men and 70 women; median age, 44 years; range, 15 to 82 years) who were referred for superficial lymph node enlargement of unknown origin entered onto the study. Of these patients, 40, 60, and 52 had palpable lymph nodes in a one, two, or three anatomic regions, respectively. Clinical indication to perform an excisional biopsy was the only inclusion criterion. Patients affected by Epstein-Barr virus, cytomegalovirus, herpes simplex virus, rubella, toxoplasma, or tuberculosis infection were excluded. A minority of patients had already had computed tomography scans, and the findings of deep-seated lymph nodes had strengthened the suspicion of a malignant systemic disease. The study was a single-center trial involving two study groups and was approved by the local ethics committee. Patients were randomly assigned to receive lymph node biopsy using one of two methods, standard excisional biopsy (nonassisted group) or excisional biopsy under power Doppler US direction (assisted group). The primary aim of the study was to evaluate the capacity to predict the lymph node status, which was measured in terms of the percentage of cases of malignant involvement detected by power Doppler US-directed excisional biopsy versus standard excisional biopsy. Additional aims were the evaluation of biopsy-related complications and the discovery of a malignant disease during the follow-up of patients who had had the first biopsy negative for malignancy. The overall diagnostic accuracy was defined as the rate of correct patient classification, on the basis of having or not having lymph nodes positive for malignancy during the follow-up. Patients were informed of the aims of the study, the potential results of the procedures, and the meaning of the randomization, and signed a consent form before the operation. All biopsy procedures were performed by one of three surgeons experienced in lymph node resection, according to standard methods.13 To avoid imbalance in infectious risk, patients in both groups received a short course of antibiotic prophylaxis (amoxicillin plus clavulanic acid, 2 g/d orally for 4 days) starting the day of biopsy.
Biopsy Procedure in the Nonassisted Group
Biopsy Procedure in the Assisted Group The main criterion used for selecting the node to be biopsied was the RI value; for each patient, the lymph node with the highest RI mean value was labeled and selected as target for biopsy. When more nodes had similar RI values, additional selection criteria were round shape, hilus absent, and intranodal hypervascularization. In 12 patients, the selected lymph node was studied by repeated power Doppler US assessments on two occasions at a 1-hour interval by the same operator (intraobserver reproducibility) and by another operator unaware of the previous result, always using the same US machine (interobserver reproducibility).17,18 The target area for biopsy was marked on the skin with indelible ink surrounding the probe contour, and the size and deepness of the lymph node were recorded. In the day-hospital regimen or as in-patients and under local or general anesthesia (at surgeon's discretion), the lymph nodes were harvested through skin-crease incision guided by the skin markings indicating the power Doppler US-selected lymph node.
Histopathologic Evaluation
Statistical Analysis
Of the 152 patients randomly assigned to a study group, 80 (53%) received standard excisional biopsy, and 72 (47%) received power Doppler US-directed excisional biopsy (a few patients were lost to follow-up after randomization and before biopsy, and this occurred by chance more frequently in the assisted group). Both groups were well matched at entry with respect to age and sex (Table 1). A total of 116 lymph nodes were removed and examined from the 80 patients in the nonassisted group, whereas only one lymph node was removed from each of the 72 patients in the assisted group. There was no significant difference between the two groups regarding the size of the lymph nodes removed. Patients in the nonassisted group had slightly more cervical and inguinal biopsies, whereas patients in the assisted group had slightly more supraclavicular and axillary biopsies.
Histology Of the 80 patients in the nonassisted group, 51 (64%) had lymph nodes positive for malignancy (B-cell non-Hodgkin's lymphoma [NHL], 26 patients; Hodgkin's disease [HD], 23 patients; and metastatic carcinoma, two patients), and 29 (36%) had lymph nodes negative for malignancy (described as benign lymphoid hyperplasia in all patients, with steato-fibrotic and/or necrotic changes in 18 of the patients). Of the 72 patients in the assisted group, 63 (87.5%) had lymph nodes positive for malignancy (B-cell NHL, 29 patients; T-cell NHL, four patients; HD, 29 patients, and metastatic carcinoma, one patient), and nine (12.5%) had lymph nodes negative for malignancy (benign lymphoid hyperplasia). There was complete agreement among the three pathologists on the histologic diagnosis (Table 2).
Overall, the 38 patients with lymph nodes negative for malignancy (defined as reactive or inflammatory) were observed for a median of 11 months (range, 1 to 40 months). During the follow-up, for 14 of 29 patients in the nonassisted group, the clinicians required a second lymph node biopsy, and a malignancy was finally detected. The second biopsy, which was performed after a median of 4 months (range, 1 to 9 months) from the first biopsy, demonstrated HD in seven patients, NHL in five patients, melanoma in one patient, and Rosai-Dorfman disease in one patient (with a severe clinical course requiring cytotoxic treatment as a lymphoma; Table 3). In contrast, none of the nine patients who had had diagnosis of a benign lesion at the first biopsy in the assisted group required a second biopsy or developed a malignancy, with a median follow-up of 21 months (range, 9 to 40 months; P = .01; Fig 1).
Therefore, the overall diagnostic accuracy of lymph node status in the nonassisted group was 82% (ie, results accurate in 66 of 80 patients), with a sensitivity of 78% (51 of 65 patients with lymph nodes positive for malignancy were identified) and a false-negative rate of 22% (14 of 65 patients with lymph nodes positive for malignancy were not identified). By contrast, the overall diagnostic accuracy and the sensitivity of the lymph node status in the assisted group were 100% (ie, no false-negative cases; Fig 2). There was a statistically significant difference between the two groups regarding diagnostic accuracy and sensitivity (P < .001).
Power Doppler US Results The average time required for power Doppler US examination was 30 minutes (range, 20 to 50 minutes). Intraobserver and interobserver reproducibility of intranodal vascular mapping and RI measurements were excellent. Of the 12 lymph nodes tested for reproducibility, 11 (91%) were classified identically by the same observer at two power Doppler US examinations 1 hour apart (r = 0.9), and 10 (83%) were classified identically by observers A and B (r = 0.88).
For each lymph node removed, shape and size were classified identically by the US operator and the pathologist. This finding consistently demonstrated that the surgeon had removed the indicated lymph node. Depth of the selected lymph nodes was between 1 and 4 cm. As for morphologic characteristics, malignant lymph nodes had a median of the long axis of 2 cm (range, 0.4 to 7.0 cm), were round in 50 cases and oval in 13 cases, and had hilus absent in 42 cases and present in 21 cases. Vascular mapping of malignant lymph nodes was mixed in 30 cases, chaotic in 24 cases, peripheral in six cases, and central/hilar in three cases (Fig 3). There were nine lymph nodes (12.5%) classified as suspected of malignancy by power Doppler US, which were shown to be reactive at histology. Of these nodes, the median of the long axis was 1.9 cm (range, 0.8 to 3.0 cm), six were oval, three were round, five were hilus present, and four were hilus absent; vascular mapping was of the hilar type in four, mixed in three, and peripheral in two. The median RI value of aggressive NHL (0.85; range, 0.7 to 0.98) was significantly (P < .01) higher than the median values of HD (0.74; range, 0.6 to 0.96), indolent NHL (0.71; range, 0.68 to 0.87), and benign lymphoid hyperplasia (0.68; range, 0.6 to 0.77; Fig 4). The metastatic carcinoma RI value was 0.8. Overall, the positive predictive value for malignancy of the parameters studied was as follows: for gray-scale US: round shape, 79%; hilus absent, 67%; and size
Biopsy Procedures and Complications Sixteen patients underwent biopsy (axillary, n = 6; supraclavicular, n = 6; and cervical, n = 4) under general anesthesia, with an average hospitalization of 2.5 days (all in the nonassisted group). All other patients underwent biopsy in a day-hospital regimen under local anesthesia. The procedures were equally distributed among the three surgeons; no surgeon had more complications compared with the others. Patients who received non-US-directed biopsy had significantly more pain, numbness, or paresthesia and larger scars than patients who underwent US-directed biopsy. Moreover, 11 patients in the nonassisted group and no patient in the assisted group developed lymphorrhea; all patients recovered from the complication after one or more liquid aspirations (between 20 and 50 mL for each patient; Table 4).
The aim of this study was to determine the ability of power Doppler US to predict the presence of intranodal malignancy, thus improving the diagnostic accuracy of excisional biopsy in patients who have enlarged lymph nodes with clinical suspicion of lymphoma. The enlargement may often involve more than one lymph node; because the biopsy procedure has only a diagnostic purpose, the surgeon will select the easiest to reach lymph nodes (usually those seated superficially in a cervical or inguinal region). However, 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.23 An affected lymph node may also undergo necrosis and/or steato-fibrotic changes, which could avert the pathologist from the correct diagnosis.3 These are all potential sources of inaccuracy in standard excisional biopsy. Preliminary reports indicating that power Doppler US might predict the presence of malignancy in superficial or deep-seated lesions have recently appeared.4–6,11,24 In the present randomized study, we used power Doppler US to identify as biopsy target the most suspected area of malignancy. The selected lymph node was fully characterized as far as anatomic location, depth, size, shape, hilus alterations, and intranodal angioarchitecture were concerned. Intranodal hypervascularization and arterial vessels with relatively high RI value fulfilled the selection requirements. Lymph nodes showing no perfusion or low vascularization (tiny flow signals), likely caused by steato-fibrotic and/or necrotic changes of intranodal tissue, were avoided. The US examination was carried out by members of the hematology staff trained in diagnostic ultrasonography; the low intraobserver and interobserver variability of power Doppler assessments proved the high reliability of the examination. The result of this study shows that power Doppler US-directed excisional biopsy is significantly more effective in identifying lymph nodes positive for malignancy than standard excisional biopsy. We would like to underline the excellent tissue samples obtained in the US-directed group, which were informative and successful (tissue adequate for a correct histologic diagnosis), establishing the specific etiology of the enlargement, in all instances. Event-free survival of patients with negative biopsy for malignancy was significantly better in the assisted group than in the nonassisted group. Fourteen patients, in whom a few months earlier a non-US-directed biopsy had provided results of a benign adenopathy, were found to have a malignant disease involving other lymph nodes. Of them, 11 patients underwent rebiopsy in an anatomic area different from that biopsied the first time. It is reasonable to assert that the malignancy was already present at the time of the first biopsy and could have been detected by selecting a more significant lymph node had a power Doppler US study been performed. The higher prevalence of biopsy in inguinal areas in the nonassisted group may not be incidental. Supraclavicular and axillary nodes are often deep seated and less detectable by physical examination and, thus, are less frequently selected by the clinician or the surgeon as target for the biopsy; in contrast, these nodes can be more specific for the basic malignant disease and, thus, more frequently selected for the biopsy by the US operator. By summing the number of patients who received diagnosis of malignancy at the first or second biopsy in the nonassisted group (51 + 14 = 65 of 80 patients), we found a percentage of malignancy similar to that observed in the assisted group (63 of 72 patients), in whom all diagnoses were made by a single biopsy. These data confirm that standard excisional biopsy may carry a significant number of false-negative results. The false-negative rate was slightly higher in HD than in NHL patients; it was also higher for inguinal nodes (30%) compared with other sites (axillary, 17%; cervical, 8%; and supraclavicular, 0%). Quantitative assessment of intranodal vascularization provided relevant information. High RI values (rapid systolic flow and poor telediastolic component) were predictive of an aggressive malignant disease (aggressive NHL or metastatic carcinoma), whereas lower RI values were found in HD, indolent NHL, and benign lymphoid hyperplasia. Interestingly, mantle-cell lymphoma, a small-cleaved lymphocytic lesion with a severe clinical course, which was considered as a low-grade lymphoma until a few years ago,22 showed RI values in the range of aggressive diseases (median RI, 0.88) that were even higher than the RI values of diffuse large B-cell lymphoma (median RI, 0.8), grade 3 follicular lymphoma (median RI, 0.8), and other B- or T-cell aggressive lymphomas (median RI, 0.85; Fig 4). The mechanism by which lymphoma lesions have such diversified angiopatterns is still unclear. In aggressive NHLs, the magnitude of neoangiogenesis is probably the most relevant factor. In situ data obtained by transmission electron microscopy in B-cell NHL showed that angiogenesis, defined as formation of new vessels and remodeling of existing vessels, increases with tumor progression (in terms of increasing malignancy grading); the network of new vessels with irregular diameter and defective wall structure leads to abnormal flow and, hence, to the aberrant Doppler spectral patterns.9 Similar findings were reported in bone marrow during progression from monoclonal gammopathy of undetermined significance to multiple myeloma.8 In indolent NHL and in HD, this mechanism could be less operative, making the differentiation from reactive or inflammatory lesions less clear cut. In such instances, power Doppler US findings of round shape, hilus absent, and intranodal hypervascularization with chaotic feature may be additional selection criteria, as described by other authors.5,11 In a small fraction of patients in the assisted group (12.5%), power Doppler US examination suggested malignancy that was neither confirmed subsequently at histology nor occurred during the follow-up. This means that power Doppler US study is highly sensitive but not absolutely specific. Power Doppler US-directed excisional biopsies were carried out always in a day-hospital regimen and under local anesthesia, whereas some patients in the nonassisted group needed general anesthesia and ward admission. The better tolerance of US-directed biopsies (less pain, less swelling, and more acceptable aesthetic scars) can be attributed to the perfect knowledge by the surgeon of the site and depth of the node to be removed, which lead to a precise incision and to the removal of a single node, thus avoiding larger cuts and intraoperative maneuvers. In conclusion, our study provides evidence justifying the use of power Doppler US assistance as part of the work-up before performing a biopsy of superficial lesions suspected of lymphoma. This method improves the diagnostic accuracy and safety of excisional biopsy for the characterization of lymphadenopathies. It reliably provides adequate tissue for a correct histologic diagnosis, obviating the risk of underdiagnosis, which may cause a harmful diagnostic delay, and reducing postbiopsy morbidity and hospitalization costs.
The authors indicated no potential conflicts of interest.
Supported by Associazione Italiana contro le Leucemie (Salerno, Italy), INTAS, Associazione Italiana per la Ricerca sul Cancro (Milano, Italy), Consiglio Nazionale della Ricerca PF Biotecnologie (Roma, Italy), Ministero dell'Università e della Ricerca Scientifica e Tecnologica-COFIN (Roma, Italy), and Regione Campania, Italy. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Aisenberg AC: Problems in Hodgkin's disease management. Blood 93:761–779, 1999 2. Gerrits CJH, van Overhagen H, van Lom K, et al: Ultrasound examination of pathological cervical lymph nodes in patients with non-Hodgkin's lymphoma and Hodgkin's disease. Br J Haematol 88:626–628, 1994[Medline] 3. Young NA, Al-Saleem TI, Ehya H, et al: Utilization of fine-needle aspiration cytology and flow cytometry in the diagnosis and subclassification of primary and recurrent lymphoma. Cancer 84:252–261, 1998[CrossRef][Medline] 4. Wu C-H, Hsu M-M, Chang Y-L, et al: Vascular pathology of malignant cervical lymphadenopathy. Qualitative and quantitative assessment with power Doppler ultrasound. Cancer 83:1189–1196, 1998[CrossRef][Medline]
5. Wu C-H, Chang Y-L, Hsu W-C, et al: Usefulness of Doppler spectral analysis and power Doppler sonography in the differentiation of cervical lymphadenopathies. Am J Roentgenol 171:503–509, 1998 6. Tschammler A, Beer M, Hahn D: Differential diagnosis of lymphadenopathy: Power Doppler vs color Doppler sonography. Eur Radiol 12:1794–1799, 2002[CrossRef][Medline]
7. Folkman J: Clinical applications of research on angiogenesis. N Engl J Med 333:1757–1763, 1995
8. Vacca A, Ribatti D, Presta M, et al: Bone marrow neovascularization, plasma cell angiogenic potential, and matrix metalloproteinase-2 secretion parallel progression of human multiple myeloma. Blood 93:3064–3073, 1999 9. Crivellato E, Nico B, Vacca A, et al: B-cell non-Hodgkin's lymphomas express heterogeneous patterns of neovascularization. Haematologica 88:671–678, 2003[Abstract] 10. Giovagnorio F, Caiazzo R, Avitto A: Evaluation of vascular patterns of cervical lymph nodes with power Doppler sonography. J Clin Ultrasound 25:71–76, 1997[CrossRef][Medline] 11. Dragoni F, Cartoni C, Pescarmona E, et al: The role of high resolution pulsed and color Doppler ultrasound in the differential diagnosis of benign and malignant lymphadenopathy. Cancer 85:2485–2490, 1999[CrossRef][Medline]
12. Bude RO, Rubin JM: Power Doppler sonography. Radiology 200:21–23, 1996 13. Suramme F, Waltieg A, Emering C: Encyclopedie Medico-Chirurgicale. Editions Scientifiques et Mèdicales. Paris, France, Elsevier, 2001
14. Picardi M, Martinelli V, Ciancia R, et al: Spleen volume measurement by ultrasound scan in patients with thrombocytosis: A prospective study. Blood 99:4228–4230, 2002
15. Picardi M, Del Vecchio L, De Renzo A, et al: Ultrasound-guided fine needle aspiration cytology combined with flow cytometric immunophenotyping for rapid characterization of deep-seated non-Hodgkin's lymphoma recurrence. Haematologica 88:356–358, 2003 16. Thompson RS, Trudinger BJ, Cook CM: Doppler ultrasound wave-form indices: A/B ratio, pulsatility index and Pourcelot ratio. Br J Obstet Gynaecol 95:581–588, 1988[Medline] 17. Chinn S: Repeatability and method comparison. Thorax 46:454–456, 1991[Medline] 18. Sacerdoti D, Gaiani S, Buonamico P, et al: Interobserver and interequipment variability of hepatic, splenic and renal arterial Doppler resistance indices in normal subjects and patients with cirrhosis. J Hepatol 27:986–992, 1997[CrossRef][Medline]
19. Harris NL, Jaffe ES, Stein H, et al: A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood 84:1361–1392, 1994
20. Harris NL, Jaffe ES, Diebold J, et al: Lymphoma classification—From controversy to consensus: The REAL and WHO classification of lymphoid neoplasms. Ann Oncol 11:3–10, 2000
21. Pileri SA, Ascani S, Sabattini E, et al: The pathologist's view point. Part I—Indolent lymphomas. Haematologica 85:1291–1307, 2000
22. Pileri SA, Ascani S, Sabattini E, et al: The pathologist's view point. Part II—Aggressive lymphomas. Haematologica 85:1308–1321, 2000
23. Gobbi PG, Broglia C, Maffè CG, et al: Lymphomatous superficial lymph nodes: Limitations of physical examination for accurate staging and response assessment. Haematologica 87:1151–1156, 2002 24. Hosoki T, Mitomo M, Chor S, et al: Visualization of tumor vessels in hepatocellular carcinoma: Power Doppler compared with color Doppler and angiography. Acta Radiol 38:422–427, 1997[Medline] Submitted February 25, 2004; accepted June 9, 2004.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
2 (P was expressed as Yates corrected) and Student's t test, analysis of variance with Bonferroni correction, Pearson correlation, and log-rank test (to compare curves representing event-free survival), were performed with SPSS for Windows software (version 9.0; SPSS, Chicago, IL). 
2 cm, 48%; and for vascular mapping by power Doppler US: mixed type, 48%; chaotic type, 38%; peripheral type, 10%; and central/hilar type, 5%. As for RI, considering a cutoff value 
