Systematic review of the effectiveness of fine-needle aspiration and/or core needle biopsy for subclassifying lymphoma.
Despite this historic trend to perform FNAC/CNB in preference to excisional biopsies when lymphoma is highly suspected, oncologists frequently question whether any method other than an excisional biopsy is adequate. Furthermore, this historic trend to greater reliance on FNAC/CNB runs counter to the recent recommendations of the European Society of Medical Oncologists, (2) the British Committee for Standards in Haematology, (3) and the National Comprehensive Cancer Network (NCCN), an alliance of 23 of the world's leading cancer centers. The NCCN4 clinical practice guidelines in oncology are quite explicit regarding the preference for excisional biopsies at the time of initial diagnosis. For example, with regard to most non-Hodgkin lymphoma (NHL) entities (follicular lymphoma, diffuse large B-cell lymphoma, marginal zone lymphoma, mantle cell lymphoma), current NCCN guidelines state, "An FNA or core needle biopsy alone is not generally suitable for the initial diagnosis of lymphoma." With regard to follicular lymphoma, the guidelines further state, "Histologic grading cannot be performed on an FNA." Clearly, expert recommendations and common clinical practice differ substantially.
The substantial literature regarding the use of FNAC/CNB for the diagnosis of lymphoma only partially addresses this disparity. Publications on FNAC/CNB for the diagnosis of lymphoma are almost exclusively case series at single institutions, and many focus on the correlation of a subset of FNAC/CNB findings with those of excisional biopsies. Although this literature suggests that the correlation is typically good, oncologists also ask how often FNAC/CNB must be followed up with an excisional biopsy because sampling or diagnostic specificity was deemed insufficient to optimally guide management. To assess the effectiveness of FNAC/CNB to provide sufficient information for therapeutic decision making, we combined data from multiple studies to address (1) how frequently FNAC/CNB results provided a specific WHO classification of lymphoma; (2) whether combining FNAC and CNB increased the rate of fully subclassified lymphomas; and (3) whether the advent of many new diagnostic methods, especially FC and molecular diagnostic assays, has substantially altered the rate at which lymphomas are fully subclassified when sampled by FNAC/ CNB procedures.
Articles were identified initially based on the references of a recent case series describing correlations between FNAC/CNB combined with ancillary studies and traditional surgical biopsy of lymph nodes. (5) The reference list of each retrieved article was reviewed for any additional references. Subsequently, a PubMed search was performed (May 2013) that combined "lymphoma, diagnosis" with numerous search terms including "fine needle aspirate," "cytology," and "core needle biopsy." Forty-two English-language publications were included based on the following 3 criteria: (1) studies including FNAC and/or CNB with any ancillary techniques (immunohistochemistry, immunocytochemistry, FC, fluorescence in situ hybridization, cytogenetics, or molecular diagnosis) performed on suspected lymphoma cases; (2) studies specifying lymphoma subtype, or studies describing a rate at which the methods failed to provide a diagnosis sufficient to guide medical management; and (3) exclusion of case studies, review articles, and letters (Tables 1 and 2).
Diagnoses were then classified as actionable or nonactionable. We included as actionable any diagnosis with subclassification in any system (WHO, Kiel, European Organisation for Research and Treatment of Cancer, working formulation, Rappaport) or that used verbiage sufficiently similar to that used in these schemes that a subclassification was strongly implied. Some publications either stated or implied full subclassification for a subset of lymphoma diagnoses without naming the specific entities. (5-7) We accepted these designations as fully classified and therefore providing optimally actionable diagnostic information (these diagnoses are included in Table 3 as "unspecified subclassification," where they comprise about 7% of all subclassified lymphomas). Regardless of NCCN guidelines, we also accepted grading of follicular lymphoma as performed by FNAC as a full subclassification and thus actionable. In short, whenever the diagnosis in the publication appeared to be ambiguous for potentially trivial reasons, or whenever it appeared that the pathologist felt the diagnosis to be congruent with full subclassification in any system, we accepted the diagnosis as actionable.
The fully subclassified lymphomas were then grouped according to specific WHO entities. Because lymphoma classification systems have changed significantly during the time period spanned by the publications, we reclassified some entities according to the more recent WHO guidelines. (1) Note that reclassification of diagnoses into WHO 2008 entities did not affect whether those diagnoses were designated as actionable or nonactionable.
Nonactionable diagnoses included those lacking full sub-classification and those described as "inadequate" or "inconclusive." Nonactionable lymphoma diagnoses included the following terms: low-grade NHL; high-grade NHL; B-cell NHL, unclassified; T-cell NHL, unclassified; NHL, unclassified; and unclassified lymphoma, Hodgkin lymphoma versus NHL. Final diagnoses of "malignant neoplasm," "lymphoma versus carcinoma or sarcoma," "suggestive of," or "suspicious for" were included as "inadequate/inconclusive."
Forty-two studies published between 1989 and 2012 fulfilled the inclusion criteria (Table 1). Each study combined FNAC and/or CNB with one or more methods (immunohistochemistry, immunocytochemistry, or FC). Some studies also used fluorescence in situ hybridization, cytogenetics, or molecular diagnosis (Table 2). The 42 studies included 5707 specimens from 5572 patients, all of whom were selected from institutional records. The median number of patients included in each study was 85 (range, 12-1119). Of the 42 studies, 7 (18%) were prospective, (8-14) whereas the remainder were retrospective. Only 1 of the 7 prospective studies reported using power calculations to predefine size. (11) Ten studies analyzed biopsy results from consecutive samples. (5,9,12,14-20) Twenty-five studies characterized their case selection criteria as "all suspected lymphoma cases," or also included cases diagnosed as inadequate or inconclusive. (5,8,9,11,12,14-33) We designated these 25 studies, which reported all results performed on "suspected lymphoma" cases regardless of the diagnoses obtained, as "intent-to-diagnose" (ITD) (Table 1).
Of the 5707 total specimens, 2967 (52%) were diagnosed as lymphoma (Table 3). Of the NHLs, 287 (11%) were classified as low-grade NHL, high-grade NHL, or NHL, unclassified; 70 lymphomas (2%) were unclassifiable as either Hodgkin lymphoma or NHL; and 824 total cases (14% of the total number of specimens) were either inadequate or inconclusive.
To assess the ability of FNAC and/or CNB to render a diagnosis sufficient to optimally guide initial patient management, we grouped the diagnoses of each study into actionable and nonactionable categories, as described in "Methods." The 42 studies had a median fraction of actionable diagnoses of 74% (Figure 1). Of the nonactionable diagnoses, 56% were inadequate/inconclusive, and 44% consisted of insufficiently subclassified lymphomas. Because some of these studies appeared to have included cases only after a diagnosis of lymphoma was confirmed (thus potentially underestimating the rate of inadequate/inconclusive results), we reassessed the subgroup of 25 ITD studies. A similar median fraction of actionable diagnoses was found (76%).
Neither the choice of sampling method (FNAC only, CNB only, FNAC + CNB) nor the addition of specific ancillary methods (FC, molecular diagnosis, cytogenetics) affected the fraction of nonactionable diagnoses (Figure 2, A). Similar results were seen when the analysis was limited to the 25 ITD studies (Figure 2, B).
In determining whether the biopsy method affected the rate of inadequate/inconclusive diagnoses (ie, those cases not diagnosed specifically because of poor sample quality), we limited our analysis to the 25 ITD studies. No significant effect of biopsy method on the inadequate/inconclusive diagnosis rate was seen, with each method or combination of methods yielding nearly identical rates (data not shown).
Given the evolution of diagnostic methodologies over time, we also asked whether the median fraction of nonactionable diagnoses decreased as a function of the publication year. No trend in the fraction of nonactionable diagnoses was seen during the 25 years spanned by all the studies (Figure 1).
We have reviewed the literature concerning the use of FNAC/CNB to diagnose and subclassify lymphoma, focusing on the rate at which these methods result in full subclassification of lymphomas adequate to guide subsequent management. With one exception, (11) this literature consists of retrospective case series based on reviews of institutional records, and emphasizes diagnostic accuracy rather than rates of achieving subclassification. We divided the diagnoses into actionable and nonactionable categories, based on whether the results could optimally guide management for a newly diagnosed patient without the need for repeat diagnostic procedures. The 42 studies had a median rate of actionable diagnoses of 74%. In contradistinction to the expert guidelines and because this is a subject of significant controversy within the pathology community, we accepted grading of follicular lymphoma by FNAC/CNB as actionable. However, adherence to NCCN guidelines would make these diagnoses nonactionable, reducing the median rate of actionable diagnoses achieved by FNAC/ CNB to 66%.
In the setting of recurrent lymphoma, a specific sub-classification is often not needed to guide therapy. Including less-specific lymphoma diagnoses as actionable increases the median actionable diagnosis rate to 87% (within the ITD studies). This represents a best-case scenario for FNAC/ CNB use in the setting of recurrent, rather than de novo, lymphoma.
Given the extended period spanned by the publications, we also asked if the ability of FNAC/CNB to subtype lymphomas improved with more widespread practice and the increased availability of ancillary methods, particularly FC and molecular diagnostics. No discernible trend during 25 years was seen. Although the diagnosis of entities characterized by specific genetic lesions, such as mantle cell lymphoma and ALK-positive anaplastic large cell lymphoma, has been simplified by ancillary testing modalities, other entities (such as nodal marginal zone lymphoma) lack such pathognomonic features. The observation that the rate of diagnostic success has not substantially increased during 25 years suggests that the increasing use of ancillary techniques (immunohistochemistry, FC, and molecular diagnosis) only occasionally compensates for the loss of diagnostic specificity inherent in limited sampling, and that sub-classification is becoming ever more complex with the discovery of new and clinically significant subtypes of NHL.
Although the literature has suggested that combining CNB with FNAC results in greater accuracy, our aggregate review suggests that the combination of approaches does not appreciably increase the rate at which it is possible to fully subclassify a lymphoma. This disparity highlights the distinction between accuracy (where the results of FNAC/ CNB are compared with those of an excisional biopsy) and reliability (where the likelihood of achieving an actionable diagnosis is assessed). Although the combination of FNAC and CNB is almost certainly advantageous in selected cases, the lack of an overt trend suggests that the number of cases for which it is critical to obtain a sample by both modalities is probably quite small. Nonetheless, it seems prudent to encourage both to be obtained whenever possible in order to maximize both accuracy and reliability.
We have not attempted to address diagnostic accuracy because we found that the definition of accuracy varied highly among the publications and the data were not available to calculate these in a uniform manner. Regardless, all the publications based on single-institution case series report or imply that FNAC and/or CNB are highly accurate. A striking counterexample is the sole publication describing centralized review of specimens submitted for a clinical trial, in which investigators report an accuracy for FNAC alone of 12%.6 This large and meticulously structured study concluded that FNAC-based diagnoses are "not helpful, not cost effective, and in addition may misguide treatment." Additional studies with a similar design (using centralized review of excisional biopsies and FNAC/CNB) are needed to assess the reproducibility of this finding.
The management options available in community practice for the various NHLs have diverged so widely in the last decade that it is now clearly preferred to distinguish among the various low-grade NHLs or among the various higher-grade NHLs. For example, the presence of a TP53 deletion carries profound therapeutic implications when seen in chronic lymphocytic leukemia/small lymphocytic lymphoma (eg, allogeneic transplant), but has no defined meaning in marginal zone lymphoma, an entity that is often CD5 positive and therefore easily confused for chronic lymphocytic leukemia/small lymphocytic lymphoma based on FC and FNAC. A diagnosis specifically of marginal zone lymphoma, as opposed to follicular lymphoma or chronic lymphocytic leukemia/small lymphocytic lymphoma, may prompt subsequent studies for microbial entities such as hepatitis C virus, Helicobacter pylori, or others, and in rare cases potential therapy with antiviral agents. A diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma could allow therapy with a Bruton tyrosine kinase inhibitor, or with other recently approved monoclonal antibodies for this disease specifically (eg, ofatumumab or obinotuzumab). Recent advances in the therapy of high-grade B-cell NHLs have made subclassification critical to the selection of induction therapies, specifically dose-adjusted R-EPOCH (Rituximab-etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) for Burkitt lymphoma and primary mediastinal large B-cell lymphoma. Similarly, therapies for aggressive T-cell malignancies have also diverged. Brentuximab vedotin has a Food and Drug Administration label for treatment of relapsed anaplastic large cell lymphoma (whether ALK negative or ALK positive) but not for peripheral T-cell lymphoma, not otherwise specified. Failure to classify a tumor as ALK-negative anaplastic large cell lymphoma could deny a therapy that appears to be a highly effective bridge to stem cell transplantation. In summary, in routine community practice in the United States in 2014, precise subclassification among NHLs has profound implications for the management plan for a significant fraction of patients.
Although we defined actionable simply as a full subclassification (by any system), practicing pathologists and clinicians recognize that these classifications do not necessarily capture all the information needed to plan therapy, and on the contrary, sometimes require distinctions that may not be currently relevant to therapeutic planning. Our interpretation is predicated on the assumption that full subclassification by the most current consensus system is the best surrogate for providing the optimal diagnostic information to inform the patient's prognosis and the oncologist's therapeutic options.
The choice of FNAC/CNB or excisional biopsy is guided by numerous considerations, which include reliability (will there be a definitive diagnosis?), accuracy (will the diagnosis be correct?), turnaround time (is a diagnosis needed urgently?), morbidity, cost-effectiveness, and patient compliance. As noted, all studies of accuracy reviewed here but one have been descriptions of single-institution experiences, and the single study associated with a multi-institution clinical trial uniquely suggested a dismal accuracy. (6) Here, we have specifically addressed reliability and find that FNAC/ CNB yields a definitive diagnosis about 65% to 75% of the time. Another consideration that leads to the selection of FNAC/CNB over excisional biopsy as a diagnostic approach is urgency and clinical instability. However, even when a diagnosis is required urgently, very strong consideration should be given to an excisional biopsy, because in about a quarter of cases, FNAC/CNB will fail to yield an actionable diagnosis, in turn further delaying therapy. Thus, despite the apparent advantages of FNAC/CNB in terms of compliance and decreased morbidity, the considerations that drive the current expert opinion, as articulated in the NCCN guidelines, to strongly encourage an excisional approach are significant. (4)
Please Note: Illustration(s) are not available due to copyright restrictions.
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John K. Frederiksen, MD, PhD; Meenal Sharma, MD; Carla Casulo, MD; W. Richard Burack, MD, PhD
Accepted for publication February 14, 2014.
From the Department of Pathology and Laboratory Medicine (Drs Frederiksen, Sharma, and Burack) and the Division of Hematology and Oncology, Department of Medicine (Dr Casulo), University of Rochester Medical Center, Rochester, New York. Dr Frederiksen is now with the Department of Pathology, University of Michigan, Ann Arbor.
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: W. Richard Burack, MD, PhD, Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, NY 14642 (e-mail: Richard_Burack@ urmc.rochester.edu).
Caption: Figure 1. Fraction of nonactionable diagnoses associated with each of the 42 studies included in the present analysis, plotted as a function of publication year. Circles, squares, and triangles denote studies that used fine-needle aspiration cytology (FNAC) only, core needle biopsy (CNB) only, or both FNAC and CNB, respectively. Closed symbols denote studies that also used flow cytometry. The solid gray line and the dashed black lines mark the median nonactionable rate and the center 2 quartiles, respectively.
Caption: Figure 2. A, Box-and-whisker plot (boxes are central 2 quartiles, divided by the median; average is small horizontal black bar) showing the fraction of nonactionable diagnoses for all 42 included studies as a function of method and/or ancillary technique. B, Analogous box-and-whisker plot for the 25 intent-to-diagnose studies. Abbreviations: CG, cytogenetics; CNB, core needle biopsy; FC, flow cytometry; FISH, fluorescence in situ hybridization; FNAC, fine-needle aspiration cytology; MD, molecular diagnostics.
Table 1. Study Characteristics No. of Source, y Location Patients Liliemark et al, (34) 1989 Europe 34 Sneige et al, (33) 1990 United States 212 Sneige et al, (14) 1991 United States 50 Sapia et al, (32) 1995 Argentina 17 Ben-Yehuda et al, (35) 1996 Asia 100 Hughes et al, (36) 1998 United States 12 Jeffers et al, (37) 1998 Europe 46 Young et al, (38) 1998 United States 87 Ravinsky et al, (31) 1999 Canada 40 Mayall et al, (20) 2000 New Zealand 73 Meda et al, (30) 2000 United States 275 Siebert et al, (29) 2000 United States 60 Demharter et al, (19) 2001 Europe 126 Dong et al, (39) 2001 United States 129 Liu et al, (18) 2001 United States 117 Ribeiro et al, (28) 2001 United States 38 Mourad et al, (40) 2003 Asia 73 Zeppa et al, (27) 2004 Europe 307 Landgren et al, (13) 2004 Europe 103 Hehn et al, (6) 2004 United States 99 Gong et al, (7) 2004 United States 74 Ravinsky et al, (41) 2005 Canada 28 Li et al, (26) 2005 Asia 80 Dey et al, (42) 2006 Asia 48 Mathiot et al, (12) 2006 Europe 74 Venkatraman et al, (43) 2006 Europe 33 De Kerviler et al, (11) 2007 Europe 180 De Larrinoa et al, (10) 2007 Europe 102 Lachar et al, (17) 2007 United States 101 Barroca et al, (9) 2008 Europe 113 Loubeyre et al, (16) 2009 Europe 112 Pfeiffer et al, (8) 2009 Europe 45 Huang et al, (44) 2010 Asia 154 Kuvezdic et al, (25) 2010 Europe 248 Pedote et al, (24) 2010 Europe 64 Senjug et al, (45) 2010 Europe 50 Yuan and Li, (15) 2010 Asia 1119 Zeppa et al, (23) 2010 Europe 446 Amador-Ortiz et al, (5) 2011 United States 263 Burke et al, (46) 2011 Europe 83 Metzgeroth et al, (22) 2012 Europe 101 Stacchini et al, (21) 2012 Europe 56 Total 5572 Source, y Case Selection Criteria Liliemark et al, (34) 1989 Diagnostic of NHL Sneige et al, (33) 1990 All suspected lymphomasa Sneige et al, (14) 1991 All suspected lymphomas Sapia et al, (32) 1995 Patients with lAd Ben-Yehuda et al, (35) 1996 Diagnostic of lymphoma Hughes et al, (36) 1998 Diagnostic of non-LBL NHL Jeffers et al, (37) 1998 Diagnostic/suspicious for NHL/BRH Young et al, (38) 1998 Diagnostic of lymphoma/BRH Ravinsky et al, (31) 1999 All suspected lymphomas Mayall et al, (20) 2000 All suspected lymphomas Meda et al, (30) 2000 All suspected lymphomasa Siebert et al, (29) 2000 All suspected lymphomas Demharter et al, (19) 2001 All suspected lymphomas Dong et al, (39) 2001 Diagnostic of lymphoma Liu et al, (18) 2001 All suspected lymphomas Ribeiro et al, (28) 2001 All suspected lymphomas Mourad et al, (40) 2003 Diagnostic of NHL Zeppa et al, (27) 2004 Lymphoproliferative processes Landgren et al, (13) 2004 Diagnostic of lymphoma Hehn et al, (6) 2004 Diagnosis of lymphoma or LAD Gong et al, (7) 2004 Diagnostic/suspicious for NHL Ravinsky et al, (41) 2005 Diagnostic of lymphoma Li et al, (26) 2005 All suspected lymphomas Dey et al, (42) 2006 Diagnostic/suggestive of NHL Mathiot et al, (12) 2006 All suspected lymphomas Venkatraman et al, (43) 2006 Diagnostic of NHL/BRH De Kerviler et al, (11) 2007 All suspected lymphomas De Larrinoa et al, (10) 2007 Diagnostic of lymphoma Lachar et al, (17) 2007 All suspected lymphomasa Barroca et al, (9) 2008 All suspected lymphomas Loubeyre et al, (16) 2009 All suspected lymphomas Pfeiffer et al, (8) 2009 All suspected lymphomas Huang et al, (44) 2010 Diagnostic of lymphoma Kuvezdic et al, (25) 2010 Head and neck LAD Pedote et al, (24) 2010 All suspected lymphomas Senjug et al, (45) 2010 Diagnostic of lymphoma/BRH Yuan and Li, (15) 2010 All suspected lymphomas Zeppa et al, (23) 2010 Diagnostic of BRH/NHLa Amador-Ortiz et al, (5) 2011 All suspected lymphomas Burke et al, (46) 2011 Diagnostic of lymphoma Metzgeroth et al, (22) 2012 All patients with LAD Stacchini et al, (21) 2012 Patients undergoing EUS-FNA/FC Total Source, y ITD Specimen Sites Liliemark et al, (34) 1989 Abdominal N/EN Sneige et al, (33) 1990 X N Sneige et al, (14) 1991 X Sup N Sapia et al, (32) 1995 X N Ben-Yehuda et al, (35) 1996 N/EN Hughes et al, (36) 1998 Mediastinum Jeffers et al, (37) 1998 N/EN Young et al, (38) 1998 N/EN Ravinsky et al, (31) 1999 X N/EN Mayall et al, (20) 2000 X N/EN Meda et al, (30) 2000 X N/EN Siebert et al, (29) 2000 X N/EN Demharter et al, (19) 2001 X N/EN Dong et al, (39) 2001 N/EN Liu et al, (18) 2001 X Sup/deep "lesions" Ribeiro et al, (28) 2001 X N/GI mucosa Mourad et al, (40) 2003 Unspecified Zeppa et al, (27) 2004 X N/EN Landgren et al, (13) 2004 N Hehn et al, (6) 2004 N/EN Gong et al, (7) 2004 N Ravinsky et al, (41) 2005 Deep N/EN Li et al, (26) 2005 X N/EN Dey et al, (42) 2006 N Mathiot et al, (12) 2006 X N/EN Venkatraman et al, (43) 2006 Unspecified De Kerviler et al, (11) 2007 X N De Larrinoa et al, (10) 2007 N/EN Lachar et al, (17) 2007 X N/EN Barroca et al, (9) 2008 X N/EN Loubeyre et al, (16) 2009 X N/EN Pfeiffer et al, (8) 2009 X Head and neck Huang et al, (44) 2010 Head and neck Kuvezdic et al, (25) 2010 X Head and neck Pedote et al, (24) 2010 X Deep N/EN Senjug et al, (45) 2010 N/EN Yuan and Li, (15) 2010 X N Zeppa et al, (23) 2010 X N/EN Amador-Ortiz et al, (5) 2011 X N Burke et al, (46) 2011 Head and neck Metzgeroth et al, (22) 2012 X N Stacchini et al, (21) 2012 X N/EN Total Classification Source, y System Liliemark et al, (34) 1989 Kiel Sneige et al, (33) 1990 IWF Sneige et al, (14) 1991 IWF Sapia et al, (32) 1995 Kiel Ben-Yehuda et al, (35) 1996 IWF Hughes et al, (36) 1998 N/A Jeffers et al, (37) 1998 REAL, Kiel Young et al, (38) 1998 REAL Ravinsky et al, (31) 1999 REAL Mayall et al, (20) 2000 REAL Meda et al, (30) 2000 REAL Siebert et al, (29) 2000 REAL Demharter et al, (19) 2001 Kiel, Rye Dong et al, (39) 2001 WHO, REAL Liu et al, (18) 2001 REAL Ribeiro et al, (28) 2001 REAL Mourad et al, (40) 2003 WHO, REAL Zeppa et al, (27) 2004 REAL Landgren et al, (13) 2004 WHO, Kiel Hehn et al, (6) 2004 WHO, REAL, IWF Gong et al, (7) 2004 WHO Ravinsky et al, (41) 2005 WHO Li et al, (26) 2005 WHO Dey et al, (42) 2006 WHO Mathiot et al, (12) 2006 WHO Venkatraman et al, (43) 2006 WHO De Kerviler et al, (11) 2007 WHO, REAL De Larrinoa et al, (10) 2007 WHO Lachar et al, (17) 2007 WHO Barroca et al, (9) 2008 REAL Loubeyre et al, (16) 2009 WHO, REAL Pfeiffer et al, (8) 2009 REAL, Rye Huang et al, (44) 2010 WHO Kuvezdic et al, (25) 2010 WHO Pedote et al, (24) 2010 WHO Senjug et al, (45) 2010 WHO Yuan and Li, (15) 2010 WHO Zeppa et al, (23) 2010 WHO Amador-Ortiz et al, (5) 2011 WHO Burke et al, (46) 2011 WHO Metzgeroth et al, (22) 2012 WHO Stacchini et al, (21) 2012 WHO Total Abbreviations: BRH, benign reactive hyperplasia; EN, extranodal; EUS-FNA, endoscopic ultrasound-guided fine-needle aspiration; FC, flow cytometry; GI, gastrointestinal; ITD, intent-to-diagnose; IWF, International Working Formulation; LAD, lymphadenopathy; LBL, lymphoblastic lymphoma; N, nodal; N-A, not available; NHL, non -Hodgkin lymphoma; REAL, revised European-American classification of lymphoid neoplasms; Sup, superficial; WHO, World Health Organization. (a) These studies excluded nonlymphoid metastatic disease. Table 2. Study Methods Study Methods FNAC CNB IHC/ FC FISH CG/MD ICC Liliemark et al, (34) 1989 X X Sneige et al, (33) 1990 X X Sneige et al, (14) 1991 X X X Sapia et al, (32) 1995 X X Ben-Yehuda et al, (35) 1996 X X Hughes et al, (36) 1998 X X X Jeffers et al, (37) 1998 X X CG Young et al, (38) 1998 X X Ravinsky et al, (31) 1999 X X Mayall et al, (20) 2000 X X X Meda et al, (30) 2000 X X Siebert et al, (29) 2000 X X X X Demharter et al, (19) 2001 X X Dong et al, (39) 2001 X X Liu et al, (18) 2001 X X Ribeiro et al, (28) 2001 X X X Mourad et al, (40) 2003 X X Zeppa et al, (27) 2004 X X X X Landgren et al, (13) 2004 X X Hehn et al, (6) 2004 X X X Gong et al, (7) 2004 X X X X Ravinsky et al, (41) 2005 X X X X Li et al, (26) 2005 X X Dey et al, (42) 2006 X X Mathiot et al, (12) 2006 X X CG Venkatraman et al, (43) 2006 X X MD De Kerviler et al, (11) 2007 X X MD De Larrinoa et al, (10) 2007 X X MD Lachar et al, (17) 2007 X X X MD Barroca et al, (9) 2008 X X X Loubeyre et al, (16) 2009 X X X X MD Pfeiffer et al, (8) 2009 X X Huang et al, (44) 2010 X X Kuvezdic et al, (25) 2010 X X Pedote et al, (24) 2010 X X Senjug et al, (45) 2010 X X Yuan and Li, (15) 2010 X X Zeppa et al, (23) 2010 X X Amador-Ortiz et al, (5) 2011 X X X X X MD Burke et al, (46) 2011 X X Metzgeroth et al, (22) 2012 X X X X Stacchini et al, (21) 2012 X X X Abbreviations: CG, cytogenetics; CNB, core needle biopsy; FC, flow cytometry; FISH, fluorescence in situ hybridization; FNAC, fine/ needle aspiration cytology; IHC/ICC, immunohistochemistry/ immunocytochemistry; MD, molecular diagnostics. Table 3. Diagnostic Categories and Numbers of Specimens (All Studies) Diagnostic Category No. Actionable diagnoses Subclassified lymphomas (a) Hodgkin lymphoma (any subtype) 314 B-cell NHLs Follicular lymphoma, graded 446 Diffuse large B-cell lymphoma 783 CLL/SLL 235 Mantle cell lymphoma 71 Marginal zone lymphoma/MALT 72 Hairy cell leukemia/lymphoma 1 Lymphoplasmacytic lymphoma 19 Burkitt lymphoma 27 T-cell-rich B-cell lymphoma 2 B-cell lymphoblastic lymphoma 24 Plasma cell neoplasia 19 T-cell NHLs Peripheral T-cell lymphoma 38 Angioimmunoblastic T-cell lymphoma 8 Anaplastic large cell lymphoma 39 T-cell lymphoblastic lymphoma 24 Natural killer cell lymphoma 5 Adult T-cell leukemia/lymphoma 1 T-cell CLL/SLL 2 Mycosis fungoides/Sezary syndrome 4 Unspecified subclassification 10 NHL, descriptive NHL in transformation 5 PTLD 2 Composite lymphoma 5 Actionable NHL diagnosis, unspecified subclassification 154 Total subclassified lymphomas 2310 Other conditions Benign reactive hyperplasia 1060 Tuberculosis 120 Other infection 5 Sarcoidosis 9 Granulomatous inflammation 22 Metastatic tumor 581 Amyloidosis 1 Kikuchi disease 30 Kimura disease 1 Cat scratch disease 8 Castleman disease 2 BOOP 1 Granulocytic sarcoma 10 Other malignancy/atypical findings 66 Total other conditions 1916 Nonactionable diagnoses Follicular lymphoma, ungraded 102 BCL-UC 180 TCL-UC 18 LGNHL 9 HGNHL 18 NHL-UC 260 Unclassified lymphoma, HL versus NHL 70 Inadequate/inconclusive 824 Total nonactionable diagnoses 1481 Abbreviations: BCL-UC, B-cell non-Hodgkin lymphoma, unclassified; BOOP, bronchiolitis obliterans-organizing pneumonia; CLL/SLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; HGNHL, high-grade non-Hodgkin lymphoma; HL versus NHL, malignant lymphoma, Hodgkin versus non-Hodgkin lymphoma; LGNHL, low-grade non-Hodgkin lymphoma; MALT, mucosa-associated lymphoid tissue lymphoma;NHL, non-Hodgkin lymphoma;NHL-UC, non-Hodgkin lymphoma, unclassified; PTLD, posttransplantation lymphoproliferative disorder; TCL-UC, T-cell non-Hodgkin lymphoma, unclassified. (a) B-cell lymphomas described as "large cell" or "immunoblastic" were classified as diffuse large B-cell lymphoma. Lymphomas described as "centrocytic," "centroblastic-centrocytic," "small cleaved," "mixed small cleaved and large cell," "follicular center cell lymphoma, predominantly small cleaved cells," and "follicular center cell lymphoma, mixed small and large cells" were included as grade 12 follicular lymphomas. "Small noncleaved cell" lymphomas were grouped with Burkitt lymphoma. Both multiple myelomas and plasmacytomas were placed within a category of plasma cell neoplasia. For T-cell lymphomas, cases of "anaplastic large cell lymphoma," "anaplastic lymphoma," "Ki-1+ anaplastic large cell lymphoma," and "large cell lymphoma CD30+" were classified as anaplastic large T-cell lymphoma. "Angioimmunoblastic lymphadenopathy-type T-cell lymphoma" was included as angioimmunoblastic T-cell lymphoma.