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Systematic review of the effectiveness of fine-needle aspiration and/or core needle biopsy for subclassifying lymphoma.

The WHO [World Health Organization] Classification of Tumours of Haematopoietic and Lymphoid Tissue (1) currently recognizes more than 60 lymphoid malignancies. The defining criteria for these diseases--and, by extension, the most appropriate therapeutic strategies--are based largely on histologic findings from surgically excised specimens. Recent years have seen an increasing reliance on fine-needle aspiration cytology (FNAC) and core needle biopsy (CNB) to evaluate lymphadenopathy. The comfort of pathologists and oncologists with this shift from excisional biopsies to FNAC/CNB has been facilitated by the advent of flow cytometry (FC), karyotypic analysis, and molecular diagnostic techniques. Numerous publications during the last 25 years have reported lymphomas with WHO-level (or equivalent) subclassification using these approaches (see Table 1). In many centers, FNAC/CNB has become the primary diagnostic procedure for patients with suspected 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.

METHODS

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."

RESULTS

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).

COMMENT

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.

References

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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.
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Author:Frederiksen, John K.; Sharma, Meenal; Casulo, Carla; Burack, W. Richard
Publication:Archives of Pathology & Laboratory Medicine
Date:Feb 1, 2015
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