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Expert second-opinion pathology review of lymphoma in the era of the World Health Organization classification
Annals of Oncology
original articles Annals of Oncology 23: 159–166, 2012 doi:10.1093/annonc/mdr029 Published online 17 March 2011
Expert second-opinion pathology review of lymphoma in the era of the World Health Organization classification M. J. Matasar1,2*, W. Shi3, J. Silberstien3, O. Lin4, K. J. Busam4, J. Teruya-Feldstein4, D. A. Filippa4, A. D. Zelenetz1 & A. Noy1 1 3
Lymphoma Service, Department of Medicine; 2Adult Stem Cell Transplant Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center; Departments of Epidemiology and Biostatistics; 4Pathology, Memorial Sloan-Kettering Cancer Center, New York, USA
Received 4 April 2010; revised 11 January 2011; accepted 18 January 2011
was designed to improve diagnostic accuracy by incorporating the latest in scientific understanding. The impact of the WHO classification on the frequency of diagnostic discrepancy in lymphoma is unknown. Methods: We reviewed all second-opinion pathology of lymphoma at our National Cancer Institute-designated Comprehensive Cancer Center (NCI-CCC) from January to June 2001 and from January to June 2006. Discrepancies between submitted and second-opinion diagnoses were scored based upon an a priori grading schema. Results: Major diagnostic revision was rendered in 65 of 365 cases (17.8%) in 2001 and 58 of 354 (16.4%) in 2006 (P = NS). Including cases reviewed and revised beforehand at another NCI-CCC, rates of major diagnostic revision were 21.4% and 18.6%, respectively (P = NS). Discrepancy rates varied by diagnosis, from Hodgkin lymphoma (10%) to Burkitt’s lymphoma (75%). No association was seen for age, gender, race/ethnicity, biopsy type, or nature of referring center. Conclusions: Clinically meaningful diagnostic revision occurs frequently with expert pathology review for a diagnosis of lymphoma. Despite the WHO classification, rates of diagnostic revision at our institution in 2001 and 2006 did not differ significantly. Given the potential harm from misdiagnosis, expert hematopathology review should be considered the standard of care. Key words: lymphoma, pathology, second opinion
introduction The appropriate management of patients with lymphoma depends on an accurate and precise pathologic diagnosis as natural history and optimal treatment vary widely among the different subtypes of lymphoma. However, diagnosis is made challenging by the clinical rarity of individual subtypes of lymphoma in most pathologists’ practices, small diagnostic specimens, and morphologic overlap across subtypes. Furthermore, laboratory advances in molecular and genetic studies have led to a greater breadth of available ancillary tests, but limitations in sensitivity and specificity of these studies demand sophistication from the interpreting pathologist. Previously, multiple competing classification systems resulted in confusion and debate [1–4]. Consequently, the need for more uniform, reliable and reproducible diagnosis of the lymphomas was a driving force behind the development and adoption of new classification schemata. In 2000, the World Health Organization (WHO) presented a new diagnostic
*Correspondence to: Dr M. J. Matasar, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 444 East 68th Street, Box 8, New York, NY 10065, USA. Tel: +1-212-639-6528; Fax: +1-212-639-2283; E-mail: [email protected]
classification built upon the older Revised European-American Classification of Lymphoid Neoplasms (REAL), reinforcing the importance of morphologic, immunophenotypic, molecular, and genetic features in defining disease entities and establishing a single unified classification system [5, 6]. The WHO classification schema has recently been updated, further emphasizing the fundamental importance of these four elements in the diagnosis of lymphoma [7]. Before the adoption of the original WHO classification, documented rates of discordance on expert review were as high as 43% [8–13]. Investigations into the pathology review since 2000 have either focused on translating diagnoses from older schemata into WHO terminology or were largely based upon pre-2000 diagnoses. Aside from data presented in abstract form [14], only one study has investigated pathology discrepancy rates between referral institutions and National Cancer Institute-designated Comprehensive Cancer Centers (NCICCCs) after the WHO classification system had been published [15]. Few data exist addressing possible demographic, pathologic, or clinical features associated with clinically significant diagnostic revisions. In order to test the hypothesis that increased familiarity with the WHO schema is associated with a change in the frequency of major diagnostic revision at
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Background: The World Health Organization (WHO) classification of hematologic malignancies, published in 2000,
original articles pathology review, we carried out a retrospective case review of all new lymphoma pathology consultations from 1 January 2001 to 30 June 2001 and from 1 January 2006 to 30 June 2006.
methods
immunohistochemical studies, was carried out on select cases as deemed necessary by the interpreting hematopathologist. Original and review pathology reports were evaluated retrospectively, with all original and review diagnoses classified according to the original WHO classification system. Criteria for classifying reports as nondiagnostic or ambiguous were defined a priori; reports were considered nondiagnostic if, after completion of all ancillary testing ordered, a final diagnosis was unable to be rendered and considered ambiguous if the final diagnosis failed to achieve the degree of specificity that would be required to generate a treatment recommendation based upon National Comprehensive Cancer Network (NCCN) guidelines. Thus, while ‘T-cell lymphoma’ is clinically ambiguous, as NCCN guidelines did not differentiate among subtypes of T-cell lymphoma, and thus was not defined as ambiguous for this study, whereas ‘B-cell lymphoma of follicular center cell origin’ could represent diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL), disease with different management per NCCN guidelines, and thus would be considered an ambiguous diagnosis in this analysis. Agreement between the submitted and review diagnosis was analyzed. For patients who had previously received second-opinion pathology consultation, the most recent diagnosis was considered the submitted diagnosis. Diagnostic discrepancies were scored according to an a priori grading schema as agreement, minor discrepancy, or major discrepancy (Figure 1). Major discrepancies were those that would alter management according to guidelines published by the NCCN, and minor discrepancies
Figure 1. Classification of diagnostic revisions. All possible diagnostic revisions were classified a priori based upon clinical relevance as defined by NCCN published guidelines on the diagnosis and management of Hodgkin and non-Hodgkin’s lymphoma. Major revisions (changes between fields in zone 1) are those associated with definite changes in management according to NCCN guidelines; minor revisions (changes between fields in zone 2) those with possible changes in management in select cases; and insignificant revisions (changes between fields in zone 3) those that would not be associated with changes in management. NCCN, National Comprehensive Cancer Network.
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This retrospective data analysis was approved by the institutional review board and determined to be exempt research. Patient consent was not required. All outside pathology is routinely reviewed at Memorial Sloan-Kettering Cancer Center (MSKCC) before a clinical opinion is finalized. Institutional standard is to solicit either 2 hematoxylin-and-eosin-stained slides and immunohistochemistry (IHC) or at least 10 unstained slides or the relevant tissue block(s) from previous biopsies. All patients receiving secondopinion pathology review from the MSKCC Department of Pathology from 1 January 2001 to 30 June 2001 and from 1 January 2006 to 30 June 2006 were deemed eligible if records of the original biopsy results were available in the electronic record or obtained after contacting the referring center; no exclusion criteria were applied. All pathologic specimens were reviewed in real time by one of the three pathologists with expertise in hematopathology (JTF, DAF, OL), with cases reviewed at weekly consensus conference. Skin biopsies were separately reviewed by a board-certified dermatopathologist (KJB). Additional evaluation, including
Annals of Oncology
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results A total of 719 patients met inclusion criteria during the two time periods assessed, 365 from 1 January 2001 to 30 June 2001 and 354 from 1 January 2006 to 30 June 2006. Patient demographic characteristics are detailed in Table 1. Predominance of white non-Hispanics and a younger median age than that reported in the general Surveillance Epidemiology and End Results population reflects referral patterns to MSKCC [18]. Hodgkin lymphoma (HL) was overrepresented in comparison with population-based statistics, and the contribution of T-cell lymphomas increased from 2001 to 2006, temporally associated with a development of a focused T-cell lymphoma program in the intervening years. This led to an imbalance between the two time periods in the distribution of referring diagnoses (P = 0.007). None the less, the distribution of lymphoma subtypes from both time periods was otherwise consistent with previous reports of relative frequencies of lymphoma subtypes [12, 16]. Rates of diagnostic revision at second-opinion pathology review are detailed in Table 2. Pathology review at MSKCC resulted in a major diagnostic revision in 65 (17.8%) of 365 cases in 2001 and in 58 (16.4%) of 355 cases in 2006 (P = 0.60). Including cases that had already undergone second-opinion pathology review by another NCI-CCC before consultation and review at MSKCC, major revisions were rendered by a comprehensive cancer center (either MSKCC or antecedent NCI-CCC pathology review) in 78 (21.3%) of 365 cases in 2001 and 66 (18.6%) of 355 cases in 2006 (P = 0.35). Additionally, minor revisions were rendered at MSKCC review in 24 patients (6.6%) in 2001 and 31 patients (8.7%) in 2006. The likelihood of major revision varied among subtypes of lymphoma both in 2001, shortly after the advent of the original WHO classification, and in 2006, 5 years later; these likelihoods were not significantly different when comparing the two time periods (Table 3). Review of submitted diagnoses of classical HL resulted in a major discrepancy for only 4 of 69 cases in 2001 and 5 of 52 in 2006, and no referred cases of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) received a major diagnostic revision in either period. Among cases with a submitted diagnosis of indolent B-cell non-
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Hodgkin’s lymphoma (NHL) revised to aggressive B-cell NHL, the most frequent revision was from grade 1 or 2 FL to FL grade 3 or grade 3b (8 of 20 cases in 2001, 5 of 11 in 2006), with a revised diagnosis of DLBCL rendered less frequently (3 of 20 in 2001, 0 in 2006). In both 2001 and 2006, one case with a submitted diagnosis of low-grade FL was felt to represent benign pathology (follicular hyperplasia or progressive transformation of germinal centers). Marginal zone lymphomas (including splenic, nodal, and extranodal subtypes) were less frequent in the referral population but when revised were most frequently reclassified as DLBCL (2 of 20 in 2001, 1 of 19 in 2006). In contrast, major revisions for cases with submitted diagnoses of aggressive B-cell NHL were most commonly reclassified as unclassifiable lymphoma (four in 2001, two in 2006), Burkitt’s lymphoma (BL; three in 2001, zero in 2006), or an indolent B-cell NHL (four in 2001, two in 2006). BL and Burkitt’s-like lymphoma (BLL) were uncommon submitted diagnoses for referrals during the study periods, with only three cases in 2001 and five in 2006. None the less, discrepancies were frequent in these patients: two of the three cases in 2001 and three of the five cases in 2006 received major revisions. In 2001, both cases (one BL and one BLL) were reclassified as DLBCL, and in 2006, three cases referred as BLL were reclassified as DLBCL; a fourth case originally diagnosed as BL had been previously revised to lymphoblastic lymphoma by another NCCN institution before review at MSKCC. T-cell lymphomas (including cutaneous T-cell lymphoma) received major diagnostic revisions in 5 of 22 cases in 2001 and 12 of 43 cases in 2006. In 2001, two cases were classified as nondiagnostic, one to unclassified B-cell lymphoma, and two to DLBCL, whereas in 2006, four were felt at review to be benign, five nondiagnostic, one to unclassifiable lymphoma, and two to aggressive B-cell lymphomas (DLBCL and T-cell-rich large Bcell lymphoma). Among cases reviewed with prior biopsies submitted as nondiagnostic specimens, a diagnosis of lymphoma was rendered based upon available tissue in six cases in 2001 and in eight cases in 2006; an additional seven cases in 2001 were nondiagnostic before review at an NCI-CCC before assessment at MSKCC. Of these 21 cases, 2 were reclassified as HL, 2 as DLBCL, 7 as T-cell lymphomas, 9 as indolent B-cell lymphomas, and 1 as ungraded FL. In an attempt to characterize what aspects of the secondopinion pathology review contributed to diagnostic revision, we sought to correlate diagnostic revision with patient demographic features, clinical variables, and components of the pathologic evaluation (Tables 4 and 5). A standard element in the routine pathology review is the review of previously carried out IHC stains and/or repeat or additional IHC carried out on unstained slides. Univariate analyses based on combined 2001 and 2006 data showed IHC carried out at MSKCC, subtype of referral diagnosis, and site of biopsy were significantly associated with major diagnostic revision (Table 4; P = 0.03, P < 0.001, and P = 0.02, respectively). Age, gender, race and ethnicity were not associated with a statistically significant difference in odds of receiving a revised diagnosis. Type of biopsy specimen [fine needle aspiration, core biopsy, or incisional biopsy], IHC reviewed at MSKCC, and additional
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were those that, while rendering a different diagnosis, would not fundamentally alter management according to NCCN recommendations [16, 17]. Potential factors associated with rate of major diagnostic revision were assessed, including available patient demographic data (age, gender, race, and ethnicity) and clinical features (original diagnosis, type of biopsy, site of biopsy, IHC reviewed at MSKCC, IHC carried out at MSKCC, additional biopsy, and type of referring pathology laboratory). In determining clinical and demographic factors associated with diagnostic revision, statistical analysis was carried out using chi-square or Fisher’s exact test for univariate analysis and logistic regression for multivariate analysis. All variables whose univariate tests resulted in a P value £0.10 and variable time period (2006 versus 2001) were considered in the multivariate mode. In addition, for individuals who had previously received a second-opinion pathology review at another NCI-CCC before review at our institution, we evaluated the pattern of revisions comparing the original diagnostic biopsy, the second opinion, and the final MSKCC diagnosis.
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Table 1. Patient and clinical characteristicsa, 2001 and 2006 Variable
2001 (N = 365 patients) n %
2006 (N = 354 patients) n %
P valueb
Mean age 6 SD Male Race/ethnicity White non-Hispanic Black non-Hispanic Hispanic Asian Other Unknown Referring diagnosis Benign Nondiagnostic Malignancy NOS Lymphoma NOS Hodgkin lymphomaa Classical Hodgkin lymphoma NLPHL T-cell neoplasmsa Cutaneous T-cell lymphoma Peripheral T-cell lymphoma, unspecified Anaplastic large-cell lymphoma Angioimmunoblastic T-cell lymphoma T-cell acute lymphoblastic leukemia/lymphoma Precursor T-lymphoblastic leukemia/lymphoma B-cell neoplasmsa B-cell lymphoma NOS Follicle center cell lymphoma NOS Highly aggressive B-cell neoplasmsa Burkitt’s lymphoma Burkitt’s-like lymphoma B-cell lymphoblastic lymphoma Plasmablastic lymphoma Aggressive B-cell neoplasmsa Aggressive B-cell lymphoma NOS Diffuse large B-cell lymphoma T-cell-rich B-cell lymphoma Grade 3 follicular lymphoma Mantle cell lymphoma Indolent B-cell lymphomasa Low-grade B-cell lymphoma NOS Low-grade composite lymphoma Follicular lymphoma, grade 1 Follicular lymphoma, grade 2 Marginal zone lymphoma Small lymphocytic lymphoma (CLL type) Lymphoplasmacytic lymphoma Multiple myeloma
53.6 6 16.4 194
53.2
55.4 6 16.2 183
51.7
0.14 0.7 0.29
308 24 14 9 1 9
84.4 6.6 3.8 2.5 0.3 2.5
301 13 13 15 0 12
85 3.7 3.7 4.2 0 3.4
6 27 2 7 72
1.6 7.4 0.6 1.9 19.7 18.9 0.8 6.0 1.9 1.9 1.9 0.5 0.3 0 62.5 3 0.8 1.1 0.5 0.3 0.3 0 25.2 0.5 16.2 0.8 3.6 4.1 32.3 3 0.3 7.7 6.8 5.5 5.5 1.9 1.6
5 17 0 1 57
1.4 4.8 0 0.3 16.1 14.6 1.7 12.1 4.5 3.1 1.1 2.5 0.3 0.3 65.4 2.5 1.1 2 0.3 1.1 0.3 0.3 26.1 0.3 18 0.6 1.7 5.6 33.4 2.2 0.3 13.8 6.5 4.8 3.7 1.7 0.3
0.007
229
43
232
a
Distributions of demographics were based on patients; distributions of referring diagnosis were based on diagnostic cases, as one patient had two unique diagnoses, and were compared based on subtype. b By Student’s t-test, chi-square test, or Fisher’s exact test. SD, standard deviation; NOS, not otherwise specified; NLPHL, nodular lymphocyte-predominant Hodgkin lymphoma; CLL, chronic lymphocytic leukemia.
biopsy were also not associated with odds of diagnostic revision. Lastly, no significant association between nature of referring pathology laboratory and odds of diagnostic revision
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was noted. Discrepancies in cases reviewed previously at another NCCN center existed; in 2001, six such cases occurred: four involved a change in degree of certainty regarding the
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classifiability (three more ambiguous, one more definitive), one changed from low-grade to grade 3 FL, and one changed from angioimmunoblastic T-cell lymphoma to T-cell-rich B-cell lymphoma. In 2006, nine such cases existed, five of which involved change in the degree of certainty (one more ambiguous, four more definitive), one from low-grade to grade
Table 2. Comparison of distributions of diagnostic revisiona, 2001 and 2006 Diagnostic revision
2001 (n = 365) n (case) %
P value
21.4
66
18.6
0.35b
17.8
58
16.4
0.60c
3.6
8
2.3
6.6
31
8.7
6.6
31
8.7
0 72.1
0 258
0 72.7
a
Based on diagnostic cases; one patient had two unique diagnoses in 2006. Chi-square test based on MSKCC and other NCI-CCC major revision versus combined minor or no diagnostic revision. c Chi-square test based on MSKCC major revision versus combined minor or no diagnostic revision. MSKCC, Memorial Sloan-Kettering Cancer Center; NCI-CCC, National Cancer Institute-designated Comprehensive Cancer Center. b
discussion In this article, we report the experience at an NCI-CCC with second-opinion pathology review for patients seen in clinical consultation. Six-month periods in 2001, the year after the official publication of the original WHO classification, and in 2006, 5 years later, were reviewed to address the hypothesis that increased familiarity with the new classification system would impact rates of diagnostic revision at expert pathology review. The WHO system, updating the REAL classification and reinforcing the central importance of morphology and immunophenotype in defining distinct clinicopathologic entities, offered the promise of a unified lexicon and pathologic approach to the rendering of an accurate and precise diagnosis of lymphoma. Nonetheless, rates of major diagnostic revision at review by hematopathology at our center, or by another NCI-CCC before consultation at our center, were not significantly different in 2001 or in 2006 (21.3% and 18.6%, respectively, P = 0.35). In both periods, individuals referred with diagnosed lymphoma were reclassified as having benign conditions: 0.3% in 2001 and
Table 3. Major revisions by diagnosis in 2001 and 2006 Original diagnosis
Revised diagnosis
2001, number reviseda (% of original dx)
2006, number reviseda (% of original dx)
Benign Lymphoma (any) Nondiagnostic/ambiguous Diagnostic/definitive HL Non-Hodgkin lymphoma Classical HL T-cell neoplasm Highly aggressive B-cell neoplasm Aggressive B-cell neoplasm Aggressive B-cell neoplasm Indolent B-cell neoplasm Highly aggressive B-cell neoplasm Aggressive B-cell neoplasm
Lymphoma (any) Benign Diagnostic/definitive Nondiagnostic/ambiguous Non-Hodgkin lymphoma HL NLPHL B-cell neoplasm Aggressive B-cell neoplasm Highly aggressive B-cell neoplasm Indolent B-cell neoplasm Aggressive B-cell neoplasm Highly aggressive B-cell neoplasm Aggressive B-cell neoplasm
3/6 1/330 26/72 13/260 3/72 1/251 1/69 3/22 2/5 3/92 6/92 16/118 0/5 0/92
1/5 6/333 25/46 12/310 2/57 1/275 1/51 2/43 3/7 0/93 3/93 8/118 1/7 1/93
(50) (0.3) (36) (5) (4) (0.4) (1) (14) (40) (3) (6) (14) (0) (0)
(20) (2) (54) (4) (4) (0.3) (2) (5) (43) (0) (3) (7) (14) (1)
a
Includes both MSKCC and other NCI-CCC revisions. dx, diagnosis; HL, Hodgkin lymphoma; NLPHL, nodular lymphocyte-predominant Hodgkin lymphoma; MSKCC, Memorial Sloan-Kettering Cancer Center; NCI-CCC, National Cancer Institute-designated Comprehensive Cancer Center.
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Major diagnostic revision MSKCC or other NCI78 CCC secondary review MSKCC revision of 65 submitted diagnosis Prior NCI-CCC revision 13 (MSKCC affirmed) Minor diagnostic revision MSKCC or other NCI24 CCC secondary review MSKCC revision of 24 submitted diagnosis Prior NCI-CCC revision 0 (MSKCC affirmed) No diagnostic revision 263
2006 (n = 355) n (case) %
3 FL, one from CD20+ HL to primary mediastinal DLBCL, and one from lymphocyte-rich classical HL to NLPHL. Multivariate logistic regression showed that IHC carried out at MSKCC [odds ratio (OR) = 1.58, 95% confidence interval (CI) 1.03–2.41] and subtype of referring diagnosis remained significantly associated with major revision after adjusting for biopsy site and time period. Relative to B-cell neoplasms, HL was significantly less likely to undergo major diagnostic revision (OR = 0.37, 95% CI 0.17–0.78, P = 0.009), while collectively, diagnoses that were individually uncommon in the referral population—those representing <5% of all referrals—as well as nondiagnostic were more likely to receive revised diagnoses (OR = 3.52, 95% CI 1.37–9.09, P = 0.009; OR = 2.24 95% CI 1.11–4.55, P = 0.03).
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Table 4. Univariate analysis of relationship between patient and clinical features and rate of diagnostic revision at MSKCC pathology review for combined 2001 and 2006 dataa Variable
69/428 53/291
16.1 18.2
0.46
60/342 62/377
17.5 16.4
0.7
100/609 5/37 7/27 6/24 0/1 4/21
16.4 13.5 25.9 25 0 19
0.65
72/449 21/73 29/197
16 28.8 14.7
0.02
10/47 26/164 86/508
21.3 15.9 16.9
0.68
63/391 59/328
16.1 18
0.5
77/513 45/206
15 21.8
0.03
109/664 13/55
16.4 23.6
0.17
74/460 17/65 14/44 9/129 3/11 3/8 2/2
16.1 26.2 31.8 7 27.3 37.5 100
<0.001
15/110
13.6
0.42b
88/508 15/78 3/9 1/14
17.3 19.2 33.3 7.1
a
Analyses were based on individual patients. Analysis was based on NCI-CCC and four categories of non-NCI-CCC referring centers. MSKCC, Memorial Sloan-Kettering Cancer Center; IHC, immunohistochemistry; NOS, not otherwise specified; NCI-CCC, National Cancer Institutedesignated Comprehensive Cancer Center.
b
2% in 2006. Clinically meaningful discrepancies for every subtype of lymphoma except NLPHL were seen, although the odds of revision did differ by lymphoma subtype, ranging from relatively low in HL (10%) to considerably higher for BL and
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BLL (63%). It is unclear from our results what elements of the expert pathology review most contributed to diagnostic revision. While the data suggest that repeat or additional IHC evaluation was predictive of major revision, it is possible that
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Age <60 ‡60 Gender Female Male Race/ethnicity White non-Hispanic Black non-Hispanic Hispanic Asian Other Unknown Biopsy site Lymph node Skin Other Biopsy type Fine needle aspiration Core biopsy Incisional biopsy IHC-stained slides from referring center reviewed at MSKCC No Yes IHC testing on unstained slides carried out at MSKCC No Yes Additional biopsy carried out on recommendation of MSKCC pathology No Yes Referral diagnosis B-cell neoplasms T-cell neoplasms Nondiagnostic Hodgkin lymphoma Benign Lymphoma NOS Malignancy NOS Referring center NCI-CCC Non-NCI-CCC Non-CCC hospital pathology Corporate pathology laboratory only Public hospital International
Major diagnostic revision rendered at MSKCC pathology review N (discrepant)/N (total) % Unadjusted P value
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Table 5. Multivariate analysis of relationship between clinical features and major diagnostic revision at MSKCC pathology review for combined 2001 and 2006 dataa Clinical feature
Adjusted P value
1 1.44 (0.76–2.75) 0.73 (0.44–1.19)
0.27
1 1.58 (1.03–2.41)
0.04 <0.001
1 1.50 2.24 0.37 3.52
(0.76–2.94) (1.11–4.55) (0.17–0.78) (1.37–9.09)
1 0.84 (0.56–1.26)
0.24 0.03 0.009 0.009
0.40
a
Data analyzed using multivariate logistic regression. Rare diagnosis indicates diagnoses that each represented <5% of referring diagnoses, including undiagnosed conditions (e.g. malignancy NOS and lymphoma NOS) and diagnoses of benign disorders. MSKCC, Memorial Sloan-Kettering Cancer Center; IHC, immunohistochemistry; NOS, not otherwise specified.
funding The Lymphoma Foundation, Mortimer J. Lacher Fellowship.
b
this additional testing was intended to confirm a suspected change in diagnosis, rather than itself single-handedly lead to a new diagnosis. Notably, a consortium of five NCCN centers reported a pathology discordance rate of 6% (43 cases total) with diagnosis at referral [15]. Of these 43 cases, 44% were rendered without additional studies, 21% with additional biopsies and 26% with additional studies, usually IHC. It is unclear why our discrepancy rate is higher than this NCCN consortium, although referral bias, geographic regional variability, and differences in pathology review practices are possibilities. Our data do not support the a priori hypothesis that rates of diagnostic discrepancy would be lower for cases originally diagnosed at another NCI-CCC before consultation at our center. There may be several factors that bias our findings toward the null: referral patterns at our center are such that few patients are seen having been originally seen at a public hospital or having had specimens reviewed only by commercial laboratories. Further, it is likely that patients who were seen previously at another NCI-CCC and sought an additional opinion at our center represent a highly selected group of patients. It is possible that such patients may in part self-select due to perceived diagnostic challenges, which would inflate the odds of diagnostic discrepancy for this group. This is further supported by the nature of the discrepant cases, as many of these occurred in diagnoses with recognized diagnostic imprecision, such as discriminating CD20+ classical HL from primary mediastinal DLBCL. Similarly, caution must be exercised in extrapolating these findings to the general
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disclosure The authors declare no conflict of interest.
references 1. Sheehan WW, Rappaport H. Morphological criteria in the classification of the malignant lymphomas. Proc Natl Cancer Conf 1970; 6: 59–71. 2. Bettini R, Chelazzi G. Prognostic value of the Kiel classification of malignant nonHodgkin’s lymphomas. Tumori 1979; 65: 207–213. 3. National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin’s Lymphoma Pathologic Classification Project. Cancer 1982; 49: 2112–2135. 4. Classification of non-Hodgkin’s lymphomas. Reproducibility of major classification systems. NCI non-Hodgkin’s Classification Project Writing Committee. Cancer 1985; 55: 91–95. 5. Harris NL, Jaffe ES, Diebold J et al. Lymphoma classification—from controversy to consensus: the R.E.A.L. and WHO Classification of lymphoid neoplasms. Ann Oncol 2000; 11 (Suppl 1): 3–10. 6. Harris NL, Jaffe ES, Diebold J et al. The World Health Organization classification of hematological malignancies report of the Clinical Advisory Committee Meeting, Airlie House, Virginia, November 1997. Mod Pathol 2000; 13: 193–207. 7. Swerdlow SH, Campo E, Harris NL et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC 2008. 8. Turner JJ, Hughes AM, Kricker A et al. Use of the WHO lymphoma classification in a population-based epidemiological study. Ann Oncol 2004; 15: 631–637. 9. Lester JF, Dojcinov SD, Attanoos RL et al. The clinical impact of expert pathological review on lymphoma management: a regional experience. Br J Haematol 2003; 123: 463–468. 10. Wetherington RW, Cooper HS, Al-Saleem T et al. Clinical significance of performing immunohistochemistry on cases with a previous diagnosis of cancer coming to a national comprehensive cancer center for treatment or second opinion. Am J Surg Pathol 2002; 26: 1222–1230. 11. Glaser SL, Dorfman RF, Clarke CA. Expert review of the diagnosis and histologic classification of Hodgkin disease in a population-based cancer registry:
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Biopsy site Lymph node Skin Other IHC carried out at MSKCC No Yes Referring diagnosis B-cell neoplasms T-cell neoplasms Nondiagnostic Hodgkin lymphoma Rare diagnosisb Year of pathology review 2001 2006
Adjusted odds ratio (95% confidence interval)
population of patients with lymphoma, as the entire cohort of patients seeking a second opinion at an NCI-CCC is a selected population, biasing the overall results in a similar fashion. As lymphoma pathologists and clinicians now begin to assimilate the newest WHO classification into practice, it is time to ask what impact the previous revisions had on the ability to render accurate and reproducible diagnosis. Unfortunately, the persistence of high rates of major revision after 5 years of experience with the original WHO schema argues that the risk of misdiagnosis remains a clinical challenge, undermining the ability to capitalize on improvements in management for specific lymphoma subtypes. While a gold standard is difficult to define in cases of major diagnostic discrepancies, expert hematopathology review is a common practice among centers of excellence. Given both the high rates of major diagnostic revision and the potential for harm when management decisions are based upon erroneous diagnoses, a clear rationale exists for routine expert second-opinion review of diagnoses of lymphoma.
original articles interobserver reliability and impact on incidence and survival rates. Cancer 2001; 92: 218–224. 12. Kronz JD, Westra WH, Epstein JI. Mandatory second opinion surgical pathology at a large referral hospital. Cancer 1999; 86: 2426–2435. 13. The Non-Hodgkin’s Lymphoma Classification Project. A clinical evaluation of the International Lymphoma Study Group Classification of Non-Hodgkin’s Lymphoma. Blood 1997; 89: 3909–3918. 14. Kukreti V, Patterson B, Callum J et al. Pathology the gold standard—a retrospective analysis of discordant ‘‘second-opinion’’ lymphoma pathology and its impact on patient care. ASH Annual Meeting Abstracts 2006; 108: 348.
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15. LaCasce AS, Kho ME, Friedberg JW et al. Comparison of referring and final pathology for patients with non-Hodgkin’s lymphoma in the National Comprehensive Cancer Network. J Clin Oncol 2008; 26: 5107–5112. 16. Zelenetz AD, Hoppe RT. NCCN: non-Hodgkin’s lymphoma. Cancer Control 2001; 8: 102–113. 17. NCCN practice guidelines for Hodgkin’s disease. National Comprehensive Cancer Network. Oncology (Williston Park) 1999; 13: 78–110. 18. Morton LM, Wang SS, Devesa SS et al. Lymphoma incidence patterns by WHO subtype in the United States, 1992–2001. Blood 2006; 107: 265–276.
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original articles Annals of Oncology 23: 159–166, 2012 doi:10.1093/annonc/mdr029 Published online 17 March 2011
Expert second-opinion pathology review of lymphoma in the era of the World Health Organization classification M. J. Matasar1,2*, W. Shi3, J. Silberstien3, O. Lin4, K. J. Busam4, J. Teruya-Feldstein4, D. A. Filippa4, A. D. Zelenetz1 & A. Noy1 1 3
Lymphoma Service, Department of Medicine; 2Adult Stem Cell Transplant Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center; Departments of Epidemiology and Biostatistics; 4Pathology, Memorial Sloan-Kettering Cancer Center, New York, USA
Received 4 April 2010; revised 11 January 2011; accepted 18 January 2011
was designed to improve diagnostic accuracy by incorporating the latest in scientific understanding. The impact of the WHO classification on the frequency of diagnostic discrepancy in lymphoma is unknown. Methods: We reviewed all second-opinion pathology of lymphoma at our National Cancer Institute-designated Comprehensive Cancer Center (NCI-CCC) from January to June 2001 and from January to June 2006. Discrepancies between submitted and second-opinion diagnoses were scored based upon an a priori grading schema. Results: Major diagnostic revision was rendered in 65 of 365 cases (17.8%) in 2001 and 58 of 354 (16.4%) in 2006 (P = NS). Including cases reviewed and revised beforehand at another NCI-CCC, rates of major diagnostic revision were 21.4% and 18.6%, respectively (P = NS). Discrepancy rates varied by diagnosis, from Hodgkin lymphoma (10%) to Burkitt’s lymphoma (75%). No association was seen for age, gender, race/ethnicity, biopsy type, or nature of referring center. Conclusions: Clinically meaningful diagnostic revision occurs frequently with expert pathology review for a diagnosis of lymphoma. Despite the WHO classification, rates of diagnostic revision at our institution in 2001 and 2006 did not differ significantly. Given the potential harm from misdiagnosis, expert hematopathology review should be considered the standard of care. Key words: lymphoma, pathology, second opinion
introduction The appropriate management of patients with lymphoma depends on an accurate and precise pathologic diagnosis as natural history and optimal treatment vary widely among the different subtypes of lymphoma. However, diagnosis is made challenging by the clinical rarity of individual subtypes of lymphoma in most pathologists’ practices, small diagnostic specimens, and morphologic overlap across subtypes. Furthermore, laboratory advances in molecular and genetic studies have led to a greater breadth of available ancillary tests, but limitations in sensitivity and specificity of these studies demand sophistication from the interpreting pathologist. Previously, multiple competing classification systems resulted in confusion and debate [1–4]. Consequently, the need for more uniform, reliable and reproducible diagnosis of the lymphomas was a driving force behind the development and adoption of new classification schemata. In 2000, the World Health Organization (WHO) presented a new diagnostic
*Correspondence to: Dr M. J. Matasar, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 444 East 68th Street, Box 8, New York, NY 10065, USA. Tel: +1-212-639-6528; Fax: +1-212-639-2283; E-mail: [email protected]
classification built upon the older Revised European-American Classification of Lymphoid Neoplasms (REAL), reinforcing the importance of morphologic, immunophenotypic, molecular, and genetic features in defining disease entities and establishing a single unified classification system [5, 6]. The WHO classification schema has recently been updated, further emphasizing the fundamental importance of these four elements in the diagnosis of lymphoma [7]. Before the adoption of the original WHO classification, documented rates of discordance on expert review were as high as 43% [8–13]. Investigations into the pathology review since 2000 have either focused on translating diagnoses from older schemata into WHO terminology or were largely based upon pre-2000 diagnoses. Aside from data presented in abstract form [14], only one study has investigated pathology discrepancy rates between referral institutions and National Cancer Institute-designated Comprehensive Cancer Centers (NCICCCs) after the WHO classification system had been published [15]. Few data exist addressing possible demographic, pathologic, or clinical features associated with clinically significant diagnostic revisions. In order to test the hypothesis that increased familiarity with the WHO schema is associated with a change in the frequency of major diagnostic revision at
ª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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Background: The World Health Organization (WHO) classification of hematologic malignancies, published in 2000,
original articles pathology review, we carried out a retrospective case review of all new lymphoma pathology consultations from 1 January 2001 to 30 June 2001 and from 1 January 2006 to 30 June 2006.
methods
immunohistochemical studies, was carried out on select cases as deemed necessary by the interpreting hematopathologist. Original and review pathology reports were evaluated retrospectively, with all original and review diagnoses classified according to the original WHO classification system. Criteria for classifying reports as nondiagnostic or ambiguous were defined a priori; reports were considered nondiagnostic if, after completion of all ancillary testing ordered, a final diagnosis was unable to be rendered and considered ambiguous if the final diagnosis failed to achieve the degree of specificity that would be required to generate a treatment recommendation based upon National Comprehensive Cancer Network (NCCN) guidelines. Thus, while ‘T-cell lymphoma’ is clinically ambiguous, as NCCN guidelines did not differentiate among subtypes of T-cell lymphoma, and thus was not defined as ambiguous for this study, whereas ‘B-cell lymphoma of follicular center cell origin’ could represent diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL), disease with different management per NCCN guidelines, and thus would be considered an ambiguous diagnosis in this analysis. Agreement between the submitted and review diagnosis was analyzed. For patients who had previously received second-opinion pathology consultation, the most recent diagnosis was considered the submitted diagnosis. Diagnostic discrepancies were scored according to an a priori grading schema as agreement, minor discrepancy, or major discrepancy (Figure 1). Major discrepancies were those that would alter management according to guidelines published by the NCCN, and minor discrepancies
Figure 1. Classification of diagnostic revisions. All possible diagnostic revisions were classified a priori based upon clinical relevance as defined by NCCN published guidelines on the diagnosis and management of Hodgkin and non-Hodgkin’s lymphoma. Major revisions (changes between fields in zone 1) are those associated with definite changes in management according to NCCN guidelines; minor revisions (changes between fields in zone 2) those with possible changes in management in select cases; and insignificant revisions (changes between fields in zone 3) those that would not be associated with changes in management. NCCN, National Comprehensive Cancer Network.
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This retrospective data analysis was approved by the institutional review board and determined to be exempt research. Patient consent was not required. All outside pathology is routinely reviewed at Memorial Sloan-Kettering Cancer Center (MSKCC) before a clinical opinion is finalized. Institutional standard is to solicit either 2 hematoxylin-and-eosin-stained slides and immunohistochemistry (IHC) or at least 10 unstained slides or the relevant tissue block(s) from previous biopsies. All patients receiving secondopinion pathology review from the MSKCC Department of Pathology from 1 January 2001 to 30 June 2001 and from 1 January 2006 to 30 June 2006 were deemed eligible if records of the original biopsy results were available in the electronic record or obtained after contacting the referring center; no exclusion criteria were applied. All pathologic specimens were reviewed in real time by one of the three pathologists with expertise in hematopathology (JTF, DAF, OL), with cases reviewed at weekly consensus conference. Skin biopsies were separately reviewed by a board-certified dermatopathologist (KJB). Additional evaluation, including
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results A total of 719 patients met inclusion criteria during the two time periods assessed, 365 from 1 January 2001 to 30 June 2001 and 354 from 1 January 2006 to 30 June 2006. Patient demographic characteristics are detailed in Table 1. Predominance of white non-Hispanics and a younger median age than that reported in the general Surveillance Epidemiology and End Results population reflects referral patterns to MSKCC [18]. Hodgkin lymphoma (HL) was overrepresented in comparison with population-based statistics, and the contribution of T-cell lymphomas increased from 2001 to 2006, temporally associated with a development of a focused T-cell lymphoma program in the intervening years. This led to an imbalance between the two time periods in the distribution of referring diagnoses (P = 0.007). None the less, the distribution of lymphoma subtypes from both time periods was otherwise consistent with previous reports of relative frequencies of lymphoma subtypes [12, 16]. Rates of diagnostic revision at second-opinion pathology review are detailed in Table 2. Pathology review at MSKCC resulted in a major diagnostic revision in 65 (17.8%) of 365 cases in 2001 and in 58 (16.4%) of 355 cases in 2006 (P = 0.60). Including cases that had already undergone second-opinion pathology review by another NCI-CCC before consultation and review at MSKCC, major revisions were rendered by a comprehensive cancer center (either MSKCC or antecedent NCI-CCC pathology review) in 78 (21.3%) of 365 cases in 2001 and 66 (18.6%) of 355 cases in 2006 (P = 0.35). Additionally, minor revisions were rendered at MSKCC review in 24 patients (6.6%) in 2001 and 31 patients (8.7%) in 2006. The likelihood of major revision varied among subtypes of lymphoma both in 2001, shortly after the advent of the original WHO classification, and in 2006, 5 years later; these likelihoods were not significantly different when comparing the two time periods (Table 3). Review of submitted diagnoses of classical HL resulted in a major discrepancy for only 4 of 69 cases in 2001 and 5 of 52 in 2006, and no referred cases of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) received a major diagnostic revision in either period. Among cases with a submitted diagnosis of indolent B-cell non-
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Hodgkin’s lymphoma (NHL) revised to aggressive B-cell NHL, the most frequent revision was from grade 1 or 2 FL to FL grade 3 or grade 3b (8 of 20 cases in 2001, 5 of 11 in 2006), with a revised diagnosis of DLBCL rendered less frequently (3 of 20 in 2001, 0 in 2006). In both 2001 and 2006, one case with a submitted diagnosis of low-grade FL was felt to represent benign pathology (follicular hyperplasia or progressive transformation of germinal centers). Marginal zone lymphomas (including splenic, nodal, and extranodal subtypes) were less frequent in the referral population but when revised were most frequently reclassified as DLBCL (2 of 20 in 2001, 1 of 19 in 2006). In contrast, major revisions for cases with submitted diagnoses of aggressive B-cell NHL were most commonly reclassified as unclassifiable lymphoma (four in 2001, two in 2006), Burkitt’s lymphoma (BL; three in 2001, zero in 2006), or an indolent B-cell NHL (four in 2001, two in 2006). BL and Burkitt’s-like lymphoma (BLL) were uncommon submitted diagnoses for referrals during the study periods, with only three cases in 2001 and five in 2006. None the less, discrepancies were frequent in these patients: two of the three cases in 2001 and three of the five cases in 2006 received major revisions. In 2001, both cases (one BL and one BLL) were reclassified as DLBCL, and in 2006, three cases referred as BLL were reclassified as DLBCL; a fourth case originally diagnosed as BL had been previously revised to lymphoblastic lymphoma by another NCCN institution before review at MSKCC. T-cell lymphomas (including cutaneous T-cell lymphoma) received major diagnostic revisions in 5 of 22 cases in 2001 and 12 of 43 cases in 2006. In 2001, two cases were classified as nondiagnostic, one to unclassified B-cell lymphoma, and two to DLBCL, whereas in 2006, four were felt at review to be benign, five nondiagnostic, one to unclassifiable lymphoma, and two to aggressive B-cell lymphomas (DLBCL and T-cell-rich large Bcell lymphoma). Among cases reviewed with prior biopsies submitted as nondiagnostic specimens, a diagnosis of lymphoma was rendered based upon available tissue in six cases in 2001 and in eight cases in 2006; an additional seven cases in 2001 were nondiagnostic before review at an NCI-CCC before assessment at MSKCC. Of these 21 cases, 2 were reclassified as HL, 2 as DLBCL, 7 as T-cell lymphomas, 9 as indolent B-cell lymphomas, and 1 as ungraded FL. In an attempt to characterize what aspects of the secondopinion pathology review contributed to diagnostic revision, we sought to correlate diagnostic revision with patient demographic features, clinical variables, and components of the pathologic evaluation (Tables 4 and 5). A standard element in the routine pathology review is the review of previously carried out IHC stains and/or repeat or additional IHC carried out on unstained slides. Univariate analyses based on combined 2001 and 2006 data showed IHC carried out at MSKCC, subtype of referral diagnosis, and site of biopsy were significantly associated with major diagnostic revision (Table 4; P = 0.03, P < 0.001, and P = 0.02, respectively). Age, gender, race and ethnicity were not associated with a statistically significant difference in odds of receiving a revised diagnosis. Type of biopsy specimen [fine needle aspiration, core biopsy, or incisional biopsy], IHC reviewed at MSKCC, and additional
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were those that, while rendering a different diagnosis, would not fundamentally alter management according to NCCN recommendations [16, 17]. Potential factors associated with rate of major diagnostic revision were assessed, including available patient demographic data (age, gender, race, and ethnicity) and clinical features (original diagnosis, type of biopsy, site of biopsy, IHC reviewed at MSKCC, IHC carried out at MSKCC, additional biopsy, and type of referring pathology laboratory). In determining clinical and demographic factors associated with diagnostic revision, statistical analysis was carried out using chi-square or Fisher’s exact test for univariate analysis and logistic regression for multivariate analysis. All variables whose univariate tests resulted in a P value £0.10 and variable time period (2006 versus 2001) were considered in the multivariate mode. In addition, for individuals who had previously received a second-opinion pathology review at another NCI-CCC before review at our institution, we evaluated the pattern of revisions comparing the original diagnostic biopsy, the second opinion, and the final MSKCC diagnosis.
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Table 1. Patient and clinical characteristicsa, 2001 and 2006 Variable
2001 (N = 365 patients) n %
2006 (N = 354 patients) n %
P valueb
Mean age 6 SD Male Race/ethnicity White non-Hispanic Black non-Hispanic Hispanic Asian Other Unknown Referring diagnosis Benign Nondiagnostic Malignancy NOS Lymphoma NOS Hodgkin lymphomaa Classical Hodgkin lymphoma NLPHL T-cell neoplasmsa Cutaneous T-cell lymphoma Peripheral T-cell lymphoma, unspecified Anaplastic large-cell lymphoma Angioimmunoblastic T-cell lymphoma T-cell acute lymphoblastic leukemia/lymphoma Precursor T-lymphoblastic leukemia/lymphoma B-cell neoplasmsa B-cell lymphoma NOS Follicle center cell lymphoma NOS Highly aggressive B-cell neoplasmsa Burkitt’s lymphoma Burkitt’s-like lymphoma B-cell lymphoblastic lymphoma Plasmablastic lymphoma Aggressive B-cell neoplasmsa Aggressive B-cell lymphoma NOS Diffuse large B-cell lymphoma T-cell-rich B-cell lymphoma Grade 3 follicular lymphoma Mantle cell lymphoma Indolent B-cell lymphomasa Low-grade B-cell lymphoma NOS Low-grade composite lymphoma Follicular lymphoma, grade 1 Follicular lymphoma, grade 2 Marginal zone lymphoma Small lymphocytic lymphoma (CLL type) Lymphoplasmacytic lymphoma Multiple myeloma
53.6 6 16.4 194
53.2
55.4 6 16.2 183
51.7
0.14 0.7 0.29
308 24 14 9 1 9
84.4 6.6 3.8 2.5 0.3 2.5
301 13 13 15 0 12
85 3.7 3.7 4.2 0 3.4
6 27 2 7 72
1.6 7.4 0.6 1.9 19.7 18.9 0.8 6.0 1.9 1.9 1.9 0.5 0.3 0 62.5 3 0.8 1.1 0.5 0.3 0.3 0 25.2 0.5 16.2 0.8 3.6 4.1 32.3 3 0.3 7.7 6.8 5.5 5.5 1.9 1.6
5 17 0 1 57
1.4 4.8 0 0.3 16.1 14.6 1.7 12.1 4.5 3.1 1.1 2.5 0.3 0.3 65.4 2.5 1.1 2 0.3 1.1 0.3 0.3 26.1 0.3 18 0.6 1.7 5.6 33.4 2.2 0.3 13.8 6.5 4.8 3.7 1.7 0.3
0.007
229
43
232
a
Distributions of demographics were based on patients; distributions of referring diagnosis were based on diagnostic cases, as one patient had two unique diagnoses, and were compared based on subtype. b By Student’s t-test, chi-square test, or Fisher’s exact test. SD, standard deviation; NOS, not otherwise specified; NLPHL, nodular lymphocyte-predominant Hodgkin lymphoma; CLL, chronic lymphocytic leukemia.
biopsy were also not associated with odds of diagnostic revision. Lastly, no significant association between nature of referring pathology laboratory and odds of diagnostic revision
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was noted. Discrepancies in cases reviewed previously at another NCCN center existed; in 2001, six such cases occurred: four involved a change in degree of certainty regarding the
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classifiability (three more ambiguous, one more definitive), one changed from low-grade to grade 3 FL, and one changed from angioimmunoblastic T-cell lymphoma to T-cell-rich B-cell lymphoma. In 2006, nine such cases existed, five of which involved change in the degree of certainty (one more ambiguous, four more definitive), one from low-grade to grade
Table 2. Comparison of distributions of diagnostic revisiona, 2001 and 2006 Diagnostic revision
2001 (n = 365) n (case) %
P value
21.4
66
18.6
0.35b
17.8
58
16.4
0.60c
3.6
8
2.3
6.6
31
8.7
6.6
31
8.7
0 72.1
0 258
0 72.7
a
Based on diagnostic cases; one patient had two unique diagnoses in 2006. Chi-square test based on MSKCC and other NCI-CCC major revision versus combined minor or no diagnostic revision. c Chi-square test based on MSKCC major revision versus combined minor or no diagnostic revision. MSKCC, Memorial Sloan-Kettering Cancer Center; NCI-CCC, National Cancer Institute-designated Comprehensive Cancer Center. b
discussion In this article, we report the experience at an NCI-CCC with second-opinion pathology review for patients seen in clinical consultation. Six-month periods in 2001, the year after the official publication of the original WHO classification, and in 2006, 5 years later, were reviewed to address the hypothesis that increased familiarity with the new classification system would impact rates of diagnostic revision at expert pathology review. The WHO system, updating the REAL classification and reinforcing the central importance of morphology and immunophenotype in defining distinct clinicopathologic entities, offered the promise of a unified lexicon and pathologic approach to the rendering of an accurate and precise diagnosis of lymphoma. Nonetheless, rates of major diagnostic revision at review by hematopathology at our center, or by another NCI-CCC before consultation at our center, were not significantly different in 2001 or in 2006 (21.3% and 18.6%, respectively, P = 0.35). In both periods, individuals referred with diagnosed lymphoma were reclassified as having benign conditions: 0.3% in 2001 and
Table 3. Major revisions by diagnosis in 2001 and 2006 Original diagnosis
Revised diagnosis
2001, number reviseda (% of original dx)
2006, number reviseda (% of original dx)
Benign Lymphoma (any) Nondiagnostic/ambiguous Diagnostic/definitive HL Non-Hodgkin lymphoma Classical HL T-cell neoplasm Highly aggressive B-cell neoplasm Aggressive B-cell neoplasm Aggressive B-cell neoplasm Indolent B-cell neoplasm Highly aggressive B-cell neoplasm Aggressive B-cell neoplasm
Lymphoma (any) Benign Diagnostic/definitive Nondiagnostic/ambiguous Non-Hodgkin lymphoma HL NLPHL B-cell neoplasm Aggressive B-cell neoplasm Highly aggressive B-cell neoplasm Indolent B-cell neoplasm Aggressive B-cell neoplasm Highly aggressive B-cell neoplasm Aggressive B-cell neoplasm
3/6 1/330 26/72 13/260 3/72 1/251 1/69 3/22 2/5 3/92 6/92 16/118 0/5 0/92
1/5 6/333 25/46 12/310 2/57 1/275 1/51 2/43 3/7 0/93 3/93 8/118 1/7 1/93
(50) (0.3) (36) (5) (4) (0.4) (1) (14) (40) (3) (6) (14) (0) (0)
(20) (2) (54) (4) (4) (0.3) (2) (5) (43) (0) (3) (7) (14) (1)
a
Includes both MSKCC and other NCI-CCC revisions. dx, diagnosis; HL, Hodgkin lymphoma; NLPHL, nodular lymphocyte-predominant Hodgkin lymphoma; MSKCC, Memorial Sloan-Kettering Cancer Center; NCI-CCC, National Cancer Institute-designated Comprehensive Cancer Center.
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Major diagnostic revision MSKCC or other NCI78 CCC secondary review MSKCC revision of 65 submitted diagnosis Prior NCI-CCC revision 13 (MSKCC affirmed) Minor diagnostic revision MSKCC or other NCI24 CCC secondary review MSKCC revision of 24 submitted diagnosis Prior NCI-CCC revision 0 (MSKCC affirmed) No diagnostic revision 263
2006 (n = 355) n (case) %
3 FL, one from CD20+ HL to primary mediastinal DLBCL, and one from lymphocyte-rich classical HL to NLPHL. Multivariate logistic regression showed that IHC carried out at MSKCC [odds ratio (OR) = 1.58, 95% confidence interval (CI) 1.03–2.41] and subtype of referring diagnosis remained significantly associated with major revision after adjusting for biopsy site and time period. Relative to B-cell neoplasms, HL was significantly less likely to undergo major diagnostic revision (OR = 0.37, 95% CI 0.17–0.78, P = 0.009), while collectively, diagnoses that were individually uncommon in the referral population—those representing <5% of all referrals—as well as nondiagnostic were more likely to receive revised diagnoses (OR = 3.52, 95% CI 1.37–9.09, P = 0.009; OR = 2.24 95% CI 1.11–4.55, P = 0.03).
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Table 4. Univariate analysis of relationship between patient and clinical features and rate of diagnostic revision at MSKCC pathology review for combined 2001 and 2006 dataa Variable
69/428 53/291
16.1 18.2
0.46
60/342 62/377
17.5 16.4
0.7
100/609 5/37 7/27 6/24 0/1 4/21
16.4 13.5 25.9 25 0 19
0.65
72/449 21/73 29/197
16 28.8 14.7
0.02
10/47 26/164 86/508
21.3 15.9 16.9
0.68
63/391 59/328
16.1 18
0.5
77/513 45/206
15 21.8
0.03
109/664 13/55
16.4 23.6
0.17
74/460 17/65 14/44 9/129 3/11 3/8 2/2
16.1 26.2 31.8 7 27.3 37.5 100
<0.001
15/110
13.6
0.42b
88/508 15/78 3/9 1/14
17.3 19.2 33.3 7.1
a
Analyses were based on individual patients. Analysis was based on NCI-CCC and four categories of non-NCI-CCC referring centers. MSKCC, Memorial Sloan-Kettering Cancer Center; IHC, immunohistochemistry; NOS, not otherwise specified; NCI-CCC, National Cancer Institutedesignated Comprehensive Cancer Center.
b
2% in 2006. Clinically meaningful discrepancies for every subtype of lymphoma except NLPHL were seen, although the odds of revision did differ by lymphoma subtype, ranging from relatively low in HL (10%) to considerably higher for BL and
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BLL (63%). It is unclear from our results what elements of the expert pathology review most contributed to diagnostic revision. While the data suggest that repeat or additional IHC evaluation was predictive of major revision, it is possible that
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Age <60 ‡60 Gender Female Male Race/ethnicity White non-Hispanic Black non-Hispanic Hispanic Asian Other Unknown Biopsy site Lymph node Skin Other Biopsy type Fine needle aspiration Core biopsy Incisional biopsy IHC-stained slides from referring center reviewed at MSKCC No Yes IHC testing on unstained slides carried out at MSKCC No Yes Additional biopsy carried out on recommendation of MSKCC pathology No Yes Referral diagnosis B-cell neoplasms T-cell neoplasms Nondiagnostic Hodgkin lymphoma Benign Lymphoma NOS Malignancy NOS Referring center NCI-CCC Non-NCI-CCC Non-CCC hospital pathology Corporate pathology laboratory only Public hospital International
Major diagnostic revision rendered at MSKCC pathology review N (discrepant)/N (total) % Unadjusted P value
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Table 5. Multivariate analysis of relationship between clinical features and major diagnostic revision at MSKCC pathology review for combined 2001 and 2006 dataa Clinical feature
Adjusted P value
1 1.44 (0.76–2.75) 0.73 (0.44–1.19)
0.27
1 1.58 (1.03–2.41)
0.04 <0.001
1 1.50 2.24 0.37 3.52
(0.76–2.94) (1.11–4.55) (0.17–0.78) (1.37–9.09)
1 0.84 (0.56–1.26)
0.24 0.03 0.009 0.009
0.40
a
Data analyzed using multivariate logistic regression. Rare diagnosis indicates diagnoses that each represented <5% of referring diagnoses, including undiagnosed conditions (e.g. malignancy NOS and lymphoma NOS) and diagnoses of benign disorders. MSKCC, Memorial Sloan-Kettering Cancer Center; IHC, immunohistochemistry; NOS, not otherwise specified.
funding The Lymphoma Foundation, Mortimer J. Lacher Fellowship.
b
this additional testing was intended to confirm a suspected change in diagnosis, rather than itself single-handedly lead to a new diagnosis. Notably, a consortium of five NCCN centers reported a pathology discordance rate of 6% (43 cases total) with diagnosis at referral [15]. Of these 43 cases, 44% were rendered without additional studies, 21% with additional biopsies and 26% with additional studies, usually IHC. It is unclear why our discrepancy rate is higher than this NCCN consortium, although referral bias, geographic regional variability, and differences in pathology review practices are possibilities. Our data do not support the a priori hypothesis that rates of diagnostic discrepancy would be lower for cases originally diagnosed at another NCI-CCC before consultation at our center. There may be several factors that bias our findings toward the null: referral patterns at our center are such that few patients are seen having been originally seen at a public hospital or having had specimens reviewed only by commercial laboratories. Further, it is likely that patients who were seen previously at another NCI-CCC and sought an additional opinion at our center represent a highly selected group of patients. It is possible that such patients may in part self-select due to perceived diagnostic challenges, which would inflate the odds of diagnostic discrepancy for this group. This is further supported by the nature of the discrepant cases, as many of these occurred in diagnoses with recognized diagnostic imprecision, such as discriminating CD20+ classical HL from primary mediastinal DLBCL. Similarly, caution must be exercised in extrapolating these findings to the general
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disclosure The authors declare no conflict of interest.
references 1. Sheehan WW, Rappaport H. Morphological criteria in the classification of the malignant lymphomas. Proc Natl Cancer Conf 1970; 6: 59–71. 2. Bettini R, Chelazzi G. Prognostic value of the Kiel classification of malignant nonHodgkin’s lymphomas. Tumori 1979; 65: 207–213. 3. National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin’s Lymphoma Pathologic Classification Project. Cancer 1982; 49: 2112–2135. 4. Classification of non-Hodgkin’s lymphomas. Reproducibility of major classification systems. NCI non-Hodgkin’s Classification Project Writing Committee. Cancer 1985; 55: 91–95. 5. Harris NL, Jaffe ES, Diebold J et al. Lymphoma classification—from controversy to consensus: the R.E.A.L. and WHO Classification of lymphoid neoplasms. Ann Oncol 2000; 11 (Suppl 1): 3–10. 6. Harris NL, Jaffe ES, Diebold J et al. The World Health Organization classification of hematological malignancies report of the Clinical Advisory Committee Meeting, Airlie House, Virginia, November 1997. Mod Pathol 2000; 13: 193–207. 7. Swerdlow SH, Campo E, Harris NL et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC 2008. 8. Turner JJ, Hughes AM, Kricker A et al. Use of the WHO lymphoma classification in a population-based epidemiological study. Ann Oncol 2004; 15: 631–637. 9. Lester JF, Dojcinov SD, Attanoos RL et al. The clinical impact of expert pathological review on lymphoma management: a regional experience. Br J Haematol 2003; 123: 463–468. 10. Wetherington RW, Cooper HS, Al-Saleem T et al. Clinical significance of performing immunohistochemistry on cases with a previous diagnosis of cancer coming to a national comprehensive cancer center for treatment or second opinion. Am J Surg Pathol 2002; 26: 1222–1230. 11. Glaser SL, Dorfman RF, Clarke CA. Expert review of the diagnosis and histologic classification of Hodgkin disease in a population-based cancer registry:
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Biopsy site Lymph node Skin Other IHC carried out at MSKCC No Yes Referring diagnosis B-cell neoplasms T-cell neoplasms Nondiagnostic Hodgkin lymphoma Rare diagnosisb Year of pathology review 2001 2006
Adjusted odds ratio (95% confidence interval)
population of patients with lymphoma, as the entire cohort of patients seeking a second opinion at an NCI-CCC is a selected population, biasing the overall results in a similar fashion. As lymphoma pathologists and clinicians now begin to assimilate the newest WHO classification into practice, it is time to ask what impact the previous revisions had on the ability to render accurate and reproducible diagnosis. Unfortunately, the persistence of high rates of major revision after 5 years of experience with the original WHO schema argues that the risk of misdiagnosis remains a clinical challenge, undermining the ability to capitalize on improvements in management for specific lymphoma subtypes. While a gold standard is difficult to define in cases of major diagnostic discrepancies, expert hematopathology review is a common practice among centers of excellence. Given both the high rates of major diagnostic revision and the potential for harm when management decisions are based upon erroneous diagnoses, a clear rationale exists for routine expert second-opinion review of diagnoses of lymphoma.
original articles interobserver reliability and impact on incidence and survival rates. Cancer 2001; 92: 218–224. 12. Kronz JD, Westra WH, Epstein JI. Mandatory second opinion surgical pathology at a large referral hospital. Cancer 1999; 86: 2426–2435. 13. The Non-Hodgkin’s Lymphoma Classification Project. A clinical evaluation of the International Lymphoma Study Group Classification of Non-Hodgkin’s Lymphoma. Blood 1997; 89: 3909–3918. 14. Kukreti V, Patterson B, Callum J et al. Pathology the gold standard—a retrospective analysis of discordant ‘‘second-opinion’’ lymphoma pathology and its impact on patient care. ASH Annual Meeting Abstracts 2006; 108: 348.
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15. LaCasce AS, Kho ME, Friedberg JW et al. Comparison of referring and final pathology for patients with non-Hodgkin’s lymphoma in the National Comprehensive Cancer Network. J Clin Oncol 2008; 26: 5107–5112. 16. Zelenetz AD, Hoppe RT. NCCN: non-Hodgkin’s lymphoma. Cancer Control 2001; 8: 102–113. 17. NCCN practice guidelines for Hodgkin’s disease. National Comprehensive Cancer Network. Oncology (Williston Park) 1999; 13: 78–110. 18. Morton LM, Wang SS, Devesa SS et al. Lymphoma incidence patterns by WHO subtype in the United States, 1992–2001. Blood 2006; 107: 265–276.
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