Evidence Summary 22-2-6
A Quality Initiative of the
Program in Evidence-Based Care (PEBC), Cancer Care Ontario (CCO)
Best Practices for Oncologic Pathology Secondary Review:
Hematologic Cancer
David Good, Glenn G Fletcher, Suhas Joshi, Vishal Kukreti, Cathy Ross,
Andre Schuh, Aaron Pollett, and John Srigley *
Report Date: June 26, 2014
This Evidence Summary is part of an eleven-report series.
Please refer to #22-2-M for background and methodology.
#22-2-M: Methods and Overview
#22-2-1: Breast Cancer
#22-2-2: Gastrointestinal Cancers
#22-2-3: Genitourinary Cancers
#22-2-4: Gynecologic Cancers
#22-2-5: Head and Neck Cancers
#22-2-6: Hematologic Cancers
#22-2-7: Lung Cancer
#22-2-8: Cutaneous Melanoma and Other Skin Cancers
#22-2-9: Central Nervous System (CNS) Tumours
#22-2-10: Bone and Soft Tissue Cancers (Sarcoma)
* Author affiliations are given in Appendix I
For information about the PEBC and the most current version of all reports, please visit the
CCO website at http://www.cancercare.on.ca/ or contact the PEBC office at:
Phone: 905-527-4322 ext. 42822 Fax: 905 526-6775 E-mail: [email protected]
ES 22-2-6
QUESTION
What types of specimens suspected to be or diagnosed as hematologic cancer1 should
or should not have routine secondary pathology review?
INTRODUCTION
This report is part of a series of reports on secondary pathology review in cancer
diagnosis. The reader should consult document #22-2-M: Methods and Overview for a more
detailed background to the project, definitions and limitations of secondary review, and the
methodology used. Only a brief summary of the methods is given below, along with any
details specific to this subproject.
METHODS
The evidence-based reports developed by the CCO Program in Evidence-Based Care
(PEBC) use the methods of the Practice Guidelines Development Cycle (1). For this project,
the core methodology used to develop the evidentiary base was the systematic review.
Evidence was selected and key details extracted by GF of the PEBC.
The body of evidence in this review is primarily comprised of comparative studies on
interobserver accuracy or agreement. The systematic review is intended to promote
evidence-based practice in Ontario, Canada. The PEBC is supported by the Ontario Ministry of
Health and Long-Term Care through CCO. All work produced by the PEBC is editorially
independent from the Ministry.
Definition of Secondary Pathology Review
In this series of documents, secondary pathology review is defined as review of
pathology specimens by a second pathologist that is usually initiated at the request of the
patient or treating clinician, multidisciplinary case conference (MCC) process, quality control
protocol, or as standard practice to review all cases at a cancer centre prior to treatment.
Consultation or review at the request of the primary pathologist or prior to the finalization of
the primary pathologist’s report is NOT included in this definition.
Literature Search Strategy and Study Selection Criteria
Details of the search strategy and inclusion/exclusion criteria are provided in report
#22-2-M of this series and only a brief summary is included here. In December 2009, a search
for practice guidelines was conducted in the National Guideline Clearing House (USA),
National Institute for Health and Clinical Excellence (NICE, UK), Scottish Intercollegiate
Guidelines Network (SIGN), American Society of Clinical Oncology (ASCO), National
Comprehensive Cancer Network (NCCN, USA), National Health and Medical Research Council
(NHMRC, Australia), New Zealand Guidelines Group (NZZG), Canadian Medical Association’s
CMA Infobase: Clinical Practice Guidelines, Association of Directors of Anatomic and Surgical
Pathology, College of American Pathologists (CAP), and the Canadian Association of
Pathologists (CAP-ACP). The SAGE Directory of Cancer Guidelines was searched in May 2012.
MEDLINE and EMBASE databases were searched from 1995 to May 7, 2013. Articles
with terms related to both pathology (including cytology or histology) and diagnostic
discrepancy were retrieved. For inclusion in this report, articles had to include review of the
same samples by a second pathologist (excluding review at the original pathologist’s request),
be related to the diagnosis of hematologic cancer and report on diagnostic discrepancy or
agreement between two (or more) pathologists.
1
Cancer includes precancerous conditions that need to be distinguished from cancer, which may
progress to cancer, or for which there is not general agreement as to whether they should be termed as
cancer.
22-2-6 Hematologic Cancer Evidence Summary
Page 1
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RESULTS
Studies from Literature Search (Table 1)
For hematologic cancer, the search resulted in 39 articles, of which 12 were
reproducibility studies. The 27 studies (2-28) that report agreement or disagreement
between the initial and secondary pathology review diagnoses in hematologic cancer are
summarized in Table 1. Nine additional studies include hematologic cancer along with other
cancers (29-37). While data from was not extracted from the reproducibility studies, these
may be of interest to some readers and address specialized areas of pathologic
interpretation, especially areas where more research or standardization is necessary. The
publications are therefore listed separately in Appendix II.
A. Acute Leukemia and Myelodysplastic syndromes (MDS)
Three studies on acute leukemia were included; one was in Japanese and could not be
fully evaluated. The others used older classification systems and are considered out of date.
No recent studies using current techniques were found.
B. Lymphoma Diagnosis
One study using fine needle aspiration (FNA) (25) found 13% of benign lymphoid
process diagnoses reclassified as Hodgkin disease or atypical lymphoid process.
C. Hodgkin Lymphoma
Anagnostopoulos et al (23) studied specimens initially diagnosed as lymphocytepredominant Hodgkin lymphoma (LPHL) and found that a diagnosis made by H&E alone is less
accurate than when immunohistochemistry (IHC) is also used. Secondary review by a panel of
pathologists resulted in a 36% discrepancy rate using only H&E and Giemsa staining and 44%
when IHC was also used. A more detailed analysis of the results indicates that there was only
70% agreement (30% disagreement) between diagnoses by the same secondary review
pathologists before and after the use of IHC, as many cases with agreement by H&E and
Giemsa staining alone were reclassified. Stevens et al (22) reported a 14% discrepancy in the
type of Hodgkin lymphoma, of which 4% were major (differential diagnosis between
lymphocyte-rich classical HL (LRcHL), non-LPHL, and diffuse large B-cell NHL (DLBCL)).
Glaser et al (24) found that the registry (initial diagnosis) and review diagnosis agreed for 245
of the 362 reviewed cases (68%), but there was a difference depending on histologic subtype
(nodular sclerosis, 95%; lymphocyte predominance, 69%; mixed cellularity, 58%; lymphocyte
depletion, 0%; not otherwise specified, 40%). Eleven cases (3%) were found not to be Hodgkin
lymphoma. Matasar et al (5) reported a 7% major discrepancy rate for classical Hodgkin
lymphoma.
D. Non-Hodgkin Lymphoma (NHL)
The body of evidence is comprised of retrospective studies with a wide range of
discrepancies in different diagnostic categories. Much of the data did not use the current
WHO 2008 classification. Discrepancy rates were generally lower in more recent studies
compared to 15 years ago, but still of concern.
LaCasce et al (8) reported a 3% discrepancy rate for common NHLs. There were no
discrepancies for specimens originally diagnosed as DLBCL, but major discrepancy rates of
4.6% for follicular lymphoma (FL) grades 1/2/NOS, 6.7% for FL grade 3, 1.8% for marginal zone
lymphomas, 12.5% for small lymphocytic lymphomas (SLL), and 3.3% for mantle cell
lymphoma (MCL). All indolent categories combined (FL1, FL2, FL NOS, marginal zone, SLL)
had a 4.9% discrepancy (i.e., change to FL3, MCL, or DLBL).
22-2-6 Hematologic Cancer Evidence Summary
Page 2
ES 22-2-6
Grading in follicular lymphoma has a high rate of variability, and there is suboptimal
interobserver concordance (38,39).
Matasar et al found a 20% major discrepancy rate, with the highest rates for the T-cell
lymphomas (26%) and non-diagnostic/ambiguous specimens (43% changed to
diagnostic/definitive) (5). Classical HL (7%), aggressive B-cell NHL (8%), and indolent NHL
(10%) were lower. Proctor et al reported an average discrepancy rate of 6.5% for the most
common lymphoid malignancies, with lower rates for classical HL (0.6%), 2.6% for plasma cell
neoplasms (PCN), and 3.5% for DLBCL (7). Clarke et al reported a 2% discrepancy for NHL
diagnosed (found not be NHL on review), but also found 41% change in the NHL subtype and
77% disagreement for cases in which the subtype had not been classified (15). Clinical
significance was not reported. Lester et al also found 17% discrepancy (8% change in
management) in lymphoma diagnosis (11).
E. Plasma Cell Neoplasms (including Multiple Myeloma)
Only one study (7) reported specifically on plasma cell neoplasms and found this to be
one of the areas with the least discrepancy (2.6% versus [vs] 27% for all lymphoid
malignancies).
22-2-6 Hematologic Cancer Evidence Summary
Page 3
ES 22-2-6
Table 1. Pathologic discrepancy rates between primary and secondary review pathologists: Hematologic cancers.
(Note: For ease of reading please print this table or enlarge (zoom) it to 120% on the computer monitor.)
Author
# 2nd
#
Year Reviewers Specimens
Reviewer
(Profession/
Training)
Type of Review, Notes
Specimen Description, Notes
Tumour Subtype, Change
or Item Compared
#
Specimens
of Subtype
Discrepancy, %
All
Major Minor
Agreement
%
Kappa
36
65
0.11
Lymphoma
Orem (2)
2012
1
118
Al-Maghrabi 2012
(3)
1
560
Michenet (4) 2012
1
54
Matasar (5)
2
720
Das (6)
2012
2012
1
10
Pathologist with
expertise in
lymphoma
analyzed at Makere University Children with suspected NHL prior
College of Health Sciences
to referral to cancer institute for
(Kampala, Uganda), then
assessment.
blinded review at an academic
center of excellence for cancer
pathology in Netherlands;
classified according to WHO
2000
Not stated
Overall
Burkitt’s lymphoma
→other NHL
Other NHL
Other cancer
→non cancer
→NHL or Burkitt’s lymphoma
Non-cancerous chronic conditions
( Non-cancerous → cancer)
Overall (lymphoma to non-lymphoma,
type of lymphoma, reactive/nondiagnostic to lymphoma)
Cases referred to2 tertiary
Specimens diagnosed as
care hospitals in Saudi Arabia lymphoma; major
for evaluation or therapy for discrepancy=significant impact on
lymphoma after diagnosis at therapy or prognostic implication;
primary institution excluded minor=no major impact on therapy
cases sent for ancillary testing (eg subtype of Hodgkin’s lymphoma
or true consults where primary or follicular lymphoma grade I vs II)
pathologist was unsure of
diagnosis
Expert
Prospective review by expert Specimens diagnosed as
Overall
after initial diagnosis at a
lymphoma; discrepancy=
(one discrepancy: Mantle cell→DLBL)
general hospital; WHO 2008 lymphoma vs other malignancy;
classification of lymphomas; subtyping disagreement with or
IHC for only 11 cases. Excluded without impact on therapy
cases for 2nd opinion or
cutaneous lymphoma
pathologist with
routine review of all outside all patients with 2nd opinion
 All reviews at MSKCC compared to
expertise in
pathology before clinical
pathology review of lymphoma;
previous diagnosis
hematopathology; opinion is finalized at
major discrepancies would alter
 classical Hodgkin’s lymphoma
skin biopsies
Memorial Sloan-Kettering
management according to NCCN
 Indolent NHL to aggressive B-cell
reviewed by
Cancer Center (MSKCC);
guidelines; minor discrepancies
NHL
dermatopathologist original (2000/2001) WHO
rendered a different diagnosis but
 Aggressive B-cell NHL to other
classification
would not fundamentally alter
 T-cell
includes 21 cases in which
management
 non-diagnostic/ambiguous
MSKCC confirmed a revised
changed to diagnostic/definitive
diagnosis already made by
second opinion at another
designated Comprehensive
Cancer Center (NCI-CCC)
Retrospective blind review
Cases with initial FNA or
 TCTBCL not confirmed in 8 FNA
histopathology diagnosis of T-cellsamples, HL→HL (MC) in one
rich B-cell lymphoma (TCRBCL), or
TCBCL indicated as one of the
possibilities
22-2-6 Hematologic Cancer Evidence Summary
118
34
43
64
35
24
64
100
31
69
74
560
9.5
54
1.85
720
28
28
13
36
0
26
7.0
2.5
90
20
8
72
121
236
7.4
10.2
184
65
118
8.2
26
43
10
90
Page 4
10
ES 22-2-6
Author
Proctor (7)
LaCasce (8)
# 2nd
#
Year Reviewers Specimens
2011
2008
1 (2)
1949
731
Reviewer
(Profession/
Training)
Type of Review, Notes
Specimen Description, Notes
Tumour Subtype, Change
or Item Compared
samples considered diagnostic or  Overall (significance assessed in
suspicious for lymphoid
350/512 discrepancies)
malignancy, excluded samples sent  Category C (insufficient information)
for consultation by a local
 10 most common lymphoid
hematopathologist unable to
malignancies (excludes Category C)
provide a firm diagnosis; impact on
 DLBL
patient management assessed by a
 FL
hematologic oncology specialist:
 PCN
A=major change to clinical
 cHL
management (e.g. inappropriate
 CLL
chemotherapy); B=Minor change to
 LPL
clinical management; C=delay to
 reactive
treatment (e.g. insufficient
 MCL
information to allow treatment in
 MZL
initial diagnosis)
 TCL
Unspecified or high-grade lymphoma
(Category C, all had review diagnosis of
more specific type)
hematopathologists central review in National
patients in database with
 all cases initially common NHLs
Comprehensive Cancer
documented pathologic diagnosis
 follicular lymphoma, (grade 1, 2 or
Network (NCCN) nonat referral center and a final
NOS grouped together)
Hodgkin's lymphoma (NHL)
pathologic diagnosis of one of the 5  follicular lymphoma, grade 3 (FL3)
database; WHO classification common B-cell NHLs grouped into 6  marginal zone lymphomas
categories (excluded Hodgkin's,
 small lymphocytic lymphoma (SLL)
Burkitt's, lymphoblastic, T-cell
 diffuse large B-cell lymphoma
lymphomas which may be more
(DLBL)
challenging)
 mantle-cell lymphoma (MCL)
 all indolent categories (follicular
Recalculated using only those with
grade 1/2/NOS, marginal zone,
initial diagnosis of above NHLs;
SLL) to non-indolent
reclassification among indolent
nationally
recognized expert in
hematopathology;
< 10% of samples
reviewed by 2
experts
centralized expert review
service for general
histopathologists in the North
Central London Lymphoma
network hospitals 2003-2008
by expert at UCLH (University
College London Hospital), used
WHO criteria
#
Specimens
of Subtype
All
Discrepancy, %
1873
27
1391
6.5
94
374
260
192
173
155
59
43
35
35
65
225
3.5
6.9
2.6
0.6
10.3
10.2
23.3
17.1
31.4
6.2
100
97
93
97
99
90
90
77
83
69
94
0
712
216
3.4
4.6
2.8
4.6
97
95
30
58
32
284
6.7
5.2
19
0
6.7
1.7
13
0
93
95
81
100
92
306
3.3
4.9
3.3
4.9
97
95
1065
15.7
11
2.0
0.9
2.0
1.5
1.5
3.6
1.5
1.5
3.6
Major Minor
3.0
11
Agreement
%
73
14
groups not considered major
Kukreti (9,10) 2006,
2009
1065
subspecialty
lymphoma
pathologists
consecutive lymphoma
patients with a referral centre
pathology report and then
clinical care at Princess
Margaret Hospital (PMH).
Policy is all outside pathology
reviewed at PMH as part of
routine clinical care. Includes
some internal cases where
discrepancy is from cytologichistologic discordance,
amendments, physician or
tumour board review. WHO
classification
Authors identified patients with
all discrepancy
change in diagnosis by reviewing
(major=moderate/severe ,
clinical and pathology records, but minor=minimal)
not actual pathology samples.
 malignant ↔ non-malignant
Discrepant cases graded by 6
 lymphoma ↔ other
blinded reviewers (pathologists,
hematological malignancy
clinicians, outside physicians) on a 4  NHL↔ Hodgkin's
level scoring system with respect to  lymphoma ↔ solid tumour
potential for harm. Level 1: no
 more ↔ less aggressive
harm, no clinical relevance (n=17);
lymphoma
Level 2-4 are of clinical relevance.
Level 2: minimal harm, no change
Note: 144/167 discrepancies are
in treatment (n=37); Level 3:
based on second opinion pathology;
moderate harm, change in
the remaining appear to be from
treatment or management (n=70); internal cases
Level 4: severe, markedly different
treatment or management (n=43)
22-2-6 Hematologic Cancer Evidence Summary
Page 5
3.5
84.3
Kappa
ES 22-2-6
Author
# 2nd
#
Year Reviewers Specimens
Lester (11)
2003
Youngson
(12)
1995
Hamdani (13) 2008
2
Mead (16)
2004
2
40
139
1
2002
Igarashi (17) 2002
1522
65
3
90
Tobinai (18) 2001
Siebert (19)
2001
#
Specimens
of Subtype
All
745
16.8
7.7
minor: reclassified within same grade
of disease, major = clinically major
(affect therapy)
498
47
24
senior registrar then second opinion at referral lab lymph node lesions initially
histopathologist
after being reported upon
reported from different centres
elsewhere; REAL/WHO
classification
comparison of diagnostic value patients with confirmed diagnosis
of biopsy and aspirates
of follicular lymphoma (FL), and
discrepancy between trephine
bone marrow (BM) biopsies and
flow cytometry of BM aspirates
all discrepancy
40
72
malignant to/from benign
40
10
samples with cytohistological
discordance
BM histology samples
flow cytometry of BM aspirates
28
28
21
11
expert
expert pathological review for
hematopathologist NHL patients in to the Greater
Bay Area Cancer Registry;
International Classification of
Diseases for Oncology (ICD-O2) system
central pathology review in
phase II chemotherapy trial:
United Kingdom Lymphoma
Group LY06 study
hematopathologists central pathology review in
(committee of 3);
phase II study (IDEC-C2B8) of
REAL classification samples from 17 institutions in
Japan; consensus of 3
hematopathologists
non-Hodgkin's lymphoma (NHL)
patients who had participated in
population-based case-control
study;
NHL rediagnosed as other (mostly
leukemia)
subtype of NHL
unclassified NHL assigned subtype on
review
1522
2
98
1496
128
41
77
59
patients (age 16-60) diagnosed with Burkitt's lymphoma (BL), all
Burkitt's lymphoma by local
discrepancies diagnosed on review as
pathologist
diffuse large B-cell lymphoma (DLBL)
65
20
80
patients (age 15-75 yrs) with
Group I: indolent B cell lymphoma
indolent B-cell lymphoma or mantle Group II: MCL
cell lymphoma (MCL) who had
relapsed or were refractory to
conventional chemotherapy
67
9.0
91
19
16
84
pathologists
lymphoid neoplasms subtyped
according to Revised EuropeanAmerican Lymphoma (REAL)
classification criteria (1994)
188
11
89
Type of Review, Notes
Specimen Description, Notes
histopathologists
central expert pathological
with expressed
review by All Wales
interest/ expertise Lymphoma Panel (AWLP) of
in hematopathology; samples from district general
hospital pathologists; REAL
and subsequently WHO
classification
samples diagnosed as lymphoma;
major = change in management
due to central review, based on
comparing hypothetical
management plan of initial
diagnosis to management received
(treatment added, removed, or
change in regime or mode
(chemotherapy, radiotherapy)
498
Schmidt (14) 2006
Clarke (15)
745
Reviewer
(Profession/
Training)
3
188
central review of cases from malignant lymphoma, age 15+,
North West Regional Cancer histologically confirmed; cases in
Registry for lymphoid leukemia registry supplemented by cases
and non-Hodgkin's lymphoma; from histopathologist,
Kiel (1974) classification
hematologists, clinicians
specializing in this area
lymphoid neoplasms
diagnosed at a community
hospital underwent blinded
retrospective review at an
academic centre
22-2-6 Hematologic Cancer Evidence Summary
Tumour Subtype, Change
or Item Compared
subtype
Discrepancy, %
Page 6
Major Minor
Agreement
%
Kappa
83
23
53
28
0.54
ES 22-2-6
Author
# 2nd
#
Year Reviewers Specimens
Non1997
Hodgkin's
Lymphoma
Classification
Project (20)
Bednar (21)
1995
Matasar (5)
2012
5
1403
Reviewer
(Profession/
Training)
Type of Review, Notes
Specimen Description, Notes
Tumour Subtype, Change
or Item Compared
consensus of 5
clinical evaluation of
up to 200 consecutive cases of non- diagnosis other than NHL on review
hematopathologists International Lymphoma Study Hodgkin's lymphoma (NHL)
Group (ILSG) classification
submitted from 9 sites, obtained
before treatment
42
pathologist
Czech Republic
hematological biopsy, mostly
malignant lymphoma
719
pathologist with
expertise in
hematopathology;
skin biopsies
reviewed by
dermatopathologist
Multidisciplinary
conference
(hematologist,
radiation oncologist,
pathologist,
radiologist, nuclear
medicine)
Hematopathologists
routine review of all outside
all patients with 2nd opinion
pathology review of lymphoma;
major discrepancies would alter
management
#
Specimens
of Subtype
All
Discrepancy, %
1403
1.8
42
45
720
28
Major Minor
Agreement
%
Kappa
98
Hodgkin Lymphoma
2
Stevens (22) 2012
125
(see lymphoma section for
further study details)
 All reviews at MSKCC compared to
previous diagnosis
 classical Hodgkin’s lymphoma
central review at Hodgkin
outpatient clinic of Hodgkin
lymphoma patients newly
diagnosed in community
hospitals
Major=adapted therapy (mainly
nodular lymphocyte predominant
sub-type); minor=no change in
treatment
Study of prevalence of T-cellrich large B-cell lymphoma
(TCRLBCL) among LPHD
samples from 16 oncological
centers
Patients age > 15 with lymphocyte H&E and Giemsa staining alone
predominance Hodgkin disease
Cases with consensus in review panel
(LPHD); excluded if insufficient for Stain + IHC
IHC or incomplete clinical data, or
→LRCHD
contained unrelated tissue (non→cHD NS/MC
lymphoid)
→unclassified
→reactive
→NHL
women age 19-79 with incident
Agreement with ICD-02 code/subtype
histologically confirmed HD
cases determined on review as not HD,
reported to a population-based
10/11 diagnosed as NHL, 1 suspected
cancer registry; Rye Classification of leukemia
subtypes, International
Classification of Diseases for
Oncology (ICD-O-2)
Anagnostopoulos (23)
2000
Panel of 4 or
6
pathologists
521
Glaser (24)
2001
1
362
Hematopathologist population based case series
to evaluate reliability of
Hodgkin disease diagnosis
Chhieng (25) 2001
2
89
pathologists
Araseki (26) 2012
[Japanese
with English
abstract]
1
105
blind review of FNA samples; patients (age 5-90) with Hodgkin
Rye Classification of subtypes disease (HD) evaluated by fine
needle aspiration (FNA) of lymph
nodes, included both primary and
recurrent HD
Type of lymphoma
Staging (based on radiology)
Overall treatment proposed
benign lymphoid process reclassified as
Hodgkin disease (n=3) or atypical
lymphoid process (n=7)
121
20
8
72
8.1
86
77
81
7.4
125
123
104
14
23
388
312
388
362
362
36
33
44
30
5
2
4
3
32
3
79
13
4
15
19
64
67
56
68
Leukemia
Central review in cases of bone Aplastic anemia (AA), idiopathic
marrow failure; bone marrow cytopenia of undetermined
trephine biopsy/ and/or
significance (ICUS), and
aspiration, cytogenetic analysis myelodysplastic syndromes (MDS)
in 93% of cases
22-2-6 Hematologic Cancer Evidence Summary
Original vs central review diagnosis
[*unclear whether same samples were
reviewed, or composite diagnosis
based on repeat sampling]
(7)*
Page 7
(93)
0.66
ES 22-2-6
Author
# 2nd
#
Year Reviewers Specimens
Reviewer
(Profession/
Training)
#
Specimens
of Subtype
All
suspected or locally confirmed
cases found on review neither MDS
pediatric myelodysplastic
nor JMML (54% of discrepancies were
syndromes (MDS) or juvenile
other leukemias)
myelomonocytic leukemia (JMML)
173
47
adults with local institutional
AML reclassified as myelodysplastic
diagnosis of acute myeloid
syndromes (MDS)
leukemia (AML), reviewed slides of
blood and marrow from all patients
at central lab
907
4
95
23
major modification in therapy or
Hematologic systems (lymph nodes)
prognosis, does not include change
only in histologic grade or stage;
limited number of cases as most
were seen by the dermatology
department
interinstitutional, at request of compared 1st and treating
Lymph nodes
clinical staff of treating
institution reports; major =clinical
institution
impact
818
1.1
2nd opinion at major referral
centre
reviewed at Aga Khan University, Lymph nodes
Pakistan; most sent by clinicians,
some by primary pathologists
major discrepancies (benign to
Lymph nodes
malignant or vice versa), different
type of neoplasm, change in N or M
of TMN classification
72
31
66
1.5
conferences, external review,
Lymph nodes
internal QA, physician request; self- bone marrow
report of 100 consecutive
specimens at 74 institutions
288
107
5.9
6.6
1.4
1.9
9.9
0.0
1.3
Type of Review, Notes
central review of peripheral
blood and bone marrow
smears and bone marrow
biopsies
Specimen Description, Notes
Tumour Subtype, Change
or Item Compared
Valera (27)
2004
1 ? (sent to
committee
for review)
173
?, WHO criteria
Bernstein
(28)
1996
3
907
morphologists;
central pathology review:
French-American - Cancer and Leukemia Group B
British (FAB) criteria (CALGB) 8461 protocols for
AML
Prescott (29) 1995
1
95
Kronz (30)
1999
1
818
Weir (31)
2003
1
38
Ahmed (32)
2004
1
72
Tsung (33)
2004
1
66
pathologists
patients referred to cancer
center for therapy or second
opinion; all cases referred to
treating institution
1
395
pathologist
review after sign-out
Renshaw (35) 2006
1
151
Internal blinded rapid review; major error leads to amendment,
1/6 of cases from new
minor error requires no action
pathologists, rest random
Hematology, all discrepancies
reviewer missed lesion
151
Lu (36)
1
339
external consultation
1
45
interinstitutional consultation, major =2 step deviation
FNA, prior to treatment or
(unsatisfactory, benign, atypical,
patient requested 2nd opinion suspicious, malignant) or change in
treatment or prognosis
Lymph nodes
Bone marrow
Lymph nodes other than cervical and
neck
317
22
45
Discrepancy, %
Major Minor
Agreement
%
Kappa
53
Studies that reported on hematologic and other cancers, specific types not indicated
Raab (34)
Bomeisl (37)
2005
2009
2009
review at regional cancer
treatment centre
General surgical
pathologist
cases with confident 1st diagnosis, Lymph nodes
excluded cases where 2nd opinion
sought
mandatory 2nd opinion; all
cases referred to treating
institution, excludes consult
cases with uncertain diagnosis
38
12
12
13
0
77
94
9.9
4
0
2.2
Abbreviations: NHL = non-Hodgkin’s lymphoma; cHL = classical Hodgkin lymphoma; DLBL = diffuse large B-cell lymphoma; FL = follicular lymphoma; PCN =
plasma cell neoplasm; CLL = chronic lymphocytic leukemia; LPL = lymphoplasmacytic lymphoma; MCL = mantle-cell lymphoma; MZL = marginal zone
lymphoma; TCL = T cell lymphoma.
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Clinical Practice Guidelines
A. Hematology
NICE (40,41), the British Committee for Standards in Haematology (BCSH) (42) (based
on NICE), and the Australian Cancer Network (43) recommend that all diagnoses of possible
hematological malignancies be reviewed by a specialist hematopathologist.
B. Leukemia
The NCCN guideline on acute myeloid leukemia (AML) (44) states that accurate
classification requires multidisciplinary diagnostic studies (by IHC, cytochemistry, or both, in
addition to molecular genetics analysis). An experienced hematopathologist should review
rare cases such as acute leukemias of ambiguous lineage (including mixed phenotype acute
leukemias, as defined by the 2008 WHO classification).
C. Lymphoma
The Australian Cancer Network (43) recommends lymphoma biopsies be reviewed by
an expert in hematopathology, and that tissue suspected of Burkitt or other high-grade
lymphoma should be referred for review by a pathologist skilled in lymphoma diagnosis. The
Alberta Health Services (45) recommends a reference lymphoma pathologist should confirm
the diagnosis, especially for core needle biopsy (CNB) samples. According to NICE (40,41), up
to 5% of people treated for lymphomas in Wales have benign conditions, and at least 10%
receive suboptimal treatment due to incorrect classification. NCCN (46) recommends NHL be
reviewed by a hematopathologist and cautions that FNA or CNB alone is unsuitable for the
initial diagnosis of lymphoma.
It is recommended that specialist or expert hematopathologists review pediatric and
neuropathology lymphomas (BCSH (42)), post-transplant lymphoproliferative disease (PTLD)
(Alberta Health Services (45)), and mature T-cell and NK-cell lymphomas (BCSH (47). Primary
central nervous system (CNS) lymphoma and intraocular lymphoma need to be reviewed by a
hematopathology, neuropathology, and/or ocular pathology specialist (BCSH (48), British
Neuro-Oncology Society (49)). Primary cutaneous B-cell lymphoma and peripheral T-cell
lymphomas require review by a hematopathologist with expertise in these diagnoses (NCCN,
(46)).
DISCUSSION
A subspecialist pathologist may be essential in some cases, including cases having less
distinct features, requiring specific tests, and being rare or unusual cancers. MCCs (also
referred to as tumour boards) are important for all cancers and are supported by CCO (50,51).
Cases with secondary pathology review, especially if there is a discrepancy, are often seen at
the tumour board. Cases may be discussed to present the original and new diagnosis to the
team, due to the need for more clinical history to provide a context for interpreting the
pathology or to decide if the case needs a third opinion. Even when the overall diagnosis is
not in question, there is still room for refining the diagnosis. Minutes should document the
discussion, and anything that affects the outcome of the case should be included in the
pathology report.
The need for second pathology review in hematopathologic malignancies is a complex
question and various issues in particular hematological malignancies, which can be quite
diverse, are discussed below.
Based on the available literature, significant variability is observed in the discrepancy
rates between the initial and secondary pathology review for hematological malignancies.
There may be a number of factors that contribute to this variability. First of all, the earlier
studies use older classification systems (i.e., prior to 2001 and 2008 WHO classification) that
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rely more on morphology and less on ancillary testing such as IHC and molecular studies
(12,13,15-21). As our understanding of the pathobiology of hematological malignancies has
evolved, the diagnostic criteria have also become better defined to aid in more uniform
classification. Secondly, at least one of the studies with a lower discrepancy rate focused on
the five most common B-cell NHL, which are typically the most straightforward to diagnose
and excluded rarer entities that usually have higher rates of diagnostic discordance (8). Many
of the larger studies were conducted in tertiary care cancer centres, which may have resulted
in enrichment for more complex patients and a subsequent upward bias to the discordance
rate. Thirdly, hematological malignancies are relatively uncommon for most surgical
pathologists, which results in a decreased level of comfort and expertise, especially in
recognizing interpretive nuances and ambiguities of ancillary testing (11) . Additionally, some
of the studies originate from countries where there is admittedly a lack of external quality
assurance programs and limited access to ancillary testing (13,21).
Nonetheless, a relatively high discrepancy rate between initial and secondary reviews
remains, even in more recent studies that are based on the current WHO classification system
that incorporates ancillary studies (4,5,7-11). This appears to be a reflection of the relative
difficulty in the diagnosis of hematological malignancies as well as the lack of expertise and
access to sufficient ancillary testing outside of academic centres and large community
hospitals. Even with some studies showing lower discrepancy rates, there is still a subset of
patients in whom treatment may have been altered as a result of the change in diagnosis,
raising some important questions. Is it possible to identify those patients who are at higher
risk of misdiagnosis and are most likely to benefit from secondary pathology review? As well,
are there processes that could be routinely implemented in all diagnostic settings that would
improve diagnostic accuracy for hematological malignancies?
Admittedly, it would be impractical for every case to be subjected to a secondary
review process. Therefore, conclusions were made based on the available literature and the
consensus of the authors in an attempt to standardize routine diagnostic processes and to
capture the areas where the highest discrepancy rates exist that would benefit from
secondary review. Before addressing the issue of secondary pathology review, it was
considered essential to provide a general framework for specimen analysis according to
recent guidelines and experience of the authors. Best pathology practice and requirements
for secondary pathology review are interrelated, as when best practice is not followed (e.g.,
features reported, use of IHC or other tests), secondary review is more often necessary.
Statements regarding best practice, while informed by the reviewed studies, are not all
directly linked to the data extracted during the evidence review.
A. Organizational and Practice Requirements
As a result of a better understanding of their pathobiology and the evolution of
classification systems to the current 2008 WHO system, a simple histological assessment is no
longer sufficient for the proper diagnosis and classification of hematological malignancies
(52). Immunophenotyping procedures including flow cytometry and IHC are vital as each
hematological entity expresses a relatively characteristic immunophenotype. Molecular
genetic testing and cytogenetic studies help to define specific entities but also play a
significant role in defining prognosis and guiding therapeutic strategies. Specimens need to
be collected appropriately so that all necessary tests can be done, and the pathologist must
be aware of the clinical need so that the specimens are processed accordingly. The integrity
of specimens and proper fixation must be ensured.
Given the necessity of ancillary testing in the diagnosis of hematological neoplasms,
ready access to these tests either in house or at a referral laboratory is vital.
Hematopathological diagnoses should be performed only in laboratories having or with access
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to flow cytometry, IHC that includes at a minimum the recommended panels for
hematolymphoid proliferations, and cytogenetic/molecular tests. Appropriate quality control
procedures must be in place. Reasonable turnaround times will vary depending on the
diagnosis and its acuity, making it difficult to define acceptable turnaround times for each
ancillary test.
The panel of antibodies chosen for flow cytometry and IHC should follow a practical
and pragmatic approach in order to best utilize resources and meet WHO criteria for diagnosis
(53).2
Cytogenetic/molecular tests are considered essential for the complete diagnosis and
prognosis of acute leukemia and may be required for the confirmation of specific lymphoma
subtypes. They may prove helpful in confirming the diagnosis of myelodysplastic syndromes
(MDS) and may reveal prognostic information and guide therapy. These ancillary studies often
have prognostic impact for lymphoma and myeloma.
For tissue samples with a suspected diagnosis of a hematolymphoid neoplasm, special
handling processes are required to achieve optimal histological sections and to ensure correct
tissue samples are provided for the required ancillary studies (54-56). This includes receiving
the material fresh so that appropriate allotment of tissue for ancillary studies requiring live
cells can be achieved. Material for histology should be thinly sliced in order to allow optimal
penetration of the fixative. Proper fixation times will depend on the fixative used. Due to
the small nuclear diameter of lymphocytes and the need to avoid nuclear superimposition for
accurate interpretation, the histologic assessment of lymphoma should be performed on thin
sections (2-3 µm) instead of the 4 µm often used for other samples (57). Both the pathologist
and treating clinician need to be aware of the growing importance of participation in clinical
trials and the resultant emergence of novel therapies that may require special collection or
handling techniques.
The pathologic results and clinical evidence must be correlated and evaluated
together in determining diagnosis. Both sufficient pathological and clinical expertise are
required. Pathologists should have other colleagues to consult with within their practice or
have connection to a regional reference centre. Particularly for lymphoma, clinicopathologic
correlation is extremely important, and, often, until both aspects come together, diagnostic
accuracy is limited. Often lymphoma is only part of a differential diagnosis at the time of
surgical biopsy; hence; the pathologist is not able to do a targeted evaluation for lymphoma
and there is often an inability to do an appropriate analyses such as flow cytometry. A similar
analogy may occur if the full clinical history at the time pathology samples are submitted is
not provided. Once further clinical information is available, there is a question of whether
this would change the pathologic interpretation, and this may be reason for a second review.
As most diagnoses in hematopathology are relatively rare, there may not be sufficient
expertise in some centres, and collaboration with other centres will be required.
B. Acute Leukemia
The field of hematopathology with respect to the diagnosis of leukemia and lymphoma
has evolved over the time period of the studies included in the literature review. Earlier
diagnoses involved only morphology, while flow cytology and then IHC developed and are now
considered essential. As the two main studies on acute leukemia use older classification
2
The Quality Management Program-Laboratory Services (QMPLS) of the Ontario Medical
Association issues consensus recommendations for its members, and in 2013 released a report
“Laboratory Investigation of Neoplastic Hematological Disorders (Flow cytometry)”. This may be of use
to Ontario hematopathologists, but is not available to the general public.
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systems and are out of date, no evidence on which to base a recommendation was found in
the literature review. Acute leukemia patients in Ontario are treated at a tertiary cancer
centre where there will be further testing on bone marrow. Review of the initial specimens
of primary diagnosis is therefore unlikely to alter treatment. Secondary pathology review
should be conducted In the event that the marrow investigations are not being repeated at a
tertiary care institution.
C. Myelodysplastic Syndromes (MDS)
While no studies on secondary pathology review in MDS were located, current
treatment strategies for MDS and related issues are summarized. Difficult cases may
comprise a large portion of cases of MDS and accurate diagnosis is essential. The precise
classification of MDS in the current WHO and prognostic schemes (such as IPSS-R or WPSS)
(52,58,59) requires cytogenetic and molecular information along with appropriate clinical and
laboratory information in addition to the morphologic parameters for optimal
subclassification. Cases must be seen in centres that can access full cytogenetic and
molecular assessment; secondary review is often needed to ensure precise classification.
Unusual or diagnostically difficult cases of MDS especially require a considerable
amount of clinical, cytogenetic, and laboratory supportive evidence and secondary pathology
review should be considered. There are some newer therapies that may be used in cases of
MDS. These therapies are generally only available in specialized centres, in which case many
of these patients are followed in these centres (60). At centres dealing only with a subset of
referral patients with high-risk diseases, secondary review of all specimens may be
appropriate. Uncertainty may arise either from the nature of the specimens or the lack of
clinical correlation including failure of a patient/disease to respond as expected to the given
treatment. The diagnosis of MDS is a rapidly changing field, and support of research
initiatives and clinical trials on diagnosis and therapy should be encouraged.
D. Lymphoma Diagnosis
FNA samples are considered inadequate for primary lymphoma diagnosis and are not
used for this purpose in Ontario. The use of FNA for a primary diagnosis is strongly
discouraged. The NCCN guideline also states that FNA or core biopsy alone is not suitable for
an initial diagnosis of lymphoma, although it may be sufficient to establish relapse. In certain
circumstances, a combination of FNA and core biopsy plus appropriate ancillary techniques
for differential diagnosis (IHC, flow cytometry, molecular/cytogenetic studies) may be
sufficient for lymph nodes that are not easily accessible for excisional or incisional biopsy
(46). One study using FNA (25) found 13% of benign lymphoid process diagnoses reclassified as
HL or atypical lymphoid process.
The field of hematopathology with respect to the diagnosis of leukemia and lymphoma
has evolved over the time period of the studies included in the literature review. Earlier
diagnoses involved only morphology, while flow cytology and then IHC developed and are now
considered essential. Some of the studies and discrepancies reflect the impact of the
different classification systems used. The current (2008) WHO classification system for
hematopoietic and lymphoid tumours states that explicit immunophenotypes are required for
proper diagnosis and classification (52). The editors of the WHO document more recently
published an article on evolving concepts and practical applications (61). The CAP
(www.cap.org) protocol for HL (54) states that immunophenotyping using IHC is necessary for
the initial diagnosis of nearly all cases of HL. The CAP protocol for NHL (55) and the protocol
for hematopoietic neoplasms involving bone marrow (56) both require immunophenotyping by
flow cytometry or IHC, each with advantages and disadvantages. The panel of antibodies
chosen should follow a practical and pragmatic approach in order to best utilize resources but
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should also follow best practice recommendations in order to meet the WHO-defined criteria
for diagnosis (57). The NHL protocol notes that molecular studies play an increasingly
important role in diagnosis. Both CAP protocols for lymphomas (54,55) give guidelines as to
the more common immunophenotyping and cytogenetic findings for various types of
neoplasms.
No lymphoma should be diagnosed without ancillary studies, including appropriate and
sufficient IHC ± flow cytometry. Specimens without the ancillary studies require a diagnosis
to be completed by the primary pathologist or secondary review. The quality of IHC analysis
is variable between laboratories. Until the procedures and quality are standardized, a
secondary pathology review may be indicated based on knowledge of the laboratory, selection
of antibodies, and completeness of the report. It is often more expedient to have secondary
pathology review by a hematopathologist at the treating centre than to correct a deficient
report. Missing information may be due to a lack of expertise or facilities, in which case
review by a second pathologist would be required.
Excisional lymph node biopsies are recommended when the lymph nodes in question
are accessible (peripheral) as a complete workup including IHC and secondary pathology
review (if required) is often not possible on CNB samples. A diagnosis of lymphomas on CNB is
difficult and should have a very low threshold for secondary review. Core needle biopsies are
often suboptimal for diagnostic purposes and further sampling may be required. Cores may
not contain enough or representative tissue. While secondary review is an encouraged
practice, the authors’ experience is that some laboratories will not submit the entire core
samples for secondary view. Availability of surgery, wait times, and adverse effects need to
be weighed against the probability of obtaining an optimal pathology diagnosis. For less
accessible lymph nodes such as mediastinal and abdominal nodes, initial CNB may be
preferred.
Bone marrow biopsies are often received in the context of staging for a prior diagnosis
of lymphoma. However, occasional bone marrow samples are received for primary lymphoma
diagnosis. Some B cell NHLs, including lymphoplasmacytic lymphoma and hairy cell leukemia,
are often limited to the bone marrow, and, therefore, this type of sample is recommended
for primary diagnosis. For most other types of NHL, a bone marrow biopsy is not
recommended as the sole biopsy type for diagnosis and classification. Although some patterns
of bone marrow involvement may suggest a particular subtype of lymphoma, significant
discordance is observed between bone marrow findings and other tissue sites (62,63). As
well, variations in the fixation and decalcification processes for marrow specimens may affect
IHC staining that may be required for accurate classification (64,65). As the current WHO
classification of lymphoid tumours is based primarily on tissue histology and
immunophenotyping, this should be the preferred sample for proper lymphoma diagnosis and
classification.
While ancillary studies such as flow cytometry, IHC, and molecular testing are
important and often required for primary diagnosis, there are situations where they may not
be necessary, as indicated in the algorithm for staging bone marrow in malignant lymphoma
(ML) by the Mayo Clinic (66). For example, these tests are not considered to add any further
diagnostic value if there is already a primary ML diagnosis and classification from lymph node
tissue and the bone marrow morphologic findings are concordant, or if the bone marrow is not
morphologically involved by ML.
a. Hodgkin Lymphoma
The data reported indicate both the need for IHC for all cases and the need for a
secondary review of rarer subtypes of classical HL and LPHD (now classified as NLPHL).
Routine secondary review is not required for nodular sclerosis classical HL diagnosed with full
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IHC panel, though should be performed for diagnoses made only by morphological assessment
of H&E stained slides.
b. Non-Hodgkin Lymphoma (NHL)
Discrepancy rates are generally lower in more recent studies but still of concern. For
common NHLs, there is approximately 5% discrepancy rate upon secondary review. We are
reluctant to recommend routine secondary review for all cases, as our experience is there is a
subset of clear-cut cases. Routine secondary pathology review may not be required for
indolent B-cell lymphomas provided that these have been diagnosed with appropriate IHC and
flow cytometry and the indolent diagnosis is concordant with the patient’s clinical
presentation. Routine secondary pathology review is not required for DLBCL when the
diagnosis has included appropriate IHC and flow cytometry and there is clinico-pathological
correlation (although additive tests may be required based on clinical presentation).
However, there should be a secondary review by a hematopathologist with expertise in
lymphoma diagnosis for specimens diagnosed as DLBCL with features suspicious of Burkitt
lymphoma or with a proliferation rate approaching 100%;
High-grade FL is more likely misdiagnosed and often downgraded, in which case
treatment will be altered; secondary review is therefore warranted. While our initial opinion
was that low-grade FL was less subject to discrepancy, data indicate that all grading in FL has
a high rate of variability and there is suboptimal interobserver concordance (38,39). Our
experience, however, is that there is a subset of cases where the diagnosis is clear from both
a pathologic and clinical view, and these specimens would not be submitted for secondary
review. Given these findings, it is difficult to form conclusions regarding routine pathology
secondary review and it needs to be determined on a case-by-case basis.
As a diagnosis of MCL often leads to upfront autologous stem cell transplant in younger
patients, greater certainty in diagnosis is warranted. Our experience is that when both cyclin
D1 and CD5 are positive and morphology and clinical presentation are consistent with MCL,
the diagnosis is accurate and a review is not required. While some studies reported
discrepancy rates for MCL, it is unclear whether they met this standard. When CD5 is weak or
negative or only detectable by flow cytometry, these cases are more likely to have a
discrepancy than if both cyclin D1 and CD5 are positive.
There should be secondary review by a hematopathologist with expertise in lymphoma
diagnosis for specimens diagnosed as high-grade B-cell lymphomas (e.g., Burkitt and B-cell
lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma);
lymphoblastic lymphoma⁄leukemia; all T-cell and NK-cell lymphomas; and rare lymphomas
(e.g., immunodeficiency-associated lymphoproliferative disorders); as well as histiocytic,
dendritic cell neoplasms, and myeloid sarcoma. Cutaneous lymphoma should be reviewed by a
hematopathologist or dermatopathologist with expertise in cutaneous lymphoma. The
appropriate ancillary diagnostic studies need to be performed.
The above conclusions are consistent with several guidelines that indicate the need for
specialist or expert hematopathologist review for all lymphoma specimens (40-43) or
subtypes, including pediatric and neuropathology lymphomas (42), PTLD (45), mature T-cell
and NK-cell lymphomas (47), and Burkitt or other high-grade lymphoma (43). NCCN
recommends that primary cutaneous B-cell lymphoma and peripheral T-cell lymphomas be
reviewed by a hematopathologist with expertise in these diagnoses (46). TheBritish NeuroOncology Society recommends that primary CNS lymphoma and intraocular lymphoma be
reviewed by a hematopathology, neuropathology, and/or ocular pathology specialist (49).
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E. Plasma Cell Neoplasms (including Multiple Myeloma)
Plasma cell neoplasms are diagnosed using a combination of morphologic, cytogenetic,
radiological, and serological testing. Only one study (7) reported specifically on plasma cell
neoplasms and found this to be one of the areas with the least discrepancy (2.6% vs 27% for
all lymphoid malignancies). While the evidence in the literature review is very limited, it is
the authors' consensus opinion that review is not required as long as the initial diagnosis is
comprehensive, including cytogenetics, and flow cytometry/IHC confirms the clonal nature of
the plasma cells.
CONCLUSIONS
A. Organizational and Practice Requirements
 Hematopathological diagnoses should be performed only in laboratories having or with
access to flow cytometry, IHC that includes at a minimum the recommended panels
for hematolymphoid proliferations, and cytogenetic/molecular tests. Appropriate
quality control procedures must be in place.
 The panel of antibodies chosen for flow cytometry and IHC should follow a practical
and pragmatic approach in order to best utilize resources and meet WHO criteria.
 Cytogenetic/molecular tests are essential for acute leukemia diagnosis and for some
lymphoma subtypes.
 Specimens need to be collected appropriately so that all necessary tests can be done,
and the pathologist must be aware of the clinical need so that specimens may be
processed accordingly. Integrity of specimens and proper fixation must be ensured.
 Histologic assessment of lymphoma should be performed on thin sections (2-3 µm)
instead of the 4 µm often used for other samples.
 The pathologic results and clinical evidence must be correlated and evaluated
together in determining diagnosis. Both sufficient pathological and clinical expertise
are required. Pathologists should have other colleagues to consult with within their
practice or have connection to a regional reference centre.
B. Acute Leukemia
 Routine secondary pathology review of acute leukemia diagnostic specimens in the
primary diagnosis of acute leukemia is not required as the provincial protocol is to
refer these patients to a tertiary care centre. Secondary pathology review should be
performed if the marrow investigations are not being repeated at a tertiary care
institution.
C. Myelodysplastic syndromes (MDS)
 Unusual or diagnostically difficult cases of MDS require a considerable amount of
clinical, cytogenetic, and laboratory supportive evidence for appropriate diagnosis and
prognostication and should have secondary pathology review. Secondary review may
also be required in other cases of MDS to ensure that the precise classification is
achieved.
D. Lymphoma Diagnosis
 Use of FNA for primary diagnosis of is strongly discouraged.
 No lymphoma should be diagnosed without ancillary studies, including appropriate and
sufficient IHC +/- flow cytometry. Specimens without the ancillary studies require
diagnosis to be completed by the primary pathologist or secondary review.
 Excisional lymph node biopsies are recommended when lymph nodes in question are
accessible (peripheral) as complete workup including IHC and secondary pathology
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review (if required) is often not possible on CNB samples. Diagnosis of lymphomas on
needle core biopsy is difficult and should have a very low threshold for secondary
review.
a. Hodgkin Lymphoma
 Diagnoses of HL based only on morphological assessment of H&E stained slides should
have secondary pathology review including an appropriate IHC panel.
 Rarer subtypes of classical HL and NLPHL should have secondary pathology review.
 Routine secondary pathology review is not required for nodular sclerosis classical HL
diagnosed with a full panel of IHC.
b. Non-Hodgkin Lymphoma (NHL)
 Routine secondary pathology review is not required for DLBCL when diagnosis has
included appropriate IHC and flow cytometry and there is clinico-pathological
correlation (although additive tests may be required based on clinical presentation).
DLBCL with features suspicious of Burkitt lymphoma or with a proliferation rate
approaching 100% should have secondary pathology review by a hematopathologist
with expertise in lymphoma diagnosis and with availability of cytogenetic facilities.
 Routine secondary pathology review is not required for MCL diagnosed using an IHC
panel that includes a positive cyclin D1 and CD5 result and provided that the
morphology and clinical features are typical.
 Routine secondary pathology review may not be required for indolent B-cell
lymphomas provided that these have been diagnosed with appropriate IHC and flow
cytometry and the indolent diagnosis is concordant with the patient’s clinical
presentation.
 Secondary pathology review by a hematopathologist with expertise in lymphoma
diagnosis should be performed for high-grade FL; high grade B-cell lymphomas (e.g.,
Burkitt and B-cell lymphoma, unclassifiable, with features intermediate between
DLBCL and Burkitt lymphoma); lymphoblastic lymphoma⁄leukemia; all T-cell and NKcell
lymphomas;
rare
lymphomas
(e.g.,
immunodeficiency-associated
lymphoproliferative disorders); histiocytic or dendritic cell neoplasms; and myeloid
sarcoma.
 It is recommended that cutaneous lymphoma be reviewed by a hematopathologist or
dermatopathologist with expertise in cutaneous lymphoma. The appropriate ancillary
diagnostic studies need to be performed.
E. Plasma Cell Neoplasms (including Multiple Myeloma)
 Routine secondary pathology review of plasma cell neoplasms is not required as long
as appropriate IHC stains and cytogenetic studies are done.
FUTURE RESEARCH
Diagnosis for high grade B cell lymphomas are difficult and even experts often cannot
reach agreement. Diagnostic accuracy and interobserver variability are of concern. Further
molecular studies will promote an understanding of the molecular mechanisms behind the
lymphomas, better subclassification, and more easily accessible tests to differentiate
between types. This would be an alternative to gene expression profiling as this is not
feasible for many cases.
Telepathology is a relatively new technology and has selected uses in pathology.
There is currently no well-defined role for telepathology in hematopathology second review.
It is expected that use of telepathology will continue to evolve and may have a role in sharing
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of cases and slides for expert review. The authors have no recommendations on telepathology
as yet but support continued investigation in this area.
UPDATING
This series of evidence summaries on secondary pathology review will be considered
current for three years. The evidence summaries will then be designated as archived and
indicated as such on the CCO website. These reports will not undergo annual assessment.
They will not be updated unless required as the basis of a new guideline by the Pathology and
Laboratory Medicine Program (PLMP).
CONFLICT OF INTEREST
In accordance with the PEBC Conflict of Interest (COI) Policy, the authors were asked
to disclose potential COIs. Potential COIs that were declared are summarized in Appendix I.
The COIs declared did not disqualify any individuals from performing their designated role in
the development of this review, in accordance with the PEBC COI Policy. To obtain a copy of
the policy, please contact the PEBC office by email at ccopgi.mcmaster.ca
ACKNOWLEDGEMENTS AND AUTHORSHIP
The Pathology & Medicine Program and the Working Group would like to thank the
following individuals for their assistance in developing this report:
 Dr John Srigley, Dr Sandy Boag, Glenn Fletcher, Dr Suhas Joshi, Dr Mahmoud Khalifa,
and Dr Brendan Mullen for taking the lead in the overall pathology secondary review
project.
 Melissa Brouwers, Sheila McNair, Hans Messersmith, Fulvia Baldassarre, and Robert
Mackenzie for providing feedback on draft versions.
 Denise Kam for providing research assistance and for managing communication among
the working group and with the reviewers.
 Max Chong and Denise Kam for conducting a data audit.
 Carol De Vito for copyediting.
 Jennifer Hart and Dana Wilson-Li of Cancer Care Ontario.
A complete list of the members of the Best Practices for Oncologic Pathology
Secondary Review: Hematologic Cancers Working with their affiliations and conflict of
interest information is provided in Appendix 1.
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Funding
The PEBC is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health
and Long-Term Care. All work produced by the PEBC is editorially independent from the Ontario
Ministry of Health and Long-Term Care.
Copyright
This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be
reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario
reserves the right at any time, and at its sole discretion, to change or revoke this authorization.
Disclaimer
Care has been taken in the preparation of the information contained in this report. Nonetheless, any
person seeking to apply or consult the report is expected to use independent medical judgment in the
context of individual clinical circumstances or seek out the supervision of a qualified clinician. Cancer
Care Ontario makes no representation or guarantees of any kind whatsoever regarding the report
content or use or application and disclaims any responsibility for its application or use in any way.
Contact Information
For information about the PEBC and the most current version of all reports,
please visit the CCO website at http://www.cancercare.on.ca/ or contact the PEBC office at:
Phone: 905-527-4322 ext. 42822 Fax: 905 526-6775 E-mail: [email protected]
22-2-6 Hematologic Cancer Evidence Summary
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Appendix I. Members of the Pathology Secondary Review Working Group.
Pathology Secondary Review Working Group: Hematologic Cancer
 Dr. David Good, Service Chief for Hematopathology, Kingston General Hospital;
Assistant Professor, Pathology and Laboratory Medicine, Queen’s University
 Dr. Suhas B. Joshi, Chief of the Department of Pathology and Regional Director of
Laboratories, Niagara Health System, St Catharines General Site, St Catharines
 Dr. Vishal Kukreti, Hematologist, Lymphoma and Myeloma Site Group, Division of
Medical Oncology and Hematology, Princess Margaret Cancer Centre/UHN; Assistant
Professor, Department of Medicine, University of Toronto
 Dr. Aaron Pollett, Pathologist, Mount Sinai Hospital, Toronto; Assistant Professor,
Laboratory and Medicine and Pathobiology, University of Toronto; Chair, Pathology and
Laboratory Medicine Program (PLMP), Cancer Care Ontario
 Dr. John Srigley, Pathologist and Chief of Laboratory Medicine, Credit Valley Hospital,
Mississauga; Professor (part-time), Pathology and Molecular Medicine, McMaster
University; Chair (until April 2013), Pathology and Laboratory Medicine Program
(PLMP), Cancer Care Ontario
 Dr. Cathy Ross, Pathologist, Hamilton Regional Laboratory Medicine Program;
Associate Professor, Anatomical Pathology, Pathology and Molecular Medicine,
McMaster University
 Dr. Andre Schuh, Hematologist and Head of Leukemia Services, Division of Medical
Oncology and Hematology, Princess Margaret Cancer Centre/UHN; Division of
Hematology, Department of Medicine, University of Toronto
 Glenn G. Fletcher, Health Research Methodologist, PEBC, Cancer Care
Ontario/McMaster University, Hamilton, Ontario
 Denise Kam, Research Assistant, PEBC, Cancer Care Ontario/McMaster University,
Hamilton, Ontario
 Jennifer Hart, Manager - Clinical Programs, Cancer Care Ontario, Toronto, Ontario
 Dana Wilson-Li, Policy and Research Analyst, Pathology and Laboratory Medicine
Program, Cancer Care Ontario, Toronto, Ontario
AS declared he is a shareholder in Aurora MSC, a software company working in the
digital telepathology area. The other authors declared no conflicts of interest.
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