ORIGINAL ARTICLE
Pathology Reporting of Neuroendocrine Tumors:
Application of the Delphic Consensus Process to the
Development of a Minimum Pathology Data Set
David S. Klimstra, MD,* Irvin R. Modlin, MD, PhD,w N. Volkan Adsay, MD,z
Runjan Chetty, MD,y Vikram Deshpande, MD,J Mithat Gönen, PhD,z Robert T. Jensen, MD,#
Mark Kidd, PhD,w Matthew H. Kulke, MD, ** Ricardo V. Lloyd, MD, PhD, w w
Cesar Moran, MD,zz Steven F. Moss, MD,yy Kjell Oberg, MD,JJ Dermot O’Toole, MD,zz
Guido Rindi, MD,## Marie E. Robert, MD,*** Saul Suster, MD,w w w Laura H. Tang, MD, PhD,*
Chin-Yuan Tzen, MD, PhD,zzz Mary Kay Washington, MD,yyy Betram Wiedenmann, MD,JJJ
and James Yao, MDzzz
Abstract: Epithelial neuroendocrine tumors (NETs) have been
the subject of much debate regarding their optimal classification.
Although multiple systems of nomenclature, grading, and
staging have been proposed, none has achieved universal accep-
tance. To help define the underlying common features of these
classification systems and to identify the minimal pathology data
that should be reported to ensure consistent clinical manage-
ment and reproducibility of data from therapeutic trials, a
From the From the Departments of *Pathology; zEpidemiology and
Biostatistics, Memorial Sloan-Kettering Cancer Center, New York,
NY; Departments of wSurgery; ***Pathology, Yale University
School of Medicine, New Haven, CT; zDepartment of Pathology,
Emory University, Atlanta, GA; yDepartment of Pathology,
Toronto General Hospital, Toronto, Ontario, Canada; JDepartment
of Pathology, Massachusetts General Hospital; **Department of
Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
#National Institute of Diabetes, Digestive and Kidney Diseases
(RTJ), Bethesda, MD; wwDepartment of Pathology (RVL), Mayo
Clinic, Rochester, MN; Departments of zzPathology; zzzGastro-
intestinal Medical Oncology, M.D. Anderson Cancer Center,
Houston, TX; yyDepartment of Medicine, Rhode Island Hospital/
Brown University, Providence, RI; JJDepartment of Medical
Sciences, University of Upsalla, Upsalla, Sweden; zzDepartment of
Medicine, St. James’s Hospital and Trinity College, Dublin, Ireland;
##Department of Pathology and Laboratory Medicine, University of
Parma, Parma, Italy; wwwDepartment of Pathology, Medical College
of Wisconsin, Milwaukee, WI; zzzDepartment of Pathology, Cathay
General Hospital, Taipei, Taiwan; yyyDepartment of Pathology,
Vanderbilt Medical School, Nashville, TN; and JJJDepartment of
Internal Medicine, Charite Hospital, University of Berlin, Berlin,
Germany.
Supported by Novartis Corporation.
David S. Klimstra, MD, Irvin R. Modlin, MD, PhD, Shared first
authorship.
Correspondence: David S. Klimstra, MD, Surgical Pathology Service,
Department of Pathology, Memorial Sloan-Kettering Cancer Center,
1275 York Avenue, New York, NY 10065 (e-mail: klimstrd@mskcc.
org).
Supplemental digital content is available for this article. Direct URL
citations appear in the printed text and are provided in the HTML
and PDF versions of this article on the journal’s Web site
(www.ajsp.com).
Copyright r 2010 by Lippincott Williams & Wilkins
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multidisciplinary team of physicians interested in NETs was
assembled. At a group meeting, the participants discussed
a series of ‘‘yes’’ or ‘‘no’’ questions related to the pathology of
NETs and the minimal data to be included in the reports. After
discussion, anonymous votes were taken, using the Delphic
principle that 80% agreement on a vote of either yes or no would
define a consensus. Questions that failed to achieve a consensus
were rephrased once or twice and discussed, and additional votes
were taken. Of 108 questions, 91 were answerable either yes or no
by more than 80% of the participants. There was agreement
about the importance of proliferation rate for tumor grading, the
landmarks to use for staging, the prognostic factors assessable
by routine histology that should be reported, the potential for
tumors to progress biologically with metastasis, and the current
status of advanced immunohistochemical and molecular testing
for treatment-related biomarkers. The lack of utility of a variety
of immunohistochemical stains and pathologic findings was
also agreed upon. A consensus could not be reached for the
remaining 17 questions, which included both minor points
related to extent of disease assessment and some major areas
such as terminology, routine immunohistochemical staining for
general neuroendocrine markers, use of Ki67 staining to assess
proliferation, and the relationship of tumor grade to degree of
differentiation. On the basis of the results of the Delphic voting,
a minimum pathology data set was developed. Although there
remains disagreement among experts about the specific classifi-
cation system that should be used, there is agreement about the
fundamental pathology data that should be reported. Examina-
tion of the areas of disagreement reveals significant opportunities
for collaborative study to resolve unanswered questions.
Key Words: neuroendocrine tumor, consensus, carcinoid tumor,
Delphic, classification
(Am J Surg Pathol 2010;34:300–313)
E pithelial neuroendocrine tumors (NETs) are a diverse
group of pathologically related neoplasms that can
arise in most epithelial organs of the body but are
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Am J Surg Pathol  Volume 34, Number 3, March 2010
particularly well-described in the lung, tubular gastro-
intestinal tract, and pancreas. As the entity of ‘‘carcinoid
tumor’’ was first proposed by Oberndorfer over 100 years
ago,56 the clinical and pathologic features of NETs have
been described by many investigators, with most studies
focusing on subsets of tumors restricted to 1 organ or
organ system.30,40,46 For this reason, and also because the
larger family of NETs is highly diverse in terms of origin,
mechanism of development, functional status, histologic
patterns, and biologic behavior, many different diag-
nostic terms and classification systems have arisen. For
example, ‘‘neuroendocrine tumor,’’ ‘‘carcinoid tumor,’’
‘‘endocrine neoplasm,’’ and ‘‘neuroendocrine carci-
noma’’ have all been applied to small intestinal pri-
maries.6,9,47,58,80 In general, carcinoid tumors of the
tubular gastrointestinal tract have been separated from
pancreatic endocrine neoplasms.8–10,28 Site-specific grad-
ing, staging, and classification systems have been devel-
oped by the World Health Organization (WHO) and the
European Neuroendocrine Tumor Society (ENETS), and
additional proposals are under development by the
American Joint Committee on Cancer (AJCC), and the
North American Neuroendocrine Tumor Society (NA-
NETS).9,10,21,28,75,76 Furthermore, multiple different in-
dividual classification schema have been published,22,30,45
and numerous studies have investigated potential prog-
nostic factors based on morphology, immunophenotype,
and molecular biology.7,11,17,31,35,44,66,74,99 Although all
of these different systems have merit and can be used
to stratify the biologic behavior of neuroendocrine
tumors,14,24,29,30,64 the specific criteria differ between the
various anatomic sites, and translation between the classi-
fication systems is not always possible.54 As promising
new therapies arise for this family of tumors,41,61,96 it is
of increasing clinical relevance to carry out accurate
classification and prognostication to properly tailor
treatment, not only for surgically resected primary tumors
but also for metastatic disease, from which only biopsy
specimens may be available. The lack of a single uniform
system of nomenclature, grading, and staging for NETs
will hamper efforts to evaluate new therapies and to
compare the results of published therapeutic trials.54
A careful examination of the major published
classification systems for NETs reveals considerable
overlap in the essential information used to derive the
specific subgroups. Tumor size, extent of invasion, and
presence of nodal or distant metastases are well-accepted
staging parameters for all primary sites.9,10,21,35,38,75,76
The proliferative index has emerged as a fundamental
grading characteristic that appears in most major
schema.1,5,6,33,62,63,93 Thus, there likely exists a compen-
dium of basic information that should be collected for all
neuroendocrine tumor specimens that would allow trans-
parent and accurate data comparisons. Whereas the stan-
dardization of the terminology and classification criteria for
all NETs of every anatomic site would be a laudable but
likely elusive goal, the development of a ‘‘minimum data
set’’ that could easily be translated into any chosen
classification system should be more easily attainable.
r 2010 Lippincott Williams & Wilkins
Pathology Reporting of Neuroendocrine Tumors
The purpose of this workshop or meeting was to
bring together recognized experts in the field of neuroen-
docrine tumors, including pathologists and surgeons,
oncologists, and gastroenterologists, to (1) review existing
classification systems, (2) evaluate the published literature
related to prognosis-related parameters or treatment-
related parameters, (3) determine which pathologic para-
meters are currently (or likely will become) important to
predict prognosis and guide therapy, (4) decide what basic
information related to diagnosis, grading, staging, and
prognosis should be included in pathology reports, and
(5) draft a checklist of the minimal pathology data set
for NETs.
METHODS
Physicians with dedicated expertise in the field of
NETs were identified. An effort was undertaken to recruit
individuals from different countries and to include both
pathologists (12 participants) and clinicians (8 partici-
pants, including 2 surgeons, 2 gastroenterologists, and
4 medical oncologists). Panel members were recruited
from the United States, Canada, Europe (Sweden, Germany,
Italy, and Ireland), and Asia. Participants in major
organizations that have developed (or will develop soon)
classification systems for NETs were selected, including
the WHO, the ENETS, the NANETS, the AJCC, and the
Cancer Committee of the College of American Patho-
logists. An effort was made to ensure balanced represen-
tation of individual groups and institutions to provide a
breadth of input from clinical, scientific, and geographic
perspectives. A biostatistician was also included. A group
meeting was held in Miami Beach, FL from February 6
to 8, 2009. Each participant was asked to prepare a
brief presentation related to specific aspects of the topic,
to collectively review the existing published data and to
ensure that the ensuing discussions would be based on
uniform background information.
The Delphic consensus process,19,25 was used to
achieve agreement on issues related to the analysis of
the pathology of NETs. Before the meeting, a series of
questions were developed and distributed to the group
for review. Each question was formatted to be answer-
able as ‘‘yes’’ or ‘‘no.’’ The questions covered aspects of
terminology, grading and staging, immunohistochemical
evaluation, assessment of prognostic factors, and other
issues, all related to the information that should be
contained in standard pathology reports of NET speci-
mens. At the meeting, the group discussed each of the
questions to debate controversial issues and achieves
agreement where possible. Consistent with the Delphic
process, some questions required modification to enable
general agreement to be reached. After the discussion
period, a formal vote was taken, and all participants were
required to vote on each question. Each question was
read aloud, and anonymous voting was conducted using
computerized electronic voting devices. The results of the
voting were immediately tabulated. The voting categories
are displayed in Supplementary (Table 1, Supplemental
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Klimstra et al
Digital Content 1, http://links.lww.com/PAS/A49). Votes
of ‘‘Agree strongly’’ and ‘‘Agree with minor reservation’’
were considered ‘‘yes’’ votes; votes of ‘‘Disagree with
major reservation (disagree moderately)’’ and ‘‘Disagree
strongly’’ were regarded as ‘‘no’’ votes. Consensus was
defined to be achieved if at least 80% of the partici-
pants voted ‘‘yes’’ or ‘‘no.’’ In the event of no immediate
consensus, the topic was reopened for discussion, and a
second vote was then taken. If 80% agreement was not
attainable, further debate to allow modification of the
proposition was then undertaken and a third vote taken.
If a consensus was still not attainable, the question was
deemed to have no agreement. The final phrasing of the
questions and the result of the final vote on each question
were recorded.
RESULTS
The complete list of Delphic questions along with the
consensus answers are presented in Supplementary (Table 2,
Supplemental Digital Content 2, http://links.lww.com/PAS/A50).
Of 108 questions, consensus was reached based on the
definition of 80% agreement for 91 (84%) of the
questions. Most of the questions upon which there was
no agreement (Supplementary Table 3, Supplementary
Digital Content 3, http://links.lww.com/PAS/A51) showed
marked polarization of opinion, participants usually
selecting a voting category to register either a ‘‘yes’’ or
‘‘no’’ vote [rather than choosing ‘‘Agree with major
reservation’’ or ‘‘Disagree with minor reservation (dis-
agree mildly),’’ votes that would have suggested no strong
opinion on the question]. For only 1 question with no
agreement would the change of a single vote have allowed
consensus to be reached. A discussion of the general areas
of consensus and disagreement is presented below, divided
into broad topic areas.
Terminology
The group did not attempt to develop a single
standard terminologic classification system for NETs, but
did address limited specific issues. The terms ‘‘endocrine’’
and ‘‘neuroendocrine’’ are variously used for this family
of tumors,4,36 and there is justification for either term.
There was agreement that these 2 terms could be used
synonymously for differentiated neoplasms with epithelial
and (neuro)endocrine differentiation in the gastro-
enteropancreatic system. It was also agreed that ‘‘carci-
noid tumor’’ has become archaic and that it should be
avoided as the primary diagnostic term. However, there
was recognition that the term has become entrenched in
the lexicon, and as a practical matter it may still be
reasonable for the foreseeable future to reference this
term (for example, parenthetically) in the pathology
report to ensure fluid communication. There was con-
siderable debate about the use of ‘‘tumor’’ versus
‘‘neoplasm’’ Although some participants pointed out
that all NETs are regarded to be neoplastic, justifying
the designation (neuro)endocrine neoplasm (44% favored
this term), others argued that the (neuro)endocrine tumor
terminology has become widely disseminated in several
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Am J Surg Pathol  Volume 34, Number 3, March 2010
major recent classification systems (that of the EN-
ETS,75,76 for example), and that to abandon the term
at this point would require excessive reeducation (44%
preferred to retain the term ‘‘tumor’’). The other termino-
logic issue that could not be resolved involves the use
of the term ‘‘carcinoma,’’ especially when applied to
well-differentiated NETs that have displayed clinically
obvious malignant behavior. The WHO classification
for small bowel and pancreatic NETs uses the term
‘‘tumor’’ for organ-confined disease and ‘‘carcinoma’’ for
otherwise identical neoplasms with metastases or gross
local invasion.9,28,38 A number (69%) of the participants
considered that this distinction reflects differences in
tumor stage rather than an inherent difference in tumor
biology, as suggested by the use of ‘‘carcinoma.’’
Conversely, others argued for the use of the ‘‘carcinoma’’
for all well-differentiated NETs. This discussion and
the lack of consensus on this issue amplified the wide
diversity of opinions about the implications of diagnostic
terminology.
Diagnostic Immunohistochemistry
Demonstration of neuroendocrine differentiation
by the use of specific immunohistochemical stains can
be helpful in the diagnosis of NETs.50 The vast majority
of well-differentiated NETs express 1 or more general
neuroendocrine markers (such as chromogranin A and
synaptophysin), and it was agreed that the use of
immunohistochemistry for diagnostic purposes should
be recommended in a majority of cases, including in all
cases of biopsies of metastatic disease. There was no
agreement that diagnostic immunohistochemistry should
be mandated for all NETs, however. Some participants
(53%) considered that routine immunohistochemical
staining is not necessary to diagnose histologically typical
examples of well-differentiated NETs (carcinoid tumors)
of the ileum, appendix, and stomach (such as the multiple
tumors in patients with hypergastrinemia-associated
neuroendocrine tumors) or certain pancreatic endocrine
tumors such as clinically functional insulinomas. The
use of diagnostic immunohistochemistry for cases with
unusual or unclear histologic features was encouraged.
The group agreed that the only 2 stains to be routinely
recommended are chromogranin A and synaptophysin.
There was agreement that staining routinely for other
neuroendocrine markers including chromogranin B,
CD56 (neural cell adhesion molecule, N-CAM), CD57
(leu7), and neuron-specific enolase was not indicated, and
that the specificity of these markers (especially neuron-
specific enolase) was questionable. There was also
consensus that stains for keratins were not to be routinely
recommended, although most well-differentiated NETs
do express keratins (in particular, cytokeratins 8 and 18,
detected by Cam5.250), and that p53 immunostaining
also was not essential. The group further agreed that there
are only limited indications to carry out stains for specific
peptide hormones or bioamines, even when the clinical
history suggests the presence of a ‘‘functional’’ NET. As
functional NETs are not defined by immunohistochemical
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Am J Surg Pathol  Volume 34, Number 3, March 2010
labeling, but rather by clinical symptoms and serology,28
a statement about the functional nature of the tumor is
not needed in the pathology report. Furthermore, there
are no histologic features that define a functional NET
and there is no difference in biologic behavior between
functional and nonfunctional NETs, independent of
other prognostic factors such as size, stage, and grade.30
Irrespective of the clinical syndrome or the bioactive
agent produced, both types are NETs and should be
regarded as a single entity. Limited peptide immunohisto-
chemistry could be done (eg, for insulin or gastrin) if there
is a clinical indication to show the production of a specific
peptide in a functional tumor, such as in a patient with
multiple endocrine neoplasia type 1 (MEN1) with more
than 1 pancreatic NET.
For patients presenting with metastatic disease
from an unknown primary, an attempt should be made
to determine the primary site because of the differing
therapeutic options available for pancreatic versus
intestinal NETs.41,61,70,96 In the case of well-differentiated
NETs, immunohistochemical staining can be helpful to
determine the primary site; stains for CDX2 and TTF1
should be carried out, which would point toward an
origin in the intestines or pancreas (for CDX2) and lung
(TTF1), respectively.32,78,84 The sensitivity and specificity
of these stains require more study, however, and negative
staining does not exclude origin in these sites. It should be
noted that staining for TTF1 is not helpful for high-grade
neuroendocrine carcinomas, such as small cell carcinoma,
as extrapulmonary examples may express this mar-
ker.13,51,81,92 Peptide immunohistochemistry was felt to
have limited value in the determination of the primary site
for NETs presenting with metastatic disease and was not
recommended. The group also recommended against the
use of silver-based histochemical stains such as argentaffin
or argyrophil reactions, as these stains have largely been
replaced by immunohistochemical markers such as
chromogranin and synaptophysin.
The possibility of carrying out immunohistochem-
ical staining for somatostatin receptors (SSTRs) was
discussed,65,91 given the therapeutic implications of SSTR
expression.55,59,72,89 However, it was agreed that these
stains are not currently routinely indicated, because well
characterized commercially available SSTR subtype
antibodies do not exist, and the information about SSTR
expression to some extent can be inferred based on
somatostatin receptor scintigraphy (SSTR 2 and 5), which
is now widely carried out in patients with NETs.60,89
Further evaluation of the clinical relevance of SSTR
subtype evaluation of individual NETs may lead to
increased application of this assessment to determine the
specific utility of SST analogues with different receptor
profiles.91
Staging
The prognostic importance of tumor stage is widely
reflected in all of the classification systems for NETs. The
discussions focused on the specific features of the primary
tumors that should be included in pathology reports that
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Pathology Reporting of Neuroendocrine Tumors
will allow proper tumor staging to be carried out using
any of the well-established systems. For all NETs, the
size of the tumor (in 3 dimensions) should be reported. In
the tubular gastrointestinal tract, the depth of maximal
invasion through the wall should be stated, using the
same landmarks as for the staging of exocrine carcinomas
of the corresponding locations.21,75,76 Reporting of the
maximal thickness of the tumor was felt to be unnecessary
however. For appendiceal NETs, invasion into the
mesoappendix should be reported, and the extent (limited
vs. extensive) should be documented. There was no
agreement concerning the measurement of the amount
of mesoappendiceal invasion however. For pancreatic
NETs, the presence of extrapancreatic invasion should be
reported.
Lymph node metastases should be reported, includ-
ing the number of involved nodes and the total number of
nodes examined. The number of nodes needed to ensure
‘‘adequate’’ staging has not been defined, but attempts
should be made to identify as many lymph nodes in the
resected specimen as possible. There was no agreement
about the necessity of distinguishing micrometastases
from macrometastases (47% favored making a distinc-
tion), in part because no universally acceptable definition
of micrometastasis has been proposed for NETs. In
addition, it was not agreed whether the size of the largest
lymph node metastasis should be documented (56%
believed the size should be reported). The group agreed
that TNM staging should be carried out using 1 of the
proposed staging systems,21,75,76 but it was also recog-
nized that several systems exist, none of which is currently
universally accepted. For this reason, it is critical to
indicate in the report which specific TNM staging system
has been used.
The status of the resection margins should be
reported, both for primary tumor resections and for
resected metastases. For resected tumors with close
margins (ie, within less than 0.5 cm), it was recommended
that the distance to the margin be indicated. It was not
agreed to be necessary to document the distance if the
tumor is more than 0.5 cm from the margin, but 74% still
thought it should be reported.
Grading
Another fundamental predictor of outcome in
NETs is the grade of the tumor. The group recognized
3 grading categories of NETs: low grade, intermediate
grade, and high grade.38,75,76,87 It was further agreed that
in general, well-differentiated NETs are regarded to be
either low grade or intermediate grade, whereas poorly
differentiated NETs are high grade by definition. The
group recognized the dramatic difference in clinical
behavior between well-differentiated NETs (which can
progress very slowly over years to decades, even in the
presence of metastatic disease) and poorly differentiated
NETs (which are high-grade carcinomas characterized by
rapid dissemination, resistance to treatment, and a
quickly fatal course). Thus, the fundamental distinction
of well differentiated from poorly differentiated NETs
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was recognized to be a critical pathologic determination.
Grade progression in well-differentiated NETs was
discussed, and it was agreed that this phenomenon can
occur.43,52,69,100 Thus, it is possible that different regions
within a single tumor (or different sites of metastasis) can
display different grades. However, there has been little
histologic documentation of grade progression and it is
not clear how often NETs may undergo this change.
There have been rare reports of high-grade transforma-
tion of well-differentiated NETs,86 but this occurrence
seems to be particularly rare; there are insufficient data
to determine the biologic behavior of such tumors. Thus,
there was no agreement about whether well-differentiated
NETs could ever be biologically high grade (68% felt
that well-differentiated NETs can never be high grade).
It was noted that in some circumstances, more than
1 primary NET may arise within a single organ. In the
case of familial multicentric NETs, it was agreed that
the different tumors can also have different grades,
but there was no agreement on this point regarding
sporadic multicentric NETs. There was a consensus that
no NETs should be reported as ‘‘benign’’ (other than
tightly defined subsets such as pancreatic or pulmo-
nary NETs less than 0.5 cm or gastric NETs less than
0.5 mm).35,37,38,83
The group recognized that different grading systems
exist for well-differentiated NETs of different anatomic
sites, and although there was consensus that a uniform
grading system applicable to all primary sites would
be desirable, the data to justify such a system do not
currently exist. The difficulty of determining which
grading scheme to apply to metastases of unknown
primary sites was acknowledged. Despite all of the
vagaries of grading NETs, there was unanimous agree-
ment that a grade should be stated in the report, with
the particular grading system used to be specified.
Furthermore, the raw information used to derive the
grade should also be reported to enable comparison
between different grading systems. It was recognized that
the proliferative index is inherently linked to the grade of
NETs but it was also appreciated that the proliferative
fraction may not be homogeneous throughout a given
NET and that there may be differences in proliferation
between the primary tumor and metastatic sites. The
simplest method to determine the proliferative index is
to count mitotic figures, and this piece of data was
unanimously accepted to be necessary for complete
pathology reports. The group agreed that the calculation
of the number of mitoses per unit area of the tumor was
the most reliable, and that the number of mitoses in 10
high-power fields (2 mm2) was a standard format used in
many classification and grading systems and should be
endorsed. It was pointed out that some grading schemes
use the number of mitoses in 50 high-power fields,22,30
and the group agreed that a total of 50 fields should be
counted, but ultimately the mitotic rate should be
expressed based on the number in 10 high-power fields.
It is not adequate to count a single randomly chosen area
of the tumor; rather, the most active regions (‘‘hot spots’’)
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Am J Surg Pathol  Volume 34, Number 3, March 2010
should be identified by scanning the slides at intermediate
magnification, and the formal mitotic count should
include the most active areas to ensure assessment of
the worst case scenario for therapeutic strategy.
Significant discussion revolved around the use of
immunohistochemical staining for Ki67 as an alternative
method to quantify the proliferative fraction.33 The
Ki67 index (expressed as the percentage of neoplastic
cells showing nuclear labeling) is used in several grading
and classification systems and is incorporated into the
recent ENETS proposals.28,75,76 In Europe, Ki67 is widely
used and reported as a critical pathologic predictor of
prognosis. In North America, however, the use of Ki67
staining has largely been restricted to selected institutions
for specific clinical or pathologic indications, and routine
reporting of this marker is not currently the standard of
practice. The group was divided regarding the advisability
of incorporating Ki67 labeling indices into reports (53%
said no), and there was no agreement that the stain
should be carried out in all cases, especially for resection
specimens, in which an accurate mitotic count can be
carried out readily. However, it was agreed that Ki67
staining can be highly useful for biopsy specimens. The
vastly different labeling rates between well-differentiated
NETs (with a labeling index typically in the 1% to 20%
range) and high-grade neuroendocrine carcinomas (such
as small cell carcinoma and large cell neuroendocrine
carcinoma, which typically show 50% to 95% labeling)
make Ki67 staining very effective for distinguishing these
groups.49,67 In addition, mitotic counting of small speci-
mens is difficult, as many of these samples will not contain
sufficient neoplastic tissue to enable 50 high-power fields
to be counted. There was consensus; therefore, that Ki67
staining should be reported for biopsies of metastases or
in other circumstances in which a larger resected portion
of the tumor is unlikely to become available.
Another important consideration was that the
optimal method to determine the Ki67 index has yet to
be defined. Only 53% of participants believed that the
Ki67 index was sufficiently reproducible between pathol-
ogists to discriminate clinically relevant subsets of NETs.
Options to quantify Ki67 labeling include a general
‘‘eyeballed’’ estimate of the percentage of positive cells,
systematically counting manually a defined number of
tumors cells (2000 as per the ENETS proposals75,76) and
calculating the positive percentage, or using a computer-
ized digital image analysis system to measure the positive
percentage.18,48 Manual counting was felt by some to be
too time-consuming for general pathology practice, and it
was agreed that image analysis, although attractive and in
use at some institutions, was not yet sufficiently available
for routine practice. There was no agreement that these 2
techniques could be advocated at this time. Seventy-five
percent felt that manual counting should not be done, and
63% believed that image analysis is not yet ready for
general use. Thus, from a practical standpoint, providing
an ‘‘eyeballed’’ estimate of the labeling percentage was
agreed to be the only method that could be strongly
advocated at present. However, there was recognition of
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many shortcomings to this approach. The interobserver
(and likely intraobserver) variability was felt to be high,
especially when a difference between 1% and 3% is used
to separate 2 grades in some systems.75,76 Furthermore, it
was recognized that there is intratumoral heterogeneity
in Ki67 labeling (Fig. 1), meaning that a small sample
of a NET (eg, a biopsy of a metastasis) may not represent
the most highly proliferative region of the tumor.15 The
group recommended to count the most densely staining
regions (‘‘hot spots’’) and to count a variety of areas
within the tumor; it was specifically noted that counting
of random areas or single regions is inadequate. The
result should be reported as a single percentage reflecting
the average of the regions counted, rather than a range of
values. Although many issues were recognized regarding
the use of Ki67 staining, it was agreed that there currently
exists no better marker of proliferation for routine use.
If multiple sites of disease are sampled, it was agreed
that separate mitotic counts should be provided for each
anatomic site (for example the primary lesion, lymph
node metastasis, liver metastasis). There was no agree-
ment whether separate Ki67 indices should be reported
for different sites of disease (61% said yes).
Some grading systems for NETs use the presence of
tumor necrosis (ie, nonischemic or infarct-like necrosis) as
a criterion to increase the tumor grade.30,87 Thus, it was
agreed that the presence of nonischemic tumor necrosis
should be documented in the pathology report.
FIGURE 1. Immunohistochemical staining for Ki67. Two images captured from a single pancreatic neuroendocrine tumor (NET)
reveal heterogeneity of labeling, from 1.4% in 1 region (A) to 21.5% in another (B).
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Pathology Reporting of Neuroendocrine Tumors
The group acknowledged that the size of the pri-
mary tumor may be associated with the mitotic rate and,
therefore, the grade, but it was agreed that the tumor size
was a parameter that helps define the stage of the tumor
rather than the grade. Thus, grade and stage should be
separately determined and reported; the size of the NET
should not be used in the determination of the grade.
Metastasis-specific Issues
Several issues specifically relate to the reporting
of metastatic disease. For resected metastases, it was
recommended to report the anatomic site, the number of
lesions resected, and the size (in 1 dimension) of the
largest metastasis. Some comment about the percentage
of involvement of the resected tissue (such as the liver)
should be provided. Owing to the potential for hetero-
geneity among different sites of metastasis, the group
advised sampling more than 1 metastasis for histology,
if multiple metastases are resected. It was recognized
that currently there is no system for substaging distant
metastatic disease, meaning that patients with limited
spread outside the regional lymph nodes are grouped
together with those having extensive, widely distributed
metastases. The desirability of a substaging system for
metastatic disease was acknowledged, as it would better
stratify the extent of disease for comparison of therapeutic
trials.
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Klimstra et al
Grading of metastases creates some special chal-
lenges, as has been partially discussed above. Although
in most cases well-differentiated NETs can be distin-
guished from poorly differentiated (high grade) neuro-
endocrine carcinomas, the distinction of low grade
and intermediated-grade NETs can be very challenging
based on biopsy material. Although the group agreed
that an attempt should be made to grade NETs on
biopsy specimens, it was only felt to be realistic when
adequate neoplastic tissue is represented in the biopsy,
and distinction of low and intermediate-grade NETs is
not possible based on fine needle aspiration cytology
specimens.
Other Prognostic Factors and
Therapeutic Biomarkers
Many different potential prognostic factors for
NETs have been reported. Histologic findings that
were of recognized significance (and therefore, should
be reported) include vascular and perineural invasion.
Immunohistochemical stains for endothelial markers
(such as CD34 or D2-40) that can aid in identifying
vascular invasion were recommended only for cases with
a histologic suspicion of vascular invasion. It was not felt
necessary to differentiate between lymphatic and blood
vessel invasion, as this distinction often cannot be made
reliably on the basis of routine histologic sections. The
various architectural growth patterns of NETs were not
considered to be prognostically relevant, nor was nuclear
atypia. Unusual histologic features in NETs (including
clear cell or oncocytic morphology, and gland-formation)
should be mentioned in the report, however, as such
features may obscure the neuroendocrine nature of the
tumor. It was not thought necessary to quantify angio-
genesis or apoptosis. Although the immunoexpression of
cytokeratin 19 (CK19) reportedly has adverse prognostic
implications in pancreatic NETs,17 the data were not felt
to be sufficiently compelling to recommend the routine
use of this marker.
Advances in targeted therapy have risen the possi-
bility that molecular testing or immunohistochemistry
may become useful to determine the treatment of NETs.
However, at present no special immunohistochemical
stains or molecular tests are routinely recommended.
Other Information
It was agreed that abnormalities in the neuroendo-
crine cells in the resected organs away from the NET
should be described in the report. These include, for
example, gastric neuroendocrine cell hyperplasia asso-
ciated with Type 1 or Type 2 gastric well-differentiated
NETs, or pancreatic endocrine microadenomas asso-
ciated with well-differentiated pancreatic endocrine tu-
mors in patients with MEN1.2,3,37,68,83 Many NETs may
exhibit stromal fibrosis, but it was agreed that there was
no indication to attempt to quantify stromal fibrosis.
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Am J Surg Pathol  Volume 34, Number 3, March 2010
DISCUSSION
Many different groups have explored the topic of
NET classification. Various systems of nomenclature,
grading, and staging have been published, but none has
gained universal acceptance. Discussion of the systems
proposed by the WHO, the ENETS, the AJCC, and other
groups9,10,21,22,30,35,38,45,75,76 revealed that essentially all of
these classifications are useful to stratify survival after
resection of NETs and to predict the rate of progression
of metastatic disease. A graphic comparison of major
grading, staging, and classification systems is presented in
Figure 2. This study was carried out in an effort to define
the essential pathologic information needed for clinical
decision-making that in fact constitutes the data under-
lying most of these NET classifications. There was no
intent to introduce another classification system, as it was
perceived that adding to the plethora of available systems
already in use would only cause greater confusion.
The application of the Delphic process19,25,77 in this
study seems to be novel for ‘‘consensus’’ groups preparing
joint statements related to NETs. Many group efforts
involve open and extensive discussions, allowing all
participants to present and defend their opinions. How-
ever, the decision-making process is often not anonymous
and introduces issues such as peer pressure, weight of
personal opinion, and vigor of personality into the
deliberations. The use of anonymous voting with an
electronic system in this study ensured that all partici-
pants had an equal opportunity to express an independent
opinion. It is possible that this methodology prevented
agreement from being reached on some issues, as the
holders of minority opinions could less readily be
swayed to change their votes. Nonetheless, agreement
was achieved for 84% of the questions.
Major areas of agreement were achieved related to
terminology, use of diagnostic immunohistochemistry,
grading parameters, staging information, relevance of
other histologic prognostic features, and utility of ther-
apeutic biomarkers. The group agreed upon the inter-
changeable use of ‘‘endocrine’’ and ‘‘neuroendocrine’’
terms to refer to these tumors and the desirability of
eventually eliminating the term ‘‘carcinoid.’’12,82 The
specific immunohistochemical stains useful to define
neuroendocrine differentiation were agreed upon, as were
the limited circumstances under which staining for
bioactive peptide or amine secretory products (hormones)
may be helpful. As some novel therapeutic agents have
shown greater efficacy against NETs from specific
primary sites (eg, temozolamide for pancreatic NETs42),
the need to attempt to determine the origin of meta-
stases from occult primary NETs was recognized, and
immunohistochemical staining for CDX2 and TTF1 was
recommended as a diagnostic aid.32,78,84 Recent data also
suggest that staining for Isl1 may also be useful to define
pancreatic origin.79 The group also recognized many
potential immunohistochemical biomarkers of therapeu-
tic responsiveness on the horizon, including somatostatin
receptor subtypes, MGMT, VEGF-r, and mTOR path-
way members26,34,42,53,73,94,97; however, none of these has
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Am J Surg Pathol  Volume 34, Number 3, March 2010 Pathology Reporting of Neuroendocrine Tumors

G r a d e

WD NET WD NET
Low Grade Intermediate Grade PD NE Carcinoma
Others

WD NE Carcinoma MD NE Carcinoma PD NE Carcinoma

HG NE Carcinoma
WHO Lung Typical Carcinoid Atypical Carcinoid Small Cell/Large Cell

ENETS G1 G2 G3
T1 T2 T3
Localized

Well Differentiated
(Neuro)endocrine Tumor
S t a g e

Poorly Differentiated
T4 N1

WHO WHO (Neuro)endocrine

Carcinoma
Regional Distant

M1

Well Differentiated
(Neuro)endocrine Carcinoma
SEER

AJCC

FIGURE 2. Comparison of various grading, staging, and classification systems for neuroendocrine tumors (NETs). The grading
systems are displayed along the x-axis (top) and the staging systems along the y-axis (left). The WHO systems for gastrointestinal
and pancreatic NETs include a combination of grading and staging information and are displayed with the box (lower right). The
various nomenclature of each system is used. The overlaps between the different systems are approximate. Abbreviations: AJCC
indicates American Joint Committee on Cancer; ENETS, European Neuroendocrine Tumors Society; HG, high grade; MD,
moderately differentiated; NE, neuroendocrine; NET, neuroendocrine tumor; PD, poorly differentiated; SEER, Surveillance,
Epidemiology, and End Results Program of the National Cancer Institute; WD, well differentiated; WHO, World Health
Organization.

been adequately validated to justify their routine use, and
data showing the correlation between immunohistochem-
ical staining and therapeutic response are still emerging.
However, it seems likely that in the future, with increasing
advances toward specific molecular characterization of
NETs in terms of transcript identification (KiSS, MAGE,
NAPI) and functional biologic components (somatostatin
receptor subtypes), that such information may become
relevant.20
Formal TNM staging of NETs has been relatively
limited compared with the staging of carcinomas. For
example, in the most recent AJCC staging classification,
gastroenteropancreatic NETs are specifically excluded
from the TNM system.27 A relatively crude staging system
exists in the Surveillance, Epidemiology, and End Results
Program database of the NCI, which categorizes the
extent of disease as ‘‘localized,’’ ‘‘regional,’’ or ‘‘dis-
tant.’’95 However, there is widespread recognition that
NETs should be staged using the TNM system, and there
is currently an ENETS proposal for staging gastro-
enteropancreatic NETs.75,76 The upcoming revision of the
AJCC staging system will also include NETs.21 Although
there may be some subtle differences between the ENETS
and AJCC systems, the fundamental staging landmarks
parallel those used for carcinomas of the corresponding
organs, and the group recommended to include the
size of the tumor, the extent of invasion based on these
landmarks, the status of regional lymph nodes, and
the presence of distant metastatic disease (if known) in
the pathology reports, in addition to indicating a specific
TNM stage. Reporting of margin status was also
recommended.

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Klimstra et al
There was universal recognition of the importance
of grading NETs. The distinction of relatively slowly
progressive well-differentiated NETs from highly aggres-
sive poorly differentiated NETs (small cell carcinoma and
large cell neuroendocrine carcinoma) was highlighted
as a critical pathologic determination.6,14,23,62 The rele-
vance of tumor cell proliferation for grading NETs was
also agreed. Mitotic rate was regarded as an essential
component of pathologic data, and specific recommen-
dations for the technique of mitotic counting were
established. The existence of 3 grades of NETs was also
agreed upon, and it was accepted that inclusion of the
grade of the tumor, along with a reference to the specific
grading system being used, should be included in all
reports on NETs. Although there was complete agree-
ment that grade can progress as NETs grow and
disseminate,43,52,69,100 this was not considered a uniform
event in the evolution of the disease. An important issue
that was widely accepted was that intratumoral hetero-
geneity of proliferative rate requires careful consideration
given its potential impact on overall assessment of the
NET aggressiveness. Thus, separate grading and mitotic
rate counting of metastases should be carried out, and
each major site of disease should be assessed indepen-
dently. The inclusion of information about nonischemic
necrosis is used in some grading systems and therefore,
should be mentioned in the reports.30,87 The use of
immunohistochemical staining for Ki67 as a measure of
proliferative rate was endorsed by the group for specific
situations (see below for further discussion about Ki67
staining). The stain is especially useful for the distinction
of high-grade neuroendocrine carcinoma from well-
differentiated NETs and should always be used when
this differential diagnosis arises (particularly on biopsy
specimens).49,67 In addition, in cases with minimal tumor
for which adequate mitotic counting is not possible, Ki67
staining should be used to determine the proliferative
rate, as it labels a greater proportion of cells than those
with active mitotic figures.
Other prognostic factors that were agreed to have
sufficient relevance for inclusion in reports included
the presence of vascular and perineural invasion. Nuclear
grading was not felt to be relevant, based on the ob-
servation that nuclear pleomorphism can be seen in
some well-differentiated NETs that lack aggressive
behavior.98 Quantification of the extent of fibrosis,
angiogenesis, and apoptosis was not considered to be
necessary. Unusual histologic features, although unlikely
to have prognostic significance, were believed to be
worthy of documentation in the reports.
The 17 questions for which no agreement could be
reached (Supplementary Table 3, Supplemental Digital
Content 3, http://links.lww.com/PAS/A51) include some
relatively minor issues related to the precision with which
the extent of disease should be reported but also more
substantive issues regarding terminology, the need for
routine immunohistochemical staining, the concept of
progression of well-differentiated NETs to high-grade
neuroendocrine carcinoma, and the use of proliferation
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Am J Surg Pathol  Volume 34, Number 3, March 2010
markers. Some of these more substantive disagreements
(particularly those related to terminology) reflect theore-
tic concerns bolstered by ‘‘personal opinions’’ and long-
held traditions of practice. Whether to use ‘‘tumor’’ or
‘‘neoplasm’’ and whether the term ‘‘carcinoma’’ should be
applied to well-differentiated NETs are important con-
siderations that could not be resolved, but the basis for
the disagreement is unrelated to a lack of understanding
of the disease or the absence of sufficient data. We
consider these to reflect the evolution of semantic
terminology and not a real disagreement in terms of the
histopathology or biology of NETs. It was clear to all
that much of the terminology (tumor or carcinoid) reflects
archaic medical lexicon and will with the passage of time
fade into medical history rather than be banned from
usage.12,16,82 The routine use of immunohistochemical
staining for general neuroendocrine markers was also
controversial, the divergent opinions reflecting varied
levels of comfort with diagnoses rendered solely on the
basis of routine histology.
Some areas of disagreement were based on a lack of
sufficient data to support specific concepts or procedures.
The concept of neoplastic progression in NETs was
accepted, but the group could not agree whether well-
differentiated NETs can progress to fully high-grade
neuroendocrine carcinomas.86 Some preliminary data
documenting this occurrence were presented, but there
have been few published examples, and it seems that, at
best, this transformation is probably rare and does not
represent the pathway of development of a vast majority
of high-grade neuroendocrine carcinomas.
Another controversial area was the use of Ki67
staining to determine the proliferative rate.33 Although
this stain is widely used, particularly to distinguish well-
differentiated NETs from poorly-differentiated NETs
such as small cell carcinoma,49,67 there was a division of
opinion about when to use it and whether it should be
carried out for all specimens of NETs, especially those
with sufficient material to allow mitotic rate counting.
The ENETS grading system includes Ki67 labeling index
as 1 of the parameters, and oncologists in Europe rely
extensively on this information for treatment.33,71,75,76,90
In the US, however, the use of Ki67 has been more
limited, reflecting concerns with rigor of the assessment
of the parameter. The interpretation of Ki67 staining was
also debated. Although it was agreed that the most
accurate assessment would involve counting nuclei to
determine the true labeling percentage, this was consid-
ered by some to be too time-consuming and cumbersome
for routine practice. Digital image analysis holds promise
for quantification of staining, but many pathologists do
not currently have access to this technology. An ‘‘eye-
balled’’ estimate was acknowledged to be inaccurate
owing to have high interobserver variability, but this
technique was agreed to be the only one that could
practically be recommended.18 Nevertheless, given the
issues with reproducibility of this technique and the
inherent heterogeneity of staining within NETs (especially
metastases, from which only limited biopsy samples are
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Am J Surg Pathol  Volume 34, Number 3, March 2010
often available15), it was not agreed that the Ki67 labeling
index is sufficiently reproducible to allow separation of
clinically relevant subsets of NETs. It is clear that much
of the debate about the use of Ki67 staining was related to
a lack of data regarding intraobserver and interobserver
reproducibility, correlation of automated quantification
with clinical outcome, assessment of intratumoral hetero-
geneity, and comparison with mitotic rate as the ultimate
determinant of outcome and indication for specific pharma-
cologic therapy. The resolution of these critical issues was
agreed upon as a priority in the future investigation and
assessment of NETs.
The areas of consensus reached by this group were
sufficient to allow the development of a Minimum Patho-
logy Data Set for the reporting of NETs (Table 1). This
Minimum Pathology Data Set includes recommenda-
tions for reporting both biopsy and resection specimens
from primary tumors and metastases, and it applies to all
NETs of the gastrointestinal tract and pancreas. In
general, the group recommended reporting only those
histologic features for which abundant data exist to
document their prognostic significance. In each of these
sites, a specific diagnosis and grade are to be reported,
and staging is to be carried out when the information is
available (ie, for resections and biopsies of metastases).
However, there was no mandate to use any specific system
of nomenclature, grading, or staging, because the infor-
mation that is used for these purposes is to be included
elsewhere in the report. For example, the mitotic rate,
with or without information about necrosis, is used to
grade NETs in all major systems; and this information
should be routinely reported. The extent of invasion is to
be reported, using similar landmarks to those used in the
AJCC staging systems for carcinomas of corresponding
organs. In fact, this should translate easily into the
upcoming AJCC staging system for NETs of the GI tract
and pancreas, which in almost every instance is based
on the corresponding carcinoma staging system. It is
important to indicate in the report which systems of
nomenclature, grading, and staging are being used to
allow ready comparison among cases.
A number of items were regarded as ‘‘optional’’ for
inclusion in reports, based upon lack of agreement among
the participants about their importance. For example,
routine staining for general neuroendocrine markers
(chromogranin and synaptophysin) of resected NETs
with classic histologic features was not agreed to be
necessary, but can be carried out and reported if the
pathologist finds it necessary or the clinical situation
requires it. Routine Ki67 staining was also deemed
optional, unless the specimen in question is a biopsy
of a primary NET in which a high-grade neuroendocrine
carcinoma could not be excluded or a biopsy of a meta-
stasis with inadequate tissue for accurate mitotic count-
ing. Measurement of the distance from the tumor to the
resection margins for cases grossly within less than 0.5 cm
was also considered optional. It was clear from the
discussions, however, that some of this optional informa-
tion might be regarded as mandatory in certain practice
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Pathology Reporting of Neuroendocrine Tumors
TABLE 1. Minimum Pathology Data Set: Information to be
Included in Pathology Reports on NETs
For resection of primary tumors:
Anatomic site of tumor
Diagnosis (functional status need not be included in pathology
report)
Size (3 dimensions)
Presence of unusual histologic features (oncocytic, clear cell, gland-
forming, etc.)
Presence of multicentric disease
(OPTIONAL: immunohistochemical staining for general
neuroendocrine markers)
Chromogranin
Synaptophysin
Peptide hormones, IF a specific clinical situation suggests that the
correlation with a functional syndrome may be helpful
Grade (specify grading system used)
Mitotic rate (number of mitoses per 10 high-power fields or 2 mm2;
count 50 high-power fields in the most mitotically active regions, count
multiple regions)
[OPTIONAL: Ki67 labeling index (count multiple regions with
highest labeling density, report average percentage; ‘‘eyeballed’’
estimate is adequate)]
Presence of nonischemic tumor necrosis
Presence of other pathologic components (eg, nonneuroendocrine
components)
Extent of invasion (use anatomic landmarks for the AJCC T-staging
of analogous carcinomas of the same anatomic sites)
Stomach: depth of invasion into/through gastric wall
Small bowel: depth of invasion into/through bowel wall
Large bowel: depth of invasion into/through bowel wall
Appendix: depth of invasion into/through appendiceal wall;
presence and extent of mesoappendiceal invasion
Pancreas: the presence of extrapancreatic invasion or invasion of
bile duct, duodenum, or ampulla
All sites: involvement of serosal/peritoneal surfaces; invasion of
adjacent organs or structures
Presence of vascular invasion (OPTIONAL: perform
immunohistochemical stains for endothelial markers if needed)
Presence of perineural invasion
Lymph node metastases
Number of positive nodes
Total number of nodes examined
TNM Staging (specify staging system utilized)
Resection margins (positive/negative/close) (OPTIONAL measure
distance from margin if within 0.5 cm)
Proliferative changes or other abnormalities in nonneoplastic
neuroendocrine cells
For Biopsy of Primary Tumors:
Anatomic site of tumor
Diagnosis (functional status need not be included in pathology report)
Presence of unusual histologic features (oncocytic, clear cell, gland-
forming, etc.)
(OPTIONAL: immunohistochemical staining for general
neuroendocrine markers)
Chromogranin
Synaptophysin
Peptide hormones, IF a specific clinical situation suggests that the
correlation with a functional syndrome may be helpful
Grade (specify grading system used)
Mitotic rate (number of mitoses per 10 high-power fields or 2 mm2;
count up to 50 high-power fields)
Ki67 labeling index, for biopsies in which a diagnosis of high-grade
neuroendocrine carcinoma cannot be excluded (count multiple regions
with highest labeling density, report average percentage; ‘‘eyeballed’’
estimate is adequate)
Presence of nonischemic tumor necrosis
Presence of other pathologic components (eg, nonneuroendocrine
components)
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Klimstra et al
TABLE 1. (continued)
For Resection of Metastatic Tumors:
Location of metastasis(es)
Diagnosis (functional status need not be included in pathology report)
Number of metastases resected
Extent of involvement of resected tissue (percentage)
Greastest dimension of largest metastasis
Presence of unusual histologic features (oncocytic, clear cell, gland-
forming, etc.)
(OPTIONAL: immunohistochemical staining for general
neuroendocrine markers)
Chromogranin
Synaptophysin
Peptide hormones, IF a specific clinical situation suggests the
correlation with a functional syndrome may be useful
Grade (specify grading system used)
Mitotic rate (number of mitoses per 10 high-power fields or 2 mm2;
count 50 high-power fields in the most mitotically active regions,
provide separate mitotic rate for each major separate site of disease)
[OPTIONAL: Ki67 labeling index (count multiple regions with
highest labeling density, report average percentage; ‘‘eyeballed’’
estimate is adequate)]
Presence of nonischemic tumor necrosis
Presence of other pathologic components
Resection margins (positive/negative/close) (OPTIONAL measure
distance from margin if within 0.5 cm)
Identification of primary site
Immunohistochemistry for CDX2, TTF1
For Biopsy of Metastatic Tumors:
Location of metastasis
Diagnosis (functional status need not be included in pathology report)
Presence of unusual histologic features (oncocytic, clear cell, gland-
forming, etc.)
Immunohistochemical staining for general neuroendocrine markers
Chromogranin
Synaptophysin
(OPTIONAL: peptide hormones, IF a specific clinical situation
suggests the correlation with a functional syndrome may be useful)
Grade for adequate biopsy specimens; FNA specimens may not be
adequate (specify grading system used)
Mitotic rate (number of mitoses per 10 high-power fields or 2 mm2;
count up to 50 high-power fields)
Ki67 labeling index (count multiple regions with highest labeling
density, report average percentage; ‘‘eyeballed’’ estimate is adequate)
Presence of nonischemic tumor necrosis
Presence of other pathologic components (eg, nonneuroendocrine
components)
Identification of primary site
Immunohistochemistry for CDX2, TTF1
situations, and close collaboration with treating clinicians
is suggested to ensure the necessary data are included in
the reports.
Although there was some disagreement about the
importance of various pathologic findings, and no
universal grading or staging system arose through this
consensus meeting, there was general agreement that it
would be preferable to develop such a system. Ideally, the
grading parameters for well-differentiated NETs would
be the same irrespective of the site of origin, and the
terminology would also be uniform. One of the reasons
for the variety of different systems is that most are
proposals based on a reasonable assessment of potentially
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Am J Surg Pathol  Volume 34, Number 3, March 2010
significant factors, rather than data-driven subgroup-
ings based on extensive study of actual cases. The group
recognized the need for improved clinicopathologic
studies of NETs based on large numbers of cases with
long-term follow-up, which almost certainly will need to
involve multiple institutions. The existing data actually
suggest that different grading parameters may optimally
separate prognostic groups from different anatomic
sites.39,62 For example, some studies have shown that a
mitotic rate of 2/10 high-power fields optimally separates
low-grade NETs from intermediate-grade NETs in the
lung,88 whereas other investigators suggest that a much
lower rate of 2/50 high-power fields should be used
for NETs in the pancreas and rectum.22,30 Many studies
have used a mitotic rate of 10/10 high-power fields
to distinguish well-differentiated (low and intermediate
grade) NETs from poorly-differentiated (high grade)
neuroendocrine carcinomas in sites such as the lung,
thymus, ampulla of Vater, and pancreas28,57,85,88; how-
ever, according to the ENETS grading scheme, a rate
of 20/10 high-power fields is preferable for this distinc-
tion.75,76 Unification of grading criteria among anatomic
sites would have the advantage of allowing grading of
metastatic NETs for which the primary site may not be
known. Until adequate data are obtained to determine
whether a unified grading system can be developed, how-
ever, it is critical to continue to collect the specific data
that underlie the grading schema being used. Namely, the
proliferative rate (mitotic rate, and/or Ki67 labeling
index) should be specifically recorded for all NETs. This
will allow translation between different systems and will
facilitate comparison of data from studies that may use
different cut-points for grading.
It must also be recognized that clinical or radio-
graphic information is useful in predicting the biology
of NETs. For patients with metastases, a decision to
treat can also be based on presence of symptoms,
whether hormone-mediated or based on the site and
burden of disease. Longitudinal radiographic studies can
be used to determine the growth rate of metastases, which
may vary among different sites of metastatic disease.73
This clinical and radiographic information must be
integrated with the pathology data for optimal thera-
peutic decision-making.
The development of a standardized approach to
the analysis of the pathology of neuroendocrine tumor
disease is a necessary step to provide a secure platform
upon which the evolving therapeutic landscape can be
based, and it is vital to establish clear parameters within
which the disease can be uniformly evaluated and rational
therapeutic strategies developed. A clear advance was
the development of a Minimum Pathology Data Set as
proposed by this group. The routine application and use
of such information will result in the accumulation of
consistent and globally applicable information about the
pathology of NETs. With time, this will translate into an
improved capability to define the disease of individual
patients and facilitate provision of a uniform basis to
prognosticate and treat patients. Widespread adoption of
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Am J Surg Pathol  Volume 34, Number 3, March 2010
this strategy will assist the more fluid translation of novel
therapeutic strategies from the research arena into routine
practice.
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