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The Royal College of PathologistsPathology: the science behind the cure
Standards and Datasets for Reporting Cancers
Dataset for tumours of the central nervous system
(2nd
edition)
Apri l 2008
Coordinators: Dr Stephen B Wharton, University of SheffieldDr David Hilton, Derriford Hospital, PlymouthDr David Levy, Weston Park Hospital, SheffieldProfessor James W Ironside, University of Edinburgh
Unique document number G069
Document name Dataset for tumours of the central nervous system (2
nd
edition)Version number 2
Produced by Dr Stephen B Wharton, University of Sheffield, Dr David Hilton, DerrifordHospital, Plymouth, Dr David Levy, Weston Park Hospital, Sheffield, andProfessor James W Ironside, University of Edinburgh, on behalf of theRCPath Cancer Services Working Group.
Date active April 2008
Date for review April 2010
Comments In accordance with the Colleges pre-publications policy, this document wasput on The Royal College of Pathologists website for consultation from 4December 14 January 2008. Four pieces of feedback were received and
the authors considered them and amended the document accordingly.Please email [email protected] you wish to see the responses andcomments. This edition replaces the Dataset for tumours of the centralnervous system, published in 2004.
Professor Carrock Sewell
Director of Communications
The Royal College of Pathologists2 Carlton House TerraceLondon, SW1Y 5AFTel: 020 7451 6700Fax: 020 7451 6701
Web: www.rcpath.org
Registered charity in England and Wales, no. 261035 2008, The Royal College of Pathologists
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CONTENTS
1 Introduction ..............................................................................................................................3
1.1 Authors.....................................................................................................................................................3
1.2 Importance and clinical application of the dataset ...................................................................................3
1.3 Site-specific issues in relation to central nervous system (CMS) tumours ..............................................4
1.4 Methods used for obtaining the dataset....................................................................................................5
1.5 Stakeholders .............................................................................................................................................5
2 Clinical information required on the request form.............................................................................5
3 Preparation of the specimen before dissection ....................................................................................6
4 Specimen handling and block selection................................................................................................6
4.1 General comments....................................................................................................................................6
4.2 Biopsies....................................................................................................................................................74.3 Intra-axial tumour resections, including lobectomy specimens ...............................................................7
4.4 Extra-axial tumours..................................................................................................................................7
4.5 Pituitary tumours......................................................................................................................................8
4.6 Section staining and use of levels ............................................................................................................8
5 Core data items.......................................................................................................................................8
5.1 Histological classification ........................................................................................................................8
5.2 Additional prognostic and predictive factors .........................................................................................10
5.3 Role of the multidisciplinary team meeting ...........................................................................................11
5.4 Summary of core data items...................................................................................................................12
5.4.1 Clinical.......................................................................................................................................12
5.4.2 Pathological ...............................................................................................................................12
6 Non-core data items .............................................................................................................................12
6.1 Clinical ...................................................................................................................................................12
6.2 Pathological............................................................................................................................................12
7 Diagnostic coding .................................................................................................................................13
8 Reporting of small biopsy specimens..................................................................................................13
9 Reporting of frozen sections and smear preparations ......................................................................13
10 References .............................................................................................................................................13
11 Appendices ............................................................................................................................................16
Appendix A SNOMED T codes........................................................................................................16
Appendix B SNOMED M codes.......................................................................................................16
Appendix C List of abbreviations .....................................................................................................17
Appendix D Reporting proforma for intra-axial tumours .................................................................18
Appendix E Reporting proforma for extra-axial tumours.................................................................19Appendix F Reporting proforma for pituitary tumours ....................................................................20
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1 INTRODUCTION
1.1 Authors
Dr Stephen B Wharton Senior Lecturer/Honorary Consultant in Neuropathology,
University of Sheffield
Dr David Hilton Consultant in Neuropathology, Derriford Hospital, Plymouth.
Dr David Levy Consultant in Clinical Oncology, Weston Park Hospital, Sheffield
Brain Tumour Clinical Lead for the NHS Cancer Dataset
Professor James W Ironside Professor/Honorary Consultant in Neuropathology,
University of Edinburgh.
1.2 Importance and clinical application of the dataset
Scope
Brain tumours account for approximately 1.6% of cancers in England and Wales,1 although there is
evidence to indicate significant under-registration of central nervous system (CNS) tumours in the
UK.2,3
CNS tumours have a high morbidity and mortality, and are the second most common form of
cancer in children. The intra-axial tumours of the CNS include those arising in the brain and spinal
cord. However, extra-axial tumours, arising from the coverings of the brain and spinal cord, present
with similar clinical symptoms to intra-axial tumours due to their impingement on the CNS. Pituitary
tumours also arise in close proximity to the brain and may impinge upon diencephalic structures and
cranial nerves. CNS intra-axial, extra-axial and pituitary tumours are dealt by neurosurgeons within
specialist neuroscience centres, their pathology is generally dealt with by neuropathologists and they
are included in the National Institute of Health and Clinical Excellence (NICE) guidance, Improving
Outcomes for People with Brain and Other CNS Tumours.4
They therefore fall within the scope ofCNS tumours for the purposes of this document.
Although the terms benign and malignant are sometimes used with reference to CNS tumours, this
distinction is less clear than it is for tumours arising outside the CNS. Many CNS tumours, even the
most malignant, do not demonstrate metastasis, but invasion occurs in most intra-axial tumours,
regardless of tumour grade. This may preclude complete surgical resection so that, even for tumours at
the benign end of the biological spectrum, there may be ongoing management issues. Furthermore,
slowly growing entities may undergo transformation into more aggressive tumours. The terms low-
grade and high-grade, representing WHO histological grades III and IIIIV respectively (see
below), as sometimes used as general descriptive terms and seem more appropriate than benign and
malignant.. Even the most indolent lesions may cause severe impairment or death from their local
effects within the confined bony box of the skull. Low-grade tumours are included in the NICEguidance,
4and are therefore included within the scope of this dataset.
Purpose of the guidelines
These guidelines are intended to assist pathologists in the provision of the core data that should be
included in the histopathological diagnostic reports of CNS tumours, and to suggest additional data
items that may be usefully included for certain categories of tumours. Accurate and standardised
histopathological data in diagnostic reports of CNS tumours are important for the following reasons:
standardised classification and grading of tumours, according to a recognised system, arenecessary for the planning of appropriate treatment for the patient
provision of appropriate histopathological data allow determination of prognosis consistency of histopathology reporting is important in communication between cancer centres
monitoring of treatment and outcomes and in clinical audit
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provision of data for epidemiological studies, for monitoring of disease patterns and trends, andfor determination of changing outcomes and survival
allowing appropriate stratification of patients for entry into clinical trials and allow meaningfulcomparison between biological research studies
provision of accurate data for cancer registries. in particular, the dataset will providepathological data for the NHS Cancer Dataset.
5
The guidelines in this document are intended to assist in the provision of appropriate data in
histopathology reports and as such are not intended as codes of practice. They should be used in the
context of appropriate measures to maintain a high standard of histopathological analysis and
diagnosis, including participation by the neuropathologist in the relevant EQA scheme and
participation of the laboratory in a CPA (UK) Ltd scheme.
Who reports CNS tumours?
CNS tumours are most commonly reported in specialist centres by neuropathologists. For the purposes
of reporting CNS tumours, the NICEImproving Outcomesguidance defines a neuropathologist as an
accredited pathologist who is registered as a neuropathologist or histopathologist, has specialist
expertise in neuro-oncology, and takes part in the national External Quality Assurance (EQA) schemefor neuropathology organised by the British Neuropathological Society.4 NICE guidelines also
emphasise the central role of the multidisciplinary team (MDT) meeting in the management of CNS
tumours. Pathologists reporting CNS tumours should attend and contribute to these meetings.
1.3 Site-specific issues in relation to CNS tumours
The staging of tumours and assessment of resection margins, essential information for many tumour
types, are in general not applicable to CNS tumours and have therefore not been included in other
published protocols. Generally, CNS tumour specimens are received in a fragmented state, precluding
any systematic assessment of the margins. In the case of lobectomy specimens, assessment of apparent
involvement of margins by tumour may be possible. However, most intra-axial tumours, particularly
gliomas, demonstrate a diffuse pattern of infiltration that effectively precludes total surgical resection. 6
Infiltrating tumour cells are present in apparently normal brain tissue surrounding these lesions, from
which recurrences may arise. This applies to both low- and high-grade diffuse gliomas and therefore a
statement that resection margins are free of tumour is inappropriate for these types of tumour.
Assessment of resection margins, therefore, has not been included as a field for the core dataset for
intra-axial CNS tumours.
The extent of tumour resection is, however, of predictive value for many CNS tumours.7,8
It is of value
to record an approximate aggregate size of tumour removed as an indicator of the sample on which the
diagnosis has been based. It should be noted, though, that not all of the resected tumour may reach the
Pathology Department, especially with the use of neurosurgical techniques such as the CUSA. The
pathological estimate of resected tumour volume may therefore underestimate the true extent ofresection in many cases, and neurosurgical/neuroradiological data may give a more accurate
assessment of tumour volume.7,8
CNS tumours generally progress through local growth and extension. Extracranial metastases are very
rare and spread to lymph nodes is extremely uncommon. Staging of specimens of CNS tumours is
therefore not possible using the criteria employed for non-CNS tumours, and the current TNM
classification does not include a staging scheme for CNS tumours.9CNS tumours can, however, be
staged by other criteria, for example, neuroradiological evidence of metastases to other regions of the
CNS via the cerebrospinal fluid pathway, but these criteria vary according to tumour type and are
therefore not included as core data items.
The histopathological report on a CNS intra-axial tumour may document patterns of spread,particularly across tissue boundaries, if the specimen allows such assessment (e.g. across the pia mater
and into the subarachnoid space). Assessment of multi-focality is generally not possible in most CNS
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tumour specimens. Thus, whilst inclusion of these items in the report may be useful, they have not
been included as core items in the histopathological dataset.
For many extra-axial tumours, histological assessment of resection margins is rarely practicable in
fragmented specimens, although it may be commented on for specimens submitted intact.
Meningiomas have the capacity to invade the underlying brain, and to infiltrate into the skull and
scalp. These latter patterns of growth may make a complete surgical resection impossible. Invasion of
underlying brain tissue, however, may not be evident to the neurosurgeon, and requires histologicalassessment of the interface between the tumour and the brain. Brain invasion is of prognostic
significance and is associated with a higher risk of tumour recurrence.10
For this reason, histological
assessment of the brain/tumour interface for brain invasion is required for meningiomas whenever
possible; it cannot be performed in all cases since the interface may not be present in the submitted
specimen (see below). For pituitary tumours, invasion of surrounding structures (particularly the dura
mater) is associated with a higher risk of tumour recurrence and should be commented upon whenever
possible, although it is recognised that the dura mater and other surrounding structures are not always
submitted for histological examination.11,12
For these reasons, although it is desirable to comment upon
brain invasion in meningiomas and local invasion in pituitary tumours whenever possible in
histopathological reports, these items have not been included in the core histopathological datasets for
these tumours.
It should be emphasised that there is a need for an adequate amount of tissue to be submitted to
neuropathology if a reliable diagnosis, based on representative material, is to be made. This may be a
particular problem with increasingly small biopsies obtained stereotactically or endoscopically. If a
specimen is felt to be inadequate for reliable evaluation, this should be stated in the body of the
neuropathology report. Discussion of cases at the MDT meeting provides a further opportunity for
evaluation of specimen adequacy (section 5.3)
1.4 Methods used for obtaining dataset
Recommendations in this dataset are based on: factors used in clinical management as reported in the
literature; the WHO classification of Tumours of the Nervous System13 and the NICE guidelines,Improving Outcomes for People with Brain and Other CNS Tumours.
4
1.5 Stakeholders
Society of British Neurosurgeons
British Neuropathological Society
British Neuro-Oncology Society
Childhood Cancer and Leukaemia Group.
2 CLINICAL INFORMATION REQUIRED ON THE REQUEST FORM
Clinical details, as provided by the submitting clinician on the request form, should be recorded on the
pathology report.14,15
Clinical history is very valuable, and sometimes essential to ensure proper
interpretation of the histological findings. This should include:
type of specimen/procedure biopsy (stereotactic or open) or resection
if multiple specimens are submitted representing different areas, this should be recorded.
previous relevant diagnoses, biopsies or therapies should be noted. Radiotherapy, radiosurgicalinterventions and systemic chemotherapy may considerably modify appearances, and for
gliomas present difficulties in the interpretation of the histology findings and assignment of
grade. Pre-operative embolisation of meningiomas may produce necrosis that may affect tumour
grading if this information is not known
the site of the tumour and neuroradiological findings. Because of the nature of mostneurosurgical specimens, the neuropathologist does not often have the benefit of a good
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appreciation of the macroscopic appearances of a lesion. neuroradiological findings thus provide
information helpful in diagnosis and provide an alert to discrepant diagnoses; for example, the
presence of radiological contrast enhancement in a low grade diffuse glioma
duration and nature of symptoms.
Some of these factors have been included as non-core items for the purposes of data recording in the
dataset, but it should be noted that adequate clinical history is essential to the proper interpretation ofhistological findings.
3 PREPARATION OF THE SPECIMEN BEFORE DISSECTION
Most specimens are received in fixative (usually 10% neutral buffered formalin) and should bein an adequately sized specimen pot. Depending on the size of the specimen up to 24 hours
fixation may be required before dissection.
Submission of a fresh specimen is necessary in cases for which intra-operative diagnosis isrequested (see section 9). Residual tissue should be fixed for conventional paraffin sections.
In cases where it is likely that genetic analysis may be useful, the specimen should be receivedfresh so that a frozen sample of tumour, and sometimes non-tumour tissue, can be frozen for
nucleic acid extraction.
Frozen tissue may be required for genetic or other analyses for some clinical trials.
In appropriate cases where it is suspected that ultrastructural examination of the specimen islikely to be required, a small sample of the tumour should be placed in glutaraldehyde.
Some very large specimens may benefit from incision prior to dissection to allow adequatepenetration of fixative.
Bony and heavily calcified specimens may need to be placed in a decalcifying solution followingfixation prior to dissection.
Where possible and approved, frozen material should be archived and the availability of frozen tissue
recorded, as it may allow future molecular genetic studies for diagnostic or for research/clinical trials
purposes, subject to appropriate ethical constraints, consents and governance mechanisms. In addition
to local research initiatives, this will become more important with time as national initiatives for adult
and paediatric brain tumours develop (e.g. NCRI, UKCCSG).16,17
For an increasing range of tumours (see below), conventional histology may be supplemented by
molecular genetic or cytogenetic analyses. Fresh frozen tissue may be of value for these, whilst
conventional cytogenetics may require a portion tissue, fresh or in medium, to be transported promptly,
from the histopathology laboratory or directly from theatre, to the cytogenetics laboratory if the
production of metaphase spreads is required. In some centres, smear preparations, fixed in, forexample, ethanol, may be prepared for interphase cytogenetic analysis (e.g. using FISH). Increasingly,
however, both PCR-based and cytogenetic techniques may be applied to paraffin based sections. This
has the advantage of convenience, applicability to archival cases and means that the need for
investigation does not have to be anticipated prior to histological diagnosis.
4 SPECIMEN HANDLING AND BLOCK SELECTION
4.1 General comments
There is a limited evidence base for the handling of specimens from CNS tumours, although there are
some published guidelines.14,15
The specimen should be measured in 3 dimensions and, if very large, weighed. In many cases,specimens will be in the form of multiple fragments, but an aggregate measurement should be
taken.
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The specimen should be described fully, including the following features: recognisableanatomical structures; colour, consistency and dimensions of the tumour; distance of tumour
from resection margins; the presence of calcification, necrosis, haemorrhage or cystic change.
4.2 Biopsies
These should usually be embedded in their entirety for processing.
Levels (step sections) should be considered to increase the sampling.
4.3 Intra-axial tumour resections, including lobectomy specimens
Resection specimens may be received as intact lobectomy specimens or as fragmented specimens
removed piecemeal. For diffuse gliomas, complete resection is, with only rare exceptions, precluded
because of the infiltrative nature of the lesion, and a resection is therefore subtotal.
Where possible the specimen should be orientated and any anatomical structures identified.
Lobectomy specimens may be sliced at approximately 5 mm intervals, generally perpendicularto the long axes of the specimen and through the pial surface.
The tumour should be described with particular attention to foci of necrosis, which may be ofprognostic significance. Gross extension of tumour into leptomeninges or to resection margins
should be noted.
In a number of studies, the extent of resection has been shown to be a prognostic factor. 7,8,18Neuroradiological assessment from post-operative imaging/computer-assisted volumetric studies
is a better measure of this than pathological measures. Nevertheless pathological assessment to
tumour volume removed provides some indication of the extent of excision and so an
approximate measurement of tumour size in three dimensions should be given.
Photography may be helpful in selected cases to confirm the orientation of the specimen with theneurosurgeon and to demonstrate the tumour extent at MDT meetings.
The tumour extent and distance from margins should be measured as far as possible, and bothshould be sampled. For resections received as fragments of tumour the assessment of margins is
precluded. In the cases of lobectomy specimens assessment of margins may be possible. For
diffuse gliomas however (both low and high grade), because of their infiltrative behaviour,6
histological evaluation of resection margins is not meaningful and does not require formal
assessment.14A field for margins has, however, been included in non-core items for appropriate
circumstances where this can be assessed.
Although evidence-based guidelines are not available, it would seem reasonable to conclude that thepresence of heterogeneity within tumours requires that multiple blocks should be taken to allow for
adequate sampling. The entire specimen should be blocked out on serial faces unless the tissue is
very large in which case enough blocks must be taken to avoid a sampling error, although
evidence-based guidelines for the number of blocks to be taken are not available.
Similar principles of thorough sampling apply to piecemeal resections.
In some cases gliomas may involve multiple lobes or may be multi-focal, and this informationform neuroimaging and the request form should be recorded. The resection specimen or biopsy
may, however, include only one lesion. If both are submitted in a specimen, histology blocks
should be made from both, to allow a separate histological assessment of these areas and to
ensure that the area of higher histological grade is represented.
4.4 Extra-axial tumours
The most common tumour at the site is the meningioma, but a range of tumour types may occur. As forintra-axial tumours, specimens are often resected piecemeal, making assessment of anatomical extent
and margins difficult, and the approach below will need to be modified according to the limits imposed
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comparative studies and multi-centre trials. Since the previous edition of the scheme in 2000, a number
of new entities have been described and accepted in current authoritative textbooks.20
The WHO
classification has now been revised by an international panel of experts and the new version published
in 2007. The latest edition of the classification includes new entities as well as some changes to
classification of existing entities. The latest, 2007, edition of the WHO scheme should therefore now
be the basis of classification and grading13
.
Haematoxylin and eosin stained sections remain the cornerstone of histological evaluation but in manycases they will be supplemented by special stains and by an increasingly powerful range of
immunohistochemistry, the use of which is in general an aid to classification. The use of
immunohistochemistry should be subject to appropriate internal and external quality controls. This
should involve the use of appropriate controls and the laboratory should be a participant in
UKNEQAS-ICC.21
Table 1 WHO grading scheme for astrocytomas
WHO grade Histological designation Histological features
I Pilocytic astrocytoma Circumscribed tumour with bipolar astrocytic cells
in a biphasic solid/cystic pattern
II Diffuse astrocytoma Diffusely infiltrating astrocytic cells with
pleomorphism allowed
III Anaplastic astrocytoma As above + mitotic activity
IV Glioblastoma As above + vascular proliferation +/or necrosis
The WHO classification also includes a widely accepted scheme for tumour grading (table 1) that has
largely replaced older schemes such as Ringertz, Kernohan and St Anne Mayo.13
The scheme is
somewhat unlike other histology-based grading schemes for other organ systems in that it was
originally devised as a malignancy scale covering a wide variety of intracranial neoplasms in the
context of no, or limited effective, therapy. The scheme is widely accepted by neuropathologists,
neuro-oncologists and neurosurgeons, and WHO grading is required as part of the BNS EQA scheme.
WHO grading therefore forms a core dataset item for primary CNS tumours. WHO grading is a four-
point scheme for which the astrocytomas are the prototypic group. The scheme is applied to other CNS
tumours, intra and extra-axial, in comparison to this group.
For the astrocytomas, the scheme is similar to the older St Anne/Mayo system,22 but in the WHO
scheme grade I is applied to distinct tumour entities such as pilocytic astrocytoma. The diffuseastrocytomas form a distinct clinical and biological group. For these, there is spectrum of malignancy
so that the scheme represents a true grading scheme, with grades II to IV representing increasing
biological aggression with associated poorer prognosis. Within the astrocytomas, distinction of grade
IV (glioblastoma) from grade III (anaplastic astrocytoma) is usually straightforward, if representative
samples have been taken, because it is based on the assessment of qualitative criteria, namely vascular
proliferation and necrosis. Distinction of grade III from grade II astrocytomas is based on mitotic
activity and may be problematic in some cases. In the St Anne/Mayo system the presence of a single
mitosis was sufficient, but there may be a difference between a small biopsy and a larger resection,
where a diligent search of many fields may raise the probability of finding a mitosis. In the latter
context, the presence of an isolated mitosis does not predict worse behaviour.23
Therefore, in the WHO
scheme a single mitosis is no longer an absolute criterion for the distinction of grade II from grade III
astrocytoma.24 This, however, creates the potential for greater subjectivity in grading. There are,
however, little published data on inter-observer variability for the WHO scheme for astrocytomas,
though a study based on older grading schemes suggests that there can be difficulty in inter-pathologist
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recognition of histological features used as grading criteria.25
Nevertheless the grading scheme works
well for prognostic purposes, although its application to the individual patient is also limited by
variations in tumour behaviour and by overlaps in the prognosis between tumour grades. This is
particularly the case for the grade II astrocytoma. Here, a grading of II does not distinguish between
tumours that will show indolent versus progressive behaviour, so that there is a need for the
development of better markers.26
Comparable problems exist for the application of grading to other
neuroepithelial tumours such oligodendrogliomas and ependymomas where grading criteria remain
somewhat subjective and imprecise.13
To an extent, the difficulties encountered in some borderline cases are a reflection of the attempt to
impose discrete categories on a biological continuum. In practice, assessment of borderline tumours for
prognostic and therapeutic purposes may be aided by discussion in an MDT meeting, where additional
clinical and radiological factors, such as patient age, tumour size, the presence of contrast enhancement
and rate of growth and serial scans provide additional information. In grade II astrocytomas, for
example, factors such as patient age, pre-operative neurological deficits, tumour diameter and tumour
crossing the midline can help to identify lower and higher risk groups.27
WHO grade may therefore
form one, albeit important, component of an integrated prognostic assessment.
Whilst forming a true grading scheme for the astrocytomas and some other groups, for some tumour
types it is in essence a statement of degree of malignancy,24
as these tumour types have only one
histological grade (e.g. medulloblastomas are all WHO grade IV). Nevertheless, it is recommended
that the WHO grade is given as well as the diagnosis for all primary CNS tumours where the WHO
scheme has assigned a grade, reflecting practice in the BNS EQA scheme. Compared to the earlier,
1993, version of the WHO scheme, the current scheme provides better grading criteria for
meningiomas, based on careful histological study in a large patient series.10,28
Although retrospective,
this has resulted in more clearly defined criteria for grading, including the introduction of mitotic rate
cut-offs for the diagnosis of atypical and malignant meningiomas. Inclusion of mitotic counts has
increased objectivity, although some of the criteria remain subjective. In comparison to the older
grading method, application of the new scheme appears in practice to result in the diagnosis of a higher
proportion of meningiomas as atypical.29
Pituitary tumours are now classified to according to cell type based on hormone production within the
tumour cells.11
This is generally determined by immunohistochemistry to the conventional
adenohypophysial hormones (ACTH, LH, FSH, alpha-subunit, TSH, prolactin, growth hormone),
though in some cases ultrastructural examination may aid classification; for example the differential
diagnosis of adenomas showing growth hormone and prolactin positivity, where it may aid in the
recognition of the more aggressive acidophil stem cell variant. Histological prognostic factors are
poorly defined for pituitary tumours. Retrospective studies have shown that the Ki67 proliferation
labelling index increases progressively in invasive adenomas and pituitary carcinomas, but cut-off
levels and methodology for assessment are not defined. Thus, whilst Ki67 assessment may be of value
to the neuropathologist, it is not included in the core dataset.
5.2 Addit ional prognostic and predictive factors
Immunohistochemical markers
In general, evaluation of prognostic and predictive factors by immunohistochemistry is poorly
validated for CNS tumours and does not form a core dataset item. The use of proliferation markers,
such as Ki67, is widespread in diagnostic practice and gives a useful impression of proliferative
potential, particularly in a small biopsy. Ki67 labelling indices (mostly using the MIB-1 antibody)
have been demonstrated to have prognostic value in a number of tumour types, including gliomas and
meningiomas.19,23,26,30,31
The relative rate of proliferation, as assessed by visual inspection, may be of
particular use in the assessment of borderline tumours, and in identifying areas in which mitotic
figures, which are validated prognostic factors, should be sought. However, in most cases there is littleevidence that assessment of Ki67 adds much of independent value to the standard pathological
assessment. There are also issues related to tumour heterogeneity, sampling and variation in
methodology, which may affect standardisation of the determination of tumour labelling index
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between centres.32
Reproducible cut-off values for diagnostic categories have also not been
established. Therefore, although a valuable technique at the discretion of the pathologist, the inclusion
of a Ki67 labelling index count in the core dataset is not warranted.
Molecular and cytogenetic markers
Cytogenetic and molecular genetic analyses of tumours have made considerable in-roads into an
improved understanding of the pathogenesis of brain tumours and are contributing towards a betterclassification of brain tumours. An example here is the glioblastoma, for which there appear to be
several molecular genetic routes to the development a tumour.33,34
These molecular subgroups cannot
be distinguished by conventional histopathological correlates. In the future, expression profiling of
molecular pathways may be used to provide additional prognostic information and a guide to specific
therapy. Although few of these markers yet have an evidence base for a practical role in clinical
practice, evidence is emerging for the utility of a number of markers and a field for molecular or
cytogenetic findings is included in the non-core data items. In particular, evidence for the value of two
predictive markers is emerging from clinical trials in the glioma field.
1. Approximately two thirds of oligodendrogliomas show loss from chromosomes 1p and 19q thatmay be demonstrated by a number of techniques, including FISH, PCR-based methods and more
classical cytogenetic methods.35,36
Although tumours with 1p,19q deletion are more likely to
show classical oligodendroglioma features, classical histopathology cannot reliably predict
deletion status, and demonstration of 1p,19q deletion provides additional information to classical
histopathological analyses.37
A number of small studies have suggested that 1p,19q status
predicts better prognosis and better response to combination chemotherapy, suggesting that this
is both a prognostic and predictive marker.38
Two large recent trials have confirmed that 1p,19q
delection identifies a subgroup of oligodendrogliomas with better prognosis, that appear to be
less biologically aggressive.39,40
Although further evidence is required, testing offers additional
information to histopathology. Testing for 1p,19q status is becoming more widely available in
the UK.
2. Glioblastoma is the most common primary brain tumour and continues to have a poor prognosis,despite therapies. Recent evidence has emerged to indicate that testing for MGMT (O6
methylguanine-DNA methyl transferase) status is of predictive value for treatment with
alkylating agents such as temozolamide.41
MGMT is a DNA repair enzyme that can repair the
damage induced by chemotherapeutic alkylating agents. In some glioblastomas, MGMT is
inactivated by methylation of its promoter. Detection of MGMT promoter methylation may
therefore predict responsiveness to temozolamide treatment whilst absence of methylation
predicts resistance. Thus MGMT shows promise as a marker for temozolamide sensitivity, but
further trials are underway to confirm this.
5.3 Role of the multidisciplinary team meeting
Cases of neuro-malignancy will in general be discussed in the context of the multidisciplinary team
(MDT) meeting, which is regarded in the NICE guidelines as central to patient management.4In the
context of the pathology dataset, discussion in this forum allows review of the biopsy with clinical and
neuroradiological information. This may be of particular value in the assessment of small biopsies to
ensure that the tissue is likely to be representative of the lesion. Thus, the pathological and radiological
findings can be compared and integrated and, if necessary, a final neuropathological report produced in
the light of this additional information.
Date and coding
The final report should include a date of report and SNOMED codes for statistical purposes.
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5.4 Summary of core data items
The minimum dataset for brain tumours is summarised in the proforma, but these data may also be
provided in the form of a conventional free-text report. Separate proformas are provided for:
intra-axial CNS tumours
extra-axial CNS tumours
pituitary tumours.
5.4.1 Clinical
Anatomical location of the lesion.
Type of operative procedure.
5.4.2 Pathological
Macroscopic items
Estimate tumour size in three dimensions.
Microscopic items
Tumour type.
Tumour sub-type relevant to grading and prognosis.
Tumour grade (WHO 2000).
6 NON-CORE DATA ITEMS
6.1 Clinical
Clinical presentation.
Neuro-radiological findings.
Pre-operative treatment to the lesion.
Previous procedures related to the CNS lesion.
Patient consents and preferences.
6.2 Pathological
Histological subtype of tumour not relevant to grading or prognosis.
Anatomical structures involved by tumour (formal staging not applicable).
Assessment of resection margin.
Molecular/cytogenetic abnormalities.
Frozen tissue archived.
Tissue banked in research tissue archives.
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7 DIAGNOSTIC CODING
TNM staging not applicable.
Use of SNOMED T and M codes is recommended (see Appendices A and B).
8 REPORTING OF SMALL BIOPSY SPECIMENS
Diagnostic biopsies may be obtained using conventional open biopsy, stereotactic or endoscopic
techniques. These are often necessarily small, and in such cases all of the tissue should be processed
for diagnostic purposes. Small portions may be archived frozen if this is felt by the neuropathologist
not to prejudice the diagnosis. Correctly targeted stereotactic diagnostic biopsies, their location
determined on the basis of radiological findings, are generally sufficient to establish the core dataset
items and there may be sufficient material for molecular investigations in appropriate cases.
Particularly for intra-axial tumours, neurosurgical sampling may be limited to the diagnostic biopsy,
without further definitive resection.
9 REPORTING OF FROZEN SECTIONS AND SMEAR PREPARATIONS
Either smear preparations or frozen sections may be used.42
Intra-operative diagnosis shows good
prediction of final histology, but may use up precious tissue. In the current imaging era, the evidence
base for the benefit of the technique is very limited and its use in diagnosis varies according to local
protocols and preferences. It may be useful in certain circumstances and NICE recommends its
availability in neurosurgical centres.4 It should be noted, however, that final diagnosis, treatment
planning and patient counselling should be based on the final report of the paraffin histology. Any
diagnostic information present in the intra-operative preparations should be included in the final
analysis. The fact of, and the result given from intra-operative diagnosis should be recorded for audit
purposes but, being incorporated in the final diagnosis, is not a core dataset item.
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2. Pobereskin LH, Chadduck JB. Incidence of brain tumours in two English counties: a population based
study.J Neurol Neurosurg Psychiatry 2000;69:464471.
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other CNS Tumours. Guidance on Cancer Services.London: National Institute for health and Clinical
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Tumors of the Nervous System (7thedition).London: Hodder Arnold, 2006.
7. Berger MS, Deliganis AV, Dobbins J, Keles GE. The effect of extent of resection on recurrence in
patients with low grade cerebral hemisphere gliomas. Cancer1994;74:17841791.
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8. Keles GE, Chang EF, Lamborn KR, Tihan T, Chang CJ, Chang SM et al.Volumetric extent of
resection and residual contrast enhancement on initial surgery as predictors of outcome in adult
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9. Sobin LH and Wittekind C (editors). TMN Classification of Malignant Tumours. International Union
Against Cancer. New York, Wiley-Liss, 2002.
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11. Ironside JW. Best Practice No 172: pituitary gland pathology.J Clin Pathol2003;56:561568.
12. Al-Brahim NY, Asa SL. My approach to the pathology of the pituitary gland.J Clin Pathol
2006;59:12451253.
13. Louis DN, Ohgaki H, Wiestler OD, Cavanee WK. WHO Classification of Tumours of the Central
Nervous System 4thEdition. Lyon: IARC, 2007.
14. Karpinski NC, Min KW, Bauserman SC; Cancer Committee, College of American Pathologists.
Protocol for the examination of specimens from patients with tumors of the brain/spinal cord: a basis
for checklists.Arch Pathol Lab Med2001;125:11621168.
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16. NCRI. National Cancer Research Institute. www.ncri.org.uk
17. UKCCSG. United Kingdom Childrens Cancer Study Group. www.ukccsg.org.uk
18. Lacroix M, Abi-Said D, Fourney DR, Gokaslan ZL, Shi W, DeMonte F et al.A multivariate analysis
of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival.J Neurosurg
2001;95:190198.
19. British Neuropathological Society. www.bns.org.uk
20. McLendon RE, Rosenblum MK, Bigner DD.Russell and Rubinsteins Pathology of Tumors of the
Nervous System (7thedition).London: Hodder Arnold, 2006.
21. UK National External Quality Assessment Scheme. www.ukneqas.org.uk
22. Daumas-Duport C, Scheithauer B, OFallon J, Kelly P: Grading of astrocytomas. A simple and
reproducible method. Cancer1988;62:21522165.
23. Giannini C, Scheithauer BW, Burger PC, Christensen MR, Wollan PC, Sebo TJ et al.Cellularproliferation in pilocytic and diffuse astrocytomas.J Neuropathol Exp Neurol1999;58:4653.
24. Kleihues P, Louis D, Scheithauer B, Rorke L, Reifenberger G, Burger P, Cavanee W: The WHO
classification of tumors of the nervous system.J Neuropathol Exp Neurol 2002;61:215225.
25. Coons SW, Johnson PC, Scheithauer BW, Yates AJ, Pearl DK. Improving diagnostic accuracy and
interobserver concordance in the classification and grading of primary gliomas. Cancer1997;
79:13811393.
26. Wessels PH, Weber WE, Raven G, Ramaekers FC, Hopman AH, Twijnstra A. Supratentorial grade II
astrocytoma: biological features and clinical course.Lancet Neurol2003;2:395403.
27. Pignatti F, van den Bent M, Curran D, Debruyne C, Sylvester R, Therasse P et al.Prognostic factors
for survival in adult patients with cerebral low-grade glioma.J Clin Oncol2002;20:20762084.
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28. Perry A, Stafford SL, Scheithauer BW, Suman VJ, Lohse CM. Meningioma grading: an analysis of
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29. Willis J, Smith C, Ironside JW, Erridge S, Whittle IR, Everington D. The accuracy of meningioma
grading: a 10 year retrospective audit.Neuropathol Appl Neurobiol2005;31:141149.
30. Kirkegaard LJ, DeRose PB, Yao, B, Cohen C. Image cytometric measurement of nuclear proliferationmarkers (MIB-1, PCNA) in astrocytomas. Prognostic significance.Am J Clin Pathol1998;109:6974.
31. Nakasu S, Li DH, Okabe H, Nakajima M, Matsuda M. Significance of MIB-1 staining indices in
meningiomas: comparison of two counting methods.Am J Surg Pathol2001;25:472478.
32. Prayson RA. Cell proliferation and tumors of the central nervous system, part II: radiolabeling,
cytometric, and immunohistochemical techniques.J Neuropathol Exp Neurol2002;61:663672.
33. Kleihues P and Ohgaki H. Primary and secondary glioblastomas: from concept to clinical diagnosis.
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34. Ichimura K, Ohgaki H, Kleihues P, Collins VP. Molecular pathogenesis of astrocytic tumours.
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35. Reifenberger J, Reifenberger G, Liu L, James CD, Wechsler W, Collins VP. Molecular genetic
analysis of oligodendroglial tumors show preferential allelic deletions on 19q and 1p.Am J Pathol
1994;145:11751190.
36. Reifenberger G, Louis DN. Oligodendroglioma: toward molecular definitions in diagnostic neuro-
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37. Sasaki H, Zlatescu MC, Betensky RA, Johnk LB, Cutone AN, Cairncross JG at el.Histopathological-
molecular genetic correlations in referral pathologist-diagnosed low-grade oligodendroglioma.J Neuropathol Exp Neurol 2002;61:5863.
38. Cairncross JG, Ueki K, Zlatescu MC, Lisle DK, Finkelstein DM, Hammond RR et al.Specific genetic
predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas.J
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39. Intergroup Radiation Therapy Oncology Group Trial 9402, Cairncross G, Berkey B, Shaw E, Jenkins
R, Scheithauer B et al.Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy
alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology
Group Trial 9402.J Clin Oncol2006;24:27072714.
40. van Den Bent MJ, Carpentier AF, Brandes AA, Sanson M, Taphoorn MJ, Bernsen HJ et al.Adjuvantprocarbazine, lomustine and vincristine improves progression-free survival but not overall survival in
newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European
Organisation for Research and Treatment of Cancer phase III trial.J Clin Oncol2006;24:27152722.
41. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M et al.MGMT gene silencing
and benefit from temozolomide in glioblastoma.N Engl J Med2005;352:9971003.
42. Ironside JW, Moss TH, Louis DN, Lowe JS, Weller RO.Diagnostic Pathology of Nervous System
Tumours. Chapter 3: Intraoperative Diagnosis. Edinburgh: Churchill Livingstone 2002.
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11 APPENDICES
APPENDIX A SNOMED T CODES
T-A0100 Brain
T-A6000 CerebellumT-A2000 Cerebral hemisphere
T-A1900 Choroid plexus
T-A8000 Cranial nerve
T-A1110 Meninges NOS
T-B2000 Pineal gland
T-B1000 Pituitary gland
T-11100 Skull
T-A7010 Spinal cord NOST-A7160 Spinal nerve root
T-11500 Spine
APPENDIX B SNOMED M CODES
M-81406 Adenocarcinoma, metastatic
M-81400 Adenoma
M-94003 Astrocytoma
M-94013 Astrocytoma, anaplastic type
M-80106 Carcinoma, metastatic
M-93703 Chordoma
M-93900 Choroid plexus papilloma
M-93903 Choroid plexus papilloma, malignant
M-93923 Ependymoblastoma
M-93913 Ependymoma
M-93923 Ependymoma, anaplastic
M-93941 Ependymoma, myxopapillary
M-94900 Gangliocytoma
M-95051 Ganglioglioma
M-90643 Germinoma
M-94403 Glioblastoma
M-91501 Haemangiopericytoma
M-91611 Haemangioblastoma
M-95903 Lymphoma NOS
M-95403 Malignant peripheral nerve sheath tumour
M-87203 Melanoma
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M-94703 Medulloblastoma
M-95013 Medulloepithelioma
M-95300 Meningioma
M-95303 Meningioma, malignant
M-95003 Neuroblastoma
M-95060 Neurocytoma
M-95400 Neurofibroma
M-94503 Oligodendroglioma
M-94513 Oligodendroglioma, anaplastic type
M-86801 Paraganglioma
M-94213 Pilocytic astrocytoma
M-93601 Pinealoma
M-93623 Pineoblastoma
M-88003 Sarcoma NOS
M-95600 Schwannoma
M-93841 Subependymal giant cell astrocytoma
M-93831 Subependymoma
M-90801 Teratoma
Other T and M codes may be used if appropriate.
APPENDIX C LIST OF ABBREVIATIONS
CNS Central nervous system
CPA Clinical Pathology Accreditation (UK) Ltd
EQA External quality assurance
FISH Fluorescence in situ hybridisation
MDT Multidisciplinary team
MGMT O6 methylguanine-DNA methyl transferase
NICE National Institute for Health and Clinical Excellence
NCRI National Cancer Research Institute
PCR Polymerase chain reaction
UKCCSG United Kingdom Childrens Cancer Study Group
WHO World Health Organization
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APPENDIX D REPORTING PROFORMA FOR INTRA-AXIAL TUMOURS
Surname Forenames. Date of birth.. Sex..
Hospital. Hospital no .. NHS no.
Date of receipt.. Date of reporting. Report no .
Pathologist Clinician
CORE ITEMS
Clinical details
Site of lesion
Cerebrum Cerebellum Brainstem Spinal cord
Left Right Unifocal Multifocal
Details of location
Type of procedure
Biopsy Resection: partial Total macroscopic Extent uncertain
Macroscopic items
Specimen dimensions Estimated tumour dimensions ..
Microscopic items
Tumour type Tumour subtype (if relevant)
WHO tumour grade: I II III IV
ADDITIONAL (NON-CORE) DATA ITEMS
Clinical
Length of history . Symptoms ..Neuroradiological appearance ...
Pre-operative treatment to lesion: Yes No Details
Past history CNS lesion: First biopsy/resection Previous biopsy
Past treatment of CNS lesion: Yes No Details .
History of other tumours
Pathological
Additional information on subtyping ..
Involvement of anatomical structures .
Resection margins: Not assessed Negative Involved
Molecular/cytogenetic investigations
Test .. Result ..Frozen tissue
Archived: Yes No
Banked in specific research tissue archive: Yes No Details .
Recorded patient consent
Generic research consent: Yes No Not known
Project specific consent: Yes No Not known
Details ..
Signature ... Date ..
SNOMED codes: T . M .
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APPENDIX E REPORTING PROFORMA FOR EXTRA-AXIAL TUMOURS
Surname Forenames. Date of birth.. Sex..
Hospital. Hospital no .. NHS no.
Date of receipt.. Date of reporting. Report no .
Pathologist Clinician
CORE ITEMS
Clinical details
Site of lesion
Intradural Extradural Skull Paraspinal
Left Right Unifocal Multifocal
Details of location
Type of procedure
Biopsy Resection: Partial Total macroscopic Extent uncertain
Macroscopic items
Specimen dimensions Estimated tumour dimensions ..
Microscopic items
Tumour type Tumour subtype (if relevant)
WHO tumour grade: I II III IV N/A
ADDITIONAL (NON-CORE) DATA ITEMS
Clinical
Length of history . Symptoms ..
Neuroradiological appearance ...Pre-operative treatment to lesion: Yes No Details
Past history CNS lesion: First biopsy/resection Previous biopsy
Past treatment of CNS lesion: Yes No Details .
History of other tumours
Pathological
Additional information on subtyping ..
Involvement of anatomical structures .
Resection margins: Not assessed Negative Involved
Lymph nodes: Not assessed Negative Involved No.
Tumour grading (non-WHO CNS) .
Molecular/cytogenetic investigationsTest .. Result ..
Frozen tissue
Archived: Yes No
Banked in specific research tissue archive: Yes No Details .
Recorded patient consent
Generic research consent: Yes No Not known
Project specific consent: Yes No Not known
Details ..
Signature ... Date ..
SNOMED codes: T . M .
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APPENDIX F REPORTING PROFORMA FOR PITUITARY TUMOURS
Surname Forenames. Date of birth.. Sex..
Hospital. Hospital no .. NHS no.
Date of receipt.. Date of reporting. Report no .
Pathologist Clinician
CORE ITEMS
Site of lesion
Intrasellar Suprasellar Both
Type of procedure
Biopsy Resection: partial total macroscopic extent uncertain
Macroscopic items
Specimen dimensions Estimated tumour dimensions ..
Microscopic items
Tumour type
Hormone expression by immunohistochemisty:
ACTH GH Prl FSH LH Alpha sub-unit TSH
ADDITIONAL (NON-CORE) DATA ITEMS
Clinical
Length of history . Symptoms ..
Serum hormone production ...
Pre-operative treatment to lesion: Yes No Details
First biopsy/resection Previous biopsy
Past treatment of lesion: Yes No Details
History of other tumours
Pathological
Involvement of anatomical structures .
Resection margins: Not assessed Negative Involved
Lymph nodes: Not assessed Negative Involved No.
Ultrastructural investigations:
Result
Molecular/cytogenetic investigations
Test .. Result ..
Frozen tissue
Archived: Yes No
Banked in specific research tissue archive: Yes No Details .
Recorded patient consent
Generic research consent: Yes No Not known
Project specific consent: Yes No Not known
Details ..
Signature ... Date ..
SNOMED codes: T . M .