8438_april_08 royal college of pathologists, cns dataset

8/13/2019 8438_April_08 Royal College of Pathologists, CNS Dataset

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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.

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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.

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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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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





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


Microscopic items

Tumour type Tumour subtype (if relevant)

WHO tumour grade: I II III IV N/A


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 .


Pathological

Additional information on subtyping ..



Lymph nodes: Not assessed Negative Involved No.

Tumour grading (non-WHO CNS) .

Molecular/cytogenetic investigationsTest .. Result ..

Frozen tissue

Archived: Yes No





Details ..




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APPENDIX F REPORTING PROFORMA FOR PITUITARY TUMOURS





CORE ITEMS

Site of lesion

Intrasellar Suprasellar Both

Type of procedure

Biopsy Resection: partial total macroscopic extent uncertain

Macroscopic items


Microscopic items

Tumour type

Hormone expression by immunohistochemisty:

ACTH GH Prl FSH LH Alpha sub-unit TSH


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


Pathological



Lymph nodes: Not assessed Negative Involved No.

Ultrastructural investigations:

Result

Molecular/cytogenetic investigations

Test .. Result ..

Frozen tissue

Archived: Yes No





Details ..



8438_april_08 royal college of pathologists, cns dataset

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