Guidance for reporting the interpretation of cytogenomic test results in haematological neoplasms

Guidance for reporting the interpretation of cytogenomic test results in haematological neoplasms

 

Katrina Rack¹, Eva van den Berg², Claudia Haferlach³, Berna Beverloo⁴, Blanca Espinet⁵, Nicola Foot⁶, Kate Martin⁷, Sheila O'Connor⁸, Jacqueline Schoumans⁹, Polly Talley¹⁰, Sabine Stioui¹¹, Zuzana Zemanova¹², Isabelle Luquet¹³, Ros Hastings¹

¹ GenQA, John Radcliffe Hospital, Oxford, UK; Katrina.Rack@ouh.nhs.uk; Ros.Hastings@ouh.nhs.uk;
² Department of Genetics University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; e.van.den.berg-de.ruiter@umcg.nl;
³ MLL-Munich Leukemia Laboratory, Munich, Germany; claudia.haferlach@mll.com;
⁴ Department of Clinical Genetics, Erasmus MC, University medical center Rotterdam, Rotterdam, The Netherlands; b.beverloo@erasmusmc.nl;
⁵ Laboratori de Citogenètica Molecular, Servei de Patologia, Grup de Recerca,Translacional en Neoplàsies Hematològiques, Cancer Research Program,Hospital del Mar, Barcelona, Spain; BEspinet@parcdesalutmar.cat;
⁶ Viapath Genetics laboratory, Guys Hospital, London, UK; Nicola.Foot@viapath.co.uk;
⁷ Department of Cytogenetics, City Hospital Campus, Nottingham, UK; Katherine.Martin@nuh.nhs.uk;
⁸ Haematological Malignancy Diagnostic Service, St James’s University Hospital, Leeds, UK; sheila.oconnor@nhs.net;
⁹ Laboratoire d’oncogénomique, Service d’hématologie Centre Hospitalier Universitaire, Vaudois, Switzerland; Jacqueline.Schoumans@chuv.ch;
¹⁰ Haematological Malignancy Diagnostic Service, St James’s University Hospital, Leeds, UK; polly.talley@nhs.net;
¹¹ Laboratorio di Citogenetica e Genetica Molecolare - Laboratorio Analisi, Humanitas Research Hospital, Rozzano, Milan, Italy; sabine.stioui@humanitas.it;
¹² Center of Oncocytogenetics, Institute of Clinical Biochemistry and Laboratory Diagnostics, General University Hospital and First Faculty of Medicine, Charles University,Prague, Czech Republic; zemanova.zuzana@vfn.cz;
¹³ Laboratoire d’Hématologie, IUCT-O, Toulouse, France; luquet.i@chu-toulouse.fr.

 

May 2019

 

Specific recommendations for reporting the results of diagnostic genetic testing have previously been published1. However the focus has been on germline testing and although many of the reporting requirements are the same, the considerations for the interpretation of acquired abnormalities are different. General guidance on report format and content is also provided in the recommendations for cytogenomic testing in haematological neoplasms2. Review of cytogenomic test reports of laboratories participating in external proficiency testing schemes has highlighted a large variation in the content and detail of the interpretation of the results. This document aims to provide supplementary specific guidance for the format and information to be included in the result interpretation. The interpretation should provide clear concise information and long reports should be avoided as this detracts from the clarity of the results. Genetic testing can be undertaken for diagnostic, prognostic and predictive reasons or at follow up for disease monitoring and this should be addressed in the report.

Relationship of any abnormalities found to the referral reason
The report should include a description of the abnormality identified and the results should be interpreted with respect to the referral reason, or any subsequent information received regarding the patient (e.g. information subsequently communicated by referring clinician). For haematological samples the final diagnosis may or may not be known at time of sample collection and consequently the referral reason can be a confirmed diagnosis, a presumptive diagnosis, a differential diagnosis or a description of clinical symptoms or findings.

• Where a diagnosis is confirmed, the report should state whether the result is consistent with this diagnosis. It is unhelpful to discuss the association of the abnormality with other disease entities as it may bring the diagnosis into question.
• Where the diagnosis is unconfirmed the report should state whether the result supports the proposed/presumptive diagnosis. When there is a differential diagnosis the report should discuss the result in relation to the different neoplasms considered.
• Where no specific diagnosis has been stated on the referral card, and only clinical information has been provided, it is advised to contact the clinician or the pathology/haematology laboratory for more information before reporting. However, when this is not possible, the report should provide information on its association with specific disease entities.
• In some cases an abnormality may be identified that is inconsistent with the referral reason. It is known that some patients with a haematological malignancy have a second haematological neoplasm and it is not unusual in these cases to identify an abnormal clone containing recurrent abnormalities associated with one or both neoplasms. For example, in a patient referred for CLL, a clone with a deletion 20q may be detected. In such cases it is advised to contact the clinician for further information before reporting. However, when this is not possible, the report should state that the abnormality detected neither supports nor excludes the diagnosis indicated on the referral form and should provide information of any association with other specific disease entities. As a further example, in a patient referred for CLL, two independent clones may be detected, one with a trisomy 12 and one with a monosomy 7. Information pertaining to both abnormalities should be provided on the report.
• In some cases the abnormality detected may be suspected to have a constitutional rather than acquired origin and this should be discussed in the report. Depending on the nature of the abnormality, and considering any reproductive implications for the patient’s extended family, confirmation of the patient’s constitutional cytogenomic testing can be suggested.
• The most recent WHO (currently 2017) nomenclature should be used in relation to the disease category, where appropriate.

Reporting normal results
The probability of detecting an abnormality depends on the pathology and methodology used. Laboratories should ensure that the most appropriate testing strategy is undertaken. Interpretation of normal test results needs careful consideration.

• Where an abnormal clone cannot be excluded, for example where insufficient metaphases have been obtained or cell enrichment is not optimal (such as low purity of CD138+), the report should include a statement to this effect. In addition, appropriate additional testing should be recommended in the report if not already undertaken.
• Where a prognostic test is performed the report should clearly state that no high risk/ adverse prognostic factors were detected.

Reporting complex results
Reporting complex test results can be challenging and it is important that the information provided is succinct and clear to the reader of the report.

• The report should summarise the main diagnostic or prognostic abnormalities in a clear statement or in tabular form, if possible near the beginning of the report.
• It should be clear which pertinent prognostic factors have been tested and the report should state whether high risk or established abnormalites have been detected or not detected (for example TP53 deletion or mutation not detected).
• The complex nature of the test result should be highlighted although a full description of all the abnormalities is not required. If included these should be listed elsewhere in the report so as not to detract from the major findings.
• Some pathologies, such as multiple myeloma, demonstrate high intraclonal variability and the FISH signal patterns observed can be very heterogeneous. It is recognised that such cases can be difficult to report and therefore complex signal patterns do not need to be described in detail. However, the report should state an atypical heterogeneous signal pattern was detected showing gene rearrangement, gain, loss or amplification.

Prognostic and predictive information
It is good practice to include prognostic and predictive information in the report. However, it is recognised that local policy and national recommendations need be taken into account when deciding whether to include this information in the report. For example, inclusion of this information may not be required when it will be summarised in an integrated multidisciplinary report or inclusion may be unhelpful in cases where the report is given directly to the patient. In the latter case, information regarding prognosis should be reported with caution as there are always exceptions on a patient level: e.g. cases with CLL and TP53 aberrations that do perform well, etc. Similarly, inclusion of predictive response to therapy in the report can be unhelpful as choice of adequate therapeutic option by the clinician needs to take into account the patients co-morbidities and other clinical issues. Where laboratory policy is not to include this information in the report the laboratory may choose to make this information, and any new predicitive data, available to the clinician outside the report (telephone, extra fact sheet, link to laboratory website, separate appendix).

Where prognostic information is included or has been specifically requested a prognostic statement must be provided.

• When no informative prognostic genetic bio-markers have been identified this should be stated.
• Where the prognostic information is currently contentious this should be highlighted and referenced in the report.
• Where the abnormality is a predictive marker for response to therapy it is recommended to mention it in the report.
• Prognostic information provided should relate to robust data from multiple publications/international trials/trial protocols or widely accepted prognostic systems exists (e.g. IPSS-R in MDS, ELN recommendations and MRC prognostic system in AML), or evidence from large randomised control trials of patients undergoing similar relevant treatment or meta-analysis/systematic review of multiple studies.
• Multiple concordant studies can be used and should be referenced.
• Small and isolated studies should not be used to derive prognosis although this information can be given in the report if put in context and referenced.
• It should be noted that the prognostic impact of a distinct marker relates to the specific treatment regimen used in the respective study, e.g. prognosis of APL with t(15;17)(q24;q21) is only favourable if treatment protocols including ATRA and/or arsenic trioxide are used.
• Cytogenomic results are just one component of establishing the patients overall prognosis. For some diseases a combined scoring system is used to establish risk that incorporates risk scores from multiple different tests. For these neoplasms it is recommended to state the cytogenetic risk score in the report to avoid any confusion with the overall risk score which may be different.

Recommendations
Where additional testing, not already undertaken, is required to clarify the significance of the results this should be stated on the report.

Follow up testing
The interpretation of follow up testing must relate the current results to the previous test results and the previous test reference number and sample date should be provided in the report.

Technical reports and provisional reports for discussion at multi discipline meetings
In some circumstances a provisional or abbreviated report is issued prior to discussion at a multi-disciplinary team meeting (MDT) or before the results of other ongoing testing are available. If a purely technical report is issued it should be made clear that the interpretation of the results will be incorporated into a final integrated report.

Bibliography

Recommendations for reporting results of diagnostic genetic testing (biochemical, cytogenetic and molecular genetic)

Claustres M, Kožich V, Dequeker E, Fowler B, Hehir-Kwa JY, Miller K, Oosterwijk C, Peterlin B, van Rave nswaaij-Arts C, Zimmermann U, Zuffardi O, Hastings RJ, Barton DE; European Society of Human Genetics

Eur J Hum Genet 2014 Feb;22(2):160-70

PMID 23942201

European Recommendations and Quality Assurance for Cytogenomic Analysis of Haematological neoplasms.

Rack K, et al

Leukemia https://doi.org/10.1038/s41375-019-0378-z

Written	2019-05	Katrina Rack, Eva van den Berg, Claudia Haferlach, Berna Beverloo, Blanca Espinet, Nicola Foot, Kate Martin, Sheila O'Connor, Jacqueline Schoumans, Polly Talley, Sabine Stioui, Zuzana Zemanova, Isabelle Luquet, Ros Hastings
		John Radcliffe Hospital, Oxford, UK (KR, RH), Department of Genetics University Medical Center Groningen, University of Groningen, Groningen, The Netherlands(EvdB); MLL-Munich Leukemia Laboratory, Munich, Germany (CH); Department of Clinical Genetics, Erasmus MC, University medical center Rotterdam, Rotterdam, The Netherlands (BB); Laboratori de Citogenètica Molecular, Servei de Patologia, Grup de Recerca,Translacional en Neoplàsies Hematològiques, Cancer Research Program,Hospital del Mar, Barcelona, Spain (BE); Viapath Genetics laboratory, Guys Hospital, London, UK (NF); Department of Cytogenetics, City Hospital Campus, Nottingham, UK (KM); Haematological Malignancy Diagnostic Service, St James's University Hospital, Leeds, UK (SOC); Laboratoire d'oncogénomique, Service d'hématologie Centre Hospitalier Universitaire, Vaudois, Switzerland (JS); Haematological Malignancy Diagnostic Service, St James's University Hospital, Leeds, UK (PT); Laboratorio di Citogenetica e Genetica Molecolare - Laboratorio Analisi, Humanitas Research Hospital, Rozzano, Milan, Italy (SS); Center of Oncocytogenetics, Institute of Clinical Biochemistry and Laboratory Diagnostics, General University Hospital and First Faculty of Medicine, Charles University,Prague, Czech Republic (ZZ); Laboratoire d'Hématologie, IUCT-O, Toulouse, France (IL). Corresponding author: Katrina Rack

Citation

This paper should be referenced as such :

Rack K, van den Berg E, Haferlach C, Beverloo B, Espinet B, Foot N, Martin K, O'Connor S, Schoumans J, Talley P, Stioui S, Zemanova Z, Luquet I, Hastings R

Guidance for reporting the interpretation of cytogenomic test results in haematological neoplasm

Atlas Genet Cytogenet Oncol Haematol. in press

On line version : http://AtlasGeneticsOncology.org/Deep/GuidanceReportInterpretationCytogenomicID20150.htm