Pertinence of the WHO 2010 guideline on NEC diagnosis Reliable pathology reporting of extra-pulmonary large cell NEC JM van der Zwan Ph.D., IACR, Vancouver 2019

Conflict of Interest Disclosure Form in accordance with the rules of the Health Care Inspectorate (IGZ) name: Jan Maarten van der Zwan affiliation: Netherlands Comprehensive Cancer Organisation  I have no potential conflict of interest to report

Background Extra pulmonary neuroendocrine carcinomas (EP-NEC) are rare tumors, therefore many publications concern small cohorts only. A correct diagnosis and grading is of great importance for the treatment of choice. Population based Cancer Registry data gives the opportunity to study these poor surviving patients. According to the international definition, small and large cell NEC of the lung are not rare cancers [7]. Although accurate information about the incidence of EP-NEC is unavailable. It is estimated to cover 1-3 % of all NEN. For this study we focused on the extrapulmonary NEC and the WHO 2010 guideline for this selection of Neuroendocrine malignancies.

Background (cont.) Classification of neuroendocrine neoplasms (NEN) changed through time. Embryonal origin Morphology (well vs poorly differentiated) (year 2000) Proliferative activity (year 2010) navragen

Background (cont.) Classification of neuroendocrine neoplasms (NEN) Proliferative activity (2010) NET G1 <2 mitoses / 10hpf AND <3% Ki67 index NET G2 2-20 mitoses / 10hpf OR 3%-20% Ki67 index NEC G3 >20 mitoses / 10hpf OR >20% Ki67 index In the WHO 2017 guideline they introduced Carcinomas with a low proliferative activity, which result in a Grade 1 or 2 Neuroendocrine Carcinoma. This new standard can only be properly registered if having information on both the morphology and Ki67 and/or mitoses index. Since 2016 we include both the mitoses and Ki67 in our registry. For this study we rely on the standards as applicable for the period 2010 to 2016 Klimstra et al., Pancreas Volume 39, number 6, August 2010

Aim of the study Demonstrate a change in pathology reporting after the implementation of the WHO 2010 guideline.  Did the implementation of the WHO 2010 result in a more uniform diagnostic pattern?

The NCR The Netherlands Cancer Registry (NCR) receives their notification from the National pathology archive (PALGA) Information is mainly retrieved from the pathology report and patient files. As you can see the Netherlands is the centre of the world (joking) We have a population of 17 million people and register about 110.000 new cancer cases annually The quality of the NCR is relying on the quality of both the content of the pathology reports and patient files. We follow the patient for about 9 months, which is expected to be sufficient for these poor surviving patients.

Methods Selection: Pathology reviewed on: Compare: EP-NEC NEC with unknown primary localization M8013 & M8246 Years 2008 – 2012 Pathology reviewed on: Morphology Immunohistochemistry Grading Compare: 2008-2010 (baseline) 2011-2012 We selected our cases from the Netherlands cancer registry and merged our information with the original pathology reports and reviewed the pathology conclusions. With this review we focussed on the completeness of the pathology report including the morphology, immmunohistochemistry and Grading (ki67 / mitosis index). Automatically mistakes made by the cancer registry were retrieved, however it was difficult to see where mistakes were made (pathologist or the datamanager). If the mitosis and Ki67 draw different conclusions we relied the diagnosis on the highest grade. And if no Ki67 and mitosis were available they were seen as NEN unknown grade

Review pathology reports

Review: Flow chart Period 2008-2012 The NCR included 591 EP-NEC cases. 591 cases were selected in the NCR for the period 2008-2012. Cases being EP-NEC but not registered as EP-NEC in our registry are missing. We expect this to be a minor group of patients and would rather be an overreporting as we are aware that sometimes we register a NEC while it should be a NET G1-G2

Review: Flow chart Carcinomas with neuroendocrine characteristics and NET G1 & G2 7 cases were diagnosed before 2008 and therefore excluded for this study. 55 cases did not have microscopy or Immuno histochemical staining and therefore excluded. Still they could correct EP-NEC As already suggested we found 93 cases (out of the 591 cases) not to be a NEC. This can be because the pathologist was unclear in there written conclusions while staining and grading was clear in the pathology report. These are difficult cases for our datamanagers as they most rely on the written summary conclusions from the pathologists.

Review: Flow chart Carcinomas with neuroendocrine characteristics and NET G1 & G2 Negative staining for NET/NEC For 77 cases the neuroendocrine differentiation could not be confirmed by immunohistochemistry (synapthophysin or chromogranin) and therefore seen as Large Cell Carcinoma Not Otherwise specified. - 28 cases weakly positive As this information was missing it could not be garanteed to be EP-NEC. The use of CD56 was positive in 65% and could explain why they were (incorrectly) classified as NEC.

Review: Flow chart Carcinomas with neuroendocrine characteristics and NET G1 & G2 Negative staining for NET/NEC 93 cases had no grade due to missing Ki67 and or mitosis and could therefor not be graded. So it could not be guaranteed to be a NEC 93 cases no Grading

Review: Flow chart Carcinomas with neuroendocrine characteristics and NET G1 & G2 Negative staining for NET/NEC 58 cases had a NET grade 1 or 2 not being a NEC. 93 cases no Grading 58 cases low Grade

Review: Flow chart Carcinomas with neuroendocrine characteristics and NET G1 & G2 Negative staining for NET/NEC So finally for 196 cases EP-NEC the conclusion could be confirmed following the WHO2010 guideline. Which does not directly imply that all other cases are non EP-NEC 93 cases no Grading 58 cases low Grade 196 cases confirmed NEC

Results navragen

Completeness pathology 2008: 50% of the reports included IHC and Grading 2012: 69% of the reports included IHC and Grading Grade is considered to be the most important prognostic factor for patients with a neuroendocrine malignancy Completeness of pathology reports of neuroendocrine carcinomas from 2008 to 2012 (percentage) Any neuroendocrine IHC: either synaptophysin or chromogranin was reported

Completeness pathology 2008: 50% of the reports included IHC and Grading 2012: 69% of the reports included IHC and Grading Mainly the result of reporting Grade (63% vs 74%) Still the use of Ki67 and mitosis index is lacking in the pathology report, however with the introduction of the WHO2010 we see improvement. Completeness of pathology reports of neuroendocrine carcinomas from 2008 to 2012 (percentage) Any neuroendocrine IHC: either synaptophysin or chromogranin was reported

Overall survival Overall survival patterns are in accordance with the histopathological classification. Low grade NET: Mean survival of 2.2yrs Small cell NEC: Mean survival of 1.1 yrs Confirm our findings by calculating the survival. We confirm the group of NEC actually being a NET to have a better survival. Take into account that these survival of NET is not the actuall NET survival as this is a subselection based on our dataset with including NEC as starting point. In relation to NET in general (G1 5 yr rel surv = 79%) the rel surv is still low. In addition it might therefor be of interest to take the stage of disease into account for comparison, still this study and the WHO2010 guideline is not focussing on stage. Kaplan-Meier analysis of overall survival (p=0.02)

Take home message EP-NECs are difficult malignancies to diagnose  Expert pathologists might improve quality diagnoses There are discrepancies in the pathology reports Expert datamanagers might improve data-quality Reporting neuroendocrine markers and grade are important as prognostic factors and to select the treatment of choice  Consider the involvement of Expert Centres.

Conclusion Although publication of guidelines improves the use of essential parameters, the implementation may require a considerable period of time (sometimes even years).  Synoptic reporting might give an important boost to meet requirements more quickly.

Acknowledgements Wouter Zandee Ph.D. MD Wouter de Herder Ph.D. MD Marie-Louise van Velthuysen Ph.D. MD

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