Prognostische Relevanz der intertumoralen Heterogenität in Bezug auf typische pathologische Marker bei multifokalen neuroendokrinen Tumoren des Dünndarms (SI-NEN)
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Philipps-Universität Marburg
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Abstract
The origin of neuroendocrine tumors of the jejunum and ileum, as well as their
genetic causes and triggers, remain unclear to date. A 2021 whole-genome
sequencing study failed to detect genomic overlap between the suspected
primary tumors and synchronous secondary tumors, suggesting genetic
independence of the individual tumors. However, it is still unclear whether the
findings of somatic independence can also be represented at the
morphological level.
The aim of this work was to investigate the tumor heterogeneity between
primary and multifocal lesions with basic diagnostic markers, WHO grade,
SSTR2 receptor status, and immunogenic tumor microenvironment and their
potential impact on diagnostic algorithms and overall patient survival. The
study included 146 tumors from 28 patients with multifocal SI-NEN.
The results showed that in almost 80% of the cases studied, the WHO grade,
based on the Ki-67 index, was matched in the largest tumors and synchronous
secondary tumors. In few cases, there was no concordance of WHO grade
between the leading primary tumor and the synchronous tumors. Most cases
were higher-grade findings of the largest tumor with additional smaller tumors
of lower grade.
The neuroendocrine markers synaptophysin and chromogranin A were found
to be strongly and diffusely expressed in all tumors. For the markers CDX2 and
serotonin, typical of SI-NEN, a large variability in expression was observed
within patients. Differences in CDX2 expression between the largest primary
tumor and secondary tumors occurred in 50% of cases, and aberrant serotonin
expression was observed in 32% of cases.
Aberrant findings could be depicted in somatostatin receptor 2a (SSTR2a)
expression. Strikingly, at least one tumor showed a strong expression of
SSTR2a in most patients, whereas other synchronous tumors were negative.This finding provides a possible explanation for the fact that functional
somatostatin receptor imaging often fails to diagnose multifocal SI-NEN.
In the final statistical analysis of the study of intertumoral heterogeneity of
multifocal SI-NENs compared with survival data of patients with unifocal SINETs,
no significant impact on the overall survival of patients compared with
unifocal tumors could be presented.
In conclusion, the study underlying this dissertation was able to demonstrate
for the first time that the primary and multifocal lesions are characterized by
morphologic heterogeneity based on standard histopathologic markers. At
the same time, this study highlights that the above described heterogeneity
has a limited clinical relevance in terms of disease progression and overall
patient survival. A single patient histopathologic diagnosis and analysis of each
single lesion would not ameliorate the patient prognosis.
In particular, the assessment of the tumor grade in the primary lesion could be
sufficient for the secondary lesions, thus excluding any further diagnostics.
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Dates
Created: 2024Issued: 2025-04-23Updated: 2025-04-23
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
DFG-subjects
PathologySI-NENIleal NETCancer
DDC-Numbers
610
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Poppinga, Jelte: Prognostische Relevanz der intertumoralen Heterogenität in Bezug auf typische pathologische Marker bei multifokalen neuroendokrinen Tumoren des Dünndarms (SI-NEN). : Philipps-Universität Marburg 2025-04-23. DOI: https://doi.org/10.17192/z2025.0194.