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Abstract
BackgroundAccurate neuroendocrine neoplasia (NEN) staging is vital for determining prognosis and therapeutic strategy. The great majority of NENs express chromogranin A (CgA) which can be detected at a protein or transcript level. The current standards for lymph node metastasis detection are histological examination after Hematoxylin and Eosin (H&E) and CgA immunohistochemical (IHC) staining. We hypothesized that detection of CgA mRNA transcripts would be a more sensitive method of detecting these metastases.FindingsWe compared these traditional methods with PCR for CgA mRNA extracted from formalin fixed paraffin embedded slides of lymph nodes (n = 196) from small intestinal NENs, other gastrointestinal cancers and benign gastrointestinal disease. CgA PCR detected significantly more NEN lymph nodes (75%) than H&E (53%) or CgA IHC (57%) (p = 0.02). PCR detected CgA mRNA in 50% (14 of the 28) of SI-NEN lymph nodes previously considered negative. The false positive rate for detection of CgA mRNA was 19% in non-neuroendocrine cancers, and appeared to be due to occult neuroendocrine differentiation or contamination by normal epithelium during histological processing.ConclusionsMolecular pathological analysis demonstrates the limitations of observer-dependent histopathology. CgA PCR analysis detected the presence of CgA transcripts in lymph nodes without histological evidence of tumor metastasis. Molecular node positivity (stage molN1) of SI-NEN lymph nodes could confer greater staging accuracy and facilitate early and accurate therapeutic intervention. This technique warrants investigation using clinically annotated tumor samples with follow-up data.
Highlights
Accurate neuroendocrine neoplasia (NEN) staging is vital for determining prognosis and therapeutic strategy
chromogranin A (CgA) Polymerase chain reaction (PCR) analysis detected the presence of CgA transcripts in lymph nodes without histological evidence of tumor metastasis
Since it is evident that anti neoplastic therapy is more effective as tumor burden decreases [11], and the presence of lymph node metastases has been validated as a key prognostic variable in NENs [12,13] the identification of lymph node metastasis has significant implications on the timing of therapy and its efficacy
Summary
Regional mesenteric lymph nodes from resected SI-NENs were examined for the histological presence of metastasized NEN cells, the immunohistochemical presence of CgA protein, or the presence of CgA mRNA by PCR. We have demonstrated that the PCR detection of CgA transcripts from paraffin embedded lymph node tissue is a feasible technique with potential clinical utility. Proportion of lymph nodes that show detectable CgA transcripts in the absence of histological evidence of neuroendocrine tumor according to the presence of extraneous tissue. 3 of the 6 lymph nodes with adenocarcinoma cells visible on histological examination demonstrated CgA IHC positivity, consistent with detection of neuroendocrine differentiation by CgA PCR. Authors’ contributions BL; study design, qRT-PCR, statistical analysis, manuscript preparation. BS; study design, histopathological and immunohistochemical assessment, manuscript preparation.
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