New markers targeting neuroendocrine neoplasms NENs

A neuroendocrine neoplasm (NEN) begins in the cells of the neuroendocrine system. These cells have traits of both hormone-producing endocrine cells and nerve cells. The advent of second-generation NEN markers for use in immunohistochemistry has considerably expanded the pathology toolbox for diagnosing and classifying NENs. Atlas Antibodies has released new monoclonal markers targeting NENs. Read more in our new blog post!

What are neuroendocrine neoplasms?

Neuroendocrine neoplasms (NENs) constitute a group of tumors that derive from the sensory and secretory neuroendocrine cells (the cells that release hormones into the bloodstream and act as an interface between the endocrine system and the nervous system) of the diffuse endocrine system.

These cells are found in many organs of our body. Consequently, NENs are heterogeneous and may arise almost in every organ. However, they are predominately found in the gastrointestinal (61%) and bronchopulmonary (25%) systems, followed by the pancreas (8%), reflecting the high density of neuroendocrine cells in these organs. 

Neuroendocrine neoplasms can either be classified as functioning (producing excess hormones causing symptoms) or non-functioning (not producing excess hormones or not enough to cause symptoms).

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Download the infographic: Neuroendocrine Neoplasms 

How are NENs diagnosed?

A correct diagnosis is imperative for the patient to obtain the most ef´Čücient treatment. However, diagnosing NENs is challenging because symptoms are often nonspecific, such as chronic fatigue or pain unrelated to a specific injury. Often, NENs are found incidentally while testing for other conditions.

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The ultimate NEN diagnosis can only be established with tissue biopsy and further tumor grading based on combining the proliferative index with cell mitotic rate.

Standard laboratory diagnosis assessment relies mainly on markers such as Chromogranin A (CHGA), neuron-specific enolase (NSE), synaptophysin (SYP), and neural cell adhesion molecule 1 (NCAM1 or CD56). However, while virtually all carcinoids are positive for SYP and CHGA, their expression is highly variable in NENs.

Therefore, the immunohistochemical assessment of the complex biomarkers expression patterns in targeted biopsies is fundamental and instrumental in all phases of the diagnostic process, such as differentiation (neuroendocrine or epithelial origin) and proliferation (grading and staging).

 

Overview of NENs diagnosis in targeted biopsies (first-generation markers)

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Second-generation IHC markers for NENs differentiation

The advent of second-generation NEN markers for IHC has considerably expanded the pathology toolbox, constituting markers that often retain expression even in poorly differentiated NECs.

Atlas Antibodies’ second-generation IHC monoclonal markers for NENs include:

  • Anti-ISL1 (Isl Lim homeobox1, AMAb91729)
  • Anti-INSM (Insm transcriptional repressor1, AMAb91727)
  • Anti-SCGN (Secretagogin, AMAb90630, and AMAb90632)
  • Anti-OTP (Orthopedia homeobox, AMAb91695, and AMAb91696)

As non-NENs rarely express these antigens, their specificity makes them welcome additions to clinical practice.

Immunohistochemical staining on human tissues.

Figure 1. Immunohistochemical staining on human tissues.
A. Polyclonal anti-ISL (HPA057416) on the human liver shows solid nuclear positivity in hepatocytes.
B. Monoclonal anti-INSM1 (AMAb91727) on the human pancreas shows solid nuclear positivity in islets of Langerhans, in brown.
C. Monoclonal anti-SCGN (AMAb90630) on human duodenum shows strong immunoreactivity in the neuroendocrine cells and the local ganglionic cells, in brown.
D. Monoclonal anti-OTP (AMAb91696) on human lung tumors (typical carcinoid) shows strong nuclear positivity in tumor cells in brown.

 

From a biological context, second-generation immunohistochemical NEN markers (functionally distinct from CHGA and SYP) are more consistent in terms of expression, even if the NEN downregulates its secretory machinery as part of the dedifferentiation process.

The combination of classical and new IHC markers should thus be part of the clinical routine arsenal to improve the diagnostic capability, as well as aid in therapy stratification and clinical follow-up (Fig. 2).

Multiplexed IHC-IF staining on human tissues.

Figure 2. Multiplexed IHC-IF staining on human tissues.
A. Human duodenum showing CHGB and CHGA expression in an enteroendocrine cell, using the Anti-CHGB monoclonal antibody AMAb91709 (cytoplasmic, in green) and the Anti-CHGA polyclonal antibody HPA017369 (cytoplasmic, in red). Note the colocalization of markers in the enteroendocrine cell. Nuclei are counterstained by DAPI (in blue).
B. Human pancreas showing CHGB and SCGN expression in pancreatic islet, using the Anti-CHGB monoclonal antibody AMAb91709 (cytoplasmic, in green) and the Anti-SCGN monoclonal antibody AMAb90632 (cytoplasmic and nuclear, in red). Nuclei are counterstained by DAPI (in blue).
C. Human pancreas showing CHGB and CHGA expression in pancreatic islet, using the Anti-CHGB monoclonal antibody AMAb91709 (cytoplasmic, in green) and the Anti-CHGA polyclonal antibody HPA017369 (cytoplasmic, in red). Nuclei are counterstained by DAPI (in blue).
D. Human pancreas showing INSM1 and CHGA expression in pancreatic islet, using the Anti-INSM1 monoclonal antibody AMAb91727 (nuclear, red) and the Anti-CHGA polyclonal antibody HPA017369 (cytoplasmic, green). Nuclei are counterstained by DAPI (blue).

In conclusion, first-generation markers such as CHGA and SYP are still considered the gold standard in endocrine pathology. However, the combined IHC analysis utilizing second-generation markers may constitute additional sensitive and specific clinical use panels. This appears to be a promising approach for identifying tumors with NEN differentiation and a potential tool for NEN diagnosis.

 

Download the white paper: Neuroendocrine Neoplasms Markers

 

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