The diagnostic challenges of functioning neuroendocrine tumors: balancing accuracy, availability, and personalized care

KEYWORDS:

• Circulating markers
• functioning neuroendocrine neoplasms
• gastro-entero-pancreatic neuroendocrine tumors
• neuroendocrine
• specific markers

1.

Neuroendocrine neoplasms (NENs) represent a complex and multifaceted group of tumors, drawing attention to their intriguing characteristics and clinical implications. Their incidence has increased worldwide in recent decades [1,2]. These neoplasms exhibit an exceptional ability to intertwine both endocrine and oncological aspects, posing distinctive challenges to physicians seeking to unravel their complexities. Indeed, NENs represent heterogeneous tumors, with different biological aggressiveness and encompass a diverse spectrum of tumors that can be divided into two groups, functioning and nonfunctioning NENs, based on whether or not they produce peptides/hormones [3]. While nonfunctioning tumors constitute the dominant manifestation within the spectrum of NENs [3,4], the more intricate domain of functioning NENs has often remained in the shadows.

The accurate diagnosis of functioning NENs is increasingly challenging for several reasons.

Due to their rarity, a knowledge gap exists concerning the various syndromes characterizing functioning NENs, with only a few well-known syndromes gaining recognition. Apart from the well-recognized syndromes such as carcinoid and Zollinger-Ellison syndrome (ZES), other hormonal syndromes such as glucagonoma, somatostatinoma, and VIPoma syndrome have limited recognition among medical professionals (Table 1). Furthermore, the clinical presentation of the more common ZES has evolved to more subtle shades due to the widespread use of proton pump inhibitors [5]. This makes the distinction between functioning and nonfunctioning tumors a complex task. This evolving terrain of diagnostic subtleties requires skillful differentiation between functioning and nonfunctioning tumors. However, this distinction, although challenging, is pivotal, as it influences treatment decisions, including the need for surgery, and personalized patient care. For instance, even small functioning pancreatic tumors might necessitate surgical intervention if they are indeed functioning, in contrast to nonfunctioning small pancreatic NENs [6–8]. Although the medical therapeutic implications may not be significantly different, personalized patient care requires a nuanced understanding of the disease. However, this knowledge gap hinders early detection and appropriate management. Indeed, it is now recommended that the assessment of circulating markers be performed only in specific circumstances [9,10], necessitating a deep understanding of the different clinical contexts that warrant marker assessment. Whether diagnosing functioning NENs or determining the course of a treatment plan, recognizing these circumstances becomes the cornerstone for accurate decision-making.

Table 1. Main clinical syndromes associated with functioning digestive NENs due to the excessive production and secretion of hormones or bioactive substances.

Syndrome	Description	Hormones or bioactive substances	Circulating marker	Tumor
Carcinoid syndrome	The syndrome is often linked to midgut NENs and is characterized by flushing of the skin, diarrhea, bronchoconstriction, and occasional cardiac involvement	Serotonin and other vasoactive substances	Urinary 5-Hydroxy-indoleacetic Acid (5-HIAA)	Midgut NEN Lung NEN Rarely in pancreatic serotoninoma
Insulinoma Syndrome	Insulinomas produce excessive insulin secretion. This results in symptoms like sweating, tremors, confusion, and palpitations.	Insulin	Insulin, pro-insulin, C-peptide	Insulinomas usually arise from the pancreatic islet cells
Zollinger Ellison Syndrome	ZES results from gastrin excessive production that stimulates excessive chlorhydric acid production, leading to recurrent peptic ulcers, gastro-esophageal reflux disease, diarrhea, and abdominal pain.	Gastrin	Gastrin	Pancreatic or duodenal gastrin-secreting tumors
Glucagonoma syndrome	A syndrome characterized by a characteristic rash/dermatitis (necrolytic migratory erythema), diabetes, depression, deep vein thrombosis (4 D syndrome)	Glucagon	Glucagon	Glucagonoma originating from the pancreatic alpha cells
Somatostatinoma syndrome	A syndrome characterized by diabetes, diarrhea, steatorrhea (fatty stools), and gallstones due to the elevated secretion of somatostatin	Somatostatin	Somatostatin	Somatostatinomas usually arise from the delta cells of the duodenum or pancreas
VIP-oma	VIP-oma typically causes the Werner-Morrison Syndrome (also called pancreatic cholera) characterized by profuse watery diarrhea, hypokalemia, hypochlorhydria with electrolyte imbalances, and facial flushing due to the excess secretion of vasoactive intestinal peptide	VIP (vaso-intestinal peptide)	VIP	VIP-omas are typically found in the pancreas

This feature introduces notable complexity, demanding an intricate grasp of both endocrinology and oncology. This convergence of disciplines creates a challenge for oncologists who might be less accustomed to managing the intricacies of hormone-associated disorders, often focusing solely on the disease itself, regardless of whether the NEN is functioning or not [11]. The distinct clinical presentations resulting from hormone hypersecretion, coupled with their potential to mimic a range of other medical conditions, further amplify the complexity of accurate diagnosis and management.

A decreasing tendency to evaluate circulating markers has been observed in recent years. Indeed, over time, questions have arisen regarding the diagnostic adequacy of circulating markers such as circulating CgA. This has led the medical community to limit their utility in clinical practice. While it might be reasonable to reduce testing for general markers like circulating CgA, due to its limited diagnostic and prognostic accuracy [12–14] and the associated prevalence of false positive and negative results [15], the question is somewhat different for specific markers (e.g. gastrin, glucagon, VIP, somatostatin, etc.) used to diagnose functioning NENs [9,10]. Regrettably, this inadvertently promotes the notion that all markers, including the specific ones, have become optional, leading to the underdiagnosis of functioning NENs [16]. This change in perspective has led to the underdiagnosis of functioning NENs or their misidentification as nonfunctioning NENs. Therefore, it is of utmost importance to emphasize the importance of testing these specific circulating markers, elucidating that they are not optional but indispensable tools for precise diagnosis and effective management [9,10]. Moreover, clinical data demonstrate that monitoring the reduction of specific hormonal tumor markers, such as urinary 5-HIAA, insulin/C-peptides, glucagon, gastrin, and VIP, after either radical surgery or systemic therapies, provides valuable insights into the natural history, progression, or recurrence of functioning NENs [17]. Therefore, measurement of these specific hormonal tumor markers is currently recommended for monitoring, as outlined in the most recent ENETS guidelines [18]. Therefore, it is essential to emphasize the importance of evaluating these specific circulating markers and reiterate that they are essential for accurate diagnosis and effective management and are not merely an option.

Furthermore, the challenge of obtaining these measurements often limited to a few specialized centers, exacerbates the diagnostic dilemma. Even if centralization of testing is advisable in optimizing resources, on the other hand, it leads to a more complex patient journey. Indeed, the availability of these specialized centers creates a substantial obstacle, with limited access hindering ease of testing and subsequently leading to delayed diagnoses and compromised patient care. Additionally, the lack of reimbursement by national health-care systems further worsens the problem, making it difficult for patients to access essential diagnostic tools. As a result, the diagnostic journey for patients with functioning NENs is fraught with obstacles, hindering timely and appropriate patient care.

Addressing the challenges tied to the diagnosis of functioning NENs demands a multifaceted approach. Firstly, improving medical education and promoting greater awareness of the various NEN syndromes, especially in the oncologic setting, will enable timely and accurate diagnosis.

Secondly, centralizing the assessment of these circulating gut hormones within capable laboratories is advisable to streamline hormone level measurements, but it should be codified and recognized. This centralized strategy would enhance the cost-effectiveness of this service within specialized laboratories.

Finally, efforts should focus on improving diagnostic techniques beyond circulating markers. Integrating clinical information with molecular profiling techniques or exploring the possibility of distinguishing between functioning and nonfunctioning NEN by the measurement of multiple NEN-related transcripts [16] could enhance diagnostic accuracy. Transcriptomic profiling can indeed identify unique gene expressions associated with hormone production, hormone receptors, and other molecular markers associated with specific functioning tumors. However, it’s important to acknowledge that while this approach holds promise, its clinical application and accuracy in routine diagnostic settings might still need further validation [9,16]. Incorporating these innovations may yield new biomarkers for more precise differentiation and prognosis of functioning NENs.

In conclusion, dealing with functioning NENs remains challenging due to accessibility issues and limited awareness of NEN syndromes. Differentiating functioning from nonfunctioning tumors remains paramount for tailored patient management. Therefore, a comprehensive approach that embraces diagnostic advancements, enhances accessibility, and improves medical education is requisite to meet the evolving diagnostic needs of NEN patients and provide personalized care [19,20].

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

This paper was not funded.