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Management of follow-up of neuroendocrine neoplasias

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Neuroendocrine neoplasias (NEN) comprise heterogeneous epithelial neoplasms with a large variety of clinical presentations, treatment options and outcomes. Since potentially all NEN bear malignant potential it is important for long-term clinical management and improvement of outcome to decide on successful and oncologically and economically meaningful follow-up strategies. Evidence-based outcome data validating specific follow-up strategies are, however, not available to date and thus outcome data, known prognostic factors and clinical experience guide the decisions on follow-up regimens. The review summarizes general recommendations as well as specific considerations based on tumor entities, clinicopathological tumor characteristics and clinical experience. Follow-up shall serve the patient to improve outcome, benefit from more effective therapies and suffer less from unnecessary and/or toxic therapeutic interventions and finally preserve or gain a good quality of life.

Introduction

Neuroendocrine neoplasias (NEN) most frequently occur within the gastroenteropancreatic and bronchopulmonary system ∗[1], [2], [3], [4], comprise heterogenous etiologies and tumor biologies [5] and present with quite variable prognoses ∗[1], [2], [3], [4], [6], [7], [8]. This makes NEN not only a challenge to diagnosis but also to treatment and ultimately – for the managing physician – to follow-up ∗[9], ∗[10], ∗[11], ∗[12], ∗[13], ∗[14], ∗[15], ∗[16], ∗[17]. It is, therefore, important to understand and apply the clinical and tumor biological characteristics of these heterogeneous tumor diseases to conclude how to follow-up on these patients [9]. Due to a large subgroup of patients presenting with low-grade and early disease stages ∗[1], [18] these NEN may not even be needed to be followed up upon. However, to day all NEN are considered to carry a malignant potential, i.e. uncontrolled growth, autonomous hormone or transmitter release, invasive growth properties, and propensity to metastasis [5], [19]. Thus, even though many NEN present with a slow growth and thus an excellent long-term prognosis when compared to other solid, epithelial neoplasms of corresponding stage, many of the patients with advanced disease ultimately die of their NEN [2], [3], [7], [20]. This underlines the necessity of regular long-term follow-up, even in clinically “stable” patients [9]. On the other side, a small but significant subgroup of NEN present with highly malignant features and rapid tumor growth necessitating regular follow-up visits for early detection of both recurrence and progression to install appropriate treatment regimens. Just as well detection of remission is crucial to limit toxicities from therapeutic interventions, which may also cause harm, reduce quality of life and may even shorten the remaining life span [17].

The follow-up of patients with multiple endocrine neoplasia syndrome type-1 (MEN-1) is even more complex and covered by specific guidelines and will thus not be part of this review [21].

Section snippets

Criteria for stratification of follow-up

Long-term prognosis of NEN is determined by several prognostic factors which have either been long known or more recently been more detailedly characterized [2], [3], [5], [6], [7], [8], [18], [19]. The important factors established and available for clinical judgment include:

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    Primary tumor localization

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    Proliferative capacity as assessed by Ki67-index or mitotic count (i.e. WHO-grading)

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    Tumor stage at initial diagnosis (i.e. TNM-staging)

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    Resection status after curative surgery

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    Ongoing or previous

Clinical follow-up situations

Follow-up of NEN – as in other neoplastic diseases – implies a previous and specific diagnosis and in most cases - except for those in whom a “watch-and-wait” strategy is appropriate – a specific antitumor treatment. Thus, from these considerations various situations may result:

  • 1.

    Curative resection by surgery or in few cases endoscopy, with even complete histological resection (R0-resection) and no evidence of any other NEN-manifestations; in this situation as-early-as-possible detection of

Clinical methods for follow-up

The methods used in clinical practice for follow-up are the same as for diagnostic assessment of NEN; in fact, follow-up is per se a repetitive diagnostic assessment for possible tumor growth (progressive disease; PD), stability (stable disease; SD) or shrinkage (partial or complete remission/response; PR or CR) and/or increased, stable or decreased functional or symptomatic activity of the respective NEN [2], [3], ∗[9], ∗[10], ∗[11], ∗[12], ∗[13], ∗[14], ∗[15], ∗[16], ∗[17], [21], [26], [27],

Follow-up recommendations for specific NEN subentities

As indicated the primary tumor localization not only serves as a prognostic parameter but also describes specific subentities of NEN as well as it stratifies specific diagnostic and thus follow-up approaches. The current most reasonable and recommended approaches to follow-up are thus discussed following this clinically relevant consideration ∗[10], ∗[11], ∗[12], ∗[13], ∗[14], ∗[15], ∗[16], ∗[17].

Follow-up of bronchopulmonary NET

NET arise in the bronchopulmonary tract (bNET) and are also termed “carcinoids” according to WHO [10]. Curative treatment of local or locoregional bNET disease is never sufficient by endoscopy and requires surgical intervention which then is a very successful treatment modality in most bNET patient [33]. When successfully resected post-surgical restaging by cross-sectional imaging every 6–12 months for the initial year and every 12 months thereafter is probably sufficient [10]. In more

Follow-up of gastric NET

Gastric NEN (gNEN) are to be sub-stratified into four subtypes. Gastric NET (gNET; G1/2) have to be considered according to underlying pathophysiology. While type-1 gNET arise as neuroendocrine hyperplasia and ultimately neoplasia in the context of achlorhydric hypergastrinemia due to chronic atrophic (autoimmune) gastritis, type-2 gNET appear as a result of hyperchlorhydric (hyperacidic) hypergastrinemia due to Zollinger-Ellison-syndrome caused by one (or several) duodenal or pancreatic

Follow-up of duodenal NET

Duodenal NET (dNET) may be curatively resected either by endoscopy if not from the periampullary region or by surgery in all of the latter cases or any tumors of size >1 cm or with invasion of muscularis propria or more advanced regional lymph node or distant resectable disease. After endoscopic resection of T1-tumors endoscopic follow-up in 3-month intervals for the first year, 6-month intervals for the second year and annual thereafter is currently considered appropriate ∗[9], ∗[11]. In more

Follow-up of small intestinal NET

Small intestinal NET (siNET) always require surgery for sufficient curation, particularly because multicentricity may be present in approximately 30% of cases [3], [7], ∗[13], [18]. Follow-up after curative resection should be performed in G1-siNET at 6-month intervals and 3-month intervals in G2-siNET for the first year after resection and 6 month intervals thereafter as long as no recurrence is noted which will reset the follow-up regimen ∗[9], ∗[13]. It is unclear whether 12-month intervals

Follow-up of appendix NET

NET of the appendix (appNET) are frequently encountered as a coincidental finding on appendectomy for other reasons (usually acute appendicitis) [14]. If located at the tip or middle part of the appendix, <1 cm, R0-resected and without mesoappendiceal invasion no follow-up seems required. If the same applies except for a size of the appNET between 1 and 2 cm the same seems to be reasonable but has not been proven, yet. In all other cases – curative surgical resection presupposed – including

Follow-up of colorectal NET

Colorectal NET (crNET) are relatively infrequent but are being recognized more frequently particularly within the rectum due to colorectal cancer-screening by ileo-colonoscopies [15]. After curative (histopathologically proven R0) endoscopic or (rarely) surgical resection of crNET <1 cm probably no specific long-term follow-up is required. However, because prior to snare or even forceps polypectomy the submucosal extension within the rectal mucosa is frequently unknown and thus the resection

Follow-up of pancreatic NET

As with siNET pancreatic NET (pNET) can only be cured by surgery and always require regular follow-up with cross-sectional radiologic imaging at 6- (G1-pNET) or 3-(G2-pNET) month intervals during the first two postoperative years and at 6-month intervals thereafter (Table 1) ∗[9], ∗[12]. It is unclear whether annual follow-up is sufficient after 5 years without tumor recurrence but this may be considered (Table 1). In all other cases, including advanced and non-resectable or metastatic pNET

Follow-up of CuP-NET

NET with non-detectable primary tumors although extensive and thorough clinical and imaging investigations have been performed are considered “cancer or unknown primary” (CuP) according to common oncological terminology (CuP-NET). CuP-NET should thus be considered metastatic NET and therefore regularly be followed-up upon (Table 3) ∗[9], ∗[16]. Only very few cases may undergo curatively intended surgery due to the possibility of a intrahepatic primary tumor and for this extremely rare situation

Follow-up of NEC

NEN with a proliferative Ki67-index >20% (G3) are usually considered neuroendocrine carcinomas (NEC) with a considerably poorer prognosis than NET (G1/2) ∗[1], [2], [3], [4], [6], [7], [8], ∗[17], [19], [23]. Due to the more aggressive malignant behavior in general regular follow-up studies in 3-month intervals are strongly recommended (Table 4) [9]. Only very few cases appear at a curatively resectable early tumor stage and without long-term recurrence beyond 5 years after initial diagnosis;

Summary

Follow-up of NEN-patients largely relies on stratification of important prognostic factors such as grading, staging, primary tumor localization, curative resection and resection status. Thus all of these help in deciding on a specific follow-up regimen in an individual patient and are summarized in Table 1, Table 2, Table 3, Table 4. Follow-up should provide the treating physician with information on either local or locoregional tumor recurrence after curative resection or progression of

Conflicts of interest

The authors declare no conflict of interest in relation to the topic and contents of this article.

Acknowledgments

The authors are grateful to ongoing support of patient management by C. Degenhardt, A. Lischewsky, M. Möbius and S. Steglich from the ENETS Center of Excellence for Neuroendocrine Tumors at Charité University Medicine Berlin, Germany.

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