Elsevier

Cancer Treatment Reviews

Volume 50, November 2016, Pages 61-67
Cancer Treatment Reviews

Controversy
Heterogeneity of grade 3 gastroenteropancreatic neuroendocrine carcinomas: New insights and treatment implications

https://doi.org/10.1016/j.ctrv.2016.08.006Get rights and content

Highlights

  • G3 GEP NECs are more heterogeneous than expected according to WHO classification.

  • 6 studies investigating large series of G3 GEP-NECs have been published.

  • Tumor morphology and Ki-67 emerged as potential prognostic factors.

  • This has important prognostic and therapeutic implications.

Abstract

Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are currently classified as grade (G) 1, G2 and G3, in accordance with the 2010 WHO classification. G1 and G2 are named neuroendocrine tumors (NETs) whereas G3 neuroendocrine carcinomas (NECs). While advanced G1 and G2 are usually treated with several different therapies, including somatostatin analogs, chemotherapy, interferon, molecular targeted agents, peptide receptor radionuclide therapy (PRRT) and liver-directed treatments, advanced G3 NECs are usually treated with a platinum-etoposide chemotherapy, trusting their clinical homogeneity is similar to that of small cell lung cancer.

However, over the last years a number of reports suggested that 2010 WHO G3 GEP NECs are more heterogeneous than expected. Therefore, we critically reviewed the literature about this topic and reported pathological and clinical considerations on 2010 WHO G3 GEP NEC category proposing new sub-categories. Over the last five years, six studies specifically investigating large series of G3 GEP NECs have been published, including around 800 patients. Tumor morphology and Ki-67 Labeling Index (that will be mentioned as Ki-67 in this manuscript) combination has been reported as a tool to define two or even three subgroups of this category with different prognosis and potentially different therapeutic approach. Prospective trials are warranted to investigate if several types of therapy other than the platinum/etoposide chemotherapy can be effective in well differentiated GEP NEN with 21–55% Ki-67 and alkylating-based chemotherapy in poorly differentiated GEP NEN with 21–55% Ki-67.

Introduction

Gastroenteropancreatic neuroendocrine neoplasms (GEP NENs) comprise two main categories, well differentiated (WD) and poorly differentiated (PD), also called G1/G2 and G3, respectively [1]. Poorly differentiated or G3 NENs represent less than one third of all GEP NENs [2], [3], [4] and are usually considered a quite homogeneous category to be treated with a platinum-based chemotherapy [5].

Over the last years an increasing number of publications reported that the G3 GEP NENs category is less homogeneous than expected. Tumor morphology and Ki-67 were defined as prognostic factors that can separate this category in two or even three subgroups with significantly different survival.

Therefore a better characterization of the G3 GEP NENs could have practical therapeutic implications. For instance WD GEP NENs with Ki-67 >20% could be treated differently from PD GEP NENs with Ki-67 >70%.

This manuscript reports the current state of the art about this particular topic and personal view by a medical oncologist and a pathologist specifically dedicated to GEP NENs.

Section snippets

Selection of evidence

Articles for consideration in the present paper were retrieved by a keyword-based MEDLINE search using pertinent keywords (gastrointestinal OR gastric OR intestinal OR pancreatic OR pancreas OR gastroenteropancreatic) AND (neuroendocrine AND (neoplasm OR carcinoma) AND (classification OR “predictive factor” OR “prognostic factor” OR chemotherapy OR grading OR Ki-67 OR proliferative index OR heterogeneity OR morphology). Only papers published in English and for which an abstract was available

Neuroendocrine or endocrine

These terms may be considered synonymous [6]. Endocrine cells origin from the embryonic neural crests. Neuroendocrine neoplasms (NENs) are epithelial neoplasms prevalently composed of cells of endodermal origin [1], [7], [8]. The term “neuroendocrine” will be preferentially used here.

Neoplasm, tumor and carcinoma

The last 2010 WHO classification recommended the more popular, but not fully-biologically adequate term “Tumor” instead of the biologically-correct “Neoplasm”. On the other hand, the European Neuroendocrine Tumor

GEP NEN classification: critical comparison between WHO 2000 and 2010 editions

The 2000 classification [7], [8] was based on the identification of the following criteria as major predictors of tumor outcome: tumor differentiation, functionality, size, extent of local invasion, lymphovascular invasion giving three classes as listed in Table 3:

  • (1)

    Well Differentiated Endocrine Tumor (WDET).

  • (2)

    Well Differentiated Endocrine Carcinoma (WDEC)

  • (3)

    Poorly Differentiated Endocrine Carcinoma (PDEC).

The two main clinical implications of this classification are based on the distinction of benign

General considerations

Over the last five years, six studies specifically investigating large series of G3 GEP-NECs and including about 800 patients have been published (Table 1). All studies analyzed G3 category heterogeneity [44], [45], [34], [39], [46]. On these bases, the broad interval of G3 disease (21–100%) may include largely different neoplasms, with different responses to therapy.

The first clinical report indicating that GEP NECs according to 2010 WHO classification can be a heterogeneous category was from

Concluding remarks

Although the prognostic value of WHO 2010 classification of GEP NENs was validated in large clinical series of pancreatic NETs [17], its predictive role for therapy response remains uncertain. While in patients with advanced G1/G2 GEP NETs a number of different medical therapies, radiotherapies, liver-directed treatments and even surgical resections can be considered within a therapeutic strategy planned by a multidisciplinary team, systemic chemotherapy is the only therapy proposed in advanced

Funding source

None.

Disclosure

Both Authors participated in the discussion of evidence and article preparation.

Conflicts of interests

None.

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