Endocr Pathol DOI 10.1007/s12022-013-9292-5

25 Years of Neuroendocrine Neoplasms of the Gastrointestinal Tract G. Rindi & G. Petrone & F. Inzani

# Springer Science+Business Media New York 2014

Abstract This paper provides a personal pathologist’s view of how neuroendocrine tumors (NET) were perceived and defined in the last quarter of a century. In years when the Helicobacter pylori, omeprazole and the adenoma–carcinoma sequence in colon carcinogenesis significantly impacted on gastrointestinal (GI) pathology daily practice, neuroendocrine neoplasms of the GI tract passed from the original carcinoid definition to the current NET and neuroendocrine carcinoma (NEC) definitions. The development of different concepts, basic tumor biology knowledge, tools for pathology diagnosis and the various World Health Organization (WHO) classifications from 1980 through 2010 are briefly reviewed and discussed.

aims at providing a very personal view of what was felt as relevant or what subsequently resulted so in the daily practice of pathologists facing the diagnosis of GI NENs. We certainly will not mention many contributions, so the reader is invited to forgive our limited approach and to follow this story with a light attitude. The paper is divided into two parts, the first dealing with the way GI NENs was considered and stood in the pathology and medical community in the past 25 years, and the second brief part dealing with the present day.

Keywords Tumor . Carcinoma . Endocrine . Neuroendocrine . Immunohistochemistry . Chormogranin A . Synaptophysin . Ki67

The Gastrointestinal Pathology Landscape in 1989

Introduction This paper will attempt to briefly describe the evolution of knowledge, definition and classification of gastrointestinal (GI) neuroendocrine neoplasms (NEN) as personally experienced by pathologists in the last 25 years. We do not aim to write a comprehensive and complete review of the multiple and diverse pieces of information accumulated slowly and with many difficulties along these years. Rather this paper G. Rindi : G. Petrone : F. Inzani Institute of Pathology, Università Cattolica del Sacro Cuore – Policlinico A. Gemelli, Largo A. Gemelli, 8, 00168 Rome, Italy G. Rindi (*) Institute of Anatomic Pathology, Università Cattolica del Sacro Cuore – Policlinico Gemelli, Largo A. Gemelli, 8, 00168 Roma, Italy e-mail: [email protected]

25 Years Ago till Today

In the 1980s, several events occurred that were bound to significantly impact on the daily practice of GI pathologists. After years of skepticism, the scientific community accepted Helicobacter pylori (Hp) as the cause of peptic ulcer disease and its potential role for promoting gastric mucosa-associated lymphoid tissue (MALT) lymphoma and adenocarcinoma [1–3]. Hp detection on gastric samples is now the gold standard tool for infection detection and gastric cancer prevention. Omeprazole was also introduced as first prescription proton pump inhibitor (PPI) and main co-actor with antimicrobial therapy for Hp eradication [4]. At the same time, the first genetic multistep model of cancerogenesis was unveiled and this was for colorectal cancer [5]. Surveillance and removing of adenomatous polyps by colonoscopy soon became the main prevention tool leading to the current screening programs [6]. Overall the digestive tract became the source of multiple preventive and diagnostic investigations, mainly, but not only, by endoscopic means, and this resulted in a large volume of samples for GI pathologists. More NENs were soon to be detected.

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General Concepts Since 1907 when Sigfried Oberndorfer published his seminal paper [7], the word “carcinoid” defined with extreme success a specific neoplastic entity. Not quite like the “conventional” digestive cancer, the carcinoid soon proved to have specific histochemical features [8] entering the fancy world of “rare” and possibly benign lesions. A marked benign connotation was indeed associated with this tumor disease, and this information was essentially entrenched within the carcinoid word. This concept was transferred to the medical community, and there rested within this diagnosis till recently. When the amine precursors uptake and decarboxylation (APUD) properties of GI endocrine cells were unveiled and the neuroendocrine concept proposed by Professor A.G.E. Pearse [9], the carcinoid regained the attention of the medical and scientific community. Carcinoids, since composed of transformed cells with APUD features, were defined “apudomas”, again a sounding-alike definition, mimicking the word adenoma and thus recalling its benign nature [10]. Despite its rich and fascinating significance, but possibly because of this, the apudoma tumor definition was not as broadly successful as “carcinoid”. The neuroendocrine idea was however seeded. This concept highlights a unique epithelial cell phenotype with shared expression of antigens common to nerve and endocrine elements. However this term was originally coined to indicate the putative neuroectodermal origin of GI hormone-producing cells. This hypothesis was subsequently demonstrated incorrect [11]. As a direct consequence, the term “neuroendocrine” was dropped and such cell types and the apudomas/carcinoid tumors re-entered the endocrine-only world and stayed there until very recently (see classifications). Today the neuroendocrine definition has regained popularity, losing any embryological implication and simply used as a descriptor of the unique features of such cell types and their transformed tumor counterparts. Basic Knowledge: Electron Microscopy, Genes and Transgenes In the 1980s, much work was devoted to the detailed profiling of cells with endocrine properties dispersed in different organs. Special attention was devoted to the unparalleled variety of cells observed within the GI tract and pancreas. This effort resulted in the definition of at least 14 cell types [12]. This story follows the isolation of novel hormones and the application of immunohistochemical techniques on tissue sample at the ultrastructural level by the use of the transmission electron microscope [13]. Similar features were recognized in carcinoids at different anatomical sites, paving the way to an organspecific carcinoid subtyping [14]. In fact, it soon became apparent that, far from being equal at any site, the carcinoids

are a family of neoplastic diseases diverse in tumor cell composition depending on their anatomical location (Table 1) [15, 16]. On the genetic side, great impetus to the basic knowledge of GI endocrine cells derived from embryo gene transfer techniques. Historically chicken embryo manipulation had been used to demonstrate the endodermal origin of GI endocrine cells, at variance from the neuroectodermal origin of nerve elements of the myoenteric and submucous plexuses of the gut [11, 17]. With the aim of assessing the regulatory properties of the 5′ region of hormone genes, transgenes were built and transferred into mouse embryos [18]. The use of cancer-inducing reporter genes like the early region of simian virus 40, elicited the development of tumors into the endocrine compartment of organs like the pancreas and the GI tract providing new models for pancreas and gut “carcinoids” [18–21]. Molecular techniques were also timidly entering the pathology laboratory, and for neuroendocrine cells mainly utilized to demonstrate gene expression at light microscopy level, by in situ hybridization [22–24]. Still major obstacles for a broad approach to pathology at that time were the costs of such sophisticated technologies, their apparently limited application to fresh frozen samples and the use of radiolabeled probes. Tools for Diagnosis: Histochemistry vs. Immunohistochemistry During the 1980s, pathology laboratories were still much involved in histochemical techniques, special stains used to identify given molecules demonstrated via a chemical approach. Silver impregnation techniques were those that since almost the beginning of the carcinoid story were in use to help making such diagnosis [8, 25]. Cheap and effective, such techniques were challenged by the use of antibodies, polyclonal sera or monoclonal antibodies that started to be developed in those years. The extreme specificity of this new technique named immunohistochemistry (IHC), its wider efficacy, high flexibility and the promise of limited costs opened the way for its diffusion in pathology laboratories. Molecules were identified as general and specific markers of endocrine cells, either peptide hormones and amines or components of endocrine granules (large dense-core vesicles, LDCV, and small synaptic-like vesicles, SSV) [26]. Chromogranin A and synaptophysin were identified and gained the attention of endocrine pathologists as reliable and effective markers of neuroendocrine differentiation [27–32]. Of the two molecules, chromogranin A is considered as the most robust and specific. Synaptophysin, though not always loyal to neuroendocrine cells only, is equally robust and especially effective in less differentiated neuroendocrine cancers. These features reflect their different molecular targets, respectively the LDCVs for chromogranin A and the SSVs for synaptophysin [31].

Endocr Pathol Table 1 Neuroendocrine neoplasms of the gut and pancreas, their site distribution, cell phenotype and associated syndrome, if present NEN grade

Main cell type

Stomach

Intestine

Syndrome

Small Pa G1–G2

G3

B A PP D EC ECL G L Ghrelin s/i

+ + + + +

CF

+ + +

+ + +

+ +

An

D

Large J

I

Ap

C

R

+ +

+

+

+

+

+

+

+ +

+ +

+ +

+ +

+

+

+

+

+

+

+

+

+

+

PHH Glucagonoma Somatostatinoma “Carcinoid” “Atypical carcinoid” ZES (?) -

Pa pancreas, CF corpus-fundus, An antrum, D duodenum, J jejunum, I ileum, Ap appendix, C colon, R rectum, + presence of neoplasm, EC enterochromaffin cell, ECL enterochromaffin-like cell, PHH persistent hyperinsulinemic hypoglycemia, ZES Zollinger–Ellison syndrome, - not defined, s/i small–intermediate cells. From John Libbey Eurotext © Rindi, G. et al. 1999 [56], modified

Terminology and Classification: WHO 1980, WHO 2000 and WHO 2004 Nothing is better than flying through the various classification schemes as provided by the World Health organization (WHO) to see how much the digestive neuroendocrine world has changed during these 25 years. A Table with the three classification schemes is provided (Table 2). From this comparison, it appears clear that each classification reflects the status of the knowledge on this topic at the time they were developed and published. So in the 1980s existed a specific classification for neoplasms of the diffuse endocrine system of the gut and including the carcinoid [33]. This classification was separated from a similar one for the pancreas, disconnecting insulinomas (benign and malignant) from tumors of the diffuse endocrine system. This classification

contained the seeds for the more comprehensive classifications of 2000 [34] and 2004 [35]. Twenty years later, in the 2000s, the classifications collected the many ideas developed upon evidence in the 1980s and 1990s on this topic, making a synthetic mise au point. The major novelty was the concept that tumors were different at different anatomical sites depending on the tumor cell types (Table 1), the so-called clinical-pathological correlations [34]. A simple three-tier classification scheme was also introduced as common to all anatomical sites, each with comparable dignity. The malignant potential of carcinoids was declared and the word carcinoma (malignant epithelial cell neoplasia) was introduced. Tumors were defined well-differentiated endocrine tumors (WDET) and endocrine carcinomas (WDEC) depending on proven malignancy (presence of metastases and/or deep wall invasion), and these were in contrast to the highly malignant

Table 2 definitions of gastrointestinal neuroendocrine neoplasm in the WHO classifications 1980, 2000 and 2010 WHO 1980

WHO 2000

WHO 2010a

I—Carcinoid

1-Well differentiated endocrine tumor (WDET)

1-NET G1 (WDET or WDEC according to staging) 2-NET G2 (WDET or WDEC according to staging) 3-NEC G3 (PDEC)

2-Well-differentiated endocrine carcinoma (WDEC)

II—mucocarcinoid III—mixed forms carcinoid-adenocarcinoma IV—pseudotumor lesions

3-poorly differentiated endocrine carcinoma/small-cell carcinoma (PDEC) 4-mixed exocrine–endocrine carcinoma (MEEC) 5-tumor-like lesions (TLL)

G grade, NET neuroendocrine tumor, NEC neuroendocrine carcinoma a

WHO 2000 definitions in bracket. From IARC Press © Rindi et al. 2010 [43]

4-mixed exocrine–endocrine carcinoma, MANEC (MEEC) 5-tumor-like lesions (TLL)

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Fig. 1 Grading NEN according to WHO 2010: three examples. a–b Neuroendocrine tumor with trabecular structure in absence of necrosis and very mild atypia (a), Ki67 index well below 2 % (b) and thus corresponding to G1. This was a tiny (size 0.4 cm), nonfunctioning, gastrin-producing cell (not shown) NET of the duodenal mucosa with one lymph node metastasis (pT1 pN1) incidentally found in a patient with multiple pancreatic metastases from renal cell carcinoma. c–d Neuroendocrine tumor with solid-glandular structure in the absence of necrosis, mild to moderate atypia, no mitosis (c), Ki67 index of about 5 % (d) and thus corresponding to G2. Composed of serotonin-producing enterochromaffin cell (EC; not shown), but void of any functional syndrome, this

was a liver metastasis of a NET from a so far unknown primary (pTX pNX pM1). The intense CDX2 expression observed (not shown) indicated a highly possible gut origin. e–f NEC with solid structure, necrosis (lower left corner of the micrograph), moderate to severe atypia with evident mitosis; cells are intermediate to large in size, show evident nucleoli and abundant cytoplasm (e), thus allowing a definition of NEC large cell variant, and with a Ki67 of about 70 % and thus corresponding to G3 (f). This was a large, ulcerated neuroendocrine cancer of the caecum, deeply infiltrating the intestinal wall and with one lymph node metastases (pT3 pN1). a, c and e Hematoxylin and eosin; b, d and f immunoperoxidase; original magnification 400×

poorly differentiated endocrine carcinomas (PDEC). These revolutionary concepts and the resulting terminology change, encountered some resistance in the medical community. Specifically, the malignancy concept was challenged, the medical community still trying to keep the benign assumption embedded within the carcinoid word. Compelling epidemiological evidences however soon helped towards such change [36–39]. Between GI pathologists, some perplexity also existed for the need for consultation on the specific clinicalpathological correlations, considered as a cumbersome addition in the busy diagnostic routine. They also questioned the existence within the WDET class of the subcategories of “benign behavior” and “uncertain behavior” [34]. This latter subdivision besides being often ineffective in separating cases for

prognostic purposes [40] also exposed the pathologist to potential legal problems. It was indeed possible that a case originally diagnosed as tumor (WDET) in a small biopsy, could then switch to carcinoma (WDEC) at the definitive surgical sample, thus eliciting potential insurance/legal actions.

Current Status Today’s status is better reflected by the current WHO classification (WHO 2010) [41]. The neuroendocrine definition is reintroduced. This does not imply any embryological concept but simply reflects the peculiar features of NE cells and their neoplastic counterpart. The whole NE cancer family is defined

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as NE neoplasms, this definition thus comprises low to highgrade cancers, from the old carcinoid to the small cell carcinoma. All NENs are definitely accepted as potentially malignant. A three-tier grading system (G1, G2, and G3) has been introduced, largely based on proliferation fraction of tumor cells according to Ki67 index and mitotic count [42, 43]. Neuroendocrine tumor (NET) definition is introduced to describe G1 and G2 NENs (previously carcinoids) and neuroendocrine carcinoma (NEC) for G3, to mark a separation between lowto intermediate-grade versus high-grade NENs. Morphological descriptors are still there, but are substantially disconnected from the grade definition. In specific, the concept of differentiation as utilized in the previous WHO 2000 and 2004 classifications is now dropped in WHO 2010. Indeed the classical carcinoid most of the time lies within the G1 category, but the G2 with a similar morphology is there too, with proven worse prognosis [44–50]. Further, many carcinoids that originally were approximately baptized as “atypical”, especially in the stomach (type III cases) and in the colon/ rectum, are now reclassified as high-grade G3 NENs [45, 47, 48, 50]. They are mostly large to intermediate cell subtypes, not necessarily showing the small cell morphology extremely rare in the GI tract (Fig. 1). This seems to have removed the diagnostic vagueness accompanying some so-called atypical carcinoids that misbehaved leading to death of the patient in a short time [51]. In synthesis, the current grading is aimed at preventing an NE cancer diagnosis being made on subjective morphology and introducing hopefully more objective and reliable diagnostic tools. A site-specific staging system has been developed, using the classical Tumor–Node–Metastasis (TNM) scheme. The system was generated based on the current one for exocrine cancer, but introduced TNM NE specific limits as identified at different anatomical locations based on published evidence [42, 52]. Current data seem to support its efficacy [44, 45, 47, 48, 50]. The actual diagnosis should comprise the new definition (NET and NEC), the relative grade specification (G1–G3) and the TNM status [43, 53].

What is Next and Conclusions Indeed these 25 years have witnessed the slow, multistep struggle to regain the “carcinoid” tumor entity to the world of GI cancer and to a more appropriate clinical management of patients. The latest WHO classification (2010) attempted to make life easier for pathologists and clinicians, defining potentially user-friendly standards. Only data generated by applying consistently this classification on large tumor series will prove its efficacy and will identify the potential adjustments required or if a better tool is needed. And indeed data obtained with these new tools are already providing new insights into NEN disease,

such as the suggestion for different site-specific cutoffs for pancreas and the GI tract [16, 40] and the potentially different behavior within G3 NENs [48]. We do think this is the right direction to go. But much more is expected from the promising data generated by the application of high throughput molecular techniques [54, 55]. Multiple compelling questions are in fact awaiting an answer. We need a better understanding of the molecular events leading to NE cancer development and specifically driving invasion and metastasis. Better markers of benign/aggressive behavior are needed, as well as effective tools to predict patients’ response to targeted therapy. The technology is here and the hope as well. Acknowledgments This work was in part supported by internal university grants to GR (line D1/2011-2012, Università Cattolica).

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25 Years of neuroendocrine neoplasms of the gastrointestinal tract.

This paper provides a personal pathologist's view of how neuroendocrine tumors (NET) were perceived and defined in the last quarter of a century. In y...
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