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23 EPIDEMIOLOGY, PATHOLOGY, DIAGNOSIS, PREVENTION, AND MANAGEMENT OF GI STROMAL TUMORS 467
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Other GI Sarcomas
Introduction
Although GIST are by far the most common subtype of softtissue sarcoma diagnosed in the GI tract, other GI sarcomas
have been described. Given their rarity, their epidemiology is
difficult to establish. Moreover, their clinical characteristics
and prognosis are significantly influenced by the underlying
histology. The most frequently GI sarcomas other than GIST
are GI leiomyosarcomas, undifferentiated pleomorphic sarcomas (UPS) and liposarcomas.
GI Leiomyosarcomas
GI leiomyosarcomas are distinguished by GIST based on the
immunohistochemical expression of smooth muscle markers
and absence of driver mutations. They can be found in any part
of the GI tract, and appear to be evenly divided between the
stomach, the small intestine, and the colon. They often present
with symptoms of obstruction/intussusception and are characterized by a high tendency to metastatic spread despite optimal
surgery and poor outcomes (Senapathi et al. 2021; Smrke et al.
2021).
GI Ups
UPS are aggressive undifferentiated sarcomas with poor
outcomes. Fewer than 50 cases of GI UPS have been reported
in the literature, evenly distributed between gastric and
colonic UPS. As for extra-GI UPS, there is a higher incidence in males in their sixth or seventh decade of life.
Treatment often included surgery, but recurrence and metastatic spread are frequent (Han et al. 2022; Kabashima et al.
2017; Oguri et al. 2018).
the treatment. This is particularly important because, although
relatively limited information is available on the outcomes of
non-GIST GI sarcomas, they are often associated with a poor
prognosis.
Key Take Home Messages
• Most gastrointestinal sarcomas are GIST, which are characterized by well-defined histopathological and molecular characteristics, such as mutations in the KIT and PDGFRA genes.
• Treatment of patients with localized GIST is mainly surgical.
Neoadjuvant and adjuvant systemic therapy with imatinib can
be respectively considered depending on preoperative surgical
risks and postoperative risk of recurrence.
• In the advanced setting, tyrosine kinase inhibitors represent
the main treatment. Imatinib should be started as soon as possible in imatinib-sensitive GIST patients, as it is associated to
good symptomatic benefit. Locoregional therapies can have an
important role in patients with advanced GIST.
• Rare non-GIST gastrointestinal sarcomas include leiomyosarcomas, undifferentiated pleomorphic sarcomas and liposarcomas. Their prognosis is usually poor.
Areas for Further Research
• Prognostic and predictive biomarkers
• Longitudinal non-invasive evaluation of tumor heteroge-
neity and evolution (e.g., with circulating DNA) to inform
therapeutic choices
• Novel therapies for patients without the most common
driver mutations and for patients with advanced disease
refractory to current therapies
Trusted Websites for Further Reading
GI Liposarcomas
Primary GI liposarcomas have been described in any part of
the GI tract, more frequently in the stomach, in the small
intestine, and in the large intestine, less frequently in the esophagus and rectum. Histologically, GI liposarcomas are well-differentiated or de-differentiated liposarcomas characterized by
MDM2 amplification, and compared to those arising in other
sites they are more frequently high-grade dedifferentiated
tumors and biologically aggressive (Gajzer et al. 2020).
Conclusion
Non-GIST GI sarcomas are exceedingly rare and only case
reports or small series have been reported. It is clinically important to be aware of their existence, as they might represent preoperative differential diagnosis of the more common GI
carcinomas and GIST. Whenever possible, pre-operative histological diagnosis is therefore fundamental to accurately plan
• Adult GIST: https://www.cancer.gov/types/soft-tissue-sar coma/
hp/gist-treatment-pdq
• Childhood GIST: https://www.cancer.gov/types/soft-tissuesarcoma/hp/child-gist-treatment-pdq
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24 Neuroendocrine Neoplasms of the
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Digestive System
Edited by Irene Esposito
1
Günter Klöppel
4
Dizdar
Villard
, Wolfram Trudo Knoefel4, Matthias Schott5, Clarisse Dromain6, Nicolas
6
, Lena Häberle7, Björn Konukiewitz8, Aurel Perren9, Ilaria Marinoni9,
Bence Sipos
Christoph Roderburg
16
György
Pulvirenti
1
Institute of Pathology, Technical University of Munich, Munich, Germany
2
Institute of Pathology, Heinrich-Heine University and University Hospital and of Dusseldorf, Germany
3
Unit of Pathology, Department of Medicine and Surgery, University of Insubria and ASST Sette Laghi, Varese, Italy
4
Department of Surgery, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany
5
Division for Specific Endocrinology, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany
6
Department of Radiology, Lausanne University Hospital (CHUV), Rue du Bugnon 46, Lausanne, Switzerland
7
Institute of Pathology, Heinrich-Heine University and University Hospital and of Dusseldorf, Germany
8
Department of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
9
Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
10
ENETS Center of Excellence, Department of Medical Oncology and Pneumology, University Hospital Tuebingen, Tuebingen, Germany; Private
Practice of Pathology and Molecular Pathology, Stuttgart, Germany; Private Practice of Molecular Pathology, Baden-Württemberg, Germany
11
Institute of Pathology and Cytology, St. Vincenz Hospital Limburg, Limburg, Germany
12
Institute of Pathology, Phillips University Marburg and University Hospital Marburg, Marburg, Germany
13
Unit of Pathology, Department of Medicine and Surgery, University of Insubria and ASST Sette Laghi, Varese, Italy; Department of Biomedical
Sciences, Humanitas University and Department of Pathology, IRCCS Humanitas Research Hospital, Milan, Italy
14
Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University
Düsseldorf, Düsseldorf, Germany
15
Department of Hepatology and Gastroenterology, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Charité
Universitätsmedizin Berlin, Berlin, Germany
16
Department of Nuclear Medicine, Heinrich-Heine University and University Hospital of Düsseldorf, Düsseldorf, Germany
17
Section of Pathology, Department of Diagnostics and Public Health, University of Verona, Verona, Italy
18
Department of Surgery, The Pancreas Institute, University of Verona, Verona, Italy
19
Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy; ARC-Net Research Center, University of
Verona, Verona, Italy
, Frederik L Giesel16, Pietro Antonini17, Antonio Pea18, Alessandra
18
, Irene Esposito2, Atsuko Kasajima1, Stefano La Rosa3, Levent
10
, Inga Boeck11, Martin Anlauf11, Moritz Jesinghaus12, Silvia Uccella13,
14
, Henning Jann15, Emil Novruzov16, Katalin Mattes-
& Claudio Luchini
19
[Aspects of disease that affect the small bowel are also covered in Chapter 8].
Gastrointestinal Oncology: A Critical Multidisciplinary Team Approach,
Second Edition. Edited by Janusz A. Z. Jankowski.
© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
470
24 NEUROENDOCRINE NEOPLASMS OF THE DIGESTIVE SYSTEM 471
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Introduction
Günter Klöppel & Irene Esposito
General Characteristics
Terminology and Definition
The term “neuroendocrine” characterizes a cell that expresses
markers such as synaptophysin and chromogranin A. Using these
markers, neuroendocrine cells have been detected almost everywhere in the body and have built up a neuroendocrine cell system
across the organs. Despite the uniformity of this cell system, the
neoplasms that result from it are heterogeneous. The neuroendocrine neoplasms (NENs) consist of two families, which differ significantly in terms of morphology, genetics, epidemiology, and
clinics (Klimstra etal. 2019; Klöppel 2017; Yachida etal. 2021). In
the first group of neoplasms, which also bear the name carcinoids, growth and behavior are slower and individually more different than in the second group of neoplasms with their generally
much faster growth and more aggressive behavior. Both groups of
NENs can develop almost anywhere in the body but are most
common in the gastroenteropancreatic and bronchopulmonary
system, where 70–90% of all NENs occur (Kasajima etal. 2020).
The denomination “neuroendocrine” derives from the fact
that these cells share certain structures and antigens with neural
cells. Typical cellular antigens and structures are peptide
hormones and/or biogenic amines, which are stored in electron-dense membrane-bound secretory granules. The membranes of these hormone granules contain the protein
chromogranin A, which can be readily detected by immunohistochemistry and represents a general neuroendocrine
marker with high specificity. Since chromogranin A is released
together with the cell-specific hormone into the circulation, it
also serves as serum marker for secreting NENs. Another general neuroendocrine marker is synaptophysin, which resides in
the membrane of presynaptic-like vesicles that are located with
the hormone granules in the cytoplasm of all neuroendocrine
cells (Rindi and Wiedenmann 2020). Recently, the panel of
highly specific neuroendocrine markers has been extended by
a transcriptional factor, called insulinoma-associated protein 1
(INSM1) (Rosenbaum etal. 2015).
NETs and NECs
Since NENs of the digestive system are the most common NENs in
the body, they paved the way for an elaborate WHO classification
with clinical relevance. The 2019 WHO classification of digestive
system NENs distinguishes between well- and poorly differentiated neoplasms. NENs showing a well-differentiated histology and
a low proliferation rate are called neuroendocrine tumors (NETs),
while NENs displaying a poorly differentiated histology and high
proliferation rate are called neuroendocrine carcinomas (NECs)
(Klimstra et al. 2019). NETs show organoid growth patterns
with solid-nested, trabecular-gyriform, and/or pseudoglandular
growth patterns resembling those of non-neoplastic counterparts
such as the islets of Langerhans, while NECs lack the similarity
with non-neoplastic endocrine structures and are composed of
diffuse sheets of neoplastic cells or poorly formed solid cell nests,
often interspersed with necrosis. NECs with a diffuse sheet pattern
usually represent the small cell subtype, while NECs with poorly
formed solid nests are usually ascribed to the large cell subtype.
Since the two NEN families are also recognized in organs
outside the digestive system such as the lung, the WHO published
a uniform classification framework for all NENs of the body with
the aim to improve the understanding and comparability and
finally the treatment of these neoplasms (Rindi etal. 2018).
The 2019 WHO classification also includes the category of mixed
neuroendocrine non-neuroendocrine neoplasms (MiNENs), formerly referred to as mixed adenoneuroendocrine carcinomas
(MANECs) (Table 1). MiNEN is a conceptional approach to a group
of tumors that is not really an entity but consists of neoplasms, which,
although mostly monoclonal, show a variable mixture of non-neuroendocrine cell elements (i.e., adenocarcinoma or squamous cell
carcinoma) with a usually poorly differentiated neuroendocrine component (Klimstra etal. 2019). The WHO classification of digestive
system tumors defines MiNENs as neoplasms, in which each component accounts for more than 30% of the tumor cell population.
Grading of NETs
In addition to histological differentiation, proliferative activity
characterizes the individual NEN in terms of categorization and
prognosis. Grading of the neoplasm’s proliferative activity, as
assessed by Ki67 index and/or mitotic rate, contributes greatly to
Morphological differentiation Mitotic count/2 mm2Ki67-index
NET G1 Well-differentiated <2 <3%
NET G2 Well-differentiated 2–20 3–20%
NET G3 Well-differentiated >20 >20%
NEC Poorly differentiated >20 >20%
MiNEN Well or poorly differentiated* Variable* Variable*
NET: neuroendocrine tumor; NEC: neuroendocrine carcinoma.
MiNEN: mixed neuroendocrine/non-neuroendocrine neoplasm.
*referred to the neuroendocrine component.
Table 1 WHO classification of digestive
neuroendocrine neoplasms.
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Table 2 Immunohistochemical profile of most common gastroenteropancreatic neuroendocrine neoplasms.
Tumor type Site Hormone Transcriptional factor Molecular marker
NET Esophagus None None No aberrant expression of P53,
Stomach ECL-histamine* CDX2
Duodenum Gastrin, somatostatin, serotonin, PP** CDX2, islet 1
Ileum Serotonin CDX2
Appendix Serotonin, Glucagon*** CDX2
Colon Serotonin CDX2
#
Rectum
Pancreas Insulin, glucagon, PP, somatostatin, serotonin,
NEC See NET None Aberrant expression
Abbreviation: NET neuroendocrine tumor, NEC neuroendocrine carcinoma, PP pancreatic polypeptide, SSTR2 somatostatin receptor 2.
#
chromograninA is rarely expressed.
* VMAT2 as surrogate marker.
** in composite gangliocytoma/neuroma and neuroendocrine tumor (CoGNET), previously known as gangliocytic paraganglioma.
*** in tubular type NET.
****VIP, ACTH, calcitonin.
+
occasionally.
the distinction between NETs and NECs, and to the biologic
stratification of NETs. Since nuclear labeling with Ki67 has largely
replaced the cumbersome counting of mitoses, the exact
assessment of the proportion of Ki67-labeled cells as the basis for
the calculation of the Ki67 index has emerged as indispensable for
the three-tiered grading of NETs into G1, G2, and G3 (Klöppel
and La Rosa 2018, Reid etal. 2015) (Table 1). G3 represents a new
category that defines the NETs with Ki67 above 20%. It has no
defined upper Ki67 rate limit; however, usually the Ki67 index
does not exceed 50%. Most G3 NETs appear to develop from
low-grade NETs, since they often manifest themselves as metastases in patients with a prior history of a G1 or G2 NET (Kasajima
etal. 2022). NECs as poorly differentiated NENs are not graded,
but usually present with Ki67 values between 50% and 90%.
Glucagon, PP Islet 1, SATB2
gastrin, various hormones****
The immunohistochemical profile of small and large cell
NECs includes, akin to NETs, the expression of cytokeratin,
synaptophysin, INSM1, chromogranin A, as well as the overexpression/deletion of p53 and/or the loss of nuclear RB1 staining
(Table 2). In small cell type NECs, cytokeratin labeling may
show a punctuate pattern, and in exceptional cases, cytokeratin
labeling can even be lacking. A few NECs also express vimentin. Synaptophysin is typically diffusely but faintly and somewhat patchy expressed, often displaying a dot-like pattern.
Chromogranin A is usually focally and scarcely expressed and
may even be lacking, since neurosecretory granules, whose
membranes contain chromogranin A, are rare in NEC cells.
CD56 labels the membranes of NECs broadly, but it should be
never the only neuroendocrine marker on which the diagnosis
Islet 1
possible
+
+
Aberrant expression of p53,
Rb1SSTR2 Expression uncommon
of a NEC is based, since it is highly nonspecific.
Immunohistochemical Features
The immunohistochemical profile of NENs that is essential to
establish the diagnosis includes the expression of cytokeratin,
synaptophysin, and chromogranin A (Perren et al. 2017).
Labeling for cytokeratin proves the epithelial nature of a NEN
in cases where a neuroectodermal tumor such as a paraganglioma must be excluded. Diffuse and intense cytoplasmic expression of synaptophysin and chromogranin A and nuclear
staining for INSM1 (Tanigawa etal. 2018) reveals the tumor’s
neuroendocrine differentiation, the common denominator of
NENs. The staining of peptide hormones, of the somatostatin
receptor 2A (SSTR2A), or the site-specific transcription factors
ISLET-1 and CDX2, is indicated there, where the diagnosis
needs it to be complete (Table 2) (Agaimy etal. 2013; Kasajima
and Klöppel 2020; Konukiewitz etal. 2018, 2017; Vanoli etal.
2016). p53 and RB1 are highly recommended as markers for
the distinction of NETs from NECs (Kasajima etal. 2022).
Morphogenetic Features
The dichotomy of the morphological features of NETs and NECs is
reflected in the genetic profiles of the two groups. The key driver
genes of NETs occurring in the upper gastrointestinal tract
(stomach, duodenum) are MEN1 and, in the pancreas, ATRX or
DAXX (de Wilde etal. 2012; Heaphy etal. 2011; Jiao etal. 2011;
Marinoni etal. 2014; Scarpa etal. 2017; Asa etal. 2021). The molecular profile of NECs is characterized by TP53 and RB1 mutations
(Konukiewitz etal. 2018; Yachida et al. 2021, Uccella etal. 2021).
The pathogenetic role of MEN1, ATRX, DAXX, and their association
with an alternative lengthening of telomeres (ALT) has been especially studied in pancreatic NETs and is discussed below. The
molecular features of colonic and rectal NETs are largely not known.
NETs of the ileum have a genetic profile that is unique and
not comparable to that of the other GEP-NETs. Ileal NETs rarely
show somatic mutations but frequently reveal chromosome 18
24 NEUROENDOCRINE NEOPLASMS OF THE DIGESTIVE SYSTEM 473
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deletions (Karpathakis et al. 2016). In addition, many of these
tumors have epigenetic changes, which are to some extent
linked to the prognosis of the tumors (see subchapter on ileal
NETs) (Karpathakis et
al. 2016).
The majority of MiNENs are poorly differentiated and composed of large cell NECs and cribriform adenocarcinomas.
Genetically, MiNENs are closely related to the respective sitespecific adenocarcinomas. So MiNENs of the colon, where
most of the MiNENs of the gastroenteropancreatic system
occur, show mutations of KRAS, BRAF, and APC, which are
typically seen in the conventional adenocarcinomas of the colon
(Jesinghaus etal. 2017). This suggests that the tumorigenesis is
closely linked to that of conventional adenocarcinomas.
Prognostic and Predictive Biomarkers
Despite relevant progresses in our understanding of the
biology and genetics of NENs, the most relevant prognostic
factors remain the disease stage and the tumor grade, which
should always be assessed. Biomarkers predictive for therapy
response are missing or not largely validated. A recent review
about available biomarkers is provided in Bocchini et al.
(Bocchini etal. 2020). Entity-specific prognostic and predictive biomarkers will be discussed in detail in the following
sections.
References
Agaimy, A., Erlenbach-Wunsch, K., Konukiewitz, B. et al. (2013). ISL1
expression is not restricted to pancreatic well-differentiated neuro-
endocrine neoplasms, but is also commonly found in well and poorly
differentiated neuroendocrine neoplasms of extrapancreatic origin.
Mod Pathol 26 (7): 995–1003.
Asa, S.L., La Rosa, S., Basturk, O. etal. (2021). Molecular pathology of well-
differentiated gastro-entero-pancreatic neuroendocrine tumors. Endocr
Pathol 32 (1): 169–191.
Bocchini, M., Nicolini, F., Severi, S. etal. (2020). Biomarkers for Pancreatic
Neuroendocrine Neoplasms (PanNENs) Management-An Updated
Review. Front Oncol 10: 831.
de Wilde, R.F., Heaphy, C.M., Maitra, A. etal. (2012). Loss of ATRX or
DAXX expression and concomitant acquisition of the alternative
lengthening of telomeres phenotype are late events in a small subset of
MEN-1 syndrome pancreatic neuroendocrine tumors. Mod Pathol 25
(7): 1033–1039.
Heaphy, C.M., de Wilde, R.F., Jiao, Y. etal. (2011). Altered telomeres in
tumors with ATRX and DAXX mutations. Science 333 (6041): 425.
Jesinghaus, M., Konukiewitz, B., Keller, G. etal. (2017). Colorectal mixed
adenoneuroendocrine carcinomas and neuroendocrine carcinomas are
genetically closely related to colorectal adenocarcinomas. Mod Pathol 30
(4): 610–619.
Jiao, Y., Shi, C., Edil, B.H. etal. (2011). DAXX/ATRX, MEN1, and mTOR
pathway genes are frequently altered in pancreatic neuroendocrine
tumors. Science 331 (6021): 1199–1203.
Karpathakis, A., Dibra, H., Pipinikas, C. etal. (2016). Prognostic impact of
novel molecular subtypes of small intestinal neuroendocrine tumor.
Clin Cancer Res 22 (1): 250–258.
Kasajima, A. and Klöppel, G. (2020). Neuroendocrine neoplasms of lung,
pancreas and gut: a morphology-based comparison. Endocr Relat
Cancer 27 (11): R417–R32.
Kasajima, A., Konukiewitz, B., Schlitter, A.M. etal. (2022). An analysis of
130 neuroendocrine tumors G3 regarding prevalence, origin, metastasis,
and diagnostic features. Virchows Arch 480 (2): 359–368.
Klimstra, D., Klöppel, G., La Rosa, S., et al. (2019). Classification of
neuroendocrine neoplasms of the digestive system. In: WHO Classification
of Tumours Digestive System Tumours. WHO Classification of Tumours, 5e
(ed. Board TWCoTE), 16–21. Lyon: IARC Press.
Klöppel, G. (2017). Neuroendocrine neoplasms: dichotomy, origin and
classifications. Visc Med 33 (5): 324–330.
Klöppel, G. and La Rosa, S. (2018). Ki67 labeling index: assessment and
prognostic role in gastroenteropancreatic neuroendocrine neoplasms.
Virchows Arch 472 (3): 341–349.
Konukiewitz, B., Jesinghaus, M., Steiger, K. et al. (2018). Pancreatic
neuroendocrine carcinomas reveal a closer relationship to ductal
adenocarcinomas than to neuroendocrine tumors G3. Hum Pathol 77:
70–79.
Konukiewitz, B., Schlitter, A.M., Jesinghaus, M. etal. (2017). Somatostatin
receptor expression related to TP53 and RB1 alterations in pancreatic
and extrapancreatic neuroendocrine neoplasms with a Ki67-index
above 20. Mod Pathol 30 (4): 587–598.
Marinoni, I., Kurrer, A.S., Vassella, E. etal. (2014). Loss of DAXX and ATRX are
associated with chromosome instability and reduced survival of patients with
pancreatic neuroendocrine tumors. Gastroenterology 146 (2): 453–60 e5.
Perren, A., Couvelard, A., Scoazec, J.Y. etal. (2017). ENETS consensus
guidelines for the standards of care in neuroendocrine tumors:
pathology: diagnosis and prognostic stratification. Neuroendocrinology
105 (3): 196–200.
Reid, M.D., Bagci, P., Ohike, N. etal. (2015). Calculation of the Ki67 index
in pancreatic neuroendocrine tumors: a comparative analysis of four
counting methodologies. Mod Pathol 28 (5): 686–694.
Rindi, G., Klimstra, D.S., Abedi-Ardekani, B. et al. (2018). A common
classification framework for neuroendocrine neoplasms: an International
Agency for Research on Cancer (IARC) and World Health Organization
(WHO) expert consensus proposal. Mod Pathol 31 (12): 1770–1786.
Rindi, G. and Wiedenmann, B. (2020). Neuroendocrine neoplasia of the
gastrointestinal tract revisited: towards precision medicine. Nat Rev
Endocrinol 16 (10): 590–607.
Rosenbaum, J.N., Guo, Z., Baus, R.M. et al. (2015). INSM1: a novel
immunohistochemical and molecular marker for neuroendocrine and
neuroepithelial neoplasms. Am J Clin Pathol 144 (4): 579–591.
Scarpa, A., Chang, D.K., Nones, K. etal. (2017). Whole-genome landscape
of pancreatic neuroendocrine tumours. Nature 543 (7643): 65–71.
Tanigawa, M., Nakayama, M., Taira, T. etal. (2018). Insulinoma-associated
protein 1 (INSM1) is a useful marker for pancreatic neuroendocrine
tumor. Medical Mol Morphol 51 (1): 32–40.
Uccella, S., La Rosa, S., Metovic, J. etal. (2021). Genomics of high-grade
neuroendocrine neoplasms: well-differentiated neuroendocrine tumor
with high-grade features (G3 NET) and neuroendocrine carcinomas
(NEC) of various anatomic sites. Endocr Pathol 32 (1): 192–210.
Vanoli, A., La Rosa, S., Klersy, C. etal. (2016). Four neuroendocrine tumor
types and the neuroendocrine carcinoma of the duodenum. Analysis of
203 cases. Neuroendocrinology 104 (2): 112–125.
Yachida, S., Totoki, Y., Noe, M. et al. (2021). Comprehensive genomic
profiling of neuroendocrine carcinomas of the gastrointestinal system.
Cancer Discov 12 (3): 692–711.
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Esophagus – Stomach – Duodenum
Esophagus
Epidemiology and Pathology
Atsuko Kasajima, Günter Klöppel & Stefano La Rosa
Epidemiology
Esophageal neuroendocrine neoplasms (NENs) are rare,
accounting for only 0.04–1% of gastro-entero-pancreatic (GEP)
NENs and representing 0.03–0.05% of all esophageal malignancies
(Dasari etal. 2017; Giannetta etal. 2019). The mean age at diagnosis is 66 years with a male predominance (Mastracci etal. 2021).
Classification
Esophageal NENs are classified according to the same criteria
as the NENs of the digestive system into NETs, NECs of small
and large cell type, and MiNENs (Klimstra etal. 2019).
Pathology
NETs of the esophagus are extremely rare and outnumbered by
NECs and MiNENs. NETs show the histologic features of welldifferentiated NENs. NECs and MiNENs are poorly differentiated carcinomas and usually present as large and ulcerated
neoplasms in the lower third of the esophagus (Maru et al.
2008). The non-neuroendocrine component consists of either
squamous cell carcinoma or adenocarcinoma.
Prognosis
The overall survival of patients with esophageal NETs ranges from
1 to 23 years and depends on tumor stage, while the prognostic
role of proliferative activity is not known due to very limited available information. Esophageal NECs are aggressive with a median
overall survival time ranging from 8 to 15 months, with most
patients dying within 2 years from the diagnosis. The median
survival time of MiNENs is about 20 months (Maru etal. 2008).
Clinical Presentation, Diagnosis, and
Staging
The most common presenting symptoms of esophageal NENs
are dysphagia, weight loss, pain, and signs related to upper-GI
bleeding, such as melena. Incidental diagnosis as well as diagnosis due to metastases (carcinoid syndrome) or paraneoplastic
syndromes (especially in NECs) are also possible (Lee etal. 2014).
Diagnosis is usually performed at esophagogastroduodenoscopy,
where NENs present as polypoid or nodular elevated masses with
smooth surface; ulceration is possible, especially in larger tumors (Ye
etal. 2019). Staging is performed via endoscopic ultrasound (EUS),
computed tomography (CT), and positron emission tomography/
CT (PET/CT) (Giannetta etal. 2019; Tirosh and Kebebew 2018).
Surgical Treatment
Levent Dizdar & Wolfram Trudo Knoefel
Esophageal NENs are characterized by an aggressive biological
behavior with early dissemination and poor prognosis, probably reflecting the fact that the predominant histologic subtype
is poorly differentiated NECs (Estrozi and Bacchi 2011;
Mastracci etal. 2021). Due to its extreme rarity, the optimal
treatment, including surgical therapy, is unfortunately not standardized so far (Estrozi and Bacchi 2011; Mastracci etal. 2021).
Few data suggest that endoscopic resection is sufficient for
well-differentiated esophageal NETs without evidence of nodal
or distant metastases or lymphovascular invasion (Lee et al.
2014). Patients with more advanced tumors should be evaluated regarding surgical resection. Several studies suggest that
patients with stage I and II disease (according to the American
Joint Committee on Cancer (AJCC) TNM staging system for
esophageal squamous cell carcinoma) benefit from surgical
resection (Deng et al. 2016; Erdem et al. 2020; Wong et al.
2017). However, there are conflicting reports regarding the
prognostic benefit and indication for surgical resection in stage
III disease (Deng etal. 2016; Erdem etal. 2020; Schizas etal.
2017). Esophageal NECs with distant metastases represent an
absolute contraindication to surgical intervention (GarciaCarbonero etal. 2016).
Regarding surgical procedures, esophageal NENs are
resected using the same methods used to treat adenocarcinoma or squamous cell carcinoma of the esophagus. The standard procedure for resection of esophageal NENs should be
thoracoabdominal esophagectomy. Depending on the tumor
location, this procedure can be performed with a thoracic
or cervical anastomosis. The use of minimally invasive techniques, especially for the thoracic part of surgery, is associated
with improved postoperative outcomes and quality of life with
comparable oncologic results provided adequate experience
(van der Sluis etal. 2020).
References
Dasari, A., Shen, C., and Halperin, D. (2017). Trends in the incidence,
prevalence, and survival outcomes in patients with neuroendocrine
tumors in the United States. JAMA Oncol 3: 1335–1342.
Deng, H.Y., Ni, P.Z., Wang, Y.C. etal. (2016). Neuroendocrine carcinoma of
the esophagus: clinical characteristics and prognostic evaluation of 49
cases with surgical resection. J Thorac Dis 8 (6): 1250–1256.
Erdem, S., Troxler, E., Warschkow, R. etal. (2020). is there a role for surgery
in patients with neuroendocrine tumors of the esophagus? a
contemporary view from the NCDB. Ann Surg Oncol 27 (3): 671–680.
Estrozi, B. and Bacchi, C.E. (2011). Neuroendocrine tumors involving the
gastroenteropancreatic tract: a clinicopathological evaluation of 773
cases. Clinics (Sao Paulo) 66 (10): 1671–1675.
Garcia-Carbonero, R., Sorbye, H., Baudin, E. etal. (2016). ENETS consensus
guidelines for high-grade gastroenteropancreatic neuroendocrine tumors
and neuroendocrine carcinomas. Neuroendocrinology 103 (2): 186–194.
Giannetta, E., Guarnotta, V., Rota, F. et al. (2019). A rare rarity:
neuroendocrine tumor of the esophagus. Crit Rev Oncol Hematol 137:
92–107.
24 NEUROENDOCRINE NEOPLASMS OF THE DIGESTIVE SYSTEM 475
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Klimstra, D., Klöppel, G., La Rosa, S. et al. (2019). Classification of
neuroendocrine neoplasms of the digestive system. In: WHO
Classification of Tumours Digestive System Tumours. WHO Classification
of Tumours, 5e (ed. Board TWCoTE), 16–21. Lyon: IARC Press.
Lee, C.G., Lim, Y.J., Park, S.J. et al. (2014). The clinical features and
treatment modality of esophageal neuroendocrine tumors: a multicenter
study in Korea. BMC Cancer 14: 569.
Maru, D.M., Khurana, H., Rashid, A. etal. (2008). Retrospective study of
clinicopathologic features and prognosis of high-grade neuroendocrine
carcinoma of the esophagus. Am J Surg Pathol 32 (9): 1404–1411.
Mastracci, L., Rindi, G., Grillo, F. etal. (2021). Neuroendocrine neoplasms
of the esophagus and stomach. Pathologica 113 (1): 5–11.
Schizas, D., Mastoraki, A., Kirkilesis, G.I. et al. (2017). Neuroendocrine
tumors of the esophagus: state of the art in diagnostic and therapeutic
management. J Gastrointest Cancer 48 (4): 299–304.
Tirosh, A. and Kebebew, E. (2018). The utility of (68) Ga-DOTATATEpositron-
emission tomography/computed tomography in the diagnosis, management,
follow-up and prognosis of neuroendocrine tumors. Future Oncol 14 (2):
111–122.
van der Sluis, P.C., Schizas, D., Liakakos, T., and van Hillegersberg, R.
(2020). Minimally invasive esophagectomy. Dig Surg 37 (2): 93–100.
Wong, A.T., Shao, M., Rineer, J. et al. (2017). Treatment and survival
outcomes of small cell carcinoma of the esophagus: an analysis of the
national cancer data base. Dis Esophagus 30 (2): 1–5.
Ye, L., Lu, H., Wu, L. et al. (2019). The clinicopathologic features and
prognosis of esophageal neuroendocrine carcinomas: a single-center
study of 53 resection cases. BMC Cancer 19 (1): 1234.
Stomach
Epidemiology and Pathology
Atsuko Kasajima, Günter Klöppel & Stefano La Rosa
Epidemiology
Classification
Gastric NENs are classified according to the 2019 WHO criteria
into NET G1, G2, and G3 (Table 1), NEC, and MiNEN (Klimstra
et al. 2019; La Rosa etal. 2019). In addition, they should be
assigned to other prognostic categories considering clinicopathologic criteria such as gastrin serum level, morphology of
the peritumoral mucosa, and presence or absence of an associated MEN1 syndrome (La Rosa and Vanoli 2014; Rindi etal.
1993) (Table 3). Five types are currently distinguished. Type 1
comprises the histamine-producing ECL-cell NETs that are
associated with autoimmune chronic atrophic gastritis and type
2 the ECL-cell NETs associated with MEN1-gastrinomas. In
type 3, which is neither associated with autoimmune gastritis
nor gastrinoma (La Rosa and Vanoli 2014; Rindi etal. 1993),
only a fraction of the tumors is really composed of typical ECLcells. Therefore, the designation “ECL-cell” has been removed
in the last WHO classification (La Rosa etal. 2019). Types 4 and
5 are infrequent. The type 4 ECL-cell NET (La Rosa and Vanoli
2014) occurs in patients with hypergastrinemia, achlorhydria,
and parietal cell hyperplasia, but without gastrinoma and
MEN1 syndrome (Abraham et al. 2005; Ooi et al. 1995). The
type 5 ECL-cell NET occurs in patients with moderate hypergastrinemia without chronic atrophic gastritis or gastrinoma,
who had been continuously treated for a long time with proton
pump inhibitors (La Rosa and Solcia 2020; Trinh etal. 2020).
These five types can be further divided into two prognostically
relevant groups according to the patients’ gastrin levels (Table 3
and Figure 1), because NET patients with hypergastrinemia
have a better outcome than NET patients with normogastrinemia. The NETs that arise in the antrum include rare examples
of gastrin-, somatostatin- or serotonin-producing tumors.
Gastric NECs and MiNENs differ in morphology and, especially, in genetics, pathogenesis, response to therapy, and outcome and must therefore clearly be distinguished from NETs
(Jesinghaus etal. 2017; La Rosa and Uccella 2021; Uccella and
La Rosa 2020).
The incidence of gastric NENs is estimated to be 0.4
cases/100,000 person (Dasari et al. 2017; La Rosa and Vanoli
2014). They represent 4% of all NENs, although regional differences among countries have been described (Das and Dasari
2021). Gastric NETs represent 8% of GEP NETs (Alwan etal.
2020), gastric NECs 15–20% of GEP NECs (Milione etal. 2017),
and gastric MiNENs 20% of GEP MiNENs (Milione etal. 2017).
Gastric NETs occur most frequently in the sixth decade
(Lawrence etal. 2011; Yao etal. 2008). In the very common subtype 1 (80–90% of cases), women are particularly affected, while
subtype 2 (5–7% of cases) shows an equal sex distribution, and
subtype 3 (10–15% of cases) a predominance of men. NETs arising in the antral mucosa are much rarer (about 5%) than the
NETs of the oxyntic-fundic region (La Rosa etal. 2011).
Both gastric NECs and MiNENs are more frequent in males
(male/female ratio of 2:1) with an average age at diagnosis of 65
years (range 41–76 years).
Pathology and Pathogenesis
Gastric NETs
ECL-cell NETs are usually located in the oxyntic mucosa and
composed of well-differentiated cells forming small microlobular
and/or trabecular structures (Klöppel and La Rosa 2018). In most
of cases, ECL-cell NETs express the somatostatin receptor 2A
(SSRT2A) and the vesicular monoamine transporter 2 (VMAT2),
as well as histidine decarboxylase. Since the NET subtypes have
similar histologic features, they have to be distinguished according
to the histopathology of the peritumoral mucosa (Figure 2) and
the clinico-pathologic context (La Rosa and Vanoli 2014).
Type 1 ECL-cell NETs are usually multiple and small (<1 cm)
tumors arising in an atrophic oxyntic mucosa with chronic
inflammation, intestinal and pseudopyloric metaplasia, and
linear and micronodular ECL-cell hyperplasia. Most of them
are G1 NETs although exceptions have been reported (La Rosa
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Table 3 Classification and clinico-pathologic features of gastric ECL-cell NETs.
Average
% M:F ratio
Associated with
hypergastrinemia
Type 1 80-90% 1:2.5 64 Autoimmune
Type 2 5-7% 1:1 50 Gastrinoma in
Type 4 Rare Unknown 50 Hashimoto
Type 5^ unknown 1.7:1 60 PPI-treated
Not associated with
hypergastrinemia
Type 3* 10-15% 2.8:1 60 None Normal No specific
M: male; F: female; PPI: proton pomp inhibitors.
^ patients show moderate hypergastrinemia.
* only a fraction of type 3 NETs are composed of ECL-cells.
age (years)
Associated
disease
gastritis
MEN1
syndrome
thyroiditis
dyspeptic
disease
Acid
secretion
Low or absent Atrophic
High Hypertrophic
Low or absent Parietal cell
Not evaluated PPI effects Yes -G1
Peritumoral
mucosa
gastritis
gastropathy
hypertrophy
change
ECL-cell
proliferations Grade Metastasis
Yes -G1
-G2, rare
-G3, rare
Yes -G1
-G2, rare
Yes Unknown Unknown Unknown
-G2
-G3, rare
No -G1, rare
-G2
-G3, rare
1-3% about
10-30% 60-90%
15-17% about
50% <50%
5-year
survival
100%
100%
Figure 1 Practical algorithm to diagnose gastric neuroendocrine tumors arising in the oxyntic mucosa. (Reprinted with permission from the article: La
Rosa S, Solcia E. New insights into the classification of gastric neuroendocrine tumors, expanding the spectrum of ECL-cell tumors related to
hypergastrinaemia. Histopathology 77:862–864, 2020).
etal. 2011), are limited to mucosa or submucosa, and lack any
necrosis (Vanoli etal. 2018).
The development of type 1 ECL-cell NETs as well as type 2, 4,
and 5 (Sundaresan etal. 2017) is linked to a long-standing hypergastrinemia. However, hypergastrinemia alone seems not to be
sufficient for tumor development. In type 1 ECL-cell NETs, gastrin
stimulation seems to cooperate with TGF-α and bFGF actions
(Bordi 2014). The fact that loss of heterozygosity for MEN1 gene
locus and/or MEN1 mutations have also been identified in 17–73%
of type 1 ECL-cell NETs (Bordi 2014), and the recent identification
of a familial cluster bearing mutation of the ATP4A proton pump
gene (Calvete etal. 2015) further support the notion that genetic,
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