Best Practice & Research Clinical Endocrinology & Metabolism 30 (2016) 3e17

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Best Practice & Research Clinical

Endocrinology & Metabolism
journal homepage: www.elsevier.com/locate/beem

A short history of neuroendocrine tumours

and their peptide hormones
Wouter W. de Herder, MD, PhD a, *,
Jens F. Rehfeld, MD, DMSc, DSc b, Mark Kidd, PhD, DABCC c,
Irvin M. Modlin, MD, PhD, DSc d
a
Department of Internal Medicine, Section of Endocrinology, Erasmus MC, Rotterdam, The Netherlands
b
Department of Clinical Biochemistry, The National University Hospital (Rigshospitalet), Copenhagen,
Denmark
c
Wren Laboratories LLC, Branford, CT, USA
d
Yale University School of Medicine, New Haven, CT, USA

a r t i c l e i n f o
The discovery of neuroendocrine tumours of the gastrointestinal
Article history: tract and pancreas started in 1870, when Rudolf Heidenhain
Available online 23 October 2015 discovered the neuroendocrine cells, which can lead to the
development of these tumours. Siegfried Oberndorfer was the first
Keywords: to introduce the term carcinoid in 1907. The pancreatic islet cells
Neuroendocrine were first described in 1869 by Paul Langerhans. In 1924, Seale
History Harris was the first to describe endogenous hyperinsulinism/
Tumour insulinoma. In 1942 William Becker and colleagues were the first
Insulinoma to describe the glucagonoma syndrome. The first description of
Gastrinoma
gastrinoma by Robert Zollinger and Edwin Ellison dates from 1955.
Glucagonoma
The first description of the VIPoma syndrome by John Verner and
Carcinoid
VIPoma Ashton Morrison dates from 1958. In 1977, the groups of Lars-Inge
CCKoma Larsson and Jens Rehfeld, and of Om Ganda reported the first cases
of somatostatinoma. But only in 2013, Jens Rehfeld and colleagues
described the CCK-oma syndrome. The most recently updated
WHO classification for gastrointestinal neuroendocrine tumours
dates from 2010.
© 2015 Elsevier Ltd. All rights reserved.

* Corresponding author. Department of Internal Medicine, Sector of Endocrinology, Erasmus MC, 's Gravendijkwal 230, 3015
CE Rotterdam, The Netherlands. Tel.: þ31 10 7035950; Fax: þ31 107033268.
E-mail address: [email protected] (W.W. de Herder).

http://dx.doi.org/10.1016/j.beem.2015.10.004
1521-690X/© 2015 Elsevier Ltd. All rights reserved.
4 W.W. de Herder et al. / Best Practice & Research Clinical Endocrinology & Metabolism 30 (2016) 3e17

Neuroendocrine cells and neuroendocrine tumours in the gastrointestinal tract

In 1870, the German physiologist Rudolf P.H. Heidenhain (1834e1897) (Fig. 1) was the first to
recognize the existence of a group of gastrointestinal cells that were separate from oxyntic, chief and
enteric cells and noted their “yellow” chromate staining properties [1]. This observation was amplified
in 1897 by the Russian anatomist and histologist (later he was also minister of education in the Russian
empire) Nikolai K. Kultschitzky (1856e1925) (Fig. 1) [2]. Subsequently Carme
lo Ciaccio (1877e1956)
introduced the term “enterochromaffin” in 1907 [3]. The Estonian pathologist Harry Kull (1886e1933)
noted in 1925 that the gastrointestinal tract contained cells with a morphology similar to that of
chromaffin cells [4]. In 1914, the French surgeon Antonin Gosset (1872e1944) and the French-Canadian
pathologist Pierre Masson (1880e1959) used silver impregnation techniques and demonstrated the
argentaffin-staining properties of carcinoid tumours [5,6]. They suggested that neuroendocrine (NE)
tumours (NETs) might arise from the enterochromaffin (EC) cells (Kultschitzky's cells) of the intestinal
mucosa [2,5,6]. In 1938, the Austrian pathologist Friedrich Feyrter (1895e1973) (Fig. 3) proposed that
NETs were derived from the diffuse endocrine system, based on his observation of “clear cells” (Helle
Zellen) throughout the gut and pancreas, which displayed characteristic light microscopic and histo-
chemical features in their reactions with silver salts (e.g. argentaffinity and argyrophilia) [7] (see Fig. 2).
The German pathologist Siegfried Oberndorfer (1876e1944) (Fig. 4) was the first to introduce the
term carcinoid for these NETs of the gastrointestinal tract [8]. In 1907, he presented first his obser-
vations on carcinoid tumours at the convention of the German Pathological Society (Deutsche
Gesellschaft für Pathologie) in Dresden and he subsequently published his seminal paper “Karzinoide
Tumoren des Dünndarms” [8]. He described a 48-year-old woman who had presumably died of
tuberculosis. At autopsy, four pea-sized tumours were found in the ileum. Each tumour was found in
the submucosa, with the surrounding intestinal mucosa and neighbouring serosa showing no reactive
inflammation. By using the diminutive noun “Karzinoide Tumoren”, Oberndorfer sought to distinguish
these seemingly benign tumours from malignant adenocarcinomatous lesions [8,9]. In retrospect it is
evident that the German pathologist Theodor Langhans (1839e1915) in 1867 [10], the German
pathologist Otto Lubarsch (1860e1933) in 1888 [11] and the British physician/physiologist William
Bramwell Ransom (1861e1909) in 1890 [12] had previously observed similar lesions, but they had not
been clearly recognized as a distinct entity. Langhans described a carcinoid-like tumour at autopsy in a

Fig. 1. Rudolf P.H. Heidenhain (1834e1897).

W.W. de Herder et al. / Best Practice & Research Clinical Endocrinology & Metabolism 30 (2016) 3e17 5

Fig. 2. Nikolai K. Kultschitzky (1856e1925).

Fig. 3. Friedrich Feyrter (1895e1973).

6 W.W. de Herder et al. / Best Practice & Research Clinical Endocrinology & Metabolism 30 (2016) 3e17

Fig. 4. Siegfried Oberndorfer (1876e1944).

fifty-year-old woman who had perished of tuberculosis [10]. Ransom described a fifty-year-old woman
who initially presented with two egg-sized lumps in the lower part of her abdomen, menorrhagia, and
severe diarrhoea which persisted for a further two years, at which time she presented with a large,
palpable abdominal mass and cachexia [12]. Of particular interest was the observation of severe attacks
of wheezing and diarrhea upon eating; arguably the first reported presence of carcinoid syndrome.
Upon her death soon thereafter, autopsy revealed several small nodules in the distal ileum, as well as
extensive hepatic tumours (presumably metastases) [12]. In 1895, the German pathologist-
dermatologist Albrecht von Notthafft (von Weissenstein) (1868e1950) described three tumours of
the upper jejunum found at autopsy that similarly showed invasion to the muscular layer, and he
referred to these as “beginning carcinomas” [13]. Although Oberndorfer initially believed that carci-
noids were benign tumours, he revised his opinion two decades later by reporting instances of met-
astatic lesions as evidence of their malignant propensity [9]. The carcinoid tumour then faded into
obscurity once more, and seventeen years would pass before Oberndorfer's initial unsuccessful attempt
to characterize and delineate the properties of this enigmatic neoplasm was presented. Since at that
stage he had been evicted from München, Germany by the Nazi regime because of his ethnic back-
ground and the work was published in Turkish (given that he was then employed at the University of
Istanbul in Turkey) and, therefore, failed to gain wide attention [14]. As a result the misconceptions of
the carcinoids and their malignant behaviour have remained for almost a century.
In 1948, the US anatomist-zoologist Alden B. Dawson (1892e1968) developed a technique by which
EC and enterochromaffin-like (ECL) cells of the gastrointestinal tract could be stained using silver ni-
trate [15]. Serotonin, or 5-hydroxytryptamine (5-HT), was described and isolated in 1948 by the US
biochemists Maurice M. Rapport (1919e2011) and Arda Alden Green (1899e1958) and the US physi-
ologist Irvine H. Page (1901e1991) [16]. In 1952, the Italian chemists-pharmacologists Vittorio
Erspamer (1909e1999) and Biagio Asero isolated 5-HT in the EC tissues of Octopus vulgaris and the
frog Discoglossus pictus and suggested that serotonin (“enteramine”) was the specific hormone of the
 W.W. de Herder et al. / Best Practice & Research Clinical Endocrinology & Metabolism 30 (2016) 3e17 7

EC cell system [17]. In 1953, the Austrian clinician and pharmacologist Fred Lembeck (1922e2014)
confirmed biochemically the presence of serotonin (5-HT) in an ileal carcinoid tumour, thus corrob-
orating the assumption that EC cells contained this bioactive amine [18].
Carcinoid tumours were initially classified in 1963 according to the foregut, midgut, or hindgut
derivation by the British pathologist Elizabeth D. Williams and the pharmacologist-chemist Merton
Sandler (1926e2014). This stratification was developed prior to the elucidation of the different NE cell
types and the appreciation that an embryological classification had little mechanistic or physiological
validity [19]. This concept was supplanted in 1966 by the British pathologist Anthony G. E. Pearse
(1916e2003) (Fig. 5) who identified and described common chemical characteristics in the endocrine
cells of the gastrointestinal tract, particularly the uptake of 5-hydroxytryptophan and its conversion to
5-HT [20] and established the APUD (Amine Precursor Uptake and Decarboxylation) concept [21]. In
1969, the Hungarian endocrinologist Ilona Szijj in the group of K alm cs introduced the term
an Kova
“Apudoma” when describing a patient with an adrenocorticotrophin (ACTH)-producing medullary
carcinoma of the thyroid [22].
In 1995, the Italian pathologist Carlo Capella and other European NET expert pathologists published
a revised classification of NET and suggested to further avoid the term ‘carcinoid tumours’ and instead
use the term ‘neuroendocrine tumours’ to include all NETs [23]. This classification was updated by
another Italian pathologist, Enrico Solcia and other European NET pathologists and adopted by the
World Health Organization (WHO) in 2000 [24]. The first (2000) WHO classification for NETs suggested
the following categories: a) well differentiated endocrine tumours characterised by a low grade of
malignancy and well differentiated endocrine carcinomas which are more aggressive because of the
presence of metastases; b) poorly differentiated endocrine carcinomas; c) mixed exocrineeendocrine
tumours. The main difference between poorly differentiated and well differentiated endocrine carci-
noma was evaluated by means of histological preparations. It was generally agreed that the term
“carcinoid” should no longer be used for gastrointestinal NETs. In 2010, the WHO classification for
gastrointestinal NETs was updated and the general terms neuroendocrine tumour (NET) and neuro-
endocrine carcinoma (NEC) were introduced [25].

Fig. 5. Anthony G. E. Pearse (1916e2003).

8 W.W. de Herder et al. / Best Practice & Research Clinical Endocrinology & Metabolism 30 (2016) 3e17

The carcinoid syndrome, carcinoid heart disease and serotonin

In 1927, the Dutch dermatologist Cornelis Postma (1892e1960) described the first case of flushing in
a 45-year-old male, who was later shown to suffer from a metastatic ileal carcinoid. Postma, designated
the disease as “haemangioma planum extensum” [26,27] In 1931, the Dutch pathologist Anna Scholte
performed the post-mortem examination on the patient and discovered that apart from demonstrating
the presence of an ileal tumour, noted extensive hepatic metastases and in the heart, stenosis of the
pulmonary ostium and thickening of the leaflets of the tricuspid valve [28]. In the same year, the British
physician Maurice A. Cassidy (1880e1949) described a case of a 31-year-old male patient who pre-
sented with diarrhoea and flushing, a systolic heart murmur, right sided heart failure and at autopsy
liver metastases of an “adenocarcinoma” and tricuspid valve stenosis. In the pelvis extensive fibrosis
was found, but no tumour (Fig. 6) [29,30]. At that time, the link between the carcinoid syndrome, and
gastrointestinal NETs and fibrosis was not evident.
Serotonin and its urinary metabolite 5-hydroxy indole acetic acid (5-HIAA) were identified as
plasma and urine markers of the carcinoid syndrome in 1954 by the US physiologist Irvine H. Page
(1901e1991) [31,32] and subsequently confirmed by the US pharmacologist Albert Sjoerdsma
(1924e2014) and colleagues in 1956 [9,26,33e37]. In 1952, prior to this scientific delineation of se-
rotonin, the relationship between carcinoid tumours, serotonin and carcinoid heart disease had been
suggested by the Swedish physician Gunnar Bio €rck and his colleagues [38e41].
€
In 1983, the Swedish physician Kjell Oberg and colleagues described the beneficial effects of alpha-
interferon in the treatment of the carcinoid syndrome [42] and three years later in 1986, the US
physicians Larry K. Kvols and Charles G. Moertel (1928e1994) reported on the successful control of the
carcinoid syndrome using octreotide [43]. The same group subsequently reported on the successful
treatment of a carcinoid crisis with this drug [44].

Gastrin and gastrinoma

On April 29, 1955, the US surgeons Robert M. Zollinger (1903e1992) and Edwin H. Ellison
(1918e1970) presented the case histories of two females with very severe peptic ulcer disease and

Fig. 6. Carcinoid flush described as “Showing multiple telangiectases and flushing on a previously cyanotic background” as
described by Maurice A. Cassidy in 1930 [29].
 W.W. de Herder et al. / Best Practice & Research Clinical Endocrinology & Metabolism 30 (2016) 3e17 9

associated pancreatic (NE) tumours to the American Surgical Association in Philadelphia [45]. They
postulated that these tumours produced an ulcerogenic humoral factor, but erroneously speculated
that this was glucagon [45]. However, their report was not the first to describe patients with peptic
ulcer disease, acid hypersecretion, and (NE) tumours of the pancreas. From 1946 to 1952, at least six
different reports described similar cases [46e52].
Three years after the discovery of the first hormone, secretin, by the British physiologists William M.
Bayliss (1860e1924) and Ernest H. Starling (1866e1927) [53,54], gastrin was discovered in 1905 by the
British physiologist John S. Edkins (1863e1940) [55e57]. In 1967, the British physiologist Roderick A.
Gregory (1913e1990) and co-workers extracted gastrin from a pancreatic NE tumour [58]. Since then,
the disease entity known as the Zollinger-Ellison syndrome has been linked to a tumour named
gastrinoma.

Insulin and insulinoma

The pancreatic islet cells were first described by the German pathologist Paul Langerhans
(1847e1888) (Fig. 7) in 1869, while still doing his doctorate studies as a medical student [59]. At that
time, Langerhans could only speculate on their possible function. In 1902, the Canadian pathologist
Albert George Nicholls first described a tumour - which he named “adenoma” - originating from the
pancreatic islets [60].
In 1922, the efforts of the Toronto-based researchers J James R Macleod (1876e1935), Frederick G.
Banting (1891e1941) and the medical student Charles H. Best (1899e1978) resulted in the isolation of
insulin from an extract of a dog's pancreas [61,62]. Actually, the Rumanian physiologist Nicolae Pau-
lescu (1869e1931) in fact discovered insulin earlier than the Toronto group, but was never credited for
this [63]. The US surgeon Seale Harris (1870e1957) after visiting Banting and having observed the
clinical effects of insulin overdosing was the first to identify a case of endogenous hyperinsulinism in
1924 [64,65]. In 1926, the US surgeon William J Mayo (1861e1939) (Fig. 8) performed an exploratory
laparotomy on a 39-years-old orthopaedic surgeon suffering from recurrent severe hypoglycaemia and
found an unresectable pancreatic tumour with multiple liver, lymph node and mesenteric metastases

Fig. 7. Paul Langerhans (1847e1888).

10 W.W. de Herder et al. / Best Practice & Research Clinical Endocrinology & Metabolism 30 (2016) 3e17

Fig. 8. William J Mayo (1861e1939).

[66]. In 1927, then the US physician Russel M. Wilder (1885e1959) and colleagues reported on the
necropsy of this patient. Extracts of a liver metastasis produced marked lowering of the blood glucose
levels when injected into rabbits. It seems likely that Mayo's & Wilder's patient had multiple endocrine
neoplasia type 1 (MEN-1) since he also had renal stones and his cousin had had similar symptoms and
died six years earlier [67]. In 1954, the US internist Paul Wermer (1898e1975) reported disorders of
one or more endocrine glands in five members of one family in 1954. This familial syndrome was once
called Wermer syndrome, but is nowadays better known as MEN-1 [68].
The first cure of hyperinsulinism by removal of an insulinoma by the Canadian surgeon Roscoe R.
Graham (1890e1948) was reported in 1929 by his colleague, the occupational therapist Goldwin
Howland (1875e1950) and co-workers [69,70]. In 1939, it was reported that this patient was still
disease free [71]. The US surgeon Allen O. Whipple (1881e1963) (Fig. 9) and pathologist Virginia

Fig. 9. Allen O. Whipple (1881e1963).

 W.W. de Herder et al. / Best Practice & Research Clinical Endocrinology & Metabolism 30 (2016) 3e17 11

Fig. 10. Virginia Kneeland Frantz (1896e1967).

Kneeland Frantz (1896e1967) (Fig. 10) identified the diagnostic hallmark of insulinoma called Whip-
ple's triad: 1) symptoms known or likely to be caused by hypoglycaemia, 2) a low plasma glucose
measured at the time of the symptoms and 3) relief of symptoms when the glucose is raised to normal
[72].

Glucagon and glucagonoma

In 1923, a hyperglycaemic factor named glucagon was isolated by the US physiologists Charles P.
Kimball and John R. Murlin (1874e1960) [73e75]. In 1942 the US dermatologist S William Becker
(1894e1964) and colleagues were the first to describe the typical glucagonoma skin eruption in a
patient with a pancreatic tumour [76]. In 1963, the US physician Roger Unger (1924) and colleagues
recovered glucagon from extracts of pancreatic NETs found at autopsy [77]. In 1966, the US pathologist
Malcolm H. McGavran (1923e1999) and his associates published the first report on a patient with a
glucagonoma. This 42-year-old woman presented with diabetes mellitus, anaemia, an unusual skin
eruption and a metastatic pancreatic tumour. Later in the course of the disease, elevated plasma
glucagon levels were found, the tumour was biopsied and later operated by the US surgeon Hiram C.
Polk Jr [78]. The characteristic cutaneous lesion which occurs in association with the glucagonoma
syndrome was first described by the British dermatologist Ronald E. Church (1922e2007) [79]. The UK
dermatologist Darrell Wilkinson (1919e2009) named this lesion “necrolytic migratory erythema” in
1971 [80].

VIP and VIPoma

In 1958, the Irish-US pathologist Ashton B. Morrison (1922e2008) (Fig. 11) and the US physician
John V. Verner Jr. (Fig. 12) first described the watery diarrhoea syndrome or pancreatic cholera. Apart
from the chronic, profuse, watery diarrhoea, which leads to dehydration and hypokalaemia, this
syndrome is also accompanied by achlorhydria, hyperglycaemia, and episodic flushing. It is, therefore,
12 W.W. de Herder et al. / Best Practice & Research Clinical Endocrinology & Metabolism 30 (2016) 3e17

Fig. 11. Wylie W Vale (1941e2012).

also known as the Watery Diarrhoea, Hypokalaemia, and Achlorhydria (W.D.H.A.) syndrome [81]. More
than a decade later, in 1970, vasoactive intestinal peptide (VIP) was isolated from pig upper small
intestine by the Egyptian-American physician Sami Said (1928e2013) and Estonian-Swedish
biochemist Viktor Mutt (1923e1998) in Stockholm, Sweden [82]. VIP was proven to have more
properties than its name might imply. VIP strongly stimulates the intestinal secretion of water and
electrolytes, inhibits gastric secretion, promotes glycogenesis and hyperglycaemia, and causes
hypercalcaemia. It also stimulates the production of pancreatic juice. VIP is a prominent neuropeptide
in both the central and peripheral nervous systems, but it is not produced in endocrine cells [83].
Hence, VIP is not a hormone.
Evidence that VIP is nevertheless indeed the mediator of the watery diarrhoea syndrome was
produced by the British physicians Stephen R. Bloom, Julia Polak (1939e2014) and Anthony G. Pearse in
1973, when they used a specific radioimmunoassay to show raised plasma concentrations of VIP in four
patients and established by immunohistochemistry and bioassay that pancreatic tumours in these
patients contained VIP [84].
A major breakthrough came in 1985, when Kjell Oberg€ and colleagues described the beneficial
effects of alpha-interferon and the British-US physician Paul N. Maton and colleagues described the
beneficial effects of Octreotide on the W.D.H.A. syndrome [85,86].

CCK and CCKoma

In 1928, US physiologists Andrew C. Ivy (1893e1978) and Eric Oldberg (1901e1986) found evidence
of a gallbladder-emptying hormone in extracts of the small intestine [87]. This substance was named
cholecystokinin (CCK). In 1943, the British physiologists/biochemists Alexander A. Harper and Henry S.
Raper (1882e1951) discovered a stimulator of pancreatic enzyme secretion in small intestinal extracts
and named it pancreozymin [88]. However, as shown in the 1960s by the Swedish biochemist Erik
 W.W. de Herder et al. / Best Practice & Research Clinical Endocrinology & Metabolism 30 (2016) 3e17 13

Fig. 12. The first 125I-tyr-3-octreotide scan (University Hospital Rotterdam, the Netherlands, 25 March 1988 demonstrating the
presence of a neuroendocrine pancreas tumour (A), a meningeoma (B) and a supraclavicular lymph node metastasis of the
pancreatic neuroendocrine tumor (C).

Jorpes (1894e1973) and Viktor Mutt, CCK and pancreozymin are one and the same substance [89,90],
for which now only the acronym CCK is used.
In 2013, the Danish clinical biochemist Jens Rehfeld and colleagues described the CCK-oma syn-
drome in a 58-year-old woman. This syndrome is characterized by nonwatery diarrhoea, severe weight
loss, and gallbladder and peptic ulcer disease [91], the latter because CCK is a full agonist for the
gastrin/CCK-B receptor. Obligatory, plasma gastrin concentrations should not be elevated and this can
be used to discriminate the CCKoma syndrome from that of the gastrinoma [91]. Accordingly, the
diagnosis requires an (immuno)assay without cross-reactivity with gastrin.

Somatostatin and somatostatinoma. Somatostatin receptor imaging and PRRT

In 1968, the Czech physician Ladislav Krulich (1925e2005) together with the research group of the
US physician Samuel MacDonald McCann (1925e2007) discovered a hypothalamic factor that
inhibited the secretion of growth hormone [92]. Five years later, in 1973, the research group of the
French-US endocrinologist Roger Guillemin isolated a peptide form thousands of sheep hypothalami,
which could inhibit the release of growth hormone. It was named somatostatin (SRIF) [93]. In 1977,
Roger Guillemin received the Nobel Prize in Physiology or Medicine for his discoveries. It soon became
clear that somatostatin displayed a much wider activity of release-inhibiting actions.
In 1978, the US endocrinologist Wylie W Vale (1941e2012) (Fig. 11) and colleagues reported on a
short octapeptide somatostatin analogue with full somatostatin biological activity [94]. A new so-
matostatin analogue, SMS 201e995 ¼ octreotide acetate, was developed by Wilfried Bauer and col-
leagues [95]. The use of octreotide acetate to control carcinoid syndrome and the diarrhoea of VIPoma
syndrome was approved in Europe in 1988 and the U.S.A. in 1989 following a pivotal publication by
Larry Kvols and colleagues and reports on 173 patients in the U.S.A. and in Europe [43,96]. In 1999, a
registration trial using a longer acting octreotide acetate preparation (Octreotide Long Acting
14 W.W. de Herder et al. / Best Practice & Research Clinical Endocrinology & Metabolism 30 (2016) 3e17

Repeatable, LAR) was published by the US physician Joseph Rubin and colleagues [96,97]. The FDA
approved this preparation in the same year.
Somatostatin binds with high affinity to all somatostatin subtypes 1 through 5 (sst1e5) on the cells
and tumours. However, its commercially available octapeptide analogues Octreotide and Lanreotide
(Somatuline®, BIM 23014) exert their effects only through interaction with somatostatin receptor
subtypes 2 and 5 (sst2 and sst5) [98,99]. Expression of somatostatin receptors by NETs is essential for
the control of hormonal hypersecretion and the antiproliferative actions exerted by the octapeptide
somatostatin analogues. The Swiss pathologist Jean Claude Reubi and colleagues were the leading
investigators in the discoveries of the different somatostatin receptor subtypes and for developing
methods to detect or visualize them [100e104]. On 25 March 1988, the first female MEN-1 patient
underwent a scan using 125I-tyr-3-octreotide in the University Hospital Rotterdam, the Netherlands.
The scan not only demonstrated a NE pancreas tumour and its lymph node metastases, but also several
previously undetected meningeomas (Fig. 12) [105]. In 1991, 111In-pentetreotide scintigraphy was first
performed in the same hospital by the group of Eric Krenning [106]. This product became commercially
available in 1994 and was named OctreoScan®. More recently, 68Gallium (Ga)-DOTATOC and 68Ga-
DOTATATE were developed as PET tracers for somatostatin receptor imaging [107,108]. The first peptide
receptor radiotherapy (PRRT) using the Auger electron emitter 111In-pentetreotide was performed in
1994 [109]. 90Yt and 177Lu labelled somatostatin analogues were subsequently introduced and a phase
3 trial using 177Lu-octreotide recently finished its patient enrolment [110] (https://clinicaltrials.gov/ct2/
show/NCT01578239).
Somatostatinomas generally arise from the pancreas or the periampullary region in the duodenum.
They are associated with diabetes mellitus, cholelithiasis, weight loss, steatorrhoea and diarrhea,
hypochlorhydria or achlorhydria. In 1977, the group of the Danish and Swedish physicians around Lars-
Inge Larsson and Jens Rehfeld, as well as that of the US physician Om P. Ganda reported the first two
cases of pancreatic somatostatinoma [111e113]. In 1979, a full description of the somatostatinoma
syndrome caused by a periampullary tumour was reported by the Austrian gastroenterologist Günter
Krejs and colleagues [114].

Research agenda

 The discovery of neuroendocrine tumours started in 1870, but even in 2013 a new clinical
neuroendocrine tumour syndrome was described
 Siegfried Oberndorfer was the first to introduce the term carcinoid in 1907.
 Paul Langerhans was the first to describe the pancreatic islet cells in 1869.
 Seale Harris was the first to describe endogenous hyperinsulinism/insulinoma in 1924.
 William Becker and colleagues were the first to describe the glucagonoma syndrome in 1942.
 Robert Zollinger and Edwin Ellison were the first to describe the gastrinoma syndrome in
1955.
 John Verner and Ashton Morrison were the first to describe the VIPoma syndrome in 1958.
 The groups of Lars-Inge Larsson and Jens Rehfeld, and of Om Ganda were the first to report
cases of somatostatinoma in 1977.
 Jens Rehfeld and colleagues were the first to describe the CCK-oma syndrome in 2013.

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