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`duode—
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`mp AE,
`inornas
`arm: in
`
`sonata!
`ncreas.
`3e DL,
`1993; p
`
`acts of
`
`(1996‘)
`ry 108:
`
`Neumendacrine Gastro—
`
`Entero-Pancyeatic Tumars
`
`IS
`Neumendocfine Gastro-Entero~Pancreatic {GEN
`Tumors
`
`
`R. ARNOLD, R. 66KB, M. WIED, TH. BEHR
`
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`anrea 15
`Wmmm
`
`15 Neuroendocrine Gastro-Entero-Pancreatic (‘GEP) Tumors
`R. ARNOLD, R. Gotta, M. WIED, Tn. BEHR
`
`Summary
`
`Neuroenclocrine gastro—entero—pancreatic (GEP) tumors
`are rare but present with variable, sometimes dramatic
`clinical syndromes. The majority of these tumors is non-
`functioning and most functioning and non~functioning
`tumors are malignant. This chapter describes the vari-
`ous clinical entities, has a special focus on histopathol—
`ogy of these tumors as a reliable source for prognosis
`and summarizes current state and new trends in diagno'
`sis and treatment of these tumors. The management of
`
`neuroendocrine GEP~tumors needs a multidisciplinary
`approach. Therefore, diagnostic and therapeutic aspects
`of this chapter recognize the important contributions of
`surgery; pathology, radiology, nuclear medicine and gas~
`trointestinal endocrinology.
`
`llefinition
`
`Several terms for endocrine tumors of the gastrointesti—
`nal tract are currently applied to describe the same path—
`ological entity: “carcinoid”, “neuroendo crine tumor”,
`n ts
`“neuroendocrine carcinoma”,“APUDoma , gastro—en-
`tsro~pancteatic (KEEP) tumor”,“lslel cell tumor” (in case
`of pancreatic origin), The term “carcinoid” was intro—
`duced by S. Obemdorfer in 1907 to distinguish carol-
`molds as less rapidly growing and well-differentiated
`epithelial tumors of the small intestine from the more
`aggressively growing adenocarcinoma of the gut and,
`thus, recognizing the decisive difference to carcinomas
`Which is the Very slow growth of most endocrine tumors
`and which is frequently associatedwith an uncompromi-
`zed life quality. Strictly speaking is the term “carcinoid”
`reserved for endocrine tumors of the gastrointestinal
`tract (Table 2) and not for those of the pancreas (Table i).
`Endocrine pancreatic tumors are assumed to arise from
`iSIets of Langerhans although their origin {tom the dif—
`
`fuse endocrine cell system scattered within the mucosa
`of the gastrointestinal tract and the pancreatic duct sys»
`tem cannot be excluded. At least in vertebrates, the islets
`of Langerhans arise Within an independent islet organ
`which melts together with the exocrine pancreas during
`ontogenesis. The blurredness of the term “carcinoid”
`results from its histological features which are almost
`identical with those of endocrine pancreatic tumors.
`Therefore, even pathologists frequently use the term “car-
`cinoid” to describe an endocrine pancreatic tumor. To
`avoid the dilemma, the term “carcinoid” should be used
`
`only for well-differentiated endocrine tumors of the gut
`and. the term “malignant carcinoid” to designate the cor-
`responding well differentiated endocrine carcinoma [1].
`if a “carcinoid” is associated with a clinical syndrome as
`a Zoliinger-Ellison syndrome in the case of a gastrin—
`producing endocrine tumor of the duodenum, the re-
`spective “carcinoid” should better be called gastrinoma.
`The term “neuroendocrine” reflects the origin of the
`endocrine cells of the gastrointestinal tract fom the ems
`bryonic neural crest They have been designated as “Hel-
`les Zellenorgan”by F. Feyrter. The acronytn‘iAPUDoma”
`(amine precursor uptake and decarboxylation) describes
`the potency of endocrine tumors to synthesize in addi—
`tion to hormones biogenic amines as serotonin and
`other peptides characteristic to cells originating from
`the neural crest first described by A.E.G. Pearse.
`Endocrine tumors of the gastrointestinal tract are
`epithelial tumors and differ histologically from neuronal
`tumors as neuroblastom as, pheochromo cytornas and
`paragangliomas which also arise from the diffuse nett-
`roenclocrine system and are, therefore, of neural crest
`origin.
`Amphicrine and mixed endocrine-exocrine tumors
`will not be discussed within this survey since their prog—
`nosis and biological features are determined by the exo—
`crine cell department with a predominantly unfavourable
`prognosis.
`
`
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`15 Neuroendocrine Gastm—Enteerancreatic (GE?) Tumors 196
`Tablel
`
`Classification and leading symptoms 0f the most frequent endocrine tumors of the gastrointestinal tract
` “ llamélSyndmmeJ- Llearllng Symptoms .
`
`
`._3,Ré_snonslblel ‘Othelgf
`_
`‘
`_
`_
`L
`Malignancy Llngaliiatiorl Extra-pander:
`
`- Hormone
`'
`.. Hormones ‘.
`"
`’Wsl
`_
`. hf primary ' L'cloc‘alizatlon
`,
`, _. fb'innerm.
`i-
`,
`..
`,
`Hypnglycaemia
`‘
`lnsulln
`GlUcagon.PP
`5mm,
`.
`L PantreasL
`Pancreas
`Peptic Ulcers, Diarrhea,
`Gastrin
`lnsulln,PB Glucagun, ACTH,
`>90
`Reflux Disease
`Somarustatin, Chmmngranln A
`
`L lnsnllnama‘
`Eastrinoma
`
`[Zollinger—Elllsan
`syndrome)
`
`,
`very rare LLi
`lfluodenumr Stomach,
`Mesenlerium
`
`
`
`Carcinordsyndmme- nushnranhoeanmmmar Semtonln ,
`'
`Obstruttlon
`'
`WPoma Werner.
`lntractable Diarrhea,
`WP, Pl-Il
`Morrisnn syndrome}, Hypokalemla
`Fancreaticcholera
`Glutagonoma
`
`Erythema necrolytlcans
`mlgran5, Dlabetas
`Diabetes, Steatarrhea,
`Gallstones
`
`Glucagon
`
`Somatostatin
`
`Somamstatinuma
`
`LTachykinlns, Proétaglandins,
`Chromogranln A
`PF: Glumgan, Sumarostatin,
`Chromogranln A
`
`L
`
`Ileum
`
`Pancreas (rare) _
`
`'L
`
`Pancreas
`
`PH-lnsulin,30mataslafin,
`Chromogranlnk
`PBlnsulin,Calcltonln
`
`'
`
`LSD
`
`58
`
`Pancreas
`
`Rare ,
`
`Pancreas
`
`Buodesnum
`
`GHRHoma
`
`Atriumegaly
`
`GHRH
`
`Somatosta’rlnfiastrin; Insulin
`Chromogranin A
`Gastnn, PP, Chromogranin A,
`{RH
`Cushing’s syndrame
`CRHoma, ACTHGma
`>90
`Pancreas
`Lung
`
`ACTHAdrenn-cnrtlcntmphic hormone; CRHCorticotropln releasing hurmnne; GHRH Growth harmone releasing hormone; PHI Peptide
`histidine isoleucine; PP Pancreatic peptide; VIP Vasoactive intestinal polypeptide.
`
`- 100
`
`Pancreas
`
`Lung
`
`
`
`Table 2
`
`
`
`Characteristics of extra~pancreatic endocrine gastmintesfinal miners (“carcinoids”)
`
`
`Stomach
`
`Duodenal» and
`proximal jejunum I L
`
`Distal jejunum
`and ileum
`
`Appendix
`
`Cecurn
`
`Ascending Colon
`Redoslgmuld
`Rectum
`
`tomogranin A ,
`‘
`'
`Chromogranm A lhlstaminegastnnx
`Ghrelin,VMAT~2
`
`very rarely
`
`5-HT,gastrin,‘50matostatln.FH *
`‘calcltonlnACll-l :
`,
`
`Chromngranin A, serotonin,
`substance B tachyklnins, others
`SerotonlnfiLP‘LGlP PP/PYY-
`
`‘
`
`L
`
`Serotonin
`GLP‘mLP—Z PWPW
`Seratanin,
`ELF-LGLPQ PPIPW
`
`Zalllnger—Ellison syn-
`drome :or funcflona’l
`inactive
`mostly inactive; carcnmid
`syndmme in 54%
`mostly inactive; :arclnold *
`syndrome extremely rare
`
`carcinoicl syndrome in 5%
`
`no
`
`mar sizeand lines,
`
`Grimelrus positlv
`NSE poslthe
`ECL-cells, rarely
`EC—cells, rarely G-cells
`malls, G—cells.
`SomatoStatln-cells
`
`,
`,
`,
`_
`highly variable
`
`:
`
`; 50%
`
`EC-cells
`
`EC—cellS; L‘cells
`
`EEC-cells
`L-cells
`
`ECZCElls
`L—Cells
`
`>50% in tumors
`
`larger then 1 cm
`risk factorslze >3 L
`
`and 'znvgsrm of m
`soapnendix ,-
`> 50%
`
`15%;depends on
`
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`
`Classification
`
`Endocrine GEP tumors can be subdivided according to
`their origin into those originating from the foregut {eso—
`phagus, stomach, duodenum, proximal jejunum, pan-
`creas), midgut (distal jejunum, ileum, appendix, cecum,
`righbsided colon) and hindgut (left-sided colon and
`rectum). This classification is based on the embryologic
`assignment of the different parts of the gut. Vary rarely
`endocrine tumors of the same histology can arise in the
`ovary, extrah epatic bile ducts, the liventhe kidney, testis,
`spleen> breast and larynx and other organs as the bron—
`cial system and thymus.
`Clinically more relevant is a classification according
`to the functional activity of endocrine GEP tumors. Most
`benign and malignant endocrine GEP tumors are func-
`tionally inactive and patients commonly present with
`abdominal pain... weight loss, obstructive jaundice and
`intestinal obstruction depending on the localization and
`size of the tumor. Noteworthy, many tumors are asymp-
`tomatic even in the presence of metastases and are dis-
`covered'incidcntelly during routine imaging procedures.
`Survival of patients with GEP tumors is even in the
`metastatic state much more favourable than in patients
`with other malignancys and depends on the site of the
`primary tumor and the extent of metastatic spread. Of
`pancreatic endocrine tumors the best prognosis is asso»
`
`Classification.
`
`ciated smith insulinomas which are in more that 93% of
`patients solitary and benign. In contrast, most of the
`other pancreatic entities are malignant (see Table i).
`As shown in Tables 1 and 2 the majority of function-
`ally active endocrine tumors arise within the pancreas
`(see Table 1) whereas functionally active tumors within
`the gastrointestinal tract can cause the Zollingerefillison
`syndrome if originating from the duodenum or cause
`a Carcinoid syndrome due to a metastatic tumor of the
`ileum.
`
`Endocrine GEP tumors may be benign or malignant.
`The majority of endocrine pancreatic tumors are malig—
`nant and present with metastases mostly to the liver (see
`Table 1). The malignancy rate of endocrine tumors with-
`in the gastrointestinal tract is highly variable and mostly
`depending on the size of the carcinoid.
`Endocrine GEP tumors can arise sporadic or as part
`of the Multiple Endocrine Neoplasia (MEN) syndromes
`(Table 3). MENWI syndrome is an outosomal dominantly
`inherited disorder characteriZed by the synchronous or
`metachronous occurrence of tumors in multiple endo—
`crine organs, predominantly the pancreas, parathyroid,
`pituitary and duodenum. The genetic lo we was ascribed
`to a segment of the long arm of chromosome 11, where
`the menin gene — a tumor suppressor gene - is located
`which is in MEN-I syndrome mutated [2, 3]. MEN—I
`syndrome is present in 20% of patients with gastrinoma
`
`
`
`Table 3
`MEN syndromes
`
`
`' Alteratio
`.
`drums
`V
`
`
`
`
`
`Affe'ctedorgao
`,
`.
`.
`
`ME :4 (Wermer’s momma)
`”Parathyroid gland
`
`: Hyperplasta,‘
`multiple ade’non’ias
`
`
`,istet celltumoo (Minimums,
`‘
`Pancreas“
`‘
`gamma Vii-“time, : ,-
`,
`_
`
`
`,sfiitsgommat
`
`-‘ menses (protectingiifl'HgSTltl;GH,’non—fimtioning)’
`_ Pituitary (anterior) '
`Thyroid gland
`C—cell hyperplane. medullery thyroid carcinoma
`Phaeuchmmocytoma
`Adrenal medulla
`
`Hyperplasia, multiple adenomas
`Parathyroid gland
`:Cecellhypeipiasia.
`Thyroid gland '
`l
`'
`medullarythyroidtar‘ciriomi :
`Phathhromocytoma
`‘
`Adrenal medulla
`, Neuromas
`I ” '
`Mum
`Otherabnormahses:
`'
`Msrfanmd henna. _
`Megacolbn '
`
`MEN-2A {Sippie’s syndrome)
`
`MEN-25
`
`'
`
`5
`
`.
`
`mach,
`
`ti)t
`
`
`
`:ptide
`
`
`
`
`
`
`
`”won.cw“.m.
`
`
`
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`198
`
`IS Nenwendocrine Gastro—Entem-Pancreatic (GEP) Tumors
`
`
`[4}, 4% of patients with insulinoma [s] and 13~17% of
`patients with glucagonoma [6]. However, in MEN—i
`syndrome most endocrine pancreatic tumors are non-
`functional containing mostly pancreatic polypeptide
`or glucagon {5].
`
`Epidemiology
`
`Endocrine GEP tumors are rare events. The exact inci-
`dence and prevalence of these tumors is difficult to 38*
`certain because many are asymptomatic. From autopsy
`studies an annual incidence of 8.4 gastrointestinal endo~
`crime tumors (carcinoids) per 100.0% people has been
`
`calculated [7, 8] (Table 4). 90% of these tumors were in-
`cidental autopsy findings. For endocrine pancreatic tu-
`mors an annual incidence of o,1—o,4 tumors per 100.000
`has been reported. [8]. Table 4 summarizes the publish:
`ed annual incidence rates for the most common gastro—
`intestinal (carcinoids) and pancreatic endocrine tumors.
`Endocrine tumors originating in the midgut encompass
`by far the majority of all endocrine tumors followed by
`the pancreatic endocrine tumors.
`Almost all endocrine tumors originating within the
`hindgut are asymptomatic and do not create symptoms
`as a consequence of hormone overproduction. The rea-
`son for that is unknown since many of these tumors
`contain peptides and hormones which are also pro«
`
`Table 4
`Epidemiological data of endocrine GEP minors
`Localization
`
`“
`‘ihcidenceca'ses'
`96100.6(“) peopi'
`‘
`'
`
`' Remarksit,’
`(% ofaflgastrm ._
`, acids)
`
`i.
`
`‘
`
`Duodenum
`
`Proximal‘Jernum
`DistalJejunquleum _ 028—039
`£35499]
`,AP‘
`‘
`
`' 0.074321
`
`*014-416?“
`I
`(1.01403
`(ll—0.2
`
`is '
`03050.02
`0.001~0.0l
`
`-
`
`3
`
`Pancreas
`,
`all
`‘
`lnsulinoma _
`
`(assertions
`VlPorna
`Glucagonoma
`
`mtemiles ,
`
`, poorly til ,er’ent’fate .5%’
`(22%)
`
`Eastrin—produdng:52%
`Somatostatlnaproducingtr21%
`Gangliocytic pasagenglioma’: 9%
`Undefined rumors: 5.6%
`“(1%
`L
`"
`
`(right-sided colon:8%)
`(left-sided colour 20%)
`
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`
`
`are in-
`tic tu-
`aO . DUO
`thlish-
`astro -
`LlIlOI'S.
`
`mpass
`red by
`
`in the
`atoms
`5 reae
`[more
`
`» pro-
`
`
`
`l,
`i,f,
`lt
`ilt
`il,l
`
`
`
`Histopathology 199
`
`duced in tumors responsible for the carcinoid syndrome.
`'l‘he same is true for most gastric carcinoids and carci—
`noids arising in the distal ileum. Even in metastatic me
`more a hormone mediated symptomatology is mostly
`absent. Of the endocrine pancreatic tumors almost 50%
`are functionally inactive as well [8]. 'l‘he incidence rates
`of the functionally active tumors with insulinoma as the
`most frequent tumor are listed in table 4.
`According to an analysis of 8305 cases of carcinoicl
`tumors identified by the “Surveillance: Epidemiology,
`and End, Results” (SEER) program of the American Na-
`tional Cancer Institute (NCI) from i973 .o 1991 and by
`an earlier NCI program swear survival of patients was
`50.4% [7]. The presence of regional and distant metas-
`tases reduced survival rate to 21,896.1f survival rates are
`
`
`
`calculated separately for tumors arising in the foregut,
`midgut and hindgut swear survival rates were 44.5%,
`61% and 72% respectively [7]. Most favourable survival
`have appendiceal carcinoids with 85.9%. Surveillance
`rates for endocrine GEP tumors of specific localizations
`will be discussed in more detail later in this chapter.
`
`litiology
`
`The etiology of endocrine GEP tumors is unknown. it is
`comprehensible to assume that they originate from cells
`or rather precursor cells of the diffuse neuroenclocrine
`cell system. Endocrine tumor cells display certain cyto~
`chemical properties with endocrine cells scattered with
`in the mucosa of the gastrointestinal tract and with the
`constituents of the islets of Langerhans as the expres—
`sion ofneuron—specific enolase. synaptophysin and cho-
`mogranin A and C [1, 16]. Chromogranins are acidic
`giycoproteins present in almost all endocrine and new
`ronal tissues. They are released into the circulation and
`can serve as tumor markers since they are found in more
`than 90% of patients with endocrine GEP tumors. Al-
`though endocrine pancreatic tumors are also called
`“islet cell tumors” it is unproven that pancreatic insuli—
`nomaS, gastrinornas: VlPomas etc. originate from the
`islets of Langerhans. In favour of this assumption
`are findings in experimental settings which clearly de-
`monstrate that insulinomas in rate can under defined
`conditions arise from islets. However, some endocrine
`pancreatic tumors produce hormones and peptides as
`gastrin or WP which are not synthesized from islet cells
`
`after birth. Therefore, it is conceivable to assume that
`islet tumors originate from endocrine pancreatic multi—
`potent precursor cells which are constituents of the pan—
`creatic duct epithelium [13}.
`
`General Pathophysiology
`
`The key event occurring in functionally active endo—
`crine GEP tumor cells is the loss of capacity to store
`their hormonal product as insulin in in sulinomas, gas»
`trio in gastrinornas etc. within the tumor cell. Therefore,
`inappropriately released hormones and peptides not re—
`sponding to the physiological feedback inhibition are
`responsible for the clinical manifestation of the disease.
`According to the concept of an impaired storage capac-
`ity of tumor cells, it has been shown, that insulinoma
`cells contain less insulin than normal E—cells, and the
`mean total insulin content of insulinomas was even
`
`lower than the mean insulin content of the whole pan—
`creas of the respective patient [14]. Very similar is the
`gastrin content of the majority of gastrinomas lower
`compared to the gastrin content of the whole antral mu»
`case which contains more gastrin-producing cells than
`the tumor [15].
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`Histopathology
`
`Most endocrine GE? tumors display a solid, trabecular
`or glandular arrangement of well—different (Fig. rawc)
`[1, 16]. However, not in every case these features permit
`recognition of the endocrine nature of the tumor. in
`these tumors specialstaining methods as silver methods
`or immunohistochemicsl staines for general endocrine
`markers as chromogranins (Fig. re), synaptophysin or
`neuron-specific enolase are needed for tumor identifi-
`cation [1, 16]. To characterize the tumor cell further with
`
`regard to their hormonefpeptide production specific
`antibodies against polypeptide hormones are needed to
`identify a tumor cell as insulins, gastritis, glucagon- or
`other hormones producing cell (Fig 2a, b} [16]. Endo—
`crine tumors with predominant insulin production can
`be classified as insulinoma, those with predominant
`glucagon~ or gastrin production as glucagonoma or
`gastrinoma. This does not indicate that a tumor which
`
`histologically has been diagnosed as insullnoma or glu-
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`[18}.
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`Histopathoiugicai patterns in pancreatic endocrine tumors. a trabecuiar pattern; PAS staining; b glandular pattern; PAS staining; c solid -
`pattern; PAS staining; d poorly differentiated neuroendocrine tumor; PAS staining; 1: staining with the endocrine. marker chromogranin A;
`f staining with an antibody against the proiiiérafion marker Ki—G
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`Figure laaf
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`cagonoma acts as a functionally active endocrine tumor
`responsible for hypoglycemic attacks in the case of an
`insulinoma or giving rise to the typical symptoms of a
`glucagonoma syndrome. Functional activity or inactiv—
`
`ity cannot be deducted from histology. Correspondingljf
`and most characteristicly, many endocrine tumors 35
`part of the MEN-I syndrome are functionally inactive
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`Histopathologv
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`201
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`solid
`in A;
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`1le
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`live
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`Figure 2a,!)
`Demonstration of several hormones present within the same endocrine Pancreatic’tumor, a immunohistologicsl staining £01“ insulin;
`li immunohistological staining for gastrin
`
`Most endocrine tumors are composed of more than
`one cell type. An endocrine pancreatic tumor with pre-
`dominant insullnnproclucing cells can contain additional
`somatostatin— or glucagon— or pancreatic polypeptide-
`producing cells [is]. This feature is independent on the
`functional status of the tumor and can be observed
`in functionally active and inactive tumor {is}. It is on-
`clear, why in the presence of multiple hormones within
`a single endocrine tumor only one or no clinical syna
`drome occurs. Nevertheless, in few patients, a second
`clinical syndrome can be present initially or develop
`later. This occurs preferably in patients with metastatic
`endocrine pancreatic honors or in patients with MEN-l
`syndrome and multiple endocrine pancreatic tumors
`[4]. According to own observations which are in accor-
`dance with reports from the literature the combination
`of ectopic ACTH-producing and gastrimproducing pan»
`creetic tumors giving rise to a combination of Cushing’s
`syndrome and Zollinger—Ellison syndrome is frequent,
`although the condition itself with two functionallyr ac—
`tive tumors is a rare evant.
`
`Since most endocrine tumors are well—differentia-
`ted, their mitotic index visualized by the K167 labelling
`(Fig. 1f) index [9} is low which is in accordance with
`their slow growth hehaviour. Therefore, it is difficult to
`predict the biological behaviour of well—differentiated
`tumors using classical histopathological malignancy cri-
`teria as cellular or structural atypia, necrosis, mitotic
`activity or microscopic invasion. A panel of internatio~
`nal pathologists has, therefore, proposed to classify
`
`benign and malignant endocrine tumors into the cat—
`egories listed in table 5 [1]. The basis for distinguishing
`a well-differentiated endocrine tumor from a well-dif-
`ferentiated endocrine carcinoma is the presence of me—
`tastases and/or evidence for local invasion. Benign or
`low risk endocrine tumors are distinguished from tu-
`mors with greater risk of malignancy on the basis of a
`combination or features such as tumor size, local exten-
`sion, angioinvasion, cellular atypia, proliferative activity
`and the expression of hormones regularly found in the
`specific organ (“eutopic” hormone production) or the
`expression of “ectopic” hormonal products (as ACTH in
`an endocrine pancreatic tumor).
`Poorly differentiated small cell carcinoma (Fig. ml)
`is for experienced pathologists easy to distinguish from
`well—differentiated endocrine tumors on the basis of cel—
`lular atypia, the presence of markedly liyp erchromatic
`nuclei, a high nuclear/cytoplasmic ratio, focal necrosis
`and high mitotic activity. To classify such an indiffe-
`rentiated tumor as endocrine, tumors must react for
`
`Table 5
`
`General endocrine tumor categories
`Well-differentiated endocrine tumor
`Well-differentiated endocrine carcinoma
`Poorly differentiated endocrine (small cell) carcinoma
`Mixed sxocrlneendocnne tumor
`Tumor—like lesions
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`LrI-bl-hlwvo
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`202
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`15 Neuroenclocriue Gastro»Entero—Pancreatic (GEP) Tumors
`
`cytosolic neuroendocrine markers as synaptophysin
`and neuron specific enolase [1}. However, these tumors
`are frequently negative for markers of endocrine gran-
`ules as chromogranin and for specific hormonal prod—
`ucts.
`
`Additional histopathologic characteristics and tumor
`classifications will he discussed later when specific tu-
`mors are described in more detail.
`
`Molecular Pathogenesis
`
`Sporadic GE? Tumors
`
`In sporadic pancreatic endocrine tumors (PETS) an
`allelic deletion of the tumor—suppressor gene MEN—l
`located on chromosome 11q13 has been found very fre-
`quently [33 17]. However, the mutational frequency of
`MEN—l is different in functional and nonmfunctional
`PETs: 30% of functional but only 8% of non-functional
`-~ PETS showed mutations of the MENwl gene [17,18].Fnr-
`thermore, there are differences within the group of func-
`tional PETS: Alterations in MEN—l have been found
`in 54% (15/28) of gastrinomas, 50% (4/8) of VIPomas,
`2/3 glucagonomas, 1/1 somatostatinoma but only in 7%
`(4/54) of insulinomas [17}. While such findings support
`the relevance of MEN—I for the pathogenesis of endo—
`crime neoplasms, it is important to note that the in—
`cidence of MEN—I alteration is obviously tumor-type
`related and found more frequently in gastrinomas and
`non functional PETS than in insulinomas. Other fre~
`quent genetic abherations found in 25—50% ofPBTs ana-
`lyzed are chromosomal deletions on 3p, 3q, 6q,1oq, mg,
`mp, 16p, aoq, 21c], 22:}, Kg and Y. In up to 25% of PETS
`gains on chromosomes sq, 7:}, 7p, no, no, 17p and zoo
`were found.
`
`The p53 tumor suppressor gene located on chromo-
`some 171313 encodes a nuclear protein which is involved
`in multiple cellular processes like cell cycle, DNA repair,
`replication, transcription, apoptosis and cell differentia-
`tion. p53 alterations are detectable in almost all cancers
`but are extremely rare in PETS. However, increased p53
`protein concentrations were found in malignant insuli»
`nomas most likely due to inactivating mutations result—
`ing in an increased stability or posttranslational events
`leading to overexpression [19]
`
`The p16 llNKaa, MTSI) gene located on chromo-
`some open encodes a protein that binds to cyclin-depenv
`dent kinase 4 inhibiting its interaction with cyclin. p16
`alterations do not play a role in non-functional Phil‘s and
`insulinomas, Since p16 was found abnormal in 42% of 8
`gastrinomas analyzed [so] it might play a role in gastri—
`noma tumorigenesis. However, further studies are nec-
`essary to confirm this assumption.
`DPCa/Srnada is a tumor suppressor gene located on
`chromosome 18q21 encoding a protein which is involved
`in the TGF~ll signalingpathway Previous data suggested
`that Smad4 mutations seem to be common in nonufunc—
`tional PETs {21]. However, based on a more recent study
`it is unlikely that Smad4 plays a role in tumorigenesis of
`endocrine tumors.
`
`Of the oncogenes ewmyc’. c-fos, K-ras and cuerbB-z
`poly K»ras was found to be overexpressed in PETs. How-
`ever, only to of 90 PETS analyzed in the literature show-
`ed a ras mutation indicating that this is a rare event
`in these tumors. Most PETS with ras mutations were me-
`lignant insulinomas suggesting that alterations of res
`might play a role in the pathogenesis of these tumors.
`Recent data indicate that losses of sex chromosomes
`are common in PETS and are associated with presence of
`metastases, local invasion and poor survival;
`Up to date the pathogenesis of neuroendocrine tu-
`mors of the gastrointestinal tract is not well characters
`ized. Allelic loss of the MEN-l gene located on chromo-
`some 11q13 was identified in type II ECL cell tumors
`and carcinoids of the jejunum and ileum. In type i ECL
`cell tumors abnormal. Regialpha gene was observed. In
`poorly differentiated neuroendo crine neoplasms allelic
`loss of P53 located on chromosome 17p13 were found in
`4 of 9 cases suggesting a role for p53 in the development
`of these aggressive tumors.
`
`Multiple Endocrine Neoplasia-Type 1
`
`Multiple endocrine neoplasia-type 1 (MEN-I; Wermer’s
`syndrome) is characterized by a combined occurrence
`of primary hyperparathyroidism, pancreatic endocrine
`tumors and pituitary adenomas [5]. The development of
`additional tumors in other endocrine or non-endocrine
`tissues indicates that the protein menin encoded by the
`MENJ gene might have a function in a wide. variety (If
`tissues. Most MEN~I patients (90%) exhibit primary 113’-
`
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`Chromosome ll
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`Molecular Pathogenesis
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`203
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`
`
`chromo—
`
`1—depen-
`clin. p16
`’ETS and
`;2% of 8
`t gastri—
`Eer 118’;-
`
`:ated on
`uvolvecl
`
`ggested
`u-funo
`
`u; study
`neeis of
`
`erbB—z
`4 How
`~show—
`2 event
`’I'E ma»
`
`of res
`nors.
`somes
`fnce of
`
`ne tu-
`acter—
`'orno —
`unors
`l ECL
`ed. In
`illelic
`ml in
`ment
`
`mm#1?(I)
`(U{-3nm
`
`
`
`t
`
`
`
`aaWWWMNWWmcmmmmmmmmnW,_c
`
`
`
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`
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`
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`Fire: hit; Gennline mutation (it) atone
`men-J allol
`
`
`
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`Second hit: Loss ofhetorozygosity in one
`cell in one organ; loss of menin tumor suppressor
`’ t f ‘k j 1
`:r ‘1: f \
`owl
`#3 7 activity
`
`
`
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`Figure 3
`
`Neoplasm
`
`Timiorigenesis in MEN-1 according to the two hit model described by Knudson. Patients Show a germline mutation of the MEN—l gene, Later
`they acquire another mutation in the wilduype allele resulting in no loss of suppressor function of the gene
`
`perparathyroidism. Pancreatic endocrine tumors occur
`in ~6o% anti are usually benign and nonefunctional [5].
`The most common functional tumors are. insulinomas
`and gastrinomas. The prevalence of pituitary adenomas
`is between 15—50%. A recent large study including 324
`MEN-I patients showed pituitary adeuomau in 42% of
`the cases which were larger in size and more aggressive
`than without MEN~L
`
`MENJ is an autosomal dominant inherited syn—
`drome and is related to mutations of the MEN-l gene
`located on chromosome lung [2, 3}. The tumorigenesis
`of MEN-I is supposingly a process according to the two
`hit model by Knudson (Fig. 3). Patients inherit a muta—
`ted MEN-I gene and later aquire another mutation in the
`Wild-type allel (loss of heterozygosity) in vulnerable
`endocrine tissue. This results in a loss of the tumor supw
`pressor function of the MEN-i gene. The MEN-I gene
`contains 10 exons encocling the protein menin consiting
`of 610 amino acids [2]. Two transcripts have been iden-
`tified which are most likely due alternative splicing.
`
`A 2.9 kb transcript was detected in all tissues While a
`4.2 kl: transcript was found in pancreas, stomach and
`thymus only {2]. Merlin contains two nuclear localize
`tion sites and is predominantly a nuclear protein. How»
`ever, during cell cycle menin was shown to shuttle from
`nucleus to cytoplasm.
`In Res—transformed NIHng, cells overexpreseion of
`menin resulted in decreased proliferation, suppression
`of clonogenicitv in soft agar and inhibition of tumor
`growth in mice. Merlin directly interacts with JunD, a
`transcriptional factor of the AP—i complex, via three lunD
`interacting domains and inhibits IunD activation of
`transcription [22]. However, since lunD inhibits growth
`of Ros-transformed NIH3T3 cells the repressive effect of
`menin should result in enhanced growth. This indicates
`that the mechanism of action of menin is more complex
`than we know today and probably involves other genes
`and proteins. This assumption is supported bya recent
`ohservation that menin interacts with NF-KB proteins
`and inhibits NF—KB-mediated transacti‘mtion).
`
`
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