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Pancreatic polypeptide-related tumors
Peptides 23 (2002) 339 –348
Pancreatic polypeptide-related tumors Cesare Bordi*, Cinzia Azzoni, Tiziana D’Adda, Silvia Pizzi From the Department of Pathology and Laboratory Medicine, Section of Anatomic Pathology, University of Parma, Parma, Italy
Abstract PP-producing tumors are mostly located in the pancreas and may present as three pathologic lesions: pure PP-omas, mixed tumors with minor PP cell population, and PP-cell hyperplasia. These tumors are among the most common multiple adenomas frequently found in patients with multiple endocrine neoplasia type 1. Hypersecretion and high circulating levels of PP are frequently found. They are symptomless but may be useful for the identification of the pancreatic tumors. Numerous types of extrapancreatic endocrine tumors are able to synthesize and secrete PP. They occur mostly but not exclusively in the gastrointestinal tract, particularly in the rectum. The inactivation of the MEN 1 gene at 11q13 appears to be involved in the development of pancreatic but not of rectal PP-producing tumors. © 2002 Elsevier Science Inc. All rights reserved. Received 19 March 2001; received in revised form 13 June 2001; accepted 13 July 2001
1. Introduction Soon after its localization to a specific population of human islet cells [34], pancreatic polypeptide (PP) was shown to be produced and released by pancreatic endocrine tumors (PET) [25,33]. Although in most cases PP cells represented a subpopulation in tumors with heterogeneous multihormonal cell composition, pure PP cell tumors were also identified [14,26]. Since then, further studies documented the frequent involvement of PP cells in the PETs of patients with the multiple endocrine neoplasia syndrome type 1 (MEN 1), in whom inactivation of the menin oncosuppressor gene at 11q13 results in the multiglandular development of tumors in the pituitary, the parathyroid glands and several endocrine cell systems of the organs deriving from the primitive embryonic foregut [16]. Furthermore, examples of PP cell hyperplasia, an often misdiagnosed condition, were conclusively demonstrated [39]. Finally, the extension of the immunohistochemical analysis to extrapancreatic endocrine tumors revealed PP expression in other types of tumors mostly but not exclusively located in the gastrointestinal tract. In this chapter the pathologic features of tumors and tumor-like conditions involving PP producing cells are re* Corresponding author. Tel.: ⫹39-0521-290386; fax: ⫹39-0521292710. E-mail address: [email protected]
viewed. Their still elusive clinical implications and functional significance and the emerging information on the mechanisms underlying tumor development are also discussed. PP is a part of a family of 36 aminoacid-long peptides that show extensive homology within their amidated Cterminal ends and include NPY and PPY. These peptides act on G-protein coupled receptors to inhibit cAMP accumulation [32]. In spite of some degree of cross recognition of a group of three receptor subtypes (Y1, Y2 and Y4) each peptide has unique distribution and functions [41]. The scanty available data on the production of NPY and PYY by endocrine tumors are also described in this review.
2. PP producing tumors of the pancreas Pancreatic proliferative changes involving PP cells include three conditions: a, tumors exclusively or predominantly composed of PP cells, often referred to as PP-omas; b, tumors in which PP cells are part of a mixed tumor cell population; and c, hyperplasia of PP cells 2.1. Pure PP producing tumors The first case of pure pancreatic PP-oma was found in our laboratory [14]. We feel it meaningful to briefly recapitulate here the history of the patient and of his relatives, that we have followed for over 20 years, since it appears to
0196-9781/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved. PII: P I I S 0 1 9 6 - 9 7 8 1 ( 0 1 ) 0 0 6 0 6 - 4
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Fig. 1. A. A pancreatic pure PP-oma showing abundance of PP immunoreactive cells (in black) (X240). B. Predominance of PP immunoreactive cells in one of multiple pancreatic tumors of the sister of the case shown in 1A (X240).
be illustrative of the characteristic features of these neoplasms. The tumor was discovered occasionally during an operation for duodenal ulcer as double nodules of the pancreas. Immunohistochemistry revealed plenty of PP-immunoreactive cells with negative results for gastrin as well as
for other pancreatic hormones (Fig. 1A). Electron microscopy showed abundance of small dense secretory granules (Fig. 2). Serum levels of gastrin were normal. The patients was reexamined five years later and was found to still have basal levels of PP (from 2180 to 2660 pg/ml) 12 to 15 times
Fig. 2. Electron microscopy survey of the tumor shown in Fig. 1A illustrating the abundance and basal accumulation of secretory granules (X6,000) shown at high magnification in the inset (X25,000) (Modificated from ref. 9).
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higher than the mean value of normal subjects, a finding indicative of the persistence of PP producing tumors [12]. The levels rose to 11310 pg/ml after a protein meal indicating the ability of tumor cells to promptly respond to meal stimulation. In spite of these conditions no clinical and/or functional signs related to such a sustained release of PP could be evidenced. Although a family history of peptic ulcer affecting the father and two cousins was present at the time of the first presentation in the absence of any evidence for Zollinger-Ellison syndrome, the inherited MEN 1 syndrome of this patients was not discovered until 15 years later when his sister was found to have malignant endocrine tumors of the stomach associated with hyperparathyroidism and multiple PETs mostly composed of PP cells (Fig. 1B) [9]. In conclusion, the salient aspects of this case, including the unexpected discovery of PP production by the pancreatic tumors, the absence of a specific clinical activity, in spite of unappropriately high tumor secretion and circulating levels of PP, and the association of the tumor with the MEN 1 syndrome, were all typical of PP producing tumors of the pancreas as discussed below. Although often considered to be rare, pure pancreatic PP-oma were found to account for about 10% of a large series of PETs systematically investigated by immunocytochemistry [26]. Most pure PP-omas show benign behaviour [14,26], but the whole spectrum of differentiated tumors from benign adenomas to well differentiated carcinomas metastatising to regional lymphnodes and liver and causing the patient’s death has been described [43,55,57]. They are more frequent in the pancreatic head but may occur in every region of the pancreas [55]. By electron microscopy PP-omas are found to store abundant, dense, round granules of small size (135 to 155 nm in diameter, Fig. 2) [14,26,57]. These granules are similar to those found in normal PP cells and PP have been localized to them by immunoelectron-microscopy with the protein A-gold complex technique [57]. However, they cannot be differentiated from granules with similar ultrastructural morphology found in other types of PETs [13]. 2.2. Tumors with PP cells as a minor component of mixed type tumor cell population It is known since long time that endocrine tumors in general and PETs in particular are frequently composed of different types of hormone producing cells [7]. As early as 1976 it was recognized that PP producing cells occur as a minor population in more than half the functioning PETs producing other hormones such as insulinomas, gastrinomas, VIPomas and glucagonomas [51] as well as in non functional tumors with predominance of non-hormone producing cells. In these tumors PP immunoreactive cells may be either scattered as discrete cells or clustered in focal aggregates. They appear to be associated with a significantly higher frequency with glucagonomas than with other types
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of functioning PETs [6,11,51]. The significance of this association is puzzling especially in view of the fact that in the normal pancreas glucagon and PP producing cells tend to be segregated in different regions of separate embryological origin (from dorsal and ventral primordium, respectively) [38]. The combination of these two types of hormone producing cells, however, reflects a similar condition occurring in rectal carcinoids (see below). So far only one study has investigated the distribution of PP cells in non PP tumors in different regions of the pancreas with respect to the dual embryological origin of the gland. This study showed that PP immunoreactivity was present in 78% of gastrinomas located in the pancreatic head right of the superior mesentery artery, whereas no gastrinoma to the left of the superior mesenteric artery contained PP [27]. These findings generated the hypothesis that the former gastrinomas are derived from the pancreatic region of ventral origin. 2.3. PP producing tumors in MEN 1 syndrome In patients with the MEN 1 syndrome PETs are characterized by two basic lesions, multiple islet cell microadenomas (microadenomatosis) and grossly single endocrine tumors [16]. Microadenomatosis is the most common pancreatic change in MEN 1 cases. The multiple adenomas are scattered throughout the whole pancreatic gland, may be very numerous (up to 100 in some cases) and range in size from microadenomas slightly larger than unaffected islets to macro-adenomas with a diameter larger that 0.5 cm. These multiple tumors are functionally silent and are consistently benign on both histologic and clinical ground. Large, macroscopically single PETs, undistinguishable from those found in sporadic patients, are less common in MEN 1 syndrome and usually develop on the background of islet cell microadenomatosis. Like their sporadic counterparts, these neoplasms are frequently malignant and may metastatize to the liver. As a rule the cytological composition of microadenomas reflects that of normal islets (i.e. insulin, glucagon, somatostatin and PP producing cells) whereas ectopic hormone production (gastrin, VIP, ACTH, GHRF) as found in single tumors is exceptional. The hormonal profile of the multiple adenomas does not reflects the proportion of the different cell types normally found in the islets. Instead, a definite predominance of PP and/or glucagon is most often observed [8,29,35,46,49]. The most detailed study on the distribution of different cell types in multiple PETs of MEN 1 patients was performed by Pilato et al. in our laboratory and was based on semiquantitative evaluation of 104 tumors from a single case [49]. In this study PP producing cells not only were found in 96 adenomas (93%) but exceeded 30% of the whole tumor cell population in half of them. Glucagon producing cells were found in 80 adenomas (77%) exceeding a proportion of 30% in one third. Insulin producing cells, occurring in 62 adenomas, never exceeded 30% of
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Table 1 Frequency of the endocrine cell types in 104 islet cell tumors of one patient with multiple endocrine neoplasia type and Zollinger-Ellison syndrome (From ref. 48) Cell type
Number of tumors showing a frequency score* 0
PP 8 Glucagon 24 Insulin 42 Somatostatin 62 Gastrin 104
1
2
3
4
5
9 18 40 41 0
16 13 20 1 0
22 19 2 0 0
25 17 0 0 0
24 13 0 0 0
* Score of frequency of immunoreactive cells in individual tumors: 0 ⫽ absence; 1 ⫽ rare, occasional, discrete cells; 2 ⫽ discrete or clustered cells not exceeding 10 per cent of the total tumor cell population; 3, 4 and 5 ⫽ cells ranging between 10 and 30, 30 and 60 or exceeding 60 per cent of the total tumor cell population, respectively.
tumor cells ranging below 10% in all tumors but two. Finally, somatostatin producing cells, present in 42 adenomas, were virtually always represented by rare, discrete cells (Table 1). These results suggested that in this and similar patients the largely unexplored factors governing the phenotypic hormone expression by PETs does not operate randomly but are influenced toward the production of PP and glucagon [49]. Analysis of the relation between hormone phenotypic expression and several pathologic parameters of the tumors showed that PP cells were significantly more frequent in tumors exceeding 1 mm in diameter than in those of smaller size (Table 2) whereas no differences were seen for intrapancreatic distribution (head versus tail), histologic structure (gyriform versus trabecular) or the extent of stromal fibrosis [49]. Predominance of PP and/or glucagon producing adenomas may be associated with either absence or, more commonly, presence of Zollinger-Ellison syndrome (ZES). In the latter case gastrin immunoreactivity is most often not found in multiple PETs, duodenal microgastrinomas being responsible for hypergastrinemia in these patients [50].
Table 2 Mean frequency of islet cell types in the 104 islet cell tumors subdivided according to the size (From ref. 48) Tumor Diameter (mm)
Mean frequency score* of immunoreactive cells PP
0.45–1 (n ⫽ 50) 2.82 1.1–15 (n ⫽ 54) 3.44 Difference (%) 22¶
Glucagon
Insulin
Somatostatin
2.76 1.77 ⫺36#
0.90 0.75 ⫺13¶
0.34 0.48 42
* See Table 1 Statistical significance (Student t test): ¶ P ⬍ 0.05 # P ⬍ 0.005
Fig. 3. A. Hyperplasia of PP cells in the PP-rich region of the pancreatic head of a patient with gastrinoma (X20) (for quantitative assessment see case 1, Table 3). B. Detail of PP-cell hyperplasia occupying most of the pancreatic lobule (X100) (From ref. 39).
2.4. PP cell hyperplasia Several reports described hyperplasia of pancreatic PP cells in association with different pathologic conditions including diabetes [23], watery diarrhea syndrome [47,58], chronic pancreatitis [4] and mixed multiple endocrine neoplasia syndrome [28]. It appears however that in most cases the diagnosis of PP cell hyperplasia was based on a qualitative basis alone and without adequate controls with respect to the abundance of PP cells normally found in the PP-rich region of the human pancreas, of ventral embryological origin [38]. Indeed, it has been remarked that the illustrations of alledged PP cell hyperplasia in some previous reports actually show normal patterns of PP cells in such pancreatic region [39] and that caution has to be recommended in adopting the definition of PP cell hyperplasia unless stringent methodological criteria are adopted [4]. In a study of three cases of gastrinomas conducted in our
C. Bordi et al. / Peptides 23 (2002) 339 –348 Table 3 Volume density of PP-immunoreactive cells in the pancreatic region of ventral embryological origin in three patients with functioning gastrinomas (From ref. 39) Patient no
Sex/age (yr)
PP cell Vv (%) (mean ⫾ SD)*
1 2 3
F/70 F/50 F/54
14.77 ⫾ 5.73¶ 8.94 ⫾ 2.92¶ 10.83 ⫾ 5.64¶
Control subjects (n ⫽ 15, all females) Mean 75 Range 64–83
2.20 1.54–2.93
* Each value is the mean of at least five lobules evaluated and is expressed as a percentage of the pancreatic lobule volume. ¶ P ⬍ 0.0001 vs control subjects.
laboratory [39] extratumoral PP cells were investigated with morphometric procedures and the results were compared with those of an age and sex matched control groups of normal subjects. The study revealed a pronounced hyperplasia of PP cells of the PP-rich region in all cases (Fig. 3), the PP cell volume density resulting 3-fold to 5-fold higher than that of controls (Table 3). On a qualitative basis such PP cell hyperplasia showed in two cases a pattern of multifocal adenomatosis with PP cell aggregates occupying most part of the pancreatic lobules and showing gyriform, ribbon-like histologic architecture (Fig. 3b). An additional PP cell abnormality found in one of our patients was the identification of islets with ventral type configuration displaced in the PP-poor pancreatic regions (i.e. body and tail) of dorsal embryological origin. This study definitively demonstrated PP cell hyperplasia as an established pathologic condition. The difficulty in obtaining adequate tissue samples, however, prevents more extensive studies of this condition and of its clinical and functional characteristics. In fact, the PP-rich, ventral derived region of the human pancreas is located in the posterior part of the pancreatic head [38] and it can adequately be investigated only in post-mortem examinations or in patients who underwent Whipple’s surgical operation (or total pancreatectomy), as was the case of the patients included in our study.
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early as 1976 the hypothesis of a causal implication of PP producing tumors in the watery diarrhea syndrome was proposed and gained some popularity [33,36]. However, it did not receive further support from additional observations with the exception of two studies in which the causal factor of the syndrome was assumed to be PP cell hyperplasia with all reservations relevant to the diagnostic assessment of this condition as discussed previously. The most important clinical application of serum PP determinations is concerned with the role of PP as a marker for PETs. Indeed, elevated circulating levels of PP were found in patients bearing functioning tumors secreting hormones different from PP, including insulinomas, gastrinomas, VIPomas and glucagonomas [51]. Moreover, more than 50% of patients with non-functioning PETs were reported to have elevation of PP blood values [44]. The source of such sustained circulating PP may reside in either pure PP-omas, mixed tumors, or PP cell hyperplasia. The clinical usefulness of PP determinations in sporadic PETs has been confuted [31]. In contrast, much stronger evidence has been obtained for patients with MEN 1. After a standardized meal stimulation test PP was found to be the single, most sensitive marker able to substantiate the presence of PETs in 75% of MEN 1 patients by the age of 25 years when these neoplasms are almost invariably asymptomatic [44]. In another study a plasma PP increase three times higher than the normal age specific value showed 95% sensitivity and 88% specificity for PETs as revealed by positive imaging studies [42]. These results were reported to be further improved by combined determinations of PP and gastrin. Post-prandial PP values exceeding twice the upper reference limits coupled with doubling of gastrin levels appeared to yeld absolute specificity for the presence of PETs [44]. 2.6. PP-related peptides in pancreatic endocrine tumors NPY was found to be synthesized in PETs by both immunodetermination in tissue extracts [1] and immunohistochemistry [59]. So far, no evidence has been provided for PYY production in PETs.
2.5. Clinical implications of pancreatic PP cell tumors
3. Extra-pancreatic PP producing tumors
The actions of PP are mediated by theY4 receptor and are largely inhibitory on gastric emptying, upper intestinal motility, pancreatic exocrine secretion and hepatic glucose production [41]. For reasons still unexplained the clinical presentation of PP producing tumors is usually silent and not associated with recognizable tumor syndrome(s) and/or functional effects [21,40,44]. Therefore, these tumors are usually classified among non-functioning PETs [40,55] in spite of the fact that they are frequently associated with active, abnormally high secretion of PP [51,55] which may be modulated by physiological digestive stimuli [12,57]. As
Production of PP and/or related peptides has been documented in a considerable number of endocrine tumors located outside the pancreas. Most of these tumors are located in the gastrointestinal tract or in related organs such as the liver and biliary tract. However, PP tumor production was also found in the thyroid, lung and ovary In extrapancreatic tumors, as well, the most frequent finding is represented by the occurrence of PP producing cells as a minor component of a mixed type tumor cell population. However, some tumors appear to be composed predominantly or exclusively of PP-producing cells, a con-
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dition virtually restricted to carcinoid tumors arising in the rectum and in the liver-biliary system or, more rarely, in the duodenum. 3.1. Rectal carcinoid tumors In a study of 17 rectal endocrine tumors [19], 4 neoplasms showed preponderant, pure composition of PP-immunoreactive cells. Other five tumors showed a minor population of PP-immunoreactive cells, associated with prevailing glucagon and/or glicentin immunoreactive cells in four cases and serotonin immunoreactive cells in the remaining one. In another study, in which major and minor cell populations are not specified, PP-immunoreactive cells were found in 15 of 22 rectal carcinoids being associated with glicentin-immunoreactive cells in all cases [22]. A literature survey led Fiocca et al. to calculate that immunoreactivities for PP or PP-related peptides occurs in 62% of rectal carcinoids [22]. A detailed immunocytochemical study of rectal carcinoids and of the normal endocrine cells of the human rectal mucosa using a wide panel of antisera against various glucagon- and PP-related peptides revealed that the pattern of immunoreactivities in tumor cells is fully consistent with that of L rectal cells, an endocrine cell type known to express glicentin, PP and PYY [22]. However, the study showed that tumor cells produce more PP than PYY as compared to their normal counterpart. Moreover, while in the normal mucosa most cells were found to simultaneously contain glicentin, PYY and PP, in tumor cells the immunoreactivities for these three peptides tended to occur in separate cells. From the clinico-pathologic point of view PP-immunoreactive rectal carcinoids behave similarly to those producing other peptides. They usually are small polypoid lesions (Fig. 4 A and B), located in the submucosa and showing benign behavior. Only tumors with a diameter larger than 2 cm or showing angioinvasion have a malignant potential and may cause invasion of the bowel wall and metastases to lymph node and liver [18]. An interesting and still uneplained feature of rectal carcinoids, either PP producing or not, is represented by the lack of immunostaining for chromogranin A (Fig. 4 C), the almost universal neuroendocrine marker localized to the secretory granules of normal and neoplastic neuroendocrine cells. In this regard PP-producing cells of rectal carcinoids differ from those of pancreatic tumors, which show intense chromogranin A immunoreactivity [10]. This indicates a different composition of the cell secretory granules in the PP-producing tumors of the two organs. 3.2. PP-producing tumors of the liver and biliary tract In 1980 Warner et al. described a case of a large tumor apparently arising in the liver that proved by electron mi-
croscopy and immunohistochemistry to be a PP-producing neoplasm [60]. In 1992 Tanaka et al. reported a case of PP-producing carcinoid tumor of the gallbladder and found three additional cases in the Japanese literature [56]. All gallbladder tumors were characterized by polypoid configuration, small size (below 1 cm in diameter), typical histologic appearance and benign clinical behavior. Finally, in a recent study of 7 carcinoid tumors of the extrahepatic bile ducts Maitra et al. reported one pure PP-oma and another tumor with mixed composition of cells producing PP, gastrin and serotonin, respectively [37]. Although both tumors were larger than 2 cm in diameter they showed a benign behavior. Considering the rare occurrence of endocrine tumors in the liver and biliary tract, the number of cases producing PP significantly exceed casual distribution. PPproducing biliary tumors are strongly immunoreactive for chromogranin A [37]. 3.3. Other PP-producing tumors Medullary carcinoma of the thyroid (MCT) is a tumor composed of calcitonin-producing C cells that may occurr either in a sporadic form or as a component of hereditary syndrome encompassing the whole spectrum of manifestations of multiple endocrine neoplasia type 2 (MEN 2) [30]. In a series of MCTs PP production was convincingly demonstrated by combined immunocytochemistry, radioimmunoassay and high-performance liquid chromatography (HPLC) [45]. In contrast with the diffuse intratumor distribution of calcitonin, PP immunoreactivity was found to be localized to discrete areas. On Sephadex chromatography of tumor extracts the predominant form was found to correspond to human PP in size but larger forms were also identified. The absence of PP cells in the normal thyroid gland indicates ectopic tumor production. Interestingly enough, in this study PP production by MCT appeared to be restricted to tumors of familial (MEN 2) type, suggesting its use as a differentiating marker of MEN 2 versus sporadic forms of MCT. PP production by MCT was confirmed by Scopsi et al. [52] who found a higher tumor content of another member of the family of PP-folded peptides, NPY, particularly abundant in tumors with scarcely aggressive behavior. PP immunoreactivity was also detected in carcinoid tumors of the middle ear [3]. Its association with glicentin and PYY immunoreactivity, the different peptides being colocalized in tumor cell granules by immuno-electron microscopy, reflected the features of rectal carcinoids and suggested a condition of intestinal metaplasia as shown in tumors of nasal mucosa [3]. Among lung neuroendocrine tumors, PP immunoreactivity was found in 26% of typical carcinoids ranking third in frequency after ␣-hCG and serotonin in the study of Bonato et al. [5] investigating a large number of specific neuroendocrine products, a result in full agreement with previous data on smaller series of cases [61]. In contrast, no PP could
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Fig. 4. A. Low power micrograph of a polypoid rectal carcinoid removed by endoscopy. The tumor is entirely located in the submucosa (HE X8). B. Intense immunostaining of the tumor for human PP (X70). C. Negative chromogranin A immunoreactivity of tumor cells with positive control in cells of the overlying rectal mucosa (X70).
be demonstrated in well differentiated (atypical carcinoids) and poorly differentiated neuroendocrine carcinomas [5]. PP immunoreactive cells were also detected in carcinoids tumors of the stomach [15]. The gangliocytic paraganglioma is a peculiar benign tumor of the proximal small bowel, and especially of the duodenum, that has been described as a mixture of carcinoid, paraganglioma and ganglioneuroma. Indeed, it is composed of carcinoid-like nests of epithelial cells, mature ganglion cells and neuroid spindle cells. The latter can be regarded as Schwann cells whereas the ganglion cells were
found to be intensely immunostained for somatostatin and only weakly for PP. In contrast, the immunoreactivity for PP was strong and diffuse in the epithelial, carcinoid-like component whereas several other hormonal peptides showed only weak or focal immunoreactivity [48]. On the basis of the predominant PP cell composition of the tumor, it has been suggested an origin from the ventral, PP-rich primordium of the pancreas that has recruited nerves and ganglion cells during its migration to the final location on the posterior part of the pancreatic head [48]. Ovarian carcinoids were also found to include immuno-
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underlying tumor development in MEN 1 patients. According to the Knudson’s two hit theory, in this condition, the inherited affected gene carries a germline mutation whereas a somatic lesion, usually represented by a deletion (commonly referred to a loss of heterozygosity or LOH) of the remaining wild-type allele, completes the gene inactivation and initiates tumor growth [16]. LOH at 11q13, and less frequently, MEN 1 gene mutations, were commonly observed also in the sporadic counterparts of MEN 1 tumors including PETs [20,24]. Inactivation of MEN 1 gene, therefore, appears to be the main factors responsible for the development of PP-producing PETs (Fig. 5A). In contrast, the current evidence indicates no involvement of the MEN 1 gene in endocrine tumors of the gastrointestinal tract not associated with the MEN 1 syndrome such as midgut (ileal and appendicular) and hindgut (rectal) carcinoids (D’Adda et al., in press). Thus, development of PP-producing tumors of the rectum (Fig. 5B) appears to be governed by genetic mechanism(s) different from those operating in pancreatic PP-omas
Ackowledgements Fig. 5. Allelic losses for three microsatellite markers of the MEN 1 region at 11q13 in a PP-producing pancreatic tumors. In normal tissue the alleles for each marker are indicated by black arrows whereas a gray arrow denotes the allele lost in the tumor. B. No allelic losses can be demonstrated for the same 11q13 markers in a PP-producing rectal carcinoid.
This work is supported by grants from the Italian Association for Cancer Research (AIRC), Milan and the Italian Ministry for University and Scientific and Technological Research (MURST)
reactive PP cells that appeared to be the most common endocrine cell type in a large study [54]. These tumors may be associated with oversecretion and raised circulating levels of PP [2].
References
3.4. Functional implications of extrapancreatic PPproducing endocrine tumors As for their pancreatic counterparts no specific clinical symptoms ascribed to PP hypersecretion have been described so far in extrapancreatic PP-producing endocrine tumors. With regard to diarrhea, a frequent functional finding of MTC, the lack of correlation with the tumor content of PP was remarked [45]. A PP cell ovarian carcinoid producing PYY was associated with severe constipation that disappeared upon tumor removal [53], a potential effect of the inhibitory activity of the peptide [41]. Another patient with an intestinal L cell tumor and hypersecretion of PYY also presented constipation [17].
4. Mechanism of development of PP producing tumors It is generally accepted that inactivation of the MEN 1 oncosuppressor gene located at 11q13 is the basic event
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Pancreatic polypeptide-related tumors Cesare Bordi*, Cinzia Azzoni, Tiziana D’Adda, Silvia Pizzi From the Department of Pathology and Laboratory Medicine, Section of Anatomic Pathology, University of Parma, Parma, Italy
Abstract PP-producing tumors are mostly located in the pancreas and may present as three pathologic lesions: pure PP-omas, mixed tumors with minor PP cell population, and PP-cell hyperplasia. These tumors are among the most common multiple adenomas frequently found in patients with multiple endocrine neoplasia type 1. Hypersecretion and high circulating levels of PP are frequently found. They are symptomless but may be useful for the identification of the pancreatic tumors. Numerous types of extrapancreatic endocrine tumors are able to synthesize and secrete PP. They occur mostly but not exclusively in the gastrointestinal tract, particularly in the rectum. The inactivation of the MEN 1 gene at 11q13 appears to be involved in the development of pancreatic but not of rectal PP-producing tumors. © 2002 Elsevier Science Inc. All rights reserved. Received 19 March 2001; received in revised form 13 June 2001; accepted 13 July 2001
1. Introduction Soon after its localization to a specific population of human islet cells [34], pancreatic polypeptide (PP) was shown to be produced and released by pancreatic endocrine tumors (PET) [25,33]. Although in most cases PP cells represented a subpopulation in tumors with heterogeneous multihormonal cell composition, pure PP cell tumors were also identified [14,26]. Since then, further studies documented the frequent involvement of PP cells in the PETs of patients with the multiple endocrine neoplasia syndrome type 1 (MEN 1), in whom inactivation of the menin oncosuppressor gene at 11q13 results in the multiglandular development of tumors in the pituitary, the parathyroid glands and several endocrine cell systems of the organs deriving from the primitive embryonic foregut [16]. Furthermore, examples of PP cell hyperplasia, an often misdiagnosed condition, were conclusively demonstrated [39]. Finally, the extension of the immunohistochemical analysis to extrapancreatic endocrine tumors revealed PP expression in other types of tumors mostly but not exclusively located in the gastrointestinal tract. In this chapter the pathologic features of tumors and tumor-like conditions involving PP producing cells are re* Corresponding author. Tel.: ⫹39-0521-290386; fax: ⫹39-0521292710. E-mail address: [email protected]
viewed. Their still elusive clinical implications and functional significance and the emerging information on the mechanisms underlying tumor development are also discussed. PP is a part of a family of 36 aminoacid-long peptides that show extensive homology within their amidated Cterminal ends and include NPY and PPY. These peptides act on G-protein coupled receptors to inhibit cAMP accumulation [32]. In spite of some degree of cross recognition of a group of three receptor subtypes (Y1, Y2 and Y4) each peptide has unique distribution and functions [41]. The scanty available data on the production of NPY and PYY by endocrine tumors are also described in this review.
2. PP producing tumors of the pancreas Pancreatic proliferative changes involving PP cells include three conditions: a, tumors exclusively or predominantly composed of PP cells, often referred to as PP-omas; b, tumors in which PP cells are part of a mixed tumor cell population; and c, hyperplasia of PP cells 2.1. Pure PP producing tumors The first case of pure pancreatic PP-oma was found in our laboratory [14]. We feel it meaningful to briefly recapitulate here the history of the patient and of his relatives, that we have followed for over 20 years, since it appears to
0196-9781/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved. PII: P I I S 0 1 9 6 - 9 7 8 1 ( 0 1 ) 0 0 6 0 6 - 4
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Fig. 1. A. A pancreatic pure PP-oma showing abundance of PP immunoreactive cells (in black) (X240). B. Predominance of PP immunoreactive cells in one of multiple pancreatic tumors of the sister of the case shown in 1A (X240).
be illustrative of the characteristic features of these neoplasms. The tumor was discovered occasionally during an operation for duodenal ulcer as double nodules of the pancreas. Immunohistochemistry revealed plenty of PP-immunoreactive cells with negative results for gastrin as well as
for other pancreatic hormones (Fig. 1A). Electron microscopy showed abundance of small dense secretory granules (Fig. 2). Serum levels of gastrin were normal. The patients was reexamined five years later and was found to still have basal levels of PP (from 2180 to 2660 pg/ml) 12 to 15 times
Fig. 2. Electron microscopy survey of the tumor shown in Fig. 1A illustrating the abundance and basal accumulation of secretory granules (X6,000) shown at high magnification in the inset (X25,000) (Modificated from ref. 9).
C. Bordi et al. / Peptides 23 (2002) 339 –348
higher than the mean value of normal subjects, a finding indicative of the persistence of PP producing tumors [12]. The levels rose to 11310 pg/ml after a protein meal indicating the ability of tumor cells to promptly respond to meal stimulation. In spite of these conditions no clinical and/or functional signs related to such a sustained release of PP could be evidenced. Although a family history of peptic ulcer affecting the father and two cousins was present at the time of the first presentation in the absence of any evidence for Zollinger-Ellison syndrome, the inherited MEN 1 syndrome of this patients was not discovered until 15 years later when his sister was found to have malignant endocrine tumors of the stomach associated with hyperparathyroidism and multiple PETs mostly composed of PP cells (Fig. 1B) [9]. In conclusion, the salient aspects of this case, including the unexpected discovery of PP production by the pancreatic tumors, the absence of a specific clinical activity, in spite of unappropriately high tumor secretion and circulating levels of PP, and the association of the tumor with the MEN 1 syndrome, were all typical of PP producing tumors of the pancreas as discussed below. Although often considered to be rare, pure pancreatic PP-oma were found to account for about 10% of a large series of PETs systematically investigated by immunocytochemistry [26]. Most pure PP-omas show benign behaviour [14,26], but the whole spectrum of differentiated tumors from benign adenomas to well differentiated carcinomas metastatising to regional lymphnodes and liver and causing the patient’s death has been described [43,55,57]. They are more frequent in the pancreatic head but may occur in every region of the pancreas [55]. By electron microscopy PP-omas are found to store abundant, dense, round granules of small size (135 to 155 nm in diameter, Fig. 2) [14,26,57]. These granules are similar to those found in normal PP cells and PP have been localized to them by immunoelectron-microscopy with the protein A-gold complex technique [57]. However, they cannot be differentiated from granules with similar ultrastructural morphology found in other types of PETs [13]. 2.2. Tumors with PP cells as a minor component of mixed type tumor cell population It is known since long time that endocrine tumors in general and PETs in particular are frequently composed of different types of hormone producing cells [7]. As early as 1976 it was recognized that PP producing cells occur as a minor population in more than half the functioning PETs producing other hormones such as insulinomas, gastrinomas, VIPomas and glucagonomas [51] as well as in non functional tumors with predominance of non-hormone producing cells. In these tumors PP immunoreactive cells may be either scattered as discrete cells or clustered in focal aggregates. They appear to be associated with a significantly higher frequency with glucagonomas than with other types
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of functioning PETs [6,11,51]. The significance of this association is puzzling especially in view of the fact that in the normal pancreas glucagon and PP producing cells tend to be segregated in different regions of separate embryological origin (from dorsal and ventral primordium, respectively) [38]. The combination of these two types of hormone producing cells, however, reflects a similar condition occurring in rectal carcinoids (see below). So far only one study has investigated the distribution of PP cells in non PP tumors in different regions of the pancreas with respect to the dual embryological origin of the gland. This study showed that PP immunoreactivity was present in 78% of gastrinomas located in the pancreatic head right of the superior mesentery artery, whereas no gastrinoma to the left of the superior mesenteric artery contained PP [27]. These findings generated the hypothesis that the former gastrinomas are derived from the pancreatic region of ventral origin. 2.3. PP producing tumors in MEN 1 syndrome In patients with the MEN 1 syndrome PETs are characterized by two basic lesions, multiple islet cell microadenomas (microadenomatosis) and grossly single endocrine tumors [16]. Microadenomatosis is the most common pancreatic change in MEN 1 cases. The multiple adenomas are scattered throughout the whole pancreatic gland, may be very numerous (up to 100 in some cases) and range in size from microadenomas slightly larger than unaffected islets to macro-adenomas with a diameter larger that 0.5 cm. These multiple tumors are functionally silent and are consistently benign on both histologic and clinical ground. Large, macroscopically single PETs, undistinguishable from those found in sporadic patients, are less common in MEN 1 syndrome and usually develop on the background of islet cell microadenomatosis. Like their sporadic counterparts, these neoplasms are frequently malignant and may metastatize to the liver. As a rule the cytological composition of microadenomas reflects that of normal islets (i.e. insulin, glucagon, somatostatin and PP producing cells) whereas ectopic hormone production (gastrin, VIP, ACTH, GHRF) as found in single tumors is exceptional. The hormonal profile of the multiple adenomas does not reflects the proportion of the different cell types normally found in the islets. Instead, a definite predominance of PP and/or glucagon is most often observed [8,29,35,46,49]. The most detailed study on the distribution of different cell types in multiple PETs of MEN 1 patients was performed by Pilato et al. in our laboratory and was based on semiquantitative evaluation of 104 tumors from a single case [49]. In this study PP producing cells not only were found in 96 adenomas (93%) but exceeded 30% of the whole tumor cell population in half of them. Glucagon producing cells were found in 80 adenomas (77%) exceeding a proportion of 30% in one third. Insulin producing cells, occurring in 62 adenomas, never exceeded 30% of
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Table 1 Frequency of the endocrine cell types in 104 islet cell tumors of one patient with multiple endocrine neoplasia type and Zollinger-Ellison syndrome (From ref. 48) Cell type
Number of tumors showing a frequency score* 0
PP 8 Glucagon 24 Insulin 42 Somatostatin 62 Gastrin 104
1
2
3
4
5
9 18 40 41 0
16 13 20 1 0
22 19 2 0 0
25 17 0 0 0
24 13 0 0 0
* Score of frequency of immunoreactive cells in individual tumors: 0 ⫽ absence; 1 ⫽ rare, occasional, discrete cells; 2 ⫽ discrete or clustered cells not exceeding 10 per cent of the total tumor cell population; 3, 4 and 5 ⫽ cells ranging between 10 and 30, 30 and 60 or exceeding 60 per cent of the total tumor cell population, respectively.
tumor cells ranging below 10% in all tumors but two. Finally, somatostatin producing cells, present in 42 adenomas, were virtually always represented by rare, discrete cells (Table 1). These results suggested that in this and similar patients the largely unexplored factors governing the phenotypic hormone expression by PETs does not operate randomly but are influenced toward the production of PP and glucagon [49]. Analysis of the relation between hormone phenotypic expression and several pathologic parameters of the tumors showed that PP cells were significantly more frequent in tumors exceeding 1 mm in diameter than in those of smaller size (Table 2) whereas no differences were seen for intrapancreatic distribution (head versus tail), histologic structure (gyriform versus trabecular) or the extent of stromal fibrosis [49]. Predominance of PP and/or glucagon producing adenomas may be associated with either absence or, more commonly, presence of Zollinger-Ellison syndrome (ZES). In the latter case gastrin immunoreactivity is most often not found in multiple PETs, duodenal microgastrinomas being responsible for hypergastrinemia in these patients [50].
Table 2 Mean frequency of islet cell types in the 104 islet cell tumors subdivided according to the size (From ref. 48) Tumor Diameter (mm)
Mean frequency score* of immunoreactive cells PP
0.45–1 (n ⫽ 50) 2.82 1.1–15 (n ⫽ 54) 3.44 Difference (%) 22¶
Glucagon
Insulin
Somatostatin
2.76 1.77 ⫺36#
0.90 0.75 ⫺13¶
0.34 0.48 42
* See Table 1 Statistical significance (Student t test): ¶ P ⬍ 0.05 # P ⬍ 0.005
Fig. 3. A. Hyperplasia of PP cells in the PP-rich region of the pancreatic head of a patient with gastrinoma (X20) (for quantitative assessment see case 1, Table 3). B. Detail of PP-cell hyperplasia occupying most of the pancreatic lobule (X100) (From ref. 39).
2.4. PP cell hyperplasia Several reports described hyperplasia of pancreatic PP cells in association with different pathologic conditions including diabetes [23], watery diarrhea syndrome [47,58], chronic pancreatitis [4] and mixed multiple endocrine neoplasia syndrome [28]. It appears however that in most cases the diagnosis of PP cell hyperplasia was based on a qualitative basis alone and without adequate controls with respect to the abundance of PP cells normally found in the PP-rich region of the human pancreas, of ventral embryological origin [38]. Indeed, it has been remarked that the illustrations of alledged PP cell hyperplasia in some previous reports actually show normal patterns of PP cells in such pancreatic region [39] and that caution has to be recommended in adopting the definition of PP cell hyperplasia unless stringent methodological criteria are adopted [4]. In a study of three cases of gastrinomas conducted in our
C. Bordi et al. / Peptides 23 (2002) 339 –348 Table 3 Volume density of PP-immunoreactive cells in the pancreatic region of ventral embryological origin in three patients with functioning gastrinomas (From ref. 39) Patient no
Sex/age (yr)
PP cell Vv (%) (mean ⫾ SD)*
1 2 3
F/70 F/50 F/54
14.77 ⫾ 5.73¶ 8.94 ⫾ 2.92¶ 10.83 ⫾ 5.64¶
Control subjects (n ⫽ 15, all females) Mean 75 Range 64–83
2.20 1.54–2.93
* Each value is the mean of at least five lobules evaluated and is expressed as a percentage of the pancreatic lobule volume. ¶ P ⬍ 0.0001 vs control subjects.
laboratory [39] extratumoral PP cells were investigated with morphometric procedures and the results were compared with those of an age and sex matched control groups of normal subjects. The study revealed a pronounced hyperplasia of PP cells of the PP-rich region in all cases (Fig. 3), the PP cell volume density resulting 3-fold to 5-fold higher than that of controls (Table 3). On a qualitative basis such PP cell hyperplasia showed in two cases a pattern of multifocal adenomatosis with PP cell aggregates occupying most part of the pancreatic lobules and showing gyriform, ribbon-like histologic architecture (Fig. 3b). An additional PP cell abnormality found in one of our patients was the identification of islets with ventral type configuration displaced in the PP-poor pancreatic regions (i.e. body and tail) of dorsal embryological origin. This study definitively demonstrated PP cell hyperplasia as an established pathologic condition. The difficulty in obtaining adequate tissue samples, however, prevents more extensive studies of this condition and of its clinical and functional characteristics. In fact, the PP-rich, ventral derived region of the human pancreas is located in the posterior part of the pancreatic head [38] and it can adequately be investigated only in post-mortem examinations or in patients who underwent Whipple’s surgical operation (or total pancreatectomy), as was the case of the patients included in our study.
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early as 1976 the hypothesis of a causal implication of PP producing tumors in the watery diarrhea syndrome was proposed and gained some popularity [33,36]. However, it did not receive further support from additional observations with the exception of two studies in which the causal factor of the syndrome was assumed to be PP cell hyperplasia with all reservations relevant to the diagnostic assessment of this condition as discussed previously. The most important clinical application of serum PP determinations is concerned with the role of PP as a marker for PETs. Indeed, elevated circulating levels of PP were found in patients bearing functioning tumors secreting hormones different from PP, including insulinomas, gastrinomas, VIPomas and glucagonomas [51]. Moreover, more than 50% of patients with non-functioning PETs were reported to have elevation of PP blood values [44]. The source of such sustained circulating PP may reside in either pure PP-omas, mixed tumors, or PP cell hyperplasia. The clinical usefulness of PP determinations in sporadic PETs has been confuted [31]. In contrast, much stronger evidence has been obtained for patients with MEN 1. After a standardized meal stimulation test PP was found to be the single, most sensitive marker able to substantiate the presence of PETs in 75% of MEN 1 patients by the age of 25 years when these neoplasms are almost invariably asymptomatic [44]. In another study a plasma PP increase three times higher than the normal age specific value showed 95% sensitivity and 88% specificity for PETs as revealed by positive imaging studies [42]. These results were reported to be further improved by combined determinations of PP and gastrin. Post-prandial PP values exceeding twice the upper reference limits coupled with doubling of gastrin levels appeared to yeld absolute specificity for the presence of PETs [44]. 2.6. PP-related peptides in pancreatic endocrine tumors NPY was found to be synthesized in PETs by both immunodetermination in tissue extracts [1] and immunohistochemistry [59]. So far, no evidence has been provided for PYY production in PETs.
2.5. Clinical implications of pancreatic PP cell tumors
3. Extra-pancreatic PP producing tumors
The actions of PP are mediated by theY4 receptor and are largely inhibitory on gastric emptying, upper intestinal motility, pancreatic exocrine secretion and hepatic glucose production [41]. For reasons still unexplained the clinical presentation of PP producing tumors is usually silent and not associated with recognizable tumor syndrome(s) and/or functional effects [21,40,44]. Therefore, these tumors are usually classified among non-functioning PETs [40,55] in spite of the fact that they are frequently associated with active, abnormally high secretion of PP [51,55] which may be modulated by physiological digestive stimuli [12,57]. As
Production of PP and/or related peptides has been documented in a considerable number of endocrine tumors located outside the pancreas. Most of these tumors are located in the gastrointestinal tract or in related organs such as the liver and biliary tract. However, PP tumor production was also found in the thyroid, lung and ovary In extrapancreatic tumors, as well, the most frequent finding is represented by the occurrence of PP producing cells as a minor component of a mixed type tumor cell population. However, some tumors appear to be composed predominantly or exclusively of PP-producing cells, a con-
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dition virtually restricted to carcinoid tumors arising in the rectum and in the liver-biliary system or, more rarely, in the duodenum. 3.1. Rectal carcinoid tumors In a study of 17 rectal endocrine tumors [19], 4 neoplasms showed preponderant, pure composition of PP-immunoreactive cells. Other five tumors showed a minor population of PP-immunoreactive cells, associated with prevailing glucagon and/or glicentin immunoreactive cells in four cases and serotonin immunoreactive cells in the remaining one. In another study, in which major and minor cell populations are not specified, PP-immunoreactive cells were found in 15 of 22 rectal carcinoids being associated with glicentin-immunoreactive cells in all cases [22]. A literature survey led Fiocca et al. to calculate that immunoreactivities for PP or PP-related peptides occurs in 62% of rectal carcinoids [22]. A detailed immunocytochemical study of rectal carcinoids and of the normal endocrine cells of the human rectal mucosa using a wide panel of antisera against various glucagon- and PP-related peptides revealed that the pattern of immunoreactivities in tumor cells is fully consistent with that of L rectal cells, an endocrine cell type known to express glicentin, PP and PYY [22]. However, the study showed that tumor cells produce more PP than PYY as compared to their normal counterpart. Moreover, while in the normal mucosa most cells were found to simultaneously contain glicentin, PYY and PP, in tumor cells the immunoreactivities for these three peptides tended to occur in separate cells. From the clinico-pathologic point of view PP-immunoreactive rectal carcinoids behave similarly to those producing other peptides. They usually are small polypoid lesions (Fig. 4 A and B), located in the submucosa and showing benign behavior. Only tumors with a diameter larger than 2 cm or showing angioinvasion have a malignant potential and may cause invasion of the bowel wall and metastases to lymph node and liver [18]. An interesting and still uneplained feature of rectal carcinoids, either PP producing or not, is represented by the lack of immunostaining for chromogranin A (Fig. 4 C), the almost universal neuroendocrine marker localized to the secretory granules of normal and neoplastic neuroendocrine cells. In this regard PP-producing cells of rectal carcinoids differ from those of pancreatic tumors, which show intense chromogranin A immunoreactivity [10]. This indicates a different composition of the cell secretory granules in the PP-producing tumors of the two organs. 3.2. PP-producing tumors of the liver and biliary tract In 1980 Warner et al. described a case of a large tumor apparently arising in the liver that proved by electron mi-
croscopy and immunohistochemistry to be a PP-producing neoplasm [60]. In 1992 Tanaka et al. reported a case of PP-producing carcinoid tumor of the gallbladder and found three additional cases in the Japanese literature [56]. All gallbladder tumors were characterized by polypoid configuration, small size (below 1 cm in diameter), typical histologic appearance and benign clinical behavior. Finally, in a recent study of 7 carcinoid tumors of the extrahepatic bile ducts Maitra et al. reported one pure PP-oma and another tumor with mixed composition of cells producing PP, gastrin and serotonin, respectively [37]. Although both tumors were larger than 2 cm in diameter they showed a benign behavior. Considering the rare occurrence of endocrine tumors in the liver and biliary tract, the number of cases producing PP significantly exceed casual distribution. PPproducing biliary tumors are strongly immunoreactive for chromogranin A [37]. 3.3. Other PP-producing tumors Medullary carcinoma of the thyroid (MCT) is a tumor composed of calcitonin-producing C cells that may occurr either in a sporadic form or as a component of hereditary syndrome encompassing the whole spectrum of manifestations of multiple endocrine neoplasia type 2 (MEN 2) [30]. In a series of MCTs PP production was convincingly demonstrated by combined immunocytochemistry, radioimmunoassay and high-performance liquid chromatography (HPLC) [45]. In contrast with the diffuse intratumor distribution of calcitonin, PP immunoreactivity was found to be localized to discrete areas. On Sephadex chromatography of tumor extracts the predominant form was found to correspond to human PP in size but larger forms were also identified. The absence of PP cells in the normal thyroid gland indicates ectopic tumor production. Interestingly enough, in this study PP production by MCT appeared to be restricted to tumors of familial (MEN 2) type, suggesting its use as a differentiating marker of MEN 2 versus sporadic forms of MCT. PP production by MCT was confirmed by Scopsi et al. [52] who found a higher tumor content of another member of the family of PP-folded peptides, NPY, particularly abundant in tumors with scarcely aggressive behavior. PP immunoreactivity was also detected in carcinoid tumors of the middle ear [3]. Its association with glicentin and PYY immunoreactivity, the different peptides being colocalized in tumor cell granules by immuno-electron microscopy, reflected the features of rectal carcinoids and suggested a condition of intestinal metaplasia as shown in tumors of nasal mucosa [3]. Among lung neuroendocrine tumors, PP immunoreactivity was found in 26% of typical carcinoids ranking third in frequency after ␣-hCG and serotonin in the study of Bonato et al. [5] investigating a large number of specific neuroendocrine products, a result in full agreement with previous data on smaller series of cases [61]. In contrast, no PP could
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Fig. 4. A. Low power micrograph of a polypoid rectal carcinoid removed by endoscopy. The tumor is entirely located in the submucosa (HE X8). B. Intense immunostaining of the tumor for human PP (X70). C. Negative chromogranin A immunoreactivity of tumor cells with positive control in cells of the overlying rectal mucosa (X70).
be demonstrated in well differentiated (atypical carcinoids) and poorly differentiated neuroendocrine carcinomas [5]. PP immunoreactive cells were also detected in carcinoids tumors of the stomach [15]. The gangliocytic paraganglioma is a peculiar benign tumor of the proximal small bowel, and especially of the duodenum, that has been described as a mixture of carcinoid, paraganglioma and ganglioneuroma. Indeed, it is composed of carcinoid-like nests of epithelial cells, mature ganglion cells and neuroid spindle cells. The latter can be regarded as Schwann cells whereas the ganglion cells were
found to be intensely immunostained for somatostatin and only weakly for PP. In contrast, the immunoreactivity for PP was strong and diffuse in the epithelial, carcinoid-like component whereas several other hormonal peptides showed only weak or focal immunoreactivity [48]. On the basis of the predominant PP cell composition of the tumor, it has been suggested an origin from the ventral, PP-rich primordium of the pancreas that has recruited nerves and ganglion cells during its migration to the final location on the posterior part of the pancreatic head [48]. Ovarian carcinoids were also found to include immuno-
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underlying tumor development in MEN 1 patients. According to the Knudson’s two hit theory, in this condition, the inherited affected gene carries a germline mutation whereas a somatic lesion, usually represented by a deletion (commonly referred to a loss of heterozygosity or LOH) of the remaining wild-type allele, completes the gene inactivation and initiates tumor growth [16]. LOH at 11q13, and less frequently, MEN 1 gene mutations, were commonly observed also in the sporadic counterparts of MEN 1 tumors including PETs [20,24]. Inactivation of MEN 1 gene, therefore, appears to be the main factors responsible for the development of PP-producing PETs (Fig. 5A). In contrast, the current evidence indicates no involvement of the MEN 1 gene in endocrine tumors of the gastrointestinal tract not associated with the MEN 1 syndrome such as midgut (ileal and appendicular) and hindgut (rectal) carcinoids (D’Adda et al., in press). Thus, development of PP-producing tumors of the rectum (Fig. 5B) appears to be governed by genetic mechanism(s) different from those operating in pancreatic PP-omas
Ackowledgements Fig. 5. Allelic losses for three microsatellite markers of the MEN 1 region at 11q13 in a PP-producing pancreatic tumors. In normal tissue the alleles for each marker are indicated by black arrows whereas a gray arrow denotes the allele lost in the tumor. B. No allelic losses can be demonstrated for the same 11q13 markers in a PP-producing rectal carcinoid.
This work is supported by grants from the Italian Association for Cancer Research (AIRC), Milan and the Italian Ministry for University and Scientific and Technological Research (MURST)
reactive PP cells that appeared to be the most common endocrine cell type in a large study [54]. These tumors may be associated with oversecretion and raised circulating levels of PP [2].
References
3.4. Functional implications of extrapancreatic PPproducing endocrine tumors As for their pancreatic counterparts no specific clinical symptoms ascribed to PP hypersecretion have been described so far in extrapancreatic PP-producing endocrine tumors. With regard to diarrhea, a frequent functional finding of MTC, the lack of correlation with the tumor content of PP was remarked [45]. A PP cell ovarian carcinoid producing PYY was associated with severe constipation that disappeared upon tumor removal [53], a potential effect of the inhibitory activity of the peptide [41]. Another patient with an intestinal L cell tumor and hypersecretion of PYY also presented constipation [17].
4. Mechanism of development of PP producing tumors It is generally accepted that inactivation of the MEN 1 oncosuppressor gene located at 11q13 is the basic event
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