THE AMERICAN JOURNAL OF SURGICAL PATHOLOGY
D. Wolters Kluwer
Aggressive Forms of Gastric Neuroendocrine Tumors in Multiple Endocrine Neoplasia Type I
Bordi Cesare M.D .; Falchetti, Alberto M.D .; Azzoni, Cinzia B.Sc.D .; D’Adda, Tiziana B.Sc.D .; Canavese, Gabriella M.D .; Guariglia, Achille M.D .; Santini, Donatella M.D .; Tomassetti, Paola M.D .; Brandi, Maria Luisa M.D.
The American Journal of Surgical PathologyAmerican Journal of Surgical Pathology. 21:p 1075-1082, September 1997.
Author Information
From the Institutes of Anatomic Pathology, Universities of Parma (C.B., C.A., T.D’A., G.C.) and Bologna (D.S.), Medical Clinics, Universities of Parma (A.G.) and Bologna (P.T.), and the Department of Clinical Physiopathology, Endocrine Unit, University of Florence (A.F., M.L.B.), Italy.
Address correspondence and reprint requests to Dr. C. Bordi, Istituto di Anatomia Patologica, Università di Parma, I-43100 Parma, Italy.
Abstract
In recent classifications of gastric endocrine tumors, tumors arising in patients with multiple endocrine neoplasia type 1 (MEN-1) are regarded to be regulated by the concomitant hypergastrinemia resulting from to pancreatic or, most commonly, duodenal gastrinomas and to have a benign behavior. In this article, we report on two cases of MEN-1 gastric neuroendocrine tumors having a fatal course. Case 1 was a young male with hyperparathyroidism and Zollinger-Ellison syndrome and with florid development of multiple gastric carcinoids and multiple duodenal gastrinomas. Metastases occurred in the liver, of exclusive gastric origin, in periduodenal lymph nodes, of exclusive duodenal origin, and in perigastric lymph nodes, of mixed origin. The patient died 48 months after diagnosis. Case 2 was an adult female patient with hyperparathyroidism, adrenocortical disorders, and gastric tumors but no hypergastrinemia. The patient died 3 months after tumor diagnosis. At autopsy, the stomach showed multiple benign carcinoids and two independent neuroendocrine carcinomas not reported before in MEN-1 and massively metastatizing to lymph nodes, liver, and peritoneum. Multiple islet cell tumors mostly producing pancreatic polypeptide were found, whereas
gastrinomas were seen in neither the pancreas nor the duodenum. Allelic losses at the MEN-1 gene locus in chromosome 11q13, the mechanism responsible for tumor development in MEN-1 syndrome, were demonstrated in the carcinoid tumors of case 1 and in the neuroendocrine carcinoma of case 2. We conclude that gastric neuroendocrine tumors in patients with MEN-1 may have a poor outcome, they have the same genetic mechanism as MEN-1 tumors in other organs, and they may be independent of the trophic effect of hypergastrinemia.
Carcinoid tumors of the stomach were identified as an integral part of the multiple endocrine neoplasia type 1 (MEN-1) syndrome in 1990 (29). The concept was subsequently validated by the demonstration in one of these neoplasms of allelic loss at the MEN-1 gene locus in the 11q13 region (12).
MEN-1 associated endocrine tumors of the stomach constitute the type II of recent classifications of gastric carcinoids (1,25,26), and are consistently associated with Zollinger-Ellison syndrome (ZES). In 1993, 23 acceptably documented cases of this condition were collected from either personal series or literature review (26), whereas 11 cases were brought together in a recent cumulative study from four reference centers (25). Based on an analysis of these cases, gastric endocrine tumors in patients with MEN-1 are currently regarded as having a benign and not life-threatening course for which a conservative approach and endoscopic surveillance are recommended (25,26).
Against this background, we believe it important to report here two cases of gastric neuroendocrine tumors in patients with MEN-1 that had an aggressive course and a fatal outcome. One of these cases was not associated with either hypergastrinemia or ZES. Allelic loss at the MEN-1 gene locus was documented in the gastric neoplasms of both patients.
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CASE REPORTS
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Case 1
A male patient with a strong familial history of MEN-1, born in March 1964, presented in September 1986 with typical hypoglycemic symptoms that were cured by distal pancreatectomy, including removal of three large islet cell tumors, at another institution. Soon thereafter, the patient developed ZES, with serum gastrin levels ranging from 800 to 20,000 pmol/L (normal values, 10-40 pmol/L), and a positive secretin test. A
bleeding duodenal ulcer was cured with omeprazole. In November 1989, the patient experienced complicated hyperparathy-roidism with marked elevation of blood calcium (consistently above 18 mg/dL) and parathyroid hormone levels, vomitus, dehydration, and acute renal failure. After echographic localization, an adenomatous inferior right parathyroid gland weighing 18.8 g and composed of chief cells was removed surgically. In the postoperative period, high circulating levels of prolactin hormone (72-83 ng/ml; normal values, <15 ng/ml) and moderate enlargement of the sella turcica on radiographic examination were found. Moreover, endoscopy revealed multiple gastric carcinoids and duodenal gastrinomas that were histologically and immunohistochemically confirmed. In December 1992, abdominal computed tomographic scan, selective celiac angiography, and scintiscan with 111indium-labeled octreotide distinctly showed two endocrine tumor metastases in the VII and VIII hepatic segments, whereas endoscopy revealed marked enlargement of gastric and duodenal tumors. On these bases, total gastrectomy with excision of the first duodenal segment and resection of the liver metastases were performed. The patient died in November, 1993 with persistent disease. No autopsy was performed. This case was included in the series of Rindi et al. (25).
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Case 2
A female patient born in August 1936, who had previously undergone left and right inferior parathyroidectomy for parathyroid adenomas, was admitted for evaluation of hypertension and severe hypokalemia (2.2 mmol/L) in December 1995. Her brother was previously reported to have multiple islet cell tumors secreting pancreatic polypeptide (8), and, likely, insulin and glucagon (Z), duodenal ulcer, and no hypergastrinemia. Laboratory tests excluded a primary form of aldosteronism (aldosterone: 77 µg/dL; normal values, 10-160 µg/dL; and plasma renin activity: 6.7 ng/ml/h; normal values, 0.51-2.6 ng/ml/h) but documented a complex derangement of the adrenocortical axis with high blood levels of cortisol (range, 58-92 µg/ml; normal values, <25 µg/mL) associated with loss of the circadian rhythm and not modified by high doses of dexamethasone. Blood levels of other adrenocorticotropic hormone (ACTH)-related hormones were also high (DHEA-S: 576 µg/dL; normal values, <390 µg/dL,) and androstenedione (5.81 ng/ml; normal values, <3.3 ng/ml), as were urinary levels of cortisol (>800 µg/mL; normal values, <90 µg/mL). In contrast, blood levels of ACTH were within normal range. A detailed discussion of the clinical and functional data of this case will be reported elsewhere (A.G., in preparation). Serum levels of parathyroid hormone were still elevated (206 ng/ml), whereas serum gastrin was within the normal range on repeated examinations. Multiple large liver metastases were
documented by computed tomographic scan, which was prompted by the finding of massive liver enlargement. A large, ulcerating tumor of the gastric body was demonstrated at endoscopy and was revealed to be a neuroendocrine carcinoma by histology and immunohistochemistry. The patient’s condition rapidly deteriorated, leading to her death in February, 1996. At autopsy, multiple gastric tumors (described in detail later) were found, with massive metastases in perigastric, periduodenal, and periaortic lymph nodes, as well as in the liver and in the peritoneum of the retrouterine space. No tumors were found in the duodenum, but four nodules measuring 0.8 to 1.3 cm in diameter were found in all regions of the pancreatic gland. The superior right parathyroid gland showed an adenoma measuring 1.2 cm in diameter. The pituitary gland measured 1.1 × 1 × 1 cm without apparent microadenoma. The adrenal glands were of the same size, measuring 2.2 x 1.5 x 1.2 cm. Micronodular hyperplasia of compact type cells was detected histologically.
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MATERIALS AND METHODS
Tissues obtained at surgery (case 1) or at autopsy performed 3 hours after death (case 2) were fixed in buffered formalin and (case 2) Bouin fluid and were embedded in paraffin. Sections 5 um thick were stained with hematoxylin and eosin and were immunostained for chromogranin A (CgA), gastrin, glucagon, insulin, somatostatin, pancreatic polypeptide, serotonin, a-subunit of human chorionic gonadotropin (hCG-a), ACTH, and basic fibroblast growth factor (bFGF), as detailed elsewhere (6,2). Electron microscopy was performed on tumor specimens of primary gastric carcinoids and their liver metastases and of duodenal gastrinomas in case 1 and of gastric neuroendocrine carcinomas and their liver metastases in case 2, as previously detailed (5) ..
For DNA analysis, tumor tissue samples were obtained from one of the gastric carcinoids (case 1) and from the neuroendocrine carcinoma (case 2) and were immediately frozen in liquid nitrogen. DNA was extracted according to standard methods (27). Both restriction fragment length polymorphisms (RFLPs) and microsatellite-polymerase chain reaction (PCR)-based analyses were performed. Five micrograms of DNA was digested with appropriate restriction enzyme (Taq 1) and analyzed for the following RFLPs that map close to the MEN-1 gene: D11S97/pMS51, D11S146/pHBI59, INT 2/pSS6 (all probes were purchased from American Type Culture Collection, Rockville, MD). For microsatellite-PCR analysis, approximately 50 ng of extracted DNA was PCR amplified using oligonucleotides flanking the following highly polymorphic DNA markers of chromosome 11: D11S956, D11S480, PYGM (all from the 11q12-13 region), D11S554 (from the 11p11 region), and D11S533 (from the
11q13.5 region) (American Type Culture Collection). Experimental conditions were conducted according to the original reports (19,21,23,24). A given polymorphic marker was considered informative when constitutive DNA exhibited two distinct alleles. Loss of heterozygosity was represented by a complete absence of an allele or by reduced intensity of an allele (more than 50%, resulting from contaminating normal tissue components), when compared with the intensity of the other allele from the same tumor in the Southern blotting technique. In both cases, constitutive DNA, obtained from peripheral blood (case 1) or from tumor-free muscle tissue (case 2), was informative for at least one locus.
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RESULTS
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Case 1
On gross examination, the stomach contained a fungating mass measuring 16 x 4.5 cm and located in the region of the incisura angularis. On transection, the mass was composed of ill-defined nodular structures located in the mucosa and submucosa but with no apparent invasion of the muscular wall. The remaining fundic mucosa was characterized by hypertrophic mucosal folds with scattered polypoid lesions ranging in size from 0.5 and 1.5 cm and progressively decreased toward the proximal part of the stomach. In addition, several smaller polyps measuring up to 0.8 cm were present in the antral mucosa. The duodenum showed several nodular tumors with a diameter up to 1 cm located in the mucosa and submucosa. Numerous lymph nodes containing metastases were present along the greater and lesser gastric curvature and in the periduodenal area. The liver specimen presented a multinodular, confluent tumor measuring 3 cm in its major axis.
By histologic examination, all neoplasms were found to be typical carcinoid tumors that frequently invaded the submucosa but did not infiltrate the muscularis propria. Their features partially differed in the various regions of the stomach. In the fundus and body, the carcinoids were small, with uniform solid or solid-trabecular structure. The extratumoral mucosa showed the whole spectrum of hyperplastic and dysplastic lesions of endocrine cells (28), as well as a predominance of parietal cells with the typical features of ZES (17). The highest degree of tumor development was found in the transitional zone between body and antrum. The apparently single fungating tumor was actually composed of multiple nodular carcinoids often fusing with the contiguous
tumors or leaving only narrow rims of nontumoral mucosa in between (Fig. 1). Their histologic arrangement was markedly heterogeneous, not only from one tumor to the next, but also within the same tumor, and included solid, trabecular, ribbonlike, glandular, and spindle cell patterns (see Fig. 1). The antral mucosa was characterized by small intramucosal carcinoids composed of small cells arranged in a trabecular or glandular structure. One small carcinoid was located in the cardial mucosa and extended below the adjacent squamous esophageal epithelium.
Immunohistochemically, all carcinoids showed CgA immunoreactivity, frequent and often intense expression of hCG-a, and serotonin staining of occasional, discrete cells. Gastrin immunostaining showed diffuse reactivity in two small intramucosal antral tumors associated with severe hyperplasia of antral G cells. In contrast, larger tumors
were virtually unreactive, except for occasional, isolated cells in a few of them. Negative results were obtained for all other hormones tested. The expression of bFGF was strong in preneoplastic lesions of fundic endocrine cells and heterogeneous in carcinoid tumors. DNA analysis of carcinoid tumor tissue revealed allelic losses at D11S97 and D11S146 loci but not at the PYGM locus (Eigs. 2 and 3).
| Case 1 | Case 2 | ||
|---|---|---|---|
| T C | T | C | |
| D11S554 P | |||
| q | |||
| D11S956 | |||
| D11S480 | |||
| PYGM | |||
| D11S97 | |||
| D11S146 | |||
| INT 2 | |||
| D11S533 | |||
T C
a
>
TC
>
D11S97
D11S146
b
TC
TC
>
>
D11S480 PYGM
Representative microsatellite-polymerase chain reaction analysis in cases 1 (A) and 2 (B). Analyzed loci (case 1, D11897 and D11S146; case 2, D11S480 and PYGM) are reported below each autoradiogram. Arrows indicate allelic loss in tumor DNA (lane T) in comparison with constitutive DNA (lane C).
The duodenal tumors exhibited a typical pattern characterized by a uniform, ribbonlike arrangement and strong, polarized gastrin immunostaining in virtually all tumor cells.
This diagnostic pattern was observed in all periduodenal nodal metastases and, surprisingly, in several metastatic foci found in perigastric lymph nodes of the lesser curvature (Fig. 4), together with tumor clusters fully consistent with a gastric origin in the same lymph node or in contiguous nodes. The immunohistochemical and ultrastructural features of metastatic tumor tissue in the liver indicated an exclusive origin from gastric carcinoids.
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Case 2
On gross examination (Fig. 5), two large, ulcerated tumors were found in the midbody of the stomach, one in the anterior wall close to the greater curvature and the other in the posterior wall close to the lesser curvature. They measured 4.5 and 5.5 cm in diameter, respectively. Both neoplasms extensively infiltrated the gastric wall up to the serosa. Their borders sometimes showed illdefined nodular growths. In addition, numerous polypoid tumors ranging from 0.5 to 1.5 cm in diameter were found scattered throughout the body and fundic mucosa but not in the antrum. They often extended to the submucosa but did not infiltrate the muscular wall.
D
M
M
E
Histologically, the two biggest tumors were composed of large, solid nests of round or slightly elongated cells of intermediate size and poorly formed trabeculae, sometimes showing structures resembling rosettes (Fig. 6A). Mitotic figures were well represented, and necrosis was commonly seen in central areas of tumor cell aggregates. These findings are fully consistent with gastric neuroendocrine carcinoma (26), in particular of the intermediate type according to Staren et al. (31). The nodular growths at the tumor borders, although maintaining frankly atypical characteristics, revealed a more regular trabecular arrangement and a more strongly differentiated cell appearance. The remaining gastric tumors consistently showed features of well-differentiated carcinoid tumors with a trabecular, ribbonlike pattern (see Fig. 6B). Tumor cells had abundant cytoplasm with frequent oxyphil appearance. Mitotic figures and necrosis were consistently absent. The extratumoral oxyntic mucosa was unremarkable. Metastatic tissue in the lymph nodes and liver reproduced the features of an intermediate-type neuroendocrine carcinoma. No tumors were found in the antral or duodenal mucosa. Pancreatic macronodules were represented by typical islet cell adenomas with predominant ribbon-type arrangement. They were associated with numerous, additional islet cell microadenomas.
B
A
C
By immunohistochemistry, the neuroendocrine carcinomas and their metastases revealed an irregular distribution of CgA immunoreactivity with areas diffusely immunostained intermingled with areas totally unreactive or with discrete, sparse positive cells (Fig. 6C). A variable and often conspicuous number of tumor cells expressed hCG-a, whereas rare cells showed immunoreactivity for serotonin or somatostatin. No positive results were found for all other hormones tested. Gastric carcinoids showed heterogeneous immunostaining for CgA that was inversely related to the extent of oxyphil change. Numerous discrete cells in most tumors expressed hCG-a, whereas discrete cells were immunoreactive for ACTH and bFGF. In the extratumoral oxyntic mucosa, CgA immunostaining showed mild, simple hyperplasia of endocrine cells, whereas more severe degrees of endocrine hyperplasia or dysplasia were consistently absent. A few endocrine cells were immunoreactive for hCG-a and bFGF.
Most islet cell adenomas were immunoreactive for pancreatic polypeptide that was expressed by 80% to 100% of tumor cells in six of 12 neoplasms, including all
macroadenomas, and by 10% to 30% of tumor cells in an additional four adenomas. Glucagon was expressed in 10 tumors, with 80% to 100%, 50%, and 10% to 30% of positive cells in three, two, and five adenomas, respectively. A few insulin- immunoreactive cells were found in four adenomas, whereas somatostatin and gastrin cells were not observed.
Ultrastructurally, cells of the neuroendocrine carcinomas showed an abundance of rough endoplasmic reticulum, often arranged in parallel stacks or in annulate lamellae, and enlarged Golgi structures. Neurosecretory granules varied in number among different cells and were characterized by a small, dense and eccentric core, a less dense halo and a wavy limiting membrane. Although these granules did not reflect characteristic features of known gastric endocrine cells, they were tentatively interpreted as atypical forms of enterochromaffin-like cell granules. DNA analysis of tumor tissue from the gastric neuroendocrine carcinoma exhibited allelic losses at D11S554, D11S480, PYGM, and D11S533 loci (see Figs. 2 and 3).
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DISCUSSION
In this article, we report on two cases of aggressive, metastatizing neuroendocrine tumors of the stomach associated with MEN-1 syndrome, both leading to the patient’s death 48 and 3 months after diagnosis, respectively. This poor outcome is in sharp contrast to the benign course of gastric endocrine neoplasms so far reported in patients with MEN-1 (25,26). In a study of 27 gastric carcinoids associated with ZES syndrome from either a personal series or a literature survey, 23 of which presented definite evidence of MEN-1 status, Rindi et al. found lymph node metastases in only three cases (12%) and carcinoid-related deaths in none (26). A more recent investigation of 12 cases revealed that tumor invasion beyond the submucosa was absent in all but one of 11 cases assessed, whereas lymph node metastases were present in three of 10 cases assessed, one of which, the present case 1, also had liver metastases and died of tumor disease. Our results, in contrast, demonstrate that in some patients these tumors may have a high malignant potential and may include neuroendocrine carcinoma, a form with a poor prognosis (25,31), as testified by our case 2. In this regard, the present gastric neoplasms may be included among the most malignant endocrine tumors ever reported to occur in MEN-1 syndrome.
In accordance with the usual finding in MEN-1 tumors of the stomach, the neoplasms were multiple in both patients. However, other pathologic characteristics substantially differed between the two cases. In case 1, all tumors were histologically consistent with classical carcinoid tumors of the stomach, although their histologic structure was
heterogeneous and covered the whole spectrum of patterns known to occur in gastric carcinoids. The tumors could be found in every gastric region from the cardia to the antrum. However, the highest degree of tumor development was found in the transitional region between the oxyntic and antral mucosa, in which the neoplastic proliferation was so florid as to give the impression of a single, large, fungating tumor on gross examination. That the transitional zone is the site of more intense gastric endocrine cell proliferation, either hyperplastic or neoplastic, is a common finding in patients with hypergastrinemic conditions (30 and personal unpublished observations). Case 2 was characterized by two different types of neuroendocrine tumor, both confined to the body-fundus region. The first type, represented by the two largest tumors, was an intermediate cell neuroendocrine carcinoma responsible for extensive infiltration of the gastric wall and massive metastatic spread to lymph nodes and liver. The second type, represented by the remaining tumors, consisted of multiple carcinoid tumors showing a uniform histologic appearance with a regular trabecular arrangement and a predominant oxyphil change of tumor cells. These carcinoids did not infiltrate beyond the submucosa and were not involved in metastatic growths. The relation between the two types of neuroendocrine tumors could not be defined with certainty. Owing to the occurrence of more strongly differentiated nodular structures at the periphery of neuroendocrine carcinomas, however, the possibility of an origin of these tumors from the differentiated carcinoids cannot be excluded.
In case 1, the gastric carcinoid tumors were associated with malignant duodenal gastrinomas. The latter showed diagnostic histologic features represented by a regular trabecular-ribbon-type pattern and consistent polarized gastrin immunostaining of tumor cells. Using this histologic marker, the exclusive derivation of duodenal lymph node metastases from the duodenal gastrinoma, and of the liver metastases from the gastric carcinoids, was demonstrated easily. In contrast, metastases in the perigastric lymph nodes were found to be partly of gastric and partly of duodenal origin. The potential of duodenal gastrinomas to metastatize to perigastric lymph nodes therefore must be considered before attributing these metastases to concomitant gastric tumors. Moreover, in this case, local and distant metastases of gastric carcinoids occurred in the absence of tumor infiltration of the muscularis propria, indicating a metastatic ability of these tumors similar to that of ordinary nonendocrine gastric carcinoma in the stage of early gastric cancer.
Loss of alleles (loss of heterozygosity, LOH) at the MEN-1 gene locus in 11q13 is the mechanism reputed to be responsible for the development of common neoplasms of MEN-1 syndrome, including islet cell (18), parathyroid (14), and pituitary tumors (11), as well as of MEN-1-associated multiple lipomas (22). Affected members of kindreds with the MEN-1 syndrome, in fact, have inherited the germline genetic defect in the MEN-1 gene. In these patients, somatic inactivation of the remaining allele by LOH
presumably is the causative event for tumor development. LOH was found in gastric endocrine tumors of both our patients, including the neuroendocrine carcinomas of case 2. These results confirm the observation in the single case of MEN-1 gastric carcinoids (12), and reveal that the pathogenesis of these tumors is identical to that of the other endocrine tumors that typify the syndrome. To our knowledge, this is the first demonstration that neuroendocrine carcinomas may have the same pathogenetic mechanism found in the more strongly differentiated MEN-1 endocrine tumors. The extent of LOH in chromosome 11 was far greater in the poorly differentiated neuroendocrine carcinoma of case 2 than in the more strongly differentiated carcinoids of case 1. In contrast, allelic loss at the MEN-1 gene locus was not found in a pancreatic ductal adenocarcinoma of a previously reported MEN-1 case (5), a finding suggesting a different pathogenetic mechanism for malignant nonendocrine tumors incidentally occurring in patients with MEN-1.
In case 1, both mechanisms reputed to be involved in gastric carcinoidogenesis of patients with MEN-1, that is, the loss of the MEN-1 gene and the trophic stimulus of severe hypergastrinemia, appeared to be operating (3,29). Endocrine hyperplasia and dysplasia, the carcinoid precursor lesions always present in patients with MEN-1-ZES (25), were apparent in this case. In contrast, our patient 2 did not have hypergastrinemia or gastrin-producing tumors, and this is the first reported case of gastric carcinoids occurring in a patient with MEN-1 who was not affected by ZES. This observation has important implications for our understanding of the mechanism of gastric endocrine tumorigenesis indicating that the genetic defect per se may be an adequate stimulus. In agreement with this interpretation is the finding of hyperplasia of fundic endocrine cells not evolved into carcinoid tumors in occasional patients with nonhypergastrinemic MEN-1 (2,4). Such hyperplasia, however, was negligible in the present case. In addition, the first example of a highly malignant neuroendocrine gastric carcinoma associated with MEN-1 syndrome developed in a patient not affected by hypergastrinemia. The latter condition, in fact, tends to be associated with gastric endocrine tumors of low or no malignant potential (3,15,20,26).
In both cases, the carcinoid tumors (but not the neuroendocrine carcinomas of case 2) expressed bFGF. This finding is relevant in view of the observation that patients with MEN-1 syndrome consistently have abnormally high circulating levels of a mitogenic bFGF-like substance involved in parathyroid proliferation (10,32). In case 1, the strongest expression of this substance was observed in preneoplastic and dysplastic endocrine cell lesions. In our personal experience (6), this was the most impressive example of bFGF expression ever seen in endocrine cells of the oxyntic mucosa. Whether such extensive bFGF production has some relevance with the unusually florid evolution of parathyroid adenomas and of gastric and duodenal endocrine tumors seen in our patient must be evaluated in additional cases.
In the present cases, gastric neuroendocrine tumors, including the neuroendocrine carcinomas of case 2, showed significant immunoreactivity for hCG-a, a finding also observed in a previous case of MEN-1-associated gastric carcinoids (13). The a- subunit has been widely expressed by all types of endocrine tumors occurring in the MEN-1 syndrome, including those of the pituitary, parathyroid, pancreas, duodenum, stomach, and lung, either associated with MEN-1 or in the sporadic form (11). The functional and clinical significance of this expression has not been clarified fully, but it appears to differ from one location to another. In pancreatic endocrine tumors, in fact, this expression has been found to be a marker of malignancy (16).
In gastric endocrine cells, in contrast, hCG-a is more extensively expressed in precursor lesions than in established carcinoid tumors (3), a finding suggesting its involvement in tumor induction rather than in tumor progression. Moreover, its expression closely depends on the concomitant circulating levels of gastrin, and it is virtually restricted to hypergastrinemic conditions (3). Therefore, the present results, with the unusually extensive hCG-a immunoreactivity of gastric carcinoids in case 1 and the lack of coexistent hypergastrinemia in case 2, are at variance with the usual features of gastric carcinoids and suggest an independent role of MEN-1 in the hCG-a expression by gastric neuroendocrine tumors, possibly associated with unfavorable tumor evolution similar to that found in pancreatic endocrine tumors (16).
In conclusion, we have documented that neuroendocrine tumors arising in the stomach of patients with MEN-1 may have a poor prognosis, that they have the same genetic mechanism of MEN-1 tumors in other organs, and that they may be independent of the trophic effect of hypergastrinemia.
Acknowledgments: This work is supported by grants from the Italian Association for Cancer Research (AIRC), Milan, the Italian National Research Council (CNR), Target Project “Clinical Application of Oncologic Research,” and the Italian Ministry for University and Scientific and Technological Research (MURST).
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Keywords:
Multiple endocrine neoplasia type 1; Stomach; Endocrine tumors; Hypergastrinemia; MEN-1 gene
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