Relationship between pernicious anaemia and gastric neuroendocrine cell disorders

The Netherlands Journal of Medicine 2000;56:56–62

Review

Relationship between pernicious anaemia and gastric neuroendocrine cell disorders A.M.E. Spoelstra-de Man a , *, Sj. Sc. Wagenaar b , A. van der Sluys Veer c , C.B. Brouwer a a

Department of Internal Medicine, Onze Lieve Vrouwe Gasthuis, 1 e Oosterparkstraat 279, Postbus 95500, 1090 HM Amsterdam, The Netherlands b Department of Pathology, Onze Lieve Vrouwe Gasthuis, 1 e Oosterparkstraat 279, Postbus 95500, 1090 HM Amsterdam, The Netherlands c Department of Gastroenterology, Onze Lieve Vrouwe Gasthuis, 1 e Oosterparkstraat 279, Postbus 95500, 1090 HM Amsterdam, The Netherlands Received 20 April 1999; received in revised form 20 October 1999; accepted 26 October 1999

Abstract The incidence of gastric carcinoid tumours is increasing. This rise is probably due to the number of gastroscopies and improved histological techniques. The majority (65%) of these gastric tumours is associated with chronic atrophic gastritis and pernicious anaemia. In this article two patients are presented, one with pernicious anaemia and gastric neuroendocrine cell hyperplasia and one with pernicious anaemia and multiple gastric carcinoids. These neuroendocrine cell disorders have a relatively favourable prognosis. Therefore, a wait-and-see policy was preferred. The pathogenesis, clinical symptoms, diagnosis, prognosis and treatment of these different neuroendocrine cell manifestations are discussed. We recommend performing a gastroscopy at the time of diagnosis for young patients with pernicious anaemia, and whenever abdominal problems, unexplained weight loss or aggravation of the anaemia arise.  2000 Elsevier Science B.V. All rights reserved. Keywords: Gastric carcinoid; Atrophic gastritis; Hypergastrinemia

Introduction Askanszy was the first to describe a gastric carcinoid in 1923. Ten years later Raidford attempted to treat gastric carcinoid by gastrectomy. Unfortunately the patient died postoperatively. In 1935 Pettinari performed the first successful operation and *Corresponding author. Tel.: 1 31-20-599-3503; fax: 1 31-20599-3523.

2 years later Walley performed the first endoscopic resection [1].

Patient A A 77-year-old man was admitted to our hospital in January 1998 because of dizziness and severe anaemia. Within 2 months his haemoglobin con-

0300-2977 / 00 / $ – see front matter  2000 Elsevier Science B.V. All rights reserved. PII: S0300-2977( 99 )00117-5

A.M.E. Spoelstra-de Man et al. / Gastric carcinoid Table 1 Laboratory results of patients A and B Laboratory results

Case 1

Case 2

BSE (2–6 mm / h) Hb (8.5–10.7 mmol / l) Ht (0.41–0.50 l / l) MCV (84.0–104.0 fl) MCH (1720–2200 amol) Reticulocytes (5–208 / oo ) Leukocytes (4.0–10.0 ? 10 9 / l) Vitamin B12 (148–443 pmol / l) Folate (6.8–39.0 nmol / l) Gastrin (40–200 ng / l) Antibodies intrinsic factor Antibodies parietal cells

40 3.8 0.17 116.3 2585 2 3.8 , 30 8.3 800 Positive Positive

26 6.6 0.31 116.5 2481 11 8.1 93 9.6 1050 Positive Dubious

centration decreased from 5.8 to 3.6 mmol / l. He had a history of diabetes mellitus type II and he had undergone a total hip arthroplasty in 1989. He complained of weakness and fatigue without pain, melaena, haematemesis or weight loss. Significant physical findings were pallor and a laparotomy scar of unknown origin. Laboratory results are shown in Table 1. During gastroscopy a few small sessile polyps located in the corpus and the fundus were found and biopsied. Histologic examination of the polyps revealed neuroendocrine cell hyperplasia with chronic atrophic gastritis and intestinal metaplasia of

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the nonpolypic mucosa (Fig. 1B). The clinical condition improved after blood transfusions and vitamin B12 injections.

Patient B An 88-year-old man with a history of supraventricular tachycardia was admitted to our hospital because of anaemia and severe weight loss. Laboratory investigation for his yearly cardiological check up revealed a haemoglobin concentration of 6.2 mmol / l. He suffered from fatigue and dizziness and he had lost 13 kg of weight in 6 months. He had no history of pain, haematemesis or melaena. Physical examination showed only pallor. Laboratory results are shown in Table 1. Because of anorexia and weight loss a gastroscopy was performed which showed an atrophic mucosa in the corpus and fundus of the stomach with five polyps of about 5 mm in diameter. Histologic examination of the gastric biopsy samples showed a chronic atrophic mucosa with focal intestinal metaplasia. Specimens from the polyps were consistent with the diagnosis gastric carcinoid. Chromogranin was detected in the proliferated neuroendocrine cells (Fig. 1C). Octreotide scintigraphy showed no metastases. After starting

Fig. 1. (A) Normal gastric mucosa; → 5 chromogranin stained neuroendocrine cells. (B) Biopsy of patient A; → 5 hyperplasia of ECL cells. (C) Biopsy of patient B; gastric carcinoid; → 5 invasion of ECL cells through muscularis mucosae. The Netherlands Journal of Medicine 2000;56:56 – 62

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vitamin B12 the haemoglobin concentration increased to 8.9 mmol / l. His clinical condition improved. Because of his age, his cardial condition and the size of the tumours a surgical intervention was postponed. Twenty years ago, gastric carcinoids accounted for about 2% of all carcinoids [2]. According to recent series, however, gastric carcinoids are believed to be among the most common types of carcinoid tumours, with incidences ranging from 10 up to even 41% [3,4]. The apparent increase of the incidence may be due to the widespread use of gastroscopy, application of immunohistological techniques and awareness of the association between hypergastrinemia and enterochromaffinlike (ECL) cell hyperplasia [3,4]. From 1990 to 1997, 207 patients with primary gastric carcinoid were registered at PALGA in the Netherlands (Table 2). In the Netherlands women more often develop gastric carcinoid than men and the peak incidence is reached between 60 and 80 years. Carcinoid tumours originate from neuroendocrine cells, usually the enterochromaffin (EC) or Kulchitski cells, of the tractus digestivus. However, in the Table 2 Age and sex distribution of patients with gastric carcinoid registered at PALGA (1990–1997) Age 0–19 20–29 30–39 40–49 50–59 60–69 70–79 80 1 Total

Women (%) 0 0 4 10 20 48 34 19

(0) (0) (3) (7) (15) (36) (25) (14)

135 (100)

Men (%) 0 3 2 11 10 20 21 5

(0) (4) (3) (15) (14) (28) (29) (7)

72 (100)

stomach another neuroendocrine cell, the histaminesecreting ECL cell, is the cell of origin for carcinoid tumour. Although the ECL cells have the same morphological characteristics as the EC cells, the EC cells secrete serotonin and the ECL cells histamine [5]. Gastric carcinoid tumours can be divided into three different groups. Type I Type I is associated with chronic atrophic autoimmune-mediated gastritis, mostly in combination with pernicious anaemia. It includes 65% of all gastric carcinoids. Patients with autoimmune gastritis have circulating auto-antibodies to the oxyntic cells of the gastric mucosa. The inflammatory process leads to loss of almost all oxyntic mucosal cells, resulting in less intrinsic factor, decreased vitamin B12 absorption, and finally to pernicious anaemia. Destruction of the epithelial structures is accompanied by disappearance of the acid-producing parietal cells, which can no longer be stimulated by histamine. The pH of the stomach will increase and there will be no negative feedback to the G- (gastrinproducing) cells in the antrum, which are not involved in the process of destruction. The G-cells continue their production and secretion of gastrin, leading to a chronically elevated gastrin level, which is often more than 1000 ng / l. Initially, the ECL-cells are only stimulated to secrete histamine [6]. This trophic stimulus of gastrin is the physiologic inducer of tumor genesis in type I gastric carcinoid [6] and results in 30% of the patients with pernicious anaemia in hyperplasia of the ECL cells, in 6% in dysplasia, and 5–8% in carcinoid (Table 3). These three phases can coexist in the stomach and are classified according to Solcia et al. [7,8]. This frequently used classification asks for a few

Table 3 Classification proliferation ECL cell [7] Hyperplasia

Dysplasia

Neoplasia

, 150 mm . 2 3 Normal number cells Linear Micronodular Adenomatoid

150–500 mm Enlarged micronodules Fused micronodules Microinvasive lesions Nodules with newly formed stroma

. 500 mm Intramucosal tumour Invasive tumour

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comments. To date dysplasia is defined as a gradation of a neoplastic process and malignancy is defined by (micro) invasion of dysplastic epithelium through the basement membrane. In this classification neoplasia is considered as malignancy, which is incorrect. Moreover, the gross is not a criterion of malignancy. Malignancy, including typing and grading, is a microscopic diagnosis. Endoscopically the often multifocal carcinoid tumours are mostly located in the corpus and fundus of the stomach and measure less than 1 cm in diameter [9,10]. Most carcinoids occur in patients known with pernicious anaemia. The interval between the initial diagnosis of pernicious anaemia and the establishment of gastric carcinoid varies from 1 to 18 years.

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Type III Type III is the ‘sporadic’ carcinoid [3]. Twenty percent of all gastric carcinoids belong to this group. These tumours consist of ECL, EC or X cells. The tumour cells are immunoreactive with neuronspecific enolase, chromogranin and synaptophysin [13]. They originate without any underlying previous gastric pathology or genetic predisposition and are likely a sporadic transformation. These carcinoids appear to be more related to neuroendocrine carcinomas than type I and II carcinoids. In contrast to type I and II carcinoids sporadic carcinoids are solitary, relatively large tumours, mostly . 2 cm in diameter at the time of diagnosis. They are located prepyloric and incline towards invasion and metastases.

Type II Symptoms Type II, is associated with the Zollinger-Ellison Syndrome (ZES) in combination with the MEN-I syndrome. Only two cases of gastric carcinoid in combination with sporadic ZES have been described in the literature [11]. Fifteen percent of all gastric carcinoids belong to this type. The gastrinoma causes hypergastrinemia, which leads to hypertrophy of chief-, parietal and ECL-cells [12]. Like patients with type I gastric carcinoid, patients with MENZES can develop, hyperplasia, dysplasia and eventually malignancy [7]. These patients have lost heterozygosity near the MEN-1 locus on chromosome 11q13. No association has been found between carcinoids and MEN without ZES, which pleads for the necessity of hypergastrinemia for the expansion of genetically transformed ECL cells, resulting in carcinoid [7]. It should be noted that with type I and II gastric carcinoid tumours, both associated with hypergastrinemia, hypergastrinemia per se only causes ECL proliferation, and no carcinoid tumour. Another ‘trigger’ is necessary to induce malignancy. This trigger is the mucosal factor in type I patients and the genetic factor in type II patients [1]. In studies in rats, especially the Mastomys, proton pump inhibitors lead to hypergastrinemia, with hyperplasia, and also to dysplasia. However proton pump inhibitors in human beings cause only hyperplasia [13].

The symptoms in patients with any gastric carcinoid are: epigastric pain (12–80%), vomiting (13– 19%), haematemesis (24%), diarrhoea (12%), weight loss (21%) melaena (13–31%) [14]. Of all the patients, 0.5–10% suffer from the carcinoid syndrome, in particular patients with type III gastric carcinoid. The gastric carcinoid syndrome is atypical, histamine- and tachykinin-related, and manifests itself in flushing, suffusion of eyes, headache, facial oedema and brochoconstriction. Thirty percent of the patients show no symptoms, mostly patients with type I.

Diagnosis The gold standard for diagnosis is gastroscopy with biopsy. On histologic examination all the gastric carcinoids have a positive immunoreaction with the neuroendocrine markers synaptophysin and chromogranin A. Chromogranin is a capsular protein of the neurosecretory granulae, which is typical for the neuroendocrine nature of the cell. The majority (60–80%) of gastric carcinoids stain with the cytosolic marker neuron-specific enolase [15]. Immunohistochemical investigations of specific hormones, although sometimes helpful, are not conclusive in the differentiation between the three

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subtypes of gastric carcinoids. Rindi et al. [16] studied 55 gastric neuroendocrine tumours of which 45 were carcinoids. Hormones known to be produced by gastric endocrine cells like gastrin, somatostatin, serotonin, and pancreatic polypeptide, were detected in only a minority of tumour cells (1–5%) in , 40% of cases (8–39%). Serotonin, normally found in enterochromaffin cells and in a few secretory granules of ECL cells, was expressed slightly more often in sporadic cases (type I and II: 1%; type III: 5%). One tumour in these series was composed largely of gastrin-immunoreactive cells and was diagnosed as a solitary gastrinoma not associated with MEN-ZES. Theoretically, gastric tumors could be metastases of the primary gastrinoma in MENZES. Although Rindi et al. [16] diagnosed seven cases of type II gastric carcinoids they did not detect gastric metastases of the gastrinomas. Hormonal abnormalities can also raise suspicion of gastric carcinoid. Carcinoids are APUDomas, i.e. amino precursor uptake and decarboxylation cells. In

carcinoids which are not located in the stomach but for example in the small intestines tryptophan is converted into 5-HTP by tryptophanhydroxylase. LAminoacid decarboxylase converts 5-HTP into serotonin. Serotonin is excreted in the urine as 5HIAA [17]. In gastric carcinoid the histamine concentration in the blood is often elevated and histamine metabolites are excreted in the urine. The concentration 5-HIAA in the urine is often normal. In the ECL cells histidine is converted into histamine by L-aminoacid decarboxylase. Because L-aminoacid decarboxylase is used for the conversion of histidine to histamine [18], less of this enzyme will be available for the conversion of 5-HTP to serotonin [19]. The concentration of 5-HIAA in the urine in gastric carcinoid is often normal and therefore a poor marker for gastric carcinoid in contrast to carcinoids elsewhere. 5-HTP can be excreted and partly decarboxylated in the kidney. Patients with metastasised gastric carcinoid can have a slightly elevated urinary 5-HIAA concentration (Fig. 2).

Fig. 2. Metabolism of serotonin and histamine in carcinoids. The Netherlands Journal of Medicine 2000;56:56 – 62

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Metastases

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Metastases can be diagnosed by octreotide scintigraphy. Indium pentreotide is a new available radioactive labelled analogue of somatostatine. The sensitivity of this investigation is estimated at 72– 100%. The detection level of tumors is 10 mm. [20]. Metastases can also be detected by CT scan. Liver and lymph node metastases are often found, while the primary tumour is hidden [4].

Patients with type III gastric carcinoid are treated symptomatically with octreotide. Octreotide decreases the gastrin concentration and inhibits the proliferation of the neuroendocrine cells in the stomach, like the ECL, EC, P and D cells. In contrast to antrectomy octreotide does not selectively inhibit ECL proliferation. Chemotherapy such as streptozotocine, fluorouracil, doxorubicine and cyclophosphamide result in a response in 20–40% of patients [13].

Treatment

Prognosis

A decade ago all patients with gastric carcinoid underwent a gastrectomy [7]. To date, antrectomy is performed in patients with type I tumours removing the bulk of gastrin producing G-cells. This results in normalisation of the gastrin concentration (Table 4) [21] and withdrawal of the trophic effect of hypergastrinemia on the ECL cells. It is debatable whether performing an antrectomy actually results in regression of the neoplastic process. In experimental studies in rats regression of hyperplasia and dysplasia can be found after antrectomy, but neoplasia does not regress [1]. The results of the studies of the biological behaviour of the tumours after antrectomy in humans are contradictory. In older patients with type I gastric carcinoid a conservative approach is preferred because of the indolent nature of the tumour, the lack of progression or even the spontaneous regression in some untreated patients. Patients treated with vitamin B12 injections, often show a declining gastrin concentration [7].

Type I gastric carcinoid has the best prognosis (5-year survival, 93%). Sixteen percent of these patients develop lymph node metastases and 4% liver metastases [1]. Type III tumours have the worst prognosis (5-year survival, 50%). Lymph node metastases are seen in 55% and liver metastases in 24% of cases [1]. Type II tumours have a prognosis intermediate between types I and III. The prognosis depends beside on type, also on the size of the tumour ( . 1 cm), the depth of invasion and the presence of local metastases [3]. It appears that without metastases the 5-year survival is 93%, with lymph node metastases 23% and with liver metastases 0% [6]. The prognosis of patient A is favourable, because of his age, the absence of dysplasia and normalisation of the gastrin level. The patient remains under clinical control. A control gastroscopy is not indicated, unless complaints appear. In contrast, patient B requires a yearly endoscopic examination, al-

Table 4 Treatment of gastric carcinoid [1] Type

Treatment

Type I

, 1 cm, 1–5 tumours , 1 cm, . 5 tumours . 1 cm Invasion

Endoscopic removal and control Antrectomy Antrectomy and tumour excision Gastrectomy

Type II

Gastrinoma

Surgical therapy Endoscopic therapy and control

Type III

Tumour

Gastrectomy and lymph node resection Symptomatic treatment Cytostatica

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though the gastric carcinoid type I has an indolent nature with the best prognosis. However, it is still debatable how frequently patients with a pernicious anaemia have to be endoscopically examined at follow up. Yearly gastroscopy is expensive, and not possible in practice. A sensible strategy would seem to be to perform a gastroscopy at the time of the diagnosis and in case of incomprehensible weight loss, epigastric pain, vomiting / diarrhoea or aggravation of the anaemia. In conclusion, gastric carcinoids are now diagnosed more frequently. They occur more often in women and at an older age. In the literature Solcia’s classification is often used, however this nomenclature is disputable, because dysplasia is a gradation of neoplasia, and neoplasia cannot be equated with malignancy. Type I tumours have a good prognosis and can often be treated conservatively with endoscopic control and tumour excision. Gastroscopy appears to be indicated at the time of diagnosis of pernicious anaemia and afterwards whenever abdominal complaints, incomprehensible weight loss or aggravation of the anaemia occur.

[6] [7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

Acknowledgements We are indebted to Mrs. M. Casparie (SIG, PALGA) for the provision of these data.

[16]

[17]

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