Gastric neuroendocrine tumour,atrophic gastritis and autoimmune haemolytic anaemia: a case report and review

Abstract

Gastric neuroendocrine tumours are rare. We describe a unique case of a 66-year-old male patient who presented with shortness of breath and malaise, eventually attributed to severe autoimmune haemolysis in the context of atrophic gastritis and multiple type-1 gastric neuroendocrine tumours. The patient had also positive anti-cardiolipin antibodies. A favourable outcome was attained with corticosteroids plus subtotal gastrectomy for the treatment of the underlying neoplastic disease. This case illustrates that the differential diagnosis of any associated causes of autoimmune haemolytic anaemia can be challenging, and may extend to unexpected conditions.

Keywords

Autoimmune haemolytic anaemia gastric neuroendocrine type-1 gastric carcinoid atrophic gastritis anti-cardiolipin antibodies

Introduction

Digestive neuroendocrine tumours, accounting for up to 60% of all neuroendocrine neoplasms, are rare tumours, located in any possible site within the gastrointestinal system.¹ Among them, the gastric neuroendocrine tumours (G-NETs), arising from neuroendocrine cells within the stomach, represent 7%–8% of all digestive neuroendocrine neoplasms.^2,3 According to the updated 2017 WHO classification, the G-NETs, based on particular predictive criteria of their biological behaviour (size, invasion, Ki67 index), are assigned as well-differentiated tumours, either low-grade (G1) or intermediate-grade (G2). All poorly differentiated G-NETs are high-grade (G3) and are characterised as neuroendocrine carcinomas.²

G-NETs are classified into three types.³ Type-1, the most common (75%), is associated with chronic atrophic gastritis and consequent achlorhydria. Type-2 (5%) is associated with underlying pancreatic or duodenal gastrinoma, one form of Zollinger–Ellison syndrome. Both of these types appear usually as small (5–8 mm) multicentric polypoid, neoplastic lesions that are usually restricted to the gastric mucosa or submucosa. Type-3 (20%), which is sporadic, manifests as a larger (>1–2 cm) solitary lesion that clinically and histologically is aggressive, often with local or hepatic metastases on presentation.

We describe and discuss a rare case of a well-differentiated G-NET, related histologically to atrophic gastritis, that presented acutely and without any other predisposing conditions, as autoimmune haemolytic anaemia (AIHA). AIHA is a rather rare disease of immune dysregulation and can be further classified into idiopathic or secondary to various conditions, mainly lymphoproliferative or autoimmune disorders.^4,5 While megaloblastic anaemia related to atrophic gastritis and AIHA may co-exist,^6,7 it appears that G-NET, as described in this case, triggered the autoimmune haemolytic reaction.

Case presentation

A 66-year-old man presented to the emergency department of our hospital with shortness of breath and malaise. He had a preceding two-week history of progressively worsening fatigue. He did not report fever, chest or abdominal pain, vomiting, diarrhoea, weight loss or other associated symptoms.

The patient was a farmer. His past medical history was significant for arterial hypertension and hypothyroidism, under medication. He had also a history of cholecystectomy and large bowel polyps for which he had undergone polypectomy.

On admission the patient had normal, stable vital signs and was afebrile. He was pale with mild conjunctival icterus. He had normal level of consciousness, with no neurologic signs or deficits. Cardiac examination was normal, as was pulmonary auscultation. Abdominal examination revealed moderate splenomegaly and a soft marginally palpable liver, with no signs of peritoneal irritation. No abnormal masses or lymph node enlargement were found. Thyroid gland was non-tender and not enlarged.

Basic laboratory results at presentation are depicted on Table 1 and included severe macrocytic anaemia with haematocrit (Hct) of 20.6%, mean corpuscular volume (MCV) of 117 (80–98 fL) and highly elevated reticulocytes at 20% (0.5–2). Blood film revealed a haemolytic pattern with spherocytosis, polychromatophilic red cells, 10% nucleated red blood cells, and no schistocytes. Serum biochemical markers, elevated lactic dehydrogenase (LDH) 1097 (<225 IU/L) and elevated total and indirect bilirubin, were also suggestive of haemolysis, as was urinalysis, which showed urobilinogen. There was no proteinuria, haematuria or urinary casts to suggest renal glomerular disease.

Table 1.

Laboratory evaluation.

Test	Value	Normal limits
Blood count
White cell count	7780	4–10.5 (×10³/µL)
Neutrophils/lymphocytes	62/33	40–70 (%)/25–45 (%)
Hct	20.6	42–54 (%)
Haemoglobin	6.8	12–17.5 (mg/dl)
MCV	117	80–98 (fL)
Platelets	202	140–450 (×10³/µL)
Reticulocytes	20	0.5–2 (%)
Anaemia evaluation
LDH	1097	<225(IU/L)
Direct Coombs	(++++)	0–0
Indirect Coombs	(++)	0–0
B12	<84	189–883 (pg/mL)
Anti-PCA	(−)	0–0
Anti-InF	(−)	0.1–1.1
Ferritin	194.6	5–300 (ng/ml)
Folic acid	6.1	4.8–19 (ng/mL)
Erythrocyte sedimentation rate	2	0–20 (mm/h)
Thyroid function
Thyroid-stimulating hormone	1.9	0.27–4.2 (µU/ml)
T3	98.8	80–200 (ng/dl)
FT4	1.4	0.93–1.7 (ng/dl)
Antibodies to thyroid peroxidase	(−)	0–50 IU/ml
Antibodies to thyroglobulin	(−)	0–150 IU/ml
Complement
C3	73.4	63–158 (mg/dL)
C4	3.89	14–33 (mg/dL)
Immunoglobulins
IgG	1260	690–1618 (mg/dL)
IgA	87.7	72–400 (mg/dL)
IgM	115	40–235 (mg/dL)
Free Kappa	17.2	3.3–19.4 (mg/L)
Free Lamda	10.2	5.71–26.3 (mg/L)
Free k/λ ratio	1.69	0.26–1.65
Antibodies for infectious diseases
Human immunodeficiency virus	(−)	0–0
Epstein–Barr virus	(−)	0–0
Hepatitis B, C virus	(−)	0–0
Mycoplasma pneumoniae	(−)	0–0
Chlamydia pneumoniae	(−)	0–0
Antibodies for autoimmune diseases
Anti-nuclear antibodies	(−)	0–0
Antibodies to double- stranded (ds)DNA	(−)	0–0
Perinuclear, cytoplasmic antineutrophil antibodies	(−)	0–0
Anticardiolipin IgG antibodies	16.9	0.1–20
Anticardiolipin IgM antibodies	141.5	0.1–20
Tumour markers
Non-specific enolase	20.68	0–16.3 (ng/ml)
Carcinoembryonic antigen	1.08	0–5 (ng/ml)
Cancer antigen 19-9	<2.0	0–37 (U/ml)
a-Fetoprotein	3.08	0–15 (ng/ml)

Hct: haematocrit; MCV: mean corpuscular volume; LDH: lactic dehydrogenase; Anti-InF: anti-intrinsic factor antibodies; Anti-PCA: anti-parietal cell antibodies. Note: Abnormal values are highlighted in bold.

We concluded that the anaemia could be attributed to a haemolytic process. Direct Coombs test was performed immediately and was positive (IgG 1/1024, C3d 1/512), indicating an autoimmune haemolytic anaemia (AIHA). The indirect Coombs test, was also positive. Coagulation tests including the prothrombin time (PT) and activated partial thromboplastin time (aPTT), were not prolonged. The patient also had undetectable levels of vitamin B12 (<84 pg/mL; N: 189–883) on admission. Treatment for AIHA, consisting of prednisone 1 mg/kg intravenously plus B12 supplementation, was commenced, under close monitoring of Hct and LDH level. The treatment was effective, with a steady response, reflected by a progressive elevation of Hct to normal level.

Investigation for an underlying disease, as the causative pathology of AIHA, had already begun. CT scan of thorax and abdomen was negative for lymphadenopathy/lymphoproliferative disease or solid tumours. Further evaluation for autoimmune, thyroid and infectious diseases is presented on Table 1 and was negative, except for positive anticardiolipin IgM antibodies and low C4 complement. Of note, anti-parietal cell antibodies (anti-PCA) and anti-intrinsic factor antibodies (anti-InF), were negative.

Endoscopic gastric evaluation for suspected gastric pathology related to anaemia i.e. atrophic gastritis or lymphoma confined to gastric mucosa, followed. Gastroscopy revealed multiple polyps of size 2–7 mm, located in the fundus and corpus. Multiple biopsies were obtained. Histopathological examination was specific for multifocal, well-differentiated G-NET. The neoplasm invaded the submucosa, presented Ki-67 proliferation index of 4.4%, had a mitotic index <1/10 HPF (1 HPF = 2 mm²) and expressed the somatostatin receptor SSTR2a in >50% of neoplastic cells. From these findings, according to WHO/2017 classification, the tumour was of intermediate histological grading (G2). Severe chronic metaplastic atrophic gastritis co-existed. Helicobacter pylori was not found on gastric mucosal biopsies. To exclude other occult malignancy or metastatic disease of the same neoplasm, we performed somatostatin receptor scintigraphy (111Indium-labelled octreotide scan) and supplementary positron emission computed tomography (PET-CT) scan with negative results.

Our patient’s G-NET, according to the histologic staging, was considered to present advanced gastric wall involvement. After discussion, partial gastrectomy was selected over conservative treatment (“watchful waiting”). Νeoplastic disease of the same histology was found in the resected part of the stomach.

Discussion

The patient was diagnosed with type-1, well-differentiated, G-NET. G-NETs are derived from enterochromaffin-like cells (ECLs). ECLs are located in the body and fundus of the stomach and display a key role in gastric acid secretion.⁸ Normally during a meal, the hormone gastrin is released from G cells of the antrum and acts as a chemotransmitter to the ECLs, that release histamine to parietal cells.⁸ This mechanism stimulates the acid secretion from parietal cells through signalling pathways, that upregulate protein kinases and the consequent translocation and fusion of the proton pump H+/K+ ATPase into the apical plasma membrane.^8,9

Atrophic gastritis, and more specifically severe intestinal metaplasia, as found in our patient, has a clear association with type-1 G-NETs.¹⁰ Type-1 G-NETs are considered a rare complication of atrophic gastritis.¹⁰ The underlying pathogenesis involves loss of parietal cells in the body of the stomach causing achlorhydria, resulting in chronic gastrin hypersecretion, with consequent ECL cell hyperplasia and eventually ECLs neoplastic transformation.^9,10

In this patient, the anaemia may have been multifactorial given the very low B12 level and the evidence of atrophic gastritis, as well as features of autoimmune haemolysis. However, the presentation did not suggest autoimmune gastritis and the consequent hematologic features collectively known as pernicious anaemia, where ineffective erythropoiesis and intramedullary haemolysis occur – in view of the markedly elevated reticulocytes count, the absence of pancytopenia and the negative anti-PCA and anti-InF titers, which present the hallmark serologic diagnostic tests for autoimmune gastritis.^11,12

The AIHA thus seemed to be the major cause. No other malignant triggers, such as lymphoma, for the AIHA were found.⁵ Other possible pointers might include the positive IgM anti-cardiolipin, but this is not diagnostic of anti-phospholipid syndrome in the absence of manifestations of vascular thrombosis.¹³ Systemic lupus erythematosus (SLE) itself is a possible cause¹⁴ but the diagnostic criteria were not present.¹⁵

Notably, there are reports of positive Coombs test in patients with autoimmune atrophic gastritis and/or pernicious anaemia.⁶ This association was first recognised by Rubio et al in 1957.¹⁶ The involvement of true autoimmune haemolysis in the described cases is variable.^6,7,17,18 In one case of AIHA and B12 deficiency, related to metaplastic atrophic gastritis, successful treatment was achieved with steroids and vitamin B12.⁶ In two other papers, failure to respond to B12 supplementation highlighted the AIHA diagnosis and necessity of steroid treatment,^7,17 while another patient responded to B12 therapy without resorting to steroids.¹⁸ In all the described cases, both anti-PCA and anti-InF antibodies were positive. Our case having these antibodies negative, we believe, points to an alternative trigger for the AIHA, perhaps a unique possible association of autoimmune haemolysis with G-NETs. The relevant autoimmune mechanisms are unclear.

The European Neuroendocrine Tumor Society (ENETS) position paper provides Consensus Guidelines in the diagnosis and management of G-NETs. Gastroscopy is the gold standard diagnostic tool, allowing – alongside endoscopic ultrasound (EUS) – the evaluation of locoregional disease.² Gastroscopy was performed initially to our patient for other suspected gastric pathology, such as atrophic gastritis or lymphoma.^5,19 G-NET at the initial work-up was unsuspected and confirmed only from histology results.

Treatment options for the management of type-1 GNETs consist of simple endoscopic surveillance, endoscopic selective resection of visible tumours, or gastric antrectomy.^2,3 The ENETS Guidelines strongly support conservative management over surgery for patients with type-1 G-NETs, either grade G1 or G2, since these tumours, if <1 cm, rarely invade the muscularis propria or metastasise to local lymph nodes.² Partial gastrectomy should be considered in patients with G2 grading with more advanced gastric wall involvement, and this was the treatment selected in our patient, after oncologic and surgery consultation.²⁰ Concerns were the multiple gastric small lesions that were difficult to detect and remove, and the possibility of more invasive lesions or recurrence. Among other treatment options for G-NETs, the Somatostatin analogues, although effective,²¹ have only a limited recommendation in early disease.² Data from randomised controlled trials, comparing their efficacy to endoscopic management, are lacking to enable more definitive conclusions; their use could be an option for patients with advanced disease (metastatic, unresectable or residual), proven somatostatin receptor SSTR2 expression and a low Ki-67 index.²

In conclusion, this is a rare case of simultaneous metaplastic atrophic gastritis, type-1 G-NET, B12 deficiency without anti-parietal cell or anti-InF and severe autoimmune haemolytic anaemia. We believe the G-NET may be the cause of the AIHA.

Learning points

Type-1 gastric neuroendocrine tumours represent a rare complication of atrophic gastritis.

The differential diagnosis of gastric polyps extends beyond the common various types of chronic gastritis.

Gastric neuroendocrine tumours may be a previously undescribed cause of autoimmune haemolytic anaemia.

Authors’ contribution

All authors contributed equally and approved submission.

Patient’s consent

Informed consent was obtained from the patient for the publication of information relevant to the case.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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