GIST presenting as refractory iron-deficiency anaemia in paediatric patient

Abstract

Gastrointestinal stromal tumours (GISTs) are very rare gastrointestinal (GI) mesenchymal tumours affecting only 0.02 children/million/year below the age of 14 years. We reported a 9-year-old girl presented to emergency department with pallor and haemoglobin of 50 g/L. Extensive workup for anaemia suggested iron-deficiency anaemia secondary to GI loss. Ultimately after blood transfusion of packed cells, she was discharged with a haemoglobin of 92 g/L with iron supplementation. Upper endoscopy showed incidental antral nodularity with biopsy proven helicobacter gastritis and an isolate 3–4 cm suspicious mass in the lesser curvature. Abdomen imaging confirmed the gastric mass in addition to two lesions, one retroperitoneal and one paraspinal. She undergone open laparotomy with complete surgical resection of the gastric and retroperitoneal masses with histological confirmation of GIST and paraganglioma. This case emphasises the importance of proper examination of the stomach at endoscopy and to illustrate that although anaemia is common in paediatric age group it may be reflect serious medical condition even in normal looking child.

Background

Gastrointestinal stromal tumours (GISTs) are most located in the stomach and proximal small intestine. GISTs have a reported incidence of 10–15 cases per million overall,¹ of which it is estimated that 0.5%–2.7% of patients are younger than 21 years at diagnosis² Indeed, GISTs rarely occur in paediatric patients, and have clinical, molecular and pathological features as well as natural history of disease which is distinct from that observed in adults. Compared with the adult population who have equal gender distribution, there is 70% female preponderance in the paediatric population at diagnosis of GIST. Chronic gastrointestinal bleeding is the most common presentation in paediatric GIST population, likely due to the predilection to the stomach in this age group.

Case presentation

We present a 9-year-old girl with history of refractory iron-deficiency anaemia (IDA) unresponsive to iron supplementation, who was referred to our tertiary paediatric centre for further evaluation. She presented to emergency department with history of being fatigue. She did not present with haematemesis or melena but did have mild episodic abdominal pain. She was tachycardic with normal blood pressure. General examination was unremarkable, no clinical findings suggestive of neurocutaneous stigmata. Normal liver, renal function coagulation, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), but positive haemoccult. Extensive work up for anaemia suggested IDA secondary to gastrointestinal (GI) loss. Ultimately after blood transfusion of packed cells, she was discharged home with a haemoglobin of 92 g/L with iron supplementation.

Investigations

Both haemoccult and stool antigen for Helicobacter pylori were positive so proceeded to oesophagogastroduodenoscopy (EGD). Macroscopic appearance at EGD showed mild antral nodularity and the rapid urease test was positive confirming H. pylori gastritis. On J manoeuvre retroflexion, a smooth rounded protrusion approximately 2–3 cm in diameter was visualised on the lesser curvature of the stomach. The mucosa overlying and surrounding the lesion appeared normal with no ulceration and normal vasculature (figure 1). Histological analysis subsequently confirmed the presence of Helicobacter organisms with silver Warthin-Starry stain in antral biopsy with mild chronic inactive inflammation and some features suggestive of reactive gastropathy, the biopsy from the duodenum showed normal duodenal mucosa with no significant abnormality identified. The decision not to proceed with endoscopic ultrasound or fine needle biopsy was after multidisciplinary team meeting (paediatric gastroenterology, oncology and surgery). It was decided to send family to a centre of excellence where there was more expertise in term of cytogenetics and immunohistochemistry, especially with handling of biopsy specimens. We unfortunately do not have the expertise in our centre. The parents had also chosen to travel aboard. MRI examination post intravenous contrast administration showed a well-circumscribed mass lesion 3×3×4 cm, closely indenting the lesser curve of stomach, possibly of gastric origin with exophytic growth and closely abutting the medial aspect of the left lobe of liver and anterior to the body of the pancreas (figure 2A, B). Incidentally a 1 cm diameter-enhancing lesion was present in the right para-spinal region adjacent to the posterior aspect of the right 10th rib (figure 3A) as well as a 1.8 cm nodular enhancing lesion in the left para-aortic region (figure 3B). No other abnormalities specifically liver, lung or bone metastases were identified. The clinical and radiological features of the mass favoured a GIST; therefore, a Gallium Dotatate positron emission tomography (Gallium Dotatate PET) scan was performed. This showed avid metabolic activity in the lesser curve lesion (figure 4A) with low-grade uptake in right para spinal lesion without definite extension into the adjacent neural foramina. However, the adjacent right rib head also showed mild activity suggestive of rib involvement (figure 4B). The left para-aortic node also showed mild activity. The overall impression was that of a gastric GIST with concurrent right paraspinal and left para-aortic lesions possibly representing paragangliomas. The patient subsequently underwent successful and uncomplicated laparotomy with partial gastrectomy and resection of the right paraspinal lesion. Histological analysis of the gastric mass (4.3×3.2×2.5 cm) contained predominantly epithelioid cell neoplasm, with high grade mitotic activity (15–20 mitoses per 20 high power fields) TNM stage: pT2. Surprisingly immunohistochemistry was positive for CD117(cKIT) and platelet-derived growth factor receptor (PDGFRa) while succinate dehydrogenase (SDH) was deficient. Interestingly, sequencing of both the paraganglioma and the GIST tumour did not reveal any mutation in the SDH subunits, CKIT, PDGFRA or BRAF. Histological analysis of the left para-aortic mass (2.2×2.2×1.6 cm) was consistent with paraganglioma thereby excluding metastases. Biopsy from the right 10th rib confirmed nodular fasciitis.

Figure 1.

Upper endoscopy visualising the isolated smooth rounded protrusion approximately 2–3 cm in diameter on the lesser curvature if the stomach.

Figure 2.

(A) Axial T2 MRI image shows a mass closely indenting the lesser curve of the stomach (bold arrow). Incidental finding of small right thoracic meningocele(arrowhead). (B) Coronal T2 MRI image shows a mass closely indenting the lesser curve of the stomach (bold arrow).

Figure 3.

(A) Axial T2 MRI image shows a nodular lesion in the right paraspinal region (bold arrow). (B) Axial T2 MRI image shows a nodular lesion in the left para-aortic region (bold arrow).

Figure 4.

(A) Axial fused PET-CT image showing avid activity in the primary lesion (bold arrow). (B) Axial fused PET-CT image showing mild activity in the right paraspinal lesion extending into the adjacent rib head (bold arrow). PET, positron emission tomography.

Treatment

The patient subsequently underwent successful and uncomplicated laparotomy with partial gastrectomy and resection of the right paraspinal lesion. The patient had an eventful immediate postoperative recovery, she was discharged home on the fifth postoperative day. The patient was on oral iron replacement until the resection of the tumour after which patient did not require iron therapy and the haemoccult continued to be negative.

Outcome and follow-up

Outpatient reviews at 3,6 and 12 months post discharge, the patient remained asymptomatic. Repeated haemoglobin was normal.

Discussion

IDA is by far the most common anaemia worldwide. Prevalence of IDA is up to 40% of preschool children in low/middle-income countries.³ The most common cause of iron deficiency in children is insufficient iron intake. In patients, especially in older children, other causes of IDA should be considered if medical and dietary history of the patient does not explain the cause of iron deficiency or if there is inadequate response to oral iron treatment. IDA secondary to occult GI bleeding is observed with a relatively lower rate in children and may occur as a result of gastrointestinal problems including peptic ulcer, Meckel’s diverticulum, polyp, haemangioma, inflammatory bowel disease or rarely tumours. GISTs in the paediatric and adolescent population differ significantly in clinical, histological and genetic phenotype from adults with resultant differences in the medical approach and management of paediatric cases.⁴ Multifocal gastric tumours and lymph node metastases are more common than in adults, and histopathology favours epithelioid rather than spindle cell.⁵ Activating mutations of KIT or PDGFRA proto-oncogenes are detected in 85%–90% of GISTs occurring in adult patients^{6 7} and most of these respond to tyrosine kinase inhibitors such as imatinib or sunitinib.^{8 9} However, 85% of paediatric GISTs and 10%–15% of GISTs in adults lack the KIT and PDGFRA mutations,^{10 11} accordingly these tumours are termed ‘wild-type’ GISTs and 40% of them present deficiency of SDH complex. Paediatric/WT GISTs, in addition to occurring sporadically, are also more likely to be associated with cancer syndromes such as Carney’s triad (GIST, pulmonary chondroma and extra-adrenal paraganglioma¹² and Carney-Stratakis syndrome (CSS) (GIST and paraganglioma).¹³ Another syndrome associated with GIST is Von Recklinghausen’s disease or Neurofibromatosis 1, a syndrome characterised by café au lait spots, lisch nodules, freckling and neurofibroma, GISTs are the most common non-neurological malignancy in this particular patient population.^{14 15} The most striking difference in the Paediatric/WT GIST tumour population is that the tumours tend to have an indolent course, meaning that many of the patients will live with their tumours for years.⁴

Over the last two decades a novel classification of GIST has been proposed to address these obvious differentiations in presentation. GIST can be classified as being either SDH-competent (adult GIST or KIT/PDGFRA mutation) or SDH-deficient (Paediatric/WT GIST) tumours.¹⁶ The SDH-competent GIST includes those tumours that have mutations in either KIT (75% of all the tumours), PDGRFA (5%–10% of tumours) and other rarer mutations.¹⁷ Much of the paediatric literature describes GISTs that lack CD117 immunopositivity. Sifrance et al conducted a review of the UK literature to summarise the paediatric GISTs with CD117 immunohistochemistry.¹⁸ Patients less than 18 years old were included and cases associated with syndromes were excluded. Total of 62 cases of paediatric GISTs with confirmed CD117 immunohistochemistry were reviewed of which females were 1.82 times more affected than males. The most common presentation was anaemia and the tumour location involved mainly the stomach (73%). Only 37% of the cases were determined to be SDH-deficient WT paediatric GISTs. In our reported patient, despite the absence of KIT and SDH subunits or PDGFRA germline mutations, her GIST displayed biochemical activation of KIT downstream resulting in overexpression of CD117. SDH subunit gene mutations are often germline and most commonly A (30%), and B, C or D (together 20%), with both alleles inactivated in the tumour.¹⁸ However, half of the cases are not associated with SDH-mutations and epigenetic silencing of the SDH complex is presumably the defining oncogenic event as in our patient. Extensive genomic methylation has been observed in these tumours, which is in contrast with other GISTs.¹⁹ CSS which includes GIST and paraganglioma, is an autosomal dominant with incomplete penetrance. CSS was initially described in 2002. Since then, it has been demonstrated that most of these patients harbour a germline inactivating mutation within one of the four subunits A, B, C or D of the SDH complex of the respiratory chain,^{19 20} while again in our reported patient no germline mutation was detected making CSS unlikely. Finally, the identification and confirmation of constitutional SDH deficiency by the molecular testing is critical to enable appropriate genetic counselling for future offspring. We report a case representing with Fe deficiency, a common nutritional deficiency accounting for 5% in children, however iron deficiency refractory to treatment should always warrant further subspecialist evaluation. Moreover, H. pylori gastritis is one of the most common presentations of upper gastrointestinal bleeding which can be detected as the antigen in stool, however, if the presentation is atypical as in our case being associated with profound iron deficiency, then endoscopic assessment is indicated. Any endoscopic evaluation should be extensive and should always include complete evaluation of the entire organ being examined. Although H. pylori gastritis was macroscopically typically apparent by the antral nodularity and may well have explained symptoms in our case, the failure to complete retroflexion and examine the rest of the stomach may have missed visualisation of the lesion and diagnosis of GIST.

Patient’s perspective.

I am happy to share my case with doctors all over the world. I was lucky I was diagnosed at early stage. I am back to my school. I do not want anyone to go through what I had to.

Learning points.

• Iron-deficiency refractory to treatment should always warrant further subspecialist evaluation.

• Helicobacter pylori gastritis is one of the most common presentations of upper gastrointestinal bleeding, which can be detected as the antigen in stool, however, if the presentation is atypical as in our case being associated with profound iron deficiency, then endoscopic assessment is indicated.

• Any endoscopic evaluation should be extensive and should always include complete evaluation of the entire organ being examined.

• Despite multiple disease recurrence and metastatic disease, paediatric gastrointestinal stromal tumours (GIST) appears to have a more indolent disease course than adult GIST.

Ethics statements

Patient consent for publication

Consent obtained from parent(s)/guardian(s)