Duodenal neuroendocrine tumour associated with minimal change glomerulonephritis

Abstract

Paraneoplastic glomerular disease is an increasingly well-recognised entity, and a wide range of both solid and haematological malignancies have been implicated. The most common glomerular disease associated with cancer is membranous nephropathy. Only a few case reports have described an association between neuroendocrine tumours (NETs) and glomerulonephritis and only one paediatric case in relation to minimal change disease. A 76-year-old woman with a well-differentiated duodenal NET presented with nephrotic syndrome and renal biopsy was suggestive of minimal change glomerulonephritis. Standard therapy with corticosteroids brought little benefit, but a dramatic improvement was seen following initiation of systemic anticancer therapy with lanreotide, a somatostatin analogue. Less than 1 month after initiation of lanreotide, the patient was no longer in a nephrotic state, and after a further 2 months of follow-up had shown no sign of relapse.

Background

While a variety of malignancies have been linked to glomerular disease,^{1 2} we believe this to be the first reported case of neuroendocrine tumour (NET) and minimal change glomerulonephritis in adults.³ The aetiology of glomerulopathy in cancer does not appear to be related to tumour burden, metastatic spread or the site or extent of invasion, but to the secretion of substances from the tumour cells.¹ The most commonly reported associated malignancies are lung, gastric, renal, prostate, breast and colon cancers; however, robust data on the incidence of paraneoplastic glomerular disease are lacking.² Nephrologists have not reached a consensus on the value of investigating for malignancy in patients with glomerulopathies,⁴ but as standard treatment may be less effective in a paraneoplastic glomerulopathy, prompt diagnosis is important to ensure patients do not receive ineffective and potentially harmful treatments.¹

Case presentation

A 76-year-old woman with a background of polymyalgia rheumatica and diverticular disease presented in December 2017 with a 6-week history of a change in bowel habit and right upper quadrant pain. Regular medications included prednisolone 7 mg daily.

CT of the thorax, abdomen and pelvis revealed a large mass affecting the duodenum, as well as ovarian masses. A biopsy of the duodenum was performed, and pathology showed well-differentiated NET, grade 1 (Ki67 proliferation index <1%).

A whole-body Gallium-68 positron emission tomography/CT scan showed uptake in the D3 portion of the duodenum and three mesenteric lesions, but not in the ovaries. MRI of the pelvis showed benign appearances of the ovarian masses.

In April 2018, before any therapy for NET had commenced, the patient presented with swelling in her arms and legs, shortness of breath and reduced exercise tolerance. These symptoms had developed rapidly over 10 days and prompted hospital admission.

Investigations

Initial investigations confirmed nephrotic syndrome, with widespread peripheral oedema, 11.7 g/day proteinuria and serum albumin of 23 g/L (normal range 35–50 g/L). Her renal function was well preserved with serum creatinine of 84 µmol/L (normal range 44–97 µmol/L). Treatment with intravenous furosemide and human albumin solution was commenced, and a renal biopsy was taken.

Differential diagnosis

On biopsy, four glomeruli were obtained, and histological examination showed normal light microscopy, no deposition of immunoglobulins, complement or light chains and no segmental lesion. Electron microscopy was performed on a single glomerulus and showed extensive foot process effacement and focal microvillous transformation. This was therefore most in keeping with minimal change disease (MCD), though due to the paucity of glomeruli, focal segmental glomerulonephritis could not be completely excluded.

Treatment

Treatment with high-dose corticosteroids was initiated. The patient already took 7 mg prednisolone daily for polymyalgia rheumatica, and this was increased to 70 mg daily, representing 1 mg/kg prednisolone based on the patient’s weight prior to the onset of oedema. Adjunctive treatment included ramipril, treatment-dose low molecular weight heparin and prophylactic fluconazole, aciclovir and co-trimoxazole.

Three days after commencing high-dose corticosteroid therapy, the patient’s renal function deteriorated, and the serum creatinine increased to a peak of 165 µmol/L on day 6. MCD in adults usually takes several weeks to respond to steroids,⁵ so prednisolone was continued; however, the dose of furosemide was reduced due to concerns over potential contribution to the renal burden.

We suspected that the patient’s glomerular disease was a paraneoplastic phenomenon related to the NET; hence, the patient was commenced on systemic anticancer treatment with lanreotide (120 mg, deep subcutaneous injection, on a 28-day cycle).

Outcome and follow-up

Commencement of somatostatin analogue was swiftly followed by a marked diuresis and reduction in oedema. Three weeks after administration of lanreotide, the patient’s weight had reduced by 15 kg (figure 1). The serum creatinine normalised, and urinary protein reduced significantly to 1.2 g/day (figure 1). After a further 2 weeks, the serum albumin had recovered to 38 g/L. Four months after initial presentation, the nephrotic syndrome has completely resolved. The patient continues on monthly lanreotide injections, and a gradual reduction in steroid dose has commenced with no sign of relapse.

Figure 1.

Line chart showing change in patient’s weight and urinary protein over time.

Discussion

Nephrotic syndrome is an easily diagnosed clinical entity characterised by proteinuria, hypoalbuminaemia, peripheral oedema and hyperlipidaemia (box 1). It is caused by a range of primary and secondary glomerular diseases, which are best identified on histopathological assessment. The most common paraneoplastic glomerular disease is membranous glomerulonephritis, which has been most frequently linked to lung and gastric cancers.¹ Small studies have reported remission in association with tumour control, suggesting a causal relationship.⁴ NETs have been infrequently associated with membranous glomerulonephritis, and one previous case report described clinical remission of membranous glomerulopathy following surgical resection of the primary tumour.^{2 4 6}

Box 1. Clinical features of nephrotic syndrome.

• Heavy proteinuria (≥3.5 g/24 hours).

• Hypoalbuminaemia (<30 g/L).

• Peripheral oedema.

• Hyperlipidaemia (not required for diagnosis).

MCD, however, is less common in malignancy and tends to be associated with Hodgkin’s disease, though it has also been reported in solid tumours including lung, colon and renal cancers.^{1 7} Like membranous nephropathy, remission of MCD has been reported on ablation of the tumour, suggesting a paraneoplastic process, though the precise mechanisms are not fully understood.⁷ Additionally, focal segmental glomerulosclerosis (FSGS), membranoproliferative glomerulonephritis, IgA nephropathy and rapidly progressive glomerulonephritis have been associated with malignancy, to a lesser degree.⁷

Interestingly, it has been suggested that MCD and FSGS may be part of the same disease spectrum.⁸ In particular, patients whose histology shows MCD and do not respond to steroids may go on to show histological features of FSGS in later biopsies,⁵ and the management of steroid-resistant MCD is similar to that of steroid-resistant FSGS.⁵

While paraneoplastic nephrotic syndrome appears to be rare in neuroendocrine tumours, other secretory or paraneoplastic syndromes are common. NETs are often functional and secrete biologically active substances, causing significant morbidity and mortality. Serotonin secretion from primarily small bowel NETs causes the classical carcinoid syndrome, which includes flushing, diarrhoea and respiratory symptoms.

Learning points.

• Patients with cancer who present with oedema should be investigated for nephrotic syndrome.

• Glomerulopathy in the context of cancer may not respond to standard therapies.

• Anticancer treatment should be considered and commenced if possible.