Resolution of necrolytic migratory erythema with somatostatin analogue in a patient diagnosed with pancreatic glucagonoma

Abstract

A 70-year-old man reported progressive weight loss, fatigue and a generalised rash. The rash was consistent with necrolytic migratory erythema, further investigations were performed and the patient was diagnosed with a mass in the tail of the pancreas, in keeping with a localised glucagonoma. Somatostatin analogue therapy was started for symptom control, leading to complete resolution of the skin rash and an improvement in constitutional symptoms. Subsequently, the pancreatic lesion was excised, and pathology assessment confirmed the diagnosis of well-differentiated neuroendocrine tumour with high expression of glucagon compatible with glucagonoma.

Background

We present the case of a patient diagnosed with a glucagonoma who presented with necrolytic migratory erythema (NME).

Glucagonomas are rare functional pancreatic neuroendocrine tumours (NETs) which are usually diagnosed in advanced stages. However, our patient had no evidence of distant metastases and NME was the first presenting feature. Due to the severity of NME, the patient was immediately started on somatostatin analogue (SSA) and achieved a complete resolution of skin lesions.

This case report highlights the importance of early recognition of paraneoplastic syndromes since they may be the first manifestation of malignancy and provide an opportunity for early diagnosis. In addition, it demonstrates the strong antisecretor effect of SSA and supports their immediate use in patients where there is high clinical suspicion of a functional NET and who present with debilitating symptoms.

Case presentation

A 70-year-old man presented with a 6-month history of weight loss, asthenia and generalised rash. He had a widespread erythematous eruption comprising lower back, buttocks, groin, distal legs, arms, chest and face (affecting more than 50% of the skin surface, grade 3). It was not itchy or painful and exhibited scaled areas (figure 1). Mucosae were not affected. The patient had no dermatological history, and the only comorbidity was atrial fibrillation, treated with warfarin and bisoprolol. No previous diagnosis of diabetes or glucose intolerance was reported. There was no family history of significance.

Figure 1.

Necrolytic migratory erythema before somatostatin analogue treatment.

Prior to review in the medical oncology clinic, the patient had been prescribed prednisolone 30 mg daily as a first treatment approach for the skin rash. There was an initial slight improvement which was not maintained when the steroid dose was reduced.

Investigations

Computerised tomography (CT) of thorax, abdomen and pelvis demonstrated an 8 cm mass in the tail of the pancreas with local lymphadenopathy. A cytology sample was obtained through fine needle aspiration guided by endoscopic ultrasound. The cytology showed a well-differentiated NET (WD-NET), staining strongly on immunohistochemistry for synaptophysin and showing patchy positive areas for chromogranin. There was no necrosis and the Ki67 proliferation index was 5%–20%.

Treatment

Due to the clinical suspicion of NME and the severity of the rash, treatment with SSA (octreotide LAR 30 mg intramuscular injection once in every 4 weeks) was started at the first clinical review even though the diagnosis of glucagonoma and NME was not confirmed. At the time of therapy initiation the rash was grade 3, and medical photographs were subsequently reviewed by a dermatologist who agreed with the diagnosis of NME. Fasted diagnostic blood tests were taken before SSA initiation, but the results was not available until after therapy had been commenced. They showed elevated glucagon (750 pmol/L; reference range: 0–50 pmol/L) and serum chromogranin-A levels (389 ng/mL; reference range: 0–91 ng/mL), whereas serum 5-HIAA was normal (79 nmol/L). Random plasma glucose was 7.5 mmol/L; liver function and nutritional status were conserved, with normal levels of total protein and albumin. Serum calcium level was normal.

When the patient was reviewed 4 weeks later, prior to the second SSA injection, the rash had completely resolved (figure 2), as had the asthenia. Glucagon and chromogranin-A levels had reduced to 324 pmol/L and 97 ng/mL, respectively.

Figure 2.

Resolution of necrolytic migratory erythema with somatostatin analogue treatment.

Staging investigations were completed with

• Gallium-DOTATATE positron emission tomography (PET)-CT which demonstrated intense uptake of tracer by the pancreatic mass in keeping with somatostatin receptor overexpression; no other sites of tracer uptake were identified.

• Liver and pancreatic magnetic resonance imaging (MRI) confirmed a 7 cm lesion confined to the pancreas, without main blood vessels invasion or liver metastases.

The case was discussed at the NET Multi-Disciplinary Team meeting. The tumour was deemed resectable, and the patient underwent distal pancreatectomy and splenectomy with no macroscopic residual disease.

The pathology report from the surgical specimen confirmed the diagnosis of a WD-NET in the tail of pancreas. Immunohistochemistry was positive for synaptophysin, chromogranin and CD56, as well as for glucagon (70% of tumour cells showed positivity). The mitotic count was low (less than 1 per high power fields) and Ki67 proliferation index was 1.5% (grade 1). According to the TNM Staging system (eighth edition; assessing for primary tumour (T), lymph node (N) and distant metastases (M)), the stage was pT3 (8 cm, limited to the pancreas) pN0 (none of the seven lymph nodes resected showed tumour infiltration); stage II. Resection was microscopically incomplete (R1) because the proximal pancreatic transection margin was involved. Lymphovascular space invasion was noted without evidence of perineural spread.

Outcome and follow-up

There were no immediate or late postoperative complications. Three months after surgery, a CT scan showed no evidence of local recurrence or metastatic disease, and glucagon and chromogranin levels became normal (glucagon 8 pmol/L; reference range: 0–50 pmol/L and chromogranin 69 ng/mL; reference range: 0–91 ng/mL). Hence, the patient stopped SSA therapy with no NME recurrence.

Discussion

Glucagonoma is a functioning NET defined by glucagon secretion. It is an uncommon tumour with an estimated annual incidence around 0.01 to 0.1 cases per 100 000 population. Glucagonomas usually present in the sixth decade of life, are only rarely associated with an inherited syndrome (such as multiple endocrine neoplasia type 1), usually arise in the tail of the pancreas and are typically large and metastatic at diagnosis.¹

A set of clinical signs and symptoms, the glucagonoma syndrome, has been described and associated with these tumours. However none of them are specific of this entity, which may complicate and delay the diagnosis. This syndrome comprises weight loss, NME, hyperglycaemia, stomatitis, anaemia, venous thrombosis, diarrhoea and, less commonly, neuropsychiatric disorders and dilated cardiomyopathy.^{1 2} Glucagon has a pronounced catabolic effect, stimulating lipolysis and enhancing amino acid catabolism, resulting in hypoaminoacidemia and fatty acid deficiencies. Mild anaemia and impaired liver function may also be observed.^{1 3}

Wilkinson first used the term ‘necrolytic migratory erythema’ in 1973 for a particular skin rash related with glucagonomas.⁴

Our patient presented with NME as the first manifestation of the glucagonoma, which is the case in around 70% of patients, highlighting the importance of careful assessment of the skin lesions to facilitate early diagnosis. However, NME lesions are not specific to the glucagonoma syndrome and they may be present in other entities including liver disease or malnutrition disorders (such as inflammatory bowel disease, celiac disease, pellagra, zinc deficiency and kwashiorkor).

The pathogenesis of NME remains unclear. Hypotheses include a direct action of glucagon inducing skin necrolysis, an indirect effect of rising inflammatory mediators derived from arachidonic acid or a direct consequence of nutritional deficiencies (hypoaminoacidemia, zinc deficiency, essential fatty acids deficiency).^5–7

Clinically, NME appears in friction sites, such as groin, armpits, inner thighs, buttocks, as well as periorificial areas (perioral and perineum) and lower abdomen. It is characterised by an annular eruption that exhibits scaly erythematous papules and plaques with superficial epidermal necrosis and central flaccid large blisters. Lesions typically are pruritic and painful. They extend centrifugally, resulting in a serpiginous pattern, and become confluent. The rash usually evolves over 7–14 days, with occasional spontaneous remissions and exacerbations without identifiable precipitating factors. The same process often affects mucous membranes, resulting in glossitis, angular cheilitis, stomatitis and blepharitis.^{8 9}

Regarding the pathological diagnosis, different patterns may be found depending on the timing and the area biopsied and, often, histological examination only shows non-specific subacute dermatitis. The reference centre of Hadassah-Hebrew in Jerusalem published a review of patients diagnosed with glucagonoma whose skin biopsy reports were non-specific and only one from six was clearly positive for NME, even after review of the biopsies and despite having the diagnosis of glucagonoma already confirmed.² An optimal biopsy, preferably of the edge of an early lesion, is expected to show necrolysis of the upper epidermis with vacuolated keratinocytes, leading to focal confluent necrosis. Upper layers of stratum spinosum will present necrosis too, with separation from the underlying epidermis, which is known as cleft formation and is highly characteristic of NME. Unfortunately, a skin biopsy could not be performed in our case. Regarding the treatment for glucagonomas, symptomatic relief is one of the most important aims. Neoplasm resection, whenever feasible, is the treatment of choice. Complete resection of the tumour allows better histological characterisation, achieving a rapid resolution of hyperglucagonaemia, and increased survival due to high cure rate.^{1 10} However, unfortunately, most patients diagnosed with glucagonoma have advanced disease not amenable to resection. Debulking surgery may be an option in patients with significant disease burden, especially in the presence of hepatic metastases, and can lead to good symptom palliation.⁴

When surgical treatment is not possible, medical alternatives should be explored, and SSA can offer excellent symptomatic control, with this and other case reports supporting its use.^{4 11} However, clinical improvement does not always correlate with a decrease in serum glucagon concentration, suggesting a possible additional direct effect of octreotide on the peripheral target.¹²

What makes our case exceptional is not so much the presence of NME, but rather the dramatic response to SSA, with a complete resolution after only one injection, accompanied by reduction in glucagon and chromogranin-A concentrations. This response highlights the strong antisecretory effect of SSA and supports its empirical use in patients presenting with symptoms leading to clinical suspicion of a functional NET.

Learning points.

• Glucagonomas are rare functioning neuroendocrine tumours, mostly arising from the pancreas.

• Glucagonomas are usually diagnosed in an advanced stage, when surgery cannot be performed.

• Necrolytic migratory erythema (NME) is a typical skin manifestation of these tumours; however, the pathogenesis remains poorly understood.

• Somatostatin analogue can provide a rapid and successful control of NME in patients with glucagonoma.