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A.G. Kriger

Russian Research Center of Radiology;
Russian Medical Academy of Postgraduate Education

S.V. Berelavichus

National Medical Research Center of Surgery named after A.V. Vishnevsky of Ministry of health of the Russian Federation

D.S. Gorin

National Medical Research Center of Surgery named after A.V. Vishnevsky of Ministry of health of the Russian Federation

V.I. Panteleev

Russian Research Center of Radiology

V.S. Demidova

A.V. Vishnevsky National Research Center for Surgery

P.I. Davydenko

A.V. Vishnevsky National Research Center for Surgery

A.B. Varava

A.V. Vishnevsky National Research Center for Surgery

A.R. Kaldarov

National Medical Research Center of Surgery named after A.V. Vishnevsky of Ministry of health of the Russian Federation

Pancreatic proinsulinoma


A.G. Kriger, S.V. Berelavichus, D.S. Gorin, V.I. Panteleev, V.S. Demidova, P.I. Davydenko, A.B. Varava, A.R. Kaldarov

More about the authors

Journal: Pirogov Russian Journal of Surgery. 2021;(3): 5‑10

Views: 2340

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To cite this article:

Kriger AG, Berelavichus SV, Gorin DS, Panteleev VI, Demidova VS, Davydenko PI, Varava AB, Kaldarov AR. Pancreatic proinsulinoma. Pirogov Russian Journal of Surgery. 2021;(3):5‑10. (In Russ., In Engl.)

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Organic hypoglycemia is a severe disorder of carbohydrate metabolism caused by endocrine-active neuroendocrine tumor (NET) of the pancreas. These tumors usually release insulin (insulinoma). Excessive synthesis of insulin precursor (proinsulin) is less common [1]. Currently, incidence of proinsulinoma is unknown. Only few cases of this tumor are reported in the world literature [1, 2]. Treatment strategy for NETs followed by hypoglycemia is identical and consists in total resection of tumor [3].

Clinical symptoms include spontaneous weakness, syncope, visual acuity disorders, seizures and other symptoms. Patients often appeal to neuropathologists, therapists, and psychiatrists. In most cases, physicians are not aware on detection of hypoglycemia and its causes. As a result, the correct diagnosis can be established many years after the first symptoms. The purpose of this report is to emphasize the problem of hypoglycemia on the example of 10 patients with proinsulinoma.

Material and methods

There were 82 patients with endocrine-active pancreatic NET followed by organic hypoglycemia in 2007 — 2019. As we gained experience, we drew attention to a group of hypoglycemic patients with deviations from the classic clinical picture of insulinoma. These patients had normal or slightly elevated insulin level. We identify insulin precursor (proinsulin) in addition to insulin in these patients since 2017. As a result, increased release of proinsulin at normal insulin concentration was found in 10 patients.

The same patients had atypical symptoms of disease. Clinical assessment consisted of a detailed analysis of anamnesis and physical features, including changes in body mass index (BMI). Instrumental examination included contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI). Laboratory survey comprised biochemical blood test, endocrine status (insulin, proinsulin, C-peptide). Arterial stimulated blood sampling was performed in 5 cases because X-ray data were unclear. Pathological examination of pancreatic tumors included urgent and elective histological and immunohistochemical analysis. Immunohistochemical reaction for proinsulin was not performed due to the lack of reagents.


Duration of disease from clinical manifestation of hypoglycemia to detection of proinsulinoma ranged from 6 months to 5 years. There were 7 women and 3 men aged 24 — 56 years (mean 32 years).

Fasting hypoglycemia was severe in all patients (up to 0.7 mmol / l). Various clinical manifestations of hypoglycemia were typical for this disease and consisted of typical neuroglycopenic and adrenergic symptoms. These signs had multiple individual details, but they did not differ from those in insulinoma. As a result, we were unable to determine clinical model of hypoglycemia following proinsulinoma for differential diagnosis with insulinoma.

The fundamental difference of proinsulinoma was the absence of weight gain in 7 patients and fast weight loss (from 210 to 90 kg in 9 months) in 1 patient (Table 1).

Table 1. Clinical and laboratory data of patients with proinsulinoma


































Duration of disease (months)











Weight gain

10 kg



Head, 13 mm

Body, 10 mm

Tail, 17 mm

Head, 17 mm

Tail, 9.5 mm

Body, 15 mm

Head, 16 mm

Isthmus, 11 mm

Head , 15 mm

Head , 46 mm

Minimal blood glucose (N — 3,3 — 5,5 mmol/l)











Serum insulin (N — 2,6-24,9 mIU/l)











Serum proinsulin (N M — 0,5 — 3,5; F — 0,7 — 4,3 pmol/l)











Increase of serum proinsulin (times)

Upper limit










C-peptide level











Tumor was not visualized in CT native phase. Peak contrast enhancement was noted in arterial phase. Contrast agent accumulation was intense and even in 7 patients with tumors of low (G1) malignancy potential (Fig. 1). In 3 patients with higher biological aggressiveness (G2), uneven accumulation of contrast agent was noted. The foci were not differentiated on the background of intact parenchyma throughout venous and delayed phase.

Fig. 1. G1 NET of the pancreatic head.

a — CT of the abdominal cavity, arterial phase, axial plane; b — CT of the abdominal cavity, arterial phase, frontal plane.

MR features were similar to other neuroendocrine neoplasms (moderate signal enhancement in T2WI and T2WI with fat suppression, reduced T1WI signal, various ovoid shapes, and clear uneven contours). Features of contrast enhancement were similar to CT data. No diffusion impairment on DWI was observed.

Radiological diagnosis demonstrated tumor localization in dorsal anlage of the pancreas in patients with proinsulinoma (head, body, or tail). None patient had tumor in uncinate process, while insulinomas were detected in both dorsal and ventral anlages of the pancreas (Table 1).

Arterial stimulated blood sampling was valuable to clarify localization of tumor in 5 patients (Fig. 2).

Fig. 2. Insulin levels in intra-arterial stimulation.

a — insulin level. An increased release of insulin during gastroduodenal artery stimulation determines tumor of the pancreatic head; b — C-peptide level.

All patients were operated on. Minimally aggressive interventions were applied in most cases (tumor enucleation in 6 patients, spleen-sparing distal pancreatectomy in 3 cases). Pancreatoduodenectomy with lymphadenectomy was performed in 1 patient with tumor size of 46 mm (G2) that was later confirmed by autopsy (Fig. 3). Early postoperative period was complicated by severe postoperative pancreatitis in 1 patient after pancreatic head tumor enucleation that required intensive therapy and extracorporeal detoxification. Pancreatic fistula without severe symptoms occurred in 3 patients. Stricture of hepaticojejunostomy occurred in long-term period after pancreatoduodenectomy. Stenting was effective for thic complication.

Fig. 3. Neuroendocrine tumor of the pancreatic head.

a — CT of the abdominal cavity, arterial phase, axial plane; b — CT of the abdominal cavity, arterial phase, frontal plane; c, d — histological examination.

Biopsy confirmed NET in all cases. G1 neoplasm was diagnosed in 7 cases, G2 — in 3 patients. Immunohistochemical analysis for insulin was carried out only in 4 patients. Moderate cytoplasmic expression was observed in 3 cases, mild expression — in 1 patient.


Endocrine-active pancreatic NETs represent a pool of potentially malignant neoplasms with specific clinical picture. Proinsulinoma and insulinoma result persistent disorders of carbohydrate metabolism. Hypoglycemic state destroys physiological status of patients. World data on proinsulinoma are presented by few case reports. R. Alsever et al. [4] first described proinsulin-releasing pancreatic tumor in 1975. In total, we found 20 descriptions of pancreatic proinsulinoma including 3 our patients described in previous manuscripts [1, 2, 5 — 7].

Patients with hypoglycemia describe their own feelings variously. We found no differences in clinical symptoms of hypoglycemia in case of insulinoma and proinsulinoma. These symptoms were more significant on an empty stomach and disappeared after ingestion of food or liquid rich in easily digestible carbohydrates. Feeling of hunger was absent. In long-standing disease, mental disturbances occurred (impaired intelligence and memory) [3].

At the same time, we identified a specific feature of proinsulinoma. There was no BMI augmentation despite an increased consumption of carbohydrates for a long time. Increased body weight following frequent consumption of carbohydrates for relief and prevention of hypoglycemia is well-known in patients with insulinoma. Weight gain is also due to insulin effect (suppression of lipolysis and stimulation of lipogenesis in adipocytes) on the background of its advanced release. Importantly, insulin level necessary for inhibition of lipolysis is much less than that for stimulation of glucose uptake by the muscles and suppression of glucose production in the liver [8]. Correlation between high insulin level and risk of obesity was observed in certain ethnic groups [9]. In addition, some studies confirmed the effect of hyperinsulinemia on excess body weight. In particular, body weight decrease following insulin receptor blockade in adipocyte was reported in experimental researches. Drug-induced inhibition of insulin secretion (diazoxide, analogues of somatostatin) also causes weight loss [8].

Perhaps, no weight gain in patients with proinsulinoma is caused by lower biological activity of proinsulin (10% compared to insulin) [10]. In 2017, Murtha T. et al. [1] conducted a systematic analysis of 16 patients with proinsulin-releasing pancreatic tumors. The authors showed that proinsulinomas were highly differentiated (G1) small tumors (mean 1.2 cm). These neoplasms were more common in middle-aged women and localized in the pancreatic body and tail (80%). According to our data, proinsulinomas were found in the head, body or tail of the pancreas. However, they were never located in the uncinate process. Perhaps, this is due to the peculiarities of embryogenesis. This hypothesis requires further research.

Fadini et al. described arterial stimulated blood sampling for diagnosis of proinsulinoma only. The method was ineffective because the tumor did not response to stimulation with calcium gluconate [11]. In our study, proinsulinoma showed release of insulin and C-peptide in response to stimulation with calcium gluconate in all 5 cases. Therefore, we consider this method to be justified in the diagnosis of proinsulinoma.

Resection of proinsulinoma is the only treatment, and organ-sparing procedures are preferred.

Similar to most pancreatic NETs, proinsulinomas demonstrate immunohistochemical staining for chromogranin A and synaptophysin. In 2019, Celli et al. [12] retrospectively analyzed 136 patients with pancreatic NETs. Proinsulin expression was revealed in 36 (26%) cases, simultaneous release of insulin was noted in 32 (89%) of these tumors. Among all proinsulin-releasing tumors, 9 (25%) neoplasms were functional insulinomas. These tumors showed lower blood glucose level. However, serum proinsulin was mot analyzed. In our study, proinsulin expression was not assessed due to technical reasons, insulin expression was also determined in only 4 people.

Thus, neuroendocrine proinsulin-releasing pancreatic tumors are common, and only IHC-based diagnosis of proinsulinoma is impossible. Increased serum proinsulin combined with symptoms of organic hypoglycemia and imaging data on NET are essential in the diagnosis.

Considering our own and world data, we can conclude that proinsulinoma is endocrine-active NET of the pancreas characterized by proinsulin release and hypoglycemic syndrome.

Many clinicians have no idea about the existence of proinsulinoma. Similar clinical, biochemical and radiological signs complicate differential diagnosis between proinsulinoma and pancreatic insulinoma. The diagnosis can come to a standstill in case of normal serum insulin and no obvious signs of pancreatic tumor in a patient with hypoglycemia.


Proinsulinoma is an extremely rare NET. Differential diagnostic criteria of pancreatic proinsulinoma are hypoglycemia, normal insulin level and increased serum proinsulin in a patient without weight gain. The diagnosis is verified by hypoglycemia, increased serum proinsulin and CT/MRI data on pancreatic tumor.

The authors declare no conflicts of interest.

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