Non-islet cell tumor hypoglycemia (NICTH) as a rare paraneoplastic syndrome in high-grade serous ovarian carcinoma: A case report and review of the literature

Highlights

• •This is the first reported case of non-islet cell tumor hypoglycemia (NICTH) presenting as the manifestation of high-grade serous ovarian cancer, both at initial diagnosis and at recurrence.
• •The severe hypoglycemia resulted from tumor-related secretion of high molecular weight IGF-II.
• •This rare paraneoplastic syndrome was associated with poor prognosis.

Abstract

Background

Non–islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome caused by excessive secretion of incompletely processed insulin–like growth factor–2 (IGF–2) from tumor cells. This leads to severe, refractory hypoglycemia.

Case Presentation

A 67–year–old woman presented with stage IIIC high-grade ovarian carcinoma associated with severe hypoglycemia at diagnosis, and at recurrence. Laboratory tests showed suppressed insulin and C–peptide levels, with an elevated IGF–2/IGF–1 ratio, consistent with NICTH. The patient underwent primary surgery followed by adjuvant platinum-based chemotherapy and maintenance therapy with bevacizumab and olaparib. This comprehensive treatment approach led to remission of both the carcinoma and the associated severe paraneoplastic hypoglycemia. The relapse of the disease was accompanied by a recurrence of hypoglycemia, refractory to medical treatement, which ultimately led to the patient’s death.

Conclusion

This represents the first reported case of HGSOC with NICTH, emphasizing the complexity of ovarian cancer presentations and the importance of early diagnosis and comprehensive management in rare paraneoplastic conditions.

1. Introduction

High-grade serous ovarian carcinoma (HGSOC) is the most common and most lethal subtype of epithelial ovarian cancer, usually diagnosed at an advanced stage and associated with a poor prognosis, with over 70 % of cases presenting at advanced stage.(Ledermann, 2024) Despite advances in surgical techniques and systemic treatments, the overall prognosis remains poor. Paraneoplastic syndromes are estimated to be occur in 10 % of ovarians tumors.(Ray and Kapoor, 2025) These syndromes are caused by tumor secretion of peptides, hormones, cytokines or by immune cross-reactivity between malignant and healthy tissues.(Pelosof and Gerber, 2010) In ovarian cancer, the most well-documented syndromes include hypercalcemia, anti-NMDA encephalitis (particularly in association with teratomas, caused by an auto-immune response where antibodies target neuronal antigens), and less frequently; paraneoplastic cerebellar degeneration. The latter is believed to result from immune-mediated damage to certain neuronal cells, with anti-Yo or anti-Hu antibodies implicated.(Zaborowski et al., 2015) These syndrome may precede, accompany, or follow the diagnosis ot the tumor, and ofter improve with tumor treatment.

Paraneoplastic hypoglycemia is a rare but life-threatening condition that can occur in association with various solid tumors, such as hepatocellular carcinoma or sarcoma.(Karamanolis, 2024) It is typically mediated by tumor secretion of insulin-like growth factor-2 (IGF-2), leading to non-islet cell tumor hypoglycemia (NICTH).(Ata, 2024).

We present a case of a patient diagnosed with severe paraneoplastic hypoglycemia at the time of initial diagnosis of a HGSOC. The diagnosis of NICTH was made at the time of recurrence, which led to the patient’s death due to severe hypoglycemia that was refractory to medical treatment. To our knowledge, this is the first reported case of this syndrome associated with HGSOC.

2. Case report

2.1. Initial presentation

A 67-year-old woman with a body mass index (BMI) of 22 kg/m² and a medical history of appendicular peritonitis, a transverse laparotomy for bowel obstruction, and smoking, was referred to our cancer center because of a suspicion of HGSOC. She presented with a 12 cm pelvic mass, associated with ascites, and an elevated CA 125 level of 2859 UI/mL. Initial laparoscopy revealed an omental cake, moderate ascites, and pelvic carcinomatosis, with a Peritoneal Cancer Index (PCI) score of 15. She had stage IIIC disease and biopsy confirmed HGSOC with homologous recombination deficiency. She was found to have significant malnutrition, with a 5 kg weight loss over the past 3 weeks and albumin of 3 g/dl. Additionally, she was noted to have severe hypoglycemia with a blood glucose level of 20 mg/l.

She was admitted to the hospital for preoperative nutritional support and prehabilitation.

A comprehensive biological work-up (Table 1) ruled out other potential causes of hypoglycemia, such as hyperinsulinism (evidenced by low insulin, low C-peptide and low IGF-1 levels) while imaging ruled out hepatic or adrenal tumors. Following multidisciplinary consultation (involving an endocrinologist, oncologist and gynecologic oncologic surgeon), a diagnosis of paraneoplastic hypoglycemia secondary to NICTH was considered, supported by an IGF-2/IGF-1 ratio > 10.

Table 1.

Laboratory workup results with normal ranges, and units.

Laboratory test	Results	Normal range
Glucose	20 mg/l	70 – 100 mg/l
Creatinine	5.31 mg/l	5–9.5 mg/l
Potassium	4.2 mmol/l	3.5–5 mmol/l
CA 125	2859 kU/l	< 32 kU/l
Cortisol	19.5 µg/dl	6.2–19.4 µg/dl
Insulin	< 0.4 mUI/l	2.6–16 mUI/l
C-peptide	0.0716 ng/ml	1.1–4.4 ng/ml
Pro-insulin	3.6 pmol/l	2.7–14.2 pmol/l
IGF-1	32 ng/ml	38.3–162.5 ng/ml
IGF-2	929 ng/ml	373–1000 ng/ml
IGF-2/IGF-1 ratio	29	< 10
Anti-insulin antibody	0.2 UA	< 18.0 UA
Platelets	280 G/l	150–450 G/l
Calcium	2.27 mmol/l	2.20–2.60 mmol/l
Albumin	3 g/dl	3.5–5.2 g/dl

IGF: insulin-like growth factor; CA 125: cancer antigen 125.

She was treated with oral corticosteroids and 10 % glucose-serum infusion. The patient was monitored using a continuous glucose monitoring system.

After discussion at the tumor board, primary cytoreductive surgery was validated. The surgical procedures involved extended peritonectomy, radical omentectomy, hysterectomy, bilateral salpingo-oophorectomy (BSO), and splenectomy with no macroscopic residual disease. No intra-operative or post-operative major complications occurred. Final histopathological examination confirmed a stage IIIC disease, with all surgical specimens showing tumor involvement. The patient subsequently received six cycles of carboplatin and paclitaxel, followed by maintenance therapy with bevacizumab and olaparib. Following completion of the surgical treatment, glycemic levels returned to normal, and the patient no longer presented hypoglycemia.

2.2. Relapse

Twelve months later, an increasing of CA 125 blood level (at 120 UI/ml) was observed, and a CT-scan showed a peritoneal relapse. The case was reviewed by the multidisciplinary tumor board, which recommended a second-line chemotherapy regimen consisting of six cycles of carboplatin and pegylated liposomal doxorubicin. PET-CT revealed stable disease following completion of chemotherapy. No hypoglycemia was diagnosed at this time. She was then started on metronomic oral cyclophosphamide as a maintenance therapy. Six months later, she presented with severe confusion and slurred speech, witch led to the diagnosis of severe hypoglycemia with a blood glucose level below 30 mg/l. Concurrently, radiological progression involving supradiaphragmatic lymph nodes was observed, and third-line chemotherapy with gemcitabine was initiated. After acute management of hypoglycemia, she was started on prednisolone (40 mg per day), which maintained her blood glucose between 75 mg/l and 125 mg/l.

2.3. Progression

After 5 months of gemcitabine treatment, a disease progression was observed, biologically and upon imaging. Concomitantly, the episodes of severe hypoglycemia occurred again despite the 40 mg per day of prednisolone. The treatment was then intensified with high-dose corticosteroids (up to 80 mg per day), somatostatin analogs (somatuline 120 mg every 3 weeks), and continuous infusion of 10 % glucose solution (2 L/day), which maintained her blood glucose in normal ranges.

Six weeks later, due to the worsening glycemic instability, the patient was transferred to home hospitalization care, where she was switched to a continuous 30 % glucose infusion, at rates between 70 and 100 ml/h, to maintain blood glucose levels above 70 mg/l. Despite these intensive measures, she was admitted to the emergency department two weeks after because of a coma due to a critical hypoglycemic episode (blood glucose: 20 mg/l). No further therapeutic options were available, despite comprehensive multidisciplinary management involving endocrinologists and oncologists. After thorough discussions with the patient’s family, and a final review by the medical board, a collective decision was made to discontinue active treatment. Following cessation of therapy and initiation of sedation, the patient passed away within a few hours.

3. Discussion

To the best of our knowledge, this is the first reported case of paraneoplastic hypoglycemia associated with HGSOC. According to a recent review of the literature, the most common tumors associated with NICTH are fibrous tumors (53.2 %), followed by hepatocarcinoma (9 %).(Ata, 2024) In the gynecological oncology field, two cases of NICTH associated to ovarian carcinosarcoma have been described (Elemian et al., 2024, Kojima et al., 2013), as well as one case related to a pelvis solitary fibrous tumor (Pinho Dos Santos et al., 2021). These cases provide further evidence of the diverse malignancies that can be associated with NICTH, though the link between HGSOC and this paraneoplastic syndrome remains unique in the report.

In this case, although total serum IGF-2 was within the normal range (929 ng/mL), IGF-1 was markedly suppressed (32 ng/mL), resulting in an IGF-2/IGF-1 ratio of 29. A ratio exceeding 10 is considered highly suggestive of NICTH, likely due to the tumor’s production of incompletely processed “big IGF-2″ which is not accurately captured by standard immunoassays.(Ata, 2024) Unlike regular IGF-2, ”big IGF-2″ forms smaller protein complexes that circulate more freely, enhancing its insulin-like effects while suppressing insulin and IGF-1, leading to severe hypoglycemia.

In addition to NICTH, other mechanisms of hypoglycemia have been reported in association with ovarian cancer. One such mechanism is hyperinsulinism, which can result from ectopic insulin secretion by the tumor (Battocchio, 2015). The biochemical profile during hypoglycemia is different than the one involved in NICTH, with high insulin, high C-peptide, and low IGF-2/IGF-1 ratio.

More recently, a case of AKT2 gene duplication has been described (an important role player in mediating insulin signaling and cellular growth), leading to increased insulin sensitivity and subsequent hypoglycemia, thus providing a novel genetic explanation for paraneoplastic hypoglycemia in ovarian cancer (Alkaissi et al., 2022).

Refractory hypoglycemia is a significant medical challenge, especially in the context of NICTH associated with HGSOC. This condition can be very hard to manage, as standard therapies, including glucose infusions, corticosteroids, and somatostatin analogs, often fail to provide adequate control of blood glucose level. In our case, this ultimately led to the patient’s demise. This underscores the need for early diagnosis, innovative therapeutic approaches, and a multidisciplinary management strategy, involving oncologists, endocrinologists and oncological surgeons, to address the complex nature of paraneoplastic hypoglycemia and improve patient outcomes.

Funding information

The authors received no specific funding for this work.

Ethics approval and consent to participate

Ethical approval was not required for this case report in accordance with the policies of the Ethics Committee of Institut Universitaire du Cancer de Toulouse.

Consent for publication

Written informed consent for publication was obtained from the patient’s next of kin.

Data availability

No data is available online about this case report.

Competing interests

The authors declare no conflict of interest.

CRediT authorship contribution statement

Maria Selloua: Writing – original draft, Investigation, Data curation. Giulio Ricotta: Writing – review & editing, Validation, Supervision, Methodology. Pierre Cougoul: Writing – review & editing, Validation, Methodology. Laurence Gladieff: Validation, Supervision, Project administration. Gwenaël Ferron: Writing – review & editing, Supervision, Project administration, Methodology, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.