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Background/Objective: Non–islet cell tumor hypoglycemia (NICTH) is an uncommon condition, of which only a few cases caused by malignant phyllodes tumor of the breast have been reported. We describe a case of NICTH secondary to malignant phyllodes tumor with good response to glucocorticoid therapy. Case Report: A 62-year-old woman with a rapidly enlarging left breast mass presented with drowsiness and a capillary blood glucose level of 32.4 mg/dL. Her plasma glucose and insulin levels were 36.0 mg/dL (reference range, 72-144 mg/dL) and 0.6 mIU/L (reference range, 0.0-25.0 mIU/L), respectively. Her beta-hydroxybutyrate and c-peptide levels were undetectable. The insulin-like growth factor (IGF)-I and IGF-II levels were 37 μg/L (reference range, 43-220 μg/L) and 1062 ng/mL (reference range, 333-967 ng/mL), respectively, with an IGF-II:IGF-I molar ratio of 29.4. Prednisolone 30 mg per day was initiated with improvement in hypoglycemia. Outpatient flash glucose monitoring profile was stable with mild hypoglycemia (glucose level, 54-68.5 mg/dL) detected 5% of the time. The patient underwent left mastectomy with axillary clearance 4 weeks later. Histology was reported as malignant phyllodes tumor with extensive ductal carcinoma in situ. Prednisolone was stopped after surgery. The patient was treated with letrozole and adjuvant radiotherapy. There was no recurrence of hypoglycemia during the subsequent 24-month follow-up. Discussion: The mainstay of treatment for NICTH is surgical resection of the culprit tumor. Although glucocorticoid treatment has also been widely used for NICTH, few reports have demonstrated efficacy for NICTH secondary to phyllodes tumor. Conclusion: We report a rare case of malignant phyllodes tumor of the breast resulting in NICTH and demonstrated good response to glucocorticoids as a bridge to definitive surgery.

Background Doege–Potter syndrome, characterized by solitary fibrous tumors and non‐islet cell tumor hypoglycemia, is rare. Here, we report a case of Doege–Potter syndrome in which retroperitoneal tumor resection was performed with continuous intraoperative blood glucose monitoring. Case presentation A 37‐year‐old man presented with hypoglycemia‐related symptoms, and a 10 × 12 × 9 cm tumor was found in his right kidney. Following tumor resection, insulin secretory abnormalities improved, and intraoperative blood glucose monitoring showed no hypoglycemic events. High levels of insulin‐like growth factor‐II confirmed the diagnosis of an insulin‐like growth factor‐II‐producing tumor with non‐islet cell tumor hypoglycemia. Postoperative serum insulin‐like growth factor‐II levels normalized, with no recurrence observed over 3 years. Conclusions This case highlights the rarity of primary retroperitoneal Doege–Potter syndrome, emphasizes the safety of intraoperative blood glucose levels during surgery, and suggests rapid recovery of insulin secretion postoperatively.

Paraneoplastic hypoglycemia, also known as non-islet cell tumor hypoglycemia (NICTH), is a rare but critical condition occurring in patients with different types of malignancy. This condition is commonly linked to tumors producing insulin-like growth (IGF) factors, particularly IGF-2 and its precursors, which disrupt glucose homeostasis and lead to excessive glucose consumption. The diagnosis typically involves documenting symptomatic hypoglycemia and ruling out other potential causes. Essential diagnostic tools include imaging studies and laboratory tests, specifically measuring IGF-2 levels and the IGF-2:IGF-1 ratio. Treatment strategies for NICTH are multifaceted and may include surgical resection of the tumor if feasible, pharmacological interventions such as corticosteroids to suppress IGF-2 production, or supportive measures to manage acute hypoglycemic episodes. Novel therapeutic approaches targeting IGF-2, such as monoclonal antibodies or siRNA, are also being explored and hold promise for future treatment options. This review aims to enhance understanding of paraneoplastic hypoglycemia, focusing on its pathogenesis and diagnosis, to guide optimal medical treatment.

Background: Non-islet cell tumor-induced hypoglycemia (NICTH) is a rare, lifethreatening medical condition caused by excessive insulin-like growth factor II (IGF-II) secretion from tumors of most commonly mesenchymal origin. Using next-generation sequencing, we have characterized the genome and transcriptome of the resected IGF-II-secreting solitary fibrous tumor from a patient with severe hypoglycemia accompanied by hypoglycemia unawareness. Case presentation: A 69-year-old male patient presenting with abdominal discomfort was examined using computer tomography, revealing a large lesion at the lesser pelvis extending above the umbilicus. As no bone and lymph node metastases were detected, the patient was scheduled for laparotomy. Before surgery, the patient presented with symptoms of severe hypoglycemia. Suppressed C-peptide levels and subsequent hypokalemia indicated a possible case of NICTH. The patientwas treatedwithmethylprednisolone (8 mg) to assess hypoglycemia. After the surgery, mild hypoglycemia was present for the postoperative period, and no radiological recurrences were observed 3 and 12 months after discharge. Histopathological examination results were consistent with the diagnosis of malignant solitary fibrous tumor (SFT). Overexpression of IGF-II was confirmed by both immunohistochemistry and RNA sequencing. Further NGS analysis revealed an SFT characteristic alteration--NAB2-STAT6 fusion. Additionally, three deleterious missense variants were detected in oncogenes BIRC6, KIT, and POLQ, and one homozygous in-frame deletion in the RBM10 tumor suppressor gene. Conclusion: While the NAB2-STAT6 fusions are well characterized, the mutational landscape of SFTs remains understudied. This study reports the importance of NGS to characterize SFTs as we detected four coding variants in genes (BIRC6, KIT, POLQ, and RBM10) associated with tumorigenesis that could potentially contribute to the overall pathogenesis of SFT. [ABSTRACT FROM AUTHOR]

Non-islet cell tumor hypoglycemia (NICTH) is a rarely encountered cause of hypoglycemia. It is most often caused by tumor secretion of precursor insulin-like growth factor-2 (IGF-2) which, in high concentrations, binds to insulin receptors exerting insulin-like metabolic effects. It is often associated with mesenchymal and hepatic tumors. We describe 3 cases of NICTH: a 60-year-old man with an unresectable pelvic sarcoma and two women ages 43 and 57 with metastatic hemangiopericytoma. Biochemical assessment identified hypoglycemia associated with suppressed insulin, c-peptide, and beta-hydroxybutyrate levels. Each patient was treated with oral glucocorticoids, which effectively prevented recurrence of hypoglycemia and this effect was sustained long-term. These cases highlight a rarely encountered but important cause of hypoglycemia and demonstrate the long-term efficacy of glucocorticoid treatment in preventing hypoglycemia in cases of NICTH related to surgically unresectable tumors. [ABSTRACT FROM AUTHOR]

BackgroundNon-islet cell tumor-induced hypoglycemia (NICTH) is a rare, life-threatening medical condition caused by excessive insulin-like growth factor II (IGF-II) secretion from tumors of most commonly mesenchymal origin. Using next-generation sequencing, we have characterized the genome and transcriptome of the resected IGF-II-secreting solitary fibrous tumor from a patient with severe hypoglycemia accompanied by hypoglycemia unawareness.Case presentationA 69-year-old male patient presenting with abdominal discomfort was examined using computer tomography, revealing a large lesion at the lesser pelvis extending above the umbilicus. As no bone and lymph node metastases were detected, the patient was scheduled for laparotomy. Before surgery, the patient presented with symptoms of severe hypoglycemia. Suppressed C-peptide levels and subsequent hypokalemia indicated a possible case of NICTH. The patient was treated with methylprednisolone (8 mg) to assess hypoglycemia. After the surgery, mild hypoglycemia was present for the postoperative period, and no radiological recurrences were observed 3 and 12 months after discharge. Histopathological examination results were consistent with the diagnosis of malignant solitary fibrous tumor (SFT). Overexpression of IGF-II was confirmed by both immunohistochemistry and RNA sequencing. Further NGS analysis revealed an SFT characteristic alteration—NAB2-STAT6 fusion. Additionally, three deleterious missense variants were detected in oncogenes BIRC6, KIT, and POLQ, and one homozygous in-frame deletion in the RBM10 tumor suppressor gene.ConclusionWhile the NAB2-STAT6 fusions are well characterized, the mutational landscape of SFTs remains understudied. This study reports the importance of NGS to characterize SFTs as we detected four coding variants in genes (BIRC6, KIT, POLQ, and RBM10) associated with tumorigenesis that could potentially contribute to the overall pathogenesis of SFT.

Background: Non-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome caused by a tumor-producing high molecular weight form of insulinlike growth factor 2 (IGF2) known as big IGF2. The only curative treatment for this condition is surgical resection of the responsible tumors. However, this may not be feasible in cases with multiple metastases at diagnosis of NICTH, and no standard treatment strategy for multiple tumors has been established. The effects of pharmacological therapies including somatostatin analogs are often inefficient and remain difficult to predict. Case description: A 68-year-old man was admitted to our hospital due to impaired consciousness and severe hypoglycemia. His medical history included diagnosis of a left temporal solitary fibrous tumor (SFT) at the age of 48 years, after which local recurrent and metastatic tumors were repeatedly resected. Four years before admission, multiple intraabdominal and subcutaneous tumors were detected and, being asymptomatic, were managed conservatively. Laboratory exam on admission demonstrated hypoglycemia accompanied with low serum insulin and IGF1 levels. Computed tomography (CT) scan revealed multiple intraabdominal and subcutaneous tumors increasing in size. Serum big IGF2 was detected on immunoblot analysis, and he was diagnosed as NICTH. In addition, tumor uptake was observed on 68Ga-labelled 1,4,7,10-tetraazacyclododecane-N, N’,N’’,N’’’-tetraacetic acid-d-Phe¹ -Tyr³ -octreotide positron emission tomography/CT (DOTATOC-PET/CT). Since larger tumor is more suspicious about responsible producibility of big IGF2, we planned to resect large ones preferentially and reduce the amounts of residual tumors. Debulking surgery was performed by removing eleven intraabdominal tumors; the hypoglycemia was then completely corrected. Histological analyses revealed the resected tumors to be metastases of SFT having somatostatin receptor 2 expression. In immunoblot analysis, the resected tumors were found to be positive for big IGF2; serum big IGF2 was undetectable after surgery Conclusion: We present a case of NICTH with multiple metastatic SFTs. We strategically performed debulking surgery, which led to remission of hypoglycemia. This result demonstrates a pioneering practical solution for NICTH cases with multiple tumors. In addition, in cases of SFTs presenting with NICTH, positivity of DOTATOC-PET/CT as well as single-dose administration of octreotide may be predictive of the efficacy of somatostatin-based therapy. [ABSTRACT FROM AUTHOR]

Despite multiple intracranial and extracranial relapses associated with a widely metastatic meningeal solitary fibrous tumor (formerly classified as hemangiopericytoma), a 66-year-old type 2 diabetic man was first diagnosed with paraneoplastic hypoglycemia 23 years after the original diagnosis and 12 years after the onset of extracranial metastatic disease. An enlarging mass entirely replacing the left kidney measuring 11.6 × 10 × 28 cm, which had not been locally treated before, was considered to be the putative source of IGF-2 excess. The insulin-like effects of IGF-2 not only ameliorated his long-standing type 2 diabetes mellitus, but also caused spontaneous fasting hypoglycemia. The physiopathology, clinical manifestations, diagnostic approach, and treatment of non-islet cell tumor hypoglycemia are briefly discussed here. Palliative tumor debulking improved the hypoglycemia by day 11 after radiation therapy and glucose monitoring with continuous glucose monitoring system (Dexcom G6) facilitated the patient’s management and gave him peace of mind. [ABSTRACT FROM AUTHOR]

Non-islet cell tumor hypoglycemia is an uncommon paraneoplastic phenomenon commonly associated with tumors of mesenchymal origin like gastrointestinal stromal tumors (GIST). It causes the release of insulin-like growth factor type II. GIST are frequently asymptomatic but can present with vague symptoms such as gastrointestinal bleeding, gastric pain, anorexia, nausea, and vomiting. We present an interesting case of A 62-year-old male with GIST tumor admitted for refractory hypoglycemia found to have non-islet cell tumor hypoglycemia which is a relatively uncommon cause of hypoglycemia. [ABSTRACT FROM AUTHOR]

ObjectivesTo describe the clinicopathologic findings, imaging results, surgical treatment, and outcome of a dog with renal cell carcinoma (RCC) and paraneoplastic hypoglycemia.AnimalsA 13-year-old female spayed mixed breed dog that was presented for facial twitching and neurologic decline and diagnosed with a renal mass and paraneoplastic hypoglycemia.Study designCase report.MethodsSerum chemistry revealed severe hypoglycemia and normal renal values. Abdominal ultrasonography showed a large, heterogeneous, cavitated mass associated with the left kidney and no evidence of abdominal metastatic disease. Thoracic radiographs revealed no evidence of pulmonary metastatic disease. Fasted serum insulin was low concurrently with severe hypoglycemia. No other causes of hypoglycemia were detected, and paraneoplastic hypoglycemia was suspected.ResultsAfter initial medical management of the dog's hypoglycemia, left nephroureterectomy was performed. Histopathology was consistent with RCC. Postoperatively, the dog's hypoglycemia resolved, and supplementation was discontinued. The dog remained stable and was discharged from the hospital 3 days after surgery. At 2-week, 3-month, and 5-month follow up evaluations, the dog remained euglycemic, and no definitive evidence of disease progression was detected. Eight months postoperatively, the dog was euthanized due to decline in mobility. Necropsy and histopathology revealed cerebral and spinal cord multifocal myelin sheath dilation and two primary pulmonary carcinomas with no evidence of recurrence or metastasis of the RCC.ConclusionSurgical treatment of RCC with subsequent resolution of paraneoplastic hypoglycemia has not previously been reported in veterinary medicine. In this dog, nephroureterectomy for RCC resulted in immediate and sustained resolution of paraneoplastic hypoglycemia.

BackgroundNon-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome caused by a tumor-producing high molecular weight form of insulin-like growth factor 2 (IGF2) known as big IGF2. The only curative treatment for this condition is surgical resection of the responsible tumors. However, this may not be feasible in cases with multiple metastases at diagnosis of NICTH, and no standard treatment strategy for multiple tumors has been established. The effects of pharmacological therapies including somatostatin analogs are often inefficient and remain difficult to predict.Case descriptionA 68-year-old man was admitted to our hospital due to impaired consciousness and severe hypoglycemia. His medical history included diagnosis of a left temporal solitary fibrous tumor (SFT) at the age of 48 years, after which local recurrent and metastatic tumors were repeatedly resected. Four years before admission, multiple intraabdominal and subcutaneous tumors were detected and, being asymptomatic, were managed conservatively. Laboratory exam on admission demonstrated hypoglycemia accompanied with low serum insulin and IGF1 levels. Computed tomography (CT) scan revealed multiple intraabdominal and subcutaneous tumors increasing in size. Serum big IGF2 was detected on immunoblot analysis, and he was diagnosed as NICTH. In addition, tumor uptake was observed on 68Ga-labelled 1,4,7,10-tetraazacyclododecane-N,N’,N’’,N’’’-tetraacetic acid-d-Phe1-Tyr3-octreotide positron emission tomography/CT (DOTATOC-PET/CT). Since larger tumor is more suspicious about responsible producibility of big IGF2, we planned to resect large ones preferentially and reduce the amounts of residual tumors. Debulking surgery was performed by removing eleven intraabdominal tumors; the hypoglycemia was then completely corrected. Histological analyses revealed the resected tumors to be metastases of SFT having somatostatin receptor 2 expression. In immunoblot analysis, the resected tumors were found to be positive for big IGF2; serum big IGF2 was undetectable after surgery.ConclusionWe present a case of NICTH with multiple metastatic SFTs. We strategically performed debulking surgery, which led to remission of hypoglycemia. This result demonstrates a pioneering practical solution for NICTH cases with multiple tumors. In addition, in cases of SFTs presenting with NICTH, positivity of DOTATOC-PET/CT as well as single-dose administration of octreotide may be predictive of the efficacy of somatostatin-based therapy.

Recurrent hypoglycaemia is a rare paraneoplastic syndrome associated with several cancers, including renal cell carcinoma (RCC). Here we present a curious case of a patient with type 2 diabetes mellitus (T2DM) who had numerous hospitalisations due to recurrent hypoglycaemia. A well-defined lesion at the lower pole of the right kidney and bilateral pyelonephritis were found during imaging investigations. A biopsy from the lesion confirmed clear cell carcinoma of the kidney and the most probable cause of recurrent hypoglycemia was paraneoplastic syndrome related to RCC. Analysis of Insulin-like growth factor levels revealed that recurrent hypoglycaemia might be the result of non-islet cell tumor-hypoglycaemia (NICTH). This case emphasizes how crucial it is to rule out paraneoplastic syndromes like NICTH in individuals presenting with hypoglycaemia that cannot be explained, even when pre-existing diabetes is present. Furthermore, this study emphasizes the need to include RCC in the differential diagnosis., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, S et al.)

BackgroundNon-islet cell tumor hypoglycemia (NICTH) is a rare cause of hypoglycemia due to the overproduction of high molecular weight insulin-like growth factor (big-IGF2), which activates the insulin receptor and subsequently caused hypoglycemia. But NICTH with acromegaly had rarely been reported. We firstly reported a rare case of NICTH concurrent with acromegalic facial features induced by a retroperitoneal hemangiopericytoma and reviewed similar cases in the literature.Case presentationA 30-year old man was admitted to hospital because of recurrent unconscious, which usually occurred in the late afternoon or early morning before supper or breakfast. On one unconscious occasion, his blood glucose was 2.4 mmol/L. His consciousness recovered rapidly with intravenous 50% glucose administration. Physical examination showed that he had coarse oily facial features with acne, prominent forehead and brow, broad nose, prominent nasolabial folds. At the time of hypoglycemia, suppressed serum insulin, GH and IGF-1 levels was found. Computed Tomography further revealed a large left retroperitoneal mass measuring 7.0 cm × 12.3 cm × 13.0 cm. He underwent complete surgical resection of the mass. Surgical pathology demonstrated a hemangiopericytoma and strong positive for IGF-2. He did not experience further episodes of hypoglycemia after the operation during the 2.5 years follow-up.ConclusionsFibrous origin is the most common tumor type for NICTH with acromegaly features. NICTH should be considered in non-diabetic patients who have recurrent hypoglycemia along with suppressed serum insulin and IGF-1 levels.

A 53-year-old, non-diabetic lady was evaluated for worsening breathlessness over the past 1 year. She was diagnosed with a lung lesion a year ago, but the prevailing COVID-19 situation prevented her from seeking further evaluation. She began to have early morning episodes of symptomatic hypoglycemia over the previous 4 months, which were relieved with dextrose infusions. The evaluation showed low insulin, low C-peptide, and high insulin-like growth factor-2 to insulin-like growth factor-1 ratio. High-resolution computed tomography scan of the thorax showed a 19.5 cm x 16.6 cm x 23.8 cm mass in the left hemithorax, and a microscopic examination of a biopsy specimen of which was consistent with the diagnosis of solitary fibrous tumor. The patient underwent sternotomy with left anterior thoracotomy with successful excision of the fibrous tumor. Post-operatively, histopathological diagnosis of solitary fibrous tumor was confirmed. There were no further episodes of hypoglycemia, and the patient was completely recovered. [ABSTRACT FROM AUTHOR]

A case of hypoglycemic coma caused by a giant borderline phyllodes tumor of the breast has been described. The patient, a 63-year-old woman, was admitted with recurrent unconsciousness. She had a giant breast tumor with decreased blood glucose, insulin, and C-peptide. The patient's hypoglycemia resolved rapidly after resection of the breast tumor. Pathological examination indicated a borderline phyllodes tumor of the breast, and immunohistochemistry suggested high expression of insulin-like growth factor-2 (IGF-2) in the tumor tissue. A literature review is also included to summarize the clinical characteristics of such patients and to serve as a unique resource for clinical diagnosis and treatment of similar cases. [ABSTRACT FROM AUTHOR]

Doege-Potter syndrome is a rare paraneoplastic syndrome that is often diagnosed incidentally during the workup of hypoglycemia of unclear etiology. It is characterized by a non-islet cell tumor hypoglycemia secondary to excessive production of partially processed IGF-II hormone from a solitary fibrous tumor (SFT). Often these tumors are intrathoracic, benign, and asymptomatic. Occasionally they present as a paraneoplastic event; hypertrophic osteoarthropathy in Pierre-Marie-Bamberger syndrome and hypoglycemia in Doege-Potter syndrome. The NAB2-STAT6 gene fusion is the hallmark of the SFT. Complete surgical resection of the tumor often results in resolution of symptoms and cure in most cases. Here we present the case of an 83-year-old non-diabetic female with recurrent syncopal events who was diagnosed with the Doege-Potter syndrome secondary to a SFT of pleura. Her tumor was positive for NAB2-STAT6 gene fusion on RT-PCR. Following the resection of the giant tumor mass, she became symptom-free within 24 h, and has remained asymptomatic at 4 months follow-up.

A case of hypoglycemic coma caused by a giant borderline phyllodes tumor of the breast has been described. The patient, a 63-year-old woman, was admitted with recurrent unconsciousness. She had a giant breast tumor with decreased blood glucose, insulin, and C-peptide. The patient’s hypoglycemia resolved rapidly after resection of the breast tumor. Pathological examination indicated a borderline phyllodes tumor of the breast, and immunohistochemistry suggested high expression of insulin-like growth factor-2 (IGF-2) in the tumor tissue. A literature review is also included to summarize the clinical characteristics of such patients and to serve as a unique resource for clinical diagnosis and treatment of similar cases.

Non‐islet cell tumor hypoglycemia (NICTH) is a very rare symptom of severe hypoglycemia associated with extrapancreatic tumors. It is considered to be caused by insulin‐like growth factor (IGF)‐II. There have been no autopsy cases of colorectal carcinoma with NICTH confirmed with both serum high molecular weight and tumoral IGF‐II. We report the case of a 46‐year‐old woman with advanced sigmoid colon cancer and liver metastases. She underwent open sigmoidectomy, and histologically, the lesion was a differentiated‐type tubular adenocarcinoma. Postoperative chemotherapy was initiated. However, she experienced repeated hypoglycemia attacks 10 months after the operation, while the liver metastases increased. We examined the cause of hypoglycemia, and finally diagnosed her with NICTH associated with high molecular weight IGF‐II production, which was proven by Western immunoblot of the serum. She died 12 months after surgery and was examined by autopsy. Liver metastases showed a transition from adenocarcinoma to carcinoma with neuroendocrine differentiation. Immunohistochemistry showed that both metastatic carcinoma of the liver and primary colonic adenocarcinoma were positive for IGF‐II. Neuroendocrine differentiation in liver metastases proven by an autopsy may have contributed to tumor growth, which may have exacerbated the symptoms. [ABSTRACT FROM AUTHOR]

Non-islet cell tumor hypoglycemia (NICTH) is a relatively rare paraneoplastic syndrome associated with tumors of mesenchymal and epithelial cell origin. Hypoglycemia can be the presenting symptom of NICTH or can appear later in the disease course. The cause of NICTH is stated to be due to secretion of poorly processed insulin-like growth factor (IGF)-2 and in most previous reported cases, the diagnosis of NICTH is made based on the identification of this fraction of IGF-2 or an increased ratio between total IGF-2 and IGF-1. However, in clinical setting, especially in developing countries, such tests cannot be readily available and a diagnosis of NICTH should not be delayed in a patient with a combination of solid tumor, recurrent fasting hypoglycemia, and a low serum insulin and C-peptide level. We describe in our report an 87-year-old man with a history of a pleural tumor presenting with recurrent episode of hypoglycemia. Although surgical removal of the tumor is the ideal management, it is often not feasible as exemplified in our report. In such cases, treatment with glucocorticoid is effective in alleviating the symptoms of hypoglycemia.

Non-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome characterized by insulin-like growth factor-2 (IGF-2) release, often associated with diverse tumor types. Gastrointestinal stromal tumors (GISTs), sarcomatous lesions of the gastrointestinal tract, are rarely associated with NICTH. We present a unique case of a 58-year-old patient diagnosed with a GIST exhibiting recurrent hypoglycemia suggestive of NICTH. Despite normal IGF-2 levels, the IGF-2/IGF-1 ratio supported the NICTH diagnosis, which was confirmed histologically. Imaging revealed a large intraperitoneal mass. Hypoglycemia was managed with high-dose dextrose and hydrocortisone. Treatment with the tyrosine kinase inhibitor, imatinib, was initiated. Surprisingly, imatinib not only reduced the tumor size but also improved hypoglycemia. The study highlights the complexities in managing NICTH and its underlying causes. Current diagnostic limitations, treatment modalities, and unexpected therapeutic responses challenge standard approaches. This emphasizes the need for personalized oncological strategies., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Nouira et al.)

Background: Doege-Potter syndrome, characterized by solitary fibrous tumors and non-islet cell tumor hypoglycemia, is rare. Here, we report a case of Doege-Potter syndrome in which retroperitoneal tumor resection was performed with continuous intraoperative blood glucose monitoring., Case Presentation: A 37-year-old man presented with hypoglycemia-related symptoms, and a 10 × 12 × 9 cm tumor was found in his right kidney. Following tumor resection, insulin secretory abnormalities improved, and intraoperative blood glucose monitoring showed no hypoglycemic events. High levels of insulin-like growth factor-II confirmed the diagnosis of an insulin-like growth factor-II-producing tumor with non-islet cell tumor hypoglycemia. Postoperative serum insulin-like growth factor-II levels normalized, with no recurrence observed over 3 years., Conclusions: This case highlights the rarity of primary retroperitoneal Doege-Potter syndrome, emphasizes the safety of intraoperative blood glucose levels during surgery, and suggests rapid recovery of insulin secretion postoperatively., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Author(s). IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Urological Association.)

Paraneoplastic hypoglycemia, also known as non-islet cell tumor hypoglycemia (NICTH), is a rare but critical condition occurring in patients with different types of malignancy. This condition is commonly linked to tumors producing insulin-like growth (IGF) factors, particularly IGF-2 and its precursors, which disrupt glucose homeostasis and lead to excessive glucose consumption. The diagnosis typically involves documenting symptomatic hypoglycemia and ruling out other potential causes. Essential diagnostic tools include imaging studies and laboratory tests, specifically measuring IGF-2 levels and the IGF-2:IGF-1 ratio. Treatment strategies for NICTH are multifaceted and may include surgical resection of the tumor if feasible, pharmacological interventions such as corticosteroids to suppress IGF-2 production, or supportive measures to manage acute hypoglycemic episodes. Novel therapeutic approaches targeting IGF-2, such as monoclonal antibodies or siRNA, are also being explored and hold promise for future treatment options. This review aims to enhance understanding of paraneoplastic hypoglycemia, focusing on its pathogenesis and diagnosis, to guide optimal medical treatment., Competing Interests: 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., (© 2024 The Authors. Published by Elsevier Inc.)

Background/objective: Non-islet cell tumor hypoglycemia (NICTH) is an uncommon condition, of which only a few cases caused by malignant phyllodes tumor of the breast have been reported. We describe a case of NICTH secondary to malignant phyllodes tumor with good response to glucocorticoid therapy., Case Report: A 62-year-old woman with a rapidly enlarging left breast mass presented with drowsiness and a capillary blood glucose level of 32.4 mg/dL. Her plasma glucose and insulin levels were 36.0 mg/dL (reference range, 72-144 mg/dL) and 0.6 mIU/L (reference range, 0.0-25.0 mIU/L), respectively. Her beta-hydroxybutyrate and c-peptide levels were undetectable. The insulin-like growth factor (IGF)-I and IGF-II levels were 37 μg/L (reference range, 43-220 μg/L) and 1062 ng/mL (reference range, 333-967 ng/mL), respectively, with an IGF-II:IGF-I molar ratio of 29.4. Prednisolone 30 mg per day was initiated with improvement in hypoglycemia. Outpatient flash glucose monitoring profile was stable with mild hypoglycemia (glucose level, 54-68.5 mg/dL) detected 5% of the time. The patient underwent left mastectomy with axillary clearance 4 weeks later. Histology was reported as malignant phyllodes tumor with extensive ductal carcinoma in situ. Prednisolone was stopped after surgery. The patient was treated with letrozole and adjuvant radiotherapy. There was no recurrence of hypoglycemia during the subsequent 24-month follow-up., Discussion: The mainstay of treatment for NICTH is surgical resection of the culprit tumor. Although glucocorticoid treatment has also been widely used for NICTH, few reports have demonstrated efficacy for NICTH secondary to phyllodes tumor., Conclusion: We report a rare case of malignant phyllodes tumor of the breast resulting in NICTH and demonstrated good response to glucocorticoids as a bridge to definitive surgery., Competing Interests: The authors have no conflicts of interest to disclose., (© 2024 AACE. Published by Elsevier Inc.)

Abstract Background Splenic cord capillary hemangioma is a rare benign vascular lesion classified as a splenic hamartoma. On the other hand, non-islet cell tumor hypoglycemia (NICTH) is one of the rare causes of spontaneous hypoglycemia and is considered to be one of the paraneoplastic syndromes. To the best of our knowledge, this is the first reported case of a splenic cord capillary hemangioma with NICTH. Case presentation A 25-year-old male was referred to our hospital with hypoglycemia. Except for his low blood sugar, there were no abnormal findings from laboratory tests, which included an endocrinological examination. Enhanced computed tomography confirmed the presence of a solid mass measuring about 6 cm in the retroperitoneum, and a tumorectomy was performed. During this operation, it became clear that the tumor turned out to be a splenic parenchyma, and as a result, a total splenectomy was performed. Microscopically, we diagnosed this as a cord capillary hemangioma, and through immunohistochemistry, we found that some tumor cells were positive for insulin-like growth factor -II. Fortunately, the hypoglycemia-related symptoms disappeared after surgical resection was performed. The patient is still alive and well without evidence of local tumor recurrence 15 years after the operation. Conclusions Splenic cord capillary hemangioma, one of the types of splenic hamartomas, is a very rare benign vascular lesion and might be associated with hypoglycemia thought to be NICTH.

Abstract Background Non-islet cell tumor producing insulin-like growth factor 2 involves hypoglycemia. During tumor resection, intense fluctuation of blood glucose level may occur. An artificial endocrine pancreas has been reported as beneficial for patients with insulinoma as it maintains stable glycemic levels, although scarcely described with insulin-like growth factor 2-releasing tumor. Case presentation An 84-year-old man had a recurrent left pleural solitary fibrous tumor releasing high molecular weight insulin-like growth factor 2 and experienced a frequent syncope accompanied by hypoglycemia. After anesthesia induction, an artificial endocrine pancreas, STG-55, was connected to the patient. Blood glucose level was stable at around 150 mg/dl during the resection surgery. The patient followed an uneventful course and was discharged without any complications. Conclusions An artificial endocrine pancreas may have the potential to stabilize the intraoperative blood glucose change in insulin-like growth factor 2-releasing tumor resection.

Phyllodes tumor (PT) is a special type of breast tumors, including three types: malignant, borderline, and benign. Most of these tumors form unilateral disease and can rapidly increase in size. The occurrence of axillary lymph node metastasis is rare. Tumor-associated hypoglycemia can be divided into non-islet cell tumor and insulinoma. In non-islet cell tumor hypoglycemia (NICTH), a considerable high molecular weight form of insulin like growth factor 2 (IGF-2) is formed, which abnormally binds to insulin receptors in the tissues and causes hypoglycemia. Breast phyllodes tumors with NICTH are rare and first reported in 1983. Surgical resection is the main treatment and hypoglycemia symptoms usually resolve after surgery. Nevertheless, prior to surgery, intravenous glucose infusion is used to maintain blood glucose levels. A female patient presented with a rapidly growing breast mass and was diagnosed with a phyllodes tumor with NICTH at our hospital in August 2020; she was successfully treated through surgical resection. We reviewed the relevant literature to investigate and analyze the relationship between NICTH and phyllodes tumors, as well as optimize its diagnosis and treatment.

Phyllodes tumor (PT) is a special type of breast tumors, including three types: malignant, borderline, and benign. Most of these tumors form unilateral disease and can rapidly increase in size. The occurrence of axillary lymph node metastasis is rare. Tumor-associated hypoglycemia can be divided into non-islet cell tumor and insulinoma. In non-islet cell tumor hypoglycemia (NICTH), a considerable high molecular weight form of insulin like growth factor 2 (IGF-2) is formed, which abnormally binds to insulin receptors in the tissues and causes hypoglycemia. Breast phyllodes tumors with NICTH are rare and first reported in 1983. Surgical resection is the main treatment and hypoglycemia symptoms usually resolve after surgery. Nevertheless, prior to surgery, intravenous glucose infusion is used to maintain blood glucose levels. A female patient presented with a rapidly growing breast mass and was diagnosed with a phyllodes tumor with NICTH at our hospital in August 2020; she was successfully treated through surgical resection. We reviewed the relevant literature to investigate and analyze the relationship between NICTH and phyllodes tumors, as well as optimize its diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Doege-Potter syndrome is a rare paraneoplastic syndrome that is often diagnosed incidentally during the workup of hypoglycemia of unclear etiology. It is characterized by a non-islet cell tumor hypoglycemia secondary to excessive production of partially processed IGF-II hormone from a solitary fibrous tumor (SFT). Often these tumors are intrathoracic, benign, and asymptomatic. Occasionally they present as a paraneoplastic event; hypertrophic osteoarthropathy in Pierre-Marie-Bamberger syndrome and hypoglycemia in Doege-Potter syndrome. The NAB2-STAT6 gene fusion is the hallmark of the SFT. Complete surgical resection of the tumor often results in resolution of symptoms and cure in most cases. Here we present the case of an 83-year-old non-diabetic female with recurrent syncopal events who was diagnosed with the Doege-Potter syndrome secondary to a SFT of pleura. Her tumor was positive for NAB2-STAT6 gene fusion on RT-PCR. Following the resection of the giant tumor mass, she became symptom-free within 24 h, and has remained asymptomatic at 4 months follow-up. [ABSTRACT FROM AUTHOR]

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract, mainly localized in the stomach. Most GIST derive from mutations in tyrosine kinase receptors (KIT) or platelet-derived growth factor receptor-α (PDGFRA). GISTs are rarely associated with paraneoplastic hypoglycemia caused by non-β-cells tumor. This syndrome, defined non-islet cell tumor hypoglycemia (NICTH), arises from excess tumor production of insulin-like growth factor. We describe a 67-year-old female with severe NICTH secondary to an advanced and metastatic GIST.

Insulin‐like growth factor (IGF)‐II is considered to function as an important fetal growth factor, which is structurally and functionally related to IGF‐I and proinsulin. At least in vitro, IGF‐II actions are mediated through the IGF‐I receptor and to a lesser extent the insulin receptor. After birth, the function of IGF‐II is less clear although in adults the serum level of IGF‐II exceeds that of IGF‐I several fold. The IGF‐II gene is maternally imprinted, with exception of the liver and several parts of the brain, where it is expressed from both alleles. The regulation, organization, and translation of the IGF‐II gene is complex, with five different putative promotors leading to a range of noncoding and coding mRNAs. The 180‐amino acid pre‐pro‐IGF‐II translation product can be divided into five domains and include a N‐terminal signal peptide of 24 amino acid residues, the 67 amino acid long mature protein, and an 89 residues extension at the COOH terminus, designated as the E‐domain. After removal of the signal peptide, the processing of pro‐IGF‐II into mature IGF‐II requires various steps including glycosylation of the E‐domain followed by the action of endo‐proteases. Several of these processing intermediates can be found in the human circulation. There is increasing evidence that, besides IGF‐II, several incompletely processed precursor forms of the protein, and even a 34‐amino acid peptide (preptin) derived from the E‐domain of pro‐IGF‐II, exhibit distinct biological activities. This review will focus on the current insights regarding the specific roles of the latter proteins in cancer, glucose homeostasis, and bone physiology. To address this topic clearly in the right context, a concise overview of the biological and biochemical properties of IGF‐II and several relevant aspects of the IGF system will be provided. [ABSTRACT FROM AUTHOR]

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract, mainly localized in the stomach. Most GISTs derive from mutations in tyrosine kinase receptors or platelet-derived growth factor receptor- α. GISTs are rarely associated with paraneoplastic hypoglycemia caused by a non-β-cells tumor. This syndrome, defined non-islet cell tumor hypoglycemia (NICTH), arises from excess tumor production of insulin-like growth factor. We describe the case of a 67-year-old female with severe NICTH secondary to an advanced and metastatic GIST. [ABSTRACT FROM AUTHOR]

A 10-year-old female Papillon dog that had previously developed a mammary tumor was admitted for treatment of a hypoglycemic attack. Blood examination showed severe hypoglycemia and decreased blood insulin concentration. Computed tomography indicated multiple tumors in the cranial and caudal lobes of the right lung. These tumors were resected surgically and diagnosed as pulmonary adenocarcinomas by histopathologic examination. Hypoglycemia was temporarily improved after the resection, but a hypoglycemic event occurred 2 months after the surgery. Immunohistochemistry of the tumor demonstrated the expression of insulin-like growth factor 2 in tumor cells. Western blot analysis revealed the expression of high-molecular-weight (big)–insulin-like growth factor 2 in the tumor region. Insulin-like growth factor 2 mRNA expression was also confirmed in the tumor using reverse transcription–polymerase chain reaction. These findings indicate the diagnosis of non–islet cell tumor-induced hypoglycemia caused by big-insulin-like growth factor 2 produced by the tumor in the dog. This report provides information on differentiating tumors that cause paraneoplastic hypoglycemia. [ABSTRACT FROM AUTHOR]

Background: Splenic cord capillary hemangioma is a rare benign vascular lesion classified as a splenic hamartoma. On the other hand, non-islet cell tumor hypoglycemia (NICTH) is one of the rare causes of spontaneous hypoglycemia and is considered to be one of the paraneoplastic syndromes. To the best of our knowledge, this is the first reported case of a splenic cord capillary hemangioma with NICTH. Case presentation: A 25-year-old male was referred to our hospital with hypoglycemia. Except for his low blood sugar, there were no abnormal findings from laboratory tests, which included an endocrinological examination. Enhanced computed tomography confirmed the presence of a solid mass measuring about 6 cm in the retroperitoneum, and a tumorectomy was performed. During this operation, it became clear that the tumor turned out to be a splenic parenchyma, and as a result, a total splenectomy was performed. Microscopically, we diagnosed this as a cord capillary hemangioma, and through immunohistochemistry, we found that some tumor cells were positive for insulin-like growth factor -II. Fortunately, the hypoglycemia-related symptoms disappeared after surgical resection was performed. The patient is still alive and well without evidence of local tumor recurrence 15 years after the operation. Conclusions: Splenic cord capillary hemangioma, one of the types of splenic hamartomas, is a very rare benign vascular lesion and might be associated with hypoglycemia thought to be NICTH. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor 2 is overexpressed in various cancers, and is associated with a poor prognosis. Also, it is known that insulin-like growth factor 2 is an etiology of non-islet cell tumor hypoglycemia. In this report, we describe a case of unexpected hypoglycemia caused by a dedifferentiated liposarcoma producing insulin-like growth factor 2. A large mass in the retroperitoneum was detected in a 61-year-old man who complained of appetite loss. Despite having no history of diabetes mellitus, hypoglycemia suddenly occurred after admission, but oral glucose therapy was ineffective. After total parenteral nutrition, tumor resection was attempted, but failed as a result of rigid adhesion to the surrounding organs. The patient died of the disease 21 days after surgery. Pathological diagnosis at autopsy revealed dedifferentiated liposarcoma, and immunohistochemical staining showed that the tumor excreted insulin-like growth factor 2. The possibility of an insulin-like growth factor 2-producing tumor should be taken into consideration when we encounter a patient with spontaneous hypoglycemia resistant to glucose substitution therapy. [ABSTRACT FROM AUTHOR]

An 83-year-old man underwent complete resection of a large malignant solitary fibrous tumor in the retroperitoneum in 2006 and of a local recurrent tumor in 2010. In 2011, he was admitted to our hospital because of hypoglycemia. His serum glucose level was very low, and his levels of insulin and C-peptide were low. Furthermore, he had a recurrent tumor in the retroperitoneum and pelvis. Immediately after the third surgery for complete resection, he had no hypoglycemic episodes and his serum glucose level was within the normal range. Immunoblotting analysis revealed a high-molecular-weight form of insulin-like growth factor II in the patient’s serum and in the protein extract obtained from the resected specimen in 2011. To our knowledge, this is the first report of non-islet cell tumor hypoglycemia caused by a malignant solitary fibrous tumor secreting a high-molecular-weight form of insulin-like growth factor II at the second recurrence.

Background: Non-Islet Cell Tumor Hypoglycemia (NICTH) is a rare paraneoplastic cause of hypoglycemia arising from excess tumor production of insulin-like growth factor. The objective of this report is to describe an unusual case of Extragastrointestinal Stromal Tumor (EGIST) associated NICTH. Case presentation: A 64 year-old African female was brought to the emergency room with a 1-month history of recurrent syncope, weight loss, and abdominal bloating. Serum blood glucose was discovered to 39 mg/dL, when insulin, proinsulin, and C-peptide were suppressed. Computed tomography scan revealed a diffuse extraintestinal metastatic disease process, and a biopsy confirmed the diagnosis of an Extragastrointestinal Stromal Tumor (EGIST). IGF-I and II levels were 27 ng/ml and 262 ng/ml respectively, and the ratio of IGF-II to IGF-I was calculated as 9.7:1, suggestive of IGF-II-mediated NICTH. Acutely, the patient's hypoglycemia resolved with dextrose and glucagon infusion. Long-term euglycemia was achieved with prednisone and imatinib therapy. Conclusions: NICTH should be considered when hypoglycemia occurs in the setting of low serum insulin levels. Whereas definitive treatment of EGIST involves surgical resection, immunotherapy with tyrosine kinase inhibitors and corticosteroids have been shown to alleviate hypoglycemia in cases where surgery is delayed or not feasible. [ABSTRACT FROM AUTHOR]

Background: Non-islet cell tumor hypoglycemia (NICTH) is defined as a form of hypoglycemia caused by an extrapancreatic tumor. Solitary fibrous tumor (SFT) associated with hypoglycemia is rare.Case Presentation: A 76-year-old woman, who had frequently experienced hypoglycemic symptoms such as presyncope for the prior 6 months, visited our hospital to undergo detailed examinations. Her fasting glucose level was low at 49 mg/dl. The blood levels of IRI and C-peptide were also low at 0.2 μU/ml and 0.21 ng/ml, respectively. Chest computed tomography revealed a mass measuring 15 cm in the left thoracic cavity. Percutaneous needle biopsy yielded a diagnosis of intrathoracic SFT associated with NICTH. The tumor was removed by video-assisted thoracoscopic surgery. Histological examination showed a tumor composed of simple spindle-shaped cells with an irregular arrangement. Immunohistochemical staining was positive for CD34, bcl-2, and vimentin and negative for alpha SMA and mesothelin. These results confirmed the diagnosis of SFT. Her hypoglycemic symptoms resolved rapidly after surgery. The clinical course has since remained favorable with no signs of recurrence.Conclusion: We report a case of non-islet cell tumor hypoglycemia caused by intrathoracic SFT. The high-molecular-weight IGF-II produced by the tumor has been regarded as the cause of NICTH. [ABSTRACT FROM AUTHOR]