Secondary Polycythemia and Non-Islet Cell Tumor-induced Hypoglycemia in Advanced Hepatocellular Carcinoma: A Case Report.

Continuously holding its position as the sixth most common cause of cancer and the third leading cause of cancer death, globally, Hepatocellular Carcinoma (HCC) remains as a healthcare priority. Production of various substances may result into systemic or metabolic complications, often known as paraneoplastic phenomena of HCC. A 56-year-old male with history of untreated chronic hepatitis B arrived with generalized weakness and intermittent headache in the last two days prior to admission. Laboratory findings demonstrated elevated hemoglobin (20.5 g/dl), alpha-fetoprotein (29,845 ng/dl), and d-Dimer (2,120 ng/ml) levels. Hypoglycemia (44 mg/dl) was documented with normal basal insulin level, confirming non-islet cell tumor hypoglycemia. Abdominal multiphasic CT-scan demonstrated a large solid lesion involving the whole right liver lobe, hyper-enhanced at arterial phase and wash-out pattern at venous and delayed phases, with portal vein thrombosis; thus, confirming HCC BCLC C. Further examinations revealed hypercellularity from bone marrow biopsy with the absence of JAK2 mutation. He underwent serial phlebotomy and received 80 mg acetylsalicylic acid orally, as well as cytoreductive agent to reduce the risk of thrombosis. Despite applications of different interventions, control of hypoglycemia could not be achieved without parenteral administration of high dextrose load. He was planned to receive oral multikinase inhibitor, however, he passed away due to severe hospital-acquired pneumonia. Paraneoplastic phenomena are common in HCC. Increased risk of blood hyper-viscosity and thrombosis attributed to polycythemia, as well as medical emergency resulting from hypoglycemia showed that both conditions should not be overlooked since they may worsen the patient's prognosis.

Evolution of Pleural Solitary Fibrous Tumors Causing Severe Hypoglycemia after Exceptionally Long Asymptomatic Periods: Report of Two Surgical Cases.

Non-islet cell tumor hypoglycemia (NICTH) is one of the paraneoplastic syndromes manifesting severe hypoglycemia caused by aberrant production of high-molecular-weight insulin-like growth factor 2 (big-IGF2). Two surgical cases of extremely large thoracic solitary fibrous tumors (SFT) with unusual history of NICTH are presented. One case manifested severe hypoglycemia after four years of the first complete surgical resection of the tumor with potential malignant transformation, and the other case showed severe hypoglycemia after ten years of the first detection of the tumor. Meticulous laboratory testing, including serum endocrinological tests and western immunoblotting before and after surgery was performed, and both cases were diagnosed as NICTH. Both patients underwent open thoracic surgery. The patients showed normal glucose and hormone levels immediately after the resection of responsible tumors with elevated blood insulin concentration. SFTs are generally considered benign; however, life-threatening hypoglycemia can happen regardless of treatment. Careful follow-up of the tumor growth is warranted.

Doege-Potter Syndrome: A Solitary Fibrous Tumor Causing Non-Islet Cell Tumor Hypoglycemia.

Doege-Potter syndrome occurs when incompletely processed insulin-like growth factor 2 (IGF-2), also known as big IGF-2, is produced by a solitary fibrous tumor (SFT) and results in non-islet cell tumor hypoglycemia (NICTH). We discuss here the case of a 66-year-old male who presented with a 2-week history of increasing confusion and a serum glucose of 34 mg/dL. The patient's symptoms immediately improved with dextrose. The patient did not use insulin, serum sulfonylurea screen was negative, and testing for adrenal insufficiency was unremarkable. Outpatient laboratory evaluation revealed a serum glucose of 48 mg/dL along with low insulin, C-peptide, and proinsulin levels. Further work-up showed an IGF-2 to IGF-1 ratio of 38:1. A ratio greater than 10:1 is diagnostic of NICTH. Imaging demonstrated a 21-cm mass in the lower abdomen and pelvis. The patient underwent surgical resection. The hypoglycemia resolved immediately postoperatively. Surgical pathology revealed a malignant SFT. In NICTH, big IGF-2 forms a complex that is biologically active and saturates the insulin and IGF receptors, resulting in refractory hypoglycemia. Although glucocorticoids can mitigate hypoglycemia, complete surgical resection is the only definitive treatment of NICTH. This case highlights the importance of maintaining a broad differential for seemingly simple hypoglycemia.

The cckOMA syndrome and its relation to the Zollinger-Ellison syndrome: a diagnostic challenge.

OBJECTIVE: Among patients with enteropancreatic neuroendocrine tumor syndromes only one case with a cholecystokinin (CCK) secreting tumor has been reported. She had significant hyperCCKemia leading to a specific syndrome of severe diarrheas, weight loss, repeated duodenal ulcers and a permanently contracted gallbladder with gallstones. There are, however, reasons to believe that further CCKomas exist, for instance among Zollinger-Ellison patients with normal plasma gastrin concentrations. The present review is a call to gastroenterologists for awareness of such CCKoma patients. METHOD: After a short case report, the normal endocrine and oncological biology of CCK is described. Subsequently, the CCKoma symptoms are discussed with particular reference to the partly overlapping symptoms of the Zollinger-Ellison syndrome. In this context, the diagnostic use of truly specific CCK and gastrin assays are emphasized. The discussion also entails the problem of access to accurate CCK measurements. CONCLUSION: Obviously, the clinical awareness about the CCKoma syndrome is limited. Moreover, it is also likely that the knowledge about the necessary specificity demands of diagnostic gastrin and CCK assays have obscured proper diagnosis of the CCKoma syndromes in man.

Unraveling the Whipple Triad: Non-Islet Cell Tumor-Induced Hypoglycemia.

Tumor-induced hypoglycemia (TIH) is a rare paraneoplastic phenomenon resulting from several tumor types and mechanisms. Insulinomas are the most common cause of TIH. However, non-islet cell tumors can also trigger hypoglycemia by releasing insulin-like growth factor 2 (IGF-II) or its precursor. We present a case of a 56-year-old woman experiencing spontaneous hypoglycemia due to a pleural-based solitary fibrous tumor. Diagnostic evaluations revealed diminished C-peptide levels, increased IGF-II, and a 4-fold increase in the IGF-II: IGF-I ratio, indicative of non-islet cell tumor hypoglycemia. Localization imaging identified a left pleural mass, confirming the diagnosis. Preoperatively, the patient received intravenous dextrose and corticosteroids, but surgical resection was essential for the resolution of symptoms. The identified tumor, a benign solitary fibrous tumor, was successfully removed, leading to an immediate postoperative cessation of hypoglycemia. Six years post resection, the patient remains symptom free. Managing TIH necessitates an early diagnosis aiming for complete tumor resection, with alternative approaches considered when complete resection is not possible. This case highlights the importance of a systematic diagnostic and management approach for TIH, emphasizing the need to identify the underlying cause, particularly in people without diabetes.

Hypoglycemia From Metastatic Meningeal Solitary Fibrous Tumor Occurring Over Two Decades After Initial Diagnosis.

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.

Three Cases of Non-islet Cell Tumor Hypoglycemia Highlighting Efficacy of Glucocorticoid Treatment.

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.

Solitary fibrous tumor with IGF-II-induced non-islet cell tumor hypoglycemia: a case report and molecular characterization by next-generation sequencing.

Background: Non-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 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 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. 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.

Ectopic insulinoma in a dog with insulin-induced hypoglycemia: a case report.

A 7-year-old spayed female Shih Tzu dog was presented for evaluation of recurrent hypoglycemia. Serum insulin levels during hypoglycemia were 35.3 µIU/mL. Ultrasonography and computed tomography showed a mesenteric nodule between the kidney and the portal vein, but no pancreatic mass was observed. During surgery, the nodule had neither anatomical adhesions nor vascular connections to the pancreas. Pancreatic inspection and palpation revealed no abnormalities. Hypoglycemia improved after resection of the nodule. Histopathological examination confirmed the nodule to be an islet cell carcinoma. Although extremely rare, ectopic insulinoma should be considered as a possible cause of insulin-induced hypoglycemia in dogs.

Doege-Potter Syndrome; A Case of Solitary Fibrous Pleura Tumor Associated with Severe Hypoglycemia: A Case Report in Internal Medicine.

BACKGROUND: Doege-Potter syndrome is a rare paraneoplastic entity that is often diagnosed incidentally during the work-up of hypoglycemia of unclear etiology. It is characterized by a non-islet cell tumor hypoglycemia mostly associated with solitary fibrous tumors. These uncommon tumors have been reported in <5% of solitary fibrous tumors. Although not unique in its kind, this case is extremely important as this syndrome often conceals unrecognized tumors that can be surgically resolved. CASE PRESENTATION: We present the case of a 59-year-old non-diabetic man with a 2-month history of severe and recurrent fasting hypoglycaemia presenting with severe dyspnea and sweating. Further workup revealed low insulin, C-peptide, and IGF-1 levels and a large right in-trathoracic solitary fibrous tumor. Unfortunately, bioassays for IGF-2 were unavailable at our hos-pital. Nevertheless, as hypoglycemia completely resolved after resection of the mass, Doege-Potter syndrome was highly suspected. CONCLUSION: Doege-Potter syndrome is a complication of rare tumors. If hy-poglycemia is unexplained, this syndrome should always be suspected, and the presence of un-known masses should be investigated.

Case report: Severe, refractory hypoglycemia in a 9-year-old Brittany Spaniel with renal nephroblastoma.

A 9-year-old female spayed Brittany Spaniel presented for weakness and stumbling, and was diagnosed with severe hypoglycemia. An insulin to glucose ratio was not consistent with insulinoma as a cause for hypoglycemia. Diagnostic imaging (abdominal ultrasound and computed tomography) revealed a large left renal mass and a possible metastatic lesion in the right kidney. Glucagon therapy was initiated, but hypoglycemia was refractory to therapy. A left nephrectomy was performed and hypoglycemia subsequently resolved. Histopathology of the mass was consistent with nephroblastoma and immunohistochemistry for anti-insulin-like Growth Factor-2 (IGF-2) antibody revealed immunoreactivity in over 50% of the neoplastic cells. Chemotherapeutic treatment was initiated with a combined protocol of vincristine and doxorubicin. To the authors' knowledge, this is the first case report documenting the treatment of severe, refractory non-islet cell tumor-induced hypoglycemia in a dog, suspected to be secondary to an IGF-2 secreting nephroblastoma.

Resolution of paraneoplastic hypoglycemia following nephroureterectomy for treatment of canine renal cell carcinoma: Case report.

Objectives: To describe the clinicopathologic findings, imaging results, surgical treatment, and outcome of a dog with renal cell carcinoma (RCC) and paraneoplastic hypoglycemia. Animals: A 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 design: Case report. Methods: Serum 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. Results: After 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. Conclusion: Surgical 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.

Non-islet cell tumor hypoglycemia associated with Gastrointestinal Stromal Tumor: Case report and review of the literature.

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.

Big insulin-like growth factor 2-producing multiple solitary fibrous tumors treated with debulking surgery: A case report.

Background: Non-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 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.

Non-islet cell tumor hypoglycemia concurrent with acromegalic features: A case report and literature review.

Background: Non-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 presentation: A 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. Conclusions: Fibrous 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.

An update on genetically engineered mouse models of pancreatic neuroendocrine neoplasms.

Pancreatic neuroendocrine neoplasms (PanNENs) are rare and clinically challenging entities. At the molecular level, PanNENs' genetic profile is well characterized, but there is limited knowledge regarding the contribution of the newly identified genes to tumor initiation and progression. Genetically engineered mouse models (GEMMs) are the most versatile tool for studying the plethora of genetic variations influencing PanNENs' etiopathogenesis and behavior over time. In this review, we present the state of the art of the most relevant PanNEN GEMMs available and correlate their findings with the human neoplasms' counterparts. We discuss the historic GEMMs as the most used and with higher translational utility models. GEMMs with Men1 and glucagon receptor gene germline alterations stand out as the most faithful models in recapitulating human disease; RIP-Tag models are unique models of early-onset, highly vascularized, invasive carcinomas. We also include a section of the most recent GEMMs that evaluate pathways related to cell cycle and apoptosis, Pi3k/Akt/mTOR, and Atrx/Daxx. For the latter, their tumorigenic effect is heterogeneous. In particular, for Atrx/Daxx, we will require more in-depth studies to evaluate their contribution; even though they are prevalent genetic events in PanNENs, they have low/inexistent tumorigenic capacity per se in GEMMs. Researchers planning to use GEMMs can find a road map of the main clinical features in this review, presented as a guide that summarizes the chief milestones achieved. We identify pitfalls to overcome, concerning the novel designs and standardization of results, so that future models can replicate human disease more closely.

Targeting-intratumoral-lactic-acidosis transcatheter-arterial-chemoembolization for non-islet cell tumor hypoglycemia secondary to a liver metastatic solitary fibrous tumor: A case report and literature review.

Doege-Potter syndrome is a rare paraneoplastic syndrome characterized by non-islet cell tumor hypoglycemia secondary to a solitary fibrous tumor. Doege-Potter syndrome always presents with recurrent fasting hypoglycemia, which can occasionally be life-threatening. The best choice of treatment for Doege-Potter syndrome and solitary fibrous tumor is complete resection. However, when it is unfeasible, local-regional treatment can be used as a palliative therapy. Herein, we report a case of a 46-year-old man with Doege-Potter syndrome that occurred secondary to the liver and pancreatic metastatic solitary fibrous tumors. After he received six rounds of targeting-intratumoral-lactic-acidosis transcatheter-arterial-chemoembolization (TILA-TACE) treatment in our hospital, his hypoglycemia was clinically cured, and the liver metastatic tumor was well controlled. We suggest that TILA-TACE can be considered when curative resection is unfeasible for metastatic liver solitary fibrous tumors to help a patient obtain further surgery opportunities.

Duplication of AKT2 Gene in Ovarian Cancer: A Potentially Novel Mechanism for Tumor-Induced Hypoglycemia.

Severe hypoglycemia occurs with different types of tumors, including islet cell and non-islet cell tumors. Non-islet cell tumor hypoglycemia (NICTH) is a rare and potentially life-threatening complication of malignancy. The primary underlying mechanism of NICTH proposed in the literature includes paraneoplastic overproduction of insulin-like growth factor-2 (IGF-2), the production of autoantibodies against insulin or its receptors, or the presence of extensive metastatic burden replacing hepatic tissue or adrenal glands. In this report, we propose a potentially novel mechanism underlying NICTH involving stimulation of the insulin signaling pathway in a 58-year-old woman with a rare ovarian tumor of Müllerian origin that carries a duplication of the AKT2 gene. AKT2 is a molecular mediator of insulin signaling. To our knowledge, this is the first reported case of tumor-induced hypoglycemia associated with AKT2 gene duplication. In this report also, we discuss the currently available diagnostic modalities and highlight the therapeutic rationale in patients with NICTH, a highly vulnerable population.

Severe Hypoglycemia Caused by a Giant Borderline Phyllodes Tumor of the Breast: A Case Report and Literature Review.

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.