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Magnetic resonance imaging (MRI) brain FLAIR sequence showing multiple cortical and subcortical white matter lesions in both cerebral hemispheres consistent with cerebral tubers.
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Key Clinical Message
Recurrent hypoglycemia is common, but its presentation is often insidious resulting in delays in diagnosis and significant morbidity. We describe a case of an insulinoma presenting with falls and confusion in a patient with tuberous sclerosis, demonstrating the importance of early hypoglycemia identification and a potential sha...
Context in source publication
Context 1
... 67-year-old Caucasian woman was admitted to hospital following an episode of confusion and slurred speech dur- ing hemodialysis. She had a past medical history of TSC, diagnosed aged 47 years when she presented with breath- lessness, with high-resolution computed tomography (HRCT) of her chest revealing multiple cysts and proliferation of abnormal smooth muscle (Fig. 1). In addition, she developed seizures, with magnetic resonance imaging (MRI) of her brain demonstrating multiple corti- cal and subcortical white matter lesions consistent with cerebral tubers (Fig. 2). Subsequently, she was found to have large bilateral renal angiomyolipomas, ultimately requiring bilateral nephrectomies for malignant transfor- mation. She commenced regular hemodialysis three times per week, aged 60 ...
Citations
... The first insulinoma case in TSC patients was reported in 1959 (4). After that total of 9 cases diagnosed with insulinoma in patients with TSC have been reported (4)(5)(6)(7)(8)(9)(10)(11)(12). According to our knowledge, we presented the 10th TSC patient diagnosed with insulinoma in the literature. ...
... In the literature, insulinoma was diagnosed in 9 patients followed up with TSC. The mean age of these patients was 35 (range, 18 years to 67 years), and the mean tumor diameter was 4.7 cm (range, 7 mm to 21 cm) (4)(5)(6)(7)(8)(9)(10)(11)(12). ...
... In the Mayo clinical series of 237 insulinoma patients, the mean age at diagnosis was 50 years (range 17 to 86 years), 6 % of the insulinomas (14 patients) had MEN1 syndrome, and approximately 10% of the cases were multiple (3). In TSC patients with insulinoma, the mean age at diagnosis was younger than the sporadic cases, and one case had multiple tumors (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). The common manifestations of insulinoma are fasting hypoglycemia, and the episodes of neuroglycopenic and autonomic symptoms of hypoglycemia are commonly observed in these patients (4)(5)(6)(7)(8)(9)(10)(11)(12). ...
Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disease characterized by multiple hamartomas in multiple organs. However, there is limited evidence about neuroendocrine tumors (NETs) in patients with TSC, and routine screening of NETs is not recommended in the guidelines. Insulinomas are also an extremely rare disease. According to our knowledge, we presented the 10th TSC patient diagnosed with insulinoma in the literature. Thirty-two years old male patient diagnosed with TSC at the age of 27 due to typical skin findings, renal angiomyolipoma, history of infantile seizures, and cranial involvement was referred to our clinic. The main symptoms of the patient were palpitations, diaphoresis, confusion, and symptoms were improved after consuming sugary foods. Seventy-two hours fasting test was performed, and a low glucose level at 41 mg/dl, a high insülin level at 21.65 µIU/mL, and a high C-peptide level at 7.04 ng/mL were found at the 8th hour. In addition, a 12x7 mm lesion in the pancreatic tail was detected in abdominal imaging. Ga-68 PET-CT (gallium-68 positron emission tomography-computed tomography) detected an increased uptake of Ga-68 in the pancreatic tail. The patient underwent distal pancreatectomy, and pathological evaluation was consistent with an insulinoma. The patient's symptoms improved postoperatively. Since in nearly all TSC cases, as in our case, neuropsychiatric abnormalities, such as epilepsy, are one of the main disease manifestations, and these symptoms may be confused with the clinical manifestations of hypoglycemia in insulinoma. Therefore, patients with newly developed neurological symptoms and behavioral defects should be evaluated in terms of insulinoma.
... The occurrence of these 2 rare conditions in the same patient is extremely rare worldwide and is not coincidental, since very few reports have mentioned/described the correlation between the 2 conditions. 2,3,5 Previous reports have described the relationship between tuberous sclerosis and malignant pancreatic islet cell tumor (a pancreatic NET) using deoxyribonucleic acid (DNA) analysis and immunohistochemistry. 6 While DNA analysis revealed a loss of heterogenicity (LOH) on chromosome 16p13 in malignant pancreatic islet cells, no LOH was observed in the normal variant of these cells. 6 Furthermore, immunohistochemical analysis using anti-tuberin antibodies resulted in a loss of tuberin immunostaining in the tumor cells; the rest of the pancreas were normal. ...
Pancreatic neuroendocrine tumors are rare with an incident rate of 5 cases per million individuals. Tuberous sclerosis complex is an autosomal dominant disease. This disease involves multisystem and occurs in one out of every 6,000-10,000 individuals. In this study, we describe a 47-year-old male known tuberous sclerosis patient with an insulinoma. The tumor was incidentally detected in follow-up imaging for a previous ampulla of Vater tubular adenoma. However, the patient reported symptoms of hypoglycemia. The insulinoma was enucleated successfully. Histopathology revealed a well-differentiated, grade one neuroendocrine tumor measuring around 2 cm in diameter. Seven cases were reported in the literature of tuberous sclerosis-associated insulinoma. The 7 reported cases had different hypoglycemia related symptoms. The reported tumors varied in size and location on the pancreas. This paper details the eighth case worldwide where an insulinoma occurred in a tuberous sclerosis patient.
Background
Tuberous sclerosis complex (TSC) is a rare, autosomal dominant genetic disease that arises from TSC1 or TSC2 genetic mutations. These genetic mutations can induce the development of benign tumors in any organ system with significant clinical implications in morbidity and mortality. In rare instances, patients with TSC can have malignant tumors, including renal cell carcinoma (RCC) and pancreatic neuroendocrine tumor (PNET). It is considered a hereditary renal cancer syndrome despite the low incidence of RCC in TSC patients. TSC is typically diagnosed in prenatal and pediatric patients and frequently associated with neurocognitive disorders and seizures, which are often experienced early in life. However, penetrance and expressivity of TSC mutations are highly variable. Herein, we present a case report, with associated literature, to highlight that there exist undiagnosed adult patients with less penetrant features, whose clinical presentation may contain non-classical signs and symptoms, who have pathogenic TSC mutations.
Case presentation
A 31-year-old female with past medical history of leiomyomas status post myomectomy presented to the emergency department for a hemorrhagic adnexal cyst. Imaging incidentally identified a renal mass suspicious for RCC. Out of concern for hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome, the mass was surgically removed and confirmed as RCC. Discussion with medical genetics ascertained a family history of kidney cancer and nephrectomy procedures and a patient history of ungual fibromas on the toes. Genetic testing for hereditary kidney cancer revealed a 5’UTR deletion in the TSC1 gene, leading to a diagnosis of TSC. Following the diagnosis, dermatology found benign skin findings consistent with TSC. About six months after the incidental finding of RCC, a PNET in the pancreatic body/tail was incidentally found on chest CT imaging, which was removed and determined to be a well-differentiated PNET. Later, a brain MRI revealed two small cortical tubers, one in each frontal lobe, that were asymptomatic; the patient’s history and family history did not contain seizures or learning delays. The patient presently shows no evidence of recurrence or metastatic disease, and no additional malignant tumors have been identified.
Conclusions
To our knowledge, this is the first report in the literature of a TSC patient without a history of neurocognitive disorders with RCC and PNET, both independently rare occurrences in TSC. The patient had a strong family history of renal disease, including RCC, and had several other clinical manifestations of TSC, including skin and brain findings. The incidental finding and surgical removal of RCC prompted the genetic evaluation and diagnosis of TSC, leading to a comparably late diagnosis for this patient. Reporting the broad spectrum of disease for TSC, including more malignant phenotypes such as the one seen in our patient, can help healthcare providers better identify patients who need genetic evaluation and additional medical care.
Insulinoma and glucagonoma are two rare functioning neoplasms of the neuroendocrine cells of the pancreas, respectively characterized by an uncontrolled over-secretion of insulin or glucagon, responsible for the development of the hypoglycemic syndrome and the glucagonoma syndrome. They prevalently arise as sporadic tumors; only about 10% of cases develop in the context of rare inherited tumor syndromes, such as Multiple Endocrine Neoplasia Type 1 (MEN1), Neurofibromatosis type 1 (NF1), and Tuberous Sclerosis Complex (TSC), being the result of an autosomal dominant germline heterozygous loss-of-function mutation in a tumor suppressor gene. Here, we reviewed the main epidemiological and clinical aspects of insulinoma and glucagonoma in the context of genetic syndromes.
BACKGROUND : It is known that insulinoma in approximately 5% of cases is associated with multiple endocrine neoplasia type 1 syndrome (MEN1), in which the prognosis and management tactics of patients have been developed in detail. The diagnosis of MEN1 often does not require genetic confirmation, since the syndrome has a typical clinical picture. At the same time, a combination of this tumor with other hereditary syndromes is found in the literature, which are characterized by the presence of malignant neoplasms of various localizations, primary multiple lesions, hormonal and other disorders. Thus, it is relevant to search for the genetic causes that cause the development of insulinoma, in addition to MEN1.
AIM: to evaluate the frequency of detection of genetic causes of the development of insulin-producing tumors of the pancreas, in addition to MEN1; to analyze the phenotypic characteristics of patients with such tumors.
MATERIALS AND METHODS : Based on the analysis of literature for the period up to 2020, a panel has been developed that includes coding regions of 10 genes (MEN1, VHL, TSC1, TSC2, KRAS, YY1, CDKN2A, MLH1, ADCY1, CACNA2D2) involved in the development of insulinoma. In 32 patients diagnosed with insulinoma, verified by pathomorphological examination, with the absence of clinical and/or genetic data indicating MEN1 syndrome, a panel of genes was sequenced with subsequent analysis of the identified genetic variants and phenotypic data obtained from the medical records of patients. In one patient, an additional molecular genetic study of the «Endom» panel was performed, revealing genetic variants of coding regions of 377 genes associated with endocrine diseases.
RESULTS: In 8 patients (25%, 95% CI (11%; 43%)), 9 variants of mutations were identified that were not classified as benign, at that two mutations in the TSC2 gene were detected in one patient. Frequencies of genetic variants: TSC2 — 13%, 95% CI (4%; 29%), MEN1 — 6% (1%; 21%), MLH1 — 3% (0%;16%), CDKN2A/P16INK4A — 3% (0%;16%). When comparing patients with the identified mutation, with the exception of benign (n=8), and patients without mutation or with a benign mutation (n=24), there were no differences in the Grade (degree of differentiation), Ki67 proliferation index, frequency of concomitant tumors, burdened history, multiple pancreatic lesions or recurrence of insulinoma, however, patients with germinal mutation were found at the level of statistical trend to be younger at the manifestation of insulinoma and to have bigger tumors. In a patient who underwent an additional molecular genetic study using the new «Endome» panel, previously undescribed gene variants (APC and KIF1B) associated with various sporadic tumors, including endocrine ones, were identified.
CONCLUSION: A panel of 10 genes has been developed, mutations of which are associated with insulinoma. A relatively high incidence of genetically determined insulinoma was determined (25% of cases), in half of cases — against the background of tuberous sclerosis. We consider it relevant to evaluate the effectiveness of genetic testing for patients with insulinoma. We believe that, first of all, patients with a high risk of hereditary pathology should be examined: with the manifestation of the disease at a young age and with a large tumor. The identification of a genetic mutation will make it possible to determine the prognosis of the disease, optimize the monitoring algorithm in order to timely identify concomitant diseases-components of the hereditary syndrome, and conduct genetic counseling of the family.
Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic syndrome that is caused by mutations in the tumour suppressor genes TSC1 or TSC2 which causes multiorgan growths. TSC presents at any age as a wide range of clinical and phenotypic manifestations with varying severity. The main goal of this article was to state two cases of TSC and review the most commonly reported major and minor diagnostic clinical features and the most common features that led to an investigation of possible TSC diagnosis. Herein, we report two cases of TSC, which both presented with seizures during the first 6 months of life. Case 1 presented with multiple types of seizures from 6 months of age and was diagnosed by multiple calcified subependymal nodules (SENs) detected by computed tomography and magnetic resonance imaging (MRI). Case 2 presented with seizures from 3 months of age and was diagnosed prenatally when a tumour was seen in her heart during antenatal ultrasonography. In conclusion, the literature review revealed that neurological manifestations (mainly seizures) were the main feature that led to investigation and diagnosis of TSC followed by abdominal manifestations (mainly renal features) and antenatal follow-up imaging. Other manifestations in skin, chest, eyes, teeth and heart rarely led to TSC diagnosis. In some cases, TSC was incidentally discovered by medical imaging. The cortical tubers, SENs, and subependymal giant cell astrocytomas brain lesions were the most commonly reported major features. Skin features including angiofibromas, ungual fibromas and shagreen patch were the second most common major features reported in the literature. However, skin manifestations were not a common led to investigation and diagnosis of TSC. Renal features, mainly angiomyolipomas (AMLs), were the third most common major feature reported. Medical imaging plays an essential role in diagnosis of TSC, and clinical features are important clues that lead to investigation for the disease.
Objectives:
Natural killer/T-cell lymphoma (NKTCL) is aggressive, and carries a poor prognosis worldwide. This retrospective study aimed to evaluate the clinical efficacy and safety of the LVD regimen (L-asparaginase, vincristine, and dexamethasone) combined with intensity-modulated radiation therapy (IMRT) for the treatment of early-stage nasal NKTCL in a Chinese population.
Methods:
The clinical data were collected from patients treated between March 2010 and January 2017. Patients received LVD chemotherapy combined with IMRT, and were followed for 30 to 90 months. All received radiotherapy at the end of the first/second cycle of chemotherapy. The survival curves were generated by the Kaplan-Meier method.
Results:
Among 94 patients who received 2 to 6 cycles (mean, 4 cycles) of treatments, 56 and 25 achieved complete and partial remission, respectively; 2 and 11 experienced stable disease and progressive disease. The overall objective response was 86.2%. Patients with elevated lactate dehydrogenase and skin invasion had a lower objective response rate. The progression-free survival rates at 1, 3, and 5 years were 90.3%, 73.5%, and 71.3%; the corresponding overall survival rates were 91.4%, 74.3%, and 74.3%. The main adverse events were myelosuppression (63.8% grades I to II, 12.8% grade III), gastrointestinal symptoms (63.8% grades I to II), hepatic lesion (55.3% grades I to II), hypoproteinemia (46.8% grades I to II), skin allergies (77.7% grades I to II, 3.2% grade III), and oral mucosal lesions (44.7% grades I to II, 33% grade III). No severe pancreatitis, anaphylaxis, or toxicity-related death was observed.
Conclusion:
In patients with early-stage nasal NKTCL, our LVD-IMRT regimen produced excellent, durable therapeutic benefit in most patients, with acceptable toxicity and no acute mortality.
