Insulinoma and Prolactinoma in A Young Female - Philippine ...

138 Cardino MJ T and Lantion-Ang FLdisorder and was started with Carbamazepine withescalating doses. Brain computed tomography scanand electroencephalogram were normal. Topiramatewas added to the anti-seizure regimen howeverpatient still had 4-6 seizure episodes per year. Therewere episodes of true hypoglycemia precipitatingthe seizure attacks thus a computed tomographyscan of the abdomen was done and showed a 2 x1.8cm pancreatic mass thus she was referred toEndocrinology for evaluation.Fig 1.MRI of the Abdomen Showing A 2 x 1.8cmPancreatic Nodule Enhanced By ContrastOn review, our patient started to have symptomsof generalized weakness associated with palpitations,hunger pangs and dizziness resolved with food intakefor 5 years. These symptoms usually occurredon waking up. Because of this pattern, she begangaining weight until 6 months later, she had onsetof generalized tonic seizures. Everytime she wasbrought to the emergency room, her blood sugarwas low. After giving intravenous glucose, patientregained consciousness. She gained 18 kg in 4months prior to referral to our service.Menarche was at 11 years old. Menstrual flowwas regular until a year prior to consult she hadamenorrhea. She had no dysmenorrheal, abnormaldischarges and history of contraceptive intake.Developmental history was at par with age. Shehad good school performance and even graduatedcollege. She had no history of blurring of vision, andchronic headaches. She had no family history oftumors, diabetes and hypertension.On examination, she had normal vital signs.She was obese with a BMI of 32 kg/m, 2 waistcircumference of 95 cm, hip circumference of 99cm, and waist to hip ratio was 0.95. There was noacanthosis nigricans, thyromegaly, and xanthomas.Silver striae were noted in the inner thighs. She hadno visual field cuts on confrontation test.Fig 2.Photograph of the Patient During Her Admission atPGHIn the approach to hypoglycemic patients, wehave to classify the etiology of the hypoglycemia.Our patient had fasting hypoglycemia. Differentialdiagnoses for fasting hypoglycemia includeddrugs e.g. sulfonylurea, critical illness, adrenaland pituitary insufficiency and insulinoma. Shewas not hypotensive, lethargic and weak makingthe consideration of adrenal insufficiency unlikely.Patient had no intake of sulfonylurea.The signs and symptoms of patients weresuggestive of insulinoma, thus serum insulin, C-peptide and random blood sugar were taken aftera 72-hour fast test. Baseline counter-regulatoryhormone levels were taken and then blood sugarwas monitored every 2 hours while patient fasted.Baseline 8 oÊclock morning serum cortisol (880nmol/L) was normal. A 72 hour fast test was done. Onthe 18th hour, she manifested with neuroglycopenicsymptoms. Capillary blood sugar was 38 mg/dl.A low random blood sugar at 18mg/dl with aninappropriately high serum insulin levels at 41.08uU/ml (normal: 2.6-24 uU/ml) were documented.C peptide was elevated at 25.6 ng/ml (normal: 1-5ng.ml) indicative of endogenous hyperinsulinemia.Serum insulin and C-peptide are secreted inequimolar amounts. In our patient, the serum insulinto C-peptide was 1.6 reflective of degradation of theC-peptide. The cathepsin B degrades the C terminalamino acids of C-peptide which is being determinedin the assay, resulting to higher insulin to C-peptideratio. 4

Insulinoma and Prolactinoma in A Young Female 139Table I. Review of Cases with Insulin to C-peptide Ratio inInsulinoma Patients 4AuthorLevels in InsulinomaKatabami 7.2Gin 6.3Sakai 6.1Scarlet 5.9Saudek 5Lebowitz 4.9Kondo 4.2Service 3.6Ciavarella 2.9Turner 2Fujikura 2Our Case 1.6Intraoperative ultrasound showed a 2 x 1.8 cmsolid nodule at the antero-inferior portion of the bodyof the pancreas and subsequently an enucleation ofthe nodule was done. Post-operatively, blood sugarrose to 208 mg/dl within 30 minutes from enucleationof the tumor. No symptoms of acute pancreatitis weredocumented and serum amylase was slightly elevatedonly at 178 U/ml (normal 83-110 U/ml). There wereno calcifications noted. Post-operative biopsy revealedan insulinoma. Cells were arranged in anastomosingcords separated by a vascular stroma, interspersedwith sparse collagenous stroma. Chromogranin-Aand synaptophysin staining of the tumor were positive(see figure 3). These staining results confirmed thatthe tumor was an insulinoma.Fig 3.A) 2x2 cm Pancreatic Nodule Post-Pancreatic Enucleation. B) Hematoxylin and Eosin Staining Showing Uniform Cellsin Anastomosing Cords. C) Panoramic View of the Tumor Cells in Clumps with Sparse Collagenous Stroma. D) PositiveSynaptophysin Staining of the Pancreatic Nodule. E) Positive Chromogranin Staining of the Pancreatic Nodule.

140 Cardino MJ T and Lantion-Ang FLDuring the recuperation period, she had norecurrence of the hypoglycemic episodes, seizuresand other neuroglycopenic symptoms. She wasdischarged improved on the 5th post-operative day.Two weeks from discharge, patient had a repeatinsulin determination after a 12 hour fast and resultsshowed blood sugar of 100 mg/dl and suppressedserum insulin of 0.5 uU/ml.On the 2nd month of follow-up, patient had norecurrence of any seizure episodes. No hypoglycemicattacks were claimed. Patient had significantly lostweight with a BMI of 26 kg/m 2 from a previous BMIof 32kg/m 2 .(LH), follicule stimulating hormone (FSH), thyroidstimulating hormone (TSH), adenocorticotrophichormone (ACTH), estradiol, progesterone, growthhormone, insulin like growth factor-1 (IGF-1) whichwere all normal except for elevated serum prolactinat 4423 U/ml (refer to appendix 1 for the results andreference values). Patient had normal secondarysexual characteristics. She had well-developed breastand female genital tract (Tanner V). She had coarseaxillary and pubic hairs. She had no palpable neckmasses. She had a normal free thyroxine (FT4)and thyroid stimulating hormone (TSH). To assessthe parathyroid axis, serum calcium, inorganicphosphorus and parathyroid hormone were taken andwere all normal (refer to appendix 1 for the resultsand reference values).In the stepwise approach for the diagnosis ofhyperprolactinemia, physiologic and drug-inducedetiologies must be ruled out. Pregnancy test wasnegative and she had no previous intake of neurolepticsand dopamine blockers. She had no galactorrhea.She had amenorrhea of a year duration. Ultrasoundof the ovaries showed polycystic ovaries. Polycysticovary syndrome (PCOS) may also be associated withhyperprolactinemia and may present with menstrualirregularities causing the distinction of betweenthe 2 conditions difficult. She had no evidence ofhyperandrogenism and the LH and FSH were normalmaking the consideration of PCOS unlikely. A pituitaryMRI was done. It showed a macroadenoma measuring1.2 x 1.5 x 1.3 cm enhanced by contrast thusprolactinoma was considered. Hyperprolactinemiafrom a pituitary stalk compression was less likelybecause the prolactin level was very high (4423 U/ml). Medical therapy remains to be the cornerstoneof therapy for both the microprolactinoma andmacroprolactinoma. Surgical therapy is reserved fortumor growth despite therapy and drug resistance tomore than 2 dopamine agonist drugs. Bromocriptine2.5mg three times a day was started.Fig 4.Patient at 2 Months Post-Pancreatic Encucleation.Insulinoma is common in patients 30-60 yearsold. It is a tumor of the beta cell of the pancreaticislets. The incidence is very low at 4 cases per 1million-years. 5 Diagnosis of insulinoma requires thedocumentation of hypoglycemia associated withhypersecretion of insulin and presence of pancreaticnodules by imaging techniques. Cases involvingthe younger age group are associated with multipleendocrine disorders. Four percent of insulinoma mayhave multiple endocrine neopasia-1. 2 Generally,they occur in individuals younger than 20 years old.To assess for involvement of the pituitary axis thefollowing were taken: serum luteinizing hormoneOn the 2nd month of follow-up, she hadresumption of her regular menstruation. She hadno occurrence of blurring of vision. A repeat serumprolactin of 405 U/ml was documented 6 monthsafter. Because of the significant drop in the prolactinto physiologic level and the normalization of hermenstruation, bromocriptine was decreased to2.5 mg twice a day. Prolactinoma may be the firstmanifestation of MEN-1 in fewer than 10% of patientsand less than 3% of patients with anterior pituitarytumors will have MEN-1. 6A multiple endocrine neoplasia was consideredin this case because of the involvement of 2 or moreendocrine glands. Multiple endocrine neoplasia

Insulinoma and Prolactinoma in A Young Female 141(MEN) is characterized by occurrence of tumorsinvolving two or more endocrine organs within thesame patient. The combined appearance of thetumors of the parathyroid, pancreatic islets andanterior pituitary is characteristic of MEN-1 alsoknown as WermerÊs Syndrome. However, 94.5% ofMEN-1 presented with primary hyperparathyroidismwhich was absent in our case. A variant of MEN-1with high penetrance of prolactinoma plus anotherendocrine tumor has been described.Fig 5.Pituitary Microadenoma Measuring 1.2 x 1.5 x 1.3 cm, Enhanced on Contrast with Pituitary MRIDISCUSSIONIn a review of cases of MEN-1 at the US-NationalInstitute of Health, 94.5% of cases had primaryhyperparathyroidism as the initial presentation. 6 Thedistribution of cases is depicted below.second decade which is compatible with our casehowever it is also at this age bracket where we expectpeak incidence of primary hyperparathyroidism as acomponent of MEN-1 which was not evident in ourcase. Please refer to the figure below.Parathyroid tumorGastrinomaInsulinomaProlactinomaFig 6.Schemic Representation of 220 Patients Seen withMEN-1Fig 7.Adapted from Marx et al, Annals of InternalMedicine, 1998 6As we shall see from the representation above,94.5% of cases willl have primary hyperparathyroidism.Twelve percent have combined parathyroid,pancreatic and pituitary tumors. 2 A combination ofboth a pancreatic and pituitary tumor occurs in 0.5%only. 2The peak of onset of MEN-1 occurs during theThe gene for MEN-1 is localized in chromosome11q13 by mapping studies. Menin is nuclear proteinwhich is the by-product of the gene mutation involvedin transcription regulation, genome instability andcell division. The utility of MEN-1 mutation is forearly detection amongst immediate family membersand first degree relatives. However, our case was

142 Cardino MJ T and Lantion-Ang FLmost likely sporadic. Our patientÊs immediate familymembers were screened with a fasting blood sugarand serum calcium and none had abnormal results.None in the family also complained with blurringof vision, nausea and vomiting suggestive of aspace occupying lesions. Chromosomal testing formutations involving MEN-1 gene is not available in thePhilippines. Pick-up rates by research centers in theUnited States are at best 24% for sporadic cases and68% for familial cases. 7 Clinical criteria for genetictesting for sporadic MEN-1 and rarer combinations ofMEN-1 have not been well-defined. 7 Utility of MEN-1mutation identification does not necessarily lead tomajor therapeutic intervention even in the youngerage groups, 7 unlike RET identification in MEN-2 weretotal thyroidectomy should be done long before theonset of its manifestation for prevention and cure ofmedullary thyroid cancer. In the absence of MEN-1mutational analysis, the following laboratory testsare recommended among suspected carriers ofthe disease according to the consensus guidelinesby the international working group of clinicalendocrinologists however this does not replace themutation testing. 8Table II. Program of Tests and Schedule for Suspected MEN-1carrier 8Tumor Age Biochemical test Imaging(annual)Parathyroid adenoma 8 Calcium, PTH NoneGastrinoma 20 Gastrin NoneInsulinoma 5 FBS, Insulin MRIAnterior Pituitary Tumor 5 Prolactin, IGF-1 MRIForegut Carcinoid 20 None CT-ScanCONCLUSIONWe presented a 20 year old female with varianttype of MEN-1 presenting with hypoglycemic seizuresand amenorrhea. On work-up, she had insulinoma andprolactinoma. Her insulinoma was removed by surgeryand her macroprolactinoma treated medically. Shehad favorable outcome with surgical removal of theinsulinoma and medical therapy for the prolactinoma.Young patients diagnosed with insulinoma should bescreened for other endocrine tumors that define multipleendocrine neoplasia. Because this is a rare syndrome,a high index of suspicion is a must to diagnose thisproblem and address the associated morbidity resultingfrom hormone excess.REFERENCES1. Kouvaraki M: Genotype-phenotype Analysis in MEN-1. Archof Surgery ; 137: 641, 2002.2. Farren D: Clinical Studies of MEN-1 in 220 Patients. QJMed;89:653, 1999.3. Carty, et al.: Variable Penetrance and Spectrum ofManifestations of MEN-1. Arch of Surgery; 124:1106,1998.4. Fujikura: A Case of Secretin Sensitive Insulinoma with LowC-Peptide. Endocrine Journal; 54: 113, 2007.5. Hiramoto, et al.: Intraoperative Ultrasound and Localizationof Occult Insulinoma. Arch of Surgery 136: 1020, 2001.6. Marx, et al.: MEN-1: Clinical and Genetic Topics. Annals ofInternal Medicine; 129:484, 1998.7. Ellard S, Hattersley AT, Brewer CM, Vaidya B: Detection ofAn MEN-1 Gene Mutation Depends on Clinical Featuresand Supports Current Referral Criteria for DiagnositcMolecular Genetic Testing. Clin Endocrinol; 62:169,2005.8. Brandi, et al.: Consensus Guidelines for MEN-1 and MEN-2.JCEM 86: 5658, 2001.APPENDIXTable I. Hormonal and Blood Chemistries of PatientLaboratory Tests Results Normal ValueRandom Blood Sugar 18 80-110mg/dlSerum Insulin 41 2.6-24 uU/mlC-peptide 25.6 1.1-5ng/mlIonized calcium 1.16 1.0-1.3 mmol/LPhosphorus 3.5 2.5-4.8 mg/dlIntact PTH 47.8 10-65 pg/mlFT4 0.8 0.8-2 ng/mlTSH 0.45 0.39-6.16 ulU/mlTestosterone 0.99 0.26-1.3 ng/mlEstradiol 27.9 12-166 pg/ml17-OH-progesterone 0.416 0.2-1.5 ng/mlLH 2.4 1.5-5 pg/mlFSH 5.26 3.5-12.5 pg/mlACTH (11 pm) 15.5 0-46 pg/mlIGF-1 34nmol/L 8-51 nmol/LGastrin 17 < 15 pg/mlProlactin 4423 127-637 U/ml