Insulinoma and Prolactinoma in A Young Female 137

INSULINOMA AND PROLACTINOMA IN A YOUNG FEMALE: A VARIANT OF MULTIPLE ENDOCRINE NEOPLASIA 1 (MEN-1)

Marbert John T. Cardino, M.D.1 and Frances Lina Lantion-Ang, M.D.2

137

Phil. J. Internal Medicine, 47: 137-142, May-June, 2009

Case Reports

1Fellow-in-training, Section of Endocrinology, Diabetes and Metabolism

2Consultant, Section of Endocrinology, Diabetes and Metabolism

Reprint request to: Marbert John T. Cardino, M.D., Section of Endocrinology Diabetes and Metabolism, Philippine General Hospital, Taft Avenue, Manila, Philippines.

ABSTRACT

Background: MEN-1, a rare disorder, consists of parathyroid adenoma, entero-pancreatic tumor and pituitary tumor. We report a 20-year old female with insulinoma and prolactinoma without parathyroid adenoma to complete the triad of MEN-1. A MEN-1 variant has been reported with high penetrance of prolactinoma and another endocrine tumor, however, validity of this variant is not yet universally accepted.

Clinical Presentation: A 20 year old female was referred for recurrent episodes of grandmal seizures precipitated by hypoglycemia for 5 years and a 2 x 1.8 cm pancreatic nodule on magnetic resonance imaging. Symptoms were relieved by eating. She gained 18 kg in 4 months prior to the referral. She was obese (BMI: 32kg/m2) with amenorrhea for 1 year. She had no acne, galactorrhea, and hirsutism.

Diagnostics: She was initially under a neurologist and pre l iminar y invest igat ions revea led normal electroencephalogram and brain computed tomography scan. Fasting blood sugar was 43mg/dl after 12-hour fast thus def in i t ive 72 hour fast test was done . Fast ing b lood sugar o f 18mg/d l and an inappropriately elevated insulin (41uU/ml) and C-peptide (25.6ng/ml) were noted after an 18-hour fast, thus insulinoma was considered. Baseline cortisol was normal (880nmol/L). Pre-operative localization showed a 2 x 1.8 cm pancreatic mass confirmed by an intra-operative ultrasonography. Subsequently tumor enucleation was done. Intraoperatively, blood sugar was monitored to maintain euglycemia. To work-up for her oligomenorrhea, a normal LH (2.4pg/ml), FSH (5.2pg/ml), testosterone (0.99ng/ml), estradiol (27.9pg/ml), and 17-hydroxyprogesterone (0.416ng/ml) were documented however prolactin (4423 U/ml) was elevated, thus MEN-1 was considered. Pituitary MRI showed a 1.2 x 1.3 adenoma with biochemical hyperprolactinemia confirming prolactinoma. Normal ionized calcium (1.16mmol/L), parathyroid hormone (47.8pg/ml) ruled out hyperparathyroidism to complete the triad of MEN-1. Histopathology confirmed insulinoma after staining with chromogranin and synatophysin.

Treatment and Outcome: Surgical removal of the insulinoma was uneventful and post-operatively the blood sugar remained normal even without glucose-containg fluids. Bromocriptine 5mg/day was given for the prolactinoma. Two months post-operatively she had normal menstruation, lost weight (body mass index of 26kg/m2 from 32kg/m2), and had non-recurrence of hypoglycemic seizures.

Conclusion: We report a female with a variant type of MEN-1 composed of insulinoma corrected surgically and prolactinoma treated medically with favorable outcome.

Keywords: Mu l t ip le Endocr ine Neop las ia 1 , Insulinoma, prolactinoma

INTRODUCTION

Mu l t ip l e endocr ine neop las ia (MEN) i s characterized by the occurrence of tumors involving two or more endocrine organs within the same patient. The combined appearance of the tumors of the parathyroid, pancreatic islets and anterior pituitary is characteristic of MEN-1 also known as WermerÊs Syndrome. Men-1 is generally inherited as autosomal dominant disorder or occasionally as sporadic cases. Our patient was a sporadic case in the absence of a similar condition within her immediate family. The incidence of MEN-1 is only 0.25% from randomly chosen postmortem studies; 1-18% among patients with primary hyperparathyroidism, and 3% with anterior pituitary tumors.1,3 What was striking with our patient besides its rare occurrence was its uncommon presentation. Nearly 95% of MEN-1 patients resent with primary hyperparathyroidism but our patient presented with seizure episodes triggered by hypoglycemia which on work-up was an insulinoma. Insulinoma may be the initial presentation in only 10% of MEN-1 patients.2 Generally, the interval for occurrence between the first tumor and the subsequent tumors is between 6-24 years. There had been no reported cases in Herdin.

Case Presentation and Review of Related Literature

We report a case of a 20 year old female with seizure disorder of 5 years duration. She was seen by a neurologist who diagnosed her of seizure

138 Cardino MJ T and Lantion-Ang FL

disorder and was started with Carbamazepine with escalating doses. Brain computed tomography scan and electroencephalogram were normal. Topiramate was added to the anti-seizure regimen however patient still had 4-6 seizure episodes per year. There were episodes of true hypoglycemia precipitating the seizure attacks thus a computed tomography scan of the abdomen was done and showed a 2 x 1.8cm pancreatic mass thus she was referred to Endocrinology for evaluation.

Fig 1. MRI of the Abdomen Showing A 2 x 1.8cm Pancreatic Nodule Enhanced By Contrast

On review, our patient started to have symptoms of generalized weakness associated with palpitations, hunger pangs and dizziness resolved with food intake for 5 years. These symptoms usually occurred on waking up. Because of this pattern, she began gaining weight until 6 months later, she had onset of generalized tonic seizures. Everytime she was brought to the emergency room, her blood sugar was low. After giving intravenous glucose, patient regained consciousness. She gained 18 kg in 4 months prior to referral to our service.

Menarche was at 11 years old. Menstrual flow was regular until a year prior to consult she had amenorrhea. She had no dysmenorrheal, abnormal discharges and history of contraceptive intake.

Developmental history was at par with age. She had good school performance and even graduated college. She had no history of blurring of vision, and chronic headaches. She had no family history of tumors, diabetes and hypertension.

On examination, she had normal vital signs. She was obese with a BMI of 32 kg/m,2 waist circumference of 95 cm, hip circumference of 99 cm, and waist to hip ratio was 0.95. There was no acanthosis nigricans, thyromegaly, and xanthomas. Silver striae were noted in the inner thighs. She had no visual field cuts on confrontation test.

Fig 2. Photograph of the Patient During Her Admission at PGH

In the approach to hypoglycemic patients, we have to classify the etiology of the hypoglycemia. Our patient had fasting hypoglycemia. Differential diagnoses for fasting hypoglycemia included drugs e.g. sulfonylurea, critical illness, adrenal and pituitary insufficiency and insulinoma. She was not hypotensive, lethargic and weak making the consideration of adrenal insufficiency unlikely. Patient had no intake of sulfonylurea.

The signs and symptoms of patients were suggestive of insulinoma, thus serum insulin, C-peptide and random blood sugar were taken after a 72-hour fast test. Baseline counter-regulatory hormone levels were taken and then blood sugar was monitored every 2 hours while patient fasted. Baseline 8 oÊclock morning serum cortisol (880 nmol/L) was normal. A 72 hour fast test was done. On the 18th hour, she manifested with neuroglycopenic symptoms. Capillary blood sugar was 38 mg/dl. A low random blood sugar at 18mg/dl with an inappropriately high serum insulin levels at 41.08 uU/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 in equimolar amounts. In our patient, the serum insulin to C-peptide was 1.6 reflective of degradation of the C-peptide. The cathepsin B degrades the C terminal amino acids of C-peptide which is being determined in the assay, resulting to higher insulin to C-peptide ratio.4

Insulinoma and Prolactinoma in A Young Female 139

Table I. Review of Cases with Insulin to C-peptide Ratio in Insulinoma Patients4

Author Levels in Insulinoma

Katabami 7.2 Gin 6.3 Sakai 6.1 Scarlet 5.9 Saudek 5 Lebowitz 4.9 Kondo 4.2 Service 3.6 Ciavarella 2.9 Turner 2 Fujikura 2 Our Case 1.6

Intraoperative ultrasound showed a 2 x 1.8 cm solid nodule at the antero-inferior portion of the body of the pancreas and subsequently an enucleation of the nodule was done. Post-operatively, blood sugar rose to 208 mg/dl within 30 minutes from enucleation of the tumor. No symptoms of acute pancreatitis were documented and serum amylase was slightly elevated only at 178 U/ml (normal 83-110 U/ml). There were no calcifications noted. Post-operative biopsy revealed an insulinoma. Cells were arranged in anastomosing cords separated by a vascular stroma, interspersed with sparse collagenous stroma. Chromogranin-A and synaptophysin staining of the tumor were positive (see figure 3). These staining results confirmed that the tumor was an insulinoma.

Fig 3. A) 2x2 cm Pancreatic Nodule Post-Pancreatic Enucleation. B) Hematoxylin and Eosin Staining Showing Uniform Cells in Anastomosing Cords. C) Panoramic View of the Tumor Cells in Clumps with Sparse Collagenous Stroma. D) Positive Synaptophysin Staining of the Pancreatic Nodule. E) Positive Chromogranin Staining of the Pancreatic Nodule.

140 Cardino MJ T and Lantion-Ang FL

During the recuperation period, she had no recurrence of the hypoglycemic episodes, seizures and other neuroglycopenic symptoms. She was discharged improved on the 5th post-operative day. Two weeks from discharge, patient had a repeat insulin determination after a 12 hour fast and results showed blood sugar of 100 mg/dl and suppressed serum insulin of 0.5 uU/ml.

On the 2nd month of follow-up, patient had no recurrence of any seizure episodes. No hypoglycemic attacks were claimed. Patient had significantly lost weight with a BMI of 26 kg/m2 from a previous BMI of 32kg/m2.

Fig 4. Patient at 2 Months Post-Pancreatic Encucleation.

Insulinoma is common in patients 30-60 years old. It is a tumor of the beta cell of the pancreatic islets. The incidence is very low at 4 cases per 1 million-years.5 Diagnosis of insulinoma requires the documentation of hypoglycemia associated with hypersecretion of insulin and presence of pancreatic nodules by imaging techniques. Cases involving the younger age group are associated with multiple endocrine disorders. Four percent of insulinoma may have multiple endocrine neopasia-1.2 Generally, they occur in individuals younger than 20 years old. To assess for involvement of the pituitary axis the following were taken: serum luteinizing hormone

(LH), follicule stimulating hormone (FSH), thyroid stimulating hormone (TSH), adenocorticotrophic hormone (ACTH), estradiol, progesterone, growth hormone, insulin like growth factor-1 (IGF-1) which were all normal except for elevated serum prolactin at 4423 U/ml (refer to appendix 1 for the results and reference values). Patient had normal secondary sexual characteristics. She had well-developed breast and female genital tract (Tanner V). She had coarse axillary and pubic hairs. She had no palpable neck masses. She had a normal free thyroxine (FT4) and thyroid stimulating hormone (TSH). To assess the parathyroid axis, serum calcium, inorganic phosphorus and parathyroid hormone were taken and were all normal (refer to appendix 1 for the results and reference values).

In the stepwise approach for the diagnosis of hyperprolactinemia, physiologic and drug-induced etiologies must be ruled out. Pregnancy test was negative and she had no previous intake of neuroleptics and dopamine blockers. She had no galactorrhea. She had amenorrhea of a year duration. Ultrasound of the ovaries showed polycystic ovaries. Polycystic ovary syndrome (PCOS) may also be associated with hyperprolactinemia and may present with menstrual irregularities causing the distinction of between the 2 conditions difficult. She had no evidence of hyperandrogenism and the LH and FSH were normal making the consideration of PCOS unlikely. A pituitary MRI was done. It showed a macroadenoma measuring 1.2 x 1.5 x 1.3 cm enhanced by contrast thus prolactinoma was considered. Hyperprolactinemia from a pituitary stalk compression was less likely because the prolactin level was very high (4423 U/ml). Medical therapy remains to be the cornerstone of therapy for both the microprolactinoma and macroprolactinoma. Surgical therapy is reserved for tumor growth despite therapy and drug resistance to more than 2 dopamine agonist drugs. Bromocriptine 2.5mg three times a day was started.

On the 2nd month of fol low-up, she had resumption of her regular menstruation. She had no occurrence of blurring of vision. A repeat serum prolactin of 405 U/ml was documented 6 months after. Because of the significant drop in the prolactin to physiologic level and the normalization of her menstruation, bromocriptine was decreased to 2.5 mg twice a day. Prolactinoma may be the first manifestation of MEN-1 in fewer than 10% of patients and less than 3% of patients with anterior pituitary tumors will have MEN-1.6

A multiple endocrine neoplasia was considered in this case because of the involvement of 2 or more endocrine glands. Multiple endocrine neoplasia

Insulinoma and Prolactinoma in A Young Female 141

(MEN) is characterized by occurrence of tumors involving two or more endocrine organs within the same patient. The combined appearance of the tumors of the parathyroid, pancreatic islets and anterior pituitary is characteristic of MEN-1 also

known as WermerÊs Syndrome. However, 94.5% of MEN-1 presented with primary hyperparathyroidism which was absent in our case. A variant of MEN-1 with high penetrance of prolactinoma plus another endocrine tumor has been described.

Fig 5. Pituitary Microadenoma Measuring 1.2 x 1.5 x 1.3 cm, Enhanced on Contrast with Pituitary MRI

DISCUSSION

In a review of cases of MEN-1 at the US-National Institute of Health, 94.5% of cases had primary hyperparathyroidism as the initial presentation.6 The distribution of cases is depicted below.

Fig 6. Schemic Representation of 220 Patients Seen with MEN-1

As 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 of both a pancreatic and pituitary tumor occurs in 0.5% only.2

The peak of onset of MEN-1 occurs during the

second decade which is compatible with our case however it is also at this age bracket where we expect peak incidence of primary hyperparathyroidism as a component of MEN-1 which was not evident in our case. Please refer to the figure below.

Fig 7. Adapted from Marx et al, Annals of Internal Medicine, 19986

The gene for MEN-1 is localized in chromosome 11q13 by mapping studies. Menin is nuclear protein which is the by-product of the gene mutation involved in transcription regulation, genome instability and cell division. The utility of MEN-1 mutation is for early detection amongst immediate family members and first degree relatives. However, our case was

Parathyroid tumorGastrinomaInsulinomaProlactinoma

142 Cardino MJ T and Lantion-Ang FL

most likely sporadic. Our patientÊs immediate family members were screened with a fasting blood sugar and serum calcium and none had abnormal results. None in the family also complained with blurring of vision, nausea and vomiting suggestive of a space occupying lesions. Chromosomal testing for mutations involving MEN-1 gene is not available in the Philippines. Pick-up rates by research centers in the United States are at best 24% for sporadic cases and 68% for familial cases.7 Clinical criteria for genetic testing for sporadic MEN-1 and rarer combinations of MEN-1 have not been well-defined.7 Utility of MEN-1 mutation identification does not necessarily lead to major therapeutic intervention even in the younger age groups,7 unlike RET identification in MEN-2 were total thyroidectomy should be done long before the onset of its manifestation for prevention and cure of medullary thyroid cancer. In the absence of MEN-1 mutational analysis, the following laboratory tests are recommended among suspected carriers of the disease according to the consensus guidelines by the international working group of clinical endocrinologists however this does not replace the mutation testing.8

Table II. Program of Tests and Schedule for Suspected MEN-1 carrier8

Tumor 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-Scan

CONCLUSION

We presented a 20 year old female with variant type of MEN-1 presenting with hypoglycemic seizures and amenorrhea. On work-up, she had insulinoma and prolactinoma. Her insulinoma was removed by surgery and her macroprolactinoma treated medically. She had favorable outcome with surgical removal of the insulinoma and medical therapy for the prolactinoma. Young patients diagnosed with insulinoma should be screened for other endocrine tumors that define multiple endocrine neoplasia. Because this is a rare syndrome, a high index of suspicion is a must to diagnose this

problem and address the associated morbidity resulting from hormone excess.

REFERENCES

1. Kouvaraki M: Genotype-phenotype Analysis in MEN-1. Arch of Surgery ; 137: 641, 2002.

2. Farren D: Clinical Studies of MEN-1 in 220 Patients. QJMed; 89:653, 1999.

3. Car ty, et al.: Variable Penetrance and Spectrum of Manifestations of MEN-1. Arch of Surgery; 124:1106, 1998.

4. Fujikura: A Case of Secretin Sensitive Insulinoma with Low C-Peptide. Endocrine Journal; 54: 113, 2007.

5. Hiramoto, et al.: Intraoperative Ultrasound and Localization of Occult Insulinoma. Arch of Surgery 136: 1020, 2001.

6. Marx, et al.: MEN-1: Clinical and Genetic Topics. Annals of Internal Medicine; 129:484, 1998.

7. Ellard S, Hattersley AT, Brewer CM, Vaidya B: Detection of An MEN-1 Gene Mutation Depends on Clinical Features and Supports Current Referral Criteria for Diagnositc Molecular Genetic Testing. Clin Endocrinol; 62:169, 2005.

8. Brandi, et al.: Consensus Guidelines for MEN-1 and MEN-2. JCEM 86: 5658, 2001.

APPENDIX

Table I. Hormonal and Blood Chemistries of Patient

Laboratory Tests Results Normal Value

Random Blood Sugar 18 80-110mg/dl Serum Insulin 41 2.6-24 uU/ml C-peptide 25.6 1.1-5ng/ml Ionized calcium 1.16 1.0-1.3 mmol/L Phosphorus 3.5 2.5-4.8 mg/dl Intact PTH 47.8 10-65 pg/ml FT4 0.8 0.8-2 ng/ml TSH 0.45 0.39-6.16 ulU/ml Testosterone 0.99 0.26-1.3 ng/ml Estradiol 27.9 12-166 pg/ml 17-OH-progesterone 0.416 0.2-1.5 ng/ml LH 2.4 1.5-5 pg/ml FSH 5.26 3.5-12.5 pg/ml ACTH (11 pm) 15.5 0-46 pg/ml IGF-1 34nmol/L 8-51 nmol/L Gastrin 17 < 15 pg/ml Prolactin 4423 127-637 U/ml