Diagnosis of Men-I Syndrome on 68Ga-DOTANOC PET-CT and Role of Peptide Receptor Radionuclide Therapy With 177Lu-DOTATATE

Abstract MEN-I is a rare genetic disorder classically characterized by a predisposition to tumors of the parathyroid glands, anterior pituitary gland, and pancreatic islet cells. We present a case of MEN-I syndrome diagnosed using predominantly nuclear medicine imaging followed by radionuclide therapy, thus emphasizing the role of nuclear imaging in diagnosing and treating MEN-I.


Introduction
Multiple Endocrine Neoplasia-I (MEN-I) is an autosomal dominant disease with a broad spectrum of clinical mani festations (1,2). Parathyroid hyperplasia, pancreatic neo plasia and pituitary tumors are the most frequent disease phenotypes, patients with MEN-I also infrequently develop subcutaneous lipomas, gastrointestinal, bronchial, and thy mic carcinoid tumors (3,4).
There is a very few case reports of the development of pancreatic neuroendocrine tumors (PNETs) in patients diagnosed with MEN-I syndrome related tumors. A car cinoid tumor in this case was located in the head of the pancreas, along with macroadenoma of the pituitary gland. This is the first paper to report the occurrence of PNETs in the association of a pituitary adenoma diag nosed by PET and treated with radionuclide targeting so matostatin receptors.

Case Report
71-year-old normotensive female, non diabetic present ed with abdominal pain and increasing jaundice. Patient was admitted for evaluation and management. Endo scopic ultrasound revealed a periampullary mass mea suring 5 x 5 cm in close proximity to the distal common bile duct (CBD). Fine needle aspiration cytology demon strated metastatic deposits of a round cell tumor, mor phologically resembling a neuroendocrine carcinoma. Magnetic Resonance Cholangiopancreatography per formed for assessment of loco-regional disease revealed a lobulated mass lesion (2.7 x 2.3 cm) in the head and un cinate process of the pancreas ( Figure 1). As a palliative procedure, papillotomy was done and stent was introduced into the CBD during Endoscopic Retrograde Cholangiopancreatography. Hemogram, liv er and kidney function returned to normal levels within a week after the procedure.
The patient atient was thereafter referred to the Nuclear Medicine Department for 68 Ga-DOTANOC PET-CT study for staging and identification of distant metastases. There was evidence of somatostatin receptor expression on the tumor located in head of pancreas. Surprisingly, other intracranial lesion with intense radiotracer uptake was noted corresponding to enlarged pituitary gland (Fig  ure 2a & Figure 2b). Serum Thyroid Stimulating hormone (TSH) and Prolactin were then ordered to investigate for functional status of the pituitary tumor, which were de tected to be within normal limits. MR images confirmed the presence of pituitary macroadenoma (2.2 X 1.7 X 1.1 cm) which had herniated inferiorly through Sellar floor defect ( Figure 3). Serum Parathyroid hormone (PTH) and Tc-Sestamibi parathyroid scintigraphy was also or dered. The serum PTH levels were found to be elevated with focal radiotracer uptake in the region of the left in ferior parathyroid gland ( Figure 4). Biochemical markers and thyroid profile result are shown in Table1. Serum TSH was found to be low with normal levels of T3 and T4 hor mones. The patient opted for novel radionuclide treat ment with 177 Lu-DOTATATE which would simultaneously target pancreatic and pituitary lesions to avoid conven tional surgical procedures. The patient was recruited for Peptide Receptor Radionuclide Therapy (PRRT) with 177 Lu DOTATATE and co-administered with the reno-protective amino acid mixture containing 25 g of Arginine and 25 g of Lysine. Post therapy whole body planar scans revealed intense uptake of radiotracer in head of pancreas and pi tuitary ( Figure 5a and Figure 5b). Single administration of 150 mCi 177 Lu-DOTATATE reduced serum Chromogranin A by 23%. The patient has been scheduled for next therapy 6 weeks later.

Discussion
Neuroendocrine tumors (NETs) constitute a heteroge neous group of neoplasms with common characteristics and biological features. NETs were previously referred as APUDomas, by Pearse in 1968 when he described peptide secreting endocrine cells that share an ability to take up the precursors of biologically active amines, to produce active amine through subsequent intracellular decar boxylation, hence APUD (amine precursor uptake and decarboxylation) (5). Though the majority of NETs occur spontaneously, NETs may occur also as part of complex fa milial endocrine cancer syndromes such as MEN-I, MEN-2, Neurofibromatosis type 1 (NFT type 1), Von Hippel Lindau disease, and Carney's Complex (6)(7)(8) MEN-I or Multiple Endocrine Neoplasia -Type 1, also called Wermer Syndrome, is a familial multiglandular endocrine tumor syndrome which can be variable in its presentation. The epidemiology of MEN-1 demonstrates a prevalence of 2-10 per 100,000 (9). It is 90% autosomal dominant inheritance, and is carried on the Menin gene on chromosome 11q13 (10). The clinical presentation of MEN-I is often remembered by the 3 P's: parathyroid ade nomas, PNET, and pituitary adenomas. In this case report, the patient demonstrated all three of these tumor types.
Pituitary tumors occur in approximately 40% of pa tients with MEN-I. These occur more commonly in wom en than men, and they are often more aggressive macro adenomas as compared to sporadic pituitary tumors. The most common type of pituitary adenoma in MEN-I is a prolactinoma (11). But nonfunctioning adenomas are also known. TSH levels tend to be generally low or nor mal in female patients with non-functioning pituitary  adenomas, a finding consistent with our study. However, possible causes of subclinical hyperthyroidism should be ruled out whenever possible (12). Pancreatic neuroendocrine tumors occur in the major ity of patients with MEN-I (13). Nonsecretory neuroen docrine tumors tend to be large and are often very ag gressive. Specific syndromes and clinical presentations are associated with the secretory types of neuroendo crine tumors: gastrinomas (severe gastric hyperacidity; Zollinger-Ellison syndrome), insulinomas (hyperinsulin ism and fasting hypoglycemia), glucagonomas (diabetes and migratory necrolytic erythema), VIPomas (profuse watery diarrhea, hypokalemia, and achlorhydria; Verner-Morrison syndrome), Somatostatinomas (diabetes melli tus, steatorrhea, cholelithiasis).
Numerous radiotracers are available for endocrine tu mor imaging, including 99m Tc-sestamibi, 111 In-penterotide, 18 -fluorodeoxyglucose ( 18 F-FDG) and 131 I-meta-iodobenzyl guanidine ( 131 I-MIBG). Each of these tracers has advan tages and disadvantages. 99m Tc-sestamibi, for example, concentrates on cells with high mitochondrial content and is very useful in detecting parathyroid adenomas; it has a sensitivity of approximately 90%. 111 In-penterotide is extremely beneficial in detecting NET because it acts on somatostatin receptors, making it highly tumor-spe cific. In contrast, FDG accumulates in any region with increased glucose metabolism, such as areas of inflam mation, therefore making it less tumor-specific (14). An other drawback of using FDG for neuroendocrine imag ing is that it classically causes false negative for carcinoid tumors (15) Somatostatin Receptors (SSRs) are present in several or gan systems and have an important function in the regu lation of both endocrine and exocrine secretion. SSRs are expressed in the majority of tumors of neuroendocrine origin. So far five SSRs subtypes have been identified and cloned. Several somatostatin analogs have been success fully radiolabeled for diagnostic and therapeutic use. The relative usefulness of these radiolabeld somatostatin an alogs is a function of their sensitivities and specificities of receptor binding and the characteristics of the associ ated radioisotope (16) Positron emission tomography (PET) for imaging so matostatin receptor positive tumors is desirable because of its improved spatial resolution. 68 Ga-labeled peptides show a rapid renal clearance and rapidly accumulate in the tumors (80% within 30 minutes). Concentration in tissues without expression of SSRs is low, providing high er contrast imaging. The activity administered in adults is 100-150 MBq and imaging is acquired 60 to 90 minutes after injection. 68 Ga-DOTANOC that we have used being a PET tracer is an excellent tracer for neuroendocrine tu mor imaging, and provides a high target-to-nontarget ra tio that allows for the detection of very small lesions (17).
A new treatment modality for inoperable or metasta  (19). One issue that we would like to emphasize is the benefit of 68 Ga-DOTANOC PET-CT imaging in the workup of MEN I. Information acquired from 68 Ga-DOTANOC PET imaging may confirm or reveal the presence of a lesion, detect metastases from a primary tumor, or diagnose neuroen docrine conditions in which multiple lesions exist. In ad dition, because somatostatin-receptor expression is seen more frequently in well-differentiated tumors, visualiza tion may suggest a more favorable prognosis. Patients with somatostatin receptors expressing tumors detected by 68 Ga-DOTANOC PET are amenable to treatment with 177 Lu-DOTATATE, particularly when conventional treat ment is not feasible.

Conclusions
MEN-I is a rare familial multiglandular endocrine tu mor syndrome. This case presentation describes the oc currence of all three major tumors of MEN1 (pituitary adenoma, parathyroid adenoma, and pancreatic neuro endocrine tumor) in a 71-year-old female.
Nuclear medicine diagnostic imaging namely 68 Ga DOTANOC scan is particularly helpful for identifying pi tuitary and pancreatic lesions in MEN-I. Uptake of 177 Lu DOTATATE on post therapy scan and decrease in serum chromogranin A after single administration indicate an alternative non-surgical option for treatment of patients with MEN-I.

Acknowledgments
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Funding/Support
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