Multiple Endocrine Neoplasia Syndromes: Radiological Review

Rev. Argent. Radiol. 2018;82(3): 124-130124
Abstract Multiple endocrine neoplasia (MEN) encompasses a series of familial genetic disorders in which tumors simultaneously occur in two or more endocrine glands. MEN syndromes are autosomal-dominant disorders categorized into three main patterns: MEN 1 (Wermer syndrome), MEN 2 (includes MEN 2A or Sipple syndrome and MEN 2B or Wagenmann- Froboese syndrome) and MEN 4. Parathyroid adenomas and medullary thyroid carcinoma are the most frequent tumors in MEN 1 and MEN 2 respectively. These entities are more common in younger patients, with bilateral, multiple or multifocal disease and, specially, in patients with family history of this disease. Cooperation between endocrinologists, surgeons, oncologists and radiologists is pivotal for optimizing patient treatment. Keywords: Multiple endocrine neoplasia, MEN 1, MEN 2, medullary thyroid carcinoma, pheochromocytoma
Introduction Multiple endocrine neoplasia (MEN) syndromes encompass a series of conditions with genetic abnormalities characterized by the presence of tumors involving two or more endocrine glands. MEN syndromes are autosomal-dominant disorders that include three patterns: MEN 1, MEN 2 and MEN 4. Each type is characterized by the presence of tumors in specific organs. In this article, we will describe the clinical features of each type and show their main imaging findings.
MEN 1
MEN syndrome type 1 is a rare autosomal-dominant heredi- tary condition (incidence of 2 cases in 100,000). The genetic basis of MEN 1 is a germline-inactivating mutation of MEN1 gene, located on chromosome 11q13.1 This syndrome com- bines the occurrence of tumors in the parathyroid gland, pan- creas and anterior pituitary gland. The presence of 2 of the 3 main neoplasms is enough for diagnosis. Some patients de- velop adrenocortical tumors, carcinoids, facial angiofibromas, collangenomas and lipomas (Fig. 1). 2-4
Parathyroid tumors
Parathyroid tumors are the first manifestation of this syn-
drome in over 85% of patients. Multigland disease is not always synchronous.5,6 In patients with persistent hypercalce- mia following surgery, imaging plays a very important role.7 The treatment is surgery, either subtotal or total parathyroid- ectomy with reimplantation of one gland in the spleen.8
Imaging findings
Suspected parathyroid adenomas are initially evaluated using ultrasound. Parathyroid adenomas appear as well-defined, oval hypoechoic masses posterior to the thyroid gland sup- plied by an artery in the upper and lower poles of the para- thyroid gland, generally a tributary to the inferior thyroid artery. Ultrasound also serves as a guide for interventionist procedures such as fine needle aspiration (FNA) biopsy, which contributes to the pathologic diagnosis of the lesion. Computed tomography (CT) allows identification of ectopic glands within the mediastinum and behind the trachea. Mag- netic resonance (MR) imaging has higher sensitivity than CT for the localization of adenomas but is not usually used as the first-line modality. Parathyroid adenomas appear hyper- intense on T2-weighted sequences and hypointense on T1- weighted sequences. In nuclear medicine, the use of sestamibi scintigraphy in which early and delayed images are obtained 15 minutes and 2 hours after radiotracer injection, respectively, has a high sensitivity for detecting adenomas (Fig. 2).5,7
Multiple Endocrine Neoplasia Syndromes: Radiological Review Ignacio Martín García1 Rosario Vidal Tocino2 Elisabeth Martín García3 Manuel Ángel Martín Pérez1 José Martín Marín Balbín1
1 Radiodiagnosis Department, Complejo Asistencial de Zamora, Zamora, Spain. 2 Genetic Counseling Unit, Medical Oncology Department, University Hospital of Salamanca, Salamanca, Spain 3 Ophthalmology Department, Complejo Asistencial de Zamora, Zamora, Spain
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Pancreatic neuroendocrine tumors
Pancreatic neuroendocrine tumors occur in 80% of patients. Gastrinoma is the most common neuroendocrine tumor in MEN and the main prognostic determinant due to its poten- tial malignancy. Other less common tumors include insulino- mas and glucagonomas. The main purpose of surgery is to prevent or delay the occurrence of metastasis. Gastrinomas frequently appear as small, multiple lesions, which makes complete resection difficult; therefore, awareness of the duo- denal location of these tumors leads to recommend duode- notomy, with systematic duodenal –apart from pancreatic— exploration.6,8
Fig. 1 Spectrum of disease components in multiple endocrine neoplasia (MEN) syndrome type 1.
MEN 1 -Parathyroid tumors -Pancreatic neuroendocrine tumors -Anterior pituitary tumors -Others: -Facial angiofibromas -Collangenomas -Adrenocortical tumors -Lipomas -Intestinal carcinoids
Fig. 2 Parathyroid adenoma in a patient with MEN type 2. Cross-sectional (A) and longitudinal (B) ultrasound showed a round- ed, hypoechoic mass of well-defined borders, supplied by an artery in the upper pole (C). On computed tomography (CT) with intravenous contrast administration, coronal section (D) showed a hyper-enhancing nodular lesion posterior to the thyroid gland. Sestamibi scintigraphy image in the early phase (E) shows a lesion with radiotracer uptake at the same location as the image in (b), consistent with parathyroid adenoma.
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Imaging findings
Ultrasound is usually not effective because it does not allow visualization of the tumor and it is used during surgery follow- ing palpation. Tumors appear as homogeneous hypoechoic masses. CT is usually the method of choice both for local and distant spread. These tumors are most often small and may be multiple, therefore requiring the use of water as an oral contrast medium. Without intravenous contrast admin- istration, these lesions appear isodense, avidly enhancing in the arterial phase, therefore an arterial phase should be per- formed at 25-30 seconds after the injection of contrast, since in the pancreatic phase at 35-40 seconds or in the portal phase at 60-70 seconds these lesions may appear isodense to the pancreatic parenchyma and not visible (Fig. 3). Liver metastases are typically hypervascular in the arterial phase. MR imaging has a greater sensitivity for detecting these tu- mors, which appear hypointense on T1-weighted sequences and hyperintense on T2-weighted sequences with a contrast uptake pattern similar to that of CT. In addition, somatosta- tin receptor scintigraphy with indium 111 is a whole-body imaging technique to detect occult neuroendocrine tumors; unfortunately not all neuroendocrine tumors express soma- tostatin receptors. This technique can predict if patients will respond to radionuclide therapy and allows monitoring of the response. Finally, positron-emission tomography (PET) does not play a major role in this condition, as these are well- differentiated tumors with a low metabolic rate; thus, fluoro- deoxyglucose (FDG) uptake is not visualized.5,7
Anterior pituitary adenomas
Anterior pituitary adenomas occur in 30% of patients and are usually functioning (60% prolactinomas, 25% secrete growth hormone and 5% secrete adrenocorticotropic hor-
mone). In addition to clinical features resulting from excessive hormone secretion, there may be clinical symptoms resulting from compression in large-size tumors.6,7
Imaging findings
MR imaging is the modality of choice for visualization of the pituitary gland. The use of small fields of view with sagittal and coronal T1-weighted sequences is required, as well as a dynamic contrast-enhanced technique. A microadenoma may be difficult to visualize; therefore attention should be paid to indirect signs such as convexity of the superior margin of the gland and erosion of the sellar floor. These lesions may appear hypointense on T1-weighted sequences both before and after contrast administration (Fig. 4)2 5,7
Adrenal cortical tumors
Adrenal cortical tumors are typically non-functioning adrenal adenomas occurring in up to 40% of patients with MEN 1. Tumors smaller than 4 cm usually do not require surgery; in- stead, functioning tumors may require adrenalectomy.5
Imaging findings
Approximately 70% to 80% of adenomas are rich in intra- cellular lipid. On unenhanced CT, lipid-rich adenomas have densitometry values below 10 HU. The dynamic contrast- enhanced scan must include a portal phase and a delayed phase, in addition to the unenhanced scan. Adenomas show a relative percentage washout of 40% and an absolute per- centage washout higher than 60%. T1-weighted in-phase/ out-of-phase sequence allows identification of lesions with
Fig. 3 Insulinoma in a patient with MEN type 1. Unenhanced abdominal CT scan (A) showed a rounded lesion isodense to the pancreatic parenchyma deforming its border (arrow). Contrast-enhanced abdominal CT scan in the arterial phase (B) showed a hyper-enhancing lesion located in the head of the pancreas. Contrast-enhanced abdominal CT scan in the portal phase (C) showed contrast washout, with the lesion being slightly hyperdense to the pancreatic parenchyma.
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intracellular lipid (Fig. 5). Adenomas that are poor in intracellular lipid are difficult to characterize for exhibiting values above 10 HU or for absence of chemical shift with opposed-phase sequence. In addition, adrenal carcinomas are very rare lesions and exhibit aggres- sive features with necrosis, hemorrhage and a tendency to invade neighboring structures.5,7
MEN 2
MEN 2 is a an autosomal-dominant hereditary condition with an estimated prevalence of 1 in 30,000 people, affecting both genders equally. The genetic defect in MEN 2 involves a mutation in the germline of the RET proto-oncogene on chromosome 10q11.2.9 MEN 2 is characterized by medullary
thyroid carcinoma, pheochromocytomas and hyperparathy- roidism. It is divided into three subtypes (Fig. 6): MEN 2A: Nearly all patients with MEN 2A have medullary thy- roid carcinoma, 50% have pheochromocytomas and 10-30% have hyperparathyroidism. Hirschsprung’s disease and cutane- ous lichen amyloidosis can be associated with these patients. MEN 2B: similar to 2A but with no hyperparathyroidism. Pa- tients with this syndrome have a marfanoid habitus and may develop ganglioneuromas in the intestinal tract and neuromas in other locations such as the tongue (Fig. 7).2,10 Ophthalmic abnormalities most commonly observed in these patients in- clude thickened corneal nerves, prominent eyebrows associat- ed with eyelid neuromas, subconjunctival neuromas, impaired pupillary dilation and elevated intraocular pressure.11
Familial medullary thyroid carcinoma: no development of pheochromocytomas or primary hyperparathyroidism.
Fig. 4 Pituitary adenoma in a patient with MEN type 1. Magnetic Resonance (MR) images. T2-weighted sequence in the coronal plane (A) shows a rounded hypodense lesion in the right portion of the anterior pituitary (arrow). Gadolinium-enhanced images in the coronal (B) and sagittal (C) views showed a non-enhancing nodular lesion.
Fig. 5 Adrenal adenoma in a patient with MEN type 1. CT without intravenous contrast administration (A) showed a nodular le- sion in the right adrenal gland with densitometry values below 10 HU. In-phase (B) and opposed-phase (C) magnetic resonance (MR) images showed loss of signal intensity in opposed-phase, a typical feature of adrenal adenomas.
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Medullary Thyroid Carcinoma
Medullary thyroid carcinoma is the first tumor developed in patients with MEN 2 and the most common cause of death in these patients.9 Medullary carcinoma originates from the parafollicular cells or C cells. Tumors are usually bilateral and multifocal, are associated with a worse prognosis and early occurrence.10
The first clinical symptom may be a palpable thyroid nod- ule or adenopathy and, in some cases, concomitant clinical
features of pheochromocytomas or hyperparathyroidism lead to diagnosis.12 Biochemical diagnosis is made by calcitonin measurement, which serves as an excellent marker of disease and can also predict response to treatment. Carcinoembry- onic antigen (CEA) may be useful in patients with poorly-dif- ferentiated metastatic carcinoma who may not have elevated calcitonin levels.12,13
Imaging findings
Thyroid ultrasound is the imaging test of choice for initial as- sessment of medullary carcinoma. Lesions exhibit features of malignancy: hypoechogenicity, poorly-defined margins, inter- nal vascularity and the presence of micro- or macrocalcifica- tions. Calcifications are the most significant findings of ma- lignancy in medullary carcinoma. In addition, a longitudinal diameter greater than the transversal diameter is predictive of malignancy. Ultrasound also allows detection of adenomas in patients with MEN 2A syndrome. Local invasion is common, with spread to lymph nodes in 50% of cases. Distant metastasis occurs, by frequency order, in the liver (49-62%), bone (40-74%) and lung (33-35%), occurring in 15% to 25% of cases. Therefore, a preopera- tive neck, chest and abdominal CT is recommended for stag- ing patients with lymph node enlargement. CT features are nonspecific in the case of the primary tumor and in cases of lymph node involvement, dense and irregular calcifications will be seen (Fig. 8). CT of the abdomen will allow identifica-
Fig. 6 Spectrum of disease components in MEN type 2 syn- drome.
MEN 2 - MEN 2A Medullary thyroid carcinoma Pheochromocytoma Parathyroid tumors - MEN 2B Medullary thyroid carcinoma Pheochromocytoma Associated abnormalities Marfanoid habitus Cutaneous neuromas Intestinal ganglioneuromatosis
Fig. 7 Pictures of a patient with MEN type 2B. (A) Perilimbic neuroma (arrow). (B) Lingual neuromas (arrow).
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tion of pheochromocytomas, which should be removed prior to any other surgery. Liver metastases may be hyper- or hypoechogenic on ultra- sound. These lesions are usually hypervascular, with cystic degeneration and, in some cases, they may be very small and may calcify. Bone lesions may be osteolytic, osteoblastic or both. Lung metastases may be micro- or macronodular. Bi- lateral miliary involvement has been reported in some cases, and perihilar lesions or calcified masses may also be present. PET/CT sensitivity varies depending on the degree of tumor differentiation, being less sensitive in highly dedifferentiated tumors and in patients with small metastatic lesions, and more sensitive in patients with high calcitonin levels (>1000 pg/mL). The use of novel tracers, such as 18F-dihydroxyphenyl- alanine provides more sensitivity than FDG. PET/CT may play an important role in patients with recurrent carcinoma.12,14
Pheochromocytoma
Pheochromocytoma is a tumor that originates from chromaffin cells in the adrenal medulla and which is typically bilateral. These
tumors may be asymptomatic or there may be clinical symp- toms associated with hypertension. Initial diagnosis is made by biochemical testing via urinary measurement of adrenaline, nor- adrenaline, metanephrine or normetanephrine. Imaging tests are subsequently used for localization of the tumor.1,10
Imaging findings
Ultrasound is the initial technique used to evaluate suspected pheochromocytomas and it allows an assessment of adrenal gland size and morphology abnormalities, although because of operator-dependent limitations, the patient’s own limita- tions, such as obesity, or the small size of tumors, ultrasound may have a lower sensitivity than CT or MR imaging. Pheo- chromocytomas may be visualized as a well-defined, ovoid lesion of heterogeneous echogenicity. On CT, pheochromocytomas may show calcifications in the unenhanced scan and demonstrate intense enhancement fol- lowing contrast administration; areas of necrosis may also be observed in some lesions. The use of iodinated ionic contrast material may trigger a hypertensive crisis; therefore, these agents
Fig. 8 Medullary thyroid carcinoma in a patient with MEN type 2 with associated parathyroid adenoma (asterisk). Axial ultra- sound (A) showed an hypoechoic lesion with poorly-defined margins and microcalcifications (arrow); the longitudinal section (B) with color Doppler showed a lesion with no significant flow (arrow). The CT of the chest with intravenous contrast adminis- tration showed enlarged lymph nodes at the upper paratracheal (B) and lower paratracheal (C) levels with multiple dense and irregular calcifications typical of nodal spread in this disease.
Fig. 9 Pheochromocytomas in patient with MEN type 2. Intra- venous contrast-enhanced CT (A) shows bilateral pheochro- mocytomas. Ultrasound (B) shows right pheochromocytoma with cystic areas and coarse capsule. MRI showed the same lesion as the ultrasound scan, an encapsulated and hetero- geneous lesion dependent on the right adrenal gland, which on T2-weighted sequence (C) exhibited an heterogeneous appearance and appeared hyperintense, with predominantly peripheral uptake on the gadolinium-enhanced sequence (D).
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are contraindicated. Nonionic contrast agents do not carry the same risk and can be used without α-adrenergic blockage. MR imaging is highly sensitive for detecting pheochromocy- tomas, and it is the test of choice for the detection of this tumor because of its lack of ionizing radiation. These lesions appear hypointense on T1-weighted sequences and highly hyperintense on T2-weighted sequences with heterogeneous areas due to necrosis, hemorrhage or calcification. They en- hance avidly following the injection of gadolinium (Fig. 9). Whole-body metaiodobenzylguanidine (MIBG) scintigra- phy is more sensitive than CT or MRI for detecting adrenal medullary hyperplasia, which is believed to be a precursor to pheochromocytoma and could be treated with adrenalec- tomy in patients with MEN 2. The use of novel tracers with an affinity for the sympathetic nervous system, such as 11C- hydroxyephedrine or 18F- dihydroxyphenylalanine increases sensitivity for detecting pheochromocytomas.5,7
Primary hyperparathyroidism
Primary hyperparathyroidism occurs in approximately 10% to 30% of patients with MEN 2, but it is rarely the initial mani- festation. Parathyroid hyperplasia is not differentiated from the sporadic form of hyperplasia. Generally, all four parathy- roid glands are enlarged.10
MEN 4
MEN 4 is a recently described form of the MEN spectrum with parathyroid and anterior pituitary tumors. MEN 4 pa- tients may also develop gastric and bronchial carcinoids or gastrinomas.5
Confidentiality of Data The authors declare that they have followed the protocols of their work center on the publication of patient data and that all the patients included in the study have received sufficient information and have given their informed consent in writing.
Conflicts of interest The authors declare no conflicts of interest.
Authorship contribution All authors signing the cover letter have participated in the conception and design of the study, data collection, analysis and interpretation. Authors have also contributed to drafting the article and revising it critically. All authors have approved the version of the manuscript submitted.
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