First report of concomitant pheochromocytoma and duodenal neuroendocrine tumour in a sporadic multiple endocrine neoplasia type 1

Abstract

A 77-year-old woman was diagnosed with pheochromocytoma followed by adrenalectomy at age 57. Hyperparathyroidism without osteoprosis was diagnosed at age 58. At age 75, Dual Energy X-ray Absoptiometry (DEXA) revealed osteoporosis and sestamibi scan showed a left parathyroid adenoma. Criteria for parathyroidectomy were met, and she underwent parathyroidectomy. Furthermore, she presented with haematochezia at age 75. An abdominal CT demonstrated a mass in the second portion of the duodenum. Additionally, octreoscan revealed somatostatin receptor positive tissue in the duodenum and Gallium 68 dotatate scan also showed a well-differentiated duodenal neuroendocrine tumour (NET). Genetic testing for MEN1, MEN2 and MEN4 was negative. Diagnosis of sporadic MEN1 syndrome was made. The patient underwent resection of the duodenal NET at age 76. She is in good health 21 years after her first presentation of MEN1. In summary, we present the first sporadic case of MEN1 with concomitant pheochromocytoma and duodenal NET which occurred 20 years apart.

Background

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome characterised by two or more endocrine tumours. MEN1 appears in roughly 1 in 30 000 individuals, with a prevalence of 1-10/100,000.^1–3 It affects both sexes equally and can occur in patients of any age, race or ethnicity.^3–5

The MEN1 syndrome commonly manifests in tumours of the parathyroid glands (95% of cases), gastroenteropancreatic neuroendocrine tumour (NET) (40%–70% of cases), and anterior pituitary adenomas (30%–40% of cases).^{6 7} MEN1 is also occasionally associated with non-functioning foregut NETs, including gastric (10%), thymic (2%) and bronchopulmonary NETs (2%), and adrenal tumours, including pheochromocytoma (<1%).^7–9 Most cases of MEN1 are associated with mutations in the MEN1 gene; however, as many as 10%–30% of patients with an MEN1 clinical diagnosis test negative for mutation of the MEN1 gene.^10–13

This report presents the first sporadic case of MEN1 with several distinct features. First, two rare MEN1 manifestations, pheochromocytoma and a non-gastrinoma duodenal NET, concomitantly occurred in this patient; second, the presentation of these two rare MEN1 manifestations occurred approximately 20 years apart; and third, this case was negative for any detectable mutations of the MEN1 gene.

Case presentation

A 77-year-old African-American woman, a retired military clerk, initially presented to the endocrinology clinic at age 56 with right lower abdominal pain and intermittent headaches. The patient had a benign medical history with no reported medications or allergies. She reported occasional alcohol consumption but denied tobacco or illicit drug use. The patient has never been married but has one daughter who is alive and well. Family history was significant for cancers in siblings, with no reported history of pheochromocytoma, neck masses or thyroid cancer. On review of systems, no hypertension, diaphoresis or tachycardia was reported. Vital signs including blood pressure were within normal limits. Physical examination was remarkable for right lower abdominal tenderness on palpation. Urine normetanephrines and 24 hours urine normetanephrines were elevated at 2195 μg/L (normal 122–500 μg/L) and 4938 μg/24 hours (normal 105–354 μg/24 hours), respectively. Urine metanephrines were 185 μg/L (normal 29–158 μg/L), 24 hours metanephrines were 416 μg/24 hours (normal 74–297 μg/24 hours), 24 hours urine vanillylmandelic acid was 13.2 mg/24 hours (normal <9 mg/24 hours), calcium level was 10 mg/dL (normal 8.8–10.4 mg/dL) and calcitonin level was found to be less than 1 pg/mL (normal <10 pg/mL). An abdominal CT revealed right adrenal gland adenoma. The patient underwent right adrenalectomy without complications at age 58. At the same time, she was found to have a calcium level of 10.3 mg/dL (normal 8.8–10.4 mg/dL) and an elevated intact parathyroid hormone (PTH) level of 165 pg/mL (normal 10–65 pg/mL) and was thus diagnosed with asymptomatic primary hyperparathyroidism. However, she did not meet the National Institute of Health (NIH) criteria for parathyroidectomy.¹⁴ Due to high clinical suspicion of MEN2, the patient underwent RET proto-oncogene mutation testing, which was negative. At age 66, the patient was diagnosed with osteoporosis. Since her calcium and intact PTH levels remained elevated (calcium was 10.3 mg/dL and PTH was 119 pg/mL), she met the NIH criteria for parathyroidectomy. She also underwent a sestamibi scan, which revealed a left parathyroid adenoma. A few months after diagnosis of the parathyroid adenoma, she presented to the emergency department with multiple incidents of haematochezia. An abdominal CT demonstrated a 2.9×2.9 cm duodenal tumour (figure 1A). Octreoscan demonstrated somatostatin receptor positive tissue in the second portion of the duodenum. Further workup with a Gallium 68 dotatate Positon Emission Tomography (PET) scan revealed a well-differentiated duodenal NET (figure 1B) with metastasis to the pancreas and gall bladder (figure 1C) as well as peritoneal and peripancreatic lymph nodes (figure 1D). Oesophagogastroduodenoscopy revealed a mass involving the second portion of the duodenum. Biopsy was positive for a well-differentiated duodenal NET with metastasis. The hormone and peptide serum levels related to the NET were as follows: the serum gastrin level was 36 (normal range <100 pg/mL); chromogranin A 64 (normal range <93 ng/mL); 5-hydroxyindoleacetic acid, urine 3.3 (<8.0 mg/24 hours); pancreatic polypeptide 76 (normal range <332 pg/mL); somatostatin 15 (normal range <25 pg/mL); neuron-specific enolase 16 (normal range ≤15 ng/mL); vasoactive intestinal peptide <50 (normal range <75 pg/mL); glucagon 24 (normal range <80 pg/mL); insulin serum level 11.4 (2.6–24.9 μU/mL); C peptide 2.5 (1.1–5.0 ng/mL). A pituitary MRI was negative for any pituitary mass or lesion.

Figure 1.

(A) White arrow demonstrates the duodenal neuroendocrine tumour (NET) in abdominal CT scan with contrast. (B) White arrow demonstrates the uptake of gallium 68 by duodenal NET in GA-68 dotatate scan. (C) White arrow depicts microinvasion of gall bladder by the duodenal NET on abdominal CT scan with contrast. (D) White arrows demonstrate metastasis to peripancreatic lymph nodes on abdominal CT scan with contrast.

Due to clinical suspicion of MEN1 syndrome, or of the alternate possibility of MEN4 (a MEN1-like phenotype caused by heterozygous pathogenic variants in CDKN1B), the patient’s blood sample was send to Invitae, a CLIA-certified genetic testing company, for a next-generation sequencing panel of five hyperparathyroidism associated genes: MEN1, CDKN1B, RET, CASR and CDC73. This test can detect both sequence variants and large deletions or duplications in the analysed genes, and it was negative, ruling out those genes as a germline cause of this patient’s presentation. Additionally, Sanger sequencing was performed on three other CDKI genes, CDKN2B, CDKN2C and CDKN2D, which have previously been suggested as a rare cause of MEN1-like phenotypes, but that testing was also negative.¹⁵

The patient subsequently underwent resection of duodenal NET and pancreatic head tumour as well as cholecystectomy, followed by a 3-and-1/2 half gland parathyroidectomy at age 77. Pathology report confirmed the diagnosis of a metastatic NET which tested positive for chromogranin and synaptophysin. The patient is still alive and in good health 21 years after her first presentation of MEN1. The patient has nine siblings, four have been deceased out of which two have passed away due to non-endocrine-related conditions. To our knowledge, the remaining five siblings, in addition to the patient’s only daughter have not been diagnosed with any NETs to date.

Outcome and follow-up

Our patient is alive and well 21 years after her initial diagnosis of MEN1. She is being closely followed at the NIH and has regular follow-up appointments with her endocrinologist. To date, there is no evidence of recurrence of NETs.

Discussion

Herein, we report the first rare case of sporadic MEN1 with concomitant pheochromocytoma, duodenal NET and parathyroid adenoma. This diagnosis was supported by identification of unusual clinical manifestations of MEN1, extensive biochemical and genetic testing, and diagnostic imaging studies. The most unique features of this case are severalfold: first, two rare MEN1 manifestations, pheochromocytoma and a duodenal NET, concomitantly occurred in this patient; second, the presentation of these two rare MEN1 manifestations occurred about 20 years apart; and third, this case was negative for common mutations of the MEN1 gene.

Patients with manifestations of MEN1 who also have a first-degree family member with a confirmed MEN1 syndrome are diagnosed with hereditary MEN1. A clinical diagnosis of sporadic MEN1 is indicated when one patient demonstrates at least two out of three principal MEN1-related endocrinopathies (characterised by neoplastic lesions of the parathyroid gland, anterior pituitary gland or gastroenteropancreatic tract). MEN1 can also be associated with NETs, adrenocortical and non-endocrine tumours such as lipomas, angiofibromas and collagenomas, but these are rare.^16–20

The autosomal dominant inheritance of MEN1 is located on chromosome 11q13. Approximately 10%–30% of MEN1 patients show no mutations in the MEN1 gene; these are referred to as sporadic form.²⁰ A Dutch cohort study compared MEN1 patients with positive and negative mutations.¹³ They reported duodenal NET manifestations in 59% of mutation-positive patients, compared with 23% of mutation-negative patients. Similarly, adrenal tumours were reported in 34% of mutation-positive patients but only 3.3% of those who tested mutation negative.

Hyperparathyroidism is usually the first manifestation of MEN1 as well as the most common affecting more than 90% of patients.²¹ Women with an average age of 55 years most frequently demonstrate sporadic hyperparathyroidism.²² The case presented here showed early presentation of hyperparathyroidism similar to the most common phenotypic presentation of MEN1; conversely, the most unique phenotypic presentation of this case was the early occurrence of pheochromocytoma at age 57 and a significantly delayed presentation of a rare duodenal NET at age 77.

In the Dutch cohort study,¹³ MEN1 mutation-positive and mutation-negative patients showed different clinical courses. The study also demonstrated that MEN1-negative patients developed the syndrome at a later age, had a life expectancy comparable with the general Dutch population and experienced a milder disease course as compared with their MEN1-positive counterparts.¹³ The case reported here was a sporadic form (genetic negative), developed the first MEN1 manifestation at age 57 and had a mild disease course. Our patient is alive and in good health at age 78. In fact, the first and last manifestation of MEN1 happened about 20 years apart. These clinical features of our case are similar to the findings of the Dutch cohort for genetic negative MEN1 syndrome.¹³

Hereditary MEN1 is associated with a loss-of-function mutation at the MEN1 gene, which is a tumour-suppressor gene. Hereditary MEN1 has also been linked with a high degree of penetrance, as 80%–98% of cases exhibit clinical or biochemical changes by the time the patient reaches 50 years of age.¹⁰ DNA testing of the MEN1 gene enables detection of 80%–90% of the mutations associated with hereditary MEN1.⁴ Approximately 10% of individuals with no family history of MEN1 have demonstrated somatic mutations.²³ First-degree relatives of individuals with positive mutations in the MEN1 gene are recommended to receive genetic counselling and testing. However, the first-degree relatives of patients with sporadic MEN1, similar to our patient, do not generally require such measures. Although our genetic analysis was negative for MEN1 mutations, the deletion/duplication testing of MEN1 may be warranted in this case, as large deletions possibly missed by sequencing could account for up to 5% of MEN1 syndrome cases.

Researchers have recently identified a new germline mutation called MEN4 that occurs in MEN1 mutation-negative patients. MEN4 is linked to mutations in the CDKN1B gene encoding p27kip1 (p27), which is a tumour suppressor.^{8 11 13} The CDKN1B gene causes a recessive MEN1-like syndrome, which presents with variable phenotypical manifestations that are also typical for both MEN1 and MEN2.⁸ Mutations in the CDKN1B gene are extremely rare. In the Dutch cohort described by de Laat et al,¹³ only a few MEN1 mutation-negative patients had mutations in the CDKN1B gene.^{24 25} To date, only a handful of MEN4 cases have been reported in the literature, and thus the exact phenotypical features of MEN4 have not been clearly identified. Hyperparathyroidism is the most common known feature of MEN4 (occurring in 81% of cases) followed by pituitary adenoma (41% of cases).²⁶ Our case presented with pheochromocytoma, parathyroid adenoma and a duodenal NET, leading us to suspect MEN4; however, the results of the CDKN1B gene mutation test were negative.

Sporadic MEN1 is rare but should be kept in mind in cases of concomitant pheochromocytoma and NETs. Clinical, biochemical and radiological screenings in combination with DNA testing may aid in early detection of MEN1-associated tumours in asymptomatic patients. Early detection accounts for a more favourable disease course and improves survival. Untreated patients have a lower life expectancy and higher death rates. Treatment consists of surgery and/or drug therapy, often in association with radiotherapy or chemotherapy. Prognosis is good, as demonstrated in our patient, if adequate and timely treatment is provided.

Learning points.

• Multiple endocrine neoplasia type 1 (MEN1) mainly presents with two of the three endocrinopathies including parathyroid, anterior pituitary and pancreatic tumours.

• MEN1 may present with rare tumours such as pheochromocytoma and foregut neuroendocrine tumour. It is crucial for clinicians to recognise both common and rare manifestations of MEN1.

• MEN1 can manifest at any time during a patient’s life span. The clinical manifestations may occur as many as 20 years apart from the initial MEN1 presentation.

• Genetic testing and active surveillance are paramount in the detection of MEN1-associated tumours. Early detection accounts for a more favourable disease course and improves survival in both the patients and their first-degree relatives.