An
abdominal CT scan showed one slightly hyperdense solid focal lesion of
28x27 mm localized in the pancreatic tail and bilateral nephrolithiasis
(see figure 1).
B)
Figure 1. CT scan of abdomen. A) Solid lesion located in
pancreatic tail (red arrowhead). B) Left nephrolithiasis.
Surgery was attempted and intraoperative direct pancreatic ultrasound
revealed a single homogeneous mass of 25x20 mm in the pancreatic tail. A
distal pancreatectomy plus splenectomy due to bleeding of the splenic
vessels was done. The microscopic study of the specimens showed multiple
nodules. Some of them revealed positivity for insulin and some for
glucagon. Immunohistochemical studies, revealed positivity for
cytokeratin 8-18, synaptophysin, chromogranin, E-cadherin, and a Ki-67
proliferation index <1%. Beta-catenin was negative in the
nuclei and positive in membranes and cytokeratin 7 was negative. Those
findings were consistent with multifocal neuroendocrine tumors.
Approximately 36 hours after the surgery, the patient presented an
episode of hypoglycemia of 39 mg/dL. For this reason, medical treatment
with frequent feedings and diazoxide was continued. The patient
presented post-surgical complications with a pancreatic fistula,
ascites, bilateral pleural effusion and acute renal insufficiency. Once
he was stabilized the patient was discharged with medical treatment.
However, a subsequent hospitalization was required for persistent
hypoglycemic symptoms. During the two-month follow up CT scans and an
endoscopic US (EUS) were done. Since no residual neuroendocrine tumor
could be demonstrated it was decided, in conjunction with the patient,
to continue with medical management and not perform surgical
reintervention due to the high morbidity and mortality it represented.
Genomic DNA sequence analysis and deletion/duplication testing from
peripheral blood leukocytes was done in a clinical commercial laboratory
as part of a patient initiative. Direct sequence analysis of MEN1revealed heterozygosity for a novel pathogenic 4-bp
insertion:
c.1224_1225insGTCC(p.Cys409Valfs*41)
Molecular analysis of the variant showed that while this is not
anticipated to result in nonsense mediated mRNA decay, it is expected to
disrupt the last 202 amino acids of the MEN1 protein which result in
truncation of the protein and its Nuclear Localization Signal (NLS)
domains (see figure 2). This variant is not present in population
databases (ExAC no frequency) and has not been reported in the
literature in individuals with MEN1-related disease. ClinVar database
contains an entry for this variant (Variation ID: 428066). Literature
analysis showed that several different truncations located downstream of
this variant (p.Arg516Profs*15, p.Arg516Glyfs*43 and p.Gln554*) have
been determined to be pathogenic (Cardinal et al., 2005; Langer et al.,
2001; Lemmens et al., 1997; Lemos & Thakker, 2008). This suggests that
deletion of this region of the MEN1 protein is causative of the disease.