A 37-year-old man treated for PanNEN gastrinoma with multiple liver metastases was referred to our Department of Endocrinology in May 2021 due to severe epigastric pain and a suspicion of interstitial lung disease on everolimus therapy.
The patient's medical history included Hashimoto's disease, nephrolithiasis, and chronic gender-affirming hormone treatment with Testosteronum prolongatum 100 mg every 4 weeks i.m. The patient was transgender, and at the age of 28 years, he underwent female-to-male surgery, including breast reduction surgery, hysterectomy, and bilateral salpingo-oophorectomy.
He was diagnosed with gastrinoma in 2020 following 1 year history of heartburn and epigastric pain. In 2019, repeated gastroscopies were performed, revealing recurrent and chronic inflammatory lesions in the esophagus, gastric mucosa, and duodenum. The Helicobacter pylori test was positive, and the infection was treated with no improvement. Additionally, abdominal ultrasound showed numerous lesions described then as presumably hemangiomas of the liver, which were later visualized in computed tomography (CT). He also had a 16-mm tumor of the left adrenal gland, which was first diagnosed in 2018 and verified at that time as a non-functioning adenoma with a benign imaging phenotype in CT [3 Hounsfield Units (HU) in the native phase]. In 2020, a follow-up abdominal CT scan showed a 27 x 34 mm pancreatic uncinate tumor infiltrating the superior mesenteric vein and multiple hypervascular metastases in the liver. There were nearly 30 lesions, which ranged in size from a few millimeters to 40 mm (Figures 1, 1A-D). A percutaneous liver biopsy was performed and immunohistochemical (IHC) staining revealed the following: NET G2, synaptophysin (+++), chromogranin A (+), and CD 56 (-) with a Ki-67 labeling index of 4%-5%. Somatostatin receptor scintigraphy (SRS) ([99mTc] HYNIC-TOC Tektrotyd, Polatom, PL) subsequently confirmed a pathological radiolabel uptake in the pancreatic and liver lesions presented in Figure 2, during initial SRS in June 2020 (Figure 2A). There was no pathological radiotracer accumulation in the left adrenal gland, indicating benign adenoma morphology. Laboratory tests revealed inappropriately increased gastrin levels, confirming the diagnosis of gastrinoma. Considering the advanced disease stage, the patient was disqualified from surgical intervention. He was treated at The Maria Sklodowska-Curie National Research Institute of Oncology Warsaw with somatostatin receptor ligand (SRL, octreotide LAR 30 mg every 4 weeks), and then everolimus (10 mg p.o. per day) was started in February 2021 due to progression in the liver.
At the first admission to our Department in 2021, the chest and abdominal CT scans revealed further disease progression with multiple possible metastases in the lungs and a remarkable change in left adrenal tumor density up to 47 HU in the native phase and in size of up to 24 x 18 mm, arousing suspicion of adrenal metastasis (Figures 1, 2A-D). His laboratory tests showed highly elevated gastrin and chromogranin A levels during proton pump inhibitor (PPI) and famotidine treatment, elevated PTH level, normocalcemia, and normophosphatemia with vitamin D deficiency. However, genetic testing for MEN1 syndrome, which was performed earlier, was negative. PTH levels normalized after vitamin D deficiency treatment.
Everolimus treatment was discontinued as its adverse effect in the form of nonspecific interstitial pneumonia was suspected. Later imaging studies ruled out lung metastatic lesions.
One month later, the patient was readmitted to our Department due to a sudden onset of severe hypercortisolemia, leading to severe hypokalemia (Table 1; Figure 3), increased peripheral edema, and hypertension. He presented some features of Cushing phenotype with easy bruising, weight gain, and severe psychotic symptoms and memory impairment. Hormonal results confirmed the diagnosis of ACTH-dependent Cushing syndrome most likely due to ectopic ACTH or CRH secretion by PanNEN. Head and pituitary magnetic resonance imaging (MRI) excluded the presence of brain metastases and a pituitary adenoma. Metyrapone treatment in a dose up to 2 g per day and pasireotide s.c. 600 mug bid were promptly initiated together with potassium supplementation, spironolactone, and hyperglycemia treatment, which resulted in significant clinical and biochemical improvement (Table 1; Figure 3). We considered osilodrostat treatment, but it was not available at the time. The patient qualified for bilateral adrenalectomy to treat hypercortisolemia permanently, as the primary PanNEN was inoperable. He underwent surgery after achieving stabilization of his clinical condition. However, due to intraoperative conditions (significantly enlarged liver), the patient underwent left-sided adrenalectomy only. A pathological report revealed an adenoma of the adrenal cortex: chromogranin A (-), inhibin (+), melanin A (+), and a Ki-67 labeling index of 3%-4%, with positive staining for ACTH (+). Liver lesion samples, which were also taken intraoperatively, showed NET G2 with synaptophysin (+++), ACTH (+), and a Ki-67 labeling index of 7%-8%. After adrenalectomy, hormonal results revealed a significant decrease in ACTH level, normal morning cortisol levels, and 24-h free urinary cortisol excretion, and a further increase in gastrin concentration (Table 1; Figure 3). Owing to the progression of liver metastatic lesions described in the abdominal CT and SRS and increasing gastrin and CgA levels, the patient qualified for temozolomide and capecitabine chemotherapy (with standard dosing capecitabine 750 mg/m2 bid on days 1-14 and temozolomide 150 mg/m2 p.o. on days 10-14), while continuing SRL therapy, with a good initial response in the form of a decrease in the mass of metastases and gastrin level. However, chemotherapy with temozolomide and capecitabine was discontinued after the fourth course due to recurrent severe pancytopenia with life-threatening anemia requiring multiple blood transfusions. During a follow-up hospitalization, laboratory results confirmed prolonged normalization of ACTH and cortisol levels (Table 1; Figure 3). 18F-fluorodeoxyglucose PET-CT imaging ruled out the presence of metastases in the lungs and confirmed the metabolically active process located in the pancreatic head and in the liver.
In the latest CT performed in August 2022, 9 months after the end of temozolomide and capecitabine chemotherapy, the disease was stable, without further progression in terms of intensity, number, and size of metastases, and even with some of the hepatic metastases shrinking (Figure 1).
Currently, 1 year after adrenalectomy, we found stable, slightly elevated levels of morning ACTH, normal cortisol with maintained diurnal rhythm, 24-h free urinary cortisol excretion in the upper limit of normal, testosterone concentration within the male range, and elevated but stable gastrin and chromogranin A levels (Table 1; Figure 3). The patient showed declining ZES symptoms during PPI treatment.