The MEN1 gene was first reported in 1977 , is located on chromosome 11q13 and is expressed in cells throughout the body, acting as an autosomal dominant tumor suppressor gene. At present, the theory of Knudson’s two-hit hypothesis is widely accepted as the hypothesized pathogenicity of this disease . Homozygous mice with MEN1 gene deletion die in utero. In heterozygotes with a secondary somatic frameshift mutation, nonsense mutation, missense mutation, frame deletion or insertion, site splicing, or other mutation in the MEN1 allele that occurs after birth, the organs are likely to develop the disease. The diagnosis of MEN1 includes three criteria: (1) two or more MEN1-related primary endocrine tumors (pituitary, parathyroid or pancreas) in the same individual; (2) gene detection of MEN1 gene mutations; and (3) first-degree relatives of MEN1 patients with at least one MEN1-related tumor . MEN1 can be diagnosed by satisfying any of the above criteria. In this case, this patient underwent transsphenoidal adenomectomy for a pituitary tumor 20 years ago and most recently, he was treated because of a “liver space-occupying mass.” Multiple space-occupying lesions of the whole body were found by imaging. Pathological biopsy showed that the liver and lung lesions were endocrine tumors. Genetic sequencing showed the men1c.249-252del (p.ile855erfsTer33) germline mutation, which could lead to a diagnosis of MEN1 both clinically and genetically. The incidence of this disease in nonendocrine organs is so low that clinicians do not pay enough attention to this clue. It was not until the patient returned to our hospital that MEN1 was considered after multidisciplinary consultation. Then, whole genome sequencing was performed for the patient, and 7 of his first-degree relatives were screened for the MEN1 gene.
As MEN1 is a hereditary disease, the importance of gene detection for diagnosis and treatment is self-evident. Genetic testing is recommended for the following situations [1, 2]: (1) two or more typical or atypical tumors related to MEN1; (2) parathyroid adenomas occurring before the age of 30 or multiple parathyroid diseases, multiple pancreatic neuroendocrine tumors or gastrinomas at any age; and (3) first-degree relatives of the patient as well as those in the pedigree diagnosed clinically or genetically. It has been confirmed that the survival duration of patients with MEN1 gene mutations is shorter than that of patients without gene mutations. Once a gene mutation is found, close clinical follow-up observation should be carried out according to established guidelines to achieve timely detection, timely diagnosis, timely treatment, and improve survival time. First-degree relatives of such patients are also recommended for MEN1 gene screening to identify which family members need to enter the clinical observation process. More importantly, early detection of highly malignant lesions will increase the R0 resection rate of the tumors, helping to achieve a longer survival duration [7, 9, 10]. One patient with the same MEN1 gene mutation as the proband was found in this pedigree, and there was no clinical phenotype at present. Regular imaging and haematological follow-up of the proband and his MEN1 gene mutation-positive relatives will help improve the quality of life and survival time of the patients.
At present, MEN1-related endocrine adenomas are treated based on the strategies for sporadic endocrine adenomas, and radical resection is the first choice for treatment. However, the guidelines do not clearly point out differentiation between and treatment strategies of primary and metastatic lesions found in multiple tumors at the same time. Even for highly malignant intestinal tumors, the 5-year survival rate can reach 80% with radical resection of the intestinal primary and metastatic lesions. The perioperative mortality was less than 5%. Furthermore, to improve endocrine syndrome-related symptoms and improve patient quality of life, it is feasible to perform cytoreductive surgeries to improve the overall survival and reduce the endocrine level of 95% of patients [11,12,13].
In our case, we carried out genetic testing on the patient in time (though not at the first visit) and confirmed the existence of a MEN1 gene mutation. Minimally invasive liver tumor resection combined with intraoperative liver radiofrequency ablation (RFA) was used to preserve the healthy liver tissue as much as possible. Percutaneous radiofrequency ablation of parathyroid tumors not only ensured a radical effect but also prevented the patient from undergoing too many major spinal surgeries in a short time, thus avoiding negative psychological consequences.
No scholars have suggested that MEN1-related primary tumors might occur in the liver. Although liver metastasis may occur in MEN1-related duodenopancreatic tumors  and thymic tumors , metachronous liver metastasis has been reported in only MEN1-related lung tumors . No liver metastasis has been reported in the pituitary tumor or parathyroid tumor. In our case, the discovery of liver and pulmonary tumors was synchronous, and the lesions were radically resected. As mentioned above, the level of parathyroid hormone returned to normal after uniportal thoracoscopic right middle lobectomy, liver lesion resection and RFA of the parathyroid glands. Moreover, no local tumor recurrence was observed during a follow-up of 5 months. To the best of our knowledge, there have been no similar reports.
The biggest limitation is that it is not completely clear whether the nature of the lung and liver tumors were multifocal primary tumors or metastases. However, most MEN1-related tumors are benign, and a characteristic of MEN1 is that tumors can in multiple organs and appear as multiple lesions all over the body. Moreover, liver and lung biopsies of the patient showed that the tumors belonged to a highly differentiated type, meaning that the probability of distant metastasis was relatively low , and no new lesions were found after 5 months of follow-up. We put forward the hypothesis that the liver and lung may have multifocal primary tumors at the same time. Furthermore, we propose the possibility that primary tumors of the liver can also occur in MEN1; although, this view needs further verification.
In this patient, SPECT/CT found that there was a hypermetabolic mass in each of the bilateral inferior thyroid poles, and the possibility of bilateral inferior parathyroid adenoma was considered because of the increases in parathyroid hormone level to 177 pg/ml and serum calcium. Therefore, primary hyperparathyroidism (PHPT) could be diagnosed. At present, the optimal timing and scope of parathyroid surgery are still controversial. According to the guidelines, more than 3.5 thyroid glands should be removed in such patients , but the possibility of permanent parathyroid dysfunction after extensive parathyroid surgery is as high as 40%. Severe hypercalcaemia and parathyroid carcinoma are rare in patients with MEN1-related PHPT, and the main goal of treatment is control of parathyroid hormone levels. When the number of enlarged parathyroid glands is less than 2, the scope of parathyroidectomy can be minimized as much as possible, and individualized treatment can be realized [18, 19]. It has been confirmed that ultrasound-guided radiofrequency ablation of parathyroid adenoma is effective and safe [18, 20]. The return of parathyroid hormone (20 pg/ml) to a normal range due to a decrease in parathyroid hormone (177 pg/ml) after the operation suggested that the treatment was effective and that there were no obvious complications after the operation. A limitation is that the parathyroid hormone level was not re-examined during follow-up.
Abdominal MRI also found multiple adrenal adenomas. However, haematological analysis results did not suggest aldosteronism or hypercortisolemia. However, no increased adrenal metabolism was found on PET-CT, so continued follow-up was needed. Surgical resection can be considered when symptoms occur, when the tumors obviously grow or are larger than 4 cm .
The patient recovered well after the surgical treatments. He said that he would strictly follow the doctor’s advice, adding, “I will also urge relatives who carry pathogenic genes to undergo clinical follow-up”. Both doctors and the patient are confident in achieving high-quality and long-term survival in the future.
In summary, the clinical phenotypes of MEN1 come in a variety of forms, and tumors in atypical-related organs such as the liver and lung endocrine are easy to miss diagnosis of this disease. When this disease is suspected, we should carry out comprehensive laboratory tests, imaging examinations, gene detection and other screening approaches. Furthermore, multidisciplinary consultation is recommended when MEN1 is suspected to reduce the rate of missed diagnosis. The final goal is to increase survival time and improve quality of life through timely discovery, timely diagnosis, and timely treatment.
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