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Nineteen cases of parathyroid carcinoma in patients with multiple endocrine neoplasia type 1 have been reported in the literature, of which 11 carry an inactivating germline mutation in the MEN1 gene. Somatic genetic abnormalities in these parathyroid carcinomas have never been detected. In this paper, we aimed to describe the clinical and molecular characterization of a parathyroid carcinoma identified in a patient with MEN1. A 60-year-old man was diagnosed with primary hyperparathyroidism during the postoperative period of lung carcinoid surgery. Serum calcium and parathyroid hormone levels were 15.0 mg/dL (8.4–10.2) and 472 pg/mL (12–65), respectively. The patient underwent parathyroid surgery, and histological findings were consistent with parathyroid carcinoma. Analysis of the MEN1 gene by next-generation sequencing (NGS) identified a novel germline heterozygous nonsense pathogenic variant (c.978C>A; p.(Tyr326*)), predicted to encode a truncated protein. Genetic analysis of the parathyroid carcinoma revealed a c.307del, p.(Leu103Cysfs*16) frameshift truncating somatic MEN1 variant in the MEN1 gene, which is consistent with MEN1 tumor-suppressor role, confirming its involvement in parathyroid carcinoma etiology. Genetic analysis of CDC73, GCM2, TP53, RB1, AKT1, MTOR, PIK3CA and CCND1 genes in the parathyroid carcinoma DNA did not detect any somatic mutations. To our knowledge, this is the first report of a PC case presenting both germline (first-hit) and somatic (second-hit) inactivation of the MEN1 gene.
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Background
Despite significant improvement in imaging quality and advanced scientific knowledge, it may still sometimes be difficult to distinguish different parathyroid lesions. The aims of this prospective study were to evaluate parathyroid lesions with ultrasound elastography and to determine whether strain index can help to differentiate parathyroid lesions.
Methods
Patients with biochemically confirmed hyperparathyroidism and localised parathyroid lesions in ultrasonography were included. All patients underwent B-mode US and USE examination. Ultrasound elastography scores and strain index of lesions were determined. Strain index was defined as the ratio of strain of the thyroid parenchyma to the strain of the parathyroid lesion.
Results
Data of 245 lesions of 230 patients were analysed. Histopathologically, there were 202 (82.45%) parathyroid adenomas, 26 (10.61%) atypical parathyroid adenomas, and 17 (6.94%) cases of parathyroid hyperplasia. Median serum Ca was significantly higher in atypical parathyroid adenoma patients than parathyroid hyperplasia patients (P = 0.019) and median PTH was significantly higher in APA compared to PA patients (P < 0.001). In 221 (90.2%) of the parathyroid lesions, USE score was 1 or 2. The median SI of atypical parathyroid adenomas was significantly higher than parathyroid adenomas and hyperplasia lesions (1.5 (0.56–4.86), 1.01 (0.21–8.43) and 0.91 (0.26–2.02), respectively, P = 0.003).
Conclusion
Our study revealed that SI of parathyroid lesions as well as serum calcium, parathyroid hormone levels, and B-mode US features may help to predict the atypical parathyroid adenoma. Ultrasound elastography can be used to differentiate among parathyroid lesions and guide a surgical approach.
Department of Oncology–Pathology, Cancer Centre Karolinska, Department of Biosciences and Nutrition, Department of Molecular Medicine and Surgery, Department of Surgery #4, Karolinska Institutet, Stockholm, Sweden
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Department of Oncology–Pathology, Cancer Centre Karolinska, Department of Biosciences and Nutrition, Department of Molecular Medicine and Surgery, Department of Surgery #4, Karolinska Institutet, Stockholm, Sweden
Department of Oncology–Pathology, Cancer Centre Karolinska, Department of Biosciences and Nutrition, Department of Molecular Medicine and Surgery, Department of Surgery #4, Karolinska Institutet, Stockholm, Sweden
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Department of Oncology–Pathology, Cancer Centre Karolinska, Department of Biosciences and Nutrition, Department of Molecular Medicine and Surgery, Department of Surgery #4, Karolinska Institutet, Stockholm, Sweden
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Department of Oncology–Pathology, Cancer Centre Karolinska, Department of Biosciences and Nutrition, Department of Molecular Medicine and Surgery, Department of Surgery #4, Karolinska Institutet, Stockholm, Sweden
Department of Oncology–Pathology, Cancer Centre Karolinska, Department of Biosciences and Nutrition, Department of Molecular Medicine and Surgery, Department of Surgery #4, Karolinska Institutet, Stockholm, Sweden
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Department of Oncology–Pathology, Cancer Centre Karolinska, Department of Biosciences and Nutrition, Department of Molecular Medicine and Surgery, Department of Surgery #4, Karolinska Institutet, Stockholm, Sweden
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Department of Oncology–Pathology, Cancer Centre Karolinska, Department of Biosciences and Nutrition, Department of Molecular Medicine and Surgery, Department of Surgery #4, Karolinska Institutet, Stockholm, Sweden
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Department of Oncology–Pathology, Cancer Centre Karolinska, Department of Biosciences and Nutrition, Department of Molecular Medicine and Surgery, Department of Surgery #4, Karolinska Institutet, Stockholm, Sweden
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Primary hyperparathyroidism (PHPT) is a common endocrinopathy, frequently caused by a parathyroid adenoma, rarely by a parathyroid carcinoma that lacks effective oncological treatment. As the majority of cases are present in postmenopausal women, oestrogen signalling has been implicated in the tumourigenesis. Oestrogen receptor beta 1 (ERB1) and ERB2 have been recently identified in parathyroid adenomas, the former inducing genes coupled to tumour apoptosis. We applied immunohistochemistry and slide digitalisation to quantify nuclear ERB1 and ERB2 in 172 parathyroid adenomas, atypical adenomas and carcinomas, and ten normal parathyroid glands. All the normal parathyroid glands expressed ERB1 and ERB2. The majority of tumours expressed ERB1 (70.6%) at varying intensities, and ERB2 (96.5%) at strong intensities. Parathyroid carcinomas expressed ERB1 in three out of six cases and ERB2 in five out of six cases. The intensity of tumour nuclear ERB1 staining significantly correlated inversely with tumour weight (P=0.011), and patients whose tumours were classified as ERB1-negative had significantly greater tumour weight as well as higher serum calcium (P=0.002) and parathyroid hormone levels (P=0.003). Additionally, tumour nuclear ERB1 was not expressed differentially with respect to sex or age of the patient. Levels of tumour nuclear ERB2 did not correlate with clinical characteristics. In conclusion, decreased ERB1 immunoreactivity is associated with increased tumour weight in parathyroid adenomas. Given the previously reported correlation with tumour-suppressive signalling, selective oestrogen receptor modulation (SERMs) may play a role in the treatment of parathyroid carcinomas. Future studies of SERMs and oestrogen treatment in PHPT should consider tumour weight as a potential factor in pharmacological responsiveness.
Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China
Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China
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Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China
Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China
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Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China
Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China
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Health Management Center, The Second Affiliated Hospital of Zhejiang Chinese Medicine University, Zhejiang, China
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Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China
Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China
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Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China
Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China
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Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China
Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China
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Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China
Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China
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The clinical presentation of primary hyperparathyroidism (PHPT) differs between patients from developed and developing countries. In China, the clinical pattern has changed over the past few decades. Our aim was to elucidate general changes in the clinical characteristics of PHPT from 2010 to 2021. We enrolled 343 patients with PHPT at the Qilu Hospital of Shandong University, Jinan, China, from January 2010 to May 2021, including both surgical and non-surgical patients. Patients were divided into two subgroups, 2010–2016 (group A, n = 152) and 2017–2021 (group B, n = 191), based on the time span. We compared clinical manifestations and laboratory result data between these two groups. The mean patient age was 52.59 ± 13.55 years, and the male-to-female ratio was 1:2.54. Of the 343 patients, 183 (53.35%) had symptomatic PHPT; bone pain, urolithiasis, and fatigue were the most common symptoms. Post-operative pathology showed that 96.20% of the patients had parathyroid adenoma, whereas 2.41% had parathyroid carcinoma. Great changes occurred between 2010 and 2021; the percentage of patients with asymptomatic PHPT (aPHPT) increased from 36.18% in group A to 54.97% in group B. Moreover, patients in group B showed significantly lower serum calcium, alkaline phosphatase, parathyroid hormone, and urinary phosphate levels but higher serum 25-hydroxyvitamin D levels than those in group A. Clinical presentations in group B were also milder. In conclusion, the clinical characteristics of Chinese PHPT patients changed dramatically from 2010 to 2021, with asymptomatic PHPT (aPHPT becoming the predominant type over the last 3 years.
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Immune checkpoint inhibitors (ICIs) belong to a new group of anticancer drugs targeting T-cell proteins involved in the activation of immune response toward malignancies. Their introduction into clinical practice was a milestone in modern cancer treatment. However, the significant advantage of ICIs over conventional chemotherapy in terms of therapeutic efficacy is accompanied by new challenges related to specific side effects. ICI-induced immune system activation could lead to the loss of self-tolerance, presenting as autoimmune inflammation and dysfunction of various tissues and organs. Thus, the typical side effects of ICIs include immune-related adverse events (irAEs), among which endocrine irAEs, affecting numerous endocrine glands, have been commonly recognized. This review aimed to outline the current knowledge regarding ICI-induced endocrine disorders from a clinical perspective. We present updated information on the incidence and clinical development of ICI-induced endocrinopathies, including the most frequent thyroiditis and hypophysitis, the rarely observed insulin-dependent diabetes mellitus and primary adrenal insufficiency, and the recently described cases of hypoparathyroidism and lipodystrophy. Practical guidelines for monitoring, diagnosis, and treatment of ICI-related endocrine toxicities are also offered. Rising awareness of endocrine irAEs among oncologists, endocrinologists, and other health professionals caring for patients receiving ICIs could contribute to better safety and efficacy. As immunotherapy becomes widespread and approved for new types of malignancies, increased incidences of endocrine irAEs are expected in the future.
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Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Sweden
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Objective
Autoimmune polyendocrine syndrome type 1 (APS1) is a rare autosomal recessive disorder characterized by progressive organ-specific autoimmunity. There is scant information on APS1 in ethnic groups other than European Caucasians. We studied clinical aspects and autoimmune regulator (AIRE) gene mutations in a cohort of Indian APS1 patients.
Design
Twenty-three patients (19 families) from six referral centres in India, diagnosed between 1996 and 2016, were followed for [median (range)] 4 (0.2–19) years.
Methods
Clinical features, mortality, organ-specific autoantibodies and AIRE gene mutations were studied.
Results
Patients varied widely in their age of presentation [3.5 (0.1–17) years] and number of clinical manifestations [5 (2–11)]. Despite genetic heterogeneity, the frequencies of the major APS1 components (mucocutaneous candidiasis: 96%; hypoparathyroidism: 91%; primary adrenal insufficiency: 55%) were similar to reports in European series. In contrast, primary hypothyroidism (23%) occurred more frequently and at an early age, while kerato-conjunctivitis, urticarial rash and autoimmune hepatitis were uncommon (9% each). Six (26%) patients died at a young age [5.8 (3–23) years] due to septicaemia, hepatic failure and adrenal/hypocalcaemic crisis from non-compliance/unexplained cause. Interferon-α and/or interleukin-22 antibodies were elevated in all 19 patients tested, including an asymptomatic infant. Eleven AIRE mutations were detected, the most common being p.C322fsX372 (haplotype frequency 37%). Four mutations were novel, while six others were previously described in European Caucasians.
Conclusions
Indian APS1 patients exhibited considerable genetic heterogeneity and had highly variable clinical features. While the frequency of major manifestations was similar to that of European Caucasians, other features showed significant differences. A high mortality at a young age was observed.
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Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands
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Background
Sex differences in calcium and phosphate have been observed. We aimed to assess a relation with age.
Methods
We used the laboratory values of serum calcium, phosphate and albumin from three different samples ( 2005, 2010 and 2014 years) using the hospital information system of Erasmus MC, Rotterdam. The samples were divided into three age groups: 1–17, 18–44 and ≥45 years. Sex differences in calcium and phosphate were analyzed using ANCOVA, adjusting for age and serum albumin. Furthermore, sex by age interactions were determined and we analyzed differences between age groups stratified by sex.
Results
In all three samples there was a significant sex × age interaction for serum calcium and phosphate, whose levels were significantly higher in women compared to men above 45 years. No sex differences in the younger age groups were found. In men, serum calcium and phosphate levels were highest in the youngest age group compared to age groups of 18–44 and ≥45 years. In women, serum calcium levels were significantly higher in the age group 1–17 and the age group ≥45 years compared to the 18–44 years age group. In women, serum phosphate was different between the three different age groups with highest level in the group 1–17 years and lowest in the group 18–44 years.
Conclusion
There are age- dependent sex differences in serum calcium and phosphate. Furthermore, we found differences in serum calcium and phosphate between different age groups. Underlying mechanisms for these age- and sex- differences are not yet fully elucidated.
Division of General and Emergency Medicine, University Department of Medicine, Kantonsspital Aarau AG, Aarau, Switzerland
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University Center for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital, Basel, Switzerland
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Division of General and Emergency Medicine, University Department of Medicine, Kantonsspital Aarau AG, Aarau, Switzerland
Faculty of Medicine, University Hospital Basel, Basel, Switzerland
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Division of General and Emergency Medicine, University Department of Medicine, Kantonsspital Aarau AG, Aarau, Switzerland
Faculty of Medicine, University Hospital Basel, Basel, Switzerland
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Division of General and Emergency Medicine, University Department of Medicine, Kantonsspital Aarau AG, Aarau, Switzerland
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Background
Primary hyperparathyroidism is a prevalent endocrinopathy for which surgery is the only curative option. Parathyroidectomy is primarily recommended in younger and symptomatic patients, while there are still concerns regarding surgical complications in older patients. We therefore assessed the association of age with surgical outcomes in patients undergoing parathyroidectomy in a large population in Switzerland.
Methods
Population-based cohort study of adult patients with primary hyperparathyroidism undergoing parathyroidectomy in Switzerland between 2012 and 2018. The cohort was divided into four age groups (<50 years, 50–64 years, 65–74 years, ≥75 years). The primary outcome was a composite of in-hospital postoperative complications. Secondary outcomes were intensive care unit (ICU) admission, unplanned 30-day-readmission, and prolonged length of hospital stay.
Results
We studied 2642 patients with a median (IQR) age of 62 (53–71) years. Overall, 111 patients had complications including surgical re-intervention, hypocalcemia, and vocal cord paresis. As compared to <50 year-old patients, older patients had no increased risk for in-hospital complications after surgery (50–64 years: odds ratio (OR): 0.51 (95% CI, 0.28 to 0.92); 65–74 years: OR: 0.72 (95% CI, 0.39 to 1.33); ≥75 years: OR: 1.03 (95% CI, 0.54 to 1.95), respectively. There was also no association of age and rates of ICU-admission and unplanned 30-day-readmission, but oldest patients had longer hospital stays (OR: 2.38 (95% CI, 1.57 to 3.60)).
Conclusion
≥50 year-old patients undergoing parathyroidectomy had comparable risk of in-hospital complications as compared with younger ones. These data support parathyroidectomy in even older patients with primary hyperparathyroidism as performed in clinical routine.
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Palliation of symptoms related to malignancy-associated hypercalcemia (MAH) is essential and clinically meaningful for patients, given the continued poor prognosis, with high morbidity and mortality associated with this disease process. Historically, agents have been temporizing, having no impact on patient morbidity nor survival. We suggest that cinacalcet can be an efficacious agent to be taken orally, reducing patients’ time in the hospital/clinic settings. It is well-tolerated and maintains serum calcium levels in the normal range, while targeted cancer treatments can be employed. This has a direct, major impact on morbidity. Maintaining eucalcemia can increase quality of life, while allowing targeted therapies time to improve survival. Given that our case (and others) showed calcium reduction in MAH, there is promising evidence that cinacalcet can be more widely employed in this setting. Future consideration should be given to studies addressing the efficacy of cinacalcet in calcium normalization, improvement of quality of life, and impact on survival in patients with MAH. Though the exact mechanism of action for cinacalcet’s reduction in calcium in this setting is not currently known, we can still afford patients the possible benefit from it.
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Department of Medicine, National University Hospital, Singapore
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Department of Medicine, National University Hospital, Singapore
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Purpose:
Primary hyperparathyroidism (PHPT) is a common condition affecting people of all ages and is mainly treated with parathyroidectomy. Cinacalcet has been widely used in secondary or tertiary hyperparathyroidism, but the use of cinacalcet in PHPT is less clear.
Methods:
Searches were conducted in Medline and Embase for cinacalcet use in PHPT from induction to 10 April 2020. Articles and conferences abstracts describing the use of cinacalcet for PHPT in prospective or retrospective cohorts and randomized controlled trials restricted to English language only. We initially identified 1301 abstracts. Each article went extraction by two blinded authors on a structured proforma. Continuous outcomes were pooled with weight mean difference (WMD). Quality of included articles was assessed with Newcastle Ottwa Scale and Cochrane Risk of Bias 2.0.
Results:
Twenty-eight articles were included. Normalization rate of serum Ca levels was reported at 90% (CI: 0.82 to 0.96). Serum levels of Ca and PTH levels were significantly reduced (Ca, WMD: 1.647, CI: −1.922 to −1.371; PTH, WMD: −31.218, CI: −41.671 to −20.765) and phosphate levels significantly increased (WMD: 0.498, CI: 0.400 to 0.596) after cinacalcet therapy. The higher the baseline Ca levels, the greater Ca reduction with cinacalcet treatment. Age and gender did not modify the effect of cinacalcet on serum Ca levels.
Conclusion:
The results from the meta-analysis support the use of cinacalcet as an alternative or bridging therapy to treat hypercalcemia in people with PHPT.
