Abstract
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.
Introduction
Parathyroid carcinoma (PC) is a rare endocrine malignancy, accounting for less than 1% of all primary hyperparathyroidism (PHPT) cases (1, 2). PC may occur sporadically or as part of genetic syndromes. The most frequent genetic alterations associated with sporadic PC are inactivating somatic mutations of the CDC73/HRPT2 gene. Sporadic PC may also be associated with other abnormalities, including p53 and retinoblastoma gene mutations. Alterations of the PI3K/Akt/mTOR pathway and CCND1/cyclin D1 amplifications are also potentially driver events in PC (2). PC may occur in the context of genetic syndromes in up to 15% of patients with hyperparathyroidism-jaw tumor (HPT‐JT; CDC73/HRPT2 gene), 1% of familial isolated hyperparathyroidism (FIHP; CDC73/HRPT2 and GCM2 genes) and, rarely, in multiple endocrine neoplasia type 1 (MEN1, MEN1 gene) and 2A (MEN2A; RET gene) (2, 3).
MEN1 is a rare disorder characterized by PHPT, pituitary and gastroenteropancreatic neuroendocrine tumors (NET). Less frequently, it is associated with adrenocortical and carcinoid tumors, lipomas and meningiomas (4, 5, 6). MEN1 is inherited as an autosomal-dominant syndrome and is caused by germline mutations in the MEN1 gene, which encodes MENIN, a 610-amino acid protein. The MEN1 gene is a tumor-suppressor gene, showing biallelic inactivation in syndrome-related tumors, through loss of heterozygosity (LOH) involving the MEN1 locus at chromosome 11q13 and/or somatic mutation (5).
PHPT is the most common manifestation of MEN1 and is usually caused by benign parathyroid tumors (5, 6, 7). The occurrence of PC in MEN1 is extremely rare. To date, only 19 well-documented cases of PC associated with MEN1 syndrome have been reported; in 11 of these cases, an MEN1 germline mutation was identified (8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23). The clinical presentation and the corresponding MEN1 pathogenic variant of the previous cases is shown in Table 1. LOH at the MEN1locus was assessed in three patients and no somatic mutations were detected (20, 21).
Published cases of PC in MEN1.
| Case | Author | Publication year | Sex | Age (years) | Calcium (mmol/L) | PTH (pg/mL) | MEN1 mutation |
|---|---|---|---|---|---|---|---|
| 1 | Wu et al. (8) | 1992 | Male | 48 | 4.1 | 154 | – |
| 2 | Sato et al. (9) | 2000 | Female | 51 | 2.7 | – | c.734del p.(Pro245Leufs*36) |
| 3 | Dionisi et al. (10) | 2002 | Male | 35 | 3.4 | 707 | – |
| 4 | Agha et al. (11) | 2007 | Female | 69 | 3.9 | 343 | – |
| 5 | Agha et al. (11) | 2007 | Male | 32 | 3.7 | 254 | – |
| 6 | Shih et al. (12) | 2009 | Female | 53 | 3.4 | 1354 | c.1406_1413dup p.(Gly472Serfs*90) |
| 7 | Kalavalapalli et al. (13) | 2010 | Female | 40 | 2.7 | 79 | – |
| 8 | Del Pozo et al. (14) | 2011 | Male | 44 | 3.1 | 204 | c.549G>C p.(Trp183Cys) |
| 9 | Joudele et al. (15) | 2011 | Female | 39 | 3.3 | 320 | c.129_130insA p.(Val44Serfs*73) |
| 10 | Lee et al. (16) | 2013 | Female | 59 | 3.2 | 248 | – |
| 11 | Singh Ospina et al. (17) | 2016 | Male | 62 | 3.1 | 132 | – |
| 12 | Christakis et al. (18) | 2016 | Male | 54 | 2.6 | 42 | c.703G>A p.(Glu235Lys) |
| 13 | Christakis et al. (18) | 2016 | Male | 55 | 3.4 | 673 | c.1378C>T p.(Arg460*) |
| 14 | Omi et al. (19) | 2017 | Male | 40 | 2.7 | 203 | – |
| 15 | Cinque et al. (20) | 2017 | Male | 61 | – | – | c.1252G>A p.(Asp418Asn) |
| 16 | Cinque et al. (20) | 2017 | Male | 55 | 1.5 | 286 | c.1252G>A p.(Asp418Asn) |
| 17 | Cinque et al. (21) | 2017 | Female | 48 | 2.9 | 160 | IVS2–3G>C, c.497A>T and c.499G>T |
| 18 | Di Meo et al. (22) | 2018 | Male | 62 | 2.9 | 392 | – |
| 19 | Song A et al. (23) | 2020 | Male | 51 | 2.8 | 380 | c.917T>G p.(Leu306Arg) |
| 20 | Pinheiro et al. (26) | 2020 | Male | 60 | 3.7 | 472 | c.978C>A p.(Tyr326*) |
PC, parathyroid carcinoma; PTH, parathyroid hormone.
Parathyroid adenomas (PAs) in MEN1 and parathyroid tumors (malignant and benign) in HPT-JT/FIHP syndromes, usually have LOH of MEN1 or CDC73, resulting in the loss of menin or parafibromin expression, respectively, consistent with the tumor-suppressor roles of MEN1 and CDC73 genes (3, 5). However, somatic genetic abnormalities in MEN1-related PCs have not been reported (3).
Herein we aimed to describe the clinical and molecular characterization of a PC identified in the context of MEN1 syndrome.
Clinical case
A 60-year-old man with a history of asthma and nephrolithiasis was electively admitted to the Department of General Surgery of our Institute for removal of a lung carcinoid. During admission, blood tests revealed severe hypercalcemia, hypophosphatemia and elevated parathyroid hormone (PTH) levels. Laboratory workup is described in Table 2. On physical examination, the patient was dehydrated and slightly bradycardic. Retrospectively, he reported constipation, polydipsia and polyuria for several weeks. Electrocardiogram was normal. The patient was treated with isotonic saline 0.9% 150 mL/h (titrated to a urine output of 100 mL/h), 20 mg of furosemide every 8 h and intravenous 3.5 mg zoledronic acid (adjusted to renal function). Hypercalcemia and renal function improved over the following 48 h. The patient was discharged 7 days later (calcium levels at discharge 10.7 mg/dL). Histopathological diagnosis of the lung mass was consistent with an atypical lung carcinoid (T2aN0Mx).
Initial investigation workup of hypercalcemia.
| Investigation | Result | Normal range |
|---|---|---|
| Calcium (mg/dL) | 15.0 | 8.4–10.2 |
| Phosphorus (mg/dL) | 1.5 | 2.3–4.7 |
| Magnesium (mg/dL) | 2.1 | 1.6–2.6 |
| Albumin (g/dL) | 4.1 | 3.5–5.0 |
| Parathyroid hormone (pg/mL) | 740 | 12-65 |
| Vitamin D 25, OH (ng/mL) | 15 | >20 |
| Creatinine (mg/dL) | 1.5 | 0.7–1.2 |
| ALP (UI/L) | 149 | 40–150 |
| Urine calcium (mg/24 h) | 374 | 100–374 |
ALP, alkaline phosphatase.
Imaging evaluation with neck ultrasound showed two hypoechogenic nodules, one posterior to the left thyroid lobe (27 × 15 mm) and one lateral to the right thyroid lobe (11 × 8 mm). 99mTc-sestamibi scintigraphy demonstrated increased uptake in two nodules (the left upper and the right lower parathyroid glands). The patient was started on cinacalcet and 4 mg zoledronic acid monthly due to recurrent severe hypercalcemia of 14.2 mg/dL. However, despite a progressive increase in cinacalcet dose (maximum tolerated dose 90 mg), the patient maintained hypercalcemia of 14.6 mg/dL and several admissions to the medical ward.
Patient’s family history, which is depicted in Fig. 1, was suggestive for MEN1: one son was diagnosed with PHPT and another son was diagnosed with PHPT and pancreatic NET (p-NET). The relatives of the patient live abroad, and they were treated in another hospital. For this reason, segregation analysis of the germline variant was not performed in patient’s offspring.
Family tree of the proband. This image was created with BioRender®.
Citation: Endocrine Connections 12, 9; 10.1530/EC-22-0479
En bloc excision of three parathyroid glands with the left thyroid lobe was performed. Intraoperative PTH decreased by more than 50%, from >2500 to 651 pg/mL after surgical excision of the third parathyroid gland. Histopathological analyses revealed a 26 mm PC (Fig. 2) and a 25 mm PA in the left upper and in the right lower parathyroid glands, respectively. The left lower parathyroid did not show any abnormalities. The histologic diagnosis of PC was based on the presence of vascular invasion (Fig. 2) (24). Lymph node metastases were not detected and the tumor was completely removed. The postoperative period was uneventful and serum calcium and PTH levels were substantially reduced (calcium 10.3 mg/dL, PTH 46.9 pg/mL).
Histological findings of the left upper parathyroid gland (parathyroid carcinoma). Hematoxylin and eosin staining. Arrows indicate vascular invasion.
Citation: Endocrine Connections 12, 9; 10.1530/EC-22-0479
After the identification of the MEN1 germline mutation, an investigation for other MEN1-related tumors was performed. Pituitary imaging revealed a macroadenoma with suprasellar extension without chiasm compression. Abdominal imaging detected multiple lesions of the pancreatic tail, body and head (<1 cm in diameter), which were positive in PET-68GaDOTANOC, thus suggestive of p-NET. p-NET was followed-up with an abdominal MRI. Surgical resection for p-NET was not considered because the lesions were under 1 cm and there was no evidence of significant growth or hormone overproduction. However, 3 years after diagnosis, two lesions were detected in the liver and in the rib. Treatment with somatostatin analogs was initiated 2 years ago and the disease remained stable ever since. At the last follow-up, there was diminished radiotracer uptake by both metastases on PET-Ga-DOTANOC.
After 4 years of follow-up, the patient is free from recurrence and shows stable slightly elevated calcium of 10.4 mg/dL and PTH levels of 54.7 pg/mL.
Materials and methods
The patient provided written informed consent for genetic testing, which was performed under the approval of the Ethics Committee of the Instituto Português de Oncologia de Lisboa Francisco Gentil.
Genetic analysis
DNA from peripheral blood leukocytes was extracted and purified using the Maxwell® RSC Whole Blood DNA Kit (Promega Corporation), according to the manufacturer’s protocol. The germline involvement of the MEN1 gene was evaluated by NGS in the proband’s leukocytes’ DNA, using the commercial kit TruSight Cancer panel (Illumina, CA, USA), which allows the simultaneous analysis of 94 genes associated with cancer predisposition. Copy number variations (CNVs) analysis in MEN1 and CDC73 genes was conducted by multiplex ligation-dependent probe amplification (MLPA), using SALSA MLPA probemix kit P244 and P466 (MRC Holland, Amsterdam, The Netherlands). DNA from the PC and PA was extracted from formalin-fixed paraffin-embedded (FFPE) tissue blocks, using Maxwell® RSC DNA FFPE Kit (Promega Corporation, Madison, USA), according to the manufacturer’s protocol. The cellularity of tumor cells was >90%.
Additional genetic events, occurring at the somatic level, that could lead to this rare manifestation of PC in the MEN1 context, were also investigated and compared to a PA from the same patient. Briefly, LOH, somatic mutations and/or CNVs in MEN1, CDC73, GCM2, TP53, RB1, AKT1, MTOR, PIK3CA and CCND1, together with additional hereditary cancer syndrome and solid tumor-related genes were examined in the PC and PA DNAs (NGS multigene analysis: commercial TruSight Cancer panel, Illumina, CA, USA; custom designed panel of 113 genes, protocol SureselectXT Target Enrichment System, Agilent Technologies (Supplementary Table 1, see section on supplementary materials given at the end of this article) commercial AmpliSeq for Illumina Focus Panel, Illumina). Illumina Variant Studio and Variant Interpreter software (Illumina) were used for variant annotation. Only the variants with at least 20 ± 2 total reads and variant allele frequency (VAF) ≥ 0.01 were called. To exclude false positive or DNA artifacts, we only maintained in the dataset the variants with a filter status equal to ‘PASS’ in the BaseSpace Variant Interpreter (cloud-based interpretation and reporting platform, Illumina, CA, USA). The potentially pathogenic variants identified were confirmed by polymerase chain reaction (PCR). Sequences of the PCR products were determined using the Big Dye Terminatorv1.1 Cycle Sequencing Kit (Applied BiosystemsTM) and sequencing data were analyzed with Variant ReporterTM Software v3.0 (Applied BiosystemsTM). Primer sequences and assay conditions are available on request. Sequences were compared to consensus sequences obtained from the Ensembl Genome Browser (http://www.ensembl.org) and NCBI (http://www.ncbi.nlm.nih.gov) databases. The sequence variants were described according to the recommendations of the Human Genome Variation Society (HGVS) v.20.05. Sanger sequencing analytic sensitivity is ≥99%.
High-resolution comparative genomic hybridization (HR-CGH) analysis of tumors’ chromosomal gains and losses was also performed, as previously described (25).
Results
Analysis of the MEN1 gene in the proband identified a novel heterozygous germline pathogenic variant [NM_000244:c.978C>A, NP_000235.3:p.(Tyr326*)] in the MEN1 gene, predicted to encode a truncated protein, described in ClinVar (Accession: VCV001447200.3). Segregation analysis of the germline variant was not performed in affected relatives because they do not reside in Portugal. The somatic study revealed two frameshift truncating somatic MEN1 variants, c.307del, p.(Leu103Cysfs*16) and c.206_215del p.(Pro69Leufs*47), respectively, in the PC and in the PA. The three variants (germline and somatic) identified in the MEN1 gene were confirmed by Sanger sequencing. In addition, HR-CGH analysis of the PC sample showed total gain of chromosome 19, together with partial gains and losses of several chromosomal regions, contrasting with the PA, which only presented one partial loss (Supplementary Table 2). Additional genetic events occurring at the somatic level, particularly in CDC73 gene, PI3K/Akt/mTOR pathway, were not detected.
Discussion
PHPT is the most common and typically the first endocrinopathy associated with MEN1 (90–95%) and is usually due to benign parathyroid tumors (5, 6, 7). The occurrence of PC in MEN1 is extremely rare, with an estimated prevalence of 0.28–0.7% (1/348 Mayo Clinic, 2/291 MD Anderson Cancer Center, 1/153 Peking Union Medical College Hospital) (17, 18, 23). Of the 348 MEN1 patients reported by Mayo Medical Center, only one had a diagnosis of PC (0.3%) (17). Of the 291 MEN1 patients reported by the MD Anderson Cancer Center, only two (0.7%) had PC (18). In addition, of the 153 MEN1-HPT patients admitted to Peking Union Medical College Hospital, one had PC (0.7%) (23).
Thus far, the association between PC and MEN1 has been reported in 19 cases in the literature. In 11 of these 19 cases, a MEN1 germline mutation was identified (8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23). However, patients’ germline or somatic mutation testing for CDC73 was performed in only 1/19 cases, and no coding mutation (germline or somatic) or deletion of the CDC73 gene was found (20). LOH at the MEN1locus (chromosome 11q13.1) was assessed in 3/19 patients, and no LOH was detected in PC tumor tissue (20, 21). The genetic analysis of other genes with somatic alterations commonly detected in PC was not performed in any of the 19 patients (8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23). Noteworthy, somatic mutations or LOH at the MEN1 locus has been detected in sporadic PC, suggesting the involvement of the MEN1 gene in the pathogenesis of these tumors (3, 5). However, somatic MEN1 mutations or LOH has never been detected in PC in patients with MEN1 germline mutations (3).
The results of the genetic testing performed on our patient identified a MEN1 germline variant [c.978C>A, p.(Tyr326*)]. As far as we know, this variant has not yet been described in the medical literature and has only one submission in ClinVar. The patient’s tumors were also evaluated for loss of the normal MEN1 gene copy. The detection of a truncating somatic MEN1 variant in the PC is consistent with MEN1 being a tumor-suppressor gene, suggesting its involvement in PC etiology.
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. Still, the finding of a complete inactivation of MEN1 gene in a parathyroid tumor is a usual feature in benign MEN1-related parathyroid tumors, as also demonstrated here in the patient’s PA, which harbored a truncating somatic MEN1 variant. Although no other somatic alterations commonly detected in PC (e.g. in CDC73, TP51, RB1, CCND1 genes and PI3K/AKT/mTOR pathway) were identified in the present case, CGH profiling showed that the patient’s PC, compared to the PA, had a higher number of chromosomal imbalances. Furthermore, it is also possible that epigenetic mechanisms and/or miRNAs deregulation (reviewed in Cardoso et al. 2017) may have also contributed to the malignant progression of the parathyroid lesion (3).
In previous studies, PC in MEN1 patients seems to have an equal gender distribution and is diagnosed around age 50, a decade earlier than benign PHPT (6, 17, 18). In most cases of PC, the clinical picture is dominated by the presence of hypercalcemia. The serum calcium and PTH levels in MEN1-PC are usually higher than in those with MEN1-associated benign parathyroid tumors (22, 23). Reported studies of PC in patients with or without MEN1 demonstrate serum calcium levels typically above 13 mg/dL and PTH levels at least four times the upper limit of the reference range (2, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 26). Our patient had markedly elevated serum calcium and PTH concentrations, which raised the suspicion of PC.
Although patients with very high serum PTH levels have a higher likelihood of being diagnosed with PC, the diagnosis of PC is rarely made preoperatively, unless there is evidence of local invasion or metastases and is usually based upon pathology. Histological diagnosis of PC is challenging due to the lack of specific features, which sometimes overlap with those of atypical parathyroid tumors (1, 2). The histopathologic criteria for diagnosis of PC include vascular, lymphatic or perineural invasion, local invasion into adjacent structures or documented metastatic disease. Moreover, Ki-67 index is usually >5% in malignant tumors. Other criteria, such as trabecular growth pattern, fibrous bands, and mitotic figures, although common in PC, are not definitive evidence of malignancy (24). The diagnosis of PC in our patient was based on the presence of angioinvasion, which is considered the most relevant evidence of malignant tumors (2, 24). The absence of nuclear staining for parafibromin detected by immunohistochemical analysis has a sensitivity of 70% and a specificity of 95% for the diagnosis of PC (27). However, parafibromin immunostaining as a diagnostic marker alone is limited, and it has been reported to be less reliable than CDC73 mutation analysis (3, 28, 29).
Surgery is the only curative treatment for PC, as PC is not radiosensitive and responds poorly to chemotherapy. The recommended therapy includes en bloc resection, ipsilateral thyroid lobectomy and resection of surrounding infiltrated tissues. En bloc surgery reduces the rate of recurrence and improves survival outcomes (1, 2, 26). Subtotal parathyroidectomy is still considered the first choice of treatment for PHPT in MEN1 (4, 5, 6). In the present case, subtotal parathyroidectomy together with ipsilateral hemithyroidectomy was performed because the tumor was adherent to the left lobe of the thyroid.
Herein we present the first genetically confirmed case of PC arising by an MEN1-related mechanism in a patient with MEN1 syndrome. The occurrence of PC in the setting of MEN1 disease is rare, but it should be considered when MEN1 patients present with late onset PHPT and/or with extremely high levels of PTH. The suspicion of PC during the preoperative workup is relevant, since the chance of a definitive cure depends on the more extensive initial surgery recommended for PC.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/EC-22-0479.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
The publication of this work was supported by Instituto Português de Oncologia de Lisboa Francisco Gentil.
Ethics approval
Written informed consent has been obtained from the patient for genetic analysis, publication of the submitted article and accompanying images. This case report was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.
Author contribution statement
Sara Lomelino Pinheiro wrote the case report. Ana Saramago performed the genetic analysis, providing substantial contribution for the interpretation of the genetic data, writing review and editing. Branca Maria Cavaco provided supervision, formal analysis and interpretation of the genetic data and revised critically the manuscript. Tiago Nunes da Silva was responsible for the patient management. Valeriano Leite supervised all diagnostic and treatment decisions and revised critically the manuscript. All listed authors have approved the final version of the manuscript.
Acknowledgements
The authors acknowledge Dr Isabel Fonseca and Dr Miguel Rito for the important contribution regarding the histopathological analysis. The publication of this work was supported by Instituto Português de Oncologia de Lisboa Francisco Gentil.
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