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Abstract

Parathyroid carcinoma (PC) is extremely rare in children and adolescent. PC is more often sporadic, but also it could be associated with germline mutations. The clinical features of primary hyperparathyroidism (PHPT) are nonspecific in children and adolescent, which delays the diagnosis for years. This case of PC in a pediatric patient, caused by germline heterozygous pathogenic variant in exon 1 of the CDC73 gene (c.70 G > T, p. Glu24Ter) is the first to be reported in Russia. Due to the rarity of pediatric parathyroid malignancy, the diagnosis of this endocrine neoplasm remains a challenge. The main difficulties that we faced in the management of the patient were the morphological confirmation of diagnosis, multiple surgical interventions, and disseminated PC metastases. We describe a 13-year-old girl with delayed diagnosis of PC and subsequent local recurrence after several surgeries, who underwent specific radiation therapy that allowed controlling hypercalcemia.

Keywords

adolescent case report parathyroid carcinoma radiotherapy

Background

Primary hyperparathyroidism (PHPT) is uncommon among children and adolescents with the frequency 2–5 cases per 100,000 and an equal sex ratio.^1,2 The main causes in this age group include sporadic adenomas (up to 80%) and hyperplasia.² Genetic syndromes that are associated with multiple abnormal parathyroid glands (PTG) may account for 5–10% of all cases of PHPT,³ and are especially suspicious in childhood. Parathyroid carcinoma (PC), as the underlying cause of PHPT in pediatric patients, is extremely rare. The exact etiology and pathogenesis of PC are unclear; it occurs more often sporadically. Several cases of PC have been reported in patients with a history of neck irradiation and end-stage renal disease.⁴ There is a hypothesis that the carcinoma may originate from long-term adenoma or a hyperplastic PTG, though the potential for such malignant transformation remains questionable. Another form of PC is familial, which can occur in hyperparathyroidism-jaw tumor syndrome (HPT-JT) and familial isolated PHPT, single cases have been described in multiple endocrine neoplasia type 1 and 2A (MEN1 and MEN 2A). Pediatric patients with PHPT are more often symptomatic than adult, skeletal, and renal manifestations usually present at the time of diagnosis.² There are no specific clinical features, which allow distinct PC from benign adenoma. However, it can present as a palpable cervical mass compressing the surrounding structures. There is also evidence of nonspecific PC-associated symptoms in childhood and adolescence including neurological (irritability, depression, weakness, proximal myopathy); gastrointestinal (vomiting, nausea, diarrhea, pancreatitis); and cardiovascular (long QT interval) disorders.⁵ We report a clinical case of a child with PC caused by germline heterozygous pathogenic variant in CDC73 gene who presented with severe symptoms of PHPT at the age of 6 years. This is the first case of pediatric PC described in the Russian population. The reporting of this case conforms to the CARE guidelines.⁶

Case presentation

Up to the age of 6 years, the girl grew and developed normally. Furthermore, she started to complain of weakness, fatigue, and gait disturbance. During next 5 years, there were progressive muscle weakness, pain in the upper and lower extremities. X-shaped curvature of the legs has been noticed.

At the age of 12 years, the patient noted a sharp deterioration in her condition: severe muscle weakness and pain, worsening of hallux valgus. Besides, she lost 20 kg over 3 months. Ultrasound (US) of the thyroid gland revealed a nodular formation 29 × 17 × 17 mm at the upper pole of the left lobe. Six months later, she underwent the injury of the left hip. X-ray examination showed an inhomogeneous zone in the right ilium with an osteolytic area surrounded by a rim of sclerosis (31 × 23 × 24 mm), dual-energy X-ray absorptiometry (DEXA) was not provided. During a laboratory examination, PHPT was suspected (Table 1): an elevated parathyroid hormone (PTH) level 208 pmol/L (1.9–6.9) combined with hypophosphatemia 0.9 mmol/L (1.45–1.75), highly normal total calcium (Ca) 2.5 mmol/L (2.15–2.55), deficient of 25(OH)vitamin D – 8.0 ng/mL (>30), and extremely high alkaline phosphatase (ALP) 2105 U/L (141–460).

Table 1.

Laboratory test results and treatment.

Date (age, years)	PTH (pg/mL)	Ca total (mmol/L)	P (mmol/L) (0.81–1.45)	Ca in daily urine (mmol/day)	ALP (U/L)	Creatinine (µmol/L)	25(OH)vitamin D (ng/mL)
2015 (12)	1961 (18–65)	2.5 (2.15–2.55)	0.9 (1.45–1.75)	–	2105 (141–460)	–	8
February 2016 (13)	Surgery 1 – Selective PTE (removal of the left upper PTG). Histological examination: the tumor tissue is represented by cells with light cytoplasm and round nuclei with low mitotic activity [Figure 1(a) and (b)]; a fibrous capsule with the residual PTG tissue; foci of necrosis and signs of invasion into the capsule were not found. Review the histological postoperative material: tumor structures in the lumen of some blood vessels was noted (considered as introduced during the preparation of the histological material). IHC study: PTH + [Figure 1(c)], cytokeratin 8 +, CyclinD1 +; TTF-1 −, synaptophysin −, Bcl-2 −, p53 −; Ki-67: 5%.
April 2016 (13)	122.2 (15–65)	2.34 (2.1–2.55)	1.86 (1.45–1.78)	0.32 (2.5–8)	–	39.5	–
October 2017 (14)	762 (15–65)	3.05 (2.1–2.55)	1.26 (1.45–1.78)	5.2 (2.5–8)	998 (40–150)	–	4.81
October 2017 (15)	Surgery 2 – Removal of a fragment of paratracheal tissue and thymus horn with areas of scars and muscles, altered PTG at the upper pole of the left thyroid lobe. Histological examination: invasive growth of PC with solid alveolar structure with invasive growth into skeletal muscles [Figure 2(a)]; fatty tissue with a few lymph nodes with reactive changes without signs of metastasis; thymus tissue was not found. IHC: global loss of parafibromin expression [including in the primary focus (Figures 1(d) and 2(b))], Ki-67: −7%.
October 2017 (15)	124 (15–65)	1.96 (2.1–2.55)	–	–	–	–	–
August 2018 (16)	209.8 (15–65)	2.92 (2.15–2.55)	0.88 (1.45–1.75)	10.5 (2.5–8)	–	–	–
Cinacalcet 30 mg/day with titration up to 60 mg
September 2018 (16)	Surgery 3 – Left HTE with ipsilateral lymphadenectomy, partial excision of the muscles, fatty tissue, and fascia of the anterior surface of the neck. Histological examination: a fragment of the PC of a solid trabecular structure with signs of infiltrative growth, five lymph nodes with reactive changes; adipose tissue with layers of fibrous connective tissue with blood vessels, nerve fibers, and skeletal muscles, as well as remnants of suture material without elements of tumor growth. IHC: somatostatin receptors 2 and 5 types (–).
September 2018 (16)	149 (15–65)	2.7 (2.15–2.55)	1.47 (1.45–1.78)	–	–	–	–
July 2019 (17)	Surgery 4 – Thyroidectomy (removal of the remaining right lobe of the thyroid gland) with the pretracheal lymph nodes and tissue. Histological examination: the tumor process was not detected; the tissue of the thyroid gland and PTG, lymph nodes of the usual histological structure.
July 2019 (17)	510 (15–65)	2.61 (2.15–2.55)	–	–	–	–	–
August 2019 (17)	Surgery 5 – Supraclavicular lymphadenectomy on the right side. Histological examination: recurrence of PC – a nodular formation with a diameter of 1 cm of soft-elastic consistency in the lymph node, fibrous layers in the tumor, its growth in the surrounding fibrous connective tissue.
Cinacalcet 90 mg/day
October 2020 (18)	244 (15–65)	2.69 (2.15–2.55)	1.98 (1.45–1.78)	12.6 (2.5–8)		58.9	–
November–December 2020 (18)	Remote radiation therapy on the neck area (from the thyroid cartilage to the jugular notch), the total focal dose was 50 Gy (single focal dose: 2.0; number of fractions: 25) followed by local irradiation of the local metastatic lesion (Boost single focal dose: 10 Gy).
December 2020 (18)	200 (15–65)	2.66 (2.15–2.55)	–	–	–	–	–
February 2021 (18)	144 (15–65)	2.49 (2.15–2.55)	0.88 (1.45–1.78)	7.65 (2.5–8)	–	–	–
Cinacalcet 60 mg/day
September 2022 (19)	120 (15–65)	2.77 (2.15–2.55)	–	–	–	59	23.8
February 2023 (19)	102 (15–65)	2.4 (2.15–2.55)	1.1 (1.45–1.78)	–	117 (40–150)	57.7	–
August 2023 (20)	92.3 (15–65)	2.48 (2.15–2.55)	0.91 (1.45–1.78)	–	–	66	–
Discontinuation of Cinacalcet for 7 days
October 2023 (20)	104 (15–65)	2.63 (2.15–2.55)	0.82 (1.45–1.78)	6.1 (2.5–8)	70 (40–150)	54	18.3

Cinacalcet 30 mg/day, cholecalciferol 7000 IU/day

ALP, alkaline phosphatase; HTE, hemithyroidectomy; IHC, immunohistochemical; PC, parathyroid carcinoma; PTE, parathyroidectomy; PTG, parathyroid gland, TTF-1, thyroid transcription factor 1.

Figure 1.

Parathyroid cancer (primary tumor). (a) PC’s cells with slightly eosinophilic cytoplasm and well-developed vasculature; the perinuclear rims of enlightenment are clearly visible. (b) Mitosis (→); large nucleus, a preserved nuclear–cytoplasmic ratio and perinuclear rims of enlightenment. (c) Intense expression of PTH. (d) Loss of parafibromin expression.

Figure 2.

Recurrent PC. (a) Invasive growth in soft tissues and skeletal muscles. (b) Loss of parafibromin expression.

The patient underwent selective parathyroidectomy (PTE) of the altered left upper PTG at the age of 13 years. Initially, during morphological examination, the tumor was regarded as PTG adenoma (Table 1). Laboratory data of the early postoperative period are not available.

A few months later, lab tests showed elevated PTH levels [up to 122.2 pg/mL (15–65)], as well as normocalcemia [Ca total 2.34 mmol/L (2.1–2.55)], hyperphosphatemia [1.86 mmol/L (1.45–1.78)] and reduced urinary Ca excretion with normal serum creatinine level (Table 1). US scan performed by an expert-level specialist did not detect pathologically altered PTG in the typical places. Thus, secondary hyperparathyroidism was suspected. Calcium carbonate 1000 mg/day and alfacalcidol 0.5 μg/day were prescribed following the decrease of the PTH level to 107.2 pg/mL (15–65) with normocalcemia maintained.

To specify the cause of PHPT in pediatric patient, the next-generation sequencing using the panel of nine genes (MEN1, CASR, CDC73, CDKN1A, CDKN1B, CDKN1C, CDKN2A, CDKN2C, CDKN2D) was carried out. We performed sequencing at Illumina MiSeq sequencer (Illumina, USA) and applied paired-end reads (minimum coverage depth × 100) strategy. Genomic coordinates refer to the latest version GRCh38. The genetic study demonstrated germline heterozygous pathogenic variant c.70 G > T, p. Glu24Ter in exon 1 of the CDC73 gene (Figure 3) which was previously described in PC.⁷ There is no family history of bone deformities, low-energy fractures, jaw tumors, or kidney disease (kidney cysts).

Figure 3.

Chromatogram of exon 1 of the CDC73 gene. Germline heterozygous pathogenic variant c.70 G > T, p. Glu24Ter in exon 1 of the CDC73 gene (top) and normal sequence (bottom).

Relapse of PHPT happened at the age of 14 years: PTH 762 pg/mL (15–65), Ca ionized 1.4 mmol/L (1.03–1.29), total Ca 3.05 mmol/L (2.1–2.55) (Table 1). The leading complaints were severe osteoarticular and muscle pain (Table 1). X-ray revealed no fractures, valgus deviation of the knee joints with upward and outward rotation of the patella, Looser zones, and cysts of 2–9 mm in the medial epicondyles of the femurs. We detected nephrocalcinosis in the right kidney. US scan, as well as ^99mTc-MIBI scintigraphy with single-photon emission computed tomography combined with computed tomography (SPECT-CT) revealed a lesion 8 × 4 × 6 mm at the posterior surface of the left thyroid lobe. Given the suspicion of a malignant tumor, surgeons removed a fragment of paratracheal tissue and thymus horn with areas of scars and muscles in addition to the altered PTG (Table 1). Histopathologic and immunohistochemical (IHC) examination verified the PC (Table 1, Figure 2). Moreover, the revision of histological slides after the first operation confirmed the vascular invasion (primarily regarded as a consequence of histologic processing) (Table 1). The diagnosis of PC was finally confirmed. In the early postoperative period, the patient developed hypocalcemia [total Ca 1.96 mmol/L (2.1–2.55), Ca ionized 0.99 mmol/L (1.03–1.29)] requiring Ca and alfacalcidol supplementation. However, the PTH level varied from 68.8 to 124 pg/mL (15–65).

Two years later, the disease recurred (Table 1). US scan revealed altered cervical lymph nodes – heterogeneous structures with increased blood flow on both sides 3 × 2, 6 × 3, 9 × 5, 13 × 6, and 12 × 4 mm. Metastases were confirmed by parathyroid fine needle aspiration (FNA) with PTH washout of the left and right lymph nodes (1732 and 3273 pg/mL, respectively). The extended surgery [left hemithyroidectomy (HTE) with ipsilateral lymphadenectomy, partial excision of the muscles, tissue, and fascia of the anterior surface of the neck] did not lead to the biochemical remission: PTH 149 pg/mL (15–65), total Ca 2.7 mmol/L (2.15–2.55). The ¹⁸F-FDG and ¹⁸F-choline positron emission tomography/CT imaging did not reveal any zones of increased accumulation. However, US scan and ^99mTc-MIBI scintigraphy with SPECT-CT showed multiple foci in the right anterior cervical and paratracheal lymph nodes. At follow-up the level of PTH and total Ca increased up to 253 pg/mL (16–65) and 2.8–3.05 mmol/L (2.15–2.55), respectively. We initiated therapy with Cinacalcet at a dose of 30 mg/day with titration up to 60 mg.

Taking into account the progression of the disease at the age of 17 years, 2 more operations were undertaken: a thyroidectomy with the removal of pretracheal lymph nodes and tissue on the right side followed by right lymphadenectomy of supraclavicular neck nodes (Table 1). However, there was no disease remission. Multiple surgeries have not resulted in complications (hoarseness of voice, severe neck scarring).

In October 2020 (17 years old), we were forced to increase the dose of Cinacalcet to 90 mg/day: PTH – 244.3 pg/mL (15–65), total Ca – 2.69 mmol/L (2.15–2.55), Ca ionized – 1.29 mmol/L (1.03–1.29), phosphorus (P) – 1.98 mmol/L, 24-h urine Ca – 12.6 mmol/day (2.5–8) (Table 1). US scan showed an intermuscular hypoechoic lymph node 9 × 12 × 8 mm most likely corresponding to a metastasis in the projection of the removed right PTG (in the lower third of the neck). This was inconsistent with the results of ^99mTc-MIBI scintigraphy with SPECT-CT and multislice computer tomography (MSCT) that demonstrated a low isotope uptake of an altered lymph node 12 × 10 × 10 mm in the subcutaneous fat on the front neck on the right. No hyperactive foci were identified on the SPECT in the ‘whole body’ and ‘pelvis’ modes.

Given the ineffectiveness of the previous five surgical interventions, the patient was referred to radiotherapy on the neck area followed by local irradiation of the metastatic lesion on the neck (identified on MSCT in the specialized oncological institution) (Table 1). During 3 years of follow up after radiotherapy, the level of PTH slowly got down that allowed to decrease dose of Cinacalcet from 90 to 60 mg/day (Table 1). Throughout the follow-up, bone mineral density of the spine, proximal femur, and radius, according to X-ray densitometry, remained within normal values.

US scan in February 2021 showed a hypoechoic avascular formation of irregular shape 15 × 8 × 10 mm on the anterior surface above the postoperative scar and another one near the jugular notch 12 × 6 × 10 mm. At the same time, these lesions did not accumulate ^99mTc-MIBI on SPECT-CT. US scans visualized a hypoechoic formation with uneven contours in the projection of the thyroid cartilage, dimensions 5 × 2.5 × 3 mm without blood flow (probably a cyst), normal lymph nodes. However, there were no volumetric formations on CT with contrast enhancement.

In March 2022 (18 years old), emergency mini-percutaneous nephrolithotripsy with nephrostomy on the right was performed. Postoperative MSCT of the kidneys showed small stones in the pelvis of the right kidney up to 4 mm, in the upper group of calyces of the left kidney up to 3 mm.

In October 2023 (20 years old), after discontinuation of Cinacalcet for 7 days: albumin adjusted Ca 2.63 mmol/L (2.15–2.55), PTH 104 pg/mL (15–65). Therapy with Cinacalcet 30 mg/day was continued. US scan of the neck and MSCT with contrast revealed reduction of the largest lesion to 6.5 × 7 × 5.5 mm (June 2020 – 12 × 10 × 10 mm). Screening for complications of PHPT was carried out: estimated Glomerular filtration rate using Chronic Kidney Disease Epidemiology Collaboration equation (eGFR (CKD-EPI)) 131 mL/min/1.73 m²; no signs of nephrolithiasis/nephrocalcinosis were detected on US. DEXA demonstrated increase in bone density to the Z-score in L1–L4 −1.1 SD (+11.9% compared to October 2020), left femoral neck 0 SD (+14.9% compared to October 2020), radius −1.7 SD (+43.6 compared from July 2017).

Genetic study did not reveal pathogenic variants of CDC73 gene in parents. The patient has an 11-year-old younger brother who does not undergo genetic study, but regularly tests for Ca and PTH remain normal.

Discussion

About 20 cases of PC under the age of 16 years have been previously published (Table 2).^7–26 PC is more often sporadic. In this case, the first mutation occurs de novo (first stroke) followed by a stepwise inactivation of the second allele in the same PTG somatic cell (second stroke) which leads to clonal tumor growth. Thus, the inheritance of a germline mutation at birth explains the earlier age of PHPT manifestation, which is more typical for familial forms, while sporadic ones has a later onset of the disease. Such mechanism is consistent with Knudson’s two-hit hypothesis.

Table 2.

PC in children from 1972 to 2022.

Author	Year	Sex	Age	Ca (mmol/L)	PTH (pg/mL)	Germline mutations	Heredity	Surgery	Outcome
Schatz and Castleman⁸	1973	–	13	–	–	ND	ND	–	ND
Young et al.⁹	1984	M	15	3.1	–	ND	ND	PTE	Regional lymph nodes and lung mts
McHenry et al.¹⁰	1993	M	14	3.3	353	ND	Yes	en bloc	Remission within 24 months
Meier et al.¹¹	1999	M	15	5.1	358	ND	ND	en bloc	Remission within 12 months
Hamill et al.¹²	2002	F	8	14.3 (3.5)	82	ND	Yes	PTE	Remission within 16 months
Fiedler et al.¹³	2009	M	10	3.6	300	ND	Yes	PTE	Remission within 18 months
Herrera- Hernández¹⁴	2011	F	14	3.6	2792	ND	No	HTE	Remission within 18 months
Kim¹⁵	2012	F	13	2.9	8363	ND	No	en bloc	Lung mts
Vinodh and Rajeshwari¹⁶	2012	M	11	–	1630	ND	ND	en bloc	ND
Rahman et al.⁷	2015	F	10	3	2217	ND	ND	–	ND
Davidson et al.¹⁷	2016	F	8	3.1	453	Heterozygous deletion in exon 1 of the CDC73 gene	No	PTE	Regional lymph nodes and lung mts
Niramitmahapanya et al.¹⁸	2016	M	14	4.2	1164	Heterozygous mutation c.700 C > T (Arg234X) of the CDC73 gene in exon 7	No	en bloc	Remission within 12 months
Serrano-Gonzalez et al.¹⁹	2016	F	14	3.3	1013	Heterozygous mutation c.70 G > T p. (Glu24Ter) of the CDC73 gene in exon 1	No	en bloc	Remission within 6 months
Zivalijevic et al.²⁰	2019	F	15	3.9	1170	ND	No	en bloc	Remission within 24 months
Dutta et al.²¹	2019	M	16	3.89	2028	Heterozygous mutation, deletion of the CDC73 gene	ND	en bloc	Remission within 18 months
Wang et al.²²	2020	M	10	3.84	1075	ND	No	en bloc	Remission within 18 months
Lenherr-Taube et al.²³	2020	M	13	3.85	980	ND	ND	PTE	ND
Omi et al.²⁴	2020	F	13	3.54	1302	ND	No	PTE	Lung mts
Hu et al.²⁵	2020	F	13	3.89	2970	ND	ND	en bloc	Remission within 6 months
Rahimi et al.²⁶	2021	F	13	2.69	2876	Mutation in the BRCA1	No	en bloc	ND

HTE, hemithyroidectomy; mts, metastases; ND, no data; PC, parathyroid carcinoma; PTE, parathyroidectomy; PTH, parathyroid hormone.

Mutations in the CDC73 gene play a crucial role in the pathogenesis of PC. The CDC73 gene consists of 17 exons located on chromosome 1q31.2 and encodes the parafibromin protein associated with the Paf1 protein complex (polymerase I-associated factor).²⁷ HPT-JT (OMIM#145001) is a rare syndrome characterized by PTG tumors, fibro-osseous lesions (ossifying fibroma) of the mandible or maxilla, cystic and neoplastic renal abnormalities. PHPT (in 15–20% due to carcinomas) is usually the first manifestation of the disease and occurs in >90% of HPT-JT cases. Germline pathogenic variants in the CDC73 gene are present in about 90% of patients with HPT-JT and in one-third of patients with sporadic PC with no family history.²⁸ The earliest case of hypercalcemia in a patient with HPT-JT was recorded at the age of 7 years,²⁹ and the latest in the sixth decade of life.³⁰ The median age of PHPT debut is 27 years (range 12–58).^31–33 In the presented case, clinical manifestation of PHPT was noted at the age of 6 years, but the biochemical evaluation was performed only 6 years later. We did not confirm other components of the HPT-JT syndrome.

Due to the lack of reliable preoperative diagnostic criteria, the diagnosis of PC is based on histological and IHC examinations. According to the 2022 World Health Organization (WHO) classification of endocrine and neuroendocrine tumors, the histological definition of PC still requires one of the following findings: angioinvasion (vascular invasion), lymphatic invasion, perineural (intraneural) invasion, local malignant invasion into adjacent anatomic structures, or histologically/cytologically documented metastases.³⁴ In the absence of invasive growth, but in the presence of suspicious signs for malignancy (broad fibrous bands, mitoses, adherence to surrounding structures, monotonous sheet-like or trabecular growth pattern, nuclear atypia) atypical parathyroid tumor is diagnosed.³⁴ An additional diagnostic method is an IHC analysis including oncomarkers expression. PC is associated with negative expression of parafibromin, Adenomatous Polyposis Coli (APC), E-cadherin, p27, Bcl-2a, mdm-2, and 5-hmC, and positive for PGP9.5, galectin3, human telomerase reverse transcriptase (hTERT), as well as p53 overexpression and increased Ki-67 (often >5%). The term ‘parafibromin deficient parathyroid neoplasm’ has been introduced in the 2022 WHO classification for the first time. The loss of parafibromin expression in the presence of internal positive controls (fibroblasts, endothelial cells) is an indication for genetic testing for CDC73 pathogenic variant.³⁴ Unfortunately, genetic study and IHC have limited availability in routine practice.

The difficulties of morphological diagnosis are clearly presented in the presented case. The primary tumor was not initially regarded as a ‘carcinoma’. However, in 2016, the fifth edition of the WHO classification of tumors of the endocrine system drew the attention of pathologists to the difficulties of morphological diagnosing of malignant tumors and put forward such a subgroup of tumors as atypical. Morphological diagnosis after second surgery also caused difficulties. Taking into account that the primary tumor was regarded as an ‘adenoma’ and the focus of recurrence was localized at the site of the primary operation, it was necessary to exclude the possibility of continued growth of residual PTG tissue. However, the invasion in skeletal muscles through ‘tongues of flame’ was suspicious for carcinoma recurrence. Gill et al.³⁵ described similar morphological difficulties and a long way to a correct diagnosis in a 16-year-old boy with a mutation in the CDC73 gene and loss of parafibromin expression. In the presented case, the primary tumor showed a pronounced branched vasculature, large nuclei with a preserved nuclear–cytoplasmic ratio, and a perinuclear rim [Figure 1(a) and (b)]. Subsequently, the loss of parafibromin expression in the primary tumor (first operation) [Figure 1(d)] and in pattern of recurrence tissue (second operation) [Figure 2(b)] was confirmed. The results of the IHC study correlated with genetic testing, which revealed germline heterozygous pathogenic variant in the CDC73 gene.

The main treatment option for both primary and secondary foci of PC is surgery. There are still debates on the preferred volume of primary surgery in patients with a CDC73 mutation: bilateral revision of the neck with subtotal/total PTE or selective operation.³⁶ Previously, preventive subtotal/total PTE remains the optimal strategy to reduce the risk of PC recurrence. However, this approach is associated with the high risk of postoperative hypoparathyroidism. Some authors suggested autotransplantation of PTG to avoid it.^37,38 However, autotransplantation of PTG tissue in patients with CDC73 pathogenic variant may lead to dissemination of malignant cells.³⁹

Routine cytological study of PTG formations is not recommended, since it does not allow differentiating benign from malignant lesions and can promote the spread of malignant cells along the tract of the puncture needle.⁴⁰ In our case, FNA could also contribute to tumor progression.

Five-year survival rate is 76–85%, and 10-year survival varies from 49 to 77%.⁴¹ Overall survival depends on multiple factors, including the type of primary surgery (i.e. PTE or en bloc resection), serum Ca levels and/or presence of resistant hypercalcemia, local or distant metastases, CDC73 mutation, and/or loss of parafibromin or Ca-sensing receptor protein expression. Besides hormonally inactive PC has poor prognosis.⁴² Complications associated with hypercalcemia are the main cause of death.⁴³ Relapse of the PC develops in 50% of cases, a third of them are regional metastases. Distant metastases are detected in 25% of cases, more frequently in the lungs (40%) and liver (10%), less often in the bones, pleura, pericardium, and pancreas.⁴⁴ For already developed metastases, the 5-year survival rate reduced to 50%.^45–47 Surgery remains the main treatment for PC recurrence; however, decision on its volume is made individually and depends on technical possibilities.^48–50 ‘Aggressive’ surgical approaches for recurrent disease were associated with 30% increase in overall survival.^51,52 Other treatment options for PC metastases are still challenging since there are no effective regimes of chemo- or radiotherapy.⁵³ There is a relatively successful experience of radiotherapy as an adjuvant treatment after surgery in locally invasive PC, in cases of microscopic residual disease or after multiple recurrences, but the conclusions of the study were ambiguous and based on a small sample of patients.^53–55 The American Association of Endocrine Surgeons guidelines⁵⁶ recommends reserving external radiotherapy for palliative treatment because surgery on a radiated field may be difficult. Therefore, radiotherapy may be considered for refractory disease in patients who are not candidates for re-operation.

Several cases of successful anti-PTH immunotherapy have been presented, which led to long-term control of hypercalcemia and tumor growth, and in some cases to decrease in the size of metastases.^57–59 Some authors described a successful experience of the multikinase inhibitor therapy with sorafenib for metastatic PC foci in the lungs.⁶⁰ However, the targeted therapy can be only applied if the tumor progresses and the size of the secondary lesions is appropriate.

In our case, due to the ineffectiveness of the multiple surgical interventions, the remote radiation therapy followed by local irradiation of the metastatic lesion was performed to attempt stop progression. Three years of follow-up showed us promising results of slowing decrease of level of PTH and Ca (Table 1). Further observation will allow drawing conclusions. However, the remote radiation therapy is a possible way to stabilize the aggressive course of PC, if surgical treatment is ineffective or impossible.

Conclusion

PHPT is not common in the pediatric population but often has aggressive clinical behavior. This indicates the mandatory screening for Ca and PTH levels in children with bone or kidney disorders for earlier verification of the disease. Moreover, early onset of PHPT requires the exclusion of hereditary forms. If there is a pathogenic variant in the CDC73 gene, doctors should be wary of PC and possibly an ‘aggressive’ surgical approach. Alternative treatment options such targeted and radiation therapy may be considered if surgery is ineffective.

Supplemental Material

sj-pdf-1-tam-10.1177_17588359241265222 – Supplemental material for Combination approach for CDC73-related parathyroid carcinoma in an adolescent female patient: a case report and literature review

Supplemental material, sj-pdf-1-tam-10.1177_17588359241265222 for Combination approach for CDC73-related parathyroid carcinoma in an adolescent female patient: a case report and literature review by Ekaterina Kim, Natalia Kalinchenko, Anna Eremkina, Liliya Urusova, Rustam Salimkhanov and Natalia Mokrysheva in Therapeutic Advances in Medical Oncology

Footnotes

Acknowledgements

We appreciate our patient and her family for their participation in this study.

Declarations

ORCID iD

Ekaterina Kim

Supplemental material

Supplemental material for this article is available online.

References

Menon

Dayal

Rao

, et al Childhood parathyroid adenoma: a rare but important cause of nephrolithiasis. J Pediatr Endocrinol Metab 2016; 29: 853–856.

Roizen

Levine

MA.

Primary hyperparathyroidism in children and adolescents. J Chin Med Assoc 2012; 75: 425–434.

Bilezikian

Cusano

Khan

, et al Primary hyperparathyroidism. Nat Rev Dis Primers 2016; 2: 16033.

Krupinova

Kim

Eremkina

, et al Multiple metastases of parathyroid and papillary thyroid carcinoma in a female patient treated with long-term hemodialysis. J Pers Med 2023; 13: 548.

Belcher

Metrailer

Bodenner

, et al Characterization of hyperparathyroidism in youth and adolescents: a literature review. Int J Pediatr Otorhinolaryngol 2013; 77: 318–322.

Gagnier

Kienle

Altman

, et al; CARE Group*. The CARE guidelines: consensus-based clinical case reporting guideline development. Glob Adv Health Med 2013; 2: 38–43.

Rahman

Karim

Joarder

, et al Parathyroid carcinoma in a 10 years old female child. Mymensingh Med J 2015; 24: 619–623.

Schantz

Castleman

Parathyroid carcinoma. A study of 70 cases. Cancer 1973; 31: 600–605.

Young

Saltzstein

Boman

DA.

Parathyroid carcinoma in a child: unusual presentation with seizures. J Pediatr Surg 1984: 19: 194–196.

10.

McHenry

Rosen

Walfish

, et al Parathyroid crisis of unusual features in a child. Cancer 1993; 71: 1923–1927.

11.

Meier

Snyder

3rd Dickson

, et al Parathyroid carcinoma in a child. J Pediatr Surg 1999; 34: 606–608.

12.

Hamill

Maoate

Beasley

, et al Familial parathyroid carcinoma in a child. J Paediatr Child Health 2002; 38: 314–317.

13.

Fiedler

Rossi

Gingalewski

CA.

Parathyroid carcinoma in a child: an unusual case of an ectopically located malignant parathyroid gland with tumor invading the thymus. J Pediatr Surg 2009; 44: 1649–1652.

14.

Herrera-Hernández

Aranda-Valderrama

Díaz-Pérez

, et al Intrathyroidal parathyroid carcinoma in a pediatric patient. Pediatr Surg Int 2011; 27: 1361–1365.

15.

Kim

YS.

Parathyroid carcinoma with lung metastasis in a thirteen-year-old girl. J Korean Surg Soc 2012; 82: 385–388.

16.

Vinodh

Rajeshwari

Parathyroid carcinoma presenting as genu valgum. Indian Pediatr 2012; 49: 156.

17.

Davidson

Lam

McGee

, et al Parathyroid cancer in the pediatric patient. J Pediatr Hematol Oncol 2016; 38: 32–37.

18.

Niramitmahapanya

Deerochanawong

Sarinnapakorn

, et al Somatic HRPT2 mutation (Arg234X) of parathyroid carcinoma associated with slipped capital femoral epiphysis: a first case report. J Med Assoc Thai 2016; 99(Suppl. 2): S201–S205.

19.

Serrano-Gonzalez

Shay

Austin

, et al A germline mutation of HRPT2/CDC73 (70 G > T) in an adolescent female with parathyroid carcinoma: first case report and a review of the literature. J Pediatr Endocrinol Metab 2016; 29: 1005–1012.

20.

Zivaljevic

Jovanovic

Djordjevic

, et al Case report of parathyroid carcinoma in a pediatric patient. Int J Pediatr Otorhinolaryngol 2019; 124: 120–123.

21.

Dutta

Pal

Jain

, et al Pediatric parathyroid carcinoma: a case report and review of the literature. J Endocr Soc 2019; 3: 2224–2235.

22.

Wang

Liu

, et al Parathyroid carcinoma shown on ^99mTc-sestamibi parathyroid SPECT/CT scan in a pediatric patient. Clin Nucl Med 2020; 45: 480–482.

23.

Lenherr-Taube

Lam

Vali

, et al Severe primary hyperparathyroidism caused by parathyroid carcinoma in a 13-year-old child; novel findings from HRpQCT. JBMR Plus 2020; 4: e10324.

24.

Omi

Yamamoto

Nagashima

, et al Parathyroid carcinoma in a 13-year-old girl with a long-term survival. Surg Case Rep 2020; 6: 145.

25.

Berman

Parkes

, et al MON-920 pediatric parathyroid carcinoma presenting with acute progressive genu valgum. J Endocr Soc 2020; 4(Suppl. 1): MON-920.

26.

Rahimi

Shahbazi

Nikuei

, et al A pediatric parathyroid carcinoma: an unusual clinical presentation and mini-review. Int J Endocrinol Metab 2021; 19: e110234.

27.

Carpten

Robbins

Villablanca

, et al HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat Genet 2002; 32: 676–680.

28.

Cetani

Marcocci

Torregrossa

, et al Atypical parathyroid adenomas: challenging lesions in the differential diagnosis of endocrine tumors. Endocr Relat Cancer 2019; 26: R441–R464.

29.

Pichardo-Lowden

Manni

Saunders

, et al Familial hyperparathyroidism due to a germline mutation of the CDC73 gene: implications for management and age-appropriate testing of relatives at risk. Endocr Pract 2011; 17: 602–609.

30.

Bradley

Cavaco

Bowl

, et al Parafibromin mutations in hereditary hyperparathyroidism syndromes and parathyroid tumours. Clin Endocrinol (Oxf) 2006; 64: 299–306.

31.

Bricaire

Odou

Cardot-Bauters

, et al Frequent large germline HRPT2 deletions in a French National cohort of patients with primary hyperparathyroidism. J Clin Endocrinol Metab 2013; 98: E403–E408.

32.

Iacobone

Masi

Barzon

, et al Hyperparathyroidism-jaw tumor syndrome: a report of three large kindred. Langenbecks Arch Surg 2009; 394: 817–825.

33.

van der Tuin

Tops

CMJ

Adank

, et al CDC73-related disorders: clinical manifestations and case detection in primary hyperparathyroidism. J Clin Endocrinol Metab 2017; 102: 4534–4540.

34.

Erickson

Mete

Juhlin

, et al Overview of the 2022 WHO classification of parathyroid tumors. Endocr Pathol 2022; 33: 64–89.

35.

Gill

Lim

Cheung

VKY

, et al Parafibromin-deficient (HPT-JT type, CDC73 mutated) parathyroid tumors demonstrate distinctive morphologic features. Am J Surg Pathol 2019; 43: 35–46.

36.

Iacobone

Carnaille

Palazzo

, et al Hereditary hyperparathyroidism – a consensus report of the European Society of Endocrine Surgeons (ESES). Langenbecks Arch Surg 2015; 400: 867–886.

37.

Sarquis

Silveira

Pimenta

, et al Familial hyperparathyroidism: surgical outcome after 30 years of follow-up in three families with germline HRPT2 mutations. Surgery 2008; 143: 630–640.

38.

Guarnieri

Scillitani

Muscarella

, et al Diagnosis of parathyroid tumors in familial isolated hyperparathyroidism with HRPT2 mutation: implications for cancer surveillance. J Clin Endocrinol Metab 2006; 91: 2827–2832.

39.

Mehta

Patel

Rosenberg

, et al Hyperparathyroidism-jaw tumor syndrome: results of operative management. Surgery 2014; 156: 1315–1324; discussion 1324–1325.

40.

Sriphrapradang

Sornmayura

Chanplakorn

, et al Fine-needle aspiration cytology of parathyroid carcinoma mimic hürthle cell thyroid neoplasm. Case Rep Endocrinol 2014; 2014: 680876.

41.

Brown

O’Neill

Suliburk

, et al Parathyroid carcinoma: increasing incidence and changing presentation. ANZ J Surg 2011; 81: 528–532.

42.

Marcocci

Cetani

Rubin

, et al Parathyroid carcinoma. J Bone Miner Res 2008; 23: 1869–1880.

43.

Cetani

Pardi

Marcocci

Parathyroid carcinoma. Front Horm Res 2019; 51: 63–76.

44.

Di Meo

Sgaramella

Ferraro

, et al Parathyroid carcinoma in multiple endocrine neoplasm type 1 syndrome: case report and systematic literature review. Clin Exp Med 2018; 18: 585–593.

45.

Asare

Sturgeon

Winchester

, et al Parathyroid carcinoma: an update on treatment outcomes and prognostic factors from the National Cancer Data Base (NCDB). Ann Surg Oncol 2015; 22: 3990–3995.

46.

Good

Nilubol

, et al Tumor size and presence of metastatic disease at diagnosis are associated with disease-specific survival in parathyroid carcinoma. Ann Surg Oncol 2018; 25: 2535–2540.

47.

Shane

Clinical review 122: parathyroid carcinoma. J Clin Endocrinol Metab 2001; 86: 485–493.

48.

Hundahl

Fleming

Fremgen

, et al Two hundred eighty-six cases of parathyroid carcinoma treated in the U.S. between 1985–1995: a National Cancer Data Base Report. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 1999; 86: 538–544.

49.

Bollerslev

Schalin-Jäntti

Rejnmark

, et al Management of endocrine disease: unmet therapeutic, educational and scientific needs in parathyroid disorders. Eur J Endocrinol 2019; 181: P1–P19.

50.

Flye

Brennan

MF.

Surgical resection of metastatic parathyroid carcinoma. Ann Surg 1981; 193: 425–435.

51.

Sandelin

Tullgren

Farnebo

LO.

Clinical course of metastatic parathyroid cancer. World J Surg 1994; 18: 594–598; discussion 599.

52.

Obara

Okamoto

Ito

, et al Surgical and medical management of patients with pulmonary metastasis from parathyroid carcinoma. Surgery 1993; 114: 1040–1048; discussion 1048–1049.

53.

Busaidy

Jimenez

Habra

, et al Parathyroid carcinoma: a 22-year experience. Head Neck 2004; 26: 716–726.

54.

Munson

Foote

Northcutt

, et al

Parathyroid carcinoma: is there a role for adjuvant radiation therapy?

Cancer 2003; 98: 2378–2384.

55.

Wilhelm

Wang

Ruan

, et al The American Association of Endocrine Surgeons Guidelines for definitive management of primary hyperparathyroidism. JAMA Surg 2016; 151: 959–968.

56.

Chow

Tsang

Brierley

, et al Parathyroid carcinoma – the Princess Margaret hospital experience. Int J Radiat Oncol Biol Phys 1998; 41: 569–572.

57.

Bradwell

Harvey

TC.

Control of hypercalcaemia of parathyroid carcinoma by immunisation. Lancet 1999; 353: 370–373.

58.

Horie

Ando

Inokuchi

, et al First Japanese patient treated with parathyroid hormone peptide immunization for refractory hypercalcemia caused by metastatic parathyroid carcinoma. Endocr J 2010; 57: 287–292.

59.

Betea

Bradwell

Harvey

, et al Hormonal and biochemical normalization and tumor shrinkage induced by anti-parathyroid hormone immunotherapy in a patient with metastatic parathyroid carcinoma. J Clin Endocrinol Metab 2004; 89: 3413–3420.

60.

Rozhinskaya

Pigarova

Sabanova

, et al Diagnosis and treatment challenges of parathyroid carcinoma in a 27-year-old woman with multiple lung metastases. Endocrinol Diabetes Metab Case Rep 2017; 2017: 16-0113.

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Combination approach for CDC73 -related parathyroid carcinoma in an adolescent female patient: a case report and literature review

Abstract

Keywords

Background

Case presentation

Discussion

Conclusion

Supplemental Material

sj-pdf-1-tam-10.1177_17588359241265222 – Supplemental material for Combination approach for CDC73-related parathyroid carcinoma in an adolescent female patient: a case report and literature review

Footnotes

Acknowledgements

Declarations

ORCID iD

Supplemental material

References

Supplementary Material