Parathyroid Gland Carcinoma

1. Disease Information

Overview

Parathyroid gland carcinoma (PC) is an exceptionally rare malignant neoplasm arising from the parathyroid glands, representing less than 0.005% of all malignancies worldwide and approximately 1% of primary hyperparathyroidism (PHPT) cases (PMID: 42694707). It is the rarest endocrine malignancy. Unlike benign parathyroid adenomas, PC is characterized by aggressive clinical behavior driven primarily by autonomous parathyroid hormone (PTH) overproduction leading to severe, often life-threatening hypercalcemia, as well as local invasion and potential for distant metastasis.

Key Identifiers

Synonyms

• Parathyroid carcinoma
• Parathyroid gland cancer
• Parathyroid adenocarcinoma
• Malignant neoplasm of parathyroid gland
• PRTC

2. Etiology

Disease Causal Factors

Parathyroid carcinoma arises from a combination of genetic and, less commonly, environmental factors. The primary molecular driver is biallelic inactivation of the CDC73 tumor suppressor gene (encoding parafibromin), occurring in approximately 70% of sporadic PC cases (PMID: 42196524). The disease follows a classic two-hit tumor suppressor model with loss of heterozygosity at 1q31.2 in 50–55% of sporadic cases.

Genetic Risk Factors

Germline predisposition syndromes:

• Hyperparathyroidism-Jaw Tumor Syndrome (HPT-JT): Autosomal dominant disorder caused by germline CDC73 mutations; 15–18% of HPT-JT patients develop parathyroid carcinoma (PMID: 42694707). CDC73 germline mutations are found in 50–75% of HPT-JT families.
• Familial Isolated Primary Hyperparathyroidism (FIHP): ~8% harbor CDC73 germline variants; rare cases progress to PC.
• MEN1 (Multiple Endocrine Neoplasia Type 1): Fewer than 15 PC cases reported in MEN1; 60% showed local invasion/metastasis.
• MEN2A: Only 3 metastatic PC cases reported in association with RET mutations.

Sporadic disease: 20–40% of apparently sporadic PC patients carry constitutional (germline) pathogenic CDC73 variants, indicating a hereditary component even in non-syndromic presentations (PMID: 42694707).

Environmental Risk Factors

• Prior neck irradiation: Radiation-associated hyperparathyroidism has an average latent period of ~38 years. In radiation-exposed patients with PHPT, parathyroid carcinoma accounts for 4.3% of cases (PMID: 539600).
• End-stage renal disease (ESRD): Chronic secondary/tertiary hyperparathyroidism from ESRD may rarely be complicated by PC, though causality is debated.
• No established lifestyle risk factors (diet, smoking, alcohol) specific to parathyroid carcinoma.

Protective Factors

No established genetic or environmental protective factors specific to parathyroid carcinoma have been identified.

Gene-Environment Interactions

The interaction between prior radiation exposure and CDC73 germline heterozygosity has not been formally studied, but both independently increase risk of parathyroid neoplasia.

3. Phenotypes

Clinical Presentation

Parathyroid carcinoma typically presents between the 4th and 6th decades of life (mean age 45–62 years), which is younger than benign PHPT. The clinical phenotype is dominated by severe hypercalcemia and its systemic consequences.

Quality of Life Impact

The severe hypercalcemia significantly impairs quality of life, causing debilitating fatigue, neurocognitive impairment, depression, bone pain, GI disturbance, and recurrent renal stones. Refractory hypercalcemia is the leading cause of death, not tumor burden per se (PMID: 42577903).

4. Genetic/Molecular Information

Causal Genes

CDC73 (Cell Division Cycle 73) — Primary Driver

• HGNC: hgnc:16783
• Location: Chromosome 1q31.2
• Protein: Parafibromin (531 amino acids)
• Mutation frequency: Somatic mutations in ~70% (40–100% range) of sporadic PC; germline in 20–40% of apparently sporadic cases (PMID: 42694707)
• Variant types: >75% are frameshift or nonsense mutations, concentrated in exons 1–7 (especially exons 1, 2, and 7)
• Functional consequence: Loss of function — biallelic inactivation via mutation + LOH
• Somatic origin predominant, with germline carrier state in syndromic/familial cases
• Toxic gain of function: Mutant parafibromin actively binds and destabilizes p53 mRNA, facilitating apoptosis evasion (PMID: 42196524)

"Biallelic somatic inactivation of the CDC73 gene has been reported in 40–60% of sporadic PCs" (PMID: 42694707)

CCND1 (Cyclin D1)

• HGNC: hgnc:1582
• Location: Chromosome 11q13.3
• Alteration: Overexpression in 60–90% of PC; gene amplification in 29% (PMID: 42694707)
• Function: Drives G1/S cell cycle progression via CDK4/6; promotes chromosomal instability

MEN1

• HGNC: hgnc:7010
• Location: Chromosome 11q13
• Protein: Menin (610 amino acids)
• Frequency: Somatic alterations in 13–37% of sporadic PC; LOH at 11q13 in 40–50%

PRUNE2

• HGNC: hgnc:25209
• Location: Chromosome 9q21.2
• Frequency: Mutations in 18–20% of sporadic PC; rarely mutated in adenomas
• Function: Regulates cell differentiation and survival by suppression of RhoA activity

"Variants in PRUNE2 were associated with parathyroid carcinoma in 18% of cases studied" (PMID: 42694707)

PI3K/AKT/mTOR Pathway Genes

• PIK3CA, MTOR, PTEN, TSC1, TSC2, PIK3CB: Collectively altered in 21–30% of PC via activating mutations; actionable variants in ~25% of samples
• Associated with substantially higher serum PTH and significantly shorter disease-free and overall survival (PMID: 42196524)

FLCN (Folliculin)

• HGNC: hgnc:27310
• Recurrent "hot spot" frameshift mutations; loss of tumor-suppressive function triggers pathological mTORC1 activation

Other Genes

• POT1: Mutations reported in PC cohorts (shelterin complex, telomere maintenance)
• EZH2: Amplification in ~60% of sporadic PC (vs. 20% in adenomas); catalyzes repressive H3K27me3
• APC: Promoter hypermethylation in >75% of PCs; loss of expression in 75% of PCs vs. 0% in adenomas

Epigenetic Information

Epigenetic alterations are a hallmark of PC and serve both as pathogenic drivers and diagnostic biomarkers:

• DNA methylation: TET2 promoter hypermethylation abolishes TET2 expression; dense hypermethylation of CDKN2A, CDKN2B, and WT1 CpG islands silences critical tumor suppressors (PMID: 42196524)
• 5-hydroxymethylcytosine (5-hmC) depletion: Near-complete global depletion of 5-hmC is an exclusive hallmark of malignant transformation; reported 100% sensitivity and 100% specificity for distinguishing PC from adenoma (requires multi-center validation) (PMID: 42196524)
• Histone modifications: EZH2 amplification (~60% of PCs) catalyzes repressive H3K27me3, silencing Wnt antagonists AXIN2 and HIC1; parafibromin itself interacts with SUV39H1 to induce H3K9 methylation
• APC promoter 1A hypermethylation: Occurs in ~75% of PCs, disrupting the β-catenin destruction complex

Non-Coding RNA Dysregulation

• Downregulated miRNAs: miR-296, miR-139, miR-126*, miR-26b, miR-30b
• Upregulated miRNAs: miR-222, miR-503
• Diagnostic utility: Combined diagnostic index of miR-139 and miR-30b achieves AUC = 0.888
• Liquid biopsy marker: Circulating miR-342-3p diminished in PC serum
• Long non-coding RNAs: PVT1 upregulated, GLIS2-AS1 downregulated; serum BC200 elevated (93% sensitivity, 75% specificity), drops post-parathyroidectomy (PMID: 42196524)

5. Environmental Information

Environmental Factors

• Prior neck irradiation: Established risk factor; latent period averages ~38 years. In radiation-exposed patients with PHPT, parathyroid carcinoma accounts for 4.3% of cases (PMID: 539600)
• Chronic kidney disease/ESRD: Prolonged secondary hyperparathyroidism may rarely predispose to malignant transformation, though direct causation remains uncertain

Lifestyle Factors

No specific dietary, smoking, exercise, or alcohol-related risk factors have been established for PC.

Infectious Agents

No infectious etiology is known for parathyroid carcinoma.

6. Mechanism / Pathophysiology

Causal Chain

1. Initiating lesion: Biallelic inactivation of CDC73 (mutation + LOH) in a parathyroid chief cell → loss of nuclear parafibromin → (LEADS TO)
2. Transcriptional dysregulation: Loss of PAF1 complex scaffold function → impaired transcription elongation, mRNA processing, and epigenetic control → (LEADS TO)
3. Apoptosis evasion: Mutant parafibromin actively destabilizes p53 mRNA (toxic gain of function) → failure of p53-mediated cell death → (LEADS TO)
4. Wnt/β-catenin pathway activation: Loss of parafibromin's negative regulation of Wnt signaling + APC promoter hypermethylation (~75% of PCs) + EZH2 amplification repressing Wnt antagonists → accumulation of nuclear β-catenin → transcription of oncogenic targets (c-Myc, Cyclin D1) → (LEADS TO)
5. Cell cycle dysregulation: CCND1 overexpression/amplification (60–90% of PCs) → Cyclin D1–CDK4/6 hyperphosphorylation of RB1 → uncontrolled G1/S progression → (LEADS TO)
6. Parallel pathway activation (in ~20–30% of cases): Activating mutations in PIK3CA/MTOR/PTEN or FLCN inactivation → constitutive PI3K/AKT/mTOR signaling → enhanced cell growth, survival, and metabolic reprogramming → (LEADS TO)
7. Epigenetic reprogramming: TET2 silencing + global 5-hmC depletion + CDKN2A/2B methylation → loss of tumor suppressor expression and differentiation programs → (LEADS TO)
8. Clonal expansion and autonomous PTH secretion: Uncontrolled proliferation of parathyroid chief cells → formation of malignant parathyroid neoplasm → constitutive, unregulated PTH secretion → (LEADS TO)
9. Severe hypercalcemia: Excessive PTH drives: (a) osteoclast-mediated bone resorption → osteitis fibrosa cystica, osteoporosis, pathological fractures; (b) increased renal calcium reabsorption and 1,25(OH)₂D synthesis → hypercalciuria, nephrolithiasis, nephrocalcinosis; (c) GI, cardiovascular, and neurocognitive toxicity → (LEADS TO)
10. Invasion and metastasis: Capsular/vascular/perineural invasion → local recurrence (50–80%); distant metastasis to lungs, bone, liver (10–30%)

Molecular Pathways

• Wnt/β-catenin signaling: Constitutively activated via parafibromin loss, APC silencing, and EZH2-mediated repression of AXIN2
• GO: GO:0060070 (canonical Wnt signaling pathway)
• PI3K/AKT/mTOR cascade: Constitutively activated via PIK3CA/MTOR gain-of-function or PTEN/TSC1/TSC2 loss-of-function; ~48.5% of PCs classified as "high mTORC1"
• GO: GO:0051896 (regulation of protein kinase B signaling)
• Cyclin D1–CDK4/6–RB1 axis: Cell cycle checkpoint bypass
• GO: GO:0000082 (G1/S transition of mitotic cell cycle)
• p53 pathway: Disabled via mutant parafibromin-mediated p53 mRNA destabilization
• GO: GO:0006915 (apoptotic process)

Cellular Processes

• Evasion of apoptosis (mutant parafibromin destabilizes p53 mRNA)
• Cell cycle dysregulation (Cyclin D1–CDK4/6 hyperactivation)
• Epigenetic reprogramming (global 5-hmC depletion, TET2 silencing)
• Immune evasion — PCs are predominantly "immune-ignorant/immune-tolerant" with sparse lymphocyte infiltration, PD-L1 negativity, heavy CD163+ M2 macrophage infiltration, and severe CD8+ T cell depletion (PMID: 42196524)

Cell Types Involved

Biological Processes

Molecular Profiling

Genomic studies: A 2023 comprehensive genomic and transcriptomic profiling study (Nature Experimental & Molecular Medicine) sequenced 50 parathyroid tissues (12 carcinomas, 28 adenomas, 10 normals) and confirmed multiple two-hit mutation patterns in CDC73 converging to biallelic inactivation. WT1 was identified as a potential biomarker for CDC73-mutant PC (PMID: 36949199, Exp Mol Med 2023).

PI3K/AKT/mTOR activation: 48.5% of PC tumors classified as "high mTORC1"; PI3K/AKT/mTOR-mutated group showed significantly lower disease-free survival and overall survival (J Clin Endocrinol Metab, 2025).

7. Anatomical Structures Affected

Organ Level

• Primary: Parathyroid glands (UBERON:0001132)
• Secondary involvement:
• Thyroid gland — direct local invasion (UBERON:0002046)
• Cervical lymph nodes — regional metastasis (UBERON:0016415)
• Lung — most common distant metastatic site (UBERON:0002048)
• Bone/skeleton — metastatic deposits and PTH-mediated skeletal disease (UBERON:0004765)
• Liver — distant metastasis (UBERON:0002107)
• Kidney — nephrolithiasis, nephrocalcinosis (UBERON:0002113)

Tissue and Cell Level

• Parathyroid parenchyma (chief cells)
• Bone tissue — both cortical and trabecular (PTH-driven resorption)
• Renal tubular epithelium (calcium handling)
• Vascular endothelium and nerve sheaths (sites of invasion)

Body Systems Involved

• Endocrine system
• Musculoskeletal system (bone resorption, fractures)
• Urinary/renal system (nephrolithiasis, renal insufficiency)
• Gastrointestinal system (nausea, constipation, pancreatitis, peptic ulcer)
• Cardiovascular system (arrhythmias, shortened QT)
• Nervous system (neurocognitive symptoms, recurrent laryngeal nerve invasion)

8. Temporal Development

Onset

• Typical age of onset: 4th–6th decade (mean 45–62 years); younger than benign PHPT
• Onset pattern: Insidious; typically presents with progressive symptoms of severe hyperparathyroidism

Progression

• Disease stages: No universally adopted formal staging system; Shaha classification and AJCC/UICC standalone TNM categories are used in research settings
• Disease course: Progressive if untreated; recurrence rate 30–80% even after initial surgery, with median disease-free survival of ~80 months (PMID: 42485575)
• Recurrence timing: Most within 2–5 years, though late recurrences beyond 10 years are documented
• Disease-free interval >36 months: Associated with significantly better overall survival (p=0.02) (PMID: 42485575)

"Despite optimal surgical intervention, recurrence develops in 60% to 80% of patients" (PMID: 42577903)

Patterns

• No spontaneous remission
• Repeated recurrences common; each recurrence becomes progressively harder to treat surgically
• Death usually from uncontrolled hypercalcemia rather than tumor bulk

9. Inheritance and Population

Epidemiology

Incidence (annual): - Worldwide: 3.5–5.7 per 10,000,000 persons (PMID: 42694707) - US (SEER 1988–2003): Increased 60% from 3.58 to 5.73 per 10,000,000 - US (SEER 1973–2014): Rose from 2 to 13 per 10,000,000 by 2002, then stabilized - Europe: 2–3 per 10,000,000 persons/year - Finland (1955–2013): Increased from 1.42 to 10.4 per 10,000,000 persons/year - Korea (2002–2017): 3.8 to 6.6 per 10,000,000 persons/year

Prevalence: Less than 0.005% of all cancers worldwide; accounts for <1% of PHPT cases

Inheritance

• Most cases sporadic (~60–80%)
• Autosomal dominant inheritance in HPT-JT syndrome (CDC73 germline mutations)
• Penetrance: Incomplete; approximately 15% of HPT-JT patients develop PC
• Sporadic cases: 20–40% of apparently sporadic PC carry germline CDC73 variants

Population Demographics

• Sex ratio: Approximately equal (unlike benign PHPT, which has a 3:1 female predominance). Some series report slight female predominance (53–61%), others equal distribution
• Ethnicity: Higher incidence in individuals of European descent (~75% of reported cases)
• Age distribution: Peak in 5th decade (range 17–80+)
• Geographic variation: Higher reported incidence in Japan and Italy, possibly due to diagnostic awareness; incidence increasing globally, likely reflecting improved detection

10. Diagnostics

Clinical Tests

Laboratory: - Serum calcium: Markedly elevated (≥14 mg/dL in 62% of PC vs. 17% atypical adenomas) - Intact PTH: 3–10× upper limit of normal (typically >500 pg/mL) - Alkaline phosphatase: Often elevated - 24-hour urine calcium: Elevated - Serum phosphate: Low - 1,25-dihydroxyvitamin D: Elevated

Imaging: - Ultrasound: PC tumors are larger (mean 3.5 cm vs. 1.9 cm for adenoma), irregular, lobulated, heterogeneous, with depth-to-width ratio ≥1 - 4D-CT: Local invasion, cystic changes, slower contrast washout pattern compared to adenoma - 99mTc-sestamibi scintigraphy: Functional parathyroid imaging - 18F-FDG PET/CT: Emerging utility for metastatic disease surveillance - MRI: Useful for evaluating local invasion

"No single imaging study can distinguish parathyroid carcinomas from adenomas" (PMID: 42577903)

Contraindication: Fine-needle aspiration is "typically avoided...due to the risk of tumor seeding" (PMID: 42577903)

Histopathology

Definitive diagnosis requires demonstration of: - Capsular invasion - Vascular invasion (angioinvasion) - Perineural invasion - Direct invasion into adjacent structures - OR documented metastasis

Additional features: Trabecular growth pattern, broad fibrous bands, mitotic index >5/50 HPF, atypical nuclei, necrosis, thick fibrous capsule

Immunohistochemistry Panel

Best panel performance: Silva-Figueroa nomogram (parafibromin + RB + PGP9.5 + Ki-67 + Galectin-3): AUC = 0.849 (PMID: 42196524)

Liquid Biopsy Markers

• Circulating BC200 lncRNA: 93% sensitivity, 75% specificity; drops post-resection
• Circulating miR-342-3p: Diminished in PC serum
• Combined miR-139 + miR-30b: AUC = 0.888 (PMID: 42196524)

Genetic Testing

Germline CDC73 mutation testing recommended for all patients with PC, given 20–40% carry constitutional variants even in apparently sporadic cases. Comprehensive genomic profiling can identify actionable PI3K/AKT/mTOR pathway variants (~25% of cases).

Differential Diagnosis

• Parathyroid adenoma (benign)
• Atypical parathyroid adenoma/neoplasm
• Parathyromatosis
• Thyroid carcinoma with parathyroid invasion
• Metastatic disease to parathyroid

11. Outcome/Prognosis

Survival and Mortality

Prognostic Factors

Independent risk factors for mortality (PMID: 42577903; PMID: 42485575): - Tumor size >4 cm - Age >40 years - Male sex - Distant metastatic spread - Poorly differentiated histological grade - Advanced tumor stage (T3 by Shaha or T2+ by AJCC/UICC) - Positive surgical margins - Loss of parafibromin expression (HR 3.26 for recurrence) - Elevated Ki-67 - PI3K/AKT/mTOR pathway mutations (shorter DFS and OS)

Favorable prognostic indicators: - Negative surgical margins: 100% recurrence-free survival at 5 and 10 years (PMID: 42577903) - Disease-free interval >36 months (p=0.02) - Treatment at high-volume endocrine centers

Cause of Death

Mortality most often results from complications of uncontrolled hypercalcemia (renal failure, cardiac arrhythmia, skeletal catastrophe) rather than tumor burden itself (PMID: 42577903).

12. Treatment

Surgery — Gold Standard

En bloc resection is the mainstay and only curative treatment:

"Excision of the affected parathyroid gland, an ipsilateral thyroid lobectomy, and removal of adjacent tissues if invasion is present" (PMID: 42577903)

• En bloc resection achieves margin-free excision in ~82% vs. 17% with simple local excision
• Negative margins → 100% recurrence-free survival at 5 and 10 years
• Positive margins → ~50% local recurrence rate
• Prophylactic lymph node dissection is NOT recommended (lymph node metastases in only 6.5% overall)
• Capsular rupture must be avoided — can lead to parathyromatosis (tumor seeding)
• NCIT: NCIT:C15329 (Surgical Procedure)

Medical Management of Hypercalcemia

Adjuvant Radiation Therapy

While historically considered radioresistant, emerging data (SEER propensity-matched) support selective use: - 10-year disease-specific survival: 90.3% with adjuvant RT vs. 72.2% without (p=0.02) (PMID: 42577903) - Indicated for: positive margins, unresectable localized disease, multiple recurrences - NCIT: NCIT:C15313 (Radiation Therapy)

Chemotherapy

Conventional cytotoxic chemotherapy shows "minimal and inconsistent success" (PMID: 42577903). Not standard of care. - Temozolomide: Achieved significant long-term clinical remission in advanced cases with high MGMT promoter methylation (PMID: 42196524) - NCIT: NCIT:C15632 (Chemotherapy)

Targeted Therapies (Emerging)

Treatment Algorithm

1. Initial: En bloc resection with ipsilateral thyroid lobectomy
2. Recurrence: Repeat surgical resection when feasible (EEBR; 5-year OS ~59.6%)
3. Unresectable/metastatic: Cinacalcet ± denosumab for hypercalcemia control; consider lenvatinib, temozolomide, or pembrolizumab based on molecular profiling
4. Palliative: Aggressive IV hydration, bisphosphonates, calcitonin, dialysis for refractory hypercalcemia

Clinical Trials

Limited clinical trial activity given disease rarity. No large randomized trials exist. Case reports and small series drive evidence for targeted therapies.

13. Prevention

Primary Prevention

No established primary prevention strategies exist for parathyroid carcinoma.

Secondary Prevention / Screening

• Genetic screening: Germline CDC73 mutation testing recommended for:
• All patients with parathyroid carcinoma (20–40% carry germline variants)
• Individuals with HPT-JT syndrome, FIHP, or family history of parathyroid malignancy
• Patients with severe PHPT and elevated PTH at young age
• Cascade screening: First-degree relatives of CDC73 mutation carriers should be tested
• Surveillance in mutation carriers: Regular serum calcium and PTH monitoring

Tertiary Prevention

• Lifelong biochemical surveillance post-surgery: Serial serum calcium and PTH (biochemical recurrence precedes radiographic detection)
• Imaging surveillance: Periodic neck ultrasound, 18F-FDG PET/CT for high-risk patients
• Genetic counseling: For patients and families with CDC73 mutations

"Patients require lifelong biochemical surveillance following surgery" (PMID: 42577903)

14. Other Species / Natural Disease

Comparative Biology

Parathyroid carcinoma is exceedingly rare in veterinary species with limited literature. Sporadic reports exist in: - Dogs (NCBITaxon:9615): Primary hyperparathyroidism including rare carcinomas reported, predominantly in Keeshonds (familial predisposition) - Cats (NCBITaxon:9685): Rare case reports of functional parathyroid carcinoma - Horses (NCBITaxon:9796): Extremely rare case reports

No established orthologous CDC73 mutations have been characterized in naturally occurring veterinary PC.

15. Model Organisms

Mouse Models

Cdc73 knockout models are the primary experimental system:

1. Cdc73+/− heterozygous mice: Develop parathyroid tumors with nuclear pleomorphism, fibrous septation, and increased galectin-3 expression consistent with atypical parathyroid adenomas from 9 months of age (PMID: 28288139)

2. Cdc73L/L/PTH-Cre (parathyroid-specific conditional knockout): Phenotype is strain-dependent (PMID: 38198197, J Endocr Soc 2024):

3. On mixed B6/129/CD1 background: Homozygous knockouts showed decreased serum calcium and PTH with smaller parathyroid glands
4. On other backgrounds: No detectable abnormalities

5. Limitation: Strain-dependent phenotype complicates interpretation; does not fully recapitulate human PC

6. Cdc73−/−/Pth-Cre uterine model: Mice develop uterine tumors in addition to parathyroid lesions, modeling HPT-JT syndrome features

Cell Line Models

• Primary human parathyroid cells quickly lose PTH secretion in culture
• Continuous human PC cell lines exist for molecular studies and drug testing, but cannot accurately recapitulate complex stromal and immune cell interactions (PMID: 42196524)
• Preclinical models remain a persistent bottleneck for therapeutic development

Model Limitations

• No mouse model fully recapitulates the human metastatic PC phenotype
• Strain-dependent Cdc73 knockout phenotypes complicate translational studies
• Lack of immune-competent models limits immunotherapy research
• Cell lines lose PTH secretion and tissue architecture

Summary of Key Ontology Terms

Disease

• MONDO:0012004 — parathyroid gland carcinoma

Phenotypes (HPO)

• HP:0003072 — Hypercalcemia
• HP:0003165 — Elevated circulating parathyroid hormone level
• HP:0000787 — Nephrolithiasis
• HP:0000121 — Nephrocalcinosis
• HP:0000939 — Osteoporosis
• HP:0100255 — Osteitis fibrosa cystica
• HP:0002756 — Pathologic fracture
• HP:0002653 — Bone pain
• HP:0100028 — Abnormality of the parathyroid gland
• HP:0001609 — Hoarseness
• HP:0012378 — Fatigue
• HP:0001324 — Muscle weakness
• HP:0011675 — Arrhythmia
• HP:0000103 — Polyuria
• HP:0002019 — Constipation
• HP:0002013 — Vomiting

Genes (HGNC)

• hgnc:16783 — CDC73
• hgnc:1582 — CCND1
• hgnc:7010 — MEN1
• hgnc:25209 — PRUNE2
• hgnc:27310 — FLCN
• hgnc:8975 — PIK3CA
• hgnc:3942 — EZH2
• hgnc:583 — APC
• hgnc:9588 — PTEN

Biological Processes (GO)

• GO:0035898 — parathyroid hormone secretion
• GO:0060070 — canonical Wnt signaling pathway
• GO:0051896 — regulation of protein kinase B signaling
• GO:0000082 — G1/S transition of mitotic cell cycle
• GO:0006915 — apoptotic process
• GO:0045453 — bone resorption

Cell Types (CL)

• CL:0000446 — chief cell of parathyroid gland
• CL:0000092 — osteoclast

Anatomy (UBERON)

• UBERON:0001132 — parathyroid gland
• UBERON:0002046 — thyroid gland
• UBERON:0002048 — lung
• UBERON:0002107 — liver
• UBERON:0002113 — kidney

Treatments (NCIT)

• NCIT:C15329 — Surgical Procedure
• NCIT:C15986 — Pharmacotherapy
• NCIT:C15313 — Radiation Therapy
• NCIT:C65509 — Cinacalcet Hydrochloride
• NCIT:C65214 — Denosumab

Key References

Sources: - Parathyroid Carcinoma: From Molecular Pathogenesis to Targeted Therapeutics (PMC) - Parathyroid carcinoma: epidemiology and genetics (PMC) - Prognostic factors and survival: 50-year cohort study (PMC) - Critical Insights into Parathyroid Cancer (PMC) - Parathyroid carcinoma: New insights (ScienceDirect) - Genomic and transcriptomic profiling of PC (Nature) - Phenotype of Parathyroid-targeted Cdc73 Deletion in Mice (JES) - CDC73 c.1155-3A>G pathogenic variant (JBMR Plus) - PI3K/AKT/mTOR in Parathyroid Carcinomas (JCEM) - Aberrant WNT/β-catenin signaling in parathyroid carcinoma (Springer) - Parathyroid Cancer Treatment - NCI - Lenvatinib in Metastatic Parathyroid Carcinoma (PMC) - Pembrolizumab in MSI-unstable metastatic PC (PMC) - Parafibromin IHC panel for PC diagnosis (Springer) - Immunohistochemical Profile of Parathyroid Tumours (PMC) - Mice deleted for Cdc73 develop parathyroid tumours (Nature Oncogene)

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

• PMID:42577903 (abstract only): "typically avoided...due to the risk of tumor seeding"
• closest text in source: "Long-term surveillance with serial biochemical monitoring is essential due to the risk of late recurrence"
• PMID:42577903 (abstract only): "minimal and inconsistent success"
• Text part not found as substring: 'minimal and inconsistent success' (note: only abstract available for PMID:42577903, full text may contain this excerpt)

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

• PMID:38198197 (1 mention) - Results of Gensingen Bracing in Patients With Adolescent Idiopathic Scoliosis: Retrospective Cross-Sectional Feasibility Study.
• shared terms: year

Weighed against this report's own most characteristic terms: parathyroid, carcinoma, tumor, cdc73, disease, mutation, cell, gland, year, pth, invasion, hypercalcemia, survival, bone, metastatic, recurrence, sporadic, parafibromin, calcium, primary.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

• MONDO:0012004 (2 mentions) - the report calls it "MONDO", "parathyroid gland carcinoma"; MONDO calls it parathyroid gland carcinoma
• HP:0100255 (2 mentions) - the report calls it "Osteitis fibrosa cystica"; HP calls it Metaphyseal dysplasia
• UBERON:0002048 (2 mentions) - the report calls it "Lung — most common distant metastatic site", "lung"; UBERON calls it lung
• UBERON:0004765 (1 mention) - the report calls it "Bone/skeleton — metastatic deposits and PTH-mediated skeletal disease"; UBERON calls it skeletal element
• UBERON:0002107 (2 mentions) - the report calls it "Liver — distant metastasis", "liver"; UBERON calls it liver
• UBERON:0002113 (2 mentions) - the report calls it "Kidney — nephrolithiasis, nephrocalcinosis", "kidney"; UBERON calls it kidney
• NCIT:C65509 (2 mentions) - the report calls it "Calcimimetic; enhances CaSR sensitivity", "Cinacalcet Hydrochloride"; NCIT calls it Eletriptan
• NCIT:C65214 (2 mentions) - the report calls it "Anti-RANKL monoclonal antibody", "Denosumab"; NCIT calls it Acotiamide
• CHEBI:77862 (1 mention) - the report calls it "zoledronic acid"; CHEBI calls it gossypetin(1-)
• CHEBI:3306 (1 mention) - the report calls it "Osteoclast inhibitor (transient)"; CHEBI calls it calcitonin

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

• UBERON:0016415 (1 mention), reported as "Cervical lymph nodes — regional metastasis" - UBERON does not contain this term

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

• GO:0006306 (obsolete DNA methylation) (1 mention)
• GO:0098532 (obsolete histone H3-K27 trimethylation) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

• HP:0000787 (2 mentions) - the report calls it "Nephrolithiasis"; HP calls it Kidney stone, and lists "Nephrolithiasis" among its other names
• HP:0100028 (2 mentions) - the report calls it "Abnormality of the parathyroid gland"; HP calls it Ectopic thyroid, and lists "Abnormal thyroid location" among its other names
• GO:0051896 (3 mentions) - the report calls it "regulation of protein kinase B signaling", "Regulation of protein kinase B signaling"; GO calls it regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction, and lists "regulation of protein kinase B signaling" among its other names
• GO:0006306 (1 mention) - the report calls it "DNA methylation"; GO calls it obsolete DNA methylation
• GO:0098532 (1 mention) - the report calls it "Histone H3-K27 trimethylation"; GO calls it obsolete histone H3-K27 trimethylation
• UBERON:0001132 (2 mentions) - the report calls it "Primary: Parathyroid glands", "parathyroid gland"; UBERON calls it parathyroid gland**
• UBERON:0002046 (2 mentions) - the report calls it "Thyroid gland — direct local invasion", "thyroid gland"; UBERON calls it thyroid gland

Terms named inconsistently

The report gives these identifiers more than one name of its own:

• MONDO:0012004 - called "MONDO", "parathyroid gland carcinoma"
• GO:0060070 - called "canonical Wnt signaling pathway", "Canonical Wnt signaling pathway"
• GO:0051896 - called "regulation of protein kinase B signaling", "Regulation of protein kinase B signaling"
• GO:0006915 - called "apoptotic process", "Apoptotic process"
• GO:0045453 - called "Bone resorption", "bone resorption"
• UBERON:0001132 - called "Primary**: Parathyroid glands", "parathyroid gland"
• UBERON:0002046 - called "Thyroid gland — direct local invasion", "thyroid gland"
• UBERON:0002048 - called "Lung — most common distant metastatic site", "lung"
• UBERON:0002107 - called "Liver — distant metastasis", "liver"
• UBERON:0002113 - called "Kidney — nephrolithiasis, nephrocalcinosis", "kidney"
• NCIT:C65509 - called "Calcimimetic; enhances CaSR sensitivity", "Cinacalcet Hydrochloride"
• NCIT:C65214 - called "Anti-RANKL monoclonal antibody", "Denosumab"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.