Parathyroid gland carcinoma is a rare, aggressive malignancy of the parathyroid chief cell, accounting for roughly 1% of primary hyperparathyroidism. It presents not as an incidental mass but through the hormone it secretes: autonomous parathyroid hormone output drives severe hypercalcaemia with its renal and skeletal consequences, and a palpable neck mass is often present. Biallelic inactivation of CDC73, which encodes the tumour suppressor parafibromin, is the characteristic molecular lesion and is implicated in up to 75% of familial and sporadic cases; loss of nuclear parafibromin on immunohistochemistry is the practical correlate. Recurrent changes in MEN1, CCND1 and EZH2 and in the PI3K/AKT/mTOR axis have also been described. Diagnosis rests on histological evidence of invasion rather than on cytological atypia, which is why the distinction from benign parathyroid neoplasia is difficult and why the 2022 WHO criteria are explicit. Complete en bloc resection at first operation is the only treatment with curative intent; local recurrence is common while distant metastasis is rare, and medical therapy is directed at the hypercalcaemia rather than at the tumour.
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name: Parathyroid Gland Carcinoma
creation_date: "2026-10-09T00:00:00Z"
category: Cancer
categories:
- Endocrine Cancer
- Endocrine Neoplasm
synonyms:
- parathyroid carcinoma
- parathyroid gland cancer
- parathyroid adenocarcinoma
- PRTC
- malignant neoplasm of parathyroid gland
disease_term:
preferred_term: parathyroid gland carcinoma
term:
id: MONDO:0012004
label: parathyroid gland carcinoma
parents:
- malignant tumor of parathyroid gland
notes: >-
Granularity. Curated at the histologic-entity level, which design decisions
section 3a makes the default for a new cancer entry. MONDO:0012004 is a true
leaf with no children, and none of its three parents - malignant tumor of
parathyroid gland, adenocarcinoma, hereditary disease - is bound as any entry's
disease_term, so nothing competes for the concept.
The differential is the disease. Distinguishing carcinoma from benign parathyroid
neoplasia is the central diagnostic problem here, not a footnote, and the 2022
WHO classification resolves it histologically rather than cytologically: carcinoma
requires angioinvasion, lymphatic invasion, perineural invasion, local malignant
invasion into adjacent structures, or documented metastasis. Those criteria are
curated in the diagnosis section rather than paraphrased here.
Nomenclature note, because the older term is still in wide use and appears in
sources cited here. The 2022 WHO classification "no longer endorses the use of
'atypical parathyroid adenoma'", replacing it with atypical parathyroid tumour,
a neoplasm of uncertain malignant potential. This entry uses the current term,
and where a cited study predates the change its own wording is preserved inside
the quoted snippet.
Do not reuse the deep-research report in research/ without checking it. Three of
its citations are real PMIDs for the wrong papers, and its own validator caught
only one. PMID:36949199 is listed in its reference table as "Genomic and
transcriptomic profiling reveal molecular characteristics of parathyroid
carcinoma" and cited for a WT1 biomarker claim; the paper is "RHOJ controls
EMT-associated resistance to chemotherapy", a mouse skin squamous cell carcinoma
study with no parathyroid content. PMID:38198197 is cited as a strain-dependent
Cdc73 mouse paper and is an adolescent idiopathic scoliosis bracing trial; this
is the one the validator flagged. PMID:539600 is cited for parathyroid carcinoma
accounting for 4.3% of radiation-associated hyperparathyroidism, and that paper
states the opposite - that parathyroid carcinoma has not been reported in
irradiated patients. The report's own reference_validation block also records
quotes_valid 0 of 2 with PMID:42577903 named, so quotes attributed to that paper
in the report are unreliable; the two sentences cited from it here were taken from
the cache instead. Four of its ontology bindings are wrong and are listed in the
calcimimetic treatment's review_notes and in the skeletal phenotype's explanation.
Relationship to the curated neighbours. Parathyroid_Hyperplasia.yaml binds
MONDO:0006354 and is a distinct, non-competing entity; note that the same WHO
revision narrows "parathyroid hyperplasia" largely to secondary hyperplasia of
chronic renal failure, which is a question for that entry rather than this one.
Multiple_Endocrine_Neoplasia_Type_1 and Type_2 are curated and mention carcinoma
nowhere. Hyperparathyroidism-jaw tumour syndrome, the germline CDC73
predisposition in which parathyroid carcinoma arises, is absent from kb/;
section 3a keeps germline predisposition syndromes separate from the somatic
cancers they predispose to, so it is recorded here as a gap rather than absorbed.
Deliberate omissions. The metastatic sites are unbound because no cited reference
names an organ. Osteitis fibrosa cystica is described in the literature but not
bound: the only term the deep-research report offered for it was wrong, and no
cited source here names the lesion. There is no mappings block, because the
report's identifier table disagrees with MONDO's own xrefs in more than one place
and was not trusted.
classifications:
icdo_morphology:
classification_value: Adenocarcinoma
harrisons_chapter:
- classification_value: ENDOCRINOLOGY_METABOLISM
description: >-
Parathyroid gland carcinoma is a rare, aggressive malignancy of the parathyroid
chief cell, accounting for roughly 1% of primary hyperparathyroidism. It presents
not as an incidental mass but through the hormone it secretes: autonomous
parathyroid hormone output drives severe hypercalcaemia with its renal and
skeletal consequences, and a palpable neck mass is often present. Biallelic
inactivation of CDC73, which encodes the tumour suppressor parafibromin, is the
characteristic molecular lesion and is implicated in up to 75% of familial and
sporadic cases; loss of nuclear parafibromin on immunohistochemistry is the
practical correlate. Recurrent changes in MEN1, CCND1 and EZH2 and in the
PI3K/AKT/mTOR axis have also been described. Diagnosis rests on histological
evidence of invasion rather than on cytological atypia, which is why the
distinction from benign parathyroid neoplasia is difficult and why the 2022 WHO
criteria are explicit. Complete en bloc resection at first operation is the only
treatment with curative intent; local recurrence is common while distant metastasis is rare, and
medical therapy is directed at the hypercalcaemia rather than at the tumour.
pathophysiology:
- name: CDC73 Biallelic Inactivation
biological_scale: MOLECULAR
description: >-
The characteristic lesion. Germline and somatic mutation of the tumour
suppressor CDC73 is implicated in up to 75% of familial and sporadic cases,
and mutation frequency separates carcinoma from benign parathyroid neoplasia:
60% of carcinomas in one cohort against 14% of atypical tumours and 6% of
typical adenomas.
genetic_context:
variant_origin: SOMATIC
functional_impact_category: LOSS_OF_FUNCTION
genes:
- preferred_term: CDC73
term:
id: hgnc:16783
label: CDC73
cell_types:
- preferred_term: parathyroid chief cell
term:
id: CL:0000446
label: chief cell of parathyroid gland
molecular_functions:
- preferred_term: parafibromin binding to RNA polymerase II within the PAF1 complex
modifier: LOSS_OF_FUNCTION
term:
id: GO:0000993
label: RNA polymerase II complex binding
downstream:
- target: Loss of Nuclear Parafibromin
causal_link_type: DIRECT
description: Inactivation of the gene removes its protein product from the nucleus.
evidence:
- reference: PMID:42694707
reference_title: "Parathyroid carcinoma: epidemiology and genetics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Germline and somatic mutations in the tumour suppressor gene CDC73 (encoding parafibromin) are implicated in up to 75% of familial and sporadic PC cases."
explanation: >-
Establishes CDC73 as the dominant lesion and names its protein product.
- reference: PMID:22987117
reference_title: "CDC73 mutations and parafibromin immunohistochemistry in parathyroid tumors: clinical correlations in a single-centre patient cohort."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mutations of CDC73 were observed in 9/15 (60 %) CA, 2/14 (14 %) AA, and 1/17 (6 %) TA tumors."
explanation: >-
Quantifies the mutation frequency across carcinoma, atypical and typical
tumours in one cohort, which is what makes the lesion discriminating rather
than merely present.
- reference: PMID:42196524
reference_title: "Parathyroid Carcinoma: From Molecular Pathogenesis and Diagnostic Biomarkers to Targeted Therapeutics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the biallelic inactivation of CDC73"
explanation: >-
Sources the biallelic character of the lesion, which this node is named for
and which the frequency sentences above do not establish.
- reference: PMID:15923622
reference_title: The HRPT2 tumor suppressor gene product parafibromin associates with human PAF1 and RNA polymerase II.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "It also associates with modified forms of the large subunit of RNA polymerase II"
explanation: >-
Establishes the molecular function bound on this node. Parafibromin was shown
to interact with the PAF1 complex components and with RNA polymerase II, which
is the activity CDC73 inactivation removes.
- reference: PMID:15923622
reference_title: The HRPT2 tumor suppressor gene product parafibromin associates with human PAF1 and RNA polymerase II.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "These interactions depend on a C-terminal domain of parafibromin, which is deleted in ca. 80% of clinically relevant mutations."
explanation: >-
Ties the lost interaction directly to the mutations that cause disease, which
is what makes the molecular function the right level to bind here rather than
a general transcription process.
- name: Loss of Nuclear Parafibromin
biological_scale: MOLECULAR
description: >-
Absence of nuclear parafibromin immunoreactivity is the practical correlate of
the genetic lesion, and the 2022 WHO classification gives the finding its own
designation, parafibromin-deficient parathyroid neoplasm. The operating
characteristics are asymmetric and the sources disagree on the specificity: one
series reports 58% sensitivity with 100% specificity and loss confined to
malignant tumours, while an earlier cohort found loss in 3 of 17 typical
adenomas. The defensible reading is insensitive but highly specific, which is
why a negative result does not exclude carcinoma and why diagnosis rests on the
WHO invasion criteria rather than on this stain.
downstream:
- target: Autonomous Chief Cell Proliferation
causal_link_type: DIRECT
description: >-
Loss of the tumour suppressor releases the restraint on chief cell
proliferation.
evidence:
- reference: PMID:22987117
reference_title: "CDC73 mutations and parafibromin immunohistochemistry in parathyroid tumors: clinical correlations in a single-centre patient cohort."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Absence of parafibromin nuclear staining was noted in 8/12 (67 %) CA, 2/13 (15 %) AA, and 3/17 (18 %) TA tumors."
explanation: >-
Quantifies loss of nuclear staining across the three tumour classes.
- reference: PMID:22987117
reference_title: "CDC73 mutations and parafibromin immunohistochemistry in parathyroid tumors: clinical correlations in a single-centre patient cohort."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Molecular screening and IHC are both useful tools in the differential diagnosis of parathyroid tumors, but both have limited sensitivity and specificity."
explanation: >-
Supports the limitation this node states.
- reference: PMID:35654240
reference_title: Diagnostic significance of parafibromin expression in parathyroid carcinoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the sensitivity of parafibromin staining is 58%, and the specificity is 100%."
explanation: >-
The operating characteristics, which the cohort above describes only in general
terms. This is what makes the finding insensitive but highly specific rather
than simply unreliable.
- reference: PMID:35654240
reference_title: Diagnostic significance of parafibromin expression in parathyroid carcinoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The loss of parafibromin expression only occurred in malignant tumors, including all carcinomas with metastasis (17/17)"
explanation: >-
Specificity evidence that disagrees with the single cohort cited above, where
3 of 17 typical adenomas also lost staining. Both are recorded rather than one
being chosen - see this node's description.
- name: Autonomous Chief Cell Proliferation
biological_scale: CELLULAR
description: >-
A clonal population of parathyroid chief cells proliferates without normal
restraint. In the Cdc73 mouse models this is directly measurable, with
proliferation rates more than fourfold those of wild-type parathyroid glands.
cell_types:
- preferred_term: parathyroid chief cell
term:
id: CL:0000446
label: chief cell of parathyroid gland
biological_processes:
- preferred_term: unrestrained chief cell proliferation
modifier: INCREASED
term:
id: GO:0008283
label: cell population proliferation
downstream:
- target: Unrestrained Parathyroid Hormone Secretion
causal_link_type: DIRECT
- target: Palpable neck mass
causal_link_type: DIRECT
description: Tumour growth produces the palpable mass.
- target: Local Invasive Growth
causal_link_type: DIRECT
evidence:
- reference: PMID:28288139
reference_title: "Mice deleted for cell division cycle 73 gene develop parathyroid and uterine tumours: model for the hyperparathyroidism-jaw tumour syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Parathyroid tumours in Cdc73+/-, Cdc73+/L/PTH-Cre and Cdc73L/L/PTH-Cre mice had significantly increased proliferation, with rates >fourfold higher than that in parathyroid glands of wild-type littermates (P<0.0001)."
explanation: >-
Direct measurement of the proliferative consequence of Cdc73 loss in
parathyroid tissue.
- reference: PMID:15923622
reference_title: The HRPT2 tumor suppressor gene product parafibromin associates with human PAF1 and RNA polymerase II.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "RNAi-induced downregulation of parafibromin promotes entry into S phase, implying a role for parafibromin as an inhibitor of cell cycle progression."
explanation: >-
The in vitro counterpart of the mouse proliferation result, and the step that
connects the lost molecular function to unrestrained proliferation.
- name: Unrestrained Parathyroid Hormone Secretion
biological_scale: ORGANISM
description: >-
The tumour secretes parathyroid hormone without feedback restraint, and this is
what produces the clinical disease. The hormonal output, not tumour bulk, is the
proximate cause of the presenting illness and of death in advanced disease.
cell_types:
- preferred_term: parathyroid chief cell
term:
id: CL:0000446
label: chief cell of parathyroid gland
biological_processes:
- preferred_term: autonomous parathyroid hormone secretion
modifier: INCREASED
term:
id: GO:0035898
label: parathyroid hormone secretion
downstream:
- target: Hypercalcemia
causal_link_type: DIRECT
- target: Elevated circulating parathyroid hormone level
causal_link_type: DIRECT
- target: Renal disease
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Renal end-organ disease follows the sustained hypercalcaemia rather than the
hormone directly.
- target: Skeletal disease
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Skeletal disease follows sustained PTH excess acting on bone.
evidence:
- reference: PMID:42694707
reference_title: "Parathyroid carcinoma: epidemiology and genetics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "PC is mostly characterized by severe hypercalcaemia, due to tumoral parathyroid hormone (PTH) over-secretion and a high rate of local recurrence and metastasis, making early diagnosis and surgical treatment crucial."
explanation: >-
Attributes the hypercalcaemia to tumoral PTH over-secretion, which is the
causal step this node asserts.
- reference: PMID:35326576
reference_title: "Parathyroid Carcinoma: Incidence, Survival Analysis, and Management: A Study from the SEER Database and Insights into Future Therapeutic Perspectives."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mortality is usually from complications of hypercalcemia and not due to tumor burden"
explanation: >-
Sources this node's claim that hormonal output rather than tumour bulk is the
proximate cause of death.
- reference: PMID:28288139
reference_title: "Mice deleted for cell division cycle 73 gene develop parathyroid and uterine tumours: model for the hyperparathyroidism-jaw tumour syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Cdc73+/-, Cdc73+/L/PTH-Cre and Cdc73L/L/PTH-Cre mice had higher mean serum calcium concentrations than wild-type littermates, and Cdc73+/- mice also had increased mean serum parathyroid hormone (PTH) concentrations."
explanation: >-
The model reproduces both the hormonal output and the resulting
hypercalcaemia downstream of the same genetic lesion.
- name: Local Invasive Growth
biological_scale: TISSUE
description: >-
Invasion is the definitional event: it is what makes the tumour a carcinoma
rather than an atypical parathyroid tumour, which is why diagnosis depends on
histology of the resected specimen and not on cytology. Local recurrence is
common after resection.
downstream:
- target: Distant Metastasis
causal_link_type: DIRECT
description: >-
A minority of invasive tumours go on to metastasise distantly.
evidence:
- reference: PMID:35326576
reference_title: "Parathyroid Carcinoma: Incidence, Survival Analysis, and Management: A Study from the SEER Database and Insights into Future Therapeutic Perspectives."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "PC is usually indolent and slowly progressive, with low rates of lymph node (<5%) and systemic metastasis (<2%)"
explanation: >-
Separates the two behaviours this node and its downstream node assert: local
recurrence is frequent, distant metastasis is not.
- name: Distant Metastasis
biological_scale: ORGANISM
description: >-
Distant metastasis occurs in a small minority, under 2% in the SEER-based
series, which is why this is modelled downstream of invasion rather than
alongside it.
evidence:
- reference: PMID:35326576
reference_title: "Parathyroid Carcinoma: Incidence, Survival Analysis, and Management: A Study from the SEER Database and Insights into Future Therapeutic Perspectives."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "PC is usually indolent and slowly progressive, with low rates of lymph node (<5%) and systemic metastasis (<2%)"
explanation: >-
Quantifies distant metastasis as rare. The metastatic sites are deliberately
not bound, because no reference cited in this entry names an organ.
phenotypes:
- category: Endocrine
name: Hypercalcemia
description: >-
Severe hypercalcaemia is the dominant clinical feature and the usual route to
diagnosis.
phenotype_term:
preferred_term: severe hypercalcemia
term:
id: HP:0003072
label: Hypercalcemia
severity: SEVERE
evidence:
- reference: PMID:42694707
reference_title: "Parathyroid carcinoma: epidemiology and genetics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "PC is mostly characterized by severe hypercalcaemia, due to tumoral parathyroid hormone (PTH) over-secretion and a high rate of local recurrence and metastasis, making early diagnosis and surgical treatment crucial."
explanation: Names severe hypercalcaemia as the characteristic feature.
- category: Endocrine
name: Elevated circulating parathyroid hormone level
description: >-
Markedly raised PTH accompanies the hypercalcaemia and is the biochemical
signature of autonomous secretion.
phenotype_term:
preferred_term: elevated parathyroid hormone
term:
id: HP:0003165
label: Elevated circulating parathyroid hormone level
evidence:
- reference: PMID:28288139
reference_title: "Mice deleted for cell division cycle 73 gene develop parathyroid and uterine tumours: model for the hyperparathyroidism-jaw tumour syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: "Cdc73+/-, Cdc73+/L/PTH-Cre and Cdc73L/L/PTH-Cre mice had higher mean serum calcium concentrations than wild-type littermates, and Cdc73+/- mice also had increased mean serum parathyroid hormone (PTH) concentrations."
explanation: >-
Raised PTH downstream of Cdc73 loss, in the model system. Graded INDIRECT
because it is a mouse rather than a human measurement; the human evidence is
the item below.
- reference: PMID:42577903
reference_title: Critical Insights into Parathyroid Cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "markedly elevated serum calcium and parathyroid hormone levels"
explanation: >-
The human biochemical picture, so the phenotype does not rest on
model-organism evidence alone.
- category: Neoplasm
name: Palpable neck mass
description: >-
A palpable neck mass is present in a substantial minority and, unlike in benign
parathyroid disease, is one of the features that raises suspicion of malignancy
before operation.
phenotype_term:
preferred_term: palpable parathyroid mass in the neck
term:
id: HP:0100733
label: Neoplasm of the parathyroid gland
evidence:
- reference: PMID:42577903
reference_title: Critical Insights into Parathyroid Cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "markedly elevated serum calcium and parathyroid hormone levels, palpable neck mass, and evidence of local invasion may raise suspicion for malignancy"
explanation: >-
Names the palpable neck mass among the preoperative features that distinguish
carcinoma from benign parathyroid disease.
- category: Renal
name: Renal disease
description: >-
Renal disease is one of the end-organ consequences of sustained hypercalcaemia
and may be the presenting problem. Stone disease is the classical form, but the
sources cited here say only "renal disease".
phenotype_term:
preferred_term: renal disease of hyperparathyroidism
term:
id: HP:0000077
label: Abnormality of the kidney
coarse_binding_basis: SOURCE_UNSPECIFIED
evidence:
- reference: PMID:35326576
reference_title: "Parathyroid Carcinoma: Incidence, Survival Analysis, and Management: A Study from the SEER Database and Insights into Future Therapeutic Perspectives."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "palpable neck mass, concomitant skeletal, renal disease, and features of parathyroid crisis"
explanation: >-
Names renal disease among the presenting features. Graded INDIRECT because
the source does not give a frequency and says only "renal disease".
- category: Musculoskeletal
name: Skeletal disease
description: >-
Skeletal disease from sustained PTH excess is the other major end-organ
consequence, and pathological fracture is reported.
phenotype_term:
preferred_term: skeletal disease of hyperparathyroidism
term:
id: HP:0000924
label: Abnormality of the skeletal system
coarse_binding_basis: SOURCE_UNSPECIFIED
evidence:
- reference: PMID:35326576
reference_title: "Parathyroid Carcinoma: Incidence, Survival Analysis, and Management: A Study from the SEER Database and Insights into Future Therapeutic Perspectives."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "palpable neck mass, concomitant skeletal, renal disease, and features of parathyroid crisis"
explanation: >-
Names skeletal disease among the presenting features. Graded INDIRECT for the
same reason as the renal item, and bound to a general skeletal term rather
than a specific lesion. Osteitis fibrosa cystica was considered and not bound:
the deep-research report offered HP:0100255 for it, which is Metaphyseal
dysplasia, and no cited source here names the lesion.
diagnosis:
- name: Histological criteria for malignancy
description: >-
Diagnosis is histological and rests on evidence of invasion, not on cytological
atypia. This is the criterion that separates carcinoma from atypical parathyroid
tumour, and it is why complete submission of the specimen matters.
evidence:
- reference: PMID:35175514
reference_title: Overview of the 2022 WHO Classification of Parathyroid Tumors.
supports: SUPPORT
evidence_source: OTHER
snippet: "The histological definition of parathyroid carcinoma still requires one of the following findings: (i) angioinvasion (vascular invasion) characterized by tumor invading through a vessel wall and associated thrombus, or intravascular tumor cells admixed with thrombus, (ii) lymphatic invasion, (iii) perineural (intraneural) invasion, (iv) local malignant invasion into adjacent anatomic structures, or (v) histologically/cytologically documented metastatic disease."
explanation: >-
The WHO diagnostic criteria verbatim. Graded OTHER because a classification
consensus is not a primary study.
- name: Parafibromin immunohistochemistry
description: >-
Loss of nuclear parafibromin supports the diagnosis and now carries its own WHO
designation, but it is an adjunct rather than a defining criterion.
evidence:
- reference: PMID:35175514
reference_title: Overview of the 2022 WHO Classification of Parathyroid Tumors.
supports: SUPPORT
evidence_source: OTHER
snippet: "The concept of parafibromin deficiency has been expanded upon and term \"parafibromin deficient parathyroid neoplasm\" is applied to a parathyroid neoplasm showing complete absence of nuclear parafibromin immunoreactivity."
explanation: Defines the designation and the finding it rests on.
genetic:
- name: CDC73
notes: >-
The tumour suppressor whose loss characterises this cancer, acting through its
product parafibromin. Both germline and somatic mutations occur; the germline
form gives hyperparathyroidism-jaw tumour syndrome, which is not curated in
kb/ and is deliberately not folded into this entry.
gene_term:
preferred_term: CDC73
term:
id: hgnc:16783
label: CDC73
relationship_type: SOMATIC_DRIVER
evidence:
- reference: PMID:42694707
reference_title: "Parathyroid carcinoma: epidemiology and genetics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Germline and somatic mutations in the tumour suppressor gene CDC73 (encoding parafibromin) are implicated in up to 75% of familial and sporadic PC cases."
explanation: Frequency and dual germline/somatic character of the lesion.
- reference: PMID:42694707
reference_title: "Parathyroid carcinoma: epidemiology and genetics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Additional recurrent mutations in genes such as MEN1 and PRUNE2, alterations in cell cycle regulators such as CCND1 and EZH2, and disruptions in signalling pathways including PI3K/AKT/mTOR have been identified."
explanation: >-
Sources the additional recurrent lesions this entry's description names. They
are not curated as separate genetic records; the sentence is cited so the
claim is not unsupported prose.
- reference: PMID:35326576
reference_title: "Parathyroid Carcinoma: Incidence, Survival Analysis, and Management: A Study from the SEER Database and Insights into Future Therapeutic Perspectives."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Germline CDC73 mutations are present in up to 25% of seemingly sporadic PC cases"
explanation: >-
A fact about this disease rather than about the excluded HPT-JT syndrome: a
quarter of apparently sporadic cases carry a germline lesion, which is why
germline testing is recommended without a family history. The pathophysiology
node records SOMATIC because that is the transforming event in the tumour,
not because the germline arm is absent.
prevalence:
- population: Patients with primary hyperparathyroidism
measure_type: UNKNOWN
prevalence_class: ULTRA_RARE
notes: >-
About 1% of primary hyperparathyroidism. Recorded as UNKNOWN measure_type
because the source states a proportion of a disease population rather than a
population prevalence or incidence, and no numeric rate is entered for the same
reason. The qualitative tier is permissible with UNKNOWN per the prevalence
rules in CLAUDE.md.
evidence:
- reference: PMID:42694707
reference_title: "Parathyroid carcinoma: epidemiology and genetics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Following the same trend, the incidence of parathyroid carcinoma (PC), a very rare but aggressive malignancy accounting for approximately 1% of PHPT cases, appears to be rising."
explanation: >-
Source for the 1% share of primary hyperparathyroidism and for the rising
trend recorded under progression.
- population: Not stated by the source
measure_type: ANNUAL_INCIDENCE
prevalence_class: BELOW_1_IN_1000000
rate_per_100000: 0.046
rate_low: 0.035
rate_high: 0.057
rate_denominator: POPULATION_PER_YEAR
notes: >-
3.5 to 5.7 cases per 10,000,000 population per year, normalized to per 100,000.
The figure comes from the cited paper's introduction, where it is attributed to
two further references, so it is background rather than that paper's own SEER
result; the population is left as not stated because the source names no
geography. No qualitative tier is carried: CLAUDE.md forbids pairing one with
ANNUAL_INCIDENCE.
evidence:
- reference: PMID:35326576
reference_title: "Parathyroid Carcinoma: Incidence, Survival Analysis, and Management: A Study from the SEER Database and Insights into Future Therapeutic Perspectives."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "annual incidence of parathyroid carcinoma is ~3.5-5.7 cases per 10,000,000 population."
explanation: >-
Source for the population incidence, quoted in full.
progression:
- phase: Course after resection
notes: >-
Recurrence dominates the natural history. In a 50-year single-centre series
recurrence occurred in just over half of cases and disease persisted in a
further tenth, which is consistent with the 25-80% recurrence range reported
elsewhere and with the low rate of distant metastasis.
evidence:
- reference: PMID:42485575
reference_title: "Prognostic factors and survival in parathyroid carcinoma: a 50-year single-center cohort study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Disease recurrence occurred in 16 (53.3%) cases, with disease persistence in three (10.0%)."
explanation: >-
Quantifies recurrence and persistence in a long-running cohort, which is the
course this phase records.
animal_models:
- name: Cdc73 conventional and parathyroid-specific knockout mouse
species: Mouse
genotype: Cdc73+/-, Cdc73+/L/PTH-Cre and Cdc73L/L/PTH-Cre
publication: PMID:28288139
description: >-
Conventional and parathyroid-specific Cdc73 knockout mice, aged to 18-21 months,
generated as models of the hyperparathyroidism-jaw tumour syndrome.
modeled_mechanisms:
- target: Autonomous Chief Cell Proliferation
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
model_scale: CELLULAR
description: >-
Reproduces Cdc73-driven parathyroid proliferation with raised serum calcium
and PTH, which is the proximal mechanism this entry asserts.
limitations: >-
The tumours that develop are described as consistent with atypical parathyroid
adenomas, not carcinoma, so the model captures the proliferative and hormonal
arm of the mechanism and not the invasive behaviour that defines the human
malignancy. It is a model of the germline HPT-JT lesion rather than of
sporadic somatic disease, and the mice develop uterine neoplasms that are not
part of this entry.
evidence:
- reference: PMID:28288139
reference_title: "Mice deleted for cell division cycle 73 gene develop parathyroid and uterine tumours: model for the hyperparathyroidism-jaw tumour syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Cdc73+/-, Cdc73+/L/PTH-Cre and Cdc73L/L/PTH-Cre mice developed parathyroid tumours, which had nuclear pleomorphism, fibrous septation and increased galectin-3 expression, consistent with atypical parathyroid adenomas, from 9 months of age."
explanation: >-
States both what the model reproduces and, in the same sentence, the ceiling
on its fidelity: the lesions are atypical adenomas rather than carcinoma.
histopathology:
- name: Invasive growth patterns
description: >-
The diagnostic findings are patterns of invasion - capsular, vascular and
perineural - rather than cytological features, which is why the diagnosis is
made on the resected specimen and why complete submission matters.
evidence:
- reference: PMID:42577903
reference_title: Critical Insights into Parathyroid Cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Definitive diagnosis relies on histopathologic features such as capsular, vascular, or perineural invasion."
explanation: >-
States the histopathological basis of diagnosis, which the WHO criteria in
the diagnosis section enumerate.
- name: Adenocarcinoma, not otherwise specified
description: >-
Essentially all registry-coded cases are adenocarcinoma NOS, so morphological
subtyping plays no practical role in this disease.
evidence:
- reference: PMID:35326576
reference_title: "Parathyroid Carcinoma: Incidence, Survival Analysis, and Management: A Study from the SEER Database and Insights into Future Therapeutic Perspectives."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "607 (99.7%) cases were adenocarcinoma not otherwise specified (NOS)"
explanation: >-
Registry morphology distribution, which is why no histological subtypes are
curated.
treatments:
- name: En Bloc Surgical Resection
description: >-
Complete resection at the first operation is the only treatment with curative
intent, which is why early recognition matters: the diagnosis is usually made
on the specimen, so the decision to operate adequately precedes it.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: en bloc resection of the parathyroid tumour
term:
id: NCIT:C139567
label: En Bloc Resection
target_mechanisms:
- target: Local Invasive Growth
description: Removes the invasive tumour and its local extension.
evidence:
- reference: PMID:42694707
reference_title: "Parathyroid carcinoma: epidemiology and genetics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "PC is mostly characterized by severe hypercalcaemia, due to tumoral parathyroid hormone (PTH) over-secretion and a high rate of local recurrence and metastasis, making early diagnosis and surgical treatment crucial."
explanation: >-
Supporting context on the importance of early surgery. Graded INDIRECT because
the sentence says nothing about extent of resection or curative intent, which
the next item carries directly.
- reference: PMID:41878704
reference_title: Treating microsatellite unstable metastatic parathyroid carcinoma with anti-PD1 therapy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Complete resection of malignancy is the only curative treatment, and to date, there is no effective systemic therapy for advanced disease."
explanation: >-
Sources the claim this entry's description makes, that resection is the only
treatment with curative intent, and in the same sentence the absence of
effective systemic therapy.
- name: Calcimimetic Control of Hypercalcaemia
description: >-
Cinacalcet increases the sensitivity of the calcium-sensing receptor and is used
to control the hypercalcaemia rather than to treat the tumour. This is the
characteristic shape of medical therapy in this disease: directed at the
hormonal consequence, not at the malignancy.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: calcimimetic therapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: cinacalcet
term:
id: CHEBI:48390
label: cinacalcet
target_mechanisms:
- target: Hypercalcemia
description: >-
Acts on the calcium-sensing receptor to lower serum calcium, downstream of
the PTH output rather than on the tumour.
evidence:
- reference: PMID:35326576
reference_title: "Parathyroid Carcinoma: Incidence, Survival Analysis, and Management: A Study from the SEER Database and Insights into Future Therapeutic Perspectives."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "are effective in reducing serum calcium levels by at least 1 mg/dl in 62% of patients with PC"
explanation: >-
Quantifies the calcium-lowering effect of calcimimetic therapy in this disease.
- reference: PMID:30641523
reference_title: Parathyroid Carcinoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "When the tumor is no more resectable, medical treatment of hypercalcemia has a pivotal role in the management of these patients."
explanation: >-
Establishes the role of medical therapy as control of the hypercalcaemia once
resection is no longer possible, which is the framing this treatment takes.
review_notes: >-
The deep-research report's bindings for this drug class were wrong - it gave
NCIT:C65509 for "Cinacalcet Hydrochloride", which is Eletriptan, and
NCIT:C65214 for "Denosumab", which is Acotiamide - so none of its treatment
section was used. The bindings here were resolved against OLS instead.
- name: Intravenous Bisphosphonate Therapy
description: >-
Intravenous bisphosphonates lower serum calcium by inhibiting mobilisation of
calcium from bone. Zoledronate is reported as the more effective agent in the
hypercalcaemia of this disease.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: antiresorptive therapy for hypercalcaemia
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: zoledronic acid
term:
id: CHEBI:46557
label: zoledronic acid
target_mechanisms:
- target: Hypercalcemia
description: >-
Blocks the skeletal release of calcium that the PTH excess drives, acting on
the consequence rather than on the tumour.
evidence:
- reference: PMID:35326576
reference_title: "Parathyroid Carcinoma: Incidence, Survival Analysis, and Management: A Study from the SEER Database and Insights into Future Therapeutic Perspectives."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Intravenous bisphosphonates, including zolendronate and pamidronate, are effective in treating hypercalcemia by inhibiting the mobilization of calcium from the bone into the circulation."
explanation: >-
States the effect and the mechanism by which it acts on the hypercalcaemia.
- reference: PMID:35326576
reference_title: "Parathyroid Carcinoma: Incidence, Survival Analysis, and Management: A Study from the SEER Database and Insights into Future Therapeutic Perspectives."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Zoledronate is more effective than other IV bisphosphonates in hypercalcemia associated with PC"
explanation: >-
Agent-level comparison specific to this disease, which is why zoledronic acid
is the bound agent.
- name: Denosumab
description: >-
An anti-RANKL monoclonal antibody used for hypercalcaemia refractory to other
measures, acting by blocking osteoclast formation, function and survival.
therapeutic_modality: MONOCLONAL_ANTIBODY
treatment_term:
preferred_term: antiresorptive therapy for refractory hypercalcaemia
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: denosumab
term:
id: NCIT:C61313
label: Denosumab
target_mechanisms:
- target: Hypercalcemia
description: >-
Blocks osteoclast-mediated bone resorption, lowering serum calcium.
evidence:
- reference: PMID:35326576
reference_title: "Parathyroid Carcinoma: Incidence, Survival Analysis, and Management: A Study from the SEER Database and Insights into Future Therapeutic Perspectives."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "has been used to treat refractory hypercalcemia associated with PC"
explanation: >-
Establishes the indication in this disease, specifically for refractory
hypercalcaemia.
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Record notes
Granularity. Curated at the histologic-entity level, which design decisions section 3a makes the default for a new cancer entry. MONDO:0012004 is a true leaf with no children, and none of its three parents - malignant tumor of parathyroid gland, adenocarcinoma, hereditary disease - is bound as any entry's disease_term, so nothing competes for the concept. The differential is the disease. Distinguishing carcinoma from benign parathyroid neoplasia is the central diagnostic problem here, not a footnote, and the 2022 WHO classification resolves it histologically rather than cytologically: carcinoma requires angioinvasion, lymphatic invasion, perineural invasion, local malignant invasion into adjacent structures, or documented metastasis. Those criteria are curated in the diagnosis section rather than paraphrased here. Nomenclature note, because the older term is still in wide use and appears in sources cited here. The 2022 WHO classification "no longer endorses the use of 'atypical parathyroid adenoma'", replacing it with atypical parathyroid tumour, a neoplasm of uncertain malignant potential. This entry uses the current term, and where a cited study predates the change its own wording is preserved inside the quoted snippet. Do not reuse the deep-research report in research/ without checking it. Three of its citations are real PMIDs for the wrong papers, and its own validator caught only one. PMID:36949199 is listed in its reference table as "Genomic and transcriptomic profiling reveal molecular characteristics of parathyroid carcinoma" and cited for a WT1 biomarker claim; the paper is "RHOJ controls EMT-associated resistance to chemotherapy", a mouse skin squamous cell carcinoma study with no parathyroid content. PMID:38198197 is cited as a strain-dependent Cdc73 mouse paper and is an adolescent idiopathic scoliosis bracing trial; this is the one the validator flagged. PMID:539600 is cited for parathyroid carcinoma accounting for 4.3% of radiation-associated hyperparathyroidism, and that paper states the opposite - that parathyroid carcinoma has not been reported in irradiated patients. The report's own reference_validation block also records quotes_valid 0 of 2 with PMID:42577903 named, so quotes attributed to that paper in the report are unreliable; the two sentences cited from it here were taken from the cache instead. Four of its ontology bindings are wrong and are listed in the calcimimetic treatment's review_notes and in the skeletal phenotype's explanation. Relationship to the curated neighbours. Parathyroid_Hyperplasia.yaml binds MONDO:0006354 and is a distinct, non-competing entity; note that the same WHO revision narrows "parathyroid hyperplasia" largely to secondary hyperplasia of chronic renal failure, which is a question for that entry rather than this one. Multiple_Endocrine_Neoplasia_Type_1 and Type_2 are curated and mention carcinoma nowhere. Hyperparathyroidism-jaw tumour syndrome, the germline CDC73 predisposition in which parathyroid carcinoma arises, is absent from kb/; section 3a keeps germline predisposition syndromes separate from the somatic cancers they predispose to, so it is recorded here as a gap rather than absorbed. Deliberate omissions. The metastatic sites are unbound because no cited reference names an organ. Osteitis fibrosa cystica is described in the literature but not bound: the only term the deep-research report offered for it was wrong, and no cited source here names the lesion. There is no mappings block, because the report's identifier table disagrees with MONDO's own xrefs in more than one place and was not trusted.
Pre-PR red-team review round: Parathyroid Gland Carcinoma · 2026-10-12T11:59:23Z · View source
Self-review round before opening the PR, run in a subagent for fresh context per step 7 of the initiate-new-disorder-creation skill. Verdict was REQUEST_CHANGES with nine blocking findings and nine important ones; all are addressed. Snippet count rose from 17/17 to 33/33 verified, and the reference count cited rose from 5 to 13 of the 18 cached. The single underlying finding was under-consumption: the entry rested on one mini-review summary sentence carrying four of its seventeen evidence items while a full-text SEER paper and five disease-specific reviews sat cached and unread. Blocking fixes. (1) The invasion node carried locations bound to lung and liver with lung labelled the commonest distant metastatic site; no reference cited in this entry mentions either organ, and the claim traced to the deep-research report's prose, from the very line its own term validator had flagged. A free-text preferred_term is not read by any gate, which is why it survived. The locations block was removed and the omission recorded. (2) The description's claim that resection is the only treatment with curative intent had no cited snippet; it is now sourced from PMID:41878704, which states it and the absence of effective systemic therapy in one sentence. (3) The calcimimetic treatment had zero evidence, and the stated reason in review_notes was wrong: the report's bad NCIT codes did not block anything because CHEBI:48390 cinacalcet was bound correctly anyway. Two cached sentences now support it, one quantitative. (4) A real population incidence was added from the SEER full text, 3.5 to 5.7 cases per 10,000,000 per year normalized to 0.046 per 100,000, with rate_denominator POPULATION_PER_YEAR and no qualitative tier, since CLAUDE.md forbids pairing one with ANNUAL_INCIDENCE. The existing case-fraction record keeps its tier because it states a fraction rather than a rate. (5) The invasion node asserted that recurrence and metastasis are common, which the SEER source contradicts for metastasis: lymph node under 5% and systemic metastasis under 2% against local recurrence of 25 to 80%. The node bundled two behaviours and was split into Local Invasive Growth and a downstream Distant Metastasis node. The entry had inherited the lump from a review sentence that names both in one phrase. (6) The renal and skeletal consequences the description promised were absent; kidney stone and a coarse skeletal binding were added, the latter with coarse_binding_basis SOURCE_UNSPECIFIED because the source says skeletal disease without specifying a lesion. Osteitis fibrosa cystica remains unbound: the report offered HP:0100255 for it, which is Metaphyseal dysplasia, and no cited source names the lesion. (7) A REFUTE item on the parafibromin node refuted a reading the node already disclaimed; regraded SUPPORT. (8) The claim that parafibromin loss is neither fully sensitive nor specific was a single-cohort cherry-pick. Two cached studies report 100% specificity with loss confined to malignant tumours, against one cohort finding loss in 3 of 17 typical adenomas. The description now states the disagreement and the defensible reading, insensitive but highly specific, and both sides are cited. (9) The entry had zero GO bindings; GO:0008283 and GO:0035898 were added on the proliferation and secretion nodes, matching how the sibling Parathyroid_Hyperplasia entry binds its homologous nodes. Important fixes: a specific treatment term NCIT:C139567 En Bloc Resection replacing generic Surgical Procedure; an invented preferred_term, antineoplastic-adjacent medical control of hypercalcaemia, replaced with calcimimetic therapy; the biallelic character of the CDC73 lesion sourced from PMID:42196524, having been in the node name but not its evidence; the MEN1/PRUNE2/CCND1/EZH2 and PI3K-AKT-mTOR sentence cited rather than left as unsupported description prose; two further modeled_mechanisms links on the mouse model, including a FAILS_TO_RECAPITULATE link against the invasion node evidenced by the SEER paper's statement that Cdc73-deleted mice do not develop parathyroid carcinoma, which converts a prose limitation into the typed negative claim CLAUDE.md calls first-class; progression repurposed from a secular detection trend to real natural history; a histopathology section added; the germline-in-sporadic arm recorded, since germline CDC73 is present in up to 25% of apparently sporadic cases, which is a fact about this disease rather than about the excluded HPT-JT syndrome; severity SEVERE on hypercalcaemia; a palpable neck mass phenotype; classifications; and the notes now disclose what the entry still lacks. The report's defects are now recorded in the entry's notes rather than only in history, including one the review found that I had missed: PMID:539600 is cited in the report for parathyroid carcinoma accounting for 4.3% of radiation-associated hyperparathyroidism, and that paper states the opposite, that parathyroid carcinoma has not been reported in irradiated patients. I had not cited it, but by instinct rather than by checking. The report's own validator also recorded quotes_valid 0 of 2 against PMID:42577903, so quotes attributed to that paper in the report are unreliable; the two sentences taken from it here came from the cache. Process note on my own errors in this round. I typed four reference_title values from memory instead of copying them from the cache, which just validate caught one at a time, so I wrote an audit that diffs every reference_title in the entry against its cache file; it then found four semicolon-for-colon mismatches that just validate had let through. Correcting those broke YAML on unquoted colons, and my quoting regex backtracked and mangled twenty already-quoted lines before I unmangled them; nothing was lost. I also typed HP:0000924's label from memory and got it wrong, and used HP:0000787's current HPO label Kidney stone where the committed cache says Nephrolithiasis, which 41 other entries use; the repo is cache-first so the cached form is correct. Validation after the round: 33/33 snippets verified; validate-terms, check-entity-refs, check-causal-targets, check-enum-values, check-duplicate-keys, check-qualifier-terms, check-coarse-phenotypes and the batched validate-disorders all pass; check-cancer-origin reports SOMATIC_LESION OK with a single origin CL:0000446.
Create: Parathyroid Gland Carcinoma · 2026-10-10T16:13:43Z · View source
De novo curation of parathyroid gland carcinoma (MONDO:0012004) at the histologic-entity level per design decisions section 3a. Pre-claim verification found the ID absent from kb/ on origin/main, all 22 MONDO synonyms clear apart from one reference_title mention inside Parathyroid_Hyperplasia.yaml, zero MONDO children, no parent bound as any entry's disease_term, CDC73 uncurated outside hypothesis-run gene-list CSVs, and no prior PR or issue. Deep research: falcon was requested but has no API key here, so the run used --fallback and claude_code produced the report, which records fell_back, requested_provider and provider_attempts. Both validation blocks reported needs_review: true. Because the report was still running, I fetched the core references independently from PubMed first, which is why the entry rests mainly on sources verified before the report arrived. I audited all 18 cached references by title and found TWO confabulated citations, of which the report's validator flagged one: PMID:38198197 (actually a Gensingen bracing trial in adolescent idiopathic scoliosis, the one flagged) and PMID:36949199 (actually a mouse skin squamous cell carcinoma RHOJ/EMT paper with zero parathyroid mentions, cited in the report for a WT1 biomarker claim and given a fabricated title in the report's own citation table). The validator missed the second because generic cancer vocabulary scores on-topic against a cancer report. This is the third consecutive report with real-PMID-wrong-paper confabulations, though at 2 of 18 the rate is better than the five-of-twenty-five seen twice before. Four ontology bindings the report offered were wrong and are not used: NCIT:C65509 was given as Cinacalcet Hydrochloride and is Eletriptan, a migraine agent; NCIT:C65214 was given as Denosumab and is Acotiamide; CHEBI:77862 was given as zoledronic acid and is gossypetin(1-); HP:0100255 was given as Osteitis fibrosa cystica and is Metaphyseal dysplasia. GO:0098532 is obsolete and was not used. Every CURIE in the entry was resolved against OLS at the time of writing, and the verified replacements are CHEBI:48390 cinacalcet, with NCIT:C61313 denosumab and CHEBI:46557 zoledronic acid recorded in review_notes for a later round rather than added without a cited source. A factual error in my own claim issue was caught during curation: I had written that the differential is against atypical adenoma, but the 2022 WHO classification no longer endorses that term and replaces it with atypical parathyroid tumour, a neoplasm of uncertain malignant potential. The entry uses the current term, explains the change, and preserves older wording only inside quoted snippets. The same WHO source notes that parathyroid hyperplasia is now reserved largely for secondary hyperplasia of chronic renal failure, which bears on Parathyroid_Hyperplasia.yaml rather than on this entry and is recorded in notes rather than acted on. Pathophysiology is a causal chain from CDC73 biallelic inactivation through loss of nuclear parafibromin to autonomous chief cell proliferation, branching into unrestrained PTH secretion and into local invasion and metastasis. Cell of origin is derived rather than asserted: the CDC73 node carries genetic_context variant_origin SOMATIC with CL:0000446 bound, and check-cancer-origin reports SOMATIC_LESION OK with a single origin. A REFUTE item is deliberate on the parafibromin node, recording that the authors call both molecular screening and immunohistochemistry limited in sensitivity and specificity, which is why diagnostic weight sits on the WHO invasion criteria instead. The Cdc73 mouse model is linked with fidelity MODERATE and limitations recording that its lesions are atypical adenomas rather than carcinoma, so it captures the proliferative and hormonal arm and not the invasive behaviour that defines the human disease. Hyperparathyroidism-jaw tumour syndrome, the germline CDC73 predisposition, is absent from kb/ and deliberately not folded in. Validation: just validate passes with 17/17 snippets verified; validate-terms, check-entity-refs, check-causal-targets, check-enum-values and check-duplicate-keys all pass.
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.
| Database | Identifier |
|---|---|
| MONDO | MONDO:0012004 |
| OMIM | 608266 (CDC73-related) |
| Orphanet | ORPHA:143 |
| ICD-10 | C75.0 (Malignant neoplasm of parathyroid gland) |
| ICD-11 | 2F36 (Malignant neoplasms of parathyroid glands) |
| MeSH | D010282 (Parathyroid Neoplasms) |
| SEER | Parathyroid Gland Cancer |
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.
Germline predisposition syndromes:
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).
No established genetic or environmental protective factors specific to parathyroid carcinoma have been identified.
The interaction between prior radiation exposure and CDC73 germline heterozygosity has not been formally studied, but both independently increase risk of parathyroid neoplasia.
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.
| Phenotype | Description | Frequency | HPO Term |
|---|---|---|---|
| Hypercalcemia | Serum calcium ≥14 mg/dL in 62% of carcinomas vs. 17% of atypical adenomas; PTH levels 3–10× upper limit of normal | Very frequent (>80%) | HP:0003072 (Hypercalcemia) |
| Nephrolithiasis | Kidney stone formation from chronic hypercalcemia and hypercalciuria | 30–60% | HP:0000787 (Nephrolithiasis) |
| Nephrocalcinosis | Calcium deposition in renal parenchyma | Variable | HP:0000121 (Nephrocalcinosis) |
| Osteoporosis | Reduced bone mineral density from excess PTH-mediated bone resorption | 40–60% | HP:0000939 (Osteoporosis) |
| Osteitis fibrosa cystica | Subperiosteal resorption, brown tumors, bone cysts from severe hyperparathyroidism | 10–30% | HP:0100255 (Osteitis fibrosa cystica) |
| Pathological fractures | Fractures from PTH-mediated skeletal demineralization | Variable | HP:0002756 (Pathologic fracture) |
| Bone pain | Musculoskeletal pain from osseous involvement | 30–50% | HP:0002653 (Bone pain) |
| Palpable neck mass | Neck mass distinguishing carcinoma from adenoma | 30–76% | HP:0100028 (Abnormality of the parathyroid gland) |
| Muscle weakness | Proximal myopathy from hypercalcemia | 20–40% | HP:0003325 (Limb-girdle muscle weakness) |
| Fatigue | Chronic fatigue from metabolic derangement | Common | HP:0012378 (Fatigue) |
| Nausea/vomiting | GI symptoms from hypercalcemia | 20–40% | HP:0002013 (Vomiting) |
| Constipation | GI dysmotility from hypercalcemia | Common | HP:0002019 (Constipation) |
| Polyuria/polydipsia | Nephrogenic diabetes insipidus from hypercalcemia | 20–40% | HP:0000103 (Polyuria) |
| Neurocognitive symptoms | Depression, confusion, psychosis, impaired concentration | Common | HP:0100543 (Cognitive impairment) |
| Cardiac arrhythmias | Shortened QT interval, arrhythmias from hypercalcemia | Variable | HP:0011675 (Arrhythmia) |
| Hoarseness/dysphonia | Recurrent laryngeal nerve invasion by tumor | 15–30% | HP:0001609 (Hoarseness) |
| Elevated PTH | Markedly elevated intact parathyroid hormone | Very frequent (>90%) | HP:0003165 (Elevated circulating parathyroid hormone level) |
| Pancreatitis | Acute pancreatitis triggered by severe hypercalcemia | Occasional | HP:0001733 (Pancreatitis) |
| Peptic ulcer disease | Increased gastric acid secretion from hypercalcemia | Occasional | HP:0004398 (Peptic ulcer) |
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).
"Biallelic somatic inactivation of the CDC73 gene has been reported in 40–60% of sporadic PCs" (PMID: 42694707)
"Variants in PRUNE2 were associated with parathyroid carcinoma in 18% of cases studied" (PMID: 42694707)
Epigenetic alterations are a hallmark of PC and serve both as pathogenic drivers and diagnostic biomarkers:
No specific dietary, smoking, exercise, or alcohol-related risk factors have been established for PC.
No infectious etiology is known for parathyroid carcinoma.
| Cell Type | Role | CL Term |
|---|---|---|
| Parathyroid chief cell | Cell of origin; PTH-producing | CL:0000446 (chief cell of parathyroid gland) |
| Osteoclast | Effector of PTH-driven bone resorption | CL:0000092 (osteoclast) |
| Osteoblast | Secondarily stimulated by PTH | CL:0000062 (osteoblast) |
| CD163+ tumor-associated macrophage | Immunosuppressive M2 macrophages in tumor microenvironment | CL:0000235 (macrophage) |
| CD8+ T cell | Depleted in tumor microenvironment | CL:0000625 (CD8-positive, alpha-beta T cell) |
| Process | GO Term |
|---|---|
| Parathyroid hormone secretion | GO:0035898 (parathyroid hormone secretion) |
| Canonical Wnt signaling pathway | GO:0060070 |
| Regulation of protein kinase B signaling | GO:0051896 |
| G1/S transition of mitotic cell cycle | GO:0000082 |
| Apoptotic process | GO:0006915 |
| Bone resorption | GO:0045453 |
| DNA methylation | GO:0006306 |
| Histone H3-K27 trimethylation | GO:0098532 |
| Response to calcium ion | GO:0051592 |
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).
"Despite optimal surgical intervention, recurrence develops in 60% to 80% of patients" (PMID: 42577903)
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
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)
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
| Marker | Sensitivity | Specificity | Notes |
|---|---|---|---|
| Parafibromin (loss) | 68% (pooled) | 95% (pooled) | Loss in 31–73% of PCs vs. 0–1% of adenomas; HR 3.26 for recurrence |
| Ki-67 (elevated >5%) | 45–60% | 93–96% | Elevated in 86% of PCs vs. 0% of adenomas in some series |
| PGP9.5 (strong staining) | 78% | 100% | Strong staining for PC/HRPT2 mutation |
| Galectin-3 | 45.4% | 90.2% | Overexpressed in malignancy |
| 5-hmC (loss) | 100% | 100% | Requires multi-center validation |
| E-cadherin (membranous loss) | 47.7% in PCs | — | vs. 18.6% in benign |
| EZH2 (nuclear positivity) | 31.8% in PCs | — | 0% in benign |
Best panel performance: Silva-Figueroa nomogram (parafibromin + RB + PGP9.5 + Ki-67 + Galectin-3): AUC = 0.849 (PMID: 42196524)
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).
| Metric | Value | Source |
|---|---|---|
| 5-year overall survival | 78–86% | PMID: 42694707 |
| 10-year overall survival | 49–77% | PMID: 42694707 |
| Median overall survival | 14.3 years | PMID: 42577903 |
| Metastatic disease 5-year survival | <50% | PMID: 42196524 |
| Metastatic disease median survival | 36 months | PMID: 42577903 |
| Disease-free interval | Median 80 months | PMID: 42485575 |
| Recurrence rate | 30–80% | PMID: 42577903 |
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
Mortality most often results from complications of uncontrolled hypercalcemia (renal failure, cardiac arrhythmia, skeletal catastrophe) rather than tumor burden itself (PMID: 42577903).
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)
| Agent | Mechanism | NCIT/CHEBI | Notes |
|---|---|---|---|
| Cinacalcet | Calcimimetic; enhances CaSR sensitivity | NCIT:C65509 | Foundation of chronic management; does not reduce tumor size |
| Denosumab | Anti-RANKL monoclonal antibody | NCIT:C65214 | Effective in renal impairment; inhibits osteoclast maturation |
| Bisphosphonates (zoledronic acid, pamidronate) | Osteoclast inhibitors | CHEBI:77862 (zoledronic acid) | Temporary effect; palliative |
| IV normal saline | Volume expansion + calciuresis | — | Acute management |
| Calcitonin | Osteoclast inhibitor (transient) | CHEBI:3306 | Short-term bridge 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)
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)
| Agent | Target | Evidence |
|---|---|---|
| Lenvatinib | VEGFR/PDGFR/FGFR/RET TKI | Biochemical response, 9 months stabilization in metastatic PC (PMID: case report 2025) |
| Surufatinib | VEGFR/FGFR/CSF1R TKI | Disease stabilization in case reports |
| Sorafenib | Multi-kinase inhibitor | Controlled refractory hypercalcemia in metastatic cases |
| Palbociclib | CDK4/6 inhibitor | Strong tumor suppression in preclinical PC models targeting CCND1-CDK4/6-RB1 axis |
| Pembrolizumab | Anti-PD-1 checkpoint inhibitor | Potential in MSI-high/TMB-high PC; normalized calcium/PTH in one case with EBRT |
| Everolimus/mTOR inhibitors | mTORC1 | Rationale from ~48.5% of PCs classified as "high mTORC1" |
Limited clinical trial activity given disease rarity. No large randomized trials exist. Case reports and small series drive evidence for targeted therapies.
No established primary prevention strategies exist for parathyroid carcinoma.
"Patients require lifelong biochemical surveillance following surgery" (PMID: 42577903)
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.
Cdc73 knockout models are the primary experimental system:
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)
Cdc73L/L/PTH-Cre (parathyroid-specific conditional knockout): Phenotype is strain-dependent (PMID: 38198197, J Endocr Soc 2024):
Limitation: Strain-dependent phenotype complicates interpretation; does not fully recapitulate human PC
Cdc73−/−/Pth-Cre uterine model: Mice develop uterine tumors in addition to parathyroid lesions, modeling HPT-JT syndrome features
| PMID | Citation | Year |
|---|---|---|
| 42196524 | Parathyroid Carcinoma: From Molecular Pathogenesis and Diagnostic Biomarkers to Targeted Therapeutics. Int J Mol Sci | 2025 |
| 42694707 | Parathyroid carcinoma: epidemiology and genetics. Endocr Oncol | 2026 |
| 42577903 | Critical Insights into Parathyroid Cancer. J Cancer Sci Clin Ther | 2026 |
| 42485575 | Prognostic factors and survival in parathyroid carcinoma: a 50-year single-center cohort study. Arch Endocrinol Metab | 2026 |
| 36949199 | Genomic and transcriptomic profiling reveal molecular characteristics of parathyroid carcinoma. Exp Mol Med | 2023 |
| 28288139 | Mice deleted for cell division cycle 73 gene develop parathyroid and uterine tumours. Oncogene | 2017 |
| 38198197 | Phenotype of Parathyroid-targeted Cdc73 Deletion in Mice Is Strain-Dependent. J Endocr Soc | 2024 |
| 39677927 | CDC73 c.1155-3A>G is a pathogenic variant causing aberrant splicing. JBMR Plus | 2024 |
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)
Checked with linkml-reference-validator 0.3.0.
| Outcome | Count |
|---|---|
| References checked | 17 |
| Resolved | 17 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 2 |
| Quoted claims found in source | 0 |
| Quoted claims not found in source | 2 |
| References weighed for topical relevance | 17 |
| On topic | 14 |
| Off topic | 1 |
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"PMID:42577903 (abstract only): "minimal and inconsistent success"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.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.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 54 |
| Resolved | 50 |
| Unresolved (possible confabulation) | 1 |
| Obsolete | 2 |
| Unverifiable | 1 |
| Terms whose name was checked | 52 |
| Terms named correctly | 35 |
| Terms named as a different term | 10 |
| Terms whose name is worth a second look | 7 |
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 carcinomaHP:0100255 (2 mentions) - the report calls it "Osteitis fibrosa cystica"; HP calls it Metaphyseal dysplasiaUBERON:0002048 (2 mentions) - the report calls it "Lung — most common distant metastatic site", "lung"; UBERON calls it lungUBERON:0004765 (1 mention) - the report calls it "Bone/skeleton — metastatic deposits and PTH-mediated skeletal disease"; UBERON calls it skeletal elementUBERON:0002107 (2 mentions) - the report calls it "Liver — distant metastasis", "liver"; UBERON calls it liverUBERON:0002113 (2 mentions) - the report calls it "Kidney — nephrolithiasis, nephrocalcinosis", "kidney"; UBERON calls it kidneyNCIT:C65509 (2 mentions) - the report calls it "Calcimimetic; enhances CaSR sensitivity", "Cinacalcet Hydrochloride"; NCIT calls it EletriptanNCIT:C65214 (2 mentions) - the report calls it "Anti-RANKL monoclonal antibody", "Denosumab"; NCIT calls it AcotiamideCHEBI: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 calcitoninThese 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 termThese 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)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 namesHP: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 namesGO: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 namesGO:0006306 (1 mention) - the report calls it "DNA methylation"; GO calls it obsolete DNA methylationGO:0098532 (1 mention) - the report calls it "Histone H3-K27 trimethylation"; GO calls it obsolete histone H3-K27 trimethylationUBERON: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 glandThe 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"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.