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Page 2 of 8 Costa-Guda. J Transl Genet Genom 2018;2:5 I http://dx.doi.org/10.20517/jtgg.2018.08

Table 1. Hereditary parathyroid tumor predisposition syndromes
Syndrome Gene Parathyroid cancer Other features Somatic mutations in sporadic
parathyroid tumors
MEN1 a MEN1 Rare Pituitary and enteropancreatic Adenoma ~35%
CDKN1A b None reported endocrine tumors None reported
CDKN2B b None reported None reported
CDKN2C b None reported Adenoma ~1.5%
MEN4 a CDKN1B b None reported Adenoma ~5%
MEN2A RET Rare Medullary thyroid cancer, None reported
pheochromocytoma
HPT-JT CDC73 ~10%-15% Fibro-osseous jaw tumors, Carcinoma ~77%
uterine tumors, renal lesions
Adenoma ~1.5%
NSHPT CASR None reported None reported
FIHP GCM2, others None reported None reported
a MEN1 and MEN4 are clinically indistinguishable; germline mutations of CDKN1A, CDKN2B, CDKN2C, and CDKN1B have been reported
b
in patients meeting the criteria for MEN1, however the full clinical spectrum of such patients has yet to be established. NSHPT: neonatal
severe hyperparathyroidism; FIHP: familial isolated hyperparathyroidism

unequivocal diagnosis of malignancy depends on the presence of marked invasion into adjacent structures
and/or distant metastasis. Features such as fibrous banding, mitotic figures and necrosis are suggestive of, but
not diagnostic for, parathyroid carcinoma . Historic inconsistencies in diagnostic criteria for parathyroid
[1]
cancer, in addition to its rarity, have hindered efforts to understand the genetic basis of this important
endocrine malignancy.

GENETIC ALTERATIONS IN PARATHYROID CANCER
A hallmark of many solid tumor malignancies is their progression from normal to malignant disease through
clinically and histologically-identifiable stages of tumorigenesis, caused by incremental accumulation
of acquired genetic abnormalities. Surprisingly, genetic evidence argues against such a progression for
parathyroid carcinoma. Genomic and genetic alterations common in benign parathyroid adenomas,
most prominently loss of chromosome 11q and accompanying mutation of MEN1, which occur in 35% of
parathyroid adenomas , are rarely, if ever, seen in parathyroid cancer [3,4,8,9] . The clearly distinguishable
[2-8]
patterns of genomic and genetic alterations present in parathyroid adenomas versus carcinomas suggests
that parathyroid cancer most commonly arises de novo, rather than evolving from a preexisting benign
adenoma .
[8]
Hereditary parathyroid cancer
A possible exception to the predominant process of de novo parathyroid carcinogenesis is that of hereditary
parathyroid cancer. Primary hyperparathyroidism is a feature of several hereditary tumor-predisposition
syndromes [Table 1]. While the large majority of parathyroid tumors in these syndromes are benign, rare
parathyroid carcinomas have been reported in multiple endocrine neoplasia type 1 (MEN1) and type 2a
(MEN2a). Somatic mutations of the causative genes, MEN1 and RET, respectively do not appear to contribute
to sporadic parathyroid carcinomas. A somatic mutation in CDKN2C/p18, which may cause a subset of cases
of MEN1 or a closely related syndrome , has been reported in a single parathyroid carcinoma .
[10]
[11]
Parathyroid carcinoma is highly overrepresented in the hyperparathyroidism-jaw tumor syndrome (HPT-JT),
caused by germline mutations in CDC73 (previously called HRPT2). Approximately 10%-15% of parathyroid
tumors in HPT-JT are malignant and affected patients have a lifetime risk of developing parathyroid cancer
[12]
approaching 40% . In the setting of a germline parathyroid tumor-predisposing mutation, particularly of
CDC73, patients may occasionally develop parathyroid carcinomas that have evolved from preexisting benign
or atypical adenomas. Such cases likely explain the few rare reports of apparent malignant parathyroid
tumor progression.