Clonal Emergence in Uremic Parathyroid Hyperplasia Is Not Related to MEN1 Gene Abnormality

Abstract

It is difficult to differentiate between parathyroid neoplasia and hyperplasia. In an attempt to elucidate the clonality of uremic parathyroid hyperplasia and the molecular genetic abnormalities accounting for clonal emergence, we analyzed 20 cases of uremic parathyroid hyperplasia. Clonalities were determined using the X-chromosome-linked human androgen receptor (HUMARA) gene and the phosphoglycerate kinase (PGK) gene, and multiple endocrine neoplasia type 1 (MEN1) gene abnormality was analyzed by studying loss of heterozygosity (LOH) in 11q13 and somatic mutations in the MEN1 gene. As a positive control, a case of MEN1 with Zollinger-Ellison syndrome was analyzed simultaneously. Our analysis revealed that a majority (75%) of the uremic parathyroid hyperplasia tissues, including an autograft with recurrent hyperparathyroidism, was of monoclonal origin. Clonality did not correlate with serum carboxyl-terminal parathyroid hormone (C-PTH) level, calcium level, hemodialytic duration, gland weight or pathological features. Neither LOH in 11q13 nor somatic mutation in the MEN1 gene was detected. For the MEN1 case, a germline mutation (W198X) was detected in exon 3. We concluded that a majority of the uremic parathyroid hyperplasia cases was in fact monoclonal neoplasia. MEN1 gene abnormality played a minor role, if any, in the clonal emergence in uremic parathyroid hyperplasia.Key words: Parathyroid -Uremic parathyroid hyperplasia -Clonality -MEN1 gene Uremic parathyroid hyperplasia is characterized by hypersecretion of parathyroid hormone (PTH) and enlargement of more than one gland. Because of these features, uremic parathyroid hyperplasia is traditionally interpreted as reactive hyperplasia of the parenchymal cells.1, 2) Parathyroid tumors may occur in uremic parathyroid hyperplasia but are considered rare. Recently this concept has been challenged by molecular analysis and clinical longterm follow-up. Molecular analysis has demonstrated that some uremic parathyroid hyperplasia specimens are of monoclonal origin and should therefore be interpreted as neoplastic. 3,4) Clinical studies showed that about 3% and 7% of patients receiving a subtotal parathyroidectomy developed recurrent hyperparathyroidism 5 and 7 years later, respectively. A much higher recurrence rate was observed in autografts, with a frequency of 10, 20 and 30% occurring 3, 5 and 7 years, respectively, after total parathyroidectomy and autotransplantation. 5)In these cases, pathological observation of the autografts often revealed a distinct nodular proliferation of the parenchymal cells with larger and more irregular nuclei. Occasionally, apparent mitotic activity and nuclear pleomorphism were noted. A striking finding by Klempa et al. was the presence of small nests of parathyroid tissue next to or at some distance from the autografts. 6) These observations and evidence are suggestive of a neoplastic nature of uremic parathyroid hyperplasia. However, little is known about the molecular abnormalities accounting for this neoplastic proliferation. In...

Cyclin D1 in parathyroid disease

“…Because of multigland involvement, it was assumed that this condition predominantly involves polyclonal (non-neoplastic) cellular proliferations. Although this is likely to be the case in the initial proliferative phase, it is now clear that monoclonal parathyroid expansion does occur in most patients with severe secondary or tertiary HPT (34,35). However, immunohistochemical studies have not detected overexpression of cyclin D1 in parathyroid glands from patients with uremic HPT (19), suggesting an infrequent role for cyclin D1 in the development of this disease.…”

“…However, immunohistochemical studies have not detected overexpression of cyclin D1 in parathyroid glands from patients with uremic HPT (19), suggesting an infrequent role for cyclin D1 in the development of this disease. Interestingly, acquired inactivation of the MEN1 gene, also relatively common in sporadic primary HPT, seems to play only a minor role in the clonal expansion of these lesions (35,36). Thus, the molecular genetic basis for the development of this clonal disease may differ from primary HPT.…”

Clonal Chromosomal Defects in the Molecular Pathogenesis of Refractory Hyperparathyroidism of Uremia

“…This lack of correlation might well have been expected, because these patients (all of whom required surgical intervention) were already a highly selected group. Patients with severe secondary or tertiary hyperparathyroidism are also known to exhibit a high prevalence of monoclonal parathyroid tumors (8,14), only some of which would be detectable by CGH or allelotyping.…”

“…In one study, allelic loss of 11q13, the chromosomal location of the multiple endocrine neoplasia type 1 (MEN1) gene, was detected in two of 12 parathyroid glands (16%) obtained from dialysis patients (11). Other studies failed to confirm significant 11q13 losses or frequent MEN1 mutations in parathyroid tumors obtained from such patients (8,9,(12)(13)(14). In addition, a limited (non-genomewide) allelotyping study noted LOH on 3q in a small subset of tumors obtained from uremic patients (12).…”

Evidence of a Functional Estrogen Receptor in Parathyroid Adenomas

“…(Marx, 2000) Several studies have tried to characterize the clonality of uniglandular and multiglandular PHPT; however, different results have been obtained suggesting both mono-and polyclonal origins. (Arnold et al, 1988, Noguchi et al, 1994, Sanjuan et al, 1998, Shan et al, 1999 Histopathologically the adenoma presents a fat depleted neoplasia of parenchymal cells. In 50-60% remnants of normal tissue is present adjacent to the tumor.…”