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PubMed1975

Serum parathyroid hormone: a double antibody radioimmunoassay.

A radioimmunoassay for parathyroid hormone (PTH) using a double antibody system is described. Because of the immunolgoical heterogeneity of the hormone in human serum, the standard used has been serum from a patient with parathyroid carcinoma. With the use of the synthetic 34 amino acid N-terminal fragment of PTH, the anti-PTH antiserum was determined to react primarily with the N-terminal end of the molecule. PTH was detectable in the sera of 25% of normal subjects and elevated in 18 of 19 patients with parathyroid adenoma and carcinoma. Serum PTH levels were elevated in 3 of 5 patients with parathyroid hyperplasia.

Adenoma↗

PubMed1996

CD44 isoform expression in the diffuse neuroendocrine system. II. Benign and malignant tumors.

The membrane glycoprotein CD44 may be associated with aggressive behavior, dissemination, and poor prognosis of a variety of human tumors. In order to extend our knowledge on the expression and significance of CD44 in cells of the dispersed neuroendocrine system we investigated a spectrum of 134 neuroendocrine tumors, including pituitary adenomas, medullary thyroid carcinomas, parathyroid adenomas, pheochromocytomas, neuroblastomas, small-cell lung carcinomas, and bronchopulmonary, pancreatic, and gastrointestinal neuroendocrine tumors immunohistochemically for CD44 standard and variant exon-encoded gene products (CD44v3, -v4, -v5, -v6, -v9). Furthermore, we compared protein expression with that of CD44 mRNA by reverse-transcriptase PCR and Southern blot hybridization in a subset of tumors. Our results show that CD44 expression is correlated with the "histogenetic origin" of the appropriate neuroendocrine neoplasm. Endoderm-derived tumors generally express 3'-end CD44 variant exon-containing isoforms, whereas neural crest-derived tumors rarely are positive for CD44. Furthermore, we provide evidence that CD44 expression is not correlated with metastatic disease or a particular hormonal phenotype but exhibits an association with the degree of cellular differentiation. Thus, CD44 is not useful as marker for malignancy or prognosis. The number of patients with clinical follow-up data in our study was too small to allow definite conclusions about a possible correlation between CD44 expression and prognosis. But CD44 may help to better classify neoplasms with an unclear neuroendocrine phenotype.

Biomarkers, Tumor↗

PubMed1983

Pancreatic polypeptide (PP) immunoreactivity in human parathyroid culture media.

Media from cultures of normal and abnormal human parathyroid fragments were assayed for parathyrin (PTH) and pancreatic polypeptide (PP) using sensitive radioimmunoassays. PP immunoreactivity was present in media (Day 6-7 in vitro) from cultures of 3/10 adenomas and 6/6 3 degrees hyperplastic glands (mean = 126. fmole/mg protein/day) (range = 6.-675.), and was not suppressed by 0 leads to 3 mM calcium challenge. PP was undetectable in media from cultures of one parathyroid carcinoma, one 1 degree hyperplasia, and one normal parathyroid. Medium C-terminal PTH levels were quite variable (26.-2,545,000. pg/mg protein/day). Presence of PP immunoreactivity in media from cultures of some hyperplastic parathyroids and some parathyroid adenomas suggests that PP may be released from these tissues in vitro. The significance of elevated PP levels in the MEA syndromes may be of special clinical relevance to this observation.

Adenoma↗

PubMed2003

Demonstration of human telomerase reverse transcriptase (hTERT) in human parathyroid tumours by in situ hybridization with a new oligonucleotide probe.

BACKGROUND AND OBJECTIVE: Telomerase activity is present in most malignant tumours and might provide a mechanism for unlimited replication of neoplastic cells. Expression of the gene encoding human telomerase reverse transcriptase (hTERT), the telomerase catalytic subunit gene, is associated with telomerase activity, and it is overexpressed in most parathyroid carcinomas. We have therefore studied hTERT expression in parathyroid tumours. METHODS: In the present study, we assayed telomerase activity by the telomeric repeat amplification protocol (TRAP) and used in situ hybridization (ISH) to study hTERT mRNA expression in four parathyroid metastatic cancers, six adenomas and two parathyroid hyperplasia tissue specimens. RESULTS: Telomerase activity was detected by the TRAP assay in all of the parathyroid cancers (100%) but in none of the eight parathyroid benign lesions. hTERT gene expression was detected in the nuclei of the parathyroid cancer cells in all of the lesions (100%) but in none of the eight parathyroid benign lesions. CONCLUSIONS: Our results demonstrate a correlation between telomerase activity and hTERT gene expression measured by ISH (P < 0.001) in parathyroid tumours. We succeeded in very clearly and sensitively demonstrating hTERT mRNA in parathyroid tissues by using a new probe.

Adenoma↗

PubMed2006

Correlation between clinical and histological findings in parathyroid tumors suspicious for carcinoma.

Carcinoma of the parathyroid is a rare malignancy that can be cured surgically if the proper diagnosis and treatment is given initially. Arriving to the clinical suspicion of a malignancy preoperatively is by far the most important step for a good prognosis. Our goal is to review the correlation between clinical and final histopathological findings that can arouse the suspicion of such malignancy and their true predictive value in the diagnosis. All patients that underwent surgical removal of the parathyroid mass between March of 1992 and March of 2003 were reviewed retrospectively at Providence Hospital and Medical Centers. Among 168 patients who underwent parathyroid excision, 14 (8.3%) had hyperplasia of the parathyroid, 121 (72%) had benign adenoma, 25 (14.8%) had other benign lesions, and 8 (4.7%) patients had primary carcinoma of the parathyroid confirmed by pathology. Our mean serum calcium level was 11.57 mg/dL, which was lower than the mean level (12 mg/dL) for benign hyperparathyroidism. The mean tumor size was 2.18 cm, smaller than the proposed for malignant criteria, and none of the eight patients (0%) had any symptoms of hypercalcemia at the time of diagnosis. Seven of eight patients (87.5%) had frank signs of invasion together with other histological features, and two patients had associated papillary carcinoma of the thyroid. Five patients from our series did not meet clinical criteria for malignancy (tumor size > 3 cm, palpable mass, and serum calcium > 14 mg/dL), but had undisputable histological findings (high mitotic pattern, fibrous trabeculae, capsular invasion, vascular invasion, and nodular involvement). On the other hand, 17 patients with benign histology had tumors greater than 3 cm, and an additional 18 had palpable masses on physical examination. We believe that these patients need to be followed closely. The patients with diagnosis of parathyroid carcinoma, their kindred, and those with large adenomas may benefit from genetic screening for HRTP2 gene mutations in search of early detection of tumors suspicious for malignancy. This is based on the fact that we did not find correlation between the clinical presentation and the histological features in our patients with proven malignancy.

Adenoma↗

PubMed1995

Oxyphil cell carcinoma of the parathyroid: a rare cause of hyperparathyroidism.

Oxyphil carcinoma of the parathyroid is an extremely rare tumour, only two previous patients having been reported. We report a 55-year-old woman with this condition, who presented with a picture of hyperparathyroidism, including hypercalcaemia, hypercalciuria, hypophosphataemia, increased alkaline phosphatase, and bony lesions. Biopsy of a bone lesion was consistent with brown tumour. Fine needle aspiration cytology and subsequent operative histology of the parathyroid lesion showed an oxyphil cell tumour with malignant characteristics. Following excision, the patient made a good recovery, complicated only by postoperative hypocalcaemia.

Adenocarcinoma↗

PubMed1991

Distribution of monoclonal antiparathyroid antibody E11 in mice grafted with human parathyroid adenoma and carcinoma.

One hundred six immunoincompetent mice grafted with human parathyroid adenoma or carcinoma were used to evaluate distribution of the murine monoclonal antibody E11, which recognizes a calcium sensor of high molecular weight on the parathyroid cell surface. The subcutaneous parathyroid grafts were infiltrated with murine fibrous tissue, which seemed to increase with the duration of transplantation and the size of inserted tissue pieces. Intraperitoneal injection of biotinylated or 125I-labeled E11 antibody indicated time- and dose-dependent antibody accumulation, as well as the presence of unoccupied binding sites in the transplanted parathyroid tissue. The iodinated intact immunoglobulin G and Fab fragment of the E11 antibody demonstrated low radioactivity in the lung, liver, spleen, kidney, and intestine for up to 14 days, except for the Fab fragment, which was rapidly accumulated and cleared from the kidney. The peak radioactivity ratio in the adenoma tissue versus blood averaged 2.8 for the intact antibody and 5.3 for the Fab fragment, whereas the corresponding values for the carcinoma tissue were 8.6 and 8.8, respectively. These ratios increased considerably, especially for the adenoma specimens, when weights of the excised grafts were adjusted for the calculated content of parathyroid tissue. The results support that the E11 antibody may localize even minute amounts of human parathyroid adenoma and carcinoma tissue.

Adenoma↗

PubMed2002

Distinct target regions for chromosome 1p deletions in parathyroid adenomas and carcinomas.

Primary hyperparathyroidism is a common endocrine disease with a multifaceted genetic background, the elucidation of which has only begun. Among others, loss of the short arm of chromosome 1 and somatic inactivation of the multiple endocrine neoplasia type 1 gene (MEN1) in 11q13 represent significant alterations in the tumorigenesis. In the present study deletions of 1p were characterized and the findings were evaluated in relation to the loci of MEN1 and histone deacetylase 1 gene (HDAC1), a menin interacting partner in 1p, as well as to the clinical characteristics. Overall 1p LOH was detected in 18 of the 42 tumors analyzed (43%), and from the deletion patterns a main target interval of 40 cM was identified within 1p band 32.3-36.2. The mapping of HDAC1 centromeric of the main interval, and the lack of altered mRNA expression in tumors with LOH, suggest that HDAC1 is not the main target for 1p deletions in parathyroid tumors. Twenty-five of the 42 tumors (60%) showed alteration of either 1p, of the MEN1 locus, or both. Tumors with LOH at 11q13 had a significantly higher weight than tumors with 1p LOH. In conclusion, LOH in primary sporadic parathyroid adenomas occur frequently on the distal part of chromosome 1p and are thus clearly different from parathyroid carcinomas where the deletions are more proximally located. The findings support that the short arm of chromosome 1 harbors at least two different tumor suppressor genes involved in parathyroid tumorigenesis, the exact identification of which may provide a molecular basis for differential diagnosis of benign and malignant disease in the future.

Adenoma↗

PubMed1998

Expression of the alpha- and beta-subunits of human chorionic gonadotropin by subsets of parathyroid cells in states of hyperparathyroidism.

The alpha-subunit of human chorionic gonadotropin (hCG-alpha) has previously been found to be expressed in hyperplasias and tumours of numerous endocrine tissues including all those involved in MEN-I syndrome except the parathyroid glands. In the present immunohistochemical investigation of 86 patients with various states of hyperparathyroidism, expression of hCG-alpha by subsets of parathyroid cells was shown in 46 cases (54 per cent) including all states of hyperparathyroidism investigated: primary adenoma (n = 34, 44 per cent); uraemic secondary hyperplasia (n = 34, 53 per cent); MEN-I (n = 13, 77 per cent); MEN-II (n = 2, 100 per cent); and parathyroid carcinoma (n = 3, 100 per cent). Although the number of parathyroid cells expressing hCG-alpha was in general low, the occurrence of numerous immunoreactive cells appeared to be concentrated in primary adenoma and MEN-I (20 and 33 per cent of positive cases, respectively). No expression was found in ten normal control glands, except for very rare cells in one case. Expression of hCG-alpha was in part associated with that of hCG-beta, which appeared to be more commonly expressed than hCG-alpha in cases of secondary hyperparathyroidism. In separate experiments, Bouin fixation was found to preserve the immunoreactivity of hCG-alpha and hCG-beta better than the formalin fixation used in this study, suggesting that the figures may be underestimates. These immunohistochemical results are in agreement with a previous biochemical study showing hCG-alpha and hCG-beta in extracts of parathyroid tumours and extend to the parathyroid glands the otherwise ubiquitous finding of hCG-alpha expression in MEN-I-related neoplasms.

Adenoma↗

PubMed1990

Parathyromatosis in hyperparathyroidism.

Recurrent hyperparathyroidism after parathyroidectomy may present a difficult diagnostic problem. A rare etiology is parathyromatosis (multiple nodules of hyperfunctioning parathyroid tissue scattered through the neck and mediastinum) due to spillage of otherwise benign parathyroid tissue during surgery. We present a case of recurrent hyperparathyroidism and parathyromatosis due to tissue spillage during surgical removal of probable double adenomas, a rare cause of primary hyperparathyroidism. Thus, parathyromatosis must be included in the differential diagnosis of recurrent or persistent hyperparathyroidism, distinguished from parathyroid carcinoma by histologic criteria. The surgeon must be careful of parathyroid spillage during surgery, even of benign tumors of the parathyroids.

Adenoma↗

PubMed1985

Radionuclide imaging of parathyroid tumors: historical perspectives and newer techniques.

The increasing use of automated blood chemistry screens for serum calcium levels along with improved methods in measuring parathyroid hormone (PTH) levels have made the diagnosis of parathyroid disease a common clinical problem. Parathyroid adenomas account for the majority of primary hyperparathyroidism with diffuse hyperplasia and parathyroid carcinoma occurring less frequently. Early scintigraphic techniques to identify enlarged parathyroids used selenomethionine-75 which was considered to be incorporated into PTH. In general, the sensitivity of scanning the neck using this tracer was related to the size of the enlarged parathyroid, but in large series, the overall sensitivity was less than 50%. Recent work by Ferlin et al, using a Technetium-99m/Thallium-201 subtraction scintigraphic technique has yielded a sensitivity of 92% in identifying pathologically enlarged parathyroid glands. Winzelberg et al modified this technique to allow imaging the mediastinum plus simplifying the subtraction method. In a prospective study with high-resolution sonography, similar sensitivities and specificities were found with sonography and scintigraphy. Tl-201/Tc-99m pertechnetate subtraction scintigraphy appears to be an accurate technique in identifying pathologic parathyroid enlargement. Its ultimate role in the evaluation of patients with suspected hyperparathyroidism still needs to be determined.

Adenoma↗

PubMedDate not supplied

Palpable parathyroid adenomas presenting as clinical solitary thyroid nodules and cytologically as follicular thyroid neoplasms.

BACKGROUND: A palpable parathyroid mass, in a patient with primary hyperparathyroidism, is presumed to be parathyroid carcinoma until proven otherwise, with other less common causes including parathyroid cysts and adenomas. These parathyroid pathologies can be more difficult to interpret with concomitant thyroid disease. METHODS: A retrospective review was undertaken of a series of three patients with palpable parathyroid adenomas mimicking thyroid nodules. RESULTS: Two of three patients had preoperative biochemical evidence of primary hyperparathyroidism. Sestamibi scanning confirmed the presence of parathyroid pathology in one case. Fine-needle aspiration cytology revealed probable follicular neoplasms of the thyroid in all three cases. Only one of three parathyroid adenomas was diagnosed at neck exploration; the others were diagnosed at subsequent histopathology. CONCLUSION: Parathyroid and thyroid disease often occur simultaneously. Concomitant parathyroid pathology should be considered, even in the absence of biochemical and radiological evidence, at neck exploration for thyroid disease. Macroscopic identification of parathyroid disease at neck exploration can be difficult when within the thyroid gland capsule. Cytology and imaging of parathyroid adenomas may, on occasion, mimic follicular thyroid neoplasms.

Adenocarcinoma, Follicular↗

PubMed2025

Spatial transcriptomic analysis of mouse parathyroid gland cells expressing an activating variant of Gcm2.

Glial cells missing 2 (GCM2) is an essential transcription factor for the development of parathyroid glands. Germline GCM2 variants that repress or enhance transcriptional activity predispose a subset of patients to hypoparathyroidism or hyperparathyroidism, respectively. A recurrent germline heterozygous activating missense variant of GCM2, p.Y394S has been identified in some patients with primary hyperparathyroidism. A genetically engineered knock-in mouse model of this variant corresponding to p.Y392S in the mouse Gcm2 gene (Gcm2 +/Y392S) did not show obvious parathyroid tumors. However, in GCM2-binding site mediated luciferase reporter assays in HEK293 cells, the mouse and the human variant both exhibited enhanced transcriptional activity. Therefore, we assessed the effect of this variant on gene expression in vivo in parathyroid glands from Gcm2 +/Y392S and WT mice. Using the 10x Genomics Visium platform, spatially resolved transcriptomic analysis was performed on formalin-fixed and paraffin-embedded (FFPE) tracheal tissue sections of Gcm2 +/Y392S and WT mice to capture RNA from parathyroid glands together with other cell types in the tissue sections. Transcriptome sequence data analysis detected 8 different clusters in the tissue sections based on similarity of gene expression profiles. Cluster-1, which contained parathyroid gland cells expressing Pth and Gcm2, was further evaluated for transcripts that were differentially expressed more than 2-fold in Gcm2 +/Y392S compared to WT. Increased transcript level of Lgals3 (galectin-3) was seen in Gcm2 +/Y392S parathyroid gland cells which is among markers of parathyroid carcinoma. Galectin-3 protein was detected in available FFPE human parathyroid samples of patients with germline heterozygous activating GCM2 variants, p.Y394S (n = 4/10) or p.L379Q (n = 2/2). These results indicate a potential for growth and malignancy of parathyroid glands expressing GCM2 variants. The transcriptomic data of mouse parathyroid gland cells generated in this study can serve as a valuable resource for investigating genes and pathways in normal or abnormal parathyroid gland growth and physiology.

GCM2, gene↗

PubMedDate not supplied

Ultrasound-guided fine needle aspiration cytology of parathyroid lesions. A review of 72 cases.

OBJECTIVE: To elucidate the specific cytomorphologic patterns and diagnostic pitfalls in fine needle aspiration cytology (FNAC) of parathyroid lesions. STUDY DESIGN: Seventy-two cases of surgically excised and pathologically verified hyperparathyroidism (20 cases of parathyroid hyperplasia, 51 of parathyroid adenoma and one of parathyroid carcinoma) received preoperative, ultrasound-guided FNAC examination for enlarged parathyroid glands. The smears were reviewed and analyzed. RESULTS: Parathyroid lesions were diagnosed cytologically in 60 cases (83.3%). The presence of colloidlike substance, macrophages or follicular structures in smears led to six cases (8.3%) being misinterpreted as thyroid lesions. The cellularity of the smears was insufficient for interpretation in six cases (8.3%); however, two of these cases were diagnosed by determination of parathyroid hormone (PTH) levels in the fluid. Parathyroid hyperplasia had more tightly cohesive cell clusters with monomorphism, while parathyroid adenoma had more dispersed or loosely cohesive cells with pleomorphism and anisokaryosis. High PTH concentration in an aspirate was noted in all four cases of cystic lesions.

Adenoma↗

PubMed2006

Loss of parafibromin expression in a subset of parathyroid adenomas.

Inactivation of the hyperparathyroidism-jaw tumour syndrome (HPT- JT) gene, HRPT2, was recently established as a genetic mechanism in the development of parathyroid tumours. Its encoded protein parafibromin has tumour-suppressor properties that play an important role in tumour development in the parathyroids, jaws and kidneys. Inactivating HRPT2 mutations are common in HPT- JT and parathyroid carcinomas, and have been described in a few cases of parathyroid adenomas with cystic features. In this study, 46 cases of cystic parathyroid adenomas previously investigated for HRPT2 mutations were characterized with regard to MEN1 gene mutations, cyclin D1 expression and parafibromin expression. In normal tissues and cell lines, parafibromin was ubiquitously expressed. Furthermore, parafibromin was detected as a dominating nuclear and a weaker cytoplasmic signal in transfected cell lines. In the three parathyroid tumours with inactivating HRPT2 mutations parafibromin expression was not detectable, and in one of two cases with aberrantly sized parafibromin the protein was delocalized. Both high and low cyclin D1 levels were found among HRPT2-mutated and -unmutated tumours, suggesting that these events are not mutually exclusive in parathyroid tumour development. The presented data suggest that in the majority of benign parathyroid tumours the expression of parafibromin remains unaltered, while the loss of parafibromin expression is strongly indicative of gene inactivation through mutation of the HRPT2 gene.

Adenoma↗

PubMed1989

Parathyroid histology and cytology with monoclonal antibodies recognizing a calcium sensor of parathyroid cells.

Two monoclonal antibodies reacting with surface structures on exclusively parathyroid cells and proximal kidney tubule cells were evaluated in the microscopic diagnosis of parathyroid disease. Immunostained cryosections of adenomatous and hyperplastic parathyroid glands from 30 hypercalcemic patients with primary or uremic hyperparathroidism (HPT) showed a reduced and heterogeneous staining with the antibodies. This contrasted with the intense and even staining of normal and suppressed human parathyroid glands, as well as lymph node metastases of parathyroid carcinoma. Fine-needle aspiration biopsies and imprints of the parathyroid glands showed a conspicuous antibody staining that enabled the identification of parathyroid cells. The antibodies seem to provide new means for histologic and cytologic identification of normal and pathologic parathyroid tissue, in conjunction with their highly restricted tissue reactivity. Because one of the antibodies interacts with a surface receptor mechanism of the parathyroid cells that is involved in the sensing and gating of calcium and, thereby, also with the regulation of parathyroid hormone release, the unequivocal demonstration of reduced staining of the adenomatous and hyperplastic parathyroid tissue suggests that HPT is associated with reduced expression of the calcium sensoring mechanism of the pathologic parathyroid tissue.

Adenoma↗

PubMed1988

Recurrent hyperparathyroidism due to peroperative seeding of neoplastic or hyperplastic parathyroid tissue. Case report.

The clinical course and histologic characteristics of recurrent hyperparathyroidism due possibly to peroperative seeding of parathyroid cells are described in four cases--two of parathyroid adenoma, one of parathyroid hyperplasia associated with multiple endocrine neoplasia type 1 and one of parathyroid carcinoma. The observations underline the necessity for careful handling of parathyroid lesions during extirpation, and that the multiple nodules of implanted parathyroid tissue can be curatively excised in some cases.

Adult↗

PubMed1994

Nuclear diffuseness as a measure of texture: definition and application to the computer-assisted diagnosis of parathyroid adenoma and carcinoma.

A measure of texture, the nuclear diffuseness, was formulated for use in biological classification, and specifically to characterize quantitatively chromatin texture. Nuclear diffuseness corresponds to the amount of local intensity variation in the digitized image of a nuclear profile. As a setting in which to test the efficacy of nuclear diffuseness as a diagnostic tool, the identification of parathyroid adenoma and carcinoma was considered. Digitized images of sections of parathyroid chief cell nuclei were obtained from 16 biopsies, and the nuclear diffuseness, as well as other morphometric descriptors, were computed. With just the average nuclear diffuseness and average nuclear profile area, jackknife (leave-one-out) classification using an artificial neural network was able to diagnose correctly and unambiguously the condition (normal, parathyroid adenoma, or parathyroid carcinoma) in 15 of 16 cases. In one case, the neural network assigned a higher weight to the correct diagnosis, but was unable to distinguish between normal and adenoma conclusively.

Adenoma↗