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Acute complications in the course of "mild" hyperparathyroidism.

It is generally accepted that some patients affected by mild asymptomatic primary hyperparathyroidism need not be treated with surgery, but may be medically managed without risk. However, our experience regarding 5 of these cases observed in the last two years, suggests a different approach. These patients, initially diagnosed as having mild hyperparathyroidism based on only moderately elevated serum concentrations of calcium and followed medically for years, were referred to us for a sudden worsening of their clinical course. One 35-year-old man presented hemorrhagic gastritis with severe anemia and type II AV block with syncopal attacks. Three women, aged 51, 64 and 65 years, presented with severe hypercalcemia associated with renal failure in two and with marked bone disease in another. In all these cases parathyroid neoplasms were preoperatively localized (by ultrasonography, CT scan and radioactive 201-Tl 99-Tc scan) and surgically removed. Histological examination showed a parathyroid carcinoma in the male patient and single gland enlargements in the three females. A fifth patient, a 65-year-old woman, was referred to us in critical condition: severe hypercalcemia, osteopenia with femur fracture, myocardial infarction and renal failure. She died in a few days, in spite of intensive medical care. These cases suggest that patients with hyperparathyroidism initially diagnosed as "mild" need close medical observation and preferably, in our opinion, should undergo surgery.

Acute Kidney Injury↗

Nucleolar organizer regions in normal, hyperplastic and neoplastic parathyroid glands.

Using a one-stage silver staining technique, nucleolar organizer regions (AgNORs) were studied in paraffin sections of parathyroid glands (and in two lymph node metastases) from patients operated upon because of hyperparathyroidism or thyroid disease. The parathyroids were microscopically differentiated into normal, hyperplastic, adenomatous and carcinomatous glands. AgNORs were observed as distinct black dots of varying size and somewhat varying configuration in the nuclei of all glands. The mean number of AgNORs in the hyperplastic and adenomatous glands was not significantly different from that in the normal glands, whereas the carcinomatous glands exhibited significantly increased mean AgNOR number. No evidence was obtained for a role of AgNOR counting in the differentiation between normal and hyperplastic or adenomatous parathyroids, but the results suggest a potential role of enumeration of AgNORs in the discrimination between benign and malignant parathyroid neoplasms.

Adenoma↗

[Retrosternal parathyroid gland cystic neoplasm as a cause of primary hyperparathyroidism].

Parathyroid carcinoma is a rare cause of primary hyperparathyroidism (1-2%). In this paper a case of parathyroid cancer of the right inferior parathyroid gland cyst (5 cm in diameter) localised mostly retrosternally is presented in a patient suffering from severe hypercalcaemia (Ca--3.7 mmol/l, Ca(++)--1.8 mmol/l), severe bone pains and weakness, huge osteoporosis with following L5 compression fracture and recurrent nephrolithiasis. PTH blood level before surgical treatment was 1243 pg/ml (Norm: 10-60 pg/ml). In the preoperative ultrasonography of the neck, a lesion was found, but it was considered to be a cyst in the inferior pole of the right thyroid lobe. In a fine-needle biopsy from the lesion-colloid mass without any cells was found. In a 99mTc-MIBI scintigraphy of the neck a suspicion of focus lesion in the right superior parathyroid gland was made, which was not confirmed intra-operatively. Parathyroid carcinoma was diagnosed intraoperatively in histological examination. 'En block' resection of the retrosternal parathyroid tumor and right thyroid lobe was performed from the jugular incision. Any enlarged jugular lymph nodes were not found. In a postoperative period a transient hypocalcaemia was present, which disappeared after pharmacological treatment. During 32 months of follow-up neither no features of local recurrence nor distant metastases were found. Calcium level in blood was normal, PTH 216.0 pg/ml, severity of bone pains and weakness lessened, osteoporosis in a course of pharmacological treatment--with no further progress.

Diagnosis, Differential↗

Absence of cyclin D1/PRAD1 point mutations in human breast cancers and parathyroid adenomas and identification of a new cyclin D1 gene polymorphism.

PRAD1 (cyclin D1) has been implicated in the molecular pathogenesis of a variety of tumors, including parathyroid adenomas, t(11;14)-bearing B-lymphoid tumors, and breast cancer. The sequence of the overexpressed PRAD1 genes has been directly analyzed in only two tumor specimens, a benign parathyroid adenoma and a malignant centrocytic lymphoma. Thus, little is known about PRAD1 sequence in the vast majority of human primary tumors, including breast cancers. Using single-strand conformational polymorphism (SSCP) analysis, we have examined the coding region of the PRAD1 gene in 30 primary breast cancers and 25 parathyroid adenomas. Polymerase chain reaction (PCR)-SSCP analysis of the coding region of exons 1-5 of the PRAD1 gene did not reveal any tumor-specific mutations. During the course of screening for mutations, we found and established the sequence variants of a new DNA polymorphism at codon 241 within exon 4 of the PRAD1 gene. Since this polymorphism is located within the coding region of the PRAD1 gene, it will allow determination of allele-specific expression of the gene and the detection of allele imbalance. At least in breast and parathyroid neoplasms, overexpression of the wild-type PRAD1 sequence, rather than point mutational activation, appears to be the predominant mechanism by which PRAD1 exerts its oncogenic action.

Adenoma↗

Cystic parathyroid cancer. Case report.

A patient hospitalized for the assessment of a "thyroid nodule" is presented. Scintigraphically the nodule was cold. Thin needle aspiration biopsy by which 50 ml of a clear fluid was drawn, proved the nodule to be of cystic nature. Phospho-calcium findings allowed the diagnosis of primary hyperparathyroidism though the patient presented no subjective complaints. Histologic examination of the tissue removed intraoperatively revealed a cystic parathyroid neoplasm.

Combined Modality Therapy↗

Serum levels of angiogenic growth factors in patients with thyroid gland tumors and parathyroid adenoma.

OBJECTIVE: Angiogenic growth factors bFGF and VEGF ensure vascularisation of the growing tumor tissue. We decided to investigate their peripheral serum concentrations in patients with thyroid gland adenoma and papillary carcinoma and with parathyroid adenoma. We wanted to find the possible serum marker of these tumor diseases. METHODS: 28 patients with thyroid gland tumor (14x adenoma, 14x papillary carcinoma) and 12 patients with parathyroid gland adenoma. Growth factors serum levels were measured by ELISA method. RESULTS: We found significantly higher serum levels of bFGF in both groups of patients with thyroid adenoma (4.93 +/- 3.42 ng/ml) and papillary carcinoma (5.69 +/- 5.58 ng/ml) compared to the healthy population (1.47 +/- 1.77 ng/ml). There were no significant differences of VEGF serum levels between all examined groups of patients (adenoma 213 +/- 197, papillary carcinoma 210 +/- 179, healthy 227 +/- 231 pg/ml). We found significantly higher serum levels of bFGF in patients with parathyroid gland adenoma (7.59 +/- 9.12 ng/ml) compared to those in healthy people (1.47 +/- 1.77 ng/ml). CONCLUSIONS: Higher bFGF serum concentrations in patients with thyroid and parathyroid tumors are in accordance with their immunohistochemical tissue levels described in the literature. Not so in VEGF. bFGF may be a serum marker of thyroid and parathyroid neoplasms.

Adenoma↗

Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia.

The pathogeneses of parathyroid disease in patients with uremia and nonfamilial primary parathyroid hyperplasia are poorly understood. Because of multigland involvement, it has been assumed that these common diseases predominantly involve polyclonal (non-neoplastic) cellular proliferations, but an overall assessment of their clonality has not been done. We examined the clonality of these hyperplastic parathyroid tumors using X-chromosome inactivation analysis with the M27 beta (DXS255) DNA polymorphism and by searching for monoclonal allelic losses at M27 beta and at loci on chromosome band 11q13. Fully 7 of 11 informative hemodialysis patients (64%) with uremic refractory hyperparathyroidism harbored at least one monoclonal parathyroid tumor (with a minimum of 12 of their 19 available glands being monoclonal). Tumor monoclonality was demonstrable in 6 of 16 informative patients (38%) with primary parathyroid hyperplasia. Histopathologic categories of nodular versus generalized hyperplasia were not useful predictors of clonal status. These observations indicate that monoclonal parathyroid neoplasms are common in patients with uremic refractory hyperparathyroidism and also develop in a substantial group of patients with sporadic primary parathyroid hyperplasia, thereby changing our concept of the pathogenesis of these diseases. Neoplastic transformation of preexisting polyclonal hyperplasia, apparently due in large part to genes not yet implicated in parathyroid tumorigenesis and possibly including a novel X-chromosome tumor suppressor gene, is likely to play a central role in these disorders.

Adult↗

Significance of AgNOR counts for distinguishing carcinoma from adenoma and hyperplasia in parathyroid gland.

Nucleolar organizer region proteins, which can be stained and visualized by an argyrophil technique (AgNORs), are markers of cell activities, such as DNA transcription and proliferation, and they are useful for differential diagnosis between benign and malignant tumors. We counted both AgNOR numbers in 25 parathyroid lesions (three carcinomas, 11 adenomas, 10 hyperplasias, and one hyperplasia with carcinoma) to determine if the AgNOR number could be useful as a diagnostic aid in parathyroid neoplasms and hyperplasias, because it is often difficult to histopathologically distinguish among these lesions. The AgNOR numbers were significantly higher in carcinomas (3.18 +/- 0.05) than in adenomas (1.67 +/- 0.30, P < .001) or hyperplasias (1.85 +/- 0.16, P < .001), but there was no significant difference between adenomas and hyperplasias. These results suggest that AgNORs may be useful as an adjunct to discriminating carcinomas from adenomas or hyperplasias in the parathyroid gland.

Adenoma↗

Immunohistochemical investigation of angiogenic factors in parathyroid proliferative lesions.

OBJECTIVE: The pathological distinction between parathyroid neoplasms and hyperplasias remains difficult in several cases. Endoglin (CD105) is a proliferation-associated and hypoxia-inducible protein abundantly expressed in angiogenic endothelial cells. Vascular endothelial growth factor (VEGF) induces angiogenesis and VEGF-R2 is a tyrosine kinase receptor expressed early in development by endothelial cell precursors. We attempted to examine whether immunohistochemical expression of CD105, VEGF and VEGF-R2 may be useful in distinguishing between parathyroid hyperplasia and neoplasia as well as to elucidate, to some extent, the mechanism of neovascularization in proliferative lesions of the parathyroid gland. DESIGN: Tissue specimens were taken from 38 patients with primary hyperparathyroidism (HPT) (17 adenomas and 21 primary hyperplasias) and from 30 patients with secondary HPT. Normal glands served as controls. METHODS: In a standard immunohistochemical procedure, monoclonal antibodies to endoglin, VEGF and VEGF-R2 were applied to detect angiogenic endothelial cells. Immunostaining was estimated by image analysis and statistical analysis was subsequently performed. RESULTS: Positive CD105 immunoreaction was significantly increased in parathyroid adenomas by comparison with primary hyperplasias (P = 0.033) and with secondary hyperplasias (P = 0.033). When parathyroid adenomas, primary hyperplasia and secondary hyperplasia specimens were comparatively evaluated, VEGF immunoreaction was much more common in adenomas (P = 0.018). In addition, in samples with secondary hyperplasia, VEGF-R2 immunoreactivity was positively linked with VEGF expression as well as with the apoptotic index of parathyroid cells (P = 0.038 and 0.010 respectively). In secondary hyperplasia specimens, an inverse correlation between cyclin D1 immunoexpression and angiogenic indexes, such as CD105 and VEGF, was noticed (P = 0.007 and 0.0017 respectively). CONCLUSIONS: This study shows increased angiogenesis in parathyroid adenomas compared with parathyroid proliferative lesions. In secondarily hyperplastic glands increased angiogenesis and increased apoptosis occur simultaneously; in the latter glands, the overexpression of cyclin D1 does not appear to be the genetic abnormality responsible for increased angiogenesis.

Adenoma↗

Diagnosis of parathyroid tumors in familial isolated hyperparathyroidism with HRPT2 mutation: implications for cancer surveillance.

CONTEXT: Mutations of the HRPT2 gene have recently been implicated in the development of parathyroid carcinoma. OBJECTIVE: The objective of this study was early diagnosis of parathyroid tumor in a family with germline HRPT2 mutation. PATIENTS, METHODS, AND RESULTS: In a 40-yr-old male previously treated for parathyroid atypical adenoma, we screened the 17 translated HRPT2 exons and their exon-intron boundaries and found a germline frameshift mutation in exon 7 (685delAGAG) predicting a premature stop codon at nucleotides 767-769. Nine family members (age, 33.9 +/- 19.8 yr, mean +/- SD) also carry the mutation, but eight have had normal serum calcium. Biochemical and ultrasonographic evaluation uncovered a 27-yr-old hypercalcemic carrier niece with an atypical parathyroid adenoma, and a 43-yr-old normocalcemic carrier sister was found by ultrasonography to have an extrathyroidal nodule, which proved to be parathyroid carcinoma. The index case, 12 yr after surgery, was normocalcemic, but ultrasonography revealed an extrathyroidal nodule in the contralateral hemithyroid tissue that proved to be atypical adenoma. CONCLUSIONS: Our report confirms that germline mutations of HRPT2 gene may be associated with multiple parathyroid neoplasms. Our experience suggests that longitudinal surveillance by serum biochemistry alone may not be 100% sensitive, and addition of routine neck ultrasonography is a readily accepted adjunct that may facilitate earlier disease detection in some families.

Adenoma↗

Metachronous primary hyperparathyroidism due to a parathyroid adenoma and a subsequent carcinoma: report of a case.

An extremely rare case of metachronous primary hyperparathyroidism (PHP) due to a parathyroid adenoma and subsequent carcinoma with local lymphatic spread is presented herein. A 55-year-old woman was operated on for a parathyroid adenoma in the right inferior gland. Thirteen years after the first operation, she was again hospitalized for hypercalcemia and the presence of a hard mass in the right anterior neck region. Exploratory surgery and a histological examination of the resected tumor provided evidence of a parathyroid neoplasm in the right superior gland but the malignancy was equivocal. Postoperatively, her serum parathyroid hormone (PTH) level remained at 1.5-fold the upper limit of the normal range, and hypercalcemia again gradually developed. The results of higher positive rates by Ki-67 immunohistochemical staining and an aneuploid pattern by a flow cytometric analysis of the second neoplasm were consistent with a histological diagnosis of carcinoma, and she therefore underwent further surgery. A radical neck dissection revealed two lymph node metastases which were both successfully removed. The postoperative serum PTH and calcium levels then returned to within the normal ranges. These findings indicate the usefulness of Ki-67 immunohistochemical staining and a flow cytometric analysis for differentiating malignant lesions from benign parathyroid lesions, and the importance of surgically treating cases limited to local regions without distant metastasis.

Adenoma↗

Galectin-3 expression in parathyroid carcinoma: immunohistochemical study of 26 cases.

The diagnosis of parathyroid carcinoma (PC) is difficult and based on morphological features that are not totally reliable. Several molecular markers proved useful in the evaluation of PC, but their sensitivity, specificity, or both are rather low. With the aim of identifying a marker of malignancy in parathyroid tumors, we tested the expression of galectin-3 (Gal-3), a lectin expressed in several malignant tumors, including follicular carcinomas (but not adenomas) of the thyroid. Twenty-six PCs and 30 control parathyroid adenomas (PAs) were collected. The PCs had been diagnosed based on capsular/vascular invasion (26/26 cases), extraparathyroid infiltration (16), local recurrence (9), and distant metastases (6). All cases were immunohistochemically tested for Gal-3 and for other markers claimed to be useful in the differential diagnosis of parathyroid neoplasms, namely, Ki67, p27, and bcl2. Gal-3 was expressed by 24 of the PC (92.3%), but only 1 PA (3.3%) (P < .001). All metastasizing PCs were Gal-3-positive. As expected, the Ki67 proliferative index was higher in PCs (mean, 6.7%) than in PAs (1.9%); p27 was down-regulated in 61.5% of PCs and only 33.3% of PAs, whereas bcl2 was strongly positive in most PAs and in 38.5% of PCs. In a suspected PC, the association of Gal-3 with Ki67 (using a cutoff of 6% for the proliferative activity) appeared the best marker combination (sensitivity 96.2%, specificity 90%), and the profile Gal-3-positive/Ki67 >6% was unique to PCs. We conclude that Gal-3 immunostaining is a valuable tool to support a diagnosis of PC in highly proliferating (Ki67 >6%) tumors affecting a single parathyroid gland.

Adenoma↗

[Parathyroid carcinoma].

Parathyroid carcinoma is a rare disease accounting for 1 to 5% of parathyroid neoplasms. This malignant tumour must be suspected when a severe primary hyperparathyroidism occurs with high hypercalcemia and elevated parathormon levels. At this time, a cervical mass is often palpable. Both head and neck ultrasonography and 99mTc-sestamibi scintigraphy are the best preoperative imaging tests to suspect and localize the tumour. Surgical approach with simultaneous tumorectomy and hemithyroidectomy, completed by selective neck dissection (level VI) is the treatment of choice. An elective lateral neck dissection should be performed if necessary. Tumour control should be monitored by regular measurement of calcium and parathormon levels. Local recurrence or metastasis risk is 30 to 70% and the 5 year overall survival about 50 to 80%. In case of recurrence, aggressive surgical management should be applied and adjuvant radiation therapy may be discussed.

Humans↗