This is the most common cause of primary hyperparathyroidism. Patients rarely present with a mass lesion. Instead, the diagnosis is suspected when a patient presents with elevated serum calcium, secondary to elevated levels of parathyroid hormone.
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/
Differential Diagnosis Prognosis Treatment Commonly Used Terms Internet Links
EPIDEMIOLOGY CHARACTERIZATION INCIDENCE 80% of patients with primary hyperparathyroidism AGE RANGE-MEDIAN Average 4th decade SEX (M:F) 1:3
DISEASE ASSOCIATIONS CHARACTERIZATION Ionizing radiation Possible role MEN I and II syndromes
PATHOGENESIS CHARACTERIZATION ALLELIC LOSS
Am J Surg Pathol. 2005 Aug;29(8):1049-1055. Abstract quote
Parathyroid carcinoma can be difficult to diagnose, and the final pathologic diagnosis relies on clinicopathologic correlation. Clinical features of malignancy include high preoperative calcium levels and an intraoperative impression that the gland is adherent to local structures.
Histologic features of malignancy include increased mitoses, vascular invasion, and broad bands of fibrosis.
This study used molecular genotyping to assess parathyroid neoplasia for loss of heterozygosity across a panel of known tumor suppressor genes that have been previously identified as being important in the pathogenesis of parathyroid diseases. Parathyroid adenomas, hyperplasia, and carcinomas were included in the study, and a fractional allelic loss was calculated for each lesion. Losses of 1q25, 7q13.3, 10q23, 13q14.3, and 11p15.5 were particularly prevalent. In addition, almost all adenomas and carcinomas had loss of the markers for 1p.
The benign parathyroid diseases (adenomas and hyperplasia) had low mean fractional allelic loss (11% and 15%, respectively). The parathyroid carcinomas, in contrast, showed high mean fractional allelic loss (63%). This difference in the mutational profile suggests that this type of assay may be useful as an adjunctive diagnostic test in cases of parathyroid neoplasia.
Multiple endocrine neoplasia type 2-associated RET proto-oncogene mutations do not contribute to the pathogenesis of sporadic parathyroid tumors.
Willeke F, Hauer MP, Buchcik R, Gebert JF, Hahn M, Fitze G, Mechtersheimer G, Moller P, Saeger HD, Herfarth C, Schackert HK.
Department of Surgery, Ruprecht Karls University of Heidelberg, Germany.
Surgery 1998 Sep;124(3):484-90 Abstract quote
BACKGROUND: Parathyroid disease occurs sporadically or as part of hereditary multiple endocrine neoplasia (MEN) syndrome. The aim of this study was to evaluate the possible role of the RET proto-oncogene not only in hereditary MEN 2-associated hyperparathyroidism but also in different forms of sporadic hyperparathyroidism.
METHODS: We investigated 22 patients with parathyroid disease whose family history and results of laboratory and clinical examinations excluded MEN 2 syndrome. DNA extractions of histologically confirmed tumor tissue of patients with primary hyperparathyroidism (n = 18), renal hyperparathyroidism (n = 2), and parathyroid carcinoma (n = 2) were performed. Using solid phase DNA sequencing, mutation analysis of polymerase chain reaction amplified products focused on exons 10, 11, and 16 of the RET proto-oncogene. Parathyroid tissue from four patients with known MEN 2A served as positive controls.
RESULTS: No mutations of the codons 609, 611, 618, 620, 634, and 918 were found in the sporadic parathyroid tumors analyzed. DNA sequencing revealed heterozygous mutations in codon 634 of the RET proto-oncogene in four parathyroid glands from four patients with MEN 2A.
CONCLUSIONS: Mutations of the RET proto-oncogene contributing to MEN 2 syndromes are absent in sporadic parathyroid tumors. Our data in conjunction with the literature suggest at least three different modes of tumorigenesis in parathyroid disease.
Frequent Loss of Heterozygosity at 1p36.3 and p73 Abnormality in Parathyroid Adenomas
Liang Shan, etal.
Mod Pathol 2001;14:273-278 Abstract quote
Although 1p is one of the most common loci showing loss of heterozygosity (LOH) in primary parathyroid adenoma, fine mapping has not been previously examined.
In this study, we analyzed LOH in 32 primary parathyroid adenomas using five microsatellite markers at 1p36 (proximal-D1S507-D1S450-D1S2893-D1S468-D1S243-distal). All cases were heterozygous for at least one marker. The frequency of LOH varied from 41.2% (D1S468) to 7.1% (D1S507) among the different markers. LOH was detected consistently in a group of nine adenomas (28.1%, 9/32). A single region (7 cM) showing a consistent LOH at 1p36.3 was obtained that was flanked distally by D1S468 and proximally by D1S2893. Because the p73 gene is localized within this region and acts as a tumor suppressor gene, we examined the possible involvement of p73 in the development of parathyroid tumor. Allelic loss of p73 was identified in four adenomas (25%, 4/16 informative cases) that were all from the group of the nine adenomas with LOH, but somatic mutation was not detected in the remaining allele. At the StyI polymorphism of Exon 2, four of the six adenomas with LOH at 1p36 were heterozygous and expressed the GC allele. Of the six heterozygous adenomas without LOH, 4 showed biallelic and 2 monoallelic expressions (GC allele). All adenomas mainly expressed the p73 isoform. p73 protein was observed in five of the six adenomas with LOH and in two of the six adenomas without LOH. There were no differences in p73 protein levels between the samples with and without LOH.
In conclusion, a candidate gene for parathyroid tumorigenesis is present within a 7-cM region at 1p36.3, however p73 is unlikely to be the target of the LOH at 1p36.3.
CHARACTERIZATION Serum calcium and parathyroid hormone Elevated CT scan, radioactive thallium scanning, and ultrasound All may be used for detection with sensitivities ranging from 60-90% INTRAOPERATIVE PARATHORMONE MONITORING QuiCK-Pak system (Nichols Institute Diagnostics) allows for intraoperative monitoring which will show decreased levels after removal of the hyperfunctioning gland
- Rapid intraoperative parathyroid hormone testing with surgical pathology correlations: the "chemical frozen section".
Department of Pathology, Florida Hospital Medical, Center, Orlando.
Am J Clin Pathol. 2004 Nov;122(5):704-12. Abstract quote
The classic surgical approach to patients undergoing parathyroidectomy for primary or secondary hyperparathyroidism has experienced a dramatic shift owing to preoperative localization of the affected glands and/or the use of rapid intraoperative parathyroid hormone (RI-PTH) assays, allowing for minimally invasive surgical excisions. Institutional experience with 141 patients who underwent parathyroidectomy aided by the use of RI-PTH is reviewed.
The orientation provided by the intraoperative assay is essential in guiding the surgeon in these minimally invasive procedures, it helps reveal the cases of primary hyperparathyroidism with involvement of more than 1 gland, and it replaces the need for performing frozen sections, except for cases of secondary hyperparathyroidism.
Intraoperative testing for parathyroid hormone: a comprehensive review of the use of the assay and the relevant literature.
Carter AB, Howanitz PJ.
Department of Pathology & Laboratory Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
Arch Pathol Lab Med. 2003 Nov;127(11):1424-42. Abstract quote
OBJECTIVE: The rapid intraoperative parathyroid hormone assay is transforming the parathyroidectomy procedure. We present a review of the literature on the use of the assay as an adjunct to surgery. To our knowledge, this is the first review of the literature to encompass and compare all known primary studies of this assay in parathyroidectomy patients.
DATA SOURCES: Articles were collected by searching MEDLINE databases using relevant terminology. The references of these articles were reviewed for additional studies. Supplementary articles pertinent to the parathyroidectomy procedure, preoperative parathyroid localization studies, and intraoperative parathyroid hormone assay development also were examined.
STUDY SELECTION AND DATA EXTRACTION: One hundred sixty-five references were analyzed and categorized separately into groups.
DATA SYNTHESIS: The primary studies of intraoperative data on patients undergoing parathyroidectomy were compared when possible. Studies were analyzed by type of assay used, where performed, turnaround time, and efficiency of use. Reviews of the types of parathyroid surgery and preoperative localization were included for educational purposes.Conclusions.-The intraoperative parathyroid hormone assay is a useful adjunct to preoperative imaging and parathyroid surgery because of its unique ability to detect an occult residuum of hyperfunctioning parathyroid tissue. Use of this assay will obviate the need for frozen section in most routine cases. The test facilitates minimally invasive parathyroidectomy for single parathyroid adenomas, which, in turn, improves cost-effectiveness and cosmetic outcome. Its use in patients with known preoperative multiglandular disease is promising but requires further study.
The validity of quick intraoperative parathyroid hormone assay: an evaluation in seventy-two patients based on gross morphologic criteria.
Gordon LL, Snyder WH 3rd, Wians F Jr, Nwariaku F, Kim LT.
Department of Surgery, University of Texas Southwestern Medical Center, Dallas 75235-9156, USA.
Surgery 1999 Dec;126(6):1030-5 Abstract quote
BACKGROUND: Parathyroidectomy for primary hyperparathyroidism has conventionally required identification of all parathyroid glands with excision of grossly abnormal glands. Using this approach, cure rates exceed 95%. Directed cervical exploration has been advocated using quick intraoperative parathyroid hormone (QPTH) assay with preoperative localization. Adoption of this approach requires validation of the accuracy of QPTH assay.
METHODS: Patients with primary hyperparathyroidism undergoing bilateral neck exploration during a 31-month period were reviewed. Uniglandular (UGD) or multiglandular (MGD) disease was determined by gross morphologic criteria. QPTH assays were performed before skin incision and at 5, 10, and 20 minutes after excision of each abnormal gland. A 10-minute QPTH decrease of 50% from baseline levels indicated curative excision. These data were not used to guide extent of exploration or tissue resection.
RESULTS: Of 72 patients, 55 (76%) had UGD and 17 (24%) had MGD. QPTH assay accurately predicted the disease state in 89%. Four (7%) UGD patients did not have an appropriate QPTH decline at 10 minutes. Four (24%) MGD patients had an inappropriate QPTH decline at 10 minutes.
CONCLUSIONS: Using QPTH guided exploration, 6% (4 of 72) of patients would undergo unnecessary extended exploration and 6% (4 of 72) (95% CI, 1% to 13%) may require reoperation for unidentified MGD. These results validate the accuracy of QPTH assay.
Improved success rate in reoperative parathyroidectomy with intraoperative PTH assay.
Irvin GL 3rd, Molinari AS, Figueroa C, Carneiro DM.
Department of Surgery, University of Miami School of Medicine, Jackson Memorial and Veterans Affairs Medical Centers, Florida 33101, USA.
Ann Surg 1999 Jun;229(6):874-8; discussion 878-9 Abstract quote
OBJECTIVE: The clinical usefulness of preoperative localization and intraoperative PTH assay (QPTH) in primary hyperparathyroidism have been established. However, without the use of QPTH, the parathyroidectomy failure rate remains 5% to 10% in large reported series and is probably much higher in the hands of less experienced parathyroid surgeons. Persistent hypercalcemia requires another surgical procedure. The authors compared the outcomes in 50 consecutive patients undergoing more difficult secondary parathyroidectomy with and without the adjunctive support of QPTH.
METHODS: Two groups of similar patients underwent reoperative parathyroidectomy for failed surgery or recurrent disease. The successful return to normocalcemia in group I, with QPTH used to localize and confirm complete excision of all hyperfunctioning glands, was compared with group II, who did not have this intraoperative adjunct.
RESULTS: In 31/33 patients in group I, calcium levels returned to normal. With good preoperative localization studies, 17 patients underwent successful straightforward parathyroidectomies as predicted by QPTH. In the other 14 patients, QPTH assay proved extremely beneficial by facilitating localization with differential venous sampling; measuring the increase in hormone secretion after massage of specific areas; recognizing suspicious nonparathyroid tissue excised without a decrease in hormone levels, avoiding frozen-section delay; and correctly identifying the excision of abnormal tissue despite false-positive/false-negative sestamibi scans. In group II, who underwent surgery before QPTH was available, 4 of 17 patients (24%) remained hypercalcemic after extensive reexploration.
CONCLUSION: With the intraoperative hormone assay used to facilitate localization and confirm excision of all hyperfunctioning tissue, the success rate of reoperative parathyroidectomy has improved from 76% to 94%.
Intraoperative quick parathyroid hormone versus same-day parathyroid hormone testing for minimally invasive parathyroidectomy: A cost-effectiveness study.
Agarwal G, Barakate MS, Robinson B, Wilkinson M, Barraclough B, Reeve TS, Delbridge LW.
Endocrine Surgical Unit, Royal North Shore Hospital, University of Sydney, Sydney, Australia.
Surgery 2001 Dec;130(6):963-970 Abstract quote
Intraoperative quick parathyroid hormone (QPTH) measurement is claimed to eliminate failures during minimally invasive parathyroidectomy. The cost-effectiveness of QPTH (ie, true cost of avoiding a failed operation) needs careful evaluation.
In 92 consecutive patients who underwent minimally invasive parathyroidectomy via a small lateral incision, QPTH was estimated preoperatively and at 5, 10, and 15 minutes postparathyroidectomy. QPTH results were subsequently compared with the procedure outcome. Cost-effectiveness analysis was performed for 3 subsequent theoretical management strategies: QPTH not performed, QPTH results available intraoperatively, and parathyroid hormone and serum calcium levels measured routinely with results made available the same day.
With criteria for cure being a decrease in the QPTH measurement to less than 50% of preoperative levels and to within normal range, QPTH predictions were true positive in 78 patients; false-negative in 7; false-positive in 1; and true negative in 2. The true cost of using QPTH measurement to avoid a failed operation was US $19,801.19, with 7 patients undergoing unnecessary conversion. Routine same-day parathyroid hormone and calcium measurements significantly reduced this to $624.73. Sensitivity analysis with varying cost assumptions demonstrated cost-effectiveness analysis to be robust.
The fact that 97% of patients will be cured regardless of QPTH testing combined with its false-negative rates significantly reduces the cost-effectiveness of the test when compared with same-day parathyroid hormone testing.
A spike in parathyroid hormone during neck exploration may cause a false-negative intraoperative assay result.
Yang GP, Levine S, Weigel RJ.
Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
Arch Surg 2001 Aug;136(8):945-9 Abstract quote
HYPOTHESIS: We hypothesize that false-negative results using the rapid intraoperative parathyroid hormone (IOPTH) assay can be caused by spikes in the level of parathyroid hormone that occur during mobilization of the adenoma.
DESIGN: Retrospective analysis of a case series.
SETTING: University tertiary care center.
PATIENTS: Ten consecutive patients with primary hyperparathyroidism.
INTERVENTIONS: All patients underwent neck exploration with IOPTH monitoring. Using a sampling protocol described in the literature, IOPTH values were checked at the time of incision, during mobilization of the adenoma, and 10 minutes after resection of the adenoma.
MAIN OUTCOME MEASURES: Patients were evaluated for adequate parathyroid tissue excision as determined by IOPTH levels and examination of ipsilateral glands. All patients had normal serum calcium values documented postoperatively. Parathyroid hormone half-life was calculated assuming first-order kinetic decay.
RESULTS: Nine patients had an appropriate decline in IOPTH with a mean +/- SD parathyroid hormone half-life of 3.9 +/- 1.08 minutes. Mobilization of the adenoma resulted in a spike in the IOPTH value, with 1 patient's value increasing from a baseline of 95.5 pg/mL (10.1 pmol/L) to 751 pg/mL (79.1 pmol/L). Another patient who was confirmed to have a solitary adenoma had a false-negative postexcision value. A spike in IOPTH that occurred during neck dissection was not detected by the sampling protocol and explains the false-negative value. A literature review revealed that most protocols check baseline values early in the operation and are at risk for false-negative results due to a spike from mobilization of the adenoma.
CONCLUSIONS: These data demonstrate that false-negative IOPTH assay findings can result from a spike in parathyroid hormone level during exploration, which may go unrecognized if baseline values are measured during the early stages of mobilization of the adenoma. We have altered our assay protocol and have begun measuring IOPTH at the time of neck incision, at the time the adenoma is completely removed (time zero [t(0)]), and 10 minutes after excision.
Intraoperative parathyroid hormone monitoring fails to detect double parathyroid adenomas: A 2-institution experience.
Gauger PG, Agarwal G, England BG, Delbridge LW, Matz KA, Wilkinson M, Robinson BG, Thompson NW.
University of Michigan Departments of Surgery and Pathology, Ann Arbor, Mich.
Surgery 2001 Dec;130(6):1005-1010 Abstracty quote
Background. We hypothesized that intraoperative parathyroid hormone monitoring (IOPTH) reliably would detect double parathyroid adenomas.
Methods. This was a retrospective study of 20 patients undergoing conventional parathyroidectomy with resection of exactly 2 abnormal glands. Full exploration was performed regardless of IOPTH values, which were measured after anesthetic induction and 5 and 10 minutes following removal of the first abnormal parathyroid gland. Failure to fall below 50% of baseline value by 10 minutes following resection of the first gland indicated the presence of multiglandular disease.
Results. All patients were cured. All excised glands were hypercellular on histology. Mean IOPTH values in 9 of the 20 patients with true negative results (noncurative decrease, another gland present) were 66% +/- 7% at 5 minutes and 83% +/- 15% at 10 minutes. The IOPTH values in 11 of the 20 patients with false positive results (curative decrease, another gland present) were 28% +/- 4% at 5 minutes and 18% +/- 2% at 10 minutes. The false positive rate of IOPTH was 55%.
Conclusions. We found that IOPTH failed to reliably detect the presence of double parathyroid adenomas. These data suggest that caution should be exercised when terminating limited parathyroid exploration based on a curative fall in IOPTH values.
Intraoperative parathyroid hormone testing: survey of testing program characteristics.
Hortin GL, Carter AB; College of American Pathologists Point-of-Care Testing Resource Committee.
Department of Laboratory Medicine at the Warren Magnusson Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
Arch Pathol Lab Med 2002 Sep;126(9):1045-9 Abstract quote
OBJECTIVE: To examine the number and testing characteristics of laboratories that offer intraoperative testing of intact parathyroid hormone (PTH).
DESIGN: Laboratories (n = 355) that participated in 2001 in PTH proficiency testing with the College of American Pathologists Special Ligand Survey were surveyed about intraoperative PTH testing.
RESULTS: Of the 320 laboratories that responded to the survey, 92 performed intraoperative PTH testing. Testing practices were divided nearly equally among laboratories that performed intraoperative PTH testing for all parathyroidectomies (40%), most but not all cases (31%), and less than half of cases (30%). Testing frequency usually was low, with about two thirds of laboratories reporting 5 or fewer cases per month. A surprising finding was that, although intraoperative PTH testing originally became widely practiced as a point-of-care test, 71% of laboratories performed testing in a central laboratory, 6% in satellite laboratories, and only 23% in operating suites. A survey of methods showed that 33% used the manual QuiCk-Intraoperative test, 47% used the automated Immulite Turbo intact PTH assay, and 20% used other methods.
CONCLUSIONS: Intraoperative testing of intact PTH, although relatively new, has come into widespread practice during parathyroid surgery. Service delivery has evolved from a point-of-care model toward a central laboratory model, with this test serving as an illustrative example of factors that affect the balance between point-of-care and laboratory testing.
CHARACTERIZATION General 90% occur in the head and neck but may occur anywhere parathyroid glands occur including the mediastinum, thyroid, esophagus Appearance Tan to yellow-brown Size
Some correlation between adenoma weight and serum levels of calcium, parathyroid hormone concentration, and clinical symptomatology
Am J Clin Pathol. 2005 Nov;124(5):749-54. Abstract quote
We describe 17 cases (9 women, 8 men; aged 36 to 72 years) of primary parathyroid tumors occurring primarily in the anterior mediastinum. Clinically and radiologically, all patients had an anterior mediastinal tumor.
All patients had metabolic disturbances with calcium and phosphorus. Of 17 patients, 13 had clinical primary hyperparathyroidism, 1 had secondary hyperparathyroidism due to polycystic kidney disease, and 1 had a history of prostatic carcinoma and 1 of chronic obstructive pulmonary disease. In 1 patient, the tumor was found at autopsy. Grossly, the tumors varied in size from 2 to 7 cm in greatest dimension.
Histologically, 2 tumors showed features of parathyroid carcinoma, and 15 tumors showed more conventional features of parathyroid adenomas. Six tumors were predominantly oncocytic, 6 were composed predominantly of chief cells, and 3 had mixed cellular composition. Immunohistochemical studies for chromogranin, synaptophysin, low-molecular-weight keratin (CAM 5.2), and parathyroid hormone were performed in 10 cases (8 parathyroid adenomas and 2 parathyroid carcinomas). All the tumors examined showed variable positive reaction for those antibodies.
The cases highlight the importance of keeping primary parathyroid tumors in the differential diagnosis of anterior mediastinal tumors.
HISTOLOGICAL TYPES CHARACTERIZATION General
Majority are composed of closely packed chief cells arranged in cords, glands, and sheets
May have a rim of normal or suppressed parathyroid tissue which represents normal parathyroid
Rarely papillae may occur
Mitotic figures Although mitotic figures may be present, any case with more than 1 MF/10 hpf should be carefully evaluated for the presence of other criteria of carcinoma
The parathyroid adenoma. A histopathologic definition with a study of 172 cases of primary hyperparathyroidism.
Ghandur-Mnaymneh L, Kimura N.
Am J Pathol 1984 Apr;115(1):70-83 Abstract quote
There is unanimous agreement that parathyroid adenoma lacks precise histopathologic definition. Likewise, it is generally accepted that hyperplasia may involve the parathyroid glands unequally, causing tumorous enlargement of a single parathyroid gland. On the basis of observations of the histologic features of the normal parathyroid gland and on the accepted definition of an adenoma, and based on the concept of unequal or "focal" hyperplasia, histopathologic criteria for the recognition of adenoma and its differentiation from hyperplasia were formulated.
Study of 172 cases of primary hyperparathyroidism with the use of these criteria showed that adenomas accounted for only 5.8% of cases of primary hyperparathyroidism and that hyperplasia with single gland enlargement accounted for 75.1%.
The literature and data supporting the view that solitary masses of the parathyroid glands more often represent hyperplasia than adenoma are cited.
3% of all adenomas
90% composition by oncocytic cells
Second histologically normal parathyroid
Postoperative alleviation of hypercalcemia
Broad sheets and anastomosing cords of oncocytic cells with abundant granular eosinophilic cytoplasm
Proliferation of parenchymal and stromal elements
Abundant adipose tissue with frequent areas of myxoid change and fibrosis
Prominent collections of lymphoid cells
CHARACTERIZATION Oil Red O stain Identifies fine lipid droplets in the cytoplasm versus larger coarser granules in the normal gland
DIFFERENTIAL DIAGNOSIS CHARACTERIZATION PARATHYROID HYPERPLASIA
Histologic diagnosis of primary hyperparathyroidism: a concordance analysis between three pathologists.
Bornstein-Quevedo L, Gamboa-Dominguez A, Angeles-Angeles A, Reyes-Gutierrez E, Vargas-Vorackova F, Gamino R, Herrera MF.
Department of Pathology, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico.
Endocr Pathol 2001 Spring;12(1):49-54 Abstract quote
Primary hyperparathyroidism (HPT) is caused by a parathyroid adenoma, hyperplasia or carcinoma. Difficulties for the histologic diagnosis of abnormal parathyroid tissue are widely recognized.
The aim of the study was to evaluate the reproducibility of the morphologic criteria through a concordance study among three pathologists. Representative slides of 40 patients with biochemically primary HPT stained with hematoxylin and eosin were blindly reviewed by three pathologists. Each pathologist established the diagnosis of adenoma or hyperplasia and assessed the presence of fat cells, a rim of normal tissue, a fibrous capsule, the number of cellular types, the lobular pattern, and the characteristics of the blood vessel's wall. A concordance analysis was then performed. Mean age of the group was 55 +/- 14 yr, 7 were males and 33 females. The concordance analysis among the three pathologists for the differential diagnosis between adenoma and hyperplasia, showed a Kappa index of 0.5. Kappa index for the presence of fat cells was 0.56, for the presence of a rim of normal tissue 0.47, and for the number of cellular types 0.29.
The concordance for the differential diagnosis between parathyroid adenoma and hyperplasia in this study was low.
P53 as a marker of differentiation between hyperplastic and adenomatous parathyroids.
Ricci F, Mingazzini PL, Sebastiani V, D'Erasmo E, Letizia C, De Toma G, Alo PL.
Departments of Experimental Medicine and Pathology, Internal Medicine, and Surgery "Pietro Valdoni," University of Rome La Sapienza, Rome, Italy.
Ann Diagn Pathol 2002 Aug;6(4):229-35 Abstract quote
Primary hyperparathyroidism is the clinical result of parathyroid adenoma or hyperplasia, rarely of carcinoma. Clinical, serologic, and radiologic data are unable to discriminate a single parathyroid adenoma from an enlarged hyperplastic gland. Morphologic features also overlap in adenoma and small hyperplastic gland.
Studying immunohistochemical expression of fatty acid synthase (FAS), p53, Ki67 and bcl-2, we found that among 21 adenomas 19 (90.5%) were positive for FAS, 12 (57.2%) for Ki67, 11 (52.4%) for p53, and 16 (76.2%) for bcl-2; among 12 hyperplasias, 12 (100%) were positive for FAS, 6 (50%) for KI67, 8 (66.7%) for p53, and 8 (66.7%) for bcl-2. Statistical analysis showed that FAS was associated with parathormone (PTH) (P =.001), Ki67 (P =.01), and p53 (P =.01). Moreover, FAS was associated with hyperplastic (P =.0001) and adenomatous glands (P =.0001). Ki67 was associated with both adenomatous (P =.02) and hyperplastic glands (P =.005). P53 protein were associated only with hyperplastic glands (P =.01).
The different occurrence of p53 in parathyroids adenoma and hyperplasia may enable a different management and follow-up of the patients with primary hyperparathyroidism, stratifing them into two groups. The first, with a "false" adenoma having a high risk of relapse, may necessitate exams like serum calcium levels, PTH concentrations, urinary calcium levels for 24 hours, kidney functional tests, and radiology and ultrasound every 3 to 6 months, whereas the second with "true" adenoma, at low risk of relapse, may be checked less frequently with serum calcium levels and PTH concentrations.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS-GENERAL
Parathyroid neoplasms: Clinical, histopathological, and tissue microarray-based molecular analysis.
Stojadinovic A, Hoos A, Nissan A, Dudas ME, Cordon-Cardo C, Shaha AR, Brennan MF, Singh B, Ghossein RA.
Departments of Surgery and Pathology and the Laboratory of Epithelial Cancer Biology, Memorial Sloan-Kettering Cancer Center, New York, NY.
Hum Pathol 2003 Jan;34(1):54-64 Abstract quote
We studied 45 patients with typical and 8 with atypical parathyroid adenomas as well as 20 with parathyroid carcinomas. Clinical, pathological, and molecular analyses were conducted on all adenomas. Clinical data were analyzed for 20, histopathologic slides for 16, and tissue specimens for 8 patients with carcinoma. Molecular expression profiles were investigated by immunohistochemistry (IHC) for Ki-67, p53, mdm2, p21, Bcl-2, cyclin D1, and p27 on paraffin-embedded tissues arrayed on tissue microarrays. Trabecular growth and vascular, capsular, and soft-tissue invasion were characteristic of parathyroid carcinomas but not of typical adenomas. No adenomas recurred. Seventy-four percent of carcinomas recurred, most in the neck.
Seventy-nine percent of patients with such illness died of disease after an indolent, multiply recurrent course responsive to repeated resections; the 5-year survival rate was 50%. High Ki-67 proliferative index was seen in 2% of adenomas and 25% of carcinomas, whereas p27 expression was present in 80% of adenomas and 18% of carcinomas. The molecular phenotype, p27(+)Bcl-2(+)Ki-67(-)mdm2(+), was observed in 76%, 29%, and 0% of typical and atypical adenomas and carcinomas, respectively. The complexity of molecular phenotypes increased with tumor aggressiveness.
Parathyroid carcinoma is an aggressive disease with a propensity for multiple recurrences. It is characterized by capsular, vascular, and soft-tissue invasion. Recurrence portends poor outcome.
Molecular markers, Ki-67 and p27, may distinguish parathyroid carcinoma from adenoma. The molecular phenotype, p27(+)Bcl-2(+)Ki-67(-)mdm2(+), appears to be unique to nonmalignant parathyroid tumors, and multimarker phenotypes are more complex in carcinomas.
Analysis of Parathyroid Neoplasms by Interphase Fluorescence In Situ Hybridization.
Erickson LA, Jalal SM, Harwood A, Shearer B, Jin L, Lloyd RV.
Department of Laboratory Medicine and Pathology (*Anatomic Pathology and daggerCytogenetics), Mayo Clinic and Mayo Foundation, Rochester, MN.
Am J Surg Pathol. 2004 May;28(5):578-584. Abstract quote
Recent studies have indicated that numerical chromosomal abnormalities, including changes in cyclin D1 and p53, may be involved in parathyroid tumorigenesis.
We analyzed a series of parathyroid neoplasms with DNA fluorescent probes to evaluate the diagnostic and prognostic utility of numerical abnormalities of chromosomes 1, 6, 9, 11, 13, 15, 17, and 22 and cyclin D1 and p53 gene loci. Interphase fluorescence in situ hybridization (FISH) analysis was performed on paraffin-embedded tissue sections from 15 parathyroid adenomas and 18 parathyroid carcinomas. Directly labeled fluorescent DNA probes for the centromere region of chromosomes 1, 6, 9, 11, 15, and 17, and locus-specific probes for chromosome 22 and chromosome 13 and for cyclin D1 and p53 gene loci were used for dual-probe hybridization. Sixty-seven percent (10 of 15) parathyroid adenomas and 78% (14 of 18) of parathyroid carcinomas showed chromosome gains. Seventy-three percent (11 of 15) of parathyroid adenomas and 33% (6 of 18) of parathyroid carcinomas showed chromosome losses. Normal parathyroid tissues used as controls showed no chromosomal abnormalities. Parathyroid hyperplasias averaged 1.8 gains and 0.2 losses per case.
Parathyroid adenomas averaged 2.8 gains and 0.8 losses per case, and parathyroid carcinomas averaged 3.6 gains and 0.6 losses per case. In summary, chromosome abnormalities, both gains and losses, are common in parathyroid adenomas and carcinomas. Parathyroid carcinomas tend to show gains of more chromosome than adenomas. Chromosome 11 was the most frequent chromosome loss identified in parathyroid adenomas and a frequent chromosomal gain in parathyroid carcinomas.
These results indicate that gain of chromosome 11 is associated with more aggressive biologic behavior in parathyroid neoplasms.
Recurrence of hypercalcemia following excision may occur in about 3%
May also occur if implantation occurs after surgery
TREATMENT Surgical debate whether subtotal parathyroidectomy or excision of the adenoma and biopsy of a remaining gland should be performed
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