Randall D. Gaz

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.

Monoclonality and Abnormal Parathyroid Hormone Genes in Parathyroid Adenomas

Previous work based on the relative tissue content of glucose-6-phosphate dehydrogenase isoenzymes suggested that parathyroid adenomas, like primary hyperplasia, may be multicellular (not clonal) in origin. We have reexamined this issue by using two independent molecular genetic methods. We report tumor-cell-specific restriction-fragment-length alterations involving the parathyroid hormone gene from two human parathyroid adenomas. These abnormal restriction fragments indicate that in each case a clonal proliferation of cells was present and also suggest that DNA alterations involving the parathyroid hormone locus may be important in the tumorigenesis or clonal evolution of some parathyroid adenomas. In addition, we used a restriction-fragment-length polymorphism in an X-linked gene (hypoxanthine phosphoribosyltransferase) to examine the clonality of eight parathyroid adenomas in women. Of these eight adenomas, six had the DNA hybridization pattern of monoclonality, and two had an equivocal pattern. None of five hyperplastic parathyroid glands had a monoclonal pattern. We conclude that some (and perhaps many) single parathyroid adenomas are monoclonal neoplasms. Our observations suggest that there is a fundamental biologic difference between parathyroid adenomas and primary hyperplasia--a difference that could prove useful in distinguishing these entities clinically.

Natural history of parathyroid carcinoma: Diagnosis, treatment, and results*

From 1948 to 1983, 28 patients with parathyroid carcinoma underwent treatment and analysis at the Massachusetts General Hospital. This represents about 2 percent of the 1,200 patients with hyperparathyroidism managed during the period. Patient ages ranged from 18 to 72 years (mean 45 years) with equal numbers of both sexes (14 women and 14 men). There are several hallmarks that are clues to an increased index of suspicion preoperatively. Nine of the patients (32 percent) presented with palpable neck masses. Eleven patients (39 percent) had a serum calcium level greater than 14 mg/100 ml. Significant elevations of the parathyroid hormone level were noted with values two to three times normal. The incidence and severity of metabolic complications were prominent. These complications included renal stones in 18 patients (64 percent), bone disease in 14 patients (50 percent), peptic ulcer disease in 5 patients (18 percent), parathyroid crisis in 4 patients (14 percent), and pancreatitis in 2 patients (7 percent). Eleven of the patients underwent previous surgical therapy at other institutions, and 17 patients had their initial operation at our institution. Cervical parathyroid carcinomas that ranged from 1.5 to 27 g and 1.5 to 6 cm were excised. The characteristic appearance was a gray-white, stone hard parathyroid mass with invasion of adjacent tissue. The outcome was favorable for 16 surviving patients, with 14 (50 percent) showing no evidence of recurrence 2 to 17 years postoperatively and 2 alive with persistent disease 3 years after operation. Twelve patients died. Of these, eight had unsuccessful initial operative intervention with capsular rupture and dissemination of cancer, one had advanced disease with mediastinal extension which was unresectable, and three died from unrelated causes. Recurrences became apparent within 6 months to 3 years after operation and unfortunately denoted incurable disease. The mean survival time after operation in patients with recurrent disease was 7.6 years, ranging from 1 to 22 years. Carcinoma of the parathyroid gland is a rare entity. Although it is difficult to diagnose preoperatively, there should be an increased index of suspicion in those hyperparathyroid patients with palpable neck masses, profound hypercalcemia (greater than 14 mg/100 ml), marked increase in the parathyroid hormone level to greater than twice normal, and significant metabolic complications. The initial operation must be aggressive yet meticulous with en bloc resection of the parathyroid tumor and all adjacent invaded tissues, avoiding capsular violation or tumor spillage.(ABSTRACT TRUNCATED AT 400 WORDS)

The effect of surgery and radiotherapy on outcome of anaplastic thyroid carcinoma.

AbstractBackground: Anaplastic thyroid carcinoma (ATC) is an aggressive rare tumor. We analyzed our experience for prognosis and the effect of surgery and radiotherapy on patients with ATC. Methods: We conducted a retrospective review of all patients (n=67) with ATC treated at a tertiary care center from 1969 to 1999. Survivor median follow-up was 51 months. Tumor and patient characteristics and therapy were assessed for effect on survival by multivariate analysis. Results: Patients presented with a neck mass (99%), change of voice (51%), dysphagia (33%), and dyspnea (28%). Surgery was performed in 44 of 67 patients, with 12 complete resections. The 6-month and 1- and 3-year survival rates were 92%, 92%, and 83% after complete resection; 53%, 35%, and 0% after debulking; and 22%, 4%, and 0% after no resection, respectively (P<.0001). A radiation dose of >45 Gy improved survival as compared with a lower dose (P=.02). Multivariate analysis showed that age ≤70 years, absence of dyspnea or dysphagia at presentation, a tumor size ≤5 cm, and any surgical resection improved survival (P<.05). Conclusions: Candidates for surgery with curative intent for ATC are patients ≤70 years, tumors ≤5 cm, and no distant disease. Radiotherapy >45 Gy improves outcome.

Accuracy of 4-dimensional computed tomography in poorly localized patients with primary hyperparathyroidism

BACKGROUND Four-dimensional computed tomography (4D-CT) utilizes multiplanar images and perfusion characteristics to identify abnormal parathyroid glands. We assessed the role of 4D-CT in patients with inconclusive preoperative ultrasound and sestamibi localization studies. METHODS Adult patients with primary hyperparathyroidism with negative or discordant standard imaging who underwent both localization with 4D-CT and operative intervention for curative intent were included. Patient characteristics, 4D-CT scan results compared with operative findings, and curative proportion were assessed. RESULTS Of the 60 patients, 4D-CT accurately lateralized 73% and localized 60% of abnormal glands found at operation. Single candidate lesions (46/60) were confirmed at operation in 70%. When multiple lesions were identified on 4D-CT (14/60), accuracy dropped to 29% (P = .03). The accuracy of 4D-CT was not different between primary and reoperative cases (P = .79). Of the 8 patients with multigland disease diagnosed perioperatively, 5 had multiple candidate lesions noted on 4D-CT. In 94% (48/51) of patients, a >50% drop in intraoperative parathormone (IOPTH) level was achieved after resection and 87% (48/55) had long-term cure with a median follow-up of 221 days. CONCLUSION 4D-CT identifies the more than half of abnormal parathyroids missed by traditional imaging and should be considered in cases with negative or discordant sestamibi and ultrasound. Bilateral exploration is warranted when multiple candidate lesions are reported on 4D-CT. Multigland disease remains a challenging entity.

Mutational analyses of RB and BRCA2 as candidate tumour suppressor genes in parathyroid carcinoma.

objective Strong evidence indicates that at least one key tumour suppressor gene important for the development of malignant parathyroid tumours is located on chromosome 13, but the critical target gene remains unknown. Importantly, the region of acquired DNA loss includes two established tumour suppressor genes, the retinoblastoma gene, RB (RB1) and BRCA2. Resolution of whether RB or BRCA2 is the critical 13q tumour suppressor gene in parathyroid cancer requires analysis of these genes’ sequences for intragenic inactivating mutations. Therefore, RB and BRCA2 were analysed in a group of parathyroid carcinomas in which mutations of these genes should be most readily detectable.

Clinical and Cytological Features Predictive of Malignancy in Thyroid Follicular Neoplasms

BACKGROUND The preoperative diagnosis of malignancy in nodules suspicious for a follicular neoplasm remains challenging. A number of clinical and cytological parameters have been previously studied; however, none have significantly impacted clinical practice. The aim of this study was to determine predictive characteristics of follicular neoplasms useful for clinical application. METHODS Four clinical (age, sex, nodule size, solitary nodule) and 17 cytological variables were retrospectively reviewed for 144 patients with a nodule suspicious for follicular neoplasm, diagnosed preoperatively by fine-needle aspiration (FNA), from a single institution over a 2-year period (January 2006 to December 2007). The FNAs were examined by a single, blinded pathologist and compared with final surgical pathology. Significance of clinical and cytological variables was determined by univariate analysis and backward stepwise logistic regression. Odds ratios (ORs) for malignancy, a receiver operating characteristic curve, and predicted probabilities of combined features were determined. RESULTS There was an 11% incidence of malignancy (16/144). On univariate analysis, nodule size >OR=4.0 cm nears significance (p = 0.054) and 9 of 17 cytological features examined were significantly associated with malignancy. Three variables stay in the final model after performing backward stepwise selection in logistic regression: nodule size (OR = 0.25, p = 0.05), presence of a transgressing vessel (OR = 23, p < 0.0001), and nuclear grooves (OR = 4.3, p = 0.03). The predicted probability of malignancy was 88.4% with the presence of all three variables on preoperative FNA. When the two papillary carcinomas were excluded from the analysis, the presence of nuclear grooves was no longer significant, and anisokaryosis (OR = 12.74, p = 0.005) and presence of nucleolus (OR = 0.11, p = 0.04) were significantly associated with malignancy. Excluding the two papillary thyroid carcinomas, a nodule size >or=4 cm, with a transgressing vessel and anisokaryosis and lacking a nucleolus, has a predicted probability of malignancy of 96.5%. CONCLUSIONS A combination of larger nodule size, transgressing vessels, and specific nuclear features are predictive of malignancy in patients with follicular neoplasms. These findings enhance our current limited predictive armamentarium and can be used to guide surgical decision making. Further study may result in the inclusion of these variables to the systematic evaluation of follicular neoplasms.

Parathyroid Tumor Suppressor on 1p: Analysis of the p18 Cyclin‐Dependent Kinase Inhibitor Gene As a Candidate

Loss of chromosome arm 1p DNA is the most common molecular defect thus far observed in human parathyroid adenomas, suggesting that 1p is the location of a putative tumor suppressor gene (or genes) whose inactivation contributes frequently to parathyroid tumorigenesis. To narrow the genomic location of this tumor suppressor gene, we analyzed 25 sporadic parathyroid adenomas for allelic loss of polymorphic DNA loci on chromosome 1 using 11 microsatellite markers not previously scored for this set of tumors. Allelic loss on chromosome arm 1p DNA was observed in 8 of 25 adenomas. Marker deletion patterns showed some complexity, with the regions most commonly deleted in these tumors being 1p36 and 1p35–p31. The 1p35–p31 region contains an excellent candidate tumor suppressor gene, p18, whose product is a cell cycle regulator that inhibits the cyclin D1‐associated kinase CDK6. Given that cyclin D1 is a parathyroid oncogene, inactivation of an inhibitor of cyclin D1 function, like p18, might also cause excessive parathyroid growth. To examine the involvement of p18 in parathyroid tumorigenesis, we analyzed 25 parathyroid adenomas for mutations of the p18 coding exons by single strand conformational polymorphism analysis and sequencing. No point mutations were found in any of the 25 adenomas. These observations indicate that inactivating mutation of the p18 gene occurs uncommonly, if at all, in parathyroid adenomas. In addition, the data raise the important possibility that more than a single tumor suppressor gene on 1p could contribute to parathyroid neoplasia.

Histopathologic and Clinical Features of Medullary Microcarcinoma and C-Cell Hyperplasia in Prophylactic Thyroidectomies for Medullary Carcinoma: A Study of 42 Cases

CONTEXT Prophylactic thyroidectomies are increasingly performed on patients at risk for developing medullary thyroid carcinoma (MTC); consequently, pathologists are more commonly encountering these specimens in routine practice. OBJECTIVE To describe the detailed clinicopathologic features of prophylactic thyroidectomies for medullary carcinoma. DESIGN We present a retrospective series of 42 prophylactic thyroidectomies for MTC performed for one or more of the following: family history of multiple endocrine neoplasia (MEN) or MTC, elevated serum calcitonin level, or detection of a RET proto-oncogene mutation. RESULTS Patients included 22 men and 20 women (mean age, 26.2 years). Among those with known RET proto-oncogene mutations, affected sites included exons 10, 11, 14, and 16. In 93% (n = 39) of cases, either C-cell hyperplasia (n = 36), medullary microcarcinoma (MMC; n = 29), or medullary macrocarcinoma (n = 1) was found. C-cell hyperplasia was often multifocal (n = 30) and bilateral (n = 23) and included both nonnodular and nodular patterns. A total of 94% of C-cell hyperplasia cases and all MMC cases were microscopically detectable using hematoxylin-eosin stains. The MMCs were characterized by a complex microarchitectural pattern with a desmoplastic stromal response (n = 29) and focal amyloid deposition (n = 12). Most MMCs exhibited a solid pattern (n = 24) of round, polygonal, spindled, or plasmacytoid-shaped cells. Only 1 case of MMC showed evidence of metastatic disease to a pretracheal lymph node. CONCLUSIONS Based upon our clinicopathologic findings and review of the literature, we conclude that thyroidectomies in at-risk patients are very frequently associated with C-cell hyperplasia and/or MMC; however, the clinical prognosis for these patients is very good.

Thyroid surgery in octogenarians is associated with higher complication rates

BACKGROUND The incidence of thyroid nodules increases with age and little information is available regarding the risks of thyroid surgery in elderly patients. The aim of this study was to determine whether thyroid surgery in patients > or =80 is associated with higher complication rates. METHODS Out of 3,568 patients undergoing thyroid surgery between July 2001 and October 2007 at a single institution, the records of 90 consecutive patients > or =80 years were reviewed retrospectively and compared with a cohort of 242 randomly selected patients aged 18-79, who underwent thyroid surgery during the same time period. Clinical variables included age, gender, pre-operative diagnosis, substernal component, previous surgery, final pathology, length of stay, comorbidities, American Society of Anesthesiologists (ASA) score, body mass index, postoperative complications, and mortality. RESULTS Preoperative indications for surgery included benign disease in 51% vs 39%, suspected malignancy in 19% vs 26%, and suspected follicular neoplasms in 30% vs 35% in the octogenarian patient group (> or =80 years old) vs the younger patient cohort (P = NS). Octogenarians had 20% significant malignancy on final pathology vs 27% in the younger cohort (P = NS). The overall complication rate in the octogenarian group was 24% vs 9% in the younger cohort (P < .001). Male gender and ASA > or =3 were found to be independent risk factors for perioperative complications after thyroid surgery, while age alone was not. CONCLUSION Age > or =80 is associated with higher morbidity after thyroid surgery, although not independently. Earlier operative intervention may be advised in those at high risk for disease progression, whereas follow-up strategies without operation may be advised for others.