Randomized trial of parathyroidectomy in mild asymptomatic primary hyperparathyroidism: patient description and effects on the SF-36 health survey.

BACKGROUND: The treatment of patients with asymptomatic primary hyperparathyroidism remains controversial despite a National Institutes of Health consensus statement. This statement also recommended a randomized clinical trial because none exists to address this issue. METHODS: Informed consent was obtained from 53 asymptomatic patients with confirmed asymptomatic primary hyperparathyroidism who participated in this randomized trial of parathyroidectomy versus observation. Patients completed the SF-36 Health Survey, an instrument that measures wellness, every 6 months for 2 years. Average annual changes were compared. RESULTS: Fifty-three patients (42 female, 11 male) with asymptomatic, mild (serum calcium level, 10.1-11.5 mg/dL) asymptomatic primary hyperparathyroidism who agreed to participate were randomized into either a surgical group or an observation group. The mean calcium level was 10.31 mg/dL. The only demographic difference between groups was age, with the operative group being older (66.7 vs 62.6 years; P <.03). The scores on 2 of the 9 domains of the SF-36 were significantly different (P <.007 and <.012, respectively); both favored the operative group. CONCLUSIONS: Improved function is seen after parathyroidectomy when compared with patients who did not undergo operation. This study supports surgical management of mild primary hyperparathyroidism at the time of diagnosis because many patients have reversible nonclassic symptoms of the disease.

Variable expressivity of familial medullary thyroid carcinoma (FMTC) due to a RET V804M (GTG-->ATG) mutation.

BACKGROUND: Multiple endocrine neoplasia type 2 (MEN 2) and familial medullary thyroid carcinoma (FMTC) are autosomal dominantly inherited cancer syndromes that predispose to C-cell hyperplasia and MTC. MEN 2A and FMTC are caused by mutations in the RET proto-oncogene. METHODS: We used a multiplex polymerase chain reaction-based assay to screen exons 10, 11, 13, and 14 of RET for mutations in 2 families with FMTC. We correlated mutation status with calcitonin and pathologic studies to determine genotype-phenotype correlations. RESULTS: We identified a mutation in codon 804 in exon 14 (GTG-->ATG; V804M) in both families. An 86-year-old person who was a gene carrier and other individuals over age 70 who were suspected by pedigree analysis to be gene carriers had no overt clinical evidence of MTC. Four of 21 patients who underwent a thyroidectomy also had papillary thyroid cancer. One individual in each family had metastatic MTC at age 30 and 32 years, and all 26 people having thyroidectomies had either MTC or C-cell hyperplasia, leading us to continue to recommend prophylactic thyroidectomy for all identified patients who were gene carriers. CONCLUSIONS: Because of active MTC in younger members of these families, including metastases, we have continued to advocate thyroid surgery in mutation-positive individuals. While DNA diagnosis of gene carriers and subsequent genetic counseling was relatively straightforward, the acceptance of surgical recommendations was more difficult for some individuals. These families demonstrate that the search for RET mutations should include exons 13, 14, 15, and 16 in patients whose studies in exons 10 and 11 are negative.

Effect of vitamin D nutrition on parathyroid adenoma weight: pathogenetic and clinical implications.

In primary hyperparathyroidism, adenoma size is a major determinant of disease severity and manner of presentation, but the reason for the large variation in size (>100-fold) is unknown. One factor could be the level of vitamin D nutrition, because in India, where vitamin D deficiency is endemic, adenomas are larger and the disease more severe than in the U.S. Accordingly, we determined the relationship between vitamin D nutrition, as measured by serum levels of 25-hydroxyvitamin D (25OHD), and parathyroid gland weight, expressed on a logarithmic scale, in 148 U.S. patients with primary hyperparathyroidism. A significant inverse relationship was found between log gland weight as dependent variable and serum 25OHD as independent variable (r = -0.365; P < 0.0001). The only other influence on gland weight was a weak inverse correlation with age. Log gland weight as an independent variable was significantly related to adjusted calcium, PTH, and alkaline phosphatase (AP) as dependent variables. In 51 patients with serum 25OHD levels less than 15 ng/mL, gland weight, PTH, AP, and adjusted calcium were each significantly higher than in 97 patients with 25OHD levels of 15 ng/mL or more, but 1,25-dihydroxyvitamin D levels were similarly increased in both groups. In the former group the response of adjusted calcium to PTH was blunted, and the response of AP was enhanced, based on significant differences in regression slopes (P = 0.0004 and 0.0022, respectively). Suboptimal vitamin D nutrition stimulates parathyroid adenoma growth by a mechanism unrelated to hypocalcemia or 1,25-dihydroxyvitamin D deficiency and reduces the calcemic response to PTH, so that a higher PTH level and more parathyroid cells are needed to raise the patient's serum calcium to the level corresponding to the increased set-point that is characteristic of the disease. Improved vitamin D nutrition in the population is partly, perhaps largely, responsible for the historical changes in disease severity and manner of presentation that have occurred over the last 50 yr.

Tracheal and laryngeal resections for differentiated thyroid cancer.

Extensive local invasion of the trachea or larynx by differentiated thyroid cancer has usually resulted in a conservative therapeutic approach, including at least a thyroid biopsy and external beam irradiation. Thyroidectomy, if performed, has also allowed radioactive iodine administration with variable uptake. Survival rates are rarely reported, but generally considered dismal. In light of this, an aggressive surgical approach was initiated with attempted resection of all local tumor tissue. Seven patients (five females and two males), 38 to 82 years of age (mean, 64), underwent tracheal sleeve resection for obstructing lesions (four patients) or partial laryngectomy (three patients) for locally invasive tumors. Esophageal resections were included in two patients. Follicular cancer was seen in two patients; Hürthle cell cancer was seen in three patients; and papillary cancer was seen in two patients. Patients were also treated with radioactive iodine and external beam irradiation. Patients were followed regularly postoperatively to establish survival. No operative deaths were seen. Two patients died of disease at 57 and 47 months postoperatively. One died of natural causes 24 months after surgery. Four patients are alive at 10, 29, 114, and 118 months after resection. Mean survival, to date, is 51.3 months. Aggressive attempts at surgical resection of differentiated thyroid cancers seems warranted for tumors obstructing the trachea or involving the larynx. It has been well tolerated and is associated with a >4-year average survival. A nihilistic approach no longer can be justified in these patients.

Therapeutic controversies in primary hyperparathyroidism.

There is little debate about the primacy of surgery in the management of classical PHPT. Rather, the question has been what to do about the many patients with nonclassical disease. A 1990 NIH consensus conference (55) clearly recommended surgery for patients with significant adverse effects of PHPT, for patients with complicating coexistent illnesses, for younger patients, and for those in whom consistent long-term follow-up could not be assured. It allowed that conscientious surveillance may be justified in patients with minimal hypercalcemia and no adverse effects, but it recognized that for many patients, the time and expense involved in rigorous follow-up would outweigh the burden of surgery. Nine years later, the demonstrated prevalence of nonclassical symptoms and their reversibility, the evidence of "asymptomatic" but harmful effects reversible by surgery, and the accumulating evidence for surgical reduction of increased long-term mortality risk substantially strengthen the argument for surgery in such patients. For these reasons, parathyroidectomy should generally be recommended for patients with a secure diagnosis of PHPT, even in the absence of classical symptoms.

Comparison of mammographically guided breast biopsy techniques.

OBJECTIVE: To determine which mammographically guided breast biopsy technique is the most efficient in making a diagnosis in women with suspicious mammograms. SUMMARY BACKGROUND DATA: Mammographically guided biopsy techniques include stereotactic 14-gauge core-needle biopsy (SC bx), stereotactic 11-gauge suction-assisted core biopsy (Mammotome [Mbx]), stereotactic coring excisional biopsy (Advanced Breast Biopsy Instrument [ABBI]), and wire-localized biopsy (WL bx). Controversy exists over which technique is best. METHODS: All patients undergoing any one of these biopsy methods over a 15-month period were reviewed, totaling 245 SC bx, 107 Mbx, 104 ABBI, and 520 WL bx. Information obtained included technical success, pathology, discordant pathology, and need for open biopsy. RESULTS: Technical success was achieved in 94.3% of SC bx, 96.4% of Mbx, 92.5% of ABBI, and 98.7% of WL bx. The sensitivity and specificity were 87.5% and 98.6% for SC bx, 87.5% and 100% for Mbx, and 100% and 100% for ABBI. Discordant results or need for a repeat biopsy occurred in 25.7% of SC bx, 23.2% of Mbx, and 7.5% of ABBI biopsies. In 63.6% of ABBI and 50.9% of WL bx, positive margins required reexcision; of the cases with positive margins, 71.4% of ABBI and 70.4% of WL bx had residual tumor in the definitive treatment specimen. CONCLUSION: Although sensitivities and specificities of SC bx and Mbx are good, 20% to 25% of patients will require an open biopsy because a definitive diagnosis could not be reached. This does not occur with the ABBI excisional biopsy specimen. The positive margin rates and residual tumor rates are comparable between the ABBI and WL bx. The ABBI avoids operating room and reexcision costs; therefore, in appropriately selected patients, this appears to be the most efficient method of biopsy.

Racial differences in the presentation and surgical management of breast cancer.

BACKGROUND: African American women are seen with more advanced breast cancers, are less likely to be treated with breast-conserving surgery, and generally have poorer prognoses than white women. There are a myriad of potential causes for these phenomena. The purpose of this study was to measure racial differences in the surgical treatment of breast cancer among women with comparable health care access and delivery. METHODS: The Breast Cancer Registry of the Department of Surgery at Henry Ford Hospital was accessed for all patients between January 1, 1990, and December 31, 1997 for whom data on race, tumor characteristics, stage, and treatment specifics were available. Socioeconomic information was collected with use of 1990 census block data. Proportions of women who received each treatment were compared for African Americans and whites with use of the relative risk (RR) and 95% confidence intervals (CI). We used multiple logistic regression to obtain estimates of the relative risk, controlling for potential confounding factors. RESULTS: Of the 1699 patients in the database, 1250 had sufficient information for analysis. A total of 8.7% of African American women were diagnosed with late-stage disease (i.e., stage III or IV) compared with 7.9% of whites. Nevertheless, African American women had a lower frequency of stage I disease (30.5% vs 36.2%) and a higher frequency of stage II disease (36.8% vs 31.4%). Overall and adjusted risk estimates for age, tumor stage, marital status, median income, and type of insurance revealed no substantive or statistically significant differences between African American and white patients. The adjusted RR for local excision was 1.39 (95% CI 0.78 to 2.49), for lumpectomy and axillary dissection RR 0.92 (95% CI 0.66 to 1.29), for simple mastectomy RR 0.84 (95% CI 0.41 to 1.72), and for modified radical mastectomy RR 1.00 (95% CI 0.73 to 1.36). CONCLUSIONS: In this setting of equal access to health care, African American women still have higher frequencies of stage II disease, although the frequencies for late-stage disease are similar. Nevertheless, no surgical differences were found in this population, even after the effects of socioeconomic indicators and stage at diagnosis were controlled for Survival differences between African American and white women are unlikely to be explained by differences in treatment.

Double minutes in the papillary thyroid cancer cell line PTC-1113A.

The cell line PTC-1113A was established from a metastasizing recurrent papillary thyroid cancer. The cell line was growing as monolayer and showed a complex karyotype with chromosome numbers ranging from 30 to 140/metaphase. A proportion of metaphases contained double minutes and/or pulverized chromosomes. Extrachromosomal DNA seemed to originate from a B-group chromosome. A chromosome 4 painting probe hybridized to extrachromosomal material, representing double minutes (dmin) and possibly minutes. In addition, fluorescence in situ hybridization (FISH) with the chromosome 4 library detected a translocation chromosome and a pulverized chromosome originating from chromosome 4. PTC-1113A is, to our knowledge, the single papillary thyroid cancer cell line demonstrating evidence of gene amplification.

Cytogenetic analysis of thyroid tumors after cryopreservation.

Current cytogenetic evaluation of solid tumors is performed on fresh tissue specimens requiring on-call tissue culture facilities. The application of cryopreservation to tumor samples prior to cytogenetic analysis allows collection of tumors to a desired sample size. We evaluated methods of cryopreservation for their effects on growth potential from 11 benign thyroids and one papillary thyroid cancer. Mitotic indices and thyroglobulin expression applying imunocytology were analyzed. Compared to fresh tumors, the revived tumor samples showed unaltered thyroglobulin expression. A statistically significant (p < 0.004) prolongation to develop mitotic activity occurred in samples received after the freezing of dispase digested tissues, but not in samples frozen as thinly cut pieces. In addition, the data show that cytogenetic analysis at the 400-band level can be achieved in cryopreserved thyroid tissues.

P53 gene alterations in differentiated thyroid cancers.

Analysis of 22 human thyroid cancers including papillary, follicular and medullary subtypes (PTC, FTC, MTC) by PCR-SSCP, and immunohistochemistry detected 4 deletions and 3 mutations. Deletions involved exons 1, 2-3 and 5-6 in 3 PTCs, mutations exons 2-3 in 2 MTCs and exons 8-9 in PTC4. p53 alterations occurred in 2/5 recurrent tumors and 2/3 tumors developing to cell lines. Immuno-histochemistry detected p53 mutations in differentiated areas of papillary thyroid cancers as frequent events occurring at stage T1 to T4 in contrast to prior findings by other authors which restrict p53 alterations to undifferentiated stages.

Clinical value of direct DNA analysis of the RET proto-oncogene in families with multiple endocrine neoplasia type 2A.

BACKGROUND: The multiple endocrine neoplasia type 2A gene is the RET proto-oncogene located on the long arm of chromosome 10, and many mutations within this gene have been reported. METHODS: Peripheral blood DNA was analyzed from 95 members of twelve families with multiple endocrine neoplasia type 2A and known mutations in codon 634 (of exon 11) of the RET proto-oncogene. This region was amplified by the polymerase chain reaction, followed by digestion with Cfo I, which detects restriction sites created by the most common TGC- > CGC mutation and by a TGC- > TGG mutation or with Rsa I, which detects a restriction site created by a TGC- > TAC mutation. RESULTS: Diagnoses were confirmed in 39 patients; 15 of 56 at-risk persons were gene carriers and 41 were noncarriers. The noncarriers included seven persons who had previously undergone thyroidectomies for suspected C-cell hyperplasia but were negative for the RET mutation present in affected members of their families. CONCLUSIONS: Identification of the specific gene alterations within families permits direct DNA diagnosis of at-risk family members. The 41 noncarriers will not require further testing nor need to be concerned about transmitting multiple endocrine neoplasia type 2A to their descendants. The normal DNA findings in seven of these persons emphasize the importance of DNA studies in patients with C-cell hyperplasia but no medullary thyroid cancer at operation.

Chromosomal aberrations in two adrenocortical tumors, one with a rearrangement at 11p15.

Adrenocortical tumors are detected with increasing frequency, but symptomatic cases with excessive hormone production are rare. We investigated cytogenetically one benign aldosterone-producing tumor (Conn Syndrome)(case 1) and one malignant cortisol-producing tumor (Cushing Syndrome)(case 2). Radioimmunoassay of cell culture supernatant of case 2 detected cortisol secretion during 2 months in culture. Flow cytometry of spill-out cells from case 2 showed a bimodal pattern (DNA Index 1.0, 1.4). Case 1 revealed a marker chromosome in 4/25 cells analyzed; the marker was a long acrocentric partially derived from chromosome 2,der(2q). In case 2, a cytogenetic harvest was achieved after prolonged culture time (6 weeks) and a marker chromosome, add(11)(p15), was detected in 16/22 cells. A breakpoint of 11p13, as well as loss of heterozygosity of alleles on 11p15, has been reported in the literature for other malignant adrenocortical cancers.

Chromosomal aberrations in two sporadic gastrinomas.

Results of cell culture and cytogenetic analysis (standard and fluorescent in situ hybridization, FISH) of two sporadic gastrinomas are reported. Maintenance of hormonal activity was assessed by detection of gastrin levels during the first 3 months in culture. Case 1 showed clonal aberrations consisting of two marker chromosomes: marker 1 is a large metacentric chromosome and marker 2 is a small acrocentric chromosome. Case 2 showed a constitutional polymorphism with chromosome 15p+ and a clone in the tumor cell culture with trisomy for chromosome 3. To our knowledge, this is the first cytogenetic report of sporadic gastrinomas (Zollinger-Ellison syndrome).

Hypercalcemia associated with Wegener's granulomatosis and hyperparathyroidism: etiology and management.

We report a case of hypercalcemia in a patient with coexisting hyperparathyroidism and Wegener's granulomatosis. Parathyroidectomy with removal of an adenoma resulted in a low parathyroid hormone level but high calcitriol levels and hypercalcemia persisted. In various granulomatous diseases, hypercalcemia has been shown to be the result of overproduction of 1,25-dihydroxy-vitamin D by disease-activated macrophages. Chloroquine has been demonstrated to effectively reduce the extrarenal synthesis of 1,25-dihydroxyvitamin D and serum calcium concentration in hypercalcemic patients with sarcoidosis. Hypothesizing that a similar mechanism would explain hypercalcemia in Wegener's granulomatosis as well, a therapeutic trial of chloroquine was initiated. The patient responded to chloroquine 500 mg twice daily with significant decreases in serum 1,25-dihydroxyvitamin D and calcium levels. This report extends previous observations of hypercalcemia associated with other granulomatous diseases to Wegener's granulomatosis and demonstrates an effective reduction of serum calcitriol and calcium levels in response to chloroquine therapy.

Mucin-producing parathyroid carcinoma.

A 67-year-old white male presented with symptomatic hypercalcemia (15.6 mg/dl) in December 1989. He had undergone thyroidectomy for removal of a mucin-producing adenocarcinoma of the thyroid in 1967, and after eight years of follow-up during which time no other neoplasms were detected, he was reported as a unique case of this syndrome. Mild hypercalcemia (less than 11.0 mg/dl) was first noted in 1987, and this had remained stable until shortly before the acute presentation. Multiple lung nodules were observed radiographically and presumed to be granulomatous until increased size was observed shortly before presentation. Serum intact PTH was 190 pg/ml (n 10-55), but at neck exploration no parathyroid tissue was found and surgery did not resolve the hypercalcemia. Serum PTHrP was undetectable. Biopsies from all three lobes of the right lung revealed numerous nodules of metastatic adenocarcinoma with cords of tumor cells surrounded by mucin. The histology was similar to that obtained 23 years earlier. Following left upper lobe resection with removal of a 3-cm nodule, hypercalcemia resolved. The tumor stained strongly positive with a peroxidase stain for PTH using a polyclonal antibody. Northern blot hybridization of total RNA from the tumor confirmed the presence of message for PTH but not PTHrP. The original diagnosis has been revised to that of a unique case of mucin-producing parathyroid cancer with an extraordinarily long latency period before recurrence.

Genetic markers in thyroid tumors.

Tissue from nine patients with malignant tumors and two with benign tumors was cultured briefly before cytogenetic analysis. The tumors included one goiter and one Hürthle cell adenoma, one lymphoma, one medullary carcinoma, two Hürthle cell cancers, and five papillary cancers, varying widely in clinical staging and histologic differentiation. When assessed, DNA content was aneuploid in two of six malignant tumors. Various culture conditions (oxygen levels, dissociation methods, and media) were evaluated; the end points were growth, cell differentiation, and time to first harvest. Clonal aberrations were detected in one of four successfully harvested papillary cancers: they consisted of trisomy 7 and a rearrangement of chromosome 10. The rea (10) seen in 22 of 27 cells involved bands q11-21. Two other papillary tumors and a medullary cancer (a family member with multiple endocrine neoplasia type IIA) showed tetraploidy and nonclonal numerically aberrant cells. A lymphoma and two benign lesions showed no cytogenetic abnormality. The tumor with rea (10) is of special interest because abnormalities of 10q have been reported repeatedly in thyroid tumors, including two cases of papillary thyroid tumors with a structural aberration similar to that of the presented case. This rearrangement could affect the ret-proto-oncogene, localized to 10q11.2 which is activated in some papillary thyroid carcinomas.

Cytogenetic study of a papillary thyroid carcinoma with a rearranged chromosome 10.

Cytogenetic findings of a multifocal papillary thyroid cancer and a metastatic lymph node from a 29-year-old white female patient are reported. Two clonal aberrations were observed: a trisomy 7 in one nodule, and a rearranged chromosome 10 in a separate nodule and in a lymph node. The rearrangement of 10q described here is similar to other published cases and is relevant for interpreting the molecular findings associated with thyroid cancer.

Hereditary hyperparathyroidism and multiple ossifying jaw fibromas: a clinically and genetically distinct syndrome.

A large previously reported family with hyperparathyroidism has been reinvestigated recently because of the occurrence of multiple ossifying jaw fibromas in two affected members of the third generation similar to the jaw tumors of four of five affected members of the first generation. These maxillary and mandibular tumors can be differentiated from the "brown tumors" of hyperparathyroidism because they can appear and enlarge even though the hypercalcemia is surgically corrected. These tumors are histologically distinct fibroosseous lesions without the giant cells seen in "brown tumors." The parathyroid enlargement was mostly uniglandular, with multiple tumors found occasionally. Studies in DNA linkage were performed within this large family and a similar family in Houston to determine if the gene for this syndrome, termed HRPT2, is linked to DNA markers on chromosome 11, to which the gene for multiple endocrine neoplasia (MEN) type 1 has been linked. (This linkage is supported by our findings in one family with MEN 1 reported here.) Linkage studies were also performed with markers on chromosome 10, to which the genes for MEN 2A and MEN 2B have been linked. Evidence against close linkage with chromosome 10 and chromosome 11 markers suggests that this clinically distinct syndrome is also genetically distinct.

Multiparametric deoxyribonucleic acid and cell cycle analysis of breast carcinomas by flow cytometry. Clinicopathologic correlations.

Using intact ethanol-fixed cytokeratin monoclonal (CAM 5.2) and propidium iodide dual-stained cells, we have performed two-color multiparametric flow cytometric (FCM) DNA analysis and S-phase fraction (SPF) determination on 165 mechanically dissociated breast carcinomas. Sixty-seven patients were axillary node positive, 33 patients node negative; 59 had biopsy only and in 8, FCM was performed on tissue from metastatic lesions. Overall, 62% of the tumors contained aneuploid cell populations. Abnormal cellular DNA content (aneuploidy) was significantly correlated with high nuclear grade (p less than 0.001), lack of estrogen receptors (p less than 0.001), presence of vascular invasion (p less than 0.04), high histologic grade (p less than 0.04), and tumor size (p less than 0.03) but not with patient age (p greater than 0.07) or axillary node status (p greater than 0.50). SPF values derived from ungated histograms had a positively skewed frequency distribution (range 2 to 30%, N = 152) with an overall median of 11% (diploid, 8.9%; aneuploid, 15.7%). Higher SPF values were significantly correlated with aneuploidy (p less than 0.001), presence of necrosis (p less than 0.001), lack of estrogen receptor (p less than 0.0001), high nuclear grade (p less than 0.001), vascular invasion (p less than 0.003), tumor size (p less than 0.006), and high histologic grade (p less than .004) but not the presence of lymph node metastases (p greater than 0.56). Mean SPF values were significantly higher when calculated from cytokeratin gated DNA histograms (14.1% versus 11.5%, p less than 0.001), probably due to exclusion of contaminating stromal/inflammatory cells; and significantly lower when calculated from debris subtracted histograms (7.8% versus 11.4%). Cytokeratin gated and debris subtracted SPF values both had a greater degree of correlation than ungated values with clinicopathologic factors of known prognostic significance.(ABSTRACT TRUNCATED AT 250 WORDS)

Computed tomographic evaluation of intrathoracic thyroid malignancy.

As only a few cases of intrathoracic thyroid malignancy with computed tomographic (CT) examination have been described, we reviewed the CT examinations of three patients with primary and five patients with recurrent thyroid malignancy involving the thorax. Irregular border of the thyroid mass, extension of tumor mass into mediastinal fat or chest wall, or lymphadenopathy suggested the malignant nature of the primary tumor. CT examination in recurrent disease demonstrated mediastinal, hilar and retrocrural adenopathy, compression of major vessels with collateral flow, pulmonary and bony metastases. CT was of value both in identifying the extent of disease and documenting response to treatment.