S. Thomas Bigos

Prospective multicenter study of thyroid carcinoma treatment initial analysis of staging and outcome

A novel prognostic staging classification encompassing all forms of thyroid carcinoma was created for the National Thyroid Cancer Treatment Cooperative Study (NTCTCS) Registry, with the goal of prospective validation and comparison with other available staging classifications.

Outcome after Treatment of High-Risk Papillary and Non-Hurthle-Cell Follicular Thyroid Carcinoma

The treatment of thyroid cancer has been investigated extensively, but disagreement remains about the degree of aggressiveness needed in its management. Despite the general perception that the prognosis is excellent, 9% of patients with thyroid cancer die of the disease [1]. Patients with the less differentiated types of thyroid cancer or those presenting at a more advanced stage face higher mortality rates [2, 3]. In addition, the recurrence rate after surgery is more than 20% in persons with differentiated thyroid cancer [2]. Therefore, the ability to define the most effective therapeutic interventions on the basis of patient stratification by histologic type and stage of cancer at initial presentation should improve survival and decrease recurrence rates. The initial treatment for thyroid cancer is surgery, but the extent of surgery needed to improve outcome remains controversial [4-6]. Some studies have shown that more extensive thyroid resection reduces the recurrence rate but has a less definite effect on survival [2, 7]. More extensive surgery may be associated with a higher prevalence of complications, usually hypoparathyroidism or recurrent laryngeal nerve damage (or both), in 3% to 15% of patients [8-10]. The indications for postoperative ablative radioiodine therapy and the required administered activity are also under debate. Multifocality and lymph node involvement at presentation in 46% of persons with papillary thyroid cancer (of whom 25% face persistent or recurrent disease) argue in favor of this therapy [2, 11, 12], despite the risk for sialoadenitis, gastrointestinal symptoms, occasional bone marrow suppression, and possible second cancers [13]. The role of external radiation in the treatment of differentiated thyroid cancer is also highly controversial. Increased recurrence [14], no therapeutic benefit [15-17], and improved local control [18, 19] have all been reported. The National Thyroid Cancer Treatment Cooperative Study Registry was established in 1986 to define clinical practice and to address the effectiveness of therapies on morbidity and mortality by prospectively enrolling a large population of patients from multiple institutions. Patients have been stratified by uniform criteria and followed prospectively from the time of initial diagnosis and treatment. This 9-year report from the registry describes outcomes in patients with high-risk, differentiated thyroid cancer, a group of patients expected to have substantial morbidity and mortality in this time period. Methods A total of 1607 patients in whom thyroid cancer was diagnosed on or after 1 January 1987 were prospectively enrolled in the registry by the 14 participating institutions. No more than 20% of cases came from any single institution or city. Data forwarded to the registry were coded, and individual identifiers, such as name and Social Security number, were kept confidentially by the principal investigator at each institution. Because the patients therapy was not altered by participation in the registry, requirements for informed consent were determined by the institutional review boards at each participating institution, and their mandates were followed. Age, sex, ethnic background, histologic diagnosis, size of primary tumor, multifocality, local invasiveness, and regional or distant metastases were documented. The histologic diagnosis was established at each institution. All variants of papillary cancer, including so-called mixed papillary and follicular carcinomas, were included in the papillary group. Analyses for papillary carcinomas that included and excluded the more aggressive tall-cell variant were performed. The Hurthle cell (oxyphilic) variant of follicular carcinoma was excluded from the follicular group. Patients were stratified on the basis of pathologic diagnosis, age, tumor size, local invasiveness, and extent of metastases at the time of first surgical intervention as determined by gross and histologic findings at surgery, whole-body radioiodine scans, chest radiographs, and other radiologic studies. This stratification system was established empirically before initiation of the registry by a group of experienced clinicians on the basis of information available in 1985. The criteria for categorization as high risk are noted in Table 1. Patients with preoperative vocal cord paresis or with postoperative hypocalcemia or vocal cord paresis that persisted 2 months or less were not designated as having these complications of surgery. The extent of initial surgery, use of postoperative radioiodine therapy, and application of external radiation therapy were analyzed for impact on outcome. With rare exceptions, all patients received thyroxine therapy. Table 1. Criteria for Stratification to High-Risk Groups Outcomes were death due to thyroid cancer or to complications of its treatment, progression (defined as a patient alive with progressive thyroid cancer or dead because of thyroid cancer or complications of its treatment at last follow-up), and disease-free survival (defined as a patient alive with no known residual thyroid cancer or free of thyroid cancer at the time of death from other causes). Statistical Analysis All data were extracted by using a computer-based integrated data management package (Med-log, Information Analysis Corporation, Incline Village, Nevada). Cox proportional-hazards models were performed to determine whether each predictor variable was associated on univariate analysis (Table 2) with survival, progression, and disease-free survival (SAS Institute, Cary, North Carolina). The hazard model was also used to identify the set of predictor variables that best explained the probabilities of overall survival, cancer-specific mortality, progression of disease, or disease-free survival (Table 3). A P value of 0.05 or less was considered statistically significant. Risk ratios obtained from the Cox proportional-hazards analyses are given with 95% CIs. Risk ratios less than 1 indicate improved outcome, and those greater than 1 indicate a worsened outcome. Table 2. Variables Associated with Mortality, Progression, and Disease-Free Survival (by Univariate Analysis) Table 3. Variables That Best Predict Overall Mortality, Cancer-Specific Mortality, Progression of Disease, or Disease-Free Survival (by Multivariate Analysis) Results Follow-up Three hundred three patients with papillary carcinoma and 82 patients with follicular carcinoma were considered to have high-risk thyroid cancer. Twenty patients (5.2%) were lost to follow-up. An additional 64 patients were not included in the survival analyses because no information on patient status was available (n = 60), no cause of death was recorded (n = 2), or patients were alive with no cancer status reported (n = 2). Demographic characteristics of the two groups were similar regardless of whether these cases were included. Patients were followed for a mean of 3.1 years after the date of surgery; 35% were men. The mean (SD) age at entry was 57 15 years. Sex and Age Compared with men, women with papillary cancer had a lower risk for overall mortality (risk ratio [RR], 0.03 [95% CI, 0.23 to 0.92]) but not cancer-specific mortality. Older age did not affect outcome in patients with papillary carcinoma or those with follicular carcinoma, but an age effect might be masked by the fact that age was a factor in defining these high-risk patients. Histologic Type Only 18 patients with papillary cancer had the tall-cell variant (P not significant by multivariate analysis). By univariate analysis, radioiodine therapy was associated with reduced disease progression (risk ratio, 0.10 [CI, 0.01 to 0.72]; P = 0.02). Thyroid Surgery The first surgical procedure on the thyroid and any surgical therapy of the thyroid that occurred within the next 4 months were classified as initial thyroid surgery. Data were not sufficient to allow analysis of the effect of modified neck dissections on complication rates. Of 300 patients with papillary cancer, 256 (85.3%) had a total or near-total thyroidectomy as initial thyroid surgery, 10 (3.3%) had bilateral subtotal thyroidectomy, 26 (8.7%) had lobectomy, 1 (0.3%) had lumpectomy, 4 (1.3%) had biopsy only, and 3 (1.0%) had nonspecified surgery. Of 80 patients with follicular cancer, 57 (71.3%) had total or near-total thyroidectomy as initial thyroid surgery, 2 (2.5%) had bilateral subtotal thyroidectomy, 13 (16.3%) had lobectomy, 4 (5.0%) had lumpectomy, and 4 (5.0%) had biopsy only. The charts of all patients with reported surgical complications were reviewed. The complication rate of initial surgery varied among centers. The overall rate of some type of complication was 14.4% (52 of 360 patients). Specific data on complications were available for 286 of 303 patients with papillary cancer and 74 of 82 patients with follicular thyroid cancer. Hypoparathyroidism alone occurred in 19 of 286 (6.6%) patients with papillary cancer and 3 of 74 (4.0%) patients with follicular cancer. Vocal cord palsy alone was noted in 17 of 286 (5.9%) patients with papillary cancer and 6 of 74 (8.0%) patients with follicular cancer. Combined hypoparathyroidism and vocal cord palsy occurred in 4 of 286 (1.4%) patients with papillary cancer and no patients with follicular cancer. Data were not sufficient to allow analysis of any effect of modified neck dissections on complication rates. Overall mortality from papillary cancer improved with total or near-total thyroidectomy compared with other surgical procedures (RR, 0.41 [CI, 0.20 to 0.85]) (Table 2). Progression of disease and disease-free survival were not improved by more extensive surgery, and surgery did not affect mortality, progression, or disease-free survival in patients with follicular cancer by univariate (Table 2) or multivariate (Table 3) analyses. Radioiodine Therapy Postoperative radioiodine therapy with iodine-131 was administered to 258 of 302 (85.4%) patients with papillary cancer; the init

Sarcoidosis, Hypercalcemia and Primary Hyperparathyroidism The Vicissitudes of Diagnosis

Abstract Two cases of coexistent sarcoidosis and primary hyperparathyroidism are reported from the University of Michigan Medical Center from a series of 600 consecutive cases of primary hyperparathyroidism. The histopathologic finding of noncaseating granulomas within a parathyroid adenoma in one patient has not been previously reported. Two additional patients with suspected primary hyperparathyroidism had sarcoidosis detected by paratracheal lymph node biopsy done at the time of neck exploration.

Serum growth hormone response to growth hormone-releasing hormone in non-obese and obese adults with hypopituitarism

The clinical consequences of growth hormone (GH) deficiency (GHD) in adults have not been defined. Standard methods of measuring GH reserve in children may not be reliable in adults. In addition, obesity in normal adults diminishes GH responsiveness to provocative stimuli; this inhibition of GH release is reversed with pyridostigmine (PD). We investigated the use of GH-releasing hormone (GHRH) as a method to assess pituitary GH secretory reserve (as defined by peak GH response to GHRH) in both non-obese and obese (ie, > 115% ideal body mass index [BMI]) adults with hypothalamic-pituitary tumors. Nine non-obese patients (NOP) and 10 obese patients (OP) were studied with 11 non-obese controls (NOC) and 10 obese controls (OC). All study groups received GHRH (1 microgram/kg intravenous bolus) with blood sampling at -15, 0, 15, 30, 45, 60, 75, and 90 minutes. OC and OP received 120 mg PD orally 1 hour before GHRH injection. Mean serum GH responses in NOC and OC were significantly higher (P < .05) than those in NOP and OP, respectively, 15 minutes after GHRH injection, and remained so throughout the time-course of the test. Mean +/- standard error of the mean (SEM) peak GH level (microgram/L) was lower in NOP than in NOC (5.1 +/- 1.6 v 21.2 +/- 4.4, P < .01) and lower in OP than in OC (4.6 +/- 1.8 v 15.5 +/- 2.2, P < .01). Mean +/- SEM peak GH level was also lower in NOP than in OC (5.1 +/- 1.6 v 15.5 +/- 2.2 micrograms/L, P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Case Report Isolated ACTH Deficiency Presenting as Severe Hypercalcemia

Abstract A 32-year-old woman presented five months postpartum with weight loss, dehydration, hypotension, exhaustion and hypercalcemia (serum calcium of 15.8mg/dl). Her work-up demonstrated glucocorticoid insufficiency due to isolated ACTH deficiency. Over the five years since diagnosis no additional pituitary deficits have emerged. Though isolated ACTH deficiency as a cause of adrenal insufficiency is extrememly rare, this case underscores the need to specifically consider glucocorticoid insufficiency in the patient presenting with hypercalcemia.