Role of cytological and ultrasonographic features in predicting the risk of malignancy in thyroid nodules with indeterminate cytology.

AIM: The aim of this paper was to examine the diagnostic value of several cytological and ultrasonographic features in predicting malignancy in thyroid follicular neoplasms. METHODS: The sample of the study consisted of 145 patients, who have had the diagnosis of follicular neoplasm on US guided fine-needle aspiration (FNA), and had undergone thyroidectomy. The cytological slides and the ultrasonographic images were reviewed, and several ultrasonographic and cytological features were evaluated and correlated with final histology. RESULTS: Histological diagnosis of malignancy was obtained in 14.5% of the patients, papillary carcinoma being the most frequent (66% of malignancies). The cytological and ultrasonographic features that have been associated with malignancy were: micro-fragments (P<0.00001), overlapping (P<0.005), hypercellularity (P<0.009), micronucleoli (P<0.013), atypical features (P<0.027), nodule size larger than 2 cm (P<0.029) and micro-calcifications (P<0.0002). Using the features that were statistically independent ones, which included two cytological features: micro-fragments and micronuclei, and one ultrasonographic feature: micro-calcifications, a statistical model for predicting malignancy was constructed. According to this model, it was found that the risk for malignancy is 2.65% in the absence of the three parameters, and amounts to 93.93% in the presence of all three of them. CONCLUSION: In a thyroid follicular neoplasm, the cytological and ultrasonographic features that were associated with malignancy were: micro-fragments, overlapping, hypercellularity, micronucleoli, atypical features, nodule size larger than 2 cm and micro-calcifications. In an attempt to predict malignancy, we proposed a simple statistical model using only three features derived from cytological and ultrasonographic tests.

Is there a role for low doses of mitotane (o,p'-DDD) as adjuvant therapy in adrenocortical carcinoma?

Four patients suffering from adrenocortical carcinoma were treated with low doses (1.5-2.0 g) of mitotane (o,p'-DDD) for the complete follow-up time following surgery (21-68 months). Treatment with mitotane was started shortly after surgical removal of the tumor (three patients) or the tumor and multiple lung metastasis (one patient). No significant side effects or complications from the medication were noted. Two patients remain disease free after 57 and 21 months on treatment. A third patient died of an unrelated reason (varicose vein bleeding) after 68 months on mitotane without evidence of tumor recurrence or metastasis. In the fourth patient, two lung metastasis were successfully removed after 48 months of follow-up. The patient is doing well and is disease free 6 months later. Though our series is too small to draw final conclusions, we suggest that low doses of mitotane, which are well tolerated, might offer prolonged disease-free survival in adrenocortical carcinoma. To be beneficial treatment has to be started early after surgical removal of the tumor and metastasis, and be continued for long periods of time.

Late complications in remission from Cushing disease. Recurrence of tumor with reinfarction or transformation into a silent adenoma.

Two of 4 patients who underwent spontaneous remission from Cushing disease (CD) demonstrated regrowth of the pituitary adenoma 2 and 5 years later. In the first patient, the recurrent tumor also secreted corticotropin, with subsequent relapse of fulminant cushingoid features. However, after 14 more months, it again became infarcted, and the patient underwent complete clinical remission, which has persisted for about 3 years. In the second patient, the regrowth of the tumor occurred silently, as no clinical cushingoid features or rise in cortisol levels were noticed. Because of its size, the tumor was resected and found to have immunoreactivity for corticotropin (silent corticotroph adenoma). About 4 years after the first operation, a second surgical procedure was performed because of massive regrowth of the tumor. Again, there was no concomitant elevation of cortisol levels or endocrinologic symptoms. This time, the tumor did not even stain for corticotropin. While spontaneous remission in CD is rare, recurrence is even rarer. Reremission of CD and the change from a corticotropin-secreting adenoma to a silent one are described herein for the first time (to our knowledge). These cases demonstrate that patients with CD have to receive careful follow-up, even if they undergo remission, and that the long-term outcome of such remission is unpredictable.

One microgram is the lowest ACTH dose to cause a maximal cortisol response. There is no diurnal variation of cortisol response to submaximal ACTH stimulation.

There are many suggestions in the literature that the adrenal gland is more sensitive to ACTH in the evening than in the morning. However, all these studies in humans were conducted when the basal cortisol level was not suppressed, and were based on the observation that, after stimulation, the increases in cortisol differed, though the peak values were the same. To examine this, we established the lowest ACTH dose that caused a maximal cortisol stimulation even when the basal cortisol was suppressed, and used a smaller dose of ACTH for morning and evening stimulation. The lowest ACTH dose to achieve maximal stimulation was found to be 1.0 microgram, with which dose cortisol concentration increased to 607.2 +/- 182 nmol/l, compared with 612.7 +/- 140.8 nmol/l with the 250 micrograms test (P > 0.3). The use of smaller doses of ACTH (0.8 and 0.6 microgram) achieved significantly lower cortisol responses (312 +/- 179.4 and 323 +/- 157.3 nmol/l respectively; both P < 0.01 compared with the 1 microgram test). When a submaximal ACTH dose (0.6 microgram) was used to stimulate the adrenal at 0800 and 1600 h, after pretreatment with dexamethasone, no difference in response was noted at either 15 min (372.6 +/- 116 compared with 394.7 +/- 129.7 nmol/l) or 30 min (397.4 +/- 176.6 compared with 403 +/- 226.3 nmol/l; P > 0.3 for both times). These results show that 1.0 microgram ACTH, used latterly as a low-dose test, is very potent in stimulating the adrenal, even when baseline cortisol is suppressed; smaller doses cause reduction of this potency. Our data show that there is probably no diurnal variation in the response of the adrenal to ACTH, if one eliminates the influence of the basal cortisol level and uses physiologic rather than superphysiologic stimuli.

Lithium treatment in amiodarone-induced thyrotoxicosis.

PURPOSE: Amiodarone hydrochloride is an iodine-rich drug effective in the control of various tachyarrhythmias. It is known to cause refractory to thyrotoxicosis, which usually does not respond to regular antithyroid drugs. Lithium bicarbonate is a medication used to treat psychiatric disorders; it also influences thyroid production and release of hormones. We tried it in combination with propylthiouracil (PTU) for the treatment of amiodarone-induced thyrotoxicosis. PATIENTS AND METHODS: Twenty-one patients were studied. The first group (n = 5) was treated by amiodarone withdrawal only. The second group (n = 7) received PTU (300 to 600 mg), and the third (n = 9) PTU (300 mg) and lithium (900 to 1350 mg) daily. Patient selection was not randomized. The PTU + lithium group had more severe symptoms and signs of thyrotoxicosis, as well as thyroxine levels at least 50% above the upper limit of normal. They also had been on a longer course of amiodarone treatment (34.3 +/- 11.9 months) than the PTU-only (11.4 +/- 7.5) and the no-treatment (7.8 +/- 4.2) groups. RESULTS: While there was no difference between the first two groups in time until recovery (10.6 +/- 4.0 versus 11.6 +/- 0.5 weeks, respectively), the group receiving lithium normalized their thyroid function tests in only 4.3 +/- 0.5 weeks (P < 0.01 versus both other groups). T3 levels normalized even earlier-by 3 weeks of lithium treatment. No adverse effects of lithium were encountered, and the medication was stopped 4 to 6 weeks after achieving a normal clinical and biochemical state. CONCLUSIONS: We conclude that lithium is a useful and safe medication for treatment of iodine-induced thyrotoxicosis caused by amiodarone. We would reserve this treatment for severe cases only. Further studies are needed to find out whether in patients with this troublesome complication lithium therapy could permit continuation of amiodarone treatment.

Toxic Graves' disease with thyroid hemiagenesis: diagnosis using thyroid-stimulating immunoglobulin measurements.

Two patients with hemiagenesis of the thyroid gland experienced thyrotoxicosis. They constituted 1.1% of our clinic's total population of 178 thyrotoxic patients treated in the years 1986-1990 and 1.7% of 120 patients with thyrotoxic Graves' disease encountered during that period. The diagnosis was made on the basis of unilateral homogeneous 99mTcO4 uptake on thyroid scan, no change in the scan after both cessation of propylthiouracil (PTU) treatment for 4 days and TSH stimulation test, and high thyroid-stimulating immunoglobulin (TSI) levels. Both patients went into remission after PTU treatment, and TSI levels returned to normal. The diagnosis of toxic Graves' disease with thyroid hemiagenesis was, therefore, made. This combination is rare but important to recognize because treatment as well as prognosis might be different from that of toxic adenoma.

Adrenocorticotropin stimulation test: effects of basal cortisol level, time of day, and suggested new sensitive low dose test.

Adrenal response to iv administration of 1-24 ACTH (250 micrograms) was examined in normal volunteers under various conditions. The effect of basal cortisol levels was examined by performing the tests at 0800 h with and without pretreatment with dexamethasone. The effect of time of day was evaluated by performing the tests at 0800 h and at 1600 h, eliminating possible basal cortisol influence by pretreatment with dexamethasone. In the first set of tests, despite significantly different baseline levels, 30-min cortisol levels were not different (618 +/- 50 vs. 590 +/- 52 nmol/L). Afternoon cortisol levels in response to ACTH were found to be significantly higher than morning levels at 5 min (254 +/- 50 vs. 144 +/- 36 nmol/L, p less than 0.01) and at 15 min (541 +/- 61 vs. 433 +/- 52 nmol/L, p less than 0.02). This difference in response was no longer notable at 30 min (629 +/- 52 and 591 +/- 52 nmol/L). We tried also to determine the lowest ACTH dose which will elicit a maximal cortisol response. No difference was found in cortisol levels at 30 and 60 min in response to 250 and 5 micrograms 1-24 ACTH. Using 1 micrograms ACTH, the 30-min response did not differ from that to 250 micrograms (704 +/- 72 vs. 718 +/- 55 nmol/L, respectively). However, the 60-min response to 1 microgram was significantly lower (549 +/- 61 vs. 842 +/- 110 nmol/L, p less than 0.01). Using this low dose ACTH test (1 microgram, measuring 30-min cortisol level), we were able to develop a much more sensitive ACTH test, which enabled us to differentiate a subgroup of patients on long-term steroid treatment who responded normally to the regular 250 micrograms test, but had a reduced response to 1 microgram. The stability of 1-24 ACTH in saline solution, kept at 4 C, was checked. ACTH was found to be fully stable after 2 hs in a concentration of 5 micrograms/ml in glass tube and 0.5 micrograms/ml in plastic tube. It was also found to be fully stable, both immunologically and biologically, for 4 months, under these conditions. We conclude that the 30-min cortisol response to ACTH is constant, unrelated to basal cortisol level or time of day. It is therefore the best criterion for measuring adrenal response in the short ACTH test. The higher afternoon responses at 5 and 15 min suggest greater adrenal sensitivity in the afternoon, but further studies are needed to clarify this issue.(ABSTRACT TRUNCATED AT 400 WORDS)

Spontaneous remission in Cushing's disease.

Four patients with proved Cushing's disease underwent spontaneous clinical and biochemical remission. They were part of an 11-patient group treated with methods that allowed spontaneous remission to be observed. Each patient was treated differently, one each with metyrapone tartrate, ketoconazole, bilateral adrenalectomy and adrenal autotransplantation, and no treatment. Spontaneous remission occurred 9 months to 5 years after diagnosis as evidenced by restoration of normal adrenal function occurring symptomatically in two patients and advent to hypoadrenalism with addisonian crisis in the two others. We conclude that spontaneous remission in Cushing's disease may not be a rare entity, although its actual incidence has yet to be established.