Vahab Fatourechi

The glucagonoma syndrome. Clinical and pathologic features in 21 patients.

The glucagonoma syndrome is a rare disorder characterized by weight loss, necrolytic migratory erythema (NME), diabetes, stomatitis, and diarrhea. We identified 21 patients with the glucagonoma syndrome evaluated at the Mayo Clinic from 1975 to 1991. Although NME and diabetes help identify patients with glucagonomas, other manifestations of malignant disease often lead to the diagnosis. If the diagnosis is made after the tumor is metastatic, the potential for cure is limited. The most common presenting symptoms of the glucagonoma syndrome were weight loss (71%), NME (67%), diabetes mellitus (38%), cheilosis or stomatitis (29%), and diarrhea (29%). Although only 8 of the 21 patients had diabetes at presentation, diabetes eventually developed in 16 patients, 75% of whom required insulin therapy. Symptoms other than NME or diabetes mellitus led to the diagnosis of an islet cell tumor in 7 patients. The combination of NME and diabetes mellitus led to a more rapid diagnosis (7 months) than either symptom alone (4 years). Ten patients had diabetes mellitus before the onset of NME. No patients had NME clearly preceding diabetes mellitus. Increased levels of secondary hormones, such as gastrin (4 patients), vasoactive intestinal peptide (1 patient), serotonin (5 patients), insulin (6 patients, clinically significant in 1 only), human pancreatic polypeptide (2 patients), calcitonin (2 patients) and adrenocorticotropic hormone (2 patients), contributed to clinical symptoms leading to the diagnosis of an islet cell tumor before the onset of the full glucagonoma syndrome in 2 patients. All patients had metastatic disease at presentation. Surgical debulking, chemotherapy, somatostatin, and hepatic artery embolization offered palliation of NME, diabetes, weight loss, and diarrhea. Despite the malignant potential of the glucagonomas, only 9 of 21 patients had tumor-related deaths, occurring an average of 4.91 years after diagnosis. Twelve patients were still alive, with an average age follow-up of 3.67 years.

Subclinical Hypothyroidism: An Update for Primary Care Physicians

Subclinical hypothyroidism (SCH), also called mild thyroid failure, is diagnosed when peripheral thyroid hormone levels are within normal reference laboratory range but serum thyroid-stimulating hormone (TSH) levels are mildly elevated. This condition occurs in 3% to 8% of the general population. It is more common in women than men, and its prevalence increases with age. Of patients with SCH, 80% have a serum TSH of less than 10 mIU/L. The most important implication of SCH is high likelihood of progression to clinical hypothyroidism. The possibility that it is a cardiovascular risk factor has been a subject of debate. Large-scale randomized studies are needed for evidence-based recommendations regarding screening for mild thyroid failure and levothyroxine therapy for this condition. Currently, the practical approach is routine levothyroxine therapy for persons with a persistent serum TSH of more than 10.0 mIU/L and individualized therapy for those with a TSH of less than 10.0 mIU/L.

Thyroglossal Duct Carcinoma: Report of 12 Cases

OBJECTIVE To report the relative frequency, natural history, and optimal treatment of thyroglossal duct (TGD) carcinoma. DESIGN We retrospectively reviewed all cases of TGD carcinoma surgically treated during a 44-year period at a tertiary referral center. MATERIAL AND METHODS The computerized medical records database at Mayo Clinic Rochester was searched for patients who had the diagnosis of TGD carcinoma or TGD cyst carcinoma from 1950 through 1994. Medical records and pathologic specimens of these patients were reviewed. RESULTS Twelve patients (six male and six female patients), who were 17 to 60 years old (mean, 40), were identified. The frequency of TGD carcinoma among surgically removed TGD cysts was 0.7%. A midline upper neck mass was the initial symptom in all patients. The diagnosis of cancer was made after the Sistrunk procedure in 11 of 12 cases and preoperatively (by fine-needle aspiration biopsy) in only 1 case. All patients had papillary carcinoma. Thyroid involvement was noted in three cases. Nine patients had subtotal or near-total thyroidectomy, and three received postoperative radioactive iodine. After a mean follow-up of 13 years (range, 1 to 38), no patient had a documented local recurrence or distant metastatic involvement, and no tumor-associated mortality was observed. CONCLUSION TGD carcinoma is a rare malignant tumor that is usually diagnosed postoperatively. Papillary carcinoma is the most common pathologic finding. The recommended treatment is the Sistrunk procedure followed by near-total or total thyroidectomy by a skilled thyroid surgeon because of the possibility of intrathyroidal foci of cancer. The prognosis is excellent in patients with papillary tumor.

Rarity of Encephalopathy Associated with Autoimmune Thyroiditis: A Case Series from Mayo Clinic from 1950 to 1996

Corticosteroid-responsive encephalopathy associated with autoimmune thyroiditis (also called Hashimotos encephalopathy) is a rare, life-threatening, treatable, and possibly autoimmune condition. We identified nine patients (with the diagnosis made after 1979) who had relapsing encephalopathy compatible with previous reports of Hashimotos encephalopathy and no other identifiable cause of encephalopathy at Mayo Clinic Rochester. Of these nine patients, three were clinically hypothyroid, four were subclinically hypothyroid, and two were euthyroid. Thyroid antibodies were positive in eight of eight patients in whom these measurements were made. Electroencephalographic abnormalities were identified in eight of the nine patients (89%). Magnetic resonance imaging (MRI) abnormalities considered etiologically related to encephalopathy were present in three patients (33%). An increased protein concentration was noted on cerebrospinal fluid examination in seven patients (78%). Of the six patients who received high-dose glucocorticoid therapy, 5 (83%) had improvement of neurologic symptoms. In conclusion, encephalopathy associated with autoimmune thyroiditis is rare but important to recognize because it may be responsive to high-dose glucocorticoid therapy. We believe that this condition is not caused by thyroid dysfunction or antithyroid antibodies but represents an association of an uncommon autoimmune encephalopathy with a common autoimmune thyroid disease. The term Hashimotos encephalopathy is a misnomer and should not be used.

Subclinical Thyroid Disease

The term subclinical thyroid disease is used to describe asymptomatic thyroid abnormalities found on imaging studies or laboratory tests. Thyroid nodules not palpable on physical examination but detected on imaging studies performed for other purposes are called incidentalomas. In the absence of risk factors for thyroid cancer, nodules that are less than 1 cm in diameter do not require biopsy. Subclinical hyperthyroidism is defined as suppressed serum sensitive thyrotropin (TSH) and normal serum thyroxine and triiodothyronine levels. This condition may adversely affect the heart and the bones and should be treated, especially in patients older than 60 years. Subclinical hypothyroidism, defined as mildly elevated serum TSH and normal serum thyroxine levels, is the most common thyroid dysfunction. In patients with subclinical hypothyroidism, thyroxine therapy should be given if the serum TSH level is higher than 10 mIU/L. For TSH values between 5 and 10 mIU/L, the decision for therapy should be individualized and depends on the level of TSH, presence of antithyroid antibodies, and clinical factors.

A Multicenter Phase 2 Trial of Pazopanib in Metastatic and Progressive Medullary Thyroid Carcinoma: MC057H

CONTEXT Pazopanib is a small molecule inhibitor of kinases principally including vascular endothelial growth factor receptors-1, -2, and -3; platelet-derived growth factor receptors-α and -β; and c-Kit. We previously reported a tumor response rate of 49% in patients with advanced differentiated thyroid cancer and 0% in patients with advanced anaplastic thyroid cancer. The present report details results of pazopanib therapy in advanced medullary thyroid cancer (MTC). OBJECTIVE, DESIGN, SETTING, PATIENTS, INTERVENTION, AND OUTCOME MEASURES: Having noted preclinical activity of pazopanib in MTC, patients with advanced MTC who had disease progression within the preceding 6 months were accrued to this multiinstitutional phase II clinical trial to assess tumor response rate (by Response Evaluation Criteria In Solid Tumors criteria) and safety of pazopanib given orally once daily at 800 mg until disease progression or intolerability. RESULTS From September 22, 2008, to December 11, 2011, 35 individuals (80% males, median age 60 y) were enrolled. All patients have been followed up until treatment discontinuation or for a minimum of four cycles. Eight patients (23%) are still on the study treatment. The median number of therapy cycles was eight. Five patients attained partial Response Evaluation Criteria In Solid Tumors responses (14.3%; 90% confidence interval 5.8%-27.7%), with a median progression-free survival and overall survival of 9.4 and 19.9 months, respectively. Side effects included treatment-requiring (new) hypertension (33%), fatigue (14%), diarrhea (9%), and abnormal liver tests (6%); 3 of 35 patients (8.6%) discontinued therapy due to adverse events. There was one death of a study patient after withdrawal from the trial deemed potentially treatment related. CONCLUSIONS Pazopanib has promising clinical activity in metastatic MTC with overall manageable toxicities.

Invasive fibrous thyroiditis (Riedel thyroiditis): the Mayo Clinic experience, 1976-2008.

BACKGROUND Invasive fibrous thyroiditis (IFT) is the rarest form of thyroiditis, and reports are often limited to case reports and small case series. In this study, we aimed to summarize our institutional experience with IFT since 1976. METHODS We retrospectively reviewed the cases of all patients with IFT evaluated at Mayo Clinic, Rochester, Minnesota, from 1976 through 2008, with special emphasis on clinical presentation, associated risk factors, associated comorbid conditions, complications, and treatment. RESULTS Twenty-one patients met our inclusion criteria of (i) IFT confirmed by pathologic review at our institution and (ii) evidence of extension of fibrosis outside the thyroid capsule. Most patients (17, 81%) were women (mean age, 42 years). Presenting symptoms included pain (24%), dysphagia (33%), vocal cord paralysis (29%), and tracheal narrowing (48%). Three patients had associated hypoparathyroidism. Sixteen (76%) had a history of tobacco use, and 10 (48%) were current smokers. Fibrosing mediastinitis was present in four, orbital fibrosis in one, retroperitoneal fibrosis in three, and pancreatic fibrosis in one (38% had extracervical fibrotic processes). Eighteen patients had partial thyroidectomy, 7 (39%) of whom had surgical complications involving vocal cords and parathyroid. Two required tracheostomy. Thirteen had corticosteroid therapy; six received tamoxifen. There was no cause-specific mortality, and the fibrotic process stabilized or partially resolved in all patients. CONCLUSIONS IFT often is associated with a systemic extracervical fibrotic process and tobacco use. Attempted thyroid resection often results in postoperative complications. Long-term follow-up showed no deaths from IFT and showed stability of the thyroiditis.

Clinical Spectrum of Hyperglucagonemia Associated With Malignant Neuroendocrine Tumors

OBJECTIVE To review the clinical features associated with hyperglucagonemia in malignant neuroendocrine tumors. MATERIAL AND METHODS We retrospectively reviewed the medical records of patients with hyperglucagonemia encountered at our institution from Oct. 17, 1988, through February 1993 who had a fasting serum glucagon level of at least 120 pg/mL (twice the normal value). The 71 study patients also had no evidence of a secondary cause of hyperglucagonemia and had pathologic confirmation of a neuroendocrine tumor. RESULTS The study group consisted of 46 men and 25 women with a median age of 57 years. Two patients had multiple endocrine neoplasia. Forty-nine patients had biochemically polyfunctional tumors, and 22 had hyperglucagonemia only. The most common initial symptoms were weight loss, abdominal pain, diarrhea, nausea, peptic ulcer disease, diabetes, and necrolytic migratory erythema (NME). Diabetes eventually developed in 25 patients and was associated with NME in 11. The highest median serum glucagon values occurred in patients with the glucagonoma syndrome or insulinomas, and the lowest median values were in those with carcinoid syndrome, Zollinger-Ellison syndrome, or diabetes without NME. Fasting glucagon and glucose measurements were not correlated. The most common hormonal syndromes were the Zollinger-Ellison syndrome and the glucagonoma syndrome. All the neuroendocrine tumors were malignant. Several methods of treatment, including surgical debulking, chemotherapy, somatostatin, and hepatic artery embolization, were used. Death occurred in 29 patients at a median of 2.79 years after diagnosis; 42 patients were alive at a median of 2.86 years after diagnosis. CONCLUSION A mild degree of hyperglucagonemia can commonly be associated with multifunctional neuroendocrine tumors. The glucagonoma syndrome occurs in a few patients with malignant neuroendocrine tumors and hyperglucagonemia and is associated with very high serum glucagon levels. The correlation between serum glucagon levels and the development of diabetes is limited, and other factors such as insulin may be more important than hyperglucagonemia in the development of diabetes.

Undetectable Sensitive Serum Thyroglobulin (<0.1 ng/ml) in 163 Patients with Follicular Cell-Derived Thyroid Cancer: Results of rhTSH Stimulation and Neck Ultrasonography and Long-Term Biochemical and Clinical Follow-Up

CONTEXT Surveillance of patients with differentiated thyroid cancer (DTC) is achieved using serum thyroglobulin (Tg), neck ultrasonography (US), and recombinant human TSH (rhTSH)-stimulated Tg (Tg-stim). OBJECTIVE Our primary aim was to assess the utility of rhTSH Tg-stim in patients with suppressed Tg (Tg-supp) below 0.1 ng/ml using a sensitive assay. Our secondary aims were to assess the utility of US and to summarize the profile of subsequent Tg-supp measures. DESIGN This is a retrospective study conducted at two sites of an academic institution. PATIENTS A total of 163 patients status after thyroidectomy and radioactive iodine treatment who had Tg-supp below 0.1 ng/ml and rhTSH Tg-stim within 60 d of each other were included. RESULTS After rhTSH stimulation, Tg remained below 0.1 ng/ml in 94 (58%) and increased to 0.1-0.5 in 56 (34%), more than 0.5-2.0 in nine (6%), and above 2.0 ng/ml in four (2%) patients. Serial Tg-supp levels were obtained in 138 patients followed over a median of 3.6 yr. Neck US were performed on 153 patients; suspicious exams had fine-needle aspiration (FNA). All positive FNA were identified around the time of the initial rhTSH test. Six of seven recurrences were detected by US (Tg-stim >2.0 ng/ml in one, 0.8 in one and ≤ 0.5 in four). One stage IV patient had undetectable Tg-stim. CONCLUSION In patients with DTC whose T(4)-suppressed serum Tg is below 0.1 ng/ml, long-term monitoring with annual Tg-supp and periodic neck US are adequate to detect recurrences. In our experience, rhTSH testing does not change management and is not needed in this group of patients.

SPECTRUM OF MALIGNANT SOMATOSTATIN-PRODUCING NEUROENDOCRINE TUMORS

OBJECTIVE To evaluate the clinical manifestations and outcome of patients with somatostatinomas--rare neuroendocrine tumors of pancreaticoduodenal origin. METHODS We searched the medical archives and tumor registry of our institution for somatostatinomas or somatostatin-staining tumors for the 12-year period from January 1990 to February 2002. In addition, we reviewed laboratory databases for patients who had an elevated serum somatostatin level. Patients with a neuroendocrine tumor and an elevated serum somatostatin level or somatostatin-positive tumor immunostaining were included in this study. RESULTS Eleven patients qualified (9 men and 2 women; median age at diagnosis, 45 years; age range, 22 to 73). The diagnosis of a somatostatinoma was made by immunostaining of the tumor in 9 patients and by finding elevated serum somatostatin levels in 2. Five primary tumors were of duodenal and 6 of pancreatic origin. Psammoma body formation and association with neurofibromatosis were seen only in the duodenal tumors. The known primary tumor sizes varied from 2 to 6 cm. Liver metastatic lesions were present in 6 patients, abdominal lymph node involvement was found in 10 patients, and lung, spleen, and ovarian metastatic involvement was noted in 1 patient each. Diabetes was present in 4 patients (36%) and cholelithiasis in 7 (64%). The presence of a mass led to the diagnosis in most patients with primary duodenal tumors, whereas patients with pancreatic tumors were more likely to have endocrine manifestations. A Whipple procedure was performed in 6 patients, distal pancreatectomy in 3, hepatic artery embolization or ligation in 3, and partial hepatectomy in 1. Cancer-related death occurred in 4 patients, 1 to 8 years after diagnosis (median, 4.5 years). At last follow-up, 2 patients were alive without evidence of disease (8 and 10 years after diagnosis), and 3 were alive with liver metastatic lesions. The status of 2 patients was unclear. CONCLUSION Somatostatinomas occurred with approximately equal frequency in the duodenum and the pancreas. The duodenal tumors were more likely to be pure somatostatinomas and have psammoma bodies. Pancreatic tumors were more likely to be multihormonal. Cholelithiasis and diabetes were seen in 64% and 36%, respectively, of the patients. Mass effect of the tumor was the usual manifestation leading to diagnosis. These tumors are slow growing, and long-term survival is possible.