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The chromosomal regions containing the two putative tumour suppressors, fragile histidine triad gene (FHIT) and tumour suppressor gene 101 (TSG101), are deleted frequently in thyroid tumours. We therefore analysed FHIT and TSG101 transcripts in a group of advanced thyroid tumours to establish their role in thyroid tumorigenesis.Retrospective analysis of FHIT and TSG101 mRNA transcripts and genomic DNA from cryo-preserved thyroid tumours. TP53, previously shown at the genomic level not to be mutated in this cohort of tumours, served as a control.We analysed nine follicular thyroid carcinomas (FTC), six papillary thyroid carcinomas and six follicular adenomas (FA) and histologically normal thyroid tissue from four of the FA patients.Single stage and nested reverse transcription polymerase chain reaction (RT-PCR) products of FHIT, TSG101, and TP53 were analysed by agarose or polyacrylamide gel electrophoresis and sequenced. Genomic DNA was also analysed by polymerase chain reaction and sequencing (FHIT) or by Southern blotting (TSG101). Clinical data were correlated with the results of the mutation analysis.Truncated FHIT transcripts were observed frequently alongside full length transcripts with nested RT-PCR, most often in FTC, while single stage RT-PCR revealed only normal length transcripts in all tumours. Similar results were obtained for TP53, while abnormal TSG101 transcripts were detectable by single stage RT-PCR. Sequence analysis of the truncated FHIT and TSG101 transcripts revealed mainly exon skipping and alternate RNA processing events. Only a single point mutation (of TSG101) was found. Southern blotting for the TSG101 gene, and PCR amplification and sequencing of the FHIT gene showed no evidence of genomic abnormalities in either case, and there was no evidence of splice site mutations in the FHIT gene, suggesting that the truncated transcripts result from altered RNA processing. There was no relationship between tumour stage, grade or survival and the presence of FHIT or TSG101 abnormalities.Truncated FHIT and TSG101 transcripts in thyroid tumours reflect alternate mRNA splicing events, rather than genomic deletions. Such abnormal RNA processing seems to be common and widespread in thyroid neoplasms, as similar results were obtained by analysis of transcripts of TP53, which we had previously shown not to be mutated in these specimens. Although a pathogenetic role for these aberrant transcripts remains possible, no correlation was found with stage, histological grade or outcome in this small group of advanced thyroid malignancies. Relaxation of mRNA splice control appears to be a feature of follicular cell-derived thyroid neoplasms.

Background The study aims were to characterize patients with papillary thyroid microcarcinoma (PTM) and to describe post-surgical outcome. Methods Nine hundred PTM patients had initial treatment at Mayo Clinic during 1945–2004. Mean follow-up was 17.2 years. Recurrence and mortality details were derived from a computerized database. Results Median tumor size was 7 mm; 98% were intrathyroidal. 273 patients (30%) had neck nodal involvement; 3 (0.3%) had distant metastases at diagnosis. Seven-hundred and sixty-five (85%) underwent bilateral lobar resection (BLR; total-, near-total, or bilateral subtotal thyroidectomy). Regional nodes were removed by either “node picking” (27%) or compartmental dissection (23%). Tumor resection was incomplete in 5 (0.6%). Radioiodine remnant ablation (RRA) was performed in 155 (17%). Overall survival did not differ from expected for an age and gender matched control group (P = .96); 3 patients (0.3%) died of PTM. None of the 892 patients with initial complete tumor resection developed metastatic spread during 20 postoperative years. Twenty-year and 40-year tumor recurrence rates were 6% and 8%, respectively. Higher recurrence rates were seen with multifocal tumors (P = .004) and node-positive patients (P < .001). Neither more extensive surgery nor RRA reduced recurrence rates compared to unilateral lobectomy. Conclusion More than 99% of PTM patients are not at risk of distant spread or cancer mortality. RRA after BLR did not improve postoperative outcome.

OBJECTIVE To determine whether there was a significant increase in the incidence of thyroid carcinoma in Olmsted County, Minnesota, that may be attributed to the widespread use of therapeutic head and neck irradiation between 1920 and the 1950s or to exposure to atomic fallout at the Nevada Test Site in the 1960s. METHODS Rochester Epidemiology Project resources were used to identify potential cases of thyroid carcinoma among residents of Olmsted County between 1935 and 1984. We extended this earlier study through 1999. RESULTS During the study period, thyroid carcinoma was newly diagnosed in 263 residents. In women, the age-adjusted incidence increased from 2.7 per 100,000 person-years (p-y) in 1935-1949 to 9.2 per 100,000 p-y in 1990-1999 ( P =.001); in men, the rate increased from 0.8 to 5.0 per 100,000 p-y ( P =.007). However, most of the increase occurred before 1965 and remained relatively stable thereafter. Similar trends were observed for papillary carcinoma alone. CONCLUSION Although the incidence of thyroid carcinoma increased significantly between 1935 and 1964, no significant increases have been seen since 1965, suggesting that neither atmospheric atomic fallout from the Nevada Test Site nor use of ionizing radiation to treat conditions of the head and neck significantly affected the incidence of thyroid carcinoma in Olmsted County.

The PAX8/PPARγ (PPFP) fusion-oncogene is moderately specific for follicular thyroid carcinomas (FTC). It remains unknown whether this can be translated into improved diagnosis, classification, or outcome prediction. We studied a cohort of well-characterized follicular adenomas (FA), FTC, and Hürthle cell carcinomas (HCC) from patients with complete clinical follow-up, to determine whether PPARγ immunohistochemistry (as a surrogate of PAX8/PPARγ expression) helps to distinguish FA from FTC and to assess its diagnostic accuracy as an adjunct to frozen section. We also correlated PPARγ staining with clinical outcomes to assess its role as a prognostic marker. PPARγ staining was more common in FTC (31 of 54; 57%) than in HCC (one of 23; 4%) or FA (four of 31; 13%) (P < 0.000001). Adjunctive use of PPARγ immunohistochemistry improved diagnostic sensitivity of intraoperative frozen section from 84% to 96% (P < 0.05) but reduced specificity from 100% to 90% (P < 0.05). PPARγ staining was associated with favorable prognostic indicators (female gender, better tumor differentiation, and lesser risk of metastases). PPARγ staining may be helpful in the differential diagnosis of FA, FTC, and HCC, particularly when diagnostic sensitivity of histomorphology is reduced (e.g. during intraoperative frozen section). PPARγ staining also shows an association with favorable prognosis and may have a role in risk stratification.

Approximately 10% to 20% of thyroid biopsies by fine-needle aspiration (FNA) are nondiagnostic. The management of thyroid nodules in which FNA is nondiagnostic remains controversial because few studies have addressed this issue. We retrospectively reviewed the medical records of 153 patients with nondiagnostic FNAs of the thyroid performed in 1994. Sixty patients had reaspiration biopsies performed. Thirty-seven specimens (62%) were diagnostic and 23 (38%) remained nondiagnostic. Of the 27 patients who had a thyroid operation, 10 (37%) had a malignancy. Preoperative information about physical examination, ultrasound imaging, or nondiagnostic FNA did not predict outcome. Nondiagnostic FNAs of the thyroid may be associated with a high probability of thyroid malignancy. Nondiagnostic FNAs should not be considered benign. Reaspiration followed by selective surgical treatment is recommended.

The ability of thyroid cancers to concentrate radioiodine (RAI) is dependent, in part, upon the expression and functional integrity of the sodium iodide symporter (NIS). However, some differentiated thyroid carcinomas (DTCs) and most undifferentiated thyroid carcinomas lack the ability to concentrate iodide and are thereby insensitive to 131I therapy. Variation of NIS protein expression may be an important factor in this behavior. We wished to determine whether NIS protein expression in primary DTC tumors correlated with the subsequent RAI uptake by metastatic lesions in the same patients. We obtained paraffin-embedded tissue specimens from 60 patients with metastatic thyroid cancer who had undergone total or near-total thyroidectomy at the Mayo Clinic for DTC and had known presence or absence of RAI uptake in their tumor deposits determined by total body scanning after thyroid hormone withdrawal. Tissue sections from the primary intrathyroidal tumors were subjected to immunostaining (IS) using a monoclonal antibody against human NIS. Slides were subsequently examined for specific IS by two independent reviewers. For each patient, whole body scan (WBS) uptake was recorded, and correlation between results of IS and WBS was analyzed. Of 43 patients with a positive WBS, 37 also had positive IS of their tumors. In six patients with negative IS, a positive WBS was documented, and in three of these cases TSH at the time of surgery was less than 0.3 mIU/liter. Of the 17 patients with negative WBS, 10 were also negative on IS. Positive IS accurately predicted a positive scan in our study in 84% of cases; the ability of the IS to detect all cases with a positive scan was 86%, and it increased to 90% when patients who were receiving thyroid hormone therapy at the time of surgery were excluded from the analysis. Overall, the results of our retrospective study suggest that NIS IS of the thyroidal primary tumor in patients with papillary and follicular thyroid cancers has substantial ability to predict the behavior of subsequent deposits of metastatic and recurrent cancer with respect to iodine trapping and concentration. Our findings require confirmation in prospective studies to more accurately determine the predictive ability of the test and its role in the postoperative management of patients with DTC. If confirmed, NIS IS of DTC primary lesions may prove useful in the management of patients with known or suspected metastatic thyroid cancer.

Expression of the sodium iodide symporter in human kidney. Background The human sodium iodide symporter (hNIS) is a transmembrane protein that mediates the active transport of iodide in the thyroid gland. Following cloning of NIS, NIS expression has been detected in a broad range of nonthyroidal tissues, suggesting that iodide transport in these tissues is conferred by the expression of functional NIS protein. Methods The aim of this study was to examine functional hNIS expression in kidney by reverse transcription-polymerase chain reaction (RT-PCR), ribonuclease protection assay (RPA), immunohistochemistry, and Western blot analysis accompanied by iodide accumulation studies in kidney cells. Results Using a pair of full-length hNIS-specific oligonucleotide primers, RT-PCR followed by Southern hybridization revealed hNIS mRNA expression in normal human kidney tissue. The PCR products were subjected to automated sequencing and revealed full identity with the published human thyroid-derived NIS cDNA sequence. Furthermore, positive protected bands indicating the presence of hNIS mRNA were apparent in RPA gel lanes corresponding to human kidney cells as well as Chinese hamster ovary (CHO) cells stably transfected with hNIS cDNA and Graves' thyroid tissue. Immunohistochemical analysis of normal human kidney tissue using a mouse monoclonal hNIS-specific antibody showed marked hNIS-specific immunoreactivity confined to tubular cells, while no hNIS-specific immunoreactivity was detected in the glomeruli. NIS protein expression in human kidney cells was further confirmed by Western blot analysis. In addition, accumulation of 125 I was detected in human kidney cells in vitro and was shown to be sodium dependent and sensitive to perchlorate. Conclusions Functional hNIS expression was demonstrated in the renal tubular system, suggesting that renal iodide transport may be, at least in part, an active process driven by NIS.

OBJECTIVE The chromosomal regions containing the two putative tumour suppressors, fragile histidine triad gene (FHIT) and tumour suppressor gene 101 (TSG101), are deleted frequently in thyroid tumours. We therefore analysed FHIT and TSG101 transcripts in a group of advanced thyroid tumours to establish their role in thyroid tumorigenesis. DESIGN Retrospective analysis of FHIT and TSG101 mRNA transcripts and genomic DNA from cryo-preserved thyroid tumours. TP53, previously shown at the genomic level not to be mutated in this cohort of tumours, served as a control. PATIENTS We analysed nine follicular thyroid carcinomas (FTC), six papillary thyroid carcinomas and six follicular adenomas (FA) and histologically normal thyroid tissue from four of the FA patients. MEASUREMENTS Single stage and nested reverse transcription polymerase chain reaction (RT-PCR) products of FHIT, TSG101, and TP53 were analysed by agarose or polyacrylamide gel electrophoresis and sequenced. Genomic DNA was also analysed by polymerase chain reaction and sequencing (FHIT) or by Southern blotting (TSG101). Clinical data were correlated with the results of the mutation analysis. RESULTS Truncated FHIT transcripts were observed frequently alongside full length transcripts with nested RT-PCR, most often in FTC, while single stage RT-PCR revealed only normal length transcripts in all tumours. Similar results were obtained for TP53, while abnormal TSG101 transcripts were detectable by single stage RT-PCR. Sequence analysis of the truncated FHIT and TSG101 transcripts revealed mainly exon skipping and alternate RNA processing events. Only a single point mutation (of TSG101) was found. Southern blotting for the TSG101 gene, and PCR amplification and sequencing of the FHIT gene showed no evidence of genomic abnormalities in either case, and there was no evidence of splice site mutations in the FHIT gene, suggesting that the truncated transcripts result from altered RNA processing. There was no relationship between tumour stage, grade or survival and the presence of FHIT or TSG101 abnormalities. CONCLUSIONS Truncated FHIT and TSG101 transcripts in thyroid tumours reflect alternate mRNA splicing events, rather than genomic deletions. Such abnormal RNA processing seems to be common and widespread in thyroid neoplasms, as similar results were obtained by analysis of transcripts of TP53, which we had previously shown not to be mutated in these specimens. Although a pathogenetic role for these aberrant transcripts remains possible, no correlation was found with stage, histological grade or outcome in this small group of advanced thyroid malignancies. Relaxation of mRNA splice control appears to be a feature of follicular cell-derived thyroid neoplasms.

BACKGROUND A parathyroid adenoma demonstrating intranuclear holes on aspiration cytology prompted a review of parathyroid neoplasms to determine the frequency of this phenomenon. METHODS Aspiration cytology slides from 30 parathyroid adenomas and 1 parathyroid carcinoma were reviewed. In addition, histologic slides from 136 parathyroid adenomas and 7 parathyroid carcinomas were reviewed. Twenty-two cases had both cytologic and histologic slides available for review. The presence and approximate frequency of intranuclear holes were recorded. RESULTS On cytologic smears, intranuclear holes were found in 3 of the 31 cases reviewed (2 adenomas and 1 carcinoma). The holes were frequent in only one adenoma (the index case) and moderate–rare in the other two cases. Review of tissue slides showed holes in 9 of 136 adenomas and 3 of 7 carcinomas; 2 adenomas and 2 carcinomas had frequent holes, whereas the remainder had holes infrequently. CONCLUSIONS Intranuclear holes do occur in parathyroid neoplasia, in rare cases with considerable frequency. When intranuclear holes are observed in aspiration cytology specimens from the thyroid region, various thyroid and parathyroid conditions must be considered. Cancer (Cancer Cytopathol) 2000;90:41–6. © 2000 American Cancer Society.

Making a histologic distinction between Hurthle cell adenomas and carcinomas sometimes may be difficult. We analyzed a series of Hurthle cell lesions to determine whether specific histologic features and expression of Ki67 and cyclin D1 could be useful in distinguishing Hurthle cell adenomas from carcinomas. Formalin-fixed, paraffin-embedded tissues from 128 Hurthle cell neoplasms, including 59 adenomas; 55 carcinomas; and 14 tumors classified as neoplasms of uncertain malignant behavior (UMB), which had equivocal capsular invasion but no vascular invasion, were analyzed for expression of Ki67 and cyclin D1 by immunostaining. The distribution of immunoreactivity for Ki67 with antibody MIB-1 was analyzed by quantifying the percentage of positive nuclei that was expressed as the labeling index. None of the patients with adenomas or UMB tumors developed recurrent or metastatic disease after a mean follow-up of 7.8 and 7.9 years, respectively. Of the 55 patients with Hurthle cell carcinoma, 19 were associated with metastatic disease, 13 of whom died with disease. No patient with a Hurthle cell carcinoma without vascular invasion developed metastatic disease. The mean tumor size for Hurthle cell carcinomas (4.8 cm) was significantly larger than that of Hurthle cell adenomas (3.1 cm) or UMB tumors (3.7 cm). No patient with a Hurthle cell tumor smaller than 3.5 cm developed metastatic disease, even when vascular invasion was present. The Ki67 labeling index in Hurthle cell carcinomas (10.0 +/- 1.2) was 3-fold higher than in Hurthle cell adenomas (3.2 +/- 0.3). The Ki67 labeling index in the UMB group was 5.0 +/- 0.7. Cyclin D1 showed diffuse nuclear staining in 1 of the 59 (1.7%) Hurthle cell adenomas, in 10 of the 55 (18%) Hurthle cell carcinomas, and in none of the UMB tumors. In summary, analyses of the cell cycle proteins Ki67 and cyclin D1 in Hurthle cell thyroid neoplasms indicate that these markers may assist in distinguishing some Hurthle cell carcinomas from adenomas. Among the Hurthle cell carcinomas, large tumor size and vascular invasion are associated with clinically aggressive tumors. Our study also suggests that Hurthle cell neoplasms with only equivocal capsular invasion and no vascular invasion should behave in a benign manner.

The pathologic tumor-node-metastasis (pTNM) system is universally used to define the extent of disease in human malignancies. This study evaluated the impact of initial therapy on cause-specific mortality (CSM) rates and recurrence rates in pTNM stage III papillary thyroid carcinoma.Three hundred patients (median age, 58 years) were followed on average for 14 postoperative years. Of these, 246 patients (82%) had complete primary tumor resection; 208 patients (69%) had nodal metastases; 161 (54%) had locally invasive primary tumors; 45 patients (15%) underwent initial unilateral lobectomy (UL). Bilateral lobar resection (BLR) accounted for 242 patients (near-total, 54%; total thyroidectomy, 23%).The 30-year rates for CSM, distant metastases, nodal metastases, and local recurrence (LR) were 29%, 22%, 19%, and 16%, respectively. The 20-year rates for CSM were significantly higher (50% vs 14%) when primary tumor was incompletely resected (P = .0001). After complete resection, 20-year rates for CSM and LR after BLR were 12% and 10%, respectively, which were significantly lower (P.05) than the 23% and 26% rates seen after UL. There were no significant differences in nodal metastases or distant metastases rates between UL and BLR (P.4). The 20-year LR rate after total thyroidectomy (13%) was not different (P = .5) from the 11% seen after near-total thyroidectomy.In this nonrandomized evaluation of patients with pTNM stage III papillary thyroid carcinoma, the extent of primary thyroid resection appeared to significantly impact CSM and LR but did not apparently influence regional or distant metastasis.

The human sodium iodide symporter (hNIS) is an intrinsic transmembrane protein that mediates the active transport of iodide across the basolateral membrane of thyroid follicular cells. In addition to normally functioning thyroid tissue, various extrathyroidal tissues, including salivary gland, lacrimal gland, gastric mucosa, choroid plexus, and lactating mammary gland, have been demonstrated to accumulate iodide. After cloning and molecular characterization of the sodium iodide symporter, expression of hNIS messenger ribonucleic acid has been detected in a broad range of extrathyroidal tissues using Northern blot analysis and RT-PCR. In this study we used both monoclonal and polyclonal antibodies directed against different portions of hNIS protein together with a highly sensitive immunostaining technique to assess hNIS protein expression in tissue sections derived from normal human salivary and lacrimal glands, pancreas, as well as gastric and colonic mucosa. Immunohistochemical analysis of normal human salivary and lacrimal glands revealed marked hNIS immunoreactivity in ductal cells and less intense staining of acinar cells. Further, immunostaining of gastric and colonic mucosa showed marked hNIS immunoreactivity confined to chief and parietal cells in gastric mucosa and to epithelial cells lining mucosal crypts in colonic mucosa. In normal human pancreas, hNIS immunoreactivity was located in ductal cells, exocrine parenchymal cells, and Langerhans islet cells. In conclusion, our study demonstrates the expression of hNIS protein by several human exocrine glands, suggesting that iodide transport in these glands is a specific property conferred by the expression of hNIS protein, which may serve important functions by concentrating iodine in glandular secretions.

The thyroid sodium-iodide symporter (NIS) is responsible for iodide concentrating ability within thyroid follicular cells. We sought to develop monoclonal antibodies against human NIS (hNIS) for use as reagents in structure-function studies of the protein, as well as potential tools in the assessment of NIS expression in benign and malignant thyroid tissues. Synthetic peptides corresponding to the second ExMD and to the carboxy-terminal ExMD of hNIS were produced and utilized as antigens to develop monoclonal antibodies, which were tested by Western blotting using membranes prepared from COS-7 cells transiently transfected with a pcDNA3 plasmid containing the gene for the full-length hNIS, or a control vector. Western blotting showed a major band with molecular weight (MW) of approximately 97 kDa and several minor bands with MW of approximately 160 kDa, 68 kDa, 30 kDa, and 15 kDa, all specific for hNIS-transfected cells. Immunohistochemistry was performed in various types of thyroid tissues and nonthyroidal tissues, using the monoclonal antibodies. Strong immunostaining was observed in Graves' tissue, intermediate staining in papillary and follicular thyroid cancer, and no staining in Hurthle cell cancer or in nonthyroidal tissue. The staining was specific for the follicular epithelium in each of the tissues and was most intense in the basolateral portion of the cell membrane. Overall, our observations indicate that the monoclonal antibodies are specific for hNIS and will be invaluable reagents for investigating the role of NIS in thyroid disease.

Many round, pale yellow, cytoplasmic inclusion bodies were found in hematoxylin and eosin-stained sections of a hyalinizing trabecular adenoma of the thyroid. The bodies were refractile and frequently had a microvacuolated or granular substructure. They were usually located close to the nucleus, often indented it, and rarely occurred within it. Histochemically, they showed a glycosaminoglycan, proteoglycan, and lipid content, displayed autofluorescence on exposure to ultraviolet light, and were unreactive with a variety of immunostains. Ultrastructurally, the inclusions were consistent with giant lysosomes, showing parallel whorled and arrayed membranes ("fingerprint" bodies) as a component of their substructure. Review of sections of 75 hyalinizing trabecular adenomas in our files revealed that the cytoplasmic bodies were present in all cases (100%), indicating that these inclusions most likely are a universal feature of the neoplasm.

Background: Controversy continues regarding the optimal extent of primary thyroid resection in most patients with papillary thyroid carcinoma (PTC), who are at minimal risk of cause-specific mortality (CSM). This study was designed to compare CSM and recurrence rates after either unilateral lobectomy (UL) or bilateral lobar resection (BLR) in patients with PTC considered low risk by AMES criteria. Methods: Outcome was studied in 1685 patients initially treated during 1940 through 1991 and followed for up to 54 postoperative years (mean, 18 years). One thousand six hundred fifty-six patients (98%) had complete primary tumor resection; 634 (38%) had involvement of regional nodes. One hundred ninety-five patients (12%) had UL; BLR accounted for 1468 (near-total 60%; total thyroidectomy 18%). Results: Thirty-year rates for CSM and distant metastasis were 2% and 3%, respectively. Twenty-year rates for local recurrence and nodal metastasis were 4% and 8%, respectively. There were no significant differences in CSM or distant metastasis rates between UL and BLR ( P > .2). After UL, 20-year rates for local recurrence and nodal metastasis were 14% and 19%, significantly higher ( P = .0001) than the 2% and 6% rates seen after BLR. Conclusions: UL was not associated with higher CSM rates, but it was associated with a significantly higher risk of locoregional recurrence. Thus BLR probably represents a preferable initial surgical approach to patients with low-risk PTC. (Surgery 1998;124:958-66.)

The association between thyroid cancer and familial adenomatous polyposis (FAP), albeit rare, is well known. It has been suggested that the thyroid tumors have unique histologic characteristics and may be follicular in origin. Because of their rarity, treatment and long-term prognosis are uncertain. Twelve such patients (prevalence 399/100,000) seen during 1949-1995 were retrospectively reviewed. Histology was independently re-reviewed by two pathologists. There were 11 female patients (two sisters) and 1 male patient, with a mean age of 28 years (range 15-61 years). Eight patients (66%) had multicentric tumors and five (42%) bilateral disease. Average tumor diameter was 1.8 cm (range 0.2-5.0 cm). Regional nodal metastases were present in two patients. All 12 thyroid cancers in this series were papillary. The one male patient demonstrated "typical" histology with variable papillary and follicular architecture, whereas the 11 female patients had tumors with unusual histology as described by Harach. Five patients (41%) were treated by total thyroidectomy, five with near-total thyroidectomy, and two with lobectomy alone. Mean follow-up was 142 months (range 7 months to 30 years). Regional recurrent disease occurred in two patients, one of whom died of the disease. The 5- and 20-year survivals were 90% and 77%, respectively. The results indicated that all tumors in this study were papillary, although atypical histology was encountered in 91%. The mean age (28 years) is younger than that of patients with sporadic disease. Multicentricity and bilateral disease are common. In view of this finding, total thyroidectomy should be strongly considered. Long-term prognosis is excellent. The finding of unusual histology in a young patient with papillary thyroid carcinoma should arouse the suspicion of FAP.

Management of a solitary liver mass necessitates reliable distinction between primary hepatocellular carcinoma and metastatic lesions. The histologic differentiation can be difficult even with special stains such as alpha-fetoprotein, cytokeratin, and carcinoembryonic antigen. Albumin is a specific product of hepatocytes, and in situ hybridization to reveal albumin messenger RNA (mRNA) is highly specific and sensitive for the diagnosis of primary hepatocellular carcinoma. This technique can be used on histopathologic specimens and in cytologic diagnosis. Herein we describe a patient with synchronous renal and hepatic masses, in whom the distinction had to be made between metastatic renal cell carcinoma and two separate primary tumors--one in the liver and one in the kidney. In situ hybridization for albumin mRNA proved helpful in making this distinction. In addition, we review the literature on the diagnostic use of albumin gene expression in liver tumors.

Follicular thyroid carcinoma (FTC) exhibits frequent loss of heterozygosity (LOH) on chromosomes 10q and 3p, suggesting involvement of tumor suppressor genes. We screened 14 FTC (10 Hurthle cell carcinomas and 4 nonoxyphilic FTC), 14 papillary thyroid carcinomas, and 7 follicular adenomas for LOH on chromosome arms 1p, 3p, 3q, 10p, 10q, 11p, 11q, 13q, 17p, and 17q. LOH was more frequent in FTC than in follicular adenoma or papillary thyroid carcinoma. In FTC, rates of LOH on 3p (86%), 17p (72%), and 10q (57%) were higher than the average rate of LOH (33%; P < 0.05). Most frequently involved were 3p21–25 and 17p13.1–13.3, the sites for the VHL (3p25–26) and p53 (17p13.1) tumor suppressors. We, therefore, characterized these genes by dideoxy fingerprinting and DNA sequencing. Two FTC had mutations in p53, but only 1 of these exhibited LOH at 17p. No VHL gene mutations were found. Thus, neither p53 nor VHL genes play a significant role in the pathogenesis of differentiated thyroid cancer. LOH on 17p, but not on 3p or 10q, was correlated with mortality. Accordingly, 3p and 10q LOH may represent early, and 17p LOH late, events in FTC development. The data suggest the presence of novel tumor suppressor genes on chromosomes 3p and 17p that may be important in the pathogenesis of FTC.

Objective To assess clinical factors that may improve the ability to predict the presence of a malignant lesion in thyroid nodules that are found to be "suspicious for follicular neoplasm" by tine-needle aspiration FNA cytology. Material and Methods We undertook a retrospective review of the medical records of all patients at the three Mayo Clinic facilities who underwent a thyroid surgical procedure between January 1992 and December 1994 and had a preoperative FNA report of "suspicious for follicular neoplasm." Patient and nodule characteristics were analyzed statistically for associations with the presence of cancer. Results The study cohort consisted of 219 patients with a mean age of 54.3 years. Eighty-four percent of resections were done for benign disease. Of the 35 malignant lesions, 9 were incidental papillary cancers separate from the primary nodule; thus, only 26 cancers were found in the index nodule, and only 19 (9% of the total group) were follicular carcinomas. Clinical findings associated with a malignant index nodule were larger diameter, fixation of the mass, and younger age of the patient. Conclusion Clinical characteristics may be used for more accurate assessment of the risk of the presence of a malignant lesion when FNA cytology of a thyroid nodule is reported as "suspicious for follicular neoplasm."

The association of invasive fibrous thyroiditis (IFT) with foci of extracervical fibrosclerosis is well recognized. Affected sites include the retroperitoneum, the mediastinum, the biliary tract, and the orbit. The development of subcutaneous fibrosclerosis, however, is extremely rare. We report a patient with known invasive fibrous thyroiditis and hypoparathyroidism who presented with localized subcutaneous fibrosclerosis of the anterior chest wall resulting in compression of his ventriculoperitoneal shunt. The aetiology of IFT has remained unclear. Several histological and serological features, including the presence of mononuclear cells within the fibrosclerotic process, the occurrence of microscopic vasculitis, and the detection of autoantibodies directed against thyroid-specific antigens in a large proportion of patients with IFT, currently support the notion of autoimmune mechanisms playing a role in the pathogenesis of this rare disease.

Background: Cutaneous metastases develop in 2% to 9% of patients with an internal malignancy. Thyroid carcinoma metastatic to the skin is a rare clinical entity. Objective: Our purpose was to study the clinical and pathologic features and outcome in patients with cutaneous metastasis from thyroid carcinoma. Methods: The study included a retrospective analysis of six patients with skin metastases from thyroid carcinoma and a review of the English-language literature since 1964. Results: Including our six patients, 43 patients with skin metastases from thyroid carcinoma have been reported. Papillary carcinoma was the most common (41%), followed by follicular (28%), anaplastic (15%), and medullary carcinomas (15%). The scalp was the most common site of metastasis. For our patients, the average length of survival after diagnosis of cutaneous metastasis was 19 months. Conclusion: Cutaneous metastasis from thyroid carcinoma is rare and occurs in the setting of disseminated neoplastic disease. (J Am Acad Dermatol 1997;36:531-7.)

Background Insular thyroid carcinoma is intermediate in aggressiveness between well differentiated and anaplastic thyroid carcinomas. Methods The authors describe two children with insular thyroid carcinoma who had markedly different outcomes. In the first case, a girl age 15 years, 2 months presented with a large pulsatile mass in the right thyroid lobe. In the second case, a girl age 16 years, 3 months presented after total thyroidectomy was performed elsewhere for confirmed pTNM Stage I insular thyroid carcinoma. Results In Case 1, total thyroidectomy was performed, and histologic examination revealed insular thyroid carcinoma with lymph node involvement. Six weeks postoperatively, neck masses reappeared. There was significant radioactive iodine uptake in the thyroid bed and in a palpable right supraclavicular lymph node; this was associated with an increased serum thyroglobulin level. Ultrasound-guided biopsy of the lymph node confirmed recurrent insular carcinoma, and neck dissection was performed. Six weeks later, there was 0.35% iodine uptake in the neck, and the patient was treated with 300 mCi of (131)I. She had no signs of recurrence when last seen 22 months postoperatively. In Case 2, the patient was given 29.9 mCi of (131)I for remnant ablation. Four months postoperatively, fine-needle aspiration biopsy of a high jugular lymph node demonstrated recurrence. The patient was given 200 mCi of (131)I but had no significant response. Right modified neck dissection was performed, followed by external beam radiation. Despite aggressive treatment with a further 500 mCi of (131)I, progressive lung and mediastinal metastases developed, followed by brain metastasis. The patient died 31 months after the initial diagnosis. Conclusions Insular thyroid carcinoma may occur and behave aggressively in children. Vigorous initial surgical and radioactive iodine treatments are warranted.

Background The incidence of metastasis to the thyroid gland in autopsy series varies from 1.25% to 24%. Metastasis to the thyroid gland is usually considered a terminal event, and the effectiveness of conventional treatment has been questioned. The authors assessed the effects of current methods of diagnosis and treatment on the course of the disease. Methods Forty-three patients with metastasis to the thyroid gland were studied retrospectively. Primary tumor origin was identified in all but two cases. Metastasis to the thyroid gland was confirmed by fine-needle aspiration cytology or histology. Data were analyzed for the frequency and types of malignant lesions, the clinical course of disease, and the prognosis after thyroid involvement. Results The kidney was the most common primary tumor site (33%), followed by lung (16%), breast (16%), esophagus (9%), and uterus (7%). The time from diagnosis of the primary tumor to metastasis to the thyroid gland was considerable for renal cell adenocarcinoma (mean, 106 months) and for adenocarcinomas of the breast (mean, 131 months) and uterus (mean, 132 months). In 12 patients, this interval was more than 120 months. Fine-needle aspiration cytology detected metastatic malignancy in 29 of 30 patients. Treatment involved surgery alone, surgery with adjuvant therapy, or nonsurgical methods. Two patients with uterine adenocarcinoma and one with breast adenocarcinoma had disease regression with no evidence of tumor recurrence. Conclusions In any patient with a previous history of malignancy, no matter how remote that history is, a new thyroid mass should be considered recurrent malignancy until proved otherwise. Although detection of metastasis to the thyroid gland often indicates poor prognosis, aggressive surgical and medical therapy may be effective in a small percentage of patients.

Needle aspiration specimens from 74 cases of hepatocellular carcinoma (HCC) diagnosed between January 1986 and December 1992 were reviewed and compared with 57 other lesions. The most specific cytologic findings for HCC included capillaries separating tumor cells (34%), bile associated with malignant cells (19%), and endothelial cells lining clusters of neoplastic cells (18%). Less specific findings included polygonal cells with central nuclei resembling normal hepatocytes and intranuclear inclusions. Tissue core fragments available in 53 cases of HCC disclosed that a weak keratin (AE1/AE3) stain (75% of HCC), a canalicular pattern of polyclonal carcinoembryonic antigen (54%), and a positive alpha-fetoprotein stain (58%) are diagnostic of HCC. All HCCs were negative for monoclonal carcinoembryonic antigen. In situ hybridization for albumin mRNA was positive in 27 of 33 cases of HCC. The diagnosis of HCC by needle biopsy should include cytologic findings and the appropriate immunohistochemical profile, along with detection of albumin mRNA by in situ hybridization.

Objectives. The prevalence of human papillomavirus deoxyribonucleic acid (DNA) in primary squamous cell carcinoma of the male urethra and corresponding control tissue was studied. Methods. The technique of polymerase chain reaction DNA amplification was used to detect specific humanpapillomavirus DNA sequences in archival pathologic and control tissue. We analyzed 16 cases of primary squamous cell carcinoma of the male urethra and 22 specimens of normal male urethra stratified by location within the urethra. Results. Primary squamous cell carcinoma of the pendulous urethra was significantly associated with humanpapillomavirus type 16 DNA (6 of 6 cases), but the control, tissue from the pendulous urethra was not (0 of 12, P

The etiology of Riedel's invasive fibrous thyroiditis (IFT) has remained obscure. This rare disorder has been confused in the past with the more common fibrous variant of Hashimoto's disease. The typical histological features of IFT, in particular the presence of an invasive fibrosclerotic process in conjunction with a prominent chronic inflammatory infiltrate, suggest that the release of fibrogenic cytokines and other factors from these cellular infiltrates may play an important role in the pathogenesis of this condition. Our observations in routinely processed tissue sections obtained from patients with documented IFT of striking tissue eosinophilia led us to hypothesize that eosinophils and their products may play a role in the evolution of this disease. Immunofluorescence staining with affinity-purified polyclonal rabbit antibody directed against human eosinophil granule major basic protein revealed marked tissue eosinophilia and abundant extracellular deposition of major basic protein in all specimens from 16 patients with IFT. By contrast, only occasional eosinophils and no extracellular major basic protein were detected in control thyroid tissues obtained from patients with multinodular goiter, Graves' disease, Hashimoto's disease, and normal thyroid tissue. The presence of marked eosinophil infiltration and extracellular major basic protein deposition in IFT and other associated fibrosclerotic conditions suggests a role for eosinophils and their products in propagating the fibrogenesis seen in IFT.

Purpose: We study the prevalence of human papillomavirus deoxyribonucleic acid (DNA) in squamous cell carcinoma and control tissue of the penis.Materials and Methods: The technique of polymerase chain reaction DNA amplification was used to detect specific human papillomavirus DNA sequences in archival pathological and control tissues. We analyzed 42 cases of invasive squamous cell carcinoma, 13 of carcinoma in situ, 12 of penile intraepithelial neoplasia, 3 of verrucous carcinoma and 25 of balanitis xerotica obliterans, as well as 29 routine neonatal circumcision specimens and 32 adult circumcision specimens.Results: Overall, the detection rates for human papillomavirus DNA in the study and control tissues were 55 percent (23 of 42 cases) for invasive squamous cell carcinoma, 92 percent (12 of 13) for carcinoma in situ, 92 percent (11 of 12) for penile intraepithelial neoplasia, 0 percent (0 of 3) for verrucous carcinoma, 4 percent (1 of 25) for balanitis xerotica obliterans, 0 percent (0 of 29) f...

Background: For accurate classification of cutaneous metastatic carcinoma, reliable tumorspecific immunohistochemical markers would be valuable. Objective: Our purpose was to analyze the sensitivity, specificity, and positive predictive value of gross cystic disease fluid protein-15 (GCDFP-15) and estrogen receptor protein (ERP) for diagnosing cutaneous metastatic breast carcinoma. Methods: Tissue sections from 68 consecutive cases of cutaneous metastatic carcinoma were stained for GCDFP-15 and ERP. Hematoxylin-eosin-stained slides and immunostained slides were reviewed in a blinded fashion before retrospective chart review to ascertain the underlying primary tumor type. Results: Of 42 cases of cutaneous metastatic breast carcinoma, 30 were positive for GCDFP-15. Of 41 cases of metastatic breast carcinoma, 30 were positive for ERP. Calculated sensitivity, specificity, and positive predictive value for GCDFP-15 for diagnosing cutaneous metastatic breast carcinoma were 71%, 91%, and 94%, respectively, and 73%, 100%, and 100% for ERP, respectively. Combined values of these indices for both stains were 83%, 91%, and 95%, respectively. Conclusion: GCDFP-15 and ERP are valuable markers for cutaneous metastatic breast carcinoma and should be used in combination.

Fine-needle aspiration (FNA) biopsy of the thyroid is a reliable, safe, cost-effective, and widely used test. Its introduction and application have had a significant impact in the management of nodular thyroid diseases in adults. However, its utility in pediatric practice is not recognized or emphasized. During the last 12 years we performed 10,971 FNAs; 57 (0.5%) were in patients younger than age 17 years. Among 47 of these biopsies, 66% were benign, 15% were malignant, 6% were suspicious for malignancy and 13% were nondiagnostic. Biopsy was most often (96%) performed for the evaluation of diffuse or nodular goiter. The most common benign cytologic diagnosis was colloid goiter in 17 of 31 patients (55%) and Hashimoto's thyroiditis in 9 of 31 patients (29%). There were no false-positive results and there was one false-negative cytologic result. Among patients who had malignancy proved histologically, nine patients (75%) had papillary thyroid cancer. In this study, FNA biopsy was crucial in deferring surgery in 28 of 47 patients (60%). It is clear that the application of FNA biopsy prevents unnecessary surgery and improves surgical selection of patients with thyroid malignancy. On the basis of our extensive experience, we recommend FNA biopsy as the first diagnostic test for pediatric patients with nodular thyroid lesions.

OBJECTIVE: The aims of this study were to analyze the natural history of patients with pseudomyxoma peritonei (PMP), evaluate clinical and pathologic variables as prognostic indicators, and review the authors' experience with different treatments. SUMMARY BACKGROUND DATA: PMP is an unusual form of intra-abdominal neoplasm that presents with large amounts of extracellular mucin. Diffuse peritoneal spread occurs in most patients with PMP, and distant metastasis is infrequent. Debulking surgery, radiation therapy (radioisotope and external beam), and chemotherapy (both intraperitoneal and systemic) have all been advocated for optional patient management, but the variability of patients studied, the small patient numbers, and the prolonged course of this disease make the evaluation of results difficult. METHODS: Fifty-six patients were treated for PMP at the Mayo Clinic between 1957 and 1983. The data were collected retrospectively. Univariate (log-rank test) and multivariate (Cox regression model) analyses were performed for disease recurrence and patient survival. RESULTS: Most patients with PMP had carcinomas of the appendix (52%) or ovary (34%). All gross tumor could be removed only in the 34% of patients with limited disease. Although tumor progression occurred in 76% of patients, the 1-, 5-, and 10-year survival rates were 98%, 53%, and 32%, respectively. Adverse predictors of patient survival included weight loss (p = 0.001), abdominal distention (p = 0.004), use of systemic chemotherapy (p = 0.005), diffuse disease (p = 0.038), and invasion of other organs (p = 0.04). Intraperitoneal chemotherapy (p = 0.009) and radioisotopes (p = 0.0043) both were effective in prolonging the recurrence time of symptomatic PMP. CONCLUSIONS: Although PMP is an indolent disease, aggressive surgical debulking followed by intraperitoneal radioisotopes and/or chemotherapy should be considered because of the diffuse peritoneal involvement.

Fine-needle aspiration biopsy of the thyroid should be used routinely in the evaluation and management of nodular thyroid disease. Our extensive experience (11,000 biopsies) confirms the high sensitivity (98%) and the predictive value (99%) of the procedure for the detection of malignancy. Application of fine-needle aspiration biopsy has increased the surgical yield of cancer (from 14% to 39%). Complications are extremely rare, and the procedure is cost effective.

From January 1980 through December 1988, 8,219 thyroid smears were obtained by fine-needle aspiration (FNA) biopsy from patients at the Mayo Clinic, of which 918 (11%) were classified as "suspicious" cytologic findings. We analyzed the outcome in 208 patients with such findings who did not undergo immediate surgical treatment at the Mayo Clinic; follow-up data on thyroid status were available for 187 patients. Of 99 patients who underwent late surgical treatment (more than 30 days after FNA biopsy) and for whom tissue was available for diagnosis, thyroid malignant disease was found in 29. No clinical, scintigraphic, or ultrasonographic characteristics predicted the presence of a malignant lesion. On repeated FNA biopsy in 41 patients, findings were suspicious for a malignant lesion in 19 and benign in 22. Surgical excision was performed in 13 of the 41 patients. For 11 patients with suspicious cytologic findings on two FNA biopsies, malignant disease was confirmed in 5 and benign disease in 6. Two patients had benign histopathologic findings after cytologic results were benign on a second FNA biopsy. Follow-up data for the 208 patients revealed that 86 were alive with no evidence of thyroid disease, 76 were alive with some evidence of thyroid disease, 23 had died of nonthyroid illnesses, 2 had died of a thyroid malignant lesion, and 6 had died without undergoing surgical treatment (thyroid status unknown at the time of death); follow-up information was unavailable in 15 patients. The median duration of follow-up for those alive was 4.9 years. Our findings support the current practice of recommending immediate or late surgical treatment for all patients with suspicious thyroid cytologic results. Because repeated FNA biopsy adds little information, it is not recommended.

We retrospectively reviewed the medical records of 65 consecutive patients with medullary thyroid carcinoma, who had had their primary surgical treatment at the Mayo Clinic during the years 1946 through 1970. Of these patients, 58 had sporadic and 7 had familial medullary thyroid carcinoma. Thyroid nodules were the most common initial manifestation. Near-total thyroidectomy was the most frequent initial operation. Survival was affected by the following factors: male sex, familial inheritance, size of the tumor, stage of the tumor (American Joint Committee on Cancer), and completeness of initial resection of the tumor. The mean duration of follow-up was 23.5 years, and the maximal follow-up was 36 years. Among 52 patients without initial distant metastatic involvement and with complete resection of the tumor, 20-year survival free of distant metastatic lesions was 81%. Overall 10- and 20-year survival rates were 63% and 44%, respectively. Because of the substantial morbidity and mortality associated with medullary thyroid carcinoma, early diagnosis and thorough initial resection of the tumor are important.

The histologic and immunohistochemical characteristics of 49 skin biopsy specimens from 49 patients with extramammary Paget's disease were studied. Patients with extramammary Paget's disease with and without underlying malignant disease were identified. Associated malignant lesions, present in 16 patients (33%), were transitional cell carcinoma of the bladder (n = 8), adenocarcinoma underlying the skin (n = 3), adenocarcinoma of the anus (n = 1), adenocarcinoma of the vulva (n = 1), apocrine carcinoma (n = 1), prostate carcinoma (n = 1), and carcinoma metastatic to the lung (n = 1). The main histologic feature was the presence of Paget's cells, predominantly at the base of the epidermis. In 6% of the cases, well-defined nests of large Paget's cells mimicked melanocytic nests. Carcinoembryonic antigen and Cam 5.2 (a monoclonal antibody that stains 40-kDa, 45-kDa, and 52.5-kDa low molecular weight keratins) were localized to the Paget's cells in 42 of 45 (93%) and 29 of 41 cases (71%), respectively. Forty-four of 46 lesions (96%) were mucin positive, as determined by Hale's colloidal iron stain. Absence of staining for colloidal iron and carcinoembryonic antigen occurred somewhat more frequently in patients with underlying malignant disease than in patients without tumors (13% vs. 0% mucin negative and 13% vs. 3% carcinoembryonic antigen negative, respectively). Although immunohistochemical staining for low molecular weight keratin may be used to confirm the diagnosis of extramammary Paget's disease, Cam 5.2 is not as sensitive as the colloidal iron or carcinoembryonic antigen stain.

In two adults who smoked cigarettes, fine needle aspiration of a neck mass suggested squamous cell carcinoma. However, both lesions proved to be benign Warthin's tumor with metaplasia of the epithelial lining mimicking squamous cell carcinoma. Several clinical and histologic features can alert the physician to this finding. Awareness of the possibility of a false-positive cytologic report with Warthin's tumor is important for all physicians treating tumors of the head and neck.

Objective To characterize malignant tumors with direct extension to the thyroid gland from adjacent organs. Methods We retrospectively studied 17 patients with direct extension of malignant tumor to the thyroid from primary lesions in the head and neck who had been examined at Mayo Clinic Rochester between 1985 and 1994. The origin of the primary tumor was identified in all cases. Thyroid involvement was confirmed histologically. Data were analyzed for the frequency and types of malignant lesions, the clinical course, and the follow-up after thyroid involvement. Results All 17 study patients had a diagnosis of a primary malignant tumor before detection of thyroid involvement. Of the 17 patients, 12 had squamous cell carcinoma (SCC) of the larynx, 2 had SCC of the tongue base, 2 had SCC of the proximal and the cervical esophagus, respectively, and 1 had synovial cell sarcoma of the proximal esophagus. The time between diagnosis of the primary tumor and detection of thyroid invasion in the patients with SCC of the larynx or tongue base ranged from 1 to 196 months (mean, 38). Only 1 of these 14 patients had thyroid gland involvement clinically evident before surgical exploration. Thyroid invasion was diagnosed after surgical intervention. All three patients with esophageal malignant tumors had thyroid involvement clinically. Conclusion SCC of the larynx, tongue base, or proximal esophagus may invade the thyroid gland directly. SCC of the larynx may have the greatest tendency to extend to the thyroid. In patients with SCC, extension of the primary malignant tumor to the thyroid gland should be considered despite lack of clinical evidence. (Endocr Pract. 1999;5:69-71)

Cytogenetic studies may provide important clues to the molecular pathogenesis of thyroid neoplasia. Thus, the authors attempted cytogenetic studies on 12 thyroid carcinomas: seven papillary, three follicular, and two anaplastic. Successful cytogenetic results were obtained on all 12 tumors; nine (75%) had one or more chromosomally abnormal clones. Four of the papillary carcinomas had a simple clonal karyotype, and three had no apparent chromosome abnormality. All four abnormal papillary tumors contained an anomaly of a chromosome 10q arm. In one instance, an inv(10)(q11.2q21.2) was observed in a Grade 2 papillary carcinoma as the sole acquired abnormality. In another case, an inversion or insertion involving 10q21.2 was found in a Grade 1 papillary tumor. The karyotype of a third tumor, a Grade 1 papillary carcinoma, was 46,XX,der(5)t(5;10)(p15.3;q11),der(9)t(9;?)(q11;?). A fourth abnormal papillary carcinoma, a Grade 1 tumor, had a t(6;10)(q21;q26.1) as the sole abnormality. Each of the five follicular or anaplastic carcinomas had a complex clonal karyotype. The three follicular carcinomas contained an abnormality of 3p25-p21, along with several other chromosome abnormalities.

The Society of Radiologists in Ultrasound convened a panel of specialists from a variety of medical disciplines to come to a consensus on the management of thyroid nodules identified with thyroid ultrasonography (US), with particular focus on which nodules should be subjected to US-guided fine needle aspiration and which thyroid nodules need not be subjected to fine-needle aspiration. The panel met in Washington, DC, October 26–27, 2004, and created this consensus statement. The recommendations in this consensus statement, which are based on analysis of the current literature and common practice strategies, are thought to represent a reasonable approach to thyroid nodular disease. © RSNA, 2005

To evaluate preoperative hypercalcitonine-mia further as a marker of prognosis in patients with medullary thyroid carcinoma (MTC).We reviewed the clinical and laboratory data in six patients (four men and two women, 39 to 76 years old)--three with sporadic MTC, one with familial MTC, and two with multiple endocrine neoplasia type 2A--who had preoperative basal serum calcitonin levels of 400 to 16,000 pg/mL (normal, 0 to 19). Pentagastrin stimulation was performed in patients who had preoperative basal calcitonin levels less than 1,000 pg/mL, and responses ranged from 2,600 to 8,500 pg/mL. Thyroidectomy revealed intrathyroidal MTC in four patients; MTC and nodal metastatic lesions were present in two. The tumor cells were immunoreactive with anti-calcitonin immunoperoxidase staining.Serum calcitonin and carcinoembryonic antigen levels were normal postoperatively. In serial postoperative evaluation during a follow-up period of 2 to 9 years, stimulated peak plasma calcitonin levels after pentagastrin or calcium infusion were normal (in five patients) or near normal (in one patient), without clinical evidence of recurrent disease. The two patients with nodal metastatic disease have had normal calcitonin levels during a mean duration of follow-up of approximately 3 years.Pronounced preoperative hypercalci-toninemia does not necessarily preclude a favorable short-term outcome in patients with MTC.

Context.—Cytoplasmic yellow bodies are a common and frequent histologic finding in hyalinizing trabecular adenoma of the thyroid gland, a morphologically distinctive neoplasm, and are visible in fine-needle aspiration biopsy of the tumor. Objective.—To determine the prevalence and frequency of cytoplasmic yellow bodies in common thyroid tumors. Design.—Microscopic slides of random cases of papillary carcinoma (61 cases), follicular adenoma (27 cases), and Hürthle cell adenoma (12 cases) were searched for cytoplasmic yellow bodies. Setting and Patients.—Slides were from patients who had undergone surgery at Mayo Clinic, Rochester, Minn, and were obtained from the Mayo Clinic Tissue Registry. Main Outcome Measure.—Presence or absence of cytoplasmic yellow bodies. Results.—Cytoplasmic yellow bodies were found in papillary carcinoma (62%), follicular carcinoma (22%), and Hürthle cell adenoma (83%) but were very infrequent numerically in each tumor type. Conclusions.—Cytoplasmic yellow bodies may be present in papillary carcinoma and in follicular and Hürthle cell adenomas, but because they are uncommon in these tumors, they are unlikely to be found in fine-needle aspiration biopsy smears. Therefore, cytoplasmic yellow bodies are a useful cytomorphologic indicator of hyalinizing trabecular adenoma of the thyroid gland.

Rosai-Dorfman disease (RDD), otherwise known as sinus histiocytosis with massive lymphadenopathy, is a rare histiocytic syndrome of unknown etiology, dominated by histiocytic and lymphocytic infiltration of enlarged lymph nodes. Thyroid involvement is rare and its impact unknown. We report a case of RDD involving the thyroid, initially diagnosed and managed as anaplastic carcinoma, and review the literature for previously reported cases of thyroid involvement. A 71-year-old woman sought further evaluation after treatment elsewhere for a 4-month history of a rapidly enlarging goiter causing local compression. Pathology was reported to show anaplastic thyroid carcinoma with prominent histiocytic infiltration. On review, we found characteristic features of RDD within the thyroid and cervical lymph nodes. The patient showed serologic evidence of autoimmune thyroid disease. Two years after thyroidectomy, there was no evidence of recurrent disease. We have identified only three previously reported cases of RDD involving the thyroid, all of them in women. In all cases, the patient has survived without evidence of disease progression, suggesting that thyroid involvement may not change the generally good prognosis of RDD. The description of autoimmune thyroid disease in our case and in two of the three previously reported cases, suggests a link with autoimmune thyroid disease.

Although histologic definition of follicular thyroid lesions is readily available, application of the diagnostic criteria and personal experience may lead to disagreement among pathologists. To investigate interobserver variation in assessment of encapsulated follicular lesions, eight pathologists (four American and four Japanese) reviewed the same hematoxylin and eosin-stained slide of each of 21 cases of thyroid lesions showing encapsulation and follicular growth pattern. In 10% of the cases, there was complete agreement. At least seven pathologists agreed on the diagnosis in 29% of the cases, and at least six in 76% of the cases. American and Japanese pathologists agreed among themselves in 33% and 52% of cases, respectively. The frequency of diagnosis of adenomatous goiter among Japanese pathologists (31%) was considerably higher than that among American pathologists (6%). In contrast, the frequency of diagnosis (25%) of papillary carcinoma among American pathologists was considerably higher than that (4%) among Japanese pathologists. Our analysis revealed three main factors affecting observer variation: 1) interpretation of the significance of microfollicles intimately related to capillaries within the tumor capsule, 2) evaluation of what constituted the type of nuclear clearing indicative of papillary carcinoma, and 3) absence of clear morphologic criteria for separation of adenomatous goiter and follicular adenoma. To reduce observer variation of encapsulated follicular lesions, it will be necessary to provide more explicit criteria for diagnosis.

Background. Eighty-five percent of all Merkel cell carcinomas appear on sun-exposed areas, with 50% to 55% occurring on the head and neck. Methods. A chart review was performed on 22 patients treated for Merkel cell carcinoma of the head and neck between 1981 and 1998. Results. Fifteen patients were men (68%). The average age at operation was 69.9 years (range, 24-84 years). The average duration of follow-up was 3.6 years (range, 3 days-8.6 years). Overall survival at 1, 2, and 3 years postoperatively was 78%, 68%, and 68%, respectively. The only independent predictor of survival was the type of surgical therapy. All patients who underwent wide local excision (WLE) of the primary tumor with dissection of the lymphatic drainage basin were alive at 2 years as opposed to 68% who had WLE alone and 33% who had Mohs surgery. Conclusions. WLE and dissection of the lymphatic drainage basin provided the best overall survival.

There is strong evidence in many tumor types, including thyroid cancer, for a novel tumor suppressor gene (TSG) at 17p13. To identify the putative thyroid 17p13 TSG we mapped thyroid tumor loss of heterozygosity (LOH) at high resolution within this region. We examined 20 typical follicular thyroid carcinomas (FTC), 19 Hurthle cell carcinomas (HCC), 15 papillary thyroid carcinomas (PTC), and 7 follicular adenomas (FA) for LOH at 17p13 using 18 probes. Complete clinical follow-up data were available for all patients. We confirmed a high 17p13 LOH rate in FTC (18 of 20) and HCC (13 of 19) and showed an association between 17p13 LOH and advanced tumor grade. Only 4 of 15 PTC and 1 of 7 FA displayed 17p13 LOH. In the HCC we identified a narrow minimal common deleted region between D17S1308 (285 kb from the p-telomer) and D17S695 (696 kb from the p-telomer). This region was flanked centromerically by a breakpoint cluster, further suggesting nonrandom deletion. All but 1 of the PTC and FA with 17p LOH and 50% of the affected FTC also showed LOH in this region. These data suggest that a TSG, involved in HCC pathogenesis, is contained within the D17S1308-D17S695 interval. There are several potential candidate TSGs in this region that are worthy of further study. (J Clin Endocrinol Metab 87: 4715– 4721, 2002)

2,512 consecutive patients with papillary thyroid carcinoma (PTC) were managed during 1940 through 2000 at the Mayo Clinic. During that period, there were two significant therapeutic trends. The first was a change in surgical practice during 1940-69 from an initial unilateral lobectomy (UL) to a bilateral lobar resection (BLR). The second was the increasing use since 1970 of I-131 for radioactive-iodine remnant ablation (RRA). The advent of BLR resulted in significantly improved tumor recurrence (TR) rates in both low-risk (MACIS scores < 6) and high-risk (MACIS scores 6+) patients, and also reduced cause-specific mortality (CSM) in high-risk patients. By contrast, RRA did not significantly improve the outcome (either CSM or TR) in low-risk (MACIS < 6) patients previously treated with initial near-total or total thyroidectomy. These data encourage a more selective use of I-131 in PTC management and do not lend support to the current widespread use of RRA in low-risk PTC.

It is uncertain whether more extensive primary surgery and increasing use of radioiodine remnant ablation (RRA) for papillary thyroid carcinoma (PTC) have resulted in improved rates of cause-specific mortality (CSM) and tumor recurrence (TR). Details of the initial presentation, therapy, and outcome of 2444 PTC patients consecutively treated during 1940-1999 were recorded in a computerized database. Patients were followed for more than 43,000 patient-years. The 25-year rates for CSM and TR were 5% and 14%, respectively. Temporal trends were analyzed for six decades. During the six decades, the proportion with initial MACIS (distant Metastasis, patient Age, Completeness of resection, local Invasion, and tumor Size) scores

The objective of this study was to evaluate the technique, efficacy, and side effects of percutaneous ethanol injection in patients with limited cervical nodal metastases from papillary thyroid carcinoma.Fourteen patients who had undergone thyroidectomy for papillary thyroid carcinoma presented with limited nodal metastases (one to five involved nodes) in the neck between May 1993 and April 2000. All patients had received previous iodine-131 ablative therapy with a mean total dose per patient of 7,548 MBq. Ten of the patients either were considered poor surgical candidates or preferred not to have surgery, and all were unresponsive to iodine-131 therapy. Each metastatic lymph node was treated with percutaneous ethanol injection, and patients received both clinical and sonographic follow-up.Twenty-nine metastatic lymph nodes in our 14 patients were injected. Mean sonographic follow-up was 18 months (range, from 2 months to 6 years 5 months). All treated lymph nodes decreased in volume from a mean of 492 mm(3) before percutaneous ethanol injection to a mean volume of 76 mm(3) at 1 year and 20 mm(3) at 2 years after treatment. Six nodes were re-treated 2-12 months after initial percutaneous ethanol injection because of persistent flow on color Doppler sonography (n = 4), stable size (n = 1), or increased size (n = 1). Two patients developed four new metastatic nodes during the follow-up period that were amenable to percutaneous ethanol injection. Two patients developed innumerable metastatic nodes that precluded retreatment with percutaneous ethanol injection. No major complications occurred. All patients experienced long-term local control of metastatic lymph nodes treated by percutaneous ethanol injection. In 12 of 14 patients, percutaneous ethanol injection was successful in controlling all known metastatic adenopathy.Sonographically guided percutaneous ethanol injection is a valuable treatment option for patients with limited cervical nodal metastases from papillary thyroid cancer who are not amenable to further surgical or radioiodine therapy.

Anaplastic thyroid carcinoma (ATC) is among the most aggressive of human malignancies. However, there have been few large studies of histologically well-defined ATC. We report the results of a 50-year experience of this lethal malignancy.We reviewed all cases of ATC managed in this institution between 1949 and 1999. One pathologist (J.R.G.) reviewed all pathologic material. Clinical details were obtained from medical records, and current status of all patients was determined.There were 134 cases, with a female-to-male ratio of 1.5:1 and a mean age of 67 years. Benign thyroid disease was present in 27 cases (20%) and well-differentiated thyroid carcinoma in 31 (23%). Sixty-two patients (46%) had distant metastases at diagnosis, and 98% of the tumors were locally invasive. Primary treatment was surgical for 96 patients (72%). Complete resection was achieved in 29 cases (30%), with "minimal residual disease" in 25. Neither extent of operation nor completeness of resection affected survival (P.4). Postoperative radiotherapy gave slightly longer median survival (5 vs 3 months), which was not significant (P.08). Multimodal therapy, including operation, chemotherapy, and radiotherapy, did not improve survival.The outlook for patients with ATC remains grim. Novel treatments for ATC are desperately needed.