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INTRODUCTION Breast cancer-related extremity lymphedema is a potentially devastating condition. Vascularized lymph node transfer (VLNT) has shown benefit in lymphedema treatment. Due to concerns over potential iatrogenic complications, various donor sites have been described. The current study aims at defining the deep inferior epigastric lymph node basin as a novel donor site for VLNT. METHODS A retrospective study was performed on patients undergoing routine abdominal-based breast reconstruction. Resection of all perivascular adipose and lymphatic tissue surrounding the proximal deep inferior epigastric pedicle was performed at the time of pedicle dissection and submitted for Pathologic evaluation. Patient demographics and pertinent medical/surgical history was obtained from medical records. RESULTS Specimens were obtained from 10 consecutive patients. Seven patients underwent bilateral reconstruction for a total of 17 specimens obtained. Mean patient age and BMI were 48 years ± 9.4 and 27 ± 4.2, respectively. Fourteen out of 17 (82%) specimens contained viable lymph nodes displaying a thin fibrous connective tissue capsule overlying an unremarkable subcapsular sinus with a cortex and paracortex containing germinal centers composed of B lymphocytes, tangible body macrophages, and T-cells. The medullary sinus space displayed a fatty unremarkable hilum. The mean number and size of lymph nodes were 2.6 ±1.2 nodes/specimen and 3.67 mm ± 2.3, respectively. All patients experienced an uneventful postoperative course without evidence any of compromised flap viability. CONCLUSION Lacking previous description, the deep inferior epigastric lymph node basin is a readily accessible donor site with significant anatomic advantages for potential VLNT during autologous breast reconstruction.

Most BRCA1-associated breast tumours are basal-like yet originate from luminal progenitors. BRCA1 is best known for its functions in double-strand break repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions fully explains the cell lineage-specific tumorigenesis. In vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Here we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers. Furthermore, R-loops are enriched at the 5′ end of those genes with promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of Cobra1, which encodes a Pol II-pausing and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1-knockout mouse mammary epithelium. Our studies show that Pol II pausing is an important contributor to BRCA1-associated R-loop accumulation and breast cancer development., The vast majority of BRCA1-driven breast cancers derive from luminal progenitor cells but the mechanisms of this lineage specificity are unclear. Here the authors show that dangerous accumulation of DNA-RNA hybrid structures due to RNA polymerase II pausing, occurs specifically in luminal epithelial cells.

Background Acquisition of negative resection margins is paramount in the surgical management of operable breast cancer. Management of positive margins following mastectomy and immediate breast reconstruction is presently poorly defined. Objectives The present study aims at defining morbidity and cosmetic sequela of re-excision procedures aimed at clearing involved mastectomy margins in the setting of immediate autologous breast reconstruction. Oncologic outcomes are recorded. Methods A retrospective study of patients that underwent skin-sparing mastectomy followed by immediate deep inferior epigastric perforator flap breast reconstruction was performed. Patients found to have positive mastectomy margins underwent margin re-excision during a separate procedure. Method of positive margin exposure and resection is described. Flap morbidity and cosmetic outcome following margin re-excision was compared between reconstructed breasts that underwent re-excision vs those reconstructed after prophylactic mastectomy (controls). Cancer recurrence was recorded during the follow-up period. Results Thirty-six (2.5%) out of 1443 patients were found to have positive mastectomy margins following immediate breast reconstruction between May 2007 and November 2012. Location of positive margins was evenly distributed in all breast regions. Although flap morbidity was similar, a trend (P > 0.05) toward higher seroma formation and fat necrosis was reported in breasts following re-excision vs controls. With a mean follow-up period of 28 months, cosmetic outcome between breasts that underwent re-excision vs controls were similar. Cancer recurrence was reported in 3 (8.3%) patients. Conclusions Re-excision of positive mastectomy margins following immediate autologous breast reconstruction requires a multidisciplinary approach and may be performed with minimal additional morbidity while preserving optimal cosmetic outcome. Level of evidence 3.

Papillary thyroid carcinomas (PTC) with BRAF V600E mutation are morphologically distinctive. They are typically classic or tall cell variants, show infiltrative borders, and are associated with desmoplasia/fibrosis, psammoma bodies, and well-developed nuclear features of papillary carcinoma. We hypothesize that morphologic features of PTC can help in the prediction of BRAF V600E mutation, and we evaluate the accuracy and the interobserver reproducibility of such prediction. Hematoxylin and eosin-stained sections from 50 PTCs comprising of 26 mutation-positive and 24 mutation-negative tumors were examined. BRAF V600E mutation was predicted correctly in 42/50 tumors (accuracy, 84 %) with 96 % sensitivity, 71 % specificity, and 78 % positive and 94 % negative predictive values (NPV). Subtle nuclear features of PTC (n = 10) had the highest (100 %) negative predictive value followed by well-circumscribed non-infiltrative tumor borders (17/22 mutation-negative tumors, 95 % NPV). The positive predictive value of infiltrative tumor borders (21/28 [75 %] mutation-positive), desmoplasia/fibrosis (23/31 [74 %] mutation-positive), and psammoma bodies (13/20 [65 %] mutation-positive) increased to 100 % when all three features were present (n = 8/8 mutation-positive). To assess interobserver reproducibility, two pathologists blinded to the mutational status evaluated 30 PTCs (15 mutation-positive and 15 mutation-negative) after self-training on 10 PTCs with known BRAF V600E mutational status (five mutation-positive and five mutation-negative). The prediction of the mutation was achieved with substantial agreement (κ value, 0.79) and accuracy (25/30, 83 %). This study demonstrates that BRAF V600E mutation in papillary thyroid carcinoma can be predicted on morphology with accuracy and with substantial interobserver agreement.

BACKGROUND: Thyroid fine-needle aspiration (FNA) biopsy, the preoperative diagnostic standard of care for patients with thyroid nodules, has limitations. Spectral imaging captures visible light information that is beyond the capability of the human eye, potentially increasing the accuracy of FNA biopsy. In the current study, the authors demonstrated the feasibility of using spectral imaging in combination with automated spatial analysis based on trainable pattern recognition as an adjunct test for thyroid FNA classification by developing an algorithm that distinguishes between images of papillary thyroid carcinoma (PTC) and benign goiter (BG). METHODS: A multispectral camera was used to capture spectral images representing 100 cases of PTC and BG. Used in conjunction with commercial software, 10 cases were used as a training set to develop a “classifier,” a classification algorithm that segments digitized multispectral images into regions of PTC, BG, and “nonfeature.” This algorithm was used to generate a screening test and a diagnostic test that were validated on an independent set of images representing 30 cases of PTC and 30 cases of BG. RESULTS: The area under the receiver operating characteristic for the PTC/BG classifier was 0.90. The screening test had a sensitivity of 0.93 and a specificity of 0.73. The diagnostic test had a sensitivity of 0.70 and a specificity of 0.90. CONCLUSIONS: The authors developed image classification tests that distinguish between FNAs of PTC and BG, demonstrating the potential value of spatial spectral imaging as an adjunct test for the classification of thyroid FNA samples. The data support prospective testing to determine the value of the PTC/BG classifier in routine clinical use. Cancer (Cancer Cytopathol) 2013. © 2012 American Cancer Society.

Merkel cell carcinoma (MCC) is a rare and highly aggressive primary neuroendocrine carcinoma of the skin with a high propensity for local, regional, and distant spread. Distant metastasis of MCC to the pancreas is uncommonly seen and may impose a diagnostic challenge cytologically. Here we report a case of MCC with pancreatic metastasis, which was diagnosed by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). The aspirates revealed both single and clustered epithelial cells with scant cytoplasm and round nuclei with stippled chromatin and inconspicuous nucleoli. Immunocytochemically, the tumor cells were positive for CK20, synaptophysin, CD56, and CD117. The neoplastic cells were also identified by flow cytometry as non-hematopoietic cells which were positive for CD56 and negative for CD45. To our knowledge, this is only the second case report of MCC metastatic to the pancreas diagnosed by EUS-FNA. There have been several reports of MCC metastatic to the pancreas diagnosed only at the time of surgical resection. However, a preoperative diagnosis allows for appropriate management while sparing a patient the morbidity of unnecessary procedures.

Finkelstein A, Levy G H, Hui P, Prasad A, Virk R, Chhieng D C, Carling T, Roman S A, Sosa J A, Udelsman R, Theoharis C G & Prasad M L (2012) Histopathology 60, 1052–1059 Papillary thyroid carcinomas with and without BRAF V600E mutations are morphologically distinct Aims: The BRAF V600E mutation resulting in the production of an abnormal BRAF protein has emerged as the most frequent genetic alteration in papillary thyroid carcinomas (PTCs). This study was aimed at identifying distinctive features in tumours with and without the mutation. Methods and results: Thirty-four mutation-positive and 22 mutation-negative tumours were identified by single-strand conformation polymorphism of the amplified BRAF V600E region in the tumour DNA. Mutation-positive tumours were more common in patients older than 45 years (24/33, P = 0.05), in classic (23/30, P = 0.01), tall cell (4/5) and oncocytic/Warthin-like (2/2) variants of PTC, and in subcapsular sclerosing microcarcinomas (4/4). In contrast, all 12 follicular variants (P

The molecular work-up of thyroid nodules on fine needle aspiration (FNA) cytology samples has given clinicians a new level of diagnostic information. We focus this review on the molecular techniques used in the diagnosis of thyroid cancer, especially BRAF, and the resulting management considerations that are raised.BRAF testing offers both diagnostic and prognostic information; it has been used along with the Bethesda Thyroid FNA Classification System to offer preoperative guidance in the management of thyroid nodules. Various authors have successfully utilized molecular panels on cytologic specimens including mutations and rearrangements such as RAS and RET/PTC. Preoperative mutation detection allows initial management decisions to be made with a greater clinical confidence.BRAF molecular testing holds promise as a possible diagnostic tool for indeterminate FNAs, and as a determinant for planning initial clinical management of thyroid nodules. Further developments in the molecular approach to thyroid cancer are expected to allow greater individualization of patient care.

The Bethesda 2007 Thyroid Cytology Classification defines follicular lesion of undetermined significance as a heterogeneous category of cases that are not convincingly benign nor sufficiently atypical for a diagnosis of follicular neoplasm or suspicious for malignancy. In our institution, we refer to these cases as indeterminate, and they are further sub-classified into two: (1) low cellularity with predominant microfollicular architecture and absence of colloid (IN(a)) and (2) nuclear features not characteristic of benign lesions (nuclear atypia) (IN(b)). We reviewed these indeterminate cases to document the follow-up trend using this two-tier classification. A search of the cytology records was performed for the period between January 2008 and June 2009. All thyroid fine-needle aspiration (FNA) cases were reviewed and the ones diagnosed as indeterminate were identified. Correlating follow-up FNA and/or surgical pathology reports were reviewed. The percentage of cases showing a malignancy was calculated. One hundred and seventy-one indeterminate cases were identified, representing 2.8% of the 6,205 thyroid FNA cases examined during the time under review (107 IN(a), 64 IN(b)). Records of follow-up procedures were available in 106 (61%) cases. Malignancy was identified in 27% of all indeterminate cases. This was disproportionately more in the IN(b) (56%) compared to the IN(a) (7%) cases. A diagnosis of "IN(a)" does not carry the same implication as that of "IN(b)". The IN(b) category needs a more aggressive follow-up than the IN(a) category and may justify an immediate referral for lobectomy. Despite the vague morphologic criteria for this diagnostic category, the indeterminate rate remains relatively low and falls within the NCI recommendation (

The clinical and pathological characteristics of hyperparathyroidism-induced hypercalcemic crisis (HIHC) are incompletely described. The present study was designed to elucidate the nature and effects of HIHC in patients undergoing parathyroidectomy in our unit.A prospective database of 1,754 consecutive patients with primary hyperparathyroidism (PHPT) who underwent parathyroidectomy from 1991-2009 identified 67 (41 women) patients presenting with HIHC. Hyperparathyroidism-induced hypercalcemic crisis was defined as symptoms and signs of acute calcium intoxication with a concomitant total albumin corrected calcium level13.5 mg/dl (range: 8.8-10.2 mg/dl). Clinical and pathological characteristics were evaluated. Data are expressed as mean±SEM.Mean age at presentation was 56.7±2.2 years. Twenty-four of 67 patients (35%) required preoperative in-hospital management. Of these, all were treated with saline resuscitation, whereas 20/24 (83%) were treated pharmacologically. Neurocognitive derangements and nephrolithiasis with associated hematuria were the most common presenting symptoms and signs. Preoperative serum calcium and the intact parathyroid hormone level (PTH) were 14.0±0.19 mg/dl and 393±43 pg/ml (reference range: 12-65 pg/ml), respectively. Minimally invasive parathyroidectomy under local cervical block was performed in 28/67 patients (42%); the remainder underwent standard cervical exploration. All patients had postoperative normalization of serum calcium and intact PTH. Hyperparathyroidism-induced hypercalcemic crisis was due to parathyroid carcinoma in 3/67 patients (4.5%), whereas the remainder of patients displayed a single parathyroid adenoma (n=57) or multiglandular hyperplasia (n=7). Histopathological evaluation from HIHC patients revealed a chief cell microcystic pattern in 15/21 (71.4%) of examined parathyroid tumors.Hyperparathyroidism-induced hypercalcemic crisis is most commonly due to a single parathyroid adenoma, often associated with a microcystic histopathological pattern. The condition is optimally managed with saline hydration and urgent parathyroidectomy.

Nature Communications 8: Article number: 15908 (2017); Published 26 June 2017; Updated 30 March 2018 The original version of this Article omitted the following from the Acknowledgements: ‘The work was also supported by a grant to Y.H. from the Cancer Prevention Research Institute of Texas CPRIT RP170126.

PURPOSE Central venous catheter dysfunction can be caused by thrombosis (of the catheter or vessel itself), fibrin sheath formation, or infection. These sequelae can lead to costly interventions, loss of the access device, or loss of access sites in as many as one-third of patients. This study examined the histologic changes in the access vein and superior vena cava wall that is adjacent to central venous catheters in humans. MATERIALS AND METHODS The access vein, brachiocephalic vein, and superior vena cava were excised en bloc at autopsy from six patients with central venous catheters. The specimens were processed and stained with hematoxylin and eosin. The specimens were examined for histologic changes in the vein wall adjacent to the catheters, changes in the intima, and the presence of associated thrombus. RESULTS Three catheters had been in place 90 days (long term). Two microscopic patterns were observed. The short-term catheters displayed foci of local intimal injury with endothelial denudation and a layer of adherent thrombus. The second pattern, seen in the long-term catheters, consisted of smooth muscle cell proliferation leading to vein wall thickening. Focal areas of catheter attachment to the vein wall, composed of thrombus in varying stages of organization, collagen, and endothelial cells, were also observed. CONCLUSIONS After short-term catheter placement, focal areas of endothelial injury were seen in the vein wall adjacent to the catheter. Associated thrombus may or may not be present. Long-term catheters displayed vein wall thickening and bridges from the vein wall to the catheter. These observations represent a progressive reaction of the human vein wall to access devices.

Background: Thyroid nodules are frequently diagnosed in everyday clinical practice. Strategies for the evaluation of their potential malignant risk and clinical management approaches have been widely developed by multiple endocrine and surgical societies. These guidelines are dynamically changing and the malignant potential of a hot thyroid nodule has become a matter of debate. Methods: All thyroid scans (n=137) performed at our institution over nine years (January 2003 to December 2012), for which a cytopathology result was available for review were retrospectively reanalyzed by an experienced nuclear medicine physician. 65 scans demonstrated clearly hot nodules and were correlated with cytopathology results. Results: Only one of sixty-five nodules (1.5%) was found to be malignant: a Hurthle cell carcinoma. An additional papillary thyroid carcinoma was found incidentally in another patient, however corresponding to a cold nodule in the contralateral lobe to the hot nodule. Conclusions: A hot nodule on a thyroid scan likely confers an overall low but non-negligible risk for malignancy. Further studies on larger datasets pooled from various centers would be valuable.

Various ultrasonographic characteristics of thyroid nodules have been associated with a higher likelihood of malignancy, and certain clinical features may also increase the likelihood of malignancy in patients. This study is designed to determine the ultrasonographic and clinical predictors of malignancy in the atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) category. A search through the cytology files at our institution was made for cases with diagnosis of AUS/FLUS. The clinical and radiologic findings were correlated with the final surgical pathology diagnosis. A total of 140 cases of AUS/FLUS with corresponding surgical intervention were identified (112 females and 28 males). There was a 79 % malignancy rate in nodules with irregular contours, compared to 51 % in nodules with regular outlines. Nodules demonstrating calcifications showed a 57 % malignancy rate, compared to 50 % in nodules without calcifications. Sixty-one percent of cases with an ultrasonographic diagnosis of indeterminate to suspicious were malignant following surgical resection. The rates of malignancy in patients with radiation exposure, symptomatic nodules, and positive family history of thyroid cancer were 22, 59, and 33 %, respectively. BRAF mutation was demonstrated in 57 % of malignant cases and in none of benign cases. No single clinical or ultrasonographic feature or combination of features is adequately sensitive or specific to identify all malignant nodules. However, a combination of solid nodules, nodules with irregular contours, symptomatic nodules, and positive BRAF mutation has high predictive value for malignancy in patients with a cytologic diagnosis of AUS/FLUS.

BACKGROUND: Fine-needle aspiration (FNA) is the most accurate and cost-effective method for evaluating thyroid nodules. However, FNA-induced secondary changes completely replacing thyroid tumors (vanishing tumors) may create a novel problem. In this study, we highlight the diagnostic and management issues associated with the unintended consequences of ultrasonography (US)-guided FNA. METHODS: Fourteen thyroid glands (11 women and 3 men, ages 33–64 years) with vanishing tumors were prospectively identified between 2009 and 2012 upon surgical resection. Cytology and histopathology slides were reviewed, and second opinions were obtained when necessary. RESULTS: The cytology of the 14 vanishing tumors was suspicious/positive for papillary thyroid carcinoma (PTC) in 5, indeterminate (atypia of unknown significance) in 5, benign in 2, follicular neoplasm in 1, and nondiagnostic in 1 nodule. Upon thyroidectomy, the vanishing tumors ranged in size from 0.4 to 3.5 cm (median 0.7 cm). Microscopically, the nodules showed cystic degeneration, organizing hemorrhage, granulation tissue, fibrosis, and microcalcifications. In seven tumors, a few residual malignant cells (PTC in five) or residual benign follicles (hemorrhagic cyst in two) at the periphery of the vanishing tumors helped with the final diagnosis. The remaining seven tumors were completely replaced by FNA-induced secondary changes, and had the cytology diagnosis of benign in one, follicular neoplasm in one, and suspicious/positive for PTC in five. Of the latter five, two showed additional separate foci of PTC, while three vanishing tumors (0.5, 1.2, and 1.6 cm) had no residual malignant cells and no additional carcinoma leading to a final diagnosis of negative for malignancy. CONCLUSIONS: US-guided FNA may lead to complete obliteration of thyroid nodules, rendering final diagnosis upon thyroidectomy difficult or impossible. In these unusual circumstances, the possibility that the surgical pathology may be nonrepresentative should be considered if the cytologic features on FNA are sufficient by themselves to support a definitive diagnosis of PTC.

Recently, a six-tiered diagnostic risk classification system was created based on the recommendations of the National Cancer Institute (NCI) sponsored NCI Thyroid Needle Aspiration State of the Science Conference at Bethesda, MD in October 2007. The objective of the current study was to compare the frequency distribution of the various diagnostic categories to evaluate its diagnostic performance before and after implementation of The Bethesda System (TBS). A total of 5,897 thyroid Fine needle aspirations (FNAs) were reviewed; 3,207 were from 2008 after TBS implementation, and 2,690 were from 2007 immediately before TBS implementation. Follow-up consisted of reviewing corresponding histologic results. The rates of “Nondiagnostic” specimens and cases with a diagnosis of “Follicular Neoplasm” decreased from 13.1 to 11.1% and 8.6 to 5.5%, respectively, after implementation of TBS, while the rate of negative specimens increased from 68.2 to 73.8%. The other categories remained relatively stable. In addition, there also was a significant decrease in the use of noncommittal descriptive diagnoses. The diagnostic performance of thyroid FNA in identifying a neoplastic process as measured by area under the receiver operating characteristic curve increased from 0.88 to 0.89; the difference was statistically significant (P=0.03). Implementation of TBS showed a significant reduction of: nondiagnostic thyroid FNAs, of FNAs with a diagnosis of “Follicular Neoplasm,” as well as cases with descriptive noncommittal diagnoses. TBS results in improved diagnostic performance and therefore more consistent and uniform reporting of thyroid FNA. Diagn. Cytopathol. 2013;41:858–863. © 2013 Wiley Periodicals, Inc.

Recently, a six-tiered diagnostic risk classification system was created based on the recommendations of the National Cancer Institute (NCI) sponsored NCI Thyroid Needle Aspiration State of the Science Conference at Bethesda, MD in October 2007. The objective of the current study was to compare the frequency distribution of the various diagnostic categories to evaluate its diagnostic performance before and after implementation of The Bethesda System (TBS). A total of 5,897 thyroid Fine needle aspirations (FNAs) were reviewed; 3,207 were from 2008 after TBS implementation, and 2,690 were from 2007 immediately before TBS implementation. Follow-up consisted of reviewing corresponding histologic results. The rates of "Nondiagnostic" specimens and cases with a diagnosis of "Follicular Neoplasm" decreased from 13.1 to 11.1% and 8.6 to 5.5%, respectively, after implementation of TBS, while the rate of negative specimens increased from 68.2 to 73.8%. The other categories remained relatively stable. In addition, there also was a significant decrease in the use of noncommittal descriptive diagnoses. The diagnostic performance of thyroid FNA in identifying a neoplastic process as measured by area under the receiver operating characteristic curve increased from 0.88 to 0.89; the difference was statistically significant (P=0.03). Implementation of TBS showed a significant reduction of: nondiagnostic thyroid FNAs, of FNAs with a diagnosis of "Follicular Neoplasm," as well as cases with descriptive noncommittal diagnoses. TBS results in improved diagnostic performance and therefore more consistent and uniform reporting of thyroid FNA.

Thyroid fine-needle aspiration (FNA) biopsy, the preoperative diagnostic standard of care for patients with thyroid nodules, has limitations. Spectral imaging captures visible light information that is beyond the capability of the human eye, potentially increasing the accuracy of FNA biopsy. In the current study, the authors demonstrated the feasibility of using spectral imaging in combination with automated spatial analysis based on trainable pattern recognition as an adjunct test for thyroid FNA classification by developing an algorithm that distinguishes between images of papillary thyroid carcinoma (PTC) and benign goiter (BG).A multispectral camera was used to capture spectral images representing 100 cases of PTC and BG. Used in conjunction with commercial software, 10 cases were used as a training set to develop a "classifier," a classification algorithm that segments digitized multispectral images into regions of PTC, BG, and "nonfeature." This algorithm was used to generate a screening test and a diagnostic test that were validated on an independent set of images representing 30 cases of PTC and 30 cases of BG.The area under the receiver operating characteristic for the PTC/BG classifier was 0.90. The screening test had a sensitivity of 0.93 and a specificity of 0.73. The diagnostic test had a sensitivity of 0.70 and a specificity of 0.90.The authors developed image classification tests that distinguish between FNAs of PTC and BG, demonstrating the potential value of spatial spectral imaging as an adjunct test for the classification of thyroid FNA samples. The data support prospective testing to determine the value of the PTC/BG classifier in routine clinical use.

Whereas, over time, the scalpel has come to identify the surgeon, so the microscope has come to identify the pathologist. Recent technological developments, however, have expanded the tools available to the surgeon in the practice of surgery, e.g., robot-assisted (da Vinci) minimally invasive surgery. Similarly, revolutionary leaps in the field of molecular biology have exponentially shifted the information available to the pathologist from the cellular morphologic realm to the submicroscopic.

Background/Objective: The Bethesda 2007 Thyroid Cytology Classification defines atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) as a heterogeneous category of cases that are neither convincingly benign nor sufficiently atypical for a diagnosis of follicular neoplasm or suspicious for malignancy. At our institution, we refer to these cases as ‘indeterminate’ and they are further subclassified into two categories. BRAF mutation occurs in 40–60% of papillary thyroid carcinoma (PTC). In this study, we examined cases in the AUS/FLUS category in correlation with BRAF mutation analysis and surgical pathology outcome. Study Design: Thyroid fine-needle aspiration (FNA) cytology specimens interpreted as ‘indeterminate’ were selected from our files, and available remnants of thin-layer processed specimens were used for BRAF mutation analysis. Surgical pathology reports were reviewed for the final outcomes in these patients. Results: Of the 84 indeterminate cases with BRAF mutation analysis, only 49 had follow-up with surgical intervention. Sixteen cases had BRAF mutation. All of the BRAF-positive cases had a final diagnosis of PTC. Conclusions: The sensitivity and specificity of BRAF mutation in detecting PTC in FNA specimens with indeterminate diagnosis was 59.3 and 100%, respectively, while the positive and negative predictive values were 100 and 65.6%, respectively. The limited data supports the use of BRAF mutation analysis to predict the risk of malignancy in patients with indeterminate thyroid FNAs.

The BRAF V600E mutation has been reported in 50%-80% of papillary thyroid carcinoma (PTC) cases and is highly specific for PTC. Reflex BRAF testing may improve the diagnostic accuracy of thyroid fine-needle aspiration (FNA) tests having equivocal cytologic interpretations and provide prognostic information that helps guide management in patients with PTC.Cases with equivocal thyroid FNA readings (indeterminate and suspicious for PTC) or a positive diagnosis for PTC and concomitant BRAF mutation analysis were included in this prospective study. BRAF mutation analysis was performed by polymerase chain reaction combined with single-strand conformation polymorphism gel electrophoresis using lavage fluid obtained from needle rinsing. The results of histopathologic follow-up were correlated with the cytologic interpretations and BRAF status.One hundred fifty-seven FNAs with equivocal or positive cytologic interpretations were eligible for the study. All but one (99.4%) FNAs were found to have sufficient DNA quality and quantity for the assay. Based on the follow-up diagnosis of nodules after surgical resection, the sensitivity for diagnosing PTC was 63.3% with cytology alone and 80.0% with the combination of cytology and BRAF testing, respectively. No false positives were noted with either cytology or BRAF mutation analysis. All PTCs with extrathyroidal extension and of tall-cell variant were postive for BRAF mutation.BRAF V600E mutation analysis can be easily performed on cytologic preparation using lavage fluids obtained from needle rinsing. By combining morphologic evaluation and BRAF testing, there is a substantial improvement in the preoperative identification of PTC when compared with cytology alone. Patients with equivocal cytologic diagnosis and BRAF V600E mutation are candidates for total thyroidectomy ± central lymph node dissection.

Objective To present a case of an insular variant of poorly differentiated thyroid carcinoma (PDTC) and to review the literature related to diagnosis, natural history, and treatment of this unusual form of thyroid cancer. Methods We present the clinical, laboratory, and pathologic findings of the study patient and review Englishlanguage literature related to PDTC published between 1970 and the present. Results PDTC is a controversial and rare epithelial thyroid cancer, intermediate between differentiated thyroid carcinoma and anaplastic thyroid carcinoma that exhibits increased aggressiveness, propensity to local recurrence, distant metastases, and increased mortality. PDTC warrants aggressive management with total thyroidectomy followed by radioactive iodine ablation and potentially additional therapy for residual or recurrent disease. Some carcinomas do not take up radioactive iodine, and dedifferentiated clones of distant metastases may evolve. It is unclear whether chemotherapy is beneficial. Use of additional imaging modalities, including positron emission tomography, 18-fludeoxyglucose positron emission tomography/computed tomography, 18-fludeoxyglucose positron emission tomography/computed tomography/magnetic resonance imaging, 124I positron emission tomography/computed tomography, positron emission tomography/magnetic resonance imaging fusion studies, and recombinant human thyrotropin-stimulated radioactive iodine uptake for cancer surveillance are discussed. Conclusions PDTC is an unusual and aggressive form of thyroid cancer. Fine-needle aspiration cytology may not yield sufficient information to specifically diagnose PDTC. Aggressive management with total thyroidectomy and neck dissection followed by high-dose radioactive iodine remnant ablation is standard. Iodine I 131 whole body scanning is often the initial test for tumor surveillance, with other imaging modalities applied as needed. (Endocr Pract. 2011;17:115-121)

Fine-needle aspiration (FNA) may be the procedure of choice in the preoperative evaluation of thyroid nodules, yet it suffers as a modality both because of its inherent limitations as well as variability in its diagnostic terminology. The National Cancer Institute recently proposed a classification system. The objective of this study was to report our experience in using this new reporting system to review the distribution of diagnosis categories and to evaluate the specificity of the system based on the cytologic-histologic correlation.A total of 3207 thyroid nodules underwent FNA, that is, 3207 FNAs from 2468 patients were examined at our institution between January 1, 2008 and December 31, 2008. All FNAs were classified prospectively into unsatisfactory, benign, indeterminate (cells of undetermined significance), follicular neoplasm (FN), suspicious for malignancy, and positive for malignancy.The distribution of these categories from 3207 evaluated nodules was as follows: 11.1% unsatisfactory, 73.8% benign, 3.0% indeterminate, 5.5% FN, 1.3% suspicious, and 5.2% malignant. Of the 2468 sampled patients, 378 (15%) underwent thyroidectomy. The distribution of diagnoses of patients who underwent surgery was as follows: 10% unsatisfactory, 4.6% benign, 30.3% indeterminate, 61.4% FN, 76.9% suspicious, and 77.2% malignant. There was an excellent association between the categories and in predicting benign versus malignant thyroid nodules (p0.0001). However, the false-negative rate cannot be calculated because only a small number of patients with benign diagnosis underwent surgery. The false-positive rate was 2.2%; all were diagnosed as suspicious cytologically. Given that only 15% of the patients underwent surgery, at this time the sensitivity of thyroid FNA for diagnosing malignant thyroid nodules cannot be calculated, nor can the sensitivity of thyroid FNA as a screening test for all neoplasms be accurately estimated. The specificity for diagnosing malignant thyroid nodules was 93%, whereas the specificity as a screening test for all neoplasms was 68%. The positive predictive values for an FN, suspicious, and positive cytologic diagnosis were 34%, 87%, and 100%, respectively.These data demonstrate that the recently proposed classification system is excellent for reporting thyroid FNAs. Each diagnostic category conveys specific risks of malignancy, which offers guidance for patient management.

Uveal melanoma spreads exclusively via a hematogenous route and is notable for its latency. Liver metastases are common; however, metastatic spread to unusual sites has been encountered. We report the case of metastatic uveal melanoma in a woman with multinodular goiter and primary hyperparathyroidism. The patient presented with hypercalcemia and an elevated intact parathyroid hormone level, in conjunction with a follicular neoplasm in the setting of goiter. She underwent an uneventful total thyroidectomy and parathyroidectomy. Postoperatively, she became normocalcemic. Histopathologic analyses revealed metastatic uveal melanoma cells within both the multinodular goiter and parathyroid adenoma. At present, she is enrolled in a phase II trial for disseminated uveal melanoma. This is a report of uveal melanoma metastatic to both a parathyroid adenoma and a nodular hyperplastic thyroid. Additionally, this case serves to display the unusual metastatic potential of uveal melanoma.

To evaluate the development and histologic features of jugular vein catheter-related (fibrin) sheaths in a swine model.The proposal was approved by the University Committee on the Use and Care of Animals. Tunneled silicone 7-F catheters were placed via a jugular vein in eight swine. The animals were separated into four groups of two pigs each according to catheter indwelling times of 7, 14, 30, and 45 days. After the animals were sacrificed, the catheter, access vein, and cranial vena cava were dissected, removed en bloc, and fixed in formalin. Histologic evaluation was performed by using standard light microscopy on hematoxylin-eosin stained specimens; immunohistochemistry was also performed to confirm specific cell populations.Catheter-related sheaths that covered 33%-100% of the intravascular catheter length were identified in all eight catheter specimens. After 7 days, catheters had a partial or circumferential mixed cellular and noncellular covering consisting of smooth muscle cells, thrombus, and areas with endothelial cell populations. Sheaths from catheters excised at 14 days were characterized by prominent endothelial cell and smooth muscle cell proliferation. Catheters excised at 30 and 45 days showed less prominent cellularity and more prominent collagen content, in a well-developed sheath, than did those excised at 7 and 14 days. With longer catheter indwelling times, an endothelial layer, indistinguishable from the adjacent vein wall, covered the catheter surface.The sheath that develops around central venous catheters in the swine model consists of cellular and noncellular components. A substantial proportion of the sheath is made up of a smooth muscle cell and collagen layer with overlying endothelial cells.

Cardiac tamponade is defined as an accumulation of fluid within the pericardial sac that is large enough to impair the diastolic filling of the ventricles. There are numerous causes, including cardiac disease, malignancy, and trauma (penetrating, blunt, and iatrogenic). With increasing complexity of percutaneous endovascular interventions, interventional radiologists must learn to recognize the preexisting and iatrogenic presence of cardiac tamponade during procedures and be familiar with its treatment. Two cases of pericardial tamponade complicating central venous interventions are described. In addition, the clinical condition is discussed and its diagnosis and treatment are reviewed.

Mild consternation must often have afflicted browsers looking for T. E. Lawrence’s Seven Pillars of Wisdom in bookstores. Without the kind of help provided by overqualified clerks in such academic enclaves as Cambridge or Hyde Park, the aspirant reader may very well travel from the autobiography section of the store to the history section and then to the gay and lesbian section and then to the Middle East section only accidentally to see the book shelved with other memoirs. The classification problem that Lawrence’s masterpiece poses for those engaged in literature as a commercial venture and for those pursuing reading as an edifying mode of leisure is, admittedly, trivial. But for those who read to enhance or discover a mode of life—for those, in other words, who read in the great tradition Lawrence clearly appeals to throughout this book—its unusual formal structure, the problems of classification it poses, are not trivial vexations but extraordinary calls to transcendence. On its title page Lawrence christened the book “a triumph.” What would it mean to take him at his word, to think of Seven Pillars of Wisdom as not only about triumph, but to think of it as a new genre called “a triumph,” a new literary form that imaginatively instantiates, and so permanently makes known, whatever value Lawrence thought “triumph” gave to life?

Background: Patients with metastatic colorectal cancer that is limited to a few lesions in the lungs or liver may benefit from the complete surgical removal of all deposits of metastatic cancer (referred to as a curative metastasectomy). Although the outcome after this curative-intent surgery is considerably better than patients with more extensive metastatic cancer, only a third of the surgical patients are actually cured. As a result, there is a great need for a mechanism to predict outcome after surgery for limited metastatic cancer, in order to better match patients with effective therapy. Fascin is an actin bundling protein linked to epithelial to mesenchymal transformation and metastatic progression. Fascin expression has previously demonstrated prognostic potential in patients with extensive metastatic colorectal cancer. We hypothesized that Fascin expression within surgically removed colorectal cancer metastases would correlate with survival after curative-intent surgery. Methods: 82 paraffin embedded colorectal metastases collected after curative-intent surgery between 1990 and 2008 were incorporated into tissue microarrays (TMAs) in two fold redundancy. Fascin expression within the metastases was determined by quantitative immunofluorescence using Automated Quantitative Analysis (AQUA), and normalized based on a panel of cell lines (AQUA score range 0-72). The median follow up was 2.8 years and thus far 51 patients have died (62%). Results: The majority of colorectal cancer metastases had been removed from the liver (70 patients), while 12 represented pulmonary metastases. There were no differences in survival by location of metastases (p = .65). Survival was analyzed based on high (top quartile, n = 21) and low (bottom three quartiles, n = 61) expression of Fascin (AQUA score cut point of 3.4). High expression of Fascin correlated with a worse prognosis, HR 1.97; 95% CI 1.07-3.62 p = .009. Conclusions: Fascin expression within colorectal cancer metastases may be used to predict outcome after curative-intent surgery. Patients with high Fascin expression may be considered for additional therapy or may be advised against particularly high risk procedures. Further study is warranted to validate the role of Fascin expression analysis in this patient cohort. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 349. doi:10.1158/1538-7445.AM2011-349