Deep inferior epigastric lymph node basin: Analysis of novel donor site for vascularized lymph node transfer among 10 consecutive patients.

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.

Positive Margin Re-Excision Following Immediate Autologous Breast Reconstruction: Morbidity, Cosmetic Outcome, and Oncologic Significance.

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.

BRAFV600E mutation in papillary thyroid microcarcinoma: a genotype-phenotype correlation.

BRAF(V600E) mutation has emerged as a marker of aggressive behavior in papillary thyroid carcinoma but its significance in microcarcinoma is not entirely clear. One-hundred and twenty-nine papillary thyroid microcarcinomas were tested for BRAF(V600E) mutation by single-strand conformation polymorphism, and their clinicopathologic features (age, sex, tumor size, multifocality, nodal metastases, histologic subtype, tumor cell morphology, architecture, tumor-associated stromal reaction, tumor interface to non-neoplastic thyroid (well circumscribed vs infiltrative), extrathyroidal extension, lymphovascular invasion, intratumoral multinucleated giant cells, and adjacent non-neoplastic thyroid pathology) were examined. Compared with tumors without the mutation (39/129, 30%), the mutated microcarcinomas (90/129, 70%) showed significantly higher prevalence of infiltrative tumor borders (78/90 vs 23/39, P=0.001), tumor-associated stromal desmoplasia/fibrosis and/or sclerosis (80/90 vs 25/39, P=0.002), classic nuclear features of papillary thyroid carcinoma (90/90 vs 35/39, P=0.008) and cystic change (43/90 vs 11/39, P=0.05). BRAF(V600E) mutation was more frequent in classic (75%), tall cell (91%), and other variants (>70%) than in follicular variant (21%) of papillary thyroid microcarcinoma. Tumors without the mutation were significantly more likely to be solid, well circumscribed, and lacked desmoplasia/fibrosis or sclerosis. However, on multivariate analysis, only the follicular variant of papillary microcarcinoma was significantly associated with the absence of mutation (odds ratio (95% confidence interval): 0.09 (0.01-0.54)). Lymph node metastases (n=24) were more frequent in microcarcinomas with mutation than without (21/24 vs 3/24, P=0.02). All patients with lateral cervical node metastasis (n=9), and all but one tumor with extrathyroidal extension (n=17/18) showed BRAF(V600E) mutation. No significant differences were noted in age, sex, tumor size, multifocality, lymphovascular invasion, psammoma bodies, stromal calcification, intratumoral multinucleated osteoclastic-type giant cells, and lymphocytic infiltration between the two groups of tumors. BRAF(V600E) mutation is an early event in thyroid carcinogenesis, and is associated with distinctive morphology and aggressive features even in papillary thyroid microcarcinomas.

The molecular diagnosis and management of thyroid neoplasms.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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.

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 < 0.0001) and two diffuse sclerosing variants were negative for the mutation. Mutation-positive tumours displayed infiltrative growth (32/34, P = 0.02), stromal fibrosis (33/34, P < 0.001), psammoma bodies (17/34, P = 0.05), plump eosinophilic tumour cells (22/34, P = 0.01), and classic fully developed nuclear features of PTC (33/34, P = 0.0001). Encapsulation was significantly associated with mutation-negative tumours (15/22, P = 0.02). CONCLUSIONS: BRAF V600E mutation-positive and negative PTCs are morphologically different. Recognition of their morphology may help in the selection of appropriate tumours for genetic testing.

Clinical and histopathological characteristics of hyperparathyroidism-induced hypercalcemic crisis.

BACKGROUND: 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. METHODS: 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 level>13.5 mg/dl (range: 8.8-10.2 mg/dl). Clinical and pathological characteristics were evaluated. Data are expressed as mean±SEM. RESULTS: 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. CONCLUSIONS: 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.

BRAF mutation testing of thyroid fine-needle aspiration specimens enhances the predictability of malignancy in thyroid follicular lesions of undetermined significance.

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.

Multinodular goiter and primary hyperparathyroidism: a circuitous route to diagnosing metastatic uveal melanoma.

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.

Author Correction: Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis.

This corrects the article DOI: 10.1038/ncomms15908.

Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis.

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.

Morphology predicts BRAF (V6°°E) mutation in papillary thyroid carcinoma: an interobserver reproducibility study.

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.

Endoscopic ultrasound-guided fine-needle aspiration diagnosis of Merkel cell carcinoma metastatic to the pancreas.

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.

Spatial spectral imaging as an adjunct to the Bethesda classification of thyroid fine-needle aspiration specimens.

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.

The use of immunocytochemical study in the cytologic diagnosis of melanoma: evaluation of three antibodies.

There are limited studies on the utility of immunostaining in cytologic specimens suspected of melanoma. In this study, we examined the performance of the most commonly used antibodies including monoclonal antibodies against Melan-A (A103), S-100, and HMB-45 antigens. Immunostains were performed on formalin-fixed, paraffin-embedded cell blocks prepared from 100 cytologic specimens. The specimens consisted of 57 melanomas and 43 nonmelanocytic neoplasms. Of 57 melanomas, 53 showed positive reaction to Melan-A antibody while 51 and 41 revealed positive immunostaining for S-100 and HMB-45, respectively. Of 43 nonmelanocytic neoplasms, 10, 4, and 8 specimens stained positive with an antibody against S-100, HMB-45, and Melan-A, respectively. However, the false-positive immunostaining for Melan-A was eliminated in seven of the eight specimens after applying the pretreatment with avidin/biotin blocking reagents. Overall, the highest sensitivity and negative predictive value (NPV) were achieved in Melan-A antibody (93 and 90%) compared with antibodies to S-100 (89 and 85%), and HMB-45 (72 and 71%). Initially, an intermediate specificity and positive predictive value (PPV) were obtained for Melan-A antibody (81 and 87%) that were greater than S-100 (77 and 84%), and lower than HMB-45 (91 and 91%). However, the aforementioned treatment with avidin/biotin blocking reagents improved both specificity (98%) and PPV (98%) for Melan-A antibody. In conclusion, by blocking endogenous biotin, Melan-A antibody offers the greatest performance. In terms of cost-effectiveness, we suggested that Melan-A antibody should be used as the first-line antibody for detecting melanoma in the cytologic specimens.

The impact of implementing The Bethesda System for reporting of thyroid FNA at an academic center.

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.

Radiologic and clinical predictors of malignancy in the follicular lesion of undetermined significance of the thyroid.

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.

Vanishing thyroid tumors: a diagnostic dilemma after ultrasonography-guided fine-needle aspiration.

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.

Thyroid follicular lesion of undetermined significance: Evaluation of the risk of malignancy using the two-tier sub-classification.

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 (<7%).

Insular variant of poorly differentiated thyroid carcinoma.

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 English-language 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, (124)I 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.

Reflex BRAF testing in thyroid fine-needle aspiration biopsy with equivocal and positive interpretation: a prospective study.

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.