Spindle epithelial tumor with thymus-like differentiation in fine needle aspiration of thyroid gland: Report of two cases.

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a rare, malignant tumor of the thyroid gland that typically affects young males and has a propensity for late metastasis. With fine needle aspiration (FNA) being a primary tool for diagnosis of thyroid lesions, there are rare reports of cytological features of SETTLE on FNA since its initial characterization 30 years ago . Here we report two cases of SETTLE, involving 9-year-old and 15-year-old male patients. Both patients underwent US-guided FNA with a subsequent resection confirming the diagnosis of SETTLE. In the first patient the thymic origin of the tumor was suspected on FNA, but the diagnosis of SETTLE was established only after resection. Five years later, this patient presented with an enlarged ipsilateral cervical lymph node. Needle biopsy confirmed it to be a metastatic tumor compatible with SETTLE. In the second patient the diagnosis of SETTLE was suggested on FNA. Cytology of the thyroid gland nodule on FNA from both patients showed loosely cohesive and single spindle-shaped epithelial cells associated with metachromatic stroma. The differential diagnosis of spindle cell lesions of the thyroid should include SETTLE based on characteristic morphological features, after more common entities of thyroid gland such as medullary carcinoma are excluded.

Spindle cell lesion on fine needle aspiration as an initial step for diagnosis of lymphangioleiomyomatosis: Report of a rare case.

Lymphangioleiomyomatosis (LAM) is a rare systemic disease of women of reproductive age characterized by proliferation of abnormal smooth muscle like cells (LAM cells). Patients with LAM characteristically present with chronic dyspnea and cough and less commonly with spontaneous pneumothorax. Manifestation of extrapulmonary LAM as an initial presenting symptom is rare with a renal angiomyolipoma and lymphangioleiomyoma being most common. Although histologic findings of LAM are well-described, the cytological features; however, have been described only in few case reports, which focus on pulmonary LAM. Here, we report a case where initial diagnosis of LAM was made on pelvic "lymph node" fine needle aspiration (FNA) and biopsy in otherwise asymptomatic 25-year-old female, leading to further investigation and detection of developing cystic lung lesions. FNA cytology from the pelvic "lymph node" yielded proliferation of spindle cells without cytologic atypia. This case presented both clinical and histopathologic challenge, requiring clinical correlation and immunohistochemical staining for diagnosis. While rare, it is important to consider LAM in the differential diagnosis of spindle cell lesions in aspirate from nodules around vascular bundles in women of reproductive age even without history of lung lesion.

Acute Respiratory Distress Syndrome Secondary to Histoplasmosis-induced Hemophagocytic Lymphohistiocytosis / Síndrome de distrés respiratorio agudo secundario a linfohistiocitosis hemofagocítica inducida por histoplasmosis

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Metabolomic profiling of breast tumors using ductal fluid.

Identification of new biomarkers for breast cancer remains critical in order to enhance early detection of the disease and improve its prognosis. Towards this end, we performed an untargeted metabolomic analysis of breast ductal fluid using an ultra-performance liquid chromatography coupled with a quadrupole time-of-light (UPLC-QTOF) mass spectrometer. We investigated the metabolomic profiles of breast tumors using ductal fluid samples collected by ductal lavage (DL). We studied fluid from both the affected breasts and the unaffected contralateral breasts (as controls) from 43 women with confirmed unilateral breast cancer. Using this approach, we identified 1560 ions in the positive mode and 538 ions in the negative mode after preprocessing of the UPLC­QTOF data. Paired t-tests applied on these data matrices identified 209 ions (positive and negative modes combined) with significant change in intensity level between affected and unaffected control breasts (adjusted p-values <0.05). Among these, 83 ions (39.7%) showed a fold change (FC) >1.2 and 66 ions (31.6%) were identified with putative compound names. The metabolites that we identified included endogenous metabolites such as amino acid derivatives (N-Acetyl-DL-tryptophan) or products of lipid metabolism such as N-linoleoyl taurine, trans-2-dodecenoylcarnitine, lysophosphatidylcholine LysoPC(18:2(9Z,12Z)), glycerophospholipids PG(18:0/0:0), and phosphatidylserine PS(20:4(5Z,8Z,11Z,14Z). Generalized LASSO regression further selected 21 metabolites when race, menopausal status, smoking, grade and TNM stage were adjusted for. A predictive conditional logistic regression model, using the LASSO selected 21 ions, provided diagnostic accuracy with the area under the curve of 0.956 (sensitivity/specificity of 0.907/0.884). This is the first study that shows the feasibility of conducting a comprehensive metabolomic profiling of breast tumors using breast ductal fluid to detect changes in the cellular microenvironment of the tumors and shows the potential for this approach to be used to improve detection of breast cancer.

MicroRNA analysis of breast ductal fluid in breast cancer patients.

Recent studies suggest that microRNAs show promise as excellent biomarkers for breast cancer; however there is still a high degree of variability between studies making the findings difficult to interpret. In addition to blood, ductal lavage (DL) and nipple aspirate fluids represent an excellent opportunity for biomarker detection because they can be obtained in a less invasive manner than biopsies and circumvent the limitations of evaluating blood biomarkers with regards to tissue of origin specificity. In this study, we have investigated for the first time, through a real-time PCR array, the expression of 742 miRNAs in the ductal lavage fluid collected from 22 women with unilateral breast tumors. We identified 17 differentially expressed miRNAs between tumor and paired normal samples from patients with ductal breast carcinoma. Most of these miRNAs have various roles in breast cancer tumorigenesis, invasion and metastasis, therapeutic response, or are associated with several clinical and pathological characteristics of breast tumors. Moreover, some miRNAs were also detected in other biological fluids of breast cancer patients such as serum (miR-23b, -133b, -181a, 338-3p, -625), plasma (miR-200a), and breast milk (miR-181a). A systems biology analysis of these differentially expressed miRNAs points out possible pathways and cellular processes previously described as having an important role in breast cancer such as Wnt, ErbB, MAPK, TGF-ß, mTOR, PI3K-Akt, p53 signaling pathways. We also observed a difference in the miRNA expression with respect to the histological type of the tumors. In conclusion, our findings suggest that miRNA analysis of breast ductal fluid is feasible and potentially very useful for the detection of breast cancer.

Impact of human papillomavirus (HPV) 16 and 18 vaccination on prevalent infections and rates of cervical lesions after excisional treatment.

BACKGROUND: Human papillomavirus vaccines prevent human papillomavirus infection and cervical precancers. The impact of vaccinating women with a current infection or after treatment for an human papillomavirus-associated lesion is not fully understood. OBJECTIVES: To determine whether human papillomavirus-16/18 vaccination influences the outcome of infections present at vaccination and the rate of infection and disease after treatment of lesions. STUDY DESIGN: We included 1711 women (18-25 years) with carcinogenic human papillomavirus infection and 311 women of similar age who underwent treatment for cervical precancer and who participated in a community-based trial of the AS04-adjuvanted human papillomavirus-16/18 virus-like particle vaccine. Participants were randomized (human papillomavirus or hepatitis A vaccine) and offered 3 vaccinations over 6 months. Follow-up included annual visits (more frequently if clinically indicated), referral to colposcopy of high-grade and persistent low-grade lesions, treatment by loop electrosurgical excisional procedure when clinically indicated, and cytologic and virologic follow-up after treatment. Among women with human papillomavirus infection at the time of vaccination, we considered type-specific viral clearance, and development of cytologic (squamous intraepithelial lesions) and histologic (cervical intraepithelial neoplasia) lesions. Among treated women, we considered single-time and persistent human papillomavirus infection, squamous intraepithelial lesions, and cervical intraepithelial neoplasia 2 or greater. Outcomes associated with infections absent before treatment also were evaluated. Infection-level analyses were performed and vaccine efficacy estimated. RESULTS: Median follow-up was 56.7 months (women with human papillomavirus infection) and 27.3 months (treated women). There was no evidence of vaccine efficacy to increase clearance of human papillomavirus infections or decrease incidence of cytologic/histologic abnormalities associated with human papillomavirus types present at enrollment. Vaccine efficacy for human papillomavirus 16/18 clearance and against human papillomavirus 16/18 progression from infection to cervical intraepithelial neoplasia 2 or greater were -5.4% (95% confidence interval -19,10) and 0.3% (95% confidence interval -69,41), respectively. Among treated women, 34.1% had oncogenic infection and 1.6% had cervical intraepithelial neoplasia 2 or greater detected after treatment, respectively, and of these 69.8% and 20.0% were the result of new infections. We observed no significant effect of vaccination on rates of infection/lesions after treatment. Vaccine efficacy estimates for human papillomavirus 16/18 associated persistent infection and cervical intraepithelial neoplasia 2 or greater after treatment were 34.7% (95% confidence interval -131, 82) and -211% (95% confidence interval -2901, 68), respectively. We observed evidence for a partial and nonsignificant protective effect of vaccination against new infections absent before treatment. For incident human papillomavirus 16/18, human papillomavirus 31/33/45, and oncogenic human papillomavirus infections post-treatment, vaccine efficacy estimates were 57.9% (95% confidence interval -43, 88), 72.9% (95% confidence interval 29, 90), and 36.7% (95% confidence interval 1.5, 59), respectively. CONCLUSION: We find no evidence for a vaccine effect on the fate of detectable human papillomavirus infections. We show that vaccination does not protect against infections/lesions after treatment. Evaluation of vaccine protection against new infections after treatment and resultant lesions warrants further consideration in future studies.

Effect of different human papillomavirus serological and DNA criteria on vaccine efficacy estimates.

Two trials of clinically approved human papillomavirus (HPV) vaccines, Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE I/II) and the Papilloma Trial Against Cancer in Young Adults (PATRICIA), reported a 22% difference in vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 2 or worse in HPV-naïve subcohorts; however, serological testing methods and the HPV DNA criteria used to define HPV-unexposed women differed between the studies. We applied previously described methods to simulate these HPV-naïve subcohorts within the Costa Rica HPV16/18 Vaccine Trial and assessed how these criteria affect the estimation of VE. We applied 2 enzyme-linked immunosorbent assay (ELISA) thresholds for HPV16 and HPV18 seropositivity (8 and 7 ELISA units/mL, respectively, for PATRICIA; 54 and 65 ELISA units/mL, respectively, for FUTURE I/II (to approximate the competitive Luminex immunoassay)) and 2 criteria for HPV DNA positivity (12 oncogenic HPV types, plus HPV66 and 68/73 for PATRICIA; or plus HPV6 and 11 for FUTURE I/II). VE was computed in the 2 naïve subcohorts. Using the FUTURE I/II and PATRICIA criteria, VE estimates against cervical intraepithelial neoplasia grade 2 or worse, regardless of HPV type, were 69.0% (95% confidence interval: 40.3%, 84.9%) and 80.8% (95% confidence interval: 52.6%, 93.5%), respectively (P = 0.1). Although the application of FUTURE I/II criteria to our cohort resulted in the inclusion of more sexually experienced women, methodological differences did not fully explain the VE differences.

The added value of using mutational profiling in addition to cytology in diagnosing aggressive pancreaticobiliary disease: review of clinical cases at a single center.

BACKGROUND: This study aimed to better understand the supporting role that mutational profiling (MP) of DNA from microdissected cytology slides and supernatant specimens may play in the diagnosis of malignancy in fine-needle aspirates (FNA) and biliary brushing specimens from patients with pancreaticobiliary masses. METHODS: Cytology results were examined in a total of 30 patients with associated surgical (10) or clinical (20) outcomes. MP of DNA from microdissected cytology slides and from discarded supernatant fluid was analyzed in 26 patients with atypical, negative or indeterminate cytology. RESULTS: Cytology correctly diagnosed aggressive disease in 4 patients. Cytological diagnoses for the remaining 26 were as follows: 16 negative (9 false negative), 9 atypical, 1 indeterminate. MP correctly determined aggressive disease in 1 false negative cytology case and confirmed a negative cytology diagnosis in 7 of 7 cases of non-aggressive disease. Of the 9 atypical cytology cases, MP correctly diagnosed 7 as positive and 1 as negative for aggressive disease. One specimen that was indeterminate by cytology was correctly diagnosed as non-aggressive by MP. When first line malignant (positive) cytology results were combined with positive second line MP results, 12/21 cases of aggressive disease were identified, compared to 4/21 cases identified by positive cytology alone. CONCLUSIONS: When first line cytology results were uncertain (atypical), questionable (negative), or not possible (non-diagnostic/indeterminate), MP provided additional information regarding the presence of aggressive disease. When used in conjunction with first line cytology, MP increased detection of aggressive disease without compromising specificity in patients that were difficult to diagnose by cytology alone.

Solid-pseudopapillary neoplasm of the pancreas: awareness of unusual clinical presentations and morphology of the clear cell variant can prevent diagnostic errors.

Solid-pseudopapillary neoplasm (SPN) of the pancreas is a rare neoplasm predominantly reported in young women. It classically presents as a large tumor with cystic and solid components. The major differential diagnosis includes pancreatic neuroendocrine tumor (PanNET). This study presents our experience with this tumor with emphasis on the morphologic features of the clear cell variant of SPN. Fifteen histologically confirmed SPN were identified in our files. Endoscopic ultrasound-guided fine needle aspirations (EUS-guided FNA) were performed in 8/15 cases. Patients' demographics, cytohistologic correlation and tumor characteristics were evaluated. Eleven of the 15 subjects were female and four were male with an age range of 17-73 years. Twelve SPN were located in the pancreatic body/tail, and three in the head. Tumor size ranged from 1.5 to 8.5 cm and 11 were solid. Of the eight EUS-guided FNA, four were diagnosed as SPN, two as SPN vs. PanNET, one as malignant with signet ring features, and one was nondiagnostic. Immunohistochemistry was performed on six/eight FNA cell blocks and 13/15 surgical specimens. Two of the 15 cases were classified as clear cell variants of SPN. Our study shows that SPN may occur in males and older adults, and present as a small or solid tumor. The clear cell variant of SPN, characterized by vacuolated cytoplasm and signet cell morphology, may pose a diagnostic challenge on FNA. Awareness of the wide spectrum of SPN clinical presentations, the morphology of its clear cell variant and the appropriate use of ancillary immunohistochemistry can prevent diagnostic errors.

Does on-site adequacy evaluation reduce the nondiagnostic rate in endoscopic ultrasound-guided fine-needle aspiration of pancreatic lesions?

BACKGROUND: This retrospective study compared the nondiagnostic rate for endoscopic ultrasound-guided (EUS) fine-needle aspiration (FNA) of pancreatic lesions in 2 settings: 1 with and 1 without on-site evaluation. METHODS: The authors reviewed 381 consecutive cases and divided them into groups with and without on-site adequacy evaluation. For the group with on-site evaluation, cytopathology personnel prepared and evaluated Diff-Quik-stained direct smears and rinsed the remaining material in CytoLyt solution (Cytyc Corporation, Marlborough, Mass). The group without on-site evaluation was divided into 2 subgroups: the clinical team either prepared an air-dried smear for each FNA pass and then rinsed the remaining material in CytoLyt, or the entire sample was rinsed in CytoLyt. The cytologic diagnoses were reviewed and the nondiagnostic rates for each group were calculated. RESULTS: On-site evaluation was provided for 167 cases with a nondiagnostic rate of 25.8% (43 of 167 cases). On-site evaluation was not provided for 214 cases with a nondiagnostic rate of 24.3% (52 of 214 cases). The nondiagnostic rate for the subgroup with air-dried smears prepared by the clinical team was 25.6% (43 of 168 cases) and that for the subgroup with the entire sample rinsed in CytoLyt was 19.6% (9 of 46 cases). There were no significant statistical differences in nondiagnostic rates noted among the different groups or subgroups. CONCLUSIONS: The results of the current study indicate that when experienced operators perform EUS FNA of pancreatic lesions, on-site adequacy evaluation offers no benefit in reducing the nondiagnostic rate. Optimizing visualization of the sampled material by omitting the preparation of direct smears and rinsing the entire sample in liquid-based media demonstrated a trend toward improving the diagnostic rate.

Telomere length variation in normal epithelial cells adjacent to tumor: potential biomarker for breast cancer local recurrence.

A better understanding of the risk of local recurrence (LR) will facilitate therapeutic decision making in the management of early breast cancers. In the present study, we investigated whether telomere length in the normal breast epithelial cells surrounding the tumor is predictive of breast cancer LR; 152 women who were diagnosed with breast cancer at the Lombardi Comprehensive Cancer Center were included in this nested case-control study. Cases (patients had LR) and controls (patients had no LR) were matched on year of surgery, age at diagnosis and type of surgery. Telomere fluorescent in situ hybridization was used to determine the telomere length using formalin fixed paraffin-embedded breast tissues. Small telomere length variation (TLV), defined as the coefficient variation of telomere lengths among examined cells, in normal epithelial cells adjacent to the tumor was significantly associated with a 5-fold (95% confidence interval = 1.2-22.2) increased risk of breast cancer LR. When the subjects were categorized into quartiles, a significant inverse dose-response relationship was observed with lowest versus highest quartile odds ratio of 15.3 (P(trend) = 0.012). Patients who had large TLV had significantly better 10 year recurrence free survival rate compared with patients who had small TLV (80 versus 33%). The present study revealed that TLV in normal epithelial cells adjacent to tumor is a strong predictor of breast cancer LR. If confirmed by future studies, TLV in normal epithelial cells adjacent to tumor has the potential to become a promising biomarker for predicting breast cancer LR after breast conserving surgery.

Nipple-sparing mastectomy for prophylactic and therapeutic indications.

BACKGROUND: Nipple-sparing mastectomy remains controversial and its adoption has been slow because of oncologic and surgical concerns. METHODS: A retrospective study evaluated all nipple-sparing mastectomies performed at a single institution for therapeutic or prophylactic indications for which records were available. RESULTS: Between 1989 and 2010, 162 nipple-sparing mastectomies were performed in 101 women. Forty-nine (30 percent) were performed for therapeutic purposes on 48 patients. A subareolar biopsy specimen was taken in 39 of 49 breasts (80 percent); four (10 percent) revealed ductal carcinoma in situ, and the nipple or nipple-areola complex was later removed. Four of 49 breasts (8 percent) in the therapeutic group had ischemic complications involving the nipple-areola complex, one of which (2 percent) was excised. With a mean follow-up of 2 years 6 months (range, 5 months to 9 years 5 months), no patients developed cancer in the nipple-areola complex. The remaining 113 mastectomies (70 percent) were performed prophylactically on 80 patients. The subareolar tissue was biopsied in 80 breasts (71 percent). One biopsy revealed lobular carcinoma in situ; none had ductal carcinoma in situ or invasive cancer. Two nipple-areola complexes (1.8 percent) were ischemic and excised. With a mean follow-up of 3 years 7 months (range, 5 months to 20 years 6 months), no patients developed new primary cancers in the nipple-areola complex. CONCLUSIONS: Nipple-sparing mastectomy can be safe in properly selected patients. A subareolar biopsy can effectively identify nipple-areola complexes that may harbor cancerous cells. Ischemic complications resulting in nipple loss can be minimized, and long-term follow-up suggests that this technique deserves further investigation in properly selected patients. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Diagnostic terminology and morphologic criteria for cytologic diagnosis of thyroid lesions: a synopsis of the National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference.

The National Cancer Institute (NCI) sponsored the NCI Thyroid Fine-needle Aspiration (FNA) State of the Science Conference on October 22-23, 2007 in Bethesda, MD. The two-day meeting was accompanied by a permanent informational website and several on-line discussion periods between May 1 and December 15, 2007 (http://thyroidfna.cancer.gov). This document summarizes matters regarding diagnostic terminology/classification scheme for thyroid FNA interpretation and cytomorphologic criteria for the diagnosis of various benign and malignant thyroid lesions. (http://thyroidfna.cancer.gov/pages/info/agenda/).

Association of race, age and body mass index with gross pathology of uterine fibroids.

OBJECTIVE: To determine the associations of race, age and body mass index (BMI) with the gross pathology parameters of uterine leiomyomas in premenopausal women undergoing hysterectomy or myomectomy. STUDY DESIGN: Participants (N = 107) were recruited from surgical rosters of the George Washington University (GWU) Medical Center Gynecology Department as part of the National Institute of Environmental Health Sciences Fibroid Study. Tumor data and patient demographics were obtained from clinical reports, pathology forms and interviews. RESULTS: Surgical cases consisted of 78% African Americans, 13% Caucasians and 9% others (non-African American, non-Caucasian or race unknown). This proportion of African Americans was significantly higher than the distribution of GWU health plan participants. Fibroids were localized predominantly within the intramural region. Subserosal tumors were more common in patients with more than 9 tumors. African Americans had the highest mean BMI and mean myomatous uterine weight. CONCLUSION: African Americans were the disproportionate majority coming to surgery for fibroids. The average BMI and uterine weight were greater in African Americans than in Caucasians, although these differences were marginal. Race did not influence the size, location or number of fibroids in these surgical cases. Subserosal tumors were more common in patients with more than 9 tumors.

Real-time imaging and characterization of human breast tissue by reflectance confocal microscopy.

Real-time technologies can increase the efficiency of obtaining informative biopsies and accelerate interpretation of biopsy pathological review. Cellular aberrations inherent to cancer cells, including nuclear size, can currently be detected, but few technologies are available to evaluate adequacy of specimens in real time. The aims of this study are: 1. to determine if near-infrared reflectance confocal microscopy (RCM) can be used to assess epithelial/stromal content of core needle breast biopsy samples in real time, 2. to determine if epithelial cell nuclear size can be measured on RCM images, and 3. to test if RCM images can be accurately read for presence/absence of histologically relevant features of malignancy. Breast biopsies are obtained following a medically indicated breast core needle diagnostic biopsy for RCM examination. Acetic acid is used as a contrast agent to visualize structures within breast tissue. Structures are identified and optically serially sectioned, and digital images are cataloged. Relative amounts of epithelial, fatty, and collagenous tissue are determined. RCM biopsies are formalin-fixed and stained for hematoxylin and eosin (H and E) comparison with RCM images. RCM data are comparable to data from H and E sections. Epithelial cell nuclear size is measured on stored digital RCM images. We compare RCM and H and E images from 16 patients and 25 core needle biopsy samples.

Construction and validation of tissue microarrays of ductal carcinoma in situ and terminal duct lobular units associated with invasive breast carcinoma.

Construction of tissue microarrays (TMAs) to efficiently characterize large sets of noninvasive epithelial lesions in the breast by immunohistochemistry is an appealing investigative approach, but presents technical challenges. We report methodologic studies performed to optimize methods for building TMAs from noninvasive breast tissues collected in a large case-control study of breast cancer. Using a manual arraying technique with 2.0-mm diameter needles, we constructed TMAs from specimens obtained from 32 women with breast cancer containing the following targets: (1) 28 terminal duct lobular units (TDLUs); (2) 28 ductal carcinomas in situ, and (3) 23 invasive carcinomas. Using careful target selection, we achieved representation of approximately 80% of noninvasive targets with sustained preservation through section 30 of the TMAs. Immunohistochemical staining of TDLU targets demonstrated positive staining for estrogen receptor (ER) in 30.8% of tubules and for progesterone receptor (PR) in 50.0%. To establish an efficient method to evaluate staining results in TDLUs, we created a categorical scoring system to approximate the percentage of tubules containing positive stained cells (<10%, 10% to 50%, >or=50%), and compared the results with those obtained by tubule counting. Comparison between the two methods demonstrated exact agreement for 70.8% of ER and 79.2% of PR stains without two-category discrepancies. ER/PR expression levels in multiple (up to 4) noninvasive targets of the same tissue type (TDLU or DCIS) from a single block showed good correlation. These data suggest that it is feasible to produce TMAs of noninvasive breast structures, albeit with careful selection of targets, and that immunostains of such cores may permit efficient immunohistochemical characterization of peritumoral tissues. Additional exploration of this approach is needed.