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Background: Thyroid fine needle aspiration (T-FNA) is a mainstay in management of thyroid nodules. However, the preparation of T-FNA specimens varies across institutions. Prior studies have compared diagnostic rates between different specimen preparations of T-FNA specimens and their associated advantages and disadvantages. However, few have compared the rates of all diagnostic categories of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) between liquid-based preparations (LBPs) and a combination of LBP and conventional smear (CS) preparations. Our study compares TBSRTC diagnostic rates between these 2 cohorts and correlates cytologic diagnoses with subsequent thyroid resections to evaluate rates of neoplasia (RON) and malignancy (ROM). Methods: 584 consecutive thyroid FNA specimens were collected and stratified by preparation type (ThinPrep [TP] vs. CS & TP). Diagnostic rates for each TBSRTC diagnostic category were calculated. The institution’s electronic medical records database was searched for histologic diagnoses of previously sampled thyroid nodules to evaluate the RON and ROM. Results: Of 584 thyroid FNA specimens, 73 (12.5%) and 511 (87.5%) were evaluated by TP only and CS & TP, respectively, reflecting the predominance of rapid on-site evaluation (ROSE) with CS for T-FNAs at our institution. Of the TP only and CS & TP cohorts, 29 (39.7%) and 98 (19.2%) had subsequent resections, respectively. The frequency of non-diagnostic cases was lower in the CS & TP cohort (12.7% vs. 26%). While the diagnostic rate of follicular lesion of undetermined significance was similar for both cohorts, SFN categorization was only utilized in the CS & TP cohort (1.5% vs. 0%). Although RON and ROM were similar between cohorts in many of the TBSRTC categories, there was a higher RON associated with non-diagnostic specimens in the TP only cohort when the denominator included all non-diagnostic cases. Conclusion: The combination of CS and LBP may potentially decrease the non-diagnostic rate of T-FNA specimens as well as the number of passes required for diagnosis, particularly with ROSE. Evaluation of morphologic features highlighted in conventional smears may facilitate diagnostic categorization in the “suspicious for follicular neoplasm” category.

BACKGROUND Few studies focus on pediatric thyroid nodules categorized under indeterminate diagnostic categories. The current study was conducted to assess the risk of malignancy of indeterminate pediatric thyroid nodules. METHODS A search of the institutional electronic pathology database from 01/2011 to 09/2018 was performed to identify pediatric (

Background Afirma gene expression classifier (GEC) is an adjunct to thyroid fine needle aspiration shown to improve pre-operative risk assessment and reduce unnecessary surgery of indeterminate thyroid nodules. Genomic sequencing classifier (GSC) is a newer version aiming to improve specificity and positive predictive value (PPV) of Afirma testing. There are limited studies comparing GSC vs GEC. This study was undertaken to compare these classifiers in terms of diagnostic performance and effect on clinical management of indeterminate thyroid nodules. Methods The study cohort consisted of patients with thyroid nodules that had a recurrent cytologic diagnosis of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) and were tested by either GEC or GSC. Patient demographics, nodule size, and clinical follow-up were recorded. Benign call rate (BCR) of Afirma testing, rate of subsequent surgery (RSS), rate of histology-confirmed malignancy (RHM), as well as diagnostic sensitivity, specificity, PPV, negative predicative value (NPV), and accuracy were calculated and compared between GSC and GEC cohorts. Results Among 264 AUS/FLUS thyroid nodules, 127 and 137 were tested with GEC and GSC, respectively. Compared to GEC, GSC demonstrated increased BCR (77.3% vs 52%), decreased RSS (31.4% vs 51.2%), greater RHM (29% vs 9.8%) associated with a suspicious Afirma result, as well as improved specificity (82.8% vs 54.5%), PPV (29% vs 9.8%), and diagnostic accuracy (83.9% vs 56.7%), while maintaining high sensitivity and NPV. Conclusion Afirma GSC substantially improved BCR, RSS, RHM, and diagnostic performance, enhancing appropriate triage and thereby helped avoid unnecessary surgery in AUS/FLUS thyroid nodules.

Introduction The rate of malignancy (ROM) in thyroid fine needle aspirations (FNA) classified under "atypia of undetermined significance (AUS)/follicular lesion of undetermined significance (FLUS), including Hurthle cell type (HLUS)" category of The Bethesda system for reporting thyroid cytopathology (TBSRTC) in literature is highly variable. The 2018 TBSRTC was updated to note a preferred categorization of AUS cases into subcategories. This study evaluates the impact of AUS subclassification on rates of neoplasia (RON), rates of malignancy (ROM), and cytopathologist (CP) concordance. Methods 93 thyroid FNAs previously diagnosed as FLUS or HLUS from January 1, 2013 to December 31, 2014 with subsequent surgical resection were identified. Four CPs reclassified these cases using TBSRTC AUS subcategories of follicular cells with architectural and/or cytologic atypia, predominantly Hurthle cells, and atypical lymphocytes. RON and ROM were calculated for each diagnostic subcategory for each CP. Results The original RON and ROM for FLUS cases were 31.4% and 15.1% and were 77.8% and 22.2% for HLUS cases. 10.8% of cases showed diagnostic concordance amongst the four CPs. The most frequently utilized subcategory was architectural atypia. RON ranges for architectural atypia, cytologic atypia, architectural and cytologic atypia, and predominantly Hurthle cells were 28.1% to 35.7%, 0% to 33.3%, 35.3% to 66.7%, and 57.1% to 87.5%. The range of ROM was 13.9% to 16.7%, 0% to 33%, 0% to 42.9%, and 0% to 25%, respectively. Conclusion RON for AUS predominantly Hurthle cells subcategory was higher than previously reported, which may indicate use for tailored patient management pathways. AUS subclassification can result in significant interobserver variability. Therefore, institutions may consider consensus/quality control sessions to optimize diagnostic concordance.

Introduction Low-grade squamous intraepithelial lesion (LSIL) Papanicolaou test is associated with moderate risk of high-grade squamous intraepithelial lesion (HSIL) at colposcopic biopsy. High-risk human papillomavirus (hrHPV) cotesting risk stratifies patients with LSIL Papanicolaou test, with higher rates of HSIL for those hrHPV+. hrHPV genotyping is not considered in current LSIL management algorithms. Materials and methods We performed a 2-year retrospective review of LSIL Papanicolaou tests in patients 25 to 65 years old to assess rates of follow-up and HSIL at biopsy. Patient age, hrHPV cotest and genotype results, prior screening results, and follow-up testing for 3 years were recorded. Results A total of 71.5% (376 of 526) of patients had at least 1 follow-up colposcopic biopsy; 18% had HSIL on follow-up, including 20% of hrHPV+ and 12% of hrHPV−. HSIL at biopsy was most common when HPV16/18 was present (32%) and when multiple subtypes were detected (46%) versus when non-16, non-18 hrHPV alone was present (16%) or hrHPV was negative (12%). Of those hrHPV−, 5 of 22 (23%) with a prior screening abnormality had HSIL versus 1 of 27 (4%) for those without prior abnormalities. Follow-up occurred more commonly for hrHPV+ cotests (82%) than hrHPV− cotests (54%). No differences in follow-up rate based on hrHPV genotyping was seen. Conclusions The highest HSIL rates were seen when HPV16/18 was present (32%). HSIL rates were similar for those hrHPV− (12%) and non-16, non-18 hrHPV+ (16%). Follow-up was more common for those hrHPV+, but genotype results did not impact follow-up rates. Past screening results may impact risk of HSIL for hrHPV− cases.

Background Delayed autologous breast reconstruction is commonly recommended in patients requiring postmastectomy radiation. This study examines gross and histologic changes in the breast skin of patients who have undergone postmastectomy radiation to help determine when radiation-induced skin changes begin to stabilize. Methods A prospective pilot study was conducted on eight patients with invasive breast cancer who required mastectomy and radiotherapy. At the time of mastectomy and 2, 4, 6, 8, and 12 months after completion of radiotherapy, a punch biopsy was taken from the radiated mastectomy skin of each patient. Serial standardized photographs were taken before and after radiotherapy to evaluate the degree of hyperpigmentation and graded by three blinded plastic surgeons. Skin biopsies were processed for histologic assessment of inflammation, elastin organization, and vascularity. Results Grading of patient photographs revealed an increase in hyperpigmentation after radiotherapy compared with baseline with a gradual improvement over time. SMAD3 immunostaining demonstrated a trend toward an increase in inflammation over 12 months. The elastin distribution within samples showed an increase in fiber disorganization, thickening, and clumping, with no improvement throughout the study period. The average number of vessels per high powered field decreased steadily through the duration of the study. Conclusion Histologic changes in dermal inflammation, elastin organization, and vascularity do not appear to correspond with the gradual improvement of hyperpigmentation, resulting from postmastectomy radiation. These histologic changes persist beyond the 12 month observation period and will require clinical correlation to determine the potential impact on postoperative outcomes.

Metastases to the thyroid are uncommon [

Objectives To determine the frequency of estrogen receptor (ER), progesterone receptor (PR), and HER-2/ neu (HER2) testing multiple foci of ipsilateral invasive breast carcinoma at our institution and to evaluate resulting change in treatment recommendation. Methods We identified 165 consecutive cases of multifocal invasive breast cancer over a 10-year period (2005–2014). Clinicopathologic features and treatment recommendation were assessed by slide and chart review. Results Seventy (42.4%) of 165 patients had two or more foci tested. In the first 6 years (2005–2010), frequency of testing two or more foci was 31.6% and increased to 70.6% in 2014. Seven (10%) of 70 had a clinically significant difference in ER/PR and/or HER2 status, five (7.1%) with a difference in HER2, one (1.4%) in ER/PR, and one (1.4%) in both ER/PR and HER2. All cases with difference in status had different histology and/or the largest focus was the most positive one. Conclusions Our findings support current recommendations to evaluate additional smaller tumor foci in multifocal invasive breast cancer if the focus is of different grade or histology. Additional features, including specific histology, grade, and ER, PR, and HER2 status of the largest focus, should also be considered when selecting cases for which testing of additional foci may be of benefit.

Metastatic lesions in the pancreas are very uncommon and may be difficult to differentiate from the more commonly encountered primary neoplasms derived from the exocrine and endocrine pancreas because of the significant overlap in clinical presentation, imaging, and cytologic features. Metastasis to the pancreas may occur years after treatment of the primary neoplasm and is often not considered on initial evaluation because of the rarity of such events. The possibility of a metastasis to the pancreas should be entertained in patients with any prior history of malignancy because a proper diagnosis is essential in identifying surgical candidates, or avoiding potentially unnecessary surgery and facilitating triage to more appropriate nonoperative therapy. Herein, we describe intrapancreatic metastases secondary to renal cell carcinoma, melanoma, and lung carcinoma, as documented by cytologic examination of endoscopic ultrasound-guided fine-needle aspiration of the pancreatic masses.

BACKGROUND It is not uncommon to encounter challenges in the immunohistochemical confirmation of metastatic breast cancer given the limited sensitivities of mammaglobin and gross cystic disease fluid protein 15 (GCDFP-15/BRST-2) and the significant proportion of triple-negative breast carcinomas (ie, tumors that are negative for estrogen receptor [ER], and progesterone receptor [PgR], and human epidermal growth factor 2 [HER2]). GATA binding protein 3 (GATA3) has emerged as a potentially useful immunohistochemical adjunct during the evaluation of metastatic breast carcinomas in cytology specimens. The objective of the current study was to examine GATA3 expression in the context of malignant effusions secondary to both mammary and extramammary malignancies. METHODS In total, 306 malignant effusions (from 62 metastatic breast carcinomas and 244 extramammary malignancies) were examined using GATA3 immunohistochemistry. Effusions with metastatic breast carcinoma were also examined using immunohistochemistry for additional breast markers (ER, PgR, HER2, mammaglobin, and GCDFP-15/BRST-2). RESULTS GATA3 immunohistochemistry highlighted the tumor cells in 58 of the 62 samples (93.5%) from patients with metastatic breast carcinoma, which was higher than the observed sensitivity of immunohistochemistry for ER (63.8%), PgR (41.4%), HER2 (15.5%), mammaglobin (22.4%), and GCDFP-15/BRST-2 (5.2%). GATA3 expression also was observed in a subset of malignant effusions secondary to extramammary primaries, specifically, in 28 of 244 specimens (11.5%). CONCLUSIONS GATA3 is a highly sensitive marker for the detection of metastatic breast carcinomas in effusion specimens. However, this marker is not entirely specific for malignancies of breast origin. Thus, GATA3 should be used in conjunction with additional immunohistochemical markers during the cytologic evaluation of malignant effusions. Cancer (Cancer Cytopathol) 2015;123:576-81. © 2015 American Cancer Society.

Introduction Fine-needle aspirations (FNAs) of palpable masses are often performed by cytopathologists without ultrasound (US) guidance. Nonetheless, variations in the actual depth of palpable masses lead to occasional challenges. US guidance allows cytopathologists to visualize the mass and guide needle placement. This study retrospectively addressed the utility of US by comparing FNAs performed by cytopathologists on palpable masses with and without US guidance. Materials and methods Cytopathologist-performed FNAs with and without US guidance from March 1, 2013 to July 1, 2014 were identified. The number of passes, location of lesions, and interpretations were recorded. Available slides were reviewed to determine the proportion of passes that contained diagnostic cellular material and cases in which diagnostic material was present on the first needle pass. Results In this study, 134 palpation-guided FNAs and 118 US-guided FNAs were analyzed. The percentage of nondiagnostic cases was significantly lower for US-guided FNAs (2.5%) than for palpation-guided FNAs (12.7%; P = 0.004). The average number of needle passes was significantly lower for US-guided FNAs (2.9) than for palpation-guided FNAs (3.6; P = 0.0002). Twenty-two of 118 of US-guided FNAs (18.6%) and 6 of 134 palpation-guided FNAs (4.5%) were completed after only a single pass ( P = 0.0008). The percentage of passes with diagnostic material was significantly higher for US-guided FNAs (73.6% versus 60%; P = 0.0002). Conclusions For palpable masses, US-guidance adds value to cytopathologists in obtaining diagnostic cellular material more often on the first pass and with fewer passes overall than by palpation alone. This has a potentially beneficial impact on patient care owing to the increased precision and accuracy of needle guidance with ultrasonography.

Objective: Malignant effusions due to papillary thyroid carcinoma (PTC) are rare, but portend a poor prognosis. PTC metastases, although rare, most frequently occur in the lungs and bone. Therefore, differentiating thyroid etiology of malignant effusions from other sites becomes clinically significant in patient management. This study examines morphologic and immunocytochemical findings in 5 cases of malignant effusions with PTC involvement. Study Design: The electronic database at the University of Michigan was searched from January 1, 1995 to December 31, 2014 for malignant pleural effusions with PTC involvement. Clinicopathologic data were obtained from electronic medical records. Cytologic slides were reviewed. Results: Five cases of malignant effusions due to PTC were identified. Characteristic cytologic features of PTC, including ovoid nuclei, irregular nuclear contours, and psammomatous calcifications, were seen. However, the predominant cytologic feature observed was moderate amounts of delicate to vacuolated cytoplasm within the tumor cells. A review of immunocytochemistry demonstrated that all 5 cases showed patchy to diffuse TTF-1 positivity and diffuse positivity for Pax-8. Thyroglobulin only showed focal to patchy positivity in 3 of 5 cases. Conclusion: Given the morphologic features found in our case series, an immunocytochemical workup for the evaluation of involvement of an effusion by a thyroid primary is crucial for accurate diagnosis and appropriate clinical treatment.

Background Breast cancer has the highest incidence in women of all cancers and its burden is expected to continue to increase worldwide, especially in middle-income countries such as Thailand. The southern region of Thailand is unique in that it is comprised of 30% Muslims, whereas the rest of Thailand is 95% Buddhist. Breast cancer incidence and survival differ between these religious groups, but the association between clinical subtype of breast cancer and survival has not yet been assessed. Methods Here we characterized differences in breast cancer survival with consideration to clinical subtype by religious group (Muslim Thai and Buddhist Thai women). We compared distributions of age, stage and clinical subtype and assessed overall survival by religion. Results Our findings show that Muslim Thai women with breast cancer are diagnosed at a younger age, at later stages and have shorter overall survival times compared to Buddhist Thai women with breast cancer. We also observe a higher proportion of triple negative tumors characterized in Muslim Thai women. Conclusions Our findings confirm previous studies that have shown lower survival rates in Muslim Thai women compared to Buddhist women with breast cancer and offer novel information on subtype distribution. To date, this is the first study assessing clinical subtypes in southern Thailand by religious status. Impact Our findings are critical in providing information on the role of clinical subtype in cancer disparities and provide evidence from the Southeast Asian region for global studies on breast cancer survival.

Background Noninvasive encapsulated follicular variant of papillary thyroid carcinoma (PTC) has recently been reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Implementation of the new terminology may alter the implied risk of malignancy (ROM) across the six categories of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). Methods The study cohort consisted of thyroid fine needle aspiration (FNA) cases which were assessed between January 2011 and June 2016 and led to surgical resections. For each case, patient demographics as well as cytologic and corresponding histologic diagnoses were recorded. The surgical specimens diagnosed as follicular variant of PTC (FVPTC) were re-reviewed to identify cases that met the diagnostic criteria for NIFTP. The ROM with and without exclusion of NIFTP from malignant categorization, as well as the relative change in ROM were calculated for individual categories of TBSRTC. Results A total of 908 FNA cases with surgical follow-up were retrieved and PTC was identified in 252 (27.8%) surgical specimens. Twenty-nine of 252 (11.5%) were initially classified as FVPTC, of which 17 (6.7%) were reclassified as NIFTP. The cytologic interpretations for the majority of NIFTP cases were atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS, n = 8) or follicular neoplasm/suspicious for neoplasm/(FN/SFN, n = 4). Excluding NIFTP from malignant categorization resulted in a relative decrease in ROM in AUS/FLUS (25.8%) and FN/SFN (22.3%) categories. Conclusion Our institutional data demonstrates that eliminating NIFTP from malignant categorization may result in a reduction of the implied ROM for AUS/FLUS and FN/SFN categories.

Women with African ancestry in western, sub-Saharan Africa and in the United States represent a population subset facing an increased risk of being diagnosed with biologically aggressive phenotypes of breast cancer that are negative for the estrogen receptor, the progesterone receptor, and the HER2/neu marker. These tumors are commonly referred to as triple-negative breast cancer. Disparities in breast cancer incidence and outcome related to racial or ethnic identity motivated the establishment of the International Breast Registry, on the basis of partnerships between the Komfo Anokye Teaching Hospital in Kumasi, Ghana, the University of Michigan Comprehensive Cancer Center in Ann Arbor, Michigan, and the Henry Ford Health System in Detroit, Michigan. This research collaborative has featured educational training programs as well as scientific investigations related to the comparative biology of breast cancer in Ghanaian African, African American, and white/European American patients. Currently, the International Breast Registry has expanded to include African American patients throughout the United States by partnering with the Sisters Network (a national African American breast cancer survivors’ organization) and additional sites in Ghana (representing West Africa) as well as Ethiopia (representing East Africa). Its activities are now coordinated through the Henry Ford Health System International Center for the Study of Breast Cancer Subtypes. Herein, we review the history and results of this international program at its 10-year anniversary.

Context.—Intradepartmental consultation is a routine practice commonly used for new diagnoses. Expert interinstitutional case review provides insight into particularly challenging cases.Objective.—To investigate the practice of breast pathology consultation at a large tertiary care center.Design.—We reviewed breast pathology cases sent for private consultation and internal cases reviewed by multiple pathologists at a tertiary center. Requisitions and reports were evaluated for diagnostic reason for consultation, rate of multiple pathologist review at the tertiary center, use of immunohistochemistry, and, for private consultation cases, type of sender and concordance with the outside diagnosis.Results.—In the 985 private consultation cases, the most frequent reasons for review were borderline atypia (292 of 878; 33.3%), papillary lesion classification (151 of 878; 17.2%), evaluating invasion (123 of 878; 14%), subtyping carcinoma (75 of 878; 8.5%), and spindle cell (67 of 878; 7.6%) and fibroepithelial (65 of 878; 7.4%) lesion classification. Of 4981 consecutive internal cases, 358 (7.2%) were reviewed, most frequently for borderline atypia (90 of 358; 25.1%), subtyping carcinoma (63 of 358; 17.6%), staging/prognostic features (59 of 358; 16.5%), fibroepithelial lesion classification (45 of 358; 12.6%), evaluating invasion (37 of 358; 10.3%), and papillary (20 of 358; 5.6%) and spindle cell (18 of 358; 5.0%) lesion classification. Of all internal cases, those with a final diagnosis of atypia had a significantly higher rate of review (58 of 241; 24.1%) than those with benign (119 of 2933; 4.1%) or carcinoma (182 of 1807; 10.1%) diagnoses. Immunohistochemistry aided in diagnosis of 39.7% (391 of 985) and 21.2% (76 of 359) of consultation and internally reviewed cases, respectively.Conclusions.—This study confirms areas of breast pathology that represent diagnostic challenge and supports that pathologists are appropriately using expert consultation.

Endoscopic ultrasound-guided fine-needle aspiration and bile duct brushings are utilized in the cytologic evaluation of solid and cystic pancreaticobiliary tract lesions. We sought to determine the diagnostic accuracy of cytology.Five hundred seventy-nine pancreatic resections with 727 corresponding cytology specimens were identified from 1997 to 2012. Histologic diagnoses included benign, carcinoma, pancreatic endocrine neoplasm (PEN), nonepithelial neoplasms, cystic neoplasms, and ampullary adenomas. Standard interpretative categories-nondiagnostic, negative, atypical, suspicious, and positive--were utilized for preoperative cytology specimens.For solid masses, the sensitivity and specificity of positive fine-needle aspiration (FNA) cytology for detecting carcinoma were 74 and 100 %, respectively. FNAs performed better than brushings (sensitivity, 40 %; specificity, 98 %) in detecting carcinomas. Similar findings were seen for PENs and nonepithelial neoplasms. For cystic lesions, the sensitivity of FNA for predicting malignancy was lower (24 %) with a specificity of 97 %. Sequentially combining suspicious and atypical categories with the positive category resulted in increases in sensitivity and decreases in specificity for all cases except for cystic lesions.Cytology adds to the assessment of solid masses, but its utility in cystic lesions is less clear. Consideration of a suspicious cytologic interpretation as a positive diagnosis for triaging patients to surgery is supported by our study.

Spindle cell lesions of the gastrointestinal tract are relatively uncommon compared with the frequency of their epithelial counterparts. Although gastrointestinal stromal tumors and leiomyomas are the most commonly encountered spindle cell lesions in the stomach and esophagus, respectively, there are other less common diagnostic entities that should be considered for accurate diagnoses as well as appropriate patient treatment and clinical follow-up. Given the morphologic overlap of low-grade spindle cell lesions on cytologic preparations, ancillary studies play a key role in differentiating these lesions from one another.

The cytologic diagnosis of synovial sarcoma (SS) can be difficult when it occurs in unusual locations, atypical age groups, and/or have unusual morphology. We report a case of primary mediastinal SS in a 65-year-old male with a long smoking history who presented with increasing shortness of breath and was found to have a 14.2 cm mediastinal mass. Smears from the endobronchial ultrasound guided fine needle aspiration of the mass were moderately cellular consisting of loosely cohesive clusters, some of which demonstrated nuclear molding, and dispersed single cells. The relatively uniform tumor cells had a high nuclear-to-cytoplasmic ratio, finely granular chromatin, and inconspicuous nucleoli. Some of the single cells had spindled morphology with unipolar wispy tails and naked nuclei. Based on the clinical presentation and the cytomorphologic features, our initial differential diagnoses included atypical carcinoid, small cell carcinoma, basaloid squamous cell carcinoma, sarcoma, and lymphoma. Immunohistochemical studies on the cell block sections revealed that the tumor cells were focally positive for cytokeratin and diffusely positive for CD56, while negative for CD45, synaptophysin and chromogranin. Ultimately, an immunohistochemical stain for TLE-1 demonstrated diffusely strong nuclear positivity and molecular studies showed the presence of the t(X; 18) SYT/SSX1 translocation confirming the diagnosis of SS. In this report, we describe the cytomorphologic features of SS, its diagnostic pitfalls, and potential mimics in the mediastinum.

BACKGROUND: Breast cancers that are negative for the estrogen receptor (ER), the progesterone receptor (PR), and the HER2 (human epidermal growth factor receptor 2) marker are more prevalent among African women, and the biologically aggressive nature of these triple-negative breast cancers (TNBCs) may be attributed to their mammary stem cell features. Little is known about expression of the mammary stem cell marker aldehyde dehydrogenase 1 (ALDH1) in African women. Novel data are reported regarding ALDH1 expression in benign and cancerous breast tissue of Ghanaian women. METHODS: Formalin-fixed, paraffin-embedded specimens were transported from the Komfo Anoyke Teaching Hospital in Kumasi, Ghana to the University of Michigan for centralized histopathology study. Expression of ER, PR, HER2, and ALDH1 was assessed by immunohistochemistry. ALDH1 staining was further characterized by its presence in stromal versus epithelial and/or tumor components of tissue. RESULTS: A total of 173 women contributed to this study: 69 with benign breast conditions, mean age 24 years, and 104 with breast cancer, mean age 49 years. The proportion of benign breast conditions expressing stromal ALDH1 (n = 40, 58%) was significantly higher than those with cancer (n = 44, 42.3%) (P = .043). Among the cancers, TNBC had the highest prevalence of ALDH1 expression, either in stroma or in epithelial cells. More than 2-fold higher likelihood of ALDH1 expression was observed in TNBC cases compared with other breast cancer subtypes (odds ratio = 2.38, 95% confidence interval 1.03-5.52, P = .042). CONCLUSIONS: ALDH1 expression was higher in stromal components of benign compared with cancerous lesions. Of the ER-, PR-, and HER2-defined subtypes of breast cancer, expression of ALDH1 was highest in TNBC. Cancer 2013. © 2012 American Cancer Society.

Objective: Thailand is undergoing a period of rapid economic growth, which has led to an epidemiologic transition from infectious to chronic diseases such as cancer. Preliminary research shows a difference in rates of breast cancer incidence and mortality between Buddhist and Muslim women in southern Thailand. This study examines differences in breast cancer and potential explanations for this disparity. Methods: Demographic, diagnostic, and outcome data from breast cancer patients diagnosed from 2001-2015 were collected from a population-based cancer registry in southern Thailand and matched with formalin-fixed paraffin-embedded blocks from Songklanagarind Hospital. This region was selected due to the relatively high proportion of Muslim women. Of 424 cases selected, 369 were Buddhist and 55 were Muslim. Formalin-fixed paraffin-embedded blocks were sent to Michigan Medicine and histological and subtype analyses were performed by two pathologists. Statistical analysis was performed in RStudio using chi-square tests of independence, logistic regression, and Cox proportional hazards models. Results: Muslim women were generally diagnosed at a younger age than Buddhist women (Muslim mean: 46.6 years, Buddhist mean: 52.7 years) and with later stage cancers (Muslim: 36% stage 3 and 14% stage 4, Buddhist: 20% stage 3 and 8% stage 4). Buddhist and Muslim women had similar distributions of Luminal A and B subtypes, but Muslim women were more likely to be diagnosed with Triple Negative breast cancer (Muslim: 30%, Buddhist: 18%), the histological subtype with the worst prognosis. Invasive ductal carcinoma was most common in both groups, but Buddhists had more heterogeneity in subtypes. There were no significant differences in tumor histology or subtype by religion. Conclusions: These analyses show differences in the distribution of breast cancer between Buddhist and Muslim women. Muslim women are diagnosed younger with later stage breast cancers, and with histological differences, which generally lead to lower survival rates. Lack of statistical significance may be due to small sample size, necessitating further studies. Citation Format: Kali Defever, Katie M. Rentschler, Ana Khazan, Elizabeth Pinkerton, Shama Virani, Hutcha Sriplung, Judy Pang, Celina G. Kleer, Carlos F. Mendes de Leon, Justin A. Colacino, Laura S. Rozek. Breast cancer distribution and survival among Buddhist and Muslim women in southern Thailand [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4219.

Metastases to the thyroid are uncommon [0.2% of thyroid fine needle aspirations (FNA)]. Of metastases to the thyroid, breast carcinoma is relatively common. The diagnosis of metastasis to the thyroid has important therapeutic and prognostic implications. To our knowledge, a morphologic and immunophenotypic comparison of metastatic ductal carcinoma of the breast and primary thyroid carcinomas has not been reported. Here, we report the case of a 37-year-old female with a history of metastatic ductal carcinoma of the breast (modified Bloom-Richardson grade 2; ER+, PgR+, HER2+) diagnosed 6 years prior. She developed hoarseness, prompting a CT scan. Multiple thyroid nodules were found, including a 1.5 cm hypoechoic, solid, irregularly-shaped nodule. On FNA, cells were arranged singly and in crowded groups, varied in size and degree of pleomorphism, and exhibited rare nuclear grooves, inconspicuous nucleoli, and rare intracytoplasmic lumina with no nuclear pseudoinclusions or colloid (Figs. 1A and B). These findings raised the differential of papillary thyroid carcinoma (Fig. 1C), follicular neoplasm (Fig. 1D), medullary carcinoma (Fig. 1E), parathyroid (Fig. 1F), and metastatic breast carcinoma. Immunostaining for GATA-3 (+), ER (+), PAX-8 (-), and TTF-1 (-) was consistent with metastatic breast carcinoma (Fig. 2). We conclude that metastatic breast carcinoma to the thyroid may morphologically mimic primary thyroid carcinoma on FNA; a panel of immunomarkers, such as GATA-3, hormonal marker(s), PAX-8, and TTF-1, may be useful in some cases. GATA-3 immunostaining for metastatic breast carcinoma was helpful in our case and has not been previously reported in a thyroid metastasis sampled by FNA. Diagn. Cytopathol. 2016;44:530-534. © 2016 Wiley Periodicals, Inc.

Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has become a preferred technique to evaluate pancreatic masses. The clinical management of a “suspicious for adenocarcinoma” cytological diagnosis is unclear in unresectable cases. We sought to determine whether a suspicious diagnosis in the setting of a high clinical suspicion of malignancy could be sufficient for initiating non-operative therapy, such as chemotherapy, in unresectable patients. Twenty-nine solid pancreatic mass cytology specimens obtained by EUS-FNA with a diagnosis of suspicious for adenocarcinoma were identified from 2000 to 2012. Pathology, clinical, and radiologic data were analyzed. Additional procedures were performed in 21 of the 29 patients. Sixteen of the 21 patients had confirmation of malignancy on further tissue sampling and an additional 2 had confirmed unresectable cancers during surgical exploration. Three of the 21 patients had benign diagnoses on subsequent tissue sampling. Of the remaining eight patients who did not undergo additional diagnostic procedures, six were deemed clinically malignant and treated, one died within a year of the EUS-FNA, and one was lost to follow-up. Consideration of a suspicious diagnosis on EUS-FNA of solid pancreatic masses as sufficient for initiating non-operative therapy is reasonable in the setting of a high clinical suspicion of malignancy.

When some patients with circumferential truncal excess undergo traditional abdominoplasty, the trunk is not addressed as a unit. Belt lipectomy, a procedure that combines abdominoplasty with circumferential excision of skin and fat, is often more ideal for these patients. In this article, the authors review the literature on belt lipectomy and evaluate their series of 32 patients who underwent belt lipectomy at the University of Iowa. The evolution and current preoperative markings, intraoperative surgical technique, and postoperative care are described. The patients' charts and their preoperative and postoperative photographs were examined retrospectively. It was found that belt lipectomy improved abdominal contour, abdominal wall laxity, mons pubis ptosis, back rolls, waist contour, and buttocks contour. Initially, the procedure was performed on post-weight-reduction patients only, but its indications were extended to three other groups: patients who were 30 to 50 pounds overweight, patients of normal weight who desired a significant overall truncal improvement, and an obese patient with persistent intraabdominal excess. The improvements were significant in all groups of patients except for the latter patient. Complications included a 37.5 percent seroma rate, a 9.3 percent pulmonary embolus rate, and one dehiscence that required reoperation. The authors concluded that belt lipectomy should be seriously considered for patients who present with circumferential truncal excess and for a select group of normal-weight patients. It is not recommended for the obese patient with excessive intraabdominal content. Furthermore, belt lipectomy should be undertaken only in patients who are well informed about the possible risks and complications.

Aims The aim of this study was to examine clinicopathological features of patients with core biopsy diagnoses of ductal carcinoma in situ (DCIS) that may predict invasion on subsequent excision, as upstaging has significant implications regarding the need for axillary staging via sentinel lymph node biopsy (SLNB). Methods and results We identified 186 patients with a diagnosis of DCIS as the highest-stage lesion on core biopsy. Pathological and clinical features were assessed via slide and chart review, respectively. Distorting sclerosis was defined as irregular angulation of glands involved by DCIS but lacking definite invasion according to histology and/or immunohistochemical staining for myoepithelial markers. Thirty-two of 186 (17.2%) cases had upstaging to either microinvasive (nine) or invasive (23) ductal carcinoma. SLNB was performed in 29 of 32 (90.6%) cases with upstaging and in 55 of 154 (35.7%) cases without (P

Invasive breast carcinomas are heterogeneous and exhibit distinct molecular features and biological behavior. Understanding the underlying molecular events that promote breast cancer progression is necessary to improve treatment and prognostication. TGF-β receptor III (TBR3) is a member of the TGF-β signaling pathway, with functions in cell proliferation and migration in malignancies, including breast cancer. Recent studies propose that TBR3 may function as a tumor suppressor and that its loss may correlate with disease progression. However, there are limited data on the expression of TBR3 in breast cancer in relationship to tumor type, hormonal receptor status and HER-2/neu, and patient outcome. In this study, we investigated the expression of TBR3 in a cohort of 205 primary invasive breast carcinomas in tissue microarrays (TMAs), with comprehensive clinical, pathological and follow- up information. Sections were stained for TBR3 and evaluated for intensity of reactivity based on a 4-tiered scoring system (1 to 4; TBR3 low = scores 1–2; TBR3 high = scores 3–4). Of the 205 invasive carcinomas, 123 were luminal type (95 type A, 28 type B), 8 were HER-2 type, and 62 were triple negative (TN). TBR3 was high in 112 (55 %) and low in 93 (45 %) cases. Low TBR3 was associated with higher histological grade and worse disease free and overall survival, all features of biologically aggressive breast carcinomas. TBR3 was significantly associated with the subtype of breast cancer, as low TBR3 was detected in 95 % of TN compared to 22 % of luminal tumors (p

The natural history of pancreatic neuroendocrine tumors (panNETs) is extremely variable. One of the most controversial problems in diagnosis is the accurate prediction of the clinical behavior of these tumors. PanNETs that behave aggressively with a malignant course may have bland cytologic features, while some tumors with previously described "malignant" features may behave in a benign or indolent fashion. Various classification schemes have been proposed for grading panNETs. The European Neuroendocrine Tumor Society (ENETS) and 2010 World Health Organization (WHO) classification schemes include counting the mitotic index and/or the Ki-67 proliferation index for grading. The current study was undertaken to determine whether tumors sampled by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) can be accurately graded based on the Ki-67 index when compared to surgical samples.Corresponding EUS-FNA cytology and surgical tissue specimens were obtained for 22 tumors and stained for hematoxylin and eosin (HE) and the Ki-67 proliferation marker (MIB-1 antibody). Samples were graded by scoring Ki-67 staining indices in accordance with the 2010 ENETS/WHO criteria. The grading scores assigned to the EUS-FNA cytology samples were compared with the scores assigned to the corresponding histological samples.The majority (86%) of EUS-FNA cytology samples and corresponding surgical tissue specimens demonstrated concordant grading based on Ki-67 indices.These results indicate that EUS-FNA cytology samples can be accurately graded based on the WHO Ki-67 labeling scheme. Thus, Ki-67 scoring in EUS-FNA cytology samples is an alternative approach for establishing the grade of panNETs. Accurate grading of panNETs is critical for predicting tumor biology, patient prognosis, and making informed decisions regarding patient management and treatment.

Objective:It has been demonstrated in a number of models that fetal wounds heal with little or no scar. Since collagen is an integral part of the extracellular matrix in adult scar formation, we studied the synthesis and localization of collagen in an in vitro mouse palate model for fetal wound healing.Methods:Palates, dissected from fetal mice at 15, 16, and 17 days of gestation and from newborn mice, were cultured in medium containing serum (for 8 hours); this was followed by culture in serum-free medium (for 12 hours). One-half of the samples from each age group were wounded in the midline. All samples were placed in serum-free medium containing 20 μCl/mL3H-proline for 8 hours. In addition, palates from 15-day gestation and from newborn mice were also incubated with transforming growth factor TGFβ2(10 ng/mL). Palates were washed with saline, homogenized, and radioactivity was counted. Proline uptake was calculated for each sample as counts per milligram of protein and was subjected to statistical analysis (three-way analysis of variance). Samples of the homogenate were subjected to sodium dodecyl sulfate-gel electrophoresis and Western blotting in order to determine the types of collagen that were synthesized. Immunohistochemical localization of collagen types I, III, and VI was carried out on paraffin-embedded samples from each group.Results:There were no significant differences in proline uptake between wounded mouse palates and nonwounded mouse palates at any age, and there was no histological evidence of regeneration of the palate at the site of the wound. Proline uptake was significantly greater in untreated wounded palates at 15 days’ gestation than it was in newborns. After treatment with TGFβ2, proline uptake was significantly greater in both wounded and nonwounded palates in the newborn group and had no effect on collagen synthesis in palates from 15-day gestation animals. Collagen types I and III were localized in histological specimens using immunohistochemistry and on nitrocellulose using Western blotting. No type VI collagen was demonstrated by Western blotting, but it was localized around blood vessels and on basement membranes using immunohistochemistry.Conclusion:Treatment with TGFβ2significantly increased collagen synthesis, as assessed by3H-proline uptake, in cultured palates from newborn mice as compared with palates from untreated newborn mice and from both treated and untreated palates of 15-day gestation mice. These data suggest a differential response to TGFβ2by mouse palates as a function of fetal development.

Invasive ductal carcinoma with lobular features (IDC-L) is not recognized as a distinct subtype of breast cancer, and its clinicopathologic features and outcomes are unknown. In this retrospective study, we focused on characterization of clinicopathologic features and outcomes of IDC-L and compared them to invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC). 183 cases of IDC-L from 1996 to 2011 were compared with 1,499 cases of IDC and 375 cases of ILC. Available slides of IDC-L (n = 150) were reviewed to quantify the lobular component (≤20, 21–50, 51–80, >80 %), defined as small cells individually dispersed, arranged in linear cords, or in loose aggregates without the formation of tubules or cohesive nests. E-cadherin immunostain was performed to confirm ductal origin. Compared to IDC, IDC-L was more likely to have lower histologic grade (p < 0.001), be positive for estrogen receptor (96 vs. 70 %; p < 0.0001) and progesterone receptor (84 vs. 57 %; p < 0.0001), and less likely to overexpress HER-2/neu (12 vs. 23 %; p = 0.001). Despite these favorable prognostic features, IDC-L had a higher frequency of nodal metastases (51 vs. 34 %; p < 0.0001) and a worse 5-year disease-free survival than IDC (hazard ratio = 0.454; p = 0.0004). ILC and IDC-L had similar clinicopathologic features and outcomes. The proportion of the lobular component in IDC-L had no impact on the size, nodal status, stage, or outcome. Our data suggest that although IDC-L may be a variant of IDC, with >90 % of cases being E-cadherin positive, the clinical and biological characteristics are more similar to that of ILC.

High-voltage pulsing has previously been shown to dramatically increase molecular transport across skin. The goal of this study was to examine the functional dependence of transdermal transport on pulse parameters and to make comparisons with iontophoresis. Transdermal transport of calcein, a model drug, was measured during low-voltage, constant electric fields (iontophoresis) and high-voltage pulsed electric fields (hypothesized to cause electroporation). In the first part of the study, the dependence of calcein flux caused by high-voltage pulses was determined as a function of pulse length, rate, polarity, waveform, and total pulsing time. In the second part, calcein transport numbers were calculated for both iontophoresis and high-voltage pulsing, and expressed as functions of pulse parameters. For both iontophoresis and high-voltage pulsing, transport numbers (or transport efficiency) ranged from 10−5 to 10−2 and were functions of voltage and current, but did not show dependence on pulse length, rate, energy, waveform, or total charge transferred. The resulting estimates of the area fraction of skin available to transport were larger during high-voltage pulsing ( 10−3 for small ions and 10−6 to 10−3 for calcein) than during iontophoresis (10−5 to 10−4 for small ions and 10−8 to 10−4 for calcein).

The cytologic diagnosis of synovial sarcoma (SS) can be difficult when it occurs in unusual locations, atypical age groups, and/or have unusual morphology. We report a case of primary mediastinal SS in a 65-year-old male with a long smoking history who presented with increasing shortness of breath and was found to have a 14.2 cm mediastinal mass. Smears from the endobronchial ultrasound guided fine needle aspiration of the mass were moderately cellular consisting of loosely cohesive clusters, some of which demonstrated nuclear molding, and dispersed single cells. The relatively uniform tumor cells had a high nuclear-to-cytoplasmic ratio, finely granular chromatin, and inconspicuous nucleoli. Some of the single cells had spindled morphology with unipolar wispy tails and naked nuclei. Based on the clinical presentation and the cytomorphologic features, our initial differential diagnoses included atypical carcinoid, small cell carcinoma, basaloid squamous cell carcinoma, sarcoma, and lymphoma. Immunohistochemical studies on the cell block sections revealed that the tumor cells were focally positive for cytokeratin and diffusely positive for CD56, while negative for CD45, synaptophysin and chromogranin. Ultimately, an immunohistochemical stain for TLE-1 demonstrated diffusely strong nuclear positivity and molecular studies showed the presence of the t(X; 18) SYT/SSX1 translocation confirming the diagnosis of SS. In this report, we describe the cytomorphologic features of SS, its diagnostic pitfalls, and potential mimics in the mediastinum.

Breast cancer in African-American women has a worse outcome than in Caucasian women. The ancestors of most African-American women come from West Africa, including Ghana. The Polycomb group protein EZH2 is a marker of poor outcome in breast cancers from Caucasian women. The histopathological features and biomarker expression of African breast cancers remain obscure. Here, we investigated a cohort of Ghanaian breast cancers to better define the prevalent tumor types and to test if EZH2 protein may identify aggressive tumors. A group of 169 breast tissues (100 invasive carcinomas and 69 benign) from women treated at Komfo Anoyke Teaching Hospital between 2006 and 2011 were histologically classified and investigated for EZH2 expression. EZH2 nuclear expression we defined as high or low following previously published criteria. Of the 100 invasive carcinomas, 89 % were ductal, 2 % were lobular, and 9 % were metaplastic. Basal-like pathological features were present in 30 % of the tumors. Of the invasive carcinomas, 7 % were grade 1, 41 % grade 2, and 52 % grade 3. EZH2 protein was overexpressed in invasive carcinomas compared to benign breast (p < 0.0001). In invasive carcinomas nuclear EZH2 overexpression was significantly associated with basal-like subtype (p = 0.03) and high histologic grade (p < 0.05). Cytoplasmic EZH2, which has not been previously reported, was present in 16 % of invasive carcinomas and it was associated with triple negative status (p = 0.02). Our results provide the first comprehensive histopathological study of this patient population and uncover the association of EZH2 with high grade and basal-like tumors. We provide the basis for further detailed investigations on this cohort to advance diagnosis and treatment of African and African-American women.

BACKGROUND: The cytodiagnosis of melanoma in fine-needle aspiration (FNA) specimens can be challenging, often requiring the use of immunocytochemistry. As constitutively activating mutations in the BRAF oncogene are present in at least 40% of melanomas, the use of FNA material to interrogate the BRAF mutational status is likely to increase. Because cell blocks, traditionally used for these studies, can occasionally exhibit insufficient tumor cellularity, the authors investigated the utility of direct smears for immunocytochemistry and BRAF mutational analysis. METHODS: Immunocytochemistry for S-100, HMB-45, and Mart-1 was prospectively performed on direct smears in 17 FNAs of metastatic melanoma. Next, BRAF sequencing was performed using DNA isolated from archived Diff-Quik–stained direct smears for 15 cases. In parallel, sequencing was performed using DNA obtained from corresponding cell blocks. RESULTS: S-100 positivity in the tumor cells was observed in all 17 cases. HMB-45 and Mart-1 positivity was noted in 81% and 88% of cases, respectively. All 3 markers were positive in 76% of cases. Next, of the 15 archived melanoma FNAs tested, BRAF mutations were observed in 8 (53%); 5 and 3 melanomas harbored the V600E and V600K mutation, respectively. Corresponding cell blocks were also tested for all 15 cases, yielding concordant BRAF results in 14 (93%); 1 cell block yielded a false-negative result. CONCLUSIONS: Cytologic direct smears represent a robust and valuable source of cellular material for immunocytochemistry and molecular studies, especially in instances in which inadequate cell block cellularity is anticipated or encountered. Cancer (Cancer Cytopathol) 2012. © 2011 American Cancer Society.

Introduction: The oncogene RhoC GTPase is overexpressed in highly aggressive inflammatory breast cancer (IBC) and increases cellular motility and invasiveness in mammary tissue by interacting with downstream effectors to reorganize cytoskeletal elements in the cell. A small molecule inhibitor of RhoC-effector interaction has been identified. This antagonist decreases proliferation and inhibits motility of IBC cells in vitro. Here we evaluate the in vivo effects of the novel RhoC antagonist in a transgenic mouse model of breast cancer. Methods: The PyMT-RhoC transgenic mouse model was used in this study. This double transgenic strain was created by crossing the polyoma middle T antigen (PyMT) breast cancer model to a RhoC-overexpressing strain driven by the mouse mammary tumor virus (MMTV) promoter. The RhoC inhibitor was administered by intraperitoneal injection beginning at 50 days of age. Tumor size was monitored throughout treatment. At the end of the treatment, mammary glands, tumors, and lungs were extracted, fixed, sectioned, and stained with H&E. Results: PyMT-RhoC mice treated with the RhoC inhibitor showed a statistically significant delay in time of onset of the primary tumor and exhibited slower growth of the primary tumor compared to the control group. Western blot showed decreased RhoC protein levels in the treated PyMT-RhoC group relative to control, suggesting that the drug's in vivo activity includes reducing RhoC protein expression. Finally, as determined through H&E staining of lung sections, tumor metastasis to the lungs was decreased in the treated group compared to age-matched controls. Conclusions: We conclude that this novel RhoC antagonist shows promise in vivo as an inhibitor of mammary tumor proliferation and metastasis, and has the potential to be a clinically relevant treatment for inflammatory breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5622. doi:1538-7445.AM2012-5622