Women in Academic Pathology: Pathways to Department Chair.

The Association of Pathology Chairs, an organization of American and Canadian academic pathology departments, has a record percent of women department chairs in its ranks (31%), although still not representative of the percent of women pathology faculty (43%). These women chairs were surveyed to determine what had impeded and what had facilitated their academic advancement before becoming chairs. The 2 most frequently identified impediments to their career advancement were heavy clinical loads and the lack of time, training, and/or funding to pursue research. Related to the second impediment, only one respondent became chair of a department which was in a top 25 National Institutes of Health-sponsored research medical school. Eighty-nine percent of respondents said that they had experienced gender bias during their careers in pathology, and 31% identified gender bias as an important impediment to advancement. The top facilitator of career advancement before becoming chairs was a supportive family. Strikingly, 98% of respondents have a spouse or partner, 75% have children, and 38% had children younger than 18 when becoming chairs. Additional top facilitators were opportunities to attend national meetings and opportunities to participate in leadership. Previous leadership experiences included directing a clinical service, a residency training program, and/or a medical student education program. These results suggest important ways to increase the success of women in academic pathology and increasing the percent of women department chairs, including supporting a family life and providing time, encouragement and resources for research, attending national meetings, and taking on departmental leadership positions.

Pulmonary Langerhans Cell Histiocytosis.

Pulmonary Langerhans cell histiocytosis (PLCH) is a diffuse cystic lung disease that is strongly associated with exposure to cigarette smoke. Recently, activating pathogenic mutations in the mitogen-activated protein kinase pathway have been described in the dendritic cells in patients with PLCH and have firmly established PLCH to be an inflammatory myeloid neoplasm. Disease course and prognosis in PLCH are highly variable among individual patients, ranging from spontaneous resolution to development of pulmonary hypertension and progression to terminal respiratory failure. A subset of patients with PLCH may have extrapulmonary involvement, typically involving the skeletal system in the form of lytic lesions, skin lesions, or the central nervous system most commonly manifesting in the form of diabetes insipidus. Smoking cessation is the cornerstone of treatment in patients with PLCH and can lead to disease regression or stabilization in a substantial proportion of patients. Further insight into the underlying molecular pathogenesis of PLCH has paved the way for the future development of disease-specific biomarkers and targeted treatment options directed against the central disease-driving mutations.

The Association of Pathology Chairs' Pathology Leadership Academy: Experience From the First 2 Years.

Leadership development and succession planning are critical to ensure continued strength of academic pathology. The Association of Pathology Chairs developed the Pathology Leadership Academy to prepare future academic leaders. The purpose of this report is to describe: (1) Pathology Leadership Academy's development and curriculum, (2) how Pathology Leadership Academy has met leadership development needs for individuals and academic departments in its first 2 years, (3) Pathology Leadership Academy's future directions based on program feedback. Results were analyzed from pre- and postprogram needs assessment surveys of pathology chairs and from evaluations from Pathology Leadership Academy participants in the first 2 years. Pathology Leadership Academy curriculum was developed from topics identified as priorities in the chairs' survey. Twenty-eight (90%) of 31 responding participants were very satisfied/satisfied with Pathology Leadership Academy. Of the 18 responding chairs who sent a participant to Pathology Leadership Academy, 11 (61%) reported that Pathology Leadership Academy met their faculty development goal. Of all responding chairs, 13 (32%) of 41 reported uncertainty as to whether Pathology Leadership Academy is meeting chairs' goals. Chairs reported that Pathology Leadership Academy provided value to their faculty through preparation for a future leadership role, enhancing skills for a current role, and enhancing understanding of opportunities and challenges in academic medicine. Most chairs (27/43, 66%) said Pathology Leadership Academy should be offered again; 13 (32%) of 43 were uncertain, and 1 (2%) of 43 said no. Initial experience of Pathology Leadership Academy is positive and promising and provides opportunity for leadership succession planning in academic pathology. Pathology Leadership Academy will use participant and chair feedback for ongoing curricular development to ensure topics continue to address major needs of academic pathology.

The Pathology Workforce and Clinical Licensure: The Role of the PhD Clinical Laboratorian in the United States.

There has been a recent recognition of the need to prepare PhD-trained scientists for increasingly diverse careers in academia, industry, and health care. The PhD Data Task Force was formed to better understand the current state of PhD scientists in the clinical laboratory workforce and collect up-to-date information on the training and certification of these laboratorians. In this report, we summarize the findings of the PhD Data Task Force and discuss the relevance of the data collected to the future supply of and demand for PhD clinical laboratory scientists. It is clear that there are multiple career opportunities for PhD scientists in academic medical centers, commercial clinical laboratories, biotechnology and pharmaceutical companies, and the federal government. Certified PhD scientists have and will continue to form an important resource for our technologically advancing field, bringing training in scientific methods, and technologies needed for modern laboratory medicine. The data gathered by the PhD Data Task Force will be of great interest to current and future PhD candidates and graduate PhD scientists as they make decisions regarding future career directions.

Pneumonic-type mucinous lung adenocarcinoma diagnosed by transbronchial cryobiopsy.

Primary lung adenocarcinoma with lepidic growth can mimic diffuse pulmonary parenchymal processes like infectious pneumonia or idiopathic inflammatory pneumonitis. We report a case of subacute pneumonitis refractory to antibiotic therapy and empirical corticosteroids, proven to be diffuse mucinous adenocarcinoma with lepidic growth on transbronchial cryobiopsy.

Biologic Evaluation of Diabetes and Local Recurrence in Non-Small Cell Lung Cancer.

A recent multicenter study led by our institution demonstrated that local recurrence of non-small cell lung cancer (NSCLC) was significantly more frequent in patients with diabetes, raising the possibility of different tumor biology in diabetics. Epithelial-to-mesenchymal transition (EMT) plays a key role in local tumor recurrence and metastasis. In the present study, we investigated differences of tumor microenvironment between patients with and without diabetes by examining expression of EMT markers. Seventy-nine NSCLC patients were selected from the cohort of our early multicenter study. These patients were classified into 4 groups: 39 with adenocarcinoma with (n = 19) and without (n = 20) diabetes, and 40 with squamous cell carcinoma with (n = 20) and without (n = 20) diabetes. Immunohistochemical expression of eight EMT markers was analyzed, including transforming growth factor-beta (TGF-ß), epidermal growth factor receptor (EGFR), insulin-like growth factor 1 receptor (IGF-1R), vimentin, E-cadherin, N-cadherin, HtrA1, and beta-catenin. Five markers (E-cadherin, HtrA1, TGF-ß, IGF-1R and vimentin) demonstrated significantly higher expression in diabetics than in non-diabetics in both histology types. N-cadherin had higher expression in diabetics, though the difference did not reach statistical significance. EGFR showed a higher expression in diabetics in squamous cell carcinoma only. Beta-catenin was the only marker with no difference in expression between diabetics versus non-diabetics. Our findings suggest that diabetes is associated with enhanced EMT in NSCLC, which may contribute to growth and invasiveness of NSCLC.

Trends in extramural consultation: comparison between subspecialized and general surgical pathology service models.

Academic and community hospital pathology groups are increasingly adopting subspecialized service models for surgical pathology (SP) practice. Reasons cited include improvements in sign-out efficiency, quality and accuracy, enhancement of clinician-pathologist communications, and augmentation of resident training quality. However, there is a paucity of published quantitative data regarding the outcomes of transitioning from general to subspecialized SP service coverage. Retrospective assessment of the frequencies and outcomes of SP extramural consultations requested by faculty at our institution was performed, encompassing 2 consecutive years each of subspecialized and general SP service models. The frequencies of extramural consultations between the 2 practice models were not significantly different (0.25% vs 0.21%, P = .142). Although more pathology cases were sent out in gastrointestinal (0.29% vs 0.14%, P = .007), gynecologic (0.16% vs 0.02%, P = .009), and pulmonary (1.73% vs 0.28%, P = .008) services during the "subspecialization" era, fewer pediatric cases were sent out (0.48% vs 1.69%, P = .008). Importantly, the transition to the subspecialized model was associated with a marked reduction in the frequency of major disagreements between the original diagnosis and the consultant's diagnosis (1.8% vs 9.3%, P = .018). Our study supports the value of the subspecialized SP sign-out model for increasing diagnostic accuracy and enhancing the quality of patient care.

Assessment of cytotechnologist-cytopathologist interpretative agreement using the Bethesda system for reporting thyroid cytopathology.

BACKGROUND: The Bethesda system for reporting thyroid cytopathology was proposed to provide a clinically relevant framework for interpretations to improve interobserver agreement. Limited data is available regarding the level of interobserver agreement between groups of cytotechnologists (CTs) and cytopathologists (CPs) examining the same thyroid fine needle aspirate (FNA) samples. METHODS: Retrospective review of 1,229 thyroid FNAs from 976 patients between 03/2010 and 08/2012 was performed. FNAs received preliminary evaluation by a CT followed by final interpretation by a CP. We calculated Cohen's Kappa coefficient to measure agreement between CTs and CPs, and analyzed levels of discrepancy using delta analysis. RESULTS: Overall Kappa between CTs and CPs was 0.79 (95%CI: 0.76-0.83). Kappa values were higher for the nondiagnostic (0.89), benign (0.83), and malignant (0.91) categories than for other categories. Overall Kappa did not show a trend over time, and inversely correlated with the percentage of intermediate grade lesions (coefficient of -0.8; P < 0.01). CTs overcalled more cases (n = 71) than undercalled (n = 29) (P < 0.001), as compared to CPs, with a Δ1 ratio of 2.2 and Δ2 ratio of 3.5. Most two-level discrepancies were related to follicular lesions (19/21) (P = 0.0002). Differences in sample adequacy assessment occurred in 2% of cases. CONCLUSION: Overall, there was a high level of interpretative agreement between CTs and CPs, which remained stable over time, including judgments regarding specimen adequacy. Agreement was most robust for the benign and malignant categories. Our data supports the current practice of allowing CTs to perform on-site adequacy evaluation of thyroid FNAs.

Identification of stage I non-small cell lung cancer patients at high risk for local recurrence following sublobar resection.

OBJECTIVE: An increasing proportion of patients with stage I non-small cell lung cancer (NSCLC) is undergoing sublobar resection (L-). However, there is little information about the risks and correlates of local recurrence (LR) after such surgery, especially compared with patients undergoing lobectomy (L+). METHODS: Ninety-three and 318 consecutive patients with stage I NSCLC underwent L- and L+, respectively, from 2000 to 2006. Median follow-up was 34 months. RESULTS: In the L- group, the LR rates at 2, 3, and 5 years were 13%, 24%, and 40%, respectively. The risk of LR was significantly associated with tumor grade, tumor size, and T stage. The crude risk of LR was 33.8% (21 of 62) for patients whose tumors were grade ≥ 2. In the L+ group, the LR rates at 2, 3, and 5 years were 14%, 19%, and 24%, respectively. The risk of LR significantly increased with increasing tumor size, length of hospital stay, and the presence of diabetes. The L- group experienced a significant increase in failure in the bronchial stump/staple line compared with the L+ group (10% vs 3%; P = .04) and nonsignificant trends toward increased ipsilateral hilar and subcarinal failure rates. CONCLUSIONS: Patients with stage I NSCLC who undergo L- have an increased risk of LR compared with patients undergoing L+, particularly when they have tumors grade ≥ 2 or tumor size > 2 cm. If L- is considered, additional local therapy should be considered to reduce this risk of LR, especially with tumors grade ≥ 2 or size > 2 cm.

Immunohistochemistry: applications to the evaluation of lung and pleural neoplasms: part 1.

Immunohistochemistry has come to occupy a key position among the armamentarium of tools pathologists apply to the evaluation of lung and pleural neoplasms. This technique uses antibodies that bind to specific antigens, usually proteins, enabling microscopic detection of the antigens. Over the last several decades, an impressive array of antibodies has become commercially available, and many of these antibodies have become integrated into the routine practice of pathology. Evaluation of tissue or cytology samples with these antibodies can facilitate determination of tumor type and site of origin. Comments citing results of immunohistochemical staining with these antibodies frequently appear in pathology reports and may be difficult to translate for those less familiar with the technique. This review presents, in two parts, common diagnostic applications of immunohistochemistry, with information about strategies taken for frequently encountered differential diagnostic scenarios. This, the first of two parts, offers a basic overview of the technique and discusses its applications in the diagnosis of common primary lung carcinomas.

Immunohistochemistry: applications to the evaluation of lung and pleural neoplasms: part 2.

Immunohistochemistry has come to occupy a key position among the armamentarium of tools pathologists apply to the evaluation of lung and pleural neoplasms. This technique uses antibodies that bind to specific antigens, usually proteins, enabling microscopic detection of the antigens. Over the last several decades, an impressive array of antibodies has become commercially available, and many of these antibodies have become integrated into the routine practice of pathology. Evaluation of tissue or cytology samples with these antibodies can facilitate determination of tumor type and site of origin. Comments citing results of immunohistochemical staining with these antibodies frequently appear in pathology reports and may be difficult to translate for those less familiar with the technique. This review presents, in two parts, common diagnostic applications of immunohistochemistry with information about strategies taken for frequently encountered differential diagnostic scenarios. This article is the second of the two parts and focuses on immunohistochemical approaches to differentiating primary pulmonary from metastatic adenocarcinomas, mesotheliomas from carcinomas, and various types of spindle cell neoplasms. Potential future directions involving therapeutic and prognostic biomarkers are also discussed.

Causes of pulmonary granulomas: a retrospective study of 500 cases from seven countries.

BACKGROUND: The frequencies of various causes of pulmonary granulomas in pathological material are unknown, as is the influence of geographical location on aetiology. The aim of this study was to identify the causes of pulmonary granulomas in pathological specimens, to define their frequencies, and to determine whether these causes vary by geographical location. METHODS: 500 lung biopsies and resections containing granulomas were reviewed retrospectively by expert pulmonary pathologists from 10 institutions in seven countries. Fifty consecutive cases from each location were assigned a diagnosis based on histological features and available clinical/microbiological data. RESULTS: A specific cause was identified in 58% of cases (290/500), most commonly sarcoidosis (136, 27%) and mycobacterial or fungal infections (125, 25%). Mycobacteria were identified in 19% of cases outside the USA versus 8% within the USA. In contrast, fungi accounted for 19% cases in the USA versus 4% in other locations. Fungi were mostly detected by histology, whereas most mycobacteria were identified in cultures. In 42% of cases (210/500) an aetiology could not be determined. CONCLUSIONS: Across several geographical settings, sarcoidosis and infections are the most common causes of pulmonary granulomas diagnosed in pathological specimens. Fungi are more commonly identified than mycobacteria in the USA, whereas the reverse is true in other countries. A definite aetiology cannot be demonstrated in more than a third of all cases of pulmonary granulomas, even after histological examination. These findings highlight the need to submit material for histology as well as cultures in all cases in which granulomatous disease enters the differential diagnosis.

MiR-365 regulates lung cancer and developmental gene thyroid transcription factor 1.

Thyroid transcription factor 1 (TTF-1 or NKX2-1) is an essential fetal lung developmental factor, which can be recurrently activated by gene amplification in adult lung cancer. We have discovered the first microRNA (i.e., miR-365) that directly regulates TTF-1 by interacting with its 3'-untranslated region. By gene expression profiling, we identified other putative targets of miR-365 and miR-365*. In line with the microRNA/target relationship, the expression patterns of miR-365 and TTF-1 were in an inverse relationship in human lung cancer. Exploration of human lung cancer genomics data uncovered that TTF-1 gene amplification was significantly associated with DNA copy number loss at one of the two genomic loci encoding the precursor RNA of mature miR-365 (i.e., mir-365-1). This implies the existence of genetic selection pressure to lose the repressive miR-365 that would otherwise suppress amplified TTF-1. We detected a signaling loop between transforming growth factor beta (TGFb) and miR-365 and this loop reinforced suppression of TTF-1 via miR-365. Mir-365 also targeted an epithelial mesenchymal transition (EMT)-promoting gene HMGA2. In summary, these data connect the lung transcriptional program to the microRNA network.

ß-catenin expression in benign and malignant pleural disorders.

Benign and malignant pleural processes display a large and overlapping spectrum of morphological appearances, and can be difficult to distinguish, histologically, from each other. ß-catenin, a participant in the wingless-type (Wnt) transduction pathway, is involved in the pathogenesis of malignant mesothelioma and has received limited evaluation for its ability to serve as a diagnostic aid for distinguishing between individual pleural disorders. We performed immunohistochemistry for ß-catenin on 10 pleural malignant mesotheliomas, 10 examples of mesothelial hyperplasia and 18 cases of organizing pleuritis. Although differences were noted in staining intensity between the mesothelioma and mesothelial hyperplasia groups, extensiveness and cellular location were similar. Staining intensity (mean +/- s.d.) in mesotheliomas (2.00 +/- 0.67) was significantly less intense than in mesothelial hyperplasia cases (3.00 +/- 0.00) (p=0.0005). Stromal cell staining was cytoplasmic in all cases, and endothelial cell staining was membranous, submembranous and cytoplasmic. Nuclear expression of ß-catenin was not observed in any of the cases studied. This lack of nuclear staining in the stromal cells of organizing pleuritis differs markedly from the previously reported high frequencies of nuclear ß-catenin expression in other pleural spindle cell proliferations (desmoid tumors and solitary fibrous tumors). In summary, the current study adds to previous work indicating a role for ß-catenin in the genesis of pleural conditions including organizing pleuritis, mesothelial hyperplasia and malignant mesothelioma. Although IHC for ß-catenin does not appear to be conclusive for separating benign from malignant mesothelial proliferations, it may be valuable for assisting in the differential diagnosis of mesothelial and spindle cell proliferations in the pleura.

Should large cell neuroendocrine lung carcinoma be classified and treated as a small cell lung cancer or with other large cell carcinomas?

BACKGROUND: To compare the presenting and prognostic characteristics of patients with large cell neuroendocrine lung cancer (LCNELC) with those of patients with small cell lung cancer (SCLC) or other large cell carcinomas (OLCs) and to compare overall survival (OS) and lung cancer-specific survival (LCSS) rates for patients undergoing definitive resection without radiotherapy (S-NoRT). METHODS: The Surveillance Epidemiology and End Results Database-17 from 2001 to 2007 was used. Differences between population characteristics were compared using χ(2) and Wilcoxon tests. The log-rank test and Cox models were used to compare differences in OS and LCSS. RESULTS: There were 1211 patients with LCNELC (324 in the S-NoRT group), 8295 patients with OLC (1120 S-NoRT), and 35,304 patients with SCLC (355 S-NoRT). The proportion of all large cell carcinomas constituted by LCNELC increased from 8 to 21% during the study period; and the proportion of patients with large cell carcinoma undergoing S-NoRT increased from 16 to 26%. Presenting and histopathologic characteristics and treatment factors of patients undergoing S-NoRT for patients with LCNELC were more similar to those of patients with OLC than to those with SCLC. OS and LCSS rates for patients with LCNELC undergoing resection without radiation were similar to those of patients with OLC and better than those for patients with SCLC, but the differences were not statistically significant on multivariate analysis. CONCLUSIONS: The clinical, histopathologic, and biologic features of LCNELC are more similar to OLC than to SCLC. Therefore, LCNELC should continue to be classified and treated as a large cell carcinoma.

Immune functional assay for immunosuppressive management in post-transplant malignancy.

Immunosuppression management in post-transplant malignancy is challenging because of a lack of objective immunologic assessment tools. The ImmuKnow assay measures the ATP level from CD4 T cells, quantifying cell-mediated immunity and providing an insight into the immune status of transplant recipients. Its potential use in patients with post-transplant de novo malignancy was evaluated. Thirteen adult transplant patients with de novo malignancy were divided into survivors (n = 9) and non-survivors (n = 4) after malignancy treatment. Tacrolimus and the ImmuKnow levels were monitored before, during, and after malignancy treatment. The ImmuKnow level in non-survivors group was significantly lower before and after malignancy treatment compared to survivors group (p = 0.013 and 0.0014 respectively). In survivor group, the ImmuKnow level was significantly decreased during malignancy treatment (p = 0.019) but recovered to the initial level after the treatment. However, in non-survivor group, the ImmuKnow level remained suppressed throughout the observed period despite a reduction in immunosuppressive drug levels. The ImmuKnow assay can be an objective means evaluating immune status of patients with de novo malignancy. The ImmuKnow assay can express the degree of immune suppression induced by chemotherapeutic or radiation therapy and may be a useful tool in optimizing the timing of re-introduction of immunosuppression after malignancy treatment.

High levels of expression of human stromal cell-derived factor-1 are associated with worse prognosis in patients with stage II pancreatic ductal adenocarcinoma.

BACKGROUND: Stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4, have been shown to mediate invasiveness and metastatic behavior in a number of cancers, including ovarian, prostate, bladder, breast, and pancreatic cancers. The expression and significance of SDF-1 in pancreatic ductal adenocarcinoma (PDA) have not been systematically studied. METHODS: We examined the expression of SDF-1 by immunohistochemistry using a mouse anti-human SDF-1/CXCL12 antibody (dilution 1:300) and a tissue microarray consisting of 72 stage II PDAs from pancreaticoduodenectomy specimens. The staining results were categorized as SDF-1-high (SDF-1-H; cytoplasmic staining of ≥10% of tumor cells) or SDF-1-low (SDF-1-L; no staining or staining of <10% of tumor cells). The results of SDF-1 expression were correlated with clinicopathologic parameters and survival. Statistical analyses were done using SPSS software. RESULT: Of the 72 stage II PDAs, 25 (35%) showed high levels of SDF-1 expression. The median overall and recurrence-free survival for patients with SDF-1-H PDAs were 26.1 and 11.1 months, respectively, compared with 44.3 and 22.3 months for patients with SDF-1-L tumors (log-rank test, P = 0.047 and P = 0.021). In multivariate analysis, high SDF-1 expression correlated with poor overall and disease-free survival (P = 0.02 and P = 0.02) independent of tumor size, differentiation, and lymph node status. CONCLUSION: High levels of SDF-1 expression were associated with poor overall and disease-free survival in patients with stage II PDA. SDF-1 may serve as a useful prognostic marker for stage II PDA. IMPACT: Our results suggest that SDF-1-CXCR4 or SDF-1-CXCR7 pathways may represent a potential target for therapeutic intervention as well as prediction of prognosis in PDA.