Susanne K. Jeffus

Interobserver variability in the application of a proposed histologic subclassification of endocervical adenocarcinoma.

A histologic pattern-based system of risk stratification for endocervical adenocarcinoma has been recently proposed on the basis of tumor-stroma interface and lymph-vascular invasion. The key utility of the system lies in separating cases with very low risk for nodal metastases (pattern A) from those with higher risk (patterns B and C), which may alter the treatment approach. In this study, we determine the reproducibility of applying this system among gynecologic pathologists from 2 institutions using blinded review of 49 adenocarcinomas from 2003 to 2013. &kgr; values and pairwise differences are calculated for the proposed 3-tier system (patterns A, B, and C) as well as a modified version comparing pattern A versus patterns B and C combined (2-tier system). Consensus diagnosis for the 3-tier system is reached in 50% of cases, with majority of &kgr; values indicating fair to almost perfect agreement (range, 0.24 to 0.84). When condensed to 2 tiers, consensus is reached in 81.3% of cases with &kgr; values showing modest improvement (range, 0.33 to 0.92). Pairwise difference analysis reveals diagnosis trends for specific pathologists on the 3-tier system that decrease with 2 tiers. Interpretive variability may be of practical significance in application of the proposed 3-tier pattern–based approach to endocervical adenocarcinoma. Additional studies with larger patient cohorts are needed to confirm the negligible risk for lymph node involvement seen in pattern A patients and to further evaluate the applicability of this new classification system.

A phase I dose-escalation clinical trial of a peptide-based human papillomavirus therapeutic vaccine with Candida skin test reagent as a novel vaccine adjuvant for treating women with biopsy-proven cervical intraepithelial neoplasia 2/3

PURPOSE: Non-surgical treatments for cervical intraepithelial neoplasia 2/3 (CIN2/3) are needed as surgical treatments have been shown to double preterm delivery rate. The goal of this study was to demonstrate safety of a human papillomavirus (HPV) therapeutic vaccine called PepCan, which consists of four current good-manufacturing production-grade peptides covering the HPV type 16 E6 protein and Candida skin test reagent as a novel adjuvant. PATIENTS AND METHODS: The study was a single-arm, single-institution, dose-escalation phase I clinical trial, and the patients (n = 24) were women with biopsy-proven CIN2/3. Four injections were administered intradermally every 3 weeks in limbs. Loop electrical excision procedure (LEEP) was performed 12 weeks after the last injection for treatment and histological analysis. Six subjects each were enrolled (50, 100, 250, and 500 μg per peptide). RESULTS: The most common adverse events (AEs) were injection site reactions, and none of the patients experienced dose-limiting toxicities. The best histological response was seen at the 50 μg dose level with a regression rate of 83% (n = 6), and the overall rate was 52% (n = 23). Vaccine-induced immune responses to E6 were detected in 65% of recipients (significantly in 43%). Systemic T-helper type 1 (Th1) cells were significantly increased after four vaccinations (P = 0.02). CONCLUSION: This study demonstrated that PepCan is safe. A significantly increased systemic level of Th1 cells suggests that Candida, which induces interleukin-12 (IL-12) in vitro, may have a Th1 promoting effect. A phase II clinical trial to assess the full effect of this vaccine is warranted.

Squamous Cell Carcinoma Variants of the Upper Aerodigestive Tract A Comprehensive Review With a Focus on Genetic Alterations

CONTEXT Squamous cell carcinoma of the upper aerodigestive tract is a heterogenous entity. Although conventional squamous cell carcinomas are easily recognized, the morphologic variants of squamous cell carcinoma can present a diagnostic challenge. Familiarity with these variants is necessary because many are associated with unique risk factors and are characterized by specific molecular alterations (eg, nuclear protein in testis midline carcinomas). Perhaps the most important distinction is in identifying viral-related from nonviral-related carcinomas. The accurate diagnosis of these variants is necessary for prognostic and therapeutic reasons. OBJECTIVES To provide a clinicopathologic overview and summary of the molecular alterations of the common squamous cell carcinoma variants, including verrucous, spindle cell, acantholytic, adenosquamous, basaloid, and papillary squamous cell carcinoma, as well as nuclear protein in testis midline carcinoma, and to discuss the distinguishing features of human papillomavirus- and Epstein-Barr virus-related squamous cell carcinomas. DATA SOURCES Published peer-reviewed literature. CONCLUSIONS Familiarity with squamous cell carcinoma variants is essential for proper diagnosis and to guide appropriate clinical management. Further insight into the molecular alterations underlying those variants may lead to alterations in existing treatment approaches and to evolution of novel treatment modalities.

Left Adrenal Biopsy Using the Convex Curvilinear Ultrasound Scope

Effective use of the convex curvilinear ultrasound bronchoscope in the esophagus (EUS-B) is well described. EUS-B has not been described for diagnostic sampling of the left adrenal gland. We describe 6 cases of diagnostic fine-needle aspiration of the left adrenal gland using EUS-B. This capacity increases the diagnostic capabilities of the pulmonologist experienced in EUS-B.

Rapid onsite evaluation: A comparison of cytopathologist and pulmonologist performance.

Rapid onsite evaluation (ROSE) has several potential benefits but also can prolong procedures if one must wait for a cytopathologist, and it can involve a considerable time commitment on the part of the cytopathologist. At the University of Arkansas for Medical Sciences, interventional pulmonologists have routinely reviewed cytology specimens. This study was performed to determine prospectively how accurately pulmonologists could perform ROSE and whether they could contribute to the efficiency of the process.

A fibromyxoid stromal response is associated with an infiltrative tumor morphology, perineural invasion, and lymph node metastasis in squamous cell carcinoma of the vulva.

Patterns of invasion and stromal response are understudied in vulvar squamous cell carcinoma. The aim of this study was to explore whether histologic features such as an infiltrative pattern of invasion and fibromyxoid stromal response (FMX-SR) are meaningful prognostic factors. We reviewed 143 vulvar squamous cell carcinoma resections and correlated patterns of invasion and stromal response with patient age, ethnicity, depth of invasion, tumor size, perineural invasion (S100/AE1/3 stain), lymph node involvement (LNI), extranodal extension, margin status, pathologic stage, and recurrence. Univariate analyses of continuous variables were performed using t tests, whereas Pearson &khgr;2 tests were used for categorical variables. Logistic regression analyses examined the relationship between histopathologic characteristics and clinical outcomes. There was a statistically significant association between infiltrative tumors and an FMX-SR in comparison with noninfiltrative tumors (P<0.001). Tumors with FMX-SR were significantly more deeply invasive (P=0.0025) and more likely to have LNI (P=0.0364), extranodal extension (P=0.0227), and perineural invasion (P=0.0011) compared with tumors without FMX-SR. For cases with negative surgical margins, the association between tumors with FMX-SR and LNI was significantly strengthened (odds ratio=4.73, P=0.0042), even after adjustments for age, race, and depth of invasion (odds ratio=4.34, P=0.0154). The presence of both FMX-SR and an infiltrative pattern of invasion in tumors with negative margins was significantly associated with LNI (P=0.0235) and recurrence (P=0.0124). These results suggest that interactions between nerve, tumor, and stromal cells play a role in tumor progression and represent additional prognostic factors that help stratify those patients at highest risk for LNI, extranodal extension, and recurrence.

Perineural Invasion Is an Independent Pathologic Indicator of Recurrence in Vulvar Squamous Cell Carcinoma.

Objectives:Vulvar squamous cell carcinoma (vSCC) is a gynecologic malignancy diagnosed in nearly 4500 women in the United States each year. Current criteria for treatment planning provide inadequate assessment of aggressive vSCC cases, resulting in insufficient use of adjuvant treatments and high rates of vSCC recurrence. Perineural invasion (PNI) is a pathologic feature inconsistently included in the assessment of vSCC, because its relevance to clinical outcomes in these women is not well defined. The purpose of this study was to determine the association between PNI and relevant clinical parameters such as recurrence. Methods:A total of 103 cases of vSCC were evaluated for PNI using pathology report review and immunohistochemistry dual-chromogen staining for S100 and AE1/3. Medical records were reviewed for clinical and follow-up data. Data were analyzed using univariate and multivariate logistic regression statistical methods. Results:Patients with vSCC containing PNI had a greater risk for cancer recurrence than those whose tumors did not contain PNI (odds ratio=2.8, P=0.0290). There was no significant correlation between the presence of PNI and nodal involvement, stage, or lymphovascular invasion. Tumors with PNI had greater depth of invasion (DOI) (P=0.0047); however, DOI was not associated with recurrence (P=0.2220). When analyzed using a multivariable logistic regression model, PNI was an independent predictor of recurrence in vSCC (adjusted odds ratio=2.613, P=0.045). Conclusions:PNI is an independent indicator of risk for recurrence in vSCC. The association of PNI with increased risk for recurrence, independent of DOI, nodal involvement, lymphovascular invasion, or stage, should encourage practicing pathologists to thoroughly search for and report the presence of PNI in vSCC.

Pax2 expression in simultaneously diagnosed WHO and EIN classification systems.

PAX2 has been cited as a technically robust biomarker which nicely delineates precancerous lesions of the endometrium when the endometrial intraepithelial neoplasia (EIN) classification scheme is used. Its utility in distinguishing between atypical and nonatypical hyperplasia when applied within the 1994 World Health Organization classification system is questionable. The purpose of this study was to evaluate PAX2 in a side by side comparison of its staining patterns in a series of endometrial samples that were classified using both systems. A total of 108 precancerous endometrial cases were identified, of which 30 cases were deemed nonhyperplastic by consensus agreement and 11 cases lost the tissue of interest on deeper sections. The remaining 67 cases were categorized according to the 1994 World Health Organization criteria and EIN scheme by 2 gynecologic pathologists. PAX2 staining was scored in lesional tissue as normal or altered (lost, increased, or decreased) compared with nonlesional background. The most common pattern of alteration was complete loss of nuclear PAX2 staining (86.3%) followed by decreased staining (11.3%) and markedly increased staining (2.3%). PAX2 alterations correlated well with EIN diagnoses (33/36, 92%) compared with benign hyperplasia (2/13, 15%) but were less useful when the 1994 World Health Organization classification system was applied (PAX2 alteration in 22/25 (88%) of atypical hyperplasia cases versus 16/25 (64%) of nonatypical hyperplasia cases). Forty-five percent of follow-up hysterectomies with a previous PAX2-altered biopsy case harbored adenocarcinoma. In conclusion, PAX2 may be a helpful adjunct stain and training tool when the features of atypical hyperplasia/EIN are in question.

Hyalinizing Clear Cell Carcinoma of the LungCase Report and Review of the Literature

Objectives Hyalinizing clear cell carcinoma (HCCC) is common in head and neck sites but extremely rare in the lung. This case report describes an HCCC in the lung of a 54-year-old female patient. Methods We summarize the histomorphologic, immunophenotypic, and molecular features for our and three previously reported HCCCs of the lung with emphasis on potential diagnostic pitfalls. Results Sections of a well-circumscribed 3.5-cm lung mass were characterized by a bronchocentric tumor growing in sheets, nests, and cords in a background of hyalinized stroma. Tumor cell appearance was clear to eosinophilic, lacking significant pleomorphism or mitotic activity. By immunohistochemistry, the tumor cells were strongly positive with antibodies to pan-keratin, p63, and CK5/6 while negative for CK7, CK20, thyroid transcription factor 1, napsin A, chromogranin, and synaptophysin. Next-generation sequencing demonstrated an EWSR1-ATF1 fusion transcript. Conclusions Awareness of key morphologic features of pulmonary HCCC is crucial for the recognition of this rare entity in the lung. Ancillary studies, including immunohistochemistry and molecular testing, are essential for the distinction from its mimics.

A novel use of a statewide telecolposcopy network for recruitment of participants in a Phase I clinical trial of a human papillomavirus therapeutic vaccine.

Background: Historically, recruitment and retention of young women in intervention-based clinical trials have been challenging. In August 2012, enrollment for a clinical trial testing of an investigational human papillomavirus therapeutic vaccine called PepCan was opened at our institution. This study was an open-label, single-arm, single-institution, dose-escalation Phase I clinical trial. Women with recent Papanicolaou smear results showing high-grade squamous intraepithelial lesions or results that could not rule out high-grade squamous intraepithelial lesion were eligible to enroll. Patients with biopsy-confirmed high-grade squamous intraepithelial lesion were also eligible. Colposcopy was performed at the screening visit, and participants became eligible for vaccination when the diagnosis of high-grade squamous intraepithelial lesion was confirmed with biopsy and other inclusion criteria were met. The aim of this study was to identify strategies and factors effective in recruitment and retention of study participants. Methods: Potential vaccine candidates were recruited through direct advertisement as well as referrals, including referrals through the Arkansas telecolposcopy network. The network is a federally funded program, administered by physicians and advanced practice nurses. The network telemedically links rural health sites and allows physician-guided colposcopy and biopsies to be conducted by advanced practice nurses. A variety of strategies were employed to assure good retention, including face-to-face contact with the study coordinator at the time of consent and most of study visits; frequent contact using text messaging, phone calls, and e-mails; and creation of a private Facebook page to improve communication among research staff and study participants. A questionnaire, inquiring about motivation for joining the study, occupation, education, household income, number of children, and number of sexual partners, was administered at the screening visit with the intent of identifying factor(s) associated with recruitment and retention. Results: A total of 37 participants were enrolled between September 2012 and March 2014. The largest proportion of participants (46%) was enrolled from the telecolposcopy network. Others were enrolled through outside institutions (43%), in-house referrals (8%), or direct advertisement (3%). Most participants were motivated to join the study to take care of their health issues. Only two participants joined the Facebook private page. Of the 24 participants who qualified for vaccination, only 1 terminated early due to an unanticipated move. Conclusion: The availability of a large number of potential participants from the telecolposcopy network increased recruitment to this clinical trial by 85% over other traditional means of recruitment. The telecolposcopy network is not only a means of providing a gynecological service to women who otherwise would forego care but also a novel and valuable resource in recruiting participants for a clinical trial.