The Future Role of Cytology in Cervical Cancer Screening in the Era of HPV Vaccination.

BACKGROUND: Up until recently, cervical cytology was the mainstay for cervical cancer screening. However, the established association between human papillomavirus (HPV) infection and cervical cancer has led to changes in preventive strategies, with cytology being replaced by the use of high-risk HPV (hrHPV) testing and primary prevention being achieved by HPV vaccination. In this context, the role of cervical cytology is shifting to secondary triage of HPV-positive women. As vaccination is leading to decreased HPV infections and significant cervical abnormalities (CIN2+), data on the impact of HPV vaccination on cervical cytology metrics, including positive predictive value (PPV) and negative predictive value (NPV), are starting to emerge. SUMMARY: This is a review of updates in cervical cancer screening, including the use of primary HPV testing and the impact of HPV vaccination on cytology as part of cervical cancer screening. KEY MESSAGES: Cervical cancer screening and prevention are undergoing significant changes as there is widespread implementation of HPV vaccination and hrHPV testing is becoming the entry point for secondary prevention. Optimal screening approaches and intervals in this setting are currently being analyzed including the use of cytology and other ancillary techniques for triage of positive cases, as well as the effect of vaccination on the PPV and NPV of cytology in the detection of CIN2+.

Overview of Ancillary Techniques in Cervical Cytology.

BACKGROUND: The association between high-risk serotypes of human papillomavirus (hr-HPV) and cervical cancer is well-established. SUMMARY: In order to improve the sensitivity of cervical cytology testing, hr-HPV testing has rapidly become part of routine cervical cancer screening, either in conjunction with cytology or as primary testing. In this review, we discuss the overall utility and strategies of hr-HPV testing, as well as the advantages and limitations of potential triage strategies for hr-HPV-positive women, including HPV genotyping, p16/Ki-67 dual staining, and methylation assays. KEY MESSAGE: hr-HPV testing is discussed as primary screening and HPV genotyping, p16/Ki-67 dual staining, and methylation assays are discussed as ancillary techniques to cytology in the triage of hr-HPV-positive women undergoing cervical cancer screening.

Prognostic Significance of Size, Location, and Number of Lymph Node Metastases in Endometrial Carcinoma.

Regional lymph node metastasis is a well-established negative predictive prognostic factor in endometrial carcinomas. Recently, our approach to the pathologic evaluation of lymph nodes in endometrial carcinomas has changed, mainly due to the utilization of immunohistochemical stains in the assessment of sentinel lymph nodes, which may result in the identification of previously unrecognized disease [particularly isolated tumor cells (ITCs)] on hematoxylin and eosin stained slides. However, the clinical significance of this finding is not entirely clear. Following the experience in other organs systems such as breast, the Eight Edition of the American Joint Committee on Cancer's Cancer Staging Manual has recommended utilizing the N0(i+) terminology for this finding, without impact in the final tumor stage. We performed a comparative retrospective multi-institutional survival analysis of 247 patients with endometrial carcinoma with regional lymph node metastasis of various sizes identified in nonsentinel lymphadenectomy, demonstrating that the cumulative survival of patients with isolated tumor cells in regional lymph nodes is not statistically different from patient with negative lymph nodes, and is statistically different from those with lymph nodes showing micrometastasis or larger metastatic deposits. In addition, we evaluated the prognostic implications of the number of involved regional lymph nodes, demonstrating a worsening prognosis as the number of involved lymph nodes increases from none to one, and from one to more than one. Our data suggests that regional lymph nodes with isolated tumor cells in patients with endometrial carcinoma should likely be considered, for staging purposes, as negative lymph nodes, simply indicating their presence with the (i+) terminology.

Integrated Analysis of Ovarian Juvenile Granulosa Cell Tumors Reveals Distinct Epigenetic Signatures and Recurrent TERT Rearrangements.

PURPOSE: Adult granulosa cell tumor (AGCT) is characterized by the somatic FOXL2 p.C134W mutation, and recurrences have been associated with TERT promoter and KMT2D-truncating mutations. Conversely, the molecular underpinnings of the rare juvenile granulosa cell tumor (JGCT) have not been well elucidated. To this end, we applied a tumor-only integrated approach to investigate the genomic, transcriptomic, and epigenomic landscape of 31 JGCTs to identify putative oncogenic drivers. EXPERIMENTAL DESIGN: Multipronged analyses of 31 JGCTs were performed utilizing a clinically validated next-generation sequencing (NGS) panel targeting 580 cancer-related genes for genomic interrogation, in addition to targeted RNA NGS for transcriptomic exploration. Genome-wide DNA methylation profiling was conducted using an Infinium Methylation EPIC array targeting 866,562 CpG methylation sites. RESULTS: We identified frequent KMT2C-truncating mutations along with other mutated genes implicated in the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, in addition to previously reported hotspot AKT1 and DICER1 mutations. Targeted transcriptome sequencing revealed recurrent TERT rearrangements (13%) involving partners CLPTM1L or DROSHA, and differential gene expression analysis showed FGFR1 upregulation in the TERT non-rearranged JGCTs under direct promoter control. Genome-wide DNA methylation rendered a clear delineation between AGCTs and JGCTs at the epigenomic level, further supporting its diagnostic utility in distinguishing among these tumors. CONCLUSIONS: This is the largest comprehensive molecular study of JGCTs, where we further expand our current understanding of JGCT pathogenesis and demonstrate putative oncogenic drivers and TERT rearrangements in a subset of tumors. Our findings further offer insights into possible targeted therapies in a rare entity.

Assessment of Pathology Learning Modules With Virtual Microscopy in a Preclinical Medical School Curriculum.

OBJECTIVES: To evaluate the ability of pathology modules to promote learning of pathology-related course content in a preclinical medical education curriculum. METHODS: Pathology modules were created for the "Hematology/Oncology" and "Women's Health" (WH) courses. Students were recruited over 2 consecutive academic years; cohorts 1 and 2 refer to 2 separate groups of students in years 1 and 2, respectively, of the study. Course performance data were collected. RESULTS: Use of pathology modules resulted in a statistically significant higher correlation between performance on the final examination and pathology-related questions in the Hematology/Oncology course and written examination and pathology-related questions in cohort 1 in the WH course. There was statistically significant improvement (P = .026) on pathology-related laboratory practical examination questions in the WH course for cohort 1, and no other statistically significant improvement for the other cohorts and examinations. The percentage of students completing all or part of the modules was highest in the WH course for cohort 1 (60%) compared with WH course cohort 2 (33%) and Hematology/Oncology cohort 1 (30%) and cohort 2 (39%). CONCLUSIONS: Pathology modules may improve acquisition and retention of pathology-related course content when used appropriately.

Clear Cell Papillary Cystadenoma of the Ovary Masquerading as Metastatic Clear Cell Renal Cell Carcinoma: A Case Report and Review of the Literature.

Clear cell papillary cystadenoma of the epididymis is an uncommon benign neoplasm, usually seen in patients with von Hippel-Lindau disease. Morphologic and immunohistochemical examination aid in distinguishing clear cell papillary cystadenoma from malignant histologic mimics including low-grade mesothelial proliferations and metastatic clear cell renal cell carcinomas. Analogous lesions have been described in the female genital tract, often posing diagnostic challenges due to their low incidence. Here, we present the difficult diagnostic aspects of the first case of clear cell papillary cystadenoma involving the ovary, including the salient immunohistochemical, ultrastructural, and molecular characteristics.

Uterine Tumor Resembling Ovarian Sex Cord Stromal Tumor (UTROSCT): A Series of 3 Cases With Extensive Rhabdoid Differentiation, Malignant Behavior, and ESR1-NCOA2 Fusions.

ESR1 and GREB1 fusions have recently been described in uterine tumor resembling ovarian sex cord tumor (UTROSCT). Thus far, recurrences have been documented in a subset of those harboring GREB1 fusions, but not in those with ESR1 rearrangements. Here we describe the clinicopathologic features of 3 recurrent UTROSCTs with striking rhabdoid morphology (an unusual feature of these tumors overall) and ESR1-NCOA2 fusions. The patients were 32, 37, and 54 years at initial diagnosis and first recurrence occurred at 7, 9, and 32 years. The primary tumors (available in two cases) were centered in the myometrium and showed infiltrative borders. They predominantly grew in sheets and cords, but also had a pseudopapillary appearance. Cells were uniformly epithelioid with eccentric nuclei, prominent nucleoli, abundant eosinophilic globular/glassy (rhabdoid) cytoplasm, and infrequent mitoses (≤4/10 high-power fields [HPFs]). Recurrences were morphologically identical to the primary tumors, but demonstrated brisk mitotic activity (≥16/10 HPFs). The third tumor (with only recurrences available) had multiple patterns, including diffuse, corded, trabecular, and a focal retiform growth. Rhabdoid cells were conspicuous, but only comprised ~50% of the tumor, and mitoses numbered up to 2/10 HPFs. All tumors were strongly and diffusely positive for WT1, CAM5.2, ER, and PR, but negative for inhibin. Diffuse calretinin and desmin expression, as well as focal melan-A positivity, was noted in one tumor, but was negative in the others. In all 3 tumors, INI-1 and BRG-1 were retained, and ESR1-NCOA2 fusions were detected by targeted RNA sequencing. This study is the first to highlight an association between UTROSCTs with extensive rhabdoid differentiation, ESR1-NCOA2 fusions, and aggressive behavior. UTROSCTs are considered neoplasms of uncertain malignant potential, but have a benign course in most cases. Thus, it is important to be aware of these specific features and recommend long-term follow-up due to their propensity for late recurrences.

Role of Ancillary Techniques in Gynecologic Cytopathology Specimens.

The association between high-risk genotypes of human papillomavirus (hr-HPV) and cervical cancer is well established. As hr-HPV testing is rapidly becoming a part of routine cervical cancer screening, either in conjunction with cytology or as primary testing, the management of hr-HPV-positive women has to be tailored in a way that increases the detection of cervical abnormalities while decreasing unnecessary colposcopic biopsies or other invasive procedures. In this review, we discuss the overall utility and strategies of hr-HPV testing, as well as the advantages and limitations of potential triage strategies for hr-HPV-positive women, including HPV genotyping, p16/Ki-67 dual staining, and methylation assays.

Cytomorphologic features of metastatic endometrioid carcinoma by fine needle aspiration.

BACKGROUND: Although metastatic disease is commonly seen in high grade carcinomas of gynecologic origin, it also occurs in low to intermediate grade endometrioid carcinomas (LGEMCAs), and may even be the primary presentation of disease. Tissue confirmation is necessary to guide therapy, but performing biopsies might not always be feasible or practical. In such instances, fine needle aspiration (FNA) is a safe and efficient alternative. No comprehensive series describing the cytomorphologic features of metastatic LGEMCA on FNA samples has been published. This study describes clinical and cytomorphologic features of metastatic LGEMCA diagnosed by FNA. METHODS: The pathology archives at 2 academic institutions were searched for patients with endometrial or ovarian endometrioid carcinoma, with concurrent or subsequent sampling of metastatic sites by FNA. RESULTS: Twelve cases were identified; all slides were reviewed and cytomorphologic features recorded. Four cases were obtained from metastatic sites as primary presentation of disease, and 8 cases were obtained from metastatic sites in patients with known history of LGEMCA. Metastatic LGEMCAs generate cellular specimens composed of cohesive clusters of cells with areas of gland formation. Consistent cytomorphologic features included nuclear overlapping, low to intermediate nuclear to cytoplasmic ratios, round to elongated nuclear shape, finely vacuolated cytoplasm, mild to moderate nuclear membrane irregularities, squamous metaplasia, and inconspicuous nucleoli. Variability was seen with regards to the presence of necrosis (50% of cases) and mitosis (25% of cases). CONCLUSION: The presence of these features on FNA samples should raise concern for an underlying gynecologic malignancy.

Radiologic images of an aggressive implant-associated fibromatosis of the breast and chest wall: case report and review of the literature.

Fibromatosis of the breast is a rare benign disease compromising <0.2% of all primary breast tumors. Although the chest wall is a common location, occurrences of implant-associated fibromatosis of the breast are extremely rare; only 33 cases have been reported. We present a case of a 42-year-old female who underwent breast augmentation with silicone breast implants, and 2 years later developed an aggressive implant-associated fibromatosis of the breast and chest wall. On imaging studies, the tumor mimicked breast carcinoma, and despite chemotherapy, the fibromatosis rapidly enlarged and was locally invasive requiring wide surgical excision. Unlike previously reported imaging findings, magnetic resonance imaging revealed an oval circumscribed mass with fringe-like internal architecture. We provide a review of the literature and discuss the imaging features of implant-associated fibromatosis of the breast.

Cervical cancer screening in the era of HPV vaccination: A review of shifting paradigms in cytopathology.

Significant changes in cervical cancer screening practice, guidelines, and prevention of cervical cancer have taken place in recent years including the raising of initial cervical cancer screening age, changes in frequency of cytology screening, and the adoption of high risk HPV and cytology co-testing for some patients; the introduction of the bivalent, quadrivalent, and 9-valent HPV vaccines; and the recent approval of high risk HPV testing as primary screening with the use of cytology as triage in positive cases. This review discusses the significance of primary HPV screening, the impact of HPV vaccination in the prevalence of cervical cancer and its precursors, the interplay between high risk HPV testing and vaccination, and the implications for clinical and cytological management. Future strategies for cervical screening in the post-vaccination era are also discussed.

Cytologic findings following intraoperative use of FlosealR hemostatic matrix: A potential diagnostic pitfall in fluid aspiration cytology.

We report the case of a 62-year-old woman who underwent laparoscopic hysterectomy, bilateral salpingo-oophorectomy, and lymph node dissection for endometrial endometrioid carcinoma FIGO grade 1. Cytologic examination of the pelvic washing specimen showed an acellular matrix with frayed edges and cracking artifact. Upon investigation, it became apparent that this could represent hemostatic matrix FlosealR that had been used intraoperatively at the lymphadenectomy site. Laboratory replication of the cytologic findings with a FlosealR sample confirmed it. This is the first reported case of FlosealR in pelvic washing cytology and represents a potential diagnostic pitfall. Diagn. Cytopathol. 2016;44:1117-1119. © 2016 Wiley Periodicals, Inc.

Epithelioid Glomus Tumor of the Uterine Cervix: A Case Report and Review.

Herein, we report a case of epithelioid glomus tumor involving the uterine cervix. A 67-yr-old woman with a long-standing history of cervical dysplasia underwent cervical conization. In addition to the patient's high-grade squamous intraepithelial lesion, histologic examination demonstrated an incidental, 0.2-cm glomus tumor in the cervical submucosa. The tumor was composed of bland epithelioid cells in scattered nests closely associated with small-caliber blood vessels. Immunohistochemically, the tumor cells were diffusely positive for smooth muscle actin and caldesmon and only focally positive for desmin and CD34. To our knowledge, only 2 similar case reports exist in the literature. The present case is the first cervical case seen with epithelioid features and in association with cervical dysplasia.

Utility of ProExC and IMP3 immunocytochemical staining in atypical glandular cells of undetermined significance in liquid-based cervical cytology.

The diagnosis of atypical glandular cells of undetermined significance (AGUS) in liquid-based cervical cytology specimens shows significant underlying pathology in only 30% of cases, while the remaining cases are found to be benign (reactive, reparative/metaplastic). Previous studies have reported positive ProExC and IMP3 staining in neoplastic glandular lesions of the uterine cervix and corpus. We present our experience with the utility of these markers in the evaluation of AGUS cases in liquid-based cervical cytology. The case cohort included 34 cases diagnosed as AGUS. ProExC and IMP3 immunocytochemical (ICC) stains were performed on ThinPrep® slides and the results correlated with subsequent biopsy findings. Positive expression was classified as strong diffuse nuclear immunostaining for ProExC and granular cytoplasmic for IMP3. The presence of AGUS cells on the ICC stained slides was confirmed in all cases. IMP3 was positive in 80% of glandular neoplasms and negative in 93% non-glandular lesions/cases negative for squamous intraepithelial lesion (SIL). ProExC was positive in 60% of glandular neoplasms and negative in 83% non-glandular lesions/cases negative for SIL. When used as a panel (ProExC + IMP3), at least one stain was positive in 100% of glandular neoplasm cases and they were both negative in 83% of non-glandular lesions/cases negative for SIL. Based on this study, both ProExC and IMP3, when used as an immuno panel, can predict the presence of glandular lesions on subsequent biopsies and can serve as an aid in the diagnosis and management of AGUS cases.

Endoscopic endonasal resection of anterior skull base meningiomas and mucosa: implications for resection, reconstruction, and recurrence.

BACKGROUND: Meningiomas of the anterior skull base are attractive tumors for resection via an endoscopic endonasal route. The use of the vascularized Hadad-Bassagasteguy nasoseptal flap has dramatically reduced the cerebrospinal fluid (CSF) leak rate-the veritable Achilles heel of this surgical approach. Benign meningiomas, however, can erode through the nasal mucosa-the very same mucosa that is used to reconstruct the anterior cranial fossa floor. The goal of this study was to describe the presence of meningioma invasion into the mucosa in patients who underwent endoscopic endonasal resection of ventral skull base meningiomas. The implications of this finding are discussed with respect to resection, reconstruction, and recurrence. PATIENTS, MATERIALS, AND METHODS: This is a retrospective review of three patients who underwent endoscopic endonasal complete resection of ventral skull base meningiomas. Surgically excised tissues were processed for routine histopathological analysis. RESULTS: A complete resection of the bone, dura, and tumor was performed in all three cases. Both patients with visual deficits improved. The first patient to undergo endoscopic surgical resection developed a CSF leak, but the later two patients with larger tumors did not. Histopathological analysis demonstrated mucosal invasion by World Health Organization (WHO) grade I meningioma in two of the three cases. CONCLUSION: Ventral anterior skull base meningiomas can invade through bone into the mucosa. Because the endoscopic endonasal resection of these meningiomas often requires the use of a vascularized nasoseptal flap to minimize CSF leak complications, it is possible that the nasoseptal flap itself may be compromised by tumor tissue. The creation of the nasoseptal flap should take the findings of this study into consideration to minimize late recurrence.

Neurofibroma of the cervix presenting as cervical stenosis in a patient with neurofibromatosis type 1: a case report.

Neurofibromatosis type 1 is an autosomal dominant disorder characterized by the presence of cutaneous and subcutaneous neurofibromas as well as deep-seated plexiform neurofibromas. Although unusual, these lesions have been described in the gynecologic tract, including the cervix; however, when arising in this location, they are commonly asymptomatic or present with lower abdominal pain. Cervical neurofibromas presenting as cervical stenosis have not been described. Awareness by both the clinician and the pathologist of a patient's history is of great help when dealing with a specimen of a patient with neurofibromatosis type 1.

Utility of the Thin Prep Imaging System® in the detection of squamous intraepithelial abnormalities on retrospective evaluation: can we trust the imager?

Prospective studies analyzing the ThinPrep Imaging System (TIS) have demonstrated a significant decrease in screening time and detection rates comparable or better than manual screening. We retrospectively analyzed the accuracy of the TIS in detecting cervical abnormalities. Our study included all new HSIL diagnoses in 2007 with previous negative (NIL) pap tests screened with TIS. The original 22 fields of view (FOV) were reviewed by 2 blinded screeners followed by manual screening of all slides. Any ASC-US or above was considered "abnormal." Of a total of 111,080 pap tests performed in 2007, 180 were reported as HSIL. Of these, 45 cases had a previous NIL pap diagnosed within the last year, screened with TIS. Following re-examination of the NIL pap, 31 diagnoses remained unchanged and 9 were reclassified as abnormal on the basis of cells present within the original FOV. When manually reviewed, all nine cases were confirmed as abnormal. Four cases were reclassified as abnormal on the basis of the manual screen (abnormal cells absent in the FOV). The sensitivity of TIS for the detection of abnormality was 99.95% (false-negative rate FNR: 0.05%) and the sensitivity for detection of HSIL was 99.07% (FNR: 0.92%). When analyzing the cytotechnologist interpretation of the FOV, the sensitivity for detection of abnormality and HSIL was 99.89% (FNR: 0.1%), and 99.53% (FNR: 0.4%), respectively. On retrospective analysis based on newly diagnosed HSIL cases, the sensitivity of TIS was comparable to that of manual screening with a slightly decreased rate of false negatives.