Possible high-grade squamous intraepithelial lesion (pHSIL) in the new cervical screening paradigm: The outcomes and the role of clinicopathological review.

BACKGROUND: A renewed National Cervical Screening Program (NCSP) was introduced in Australia in December 2017. Under the renewed NCSP, there are limited data to guide the management of discordant colposcopy and biopsy results after a liquid-based cytology (LBC) finding of 'possible high-grade squamous intraepithelial lesion' (pHSIL). AIMS: This study aims to determine the proportion of women referred with pHSIL who are found to have HSIL, identify influencing factors of women most at risk, and examine the role that cytopathology review plays in management decisions. MATERIALS AND METHODS: Two-hundred and thirty-two women presenting to a tertiary women's hospital in Australia with pHSIL since December 2017 were identified. Women with HSIL following colposcopy directed biopsy were referred for treatment. When HSIL was not identified, these patients were referred for multidisciplinary clinicopathological review. Pathological outcomes and treatment recommendations are included. MAIN OUTCOME MEASURES: The primary outcome of the study was histological confirmation of HSIL. RESULTS: Primary outcome data were available for 182 women (78.5%); 62 (34.1%) had HSIL on histology, three (1.7%) had adenocarcinoma in situ (AIS) and one (1%) had cervical squamous cell carcinoma (SCC). There was no association between age and the presence of HSIL. The presence of human papillomavirus 16 and/or 18 increased the likelihood of HSIL on histology (relative risk 1.9; 95% CI 1.27-2.80, P = 0.002). Fifty-nine (25.4%) women were referred for observation who had low-grade squamous intraepithelial lesion/no dysplasia. CONCLUSIONS: Clinicopathological review optimises management and triage of patients with pHSIL on referral cytology. Understanding outcomes in these patients informs counselling and management.

Tumour infiltrating lymphocyte status is superior to histological grade, DNA mismatch repair and BRAF mutation for prognosis of colorectal adenocarcinomas with mucinous differentiation.

Mucinous colorectal adenocarcinoma (CRC) is conventionally defined by extracellular mucin comprising >50% of the tumour area, while tumours with ≤50% mucin are designated as having a mucinous component. However, these definitions are largely arbitrary and comparisons of clinico-molecular features and outcomes by proportion of mucinous component are limited. A cohort of 1643 patients with stage II/III cancer was examined for tumour mucinous component, DNA mismatch repair (MMR) status, BRAF mutation and tumour infiltrating lymphocytes (TILs). Tumours with ≤50% mucinous component exhibited similar characteristics as mucinous tumours, including association with female gender, proximal location, high grade, TIL-high, defective MMR (dMMR) and BRAF mutation. Proportion of mucinous component did not stratify disease-free survival (DFS). In univariate analysis dMMR status, but not histological grade, stratified survival for mucinous and mucinous component tumours; however, in multivariate analysis dMMR status was not an independent predictor. BRAF mutation prognostic value depended on mucinous differentiation and MMR status, with poor prognosis limited to non-mucinous pMMR tumours (HR 2.61, 95% CI 1.69-4.03; p < 0.001). TIL status was a strong independent predictor of DFS in mucinous/mucinous component tumours (HR 0.40, 95% CI 0.23-0.67; p < 0.001), and a superior predictor of prognosis compared with histological grade, MMR and BRAF mutation. Mucinous component and mucinous stage II/III CRCs exhibit clinico-molecular resemblances, with histological grade and BRAF mutation lacking prognostic value. Prognosis for these tumours was instead strongly associated with TIL status, with the most favourable outcomes in TIL-high dMMR tumours, whilst TIL-low tumours had poor outcomes irrespective of MMR status.

Lymphocytic response to tumour and deficient DNA mismatch repair identify subtypes of stage II/III colorectal cancer associated with patient outcomes.

OBJECTIVE: Tumour-infiltrating lymphocyte (TIL) response and deficient DNA mismatch repair (dMMR) are determinants of prognosis in colorectal cancer. Although highly correlated, evidence suggests that these are independent predictors of outcome. However, the prognostic significance of combined TIL/MMR classification and how this compares to the major genomic and transcriptomic subtypes remain unclear. DESIGN: A prospective cohort of 1265 patients with stage II/III cancer was examined for TIL/MMR status and BRAF/KRAS mutations. Consensus molecular subtype (CMS) status was determined for 142 cases. Associations with 5-year disease-free survival (DFS) were evaluated and validated in an independent cohort of 602 patients. RESULTS: Tumours were categorised into four subtypes based on TIL and MMR status: TIL-low/proficient-MMR (pMMR) (61.3% of cases), TIL-high/pMMR (14.8%), TIL-low/dMMR (8.6%) and TIL-high/dMMR (15.2%). Compared with TIL-high/dMMR tumours with the most favourable prognosis, both TIL-low/dMMR (HR=3.53; 95% CI=1.88 to 6.64; Pmultivariate<0.001) and TIL-low/pMMR tumours (HR=2.67; 95% CI=1.47 to 4.84; Pmultivariate=0.001) showed poor DFS. Outcomes of patients with TIL-low/dMMR and TIL-low/pMMR tumours were similar. TIL-high/pMMR tumours showed intermediate survival rates. These findings were validated in an independent cohort. TIL/MMR status was a more significant predictor of prognosis than National Comprehensive Cancer Network high-risk features and was a superior predictor of prognosis compared with genomic (dMMR, pMMR/BRAFwt /KRASwt , pMMR/BRAFmut /KRASwt , pMMR/BRAFwt /KRASmut ) and transcriptomic (CMS 1-4) subtypes. CONCLUSION: TIL/MMR classification identified subtypes of stage II/III colorectal cancer associated with different outcomes. Although dMMR status is generally considered a marker of good prognosis, we found this to be dependent on the presence of TILs. Prognostication based on TIL/MMR subtypes was superior compared with histopathological, genomic and transcriptomic subtypes.

The Role of the Mirena Intrauterine Device in the Management of Endometrial Polyps: A Pilot Study.

STUDY OBJECTIVE: To study the hypothesis that the levonorgestrel intrauterine device (LNG-IUD) can have a role in the treatment of endometrial polyps confirmed at outpatient hysteroscopy in premenopausal women. DESIGN: Canadian Task Force classification level II1 (a controlled trial that is not randomised). SETTING: Outpatient hysteroscopy. PATIENTS: Premenopausal women who had a polyp diagnosed at outpatient hysteroscopy. INTERVENTIONS: Premenopausal women who had a polyp diagnosed at outpatient hysteroscopy and had a LNG-IUD inserted were booked for general anesthesia hysteroscopy and polypectomy through the standard booking process. A contemporaneous control was taken sequentially from the outpatient hysteroscopy database to match the case. MEASUREMENTS AND MAIN RESULTS: The presence of a polyp at hysteroscopy under general anesthesia. A total of 39 patients were included in the study, with 19 in the intervention group and 20 in the control group. The mean age was 43.6 (standard deviation = 5.6) and 43.2 (standard deviation = 8.1) years in the 2 groups, respectively. No difference was found in the time interval between the 2 procedures in the intervention and control groups (mean = 92 vs 84 days, p = .73). However, the proportion of polyps present at the second procedure was significantly higher in the control group (80% vs 37%; relative risk = 2.17; 95% confidence interval, 1.16-4.07; p = .0062). CONCLUSION: Our case-control study found that the LNG-IUD can have a role in the treatment of polyps for women who have heavy menstrual bleeding. This is the first study to show regression of endometrial polyps after treatment with LNG-IUD by direct visualisation at hysteroscopy.

Looking beyond human papillomavirus (HPV) genotype 16 and 18: Defining HPV genotype distribution in cervical cancers in Australia prior to vaccination.

Australia has implemented a high-coverage HPV vaccination program but has not, to date, established the distribution of HPV types that occur in cervical cancers in Australia. This information is important for determining the potential for cervical cancer prevention with both current and broader spectrum HPV vaccines. We analysed 847 cervical cancers diagnosed 2005 to 2015 in tertiary centres in the three most populous Australian states with resolution of specimens containing multiple HPV types using laser-capture microdissection. Archived FFPE tissue was reviewed by specialist pathologists, sandwich sectioned, and initially whole-tissue sections genotyped for HPV. Samples were first genotyped using SPF10-LiPA25 (version 1). Negative samples were screened with DNA ELISA kit HPV SPF10, followed by genotyping with SPF+ LiPA if ELISA positive. If still negative, samples were tested on a qPCR assay targeting the E6 region of HPV16, 18, 45 and 33. Of the 847 cancers (65.1% squamous, 28.7% adenocarcinoma, 4.3% adenosquamous, 2.0% other), 92.9% had HPV detected. Of the HPV-positive cancers, 607 of 787 (77.1%) contained HPV16 or 18, 125 of 787 (15.9%) contained HPV31/33/45/52 or 58, and 55 (7.0%) another HPV type. There was a strong correlation between HPV type and age, with younger women most likely to have HPV16/18 detected and least likely HPV negative. Our findings indicate that cervical cancers diagnosed in Australia more frequently contain HPV16/18 than in international series. This could be due to cervical screening in Australia increasing the proportion of adenocarcinomas, in which types 18 and 16 more strongly predominate, due to prevention of squamous cancers.

Incidence and Characteristics of Unsuspected Neoplasia Discovered in High-Risk Women Undergoing Risk Reductive Bilateral Salpingooophorectomy.

OBJECTIVE: Risk reducing salpingooophorectomy is recommended to women with a BReast CAncer susceptibility gene (BRCA) 1 or 2 germline mutation to reduce the risk of ovarian cancer. The incidence of unsuspected neoplasia varies in the literature. The purpose of this study was to identify the rate of unsuspected neoplasia in a high-risk Australian population, discuss their management, and assess the clinical outcome. METHOD: This is a retrospective review of all women undergoing risk reductive salpingooophorectomy between January 2006 and December 2014. The medical, operative, and pathology results were reviewed. The specimens were assessed using the Sectioning and Extensively Examining the Fimbriated End protocol to the fallopian tube, and the ovary was also examined using 2 to 3 mm sectioning. RESULTS: During the study period, 138 patients underwent risk-reducing salpingooophorectomy for a known BRCA 1 or 2 germline mutation or a high-risk personal or family history of ovarian cancer. Five patients with neoplasia were identified, 2 with invasive tubal carcinoma and 3 with serous tubal intraepithelial carcinoma (STIC), giving an overall incidence of 3.62%. Invasive tubal carcinoma occurred in 1 woman with a BRCA 1 mutation and 1 woman with a BRCA 2 mutation. The incidence of carcinoma in women with either a BRCA 1 or 2 germline mutation was subsequently 2.78%. STIC occurred in 2 women with a BRCA 1 germline mutation and 1 woman carrying a BRCA 2 germline mutation. The incidence of STIC in women with either a BRCA 1 or 2 germline mutation was subsequently 4.17%. Of the patients with STIC, all 3 remain disease free at an average follow-up period of 79.33 months. CONCLUSIONS: In this retrospective review, we found the incidence of neoplasia within a high-risk Australian population undergoing risk-reducing bilateral salpingo-oophorectomy to be 3.62%. The incidence of STIC was 2.17%. During our follow-up period, all patients with STIC remained disease free.

Are endometrial nerve fibres unique to endometriosis? A prospective case-control study of endometrial biopsy as a diagnostic test for endometriosis in women with pelvic pain.

STUDY QUESTION: Can the presence of endometrial nerve fibres be used as a diagnostic test for endometriosis in women with pelvic pain? SUMMARY ANSWER: Endometrial fine nerve fibres were seen in the endometrium of women both with and without endometriosis, making their detection a poor diagnostic tool for endometriosis. WHAT IS KNOWN ALREADY: Laparoscopy and biopsy are currently the gold standard for making a diagnosis of endometriosis. It has been reported that small density nerve fibres in the functional layer of the endometrium are unique to women with endometriosis and hence nerve fibre detection could function as a less invasive diagnostic test of endometriosis. However, it may be that other painful conditions of the pelvis are also associated with these nerve fibres. We therefore focused this prospective study on women with pelvic pain to examine the efficacy of endometrial nerve fibre detection as a diagnostic test for endometriosis. STUDY DESIGN, SIZE, DURATION: This prospective case-control study conducted between July 2009 and July 2013 included 44 women with pelvic pain undergoing laparoscopic examination for the diagnosis of endometriosis. Immunohistochemical nerve fibre detection in endometrial curettings and biopsies using anti-protein gene product 9.5 was compared with surgical diagnosis. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Paired endometrial biopsies and curettings were taken from patients with (n = 22, study group) and without (n = 22, control group) endometriosis. Tissue was analysed by immunohistochemistry and nerve fibres were counted whenever they were present in the functional layer of the endometrium. MAIN RESULTS AND THE ROLE OF CHANCE: Fine nerve fibres were present in the eutopic endometrium of patients both with and without endometriosis. The presence of nerve fibres in curettings was not effective for either diagnosing or excluding endometriosis; sensitivity and specificity were 31.8 and 45.5% respectively, positive predictive value was 36.8% and negative predictive value was 40.0%. Few endometrial biopsy specimens were found to have nerve fibres present; sensitivity and specificity for endometrial biopsy were 13.6 and 68.2% respectively, positive predictive value was 30.0% and negative predictive value was 44.1%. LIMITATIONS, REASONS FOR CAUTION: This was a relatively small sample size and studies like this are subject to the heterogeneous nature of the patient population and tissue samples, despite our best efforts to regulate these parameters. WIDER IMPLICATIONS OF THE FINDINGS: Our results demonstrate that fine nerve fibres are present in women with and without endometriosis. Future work should focus on the function of endometrial nerves and whether these nerves are involved with the subfertility or pain that endometriosis sufferers experience. Our study does not support the detection of endometrial nerve fibres as a non-invasive diagnostic test of endometriosis in women with pelvic pain.

Viral cytopathic changes in sputum cytology in a patient with known human metapneumovirus.

INTRODUCTION: Viral cytopathic changes seen in sputum cytology have been described in association with infection by viruses such as cytomegalovirus (CMV), herpes simplex virus (HSV), adenovirus, and even measles. However, viral cytopathic changes due to human metapneumovirus (hMPV) have not yet been well described in cytology. Human metapneumovirus is a relatively new entity, discovered in 2001. It is known to cause upper and lower respiratory tract infections in children, the elderly, and immunocompromised patients. CASE PRESENTATION: We describe the viral cytopathic changes seen in sputum in a 63-year-old male patient with known hMPV. These changes include multinucleation, nuclear enlargement, homogenised nuclei, basophilic nuclear inclusions with perinuclear halos, and small eosinophilic cytoplasmic inclusions. CONCLUSION: We aim to raise awareness that hMPV can cause viral cytopathic changes and to describe these cytological features, which have been elucidated in only one case report thus far. Distinction from other viruses with similar changes, such as HSV and CMV, is important due to their differing clinical implications.

Cell Block Optimization: A Comparative Study of Quality Variables in 4 Different Cell Block Methods.

OBJECTIVE: The cell block (CB) is an important adjunct to cytological preparations in diagnostic cytopathology. Optimizing cellular material in the CB is essential to the success of ancillary studies such as immunohistochemistry (IHC) and molecular studies (MS). Our aim was to identify which CB method was most suitable in a variety of specimen types and levels of cellularity. STUDY DESIGN: We assessed 4 different CB methods, thrombin clot method (TCM), MD Anderson method (MDAM), gelatin foam method (GFM), and agar method (AM), with descriptive observations and ranking of the methods based on quantity of cells and morphological features. RESULTS: TCM performed best in ranking for both quantity of cells and morphological features, followed by MDAM, GFM, and AM. Lack of adjuvant in the MDAM resulted in some unique morphological advantages which, however, also resulted in inconsistent performance. In low cellularity cases insufficient cells were frequently identified on slides from MDAM and AM CBs. Technique touch time was similar for all methods, with total processing time being shortest for TCM followed by MDAM, GFM, and AM. CONCLUSIONS: TCM was the most robust CB technique, retaining high scores for ranking of quantity and morphology in a variety of specimen cellularities and specimen types.

Seborrheic Keratosis-Like Lesion of the Cervix: First Report of the Cytological Features of a Low-Risk HPV 42-Associated Lesion.

INTRODUCTION: Seborrheic keratosis-like lesion of the cervix and vagina is a rare lesion and shows similar morphology to vulvar seborrheic keratosis; 3 of the 7 previously reported cases were associated with low-risk human papillomavirus (HPV) type 42. We report a case of seborrheic keratosis-like lesion of the cervix and provide the first description of the cytological features of this lesion. CASE PRESENTATION: A woman in her late forties presented with postcoital bleeding. She had a cervical screening test following which she underwent cervical biopsy, endocervical and endometrial curettage, large loop excision of the transformation zone of the cervix, and hysterectomy. RESULTS: The liquid-based cytology preparation showed cohesive groups of mildly atypical squamoid cells with a spindle cell morphology, mildly increased nuclear to cytoplasmic ratio, prominent nucleoli, and occasional nuclear grooves. No koilocytes were identified. Molecular genotyping revealed positivity for HPV type 42. DISCUSSION/CONCLUSION: This represents the first description of the cytological features of a seborrheic keratosis-like lesion of the cervix, which are distinctive and unusual. Whilst the mild squamous atypia raised the possibility of a low-grade squamous intraepithelial lesion, no koilocytes were identified. The association in our case with a low-risk HPV type, HPV 42, provides further evidence for a role of this HPV type in the pathogenesis of these lesions.

Well-differentiated papillary mesothelioma in association with endometrial carcinoma: a case report.

BACKGROUND: Well-differentiated papillary mesothelioma (WDPM) is an uncommon tumor usually arising in the peritoneum and mostly an incidental finding during abdominal and pelvic surgery. Its natural history and association with other neoplasms is not clearly understood. We present a rare case of WDPM in association with high-grade endometrial carcinoma. To our knowledge, there are only two previously reported cases in the English literature of WDPM in association with endometrial carcinoma. CASE: A 62-year-old woman underwent pelvic surgery for a high-grade endometrial adenocarcinoma. At laparotomy an extensive peritoneal nodular fibrotic reaction was present, raising the clinical possibility of metastatic disease; however, intraoperative frozen section reported this as a mesothelial reaction. Cytologic examination of peritoneal washings revealed cohesive clusters of reactive-appearing mesothelial cells, some with papillary morphology, and no evidence of adenocarcinoma. The peritoneal biopsies showed no metastatic carcinoma. The endometrial tumor was an endometrioid adenocarcinoma. CONCLUSION: The cytologic diagnosis of WDPM may be difficult because it is an uncommon entity and there are overlapping features with other neoplastic and nonneoplastic lesions of the female genital tract and peritoneum. Compounding this, WDPM may occur in association with other neoplasms. We highlight the potential for surgical and pathologic misinterpretation of this entity.

Highlighted issues from the second edition RCPA Endometrial Cancer Structured Reporting Protocol.

Endometrial cancer is the most common malignancy of the female genital tract in the Western world. The second edition Endometrial Cancer Structured Reporting Protocol was published to the Royal College of Pathologists of Australasia (RCPA) website in December 2019, and relates to the reporting of endometrial cancer in hysterectomy specimens. This editorial discusses selected key issues from the second edition of the RCPA protocol, and addresses future challenges in pathology reporting of endometrial cancer.

Observations on the application of the Papanicolaou Society of Cytopathology standardised terminology and nomenclature for pancreaticobiliary cytology.

In 2014 the Papanicolaou Society of Cytopathology (PSC) published a system of standardised terminology and nomenclature for pancreaticobiliary cytology (STNPC). In the present study, 232 previously reported pancreaticobiliary cytology specimens were categorised according to this set of guidelines in order to identify potential challenges to implementation of the PSC system into routine practice. Overall, 207 (89%) of the cases were found to comply with the PSC scheme in their original form. Twenty-five cases (11%) demonstrated that the application of the PSC system would result in a change of category. In the majority of these cases, the change was related to the method of categorising low grade and premalignant neoplasms, using the categories of 'Neoplastic: other' (a new category unique to STNPC classification scheme) and 'Atypical', for specimens deemed to be diagnostic of or suspicious for these lesions, respectively. The study also highlighted the emphasis on the inclusion of imaging context and cyst fluid analysis in the interpretation of endoscopic ultrasound guided fine needle aspiration specimens in the guidelines. The STNPC offers an approach to pancreaticobiliary cytology that reflects the considerable variation in the nature and treatment of the entities that may be encountered in these specimens. Challenges in utilisation of the scheme include awareness of the unique approach to the categorisation of premalignant and low grade neoplasms, and the amount and quality of available clinical and imaging information.

Development of a silver in situ hybridisation based assay for the determination of ploidy status in molar pregnancy diagnosis.

The aim of this study was to establish a scoring method for ploidy analysis using silver in situ hybridisation (SISH) with a chromosome 17 centromere probe. SISH was performed using the Ventana chromosome 17 centromere probe on sections from formalin fixed, paraffin embedded archival cases of complete hydatidiform moles, partial hydatidiform moles and hydropic products of conception with previously established ploidy status (determined by flow cytometry or karyotyping). In order to determine ploidy status, a scoring method was developed based on both the average number of signals per nucleus (ASN) and the percentage of nuclei with three signals (N3S), enumerated in 50 villous cytotrophoblastic and/or stromal cells. The results of four independent observers were compared individually and collectively with previously established ploidy status. There was a highly statistically significant difference between diploid and triploid gestations for ASN (1.86 ±â€Š0.13 and 2.70 ±â€Š0.16 respectively, Student t-test, p < 0.0001) and for N3S (1.14 ±â€Š1.65 and 71.59 ±â€Š14.25 respectively, Student t-test, p < 0.0001). The sensitivity and specificity of the SISH-based assay was 99.1% and 100% respectively for ASN, and 100% and 100% respectively for N3S. A chromosome 17 centromere probe SISH-based assay can reliably distinguish between diploid and triploid gestations. This test has diagnostic utility in distinguishing partial hydatidiform moles from histological mimics.