BK viraemia as a cause of anaemia in after ABO-incompatible liver transplant: a case report.

BACKGROUND: While anaemia following liver transplant is common, anaemia in the context of BK viraemia is not a commonly recognised phenomenon. CASE PRESENTATION: We present the case of 59-year old gentleman with severe anaemia in the context of BK viraemia and nephropathy following ABO incompatible liver transplant. Severity of anaemia appeared to correlate with high titres of BK virus in the serum. Bone marrow biopsy revealed hypocellular marrow with normal cytogenetics. Anaemia improved with treatment with cidofovir, intravenous immunoglobulin, reduction in immunosuppression and erythropoietin stimulating agent. CONCLUSION: To our knowledge, this is the first case of anaemia post liver transplant contributed to by BK viraemia.

Dedifferentiated umbilical metastases from low grade endometrioid endometrial adenocarcinoma complicated by super-obesity: A case report.

INTRODUCTION: Umbilical metastases are uncommon and rarely associated with endometrial cancer. In this report we describe a unique case of a patient with low-grade endometrioid adenocarcinoma (EAC) who developed an umbilical metastasis containing dedifferentiated endometrial carcinoma, in the context of super-morbid obesity with a body mass index (BMI) of 80 kg/m2. PRESENTATION OF CASE: A 55-year-old female with atypical endometrial hyperplasia was treated with progestogens whilst attempting weight loss prior to definitive surgery, given the impact of her obesity on surgical risk. She progressed to grade 1 EAC of the uterus and then to metastatic disease in the umbilicus and inguinal lymph nodes. After adequate weight loss, cytoreductive surgery was completed via robotic hysterectomy and bilateral salpingoophorectomy (BSO) and resection of metastatic disease. Differing histological grades were seen across all disease sites with dedifferentiated endometrial carcinoma at the umbilicus. Immunohistochemistry suggested a common uterine origin due to loss of MLH1 and PMS2 proteins. DISCUSSION: There are no clear management pathways for the rare umbilical metastases related to endometrial cancer. Our patient's significant obesity complicated their clinical course and highlights the risks of progestogen therapy whilst attempting weight loss prior to definitive surgery for low-grade EAC. Differing grades of disease across metastatic sites in EAC is rare and may reflect the recently recognized intratumoral genetic heterogeneity in endometrial cancers. CONCLUSION: Management of umbilical metastases should be individualized to patient factors and local resources. More research is needed into pathways of care for women with low grade EAC with obesity preventing routine surgical management.

Older age should not be a barrier to testing for somatic variants in homologous recombination DNA repair-related genes in patients with high-grade serous ovarian carcinoma.

BACKGROUND: Somatic pathogenic variants (PVs) in homologous recombination DNA repair (HR)-related genes found in high-grade serous ovarian carcinomas (HGSC) are not well-characterised in older patients (≥70 years). This may reflect low testing rates in older patients. METHODS: Data from 1210 HGSC patients in AACR Project GENIE and 324 patients in an independent dataset INOVATe were analysed. Cases where somatic variants could be distinguished from germline variants were included, and analysis was restricted to those with a somatic TP53 variant, to ensure cases were HGSC. RESULTS: Of 1210 patients in GENIE, 27% (n = 325) were aged ≥70 years at testing. Patients with somatic-only PVs in BRCA2 were older compared with BRCA1 (median 71 vs 60 years, p = 0.002). Median age for 21 patients with somatic-only PVs in 11 other HR-related genes ranged from 40 to 67 years. In older patients, 7% (n = 22) had somatic BRCA1/2 PVs, and 1% (n = 2) had PVs other HR-related genes; this rate was not significantly different to younger patients (<70 years), 7% (n = 62) BRCA1/2 and 2% (n = 19) other HR-related genes (p = 0.36). The overall frequency of somatic BRCA1/2 PVs was similar in INOVATe (n = 25; 7.7%) and somatic-only BRCA2 PVs were again found in older patients compared with BRCA1 (median age: at testing, 70 vs 63 years; at diagnosis, 68 vs 60 years). CONCLUSIONS: The overall frequency of somatic-only PVs in HR-related genes was similar in older and younger patients with HGSC, highlighting the importance of somatic testing irrespective of age. Limiting somatic testing by age may exclude patients who could benefit from maintenance poly(ADP-ribose) polymerase (PARP) inhibitors.

Ruptured ectopic molar pregnancy and ruptured uterine fibroid: a challenging rare diagnosis.

Although rare and unusual occurrences, a ruptured ectopic molar pregnancy (MP) and a ruptured uterine fibroid can lead to significant maternal morbidity and mortality. We present a unique case of these complications developing concurrently-resulting in the haemodynamic compromise of an otherwise healthy young female patient. The patient underwent a diagnostic laparoscopy which converted into a laparotomy, salpingectomy and myomectomy. Comprehensive histopathology confirmed the diagnosis of a ruptured ectopic complete MP and ruptured uterine fibroid. The patient recovered quickly within days. Prompt definitive management, conclusive histopathology and adequate follow-up were the hallmarks of this singular case. These key factors lead to the rare diagnosis of ruptured ectopic MP and uterine fibroid, prevention of adverse outcomes and provision of comprehensive patient care.

Data Set for the Reporting of Endometrial Cancer: Recommendations From the International Collaboration on Cancer Reporting (ICCR).

Endometrial cancer is one of the most common cancers among women. The International Collaboration on Cancer Reporting (ICCR) developed a standardized endometrial cancer data set in 2011, which provided detailed recommendations for the reporting of resection specimens of these neoplasms. A new data set has been developed, which incorporates the updated 2020 World Health Organization Classification of Female Genital Tumors, the Cancer Genome Atlas (TCGA) molecular classification of endometrial cancers, and other major advances in endometrial cancer reporting, all of which necessitated a major revision of the data set. This updated data set has been produced by a panel of expert pathologists and an expert clinician and has been subject to international open consultation. The data set includes core elements which are unanimously agreed upon as essential for cancer diagnosis, clinical management, staging, or prognosis and noncore elements which are clinically important, but not essential. Explanatory notes are provided for each element. Adoption of this updated data set will result in improvements in endometrial cancer patient care.

Metastatic ovarian disease following surgical management of grade 1 endometrial endometrioid adenocarcinoma confined to the endometrium; a case report and review of the literature.

Endometrial endometrioid type cancer is a common gynaecological cancer for which the standard surgical management includes hysterectomy and bilateral salpingo-oophorectomy. The value of oophorectomy is to remove occult ovarian disease. It is estimated that 5 % of low grade endometrioid adenocarcinoma will have concurrent ovarian involvement (3 % synchronous tumours, 2 % ovarian metastases), of which only 1 % will be microscopic. Ovarian preservation at the time of surgery can be considered, especially in early-stage disease or premenopausal women. We describe a case of metastatic ovarian disease following surgical management of grade 1 endometrial endometrioid adenocarcinoma confined to the endometrium (FIGO stage 1a), in a postmenopausal woman who declined primary oophorectomy. This case was without genetic predisposition and recurred 12 months after initial surgical treatment. This case is incongruent with what has previously been understood for FIGO stage 1a endometrial endometrioid adenocarcinoma and highlights that even disease seemingly confined to the endometrium can metastasise microscopically to the ovaries.

Radiology-pathology correlation of endometrial carcinoma assessment on magnetic resonance imaging.

Endometrial carcinoma is the most common gynaecological cancer in developed countries. Most cases are low-volume/low-grade tumour at presentation; however, high-grade subtypes may present with locally advanced disease with higher propensity for spread outside of the pelvis. MRI has a role in local staging of the tumour and helping the clinicians in treatment decision making. This pictorial essay gives examples of endometrial carcinoma at different stages with histological correlation. It also explores the potential limitations and pitfalls of imaging in this context.

Patterns of biopsy-proven renal disease in people living with HIV: 10 years experience in Sydney, Australia.

BACKGROUND: Acute and chronic kidney diseases are important comorbidities in People Living With HIV (PLWH). Biopsy is often pursued in this cohort with ongoing renal impairment without a clear aetiology, in order to establish the diagnosis and to guide management. Despite the importance of renal disease in PLWH, there is a paucity of biopsy data-especially in the Australian setting. Consequently, who and when to biopsy is mainly based on clinical experience. The aims of this study were to describe biopsy-proven renal disease in PLWH at our institution and to assess for correlation between any demographic or laboratory characteristics with histological diagnosis. METHODS: A retrospective review of all PLWH who underwent renal biopsy between January 2010 and December 2020 at Royal Prince Alfred Hospital, Sydney, Australia was performed. All PLWH over 18 years, who were not transplant recipients were included. Demographic, laboratory and biopsy data was extracted from the electronic medical records. Basic descriptive statistics were performed, and correlation was assessed using chi square and Kendall's coefficient of rank test. RESULTS: 19 renal biopsies were included in the study. The majority of PLWH were Australian born (53%), male (84%) and had a mean age of 48 years (SD 13). Comorbid hypertension and diabetes were present in 74% and 21% of people respectively. The mean serum creatinine was 132 µmol/L (SD 55) and the mean estimated glomerular filtration rate (eGFR) was 61 ml/min/1.73m2 (SD 24). The most common histological diagnosis was tubulointerstial nephritis in 5 people (24%). Hypertensive glomerulosclerosis and IgA nephropathy were present in 4 (19%) and 3 (14%) people respectively. There were no cases of HIV-associated nephropathy. There was no significant correlation between any cohort characteristics and diagnoses. CONCLUSIONS: This study represents the first description of biopsy-proven kidney disease in the HIV-infected population of Australia. Our results support the use of renal biopsy in PLWH with ongoing renal impairment for accurate diagnosis and to guide further management. Although a small sample size, our study is larger than other published international biopsy studies.

The impact of primary human papillomavirus screening on negative loop excision histology following biopsy-proven high-grade cervical intra-epithelial lesions: A review from a large tertiary colposcopy unit.

BACKGROUND: The renewed National Cervical Screening Program incorporating primary human papillomavirus (HPV) screening was implemented in Australia in December 2017. In a previous study conducted in the UK, primary HPV screening was found to be associated with a 25% reduction in the incidence of negative histology following loop electrosurgery excision procedure (LEEP). AIM: To examine the change in incidence and associated risk factors for a negative LEEP with introduction of primary HPV screening. MATERIALS AND METHODS: A retrospective review of the records of all patients undergoing a LEEP excision for biopsy-proven high-grade cervical intra-epithelial lesions between 1 January 2014 and 30 June 2019 in a specialised centre. RESULTS: There were 1123 patients who underwent a LEEP included in the analysis. The incidence of a negative LEEP specimen was 7.5% (59/784) and 5.3% (18/339) in the pre- and post-HPV screening cohort. More patients in the post-HPV screening group had low-grade cytology on referral (P < 0.001), smaller cervical lesions on colposcopy (P = 0.012) and longer biopsy to treatment interval (P = 0.020). Primary HPV screening was associated with a significant reduction in the incidence of a negative LEEP specimen in a propensity matched cohort (11.2% to 5.1%, P = 0.006) and a 41% (P = 0.045) decreased relative risk of a negative LEEP on multivariate analysis. CONCLUSIONS: Primary HPV screening results in a lower incidence of negative LEEP histology, despite a longer biopsy to treatment wait time and higher proportion of low-grade cytology at triage.

Programmed death ligand-1 (PD-L1) as a predictive marker for immunotherapy in solid tumours: a guide to immunohistochemistry implementation and interpretation.

Immunotherapy with checkpoint inhibitors is well established as an effective treatment for non-small cell lung cancer and melanoma. The list of approved indications for treatment with PD-1/PD-L1 checkpoint inhibitors is growing rapidly as clinical trials continue to show their efficacy in patients with a wide range of solid tumours. Clinical trials have used a variety of PD-L1 immunohistochemical assays to evaluate PD-L1 expression on tumour cells, immune cells or both as a potential biomarker to predict response to immunotherapy. Requests to pathologists for PD-L1 testing to guide choice of therapy are rapidly becoming commonplace. Thus, pathologists need to be aware of the different PD-L1 assays, methods of evaluation in different tumour types and the impact of the results on therapeutic decisions. This review discusses the key practical issues relating to the implementation of PD-L1 testing for solid tumours in a pathology laboratory, including evidence for PD-L1 testing, different assay types, the potential interchangeability of PD-L1 antibody clones and staining platforms, scoring criteria for PD-L1, validation, quality assurance, and pitfalls in PD-L1 assessment. This review also explores PD-L1 IHC in solid tumours including non-small cell lung carcinoma, head and neck carcinoma, triple negative breast carcinoma, melanoma, renal cell carcinoma, urothelial carcinoma, gastric and gastroesophageal carcinoma, colorectal carcinoma, hepatocellular carcinoma, and endometrial carcinoma. The review aims to provide pathologists with a practical guide to the implementation and interpretation of PD-L1 testing by immunohistochemistry.

Glomangiomyoma of the clitoris: A case report and literature review.

Glomus tumor is an uncommon, benign, soft-tissue lesion in which the cells recapitulate the structure of the normal modified smooth muscle cells of the glomus body. Glomus tumors usually occur in tissues that normally contain glomus bodies; only rarely can they develop in sites where glomus bodies are normally sparse or absent. There are three subtypes of glomus tumor, with glomangiomyoma being the rarest. No more than 10 cases of glomus tumor in female genitalia have previously been reported, involving the vulva, vaginal area, periurethral area and clitoris. A clitoral glomangiomyoma is extremely rare. This is a case report of a glomangiomyoma in the clitoral area. Published reports of glomus tumor in the female external genitalia are reviewed.

Precaval recurrent endometrial cancer treated with en-bloc resection of the inferior vena cava and reconstruction using bovine pericardium. A case report and review of the literature.

•Bovine pericardium for IVC reconstruction has significant advantages comparing to vascular ligation, autogenous or PTFE grafts.•En-bloc resection of metastatic precaval lymph nodes and reconstruction of the IVC is feasible.•Recurrence of endometrial cancer at para-aortic lymph nodes is good candidate for secondary cytoreduction with MDT approach.

Excisional treatment comparison for in situ endocervical adenocarcinoma (EXCISE): A phase 2 pilot randomized controlled trial to compare histopathological margin status, specimen size and fragmentation after loop electrosurgical excision procedure and cold knife cone biopsy.

OBJECTIVE: Adenocarcinoma in situ (AIS) of the cervix is a precursor to cervical adenocarcinoma. When AIS is detected by cervical screening an excision biopsy is mandatory to exclude invasion. We aimed to compare margins status, specimen size and fragmentation after loop electrosurgical excision procedure (LEEP) and 'cold knife cone biopsy' (CKC). METHODS: The EXCISE Trial was an investigator-initiated, multicenter, open-label, parallel-group, phase 2, randomized study. Patients were enrolled at seven hospitals in Australia and New Zealand. We randomly assigned women aged ≥18 to ≤45 years with screen detected AIS to LEEP or CKC. Co-primary endpoints were margin status, specimen size and fragmentation. Analysis was by intention-to-treat. RESULTS: Between August 2, 2017 and September 6, 2019, 40 patients were randomly assigned 2:1 to LEEP or CKC. Margin status was evaluable in 36 cases. The proportion of patients with involved margins did not differ between groups. 25 of 26 LEEP and all 14 CKC biopsies were excised as single specimens (p = 1·00). There were no differences in specimen dimensions. Patients in the CKC group had more post-operative complications (64.3% compared to 15.4% for LEEP p = ·00). There were no differences in grade three complications (p = ·65). CONCLUSIONS: LEEP was not associated with a greater likelihood of positive margins, specimen fragmentation or smaller excision compared to CKC when performed according to a standardized protocol. However, the study was not powered to establish non-inferiority of LEEP and a definitive phase 3 trial to compare margin status and rates of treatment failure after LEEP and CKC is warranted.

Follow-up after treatment of high-grade cervical dysplasia: The utility of six-month colposcopy and cytology and routine 12-month colposcopy.

BACKGROUND: Australian Cervical Screening Program guidelines no longer recommend colposcopy and cytology at six months following treatment of cervical intraepithelial neoplasia (CIN2/3) and a co-test of cure can be performed at 12 months without colposcopy. AIMS: To determine the usefulness of six-month colposcopy and cytology and routine colposcopy with co-testing at 12 months in detecting persistent or recurrent disease in patients treated for CIN2/3. MATERIALS AND METHODS: We conducted a review of all patients with histologically proven CIN2/3 who underwent a cervical excisional procedure between March 2012 and March 2017 in one specialised centre. RESULTS: We examined 1215 cases and 750 remained after exclusions for analysis. At six months (722 cases, 96.2%) seven of 42 (16.7%) patients with high-grade cytology had a high-grade colposcopy and 24 of 42 (57.1%) had a normal colposcopy. Persistent CIN2/3 was diagnosed in 12 cases (1.7%) and only 1/3 had a high-grade colposcopy. Cytology was more useful than colposcopy in detecting persistent disease. At 12 months (638 cases, 85%) routine colposcopy at the time of co-testing had a high false positive rate with all high-grade changes negative on biopsy and co-test. Recurrent CIN2/3 was diagnosed in five cases, and four had normal colposcopy at co-testing. CONCLUSIONS: There may be a delay in detection of persistent/recurrent CIN2/3 in a small number of cases without six-month colposcopy and cytology; however, it is not likely to negatively impact overall clinical outcome. Co-testing at 12 months following treatment of CIN2/3 without colposcopy is safe and routine colposcopy at collection of the co-test can be omitted.

Strongyloides hyperinfection in an HIV-positive kidney transplant recipient: a case report.

BACKGROUND: Strongyloidiasis is caused by the helminth Strongyloides stercoralis and is well-recognised amongst transplant recipients. Serious complications, including Strongyloides hyperinfection which is a syndrome of accelerated autoinfection, or disseminated disease, can occur post-transplantation, resulting in significant morbidity and mortality. Here we present the first published case we are aware of, describing post-transplant Strongyloides hyperinfection in an HIV-positive kidney transplant patient. We discuss the diagnostic challenges and the role of pre-transplant screening. CASE PRESENTATION: A 58-year-old African-American male, originally from the Caribbean, received a deceased donor kidney transplant for presumed focal segmental glomerulosclerosis. He was known to be HIV-positive, with a stable CD4 count, and an undetectable viral load. Five months post-transplant, he developed gastrointestinal symptoms and weight loss. He had a normal eosinophil count (0.1-0.2 × 109/L), negative serum cytomegalovirus DNA, and negative blood and stool cultures. His Strongyloides serology remained negative throughout. A diagnosis of Strongyloides hyperinfection was made by the histological examination of his duodenum and lung, which identified the parasites. He completed his course of treatment with Ivermectin but exhibited profound deconditioning and required a period of total parenteral nutrition. He was subsequently discharged after a prolonged hospital admission of 54 days. CONCLUSIONS: This case highlights the challenges in diagnosing Strongyloides infection and the need to maintain a high index of clinical suspicion. Non-invasive techniques for the diagnosis of Strongyloides may be insufficient. Routine pre-transplant serological strongyloidiasis screening is now performed at our centre.

Proteogenomic analysis of Inhibitor of Differentiation 4 (ID4) in basal-like breast cancer.

BACKGROUND: Basal-like breast cancer (BLBC) is a poorly characterised, heterogeneous disease. Patients are diagnosed with aggressive, high-grade tumours and often relapse with chemotherapy resistance. Detailed understanding of the molecular underpinnings of this disease is essential to the development of personalised therapeutic strategies. Inhibitor of differentiation 4 (ID4) is a helix-loop-helix transcriptional regulator required for mammary gland development. ID4 is overexpressed in a subset of BLBC patients, associating with a stem-like poor prognosis phenotype, and is necessary for the growth of cell line models of BLBC through unknown mechanisms. METHODS: Here, we have defined unique molecular insights into the function of ID4 in BLBC and the related disease high-grade serous ovarian cancer (HGSOC), by combining RIME proteomic analysis, ChIP-seq mapping of genomic binding sites and RNA-seq. RESULTS: These studies reveal novel interactions with DNA damage response proteins, in particular, mediator of DNA damage checkpoint protein 1 (MDC1). Through MDC1, ID4 interacts with other DNA repair proteins (γH2AX and BRCA1) at fragile chromatin sites. ID4 does not affect transcription at these sites, instead binding to chromatin following DNA damage. Analysis of clinical samples demonstrates that ID4 is amplified and overexpressed at a higher frequency in BRCA1-mutant BLBC compared with sporadic BLBC, providing genetic evidence for an interaction between ID4 and DNA damage repair deficiency. CONCLUSIONS: These data link the interactions of ID4 with MDC1 to DNA damage repair in the aetiology of BLBC and HGSOC.

Endometrial adenocarcinoma arising in a pelvic implant following uterine morcellation: A case report.

We report a unique case of a 60-year-old woman developing endometrial cancer in a uterine deposit 18 years after she had undergone laparoscopic subtotal hysterectomy with morcellation for benign pathology. She had used unopposed estrogen as menopausal hormone therapy. She presented with a pelvic mass that was causing pressure symptoms. On imaging, the mass had an enhancing vascular nodular component and appeared to abut normal ovaries and the residual cervix. She proceeded to laparotomy, where a 12 cm pelvic mass was found morbidly adherent to the bladder anteriorly and to the cervical stump. The pelvic mass was excised, and trachelectomy and bilateral salpingo-oophorectomy were performed. Adjacent to this mass was a separate, 5 cm adnexal mass, which was also excised. Histopathology of the smaller pelvic mass was consistent with endometrial adenocarcinoma grade 1, arising in complex endometrial hyperplasia with atypia surrounded by myometrium consistent with a uterine implant. This case highlights the need for consideration and discussion of possible risks of subtotal hysterectomy and morcellation of the uterus for benign disease. Furthermore, given the results in this patient, the use of unopposed estrogen in such patients is discouraged due to possible effects on any residual endometrium still present.

The Lymphatic System in Endometriosis: a Pilot Study of Endometrial-Like Cells and Immune Cell Populations in Lymph Nodes Associated with Deep Infiltrating Bowel Lesions.

In endometriosis, the lymphatic and immune systems are implicated in disease establishment and progression. The objective of this pilot study was to examine endometrial-like, and for the first time, immune cell populations in lymph nodes associated with deep infiltrating endometriosis (DIE) bowel lesions. Premenopausal women undergoing excision of endometriosis and/or hysterectomy were included. DIE bowel lesion-associated (n = 10) and other pelvic (n = 15) lymph nodes were studied. Samples were immunohistochemically stained for endometrial-like cells (CD10), T cells (CD3, CD4, CD8, and FoxP3), dendritic cells (DC; DC-Lamp and DC-Sign), B cells (CD20, CD79 and plasma), macrophages (CD68), and natural killer cells (NK; CD57). Cell abundance (percentage positive area) and antigen expression (optical density; OD) were quantified. Endometrial-like cells and each immune cell population were present in all studied nodes. The DIE bowel lesion-associated nodes showed features of immune activation, with T cell proliferation (CD3+ area p = 0.007, CD4+ area p = 0.015 compared with other pelvic nodes); and a mixture of helper and regulatory T cells, B cells, DCs, macrophages, and plasma cells present in the paracortex. In DIE bowel lesion-associated compared with other pelvic nodes, CD10+ endometrial-like cells were reduced (percentage positive area p < 0.001, OD p = 0.004). This study provides new insight into lymphatic and immune system involvement in advanced endometriosis. In particular, we have shown evidence of immune activation in DIE lesion-associated nodes. This was despite lower endometrial-like cell numbers compared with other pelvic nodes. The observations contribute to a developing understanding of the local immune response to advanced disease.