Comparing fluorodeoxyglucose positron emission tomography with computed tomography in staging for nodal and distant metastasis in urothelial/bladder cancer.

Objectives: We aim to assess the clinical value of 18F-fluorodeoxyglucose positron (18F-FDG-PET) scan in detecting nodal and distant metastasis compared with computed tomography (CT) scan in patients with urothelial carcinoma or bladder cancer, aiming to improve staging accuracy and thereby better prognosticate and determine therapy. Methods: A retrospective review of 75 patients with invasive bladder cancer (≥T1) who were staged with both CT and 18F-FDG-PET within an 8-week interval was performed for the period between 2015 and 2020. Seventy-two per cent (54/75) had formal pelvic lymph node (LN) dissection or biopsy of lesions suspicious for metastases. FDG-PET definitions for positive sites were assessed depending on SUV Max (nodes with SUVmax >4 at any size, SUV > 2 for lymph nodes >8 mm, or any SUV if the lymph node was >10 mm on axial images). For CT scanning, enlarged LN by RECIST 1.1 criteria (>10 mm) as well as qualitative findings suggesting metastasis were considered positive. The analysis was based on the comparison of CT and 18F-FDG-PET findings to histopathology results from LN dissection or biopsies. Results: Sensitivity, specificity, positive predictive values (PPV) and negative predictive value (NPV) of CT versus FDG-PET for detecting metastasis, in patients who underwent pelvic LN dissection or biopsy of lesions suspicious of metastases, were 46.6% (95% CI: 21%-70%) versus 60% (95% CI: 32%-84%), 100% (95% CI: 91%-100%) versus 83.78% (95% CI: 69%-94%), 100% (95% CI: 63%-100%) versus 60% (95% CI: 32%-84%), and 82.2% (95% CI: 68%-92%) versus 83.78% (95% CI: 69%-94%), respectively. 7/75 (9.3%) patients avoided cystectomy due to 18F-FDG-PET features of metastases that were not detected by CT. Conclusion: FDG-PET may be more sensitive than CT for metastases in the staging of bladder cancer, which resulted in significant avoidance of aggressive local management in cases with occult metastasis.

The SUB-urothelial DUrvalumab InjEction-1 (SUBDUE-1) trial: first-in-human trial in patients with bladder cancer.

OBJECTIVES: To assess the safety of sub-urothelial injection of durvalumab and examine the impact on tissue and circulating immune cell populations. PATIENTS AND METHODS: The patients were chemotherapy and immunotherapy naïve (bacille Calmette-Guérin allowed) with non-metastatic muscle-invasive bladder cancer or non-muscle-invasive bladder cancer planned for radical cystectomy (RC). The study was a Phase Ib 3 + 3 dose-escalation design with sub-urothelial injection of durvalumab at three pre-determined doses (25, 75, 150 mg) diluted in 25 mL normal saline, injected at 25 locations (25 × 1 mL injections), at least 2 weeks before RC. RESULTS: A total of 11 patients were recruited (10 male, one female). No significant changes were reported on American Urological Association Symptom Score or O'Leary Interstitial Cystitis Scale. In all, 14 adverse events (AEs) were reported (10 Grade 1, three Grade 2, one Grade 3), none considered immune-related. No Grade 4 or 5 AEs were recorded. All the patients underwent RC. Tissue immune populations changed following durvalumab injection (P = 0.012), with a statistically significant increase in M2-macrophage (CD163) when comparing the 25-150 mg dose (P = 0.021). Basal/mixed cancers showed a larger CD163 increase than luminal cancers (P = 0.033). CONCLUSION: Sub-urothelial injection of durvalumab is feasible and safe without immune-related AEs and shows local immunological effects.

Solitary fibrous tumour of the urinary bladder - A rare and potentially malignant neoplasm.

Solitary fibrous tumours (SFTs) of the urinary bladder are a rare mesenchymal neoplasm that occasionally has malignant potential. The tumour is characterised by haphazardly arranged spindle-shaped to ovoid cells, with a prominent, branching, thin-walled, dilated vasculature and NAB2-STAT6 gene rearrangement. While most SFTs are indolent in nature, difficulty arises predicting which SFTs are potentially malignant. There are now validated risk stratification tools to help identify which SFTs are likely to metastasize and help clinicians determine management. The mainstay of treatment for SFTs remains surgery, with emerging evidence in the combined use of surgery and radiotherapy.

Lymph node assessment technique matters in radical cystectomy for bladder cancer.

BACKGROUND: For patients undergoing radical cystectomy with pelvic lymph node dissection for urothelial cancer, a lymph node count of at least 16 is associated with improved cancer-specific and overall survival. Lymph node yield is presumed to relate directly to extent of dissection and surgical quality, however limited studies have reviewed the impact of the pathological assessment process of lymph nodes on lymph node yield. METHOD: A retrospective assessment of 139 patients who had radical cystectomy for urothelial cancer between March 2015 and July 2021 from Fiona Stanley Hospital (Perth, Australia) by a single surgeon was assessed. A change in pathological assessment process from assessment of only palpable lymph nodes to microscopic assessment of the entire submitted specimens occurred in August 2018. Patients were divided into two groups accordingly and other relevant demographic and pathological data was recorded. The impact of pathological processing technique on lymph node yield was assessed using the Student T test and logistical regression was used to assess the impact of other demographic variables. RESULTS: The mean lymph node yield was 16.2 nodes (IQR 12-23) in 54 patients in the pre-process change group compared to 22.4 nodes (IQR 15-28.4) in 85 patients in the post-process change group (P < 0.0001). 53.7% had 16 or more nodes in the pre-process change group compared to 71.3% in the post-process change group (P = 0.04). Age, BMI, and gender were not significant predictors of lymph node yield. CONCLUSION: The current study demonstrates that the microscopic assessment of all lymph node tissue detects significantly more lymph nodes than only examining palpably abnormal tissue. Pathologic assessment protocols should be standardized to this technique to ensure the utility of lymph node yield as a quality metric.

Isolated, PSMA-negative penile metastasis from castration resistant prostate adenocarcinoma, identified by FDG-PET.

Penile metastases are a rare entity and are associated with widespread metastatic disease. It is associated with significant morbidity with a poor prognosis. There have been few case reports about metastatic prostate adenocarcinoma to the penis. Diagnosis is often clinical, however, the use of PSMA PET has a high sensitivity. We report the first case of metastatic castration resistant prostate cancer with an isolated penile metastatic site. This was not identified on conventional staging or PSMA PET, but using FDG PET. A radical penectomy was performed with ongoing survival.

Technetium-99 m-sestamibi single-photon emission computerised tomography (CT)/CT in the prediction of malignant versus benign small renal masses.

OBJECTIVES: To determine the effectiveness of technetium-99m (99m Tc)-sestamibi single-photon emission computerised tomography/computerised tomography (SPECT/CT) in distinguishing between malignant and benign renal lesions. PATIENTS AND METHODS: Between June 2018 and October 2020 all patients with new indeterminate small renal masses (SRMs) underwent 99m Tc-sestamibi renal SPECT/CT before biopsy or surgery. The accuracy of 99m Tc-sestamibi imaging diagnoses was assessed against histopathology. Receiver operating characteristic (ROC) analysis was used to determine the optimum cut-off for the tumour:normal uptake ratio. Logistic regression was used to determine if quantitative analysis significantly added to visual interpretation alone. RESULTS: A total of 74 patients with SRMs were investigated with 99m Tc-sestamibi SPECT/CT. The SPECT/CT correctly identified 49 malignant tumours and 11 benign tumours, resulting in a sensitivity of 0.89 (95% confidence interval [CI] 0.77-0.95) and a specificity of 0.73 (95% CI 0.45-0.91). The ROC analysis of uptake ratios demonstrated that a tumour:normal uptake ratio of 0.41 provided optimal diagnostic accuracy (sensitivity 0.81, specificity 0.88, area under the curve 0.883 [95% CI 0.794-0.971]). The uptake ratio was also highly significant in excluding malignancy on univariate logistic regression analysis whereby the higher the uptake ratio, the lower the chances were for malignancy (odds ratio 0.009, 95% CI 0.001-0.118, P < 0.001). However, this did not improve diagnostic accuracy when compared to visual interpretation alone. CONCLUSION: 99m Tc-sestamibi SPECT/CT is a non-invasive technique with good accuracy in determining if a SRM is benign or malignant.

Unique case of IgG4-related disease of the renal pelvis involving the inferior vena cava masquerading as locally advanced urothelial cancer.

Immunoglobulin G4-related disease (IgG4-RD) is a systemic disease which can affect any organ or tissue in the body but most commonly affects the pancreas, biliary ducts, salivary glands, ocular system and lymph nodes; renal involvement is relatively uncommon and there are no previous reported cases of inferior vena cava involvement. Herein, a 48-year-old Asian man with an unremarkable medical history was found to have an obstructing right renal pelvis mass extending to and involving the inferior vena cava, highly suspicious for upper tract urothelial carcinoma that could not be ruled out based on ureteroscopy and urine cytology. Open radical nephroureterectomy with enbloc resection of a segment of the inferior vena cava and left renal vein ostium was performed, with reconstruction of the inferior vena cava and left renal vein with polytetrafluoroethylene grafts. Final histopathology confirmed the diagnosis of IgG4-related disease. This case demonstrates that IgG4-related disease can mimic upper tract urothelial cancer and should be considered as a diagnosis in atypical presentations of tumours of the upper urinary tract.

A phase I open label dose-escalation study to evaluate the tolerability, safety and immunological efficacy of sub-urothelial durvalumab injection in adults with muscle-invasive or high-risk non-muscle-invasive bladder cancer (SUBDUE-1, SUB-urothelial DUrvalumab injection-1 study): clinical trial protocol.

OBJECTIVES: This article presents the clinical trial protocol for a phase I open label dose-escalation study to evaluate the tolerability, safety and immunological efficacy of sub-urothelial durvalumab injection in adults with muscle-invasive or high-risk non-muscle-invasive bladder cancer (NMIBC), the SUB-urothelial DUrvalumab injection-1 study (SUBDUE-1). The primary objectives of this study are to assess the safety of sub-urothelial injection of durvalumab using patient reported outcome measures and observed local or systemic adverse events. The secondary objectives are to examine the local immunological efficacy of sub-urothelial administration of durvalumab. PATIENTS AND METHODS: The SUBDUE-1 trial will include adult patients with either high-risk NMIBC or MIBC, who are scheduled for radical cystectomy or who have refused or are unsuitable for systemic neoadjuvant chemotherapy. Three fixed total dose levels of durvalumab (25, 75, 150 mg) will be studied to identify a dose suitable to be taken forward into phase II trials. The primary endpoint is to evaluate the safety and tolerability of the trial intervention in terms of the incidence and severity of adverse events and the potential establishment of dose-limiting toxicities. The secondary efficacy endpoints include rates of pT0 status at resection, lymph node status, as well as the change in distribution of tumour-infiltrating lymphocytes and tumour-activated macrophages between pre- and post-injection bladder biopsies. Translational studies will focus on bladder tumour molecular sub-typing, immune infiltrate characterisation, and immune checkpoint protein expression relative to efficacy end-points. OUTCOME AND SIGNIFICANCE: If proven safe and effective, this novel strategy comprising sub-urothelial durvalumab injections aimed at promoting an anti-tumour immune reaction, will provide additional treatment options for reducing tumour recurrence and progression in treatment-naïve patients with high-risk NMIBC or in patients with bacille Calmette-Guérin-refractory NMIBC. Local administration of durvalumab may be associated with a reduced rate of immunological side-effects and lower costs when compared to systemic delivery.

Adenocarcinoma of the urethra: A rare subtype of urethral cancer.

Urethral adenocarcinoma (UA) is a rare type of urethral cancer with a poor prognosis. We present a case of UA of intestinal subtype in a 57-year-old patient who initially had lower urinary tract symptoms and was subsequently found to have a urethral lesion in a urethral diverticulum on pelvic MRI which was confirmed on biopsy. She had neoadjuvant chemotherapy followed by open anterior pelvic exenteration, complete urethrectomy and ileal conduit urinary diversion. She required adjuvant chemotherapy for local invasion and a metastasis in the uterus but developed progressive metastatic disease and succumbed to the disease 13-months after surgery.

Interobserver variability in the diagnosis of circumscribed sebaceous neoplasms of the skin.

AIMS: Separation of sebaceous adenoma, sebaceoma and well differentiated sebaceous carcinoma is a clinically important distinction which relies on a number of subjective criteria. In routine practice we had noted significant interobserver variability in the classification of these lesions. This study sought to determine the degree of interobserver variability between general surgical pathologists and dermatopathologists in the diagnosis of well differentiated cutaneous sebaceous neoplasms. METHODS: We circulated 61 examples of well circumscribed cutaneous sebaceous neoplasms to nine pathologists, including dermatopathologists and general surgical pathologists who were asked to submit a diagnosis for each case. Fleiss' kappa statistic was used for assessment of interobserver agreement. RESULTS: We found that only seven cases (11%) had consensus agreement across all nine pathologists. Many cases had multiple diagnoses suggested, with three or more submitted diagnoses in 26 cases (43%), while 38 cases (62%) were diagnosed as sebaceous carcinoma by at least one pathologist. There was marked variability amongst the individual pathologists in the proportion of cases diagnosed as carcinoma, ranging from 5% to 57% of cases. Fleiss' kappa statistic for all pathologists across all diagnostic categories was 0.44, amounting to only fair to moderate agreement. CONCLUSIONS: These data indicate that there is substantial interobserver variability in the diagnosis of well circumscribed sebaceous neoplasms. This was seen in both the separation of benign and malignant lesions, as well as in the classification of the benign entities. This interobserver variability is likely to have significant clinical implications in terms of potential for over- or under-treatment, as well as in selection of cases for mismatch repair protein evaluation.

Diagnosis of pulmonary hamartoma by fine needle biopsy.

OBJECTIVE: To review the features of pulmonary hamartoma (PH) on fine needle biopsy (FNB), with emphasis on features that allow specific diagnosis. STUDY DESIGN: Fourteen cases of PH diagnosed on FNB were reviewed. The presence and volume of aspirate components were recorded. Attention was paid to features that might lead to false positive diagnosis of malignancy. Immunohistochemical staining for S100 was performed on cell block material. RESULTS: Fibromyxoid stroma and chondroid material were seen in 93% and 79% of cases, respectively; 71% demonstrated both components. Fibromyxoid stroma was prominent in the majority of cases; chondroid material was less abundant, being scanty in over half of cases. There were no cases in which epithelial cells represented the sole prominent component, and significant epithelial atypia was not identified. S100 staining was demonstrable in all cases in which stromal material was present in the cell block. CONCLUSION: A correct specific diagnosis of pH requires identification and correct interpretation of either fibromyxoid stroma or cartilaginous material. These components may show variable appearance on smears, with a range of potential mimics and pitfalls, but specific features are recognizable. Immunohistochemical staining of stromal material with S100 may lend support to the diagnosis.

Diagnosis of extramammary malignancy metastatic to the breast by fine needle biopsy.

AIMS: To review and illustrate the findings in fine needle biopsy (FNB) of extramammary malignancies presenting with breast metastases (MMB). METHODS: We reviewed 32 cases of MMB diagnosed on breast FNB. The clinical data, with particular attention to the history of a known primary malignancy, previous systemic metastatic disease in other sites and presentation with extramammary disease in addition to a breast mass were examined. The morphological appearances were reviewed and are illustrated, focusing on those features which allow the pathologist to recognise the possibility of metastatic disease and undertake appropriate steps to investigate this. RESULTS: The 32 cases included metastases from a wide range of sites, including cutaneous melanoma (10), lung (8), non-Hodgkin's lymphoma (5), soft tissue (4), colon (2), endometrium, ovary and bladder. There was a history of extramammary malignancy in 26, while in six patients the breast mass was detected at initial presentation with malignant disease. Of the latter six patients, four had evidence of widespread metastases, while one presented with multiple breast masses. In 16 cases the cytological features allowed the possibility of metastases to be recognised without clinical data, while in the other 16 there was sufficient overlap with primary mammary carcinoma that the possibility of metastases could be missed. Only one case was initially mistaken for a primary tumour, in this case the history of prior malignancy with systemic metastases was not provided to the reporting pathologist. CONCLUSION: The majority (81%) of cases of MMB have a history of primary malignancy, although only a minority have a history of systemic metastases at other sites. Of those patients without known prior malignancy, the majority present with systemic disease or multiple breast lesions. The cytological features allow metastatic disease to be suspected in half of the cases, although in the others, particularly patients with metastatic adenocarcinoma, diagnosis without recourse to immunohistochemistry is difficult or impossible. A combination of complete clinical history, attention to the cytological features and suspicion in cases with metastatic disease beyond the axilla should allow most cases of MMB to be suspected, and suitable material for ancillary confirmatory testing to be obtained.