PD-L1 and nectin-4 expression and genomic characterization of bladder cancer with divergent differentiation.

BACKGROUND: Bladder cancer with divergent differentiation (BCDD) comprises a heterogenous group of tumors with a poor prognosis, and differential expression of nectin-4 and programmed death ligand-1 (PD-L1) has been reported in BCDD. Importantly, nectin-4 expression in bladder cancer is associated with response to enfortumab vedotin, and PD-L1 expression is associated with responses to immune checkpoint inhibitors (ICIs). METHODS: The authors conducted a retrospective review identifying 117 patients with advanced or metastatic BCDD who were treated at Winship Cancer Institute from 2011 to 2021. They performed immunohistochemistry staining for nectin-4 and PD-L1 expression by histologic subtype as well as genomic analysis of these patients, including RNA sequencing, whole-exome sequencing, and fusion detection analysis as well as a subgroup genomic analysis of patients with BCDD who received ICIs. RESULTS: The results indicated that nectin-4 expression was highest in the groups who had the squamous and plasmacytoid subtypes, whereas the group that had the sarcomatoid subtype (70.8%) had the highest proportion of PD-L1-positive patients. Genomic analysis yielded several key findings, including a 50% RB1 mutation rate in patients who had small cell BCDD, targetable PIK3CA mutations across multiple subtypes of BCDD, and significantly higher expression of TEC in responders to ICIs. CONCLUSIONS: In this study, the authors identified clinically relevant data on nectin-4 and PD-L1 expression in patients with rare bladder tumors. They also identified several novel findings in the genomic analysis that highlight the role of precision medicine in this population of patients. Larger, prospective studies are needed to validate these hypothesis-generating data.

Proposal for an optimised definition of adverse pathology (unfavourable histology) that predicts metastatic risk in prostatic adenocarcinoma independent of grade group and pathological stage.

AIMS: Histological grading of prostate cancer is a powerful prognostic tool, but current criteria for grade assignment are not fully optimised. Our goal was to develop and test a simplified histological grading model, based heavily on large cribriform/intraductal carcinoma, with optimised sensitivity for predicting metastatic potential. METHODS AND RESULTS: Two separate non-overlapping cohorts were identified: a 419-patient post-radical prostatectomy cohort with long term clinical follow-up and a 209-patient post-radical prostatectomy cohort in which all patients had pathologically confirmed metastatic disease. All prostatectomies were re-reviewed for high-risk histological patterns of carcinoma termed 'unfavourable histology'. Unfavourable histology is defined by any classic Gleason pattern 5 component, any large cribriform morphology (> 0.25 mm) or intraductal carcinoma, complex intraluminal papillary architecture, grade 3 stromogenic carcinoma and complex anastomosing cord-like growth. For the outcome cohort, Kaplan-Meier analysis compared biochemical recurrence, metastasis and death between subjects with favourable and unfavourable histology, stratified by pathological stage and grade group. Multivariable Cox proportional hazards models evaluated adding unfavourable histology to the Memorial Sloan Kettering Cancer Center (MSKCC) post-prostatectomy nomogram and stratification by percentage of unfavourable histology. At 15 years unfavourable histology predicted biochemical recurrence, with sensitivity of 93% and specificity of 88%, metastatic disease at 100 and 48% and death at 100 and 46%. Grade group 2 prostate cancers with unfavourable histology were associated with metastasis independent of pathological stage, while those without had no risk. Histological models for prediction of metastasis based on only large cribriform/intraductal carcinoma or increasing diameter of cribriform size improved specificity, but with lower sensitivity. Multivariable Cox proportional hazards models demonstrated that unfavourable histology significantly improved discriminatory power of the MSKCC post-prostatectomy nomogram for biochemical failure (likelihood ratio test P < 0.001). In the retrospective review of a separate RP cohort in which all patients had confirmed metastatic disease, none had unequivocal favourable histology. CONCLUSIONS: Unfavourable histology at radical prostatectomy is associated with metastatic risk, predicted adverse outcomes better than current grading and staging systems and improved the MSKCC post-prostatectomy nomogram. Most importantly, unfavourable histology stratified grade group 2 prostate cancers into those with and without metastatic potential, independent of stage. While unfavourable histology is driven predominantly by large cribriform/intraductal carcinoma, the recognition and inclusion of other specific architectural patterns add to the sensitivity for predicting metastatic disease. Moreover, a simplified dichotomous model improves communication and could increase implementation.

Vascular, adipose tissue, and/or calyceal invasion in clear cell tubulopapillary renal cell tumour: potentially problematic diagnostic scenarios.

AIMS: The 2022 WHO classification for kidney tumours recently downgraded clear cell tubulopapillary (also known as clear cell papillary) renal cell carcinoma (RCC) to a benign neoplasm (i.e. clear cell tubulopapillary renal cell tumour) based on the overwhelmingly banal nature of this neoplasm. However, it has been recognized that some clear cell tubulopapillary renal cell tumours demonstrate vascular, adipose or pelvicalyceal invasion, raising the possibility of more aggressive behaviour. The goal of this study was to determine if these 'high stage' features have an effect on tumour prognosis, warranting a carcinoma designation. METHODS AND RESULTS: After excluding cases with tissue artefact (i.e. prior core biopsy track changes) and other RCC subtypes with next-generation sequencing, nine clear cell tubulopapillary renal cell tumours with these so-called 'high stage' features, and otherwise classic morphologic and immunophenotypic findings, including low-grade cytology and 'cup-like' CA9 expression, were evaluated. Median tumour size was 2.2 cm with a range of 0.8 to 6.7 cm. Eight cases (89%) demonstrated perinephric or hilar adipose tissue invasion, although most of these cases showed a bulging (in contrast to an infiltrative) growth pattern. One case demonstrated renal vascular invasion in addition to hilar adipose tissue invasion, and one case demonstrated extension into the pelvicalyceal system. There were no recurrences or evidence of metastatic disease. CONCLUSION: These overall findings continue to support the benign designation for clear cell tubulopapillary renal cell tumours, despite morphologic features that might raise the possibility of a 'higher stage' neoplasm.

Noninvasive Papillary Urothelial Carcinoma of the Bladder: An Institutional Experience Focusing on Tumors With Borderline Features.

CONTEXT.­: Noninvasive papillary urothelial carcinomas (PUCs) comprise most urinary bladder tumors. Distinction between low-grade (LG-PUC) and high-grade (HG-PUC) PUCs is pivotal for determining prognosis and subsequent treatment. OBJECTIVE.­: To investigate the histologic characteristics of tumors with borderline features between LG-PUC and HG-PUC, focusing on the risk of recurrence and progression. DESIGN.­: We reviewed the clinicopathologic parameters of noninvasive PUC. Tumors with borderline features were subcategorized as follows: tumors that look like LG-PUC but have occasional pleomorphic nuclei (1-BORD-NUP) or elevated mitotic count (2-BORD-MIT), and tumors with side-by-side distinct LG-PUC and less than 50% HG-PUC (3-BORD-MIXED). Recurrence-free, total progression-free, and specific invasion-free survival curves were derived from the Kaplan-Meier method, and Cox regression analysis was performed. RESULTS.­: A total of 138 patients with noninvasive PUC were included, with the following distribution: LG-PUC (n = 52; 38%), HG-PUC (n = 34; 25%), BORD-NUP (n = 21; 15%), BORD-MIT (n = 14; 10%), and BORD-MIXED (n = 17; 12%). Median (interquartile range) follow-up was 44.2 months (29.9-73.1 months). Invasion-free survival was different between the 5 groups (P = .004), and pairwise comparison showed that HG-PUC had a worse prognosis compared with LG-PUC (P ≤ .001). On univariate Cox analysis, HG-PUC and BORD-NUP were 10.5 times (95% CI, 2.3-48.3; P = .003) and 5.9 times (95% CI, 1.1-31.9; P = .04) more likely to invade, respectively, when compared to LG-PUC. CONCLUSIONS.­: Our findings confirm a continuous spectrum of histologic changes in PUC. Approximately a third of noninvasive PUCs show borderline features between LG-PUC and HG-PUC. Compared with LG-PUC, BORD-NUP and HG-PUC were more likely to invade on follow-up. BORD-MIXED tumors did not statistically behave differently from LG-PUC.

Genetic Profiling of African American Patients With Prostatic Adenocarcinoma Metastatic to the Lymph Nodes: A Pilot Study.

CONTEXT.­: Genetic profiling data of prostatic adenocarcinoma are derived from predominantly White patients. In African Americans, prostatic adenocarcinoma has a poorer prognosis, raising the possibility of distinct genetic alterations. OBJECTIVE.­: To investigate the genomic alterations of prostatic adenocarcinoma metastatic to regional lymph nodes in African American patients, with an emphasis on SPOP mutation. DESIGN.­: We retrospectively reviewed African American patients with pN1 prostatic adenocarcinoma managed with radical prostatectomy and lymph node dissection. Comprehensive molecular profiling was performed, and androgen receptor signaling scores were calculated. RESULTS.­: Nineteen patients were included. The most frequent genetic alteration was SPOP mutations (5 of 17; 29.4% [95% CI: 10.3-56.0]). While most alterations were associated with a high androgen receptor signaling score, mutant SPOP was exclusively associated with a low median and interquartile range (IQR) androgen receptor signaling score (0.788 [IQR 0.765-0.791] versus 0.835 [IQR 0.828-0.842], P = .003). In mutant SPOP, mRNA expression of SPOP inhibitor G3BP1 and SPOP substrates showed a significantly decreased expression of AR (33.40 [IQR 28.45-36.30] versus 59.53 [IQR 53.10-72.83], P = .01), TRIM24 (3.95 [IQR 3.28-5.03] versus 9.80 [IQR 7.39-11.70], P = .008), and NCOA3 (15.19 [IQR 10.59-15.93] versus 21.88 [IQR 18.41-28.33], P = .046). CONCLUSIONS.­: African American patients with metastatic prostate adenocarcinoma might have a higher prevalence of mutant SPOP (30%), compared to ∼10% in unselected cohorts with lower expressions of SPOP substrates. In our study, in patients with mutant SPOP, the mutation was associated with decreased SPOP substrate expression and androgen receptor signaling, raising concern for suboptimal efficacy of androgen deprivation therapy in this subset of patients.

Aberrant expression of GATA3 in metastatic adenocarcinoma of the prostate: an important pitfall.

AIMS: The distinction of high-grade prostate cancer (PCa) from poorly differentiated urothelial carcinoma (UC) can be somewhat challenging on clinical and morphological grounds alone, yet it is of great importance for prognostication and choice of treatment. GATA3 is a useful immunohistochemical marker to confirm urothelial origin. However, recent works report strong GATA3 immunoexpression in primary high-grade PCa. The aim of this study was to explore GATA3 expression specifically in metastatic PCa. METHODS AND RESULTS: The pathology databases of four tertiary institutions were queried for cases of metastatic PCa. Available slides and clinical records were reviewed by experienced genitourinary pathologists. Prostatic markers (PSA, PSAP, NKX3.1) and GATA3 immunohistochemistry were performed. A total of 163 metastatic PCa cases were included. At least one prostate marker was positive in each case of non-regional distant metastasis, confirming prostatic origin. GATA3 strong staining was found in four (2.5%) cases: two liver, one bone and one non-regional lymph-node metastases. All four patients had Grade Group 5 PCa at the initial diagnosis. The metastatic prostatic adenocarcinomas were solid, either with no gland formation (n = 3) or with only focal cribriforming (n = 1). CONCLUSIONS: To our knowledge, this is the first study exploring GATA3 expression specifically in metastatic PCa. Despite being infrequent, GATA3 positivity in high-grade PCa may lead to misdiagnosis, with clinical implications. We recommend a panel of immunohistochemical markers, both prostatic and urothelial, for ruling out UC, either in primary tumour samples or in the event of metastases of unknown primary, when a genitourinary origin is suspected.

The Genomic Landscape of Urothelial Carcinoma with High and Low ERBB2 Expression.

BACKGROUND: Recent data suggests that HER2-targeted treatment is efficacious in urothelial carcinoma (UC). We investigated the genomic, transcriptomic, and immune landscapes and clinical outcomes in UC segmented by ERBB2 expression. METHODS: NextGen DNA/RNA sequencing was performed for 4743 UC tumors. A total of 3% (124/4125) of tumors had HER2 IHC and whole transcriptome sequencing (WTS) data. ERRB2-high and -low tumors were defined by ≥75th and <25th percentiles of ERBB2 expression, respectively. PD-L1 (SP142) positive staining was defined as ≥2+ and ≥5%. HER2 (4B5) positive staining was defined as ≥3+ and >10% or 2+ and >10% with positive HER2 in situ hybridization (ISH). RESULTS: Of the patients who were ERBB2-high, 79% (61/77) were HER2 positive via IHC. Tumors from lower tract UC had higher ERBB2 expression compared to upper tract UC (50 v 40 median TPM (mTPM), p < 0.001). ERBB2 expression was similar between primary and metastatic tumors (47 v 47 mTPM, p = 0.95). ERBB2-high tumors had a higher prevalence of pathogenic mutations in pTERT, ERBB2, and ELF3 versus ERBB2-low tumors, p < 0.001. ERBB2-high tumors had higher expressions of ADC target genes NECTIN4 (12 v 8 mTPM) and TACSTD2 (366 v 74 mTPM) versus ERBB2-low (p < 0.001), as well as better overall survival from time of tissue sampling than ERBB2-low (HR 1.71, p < 0.001). CONCLUSION: Our study demonstrated a high concordance between HER2 expression by IHC and ERBB2 gene expression by WTS in UC. Differences in ADC target expression between ERBB2-high vs. ERBB2-low UC may provide a rationale for combination treatment strategies with HER2-ADC. The association between high ERBB2 expression and survival advantage warrants further investigation.

Solitary fibrous tumours involving the genitourinary tract: a case series in rare locations, highlighting the role of STAT6 immunohistochemistry.

Solitary fibrous tumour (SFT) is a mesenchymal neoplasm with variable behaviour, very rarely involving the genitourinary (GU) tract. Most reported cases correspond to isolated case reports. STAT6 immunohistochemistry is a more recent and reliable diagnostic marker. The pathology database of two tertiary institutes was searched for SFTs involving the GU tract. STAT6 strong diffuse nuclear staining confirmed the diagnosis in all four cases, and the NAB2::STAT6 fusion was demonstrated by NGS in one case. Two cases were diagnosed in needle biopsy, one involving the prostate and the other involving the seminal vesicle. One case corresponded to a pelvic mass inseparable from and infiltrating the prostate and bladder. The remainder represented an exceedingly rare involvement of the spermatic cord. Involvement by a SFT should be considered in the differential diagnosis of spindle cell lesions involving GU organs. STAT6 strong diffuse nuclear staining is an important ancillary tool, particularly in a biopsy.

Case Report: Exceptional response to nivolumab plus cabozantinib in a patient with extrarenal clear cell renal cell carcinoma.

Extrarenal clear cell renal cell carcinoma (eccRCC) is a rare type of RCC that arises in areas other than the kidney. Given its rarity, consensus guidelines for optimal treatment of eccRCC have not been established, and the literature is lacking any reports of patient response to systemic therapy and any reports of administration of immunotherapy to patients with ecRCC. Here, we present the case of a patient in their 60s with eccRCC arising in the spleen. The patient underwent splenic resection and then received systemic therapy, due to disease recurrence, with a combination of immunotherapy (IO) and tyrosine kinase inhibitor targeted therapy (VEGF-TKI). The patient had an excellent and durable response to this therapeutic regimen with minimal adverse effects, completing 2 years of therapy of nivolumab and cabozantinib. At the time of this report, the disease remains stable. This case demonstrates that combination therapy with IO+VEGF-TKI represents a reasonable and well-tolerated treatment option with activity in eccRCC and reveals interesting correlative data, including nests of stem-like CD8+T-cell infiltration in tumor tissue, which provide important biological context to this patient's exceptional therapeutic response.

Challenges and opportunities in the management of non-urothelial bladder cancers.

Urothelial carcinoma accounts for approximately 90% of all bladder cancer diagnoses. Localized, muscle-invasive disease is often managed with a multidisciplinary approach including either neoadjuvant chemotherapy (NAC) followed by radical cystectomy or concurrent chemoradiation, whereas multiple immunotherapies and novel antibody drug conjugates have recently joined platinum-based chemotherapy as standard of care therapy for metastatic disease. However, the clinical trials leading to these standards often require majority if not complete urothelial histology for eligibility. As many as one quarter of patients diagnosed with bladder cancer will have either divergent differentiation of their urothelial carcinoma or an alternate epithelial tumor such as squamous cell carcinoma, adenocarcinoma, or small cell carcinoma; even more rare are non-epithelial tumors such as sarcoma. The rarity of these diseases and their general exclusion from treatment within prospective clinical trials has created a challenging situation where treatment plans are often derived from case series or extrapolated from other disease types and outcomes are poor compared to pure urothelial carcinoma. In this review, we summarize the existing data on the diagnosis and treatment of epithelial, non-urothelial bladder cancers including adenocarcinoma, squamous cell carcinoma, and small cell carcinoma in their localized and advances stages. We will also review the current clinical trial landscape investigating novel approaches to these diseases.

Durable complete response for oligometastatic renal cell carcinoma with immune checkpoint inhibition and cytoreductive nephrectomy in a Jehovah's witness: A case report.

The role of cytoreductive nephrectomy in patients with metastatic renal cell carcinoma is a subject of debate. We report a durable complete response in a 62-year-old man Jehovah's Witness with metastatic clear cell renal cell carcinoma who received two cycles of nivolumab/ipilimumab followed by radical nephrectomy and metastasectomy of known pulmonary disease site, both without a clinical need for perioperative blood transfusions. The patient continues to be without evidence of disease and without additional need for systemic therapy over a year after his radical nephrectomy. The case highlights that cytoreductive nephrectomy continues to play a role in the era of immune checkpoint inhibitors.

Granulomas associated with renal neoplasms: A multi-institutional clinicopathological study of 111 cases.

AIMS: Formal depiction of granulomatous inflammation associated with renal neoplasms has mainly consisted of case reports. Herein, we investigate the clinicopathological features and potential significance of granulomas associated with renal tumours from a large multi-institutional cohort. METHODS AND RESULTS: One hundred and eleven study cases were collected from 22 institutions, including 57 partial nephrectomies and 54 radical nephrectomies. Patient ages ranged from 27 to 85 years (average = 60.1 years; male = 61%). Renal neoplasms included clear cell renal cell carcinoma (RCC; 86%), papillary RCC (8%), chromophobe RCC (3%), clear cell papillary RCC (1%), mixed epithelial stromal tumour (1%) and oncocytoma (1%). Granulomas were peritumoral in 36%, intratumoral in 24% and both in 40% of cases. Total granuloma count per case ranged from one to 300 (median = 15) with sizes ranging from 0.15 to 15 mm (mean = 1.9 mm). Necrotising granulomas were seen in 14% of cases. Histochemical stains for organisms were performed on 45% of cases (all negative). Sixteen cases (14%) had a prior biopsy/procedure performed, and eight patients had neoadjuvant immunotherapy or chemotherapy. Eleven patients (10%) had a confirmed diagnosis of sarcoidosis, including five in whom sarcoidosis was diagnosed after nephrectomy. CONCLUSION: Based on this largest case-series to date, peri-/intratumoral granulomas associated with renal neoplasms may be more common than initially perceived. The extent of granulomatous inflammation can vary widely and may or may not have necrosis with possible aetiologies, including prior procedure or immunotherapy/chemotherapy. Although a clinical association with sarcoidosis is infrequent it can still occur, and the presence of granulomas warrants mention in pathology reports.

Risk Stratification of Prostatic Adenocarcinoma Metastatic to the Lymph Nodes.

CONTEXT.­: The pathologic nodal staging of prostatic adenocarcinoma is binary for regional lymph nodes. Stages pN0 and pN1 indicate the absence or presence of regional nodal metastasis, respectively, whereas patients with metastasis to nonregional lymph nodes are staged as pM1a. OBJECTIVE.­: To determine the risk of recurrence of pN1 prostatic adenocarcinoma patients based on the extent of nodal tumor burden. DESIGN.­: We retrospectively reviewed pN1 patients with prostatic adenocarcinoma managed with radical prostatectomy seen between 2011 and 2019. Kaplan-Meier and Cox regression analyses were performed to compare disease-free survival. RESULTS.­: Ninety-six patients were included (median [interquartile range] age, 62 years [57-67 years]; 70 of 96 [73%] White). On univariate analysis, age >65 years (P = .008), ≥2 positive regional lymph nodes (P < .001), and a maximum size of the tumor deposit ≥2 mm (P = .004) were significantly associated with an unfavorable outcome. Controlling for age, stage, metastatic deposit size, margin status, and the presence of extranodal extension, patients with ≥2 positive regional lymph nodes were 3.03 times more likely (95% confidence interval, 1.39-6.60; P = .005) to have an unfavorable outcome. Patients with pN1M1a stage showed a disease-free survival similar to that of pN1M0 patients, after controlling for the number of positive regional lymph nodes (P = .36). CONCLUSIONS.­: Overall, pN1 patients with ≥2 positive regional lymph nodes are 3 times more likely to have an unfavorable outcome. The results suggest a benefit in further stratifying patients with metastatic prostatic adenocarcinoma to the lymph nodes into prognostically significant risk categories that could help the treating clinicians tailor subsequent patient follow-up and therapy.

Diagnostic approach in TFE3-rearranged renal cell carcinoma: a multi-institutional international survey.

Transcription factor E3-rearranged renal cell carcinoma (TFE3-RCC) has heterogenous morphologic and immunohistochemical (IHC) features.131 pathologists with genitourinary expertise were invited in an online survey containing 23 questions assessing their experience on TFE3-RCC diagnostic work-up.Fifty (38%) participants completed the survey. 46 of 50 participants reported multiple patterns, most commonly papillary pattern (almost always 9/46, 19.5%; frequently 29/46, 63%). Large epithelioid cells with abundant cytoplasm were the most encountered cytologic feature, with either clear (almost always 10/50, 20%; frequently 34/50, 68%) or eosinophilic (almost always 4/49, 8%; frequently 28/49, 57%) cytology. Strong (3+) or diffuse (>75% of tumour cells) nuclear TFE3 IHC expression was considered diagnostic by 13/46 (28%) and 12/47 (26%) participants, respectively. Main TFE3 IHC issues were the low specificity (16/42, 38%), unreliable staining performance (15/42, 36%) and background staining (12/42, 29%). Most preferred IHC assays other than TFE3, cathepsin K and pancytokeratin were melan A (44/50, 88%), HMB45 (43/50, 86%), carbonic anhydrase IX (41/50, 82%) and CK7 (32/50, 64%). Cut-off for positive TFE3 fluorescent in situ hybridisation (FISH) was preferably 10% (9/50, 18%), although significant variation in cut-off values was present. 23/48 (48%) participants required TFE3 FISH testing to confirm TFE3-RCC regardless of the histomorphologic and IHC assessment. 28/50 (56%) participants would request additional molecular studies other than FISH assay in selected cases, whereas 3/50 participants use additional molecular cases in all cases when TFE3-RCC is in the differential.Optimal diagnostic approach on TFE3-RCC is impacted by IHC and/or FISH assay preferences as well as their conflicting interpretation methods.

Case Report: Exceptional Response to Nivolumab Plus Ipilimumab in a Young Woman With TFE3-SFPQ Fusion Translocation-Associated Renal Cell Carcinoma.

Translocation-associated renal cell carcinoma (tRCC) is a rare, aggressive malignancy that primarily affects children and young adults. There is no clear consensus on the most effective treatment for tRCC and there are no biomarkers of response to treatments in these patients. We present a case of a 23 year-old female with metastatic tRCC to the lungs who was started on treatment with nivolumab and ipilimumab. She had a complete radiographic response to treatment and has been progression-free for over 18 months. Immunofluorescence imaging performed on the baseline primary tumor sample showed significant intratumoral immune infiltration. Importantly, these cells are present in niches characterized by TCF1+ CD8+ T cells. Histopathologic investigation showed the presence of lymphocytes in the fibrovascular septae and foci of lymphovascular invasion. Furthermore, lymphovascular invasion and intratumor niches with TCF1+ CD8+ T cells may predict a favorable response to treatment with nivolumab and ipilimumab. These findings have significant clinical relevance given that immune checkpoint inhibitors are approved for several malignancies and predictive biomarkers for response to treatment are lacking. Importantly, the identification of these TCF1+ CD8+ T cells may guide treatment for patients with tRCC, which is a rare malignancy without a consensus first-line treatment option.

Poorly Differentiated Neuroendocrine Tumor With 18F-Fluciclovine Uptake in a Patient With Metastatic Castrate-Resistant Prostate Cancer.

ABSTRACT: 18F-Fluciclovine is an amino acid-based radiopharmaceutical used primarily for PET imaging of patients with biochemical recurrence of prostate cancer. We report a case of a 66-year-old man with recently diagnosed metastatic castrate-resistant prostate cancer and a left supraclavicular lymph node with incidental radiotracer uptake on 18F-fluciclovine PET/CT. Left neck core needle biopsy confirmed high-grade, poorly differentiated carcinoma with neuroendocrine features positive for synaptophysin and chromogranin, and negative for prostate markers.

Exuberant Malakoplakia of the Prostate Presenting as Prostatic Abscesses in an Immunocompromised Patient.

Background: Malakoplakia is a rare benign lesion, usually associated with deficient intralysosomal degradation of microorganisms, more commonly, Escherichia coli. Malakoplakia occurs in various organ systems, the most frequently affected site being the urinary bladder. We report a rare case of isolated extensive malakoplakia involving the prostate, diagnosed on transurethral resection performed for radiologically suspected prostatic abscesses. Case Presentation: A 61-year-old African American male presented with symptoms of urinary obstruction for the past 2 months. His medical history was significant for immunosuppression (liver transplantation 3 months prior and diabetes mellitus). He reported four episodes of E. coli-associated urinary tract infection after his liver transplantation. Serum prostate specific antigen was 1.83 ng/cc (normal inferior to 4 ng/cc), and urine culture was positive for E. coli sensitive to ceftriaxone. Pelvic magnetic resonance imaging was suggestive of prostatitis with prostatic abscesses; cystoscopy was unremarkable. The patient was started on intravenous ceftriaxone therapy. A standard bipolar transurethral resection of the prostate was performed, and purulent-like material was encountered in the resected tissue. Histologic examination demonstrated extensive infiltration and replacement of the prostatic tissue by sheets of pink histiocytes with targetoid inclusions consistent with Michaelis-Gutmann bodies, ultimately confirming malakoplakia of the prostate. Conclusion: Prostatic malakoplakia is an unexpected diagnosis in patients suspected of having malignancy or prostatitis. Its exact pathogenesis is unknown, but it involves defective bacterial degradation after phagocytosis. E. coli is often cultured from the patients' urine. Immunosuppression, present in our patient, is a well-known associated factor. Prostatic malakoplakia can radiologically masquerade as prostatic adenocarcinoma, despite the use of cutting-edge imaging technology. With the growing use of multiparametric 3T prostate magnetic resonance imaging to screen for prostate cancer, it is possible that urologists, radiologists, and pathologists will encounter prostatic malakoplakia more frequently in the future.

Urothelial Carcinomas With Trophoblastic Differentiation, Including Choriocarcinoma: Clinicopathologic Series of 16 Cases.

Trophoblastic differentiation (including choriocarcinoma) arising in urothelial carcinoma has been described in numerous case reports, but never in a single series. We present a series of these tumors, describing the morphologic spectrum, applying traditional and novel immunohistochemical stains, and characterizing clinical follow-up. We identified 16 cases, arising predominantly in the bladder (N=14), but also the ureter (N=1) and prostatic urethra (N=1). Six of our cases (38%) contained invasive urothelial carcinoma with admixed syncytiotrophoblasts, 8 cases (50%) consisted of invasive urothelial carcinoma with choriocarcinoma, 1 case (6%) showed urothelial carcinoma in situ with associated choriocarcinoma, and 1 case (6%) consisted of pure choriocarcinoma. Other subtypes of variant morphology were seen in 5 of our cases (31%) and included squamous, glandular, lipoid, chordoid/myxoid, and sarcomatoid features. Given the limited specificity of human chorionic gonadotropin immunohistochemistry, we also studied the expression of a novel specific trophoblastic marker, hydroxyl-δ-5-steroid dehydrogenase, as well as Sal-like protein 4. Human chorionic gonadotropin expression was seen in nearly all cases (93%) but was often not limited to the trophoblastic component, staining the urothelial component also in 85% of the cases. Expression of hydroxyl-δ-5-steroid dehydrogenase was more sensitive and more specific, staining 100% of the cases and limited to trophoblasts in all but 1 case. Sal-like protein 4 expression was variable, staining trophoblast in only 50% of cases and staining the urothelial carcinoma component in 43% of those positive cases. Most of our tumors presented at a high stage and were associated with poor clinical outcomes, with at least muscle-invasive disease (pT2) in 10 of the 14 bladder tumors (71%), periureteric fat invasion in the ureter tumor (pT3), distant metastases in 7 of 16 cases (44%) and death of disease in 3 of the 15 patients with follow-up (20%). Our study describes a series of urothelial carcinomas with trophoblastic differentiation, demonstrating the morphologic spectrum of this entity, its frequent association with other subtypes of variant morphology, its characteristic immunoprofile, and its aggressive clinical behavior.

Neoadjuvant Cabozantinib in an Unresectable Locally Advanced Renal Cell Carcinoma Patient Leads to Downsizing of Tumor Enabling Surgical Resection: A Case Report.

INTRODUCTION: Cabozantinib (XL-184) is a small molecule inhibitor of the tyrosine kinases c-Met, AXL, and VEGFR2 that has been shown to reduce tumor growth, metastasis, and angiogenesis. After the promising results from the METEOR and CABOSUN trials, cabozantinib was approved for use in the first- and second-line setting in patients with advanced RCC. Previously, targeted therapies have been used in the neoadjuvant setting for tumor size reduction and facilitating nephrectomies. The increased response rates with cabozantinib in metastatic renal cell carcinoma (mRCC), along with the other neoadjuvant TKI data, strongly support an expanded role for cabozantinib in the neoadjuvant setting. CASE DESCRIPTION: We report on a 59-year-old gentleman presenting with an unresectable 21.7 cm left renal cell carcinoma (RCC) with extension to soft tissue and muscles of the thoracic cage, psoas muscle, posterior abdominal wall, tail of pancreas, splenic flexure of colon, and inferior margin of spleen. Presurgical, neoadjuvant systemic therapy with cabozantinib was initiated for 11 months in total. Initially after 2 months of cabozantinib, magnetic resonance imaging (MRI) revealed a significant reduction (44.2%) in tumor diameter from 21.7 to 12.1 cm with decreased extension into adjacent structures. After 11 months total of cabozantinib, the corresponding MRI showed grossly stable size of the tumor and significant resolution of invasion of adjacent structures. After washout of cabozantinib, radical resection, including nephrectomy, was successfully performed without any major complications, either intra-operative or perioperative. Negative margins were achieved. CONCLUSIONS: This is a report of neoadjuvant cabozantinib downsizing a tumor and enabling surgical resection in this patient with locally advanced RCC. Our findings demonstrate that neoadjuvant cabozantinib to facilitate subsequent surgical resection may be a feasible option for patients presenting with unresectable RCC.