Aggressive Histologic Variant Research Articles

Are Higher Body Mass Index and Worse Metabolic Parameters Associated with More Aggressive Differentiated Thyroid Cancer? A Retrospective Cohort Study.

Obesity is a risk factor for differentiated thyroid cancer (DTC), but the association with DTC aggressiveness is controversial. To evaluate the association between preoperative body mass index (BMI)/other metabolic parameters and DTC aggressiveness in our surgical cohort, we retrospectively evaluated patients following thyroid surgery who were diagnosed with DTC between December 2013 and January 2021. Baseline characteristics, histopathological features, treatment modalities, and follow-up data were studied. We conducted logistic regression to analyze the association between BMI/other metabolic parameters and adverse DTC features. The final study cohort included 211 patients (79.6% women; mean age± standard deviation 48.7 ± 15.9 years): 66 (31.3%) with normal weight, 81 (38.4%) with overweight, and 64 (30.3%) with obesity. The median follow-up was 51 months (range 7-93). Complete versus partial thyroidectomy was more common among patients living with overweight or obesity than in normal weight patients (79.7% versus 61.7%, p = 0.017, respectively). Logistic regression demonstrated that higher BMI was associated with mildly increased risk for lymph nodes metastases (odds ratio [OR] 1.077, 95% CI: 1.013-1.145), and higher triglycerides/high-density lipoprotein-cholesterol (TG/HDL-C) ratio was associated with aggressive histological variants of DTC (OR 1.269, 95% CI 1.001-1.61). To conclude, specific adverse clinical and histopathological DTC features were indeed associated with higher BMI and higher TG/HDL-C ratio.

Minimal Extrathyroid Extension (mETE) as the Only Risk Factor in Patients with Papillary Thyroid Carcinoma (PC): Its Clinical Impact on Recurrence and Outcome during Long-Term Follow-Up.

Minimal extrathyroid extension (mETE) effect on papillary thyroid carcinoma (PC) prognosis is still debated even more so now that this factor has been removed in the 8th AJCC Edition, supporting the hypothesis that mETE is not associated with aggressive tumors. We retrospectively enrolled 91 PC patients (Group 1) submitted to total thyroidectomy and radioiodine ablation. At the time of the primary tumor surgery, mETE was ascertained in all patients with no other risk factors, such as multifocality, vascular invasion, neck and distant metastases, and aggressive histological variants. As controls, 205 consecutive matched PC patients (Group 2) without mETE and the aforementioned risk factors were enrolled. During the follow-up (average 8 years), 16/91 (17.58%) Group 1 patients and 15/205 (7.32%) Group 2 patients developed metastases (p = 0.0078). Cox regression analysis showed an increased risk of metastases in patients with mETE (HR: 2.58 (95% CI 1.28-5.22) p = 0.008). Disease-free survival (DFS) was significantly lower in patients with mETE than in controls (p = 0.0059). The present study seems to demonstrate that mETE can be associated with an aggressive PC and can be considered, even alone without other risk factors, an independent factor of unfavorable DFS. Thus, by excluding mETE in the 8th AJCC Edition, patient care and management could be compromised.

Characterizing the Genomic Landscape of the Micropapillary Subtype of Urothelial Carcinoma of the Bladder Harboring Activating Extracellular Mutations of ERBB2

The micropapillary subtype of urothelial carcinoma (MPUC) of the bladder is a very aggressive histological variant of urothelial bladder cancer (UBC). A high frequency of MPUC contains activating mutations in the extracellular domain (ECD) of ERBB2. We sought to further characterize ERBB2 ECD-mutated MPUC to identify additional genomic alterations that have been associated with tumor progression and therapeutic response. In total, 5,485 cases of archived formalin-fixed, paraffin-embedded UBC underwent comprehensive genomic profiling to identify ERBB2 ECD-mutated MPUC and evaluate the frequencies of genomic co-alterations. We identified 219 cases of UBC with ERBB2 ECD mutations (74% S310F and 26% S310Y), of which 63 (28.8%) were MPUC. Genomic analysis revealed that TERT, TP53, and ARID1A were the most common co-altered genes in ERBB2-mutant MPUC (82.5%, 58.7%, and 39.7%, respectively) and did not differ from ERBB2-mutant non-MPUC (86.5%, 51.9%, and 35.3%). The main differences between ERBB2 ECD-mutated MPUC compared with non-MPUC were KMT2D, RB1, and MTAP alterations. KMT2D and RB1 are tumor-suppressor genes. KMT2D frequency was significantly decreased in ERBB2 ECD-mutated MPUC (6.3%) in contrast to non-MPUC (27.6%; P < .001). RB1 mutations were more frequent in ERBB2 ECD-mutated MPUC (33.3%) than in non-MPUC (17.3%; P = .012). Finally, MTAP loss, an emerging biomarker for new synthetic lethality-based anticancer drugs, was less frequent in ERBB2 ECD-mutated MPUC (11.1%) than in non-MPUC (26.9%; P = .018). Characterizing the genomic landscape of MPUC may not only improve our fundamental knowledge about this aggressive morphological variant of UBC but also has the potential to identify possible prognostic and predictive biomarkers that may drive tumor progression and dictate treatment response to therapeutic approaches.

Surgical Management and Oncologic Outcomes of Renal Cell Carcinoma and Inferior Vena Caval Thrombi With Aggressive Histologic Variants

To characterize the surgical management, perioperative, and cancer-specific outcomes, and the influence of aggressive histologic variants (AHV) on operative management among patients with renal cell carcinoma (RCC) and inferior vena cava (IVC) thrombus. RCC with rhabdoid and/or sarcomatoid differentiation, which we defined as AHV, portends a worse prognosis. AHV can be associated with a desmoplastic reaction which may complicate resection. We reviewed patients undergoing radical nephrectomy and IVC thrombectomy between 1990 and 2020. Comparative statistics were employed as appropriate. Survival analysis was performed according to the Kaplan-Meier method, and intergroup analysis performed with log-rank statistics. Multivariable cox proportional hazards regression was used to assess the effect of AHV, age, thrombus level, vena cavectomy, metastases, and medical comorbidities on recurrence and overall survival (OS). Ninety-four of 403 (23.3%) patients had AHV, including 43 (46%) rhabdoid, 39 (41%) sarcomatoid, and 12 (13%) with both. AHV were more likely to present with advanced disease; however, increased perioperative complications or decreased OS were not observed. Median (IQR) survival was 16.7 (4.8-47) months without AHV and 12.6 (4-29) months with AHV (P=.157). Sarcomatoid differentiation was independently associated with worse OS (HR=2.016, CI 1.38-2.95, P<.001), whereas rhabdoid alone or with sarcomatoid demonstrated similar OS (P=0.063). RCC and IVC thrombus with AHV are more likely to present with metastatic disease, and sarcomatoid differentiation is associated with a worse OS. Resection of tumors with and without AHV have similar perioperative complications, suggesting that surgery can be safely accomplished in patients with RCC and IVC thrombus with AHV.

Hashimoto's Thyroiditis and Papillary Thyroid Carcinoma: A Follow-Up Study in Patients with Absence of Aggressive Risk Factors at the Surgery of the Primary Tumor.

Hashimoto's thyroiditis (HT) is often associated with papillary thyroid carcinoma (PC); it is still a matter of controversy whether the behavior of carcinoma is more aggressive or not. During the follow-up, we retrospectively enrolled 97 patients with PC/HT after thyroidectomy without risk factors at the surgery of the primary tumor, such as multifocality/multicentricity, extrathyroid tumor extension, vascular invasion, neck and distant metastases, and aggressive histological variants. HT diagnosis was confirmed by histology and serum thyroid antibodies. Tumor size was ≤10 mm in 64 cases (microcarcinomas); 206 matched PC patients after thyroidectomy without HT and risk factors were enrolled as controls, totaling 122 microcarcinomas. During follow-up, metastases occurred in 15/97 (15.5%) PC/HT cases, eight microcarcinomas, and in 16/206 (7.8%) without HT, eight microcarcinomas (p = 0.04). Considering both PC/HT and PC patients without HT who developed metastases, univariate analysis showed an increased risk of metastases in patients with HT coexistence, OR: 2.17 (95% CI 1.03-4.60) p = 0.043. Disease-free survival (DFS) was significantly (p = 0.0253) shorter in PC/HT than in the controls. The present study seems to demonstrate that HT is not a cancer protective factor in PC patients given the less favorable outcomes and significantly shorter DFS. HT may also represent an independent recurrence predictor without other risk factors.

Impact of neoadjuvant chemotherapy on pathological stage and survival in sarcomatoid bladder cancer.

530 Background: Sarcomatoid bladder cancer is an extremely rare and aggressive histological variant with poor prognosis and limited consensus regarding its management given rarity and lack of high-quality data. Radical cystectomy (RC) is the mainstay of treatment in muscle-invasive disease and adjuvant therapy is often offered to eligible patients with high-risk features. Data regarding the role of neoadjuvant chemotherapy (NAC) for this variant is limited. Methods: The National Cancer Database was queried to identify patients diagnosed with sarcomatoid bladder cancer from 2004 to 2018. Patients older than 18 years with cT2-4aN0-1M0 sarcomatoid bladder cancer who received curative-intent surgery were included in the analyses. Clinical T4b/N2-3/M1 disease and receipt of adjuvant chemotherapy were employed as exclusion criteria. The population was divided into two cohorts based on the receipt of NAC. Chi-Square and Mann Whitney U tests were used to compare frequency distributions. Cox Proportional Hazards regression was employed to adjust for confounding factors associated with overall survival. Models were adjusted for age, race, sex, income, stage, insurance status, and the Charlson Comorbidity Index. Results: A total of 573 patients were identified - 70% were males and 93% were White; 139 (25%) received NAC (NAC+) while 434 (75%) did not (NAC-). NAC+ patients were younger (65 vs 71 years, p &lt; 0.001). Downstaging to pT0-1N0 at the time of RC was significantly more frequent in the NAC+ group compared to the NAC- group (32 (24.5%) vs. 28 (6.8%), p = 0.001). Overall survival (OS) was also significantly longer in the NAC+ group (median of 40.8 vs. 19.4 months, log-rank p = 0.003). On multivariable analysis, NAC+ (Hazard Ratio (HR) = 0.73, 95% CI 0.56-0.91, p = 0.02), pathological downstaging to pT0-1N0 (HR = 0.5, 95% CI 0.31- 0.8, p &lt; 0.001), and any pathological upstaging (HR 4.1, 95% CI 1.5-6.6, p &lt; 0.001) were independently associated with all-cause mortality, while other factors were not (Table). Conclusions: In this large retrospective analysis, administration of NAC in muscle-invasive sarcomatoid bladder cancer was associated with higher rates of downstaging to non-muscle-invasive disease at the time of RC and reduced all-cause mortality. [Table: see text]

Neoadjuvant chemotherapy plus radical cystectomy (NAC-RC) versus trimodality therapy (TMT) in early-stage small cell bladder cancer: Comparison of outcomes.

476 Background: Small cell bladder cancer is a rare and aggressive histological variant with a paucity of data to guide the optimal management strategy in non-metastatic disease. NAC-RC and TMT (maximal transurethral resection of bladder tumor + chemoradiation) have been variably employed based on institutional preferences, and we aim to compare outcomes between these two approaches. Methods: We queried the National Cancer Database for adult patients with small cell bladder cancer diagnosed during the years 2004 to 2018. Patients with small cell histology and early-stage clinically node-negative bladder cancer (cT1-4N0M0) were included and divided into two groups based on the treatment strategy employed – NAC-RC or TMT. Patients who did not receive any definitive local therapy and those who received chemotherapy or radiation in the adjuvant setting were excluded. Fisher’s exact and Mann Whiney U tests were used to compare frequency distributions. Cox Proportional Hazards regression was employed for multivariate analysis of factors associated with overall survival. Models were adjusted for age, sex, race, income, educational level, clinical T stage, insurance status, and the Charlson Comorbidity Index. Results: A total of 1262 patients were identified – 629 (49.8%) underwent NAC-RC while 633 (50.2%) received TMT. Patients in the NAC-RC group were younger (median 67 vs. 74 years, P &lt;0.001) and more frequently Males (81% vs 76%, p = 0.02). Clinical T stage was comparable between the groups (P = 0.38). Patients with private insurance (P &lt; 0.001) and higher income tiers (P = 0.04) were more likely to receive NAC-RC in lieu of TMT. Overall survival in the NAC-RC group was significantly longer than the TMT group (median of 41.3 vs. 25.4 months, log-rank P &lt; 0.001). On multivariable analysis, only the type of treatment modality employed was independently predictive of overall survival (Hazard Ratio of 1.22 for TMT, with 95% CI 1.05-1.43, P = 0.01). Conclusions: In early-stage clinically node-negative small cell bladder cancer, NAC-RC was associated with significantly longer overall survival compared to TMT.

Carcinoma micropapilar infiltrante de la mama. Pronóstico a largo plazo

IntroductionInvasive Micropapillary Carcinoma of the breast (IMPC) is an unusual and aggressive histological variant characterized for the first time in 1993 by Siriangkul et al. and classified by the World Health Organization in 2003 as an epithelial breast tumor. It represents less than 2% of all invasive carcinomas of the breast and is presumed to have an unfavorable prognosis compared to other conventional carcinomas due to its high vascular and lymphatic tropism. Material and methodsUntil now, there is no study with a large number of patients from a single center with a long follow-up period that compares the survival of IMPC with other conventional non-micropapillary carcinomas. A retrospective, observational study has been carried out with a total of 401 patients: 174 with IMPC and 227 with other conventional carcinomas. ResultsIMPC has a higher histological grade, greater lymph node involvement and a higher risk of distant metastasis compared to other conventional carcinomas. However, in the multivariate analysis considering date of diagnosis, age, tumor size, lymph node involvement and histological grade as variables, no statistically significant differences were observed for overall and disease- free survival between IMPC and other conventional carcinomas. ConclusionOverall and disease-free survival is similar between IMPC and other conventional carcinomas considering same age, tumor size, histological grade, and lymph node involvement.

Cardiovascular Involvement of a CD138-Negative Anaplastic Myeloma: A Diagnostic Dilemma

Anaplastic myeloma (AM) is an extremely rare and aggressive histological variant of myeloma. It is characterized by extramedullary presentation in the young and has a poor prognosis. It can be a diagnostic challenge when myeloma is not suspected and even more when the immunophenotype is unexpected. We present a rare presentation of anaplastic myeloma with cardiovascular involvement. Though the patient did not have the typical clinical features of myeloma, except lytic lesion in the femur, the cardiac biopsy showed sheets of anaplastic cells, and some with multinucleation. There were also some areas with a more plasmacytoid appearance. The initial immunohistochemical panel was negative for CD3, CD20, CD138, AE1/3, and kappa. It was positive for lambda. This led to an extended panel which showed positivity for CD79a and MUM1 and negative for LMP-1, HHV-8, CD43, CD117, CD56, and CD30. Even the flow cytometry on the bone marrow showed a small population of atypical cells positive for CD38 and negative for CD138 with lambda restriction. This is an unusual case of anaplastic myeloma with cardiovascular involvement and CD138 negativity. This case highlights the need to add a panel of plasma cell markers when myeloma is suspected, and it is pertinent to read flow cytometry with caution to avoid missing atypical plasma cells which maybe CD38+/CD138-.

PMON324 Crooke Cell Corticotroph Adenoma: A rare but Real Possibility in Children

Abstract Background Cushing disease (CD) is uncommon in the pediatric population and is usually caused by benign pituitary corticotroph microadenomas. In some adults with CD, Crooke cell adenoma (CCA), a more aggressive histologic variant of corticotroph adenomas, has been described. CCA has rarely been reported in children as the etiology of CD and its course is not well described. Objectives To report a pediatric case of CCA, the youngest to our knowledge Case An 11-year-old African American female presented to the endocrinology clinic with concerns for diabetes, excessive weight gain and linear growth arrest. Workup for possible etiology showed: midnight salivary cortisol 0.924 (normal &amp;lt; 0.112 µg/dL), ACTH 119(6-48 pg/mL), morning cortisol 8.5 (normal &amp;lt; 1.8 µg/dL) post 1 mg dexamethasone mg/dL, consistent with the diagnosis of CD. Magnetic resonance imaging (MRI) showed a 4 mm pituitary microadenoma in the left anterior side of the adenohypophysis for which she underwent endoscopic endonasal transsphenoidal resection. Histopathologic examination revealed pituitary adenomatous tissue consisting of a uniform population of basophilic cells with granular cytoplasm, arranged in trabeculae and small nests with bundles encircling the nuclei, findings pathognomonic of CCA. Given persistence of hypercortisolemia, another transsphenoidal gross total resection of residual adenomatous tissue was performed 4 months later. This led to resolution of CD as evidenced by weight loss and linear growth. Twelve months following the second surgery, the patient experienced rapid weight gain and a decelerated linear growth accompanied by pubertal arrest. Another pituitary MRI showed a recurrent left sided adenoma (8×8×7 mm). Biochemical investigation this time again showed elevated midnight salivary cortisol and 24- hour urine free cortisol (UFC). In addition, AM cortisol was unsuppressed following 1 mg overnight dexamethasone administration. In response, repeat transsphenoidal gross total resection was performed, however residual microscopic disease in the cavernous sinus wall was highly suspected intraoperatively. A spine MRI did not show disseminated disease. Despite this, hypercortisolemia persisted both clinically and biochemically. The patient subsequently underwent proton beam radiation therapy in combination with adjuvant adrenolytic therapy with mitotane. The patient responded to these interventions with normalization of 24-hour UFC, resumption of linear growth, and pubertal progression. The treatment course was complicated by the development of isolated TSH deficiency requiring thyroid hormone replacement. Conclusion CCA is an aggressive entity described in the adult literature as a cause of CD. The current report adds to the limited pediatric cases of this disease. CCA can be equally aggressive in children and refractory to surgical treatment. Here, we show that it may respond to proton beam radiation and adrenolytic therapy. Pediatric endocrinologists should be aware of the rare occurrence of CCA in children and tailor treatment accordingly using a multi-disciplinary approach. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Outcomes and Patterns of Failure in Early-Stage, High-Risk Histology Endometrial Cancer Treated with Vaginal Cuff Brachytherapy

<h3>Purpose/Objective(s)</h3> The majority of patient diagnosed with endometrial cancer have low-risk endometrioid histology with an excellent prognosis. There is a small subset of patients however, who are diagnosed with a histology for which the outcomes are not as good. Serous, clear cell, carcinosarcoma and neuroendocrine carcinomas are more aggressive histological variants with a propensity for early extrauterine spread resulting in higher rates of death. They typically receive upfront chemotherapy but questions remain as to whether the increased risk of spread warrants adjuvant pelvic radiation or whether the risk can be mitigated with vaginal cuff brachytherapy (VCB). We aim to describe the outcomes and patterns of failure in early-stage, high-risk histology patients in which pelvic radiation was omitted, in order to shed light on the risk of pelvic failure. <h3>Materials/Methods</h3> A retrospective chart review was performed on patients treated for high-risk histology, early-stage uterine cancer at our institution. Patients receiving adjuvant VCB +/- chemotherapy were included. Demographic and clinical data was collected. Descriptive statistics were used to summarize variables. Kaplan-Meier analysis was used to estimate the survival probabilities. For all time to event outcomes, univariate cox proportional hazard regression models were built for clinically correlated variables. A two-tailed p<0.05 was considered statistically significant. <h3>Results</h3> 77 patients with early-stage carcinosarcoma (23.4%), clear cell (35.1%), serous (40.3%) and neuroendocrine carcinoma (1.3%) of the uterus were reviewed. Median follow up was 43 months (range 7-117 months). 2yr and 5yr overall survival (OS), metastasis free survival (MFS) and progression free survival (PFS) were 95% and 92%, 95% and 90% and 91% and 82% respectively. Of the 9 patients (11.7%) that recurred, 2 patients (2.6%) had isolated vaginal cuff recurrences, 4 patients (5.2%) had isolated pelvic recurrences and 3 patients (3.9%) had both a local and distant failure. Of the 27 individual sites of recurrence, 21 (77.8%) were below the level of L4. <h3>Conclusion</h3> In patients with early stage, high risk histology endometrial cancer treated with adjuvant VCB +/- chemotherapy, the 2yr and 5yr PFS was 91% and 82% respectively. All patients that recurred had some component of pelvic failure.

Clinically undetected plasmacytoid urothelial carcinoma of the urinary bladder with non-mass-forming metastases in multiple organs: an autopsy case.

This case report outlines a clinically undetected urinary bladder plasmacytoid urothelial carcinoma (PUC) with multiple metastases detected at autopsy. An 89-year-old man presented with edema in the lower limbs. Pleural fluid cytology revealed discohesive carcinomatous cells, although imaging studies failed to identify the primary site of tumor. The patient died of respiratory failure. Autopsy disclosed a prostate tumor and diffusely thickened urinary bladder and rectum without distinct tumorous lesions. Histologically, the tumor consisted of acinar-type prostate adenocarcinoma with no signs of metastasis. Additionally, small, plasmacytoid tumor cells were observed in the urinary bladder/rectum as isolated or small clustering fashions. These metastasized to the lungs, intestine, generalized lymph nodes in a non-mass-forming manner. Combined with immunohistochemical studies, these tumor cells were diagnosed PUC derived from the urinary bladder. Both clinicians and pathologists should recognize PUC as an aggressive histological variant, which can represent a rapid systemic progression without mass-forming lesions.

Defining Diagnostic Criteria for Prostatic Ductal Adenocarcinoma at Multiparametric MRI.

Background Prostatic ductal adenocarcinoma (DAC) is an aggressive histologic variant of prostate cancer that often warrants multimodal therapy and poses a significant diagnostic challenge clinically and at imaging. Purpose To develop multiparametric MRI criteria to define DAC and to assess their diagnostic performance in differentiating DAC from prostatic acinar adenocarcinoma (PAC). Materials and Methods Men with histologically proven DAC who had multiparametric MRI before radical prostatectomy were retrospectively identified from January 2011 through November 2018. MRI features were predefined using a subset of nine DACs and then compared for men with peripheral-zone DACs 1 cm or greater in size and men with matched biopsy-confirmed International Society of Urological Pathology grade group 4-5 PAC, by four independent radiologists blinded to the pathologic diagnosis. Diagnostic performance was determined by consensus read. Patient and tumor characteristics were compared by using the Fisher test, t-tests, and Mann-Whitney U test. Agreement (Cohen κ) and sensitivity analyses were also performed. Results There were 59 men with DAC (median age, 63 years [interquartile range, 56, 67 years]) and 59 men with PAC (median age, 64 years [interquartile range, 59, 69 years]). Predefined MRI features, including intermediate T2 signal, well-defined margin, lobulation, and hypointense rim, were detected in a higher proportion of DACs than PACs (76% [45 of 59] vs 5% [three of 59]; P < .001). On consensus reading, the presence of three or more features demonstrated 76% sensitivity, 94% specificity, 94% positive predictive value [PPV], and 80% negative predictive value [NPV] for all DACs and 100% sensitivity, 95% specificity, 81% PPV, and 100% NPV for pure DACs. The DACs and PACs showed no difference in contrast enhancement (100% vs 100%; P >.99, median T2 signal intensity (254 vs 230; P = .99), or apparent diffusion coefficient (median, 677 10-6 mm2/sec vs 685 10-6 mm2/sec; P = .73). Conclusion The presence of intermediate T2 signal, well-defined margin, lobulation, and/or hypointense rim, together with restricted diffusion and contrast enhancement at multiparametric MRI of the prostate, suggests prostatic ductal adenocarcinoma rather than prostatic acinar adenocarcinoma. © RSNA, 2022 Online supplemental material is available for this article.

Non-muscle invasive micropapillary urothelial carcinoma of the bladder: Variable use of initial cystectomy versus intravesical bacillus calmette-guérin

Introduction and Objective Micropapillary urothelial carcinoma (MPUC) is a rare and aggressive histologic variant of bladder cancer. Treatment guidelines recommend forgoing Bacillus Calmette-Guérin (BCG) therapy in favor of early radical cystectomy for non-muscle invasive (NMI)-MPUC due to high rates of disease progression. We aimed to evaluate its management in patients with immediate cystectomy and BCG across various centers. Methods Patients with MPUC were identified from the National Cancer Database (2004-2017). Treatment trends and rates of pathological upstaging were identified. Bivariate and multivariate analyses were performed to assess differences in outcomes by treatment approach. Results 1,685 patients were diagnosed with MPUC during the study period with 531 identified with localized Ta, T1, or Tis disease. BCG was administered as an initial therapy in 24.1% of NMI-MPBC patients and in 16.3% of NMI-non-MPUC patients (p&lt;0.001). Cystectomy was performed as primary therapy for NMI disease in 29.9% of MPUC and in 2.7% of non-MPUC patients (p&lt;0.001). Of the patients who underwent primary cystectomy, upstaging from NMI-MPUC to T2-T4 disease was seen in 46.5% of the MPUC patients compared to 37.3% in patients with non-MPUC (p=0.025). Upstaging to pathologic N1-3 disease was observed in 33.1% of MPUC patients compared to 11.9% non-MPUC patients (p&lt;0.001). Cox regression analysis, adjusting for patient age, sex, race, comorbidities, and disease stage, care at academic cancer centers were associated with increased odds of having cystectomy as primary therapy compared to community cancer centers (OR = 4.29, 95% CI 2.73-6.76). Conclusion The current study lends evidence to current practice guidelines by reporting treatment patterns for patients with micropapillary bladder cancer across a broad spectrum of clinical practice. NMI-MPUC patients treated at academic cancer centers were more likely to receive radical surgery as primary treatment compared to patients at the community cancer centers.

Non-muscle invasive micropapillary urothelial carcinoma of the bladder: Variable use of initial cystectomy versus intravesical bacillus calmette-guérin

Introduction and Objective Micropapillary urothelial carcinoma (MPUC) is a rare and aggressive histologic variant of bladder cancer. Treatment guidelines recommend forgoing Bacillus Calmette-Guérin (BCG) therapy in favor of early radical cystectomy for non-muscle invasive (NMI)-MPUC due to high rates of disease progression. We aimed to evaluate its management in patients with immediate cystectomy and BCG across various centers. Methods Patients with MPUC were identified from the National Cancer Database (2004-2017). Treatment trends and rates of pathological upstaging were identified. Bivariate and multivariate analyses were performed to assess differences in outcomes by treatment approach. Results 1,685 patients were diagnosed with MPUC during the study period with 531 identified with localized Ta, T1, or Tis disease. BCG was administered as an initial therapy in 24.1% of NMI-MPBC patients and in 16.3% of NMI-non-MPUC patients (p&lt;0.001). Cystectomy was performed as primary therapy for NMI disease in 29.9% of MPUC and in 2.7% of non-MPUC patients (p&lt;0.001). Of the patients who underwent primary cystectomy, upstaging from NMI-MPUC to T2-T4 disease was seen in 46.5% of the MPUC patients compared to 37.3% in patients with non-MPUC (p=0.025). Upstaging to pathologic N1-3 disease was observed in 33.1% of MPUC patients compared to 11.9% non-MPUC patients (p&lt;0.001). Cox regression analysis, adjusting for patient age, sex, race, comorbidities, and disease stage, care at academic cancer centers were associated with increased odds of having cystectomy as primary therapy compared to community cancer centers (OR = 4.29, 95% CI 2.73-6.76). Conclusion The current study lends evidence to current practice guidelines by reporting treatment patterns for patients with micropapillary bladder cancer across a broad spectrum of clinical practice. NMI-MPUC patients treated at academic cancer centers were more likely to receive radical surgery as primary treatment compared to patients at the community cancer centers.

EZH2 expression is associated with inferior overall survival in mantle cell lymphoma

Enhancer of zeste homolog 2 (EZH2) is a catalytic component of the polycomb repressive complex 2 (PRC2) which reduces gene expression via trimethylation of a lysine residue of histone 3 (H3K27me3). Expression of EZH2 has not been assessed systematically in mantle cell lymphoma (MCL). Expression of EZH2 was assessed by immunohistochemistry in 166 patients with MCL. We also assessed other PRC2 components and H3K27me3. Fifty-seven (38%) of MCL patients were positive for EZH2 using 40% cutoff. EZH2 expression was associated with aggressive histologic variants (65% vs. 29%, p < 0.001), high Ki-67 proliferation rate (median, 72% vs. 19%, p < 0.001), and p53 overexpression (43% vs. 2%, p < 0.001). EZH2 expression did not correlate with expression of other PRC2 components (EED and SUZ12), H3K27me3, MHC-I, and MHC-II. Patients with EZH2 expression (EZH2+) had a poorer overall survival (OS) compared with patients without EZH2 expression (EZH2−) (median OS: 3.9 years versus 9.4 years, respectively, p < 0.001). EZH2 expression also predicted a poorer prognosis in MCL patients with classic histology (median OS, 4.6 years for EZH2+ and 9.6 years for EZH2-negative, respectively, p < 0.001) as well as aggressive histology (median OS, 3.7 years for EZH2+ and 7.9 years for EZH2-negative, respectively, p = 0.046). However, EZH2 expression did not independently correlate with overall survival in a multivariate analysis. Gene expression analysis and pathway enrichment analysis demonstrated a significant enrichment in cell cycle and mitotic transition pathways in MCL with EZH2 expression. EZH2 expression detected by immunohistochemistry is present in 38% of MCL cases and it is associated with high proliferation rate, p53 overexpression, aggressive histologic variants, and poorer OS. Based on gene expression profiling data, EZH2 expression could potentiate cell cycle machinery in MCL. These data suggest that assessment of EZH2 expression could be useful to stratify MCL patients into low- and high-risk groups.

Reciprocal YAP1 loss and INSM1 expression in neuroendocrine prostate cancer.

Neuroendocrine prostate cancer (NEPC) is a rare but aggressive histologic variant of prostate cancer that responds poorly to androgen deprivation therapy. Hybrid NEPC-adenocarcinoma (AdCa) tumors are common, often eluding accurate pathologic diagnosis and requiring ancillary markers for classification. We recently performed an outlier-based meta-analysis across a number of independent gene expression microarray datasets to identify novel markers that differentiate NEPC from AdCa, including up-regulation of insulinoma-associated protein 1 (INSM1) and loss of Yes-associated protein 1 (YAP1). Here, using diverse cancer gene expression datasets, we show that Hippo pathway-related genes, including YAP1, are among the top down-regulated gene sets with expression of the neuroendocrine transcription factors, including INSM1. In prostate cancer cell lines, transgenic mouse models, and human prostate tumor cohorts, we confirm that YAP1 RNA and YAP1 protein expression are silenced in NEPC and demonstrate that the inverse correlation of INSM1 and YAP1 expression helps to distinguish AdCa from NEPC. Mechanistically, we find that YAP1 loss in NEPC may help to maintain INSM1 expression in prostate cancer cell lines and we further demonstrate that YAP1 silencing likely occurs epigenetically, via CpG hypermethylation near its transcriptional start site. Taken together, these data nominate two additional markers to distinguish NEPC from AdCa and add to data from other tumor types suggesting that Hippo signaling is tightly reciprocally regulated with neuroendocrine transcription factor expression. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

MP59-20 THE EFFECT OF AGGRESSIVE HISTOLOGIC VARIANTS ON NEPHRECTOMY AND IVC THROMBECTOMY FOR RENAL CELL CARCINOMA

You have accessJournal of UrologyKidney Cancer: Localized: Surgical Therapy V (MP59)1 Sep 2021MP59-20 THE EFFECT OF AGGRESSIVE HISTOLOGIC VARIANTS ON NEPHRECTOMY AND IVC THROMBECTOMY FOR RENAL CELL CARCINOMA Molly DeWitt-Foy, Mohamed Eltemamy, Scott Lundy, and Venkatesh Krishnamurthi Molly DeWitt-FoyMolly DeWitt-Foy More articles by this author , Mohamed EltemamyMohamed Eltemamy More articles by this author , Scott LundyScott Lundy More articles by this author , and Venkatesh KrishnamurthiVenkatesh Krishnamurthi More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002094.20AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Though the presence of rhabdoid and/or sarcomatoid differentiation on final pathology has been identified as a poor prognostic indicator for patients with renal cell carcinoma (RCC), the impact of these features on RCC with inferior vena cava (IVC) thrombus has not yet been described. These aggressive histologic variants (AHV) are thought to cause a desmoplastic reaction which may complicate resection and carry worse longterm prognosis. We aim to describe the effect of AHV on the operative management and overall outcome of patients with RCC and IVC thrombus. METHODS: Retrospective chart review was performed for 383 patients with RCC who underwent nephrectomy and IVC thrombectomy at a single institution between 1990 and 2018. Baseline demographics, pre-, intra-, and postoperative details, radiology and pathology reports were reviewed. Data analysis was conducted using Fisher's exact and chi-square tests, Kaplan-Meier curves, and Wilcoxon tests as appropriate. RESULTS: AHV was demonstrated on final pathology in 78(20.37%) patients. There was no statistically significant difference between thrombus level, tumor size, operative time, or blood loss between those with and without AHV. As compared to RCC without sarcomatoid or rhabdoid differentiation, patients with AHV were more likely to require partial or total caval resection at the time of IVC thrombectomy (25.32% v 14.48%, P=0.0196) and to have pathologic node positive disease (41.07% v 23.35%, p=0.0061), metastatic disease (31.82% v 16.80%, P=0.0068), and sinus fat invasion (91.89% v 78.23%, p=0.0074). Rates of perioperative death and postoperative complications did not differ between groups. Though the difference in median survival time was not statistically significant between AHV+RCC group and RCC group (16.8 v 26.9 months, p=0.0648), subgroup analysis for RCC with sarcomatoid differentiation alone conveyed worse prognosis than RCC without AHV (12.25 v 25.7 months, p=0.0142). CONCLUSIONS: In this large single center series of RCCs with associated IVC thrombi, tumors with rhabdoid and/or sarcomatoid differentiation were more likely to metastasize and invade locally on the kidney and IVC level. The presence of AHV appears to result in a more adherent tumor thrombus, as evidenced by the higher rate of partial or total IVC resection in this group. In our experience these aggressive tumors do not necessarily portend worse operative risk, as demonstrated by equivalent operative time, blood loss, and intraoperative complications. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e1038-e1039 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Molly DeWitt-Foy More articles by this author Mohamed Eltemamy More articles by this author Scott Lundy More articles by this author Venkatesh Krishnamurthi More articles by this author Expand All Advertisement Loading ...

DHES0815A, a novel antibody-drug conjugate targeting HER2/neu, is highly active against uterine serous carcinomas in vitro and in vivo

ObjectiveUterine serous carcinoma (USC) is an aggressive histologic variant of endometrial cancer which portends a poor prognosis. DHES0815A is a novel antibody-drug-conjugate (ADC) which binds specifically to HER2 overexpressing tumors at a distinct epitope from that bound by trastuzumab and pertuzumab after which it delivers the toxic payload, PBD-MA, a DNA mono-alkylating agent. The objective of this study was to evaluate the preclinical activity of DHES0815A against primary USC cell lines and xenografts. MethodsTwelve primary USC cell lines were assessed by immunohistochemistry (IHC) for HER2 protein expression and for C-erbB2 gene amplification using fluorescent in situ hybridization (FISH) analysis. Cell viability and bystander killing in USC cell lines after exposure to DHES0815A, the non-targeted ADC, and the unconjugated antibody (i.e. MHES0488A) were evaluated using flow cytometry-based-assays. In vivo activity of DHES0815A was tested against HER2/neu overexpressing USC xenografts. ResultsHigh HER2/neu protein expression was seen in 25% (3/12) of the primary USC cell lines. USC cell lines overexpressing HER2/neu were significantly more sensitive to DHES0815A when compared to the non-targeted control ADC (p < 0.001). DHES0815A did not induce significant bystander killing of HER2/neu negative tumors when admixed with HER2/neu positive tumors. DHES0815A caused growth-inhibition and increased survival in USC HER2/neu overexpressing xenografts when compared to controls (p < 0.01). ConclusionsDHES0815A is both highly selective and toxic to USC tumors overexpressing HER2/neu both in vitro and in vivo. HER2-directed ADCs, alone or in combination with other HER2/neu targeted agents may represent a novel treatment option for patients with tumors harboring HER2/neu overexpression refractory to trastuzumab and traditional chemotherapy.

In vitro and in vivo activity of DHES0815A, an antibody-drug conjugate targeting HER2/neu in uterine serous carcinoma

<h3>Objectives:</h3> Uterine serous carcinoma (USC) is an aggressive histologic variant of endometrial cancer which portends a poor prognosis. DHES0815A is a novel antibody-drug-conjugate (ADC) which binds specifically to HER2-amplified USC tumors at a distinct epitope from that bound by trastuzumab, pertuzumab, and T-DM1 (trastuzumab emtansine) after which it delivers the toxic payload, PBD-MA, a DNA mono-alkylating agent. The objective of this study was to evaluate the preclinical activity of DHES0815A as a single agent against primary USC cell lines and xenografts. <h3>Methods:</h3> Twelve primary USC cell lines were assessed by immunohistochemistry (IHC) for HER2 protein expression and for <i>C-erbB2</i> gene amplification using fluorescent in situ hybridization (FISH) analysis. Cell viability in USC primary cell lines after exposure to DHES0815A, the non-targeted ADC, the unconjugated antibody MHES0488A, and T-DM1 were evaluated using flow cytometry-based-assays. <i>in vivo</i> activity of these respective agents was tested against HER2/neu overexpressing USC (ARK2) xenografts. <h3>Results:</h3> High HER2/neu protein expression by IHC and <i>C-erbB2</i> gene amplification by FISH was seen in 25% (3/12) of the primary USC cell lines. Primary tumor cell lines overexpressing HER2/neu were significantly more sensitive to DHES0815A when compared to the non-targeted control ADC (<i>p<0.05</i>). DHES0815A caused growth-inhibition and increased survival in HER2/neu overexpressing xenografts when compared to controls (<i>p<0.05</i>). The animals also tolerated DHES0815A treatment with no significant change in their body weight [Figure 1]. <h3>Conclusions:</h3> DHES0815A as a single agent is both highly selective and toxic to USC tumors overexpressing HER2/neu both <i>in vitro</i> and <i>in vivo.</i> HER2-directed ADCs, alone or in combination with other HER2/neu targeted agents may represent a novel and less toxic treatment option for patients with tumors harboring HER2/neu overexpression refractory to trastuzumab and traditional chemotherapy.