Micropapillary Features Research Articles

Is GATA3 Expression Maintained in Regional Metastases?

GATA3 has been recognized as a promising marker for primary urothelial carcinoma (UC), consistently showing higher expression levels than urothelial markers thrombomodulin and uroplakin III. However, expression of GATA3 in comparison with UC-associated markers CK7 and p63 has not been systematically studied. Moreover, no studies have been conducted to establish GATA3 sensitivity in regional metastases. In this study, high-density tissue microarrays were constructed from 69 matched paired primary and metastatic bladder tumors including pure urothelial UCs with papillary (n=48) or flat phenotype (n=9), mixed tumors with micropapillary, glandular, small cell, squamous, giant cell, and plasmacytoid features (n=9), and 3 adenocarcinomas. GATA3 was expressed in 62/69 (90%) primary UC and 64/69 (93%) metastases, with significantly higher staining intensity in nodal metastases (P=0.03). In primary tumors, GATA3 was positive in 44/48 (92%) papillary UCs, 9/9 (100%) flat UCs, 8/9 (89%) mixed UCs, and 1/3 (33%) adenocarcinomas, whereas in metastases these numbers were 45/48 (94%), 9/9 (100%), 8/9 (89%), and 2/3 (67%), respectively. The majority of positive cases showed strong diffuse nuclear reactivity: 75% of primary UCs and 79% of metastases. GATA3 sensitivity in primary and metastatic UCs was comparable to that of CK7 and superior to that of p63 (P<0.05). GATA3 specificity was computed in comparison with its morphologic mimics expressing CK7 and p63, including 208 primary and 24 metastatic tumors from the lung, cervix, and head and neck regions. Strong GATA3 expression was present in 2/51 (4%) cervical carcinomas, whereas weak GATA3 expression was present in 7/51 (14%) cervical, 6/74 (8%) head and neck cancers, and 2/83 (3%) lung carcinomas. Remaining 191 primary and 24 metastatic tumors were GATA3 negative. Therefore, specificity of GATA3 calculated on the basis of morphologic and immunophenotypic UC mimics from lung, cervix, head and neck was 92%. Our findings demonstrate high sensitivity and specificity of the GATA3 diagnostic marker, with not only maintained but increased expression in regional metastases.

Refining Patient Selection for Neoadjuvant Chemotherapy before Radical Cystectomy

We evaluated the survival of patients with muscle invasive bladder cancer undergoing radical cystectomy without neoadjuvant chemotherapy to confirm the utility of existing clinical tools to identify low risk patients who could be treated with radical cystectomy alone and a high risk group most likely to benefit from neoadjuvant chemotherapy. We identified patients with muscle invasive bladder cancer who underwent radical cystectomy without neoadjuvant chemotherapy at our institution between 2000 and 2010. Patients were considered high risk based on the clinical presence of hydroureteronephrosis, cT3b-T4a disease, and/or histological evidence of lymphovascular invasion, micropapillary or neuroendocrine features on transurethral resection. We evaluated survival (disease specific, progression-free and overall) and rate of pathological up staging. An independent cohort of patients from another institution was used to confirm our findings. We identified 98 high risk and 199 low risk patients eligible for analysis. High risk patients exhibited decreased 5-year overall survival (47.0% vs 64.8%) and decreased disease specific (64.3% vs 83.5%) and progression-free (62.0% vs 84.1%) survival probabilities compared to low risk patients (p <0.001). Survival outcomes were confirmed in the validation subset. On final pathology 49.2% of low risk patients had disease up staged. The 5-year disease specific survival of low risk patients was greater than 80%, supporting the distinction of high risk and low risk muscle invasive bladder cancer. The presence of high risk features identifies patients with a poor prognosis who are most likely to benefit from neoadjuvant chemotherapy, while many of those with low risk disease can undergo surgery up front with good expectations and avoid chemotherapy associated toxicity.

The impact of clinically significant discrepancies from primary pathological review of transurethral bladder resection specimens upon repeat review at a tertiary care center.

4552 Background: Internal review of outside pathology slides is a common practice among urologic oncologists at tertiary care facilities, and discrepancies have a potential to directly affect the choice of treatment. While repeat prostate biopsy review has been extensively studied, there is little data available on the impact of repeat reviews of bladder biopsies. The purpose of the current study is to perform a standardized comparison of original and internal pathology reviews of identical bladder specimens to characterize the impact of repeat review on treatment decisions. Methods: Using the Columbia Urologic Oncology Database, a retrospective analysis of 91 consecutive patients who underwent bladder resections at outside institutions from 2008-2012 with secondary referral to a single urologist and internal review at our institution was conducted. Characteristics of both original pathology reports and internal reviews were collected and compared by blinded reviewers. A discrepancy in one of the following characteristics was considered treatment-altering: presence of muscularis in specimen or tumor involvement in muscularis. Additional clinically-significant discrepancies including presence of secondary histology, carcinoma in situ, lymphovascular invasion, micropapillary features, tumor stage, and overall accumulative discrepancy rate were also analyzed. Results: Median time from original procedure to internal review was 34 days (range: 9-368). 56/91 (62%) patients had at least one of the predefined clinically-significant discrepancies. 27/91 (30%) patients had at least one treatment-altering discrepancy, including 25 with discrepant muscle in specimen and 11 with discrepant muscle invasion. Regarding tumor stage, 8 patients were upstaged, 71 were unchanged, and 12 were downstaged on internal review. Conclusions: Repeat pathologic review of primary bladder specimens at a tertiary care center has the potential to alter clinical care for the majority of patients. Further studies are needed to determine if these discrepancies and the decisions they influence have a significant impact on patient outcomes.

Invasive Micropapillary Carcinoma of the Breast: Imaging Features With Clinical and Pathologic Correlation

The purpose of this article is to present imaging findings of invasive ductal carcinoma with micropapillary features with clinical and pathologic correlation. We retrospectively searched our institution's surgical pathology database for patients with pathologically proven invasive ductal carcinoma with micropapillary features. Forty-one patients with images available for review were included in the study. Mammographic, sonographic, and MRI findings were assessed using the American College of Radiology's BI-RADS lexicon. Molecular breast imaging findings were reviewed using a molecular breast imaging lexicon. Imaging findings were correlated with clinical presentation and pathologic findings. Mammographically, the most common finding was an irregular spiculated mass. Sonographically, the most common finding was an irregular hypoechoic mass with spiculated margins and posterior acoustic shadowing. With MRI, the most common finding was an irregular mass with washout kinetics, but we also observed diffuse heterogeneous nonmasslike enhancement throughout the breast. Molecular breast imaging was available for one patient and showed multicentric radiotracer uptake. Analysis of 39 pathologic specimens showed 27 (69%) with angiolymphatic invasion. Axillary nodal metastases were present in 23 patients (59%), nine (23%) with extranodal extension. The imaging features of invasive ductal carcinoma of the breast with micropapillary features typically were highly suggestive of malignancy. The malignancies were strongly associated with lymphovascular invasion and lymph node metastases. Radiologists should be aware of the imaging features of this unusual variant and should consider axillary sonography if this entity is found in a core needle biopsy specimen.

Low-grade Serous Neoplasms of the Ovary With Transformation to High-grade Carcinomas

Ovarian borderline tumors usually occur in young patients and are associated with good clinical outcomes. A proportion of these tumors, particularly those with micropapillary features, may progress to low-grade serous carcinomas. Evolution of low-grade serous neoplasms to high-grade carcinomas is rare and infrequently reported. In this case report, we describe 3 cases of serous borderline tumor that progressed to high-grade carcinoma. Patient ages were 22, 35, and 47 yr. Two patients were initially diagnosed with ovarian serous borderline tumor, and recurred in the pelvis 3 and 10 yr later with sarcomatoid carcinoma. The third patient presented with low-grade serous carcinoma arising in a micropapillary serous borderline tumor, and recurred with a carcinosarcoma 3 yr later. All 3 patients had an aggressive clinical course: 2 died of disease and 1 patient has disease progression on chemotherapy. Occasional low-grade serous tumors of the ovary may transform to high-grade carcinomas, which can occur many years after initial diagnosis. The presence of a high-grade component significantly worsens patient outcomes.

Borderline ovarian tumors diagnosed during pregnancy exhibit a high incidence of aggressive features: results of a French multicenter study

The purpose of the current study was to evaluate the characteristics of borderline ovarian tumors (BOTs) diagnosed during pregnancy. We conducted a retrospective multicenter study of 40 patients with BOTs diagnosed during pregnancy between 1997 and 2009 at five tertiary universitary departments of Gynecology and Obstetrics and one French cancer center. The medical records were reviewed to determine surgical procedure, histology, restaging surgery and recurrence. Mean patient age was 30.2 ± 5.4 years. Most BOTs were diagnosed during the first trimester of pregnancy (62%). Salpingo-oophorectomy (N = 24) was more frequently performed than cystectomy (N = 11) during pregnancy (P = 0.01). Only two patients had an initial complete staging. BOTs were mucinous, serous and mixed in 48%, 42% and 10% of patients, respectively. Twenty-one percent of mucinous BOTs exhibited intraepithelial carcinoma or microinvasion. Forty-seven percent of serous BOTs exhibited micropapillary features, noninvasive implants or microinvasion. Restaging surgery performed in 52% patients resulted in upstaging in 24% of cases. Recurrence rate in patients with serous BOT with micropapillary features or peritoneal implants was 7.5%. BOTs diagnosed during pregnancy exhibit a high incidence of aggressive features and are rarely completely staged initially. Given this setting, up-front salpingo-oophorectomy should be considered and restaging planned.

Lymphovascular Invasion in Micropapillary Urothelial Carcinoma: A Study of 22 Cases

Micropapillary urothelial carcinoma (MPUC) is a known aggressive variant of urothelial carcinoma. However, the reasons for its aggressiveness remain unclear. To investigate the frequency of lymphovascular invasion in 22 cases of MPUC. Consecutive tissue sections were stained with D2-40 and CD34 to highlight lymphovascular channels associated with MPUC. Spaces containing tumor cells were scored as positive for lymphovascular invasion if the staining pattern on immunohistochemistry was distinct and circumferential. Of 22 cases, 21 (95%) had lymphovascular invasion on immunohistochemical staining, with 91% lymphatic invasion and 4% vascular invasion. Interestingly, 8 cases were originally signed out as negative for lymphovascular invasion on the basis of hematoxylin-eosin-stained sections; of these, 7 (88%) had focal lymphovascular invasion evident on immunohistochemical staining. Our results confirm that micropapillary lacunae are not lymphovascular channels. However, nearly all MPUC tumors (95% in this series) have evidence of lymphovascular invasion by immunohistochemical analysis. Our data support the use of micropapillary features as a morphologic marker for lymphovascular invasion and MPUC as an adverse histologic type of urothelial carcinoma.

Neoadjuvant chemotherapy with DD-MVAC and bevacizumab in high-risk urothelial cancer: Results from a phase II trial at the University of Texas M. D. Anderson Cancer Center.

4523 Background: DD-MVAC has shown an improved 5-year survival in metastatic urothelial cancer; however, there is no prospective data on its use in the neoadjuvant setting. Previous work suggested that over-expression of VEGF was associated with a high risk of relapse in our neoadjuvant patients, leading to the hypothesis that combining a VEGFR inhibitor with chemotherapy may improve patient outcomes. Methods: Between 8/07 and 12/10, 60 patients with urothelial carcinoma of the bladder or upper tract tumor were enrolled on a prospective phase II clinical trial. Eligibility requirements included at least one of the following: 3-D mass on EUA (cT3b disease), LVI, hydronephrosis, micropapillary features, tumor in a diverticula, and for upper tract tumors a high grade tumor or radiographically measurable sessile mass. The primary endpoint was pathologic down-staging to &lt;=pT1N0M0. Results: Forty-four patients with bladder/urethral tumors and 16 patients with upper tract tumors were enrolled. Pathologic down-staging to &lt;= pT1N0M0 occurred in 53% of patients overall (bladder/urethra 45%, upper tract 75%), and to &lt;= pT0N0M0 in 38% overall (bladder/urethra 39%, upper tract 38%). At a median follow-up of 26 months, the 2-year OS and DSS was 78% and 82%, respectively (bladder 2-yr OS and DSS 75%, 78%; upper tract 93%, 93%). The median OS and DSS have not yet been reached. The most common grade 3 or greater toxicity was neutropenia in 27% of patients, followed by fatigue in 10%. The following grade 3 toxicities were observed in &lt; 10% of patients: mucositis, DVT/PE, hypertension, nausea/vomiting, thrombocytopenia. One patient experienced cardiac ischemia. Conclusions: Neoadjuvant chemotherapy leads to pathologic down-staging in 45% of patients with bladder cancer. DD-MVAC appears an acceptable alternative to traditional M-VAC in the neoadjuvant setting. Although bevacizumab did not impact down-staging based upon historical expectations, determining the effect on recurrence requires longer follow-up.

390 THE IMPACT OF MIXED HISTOLOGAL FEATURES ON SURVIVAL FOLLOWING RADICAL CYSTECTOMY FOR UROTHELIAL CARCINOMA

You have accessJournal of UrologyUrothelial Cancer: Natural History & Pathophysiology/Marker1 Apr 2012390 THE IMPACT OF MIXED HISTOLOGAL FEATURES ON SURVIVAL FOLLOWING RADICAL CYSTECTOMY FOR UROTHELIAL CARCINOMA Simon Kim, Igor Frank, John Cheville, R. Houston Thompson, Christopher Weight, Prabin Thapa, and Stephen Boorjian Simon KimSimon Kim Rochester, MN More articles by this author , Igor FrankIgor Frank Rochester, MN More articles by this author , John ChevilleJohn Cheville Rochester, MN More articles by this author , R. Houston ThompsonR. Houston Thompson Rochester, MN More articles by this author , Christopher WeightChristopher Weight Rochester, MN More articles by this author , Prabin ThapaPrabin Thapa Rochester, MN More articles by this author , and Stephen BoorjianStephen Boorjian Rochester, MN More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.454AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The presence of mixed histological features (MH) in patients with urothelial carcinoma (UC) of the bladder has been associated with locally-advanced disease at radical cystectomy (RC), and has been suggested to predict response to neoadjuvant chemotherapy. The impact of MH on survival, however, remains to be defined. We investigated comparative clinical and pathologic outcomes of patients undergoing RC for pure UC versus those with UC and MH. METHODS We identified 1,150 patients who underwent RC at Mayo Clinic between 1980-2007, including 827 (72%) with pure UC and 323 (28%) with UC and MH. MH patients included those with squamous differentiation (n=132), glandular differentiation (n=41), or both (n=13); micropapillary features (n=67); nested variant of UC (n=49); and UC with sarcomatoid histology (n=21). All specimens were re-reviewed by a single genitourinary pathologist. Cancer specific survival (CSS) was estimated using the Kaplan-Meier method and compared with the log-rank test. The association of MH with death from UC was evaluated using multivariable Cox proportional hazard regression analysis. RESULTS Median follow-up after RC was 8.4 years (interquartile range 3.0, 13.5). In total, 502 patients died of bladder cancer, including 147 with MH and 355 with pure UC. No significant difference between the cohorts was noted with regard to patient age (p=0.78), gender (p=0.26), ECOG (p=0.29), or surgical margin status (p=0.41). Patients with UC and MH were more likely to have pT3-T4 tumors (69.3% vs 38.7%; p<0.0001) and pN+ disease (26.3% vs 15.4%; p<0.0001) compared to patients with pure UC. Interestingly, however, postoperative 10-year CSS did not significantly differ between patients with UC and MH and patients with pure UC (47% vs 51%; p=0.18). Moreover, after adjusting for clinicopathologic features (Table). the presence of MH was associated a decreased risk of death from UC (HR 0.82; p=0.05). Multivariate Analysis of Clinicopathologic Variables Associated with Death from UC after RC Variable HR 95% CI p Value Age at RC 1.01 0.99,1.01 0.34 ECOG PS 1.34 1.08,1.65 0.007 pT2 (vs pTa/Tis/T1) 1.61 1.20,2.15 0.002 pT3 (vs pTa/Tis/T1) 3.22 2.45,4.23 <0.0001 pN+ 1.44 1.16,1.78 0.001 Positive surgical margin 1.60 1.15,2.22 0.005 UC with MH (vs pure UC) 0.82 0.67,1.00 0.05 CONCLUSIONS Patients with UC and MH at RC were more likely to have extravesical tumors and node-positive disease. Nevertheless, these patients did not have adverse CSS compared to patients with pure UC. In fact, the presence of MH was associated with a nearly 20% lower risk of death from UC. Additional studies are needed to further define prognostic factors for the individual sub-types of UC that encompass MH. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e160 Peer Review Report Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Simon Kim Rochester, MN More articles by this author Igor Frank Rochester, MN More articles by this author John Cheville Rochester, MN More articles by this author R. Houston Thompson Rochester, MN More articles by this author Christopher Weight Rochester, MN More articles by this author Prabin Thapa Rochester, MN More articles by this author Stephen Boorjian Rochester, MN More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Neoadjuvant chemotherapy with DD-MVAC and bevacizumab in high-risk urothelial cancer: Results from a phase II trial at the M. D. Anderson Cancer Center.

261 Background: DD-MVAC has shown an improved 5-year survival in metastatic urothelial cancer; however, there is no prospective data on its use in the neoadjuvant setting. Previous work suggested that over-expression of VEGF was associated with a high risk of relapse in our neoadjuvant patients, leading to the hypothesis that combining a VEGFR inhibitor with chemotherapy may improve patient outcomes. Methods: Between 8/07 and 12/10, 60 patients with urothelial carcinoma of the bladder or upper tract tumor were enrolled on a prospective phase II clinical trial. Eligibility requirements included at least one of the following: 3-D mass on EUA (cT3b disease), LVI, hydronephrosis, micropapillary features, tumor in a diverticula, and for upper tract tumors a high grade tumor or radiographically measurable sessile mass. The primary endpoint was pathologic down-staging to &lt;=pT1N0M0. Results: Forty-four patients with bladder/urethral tumors and 16 patients with upper tract tumors were enrolled. Pathologic down-staging to &lt;= pT1N0M0 occurred in 53% of patients overall (bladder/urethra 45%, upper tract 75%), and to &lt;= pT0N0M0 in 38% overall (bladder/urethra 39%, upper tract 38%). At a median follow-up of 21 months, the 2-year OS and DSS was 78% and 85%, respectively (bladder 2-yr OS and DSS 75%, 82%; upper tract 93%, 93%). The median OS and DSS have not yet been reached. The most common grade 3 or greater toxicity was neutropenia in 27% of patients, followed by fatigue in 10%. The following grade 3 toxicities were observed in &lt; 10% of patients: mucositis, DVT/PE, hypertension, nausea/vomiting, thrombocytopenia. One patient experienced cardiac ischemia. Conclusions: Neoadjuvant chemotherapy leads to pathologic down-staging in 45% of patients with bladder cancer. DD-MVAC appears an acceptable alternative to traditional M-VAC in the neoadjuvant setting. Although bevacizumab did not impact down-staging based upon historical expectations, determining the effect on recurrence requires longer follow-up.

Clinical Features and Outcome of Patients With Non–Small-Cell Lung Cancer Harboring BRAF Mutations

To investigate the prevalence, distribution, and prognostic role of BRAF mutations in a large cohort of white patients with non-small-cell lung cancer (NSCLC). A retrospective series of 1,046 NSCLCs-comprising 739 adenocarcinomas (ADCs) and 307 squamous cell carcinomas (SCCs)-was investigated for BRAF mutations. High-resolution melting analysis followed by sequencing and strip hybridization assay were used. All patients were also analyzed for KRAS and EGFR mutations. BRAF mutations were present in 36 ADCs (4.9%) and one SCC (0.3%; P = .001). Twenty-one of the mutations (56.8%) were V600E, and 16 (43.2%) were non-V600E. V600E mutations were significantly more prevalent in females (16 of 187 patients; 8.6%) than in males (five of 552 patients; 0.9%), as indicated by multivariate logistic regression analysis (hazard ratio [HR], 11.29; P < .001). V600E-mutated tumors showed an aggressive histotype characterized by micropapillary features in 80% of patients and were significantly associated with shorter disease-free and overall survival rates on both univariate (HR, 2.67; P < .001 and HR, 2.97; P < .001, respectively) and multivariate analyses (HR, 2.19; P = .011 and HR, 2.18; P = .014, respectively). All non-V600E mutations were found in smokers (P = .015) and were associated with neither clinicopathologic parameters nor prognosis. BRAF and EGFR were concomitantly mutated in two tumors. We report for the first time to our knowledge that V600E and non-V600E BRAF mutations affect different patients with NSCLC. V600E mutations are significantly associated with female sex and represent a negative prognostic factor. In addition, we identified a number of other clinicopathologic parameters potentially useful for the selection of patients carrying BRAF mutations.

1247 THE SENSITIVITY OF INITIAL TURB ON DETECTING BLADDER CANCER VARIANTS ON RADICAL CYSTECTOMY

You have accessJournal of UrologyBladder Cancer: Detection and Screening1 Apr 20111247 THE SENSITIVITY OF INITIAL TURB ON DETECTING BLADDER CANCER VARIANTS ON RADICAL CYSTECTOMY Ahmed Abd El-Latif, Amr Fergany, and Donna E. Hansel Ahmed Abd El-LatifAhmed Abd El-Latif Cleveland, OH More articles by this author , Amr FerganyAmr Fergany Cleveland, OH More articles by this author , and Donna E. HanselDonna E. Hansel Cleveland, OH More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.918AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Conventional urothelial cancer (cUC) is the most frequently encountered form of bladder cancer on pathology evaluation. The majority of cUC presents initially as clinically localized disease. However, other less common pathological variants including urothelial carcinoma with squamous or glandular differentiation or sarcomatoid, small cell, nested and micropapillary variants, often present at a more advanced stage. We evaluated the sensitivity of initial transurethral resection (TURB) on predicting the final pathological variants in patients who were treated with radical cystectomy (RC) for bladder cancer. METHODS Between years 2008–2010, 402 patients underwent RC after initial TURB diagnosis of bladder cancer. Of this cohort, 159 (40%) patients had one or more of the pathological variants identified either on initial TURB, or on final pathology post RC, or both. Pathology data was retrospectively obtained from the pathology electronic database at our institution. RESULTS The sensitivity of the TURB detection of the variants on final post-RC pathology included: 44/88 (50%) for squamous differentiation, 6/13 (46%) for small cell differentiation, 6/17 (35%) for micropapillary features, 3/13 (23%) for glandular differentiation, 4/19 (21%) for nested variants, 2/13 (15%) for sarcomatoid differentiation, 0/3 (0%) for trophoblastic features, 0/3 (0%) for plasmacytoid features, 0/1 (0%) for microcystic features. A small subset of patients 11/159 (7%) had an initial TURB diagnosis of a urothelial carcinoma variant, although final pathology on RC failed to identify variants in the larger resection. Overall, the sensitivity of the initial TURB was 40%. CONCLUSIONS The sensitivity of the initial TURB in predicting urothelial carcinoma variants in radical cystectomies is relatively low, with the best sensitivity for squamous differentiation (50%). This finding is especially critical, as the initial diagnosis may affect treatment decisions and patient prognosis – especially in the context of aggressive urothelial carcinoma variants. Further prospective studies that evaluate the sensitivity of TURB and impact on treatment in instances of variant forms of urothelial carcinoma is warranted. Until then, urologists should maintain a high index of clinical suspicion in patients with less common forms of urothelial carcinoma. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e499 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ahmed Abd El-Latif Cleveland, OH More articles by this author Amr Fergany Cleveland, OH More articles by this author Donna E. Hansel Cleveland, OH More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Abstract P6-01-03: Invasive Micropapillary Carcinoma (IMPC) of the Breast: An Uncommon but Aggressive Special Type of Breast Cancer

Abstract IMPC is an uncommon type of invasive breast cancer. However, in comparison to invasive ductal carcinoma of no special type (IDC), it is reported to have a more aggressive behavior. Our objective was to compare and contrast IMPC with IDC in terms of clinicopathologic features and outcome. One hundred-thirty-one IMPC cases were compared to 1295 IDC and 189 invasive lobular carcinoma (ILC). Medical records and pathology slides were reviewed for traditional factors (tumor grade, lymphatic invasion [LVI], lymph node [LN] status, stage, receptor status, treatment) and specific tumor features (extent of retraction artifact [RA]). Clinicopathologic features between groups were compared and clinical outcome of IMPC was recorded. All patients were women with a median age of 57.6 yrs (range 22-93) for IMPC, 56.3 yrs (range 22-96) for IDC and 60.7 (range35-85) for ILC, respectively (P&amp;lt;0.0001). There were no differences noted for family history, race, or presentation (symptomatic vs. screening). Surgical treatment was partial mastectomy in 770 (47.7%) and mastectomy in 845 (52.3%). All patients had axillary lymph node biopsy. The median tumor size was 2.2 (range 0.3-15.2) cm for IMPC, 2.0 (range 0.05-11.0) cm for ILC and 1.7 (range 0.05-19.0) cm for IDC, respectively (P&amp;lt;0.). The extent of micropapillary features in IMPC ranged from 3% to 100% with a median value of 20%. LVI was more likely to be present in IMPC (67.9%) compared to IDC (28.3%) and ILC (6.9%) (P&amp;lt;0.0001). Axillary LN metastases were seen in 71.8% of IMPC compared to 44.1 % of IDC and 54.5% of ILC (P&amp;lt;0.0001). IMPC and ILC was significantly more frequently ER and PR positive (P&amp;lt;0.0001 each) compared to IDC, while ILC was significantly less frequently HER2 positive (2.8%) compared to IDC (17.9%) and IMPC (8.2%). The mean percent of tumors showing retraction artifact (RA) was 60.2% in IMPC compared to 25.4% in IDC and 3.8% in ILC (P&amp;lt;0.0001). During a median follow-up of 24.3 months 19 (14.5%) and 17 (13.0%) IMPC patients developed local and distant recurrence, respectively. IMPC is an uncommon special type of invasive breast cancer but it is more aggressive in reference to IDC and ILC based on larger tumor size and more frequent the presence of LVI and LN metastases. The presence of IMPC features in breast cancers, even if present focally, should alert the clinician for the high likelihood of lymphatic tumor spread and an adverse biologic behavior. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-01-03.

Invasive Ductal Carcinomas of the Breast Showing Partial Reversed Cell Polarity are Associated With Lymphatic Tumor Spread and may Represent Part of a Spectrum of Invasive Micropapillary Carcinoma

Invasive micropapillary carcinomas (IMPC) of the breast are aggressive tumors frequently associated with lymphatic invasion and nodal metastasis even when micropapillary (MP) differentiation is very focal within the tumors. We have noticed that some breast carcinomas showing lymphatic spread but lacking histologic features of IMPC have occasional tumor cell clusters reminiscent of those of IMPC without the characteristic prominent retraction artifact. To study the clinicopathologic significance of such features, we prospectively selected 1323 invasive ductal carcinomas and determined the presence and extent of MP differentiation and retraction artifact in the tumors. One representative tumor block per case was used for immunostaining for epithelial membrane antigen (EMA). Partial reverse cell polarity (PRCP) was defined as prominent linear EMA reactivity on at least part of the periphery of tumor cell clusters usually associated with decreased cytoplasmic staining. The clinicopathologic features of carcinomas with PRCP were compared with IMPC and invasive ductal (no special type) carcinomas without this feature. Of the 1323 cases, 96 (7.3%) and 92 (7.0%) showed MP features and the presence of PRCP, respectively. We found that the presence of both PRCP and MP features were strongly associated with decreased cytoplasmic EMA immunoreactivity and the presence of lymphatic invasion and nodal metastasis, even if such features were present only very focally. Our results suggest that breast carcinomas with PRCP may have the same implication as MP differentiation and these tumors may represent part of a spectrum of IMPC. Complete or partial reversal of cell polarity may play a significant role in lymphatic tumor spread.

Urothelial carcinoma of the bladder with transmural and direct prostatic stromal invasion: does extent of stromal invasion significantly impact patient outcome?

Urothelial carcinoma of the bladder with prostatic stromal invasion is included in stage pT4a of the new 2010 American Joint Committee on Cancer/Tumor-Node-Metastasis classification. Despite being a strong indicator of poor prognosis, there have been few large studies investigating the impact of extent of prostatic stromal invasion on patient outcome. A search of the surgical pathology and expert consultation files at our institution was made for cystoprostatectomy specimens diagnosed as urothelial carcinoma with prostatic stromal invasion from 2002 to 2009. Cases were further stratified as follows: group 1--focal prostatic stromal invasion and group 2--extensive prostatic stromal invasion. Only patients who had surgery as monotherapy and those with available follow-up information were selected for this study. Thirty-five cases of urothelial carcinoma with prostatic stromal invasion and follow-up information were identified. Mean patient age was 70 years (range, 44-88 years). Of these 35 patients, 15 (43%) had focal prostatic stromal invasion and 20 (57%) had extensive prostatic stromal invasion. Angiolymphatic invasion was identified in 93% of group 1 cases and 79% of group 2 cases. Positive margins were identified in 50% of group 1 cases and 45% of group 2 cases. Incidence of nodal metastasis was 64% for group 1 and 60% for group 2. Four (27%) of 15 cases in group 1 and 6 (30%) of 20 cases in group 2 had various histologic variants identified. In group 1, there were 2 cases of urothelial carcinoma with micropapillary features and urothelial carcinoma with focal squamous differentiation. In group 2, there were 3 cases of urothelial carcinoma with focal squamous differentiation, 2 cases of urothelial carcinoma with focal sarcomatoid differentiation, and 1 case of urothelial carcinoma with focal micropapillary features. One- and 3-year overall survival for group 1 was 53% and 27%, respectively. One- and 3-year overall survival for group 2 was 47% and 12%, respectively. Mean survival was 17.4 and 16.3 months for groups 1 and 2, respectively. Overall survival curves did not show a statistically significant difference between the 2 groups from initial diagnosis (P = .889) and radical cystoprostatectomy (P = .369). Our study suggests that extent of prostatic stromal invasion by urothelial carcinoma of the bladder as an independent factor does not impact overall patient survival. Other well-known prognostic factors including positive margin status, presence of aggressive histologic variants of urothelial carcinoma, angiolymphatic invasion, and distant metastasis likely play more critical roles in predicting outcome in male patients who have urothelial carcinoma with prostatic stromal invasion.

Micropapillary Carcinoma of Stomach

Micropapillary carcinoma (MPC) of the stomach is a rare, newly recognized entity, and only 2 patients with this histology have been reported. We investigated clinicopathologic features, expression of mucin (MUC2, MUC5AC, MUC6, CD10) and cytokeratin profiles (CK7 and CK20), epidermal growth factor receptors (EGFR and HER2), prognostic markers (p53 and Ki-67), and outcomes in 11 MPCs of the stomach. The proportion of MPC component ranged from 5% to 70%. Micropapillary features were often found at the deep advancing edge of the tumor. Endolymphatic tumor emboli were found in 10 cases (91%) and lymph node metastases were found in 4 cases (36%). In MPCs, positive expression was observed for Ki-67 (82%), CK7 (73%), EGFR (64%), p53 (64%), MUC5AC (45%), MUC6 (36%), and CK20 (27%). However, MUC2, CD10, and HER2 expression was negative in all cases. In 9 conventional adenocarcinomas and 11 papillary adenocarcinomas with multiple endolymphatic tumor emboli, used as control, positive expression was observed for Ki-67 (100%), CK7 (90%), EGFR (80%), CK20 (70%), p53 (70%), MUC5AC (70%), MUC6 (60%), MUC2 (40%), CD10 (25%), and HER2 (15%). Expression of MUC2, CK20, and the Ki-67 labeling index was significantly higher in control adenocarcinomas as compared with MPCs (P<0.05). However, there was no significant difference in other clinicopathologic features and overall patient survival. Subclassification of MPCs into 2 subgroups according to the proportion of micropapillary component (cut-off value was 20%) failed to find any significant clinicopathologic differences (P>0.05). Although MPCs in other organs show a poor prognosis, this does not seem to be true for gastric MPCs. Further larger studies are necessary to confirm our initial findings.

Rare histological patterns of prostatic ductal adenocarcinoma

Prostatic ductal adenocarcinomas account for 1% of prostate cancers. Most commonly, these lesions grow in large cribriform and/or papillary patterns or, as recently described, in a manner resembling prostatic intraepithelial neoplasia (i.e., 'PIN-like' prostatic ductal adenocarcinoma). This study aims to report rare variants of ductal adenocarcinoma. Ten cases of rare patterns of prostatic ductal adenocarcinoma that have not been formally investigated prior to this study, primarily from one author's consultation service (1987-2009), were selected. Two (n = 2) cases were prostatic ductal adenocarcinoma with mucinous and goblet cell features. Three (n = 3) cases are the first described cases of foamy gland prostatic ductal adenocarcinoma. Other unique cases were prostatic duct adenocarcinomas with associated Paneth cell-like neuroendocrine (n = 2), micropapillary (n = 2), and cystic papillary features (n = 1). Prostatic origin was confirmed with immunohistochemical studies for prostate specific antigen (PSA), P501S, and prostate specific membrane antigen (PSMA). High-grade PIN was ruled out with negative stains for high molecular weight cytokeratin (HMWCK) and p63. Four prostatic ductal adenocarcinomas had no evidence of disease at 2-8 years follow-up: foamy gland, Paneth cell-like, and micropapillary (two cases). One mucinous prostatic ductal adenocarcinoma resulted in the patient's death and the other mucinous case was alive at 7 years and 2 months, yet with no information as to status of disease. The remaining four cases were lost to follow-up, died of other causes, or were recent. In summary, we report several rare and unique histological patterns of prostatic ductal adenocarcinoma. The practical importance of recognising these histological variations is that in some cases they may be misdiagnosed as non-prostatic tumours. These unusual cases also provide further support for the relationship between acinar and ductal adenocarcinoma.

Emerging Concepts in Micropapillary Urothelial Carcinoma

Micropapillary urothelial carcinoma is a relatively uncommon variant of urothelial carcinoma, but its recognition carries important prognostic and treatment implications. Micropapillary morphology occurs in neoplasms arising in many different organ systems and displays aggressive biologic behavior regardless of its site of origin. On account of this association, micropapillary features in urothelial carcinoma should be reported regardless of whether the pattern is focal or dominant. The overall prognosis for micropapillary urothelial carcinoma is poor and recent studies suggest that early treatment with cystectomy could improve outcome, as these tumors are unlikely to respond to chemotherapy when used as a secondary treatment modality. This review discusses the histologic features required for diagnosis and the clinical significance of rendering a diagnosis of micropapillary urothelial carcinoma.

Abstract 2164: Lung adenocarcinoma subtypes have unique gene mutations (EGFR, TP53), DNA copy number alterations (3q26, 16p13), and patient smoking histories

Abstract Introduction: Lung adenocarcinoma is a clinically and genetically heterogenous disease. Recently, three validated and clinically relevant gene expression subtypes (Magnoid, Bronchioid, and Squamoid) have been described (Hayes, 2006); however, the subtypes’ origins are unknown. We hypothesized that the subtypes are the result of unique gene mutations and DNA copy number alterations in unique patient populations. Methods: 85 lung adenocarcinomas were collected and assayed for gene expression and DNA copy number (CN), using Agilent 44K and Affymetrix 250K_Sty microarrays. 376 lung adenocarcinomas with gene expression microarrays and CN arrays or gene mutations were obtained from three published cohorts (Ding, 2008; Tomida, 2009; Chitale, 2009). Tumor subtype classification was completed using published methods. CN was calculated and significantly altered CN segments were detected (Beroukhim, 2007; Bengtsson, 2008). Subtype segment CN was compared by z -scores (FDR &amp;lt; 1%). Mutations and clinical variables were compared by Cochran-Mantel-Haenszel tests adjusting for cohort and by Kruskal-Wallace tests. Subtype 3-year survival was compared by log rank tests and Cox proportional hazards models adjusted by cohort. Results: Three gene expression subtypes were detected in each of four cohorts and uniquely corresponded to the known Magnoid (M), Bronchioid (B) and Squamoid (S) subtypes. Gene mutations were significantly associated with subtype, including EGFR increased in B (M/B/S: 16%, 39%, 23%; P ≪ 0.01) and TP53 increased in M (M/B/S: 45%, 24%, 15%; P ≪ 0.01). Additionally, numerous genomic regions had significantly different mean DNA copy number across the subtypes including amplifications (M: 3q26, 7q31; B: 5q34, 16p13) and deletions (M: 4q35.1, 17p12). Interestingly, a more broad measure of overall genomic stability (chromosome arm variation) was also significantly different among subtypes, with M having the highest instability (P ≪ 0.01). In terms of clinical significance, 3-year subtype patient survival was significantly different (M/B/S − 66%, 87%, 83%; P ≪ 0.01), and remained so after adjustment for mutations, stage, and sex. Patient smoking history was significantly different among the subtypes (pack year median M/B/S: 40/10/34; P ≪ 0.01). Also, previously reported associations of subtype and morphology were confirmed, with lower grade (P ≪ 0.01) and increased micropapillary features in B (P = 0.04). Conclusions: Lung adenocarcinoma gene expression subtypes have different levels of EGFR and TP53 gene mutations, global genomic instability, specific DNA copy number alterations, and clinical and morphologic characteristics. This integrated analysis supports that different mutation events in concert with different patient populations contribute to produce these distinct and clinically relevant gene expression subtypes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2164.

CD138-Positive Plasmacytoid Urothelial Carcinoma of Urinary Bladder with Focal Micropapillary Features

Both the plasmacytoid and micropapillary types of urothelial carcinoma of the urinary bladder are uncommon, distinct clinical and pathological findings. To date, several reports in the English medical literature have been published on either of these variants. CD138 is commonly used as a marker for tumors of plasma cell origin. However, few authors have described positive immunoreactivity of plasmacytoid cells in urothelial carcinoma. Mixed histological differentiation is thought to be a phenotype of locally aggressive and advanced urothelial carcinoma. Therefore, a precise histopathological diagnosis should be made and awareness of all the entities is crucial. We report a case of CD138-positive plasmacytoid urothelial carcinoma of the bladder with focal micropapillary features. To our knowledge this is the first case of these two rare subtypes of urothelial carcinoma combined in a single cystectomy specimen.