Non-Hodgkin's Lymphoma (NHL) rarely presents during pregnancy and primary mediastinal large B-cell lymphoma (PMLBCL) accounts for approximately 2.5% of patients with NHL. The case of a 22-year-old woman who was diagnosed with Stage IIA PMLBCL during week 13 of her intrauterine pregnancy is described. The staging consisted in computed tomography (CT) of the chest and magnetic resonance imaging (MRI) of the abdomen and pelvis. She was managed with R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) for a total of six cycles and, because of the early presentation during the second trimester, she received the entire chemotherapy course during the pregnancy. She delivered a healthy baby at 34 weeks of pregnancy and a 18FDG-PET/CT scan demonstrated complete remission after delivery. After 20 months of follow up she remains with no evidence of disease and her 1-year-old son has shown no developmental delays or physical abnormalities. PMLBCL, although an uncommon subgroup of DLBCL, may present during pregnancy and R-CHOP should be considered as one suitable option in this complex scenario.

Previous studies have suggested that CD30 may be expressed in diffuse large B-cell lymphomas (DLBCLs). However, the prevalence of CD30 + DLBCLs and extent of CD30 expression within an individual tumor have not been fully evaluated. The aim of this study was to determine the frequency and extent of CD30 expression in DLBCLs, and explore possible relationships between CD30 expression and clinical and biologic variables. We retrospectively identified and analyzed 167 cases of CD30 + DLBCLs from our pathology archive. Twenty-one percent (95% confidence interval [CI]: 14.8-27.1%) of these cases expressed CD30, and in 52% of them CD30 was positive in > 80% of tumor cells. CD30 expression was more frequent in DLBCLs with non-germinal center origin phenotype, BCL2 + DLBCLs and in patients ≤ 47 years old. There was significant interaction of BCL2 expression with age and subtype of DLBCL. A multivariate analysis performed in BCL2 + DLBCLs showed a higher frequency of CD30 + cases in non-germinal center DLBCLs (odds ratio [OR]: 6.5, 95% CI: 1.1-36.5) and in patients ≤ 47 years old (OR: 6.9, 95% CI: 1.5-29.5). These associations could suggest a common biologic pathogenesis. The effectiveness of anti-CD30 drugs in other lymphomas opens the possibility for their use in patients with CD30 + DLBCLs.

Context.-We reported previously that more than onethird (37%) of primary bladder squamous cell carcinomas (SCCs) demonstrate diffuse p16 immunoreactivity independent of gender. This observation made us question whether p16 overexpression in bladder carcinoma is due to human papillomavirus (HPV)-dependent mechanisms.Objective.-To determine whether the presence of highrisk HPV (HR-HPV) DNA could be detected in these tumor cells.Design.-Fourteen cases of primary bladder SCC, which were positive for p16 by immunohistochemistry, were probed for the detection of HR-HPV by in situ hybridization and the signal amplification Invader assay. Samples positive for detection of HR-HPV by Invader assay were amplified by using HR-HPV type-specific primers, and amplification products were DNA sequenced.Results.-Detection of HR-HPV by the in situ hybridization method was negative in all cases (0 of 14). However, in 3 of 14 cases (21.4%), the presence of HR-HPV DNA was detected with the Cervista HPV HR Invader assay, which was followed by identification of genotype. All positive cases were confirmed by using HR-HPV typespecific amplification followed by DNA sequencing. Identified HR-HPV genotypes included HPV 16 (2 cases) and HPV 35 (1 case).Conclusions.-High-risk HPV DNA is detectable in a subset of primary bladder SCCs. Based on the welldocumented carcinogenic potential of HR-HPV, there is a necessity for additional studies to investigate the role of HR-HPV in bladder carcinogenesis.(Arch Pathol Lab Med. 2013;137:1088-1093; doi: 10.5858/arpa.2012-0122-OA) B ladder cancer is the second most common malignancy of the genitourinary tract diagnosed in the United States 1 with approximately 70 000 newly diagnosed cases and 14 000 deaths from disease annually. To date, wellestablished risk factors for the development of bladder squamous cell carcinoma (SCC) include increasing age (peak incidence at 50-70 years), male sex (male to female ratio, 3:1), smoking, exposure to carcinogenic chemicals, and chronic bladder inflammation and/or repeated urinary infections, and molecular/genetic factors. Although the oncogenic role of human papillomavirus (HPV) has been well documented in many epithelial cancers, including most cervical carcinomas, anogenital cancers, and carcinomas of the head and neck, its role in bladder carcinogenesis has been controversial throughout the literature.In gynecologic malignancies, the presence of high-risk HPV (HR-HPV) is often associated with overexpression of p16 protein. Immunohistochemistry for p16 is therefore used to screen for the presence of HR-HPV in primary cervical carcinomas.2 In a recent study, 3 we reported that more than-one third (37%) of primary bladder SCCs demonstrated diffuse p16 immunoreactivity independent of gender or tumor differentiation. From this study, we concluded that in tumors involving the pelvic cavity, the presence of p16 immunoreactivity alone cannot be used to distinguish tumors from gynecologic or urothelial origin. Our observed p16 overexpression in a significant proportion of...

(1) The majority of SCCs of uterine cervix express p16. (2) More than a third of urinary bladder SCCs express p16. (3) SCCs of urinary bladder express p16 independent of gender. (4) p16 immunohistochemical expression alone cannot be used to discriminate between SCCs arising from uterine cervix versus urinary bladder.

A limited immunohistochemical panel including pan-cytokeratin, synaptophysin, and p63 discriminates HGNEC/SmCC from high-grade UC.

1592 Background: CD30 is a well-known diagnostic marker in both anaplastic large cell lymphoma (ALCL) and classical Hodgkin's lymphoma (CHL). Recently the chimeric drug brentuximab vedotin that combines an anti-CD30 monoclonal antibody with the anti-tubulin agent monomethyl auristatin E demonstrated activity in patients with relapsed ALCL and CHL. Previous observational studies have suggested that CD30 may be expressed in 10 to 20% of DLBCLs. It is possible that CD30+ DLBCLs may show different biologic behavior and be amenable to anti-CD30 therapy. The aim of this study was to determine the prevalence of CD30 expression in DLBCL by immunohistochemistry and explore possible relationships with important clinical and biologic variables of DLBCL. Methods: We retrospectively identified cases of DLBCL diagnosed between July 2003 and July 2012 at our institution. Eligible cases included patients with diagnosis of DLBCL irrespective of anatomic site or tumor stage. The diagnosis of DLBCL was based on the current WHO 2008 criteria. The following large B cell lymphoma subtypes were excluded from this analysis: post-transplant lymphoproliferative disorders with DLBCL morphology, Primary Mediastinal large cell lymphoma and the unclassifiable lymphomas with features intermediate between either DLBCL and Burkitt's lymphoma or between DLBCL and Hodgkin's lymphoma. Immunohistochemistry was performed as part of the routine workup of the cases (Monoclonal Mouse Anti-Human CD30, Dako) and CD30 was considered positive when ≥30% of neoplastic cells stained positive. DLBCLs were classified into germinal center (GC) or non-GC subtypes applying the Hans algorithm. Logistic regression analysis was performed to assess association between selected variables and CD30 expression. Results: A total of 333 cases of DLBCL were eligible for this study and of these 148 cases (44.4%) had CD30 results available. Selected demographic, clinical and histological characteristics were similar between cases on which CD30 IHC was performed compared to those in which CD30 IHC was not performed (data not shown), arguing against a selection bias in the performance of CD30 immunohistochemistry in these cases. Twenty-three percent (95% CI: 16.2% – 29.8%) of DLBCL tumors expressed CD30. CD30 expression was not significantly different between females and males (27.6% and 20.0% respectively, p = 0.28). The patients with CD30+ DLBCLs were 11.6 years younger than those with CD30- DLBCLs (95% CI: 5.3 – 17.9 years). The optimal cutoff age for CD30 expression was 47 years (ROC area under the curve: 0.70, p < 0.001). CD30 expression was more frequent in nodal and BCL2+ DLBCLs (Table 1). There was a non-significant difference between the expression of CD30 in non-GC type compared to GC type DLBCL with a pronounced trend for higher proportion of CD30 positivity in non-GC DLBCL (Table 1). CD30 expression was not significantly different in Epstein-Barr virus positive (EBV) compared to EBV negative DLBCLs (Table 1). Conclusions: CD30 is expressed in approximately 20% of all DLBCL and is more frequently expressed in younger patients and in BCL2+ DLBCLs. Although statistical significance was not reached, a trend towards more frequent CD30 expression in non-GC DLBCLs was observed. The increased expression of CD30 in the younger age group is intriguing, as other CD30+ neoplasms (CD30+ ALCL, CHL, and embryonal carcinoma) are also commonly observed in younger patients. The development of brentuximab vedotin and its well established effectiveness in other types of relapsed lymphomas opens the possibility of its applicability in CD30+ DLBCLs. Disclosures: No relevant conflicts of interest to declare.

Background. Malignant cells frequently exhibit dysregulation of nutrient/energy metabolism that can be exploited for development of novel targeted molecular therapy. Transcriptional repression of ASS, an enzyme essential for arginine production, in certain cancers and not normal cells makes these tumor cells selectively auxotrophic (dependent on external source) of this semi-essential amino acid and extremely susceptible to arginine depletion. One of the clinically applicable strategies to deplete extracellular arginine is systemic administration of the enzyme arginine di-iminase (ADI) conjugated with polyethylene glycol (PEG20) for optimal bioavailability. While well characterized in malignant pleural mesothelioma, melanoma and hepatocellular carcinoma, the status of ASS expression and sensitivity to ADI-PEG20 has not previously been investigated in NSCLC and this is the overarching objective of this study. Materials and Methods. ASS expression in 12 NSCLC cell lines and normal cells is determined by quantitative RT-PCR, western blots. ASS expression in lung cancers is quantified by immunohistochemistry (IHC) of tissue microarray of 72 NSCLC tumors. ADI-PEG20-mediated inhibition of cell viability, autophagy activation, induction of apoptosis and cell cycle arrest are assayed using MTT, fluorescence microscopy, AnnexinV/PI staining with flow cytometry respectively. Methylation of the promotor region of the ASS gene in ASS-negative cells is evaluated by methylation-specific PCR. Results. Six of 12 NSCLC cells have no or extremely low basal expression of ASS mRNA and protein and are, thus, exquisitely sensitive to ADI-PEG20 treatment (IC50 values: 45± 5 to 90±8 ng/ml (mean ± standard deviation, n=6)). ASS+ NSCLC cells and normal cells (primary or immortalized human fibroblasts) are totally resistant to ADI-PEG20. About 80% of NSCLC tumors do not express ASS by IHC using a well-validated anti-ASS antibody (Santa Cruz, clone H231). ADI-PEG20 treatment strongly activates autophagy with accumulation of autophagic vacuoles detected by fluorescence microscopy. Significant induction of apoptosis (15±3% to 55±6%, n=4) is noted in 5 NSCLC cells treated with ADI-PEG20 (100 or 200 ng/ml for 4 or 7 days) as well as cell cycle arrest. Two cell lines have methylated ASS promotor (one complete, one partial) as the cause of gene silencing. Conclusion. Up to 50% of NSCLC cell lines and 80% of NSCLC tumors lack ASS expression. ASS- NSCLC are selectively and significantly susceptible to ADI-PEG20-mediated arginine depletion in vitro. Induction of autophagy, apoptosis and cell cycle arrest collectively contribute ADI-PEG20-mediated cytotoxicity. As ADI-PEG20 is currently in phase II clinical trials for other carcinomas with encouraging results, it can be used to develop novel targeted molecular therapy for NSCLC tumors lacking ASS. Citation Format: Min You, Medhi Wangpaichitr, Jonathan D. Nguyen, Jennifer R. Chapman, Maureen Cioffi-Lavina, Niramol Savaraj, Dao M. Nguyen. Exploiting obligate arginine auxotrophy in tumor cells lacking arginino-succinate synthetase (ASS) expression to develop targeted molecular therapy for non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1435. doi:10.1158/1538-7445.AM2014-1435

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