Maureen Cioffi-Lavina

Frequency and extent of CD30 expression in diffuse large B-cell lymphoma and its relation to clinical and biologic factors: a retrospective study of 167 cases

Abstract 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.

Primary Mediastinal Large B-Cell Lymphoma during Pregnancy

Non-Hodgkins 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.

Distinction of high-grade neuroendocrine carcinoma/small cell carcinoma from conventional urothelial carcinoma of urinary bladder: An immunohistochemical approach

Context High-grade neuroendocrine carcinomas and small cell carcinomas (HGNEC/SmCC) of the urinary bladder are uncommon but aggressive neoplasms. Differentiation of HGNEC/SmCC from high-grade urothelial carcinoma (UC) is based on histomorphologic features, but can be difficult in small biopsies and cases with mixed morphology. Objective We attempt to identify a limited immunohistochemical panel that aids in this distinction. Design We selected 39 cases of bladder carcinoma with small cell morphology: 7 HGNEC/SmCC, 21 high-grade UC with neuroendocrine-like pattern, and 11 mixed neoplasms. Immunohistochemistry for pan-cytokeratin, synaptophysin, chromogranin, p63, and thyroid transcription factor-1 was performed. Results Pan-cytokeratin was positive in 6 of 7 cases (86%) of the HGNEC/SmCC group. All 7 tumors were positive for synaptophysin, 6 of them were negative for p63 and chromogranin, and 1 was positive for p63 and chromogranin. All 21 high-grade UC with neuroendocrine-like pattern of growth showed positive staining for pan-cytokeratin, and were all negative for synaptophysin and chromogranin. Sixteen (76%) of high-grade UC were also positive for p63. All 11 mixed tumors were positive for pan-cytokeratin. In 10 of the 11 mixed tumors (91%), synaptophysin was positive in the neuroendocrine differentiated areas and it was negative in the urothelial component. In 2 of the 11 mixed tumors (18%) chromogranin was also positive. Three (27%) of the 11 mixed cases were positive for p63 in the UC foci. Chromogranin was negative in 6 of the pure HGNEC/SmCC and in 8 of the mixed tumors. None of the 39 samples were reactive for thyroid transcription factor-1. Conclusions A limited immunohistochemical panel including pan-cytokeratin, synaptophysin, and p63 discriminates HGNEC/SmCC from high-grade UC.

P16 expression in squamous cell carcinomas of cervix and bladder

Context/Objectivep16 is a widely used immunohistochemical marker in gynecologic pathology. Strong and diffuse cytoplasmic and nuclear expression of p16 in squamous cell carcinomas (SCC) of the female genital tract is strongly associated with high-risk human papilloma virus infection and neoplasms of cervical origin. However, p16 can be expressed in other neoplasms and in several normal human tissues. Occasionally, SCCs may involve both uterine cervix and urinary bladder. Accurate identification of the site of origin in such cases has therapeutic and prognostic implications. We investigate the potential value of p16 expression in this distinction. DesignWe reviewed 74 SCCs, 38 (51%) from urinary bladder and 36 (49%) from uterine cervix obtained between 2003 and 2008. Of the 38 cases of bladder carcinoma, 21 occurred in females and 17 in males. Immunohistochemical analysis for p16 (DAKO M7247, clone 484, dilution of 1:50) expression was done in all cases using the labeled streptavidin-biotin method. ResultStrong and diffuse nuclear and cytoplasmic p16 positivity was observed in 45 cases (61%). Of the 38 SCCs of urinary bladder, 14 (37%) expressed p16 (8 males, 6 females). Of the 36 SCCs of uterine cervix, 31 (86%) were positive for p16. Conclusions(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.

High-Risk Human Papillomavirus DNA Detected in Primary Squamous Cell Carcinoma of Urinary Bladder

CONTEXT We reported previously that more than one-third (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. OBJECTIVES To determine whether the presence of high-risk 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 type-specific 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 well-documented carcinogenic potential of HR-HPV, there is a necessity for additional studies to investigate the role of HR-HPV in bladder carcinogenesis.

Anaphylactic reaction to platelet transfusion as the initial symptom of an undiagnosed systemic mastocytosis: a case report and review of the literature

IntroductionThe association between anaphylactic reactions and systemic mastocytosis is well documented. However, platelet transfusion has not previously been reported as a potential elicitor of anaphylaxis in the context of systemic mastocytosis.Case presentationWe describe the clinicopathological findings of a 59-year-old Latin American man who presented to the emergency room with fatigue, leukocytosis, thrombocytopenia and mild hepatosplenomegaly. He developed two separate, temporally associated and severe anaphylactic reactions after receiving platelet transfusions. The result of a laboratory investigation for clerical errors and Coombs test was negative. Pre- and post-transfusion urine samples were negative for hemolysis. Bone marrow biopsy and aspirate smears performed demonstrated involvement by systemic mastocytosis, which had been previously undiagnosed.ConclusionsWe posit the transfusion reaction to be an anaphylactic reaction to transfused products as a result of heightened allergic sensitivity due to the underlying systemic mastocytosis. To the best of our knowledge, this is the first reported case of a severe anaphylactic-type reaction to blood products occurring in the setting of a previously undiagnosed systemic mastocytosis. Furthermore, it seems there are no published studies closely examining the relationship between hematopoietic neoplasms and transfusion reactions in general.

Abstract 1435: 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)

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA 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

Abstract 5502: Absence of ERCC1 expression is predictive of complete pathologic response to platinum-based therapy for women with triple negative breast cancer

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Background: Platinum-based chemotherapy exerts its cytotoxic effects by forming intra-strand DNA adducts that inhibit replication. Excision Repair Cross Complementing group 1 protein (ERCC1) plays a critical, yet undesirable, role in repair of DNA damage induced by platinum. Absence of immunohistochemical expression of ERCC1 has been shown to be associated with response to platinum-based chemotherapy regimens in non small cell lung carcinomas. Experimental data suggests that triple negative breast cancers may have increased sensitivity to platinum-based chemotherapy, particularly in BRCA1 mutation carriers, whose cancers cluster among the basal-like subtype, as defined by gene expression profiling. We investigated the immunohistochemical expression of ERCC1 in relation to response to neoadjuvant platinum-based chemotherapy in a cohort of patients with triple negative breast cancers. Materials and Methods: We reviewed the diagnostic core biopsies of 32 triple-negative breast cancer patients treated with neoadjuvant docetaxel plus platinum-based salts at our institution between 1999 and 2007. Fifteen (46.9%) study patients had pathologic complete response (pCR), defined by the absence of invasive carcinoma in the breast and axilla. Immunohistochemistry for ERRC1 (ABCAM) was performed in all cases using the LSAB method. A nuclear immunohistochemical reaction in >1% of the tumor cells was scored as positive for ERCC1. Fishers exact test was used to compare pCR rates by ERCC1 status. Results: Sixteen of 32 (50%) triple negative breast carcinomas were positive for ERCC1 by immunohistochemistry. Reactivity was present in 10 to 50% of the tumor cell nuclei. The remaining 16/32 (50%) carcinomas were definitively negative for ERCC1. Significantly higher pCR rates were found in patients with ERCC1(−) tumors, 11/16 (68.8%), compared to 4/16 (25%) patients with ERCC1(+) tumors, p=0.032. Findings were similar for pCR confined to the breast (75.0 v 31.3%, p=0.032), and for pCR in the axilla (75.0 v 43.8%), although the latter result lost statistical significance, p=−0.149. Conclusion: Absence of immunohistochemical expression for ERCC1 is predictive of pathologic complete response to platinum-based neoadjuvant chemotherapy for patients with triple negative breast cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5502. doi:10.1158/1538-7445.AM2011-5502