Histologic Subtype Of Disease Research Articles

Abstract MIP-046: BLOOD TYPE, ABO GENETIC VARIANTS, AND OVARIAN CANCER SURVIVAL

Abstract INTRODUCTION: In addition to a fundamental role in transfusion, blood type is also implicated in disease. Blood type antigens on red blood cells are determined by genetic variants in the ABO gene; both phenotype and genotype have been significantly associated with ovarian cancer risk. Meta–analysis of eight case–control studies indicated that women with genetic variants corresponding to blood type A had 9% greater ovarian cancer risk than women with variants corresponding to blood type O. Only one study to date has evaluated ovarian cancer prognosis; among 256 Chinese women, cases with blood type A had more than two–fold worse survival than cases with other blood types (B, AB, and O). AIMS: To evaluate blood type phenotype and genotype in relation to overall ovarian cancer survival in a predominantly Caucasian study population. APPROACH: Tumor registry confirmed ovarian or fallopian tube primary malignancies were identified from the Synthetic Derivative, a de–identified mirror of electronic medical records (EMR) from the Vanderbilt University Medical Center (VUMC). Blood type was ascertained from EMR linked laboratory reports. Ten common variants (minor allele frequency ≥0.05) in the ABO gene were ascertained using the Illumina Exome BeadChip. Subject vital status was determined from EMR and linkage to the National Death Index. Associations with overall survival were evaluated with proportional hazards regression in multivariable models that included adjustment for age, stage, grade, histologic subtype of disease, and year of diagnosis. RESULTS: Blood type phenotype and genotype were available for 556 and 154 tumor registry confirmed ovarian cancer cases, respectively. Among all women, cases with blood type A had significantly better overall survival compared to either blood type O (Hazard ratio (HR): 0.79, 95% confidence interval (CI): 0.63–0.99) or to cases with any blood type other than A (HR: 0.80, 95% CI: 0.65–0.98). A missense variant in exon 7 (rs1053878) with moderate linkage to a variant corresponding to the A phenotype was also associated with better overall survival in a dominant manner (HR: 0.50, 95% CI: 0.25–0.99). While our phenotype association differed by race (p–interaction=0.049) and was evident only among Caucasian cases (HR: 0.75, 95% CI: 0.60–0.93), our genotype association did not vary by race (p–interaction=0.279). CONCLUSIONS: Women with blood type A had better overall ovarian cancer survival, regardless of whether blood type was directly assayed, or inferred by genotype. These findings contradict the only existing ovarian cancer survival study to date, but include a larger, and predominantly Caucasian study population. Additional research is needed to either replicate or refute our ovarian cancer survival finding, and to determine if ABO variants and blood type are causally related to cancer development and progression. Citation Format: Hilary Toole, Rebecca T. Levinson, Gabriella D. Cozzi, Angie Deng, Jason T. Fromal, Malcolm–Robert Snyder, Dineo Khabele, Alicia Beeghly–Fadiel . BLOOD TYPE, ABO GENETIC VARIANTS, AND OVARIAN CANCER SURVIVAL [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr MIP-046.

Abstract 3404: Thrombocytosis and epithelial ovarian cancer survival: relevant time frame of platelet count measurement and diagnostic threshold for thrombocytosis

Abstract INTRODUCTION: Ovarian cancer is rapidly progressive and lethal disease. Thrombocytosis has been associated with poor prognosis; mechanisms underlying this association include paracrine signaling between platelets and cancer cells, resulting in tumor cell proliferation. However, the relevant timing of platelet measurement in relation to diagnostic operation and a threshold to define thrombocytosis as a prognostic indicator have not been evaluated. METHODS: Tumor Registry confirmed epithelial ovarian and fallopian tube cancer cases with pre-diagnosis platelet counts were identified from the Synthetic Derivative, a de-identified mirror of electronic medical records from the Vanderbilt University Medical Center. Thrombocytosis was defined with two thresholds: platelet count greater than 400 or 450 × 109/L. The relevant time frame of platelet measurement was evaluated within 5 time intervals: on the date of diagnosis, and 1, 2, 4, and 8 weeks before and including the date of diagnosis. Prognostic significance was evaluated using Cox proportional hazards regression to calculate hazard ratios (HR) and confidence intervals (CI); adjustment included age, stage, grade, and histologic subtype of disease. RESULTS: Measured platelet values were available for 136, 241, 280, 297, and 304 cases within the five time intervals. The prevalence of thrombocytosis was 31.6, 39.4, 38.2, 38.1, and 37.5% for 400 × 109/L, and 19.9, 26.1, 25.7, 24.9, and 25.0% for 450 × 109/L across the five intervals, respectively. Thrombocytosis was significantly associated with higher stage and grade, regardless of threshold used. In both unadjusted and multivariable adjusted analysis, thrombocytosis was significantly associated with worse survival. Associations were similar across thresholds and time frames, but were generally larger on the date of diagnosis (HR(400): 1.96, 95% CI 1.23-3.13; HR(450): 1.90, 95% CI: 1.12-3.23), and smaller as time to diagnosis increased up to 8 weeks (HR(400): 1.54, 95% CI: 1.14-2.09; HR(450): 1.55, 95% CI: 1.11-2.15). CONCLUSIONS: Depending upon the threshold used and the timing of measurement, thrombocytosis was identified in 20-40% of epithelial ovarian cancer cases. Regardless of threshold or timing, preoperative thrombocytosis was associated with more aggressive disease characteristics and was an independent negative prognostic factor. These preliminary results support use of a lower thrombocytosis threshold and indicate that platelet count measurements collected up to 8 week preoperatively may be used to inform ovarian cancer prognosis. Citation Format: Gabriella D. Cozzi, Jacob M. Samuel, Jason T. Fromal, Spencer Keene, Marta A. Crispens, Dineo Khabele, Alicia C. Beeghly-Fadiel. Thrombocytosis and epithelial ovarian cancer survival: relevant time frame of platelet count measurement and diagnostic threshold for thrombocytosis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3404.

Abstract A63: The importance of cyclooxygenase 1 and 2 expression in ovarian cancer survival: Notable differences by histologic subtype.

Abstract Background: Cyclooxygenase (COX) enzymes catalyze key reactions of prostaglandin biosynthesis. COX-2 is implicated in inflammation, and high expression has been associated with lower survival from several malignancies, including ovarian cancer. COX-1 is thought to contribute primarily to normal physiology, so cancer outcomes have been evaluated less frequently. However, COX-1 is highly expressed in ovarian cancer, and both COX enzymes have differences in expression across histologic subtypes of disease. This study was undertaken to evaluate COX-1 and COX-2 expression in relation to ovarian cancer survival, including differences between serous and non-serous disease subtypes. Methods: A tissue microarray was created from primary ovarian, fallopian, or peritoneal cancers diagnosed at the Vanderbilt University Medical Center. COX-1 (Santa Cruz Biotechnology, Dallas, TX) and COX-2 (Thermo Fisher Scientific, Inc., Waltham, MA) immunostaining was performed; semi-quantitative measurement was conducted using the automated Ariol® SL-50 Platform. Outcomes and clinical characteristics, including age, stage, grade, histologic subtype, residual disease, and race were collected by medical record abstraction. Progression-free and overall survival were evaluated using proportional hazards regression to calculate Hazard Ratios (HR) and Confidence Intervals (CI). Results: Among 191 epithelial ovarian cancer cases, 57 had documented disease progression, and 121 deaths occurred. COX expression was categorized into tertiles; significant differences were found in regards to histologic subtype, disease stage, and residual disease. In multivariate models among all cases, increasing tertiles of COX-2 expression was significantly associated with increased hazards of disease progression (HR: 1.43, 95% CI: 1.01-2.02) but not death (HR: 1.02, 95% CI: 0.79-1.30). Among serous subtypes, higher COX-2 expression was significantly associated with worse overall survival (HR: 1.53, 95% CI: 1.04-2.23). Among non-serous subtypes, higher COX-1 expression was associated with better overall survival (HR: 0.46, 95% CI: 0.24-0.90). Differences by histology were suggestive for COX-2 (P-value for interaction=0.090) and significant for COX-1 (P-value for interaction=0.013). Conclusions: This single institution retrospective study demonstrates distinct associations between COX enzymes and ovarian cancer disease outcomes across histologic subtypes. If replicated, these findings imply that histologic subtype of disease may be important for the appropriate selection and application of COX inhibitors for ovarian cancer treatment. Citation Format: Alicia Beeghly-Fadiel, Meral El Ramahi, Andrew Wilson, Spencer Keene, Oluwole Fadare, Marta A. Crispens, Dineo Khabele. The importance of cyclooxygenase 1 and 2 expression in ovarian cancer survival: Notable differences by histologic subtype. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A63.

Body mass index, height and risk of lymphoid neoplasms in a large United States cohort

Results from epidemiologic studies examining associations between body size and risk of non-Hodgkin lymphoma (NHL) are inconsistent, and etiology may vary by histologic subtype of disease. Using Cox proportional hazards regression, multivariable relative risks (RRs) and 95% confidence intervals (CIs) were computed for associations of body mass index (BMI) and height with NHL in the prospective American Cancer Society Cancer Prevention Study-II Nutrition Cohort. From 1992 to 2007, 2074 incident cases of NHL were identified among 152 423 men and women. Obese individuals (BMI ≥ 30 kg/m2) had 23% higher incidence of NHL (95% CI 1.08–1.40) compared to those with normal weight (BMI 18.5–< 25 kg/m2). Height was positively associated with NHL (RR = 1.25, 95% CI 1.10–1.43, sex-specific quintile 5 vs. 1). BMI associations were strongest for diffuse large B-cell lymphoma. Height was most strongly associated with chronic lymphocytic leukemia/small lymphocytic lymphoma and to a lesser extent with multiple myeloma. These findings provide further evidence that body size may play a role in the etiology of NHL, which is of public health importance given the rapid rise in obesity worldwide.

Pediatric non-Hodgkin lymphoma

Non-Hodgkin lymphoma (NHL) accounts for 7% of cancer in children and adolescents in the United States, or approximately 1000 cases annually. NHL in the pediatric population differs from that observed in adult patients with respect to staging systems, histologic subtypes of disease, treatment, and outcomes. Although more than 90% of pediatric NHL is of high-grade histology, more than 80% of patients achieve long-term event-free survival with modern therapy. This review focuses on current treatments for pediatric NHL and some of the differences between NHL observed in pediatric and adult patients.

Pediatric non-Hodgkin’s lymphoma

Non-Hodgkin's lymphoma (NHL) accounts for 7% of cancer in children and adolescents in the United States, or approximately 1000 cases annually. NHL in the pediatric population differs from that observed in adult patients with respect to staging systems, histologic subtypes of disease, treatment, and outcomes. Although more than 90% of pediatric NHL is of high-grade histology, more than 80% of patients achieve long-term event-free survival with modern therapy. This review focuses on current treatments for pediatric NHL and some of the differences between NHL observed in pediatric and adult patients.

Pleuropulmonary blastoma

Pleuropulmonary blastoma (PPB) is a unique dysontogenetic neoplasm of childhood that appears as a pulmonary and/or pleural-based mass and is characterized histologically by a primitive, variably mixed blastematous and sarcomatous appearance. Histologic material from all cases was reviewed and the tumors subclassified as type I (purely cystic), type II (cystic and solid), or type III (purely solid). Data regarding presenting symptoms, family history, operative findings, pathologic subtypes, therapeutic interventions, and outcome were correlated with survival by standard statistical methods. The series was comprised of 24 males and 26 females. Respiratory difficulty with or without fever was the most common clinical symptom reported. Cyst formation in the affected lung was identified radiographically in 19 children (38%) at or before the definitive pathologic diagnosis. The ages at presentation of the 7 type I, 24 type II, and 19 type III PPBs were significantly different: 10, 34, and 44 months, respectively (P < 0.001). Local recurrence developed in 1 of 7 type I PPBs (14%) and in 18 of 43 type II and III PPBs (46%); distant metastasis occurred in 13 patients, chiefly to the brain/spinal cord or bone, and was observed only in those with type II or type III PPB. Patients with pleural or mediastinal involvement fared significantly worse than those without such involvement. Five-year survival was 83% for type I and 42% for types II and III. Survival differences on the basis of pathologic subtype did not reach statistical significance. PPB is an aggressive, intrathoracic neoplasm of early childhood with an unfavorable outcome. Although survival differences among patients with different histologic subtypes of disease did not reach statistical significance, the apparently better outcome for patients with purely cystic type I tumors may be borne out in a large series. These observations support the premise that type I and III PPB are bridged morphologically by type II PPB with its combined cystic and solid features. The PPB should be regarded as the pulmonary dysontogenetic analogue to Wilms' tumor in the kidney, neuroblastoma in the adrenal gland, and hepatoblastoma in the liver. Molecular genetic investigations, especially in constitutional PPB, should be revealing. In view of the poor outcomes for patients with types II and III, new and aggressive therapies must be developed.

Pleuropulmonary blastoma

BACKGROUND Pleuropulmonary blastoma (PPB) is a unique dysontogenetic neoplasm of childhood that appears as a pulmonary and/or pleural-based mass and is characterized histologically by a primitive, variably mixed blastematous and sarcomatous appearance. METHODS Histologic material from all cases was reviewed and the tumors subclassified as type I (purely cystic), type II (cystic and solid), or type III (purely solid). Data regarding presenting symptoms, family history, operative findings, pathologic subtypes, therapeutic interventions, and outcome were correlated with survival by standard statistical methods. RESULTS The series was comprised of 24 males and 26 females. Respiratory difficulty with or without fever was the most common clinical symptom reported. Cyst formation in the affected lung was identified radiographically in 19 children (38%) at or before the definitive pathologic diagnosis. The ages at presentation of the 7 type I, 24 type II, and 19 type III PPBs were significantly different: 10, 34, and 44 months, respectively (P < 0.001). Local recurrence developed in 1 of 7 type I PPBs (14%) and in 18 of 43 type II and III PPBs (46%); distant metastasis occurred in 13 patients, chiefly to the brain/spinal cord or bone, and was observed only in those with type II or type III PPB. Patients with pleural or mediastinal involvement fared significantly worse than those without such involvement. Five-year survival was 83% for type I and 42% for types II and III. Survival differences on the basis of pathologic subtype did not reach statistical significance. CONCLUSIONS PPB is an aggressive, intrathoracic neoplasm of early childhood with an unfavorable outcome. Although survival differences among patients with different histologic subtypes of disease did not reach statistical significance, the apparently better outcome for patients with purely cystic type I tumors may be borne out in a large series. These observations support the premise that type I and III PPB are bridged morphologically by type II PPB with its combined cystic and solid features. The PPB should be regarded as the pulmonary dysontogenetic analogue to Wilms' tumor in the kidney, neuroblastoma in the adrenal gland, and hepatoblastoma in the liver. Molecular genetic investigations, especially in constitutional PPB, should be revealing. In view of the poor outcomes for patients with types II and III, new and aggressive therapies must be developed. Cancer 1997; 80:147-61. © 1997 American Cancer Society.

Intrapleural chemotherapy for patients with incompletely resected malignant mesothelioma: the UCLA experience.

From 1986 to 1993, 15 patients with malignant pleural mesothelioma were treated by pleurectomy/decortication and intrapleural cisplatin (100 mg/m2) and cytosine arabinoside (1,200 mg). All patients were without known extrathoracic disease and had a mean age of 63 +/- 7.9 years (range 51-78); 13 were male. Histologic subtype of disease were epithelial (47%), sarcomatoid (27%), and mixed-biphasic (27%). The major morbidity and mortality rates were 13% and 0%, respectively. The mean length of hospital stay was 6.5 +/- 2.1 days. Postoperatively, adjuvant chemotherapy and radiation therapy were given to 46% and 73% of the patients respectively. Median survival from date of treatment was 11.5 months. Those patients with an epithelial histologic subtype experienced significantly improved survival compared to those of sarcomatoid subtype (P = 0.024). Whether adjuvant chemotherapy or radiation therapy were given had no significant effect on survival. These data suggest that although this treatment regimen can be administered with very limited morbidity and no mortality, the role of this approach in the treatment of malignant pleural mesothelioma appears limited and cannot currently be recommended.