7.03 Sentinel Lymph Node Biopsy Is Accurate In Merkel Cell Cancer

Posted on December 22, 2014

A. C. Gasior1, A. Gingrich1, S. Deas1, J. Mammen1  1University Of Kansas,Surgery,Kansas City, KS, USA

Introduction:
Merkel cell cancer (MCC) is a rare and aggressive cutaneous neuroendocrine neoplasm. Sentinel lymph node biopsy (SLNB) is often used to assess for nodal metastases in breast cancer and melanoma, but the accuracy of SLNB for MCC is less well described with false negative rates varying from 0 to 50% (most studies based on administrative databases without consistent follow-up).  In this study, we evaluated a single institution retrospective database of patients diagnosed with MCC to establish the accuracy of SLNB.

Methods:
After IRB approval, a single institution database was created spanning from January 2007 through December 2013. Patients had the standard SLNB technique of dual tracer evaluation (vital blue dye and radiolabelled sulfur colloid.) Patients were scheduled for surveillance every 6 months after surgery. Descriptive and chi-square analysis were used for statistical evaluation.

Results:
Of our 17 patients, the majority (64.7%) were male and over 66 years of age (52.9%). 15 patients (88.2%) had SLNB. The mean number of lymph nodes removed for sentinel lymph node biopsy was 2.6. 13/15 (86.7%) of SLNB were negative. Neither age, cancer site, nor size were independent predictors of nodal positivity. Of the 2 patients with positive SLNBs, only one patient had non-sentinel nodes (3/15) positive on subsequent lymphadenectomy. Of patients with negative SLNBs, there was no evidence of lymph basin only recurrence at follow-up in any patients (false negative rate of 0%).  Median length of follow-up was 12 months. 

Conclusion:
Previous MCC studies show extent of disease at presentation to be the greatest factor predictive of survival.  In our study of early clinical stage MCC, patient factors were not identified to predict pathologic nodal involvement.   In one of the largest series of patients with MCC evaluated with SLNB, the false negative rate was identified to be 0% suggesting that SLNB is an accurate technique to stage MCC patients for nodal metastases.

7.04 Goblet Cell Neuroendocrine Carcinomatosis treated with Cytoreductive Surgery and HIPEC

Posted on December 22, 2014

R. W. Randle1, K. F. Griffith1, K. R. Swett2, J. H. Stewart1, P. Shen1, E. A. Levine1, K. I. Votanopoulos1  1Wake Forest University Baptist Medical Center,Surgery,Winston-Salem, NORTH CAROLINA, USA 2Wake Forest University Baptist Medical Center,Biostatistics,Winston-Salem, NORTH CAROLINA, USA

Introduction:  Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is an aggressive treatment for patients suffering with peritoneal carcinomatosis.  It is commonly applied to low-grade mucinous tumors of the appendix disseminated throughout the peritoneal cavity, yet some high volume centers have extended this therapy to carcinomatosis from a variety of more aggressive primary malignancies.  Therefore we decided to review our experience with CRS-HIPEC for patients with carcinomatosis from goblet cell neuroendocrine carcinomas.

Methods:  Patients with carcinomatosis and final pathology confirming goblet cell features were identified in a prospectively maintained database of 1069 CRS-HIPEC procedures performed between 1991 and 2013.  Patient demographics, disease characteristics, morbidity, mortality, and survival were reviewed.  

Results:  A total of 25 patients with goblet cell neuroendocrine carcinomatosis underwent CRS-HIPEC during the study period.  Tumors originated in the appendix in 23 (92%) patients and in the colon in 2 (8%).  Patients were generally young (mean age 53 years) and otherwise healthy (84% without comorbidities) with good performance status (92% ECOG 0 or 1).  The mean number of visceral resections was 3.6, and complete cytoreduction of all macroscopic disease was accomplished in 36% prior to HIPEC.  The 30-day major morbidity and mortality were 36% and 8%, respectively.  Median overall survival for all patients was 16.5 months.  In univariate analysis, significant predictors of decreased survival included worse performance status (hazard ration [HR] 2.2, 95% confidence interval [CI] 1.1–4.4, p=0.03) and nodal involvement (HR 9.6, 95% CI 1.2–73.8, p=0.03).  Despite similar volume of peritoneal disease, patients with negative nodes had better survival than those with positive nodes (median overall survival 32.7 months vs. 9.9 months), respectively (p=0.01).  While complete cytoreduction was associated with longer survival following CRS-HIPEC in all patients (R0/R1 median overall survival 28.5 months vs. R2 median overall survival 9.9 months, p=0.19) and in those with nodal disease (R0/R1 median overall survival 16.5 months vs. R2 median overall survival 8.5 months, p=0.07), neither observed difference reached statistical significance.

Conclusion:  CRS-HIPEC may improve survival in patients with node negative goblet cell neuroendocrine carcinomatosis when a complete cytoreduction is achieved.  Patients with disease not amenable to complete cytoreduction should not be offered CRS-HIPEC.

 

7.05 Recurrence and Prognostic Factors after Cytoreductive Surgery and HIPEC for Appendiceal Cancer

Posted on December 22, 2014

M. Mavros1, L. Bijelic1, U. Hyder1, A. Firoozmand1, C. Ihemelandu1, P. Sugarbaker1  1MedStar Washington Hospital Center,Department Of Surgery,Washington, DC, USA

Introduction: Appendiceal cancer most commonly metastasizes to the peritoneum. Cytoreductive surgery (CRS) with heated intraperitoneal chemotherapy (HIPEC) has become the leading treatment modality for peritoneal metastases. We sought to analyze clinical outcomes after CRS and HIPEC for appendiceal cancer in a recent cohort of patients treated at a large referral center and identify prognostic factors and predictors of recurrence.

Methods: Patients undergoing CRS with HIPEC for appendix cancer in a large tertiary care referral center between January 2007 and December 2009 were identified. Prospectively collected data were analyzed, including standard preoperative, intraoperative, and postoperative variables; the impact of prior surgical score (PSS), peritoneal cancer index (PCI), and completeness of cytoreduction score (CCS) was specifically assessed. Multivariate Cox regression models were developed to identify factors independently predicting overall survival and recurrence.

Results: A total of 134 patients were analyzed. Median age was 51 years and 53% were female. Roughly half had previous abdominal operations (PSS≥2, 53%), extensive peritoneal dissemination (PCI≥21, 52%), or the PMCA variant (54%); few had lymph node metastases (11%). Median operative time was 9 hours, and most of the patients received RBC (73%) or FFP (47%) transfusions; 30-day mortality was 0.7%. Half of the patients underwent early postoperative intraperitoneal chemotherapy (49%), and a large proportion experienced at least one postoperative complication (minor, 37%; major, 25%). Overall survival (OS) at 5 years was 74.4%; 5-year recurrence-free survival (RFS) of patients with a complete cytoreduction (CCS≤1) was 65.5%. Factors independently predicting shorter survival included the PMCA variant [Hazards Ratio (HR)=12.74, 95% CI: 3.77–43.05)], lymph node metastasis [HR=2.58 (1.15–5.79)], and incomplete cytoreduction [CCS≥2, HR=5.93 (2.85–12.34)]. Similarly, factors predicting recurrence included the PMCA variant [HR=7.03 (3.35–14.78)] and lymph node metastasis [HR=4.00 (1.74–9.19)]. An incomplete cytoreduction was associated with the PMCA variant (p<0.001), but also more advanced peritoneal disease (PCI≥11, p=0.012) and prior abdominal surgeries (PSS≥2, p=0.033).

Conclusion: CRS with HIPEC can be performed with acceptable morbidity and mortality at an experienced referral center and achieve long term survival for patients with advanced appendix cancer. Histologic subtype and lymph node metastasis, along with complete cytoreduction are the most important predictors of overall survival. Efforts should be made for timely definitive CRS/HIPEC, avoiding prior non-definitive abdominal operations when possible.

7.06 Advanced Nutritional Support after Esophagectomy for Esophageal Cancer

Posted on December 22, 2014

S. Ajmal1, T. Ng1, A. M. Blakely1, W. G. Cioffi1, T. J. Miner1  1Brown University School Of Medicine,Department Of Surgery,Providence, RI, USA

Introduction:  Various modalities are employed to provide nutritional support to patients after esophagectomy for esophageal cancer. Routine Jejunostomy tubes are placed in patients with esophageal cancer to provide nutritional supplementation in perioperative setting. Total parenteral nutrition is also utilized when patients have complications or delayed oral intake. We sought to study the utility and complications associated with these nutritional support modalities.

Methods:  We performed a retrospective chart review of all adult patients who underwent esophagectomy for esophageal cancer from 2001 to 2014 at a single tertiary care institution. We reviewed the utility of jejunostomy tube and complications associated with jejunostomy tubes.

Results: 182 patients underwent esophagectomy for esophageal cancer during the study period. Esphageal cancer types included 158 adenocarcinomas, 15 squamous cell carcinomas, 8 high grade dysplasias and 1 neuroendocrine tumor. 107 patients had Transhiatal resection, 55 had Ivor-lewis esophagectomy, 9 had Thoraco-abdominal resection and 10 patients had Three incision esophagectomy. 181 patients had a jejunostomy tube placed. At the time of discharge 88 (48.6%) patients were receiving nutrition through tube feeds. Out of these 88 patients, 34 (18.7%) had partial tube reliance while 53 (29.3%) had total tube reliance. 6 patients (3.3%) needed both jejunostomy tube feeds and total parenteral nutrition (TPN) while only one patient was just placed on TPN. Patient group that required tube feeds on discharge were more likely to have a complicated course than patients not on tube feeds (61 vs 12; p<0.05). Out of 181 patients with jejunostomy tubes, only 1 patient required surgical intervention due to catheter related complication. No mortality was reported due to catheter related complications.

Conclusion: Our data reveals that a significant number of patients require tube feeds at discharge. Serious morbidity secondary to jejunostomy feeding tube was rare. This further supports the current practice of placing routine feeding J-tubes for esophagectomies.

 

7.07 Patient Demographics and Clinical Outcomes in Pancreatic Cancer Based on Histological Subtype.

Posted on December 22, 2014

N. Poulsen1, S. Patil1, R. S. Chamberlain1  2Saint George’s University,Grenada, Grenada, Grenada 1Saint Barnabas Medical Center,Surgery,Livingston, NJ, USA

Introduction:  Pancreatic ductal adenocarcinoma (PDC) makes up more than 90% of pancreatic tumors; however, other less common histological subtypes exist including acinar cell carcinoma (ACC), islet cell tumors (IC), neuroendocrine tumors (NE) and squamous cell carcinoma (SCC). While information on the clinical course, management and outcomes associated with adenocarcinoma of the pancreas has been extensively studied, information on other histological subtypes is limited. 

Methods:  Data on 100,727 patients with pancreatic cancer from the Surveillance Epidemiology and End Results (SEER) database (1973- 2008) was abstracted. Patients with PDC, ACC, IT, NE, and SCC were separately analyzed for age, gender, race, stage, treatment, and long-term survival. Categorical variables were compared using the Chi square test, and continuous variables were compared using ANOVA.

Results: PDC (N=95,271; 94.6%) was the most common form of pancreatic cancer identified followed by NE (N=2,922; 2.90%), IC (N=1,845; 1.83%), SCC (N=355; 0.34%) and ACC tumors (N=334; 0.33%). Pancreatic cancer occurs most commonly in Caucasian men in the 6th decade of life, however patients with IC tumors and NE tumors were significantly younger than those with PDC, ACC and SCC. All five subtypes presented most commonly with metastatic disease (PDC: 57.2%; ACC: 48.8%; IC: 48.3%; NE: 60.8%; and SCC: 60.0%). Overall survival was 1.43 years. Patients with IC tumors had the greatest mean survival (5.08 years), followed by NE tumors (2.96 years), ACC (2.79 years), and PDC/SCC (1.31 years each) (p< 0.001). Mortality was significantly greater in patients with SCC and PDC (96.3% and 93.9% respectively, p<0.001) compared to all other subtypes. Combination surgery and radiation therapy demonstrates the greatest 5- and 10-year survival rate in patients with PDC (19% and 10%), ACC (54% and 37%), and SCC (25% and 13%) (p<0.001). Surgical intervention alone demonstrates the greatest 5- and 10-year survival in IC tumors (74% and 56%) and NE tumors (76% and 58%) (p< 0.001). PDC and SCC had the lowest 5- and 10-year survival for all treatment modalities.

Conclusion: Pancreatic cancer is a devastating disease with an overall mortality greater than 65% independent of histological subtype. PDC and SCC demonstrate the lowest mean survival, highest mortality and appear to follow a similar clinical course independent of treatment modality. Despite an overall mortality rate of 66% and a mean survival of 5 years, pancreatic IC tumors are the most indolent pancreatic tumors. Surgical intervention appears to offer the greatest survival benefit to patients with IC and NE tumors, while combined surgical and radiation therapy appears to offer the greatest survival benefit to patients with PDC, SCC and ACC.      

7.08 Effect of High-Grade Disease on Colon Cancer Outcomes

Posted on December 22, 2014

R. Amri1,2, L. G. Bordeianou1,2, P. Sylla1,2, D. L. Berger1,2  1Massachusetts General Hospital,General And Gastrointestinal Surgery,Boston, MA, USA 2Harvard Medical School,Surgery,Brookline, MA, USA

Introduction:
Tumor grade is one of the cardinal characteristics used in the surgical pathological assessment of a malignancy. High-grade disease invariably has a negative impact on the eventual outcomes of the concerned malignancy. We aimed to measure the magnitude of its influence as well as its stage-independent effect in colon cancer. 

Methods:
All patients treated surgically at our center (2004 through 2011) with known disease grade were included in an institutional review board-approved database. We measured the relative risk (RR) of encountering distant and nodal spread of the disease in baseline pathology, as well as the risk of recurrence and overall and disease-specific mortality. In addition, a multivariate logistic regression adjusted for stage was used to assess the stage-adjusted odds ratio (OR).

Results:
A total of 961 patients with specified tumor grade were included for analysis. Of these, 191 (19.9%) patients had high-grade disease on baseline pathology. These patients were invariably at far higher risk of lymph node metastasis (63.7 vs. 38.2%; RR: 1.67) and metastatic presentation (30.9 vs. 15.3%; RR: 2.02) (both P<0.001). These baseline differences also led to a significantly higher risk of poor outcomes (all P<0.001), including disease recurrence (23.5 vs. 11.8%; RR: 1.99), overall mortality (56.5 vs. 31.8%; RR: 1.77) and colon cancer-specific mortality (34.6 vs. 16.6%; RR: 2.08). All of these findings were still statistically significant and within the same order of magnitude after adjusting of odds ratios for baseline staging in multivariate analysis.

Conclusion:
High-grade disease on baseline colon cancer surgical pathology is associated with a considerably higher rate of nodal and distant metastasis. As a result, the colon cancer-related mortality doubles for patients with high-grade disease. More interestingly, all of these findings were shown to be independent of baseline staging, confirming that high tumor grade is a stage-independent factor greatly influencing colon cancer outcomes and mortality.
 

7.09 Colon Cancer Patients with Inflammatory Bowel Disease Do Not Necessarily Have Worse Outcomes

Posted on December 22, 2014

R. Amri1,2, L. G. Bordeianou1,2, P. Sylla1,2, D. Berger1,2  1Massachusetts General Hospital,General And Gastrointestinal Surgery,Boston, MA, USA 2Harvard Medical School,Surgery,Boston, MA, USA

Introduction:
Inflammatory bowel disease (IBD) is associated with a high risk of developing colon cancer. Its relationship with the eventual outcomes is less evident, although recent reports have indicated that comorbid IBD may be associated with worse survival. We therefore aimed to review characteristics of colon cancer associated with IBD in our population.

Methods:
We evaluated outcomes of a patient cohort operated on for colon cancer between 2004 through 2011 in a public tertiary care center in a state providing universal healthcare, focusing on comparing surgical pathological characteristics and long-term outcomes between IBD patients and the remainder of the population.

Results:
We included 1071 patients, of whom 38 (3.5%) had a concurrent diagnosis of IBD: 21 (2.0%) having Crohn’s, 16 (1.5%) having ulcerative colitis, and 1 patient with a mixed form. IBD patients were significantly younger (median age 59.5 vs. 67 years; P<0.001). These patients had a significantly higher rate of high-grade disease (33.3 vs. 19.4%; P=0.034) and borderline significantly higher rates of AJCC stage I disease (36.8 vs. 24.4%; P=0.06). In terms of outcomes however, no statistically significant differences were encountered between patients with or without IBD. Clinically significant but not statistically significant differences demonstrated lower rates of lymph-node metastasis (31.6 vs. 40.6%; P=0.27) and metastatic presentation (13.2 vs, 17%; P=0.54), as well as better outcomes in terms of metastatic recurrence (9.1 vs. 12.7%; P=0.55), and colon cancer mortality (26.3 vs. 35.6% P=0.27). Point estimates in multivariate analysis adjusted for age and staging where appropriate showed no changes in these trends.

Conclusion:
IBD patients who develop colon cancer appear to have relatively better staging and outcomes compared to non-IBD patients. These differences were present despite significantly higher-grade disease on presentation. More aggressive tumor characteristics in colon cancer patients with comorbid IBD fit the findings in earlier literature, while slightly better outcomes in IBD patients are an uncommon finding. This incongruence may potentially be explained by regular surveillance in patients with IBD, which may provide a protective effect through early detection of cancers. Differences with earlier reports in outcomes and staging could potentially be related to universal healthcare in our state, facilitating comprehensive IBD follow-up at our center. These findings suggest that under adequate and regular follow up, IBD patients are not necessarily inherently worse off when diagnosed with colon cancer.

7.10 Predicting Success in Small Renal Mass Biopsy

Posted on December 22, 2014

J. M. Prince1, E. M. Bultman2, A. Drewry1, J. L. Hinshaw2, E. J. Abel1  1University Of Wisconsin,Department Of Urology,Madison, WI, USA 2University Of Wisconsin,Department Of Radiology,Madison, WI, USA

Introduction:   Percutaneous biopsy may provide important information for patients with small renal masses (SRM) prior to treatment.  However, 15-20% of patients undergoing biopsy receive indeterminate results, and thus do not benefit from the procedure.  The objective of this study was to evaluate clinical and anatomical factors that are predictive of obtaining indeterminate results from percutaneous SRM biopsy.

Methods:   Comprehensive clinical and anatomical factors were reviewed for consecutive SRM (≤4cm) patients treated with renal mass biopsy at the University of Wisconsin Hospital from 2000 to 2014.  Univariable and multivariable logistic regression analysis was performed to determine which factors were associated with indeterminacy. 

Results:  A total of 413 SRM biopsies were performed in 386 patients.  The median tumor size was 2.35 cm (IQR 1.90-2.95).  15.5% of the masses were cystic and 84.5% were solid.  Enhancement (>20 HU ) was seen in 84.0%, while 5.3% were pseudo-enhancing (10-20 HU), and 1.9% were non-enhancing.  A skin-to-tumor distance of ≥14 cm was observed in 4.1% of the masses.  Similar to previous studies, we observed an indeterminate rate of 17.4% in the entire cohort and among cystic lesions, the indeterminate rate was 43.8%.

After multivariable analysis, independent predictors of indeterminate biopsy included: cystic features (OR 4.91, 95% CI 2.46-9.83, p < 0.0001), tumor diameter (OR 0.59, 95% CI 0.39-0.90, p = 0.015), skin-to-tumor distance ≥14cm (OR 4.29, 95% CI 1.50-12.25, p = 0.0065), and radiographic enhancement (OR 3.61, 95% CI 1.52-8.56, p = 0.0036).

Other factors evaluated but not significant to predict indeterminate biopsy included: exophytic shape, hemorrhage, necrosis, fat content, calcifications, type of imaging modality used prior to and for guidance during biopsy, biopsy type (i.e. core or fine needle aspiration), patient BMI, proximity to adjacent organs, anteroposterior and polar positioning within the kidney and laterality of the mass.

Conclusion:  Four independent predictors for indeterminate biopsy are described including: cystic features, mean mass size, enhancement ≤20 HU, and skin-to-tumor distance ≥14cm.  These factors can be used to identify patients with a significant risk for a non-diagnostic biopsy result and facilitate better patient selection for this procedure.

7.11 Robotic and Laparoscopic Surgery for Colorectal Cancer Offer Comparable 3-5 Year Oncologic Outcomes

Posted on December 22, 2014

F. G. Wilder1,2, A. Burnett1, J. Oliver1, R. J. Chokshi1  1Rutgers – New Jersey Medical School,Surgery,Newark, NJ, USA 2Memorial Sloan-Kettering Cancer Center,New York, NY, USA

Introduction: Robotic surgery has been demonstrated to be a viable option for the resection of benign and malignant colorectal diseases. However, data thus far is lacking with regards to long-term oncologic outcomes. We sought to compare the longer term oncologic outcomes of robotic versus laparoscopic resection of colorectal cancer.

Methods: A literature search was performed using the Pubmed, EMBASE, Cochrane, and Medline databases for studies published between 2000 and 2014.  Search terms were: colon, rectal, robot, cancer, laparoscopic, oncologic and outcomes.  Studies that compared the overall and disease free survival of robotic versus laparoscopic surgery for patients with colon or rectal cancer were included.  Meta-analysis was performed using OpenMeta[Analyst] for Windows 8.

Results:There were 5 studies published between 2000-2014 that reported on overall survival (OS), disease free survival (DFS), lymph node (LN) extraction, circumferential resection margin (CRM), short and long-term recurrence. 317 patients across the 5 studies underwent either totally robotic or hybrid (robotic-assisted) resection of colon or rectal cancer.  Mean DFS with laparoscopic resection versus robotic resection was 86.2% (±4.4) and 86.9% (±4.0), respectively.  Mean OS with laparoscopic resection versus robotic resection was 93.4% (±3.2) and 91.3% (±4.1), respectively. Except for the Park study whose values were at 5 years, all groups reported DFS and OS at 3 years. At 5 years, Park found a DFS of 78.7% (±4.5) for LCS and 81.9% (±3.3) for RCS.  OS was 93.5% (±3.2) for LCS and 92.8% (±2.2) for RCS.  Robotic surgery was associated with slightly smaller resection margins (0.318cm, p=0.042), resection of fewer nodes (2.173 fewer nodes, p=0.0001), but equivalent odds of a positive CRM (OR 1.08, p=0.859).  

Conclusion: Robotic surgery offers comparable overall and disease free survival when compared to laparoscopic surgery for colorectal cancer.  However, longer-term follow up and larger patient populations need to be studied before official recommendations can be made.

 

69.06 Increased Rate of Incidental Papillary Thyroid Cancer in Surgical Patients with Benign Thyroid Disease

Posted on December 22, 2014

A. R. Marcadis1, S. Liu1, M. Rodriguez1, J. I. Lew1  1University Of Miami Miller School Of Medicine,Division Of Endocrine Surgery,Miami, FL, USA

Introduction: Patients who undergo surgical resection for benign thyroid disease may have incidental papillary thyroid cancer (PTC) discovered on final pathology. The incidence of PTC has historically been between 5 to 10% in patients treated operatively for benign thyroid disease. This study attempts to determine if there are any preoperative factors for incidental PTC that may help determine the extent of thyroidectomy in patients with benign thyroid disease.

Methods: A retrospective review of prospectively collected data of 1822 consecutive patients who underwent thyroidectomy at a single institution was performed. Of these patients, 355 underwent surgical resection for benign thyroid disease. Indications for surgery were obstructive or compressive symptoms (n=142), hyperthyroid symptoms including Graves’ disease (n=111), goiter size >4 cm (n=92), and substernal goiter (n=10). Patients with indeterminate or malignant preoperative FNA results were excluded. Of all patients, 74% (n=263) underwent total thyroidectomy, and 26% (n=93) underwent a lobectomy. Benign final pathology included nontoxic multinodular goiter (MNG) (n=136), toxic MNG (n=75), nontoxic solitary nodule (n=67), toxic solitary nodule (n=21) and Graves’ disease (n=6). Incidental cancers were defined as PTC discovered only upon final pathology. Age and gender were examined to determine if certain subsets of these categories had a higher indication for incidental cancers, using a two-tailed Z-test at a significance of 0.05.

Results: Overall, 14% (50/355) of patients who underwent surgical resection for benign thyroid disease had incidental PTC on final pathology. Women constituted 90% (n=322) of patients. There was no significant difference between incidental PTC rates in women (14%, 46/322) and men (12%, 4/33). Patients treated for obstructive symptoms had the highest incidental PTC rate at 19% (27/142), followed by goiters >4 cm at 15% (14/92), hyperthyroidism at 8% (9/111). Patients <50 years of age with benign indications for surgical resection had incidental PTC rates of 18% (33/187) compared to a 10% (17/169) incidental PTC rate for patients >50 years of age. Patients <50 years of age with benign thyroid disease had a significantly higher percentage of incidental PTC on final pathology than those patients >50 years of age (p=0.0394).

Conclusion: There is a higher than expected rate of incidental PTC in patients who undergo operations for benign thyroid disease, especially in patients <50 years of age. Therefore, total thyroidectomy by an experienced surgeon should be strongly considered when managing benign thyroid disease in such patients.

 

69.07 Accuracy of data collected in a hereditary cancer registry, the MEN2 experience

Posted on December 22, 2014

Z. Farhood1, C. Trotter1, M. Hu2, M. Cabanillas2, M. Jackson3, T. Rich1,3, P. Graham1, J. Lee1, N. Perrier1, E. G. Grubbs1  2University Of Texas MD Anderson Cancer Center,Department Of Endocrine Neoplasia & Hormonal Disorders, Division Of Internal Medicine,Houston, TX, USA 3University Of Texas MD Anderson Cancer Center,Clinical Cancer Genetics Department,Houston, TX, USA 1University Of Texas MD Anderson Cancer Center,Surgical Oncology,Houston, TX, USA

Introduction:  Hereditary cancer registries have been established globally to identify and educate at-risk relatives and to pool genotypic and phenotypic data from a large number of patients, allowing research in rare hereditary syndromes. We recently initiated an international Multiple Endocrine Neoplasia Type 2 (MEN2) Registry including components of both an online patient questionnaire (PQ) and collection of medical records (MR). We have evaluated registrants enrolled within the first 18 months to determine how the PQ correlates with the MR, identifying in what instances the more easily acquired PQ may be used as a surrogate in this complicated hereditary disease and also areas in which patient education may be improved.

Methods:  A retrospective review was conducted of MEN2 registrants who submitted a PQ and had a complete MR obtained through the MEN2 Registry from 7/2012 to 3/2014.  The PQ is a comprehensive 83-item document containing demographic, genetic, specific disease (medullary thyroid cancer (MTC)/hyperparathyroidism/pheochromocytoma) pathology and treatment history, general health, and family history data available in English and Arabic.  PQ answers were compared to MR variables and the level of agreement scored as discordant, concordant, registrant did not report, and records did not report. Potential demographic predictors of discordance were evaluated.

Results: 117 registrants (rt) were eligible for this study; 70 females and 47 males with a median age of 48 years (range 3 to 74). Concordance between PQ and MR was >85% in 23/31 (74%) of the key variables. Variables in which concordance occurred in <80% of cases included whether the rt had undergone RET testing (79%), current status of MTC (disease free vs. alive with disease) (79%), and pathology results from thyroid surgery (68%). Non-Caucasian races were less likely to provide concordant answers for MTC status (85% vs. 43%, p=0.03).  Female, Caucasian, married rt with greater than a high school education were significantly more likely to know their RET testing status. Reasonable concordance was found for diagnosis and current status of adrenal (97%) and parathyroid (90%) disease. Rt were accurate in reporting their age at MEN2 diagnosis (96% within 1yr), the year in which they underwent RET testing (99% within 1 yr), and their thyroid surgery date (98% within 1yr).

Conclusion: In the majority of self-reported data acquired through a MEN2 registry questionnaire, registrants’ answers exhibited an acceptable concordance with the medical record suggesting that a rt questionnaire may be a reliable source of data. Notable exceptions were status of RET testing and treatment course of MTC in which interrogation of the medical record remains necessary. Need for further patient education in these discordant fields is essential with special attention to those with certain demographics. Ability to rely on registrant-generated data is important for research in such rare diseases.

69.08 Family History of Thyroid Cancer Correlates with More Aggressive Papillary Thyroid Cancer Variants

Posted on December 22, 2014

A. R. Marcadis1, S. Liu1, M. Rodriguez1, J. I. Lew1  1University Of Miami Miller School Of Medicine,Division Of Endocrine Surgery,Miami, FL, USA

Introduction: Thyroid malignancy is the most common endocrine cancer in the United States. Papillary thyroid cancer (PTC) is the most common form, comprising 85% of all thyroid cancers. Although most PTC occurs sporadically, about 5% may be familial in origin. Furthermore, family history has shown to be an influential risk factor for papillary thyroid cancer (PTC). Whether these familial forms of PTC are more aggressive than its sporadic form, however, remains unclear. This study determines if patients with a family history of thyroid cancer harbor more aggressive variants of PTC than patients without a positive family history.

Methods: A retrospective review of prospectively collected data of 1822 consecutive patients who underwent thyroidectomy at a single institution was performed. Patients with malignancies other than PTC were excluded from the study (n=447). Remaining patients were divided into 2 groups: those patients who had a history of PTC in first degree relatives (n=39), and those who did not (n=1336). Patients with PTC on final pathology were further subdivided into those with less aggressive (classic and follicular), and those with more aggressive (diffuse sclerosing and tall cell) variants of PTC. A two tailed Z test at a significance level of 0.05 was used to compare both groups.

Results: Of the 1375 patients included, 3% (39/1375) of patients had a family history of PTC in first degree relatives. Of these patients with a positive family history, 54% (21/39) had PTC on final pathology whereas 28% (374/1336) of patients with no family history had PTC on final pathology. Patients with a family history of PTC had 21% (8/39) follicular, 10% (4/39) diffuse sclerosing, 10% (4/39) classic, 8% (3/39) combined follicular and classic, and 5% (2/39) tall cell variants of PTC.  Patients with no familial history of PTC had 19% (257/1336) follicular, 4% (55/1336) classic, 2% (25/1336) both classic and follicular, 1% (9/1336) both diffuse sclerosing and tall cell, 1% (10/1336) tall cell only, and 1% (18/1336) diffuse sclerosing only variants of PTC. Of those patients with a positive family history, there was a significantly increased incidence of more aggressive variants (diffuse sclerosing and tall cell) of PTC at 15% (6/39) compared to those patients with no family history of PTC at 3% (37/1336) (p<0.05).

Conclusion: Patients with a positive family history of PTC have a significantly higher incidence of more aggressive PTC variants. Any positive PTC family history, therefore, should be considered a risk factor for more aggressive disease that may necessitate earlier recognition and treatment for PTC in these patients and their affected family members.

 

69.09 Surgeon Performed Ultrasound Can Predict More Aggressive Variants of Papillary Thyroid Cancer

Posted on December 22, 2014

A. R. Marcadis1, B. Wang1, M. Rodriguez1, S. Liu1, J. I. Lew1  1University Of Miami,Division Of Endocrine Surgery,Miami, FL, USA

Introduction: Surgeon performed ultrasound (SUS) has been shown to be a valuable imaging modality in the preoperative prediction of malignancy or benignity of thyroid nodules. While patients with papillary thyroid cancer (PTC) are generally considered to have an excellent prognosis, there are some variants of PTC that exhibit more aggressive behavior and may constitute a worse prognosis. The purpose of this study is to determine if SUS can further predict not only malignancy in thyroid nodules, but also more aggressive variants of PTC.

Methods: A retrospective review of 1822 consecutive patients who underwent thyroidectomy at a single institution was performed. Only patients with final pathology confirming the presence of variant PTC and who underwent SUS prior to thyroidectomy were included (n=400). More aggressive variants of PTC were defined as diffuse sclerosing and tall cell variants, whereas classic and follicular variants of PTC were considered less aggressive. SUS characteristics of thyroid nodules were studied, including type (solid, mostly cystic, mixed), calcifications (micro-, coarse, none), borders (irregular, regular), shape (taller greater than wider), and echogenicity (hyper-, hypo-, isoechoic). SUS features were correlated with final histopathology using univariate regression analysis. For SUS features that are statistically significant (p<0.05), odds ratio (OR), confidence interval (CI), and p-values are presented.

Results: On final histopathology, 49 patients (12%) had more aggressive variants of PTC. On univariate analysis, hypoechogenicity (p<0.005, OR=2.700, CI [1.382-5.248]), microcalcifications (p<0.005, OR=2.389, CI [1.306-4.369]) and irregular border (p=0.043, OR=1.853, CI [1.014-3.387]) were SUS features that correlated significantly with more aggressive variants of PTC. Combining 2 of these features increased the predictive value of SUS for aggressive variants (hypoechogenicity and microcalcifications p<0.005, OR=5.757, CI [2.192-15.121]; hypoechogenicity and irregular border p<0.005, OR=3.810, CI [1.590-9.125]; irregular border and microcalcifications p<0.005, OR=2.787, CI [1.384-5.613]). The combination of all three SUS features of hypoechogenicity, microcalcifications, and irregular border had the strongest association for aggressive variants of PTC (p<0.005, OR = 7.054, CI [2.418-20.574]).

Conclusion: The combination of all three SUS features of hypoechogenicity, microcalcifications, and irregular border strongly predicts more aggressive variants of PTC with a 7-fold higher likelihood of being diffuse sclerosing or tall cell variants on final pathology. SUS, therefore, can potentially predict the biologic behavior of PTC at time of diagnosis, and help guide the surgeon in the operative and peri-operative management of these patients.

69.10 Underlying Abnormal Thyroid Pathology In Patients With Metastatic Disease To The Thyroid Gland

Posted on December 22, 2014

K. L. Long1, S. Spires2, C. Lee1, D. Sloan1  1University Of Kentucky,Division Of General Surgery,Lexington, KY, USA 2University Of Kentucky,Division Of Pathology,Lexington, KY, USA

Introduction:  Metastatic disease to the thyroid gland is an uncommon clinical occurrence, accounting for 1.4-3% of patients undergoing thyroid surgery.  Commonly reported cancers found in the thyroid gland include renal cell carcinoma, lung cancer, and breast cancer.  Questions remain as to whether thyroid metastases from non-thyroid malignancies (NTM) have a predilection for abnormal thyroid glands.  We hypothesized that patients with metastatic disease to the thyroid gland are more likely to have underlying thyroid pathology, including thyroid cancer. 

Methods:  A 5-year retrospective case review was performed using an IRB-approved protocol (13-0532-P6H) for patients undergoing thyroid surgery at our institution from July 2008 through June 2013.  During this time, 1708 thyroid procedures were performed. 

Results:  Six patients with NTM were identified, 4 of which were diagnosed with renal cell carcinoma metastatic to the thyroid (66%).  One patient was found to have metastatic small cell lung cancer, and one patient was diagnosed with metastatic breast cancer.  The average age at presentation was 65.1 years.  4 of 6 patients were female.  Additionally, 4 of the 6 patients had a history of metastatic disease to organs other than the thyroid gland.  The average time from initial cancer diagnosis to the first diagnosis of metastatic disease was 8.8 years (range 0 to 26 years).  The average time from initial diagnosis to evidence of thyroid involvement was 11.5 years (0 to 27 years).  In final pathologic specimens, 2 of 6 patients had incidental findings of papillary thyroid cancer.  2 additional patients were noted to have abnormal thyroid pathology.

Conclusion:  Non-thyroid malignancy metastatic to the thyroid remains a rare but distinct entity.  Any patient presenting with a thyroid mass and even a remote history of cancer should be evaluated for metastatic disease to the thyroid gland.  Metastatic disease to the thyroid gland can present at any time after a primary cancer diagnosis and includes a wide range of tumor types.  Likewise, the incidence of associated thyroid pathology remains high in these patients, and operative planning should account for these factors. 

 

69.11 Ultrasound Guided Ethanol Ablation of Recurrent Metastatic Papillary Thyroid Cancer

Posted on December 22, 2014

J. D. Pasternak1, N. Seiser1, J. E. Gosnell1, I. Suh1, Q. Duh1, W. T. Shen1  1University Of California – San Francisco,Endocrine Surgery,San Francisco, CA, USA

Introduction:

Up to 20% of patients with Papillary Thyroid Cancer (PTC) are found to have postoperative nodal metastases in the neck.  While reoperative lymphadenectomy remains the most common method for addressing recurrent/persistent disease, new methods which avoid surgical risk are being sought to address small, asymptomatic lesions.  Ethanol (ETOH) ablation of metastatic thyroid cancer in the neck has been described as a potential safe and effective alternative to surgery. 

Methods:

We report consecutive ultrasound guided ETOH ablation treatments in patients with recurrent, metastatic PTC at a tertiary care Endocrine Surgery Unit over the past 5 years.  A retrospective review of prospectively collected data was undertaken.  Patient demographics, pathology, imaging and operative history, ETOH injection complications as well as post injection thyroglobulin (Tg) and sonographic trends were studied.  Technique of ETOH injection was standardized with ultrasound guidance and the use of 1cc/cm3 of 100% ethanol solution.

Results:

Five treatments of ultrasound guided percutaneous ethanol injection in 4 patients with recurrent metastatic papillary thyroid cancer were studied.  All patients had been previously treated with radioactive iodine (Mean: 1.25 treatments of 174mCi), however, in the 3 cases with a pretreatment I-131 scan, there was no uptake of radioiodine in the treated disease.  In the 4 cases with pre-treatment FDG-Positron Emission Tomography (PET), all showed the treated lesions to be FDG-avid.  Median follow-up time from the most recent treatment was 28.5 months, with no progression of disease in all of the treated lesions.  There were no complications, including post treatment pain, hoarseness or dysphagia.  Detected serum Tg in patients without Tg-antibody decreased after treatment.

Conclusion:

With the growing body of literature focusing on the indolence of metastatic PTC, surgeons seeking a less invasive approach to deal with smaller asymptomatic nodal metastases in the neck can consider ETOH ablation.  The authors' proposed criteria for ETOH ablative treatment includes small lesions that 1) would be difficult to surgically resect, such as deep nodes in a previously irradiated and/or re-operative neck, 2) are sonographically visible and 3) are negative on radioiodine scan and positive on FDG-PET.  As demonstrated by a small set of patients in a tertiary care endocrine surgery unit, ETOH ablation is safe and effective at controlling progression of targeted local disease.

62.20 Characterizing Myeloid-derived Suppressor Cells by Expression of LIGHT and its Cognate Receptors

Posted on December 22, 2014

J. F. Calata1, S. Jayaraman1, B. S. Prabhakar1, A. V. Maker1  1University Of Illinois At Chicago,Chicago, IL, USA

Introduction:

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that negatively regulate immune responses during tumor progression. There remains a significant gap in our understanding of their phenotypical and functional heterogeneity. We have previously demonstrated that the immunostimulatory cytokine LIGHT (TNFSF14) can mature certain myeloid cells, and that its presence in the tumor microenvironment can stimulate an anti-tumor T-cell response.  We, therefore, determined to define the expression of LIGHT and its cognate receptors on MDSCs.

Methods:

Female BALB/c mice, 6-8 weeks of age, were injected subcutaneously with 1×106 CT26 cells (murine colorectal carcinoma cell line).  When tumors reached 1 cubic centimeter, splenectomy was performed.  Splenocytes were isolated and evaluated with flow cytometry for expression CD11b, Ly6G, Ly6C, HVEM, LTBR, and LIGHT.

Results:

Monocytic-MDSC (M-MDSC, CD11b+/Ly6G+) and granulocytic-MDSCs (G-MDSC, CD11b+/Ly6C+) were identified in tumor bearing mice.  LIGHT was expressed preferentially on G-MDSCs (94% vs. 39%, p= 0.0006).  The LIGHT receptors HVEM and LTBR were also expressed on MDSC subsets. LTBR expression was high in both populations, but increased in G-MDSC compared to M-MDSC (p=0.018), while HVEM expression was lower in G-MDSC (84% vs. 40%, p=<0.0001).  Populations of M-MDSC were, therefore, characterized as LIGHTlowLTBRlowHVEMhi while G-MDSC were LIGHThiLTBRhiHVEMlow.

Conclusion:

MDSCs can be characterized by their expression of LIGHT and its cognate receptors.  Based on this data, the effect of LIGHT and LIGHT receptor blockade on MDSC function warrants further investigation since inhibition of immunosuppressive MDSC may be a promising strategy for tumor immunotherapy.

 

63.01 Screening of Novel Synthesized Analoges Targeting Histone Deacetylase in Aggressive Thyroid Cancers

Posted on December 22, 2014

S. Jang1, X. Yu1, S. K. Odorico1, M. Clark1, C. Schienebeck2, W. Tang2, H. Chen1  1University Of Wisconsin,Department Of Surgery,Madison, WI, USA 2University Of Wisconsin,Department Of Chemistry,Madison, WI, USA

Introduction: There are limited effective therapies for aggressive thyroid malignancies including anaplastic and poorly differentiated cancers. Compounds targeting histone deacetylases (HDAC) have shown promising antitumor activities in others cancers.  In order to develop novel therapies for these aggressive thyroid cancers, we synthesized a new group of analogues targeting HDACs named AB1 to AB13 which has different linkers between a metal chelating group and a hydrophobic cap. Therefore, the purpose of this study was to screen out the most effective compounds and evaluate the therapeutic efficacy in aggressive thyroid cancers.

Methods: Anaplastic (HTh7 and 8505C) and metastatic follicular (FTC236) thyroid cancer cells were treated with thirteen AB analogues using various concentrations, and the IC50 was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.  The most effective compounds were selected based on the IC50 to further study the molecular mechanisms of growth regulation. Both cell cycle regulatory proteins and apoptosis markers were analyzed by the Western blot. In addition, the expression levels of the thyrocyte-specific genes were quantified by real-time PCR to assess the drug potency of inducing re-differentiation in aggressive thyroid cancer cells.

Results: Among all the analogues, AB1, 4, 5, 6, 13 showed very limited cytotoxicity effect while AB7, 8, 9, 11, and 12 presented with moderate efficacy to inhibit cell growth. AB2, AB3, and AB10 demonstrated the lowest IC50 values of the thirteen screened drug analogues (Table 1). The AB analogues showed less cytotoxicity against human fibroblasts WI38. AB2, AB3, and AB10 treatment resulted in an increase of apoptosis markers including cleaved poly adenosine diphosphate ribose polymerase (PARP) and cleaved caspase 3 in a dose dependent manner in all three cancer cell lines. Additionally, the expression of cell cycle regulatory proteins p21/WAF1 and p27 Kip increased with the treatment of ABs while cyclin D1 decreased dose-dependently. Furthermore, AB2, AB3, and AB10 were able to induce various of thyrocyte specific genes in all the cell lines indicated by increased level of sodium iodide symporter (NIS), paired box gene 8 (PAX8), thyroid transcription factor 1 (TTF1), TTF2, and thyroid stimulating hormone receptors (TSHR).

Conclusion: Novel synthetic HDAC inhibitors AB2, AB3 and AB10 suppress thyroid cancer cell growth via cell cycle arrest and apoptosis. They also induce cell re-differentiation which could make aggressive thyroid cancer cells more susceptible to radioactive iodine therapy. Therefore, these compounds could be new options for patients with aggressive thyroid cancers.

 

63.07 Targeting KRAS in Pancreatic Cancer Using a Novel Method of Gene Silencing: U1 Adaptors

Posted on December 22, 2014

A. T. Tsang1,2, X. Yu1, R. Goraczniak5, M. Brenneman1,5, S. Gunderson3,5, D. R. Carpizo1,2,4  4Rutgers University,Department Of Pharmacology,Piscataway, NJ, USA 5Silagene Inc.,Hillsborough, NJ, USA 1Cancer Institute Of New Jersey,Division Of Surgical Oncology,New Brunswick, NJ, USA 2Robert Wood Johnson – Rutgers,Department Of Surgery,New Brunswick, NJ, USA 3Rutgers University,Department Of Molecular Biology And Biochemistry,Piscataway, NJ, USA

Introduction:

Activating mutations of the KRAS gene are key drivers of pancreatic cancer. However, despite decades of effort, the KRAS protein has proved refractory to small-molecule targeting. Many RNA interference-based studies targeting RAS have demonstrated therapeutic effects, but technical difficulties of delivery in vivo have impeded translation of this approach to the clinic. U1 Adaptors are synthetic oligonucleotides that enable the U1 small nuclear ribonucleoprotein complex to stably bind within the terminal exon of any chosen pre-mRNA target. This interferes with the obligatory polyadenosine tail addition step in mRNA maturation, resulting in selective destruction of the mRNA in the nucleus. The U1 Adaptor gene silencing mechanism is thus distinct from those of siRNA or antisense oligonucleotides, and offers important advantages for their use as therapeutic agents. In a proof-of-concept study, U1 adaptors targeting BCL2 and GRM-1 oncogenes effectively suppressed growth of human melanoma xenograft tumors in mice.

Methods:
We sought to translate this technology to target human KRAS in pancreatic cancer. We first screened a set of U1 Adaptors targeting human KRAS pre-mRNA at eight different positions within the terminal exon coding sequence and untranslated region. Adaptors were evaluated in vitro using the human pancreatic cancer cell line MiaPaca-2 (KRASG12C). KRAS mRNA was measured by quantitative PCR, and KRAS protein expression was determined using standard Western blot techniques. Cell growth inhibition assays were performed and viable cells were counted using flow cytometry over 12 days. Adaptors that gave the best in vitro results were then evaluated in MiaPaca-2 xenografts. For in-vivo delivery, Adaptors were complexed with nanoparticles linked to a tumor-targeting peptide, cRGD, and administered by tail vein injection twice weekly. Tumors were then evaluated for KRAS gene and protein expression.

Results:
U1 Adaptor screening revealed a range of KRAS gene silencing as measured by quantitative PCR. Candidate Adaptors 1, 2 and 3 reduced KRAS mRNA expression by 65%, 73% and 76% respectively; as effectively as an siRNA control. We demonstrated potent inhibition of MiaPaca-2 cell growth and knockdown of KRAS protein expression, using Adaptors modified with locked nucleic acid (LNA). We then evaluated Adaptors 2 and 3 in mice bearing MiaPaca-2 xenografts. We observed significant tumor growth inhibition, by as much as 68% using Adaptor 3 (p=0.0002), compared to the vehicle control by day 34. Tumors were then analyzed and found to have KRAS protein reduction.

Conclusion:
We have demonstrated that the U1 Adaptor method of gene silencing can be successfully applied to target human KRAS both in vitro and in vivo.  These results support the continued investigation of U1 Adaptor technology as a strategy for therapeutic targeting of RAS oncogenes.

63.09 Memory T cell infiltration in hepatic colorectal adenocarcinoma metastases

Posted on December 22, 2014

J. V. Meyers1, S. Sen1, A. J. Tatar1, A. Contreras1, P. Srinand1, C. S. Cho1  1University Of Wisconsin,Section Of Surgical Oncology,Madison, WI, USA

Introduction:   Previous studies in primary colorectal adenocarcinoma have suggested that intratumoral infiltration by memory T cells may be strongly protective against the likelihood of metastatic disease dissemination.  The prevalence and prognostic significance of memory T cell infiltration within metastatic foci are unknown.  We hypothesized that memory T cell infiltration within resected hepatic colorectal metastases would be associated with favorable oncological characteristics.

Methods:   Frozen samples from resected hepatic colorectal adenocarcinoma metastases were obtained from a prospectively maintained and institutionally-approved tumor bank.  Thawed samples were fixed and analyzed by hematoxylin/eosin staining and by immunochemical analysis for expression of CD3 and CD45RO.  CD3 (T cell) and CD45RO (memory T cell) expression was quantified under low power magnification by two blinded observers using a two-tiered low versus medium/high grading system.  Clinicopathological and survival data were obtained from a prospectively-maintained institutional database.  The approximate risk of disease recurrence was stratified using the Memorial Sloan-Kettering Cancer Center Clinical Risk Score (CRS).  Comparison of categorical variables was performed using chi-square analysis, and differences in Kaplan-Meier estimates of overall and recurrence-free survival were compared using the log-rank test.

Results:  Samples from ten resected tumors were obtained for this preliminary analysis.  Eight tumors exhibited medium/high CD3 expression and 6 tumors exhibited medium/high CD45RO expression.  The prevalence of T cell infiltration was somewhat higher among patients with a CRS ≥ 2 (100%) than patients with a CRS < 2 (33%) (p=0.07).  The prevalence of memory T cell infiltration was higher among patients with a CRS ≥ 2 (86%) than patients with a CRS < 2 (0%) (p=0.03).  T cell and memory T cell infiltration were not associated with differences in overall or recurrence-free survival.

Conclusion:  There is a high prevalence of memory T cell infiltration within resected hepatic colorectal adenocarcinoma metastases.  Contrary to our hypothesis, intratumoral memory T cell infiltration alone is not obviously associated with differences in survival outcome, and its prevalence may be paradoxically higher in conditions of adverse tumor characteristics.  Ongoing studies will explore the hypothesis that intrametastatic memory T cell infiltration may exert a protective influence that mitigates the prognostic impact of adverse tumor characteristics.

 

61.07 SIGIRR/TIR8 Predicts Biochemical Recurrence After Prostatectomy in Low-grade Prostate Carcinomas

Posted on December 22, 2014

T. M. Bauman1, A. J. Becka1, P. D. Sehgal1, W. Huang2, W. A. Ricke1  1University Of Wisconsin School Of Medicine And Public Health,Department Of Urology,Madison, WI, USA 2University Of Wisconsin School Of Medicine And Public Health,Department Of Pathology And Laboratory Medicine,Madison, WI, USA

Introduction: Single Ig IL-1-related receptor (SIGIRR) is a negative regulator of toll-like receptor (TLR) 4 and IL-1 mediated activation of NF-κB. A tumor suppressive role of SIGIRR has previously been established in certain carcinomas, but the role and expression of SIGIRR in normal prostate, benign prostatic hyperplasia (BPH), and prostate cancer (PCa) has yet to be investigated. The purpose of this study was to characterize SIGIRR protein expression in human prostate tissues.

 

Methods: Nuclear and cytoplasmic SIGIRR expression were quantified in glandular prostate tissue using immunohistochemistry and multispectral imaging. Expression was compared between tumor-adjacent normal prostate (n=48 patients), BPH (n=24), high-grade prostatic intraepithelial neoplasia (HGPIN; n=25), PCa (n=73), and metastases (n=22), and SIGIRR expression was evaluated in relation to clinico-pathological features of PCa (Gleason score, pathological stage, tumor volume, surgical margin status, serum PSA). Kaplan-Meier analysis and Cox proportional hazards regression was used to investigate the association of SIGIRR expression and PSA biochemical recurrence. Patient outcomes were reanalyzed in subgroupings of low Gleason score (≤6 or 3+4) and high Gleason score (4+3 and ≥8).

 

Results: Compared to normal prostate, cytoplasmic SIGIRR expression was similar in BPH (p=0.37), HGPIN (p=0.20), PCa (p=0.40), and metastases (p=0.31). No significant changes in nuclear SIGIRR expression were found in BPH (p=0.07), HGPIN (p=0.37), or PCa (p=0.06), but a significant decrease in expression was found in metastasis samples (p=0.04). Decreased nuclear SIGIRR expression was observed in patients with high Gleason score (4+3 and ≥8; p=0.03), but no significant changes were found in cytoplasmic SIGIRR expression (p=0.08). Both cytoplasmic and nuclear SIGIRR expression were not related to pathologic stage, tumor volume, surgical margin status, or serum PSA (p>0.05).

Nuclear SIGIRR expression (p=0.96) and cytoplasmic SIGIRR expression (p=0.89) as continuous variables were not associated with biochemical recurrence in univariable analysis when all patients were analyzed. In sub-analysis of low Gleason score patients, high cytoplasmic SIGIRR expression was associated with increased biochemical recurrence in both univariable (p=0.01) and multivariable (HR 2.31 [95% CI 1.05-5.06] p=0.04) analysis, independent of pathologic stage, tumor volume, and margin status.

 

Conclusions: SIGIRR predicts biochemical recurrence in patients with low Gleason score prostate cancer, but is not associated with recurrence in high Gleason score patients. These findings highlight a potential mechanistic role of NF-κB signaling specifically in low grade PCa.

 

 

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