Keith F. Fournier

Systemic chemotherapy and surgical cytoreduction for poorly differentiated and signet ring cell adenocarcinomas of the appendix

BACKGROUND Poorly differentiated and signet ring cell adenocarcinomas of the appendix represent a subset with aggressive tumor biology and poor outcomes with few studies evaluating the impact of systemic chemotherapy and cytoreductive surgery (CRS). PATIENTS AND METHODS A retrospective chart review of patients with either poorly differentiated and signet ring cell appendiceal adenocarcinomas was completed from 1992 to 2010. RESULTS One hundred forty-two patients were identified. Seventy-eight patients with metastatic disease received chemotherapy. Radiographic response was 44%, median progression-free survival (PFS) was 6.9 months, and median overall survival (OS) was 1.7 years. In multivariate analysis, response to chemotherapy [hazard ratio (HR) 0.5; P = 0.02] predicted improved PFS, and complete CRS (HR 0.3; P = 0.004) predicted improved OS. Patients who underwent complete CRS (n = 26) had a median relapse-free survival (RFS) of 1.2 years and a median OS of 4.2 years. In multivariate analysis for this subset, complete cytoreduction score of 0 was significantly correlated with improved RFS (HR 0.07; P = 0.01) and OS (HR 0.02; P = 0.01). CONCLUSIONS Systemic chemotherapy appears to be a viable treatment option for patients with metastatic poorly differentiated and signet ring cell appendiceal adenocarcinomas. Complete CRS is associated with improved RFS and OS, though part of this benefit likely reflects the selection of good tumor biology.BACKGROUND Poorly differentiated and signet ring cell adenocarcinomas of the appendix represent a subset with aggressive tumor biology and poor outcomes with few studies evaluating the impact of systemic chemotherapy and cytoreductive surgery (CRS). PATIENTS AND METHODS A retrospective chart review of patients with either poorly differentiated and signet ring cell appendiceal adenocarcinomas was completed from 1992 to 2010. RESULTS One hundred forty-two patients were identified. Seventy-eight patients with metastatic disease received chemotherapy. Radiographic response was 44%, median progression-free survival (PFS) was 6.9 months, and median overall survival (OS) was 1.7 years. In multivariate analysis, response to chemotherapy [hazard ratio (HR) 0.5; P = 0.02] predicted improved PFS, and complete CRS (HR 0.3; P = 0.004) predicted improved OS. Patients who underwent complete CRS (n = 26) had a median relapse-free survival (RFS) of 1.2 years and a median OS of 4.2 years. In multivariate analysis for this subset, complete cytoreduction score of 0 was significantly correlated with improved RFS (HR 0.07; P = 0.01) and OS (HR 0.02; P = 0.01). CONCLUSIONS Systemic chemotherapy appears to be a viable treatment option for patients with metastatic poorly differentiated and signet ring cell appendiceal adenocarcinomas. Complete CRS is associated with improved RFS and OS, though part of this benefit likely reflects the selection of good tumor biology.

Neuroendocrine and mucinous differentiation in signet ring cell carcinoma of the stomach: Evidence for a common cell of origin in composite tumors

Composite tumors are rare neoplasms containing a mixture of 2 different cellular components present in roughly equal proportions. It is hypothesized that composite tumors arise from a multipotential stem cell with subsequent bidirectional differentiation. We present an unusual composite tumor of the stomach composed equally of signet ring cell carcinoma and low-grade neuroendocrine carcinoma. Twenty-one additional patients with signet ring cell carcinomas of the stomach were studied to determine the prevalence of neuroendocrine differentiation by morphology and immunohistochemistry for synaptophysin and chromogranin A. Immunohistochemistry for mucins 5AC and 2 was performed to assess for divergent differentiation toward foveolar and intestinal mucin phenotypes, respectively, and to evaluate for any potential relationship with neuroendocrine differentiation. We found morphologic evidence of neuroendocrine carcinoma in 4 (19%) of 21 consecutive signet ring carcinomas. E-cadherin immunostaining was subsequently performed on these 4 tumors plus the index case. All 5 tumors demonstrated concordance between the signet ring and neuroendocrine components. There was no distinct relationship to mucin 5AC/mucin 2 profiles, with the exception that all 11 intramucosal signet ring cell carcinomas from 4 patients with germ line cadherin 1 gene mutations were composed exclusively of mucin 5AC+ signet ring cells that lacked intestinal mucin and neuroendocrine differentiation. The concordant E-cadherin status in the neuroendocrine and signet ring cell tumor components and the frequent admixture of mucin 5AC+ cells with foveolar differentiation and mucin 2+ cells with intestinal differentiation may support the hypothesis that composite tumors arise from a common stem cell with bilineage or multilineage differentiation.

Predictors of Survival in Patients with Resectable Gastric Cancer Treated with Preoperative Chemoradiation Therapy and Gastrectomy

BACKGROUND The purpose of this study was to determine the overall survival (OS) of patients with resectable gastric cancer treated with preoperative chemoradiation therapy and gastrectomy. STUDY DESIGN The medical records of patients with gastric adenocarcinoma presenting to our institution (January 1995 to August 2012) were reviewed to identify patients who underwent diagnostic laparoscopy, preoperative chemoradiation, and gastrectomy. Associations between various clinicopathologic factors and OS were examined with Cox proportional hazards models. RESULTS Of 192 patients who met inclusion criteria, 103 (54%) required total gastrectomy. One hundred sixty-eight patients (88%) had an extended lymph node dissection, 26 (14%) had resection of adjacent organs, and 178 (93%) had an R0 resection. Median follow-up time for surviving patients was 4.2 years. Median OS for all patients was 5.8 years, and 5-year OS rate was 56%. Multivariable Cox regression model results identified variables associated with diminished OS including age ≥ 65 years (hazard ratio [HR] 1.62; 95% CI 1.05 to 2.51), male sex (HR 1.76; 95% CI 1.13 to 2.74), adjacent organ resection (HR 1.97; 95% CI 1.16 to 3.35), R1 status (HR 2.29; 95% CI 1.17 to 4.48), pathologic N1 stage (HR 1.92; 95% CI 1.24 to 2.98), N2 stage (HR 2.58; 95% CI 1.01 to 6.58), and N3 stage (HR 6.54; 95% CI 2.69 to 15.93). Five-year OS rates for patients with pathologic N0, N1, N2, and N3 disease were 67%, 42%, 43%, and 0%, respectively. CONCLUSIONS Patients with gastric cancer who undergo diagnostic laparoscopy, preoperative chemoradiation, and gastrectomy have a high frequency of obtaining an R0 resection and excellent OS rates. Nodal status after surgery remains an important determinant of OS.

Varying malignant potential of appendiceal neuroendocrine tumors: Importance of histologic subtype

Neuroendocrine tumors (NETs) of the appendix include malignant carcinoid tumor (MCT), goblet cell carcinoid (GCT), and composite goblet cell carcinoid‐adenocarcinoma (CGCC‐A).

High-level microsatellite instability in appendiceal carcinomas.

High-level microsatellite instability (MSI-high) is found in approximately 15% of all colorectal adenocarcinomas (CRCs) and in at least 20% of right-sided cancers. It is most commonly due to somatic hypermethylation of the MLH1 gene promoter region, with familial cases (Lynch syndrome) representing only 2% to 3% of CRCs overall. In contrast to CRC, MSI-high in appendiceal adenocarcinomas is rare. Only 4 MSI-high appendiceal carcinomas and 1 MSI-high appendiceal serrated adenoma have been previously reported, and the prevalence of MSI in the appendix is unknown. We identified 108 appendiceal carcinomas from MD Anderson Cancer Center in which MSI status had been assessed by immunohistochemistry for the DNA mismatch-repair proteins MLH1, MSH2, MSH6, and PMS2 (n=83), polymerase chain reaction (n=7), or both (n=18). Three cases (2.8%) were MSI-high, and 1 was MSI-low. The 3 MSI-high cases included: (1) a poorly differentiated nonmucinous adenocarcinoma with loss of MLH1/PMS2 expression, lack of MLH1 promoter methylation, and lack of BRAF gene mutation, but no detected germline mutation in MLH1 from a 39-year-old man; (2) an undifferentiated carcinoma with loss of MSH2/MSH6, but no detected germline mutation in MSH2 or TACSTD1, from a 59-year-old woman; and (3) a moderately differentiated mucinous adenocarcinoma arising in a villous adenoma with loss of MSH2/MSH6 expression, in a 38-year-old man with a strong family history of CRC who declined germline testing. When the overall group of appendiceal carcinomas was classified according to histologic features and precursor lesions, the frequencies of MSI-high were: 3 of 108 (2.8%) invasive carcinomas, 3 of 96 (3.1%) invasive carcinomas that did not arise from a background of goblet cell carcinoid tumors, and 0 of 12 (0%) signet ring and mucinous carcinomas arising in goblet cell carcinoid tumors. These findings, in conjunction with the previously reported MSI-high appendiceal carcinomas, highlight the low prevalence of MSI in the appendix as compared with the right colon and suggest that MLH1 promoter methylation is not a mechanism for MSI in this location.

Varying malignant potential of appendiceal neuroendocrine tumors

Neuroendocrine tumors (NETs) of the appendix include malignant carcinoid tumor (MCT), goblet cell carcinoid (GCT), and composite goblet cell carcinoid‐adenocarcinoma (CGCC‐A).

The Palliative Index: Predicting Outcomes of Emergent Surgery in Patients with Cancer

BACKGROUND The role of emergent palliative surgery in the setting of advanced malignancy remains a subject of controversy. OBJECTIVE The purpose of this study was to identify clinical predictors of outcome in patients with cancer who undergo nonelective abdominal surgery. SETTING/SUBJECTS Individuals who underwent urgent and emergent abdominal operations between 2006 and 2010 at a tertiary cancer center were identified. MEASUREMENTS Analyses were performed to identify predictors of 30-day morbidity and mortality as well as overall survival (OS). A risk score was derived from predictors of OS. RESULTS Of 143 patients, 93 (65%) had active disease (AD; defined as evidence of malignancy at time of surgery). Thirty-day morbidity and mortality were 36.4% and 9.8%, respectively. Independent predictors of 30-day mortality included ASA score >3 (p=0.009) and albumin <2.8 (p=0.040). Median OS was 5.4 months in patients with AD and was not reached in patients without AD (p<0.001). Independent predictors of decreased OS included AD; ASA >3; creatinine >1.3; and a tumor-related indication (i.e., bleeding, obstructing, or perforating tumor). A risk or palliative index (PI) score stratified patients into groups with discreet outcomes. CONCLUSIONS Although AD did not predict 30-day morbidity, it was the dominant independent predictor of postoperative OS. In cancer patients undergoing emergency abdominal surgery, outcome is anticipated by disease status and other independent predictors of OS.

Impact of molecular alterations and targeted therapy in appendiceal adenocarcinomas

UNLABELLED Appendiceal adenocarcinomas (AAs) are rare and this has limited their molecular understanding. The purpose of our study was to characterize the molecular profile of AA and explore the role of targeted therapy against cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR). PATIENTS AND METHODS We performed a retrospective review of 607 patients with AA at a single institution. A total of 149 patients underwent molecular testing for at least one of the following: activating mutations in KRAS, BRAF, cKIT, EGFR, or PI3K; protein expression of c-KIT or COX-2; or microsatellite instability (MSI) status by immunohistochemistry. Kaplan-Meier product limit method and log-rank test were used to estimate overall survival (OS) and to determine associations among OS, COX-2 expression, KRAS mutations, and other characteristics. RESULTS Age, grade, stage, signet ring cells, mucinous histology, and completeness of cytoreduction score correlated with survival outcomes. COX-2 expression, KRAS, PI3K, and BRAF mutations were seen in 61%, 55%, 17%, and 4% of patients, respectively. High MSI was seen in 6% of patients. KRAS mutation was strongly associated with well differentiated or moderately differentiated AA (p < .01). COX-2 expression (p = .33) and the presence of KRAS mutation (p = .91) had no impact on OS. The use of celecoxib in patients whose tumors expressed COX-2 (p = .84) and the use of cetuximab or panitumumab in patients with KRAS wild-type tumors (p = .83) also had no impact on OS. CONCLUSION In this cohort, we demonstrated that COX-2 expression and KRAS mutations were frequently seen in AA, although neither exhibited any prognostic significance. MSI was infrequent in AA. Targeted therapy against COX-2 and EGFR appeared to provide no clinical benefit. Well and moderately differentiated AA were molecularly distinct from poorly differentiated AA.

Racial disparities in preoperative chemotherapy use in gastric cancer patients in the United States: Analysis of the National Cancer Data Base, 2006-2014

No studies have investigated whether race/ethnicity is associated with the recommended use of preoperative chemotherapy or subsequent outcomes in gastric cancer. To determine whether there is such an association, analyses of patients with gastric cancer in the National Cancer Data Base (NCDB) were performed.

Localized Gastric Cancer Treated with Chemoradation without Surgery: UTMD Anderson Cancer Center Experience

Background: In patients with localized gastric cancer (LGC) who are unfit for surgery, decline surgery, or have unresectable cancer, chemoradiotherapy may provide palliation; however, data in the literature are sparse. Methods: We identified 66 LGC patients who had definitive chemoradiation but no surgery. All patients had baseline and postchemoradiation staging including an endoscopic biopsy. Multiple statistical methods were used to analyze outcomes. Results: Most patients were men and most had stage III or IV cancer. Five patients were surgery eligible but declined to have surgery. The median follow-up time was 33.9 months (95% CI 18.3–49.6). The median survival time (MST) for 66 patients was only 14.5 months (95% CI 10.8–19.7) and the median relapse-free survival (RFS) was 5.03 months (95% CI 4.67–6.40). The estimated overall survival (OS) and RFS rates at 3 years were 22.6% (95% CI 13.7–37.3) and 7.7% (95% CI 3.2–18.6), respectively. Twenty-three (35%) patients who achieved a clinical complete response (cCR; negative postchemoradiation biopsy and no progression by imaging) fared better than those who achieved less than cCR (<cCR) [cCR: MST 30.7 months (95% CI 20.4–NA); <cCR: MST 10.6 months (95% CI 8.43–14.9); p < 001]. In multivariate analysis, cCR was the only independent prognosticator for OS [hazard ratio (HR) = 0.32, p < 0.0012] and RFS (HR = 0.12, p < 0.0001). Conclusion: Our data demonstrate that in the absence of surgery, outcomes with definitive chemoradiation are only modest. A third of the patients achieved cCR and had a longer OS and RFS than those who achieved <cCR.