Reconnaissance of tumor immune microenvironment spatial heterogeneity in metastatic renal cell carcinoma and correlation with immunotherapy response.

A clearer understanding of the tumor immune microenvironment (TIME) in metastatic clear cell renal cell carcinoma (ccRCC) may help to inform precision treatment strategies. We sought to identify clinically meaningful TIME signatures in ccRCC. We studied tumors from 39 patients with metastatic ccRCC using quantitative multiplexed immunofluorescence and relevant immune marker panels. Cell densities were analyzed in three regions of interest (ROIs): tumor core, tumor-stroma interface and stroma. Patients were stratified into low- and high-marker density groups using median values as thresholds. Log-rank and Cox regression analyses while controlling for clinical variables were used to compare survival outcomes to patterns of immune cell distributions. There were significant associations with increased macrophage (CD68+ CD163+ CD206+ ) density and poor outcomes across multiple ROIs in primary and metastatic tumors. In primary tumors, T-bet+ T helper type 1 (Th1) cell density was highest at the tumor-stromal interface (P = 0·0021), and increased co-expression of CD3 and T-bet was associated with improved overall survival (P = 0·015) and survival after immunotherapy (P = 0·014). In metastatic tumor samples, decreased forkhead box protein 3 (FoxP3)+ T regulatory cell density correlated with improved survival after immunotherapy (P = 0·016). Increased macrophage markers and decreased Th1 T cell markers within the TIME correlated with poor overall survival and treatment outcomes. Immune markers such as FoxP3 showed consistent levels across the TIME, whereas others, such as T-bet, demonstrated significant variance across the distinct ROIs. These findings suggest that TIME profiling outside the tumor core may identify clinically relevant associations for patients with metastatic ccRCC.

Case of an appendiceal mucinous adenocarcinoma presenting as a left adnexal mass.

INTRODUCTION: Appendiceal mucinous neoplasms represent an exceptionally rare form of pathology with an incidence rate ranging between 0.2 and 0.3% of all appendectomies.(1,2) The most common presentation is right lower quadrant pain with a palpable abdominal mass present in 50% of cases.(8-12) Patients may also present with nausea, vomiting, change in bowel habits, weight loss, appendicitis, intestinal obstruction, ureteral compression, or lower gastrointestinal bleeding. Early diagnosis and proper surgical precautions must be implemented to prevent iatrogenic rupture of the appendix and the widespread seeding of potentially malignant mucin-producing cells throughout the peritoneal cavity. PRESENTATION OF CASE: A 50-year-old African-American female presented with complaints of left-sided pelvic pain. Pelvic examination revealed adnexal fullness with thickening behind the cervix. An adnexal mass was revealed on ultrasound and MRI. The patient was subsequently taken to the operating room for a planned robotic salpingectomy. During the procedure, she was unexpectedly found to have an abnormally large appendix displaced to the left lower quadrant. General surgery was consulted intra-operatively to perform an appendectomy. The final pathology report revealed a low-grade mucinous adenocarcinoma with mucin dissecting into the wall of the appendix. DISCUSSION: Appendiceal mucinous cystadenomas are characterized by hyperplasia of glandular epithelium along with hypersecretion of mucous resulting in a grossly dilated appendix. The clinical manifestation of appendiceal mucoceles is often non-specific. The prevalence is higher in women than men (4:1) with the average age at the time of diagnosis being 54 years-old.(14-17) Appendiceal mucinous cystadenomas can be particularly problematic for women as these tumors are commonly misdiagnosed pre-operatively as right-sided adnexal masses due to commonalities in clinical presentation and diagnostic findings.(8-12) It is estimated that based on imaging studies only 15-29% of appendiceal mucinous cystadenomas are correctly diagnosed prior to surgical intervention.(13) CONCLUSION: To the best of our knowledge, only one other case of appendiceal adenocarcinoma with left-sided presentation has been reported. Appendiceal carcinomas can create a diagnostic dilemma due to non-specific clinical findings and inadequate imaging studies. Early recognition and careful intra-operative precautions must be taken to maintain the integrity of the appendix to prevent iatrogenic rupture and the spread of potentially malignant mucin-producing cells throughout the peritoneal cavity.