Circulating tumor DNA-based molecular residual disease detection for treatment monitoring in advanced melanoma patients.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have substantially improved overall survival in patients with advanced melanoma; however, the lack of biomarkers to monitor treatment response and relapse remains an important clinical challenge. Thus, a reliable biomarker is needed that can risk-stratify patients for disease recurrence and predict response to treatment. METHODS: A retrospective analysis using a personalized, tumor-informed circulating tumor DNA (ctDNA) assay on prospectively collected plasma samples (n = 555) from 69 patients with advanced melanoma was performed. Patients were divided into three cohorts: cohort A (N = 30), stage III patients receiving adjuvant ICI/observation; cohort B (N = 29), unresectable stage III/IV patients receiving ICI therapy; and cohort C (N = 10), stage III/IV patients on surveillance after planned completion of ICI therapy for metastatic disease. RESULTS: In cohort A, compared to molecular residual disease (MRD)-negative patients, MRD-positivity was associated with significantly shorter distant metastasis-free survival (DMFS; hazard ratio [HR], 10.77; p = .01). Increasing ctDNA levels from the post-surgical or pre-treatment time point to after 6 weeks of ICI were predictive of shorter DMFS in cohort A (HR, 34.54; p < .0001) and shorter progression-free survival (PFS) in cohort B (HR, 22; p = .006). In cohort C, all ctDNA-negative patients remained progression-free for a median follow-up of 14.67 months, whereas ctDNA-positive patients experienced disease progression. CONCLUSION: Personalized and tumor-informed longitudinal ctDNA monitoring is a valuable prognostic and predictive tool that may be used throughout the clinical course of patients with advanced melanoma.

Validation of PRKCB Immunohistochemistry as a Biomarker for the Diagnosis of Ewing Sarcoma.

Background: Ewing sarcoma (ES) can be confirmed by identifying the EWSR1-FLI1 fusion transcript. This study is to investigate whether immunostaining (IHC) of PRKCB-a protein directly regulated by EWSR1-FLI1 is a surrogate maker for diagnosing ES in routine practice. Methods: Microarray gene expression analyses were conducted. RKCB IHC was applied to 69 ES confirmed by morphology and molecular methods, and 41 non-Ewing small round cell tumors. EWSR1 rearrangement, EWSR1-FLI1 fusion or t(11;22)(q24;q12) were identified by fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, or cytogenetic analysis, respectively. Results: Gene array analyses showed significant overexpression of the PRKCB in ES. PRKCB IHC was positive in 19 cases of ES with EWSR1-FLI1 fusion, 3 cases with cytogenetic 11:22 translocation and 59 cases with EWSR1 rearrangement while negative in only one EWSR1 rearranged case. PRKCB IHC is sensitive (98%) and specific (96%) in detecting EWSR1 rearranged ES. Conclusions: PRKCB is a reliable antibody for diagnosing ES in routine practice.

Overexpression of Vascular Endothelial Growth Factor A in Invasive Micropapillary Colorectal Carcinoma.

BACKGROUND: Invasive micropapillary carcinoma (IMPC) is a rare variant of colorectal cancer with an adverse prognosis. "Retraction artifact" around tumor cells is a feature of IMPC. The aim of this study was to assess the nature of the retractions around the tumor cells and to describe the histopathological features of a group of 18 cases of IMPC. METHODS: A pathology review of 128 consecutive colorectal cancers identified 18 cases of histologically proven IMPC using 5% of the total tumor volume comprised of a micropapillary component as the diagnostic criterion. Immunostains for D2-40, CD31, CD34, vascular endothelial growth factor A (VEGF-A), and mucin 1 (MUC-1) were performed using the avidin-biotin complex method. RESULTS: Cases of IMPC were characterized by pseudomicropapillae surrounded by lacunar-like clear spaces. These structures exhibited the inside-out growth pattern as highlighted by MUC-1 staining. The lining of the lacunar spaces was immunoreactive to CD31 but not CD34 or D2-40, indicating that they are neovascular structures. Furthermore, the tumor cells strongly and diffusely expressed VEGF-A. CONCLUSIONS: The strong coexpression of VEGF-A and CD31 suggests a prominent role of neoangiogenesis in these tumors.

Histopathological and immunophenotypical features of intestinal-type adenocarcinoma of the gallbladder and its precursors.

BACKGROUND: Intestinal-type adenocarcinoma of the gallbladder is an unusual malignancy associated with low- and high-grade intraepithelial neoplasms. The literature on the clinicopathologic characteristics of the precursor lesions of gallbladder cancer is limited, due in part to the variability in its definition and terminology. METHODS: Here we report one case of intestinal-type adenocarcinoma of the gallbladder with distinctive morphology and associated precursor lesions. All of the hematoxylin and eosin stained slides were reviewed. Immunostains were performed using the avidin-biotin complex method for CK20, CK7, CDX2, MUC1, MUC2, and MUC-5AC. We also reviewed the literature discussing the current terminology from the World Health Organization for these lesions. RESULTS: A 70-year-old man presented with epigastric abdominal pain and bloating. Computed tomography demonstrated a large heterogeneous gallbladder mass. Macroscopically, the gallbladder was 7.5 x 5.5 x 4.5 cm with smooth serosa. The lumen was occupied by a 5.0 x 4.5 x 3.0 cm irregular friable exophytic mass. The remaining mucosa had a tan brown to pink color with granular/papillary excrescences of up to 0.7 cm in thickness. Histologically, the tubulopapillary adenoma was lined by pseudostratified columnar epithelium with low and extensive high-grade dysplasia. Goblet cell and cystic dilatation were present in some glands. Immunohistochemistry showed that the intestinal type was positive for CK20, CK7, and CDX2, focally positive for MUC1/2, and negative for MUC-5AC. CONCLUSION: This case showed the complete spectrum of the progression of intestinal-type intracholecystic papillary-tubular neoplasms of the gallbladder.

Pathology of Seminoma Coinciding With Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia.

We present the case of a 71-year-old male with an incidental diagnosis of seminoma coinciding with small lymphocytic lymphoma/chronic lymphocytic leukemia in the retroperitoneum. This case report illustrates the cytology, histology, immunohistochemistry, flow cytometry, and fluorescence in situ hybridization features of this exceptional case and sheds light on the importance of a collaborative multidisciplinary team in delivering quality patient care.

RRM1, ERCC1 and TS1 Immunofluorescence Expression in Leiomyosarcoma: A Tissue Microarray Study with Clinical Outcome Correlation Analysis.

UNLABELLED: ERCC1, RRM1 and TS1 are reportedly linked to chemotherapy resistance in lung and other cancers. However, there are currently no studies reporting the relationship between these genes and clinical parameters in leiomyosarcomas. METHOD: This study investigated the expression pattern of ERCC1, RRM1 and TS1 in forty-four leiomyosarcoma samples by the use of tissue microarray (TMA), immunofluorescence and AQUA methods. The results were then analyzed for expression level and correlations were made with clinical outcome to determine their potential prognostic value in leiomyosarcoma. RESULTS: In the forty-four samples studied, the expression level of these three proteins can be well quantified in the AQUA system and reflected by the AQUA score. RRM1 and ERCC1 expression levels did not show any relationship with overall survival. However, a correlation was found between TS1 expression in the cytoplasm and overall survival. The high expression group had a shorter overall survival time (log-rank p = 0.0498). This trend was confirmed by the Cox proportional hazards model. DISCUSSION: The poor overall survival of leiomyosarcoma is linked to TS1 cytoplasm expression which may be useful in predicting prognoses of this tumor, methods targeting expression of TS1 may lead to improved overall survival in leiomyosarcoma, though more detailed information regarding treatment information and a larger sample size is needed to confirm this phenomenon.

Epstein-Barr virus positive inflammatory pseudotumor of the liver: report of a challenging case and review of the literature.

Inflammatory pseudotumor (IPT) is an uncommon, benign lesion of unclear etiology, which is sometimes associated with Epstein-Barr virus (EBV). In this study, we discuss a case of hepatic EBV positive IPT and discuss mimickers, prognosis, and treatment. The case we describe was located in the liver and composed of a mixture of spindle cells and polymorphic inflammatory cells with areas of necrosis. The spindle cells were negative for CAM5.2, ALK1, CD21, CD23, CD35, actin, S-100, and CD34. EBV-encoded small RNA in situ hybridization showed a large number of EBV positive cells. The diagnosis of hepatic EBV positive IPT with uncertain biological behavior was issued, presenting numerous difficulties with diagnostic and therapeutic challenges.