DNA Damage Repair Profiles Alteration Characterize a Hepatocellular Carcinoma Subtype With Unique Molecular and Clinicopathologic Features

Hepatocellular carcinoma (HCC) is one of the most common malignancies and displays high heterogeneity of molecular phenotypes. We investigated DNA damage repair (DDR) alterations in HCC by integrating multi-omics data. HCC patients were classified into two heterogeneous subtypes with distinct clinical and molecular features: the DDR-activated subtype and the DDR-suppressed subtype. The DDR-activated subgroup is characterized by inferior prognosis and clinicopathological features that result in aggressive clinical behavior. Tumors of the DDR-suppressed class, which have distinct clinical and molecular characteristics, tend to have superior survival. A DDR subtype signature was ultimately generated to enable HCC DDR classification, and the results were confirmed by using multi-layer date cohorts. Furthermore, immune profiles and immunotherapy responses are also different between the two DDR subtypes. Altogether, this study illustrates the DDR heterogeneity of HCCs and is helpful to the understanding of personalized clinicopathological and molecular mechanisms responsible for unique tumor DDR profiles.

Clinicopathological and Molecular Analysis of 45 Cases of Pure Mucinous Breast Cancer

Pure mucinous breast carcinoma (PMBC) is characterized by clusters of tumor cells floating in abundant extracellular mucin and can be classified into paucicellular (Type A) and hypercellular (Type B) subtypes. However, the clinicopathological and genomic differences between these two subtypes have not been well characterized. We retrospectively investigated the clinicopathologic features of 45 cases of surgically removed PMBC (31 Type A and 14 Type B). We also performed whole-exome sequencing (WES) in eight cases of PMBC. We found that Type B PMBC occurs at an older age and shows more aggressive clinical behavior than Type A. WES analysis revealed that HYDIN was the most frequently mutated gene in both types of PMBC. Although Type B PMBC showed a tendency toward more frequent genetic alterations, there were no statistically significant differences between the two subtypes in single nucleotide variants or insertions or deletions of bases associated with moderate or high effects. Our results provide additional evidence that PMBCs are clinicopathologically and genetically heterogeneous and lack pathognomonic genetic alterations. Further, Type B PMBC is more frequently associated with lymph node metastasis than Type A.

Cancer of Unknown Primary: Challenges and Progress in Clinical Management

Distant metastases are the main cause of cancer-related deaths in patients with advanced tumors. A standard diagnostic workup usually contains the identification of the tissue-of-origin of metastatic tumors, although under certain circumstances, it remains elusive. This disease setting is defined as cancer of unknown primary (CUP). Accounting for approximately 3–5% of all cancer diagnoses, CUPs are characterized by an aggressive clinical behavior and represent a real therapeutic challenge. The lack of determination of a tissue of origin precludes CUP patients from specific evidence-based therapeutic options or access to clinical trial, which significantly impacts their life expectancy. In the era of precision medicine, it is essential to characterize CUP molecular features, including the expression profile of non-coding RNAs, to improve our understanding of CUP biology and identify novel therapeutic strategies. This review article sheds light on this enigmatic disease by summarizing the current knowledge on CUPs focusing on recent discoveries and emerging diagnostic strategies.

Chondromyxoid Fibroma-Like Osteosarcoma in a 13 Years Old Girl: A Report of a New Case

Osteosarcoma (OS) is the most common primary non hematopoietic malignant tumor of bone with a strict histologic definition: the presence of unequivocal osteoid produced by neoplastic cells. Rare variants displaying low-grade histological features have been described; among which chondromyxoid fibroma-like (CMF-OS) is the rarest. However, despite its bland morphology; CMF-like OS has an aggressive clinical behavior and a poor prognosis. To the best of our knowledge, only 3 cases of CMF-OS have been previously reported in children. Because of its atypicality and scarcity; misdiagnosis is more likely to occur. Herein we describe a new case of CMF-OS in a 13 years old girl with fatal outcome. Diagnosis was based on focal malignant bone formation and correlation with imaging studies. The aim of the present case presentation is to raise awareness of this rare entity and to highlight the challenging diagnosis

DIPG-25. KETOGENIC DIET IN DIFFUSE INTRINSIC PONTINE GLIOMA IN CHILDREN: A RETROSPECTIVE STUDY INVESTIGATING THE FEASIBILITY

PURPOSE Diffuse Intrinsic Pontine Glioma (DIPG) is one of the most devastating diseases amongst children with cancer, thus novel strategies are urgently needed. We aimed to retrospectively evaluate the feasibility of the carbohydrate restricted ketogenic diet (KD) in DIPG patients. METHODS Searches of MEDLINE and Embase identified four publications meeting the inclusion criteria (diagnosis of DIPG and exposition to a KD ≥ 3 months). One additional case was identified by contact with experts. The minimal feasibility criteria were defined as the ability to use the KD for ≥ 3 months. Individual patient data were extracted from the publications or obtained from investigators. RESULTS Five patients (males, n=3; median age 4.4 years; range, 2.5–17 years) met the inclusion criteria (one patient – identified and not included - was on KD < 3 months due to disease progression). Further feasibility analyses showed a duration of the KD of ≥ 3 months and less than 7 months (n=2), > 7 months and less than 1 year (n= 2), and two years (n=1), respectively. CONCLUSION These results – based on a small patient population – suggest that the KD appears to be a feasible treatment option for children with DIPG. The potential duration of the KD is limited by the aggressive clinical behavior of DIPG. The safety analysis is currently being retrospectively assessed. These data should encourage further studies on a larger scale; ideally assessing the impact of the KD in DIPG patients in a randomized controlled trial.

Esophageal Rhabdoid-Like Tumor: A Rare Disease With Aggressive Clinical Behavior

Background: Malignant rhabdoid tumor is a kidney childhood tumor with aggressive clinical behavior and a wide spectrum of histologic, immunophenotypic, and cytogenetic findings. Extra-renal rhabdoid tumors have been reported in the brain, breast, liver, pancreas, bladder, vulva, prostate, and colon. To date, only nine cases of esophageal rhabdoid tumors have been described, all in patients over 50-year old. We add to the current literature the case of an esophageal, poorly differentiated rhabdoid tumor occurring in a young man.Case Report: A 24-year-old man was referred for progressive dysphagia, retrosternal pain, nausea, and food regurgitation. Esophagogastroduodenoscopy showed an obstructing neoplastic lesion of the distal esophagus associated with Barrett's esophagus. Biopsies revealed undifferentiated esophageal cancer with epithelial morphology and immunohistochemistry positive for CK pan, CK 7 e CK 8-18. Minimally invasive esophagectomy and extended lymphadenectomy was performed. Histopathology showed a poorly differentiated tumor, with morphologic characteristics of rhabdoid tumor, central necrosis and transmural infiltration of the esophageal wall. Definitive immunohistochemistry was positive for vimentin, CD34, synaptophysin, and INI1.Conclusion: Esophageal rhabdoid tumor is extremely rare and highly aggressive, with only few patients alive at 1 year follow-up, according to our review. Immunohistochemistry characterization is critical for diagnosis. Minimally invasive esophagectomy is an appealing and possibly less morbid option compared to open surgery. However, further research is needed to investigate the potential role of targeted immunotherapy.

BAP1-Mutated Clear Cell Renal Cell Carcinoma

Objectives While aberrations in the VHL gene and chromosome 3p resulting in clear cell renal cell carcinoma (CCRCC) are well established, we know that additional mutations in chromatin remodeling genes PBRM1, SETD2, and BRCA1-associated protein 1 (BAP1) contribute to pathogenesis in some cases. Given the known aggressive clinical behavior of BAP1-mutated CCRCC, we sought to define the pathologic phenotype of BAP1-mutated CCRCC. Methods We identified 14 cases of molecularly proven BAP1-mutated CCRCC and investigated their clinicopathologic features. Results BAP1-mutated CCRCC frequently showed papillary, tubulopapillary, or expanded nested architecture; demonstrated granular to diffusely eosinophilic cytoplasm with prominent eosinophilic globules; and contained high-grade nuclei. This morphology demonstrates significant overlap with Xp11 translocation renal cell carcinoma (RCC). Immunohistochemistry notably demonstrates loss of BAP1 expression in almost all tumors, in addition to strong p504S expression. A conventional CCRCC component was frequently present adjacent to the characteristic BAP1 areas and showed retained BAP1 expression and only patchy p504S. Approximately two-thirds of BAP1-mutated CCRCCs were stage pT3, renal vein invasion was common, and 50% developed metastases. Conclusions Herein, we describe the histologic and immunohistochemical findings in BAP1-mutated CCRCC, which has important implications for utilization of molecular testing, prognosis, future therapeutics, and distinction from other RCC subtypes such as Xp11 translocation RCC.

CK20 and CK5/6 Immunohistochemical Staining of Urothelial Neoplasms: A Perspective

Cytokeratins belong to the family of intermediate filaments. They are expressed in a highly specific manner in epithelial cells where they play a crucial role in the integrity and mechanical stability of the cells. Several types of cytokeratins have been described in normal as well as neoplastic urothelium. In the case of urothelial neoplasms expression of CK20 and CK5/6 has been shown in several studies to have diagnostic and prognostic implications. Thus, low-grade urothelial carcinoma manifests CK expression limited to the umbrella cells, while high-grade tumors usually have an expression in the entire thickness of the urothelium except for the basal layer. CK5/6 expression on the other hand is expressed in the basal cells in all low-grade and some high-grade urothelial carcinomas. Diffuse CK20 staining accompanied by loss of CK5/6-positive basal layer is usually associated with aggressive clinical behavior. Double staining of the slides for these cytokeratins may facilitate proper interpretation and correlation.