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Objectives Cerebral hyaline protoplasmic astrocytopathy (HPA) is a clinicopathologic entity characterized by eosinophilic cytoplasmic inclusions within astrocytes. It has been observed in a subset of patients with early-onset epilepsy, brain malformations, and developmental delay. The exact association of this entity with epilepsy is still unknown. This report, with its review of the literature, aims to summarize HPA features to raise awareness regarding this entity. Methods We report on 2 HPA cases and critically review the literature. Results Approximately 42 cases of HPA have been reported, including the 2 cases presented here, consisting of 23 female and 19 male patients. Patient age ranged from 3 to 39 years. All patients had early-onset seizures (3-20 months of age), ranging from partial to generalized, that were refractory despite treatment with antiepileptic drugs. Postoperative follow-up intervals ranged from 2 to 93 months, and the clinical outcome was graded according to the Engel classification, showing variable results. Conclusions Clinicians should consider HPA in differential diagnosis in patients with intractable seizures, especially when they are associated with developmental delay and brain malformations. Increasing awareness of this entity among pathologists may promote better understanding of this condition as well as better diagnosis and treatment for these patients.

Cerebellar liponeurocytoma (CL) is an unusual tumor, histologically composed of a mixture of small to medium-sized, rounded neurocytic cells and a variable lipomatous component. Although CL was originally considered as a subtype of medulloblastoma, subsequent molecular studies demonstrated that this tumor was a distinct entity, exhibiting the tumor protein p53 gene (TP53) missense mutations in 20% of cases, chromosome 17 deletion, and the absence of mutations in the adenomatous polyposis coli gene (APC), the protein patched homolog gene (PTCH), the kinase insert domain receptor gene (KDR), and the β-catenin gene (CTNNB). Apart from these molecular features, little is known about the pathogenesis and the genetic landscape of CL to date. In order to characterize the mutational landscape of CL and identify alterations that are driving tumorigenesis, we report a series of three cases, including one recurrent tumor, analysed by next-generation sequencing (NGS), which identified a total of 22 variants, of which four were missense mutations, nine were synonymous variants, and nine were located on intronic regions. In particular, DNA sequencing identified missense mutations in APC, KDR, and TP53 that could be implicated in promoting tumor progression and angiogenesis of CL. Furthermore, the NGS analysis revealed that recurrent CL did not have additional genetic changes compared with the primary tumor. Moreover, the high frequencies of detected mutations suggested that the identified alterations are germline variants. Indeed, an additional NGS on the genomic DNA obtained from one of the three patients confirmed the presence of the variants in the germline DNA. In conclusion, the obtained data support the hypothesis that CL is a distinct pathological entity that does not show specific somatic alterations driving tumorigenesis.

Neoplastic cells acquire the ability to proliferate endlessly by maintaining telomeres via telomerase, or alternative lengthening of telomeres (ALT). The role of telomere maintenance in pituitary neuroendocrine tumors (PitNETs) has yet to be thoroughly investigated. We analyzed surgical samples of 24 adult recurrent PitNETs (including onset and relapses for 14 of them) and 12 pediatric primary PitNETs. The presence of ALT was assessed using telomere-specific fluorescence in situ hybridization, methylation of telomerase reverse transcriptase promoter (TERTp) by methylation-specific PCR, and ATRX expression by immunohistochemistry. Among the adult recurrent PitNETs, we identified 3/24 (12.5%) ALT-positive cases. ALT was present from the onset and maintained in subsequent relapses, suggesting that this mechanism occurs early in tumorigenesis and is stable during progression. ATRX loss was only seen in one ALT-positive case. Noteworthy, ALT was observed in 3 out of 5 aggressive PitNETs, including two aggressive corticotroph tumors, eventually leading to patient's death. ALT-negative tumors (87.5%) were classified according to their low (29.2%), medium (50%), and high (8.3%) telomere fluorescence intensity, with no significant differences emerging in their molecular, clinical, or pathological characteristics. TERTp methylation was found in 6/24 cases (25%), with a total concordance in methylation status between onset and recurrences, suggesting that this mechanism remains stable throughout disease progression. TERTp methylation did not influence telomere length. In the pediatric cohort of PitNETs, TERTp methylation was also observed in 4/12 cases (33.3%), but no case of ALT activation was observed. In conclusion, ALT is triggered at onset and maintained during tumor progression in a subset of adult PitNETs, suggesting that it could be used for clinical purposes, as a potential predictor of aggressive behavior.

Aim Diffuse midline glioma (DMG) H3 K27M-mutant is a specific entity that, as the name indicates, tends to occur in midline structures including the thalamus, brainstem, and spinal cord. DMG predominates in children, is an aggressive tumor with poor prognosis, and is considered a WHO grade IV tumor regardless of histological features. The exact frequency of these mutations in adults diagnosed with glioma in the midline is unknown. Materials and methods We report a series of 6 more adult cases, and we critically review the current literature on adults with DMG H3 K27M-mutant. Results There were 5 males and 1 female. The age ranged from 26 to 52 years (median 39 years). All cases showed astrocytic differentiation, with positive staining for H3 K27M protein, and loss of H3 K27me in the tumor cells confirming the diagnosis. Conclusion H3 K27M-mutant midline glioma can occur in adults, affecting midline structures. Increasing awareness of the reporting pathologists of this entity might help in a better determination of the frequency of mutant DMG in adults as well as better diagnosis and patient counseling of the outcome.

BackgroundAngiogenesis is mandatory for tumor growth and progression. The modest response to the anti-angiogenic therapies in non-small cell lung cancer reflects the presence of confounding molecular factors. The aims of this study were to investigate the expression levels of VEGF-A, CD31 and GRP78 and test for significant correlations between them.MethodsParaffin-embedded NSCLC tissue samples (71 adenocarcinoma and 23 squamous cell carcinoma) were retrospectively collected from 94 patients who underwent surgical resection between 2008 and 2015; and did not receive chemotherapy or radiotherapy prior to surgery. The expressions of VEGF-A, CD31 and GRP78 were determined by immunohistochemistry. ResultsHigh expression levels of VEGF-A, CD31 and GRP78 were observed in 15, 36 and 74 cases, respectively. Adenocarcinomas expressed higher levels of the aforementioned proteins as compared with squamous cell carcinomas (p-value < 0.05). Moreover, a statistically significant association was found between VEGF-A and CD31 expression levels (p-value = 0.006).ConclusionsOur study was the first to investigate the associations between GRP78 and the angiogenesis markers CD31 and VEGF-A in NSCLC patients. High GRP78 expression was revealed in the majority of the investigated samples. Nevertheless, no relationship was found between GRP78 and VEGF-A or CD31 which could be attributed to small sample size. On the other hand, the positive association between VEGF-A and CD31 expression levels suggests that VEGF-A may cooperate with CD31 to promote angiogenesis in NSCLC.

INTRODUCTION Pediatric brain tumors (PBT) represent the second most common pediatric cancer, with the highest mortality rate among childhood malignancies. Improvement of PBT diagnostic accuracy is fundamental to optimize treatment strategy. OBJECTIVES: We aimed to explore the impact of DNA methylation arrays implementation in PBT clinical practice. METHODS 214 PBT were analyzed by Illumina 850KEPICmethylation array. Low score and discordant cases were collegially reviewed. RESULTS Calibrated score was 0.8 or higher in 159 cases (74.3%), with pathological diagnosis confirmation in 132 cases and molecular subgroup definition in 47 of them, including cases of medulloblastoma, CNS neuroblastoma FOXR2, HGNET MN1; methylation profiling amended diagnosis in 10 cases, e.g. HGNET BCOR and anaplastic PXA, was non-contributory in 4 and misleading in 12 cases, including glioneural tumors and tumors arising in syndromic contexts. Calibrated score ranged between 0.8 and 0.3 in 37 cases (17.3%) and was below 0,3 (no match) in 18 cases (8.4%). Calibrated score below 0,8 was more frequently assigned to low grade gliomas and low grade glioneural tumors (p CONCLUSION Methylation profiling refine on diagnostic accuracy in PBT classification. Improvements are needed in classifying low grade glioma/glioneuronal tumors and challenging/very rare PBT. In syndromic cases, there is a high rate of misleading profiles and/or low scores.

TMPRSS2/ERG fusion was found to be the most common genetic event in prostate adenocarcinoma. There is a strong correlation between the fusion and ERG-positive immunostaining. Many studies showed racial variation in ERG expression in prostate cancer patients. There is no data however on the rate of ERG-positive cancer in Jordanian or Arab population. We evaluated the frequency and the significance of ERG fusion in Jordanian-Arab population using immunohistochemistry for ERG. The cohort included 193 prostate cancer specimens: 109 needle core biopsies, 45 radical prostatectomies, 37 transurethral resections of prostate, and 2 enucleation specimens. We found ERG reactivity in 64 (33.2%) of evaluated cases. The observed ERG frequency in the Jordanian-Arab population is lower than the one documented in North America, but it is higher than in Asian patient cohorts. The ERG positivity was significantly associated with lower baseline prostate-specific antigen but was unrelated to patient age, Gleason Score, or the novel Gleason Grade Groups. In the 45 prostatectomy cases, ERG did not correlate with the pathologic stage, margin, nodal status, and the biochemical recurrence, and it did not appear to represent an important prognosticator.

e20500 Background: Neovascularization is essential for the growth and progression of tumor tissues. GRP78 is frequently overexpressed in various types of cancers and has been suggested as a proangiogenic factor. Methods: In order to evaluate GRP78 expression and its role in angiogenesis of non-small cell lung cancer (NSCLC), paraffin-embedded NSCLC tissue samples (66 adenocarcinoma and 24 squamous cell carcinoma) were retrospectively collected from 90 patients who underwent surgical resection between 2008 and 2015; and did not receive chemotherapy or radiotherapy prior to surgery. Then we performed immunohistochemistry to examine GRP78 expression and we analyzed the relationships between GRP78 and the angiogenesis marker VEGF-A and the microvessel density marker (MVD) CD31. Additionally, we analyzed the association of GRP78 with clinicopathological characteristics of the patients. Results: Strong GRP78 expression was evident in about 86% of the tumor tissues (77/90). There was significant difference in GRP78 expression between poorly-differentiated and well-differentiated tumors (OR = 0.023, 95% CI = 0.001-0.419, p = 0.011). Moreover, there was a statistically significant association between VEGF-A and CD31 (χ² = 12.00, p = 0.001). Indeed, CD31 and VEGF-A expression significantly associated with histological type. Among the tissues expressing high CD31, approximately 86% of them were adenocarcinoma (χ² = 5.009, p = 0.025); and among the tissues expressing positive VEGF-A, about 79% were adenocarcinoma tissues (χ² = 6.545, p = 0.021). Conclusions: Strong GRP78 may be related to good prognosis of NSCLC. Nevertheless, further studies investigating large number of samples of all histological subtypes are required.