Jesse Kresak

Increased proportion of FoxP3+ regulatory T cells in tumor infiltrating lymphocytes is associated with tumor recurrence and reduced survival in patients with glioblastoma.

Glioblastoma multiforme (GBM) is an aggressive malignancy associated with profound host immunosuppression mediated in part by FoxP3 expressing regulatory CD4+ T lymphocytes (Tregs) that down-regulate anti-tumor immunity. In order to assess whether FoxP3 was an independent driver differentially expressed in primary versus recurrent GBMs, we stained resected primary and recurrent GBM tumors for CD3, CD4, CD8 and FoxP3 expression using standard immunohistochemistry. Slides were scanned with a high-resolution scanner (ScanScope CS; Aperio), and image analysis software (Aperio ScanScope) was used to enumerate lymphocyte subpopulations allowing for high-throughput analysis and bypassing manual selection bias. As shown in previous studies, enumeration of individual lymphocyte populations did not correlate with clinical outcomes in patients with GBM. However, the CD4+ to regulatory FoxP3+ T cell ratio was diminished in recurrent disease, and increased CD3 and CD8+ to regulatory T cell ratios showed a positive correlation with survival outcomes in primary GBM. These results suggest that while absolute numbers of tumor infiltrating lymphocytes may not be informative for predicting clinical outcomes in patients with GBM, the effective balance of CD3, CD4 and CD8+ T cells to immunosuppressive FoxP3+ regulatory cells may influence clinical outcomes in this patient population.

Neurofibromatosis: A Review of NF1, NF2, and Schwannomatosis.

The neurofibromatoses are a heterogeneous group of hereditary cancer syndromes that lead to tumors of the central and peripheral nervous systems, as well as other organ systems. By far the most common form is neurofibromatosis 1 (96%), followed by neurofibromatosis 2 (3%), and a more recently recognized, lesser known form, schwannomatosis. The diagnostic criteria, pathogenesis, molecular considerations, and clinical manifestations are discussed in this review article.

FGFR1 N546K and H3F3A K27M mutations in a diffuse leptomeningeal tumour with glial and neuronal markers

1. Lee W, Teckie S, Wiesner T et al. PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nat. Genet. 2014; 46; 1227–1232. 2. De Raedt T, Beert E, Pasmant E et al. PRC2 loss amplifies Rasdriven transcription and confers sensitivity to BRD4-based therapies. Nature 2014; 514; 247–251. 3. Zhang M, Wang Y, Jones S et al. Somatic mutations of SUZ12 in malignant peripheral nerve sheath tumors. Nat. Genet. 2014; 46; 1170–1172. 4. Schaefer IM, Fletcher CD, Hornick JL. Loss of H3K27 trimethylation distinguishes malignant peripheral nerve sheath tumors from histologic mimics. Mod. Pathol. 2016; 29; 4–13. 5. Prieto-Granada CN, Wiesner T, Messina JL et al. Loss of H3K27me3 expression is a highly sensitive marker for sporadic and radiationinduced MPNST. Am. J. Surg. Pathol. 2016; 40; 479–489. 6. Plath K, Fang J, Mlynarczyk-Evans SK et al. Role of histone H3 lysine 27 methylation in X inactivation. Science 2003; 300; 131–135.

Duodenal gangliocytic paraganglioma: A case report and literature review

Highlights • Differentiation between GP and GIST alters treatment algorithms.• Primary management of duodenal GP consists of resection with negative margins.• Surveillance alone is safe and effective following resection with negative margins.• For regionally advanced disease, consider adjuvant radiotherapy.

Nitrous Oxide Abuse and Vitamin B12 Action in a 20-Year-Old Woman: A Case Report

Herein, we report a case of a 20-year-old (ethnicity not reported) woman with a history of nitrous oxide abuse and clinical symptoms consistent with spinal cord subacute combined degeneration with associated low serum concentrations of vitamin B12, elevated methylmalonic acid levels, and radiologic evidence of demyelination of the dorsal region of the spinal column. The health of the patient improved dramatically with B12 supplementation. In this case, we discuss the interaction of nitrous oxide with the enzymatic pathways involved in the biochemistry of vitamin B12.

Embryonal tumor with multilayered rosettes of the fourth ventricle: case report

Embryonal tumor with multilayered rosettes (ETMR) is a recently described pathological entity. These primitive central nervous system tumors harbor amplification of the 19q13.42 locus and resultant overexpression of the LIN28A protein. Although the WHO currently recognizes 3 distinct histopathological entities-embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, and medulloepithelioma-recent studies indicate that these tumors have a common molecular profile and clinical course and that they are now classified as a single entity. Here the authors present a case of ETMR located in the fourth ventricle in a 12-month-old boy. The histopathology featured areas of neuropil-like stroma and highly cellular foci with characteristic multilayered rosettes. The authors discuss the clinical, radiological, and histopathological findings in this case and compare them with data in previously published cases in the literature. A review of studies assessing the molecular mechanisms underlying these tumors is also presented.

Liver Cell Dysplasia and the Development of HCC

Hepatocellular carcinoma (HCC) is the fifth most common cancer and second leading cause of cancer-related death worldwide [1–4]. Due to a lack of specific symptomatology, HCC is most often diagnosed at an advanced stage leading to limited treatment options and a dismal prognosis [5]. Studies have shown that, when compared to smaller tumors, cure rates for HCC larger than 2 cm decrease and curative treatment become even less likely for lesions larger than 3 cm [6]. Therefore, the ability to identify the precursor lesions at an earlier stage in which resection and cure are still possible has received increased attention in recent years [2, 5, 7].

Analysis of immunobiologic markers in primary and recurrent glioblastoma

Glioblastoma (GBM) generates a varied immune response and understanding the immune microenvironment may lead to novel immunotherapy treatments modalities. The goal of this study was to evaluate the expression of immunologic markers of potential clinical significance in primary versus recurrent GBM and assess the relationship between these markers and molecular characteristics of GBM. Human GBM samples were evaluated and analyzed with immunohistochemistry for multiple immunobiologic markers (CD3, CD8, FoxP3, CD68, CD163, PD1, PDL1, CTLA4, CD70). Immunoreactivity was analyzed using Aperio software. Degree of strong positive immunoreactivity within the tumor was compared to patient and tumor characteristics including age, gender, MGMT promoter methylation status, and ATRX, p53, and IDH1 mutation status. Additionally, the TCGA database was used to perform similar analysis of these factors in GBM using RNA-seq by expectation–maximization. Using odds ratios, IDH1 mutated GBM had statistically significant decreased expression of CD163 and CD70 and a trend for decreased PD1, CTLA4, and Foxp3. ATRX-mutated GBMs exhibited statistically significant increased CD3 immunoreactivity, while those with p53 mutations were found to have significantly increased CTLA4 immunoreactivity. The odds of having strong CD8 and CD68 reactivity was significantly less in MGMT methylated tumors. No significant difference was identified in any immune marker between the primary and recurrent GBM, nor was a significant change in immunoreactivity identified among age intervals. TCGA analysis corroborated findings related to the differential immune profile of IDH1 mutant, p53 mutant, and MGMT unmethylated tumors. Immunobiologic markers have greater association with the molecular characteristics of the tumor than with primary/recurrent status or age.

Granulomatous meningitis secondary to Avitene (microfibrillar collagen)

Avitene, generically termed microfibrillar collagen, is a surgical hemostatic agent. Collagen-based hemostats are widely used to trigger platelet aggregation and reinforce the fibrin clot. Rarely, Avitene has been reported to induce a granulomatous reaction in the CNS, usually as a mass-forming lesion known as a textiloma. We report a case of Avitene-induced granulomatous inflammation presenting as meningitis after neurosurgery for WHO grade II atypical meningioma.

Pathology Residents Comprise Inspection Team for a CAP Self-Inspection

We report our experience at the University of Florida in which residents and fellows served as the inspection team for a College of American Pathologists (CAP) self-inspection. We aimed to determine whether the CAP self-inspection could serve as a learning opportunity for pathology residents and fellows. To prepare for the inspection, we provided a series of 4 lunchtime seminars covering numerous laboratory management topics relating to inspections and laboratory quality. Preparation for the inspection began approximately 4 months prior to the date of the inspection. The intent was to simulate a CAP peer inspection, with the exception that the date was announced. The associate residency program director served as the team leader. All residents and fellows completed inspector training provided by CAP, and the team leader completed the team leader training. A 20 question pre- and posttest was administered; additionally, an anonymous survey was given after the inspection. The residents’ and fellows’ posttest scores were an average of 15% higher than on the pretest (P < .01). The surveys as well as subjective comments were overwhelmingly positive. In conclusion, the resident’s and fellow’s experience as an inspector during a CAP self-inspection was a useful tool to learn accreditation and laboratory management.