Soo-Yong Tan

Complete Tumor Response Following Intratumoral 32P BioSilicon on Human Hepatocellular and Pancreatic Carcinoma Xenografts in Nude Mice

Purpose:32P BioSilicon is a new, implantable, radiological medical device that comprises particles of highly pure silicon encapsulating 32phosphorus (32P) for the treatment of unresectable solid tumors. Prior to administration, the device particles are suspended in a formulant which provides an even suspension of the intended dose for implantation. The primary objective of this animal trial study was to investigate the effects of intratumoral injection of 32P BioSilicon on human hepatocellular (HepG2) and pancreatic carcinoma (2119) xenografts implanted in nude mice (BALB/c). A secondary objective was the histopathologic examination of the tumor foci and surrounding tissue during the study. Methods: Cultured human carcinoma cells (HepG2 and 2119) were injected s.c. into the gluteal region of nude mice. When the implanted tumors were ∼1 cm in diameter, 32P BioSilicon (0.5, 1.0, and 2.0 MBq) or formulant was injected into the tumors. Implanted tumor size was measured once a week for 10 weeks. At study termination, the tumor and surrounding normal tissue were collected and fixed in 10% formalin and processed for histopathologic analysis. Results:32P BioSilicon produced a reduction in HepG2 tumor volume when compared with formulant control, and complete response was observed among tumors in the 1.0 and 2.0 MBq treatment groups after week 8. There was also significant reduction in 2119 tumor volume in all treated groups, with the complete response rate of 67% in the 2.0 MBq group. Conclusion:32P BioSilicon suppressed the growth of both human hepatocellular and pancreatic carcinoma xenografts implanted in nude mice and complete responses were also observed in tumors at higher radiation doses.

Clinical and testing protocols for the analysis of epidermal growth factor receptor mutations in East Asian patients with non-small cell lung cancer: a combined clinical-molecular pathological approach

Background: Several randomized phase III studies in advanced stage non-small cell lung cancer (NSCLC) confirmed the superior response rate and progression-free survival of using epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor as first-line therapy compared with chemotherapy in patients with activating EGFR mutations. Despite the need for EGFR mutation tests to guide first-line therapy in East Asian NSCLC, there are no current standard clinical and testing protocols. Methods: A consensus meeting was held involving expert oncologists, pulmonologists, and pathologists to discuss the current status and variations in EGFR mutation testing of NSCLC across Asia and to recommend a standard clinical and laboratory testing approach for future use. Results: Currently, EGFR mutation tests are only routinely performed in some East Asian countries and medical centers. The consensus recommendation was to perform the test in all newly diagnosed patients with advanced stage nonsquamous lung cancer and some squamous patients with clinical features associated with higher prevalence of EGFR mutations. To increase the sensitivity and specificity of the EGFR mutation tests, tissue acquisition and pretest sample evaluation are important steps in addition to standardization of the EGFR mutation test methodology. Conclusion: A standardized EGFR mutation testing protocol is an essential step toward realization of personalized medicine in East Asian NSCLC treatment.

Cardiac Structural Abnormalities Associated With IgG4-Related Coronary Periarteritis and Inflammation Revealed by Multimodality Imaging

A man presented with shortness of breath, and a globular heart was seen on a chest radiograph. An echocardiogram showed masses at the atrioventricular grooves. Computed tomography (CT) coronary angiography and fluorine-18 ((18)F) fluorodeoxyglucose positron emission tomography (FDG-PET)/CT confirmed coronary aneurysms with hypermetabolic perivascular masses at the coronary arteries and right internal iliac artery. Histologic features were highly suspicious for IgG4-related disease (IgG4-RD). IgG4-RD is a recently recognized fibroinflammatory condition, and FDG-PET/CT can provide information about the disease pattern, which may suggest IgG4-RD, as well as the optimal biopsy site.

Diagnosis of type II enteropathy-associated T-cell lymphoma should be limited to EBER-cases.

We read with interest the series of Type II enteropathy-associated T-cell lymphoma (EATL) by Tse et al. [1]. As this is a rare disease that is more commonly encountered in Asia, such an attempt to assemble cases from the region in order to define its clinicopathological features is laudable. Nevertheless, we would express some concern over the inclusion of three cases with extensive EBV encoded RNA (EBER) expression in the study. These cases were included because they were morphological mimics of Type II EATL, lacked angiocentricity, and showed clonal rearrangement of TCR gene. Similar cases have been documented to be of T-cell lineage by double labeling and T-cell clonality study [2]. In addition, the lack of features such as angiocentricity and necrosis does not exclude extranodal NK/T-cell lymphoma (ENKL) and this neoplasm may also include cases of both NK and Tcell origins [3,4]. EBER-positivity is characteristic of ENKL, both in cases with NK-lineage (the majority of cases) or T-cell lineage (around 10% of cases, but up to 27% has been reported) [5]. In contrast, the overwhelming majority of Type II EATL has been shown to be EBER2 [6–8] and isolated EBER1 cells in this neoplasm are in fact EBV-infected B-cells (Fig. 1). Type II EATL is a newly recognized entity that needs to be properly defined and understanding of this disease is being accumulated gradually with increasing experience. It would be prudent to keep this entity pure at this stage and limit it to EBER2 cases. The occasional EBER1 cases can be incorporated at a later stage when more evidence emerges to support its inclusion.

Expression of heparan sulfate in gastric carcinoma and its correlation with clinicopathological features and patient survival

Aim To determine the expression pattern and prognostic value of heparan sulfate in gastric cancer. Method The 10E4 antiheparan sulfate monoclonal antibody was used to examine the expression pattern of heparan sulfate in tissue microarrays consisting of 162 cases of gastric carcinoma by immunohistochemistry. The immunoreactivities of both epithelial and stromal components of the specimens were examined and analysed statistically for significant associations with clinicopathological parameters, including histological grade of the tumour, extent of cancer infiltration and presence of lymph-node metastases, lymphovascular invasion, perineural invasion, perforation of gastric wall and stromal reaction. The potential use of heparan sulfate as a predictive factor for patient survival was also evaluated. Results Reduced expression of heparan sulfate in the epithelial component was associated with higher histological grades of gastric cancer as well as the presence of more extensive tumour infiltration. Furthermore, this decrease in heparan sulfate expression was found to be predictive of reduced patient survival after tumour recurrence. Conclusion The data suggest that heparan sulfate may play an important role in regulating the biology of gastric cancer, and that it may be a useful prognostic marker of this tumour.

An algorithmic approach to the diagnosis of NK and T cell lymphomas.

Summary Lymphomas of natural killer (NK) and T cell lineages are uncommon disorders, although as a group they are more usually encountered in Asia compared to Western populations. In part due to their rarity, diagnosis and classification of T cell lymphomas often pose a challenge to clinicians and pathologists. Although there are morphological features that are characteristic of certain subtypes, correct classification of NK and T cell neoplasms relies heavily on the immunophenotype. With few exceptions, non-random genetic alterations such as translocations are less often seen in T cell neoplasms, adding to the diagnostic difficulty. Given these limitations, pathological diagnosis and classification of NK and T cell lymphomas are anything but straightforward. This paper attempts to present a practical algorithmic approach for the general pathologist who is confronted with these neoplasms.

Aberrant immunoarchitecture distinguishes hyperplastic germinal centres in pattern 1 angioimmunoblastic T‐cell lymphoma from reactive follicles

We compare 30 biopsies each of Pattern 1 angioimmunoblastic T‐cell lymphoma (AITL1) and reactive lymphoid hyperplasia (RLH) by immunohistology, in‐situ hybridization for Epstein‐Barr virus‐encoded RNA and T‐cell receptor‐γ (TRG)‐clonality. AITL1 cases, more often than RLH controls, were older [median ages 61 (range 23–79) vs 46 (range 11–59) years, p < 10‐4], non‐Chinese [16/30 (53%) vs 8/28 (29%), p = 0.035], presented nodally [29/30 (97%) vs 23/30 (77%), p = 0.024], showed: pan‐T cell antigen attenuation [25/29 (86%) vs 5/21 (24%), p = 1.0 × 10‐5], CD4 predominance [25/28 (89%) vs 12/23 (52%), p = 3.4 × 10‐3], interfollicular lymphoid CD10‐positivity [16/30 (53%) vs 1/29 (3%), p = 1.5 × 10‐5], TRG clonality [16/28 (57%) vs 1/20 (5%), p = 1.4 × 10‐4], higher maximum number of Epstein‐Barr virus‐encoded RNA + nuclei per 0.5‐mm high‐power field [median 6 (range 0–70) vs 1 (range 0–40), p = 0.012] and interfollicular Ki‐67 proliferation fraction [median 40% (range 10–80%) vs 20% (range 5–40), p < 10‐4], whereas their germinal centres (GCs) more often showed attenuation of CD10 [30/30 (100%) vs 11/29 (38%), p = 5.3 × 10‐8] and CD57 [18/25 (72%) vs 4/22 (18%), p = 2.4 × 10‐4] (respectively). GC‐predominant PD‐1 and ICOS immunoreactivity were more often seen in RLH [20/22 and 9/19 controls (91% and 47%)] than AITL1 [9/25 and 3/19 cases (36% and 16%), p = 1.0 × 10‐4 and 0.033, respectively]. Significant independent predictors against AITL1 were: solid GC CD10 immunoreactivity {p = 0.023, odds ratio (OR) for AITL1 0.01 [95% confidence interval (CI): 0.0002–0.529]}; lower interfollicular proliferation fraction [p = 0.047, OR for AITL1 1.1 (95% CI: 1.001–1.209) per % rise in Ki‐67]; younger presenting age [p = 0.028, OR for AITL1 1.136 (95% CI: 1.014–1.272) per year older]. Hence, GCs and perifollicular zones in AITL1 are distinct from those in RLH. Copyright

Occult recurrence of monomorphic epitheliotropic intestinal T-cell lymphoma and the role of MATK gene expression in diagnosis

Monomorphic epitheliotropic intestinal T‐cell lymphomas (MEITL), formerly Type II enteropathy‐associated T‐cell lymphomas (EATL), are rare peripheral T‐cell lymphomas. They are associated with poor survival outcomes, in part because of their late diagnosis. Although MEITLs may be reliably diagnosed based on histological and immunophenotypic findings, overlaps with other NK/T and T‐cell lymphomas may confound the diagnosis. The distinctive high‐level nuclear staining of the novel marker Megakaryocyte‐associated tyrosine kinase (MATK) in MEITLs is an invaluable tool in distinguishing MEITL from classical EATL and other NK/T or T‐cell lymphomas. 18‐Fluorine‐2‐fluorodeoxyglucose positron emission tomography (18F‐FDG PET) has been shown to be a useful tool in the staging and follow‐up of aggressive lymphomas. Herein, we describe an unusual case of occult hepatic recurrence of MEITL that was non‐avid on 18F‐FDG PET, in which diagnosis was confirmed based on the expression of MATK in tumour cells. Copyright

Double Immunofluorescence Shows Coexpression of Bcl-x with GFAP in a Variety of Glial Lesions

Bcl-x is an important member of the bcl-2 family of proteins that has been shown to be expressed by both native nervous system tissue and several nervous system tumors. Its anti-apoptotic activity is believed to contribute to nervous system tumorigenesis. We seek to compare the staining characteristics of Bcl-x and GFAP in various neuronal and glial lesions, both neoplastic and non-neoplastic. We also use a double immunofluorescence technique to assess for coexpression of Bcl-x and GFAP by the same lesional cells. Forty cases of brain tumors and reactive brain conditions were reviewed. The former included astrocytomas, GBMs, ependymomas, oligodendrogliomas, gangliogliomas, subependymomas and neurocytomas. The latter included cases of gliosis, cerebritis and mesial temporal sclerosis. Immunohistochemistry for Bcl-x and GFAP was performed. Double immunofluorescent labeling using antibodies to both GFAP and Bcl-x was also carried out. Expression of Bcl-x closely follows that of GFAP with strong expression in both reactive astrocytes and astrocytomas. There is more focal expression in other gliomas. Immunostaining for Bcl-x is generally more intense and distinct, compared to that for GFAP. Expression of both GFAP and Bcl-x is more focal in oligodendrogliomas, with staining of␣mainly intervening astrocytic processes. Double immunolabelling confirms the coexpression of Bcl-x and GFAP in various gliomas and reactive brain conditions. As immunostaining for Bcl-x is generally more distinct and intense than that for GFAP, it may serve as a useful alternative to help highlight glial cells in selected diagnostic settings.

Oncogenic activation of the STAT3 pathway drives PD-L1 expression in natural killer/T-cell lymphoma

Mature T-cell lymphomas, including peripheral T-cell lymphoma (PTCL) and extranodal NK/T-cell lymphoma (NKTL), represent a heterogeneous group of non-Hodgkin lymphomas with dismal outcomes and limited treatment options. To determine the extent of involvement of the JAK/STAT pathway in this malignancy, we performed targeted capture sequencing of 188 genes in this pathway in 171 PTCL and NKTL cases. A total of 272 nonsynonymous somatic mutations in 101 genes were identified in 73% of the samples, including 258 single-nucleotide variants and 14 insertions or deletions. Recurrent mutations were most frequently located in STAT3 and TP53 (15%), followed by JAK3 and JAK1 (6%) and SOCS1 (4%). A high prevalence of STAT3 mutation (21%) was observed specifically in NKTL. Novel STAT3 mutations (p.D427H, E616G, p.E616K, and p.E696K) were shown to increase STAT3 phosphorylation and transcriptional activity of STAT3 in the absence of cytokine, in which p.E616K induced programmed cell death-ligand 1 (PD-L1) expression by robust binding of activated STAT3 to the PD-L1 gene promoter. Consistent with these findings, PD-L1 was overexpressed in NKTL cell lines harboring hotspot STAT3 mutations, and similar findings were observed by the overexpression of p.E616K and p.E616G in the STAT3 wild-type NKTL cell line. Conversely, STAT3 silencing and inhibition decreased PD-L1 expression in STAT3 mutant NKTL cell lines. In NKTL tumors, STAT3 activation correlated significantly with PD-L1 expression. We demonstrated that STAT3 activation confers high PD-L1 expression, which may promote tumor immune evasion. The combination of PD-1/PD-L1 antibodies and STAT3 inhibitors might be a promising therapeutic approach for NKTL, and possibly PTCL.