Neuronal survival factor VGF promotes chemoresistance and predicts poor prognosis in lung cancers with neuroendocrine feature.

High-grade neuroendocrine tumors (NETs) of the lung consist of small-cell lung cancer (SCLC) and large-cell neuroendocrine carcinoma (LCNEC). Both exhibit aggressive malignancy with poor prognosis. The transformation of lung adenocarcinoma (ADC) to SCLC or LCNEC also contributes to acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). Despite initially being responsive to chemotherapy, high-grade NET patients inevitably develop drug resistance; thus, novel therapeutic targets are urgently needed for these patients. Our study reported that VGF (nerve growth factor inducible), a factor mainly expressed in neurons during neural development, is highly expressed in SCLC and LCNEC as well as in a subset of ADCs, whereas targeting VGF attenuates cancer cell growth and tumor formation. High VGF expression was associated with advanced stage SCLC and predicted poor prognosis in lung ADC. In addition, EGFR-TKI selection enriched VGF expression in TKI-resistant ADC under epigenetic control. The VGF locus possessed the HDAC1 binding site, and treatment of ADC cells with the HDAC1 inhibitor induced VGF expression. High VGF expression was associated with chemoresistance, and silencing VGF induced BMF and BCL2L11 expression and rendered lung cancer cells sensitive to chemotherapy drugs. These findings suggested the potential of VGF as a prognostic factor and therapeutic target in lung cancers with neuroendocrine feature.

ID4 predicts poor prognosis and promotes BDNF-mediated oncogenesis of colorectal cancer.

Inhibitors of DNA binding and cell differentiation (ID) proteins regulate cellular differentiation and tumor progression. Whether ID family proteins serve as a linkage between pathological differentiation and cancer stemness in colorectal cancer is largely unknown. Here, the expression of ID4, but not other ID family proteins, was enriched in LGR5-high colon cancer stem cells. Its high expression was associated with poor pathological differentiation of colorectal tumors and shorter survival in patients. Knockdown of ID4 inhibited the growth and dissemination of colon cancer cells, while enhancing chemosensitivity. Through gene expression profiling analysis, brain-derived neurotrophic factor (BDNF) was identified as a downstream target of ID4 expression in colorectal cancer. BDNF knockdown decreased the growth and migration of colon cancer cells, and its expression enhanced dissemination, anoikis resistance and chemoresistance. ID4 silencing attenuated the epithelial-to-mesenchymal transition pattern in colon cancer cells. Gene cluster analysis revealed that ID4 and BDNF expression was clustered with mesenchymal markers and distant from epithelial genes. BDNF silencing decreased the expression of mesenchymal markers Vimentin, CDH2 and SNAI1. These findings demonstrated that ID4-BDNF signaling regulates colorectal cancer survival, with the potential to serve as a prognostic marker in colorectal cancer.

MYD88 L265P mutation analysis is a useful diagnostic adjunct for lymphoplasmacytic lymphoma with pleural effusion.

Lymphoplasmacytic lymphoma (LPL) is a marrow-based lymphoma, rarely involving extramedullary sites, particularly the pleural cavities. The distinction of lymphomatous pleural effusion (PE) in LPL patients from benign effusion is challenging. We conducted this study to examine whether MYD88 L265P mutation analysis is useful in distinguishing benign from lymphomatous PE in four patients with LPL, in which the initial marrow specimens were all positive for MYD88 mutation. In one case each with plasma cell- or lymphocyte-predominant PE, MYD88 mutation was positive, confirming lymphomatous effusion. The other lymphocyte-predominant PE was negative for MYD88 mutation, but was clonally related to a previous nodal biopsy and this PE was also considered to have LPL involvement. The fourth case developed large B-cell lymphoma in the PE 30 months later. The PE specimen was negative for MYD88 mutation but was clonally related to the diagnostic marrow tissue, indicating large cell transformation. Four cases of small lymphocyte-predominant benign PE from patients without history of lymphoma were examined and were all negative for MYD88 L265P mutation. In conclusion, in this small case series we showed that MYD88 L265P mutation analysis could serve as a useful adjunct in distinguishing benign from lymphomatous PE in patients with LPL.

3-D illustration of network orientations of interstitial cells of Cajal subgroups in human colon as revealed by deep-tissue imaging with optical clearing.

Morphological changes of interstitial cells of Cajal (ICC) have been proposed to characterize motility disorders. However, a global view of the network orientations of ICC subgroups has not been established to illustrate their three-dimensional (3-D) architectures in the human colon. In this research, we integrate c-kit immunostaining, 3-D microscopy with optical clearing, and image rendering to present the location-dependent network orientations with high definition. Full-depth colonic tissues were obtained from colectomies performed for nonobstructing carcinoma. Specimens of colon wall were prepared away from the tumor site. C-kit and nuclear fluorescent staining were used to identify the ICC processes and cell body. Optical clearing was used to generate transparent colon specimens, which led to panoramic visualization of the fluorescence-labeled ICC networks at the myenteric plexus (ICC-MY), longitudinal (ICC-LM) and circular (ICC-CM) muscles, and submucosal boundary (ICC-SM) up to 300 µm in depth via confocal microscopy with subcellular level resolution. We observed four distinct network patterns: 1) periganglionic ICC-MY that connect with ICC-LM and ICC-CM, 2) plexuses of ICC-LM within the longitudinal muscle and extending toward the serosa, 3) repetitive and organized ICC-CM layers running parallel to the circular muscle axis and extending toward the submucosa, and 4) a condensed ICC-SM layer lining the submucosal border. Among the four patterns, the orderly aligned ICC-CM layers provide an appropriate target for quantitation. Our results demonstrate the location-dependent network orientations of ICC subgroups and suggest a practical approach for in-depth imaging and quantitative analysis of ICC in the human colon specimen.

LC3A-mediated autophagy regulates lung cancer cell plasticity.

ABBREVIATIONS: ATG14: autophagy related 14; CDH2: cadherin 2; ChIP-qPCR: chromatin immunoprecipitation quantitative polymerase chain reaction; CQ: chloroquine; ECAR: extracellular acidification rate; EMT: epithelial-mesenchymal transition; EPCAM: epithelial cell adhesion molecule; MAP1LC3A/LC3A: microtubule associated protein 1 light chain 3 alpha; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAP1LC3C/LC3C: microtubule associated protein 1 light chain 3 gamma; NDUFV2: NADH:ubiquinone oxidoreductase core subunit V2; OCR: oxygen consumption rate; ROS: reactive oxygen species; RT-qPCR: reverse-transcriptase quantitative polymerase chain reaction; SC: scrambled control; shRNA: short hairpin RNA; SNAI2: snail family transcriptional repressor 2; SOX2: SRY-box transcription factor 2; SQSTM1/p62: sequestosome 1; TGFB/TGF-ß: transforming growth factor beta; TOMM20: translocase of outer mitochondrial membrane 20; ZEB1: zinc finger E-box binding homeobox 1.

Targeted Next-generation Sequencing Reveals a Wide Morphologic and Immunophenotypic Spectrum of Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma.

Primary intestinal T-cell lymphoma (PITL) is highly aggressive and includes celiac disease-related enteropathy-associated T-cell lymphoma (EATL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), and primary intestinal peripheral T-cell lymphoma, not otherwise specified (ITCL-NOS). MEITL is the most common PITL in Asia, comprising of monomorphic medium-sized cells typically expressing CD8, CD56, and cytotoxic granules. Occasional cases with intermediate features between MEITL and ITCL-NOS are difficult to be classified and warrant further investigation. We collected 54 surgically resected PITLs from Taiwan, with 80% presenting with bowel perforation. The overall outcome was poor with a median survival of 7 months. Based on histopathology (monomorphic vs. pleomorphic) and immunophenotype, we classified these cases into 4 groups: MEITL with typical immunophenotype (n=34), MEITL with atypical immunophenotype (n=5), pleomorphic PITL with MEITL-like immunophenotype (n=6), and ITCL-NOS (n=9). There was no EATL in our cohort. Targeted next-generation sequencing of the first 3 groups showed highly prevalent loss-of-function mutations for SETD2 (85%, 80%, and 83%, respectively) and frequent activating mutations for STAT5B (64%, 60%, and 50%, respectively) and JAK3 (38%, 20%, and 50%, respectively). In contrast, ITCL-NOS cases had less frequent mutations of SETD2 (56%) and STAT5B (11%) and rare JAK3 mutations (11%). Our results suggest that there is a wider morphologic and immunophenotypic spectrum of MEITL as currently defined in the 2017 WHO classification. MEITL with atypical immunophenotype and PITL with MEITL-like immunophenotype shared clinicopathologic and molecular features similar to MEITL but distinct from ITCL-NOS, indicating that such cases may be considered as immunophenotypic or histopathologic variants of MEITL.

Cutaneous peripheral T-cell lymphoma of cytotoxic phenotype mimicking extranodal NK/T-cell lymphoma.

Cutaneous peripheral T-cell lymphoma unspecified is a rare neoplasm that is infrequently associated with Epstein-Barr virus (EBV) infection. In contrast, extranodal natural killer (NK)/T-cell lymphoma, although also rare, is known to be strongly associated with EBV and occurs most commonly in the nasal region. We report the case of a 55-year-old male who presented with fever and an indurated cutaneous plaque with ulceration. This cutaneous neoplasm showed diffuse dermal lymphomatous infiltration and tumor necrosis, with neoplastic cells expressing CD2, cytoplasmic CD3 (CD3ε), CD8, CD16, CD30, T-cell intracellular antigen-1, and granzyme B but not CD56, BF1, or T-cell receptor (TCR) δ1. Furthermore, the tumor cells were noted to be diffusely positive for EBV by in situ hybridization. A monoclonal TCR gene rearrangement was demonstrated. The disease showed an aggressive clinical course, and the patient died within 3 weeks of diagnosis without complete staging or chemotherapy. According to the 2005 World Health Organization/European Organization for Research and Treatment of Cancer scheme for cutaneous lymphoma and the 2008 WHO classification for lymphoid neoplasms, our case would have been classified as a nasal type extranodal NK/T-cell lymphoma with T-cell lineage. However, the expressions of CD8 and CD16, in addition to a monoclonal TCR gene rearrangement, are unusual findings in NK/T-cell lymphoma, and we believe such a phenotype/genotype should be more appropriately classified as an EBV-positive peripheral T-cell lymphoma, unspecified with a cytotoxic phenotype. Detailed clinicopathologic and molecular studies of similar cases may shed light on the prognostic impact of NK vs. T-cell lineage on extranodal NK/T-cell lymphomas.

Lymphomatous effusion of monomorphic epitheliotropic intestinal T-cell lymphoma is characterized by azurophilic granules and is a dismal sign: Report of two new cases with literature review.

Lymphoma involving serous effusion is uncommon. The diagnosis of effusion lymphoma may be challenging, particularly when the lymphoid cells are small to medium-sized, which would be difficult for differentiating reactive effusions from low grade lymphomas. Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is an uncommon type of aggressive intestinal T cell lymphoma with a median survival of 7 months. MEITL rarely disseminates to the body cavities. To date, there are only three reported cases of MEITL with malignant effusion. Here we report two additional cases of MEITL with lymphoma cells involving the pleural effusion and the ascites, respectively. Review of the three literature cases and our two new cases of MEITL with malignant effusion, cytoplasmic azurophilic granules were identified in both the two cases with Liu stain. The median survival time was 1.5 months after the occurrence of malignant effusion, even shorter than the median survival in patients with MEITL. Although the case number is small, malignant effusion seems to be a poor prognostic factor of MEITL.

Paraneoplastic Leukemoid Reaction after Primary Tumor Resection in Patients with Urothelial Carcinoma: A Report of 2 Cases.

Leukemoid reaction (LR), which is defined as leukocytosis with a white blood cell (WBC) count above 50 000/µL, can be caused by various conditions, while paraneoplastic leukemoid reaction (PLR), a rare type of paraneoplastic syndrome, occurs in cases of solid tumors. Here we report 2 cases of high-grade urothelial carcinoma (HGUC) with PLR accompanied by rapid tumor progression after complete resection of the primary tumor. We reviewed the patient's clinical history, histopathology, and the results of laboratory tests to rule out LR induced by non-tumor causes. In both cases, PLR appeared after primary tumor resection, and the patients died of disease at the peak of PLR at 6 and 8 weeks. Immunohistochemistry for granulocyte colony-stimulating factor and its receptor was performed on tumor tissues. Patients with HGUC and PLR are rare and have an extremely poor prognosis. The mechanism by which solid tumors are associated with PLR and rapid tumor progression after surgical resection of the primary tumor is incompletely understood and will be discussed here.

Evaluation of the diagnostic accuracy of bronchial brushing cytology in lung cancer: A meta-analysis.

BACKGROUND: Flexible bronchoscopy is commonly used to examine patients suspected to have lung cancer. Bronchial brushing is one of the cytological technologies for lung specimens obtained through a bronchoscope. However, the accuracy of bronchial brushing cytology (BBC) for lung cancer diagnosis is still inconclusive. The aim of this study was to evaluate the diagnostic accuracy of BBC. METHODS: A literature search was conducted with PubMed, Embase, the Cochrane Library, Web of Science, Biomed Central, Clinical Key, and ClinicalTrials.gov. Studies that assessed the efficacy of BBC in detecting lung cancer were included. Articles that estimated the accuracy on a per-patient basis were included. Review articles, case reports, and research that provided insufficient data to construct a 2 × 2 table were excluded. Both prospective trials and retrospective studies were included. English language studies were reviewed. Data synthesis was performed with a random-effects model. RESULTS: Seventeen studies with 2538 patients were included in the study. The meta-analysis for BBC generated a pooled sensitivity of 0.67 (95% confidence interval [CI], 0.65-0.70) and a pooled specificity of 0.91 (95% CI, 0.89-0.93). The pooled diagnostic odds ratio for BBC was 24.55 (95% CI, 12.39-48.66). The subgroup analysis for studies using liquid-based cytology (LBC) generated a pooled sensitivity of 0.68 and a pooled specificity of 0.92. The pooled diagnostic odds ratio of studies using LBC was 114.18. CONCLUSIONS: These findings indicate that BBC is a discriminative diagnostic approach with moderate sensitivity and high specificity for diagnosing peripheral pulmonary lesions. BBC using LBC has higher diagnostic performance.

Aberrant TTF-1 Expression in Peripheral T-Cell Lymphomas: A Diagnostic Pitfall.

BACKGROUND: Thyroid transcription factor-1 (TTF-1) is a useful marker for identifying thyroid and lung cancers in diagnostic pathology, particularly for the investigation of unknown primary cancers. However, some other tumors such as colorectal cancer might aberrantly express TTF-1, particularly with the less specific clone SPT24. Occasional diffuse large B-cell lymphoma (DLBCL) cases have been reported to be TTF-1-positive, yet there is no information on TTF-1 expression in peripheral T-cell lymphoma (PTCL). METHODS: We investigated a series of PTCL and DLBCL by immunohistochemistry for TTF-1 expression using 2 commercially available clones. RESULTS: We found that 33% (5/15) adult T-cell leukemia/lymphomas (ATLLs) and 25% (2/8) angioimmunoblastic T-cell lymphomas (AITLs) were positive by clone SPT24 and only 2ATLL cases were positive by clone 8G7G3/1. Overall TTF-1 expression rates of PTCL by SPT24 and 8G7G3/1 were 16% (7/43) and 5% (2/43), respectively. All DLBCLs were negative. CONCLUSION: Although TTF-1 is a relatively specific marker for thyroid and lung cancers, it might be expressed in some lymphomas, particularly PTCL when using clone SPT24. Pathologist should be aware of this possible diagnostic pitfall when using TTF-1 in investigating tumors of unknown origin.

Effective treatment of tubal angiomyofibroblastoma via laparoscopic complete resection.

Angiomyofibroblastoma is a rare mesenchymal tumor usually originating from the vulva and vagina with only one reported case arising from fallopian tube. We describe a second case of tubal angiomyofibroblastoma treated successfully with laparoscopic complete resection.

Primary cutaneous peripheral T-cell lymphoma with a late relapse solely in the ileum mimicking monomorphic epitheliotropic intestinal T-cell lymphoma.

BACKGROUND: Primary cutaneous peripheral T-cell lymphomas (PC-PTCLs) are classified into mycosis fungoides (MF) and other rare specific types; and those do not fit into any specific entities are designated as PTCL, not otherwise specified (NOS), an aggressive neoplasm. Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is an aggressive primary intestinal T-cell lymphoma with enteropathy in the non-neoplastic mucosa. We report a rare case of PC-PTCL-NOS with a late relapse solely in the ileum after complete remission. We discuss the importance of evaluating enteropathy, megakaryocyte-associated tyrosine kinase (MATK) immunostaining, and the implication of clonal relationship of metachronous lymphomas. CASE REPORT: We reviewed the histopathology and immunohistochemistry of the skin tumor from a 68-year-old female and the relapsed intestinal T-cell lymphoma. The tumor cells "trans-regressed" from large and pleomorphic in the skin to small/medium-sized cells with clear cytoplasm in the ileum; and furthermore, there was immunophenotypic alteration. However, there was no enteropathy in the non-tumoral ileal mucosa adjacent to the tumor proper and both the cutaneous and ileal tumors were negative for MATK. Clonality study showed clonal TRG and TRB rearrangement with identical band sizes of the amplicons, confirming primary cutaneous tumor with a late relapse in the ileum. CONCLUSIONS: Although PC-PTCL-NOS is an aggressive neoplasm, rare cases such as this might have a long-term survival. Furthermore, the late relapse mimicking MEITL is intriguing and exceptional, in spite the fact that MEITL is a primary intestinal T-cell lymphoma with a typical histopathology and immunophenotype. Detailed clinicopathological and molecular studies are mandatory to elucidate the clonal relationship of metachronous lymphomas, as this has important clinical implication for treatment. Evaluation of the non-tumoral intestinal mucosa for enteropathy and immunostaining for MATK might help to differentiate a mimicker from a true MEITL.

Crosstalk between SOX2 and cytokine signaling in endometrial carcinoma.

Endometrial carcinoma is a cancer derived from oncogenesis of the regenerating uterine cavity, in which cytokine stimulation shapes cell differentiation and tissue remodeling. Expression of the stem cell factors SOX2, OCT4, NANOG, and MYC has been linked to tumor malignancy in several cancers. However, how these stem cell factors crosstalk with cytokine signaling to promote malignancy in endometrial carcinoma is still elusive. Here we report that the expression of SOX2 and MYC, but not that of OCT4 and NANOG, correlate with poor histological differentiation and prognosis, while SOX2 expression is negatively associated with MYC level. We found that SOX2-high endometrial carcinoma cells possessed a higher colony-forming ability than their SOX2-low counterparts, and knockdown of SOX2 attenuated the colony-forming ability. We observed that SOX2 regulated EGFR expression in a SOX2-EGFR positive feedback loop. EGF stimulation induced SOX2 expression and promoted migration of endometrial carcinoma cells, whereas TGF-ß stimulation inhibited SOX2 expression and attenuated the colony-forming ability. Immunohistochemistry analysis revealed that SOX2 expression correlated with lymph node infiltration of endometrial carcinoma. Our findings support that cytokine-induced stem cell factor SOX2 possesses oncogenic properties, with the potential to serve as a prognostic biomarker in endometrial carcinoma.

Micronodular Thymoma with Lymphoid Stroma Diagnosed with Core Needle Biopsy. A Case Report.

BACKGROUND: Micronodular thymoma with lymphoid stroma (MNT) is an unusual type of thymoma characterized by multiple, discrete, small epithelial nodules with cytological features of type A thymoma that are separated by abundant reactive lymphoid tissue. Diagnosis of MNT usually relies on surgical specimens and could be challenging with needle biopsies. We present a case diagnosed via a core needle biopsy since the patient was unfit for and refused surgery. CASE: The patient was a 79-year-old man with an incidentally found mediastinal mass. Subsequent computed tomography scans showed that the tumor measured 10.7 x 10.0 x 9.0 cm in size and invaded the pericardium. Needle core biopsies revealed small nodules of bland-looking epithelial cells in a background of prominent lymphoid stroma with germinal center formation. The lymphoid stroma was composed mainly of B-cells admixed with scattered T-cells. The patient was unfit for and refused surgery and was discharged under stable condition with no evidence of metastasis 6 months later. CONCLUSION: Our case demonstrates that the diagnosis of MNT could readily be made even with a core needle biopsy specimen when the characteristic morphologic and immunohistochemical features are present. Our literature review shows some ethnic and/or geographic differences in MNTs between Asian and Western populations.

Perivascular Interstitial Cells of Cajal in Human Colon.

BACKGROUND & AIMS: Interstitial cells of Cajal (ICC) closely associate with nerves and smooth muscles to modulate gut motility. In the ICC microenvironment, although the circulating hormones/factors have been shown to influence ICC activities, the association between ICC and microvessels in the gut wall has not been described. We applied three-dimensional (3D) vascular histology with c-kit staining to identify the perivascular ICC and characterize their morphologic and population features in the human colon wall. METHODS: Full-thickness colons were obtained from colectomies performed for colorectal cancer. We targeted the colon wall away from the tumor site. Confocal microscopy with optical clearing (use of immersion solution to reduce scattering in optical imaging) was performed to simultaneously reveal the ICC and vascular networks in space. 3D image rendering and projection were digitally conducted to illustrate the ICC-vessel contact patterns. RESULTS: Perivascular ICC were identified in the submucosal border, myenteric plexus, and circular and longitudinal muscles via high-definition 3D microscopy. Through in-depth image projection, we specified two contact patterns-the intimate cell body-to-vessel contact (type I, 18% of ICC in circular muscle) and the long-distance process-to-vessel contact (type II, 16%)-to classify perivascular ICC. Particularly, type I perivascular ICC were detected with elevated c-kit staining levels and were routinely found in clusters, making them readily distinguishable from other ICC in the network. CONCLUSIONS: We propose a new subclass of ICC that closely associates with microvessels in the human colon. Our finding suggests a functional relationship between these mural ICC and microvessels based on the morphologic proximity.

Extranodal natural killer/T-cell lymphoma, nasal type in Taiwan: a relatively higher frequency of T-cell lineage and poor survival for extranasal tumors.

Extranodal natural killer (NK)/T-cell lymphoma, nasal type, is a predominantly extranodal lymphoma associated with Epstein-Barr virus occurring most frequently in the upper aerodigestive tract. There are limited reports on cellular origin and prognostic factors. We retrospectively investigated 73 cases with a median age of 54 years and a male-female ratio of 2.0:1. The upper aerodigestive tract (nasal group) was the most common site of involvement (51 cases; 70%). The other organs (n = 22; extranasal group) included the skin (12 cases; 16%) and gastrointestinal tract (5; 7%). Of the 70 cases with complete staging, 71% had stage I/II disease. All cases were positive for Epstein-Barr virus by in situ hybridization. Using immunohistochemistry and clonality assay for T-cell receptor gene rearrangement, these tumors were classified into NK (n = 39; 53%), T (n = 13; 18%), and indeterminate lineage (n = 21; 29%). The only clinicopathological difference among these 3 groups was rare CD5 expression in the NK-cell group. Nasal tumors were more frequently of NK-cell origin, and extranasal tumors were equally of either T- or NK-cell origin. The 5-year overall survival rate was 35.6%. The overall survival time was shorter in the extranasal group, although there was no statistical difference in age, sex, and histologic or immunophenotypic features between the 2 groups. Excluding the cases with indeterminate lineage, 75% of cases were of NK lineage; and 25%, T lineage. Extranasal tumors were more aggressive than their nasal counterparts. A prospective national study is warranted for a better understanding of the clinicopathological and genetic features of this uncommon tumor and the prognostic factors.

Follicular Dendritic Cell Sarcoma of the Inflammatory Pseudotumor-like Variant Presenting as a Colonic Polyp.

Follicular dendritic cell (FDC) sarcoma is rare and is classified either as conventional type or inflammatory pseudotumor (IPT)-like variant. Extranodal presentation is uncommon and nearly all gastrointestinal FDC tumors are of the conventional type. IPT-like variant tumors occur almost exclusively in the liver and spleen and are consistently associated with Epstein-Barr virus (EBV). Here we report the case of a 78-year-old woman with an IPT-like FDC sarcoma presenting as a pedunculated colonic polyp. Histologically, scanty atypical ovoid to spindle cells were mixed with a background of florid lymphoplasmacytic infiltrate, which led to an initial misdiagnosis of pseudolymphoma. These atypical cells expressed CD21, CD23, CD35, and D2-40, and were positive for EBV by in situ hybridization, confirming the diagnosis. The patient was free of disease five months after polypectomy without adjuvant therapy. Although extremely rare, the differential diagnosis for colonic polyp should include FDC sarcoma to avoid an erroneous diagnosis. A review of the 24 cases of IPT-like FDC sarcoma reported in the literature reveal that this tumor occurs predominantly in females with a predilection for liver and spleen, and has a strong association with EBV.

Lymphoepithelioma-like carcinoma of the urinary bladder: a report of two cases.

BACKGROUND: Lymphoepithelioma-like bladder carcinoma (LELBC) is a rare variant of infiltrating urothelial carcinoma according to the recent World Health Organization classification, with only 3 previously reported cases from Asia. Histologically, LELBC is classified into pure, predominant and focal forms, depending on the relative amount of the lymphoepithelioma-like component. The tumor may have a concurrent component of other histological types, usually high-grade urothelial carcinoma. Patients with the pure and predominant forms have a better response to chemotherapy and outcome than those with a focal form. Unlike its histological counterpart in the nasopharynx, which is prevalent among Southeastern Asia and has a strong association with Epstein-Barr virus (EBV), LELBC is universally EBV negative. CASE: We report 2 new cases of LELBC, one treated with transurethral resection and the other, cystoprostatectomy. Histologically, both tumors were of the predominant form and were both negative for EBV by in situ hybridization. Both patients were subsequently treated with chemotherapy and were free of disease 6 months after diagnosis. CONCLUSION: Our detailed clinicopathological report adds 2 new Asian cases to our understanding of this extremely rare variant of urothelial carcinoma.

3-D visualization and quantitation of microvessels in transparent human colorectal carcinoma [corrected].

Microscopic analysis of tumor vasculature plays an important role in understanding the progression and malignancy of colorectal carcinoma. However, due to the geometry of blood vessels and their connections, standard microtome-based histology is limited in providing the spatial information of the vascular network with a 3-dimensional (3-D) continuum. To facilitate 3-D tissue analysis, we prepared transparent human colorectal biopsies by optical clearing for in-depth confocal microscopy with CD34 immunohistochemistry. Full-depth colons were obtained from colectomies performed for colorectal carcinoma. Specimens were prepared away from (control) and at the tumor site. Taking advantage of the transparent specimens, we acquired anatomic information up to 200 µm in depth for qualitative and quantitative analyses of the vasculature. Examples are given to illustrate: (1) the association between the tumor microstructure and vasculature in space, including the perivascular cuffs of tumor outgrowth, and (2) the difference between the 2-D and 3-D quantitation of microvessels. We also demonstrate that the optically cleared mucosa can be retrieved after 3-D microscopy to perform the standard microtome-based histology (H&E staining and immunohistochemistry) for systematic integration of the two tissue imaging methods. Overall, we established a new tumor histological approach to integrate 3-D imaging, illustration, and quantitation of human colonic microvessels in normal and cancerous specimens. This approach has significant promise to work with the standard histology to better characterize the tumor microenvironment in colorectal carcinoma.