Xiao Yan Zhou

Subcutaneous panniculitis-like T-cell lymphoma: a clinicopathologic, immunophenotypic, and molecular study of 22 Asian cases according to WHO-EORTC classification.

Subcutaneous panniculitis-like T-cell lymphoma (SPTL) is defined as a rare cytotoxic α/β T-cell lymphoma characterized by primary involvement of subcutaneous tissue mimicking panniculitis and a predominant CD3+/CD4−/CD8+ phenotype in 2005 World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification for cutaneous lymphomas. We presented a detailed study of SPTL, describing clinicopathologic, immunophenotypic, and molecular features of 22 cases in China. Strict diagnostic criteria according to the WHO-EORTC definition were applied to the diagnosis of all SPTL cases. Besides the common features described before, unusual CD4+/CD8− and CD4−/CD8− T-cell phenotypes were noted in 2 of our cases, respectively. CD30 was negative in all cases and CD56 was focally positive in 2 cases. Mortality in cases with angioinvasion (75%) was significantly higher than that in cases without angioinvasion (14.3%). Epstein-Barr virus (EBV) infection was detected in 1 immunocompetent patient by in situ hybridization. The frequency of rearranged TCRB, TCRG, and TCRD genes detected by BIOMED-2 multiplex polymerase chain reaction tubes was 80%, 67%, and 13%, respectively, with a total clonality detection rate of 100%. Clinical follow-up was available in 18 patients, ranging from 6 to 80 months. Most patients obtained complete or partial remission after therapy including one accompanied with EBV infection; 5 patients died: 3 of disease progression, 1 of severe infection, and 1 of complications caused by diabetes and hypertension. We conclude that SPTL as a cytotoxic lymphoma derived from α/β T cell has a predominant CD4−/CD8+ phenotype, but unusual CD4+/CD8− and CD4−/CD8− phenotypes do exist. Owing to its indolent clinical course and relatively high survival rate, SPTL should be differentiated from cutaneous γ/δ T-cell lymphoma. EBV is generally absent in SPTL but can rarely be detected especially in Asian population. Angioinvasion is a poor prognostic factor in SPTL.

Expression of follicular helper T cell markers in nodal peripheral T cell lymphomas: a tissue microarray analysis of 162 cases

Aims To evaluate the role of the follicular helper T (TFH) cell markers, CD10, BCL6, programmed death-1 (PD-1) and CXCL13, in the differential diagnosis of nodal peripheral T cell lymphomas (PTCLs) and to determine whether PTCL subtypes other than angioimmunoblastic T cell lymphoma (AITL) express TFH cell markers. Methods 162 nodal PTCL specimens and 53 other lymphoid pathology specimens were collected. Immunohistochemistry for CD10, BCL6, PD-1 and CXCL13 was performed on tissue microarray sections. Morphological feature analysis and double labelling assay were also performed. Results For AITL cases, the rate of CD10, BCL6, PD-1 and CXCL13 expression was 75.0% (36/48), 66.7% (32/48), 93.8% (45/48) and 97.9% (47/48), respectively. Expression of CD10, PD-1 and CXCL13 in the AITL group was significantly higher than in other nodal PTCLs and the control group (p<0.05). The rate of coexpression of three or four (≥3) markers was 83.3% for AITL cases, which was significantly higher than that for any of the non-AITL cases (0–4.9%; p<0.05). The rate of coexpression of PD-1 and CXCL13 (91.7%, 44/48) was significantly higher than that of CD10 and BCL6 (56.3%, 27/48) (p=0.000) in the AITL group. Seventeen cases of PTCL not otherwise specified (PTCL, NOS) expressed CXCL13, including both cases of the follicular variant of PTCL, NOS (FVPTCL, NOS), three of the four cases of the lymphoepithelioid variant of PTCL, NOS (LVPTCL, NOS), and the remaining 12 cases which displayed one or more features of AITL. Conclusions The combined detection of CD10, BCL6, PD-1 and CXCL13 has high specificity and sensitivity for the differential diagnosis of AITL. PD-1 and CXCL13 are more sensitive, superior diagnostic markers for AITL than CD10 and BCL6. Currently, TFH cell markers are the only available markers that show high specificity for AITL. LVPTCL, NOS and/or FVPTCL, NOS may also arise from TFH cells and fall within the spectrum of AITL.

Characteristics and prognosis of primary thyroid Non-Hodgkin's lymphoma in Chinese patients

There exists no universally accepted treatment for primary thyroid non‐Hodgkins lymphoma (TNHL) due to the rarity of this entity. The aim of this study is to assess the role of surgery and to explore prognostic factors in Chinese TNHL patients.

Microcystic stromal tumour of the ovary: frequent mutations of β-catenin (CTNNB1) in six cases.

To analyse the clinicopathological, immunohistochemical and β‐catenin (CTNNB1) mutation characteristics of six cases of microcystic stromal tumour of the ovary (MCST).

KRAS and BRAF gene mutations in correlation with clinicopathologic features of colorectal carcinoma in Chinese

OBJECTIVEnTo retrospectively analyze KRAS and BRAF gene mutation features in Chinese colorectal cancer (CRC) and their clinicopathologic relationship.nnnMETHODSn557 colorectal cancer cases were collected, including 325 colon cancer and 232 rectal cancer. PCR amplification and DNA sequencing were used to detect mutations in exon 2 of KRAS gene and exon 15 of BRAF gene mutation.nnnRESULTSn(1) KRAS mutation was found in 40.4% (225/557) colorectal cancer. The most common mutation locations were in codon 12(79.1%, 178/225) and codon 13 (20.4%, 46/225). The most common mutation types were GGT > GAT (G12D) (37.8%, 85/225), GGT > GTT(G12V) (20.0%, 45/225) in codon 12 and GGC > GAC (G13D) in codon 13 (19.6%, 44/225). These three point mutations accounted 77.3% (174/225) in total KRAS gene mutation cases. All cases showed only one of point mutation types. (2) Among 557 CRC cases, KRAS mutation was significantly higher in female (46.2%, 92/199) than in man (37.2%, 133/358; P < 0.05). KRAS gene codon 13 mutation was higher in right colon cancer (11.3%, 12/106) than that in left colon cancer (4.8%, 6/124), but it didnt show any statistical significance (P > 0.05). (3) BRAF gene mutation was 5.1% (10/197) in colorectal cancer and 8/10 were the point mutation of GTG > GAG (V600E). Eight colorectal cancer cases with GTG > GAG (V600E) were not showing KRAS gene mutation. Both two cases with mutation on codon 600 (GTG > ATG, V600M) and codon 606 (GGG > AGT, G606S) showed codon 12 mutation of KRAS gene. (4) BRAF (V600E) gene mutation was higher in female (8.5%, 6/71) than that in male (1.6%, 2/126; P = 0.05); BRAF mutation in colon cancer (8.3%, 6/72) was higher than that in rectum cancer (2.1%, 2/94), but hadnt statistical significance (P > 0.05).nnnCONCLUSIONSn(1) Codon 12, 13 in KRAS gene and codon 600 in BRAF gene are the most common mutation points in Chinese colorectal cancer. KRAS and BRAF mutations are mutually exclusive. (2) KRAS and BRAF gene mutation is higher in female than that in male, suggesting that RAS-RAF-MAPK signal pathway is probably related to hormones directly or indirectly. (3) There is a trend that codon 13 mutation in KRAS and codon 600 mutation in BRAF in right colon cancer are higher than that in left colon cancer, respectively, however, which needs more cases to be further verified.

Loss of B-cell Receptor Expression Defines a Subset of Diffuse Large B-cell Lymphoma Characterized by Silent Bcr/pi3k/akt Signaling and a Germinal Center Phenotype Displaying Low-risk Clinicopathologic Features

B-cell receptor (BCR) signaling is crucial for the survival of normal and neoplastic B cells, and inhibitors targeting BCR signaling pathways have shown promising therapeutic outcomes for patients with B-cell lymphomas. In the current study, we analyzed de novo diffuse large B-cell lymphoma without BCR expression (DLBCL, BCR−) in 25 cases to determine the BCR/phosphatidylinositol-3-kinase/AKT (BCR/PI3K/AKT) signaling status, clinicopathologic features, and underlying causes leading to the loss of BCR. On the basis of clinical features, 15 (60%) DLBCL, BCR− patients were classified into the low-risk group, and 18 (86%) experienced complete remission. Morphologically and immunophenotypically, DLBCL, BCR− demonstrated centroblastic cytology (21/25, 84%) and germinal center B-cell-like cell origin (18/25, 72%). Other components in BCR complexity remained intact, on the basis of immunohistochemical findings. Epstein-Barr virus infection, deficiency in B-lineage transcription factors (PAX5, Oct-2, and Bob.1), and oncogene rearrangement did not seem to be associated with BCR loss. The activated form of signaling proteins (pSYK and pAKT) involved in the BCR/PI3K/AKT pathway were expressed at low levels in DLBCL, BCR− tissue. In vitro validation revealed that in DLBCL, BCR− cell lines, the BCR/PI3K/AKT pathway did not respond to BCR stimulation or inhibition. Our findings suggest that DLBCL, BCR− was characterized by a silent BCR/PI3K/AKT pathway, germinal center phenotype, and low risk and may not be a candidate for BCR-targeted therapies.

Two novel germline mutations of MLH1 and investigation of their pathobiology in hereditary non-polyposis colorectal cancer families in China

AIMnTo detect germline mutations of MLH1, and investigate microsatellite instability and expression of MLH1 in tumor tissues of hereditary non-polyposis colorectal cancer (HNPCC) with two novel germline mutations, and further investigate the pathobiology of the two novel mutations of MLH1.nnnMETHODSnRNA was extracted from the peripheral blood of 12 patients from 12 different families that fulfilled the Amsterdam II Criteria for HNPCC. Germline mutations of MLH1 were determined by RT-PCR, followed by cDNA sequencing analysis. PCR-GeneScan analysis was used to investigate microsatellite instability with a panel of five microsatellite markers (BAT26, BAT25, D5S346, D2S123 and mfd15), along with immunohistochemical staining to detect the expression of MLH1 protein in two patients tumor tissues with novel mutations.nnnRESULTSnThree germline mutations were found in four patients, one of the mutations has previously been reported, but the other two, CGC right arrow TGC at codon 217 of exon 8 and CCG right arrow CTG at codon 581 of exon 16, have not been reported. The two patients tumor tissues with novel mutations had high-frequency microsatellite instability that showed more than two unstable loci, and both tumors lost their MLH1 protein expression.nnnCONCLUSIONnThe two novel germline mutations of MLH1 in HNPCC families i.e. CGC right arrow TGC at codon 217 of exon 8 and CCG right arrow CTG at codon 581 of exon 16, are very likely to have pathological significance.

Primary Intestinal Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type: A Comprehensive Clinicopathological Analysis of 55 Cases

Purpose To investigate the clinicopathological features, survival and prognostic factors of primary intestinal extranodal natural killer/T-cell lymphoma, nasal type (PI-ENKTCL). Methods Clinical and histological characteristics of PI-ENKTCL cases were retrospectively evaluated. Immunohistochemical phenotype and status of Epstein-Barr virus (EBV) and T-cell receptor (TCR) gene rearrangement were examined. The overall survival and prognostic parameters were also analyzed. Results Fifty-five (2.7%) cases with PI-ENKTCL were identified out of 2017 archived ENKTCL cases, with a median age of 39 years and a male to female ratio of 2.1:1. The most common symptom was abdominal pain (90.9%), accompanied frequently with fever and less commonly with intestinal perforation or B symptoms. Small intestine (50.9%) was the most common site to be involved. 47.3% and 36.4% cases presented with stage I and II diseases, respectively. Histologically, most cases displayed characteristic morphologic changes of ENKTCL. Cytoplasmic CD3, TIA-1 and CD56 expression was found in 100%, 94.5% and 89.1% of cases, respectively. In situ hybridization detection for EBV demonstrated positive results in all cases. Monoclonal TCR gene rearrangement was found in 52.9% of tested cases. Chemotherapy with a DICE or L-asparaginase/peg-asparginase-containing regimen was most often employed. Both advanced tumor stage and B symptoms were independent inferior prognostic factors (p = 0.001 and p = 0.010). Noticeably, 6 cases demonstrated a CD4-positive phenotype. These cases featured a relatively older median age (58 years), predominance of small/medium-sized neoplastic cells, a higher rate of TCR rearrangement and slightly favorable outcome. Conclusion We reported by far the largest series of PI-ENKTCL, and demonstrated its heterogeneity, aggressive clinical behavior and unsatisfying response to the current therapeutic strategies. Those CD4-positive cases might represent a unique subtype of PI-ENKTCL or distinct entity. Further investigations are required for the better understanding and management of this unusual disease.

MYC protein-positive diffuse large b-cell lymphoma features an activated b-cell receptor signal pathway

Components of the B-cell receptor (BCR) signaling pathway represent promising therapeutic targets in diffuse large B-cell lymphoma (DLBCL) and other B-cell malignancies. MYC, a transcriptional factor and oncoprotein, is overexpressed in a fraction of DLBCL and indicates poor prognosis and aggressive clinical course when treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, BCR signaling status in MYC-positive DLBCL cases and the potential efficacy of BCR signal inhibitors in treating this aggressive disease are unknown. To further elucidate the BCR signaling pathway in MYC-positive DLBCL, we analyzed the levels of BCR-associated genes according to MYC gene status, detected phosphorylated protein with primary DLBCL samples, and estimated the patient survival with MYC expression. In addition, we manipulated MYC gene expression and tested its effects on BCR signaling in vitro. We found that CD19, SYK, and BLK were highly expressed in DLBCL with MYC gene overexpression. MYC-positive DLBCL had higher levels of pSYK and pBLK, but only pSYK level correlated with patient survival. The in vitro studies demonstrated that overexpression of the MYC gene augmented BCR signaling, whereas MYC gene knockdown attenuated BCR signaling. Thus, MYC protein–positive DLBCL features highly activated BCR signaling and may represent a potential candidate for BCR inhibitor therapy.

Breast carcinoma in sclerosing adenosis: a clinicopathological and immunophenotypical analysis on 206 lesions

Aims To fully elucidate the clinicopathological features of breast carcinoma in sclerosing adenosis (SA-BC). Methods Clinical and histological characteristics of 206 SA-BCs from 180 patients were retrospectively evaluated. Immunohistochemical phenotype was examined. The clinicopathological relevance of the topographical pattern of SA-BCs was analysed. Results Overall, up to 46 patients (25.6%) had contralateral cancer, either SA associated or not. Of 99 cases who underwent core needle biopsy (CNB), 36 were underestimated as adenosis or atypical ductal hyperplasia at CNB, 5 invasive cases were misinterpreted as in situ carcinomas, whereas 4 ductal carcinoma in situ (DCIS) cases were overdiagnosed as invasive carcinoma. Microscopically, 163 tumours were in situ, including 136 DCIS, 19 lobular carcinomas in situ (LCIS) and 8 mixed DCIS/LCIS; of these carcinomas in situ (CIS), 37 had microinvasion. The DCIS group exhibited low, intermediate and high grades in 53.7%, 34.6% and 11.8% of cases, respectively, mostly with solid (43.4%) or cribriform (41.9%) pattern. Forty out of 43 invasive cases were invasive ductal carcinoma (IDC), mostly DCIS predominant. Immunophenotypically, luminal A phenotype was identified in 55.1%, 63.2% and 45.0% of DCIS, LCIS and IDC cases, respectively. Topographical type A group (carcinoma being entirely confined to SA, n=176) was characterised by smaller size, less invasiveness, lower grade and more frequency of luminal A immunophenotype compared with type B group (≥ 50% but not all of the carcinomatous lesion being located in SA, n=30) (all P<0.05). Conclusions CIS, especially non-high-grade DCIS, represents the most common variant of SA-BC, and luminal A is the most predominant immunophenotype. CNB assessment might be challenging in some SA-BCs. The topographical pattern has great clinicopathological relevance. Careful evaluation of the contralateral breast and long-term follow-up for patients with SA-BC is necessary given its high prevalence of bilaterality.