MNDA expression and its value in differential diagnosis of B-cell non-Hodgkin lymphomas: a comprehensive analysis of a large series of 1293 cases.

AIMS: MNDA (myeloid nuclear differentiation antigen) has been considered as a potential diagnostic marker for marginal zone lymphoma (MZL), but its utility in distinguishing MZL from other B-cell non-Hodgkin lymphomas (B-NHLs) and its clinicopathologic relevance in diffuse large B-cell lymphoma (DLBCL) are ambiguous. We comprehensively investigated MNDA expression in a large series of B-NHLs and evaluated its diagnostic value. METHODS: MNDA expression in a cohort of 1293 cases of B-NHLs and 338  cases of reactive lymphoid hyperplasia (RLH) was determined using immunohistochemistry and compared among different types of B-NHL. The clinicopathologic relevance of MNDA in DLBCL was investigated. RESULTS: MNDA was highly expressed in MZLs (437/663, 65.9%), compared with the confined staining in marginal zone B-cells in RLH; whereas neoplastic cells with plasmacytic differentiation lost MNDA expression. MNDA expression was significantly higher in mantle cell lymphoma (MCL, 79.6%, p = 0.006), whereas lower in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL, 44.8%, p = 0.001) and lymphoplasmacytic lymphoma (LPL, 25%, p = 0.016), and dramatically lower in follicular lymphoma (FL, 5.2%, p < 0.001), compared with MZL. 29.6% (63/213) of DLBCLs were positive for MNDA. The cases in non-GCB group exhibited a higher rate of MNDA positivity (39.8%) compared to those in GCB group (16.3%) (p < 0.001), and MNDA staining was more frequently observed in DLBCLs with BCL2/MYC double-expression (50%) than those without BCL2/MYC double-expression (24.8%) (p = 0.001). Furthermore, there was a significant correlation between MNDA and CD5 expression in DLBCL (p = 0.036). CONCLUSIONS: MNDA was highly expressed in MZL with a potential utility in differential diagnosis between MZL and RLH as well as FL, whereas its value in distinguishing MZL from MCL, CLL/SLL is limited. In addition, MNDA expression in DLBCL was more frequently seen in the non-GCB group and the BCL2/MYC double-expression group, and demonstrated a correlation with CD5, which deserves further investigation. The clinical relevance of MNDA and its correlation with the prognosis of these lymphomas also warrant to be fully elucidated.

Response to anti-HER2 neoadjuvant chemotherapy in HER2-positive invasive breast cancers with different HER2 FISH patterns.

AIMS: Human epidermal growth factor receptor 2 (HER2)-positive patients with breast cancer may have different HER2/CEP17 ratios and HER2 copy numbers, with inconsistent responses to anti-HER2 neoadjuvant chemotherapy (NACT). Our study aimed to explore the relationship between different HER2 fluorescence in situ hybridisation (FISH) patterns in HER2-positive patients with breast cancer and responses to anti-HER2 NACT. METHODS: 527 patients with HER2-positive invasive breast cancer who received anti-HER2 NACT from 2015 to 2022 were included and divided into three groups by FISH results, namely group A: HER2/CEP17<2.0 and HER2 copy numbers ≥6.0, HER2 immunohistochemistry 2/3+; group B: HER2/CEP17≥2.0 and HER2 copy numbers ≥4.0 and <6.0; group C: HER2/CEP17≥2.0 and HER2 copy numbers ≥6.0. We compared clinicopathological characteristics and pathological complete response (pCR) rates of different groups. RESULTS: According to HER2 FISH results, 12 patients (2.3%, 12/527) were in group A, 40 (7.6%, 40/527) were in group B and 475 (90.1%, 475/527) were in group C. The pCR rate was the lowest in group B (5.0%), while the pCR rates in group A and group C were 33.3% and 44.4%, respectively (p (group A vs. B) =0.021, p (group C vs. B) < 0.001). Both univariate and multivariate analyses revealed that HER2 FISH pattern was correlated with pCR rate (p (group C vs. B) < 0.001, p (group C vs. B) = 0.025). CONCLUSIONS: Patients with HER2/CEP17≥2.0 and HER2 copy numbers ≥4.0 and <6.0 do not benefit to the same extent from current anti-HER2 therapies as FISH-positive patients with other patterns.

FOXC1 and SOX10 in Estrogen Receptor-Low Positive/HER2-Negative Breast Cancer: Potential Biomarkers for the Basal-like Phenotype Prediction.

CONTEXT.­: Breast cancer with low (1%-10%) estrogen receptor (ER) expression (ER-low positive) constitutes a small portion of invasive breast cancers, and the treatment strategy for these tumors remains debatable. OBJECTIVE.­: To characterize the features and outcomes of ER-low positive patients, and clarify the clinical significance of FOXC1 and SOX10 expression in ER-low positive/HER2-negative tumors. DESIGN.­: Among 9082 patients diagnosed with primary invasive breast cancer, the clinicopathologic features of those with ER-low positive breast cancer were characterized. FOXC1 and SOX10 mRNA levels were analyzed in ER-low positive/HER2-negative cases from public data sets. The expression of FOXC1 and SOX10 in ER-low positive/HER2-negative tumors was evaluated by immunohistochemistry. RESULTS.­: The clinicopathologic study of ER-low positive tumors indicated more aggressive characteristics compared with those tumors with ER >10%, while they had more overlapping features with ER-negative tumors irrespective of the HER2 status. The intrinsic molecular subtype of ER-low positive cases with high FOXC1 and SOX10 mRNA expression was more likely to be nonluminal. Among the ER-low positive/HER2-negative tumors, 56.67% (51 of 90) and 36.67% (33 of 90) were positive for FOXC1 and SOX10, respectively, which was significantly positively correlated with CK5/6 expression. In addition, the survival analysis demonstrated no significant difference between patients who received and who did not receive endocrine therapy. CONCLUSIONS.­: ER-low positive breast cancers biologically overlap more with ER-negative tumors. ER-low positive/HER2-negative cases demonstrate a high rate of FOXC1 or SOX10 expression, and these cases might be better categorized as a basal-like phenotype/subtype. FOXC1 and SOX10 testing may be used for the intrinsic phenotype prediction for ER-low positive/HER2-negative patients.

A clinicopathological study and survival analysis of 99 breast cancers with HER2/CEP17 ratio ≥ 2.0 and an average HER2 copy number < 4.0 per cell in China.

BACKGROUND: Breast cancer patients of American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) Group 2 were all HER2-negative according to the 2018 guideline, not HER2-positive as defined in the 2013 guideline. METHODS: We aims to elucidate the unique clinicopathological features of ASCO/CAP Group 2 patients by comparing with classic HER2-nonamplified cancers, and reveal the efficacy of the former to anti-HER2 therapy. The clinicopathological features, treatment and prognosis information of 99 patients between 2014 and 2018 were collected. HER2 status was re-defined using the updated recommendations. RESULTS: Of the 99 ASCO/CAP Group 2 tumors, 25.5% (25/99) tumors were immunohistochemical (IHC) 0/1+ and 74.7% (74/99) tumors were IHC 2+. According to the updated 2018 guideline, all of them were HER2 negative. When compared to ASCO/CAP Group 5, patients of ASCO/CAP Group 2 displayed higher ratio of histological grade 3 (P = .03), high Ki67 proliferation index (P = .03) and pN3 (more than 9 lymph nodes metastasis, P = .02), and lower estrogen receptor (ER) positivity (P = .04). There was no statistical difference in the survival of patients received anti-HER2 therapy and patients not received anti-HER2 therapy. CONCLUSIONS: Patients of ASCO/CAP Group 2 did not received apparent benefit from anti-HER2 treatment. Although according to the updated guidelines and latest reports, HER2 is negative, but when compared with classic HER2-nonamplified cancers, patients of this group seemed to be more aggressive. We suggest that this group still be regarded as an independent category, in order to accumulate more cases in the future to expand the scope of research.

FOXC1.

CONTEXT.­: Few studies have investigated the features of FOXC1 protein expression in invasive breast cancer subtypes as defined by immunohistochemistry (IHC)-based surrogate molecular classification. OBJECTIVE.­: To investigate the diagnostic utility of the IHC-based FOXC1 test in breast cancer subtyping and to evaluate the correlation between FOXC1 expression and clinicopathologic parameters in triple-negative breast cancer (TNBC). DESIGN.­: FOXC1 expression was evaluated with IHC in a large cohort of 2443 patients with breast cancer. Receiver operating characteristic (ROC) curves were used to assess the diagnostic ability of FOXC1 expression to predict the triple-negative phenotype and to identify the best cutoff value. FOXC1 expression was correlated with the clinicopathologic parameters of TNBC. RESULTS.­: The expression rate of FOXC1 in TNBC was significantly higher than in other subtypes. The area under the ROC curve confirmed the high diagnostic value of FOXC1 for the prediction of the triple-negative phenotype. The cutoff value of 1% showed a maximized sum of sensitivity and specificity. In TNBC, FOXC1 expression was significantly associated with aggressive tumor phenotypes. Furthermore, FOXC1 expression was primarily observed in invasive breast carcinoma of no special type and metaplastic carcinoma but rarely in invasive carcinoma with apocrine differentiation. Correspondingly, FOXC1 expression was significantly associated with the expression of basal markers but was negatively correlated with apocrine-related markers in TNBC. CONCLUSIONS.­: In conclusion, FOXC1 is a highly specific marker for the triple-negative phenotype. Moreover, IHC detection of FOXC1 expression can be used as an additional diagnostic tool for the triple-negative phenotype and subclassification in TNBC.

The clinicopathological relevance of uniform CD56 expression in anaplastic large cell lymphoma: a retrospective analysis of 18 cases.

BACKGROUND: Anaplastic large cell lymphoma (ALCL) with uniform CD56 expression is a rare condition, that has been described in limited literature, and its clinicopathological features have not yet been well illustrated. The aim of our study was to fully investigate the clinical, histological, immunohistochemical and molecular features of CD56+ ALCL. METHODS: The clinical and histological characteristics of CD56+ ALCL cases were retrospectively evaluated. The immunohistochemical phenotype, status of Epstein-Barr virus (EBV) and T-cell receptor (TCR) gene rearrangement were examined. Overall survival was also analyzed. RESULTS: Eighteen (5.8%) cases with diffuse CD56 expression were identified out of 313 archived ALCL cases with CD56 test. CD56 expression was significantly higher in ALK+ systemic ALCLs (sALCLs) (13/64, 20.3%) than in ALK- sALCLs (3/101, 3.0%) (p < 0.001) as well as primary cutaneous ALCLs (2/148, 1.4%) (p < 0.001). Regarding the CD56+ ALK+ sALCLs, the median age was 20 years (range, 8-60 years) with a male-to-female ratio of 2.3:1, and these cases more frequently affected extranodal sites (11/38, 28.9%) rather than lymph nodes (2/26, 7.7%) (p = 0.038). Eleven (84.6%) cases presented with stage I-II diseases, which was significantly more than their CD56- ALK+ counterparts (45.5%) (p = 0.015). Histologically, 2 ALK+ cases were of small cell variant and all the others displayed characteristic morphology of classic ALCL. Regarding the immunophenotype, both CD30 and CD56 were diffusely positive in all cases. CD3, CD43, anaplastic lymphoma kinase-1 (ALK1), TIA-1, EMA expression was observed in 30.8% (4/13), 90.9% (10/11), 100% (13/13), 100% (9/9), and 80.0% (8/10) cases, respectively. EBV infection was consistently absent. Monoclonal TCR gene rearrangement was found in 100% (5/5) of investigated ALK+ cases. Chemotherapy with a CHOP regimen was most frequently employed. The 3-year overall survival (OS) rate for CD56+ ALK+ patients was 92.0%, compared with 73.0% for their CD56- counterparts, but there was no significant difference in OS between the two groups (p = 0.264). CONCLUSIONS: Uniform CD56 expression is an unexpected condition in ALCL. Of ALK+ ALCLs, CD56 expression correlated with a high frequency of early stage and an extranodal predominance. It is of great importance to raise awareness of this condition and familiarity with its characteristic features to avoid diagnostic and therapeutic pitfalls. Further investigations are warranted for a better understanding of this unusual phenotype and the significance of CD56 expression in ALCL.

Invasive apocrine carcinoma of the breast: clinicopathologic features and comprehensive genomic profiling of 18 pure triple-negative apocrine carcinomas.

Pure invasive apocrine carcinoma is a rare type of primary breast cancer, constituting ~1% of all breast cancers. Since most pure invasive apocrine carcinomas are triple negative, the lack of targeted therapies for triple-negative breast cancer has fostered efforts to discover actionable molecular targets in these tumors. In this study, we analyzed the clinicopathologic characteristics and comprehensive genomic profiling of 18 patients with pure triple-negative apocrine carcinomas (TNACs) using a 324-gene panel assay (FoundationOne CDx). The median age of these patients was 55.5 years, and the postmenopausal status rate was 77.8%. In total, 83.3% of patients were diagnosed with histological grade II, and 16.7% were diagnosed with grade III. The majority of patients presented at an early tumor-node-metastasis (TNM) stage (I: 38.9%; II: 50.0%; and III: 11.1%). The mean Ki-67 index was 9.7%, and the percent of PD-L1 positivity was 11.7%. With a median follow-up period of 76.5 months, one patient died, and two experienced distant metastases. There were 61 clinically relevant genomic alterations among all 18 pure TNACs, and the mean tumor mutation burden (TMB) was 3 Mut/Mb. The top ranked altered genes were PIK3CA (72.2%), PTEN (33.3%) and TP53 (27.8%). There were four novel mutations found in PTEN and an actionable rearrangement involving FGFR2-TACC2 that has not been reported in breast cancer before. In total, 88.9%, 50%, 44.4%, and 16.7% of TNACs had at least one clinically relevant genomic alteration in genes involved in the PI3K/mTOR, cell cycle, RAS/RAF/MEK and growth factor receptor-related pathways, respectively. All patients had at least one clinically relevant genomic alteration, and 94.4% had at least one actionable alteration. To the best of our knowledge, this study is the largest genomic sequencing cohort of pure TNACs. Incorporation of comprehensive genomic profiling into TNACs might shed light on potential therapeutic opportunities for both targeted drugs and immune checkpoint inhibitors.

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.

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.

Male breast carcinoma: a clinicopathological and immunohistochemical characterization study.

Male breast carcinoma is a relatively rare disease. This study retrospectively investigated the clinicopathological features of 73 cases of male breast carcinoma in Chinese population, and classified the molecular subtype based on surrogate immunohistochemical definitions. The expression of GCDFP15, MGB, AR and FOXP1 were evaluated. Invasive carcinoma of no special type was the most common histological type in the study group (71.2%, 52/73). The luminal A and B subtypes were the major types of male breast carcinoma (60.9%, 34.8% respectively). AR and FOXP1 are expressed in 84.2% (48/57) and 71.9% (41/57) of the studied cases. Carcinoma of the luminal A subtype expressed GCDFP15 (73.5%, 25/34) and MGB (58.8%, 20/34) more frequently than cases of the luminal B subtypes (34.8%, 8/23 and 43.5%, 10/23, respectively; P = 0.004, P = 0.255, respectively). In conclusion, invasive carcinoma of no special type was the most common histological type in male breast carcinoma among Chinese population. Our study revealed that the luminal A and B subtypes were the major types of male breast carcinoma. AR and FOXP1 are highly expressed in male breast cancer. The luminal A subtype tends to express GCDFP15 and MGB more frequently than the luminal B subtype.

Down-regulated MYH11 expression correlates with poor prognosis in stage II and III colorectal cancer.

The MYH11 gene may be related to cell migration and adhesion, intracellular transport, and signal transduction. However, its relationship with prognosis is still uncertain. The aim of this study was to investigate correlations between MYH11 gene expression and prognosis in 58 patients with stage II and III colorectal cancer. Quantitative real-time polymerase chain reaction was performed in fresh CRC tissues to examine mRNA expression, and immunohistochemistry was performed with paraffin-embedded specimens for protein expression. On univariate analysis, MYH11 expression at both mRNA and protein levels, perineural invasion and lymphovascular invasion were related to disease-free survival (p<0.05; log-rank test). Cancers with lower MYH11 expression were more likely to have a poor prognosis. Otherwise, MYH11 expression was unrelated to patient clinicopathological features. On multivariate analysis, low MYH11 expression proved to be an independent adverse prognosticator (p<0.05). These findings show that MYH11 can contribute to predicting prognosis in stage II and III colorectal cancers.

[Metastases to the breast from non-mammary malignancies: a clinicopathologic study of 28 cases].

OBJECTIVE: To investigate the clinicopathologic characteristics and differential diagnosis of the metastases to the breast from non-mammary malignancies. METHODS: Twenty-eight cases were collected from 2004 to 2012;microscopic pathologic examinations and immunohistochemistry (EnVision method) were performed. RESULTS: (1) All except one patients were female, ranging from 16 to 77 years old (average 45.8 years). Twenty-six (92.9%) patients initially presented with the primary site lesions; while the other two (7.1%) patients initially presented with breast lesions. The mean interval from primary diagnosis to detection of metastatic breast lesions was 32 months (0-228 months). Fifteen patients (53.6%) had other metastases detected simultaneously or preceded the breast lesions. (2) Macroscopically, all the tumors were relatively circumscribed, with a mean diameter of 4.0 cm (0.6-12.0 cm). The histological types of the corresponding primary tumors were as follows: eight (28.6%) cases from lung adenocarcinoma, five (17.8%) from high-grade ovarian serous carcinoma, three (10.7%) from gastric adenocarcinoma, two (7.1%) from rectal adenocarcinoma, one (3.6%) from pancreatic neuroendocrine carcinoma, one (3.6%) from prostatic carcinoma, four (14.3%) from melanoma, and four (14.3%) from mesenchymal malignant tumors (three rhabdomyosarcomas and one epithelioid malignant peripheral nerve sheath tumor, MPNST). (3) Histologically, the metastatic tumors showed the morphologic characteristics of the primary tumors. Lymph-vascular invasion was observed in 19 cases. Immunohistochemical features of metastatic tumors were consistent with the primary tumors. Molecular markers for breast such as GCDFP15 and mammaglobin were negative. Metastatic tumors from lung adenocarcinoma expressed TTF-1 (8/8). Ovarian serous carcinoma metastases were positive for PAX8 (5/5) and WT1 (4/5). Gastric adenocarcinoma metastases were positive for CDX2 (3/3) and villin (1/3). Rectal adenocarcinoma metastases were positive for CDX2 (2/2). Pancreatic neuroendocrine tumor metastasis was positive for Syn and CgA (both 1/1). Prostate carcinoma metastasis was positive for AR, PSA and P504S (all 1/1). Melanoma metastases were positive for HMB45 (2/3) and S-100 protein (3/3). Rhabdomyosarcoma metastases were positive for vimentin, desmin and myoD1 (all 3/3). MPNST metastasis was positive for S-100 protein (1/1). (4) Follow-up data was available in 17 patients, with median follow-up time 54 months. The median survival from diagnosis to breast metastasis was 24 months.Seven of 17 patients died. CONCLUSIONS: Metastases to the breast from non-mammary malignancies are rare and show pathologic features of primary tumors. It is usually presumed to be a primary breast carcinoma. Histopathologic features and clinical history in conjunction with the immunohistochemical results should be considered in differentiating a secondary mass from a primary breast carcinoma.

The spectrum of primary mucosal CD30-positive T-cell lymphoproliferative disorders of the head and neck.

OBJECTIVE: To retrospectively investigate the clinicopathologic spectrum of primary mucosal CD30-positive T-cell lymphoproliferative disorders (PTCLDs) of the head and neck. STUDY DESIGN: Archives of PTCLDs primarily arising in head and neck mucosa were reviewed. Immunostaining of CD20, CD3, CD4, CD8, CD30, CD56, anaplastic lymphoma kinase (ALK), epithelial membrane antigen (EMA), cytotoxic molecules (TIA-1, granzyme B, or perforin), and Ki67; in situ hybridization for Epstein-Barr virus; and T-cell receptor gene rearrangement analysis were performed. RESULTS: Fourteen cases of primary mucosal anaplastic large cell lymphoma (M-ALCL) were identified, and no lymphomatoid papulosis (LyP) cases were found. All cases demonstrated atypical mononuclear neoplastic cells with diverse histology and cytomorphology. The typical immunophenotype of neoplastic cells was CD3-positive, CD4-positive, CD8-negative, CD30-positive, ALK-negative, and cytotoxic molecules-positive. Infiltration of inflammatory cells was common. All cases presented an indolent course, regardless of therapy. CONCLUSIONS: PTCLDs of the head and neck provisionally included M-ALCL alone.

[Detection of chromosomal translocations involving ALK gene in anaplastic large cell lymphoma by fluorescence in-situ hybridization and its clinical significance].

OBJECTIVE: To investigate clinicopathologic features and clinical value of the chromosomal translocation involving anaplastic lymphoma kinase (ALK) in anaplastic large cell lymphoma (ALCL) by fluorescence in situ hybridization (FISH). METHODS: A total of 55 cases, including 45 cases of ALCL and 10 reactive lymphoid hyperplasia, were collected during 1999 to 2006 in the Department of Pathology, Fudan University Shanghai Cancer Center, and Xinhua Hospital Affiliated to Shanghai Jiaotong University. All cases were studied by FISH using dual color break apart probes of ALK for detection of chromosomal translocation, compared with the previous results of immunohistochemistry (IHC) and reverse-transcriptase polymerase chain reaction (RT-PCR) for the detection of ALK aberrations. RESULTS: The result of FISH showed that the clear red and green fluorescence signals were detected in 38 cases of ALCL, in which conspicuous split signals were observed in tumor cells in 24 cases (63.2%), suggesting the rearrangement of the ALK locus, with multiple copies of ALK gene in one case. In addition, the rearrangement of the ALK locus was not identified in 14 of 38 cases (36.8%); and the FISH results were unable to be evaluated in 7 cases, because no fluorescent signals involving ALK gene were found or signals were too weak to be analyzed. The concordance for the detection ALK aberrations in ALCL between FISH and RT-PCR, FISH and IHC were both statistically significant (P < 0.01). Chromosomal translocation involving ALK gene was not found in all 10 cases of reactive lymphoid hyperplasia. CONCLUSIONS: ALCL is an entity of lymphoma characterized by special clinical presentation, morphology, and ALK aberrations. FISH is helpful for detection of the chromosomal translocations involving ALK in ALCL, however, the detection efficiency by FISH may be affected by storage time of the paraffin-embedded tissue; and therefore combined detection with IHC and RT-PCR could complement each other and help for differential diagnosis of ALK(+)ALCL from ALK(-)ALCL.

Measuring ß-tubulin III, Bcl-2, and ERCC1 improves pathological complete remission predictive accuracy in breast cancer.

Weekly PCb (paclitaxel + carboplatin) in neoadjuvant chemotherapy (NCT) for breast cancer has a high pathological complete remission (pCR) rate. The present study was to identify pCR predictive biomarkers and to test whether integrating candidate molecular biomarkers can improve the pCR predictive accuracy. Ninety-one breast cancer patients treated with weekly PCb NCT were retrospectively analyzed. Eleven candidate molecular biomarkers (Tau, ß-tubulin III, PTEN, MAP4, thioredoxin, multidrug resistance-1, Ki67, p53, Bcl-2, BAX, and ERCC1) were detected by immunohistochemistry in pre-NCT core needle biopsy specimens. We analyzed the relationship between these biomarkers and pCR. Univariate analysis showed that estrogen receptor, progesterone receptor, molecular classification (clinicopathological markers), and Tau, ß-tubulin III, p53, Bcl-2, ERCC1 (candidate molecular biomarkers) expression were associated with pCR rate; however, multivariate analysis revealed that only ß-tubulin III, Bcl-2, and ERCC1 were independent pCR predictive factors. Patients with ß-tubulin III negative, Bcl-2 negative, or ERCC1 negative tumors were associated with higher pCR rate, with OR (odds ratios) 6.03 (95% confidence interval [CI], 1.44-25.24, P = 0.014), 7.54 (95% CI, 1.52-37.40, P = 0.013), and 4.09 (95% CI, 1.17-14.30, P = 0.028), respectively. To compare different logistic regression models, built with different combinations of these variables, we found that the model integrating routine clinical and pathological variables, as well as the ß-tubulin III, Bcl-2, ERCC1 molecular biomarkers had the highest pCR predictive power. The area under the ROC curve for this model was 0.900 (95% CI, 0.831-0.968), indicating that it deserves further investigation. Trial name: Weekly Paclitaxel Plus Carboplatin in Preoperative Treatment of Breast Cancer.

Secretory breast carcinoma: a clinicopathological and immunophenotypic study of 15 cases with a review of the literature.

Secretory breast carcinoma is a rare breast cancer with indolent clinical behavior. Recent research showed that secretory breast carcinoma belongs to the phenotypic spectrum of basal-like breast carcinomas. In this study, a clinicopathological and immunophenotypic analysis of secretory breast carcinomas from 15 Chinese patients was conducted. This patient group consisted of 2 males and 13 females, with ages ranging from 10 to 67 years old (median, 36 years old). All patients presented with a painless and firm mass. Tumor size ranged from 10 to 55 mm. Most tumors were located in the outer upper quadrant of the breast. Two patients (2 of 13, 15%) displayed positive axillary lymph nodes. At the microscopic level, the presence of intracellular and extracellular secretory material was the most remarkable feature. Most cases showed mild dysplasia cytologically. All cases were negative for estrogen receptor, progesterone receptor and HER2. The expression rate of the basal-like marker (CK5/6 or epidermal growth factor receptor) was 87% (13 of 15). The basal-like phenotype was identified in 13 cases (87%). Follow-up time ranged from 10 to 55 months (median, 19 months). None of the cases had evidence of recurrence and metastasis. Our study reveals that secretory breast carcinoma is a distinct subset of invasive breast carcinoma, with expression of basal-like markers. It should be noted that secretory breast carcinoma is different from conventional basal-like breast carcinomas. Future studies are required to further understand the prognostic significance of the basal-like markers expression in secretory breast carcinomas.

Genetic alterations and protein expression of HER2 and chromosome 17 polysomy in breast cancer.

HER2/neu alteration detection in breast cancer is important for decision making of the HER2-targeted therapy. We retrospectively analyzed the HER2/neu status by fluorescence in situ hybridization and HER2 protein expression by immunohistochemistry in a cohort of 481 patients with invasive breast cancer. Fluorescence in situ hybridization showed that 57.4% of cases exhibited HER2 amplification but 41.4% did not, and 1.2% exhibited an equivocal status. Immunohistochemistry showed that 10.4%, 16.8%, 38.3%, and 34.5% of cases had scores of 0, 1+, 2+, and 3+, respectively. The HER2 status showed a moderate agreement with HER2 expression with a score of 0, 1+, and 3+ (κ = 0.576, P < .05), and the concordance rate was 90%, 61.7%, and 83.1%, respectively. The HER2 amplification occurred more likely in cases with higher immunohistochemistry scores (P < .001), and polysomy 17 was observed in 28.3% of cases, but more frequently in the HER2 amplification subgroup (33.3%) than in the HER2 nonamplification subgroup (20.1%) (P < .05). There was no significant correlation between the frequency of polysomy 17 and immunohistochemistry scores (P > .05). In the immunohistochemistry 2+ group, 56.5% cases showed HER2/neu amplification, and polysomy 17 occurred more likely in the HER2 amplification subgroup (34.6%) than in the HER2 nonamplification group (13.0%) (P < .001). We concluded that the HER2 status was correlated with HER2 protein expression levels, and it is necessary to determine the HER2 status for cases with immunohistochemistry 2+. The frequency of polysomy 17 was correlated with the HER2 copy number and partially contributed to HER2/neu amplification but not HER2 protein expression.

Matrix-producing carcinoma of the breast in the Chinese population: a clinicopathological study of 13 cases.

Matrix-producing carcinoma (MPC) of the breast is an extremely rare variant of metaplastic carcinoma. The aim of this study was to evaluate the clinicopathological features and immunohistochemical expression profile of this rare tumor in Chinese population. Thirteen cases of MPC were evaluated using morphology observation and immunohistochemistry. All tumors had invasive carcinoma with an abrupt transition to chondromyxoid matrix without an intervening spindle cell sarcomatoid component. The distribution of tumor cells was diffuse in eight cases and peripheral in five cases. Matrix distribution was diffuse or multifocal. Necrosis was present in 11 cases. An overt invasive ductal carcinoma was observed in 11 cases and the other two tumors were consistent with MPC arising in microglandular adenosis. Ten of 13 cases were triple negative (ER-, PR-, Her2/neu-). Eight of 10 triple negative cases were cytokeratin 5/6, cytokeratin 14 or epidermal growth factor receptor positive, consistent with the basal-like phenotype. S-100 protein was positive in all cases. At the time of initial diagnosis, one of 13 patients had lung metastasis and axillary lymph nodes metastasis. Follow-up time ranged from 6 to 30 months. All patients remained alive. One patient developed a soft tissue metastasis 24 months after surgery.

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 (T(FH)) 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 T(FH) 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, T(FH) cell markers are the only available markers that show high specificity for AITL. LVPTCL, NOS and/or FVPTCL, NOS may also arise from T(FH) cells and fall within the spectrum of AITL.