Clinicopathological findings, prognosis, and Epstein-Barr virus infection in rheumatoid arthritis patients with other iatrogenic immunodeficiency-associated T- and NK-cell lymphoproliferative disorders.

BACKGROUND: Other iatrogenic immunodeficiency-associated (OIIA) T- and natural killer (NK)-cell lymphoproliferative disorders (TNK-LPDs) are rare in patients with rheumatoid arthritis (RA). METHODS: We investigated the clinicopathological characteristics, Epstein-Barr virus (EBV) infection, genetic findings, therapeutic response, and prognostic factors in 21 RA patients with OIIA TNK-LPDs and compared these with those of 39 with OIIA B-cell LPDs (B-LPDs) and 22 with non-OIIA B-LPDs. RESULTS: Immunohistologically, 11 patients (52%) showed CD4+ T-LPDs, and 7 had a T follicular helper (TFH) phenotype. The other nine patients (43%) showed CD8+ T-LPDs, and the remaining one (5%) had features of CD3+ CD4- CD8- nasal type TNK-cell lymphoma. CD30+, p53+, and CMYC+ atypical lymphocytes were identified in seven (33%), eight (38%), and five (24%) patients, respectively. In situ hybridisation detected EBV-encoded RNA (EBER) + large atypical lymphocytes in five patients (24%). Nine of 17 patients (53%) showed clonal peaks of TCRγ by polymerase chain reaction. Withdrawal of MTX and biologic drugs was effective in 12 patients (57%), and 8 (38%) received chemotherapies. Two patients with TFH+ or EBV+ CD4+ CD30+ large cell peripheral T-cell lymphoma, one with CD8+ systemic anaplastic large cell lymphoma, and two with systemic EBV+ CD8+ T-cell lymphoma of childhood showed a lethal progressive clinical course within 13 months. Moreover, > 500 U/L LDH, large atypical lymphocytes, expression of CD30, p53, and CMYC, and EBER+ atypical lymphocytes were significantly poor prognostic factors for overall survival (p < 0.05). Median interval from RA onset to OIIA TNK-LPDs was 72 months, which was shorter than 166 months in OIIA B-LPDs (p = 0.003). EBV+ atypical and reactive lymphocytes were frequently found in 15 patients with OIIA TNK-LPDs (71%), in 27 with OIIA B-LPDs (69%), and only in 3 with non-OIIA B-LPDs (14%). CONCLUSIONS: OIIA TNK-LPDs occurred in early phase of RA, compared with OIIA B-LPDs, and occasionally showed a lethal progressive clinical course. Detection of OIIA TNK-LPD patients with poor prognostic factors is necessary. EBV infection in immunosuppressed patients due to persistent RA, MTX, and biologic drugs may play a role in forming the tumour microenvironment and lymphomagenesis of TNK-LPDs.

Robot-assisted thoracic surgery for intercostal cavernous hemangioma.

Intercostal cavernous hemangioma is extremely rare among benign vascular tumors. Achieving a definitive diagnosis preoperatively by radiographic examination alone is difficult; surgical resection is usually needed. Occasional cases are found as giant tumors, and some grow substantially during observation without treatment. Such tumors require extended surgical resection; however, small tumors can be completely resected by tumor extirpation alone. Thus, immediate surgical resection while the tumor is small might help to avoid invasive surgery. We herein describe cases of intercostal cavernous hemangioma with no invasion to the surrounding tissues, successfully treated by complete tumor resection using robot-assisted thoracic surgery.

Induction immunotherapy followed by surgery for hilar unicentric Castleman disease.

Castleman disease is a rare disease borne of a B cell lymphoproliferative disorder of uncertain cause. Standard therapy for the unicentric type of Castleman disease localized as a single mass or single lymph-node station is surgical extirpation. Nevertheless, in the thoracic cavity, unresectable cases or cases of incomplete extirpation of the tumor without lung scarring owing to tumor size/location have been noted. In such cases, lung resection (e.g., lobectomy, pneumonectomy) or additional therapy (immunotherapy, chemotherapy, radiotherapy) after resection is required. However, few instances of patients receiving induction immunotherapy or chemotherapy followed by surgery have been reported. Here, we describe a 21-year-old woman with unicentric Castleman disease originating from the left hilum. The tumor seemed to involve/be in contact with the pulmonary vein and bronchus. Tumor location indicated that initial resection was necessary to sacrifice upper and lower pulmonary lobes. To avoid these pulmonary resections, induction therapy followed by surgery was selected. Induction therapy using rituximab was very efficacious. Resection after induction therapy was completed only by tumor extirpation, and resulted in preservation of pulmonary function. Thoracic surgeons might consider induction therapy followed by resection if the tumor is resectable UCAD, but initial resection is needed and sacrifices a large amount of pulmonary function.

Programmed cell death-ligand 1 (PD-L1)+ tumour cells and low-reacting programmed cell death 1 (PD1)+ tumour-infiltrating lymphocytes predict poor prognosis in Epstein-Barr virus+ diffuse large B-cell lymphoma.

Epstein-Barr virus (EBV)+ diffuse large B-cell lymphoma (DLBCL) has specific tumour cell characteristics, and these patients have worse outcomes than EBV-negative DLBCL patients. We compared 38 EBV+ DLBCL patients with 43 methotrexate-associated EBV+ B-cell lymphoproliferative disorders (MTX+/EBV+ BLPDs) and 30 non-germinal centre (GC) subtype DLBCL. Lymphoma cells of the EBV+ DLBCL group were positive for BCL2 in 17 patients (44.7%), CMYC in 23 patients (60.5%), and p53 in 33 patients (86.8%), which was significantly higher than in the MTX+/EBV+ BLPD group (P < 0.05), and were positive for CD30 in 29 patients (76.3%), compared with two in non-GC subtype DLBCL (6.7%) (P < 0.0001). Significantly more EBV+ DLBCL patients (n = 16, 42.1%) had programmed cell death-ligand 1 (PD-L1)+ tumour cells than patients with non-GC subtype DLBCL (n = 5, 16.7%; P = 0.024), and PD-L1+ tumour cells were more common in advanced stages than in early stages (P = 0.048). Twenty-five EBV+ DLBCL patients (69.4%) had few reactive PD1+ tumour-infiltrating lymphocytes (TILs), compared with 12 patients with MTX+/EBV+ BLPDs (37.5%) (P = 0.008). In the EBV+ DLBCL group, CD30, BCL2, CMYC, and p53 expression was not related to patient prognosis. Poor outcomes were associated with PD-L1+ tumour cells (P = 0.001) and low-reacting PD1+ TILs (P = 0.02), while their combination conferred a worse outcome (P < 0.0001). Immune evasion by PD-L1+ tumour cells and exhaustion of PD1+ TILs may occur in EBV+ DLBCL patients, and PD-L1/PD1 interactions may influence tumour progression and poor prognosis.

Large cell morphology, CMYC+ tumour cells, and PD-1+ tumour cell/intense PD-L1+ cell reactions are important prognostic factors in nodal peripheral T-cell lymphomas with T follicular helper markers.

BACKGROUND: The clinicopathological characteristics and prognostic factors in nodal peripheral T-cell lymphomas (PTCLs) with two or more T follicular helper markers (TFH+) are not adequately investigated. METHODS: Immunohistologically, we selected 22 patients with TFH+ lymphoma (PTCL-TFH) in 47 of PTCL-not otherwise specified (NOS), and subclassified into large and small cell groups. We compared the two groups with 39 angioimmunoblastic T-cell lymphoma (AITL) and seven follicular T-cell lymphoma (F-TCL) patients. Prognostic factors were analysed by overall survival in patients with three types of TFH+ PTCLs. RESULTS: Thirteen large cell and nine small cell PTCL-TFH patients had more than two TFH markers including programmed cell death-1 (PD-1). Large cell PTCL-TFH showed frequent CMYC expression in 10 patients (77%), and four of 11 large cell group (36%) had somatic RHOA G17V gene mutation by Sanger sequencing. Large cell PTCL-TFH patients showed significantly worse prognosis than those of the small cell group, AITL, and F-TCL (p < 0.05). In TFH+ PTCLs, CMYC+ tumour cells, and combined PD-1 ligand 1 (PD-L1) + tumour cells and intense reaction of PD-L1+ non-neoplastic cells (high PD-L1+ cell group) were significantly poor prognostic factors (p < 0.05). Combinations of CMYC+ or PD-1+ tumour cells and high PD-L1+ cell group indicated significantly poor prognosis (p < 0.01). CONCLUSION: Large cell PTCL-TFH indicated poor prognosis in TFH+ PTCLs. These data suggested that CMYC+ tumour cells and intense PD-L1+ cell reaction influenced tumour cell progression in TFH+ PTCLs, and PD-1+ tumour cell/intense PD-L1+ cell reactions may play a role in immune evasion.

A case of small cell neuroendocrine carcinoma of the ampulla of Vater.

BACKGROUND: Gastroenteric neuroendocrine carcinomas (NECs) account for 6.2% of gastroenteric neuroendocrine tumors (NETs), and only 1% or less of gastroenteric NETs occur in the ampulla of Vater (AoV). Clinical features of NEC of the AoV remain obscure. CASE PRESENTATION: A 65-year-old man visited a general practitioner because of jaundice, and an abdominal contrast-enhanced computed tomography scan revealed a tumor of 11 mm in diameter, which was enhanced in the arterial phase at the duodenal papilla, with dilation of the upstream bile duct. Gastrointestinal scope revealed an unexposed tumor of the AoV. Based on a biopsy of the site, a moderately differentiated tubular adenocarcinoma was suspected, and pancreatoduodenectomy was performed. Histopathological examination revealed dysplasia and highly proliferative small tumor cells, with solid and nodular formation at the AoV. Histological analysis showed a high mitotic count, and immunohistochemical staining revealed a Ki-67 index of 40-50% and cells positive for synaptophysin, chromogranin A, and p53. Small cell-type NEC was finally diagnosed. Four months post pancreatoduodenectomy, multiple liver metastases developed, and systemic chemotherapy was administered. Salvage liver resection for liver metastases was performed 14 months after the pancreatoduodenectomy. Unfortunately, multiple liver metastases developed 2 months after liver resection, and the patient died 18 months after the pancreatoduodenectomy. CONCLUSIONS: Neuroendocrine carcinoma originating from the bile duct is very rare; therefore, in this article, we provide a review of the literature and a case report.

Clinical and cytopathological characteristics of HTLV-1+ hodgkin lymphoma.

BACKGROUND: Human T-lymphotropic virus-1 (HTLV-1)+ Hodgkin lymphoma (HL) is difficult to differentiate from adult T-cell leukemia/lymphoma (ATLL) with HL-like histology (HL-like ATLL). METHODS: Cytological and immunohistological features, HTLV-1 proviral DNA integration, and rearrangements of the T-cell receptor (TCR) Cß1 gene were examined in 11 HTLV-1+ patients with HL-like disease. RESULTS: Six patients were classified as HTLV-1+ HL and five as HL-like ATLL in accordance with genetic findings of HTLV-1 proviral DNA integration and rearrangements of the TCR Cß1 gene. Small ordinary looking lymphocytes with round nuclei were detected in the background of six patients with HTLV-1+ HL, which were immunohistochemically negative for CD25 and CC chemokine receptor (CCR)4 and had a low MIB1 labeling index (mean: 28.3%). In the HL-like ATLL specimens, small- and medium-sized atypical lymphocytes with indented and irregular-shaped nuclei were found, and were diffusely positive for CD25 and CCR4, with high MIB1 labeling (mean: 76%). Both groups had scattered CD30+ and CD15+ Hodgkin and Reed Sternberg (RS) giant cells, with or without CD20 expression and Epstein-Barr virus infection. The 50% overall survival period was significantly longer for the HTLV-1+ HL group (180 months) than for the HL-like ATLL group (7.8 months; P = .004). CONCLUSIONS: HTLV-1+ HL showed typical small lymphoid cells with a low MIB1 labeling index in a background of Hodgkin and RS cells, with some scattered CD25+ and CCR4+ lymphocytes. In HTLV-1 endemic areas, distinguishing HTLV-1+ HL from HL-like ATLL is important because of their differing treatment strategies and prognoses.

Cytological tumour cell characteristics and reactive small lymphocytes influence patient prognosis in acute and lymphoma type adult T-cell leukaemia/lymphoma.

OBJECTIVE: Acute and lymphoma type adult T-cell leukaemia/lymphoma (ATLL) patients show an aggressive clinical course. While some clinical signs indicate good prognosis, definitive cytohistological prognostic factors have yet to be described. METHODS: We classified 65 ATLL patients into three groups by tumour cell size and nuclear pleomorphism on fine-needle aspiration and tumour touch smear samples. Semi-quantitative analysis of background small lymphocytes, reactive CD20-positive B cells and CD8-positive T cells was performed. RESULTS: Thirty-one patients had pleomorphic lymphoma with predominantly medium-sized cells and coarse granular nuclei. Another 24 patients showed pleomorphic large cell lymphoma with stippled chromatin. The remaining 10 demonstrated monomorphic large lymphoma cells with fine granular chromatin. Patients with pleomorphic lymphoma with medium-sized cells showed significantly higher serum lactate dehydrogenase and lower CD30 and C-MYC expression in lymphoma cells than the other two groups (P = .0216, P < 0.01, respectively). Patients with pleomorphic medium-sized ATLL had few usual small lymphocytes observed on routine morphological examination and showed less concurrent detection of CD20-positive B cells and CD8-positive T cells, both of which were lower than in the other two groups (P = .006, P = .019, respectively). Furthermore, ATLL patients with predominantly medium-sized lymphocytes exhibited a worse prognosis than patients with pleomorphic large cells (P = .0197). Background small lymphocytes and concurrent detection of CD20-positive B cells and CD8-positive T cells may thus be good prognostic factors (P = .011, P = .021, respectively). CONCLUSIONS: Morphological features, size of neoplastic cells and background non-neoplastic lymphocyte (B cells and CD8-positive T cells) volume appear to influence the prognosis of patients with aggressive-type ATLL.

A case of metastatic brain tumor mimicking an expanding thalamic hematoma.

BACKGROUND: Brain tumor are a major etiology of secondary intracranial hemorrhage (ICH) because ICH in patients with cancer often occurs from an intratumoral hemorrhage. However, it is sometimes difficult to detect a tumor when it is tiny and buried, especially during initial examination. CASE DESCRIPTION: A 65-year-old woman who was diagnosed with pulmonary small cell carcinoma 6 months previously developed sudden-onset consciousness disturbance and left hemiparesis. Head computed tomography (CT) showed a round, high-density lesion with a diameter of 31 mm in the right thalamus. There was no enhancement with administration of contrast agent. Five days later, CT revealed significant progression of the hematoma in the thalamus with perifocal edema. She underwent total removal of the hematoma. Histopathological examination revealed a tiny cluster of metastatic cancer tissue within the hematoma. CONCLUSIONS: When cerebral hemorrhage occurs in a cancer patient, we must consider the possibility of hemorrhage due to a brain metastasis.

Multiple Brain Metastases from Pancreatic Adenocarcinoma Manifesting with Simultaneous Intratumoral Hemorrhages.

BACKGROUND: Pancreatic adenocarcinoma rarely metastasizes to the brain, and clinical features of brain metastasis in such cases remain elusive. To the best of our knowledge, only 21 cases of brain metastasis from pancreatic adenocarcinoma have been previously reported in the English language literature. CASE DESCRIPTION: A 61-year-old woman was diagnosed with pancreatic adenocarcinoma and began chemotherapy 1 year 4 months before the current admission. Three days before the current admission, she developed acute dysarthria. She was referred to a cancer center, where neuroradiologic examination showed multiple metastatic brain tumors, including a 30-mm-diameter tumor in the right cerebellar region. She was transferred to our institute. Three days after admission, she developed sudden-onset disturbance of consciousness and left hemiparesis. Computed tomography and magnetic resonance imaging of the head showed that the metastatic lesions had increased in size with development of intratumoral hemorrhage and obstructive hydrocephalus. She underwent urgent removal of the tumor in the cerebellum. Obstructive hydrocephalus was relieved, and her consciousness improved immediately after surgery. She was transferred to the palliative care unit of the cancer center and died under hospice care 3 weeks after surgery. CONCLUSIONS: This case demonstrates that brain metastases from pancreatic adenocarcinoma can enlarge suddenly and simultaneously with intratumoral hemorrhage even without coagulation disorders, resulting in neurologic deterioration in a short time. Surgical resection of metastatic brain lesions from pancreatic adenocarcinoma has an extremely limited role, but such treatment can remove neurologic symptoms and temporarily improve the patient's quality of life in selected cases.

Analysis of centromere signal patterns in breast cancer cells with chromosomal instability using image cytometry combined with centromere fluorescence in situ hybridization.

Fluorescence in situ hybridization (FISH) with centromeric probes is a method used to detect chromosomal instability (CIN), a hallmark of most cancers. However, no studies thus far have investigated the relationship between centromeric FISH signals and the cell cycle in cancer cells. In this study, the chromosome content in each cell cycle phase was evaluated with respect to the number of centromeric FISH signals in two breast cancer cell lines and eight surgically resected breast cancer specimens using image cytometry. Variations in chromosome number were detected at each phase of the cell cycle but were not associated with proliferative capacity in the cell lines. Furthermore, the chromosome doubling frequency differed in each cell line and clinical specimen. These results reveal two aspects of centromeric FISH signal variation in breast cancers that exhibit CIN, and suggest that chromosome doubling is a remarkable occurrence that may increase the heterogeneity of tumors.

Copy number aberrations using multicolour fluorescence in situ hybridization (FISH) for prognostication in non-muscle-invasive bladder cancer (NIMBC).

OBJECTIVE: To investigate if detection of copy number aberrations of chromosomes 3, 7, 9p21, and 17 using multicolour fluorescence in situ hybridization (FISH) predicts patient outcome in non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: In all, 118 bladder wash samples were prospectively collected from patients who underwent transurethral resection of bladder tumour (median age 50.5 years, male/female: 91/27, tumour grade 1/2/3: 18/52/42, stage pTis/Ta/T1: 8/62/42) from 2007 to 2010. The 118 samples were analysed using the UroVysion® kit to detect the copy numbers of chromosomes 3, 7, 9p21, and 17. The variant fraction (VF; the sum of the non-modal copy number fraction of each chromosome) was defined as abnormal when the percentage was ≥16%. The percentage deletion of 9p21 (fraction of null or one copy number of the 9p21 locus) was defined as abnormal when the percentage was ≥12%. Maffezzini risk criteria were also analysed in our cohorts. RESULTS: There was recurrence in 57 (48.3%) patients and disease progression in 12 (10.1%), with a median follow-up of 35.7 months. Multivariate analysis showed that the percentage 9p21 loss (>12%) was an independent prognostic factor for recurrence (P < 0.001, odds ratio [OR] 3.24, 95% confidence interval [CI] 1.85-5.62). For disease progression, tumour grade, positive urine cytology, concurrent carcinoma in situ, and a mean VF of >16% were significant prognostic factors in univariate analysis. In multivariate analysis, a mean VF of >16% was a prognostic factor for disease progression (P = 0.048, OR 6.07, 95% CI 1.02-57.45). CONCLUSIONS: Multicolour-FISH analysis using a commercially available kit could be a powerful tool not only for diagnosis, but also for prognostication in patients with NMIBC.

Elucidation of proliferative capability of mononuclear tetraploid cells, emerging spontaneously from diploid cells, using image cytometry and fluorescence in situ hybridization.

OBJECTIVES: Proliferation of tetraploid cells (TCs) emerging from diploid cells is considered to be a critical event toward tumourigenesis, or cancer progression. Recently, several studies have reported that binuclear TCs emerging from normal cells are capable of mitosis, however, it has not been confirmed directly whether mononuclear TCs emerging from normal cells could proliferate, even cancer cells. The aim of this study is to detect mononuclear TCs in vitro, spontaneously emerging from diploid cells and to elucidate their proliferative capability directly. For this purpose, we have developed a novel method. MATERIALS AND METHODS: In this study, two completely disomic cell lines were used, TIG-7, a fibroblast cell line and CAL-51, a breast cancer cell line. Cells were cultured on microscope slides and their DNA content was determined using an image cytometer. On the same slides, chromosome numbers were scored using centromere fluorescence in situ hybridization (FISH). For evaluating proliferative capability of TCs, bromodeoxyuridine (BrdUrd) incorporation and colony-forming ability were examined. RESULTS: Using our method, spontaneous emergence of mononuclear TCs was detected in both TIG-7 and CAL-51. Colonies of TIG-7 TCs were not observed, but were observed of CAL-51 TCs. CONCLUSIONS: Our method enables detection of mononuclear TCs and elucidation of their proliferative capability, directly; this evidence reveals that mononuclear TIG-7 TCs do not proliferate but that mononuclear CAL-51 TCs are able to.

Degenerate polymerase chain reaction strategy with DNA microarray for detection of multiple and various subtypes of virus during blood screening.

BACKGROUND: The risk of transferring blood-borne infections during transfusion is continually increasing because of newly emerging and reemerging viruses. Development of a rapid screening method for emerging viruses that might be transmitted by transfusion is required to eliminate such pathogens during blood donor screening. Owing to increased use of human materials in organ transplants and cell therapy, the risk of donor-transmitted viral infections is also increasing. Although nucleic acid amplification technology (NAT) is dedicated to blood screening, a small, convenient detection system is needed at the laboratory and hospital level. STUDY DESIGN AND METHODS: We developed a new pathogen detection system that can detect multiple viruses simultaneously, using originally designed degenerate polymerase chain reaction primers to amplify a wide range of viral genotypes. Amplified samples were identified using a DNA microarray of pathogen-specific probes. RESULTS: We detected very low copy numbers of multiple subtypes of viruses, such as human hepatitis C virus (HCV), human hepatitis B virus (HBV), human parvovirus B19 (PVB19), and West Nile virus (WNV), using a single plate. We also detected all genotypes of human immunodeficiency virus (HIV) but sensitivity was less than for the other viruses. CONCLUSION: We developed a microarray assay using novel primers for detection of a wide range of multiple pathogens and subtypes. Our NAT system was accurate and reliable for detection of HIV, HBV, HCV, PVB19, and WNV, with respect to specificity, sensitivity, and genotype inclusivity. Our system could be customized and extended for emerging pathogens and is suitable as a future NAT system.

Germline copy number variations associated with breast cancer susceptibility in a Japanese population.

Although copy number variations (CNVs) are expected to affect various diseases, little is known about the association between CNVs and breast cancer susceptibility. Therefore, we investigated this relation. Array comparative genomic hybridization was performed to search for candidate CNVs related to breast cancer susceptibility. Subsequent quantitative real-time polymerase chain reaction was carried out for confirmation. We found seven CNV markers associated with breast cancer risk. The means of the relative copy numbers of patients with a history of breast cancer and women in the control group were 0.8 and 1.8 for Hs06535529_cn on 1p36.12 (P < 0.0001), 2.9 and 2.2 for Hs03103056_cn on 3q26.1 (P < 0.0001), 1.2 and 1.8 for Hs03899300_cn on 15q26.3 (P < 0.0001), 1.0 and 1.5 for Hs03908783_cn on 15q26.3 (P < 0.0001), and 1.1 and 1.7 for Hs03898338_cn on 15q26.3 (P < 0.0001), respectively. Interestingly, nine or more copies of Hs04093415_cn on 22q12.3 were found only in 8/193 (4.1 %) patients with a history of breast cancer and in none of the controls (P = 0.0081). Similarly, 12 or more copies of Hs040908898_cn on 22q12.3 were found only in 7/193 (3.6 %) patients with a history of breast cancer and in none of the controls (P = 0.016). A combination of two CNVs resulted in 80.3 % sensitivity, 80.6 % specificity, 82.4 % positive predictive value, and 78.3 % negative predictive value for the prediction of breast cancer susceptibility. These findings may lead to a new means of risk assessment for breast cancer. Confirmatory studies using independent data sets are needed to support our findings.

Synovial sarcoma arising in the vulva cytogenetically confirmed by SYT break-apart rearrangement fluorescence in situ hybridization: A case report and discussion of diagnostic methods.

Synovial sarcoma (SS) is a soft tissue sarcoma of unknown histogenesis that rarely occurs in the female genital tract. We report a case of SS occurring in the right vulva of a young Japanese female. The tumor was composed of poorly differentiated rounded cell areas, surrounded by fibroblastic spindle-shaped cell areas. Immunohistochemically, the tumor cells were focally positive for cytokeratin, vimentin, CD99, Bcl-2 and neuron-specific enolase. The tumor was suspected, but was difficult to confirm as it was an SS based solely on light-microscopic and immunohistochemical findings. Although reverse transcription polymerase chain reaction (RT-PCR) failed to detect SS-specific SYT-SSX fusion gene transcripts using an RNA sample extracted from the formalin-fixed paraffin-embedded tumor tissue, SYT break-apart rearrangement fluorescence in situ hybridization (SYT bar-FISH) successfully confirmed our diagnosis of SS for the tumor. Thus, SYT bar-FISH may be more suitable for the purpose of the molecular diagnosis of SS than conventional RT-PCR when using archival formalin-fixed paraffin-embedded tissue specimens.

DNA copy number aberrations associated with lymphovascular invasion in upper urinary tract urothelial carcinoma.

Recent studies have reported that lymphovascular invasion (LVI) is a predictor of patient prognosis in upper urinary tract urothelial carcinoma (UUTUC). DNA copy number aberrations (DCNAs) identified by array-based comparative genomic hybridization (aCGH) had not previously been examined in UUTUC. We therefore examined DCNAs in UUTUC and compared them with DCNAs in LVI. We applied aCGH technology using DNA chips spotted with 4,030 BAC clones to 32 UUTUC patients. Frequent copy number gains were detected on chromosomal regions 8p23.1 and 20q13.12, whereas frequent copy number losses were detected on chromosomal regions 13q21.1, 17p13.1, 6q16.3, and 17p11.2. DCNAs occurred more frequently in tumors with LVI than in those without it (P = 0.0002), and this parameter was more closely associated with LVI than with the tumor grade or pT stage. Disease-specific survival rate was higher in tumors without LVI than in those with it (P = 0.0120); however, tumor grade and stage were not significant prognostic factors of patient outcome. These data support our hypothesis that tumors with LVI have more genetic alterations in terms of total numbers of DCNAs than those without, and provide proof that aggressive adjuvant therapy should be considered for UUTUC patients with LVI.

Luminal A and luminal B (HER2 negative) subtypes of breast cancer consist of a mixture of tumors with different genotype.

BACKGROUND: The St Gallen International Expert Consensus 2011 has proposed a new classification system for breast cancer. The purpose of this study was to elucidate the relationship between the breast cancer subtypes determined by the new classification system and genomic characteristics. METHODS: Invasive breast cancers (n = 363) were immunohistochemically classified as follows: 111 (30.6%) as luminal A, 95 (26.2%) as luminal B (HER2 negative), 69 (19.0%) as luminal B (HER2 positive), 41 (11.3%) as HER2, and 47 (12.9%) as basal-like subtypes. RESULTS: The high expression of Ki-67 antigen was detected in 236 tumors; no cases of luminal A subtype showed high expression of the Ki-67 antigen, but more than 85% of tumors of the other subtypes showed high expression. In addition, DNA ploidy and chromosomal instability (CIN) were assessed using imaging cytometry and FISH, respectively. In this series, 336 (92.6%) tumors consisted of 129 diploid/CIN- and 207 aneuploid/CIN + tumors. Diploid/CIN- and aneuploid/CIN+ features were detected in 64.9% and 27.9% of luminal A, 41.1% and 49.5% of luminal B (HER2-), 11.6% and 81.2% of luminal B (HER2+), 4.9% and 90.2% of HER2, and 17.0% and 76.6% of basal-like subtypes, respectively. Unlike the luminal B (HER2+), HER2 and basal-like subtypes, the luminal A and luminal B (HER2-) subtypes were heterogeneous in terms of DNA ploidy and CIN. CONCLUSIONS: It is reasonable to propose that the luminal A and luminal B (HER2-) subtypes should be further divided into two subgroups, diploid/CIN- and aneuploid/CIN+, based on their underlying genomic status.

Loss of 6q or 8p23 is associated with the total number of DNA copy number aberrations in adenoid cystic carcinoma.

We analyzed 10 adenoid cystic carcinomas (ACCs) of the salivary glands by array-based comparative genomic hybridization (a-CGH) using DNA chips spotted with 4,030 bacterial artificial chromosome clones. After the data smoothing procedure was applied, a total of 88 DNA copy number aberrations (DCNAs) were detected. The frequent (≥30%) DCNAs were loss of 6q23-27 and 8p23, and gains of 6p, 6q23, 8p23 and 22q13. High-level gains were detected on 12q15, including MDM2 in two cases. These two cases showed an immunohistochemically high-level (>50%) expression of MDM2 and a low-level expression of p53 (<20%). Furthermore, the total number of DCNAs was significantly greater in ACCs with loss of 6q compared to other ACCs, and in ACCs without the loss of 8p23 compared to other ACCs, respectively. Although limitations exist, a-CGH detected several candidate chromosomal imbalances associated with accumulation of DCNAs in ACCs.