Apmis

BENHARROCH, DANIEL; EINAV, INBAL; FELDMAN, ALEXANDRA; LEVY, AMALIA; ARIAD, SAMUEL; GOPAS, JACOB

doi: 10.1111/j.1600-0463.2010.02600.xpmid: 20477808

Benharroch D, Einav I, Feldman A, Levy A, Ariad S, Gopas J. Apoptosis of Hodgkin–Reed–Sternberg cells in classical Hodgkin lymphoma revisited. APMIS 2010; 118: 339–45. We scrutinized the role of apoptosis of the Hodgkin–Reed–Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL) and critically reviewed its features in the light of conflicting evidence. In this study, we found that tumor cells in this neoplasm showed inhibition of apoptosis in 55% of the 217 cHL cases only. It is also suggested that the two factors considered responsible for apoptosis inhibition in HRS cells, nuclear factor‐κB and the latent membrane protein‐1 of the Epstein–Barr virus, do not correlate with apoptosis inhibition, in contrast with the findings in the consensual pathogenetic scheme. The most significant association of HRS cell apoptosis was with p53, the negative expression of which related with a high apoptotic index (p = 0.001). These findings support our contention that the role of apoptosis in the HRS cells of Hodgkin lymphoma has not been completely elucidated and is at variance with that in the consensus.

MEJLHEDE, NINA; PEDERSEN, BO V.; FRISCH, MORTEN; FOMSGAARD, ANDERS

doi: 10.1111/j.1600-0463.2010.2602.xpmid: 20477809

Mejlhede N, Pedersen BV, Frisch M, Fomsgaard A. Multiple human papilloma virus types in cervical infections: competition or synergy? APMIS 2010; 118: 346–52. Coinfection with multiple human papilloma virus (HPV) types is common in cervical HPV infection. To evaluate if infections with different HPV types occur independently, we examined 3558 women above 15 years of age suspected of cervical HPV infection. Among them, 1842 (52%) women were HPV negative and 1716 (48%) were HPV positive as analysed by a PCR‐based commercial microarray assay for mucosal types. Of the HPV‐positive samples, 824 (48%) had single infections, while 892 (52%) had multiple infections. Observed numbers of concurrent HPV types differed from expected numbers under the assumption of independence between infections by the various HPV types. Significant positive associations were observed for 16 pairs of HPV types in statistical analysis accounting for mass significance. Significant negative associations were also found, i.e. women with HPV‐16 infection had 0.4 times the odds of having HPV‐51 compared with women not infected with HPV‐16. HPV‐16 was the only type with odds ratios <1 for all pairwise combinations. While our findings of statistically significant coexistence do not prove biological dependence among HPV types, they do suggest that infections with some HPV types may depend on the existence of certain other HPV types. Any interaction between coexisting HPV types could either decrease or increase the efficacy of current HPV vaccines that offer mainly type‐specific protection, depending on whether the types vaccinated against compete with other HPV types or not.

LI, XIN; DU, WEN; LIU, WEI; LI, XIAOQING; LI, HONGRUI; HUANG, SHI‐ANG

doi: 10.1111/j.1600-0463.2010.02603.xpmid: 20477810

Li X, Du W, Liu W, Li X, Li H, Huang S‐A. Comprehensive flow cytometry phenotype in acute leukemia at diagnostic and at relapse. APMIS 2010; 118: 353–59. Multiparameter flow cytometry (MFC) plays a vital role in the detection of minimal residual disease (MRD) and diagnosis of relapse in acute leukemia. However, application of a limited panel of antibodies in MFC leads to high rates of false‐negative and false‐positive results. Thirteen patients with acute lymphoblastic leukemia (ALL) and 12 patients with acute myeloid leukemia (AML) were immunophenotyped by MFC at diagnosis and at relapse using a comprehensive panel of monoclonal antibodies (McAbs) to 27 antigens and CD45/SSC gating. In 23 of 25 patients (92.3%), changes in at least one of progenitor‐associated, myeloid and lymphoid antigens between diagnosis and relapse were observed. Antigen changes were observed in 92 of 239 antigens (38.5%) expressed in 25 patients, in 49 of 117 antigens (41.9%) expressed in 13 ALL patients, and in 43 of 122 antigens (35.2%) expressed in 12 AML patients. Phenotypic changes were characterized by the expression of cross‐lineage antigens. The intralineage change was observed in the majority of patients. However, myeloid lineage shift was identified by MFC in two patients with T‐ALL. Multiple panels of three or more McAbs are likely to be required in the monitoring of MRD and diagnosis of relapse in acute leukemia by MFC.

VALDMAN, ALEXANDER; JARAJ, SARA JONMARKER; COMPÉRAT, EVA; CHARLOTTE, FRÉDERIC; ROUPRET, MORGAN; PISA, PAVEL; EGEVAD, LARS

doi: 10.1111/j.1600-0463.2010.02604.xpmid: 20477811

Valdman A, Jaraj SJ, Compérat E, Charlotte F, Roupret M, Pisa P, Egevad L. Distribution of Foxp3‐, CD4‐ and CD8‐positive lymphocytic cells in benign and malignant prostate tissue. APMIS 2010; 118: 360–5. Foxp3 is a transcription factor that inhibits antitumor immune response and is expressed in regulatory T cells (Tregs). High levels of Tregs have been reported in several human cancers. This study investigates the distribution of cells positive for Foxp3, CD4 and CD8 in benign prostatic tissues and prostatic carcinoma. Tissue microarrays were constructed from radical prostatectomy specimens of 36 patients. From each patient, six cores were taken: two cores from cancer, one from benign tissue of each of the peripheral (PZ), transition (TZ) and central zones (CZ) and one from atrophy. Foxp3‐, CD4‐ and CD8‐positive cells were more common in cancer than in non‐atrophic benign tissue (p < 0.01) and more common in atrophy than in non‐atrophic PZ, but did not differ significantly between cancer and atrophy. Cells positive for Foxp3 and CD4 were less prevalent in CZ than in PZ and TZ. Tregs infiltrate more in prostate cancer (PC) than in benign tissue. Their presence in atrophy may have relevance for the hypothesis on atrophy as a potential precursor lesion of PC. CZ has the lowest Treg levels, and a possible role for the low rate of cancer in this zone remains to be investigated.

ZAVADSKA, DACE; BĒRZIŅA, DACE; DRUKAĻSKA, LĪGA; PUGAČOVA, ŅINA; MIKLAŠEVIČS, EDVĪNS; GARDOVSKA, DACE

doi: 10.1111/j.1600-0463.2010.02607.xpmid: 20477812

Zavadska D, Bērzin¸a D, Drukal¸ska L, Pugačova N¸, Miklaševičs E, Gardovska D. Macrolide resistance in group A beta haemolytic Streptococcus isolated from outpatient children in Latvia. APMIS 2010; 118: 366–70. Group A streptococci (GAS) are responsible for up to 30% of cases of pharyngitis in children, and such children do not benefit from treatment with antibiotics. During the last decade, increased resistance to macrolides has emerged as a critical issue in the treatment of GAS pharyngitis. The objective of this study was to determine the antimicrobial resistance of group A beta haemolytic Streptococcus isolated from outpatient children. From 2002 to 2006, 96 GAS strains were obtained from the pharynx of outpatients having symptoms of acute pharyngitis. Antibiotic resistance was determined by disc susceptibility tests according to CLSI standards. The presence of ermA, ermB and mefA was established by the amplification of streptococcal DNA with specific primers. Antimicrobial susceptibility tests revealed that all the strains tested were sensitive to vancomycin, linezolid, penicillin and ceftriaxone. Simultaneously, high levels of resistance to macrolides were evident; 78% of the isolates were resistant to clindamycin and erythromycin. No significant change in the yearly or seasonal incidence of resistance was observed. We describe high antimicrobial resistance of GAS to macrolides in outpatient children (78%), which can be explained by the frequent use of macrolides in the treatment of such individuals. Therefore, macrolides should not be the first drug of choice.

AL‐SHIBLI, KHALID; AL‐SAAD, SAMER; ANDERSEN, SIGVE; DONNEM, TOM; BREMNES, ROY M.; BUSUND, LILL‐TOVE

doi: 10.1111/j.1600-0463.2010.02609.xpmid: 20477813

Al‐Shibli K, Al‐Saad S, Andersen S, Donnem T, Bremnes RM, Busund L‐T. The prognostic value of intraepithelial and stromal CD3‐, CD117‐ and CD138‐positive cells in non‐small cell lung carcinoma. APMIS 2010; 118: 371–82. The major value of prognostic markers in potentially curable non‐small cell lung carcinoma (NSCLC) should be to guide therapy after surgical treatment. Although tumor‐infiltrating T lymphocytes and plasma cells have been documented in NSCLC, a clear association with clinical outcome, especially for the stromal component, has not been well established. The aim of this study was to elucidate the prognostic significance of these cells/markers in the epithelial and stromal compartments of NSCLC. Tissue microarrays from 335 resected, stage I‐IIIA, NSCLC were constructed by duplicate cores from viable neoplastic epithelial and stromal areas. Immunohistochemistry was used to evaluate the infiltration of CD3+, CD117+ as well as CD138+ cells in epithelial and stromal areas. In univariate analyses, increasing numbers of stromal CD3+ (p = 0.001) and epithelial CD3+ cells (p = 0.004) correlated significantly with an improved disease‐specific survival. No such relation was noted with CD3+ or CD117+ cells. In the multivariate analysis, stromal CD3+ cells was an independent prognostic factor for disease‐specific survival (HR 1.925, CI 1.21–3.04, p = 0.005). Increased presence of the pan T‐cell marker, CD3, which is an independent factor, correlates with improved clinical outcome in NSCLC. This prognostic impact of T cells is clearer in the tumor stroma. Neither plasma cells nor mast cells were prognostic indicators in our cohort.

JARAJ, SARA JONMARKER; EGEVAD, LARS

doi: 10.1111/j.1600-0463.2010.02611.xpmid: 20477814

Jaraj SJ, Egevad L. Formalin fixation and immunoreactivity in prostate cancer and benign prostatic tissue. APMIS 2010; 118: 383–8. For better fixation, formalin injection of radical prostatectomy (RP) specimens has been suggested. We aimed to assess its effect on immunoreactivity using immunohistochemistry (IHC). A tissue microarray of cancer and benign tissues from 42 RP specimens was constructed. Twenty‐one of the prostates had been injected with formalin prior to formalin immersion. IHC staining was performed using 15 antibodies, including nuclear and cytoplasmic markers known to be positive in prostate tissue: pan cytokeratin, P504S, high molecular weight (HMW) keratin, PSA, vimentin, actin HHF35, thioredoxin‐1, peroxiredoxin‐2, PDX‐1, BAX, p27, androgen receptor (AR) and heat shock proteins (HSP) 27, 60 and 70. Differences in staining intensity in cancer and benign tissues were compared separately except for HMW keratin. Only 7 of 29 analyses showed significant differences between groups, including 5 of 15 antibodies. The expression of AR and HSP 27 was stronger in formalin‐injected tissue, while the opposite was true for HSP 60, HSP 70 and peroxiredoxin‐2. For most antibodies, formalin injection does not significantly affect immunoreactivity in prostate tissue. The staining variability caused by inter‐ and intratumoral heterogeneity may be greater than that caused by the fixation method.

SONG, SANG YONG; KANG, MI RAN; YOO, NAM JIN; LEE, SUG HYUNG

doi: 10.1111/j.1600-0463.2010.02612.xpmid: 20477815

Song SY, Kang MR, Yoo NJ, Lee SH. Mutational analysis of mononucleotide repeats in dual specificity tyrosine phosphatase genes in gastric and colon carcinomas with microsatellite instability. APMIS 2010; 118: 389–93. Coordinated protein phosphorylation and dephosphorylation are crucial in the regulation of cell signaling, and disruption of the coordination is known to play important roles in cancer development. Recent reports revealed that classical protein tyrosine phosphatase (PTP)‐encoded genes are somatically mutated in human colorectal cancer. However, data on dual specificity phosphatase (DPTP) gene mutations in human cancers are lacking. By analyzing a public genomic database, we found that five DPTP genes, CDC14A, MTM1, MTMR3, SSH1, and SSH2, have mononucleotide repeats in their coding DNA sequences. To see whether these genes are mutated in cancers with microsatellite instability (MSI), we analyzed the mononucleotide repeats in 26 gastric cancers (GC) with MSI (MSI‐H), 12 GC with low MSI (MSI‐L), 45 GC with stable MSI (MSS), 33 colorectal cancers (CRC) with MSI‐H, 14 CRC with MSI‐L, and 45 CRC with MSS by single‐strand conformation polymorphism (SSCP). We found CDC14A and MTMR3 mutations in five and one cancer (s), respectively. These mutations were detected in MSI‐H cancers, but not in MSI‐L or MSS cancers. The GC and CRC with MSI‐H harbored the mutations in 15% and 6%, respectively. The CDC14A and MTMR3 mutations detected in the GC and CRC were deletion or duplication mutations of one base in the nucleotide repeats that would result in premature stops of the amino acid syntheses. Our data show that frameshift mutations of DPTP genes in MSI‐H cancers occur at moderate frequencies. The data suggested that alterations in the CDC14A and MTMR3 genes may play a role in the development of GC and CRC with MSI‐H by deregulating phosphatase functions possibly together with mutations of classical PTP genes.

SURA, RADHAKRISHNA; GAVRILOV, BORIS; FLAMAND, LOUIS; ABLASHI, DHARAM; CARTUN, RICHARD; COLOMBEL, JEAN‐FRÉDÉRIC; VAN KRUININGEN, HERBERT J.

doi: 10.1111/j.1600-0463.2010.02613.xpmid: 20477816

Sura R, Gavrilov B, Flamand L, Ablashi D, Cartun R, Colombel J‐F, Van Kruiningen HJ. Human herpesvirus‐6 in patients with Crohn’s disease. APMIS 2010; 118: 394–400. Human herpesvirus‐6 (HHV‐6) infections are usually asymptomatic reactivations in immunocompetent persons, but may be severe in immunocompromised individuals. Although primary HHV‐6 infection is mainly associated with roseola infantum, it has also been associated with gastroenteritis, diarrhea, and nausea in children. In this study, we investigated the potential role of HHV‐6 in Crohn’s disease (CD). Evidence of HHV‐6 infection in CD patients and controls was determined by immunohistochemistry (IHC), polymerase chain reaction (PCR), and quantitative real‐time PCR (qPCR). Fifty‐one tissue blocks from 23 CD patients and 20 tissue blocks from 20 controls were examined. Quantitativereal‐time PCR was used to assess HHV‐6 viral loads. IHC, PCR and qPCR indicated the presence of HHV‐6 in both CD patients and controls. Immunohistochemistry of tissues revealed an almost equal frequency and distribution of positive cells; however, non‐specific immunostaining confounded interpretation. HHV‐6 DNA was detected in 52% (12/23) of CD and 55% (11/20) of control patients by PCR and in 69.5% (16/23) of CD cases and 65% (13/20) of controls by qPCR. Mean viral load in intestinal tissues was similar in CD and controls (33.4 and 57.9 copies μg−1 DNA, respectively). Finding equal evidence of HHV‐6 in patients and controls by multiple methods suggests that this virus is ubiquitous and probably not a cause of CD.

TANAHASHI, JIN; KASHIMA, KENJI; DAA, TSUTOMU; YADA, NAOMI; TANAKA, KO‐ICHI; KAWANO, YOZOH; YOKOYAMA, SHIGEO

doi: 10.1111/j.1600-0463.2010.02606.xpmid: 20477817

Tanahashi J, Kashima K, Daa T, Yada N, Tanaka K‐I, Kawano Y, Yokoyama S. Pulmonary myoepithelial carcinoma resembling matrix‐producing carcinoma of the breast: case report and review of the literature. APMIS 2010; 118: 401–6. We report a case of pulmonary myoepithelial carcinoma with extensive myxohyaline stroma, resembling matrix‐producing carcinoma of the breast. A 76‐year‐old Japanese man presented with a nodular lesion in the left lung (S8), and underwent partial resection of the left lower lobe. Microscopically, the resected tumor was relatively well circumscribed with central hypocellular myxohyaline and peripheral hypercellular area. In the central area, eosinophilic and clear polygonal cells proliferated in a cord‐like or reticulated pattern with extensive myxohyaline stroma, while the peripheral area was composed of solid lobules of different shapes and sizes with occasional comedonecrosis. The tumor cells were markedly atypical with frequent mitotic figures. Vascular and lymphatic invasion was evident with regional lymph node metastasis. No squamous or glandular differentiation was evident in the tumor. Immunohistochemical staining implied myoepithelial differentiation. The patient developed multiple brain metastases, and died of the disease 11 months after the surgery. In this report, we discuss the histopathologic uniqueness of the present case together with a review of the literature.