Peripheral Blood Lymphocytosis Research Articles

Histological varieties of Epstein–Barr virus-related lymph node lesion resembling autoimmune disease-like clinicopathological findings in middle-aged and elderly patients: A study of six cases

Six cases were studied to further clarify clinicopathological findings of Epstein–Barr virus (EBV)-related lymph node lesions showing autoimmune disease-like clinicopathological findings (EBVAID) in middle-aged and elderly patients. The patients, four males and two females, ranged in age from 53 to 74 years, with a median age of 62 years. Clinically, they were characterized by systemic lymphadenopathy, “B”symptoms, polyclonal hypergammaglobulinemia, elevated serum lactate dehydrogenese and a transient presence of various autoantibodies, as well as an infrequent presence of atypical lymphocytosis in peripheral blood. Two cases were associated with idiopathic thrombocytopenic purpura. The clinical course was self-limiting. Histologically, three patterns could be delineated: pattern A, follicular hyperplasia with pronounced arborizing vasculature in the expanded paracortex ( n=3); pattern B, follicular hyperplasia with pronounced interfollicular B-immunoblastic/plasma cell proliferation ( n=2); and pattern C, paracortical hyperplasia containing numerous large transformed lymphocytes ( n=1). In situ hybridization demonstrated a varying number of EBV-infected lymphocytes in the germinal center and in the interfollicular area. Polymerase chain reaction analysis demonstrated that neither clonal rearrangement of T-cell receptor gamma-chain nor immunoglobulin heavy-chain rearrangement was detected in the three cases examined. Although EBVAID appears to be rare in middle-aged and older adults, EBVAID exhibits histological variations and should be added to the differential diagnosis of various atypical or malignant lymphoproliferative disorders, in particular autoimmune-disease-associated lymphadenopathy and angioimmunoblastic T-cell lymphoma with a hyperplastic germinal center in middle-aged and elderly patients.

Subclinical chronic lymphocytic leukaemia associated with a 13q deletion presenting initially in the skin: apropos of a case

B-cell chronic lymphocytic leukaemia (B-CLL) represents a low-grade B-cell lymphoproliferative disease that is the most common leukaemia in adults. The neoplastic cell is an autoreactive CD5 CD23 B lymphocyte. B-CLL may involve the skin, typically in the context of known disease. We present a case of subclinical B-CLL presenting initially in the skin. A 73-year-old male developed a lesion on his right cheek in April 2003 compatible with basal cell carcinoma. The re-excision specimen contained a well-differentiated atypical lymphocytic infiltrate consistent with B-CLL along with residual carcinoma. Subsequent laboratory studies revealed peripheral blood lymphocytosis with smudge cells. A diagnosis was made of Rai stage 0 CLL. Chromosomal studies on peripheral blood showed a deletion at 13q14.3. Excision of a second primary skin carcinoma revealed a squamous cell carcinoma in association with B-CLL that was identical to his previously diagnosed skin involvement. This case identifies a cutaneous presentation of subclinical B-CLL. There are two prior reports describing B-CLL presenting initially in the skin. In one case, the infiltrates were incidental on a re-excision specimen. The second report suggests 16% of B-CLL patients have cutaneous manifestations as the first sign of disease.

Serum levels of syndecan-1 in B-cell chronic lymphocytic leukemia: Correlation with the extent of angiogenesis and disease-progression risk in early disease

Syndecan-1 is a transmembrane proteoglycan generally not expressed in mature B-cell neoplasias like chronic lymphocytic leukemia (CLL). Moreover, information dealing with the evaluation of soluble syndecan-1 in CLL are lacking. We measured syndecan-1 concentrations in serum drawn at the time of diagnosis from 67 B-cell CLL patients (Binet stage A, 46; stage B, 7; stage C, 14). For this purpose a syndecan-1 enzyme-linked immunosorbent assay (ELISA, Diaclone, Besancon, France) was used. Detectable levels of syndecan-1 were found in all patients, although serum concentrations were significantly lower in CLL patients in comparison to age- and sex-matched controls (P = 0.02; Mann-Whitney test). No correlation was found with Binet clinical stages (P = 0.796), β2-microglobulin (P = 0.923), hemoglobin level (P = 0.605), platelet count (P = 0.992) and lymphocyte doubling time (P = 0.709). Only an association with absolute peripheral blood lymphocytosis (PBL) (P = 0.01) and LDH (P = 0.05) could be detected. Serum levels of syndecan-1 did not parallel those of several angiogenic cytokines such as vascular endothelial growth factor (VEGF) (P = 0.963), basic fibroblastic growth factor (FGF-2) (P = 0.216), angiogenin (P = 0.478), metalloproteinase-9 (MMP-9) (P = 0.125) as well as bone marrow (BM) microvessel density (P = 0.110). The same applied with adhesion molecules such as CD54 (P = 0.233), CD108 (P = 0.799), CD44 (P = 0.816) and CD31 (P = 0.508). Interestingly, the inverse correlation (r = −0.4967; P = 0.03) between serum concentrations of syndecan-1 and plasma levels of stromal derived growth factor-1 (SDF-1) is in keeping with the different function, respectively, pro- and anti-apoptotic, of these molecules. In 46 Binet stage A patients, serum levels of syndecan-1 were further evaluated as a dichotomous variable with respect to progression-free survival (PFS), an end-point surrogate for overall survival in early B-cell CLL. The best separation of curves was seen with a cut-off point at the median value of syndecan-1 (i.e. 36.5 pg/ml). Median PFS was not reached in the patient group with low syndecan-1, compared to a median of 34 months observed in the remaining patients (P = 0.018; HR = 0.208; 95% CI = 0.115 – 0.816). At the multivariate analysis performed including variables significant in the univariate analysis [i.e. PBL (P = 0.03) and syndecan-1 (P = 0.01)], only syndecan-1 retained a trend of significance (P = 0.08).Despite the pro-angiogenic activity of syndecan-1 which mediates FGF-2 binding and activity, no correlation with either angiogenic cytokines or the extent of BM angiogenesis was found in CLL. The inverse correlation with plasma levels of SDF-1 suggests an involvement in the processes leading to apoptosis. Finally, our results highlight the involvement of syndecan-1 in the mechanisms of disease-progression of early CLL.

Differences between Peripheral Blood, Lymph Nodes and Bone Marrow in Expression of Integrins, ICAMs, CD38 and CD31 Correlate with Clinical Characteristics in B-CLL.

B-CLL patients have variable tumor mass distribution within major cell compartments, and as a consequence different clinical presentation. Adhesion molecules (AM) expression phenotype of integrins (CD11a, CD11b, CD11c, CD18, CD29, CD49c, CD49d and CD61), ICAMs (CD54, CD102 and CD50), CD38 and CD31 was determined in samples taken from peripheral blood (PB), bone marrow (BM) and lymph nodes (LN) by two/three color flow cytometry in 33 B-CLL patients. Differences for particular AM expression between compartments were quantified to express respective intensity and direction (gradients). We found following significant differences: stronger expression for CD11a and CD102 in PB than in BM, while CD54 was stronger in BM than in PB; CD11b and CD102 were stronger in PB than in LN, opposite to CD54 and CD38; CD102 was stronger in BM than in LN, while CD18, CD11a, CD11c and CD38 were stronger in LN then in BM. Observed gradients were compared with clinical and laboratory parameters: PB lymphocytosis, LN size, Spleen size, Total Tumor Mass score (TTM), TTM distribution (TD), BM failure (BMF), Rai and Binet stages. Peripheral blood lymphocytosis positively correlated with LN to PB gradient for CD11a, CD11b, CD18 and CD31 (p<0.05). Lymph node size negatively correlated with LN to PB gradient for CD11b and with BM to PB gradient for CD54 and CD61 (p<0.05). Spleen size negatively correlated with BM to PB gradient for CD11c and CD102 (p<0.05). TTM negatively correlated with BM to PB gradient for CD11c, CD61 and CD102 (p<0.05). TD positively correlated with LN to PB gradient for CD11b and CD102, and with BM to PB gradient for CD11c and CD102 (p<0.05). Isolated BMF irrespective of tumor load, as well as clinical stages that incorporate BMF (Rai and Binet) were associated with significant PB to BM gradient for CD18, CD11a, CD11c, CD49d, CD54 and CD102, and with PB to LN gradient for CD102 (p<0.05). Cluster analysis corroborated these findings. This study shows that expression of selected integrins, ICAMs, CD38 and CD31on B-CLL cells is significantly different among lymphoid compartments suggesting possible role in resulting clinical presentation. Taking together, this investigation disclosed yet unexplained interesting interactions and warrants further studies of AM role in B-CLL.

A phase II study of denileukin diftitox (ONTAK) in patients with fludarabine-refractory B-cell chronic lymphocytic leukemia

6649 Background: Some chronic lymphocytic leukemia (CLL) cells express CD25, a component of the IL-2 receptor. Denileukin diftitox (ONTAK, Ligand Pharmaceuticals) is a fusion protein of the enzymatically active domain of diphtheria toxin with interleukin-2 (IL-2),targeting malignancies expressing the medium and high affinity IL-2 receptors. We performed a phase II study to evaluate the efficacy and toxicity of ONTAK in patients with fludarabine-refractory CLL. Methods: Denileukin diftitox dose was 18μg/kg IV daily for 5 days every 3 weeks, for a maximum of 8 cycles. Patients were evaluated for response by clinical criteria. Results: Sixteen patients have been enrolled, with 11 patients being evaluable for response (completed 3 cycles), and 13 evaluable for toxicity (completed at least one full 5-day cycle). Fifty-six percent (9/16) were Rai stage III-IV, with a median of 3 prior therapies (range 1–6). Seven of 15 evaluated patients had more than 20% CD25(+) cells. The overall response was 27%, with 1 CR (9%, duration of response 9+ months) and 2 PR (18%, duration of response 5+, and 7+ months). One patient had a 71% decrease in absolute lymphocyte count while his lymphadenopathy increased on treatment. Four patients (45%) had progressive disease after cycles 3, 4, 4, and 7, respectively. Three of 16 patients treatment, and an additional 3/16 were removed from study by the investigators for toxicity. The grade 3/4 toxicities encountered were: neutropenia 4/13, thrombocytopenia 4/13, vascular leak syndrome 3/13, left ventricular cardiac dysfunction 1/13, hypotension 2/13, tachyarrhythmia 3/13, elevated PT 1/13, fatigue 1/13, rash 1/13, SIADH 1/13, constipation 1/13, vomiting 2/13, petechiae 1/13, transient elevation of GGT 1/13, transient elevation of AST/ALT 7/13, hyperglycemia 4/13, electrolyte imbalance 8/13, infection and/or febrile neutropenia 4/13, insomnia 1/13, visual disturbance 1/13, dyspnea 2/13, hypoxia 2/13. Conclusions: Denileukin diftitox has moderate activity in CLL, with toxicities that can be managed with adequate premedication and close monitoring. Two of three responses in peripheral blood lymphocytosis were seen in subjects with CD25(+) CLL cells. No significant financial relationships to disclose.

Primary Sézary Syndrome Commonly Shows Low-Grade Cytologic Atypia and an Absence of Epidermotropism

The dermatopathologic findings in cases of Sezary syndrome (SS) that arise in patients without a previous diagnosis of mycosis fungoides have not been well characterized. We evaluated the histologic findings in skin biopsy specimens from 31 patients with such primary SS and correlated them with clinical and hematologic parameters at the time of biopsy. The most characteristic histologic finding was the presence of a dermal perivascular lymphoid infiltrate, usually with mild to moderate cytologic atypia and variable numbers of eosinophils; epidermotropism was absent or minimal in 19 cases (61%). Reactive epidermal changes such as spongiosis, parakeratosis, and acanthosis also were present frequently (27 [87%], 17 [55%], 19 [61%] cases, respectively). The number of eosinophils present in skin biopsy specimens correlated with the level of peripheral blood lymphocytosis. In erythrodermic patients or patients with persistent xerosis and pruritus, it is important to carefully evaluate the degree of lymphocyte atypia in the dermal perivascular infiltrate and correlate with blood flow cytometric findings to diagnose primary SS. Many cases will lack the epidermotropism usually seen in mycosis fungoides.

Primary Sézary Syndrome Commonly Shows Low-Grade Cytologic Atypia and an Absence of Epidermotropism

The dermatopathologic findings in cases of Sézary syndrome (SS) that arise in patients without a previous diagnosis of mycosis fungoides have not been well characterized. We evaluated the histologic findings in skin biopsy specimens from 31 patients with such primary SS and correlated them with clinical and hematologic parameters at the time of biopsy. The most characteristic histologic finding was the presence of a dermal perivascular lymphoid infiltrate, usually with mild to moderate cytologic atypia and variable numbers of eosinophils; epidermotropism was absent or minimal in 19 cases (61%). Reactive epidermal changes such as spongiosis, parakeratosis, and acanthosis also were present frequently (27 [87%], 17 [55%], 19 [61%] cases, respectively). The number of eosinophils present in skin biopsy specimens correlated with the level of peripheral blood lymphocytosis. In erythrodermic patients or patients with persistent xerosis and pruritus, it is important to carefully evaluate the degree of lymphocyte atypia in the dermal perivascular infiltrate and correlate with blood flow cytometric findings to diagnose primary SS. Many cases will lack the epidermotropism usually seen in mycosis fungoides.

A gender-based score system predicts the clinical outcome of patients with early B-cell chronic lymphocytic leukemia

To facilitate the development of a prognostic model for early B-cell chronic lymphocytic leukemia (CLL), the Gruppo Italiano Malattie EMatologiche Maligne dell'Adulto (GIMEMA) proposes its multi-institutional effort as a working model. In total, 1138 newly diagnosed Binet stage A patients managed over the last 10 years outside the setting of clinical trials according to a "wait and see" policy form the basis of the present study aimed at investigating prognostic variables affecting disease progression, a surrogate endpoint for overall survival. A 3-stage risk system, simply obtained by summing the variables that proved significant in the multivariate analysis (i.e. short lymphocyte doubling time, advanced Rai substage, high peripheral blood lymphocytosis), is proposed. Clear-cut differences in the 10 year progression-free survival (PFS) were observed among patients scoring 0 (low risk), 1 (intermediate risk), 2-3 (high risk): 67.8, 41.0 and 24.8%, respectively (P<0.0001). The results of the Medical Research Council (MRC) suggesting a better clinical outcome for females prompted us to verify such a gender-related difference within our prognostic categories. Because changes in PFS only reflected gender for patients scoring 0 (P=0.04), the following prognostic subgroups are proposed: (1) females scoring 0; (2) males scoring 0; (3) patients scoring 1-3 whatever gender (10 year PFS: 76.2, 61.4 and 37.8%; P<0.00001). Our long-term database provides an adequate patient sample to generate a generalized risk stratification model based on clinical data. The indolent clinical outcome of women with early CLL is also supported by the higher frequency of the immunoglobulin heavy-chain variable (IgVH) mutational status and lower proportion of 17p and 11q deletions found in such a patient subset in the MRC CLL4 trial.

Polyclonal B-Cell Lymphocytosis Mimicking Malignant Lymphoma in a Newborn

We describe a 17-day-old newborn with fever and peripheral blood lymphocytosis. The circulating lymphocytes were large with lobulated and nucleolated nuclei. Their immature and uniform appearance raised the possibility of malignant lymphoma in the leukemic phase. Immunophenotypic study, however, showed that the lymphocytes were CD19(+) B cells with expression of both kappa and lambda light chains. Molecular biology study confirmed a polyclonal nature of the immunoglobulin heavy-chain gene. Cytogenetic analysis showed a normal karyotype, and viral cultures and serologic studies yielded negative results. The polyclonal lymphocytosis was self-limiting and disappeared within a month.

Therapy of Chronic Lymphocytic Leukaemia with Purine Nucleoside Analogues

Chronic lymphocytic leukaemia (CLL) is a neoplastic disease of unknown aetiology characterised by an absolute lymphocytosis in peripheral blood and bone marrow. The disease is diagnosed most commonly in the elderly with the median age at diagnosis being about 65 years. The purine nucleoside analogues (PNAs) fludarabine, cladribine (2-chlorodeoxyadenosine) and pentostatin (2'-deoxycoformycin) are highly active in CLL, both in previously treated and in refractory or relapsed patients. These three agents share similar chemical structures and mechanisms of action such as induction of apoptosis. However, they also exhibit significant differences, especially in their interactions with enzymes involved in adenosine and deoxyadenosine metabolism. Recent randomised studies suggest that fludarabine and cladribine have similar activity in CLL. However, clinical observations indicate the existence of cross-resistance between fludarabine and cladribine. Patients who received PNAs as their initial therapy and achieved long-lasting response can be successfully retreated with the same agent. PNAs administered in combination with other chemotherapeutic agents and/or monoclonal antibodies may produce higher response rates, including complete response (CR) or molecular CR, compared with PNAs alone or other treatment regimens. Management decisions are more difficult in elderly patients because of the apparent increase in toxicity of PNAs in this population. In elderly patients, we recommend chlorambucil as the first-line treatment, with PNAs in lower doses in refractory or relapsed patients. Myelosuppression and infections, including opportunistic varieties, are the most frequent adverse effects in patients with CLL treated with PNAs. Therefore, some investigators recommend routine antibacterial and antiviral prophylaxis during and after PNA treatment. This review presents current results and treatment strategies with the use of PNAs in CLL, especially in elderly patients.

Subclinical Chronic Lymphocytic Leukemia Associated with a 13Q Deletion Presenting Initially in the Skin: A Propos of a Case.

Introduction: B‐cell chronic lymphocytic leukemia (B‐CLL) represents a low grade B cell lymphoproliferative disease with overlapping features with small lymphocytic lymphoma. The neoplastic cell is an autoreactive CD5 CD23 B lymphocyte. B‐CLL may involve the skin, typically in the context of known disease. We present a case of subclinical B‐CLL presenting initially in the skin. Results: A 73‐year‐old male developed a lesion on his right cheek in April 2003 compatible with basal cell carcinoma. The re‐excision specimen contained a well differentiated atypical lymphocytic infiltrate consistent with B‐CLL along with residual carcinoma. Subsequent laboratory studies revealed slight thrombocytopenia and mild peripheral blood lymphocytosis. A diagnosis was made of stage 0 CLL. Chromosomal studies on peripheral blood showed a deletion at 13q14.3. Conclusion: This case represents a cutaneous presentation of subclinical B‐CLL. There are two prior reports describing B‐CLL presenting initially in the skin. In one case the infiltrates were incidental on a re‐excision specimen. The second report suggests 16% of B‐CLL patients have cutaneous manifestations as the first sign of disease. Data indicates that 13q14 deletion in B‐CLL in early stage disease may portend a more aggressive course, possibly explaining its early presentation in the skin in our case.

Serum angiogenin is not elevated in patients with early B-cell chronic lymphocytic leukemia but is prognostic factor for disease progression.

The association between angiogenin and cancer progression and poor outcome in solid tumors has been documented, but its significance in leukemias has not been evaluated. Using an ELISA technique (Quantikine Human Angiogenin Immunoassay; R&D Systems), we measured serum angiogenin levels in 77 previously untreated Binet stage A B-cell chronic lymphocytic leukemia (CLL) patients. No difference in angiogenin serum levels could be found between patients (median: 295 ng/mL; range: 74-1700) and 15 age- and sex-matched healthy controls (median: 264 ng/mL; range: 29-1835) (P = NS; Mann-Whitney test). Increased angiogenin serum level was associated with higher LDH (P = 0.03) and beta2-m (P = 0.007) concentrations. However, angiogenin did not reflect the extent of bone marrow (BM) angiogenesis as evaluated by microvessel area (P = 0.611), circulating levels of vascular endothelial growth factor (VEGF) (P = 0.873) and basic fibroblastic growth factor (FGF-2) (P = 0.421). When the 25 patients with available data were stratified into the four major cytogenetic categories (normal karyotype, 13q as a sole aberration, 12q trisomy, 11q or 17p deletion) and aberrations were compared with angiogenin serum levels, no correlation was found (P = 0.651; Kruskall-Wallis test). A cut-off of angiogenin serum level corresponding to median (i.e. 330 ng/mL) or higher identified later upstaging and longer progression-free survival (PFS). The 5-yr PFS was 51.5% for patients with angiogenin levels lower than median and 85% for patients with higher values [P = 0.03; hazard ratio (HR) = 2.86; 95% CI: 1.08-6.72]. Although in multivariate analysis only Rai substages (P = 0.00001) and peripheral blood lymphocytosis (P = 0.009) retained their prognostic significance, angiogenin could be incorporated into the Rai substages thus leading to the identification of the following risk categories: (i) stage 0 (angionenin >330 ng/mL); (ii) stage 0 (angiogenin <330 ng/mL) + stage I-II (angiogenin >330 ng/mL); and (iii) stage I-II (angiogenin <330 ng/mL). The 40-month PFS were as follows: 85%, 65%, 25% (chi(2) for trend = 6.33; d.f. = 1; P = 0.01). In conclusion, serum angiogenin levels although not increased in comparison with healthy controls, may predict clinical outcome of patients with early CLL and help to refine Rai's stratification.

Confirmation of the Activity of the Interleukin-2 Fusion Toxin Denileukin Diftitox against Chemorefractory Chronic Lymphocytic Leukemia, including Cases with Chromosome 17p Deletions and without Detectable CD25 Expression

Confirmation of the Activity of the Interleukin-2 Fusion Toxin Denileukin Diftitox against Chemorefractory Chronic Lymphocytic Leukemia, including Cases with Chromosome 17p Deletions and without Detectable CD25 Expression

T‐cell responses in atopic eczema

T‐cell responses in atopic eczema

Increased serum levels of matrix metalloproteinase-9 predict clinical outcome of patients with early B-cell chronic lymphocytic leukaemia.

Serum levels of matrix metalloproteinase-9 (MMP-9) which agree with progression in solid and haematological tumours were correlated to the risk of disease progression in 62 patients with early (Binet stage A) B-cell chronic lymphocytic leukaemia (CLL). Sera were taken at diagnosis and tested by an enzyme-linked immunosorbent assay. MMP-9 levels positively correlated with haemoglobin levels (P = 0.03) and platelet count (P = 0.03). No association was found with main clinico-haematological features representative of tumour mass, such as peripheral blood lymphocytosis, bone marrow histology, Rai substages and beta-2 microglobulin (beta-2m). A cut-off of MMP-9 levels corresponding to 33rd percentile (203 ng/mL) or higher identified earlier upstaging and shorter progression-free survival. MMP-9 was a significant prognostic marker in multivariate analysis and partially independent of Rai substages, which suggests its inclusion into such a staging system to better stratify prognostically Rai stages I and II patients. MMP-9 serum levels predict disease behaviour and help to refine the prognosis of stage A CLL patients.

CD5‐Negative, CD10‐Negative small B‐cell leukemia: Variant of chronic lymphocytic leukemia or a distinct entity?

CD5- and CD10-negative chronic lymphocytic leukemias are quite uncommon as compared to the CD5-positive CLL. We reviewed 250 sequential cases of peripheral blood lymphocytosis to characterize cases of small B-cell lymphoproliferative disorders, submitted with a clinical diagnosis of chronic lymphocytic leukemia exhibiting a non-classic immunophenotypic profile. Six cases of CD5-, CD10-negative chronic lymphocytic leukemias and no tissue involvement were identified that revealed high-density surface-membrane immunoglobulin and CD20 expression, with variable expression of CD11c, CD23, and CD25. Most had a profound leukocytosis (mean WBC 180 x 10(9)/L) with proliferation of mature-appearing lymphocytes. Subsequent bone marrow biopsies showed diffuse infiltration by neoplastic cells in all evaluated patients. The clinical course appeared indolent, with follow-up revealing three patients alive (survival time 38-68 months), while two died of unrelated causes and one was lost to follow-up soon after diagnosis. These cases may represent somewhat unusual chronic lymphoproliferative disorders, with morphologic features and immunophenotypic profile not readily classifiable, but which are certainly atypical for classic chronic lymphocytic leukemia. Some of these features are reminiscent of those seen in marginal-zone lymphoma. However, it is most unusual for this known to be tissue-based disease to present primarily as leukemia rather than lymphoma.

Leukemic Phase of B-Cell Lymphomas Mimicking Chronic Lymphocytic Leukemia and Variants at Presentation

Six cases of non-Hodgkin B-cell lymphoma that mimicked either chronic lymphocytic leukemia (CLL) or a CLL variant at presentation are reported. The patients ranged from 54 to 89 years and included three females and three males. All six patients had prominent peripheral blood lymphocytosis at presentation; the initial morphologic impression was CLL in three cases, CLL/prolymphocytic leukemia (PLL) in two cases, and PLL in one. Five patients had bone marrow biopsies; each showed a lymphoid infiltrate in a focally random, interstitial, and/or diffuse pattern. Flow cytometric immunophenotyping showed CD20-positive B cells with surface immunoglobulin (Ig) light chain restriction in all six patients. The five cases resembling CLL or CLL/PLL had at least a subset of CD5-positive B cells, whereas CD5 was absent in the one case that resembled PLL. CD23 was positive in three of the four cases studied that resembled CLL or CLL/PLL; CD79b was positive in three, FMC7 was positive in two, and surface Ig and CD20 were brightly positive in three. A t(11;14) (q13;q32) was found in four cases that resembled CLL or CLL/PLL; they were subsequently diagnosed as mantle cell lymphoma. The remaining two cases mimicking CLL or PLL were diagnosed as lymphomas of follicle center origin with leukemic phase based on the presence of t(14;18) (q32;q21). Thus although the morphology of these six cases resembled CLL or variants, and immunophenotyping by flow cytometry showed overlapping features, genetic studies enabled distinction of these leukemic non-Hodgkin lymphoma from chronic lymphocytic leukemia or variants.

Clinicoprognostic implications of increased serum levels of vascular endothelial growth factor and basic fibroblastic growth factor in early B-cell chronic lymphocytic leukaemia.

To assess the relative merit of increased serum levels of vascular endothelial growth factor and basic fibroblastic growth factor in predicting the risk of disease progression of patients with early B-cell chronic lymphocytic leukaemia we analyzed 81 Binet stage A patients whose sera were taken at the time of diagnosis and evaluated for the presence of vascular endothelial growth factor and basic fibroblast growth factor using an enzyme-linked immunosorbent assay. Serum levels of vascular endothelial growth factor positively correlated with Rai sub-stages (P=0.03), peripheral blood lymphocytosis (P=0.03), bone marrow histology (P=0.04) and β2-microglobulin (β2-m) (P=0.006). When dealing with basic fibroblast growth factor only a correlation with Rai sub-stages (P=0.02) could be found. Different cut-offs set on the basis of a stratification in quartiles, failed to demonstrate any correlation between serum levels of basic fibroblast growth factor and disease progression. In contrast, patients with increased serum levels of vascular endothelial growth factor (above median value, 203 pg ml−1) had a three times increased risk of disease progression, although, in multivariate analysis only Rai sub-stages (P=0.0001) and lymphocyte doubling time (P=0.002) retained their prognostic significance. Low levels of vascular endothelial growth factor were indicative of good clinical outcome in the subgroup of patients with either low (P=0.02) or high (P=0.03) β2-m concentration. Finally, the highest prognostic power was obtained when serum vascular endothelial growth factor and β2-m were examined in combination. Median of progression-free survival of patients who had both serum vascular endothelial growth factor and β2-m higher than median value was only 13 months, in contrast median progression-free survival of patients with one marker increased (i.e. above the 50th percentile) was 40 months. Patients with both markers below the median experienced the best clinical outcome (median progression-free survival not reached at 40 months). In conclusion, serum levels of either vascular endothelial growth factor or basic fibroblast growth factor are high in patients with early chronic lymphocytic leukaemia, however, only vascular endothelial growth factor predicts behaviour of disease and helps to refine the prognosis of stage A patients.British Journal of Cancer (2002) 86, 31–35. DOI: 10.1038/sj/bjc/6600022 www.bjcancer.com© 2002 The Cancer Research Campaign

A Mouse Model for Infectious Mononucleosis

Epstein-Barr virus (EBV) is a ubiquitous human gamma-herpesvirus that establishes life-long latency and is associated with lymphoproliferative disorders and the development of several malignancies. EBV infection is frequently, but not always, associated with the development of a syndrome termed infectious mononucleosis. The recent isolation and characterization of a murine gamma-herpesvirus, MHV-68 (gammaHV-68) has provided the first small animal model for studying immunity and pathogenesis of a gamma-herpesvirus in its natural host. MHV-68 has important biological and genetic similarities with the human gamma-herpesviruses. Following intranasal infection of mice with MHV-68, an acute respiratory infection in the lung develops and is cleared, followed by the establishment of latency. Similar to EBV, MHV-68 latency is largely established in B cells, although other cell types can be latently infected. The establishment of latency correlates with a prominent splenomegaly, polyclonal B cell activation with associated autoantibody production, and CD8+ T cell-dominated peripheral blood lymphocytosis, in many aspects mirroring EBV-induced infectious mononucleosis. There are key differences in the MHV-68- and EBV-induced CD8+ T cell responses however. Whereas the expanded CD8+ T cells associated with EBV-induced mononucleosis are largely the outgrowth of T cells responding to lytic viral epitopes elicited during the acute phase of the response, the CD8+ T cell lymphocytosis associated with MHV-68-induced infectious mononucleosis is dominated by an oligoclonal population of T cells expressing Vbeta4+ T cell receptors that are not reactive to acute viral epitopes. The focus of this article will be to highlight the similarities and differences in the infectious mononucleosis syndrome associated with human and murine gamma-herpesviruses.

Macrophages are increased in cervical epithelium of women with cervicitis

Background: Sexually transmitted diseases (STIs) are major causes of morbidity in women. The mechanisms involved in establishment of genital mucosal infection are poorly defined. Objective: To investigate changes in cervical...