Kenneth A. MacLennan

Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from the International Peripheral T-cell Lymphoma Project

The International Peripheral T-cell Lymphoma Project is a collaborative effort to better understand peripheral T-cell lymphoma (PTCL). A total of 22 institutions submitted clinical and pathologic material on 1314 cases. One objective was to analyze the clinical and pathologic features of 340 cases of PTCL, not otherwise specified. The median age of the patients was 60 years, and the majority (69%) presented with advanced stage disease. Most patients (87%) presented with nodal disease, but extranodal disease was present in 62%. The 5-year overall survival was 32%, and the 5-year failure-free survival was only 20%. The majority of patients (80%) were treated with combination chemotherapy that included an anthracycline, but there was no survival advantage. The International Prognostic Index (IPI) was predictive of both overall survival and failure-free survival (P < .001). Multivariate analysis of clinical and pathologic prognostic factors, respectively, when controlling for the IPI, identified bulky disease (≥ 10 cm), thrombocytopenia (< 150 × 10(9)/L), and a high number of transformed tumor cells (> 70%) as adverse predictors of survival, but only the latter was significant in final analysis. Thus, the IPI and a single pathologic feature could be used to stratify patients with PTCL-not otherwise specified for novel and risk-adapted therapies.

Marginal Zone B-Cell Lymphoma: A Clinical Comparison of Nodal and Mucosa-Associated Lymphoid Tissue Types

PURPOSE In the International Lymphoma Study Group classification of lymphoma, extranodal marginal zone B-cell lymphoma (MZL) of mucosa-associated lymphoid tissue (MALT) type is listed as a distinctive entity. However, nodal MZL is listed as a provisional entity because of questions as to whether it is truly a disease or just an advanced stage of MALT-type MZL. To resolve the issue of whether primary nodal MZL without involvement of mucosal sites exists and whether it is clinically different from extranodal MALT-type lymphoma, we compared the clinical features of these two lymphomas. PATIENTS AND METHODS Five expert hematopathologists reached a consensus diagnosis of MZL in 93 patients. Seventy-three were classified as having MALT-type MZL because of involvement of a mucosal site at the time of diagnosis, and 20 were classified as having nodal MZL because of involvement of lymph nodes without involvement of a mucosal site. RESULTS A comparison of the clinical features of nodal MZL and MALT-type MZL showed that more patients with nodal MZL presented with advanced-stage disease (71% v 34%; P =. 02), peripheral lymphadenopathy (100% v 8%; P <.001), and para-aortic lymphadenopathy (56% v 14%; P <.001) than those with MALT-type MZL. However, fewer patients with nodal MZL had a large mass (> or = 5 cm) than those with MALT-type MZL (31% v 68%; P =.03). The 5-year overall survival of patients with nodal MZL was lower than that for patients with MALT-type MZL (56% v 81%; P =.09), with a similar result for failure-free survival (28% v 65%; P =.01). Comparisons of patients with International Prognostic Index scores of 0 to 3 showed that those with nodal MZL had lower 5-year overall survival (52% v 88%; P =.025) and failure-free survival (30% v 75%; P =.007) rates than those with MALT-type MZL. CONCLUSION Nodal MZL seems to be a distinctive disease entity rather than an advanced stage of MALT-type MZL because the clinical presentations and survival outcomes are different in these two types of MZL. Clinically, nodal MZL is similar to other low-grade, node-based B-cell lymphomas, such as follicular and small lymphocytic lymphomas.

Comparison of ABVD and Alternating or Hybrid Multidrug Regimens for the Treatment of Advanced Hodgkin's Lymphoma: Results of the United Kingdom Lymphoma Group LY09 Trial (ISRCTN97144519)

PURPOSE To perform an open-label, randomized, controlled trial comparing treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with two multidrug regimens (MDRs) for advanced Hodgkins lymphoma (HL). PATIENTS AND METHODS Eight hundred seven patients with advanced HL (stage III to IV, or earlier stage with systemic symptoms or bulky disease) were randomly assigned between ABVD and MDR specified before randomization as alternating chlorambucil, vinblastine, procarbazine, and prednisolone (ChlVPP) with prednisolone, doxorubicin, bleomycin, vincristine, and etoposide (PABIOE), or hybrid ChlVPP/etoposide, vincristine, and doxorubicin (EVA). Radiotherapy was planned for incomplete response or initial bulk disease. RESULTS At 52 months median follow-up, 212 event-free survival (EFS) events (disease progression or any death) were reported. In the primary comparison, at 3 years EFS was 75% (95% CI, 71% to 79%) for ABVD and 75% (95% CI, 70% to 79%) for MDRs (hazard ratio [HR] = 1.05; 95% CI, 0.8 to 1.37; HR more than 1.0 favors ABVD). The 3-year overall survival (OS) rates were 90% (95% CI, 87% to 93%) in patients allocated ABVD and 88% (95% CI, 84% to 91%) in patients allocated MDRs (HR = 1.22; 95% CI, 0.84 to 1.77). Patients receiving MDRs experienced more grade 3/4 infection, mucositis, and neuropathy. One occurrence of myelodysplastic syndrome was reported, but no acute leukemia was reported. When the two MDRs are compared separately with ABVD, neither the alternating nor the hybrid regimen showed a statistically significant difference from ABVD for EFS or OS. Subgroup analysis suggested that MDRs may be associated with poorer outcomes in older patients (heterogeneity test of OS older or younger than 45 years, P = .020). CONCLUSION There was no evidence of significant difference in EFS or OS between ABVD and MDRs in the trial overall or if the two MDR versus ABVD comparisons are considered separately. ABVD remains the standard for treatment of advanced HL.

Enhanced large intestinal potassium permeability in end-stage renal disease.

The capacity of the colon for potassium (K+) secretion increases in end‐stage renal disease (ESRD), to the extent that it makes a substantial contribution to K+ homeostasis. This colonic K+ adaptive response may reflect enhanced active K+ secretion, and be associated with an increase in apical membrane K+ permeability. In this study, this hypothesis was tested in patients with normal renal function or ESRD, by evaluating the effect of barium ions (a K+ channel inhibitor) on rectal K+ secretion using a rectal dialysis technique, and the expression of high conductance (BK) K+ channel protein in colonic mucosa by immunohistochemistry. Under basal conditions, rectal K+ secretion was almost threefold greater (p < 0.02) in ESRD patients (n = 8) than in patients with normal renal function (n = 10). Intraluminal barium (5 mmol/l) decreased K+ secretion in the ESRD patients by 45% (p < 0.05), but had no effect on K+ transport in patients with normal renal function. Immunostaining using a specific antibody to the BK channel α‐subunit revealed greater (p < 0.001) levels of BK channel protein expression in surface colonocytes and crypt cells in ESRD patients (n = 9) than in patients with normal renal function (n = 9), in whom low levels of expression were mainly restricted to surface colonocytes. In conclusion, these results suggest that enhanced colonic K+ secretion in ESRD involves an increase in the apical K+ permeability of the large intestinal epithelium, which most likely reflects increased expression of apical BK channels. Copyright

Prostate-specific membrane antigen: evidence for the existence of a second related human gene.

Prostate-specific membrane antigen (PSM) is a glycoprotein recognised by the prostate-specific monoclonal antibody 7E11-C5, which was raised against the human prostatic carcinoma cell line LNCaP. A cDNA clone for PSM has been described. PSM is of clinical importance for a number of reasons. Radiolabelled antibody is being evaluated both as an imaging agent and as an immunotherapeutic in prostate cancer. Use of the PSM promoter has been advocated for gene therapy applications to drive prostate-specific gene expression. Although PSM is expressed in normal prostate as well as in primary and secondary prostatic carcinoma, different splice variants in malignant tissue afford the prospect of developing reverse transcription-polymerase chain reaction (RT-PCR)-based diagnostic screens for the presence of prostatic carcinoma cells in the circulation. We have undertaken characterisation of the gene for PSM in view of the proteins interesting characteristics. Unexpectedly, we have found that there are other sequences apparently related to PSM in the human genome and that PSM genomic clones map to two separate and distinct loci on human chromosome 11. Investigation of the function of putative PSM-related genes will be necessary to enable us to define fully the role of PSM itself in the development of prostatic carcinoma and in the clinical management of this malignancy.

Strong BCL10 nuclear expression identifies gastric MALT lymphomas that do not respond to H pylori eradication.

Approximately 75% of gastric mucosa associated lymphoid tissue (MALT) lymphomas can be cured by Helicobacter pylori eradication.1 It would be very useful to identify, at the time of diagnosis, the 25% of cases of gastric MALT lymphoma that will not respond to H pylori eradication. In general, lymphomas at stage IIE or above do not respond to H pylori eradication.2–4 However, the prognostic value of staging in stage IE cases is very limited, although tumours that involve the muscularis propria or serosa (stage IE2) show a higher failure rate than those restricted to the mucosa and submucosa (stage IE1).2–4 Paradoxically, the majority of gastric MALT lymphomas at diagnosis are at stage IE but 20% of these cases will not respond to H pylori eradication. In a previous study, we have examined the value of t(11;18)(q21;q21) in prediction of the response …

Biochemical Detection of Novel Anaplastic Lymphoma Kinase Proteins in Tissue Sections of Anaplastic Large Cell Lymphoma

The (2;5) translocation, found in many T-cell and null cell anaplastic large cell lymphomas (ALCLs), creates a hybrid gene encoding the 80-kd NPM-ALK protein. Typically neoplastic cells show labeling of both nucleus and cytoplasm for anaplastic lymphoma kinase (ALK) and for the N-terminus of nucleophosmin (NPM). However, 10-20% of cases exhibit cytoplasmic labeling only for ALK, indicating the probable presence of variants of the classical (2;5) translocation that do not involve the NPM gene. We report the detection (using Western blotting and an in vitro kinase assay) in seven such ALCL cases, of ALK proteins with molecular masses of 85 kd, 97 kd (one case exhibiting a (2;3)(p23;q21) translocation), 104 kd (one case carried a (1;2)(q21;p23) translocation), and 113 kd. Tyrosine kinase activity was detected in four of these proteins, but the N-terminal portion of NPM could not be detected. These results show how ALCL cases that express ALK proteins other than NPM-ALK can be detected by sensitive biochemical techniques using routine cryostat sections.

Classification of non-Hodgkin lymphoma in Central and South America: a review of 1028 cases

The distribution of non-Hodgkin lymphoma (NHL) subtypes differs around the world but a systematic study of Latin America has not been done. Therefore, we evaluated the relative frequencies of NHL subtypes in Central and South America (CSA). Five expert hematopathologists classified consecutive cases of NHL from 5 CSA countries using the WHO classification and compared them to 400 cases from North America (NA). Among the 1028 CSA cases, the proportions of B- and T-cell NHL and the sex distribution were similar to NA. However, the median age of B-cell NHL in CSA (59 years) was significantly lower than in NA (66 years; P < .0001). The distribution of high-grade (52.9%) and low-grade (47.1%) mature B-cell NHL in CSA was also significantly different from NA (37.5% and 62.5%; P < .0001). Diffuse large B-cell lymphoma was more common in CSA (40%) than in NA (29.2%; P < .0001), whereas the frequency of follicular lymphoma was similar in Argentina (34.1%) and NA (33.8%), and higher than the rest of CSA (17%; P < .001). Extranodal NK/T-cell NHL was also more common in CSA (P < .0001). Our study provides new objective evidence that the distribution of NHL subtypes varies significantly by geographic region and should prompt epidemiologic studies to explain these differences.

Clinical significance of follicular lymphoma with monocytoid B cells

Although follicular lymphoma (FL) is very common in the Western world, very little information is available regarding the frequency and significance of monocytoid B cells (MBC) in FL. We recently completed a clinicopathologic study of 1,378 cases of non-Hodgkins lymphoma. In this study, a research data sheet was designed to conduct research on several types of lymphomas, one part of which was evaluating the presence of intrafollicular clear cells and extrafollicular MBC in 326 cases diagnosed as FL by one of the pathologists (B.N.N.). For each case diagnosed as FL, the presence of intrafollicular clear cells or extrafollicular MBC was scored as pure FL (no intrafollicular clear cells or extrafollicular MBC), FL with intrafollicular clear cells, FL with less than 5% MBC, and FL with greater than 5% MBC. Of 326 cases classified as FL, 252 (77%) had no intrafollicular clear cells or extrafollicular MBC and therefore were called pure FL. In 36 cases (11%), intrafollicular clear cells were seen, but no extrafollicular MBC. There were no clinical differences between such cases and the 252 cases of pure FL. In eight cases of FL (2%), MBC clusters were rare (<5%). In contrast, 30 cases of FL (9%) had a prominent (>5%) proliferation of extrafollicular MBC; these 30 cases had a significantly shorter failure-free survival (P = .001) and overall survival (P = .04) than the 252 cases of pure FL. The shorter survival of these 30 cases appeared to be independent of the international prognostic index (IPI), stage, and treatment. The FFS of this group remained shorter than that of cases with pure FL when the analysis was restricted to patients treated with Adriamycin-containing regimens and either a favorable (0 to 3) IPI score (P = .001) or advanced stage (III/IV) disease (P = .015). In conclusion, FL with a prominent (>5%) MBC component constitutes a substantial proportion (9%) of FL and has distinctive morphology, and these patients have a significantly shorter survival than those with pure FL.

Bone marrow micrometastases predict early post-operative recurrence following surgical resection of oesophageal and gastric carcinoma

AIM Tumour cells in the bone marrow of patients with gastrointestinal cancer may detect patients at higher risk of disease recurrence and death following potentially curative surgery. METHODS Immunocytochemistry using the monoclonal antibody Ber-EP4, which detects tumour cells from squamous and adenocarcinomas was used. In preliminary spiking experiments to define sensitivity, tumour cells were detected in blood at 10(3)/ml. Bone marrow samples from 74 patients with oesophago-gastric cancer and from 14 control patients was examined. RESULTS 27 (36.5%) patients with cancer and one control patient had stained cells present in their bone marrow at the time of resection. During the follow up period (mean 14 months), relapse and disease-specific death were commoner in patients whose marrow contained tumour cells. Multivariate analysis confirmed bone marrow micrometastasis as an independent prognostic variable for both recurrence and survival. CONCLUSIONS Bone marrow immunocytochemistry using Ber-EP4 may identify those patients at highest risk of early relapse following RO resection of oesophageal or gastric cancer.