The disseminated presentation of AIDS-related non-Hodgkin's lymphomas (NHL) has been attributed to immunosupression, but few investigations have been carried out on adhesion molecule expression [1–3]
CD44 is a glycoprotein codified by 20 exons, of which the first and the last five are constant and codify the standard isoform (CD44s), whereas the remaining 10 exons (v1–v10) are subjected to splicing and constitute different isoforms. The increased expression of CD44s and CD44v6 has been correlated with metastases and poor prognosis in several malignancies [4–10] [11–17]
The following groups were studied: patients with AIDS-related NHL diagnosed from 1989 to 1997 (group 1, n = 31), HIV-negative patients with high-grade B cell NHL (group 2, n = 30), healthy blood donors (group 3, n = 30), HIV-infected patients with CD4 lymphocyte counts of over 0.5 × 109 /l (group 4, n = 29), and HIV-positive patients with a CD4 lymphocyte count of less than 0.5 × 109 /l (group 5, n = 31).
Among AIDS-related NHL, 25 patients had systemic B cell NHL (diffuse large cell, 23; Burkitt-like, two) and six had primary central nervous system (CNS) NHL, whereas in HIV-negative NHL 26 cases were diffuse large cell and four were Burkitt-like. Patients with NHL were treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and received CNS prophylaxis with methotrexate, cytarabine and hydrocortisone [18]
Serum levels of CD44s and CD44v6 were measured by enzyme-linked immunoassay (sCD44std and sCD44var(6), respectively; ELISA Test Kit, Bender MedSystems, Boehringer Ingelheim, Germany). In NHL patients, the samples were collected before treatment. In all cases specimens were stored at −80°C.
The 95 percentile of the blood donors group was taken as a cut-off value for normal range (532 ng/ml for CD44s and 339 ng/ml for CD44v6). Twenty-one (67.7%) patients with AIDS-related NHL had elevated CD44v6 levels and nine (26.5%) increased CD44s. Patients with AIDS-related NHL had a mean (SD) value of serum CD44s of 489 (179) ng/ml, which was significantly higher than that of groups 3 and 5 (P < 0.001). The serum levels of CD44v6 were also significantly higher in group 1 patients than in those from groups 2, 3, 4 and 5 (P < 0.001) (Table 1 ). Among lymphoma patients, the results did not change when the patients with primary CNS lymphoma were excluded from the AIDS-related NHL group. In the analysis of sensitivity, the best result was obtained for CD44v6 (96.8%) when a 95 percentile in group 5 was considered. In AIDS-related NHL patients, no differences were found between the serum levels of both CD44s and CD44v6 and clinicobiological parameters. Increased levels of serum CD44s and CD44v6 did not have prognostic significance for response to therapy, event-free survival or overall survival in HIV-positive patients with NHL.
Table 1: Expression of serum CD44s and CD44v6.
Increased serum levels of CD44 have been detected at the time of diagnosis and in progression of NHL, and have been associated with poor prognosis [15,16,19] 9 /l. The serum CD44v6 level was significantly higher in AIDS-related NHL than in HIV-negative NHL, healthy controls, HIV-infected patients with normal CD4 lymphocyte counts, and HIV patients with CD4 lymphocyte counts lower than 0.5 × 109 /l. When CD44v6 levels were compared between AIDS-related NHL (group 1) and the most immunosuppressed HIV-infected patients (group 5), the difference was the greatest: at a CD44v6 cut-off level of 198 ng/ml (95 percentile for group 5), 30 patients with AIDS-related NHL had increased serum CD44v6 levels (P < 0.001). As a consequence, the sensitivity of the CD44v6 test in serum was very high (96.8%) for the detection of NHL, when this measurement was performed in severely immunosuppressed HIV-infected patients (CD4 lymphocyte counts < 0.5 × 109 /l). This is of special interest because HIV-infected patients with low CD4 lymphocyte counts theoretically have the highest risk of developing NHL. The fact that the most immunosuppressed patients have lower levels of CD44s and CD44v6 could be explained by the depletion of CD44 from the surface of HIV-infected cells [20]
The finding of significantly increased serum levels of CD44s and CD44v6 in patients with AIDS-related NHL at the time of diagnosis, together with the low serum levels of both glycoproteins (mainly CD44v6) in the most immunosuppressed HIV-infected patients, suggests that serial measurement of these glycoproteins could be evaluated in the latter group of patients as an early marker for the presence of NHL.
José-Tomás Navarroa
Josep-Maria Riberaa
Manuel Vaquerob
María-Cruz Pastorc
Albert Oriola
Joan Romeud
Montserrat Batllea
Fuensanta Milláa
Evarist Feliua
References
1. Tirelli U, Franceschi S, Carbone A.
Malignant tumors in patients with HIV infection. BMJ 1994, 308: 1148 –1153.
2. DeMario MD, Liebowitz DN.
Lymphomas in the immunocompromised patient. Semin Oncol 1998, 25: 492 –502.
3. Kersten MJ, Van Gorp J, Pals ST, Boon F, Van Oers MHJ.
Expression of Epstein–Barr virus latent genes and adhesion molecules in AIDS-related non-Hodgkin's lymphomas: correlation with histology and CD4-cell number. Leuk Lymphoma 1998, 30: 515 –524.
4. Naor D, Sionov RV, Ish-Shalom D.
CD44: structure, function and associaton with the malignant process. Adv Cancer Res 1997, 71: 241 –319.
5. Wielenga VJM, Heider K-H, Offerhaus GJA. et al.
Expression of CD44 variant proteins in human colorrectal cancer is related to tumor progression. Cancer Res 1993, 53: 4754 –4756.
6. Mayer B, Jauch KW, Günthert U. et al.
De-novo expression of CD44 and survival in gastric cancer. Lancet 1993, 342: 1019 –1022.
7. Guo YJ, Liu G, Wang X. et al.
Potencial use of soluble CD44 in serum as indicator of tumor burden and metastasis in patients with gastric or colon cancer. Cancer Res 1994, 54: 422 –426.
8. Washington K, Gottfried M, Telen MJ.
Expression of the cell adhesion molecule CD44 in gastric adenocarcinomas. Hum Pathol 1994, 25: 1043 –1049.
9. Dall P, Heider K-H, Sinn H-P. et al.
Comparison of immunohistochemistry and RT–PCR for the detection of CD44v-expression, a new prognostic factor in human breast cancer. Int J Cancer 1995, 60: 471 –477.
10. Yamaguchi A, Urano T, Goi T. et al.
Expression of a CD44 variant containing exons 8 to 10 is a useful independent factor for the prediction of prognosis in colorrectal cancer patients. J Clin Oncol 1996, 14: 1122 –1227.
11. Pals ST, Horst E, Ossekoppele GJ, Figdor CG, Scheper RJ, Meijer CJLM.
Expression of lymphocyte homing receptor as a mechanism of dissemination in non-Hodgkin's lymphoma. Blood 1989, 73: 885 –888.
12. Jalkanen S, Joensuu H, Söderström KO, Klemi P.
Lymphocyte homing and clinical behavior of non-Hodgkin's lymphoma. J Clin Invest 1990, 87: 1835 –1840.
13. Joensuu H, Ristamäki R, Klemi PJ, Jalkanen S.
Lymphocyte homing receptor (CD44) expression is associated with poor prognosis in gastrointestinal lymphoma. Br J Cancer 1993, 68: 428 –432.
14. Stauder R, Eisterer W, Thaler J, Günter U.
CD44 variant isoforms in non-Hodgkin's lymphoma: a new independent prognostic factor. Blood 1995, 85: 2885 –2899.
15. Ristamäki R, Joensuu H, Salmi M, Jalkanen S.
Serum CD44 in malignant lymphoma: an association with treatment response. Blood 1994, 84: 238 –243.
16. Ristamäki R, Joensuu H, Lappalainen K, Teerenhovi L, Jalkanen S.
Elevated serum CD44 level is associated with unfavorable outcome in non-Hodgkin's lymphoma. Blood 1997, 90: 4039 –4045.
17. Inagaki H, Banno S, Wakita A, Ueda R, Eimoto T.
Prognostic significance of CD44v6 in diffuse large B-cell lymphoma. Mod Pathol 1999, 12: 546 –552.
18. Navarro JT, Ribera JM, Oriol A. et al.
International Prognostic Index is the best prognostic factor for survival in patients with AIDS-related non-Hodgkin's lymphoma treated with CHOP. :
A multivariate study of 46 patients. Haematologica 1998, 83: 508 –513.
19. Ristamäki R, Joensuu H, Jalkanen S.
Serum CD44 in non-Hodgkin's lymphoma. Leuk Lymphoma 1999, 33: 433 –440.
20. Lee Guo MM, Hildreth JEK.
HIV-induced loss of CD44 expression in monocytic cell lines. J Immunol 1993, 151: 2225 –2236.
