Although mycosis fungoides (MF) may arise through persistent antigen stimulation, cytomegalovirus (CMV) is not a known risk factor. To study the incidence of seropositivity to viral infections, we compared MF and Sézary Syndrome (SS) patients to healthy bone marrow donors and other historical control groups. Baseline screening serologies at baseline were performed on 116 biopsy-proven MF/SS patients at MD Anderson Cancer Center from 1992 to 2001 and on healthy bone marrow donors evaluated by the transplant service from 1988 to 2001. Antibodies to HTLV-I/II, HIV-1, EBV, and CMV were measured using standard enzyme-linked immunosorbent (ELISA) and membrane enzyme immunoassay (MEIA) assays. One hundred thirteen (97.4%) of all MF/SS patients had positive CMV IgG serologies at initial presentation. Early- and late-stage patients' seropositivity rates were significantly higher than healthy bone marrow donor controls (χ2.05(df=1) = 71.79). By stage, 98.1% of early-stage MF patients (IA, IB, IIA; 52/53) and 96.8% of late-stage MF and SS patients (IIB-IVB; 61/63) were seropositive compared with healthy bone marrow donors whose seropositivity rate was 57.3% (757/1322). Because the rate of CMV seropositivity increases with age, a subset of cutaneous T-cell lymphoma (CTCL) patients 55 years or younger were compared to age-matched healthy donor controls; their seropositivity rate for CMV was also significantly higher (χ2.05 05(df=1) = 20.4). EBV titers were positive by serology in 13 patients who were examined prospectively. CMV seropositivity is highly associated with MF and SS, even in the earliest stages of the disease, and is significantly higher than that of healthy and immunocompromised controls.

Cutaneous T-cell lymphomas (CTCLs) are clonal T-cell malignancies with primary cutaneous manifestations. The most common variant of CTCL is mycosis fungoides (MF), an indolent lymphoma characterized histologically by atypical epidermotropic CD4+helper/CD45Ro+ memory T-cell clones. Sézary syndrome (SS) is the erythrodermic, leukemic variant of MF.1 MF is hypothesized to arise through persistent antigenic stimulation, leading to an accumulation of skin-homing T cells that are defective in apoptotic programmed cell death.2,3 Although viruses are known to provide chronic immune stimulation, cytomegalovirus (CMV) has not previously been identified as a risk factor for MF/SS.

Human cytomegalovirus (CMV) is a member of the herpes family of viruses. Primary infection is followed by latency. Polymorphonuclear leukocytes, T cells, endothelial cells, and salivary glands have all been shown to harbor CMV in latent form.4 Active CMV infection causes characteristic changes in specific lymphocyte populations, ie, CD8+ T-cell lymphocytes and natural killer (NK) cells.5,6 CMV has an array of immune escape strategies for establishing life-long latency. CMV inhibits major histocompatibility complex (MHC) class I expression within infected cells and impairs MHC class II–dependent antigen presentation by macrophages.7 It also encodes proteins that interfere with the presentation of viral peptide antigens to T cells.

CMV is a common opportunistic pathogen in both the transplant and human immunodeficiency virus–infected (HIV+) populations, reflecting the T-cell deficiency in these patients.8Patients with CTCL also have profound immunodeficiency in later stages of the disease with diminished T-cell function and disappearance of the CD8 cytotoxic population.9 Infectious syndromes resulting from CMV in immunocompromised hosts include pneumonitis, gastroenteritis, hepatitis, pancreatitis, encephalitis, retinitis, and bone marrow suppression. CMV-induced skin lesions are nonspecific and generally localized and ulcerative or are generalized and maculopapular.10 In patients receiving solid-organ transplants, CMV infection causes direct injury to transplanted organs and contributes to both acute and chronic transplant rejection.11 CMV has been implicated in the development of accelerated atherosclerosis in the coronary arteries of transplanted hearts.12 In healthy individuals, infection manifests most commonly as a self-limited mononucleosislike syndrome or is entirely asymptomatic. The seropositivity rate in the general population is generally increased with parity and age.

Study population

This was a retrospective study of new patients with MF and SS undergoing study evaluation at the MD Anderson Cancer Center Skin Center from 1992 to the present. All patients with CTCL had a viral serology panel drawn as part of their baseline routine evaluation, and all gave written consent to have tissue and data used for research studies. Control subjects were bone marrow donors who gave consent to be prospectively evaluated for CMV seropositivity at baseline and who were retrospectively analyzed for seropositivity data. Patients and control subjects are grouped as seropositive or seronegative. Staging of patients with CTCL is done by the tumor, node, metastases (TNM) classification method.13 The demographics of patients and controls are shown in Table1.

Table 1.

Demographics of CTCL patients and healthy bone marrow donors

CTCL patients (n = 116)Bone marrow donors (n = 1322)
Male (n = 59)Female (n = 57)Male (n = 649)Female (n = 673)
Median age, y (range) 70 (30-86) 60 (13-86) 41 (2-79) 43 (3-81) 
White 46 39 469 475  
Black 13 42 46 
Hispanic 127 135 
Asian 11 17 
CTCL patients (n = 116)Bone marrow donors (n = 1322)
Male (n = 59)Female (n = 57)Male (n = 649)Female (n = 673)
Median age, y (range) 70 (30-86) 60 (13-86) 41 (2-79) 43 (3-81) 
White 46 39 469 475  
Black 13 42 46 
Hispanic 127 135 
Asian 11 17 

Serology testing methods

Serology methods for measuring CMV immunoglobulin G (IgG) used by the MD Anderson Diagnostic Laboratory are the commercially available ELISA (enzyme-linked immunosorbent assay) and MEIA (membrane enzyme immunoassay). HIV, human T-cell leukemia virus type I and II (HTLV-I and II, and Epstein-Barr virus (EBV) serologies are also measured by using ELISA.

Statistical analyses

Chi-square analyses using 2 × 2 tables were performed to compare CMV seropositivity in all CTCL patients, in early-stage patients, and in late-stage patients with healthy bone marrow control subjects. In order for a chi-square value to be significant with one degree of freedom, and P = .05, that value must be more than 3.841.

In addition, chi-square analysis and independent samples ttest were used to compare CMV seropositivity in CTCL patients aged 55 years or younger with bone marrow donors aged 55 years or younger.

The demographics of the patients with CTCL between 1992 and the present who had prospective evaluations done at baseline for CMV seropositivity are shown in Table 1. Of 116 MF/SS CTCL patients, 113 (97.4%) had positive CMV-IgG serologies, including 59 men and 57 women, and are equally distributed in our population. Only 3 CTCL patients were found to be seronegative. Those were 2 women and 1 man, stages IA, IIB, and IVB, respectively (Table2). Of 53 patients with early-stage MF (IA, IB, IIA), 52 were CMV seropositive (98.1%). Patients with late-stage MF/SS (IIB-IVB) had a 96.8% (61 of 63) seropositivity rate. In contrast, the seropositivity rate among healthy bone marrow donors evaluated at MD Anderson since 1988 was 57.3% (757 of 1322).

Table 2.

Rate of CMV seropositivity in MF patients by stage of disease

MF stageMedian age, y (range)N = 116CMV positive
(n = 113)
CMV negative
(n = 3)
IA 65.5 (22-86) 28 27 
IB 63.5 (13-81) 20 20 
IIA 74 (59-76) 
IIB 69 (23-85) 20 19 
III 65.5 (47-85) 22 22 
IVA 64 (46-76) 
IVB 69.5 (30-86) 15 14 
MF stageMedian age, y (range)N = 116CMV positive
(n = 113)
CMV negative
(n = 3)
IA 65.5 (22-86) 28 27 
IB 63.5 (13-81) 20 20 
IIA 74 (59-76) 
IIB 69 (23-85) 20 19 
III 65.5 (47-85) 22 22 
IVA 64 (46-76) 
IVB 69.5 (30-86) 15 14 

MF/SS patients as a group had a significantly higher rate of CMV seropositivity compared with healthy control subjects (χ205(df=1) = 71.79). Compared with controls, the rate of CMV seropositivity in patients with early-stage MF is also significantly higher (χ205(df=1) = 34.98). Significantly higher CMV seropositivity was also noted among patients with late-stage MF/SS when compared with control subjects (χ205(df=1) = 38.9). By independentt test, the incidence of CMV seropositivity is significantly higher in all stages of MF compared with healthy bone marrow donor control subjects (P = .001).

We also examined serologies for other viruses such as HIV-1 and viruses implicated in CTCL and HTLV-I and II.14 One hundred thirteen patients with MF/SS were tested for HIV, and all were negative by ELISA. Of 114 patients tested for HTLVI/II, only one was positive. Only 13 patients had EBV serologies drawn, but all were seropositive (Table3).

Table 3.

Viral serologies of patients with CTCL

EBV (n = 13)HIV (n = 113)HTLV I/II (n = 114)
Negative 0/13 113/113 113/114 
Positive 13/13 0/113 1/114 
EBV (n = 13)HIV (n = 113)HTLV I/II (n = 114)
Negative 0/13 113/113 113/114 
Positive 13/13 0/113 1/114 

Recognizing that the rate of CMV seropositivity increases with age, we also compared CMV seropositivity rates in CTCL patients with CTCL patients that were aged 55 years or younger with age-matched, healthy bone marrow donors aged 55 years or younger. Again, CMV seropositivity was significantly higher among “young” CTCL patients compared with healthy bone marrow donors (χ205(df=1) = 20.4). Thirty of 32 (93%) CTCL patients younger than age 55 were CMV seropositive in contrast to only 591 of 1103 (53.6%) bone marrow donors aged 55 or younger.

This study shows for the first time that more than 97% of patients at all stages of CTCL (MF and SS) have evidence for previous infection with human CMV. The seropositivity rates are significantly higher compared with healthy donor control subjects from bone marrow transplant donors and are high even in the subset of young patients. Surprisingly, the rate of seropositivity of CTCL patients exceeded that of patients who are historically considered to be in high-risk groups, including homosexual men and patients with HIV/AIDS (Table4). Patients with CTCL also develop profound immunodeficiency with disease progression, and their gradual loss of the CD8+cytotoxic T-cell population is associated with poor prognosis and has been attributed to the overgrowth of the malignant clone.9Apoptosis of CD8+ tumor-infiltrating lymphocytes may also be mediated by tumor cells with Fas ligand (FasL) expression, resulting in immunosuppression with time.27 

Table 4.

Seropositivity rate of historical control populations

GroupCMV seropositivity rateOR or OSReference
Group 1Group 2
Personnel providing services to disabled children Before exposure to mentally retarded children Seronegative persons converting in 1 y — De Schryver et al15 
 Educators (n = 283) 15.9% 1.03% — — 
 Nurses (n = 294) 18.4% 1.42% — — 
Kindergarten employees     
 Teachers/administrators (n = 494) Childless women: 16.4% ≥ 1 child at home: 33.7% Raising children: 2.25 Kiss et al16 
   Kindergarten teacher: 1.54  
Couples receiving artificial insemination (n = 433) Women in couples: 37% Men in couples: 31% No effect of age on seropositivity rate Greenhalgh et al17 
Health care workers caring for:    Sobaszek et al18 
 Pediatric inpatients (n = 283) 44.5% — — — 
 Immunosuppressed adults (n = 117) 43.6% — — — 
Home child care providers (n = 132) Overall baseline rate: 57.6% Annual seroconversion rate: 6.8% Caring for child < 2 y: 2.37 Bale et al19 
Cared for child <2 y: 67%  Employed > 6 y: 3.27  
Cared for child >2 y: 46%    
Japanese pregnant women (n = 573) Aged < 25 y: 67.7% Aged > 40 y: 85.7% — Nishimura et al20 
Men attending STD clinic (n = 430) Heterosexual: 42% Homosexual: 80% — Berry et al21 
Homosexual men living in San Francisco (n = 1123) 96% — — Dylewski et al22 
HIV+/−adolescents HIV+ females: 78.5% HIVfemales: 61.4% — Holland et al23 
 HIV+ males: 79.7% HIV males: 50%   
German case-control subjects    Rothenbacher et al24 
 Subjects with CAD (n = 312) 54.5% — — — 
 Blood donors (n = 479) 49.9% — — — 
Renal transplantation recipients
(n = 47 146) 
Age > 60 y: 80% Blacks: 71% — Hirata et al25 
 Asians: 80% Whites: 56%   
BMT recipients from unrelated donor
(n = 125) 
60.8% — OS at 3 years: Kroger et al26 
   CMV+ pts: 29%  
   CMV pts: 70%  
GroupCMV seropositivity rateOR or OSReference
Group 1Group 2
Personnel providing services to disabled children Before exposure to mentally retarded children Seronegative persons converting in 1 y — De Schryver et al15 
 Educators (n = 283) 15.9% 1.03% — — 
 Nurses (n = 294) 18.4% 1.42% — — 
Kindergarten employees     
 Teachers/administrators (n = 494) Childless women: 16.4% ≥ 1 child at home: 33.7% Raising children: 2.25 Kiss et al16 
   Kindergarten teacher: 1.54  
Couples receiving artificial insemination (n = 433) Women in couples: 37% Men in couples: 31% No effect of age on seropositivity rate Greenhalgh et al17 
Health care workers caring for:    Sobaszek et al18 
 Pediatric inpatients (n = 283) 44.5% — — — 
 Immunosuppressed adults (n = 117) 43.6% — — — 
Home child care providers (n = 132) Overall baseline rate: 57.6% Annual seroconversion rate: 6.8% Caring for child < 2 y: 2.37 Bale et al19 
Cared for child <2 y: 67%  Employed > 6 y: 3.27  
Cared for child >2 y: 46%    
Japanese pregnant women (n = 573) Aged < 25 y: 67.7% Aged > 40 y: 85.7% — Nishimura et al20 
Men attending STD clinic (n = 430) Heterosexual: 42% Homosexual: 80% — Berry et al21 
Homosexual men living in San Francisco (n = 1123) 96% — — Dylewski et al22 
HIV+/−adolescents HIV+ females: 78.5% HIVfemales: 61.4% — Holland et al23 
 HIV+ males: 79.7% HIV males: 50%   
German case-control subjects    Rothenbacher et al24 
 Subjects with CAD (n = 312) 54.5% — — — 
 Blood donors (n = 479) 49.9% — — — 
Renal transplantation recipients
(n = 47 146) 
Age > 60 y: 80% Blacks: 71% — Hirata et al25 
 Asians: 80% Whites: 56%   
BMT recipients from unrelated donor
(n = 125) 
60.8% — OS at 3 years: Kroger et al26 
   CMV+ pts: 29%  
   CMV pts: 70%  

OR, odds ratio; OS, overall survival; STD, sexually transmitted disease; BMT, bone marrow transplant; CAD, coronary artery disease; and pts, patients.  —  indicates not applicable.

Cytomegalovirus is a latent virus and has been implicated in bone marrow suppression and with fatal pneumonia in our transplant population.28 CMV seropositivity is a negative independent prognostic factor for overall survival among patients receiving bone marrow transplants.26 Because CMV seropositivity increases with age, we also examined a subset of the patients and found that the seropositivity rate among younger CTCL patients was 93%, with only 2 of 32 patients seronegative. In fact, only 3 patients in the entire cohort were negative for CMV. We also examined the rate of Epstein-Barr virus seropositivity in the same group of patients. Of the 13 patients in the group who were tested, all 13 were positive.

Viruses have been implicated in a variety of autoimmune diseases and may share host antigens (molecular mimicry), resulting in inappropriate immune stimulation against host proteins. Autoimmune diseases are almost always associated with certain human histocompatibility antigens thought to confer disease susceptibility or be correlated with the development of specific antibodies.29 Epstein-Barr virus infection has been previously implicated in several kinds of lymphomas, including Hodgkin disease, Burkitt lymphoma, NK-T nasopharyngeal tumors, peripheral T-cell lymphomas, and posttransplantation lymphoproliferative disorders.30,31 EBV is also associated with autoimmune diseases such as childhood lupus erythematosus and rheumatoid arthritis.32 HTLV-1 is found in adult T-cell lymphoma and leukemia, and it has been implicated by several studies in CTCL.33-35 Others have not been able to confirm this finding.36,37 In this study, all except one of the patients with CTCL had negative HTLV-1 serology studies at baseline.

We have previously shown that patients with MF and SS have a significant association with major histocompatibility class II HLA-DR5 (w11) and HLA-DQB*03 alleles.38 Staphylococcal superantigens were also commonly associated with erythrodermic MF/SS patients in our previous study and can stimulate proliferation of CTCL cells.3,39 The HLA-DR5 allele is also associated with melanoma progression, scleroderma, Hashimoto thyroiditis, and alopecia areata,40 all characterized by a T-cell–mediated immune response. Of interest, the DR5 antigen is also exquisitely sensitive to stimulation by staphylococcal superantigen.41 HLA alleles may also influence the incidence of CMV infection and subsequent seropositivity within a population group.42 

A chlamydia-related factor found to stimulate proliferation of Sézary cells led to the finding of chlamydia organisms within MF lesions and has been suggested to contribute to the pathogenesis of MF/SS as a persistent antigen.43 Chlamydia organisms and also CMV have been implicated in inflammation initiating coronary artery disease.44 However, in one study of angiography patients in Spain, 97% had CMV seropositivity regardless of the presence of atherosclerotic plaques at catherization.45 A prospective, well-designed case-control study of healthy postmenopausal women with (n = 122) and without (n = 244) coronary artery disease (CAD) also found no significant differences in seropositivity rates for CMV, Chlamydia, andHelicobacter pylori.46 Thus, there is conflicting data on the role of infectious agents in mediating the chronic inflammation that is associated with both MF and atherosclerosis.

Risk factors for CMV infection reported in the literature include age, number of children, and immune status. Patients with HIV or allogeneic stem cell transplants (ie, T-cell deficiencies) are highly susceptible to CMV infection and may succumb to it.8 In patients with CTCL, there was no evidence for active CMV infection. In addition, most of the patients were not immunosuppressed and would be expected to have a rate of seropositivity equal to age-matched healthy controls. However, CMV IgG seropositivity is highly associated with MF and SS even in the earliest stages of the disease, when compared with healthy control subjects as well as various historical groups reported in the literature that are listed in Table 4. One variable is that the median age of our patient population was higher than all control groups, including bone marrow donors and patients with HIV and CAD. However, when we considered the CTCL patients younger than age 55 separately, 93% (30 of 32) were CMV seropositive and also were significantly higher than age-matched controls. Of the 28 patients with stage IA MF and only minor skin involvement, 27 were positive for CMV, making it unlikely that the cutaneous disease predisposed these patients to serologic conversion.

Of the 3 seronegative patients, 2 presented before age 25. One was a 21-year-old black woman with stage IVB MF whose course was characterized by persistent Staphylococcus aureus and mucocutaneous candidiasis infections. Her CTCL has been refractory to multiple treatment modalities. Another seronegative female patient presented with stage IIB rapidly progressive disease and succumbed at age 23 during bone marrow transplantation from staphylococcal sepsis. The third seronegative patient was a 59-year-old man with stage IA disease who had long-term remission with conservative topical therapy.

When compared with historical control groups reported in the literature (Table 4), patients with CTCL exceed seropositivity rates of virtually all groups reported. We were intrigued to find that CMV seropositivity was higher than in high-risk groups such as HIV+ men (86%),23 health care workers caring for children (44.5%), immunocompromised patients (43.6%),18 and patients with coronary artery disease (54.5%).24 Even patients with early-stage MF with normal immune systems and minimal skin involvement have significantly higher CMV seropositivity rates than do control subjects, and they are similar to late-stage patients who tend to become immunocompromised with disease state and therapy. The significance of this observation is not clear. Latent CMV and/or EBV infection could play a potential role in the susceptibility to or pathogenesis of CTCL. They could provide chronic antigen stimulation, induce T-cell proliferation, and adversely affect apoptosis of skin-homing memory/helper T-cells.

Prepublished online as Blood First Edition Paper, November 21, 2002; DOI 10.1182/blood-2002-07-2247.

Supported in part by grants K24 86815 (National Institutes of Health) and CA16672 (National Cancer Institute) and by the Sherry L. Anderson CTCL Research Fund.

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 U.S.C. section 1734.

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Author notes

Madeleine Duvic, The University of Texas MD Anderson Cancer Center, Department of Dermatology, Box 434, 1515 Holcombe Blvd, Houston, TX 77030-4095; e-mail:mduvic@mdanderson.org.

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