Cytomegalovirus Hemorrhagic Cystitis in a Malignant Glioma Patient Treated with Temozolomide.

Temozolomide, a key drug in the treatment of malignant glioma, can cause profound lymphopenia and various opportunistic infectious diseases. A 79-year-old woman with anaplastic oligodendroglioma developed a fever and gross hematuria after 8 weeks of standard radiotherapy with concomitant temozolomide treatment. A cytomegalovirus (CMV) antigen test for pp65 antigenemia was positive (137 cells per 75,800 leukocytes), and the findings from a urine cytology test were consistent with CMV-induced hemorrhagic cystitis. She was treated with ganciclovir, and her condition improved. CMV monitoring is needed when patients develop symptoms related to opportunistic infections during temozolomide treatment for malignant glioma.

Introduction

Patients with high-grade malignant glioma are treated with surgical resection followed by radiation plus concomitant and adjuvant temozolomide. Temozolomide is an oral alkylating agent that produces myelotoxic effects (1). When administered in combination with corticosteroids, which are routinely used to control the mass effect of tumors and peritumoral edema, temozolomide often induces profound lymphopenia. Deficiency in cell-mediated immunity leads to a variety of opportunistic infectious diseases.

We herein report a case of opportunistic cytomegalovirus infection, the manifestation of which was hemorrhagic cystitis, in a patient with anaplastic oligodendroglioma.

Case Report

A 79-year-old woman presented with worsening headache, an altered mental state, and left hemiparesis. Magnetic resonance imaging (MRI) showed an ill-defined mass in the right frontal lobe of the brain (Fig. 1). She underwent surgical resection, and the tumor was pathologically diagnosed as anaplastic oligodendroglioma [The 2016 World Health Organization Classification (2)]. Standard 6-week radiotherapy (60 Gy/30 Fr) and concomitant temozolomide (75 mg/m2/day) were started after surgery. She received dexamethasone 2 mg/day to control the peritumoral edema and trimethoprim-sulfamethoxazole (80-400 mg once a day) for prophylaxis against pneumocystis pneumonia.

Figure 1.

Magnetic resonance imaging (FLAIR) showed an ill-defined mass in the right frontal lobe of the brain that was pathologically diagnosed as anaplastic oligodendroglioma.

At 8 weeks after the initiation of radiotherapy and concomitant temozolomide treatment, the patient developed a high fever, abdominal pain, gross hematuria and diarrhea. The blood count showed lymphopenia; the absolute lymphocyte count was 330/mm3, and the CD4+ T-cell count was 77/mm3. The cytomegalovirus (CMV) IgM index was negative, the IgG index was positive (8.2), and a CMV antigen test for pp65 antigenemia was positive (137 cells per 75,800 leukocytes). Urine cytology showed a large number of neutrophils with a small number of degenerated atypical cells (Fig. 2). Cystoscopy was not performed due to the risk of perforation. Urine culture was negative for bacteria. Although she had diarrhea, colonoscopy did not show CMV colitis, and a fecal culture was negative for bacteria causing enterocolitis. No retinitis was noted on an ophthalmological examination. Computed tomography showed no evidence of other complications, such as viral pneumonia. We examined her cerebrospinal fluid, which showed no signs of meningitis. CMV-DNA was not detected in her cerebrospinal fluid by polymerase chain reaction.

Figure 2.

Urine cytology (light green staining) showed a large number of neutrophils with a small number of degenerated atypical cells.

We diagnosed her condition as CMV viremia with hemorrhagic cystitis. Intravenous ganciclovir (5 mg/kg twice a day) was administered for 14 days, and gross hematuria and diarrhea improved during the treatment. A CMV antigenemia assay was negative once ganciclovir treatment had finished. The CMV IgM index turned positive (7.05), and the IgG index increased (10.6) at 4 weeks after the first test. At 8 weeks after the completion of concomitant temozolomide treatment, the absolute lymphocyte count increased to 910/mm3; however, the CD4+ T-cell count remained as low as 74/mm3. Her general condition worsened. She did not receive further treatment for her brain tumors and was transferred to a nursing care hospital.

Discussion

We reported a case of CMV infection with hemorrhagic cystitis that developed during temozolomide therapy for anaplastic oligodendroglioma.

Malignant glioma is one of the most common primary brain tumors and is treated with a combination of surgery, radiation, temozolomide, and systemic corticosteroids (1).

Temozolomide is an orally administered alkylating drug that is well-tolerated by glioma patients; however, its myelotoxic effect can be severe and long-lasting. A prospective study showed that grade III-IV lymphopenia (absolute lymphocyte count <500 cells/mm3) and CD4 lymphopenia (CD4 lymphocyte count <200 cells/mm3) occurred in 40% of patients with high-grade astrocytoma (3), and another study reported that lymphopenia remained throughout a 48-week observation period (4).

In addition, we must consider that patients with brain tumors routinely receive corticosteroids to control the mass effect of tumors and peritumoral edema. The systemic administration of corticosteroids causes lymphopenia. The number of T cells tends to be more strongly affected than the number of B cells (5).

It is difficult to differentiate the effects of temozolomide from those of corticosteroids on the immunological condition in patients with brain tumors. One study on melanoma patients treated with temozolomide showed that 60% of patients developed lymphopenia (6). Since these patients did not receive routine corticosteroids, the findings indicated that temozolomide itself had potential myelotoxic effects. Temozolomide causes severe lymphopenia, and corticosteroids probably augment the effect.

Various opportunistic infections have been reported as complications of temozolomide therapy, including pneumocystis pneumonia (7), reactivation of hepatitis B virus infection (8), aspergillosis (9), cryptococcal meningitis (10), disseminated strongyloidiasis (11), and CMV infection (12-17). Routine prophylaxis against pneumocystis pneumonia is advised for patients being treated with temozolomide (7); however, no recommendation has been made for prophylaxis against other infectious diseases.

CMV infections frequently occur among patients with human immunodeficiency virus (HIV) infections and organ transplant recipients. In most cases, CMV infections occur in patients with a CD4 cell count <50 cells/mm3 (18). The most common manifestations of CMV infections are retinitis, gastrointestinal diseases (e.g. gastritis, colitis, esophageal ulcers), and pneumonitis.

Our patient developed gross hematuria, and we diagnosed her condition as CMV-induced hemorrhagic cystitis. She did not have risk factors of hemorrhagic cystitis, such as coagulation disorders, antithrombotic use, hepatic disorders, diabetes mellitus, and abnormalities in the urinary tract. Some chemotherapeutic drugs can cause hemorrhagic cystitis. Cyclophosphamide, for example, causes hemorrhagic cystitis by the urinary excretion of acrolein, a hepatic metabolite of cyclophosphamide (19). Temozolomide and its analog dacarbazine have also been reported to cause hemorrhagic cystitis in a few case reports (20, 21). In drug-induced hemorrhagic cystitis, urothelial cells often demonstrated an increase in the size of the nucleus and also become bizarrely shaped (22). It is not possible to morphologically differentiate drug-induced hemorrhagic cystitis from viral-induced condition by urine cytology, so an examination of the suspected virus is needed to rule out the possibility of viral infection.

A few case reports have shown the clinical course of CMV cystitis in patients with conditions associated with the severe malfunction of cell-mediated immunity [i.e. HIV infection (23), kidney transplantation (24), and peripheral blood stem cell transplantation (25)]. CMV infection has been reported to be a risk factor for late-onset hemorrhagic cystitis during the course of allogeneic hematopoietic stem cell transplantation (26). Our case suggested that temozolomide treatment combined with corticosteroids can induce severe immunodeficiency, similar to that observed in patients with HIV infection or organ transplantation recipients.

Seven cases of CMV infection have been reported in patients using temozolomide (12-17). The mean age was 59 years (range: 45-70 years). Three cases were men, and four were women. At the development of CMV infection, their absolute lymphocyte count ranged from 60 to 703, and their CD4+ T-cell count ranged from 36 to 260. The reported manifestations of CMV infections are various and include pneumonitis (12, 16), colitis (12, 13), colonic pseudotumor (15), transverse myelitis (13), and hepatitis (17).

Neither routine screening nor preemptive therapy for CMV infections is recommended among patients using temozolomide, partly because of the small number of reported cases. However, physicians must recognize that malignant glioma treatment can induce severe CD4+ T-cell lymphopenia, and that patients have an increased risk of CMV infection both during and after treatment with temozolomide.

In summary, we reported a case of CMV infection that manifested as hemorrhagic cystitis in a patient with malignant glioma. Combination therapy with temozolomide and corticosteroids can cause severe immunodeficiency and result in various opportunistic infections. When administering standard malignant glioma treatment, physicians should pay close attention to signs and symptoms that might be associated with CMV-induced hemorrhagic cystitis, such as gross hematuria.

The authors state that they have no Conflict of Interest (COI).