Systemic Candida abscess after hypofractionated radiotherapy with temozolomide for glioblastoma in an older patient: illustrative case

Abstract

BACKGROUND

Hypofractionated radiotherapy with temozolomide is recommended for older patients with glioblastoma. Nevertheless, a potential complication of treatment is opportunistic infections with immunosuppression.

OBSERVATIONS

An 86-year-old man presented with hemiparesis, prompting an investigation that revealed a right frontotemporal glioblastoma, isocitrate dehydrogenase wildtype. After the diagnostic biopsy, hypofractionated radiotherapy with temozolomide was administered. Lymphocytopenia was observed before the start of chemoradiotherapy and gradually worsened until 2 months later, possibly as a side effect of the treatment. One month after the completion of the initial treatment, the patient developed septic shock, leading to death within 2 days. Postmortem examination with autopsy revealed evidence of an invasive Candida infection possibly originating from the urinary catheter.

LESSONS

Immunodeficiency, which is a side effect of radiation therapy with temozolomide, can cause rare and potentially fatal invasive Candida infections, especially in older and frail patients with newly diagnosed glioblastoma, even with short-term hypofractionated chemoradiotherapy.

https://thejns.org/doi/10.3171/CASE24175

Glioblastoma is the most common malignant brain tumor in adults,¹ and the median survival after multidisciplinary treatment is 20.9 months.² Age is an important prognostic factor, and treatment selection is often problematic in older patients with newly diagnosed glioblastoma. Chemoradiotherapy with temozolomide (TMZ) is recommended for them when in good general condition.³ The side effects of chemoradiation include decreased lymphocyte and other immune dysfunctions, which can sometimes lead to serious opportunistic infections such as Pneumocystis jirovecii pneumonia, cytomegalovirus infection, and aspergillosis.^4–8Candida infections have been reported; however, invasive ones are rare.⁹ Here, we report a case of systemic invasive Candida infection caused by an indwelling urinary catheter after hypofractionated radiotherapy with TMZ.

Illustrative Case

An 86-year-old man presented with incomplete left hemiplegia and visited a previous physician. Magnetic resonance imaging (MRI) of the head showed a ring-shaped contrast-enhanced lesion with a maximum diameter of 46 mm, mainly located in the right frontoparietal lobes with chronic ischemic change (Fig. 1A and B). An open biopsy was performed, and the patient was diagnosed with glioblastoma, isocitrate dehydrogenase (IDH) wildtype, central nervous system World Health Organization grade 4, with unmethylated O6-methylguanine-DNA methyltransferase promoter (Fig. 1C–F). The patient was referred to our hospital for radiation chemotherapy. At the time of his first visit to our hospital, he had left hemiplegia and left hemispatial neglect with a Karnofsky Performance Status of 60%. Blood tests showed mild lymphocytopenia (750/μl) without abnormalities that would interfere with TMZ induction. He was hospitalized and treated with chemoradiotherapy (TMZ 75 mg/body surface area/day and extended local radiation of 40 Gy/15 fractions) according to the Stupp protocol.²

FIG. 1.

Preoperative axial gadolinium-enhanced T1-weighted image (A) and fluid-attenuated inversion recovery image (B) demonstrating multiple ring-enhanced tumors with edema in the right frontoparietal lobes. Microscopic image of right frontoparietal lesion obtained by biopsy (C). Hematoxylin and eosin staining revealed small round cells with irregular karyotype proliferation, and necrosis was evident. R132H-mutated isocitrate dehydrogenase-1 immunoreactivity was not detected (D). Glial fibrillary acidic protein immunoreactivity was positive (E). The Ki-67 labeling index was approximately 39% (F). Original magnification ×200 (C) and ×400 (D–F).

The patient developed a neurogenic bladder, dysuria due to benign prostatic hyperplasia, and urinary incontinence. A urinary catheter was placed to avoid exposure of the urine to the patient and healthcare workers before the start of treatment. Seven days after the start of treatment, the lymphocyte count was 600/μl (lymphocytopenia, Common Terminology Criteria for Adverse Events grade 2), and oral administration of sulfamethoxazole 400 mg and trimethoprim 80 mg every other day was started to prevent pneumocystis pneumonia. The steroid dexamethasone, 3 mg/day, was also initiated for the antiperitumoral edema. The patient completed the initial treatment, and the local contrast lesions were slightly enlarged within the acceptable limits of the clinical course (Fig. 2A). He continued to be hospitalized for respite care due to a significant decline in daily activities of living (ADLs), with lymphopenia persisting during the course. After removal of the urinary catheter at the end of treatment, spontaneous voiding was not observed due to neurogenic bladder and benign prostatic hyperplasia. Therefore, the catheter remained in place during hospitalization. Neutropenia, thrombocytopenia, or other decreases in blood cell counts suggestive of pancytopenia were not observed during the clinical course. Thirty days after completion of the initial treatment, the patient developed a fever. Although the fever resolved, 5 days later, he developed impaired consciousness and respiratory disturbance. A computed tomography (CT) scan of the head revealed no new lesions that could be the cause of the severe disturbance of consciousness (Fig. 2B), and chest CT revealed significant pleural effusion and fluid retention (Fig. 2C). Blood and urine cultures detected gram-negative bacilli and Enterobacter aerogenes, and multiple organ failure due to septic shock was suspected, leading to his death within 2 days. A pathological autopsy was performed. The clinical course is shown in Fig. 2D.

FIG. 2.

Radiological imaging and follow-up chart after postadjuvant therapy. Gadolinium-enhanced T1-weighted image after chemoradiotherapy showing a locally controlled right frontoparietal lesion (A). At the emergency department, head CT showed no obvious new intracranial lesions (B), but chest CT showed marked pleural effusion (C). The patient’s clinical course is shown graphically (D), along with information on treatment and white blood cell count. The dotted line represents neutrophils, and the solid line represents lymphocytes. fr = fractions; RT = radiotherapy.

Histopathological Autopsy Findings

In the brain specimen, the glioblastoma was limited to local extension with no evidence of distant metastasis. Candida microabscesses were found in multiple organs, including the central nervous system (Fig. 3A–F). Because renal microabscesses were particularly prominent (Fig. 3A–C), candidemia due to ascending infection from a urethral catheter was suspected to be the cause of death. Blood cultures identified Candida albicans. The patient was diagnosed with invasive candidiasis caused by an ascending urinary tract infection with C. albicans.

FIG. 3.

At autopsy, a macrophotograph (A) and microscopic images (B–F) of multiple organs were obtained. In the kidney specimen, multiple abscesses were observed on a macrophotograph (arrowheads, A) and microabscesses due to aggregation of Candida with neutrophil infiltration on histopathological examinations by periodic acid Schiff (PAS) staining (B) and Grocott staining (C). PAS staining of some organs of the body showed Candida proliferation in the pons of the brain (D), myocardium of the heart (E), and liver (F). Reactive multinucleated giant cells were also present (D and E). Original magnification of ×400 (B–F).

Patient Informed Consent

The necessary patient informed consent was obtained in this study.

Discussion

Observations

The patient had fatal infectious complications against a background of immunodeficiency due to decreased lymphocyte counts after hypofractionated radiotherapy with TMZ in an older patient with glioblastoma, IDH wildtype.

Radiation therapy with TMZ is recommended as the initial therapy for glioblastoma.¹⁰ In patients older than 65 years of age, hypofractionated radiotherapy with TMZ significantly prolongs survival compared to radiation alone with preserved physical status.³ Lymphopenia is a frequent complication of radiation therapy using TMZ. The peak of lymphocytopenia was considered to occur 2 months after the start of treatment.⁶ Patients with lymphocytopenia prior to the start of chemoradiotherapy and radiation therapy have a poorer prognosis than those without lymphocytopenia.¹¹ In the present case, lymphocytopenia was present before treatment and persisted. Decreased immunocompetence due to lymphocytopenia may have contributed to the development of infection.

The frequency of opportunistic infections in radiation therapy with temozolomide is not high (0.7%–3%), but they are sometimes fatal.^{3, 6, 10} Pneumocystis pneumonia is well-known, and prophylactic administration of sulfamethoxazole-trimethoprim is recommended when lymphopenia is observed during treatment.^{5, 12} Hepatitis B virus reactivation, cytomegalovirus infection, and Aspergillus infection have also been reported. Invasive Candida infection is rare, although mucosal infections have been frequently reported.^{4, 7–9, 13} Ascending urinary tract infections with Candida are relatively rare. However, Enterobacter species may promote Candida ascending urinary tract infections.¹⁴ In this case, the urinary tract infection of Enterobacter may have contributed to the Candida infection. Invasive Candida infection is a serious disease with a mortality rate of over 70%. Risk factors include central venous catheterization, broad-spectrum antimicrobial agents, prolonged intensive care unit stay, major surgery, necrotizing pancreatitis, dialysis, complete tube feeding, and medically induced immunosuppression.¹⁵ Steroids are often used in the treatment of glioblastoma, and it has been reported that the use of dexamethasone 4 mg/day or higher is associated with a poor prognosis due to decreased immune function.¹⁶ In the present case, the dose was 3 mg/day, which may have contributed to Candida infection, in combination with decreased lymphocyte counts and associated immunosuppression caused by TMZ combination radiation therapy.

There is no consensus on treatment in older patients with glioblastoma. Active treatment may not be recommended due to the risk of complications, decreased ADLs during treatment and hospitalization, and lack of a prognostic prolonging effect. The noninferiority of hypofractionated radiotherapy to radiation alone has been reported in older and frail patients.¹⁷ A clinical trial of short-course radiotherapy (25 Gy/5 fractions) combined with TMZ is underway, and the results are awaited.¹⁸ Especially in older patients with primary glioblastoma, where lymphocytopenia and other immunodeficiencies are expected, radiation monotherapy or more short-term treatment might be necessary to prevent infectious complications.

Lessons

Immunodeficiency, a side effect of radiation therapy with TMZ, can cause rare and potentially fatal invasive Candida infections, especially in older and frail patients with newly diagnosed glioblastoma, even with short-term hypofractionated chemoradiation.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Kinoshita, Nambu, Tamai. Acquisition of data: Kinoshita, Nambu, Tamai, Nakajima. Analysis and interpretation of data: Kinoshita, Nambu, Tamai, Harada. Drafting the article: Nambu. Critically revising the article: Kinoshita, Sato, Nakada. Reviewed submitted version of manuscript: Kinoshita, Nakajima, Harada, Nakada. Approved the final version of the manuscript on behalf of all authors: Kinoshita. Administrative/technical/material support: Sato. Performed autopsy: Sato.

Correspondence

Masashi Kinoshita: Kanazawa University, Kanazawa, Ishikawa, Japan. m-kinoshita@med.kanazawa-u.ac.jp.