Multifocal Intracranial Cryptococcoma with Treatment Resistance, Recurrence, and Mortality: A Case Report and Literature Review

Masashi HIGASHINO; Eiji KURIHARA; Ryuichi KURODA; Satoshi INOUE; Te-Jin LEE; Takashi MIZOWAKI; Takayuki NAKASHO; Daiki TANABE; Naoya TAKEDA

doi:10.2176/jns-nmc.2025-0209

Abstract

Intracranial cryptococcoma is an uncommon manifestation of central nervous system cryptococcosis. Imaging commonly shows ring-enhancing lesions that resemble malignant tumors radiologically. Early diagnosis and extended antifungal treatment are crucial for decreasing morbidity and enhancing outcomes. Treatment typically involves a minimum of six weeks of induction therapy, followed by 6-18 months of maintenance therapy. Limited information is available on the complete clinical progression in cases where remission is not attained with initial treatment. A 66-year-old immunocompetent man presented with ten ring-enhancing lesions in the brain parenchyma and an infiltrative lesion in the lungs. Complete resection of the largest lesion in the left frontal lobe confirmed a histopathological diagnosis of cryptococcoma. Despite receiving eight weeks of induction therapy with liposomal amphotericin B and oral flucytosine, exceeding standard recommendations, the lesions only partially regressed, failing to achieve complete remission. Fluconazole maintenance therapy was initiated. At five months, lesion recurrence was observed. Induction therapy was resumed for three weeks, followed by a switch back to fluconazole. However, the patient's level of consciousness deteriorated, making oral medication impossible. The patient died 15 months after the initiation of antifungal treatment.

Cryptococcoma is a critical diagnostic complication. When chest imaging findings are not characteristic of a typical malignancy, a biopsy is essential before determining the appropriate treatment strategy. When lesions do not completely resolve after induction therapy, careful clinical and radiological follow-up is crucial because the risk of recurrence remains significant.

Introduction

Cryptococcoma is a localized tumor-like mass caused by the encapsulated yeast Cryptococcus. This fungal infection can affect various organs, including the brain, lungs, kidneys, and heart. Intracranial cryptococcoma is a rare form of central nervous system (CNS) cryptococcosis characterized by granulomatous lesions due to infection with Cryptococcus species, primarily, C. neoformans and C. gattii. These lesions can present as mass-occupying entities within the brain and pose several clinical challenges. According to the Infectious Diseases Society of America (IDSA), cryptococcoma can cause significant short-term and long-term neurological morbidity and necessitate prolonged antifungal therapy.¹⁾ Imaging studies, particularly, magnetic resonance imaging, typically reveal ring-enhancing lesions that can be mistaken for malignancies or abscesses.¹^,²⁾ Delayed diagnosis is a critical issue because it can lead to increased morbidity and mortality. An early and accurate diagnosis is essential for improved outcomes.³⁾

There are few reports describing the long-term clinical course of cases in which lesions persist after initial treatment. Here, we present the case of a patient who developed multifocal intracranial cryptococcoma, whose lesions persisted after induction therapy and died 15 months later.

Case Report

Patient's background and medical history

The patient was a 66-year-old man who worked in the steel industry. He had no history of overseas travel and no recent exposure to pigeons; however, he resided in a deteriorated wooden house. He had no significant past medical history, was not taking any regular medications, had no relevant family history, and reported no preceding infection.

Initial clinical symptoms

The patient presented with worsening weakness in the left upper extremity over the last three months. Approximately two months before hospitalization, he had a 1-min clonic seizure in his left upper extremity. The weakness progressed, leading to an urgent admission. Upon arrival, the patient was nearly unconscious, with no fever or signs of meningeal irritation evident.

Initial laboratory findings at hospitalization

On admission, his white blood cell count was 7,400/μL (reference: 3,500-9,000), C-reactive protein was 1.1 mg/dL (0-0.3), and procalcitonin was 0.06 ng/mL (0-0.05). Serum total protein was 6.7 g/dL (6.4-8.2), and albumin was 3.5 g/dL (3.8-5.3). Glycated hemoglobin A1c was 5.5% (4.55-6.24). Liver and renal function tests were within normal limits. Overall, these findings suggested mild systemic inflammation.

Imaging and initial evaluation

Contrast-enhanced brain magnetic resonance (MR) imaging revealed ten ring-enhancing lesions within the brain parenchyma, accompanied by marked perilesional edema (Fig. 1A-H). No evidence of sinusitis or otitis media was observed. Chest X-ray and computed tomography scans revealed an infiltrative lesion with cavitation in the left upper lung lobe (Fig. 1G and H). In addition, small nodular shadows around the bronchi in both upper lobes were observed, with no lymphadenopathy or pleural effusion detected (Fig. 1I and J). Three sputum smears for Ziehl-Neelsen staining were negative, and polymerase chain reaction testing for acid-fast bacilli yielded negative results. Based on these findings, the differential diagnoses included brain abscess, metastatic brain tumor, glioblastoma, and primary CNS lymphoma. At this stage, the likelihood of toxoplasmosis, fungal infections, tuberculoma, and neurocysticercosis was considered low due to the absence of immunosuppression, negative Ziehl-Neelsen staining results, and no history of travel to developing countries. The brain lesions presented as multiple ring-enhancing masses with low signal intensity on diffusion-weighted imaging, making metastatic brain tumors the most likely diagnosis. However, due to the atypical appearance of lung cancer, the largest brain lesion located in the anterior left frontal lobe was resected for diagnostic purposes.

Fig. 1

Preoperative images. The arrows indicate the largest lesion in the left frontal lobe, which was surgically removed for diagnostic purposes. A-D: Axial and sagittal post-contrast T1-weighted magnetic resonance images show multiple ring-enhancing lesions within the brain parenchyma. E: Fluid attenuated inversion recovery image reveals marked perilesional edema. F-H: The lesion exhibits low signal intensity on diffusion-weighted images and high signal on apparent diffusion coefficient map and iso- to low density without calcification on computed tomography scans. I and J: Chest X-ray and computed tomography scan revealing an infiltrative lesion with cavitation in the left upper lung lobe.

Surgical intervention

The left frontal craniotomy was conducted. A well-demarcated mass surrounded by gliosis was identified and completely resected en bloc from the front part of the left frontal lobe (Supplementary Movie 1). After the surgery, glycerol and low-dose corticosteroids were administered.

Pathological diagnosis and further evaluation

The histopathological examination confirmed the diagnosis of cryptococcoma (Fig. 2). Subsequent testing was commenced to evaluate immunosuppression and CNS involvement. C. neoformans (3+) and C. gattii (1+) were identified in sputum cultures. The serum and cerebrospinal fluid (CSF) tested positive for cryptococcal antigens. CSF analysis revealed a cell count of 1/μL, an opening pressure of 13 cm H₂O, negative India ink staining, and negative CSF culture. Tests for human immunodeficiency virus antigen/antibody and human T-cell leukemia virus type 1 antibody yielded negative results, and no other immunosuppressive conditions were detected.

Fig. 2

Histopathological examination (hematoxylin and eosin staining) revealing fungal capsules (yellow arrow) embedded within fibrous tissue, along with a dense infiltration of inflammatory cells.

Antifungal treatment and clinical course

The clinical course is illustrated in Fig. 3. The induction therapy commenced with liposomal amphotericin B (L-AMB) and oral flucytosine. A follow-up contrast MR imaging after six weeks revealed lesion shrinkage, yet residual masses persisted. Paralysis recurred upon corticosteroid withdrawal due to a mass effect near the right motor cortex. After eight weeks of induction therapy, maintenance treatment with fluconazole (400 mg/day) was started. Follow-up MR imaging indicated a slight additional decrease in lesion size, although a substantial residual mass persisted (Fig. 4A-E).

Fig. 3

Clinical time course of the patient. Temporal relationships of neurological symptoms (epilepsy, paralysis, disturbance of consciousness), antifungal and antiepileptic therapies, betamethasone dosage, CSF cell counts, and radiological changes are illustrated. Key clinical events such as surgery, recurrence, and death are indicated. Symbols for radiological findings: ↑= lesion enlargement; ↓= lesion reduction; → = no change in lesion size. 5-FC: flucytosine; CSF: cerebrospinal fluid; L-AMB: liposomal amphotericin B; LCM: lacosamide; PER: perampanel

Fig. 4

Axial post-contrast, T1-weighted, fluid-attenuated inversion recovery magnetic resonance images and computed tomography images obtained during antifungal therapy. A-E: Images obtained after completion of eight weeks of induction therapy, showing a reduction in lesion sizes and perilesional edema. F-J: Images obtained after four weeks of maintenance therapy, demonstrating further lesion shrinkage with calcification, indicating organization. K-O: Images obtained after four months of maintenance therapy, confirming recurrence of the lesions.

MR images obtained after induction therapy, followed by four weeks of maintenance therapy, showed an additional reduction in lesions, indicating the efficacy of the current treatment regimen (Fig. 4F-J). Two months after starting maintenance therapy, the patient still had gait instability and was then moved to a rehabilitation hospital.

After four months of maintenance therapy, the patient experienced a focal seizure in his left upper extremity, followed by Todd's paralysis, leading to readmission to our hospital. MR images confirmed lesion recurrence, and treatment with L-AMB and flucytosine was resumed (Fig. 4K-O). After three weeks of therapy, a reduction in tumor size was noted, leading to a switch back to fluconazole in the treatment regimen.

Around the same time, the patient started showing signs of altered consciousness. Electroencephalography confirmed the presence of non-convulsive status epilepticus. MR images revealed no enlargement of the lesions and edema, no disseminated lesions, and no increase in CSF cell count; therefore, disease progression and meningitis were considered unlikely. The patient's consciousness worsened, making oral medication infeasible, and further aggressive treatment was refused. The patient passed away 15 months after starting antifungal therapy. Throughout the initial maintenance therapy, relapse, and subsequent treatment, CSF analyses consistently indicated normal cell counts with negative cultures.

Discussion

Difficulty of diagnosis

In imaging studies, intracranial cryptococcoma may resemble neoplasms, potentially causing misdiagnosis. Cryptococcomas can exhibit radiological characteristics similar to primary or metastatic brain tumors, as demonstrated in a case where cryptococcosis mimicked lung carcinoma with brain metastases.⁴^-⁷⁾ In addition, cryptococcoma can imitate demyelinating diseases such as multiple sclerosis⁸⁾ and may be mistaken for tuberculous infections, requiring histopathological or CSF analysis for an accurate diagnosis.⁹^-¹¹⁾ Three cases were reported wherein cryptococcoma can be complicated with cerebral infarction.¹²^-¹⁴⁾ Differential diagnosis is more challenging in immunocompetent patients in whom cryptococcoma is less expected. For instance, a study reported cryptococcoma in an immunocompetent patient initially suspected of a neoplasm.¹⁵^-¹⁸⁾

In elderly patients, particularly, those with a poor performance status, the risks of biopsy may outweigh the potential benefits due to frailty and comorbidities. A study outlined a less-invasive treatment strategy for patients with suspected glioblastoma and poor performance status, omitting histological confirmation. However, cryptococcoma poses a significant diagnostic challenge in such biopsy-omitted strategies.¹⁹⁾ In our case, the initial considerations for the differential diagnosis included metastatic brain tumors and tuberculomas. Typical imaging findings in lung cancer include spiculated, lobulated, or irregular nodules or masses. Chest imaging findings are not characteristic of typical lung cancers, making it essential to obtain a definitive diagnosis before determining an appropriate treatment strategy.

There have been reports of CSF culture-proven intracranial cryptococcoma,²^,¹³^,¹⁵^,¹⁸^,²⁰^,²¹⁾ and, when meningitis is present, a diagnosis can often be made through a lumbar puncture. However, in the present case, repeated CSF examinations showed that meningitis did not develop consistently throughout the disease course. Therefore, the diagnosis could not be confirmed using CSF analysis, necessitating an invasive biopsy.

Prognosis and management challenges

The prognosis of intracranial cryptococcoma can significantly vary based on factors such as the patient's immune status, timeliness of diagnosis, and adequacy of treatment.

A study reported that immunocompetent patients generally had a favorable prognosis, with 80% achieving good outcomes after surgical decompression combined with antifungal therapy.²⁾ However, the prognosis was poorer for immunocompromised patients; of the five patients in the study, one developed multiorgan failure and died two months post-surgery. A multicenter study found that severe neurological symptoms at presentation were the strongest predictors of mortality in patients with cryptococcal infections, emphasizing the importance of early diagnosis and aggressive management.²²⁾ According to the IDSA, corticosteroids are recommended for managing brain edema surrounding intracranial cryptococcoma lesions, particularly, if there are neurological deficits.¹⁾ In our case, the patient was immunocompetent; however, the tumor masses did not completely resolve with treatment. Neurological symptoms progressively worsened in the absence of corticosteroids, resulting in an unstable clinical course that ultimately led to death.

Surgical intervention may be required for large lesions or those causing significant mass effects.¹⁾ In our case, surgical resection of the residual lesion near the right precentral gyrus was considered; however, complete removal was not feasible due to its multifocal nature. Lesions that impact a patient's motor function pose a risk of worsening paralysis with surgery. Moreover, the tumor exhibited a partial response to antifungal therapy, influencing the decision to forego further surgeries.

Literature review and patient immune status

We reviewed case reports describing intracranial cryptococcoma published in the past 10 years (Table 1).⁴^-⁸^,¹²^-¹⁸^,²⁰^,²¹^,²³^-²⁹⁾ Cryptococcosis is classically associated with immunosuppressive conditions, such as human immunodeficiency virus infection, organ transplantation, and the use of immunosuppressive drugs.¹⁾ However, our review, which included immunocompetent and immunocompromised patients, showed that intracranial cryptococcoma can also occur in the absence of identifiable immune deficits. This finding aligns with previous reports indicating that a substantial proportion of cases are diagnosed in immunocompetent individuals. In these patients, a granulomatous inflammatory response may contribute to localized lesion formation, whereas immunocompromised patients are more likely to present with multifocal disease and higher CSF fungal burdens. These differences in immune status have important implications for diagnosis and management. Our review underscores the need to consider cryptococcoma even in patients without known immunosuppression and to tailor therapeutic strategies according to the patient's immune status.

Table 1

Reported Cases of Intracranial Cryptococcoma Published in the Past 10 Years, Stratified by Immune Status

Author	Year	Country	Age	Sex	Immune status	Location	CSF examination				Neurosurgical procedure	Antifungal treatment	Outcome
Author	Year	Country	Age	Sex	Immune status	Location	Meningitis	WBC (cells/μL)	Protein (mg/dL)	Others	Neurosurgical procedure	Antifungal treatment	Outcome
↑: above normal range, exact value not reported; 5-FC: flucytosine; AmB: amphotericin B deoxycholate; CrAg: cryptococcal antigen; CSF: cerebrospinal fluid; ETV: endoscopic third ventriculostomy; HIV: human immunodeficiency virus; L-AMB: liposomal amphotericin B; NA: not available; VPS: ventriculoperitoneal shunt
Otsuka et al.¹²⁾	2025	Japan	58	Male		Single lesion in right parietal lobe	(+)	183	250	NA	Biopsy	L-AMB + 5-FC	Survived
Feeroz et al.¹³⁾	2024	USA	59	Male		Single lesion in right paramedian pons	(+)	629	NA	Culture (+), CrAg 1:60	None	L-AMB + Fluconazole	Survived
Fujishita et al.²³⁾	2024	Japan	58	Male		Multiple lesions in bilateral ventricles and subarachnoid space	(+)	302	306	NA	Biopsy	L-AMB + 5-FC + Maintenance treatment	Survived
Li et al.¹⁴⁾	2023	Taiwan	40	Male		Two lesions in right middle frontal lobe and right caudate head	NA				Resection	AmB + 5-FC + Fluconazole	Survived
Malhotra et al.²⁴⁾	2023	USA	52	Male		Single lesion in left pars marginalis	(+)	495	127	CrAg 1:4	None	L-AMB + 5-FC + Fluconazole	NA
Boa et al.⁵⁾	2022	Brazil	64	Male		Single lesion in right temporal lobe	NA				Resection	AmB + 5-FC + Fluconazole	Survived
Echieh et al.⁷⁾	2022	Nigeria	33	Male		Single lesion in left cerebellar hemisphere	NA				None	AmB + 5-FC + Fluconazole	Survived
Chang et al.²⁰⁾	2022	Malaysia	46	Male		Bilateral basal ganglia	(+)	25	NA	India ink (+), Culture (+), CrAg >1:512	VP shunt	AmB + 5-FC + Fluconazole	Survived
Brunasso et al.²⁵⁾	2021	Italy	32	Female		Single lesion in right mesial temporal lobe	(–)	NA	NA	Unremarkable	Resection	None	Survived
Wei et al.⁸⁾	2020	China	40	Male	Immunocompetent	Single lesion in corpus callosum	(–)	0	364	India ink (+), Culture (–), CrAg 1:640	None	AmB + 5-FC	Died
Santander et al.¹⁵⁾	2019	Spain	41	Female	Immunocompetent	Single polylobular lesion involving bilateral lateral ventricles	(+)	NA	NA	Culture (+)	Resection + ETV + VPS	AmB + 5-FC	Died
Akyeampong et al.²⁶⁾	2019	Grenada	30	Male		Two lesions in right frontoparietal lobe and parietooccipital lobe	(–)	NA	NA	Culture (–), CrAg (–)	Resection	NA	Survived
Salvador et al.¹⁶⁾	2019	Brazil	26	Female		Single lesion in left parietal lobe	NA				Resection	NA	NA
Kelly et al.¹⁷⁾	2018	Africa	19	Male		Two lesions in left frontal and temporal lobes	NA				Resection	Fluconazole	Survived
Quah et al.²¹⁾	2018	Singapore	50	Male		Multiple lesions in cerebral and cerebellar hemispheres	(+)	260	115	India ink (–), Culture (+), CrAg (+)	None	AmB + 5-FC + Fluconazole	NA
Paiva et al.¹⁸⁾	2017	Brazil	54	Female		Two lesions in left occipital lobe	(+)	NA	↑	Large numbers of Cryptococcus	Biopsy	AmB + Fluconazole	Died
Ulett et al.⁶⁾	2017	Australia	55	Male		Single lesion in right frontoparietal lobe	(–)	NA	370	India ink (+), Culture (–), CrAg 1:8	Resection after lesion growing during treatment	L-AMB + 5-FC + Fluconazole	Survived
Ang et al.⁴⁾	2016	Singapore	59	Male		Two nodules in right frontal lobe	(–)	NA	NA	Unremarkable	None	Fluconazole + 5-FC + AmB	Survived
Amburgy et al.²⁷⁾	2016	USA	Middle age	Male		Three lesions in left basal ganglia, subcortical white matter and spinal cord	(+)	NA	NA	India ink (+), CrAg 1:512, Molecular typing (+)	VPS	AmB + 5-FC	Survived
Misra et al.²⁸⁾	2020	India	55	Male	Natural killer cell deficiency	Single lesion in left frontal lobe	(+)	350	130	India ink (+), CrAg (+)	Resection	AmB + 5-FC + Fluconazole	Survived
Pettersen et al.²⁹⁾	2015	USA	30	Male	HIV	Multiple lesions in right caudate head and right temporal lobe	(+)	64	NA	CrAg 1:4	Biopsy	L-AMB + 5-FC + Fluconazole	Died
Pettersen et al.²⁹⁾	2015	USA	40	Male	HIV	Two lesions in left frontotemporal lobe	(+)	2	NA	CrAg 1:64	Biopsy	L-AMB + 5-FC + Fluconazole	Survived

Possible causes of residual masses following induction therapy

The IDSA recommends initiating therapy with L-AMB combined with flucytosine for a minimum of six weeks and continuing with fluconazole for 6-18 months.¹⁾ However, the optimal duration of induction therapy in specific cases remains unclear. In our case, the induction therapy was extended to eight weeks, yet multiple lesions persisted, indicating the need for a considerably longer treatment duration. According to the IDSA, brain lesions might endure despite effective antifungal therapy due to the host's immune response to cryptococcal meningoencephalitis. This immune reaction can lead to perilesional edema and persistent imaging findings despite clinical progress.¹⁾ However, in our case, the residual lesions reappeared during maintenance therapy, suggesting that they were not merely immunological remnants. Therefore, the prolonged presence of mass lesions post-induction therapy necessitates vigilant monitoring because the risk of recurrence remains significant.

Although uncommon, antifungal resistance can contribute to the persistence of lesions. In such instances, switching to an L-AMB-based regimen, ideally combined with flucytosine, should be considered.³⁰⁾ Susceptibility testing can help adjust therapy and determine the need for alternative agents. L-AMB shows a low resistance rate against Cryptococcus species, whereas flucytosine carries a higher risk of resistance development, supporting its use in combination regimens.³¹^,³²⁾ In a prospective cohort study of patients with neurological cryptococcosis, the median duration of L-AMB-based induction therapy was six weeks. The presence of cryptococcoma is independently associated with higher rates of mycological treatment failure.²^,³³⁾ Further research and clinical data accumulation are necessary to determine the appropriate duration of induction therapy when mass lesions persist beyond the initial treatment phase.

Conclusions

We observed a case of intracranial cryptococcoma in which the lesions persisted after induction therapy and recurred during maintenance treatment, and the patient ultimately died 15 months later. In cases presenting multiple brain lesions and pulmonary findings that are atypical for malignant brain tumors, it is crucial to confirm the histopathological diagnosis. In situations where lesions do not fully resolve with induction therapy, meticulous follow-up is essential due to the potential for recurrence.

Acknowledgments

We would like to thank Editage (www.editage.jp) for English language editing.

Conflicts of Interest Disclosure

All authors have no conflict of interest.

Informed Consent

Informed consent was obtained from the patient for publication of this case report and accompanying images.

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