Pituitary cryptococcoma in an immunocompetent patient with panhypopituitarism: illustrative case

Abstract

BACKGROUND

Cryptococcosis is the most common mycosis of the central nervous system. It may develop in immunocompetent and immunocompromised patients, the latter representing most cases. The most common presentation of the disease is meningitis, whereas intra-axial lesions in the form of cryptococcoma are less frequent with a greater tendency to present in immunocompetent patients. The presentation of pituitary cryptococcoma is exceptional. To the best of the authors’ knowledge, there is only one case published in the medical literature.

OBSERVATIONS

The authors present the case of a 30-year-old male without a relevant medical history. He was referred to our center with a pituitary mass on magnetic resonance imaging and panhypopituitarism. The patient underwent endonasal endoscopic transsphenoidal tumor resection, and a histopathological diagnosis of pituitary cryptococcoma was made. Medical management included fluconazole and intravenous amphotericin.

LESSONS

This case underscores the neurosurgical and medical management of an exceptional clinical presentation of pituitary cryptococcoma in an immunocompetent patient. To the best of the authors’ knowledge, there is only one case published in the medical literature. This case provides an invaluable review of the clinical, imaging, and therapeutic considerations regarding this exceptional clinical entity.

Mycosis of the central nervous system is a rare clinical entity, with cryptococcosis the most prevailing form of the disease. There are three varieties of Cryptococcus neoformans species, with C. neoformans var. neoformans the most frequent agent in immunocompromised patients and the major causative organism of intracranial cryptococcoma (ICC).^1,2 By contrast, C. neoformans var. gattii usually affects immunocompetent patients.^1,3

The clinical spectrum of central nervous system (CNS) cryptococcosis includes meningitis, encephalitis, and, less frequently, ICC.¹ Most of the cryptococcal infections occur in patients with immune deficiencies, as opposed to intracranial cryptococcoma, which largely affects healthy patients, reflecting an adequate immune host response to the infectious insult.⁴

Cerebral cryptococcomas are extremely rare lesions that frequently represent diagnostic challenges. ICCs are often initially misdiagnosed as neoplasms or pyogenic abscesses. This review highlights the case of a sellar lesion in a patient with panhypopituitarism that was diagnosed and treated as a neuroendocrine pituitary tumor. Nonetheless, pathological inspection of the resected tumor led to the diagnosis of pituitary cryptococcoma, and prompt standard medical therapy was initiated.

Illustrative Case

A 30-year-old male with no relevant medical history, other than the regular use of intranasal cocaine for the last 12 years, presented to an external primary care clinic with a 1-week history of severe headaches with photophobia and phonophobia without visual deficits. He was diagnosed with a pituitary mass on magnetic resonance imaging (MRI; Fig. 1A) by a general practitioner, and symptomatic treatment was started. The physician did not refer the patient to an endocrinology or neurosurgery service, arguing that there was a lack of correlation between the clinical picture and the imaging study. Complementary laboratory studies were not requested.

FIG. 1.

Preoperative sagittal T1-weighted MRI performed 4 years before the patient presented to our center (A), demonstrating a 0.4-cm growth in the dorsoventral diameter of the lesion. Preoperative sagittal T1-weighted MRI (B) demonstrating a sellar lesion with upward displacement of the optic chiasm; after contrast administration (C), it demonstrated peripheral enhancement. Preoperative coronal T1-weighted MRI with contrast (D). Preoperative sagittal T2-weighted MRI (E). A CT scan of the paranasal sinuses (F) showed a sellar lesion with heterogeneous density with a hyperdense area in the center of the lesion. Preservation of the sella turcica can be seen.

Four years later, the patient presented with asthenia, adynamia, decreased libido with hair loss in androgynous areas, involuntary loss of 15 kg in 2 months, and sexual intercourse with pain after orgasm without ejaculation. The patient attended the family medicine clinic at our institution, where he was evaluated and referred to our service. Laboratory studies were performed, confirming panhypopituitarism (Table 1). The results of the rest of the serum analysis were normal.

TABLE 1.

Results of the patient’s hormonal profile

Test	Value	Normal Range
Serum cortisol (simple 8:00 am)	2.6 µg/dL	6.7–22.6 µg/dL
Follicle-stimulating hormone	1.0 mUI/mL	1.3–19.3 mUI/mL
Luteinizing hormone	0.5 mUI/mL	1.2–8.6 mUI/mL
Prolactin	2.2 ng/mL	0.0–16.0 ng/mL
Testosterone	2.0 ng/dL	240–950 ng/dL
Total T3	134.39 ng/dL	60–180 ng/dL
Free T4	0.31 ng/dL	0.8–1.7 ng/dL
Total T4	4.5 µg/Dl	4.5–12.0 µg/dL
Thyroid-stimulating hormone	1.429 mUI/L	0.380–5.330 mUI/L
Growth hormone (simple)	0.3 ng/mL	0.4–10 ng/mL
Insulin like growth factor 1	109 ng/mL	122–400 ng/mL

T3 = triiodothyronine; T4 = thyroxine.

The patient presented to our clinic in 2022 with a normal neurological examination and the absence of visual fields defects on ophthalmological examination. Hormone replacement therapy was started by the endocrinology service including testosterone, prednisone, and levothyroxine, leading to resolution of the previously described symptoms.

The patient underwent brain MRI, which showed a well-circumscribed, 1.9 × 2.2 cm pituitary lesion with thickened borders and suprasellar extension with upward displacement of the optic chiasm. The mass was T1-isointense with peripheral contrast enhancement and T2-hypointense (Fig. 1B–E). Computed tomography (CT) scanning of the paranasal sinuses for surgical planning (Fig. 1F) showed a sellar lesion with heterogeneous density with a hyperdense area in the center of the lesion, and preservation of the sella turcica was also observed. After comparing the tumor with the MRI studies from 4 years earlier, we noted a 0.4-cm growth in the dorsoventral diameter of the lesion with preservation of the rostroventral and transverse diameter (1.9 vs 1.4 cm).

The patient underwent endonasal endoscopic transsphenoidal resection in collaboration with otorhinolaryngology. Intraoperatively, the mass appeared hardened and strongly adhered to the sellar diaphragm. Leakage of cerebrospinal fluid (CSF) was documented intraoperatively, and a subarachnoid catheter was placed at the end of surgery. Postoperatively, the patient presented with nasal CSF leakage despite the established management, and 7 days later he underwent endoscopic dural repair with a collagen-based dural graft. The CSF leak was solved without notable neurological deficits.

Definitive diagnosis could be made 5 days after surgery. After diagnostic confirmation, the patient started treatment with fluconazole and intravenous (IV) amphotericin B, as prescribed by the infectiology service. Serum analysis was negative for human immunodeficiency virus.

Histopathology

On the microscopic examination, an inflammatory lesion was identified. It was characterized by a necrotic center followed by a fibrous band with chronic lymphoplasmacytic infiltrate and epithelioid cells. Residual pituitary glandular parenchyma was also identified (Fig. 2A–D). In some areas, there were granulomas with central necrosis and microorganisms characterized by yeast of 10–15 µm with a capsule compatible with Cryptococcus spp. The microorganisms are better demonstrated with Periodic acid–Schiff and Alcian blue stains. Some areas show fibrosis with sparse lymphocytes (Fig. 3A–D).

FIG. 2.

A: Panoramic view with mural segment of the lesion (hematoxylin and eosin [H&E]). B: Panoramic view showing residual pituitary parenchyma (synaptophysin immunohistochemistry). C: Magnification of the wall composed of a fibrous band with chronic inflammatory infiltrate (H&E). D: Magnification of the wall with residual pituitary parenchyma (synaptophysin immunohistochemistry).

FIG. 3.

A: Granulomatous inflammation (H&E). B: Fibrous area with patchy chronic infiltrate (H&E). C: Center of the lesion with an aggregate of yeasts (H&E). D: Yeasts stained with Alcian blue.

Discussion

Observations

Cerebral cryptococcomas are rare and challenging diagnoses that can be overlooked because their clinical presentation mimics tumors, with mass effect the main cause of symptoms. Although it is acknowledged that cryptococcosis frequently affects immunocompromised patients, this infectious entity can occur in healthy patients.¹

Ramanzini et al.⁵ analyzed 29 cases of CNS cryptococcoma reported in the literature. Cases included 19 males and 10 females with a mean age of 43 years. Reported clinical symptoms were relevant for headache with or without vomiting, which was the most common symptom and was often progressive in nature. Other symptoms less commonly described were fever, change in mental status, and hemiparesis among others that presented depending on the location of the lesion. The great majority of lesions were located at the basal nuclei and cerebral lobes. Radiological analysis was relevant for lesions that were usually either hyperintense or hypointense at T1 and hyperintense at T2. To further complicate the radiological diagnosis, almost all lesions displayed edema and peripherical contrast enhancement. For these reasons, initial diagnoses were gliomas and metastases.⁵ Chastain et al.⁶ also provided a review of 47 cerebral cryptococcomas based on a scoping review using PubMed and Web of Science (Table 2).

TABLE 2.

Epidemiological profile of 47 cerebral cryptoccocomas presented by Chastain et al.⁶

Characteristic	Value
Sex
Male	35 (75)
Female	12 (25)
Median age in y (range)	48.5 (19–75)
Past medical history, no. (%)
Negative	19 (40)
Positive	28 (60)
HIV infected	10 (36)
Hypertension	6 (21)
Diabetes mellitus	5 (18)
Other (pregnancy, polycythemia   vera, monoclonal gammopathy   of unknown significance,   contact w/ pigeons, cocaine abuse)	7 (25)
Causative agent
Cryptococcus neoformans	25 (53)
Cryptococcus gatti	9 (19)
Cryptococcus spp.	13 (28)
Clinical manifestations, no. (%)
Headache	26 (58)
Altered mental status &/or confusion	17 (38)
Vomiting	14 (31)
Fever	8 (18)
Papilledema	8 (18)
Fatigue	7 (16)
Seizures	6 (13)
Visual disturbance	5 (11)
Location
Frontal	9 (21)
Basal ganglia	9 (21)
Parietal	8 (19)
Thalamus	2 (5)
Pons	1 (2)

HIV = human immunodeficiency virus.

However, the occurrence of a pituitary cryptococcoma has only been reported once by Yu et al.⁷ They described the case of an immunocompetent male in his thirties with a 4-month history of episodic headaches, sexual dysfunction, and diabetes insipidus. Brain MRI depicted a pituitary mass that conditioned chiasmal displacement and was hypointense at T1 with homogeneous contrast enhancement. Retrospectively, meningeal contrast enhancement was found to be indicative of meningitis. Diagnosis was obtained by means of a needle biopsy.

With the studies previously mentioned, it is evident that cerebral cryptococcoma is a disease of adulthood, and most patients are immunocompetent,^1,2 which may suggest that immunocompromised patients tend to present with diffuse forms of the disease (meningitis and meningoencephalitis) because their immune system cannot form granulomas against infectious agents. Moreover, initial diagnoses are never cryptococcoma and in our patient, the exceptional location in the pituitary was never thought to be fungal in origin. Severe headache may be a clue to a fungal pathology in the context of a cerebral mass because almost all case reports were emphatic on that.^8,9 Additionally, in our case, severe headaches were not explained at all by the lesion itself. Because cryptococcomas are rare, the best standard therapy remains to be defined.^1,2 At our institution, we treat patients with an initial scheme of 6 weeks of IV amphotericin B with oral fluconazole (400 mg/d). Consolidation therapy is established with fluconazole orally for a minimum of 12 weeks with the same dose previously established. It is important to expect common serious side effects, such as nephrotoxicity and hypokalemia.

Favorable outcomes are reported in 65% of patients with ICC. Immunocompromised patients and lesions not amenable to surgical treatment were clinical factors that predicted poorer outcomes.^1,3,10

Lessons

ICC is an extremely rare entity and a diagnostic challenge. C. gatti is often implicated in ICC, and a pituitary location has been reported only once. Ours is the second case ever reported that shows that surgical and medical antifungal treatment can result in an excellent prognosis. ICC remains to be a challenge frequently overlooked by clinicians and neurosurgeons, and pathological diagnosis is invaluable as it sheds light in solving this diagnostic enigma. Therefore, this clinical entity must be suspected by neurosurgeons in patients living in endemic regions presenting with pituitary tumors with unusual clinical and/or radiological behavior.

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: Maciel-Ramos, Castillejo-Adalid, Rodríguez-Hernández, López-Félix, Rodríguez-Florido. Acquisition of data: Maciel-Ramos, Castillejo-Adalid, Rodríguez-Hernández, Vázquez-Lima, López-Félix. Analysis and interpretation of data: Maciel-Ramos, Vázquez-Lima. Drafting the article: Maciel-Ramos, Castillejo-Adalid. Critically revising the article: Maciel-Ramos, Castillejo-Adalid, Rodríguez-Hernández. Reviewed submitted version of manuscript: Maciel-Ramos, Castillejo-Adalid. Approved the final version of the manuscript on behalf of all authors: Maciel-Ramos. Administrative/technical/material support: Maciel-Ramos, Vázquez-Lima, Rodríguez-Florido. Study supervision: Vázquez-Lima, López-Félix.