Lung aspergilloma with pituitary invasive aspergillosis presenting as headache and hyponatraemia

Abstract

Fungal infections involving the pituitary gland are rare and can be life threatening. A 75-year-old man with hypertension and diabetes mellitus presented with headache and hyponatraemia. Imaging study showed right upper lung mass, and mass resection showed aspergilloma without tissue invasion on histology. The patient developed visual impairment a few weeks later, and MRI of the brain revealed bilateral sphenoid sinusitis and pituitary invasion. The trans-sphenoidal biopsy confirmed invasive Aspergillus infection. His sphenoidal sinuses were endoscopically debrided, and he was treated with oral voriconazole. Pituitary aspergillosis should be considered in the differential diagnosis in patients with lung aspergilloma with headache and sinusitis. Prompt biopsy and antifungal treatment are important due to the high mortality rate of the infection.

Background

Non-invasive pulmonary aspergilloma is often treated with surgical resection and no additional antifungal therapy is required. However, it can be life threatening if it involves other organs such as the pituitary gland. We report a case of lung aspergilloma with invasive aspergillosis involving the pituitary gland and multiple sinus cavities presented as hypopituitarism. This case demonstrates that other possible fungal infection sites should be evaluated even for patients with lung aspergilloma.

Case presentation

A 75-year-old man with a history of hypertension, diabetes mellitus and chronic renal disease presented with a non-specific headache for several months and haemoptysis for 1 week. He did not have HIV infection and had not undergone any chemotherapy. He had suffered left inferior orbital rim fracture 8 years previously due to a motor vehicle accident, and an open reduction had been performed. On admission, he had a blood pressure of 120/70 mm Hg, a heart rate of 90 beats/minute and a body temperature of 36.8°C. His neurological examination was unremarkable.

Investigations

Routine laboratory examination revealed mild anaemia (11.3 g/dL), but his liver function tests and C reactive protein were normal. Hypo-osmolar hyponatraemia (serum osmolality: 241 mOsm/kg, serum Na: 118 mmol/L) was present. Urine osmolality and sodium concentration were also high (urine osmolarity: 444 mOsm/kg, urine Na: 51.6 mmol/L). Thyroid function tests revealed low-normal free thyroxine (0.76 ng/dL) and normal thyroid-stimulating hormone (TSH) (6.31 ug/dL). His basal cortisol and adrenocorticotrophic hormone (ACTH) levels were not suppressed (6.31 µg/dL and 17.7 pg/mL, respectively). This suggested that he had the syndrome of inappropriate antidiuretic hormone (SIADH). His haemoglobin A1c level was 6.5%.

Plain chest X-ray showed a lung mass in the right upper lobe, and CT of the chest showed a 23-mm nodule with pleural invasion in the right upper lung (figure 1A). He had bilateral enlargement of his mediastinal lymph nodes, suggestive of lung cancer. CT of the brain was performed to evaluate headache and showed bilateral sphenoidal sinusitis.

Figure 1.

(A) CT of the chest: suspicious nodule (arrow) in the right upper lung abutting the pleura, suggesting lung cancer. (B) PET CT: hypermetabolic mass (arrow) in the right upper lung, which is strongly suggestive of lung cancer. PET, positron emission tomography.

Differential diagnosis

The patient denied smoking, but considering the high prevalence of smoking and the patient’s old age, lung cancer was first suspected. Percutaneous CT-guided needle biopsy of the nodule was conducted to obtain tissue sample for pathologic diagnosis. The histology showed a fibroinflammatory lesion with lymphoplasmacytic infiltration, but lung cancer could not be ruled out. Positron emission tomography (PET) CT was conducted to stage the lung cancer; it showed a hypermetabolic right upper lung mass and a pituitary nodular lesion (figure 1B). Pituitary adenoma was suspected (figure 2A), but the patient refused MRI of the brain.

Figure 2.

(A) PET-CT of the brain: hypermetabolic nodular lesion (arrow) in the pituitary gland. (B) Pituitary MRI: bilateral sphenoid sinusitis with asymmetrical enhancement (arrows) of the right orbital apex, optic nerve sheath and cavernous sinus. Equivocal heterogeneous enhancement of the pituitary gland. (C) Paranasal sinus CT: bone destruction (arrows) of sphenoidal sinuses. PET, positron emission tomography.

For final diagnosis, video-assisted thoracoscopic wedge resection of the right upper lung mass was performed. The mass was irregular and 2 cm in size. Microscopy revealed hyphae with frequent septation but no invasion to the adjacent tissues or vessels. Non-invasive aspergilloma was diagnosed, and no further treatment was provided. His hypo-osmolar hyponatraemia was corrected with an infusion of 3% sodium chloride solution and water restriction. Vasopressin antagonist was not administered because the sodium levels were maintained after the hypertonic saline infusion. His headache improved, and he was discharged.

However, he came to the emergency department 2 weeks later with a worsening headache and visual impairment of his right eye. On admission, he had hypo-osmolar hyponatraemia (serum osmolarity: 241 mOsm/kg, serum Na: 114 mmol/L). For further evaluation, basal pituitary hormone tests were performed. His free thyroxine was low, but TSH was not elevated (0.40 ng/dL and 3.87 µIU/mL, respectively). His basal ACTH levels were also low (4.1 pg/mL), and hypopituitarism was suspected. Pituitary MRI showed bilateral enhancement of the sphenoidal sinuses, right orbital apex, cavernous sinus and pituitary gland (figure 2B). He did not have definite leptomeningeal enhancement, and his cerebrospinal fluid examination was normal. Paranasal sinus CT showed bone destruction within the sphenoidal sinuses (figure 2C).

With underlying diabetes and rapidly progressing symptoms, invasive fungal disease, including aspergillosis or mucormycosis, was suspected. Endoscopic biopsy of sphenoidal sinuses was carried out, and empirical intravenous amphotericin B was administered. Histology confirmed a diagnosis of invasive aspergillosis (figure 3). We concluded that headache, visual disturbance, hormonal abnormality and pituitary enhancement were caused by the pituitary invasion of Aspergillus.

Figure 3.

(A) Endoscopic sphenoid sinus biopsy: hyphae with frequent septation, acute branching angles and diameter ranges from 2.5 µm to 4.5 µm, consistent with Aspergillus spp on Grocott methenamine silver stain. (B) Aspergillus in vessels (arrow), which is consistent with angioinvasion.

Treatment

Sphenoidal sinus debridement was performed during the biopsy procedure. Amphotericin B was changed to oral voriconazole, 200 mg two times per day.

Outcome and follow-up

Serum trough voriconazole level was stable (2 µg/mL). He fully recovered after a 9-month course of oral voriconazole. He is currently free of headaches with recovered eyesight.

Discussion

Aspergillus spp are ubiquitous in the environment. Inhalations of fungal spores is the usual point of entry. Paranasal sinuses and the lungs are the most commonly affected sites, but pituitary aspergillosis is rare. Although seen in immunocompetent patients, immunocompromised patients, such as those with hematopoietic stem cell transplants, solid organ transplants, inherited or acquired immunodeficiency, critically illnesses, diabetes mellitus and corticosteroid use patients, are most susceptible to invasive aspergillosis.¹ Other than previous facial trauma and well-controlled diabetes mellitus, this patient did not show indication of immunodeficiency. Invasive aspergillosis can sometimes lead to severe invasive sequelae, such as meningoencephalitis and death.

Fungal sinusitis due to Aspergillus can have both invasive and non-invasive forms. The non-invasive form does not show adjacent tissue invasion. The invasive form involves angioinvasion and infection through sinus walls. Mortality of invasive central nervous system aspergillosis can be as high as 50%.² Pituitary aspergillosis usually involves haematogenous spread from other sites, iatrogenic spread after neurosurgical procedures or extracranial extension from the nasal cavity or sinuses.³ In our patient, Aspergillus infection spread from sphenoidal sinuses to pituitary fossa.

Symptoms of pituitary aspergillosis are usually non-specific and similar to those of a pituitary tumour. Headache, focal neurologic deficit, visual disturbance and endocrine failure are common symptoms and signs.^3–5 In this case, the patient had a prolonged headache and SIADH, but he did not develop a visual disturbance until the disease progressed. If pituitary aspergillosis is suspected, MRI is the best imaging method that can visualise soft tissue. Lesions may appear as a hypointense or isointense mass on T1 weighted imaging and as hyperintense mass on T2 weighted imaging.⁶ Focal loss of enhancement of sinus mucosa is usually present in invasive fungal sinusitis due to mucosal ischaemia. However, enhancement may be present in the pituitary gland.^{7 8} CT scan shows a soft tissue mass with the destruction of surrounding bone tissue.⁴ In this case, the focal loss of enhancement was not apparent but showed heterogeneous enhancement. This may suggest that extensive necrosis was not present in this patient.

Diagnosis is based on histopathology. Special stains with periodic acid-Schiff or Grocott methenamine silver stain show hyphae with frequent septation, and the diameter ranges from 2.5 µm to 4.5 µm. Compared with mucormycosis, aspergillosis shows branching at acute angles.⁵ Correlation with tissue cultures may be helpful. Tissue culture was not done in this case; however, the morphology was sufficiently characteristic of diagnosing aspergillosis.

Surgical evacuation is important for pituitary aspergillosis treatment.^{4 6} Voriconazole is the first-line therapy for the aspergillosis of the central nervous system.¹ The patients’ symptoms and SIADH improved after antifungal treatment. Follow-up MRI showed an improved state of pituitary and periorbital lesions. Our patient’s serum trough level of voriconazole remained stable, which helped successful treatment.

None of the patients featured in the previous case reports of invasive pituitary aspergillosis had a concurrent pulmonary aspergilloma. Since respiratory colonisation is common with inhalation of fungal spores, fungal sinusitis and lung aspergilloma may have coexisted in some of the patients, with sinusitis later developing into an invasive form.

Patient’s perspective.

I first declined MRI of the brain due to the high cost of the test, but now I thank my doctors for persuading me to take the test.

Learning points.

• Other sites of fungal infection should be suspected for patients with lung aspergilloma.

• Invasive aspergillosis of the pituitary gland could be considered in the differential diagnosis of a pituitary mass, particularly if a lung aspergilloma is present.

• Simultaneous intensive antifungal therapy with thorough debridement is important due to the high mortality rate of the disease.