A young woman presented with primary amenorrhoea, progressive haemiparesis, visual disturbance, dementia and focal motor seizures. Investigations showed hypopituitarism, unilateral cerebral atrophy and inflamed cerebrospinal fluid. A trans-sphenoidal biopsy gave a unifying diagnosis of a pituitary germinoma.
- paediatric neurology
- paediatric neuropathology
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A 20-year-old right-handed woman presented with a 4-year history of progressive left-sided weakness and behavioural change. When aged 16 years, she had first noted weakness, with dragging of her left leg. Within a year, she had difficulty with fine movements in the left hand. After 2 years, she showed behavioural changes, with aggressiveness, childish behaviour (asking for pacifier) and an obsessive concern with cleanliness. She also had progressive ‘visual blurring’. For 1 year, her family had noted intermittent left arm jerks. She also had primary amenorrhoea.
On examination, there were no dysmorphic features. She had a left haemiparesis with occasional brief clonic jerks of the left arm, suggesting focal motor seizures. She had bilaterally reduced visual acuity with afferent pupillary defects, bilateral optic disc pallor, left homonymous haemianopia and a right Horner’s syndrome. Neuropsychological evaluation identified executive dysfunction, impaired working memory and naming, dressing and constructional apraxia, and impaired visuospatial skills.
Initial investigations showed hypopituitarism, with decreased plasma morning cortisol, random growth hormone and insulin-like growth factor 1, and normal thyroid-stimulating hormone and free thyroxine concentrations. Serum beta human chorionic gonadotropin and alpha-fetoprotein were normal. An ultrasound scan of the pelvis showed a small uterus and ovaries, with normal morphology.
Cerebrospinal fluid (CSF) analysis showed 38×106 leucocytes/L (≤5) (77% lymphocytes, 16% monocytes), protein 0.41 g/L (0.15–0.45), with normal glucose and lactate, and positive oligoclonal bands. Cytology and flow cytometry found no atypical cells. Beta human chorionic gonadotropin and alpha-fetoprotein were absent. A comprehensive survey for viral, bacterial, mycobacterial and fungal infections in serum and CSF was unrevealing (table 1). Electroencephalogram showed slowed waveforms over the right hemisphere.
MR scan of the brain showed right cerebral haemiatrophy, involving the basal ganglia and thalamus, with a subtle T2 hyperintensity in the corresponding internal capsule, an enlarged pituitary with heterogeneous contrast enhancement and T2 hyperintensity in the optic chiasm (figure 1). [18F]-fluorodeoxyglucose positron emission tomography(FDG PET) scan of the head (figure 2) showed increased glycolytic metabolism in the pituitary and decreased metabolism in the right cerebral and left cerebellar hemispheres.
This patient’s prominent features included progressive left haemiparesis, left haemianopia, constructional and dressing apraxia, executive dysfunction, left arm focal motor seizures and a right-sided Horner’s syndrome. These findings indicated progressive right hemisphere cortical (constructional and dressing apraxia, haemianopia, seizures) and subcortical (Horner’s) structure involvement. Neuroimaging showed cerebral haemiatrophy with marked involvement of the internal capsule, thalamus and basal ganglia.
Her primary amenorrhoea and hypopituitarism, together with the ophthalmological findings of bilateral disc pallor, decreased visual acuity and afferent pupillary defects, suggested a pituitary pathology. We therefore suspected a pituitary mass lesion that was involving the optic chiasm.
It would have been challenging to establish a unified diagnosis based solely on clinical and radiological features. The protracted disease course and heterogeneous sellar MR scan enhancement suggested either a primary pituitary tumour (such as adenoma or germ cell tumour) or an inflammatory (hypophysitis, sarcoidosis) or infiltrative disease (Langerhans cell histiocytosis). An intracranial germinoma could cause both cerebral haemiatrophy and a pituitary mass, but concurrent cerebral hemisphere involvement would be unexpected. Moreover, an intracranial germinoma would not usually explain inflammatory CSF findings and epilepsy. Conversely, Rasmussen’s encephalitis would reasonably explain the seizure disorder, haemiatrophy and central nervous system (CNS) inflammation, but not the pituitary involvement.
A trans-sphenoidal pituitary biopsy yielded a specimen comprising mainly large neoplastic cells with abundant cytoplasm and round, vesicular nuclei, and discrete membranes, arranged in sheets. There were delicate fibrovascular septa with lymphocyte infiltration, but with no granulomas. Immunohistochemistry was positive for CD117 (membrane pattern), Oct4 (nuclei), anti-placental alkaline phosphatase (cytoplasmic and membrane patterns) and podoplanin (cytoplasmic and membrane patterns); immunohistochemistry was negative for chromogranin A, 35βH11 cytokeratin cocktail, CD30 and S100 protein. Additionally, we noted focal positivity for CD3 (T lymphocyte), CD20 (B lymphocyte), CD138 (plasma cell) and CD69 (macrophage) (figure 3). These findings are suggested as a germinoma, according to WHO central nervous system tumour classification.1
We scheduled radiation therapy for a few weeks after the initial diagnosis. However, she and her family declined further treatment, despite having a potentially curable disease, and she was lost to follow-up.
The differential diagnosis of acquired, progressive cerebral haemiatrophy includes haemiconvulsion–haemiplegia–epilepsy syndrome, Rasmussen’s encephalitis, basal ganglia germ cell tumours, progressive haemifacial atrophy or Parry-Romberg syndrome, and linear scleroderma. Distinguishing between these conditions can be challenging.
Haemiconvulsion–haemiplegia–epilepsy syndrome manifests as prolonged unilateral seizures or status epilepticus that usually occur in children under 4 years of age, followed a short time later by haemiplegia and cerebral haemiatrophy. Late-onset epilepsy, often refractory to medical treatment, ensues in more than half of cases, usually within 1 year of disease onset, delineating the full syndrome.2 Despite this patient’s presentation with epilepsy and cerebral haemiatrophy, we considered that haemiconvulsion–haemiplegia–epilepsy syndrome was unlikely because of the presentation in late adolescence and the lack of a precipitating febrile illness. Moreover, there was no precipitating status epilepticus, and seizures developed 3 years after disease onset.
Parry-Romberg syndrome3 and linear scleroderma4 are possibly related, with the common feature of progressive atrophy of the facial skin and underlying soft tissue. In both disorders, focal unilateral atrophy (mostly facial in Parry-Romberg syndrome and frontal in linear scleroderma) may involve deep ipsilateral structures such as the skull, brainstem and brain parenchyma. In this case, however, the absence of facial atrophy excludes both Parry-Romberg syndrome and linear scleroderma.
The cardinal clinical features of Rasmussen’s encephalitis are refractory focal epilepsy, focal hemispheric EEG slowing and cerebral haemiatrophy. This patient fulfilled all major proposed diagnostic criteria for Rasmussen’s encephalitis.5 CSF inflammation is common in Rasmussen’s encephalitis. Unlike haemiconvulsion–haemiplegia–epilepsy syndrome, the seizures in Rasmussen’s encephalitis can occasionally be mild to absent in the initial years. Adult-onset Rasmussen’s encephalitis cases may also occur.
Intracranial germinomas that are off-midline (mainly basal ganglia) may present as progressive hemispheric dysfunction.6 Most present with haemiparesis and about half of patients develop cognitive decline. MR scan of the brain usually shows T2 hyperintensities with or without mass lesions or contrast enhancement. In this patient, the MR scan of the brain showed no basal ganglia mass lesions or contrast enhancement, although there were faint T2 hyperintensities. Patients with this radiological presentation have a protracted course with longer symptom duration before diagnosis.7
There are several possible mechanisms for the ipsilateral cerebral haemiatrophy with thalamic or basal ganglia germinomas.8 Neoplastic infiltration of thalamic ganglionic cells may affect afferent and efferent pathways, leading to Wallerian degeneration. Atrophy is also prominent when tumours invade the internal capsule. Wallerian degeneration could follow long tract involvement in the internal capsule rather than in the thalamic grey matter.
Although in this case we did not have a pathological sample from the internal capsule or basal ganglia, we hypothesise that her haemiatrophy resulted from tumour invasion of these structures. Her clinical and radiological presentation was in keeping with previous reports of haemiatrophy and germinomas without mass lesions.7 Our conservative approach, starting with biopsy of the pituitary rather than the internal capsule, is similar to that in another case of a pituitary germinoma that presented with haemiatrophy and diabetes insipidus. In that case, chemotherapy caused the suprasellar mass to disappear, the white matter abnormalities to improve and the haemiatrophy to stop progressing, suggesting concurrent involvement of both structures with tumoural germ cells.9
CNS germinomas comprise 0.5%–2.1% of intracranial tumours, with a peak incidence in the second decade of life. They most commonly arise in midline structures, especially the suprasellar and pineal regions. Pineal tumours occur twice as often as suprasellar germ cell tumours, with a 2:1–3:1 male preponderance. Intracranial germinomas arise in off-midline regions, such as the basal ganglia, thalamus and cerebral hemispheres, in 4%–20% of cases.6 Pineal lesions usually present with early signs and symptoms of raised intracranial pressure from obstructive hydrocephalus, such as headache, papilloedema and altered mental status. Alternatively, some patients may present with dorsal midbrain (Parinaud’s) syndrome secondary to local compression from pineal enlargement. Suprasellar lesions usually present with hypothalamic or pituitary dysfunction, including hypothyroidism, delayed puberty or growth hormone deficiency with diabetes insipidus. Chiasm and optic nerve involvement may cause visual disturbances, such as bitemporal haemianopia or optic atrophy. Clinicians should consider intracranial germinoma in any child or adolescent presenting with hypopituitarism, obstructive hydrocephalus or dorsal midbrain syndrome.
Inflammatory CSF findings, with pleocytosis, elevated protein, elevated IgG index or oligoclonal bands, can occur with intracranial germinomas, though they may be initially misdiagnosed as multiple sclerosis, sarcoidosis or Behçet’s disease. In addition, there are reports of biopsy showing granulomatous infiltrates that may overshadow the diagnosis of germinoma. In these cases, careful review of pathology identified focal germ cell nests within a granulomatous inflammatory background, particularly using specific histochemistry.10 Although unexpected, inflammatory findings on CSF analysis or biopsy are still consistent with intracranial germinoma.
Intracranial pure germinomas have an excellent prognosis and are distinctively sensitive to radiotherapy, the mainstay of their treatment. Radiation therapy alone may give long-term progression-free survival rates of over 90%. Whole-ventricular radiation has replaced the more aggressive craniospinal radiation as the standard of care, with excellent tolerability. Platinum-based neoadjuvant chemotherapy is sometimes added.11
Although both cerebral haemiatrophy and pituitary masses have broad differential diagnoses, the concurrence of both disorders was key to establishing the diagnosis in this case. Germinomas with simultaneous midline and off-midline structure involvement are rare.9
Acquired hypopituitarism with suprasellar enhancing masses can be caused by inflammatory or infiltrative diseases and tumours.
Intracranial germinomas usually occur in the pineal or suprasellar regions, but up to 20% of tumours may present in the thalami or basal ganglia.
Intracranial germinomas may present with cerebral haemiatrophy without mass lesions on neuroimaging.
Inflammatory cerebrospinal fluid or biopsy findings are still consistent with a diagnosis of intracranial germinoma.
BF and MN contributed equally.
Contributors BFG, MNPS: background research. BJAPB, MNPS: clinical data collection. FPF: pathological specimen analysis and manuscript draft. LTL: revision of CT/MRI findings for the case report and manuscript revision. CRO: revision of nuclear imaging findings for the case report and manuscript revision. LHMC, MNPS, BJAPB, MMS: participated in patient care. RN, BFG, MNPS, BJAPB, LHMC: manuscript draft/revision. MMS: conceptualised and revised the manuscript.
Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent Guardian consent obtained.
Provenance and peer review Not commissioned; externally peer reviewed. This paper was reviewed by Jeremy Rees, London, UK.