Primary Central Nervous System Lymphoma with Central Diabetes Insipidus and Hypopituitarism: Diagnostic Pitfalls in the “Ghost Tumor” with Steroid-induced Lymphocytolysis

Abstract

Primary hypothalamic involvement in primary central nervous system lymphoma is rare and can present with nonspecific neurological and endocrine manifestations, resulting in significant diagnostic delays. We report the case of an immunocompetent 29-year-old female who presented with intermittent fever, seizures, progressive behavioral changes, central diabetes insipidus, and hypopituitarism. She was initially treated empirically for encephalitis with anti-epileptics and corticosteroids. Neuroimaging subsequently demonstrated a homogeneously enhancing lesion along the chiasmatic–hypothalamic axis. Initial biopsy was nondiagnostic due to corticosteroid pretreatment, necessitating repeat biopsy via craniotomy, which confirmed diffuse large B-cell lymphoma. This case illustrates the importance of recognizing endocrine red flags in hypothalamic lesions, emphasizes the negative impact of prebiopsy steroid exposure on diagnostic yield, obscuring histopathology even in the absence of radiological regression.

INTRODUCTION

Primary central nervous system lymphoma (PCNSL) is a rare form of extranodal non-Hodgkin lymphoma, accounting for approximately 3% of all primary brain tumors, with diffuse large B-cell lymphoma (DLBCL) representing the vast majority of cases.[1] While typical lesions manifest in periventricular white matter, basal ganglia, and corpus callosum, isolated involvement of the hypothalamic–pituitary axis is uncommon. Historical reviews have identified merely 19 cases of isolated involvement in literature, often presenting with a complex admixture of neurological, psychiatric, and endocrine symptoms.[2] These atypical symptoms can mimic encephalitis, leading to misdiagnosis and inappropriate empirical therapy. A critical diagnostic pitfall in PCNSL is of empirical corticosteroid use before tissue diagnosis, as these induce rapid apoptosis, the ghost tumor effect, which causes transient tumor regression and renders biopsy specimens nondiagnostic.[3,4,5] Guidelines from NCCN and ESMO strongly recommend deferring steroid administration until tissue diagnosis is established, unless urgent intervention is required for life-threatening mass effect.[6] We present a rare case of PCNSL involving the chiasmatic–hypothalamic axis in a young immunocompetent patient, which highlights the same diagnostic challenges.

CASE REPORT

A 29-year-old immunocompetent female presented with intermittent fever, chills, and progressive behavioral changes for a month, including aggression and visual hallucinations. Her family was also informed of prosopagnosia. She also suffered generalized tonic–clonic seizures with postictal confusion, and a presumptive diagnosis of infectious encephalitis was made, for which anti-epileptic therapy and empirical intravenous corticosteroids were given. Due to progressive cognitive decline and persistent fever, she was admitted to our tertiary care.

Upon admission, the patient was disoriented, yet had no focal motor deficits and a normal visual field. She had mild anemia and leukocytosis (13,300/µL). Electrolytes showed hypernatremia (160 mmol/L), hypokalemia (3.5 mmol/L), and hyperchloremia (110 mmol/L). Arterial blood gas showed alkalemia with high bicarbonates, expected with contraction alkalosis.

Further evaluation confirmed profound endocrine dysfunction. Serum osmolality was high (310 mOsm/kg) while urine osmolality was low (157 mOsm/kg), confirming central diabetes insipidus (CDI). Hormonal profiling indicated central hypopituitarism of hypothalamic origin, evidenced by low prolactin (2.44 ng/mL), suppressed luteinizing hormone (<0.07 mIU/mL), low-normal follicle-stimulating hormone (1.75 mIU/mL), and decreased total thyroxine (3.71 µg/dL), alongside an inappropriately normal thyroid-stimulating hormone. The analysis of cerebrospinal fluid showed diminished glucose, increased protein, and lymphocytic pleocytosis with no malignant cells.

Magnetic resonance imaging (MRI) of the brain demonstrated a well-defined suprasellar homogeneously enhancing solid lesion measuring 2.1 cm × 2.2 cm × 2 cm centered in the hypothalamic–chiasmatic axis with perilesional edema [Figure 1], appearing T1 isointense, T2/FLAIR hyperintense, mild restricted-diffusion on diffusion-weighted imaging-apparent diffusion coefficient, involving lamina terminalis anteriorly, tuber cinereum, and abutting the infundibular stalk superiorly. Magnetic resonance spectroscopy showed elevated choline with reduced N-acetylaspartate. The pituitary gland and stalk appeared structurally preserved. Contrast-enhanced computed tomography brain (Navigation protocol) revealed a suprasellar hyperdense lesion in the chiasmatic–hypothalamic axis, showing avid enhancement and perilesional oedema. This narrowed differentials to chiasmatic–hypothalamic glioma, lymphoma, or solid craniopharyngioma.

Figure 1.

Magnetic resonance imaging of the brain. Suprasellar chiasmatic–hypothalamic mass appearing hyperintense on T2W (yellow arrow), (a) and FLAIR sequences with perilesional edema (b and c), and mild restricted diffusion on diffusion-weighted imaging-apparent diffusion coefficient (d and e). Located posterosuperior to the dorsum sellae, appearing T1 iso-hypointense (blue arrow, f) with homogeneous post-contrast enhancement on coronal T1-weighted Fat-Suppressed sequence (T1FS) (g), (h and i) magnetic resonance spectroscopy: elevated choline peak, reduced N-acetylaspartate. Differentials – chiasmatic–hypothalamic glioma, lymphoma, or solid craniopharyngioma

Due to the patient’s deteriorating condition, maximal safe resection of the mass was performed through a right frontal craniotomy [Figure 2a]. Histopathological examination (HPE) showed only reactive gliosis and nonspecific inflammatory changes. However, given the strong radiological suspicion of neoplasm, corticosteroids were withheld, and a repeat biopsy was undertaken 20 days later [Figure 2b]. HPE revealed large atypical lymphoid cells with hyperchromatic nuclei and prominent nucleoli. Immunohistochemistry confirmed DLBCL with a Ki-67 proliferation index of nearly 80% [Figure 3]. The initial non-diagnostic biopsy was attributed to steroid-induced lymphocytolysis. Postoperatively, the patient developed obstructive hydrocephalus due to edema at the floor of the third ventricle, necessitating external ventricular drainage [Figure 2c]. Follow-up computed tomography showed resolution after 1 month [Figure 2d], and the patient was started on chemotherapy with high-dose methotrexate and rituximab. Oral desmopressin for CDI was given with serial monitoring of electrolyte-fluid balance. At the 3-month follow-up, there was a gradual improvement in neuropsychiatric symptoms, but some aggressiveness and partial endocrine deficits persisted.

Figure 2.

Postoperative non-contrast computed tomography (NCCT) brain: (a) Maximal safe resection through right fronto-temporal craniotomy; suprasellar pneumocephalus (yellow arrow) along residual lesion, (b) Repeat biopsy 20 days later, pneumocephalus adjacent to the residual lesion (blue arrow) - positive for diffuse large B-cell lymphoma, (c) Development of Hydrocephalus – with extra-ventricular drain in situ, (d) One-month follow-up NCCT shows resolution of hydrocephalus with external ventricular drain in situ

Figure 3.

Histopathology: Histopathological examination showed large atypical lymphoid cells with hyperchromatic nuclei and prominent nucleoli within neuroglial tissue (a) (H and E stain, ×100). Immunohistochemistry stained positive for CD20 (b), B-cell lymphoma-2 (BCL-2) (c), and BCL-6 (d) confirming diffuse large B-cell lymphoma with high Ki-67 proliferation index

DISCUSSION

Hypothalamic involvement in PCNSL is rare, particularly in immunocompetent individuals. Unlike classical PCNSL, which typically presents with focal motor deficits, hypothalamic lymphomas manifest with a distinct constellation of behavioral changes, sleep disturbances, and endocrine dysfunction.[2,7] In our patient, fever, seizures, and neuropsychiatric symptoms led to an initial misdiagnosis of encephalitis. This is a documented diagnostic pitfall; hypothalamic lymphoma can resemble infectious or autoimmune encephalitis, sarcoidosis, or chiasmatic–hypothalamic gliomas.[8] Radiological features such as homogeneous enhancement and restricted diffusion on MRI were suggestive of high cellularity, a hallmark of lymphoma that helps differentiate it from gliomas or craniopharyngiomas.[9] However, imaging alone is insufficient for diagnosis, and histopathological confirmation can be obscured by steroid-induced lymphocytolytic effect – through the glucocorticoid receptor, triggering rapid apoptosis of lymphoma cells, which depletes malignant cells, leaving only reactive gliosis and T-cell infiltrates in biopsy specimens.[3,4] Crucially, our case demonstrates that a nondiagnostic biopsy can occur due to microscopic tumor depletion even in the absence of radiological regression.[5] This reinforces the EHA-ESMO and NCCN guidelines about deferring corticosteroid therapy in suspected PCNSL until tissue is obtained, unless necessary for life-threatening mass effect.[6] Endocrine manifestations provided pivotal diagnostic clues. CDI in this context results from disruption of the hypothalamo-neurohypophyseal tract.[7] Concurrently, the patient exhibited hypopituitarism despite a structurally preserved pituitary gland, indicating hypothalamic dysfunction rather than primary pituitary failure. The triad of rapid-onset behavioral changes, CDI, and hypopituitarism should strongly raise suspicion of a hypothalamic malignancy.[2] CDI may be partially reversible following chemotherapy, while endocrine deficits often require long-term management.[10]

Finally, prosopagnosia is an unusual symptom for a hypothalamic lesion, either reflecting disruption of associative pathways connecting the limbic system to the temporal visual cortex or transient mass effect and edema. This underscores the extensive functional disruption caused by infiltrative hypothalamic lesions.

CONCLUSION

Primary hypothalamic DLBCL should be considered in patients presenting with encephalitis-like symptoms, CDI, and panhypopituitarism. Empirical corticosteroid administration before biopsy may compromise histopathological diagnosis; however, judicious use is encouraged to counter mass effect and cerebral edema. Early recognition of endocrine red flags, adherence to interval biopsy protocols, and multidisciplinary management are essential to ensure timely diagnosis and optimize patient outcomes.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.