A rare case report of panhypopituitarism and suspected pituitary apoplexy secondary to Rathke cleft cyst

Introduction

Rathke cleft cysts (RCCs) are benign, epithelium-lined sellar lesions derived from remnants of Rathke’s pouch, typically following an indolent clinical course. ¹ Rarely, RCCs may undergo acute hemorrhagic or inflammatory transformation, a phenomenon first systematically characterized by Chaiban et al. as “Rathke cleft cyst apoplexy,” which can mimic the clinical presentation of pituitary adenoma apoplexy with sudden-onset headache, visual disturbance, and hypopituitarism. ² This entity remains exceedingly rare; the largest published series identified only 21 confirmed cases over a decade-long period. ² Compared to pituitary adenoma apoplexy, RCC apoplexy tends to present with less severe symptoms, a lower prevalence of pituitary dysfunction, and smaller mass lesions.^2,3 Hemorrhagic and nonhemorrhagic RCCs mimicking pituitary apoplexy have been described in small case series, with transsphenoidal surgery generally yielding favorable outcomes.^4,5 Although pituitary apoplexy of any etiology carries a theoretical risk of mortality, primarily from acute adrenal insufficiency due to corticotroph deficiency, no deaths attributable to RCC apoplexy have been reported in the published literature to date.^6,7

Despite the rarity of symptomatic disease, RCCs are among the most common incidental findings of the sellar region. Autopsy studies have identified RCCs in 13%–33% of normal pituitary glands, and brain magnetic resonance imaging (MRI) detects them in approximately one in six healthy volunteers.^8,9 The vast majority of these incidentally discovered cysts remain asymptomatic. In large observational cohorts, 57%–87% of conservatively managed RCCs remain stable in size, 15%–21% spontaneously regress, and only 10%–16% demonstrate progression over follow-up periods of up to 10 years.^10,11,12 Symptomatic RCCs requiring surgical intervention account for only 5%–15% of all surgically resected sellar lesions.^8,9 RCCs demonstrate a female predominance, with women comprising 68%–81% of surgical cohorts, and the mean age at diagnosis ranges from 37 to 45 years across published series from North America, Europe, and Asia.^8,13,12 The largest population-based data come from the Swedish Pituitary Registry, which identified 434 patients with RCCs (73% female, mean age 45 years), and a Japanese cohort of 410 patients diagnosed by MRI, of whom 68% were managed conservatively.^13,14 Notably, the increasing utilization of brain MRI globally has led to a rise in the incidental discovery of RCCs, further underscoring the discrepancy between the high prevalence of these lesions and the extreme rarity of RCC apoplexy.^15,8

Current evidence supports conservative management for small RCCs; cysts smaller than 10 mm rarely progress, with fewer than 3% causing hormonal or visual deficits over 5 years. ¹³ Cysts exceeding 10 mm or with suprasellar extension carry higher progression rates (up to 25–30%), warranting closer surveillance. ¹⁴ Surgical intervention is reserved for symptomatic, enlarging lesions, with current guidelines recommending individualized management at multidisciplinary pituitary centers.^16,17

Herein, we present a case of panhypopituitarism resulting from RCC apoplexy, contributing to the limited body of literature on this rare clinical entity.

Case presentation

A 78-year-old male with a past medical history of Hashimoto’s thyroiditis, prostate cancer (2022), coronary artery disease, peripheral artery disease, hypertension, chronic obstructive pulmonary disease, and benign prostatic hyperplasia presented with 6 months of fatigue, dizziness, cognitive slowing, and alternating constipation and diarrhea that has worsened over the previous 2 weeks. Two weeks prior to admission, his levothyroxine dose had been decreased from 50 to 25 mcg due to low thyroid stimulating hormone (TSH), as his primary care physician believed his hypothyroidism was due to his previously established Hashimoto’s thyroiditis rather than pituitary dysfunction. His endocrinologist observed a marked decline in his usual baseline functioning, reporting that he was not upbeat and cracking jokes like his usual behavior during their clinic visits, and referred him to the emergency department. The patient reported no family history of endocrine or autoimmune disorders.

On admission, the patient was alert but exhibited slowed speech and impaired short-term memory. Vital signs revealed sinus bradycardia with stable blood pressure and oxygenation. Physical examination showed no focal neurological deficits, including no visual field deficits or blurry vision.

Laboratory findings

Laboratory evaluation showed: TSH 0.5430 µIU/mL (low-normal), free T4 0.6 ng/dL (low), prolactin 1.26 ng/mL (low), leutinizing hormone (LH) 0.48 IU/L (low), testosterone <12.98 ng/dL (low), and morning cortisol 5.3 µg/dL with adequate cosyntropin stimulation testing (30 min 16.8 µg/dL; 60 min 20.1 µg/dL). Serum electrolytes and basic metabolic panel were unremarkable.

Imaging

MRI of the pituitary revealed a sellar lesion measuring less than 10 mm, radiographically consistent with a RCC (Figures 1–4) as it had T1 hyperintensity, reflecting the proteinaceous or mucoid material characteristic of an RCC versus a pituitary tumor. The endocrinology team noted radiologic features and clinical deterioration concerning for pituitary apoplexy. Thyroid ultrasound demonstrated Hashimoto’s thyroiditis with a 1.5 cm solid hypoechoic nodule.

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Figure 1.

Sagittal T1-weighted noncontrast magnetic resonance image of the brain. A sagittal T1-weighted noncontrast MRI demonstrating a 6 × 7 mm well-defined, round lesion along the superior aspect of the pituitary gland, indicated by the blue arrow. The lesion appears hyperintense on T1-weighted imaging, consistent with proteinaceous or mucoid content typical of a Rathke cleft cyst.

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Figure 2.

Sagittal T1-weighted postcontrast magnetic resonance image of the brain. A sagittal T1-weighted MRI obtained after intravenous gadolinium administration showing no significant enhancement of the pituitary lesion, indicated by the blue arrow. The lack of postcontrast enhancement supports the diagnosis of a Rathke cleft cyst rather than a pituitary adenoma.

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Figure 3.

Axial T2-weighted FLAIR magnetic resonance image of the brain. An axial T2-FLAIR image demonstrating the same 6 × 7 mm pituitary lesion indicated by the blue arrow, which appears hypointense on T2-weighted imaging. The signal characteristics are compatible with a cystic lesion containing proteinaceous material.

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Figure 4.

Coronal T1-weighted noncontrast magnetic resonance image of the brain. A coronal T1-weighted noncontrast MRI showing the T1-hyperintense, non-enhancing lesion situated along the superior aspect of the pituitary gland indicated by the blue arrow. The lesion’s well-circumscribed borders and signal profile are characteristic of a Rathke cleft cyst.

Diagnosis and management

The patient was diagnosed with acute metabolic encephalopathy secondary to hypopituitarism from RCC with suspected apoplexy. His low levels of TSH, prolactin, and LH were attributed to this, as these hormones are produced in the pituitary gland, which is now dysfunctional. His low levels of cortisol were also attributed to hypopituitarism rather than primary adrenal insufficiency, given that his cosyntropin stimulation testing produced an adequate response with the rise in cortisol from exogenous adrenocorticotropic hormone (ACTH), indicating that his adrenal gland was functioning properly, and that his pituitary gland was likely not producing enough ACTH to stimulate normal cortisol production. Levothyroxine was increased to 88 µg once daily in the morning, and hydrocortisone 10 mg once daily in the morning was initiated. Cardiology evaluated his sinus bradycardia, which was determined to be asymptomatic and likely related to inadequate levels of thyroid hormone. Despite his known history of coronary artery disease, the decision was made to increase his levothyroxine dose considering his symptomatic panhypopituitarism causing acute metabolic encephalopathy, dizziness, and bradycardia.

Over 4 days of inpatient hormone replacement therapy, the patient experienced marked improvement in fatigue, cognitive function, and dizziness, and tolerated the new hydrocortisone medication and the increased levothyroxine dose very well. The patient verbalized appreciation for the thorough investigation of his symptoms and reported satisfaction with his care and the resolution of his symptoms. He was discharged home on levothyroxine and hydrocortisone with close outpatient endocrinology follow-up.

Discussion

RCCs are generally benign and stable over time; however, a small subset becomes symptomatic due to mass effect or pituitary dysfunction. ⁸ Several studies have demonstrated that cyst size does not reliably predict endocrine dysfunction, and pituitary hormone deficiencies can occur even in cysts measuring less than 10 mm.^8–10 This patient presented with panhypopituitarism and evidence of apoplexy, underscoring this clinical reality.

Panhypopituitarism is the deficiency of all anterior pituitary hormones (ACTH, TSH, LH, follicle-stimulating hormone, growth hormone, and prolactin), with or without posterior pituitary involvement. ⁷ The anterior pituitary functions under hypothalamic regulation via releasing hormones delivered through the hypophyseal portal system, with each axis maintained by negative feedback from target hormones. ⁷ Any process disrupting the hypothalamus, pituitary stalk, or pituitary gland can produce multiple hormone deficiencies. ⁷ Common acquired causes include pituitary adenomas and their treatment, pituitary apoplexy, Sheehan syndrome, lymphocytic and immune checkpoint inhibitor-induced hypophysitis, infiltrative diseases, cranial radiotherapy, and traumatic brain injury.^6,7 Congenital forms result from mutations in pituitary transcription factors such as PROP1 and POU1F1. ⁷

Panhypopituitarism requires lifelong, multi-hormonal replacement therapy targeting each deficient hypothalamic-pituitary axis, with the guiding principle of achieving replacement as close to the physiological pattern as possible. ⁶ The Endocrine Society recommends that glucocorticoid replacement be initiated first, as thyroid hormone and growth hormone interfere with cortisol metabolism and their initiation can precipitate adrenal crisis in patients with untreated hypoadrenalism.^7,20 Hydrocortisone is the preferred glucocorticoid, administered at a total daily dose of 15–20 mg in two to three divided doses, with the largest dose taken upon awakening to simulate the normal circadian rhythm of cortisol secretion.^6,21 Fludrocortisone is not required in secondary adrenal insufficiency, as mineralocorticoid secretion via the renin-angiotensin-aldosterone system is preserved.^6,7

Once glucocorticoid replacement is established, levothyroxine is initiated for central hypothyroidism, with a target dose of approximately 1.2–1.6 µg/kg/day in otherwise healthy adults younger than 60 years, and 1.0–1.2 µg/kg/day in older adults. ⁷ Monitoring is guided by free T₄ levels (aiming for the upper half of the normal range), as TSH is unreliable in central hypothyroidism.^7,22 In this case, the team, along with the consulting endocrinologist, implemented a conservative approach to initiating glucocorticoid replacement, starting with a modest dose of 10 mg of oral hydrocortisone, with the plan to titrate the dose as necessary based on the patient’s symptomatic response.

Several published cases share notable similarities with the present case. Chaiban et al. first systematically characterized RCC apoplexy in 2011, identifying 21 confirmed cases over a decade-long period, the classical presentation including sudden-onset severe headache, visual disturbances, and impaired pituitary function. ² However, our patient’s presentation diverged from this pattern, as the clinical picture was dominated by a subacute, progressive course of fatigue, cognitive slowing, and metabolic encephalopathy rather than acute headache or visual compromise. Jung et al. compared 22 RCC patients and 24 pituitary adenoma patients with apoplexy-like symptoms and confirmed that the RCC group had smaller tumors and lower incidences of visual deficits and cranial nerve palsy, though rates of endocrine dysfunction and decreased consciousness were not significantly different between groups. ³ Binning et al. reported six cases of hemorrhagic and nonhemorrhagic RCCs mimicking pituitary apoplexy, all presenting with sudden headache and managed surgically via transsphenoidal resection. ⁴ Similarly, Komatsu et al. described five patients with acute-onset symptoms caused by RCCs, including headache, general malaise, polyuria, and fever, all of whom underwent transsphenoidal surgery. Postoperatively, all symptoms except hypopituitarism improved. ⁵ In contrast, our patient was managed conservatively with hormone replacement therapy alone and experienced marked clinical improvement, highlighting that surgical intervention is not universally required in RCC apoplexy when visual symptoms are absent and the patient is clinically stable.

The degree of panhypopituitarism relative to the small cyst size in our patient raises the possibility of an inflammatory component contributing to pituitary dysfunction, a mechanism increasingly recognized in the literature. Ehara et al. recently described a distinct subset of RCCs with secondary hypophysitis, characterized by significantly higher rates of panhypopituitarism (90.9% vs 24.2%, p = 0.001) and diabetes insipidus (90.9% vs 21.1%, p = 0.001) compared to common RCCs. ²³ Amano et al. analyzed 262 surgically treated RCCs and found that those with inflammatory change had a mean of 3.9 impaired pituitary axes compared to 1.1 in non-inflammatory cases (p = 0.001), with circumferential rim enhancement and mixed T2 signal on MRI serving as key preoperative predictors of inflammation. ²⁴ Hama et al. demonstrated that inflammation in RCCs can extend into the adjacent adenohypophysis and neurohypophysis, with progressive inflammation correlating with worsening growth hormone (p = 0.019), cortisol (p = 0.027), and TSH (p = 0.039) responses, ultimately resulting in panhypopituitarism. ²⁵ Although our patient did not undergo surgical biopsy to confirm or exclude secondary hypophysitis, his pre-existing Hashimoto’s thyroiditis, an autoimmune condition, may represent a predisposing factor for pituitary inflammation, as autoimmune comorbidities have been associated with lymphocytic hypophysitis secondary to RCC rupture. ²⁶ This association warrants further investigation and underscores the importance of considering inflammatory mechanisms when small RCCs present with disproportionate endocrine dysfunction.

The natural history of RCC is generally benign: most lesions remain stable, but approximately 10%–15% may enlarge or cause new deficits over time.^10,27,28 Long-term follow-up with serial MRI and endocrine testing is therefore recommended. In this case, conservative therapy led to clinical stabilization without the need for surgery.

Conclusion

This case demonstrates that RCCs measuring less than 10 mm can cause clinically significant panhypopituitarism and apoplexy, and that conservative management with hormone replacement therapy can achieve meaningful clinical improvement without surgical intervention in the absence of visual compromise. The key clinical take-away is twofold. First, a low or inappropriately normal TSH in a patient with low free T4 should prompt evaluation for central hypothyroidism and broader pituitary dysfunction, rather than adjustment of levothyroxine based on TSH alone, a diagnostic pitfall illustrated by this patient’s initial management. Second, the degree of panhypopituitarism disproportionate to cyst size raises the possibility of secondary hypophysitis as a contributing mechanism, particularly in patients with pre-existing autoimmune conditions such as Hashimoto’s thyroiditis.

This report has several limitations. As a single case without histopathological confirmation, the diagnosis of RCC apoplexy was based on radiographic and clinical criteria rather than surgical pathology, and the potential contribution of secondary hypophysitis could not be confirmed or excluded without biopsy. The absence of prior pituitary MRI precludes determination of whether the cyst had undergone interval change. Additionally, the follow-up period at the time of this report was limited, and long-term endocrine and radiographic outcomes remain to be determined.