Metastatic large cell neuroendocrine carcinoma: a rare cause of hypopituitarism

Abstract

Pituitary metastases from pulmonary large cell neuroendocrine carcinoma (LCNEC) are exceedingly rare but should be considered in patients presenting with arginine vasopressin deficiency and panhypopituitarism in the context of known or suspected metastatic lung cancer. Early recognition and prompt initiation of hormonal replacement therapy are essential to prevent life-threatening endocrine crises and to improve symptom burden. We describe a case of a 43-year-old male who presented with dyspnea, weight loss, and weakness who was found to have metastatic LCNEC involving the liver. Endocrine evaluation revealed central hypothyroidism, central adrenal insufficiency, and later arginine vasopressin deficiency manifested by polyuria and hypernatremia. Additional pituitary testing demonstrated central hypogonadism and growth hormone deficiency consistent with panhypopituitarism. Magnetic resonance imaging showed a sellar mass with pituitary stalk thickening consistent with metastatic disease. Alternative infectious and infiltrative etiologies were excluded. Although the prognosis remains poor due to the aggressive nature of LCNEC, this case underscores the importance of a multidisciplinary approach with endocrinology, oncology, and palliative care to optimize management and quality of life in patients with advanced disease.

Introduction

Large cell neuroendocrine carcinoma (LCNEC) is a rare, high-grade neuroendocrine tumor, comprising approximately 3% of all lung malignancies. It is defined by a high mitotic rate, extensive necrosis, and an aggressive clinical course characterized by frequent metastases to the liver, bone, and brain [1]. Pituitary involvement, however, is exceedingly rare. The prognosis is generally poor, with a median overall survival for metastatic disease reported to be 8 months [2].

Pituitary metastases represent less than 1% of all cranial metastases, with lung and breast cancers being the most common sources [3]. Visual disturbances, including decreased acuity, visual field defects, and ophthalmoplegia, are common and may be the initial manifestation, especially with suprasellar involvement. Arginine vasopressin deficiency (AVP-D) is also a common presenting symptom due to posterior pituitary and stalk involvement. Anterior pituitary deficiencies, including central hypothyroidism and central adrenal insufficiency, are frequently observed as the lesion expands [4].

Metastatic involvement of the pituitary gland from LCNEC of the lung, however, is exceedingly rare, with only a few isolated cases described in the literature. Our case describes a patient with metastatic LCNEC uniquely presenting with panhypopituitarism and AVP-D from pituitary and suprasellar metastases, underscoring the need for a multidisciplinary approach to manage both the underlying aggressive malignancy and the life-threatening endocrine complications.

Case presentation

This case details a 43-year-old male who was found to have hypopituitarism secondary to metastatic LCNEC who presented with central hypothyroidism, central adrenal insufficiency, and arginine vasopressin deficiency.

The patient initially presented to the hospital with shortness of breath and generalized weakness. He noted poor oral intake for the last 2 to 3 months, as well as unintentional weight loss of 10 pounds in the last year. The patient denied any notable family history.

Diagnostic assessment

Vital signs and physical examination were unremarkable. Complete blood count was normal. A comprehensive metabolic panel showed mild hyponatremia. Computed tomography (CT) chest showed a heterogeneous consolidation in the right upper lobe measuring 6 × 4.5 cm. He was admitted for further workup of this mass. Subsequent CT abdomen/pelvis showed multiple liver lesions concerning for metastatic disease. Targeted biopsy of the liver lesions showed metastatic LCNEC with Ki-67 proliferation index of 90%.

Additional laboratory testing showed slightly suppressed TSH of 0.27 μIU/mL (SI: 0.27 mIU/L) (reference range, 0.3-5 μIU/mL [SI: 0.3-5 mIU/L]). Endocrine was consulted for abnormal thyroid function testing. Additional laboratory testing showed low free thyroxine levels of 0.4 ng/dL (SI: 5.16 pmol/L) (reference range, 0.7-1.7 ng/dL [SI: 10-21.9 pmol/L]) concerning for central hypothyroidism. Early morning cortisol was checked and found to be 1.4 μg/dL (SI: 38.6 nmol/L) (reference range, 6.2-19.4 μg/dL [SI: 171-535 nmol/L]). ACTH was suppressed. He underwent cosyntropin stimulation testing, which showed a suboptimal response to cosyntropin, thereby confirming central adrenal insufficiency. Further pituitary testing showed central hypogonadism and growth hormone deficiency. He was started on stress dose steroids and later started on levothyroxine replacement. On hospital day 4, he reported polyuria and was found to have greater than 3 liters of urine output over 24 hours. Laboratory testing showed hypernatremia and urine testing confirmed low osmolality consistent with AVP-D. He was started on intranasal desmopressin with improvement in polyuria.

Magnetic resonance imaging (MRI) of the pituitary gland showed a sellar mass measuring approximately 1.3 × 1.5 × 1.7 cm and mass-like thickening of the pituitary stalk concerning for metastatic disease. It was determined that the patient had panhypopituitarism due to metastatic neuroendocrine tumor as evidenced by central adrenal insufficiency, central hypothyroidism, and AVP-D. Other etiologies for infiltrative pituitary lesions, including tuberculosis and toxoplasmosis, were ruled out. There was no suggestion of an additional primary malignancy such as lymphoma on his imaging studies.

Treatment

Management for this patient included stress-dose glucocorticoids for central adrenal insufficiency, levothyroxine for central hypothyroidism, and intranasal desmopressin for AVP-D. Supportive measures, including fluid and electrolyte management, were implemented as well.

Outcome and follow-up

After discharge, the patient was evaluated by outpatient medical oncology and initiated palliative systemic therapy with carboplatin and etoposide in combination with atezolizumab. He was also evaluated by endocrinology and maintained on glucocorticoid replacement, levothyroxine, and intranasal desmopressin. Despite systemic therapy, follow-up imaging showed progression of pulmonary, hepatic, and renal metastases. CT head noted increased density within the sella. The patient and family had ongoing goals of care discussion in the setting of uncontrolled pain and poor prognosis, given extensive metastatic disease. Unfortunately, the patient passed away 5 months following his initial diagnosis.

Discussion

Pituitary metastases from LCNEC are clinically significant due to their potential to cause panhypopituitarism, which can manifest as central hypothyroidism, central adrenal insufficiency, and AVP-D. In our patient's case, central hypothyroidism was the initial diagnostic clue that he likely had pituitary metastases, prompting further diagnostic imaging.

Pituitary metastases account for fewer than 1% of intracranial metastatic lesions. They are most frequently associated with breast and lung cancers [3]. Metastatic involvement of the pituitary from LCNEC of the lung, however, is exceedingly rare, with only a few isolated cases described in the literature [5]. LCNEC is a high-grade neuroendocrine tumor characterized by aggressive clinical behavior, rapid disease progression, and poor overall prognosis.

The clinical presentation of pituitary metastases can vary, but AVP-D remains the most frequent initial symptom due to preferential involvement of the posterior pituitary and infundibulum. In our patient's case, treatment of central adrenal insufficiency unmasked his underlying AVP-D. Glucocorticoid deficiency has been shown to increase plasma concentrations of arginine vasopressin [6]. Glucocorticoid replacement subsequently suppresses arginine vasopressin release, thereby increasing free water excretion and unmasking AVP-D. Other manifestations of pituitary metastases, such as headache, visual disturbances, and symptoms of anterior pituitary hormone deficiencies (eg, adrenal insufficiency, hypothyroidism, or hypogonadism), can occur as tumor infiltration progresses [4]. In this case, our patient's presentation with polyuria, visual changes, headaches, and biochemical evidence of panhypopituitarism underscores the multifaceted endocrine and neurologic impact of pituitary involvement.

The diagnosis of pituitary metastases can be challenging, particularly in patients with multiple systemic comorbidities or disseminated disease. MRI typically demonstrates sellar or suprasellar masses with features suggestive of metastatic disease, including rapid progression, infundibular thickening, or concomitant brain lesions [5]. Histologic confirmation is often difficult, and in most cases, diagnosis is inferred based on systemic malignancy, imaging characteristics, and associated hormonal deficiencies. In our case, biopsy of the liver lesion provided a definitive diagnosis of LCNEC, and the presence of sellar, suprasellar, and pineal lesions on MRI strongly supported intracranial metastatic spread.

Management of pituitary metastases focuses primarily on palliation and restoration of endocrine function. Hormone replacement therapy, specifically glucocorticoid, thyroid, and vasopressin analog replacement, is crucial for symptom control and improving quality of life. Local therapies such as whole brain radiation or stereotactic radiosurgery may offer transient symptom relief, although responses are typically limited by the extent of systemic disease and overall prognosis. Systemic chemotherapy remains the mainstay of treatment for LCNEC; however, outcomes are generally poor, with median overall survival reported to be 8 months with metastatic disease [2]. In this case, despite initiation of chemotherapy and immunotherapy, the patient experienced rapid disease progression and passed away within 5 months of diagnosis.

This case highlights several challenges in the management of LCNEC with pituitary involvement. Furthermore, patient-related factors, including comorbidities and treatment adherence, can further complicate disease management and impact survival outcomes.

Learning points

• Pituitary metastases, although rare, should be considered in patients with aggressive malignancies who present with new-onset central endocrine deficiencies.

• Large cell neuroendocrine carcinoma of the lung can rarely metastasize to the pituitary gland and may present initially with panhypopituitarism rather than neurologic symptoms.

• Management of pituitary metastases requires a multidisciplinary approach, integrating endocrine stabilization with oncologic care and goals of care discussion.

Contributors

All authors made individual contributions to the authorship. J.W. was involved in the diagnosis and management of this patient as well as the preparation and submission of this manuscript. T.A. and S.N. contributed to data collection, literature review, and manuscript preparation. All authors reviewed and approved the final manuscript.

Funding

No public or commercial funding.

Disclosures

None declared.

Informed patient consent for publication

Signed informed consent could not be obtained from the patient but has been approved by the treating institution.

Data availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.