TTF-1–positive primary papillary epithelial tumor of the sella with long-term recurrence after multiple resections

Abstract

Primary papillary epithelial tumor of the sella is an extremely rare thyroid transcription factor-1 (TTF-1) positive tumor arising from the posterior pituitary and infundibular area and is often mistaken for a nonfunctioning pituitary adenoma. We report a young woman with a recurrent sellar–suprasellar mass over nearly a decade despite multiple transsphenoidal surgeries. The tumor showed progressive enlargement without hormone hypersecretion. Histopathology revealed a papillary epithelial neoplasm composed of bland cuboidal-to-columnar cells with apical snouting and inflammatory fibrovascular cores. Immunohistochemistry showed strong pancytokeratin, cytokeratin 7, and diffuse nuclear TTF-1 positivity, with negative pituitary hormone and transcription factor markers, confirming the diagnosis. The proliferation index was low. Complete excision was not feasible due to anatomical constraints, resulting in persistent residual disease. This case highlights the need to reconsider the diagnosis in long-standing recurrent sellar masses and emphasizes the importance of expert pathological assessment and prolonged follow-up in these rare tumors.

Introduction

Sellar and suprasellar lesions are most commonly pituitary adenomas; however, a clinically important minority represent rare non-adenomatous tumors that can closely mimic adenomas on clinical and radiological evaluation [1]. Advances in neuropathology over the past decade have defined a distinct group of posterior pituitary neoplasms characterized by diffuse nuclear expression of thyroid transcription factor-1 (TTF-1), collectively termed the TTF-1–positive posterior pituitary and third ventricular area tumor spectrum [2]. This group includes pituicytoma, spindle cell oncocytoma, granular cell tumor, and the recently recognized primary papillary subtype, all believed to arise from pituicytes of the neurohypophysis and infundibulum. Pituicytes are specialized astroglial cells located in the neurohypophysis and pituitary stalk that provide structural and functional support to neurohypophyseal axons. Ultrastructurally, they may show intermediate filaments, granular lysosomes, oncocytic mitochondria, and ependymal-type microvilli and gap junctions, with variations depending on the tumor subtype.

Within this spectrum, primary papillary epithelial tumor of the sella is an exceptionally rare, recently recognized entity first described by Roncaroli et al, characterized by papillary architecture of cuboidal-to-columnar epithelial cells with apical snouting, diffuse nuclear TTF-1 expression, epithelial marker positivity (pancytokeratin, Cytokeratin 7), and absence of pituitary hormone and pituitary transcription factors staining [3]. Clinically, patients typically present with mass-effect symptoms (headache, visual impairment, hypopituitarism) rather than hormone hypersecretion, making preoperative distinction from nonfunctioning pituitary adenomas challenging.

Accurate recognition of these tumors is clinically important because it guides management and prognosis. TTF-1–positive posterior pituitary tumors arise from the infundibulum or posterior lobe and often show local adherence, limiting complete resection and predisposing to persistence or recurrence [2, 4]. Therefore, long-term radiological follow-up is recommended, with adjuvant radiotherapy reserved for progressive residual or recurrent disease rather than routine postoperative use.

Recent molecular studies, including deoxyribonucleic acid (DNA) methylation profiling, support the biological distinctiveness of TTF-1–positive sellar tumors and suggest epigenomic subgrouping, although validated molecular classifiers for routine clinical use remain under development [5]. These findings underscore the need for greater clinical and pathological awareness of this tumor spectrum, especially in recurrent, nonfunctioning sellar lesions with aggressive local behavior.

We report a rare primary papillary epithelial tumor of the sella with nearly a decade of follow-up and a recurrent course, initially misdiagnosed as a hemorrhagic pituitary macroadenoma before definitive diagnosis. This case highlights key clinical, radiological, and pathological features that may facilitate earlier recognition and inform appropriate long-term surveillance and management.

Case presentation

A 28-year-old woman presented to our tertiary care center with rapidly progressive bilateral visual loss, worse in the right eye, evolving over eight days, and accompanied by worsening frontal headache. This occurred in the setting of a relapsing sellar disorder spanning nearly a decade. She also reported long-standing menstrual irregularity, progressing from oligomenorrhoea to secondary amenorrhea over the preceding two to three years.

Formal ophthalmological evaluation revealed markedly reduced visual acuity with bilateral temporal visual field defects consistent with chiasmal compression. Serial follow-up assessments demonstrated partial visual improvement following surgical decompressions, although residual field deficits persisted at long-term follow-up.

Her illness was first recognized in 2015, at 18 years of age, when she presented with visual symptoms and menstrual disturbances. Neuroimaging revealed a large lobulated heterogeneously enhancing sellar–suprasellar mass measuring approximately 3.5 × 5.3 × 5.4 cm with suprasellar extension (Fig. 1A-1H). The lesion was diagnosed as a pituitary macroadenoma, and she underwent surgical resection, leaving behind a small residual tumor, which resulted in transient visual improvement followed by disease relapse.

Figure 1.

Composite neuroimaging showing baseline and follow-up characteristics of a large sellar–suprasellar mass. (A–H) Baseline imaging (2015): Coronal T1-weighted MRI pre- and post-contrast images show a large intrasellar necrotic mass with peripheral enhancement and suprasellar extension, causing distortion of the third ventricle. Axial non-contrast CT head demonstrates a large sellar–suprasellar lesion without calcification. Sagittal T1-weighted pre-contrast MRI shows a large mass measuring 3.5 × 5.3 × 5.4 cm (anteroposterior × transverse × craniocaudal) with preserved normal pituitary tissue and posterior pituitary bright spot. Post-contrast images demonstrate mixed solid enhancing and predominantly cystic components. Coronal T1 pre-contrast images show areas of intrinsic hyperintensity suggestive of hemorrhagic content. Coronal post-contrast images demonstrate an expansile mass without cavernous internal carotid artery invasion, with suprasellar extension and compression of the third ventricle. T2-weighted images show a predominantly hyperintense solid–cystic lesion with internal septations. (I–N) Follow-up imaging (2025): MRI demonstrates marked interval reduction in tumor size to 3.7 × 4.4 × 3.5 cm, with persistent mixed solid–cystic morphology and imaging characteristics similar to baseline. “(Red arrows indicate the lesion)”.

In 2016, follow-up imaging demonstrated a residual or recurrent solid–cystic sellar lesion measuring approximately 2.7 × 2.6 × 3.4 cm, prompting repeat transsphenoidal surgery. Postoperative imaging showed partial tumor reduction. Subsequent serial imaging over the following years demonstrated persistent disease with slow progression.

By 2017, magnetic resonance imaging (MRI) showed a lobulated sellar–suprasellar mass measuring approximately 3.8 × 2.6 × 2.3 cm with heterogeneous T2 signal and persistent suprasellar extension. Despite further surgical decompressions, the lesion progressed, enlarging between 2018 and 2019 to approximately 6.7 × 5.3 × 5.5 cm with extensive suprasellar and parasellar extension and optic chiasmal compression.

In view of progressive visual impairment, repeat transsphenoidal surgeries were performed in 2019 for residual disease, although postoperative imaging confirmed incomplete resection. In 2023, MRI again revealed a recurrent cystic-solid sellar–suprasellar lesion with heterogeneous enhancement, abutting bilateral cavernous sinus, inferior extension into the sphenoid sinus, and marked optic chiasmal compression.

At the current presentation in September 2023, MRI demonstrated a large recurrent sellar–suprasellar mass with mixed solid and cystic components, splaying the internal carotid arteries bilaterally within the cavernous sinuses and causing severe elevation and compression of the optic chiasm. The persistent recurrence despite multiple surgical interventions and atypical radiological features raised suspicion of a non-adenomatous sellar neoplasm.

Throughout the disease course, there were no features of pituitary hormone hypersecretion. Endocrine evaluation consistently demonstrated hypogonadotropic hypogonadism, explaining her menstrual dysfunction, with preservation of other anterior pituitary axes and intact posterior pituitary function.

Diagnostic assessment

At the time of the most recent presentation in September 2023, endocrine evaluation demonstrated hypogonadotropic hypogonadism with low gonadotropins and inappropriately low estradiol. Serum prolactin was mildly elevated at 42 ng/mL (42 µg/L) (reference range: 5-25 ng/mL [5-25 µg/L]), consistent with pituitary stalk compression. Thyroid, adrenal, and growth hormone axes were preserved, with no evidence of hormone hypersecretion (Table 1). There were no clinical symptoms of polyuria or polydipsia. Serum sodium levels remained within the normal range, with no clinical or biochemical evidence of diabetes insipidus.

Table 1.

Summary of pituitary hormonal evaluation at presentation

Axis	Test	Result (Conventional Units)	Result (SI Units)	Reference Range
Gonadal axis	LH	1.2 IU/L	1.2 IU/L	2-12 IU/L
	FSH	2.1 IU/L	2.1 IU/L	3-10 IU/L
	Estradiol	18 pg/mL	66 pmol/L	30-400 pg/mL (110-1468 pmol/L)
Prolactin	Serum prolactin	42 ng/mL	42 µg/L	5-25 ng/mL (5-25 µg/L)
Thyroid axis	TSH	2.3 mIU/L	2.3 mIU/L	0.4-4.0 mIU/L
	Free T4	1.2 ng/dL	15.4 pmol/L	0.8-1.8 ng/dL (10-23 pmol/L)
Adrenal axis	Morning cortisol	14.6 µg/dL	403 nmol/L	5-25 µg/dL (138-690 nmol/L)
Growth hormone axis	IGF-1	224 ng/mL	29.3 nmol/L	117-329 ng/mL (15-43 nmol/L)
Posterior pituitary	Serum sodium	139 mmol/L	139 mmol/L	135-145 mmol/L

Abbreviations: FSH, follicle-stimulating hormone; IGF-1, insulin-like growth factor-1; LH, luteinizing hormone; TSH, thyroid-stimulating hormone; T4, Thyroxine.

Reference ranges are laboratory-specific and represent institutional standards at the time of testing.

Hormonal evaluation was performed at the time of the most recent presentation in September 2023.

Serial contrast-enhanced MRI showed a progressively enlarging sellar–suprasellar lesion with heterogeneous enhancement, mixed solid–cystic components, parasellar, and without bilateral cavernous sinus invasion, and worsening optic chiasmal compression. The aggressive local growth, repeated recurrence, and lack of hormonal hypersecretion were atypical for a pituitary adenoma.

Earlier surgical specimens were initially interpreted as nonfunctioning pituitary adenoma, reflecting the diagnostic framework at the time and the absence of pituitary hormone expression on immunohistochemistry.

Histopathological examination of both the recent and prior biopsy specimens (Fig. 2A–2B), received in multiple fragments, showed a papillary neoplasm composed of well-formed papillae lined by cuboidal-to-columnar epithelial cells with basally located round-to-oval nuclei, bland chromatin, and abundant eosinophilic cytoplasm with apical snouting. The fibrovascular cores contained a dense inflammatory infiltrate predominantly of plasma cells, with admixed lymphocytes, histiocytes, and occasional multinucleated giant cells. No nuclear atypia, necrosis, or increased mitotic activity was identified, and normal brain parenchyma was not seen.

Figure 2.

(A) Immunohistochemistry demonstrating diffuse strong nuclear positivity for thyroid transcription factor-1 (TTF-1), confirming a TTF-1–positive posterior pituitary epithelial tumor. (B) Corresponding hematoxylin and eosin–stained section showing papillary architecture with epithelial lining and inflammatory fibrovascular cores, consistent with a primary papillary epithelial tumor of the sella.

Immunohistochemistry (IHC) showed strong pancytokeratin and cytokeratin 7 positivity with diffuse nuclear TTF-1 expression, confirming epithelial differentiation. Epithelial membrane antigen highlighted apical snouting, and INI-1 was retained. The tumor was negative for GFAP, SALL4, PAX8, thyroglobulin, BRAF v600e, c-Kit, CK20, S-100, Napsin A, and Olig-2, excluding glial, germ cell, Müllerian, renal, thyroid, and other epithelial origins. The Ki-67 index was <1%, indicating low proliferative activity. IHC staining for pituitary hormones, including adrenocorticotropic hormone (ACTH), growth hormone, prolactin, thyroid-stimulating hormone, follicle-stimulating hormone, and luteinizing hormone, was negative. Staining for pituitary lineage transcription factors, including Pit-1, T-Pit, and steroidogenic factor-1 (SF-1), was also negative, further excluding a nonfunctioning pituitary adenoma. Together with the histomorphology, these findings established the diagnosis of primary papillary epithelial tumor of the sella, a rare TTF-1–positive neoplasm of the posterior pituitary tumor spectrum.

Treatment

Owing to rapidly progressive visual loss and severe optic chiasmal compression, the patient underwent repeat endoscopic transsphenoidal debulking for maximal safe resection. The tumor was moderately vascular and densely adherent to critical neurovascular structures, particularly within the cavernous sinuses, precluding gross-total excision; therefore, a subtotal resection was performed to decompress the optic apparatus.

The postoperative course was uneventful, with no cerebrospinal fluid leak, new cranial nerve deficits, or diabetes insipidus, and vision improved partially before stabilizing. Given the indolent histology, low proliferative index, and incomplete resection, multidisciplinary review recommended active surveillance, reserving radiotherapy for clinical or radiological progression.

Outcome and follow-up

Preoperatively, the tumor measured approximately 6-7 cm. Postoperative MRI demonstrated marked volume reduction with effective decompression of the suprasellar component and optic chiasm. On latest follow-up (Fig. 1I–1N), a residual 3-3.5 cm sellar–parasellar mass persists, predominantly within the sellar compartment and abutting the cavernous sinus, where complete excision was not feasible, without evidence of rapid growth or new intracranial extension.

Clinically, visual function remains stable, with persistent hypogonadotropic hypogonadism and preserved remaining pituitary axes. The patient continues under long-term multidisciplinary surveillance with regular ophthalmological assessment and serial neuroimaging, given the propensity of TTF-1–positive posterior pituitary tumors for local recurrence after subtotal resection.

Although histopathological images from this case have been published previously [3], we provide extended clinical, endocrine, radiological, and outcome follow-up, adding valuable natural-history data for this exceptionally rare TTF-1–positive sellar neoplasm.

Discussion

This case highlights the diagnostic vulnerability of long-standing, nonfunctioning sellar lesions that recur despite appropriate surgery. Its prolonged course underscores how reliance on clinicoradiological impressions may perpetuate misclassification, especially when progressive growth, parasellar extension, and lack of durable surgical control deviate from the typical behavior of pituitary adenomas.

Long-term studies of non-adenomatous sellar tumors suggest that clinical behavior is driven more by anatomical location and growth pattern than by cytological aggressiveness. Posterior pituitary and infundibular tumors often involve the cavernous sinus, optic apparatus, and adjacent vascular structures, limiting complete resection and predisposing to residual disease; thus, recurrence largely reflects anatomical constraints rather than malignant potential [6].

Radiological interpretation is a critical inflection point in such cases. Neuroradiological studies indicate that posterior pituitary tumors often lack distinctive imaging features at presentation and may closely mimic pituitary adenomas or other cystic sellar lesions [7].

However, serial imaging may reveal red flags, including progressive lobulation, increasing heterogeneity, bony remodeling, and vascular encasement, which are less typical of adenomas after debulking. Key radiological features included marked signal heterogeneity, mixed cystic-solid architecture, progressive lobulation, and encasement of adjacent vascular structures, which are atypical for recurrent pituitary adenomas. Lack of calcification on non-contrast CT reasonably excludes craniopharyngioma. In retrospect, the evolving imaging phenotype in our patient was more consistent with a rare sellar neoplasm than with recurrent adenoma.

Histopathology remains the cornerstone of definitive diagnosis. The papillary architecture, epithelial differentiation, and inflamed fibrovascular cores seen in this case are increasingly recognized as characteristic of papillary epithelial tumors of the posterior pituitary. Notably, these tumors often show bland cytology and very low proliferative indices, underscoring that histological grade alone does not predict clinical behavior [8]. This discordance between microscopic appearance and macroscopic course is a recurring feature of posterior pituitary tumors.

TTF-1 is a 38-kDa nuclear DNA-binding protein of the NKX2 homeodomain transcription factor family that regulates embryonic development and gene expression in the thyroid, lung, and certain neoplasms. It is also expressed in hypothalamic neurons, ependymal cells, tanycytes, and pituicytes, supporting the classification of these lesions within the broader group of TTF-1–lineage tumors of the third ventricular and basal forebrain region [3].

Recent clinicopathological series highlight the importance of repeat tissue evaluation in recurrent sellar masses. With multiple resections over time, evolving histological features, and expanded immunohistochemical panels, the true diagnosis may ultimately be clarified [9]. Our case exemplifies this principle, as definitive identification was achieved only after detailed reassessment of tumor morphology and immunophenotype following repeated recurrences. In our case, archived histopathological specimens from earlier surgeries were retrospectively reviewed and compared with recent samples, which confirmed prior misclassification and demonstrated consistent morphological features on re-evaluation.

Surgery is the primary treatment for symptom relief, especially visual compromise, with maximal safe resection preferred when tumors adhere to critical neurovascular structures [10]. Adjuvant radiotherapy is used selectively for progressive or symptomatic residual disease [11]. Recurrence occurs in about 21 of 117 reported cases. In our patient, radiotherapy was considered due to repeated recurrence and refusal of further surgery; however, it has not been administered, and the patient remains under surveillance. This case highlights the need for vigilance in recurrent nonfunctioning sellar masses; recognizing atypical patterns, reassessing pathology, and multidisciplinary care help reduce delays and improve outcomes.

Learning points

• Recurrent or locally invasive nonfunctioning pituitary region masses with heterogeneous imaging—mixed solid–cystic components, variable signal intensity, progressive lobulation, or vascular encasement—should prompt consideration of non-adenomatous sellar tumors.

• Primary papillary epithelial tumor of the sella is a rare TTF-1–positive neoplasm characterized by papillary epithelial architecture, epithelial marker positivity, and absence of pituitary hormone and transcription factor expression.

• Despite low proliferative indices, incomplete resection is common due to local anatomy, leading to recurrence and the need for long-term radiological surveillance.

Contributors

V.J., A.S., V.K., and P.D. were involved in the diagnosis, clinical management of the patient, and preparation of the manuscript. D.C. contributed to the final histopathological diagnosis and interpretation. P.S. provided radiological expertize and manuscript editing. All authors critically reviewed the manuscript, approved the final version, and agreed to be accountable for all aspects of the work.

Funding

No public or commercial funding.

Disclosures

None declared.

Informed patient consent for publication

Signed informed consent was obtained directly from the patient.

Data availability

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