Importance of symptoms acuity for clinical diagnosis of primary sellar atypical teratoid/rhabdoid tumor

Abstract

The predominance of pituitary adenoma in the etiology of sellar masses often leads to the diagnostic fallacy of “availability bias” so that pituitary adenoma is almost always considered the most likely diagnosis of all sellar masses, even when clinical evidence suggests otherwise. Primary sellar atypical teratoid/ rhabdoid tumor (AT/RT) is the most aggressive sellar tumor. Most patients with sellar AT/RT are initially misdiagnosed with pituitary macroadenoma. Early diagnosis of sellar AT/RT is of paramount importance to counsel patients and family on the grave prognosis and to avoid futile surgical procedures. Since there are no discerning imaging features to differentiate AT/RT from other sellar tumors, the acuity of sellar compression symptoms characteristic of AT/RT is the only evidence indicative of the AT/RT diagnosis. Based on the biological and anatomical properties of the sella turcica and its surrounding structures, the nature, order of manifestation, and acuity of the sellar compression symptoms in response to sellar content expansion are mostly predictable. It is concluded that rapidly progressive headache and subsequent similarly rapidly progressive visual symptoms in a female with a large sellar mass are pathognomonic of sellar AT/RT (the “Yu rule”).

Key Words: Sellar atypical teratoid/rhabdoid tumor; Sellar compression symptoms; Headache; Visual symptoms; Symptom acuity; Clinical diagnosis

Core Tip: The biological and anatomical characteristics of the sella turcica and its surrounding structures determine the nature, order of manifestation, and acuity of the sellar compression symptoms. The acuity of sellar compression symptoms is critically important to make a correct diagnosis of a non-adenoma sellar mass. In particular, rapidly progressive headache and subsequent similarly rapidly progressive visual symptoms in a female with a large sellar mass are pathognomonic of sellar atypical teratoid/rhabdoid tumor.

INTRODUCTION

Sellar mass is encountered frequently in clinical practice[1]. Although a sellar mass can be neoplastic, hyperplastic, inflammatory, infiltrative, vascular, or hemorrhagic in nature, the vast majority of sellar masses are pituitary adenomas (also known as pituitary neuroendocrine tumors) with a prevalence close to 1 in 1000 in the general population[1,2]. The predominance of pituitary adenoma in the etiology of sellar masses often leads to the diagnostic fallacy of “availability bias” (limiting differential diagnoses to what readily come to mind)[3]. In my experience, pituitary adenoma is almost always considered by radiologists and clinicians as the most likely diagnosis of all sellar masses, and clinicians often rely too heavily on the radiological diagnosis of a sellar mass, not realizing that although a single pituitary magnetic resonance imaging can describe a sellar mass in detail, it cannot convincingly differentiate a pituitary adenoma from non-adenoma lesions in most cases[4,5]. The notion that a sellar mass is pituitary adenoma until proven otherwise can cause harm. For example, a postpartum female with hypophysitis can be misdiagnosed as having a pituitary macroadenoma and inappropriately receive transsphenoidal hypophysectomy, resulting in hypopituitarism[6]. In this article, I will summarize the biological and anatomical properties of the sella turcica and its surrounding structures and their responses to sellar masses and conclude that clinical symptoms are critically important to make a correct diagnosis of a non-adenoma sellar mass, particularly primary sellar atypical teratoid/rhabdoid tumor (AT/RT), which is very rare with only about 60 definitively diagnosed cases reported so far (to be discussed below).

AT/RT

AT/RT is a very aggressive malignancy of the central nervous system[7,8]. AT/RT is derived from primitive cells in the central nervous system, affects both children and adults, and can arise in any region of brain and spinal cord, including the sellar area. Histological diagnosis of AT/RT can be challenging due to poorly differentiated cellular morphology[9]. At the molecular level, AT/RT exhibits loss of the integrase interactor 1 [encoded by switch defective/sucrose non-fermentable (SWI/SNF) related BAF chromatin remodeling complex subunit B1] protein expression in most cases or the Brahma-related gene 1 (encoded by SWI/SNF related BAF chromatin remodeling complex subunit ATPase 4) protein expression in some, which is used to establish the molecular diagnosis by either immunostaining of integrase interactor 1 or sequencing of the SWI/SNF related BAF chromatin remodeling complex subunit B1 gene)[7]. Primary sellar AT/RT belongs to the MYC sub-group, World Health Organization grade 4, by DNA methylation classification of AT/RT, and is mostly found in adult females[10].

PRIMARY SELLAR AT/RT

Primary sellar AT/RT is the most aggressive sellar tumor[11]. No other sellar tumors, including metastatic small cell lung cancer to the sella, are as aggressive as AT/RT[12]. Most patients inflicted with sellar AT/RT are otherwise healthy but unfortunately follow a typical and tragic clinical course[11,13,14]. They would present with acute headache for weeks and visual changes for days, get a pituitary magnetic resonance imaging, be clinically diagnosed with a pituitary macroadenoma (with the implication that the sellar tumor is benign and manageable), receive transsphenoidal resection, and unexpectedly be diagnosed with AT/RT, a devastating malignancy, based on histology and molecular studies. Sellar AT/RT would grow back quickly and the patients almost invariably succumb to the tumor after re-operation, chemotherapy, and radiotherapy, not to mention the lack of a clear chemotherapy regimen anyway. I have personally seen 3 patients with sellar AT/RT[13,14]. What struck me most was the confusion and frustration of the patients and their family when they had to face the sudden and precipitous deterioration of the patients’ heath after initially being told that the tumor was benign. Early diagnosis of sellar AT/RT is thus of paramount importance to counsel patients and family on the grave prognosis and to avoid futile surgical procedures, and perhaps to guide treatment. Admittedly, no definitive treatment is available; based on retrospective case reviews, early initiation of chemotherapy and radiation seems to be beneficial[11].

SYMPTOMS ACUITY IN CLINICAL DIAGNOSIS OF SELLAR AT/RT

In 2015, in a case report on the first sellar AT/RT patient I saw, we proposed that “short duration of headache and visual changes associated with a large sellar mass are diagnostic clues for sellar AT/RT or other rapidly expanding sellar masses[13]”. Based on that observation, I was able to raise the concern of sellar AT/RT in the subsequent 2 cases I saw as they both presented with rapidly progressive sellar compression symptoms[14]. Further clinical experience and literature review now convince me that the acuity (and implicitly severity) of sellar compression symptoms is critically important to make a correct diagnosis of a non-adenoma sellar mass. In particular, rapidly progressive headache and subsequent similarly rapidly progressive visual symptoms are pathognomonic of sellar AT/RT.

Sellar compression symptoms

Sellar compression symptoms, including headache and visual symptoms, are results of the increase of the volume of sellar content. To best understand the nature, order of manifestation, and acuity of the sellar compression symptoms, two main characteristics of the sella and the surrounding structures need to be emphasized. First, biologically the sella and its surrounding structures such as cavernous sinus and optic chiasm are plastic and can adapt to the expansion of sellar content so long as the expansion is slow[15,16]. Second, anatomically the dura of the sella and the diaphragma sella are the first structure to be affected by the expansion of sellar content (causing headache) while optic chiasm and cranial nerves III, IV, VI, and V (in order of the distance from sella, closest one first) are more distal to the sellar content thus visual symptoms usually occur after headache. When the expansion of sellar content is hyperacute with inflammatory reactions such as in pituitary apoplexy, the sella and its surrounding structures do not have time to adapt so that the sellar compression symptoms are also hyperacute with thunderclap headache and sudden-onset visual impairments[17]. Conversely when the expansion is gradual and slow as in pituitary adenoma, the sella would also gradually expand by tissue remodeling and the optic chiasm and the cranial nerves III, IV, VI, and V are gradually displaced so that sellar compression symptoms are subtle and progress slowly over many months[18,19]. Sellar lymphoma, sellar metastatic malignancies, and hypophysitis have variable, but comparable speed of expansion to that of pituitary adenoma, resulting in slow or subacute symptoms of sellar compression symptoms[20-22].

Sellar compression symptoms in sellar AT/RT

The only known sellar tumor that expands acutely and invades into the surrounding structures aggressively is sellar AT/RT. Sellar AT/RT exhibits extremely high proliferation rates without significant local inflammatory reaction, regardless of the specific histological features of the tumor[7-9]. As sellar AT/RT rapidly grows and invades into the sellar and cavernous sinus, the sella cannot remodel itself timely to accommodate so that the nerves in sellar dura and diaphragma sella are irritated progressively, causing headache initially. When the growth and invasion of AT/RT reach the optic chiasm and cranial nerves III, IV, VI, and V, visual symptoms such as double vision, blurry vision, and eye pain begin to manifest (Figure 1). In all the 3 cases I have seen, headache lasted for about 1 month and visual symptoms about 1 week until they were sufficiently severe and patients felt they needed to be urgently evaluated by medical professionals[13,14].

Figure 1 Pituitary magnetic resonance imaging of a patient with sellar atypical teratoid/rhabdoid tumor. Left, coronal view; right, sagittal view. Note the extensive bilateral cavernous sinus invasion and optic chiasm displacement. Arrows: Tumor. Reproduced from Yu[14]. Citation: Yu R. Sellar Mass in 2 Patients With Acute-Onset Headache and Visual Symptoms: Not Your Usual Pituitary Adenoma. AACE Clin Case Rep 2023; 9: 197-200. Copyright © 2015 Elsevier Inc. Published by Elsevier Inc. This is an open access article with User License: Creative Commons Attribution-NonCommercial-NoDerivs (CC BY-NC-ND 4.0). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

To my knowledge, there have been 62 cases of primary sellar AT/RT with molecular diagnosis so far reported in the literature, including the 3 cases I have seen (Table 1)[11,13,14,23-55]. The duration of sellar compression symptoms before the patients present to their physicians is unfortunately only described in 1/3 of them. Even among those cases, the description of the duration is incomplete in some. In all the cases where the duration of sellar compression symptoms is described, the headache and visual symptoms manifest acutely and progressively, similar to the clinical course of the 3 cases I have seen. Since duration of any symptoms is essential in the differential diagnosis of the symptoms, I assume that duration of headache and visual symptoms are omitted or neglected in the reports of sellar AT/RT in most cases due to the authors’ unawareness of the critical importance of this information in diagnosing a sellar mass (Table 2).

Table 1 Primary sellar atypical teratoid/rhabdoid tumor cases confirmed by molecular studies.

Ref.	Age	Sex	Molecular diagnosis	Headache duration	Visual symptoms duration	Pituitary hormones	Imaging features	Surgery	Chemotherapy	Radiation	Outcome
Zamudio-Coronado et al[23], 2023	60	F	Loss of INI1 SMARCB1 mutations	No headache	2 months	Normal	1.3 cm with cavernous sinus invasion	Total resection, rapid recurrence	Yes	Yes	Did not specify
Aldhafeeri et al[24], 2023	32	M	Loss of INI1	4 days	ND	Hypopituitarism	Large sellar mass with suprasellar distension	Debulking	No	No	Died 3 months after presentation
Yu[14], 2023	45	F	Loss of INI1 (Met)	3 weeks	1 week	Hypopituitarism	1.9 cm × 2.2 cm × 1.8 cm	Debulking	No	No	Alive 1 month after presentation
Yu[14], 2023	32	F	Loss of INI1 (Met)	1 month	1 week	Normal	2.1 cm	Debulking	No	Yes	Died 4 months after presentation
Baiano et al[25], 2022	32	F	Loss of INI1 (Met)	2 months	10 days	Elevated prolactin	Large	Debulking	Yes	No	Died 2 months after presentation
Baiano et al[25], 2022	42	F	Loss of INI1 (Met)	Intense	ND	ND	Large	Debulking	Yes	No	Died 2 months after presentation
Baiano et al[25], 2022	41	F	Loss of INI1 (Met)	ND	ND	Hypopituitarism	Large	Debulking	No	No	Died 1 month after presentation
Baiano et al[25], 2022	50	F	Loss of INI1	Intense	ND	Hypopituitarism	Large	Debulking	Yes	No	Alive 18 months after presentation
Major et al[11], 2022	70	F	Loss of INI1	3 months	4 months	ND	1.8 cm × 2.2 cm × 1.7 cm	Debulking	Yes	Yes	Died 8.5 months after presentation
Duan et al[26], 2022	47	F	Loss of INI1 (Met)	ND	ND	6/7 have hypopituitarism	Large	Debulking	No	No	Died 6 months after presentation
Duan et al[26], 2022	52	F	Loss of INI1 (Met)	ND	ND	6/7 have hypopituitarism	Large	Debulking	No	No	Died 2.5 months after presentation
Duan et al[26], 2022	47	M	Loss of INI1 (Met)	ND	ND	6/7 have hypopituitarism	Large	Debulking	No	Yes	Died 1 month after presentation
Duan et al[26], 2022	46	F	Loss of INI1 (Met)	ND	ND	6/7 have hypopituitarism	Large	Debulking	No	No	Died 6 months after presentation
Duan et al[26], 2022	45	F	Loss of INI1 (Met)	ND	ND	6/7 have hypopituitarism	Large	Debulking	No	No	Died 1 month after presentation
Duan et al[26], 2022	73	F	Loss of INI1 (Met)	ND	ND	6/7 have hypopituitarism	Large	Debulking	No	No	Died 3 months after presentation
Duan et al[26], 2022	41	F	Loss of INI1 (Met)	ND	ND	6/7 have hypopituitarism	Large	Debulking	No	No	Alive 11 months after presentation
Fukuda et al[27], 2021	45	F	Loss of INI1	ND	A few weeks	Hypopituitarism	Large	Debulking	Yes	Yes	Died 5 months after presentation
Liu et al[28], 2020	43	F	Loss of INI1	1 month	1 month	Normal	4.5 cm	Debulking	No	Yes	Died 4 months after presentation
Liu et al[28], 2020	52	F	Loss of INI1	2 weeks	ND	Hypopituitarism	2.8 cm	Debulking	No	No	Died 2 months after presentation
Liu et al[28], 2020	50	F	Loss of INI1	2 months	2 months	Hypopituitarism	2.7 cm	Debulking	No	No	Died 1 month after presentation
Liu et al[28], 2020	29	F	Loss of INI1	4 months	ND	Hypopituitarism	1.9 cm	Debulking	Yes	Yes	Died 8 months after presentation
Liu et al[28], 2020	80	F	Loss of INI1	2 weeks	2 weeks	Hypopituitarism	2.2 cm	Debulking	No	No	Died 1 month after presentation
Bokhari et al[29], 2020	40	F	Loss of INI1	Severe	ND	ND	2.9 cm × 1.7 cm × 2.3 cm	Debulking	None	None	ND
Madhavan et al[30], 2020	58	F	Loss of INI1	ND	ND	Hypopituitarism	2.1 cm sellar mass with 3.1 cm suprasellar extension	Debulking	No	No	ND
Siddiqui et al[31], 2019	55	F	Loss of INI1	1 week	1 week	ND	3.5 cm × 1.7 cm	Debulking	No	No	Died 1 .5 months after presentation
Asmaro et al[32], 2019	62	F	Loss of INI1	Several months	ND	Hypopituitarism	Large	Debulking	No	No	Died 2 months after presentation
Lawler and Robertson[33], 2019	27	F	Loss of INI1	ND	ND	ND	Large	Debulking	ND	ND	ND
Su and Su[34], 2018	37	F	Loss of INI1	ND	2 months	ND	2.57 cm × 1.96 cm × 3.63 cm	Debulking	No	No	Died 3 months after presentation
Nishikawa et al[35], 2018	42	F	Loss of INI1	Rapid	Rapid	ND	1.9 cm × 2.0 cm	Debulking	Yes	Yes	Died 11 months after presentation
Barresi et al[36], 2018	59	F	Loss of INI1	Days	Days		2.3 cm × 1.2 cm	Debulking	No	No	Died 2 months after presentation
Paolini et al[37], 2018	31	F	Loss of INI1	ND	ND	ND	ND	Debulking	No	No	Died 2 months after presentation
Paolini et al[37], 2018	36	F	Loss of INI1	ND	ND	ND	ND	Debulking	Yes	Yes	Alive 22 months after presentation
Paolini et al[37], 2018	46	F	Loss of INI1	ND	ND	ND	ND	Debulking	No	No	Died after 2nd resection
Paolini et al[37], 2018	47	F	Loss of INI1	ND	ND	ND	ND	Debulking	Yes	Yes	Alive 62 months after presentation
Paolini et al[37], 2018	65	f	Loss of INI1	ND	ND	ND	ND	Debulking	Yes	Yes	Died 23 months after presentation
Johann et al[38], 2018	20	F	Loss of INI1 (met)	ND	ND	ND	ND	Debulking	Yes	No	Died 10 years after presentation
Johann et al[38], 2018	48	F	Loss of INI1 (Met)	ND	ND	ND	ND	Debulking	No	No	Alive 4 months after presentation
Huq et al[39], 2018	62	F	Loss of INI1	2 months	Finally	Hypopituitarism	Large	Debulking	No	No	Died 2 months after presentation
Pratt et al[40], 2017	47	F	Loss of INI1	Severe	ND	ND	2.6 cm × 3.9 cm × 3.2 cm	Debulking	No	Yes	ND
Nakata et al[41], 2017	31	F	Loss of INI1	ND	ND	ND	ND	Debulking	Yes	Yes	Died 28 months after presentation
Nakata et al[41], 2017	56	F	Loss of INI1	ND	ND	ND	ND	Debulking	No	Yes	Died 23 months after presentation
Nakata et al[41], 2017	44	F	Loss of INI1	ND	ND	ND	ND	Debulking	Yes	Yes	Died 17 months after presentation
Nakata et al[41], 2017	26	F	Loss of INI1	ND	ND	ND	ND	Debulking	Yes	Yes	Died 33 months after presentation
Nakata et al[41], 2017	21	F	Loss of INI1	ND	ND	ND	ND	Debulking	Yes	Yes	Died 35 months after presentation
Nakata et al[41], 2017	69	F	Loss of INI1	ND	ND	ND	ND	Debulking	Yes	Yes	Alive 37 months after presentation
Almalki et al[42], 2017	36	F	Loss of INI1	3 months	1 month	Hypopituitarism	Large	Debulking	Yes	Yes	Alive 3 years after presentation
Elsayad et al[43], 2016	66	M	Loss of INI1	ND	ND	ND	2.2 cm × 1.6 cm × 1.4 cm	Debulking	No	Yes	Alive 4 years after presentation
Larran-Escandon et al[44], 2016	43	F	Loss of INI1	3 months	2 weeks	Hypopituitarism	2.0 cm × 2.3 cm	Debulking	No	No	Died 1 month after presentation
Nobusawa et al[45], 2016	69	F	Loss of INI1 (Met)	ND	Nost specified. Progressed over a few days	ND	2.8 cm × 1.6 cm	Debulking	Yes	Yes	Alive 2 years after presentation
Lev et al[13], 2015	36	F	Loss of INI1	1 months	6 days	Hypopituitarism	3.3 cm × 3.2 cm × 2.3 cm	Debulking	Yes	Yes	Died 2.5 years after presentation
Biswas et al[46], 2015	48	F	Loss of INI1	ND	2 weeks	ND	ND	Debulking	Yes	Yes	Died 2 months after presentation
Regan et al[47], 2015	45	F	Loss of INI1	9 days	9 days	ND	Large	Debulking	No	Yes	Died 6 months after presentation
Park et al[48], 2014	42	F	Loss of INI1	ND	Progressive	ND	Large	Debulking	Yes	Yes	Alive 2 years after presentation
Shitara and Akiyama[49], 2014	44	F	Loss of INI1	ND	2 months	ND	Large	Debulking	Yes	Yes	Alive 17 months after presentation
Moretti et al[50], 2013	60	F	Loss of INI1	ND	ND	ND	Large	Debulking	Yes	Yes	Alive 30 months after presentation
Chou et al[51], 2013	43	F	Loss of INI1	10 days	10 days	ND	2 cm	Debulking	No	Yes	Alive at 2 weeks
Schneiderhan et al[52], 2011	61	F	Loss of INI1 (Met)	ND	ND	ND	2 cm	Debulking	No	No	Died 3 months after presentation
Schneiderhan et al[52], 2011	57	F	Loss of INI1	ND	ND	ND	2 cm	Debulking	Yes	Yes	Alive 6 months after presentation
Las Heras and Pritzker[53], 2010	46	F	Loss of INI1	ND	ND	ND	ND	Debulking	ND	ND	ND
Arita et al[54], 2008	56	F	Loss of INI1 (Met)	2 months	2 months	ND	2.5 cm	Debulking	No	Yes	Died 23 months after presentation
Raisanen et al[55], 2005	31	F	Loss of INI1	ND	ND	ND	1.6 cm	Debulking	No	Yes	Died 9 months after presentation
Raisanen et al[55], 2005	20	F	Loss of INI1	ND	ND	ND	2.0 cm	Debulking	Yes	Yes	Alive 28 months after presentation

F: Female; M: Male; Met: DNA methylation classification; ND: Not described; INI1: Integrase interactor 1; SMARCB1: Switch defective/sucrose non-fermentable related BAF chromatin remodeling complex subunit B1.

Table 2 Sellar compression symptoms, pituitary hormone status, and pituitary magnetic resonance imaging findings of major sellar lesions.

	Acuity of sellar compression symptoms	Pituitary hormone status	Pituitary MRI	Other clinical clues
Apoplexy	Hyperacute (hours)	Hypopituitarism	With hemorrhage	Known history of pituitary adenoma
Sellar AT/RT	Acute (days to weeks)	Hypopituitarism	Invasive mass	Predominantly in females
Pituitary adenoma	Chronic (months)	Pituitary hormone excess or deficiency	Noninvasive or invasive	History of genetic syndromes
Sellar lymphoma	Chronic (months)	Hypopituitarism	Invasive mass	Unclear
Sellar metastasis	Chronic (months)	Hypopituitarism	Invasive mass	Known malignancies
Hypophysitis	Chronic (months)	Hypopituitarism	Thickened stalk	Postpartum females

MRI: Magnetic resonance imaging; AT/RT: Atypical teratoid/rhabdoid tumor.

CONCLUSION

In summary, the acuity of sellar compression symptoms is critically important to make a correct diagnosis of a non-adenoma sellar mass. In particular, rapidly progressive headache and subsequent similarly rapidly progressive visual symptoms in a female with a large sellar mass are pathognomonic of sellar AT/RT, which I term the “Yu rule” to facilitate usage and discussion. I recognize that the exact duration of sellar compression symptoms can be challenging to assess in some cases but that at least the acuteness of these symptoms is nonetheless evident in all cases of AT/RT in which these symptoms are described.