Neurosurgical Review

https://doi.org/10.1007/s10143-021-01615-0

REVIEW

Strictly third ventricle craniopharyngiomas: pathological

verification, anatomo‑clinical characterization and surgical results
from a comprehensive overview of 245 cases
Ruth Prieto1 · Laura Barrios2 · José M. Pascual3

Received: 1 April 2021 / Revised: 29 June 2021 / Accepted: 22 July 2021

© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021

Abstract
The strictly third ventricle craniopharyngioma topography (strictly 3V CP) defines the subgroup of lesions developed above
an anatomically intact third ventricle floor (3VF). The true existence of this exceedingly rare topographical category is highly
controversial owing to the presumed embryological CP origin from Rathke’s pouch, a structure developmentally situated
outside the neural tube. This study thoroughly analyzes the largest series of strictly 3V CPs ever collected. From 5346 CP
reports published between 1887 and 2021, we selected 245 cases with reliable pathological, surgical, and/or neuroradiologi-
cal verification of an intact 3VF beneath the tumor. This specific topography occurs predominantly in adult (92.6%), male
(64.4%) patients presenting with headache (69.2%), and psychiatric disturbances (59.2%). Neuroradiological features defining
strictly 3V CPs are a tumor-free chiasmatic cistern (95.9%), an entirely visible pituitary stalk (86.4%), and the hypothalamus
positioned around the tumor’s lower pole (92.6%). Most are squamous papillary (82%), showing low-risk severity adhesions
to the hypothalamus (74.2%). The adamantinomatous variant, however, associates a higher risk of severe hypothalamic
adhesion (p < .001). High-risk attachments are also associated with psychiatric symptoms (p = .013), which represented the
major predictor for unfavorable prognoses (83.3% correctly predicted) among cases operated from 2006 onwards. CP recur-
rence is associated with infundibulo-tuberal symptoms (p = .036) and incomplete surgical removal (p = .02). The exclusive
demographic, clinico-pathological and neuroradiological characteristics of strictly 3V CPs make them a separate, unique
topographical category. Accurately distinguishing strictly 3V CPs preoperatively from those tumors replacing the infun-
dibulum and/or tuber cinereum (infundibulo-tuberal or not strictly 3V CPs) is critical for proper, judicious surgical planning.

Keywords Craniopharyngioma · Hypothalamus · Psychiatric symptoms · Strictly intraventricular · Third ventricle floor ·
Third ventricle tumor

Abbreviations MRI Magnetic resonance imaging

ACP Adamantinomatous craniopharyngioma PCP Papillary craniopharyngioma
CP Craniopharyngioma Tc Transcallosal
EETS Endoscopic endonasal transsphenoidal TLT Translamina terminalis
FTV Frontal transventricular TS Transsphenoidal
HICP High intracranial pressure 3V Third ventricle
3VF Third ventricle floor

* Ruth Prieto
rprieto29@hotmail.com Introduction
1
Department of Neurosurgery, Puerta de Hierro University
Hospital, Manuel de Falla 1, 28222 Majadahonda, Madrid, Craniopharyngiomas (CPs) are histologically benign epithe-
Spain lial lesions originating from the infundibulum-pituitary stalk
2
Statistics Department, Computing Center, CSIC, Madrid, complex [1, 2]. Therefore, a high proportion of CPs occupy
Spain the third ventricle (3V) region during their growth. The type
3
Department of Neurosurgery, La Princesa University of 3V involvement may vary from a secondary occupation
Hospital, Madrid, Spain by lesions originated below the 3V floor (3VF), either by

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breaking through it or pushing it upwards, to a primary
growth within the 3V [3, 4]. The vast majority of the latter
develop subpially within the 3VF neural tissue that forms
the median eminence and/or the tuber cinereum, and are thus
termed infundibulo-tuberal CPs [5, 6]. However, some CPs
may originate subependimally and grow exclusively within
the 3V chamber, a category for which we proposed the term
“strictly 3V CPs” [3, 7]. Grouping all these different CP-3V
relationships into the very imprecise term “intraventricular”
often leads to wrong definition of CP topography [3, 8].
Only those CPs growing above an intact 3VF are strictly
intraventricular [3, 5, 9]. Accurately defining this topogra-
phy is critical to subsequent therapeutic decisions. Tumor
seclusion within the 3V boundaries implies selecting trans-
ventricular surgical routes rather than the extra-ventricular
approaches usually employed to reach the sellar/suprasellar
compartments. Misidentifying the strictly 3V topography
may lead to inappropriate surgical planning and undue injury
to the hypothalamic nuclei [10, 11]. Finally, the exception-
ally high rate of squamous-papillary CPs (PCPs) among this
category opens up alternative treatment strategies based on
promising oncogenetic targets recently identified [12, 13].
To date, only a handful of small case series focusing
on 3V CP treatment have been published, most including
infundibulo-tuberal as well as strictly 3V CPs [11, 14–19].
Moreover, the medical literature contains very few reviews
of individual 3V CP cases: in the early 1990s Fukushima
et al. [20] and Iwasaki et al. [21] published the first two
such works, collecting up to 29 cases; a decade later our
group published a systematic review including 36 strictly
3V cases [3]; and, more recently, Jung et al. reported on 38
patients, but only half had exclusive 3V growth [17]. The
lack of comprehensive research into the strictly 3V topogra-
phy motivated the present study. By methodically analyzing
the status of the 3VF in well-described individual CP reports
published from the late nineteenth century to the present, in
addition to some personal cases, we collected a total of 245
cases with strong evidence of an anatomically intact 3VF
beneath the tumor.
Our research pursued two major goals: (i) to establish
definitive anatomical proof of the topographical category of
strictly 3V CPs, either in brain specimens of non-operated
CPs or in surgically treated tumors (Fig. 1) and (ii) to charac-
terize the distinctive epidemiological, clinical, pathological,
neuroradiological, therapeutic, and outcome features of this
topography. Inclusion of cases published over the course
of a century serves to enrich our understanding of this rare
and challenging CP topography, as these seemingly “old”
cases actually provide invaluable complementary sources
of information. Studies based on whole CP brain specimens
published before the computed tomography (CT)/magnetic
resonance imaging (MRI) era allow to make precise com-
parisons between anatomical/pathological information and
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Neurosurgical Review
the surgical/neuroradiological findings described in modern
studies, fundamental for accurately defining the CP topog-
raphy on neuroradiological studies and surgical images.
Moreover, the “old” cases generally provide more detailed
reports about clinical manifestations observed in CP patients
while “modern” reports supply contemporary data concern-
ing CP diagnosis, treatment strategies and outcome. As a
result, we hope this comprehensive study proves helpful in
offering further insight into the strictly 3V CP topography.
Methods
Database and case selection criteria
This systematic review was conducted according to the Pre-
ferred Reporting Items for Systematic Reviews and Meta-
Analyses (PRISMA) criteria [22] (Fig. 2). We conducted
a careful search of well-reported CP cases published in the
scientific literature from 1887 to the present. This survey
involved both individual CP reports in medical journals and
monographs focused on the fields of neurosurgery, neu-
ropathology, neuroendocrinology, and neuroradiology, as
well as tumors included and described in large CP series.
First, a thorough search of multilanguage literature was per-
formed in biomedical databases using the English key words
“craniopharyngioma” or “pituitary/suprasellar/hypophyseal
tumor.” Second, reference lists from records going back to
the nineteenth century were reviewed at some of the larg-
est and most prestigious American and European university
medical libraries (the list of medical libraries investigated
can be seen on our previous publications) [3–5, 23]. Finally,
additional cases were retrieved from our own surgical series,
web pages, and from the collection of CP specimens stored
at the Pathological-Anatomical Museum in Vienna. Our
initial database included 5346 scientific documents, from
which we selected a total of 245 strictly 3V CPs (Online
Supplementary Table 1). All cases included met the fol-
lowing criteria: (1) CP diagnosis was verified, either by the
original author or by indisputable evidence from pathologi-
cal descriptions or pictures provided; (2) every CP report
depicted high-quality necropsy sections of the lesion or
surgical/neuroradiological images proving the strictly 3V
topography; or (3) A detailed description verifying that
tumor growth occurred exclusively within the 3V cavity,
above an intact 3VF, was available.
Variables analyzed
The epidemiological, clinical, pathological, therapeutic, and
outcome variables considered for the analysis of this cohort
and their descriptive findings are shown in Table 1. The
most relevant ones are described henceforth. Five clinical
Neurosurgical Review
Fig. 1  Strictly or truly third ventricle craniopharyngioma topography:
pathological, surgical, and radiological evidence criteria. The cen-
tral picture represents the academic anatomical concept of a strictly
3V CP, which is a tumor (t) growing above an intact third ventricle
floor (3VF). This floor has three layers: (1) pia mater; (2) neural tis-
sue, including the hypothalamic nuclei; and (3) ependymal layer. MB:
mamillary body; MBA: mamillary body angle; the MBA is calcu-
lated by measuring the angle formed by the intersection of a plane
tangential to the MB base with the plane tangential to the fourth ven-
tricle floor; OC: optic chiasm; PG: pituitary gland; PS: pituitary stalk.
Pathological evidence (a–c). a Midsagittal brain histological section
showing a tumor (t) confined to the third ventricle with a small-ses-
sile attachment to the ependymal lining of the 3VF. Note how the
3VF is intact below the lesion. From “Mott FW, Barratt JOW (1899)
Three cases of tumor of the third ventricle. Arch Neurol Path Lab
London County Asyl Claybury 1:417–439.” Public domain. b Mid-
sagittal brain gross section showing the autopsy specimen of a solid
papillary CP (t) with a pedicle attachment (black and white arrow) to
the intact 3VF below. This illustration has been drawn from the arti-
cle “Schmidt B, Gherardi R, Poirier J, Caron JP (1984) Craniophar-
yngiome pedicule du troisieme ventricule. Rev Neurol 140:281–283”
Copyright © 1984 Editions Masson. All rights reserved. Reproduc-
tion with permission. c Authors’ picture of a coronal specimen show-
syndromes were considered: (i) high intracranial pressure
(HICP): headache, vomiting and/or papilledema; (ii) chias-
mal: visual acuity and/or field loss; (iii) pituitary: isolated
sexual disturbances, fatigue, hair loss or atrophic skin altera-
tions; (iv) infundibulo-tuberal: hyperphagia/obesity, diabe-
tes insipidus, somnolence or Fröhlich’s syndrome; and, (v)
hypothalamic: psychiatric disturbances, body temperature or
autonomic nervous system alterations, gait unsteadiness, or
sphincter incontinence. Beyond simply considering the pres-
ence or absence of psychiatric disturbances, these symptoms
were classified into 6 major categories: (i) memory defi-
cits: short-term amnesia, amnesic defects with confusion/
disorientation or Korsakoff-like syndrome, (ii) behavior or
ing a solid papillary CP (t) with a small basal attachment (black
arrow) to the 3VF (red arrows). From the collection of brain tumor
specimens stored at the Pathologisch-anatomische Sammlung im Nar-
renturn-NHM, Vienna. Surgical evidence (d and e). d Surgical view
through a right pterional translamina terminalis approach showing the
pedicle attachment (arrow) of a solid CP (t) to the 3VF below. e1:
Preoperative T2-weighted MRI scan of a solid intraventricular CP (t).
Note the intact pituitary stalk (PS) below the tumor and the down-
wardly displaced optic chiasm (OC). LT: lamina terminalis. e2: Endo-
scopic closeup view of the same patient through the transsphenoidal
approach showing an intact PS and 3VF with no trace of tumor in the
suprasellar compartment. LICA: left internal carotid artery. E1 and
E2 from “Gu Y, Zhang X, Hu F, Yu Y, Xie T, Sun C, Li W (2015)
Suprachiasmatic translaminar terminalis corridor used in endoscopic
endonasal approach for resecting third ventricular craniopharyn-
gioma. J Neurosurg 122:1166–1172”. JNSPG. All rights reserved.
Reproduction with permission. Radiological evidence (f). f1: Preop-
erative midsagittal T1-weighted MRI scan of an intraventricular CP
(t) above the intact PS. The MB is clearly identifiable at the lower
back part of the tumor and the whole 3VF (red arrow) can be traced
below the tumor. f2: Postoperative MRI scan following total tumor
removal evidences a completely intact 3VF (red arrow)
personality changes: indifference, childish/moria-like behav-
ior and/or carelessness regarding personal responsibilities
and hygienic practices; (iii) impaired emotional expression/
control: fits of unprovoked rage, emotional lability and/or
apathy; (iv) cognitive impairments: from slowness of lan-
guage/psychomotor reactions to dementia-like status; (v)
mood alterations: anxiety, depression, hypomania or bipolar
disorders; (vi) psychotic symptoms: delusional ideations or
visual/auditory hallucinations [24].
Assessment of macroscopic features included tumor char-
acteristics, anatomical distortions caused to the pituitary-
hypothalamic structures and tumor occupation of the com-
partments along the sella-3V axis. Moreover, the mamillary
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Fig. 2  PRISMA flow diagram
showing our systematic litera-
ture search. A thorough study of
5346 craniopharyngioma (CP)
records led us to identify 217
eligible records, some of them
reporting multiple strictly 3V
CP cases. A total collection of
245 strictly 3V CPs described
in these 217 documents met
the criteria of strictly intraven-
tricular tumors and were finally
included in this cohort for
analysis
body angle (MBA), formed by the intersection of a plane
tangential to the base of one of the mamillary bodies with
the plane tangential to the fourth ventricle floor, was meas-
ured preoperatively on midsagittal MRI sections (Fig. 1).
This angle allows to reliably discriminate the type of CP-
3VF anatomical relationship and tumor topography based on
the direction and degree of displacement of the mammillary
bodies caused by the tumor. Lesions expanding under the
3V push upwards the 3VF (together with the mammillary
bodies) causing the MBA shifts to an obtuse (> 90º) value,
whereas infundibulo-tuberal CPs growing within the 3VF
itself usually displace downward the mammillary bodies
making the MBA shifts to an hyperacute value (< 30º). In
contrast, strictly 3V CPs do not usually cause severe dis-
tortions on the 3VF and the MBA value is kept within its
normal range of acute values (60–90º) [4]. Tumor consist-
ency was classified into 5 categories: (i) pure solid; (ii) pure
cystic; (iii) mixed consistency, with intermingled solid and
cystic components; (iv) mixed with an upper cystic compo-
nent and a solid basal portion; and, (v) cystic lesion with a
solid cauliflower-like nodule. Based on the CP adherence
classification scheme designed by our group, that proved
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Neurosurgical Review
the relationship between severity of CP attachment and post-
operative hypothalamic injury or patient outcome [23, 25],
we analyzed in the present study the extent and strength
of adhesion to the adjacent 3VF/walls containing the hypo-
thalamic nuclei. The extent of tumor attachment may vary
from small areas, either pedicle (gliovascular stem) or ses-
sile (patch-like), to wide surfaces, either bowl-like (lower
tumor half) or circumferential (entire tumor surface). The
adhesion strength may vary from loose (easily dissectible)
to tenacious adhesions, either due to fusion (lack of a cleav-
age plane) or replacement (unrecognizable brain structure
attached). Accordingly, two major levels of adherence sever-
ity to the hypothalamus were distinguished: (i) low risk, for
CPs with either small pedicle/sessile attachments or with
loose adhesions whose removal leaves the 3VF/walls intact;
(ii) high risk, for tumors with wide and tenacious adhesions
to the 3VF/walls (hypothalamic region). Histological type
was defined only for the cases providing an unequivocal
description of the CP variant.
Finally, patient outcome, follow-up time and tumor
recurrence/regrowth after treatment were also examined.
Overall outcome was classified with the same 4-category
Neurosurgical Review

Table 1  Categorization of epidemiological, clinical, pathological, treatment, and outcome variables analyzed in a cohort of 245 strictly 3V CPs
Variable Categories No. of cases (%) No. of cases w/valid data

Evidence of 3V strict location 245

Pathological (autopsy) 78 (31.8%)
Non-operated specimen 73 (29.8%)
Operated specimen 5 (2%)
Surgical 104 (42.5%)
Only surgery data 22 (9.4%)
Also provides MRI 82 (33.1%)
Neuroradiological 63 (25.7%)
Pre- and postop studies 32 (13.1%)
Only preop studies 31 (12.6%)
Gender Male/female 141 (64.4%) / 78 (35.6%) 219
Age 230
≤ 17 years 17 (7.4%)
18–30 years 33 (14.3%)
31–40 years 41 (17.8%)
41–50 years 67 (29.1%)
51–60 years 44 (19.1%)
≥ 61 years 28 (12.2%)
Clinical variables
Symptoms 201
Seizures 10 (5%)
Dizziness 12 (6%)
Fatigue 29 (14.4%)
Headache 139 (69.2%)
Vomiting 42 (20.9%)
Visual deficits 90 (44.6%)
Endocrine deficits 40 (19.9%)
Hypogonadism 43 (21.4%)
Weight gain/hyperphagia 26 (12.9%)
Fröhlich’s syndrome 16 (8%)
Diabetes insipidus 32 (15.9%)
Somnolence 58 (28.9%)
Consciousness impairment 20 (10%)
Cachexia/poor appetite 16 (8%)
Gait disturbance 46 (22.9%)
Incontinence 18 (9%)
Temperature alterations 19 (9.5%)
Psychiatric symptoms 119 (59.2%)
Memory deficits 84 (41.8%)
Behavior changes 59 (29.4%)
Emotion alterations 39% (19.4%)
Cognitive impairments 42 (20.9%)
Mood alterations 20 (10%)
Psychotic symptoms 19 (9.5%)
Clinical syndromes 201
High intracranial pressure sd 88 (43.8%)
Chiasmal sd 82 (40.8%)
Pituitary sd, 16 (8%)
Infundibulo-tuberal sd 94 (46.8%)
Hypothalamic sd 131 (65.2%)

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Table 1  (continued)
Variable Categories No. of cases (%) No. of cases w/valid data
Pathological-radiological variables
Tumor consistency 237
Solid 126 (53.2%)
Cystic 42 (17.7%)
Mixed 18 (7.6%)
Upper-cystic basal-solid 21 (8.9%)
Cystic cauliflower-like 30 (12.7%)
Calcifications Overall 25 (19.4%) 129
In adamantinomatous 16 (76.2%) 21
In squamous papillary 6 (6.4%) 94
Tumor shape 227
Round 174 (76.7%)
Elliptical 53 (23.3%)
Tumor size 237
≤ 2.5 cm 56 (23.6%)
2.6–3.4 cm 74 (31.2%)
3.5–4.4 cm 95 (40.1%)
≥ 4.5 cm 12 (5.1%)
Hydrocephalus Present 147 (64.5%) 228
Chiasmatic cistern 222
Tumor-free 213 (95.9%)
Partially occupied by tumor 9 (4.1%)
Chiasm morphology 147
Normal 36 (24.5%)
Compressed 110 (74.8%)
Compressed downward 80 (54.4%)
Compressed forward 17 (11.6%)
Infiltrated 1 (0.7%)
Pituitary stalk morphology 184
Normal 159 (86.4%)
Amputated 25 (13.6%)
Hypothalamus relative position 190
Lower-third 176 (92.6%)
Middle-third 14 (7.4%)
Mamillary body angle 130
≤ 29º 26 (20%)
30–59º 76 (58.5%)
60–89º 27 (20.8%)
≥ 90º 1 (0.8%)
3V floor morphology before treat- 125
ment (in cases with available
preoperative MRI)
Wholly visible 53 (42.4%)
Only mamillary bodies 67 (53.6%)
Not visible 5 (4%)
Tumor adherence
Adherence pattern 186
None (free in 3V) 3 (1.6%)
Pedicle-like 35 (18.8%)
Sessile 93 (50%)

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Table 1  (continued)
Variable Categories No. of cases (%) No. of cases w/valid data
Bowl-like 37 (19.9%)
Circumferential 18 (9.7%)
Adherence strength 180
None (free in 3V) 3 (1.7%)
Loose 28 (15.6%)
Tight 116 (64.4%)
Fused 32 (17.8%)
Replacement 1 (0.6%)
Level of adhesion severity to the 194
hypothalamus
Low risk 144 (74.2%)
High risk 50 (25.8%)
Histology 222
Adamantinomatous 33 (14.8%)
Squamous papillary 182 (82%)
Mixed 7 (3.2%)
Treatment variables
Periods of treatment 237
1910–1980 64 (27%)
1981–2005 80 (33.8%)
2006–2021 93 (39.2%)
Type of treatment* Overall (n=225) 1981–2005 (n=72) 2006–2021 (n=85)
Not treated 45 (20%) 7 (9.7%) 2 (2.4%)
Surgery 148 (65.8%) 43 (59.7%) 75 (88.2%)
Radiotherapy 4 (1.8%) 2 (2.8%) 0 (0%)
Surgery + radiotherapy 27 (12%) 19 (26.4%) 8 (9.4%)
Surgery + chemotherapy 1 (0.4%) 1 (1.4%) 0 (0%)
Surgical approach* Overall (n=162) 1981–2005 (n=55) 2006–2021 (n=76)
Sf/pterional/interhemispheric 23 (14.2%) 5 (9.1%) 14 (18.4%)
Translamina-terminalis 43 (26.5%) 19 (34.5%) 22 (28.9%)
FTV/transcallosal 61 (37.7%) 23 (41.8%) 23 (30.3%)
TS/EETS 15 (9.3%) 0 (0%) 14 (18.4%)
Combined approaches 5 (3.1%) 3 (5.5%) 2 (2.6%)
Trepanat/stereotac. biopsy 12 (7.4%) 5 (9.1%) 1 (1.3%)
Decompressive craniectomy 3 (1.9%) 0 (0%) 0 (0%)
Degree of surgical removal* Overall (n=165) 1981–2005 (n=61) 2006–2021 (n=74)
None 13 (7.9%) 2 (3.3%) 2 (2.7%)
Biopsy/cyst drainage 19 (11.5%) 11 (18%) 4 (5.4%)
Partial 21 (13.3%) 7 (11.5%) 7 (9.5%)
Subtotal 26 (15.2%) 9 (14.8%) 12 (16.2%)
Total 86 (52.1%) 32 (52.5%) 49 (66.2%)
Degree of reduction following 17
radiotherapy/chemotherapy
None 1 (5.9%)
Partial 1 (5.9%)
Subtotal 13 (76.5%)
Total 2 (11.8%)
Outcome variables
Patient outcome* Overall (n=143) 1981–2025 (n=51) 2006–2021 (n=61)
Good 73 (51%) 37 (72.58%) 30 (49.2%)

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Table 1  (continued)
Variable Categories No. of cases (%) No. of cases w/valid data
Fair 29 (20.3%) 8 (15.7%) 19 (31.1%)
Poor 22 (15.4%) 5 (9.8%) 10 (16.4%)
Death 19 (13.3%) 1 (2%) 2 (3.3%)
Postoperative symptoms of hypotha- Overall (n=123) 1981–2005 (n=46) 2006–2021 (n=57)
lamic injury*
Present 25 (20.3%) 4 (8.7%) 13 (22.8%)
Postoperative diabetes insipidus 49
Yes (total) 41 (83.7%)
Yes-transitory 9 (18.4%)
No 8 (16.3%)
Postoperative hormonal replacement 33 (73.3%) 45
therapy
Visual outcome (in patients present- 37
ing with visual deficits)
Improved 28 (75.7%)
Unchanged/worsened 9 (24.3%)
Psychiatric outcome (in patients pre- 46
senting with mental disturbances)
Improved 30 (65.2%)
Unchanged / Worsened 16 (34.8%)
Follow-up after treatment 110
< 6 months 33 (30%)
6–11 months 16 (14.5%)
1–3 years 34 (30.9%)
≥ 3 years 27 (24.5%)
Tumor recurrence 110
Yes 15 (14.6%)
No (follow-up < 1 year) 45 (40.9%)
No (follow-up ≥ 1 year) 50 (45.5%)
Time to recurrence 15
< 1 year 7 (46.7%)
1–3 years 5 (33.3%)
≥ 3 years 3 (20%)

EETS, extended endoscopic transsphenoidal approach; FTV, frontal trans-ventricular approach; MRI, magnetic resonance imaging; Sf, subfrontal
approach; Trepanat, exploratory trepanation; TS, transsphenoidal approach; Stereotac.biopsy, stereotactic biopsy; 3V, third ventricle. *Figures
are indicated for the overall cohort and for the two most recent treatment periods (1981–2005 and 2006–2021)

scheme used in our previous works, based, with slight
modifications, on the scheme designed by Rudolf Fahl-
busch [3, 25–27]: (i) good: long-term survival with nei-
ther tumor recurrence nor new permanent neurological,
hypothalamic or hypophyseal deficits, except adequately
treated diabetes insipidus or hormonal deficits; (ii) fair:
new permanent but not disabling neurological/hypotha-
lamic deficits, cerebrospinal fluid fistula, meningitis or
tumor recurrence requiring additional treatments; (iii)
poor: severe hypothalamic derangement that considerably
impair the patients’ quality of life, or tumor recurrence
leading to death within the first year; and, (iv) death,
resulting from severe complications within one month
of surgery.
Statistical analysis
Analyses were performed using IBM SPSS Statistics
27. Frequencies and descriptive statistics on the dif-
ferent categorical variables under study were obtained
first (Table 1), followed by testing of bilateral rela-
tions using asymptotic and χ 2 Monte Carlo exact tests
(Table 2). For those variables related to clinical presen-
tation, tumor features and anatomical distortions of the

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Table 2  Bivariate relationships in the cohort of 245 strictly 3V CPs

A. Relationships between epidemiological/clinical/pathological variables and histological type

Variable P value Type of relation
Age < 0.001 Highest rate of ACPs in pediatric age (< 18 years)
Tumor consistency < 0.001 Solid and cystic cauliflower-like, associated with PCPs
Calcifications < 0.001 Present, associated with ACPs
Pituitary stalk appearance < 0.001 Amputated, associated with ACPs
Chiasmatic cistern appearance 0.005 Partial tumor occupation, associated with ACPs
CP adherence
Adherence extension 0.003 Small attachments (pedicle/sessile-like) associated with PCPs
Adhesion strength 0.039 Tumor fused to or replacing the 3VF/walls associated with ACPs
Level of adhesion severity < 0.001 Highest rate of low-risk adhesion to the hypothalamus in PCPs
B. Relationships between clinical presentation and epidemiological/pathological variables
Variable P value Type of relation
Headache/vomiting / HICP sd < 0.001 Present, associated with pediatric age (< 18 years)
Fröhlich’s syndrome 0.014 Present, with attachment to the 3VF/walls
Consciousness / Gait impairment 0.004 Present, with hydrocephalus
Psychiatric symptoms 0.010 Absent, with solid consistency
Hypothalamic syndrome 0.013 Absent, with solid consistency
Infundibulo-tuberal syndrome 0.018 Present, with compressed/not visible mamillary bodies
C. Clinical and pathological factors associated with the type of CP adherence
Variable P value Type of relation
Psychiatric symptoms 0.013 Present, with high-risk adhesion to the hypothalamus
Hypothalamic syndrome 0.01 Present, with high-risk adhesion to the hypothalamus
Infundibulo-tuberal syndrome 0.024 Present, with high-risk adhesion to the hypothalamus
High intracranial pressure syndrome 0.014 Present, with low-risk adhesion to the hypothalamus
Tumor consistency < 0.001 Solid lesions associated with low-risk adhesion
Hydrocephalus 0.034 Present, with low-risk adhesion to the hypothalamus
Calcifications 0.032 Present with high-risk adhesion to the hypothalamus
D. Factors associated with surgical approach and degree of CP removal
Variable P value Type of relation
Period of treatment < 0.001 [1910–1980] associated with trepanation/biopsy & decompressive craniectomy
[1981–2005] associated with TLT and FTV/Tc
[2006–2021] associated with TS/EETS and highest rate of total removal
Level of adhesion severity 0.002 Low-risk adhesion to the hypothalamus associated with total removal
Surgical approach < 0.001 Highest rate of radical removal with FTV/Tc in [1981–2005] period
Highest rate of radical removal with TLT and TS/EETS in [2006–2021] period
E. Factors associated with postoperative hypothalamic injury and tumor recurrence
Variable P value Type of relation
Treatment period 0.013 Highest rate of hypothalamic injury in [1910–1980]
Psychiatric symptoms < 0.001 Present, associated with hypothalamic injury
Hypothalamic syndrome 0.014 Present, with hypothalamic injury
Major presenting syndrome 0.002 Infundibulo-tuberal sd, with the highest rate of tumor recurrence
Degree of tumor removal 0.02 Total removal, with the lowest rate of CP recurrence in [2006–2021]
F. Factors associated with patient outcome
Variable P value Type of relation
Headache/vomiting 0.001 Present, with poor outcome/death
Psychiatric symptoms 0.012 Present, with poor outcome / death
Major presenting syndrome 0.007 Hypothalamic and HICP sd. with poor outcome/death
Treatment period < 0.001 Highest rate of poor outcome / death in [1910–1980]
Surgical approach 0.015 Highest rate of poor outcome / death with FTV/Tc

ACP, adamantinomatous craniopharyngioma; CP, craniopharyngioma; EETS, endoscopic endonasal transsphenoidal approach; FTV, frontal
trans-ventricular approach; HICP sd., high intracranial pressure syndrome; PCP, papillary craniopharyngioma; Tc, transcallosal approach; TLT,
translamina terminalis approach; TS, transsphenoidal approach; 3V, third ventricle; 3VF, third ventricle floor

13

pituitary-hypothalamic axis, all cases of the cohort were
analyzed together. However, the analysis of surgical strat-
egies and patient outcome was made separately for each of
the three major historical periods of treatment considered,
according to the major breakthroughs in diagnostic and
surgical techniques with a definite impact on CP patient
outcome, in order to achieve more reliable conclusions.
The first period included cases treated between 1910 and
1980, before microsurgical techniques and high-quality
neuroimaging became available. The second period spans
1981 to 2005 in which wide-spread use of CT/MRI and
microsurgery was the rule. The last period, 2006–2021,
coincides with the growing use of endoscopic endonasal
transsphenoidal (EETS) approach.
To preoperatively distinguish adamantinomatous (ACPs)
from PCPs, those variables showing significant relation-
ships with the histological variant were further investi-
gated using a binary logistic regression (stepwise forward
analysis). Goodness-of-fit measure for the selected model
was the correct prediction of ACPs. The variables showing
significant relationships with patient outcome were also
investigated using a multivariate classification and regres-
sion tree method to identify the major outcome predictors.
This hierarchical, stepwise procedure created a tree-based
classification model splitting data into outcome groups.
Based on the dramatic change in outcome after 1980, only
the cases treated from that time onwards were included.
Moreover, due to the low number of deaths, outcome cat-
egorization was simplified into favorable (combining good
and fair) and unfavorable (poor outcomes and deaths).
Results
Strictly 3V CP topography: criteria for inclusion
Evidence of 3VF anatomical integrity beneath the tumor was
substantiated by three major characteristics (Fig. 1):
1. Pathological: 3VF intactness was verified in 78 autop-
sied whole-brain CP specimens (73 non-operated).
2. Surgical: intraoperative findings confirmed 3VF integ-
rity beneath the tumor in 104 cases, either based on the
description/depiction of a preserved 3VF after radi-
cal CP removal through transcranial–transventricular
approaches or by observing an intact pial layer covering
the infundibulum and a tumor-free chiasmatic cistern
through the EETS pathway.
3. Neuroradiological: tumor confinement to the 3V was
confirmed in 32 treated CP cases by the lack of 3VF
13
Neurosurgical Review
tearing or breakage shown on post-treatment MRI stud-
ies obtained following radical tumor removal and/or
radiotherapy; the remaining 31 cases provided preopera-
tive coronal-transinfundibular and/or midsagittal MRI
scans, on which either an intact 3VF could be identified
as a separate layer of tissue beneath the tumor or the
conical lower part of the tumor perfectly fitted into the
chiasmal and infundibular 3V recesses above the 3VF
level.
Strictly 3V CPs: a historical cohort of 245 cases
Table 1 summarizes the epidemiological, clinical, pathologi-
cal, surgical, and prognostic variables analyzed, the most
relevant being discussed below.
Demographics and clinical presentation
This series mostly includes male patients (male/female
ratio: 1.8) and has only one incidence peak between 41 and
50 years of age (29%) (Fig. 3ab). The hypothalamic syn-
drome (65.2%) was the most commonly observed one, fol-
lowed by the infundibulo-tuberal (46.8%) and HICP (43.8%)
syndromes (Fig. 3c). Psychiatric disturbances were reported
in 59.2% of patients, the most common being memory
impairment (41.8%) and behavior alterations (29.4%). Visual
and endocrine alterations occurred in 44.6% and 19.9% of
cases, respectively.
Pathological tumor features: histological type and tumor
adhesion
Histological distribution among the 222 cases providing
this information was 182 PCPs (82%), 33 ACPs (14.8%),
and 7 tumors with mixed histology (3.2%) (Fig. 3d). A
significant relationship between histology and type of CP-
hypothalamic adherence was found (Table 2). The exten-
sion of tumor adhesion was smaller in PCPs (p = 0.003),
around 80% presenting pedicle-like or sessile attachments
to the 3V lining, whereas more than 60% of ACPs had wide
bowl-like or circumferential attachments to the 3VF. Adhe-
sion strength was also lower among PCPs (p = 0.039), only
12.3% of them being fused to the 3VF/walls and none hav-
ing replaced the adjacent nervous tissue. Conversely, the
fusion and replacement rates were tripled in ACPs. Accord-
ingly, low-risk adhesion to the hypothalamus was much
higher in PCPs (83.6%) than in ACPs (41.9%) (p < 0.001,
Fig. 4a). Although not reaching statistical significance, it
is striking that the number of ACP patients with postop-
erative hypothalamic injury almost doubled (32%) that of
PCPs (17%).
Neurosurgical Review
Fig. 3  Epidemiological, clinical, and histological characterization
of the cohort of 245 strictly 3V CPs analyzed in this study. a Simple
bar chart showing the age distribution percentage of 230 cases (age
unknown in 15 cases). Note that only 7.4% of patients were under 18.
b Bar graph displaying the gender distribution (gender unknown in
Overall, less than 20% of cases had calcifications, but
this number increased to 76.2% in ACPs (p < 0.001). In this
series, most CPs had a smooth round shape (77%). More
than half of cases had a solid consistency (53%), which was
associated with the PCP histology (p < 0.001, Fig. 4b) and
low-risk severity adhesions (p < 0.001, Fig. 4c).
Anatomical distortions of the hypothalamic‑pituitary axis
A wholly visible 3VF could be seen in 42.4% of the 125
cases with available midsagittal MRI, a rate increasing to
68.8% among PCPs (p = 0.037). The pituitary stalk had a
normal appearance in 86.4% of cases, and its surrounding
arachnoid cistern (chiasmatic cistern) was tumor-free in
95.9% of patients in this strictly 3V CP cohort. ACPs, how-
ever, associate with pituitary stalk amputation (p < 0.001,
Fig. 4d) and partial occupation of the chiasmatic cistern
(Table 2, p = 0.005). Overall, the hypothalamus could be
26 cases). c Distribution of the main clinical syndromes (symptoms
unknown in 44 cases). Sd = syndrome; HICP: high intracranial pres-
sure. d Bar graph showing the histological distribution of strictly 3V
CPs (histology unknown in 23 cases). Adamant: adamantinomatous
histological CP variant
identified around the lower third of the tumor in 92.6%
of cases, and a slight chiasm compression (downwardly
compressed, 54.4%) or a non-distorted chiasm (24.5%)
predominated. Finally, in most cases, the MBA, a sign
measuring the direction and degree of 3VF displacement
caused by the tumor, fell within normal values (30º–70º)
[4].
Multivariate prediction model of CP histology
All variables related to CP histology were analyzed
through a binary logistic regression model, with two
finally being included: calcifications and pituitary stalk
appearance. The percentage of correct classification
into one of the two fundamental histological groups was
91.5% overall (Nagelkerke R2, 0.755), increasing to 93.8%
for ACPs, the latter characterized by the presence of cal-
cifications and an amputated stalk.
13

Fig. 4  Major histology and consistency relationships for the strictly
3V CP topography. a Stacked bar percent of histology by severity of
CP adherence. In almost 84% of papillary CPs, their attachment to
the 3VF/walls had a low-risk severity level, while this rate decreased
to 42% in the adamantinomatous (adamant) histological variant
(p < 0.001). b Stacked bar percent of histology by tumor consistency.
Note that solid (65.9%) and cystic cauliflower-like (17%) consisten-
Treatment of strictly 3V CPs: surgical procedures
and degree of resection
A total of 176 out of the 180 patients treated underwent
surgical tumor removal (Table 1). The most commonly used
procedures were transcranial–transventricular approaches,
either through upper routes (37.7%)─after crossing the cor-
pus callosum (Tc) or the frontal cortex (FTV)─or through a
basal-translamina terminalis (TLT) approach (26.5%). Since
2006, 18.4% of tumors were removed through the EETS
13
Neurosurgical Review
cies are the prevailing ones among papillary tumors (p < 0.001). c
Stacked bar percent of consistency by adherence severity. Note that
the rate of low-risk adherence severity level was significantly higher
in solid lesions (86%, p < 0.001). d Stacked bar percent of histol-
ogy by appearance of the pituitary before CP treatment. The rate of
tumors showing an amputated stalk was significantly higher in ACPs
(40%, p < 0.001)
approach. Overall, half of the tumors were totally removed,
but this rate increased after 1980 (p < 0.001), reaching 66%
of cases in the most recent period (2006–2021).
Psychiatric, visual, and overall postoperative outcome
Among the patients presenting with psychiatric or visual
disturbances, postoperative improvement of these symp-
toms was observed in 65.2% and 75.7% of cases, respec-
tively. Overall outcome information following treatment
Neurosurgical Review
was available in 143 cases. The association found between
presentation with psychiatric disturbances and high-risk
CP adhesion to the hypothalamus (p = 0.013, Fig. 5a)
probably underlies the higher rate of postoperative hypo-
thalamic injury (p < 0.001, Fig. 5b) and unfavorable out-
comes (p = 0.012 Fig. 5c) for the patients showing such
symptoms. Likewise, the hypothalamic and HICP syn-
dromes associated with unfavorable outcomes (p = 0.007,
Fig. 5d).
There was a marked outcome improvement after 1980
(p < 0.001), as the death rate decreased from 48% in the first
period (1910–1980) to only 2–3% in the subsequent periods.
The rising trend in poor outcomes between the second (10%,
1981–2005) and the most recent period (16%, 2006–2021),
Fig. 5  Major clinical factors related to CP adherence severity and
patient outcome. a Stacked bar percent of psychiatric symptoms by
severity of CP adherence. Presentation with psychiatric symptoms
was associated with high-risk severity adherences between the tumor
and the 3VF/walls containing the hypothalamic nuclei (p = 0.013). b
Stacked bar percent of psychiatric symptoms by hypothalamic injury.
Postoperative hypothalamic injury was significantly higher in patients
however, is worth mentioning. Similarly, development of
symptoms related to hypothalamic damage following sur-
gery rose from 8.7% in the second period to 22.8% in the
third (Fig. 6ab).
Multivariate prediction model of patient outcome
The multivariate regression tree method for the cases
treated after 1980 identified the use of upper transventricu-
lar approaches (FTV or Tc) and the presence of psychiatric
symptoms as the two major predictors of an unfavorable
outcome. Psychiatric disturbances prevailed as the main
predictor of poor outcome among the patients operated on
from 2006 to the present (Fig. 6c). The model for this period
presenting with psychiatric disturbances (p < 0.001). c Stacked bar
percent of psychiatric symptoms by patient outcome. Poor/fatal out-
comes were significantly higher among patients presenting with
mental alterations (p = 0.012). d Stacked bar percent of major pre-
senting syndrome by patient outcome. A significantly worse outcome
occurred among patients presenting with hypothalamic and high
intracranial pressure syndromes (p = 0.007)
13

correctly predicted an unfavorable outcome in 83.3% of the
patients showing psychiatric and HICP symptoms.
Follow‑up time and craniopharyngioma recurrence
Median follow-up time for the 110 cases providing such
information was 12 months. Only a quarter of the follow-
ups went beyond 3 years (Table 1). Thus, the reported 14.6%
13
Neurosurgical Review
rate of tumor recurrence certainly underestimates the true
figure. Despite these limitations, our cohort supports that
tumor recurrence/regrowth most likely occurs within the first
three years following treatment. Analysis into its predictive
factors in the most recently treated cases demonstrated that
CP recurrence was notably higher in cases presenting with
the infundibulo-tuberal syndrome (p = 0.036, Fig. 6d) or
 Neurosurgical Review
◂Fig. 6  Outcome of craniopharyngioma surgery: changes over time
and predictors of patient outcome and tumor recurrence in the most
recent period. a Percentage stacked bar chart displaying the distri-
bution of the 4 major outcome categories within each period of CP
treatment. A favorable outcome prevailed after 1980 (p < 0.001). Nev-
ertheless, note that the percentage of cases with a fair or poor out-
come increased between the second period (15.7% and 9.8% respec-
tively) and the third (31.1% and 16.4%, respectively). b Stacked bar
percent of the period of CP treatment by hypothalamic injury. Note
that the highest rate of hypothalamic injury occurred in the first
period (40%) (p = 0.013). It is noteworthy, however, its increasing
tendency between the second (8.7%) and third periods (22.8%). c
Multivariate tree classification model showing the variables selected
to define the outcome of the patients treated in the most recent period
(2006–2021, n = 60 cases). The presence of psychiatric symptoms
was chosen in the first step as the major predictor of a poor or fatal
outcome (node 2). Among cases without psychiatric symptoms, those
whose major presenting syndrome was high intracranial pressure
associated a poor or fatal outcome (node 3). Correct prediction of
either poor or fatal outcomes reached 83.3%. d Stacked bar percent of
the major presenting syndrome by tumor recurrence in the subgroup
of patients treated from 2006–2021 (n = 41). Note that cases present-
ing with the infundibulo-tuberal syndrome experienced the highest
rate of tumor recurrence (44%) (p = 0.036). e Stacked bar percent of
the degree of tumor removal by tumor recurrence in the subgroup of
patients treated from 2006–2021 (n = 39). Note that the recurrence
rate decreased from 33.3% in cases that underwent incomplete resec-
tion to only 4.8% following total removal (p = 0.02)
undergoing an incomplete tumor removal (Table 2, p = 0.02,
Fig. 6e).
Discussion
The strictly 3V CP topography: definition
and controversial pathogenesis
The term “strictly 3V CP” should only be assigned to those
tumors confined within the 3V boundaries, above an ana-
tomically intact 3VF and lacking any tumoral extension to
the chiasmatic cistern (Fig. 1) [20, 21, 28–33]. Since the
beginning of CP surgery, neurosurgeons have struggled to
properly identify strictly 3V lesions [34]. Harvey Cushing
was the first to describe a PCP hidden in the 3V during an
autopsy after a failed surgical exploration [35–37]. About
half a century later, Juraj Steno presented the most conclu-
sive stereoscopic and light microscopic autopsy study of a
strictly 3V CP whose inferior pole rested on the anatomically
intact tuber cinereum containing normal-looking neurons
[38]. The distinctive demographic, clinical, and pathological
features identified in the present cohort support recognizing
strictly 3V CPs as a separate topographical category. Even
so, since the original description of CPs by Jakob Erdheim
in 1904, the existence of cases exclusively located within the
3V has been frequently questioned [39, 40]. Some authors
have considered the 3V, along with the posterior fossa or
sphenoid sinus, very unusual ectopic locations for CPs [2,
20, 41]. Others have questioned the validity of this topog-
raphy, arguing the typical primary extra-pial origin of CPs
[6, 42]. Moreover, a clear distinction between infundibulo-
tuberal (or not strictly) and strictly 3V CPs is not always
possible as both categories largely occupy the 3V [9, 43].
Anatomical 3VF intactness may vary depending on the orig-
inal point of CP development (subpial or subependymal), the
speed of tumor growth, and, above all, the wide spectrum
of preexisting 3VF morphologies, ranging from a tenuous
ependymal-pia/arachnoid layer to a thick neuroglial layer
[9, 44, 45].
A major challenge to accepting the strictly 3V category
is the presumed embryological origin of CPs from either
Rathke’s pouch cells or cell remnants of the craniopharyn-
geal duct included within the pars tuberalis, the tongue-like
sheet of adenohypophyseal tissue partially encasing the
pituitary stalk [39]. Nevertheless, during human hypophysis
formation, the upward migration of Rathkes’s pouch’s lower
portion against the diencephalic vesicle brings pars tuberalis
precursors into close contact with the infundibulum-tuber
cinereum, precisely the usual attachment areas of strictly 3V
CPs [46–48]. Accordingly, Ivan Ciric proposed in 1980 that
the original CP cells might become embedded within the
3VF at early stages of pituitary gland development, before
arachnoid-pia mater formation [49]. Further studies are nec-
essary to elucidate the pathogenetic mechanisms accounting
for the predominant strictly 3V topography among PCPs
[50, 51]. The age-related increased frequency of squamous
epithelial nests within the pars tuberalis [39, 52], led to the
concept that the squamous metaplasia of adenohypophyseal
cells of the pars tuberalis could give origin to PCPs in adults
[1, 2, 53]. But the fact that most PCPs develop above the
3VF is a major argument against the squamous metaplasia
theory and strongly points to the role played by paracrine
cell interactions between Rathke’s pouch’s CP precursors
and hypothalamic tissue at early stages of embryonic devel-
opment [54].
Strictly 3V CP epidemiological and clinical
characterization
According to modern surgical series, the strictly 3V loca-
tion represents 3–11% of all CP topographies [9, 11, 14,
18, 55]. The rarity of this topography makes detailed
information about it equally scarce. This historical cohort
of 245 well-described CPs represents the largest series
of strictly 3V CPs ever documented. It includes whole
CP brain specimens from non-operated patients, a valu-
able source of information to verify 3VF integrity and to
correlate the anatomical distortions caused by the tumor
with both the clinical picture and the findings of modern
neuroradiological studies [56]. Conversely, the major limi-
tations of this study are the incompleteness of available
13

information in many CP records, in particular the effects
of treatment on clinical outcomes and quality of life. This
shortcoming, in addition to the short follow-up of most
patients, prevented us from performing more comprehen-
sive analyses of survival and long-term quality of life, as
well as a conclusive account of tumor recurrence in CP
cases with this rare topography.
Consistent with prior works [9, 14, 19–21], we found a
predominance of strictly 3V CPs in adult males, in contrast
to the bimodal age (first peak in children) and balanced
male-to-female distributions that characterize CP series
including all topographical categories [2, 57, 58]. Likewise,
this cohort shows a marked predominance of symptoms sec-
ondary to hypothalamus impairment [3, 9, 20, 21]. Almost
60% of the patients presented psychic disturbances, symp-
toms rarely mentioned in other 3V CP series [14, 17, 24]. A
possible relationship between personality changes and 3V
tumors was first proposed by Cushing [59], and his disci-
ples Bailey and Fulton definitively proved the association
between altered mental states and hypothalamic derange-
ment [60, 61]. Memory deficits were the most common type
of mental disturbance reported in our series (42%), linked
to the functional impairment of the fornices, mammillary
bodies and ventromedial hypothalamus caused by 3V-tumor
expansion [21, 24, 62–66].
Tumor growth within the 3V often blocks normal cer-
ebrospinal fluid flow [11, 20, 21]. Nonetheless, despite two-
thirds of our cases showing hydrocephalus, only 44% had
HICP symptoms, a rate similar to other studies [9]. Finally,
the rather low incidence of endocrine (19.9%) and visual
(44.6%) disturbances is related to the anatomical-functional
integrity of the hypothalamic-pituitary axis and visual
pathways in this rare location [9, 11, 18], in contrast to the
Fig. 7  MRI findings pointing to the strictly 3V CP topography. Upper
row shows midsagittal images of two illustrative tumors (t) with dif-
ferent consistencies, solid (a1) and cystic with a cauliflower-like nod-
ule (b1). Lower row displays coronal-transinfundibular sections of
the same cases (a2, b2). Note the cystic (c) and solid cauliflower-like
13
Neurosurgical Review
common hormonal/visual deficits reported for other CP
topographies growing at lower positions [2, 27].
MRI diagnosis of strictly 3V CPs
The revolutionary impact of modern diagnostic methods
for accurately defining strictly 3V CPs is reflected in the
noticeable decrease of failed surgeries from 25% before the
introduction of MRI to less than 3% afterwards [11, 18, 28,
29, 55]. Despite current MRI techniques being insufficient
to demonstrate the anatomical 3VF integrity in all strictly
3V CPs (42% in our cohort) [9], the anatomical status of
the pituitary-hypothalamic axis and surrounding cisterns
depicted by conventional MRI sequences can in most cases
correctly define this topography [67].
The autopsy-surgical-MRI correlations found in this
study support that tumor-free chiasmatic cistern, in addi-
tion to the normal appearance of the pituitary stalk and a
hypothalamus positioned around the lower tumor pole are
valuable predictors of the strictly 3V topography (Fig. 7)
[67]. Exclusive tumor growth within the 3V also explains
the minimal (compressed downward) or absent optic chiasm
distortion of most cases [67, 68]. Likewise, the minimal dis-
tortion caused to the 3VF is in agreement with the normal
MBA values (30–70º) found in most cases, unlike the usually
hyperacute values (< 30º) of infundibulo-tuberal CPs and the
obtuse angles (> 90º) of pseudointraventricular lesions [4,
68]. In contrast to the usual mixed solid-cystic and multi-
lobulated macroscopic appearance of other CP topographies,
a solid consistency and round shape predominated in this
cohort [9, 17–19, 21]. Finally, the solid consistency proved
to be a distinctive radiological feature of PCPs (Fig. 4b),
while the combination of calcifications and pituitary stalk
(s-c) components of the second tumor (b2). Ch cs: chiasmatic cistern;
MB: mamillary body; OC: optic chiasm; PS: pituitary stalk. The blue
angle corresponds to the mamillary body angle. The red arrows point
to the intact third ventricle floor. The table on the right summarizes
the MRI signs typically observed in this topography
Neurosurgical Review
amputation was a strong predictor of ACPs (Fig. 4d). Correct
preoperative distinction between both histological groups is
particularly relevant for adequate treatment planning, due to
their different attachment patterns and to the potential use of
the recently described tumorigenesis-associated gene muta-
tions (β-catenin/CTNNB1 in ACPs and ­BRAFV600E in PCPs)
as chemotherapy targets [51].
Histology and tumor adherence in strictly 3V CPs
This cohort conclusively shows the exclusive histological
distribution into PCPs and ACPs present among strictly 3V
CPs, as well as their specific patterns of tumor adhesion to
the hypothalamus. Consistent with prior reviews, more than
80% of the cases correspond to PCPs [20, 21], whereas this
histology represents only 10–20% of cases in general CP
series [1, 2, 57, 58]. Despite ACPs predominating in the
pediatric age group in our cohort, the PCP rate in children
was about seven times higher (35.7%) than that reported in
pediatric CP series overall [57].
Approximately 75% of strictly 3V CPs present low-risk
severity adhesions to the hypothalamus, in contrast to the
high-risk adhesion patterns observed in 95% of CPs origi-
nating within the 3VF (infundibulo-tuberal) or secondarily
invading the 3V [6, 25, 32, 42]. Subependymal develop-
ment of strictly 3V CPs may explain their small and/or
loose attachments to the infundibulum recess. Therefore,
a large proportion of these lesions can be usually easily
severed without inflicting serious hypothalamic injury.
Nonetheless, the extension and strength of tumor adhesion
within this topography are both very much determined by
the histological subtype, as the rate of low-risk adhesions
to the hypothalamus drops from 84% in PCPs to 42% in
ACPs (Fig. 4a). Moreover, the thorough analysis of tumor
boundaries in 17 pure 3V CPs by Pan et al. demonstrated
the relationship between wide tenacious adhesions and the
presence of a thin layer of hypothalamic nervous-gliotic
tissue covering the tumor surface in ACPs, such a nervous/
gliotic encasement being absent in PCPs with loose attach-
ments [9].
Treatment strategies for strictly 3V CPs
Surgical removal remains the gold standard for CPs, regard-
less of tumor topography. According to the predominance
of low-risk hypothalamic adhesions in strictly 3V CPs, this
category would theoretically be more amenable to radi-
cal removal. Nevertheless, total removal in our cohort is
below 70% even in the most recent period, a rate substan-
tially lower than that reported in many modern CP series
[8, 69, 70]. This might be due to the difficulty of opti-
mally exposing the tumor cleavage plane inside the 3V.
Transcranial–transventricular approaches providing access
to the 3V through either upper (Tc or FTV) or basal (TLT)
routes, or a combination of both, have been preferentially
used for intraventricular CPs [9, 11, 17, 18, 42, 55]. No
approach has proved clearly superior to any other, but our
series points to poorer outcomes with upper Tc/FTV routes,
a fact plausibly related to the blind manipulation of the
tumors’ basal attachments during early debulking stages [3].
A major shift in thinking has recently taken place regarding
the potential usefulness of the transsphenoidal (TS) route
for purely 3V CPs. Acknowledging the close relationship
between 3V CPs and the hypothalamus, Cushing abandoned
the TS approach early in his career and replaced it with the
subfrontal-TLT, a better route for safely debulking intra-3V
tumors and one still widely in use today [9, 10, 37, 42]. Nev-
ertheless, the growing surgical expertise with endoscope-
assisted technology has led to the increasing use of the EETS
approach for removing strictly 3V CPs, representing almost
20% of the procedures after 2006 in this series [9, 11, 15,
42, 55, 71, 72]. Through the EETS route, most surgeons
usually access the 3V between the chiasm and the infundibu-
lum [15, 19], even though this involves flagrantly violating
the 3VF and possibly injuring the basal hypothalamus. The
suprachiasmatic TLT might be a more reasonable corridor
to enter the 3V [16]. Moreover, despite the wide view of
the CP-hypothalamus interface offered by the EETS, this
approach should be weighed against the considerable risk
of cerebrospinal fluid leakage [15, 16, 19, 71].
Finally, the predominance of the papillary variant among
strictly 3V CPs has unique additional therapeutic implica-
tions [8]. Firstly, stereotactic radiosurgery seems to be a suc-
cessful primary alternative treatment [73, 74], although a
reliable comparison with standard surgical treatments was
not possible in our series. Also, the presence of ­BRAFV600E
mutations in most PCPs offers a promising therapeutic
option by employing BRAF/MEK inhibitors as a primary
treatment for this histological type [12, 75, 76]. However,
the effectiveness of these drugs must be further tested, as
experience to date is mainly limited to individual recurrent
PCP cases [51, 76].
Strictly 3V CP prognosis
This work supports a more favorable postoperative out-
come for the strictly 3V topography than the remain-
ing CP categories involving the 3V. Such a better out-
come is greatly related to the predominance of low-risk
CP-hypothalamic adhesions in strictly 3V CPs [77]. On
the one hand, the rate of improvement of psychiatric and
visual alterations in this historical 3V CP cohort reached
65% and 75%, respectively, both rates higher than those
reported in similar historical CP cohorts including all
topographies [24, 27]. Likewise, overall, surgery-related
13

mortality in this series was 13.3%, a rate markedly lower
than that observed for historical CP cohorts including all
topographies [23]. This more favorable prognosis per-
sists when analysis is restricted to the cases treated in the
MRI-era, as perioperative death in strictly 3V CPs (2.7%)
is roughly half the average rate reported in modern CP
surgical series [23].
Our analysis showed that preoperative clinical status, spe-
cifically the presence of psychiatric symptoms, is a major
predictor of unfavorable outcomes (Fig. 6c), possibly due to
the high-risk hypothalamic adherences present in these cases
(Fig. 5a). Thus, we advocate more cautious tumor handling
for strictly 3V CPs in patients with psychic disturbances,
particularly for ACPs. Lastly, although the lack of a long-
term follow-up prevents us from reaching sound conclusions
regarding the recurrence of strictly 3V CPs, presentation
with the infundibulo-tuberal syndrome should promote a
close follow-up in addition to the well-established incom-
plete tumor removal [77].
Conclusions
This historical cohort of 245 well-described strictly 3V
CPs represents the largest body of evidence to date about
this particularly challenging topography. Most of these CPs
growing above an intact 3VF are papillary and occur in adult
males, who typically present with psychiatric disturbances.
These tumors are usually round and do not extend into the
chiasmatic cistern or distort the pituitary stalk. A major-
ity show low-risk severity adherences to the hypothalamus,
contributing to a more favorable surgical outcome. These
distinctive epidemiological, clinical, histological, radiologi-
cal, and surgical characteristics validate their consideration
as a separate clinico-topographical category.
Supplementary Information The online version contains supplemen-
tary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 10143-0​ 21-0​ 1615-0.
Acknowledgements The authors wish to especially thank Crystal
Smith and Liliya Gusakova, Reference Librarians at the National
Library of Medicine, National Institutes of Health (Bethesda, MD),
Lucretia Maclure and Jack Eckert, Librarians at the Francis Countway
Medical Library at Harvard Medical School (Boston, MA), as well
as Melissa Grafe, John R. Bumstead Librarian for Medical History,
Head of the Medical Library of the Cushing/Whitney Medical Library
and Bill Landis of the Manuscript and Archives Department of the
Sterling Memorial Library, Yale University (New Haven, CT) for their
invaluable assistance during the process of searching and retrieving
the original works used in this study. We are very grateful to Maria
Rosdolsky for assisting with the translation of German works. We are
also indebted to Eduard Winter and Verena Hofecker from the Pathol-
ogisch-anatomische Sammlung im Narrenturm-NHM, Vienna, Aus-
tria for allowing us access to the collection of brain tumor specimens.
Finally, we are grateful to George Hamilton for his critical review of the
13
Neurosurgical Review
language and style of the manuscript. This work is dedicated in loving
memory to Ricardo Prieto (1948–2021).
Author contributions Ruth Prieto: conceived and designed the analysis,
collected the data, performed the statistical analysis and interpretation
of data, wrote the paper, and approved the final version of the manu-
script; Laura Barrios: performed the statistical analysis and approved
the final version of the manuscript; José M. Pascual: conceived and
designed the analysis, collected the data, critically revised the article,
and approved the final version of manuscript.
Declarations
Conflict of interest The authors declare no competing interests.
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