J Neurosurg Case Lessons 6(10): CASE23264, 2023

DOI: 10.3171/CASE23264

Rare solitary pituitary metastasis of maxillary ameloblastic carcinoma: illustrative case

Souma Arikawa, MD,1 Takashi Watanabe, MD, PhD,1 Hideki Yamaguchi, MD, PhD,2 Yuichiro Sato, MD, PhD,3 Fumitaka Matsumoto, MD,
PhD,1 Kiyotaka Yokogami, MD, PhD,1 and Hideo Takeshima, MD, PhD1

Departments of 1Neurosurgery, 2 Internal Medicine, and 3Diagnostic Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan

BACKGROUND Ameloblastic carcinoma (AC) is a rare odontogenic carcinoma with histological features resembling ameloblastoma. Metastasis to
distant organs and direct expansion into the skull base structures are associated with a poor clinical outcome. This rare case of AC metastasis to the
pituitary gland presented without local recurrence at the primary focus of the maxilla.
OBSERVATIONS A 47-year-old man had a 2-year history of AC in the right maxilla. Computed tomography for his regular checkup incidentally
demonstrated pituitary tumor, rapidly growing over 2 months. He presented with the recent onset of panhypopituitarism and visual field defect.
Magnetic resonance imaging showed a large, irregularly shaped intrasellar and suprasellar lesion with chiasmal compression. Endoscopic endonasal
transsphenoidal surgery was performed for decompression of the optic apparatus to avoid intracranial spread. Histopathology confirmed metastatic AC,
and a genetic panel test confirmed BRAF V600E mutation. Stereotactic radiotherapy (SRT) with the CyberKnife system was administered to the
residual tumor. Remarkable tumor shrinkage was obtained, and panhypopituitarism was resolved 12 months later.
LESSONS A multidisciplinary treatment strategy including maximal safe resection to avoid dissemination in combination with SRT may be crucial for
local control with the preservation of pituitary and visual functions in patients with solitary pituitary metastatic AC.

https://thejns.org/doi/abs/10.3171/CASE23264
KEYWORDS ameloblastoma; metastasis; pituitary gland; stereotactic radiotherapy

Ameloblastic carcinoma (AC) is a rare, odontogenic, locally destructive Illustrative Case

malignant tumor that accounts for 1.6%–2.2% of all odontogenic tumors.1
AC is regarded as a primary odontogenic carcinoma, which is closely re-
lated to benign ameloblastoma according to the fifth edition of the World
Health Organization Classification of Head and Neck Tumors,2 which re-
vised the previous definition as a malignant transformation from preexisting
benign ameloblastoma.3,4 AC frequently has a primary origin in the maxilla
or mandible. However, the aggressive behavior of AC tends to result in lo-
cal recurrence, metastasis to other distant organs or regional lymph nodes,
and direct invasion into skull base structures, implying a poor prognosis.5–7
The etiology, clinical course, and optimal management of this very rare dis-
ease remain unclear, especially in patients with metastasis. We describe
an unusual case of AC with hematogenous metastasis to the pituitary
gland without direct invasion and local recurrence at the primary site,
which was successfully managed with cytoreductive safe resection follow-
ing stereotactic radiotherapy (SRT) using the CyberKnife system.
A 47-year-old man with no previous medical history had undergone
resection of an AC in the right maxilla 2 years earlier and subsequently
underwent subtotal maxillectomy for local recurrence 1 year previously.
Computed tomography (CT) of the head and neck just before the sec-
ond surgery showed no abnormal appearance around the intrasellar
and parasellar structures (Fig. 1A and B). The patient was referred to
our department because a regular checkup with CT of the head and
neck had shown incidental detection of a sellar tumor measuring 15 mm
in the craniocaudal dimension without abnormal bony destruction around
the sinonasal tract or skull base structure (Fig. 1C and D). Endoscopic
nasal examination confirmed no local recurrence or direct invasion to
the skull base. Physical examination revealed general fatigue, chills, and
muscle weakness. Laboratory studies confirmed panhypopituitarism with
concurrent mild hyperprolactinemia (Table 1). Central diabetes insipidus
did not become apparent even after the start of hormone replacement

ABBREVIATIONS AC 5 ameloblastic carcinoma; CT 5 computed tomography; MR 5 magnetic resonance; SRT 5 stereotactic radiotherapy.
INCLUDE WHEN CITING Published September 4, 2023; DOI: 10.3171/CASE23264.
SUBMITTED May 16, 2023. ACCEPTED July 12, 2023.
© 2023 The authors, CC BY-NC-ND 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

J Neurosurg Case Lessons | Vol 6 | Issue 10 | September 4, 2023 | 1

 TABLE 1. Baseline anterior pituitary function tests before and
after treatment
Results
Reference
Test Pretreatment Post-treatment Range
Free cortisol, mg/dL 1.1 10.0 3.7–19.4
ACTH, pg/mL 28.9 30.4 7.2–63.3
FT4, ng/dL 0.49 0.96 0.7–1.48
TSH, mIU/L 0.41 0.85 0.35–4.94
IGF-1, ng/mL 68 69 90–250
GH, ng/mL 0.71 0.14 <2.47
FSH, mIU/mL 1.3 4.9 2–8.3
LH, mIU/mL 0.3 1.7 1.2–7.1
PRL, ng/mL 25.3 3.8 3.5–19.4
Free testosterone, pg/mL 0.2 0.4 4.6–16.9
ACTH 5 adrenocorticotropic hormone; FSH 5 follicle-stimulating hormone; FT4
5 free thyroxine; GH 5 growth hormone; IGF-1 5 insulin-like growth factor-1;
LH 5 luteinizing hormone; PRL 5 prolactin; TSH 5 thyroid-stimulating
hormone.

FIG. 1. Coronal (A) and sagittal (B) CT scans before the secondary sur-
gical excision of recurrent primary tumor showing no abnormal appear-
ance around the pituitary gland and skull base structures. Coronal
(C) and sagittal (D) CT scans at the regular checkup after 1 year
showing an incidental sellar lesion measuring 15 mm in the craniocau-
dal dimension without abnormal destruction of the bony structures sur-
rounding the sinonasal cavity and anterior skull base. Coronal (E) and
sagittal (F) postcontrast T1-weighted MR images for evaluation of pitui-
tary metastasis after 1 month revealing a heterogeneously enhanced,
irregularly shaped sellar lesion (20 mm). Coronal (G) and sagittal
(H) postcontrast T1-weighted MR images before surgery for pituitary
metastasis showing progressive enlargement (26 mm) of the tumor
over 2 months.
the craniocaudal dimension within 1 month (Fig. 1E and F). Normal pitui-
tary gland could not be identified around the lesion. 18F-fluorodeoxyglucose
positron emission tomography CT demonstrated no evidence of abnormal
accumulation in the sellar lesion as well as other organs.
Binostril endoscopic endonasal resection of the sellar lesion was
scheduled because of the rapid tumor enlargement, which required
chiasmal decompression and histological diagnosis. Preoperative
MR imaging revealed further progressive enlargement of the tumor
to 26 mm over 2 months (Fig. 1G and H). Intraoperatively, no ab-
normal lesion or bony destruction was observed within the surgical
fields from the primary operative site of the maxilla to the sella tur-
cica. After drilling of the intact sellar floor and incision of the normal
dura mater, the elastic hard tumor was removed piecemeal. Cytore-
ductive debulking resection was performed to avoid cerebrospinal
fluid leakage and intracranial spread of the tumor. Postoperative
MR imaging showed residual sellar tumor (Fig. 2).
Histopathological examination of the surgical specimen showed the
typical features of AC with high-grade nuclear atypia, peripheral stellate re-
ticulum, and basement membrane layer (Fig. 3, left). The MIB-1 labeling
index was 4.6%, and mitotic activity was 1/10 high-power fields. These
findings were similar to those of the specimen obtained from the previous

therapy. Ophthalmological examination confirmed left lateral upper quad-

rantanopia. Magnetic resonance (MR) imaging revealed an irregularly FIG. 2. Coronal (left) and sagittal (right) postcontrast T1-weighted MR
shaped, heterogeneously enhanced, intrasellar and suprasellar tumor images after surgery showing cytoreductive partial resection of the
tumor.
mass with chiasmal compression, which had rapidly grown to 20 mm in

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FIG. 3. Histopathological examination of the specimen obtained during
surgery. Left: Hematoxylin and eosin staining of tumor specimen area
showing the typical features of AC with high-grade nuclear atypia, periph-
eral stellate vesicles, and basement membrane layer. Right: Immunohis-
tochemical staining using VE1 antibody showing homogeneous
distribution of BRAF V600E expression in the tumor cells. Bars, 100 mm.
surgery, so a diagnosis of AC metastasis to the pituitary gland was estab-
lished. A commercially available next-generation sequencing comprehen-
sive genomic profiling testing assay (FoundationOne CDx assay) was
conducted for identification of any treatable genetic mutations, and de-
tected BRAF p.V600E, BCOR p.E485fs*43, FGF14 p.A236V, MED12
p.G44S, FANCA p.E1240fs*36, and EPHB4 p.R312H. Confirmatory cyto-
plasmic anti-BRAF V600E immunohistochemical staining was detected on
the surgical specimen (Fig. 3, right).
The postoperative course was uneventful, and no new neurologi-
cal deficits were observed. The patient was discharged home and
immediately referred for further SRT with the CyberKnife system for
residual sellar lesion (54 Gy in 30 fractions). Follow-up MR imaging
12 months after SRT revealed remarkable shrinkage of the tumor
(Fig. 4). The patient experienced progressive resolution of the visual
disturbance and panhypopituitarism (Table 1).
Patient Informed Consent
The necessary patient informed consent was obtained in this study.
Discussion
Observations
The present case of maxillary AC metastasis to the pituitary
gland occurred without local recurrence or direct expansion. Intra-
cranial and skull manifestations of ameloblastoma are very rare, ac-
counting for less than 1% of cases.8 The few cases of AC involving
the anterior skull base or intracranial space have usually been as-
sociated with destruction of the skull base bony structures by local
invasion through the nasal and paranasal cavity.7,9–11 No other
FIG. 4. Coronal (left) and sagittal (right) postcontrast T1-weighted MR
images 12 months after SRT showing significant shrinkage of the sellar
tumor.
case of AC with direct invasion into the pituitary gland has been re-
ported. In the present case, distant metastasis to the pituitary gland
from the primary site in the maxilla was suggested because flexible
nasal endoscopy and neuroimaging studies found no evidence of
local recurrence, invasion through the sinonasal tract, or skull base
destruction. Development of distant metastasis is possible even in
the absence of local or regional recurrence.12 The lung and regional
lymph nodes are the most common sites of AC metastasis, and
later to the liver, bone, brain, kidney, small intestine, and myocar-
dium, but pituitary metastasis has never been reported.5,6,13 Distant
metastasis of AC has been associated with a significant decrease
in overall survival.14
Metastatic pituitary tumor is also uncommon, with an incidence of
only 0.7% of metastatic brain tumors in Japan,15 1%–3.6% in large
autopsy series,16,17 and only 1% of surgically treated pituitary tu-
mors.18 The most common primary tumor is lung cancer, followed by
breast and renal cell cancers.19,20 Preoperative diagnosis of solitary
pituitary metastasis is extremely difficult in cases with presentation as
the first manifestation of an underlying malignancy. Furthermore, the
general characteristics of pituitary metastasis, including no specific
findings in clinical, laboratory, and radiological examinations, further
complicate definitive diagnosis.19,20 Unlike in pituitary neuroendocrine
tumors, central diabetes insipidus is thought to be the most common
clinical manifestation of pituitary metastasis because of the direct ar-
terial blood supply to the posterior lobe.21 In the present case, early
diagnosis of the pituitary metastatic AC was extremely difficult be-
cause of several clinical findings, including panhypopituitarism with
concurrent mild hyperprolactinemia and the absence of central diabe-
tes insipidus, no evidence of local recurrence or direct invasion to
skull base structures, and the absence of other metastatic lesions
throughout the whole body. Therefore, pathological analysis using
the endoscopic endonasal approach was essential because of the
rapid growth of the tumor during diagnostic work-up.
The overall prognosis of pituitary metastasis is poor, with a me-
dian survival of approximately 12 months, despite current improve-
ments in prognosis and advances in cancer treatments.19–22 The
treatment strategy in pituitary metastasis is still under discussion
because of its rarity. Recent reports have suggested that age, pri-
mary cancer site, and surgery are prognostic factors.22 Another
study demonstrated that younger age, late metastasis to the pitui-
tary gland, smaller size, and radiation therapy all suggest good
prognosis.19 Higher score of recursive partitioning analysis classifi-
cation, solitary pituitary metastasis, and treatment with surgery and/
or radiation therapy are also associated with a good prognosis.20
These findings suggest that surgery and/or radiation therapy may
be indicated in younger patients with small, solitary pituitary metas-
tasis, but the therapeutic response determining prognosis is remark-
ably variable, depending on the biological properties of the primary
cancer.23
No high-quality evidence is available to guide the treatment of
AC because of the extremely rare malignancy, but surgery is cura-
tive and the treatment of choice in most patients. The goal of sur-
gery is complete removal of the lesion with adequate bony margins
to prevent local recurrence.24 However, complete en bloc excision
with sufficient margins is impossible for pituitary metastatic AC, de-
spite current advances in endoscopic neurosurgical techniques, be-
cause of the unique operative challenges posed by the proximity of
surrounding critical neurovascular structures, including the optic
nerves, internal carotid arteries, and cavernous sinus. Therefore,
J Neurosurg Case Lessons | Vol 6 | Issue 10 | September 4, 2023 | 3
the invasive nature of AC carries the potential risk of intracranial
dissemination. Consequently, some type of adjuvant therapy is re-
quired for this unique situation.
Well-documented evidence concerning the effectiveness of radiation
therapy for AC is still limited, although ameloblastoma is generally con-
sidered to be radioresistant.25 However, recent evidence has suggested
that radiotherapy for AC may be acceptable in patients with a poor gen-
eral status or unresectable tumor.9 A recent systematic review and meta-
analysis of AC demonstrated that young individuals (age <25 years),
male sex, AC involving other regions, palliative or no treatment, and dis-
tant metastasis are all indicators of a poor prognosis. The most favorable
treatment option is considered to be early resection with or without radio-
therapy, as determined by the positional relationship.26 In the present
case, a favorable clinical outcome was obtained after visual and endocri-
nological sparing treatment using cytoreductive safe resection followed
by SRT.
Recent genomic studies have found that BRAF V600E mutations
are detected in high frequency predominantly in mandibular amelo-
blastomas, whereas SMO L412F mutations have shown a marked
preponderance in maxillary ameloblastomas.27–29 These two driver
mutations are considered to indicate exclusive, independent genetic
etiologies and reflect distinctive odontogenic pathways. Therefore,
dual BRAF/MEK inhibition with dabrafenib and trametinib was effec-
tive in patients with distant metastasis of BRAF V600E-mutated
ameloblastoma.30,31 A recent study of the clinical and biological
characteristics of AC demonstrated that the BRAF V600E mutation
may be related to the aggressive characteristics of AC because this
driver mutation was detected in one maxillary and four mandibular
ACs among the five patients examined.3 In the present case, the
BRAF V600E mutation was detected by the genetic panel test,
whereas the SMO L412F mutation was not identified despite the
maxillary origin. Our present and previous findings suggest that the
BRAF V600E mutation could be a crucial biological marker and
promising therapeutic target for AC in the future.
Lessons
This unique case provides valuable management lessons about
pituitary metastasis from maxillary AC. Physicians and neurosur-
geons should be aware of the possibility of AC metastasis in patients
with sellar lesions and a known cancer history, unless caused by
direct expansion or local recurrence. Close follow-up neuroimaging
study is required for incidental asymptomatic cases. A favorable clini-
cal outcome in our patient was obtained after partial removal of the
sellar and suprasellar lesion combined with postoperative SRT. Ge-
netic diagnosis and detection of BRAF V600E mutations may be use-
ful for molecular targeted therapy in the future.
References
1. Rizzitelli A, Smoll NR, Chae MP, Rozen WM, Hunter-Smith DJ. Inci-
dence and overall survival of malignant ameloblastoma. PLoS One.
2015;10(2):e0117789.
2. Soluk-Tekkesin M, Wright JM. The World Health Organization classi-
fication of odontogenic lesions: a summary of the changes of the
2022 (5th) edition. Turk Patoloji Derg. 2022;38(2):168–184.
3. Niu Z, Li Y, Chen W, et al. Study on clinical and biological charac-
teristics of ameloblastic carcinoma. Orphanet J Rare Dis. 2020;
15(1):316.
4. Deng L, Wang R, Yang M, Li W, Zou L. Ameloblastic carcinoma:
clinicopathological analysis of 18 cases and a systematic review.
Head Neck. 2019;41(12):4191–4198.
4 | J Neurosurg Case Lessons | Vol 6 | Issue 10 | September 4, 2023
5. Moro A, Foresta E, Gasparini G, et al. Ameloblastic carcinoma of
the maxilla: a case report and an updated review of the literature.
Oncol Lett. 2016;12(6):4339–4350.
6. Alexander C, Maleki Z. Ameloblastic carcinoma with metastasis to
the parotid gland. Diagn Cytopathol. 2018;46(2):162–164.
7. Yildirim AE, Divanlioglu D, Karaoglu D, Kayacetin S, Belen AD.
Massive skull base ameloblastic carcinoma with intracranial
extension. Turk Neurosurg. 2017;27(6):1016–1020.
8. Olaitan AA, Adeola DS, Adekeye EO. Ameloblastoma: clinical
features and management of 315 cases from Kaduna, Nigeria.
J Craniomaxillofac Surg. 1993;21(8):351–355.
9. Aoki T, Akiba T, Kondo Y, Sasaki M, Kajiwara H, Ota Y. The use of
radiation therapy in the definitive management of ameloblastic carci-
noma: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol.
2019;127(2):e56–e60.
10. Ozlugedik S, Ozcan M, Basturk O, et al. Ameloblastic carcinoma
arising from anterior skull base. Skull Base. 2005;15(4):269–273.
11. Perumal CJ. Ameloblastic carcinoma of the maxilla with extension
into the ethmoidal air cells and close proximity to the anterior skull
base: a rare case presentation. Craniomaxillofac Trauma Reconstr.
2012;5(3):169–174.
12. Simko EJ, Brannon RB, Eibling DE. Ameloblastic carcinoma of the
mandible. Head Neck. 1998;20(7):654–659.
13. Uzawa N, Suzuki M, Miura C, Tomomatsu N, Izumo T, Harada K.
Primary ameloblastic carcinoma of the maxilla: a case report and
literature review. Oncol Lett. 2015;9(1):459–467.
14. Yoon HJ, Hong SP, Lee JI, Lee SS, Hong SD. Ameloblastic
carcinoma: an analysis of 6 cases with review of the literature.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;108(6):
904–913.
15. Brain Tumor Registry of Japan (2005–2008). Neurol Med Chir
(Tokyo). 2017;57(1 Suppl):9–102.
16. Kovacs K. Metastatic cancer of the pituitary gland. Oncology. 1973;
27(6):533–542.
17. Max MB, Deck MD, Rottenberg DA. Pituitary metastasis: incidence
in cancer patients and clinical differentiation from pituitary adenoma.
Neurology. 1981;31(8):998–1002.
18. Chon H, Yoon K, Kwon DH, Kim CJ, Kim MS, Cho YH. Hypofractionated
stereotactic radiosurgery for pituitary metastases. J Neurooncol. 2017;
132(1):127–133.
19. Habu M, Tokimura H, Hirano H, et al. Pituitary metastases: current
practice in Japan. J Neurosurg. 2015;123(4):998–1007.
20. Hong S, Atkinson JL, Erickson D, et al. Contemporary treatment
outcome of metastases to the pituitary gland. World Neurosurg.
2023;172:e684–e694.
21. Komninos J, Vlassopoulou V, Protopapa D, et al. Tumors metastatic
to the pituitary gland: case report and literature review. J Clin
Endocrinol Metab. 2004;89(2):574–580.
22. Patel KR, Zheng J, Tabar V, Cohen MA, Girotra M. Extended
survival after surgical resection for pituitary metastases: clinical
features, management, and outcomes of metastatic disease to the
sella. Oncologist. 2020;25(5):e789–e797.
23. Obenauf AC, Massague J. Surviving at a distance: organ-specific
metastasis. Trends Cancer. 2015;1(1):76–91.
24. Li J, Du H, Li P, Zhang J, Tian W, Tang W. Ameloblastic carcinoma:
an analysis of 12 cases with a review of the literature. Oncol Lett.
2014;8(2):914–920.
25. Gardner DG. Radiotherapy in the treatment of ameloblastoma. Int J
Oral Maxillofac Surg. 1988;17(3):201–205.
26. Saluja TS, Hosalkar R. Reconnoitre ameloblastic carcinoma: a
prognostic update. Oral Oncol. 2018;77:118–124.
27. Kokubun K, Yamamoto K, Akashi Y, Chujo T, Nakajima K, Matsuzaka
K. Genetic study of BRAF V600E and SMO L412F mutations in
Japanese patients with ameloblastoma. Int J Surg Pathol. 2022;
30(4):378–384.
28. Kurppa KJ, Caton J, Morgan PR, et al. High frequency of
BRAF V600E mutations in ameloblastoma. J Pathol. 2014;232(5):
492–498.
29. Sweeney RT, McClary AC, Myers BR, et al. Identification of
recurrent SMO and BRAF mutations in ameloblastomas. Nat Genet.
2014;46(7):722–725.
30. Kennedy WR, Werning JW, Kaye FJ, Mendenhall WM. Treatment
of ameloblastoma and ameloblastic carcinoma with radiotherapy.
Eur Arch Otorhinolaryngol. 2016;273(10):3293–3297.
31. Kaye FJ, Ivey AM, Drane WE, Mendenhall WM, Allan RW. Clinical
and radiographic response with combined BRAF-targeted therapy
in stage 4 ameloblastoma. J Natl Cancer Inst. 2014;107(1):378.
Disclosures
The authors report no conflict of interest concerning the materials or
methods used in this study or the findings specified in this paper.
Author Contributions
Conception and design: Arikawa, Watanabe. Acquisition of data: Arikawa,
Watanabe, Yamaguchi, Sato. Analysis and interpretation of data: Arikawa,
Watanabe, Yamaguchi, Sato. Drafting the article: Arikawa, Watanabe.
Critically revising the article: Arikawa, Watanabe. Reviewed submitted
version of manuscript: Arikawa, Watanabe, Yamaguchi, Sato, Matsumoto,
Yokogami, Takeshima. Approved the final version of the manuscript on
behalf of all authors: Arikawa. Administrative/technical/material support:
Mastumoto, Yokogami. Study supervision: Watanabe, Takeshima.
Correspondence
Souma Arikawa: University of Miyazaki, Miyazaki, Japan.
souma_arikawa@med.miyazaki-u.ac.jp.
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