Keywords
esthesioneuroblastoma - pituitary adenoma - acromegaly - endoscopic skull base surgery
- craniofacial resection
Introduction
Esthesioneuroblastoma is an uncommon malignant neoplasm that arises from the olfactory
neuroepithelium[1] and is typically located in the upper nasal cavity and cribriform plate.[2] In this article we report a case of esthesioneuroblastoma presenting concomitantly
with a growth-hormone (GH)-secreting pituitary macroadenoma. The combined open and
endoscopic management of this patient is described, and a review of the literature
presented.
Case Report
The patient is a 52-year-old woman who presented with a 9-month history of recurrent
sinusitis refractory to a repeated course of antibiotics. She was seen by an outside
ear nose and throat surgeon who operated on her for suspected nasal polyps. A partial
debulking of an intranasal lesion disclosed a low-grade esthesioneuroblastoma. She
complained of right orbital pain postoperatively and was also treated for a postoperative
sinusitis. In retrospect, she admitted to a 4-month history of anosmia, although she
denied any alteration of taste. Neurosurgical clinical evaluation revealed frank acromegalic
features. Visual acuity was 20/30-1 in both eyes with a very mild bitemporal hemianopia.
Her eye movements were full and facial sensation was normal. Subsequent computed tomography
and magnetic resonance imaging (MRI) of the brain and sinuses demonstrated an enhancing
mass along the anterior skull base with extension through the right cribriform plate,
with a lobular component displacing the right gyrus rectus, along the right medial
orbital wall and into the nasal cavity. Also seen was a large sellar and suprasellar
unrelated macroadenoma ([Fig. 1]). A preoperative cervical MRI was negative for metastatic disease.
Fig. 1 (A) Sagittal, (B) coronal, and (C) axial T1 weighted magnetic resonance imaging (MRI)
with gadolinium demonstrating anterior skull base esthesioneuroblastoma with involvement
of the right lamina papyracea and extension through the cribriform plate and dura,
and a noncontiguous pituitary macroadenoma. (D–F) MRI after intial gross total resection
of esthesioneuroblastoma. (G–I) MRI after a second-stage endoscopic transsphenoidal
resection of pituitary macroadenoma, with reconstitution of the normal residual pituitary
gland.
Her preoperative insulinlike growth factor (IGF)-1 level was 154.00 nmol/L (normal:
7.60–25.20 nmol/L), and prolactin was mildly elevated at 36.2 µg/L (normal: 3.9–29.5
µg/L). In light of the tumor size, the right lamina papyracea destruction, and significant
intradural involvement, the tumor stage was classified as T4N0M0 based on the Dulguerov
TNM system[3] and Kadish stage C.[4] A recommendation of staged resection of the esthesioneuroblastoma followed by the
pituitary macroadenoma was made. For the first stage, a combined open and endoscopic
resection was proposed, to facilitate a true en bloc resection and to harvest a generous
pericranial flap for repair. Following this, the patient would undergo stereotactic
radiation to the tumor bed, and she would return electively for endoscopic resection
of the pituitary macroadenoma.
The first-stage operation was performed as follows. An extended subfrontal approach
was completed first, consisting of a bicoronal incision, bifrontal craniotomy, and
bilateral orbital osteotomy sparing the cribriform plate. The tumor was immediately
identified violating the dura. A generous extracapsular dissection of the intradural
portion of the tumor was completed as well as a wide dural incision around the tumor,
including posteriorly at the posterior aspect of the planum sphenoidale. The endonasal
endoscopic approach was then performed ([Fig. 2]), consisting of a right middle turbinectomy, complete sphenoethmoidectomies, and
a superior septectomy. The lamina papyracea component of tumor was resected with the
aid of a handheld retractor protecting the periorbita from the orbitotomy above ([Video 1]). The anterior and posterior ethmoidal arteries were cauterized and divided. The
left side of the planum was drilled out as was the posterior planum, releasing the
tumor as a single specimen. As such, an en bloc resection was completed without violation
of the tumor. The dural defect was reconstructed with a free pericranial graft, and
a second pedicled pericranial flap was mobilized over the dural closure prior to replacement
of the orbital osteotomy and craniotomy flap. Postoperatively she developed symptomatic
pneumocephalus that was thought to be secondary to lumbar drain placement. The pneumocephalus
resolved with 100% oxygen and discontinuation of the lumbar drain. There were no other
complications postoperatively, and the patient was discharged home on postoperative
day 7. The rationale for staging was to avoid potential complications during the esthesioneuroblastoma
resection, such as a separate cerebrospinal fluid (CSF) leak or hypopituitarism, and
possibly delaying adjuvant radiation therapy. Following complete resection of the
esthesioneuroblastoma and radiation therapy, the patient returned to electively manage
the pituitary tumor.
Fig. 2 Endonasal endoscopic view of esthesioneuroblastoma with exophytic growth in the right
nasal cavity.
Pathologic examination ([Fig. 3]) revealed a small blue cell tumor arranged in lobules and with mild nuclear pleomorphism.
Rosettes were infrequent. There was positive staining for chromogranin A and synaptophysin.
Sustentacular cells were present and stained positive for S-100 protein. The specimen
was consistent with a Hyams grade 2 esthesioneuroblastoma.[5] Postoperative MRI confirmed gross total resection of the esthesioneuroblastoma ([Fig. 1D–F]). Postoperatively, the patient underwent fractionated intensity-modulated radiation
therapy to the resection area. A total of 60 Gy over 30 fractions were administered,
after which six cycles of carboplatin and paclitaxel were given.
Fig. 3 (A) Hematoxylin and eosin preparation demonstrating a small blue cell tumor arranged
in lobules and with mild nuclear pleomorphism. (B) There was positive staining for
chromogranin A and synaptophysin. (C) Sustentacular cells were present and stained
positive for S-100 protein. The specimen was consistent with a Hyams grade 2 esthesioneuroblastoma.
(D) In a second stage, a typical pituitary macroadenoma was removed.
As a second stage, 8 months following the first surgery, the patient underwent a complete
endoscopic transsphenoidal removal of the pituitary macroadenoma ([Fig. 4]). There was a mild intraoperative CSF leak at the end of the resection, and a right
nasoseptal flap was harvested in this case to repair the sella as well as autologous
fascia lata. The pericranial repair from the craniofacial resection site was pristine.
She was discharged home on postoperative day 2 without complications. Pathology for
the pituitary tumor was consistent with a pituitary adenoma, with both prolactin and
GH positivity ([Fig. 3D]). By 2-week follow-up, there was marked improvement in her acromegalic features,
the patient's facial complexion had improved and the finger breadth diminished ([Fig. 5]).
Fig. 4 Stage 2 resection of the pituitary macroadenoma. (A) Endoscopic view right nasal
cavity demonstrating pristine pericranial repair of anterior skull base resection.
(B) Transsphenoidal resection of pituitary macroadenoma with (C) nasoseptal flap reconstruction.
Fig. 5 (A) Patient postoperative day 2 combined open and endoscopic resection of esthesioneuroblastoma.
(B) Patient 2 weeks after endoscopic resection of growth-hormone-secreting pituitary
macroadenoma, demonstrating early resolution of acromegalic facies.
Postoperatively, her IGF-1 level normalized, from 154.00 to 22.00 nmol/L, consistent
with endocrinologic cure.[6] The remainder of her pituitary hormonal panel is otherwise normal. Her last ophthalmologic
assessment revealed 20/20-1 visual acuity in both eyes with no evidence of optic neuropathy
or visual field deficit. Her most recent MRI demonstrated complete resection of the
pituitary macroadenoma with reconstitution of the normal residual pituitary gland
([Fig. 1G–I]). The patient remains free from recurrence of esthesioneuroblastoma through 14 months
thus far.
Discussion
To our knowledge this is the first case of synchronous esthesioneuroblastoma and macroadenoma,
in this case GH secreting, described in the literature. Esthesioneuroblastoma has
been described as a secondary tumor occurring many years after treatment for pituitary
neoplasms,[7]
[8] presumably from radiation therapy. Several cases of primary intrasellar esthesioneuroblastoma
or neuroblastoma in the absence of pituitary adenoma have also been reported.[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17] Esthesioneuroblastoma can mimic pituitary adenomas in imaging appearance, and misdiagnoses
of pituitary adenoma have been reported.[18] Positive immunoreactivity for neuron-specific enolase and synaptophysin are distinguishing
features.[2]
No etiologic basis or risk factors for esthesioneuroblastoma formation have been described,
although several cases have been identified following radiation therapy or exposure[19]
[20]
[21] including two cases following remote radiation for pituitary adenomas.[7]
[8] One case of esthesioneuroblastoma was described followed kidney transplant and immunosuppression
therapy.[22] Very rarely esthesioneuroblastoma presents in association with ectopic adrenocorticotropic
hormone secretion.[23]
Patients with acromegaly have an increased risk of several neoplasms including colorectal
and thyroid cancer and possibly breast, prostate, and hematologic malignancies.[24] Both GH and IGF-1 are known to promote cellular growth and proliferation, and they
may also have mitogenic, proangiogenic, and antiapoptotic properties.[25]
[26] Several authors have observed an association between high serum IGF-1 levels and
colorectal malignancy in acromegalic patients.[27]
[28]
[29] A meta-analysis of 21 studies and 3609 cases found associations between high IGF-1
levels and prostate and premenopausal breast cancer.[30] In a prospective study, fasting and 2-hour GH levels were also associated with increased
mortality from combined malignancies among nonacromegalic cohorts.[31] Other possible mechanisms of carcinogenesis include altered cellular immunity, related
to an altered lymphocyte subset pattern. Colao et al found a significant reduction
in cluster of differentiation (CD) 19 and 20, and an increase in CD3 from the lamina
propria of polyps in patients with acromegaly.[28]
Standard surgical management of anterior skull base malignancies including esthesioneuroblastomas
is typically in the form of an open craniofacial resection. The management of malignant
tumors of the anterior skull base has received considerable attention in the recent
literature owing to increasing trends of purely endoscopic or combined open and endoscopic
oncologic resection. In one meta-analysis of all sinonasal malignancies, no statistically
significant difference in outcome between open and endoscopic resection was found
for low-grade (T1–2 or Kadish A–B) malignancies.[32] A second meta-analysis for esthesioneuroblastomas including 379 subjects did not
demonstrate inferiority of purely endoscopic resection; however, the authors acknowledge
significant sources of error from publication bias, limited follow-up duration, and
more advanced tumor stage in the open craniofacial resection group.[33] In a multicenter study incorporating 23 patients, complete resection was achieved
in this carefully selected cohort in 17 of 23 patients.[34] CSF leaks occurred in 4 of 23 patients. All patients were disease free at a mean
follow-up of 45.2 months. In summary, it remains to be determined whether true en
bloc resection of esthesioneuroblastomas is superior to endoscopic intralesional resection,
albeit with negative margins.
Purely endonasal resection of anterior skull base malignancies has been generally
reserved for patients with relatively earlier disease stage and no or limited skull
base invasion.[35] Significant invasion of the fovea ethmoidalis or the cribriform plate, significant
dural involvement or transdural spread,[35] involvement of the soft tissues of the face,[36] lateral extension over the orbital roof, extensive frontal sinus involvement, and
invasion through the lamina papyracea into the intraorbital space all increase the
level of difficulty of achieving a gross total resection via an endoscopic approach.[37] In our case, endoscopic visualization of the inferior cuts facilitated a true en
bloc resection of the esthesioneuroblastoma, without the use of facial incisions or
intralesional debulking.
It is generally accepted that complete resection followed by adjuvant radiation therapy
reduces the rate of local recurrence in patients with esthesioneuroblastoma[38] and improves disease-free survival.[39]
[40] Chemotherapy remains a matter of debate in upfront treatment, with typical indications
being high-grade, recurrent, metastatic, or unresectable tumors.[41] In some centers, neoadjuvant chemotherapy has been used with success prior to standard
craniofacial resection [42]
[43]
Conclusion
In this patient, complete resection of an esthesioneuroblastoma was achieved using
a combined open craniofacial and endoscopic approach, followed by a complete endoscopic
resection of a GH-secreting pituitary macroadenoma, resulting in endocrinologic cure.
The relative indications and advantages of the expanded endonasal approach for anterior
skull base malignancies are illustrated.
