Intraoperative confocal laser endomicroscopy for interpretation of a sellar hemangioblastoma: illustrative case

Abstract

BACKGROUND

Intraoperative frozen sections play a critical role in surgical strategy because of their ability to provide rapid histopathological information. In cases in which intraoperative biopsy carries a significant risk of bleeding, intraoperative confocal laser endomicroscopy (CLE) can assist in decision-making.

OBSERVATIONS

The authors present a rare case of a large sellar hemangioblastoma. Preoperative radiographic imaging and normal pituitary function suggested a differential diagnosis that included hemangioblastoma. The patient underwent partial preoperative embolization and a right-sided pterional craniotomy for resection of the lesion. Gross intraoperative examination revealed a highly vascular sellar lesion requiring circumferential dissection to minimize blood loss. The serious vascularity precluded intraoperative frozen section analysis, and CLE imaging was performed. CLE imaging provided excellent visualization of the remarkable vascular structure and characteristic histoarchitecture with microvasculature, intracytoplasmic vacuoles, and atypical cells consistent with hemangioblastoma. Resection and decompression of the chiasm was accomplished, and the patient was discharged with improved vision. The final histopathological diagnosis was hemangioblastoma.

LESSONS

When the benefits of obtaining intraoperative frozen sections greatly outweigh the associated risks, CLE imaging can aid in decision-making. CLE imaging offers real-time, on-the-fly evaluation of intraoperative tissue without the need to biopsy a vascular lesion.

Intraoperative decision-making during brain surgery is dependent on the nature of the lesion.¹ Historically, frozen sections have played a crucial role in the intraoperative strategy by providing relatively rapid histopathological information.^2,3 The information obtained from frozen sections aids critical decision-making during the operation, determining the extent of resection, identifying tumor boundaries, and deciding whether further tissue sampling or additional surgical procedures are necessary. However, caution is necessary when harvesting tissue for frozen sections from highly vascularized lesions. Such lesions can be associated with unwanted extensive bleeding or false-negative findings because of the bloody background.⁴

In such cases, intraoperative confocal laser endomicroscopy (CLE) can assist in tailoring the surgical strategy.^5–9 CLE is an emerging handheld fluorescence imaging technology that enables real-time visualization of brain tissue at the cellular level. It has recently received clearance from the United States Food and Drug Administration.⁹ By utilizing sodium fluorescein, which accumulates in areas of the brain with a disrupted blood-brain barrier, and matching the excitation energy of the light source, CLE captures high-resolution images during surgery without the need for physical tissue extraction. This advanced clinical-grade technology incorporates a surgical telepathology software platform (TSP), which facilitates intraoperative communication between the neurosurgeon performing CLE and the pathologist, who is located outside the operating room.^8,10 The integration of TSP and CLE has the potential to enhance intraoperative workflow between neurosurgeons and pathologists, ultimately improving surgical decision-making.⁸

This study reports a rare hypervascularized, large sellar lesion managed intraoperatively using CLE imaging for surgical decision-making that did not require intraoperative frozen sections. The lesion was ultimately diagnosed as a hemangioblastoma on the final histopathological analysis.

Illustrative Case

History and Examination

A right-handed male in his early 70s presented with progressive blurry vision and chronic headache. The patient had a history of hemangioblastoma resection in 2001 but no known family history of von Hippel-Lindau (VHL) syndrome, renal cell carcinoma, or multiple neuroendocrine neoplasia syndrome type 2. Ophthalmological examination findings included bitemporal hemianopsia and visual loss in both eyes. Contrast-enhanced T1-weighted magnetic resonance imaging (MRI) demonstrated a large (2.2 × 2.8 × 2.0 cm), hyperintense sellar mass with marked vasculature and severe optic chiasm compression (Fig. 1). Pituitary and endocrine workups found no hormonal abnormalities. Based on these imaging and laboratory findings, hemangioblastoma in an unusual location was included in the differential diagnosis, and embolization with subsequent resection was planned. Angiography revealed feeding arteries arising from the ethmoidal artery branches bilaterally, the anterior cerebral artery, and the distal branches of the right internal maxillary arteries (Figs. 2A and B). After embolization, partial occlusion of the vascular supply was accomplished, with occlusion of the branches of the right internal maxillary arteries (Fig. 2C).

FIG. 1.

Preoperative contrast-enhanced T1-weighted MRI of the sellar lesion in the coronal (A), sagittal (B), and axial (C) planes and T2-weighted MRI in the coronal plane (D).

FIG. 2.

Preoperative angiograms showing the blood supply of the sellar lesion with a branch of the right internal maxillary artery (A) and ethmoidal artery (B). An angiogram (C) of the sellar lesion after partial embolization with right internal maxillary artery occlusion showing a residual blood supply from the anterior cerebral artery. Arrows indicate a vessel responsible for the blood supply of the sellar lesion.

Intraoperative Findings

Through a right-sided pterional craniotomy, the Sylvian fissure dissection was continued to the parasellar region, exposing the optical carotid cistern with a markedly vascular tumor readily visible between the optic nerve, which was compressed from inferiorly on the right side, and the internal carotid artery (Fig. 3A). Extreme vascularity remained, and obtaining an intraoperative frozen section was not possible without extensive multifocal bleeding in a restricted location. CLE imaging was used in tandem with TSP to enable a real-time intraoperative consultation with the pathologist over the internet (Fig. 3B). CLE imaging provided excellent visualization of the mass histoarchitecture, including classic microvasculature, intracytoplasmic vacuoles, and atypical cells consistent with hemangioblastoma (Fig. 4, Video 1). The meticulous process of circumferentially cauterizing the tumor margin was performed with minimally invasive bipolar cautery and sharp microdissection of the tumor from the critical vascular structures. A subtotal resection was accomplished with complete decompression of the bilateral optic nerves and chiasm, with preservation of the carotid artery vasculature, the anterior cerebral arteries, and the optic sheath and chiasm. The surgical specimen was sent for permanent pathology.

FIG. 3.

A: Intraoperative photograph showing a right parasellar region with an exposed vascular-appearing tumor between the right optic nerve and the right internal carotid artery. B: Intraoperative photograph showing a CLE probe being used for intraoperative discrimination of the sellar lesion. ICA = internal carotid artery; ON = optic nerve.

FIG. 4.

A: Intraoperative CLE image showing a surface of the sellar lesion stacked with vessels (orange arrows). B: Intraoperative CLE image of the core of the sellar lesion showing remarkable microvasculature with erythrocytes in the vessel lumen (yellow arrowheads), intracytoplasmic vacuoles (orange circles), and atypical cells consistent with hemangioblastoma. A black spot in the lower left corner represents the artifact on the CLE probe.

VIDEO 1. Clip showing video-flow CLE images of the optical biopsy from the sellar lesion that was acquired and discussed intraoperatively by the neurosurgeons and the pathologist using a surgical TSP. The optical biopsy shows lesional tissue (blue areas), remarkable microvasculature with erythrocytes in the vessel lumen (yellow arrows), and intracytoplasmic vacuoles (red circles) consistent with a hemangioblastoma. Used with permission from Barrow Neurological Institute, Phoenix, Arizona. Click here to view.

Final Histopathological Analysis

Microscopic evaluation revealed a cellular neoplasm with prominent vascular features. The cellular component consisted of cells bearing moderately atypical nuclei with eosinophilic to vacuolated cytoplasm, as well as a background of extensive acute hemorrhage and thermal artifact (Fig. 5A). Immunohistochemistry results were positive for inhibin and demonstrated the absence of cytokeratin (Fig. 5B), which confirmed the diagnosis of hemangioblastoma.

FIG. 5.

A: Hematoxylin and eosin–stained biopsy specimen taken from the sellar lesion reveals moderately atypical nuclei with eosinophilic to vacuolated cytoplasm, as well as a background of extensive acute hemorrhage and thermal artifact. B: Immunohistochemistry of the tissue taken from the sellar lesion has findings positive for inhibin (indicated by the diffuse brown color) and demonstrates the absence of cytokeratin, confirming the diagnosis of a hemangioblastoma. Original magnification ×200 (A and B).

Postoperative Outcome and Follow-Up

The patient tolerated the procedure well, with excellent postoperative improvement in visual function, and underwent adjuvant outpatient radiation therapy for the residual tumor. In addition, the tumor was sent for whole exome sequencing to determine eligibility for adjuvant medical oncological therapy, specifically belzutifan (if the tumor was positive for the VHL mutation) or bevacizumab (if the tumor was negative for germline mutations).

Patient Informed Consent

The necessary patient informed consent was obtained in this study.

Discussion

Observations

The differential diagnosis for this case included pituitary adenoma and sellar hemangioblastoma. Surgical techniques for the resection of these lesions are categorically different. A piecemeal resection, commonly used for pituitary adenomas, can be devastating for the management of a sellar hemangioblastoma. In this case, the location of the mass increased the complexity of the resection. Hemangioblastomas are generally resected en bloc to minimize bleeding. Intraoperative confirmation of the sellar hemangioblastoma would typically prompt the use of a more aggressive surgical technique involving coagulation to control the intraoperative bleeding or en bloc resection while avoiding internal debulking of the mass.

Hemangioblastomas of the central nervous system account for 1.1% to 2.5% of all intracranial tumors; supratentorial hemangioblastomas comprise 1% of those tumors.^11,12 The infundibular and sellar hemangioblastomas are extremely rare and are most prevalent among patients with VHL syndrome, making the sellar region the most common location for supratentorial hemangioblastomas.¹² Typical infratentorial and spinal cord hemangioblastomas normally have a distinctive appearance under the operative microscope, have noninvasive growth, and do not require the guidance of a neuropathologist during surgery. However, considering the unusual location of the hemangioblastoma and our patient’s medical history, which showed no signs of VHL syndrome or other associated genetic disorders, the preoperative diagnosis was ambiguous. Therefore, the intraoperative diagnosis was crucial for the surgical strategy.

Based on the imaging features of the lesion, the surgeon considered the possibility that it was a hemangioblastoma in an unusual location rather than a pituitary adenoma. The solitary presentation, with marked vasculature found on the imaging and homogeneous contrast enhancement, suggested hypervascularity of the lesion. Solitary hemangioblastomas are highly vascularized tumors that can pose challenges in controlling intraoperative bleeding and lead to significant postoperative morbidity. Sakamoto et al.¹³ reported three cases of hemangioblastoma with catastrophic intraoperative bleeding despite preoperative embolization of the tumor-supplying vessels, resulting in severe disability and even postoperative death. Therefore, given the partial embolization of the presumed sellar hemangioblastoma, harvesting tissue for intraoperative frozen section could have been associated with extensive bleeding in a difficult location.

Because of these risks, there is an application for CLE to aid in interpreting brain tissue and in surgical decision-making. The clinical-grade CLE has sensitivity and specificity comparable to the gold-standard frozen sections.^5,9 Furthermore, CLE imaging can dramatically improve operative efficiency. CLE is faster than obtaining frozen sections and can provide meaningful intraoperative images within seconds of scan initiation.^5,8,9 The performance of CLE can be enhanced by using it in combination with TSP.^8,10 Developed to support intraoperative CLE, TSP facilitates real-time feedback from a remote pathologist who assesses the live stream of CLE data. TSP integration increases the diagnostic concordance of CLE findings and the final histopathological diagnosis by 33%.⁸ Although CLE technology was not designed for diagnosis, certain lesion types, such as hemangioblastoma, metastatic tumors, and reactive brain tissue, can be interpreted confidently with CLE.^5,8,9

Interestingly, in this case, CLE imaging resulted in better discrimination of cellular histoarchitecture than conventional hematoxylin and eosin–stained sections. The presence of intracytoplasmic vacuoles is a cellular pattern that strongly suggests hemangioblastoma.¹⁴ This pattern was visible during CLE imaging and was somewhat distorted on histopathomorphologic sections because of thermal artifacts. The heat generated from the electrocautery can cause tissue alterations during microscopic examinations.¹⁵ Although electrocautery makes interpretation of the tissue more difficult, its use is desirable because it aids hemostasis in highly vascularized tumors. In such cases, CLE imaging, with its ability to visualize brain histoarchitecture in vivo in real time, could be more advantageous than conventional histopathological assessment.

CLE is not intended to replace conventional histopathological assessment; rather, it serves as an additional tool for guiding surgical strategy, and the need to biopsy tissue will exist for molecular analysis and research. Using CLE and TSP in tandem would increase the likelihood of obtaining positive intraoperative frozen sections, with less time spent acquiring meaningful tissue. By providing immediate feedback on tissue histoarchitecture, CLE imaging can indicate whether the interrogated region of interest is inadequate or does not represent the lesion, and the surgeon can assess additional regions to obtain a more accurate biopsy or resect additional tissue if required.

Limitations

Several limitations are inherent to CLE technology. First, this technology relies on a multidisciplinary team trained in using the CLE station and interpreting CLE data in real time. The operating surgeon should also realize that expertise is required to develop the dynamic steadiness necessary for CLE probe manipulation. There is also a learning curve before the CLE-trained pathologist can gain enough familiarity with the CLE images to guide neurosurgeons intraoperatively.⁹ Significantly, at its present stage of development, CLE image interpretation must be correlated to gold-standard histological assessment and cannot yet be independently used for clinical judgment and intraoperative decision-making. In the case reported here, CLE was used as an adjunct to support other clinical findings suggestive of hemangioblastoma. Second, the accuracy and completeness of CLE are limited when compared with a full histopathological examination. The 475 × 267 μm field of view of the CLE probe includes only a small portion of the lesion and may not fully represent the lesion’s characteristics. For example, when the marginal regions of diffuse gliomas are unclear, relying solely on the interpretation of a single imaging spot can potentially result in suboptimal surgical decisions. Despite the limitations of CLE, we believe this technology represents an advance in operating room communication between the surgeon and the pathologist because of its digital basis in real-time CLE imaging.

Lessons

Although rare, hemangioblastomas can present in the sellar region and are commonly associated with VHL syndrome. When the risk associated with obtaining an intraoperative frozen specimen is high, CLE imaging can augment surgical decision-making by providing a real-time, preliminary assessment of surgical tissue without requiring a biopsy. In addition, CLE imaging can be enhanced by real-time intraoperative communication with a CLE-experienced pathologist over TSP for higher diagnostic accuracy.

Acknowledgments

We thank the staff of Neuroscience Publications at Barrow Neurological Institute for assistance with manuscript and video preparation.

Author Contributions

Conception and design: Preul, Abramov, Xu, Eschbacher, Smith. Acquisition of data: Abramov, Furey, Xu, Eschbacher. Analysis and interpretation of data: Preul, Abramov, Eschbacher. Drafting the article: Abramov, Furey, Eschbacher. Critically revising the article: Preul, Abramov. Reviewed submitted version of manuscript: Preul, Eschbacher. Approved the final version of the manuscript on behalf of all authors: Preul. Study supervision: Preul, Smith.

Supplemental Information

Videos

Video 1. https://vimeo.com/855040101.