Keywords
5-aminolevulinic acid - calvarial metastases - fluorescence surgery - metastases -
skull metastases - surgical margins
Palavras-chave
ácido 5-aminolevulinico - metástases da calvária - cirurgia por fluorescência - metástases
- metástases cranianas - margens cirúrgicas
Introduction
Skull metastases are a common condition in patients with disseminated bone metastatic
disease. It may disseminate through blood, lymphatic transport or retrograde transport
through the midline venous system.[1] Metastases to the calvarium are the commonest cranial tumors in adults and have
less impact in the cancer evolution than intraparenchymal metastatic lesions.[2] They are often asymptomatic.
Early diagnosis of calvarial metastases is crucial for treatment success. The clinical
presentation can be local pain or a palpable mass under the scalp. The disease was
frequently underdiagnosed, often described in autopsies until the advances in imaging
techniques increased the identification of previously asymptomatic lesions.[2]
[3]
Dural infiltration due to direct extension from calvarial metastasis is commonly observed,
especially in patients with bone disease, and may account for > 60% of pachymeningeal
metastasis cases. The disease may also extent to the scalp, the subdural space and
the brain parenchyma in ∼ 34% of cases in some series.[4] Proximity to dural sinuses, cranial nerves or eloquent cortex can cause severe neurological
impairment, compromising treatment efficacy and survival prognosis.[5]
[6]
In patients with controlled systemic disease and Karnofsky performance status (KPS) ≥ 70%,
surgical management can be a safe treatment modality aiming total removal with oncological
margins,[4]
[6] possibly avoiding the necessity of local adjuvant irradiation.
5-aminolevulinic acid (5-ALA) fluorescence-guided surgery was first introduced in
glioblastoma[7] and has been a reliable standard for complete tumor removal and better progression
free survival. The 5-ALA accumulated in the malignant lesion is converted to protoporphyrin
IX (PpIX) and, under a blue filter illumination, shows a selective fluorescence, differing
normal from infiltrated tissue with high sensitivity and specificity.[8]
About 40 to 62% of brain metastasis[9]
[10]
[11] and 77 to 96% of intracranial meningiomas[12] can also exhibit 5-ALA fluorescence, so its use may improve the extent of surgical
resection. In these cases, there is a special focus in avoiding missed residual tumors,
which can compromise local-recurrence rate and progression free survival. Although
the benefits of 5-ALA fluorescence in meningioma surgery for the identification and
removal of bone infiltration or hyperostosis has been described,[13] there is few current data about its application for calvarial metastases with or
without contiguous tissues (scalp and dura-mater) involvement.[3]
The present article aims to analyze the use of 5-ALA guided surgery in calvarial metastases
with dural infiltration correlated with intraoperative pathology to improve the oncological
safe margins to possibly reduce the risk of recurrence or the necessity of adjunct
local treatment.
Materials and Methods
Between November 2015 and August 2019, 200 consecutive patients underwent 5-ALA fluorescence
surgery in the Instituto de Neurologia de Curitiba, Curitiba, PR, Brazil. There were
25 patients with brain metastases and 2 patients with solitary metastatic tumor located
in the calvarium without intraparenchymal disease. We retrospectively reviewed these
two 5-ALA positive cases eligible for the study. Both cases were studied with magnetic
resonance imaging (MRI) with aid of computed tomography (CT) scans to evaluate the
extent of bone disease.
5-aminolevulinic acid is provided by Carbolution Chemicals (St. Ingbert, Germany).
All of the patients signed an informed consent form, and the study was approved by
the Institutional Ethical Review Board. The 5-ALA solution was orally administered
at a dose of 20 mg/kg 3 hours prior to the surgery. Patients care (anesthesia induction,
positioning, etc.) were all performed as routine, including image-guidance with neuronavigation,
although both cases showed a palpable mass below the scalp.
The Zeiss OPMI PENTERO 800 (Carl Zeiss, Oberkochen, Germany) with a special blue-light
filter was used to identify 5-ALA-induced PpIX fluorescence and was graduated in strong,
poor or negative. A curvilinear C-shape incision in the scalp was made around the
mass, respecting the arterial pedicle, preserving the pericranium and incised circumferentially
with a margin around the lesion. A single burr hole was performed, followed by the
craniotomy. The specimen was removed with the galea and the inner table of the bone
flap was inspected with the surgical microscope, first with the white and then with
the blue light ([Fig. 1]). The outer layer of the dura-mater in direct contact with the lesion was also inspected
for 5-ALA graduation and was removed, avoiding entering the subdural space ([Fig. 2]). Frozen section procedure was performed in the pericranium and dural margins to
determine if tumoral tissue was present ([Fig. 3]). After the resection, cranioplasty was performed and the skin was closed primarily.
The entire specimen was inspected again under the microscope, to visualize the infiltration
to the pericranium and the dura-mater.
Fig. 1 Outer (a) and inner (b) table of calvarium inspected under blue light filter, showing
lesion with a 5-ALA strong positiveness.
Fig. 2 Outer layer of dura-mater in direct contact with the mass inspected with the blue
light filter, showing 5-ALA poor positiveness (a).
Fig. 3 Intraoperative pathology findings in 5-ALA positive outer dural margins, confirming
tumor infiltration.
Both patients studied retrospectively had diagnosis of solitaire metastatic calvarial
lesion from breast cancer, age < 70 years old, KPS of 90-100% and controlled systemic
disease with first line treatment. [Table 1] shows the characteristics and findings of each case.
Table 1
5-aminolevulinic acid fluorescence and intraoperative pathology findings
|
Patient
|
Age (years old)/Gender
|
Pathology
|
Tumor fluorescence
|
Pericranium fluorescence
|
Dura-mater fluorescence
|
Intraoperative pathology
|
|
1
|
33F
|
HER-2 negative, ER and PR positive
|
Strong
|
Negative
|
Outer layer: poor; Internal layer: negative
|
Pericranium negative; Bone tumor and outer dural layer positive; internal dural layer
negative
|
|
2
|
40F
|
HER-2 negative, ER positive PR negative
|
Strong
|
Strong
|
Outer layer: negative; Internal layer: negative
|
Pericranium positive; Bone tumor positive; Dura-mater negative
|
Abbreviations: Her-2, human epidermal growth receptor 2; ER, estrogen receptor; PR,
progesterone receptor.
Results
Pericranium Findings
In one case, the inner layer, in direct contact with the bone mass, was 5-ALA strong
positive. The intraoperative pathology confirmed tumor infiltration. The other case
was 5-ALA negative, also corroborated with the histopathological analysis.
Bone Flap Findings
Both specimens showed an intraosseous mass, removed en bloc. The outer and the inner table were 5-ALA strong in the tumor and the margins were
visible even with white microscope light.
Dural Findings
In one case, the outer dural layer was 5-ALA poor positive. It was removed preserving
the inner layer to avoid the subdural space. In the other case, the 5-ALA finding
was negative. Both diagnoses were corroborated with intraoperative pathology.
There were no postoperative complications. Both patients had MRI scan 24 hours, 1
month, 3 month and 6 months after the surgery, without signs of local disease progression
or KPS worsening until the end of the writing of the present article. No local adjuvant
treatment was realized.
Discussion
Bone metastasis is a frequent complication of cancer and is especially higher among
patients with more advanced disease, but the exact incidence of calvarial metastases
remains unknown. Dissemination may occur due to direct extension or by hematogenic
pathway, with cancer cells adhering to the endosteal surface and invading the bone
marrow.[2]
[3]
[6]
Breast, lung and prostate adenocarcinoma are the commonest primary lesions to metastasize
to the skull due to a distinct bone tropism, but various other histologies have been
reported.[14]
[15] Mitsuya et al reported 55% of skull metastases from breast cancer in a series of
175 patients, with a preponderance female versus male of 7:3 patients.[16] Once dissemination to the skull is diagnosed, the expected median survival rate
is 20 months. In a retrospective study by Stark et al,[2] there was an average period of 4 years between the initial primary cancer diagnosis
and the detection of intraosseous metastasis.
While cranial nerves impairment is the commonest clinical presentation of skull base
cancer, patients with calvarial circumscribed intraosseous metastasis can be completely
asymptomatic. In cases of circumscribed invasive dural extension, ∼ 18% of the patients
can present pain and brain swelling. Cranial metastases overlying or invading the
dural venous sinuses can turn into symptomatic and predict worst outcomes. Frontal
and parietal bones are the most common sites of calvarial metastases, often presenting
a well-circumscribed asymptomatic mass under the scalp.[4]
[5]
[16]
In the diagnostic evaluation, the following aspects are particularly useful to be
considered in the diagnosis: localization of the lesion in the calvary or in the skull
base; local, multiple or diffuse bone distribution; and intraosseous invasion to the
scalp or dura-mater. Computed tomography scanning may help the identification of calvarial
metastases as lytic or sclerotic. Magnetic resonance imaging findings present hypointense
signal in T1-weighted noncontrast sequence and often homogeneous gadolinium enhancement.
Fat subtraction is important to determine tumor margins.[4]
[6]
Management of calvarial metastases may depend on symptomatology, patient KPS, relationship
with dural sinuses and eloquent cortex, histopathology, extent of spread and scalp
infiltration.[3]
[5]
[6]
[16] Surgical treatment can be a safe palliative option for symptomatic patients, even
when indicated after failed attempt with irradiation and/or chemotherapy.
In patients with a solitary metastatic mass, aggressive local treatment can sometimes
result in prolonged survival.[3]
[4] Although surgical resection may quickly relieve symptoms, it can be challenging
and increase surgery morbidity, especially in patients with delayed diagnosis or uncontrolled
systemic disease. The pericranium can also be directly infiltrated, and, in these
cases, en bloc removal can be performed with scalp resection with the bone mass.[6] Direct dural infiltration is related to higher local recurrence rates in cases of
underlying sinus involvement due to the difficulties for complete resection.[5] These cases also predict a more aggressive disease with worst neurological impairment
and shorter survival. Irradiation is a treatment option alone, when surgery is contraindicated,
or adjuvant to control tumor growth.
5-aminolevulinic acid is the metabolic precursor of hemoglobin that induces the synthesis
of protoporphyrin IX (PpIX), a fluorescent compound in appropriately violet-blue filtered
light. The PpIX stored in malignant lesions aids the differentiation between normal
brain and tumor tissue with high sensitivity and specificity. 5-aminolevulinic acid-guided
fluorescence was first introduced in malignant glioma surgery as an adjuvant tool
for optimizing the removal of these tumors,[7]
[16]
[17] leading to increased progression free survival.[7]
[8]
[17] Over the years, its vibrant application has been introduced and studied in other
intracranial neoplasms, such as brain[9]
[10]
[11] and spinal cord metastases[18]
[19]
[20] and meningiomas.[12]
[13]
[21]
There is a 5-ALA positive fluorescence ranging from 77 to 96% of the intracranial
meningiomas. The graduation in poor or strong may vary in the literature, but in an
intratumoral homogenous fluorescence, it is observed in > 75% of the cases. There
is no apparent correlation between histopathological findings and 5-ALA intraoperative
fluorescence.[13] The method can detect bone infiltration with 100% specificity and 89% sensitivity,[21] confirming suspected invasion on preoperative evaluation.[12]
More than 60% of intracranial metastases demonstrate a 5-ALA positive fluorescence,
but it may range between 28 and 81.8% in large series.[10] Adjacent brain tissue may be 5-ALA positive without necessarily containing metastatic
infiltration.[8] Furthermore, a heterogeneous positivity may be expected and even the previous administration
of neoadjuvant chemotherapy can be a potential bias for fluorescence response.[9]
[10]
PpIV positive fluorescence is also related with a more benign behavior of brain metastases,
while a negative fluorescence can be a more aggressive tumor with worse prognosis.[9] Yang et al[22] described the use of ALA for imaging and photodynamic targeting human epidermal
growth receptor 2 (HER-2) positive tumors. Human epidermal growth receptor 2 is a
driver oncogene with special importance in breast cancer classification, with sensitive
ALA-mediated photodynamic therapy.
Both cases presented in our article were HER-2 positive and 5-ALA strong positive.
We are routinely using 5-ALA fluorescence for intracranial gliomas and metastases
since 2015,[18]
[19] and a primary diagnosis of breast cancer HER-2-positive may support this method
of intraoperative guidance. There is not any study about 5-ALA fluorescence surgery
aiming complete removal of calvarial metastasis. The management of these lesions can
be controversial in the postoperative due to the decision about irradiation. Whole-brain
radiotherapy is often elected in cases of diffuse calvarial involvement, while solitaire/oligometastatic
disease supports local treatment.[3]
[4]
[6] Modifications in the chemotherapy may also be needed at the time of diagnosis. With
the free oncological margins in both cases, local adjuvant irradiation was not indicated.
Patients continue to perform periodic MRI for evaluation.
Conclusion
5-aminolevulinic acid fluorescence surgery for calvarial metastases may provide a
simple and reliable guide to determine the oncological limits with the pericranium
and underlying dura-mater.
