Abstract
Background/Aim: Intramedullary spinal cord metastases (ISCM) are deemed extremely aggressive, as confirmed by the low life expectancy since the diagnosis. Up to 26.5% of total ISCM stem from breast cancer (BC), representing the second most frequent primary site after the lung. The increasing incidence of BC and the widespread use of MRI for the diagnosis could therefore lead to an earlier diagnosis and, therefore, to a progressively longer survival in patients affected by ISCM from BC. This systematic review is intended to provide an orientation through a management algorithm for the most appropriate therapeutic approach in these patients. Materials and Methods: The research strategy initially relied on title and abstract analysis. The article’s full text was retrieved for further investigation if the title and abstract met the inclusion criteria. The extracted data included the following: authors, publication time, study design, patient characteristics, ISCM location, treatment modalities, time interval from initial cancer diagnosis to ISCM diagnosis, clinical outcomes, and survival time. Results: This systematic search regarding ISCM from BC yielded 574 articles. After screening, a total of 44 studies were included in this systematic review. A total of 123 patients were evaluated. The mean patient age was 53.2 years with a standard deviation of 10.4 years. Female patients were 122. There was only one male patient. Conclusion: ISCM from BC have a better prognosis than lung metastases and, thanks to recent advances in diagnostic imaging and intraoperative planning and neuromonitoring, an early diagnosis and a prompt multidisciplinary treatment may be accomplished. Prospective studies to generate evidence-based data regarding the most appropriate treatment for ISCM are mandatory.
Remote metastases to the central nervous system are common, and spinal cord involvement represents a small percentage of all the involved sites. Autopsy series performed on cancer patients determined an average frequency of intramedullary spinal cord metastases (ISCM) below 2% (1-3). ISCM are characterized by a rapid neurological impairment and progression, as they exert highly malignant tumor evolution. Notably, ISCM are deemed extremely aggressive, as confirmed by the low life expectancy since the diagnosis, which ranges from 3 to 12 months (2, 4, 5). Yet, on average, approximately 8% of the patients are asymptomatic at the time of diagnosis (4, 6). Once early signs appear, they typically advance quickly and progress into a sensory and/or motor deficit within 4 weeks (6-8).
Hence, early diagnosis and prompt treatment are pivotal to improve the prognosis and the neurological condition of these patients (6). Therefore, when a spinal involvement is suspected, patients with a previous oncological history, should undergo a high-resolution spine MRI with Gadolinium enhancement (8).
However, due to the low occurrence of such conditions – and the consequent limited literature in this field – a clear consensus regarding the most appropriate management is missing, and a standard therapeutic protocol is far from being defined. In clinical practice, therapeutic options are mainly reduced to either fractionated external beam radiotherapy (RT), surgical removal and palliative care, with the treatment choice still based only on the experience of the physician (1, 6).
Up to 26,5% of total ISCM stem from BC, representing the second most frequent primary site after the lung (2, 4). Nevertheless, the detection of BC intradural metastases is expected to rise, albeit only incidentally at this stage.
Indeed, the increasing incidence of BC, the heavy use of MRI for the diagnosis and follow-up, as well as the availability of more effective therapeutic protocols, could therefore lead to progressively longer survival and so to earlier diagnosis in patients affected by ISCM from BC. This observation clearly raises some issues regarding their management (1, 9). Hence, in this systematic review the authors searched the literature to investigate and discuss the history, the advances and the limitations currently related to the management of ISCM from BC.
Materials and Methods
Literature search. Preferred Reporting Items for Systematic reviews and Meta-analyses guidelines (PRISMA) were followed to conduct and report this systematic literature review, registered to “Research Registry” (ID: researchregistry8415) (Figure 1) (1). The authors performed a broad systematic literature search in PubMed for all studies investigating the presence of ISCM in BC patients. The authors searched for studies published up to the 29th of April 2022 without backward limits, using the following Mesh and free text terms “Intramedullary”, “Spinal Cord”, “Metastasis”, “Breast Cancer”, combined using Boolean operators “AND” and “OR”. To avoid the potential omission of relevant studies, additional databases, such as greynet.org and opengrey.eu for gray literature were reviewed. Reference lists of articles included and previous systematic reviews and meta-analyses regarding ISCM, and breast cancer were also manually screened. Duplicate articles were eliminated using Microsoft Excel 16.37.
PRISMA flow chart of selection process.
Study selection and risk of bias assessment. The research strategy initially relied on title and abstract analysis. The article’s full text was retrieved for further investigation if the title and abstract met the inclusion criteria. Two authors (L.B and E.A.G) independently assessed eligibility based on “a priori” criteria, and differences were resolved with the help of a third author (R.C). We used the Joanna Briggs Institute (JBI) Critical Appraisal tools for the risk of bias assessment of included studies (2). JBI Critical appraisal tools have been developed by the JBI and collaborators and approved by the JBI Scientific Committee following extensive peer review. It consists of an 8-question checklist for case reports and a 10-question checklist for case series or cohort studies. The reviewer can answer yes, no, unclear, or not applicable. The data collection process was conducted without using any automated tools. No ethical approval was required for this study.
Eligibility criteria. The articles were selected according to the following inclusion criteria: full article in English, Clinical studies (case reports, case series, retrospective studies), patient age ≥18 years, patients affected by breast cancer, studies focusing on patients with ISCM.
Exclusion criteria were articles not in English language, literature reviews, systematic reviews, and meta-analysis, patient age <18 years, patients with other type of tumors isolated or associated to BC, and studies not assessing ISCM.
Data extraction. According to the criteria above, all articles were identified by two reviewers (L.B and E.A.G). In case of a discrepancy, the senior author (R.C) arbitrated until a consensus among the authors was reached. The extracted data included the following: author, publication time, country, study design, patient characteristics, ISCM location, treatment modalities, time interval from primitive cancer diagnosis to ISCM diagnosis, clinical outcomes, and survival time.
Results
Study selection. Our systematic search regarding intramedullary spinal cord metastases from BC yielded 574 articles. Another 11 articles were included after reading the bibliography and after analyzing the gray literature about the topic. After removing duplicates, the papers screened were 473. After reading the title and abstract 384 articles were excluded. Twenty-two articles were not retrieved due to the inability to obtain the full text. Finally, we excluded another 23 articles not conforming due to incompatibility with our eligibility criteria. Forty-four articles were included in our review. Demo-graphical and study design data were summarized in Table I.
Summary of demographical and clinical data.
Risk of bias assessment. We stratified the risk of Bias and thus the quality of each included paper into three groups (low, moderate, and high quality). The bias risk assessment showed that, among the included case reports, thirteen respected the JBI criteria for a high-quality study (with six or more positive answers), six had a moderate quality (four/five positive answers), while the other six case reports demonstrated a low quality with a high risk of bias (less than three positive answers). Regarding the case series or cohort studies included, thirteen respected the JBI criteria for high-quality research, with a low risk of bias, one presented a moderate risk of bias, and four presented low-quality evidence. Most studies didn’t assess the presence of confounding factors and a strategy to deal with them. Furthermore, many studies included in this review are case reports or case series with few patients because of the extreme rarity of ISCM from BC. For this reason, the authors limited themselves to presenting demographic, clinical and treatment type data, without providing descriptive (mean, median, standard deviation, range) or even inferential statistical analysis. However, because of the condition’s rarity, we included all selected studies. As a matter of fact, each paper summarized key lessons regarding the background of such disease, clinical practice, and outcomes.
Study characteristics. Of the selected studies, 30 (68.18%) are case reports, 5 (11.36%) case series, 5 (11.36%) retrospective studies, 1 multicenter study (2.27%), and 3 (6.81%) original articles.
Key patient characteristics and treatment information were not uniformly or consistently reported across the included studies. The articles included in our review span the period from 1909 to 2022, with most of the studies conducted after 2000 (32 of 44; 72.7%).
All studies focused on the presence of ISCM in BC patients. Each study considered and analyzed patients’ sex, age, clinical symptoms of onset, localization of metastases, presence of metastases in other organs, therapeutic management, clinical out-come, interval between diagnosis of ISCM and primary tumor and, finally, survival time (Table II).
Studies included in systematic review.
Study synthesis. A total of 123 patients were evaluated. The mean patient age was 53.24±10.40 years. Female patients were 122, while only one male patient was reported, with a M/F ratio of 0.08. A 53.6% of patients included in this review presented with clinical symptoms of motor disturbances, varying from upper limbs or leg weakness to complete tetra or paraplegia; 41.4% of patients reported sensory disturbances of various degree, including paresthesia, hypo-dysesthesias until complete anesthesia, based on the spinal cord metamer affected. Pain and dysautonomia (bowel and/or bladder dysfunctions) represented two other clinical symptoms reported by patients, accounting for 23.5% and 46.3% of all cases, respectively. Only 5.6% of patients were asymptomatic at the time of ISCM metastasis.
The portion of the spinal cord predominantly affected by metastasis is the thoracic spine (47.9%), followed by the cervical (41.4%) and lumbosacral (14.6%) tracts. In 4.8% of the studies included in our review the metastasis localization was not reported.
Therapeutic options in the treatment of ISCM from BC included three different strategies: surgery, radiotherapy, and medical therapy, alone or in combination. In our review most patients received radiation therapy (60.1%), delivered using various types of irradiations (Rx-therapy, external beam radiation therapy, volumetric modulated arc therapy/image guided radiation therapy, CyberKnife or robotic radiosurgery) according to historical and hospital facility availability. A 29.2% of patients were managed with surgery, while chemotherapy or palliative care was administered only in 14.6% of patients.
Clinical outcome improved in 21.1% of cases, deteriorated in 27.6% and was stable in 17.8%. However, in 34.9% of patients the postoperative outcome was not reported, leading to a high risk of bias in the assessment of the optimal therapeutic strategy.
Other preferential metastatic localization in addition to ISCM metastasis was the brain (32.5%), bone (17.8%), visceral (16.2%) and lungs (13.8%). 8.1% of patients did not present any evolution other than ISCM. In almost half of the cases (47.1%), however, there were no data on the presence or absence of other metastatic localizations.
Mean interval from the diagnosis of primary BC and ISCM was 50.98±50.91 months. Mean survival time was 7.25±8.08 months.
Discussion
BC represents the most common tumor reported in female patients, with the bones as the main site of metastases (50). It is the second cause of ISCM, following lung cancer (51). ISCM occurrence is exceedingly rare (6) and radiological advances during last years led to an improving in ISCM detection and diagnosis. ISCM represent a severe condition since it could cause severe neurological deficit up to life-threatening condition.
There is no literature data about a predominant spinal tract for ISCM localization, but our results have shown a prevalence of ISCM in the thoracic spine (47.9%), followed by cervical and lumbar spine (8).
At the time of diagnosis, ISCM are often associated to metastatic brain disease (6). Lee et al. postulated a hypothetic hematogenous spreading to spinal cord through Batson venous plexus or the arterial system and/or a leptomeningeal diffusion by drop metastasis secondary to cerebral brain metastases (51). Furthermore, Jayakumar et al. (44) proposed a perineural invasion of the spinal cord parenchyma and a direct invasion through nerve roots from the epidural space (4).
Clinical features and diagnosis. Based on the results obtained, it was possible to create a diagnosis and management algorithm for patients affected by ISCM form BC (Figure 2).
Management algorithm of patients affected by intramedullary spinal cord metastases (ISCM) from breast cancer. MRI: Magnetic resonance imaging; CT: computed tomography; RT: radiotherapy.
The clinical and neurological onset symptoms strongly affect the recovery. According to Mut et al., the neurological deficit worsens usually quickly, and it is a typical clinical feature of ISCM, distinguishing it from other intramedullary tumors, such as gliomas (6, 8). Usually, it is the cause of a rapidly progressive myelopathy over weeks (18).
Common clinical findings include paresthesia, pain – usually followed by a level of sensory loss– sphincter disturbances, paresis, and the eventual progression to a spinal cord transverse hemi section (Brown-Sequard) syndrome or full cord transection (6-8, 50).
Patients affected by metastatic cancer may also present a paraneoplastic necrotizing myelopathy and post- radiation spinal necrosis (51).
A possible diagnostic tool is represented by the lumbar puncture. It usually does not show increase of CSF pressure, but it could document a hyperprotidorrhachia, in the absence of any cell alterations (6, 15).
Spinal MRI with contrast enhanced is the gold standard in ISCM diagnosis. It usually appears as a circumscribed lesion with perilesional edema in T2-weighted images. The lesion may appear as T2-hyperintense and T1-isointense, usually homogenous, and nodular, or in rare cases, heterogeneous with a ring-enhancement (4, 51). In selected cases, when spine MRI is not feasible, CT-myelography may improve sensitivity in ISCM detection (51).
Treatment options. The rare occurrence of ISCM from breast cancer has created a non-stop debate on the identification the appropriate management of these lesions, especially because of the lack of cases reported in the literature. In the last years, several treatments were proposed: external beam radiation combined to corticosteroid treatment before the advent of paraplegia, stereotactic radiosurgery, and aggressive surgery. Adjuvant therapy seemed to prolong the overall survival (OS) even if causing a certain grade of side effects. Indeed, according to Mut et al. since breast metastases are radiosensitive, fractionated radiotherapy may represent an effective treatment for these lesions; nevertheless, it seems that just the radiosensitivity of metastasis has ensured a partial neurological improvement in half of patients (8, 52). Another valuable option is represented by radiotherapy, before chemotherapy, in selected cases with symptomatic lesion. A whole spine irradiation may be also considered if seeding metastases occur.
To our knowledge, few cases presented details and evaluated the role of radiation therapy (RT) in the treatment of ISCM from BC (1, 6, 25, 27, 36).
Aiello et al. (1) described a patient that was treated with RT with a total dose of 20 Gy in 5 fractions through a volumetric modulated arc therapy with daily image-guided RT (VMAT/IGRT). After 4 months, a complete response was documented, with subsequent neurologic symptoms improvement.
Lee et al. (6) included 6 patients affected by ISCM from BC that received fractionated external beam radiotherapy with total doses from 2,000-3,000 cGy (median 3,000 cGy). Despite radiotherapy, neurologic status progressively deteriorated. Median survival after ISCM diagnosis was 5.5 months.
Kosmas et al. (25) reported four cases of ISCM form infiltrating ductal carcinoma. Case 1, 3 and 4 were treated for approximately 1–3 years for systemic metastatic disease. In case 4, concomitant brain localization was present at the time of cervical ISCM diagnosis, and the patient died after few weeks despite steroids and local radiotherapy. Case 2 developed ISCM at the lumbar spine after brain metastatic disease. She underwent radiotherapy (50 Gy) and steroids and died after 5 months with a generalized central nervous system disease.
Shin et al. (27) analyzed 3 cases of cervical ISCM from BC treated with linear accelerator-based stereotactic radiosurgery with a mean dose of 14.4 Gy for each lesion They presented clinical improvements and a partial response.
Veeravagu et al. (36) reported the outcomes of five cases of ISCM from BC treated with fractionated stereotactic RT. Only in 3 cases RT details were described. Patients were treated with the following schedule: 18 Gy/2, 20 Gy/2, 21 Gy/3 using CyberKnife. None of the presented cases showed a complete response.
However, surgery is rarely indicated, because of the difficult surgical site and the late diagnosis in patients with multiple locations. Surgery, indeed, can be considered in patients with non-plurimetastatic radio-resistant tumor and discrete solitary intramedullary metastasis, without leptomeningeal involvement (8). Yet, Connolly et al. have suggested surgical treatment in those cases with rapid neurological deficit with the aim of a subtotal resection, since the prognosis is poor, to preserve existing functions; gross total resection is amenable only in few selected cases with a well circumscribed metastasis (51).
The goal of neurological improvement still represents a critical point in the decision-making process if it means improvement in quality of life: Mackel et al. have shown that more than half of the cases underwent surgery experienced improvement in motor deficit, reduction in pain and sphincteric disfunction (4).
Despite the recent progress in microsurgical and electroneurophysiological techniques, ISCM from BC remain complex and challenging, and the histological type is a major predictor of tumor resectability. In preoperative planning, diffusion tensor imaging (DTI) in patients with ISCM can predict the resectability of the lesion. Furthermore, a prospective study is needed to confirm this, and its burden on patient outcome (52-54).
Instead, particularly in the case of unresectable lesions, in the last years, robotic radiosurgery (RRS) was proven to be a safe, time-saving, and effective treatment modality. In a cohort of 33 patients, local tumor progression and symptom worsening were prevented in most patients treated using RRS (47).
Outcome. Lee et al. have shown that ISCM, with the coexistence of other central nervous system metastases, reduces the median survival to 1-2 months (6): although, our results show that ISCM from BC have a better mean survival time (7.2 months) than those from lung cancer (4.6 months) (4).
A plausible explanation for these findings is the recent improvement of systemic treatments, such as immunotherapies and other targeted therapies (6, 36, 43).
Indeed, nowadays, there is a growing and emerging interest in the combined use of immunotherapy and targeted therapies for metastatic breast cancer, and the combined use of immunotherapy and chemotherapy results in longer overall survival than chemotherapy alone (55).
Gazzeri et al. stated that age ≥40 years, history of lung cancer, presence of other systemic metastases, and higher preoperative Mc Cormick score are negative prognostic factors (46).
In Mackel et al. surgical series, the average survival was from 3 to 11 months, showing that surgery minimally affected outcome and overall survival (4). However, a clear and unambiguous point of view is still missing, underlying that the choice is related to each patients’ medical history and clinical condition (6). This systematic review, indeed, hasn’t shown any statistically significant differences between the strategies proposed.
Conclusion
ISCM are insidious grim diseases commonly associated to an aggressive progression. Thanks to all the available technologies, an early diagnosis and a prompt multidisciplinary treatment may be accomplished. Nevertheless, even if there is no consensus yet about the best treatment method, the quality of life, symptoms relief and the risk of neurological deficit should guide the decision-making process. Thus, prospective studies to generate evidence-based data with an algorithm to choose the more appropriate treatment for ISCM are mandatory.
Footnotes
Authors’ Contributions
Conceptualization, G.S. and R.C.; methodology, L.B., R.C.; software, L.B.; validation, G.S., R.M., F.G., D.G.I., G.F.N., G.E.U.; formal analysis, L.P., R.C., G.S.; investigation, L.B., E.A.G.; resources, R.C., L.B., E.A.G.; data curation, L.B.; writing – original draft preparation, G.S., R.C., L.B., M.P., E.A.G.; writing – review and editing, G.S., R.C.; visualization, R.C.; supervision, G.E.U., R.C.; project administration, G.C. All Authors have read and agreed to the published version of the manuscript.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
- Received December 7, 2022.
- Revision received December 17, 2022.
- Accepted December 20, 2022.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
