The Role of Surgery in Spinal Intradural Metastases from Renal Cell Carcinoma: A Literature Review

Simple Summary Renal cell carcinoma is a highly metastatic tumor, mainly to the lungs (50%), bone (49%), lymph-nodes (6–32%), liver (8%), and brain (3%). A wide and accurate literature review has disclosed only 51 cases of intradural spinal metastasis from sporadic renal cell carcinoma, of which 32 at intramedullary and 19 at extramedullary localizations. Once detected, they represent a sign of advanced disease and often lead to rapidly progressive neurological deficits. Because of these few reported data, there are no defined guidelines of treatment and the decision making in the choice of the best strategy should consider the curative, functional and palliative aspects, accordingly the management should be tailored for each patient. The options include surgery, radiotherapy, and chemotherapy, which can be performed in isolation or various combinations at the discretion of each institution. We discuss the role of surgery in the management of spinal intradural metastases from renal cell carcinoma. Abstract Background: Due to the few reported cases of spinal intradural metastases from renal cell carcinoma (RCC), there is no unanimous consensus on the best treatment strategy, including the role of surgery. Methods: A wide and accurate literature review up to January 2022 has disclosed only 51 cases of spinal intradural metastases from RCC. Patients with extramedullary (19) and those with intramedullary (32) localization have been separately considered and compared. Demographics, clinical, pathological, management, and outcome features have been analyzed. Results: Extramedullary lesions more frequently showed the involvement of the lumbar spine, low back pain, and solitary metastasis at diagnosis. Conversely, the intramedullary lesions were most often detected in association with multiple localizations of disease, mainly in the brain. Surgery resulted in improvement of clinical symptoms in both groups. Conclusion: Several factors affect the prognosis of metastatic RCC. The surgical removal of spinal metastases resulted in pain relief and the arresting of neurological deficit progression, improving the quality of life and overall survival of the patient. Considering the relative radioresistant nature of the RCC, the surgical treatment of the metastasis is a valid option even if it is subtotal, with a consequent increased risk of recurrence, and/or a nerve root should be sacrificed.


Introduction
Renal cell carcinoma (RCC) accounts for nearly 15,000 deaths per year in the United States [1], with a poor overall survival rate at 5 years despite the advances in radiologic imaging resulting in an early diagnosis, and in the management [2,3]. Metastases occur in 35% of patients with RCC and are synchronous in 15% and metachronous in the remaining 20% of cases [4]; the most common involved location is the lung, followed by the bone and lymph-nodes [5]. To the best of our knowledge, only 51 cases of spinal intradural metastases (19 extramedullary and 32 intramedullary) from sporadic renal cell carcinoma are reported in the literature.
Metastatic lesions involving the spinal intradural space often lead to rapidly progressive neurological deficits, resulting in severe quality of life (QoL) worsening. Because of the small sample of reported cases, there is no unanimous consensus about the best strategy for treatment. The management options include surgery, radiation, and chemotherapy, administered in isolated or various combined manner, at discretion of each institution.
We report a wide and accurate literature review, including a case recently treated at our institution [6], and we discuss the role of surgery in the management of both intra-and extramedullary intradural spinal metastases from RCC.

Methods
A Medline search up to January 2022 in PubMed online electronic database was made using the following key phrases: "intradural spinal metastasis and clear renal cell carcinoma", "intradural extramedullary metastasis and clear renal cell carcinoma", and "intramedullary spinal metastasis and clear renal cell carcinoma". The inclusion criteria were surgical series, reviews, and case reports in English language, as well as papers written in other languages, but including the abstract in English. All reported cases of spinal intradural metastasis, either extra-or intramedullary, from renal cell carcinoma, meeting the inclusion criteria, were enrolled.
Patients with spinal intradural extramedullary and those with intramedullary metastases were separately considered and, after, compared.
The analyzed factors were patient sex and age at diagnosis of spinal intradural metastasis, latency between the diagnoses of renal cell carcinoma and spinal intradural metastasis, spinal level involved, presence and location of systemic metastases, presenting symptoms, management and clinical outcome of the spinal metastasis, and overall survival.
Characteristics between groups and subgroups of categorial data were compared using Pearson's chi-square test and Fisher's exact test. Survival curves were illustrated by Kaplan-Meier method with univariate survival analysis. P values of less than 0.05 were considered significant.
The follow-up, ranging from 1 to 108 months (mean 25.5 ± 25.6 SD months) among 15 cases in which it was reported, showed 12 patients (80%) alive and 3 (20%) died for progression of primary disease at last follow-up.
All these data are summarized in Table 2.
Twenty-one (66%) patients underwent surgical resection; radiotherapy was administered to 19 patients (59%) (as adjuvant in 10, combined with drugs in 6, as single treatment in 1 and associated with SRS in 1); two cases refused surgical treatment and were treated by RT alone (1) and by medical therapy (1).
Post-treatment clinical conditions were not specified in 5 cases; among the remaining 27, 16 (59%) reported an improvement in symptoms, 9 (34%) were stable, and finally, only two patients (7%) referred a worsening.
All these data are summarized in Table 2.

Intradural Extramedullary and Intramedullary Spinal Cord Metastases from RCC at Mirror
The comparative analysis between intradural extramedullary and intramedullary spinal metastases from RCC (Table 2) showed a similar distribution in terms of sex and age.
The detection of spinal metastasis was metachronous in about 3 4 of cases in both groups; nevertheless, the latency was longer in extramedullary than in intramedullary metastasis, mean 61.88 ± 65.66 months versus 28.76 ± 45.31 months, respectively.
Concerning the spinal levels involvement, the lumbar tract was most often affected in the IDEM metastasis (p < 0.00001), while the cervical one was the most affected in intramedullary lesions (p = 0.0035).
Spinal pain was referred as presenting symptom mainly in patients with extramedullary lesions (68% vs. 25%, p = 0.002) and it was mostly low back pain.
Surgery was performed in all but one case of intradural extramedullary (95%) and in 11 among 32 patients (35%) with intramedullary metastasis (p < 0.00001), and it was associated in both cases with postoperative clinical symptom improvement in most patients (Tables 4 and 5).  Finally, the overall survival was better in IDEM compared to the intramedullary metastases, with 80% versus 50% of patients alive at last follow-up and a mean survival of 25.5 ± 25.6 months versus 13.15 ± 17.09 months (p = 0.011), respectively (Figure 1).

Discussion
Spinal intradural metastases are extremely rare and may also occur after many years from the diagnosis of the primary malignancy, posing problems in differential diagnosis and management.
Metastases to the spinal intradural space can occur through the following different ways: hematogenous dissemination, venous dissemination, via perineural lymphatics, subarachnoid space, and through direct invasion from near anatomical structures [9,15,49].
Because of the few reported data concerning spinal intradural, both extra and intramedullary, metastasis from RCC, resulting from the rarity of this pathological entity, there is not a unanimous consensus about their best management; the armamentarium at disposition includes surgery, radiotherapy, and chemotherapy, performed in an isolated manner or in various associations.
Several factors must be considered before choosing the best option of treatment. First, the radio and/or chemo-resistant nature of the primary tumor, the expectancy of life of the patient, its performance status, and the presence of comorbidities that could contraindicate some procedures. Keeping in mind the curative, functional, and palliative aspects; accordingly, the management should be tailored for each patient.
Surgery represents the gold standard of treatment for spinal metastases with acute onset of neurological symptoms, with the aim of arresting the decline of neurological functions, improving clinical symptoms (neurological deficits and/or pain), and preventing new-onset, potentially irreversible neurological deficits through the decompression of neural structures. RCC is a highly vascularized tumor with a tendency to bleed as follows: a sudden bleeding in a non-expandible spinal canal leads to a mass effect on the spinal cord or nerve roots, resulting in a potentially irreversible neurological deficit.
Potential complications include approach-related morbidities, intraoperative hemorrhage, CSF leak, thromboembolism, and wound infections. Their occurrence risk may be decreased with careful preoperative planning which considers the goals of treatment in terms of subtotal or gross total tumor resection, nerve root preservation or sacrifice, based on life expectancy and functional outcome, a meticulous surgical technique, and adherence to medical guidelines supporting their prevention.
Indeed, intra-and postoperative complications have not been reported in all the described cases in our review.
The choice of the surgical approach-laminoplasty, monolateral, or bilateral laminectomydepends on the localization of the tumor in the vertebral canal, its pattern of growth, and its relationship with the spinal cord and nerve roots; the important thing is to gain adequate exposure and access to the poles of the tumor, which can be verified by ultrasound before the dura mater opening. A CO 2 laser could be useful to reduce mechanical stress. Some authors performed the tumor resection en bloc, others in fragments after internal debulking. Care should be taken to avoid the spread of tumor fragments in the subarachnoid space.
The occurrence risk of neurological morbidity can be decreased with the help of intraoperative monitoring (IOM); nerve root damage leads to variable consequences according to the involved spinal segment, from diaphragmatic paralysis for upper cervical roots to ambulation impairment for lumbar nerve root involvement. Although nerve root preservation would be desirable, it is not always achievable; in our review, the nerve root was preserved in 7 and sacrified in 8 patients.
Intraoperative hemorrhage is a serious potential complication, mainly for this highly vascularized tumor; therefore, an accurate preoperative radiological evaluation and careful tumor dissection are mandatory. CSF leak could lead to longer operation time and hospitalstay, as well as other complications such as meningitis, intracranial hypotension, cutaneous fistula; thus, a watertight closure of the dura should be performed with auto-allograft materials or sealants and bedrest for 2-7 days would be advisable.
An early and prompt diagnosis is crucial for the outcome, being the ability to recover a neurological deficit related to the duration and entity of compression; in fact, the postoperative improvement in lower-extremity function is more likely when preoperative impairment is mild [50][51][52].
The role of radiotherapy in metastatic RCC is controversial [53] and is underexplored for the following two reasons: first because in-vitro studies have indicated radio-resistance and second because data from older clinical trial have showed high rates of radiotherapyrelated deaths [54,55]. Radiation therapy is less invasive than surgery and can stop tumor and neurological deficit progression; nevertheless, is reserved for patients with smaller metastatic lesions and radiosensitive tumors.

Intradural Extramedullary (IDEM) Spinal Metastases
Several primary malignancies may metastasize to the intradural extramedullary space, including the lung, kidney, thyroid, prostate, and bone. The literature review has disclosed only the following 19 cases of IDEM metastasis from sporadic renal cell carcinoma (Table 1): spinal metastases were most commonly metachronous (74%), located in the spinal lumbar segment (75%), and isolated (42%).
The presence of intradural extramedullary metastasis is a sign of advanced disease and it is associated with decreased overall survival with a poor prognosis; accordingly, the goal of treatment-surgical, radiation therapy, or both-is often palliative to improve the quality of life.
Most of patients with intradural metastasis to the cauda equina from renal cell carcinoma undergone an early diagnosis and an appropriate and timely surgical resection, experimented immediate improvement of clinical symptoms [15], also after a simple debulking [12,16,19]. Nevertheless, very often, due to the close adherence of the lesion to a nerve root and the lack of a clear cleavage plane, a nerve root transection [19] or a subtotal resection of the lesion is necessary, with the possible consequence of neurological deficit new-onset and increased recurrence rate, respectively.
In our review, all but one case (who refused) (95%) underwent surgery, which involved nerve root preservation in seven and sacrified in eight patients, whereas adjuvant treatments were administered in thirteen cases (7 RT alone, 2 CHT alone, 2 IFN alone, 2 RT + CHT). Clinical conditions resulted in the improvement in most of the cases (80%).
According to the literature, local treatments for metastases from RCC, such as metastasectomy, showed a benefit in terms of overall survival (OS) and cancer-specific survival (CSS) [56][57][58][59], whereas RT has been shown to provide improvement in clinical symptoms and local control in RCC based on the delivered dose [60]. Furthermore, we must consider the relatively radioresistant nature of the renal cell carcinoma [61,62]. Our data agree with the literature, as shown in Table 4 as follows: clinical symptoms improved in all cases that had undergone surgery alone and in seven among eight that underwent adjuvant radiotherapy.
Besides, the surgery is not only indicated to reduce mass effect symptoms and prevent progression of neurological deficits, but also to define the nature of the underlying disease, because metastasis may be detected before the diagnosis of primary disease, or to define the nature of the metastasis that may occur several years after primary disease.

Intramedullary Spinal Cord Metastases (ISCMs)
Intramedullary spinal cord lesions are rare [63]; among them, metastases represent 4-8.5% of all central nervous system metastases; nevertheless, with the improved overall survival rates thanks to more effective treatments of primary malignancy and the early diagnosis of spinal metastasis thanks to the improvement in diagnostic techniques and protocols, their incidence is increasing.
Intramedullary spinal cord metastases mainly come from lung and breast cancers, less frequently from melanoma, thyroid, colorectal, ovarian, and renal cell carcinoma [64]. To the best of our knowledge, only 32 cases of ISCMs from renal cell carcinoma have been reported in the literature ( Table 2).
In our review, most of the lesions were metachronous (72%), located in the cervical spine (44%), and associated with pulmonary (50%) and brain metastasis (40%) (p = 0.008) at diagnosis ( Table 3). The frequent detection of spinal metastasis, associated with other secondary localizations of disease at diagnosis, represents a sign of advanced disease which, together with histological findings, life expectancy, quality of life, and neurological function affects the therapeutic iter.
Steroid drugs are administered to all patients at the onset of clinical symptoms with the aim of palliation.
Results from our review showed stationarity or improvement of clinical symptoms in all cases treated by surgery or radiotherapy, and only one case of worsening after surgery and adjuvant RT; nevertheless, the mean overall survival rate was better in patients who had undergone surgery than in those who had undergone radiotherapy alone or with adjuvant (Table 5).
Surgery represents the second choice of treatment after initial anti-edematous pharmacological therapy, and in selected cases, after radiotherapy.
The goal of surgery is to arrest preoperative neurologic function deterioration and improve the patient's quality of life through spinal cord decompression. Nevertheless, despite the continuous advances in microsurgical strategies, intraoperative tools, and imaging technologies, this aim is not always achievable. Due to the highly functional and vulnerable nature of the spinal cord, the surgery of intramedullary metastases is a challenge and ranges from biopsy to maximal allowed safe resection. Biopsy is reserved for histological diagnosis or confirmation to plan other treatments or for unresectable cases. A "wait and see" strategy, through close clinical ambulatorial and MRI follow-up each year, is indicated for asymptomatic cases incidentally discovered.
Surgery is indicated in patients with symptomatic large lesions after radiation treatment failure, in cases of sudden onset or rapidly progressive neurological deficit, good preoperative KPS score, or systemic disease with a known indolent growth pattern.

Conclusions
Several factors affect the prognosis of metastatic RCC, including the extent of disease, histology, grading, and clinical factors [65]. Exeresis of the metastasis and other local treatment strategies, such as conventional radiotherapy, stereotactic radiosurgery, and hypo-fractionated RT, can be considered. The gross-total or subtotal surgical removal of spinal metastasis, either intra or extramedullary, allows one to arrest the progression of neurological deficits and obtain pain relief, improving the quality of life and overall survival of the patient. Considering the relative radioresistant nature of the RCC, surgical treatment of the metastasis is a valid option even if a nerve root was to be sacrificed or a tumoral residue that increases the risk of recurrence was left.