Phrenic nerve reconstruction after combined resection in malignant a narrative review

Authors: Yosuke Hamada, Sakashi Fujimori, Souichiro Suzuki, Takahiro Karasaki, Shinichiro Kikunaga, Shusei Mihara

Abstract

Background and Objective

Phrenic nerve resection is sometimes necessary during tumor removal when the nerve is infiltrated by malignancies. However, this can result in diaphragmatic paralysis and respiratory insufficiency. While mechanical ventilation and diaphragmatic pacing may temporarily support respiratory function, phrenic nerve reconstruction offers a potential long-term solution. Nevertheless, its use during tumor resection remains underreported. This review assesses current evidence on phrenic nerve reconstruction, focusing on surgical techniques, nerve graft selection, and the feasibility of minimally invasive approaches.

Methods

A literature search was conducted in PubMed for phrenic nerve reconstruction studies. English-language studies published between January 1, 1980 and January 30, 2025, that focused on immediate phrenic nerve reconstruction following tumor resection were included in the review.

Key Content and Findings

Phrenic nerve reconstruction can be performed either immediately after nerve resection or as a delayed procedure. Immediate reconstruction, especially when conducted concurrently with tumor resection, has been shown to promote optimal nerve regeneration and functional recovery. In contrast, delayed reconstruction is generally associated with greater technical challenges and less predictable outcomes. Direct anastomosis is preferable when feasible; however, nerve grafting is often required due to insufficient residual nerve length to achieve a tension-free repair. Among graft options, the intercostal nerve is favorable due to its anatomical proximity and minimal additional surgical burden, whereas the use of other nerves, such as the sural nerve, requires an additional incision at a separate site, which may be less desirable. Successful reconstruction can also be achieved using minimally invasive approaches such as video-assisted thoracoscopic surgery (VATS) and robotic-assisted thoracoscopic surgery (RATS). Notably, the additional time required for reconstruction in minimally invasive procedures is manageable and does not significantly affect patient outcomes.

Conclusions

Immediate phrenic nerve reconstruction, either by direct suturing or intercostal nerve grafting, is a feasible and effective method for preserving respiratory function. The ability to perform reconstruction using minimally invasive techniques further supports its clinical adoption. Given its advantages in functional recovery and its relatively low additional surgical burden, phrenic nerve resection followed by immediate reconstruction may be considered in most cases involving phrenic nerve invasion.

Introduction

Background

In cases where mediastinal tumors or lung cancer invade the phrenic nerve, resection may be necessary to achieve oncological clearance (1). The phrenic nerves play a crucial role in controlling the left and right hemidiaphragm, an essential function for effective respiration. Damage to the phrenic nerve, whether due to trauma, surgical intervention, or pathological processes, can result in phrenic nerve dysfunction, leading to partial or complete diaphragmatic paralysis and subsequent respiratory insufficiency (2). Unilateral phrenic nerve paralysis may reduce forced vital capacity by approximately 30% in the sitting position, though individual variations exist (3). When both sides are affected, or additional complications arise, the decline in respiratory function can be even more severe (4). In particular, bilateral paralysis can lead to paradoxical abdominal movement, further complicating respiratory mechanics. Conventional treatments, such as mechanical ventilation or diaphragmatic pacing, provide only limited relief (5), highlighting the need for more effective reconstructive approaches to restore diaphragm function. Diaphragmatic plication has been shown to provide significant improvements in respiratory function; however, symptom recurrence may occur over several years. Furthermore, as the procedure is irreversible, it limits future treatment options (6-10).

Rationale and knowledge gap

Several reports have documented phrenic nerve reconstruction as a fundamental approach to restoring diaphragmatic function (11-13). However, reports on phrenic nerve reconstruction during tumor resection remain limited, and no consensus exists regarding indications, timing, surgical techniques, choice of sutures or nerve grafts, duration of functional recovery, or evaluation methods. Traditionally, extensive surgeries involving phrenic nerve reconstruction were performed via open surgery, such as thoracotomy or sternotomy (14-16). However, minimally invasive approaches, such as video-assisted thoracoscopic surgery (VATS) and robotic-assisted thoracoscopic surgery (RATS), have broadened their indications to include even advanced tumors infiltrating the phrenic nerve (11,12). This offers a compelling rationale to reconsider current surgical approaches.

Objective

This review aims to assess the current state of phrenic nerve reconstruction during tumor resection, with particular emphasis on surgical techniques, nerve graft selection, and the integration of minimally invasive approaches. It further explores how these advancements can enhance functional outcomes and expand treatment options for patients undergoing complex thoracic surgeries. We present this article in accordance with the Narrative Review reporting checklist (available at https://med.amegroups.com/article/view/10.21037/med-25-9/rc).

Methods

A literature search was conducted using the MEDLINE database accessed through PubMed, with the search terms “phrenic nerve reconstruction”, “phrenic nerve repair”, “reconstruction of phrenic nerve”, and “transfer to phrenic nerve”. There were 498 English-language reports published between January 1, 1980 and January 30, 2025, that included at least one of the search terms. Among these, studies specifically addressing immediate phrenic nerve reconstruction following tumor resection were identified through abstract screening and included in the review. The included study types were case reports, clinical studies, reviews, and systematic reviews. The search strategy is summarized in Table 1.

Anatomy of the diaphragm and the course of the phrenic nerve

The diaphragm is a dome-shaped musculotendinous structure that separates the thoracic and abdominal cavities and plays a central role in respiration by generating negative intrathoracic pressure during inspiration (17). Its function is primarily controlled by the phrenic nerves, which provide the sole motor innervation to the diaphragm and contribute sensory fibers to the central diaphragmatic pleura, pericardium, and peritoneum.

Each phrenic nerve arises predominantly from the anterior rami of the C3, C4, and C5 cervical spinal nerves, with the contribution from C4 being most significant (18). After originating in the neck, the phrenic nerve descends vertically on the anterior surface of the anterior scalene muscle, deep to the prevertebral fascia. It then enters the thoracic cavity by passing posterior to the subclavian vein and anterior to the subclavian artery, continuing its descent within the mediastinum.

In the thorax, the right phrenic nerve descends along the lateral aspect of the superior vena cava and right atrium before reaching the diaphragm near the inferior vena cava hiatus. The left phrenic nerve passes lateral to the aortic arch and anterior to the root of the left lung, ultimately piercing the diaphragm independently (19). Despite subtle anatomical variations between individuals, this general course is consistent and clinically relevant, especially during thoracic surgeries. A precise understanding of phrenic nerve anatomy, including its roots, course, and relationships with surrounding structures, is vital for both surgical planning and the assessment of patients with respiratory insufficiency potentially stemming from neural compromise.

Etiologies of phrenic nerve injury

Phrenic nerve injury may result from a diverse array of external and internal factors, which can be broadly categorized into traumatic, iatrogenic, neoplastic, and idiopathic causes (14,20-22). Given the nerve’s long and anatomically complex course as discussed in the previous chapter, it is vulnerable to insults at multiple levels.

External causes include both blunt and penetrating trauma to the neck or upper thorax, potentially disrupting the nerve along its cervical or intrathoracic course. A distinct and clinically significant subgroup of injuries arises from iatrogenic sources, particularly during surgical procedures (23). Thoracic operations such as mediastinal tumor resection, lobectomy, pneumonectomy, coronary artery bypass grafting (CABG), and pericardiectomy pose a notable risk due to the phrenic nerve’s proximity to the mediastinum, pericardium, and diaphragm. Minimally invasive approaches like VATS or RATS, although associated with decreased morbidity, may still result in inadvertent nerve damage during dissection in close anatomical regions. Importantly, the cervical origin of the phrenic nerve renders it susceptible to injury from cervical spine disorders, traumatic brachial plexus injuries, and anterior cervical surgeries, such as discectomy and fusion (24). These pathologies can result in diaphragmatic paralysis independent of thoracic involvement, highlighting the importance of comprehensive neurologic assessment and cervical imaging when evaluating patients with unexplained diaphragmatic dysfunction.

Internal causes predominantly involve neoplastic processes, including direct invasion, compression, or perineural spread from malignancies such as lung carcinoma, thymoma, or metastatic disease (14). Infectious or inflammatory etiologies, such as viral neuritis or tuberculous involvement of the mediastinum, may also affect phrenic nerve function (25). In some instances, idiopathic phrenic nerve palsy occurs in the absence of identifiable structural or pathological abnormalities. Though rare, these cases underscore the diagnostic complexity and the necessity for thorough exclusion of other causes. Overall, understanding the diverse etiologies and anatomical vulnerabilities of the phrenic nerve is crucial for accurate diagnosis, prevention, and management of diaphragmatic dysfunction across a range of clinical contexts.

Timing of phrenic nerve reconstruction

The timing of phrenic nerve reconstruction is generally classified into two immediate reconstruction and delayed reconstruction. Immediate reconstruction applies to cases, such as those discussed in this review, where the phrenic nerve is resected due to tumor infiltration and reconstructed during the same procedure. In cases of unilateral phrenic nerve paralysis, respiratory function may be preserved if the patient has sufficient respiratory reserve; however, the impact on activities of daily living (ADLs) can still be significant (2,8). Additionally, after thymectomy for mediastinal tumor resection, reports of myasthenia gravis exacerbation and subsequent respiratory decline suggest that further respiratory impairment may occur postoperatively (26). Furthermore, nerve atrophy following transection typically progresses within a year, making early reconstruction desirable for improved outcomes (14). The earlier the reconstruction, the higher the likelihood of nerve regeneration and recovery of diaphragm function. Therefore, in cases where malignancy-related phrenic nerve infiltration is suspected, simultaneous reconstruction is recommended to prevent postoperative respiratory failure. Kawashima* et al. *reported that during complete thoracoscopic surgery, direct nerve anastomosis required an average of 5.3 minutes, while anastomosis with a nerve graft took 35.3 minutes (11). These durations are not deemed sufficiently long to adversely affect the patient’s condition, highlighting the feasibility and value of simultaneous reconstruction for functional recovery.

In contrast, delayed reconstruction refers to the surgical intervention performed after a certain period has passed since the onset of phrenic nerve paralysis, and the reconstruction itself is usually the primary purpose of the surgery. Kaufman* et al. reported that among patients who underwent delayed phrenic nerve reconstruction an average of 19 months after the onset of unexpected diaphragmatic paralysis due to various causes, 88% exhibited functional improvement with the aid of short-term diaphragm pacing (13). Similarly, Latreille et al. *successfully performed phrenic nerve reconstruction in a 5-year-old girl with a traumatic spinal cord injury using the same approach (27). Generally, delayed reconstruction presents challenges for nerve regeneration, and outcomes may be suboptimal, necessitating careful patient selection. In one study, patients eligible for delayed reconstruction presented with persistent symptomatic hemidiaphragmatic paralysis, demonstrated by stable findings on nerve conduction studies and sniff tests over a period of at least 8 months (28). However, promising results from some institutions suggest that the indications for delayed reconstruction may be broadened in the future (24,28).

Surgical techniques of immediate phrenic nerve reconstruction

Reports on immediate phrenic nerve reconstruction following malignant tumor resection with concomitant phrenic nerve resection remain limited. The available cases are summarized in Table 2. Three reports describe procedures performed via open surgery, including a total of three cases (14-16), while six cases in one report were conducted entirely using VATS (11), and one case utilized RATS (12).

Immediate phrenic nerve reconstruction is generally categorized into two main direct anastomosis (Figure 1A) and nerve grafting (Figure 1B-1D). When tumor infiltration is localized and nerve resection is minimal, direct anastomosis may be feasible, provided the nerve stumps can be approximated. Care must be taken to avoid tension between the proximal and distal nerve ends, necessitating gentle manipulation for proper alignment (11,16). However, if a larger segment of the phrenic nerve is resected due to extensive tumor involvement and direct anastomosis is not feasible, interposed nerve grafting is necessary to bridge the defect. For cases requiring nerve grafting, the phrenic nerve ends and the graft itself should be sharply cut to optimize alignment. The selection of an appropriate graft is discussed later in this review, but the graft should be slightly longer than the estimated gap to prevent excessive tension. Following harvest, the graft’s proximal end is aligned with the central stump of the phrenic nerve, and the distal end is aligned accordingly before anastomosis (11,12). While the success of nerve grafting is highly dependent on surgical technique, most reviewed reports indicate functional recovery.

Nerve reconstruction, particularly in plastic surgery, is a well-established procedure that requires meticulous preparation of the nerve ends and precise alignment of the stumps (29). Especially during tumor resection, it is critical to prevent thermal injury to the nerve ends and ensure that nerve transection is performed using scissors to create flat, well-defined edges for anastomosis (11,29). Suturing is mostly performed using various monofilament sutures, including 8-0 non-absorbable sutures (14-16) and 4-0 or 6-0 absorbable sutures (11). In open surgery, magnification loupes or microscopes are commonly employed to facilitate precise suturing (14-16). Although VATS and RATS provide magnification, caution is required to avoid excessive manipulation of the nerve, as these techniques demand advanced suturing skills (11,12).

Types of nerve grafts used in phrenic nerve reconstruction

Autologous nerve grafts, harvested from the patient’s own body, are commonly used for phrenic nerve reconstruction (Figure 1B-1D). It is essential to ensure that the harvested nerve is of adequate length and caliber to effectively bridge the defect in the damaged phrenic nerve. Careful selection of the donor site is necessary, particularly when the harvested nerve performs other critical functions (30). The types of nerve grafts used for phrenic nerve reconstruction are summarized in Table 3.

Some studies have successfully utilized intercostal nerves for phrenic nerve reconstruction, reporting favorable outcomes (11,12,24). Intercostal nerves have also been used in brachial plexus reconstruction, with reports demonstrating successful motor function recovery (31). The intercostal nerve, a motor nerve that innervates the chest wall, plays a role in respiration similar to the phrenic nerve. The 7^th^ to 11^th^ intercostal nerves contain a greater number of nerve fibers than the upper intercostal nerves (31). In VATS, if the main thoracoscopic port is placed at the 6^th^ intercostal space, the 7^th^ or 8^th^ intercostal nerve may be a suitable candidate for harvesting due to improved accessibility. The average time required from intercostal nerve harvesting to phrenic nerve reconstruction is 35.3 minutes, indicating that the procedure is feasible even in a thoracoscopic setting (11). Harvesting intercostal nerves from the chest wall intrathoracically eliminates the need for an extra skin incision, making this approach less invasive compared to other grafting methods. As a drawback, this method can be technically difficult in the presence of severe pleural adhesions or limited visualization through sternotomy.

Schoeller* et al. *reported the use of the sural nerve, a sensory nerve located on the posterior aspect of the lower leg, for nerve grafting in phrenic nerve reconstruction after resecting thymoma combined with the left phrenic nerve, pericardium, pleura, lung parenchyma, and a patch of the ascending aorta through sternotomy (14). Using magnification loupes, they successfully achieved functional recovery within 9 months. The sural nerve is relatively easy to harvest, and its removal typically results in minor sensory loss without significant impact on motor function. However, a notable drawback is the creation of an additional surgical site on the lower leg, which may be less desirable in the context of minimally invasive thoracic surgery.

In a case of synovial sarcoma in the anterior mediastinum, where one-third of the right phrenic nerve and two-thirds of the left phrenic nerve were infiltrated and subsequently resected, the remaining portion of the left phrenic nerve was utilized to reconstruct the right phrenic nerve, ultimately leading to functional recovery (4,15,32). Although the use of a phrenic nerve graft resulted in favorable functional outcomes, it came at the cost of sacrificing function on one side of the diaphragm. However, if an alternative nerve graft, such as an intercostal nerve, had been used, it might have allowed for functional recovery on both sides of the diaphragm.

Evaluation of functional recovery and recovery time after immediate phrenic nerve reconstruction

Postoperative evaluation of phrenic nerve reconstruction is critical for assessing how effectively the reconstructed nerve has restored respiratory function. Various methods are employed to assess recovery, including clinical observations such as the presence of dyspnea and breathing patterns, X-rays to evaluate the expiratory and inspiratory phases during forced breathing, fluoroscopy for the sniff test, and ultrasound to visualize real-time diaphragm movement. Additionally, computed tomography (CT) and magnetic resonance imaging (MRI) are utilized to assess diaphragm shape and positioning, while quantitative pulmonary function tests, nerve conduction studies, blood gas analysis, and exercise tolerance tests provide further insights into respiratory function and recovery (22,28). A combination of these methods allows for a detailed assessment of the surgical outcome and facilitates the planning of additional treatments or rehabilitation as needed.

Reports indicate that phrenic nerve recovery times can vary, with some cases showing improvement in a few weeks to months (11,12,15,16), while others report recovery taking up to a year (14). Variations in recovery time following immediate phrenic nerve reconstruction may be influenced by multiple factors. Whether the procedure involves direct anastomosis or nerve grafting is a key determinant, as the former typically allows for more rapid reinnervation potentially due to superior vascularization at the repair site (33). Adequate blood supply may promote nerve regeneration. Other contributing factors include the extent of the initial nerve damage, the type and length of nerve graft utilized, and patient-specific variables such as age, comorbidities, and intrinsic regenerative capacity. Engagement in postoperative respiratory rehabilitation can contribute to recovery. Additionally, differences in the timing and method of postoperative evaluation may affect the interpretation of functional recovery. Basic research has demonstrated that peripheral nerves typically regenerate at a rate of approximately 1 mm per day (34). In a rat model investigating reinnervation of the cardiopulmonary vagus nerve following transection and subsequent re-anastomosis, complete recovery of nerve conduction velocity in myelinated fibers was observed within 3 to 6 months post-repair (35). Given that nerve regeneration is a gradual process, as demonstrated in both experimental and clinical studies, ongoing assessment and long-term follow-up are crucial for tracking functional recovery.

Limitations

This review has several limitations. First, the number of reported cases on immediate phrenic nerve reconstruction, particularly during tumor resection, remains limited. Second, there is no standardized approach for phrenic nerve reconstruction, resulting in considerable variability in indications, surgical techniques, and graft selection. Third, assessment of functional recovery lacks consistency, as diverse methods such as clinical observation, imaging, and nerve conduction studies yield heterogeneous results. Additionally, this study employed a narrative review format, which inherently carries limitations in validity and reproducibility compared to a systematic review, as it lacks predefined criteria for study selection and risk-of-bias assessment. Finally, no standardized tool or questionnaire was used to evaluate the quality of included studies, which may affect the robustness of the conclusions drawn.

Conclusions

Immediate phrenic nerve reconstruction represents a highly effective strategy for preserving respiratory function during tumor resection. Among nerve graft options, the intercostal nerve is particularly suitable due to its anatomical compatibility and the ability to harvest it without additional incisions. Moreover, advancements in minimally invasive approaches, such as VATS and RATS, enable precise reconstruction with minimal surgical burden. Notably, the additional time required for reconstruction is relatively short and does not significantly impact the patient’s condition. Given these advantages, immediate reconstruction with intercostal nerve grafts may be considered a feasible and beneficial approach. Future research should aim to establish standardized surgical techniques and consistent methods for evaluating functional recovery following phrenic nerve reconstruction. Larger, prospective studies are needed to clarify optimal graft choices, timing of reconstruction, and long-term outcomes, ultimately enabling the development of evidence-based clinical guidelines.

Supplementary