Neoplastic Lumbosacral Plexopathy

Etiology

Pathologic involvement of the lumbar or lumbosacral plexus can result from many causes ranging from tumors to trauma. While trauma is more common with brachial plexopathies, neoplastic processes involving adjacent pelvic organs are more commonly implicated with lumbar and lumbosacral (LS) plexopathies. The retroperitoneal and the intrapelvic location protects it from trauma. It can, however, be affected following high-velocity injuries, pelvic fractures, gunshot wounds, and rarely intrapartum from compression from the fetal head.[1][2] Radiation is a frequently used treatment modality for pelvic tumors, which can affect the lumbosacral plexus. Plexopathy of the LS spine can also be caused by microvasculitis of the plexus from conditions like diabetes or post-surgical conditions, infections of adjacent organs, or infiltrative causes such as amyloidosis.[3]

Mechanisms of Lumbar Plexus Involvement From Tumors

Neoplasms are the most common cause of lumbar plexopathy. Plexopathy is part of the initial presentation of cancer in approximately 15% of patients. Plexus involvement from cancers is seen in about 1% of the cancers.[4] The most commonly reported tumors are adenocarcinomas of the colorectum, cervical or uterine cancers, lymphomas, and retroperitoneal sarcomas. Neoplasm as the cause for LSP should be higher on the differential, especially in patients with a history of cancer. 

• Direct tumoral invasion from adjacent pelvic organs:

LSP lies near many abdominal and pelvic organs, including the bladder, colon, ovaries, and cervix, and can be involved as an infiltrative or a compressive process.

• Distant metastases

These tumors, like elsewhere, can lead to distant metastases and cause lumbosacral plexopathy. The most common ones arise from the lung, the breast, and lymphomas.

• Compression of lumbar plexus from enlarged metastatic lymph nodes:

Enlarged retroperitoneal lymph nodes can cause direct compression of the plexus and cause LSP.

•  Epineural spread or Intraneural lymphomatosis:

Lymphomas can cause direct endoneurial invasion by the neurotrophic neoplastic cells leading to an entity called intraneural lymphomatosis.[5] It is mostly seen in Non-Hodgkin’s lymphoma (NHL) patients with a reported incidence of 0.2% in all NHL patients, of which the most common is the diffuse large B cell lymphoma (DLBCL).[6] The peripheral nervous system serves as a sanctuary site for lymphoma cells can where they can escape the effects of chemotherapy and thereby can present as a primary manifestation of the lymphoma or as a relapse in patients who are otherwise in hematological remission. Clinical presentation can manifest as a very painful neuropathy that may be symmetric or asymmetric.[7][8] The tumor can invade the plexus directly or track along the connective tissue or the epineurium of nerve trunks. This tendency to infiltrate along the nerves, which is difficult to demonstrate with imaging procedures, may explain the frequent discordance between the physical exam and lack of findings on imaging such as CT or MRI.

• Perineural spread from prostate cancers[9]

This is a rare but reported mode of spread, especially in prostate cancer. Capek et al. reported a case of bilateral LSP from prostate cancer, the probable mechanism of spread was postulated to be via the dural sac, which serves as a bridge to connect to the opposite side.

• Radiation for pelvic tumors (radiation-induced lumbosacral plexopathy - RILSP).

Tumors in the lumbosacral region, which are radiation-sensitive such as ovarian, cervical, colon, testicular, and prostatic tumors, and Hodgkin’s lymphoma involving the paraaortic and pelvic nodes, can lead to RILSP. The effects of radiation can be seen even up to 6 months after the initial radiation.[3] Mechanisms of injury include direct toxic effects on axons, on the vasa nervorum, with secondary microinfarction of nerve with a dose-related escalation in effect.[10] Concomitant chemotherapy can act synergistically to increase the risk of radiation plexopathy.

• Primary neural tumors – neurofibroma, perineuroma 

Rarely, primary neural tumors can manifest with plexopathy.

Epidemiology

In cancer patients, the frequency of neoplastic lumbosacral plexopathy is 0.71% as opposed to 0.43% in neoplastic brachial plexopathy. Neoplastic lumbosacral plexopathy tends to be more common with pelvic and colorectal tumors but also has been seen in association with lymphomas and breast cancer.[11]

Pathophysiology

Neuroanatomical Considerations

For the astute clinician to localize the area of involvement, knowledge of the basic neuroanatomy of the lumbar plexus is helpful so that the clinician may employ the necessary diagnostic and therapeutic procedures. It is also important for the clinician to distinguish plexus involvement from neoplastic epidural cord compression or meningeal involvement as both phenomena can have a similar presentation and may develop simultaneously.

A lumbar plexus is a group of nerves that provides innervation to the muscles of the back and legs. It is derived from the nerve roots of L1 to S5. The lumbosacral plexus is anatomically divided into upper lumbar (L1–L4) and lower lumbar/sacral (L5–S5) portions at the border of the true pelvis. These plexuses are connected by the lumbosacral trunk (from L4–L5), which courses over the sacral ala at the pelvic brim. The lumbar plexus forms within the iliacus muscle just lateral to the L1–L4 vertebral bodies, and lies in close proximity to pelvic organs.[11]

Upper Lumbar Plexus

The iliohypogastric (L1), ilioinguinal (L1), and genitofemoral (L1, L2) nerves, which carry sensory fibers from the lower abdominal skin, lateral genitalia, and upper thigh are direct branches of the upper plexus. The L1–L4 roots join to form ventral (anterior) and dorsal (posterior) divisions.

The posterior division forms the lateral femoral cutaneous nerves of the thigh (L2–L3), which

provide sensation to the lateral hip and thigh, and the femoral nerve (from L2–L3), which supplies motor innervation of the iliopsoas and quadriceps muscles, and sensory innervation to the anterior thigh and medial upper foreleg (saphenous branch).

The anterior division forms the obturator nerve (from L2–L4), which supplies motor function to the adductors and gracilis muscles and sensory supply to the medial thigh.

Lower Lumbar Plexus

The posterior division of the lower plexus gives rise to the superior gluteal nerve (L4-S1) which supplies the gluteus medius, minimus, and tensor fascia lata, the inferior gluteal nerve (L5-S2) which supplies the gluteus maximus and the fibular portion of the sciatic nerve.

The anterior division forms the pudendal nerve (S2,3,4), posterior cutaneous nerve (S1,2,3), and the tibial portion of the sciatic nerve.

History and Physical

Clinical syndromes may present with upper plexus (L1-L4 (, lumbosacral trunk (L4-L5), and lower plexus (S1-2 S4) involvement. Plexopathy is typically unilateral but can be bilateral in 25% of the patients.

Pain is a predominant symptom (98%) with lumbar-sacral plexopathy, and the absence of pain should prompt consideration of alternative diagnosis.[10] Lumbosacral plexopathy typically begins with leg pain, which is followed soon after by numbness and weakness. The pain tends to be dull and aching, with a superimposed sharp pain in a radicular distribution. Pain is worse when the patient is supine but can be exacerbated with prolonged ambulation, sitting, or a Valsalva maneuver. If there is the involvement of the iliopsoas muscles, the patient may tend to rest with hips flexed (as seen with meningitis).[11] Pain can involve the costovertebral area radiating to the upper thigh – in lesions affecting the upper lumbar plexus.[3] Pain involves the lower back, buttocks, thighs, or hips when the lower lumbar plexus is affected.

Neurologic deficits occur in the majority of the patients (60%) and usually appear later. This is in contrast to radiation-induced plexopathy, which present with sensory disturbances before pain. The types of deficits in order of frequency of occurrence include motor weakness (86%), sensory disturbance (73%) followed by hyporeflexia (64%).[10] There may be leg edema (47%) noted in some patients. Weakness usually affects thigh muscles, and patients may have trouble getting up from a chair or walking up and down the steps.

The lower plexus, when typically involved, is associated with colorectal neoplasms and carcinoma of the cervix. The presentation is with pain radiating down the posterior leg calf or posterior thigh. There is a description of "hot, dry foot" from the involvement of corresponding sympathetic components of the lower plexus in about a third of the patients. Numbness is usually in the groin, anterolateral or posterior thigh, or over the dorsum of the foot. Occasionally a foot drop may be seen.

Bilateral involvement of the plexus can cause incontinence and impotence. Rarely, identifying a palpable rectal mass decreased anal sphincter tone, and sensory loss of the perineum may be seen.[10]

Evaluation

A detailed history and a thorough physical exam are vital. A history of cancer in a patient presenting with symptoms suggestive of LSP should raise the suspicion of neoplastic LSP. The diagnosis is more challenging in patients who had cancers that were treated with radiation to decide if the LSP is neoplastic or radiation-induced in origin. Plexopathy may present with unilateral or bilateral symptoms.[11]

Neuroimaging with CT or MRI of the LSP is useful to evaluate for underlying tumor. MRI is more sensitive to providing anatomic detail and is the preferred modality of imaging. Typically, there is an increased T2 signal in the plexus with tumor involvement and with RILSP. However, when the lumbosacral trunk is involved or if there is Gadolinium enhancement on T1 sequence, Imaging may show enlarged nerves with peripheral, irregular enhancement with accompanying cystic component in contrast to benign causes of LSP, which show smooth peripheral enhancement. If there is a regional tumor noted on clinical exam or by imaging, it may support the diagnosis of tumor plexopathy.

Positron emission tomography (PET) with 2-fluorodeoxyglucose (2-FDG) can be helpful to detect an active neoplasm in the area of the plexus.

Electromyographic studies are useful to localize the involvement of the plexus.

• Nerve conduction studies may show decreased amplitudes of compound motor and sensory nerve action potentials asymmetrically. Conduction velocities are normal or mildly reduced. A prolonged F wave may be present on the affected side.
• Needle electromyography would likely show more extensive denervation compared to the clinical findings. The absence of paraspinal muscle fibrillation with the involvement of muscles from at least two lumbosacral root levels from at least two peripheral nerves would be characteristic.
• EMG would be useful to plan radiation in cases.
• Myokymic discharges may be seen in RILSP.

Nerve biopsy: Rarely a fascicular nerve biopsy may be diagnostic in cases with neoplastic etiologies.

Cerebrospinal fluid (CSF) analysis: CSF cytology and protein may be elevated in neoplastic causes of lumbar plexopathy.

Treatment / Management

Management of neoplastic LSP usually needs radiotherapy, with slightly higher subjective than objective response rates. Treatment sometimes needs an average of 4 months before a response is seen. Response rates are better when the radiation dose is above 300cGy. Side effects of radiation include dysesthesias, causalgia, and chronic pain syndromes which in turn need a multi-modality approach including medications, lidocaine patches, transcutaneous electrical nerve stimulation (TENS) units, sympathetic ganglion blocks, and rarely plexus dissection and neurolysis.

Management of neoplastic LSP usually needs radiotherapy, with slightly higher subjective than objective response rates. Treatment sometimes needs an average of 4 months before a response is seen. Response rates are better when the radiation dose is above 300 cGy. Side effects of radiation include dysesthesias, causalgia, and chronic pain syndromes which in turn need a multi-modality approach including medications, lidocaine patches, transcutaneous electrical nerve stimulation (TENS) units, sympathetic ganglion blocks, and rarely plexus dissection and neurolysis.[10]

Pain management and physical therapy are critical components of managing lumbosacral plexopathy related to neoplastic causes. There is not a lot of data supported by randomized controlled trials. Pain management includes - physical ( heat, cold, TENS), oral pharmacologic (various classes of medications (antidepressants including tricyclics, selective serotonin receptor inhibitors, selective norepinephrine serotonin receptor inhibitors, antiepileptic medications such as gabapentin and pregabalin as well as opiates if the pain is refractory) and topical pharmacologic (lidocaine patch, capsaicin cream). In some cases, intervention with spinal cord stimulators and/or intrathecal baclofen may be required. As for physical therapy, strengthening exercises to improve motor imbalance, improve flexibility and gait would be useful. Orthotic devices are provided where it may aid with ambulation.

Differential Diagnosis

Cancer Related Differential Diagnoses of Lumbosacral Plexopathy

It is important for the clinical to consider other differential diagnoses for cancer-related lumbosacral plexopathies.

• Radiation-induced plexopathy is the most common and can be hard to differentiate.
• Intra-arterial chemotherapy with resultant chemotoxicity to the plexus
• Paraneoplastic plexopathy
• Postinfectious plexopathy
• Leptomeningeal involvement or epidural cord compression
• Primary plexus tumors. 

Radiation-induced Lumbosacral Plexopathy

Patients with pelvic tumors and other tumors with metastasis to the abdominal pelvic region receive regional radiation therapy. For the clinician, the important clinical dilemma faced is distinguishing radiation-induced plexopathy from recurrent tumor. The two conditions may coexist in the same patient adding to the complexity.

Mechanisms of plexus injury related to radiation include direct toxic effect on the axons in the vasa vasorum with secondary microinfarction. The overall frequency of radiation-induced plexopathy (cervical, brachial, lumbosacral) in treated patients is 1.8 to 4.9%. Plexopathy can develop across a wide time range from 3 months to 14 years with a median onset at about 1.5 years post-radiation. Hypofractionated regimens and lower total radiation dose decrease the risk of radiation-induced plexopathy. Chemotherapy may potentiate the development of radiation plexopathy.[11]

Certain distinguishing clinical features help differentiate radiation plexopathy from neoplastic lumbosacral plexopathy.

• Radiation plexopathy often presents with dysesthesias and numbness, and often there is lymphedema.

• Pain, unlike in neoplastic LSP, is usually less frequently encountered (10%), milder in RILSP, and appears later.
• Bilateral plexus involvement is more common with Radiation plexopathy.
• There may be periods of quiescence between periods of exacerbation.
• Progression is generally slower than with neoplastic plexopathy.
• Electromyography (EMG) in RILSP typically shows myokymic discharges, seen in up to 60% of the patients, however, this does not rule out tumor recurrence.
• An increased T 2 signal may be seen on MRI with both, but nerve enhancement is not seen with RILSP (but seen with neoplastic LSP). Local tissue necrosis may be noted with RILSP
• Positron emission tomography (PET) with 2-fluorodeoxyglucose (2-FDG) may be of value in the identification of recurrent tumors. PET scan is usually negative with RILSP. 

Management of RILSP is symptomatic, with some data supporting the use of hyperbaric oxygen. Nerve transfers/reconstruction have been tried with minimal success.

Prognosis

Patients who present with neoplastic plexopathy have a poor prognosis and a shorter life expectancy, usually as a consequence of advanced cancer stage. Measures should be aimed at managing the primary neoplasm but also at improving quality of life, and managing pain syndromes.

Complications

Side effects of radiation include dysesthesias, causalgia, and chronic pain syndromes which in turn need a multi-modality approach including medications, lidocaine patches, transcutaneous electrical nerve stimulation (TENS) units, sympathetic ganglion blocks, and rarely plexus dissection and neurolysis.