A 45-year-old female with a past medical history of invasive ductal cell carcinoma status post bilateral mastectomy and lymph node dissection 8 months ago, along with hypertension and hypothyroidism, was referred to the pain clinic by her primary care provider for progressive right-sided chest wall pain. She describes the pain as having been present since surgery, constant, and feeling like burning and stabbing. She states that the pain did not initially bother her much, but it has worsened within the past few months. She experiences intermittent paresthesias in her right hand but without noticeable weakness. In addition, she has noticed progressive swelling of her right arm. She has no recent unintentional weight loss, night sweats, or symptoms suggesting myelopathy or cauda equina syndrome. Her current pain medications include ibuprofen 600 mg three times daily as needed and oxycodone 7.5 mg every 4 hours as needed. She has been taking  oxycodone at least 2 times daily for the past 3 months.

Physical exam reveals her right upper limb is moderately edematous, has full strength, and does not demonstrate vasomotor changes. She has allodynia of her right chest wall from her mid-axillary line to her sternum ranging from ribs 4-6. Surveillance imaging last month was negative for metastatic disease, and a right upper-limb duplex ultrasound was negative for a deep vein thrombosis.

She has been undergoing physical therapy for her right upper-limb lymphedema, which has helped moderately, but she still has had significant swelling and skin changes in her right upper limb.

Today, she would like to discuss treatment options.

Questions

1. What is post-mastectomy pain syndrome and how does it typically present? 

Post-mastectomy pain syndrome (PMPS) is a chronic pain disorder defined by a cluster of symptoms that are typically observed in patients who have undergone mastectomy. The syndrome also can occur with lumpectomy, breast reconstruction, lymph node dissection, and chemoradiation therapies to the breast. PMPS presents as neuropathic pain likely due to nerve injury; it is described as sharp, stinging, burning, or shooting pain with hyperesthesia.¹ The pain is usually localized to the anterior and lateral chest wall, axillary area, and the medial aspect of the upper arm.² The pain typically persists for more than 3 months after surgery¹ with studies reporting from 3 to 6 months or longer. The International Association for the Study of Pain recognizes 3 months as the point to consider pain to be chronic but states that 6 months is preferred for study and investigation purposes.³

According to the International Agency for Research on Cancer, breast cancer is the second most commonly diagnosed cancer, after lung cancer.⁴ In 2012, an estimated 1.67 million people were diagnosed with breast cancer.⁴ PMPS affects 25%-60% of individuals who undergo procedures for breast cancer.⁵ Women who are younger, have undergone full axillary lymph node dissection, and have more advanced tumor staging and treatment with adjuvant radiation therapy are at higher risk for developing PMPS.⁶ In addition, the likelihood of developing more severe chronic pain has been associated with premorbid anxiety, depression, sleep disorders, and lower education. ^7,8

Another term for this condition, persistent post-mastectomy pain, has been used in the literature to include other complications leading to chronic pain with neuropathic etiology such as  musculoskeletal causes like frozen shoulder and lymphedema.^6,9 Lymphedema is an abnormal accumulation of interstitial fluid due to infection, injury, or congenital malformation of the lymphatics. With breast surgery, patients are at a higher risk of developing lymphedema due to the dense lymphatics within the axillary region. Women may experience a gradual onset of tightness, chest pain, or swelling.¹⁰ Chest pain is described as aching, heavy, and tight. Range of motion can be limited because of tightness from fluid accumulation. With chronic lymphedema, the tissue becomes scarred and skin becomes hyperkeratotic, with dermal thickening. Dermal thickening and scarring will further limit movement and worsen pain. On physical exam, lymphedema is usually observed ipsilaterally to the surgical site. When applying firm pressure to the edematous tissue, swelling is typically soft with pitting. Dermal thickening can be observed with dry and firm skin if the lymphedema worsens. A positive stemmer sign is also suggestive of lymphedema, which is characterized by a thickened skin fold at the base of the second digit in the upper or lower extremity.¹¹ A positive stemmer sign is when the provider cannot lift the skin of the affected limb compared to the contralateral extremity. Limb volume and circumference also should be measured on examination.

2. Based on the patient’s history of pain after her mastectomy, what are other diagnoses to consider? 

Differential diagnoses should be considered when evaluating patients with post-mastectomy pain. Although patients frequently experience post-surgical pain for a short period, it is important to rule out other conditions, especially more serious etiologies that warrant further evaluation and management. Typically, patients with post-mastectomy pain have persistent pain that is burning, sharp, tingling in nature.

Providers should always be wary of local recurrence of breast cancer and metastasis, especially when new or worsening pain is reported. When evaluating for PMPS, breast cancer recurrence should be on the differential; it is a serious, consequential diagnosis that should be definitively ruled out. According to the literature, an estimated 2%-3% of patients who undergo mastectomy will have chest wall or locoregional breast cancer recurrence.^12,13 Breast cancer recurrence is highest in the first few years of treatment.^14,15 Signs of breast cancer recurrence include lump in breast, scar tissue around the surgical site, skin that is inflamed or changing, and breast pain. Metastatic breast cancer may present with bone pain because bones are a common site of metastasis. Breast cancer recurrence can be further evaluated through history taking, physical exam, and imaging.

With any surgery, infection and inflammation are common postoperative risks. Mastitis, superficial thrombophlebitis, cellulitis, and abscess can occur early in the postoperative period.¹⁶  Phantom breast pain is another differential diagnosis, characterized as painful and distressing sensations around the areolar region or involving the entire breast. Phantom breast pain can be chronic, lasting for many years. This pain is believed to be the result of neuronal injury causing spontaneous hyperexcitability and central nervous system sensitization. If the patient has had prior chemotherapy, chemical neuropathy could be part of the differential to consider. This typically presents with distal and symmetric distribution of pain and paresthesia on physical exam and history as well as electrodiagnostic testing.¹⁷

Scarring or benign but disorganized growth of breast and axillary tissue can occur from surgical changes, causing neuromas to form.¹⁸ Neuromas can cause chronic pain that is burning, sharp, tingling, or numb. However, a solid and firm mass would be palpated on physical exam. Lymphedema can present with gradual soft tissue expansion of the arm. Lymphedema is typically seen after axillary dissection, radiation therapy, or lymphatic obstruction from tumor burden.¹⁹ Other diagnoses that can contribute to the patient’s clinical scenario include musculoskeletal disorders such as adhesive capsulitis, rotator cuff injury, tendonitis, and myofascial pain.²⁰ Radiographic imaging, history, and physical exam can help to rule out musculoskeletal etiology. In addition, cervical radiculopathy and brachial plexopathy should be considered. They can present with acute or subacute pain, paresthesias, and weakness in the upper limb. Although a rare complication, individuals who undergo radiation can develop radiation-induced brachial plexopathy months to years after treatment.²¹ However, 0.5% of individuals presenting with a plexopathy may have metastatic disease; therefore, advanced imaging must be performed.²²

3. When post-mastectomy syndrome is suspected, how should providers further evaluate the condition? 

A thorough history is vital to characterize the pain for any workup and diagnosis. Burning, electric, shooting, or stabbing pain or paresthesia of the axilla, chest wall, or ipsilateral extremity, after surgery or chemoradiation to the area are characteristic of PMPS.¹ Some patients also experience reduced range of motion in the shoulder, decreased shoulder strength, or loss of hand-grip strength.²³

Physical exam is equally important to identify post-surgical changes to the chest wall, breast, and axillary tissue, without infectious signs or cancer recurrence. Motor or sensory abnormalities in a dermatomal or nerve-like distribution are also present. Sensory changes include hyper- or hyposensitivity at the surgical site or ipsilateral extremity. Motor changes include decreased range of motion and strength on the ipsilateral extremity, such as the shoulder or arm.²⁴

Imaging is usually not necessary to confirm a PMPS diagnosis. However, further imaging can help rule out other diagnoses. A mammogram, MRI, or breast ultrasound can rule out infectious causes or cancer recurrence. X-ray can be used to determine cancer metastasis to the bone, fractures, or arthritic changes. Lab tests such as a complete blood count, cancer biomarkers, or inflammatory markers can be used to rule out rheumatologic, infectious, or cancerous etiologies. An electromyography and nerve conduction study can be performed to further evaluate for radiculopathies, plexopathies, or neuropathies.

4. What is the general pharmacologic and integrative management for PMPS and other associated complications? 

Medical and integrative management largely depends on patient preferences. For pharmacologic therapy, which is first-line in PMPS treatment, gabapentin and antiepileptic medications such as carbamazepine have been used with proven efficacy.²⁵ Serotonin-noradrenaline reuptake inhibitors, venlafaxine, duloxetine, and tricyclic antidepressants such as nortriptyline and amitriptyline are alternatives for neuropathic pain in PMPS.²⁶ In addition to oral medications, topical capsaicin, topical morphine, and perioperative application of eutectic mixture of local anesthetics cream have proven to significantly reduce pain.^27-29

Physical therapy is another treatment modality for patients with PMPS. The major principles behind physical therapy for PMPS include joint mobility restoration, myofascial release, stretching for tense muscle, and shoulder muscle strengthening.³⁰ Designing an individualized physical therapy plan addressing the four major principles in a multimodal approach has been beneficial for patients with breast cancer pain and postoperative pain.³¹ Adhesive capsulitis is a common musculoskeletal condition that occurs after mastectomy and lymph node dissection.³² Patients with cancer are at an increased risk of developing adhesive capsulitis due to inflammation related to the malignancy. When patients experience postoperative shoulder range-of-motion restrictions as well as pain and decreased active and passive range of motion at the glenohumeral joint, adhesive capsulitis should be suspected. Diagnosis is made by physical exam; however, ultrasound and/or MRI can be used to rule out other causes of shoulder pain. EMG also can be used to rule out a neurological cause of weakness, such as a radiculopathy. Early recognition of this condition is important. Glenohumeral joint steroid injection can decrease inflammation and augment physical therapy.³³

Lymphedema is another complication that can contribute to PMPS and significantly reduce quality of life. This is conservatively managed by complete decongestive therapy, which is typically led by an occupational or physical therapist.³⁴

In addition to physical therapy and pharmacological management, many patients use a form of complementary and/or alternative medicine. Due to the lack of strong evidence supporting some of the alternative therapies, providers should not rely solely on these management options. Complementary therapies include hypnosis, acupuncture, and music therapy.^35-37

Preoperative and postoperative cognitive behavioral therapy have both demonstrated significant improvement in pain outcomes of patients with breast cancer.^38,39

5. What other treatment options do patients have to augment oral medication therapy or if they have failed oral medication therapy?

Several interventional pain, surgical, and investigational procedures have been shown to provide pain relief for patients experiencing PMPS (Tables 1-3).

Table 1: Non-pharmaceutical, non-surgical treatments for post-mastectomy pain syndrome

Table 2: Surgical treatments for post-mastectomy pain syndrome

Table 3: Investigational treatments for post-mastectomy pain syndrome

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