Clinical manifestations and diagnosis of postmastectomy pain syndrome

INTRODUCTION — Postmastectomy pain syndrome (PMPS) is a type of chronic neuropathic pain disorder that can occur following breast cancer procedures, particularly those operations that remove tissue in the upper outer quadrant of the breast and/or axilla [1-5].

Pain can be severe enough to cause long-term disabilities and interfere with sleep and performance of daily activities including use of the affected arm, leading to shoulder adhesive capsulitis (frozen shoulder) or complex regional pain syndrome (causalgia) [4,6-10]. Altered sensation can also be observed within the distribution of the injured nerve, although it may not be as debilitating as chronic pain [10]. The pain can also seriously affect the patient's mood, everyday activities, and social function and create an economic burden for the health care system. (See "Frozen shoulder (adhesive capsulitis)" and "Complex regional pain syndrome in adults: Pathogenesis, clinical manifestations, and diagnosis".)

DEFINITION — Postmastectomy pain syndrome (PMPS) is a type of neuropathic pain, a complex chronic pain state that is typically associated with nerve fiber injury. (See "Evaluation of chronic non-cancer pain in adults", section on 'Neuropathic pain' and "Approach to the management of chronic non-cancer pain in adults", section on 'General approach'.)

The pain is typically localized to the anterior/lateral chest wall, axilla, and/or medial upper arm and persists more than three months after surgery when all other causes of pain, such as infection or recurrence, have been eliminated [11,12]. The characteristics include classic features of neuropathic pain such as burning, tingling, shooting, stinging, or stabbing pains and hyperesthesia [13].

The definition of PMPS has not been standardized. The current definition for PMPS used by the International Association for Study of Pain is "chronic pain in the anterior aspect of the thorax, axilla, and/or upper half of the arm beginning after mastectomy or quadrantectomy and persisting for more than three months after surgery" [14]. While some studies define PMPS as pain persisting for more than three months, and others define it as pain persisting for more than 18 months, the author of this topic defines PMPS as pain persisting for more than six months after breast surgery.

PATHOPHYSIOLOGY — Postmastectomy pain syndrome (PMPS) can be caused by direct nerve injury (eg, transection, compression, ischemia, stretching, and retraction) during the breast cancer operation or from subsequent formation of a traumatic neuroma or scar tissue [5,6,13,15-17]. Alternatively, indirect nerve injury can occur intraoperatively or postoperatively. Intraoperatively, retraction and poor arm positioning can stress and compress peripheral nerves [4]. Postoperatively, stretch and compression injuries can occur from hematoma, seroma, and scarring [18]. Different types of sensory disturbances (eg, tingling, burning, numbness) can then result from nerve injury [11].

The breast parenchyma and overlying skin are innervated by the anterior and lateral cutaneous branches of intercostal nerves T3 to T6 (figure 1). The lateral cutaneous branch of the second intercostal nerve crosses the axilla to innervate the upper medial arm and the anterolateral chest wall such that numbness or pain in the axilla and upper inner arm can be combined with pain over the upper lateral breast quadrant, and such that pain in the breast can be caused by arm movements, hence the term "intercostobrachial nerve" or ICBN [19]. The ICBN is most frequently injured during axillary dissection, which is a major risk factor for PMPS. (See 'Type of procedure' below.)

Breast cancer operations can damage the brachial plexus, ICBN, lateral cutaneous branch of the second intercostal, and long thoracic and medial and lateral pectoral nerves that innervate the breast, chest wall, and ipsilateral extremity (figure 2 and figure 3 and figure 4) [6,15]. In particular, surgical procedures in the upper outer quadrant of the breast and axilla, where major nerves traverse the operative field, are particularly vulnerable to nerve injury [17,20]. In addition, local radiation treatments and neurotoxic systemic therapy (eg, taxanes, platinum agents, vinca alkaloids) may also exacerbate PMPS [6-8,16,21,22]. (See "Postmastectomy pain syndrome: Risk reduction and management", section on 'Preservation of axillary nerves'.)

INCIDENCE — The overall incidence of nerve injury or impairment and resultant chronic pain following a breast cancer operation ranges from 20 to 72 percent [1,4,6,15,21,23-31]. This variation can be partly explained by discrepancies in terms of definitions used to ascertain postmastectomy pain syndrome (PMPS), timing of assessment, or age group of the population studied. The prevalence also depends, in part, on the extensiveness of the breast and axillary procedure performed.

In addition, the wide variation may also be due to a lack of a standard definition of PMPS, including type, site, and duration of symptoms (eg, chest wall versus ipsilateral arm pain; pain versus paresthesias) as well as the inclusion of patients undergoing immediate or delayed breast reconstructive procedures [15].

RISK FACTORS — The etiology of persistent pain after mastectomy is not clear, although it is likely multifactorial [23,32-34]. Pain is a subjective, multidimensional, and complex phenomenon whose different physiological, sensory, behavioral, sociocultural, affective, and cognitive components interact to determine pain perception and expression. (See "Approach to the management of chronic non-cancer pain in adults", section on 'General approach'.)

Based upon retrospective and prospective studies, the most common variables associated with a higher risk of developing postmastectomy pain syndrome (PMPS) include [8,10,21,35,36]:

Postoperative pain — Patients more likely to develop severe acute postoperative pain include those with preoperative anxiety and age ≤49 years [32]. Severe acute postoperative pain is a risk factor for developing chronic pain [21,22,32,36-39]. In a multivariate analysis of 509 breast cancer patients, patients with severe acute postoperative pain were significantly more likely to develop chronic pain in the ipsilateral arm compared with patients with less intense postoperative pain (odds ratio [OR] 1.68, 95% CI 1.34-2.10) [22]. Patients with severe pain were also more likely to develop chronic pain in the breast (chest wall) area (OR 1.59, 1.28-1.97).

Acute postoperative pain is a consistent modifiable risk factor for PMPS. Therefore, attention to perioperative analgesia is an increasingly important opportunity to reduce the incidence of PMPS. Enhanced recovery after surgery (ERAS) pathways resulting in decreased postoperative pain scores should be considered. Currently, the author uses a multimodality ERAS protocol [40], which includes:

●Preoperative administration of oral gabapentin and acetaminophen.

●Perioperative administration of regional nerve blocks (pectoral blocks type 1 and 2) with liposomal bupivacaine after induction of general anesthesia.

●Intraoperative administration of 5-level pectoral intercostal fascial nerve blocks and serratus nerve blocks once breast is removed off the chest wall.

●Intravenous ketorolac when medically appropriate.

●Postoperative administration of gabapentin around the clock for up to seven days after surgery.

Age at diagnosis — Many studies show increased odds of persistent pain with younger age [14,30,36,39]. The mechanism through which younger age represents a risk factor for PMPS is not well understood. It is possible that younger patients tend to present with higher-grade tumors and may undergo more aggressive treatments including surgery and adjuvant therapies, which may influence the prevalence of chronic pain following breast cancer treatment [16]. Other possible explanations include a reduction in sensitivity of pain receptors in older women [11,41] and increased nerve sensitivity in younger patients [42,43]. It is hypothesized that younger patients are more sensitive to nerve damage, are less likely to tolerate pain, and have increased anxiety, leading to more reports of pain [4,11].

Direct comparisons of studies are constrained by varying definitions of "younger age" [21,26,35].

Body mass index — Several studies have found that the odds of developing chronic pain after mastectomy are associated with higher body mass index (BMI) [37,44]. It is unclear whether this is an independent risk factor or may be attributed to higher risk of surgical complications and lymphedema.

Axillary radiation — Neuropathic pain is a side effect of radiation therapy frequently identified in patients undergoing postoperative breast/axillary radiation treatments and occurring months to years after administration [6-8,16,21,22,37,44]. Radiation fibrosis and chronic inflammation can cause nerve entrapment. In one series, postoperative radiotherapy and neurotoxic chemotherapy, in conjunction with an axillary lymph node dissection (ALND), were felt to contribute to chronic pain that developed in 21 of 30 patients (70 percent) who were pain free for several months after the operation [16].

The following retrospective studies illustrate the effect of postoperative radiation treatments on chronic pain:

●In a multivariate analysis of 509 patients, radiation treatments to the breast and/or axilla were associated with increased risk of chronic pain compared with postoperative patients not receiving radiation therapy (OR 2.18, 95% CI 1.38-3.43 and OR 2.29, 95% CI 1.47-3.58, respectively) [22].

●In a survey of 569 women undergoing breast cancer procedures, more stage I patients treated with breast conservation therapy (partial mastectomy, axillary node dissection, radiation therapy) had developed chronic pain in the breast scar compared with women undergoing a modified radical mastectomy (total mastectomy with axillary dissection) without radiation treatments (45 versus 32 percent) [7]. Women undergoing breast conservation therapy also had more chronic ipsilateral arm pain (37 versus 28 percent) as well as paresthesias in the breast scar (46 versus 35 percent) and ipsilateral arm (51 versus 38 percent).

Type of procedure — An ALND serves as a surrogate for nerve injury contributing to PMPS [16]. Intercostobrachial nerves (ICBNs) enter the axilla and pass through the posteromedial border of the upper arm with considerable anatomic variability. Thus, the ICBN is vulnerable during axillary surgery. Patients undergoing a standard ALND frequently have chronic neuropathic symptoms, while a less extensive axillary surgery (ie, sentinel lymph node dissection [SLND]) is associated with less frequent chronic pain complications [5,16,21,22,26,32,35,36,44,45]. As an example, a European Organization for Research and Treatment of Cancer Quality of Life Questionnaire survey of 317 breast cancer patients found that more women undergoing an ALND with breast surgery (n = 105) (ie, mastectomy or partial mastectomy) had chronic pain compared with women not undergoing an ALND (51 versus 23 percent) [16]. Some patients not undergoing an ALND did undergo an SLND.

In contrast, in a review of 611 patients, surgical treatment approach toward the breast, such as partial mastectomy (n = 458) or total mastectomy, or one (n = 420) or multiple breast procedures, was not associated with PMPS [46]. Surgical factors and complications, including reoperation and bilateral surgery as well as incidence of seroma, hematoma, cellulitis, or lymphedema, also did not appear to be significant contributors [47].

Although earlier reports suggested a link between immediate breast reconstruction (IBR) and PMPS [15,48], a meta-analysis published in 2020 revealed no significant difference between prevalence of persistent pain after mastectomy alone versus mastectomy and reconstruction [49]. This may be due to more aggressive preemptive analgesic techniques, including intra- and postoperative local anesthesia [50]. In addition, adoption of new implant-based techniques using acellular dermal matrices may contribute to lower rates of PMPS in the modern era of breast reconstruction [51].

Psychosocial factors — Persistent PMPS is increasingly associated with several psychosocial factors (eg, anxiety, depression, sleep disturbance, catastrophizing, somatization) [52]. In a cross-sectional cohort study of 611 patients who had a total or partial mastectomy more than six months prior to the telephone interview, 32.5 percent reported a clinically relevant pain severity of ≥3 out of 10 in the breast (34.3 percent), axilla (19.9 percent), side (8.6 percent), or arm (8.2 percent) [46]. Patients with PMPS pain ≥3 out of 10 were significantly more likely to report anxiety, depressive symptoms, sleep disturbance, somatization, catastrophizing, and perceived stress compared with women who had no PMPS.

Psychological factors, including preexisting anxiety and depression, have been associated with moderate-to-severe persistent PMPS [53-55]. Patients with preoperative anxiety are more likely to experience not only severe acute postoperative pain but also chronic postoperative pain [38,56].

Lack of physical activity may contribute to psychosocial wellbeing. In a cross-sectional study of the behavior and symptoms of 148 breast cancer survivors, multivariate analyses showed that total energy expenditure was associated with better general health and fewer depressive symptoms, while frequency of activity was linearly related to physical functioning, pain, general health, and depressive symptoms. Duration of activity was related to physical functioning, pain, and general health [57].

The presence of chronic pain prior to mastectomy may also increase the risk for PMPS [7,22,39,58,59]. The preexisting pain may or may not involve the surgical site.

Adjuvant treatments, including radiation therapy, chemotherapy, or hormonal therapy, after adjustment for multiple comparisons, have not been consistently associated with PMPS. In addition, disease status (eg, tumor size, nodes) has not been associated with PMPS [46,47].

CLINICAL FEATURES

Clinical manifestations

Patient presentation — Patients with postmastectomy pain syndrome (PMPS) typically present with burning, electric shock, or stabbing pain and/or neuropathic symptoms (eg, numbness, hyperesthesia, paraesthesia) at the operative site and/or the ipsilateral arm [3-5,8,9,26,58,60]. For example, in a survey of 223 women 16 months to 32 years from their original surgery for breast cancer, 65 percent reported pain, 81 percent numbness, and 46 percent paraesthesias [9]. Other symptoms include chest wall muscle pain, reduced range of motion of the shoulder, and reduced shoulder and/or hand grip strength [60].

A discussion on the critical components of the history for assessing chronic pain is reviewed separately. (See "Evaluation of chronic non-cancer pain in adults", section on 'Neuropathic pain'.)

Physical examination — The pertinent findings on the physical examination include sensory changes (eg, hypersensitivity, hyposensitivity) at the operative site and/or ipsilateral extremity and decreased range of motion and strength in the ipsilateral arm [61-63]. For example, intercostobrachial neuralgia pain is typically accompanied by altered sensation in the distribution of the intercostobrachial nerve, whereas neuroma pain is found in the region of the scar, which can be provoked by percussion.

In addition to sensory alterations, nerve impairment can result in decreased shoulder strength and range of motion. Methodological differences have resulted in a wide range of reported incidences, ranging from 2 to 51 percent for impairments in range of motion that interfered with normal daily activities and 17 to 33 percent for decreased muscle strength [61-64].

Radiographic studies — There are no specific radiographic findings for PMPS. In the clinical setting of pain confined to the breast, a mammogram, an ultrasound, or magnetic resonance imaging (MRI) may identify a fluid collection or evidence of recurrent disease. A plain film of the shoulder and humerus can identify local abnormalities such as a fracture, arthritic changes, metastatic disease, or benign bone cysts.

Laboratory studies — There are no specific laboratory findings for PMPS. Abnormal laboratory tests (eg, blood count, serologic markers of inflammation, cancer markers) may signify other causes of pain such as rheumatologic, infectious, or oncologic etiologies.

Neurophysiologic testing — Neurophysiologic testing, principally nerve conduction studies (NCV) and electromyography (EMG), are frequently employed in suspected disorders of the peripheral nervous system but are not commonly used in PMPS, which remains a clinical diagnosis. The usual techniques, with surface electrodes for nerve stimulation, measure activity of the largest and fastest-conducting sensory and motor myelinated nerve fibers. NCV and EMG studies may be normal in patients with polyneuropathies or focal nerve lesions with only small-fiber involvement. Abnormal findings associated with neuropathy are described separately. (See "Overview of electromyography", section on 'Motor neuronopathies'.)

DIAGNOSIS — The diagnosis of postmastectomy pain syndrome (PMPS) is made based upon characteristic symptoms of a burning, electric, or stabbing pain or paresthesias in the chest wall, axilla, and/or ipsilateral extremity following a breast cancer operation and/or local radiation therapy or chemotherapy, in the absence of an infection or recurrent disease [3-5]. The physical examination includes a breast, chest wall, and axillary examination that identifies post-treatment changes (ie, surgical, radiation) in the absence of signs of local recurrence or infection. A detailed sensory and motor neurologic evaluation of the affected sites reveals motor and/or sensory deficiencies in the distribution of the affected peripheral nerve (eg, intercostal brachial, long thoracic, thoracodorsal nerves).

Imaging studies are not necessary or useful for making the diagnosis of PMPS. However, if there is diagnostic uncertainty, imaging studies can be helpful in excluding other disorders in differential diagnosis.

DIFFERENTIAL DIAGNOSIS

●Locoregional recurrent breast cancer – Pain is not a common presenting symptom for a local recurrence of breast cancer. A locoregional recurrence is typically identified on the physical examination as a palpable mass or as an abnormality on an imaging study, such as a mammogram. (See "Clinical manifestations and evaluation of locoregional recurrences of breast cancer".)

●Metastatic breast cancer – Bones are a common site of metastasis from breast cancer, and the humerus is the most common upper extremity site [3]. Bone pain from metastatic disease is severe and debilitating and results from destruction of bone tissue. Localized bone pain may indicate a fracture or impending fracture at the site of disease. Diagnosis can be made by imaging studies. (See "The role of local therapies in metastatic breast cancer".)

●Breast inflammation/infection – Pain can accompany erythema in noninfectious breast disorders, such as postirradiation mastitis, superficial thrombophlebitis, or cellulitis and abscess. An abscess can also occur in the axilla following an axillary dissection. Infection as a cause of postmastectomy breast pain typically occurs early in the postoperative course. (See "Nonlactational mastitis in adults".)

●Phantom breast pain or phantom sensations – Chronic pain or chronic sensations can develop as phantom symptoms following a total or partial mastectomy, similar to those that occur after a limb amputation. The postsurgical nonpainful sensations are called phantom breast sensations (PBSs), while a painful sensation is called phantom breast pain (PBP). While the symptoms of PBP are similar to those of postmastectomy pain syndrome (PMPS), subjectively, patients with PBP report the persistence of sensations within their amputated breast.

•PBS includes all sensations that are experienced in the amputated breast, whereas PBP includes sensations so intense that they are experienced as pain [65-67]. The prevalence of PBS and PBP ranges from 0 to 66 percent, with the wide range most likely attributed to differences in methodologies [4,10,16,58,65-67]. PBSs are characterized by a sensation of persistence of the removed breast after its removal. PBSs are distinguishable from pain or other sensory disturbances in or around the scar.

•PBP is characterized by disturbing and painful sensations in the area of the nipple alone or involving the entire breast or segment that was resected and may persist for years after the operation. The etiology includes central nervous system sensitization and cortical reorganization, which are associated with nerve damage and are considered to have a role in pain chronification [8,16]. The injury to neurons results in spontaneous and evoked hyperexcitability. Psychological factors have also been implicated.

●Chemical neuropathy – Chemotherapeutic agents (eg, taxanes, platinum based), heavy metals, and alcohol can produce peripheral neuropathies [3]. The presentation includes a distal, symmetric distribution of pain and/or paresthesias. Electrodiagnostic testing and clinical presentation help establish the diagnosis. (See "Overview of polyneuropathy", section on 'Toxic'.)

●Lymphedema – Lymphedema can present as an insidious soft tissue enlargement of the hand and arm. It can occur as a result of injury from an axillary dissection and/or radiation therapy or from obstruction of the lymphatic channels (eg, tumor cells, mass effect). Discomfort and the sensation of heaviness is the most common presenting symptom, rather than pain. (See "Clinical features and diagnosis of peripheral lymphedema".)

●Musculoskeletal disorders – Common musculoskeletal disorders, such as bursitis, adhesive capsulitis (frozen shoulder), tendonitis, or rotator cuff injury, can present with shoulder pain and a limited range of motion. Diagnosis can be established based on the history, clinical examination, and radiographic imaging (eg, MRI). (See "Evaluation of the adult with shoulder complaints".)

●Cervical radiculopathy – Cervical radiculopathy can present with pain; paresthesias; numbness; or weakness of the shoulders, arms, or hands [3]. The onset of symptoms is most frequently acute when caused by a herniated nucleus pulposus but may be more indolent when due to spondylosis. Imaging studies, electrodiagnostic studies, and the clinical presentation can help establish the diagnosis. (See "Clinical features and diagnosis of cervical radiculopathy".)

QUALITY OF LIFE — Quality of life (QoL) is a multidimensional term that includes the physical, social, and psychological wellbeing domains. For a cancer patient, the appearance of pain may represent a continuous memory of the treatment and the disease. Additionally, pain may be incorrectly viewed as a sign of recurrent cancer and cause considerable psychological distress and a poor QoL, even in the absence of disease [6,9,16,22,26,32,35]. (See "Assessment of cancer pain" and "Overview of cancer pain syndromes".)

Retrospective studies found that postmastectomy pain syndrome (PMPS) can have a negative impact on an individual's long-term QoL [6,10,16,58]. Persistent, unremitting stress caused by chronic pain can generate detrimental long-term effects, increasing an individual's susceptibility to stress-related physical and mental health problems. A retrospective study of 55 breast cancer patients assessing impairments, disabilities, and health-related QoL in women found that pain was the most important factor in predicting health-related QoL [60]. Among breast cancer survivors in a cross-study of 148 patients, PMPS was rated as the most troublesome condition, leading to disability and psychological distress [57].

SUMMARY AND RECOMMENDATIONS

●Pathophysiology – Postmastectomy pain syndrome (PMPS) is a chronic neuropathic disorder caused by direct nerve injury (eg, transection, compression, ischemia, stretching, retraction) during the breast cancer operation or the subsequent formation of a traumatic neuroma or scar tissue and possibly exacerbated by local radiation treatments and neurotoxic chemotherapies (eg, taxanes). (See 'Pathophysiology' above.)

●Clinical presentation – Patients with PMPS typically present with burning, electric shock, or stabbing pain and/or neuropathic symptoms (eg, numbness, hyperesthesia, paraesthesia) at the operative site and/or the ipsilateral arm. Other symptoms of patients with PMPS include chest wall muscle pain, reduced range of motion of the shoulder, and reduced shoulder and/or hand grip strength. (See 'Patient presentation' above.)

●Physical findings – The pertinent findings on the physical examination include sensory changes (eg, hypersensitive, hyposensitive) at the operative site and/or ipsilateral extremity and decreased range of motion and strength in the ipsilateral arm. (See 'Physical examination' above.)

●Diagnosis – The diagnosis of PMPS is made based upon symptoms of a burning, electric, or stabbing pain or paresthesias in the chest wall, axilla, and/or ipsilateral extremity following a breast cancer operation and/or local radiation therapy or chemotherapy, in the absence of an infection or recurrent disease. (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis for PMPS includes recurrent breast cancer, metastatic breast cancer, benign inflammatory disorders, and postradiation and chemotherapy effects. (See 'Differential diagnosis' above.)