In the DFNS QST of women with chronic post-surgical NP after breast cancer surgery, we found significant sensory loss in thermal and mechanical tests both in the affected and unaffected side when compared with the DFNS normative data. The affected side presented significant sensory loss in both thermal and mechanical tests compared with the unaffected side.
Patients with spared ICBN presented with similar sensory loss compared with resected ICBN. Of the sensory profiles, “sensory loss” was the most common (52%), followed by “mechanical hyperalgesia” (37%). Only 11% of patients, all having had BCR, presented with the “thermal hyperalgesia” profile.
In BE, sensory loss was the most prevalent (98%) finding. Sensory gain in BE was present in 37% and it was associated with more intense pain.
Quantitative sensory testing
Few previous studies have conducted QST (not with the DFNS protocol) on the painful surgical area in patients operated for breast cancer [
15,
16,
29]. They report higher thermal and tactile detection thresholds in the operated side compared with the unaffected side, in line with our results. In the long-term, the post-surgical sensory dysfunction in breast cancer survivors seems to sustain with sensory loss.
Similar to our results, previous studies also report gain of function in PPT [
15,
16,
30]. However, we observed sensory gain in PPT both in the affected and unaffected side. The DFNS reference data on upper back may generate bias [
27]. However, some patients were extremely sensitive even to light pressure. Moreover, widespread pressure-evoked hyperalgesia in non-surgical areas has been reported in patients operated for breast cancer [
31]. Widespread sensory gain in PPT may reflect central sensitization in patients with NP after breast cancer treatments [
31].
The effect of ICBN handling on chronic post-surgical pain is controversial [
6]. Previously, it was reported that the risk of post-surgical pain increased if the surgeon spared ICBN [
32]. However, in another recent study, resection of ICBN increased risk for NP [
5].
We found a considerable sensory impairment in the ICBN area even when the nerve was spared from resection. This suggest that the patients who have NP in the ICBN innervation area have similarly impaired sensory function regardless of the surgical nerve handling. Therefore, other perioperative lesions (e.g., compression, stretching, and scar formation) to ICBN, not only mere resection, may play an important role in post-surgical NP. Our results highlight the importance of QST in further studies to better understand the effect of the type of nerve injury on post-surgical NP.
Interindividual differences in sensory profiles may reflect distinct pathophysiological backgrounds with different responses to medical treatments [
13,
14,
28]. A recently published algorithm stratifies patients to three different pathological phenotypes according to the sensory profile in DFNS QST [
13]. There are a few studies that support the idea of personalized NP treatments according to sensory phenotype [
10,
13,
33].
Frequencies of the three QST phenotypes vary across NP etiologies [
8]. In our cohort of chronic post-surgical NP patients, “sensory loss” was the most prevalent (52%) reflecting the loss of both small and large nerve fiber function. Pain may be generated by ectopic activity at the sites proximal to injury [
8,
34]. 37% in this cohort belonged to the “mechanical hyperalgesia” phenotype characterized by central sensitization to mechanical stimuli and sensory loss in thermal sensation [
13].
“Thermal hyperalgesia” was the most infrequent (11%) phenotype in our cohort. It is considered as a peripheral sensitization phenotype with possible response to oxcarbazepine treatment [
10,
13]. It may reflect effective nerve regeneration [
13], which could be hindered by radiotherapy after breast cancer surgery [
35]. The high prevalence of radiotherapy in our cohort (90%) may partly explain the scarcity of “thermal hyperalgesia” phenotype. However, all patients with “thermal hyperalgesia” had undergone BCR. This is in line with a previous study reporting less severe sensory impairment in BCR compared with mastectomy [
15].
The distribution of the sensory phenotypes in our cohort differs from the previously published data on patients with NP after peripheral nerve injuries reporting “thermal hyperalgesia” as the most prevalent phenotype (40%) [
13]. This may suggest that post-surgical NP after breast cancer treatment is distinct from other nerve injury derived NP (possibly due to postoperative radiotherapy) and most patients may not benefit from Na
+ -channel blockers.
Clinical BE and sensory mapping
ALND has been associated with persistent post-surgical pain [
32], which could be due to the increased risk for perioperative ICBN lesions [
15]. In our cohort, however, the presence of sensory gain in BE associated with more intense pain, but not with the type of surgery or treatment. Most patients with sensory gain in BE, reported hyperesthesia/hyperalgesia to pinprick, which may involve both central and peripheral sensitization mechanisms [
36].
Although sensory loss was the most common finding in both BE and QST, the individual outcomes of corresponding tests in BE and QST were consistent in only 29–57% of the patients. Similar results were observed in a previous study on 32 patients with traumatic partial nerve injury [
37]. The differences in the applied stimuli and conduct of the measurement may explain this inconsistency. Since QST examines a restricted area of interest with a standardized protocol, it may reveal impairment in the sensory function that does not emerge in BE [
38].
The standardized protocol, training, equipment, and reference data of the DFNS QST aim to improve quality and comparability of the data from different centers. However, although BE is more robust and mainly qualitative it is a critical step of NP diagnostics and it allows the sensory mapping of the whole affected area. BE and QST are complimentary, rather than substitutive methods of assessment of the sensory function. QST offers a means to stratify patients to certain sensory phenotypes that is not accessible by BE. This could be important to consider in the future if the sensory phenotype-based treatment design gains further support [
13].
Strengths and limitations
Strengths of the study are a relatively large and thoroughly characterized patient cohort of post-surgical NP patients. One examiner conducting BE to all patients excludes the need to consider inter-rater variability.
Most of the patients did not use regular NP medications or other analgesics. These medications may affect the sensory profile, especially the evoked pain thresholds. However, the patients reported of scarce usage of these medications.
Lack of healthy controls is a limitation of the study, since the DFNS normative data were from the back [
27]. However, we were able to compare the affected and the unaffected side with each patient as her own control. Some QST items show high levels of variation among healthy individuals [
26]. Therefore, a reliable set of normative values may require a large number of healthy controls. Normative data collected from multiple centers would benefit further studies of the sensory function in breast cancer patients.