Shear wave elastography detects novel imaging biomarkers of aromatase inhibitor–induced joint pain: a pilot study

This study was approved by the University of Arizona Institutional Review Board, and all participants provided written informed consent (IRB# 1404308335). The enrolled subjects were stage I–II breast cancer patients that were treated at the University of Arizona Cancer Center (UACC) with a non-steroidal AI for their adjuvant therapy and complained of joint pain (n = 6). None of the patients had joint pain prior to starting AI treatment. Healthy volunteers with no history of breast cancer or any type of joint pain were recruited from faculty at UACC (n = 7). None of the volunteers were taking hormone replacement of any kind. All participants were postmenopausal women.

Real-time gray-scale and power Doppler US examination of bilateral wrists and hands were performed on a General Electric Logiq E9 machine using the 18–8 MHz linear hockey stick transducer per our routine inflammatory arthritis protocol. Dorsal and volar aspects of the 2^nd, 3^rd, and 5^th metacarpophalangeal (MCP) joints were examined in their long and short axes. Additionally, all six extensor compartment tendons and tendon sheaths, as well as flexor tendons in the carpal tunnel and the median nerve, were examined in their long and short axes. US examination of the flexor and/or extensor tendons was performed along the digits/fingers.

During US examination, patients were seated with their hands resting on a small table placed between the examiner and the patient. All joints were examined for the presence of cortical erosions on gray-scale US. All joints, tendons, and tendon sheaths were evaluated for the presence of increased synovial fluid complex on gray-scale evaluation and for the presence of hyperemia on power Doppler evaluation. We also examined the median nerve for hyperemia, and patients were asked whether they experienced pain, numbness, tingling, or muscle weakness in the palm, thumb, index, middle or little fingers (“symptomatic” findings). In addition, the presence or absence of soft tissue edema was recorded. Results for each finding were scored as present (1) or absent (0).

SWE US examinations of the bilateral wrists and hands were then performed on a Siemens S3000 unit (Siemens Medical Systems) with a high-resolution 9-MHz linear transducer. The tissue elasticity (degree of stiffness) was displayed on color bar elastogram on the US screen and expressed as SW velocities in m/s. A copious amount of ultrasound gel was used to accommodate the depth. The radial aspect of the ^2nd and 3^rd MCP joints and the ulnar aspect of the 5^th MCP joints were examined in their long axes.

At the dorsal aspect of each wrist and hand, SWE of all six extensor compartment tendons was performed in the long and short axes. At the volar aspect of each wrist, SWE of the flexor tendons and the median nerves was performed, centered in the carpal tunnel region. SWE of the flexor and extensor tendons was performed along the digits/fingers.

Ultrasound B-mode DICOM images taken by the Siemens ACUSON S3000 were examined by a trained radiologist to determine regions of interest (ROIs) containing anatomical structures of interest: the 1^st, 2^nd, 4^th, and 6^th extensor compartments; the 2^nd, 3^rd, and 5^th MCP joints; the median nerve; and the volar flexors adjacent to the median nerve. The B-mode images were co-registered with SW velocity color maps. Depending on the size, each ROI contained 6,000–20,000 pixels; the average SW velocity of all the pixels contained within each ROI was calculated using color map values and tabulated. Each compartment contains multiple tendons (except the 6^th). When compartments are imaged along the short axis, multiple tendons are captured within an ROI; therefore, the reported SWE velocities represent an average of multiple tendons in a given compartment. For the longitudinal collection of the compartments, one representative tendon was chosen by the radiologist for scoring.

Ages of the healthy controls and AI patients were compared using a two-sample independent t-test. Fisher’s exact test was used to assess between-group differences in characteristics determined by US imaging. Between-group differences in SW velocity was determined using linear mixed models, initially clustered on participant and then further adjusted for area of the ROI. A p-value <0.05 was considered significant.

The mean age of healthy controls was 59.3 years (range 54–72 y) which was not different from the mean age of breast cancer patients on AI at the time of imaging (60.0 y, range 45–70 y; t-test p = 0.88). All 7 healthy controls were non-Hispanic white, whereas 4 of the breast cancer patients were non-Hispanic white and 2 were Hispanic. For the breast cancer patients, the mean duration of AI at the time of imaging was 13.2 months (range 4–20 months) (Tab. 1). Four of the patients had lumpectomy, radiation therapy and were stage I; two had a mastectomy, received chemotherapy and were stage II.

Table 2 shows presence or absence of abnormal imaging findings at the MCP joints, wrists, flexor and extensor tendons, and the median nerve using gray-scale and power Doppler US. There were no significant differences in increased joint fluid, hyperemia, or cortical irregularity between controls and the AI group. In the median nerve, there were no significant differences in the presence of hyperemia, symptomatic findings, or bifid anatomy. Taken together, 7 of 7 controls had all negative median nerve findings (no hyperemia, not symptomatic, not bifid) compared to 2 of 6 in AI group; p = 0.020.

Figure 1 illustrates representative SW US images from the 1^st extensor compartment (A, B), the median nerve (C, D), the volar flexor (C, D), and the MCP joint (E, F) from patients on AI (left panels) and control subjects (right panels). The SW velocity is represented by a color scale such that blue is the slowest (0 m/s; least stiff) and red is the fastest (15 m/s; most stiff). Faster SW velocities can be visualized for AI tendons versus control. Figure 2 illustrates the grayscale images of the locations imaged in Fig. 1 in order to assist visualization of the anatomical sites.

Fig. 1.

Fig. 2.

Table 3 presents the velocity determined by SWE, where a faster velocity indicates stiffer tendons. The 1^st extensor compartment tendons and tendon sheaths were significantly stiffer in postmenopausal women on AI than controls in both the long (p = 0.003) and short axes (p = 0.036). The 4^th extensor compartment tendons and tendon sheaths were significantly stiffer among AI women than controls (p = 0.039). Pooled extensor compartments were stiffer in AI patients than controls along both the longitudinal (p = 0.040) and short (p = 0.032) axes. The 3^rd MCP was significantly stiffer in AI than controls (p = 0.027) as well as of all MCP joints combined (p = 0.008). There was no difference between AI and control in the stiffness of the 2^nd or 6^th extensor compartments, the 2^nd or ^5th MCP joints, the median nerve, or the volar flexors.