Elastography and diffusion-weighted MRI in patients with testicular microlithiasis,normal testicular tissue,and testicular cancer: an observational study

Abstract

Background

Ultrasound elastography is increasingly available in clinical practice. Recent studies showed higher velocity stiffness in testicular tumors compared to normal testicles.

Purpose

To evaluate ultrasound elastography in combination with the apparent diffusion coefficient measurements in diffusion weighted (DW) magnetic resonance imaging (MRI) in testicles. DW can be a useful tool in evaluating testicular malignancies. However, the relationship between velocity stiffness and MRI diffusion is not well established.

Material and Methods

We prospectively included 132 patients with testicular microlithiasis (n = 53), or normal testicular tissue (n = 53), or suspected for testicular cancer (n = 26). All 132 patients underwent ultrasonography including shear wave elastography and MRI diffusion coefficient examination of the scrotum.

Results

No clinically relevant difference in velocity stiffness was found between normal and testicles with microlithiasis. There was a significant difference in stiffness between patients with testicular microlithiasis (0.78 m/s), normal testicular tissue (0.77 m/s), and patients with testicular cancer (1.95 m/s) (P ≤ 0.001). Similarly, there was a statistically significant difference in MRI diffusion values between patients with testicular microlithiasis (0.978 × 10⁻³mm²s⁻¹), normal testicular tissue (0.929 × 10⁻³mm²s⁻¹), and testicular cancers (0.743 × 10⁻³mm²s⁻¹) (P < 0.01).

Conclusion

Patients with testicular microlithiasis had no malignant characteristics measured with shear wave elastography or MRI diffusion. MRI diffusion and elastography may be useful to preoperatively differentiate benign from malignant testicular lesions.

Keywords

Magnetic resonance imaging MRI ultrasound testes calcification adults

Introduction

The prevalence of testicular microlithiasis (TML) has been reported in the range of 0.6–18.1% (1 –7) and is recognized as small concretions (1–3 mm) within seminiferous tubules, without acoustic shadowing. TML has been suggested to be part of the testicular dysgenesis syndrome, which includes infertility, atrophy, cryptorchidism, and testicular cancer (8). However, there seems to be a shift in this mindset, as the European Society of Urogenital Radiology scrotal image subcommittee has advocated that ultrasound follow-up should only be offered to TML patients with an additional risk factor such as infertility, family/personal history of testicular cancer, atrophy, or maldescent (9).

Today, combined ultrasound and elastography investigations are becoming increasingly available in clinical practice and may improve detection of testicular lesions (10). Shear wave elastography (SWE) is a quantitative method to evaluate tissue stiffness (11,12), and the basic principle of SWE is to use a short pulse < 1 ms to produce shear waves in the selected target tissue (13). SWE enables objective measurements and the method is considered operator-independent (14).

Also, diffusion-weighted (DW) magnetic resonance imaging (MRI) may be a useful tool for differentiating benign from malignant testicular lesions. Tsili et al. showed the overall accuracy of DW imaging, and also DW combined with conventional MRI in the characterization of testicular cancer with sensitivity of 85.7% and specificity of 88.8% (15). A recent study by Manganaro et al. investigated 47 small non-palpable solid testes tumors and found no statistically significant differences in DW MRI values between benign and malignant lesions, and no difference between seminoma and Leydig cell tumors (16).

The relationship between SWE and DW MRI apparent diffusion coefficient (ADC) is not well established, and few studies have combined MRI and ultrasound elastography (17 –20) when investigating tumors. No study has investigated ADC values in patients with TML.

The aim of this study was to investigate if the ADC measurements in DW MRI and ultrasound elastography in patients with TML, normal testicular tissue, and testicular tumors have similar or different characteristics, in order to evaluate TML as a possible pre-sign state. Second, we evaluated the usefulness of DW MRI and SWE in the diagnosis of testicular cancer.

Material and Methods

Patients

From September 2013 to January 2017, 98 consecutive patients with TML or testicular tumors were offered entry to the study at the Department of Radiology. TML and testicular tumors were diagnosed by ultrasound and confirmed by histopathology. As a comparison group, 53 patients with normal testicular ultrasound findings were included.

All 151 patients were referred from their general practitioner with testicular symptoms such as pain, swelling, discomfort, or notice of lump, and underwent a conventional B-mode ultrasound scrotal investigation including ultrasound elastography measurements, and were scheduled to an MRI examination. A total of 19 patients were excluded, of which 18 patients failed to undergo scrotal MRI investigation, mainly because MRI investigations was offered during working daytime hours only. One patient diagnosed with a testicular tumor was excluded, because the MRI examination was performed after the orchiectomy. In 3/26 patients under suspicion for testicular tumor, the histopathological report showed benign lesions (abscess, hypoplasia tubules, chronic inflammation, and necrosis). No patient was excluded for the reason of MRI contraindications. The final study population of 132 patients included 53 (40.2%) patients with TML, 53 (40.2%) patients with normal testicular tissue, 23 (17.4%) patients with malignant tumors, and three (2.2%) patients with benign testicular lesions.

TML were defined as ultrasonic hypo-echogenic foci with no shadowing within the testis parenchyma, 1–3 mm in size, and with five or more foci per field of view. Normal testicular tissue was defined as no ultrasonic pathology findings. Testicular tumor was defined as a hypoechoic mass within the testicle.

The 26 patients under suspension for a testicular tumor were referred to treatment at the Department of Urology; all patients underwent orchiectomy. Histology was obtained in all 26 patients.

None of the 53 patients with TML and 53 patients with normal testicular tissue developed testicular cancer in the follow-up period to December 2017, according to the national pathology database.

Imaging technique

Ultrasound

A Siemens S3000 ultrasound machine (Acuson Corporation, Siemens, Mountain View, CA, USA) with Virtual TouchTM Tissue Quantification software was used with a linear 9L4 probe, frequency bandwidth: 4–9 MHz. All images were stored in the Impax PACS (Picture Archive Communication System, Easyviz Impax Workstation, Medical Insight, Valby, Denmark).

A conventional ultrasound B-mode image helped place the region of interest (ROI) box. The ROI box was 10 × 10 mm in size and could not be altered. All patients were placed in supine position. Three measurements were obtained in each testicle and the mean SWE values were calculated for each patient. The ROI was placed in upper, middle, and lower part of the testicle in patients with TML and normal testicular tissue; in patients with testicular tumor, the ROI was placed inside the tumor.

MRI

The MRI examinations were performed with an Ingenia 1.5-T MRI unit release 4.1.3.3 with a posterior coil. First step after the localizer scan, a T2-weighted (T2W) spin-echo and a T1-weighted (T1W) sequence were obtained (Table 1). No contrast enhancement was used. DW MRI was obtained with six b-values: 0, 100, 300, 600, 900, and 1100 s/mm². The Phillips Ingenia software automatically created ADC maps in grayscale, and the ADC maps were stored in PACS. The ten ROIs were placed within the same slice, with a minimum of overlap and avoiding artifacts. The diameter of each ROI was 3.0 mm. Mean ADCs were obtained for every ROI in each case and the mean values were calculated. ADC values were given in units of 10⁻³mm²s⁻¹. The presence of a testicular tumor was visualized on the ADC map as hypo-intense area (low intensity), and all ten ROIs were placed inside the tumor volume within the same slice; and with minimum overlap. The mean ADC values for each testicle were calculated in all patients.

Table 1.

The MRI examination protocol.

Parameters	T2	T1	DWI
TR/TE (ms)	2593/100	650/10	3224/108
WFS/BW	0.932/235.2	0.815/266.5	13.121/16.6
FOV (mm)	130 × 130	110 × 110	200 × 200
Slice thickness (mm)	2	2	3
Matrix	164 × 162	140 × 137	124 × 122
Acq voxel	0.79 × 0.45 × 2	0.79 × 0.80 × 2	1.61 × 1.63 × 3
Recon voxel	0.45 × 0.45 × 2	0.69 × 0.69 × 2	1.56 × 1.56 × 3
NSA	3	3	4
Scan time (min:s)	4:14	5:00	6:04
Slice gab (mm)	0.9	0.9	0.4
b-values	NR	NR	0, 100, 300, 600, 900, 1100

DWI, diffusion-weighted imaging; WFS, water fat shift; BW, bandwidth; FOV, field of view; NSA, number of averages; NR, not relevant; Acq, acquisition.

Statistics

Descriptive statistics tested the differences in testicular tissue using the Mann–Whitney U-test.

Due to multiple investigations for the same man, and measurements from both the diseased and contralateral testicle, a multilevel mixed effects model including a random intercept for patients and another random intercept for each combination of man and testis position (left vs. right) was used (21). We adjusted for age. P < 0.05 was considered statistically significant.

All analyses were performed with STATA statistical software (version 14.1, STATA Corporation, College Station, TX, USA).

Ethics

The National Data Protection Agency and The Regional Committees on Health Research Ethics for Southern Denmark approved this study (ID: S-20120144). All participating patients signed an informed consent after receiving both oral and written information.

Results

The median age of the 53 TML patients was 48 years (age range = 22–71 years); 26 patients with testicular tumors confirmed by histopathology (23 malignant and three benign) had a median age of 38 years (age range = 23–79 years) and 53 patients with normal testicles had a median age of 47 years (age = range 27–75 years).

For the 23 testicular malignant tumor patients who had an orchiectomy performed, the histology report showed 11 seminomas and 12 non-seminomas (six mixed germ cell tumors, one embryonal carcinoma, one yolk sac, one teratoma, two Leydig cell tumors, one fibrothecoma, and one sertoli cell tumor). The tumor median diameter was 2.8 cm (range = 0.7–7.9 cm, std. error = 1.67 cm) measured with ultrasound. In the three patients with benign testicular lesions, the histology report showed abscess, hypoplasia tubules, chronic inflammation, and necrosis, as well as a mean SWE of 1.31 m/s and mean ADC of 1.069 × 10⁻³mm²s⁻¹.

The measured ADC and SWE mean values are listed in Table 2. In general, patients with testicular tumors had higher SWE values (1.93 vs. 0.77 m/s) and lower MRI ADC values (0.743 vs. 0.929 × 10⁻³mm² s⁻¹) compared to patients with TML. In patients with testicular tumors, the mean ADC value measured in the healthy, contralateral testicle was 1.247 × 10⁻³mm²s⁻¹ (range = 0.846–1.728 × 10⁻³mm²s⁻¹) and SWE was 0.84 m/s. Figure 1 shows SWE and DW imaging from a patient with seminoma.

Table 2.

Observed SWE and DW MRI ADC measurements from the groups of men with testicular cancer, TML, and normal testicular tissue.

	Median	Mean	SD	IQR	Range	P value
Elastography (m/s)
All testicular cancers	1.95	2.09	0.86	1.50–2.62	0.88–4.89	<0.001
Seminoma	1.81	1.83	0.68	1.23–2.20	0.88–3.20	<0.001
Non-seminoma	2.30	2.33	0.97	1.53–2.66	1.37–4.89	<0.001
Benign lesion	1.19	1.31	0.18	NA	1.07–1.67	NA
Testicular microlithiasis	0.78	0.82	0.15	0.72–0.85	0.64–1.39	0.293
Normal tissue	0.77	0.79	0.12	0.71–0.84	0.56–1.37	–
MRI ADC (mm² s⁻¹)
All testicular cancers	0.743	0.758	0.19	0.607–0.852	0.393–1.340	<0.001
Seminoma	0.717	0.695	0.18	0.565–0.848	0.393–0.956	<0.001
Non-seminoma	0.801	0.816	0.18	0.728–0.852	0.602–1.340	<0.001
Benign lesion	1.200	1.069	0.19	NA	0.669–1.340	NA
TML	0.978	1.091	0.30	0.859–1.243	0.705–2.012	<0.01
Normal tissue	0.929	0.961	0.16	0.861–1.028	0.758–1.569	–

P values describe difference to normal tissue.

TML, testicular microlithiasis; IQR, interquartile range; SD, standard error; NA, not applicable.

In the multilevel mixed effects model of testicular tissue velocity, we found a significant difference between patients with normal testicles and patients with seminomas (P < 0.001) and non-seminomas (P < 0.001). Age was not statistically significantly associated with testicular tissue velocity in the multilevel mixed effects model (P = 0.906). Furthermore, in patients with a unilateral cancer, the healthy contralateral testicle had higher testicular velocity, compared to patients without testicular cancer (P = 0.006). Table 3 shows small differences between patients as well as between the testicles.

Table 3.

Random variation between patient and left/right testicle.

Source of random variation	Variance
Between patients	7.66 × 10⁻²⁶
Between left/right testicle	1.09 × 10⁻²³
Residual	1.31 × 10⁻¹
Total	1.31 × 10⁻¹

Please note that the between-patient as well as the between-testicles–within-patient variation are negligible compared to the residual variation, indicating that measurement errors are the major source of variation.

Discussion

Testicles with TML have the same testicular stiffness as normal testicular tissue, in contrast to the cancer tissue that has higher velocity stiffness. Table 2 showed slightly less diffusion restriction in patients with TML compared to normal tissue, whereas tumors had an increased diffusion restriction with low ADC values. The healthy contralateral testicle in patients with cancer had higher velocity than normal testicles (0.84 vs. 0.77 m/s). To our knowledge, this is the first study investigating the combined use of SWE and ADC measurements in testicles.

TML has been suggested a premalignant condition (1,22 –24). In our study, TML and normal testicles showed no clinical relevant difference in ADC values, indicating that TML testicles may have the same mechanical properties as normal tissue.

Men previously diagnosed with testicular cancer have increased risk of testicular tumor in the contralateral testis compared to the normal population (28 –31). The healthy contralateral testis in patients with testicular tumors had significantly higher velocity compared to patients with TML/normal testicles (P = 0.006). Possibly, the increased scrotal internal lumen pressure, caused by growth of the neighboring testicle tumor, resulted in an increased velocity in the contralateral testicle as observed. On the other hand, the increased stiffness in the contralateral testis may be an early sign of malignancy.

The ADC values in malignant tumors were significantly different from patients with normal testicles and TML. Also, ADC values in malignant tumors were significant different from the three benign lesions. However, given the larger spread around the mean, the separation between the three groups was less well defined compared to SWE. Ultrasound is the first-choice modality in scrotum investigation, but a multiparametric imaging approach may provide additional information and give a higher diagnostic accuracy. Our data suggest that there may be supplementary value if using both SWE and ADC imaging in the work-up of a patient with a suspected testicular tumor. Of the 26 patients under suspicion for testicular tumor, a total of three showed no sign of malignancy on post-orchiectomy histology. Of the three patients, two were clearly separated from the remaining malignant tumors, both showing a high ADC value and a low SWE (Fig. 2). Orchiectomy is the choice of treatment in cases with testicular malignancy. In hindsight, the patients should have been offered biopsy and follow-up investigation rather than an orchiectomy. Although three patients with benign lesions is a small number, combined SWE and ADC may be a helpful tool in distinguishing malignant from benign lesions. However, this needs to be validated in a larger patient cohort as ADC and SWE could serve as a non-invasive tool for histological differentiation.

Fig. 1.

Imaging of a 33-year-old patient right testis tumor (seminoma). (a) ADC map imaging; notice the darker areas (seminoma) within the testis. (b) T2W MR image of the scrotum. The cancer is seen as darker areas within the testis. (c) T1W MR image of the scrotum. (d) Elastography values of the tumor were 1.58 m/s, 1.88 m/s, and 1.83 m/s. (e) Elastography of the contralateral testis with measurements of 1.10 m/s, 0.94 m/s, and 0.82 m/s. (f) B-mode ultrasonography image of the tumor sized 3.1 × 3.5 cm.

Fig. 2.

Elasticity using SWE (m/s) and MRI ADC (× 10⁻³mm²s⁻¹) in men with different testicular tissues. All testicular cancers were verified by histopathology, and normal testicular tissue and TML were verified by ultrasonography.

Non-seminoma tumors had less diffusion restriction with a higher ADC mean compared to seminoma tumors (Table 2), confirming previous results (25). SWE showed an increased stiffness in non-seminomas compared to seminomas, which has not been reported previously. Testicular tumors differ in their consistency from the surrounding testicle parenchyma. Seminoma is considered the most common germ cell tumor; on B-mode ultrasound, seminomas typically appear as a solid round homogeneous mass. A non-seminoma tumor is very often a combination of more than one component, e.g. teratoma, seminoma, embryonal carcinoma, and yolk sac tumor. On B-mode imaging, this type of tumor often appears inhomogeneous. As a consequence of the tumor homogeneity, the SWE and ADC measurements may have the potential to preoperatively supplement testicular biopsies and differentiate between seminomas and non-seminoma tumors. SWE and ADC are more patient-friendly examinations compared to testicular biopsy.

Patients with TML and additional risk factors are offered yearly ultrasound follow-up until the age of 55 years because of suspected increased risk of testicular cancer. Elastography may be useful in the follow-up investigation when monitoring testicles with TML, as it may give valuable information; it is also inexpensive and easy to perform. However, DW MRI is a time-consuming and expensive examination. Nonetheless, DW MRI could be of value in cases with higher SWE measurements in TML testicles, in order to rule out potential malignant lesions, as MRI and DW give an additional characterization of testicular lesions.

A total of ten ADC values were measured using a round ROI of 3.0 mm. Inoue et al. (26) studied 81 patients with endometrial cancer, showing variation in ROI methods (freehand, square, and round), and found significant differences between freehand and the other ROI methods. It is a time-consuming method to perform ten measurements per testicle or tumor, but the high number of measurements decreases errors and limits observer variation.

In a phantom study by Carlsen et al. (27), SWE showed limitations in correctly measuring stiffness in very small lesions. In our study, however, the testicular tumors had a median size of 2.8 cm; hence, most of the cancers may not be considered small lesions. In our study, the elastography measured ROI box was fixed to 10 × 10 mm in contrast to 2 × 2 mm in the phantom study by Carlsen et al. (27).

This study had some limitations. First, we did not use a 3-T MRI. It can be difficult to compare ADC values between studies, because ADC values may differ with dissimilar imaging parameters or with different types of MRI systems (32). However, other authors have not found significant differences between a 1.5-T and 3.0-T images in various organs (33 –35).

Furthermore, SWE is affected by target depth (27), but the testicles are located superficially in the scrotum with a short distance to the transducer and it is unlikely that depth affects our measurement. Other limitations are the small number of patients with testicular cancer; the patients with normal tissue were symptomatic patients and not asymptomatic volunteers.

In conclusion, both TML and normal testicular tissue had lower velocity and less diffusion restriction compared to the tissue in testicular tumors. This supports that TML testicles have no malignant characteristics as measured with SWE and DW MRI. DW MRI and SWE may be used as a supplement to inconclusive and difficult cases.

Footnotes

Acknowledgments

The authors thank Birgit Debrabant for her support on statistical methodology. They also thank all the MRI radiographers at Vejle Hospital, especially Eva Olsen and Maria Thoning for their knowledge and expertise with the MRI protocols.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was supported by the Region of Southern Denmark and the Danish Council of Radiographers.

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