The Association of the Second to the Fourth Digit Ratio with Prostate Cancer  Diagnosed by Magnetic Resonance Imaging-Transrectal Ultrasound Fusion Biopsy: A Comperative Analytical Cross-Sectional Analysis of Prospectively Recorded Data

doi:10.21203/rs.3.rs-4934408/v1

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The Association of the Second to the Fourth Digit Ratio with Prostate Cancer Diagnosed by Magnetic Resonance Imaging-Transrectal Ultrasound Fusion Biopsy: A Comperative Analytical Cross-Sectional Analysis of Prospectively Recorded Data

https://doi.org/10.21203/rs.3.rs-4934408/v1

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Background: Only a few studies that employed conventional transrectal ultrasound (TRUS) biopsy have investigated the connection between the second digit (2D)-to-fourth digit (4D) ratio and prostate cancer, and their findings have been conflicting. We aimed to investigate the correlation between the 2D:4D ratio and prostate cancer, identified through a multiparametric magnetic resonance imaging (mp-MRI)-TRUS fusion biopsy, and its association with clinically significant prostate cancer (csPCa).

Methods: Patients who underwent mp-MRI/TRUS fusion biopsy due to the Prostate Imaging Reporting and Data System 3/4/5 lesions between 2020 and 2024 were included in the study (n = 616). After applying the exclusion criteria, the patients were divided into three groups: Study group (n = 168): prostate cancer; study subgroup:csPCa (n = 95); and control group (n = 360): non-cancer. The groups were compared in terms of demographic data, patient characteristics, MRI characteristics, pathological features, cancer stages, and the right hand 2D:4D ratio.

Results: There was a significant difference between the study and control groups for total prostate-specific antigen (PSA) levels, the rate of positive digital rectal examination findings, PSA density, and prostate volume, all favoring the study group (<,001, <,001, <,001, and <,001, respectively). The study and control groups did not show any difference in terms of the right-hand 2D:4D ratio. Similarly, no difference was observed between the study subgroup and control group when the study group was evaluated specifically for csPCa.

Conclusions: The right hand 2D:4D ratio is not a dependable predictor for both overall prostate cancer and csPCa risk.

digit ratios

multiparametric magnetic resonance imaging

fusion prostate biopsy

prostatic neoplasms

The second (2D)-to-fourth (4D) digit ratio, which measures the length ratio between the second and fourth fingers, is proposed as a possible biophysir for prenatal exposure to sex hormones like testosterone and estrogen [1]. It is widely acknowledged that testosterone and androgen receptors (ARs) play a significant role in the development of prostatic tissue and the initiation of prostate cancer. Multiple studies have established a strong association between the quantity of CAG trinucleotide repeats in the AR gene and finger length. Furthermore, there is a concern that individuals with a lower number of AR CAG repeats may have an increased susceptibility to prostate cancer [2].

Currently, there have been limited investigations into the correlation between the 2D:4D ratio and prostate cancer, and the results have been inconsistent. Furthermore, all these studies employed conventional transrectal ultrasound (TRUS)-biopsy [3]. The multicenter randomized controlled PRECISION trial demonstrated that the rate of detecting prostate cancer with an International Society of Urological Pathology (ISUP) grade ≥ 2 was significantly higher in men who underwent multiparametric magnetic resonancimaging (mp-MRI)-TRUS fusion prostate biopsy compared to those who underwent conventional systemic biopsy [4]. An mp-MRI-TRUS fusion prostate biopsy study will more clearly reveal the existence of a possible relationship.

We hypothesized that the 2D:4D ratio may be an indicator for the diagnosis and severity of prostate cancer. In this context, our aim was to investigate the potential correlation between prostate cancer, identified through a multiparametric magnetic resonance imaging (mp-MRI)-TRUS fusion prostate biopsy, and the 2D:4D ratio, as well as its association with clinically significant prostate cancer (csPCa).

Compliance with ethical standards

The current study was approved by both the Institutional Medical Ethics Committee of Haseki Training and Research Hospital (May 23, 2024; approval no. 24-2024) and the Institutional Education Planning Board (approval no. 137). Prior to performing biopsies, all patients provided verbal and written consent (signed documents are available in the patient files of the hospital).

Study design

This comparative analytical cross-sectional study, a form of observational study, included a retrospective analysis of data collected prospectively in a tertiary center. The study's data was obtained from our clinic's "fusion biopsy data recording system." However, the data prior to 2019 was not included in the study, as the radiology department switched to Prostate Imaging Reporting and Data System (PIRADS) version 2.1 in 2019 [5]. Patients underwent Mp-MRI due to elevated prostate-specific antigen (PSA) (>2.5 ng/mL) and/or suspicious digital rectal examination (DRE), and among these, patients who underwent mp-MRI/TRUS fusion prostate biopsy due to the PIRADS 3/4/5 lesions that were accepted as significant lesions between January 2020 and April 2024 were included in the study (n = 616). The patients undergoing active surveillance for prostate cancer (n = 32), as well as those with a prior history of hand surgery or trauma (n = 6), missed data (n = 50) and were excluded from the study. The remaining patients were divided into two groups according to the biopsy results: Study group (n = 168): prostate cancer; Study subgroup: csPCa (n = 95); and Control group (n = 360): non-cancer (atypical small acinar proliferation, high grade prostatic intraepithelial neoplasia, prostatitis, benign prostate hyperplasia) (Figure 1). The groups were compared in terms of demographic data (age, family history, body mass index; BMI, comorbidities), patient characteristics (total PSA, PSA density, previous biopsy history, DRE), MRI characteristics (prostate volume, PIRADS score, lesion size, lesion number), patological features (number of cores, gleason score, ISUP grade), cancer stages, and right hand 2D:4D ratio. The primary endpoint was to determine the correlation with prostate cancer, while the secondary endpoint was to assess the relationship with csPCa.

Digit ratio

The measurements were conducted using a digital vernier caliper. The lengths of 2D and 4D were measured from the distal finger tip to the midpoint of each proximal crease (Figure 2). The 2D:4D ratio was determined by dividing the length of the 2D by the length of the 4D.

Prostate multiparametric magnetic resonance imaging

All mp-MRIs were conducted using either 1.5 Tesla or 3 Tesla MRI machines. The evaluated MRI sequences included T1-weighted, T2-weighted, diffusion-weighted, and dynamic gadolinium-contrast images. An experienced radiologist (XXXX) specializing in prostate MRI examined each mp-MRI image according to the parameters outlined in PI-RADS v2.1 guidelines [5]. The radiologist also determined the prostate volumes by utilizing axial and sagittal T2-weighted scans, employing the formula: height x breadth x depth/2. The radiologist was blinded to the finger measurements of the patients.

Biopsy procedure

Patients with PI-RADS 3 or more lesions underwent Mp-MRI / TRUS fusion prostate biopsy (target + systemic sampling) via transrectal technique. All patients were given antibiotic prophylaxis (fosfomycin, at a dosage of 3 g; 12 hours before and 24 hours after the biopsy, orally) and a cleansing fleet enema. The biopsies were performed using the Biojet rigid image-fusion platform (D&K Technologies GmbH, Barum, Germany) while the patient was in the lithotomy position. Local anesthesia, specifically a pudendal nerve block and periprostatic nerve block, was administered during the procedure. A disposable automatic tru-cut prostate biopsy gun with an 18G needle and biplane probe (BK-Medical, Herlev, Denmark) was utilized for sampling. A minimum of three core samples, with at least two of them being obtained from the lesion center, were taken from each suspicious lesion (Figure 3). The systematic biopsy plan involved obtaining 10–12 systematic samples from the peripheric zone of the prostate. These samples were taken from the lateral and far-lateral sections of the apical, mid, and base regions of the prostate on both sides.

Pathologic Evaluation

The formalin-fixed, paraffinized tissues were examined for pathological analysis. The tissues were appraised as 4µm thick sections and stained with Hematoxylin&Eosin (Figure 4a). The cases were evaluated by evaluating the primary and secondary Gleason patterns and categorized according to the ISUP 2014 classification (Figure 4b and 4c) [6]. Immunohistochemical analysis was employed to discriminate well-differentiated tumors from non-neoplastic glands by observing the absence of basal layer markers such as HMWCK, p63, and SMA. Immunohistochemical markers, including Nkx3, PSA, and PSAP, were employed in the assessment of poorly differentiated tumors. These markers were utilized to determine the level of differentiation and to distinguish them from other prostate tumors that share similar characteristics, such as neuroendocrine carcinoma, lymphoma, and urothelial carcinoma.

Statistical analysis

Statistical analysis of the study was performed using IBM SPSS Statistics^® version 29.0.2 software (IBM Corp., Armonk, NY, USA). Numerical variables that conform to a normal distribution were displayed using the mean ± standard deviation (sd), whereas numerical variables with a distribution that deviates from normality were displayed using the median and minimum (min.)-maximum (max.) values. Categorical variables were presented as a proportion represented by a percentage symbol (%). The normality of the quantitative variables was assessed using histogram graphics, coefficient of variation, skewness and kurtosis values, normal Q-Q plot and detrended normal Q-Q plot graphics, and the Kolmogorov-Smirnov test. Given that there were 168 and 360 patients in the respective groups, the Kolmogorov-Smirnov test was used to assess the normal distribution rather than other normality tests. In this test, data with a p-value greater than .05 were considered to demonstrate conformity with the normal distribution. The Independent-Samples T test was used to compare numerical variables (age and BMI) that exhibited a normal distribution between two independent groups. On the other hand, the Mann-Whitney U test was used to compare variables that did not exhibit a normal distribution (total PSA, PSA density, prostate volume, number of significant lesions on the mp-MRI, total number of cores in biopsy, and right hand 2D:4D ratios). The Chi-square test was used to compare categorical variables (comorbidity, DRE findings) between groups. The data were examined using a 95% confidence level, and any p-values equal to or less than .05 were accepted statistically significant.

The mean age was significantly higher in the study group compared to the control group. Groups were similar in terms of major comorbidities and metabolic syndrome (Table 1).

There was a significant difference between the study and control groups for total PSA levels, the rate of positive DRE findings, PSA density, and prostate volume, all favoring the study group. There was no significant difference in terms of the number of PIRADS 3/4/5 lesions detected on the mp-MRI and the total number of cores taken in biopsy (Table 2).

The study and control groups did not show any significant difference in terms of right-hand 2D:4D ratios (Table 3).

Similarly, no significant difference was observed between the control group and the study subgroup when the study group was evaluated specifically for csPCa instead of overall prostate cancer (Table 4).

Our study's findings indicate that there is no substantial association between the 2D:4D ratio and prostate cancer risk (both overall prostate cancer and csPCa). This finding contributes to the ongoing debate about the possible association between the 2D:4D ratio and prostate cancer, providing additional evidence to question the reliability of the 2D:4D ratio as a biomarker for the risk of prostate cancer.

A meta-analysis study examining the correlation between the 2D:4D ratio and various types of cancer found that a low 2D:4D ratio was associated with prostate cancer, gastric cancer, and brain tumors. Conversely, a high 2D:4D ratio was associated with an increased risk of breast cancer and cervical dysplasia. The study also reported that the 2D:4D ratio was not linked to the stage of prostate, breast, or gastric cancer [3].This comprehensive meta-analysis examined a total of 9 studies (8 case-control or cross-sectional studies, involving 4128 patients, and one prospective cohort study, involving 6458 men from a community sample) on prostate cancer up until 2018. The majority of the selected studies indicated that prostate cancer was linked to a lower 2D:4D ratio. However, two groups either found no association between the 2D:4D ratio and prostate cancer or reported that a higher 2D:4D ratio was associated with prostate cancer. The majority of studies included in the meta-analysis did not establish a correlation between the 2D:4D ratio and important clinical parameters such as Gleason score, presence of metastasis, family history of prostate cancer, and age at diagnosis. A single study observed a negative correlation between the 2D:4D ratio and both the amount of core cancer volume and the number of biopsy cores with a high Gleason grade. The disparate findings from all these different studies highlight the intricacy of establishing a definitive correlation between the 2D:4D ratio and prostate cancer. This is likely the result of variations in study designs, sample sizes, demographic characteristics, age, and measuring methodologies.

Our study was conducted on a Turkish community, and it is worth noting that the absence of an association between the 2D:4D ratio and prostate cancer in our dataset may be specific to this particular demographic. The studies that demonstrated an association between the 2D:4D ratio and prostate cancer were undertaken in several geographical locations, including the United States of America,Spain, Brazil,Korea,and the United Kingdom [7-12]. On the other hand, the research conducted in Australia, and a separate study conducted in the Brazilian population, which likewise did not uncover any significant connection, were more in line with our own findings [13,14]. In addition to these racial or ethnic differences and ambiguity, there is also uncertainty on the specific rates and cut-off values linked to prostate cancer. The research carried out in Spain revealed that people with a 2D:4D ratio over 0.95 were linked to the development of prostatic neoplasia. Conversely, the study conducted in Korea indicated that those with a 2D:4D ratio below 0.95 were more likely to have prostate cancer in biopsy. All these findings emphasize the necessity for more investigation to examine the potential influence of racial and geographical disparities on the correlation between the 2D:4D ratio and the risk of prostate cancer. Such investigations could provide insight into whether the 2D:4D ratio may be a more significant indicator in certain populations compared to others.

It is crucial to assess our study, taking into account both its limitations and strengths, in order to properly interpret the results. Our study's primary limitations are the use of data from a single center and its retrospective design. However, the prospective data collection mitigates this limitation. Another limitation was that we did not analyze finger lengths according to age groups. In this context, an alternative study design has the potential to reveal meaningful differences among various age groups. Despite these limitations, the significant patient population and the utilization of MR-Trus fusion biopsy, a contemporary technology, are the primary strengths that set our study apart from previous research in the field. Therefore, our research can make a valuable contribution to the existing body of literature.

Our study contributes to the existing evidence indicating that the right hand 2D:4D ratio may not be a dependable predictor for both overall prostate cancer and csPCa risk. Considering the literature data and the results of our study, there is an unclear relationship between the right hand 2D:4D ratio and prostate cancer. This emphasizes the necessity for further research to explore different new biomarkers and risk factors.

TRUS: transrectal ultrasound

2D: second digit, 4D: fourth digit

mp-MRI: multiparametric magnetic resonance imaging

csPCa: clinically significant prostate cancer

PSA: prostate-specific antigen

AR: androgen receptor

PIRADS: Prostate Imaging Reporting and Data System

BMI: body mass index

ISUP: International Society of Urological Pathology

DRE: digital rectal examination

Ethics approval and consent to participate: The current study was approved by both the Institutional Medical Ethics Committee of Haseki Training and Research Hospital (May 23, 2024; approval no. 24-2024) and the Institutional Education Planning Board (approval no. 137).

Consent for publication: Prior to performing biopsies, all patients provided verbal and written consent (signed documents are available in the patient files of the hospital)

Availability of data and materials: The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

Competing Interests: The authors have no conflicts of interest to declare

Funding: The authors did not receive support from any organization for the submitted study.

Authors' contributions

A.E. Conception and design of the study, acquisition and interpretation of data, statistical analysis, drafting of the manuscript, reviewing it critically for important intellectual content, approving the submitted version

C.D. Conception and design of the study, acquisition and interpretation of data, drafting of the manuscript, approving the submitted version

F.S.E.Conception and design of the study, acquisition and interpretation of data, drafting of the manuscript, approving the submitted version

S.S. Conception and design of the study, acquisition and interpretation of data, reviewing it critically for important intellectual content, approving the submitted version

A.M. Conception and design of the study, reviewing it critically for important intellectual content, approving the submitted version

R.T. Conception or design of the study, reviewing it critically for important intellectual content, approving the submitted version

Acknowledgements: None

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Tables 1 to 4 are available in the Supplementary Files section.

No competing interests reported.

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The Association of the Second to the Fourth Digit Ratio with Prostate Cancer Diagnosed by Magnetic Resonance Imaging-Transrectal Ultrasound Fusion Biopsy: A Comperative Analytical Cross-Sectional Analysis of Prospectively Recorded Data

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