Initial Benign Biopsy Research Articles

Abstract 3587: High resolution microCT to analyze the 3D morphology of microcalcifications in benign breast disease and breast cancer biopsy tissues

Abstract Introduction: We used micro-computed tomography (microCT), a high-resolution imaging option, to detect and characterize microcalcifications (MCs) in three dimensions within pathology blocks of benign and malignant breast tissues. Methods: A set of 44 formalin-fixed, paraffin-embedded breast tissue blocks were assessed from n=22 women at two time points: benign breast biopsy and subsequent DCIS or DCIS with invasive disease breast cancer. Blocks were scanned using the Bruker Skyscan 1276 microCT at a resolution of 10 µm. SkyScan analysis CTAn software was utilized to prepare and analyze morphological parameters and multiple MCs contained within each block were averaged. Paired morphological parameters were compared between the benign and subsequent cancer samples within women using Wilcoxon signed-rank tests. Results: Median age of patients was 53 years (range 37-77 years) at initial benign biopsy and developed breast cancer at median of 5.6 years (range: 2.3-12.8 years) later. The initial benign biopsies were for proliferative disease without atypia in the majority (59%), while 23% had non-proliferative lesions and 18% atypical hyperplasia. The average structural model index was consistent with a near rod-like shape (median 2.99, range: 2.71-3.29). Paired comparisons between benign and cancer blocks showed that the average surface area of MCs was significantly higher in the cancer samples (p=0.0467), as was the average volume of MCs (p=0.0298) (Table 1). Conclusions: Preliminarily, we demonstrate that microCT of routinely prepared pathology blocks of breast tissues may be useful in characterizing the 3-D morphometry of MCs with suggestive differences in benign and cancer tissues. Given that MCs are a sentinel radiologic marker of DCIS but are common in benign breast disease, developing improved approaches for classifying MCs may have value in breast cancer screening and management. Table 1. Comparison of MC parameters in biopsy tissues (IQR = Interquartile Range). Benign sample from women who later developed breast cancer Breast cancer after prior benign sample Paired Differences (Cancer - Benign) Wilcoxon signed-rank p value (N=22) (N=22) (N=22) Number of Objects (Median (IQR)) 43.5 (14, 789) 69.5 (33, 289) -6 (-139, 67) 0.6830 Average Surface Area (mm2)(Median (IQR)) 0.0225 (0.0134, 0.0393) 0.0342 (0.0185, 0.0656) 0.0113 (-0.0027, 0.0322) 0.0467 Average Volume (mm3) (Median (IQR)) 0.0003 (0.0001, 0.0007) 0.0007 (0.0003, 0.0022) 0.0003 (0.000002, 0.0020) 0.0298 Average Surface Area/Volume (mm−1)(Median (IQR)) 214.92 (162.25, 328.39) 199.55 (151.89, 230.52) -20.85 (-86.05, 27.04) 0.1433 Average Structural Thickness (mm)(Median (IQR)) 0.0341(0.0196, 0.0446) 0.0395 (0.0336, 0.0505) 0.0074 (-0.0062, 0.0153) 0.1173 Average Structural Model Index (Median (IQR)) 2.9758 (2.8465, 3.1175) 3.0026 (2.9281, 3.0927) 0.0075 (-0.1073, 0.1381) 0.7656 Citation Format: Sarah E. Schrup, Thomas de Bel, Tanya Hoskin, Teresa Allers, Stacey Winham, Derek Radisky, Laura Pacheco-Spann, Lisa Seymour, Amy Degnim, Mark Sherman. High resolution microCT to analyze the 3D morphology of microcalcifications in benign breast disease and breast cancer biopsy tissues. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3587.

ODP493 Malignant Struma Ovarii with Papillary Thyroid Carcinoma and concomitant High Risk Thyroid Nodule

Abstract Introduction Struma ovarii is a rare teratoma consisting of >50% thyroid tissue. Malignant transformation very seldomly occurs; most pathology shows papillary thyroid carcinoma. The risk and prevalence of concurrent thyroid gland neoplasm is unclear. Thyroid cancer surveillance post-oophorectomy in these patients may be pertinent but has not yet been established. Case Report A nulliparous 54 year-old woman with one year of menopause without HRT had pelvic and back pain. Imaging detected bilateral ovarian teratomas. Pathology from laparoscopic bilateral salpingo-oophorectomy revealed a 10.7×9.9×10.9cm noninvasive struma ovarii with focal papillary thyroid carcinoma of the left ovary and a benign teratoma of the right ovary. Importantly, the patient had a known thyroid nodule. Two years prior, a FNA of the 1.4cm hypoechoic, hypervascular nodule in the left lower pole yielded benign (Bethesda 2) cytology. After struma ovarii resection, thyroid ultrasound showed highly suspicious TIRAD5. She denied symptoms of hyper- or hypothyroidism and had a normal TSH. She consequently underwent two FNA biopsies, both of which were non-diagnostic. The patient deferred further attempts. History of an initial benign biopsy and stability of the nodule size provide some reassurance. With the patient's reluctance for surgery, serial thyroglobulin (Tg) and ultrasounds will be followed. Post-operative Tg was normal with negative Tg antibody. If Tg becomes markedly elevated, a thyroidectomy will be indicated. Discussion Given the TIRAD5 nodule, this patient's risk of thyroid malignancy is 60-70%. This is compounded with her setting of malignant struma ovarii, which may imply genetic predisposition for thyroid carcinogenesis. Since cytology could not be obtained on the two recent biopsies, definitive pathology by diagnostic lobectomy or thyroidectomy may be considered. A total thyroidectomy would provide the advantage of following Tg for cancer surveillance of both thyroid and ovarian malignancies. There is scant evidence on the treatment of malignant struma ovarii. A few small case series and a pooled review of 57 cases of low-risk (confined to the ovary) malignant struma ovarii in which 50 patients did not undergo thyroidectomy/I-131 ablation showed only a 7.5% recurrence rate at 25 years (Marti et al Thyroid 2012 Apr; 22 (4): 400-406). Hence, this study recommends reserving prophylactic thyroidectomy for patients with extra-ovarian extension or metastases. Treatment of malignant struma ovarii may be extrapolated from those used in differentiated thyroid cancer; high-risk lesions would be those measuring >4cm, have local or distant invasion, or have a BRAF mutation (indicating an aggressive tumor). In conclusion, conservative measures of the thyroid gland with a suspicious nodule may be acceptable in patients with noninvasive malignant struma ovarii, provided strict adherence to cancer surveillance of Tg with both thyroid and pelvic sonography. Presentation: No date and time listed

Long term outcomes for men in a screening trial with an initial benign biopsy: A population-based cohort

Long term outcomes for men in a screening trial with an initial benign biopsy: A population-based cohort

Racial variation in the reliability of prostate cancer indicators in men undergoing subsequent prostate biopsy.

115 Background: Many men with an initial negative prostate biopsy have a persistently elevated prostate specific antigen (PSA) prompting physicians to perform repeat biopsies. African American men (AA) are at particular risk as they have a greater prostate cancer (PCa) incidence and mortality, yet traditional PSA testing may be less reliable in this cohort. We sought to determine the predictors of PCa and PCa severity in a racially diverse population on subsequent biopsy following an initial benign biopsy. Methods: Upon receiving Institutional Review Board approval, a retrospective analysis was performed on men with repeat prostate biopsies at Tulane Medical Center and Southeast Louisiana Veterans Health Care Services in New Orleans, Louisiana from 2003-2015. Inclusion criteria included patients with a benign initial prostate biopsy and underwent subsequent repeat prostate biopsy within 5 years. Race, age, serum PSA, PSA density (PSAD), and prostate volume by transrectal ultrasound (TRUS) were evaluated to determine if they correlate with the presence and severity of PCa. Aggressive PCa was defined as Gleason score >6. Results: A total of 209 men were included; 127 (61%) were AA, and 82 (39%) were Caucasian American men (CA). The two groups were similar with respect to PSA, PSAD, and TRUS. More AA (25.2% vs. 17.1%) had a repeat biopsy showing any PCa. Of those with PCa, 28.1% of AA and 28.6% of CA had aggressive PCa. PSAD positively correlated with any PCa (p=.015). TRUS negatively correlated with any PCa (p=.008). PSA levels (p<.001) and PSAD (p<.001) positively correlated with aggressive PCa in CA but not in AA. Conclusions: The goal of prostate biopsy particularly for those with a prior negative biopsy is to detect aggressive PCa. PSA and PSAD positively correlated with finding any PCa in both AA and CA but not with aggressive PCa in AA. PSA and PSAD are less accurate predictors of aggressive PCa in AA, and novel biomarkers are needed. [Table: see text]

Histological inflammation and risk of subsequent prostate cancer among men with initially elevated serum prostate‐specific antigen (PSA) concentration in the Finnish prostate cancer screening trial

To assess whether histological signs of inflammation are associated with an increased risk of subsequent prostate cancer (PCa) in men with elevated serum prostate-specific antigen (PSA) concentrations and benign initial biopsy. Study subjects were men aged 54-67 years with an elevated PSA (≥4 ng/mL or 3-4 ng/mL and free to total PSA ratio ≤0.16 or positive digital rectal examination), but a benign biopsy result within the Finnish population-based randomised screening trial for PCa, which started in 1996. A total of 293 prostate biopsies without PCa or suspicion of malignancy from the first screening round in the Tampere centre were re-evaluated by a uropathologist to assess histological inflammation. Results of the subsequent screening rounds were obtained from the trial database and PCa diagnoses made outside the screening were obtained from the Finnish Cancer Registry. The median length of follow-up was 10.5 years. Cox regression analysis was used to assess PCa risk after the initial benign biopsy. Histological inflammation was found in 66% of the biopsies. Subjects with inflammation at the biopsy had a slightly lower PCa risk in the second screening round (18 vs 27%, rate ratio 0.69, 95% confidence interval [CI] 0.35-1.34) relative to men without inflammation. In further follow-up, the PCa risk remained nonsignificantly lower (hazard ratio [HR] 0.71, CI 0.46-1.10; P = 0.13). The risk was not appreciably affected by adjustment for age, PSA, prostate volume and family history of PCa (HR 0.67, CI 0.42-1.07; P = 0.092). Histological inflammation in a prostate biopsy among men with an initial false-positive screening test was not associated with an increased risk of subsequent PCa, but instead with a decreased risk which was of borderline significance. Inflammation in prostate biopsy is not a useful risk indicator in PCa screening.

Obesity and Future Prostate Cancer Risk among Men after an Initial Benign Biopsy of the Prostate

In general population studies, obesity has been associated with risk of high-grade prostate cancer, but little is known about obesity and future prostate cancer risk among men with an initial benign biopsy of the prostate; a high-risk population. Within a cohort of 6,692 men followed up after a biopsy or transurethral resection of the prostate (TURP) with benign findings, a nested case-control study was conducted of 494 prostate cancer cases and controls matched on age, race, follow-up duration, biopsy versus TURP and date of procedure. Body mass index at the time of the initial procedure was abstracted from medical records, and initial biopsy specimens were reviewed for the presence of prostatic intraepithelial neoplasia (PIN). Obesity was associated with the presence of PIN in the initial benign specimen [OR = 2.15; 95% confidence interval (CI) 1.13-4.11]. After adjustment for the matching variables, family history of prostate cancer, prostate-specific antigen (PSA) levels at the initial procedure, the number of PSA tests and digital rectal examinations during follow-up, obesity (OR = 1.57; 95% CI, 1.07-2.30) at the time of the initial procedure was associated with prostate cancer incidence during follow-up. Risk associated with obesity was confined to cases with follow-up less than 1,538 days, the median duration of follow-up among cases (OR = 1.95; 95% CI, 1.09-3.48). Obesity is associated with the presence of PIN in benign specimens and with future prostate cancer risk after an initial benign finding. Obesity may be a factor to consider when planning clinical follow-up after a benign biopsy.

Importance of peripheral biopsies in maximising the detection of early prostate cancer in repeat 12‐core biopsy protocols

To assess cancer-detection rates in repeat 12-core biopsy protocols, as extended multicore prostate biopsy protocols have become standard when investigating men with a raised prostate-specific antigen (PSA) level, but repeat prostate biopsy protocols are still developing. During a 4.5-year period, 241 of 590 patients with persistently high age-specific PSA levels of 2.6-10 ng/mL and an initial benign biopsy were invited for repeat transrectal ultrasonography-guided 12-core prostatic biopsy. The protocol for repeat biopsy was identical to the first biopsy, and included a periprostatic nerve block. The first six biopsies were obtained from the periphery of the gland directed more laterally at the base, mid-zone and apices. The remainder were parasagittal sextant biopsies. Pathological findings were analysed on an individual core basis. The mean age of the 241 men was 63.4 years; cancer was diagnosed in 40 (16.6%) on repeat biopsy. Men with cancer were older and had a higher median PSA level. The median Gleason score was 6, with a median of two cores positive for cancer. Maximum cancer detection rates were from peripheral apices (37.5%), basal biopsies had the lowest detection rates (23.8% and 16.3%), and parasagittal biopsies missed 35% of detected cancers. Patients with cancer also had significantly lower prostate volumes and higher PSA densities (both P < 0.001). A low cancer yield from both peripheral basal and parasagittal basal specimens on repeat biopsy indicates adequate sampling at initial biopsy. The maximum cancer yield in the peripheral mid-zones and apical zones suggests the necessity for concentrated sampling of these zones in repeat biopsy protocols.

DIFFERENTIATION OF BENIGN PROSTATIC HYPERPLASIA FROM PROSTATE CANCER USING PROSTATE SPECIFIC ANTIGEN DYNAMIC PROFILE AFTER TRANSRECTAL PROSTATE BIOPSY

Serum prostate specific antigen (PSA) level is increased after needle biopsy (Bx) of the prostate. This study tested the hypothesis that the prostate harboring malignant lesions demonstrates less leakage of PSA after prostate biopsy and this phenomenon can be helpful in discriminating benign from cancer diagnosis. This prospective study was divided into 3 separate phases. Sextant prostate biopsy was done with transrectal ultrasound guidance, and the change and PSA values after biopsy were evaluated. Phases 1 and 2 had 20 and 41 patients, respectively. PSA dynamic profiles were plotted. We defined the most appropriate timing for blood sampling and the cutoff value of the PSA ratio (post-Bx total PSA-to-pre-Bx total PSA) to be applied for further assessment. Phase 3 recruited 97 cases, of which 66 satisfied the end point criteria in which a diagnosis such as malignancy, or 3 successive benign biopsies or benign transurethral resection of prostate was obtained. From phases 1 and 2 the cutoff value for the PSA ratio was 2.0, and the timing of blood sampling was 60 minutes after the biopsy. In phase 3 of those whose PSA ratio was less than 2.0, 92.6% (25) had cancer. For those whose PSA ratio was greater than 2.0, 82.1% (32) were benign. Of the 4 cases with a PSA ratio less than 2.0 and an initial benign biopsy, 3 (75%) were proven to have cancer later. Evaluating the 1-hour PSA ratio might be helpful for clinicians to select the high risk patients who might have cancer in the prostate. Repeat biopsy should be suggested for cases with a smaller PSA ratio in spite of initial benign results.

The predictive value for prostate cancer of lesions that raise suspicion of concomitant carcinoma: an evaluation from a randomized, population-based study of screening for prostate cancer.

Suspicion of prostate carcinoma may persist after an initial negative biopsy result, and repeated biopsy is suggested. The authors assessed whether diagnostic follow-up of men with an initial diagnosis of isolated, high-grade prostatic intraepithelial neoplasia (HPIN) and a prostate biopsy suspicious for malignancy (PBSM) is needed. The frequency of isolated HPIN and PBSM was determined in 4057 participants of a population-based screening study who underwent systematic sextant transrectal biopsy. The predictive value for prostate carcinoma of HPIN and PBSM was determined by performing repeated biopsies at 6-week interval. The additional predictive value for malignant disease within a screened population was assessed by performing repeated biopsies at a 1-year interval in 462 consecutively recruited men with an initial benign biopsy result. Participants were subjected to a second screening at a 4-year interval. The biopsy and radical prostatectomy tumor features were determined. Isolated HPIN and PBSM were diagnosed in 0.8% and 2.6% of biopsied men, respectively. The detection rates on repeated biopsy were 10.0% (3 of 30 men) for isolated HPIN, 38.7% (36 of 93 men) for PBSM, and 11.0% (51 of 462 men) for those with initial benign biopsy results. Except for two men (one with PBSM and one with HPIN), all others remained free of prostate carcinoma at their second screening. Features of the tumors that were detected after PBSM were comparable to those that were detected on initial biopsy, whereas the few tumors that were diagnosed after HPIN had highly favorable features. Compared with men who have PBSM, men with isolated HPIN on initial biopsy are at no greater risk of being diagnosed with prostate carcinoma than if their initial biopsies were assessed as benign only. Moreover, the features of tumors that are diagnosed after an evaluation of HPIN warrant no early, extensive diagnostic follow-up.

PREDICTORS OF FIRST REPEAT BIOPSY CANCER DETECTION WITH SUSPECTED LOCAL STAGE PROSTATE CANCER

We determine demographic and tumor related predictors of repeat biopsy cancer detection in men with suspected stage T1c-2 prostate cancer. The study population included 298 consecutive men with suspected stage T1c-2 prostate cancer who had a benign prostate biopsy at 1 institution between January 1, 1992 and April 1, 1999 and underwent 1 repeat biopsy. Mean age plus or minus standard deviation was 66.8+/-6.7 years for 133 black (55%) and 165 white (45%) patients. Clinical measures included determination of high grade prostatic intraepithelial neoplasia in benign biopsy specimens, Gleason score of malignant biopsy specimens, prostate specific antigen (PSA), PSA density, annualized interbiopsy PSA change, percent free PSA (201 cases) and PSA velocity (171). Cancer was detected on repeat biopsy in 80 cases (27%). Significant differences between patients with benign and malignant repeat biopsies included age (p = 0.001), PSA density (p = 0.0001), percent free PSA (p = 0.0001) and PSA velocity (p = 0.009). High grade prostatic intraepithelial neoplasia in an initial benign biopsy was not predictive of cancer in repeat biopsy (p = 0.12). Multiple logistic regression analysis of all cases showed that age (p = 0.002) and PSA density (p = 0.0002) were independent predictors of cancer. Subset multiple logistic regression analysis modeled with age, PSA density and percent free PSA demonstrated that age (p = 0.002) and percent free PSA (p = 0.0001) were significant independent predictors of malignancy. Subset multiple logistic regression analysis modeled with age, PSA density, percent free PSA and PSA velocity revealed that age (p = 0.02) and percent free PSA (p = 0.0003) were significant independent predictors of cancer. There were no significant differences between the Gleason scores of cancers detected on repeat biopsy compared to 587 stage T1c-2 cancers detected on initial biopsy during the study period (p = 0.09). PSA, PSA density, percent free PSA and PSA velocity were not significantly different among men without a cancer diagnosis who had high grade neoplasia in 1 or 2 benign biopsies. Greater than 25% of this population of select patients with suspected stage T1c-2 prostate cancer had malignancy detected on repeat biopsy. Percent free PSA was the most powerful predictor of cancer. High grade prostatic intraepithelial neoplasia was not a predictor of repeat biopsy cancer detection and PSA functions were similar among men without cancer who did and did not have high grade neoplasia in 1 or more benign biopsies. This finding suggests that high grade prostatic intraepithelial neoplasia may not be a reliable indicator of clinically significant existing prostate cancer.

The significance of intraluminal prostatic crystalloids in benign needle biopsies.

Intraluminal prostatic crystalloids (IPC) are more common in prostate cancer acini than in benign acini. This study was undertaken to evaluate the hypothesis that crystalloids seen in a benign biopsy may indicate an increased risk of a concomitant prostatic carcinoma. A total of 600 patients underwent more than one prostate biopsy. For 394 patients the results of the biopsy were either negative or positive for prostate cancer. After exclusion of patients whose biopsy results were considered negative but coded as high-grade prostatic intraepithelial neoplasia or were suspicious for cancer or whose slides were unavailable for review, 331 patients remained. Biopsy results for these patients were evaluated for the presence of IPC. Also, 18 completely-embedded benign prostates from cystoprostatectomy specimens from patients with bladder cancer were evaluated for the presence of IPC. Seven hundred twenty-five biopsy specimens were reviewed; 51 (7%) contained crystalloids. Thirty-two of 634 (5%) benign biopsy specimens and 19 of 91 (21%) prostatic carcinoma biopsy specimens contained crystalloids. Sixteen of 331 patients (5%) had crystalloids in the initial benign biopsy specimen; 6 patients subsequently were determined to have carcinoma (38%), and 10 continued to have negative results (62%). Three hundred fifteen initial benign biopsies did not show crystalloids; 83 (26%) patients were subsequently diagnosed as having prostatic carcinoma (p = 0.238, Fisher's Exact Test, chi-square test). The IPC were found in 5 of 18 cystoprostatectomy prostates (28%). In this study, the presence of IPC on the initial biopsy specimens was not a significant risk factor for a subsequent diagnosis of prostate cancer. The IPC were not uncommon in prostates without cancer.