Lynn Schoenfield

Saturation Technique Does Not Improve Cancer Detection as an Initial Prostate Biopsy Strategy

PURPOSE We reported on the results of a sequential cohort study comparing office based saturation prostate biopsy to traditional 10-core sampling as an initial biopsy. MATERIALS AND METHODS Based on improved cancer detection of office based saturation prostate biopsy repeat biopsy, we adopted the technique as an initial biopsy strategy to improve cancer detection. Two surgeons performed 24-core saturation prostate biopsies in 139 patients undergoing initial biopsy under periprostatic local anesthesia. Indication for biopsy was an increased PSA of 2.5 ng/dl or greater in all patients. Results were compared to those of 87 patients who had previously undergone 10-core initial biopsies. RESULTS Cancer was detected in 62 of 139 patients (44.6%) who underwent saturation biopsy and in 45 of 87 patients (51.7%) who underwent 10-core biopsy (p >0.9). Breakdown by PSA level failed to show benefit to the saturation technique for any degree PSA increase. Men with PSA 2.5 to 9.9 ng/dl were found to have cancer in 53 of 122 (43.4%) saturation biopsies and 26 of 58 (44.8%) 10-core biopsies. Complications included 3 cases of prostatitis in each group. Rectal bleeding was troublesome enough to require evaluation only in 3 men in the saturation group and 1 in the 10-core group. CONCLUSIONS Although saturation prostate biopsy improves cancer detection in men with suspicion of cancer following a negative biopsy, it does not appear to offer benefit as an initial biopsy technique. These findings suggest that further efforts at extended biopsy strategies beyond 10 to 12 cores are not appropriate as an initial biopsy strategy.

Poor Interobserver Agreement in the Distinction of High-Grade Dysplasia and Adenocarcinoma in Pretreatment Barrett's Esophagus Biopsies

OBJECTIVE:Grading Barretts dysplasia at the lower end of the metaplasia-dysplasia spectrum (negative, indefinite, and low-grade dysplasia) suffers from poor interobserver agreement, even among gastrointestinal pathologists. Data evaluating interobserver agreement in Barretts mucosal biopsies with changes at the upper end of the dysplasia spectrum (high-grade dysplasia, intramucosal, and submucosal adenocarcinoma) have not been published. The accurate categorization of pretreatment biopsies drives therapeutic decision making, but if the diagnostic distinction between cancer and high-grade dysplasia in Barretts biopsies is inconsistent, then the use of these diagnoses to make management decisions is suspect. To this end, our aim was to assess interobserver reproducibility among a group of gastrointestinal pathologists in the interpretation of preresection biopsies.METHODS:All study pathologists agreed upon the histologic criteria distinguishing four diagnostic categories, including high-grade dysplasia; high-grade dysplasia with marked distortion of glandular architecture, cannot exclude intramucosal adenocarcinoma; intramucosal adenocarcinoma; and submucosally invasive adenocarcinoma. The histologic criteria were used to independently review preresection biopsies from 163 consecutive Barretts esophagus patients with at least high-grade dysplasia who ultimately underwent esophagectomy. Reviewers recorded the specific histologic criteria used to categorize each case and Kappa statistics were calculated to assess interobserver agreement.RESULTS:Using kappa statistics, the overall agreement was only fair (κ= 0.30). Agreement for high-grade dysplasia was moderate (κ= 0.47), while agreement for high-grade dysplasia with marked architectural distortion, cannot exclude intramucosal adenocarcinoma and intramucosal adenocarcinoma were only fair (κ= 0.21 and 0.30, respectively) and agreement for submucosal adenocarcinoma was poor (κ= 0.14).CONCLUSIONS:The overall poor interobserver reproducibility among gastrointestinal pathologists who see a high volume of Barretts cases calls into question treatment regimens based on the assumption that high-grade dysplasia, intramucosal adenocarcinoma, and submucosal adenocarcinoma can reliably be distinguished in biopsy specimens.

Importance of Additional “Extreme” Anterior Apical Needle Biopsies in the Initial Detection of Prostate Cancer

OBJECTIVES To describe our experience of adding extreme apical cores in men undergoing initial biopsy. Prostate cancer detection efforts have focused on increasing the number of cores. A more significant factor, however, may be their location. Laterally directed and apical cores have been associated with the highest cancer detection rate, especially the apical cores for men undergoing repeated biopsies. METHODS A prospective trial was conducted between September 2007 and April 2009. A total of 181 men with increased prostate-specific antigen (PSA) or abnormal digital rectal examination (DRE), or both, underwent an initial transrectal ultrasound-guided biopsy (TRUS-BX). All patients underwent a standard 12-core biopsy scheme plus 2 additional cores taken from the extreme anterior apex, defined as the site immediately lateral to the junction of apex and urethra. Each core was marked by a special colored ink for identification. Site-specific detection and tumor characteristics were reported. RESULTS Prostate cancer was detected in 86 patients (47.5%). The apical cores (3 on each side) achieved the highest cancer detection rate (73.6% of all cancers), and the additional extreme anterior apical cores (1 on each side) achieved the highest rate of unique cancer detection (P = .011). CONCLUSIONS From our experience, the apical cores, especially the extreme apical cores, increase prostate cancer detection on initial TRUS-BX and minimize the potential for misdiagnosis and need for repeat biopsy.

Saturation Technique Does Not Decrease Cancer Detection During Followup After Initial Prostate Biopsy

PURPOSE It has been reported that the prostate cancer detection rate in men with prostate specific antigen 2.5 ng/ml or greater undergoing saturation (20 cores or greater) prostate biopsy as an initial strategy is not higher than that in men who undergo 10 to 12 core prostate biopsy. At a median followup of 3.2 years we report the cancer detection rate on subsequent prostate biopsy in men who underwent initial saturation prostate biopsy. MATERIALS AND METHODS Saturation prostate biopsy was used as an initial biopsy strategy in 257 men between January 2002 and April 2006. Cancer was initially detected in 43% of the patients who underwent saturation prostate biopsy. In the 147 men with negative initial saturation prostate biopsy followup including digital rectal examination and repeat prostate specific antigen measurement was recommended at least annually. Persistently increased prostate specific antigen or an increase in prostate specific antigen was seen as an indication for repeat saturation prostate biopsy. RESULTS During the median followup of 3.2 years after negative initial saturation prostate biopsy 121 men (82%) underwent subsequent evaluation with prostate specific antigen and digital rectal examination. Median prostate specific antigen remained 4.0 ng/ml or greater in 57% of the men and it increased by 1 ng/ml or greater in 23%. Cancer was detected in 14 of 59 men (24%) undergoing repeat prostate biopsy for persistent clinical suspicion of prostate cancer. No significant association was demonstrated between cancer detection and initial or followup prostate specific antigen, or findings of atypia and high grade prostatic intraepithelial neoplasia on initial saturation prostate biopsy. Cancers detected on repeat prostate biopsy were more likely to be Gleason 6 and organ confined at prostatectomy than were those diagnosed on initial saturation prostate biopsy. CONCLUSIONS Previous experience suggests that, while office based saturation prostate biopsy improves cancer detection in men who have previously undergone a negative prostate biopsy, it does not improve cancer detection as an initial biopsy technique. We now report that the false-negative rate on subsequent prostate biopsy after initial saturation prostate biopsy is equivalent to that following traditional prostate biopsy. These data provide further evidence against saturation prostate biopsy as an initial strategy.

The incidence of high-grade prostatic intraepithelial neoplasia and atypical glands suspicious for carcinoma on first-time saturation needle biopsy, and the subsequent risk of cancer.

To investigate the detection rate and extent of high‐grade prostatic intraepithelial neoplasia (HGPIN) and atypical glands (AG) suspicious for prostate cancer, and the cancer risk in subsequent biopsies, diagnosed by a first 24‐core saturation biopsy, as although the optimum extent of biopsy is controversial there is a trend to increase the number of cores taken, and apart from detecting prostate cancer, identifying HGPIN and AG is associated with a greater risk of finding cancer in subsequent biopsies, thus warranting a closer follow‐up.

Variation of monosomy 3 status within uveal melanoma.

CONTEXT Determining the most significant prognostic variables in uveal melanoma is important for stratifying patients for metastasis surveillance and possible initiation of chemotherapy or immunotherapy. Monosomy 3, one such variable, can be determined using fluorescence in situ hybridization, either on enucleated samples, fine-needle aspiration biopsy, or tumor sample obtained by vitrector. OBJECTIVE To evaluate possible regional discordance in chromosome 3 by sites likely to be sampled by different biopsy methods. DESIGN Eighteen consecutive patients with uveal melanoma who underwent primary enucleation were studied. Representative paraffin blocks were selected based on review of hematoxylin-eosin stained sections, and the apex and base of each tumor was demarcated. Unstained paraffin sections, 4 mum in thickness, were prepared, and fluorescence in situ hybridization, looking for monosomy 3, was performed. The chromosomal analysis was also correlated with histologic evaluation for melanoma cell type (spindle vs epithelioid cell), ciliary body involvement, presence of positive periodic acid-Schiff vascular mimicry patterns, scleral or extrascleral spread and size. One case was excluded because of necrosis. RESULTS Ten of the 17 remaining cases (59%) demonstrated monosomy 3 (in either the base or both base and apex of the tumor) with 7 cases (41%) showing disomy. Seven cases (70%) with monosomy 3 demonstrated this in both the apex and the base locations, whereas 3 cases (30%) showed monosomy in one location only (always at the base). Fourteen of the 17 cases (82%) revealed concordance in chromosome 3-monosomy 3 (7 of 14, 50%) or chromosome 3-disomy 3 (7 of 14, 50%). All 3 discordant cases demonstrated the monosomy 3 at the base with disomy at the apex. Lack of concordance between the base and apex did not correlate with melanoma cell type. CONCLUSIONS Prognostic variables are important in management of neoplasms, and this study points out that the site of tissue biopsy for prognostication in uveal melanoma could affect the results obtained, at least for the presence of monosomy 3.

Orbital inflammation in IgG4-related sclerosing disease.

IgG4-related sclerosing disease is a recently described systemic inflammatory disease that should be considered when evaluating patients with nonspecific orbital inflammation (pseudotumor). Orbital biopsy is necessary to establish a diagnosis and demonstrates lymphoplasmacytic infiltration, fibrosis, obliterative phlebitis of medium and small veins, and variable degrees of eosinophilia. We report the clinical and histopathological findings of 2 patients who developed chronic orbital inflammation as a manifestation of IgG4-related sclerosing disease. The 2 cases illustrate the widely varying clinical characteristics of this elusive disease.

Activated CD11b+ CD15+ Granulocytes Increase in the Blood of Patients with Uveal Melanoma

PURPOSE To determine whether activated CD11b(+) CD15(+) granulocytes increase in the blood of patients with uveal melanoma. METHODS Peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation from the blood of patients with primary choroidal/ciliochoroidal uveal melanomas (six women, four men; age range, 46-91 years) and healthy control donors (14 women, 10 men; age range, 50-81 years). The expression of CD15 and CD68 on CD11b(+) myeloid cells within PBMCs and primary uveal melanomas was evaluated by flow cytometry. CD3zeta chain expression by CD3epsilon(+) T cells in PBMCs and within primary uveal melanomas was measured as an indirect indication of T-cell function. RESULTS The percentage of CD11b(+) cells in PBMCs of patients with uveal melanoma increased 1.8-fold in comparison to healthy donors and comprised three subsets: CD68 negative CD15(+) granulocytes, which increased 4.1-fold; CD68(-) CD15(-) cells, which increased threefold; and CD68(+) CD15(low) cells, which were unchanged. A significant (2.7-fold) reduction in CD3zeta chain expression on CD3epsilon(+) T cells, a marker of T-cell dysfunction, was observed in PBMCs of patients with uveal melanoma in comparison with healthy control subjects and correlated significantly with the percentage of CD11b(+) cells in PBMCs. CD3zeta chain expression on T cells within primary tumors was equivalent to CD3zeta expression in PBMCs of the same patient in four of five patients analyzed. CONCLUSIONS Activated CD11b(+) CD15(+) granulocytes expand in the blood of patients with uveal melanoma and may contribute to immune evasion by ocular tumors by inhibiting T-cell function via decreasing CD3zeta chain expression.

Chromosomal 3 and 8 status within hepatic metastasis of uveal melanoma.

CONTEXT Several studies have evaluated clinical, histopathologic, cytogenetic, and molecular prognostic variables in uveal melanoma. However, it is not known whether the primary tumor cells maintain these aggressive attributes at the metastatic sites. OBJECTIVE To determine the status of chromosomes 3 and 8q and c-myc amplification using fluorescence in situ hybridization on hepatic metastatic lesions of primary uveal melanoma. DESIGN Ten patients with uveal melanoma with needle core biopsy-confirmed hepatic metastasis. Representative paraffin blocks were selected based on review of hematoxylin-eosin-stained sections. Fluorescence in situ hybridization was performed for detection of monosomy 3 and amplification at the 8q24 MYC locus using standard methods. The tricolor chromosome enumeration probe 8 (CEP8)/IGH/MYC and the Urovysion probe consisting of CEP3, CEP7, CEP17, and 9P21 probes were used. A total of 200 interphase cells were scored. RESULTS Hepatic metastasis was confirmed in each case by needle core biopsy. Fluorescence in situ hybridization analysis revealed chromosome 3 monosomy in 5 of the 8 cases that could be satisfactorily evaluated. Aneusomy of chromosome 8 was observed in 2 cases. MYC amplification was observed in 5 samples. In a single case where the primary tumor was treated by enucleation, the chromosomal monosomy 3 and aneusomy of chromosome 8 were present both in the primary tumor and its hepatic metastatic lesion. CONCLUSIONS The presence of cytogenetic changes within the metastatic lesions confirms that chromosome 3 monosomy and aneusomy of chromosome 8 are not just markers of metastatic potential of the primary tumor but are also present within the hepatic metastatic lesions.

Diagnostic pitfalls of differentiating desmoplastic small round cell tumor (DSRCT) from Wilms tumor (WT): overlapping morphologic and immunohistochemical features.

Desmoplastic small round cell tumor (DSRCT) and blastemal-predominant Wilms tumor (WT) share overlapping histologic features, yet accurate distinction is critical because of differing prognosis and treatment. We encountered a neck mass in a young adult with a concomitant abdominal mass. The neck mass was initially concerning for DSRCT on the basis of the poorly differentiated morphology, desmoplastic stroma, and immunoreactivity for desmin and cytokeratin. However, focal triphasic elements and glomeruloid bodies were identified on deeper sections, WT1 immunoreactivity was seen with antibodies to both the amino-terminus and carboxy-terminus, and EWSR1-WT1 rearrangement studies were negative, supporting the ultimate diagnosis of WT. On the basis of the overlapping histologic features of DSRCT and blastemal-predominant WT, we undertook a comparison study of desmin and cytokeratin reactivity patterns. We found that, whereas desmin reactivity was more frequent in DSRCT (11 of 12) than in WT blastema (11 of 22, P=0.024), dot-like perinuclear reactivity was seen with equal frequency in desmin-reactive DSRCT (10 of 11) and WT blastema (10 of 11), illustrating an important diagnostic pitfall. Moreover, we demonstrate coexpression of desmin and cytokeratin in both DSRCT (9 of 12) and WT blastema (11 of 22). Importantly, although dot-like desmin reactivity and coexpression of desmin and cytokeratin are historically associated with DSRCT, we demonstrate that these features can be seen in either DSRCT or blastemal-predominant WT. In these challenging cases, detection of an EWSR1-WT1 rearrangement and selective WT1 carboxy-terminus immunoreactivity (characteristic of DSRCT) or dual immunoreactivity for the WT1 amino-terminus and carboxy-terminus (characteristic of WT) remain the most discriminating diagnostic tools.