Manju Aron

Magnetic Resonance Imaging–Transectal Ultrasound Image-fusion Biopsies Accurately Characterize the Index Tumor: Correlation with Step-sectioned Radical Prostatectomy Specimens in 135 Patients

BACKGROUND Prostate biopsies targeted by elastic fusion of magnetic resonance (MR) and three-dimensional (3D) transrectal ultrasound (TRUS) images may allow accurate identification of the index tumor (IT), defined as the lesion with the highest Gleason score or the largest volume or extraprostatic extension. OBJECTIVE To determine the accuracy of MR-TRUS image-fusion biopsy in characterizing ITs, as confirmed by correlation with step-sectioned radical prostatectomy (RP) specimens. DESIGN, SETTING, AND PARTICIPANTS Retrospective analysis of 135 consecutive patients who sequentially underwent pre-biopsy MR, MR-TRUS image-fusion biopsy, and robotic RP at two centers between January 2010 and September 2013. INTERVENTION Image-guided biopsies of MR-suspected IT lesions were performed with tracking via real-time 3D TRUS. The largest geographically distinct cancer focus (IT lesion) was independently registered on step-sectioned RP specimens. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS A validated schema comprising 27 regions of interest was used to identify the IT center location on MR images and in RP specimens, as well as the location of the midpoint of the biopsy trajectory, and variables were correlated. RESULTS AND LIMITATIONS The concordance between IT location on biopsy and RP specimens was 95% (128/135). The coefficient for correlation between IT volume on MRI and histology was r=0.663 (p<0.001). The maximum cancer core length on biopsy was weakly correlated with RP tumor volume (r=0.466, p<0.001). The concordance of primary Gleason pattern between targeted biopsy and RP specimens was 90% (115/128; κ=0.76). The study limitations include retrospective evaluation of a selected patient population, which limits the generalizability of the results. CONCLUSION Use of MR-TRUS image fusion to guide prostate biopsies reliably identified the location and primary Gleason pattern of the IT lesion in >90% of patients, but showed limited ability to predict cancer volume, as confirmed by step-sectioned RP specimens. PATIENT SUMMARY Biopsies targeted using magnetic resonance images combined with real-time three-dimensional transrectal ultrasound allowed us to reliably identify the spatial location of the most important tumor in prostate cancer and characterize its aggressiveness.

Immunohistochemical evaluation of novel and traditional markers associated with urothelial differentiation in a spectrum of variants of urothelial carcinoma of the urinary bladder

Data on immunohistochemical expression of novel and traditional urothelial markers in the wide range of urothelial carcinoma variants have so far been very limited. In this study, whole tissue sections from 130 bladder urothelial carcinoma and variants were stained with a panel of novel and traditional immunomarkers supportive of urothelial lineage. The positivity rates were as follows: (a) urothelial carcinomas with or without divergent differentiation: GATA3 (50%), S-100P (86%), uroplakin III (20%), thrombomodulin (40%), cytokeratin 7 (CK7) (80%), CK20 (55%), p63 (87%), and high molecular weight cytokeratin (HMCK) (89%); (b) urothelial carcinoma variants (micropapillary, plasmacytoid, nested, clear cell, and microcystic): GATA3 (88%), S-100P (96%), uroplakin III (33%), thrombomodulin (49%), CK7 (95%), CK20 (61%), p63 (69%), and HMCK (96%); and (c) undifferentiated carcinomas (lymphoepithelioma-like carcinoma, small cell carcinoma, sarcomatoid carcinoma and carcinoma with rhabdoid and giant cells): GATA3 (28%), S-100P (31%), uroplakin III (0%), thrombomodulin (22%), CK7 (50%), CK20 (3%), p63 (50%), and HMCK (49%). In urothelial carcinoma with squamous differentiation, GATA3 expression was lower (20%) in contrast to p63 and S-100P. In urothelial carcinoma with glandular differentiation, GATA3 (50%) and p63 (60%) expression was lower than S-100P (100%). p63 expression was relatively lower in micropapillary (54%) and plasmacytoid (50%) variants compared with the other urothelial carcinoma variants. This study provides comprehensive data for novel and traditionally used markers to support urothelial lineage in urothelial carcinoma variants. Our findings show that GATA3, S-100P, CK7, CK20, HMCK, and p63, in the appropriate differential diagnostic setting, are useful to support urothelial lineage of variant morphologies.

Clear cell-papillary renal cell carcinoma of the kidney not associated with end-stage renal disease: Clinicopathologic correlation with expanded immunophenotypic and molecular characterization of a large cohort with emphasis on relationship with renal angiomyoadenomatous tumor

Clear cell-papillary renal cell carcinoma (CC-Pap RCC) is a recently described renal tumor initially reported in the setting of end-stage renal disease (ESRD). It has unique morphologic and immunohistochemical features that differentiate it from the more common clear cell RCC and papillary RCC. Recently, these tumors have also been described in a sporadic setting. We studied 64 cases of CC-Pap RCC not associated with ESRD (57 CC-Pap RCCs and 7 cases with features of renal angiomyoadenomatous tumors [RAT] including 5 initially diagnosed as such). The morphologic features of all cases and the immunohistochemical profile of 59 cases were studied along with the clinical and molecular features of 30 and 12 cases, respectively. All the tumors were well circumscribed with a mean tumor size of 2.6 cm and showed a wide array of architectural patterns, usually mixed, including tubular (77%), papillary (62%), tubulocystic (52%), and compact nested (21%). Seventy-three percent of the cases showed areas in which the tumor nuclei had a distinct orientation away from the basement membrane. Ninety-two percent of the cases had a low Fuhrman nuclear grade (nuclear grade 2%‐86%, and nuclear grade 1%‐6%); however, 8% cases showed foci of Fuhrman nuclear grade 3. In 4 cases, epithelial tumor comprised <5% of the tumor; >95% of the tumor was cystic or hyalinized. The stroma varied from being minimal to occasionally prominent myxoid to hyalinized and rarely with organized amianthoid fibers or well-defined smooth muscle bundles. Pathologic stage was reliably assigned in 60 cases, of which 93.3% (56 cases) were pT1, 3.3% (2 cases) were pT2, and 3.3% (2 cases) were pT3a with extension into the perinephric fat. One case had coagulative necrosis; sarcomatoid change and vascular invasion was not identified. The tumors showed a fairly typical immunoprofile characterized by positivity for CK7 (100%), HMCK (96%), CAIX (94%), and vimentin (100%) with negativity for AMACR, RCC, and TFE3; CD10 was positive in 24%. None of the cases tested showed recurrent chromosomal imbalances by virtual karyotyping, fluorescence in situ hybridization, or 3p loss of heterozygosity analysis. VHL gene mutations were, however, noted in 3 cases (2 in exon 1 and 1 in exon 3). Clinical follow-up information was available in 47% of the patients, with a mean and median follow-up of 47 and 37 months, respectively (range, 18 to 108 mo). One case occurred in the setting of VHL syndrome and multiple benign cysts. None of the cases showed local recurrence, metastasis, or death due to disease. Morphology, immunophenotype, and molecular studies did not vary between typical cases, those with prominent smooth muscle (so-called RAT), and historically published data on cases occurring in ESRD. Our analysis confirms that CC-Pap RCC is a unique subtype of adult renal epithelial neoplasia in which tumors are frequently small, are of low nuclear grade and pathologic stage, and have extremely favorable short to intermediate range prognosis. Tumors occurring sporadically, with prominent smooth muscle stroma (so-called RAT), and occurring in ESRD are in the spectrum of the same category of tumors.

Utility of a triple antibody cocktail intraurothelial neoplasm-3 (IUN-3-CK20/CD44s/p53) and α-methylacyl-CoA racemase (AMACR) in the distinction of urothelial carcinoma in situ (CIS) and reactive urothelial atypia.

Urothelial carcinoma in situ (CIS) is a prognostically and therapeutically significant lesion with considerable morphologic overlap with reactive conditions especially in the setting of prior therapy. Various markers including CK20, CD44s, and p53 have been used as an adjunct in making this distinction; however, the utility of these markers in the posttreatment scenario is not fully established. &agr;-Methylacyl-CoA racemase (AMACR) is a tumor-associated marker that is expressed in a subset of high-grade urothelial carcinomas but has not been studied in CIS. This study was undertaken to evaluate the immunoreactivity of CK20, CD44s, and p53 as a triple antibody cocktail intraurothelial neoplasm-3 (IUN-3) in distinguishing CIS from its mimics and to compare its utility with AMACR in the diagnosis of CIS. A total of 135 specimens (7 benign ureters and 128 bladder biopsies—28 reactive, 33 posttherapy reactive, 43 CIS, 24 CIS posttherapy) were included in this study. Immunostaining for p53 (brown, nuclear), CD44s (brown, membranous), and CK20 (red, cytoplasmic and membranous) was performed as a cocktail, and the staining pattern was further classified as: malignant (full-thickness CK20 and/or full-thickness p53 with CD44s negativity), reactive/benign (CK20 limited to the umbrella cell layer, p53 negative, and CD44s positivity ranging from basal to full thickness), and indeterminate (CK20 and p53 positive but not full thickness and/or CD44s positive). AMACR staining was performed in 50 cases. Cytoplasmic staining for AMACR was graded as negative (absent to weak focal staining [<5% cells]) and positive (≥5%). The “IUN-3 malignant” pattern was observed in 84% of cases of CIS without a history of prior therapy and in 71% of the cases of CIS with a history of prior therapy. Cases with posttherapy reactive atypia showed an “IUN-3 reactive” pattern in 84% cases and “IUN-3 indeterminate” pattern in 16% of the cases; the IUN-3 malignant pattern was not identified in any of the cases. Benign and reactive urothelium (with and without a history of therapy) showed an IUN-3 reactive pattern and negative AMACR staining in all the cases (100%). AMACR positivity was observed in 78% of nontreated CIS cases and 50% of CIS posttherapy cases. In these cases, the IUN-3 cocktail showed an IUN-3 malignant pattern in 83% of untreated CIS cases and 88% of CIS posttherapy cases. AMACR positivity is a potentially useful marker of CIS. However, the IUN-3 malignant pattern is a more reliable indicator of CIS compared with AMACR, especially in the posttreatment setting. The simultaneous evaluation of all 3 markers (p53, CD44s, and CK20) in a single slide in the form of a cocktail is advantageous, especially in small biopsy specimens.

Cytologic Diagnosis of Pulmonary Nocardiosis

Background Nocardiosis is an uncommon infection and presents as an opportunistic infection in an immunocompromised host. Pulmonary infection by Nocardia may be difficult to diagnose based on clinical and radiologic features, as these are not specific. Sputum examination, bronchoalveolar lavage and transthoracic ultrasound/ computed tomography-guided fine needle aspiration cytology offer a simple means of procuring material for diagnostic evaluation. Very few articles have described the morphologic appearance of this uncommon pathogen in cytologic material. Cases Three cases occurred in patients with an underlying immunocompromised state. Patient 1 was on steroid therapy for nephrotic syndrome, patient 2 was on immunosuppressant therapy after renal transplantation, and patient 3 was HIV positive. A diagnosis of pulmonary nocardiosis was suspected on Papanicolaou stain. Modified Ziebl-Neelsen stain and silver methanamine stains were useful in confirming the diagnosis. Conclusion A high index of suspicion for nocardiosis must be maintained while assessing cytologic material in immunosuppressed individuals as it may be masked by the intense inflammatory exudate associated with this infection. A meticulous search may reveal the presence of delicate, thin, faintly stained, branching filaments of Nocardia on routine Papanicolaou stain. Special stains and culture studies are useful in confirming the diagnosis.

Fine needle aspiration cytology of follicular variant of papillary carcinoma of the thyroid: Morphologic pointers to its diagnosis.

OBJECTIVE To study the cytomorphologic features of 59 cases of histologically proven follicular variant of papillary carcinoma (FVPC), compare them to those described in the literature and highlight cytologic features that may aid in the preoperative diagnosis. STUDY DESIGN Aspiration smears from 59 histologically proven cases of FVPC were examined independently by 2 observers, and a detailed cytologic evaluation was done for architectural, cytologic and nuclear features. surgical RESULTS On initial cytology of the 59 cases, 36 (61%) were diagnosed aspapillary carcinoma, and 17 of these were subtyped as FVPC. On reviewing the smears, 50 cases were diagnosed as papillary carcinoma, and 33 of them were typed as FVPC; however, 4 cases were diagnosed as benign lesions. Most smears showed moderate to high cellularity, with 55 cases (93%) showing syncytial clusters and 48 (81%) showing microfollicular architecture. Chromatin clearing and nuclear grooves were seen in 55 (93.2%) and 54 (91.52%) cases but were easily detected in only 36 (61%) and 44 (74%) cases, respectively. Thick colloid was identified in 28 cases, and 3 of these cases also showed thin colloid in the background. CONCLUSION Our findings suggest that syncytial clusters, microfollicular architecture, chromatin clearing and nuclear grooves are strong morphologic pointers to the diagnosis of FVPC.

Identifying aggressive prostate cancer foci using a DNA methylation classifier

BackgroundSlow-growing prostate cancer (PC) can be aggressive in a subset of cases. Therefore, prognostic tools to guide clinical decision-making and avoid overtreatment of indolent PC and undertreatment of aggressive disease are urgently needed. PC has a propensity to be multifocal with several different cancerous foci per gland.ResultsHere, we have taken advantage of the multifocal propensity of PC and categorized aggressiveness of individual PC foci based on DNA methylation patterns in primary PC foci and matched lymph node metastases. In a set of 14 patients, we demonstrate that over half of the cases have multiple epigenetically distinct subclones and determine the primary subclone from which the metastatic lesion(s) originated. Furthermore, we develop an aggressiveness classifier consisting of 25 DNA methylation probes to determine aggressive and non-aggressive subclones. Upon validation of the classifier in an independent cohort, the predicted aggressive tumors are significantly associated with the presence of lymph node metastases and invasive tumor stages.ConclusionsOverall, this study provides molecular-based support for determining PC aggressiveness with the potential to impact clinical decision-making, such as targeted biopsy approaches for early diagnosis and active surveillance, in addition to focal therapy.

Neural tumours of the neck presenting as thyroid nodules: a report of three cases.

Objectives:  Neural tumours of the neck may at times secondarily involve the thyroid and manifest clinically as thyroid nodules. On cytological evaluation these nodules may be confused with other spindle lesions of the thyroid. We report two cases of schwannoma and one case of a malignant peripheral nerve sheath tumour (MPNST) of the neck, which presented as thyroid nodules and evaluate the role of cytology in identifying these tumours.

Prostate Cancer Volume Estimation by Combining Magnetic Resonance Imaging and Targeted Biopsy Proven Cancer Core Length: Correlation with Cancer Volume

PURPOSE Multiparametric magnetic resonance imaging often underestimates or overestimates pathological cancer volume. We developed what is to our knowledge a novel method to estimate prostate cancer volume using magnetic resonance/ultrasound fusion, biopsy proven cancer core length. MATERIALS AND METHODS We retrospectively analyzed the records of 81 consecutive patients with magnetic resonance/ultrasound fusion, targeted biopsy proven, clinically localized prostate cancer who underwent subsequent radical prostatectomy. As 7 patients each had 2 visible lesions on magnetic resonance imaging, 88 lesions were analyzed. The dimensions and estimated volume of visible lesions were calculated using apparent diffusion coefficient maps. The modified formula to estimate cancer volume was defined as the formula of vertical stretching in the anteroposterior dimension of the magnetic resonance based 3-dimensional model, in which the imaging estimated lesion anteroposterior dimension was replaced by magnetic resonance/ultrasound targeted, biopsy proven cancer core length. Agreement of pathological cancer volume with magnetic resonance estimated volume or the novel modified volume was assessed using a Bland-Altman plot. RESULTS Magnetic resonance/ultrasound fusion, biopsy proven cancer core length was a stronger predictor of the actual pathological cancer anteroposterior dimension than magnetic resonance estimated lesion anteroposterior dimension (r = 0.824 vs 0.607, each p <0.001). Magnetic resonance/ultrasound targeted, biopsy proven cancer core length correlated with pathological cancer volume (r = 0.773, p <0.001). The modified formula to estimate cancer volume demonstrated a stronger correlation with pathological cancer volume than with magnetic resonance estimated volume (r = 0.824 vs 0.724, each p <0.001). Agreement of modified volume with pathological cancer volume was improved over that of magnetic resonance estimated volume on Bland-Altman plot analysis. Predictability was more enhanced in the subset of lesions with a volume of 2 ml or less (ie if spherical, the lesion was approximately 16 mm in diameter). CONCLUSIONS Combining magnetic resonance estimated cancer volume with magnetic resonance/ultrasound fusion, biopsy proven cancer core length improved cancer volume predictability.

A novel technique using three-dimensionally documented biopsy mapping allows precise re-visiting of prostate cancer foci with serial surveillance of cell cycle progression gene panel

Conventional systematic biopsy has the shortcoming of sampling error and reveals “no evidence of cancer” with a rate of >50% on active surveillance (AS). The objective of this study is to report our initial experience of applying a 3D‐documented biopsy‐mapping technology to precisely re‐visit geographically documented low‐risk prostate cancer and to perform serial analysis of cell‐cycle‐progression (CCP) gene‐panel.