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Despite the benefits of digital pathology, data storage and management of digital whole slide images introduces new logistical and infrastructure challenges to traditionally analog pathology labs.Our goal was to analyze pathologist slide diagnosis patterns to determine the minimum number of pixels required during the diagnosis.We developed a method of using pathologist viewing patterns to vary digital image resolution across virtual slides, which we call variable resolution images. An additional pathologist reviewed the variable resolution images to determine if diagnoses could still be rendered.Across all slides, the pathologists rarely zoomed in to the full resolution level. As a result, the variable resolution images are significantly smaller than the original whole slide images. Despite the reduction in image sizes, the final pathologist reviewer could still proide diagnoses on the variable resolution slide images.Future studies will be conducted to understand variability in resolution requirements between and within pathologists. These findings have the potential to dramatically reduce the data storage requirements of high-resolution whole slide images.

Background Accurate risk stratification can help guide appropriate treatment decisions in men with localized prostate cancer. Here, we evaluated the independent ability of the molecular cell cycle progression (CCP) score and the combined cell-cycle clinical risk (CCR) score to predict 10-year risk of progression to metastatic disease in a large, pooled analysis of men with definitively treated prostate cancer. Methods The pooled analysis included 1,062 patients from four institutions (Martini Clinic, Durham VA Medical Center, Intermountain Healthcare, Ochsner Clinic) treated definitively for localized prostate cancer by either radical prostatectomy or radiotherapy (brachytherapy or external beam radiotherapy ± hormone therapy). The CCP score was determined using the RNA expression of 46 genes from archival formalin-fixed paraffin-embedded biopsy tissue. The CCR score was calculated using a predefined linear combination of the CCP score and the Cancer of the Prostate Risk Assessment (CAPRA) score. The scores were evaluated for association with 10-year risk of metastatic disease following definitive therapy after adjusting for other clinical variables. Results The CCP score was strongly associated with 10-year risk of metastatic disease in multivariable analysis [Hazard Ratio per unit score = 2.21; 95% confidence interval (CI) 1.64, 2.98; p = 1.9 × 10−6] after adjusting for CAPRA, treatment type, and cohort. CCR was also highly prognostic (Hazard Ratio per unit score = 4.00; 95% CI 2.95, 5.42; p = 6.3 × 10−21). There was no evidence of interaction between CCP or CCR and cohort (p = 0.79 and p = 0.86, respectively) or treatment type (p = 0.55 and p = 0.78, respectively). Observed patient CCR-based predicted risks for metastatic disease by 10 years ranged from 0.1 to 99.4%, (IQR 0.7%, 4.6%). Conclusions Both CCP and CCR scores provided independent prognostic information for predicting progression to metastatic disease after both surgery and radiation. These results further demonstrate their potential use as a risk stratification tool in patients with newly-diagnosed prostate cancer.

Better prostate cancer risk stratification is necessary to inform medical management, especially for African American (AA) men, for whom outcomes are particularly uncertain.To evaluate the utility of both a cell cycle progression (CCP) score and a clinical cell-cycle risk (CCR) score to predict clinical outcomes in a large cohort of men with prostate cancer highly enriched in an AA patient population.Patients were diagnosed with clinically localized adenocarcinoma of the prostate and treated at The Ochsner Clinic (New Orleans, LA, USA) from January 2006 to December 2011. CCP scores were derived from archival formalin-fixed, paraffin-embedded biopsy tissue. CCR scores were calculated as the combination of molecular (CCP score) and clinical (Cancer of the Prostate Risk Assessment [CAPRA] score) components.Active treatment (radical prostatectomy, radiation therapy alone, or radiation and hormone therapy) or watchful waiting.The primary outcome was progression to metastatic disease. Association with outcomes was evaluated via Cox proportional hazards survival analysis and likelihood ratio tests.The final cohort included 767 men, of whom 281 (36.6%) were AA. After accounting for ancestry, treatment, and CAPRA in multivariable analysis, the CCP score remained a significant predictor of metastatic disease (hazard ratio [HR] 2.04; p0.001), and there was no interaction with ancestry (p=0.20) or treatment (p=0.09). The CCR score was highly prognostic (HR 3.86; p0.001), and as with the CCP score, there was no interaction with ancestry (p=0.24) or treatment (p=0.32). Limitations include the retrospective study design and the use of self-reported ancestry information.A CCR score provided significant prognostic information regardless of ancestry. The findings demonstrate that AA men in this study cohort appear to have similar prostate cancer outcomes to non-AA patients after accounting for all available molecular and clinicopathologic variables.In this study we evaluated the ability of a combined molecular and clinical score to predict the progression of localized prostate cancer. We found that the combined molecular and clinical score predicted progression to metastasis regardless of patient ancestry or treatment. This suggests that the combined molecular and clinical score may be a valuable tool for determining the risk of metastasis in men with newly diagnosed prostate cancer in order to make appropriate treatment decisions.

Accurate detection and diagnosis of prostate cancer remains challenging even with MRI fusion ultrasound biopsy procedures. These challenges contribute to diagnostic errors that can lead to repeat procedures. This study explores the application of ex vivo structured illumination microscopy (SIM) to generate pathology images of fresh biopsies to inform diagnostic decisions. Samples from the lesion of interest and a benign area of each patient were obtained, stained with fluorescent H&E analog dyes, imaged on a custom SIM system and diagnosed by a pathologist. This procedure could be extrapolated to a “see-and-treat” paradigm for localized prostate cancer ablation in the future.

Background. IgG4-related ophthalmic disease is a rare, newly recognized entity with high failure rates on first-line therapy of systemic corticosteroids and no other proven management options. Case Presentation. Here, we present the clinical course of a patient with IgG4 ophthalmic disease who achieved a favorable response from radiotherapy. Our patient initially presented with a history of recurrent painful flares of orbital inflammation, a pathologic diagnosis follicular lymphoid hyperplasia from a right lacrimal gland biopsy, and MRI imaging noting expansion of the lateral rectus muscle of the right eye. Initial treatment with dacryoadenectomy and multiple courses of corticosteroids failed to keep his symptoms at bay. Further evaluation revealed florid IgG4 staining. In this context, he was evaluated for image-guided intensity-modulated radiotherapy (IG-IMRT) to the orbit to 20 Gy in 10 fractions. His ophthalmic symptoms resolved. Conclusions. This treatment experience suggests radiotherapy may be a favorable option for symptom relief in patients with IgG4-related ophthalmic disease not controlled by corticosteroids.

// Jessie Gills 1, * , Ravan Moret 2, * , Xin Zhang 2 , John Nelson 1 , Grace Maresh 2 , Linh Hellmers 2 , Daniel Canter 1 , M’Liss Hudson 1, 6 , Shams Halat 3 , Marc Matrana 4 , Michael P. Marino 5 , Jakob Reiser 5 , Maureen Shuh 2 , Eric Laborde 1 , Maria Latsis 1 , Sunil Talwar 1 , Stephen Bardot 1 and Li Li 2 1 Department of Urology, Ochsner Clinic Foundation, New Orleans, LA, USA 2 Institution of Translational Research, Ochsner Clinic Foundation, New Orleans, LA, USA 3 Department of Pathology, Ochsner Clinic Foundation, New Orleans, LA, USA 4 Department of Hematology and Oncology, Ochsner Clinic Foundation, New Orleans, LA, USA 5 Division of Cellular and Gene Therapies, The Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA 6 Current address: Memorial Urology Associates, Houston, TX, USA * These authors contributed equally to this work Correspondence to: Stephen Bardot, email: sbardot@ochsner.org Li Li, email: lli@ochsner.org Keywords: patient-derived orthotopic xenograft; high-grade/muscle invasive urothelial cell carcinoma; lymph node stromal cells Received: June 26, 2018 Accepted: August 10, 2018 Published: August 24, 2018 ABSTRACT High-grade urothelial cell carcinoma of the bladder has a poor prognosis when lymph nodes are involved. Despite curative therapy for clinically-localized disease, over half of the muscle-invasive urothelial cell carcinoma patients will develop metastases and die within 5 years. There are currently no described xenograft models that consistently mimic urothelial cell carcinoma metastasis. To develop a patient-derived orthotopic xenograft model to mimic clinical urothelial cell carcinoma progression to metastatic disease, the urothelial cell carcinoma cell line UM-UC-3 and two urothelial cell carcinoma patient specimens were doubly tagged with Luciferase/RFP and were intra-vesically (IB) instilled into NOD/SCID mice with or without lymph node stromal cells (HK cells). Mice were monitored weekly with bioluminescence imaging to assess tumor growth and metastasis. Primary tumors and organs were harvested for bioluminescence imaging, weight, and formalin-fixed for hematoxylin and eosin and immunohistochemistry staining. In this patient-derived orthotopic xenograft model, xenograft tumors showed better implantation rates than currently reported using other models. Xenograft tumors histologically resembled pre-implanted primary specimens from patients, presenting muscle-invasive growth patterns. In the presence of HK cells, tumor formation, tumor angiogenesis, and distant organ metastasis were significantly enhanced in both UM-UC-3 cells and patient-derived specimens. Thus, we established a unique, reproducible patient-derived orthotopic xenograft model using human high-grade urothelial cell carcinoma cells and lymph node stromal cells. It allows for investigating the mechanism involved in tumor formation and metastasis, and therefore it is useful for future testing the optimal sequence of conventional drugs or the efficacy of novel therapeutic drugs.

To identify molecular markers that can accurately predict aggressive tumor behavior at the time of surgery, a propensity-matching score analysis of archived specimens yielded two similar datasets of DTC patients (with and without RAI). Bioinformatically selected microRNAs were quantified by qRT-PCR. The risk score was generated using Cox regression and assessed using ROC, C-statistic, and Brier-score. A predictive Bayesian nomogram was established. External validation was performed, and causal network analysis was generated. Within the eight-year follow-up period, progression was reported in 51.5% of cases, of these, 48.6% had the T1a/b stage. Analysis showed upregulation of miR-221-3p and miR-222-3p and downregulation of miR-204-5p in 68 paired cancer tissues (p &lt, 0.001). These three miRNAs were not differentially expressed in RAI and non-RAI groups. The ATA risk score showed poor discriminative ability (AUC = 0.518, p = 0.80). In contrast, the microRNA-based risk score showed high accuracy in predicting tumor progression in the whole cohorts (median = 1.87 vs. 0.39, AUC = 0.944) and RAI group (2.23 vs. 0.37, AUC = 0.979) at the cutoff &gt, 0.86 (92.6% accuracy, 88.6% sensitivity, 97% specificity) in the whole cohorts (C-statistics = 0.943/Brier = 0.083) and RAI subgroup (C-statistic = 0.978/Brier = 0.049). The high-score group had a three-fold increased progression risk (hazard ratio = 2.71, 95%CI = 1.86–3.96, p &lt, 0.001) and shorter survival times (17.3 vs. 70.79 months, p &lt, 0.001). Our prognostic microRNA signature and nomogram showed excellent predictive accuracy for progression-free survival in DTC.

Halat S, Eble J N, Grignon D J, Lacy S, Montironi R, MacLennan G T, Lopez-Beltran A, Tan P-H, Baldridge L A & Cheng L (2011) Histopathology58, 750–758 Ectopic prostatic tissue: histogenesis and histopathological characteristics Aims: To evaluate the histological and immunohistochemical characteristics of ectopic prostatic tissue. Methods and results: We studied 20 cases of ectopic prostate. In 85% (17/20) of the cases, the ectopic prostatic tissue was located in the bladder; in the remaining cases, it was located in the urethra. In 60% of the cases (12/20), no significant inflammatory or reactive/reparative changes were identified in the adjacent tissue. Immunohistochemical stains for prostate-specific antigen, prostate-specific acid phosphatase, and prostein were positive in the glandular epithelial cells of all cases. Stains for 34βE12 and p63 confirmed the presence of basal cells in all cases. There was no overexpression of α-methylacyl-CoA racemase in any of the cases. There was cytoplasmic luminal staining for CD10 and cytoplasmic staining for cytokeratin 18 in acinar cells in all cases. In cases in which followup data were available, no patient was found to have residual or recurrent ectopic prostatic tissue and none developed prostatic adenocarcinoma. Conclusions: Ectopic prostatic tissue is occasionally encountered in the lower urinary tract, most commonly in the bladder and urethra of males. Ectopic prostatic tissue has histological and immunohistochemical characteristics that are indistinguishable from those of normal prostatic tissue, and most likely represents the persistence of embryonic structures.

A 4-month-old female infant with no current medical complaints was seen for a routine 4-month-old wellchild appointment. She was brought to the appointment by her new foster parents, who had taken over her care 1 month prior to presentation. They reported no major illnesses, but did note that her right arm and leg seemed larger than her left; a difference that they felt was particularly noticeable in the upper extremities. Other than this size discrepancy they reported no other current problems. Development was appropriate for age, with the child laughing, cooing, grabbing for objects, and able to roll from front to back on her own. There were no reported constitutional symptoms and weight gain was appropriate; the patient had no easy bruising, no jaundice, no pallor, and had appropriate formula intake and urine output. The patient was born to an HIV-positive mother who was on highly active antiretroviral therapy (HAART) and the patient was treated with zidovudine for the first 6 weeks of life. Her HIV-PCR-DNA assays at 2 weeks and 4 weeks, and testing during the present visit at 4 months of age were all negative, documenting that she was not infected. Physical examination revealed a well-nourished, normal-appearing, happy female infant in no apparent distress. Vital signs were as follows: weight 7 kg (90th percentile), length 65 cm (90th percentile), head circumference 42 cm (75th percentile), temperature 97.9°F, heart rate 119 bpm, respiratory rate 24 breaths/min, and blood pressure 85/56 mm Hg. Oropharyngeal examination revealed moist mucus membranes with a normal sized tongue and no pharyngeal erythema or exudate; the anterior fontanelle was open, soft, and flat, and pupils were equal, round, and reactive to light. There was no cervical, auricular, axillary, or inguinal adenopathy. Heart and lung examinations were within normal limits, and the abdomen was soft, nontender, nondistended, with nor moactive bowel sounds, and without any palpated organomegaly. Measurements were obtained and showed a subtle difference between the left and right side in both upper and lower extremities (Table 1). Tone and range of motion were appropriate for age. The limbs on the right were auscultated, with no bruits appreciable. Given the association between hemihyperplasia (hemihypertrophy) and malignancy, the decision was made to obtain an abdominal ultrasound of the liver and kidneys to rule out an abdominal neoplasm.

Multilocular cystic renal cell carcinoma is an uncommon low grade renal cell carcinoma with unique morphologic features. Its cytogenetic characteristics have not been fully investigated. Its relationship to typical clear cell renal cell carcinoma is uncertain. We evaluated 19 cases of multilocular cystic renal cell carcinoma diagnosed by strict morphologic criteria using the 2004 WHO classification system. The control group consisted of 19 low grade (Fuhrman grades 1 or 2) clear cell renal cell carcinomas. Chromosome 3p deletion status was determined by dual color interphase fluorescence in situ hybridization analysis. Chromosome 3p deletion was identified in 17 out of 19 (89%) of the clear cell renal cell carcinoma cases and 14 out of 19 (74%) of the multilocular cystic renal cell carcinoma cases, respectively. There was no difference in the status of chromosome 3p deletion between clear cell renal cell carcinoma and multilocular cystic renal cell carcinoma (P=0.40). These results support the concept that multilocular cystic renal cell carcinoma as a subtype of clear cell renal cell carcinoma.

INTRODUCTION: Xanthomatous hypophysitis (XH) is the rarest histological type of primary hypophysitis. It is non lymphocytic in nature, and is characterized by an infiltration of pituitary gland by lipid-laden histiocytes and macrophages. Consequent to a shared location, the clinical and radiological features of XH overlap heavily with pituitary adenomas and are prone to misdiagnosis. In this report we describe a case of newly diagnosed XH, which recurred after 1 year and was treated surgically. CASE: A 45-year-old female presented with history of menstrual irregularity for 9 months and a history of amenorrhea, galactorrhea and headache for 2 months duration. Preoperative endocrinologic studies showed increased prolactin. Magnetic resonance imaging (MRI) of the sella showed a cystic lesion with suprasellar extension suggestive of a pituitary adenoma. The patient underwent transsphenoidal resection that revealed a thick yellowish colloidal material. Histopathology demonstrated necrotic tissue with no definitive diagnosis and no identified microorganisms. The patient resumed her normal menstrual cycle with serum prolactin levels normalizing at 2-months post surgery. At 1-year post surgery her menstrual cycle again became irregular. A repeat MRI showed a recurrent mass and she underwent a second transsphenoidal resection. Repeat histopathology was consistent with XH. At present, the patient is at 5-years post initial surgery and is doing very well without evidence of recurrence. CONCLUSION: To the best of our knowledge, there are 18 prior reported cases in the literature of XH and two reported cases of recurrent disease. The clinical and radiological features of XH are undistinguished form pituitary adenoma. These lesions present similarly to nonfunctional adenomas and diagnosis is often difficult without surgical pathology, necessitating meticulous immunohistochemistry to prevent misdiagnosis. As such, XH should be considered as a rare etiology in the differential of both newly diagnosed and recurrent sellar-region lesions.

Testicular T-cell lymphoma is an extremely rare disease, with a particularly poor prognosis. This report reviews the clinical, radiologic and pathologic features of a case of testicular T-cell lymphoma, as well as the current treatment recommendations and prognosis of this disease based on current literature. A 78-year-old male presented with unilateral testicular swelling. Ultrasound confirmed an intra-testicular mass, and subsequent orchiectomy was performed. Pathologic diagnosis was consistent with primary peripheral T-cell lymphoma of the testicle. There was no evidence of metastatic disease. He is currently undergoing CHOP chemotherapy followed by intrathecal chemotherapy. Primary testicular T-cell lymphoma is a very rare disease with few case reports in the literature. Evaluation should always include CT imaging, lumbar puncture and bone marrow biopsy. The diagnosis imparts a poor prognosis, with an overall median survival of 12–24 months.

36 Background: Men with newly diagnosed, localized prostate cancer (PC) have historically been selected for active surveillance (AS) using clinicopathologic features. However, a clinical cell−cycle risk (CCR) score has been developed to include both molecular [cell cycle progression (CCP) RNA signature] and clinical [Cancer of the Prostate Risk Assessment (CAPRA)] features. Previous validations have demonstrated that this combined CCR score provides improved prognostic information relative to molecular or clinical features alone. As such, a CCR threshold score has been recently developed and validated to identify men with low−risk disease who may be candidates for AS. Here, we have evaluated the performance of the AS threshold in a contemporary cohort of men with newly diagnosed localized PC. Methods: Men with localized adenocarcinoma of the prostate who were treated at the Ochsner Clinic between 2006 and 2011 (4 patients were diagnosed in 2012−2014) were evaluated. Formalin−fixed paraffin embedded biopsy tissue and was analyzed for the RNA expression of 46 genes to obtain a CCP score. The CCR score was calculated as (0.57xCCP) + (0.39xCAPRA). A CCR score threshold of 0.8 has been previously validated in a cohort of conservatively managed men. Men with a CCR score equal to the threshold had an estimated 10−year disease−specific mortality risk of 3.3%, while men with scores below the threshold had a 2.7% risk. Results: Complete molecular and clinical information were available for 767 men with a median clinical follow−up time of 5.6 years measured from date of diagnosis. Overall, 217 men had CCR scores ≤ 0.8. Of these, 125 were treated by radical prostatectomy, 61 with radiation, 2 with radiation with hormones, 2 with hormones only, and 19 with watchful waiting. Treatment for eight men was unknown. One patient (0.5%) with a CCR score below the AS threshold progressed to metastatic disease, and was initially treated with radiation. Conclusions: We evaluated the performance of a previously validated AS threshold on a contemporary US cohort. Although the majority of the patients in this study were treated, the observed metastatic event rate of 0.5% supports that the CCR threshold can be safely used to identify candidates for AS.

Multilocular cystic renal cell carcinoma (RCC) is an uncommon renal neoplasm composed of thin fibrous septa lining multiple cystic spaces and associated with an excellent prognosis. Clear cells with generally low-grade nuclear features line the cystic spaces and may be present within the fibrous septa, although solid mass-forming areas are by definition absent. Despite the excellent prognosis, molecular-genetic alterations are similar to those of clear cell RCC. Immunohistochemical staining characteristics, however, have not been well elucidated. We studied 24 cases of multilocular cystic RCC, classified according to the 2004 World Health Organization System. Immunohistochemical analysis was performed using an automated immunostainer for CD10, cytokeratin 7 (CK7), α-methylacyl-CoA-racemase, epithelial membrane antigen (EMA), cytokeratin CAM 5.2, carbonic anhydrase IX (CA-IX), estrogen/progesterone receptors, smooth muscle actin, PAX-2, and vimentin. Twenty-four cases of grade 1 to 2 clear cell RCC were stained for comparison. Multilocular cystic RCC and control cases of clear cell RCC showed the following results, respectively: CD10 (63%, 96%), CK7 (92%, 38%), α-methylacyl-CoA-racemase (21%, 67%), vimentin (58%, 33%), estrogen receptor (8%, 8%), CAM 5.2 (100%, 96%), EMA, CA-IX, PAX-2 (all 100%), and progesterone receptor (0%). Smooth muscle actin highlighted myofibroblastic cells within the septa of multilocular cystic RCC and the fine capillary vascular network of clear cell RCC. In summary, multilocular cystic RCC showed expression of common clear cell RCC markers CA-IX, EMA, and PAX-2, supporting the hypothesis that multilocular cystic RCC is a subtype of clear cell RCC. In contrast to clear cell RCC, tumors less frequently expressed CD10 (63% and often focal vs. 96% and diffuse) and more frequently expressed CK7 (92%), often diffusely (63%). Coexpression of CA-IX and CK7 represents a point of overlap with the recently described clear cell papillary RCC, which also may show a prominent cystic architecture. However, the latter lacks mutation of the VHL gene and deletion of chromosome 3p by molecular methodologies.

To evaluate the histological and immunohistochemical characteristics of ectopic prostatic tissue.We studied 20 cases of ectopic prostate. In 85% (17/20) of the cases, the ectopic prostatic tissue was located in the bladder; in the remaining cases, it was located in the urethra. In 60% of the cases (12/20), no significant inflammatory or reactive/reparative changes were identified in the adjacent tissue. Immunohistochemical stains for prostate-specific antigen, prostate-specific acid phosphatase, and prostein were positive in the glandular epithelial cells of all cases. Stains for 34βE12 and p63 confirmed the presence of basal cells in all cases. There was no overexpression of α-methylacyl-CoA racemase in any of the cases. There was cytoplasmic luminal staining for CD10 and cytoplasmic staining for cytokeratin 18 in acinar cells in all cases. In cases in which followup data were available, no patient was found to have residual or recurrent ectopic prostatic tissue and none developed prostatic adenocarcinoma.Ectopic prostatic tissue is occasionally encountered in the lower urinary tract, most commonly in the bladder and urethra of males. Ectopic prostatic tissue has histological and immunohistochemical characteristics that are indistinguishable from those of normal prostatic tissue, and most likely represents the persistence of embryonic structures.

INTRODUCTION: Spindle cell oncocytoma of the pituitary gland (SCO) describes a rare and relatively recently described non-endocrine neoplasm of the adenohypophysis that occurs in adults. These lesions tend to follow a clinically benign course and are designated as grade I by the World Health Organization (WHO) 2007 classification of tumors of the central nervous system. Diagnosis is often difficult, as clinically these masses can present very similarly to nonfunctional pituitary macroadenomas and are radiologically indistinguishable from adenomas and lymphocytic hypophysitis. To the best of our knowledge, there are 22 prior reported cases of SCO. CASE: A 59-year-old man presented with progressive headache for 3-weeks duration. On work up he was diagnosed with nonfunctional pituitary macroadenoma, and underwent complete transsphenoidal resection of the tumor. Histopathology ultimately revealed SCO. He has been stable without evidence of recurrence for 4 years. CONCLUSION: Spindle cell oncocytomas present similarly to nonfunctional adenomas and diagnosis is often difficult without surgical pathology. Despite this, SCO carry an increased risk of recurrence, and meticulous immunohistochemistry is warranted to prevent misdiagnosis after surgery. SCO should be considered in the differential diagnosis of sellar-region lesions.

We describe a young patient with acute myeloid leukemia who, having been treated with allogenic hematopoietic stem cell transplantation, presented with acute graft-versus-host disease. One year later, leukemia relapse was treated with donor lymphocyte infusion and was followed by a new episode of acute graft-versus-host disease. The patient died 18 months after the transplantation, with evidence of chronic graft-versus-host disease in multiple organs.