<p>One-way ANOVA table for comparison between the 4 groups showing statistically significant difference of lipid droplet density for at least one group from others.</p>
Phyllodes tumors are rare primary breast neoplasms graded as benign, borderline, or malignant based on pathology characterization of the stromal component. Core-needle biopsy is recommended as the first diagnostic step for breast lesions suspicious for phyllodes. Surgical excisional biopsy is recommended for a core-needle biopsy showing cellular fibroepithelial lesion or a mass suspicious for phyllodes tumor as pathology diagnosis is challenging, especially on limited tissue specimens. Surgical treatment parallels that for soft tissue sarcoma rather than breast adenocarcinoma. Wide local excision and mastectomy, with 1 cm tumor-free margins, provide equivalent oncologic outcomes. Tumor enucleation, subtotal resection, and positive final margins should be avoided. Axillary surgery is not recommended as lymph node metastases are rare. Adjuvant radiation is not recommended as routine, nor is adjuvant chemotherapy, although either or both may be considered for primary or recurrent high-risk malignant phyllodes tumors on a case-by-case basis. Local recurrence rates are influenced by margin status and tumor grade. Distant metastases occur in up to 25% of patients with borderline/malignant tumors and bestow a poor prognosis. Recent molecular genetic analyses of phyllodes tumors have identified potentially targetable mutations that may guide future therapy for high-risk, recurrent, or metastatic phyllodes tumors. This review contains 5 figures, 5 tables, and 53 references. Key words: biomarkers, breast sarcoma, diagnosis, outcomes, pathology, phyllodes tumor, surgery, treatment
An optical microscopic examination of thinly cut stained tissue on glass slides prepared from a FFPE tissue blocks is the gold standard for tissue diagnostics. In addition, the diagnostic abilities and expertise of any pathologist is dependent on their direct experience with common as well as rarer variant morphologies. Recently, deep learning approaches have been used to successfully show a high level of accuracy for such tasks. However, obtaining expert-level annotated images is an expensive and time-consuming task and artificially synthesized histological images can prove greatly beneficial. Here, we present an approach to not only generate histological images that reproduce the diagnostic morphologic features of common disease but also provide a user ability to generate new and rare morphologies. Our approach involves developing a generative adversarial network model that synthesizes pathology images constrained by class labels. We investigated the ability of this framework in synthesizing realistic prostate and colon tissue images and assessed the utility of these images in augmenting diagnostic ability of machine learning methods as well as their usability by a panel of experienced anatomic pathologists. Synthetic data generated by our framework performed similar to real data in training a deep learning model for diagnosis. Pathologists were not able to distinguish between real and synthetic images and showed a similar level of inter-observer agreement for prostate cancer grading. We extended the approach to significantly more complex images from colon biopsies and showed that the complex microenvironment in such tissues can also be reproduced. Finally, we present the ability for a user to generate deepfake histological images via a simple markup of sematic labels.
5053 Background: Genomic aberrations associated with resistance/response to AA/P are not known. In a prospective study we assessed whole-exome/RNA-seq based aberrations in CRPC metastatic biopsies for identifying molecular markers associated with primary resistance and response duration. Methods: Sequencing of metastatic biopsies was performed for analyzing molecular aberrations that predict primary resistance (defined as progression at 12-weeks of therapy (non-responders) using PSA, RECIST, bone scan criteria per PCWG2). Gene network analysis was performed in genes mutated more frequently in non-responders and in genes differentially expressed between non-responders and responders using a “risk ratio” (RR) of ≥2. Cox regression models with multiple gene network pathways were used for determining association with time to treatment change (TTTC). Results: Of 92 enrolled pts 82 had complete whole-exome, RNA-seq & 12-week outcome data available for analysis. At 12-weeks 33/82 had progressed. Using a RR of ≥2, 113 genes were more frequently mutated in non-responders & 292 in responders. In non-responders, gene network analysis revealed frequent mutations in Wnt/β-catenin pathway genes; frequent deletion of negative regulators of Wnt pathway ( DKK4, SFRP2, LRP6). Gene expression analyses revealed significantly reduced expression levels of Wnt/β-catenin pathway inhibitors and increased expression levels of cell cycle proliferation (CCP) genes in non-responders. Median study follow up was 32 months during which time 58/82 pts progressed and switched treatments. Median TTTC was 10.1 months (IQR:4.4-24.1). In multivariate analysis CCP scores of ≥50 predicted shorter TTTC (HR = 2.11, 95% CI: 1.17-3.80; p = 0.01). Conclusions: In metastases Wnt/β-catenin pathway activation is associated with primary AA/P resistance and increased CCP with acquired drug resistance. These findings offer molecular based predictive biomarkers in CRPC stage treatment. Clinical trial information: NCT#01953640.
A 63-year-old male presented with 3 months of urinary retention, progressive bilateral lower limb muscle weakness, 18-kg weight loss and eye redness. Prior to admission, MRI revealed marked enlargement of the prostate (Fig. 1A) and prostatic biopsy found granulomatous inflammation (Fig. 1B). During admission, testing revealed a positive pANCA (perinuclear antineutrophil cytoplasmic antibody) and MPO (myeloperoxidase antibodies; >8.0 units, ref. <0.4). CRP was elevated (179.2 mg/l; ref. <8.0) but creatine kinase was normal (12 U/l; ref. 39–308). Extensive infectious workup, including metagenomic sequencing, was negative. MRI of the proximal lower extremities demonstrated diffuse T2 hyperintensity in muscles (Fig. 1C). Biceps femoris muscle biopsy showed a necrotizing vasculitic myopathy (Fig. 1D). Prednisone and rituximab were initiated for induction therapy of granulomatosis with polyangiitis (GPA), resulting in rapid improvement of muscle weakness, episcleritis and constitutional symptoms. GPA is a form of ANCA-associated vasculitis that predominately affects small vessels. The most common sites affected include the ears, nose, throat, lungs and kidneys. Urologic manifestations are rare, affecting <1% of cases [1]. Granulomatous prostatitis in GPA usually presents with obstructive symptoms and more rarely with acute urinary retention [1]. Vasculitic myopathy is similarly uncommon and typically presents with a combination of myalgias and muscle weakness but may have a normal creatine kinase [2].
Carcinomas of the bladder that resemble clear cell carcinoma of mullerian type are rare. Whether such neoplasms 1) arise from mullerian elements in the bladder and are histogenetically identical to the female genital tract cancer, 2) are a peculiar variant of vesical adenocarcinoma of nonmullerian derivation, or 3) represent a peculiar morphologic expression of transitional cell (urothelial) carcinoma with gland differentiation is often uncertain. We reviewed the clinical, conventional pathologic, and immunohistochemical features of 13 neoplasms with exclusive, or predominant, morphologic features of clear cell carcinoma. The 11 female and two male patients were 22–83 (mean 57) years of age. The clinical and gross features had no unique aspects. On microscopic examination the most common pattern, present in all cases, was tubulocystic, with a papillary pattern, present in six tumors and a predominant solid growth in one. Cells with abundant clear cytoplasm were conspicuous in nine tumors and hobnail cells were seen in eight. Four tumors showed focally recognizable patterns of transitional cell (urothelial) carcinoma in the available material. In five other tumors pseudostratified epithelium reminiscent of transitional epithelium was present focally. Endometriosis was present in two cases. In two other cases benign cysts focally lined by ciliated epithelium and surrounded by elastosis were interpreted as most likely mullerian. Immunohistochemistry was performed in 10 cases. All tumors stained for CA 125 (usually strong, ranging from focal to diffuse) and nine tumors stained for CK7 (usually strong and diffuse). CK20 was focally and weakly positive in four tumors and extensively positive in another. The same immunohistochemical panel was performed on 10 typical transitional cell carcinomas, 4 transitional cell carcinomas with gland differentiation, not otherwise specified, and 5 pure adenocarcinomas of the bladder (one of urachal origin). Minimal CA 125 positivity was seen in two transitional cell carcinomas. CA 125 staining was seen in the areas of gland differentiation in three of four transitional cell carcinomas and three of five pure adenocarcinomas but was focal in most cases. All transitional cell carcinomas and transitional cell carcinomas with gland differentiation showed extensive CK7 positivity. In contrast, only one of four positive pure adenocarcinomas showed >5% CK7-positive cells. Although all groups showed CK20 positivity, the percentage of CK20 positive cells was higher in pure adenocarcinomas. Prostate specific antigen was negative in all tumors. The cytokeratin immunoprofile of clear cell carcinomas of the bladder is closer to transitional cell carcinomas and transitional cell carcinomas with gland differentiation than pure adenocarcinomas arguing against an unusual form of adenocarcinoma. Our finding of CA 125 expression in bladder tumors of apparent urothelial origin contrasts with some studies that have regarded CA 125 expression as evidence for a mullerian origin. The frequency of gland differentiation in transitional cell carcinomas and the rarity of vesical endometriosis could be taken to suggest that these tumors are mostly of urothelial derivation, but the strong female preponderance in our series argues for a mullerian origin in at least some cases, and this is almost certain in the four cases with benign mullerian components. In the absence of endometriosis or conventional foci of transitional cell carcinoma, it may be impossible to determine whether a tumor with the morphology of clear cell carcinoma is of mullerian or transitional (urothelial) cell lineage, and at this time immunochemistry does not solve this problem.
<div>Abstract<p>Retinoblastoma (RB) protein can exert tumor suppressor functions even when it becomes phosphorylated. It is thus essential to understand how phosphorylated RB (p-RB) expression and function are regulated. Here, we demonstrated that RING finger domain protein TRIM28 bound and promoted ubiquitination and degradation of CDK4/6-phosphorylated RB protein. SETDB1, a known TRIM28 binding partner, protected p-RB from degradation through the binding of methylated RB by its Tudor domain independent of its methyltransferase activity. SETDB1 was found to be frequently overexpressed due to gene amplification and positively correlated with p-RB in prostate cancer patient specimens. Inhibition of SETDB1 expression using a gene-specific antisense oligonucleotide (ASO) reduced tumor growth but accelerated RB protein degradation, limiting the therapeutic efficacy. However, coadministration of the CDK4/6 inhibitor palbociclib blocked ASO-induced RB degradation and resulted in a much greater cancer-inhibitory effect than each inhibitor alone both <i>in vitro</i> and <i>in vivo</i>. This study identified CDK4/6-dependent, TRIM28-mediated proteasomal degradation as a mechanism of RB inactivation and reveals SETDB1 as a key inhibitor of this process. Our findings suggest that combined targeting of SETDB1 and CDK4/6 represents a viable approach for the treatment of cancers with SETDB1 gene amplification or overexpression.</p>Significance:<p>The identification of a role for TRIM28 and SETDB1 in regulating CDK4/6-phosphorylated RB stability uncovers a combination strategy using CDK4/6 and SETDB1 inhibition to decrease RB degradation and inhibit cancer growth.</p></div>
