LGALS3 cfDNA methylation in seminal fluid as a novel prostate cancer biomarker outperforming PSA.

BACKGROUND: The unmet challenge in prostate cancer (PCa) management is to discriminate it from benign prostate hyperplasia (BPH) due to the lack of specific diagnostic biomarkers. Contemporary research on potential PCa biomarkers is directed toward methylated cell-free DNA (cfDNA) from liquid biopsies since epigenetic mechanisms are strongly involved in PCa development. METHODS: In the present research, cfDNA methylation of the LGALS3 gene in blood and seminal plasma of PCa and BPH patients was assessed using pyrosequencing, as well as LGALS3 DNA methylation in tissue biopsies. Liquid biopsy samples were taken from patients with clinical suspicion of PCa, who were subsequently divided into two groups, that is, 42 with PCa and 55 with BPH, according to the histopathological analysis. RESULTS: Statistically significant higher cfDNA methylation of LGALS3 in seminal plasma of BPH than in PCa patients was detected by pyrosequencing. ROC curve analysis showed that it could distinguish PCa and BPH patients with 56.4% sensitivity and 70.4% specificity, while PSA did not differ between the two patient groups. In contrast, there was no statistically significant difference in LGALS3 cfDNA methylation in blood plasma between the two patient groups. In prostate tumor tissue, there was a statistically significant DNA hypermethylation of LGALS3 compared to surrounding nontumor tissue and BPH tissue. CONCLUSIONS: The DNA hypermethylation of the LGALS3 gene represents an event specific to PCa development. In conclusion, LGALS3 cfDNA methylation in seminal fluid discriminates early PCa and BPH presenting itself as a powerful novel PCa biomarker highly outperforming PSA.

Alpha-methyl CoA racemase (AMACR) reactivity across the spectrum of clear cell renal cell neoplasms.

a-Methylacyl coenzyme A racemase (AMACR) is traditionally considered to be a marker of papillary renal cell carcinoma. However, AMACR expression can be seen in other renal tumors. The aim of this study was to investigate AMACR immunoreactivity within the spectrum of clear cell renal cell neoplasms. Fifty-three clear cell renal epithelial tumors were used in assembling the following four cohorts: low grade (LG) clear cell renal cell carcinoma (CCRCC), high grade (HG) CCRCC, CCRCC with cystic changes, and multilocular cystic renal neoplasm of low malignant potential (MCRNLMP). Representative blocks were stained for AMACR, using two different clones (SP52 and OV-TL12/30). There were at least some AMACR immunoreactivity in 77.8 % and 68.9 % of CCRCCs (using SP52 and OV-TL12/30 clone, respectively). Moderate to strong positivity, or positivity in more than one third of the tumor (even weak in intensity) was detected in 46.7 % of CCRCCs using SP52 and in 48.9 % of CCRCC using OV-TL12/30 clone. The highest AMACR reactivity was observed in HG CCRCC (60 % by SP52 and 66.7 % by OV-TL12/30). Strong and diffuse AMACR positivity was detected in 8.9 % of all CCRCCs. AMACR immunoreactivity in MCRNLMP was 37.5 % (SP52 clone) and 25 % (OV-TL12/30 clone). We demonstrated relatively high expression rate of AMACR in CCRCC, while very variable in intensity and distribution. This finding may have diagnostic implications especially in limited samples (i.e., core biopsies), as AMACR positivity does not exclude the diagnosis of CCRCC.

Histologic diversity in chromophobe renal cell carcinoma does not impact survival outcome: A comparative international multi-institutional study.

Predicting the clinical behavior and trajectory of chromophobe renal cell carcinoma (ChRCC) by histologic features has so far proven to be challenging. It is known that ChRCC represents a heterogeneous group of neoplasms demonstrating variable, yet distinctive morphologic and genetic profiles. In this international multi-institutional study, we aimed to assess the impact of histologic diversity in ChRCC (classic/eosinophilic versus rare subtypes) on survival outcome. This is an international multi-institutional matched case-control study including 14 institutions, examining the impact of histologic subtypes of ChRCC on survival outcome. The study group (cases) included 89 rare subtypes of ChRCC. The control group consisted of 70 cases of ChRCC including classic and eosinophilic features, age- and tumor size-matched. Most of the rare subtypes were adenomatoid cystic/pigmented ChRCC (66/89, 74.2%), followed by multicystic ChRCC (10/89, 11.2%), and papillary ChRCC (9/89, 10.1%). In the control group, there were 62 (88.6%) classic and 8 (11.4%) eosinophilic ChRCC. There were no statistically significant differences between the study and control groups for age at diagnosis, gender distribution, tumor size, presence of tumor necrosis, presence of sarcomatoid differentiation, and adverse outcomes. No statistically significant differences were found in clinical outcome between the rare subtypes and classic/eosinophilic groups by tumor size, necrosis, and sarcomatoid differentiation. Further, no statistically significant differences were found in clinical outcome between the two groups, stratified by tumor size, necrosis, and sarcomatoid differentiation. Our findings corroborated previous studies that both sarcomatoid differentiation and tumor necrosis were significantly associated with poor clinical outcome in classic/eosinophilic ChRCC, and this was proven to be true for ChRCC with rare histologic subtypes as well. This study suggests that rare morphologic patterns in ChRCC without other aggressive features play no role in determining the clinical behavior of the tumor.

REVIEW OF THE BLADDER CANCER MOLECULAR CLASSIFICATION PROPOSED: A NEW ERA - NEW TAXONOMY.

The management of bladder cancer patients largely depends on pathologic staging and grading, and current morphological classification does not always show the individual patient's risk. Despite modern surgical techniques, pre- and postoperative therapies, clinical outcomes of these patients have not changed over decades. Today, there are new biomarkers for bladder cancer showing changes in tumor biology and progression, as a result of changes in the pathways affecting cell signaling, proliferation, apoptosis, epigenetic changes, angiogenesis, and modulation of host immune response. Assessment of multiple biomarkers associated with those pathways offers new understanding of tumor behavior while identifying important panels of predicting patient management and outcomes. In this review, the most important molecules and basics of the novel molecular classification of bladder cancer are presented.

SUCCESSFULLY TREATED ACUTE INTERSTITIAL PNEUMONIA.

Acute interstitial pneumonia (AIP) is a rare idiopathic interstitial pneumonia with histology finding of diffuse alveolar damage (DAD). It is characterized by progressive hypoxic respiratory failure, high mortality rate, and absence of guidelines for its treatment. Here we present a case of a 64-year-old woman with progressive dyspnea, acute respiratory failure, diffuse bilateral reticulonodular opacities on standard chest radiograph, diffuse ground-glass opacities on computed tomography, and biopsy proven DAD. Diagnosis of AIP was established after extensive work-up that excluded the known risk factors for acute respiratory distress syndrome. Oxygen therapy and high-dose parenteral corticosteroids led to gradual improvement and resulted in complete respiratory recovery. Since there are no existing guidelines for treating AIP, more case reports and case series if not randomized control trials are warranted in order to define the most effective therapeutic modality.

CORRELATION OF EXPRESSION OF TGF- ß AND MMP2 BETWEEN PROSTATIC ADENOCARCINOMA AND ADJACENT UNAFFECTED PARENCHYMA.

In prostate adenocarcinoma, both tumorous stroma and epithelium have important role in tumor progression. Transforming growth factor beta (TGF- ß) is a promotor in advanced stages of prostate cancer. Matrix Metalloproteinase 2 (MMP2), the endopeptidase that degrades extracellular matrix is considered to be overexpressed in prostatic carcinoma related to its growth and aggressiveness. Therefore, the aim was to analyze the expression of proteins TGF- ß and MMP2 between both epithelium and stroma of prostatic adenocarcinoma and adjacent unaffected parenchyma. The intensity of TGF- ß and MMP2 expression in epithelium, tumorous stroma and adjacent unaffected parenchyma was analyzed in 62 specimens of prostatic adenocarcinoma by microarray-based immunohistochemistry. TGF- ß was more expressed in tumorous than in prostate stroma (p =0.000), while no statistical significance in case of MMP2 (p = 0.097) was found. MMP2 was more expressed in tumorous than in prostate epithelium (p =0.000), while no statistical significance in case of TGF- ß (p = 0.096) was observed. The study results indicate that both tumorous stroma and epithelium have a role in tumor progression and support potential role of TGF- ß and MMP2 in prostatic adenocarcinoma progression.

ALK rearranged renal cell carcinoma (ALK-RCC): a multi-institutional study of twelve cases with identification of novel partner genes CLIP1, KIF5B and KIAA1217.

ALK rearranged renal cell carcinoma (ALK-RCC) has recently been included in 2016 WHO classification as a provisional entity. In this study, we describe 12 ALK-RCCs from 8 institutions, with detailed clinical, pathological, immunohistochemical (IHC), fluorescence in situ hybridization (FISH), and next generation sequencing (NGS) analyses. Patients' age ranged from 25 to 68 years (mean, 46.3 years). Seven patients were females and five were males (M:F = 1:1.4). Tumor size ranged from 17 to 70 mm (mean 31.5, median 25 mm). The pTNM stage included: pT1a (n = 7), pT1b (n = 1), and pT3a (n = 4). Follow-up was available for 9/12 patients (range: 2 to 153 months; mean 37.6 months); 8 patients were alive without disease and one was alive with distant metastases. The tumors demonstrated heterogeneous, 'difficult to classify' morphology in 10/12 cases, typically showing diverse architectural and cellular morphologies, including papillary, tubular, tubulocystic, solid, sarcomatoid (spindle cell), rhabdoid, signet-ring cell, and intracytoplasmic vacuoles, often set in a mucinous background. Of the remaining two tumors, one showed morphology resembling mucinous tubular and spindle cell renal cell carcinoma (MTSC RCC-like) and one was indistinguishable from metanephric adenoma. One additional case also showed a focal metanephric adenoma-like area, in an otherwise heterogeneous tumor. By IHC, all tumors were diffusely positive for ALK and PAX8. In both cases with metanephric adenoma-like features, WT1 and ALK were coexpressed. ALK rearrangement was identified in 9/11 tumors by FISH. ALK fusion partners were identified by NGS in all 12 cases, including the previously reported: STRN (n = 3), TPM3 (n = 3), EML4 (n = 2), and PLEKHA7 (n = 1), and also three novel fusion partners: CLIP1 (n = 1), KIF5B (n = 1), and KIAA1217 (n = 1). ALK-RCC represents a genetically distinct entity showing a heterogeneous histomorphology, expanded herein to include unreported metanephric adenoma-like and MTSC RCC-like variants. We advocate a routine ALK IHC screening for "unclassifiable RCCs" with heterogeneous features.

Expanding the morphologic spectrum of chromophobe renal cell carcinoma: A study of 8 cases with papillary architecture.

Although typically arranged in solid alveolar fashion, chromophobe renal cell carcinoma (RCC) may also show several other architectural growth patterns. We include in this series 8 chromophobe RCC cases with prominent papillary growth, a pattern very rarely reported or only mentioned as a feature of chromophobe RCC, which is lacking wider recognition The differential diagnosis of such cases significantly varies from the typical chromophobe RCC with its usual morphology, particularly its distinction from papillary RCC and other relevant and clinically important entities. Of 972 chromophobe RCCs in our files, we identified 8 chromophobe RCCs with papillary growth. We performed immunohistochemistry and array Comparative Genomic Hybridisation (aCGH) to investigate for possible chromosomal aberrations. Patients were 3 males and 5 females with age ranging from 30 to 84 years (mean 57.5, median 60 years). Tumor size was variable and ranged from 2 to 14 cm (mean 7.5, median 6.6 cm). Follow-up was available for 7 of 8 patients, ranging from 1 to 61 months (mean 20.1, median 12 months). Six patients were alive with no signs of aggressive behavior, and one died of the disease. Histologically, all cases were composed of dual cell population consisting of variable proportions of leaf-like cells with pale cytoplasm and eosinophilic cells. The extent of papillary component ranged from 15 to 100% of the tumor volume (mean 51%, median 50%). Sarcomatoid differentiation was identified only in the case with fatal outcome. Immunohistochemically, all tumors were positive for CK7, CD117 and Hale's Colloidal Iron. PAX8 was positive in 5 of 8 cases, TFE3 was focally positive 3 of 8 tumors, and Cathepsin K was focally positive in 2 of 8 tumors. All cases were negative for vimentin, AMACR and HMB45. Fumarate hydratase staining was retained in all tested cases. The proliferative activity was low (up to 1% in 7, up to 5% in one case). Three cases were successfully analyzed by aCGH and all showed a variable copy number variation profile with multiple chromosomal gains and losses. CONCLUSIONS: Chromophobe RCC demonstrating papillary architecture is an exceptionally rare carcinoma. The diagnosis can be challenging, although the cytologic features are consistent with the classic chromophobe RCC. Given the prognostic and therapeutic implications of accurately diagnosis other RCCs with papillary architecture (i.e., Xp11.2 translocation RCC, FH-deficient RCC), it is crucial to differentiate these cases from chromophobe RCC with papillary architecture. Based on this limited series, the presence of papillary architecture does not appear to have negative prognostic impact. However, its wider recognition may allow in depth studies on additional examples of this rare morphologic variant.

Papillary renal cell carcinoma with prominent spindle cell stroma - tumor mimicking mixed epithelial and stromal tumor of the kidney: Clinicopathologic, morphologic, immunohistochemical and molecular genetic analysis of 6 cases.

Papillary renal cell carcinoma (PRCC) is currently a well-studied type of RCC. In addition to PRCC type 1, there are a number of other subtypes and variants of PRCCs which have been reported. We describe a series of 6 PRCCs with papillary, micropapillary and/or tubulopapillary architecture and prominent spindle cell stroma, resembling stroma in mixed epithelial and stromal tumor of the kidney (MESTK) or sarcomatoid RCC. Clinicopathologic, morphologic, immunohistochemical and molecular features were analyzed. All patients were males with an age range of 44-98 years (mean 65.3, median 65.5 years). Tumor size ranged from 2.4-11.4 cm (mean 5.8, median 4.5 cm). Follow-up data were available for 4 patients, ranging from 3 to 96 months (mean 42.75, median 36 months). Epithelial cells were mostly cylindrical with eosinophilic cytoplasm, showing nuclear grade 2 and 3 (ISUP/WHO). In all cases, loose to compact prominent stroma composed of spindle cells, without malignant mesenchymal heterologous elements was detected. No atypical mitoses were found, while typical mitoses were rare in both epithelial and stromal components. Epithelial cells were positive for CK7, AMACR, and vimentin in all cases, while negative for TFE3, HMB45, desmin, CD34, and actin. The stroma was positive for vimentin, actin and focally for CD34, while negative for CK7, AMACR, TFE3, HMB45, and desmin. Estrogen and progesterone receptors were completely negative. FH and SDHB expression was retained in all analyzable cases. Proliferative index was barely detectable in stromal component and low in epithelial component, ranging 0 to 5% positive stained cells/high power field. Copy number variation was variable with no distinct pattern. No mutations in CDKN2A, BAP1, MET were detected. PRCC with MESTK-like features is a distinct variant of PRCC mimicking MESTK. Our findings add to the body of literature on ever expanding variants of PRCCs. Both epithelial and stromal components lacked true Müllerian features, which was also proven by immunohistochemistry.

Reactivity of CK7 across the spectrum of renal cell carcinomas with clear cells.

AIMS: Current available data on cytokeratin 7 (CK7) immunostaining pattern in the clear cell renal cell carcinoma (RCC) spectrum is conflicting. The aim of this study was to assess CK7 immunoreactivity within the spectrum of clear cell renal neoplasms, including clear cell RCC, multicystic renal neoplasm of low malignant potential and clear cell papillary RCC-like tumours. METHODS AND RESULTS: We analysed two clones of CK7 and two tumour blocks for a total of 75 cases divided into five distinct groups: (i) low-grade clear cell RCC, (ii) high-grade clear cell RCC, (iii) multicystic renal neoplasm of low malignant potential, (iv) clear cell RCC with cystic changes and (v) clear cell papillary RCC-like tumours. We found the highest CK7 reactivity in low-grade clear cell RCC, multicystic renal neoplasm of low malignant potential and clear cell papillary RCC-like groups, ranging from 60% to 93%. CONCLUSIONS: Our findings show that CK7 immunoreactivity in clear cell RCC is variable, and the extent of staining depends on the grade and architectural growth patterns of the tumours.

Papillary pattern in clear cell renal cell carcinoma: Clinicopathologic, morphologic, immunohistochemical and molecular genetic analysis of 23 cases.

Clear cell renal cell carcinoma (ccRCC), the most common histologic subtype of RCCs, demonstrates a wide spectrum of morphologic features (i.e., low-grade spindle cell, syncytial giant cells, and mucin-producing cells). However, papillary growth pattern in ccRCCs is rather a rare finding, which can present challenges in differential diagnostic work up. The aim of this study was to investigate ccRCCs with predominant papillary features from morphologic, immunohistochemical and molecular genetic perspectives. 23 clear cell renal cell carcinomas with papillary architecture were selected. Tumors were evaluated morphologically, immunohistochemically, and molecularly by next-generation sequencing (NGS). The diagnosis of MiT family translocation RCC was excluded by TFE3 immunohistochemistry. Mean age of patients was 65.2 years (range 42-81 years), and 19/23 were male. Tumor size ranged from 1.6 to 12.8 cm (median 6.5 cm). At a median follow-up of 2.5 years (range 1.5-9 years), 2 patients (8.7%) died of disease, 2 developed metastasis. Areas of papillary pattern accounted for approximately 40-100% of the tumor. CK7 was negative in non-papillary areas in majority of cases (20/23, 87%), and was only focally positive in 3/23 cases (13%). In papillary areas, AMACR was positive/focally positive in 17/23 (73.9%) cases and in the non-papillary areas it was positive/focally positive in 22/23 (95.6%) cases. CAIX was mainly negative in both non-papillary and papillary areas (15/23 [65%] and 16/23 [69.5%], respectively). Molecular analysis of 15 analyzable cases revealed the most frequently mutated gene to be VHL (in 9 cases), followed by PRBM1 (in 2 cases) and 29 other different mutations in various genes. Papillary growth pattern in ccRCC is not an uncommon situation. Papillary RCC with clear cells and MiT family (TFE3) translocation RCCs are the major differential diagnostic considerations in such scenarios. Our NGS molecular analysis supported classifying such tumors as a morphologic variant of ccRCC.

PRIMARY MALIGNANT MELANOMA OF THE URINARY BLADDER: CASE REPORT.

Primary malignant melanoma of the urinary bladder is rare, with only 20 cases reported to date. We present a case of an 87-year-old woman with multiple comorbidities who presented with advanced urinary bladder neoplasm. Histopathologic analysis suggested melanoma of the urinary bladder. No previous or concurrent diagnosis of cutaneous melanoma was documented. The patient underwent transurethral resection of the tumor before and during hospitalization at our hospital but died shortly after due to widespread disease. Autopsy was not performed.

Low-grade spindle cell proliferation in clear cell renal cell carcinoma is unlikely to be an initial step in sarcomatoid differentiation.

AIMS: Spindle cell proliferation within clear cell renal cell carcinoma (ccRCC) is usually considered as a sarcomatoid differentiation. Low-grade spindle cell proliferation (LG-SCP) in ccRCC was first described in 2001. This phenomenon is not common and can pose diagnostic challenges, particularly in core biopsies. The aim of this study was to describe morphological, immunohistochemical and molecular characteristics of ccRCCs with LG-SCP. METHODS AND RESULTS: Eleven cases of ccRCC with LG-SCP were retrieved from approximately 21 000 renal tumours in our registry. Ten cases of conventional ccRCC and 10 cases of typical sarcomatoid ccRCC were included as control groups. Morphological and immunohistochemical characteristics of epithelial-mesenchymal transition (EMT) were analysed. Von Hippel-Lindau syndrome gene abnormalities were also analysed using molecular genetics. Among ccRCC with LG-SCP cases, there were five males and five females (clinical information was not available in one case) with a median age of 67 years (mean: 68.5, range: 60-81 years). Average tumour size was 7.1 cm (median:7.5, range:1.7-12 cm). Follow-up data were available in nine cases (mean: 44.78 months), with no aggressive behaviour seen. On average, LG-SCP areas constituted 5-80% of tumour volume (mean: 32.3%). Necrotic/regressed areas were seen in all cases ranging from 5% to 30%. LG-SCP was clearly epithelial, with no mitoses or any evidence of mesenchymal differentiation. Immunohistochemical profile of LG-SCP was consistent with 'conventional' ccRCC. Compared with sarcomatoid ccRCC, some EMT markers showed alteration in LG-SCP, including lower expression of N-cadherin and Zeb1 as well as higher expression of E-cadherin. However, there were no significant differences in EMT markers between LG-SCP and conventional ccRCC. Abnormalities in VHL (mutations, LOH3p) were found in six of 11 cases. CONCLUSIONS: Our findings showed that LG-SCP in ccRCC have comparable immunohistochemical and molecular characteristics to those seen in 'conventional' ccRCC. Further, immunohistochemical analysis of EMT markers showed that LG-SCP did not differ from 'conventional' ccRCC. We believe that LG-SCP is a part of morphological heterogeneity in ccRCCs and that they may not represent an initial stage of sarcomatoid differentiation. This is supported further by the fact that ccRCC with LG-SCP did not display more aggressive behaviour than 'conventional' ccRCC.

Biphasic papillary renal cell carcinoma is a rare morphological variant with frequent multifocality: a study of 28 cases.

AIMS: To further characterise biphasic squamoid renal cell carcinoma (RCC), a recently proposed variant of papillary RCC. METHODS AND RESULTS: We identified 28 tumours from multiple institutions. They typically showed two cell populations-larger cells with eosinophilic cytoplasm and higher-grade nuclei, surrounded by smaller, amphophilic cells with scanty cytoplasm. The dual morphology was variable (median 72.5% of tumour, range 5-100%); emperipolesis was found in all cases. The male/female ratio was 2:1, and the median age was 55 years (range 39-86 years). The median tumour size was 20 mm (range 9-65 mm). Pathological stage pT1a was found in 21 cases, pT1b in three, and pT3a and pT3b in one each (two not available). Multifocality was found in 32%: multifocal biphasic RCC in one case, biphasic + papillary RCC in two cases, biphasic + clear cell RCC in three cases, biphasic + low-grade urothelial carcinoma of the renal pelvis in one case, and biphasic + Birt-Hogg-Dubé syndrome in one case. Positive immunostains included: PAX8, cytokeratin (CK) 7, α-methylacyl-CoA racemase, epithelial membrane antigen, and vimentin. Cyclin D1 was expressed only in the larger cells. The Ki67 index was higher in the larger cells (median 5% versus ≤1%). Negative stains included: carbonic anhydrase 9, CD117, GATA-3, WT1, CK5/6, and CK20; CD10 and 34ßE12 were variably expressed. Gains of chromosomes 7 and 17 were found in two evaluated cases. Follow-up was available for 23 patients (median 24 months, range 1-244 months): 19 were alive without disease, one was alive with recurrence, and one had died of disease (two had died of other causes). CONCLUSIONS: Biphasic papillary RCC is a rare variant of papillary RCC, and is often multifocal.

Developmental Expression Patterns of KCC2 and Functionally Associated Molecules in the Human Brain.

Work on rodents demonstrated that steep upregulation of KCC2, a neuron-specific Cl- extruder of cation-chloride cotransporter (CCC) family, commences in supraspinal structures at around birth, leading to establishment of hyperpolarizing GABAergic responses. We describe spatiotemporal expression profiles of the entire CCC family in human brain. KCC2 mRNA was observed already at 10th postconceptional week (PCW) in amygdala, cerebellum, and thalamus. KCC2-immunoreactive (KCC2-ir) neurons were abundant in subplate at 18 PCW. By 25 PCW, numerous subplate and cortical plate neurons became KCC2-ir. The mRNA expression profiles of α- and ß-isoforms of Na-K ATPase, which fuels cation-chloride cotransport, as well of tropomyosin receptor kinase B (TrkB), which promotes developmental upregulation of KCC2, were consistent with data from studies on rodents about their interactions with KCC2. Thus, in human brain, expression of KCC2 and its functionally associated proteins begins in early fetal period. Our work facilitates translation of results on CCC functions from animal studies to human and refutes the view that poor efficacy of anticonvulsants in the term human neonate is attributable to the lack of KCC2. We propose that perinatally low threshold for activation of Ca2+-dependent protease calpain renders neonates susceptible to downregulation of KCC2 by traumatic events, such as perinatal hypoxia ischemia.

Cystic and necrotic papillary renal cell carcinoma: prognosis, morphology, immunohistochemical, and molecular-genetic profile of 10 cases.

Conflicting data have been published on the prognostic significance of tumor necrosis in papillary renal cell carcinoma (PRCC). Although the presence of necrosis is generally considered an adverse prognostic feature in PRCC, we report a cohort of 10 morphologically distinct cystic and extensively necrotic PRCC with favorable biological behavior. Ten cases of type 1 PRCC with a uniform morphologic pattern were selected from the 19 500 renal tumors, of which 1311 were PRCCs in our registry. We focused on precise morphologic diagnosis supported by immunohistochemical and molecular-genetic analysis. Patients included 8 men and 2 women with an age range of 32-85 years (mean, 62.6 years). Tumor size ranged from 6 to 14 cm (mean, 9.4 cm). Follow-up data were available in 7 patients, ranging from 0.5 to 14 years (mean, 4 years). All tumors were spherical, cystic, and circumscribed by a thick fibrous capsule, filled with hemorrhagic/necrotic contents. Limited viable neoplastic tissue was present only as a thin rim in the inner surface of the cyst wall, consistent with type 1 PRCC. All cases were positive for AMACR, OSCAR, CAM 5.2, HIF-2, and vimentin. Chromosome 7 and 17 polysomy was found in 5 of 9 analyzable cases, 2 cases demonstrated chromosome 7 and 17 disomy, and 1 case showed only chromosome 17 polysomy. Loss of chromosome Y was found in 5 cases, including 1 case with disomic chromosomes 7 and 17. No VHL gene abnormalities were found. Papillary renal cell carcinoma type 1 can present as a large hemorrhagic/necrotic unicystic lesion with a thick fibroleiomyomatous capsule. Most cases showed a chromosomal numerical aberration pattern characteristic of PRCC. All tumors followed a nonaggressive clinical course. Large liquefactive necrosis should not necessarily be considered an adverse prognostic feature, particularly in a subset of type 1 PRCC with unilocular cysts filled with necrotic/hemorrhagic material.

Warthin-like papillary renal cell carcinoma: Clinicopathologic, morphologic, immunohistochemical and molecular genetic analysis of 11 cases.

Oncocytic papillary renal cell carcinoma (PRCC) is a distinct subtype of PRCC, listed as a possible new variant of PRCC in the 2016 WHO classification. It is composed of papillae aligned by large single-layered eosinophilic cells showing linearly arranged oncocytoma-like nuclei. We analyzed clinicopathologic, morphologic, immunohistochemical and molecular-genetic characteristics of 11 oncocytic PRCCs with prominent tumor lymphocytic infiltrate, morphologically resembling Warthin's tumor. The patients were predominantly males (8/11, 73%), with an average age of 59years (range 14-76), and a mean tumor size of 7cm (range 1-22cm). Tumors had the features of oncocytic PRCCs with focal pseudostratification in 8/11 cases and showed dense stromal inflammatory infiltration in all cases. Papillary growth pattern was predominant, comprising more than 60% of tumor volume. Tubular and solid components were present in 5 and 3 cases, respectively. Uniform immunohistochemical positivity was found for AMACR, PAX-8, MIA, vimentin, and OSCAR. Tumors were mostly negative for carboanhydrase 9, CD117, CK20, and TTF-1. Immunohistochemical stains for DNA mismatch repair proteins MLH1 and PMS2 were retained in all cases, while MSH2 and MSH6 were negative in 1 case. Tumor infiltrating lymphocytes (TILs) consisted of both B and T cells. Chromosomal copy number variation analysis showed great variability in 5 cases, ranging from a loss of one single chromosome to complex genome rearrangements. Only one case showed gains of chromosomes 7 and 17, among other aberrations. In 4 cases no numerical imbalance was found. Follow up data was available for 9 patients (median 47.6months, range 1-132). In 6 patients no lethal progression was noted, while 3 died of disease. In conclusion, Warthin-like PRCC is morphologically very close to oncocytic PRCC, from which it differs by the presence of dense lymphoid stroma. Chromosomal numerical aberration pattern of these tumors is variable; only one case showed gains of chromosomes 7 and 17. Warthin-like PRCC is a potentially aggressive tumor since a lethal outcome was recorded in 3/9 cases.

Impact of Positive Surgical Margins after Radical Prostatectomy on Disease Progression and Adjuvant Treatment in Pathologically Localized Prostate Cancer.

The aim of our study was to evaluate the impact of margin positivity in clinically and pathologically localized prostate cancer (pT2) after radical prostatectomy on biochemical recurrence and time to adjuvant treatment. We analyzed data from 371 patients who underwent radical prostatectomy. At the mean follow up of 36 (25-54) months, impact of margin positivity in pT2 patients on prostate specific antigen (PSA) recurrence and time to introduction of adjuvant treatment was noted. Out of 371 radical prostatectomies there were 277 (74.6%) pT2 and 94 (25.4%) pT3 (locally advanced) prostate cancers. Mean age was 67.6 years, mean Gleason score 6.78, mean preoperative PSA 11.45 ng/mL. Out of 277 pT2 pts., 233 (84%) had negative (SM-) and 44 (16%) positive surgical margins (SM+). Only 3% of SM- pts. had biochemical relapse (BCR). Among pT2 patients with SM+, 18 (41%) had BCR while 26 were free of recurrence at 3 years follow up. Positive surgical margins had an adverse impact on biochemical progression free survival (3% SM- vs. 41% SM+; p<0.001). No difference was found in age, preoperative PSA, Gleason score or follow up between BCR-SM+ and BCR+SM+ patients. Mean time to PSA recurrence in surgical margin positive pT2 patients was 15.7 months. Surgical margin status pT2 disease has an impact on biochemical progression but only 41% of margine positive patients show biochemical recurrence at 3 yr follow up. Not all SM+ patients need to receive treatment after radical prostatectomy. Longer follow up should be awaited to see the impact on overall survival in this group of patients.

Biopsy Quantitative Patohistology and Seral Values of Prostate Specific Antigen-Alpha (1) Antichymotrypsine Complex in Prediction of Adverse Pathology Findings after Radical Prostatectomy.

In this prospective study we examined the utility of parameters obtained on prostate needle biopsy and prostate specific antigen-alpha(1)-antichymotripsine complex (PSA-ACT) to predict adverse pathologic findings after radical prostatectomy. 45 consecutive patients assigned for radical prostatectomy due to clinically localized prostate cancer were included in the study. Prostate biopsy parameters such as number of positive cores, the greatest percentage of tumor in the positive cores, Gleason score, perineural invasion, unilaterality or bilaterality of the tumor were recorded. PSA-ACT was determined using sandwich immunoassay chemiluminiscent method (Bayer, Tarrytown, New York). We analyzed relationship of preoperative PSA, PSA-ACTand quantitative biopsy parameters with final pathology after prostatectomy. Adverse findings were considered when extracapsular extension of cancer (pT3) was noted. Postoperatively, 29 (64.4%) patients were diagnosed with pT2 disease and 16 (35.6%) with pT3 disease. There was a significant difference in localized vs. locally advanced disease in number of positive biopsy cores (p<0.001), greatest percentage of tumor in the core (p=0.008), localization of the tumor (p=0.003) and perineural invasion (p=0.004). Logistic regression was used to develop a model on the multivariate level. It included number of positive cores and PSA-ACT and was significant on our cohort with the reliability of 82.22%. The combination of PSA-ACT and a large scale of biopsy parameters could be used in prediction of adverse pathologic findings after radical prostatectomy. Clinical decisions and patients counselling could be influenced by these predictors but further confirmation on a larger population is necessary.