Patients with germline mutation of succinate dehydrogenase (SDH) subunit genes are prone to develop paraganglioma, gastrointestinal stromal tumor, and rarely renal cell carcinoma (RCC). However, ...SDH-deficient RCC is not yet widely recognized. We identified such tumors by distinctive morphology and confirmed absence of immunohistochemical staining for SDHB. Immunohistochemical features were evaluated using a panel of antibodies to renal tumor antigens. Targeted next-generation sequencing was performed on DNA extracted from paraffin-embedded tissue. Eleven tumors were identified from 10 patients, 22–72 years of age (median 40). Two patients had paragangliomas, 1 bilateral SDH-deficient RCC, and 1 contralateral oncocytoma. Grossly, tumors were tan or red–brown, 2–20 cm in diameter (median 4.25 cm). Fuhrman grade was 2 (n=10) or 3 (n=1). Stage was pT1a–pT2b. One patient developed widespread metastases 16 years after nephrectomy and died of disease 6 years later. All tumors were composed of uniform eosinophilic cells containing vacuoles or flocculent cytoplasmic inclusions. Architecture was primarily solid; entrapped renal tubules and intratumoral mast cells were common. By immunohistochemistry, tumor cells were negative for SDHB (11/11) and rarely SDHA (1/11). Labeling was uniformly positive for PAX8 and kidney-specific cadherin and absent for KIT, RCC, and carbonic anhydrase IX. Staining for broad-spectrum epithelial markers was often negative or focal (positive staining for AE1/AE3 in 4/10, CAM5.2 3/7, CK7 1/11, EMA 10/10). By sequencing, SDHB mutation and loss of the second allele were present in 5/6 tumors; the SDHA-deficient tumor showed no SDHB abnormality. SDH-deficient RCC is a unique neoplasm that is capable of progression, often harboring SDHB mutation. A monomorphic oncocytic renal tumor with solid architecture, cytoplasmic inclusions of flocculent material, and intratumoral mast cells should prompt evaluation of SDH status, as it may have implications for screening the patient and relatives. Negative immunohistochemistry for KIT and heterogeneous labeling for epithelial antigens are other supportive features.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary Renal oncocytoma and chromophobe renal cell carcinoma (RCC) have been long recognized as distinct tumors; however, it remains unknown if uniform diagnostic criteria are used to distinguish ...these tumor types in practice. A survey was distributed to urologic pathologists regarding oncocytic tumors. Responses were received from 17/26 invitees. Histologically, >1 mitotic figure was regarded as most worrisome (n = 10) or incompatible (n = 6) with oncocytoma diagnosis. Interpretation of focal nuclear wrinkling, focal perinuclear clearing, and multinucleation depended on extent and did not necessarily exclude oncocytoma if minor. Staining techniques most commonly used included: CK7 (94%), KIT (71%), vimentin (65%), colloidal iron (59%), CD10 (53%), and AMACR (41%). Rare CK7-positive cells (≤5%) was regarded as most supportive of oncocytoma, although an extent excluding oncocytoma was not universal. Multiple chromosomal losses were most strongly supportive for chromophobe RCC diagnosis (65%). Less certainty was reported for chromosomal gain or a single loss. For tumors with mixed or inconclusive features, many participants use an intermediate diagnostic category (82%) that does not label the tumor as unequivocally benign or malignant, typically “oncocytic neoplasm” or “tumor” with comment. The term “hybrid tumor” was used variably in several scenarios. A slight majority (65%) report outright diagnosis of oncocytoma in needle biopsies. The morphologic, immunohistochemical, and genetic characteristics that define oncocytic renal tumors remain incompletely understood. Further studies correlating genetics, behavior, and histology are needed to define which tumors truly warrant classification as carcinomas for patient counseling and follow-up strategies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Systemic inflammation may increase risk for prostate cancer progression, but the role it plays in prostate cancer susceptibility is unknown. From a cohort of over 10,000 men who had either a prostate ...biopsy or transurethral resection that yielded a benign finding, we analyzed 517 incident prostate cancer cases identified during follow-up and 373 controls with one or more white blood cell tests during a follow-up period between one and 18 years. Multilevel, multivariable longitudinal models were fit to two measures of systemic inflammation, neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR), to determine NLR and MLR trajectories associated with increased risk for prostate cancer. For both measures, we found no significant differences in the trajectories by case/control status, however in modeling NLR trajectories there was a significant interaction between race (white or Black and case-control status. In race specific models, NLR and MLR values were consistently higher over time among white controls than white cases while case-control differences in NLR and MLR trajectories were not apparent among Black men. When cases were classified as aggressive as compared to non-aggressive, the case-control differences in NLR and MLR values over time among white men were most apparent for non-aggressive cases. For NLR among white men, significant case-control differences were observed for the entire duration of observation for men who had inflammation in their initial prostate specimen. It is possible that, among white men, monitoring of NLR and MLR trajectories after an initial negative biopsy may be useful in monitoring prostate cancer risk.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Amplification of chromosome 6p has been implicated in aggressive behavior in several cancers, but has not been characterized in renal cell carcinoma (RCC). We identified 9 renal tumors with ...amplification of chromosome 6p including the TFEB gene, 3 by fluorescence in situ hybridization, and 6 from the Cancer Genome Atlas (TCGA) databases. Patients’ ages were 28 to 78 years (median, 61 y). Most tumors were high stage (7/9 pT3a, 2/9 pN1). Using immunohistochemistry, 2/4 were positive for melanocytic markers and cathepsin K. Novel TFEB fusions were reported by TCGA in 2; however, due to a small composition of fusion transcripts compared with full-length transcripts (0.5/174 and 3.3/132 FPKM), we hypothesize that these represent secondary fusions due to amplification. Five specimens (4 TCGA, 1 fluorescence in situ hybridization) had concurrent chromosome 3p copy number loss or VHL deletion. However, these did not resemble clear cell RCC, had negative carbonic anhydrase IX labeling, lacked VHL mutation, and had papillary or unclassified histology (2/4 had gain of chromosome 7 or 17). One tumor each had somatic FH mutation and SMARCB1 mutation. Chromosome 6p amplification including TFEB is a previously unrecognized cytogenetic alteration in RCC, associated with heterogenous tubulopapillary eosinophilic and clear cell histology. The combined constellation of features does not fit cleanly into an existing tumor category (unclassified), most closely resembling papillary or translocation RCC. The tendency for high tumor stage, varied tubulopapillary morphology, and a subset with melanocytic marker positivity suggests the possibility of a unique tumor type, despite some variation in appearance and genetics.
Aims
Comedonecrosis in prostate cancer has always been Gleason pattern 5. However, we aimed to evaluate how intraductal carcinoma (not graded) with comedonecrosis should be considered.
Methods and ...results
From 52 radical prostatectomy patients, 40 were informative and evaluated with immunohistochemistry for basal cells. Clinical outcome was assessed for biochemical recurrence, metastatic disease and the need for adjuvant therapy. Comedonecrosis was predominantly located in intraductal carcinoma (24, 60%). However, nine (23%) had comedonecrosis within invasive cancer and seven (18%) within both invasive and intraductal carcinoma. Extraprostatic extension rarely showed comedonecrosis (5, 13%), but rather perineural invasion within cribriform glands. Tumours were largely high‐stage (15, 38% pT3a and 19, 48% pT3b), with 15 (37%) having positive lymph nodes and four distant metastases. Most cases (25, 63%) had other patterns of Gleason pattern 5 (single cells, solid), although 10 were reclassified as containing no invasive pattern 5. Of these, most were pT3 (eight of 10), but none had positive lymph nodes. Lymph node metastases were more common in patients with invasive cancer containing comedonecrosis (P = 0.02), and the need for androgen deprivation was near significance (P = 0.07), but biochemical recurrence was not significantly different (P = 0.58).
Conclusions
Prostate cancer with comedonecrosis is often intraductal; however, these tumours are largely high‐stage, showing a higher rate of positive lymph nodes with invasive comedonecrosis. Immunohistochemistry may be considered when comedonecrosis may significantly change the tumour grade. However, it is not clear at present that excluding intraductal carcinoma from the grade is superior to including it in grading when it is associated with high‐grade invasive cancer.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Clear cell papillary renal cell carcinoma is increasingly recognized as a distinct tumor with unique morphology, immunohistochemistry, and cytogenetics. Histopathology often mimics clear cell renal ...cell carcinoma; however, metastasis has not been reported, emphasizing the clinical value of recognizing these likely nonaggressive tumors. We studied tumors with borderline morphology of clear cell papillary renal cell carcinoma, utilizing immunohistochemistry and fluorescence in situ hybridization or karyotyping. Tumors from 22 patients (ages 33 to 82 y) were analyzed. Clear cell papillary renal cell carcinoma–like morphology varied from 10% to 90% of the tumor (median 25%). Sources of resemblance includedbranched glands (95%), nuclear alignment (68%), small papillary tufts (32%), focal branching papillae (27%), and prominent papillary structures (9%). Carbonic anhydrase IX uniformly revealed diffuse positivity. Staining for cytokeratin 7 (CK7) was focal (64%) or negative (18%) in most tumors (82%); however, >50% labeling was present in 4 (18%). Reactivity for both CD10 and α-methyl-acyl-CoA-racemase (AMACR) was usually present (median 80% and 60% of cells). Seven tumors showed reactivity for high–molecular weight keratin (32%). Chromosome 3p loss was confirmed in 15 tumors (68%), including 4/7 with labeling for high–molecular weight keratin or >50% reactivity for CK7. A discordant immunohistochemical pattern typically correlates with loss of material from chromosome 3p in tumors with incomplete morphology of clear cell papillary renal cell carcinoma, supporting classification as clear cell renal cell carcinoma. Diffuse labeling for CK7 can uncommonly be observed in clear cell renal cell carcinomas confirmed to have chromosome 3p loss, although these do not exhibit the expected staining pattern of clear cell papillary renal cell carcinoma, including positivity for CD10 and AMACR.
Telomere shortening is linked to aging and may be associated with increased risk for cancer. Most cancer studies have used telomere length in leukocytes rather than in the target tissue of cancer ...origin.
A case-control study of 524 case-control pairs with a benign prostate biopsy nested within a historical cohort of 10,478 men was conducted to determine whether premalignant prostate telomere length (assessed using a modified qRT-PCR) is associated with prostate cancer risk.
Telomere lengths in benign prostate biopsies of cases versus controls were similar (1.46 ± 0.38 vs. 1.45 ± 0.42; P = 0.49). African American (AA) men had significantly shorter telomeres compared with White men (1.51 ± 0.38 vs. 1.63 ± 0.39; P < 0.0001). In race-stratified analyses, increasing telomere length was more strongly associated with prostate cancer risk in White men, wherein those with telomere length in the highest quartile had 1.9-fold greater adjusted risk of prostate cancer compared with men with prostate telomere lengths in the lowest quartile OR = 1.90; 95% confidence interval (CI) = 1.08-3.36. Men in the highest telomere length quartile also had a greater risk of aggressive prostate cancer compared with men with telomere lengths in the lowest quartile (OR = 2.78; 95% CI = 1.25-6.19).
White men have longer telomeres in benign prostate tissue compared with AA men, and those with the longest telomeres may be at increased risk for prostate cancer, particularly the more aggressive form of the disease.
Race-specific telomere length measures may be an early biomarker of aggressive prostate cancer.
We present the functional characterization of a pseudogene associated recurrent gene fusion in prostate cancer. The fusion gene KLK4-KLKP1 is formed by the fusion of the protein coding gene KLK4 with ...the noncoding pseudogene KLKP1. Screening of a cohort of 659 patients (380 Caucasian American; 250 African American, and 29 patients from other races) revealed that the KLK4-KLKP1 is expressed in about 32% of prostate cancer patients. Correlative analysis with other ETS gene fusions and SPINK1 revealed a concomitant expression pattern of KLK4-KLKP1 with ERG and a mutually exclusive expression pattern with SPINK1, ETV1, ETV4, and ETV5. Development of an antibody specific to KLK4-KLKP1 fusion protein confirmed the expression of the full-length KLK4-KLKP1 protein in prostate tissues. The in vitro and in vivo functional assays to study the oncogenic properties of KLK4-KLKP1 confirmed its role in cell proliferation, cell invasion, intravasation, and tumor formation. Presence of strong ERG and AR binding sites located at the fusion junction in KLK4-KLKP1 suggests that the fusion gene is regulated by ERG and AR. Correlative analysis of clinical data showed an association of KLK4-KLKP1 with lower preoperative PSA values and in young men (<50 years) with prostate cancer. Screening of patient urine samples showed that KLK4-KLKP1 can be detected noninvasively in urine. Taken together, we present KLK4-KLKP1 as a class of pseudogene associated fusion transcript in cancer with potential applications as a biomarker for routine screening of prostate cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Prostate cancer (PC) with lymph node metastases (LN(+)) is relatively rare, whereas it is relatively common in disease with a Gleason score (GS) 8 to 10 and virtually never seen in PC with GS 6 or ...less. It is most variable in GS 7 PC.
To determine clinicopathologic features associated with GS 7 PC with LN(+) compared with a control group without lymph node metastases (LN(-)).
We analyzed 184 GS 7 radical prostatectomies with LN(+) and the same number of LN(-) Gleason-matched controls. The LN(+) cases were GS 3 + 4 = 7 (n = 64; 34.8%), GS 4 + 3 = 7 (n = 66; 35.9%), GS 3 + 4 = 7 with tertiary 5 (n = 10; 5.4%), and GS 4 + 3 = 7 with tertiary 5 (n = 44; 23.9%).
The LN(+) cases demonstrated higher average values in preoperative prostate-specific antigen (12.2 versus 8.1 ng/mL), percentage of positive biopsy cores (59.1% versus 42.9%), prostate weight (54.4 versus 49.4 g), number of LNs submitted (12.7 versus 9.4), incidence of nonfocal extraprostatic extension (82.6% versus 63.6%), tumor volume (28.9% versus 14.8%), frequency of lymphovascular invasion (78.3% versus 38.6%), intraductal spread of carcinoma (42.4% versus 20.7%), incidence of satellite tumor foci (16.4% versus 4.3%), incidence of pT3b disease (49.5% versus 14.7%), and lymphovascular invasion in the seminal vesicles (52% versus 30%). There were differences in GS 4 patterns and cytology between LN(+) and LN(-) cases, with the former having higher volumes of cribriform and poorly formed patterns, larger nuclei and nucleoli, and more-frequent macronucleoli. All P ≤ .05.
Gleason score 7 PC with LN(+) has features highlighting a more-aggressive phenotype. These features can be assessed as prognostic markers in GS 7 disease on biopsy (eg, GS 4 pattern, intraductal spread, cytology) or at radical prostatectomies (all variables), even in men without LN dissection or LN(-) disease.
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DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Differential classification of prostate cancer grade group (GG) 2 and 3 tumors remains challenging, likely because of the subjective quantification of the percentage of Gleason pattern 4 (%GP4). ...Artificial intelligence assessment of %GP4 may improve its accuracy and reproducibility and provide information for prognosis prediction. To investigate this potential, a convolutional neural network (CNN) model was trained to objectively identify and quantify Gleason pattern (GP) 3 and 4 areas, estimate %GP4, and assess whether CNN-predicted %GP4 is associated with biochemical recurrence (BCR) risk in intermediate-risk GG 2 and 3 tumors. The study was conducted in a radical prostatectomy cohort (1999-2012) of African American men from the Henry Ford Health System (Detroit, Michigan). A CNN model that could discriminate 4 tissue types (stroma, benign glands, GP3 glands, and GP4 glands) was developed using histopathologic images containing GG 1 (n = 45) and 4 (n = 20) tumor foci. The CNN model was applied to GG 2 (n = 153) and 3 (n = 62) tumors for %GP4 estimation, and Cox proportional hazard modeling was used to assess the association of %GP4 and BCR, accounting for other clinicopathologic features including GG. The CNN model achieved an overall accuracy of 86% in distinguishing the 4 tissue types. Furthermore, CNN-predicted %GP4 was significantly higher in GG 3 than in GG 2 tumors (P = 7.2 × 10−11). %GP4 was associated with an increased risk of BCR (adjusted hazard ratio, 1.09 per 10% increase in %GP4; P = .010) in GG 2 and 3 tumors. Within GG 2 tumors specifically, %GP4 was more strongly associated with BCR (adjusted hazard ratio, 1.12; P = .006). Our findings demonstrate the feasibility of CNN-predicted %GP4 estimation, which is associated with BCR risk. This objective approach could be added to the standard pathologic assessment for patients with GG 2 and 3 tumors and act as a surrogate for specialist genitourinary pathologist evaluation when such consultation is not available.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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