Purpose Advances in minimally invasive therapies and novel targeted chemotherapeutics have provided a breadth of options for the management of renal masses. Management of renal angiomyolipoma has not ...been reviewed in a comprehensive fashion in more than a decade. We provide an updated review of the current diagnosis and management strategies for renal angiomyolipoma. Materials and Methods We conducted a PubMed® search of all available literature for renal or kidney angiomyolipoma. Further sources were identified in the reference lists of identified articles. We specifically reviewed case series of partial nephrectomy, selective arterial embolization and ablative therapies as well as trials of mTOR inhibitors for angiomyolipoma from 1999 to 2014. Results Renal angiomyolipoma is an uncommon benign renal tumor. Although associated with tuberous sclerosis complex, these tumors occur sporadically. Risk of life threatening hemorrhage is the main clinical concern. Due to the fat content, angiomyolipomas are generally readily identifiable on computerized tomography and magnetic resonance imaging. However, fat poor angiomyolipoma can present a diagnostic challenge. Novel research suggests that various strategies using magnetic resonance imaging, including chemical shift magnetic resonance imaging, have the potential to differentiate fat poor angiomyolipoma from renal cell carcinoma. Active surveillance is the accepted management for small asymptomatic masses. Generally, symptomatic masses and masses greater than 4 cm should be treated. However, other relative indications may apply. Options for treatment have traditionally included radical and partial nephrectomy, selective arterial embolization and ablative therapies, including cryoablation and radio frequency ablation, all of which we review and update. We also review recent advances in the medical treatment of patients with tuberous sclerosis complex associated angiomyolipomas with mTOR inhibitors. Specifically trials of everolimus for patients with tuberous sclerosis complex suggest that this agent may be safe and effective in treating angiomyolipoma tumor burden. A schema for the suggested management of renal angiomyolipoma is provided. Conclusions Appropriately selected cases of renal angiomyolipoma can be managed by active surveillance. For those patients requiring treatment nephron sparing approaches, including partial nephrectomy and selective arterial embolization, are preferred options. For those with tuberous sclerosis complex mTOR inhibitors may represent a viable approach to control tumor burden while conserving renal parenchyma.
It may be challenging to diagnose metastatic prostatic carcinoma (PC). This study focused on clinicopathologic correlation, and pitfalls of cytomorphology and immunostains of metastatic PCs. A total ...of 146 metastatic PCs including 134 (92%) PC without neuroendocrine differentiation—prostatic adenocarcinoma (PAC) and 12 (8%) with neuroendocrine differentiation (PC-NED) were retrieved. Triplicate tissue microarrays (TMA) of 54 surgically excised PCs were constructed for immunostains. Most cases showed Gleason 4 or 5 patterns. Nine percent of cases did not have a prior history of PC and 7% had 2 or more primary malignancies. PAC metastasized more commonly to lymph nodes (49%), and PC-NED metastasized more commonly to liver (58%). Cytologically, metastatic PCs show acini, cribriform, nest, and solid clusters. Most PACs showed conspicuous or prominent nucleoli. PC-NEDs showed typical cytologic features of low-grade or high-grade neuroendocrine neoplasm, or small cell carcinoma features. PACs could be immunoreactive to CDX2 (25%), CK20 (11%), NKX3.1 (99%), PSA (88%), PSAP (78%), and PSMA (92%). PC-NEDs were immunoreactive to neuroendocrine immunomarkers (CD56 100%, chromogranin 67%, and synaptophysin 100%) and p63 (25%), and lost expression of prostate-specific markers (NKX3.1, PSA, PSAP, and PSMA). Both PACs and PC-NEDs might be immunoreactive to CK7 (18% versus 33%), GATA3 (4% versus 0%), PAX8 (2% versus 50%, P < .05), and TTF1 (3% versus 57%, P < .05). It is critical to recognize these cytologic features and abbreviation of immunomarkers of metastatic PCs to avoid misinterpretation as metastatic carcinoma from nonprostate organs and inappropriate treatment. In addition, NED may be seen after hormone and chemoradiation treatment.
•The paper shows cytomorphology of metastatic prostatic carcinoma (PC) and pitfalls.•The paper demonstrates immunoprofiling of metastatic prostatic carcinoma.•Aberrant expression of some immunomarkers is found and the pitfalls are discussed.•The paper shows clinicopathologic correlation of metastatic prostatic carcinoma.•The paper discusses importance to recognize cytomorphology and immunoprofile of PC.
Castration-resistant prostate cancer (CRPC) that has developed resistance to the new-generation androgen receptor (AR) antagonist enzalutamide is a lethal disease. Transcriptome analysis of multiple ...prostate cancer models identified CXCR7, an atypical chemokine receptor, as one of the most upregulated genes in enzalutamide-resistant cells. AR directly repressed
by binding to an enhancer 110 kb downstream of the gene and expression was restored upon androgen deprivation. We demonstrate that CXCR7 is a critical regulator of prostate cancer sensitivity to enzalutamide and is required for CRPC growth
and
. Elevated CXCR7 activated MAPK/ERK signaling through ligand-independent, but β-arrestin 2-dependent mechanisms. Examination of patient specimens showed that CXCR7 and pERK levels increased significantly from localized prostate cancer to CRPC and further upon enzalutamide resistance. Preclinical studies revealed remarkable efficacies of MAPK/ERK inhibitors in suppressing enzalutamide-resistant prostate cancer. Overall, these results indicate that CXCR7 may serve as a biomarker of resistant disease in patients with prostate cancer and that disruption of CXCR7 signaling may be an effective strategy to overcome resistance. SIGNIFICANCE: These findings identify CXCR7-mediated MAPK activation as a mechanism of resistance to second-generation antiandrogen therapy, highlighting the therapeutic potential of MAPK/ERK inhibitors in CRPC.
Fumarate hydratase (FH) mutation causes hereditary type 2 papillary renal cell carcinoma (PRCC2). The main effect of FH mutation is fumarate accumulation. The current paradigm posits that the main ...consequence of fumarate accumulation is HIF-α stabilization. Paradoxically, FH mutation differs from other HIF-α stabilizing mutations, such as VHL and SDH mutations, in its associated tumor types. We identified that fumarate can directly up-regulate antioxidant response element (ARE)–controlled genes. We demonstrated that aldo-keto reductase family 1 member B10 (AKR1B10) is an ARE-controlled gene and is up-regulated upon FH knockdown as well as in FH null cell lines. AKR1B10 overexpression is also a prominent feature in both hereditary and sporadic PRCC2. This phenotype better explains the similarities between hereditary and sporadic PRCC2.
► Increased expression of AKR1B10 is a prominent feature of FH null cells ► Fumarate mediates the stabilization of NRF transcription factors ► The KEAP1-NRF axis is deregulated in type 2 papillary renal cell carcinomas ► Complete gene expression profiles of FH null kidney cancers are presented
Introduction: Sarcomatoid differentiation has been reported in approximately 8% of chromophobe renal cell carcinoma (RCC) and is associated with a worse prognosis. We aim to describe the ...clinicopathologic and molecular findings of chromophobe RCC with sarcomatoid differentiation. Methods: Surgical pathology database was searched to identify chromophobe RCC with sarcomatoid differentiation from January 2015 to December 2021. Results: Five patients were diagnosed with chromophobe RCC with sarcomatoid differentiation. The median age at the time of diagnosis was 57 years (range 51-61 years). Three patients died after median follow-up of 12.1 months (range 1.6-18.2 months). The median tumor size was 10.7 cm (range 5.6-13.6 cm). The median percentage of sarcomatoid component was 60% (range 10-90%), and the median percentage of necrosis was 30% (range 10-50%). One tumor demonstrated osteoid formation. PAX8, keratin 7, KIT (CD117), and Hale colloidal iron were positive in the epithelial component, whereas the sarcomatoid component was positive for vimentin, CD10, and high Ki67 proliferative index. Molecular testing was performed in three specimens: all were TP53 mutated and microsatellite stable. One aggressive tumor had RB1 frameshift mutation and copy number gains for TERT and CUL4A. Conclusion: Chromophobe RCC with sarcomatoid differentiation is a rare entity with aggressive behavior. Percentage of sarcomatoid component, necrosis, and the occurrence of metastasis is associated with worse prognosis. Molecular profiling reveals frequent TP53 mutation. While TERT promoter mutation has no prognostic implication, FLCN inactivation may be associated with a less aggressive course. The clinical significance of RB1 loss is unclear.
Nonfunctioning kidneys secondary to various etiologies display different histopathological features. Studies focused on incidence and types of renal neoplasms using the new World Health Organization ...and International Society of Urological Pathology classification system in various types of nonfunctioning kidneys are very limited. We identified 311 nephrectomies of nonfunctioning kidneys and categorized them into 5 categories: acquired cystic kidney disease (ACKD, n = 61); end-stage renal disease, nonspecific (ESRD, n = 63); adult polycystic kidney disease (APKD, n = 49); failed transplant kidney (FTK, n = 96); and those caused by obstructive conditions in the kidney (OCK, n = 42). ACKD (70%) and ESRD (43%) had higher cancer incidences than the other 3 groups (APKD = 2%, FTK = 0%, and OCK = 5%). Besides clear cell renal cell carcinoma (RCC) and papillary RCC, clear cell papillary RCC had a much higher incidence within ACKD patients (13/61) compared to other groups. ACKD-associated RCC was only identified in ACKD patients. ACKD patients had significantly longer dialysis duration compared to ESRD, APKD, and FTK. Although they had similar risk for clear cell RCC and papillary RCC, ACKD patients had a much higher risk for ACKD-associated RCC and clear cell papillary RCC than ESRD patients. Although most RCCs arising in these nonfunctioning kidneys were early pT1 stage, 6 ACKD patients and 3 ESRD patients had higher-stage diseases, which can be fatal if not treated appropriately. Therefore, precise clinicopathological classification of these nonfunctioning kidneys is important for predicting kidney cancer risk. These results indicate the need for active monitoring of the patients with high-risk nonfunctioning kidney diseases and appropriate surgical treatment when necessary.
•Need of active monitoring of patients with high risk non-functioning kidney diseases and surgical treatment when necessary.•ACKD and ESRD had higher cancer incidences than APKD, FT, and OCK.•CCRCC, PRCC and CCPRCC had a much higher incidence within ACKDs compared to other groups.•ACKD-associated RCC was only identified in ACKD patients.•ACKD patients had significantly longer dialysis duration compared to ESRD, APKD and FTK.
Immunohistochemistry (IHC) has become increasingly important in the evaluation of pathologic conditions in the genitourinary (GU) organs. In addition to careful evaluation of hematoxylin-eosin ...sections and generation of a differential diagnosis, choosing the optimal panel of IHC markers becomes even more important when the biopsy material is very limited. The following summary of our experience supplemented with relevant literature review exemplifies how to use IHC to facilitate pathologic diagnosis in the GU system.
To describe our experience with the most common immunohistochemical markers used in GU pathology.
Institutional experience and literature search comprise our data sources.
Application of IHC provides enormous benefits to the interpretation of GU pathologic conditions, including benign and malignant lesions. However, both insufficient and excessive types of use of IHC, as well as incorrect interpretations in common and rare GU conditions, could present pitfalls in diagnosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Nested variant of urothelial carcinoma (NVUC) is an uncommon variant with minimally atypical cytology, which may overlap with benign urothelial lesions such as von Brunn nests, cystitis cystica, ...cystitis glandularis, and nephrogenic adenoma. Because of the tumor’s deceptively bland appearance, these cancers can potentially be misdiagnosed as benign lesions, leading in some cases to a significant delay in correct diagnosis and appropriate treatment. Prior studies suggest that Ki67 and p53 are useful markers in distinguishing NVUC from benign lesions. However, the overlap in the rates of immunoreactivity has prevented pathologists from using these markers as reliable adjunct markers in differentiating NVUC from mimickers. In addition, large nested variant urothelial carcinoma (LNVUC), a relatively new entity, shares features of both the NVUC and papillary urothelial carcinomas with an inverted growth pattern. They also mimic benign lesions, such as proliferation of von Brunn nests and inverted urothelial papilloma. With the recent demonstration of a strong association of TERT promoter mutations and urothelial carcinoma, we hypothesized that TERT promoter mutations would be a useful marker to distinguish NVUC and LNVUC from other benign urothelial lesions. We have therefore sequenced the TERT promoter region of 20 cases of NVUC, 10 cases of LNVUC, 5 cases of von Brunn nests, 3 cases of cystitis cystica, 3 cases of cystitis glandularis, and 3 cases of nephrogenic adenoma. We found that 17 of 20 cases of NVUC and 8 of 10 cases of LNVUC had TERT promoter mutationC228T; no mutation was found in any of the benign mimickers (0/14). This result strongly suggests that TERT promoter mutation is a useful adjunct biomarker to distinguish NVUC and LNVUC from benign mimickers.
The Birt-Hogg-Dubé (BHD) disease is a genetic cancer syndrome. The responsible gene, BHD, has been identified by positional cloning and thought to be a novel tumor suppressor gene. BHD mutations ...cause many types of diseases including renal cell carcinomas, fibrofolliculomas, spontaneous pneumothorax, lung cysts, and colonic polyps/cancers. By combining Gateway Technology with the Ksp-Cre gene knockout system, we have developed a kidney-specific BHD knockout mouse model. BHD(flox/flox)/Ksp-Cre mice developed enlarged kidneys characterized by polycystic kidneys, hyperplasia, and cystic renal cell carcinoma. The affected BHD(flox/flox)/Ksp-Cre mice died of renal failure at approximate three weeks of age, having blood urea nitrogen levels over tenfold higher than those of BHD (flox/+)/Ksp-Cre and wild-type littermate controls. We further demonstrated that these phenotypes were caused by inactivation of BHD and subsequent activation of the mTOR pathway. Application of rapamycin, which inhibits mTOR activity, to the affected mice led to extended survival and inhibited further progression of cystogenesis. These results provide a correlation of kidney-targeted gene inactivation with renal carcinoma, and they suggest that the BHD product FLCN, functioning as a cyst and tumor suppressor, like other hamartoma syndrome-related proteins such as PTEN, LKB1, and TSC1/2, is a component of the mTOR pathway, constituting a novel FLCN-mTOR signaling branch that regulates cell growth/proliferation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Neuroendocrine cells are one of the epithelial populations in the prostate. Neuroendocrine differentiation (NED) has been observed in prostate cancer. In addition to small cell neuroendocrine ...carcinomas and carcinoid tumors of the prostate, prostatic adenocarcinomas may have NED. The incidence and clinical relevance of NED in prostatic adenocarcinoma is not clearly understood because of conflicting results in the reported studies, and evaluation of NED is not routinely performed in clinical practice. This review is an overall synthesis with an aim to develop a more comprehensive understanding and practical approach towards the current knowledge of neuroendocrine differentiation. In this review we are stratifying these lesions into separate subtypes based on histologic parameters such as tumor morphology, neuroendocrine cell density and distribution and clinical parameters. We also want to identify current controversies and confusing issues not totally resolved in this topic for further investigations. Eventually a clearer understanding of this phenomenon and appropriate handling NED in prostate cancer will benefit clinical practice.
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