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Immunohistochemical markers may be critical for the diagnosis of renal neoplasms in several instances, including differentiation of renal cell from non-renal cell neoplasms, histologic subtyping of renal neoplasms, accurate diagnosis [...], Context.--The diagnosis of renal cell carcinoma (RCC) remains problematic, especially in the context of metastasis or small-needle biopsies. PAX2 and PAX8 transcription factors are known to be expressed by several histologic types of renal neoplasms. Objective.--To evaluate the diagnostic utility of PAX2 and PAX8 relative to one another, which has not been studied. Design.--Consecutive tissue sections from the archival samples of 243 primary and 99 metastatic renal neoplasms were submitted to PAX2 and PAX8 immunostain. Results.--Within the primary neoplasms, PAX2 versus PAX8 expression was noted in 90 of 95 (95%) versus 92 of 95 (97%) for clear cell RCC, 29 of 38 (76%) versus 38 of 38 (100%) for papillary RCC, 14 of 25 (56%) versus 22 of 25 (88%) for chromophobe RCC, 3 of 7 (43%) versus 5 of 7 (71%) for collecting duct RCC, 6 of 8 (75%) versus 8 of 8 (100%) for acquired cystic kidney disease-related RCC, and 7 of 13 (54%) versus 11 of 13 (85%) for oncocytoma. Regardless of histologic subtype, PAX8 staining was noted in more cells and with more intense staining than PAX2. Within the metastatic RCCs, PAX8 expression was more frequently positive than PAX2 expression (88 of 99 cases; 89%; versus 75 of 99 cases; 76%). Conclusions.--Both PAX2 and PAX8 are diagnostically useful markers for both primary and metastatic renal neoplasms of a large variety of histologic types. However, PAX8 appears to be more sensitive than PAX2 in both primary and metastatic settings. PAX8 can be included in any immunohistochemical panel for the diagnosis of primary renal neoplasms. Adding PAX2 should be optional, but this would gain limited further diagnostic yield. In a metastatic setting, both PAX8 and PAX2 can be included in a panel because a small subset of metastatic RCCs are stained only with PAX2. (Arch Pathol Lab Med. 2012; 136:1541-1551; doi: 10.5858/arpa.2012-0072-OA)

Micropapillary urothelial carcinoma (MPUC) is a rare, clinically aggressive histologic variant of urothelial carcinoma (UC). It was first described by Amin et al (1) in 1994 and is characterized by [...], * Context.--Micropapillary urothelial carcinoma (MPUC) is a known aggressive variant of urothelial carcinoma. However, the reasons for its aggressiveness remain unclear. Objective.--To investigate the frequency of lymphovascular invasion in 22 cases of MPUC. Design.--Consecutive tissue sections were stained with D2-40 and CD34 to highlight lymphovascular channels associated with MPUC. Spaces containing tumor cells were scored as positive for lymphovascular invasion if the staining pattern on immunohistochemistry was distinct and circumferential. Results.--Of 22 cases, 21 (95%) had lymphovascular invasion on immunohistochemical staining, with 91% lymphatic invasion and 4% vascular invasion. Interestingly, 8 cases were originally signed out as negative for lymphovascular invasion on the basis of hematoxylineosin-stained sections; of these, 7 (88%) had focal lymphovascular invasion evident on immunohistochemical staining. Conclusions.--Our results confirm that micropapillary lacunae are not lymphovascular channels. However, nearly all MPUC tumors (95% in this series) have evidence of lymphovascular invasion by immunohistochemical analysis. Our data support the use of micropapillary features as a morphologic marker for lymphovascular invasion and MPUC as an adverse histologic type of urothelial carcinoma. (Arch Pathol Lab Med. 2012; 136:635-639; doi: 10.5858/arpa.2011-0463-OA)

Renal cell carcinoma (RCC) is the third most common cancer of the genitourinary tract and the most lethal urologic cancer, accounting for approximately 2% of all cancer deaths. (1) Approximately [...], * Context.--With the refinement of molecular and histologic classifications of renal neoplasms and the availability of more-effective molecular targeted therapy for specific renal neoplasms, immunohistochemical techniques will play an increasingly important role in the diagnosis of renal neoplasm. During the past few decades, many markers have been evaluated for their role in the diagnosis, prognosis, and prediction of treatment for renal neoplasms. The number of useful markers in our routine practice continues to increase. The challenge will be to choose among them and to decide in which situations immunohistochemistry will be truly useful. Objectives.--To review the diagnostic utility of molecular markers for renal neoplasms and common diagnostic scenarios that call for immunohistochemistry in routine practice. Data Sources.--This review is based on published literature and personal experience. Conclusions.--Some of the most important and useful markers for the diagnosis of renal neoplasm include cytokeratins, vimentin, PAX2, PAX8, RCC marker, CD10, E-cadherin, kidney-specific cadherin, parvalbumin, claudin7, claudin-8, a-methylacyl coenzyme A racemase, CD117, TFE3, thrombomodulin, uroplakin III, p63, CD57, and carbonic anhydrase IX. Each marker has its diagnostic role in a specific diagnostic setting. The common diagnostic situations that call for immunohistochemical staining are differential diagnoses of renal versus nonrenal neoplasms, histologic subtyping of renal cell carcinoma, diagnosis of rare primary renal neoplasms, diagnosis of renal neoplasms in small core-biopsy specimens, diagnosis of possible metastatic renal carcinomas, and less frequently, molecular prognostication. (Arch Pathol Lab Med. 2012; 136:410-417; doi: 10.5858/arpa.2011-0472-RA)

More than 90% of the renal cell neoplasms arise from the renal tubules. Renal cell carcinoma (RCC) is divided into 5 main histologic subtypes: clear cell, papillary, chromophobe, collecting duct, [...], Context.--Histologic diagnosis of renal neoplasm is usually straightforward by routine light microscopy. However, immunomarkers may be essential in several contexts, including differentiating renal from nonrenal neoplasms, subtyping of renal cell carcinoma (RCC), and diagnosing rare types of renal neoplasms or metastatic RCC in small biopsy specimens. Objective.--To provide a comprehensive review of the diagnostic utility of immunomarkers for renal neoplasms. Design.--This review is based on published literature and personal experience. Conclusions.--The following markers may have diagnostic utility in various diagnostic contexts: cytokeratins, vimentin, a-methylacyl coenzyme A racemase, carbonic anhydrase IX, PAX2, PAX8, RCC marker, CD10, Ecadherin, kidney-specific cadherin, parvalbumin, claudin-7, claudin-8, S100A1, CD82, CD117, TFE3, thrombomodulin, uroplakin III, p63, and S100P. Cytokeratins are uniformly expressed by RCC, albeit in a somewhat limited amount in some subtypes, requiring broad-spectrum ant-iCK antibodies, including both low- and high-molecular-weight cytokeratins. PAX2 and PAX8 are sensitive and relatively specific markers for renal neoplasm, regardless of subtype. CD10 and RCC marker are sensitive to renal cell neoplasms derived from proximal tubules, including clear cell and papillary RCCs. Kidney-specific cadherin, parvalbumin, claudin-7, and claudin-8 are sensitive markers for renal neoplasms from distal portions of the nephron, including chromophobe RCC and oncocytoma. CK7 and [alpha]-amethylacyl coenzyme A racemase are sensitive markers for papillary RCC; TFE3 expression is essential in confirming the diagnosis of Xp11 translocation RCC. The potentially difficult differential diagnosis between chromophobe RCC and oncocytoma may be facilitated by S100A1 and CD82. Thrombomodulin, uroplakin III, p63, and S100P are useful markers for urothelial carcinoma. Together with high-molecular-weight cytokeratins, PAX2, and PAX8, they can help differentiate renal pelvic urothelial carcinoma from collecting duct RCC. A sensitive marker for sarcomatoid RCC is still not available. Immunomarkers are most often used for diagnosing metastatic RCC. Compared with primary RCC, expression of the above-mentioned markers is often less frequent and less diffuse in the metastatic setting. Recognizing the variable sensitivity and specificity of these markers, it is important to include at least CD10, RCC marker, PAX2, and PAX8 in the diagnostic panel. (Arch Pathol Lab Med. 2011;135:92-109)

The diagnosis of metastatic renal cell carcinoma (RCC) remains problematic for several reasons. Renal cell carcinoma may present initially as a metastasis without clinical features referable to a primary renal [...], Context.--The diagnosis of metastatic renal cell carcinoma (RCC) remains problematic. Objective.--To evaluate the role of PAX-2, a renal tubular cell transcription factor, in the diagnosis of metastatic RCC. PAX-2 expression in metastatic RCC was compared with that of the renal cell carcinoma marker antigen (RCCM) and kidney-specific cadherin (KSC), which are 2 known markers for RcC. Design.--Immunostaining for PAX-2, RCCM, and KSC was performed on consecutive tissue sections of 95 metastatic RCCs (77 clear cell, 8 papillary, 5 sarcomatoid, and 5 collecting duct) and 183 metastatic tumors other than RCC. Results.--For PAX-2, positive immunoreactivity was detected in 77% clear cell, 75% papillary, 100% collecting duct, and 0% sarcomatoid metastatic RCCs. For RCCM, positive immunoreactivity was detected in 49% clear cell, 75% papillary, 0% collecting duct, and 0% sarcomatoid metastatic RCCs. For KSC, only 2 metastatic clear cell RCCs (3%) were positive. In combination, all markers were positive in 0% of cases; all markers were negative in 23% of cases (17 clear cell, 1 papillary, and for all 5 sarcomatoid); and at least 1 marker was positive in 76% of cases (PAX-2 only in 28% of cases [21 clear cell, 1 papillary, and 5 collecting duct] and RCCM only in 3% of cases [2 clear, 1 papillary]). Of 183 metastatic tumors other than RCC, 14 were positive for PAX-2 (nodal metastasis of carcinoma of colon [1], breast [1], endometrium [1], and ovary [1]; and omental metastasis of carcinoma of uterus or ovary [10]). Conclusions.--PAX-2 is a sensitive and specific marker for metastatic RCC. The diagnostic yield would be marginally increased by adding RCCM, but not KSC, as an immunomarker.

Identification of prostatic carcinoma invasion in the seminal vesicle is directly associated with tumor staging and is well regarded as an indication of poor prognosis. (1-3) Detection of seminal vesicle [...], * Context.--Seminal vesicle invasion by prostatic carcinoma is directly associated with tumor staging; verification is challenging when the tumor demonstrates cribriform or papillary growth patterns or there are back-to-back small-gland proliferations. P504S is overexpressed in prostatic carcinoma and high-grade prostatic intraepithelial neoplasia with cytoplasmic immunoreactivity. p63 has positive immunoreactivity in basal cell nuclei of benign prostatic glands. Many researchers use a combination of these antibodies and their different colors. Objective.--To evaluate the usefulness of a single-color P504S/p63 cocktail immunostain in verifying prostatic carcinoma within the seminal vesicle. Design.--Sections from 57 radical prostatectomy specimens of pathologic stage pT3b that contain seminal vesicle with prostatic carcinoma involvement were immunostained with primary antibodies against prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) and a cocktail of antibodies against P504S and p63. Results.--Prostatic carcinoma cells from all 57 cases were diffusely positive for P504S, PSA, and PAP with cytoplasmic staining and no p63 nuclear staining. Seminal vesicle epithelium from all 57 cases was negative for all 3 markers with distinct p63 nuclear staining of the basal cells. Benign prostatic tissue was positive for PSA and PAP, as well as for p63, but negative for P504S. Conclusions.--The P504S/p63 one-color cocktail is a practical and cost-effective stain to differentiate prostatic carcinoma that involves the seminal vesicle from seminal vesicle epithelium. It is superior to PSA or PAP when sections contain both seminal vesicle and benign glands because PSA and PAP cannot distinguish benign from malignant glands.

Renal cell carcinoma (RCC) accounts for 2% to 3% of all adult malignancies, and its incidence rate is increasing. (1) Renal cell carcinoma is clinicopathologically heterogenous and was recently subdivided [...], * Context.--Galectin-3, a member of the lectin family, was shown to be expressed in normal distal tubular cells and in renal cell carcinomas (RCC). However, its diagnostic and prognostic significance in RCC is as yet undefined. Objectives.--To describe the expression of Galectin-3 among different histologic subtypes of renal neoplasms and to determine their diagnostic and prognostic significances. Design.--The expression of Galectin-3 was evaluated in 217 renal neoplasms by tissue microarray and immunohistochemistry with semiquantitative analysis. Results.--Strong expression of Galectin-3 was observed in 92 of 217 of renal neoplasms (42.4%). Although 22 of 23 oncocytomas (95.7%) and 19 of 21 chromophobe RCCs (90.5%) express Galectin-3, only 4 of 32 papillary RCCs (12.5%) and 47 of 137 clear cell RCCs (34.3%) express Galectin-3, suggesting that it may be used as a potential diagnostic marker. Galectin-3 expression was seen in 55% of high-grade (Fuhrman nuclear grades 3 and 4) versus 21% low-grade (grades 1 and 2) clear cell RCCs (P< .001). Conclusions.--This study confirms that Galactin-3 is strongly overexpressed in renal cell neoplasms of distal tubular differentiation, that is, oncocytoma and chromophobe RCCs, suggesting it might be used as a possible differential diagnostic tool for renal cell neoplasm with oncocytic or granular cells. Furthermore, we observed a strong association of overexpression of Galectin-3 and high nuclear grade in clear cell RCC. These results also suggest a possible pivotal role for Galectin-3 in the differentiation and prognosis of clear cell RCC. (Arch Pathol Lab Med. 2010;134:90-94)

Partial or total nephrectomy is most often performed to remove renal neoplasms. Several nonneoplastic conditions that are clinically unsuspected are often identified in these specimens. For example, diabetic nephropathy or [...], * Context.--Nonneoplastic changes are often identified in nephrectomy specimens removed for renal neoplasms. Although they may be of prognostic or therapeutic importance, they are often overlooked. Nephrectomy is also performed for nonneoplastic lesions, the most frequent of which are urinary obstruction and end-stage renal disease, but the tissue diagnosis of these conditions and the implicated clinicopathologic correlation may not be well appreciated. Objective.--To outline these nonneoplastic lesions with special attention to important diagnostic caveats and clinicopathologic correlations. Data Sources.--The presented information was derived from literature, personal experience, and review of case materials at the authors&apos; institutions. Results.--Nonneoplastic lesions are seen in most (90%) nephrectomy specimens removed for renal neoplasms. Although these lesions span the spectrum of "medical" kidney diseases, the most frequent of them are hypertensive nephrosclerosis and diabetic nephropathy. Recognition of these diseases is important because they are often first diagnosed and later confirmed clinically. Furthermore, the severity of these lesions may predicate both short- and long-term renal function and thus help guide treatment. Among conditions that necessitate nephrectomy, advanced urinary obstruction, end-stage renal disease, and end-stage renal disease with acquired cystic changes are probably the most frequent. These conditions have characteristic morphologic features, but they may be associated with superimposing lesions previously not well described. These superimposing lesions may create diagnostic confusion; yet, some of them are the reason for nephrectomy. Thus, acute bacterial infection, urine polyp, granulomatous pyelitis, papillary necrosis, massive bleeding, and renal dysplasia can develop against the background of obstructive nephropathy. Renal neoplasms may develop from the background of end-stage renal disease without cystic changes. A renal neoplasm or massive bleeding with or without neoplasm is usually the reason for nephrectomy in kidney with acquired cystic kidney diseases. Thus, while nonneoplastic changes are frequent in nephrectomy specimens, they are often unrecognized. Awareness of these conditions and a familiarity with their diagnostic features as well as the implicated clinicopathologic correlation should help obviate this diagnostic problem.

Renal pathology has always been considered an 'exotic' area of pathology. Perhaps more than one reason accounts for this perception. Limited exposure to renal pathology, reflecting the fact that kidney [...]

The term undifferentiated tumor has been used in reference to a heterogeneous group of tumors with little or no evidence of differentiation. Some may link this terminology to morphologically undifferentiated [...], * Context.--"Undifferentiated tumor" refers to a heterogeneous group of neoplasms with little or no evidence of differentiation on routine light microscopic morphology. Objective.--To identify the true identity of undifferentiated tumors by immunohistochemical analysis. Data Sources.--Review of the pertinent literature and the authors&apos; experience. Conclusions.--For treatment and prognostic evaluation, it is crucial to delineate whether an undifferentiated neoplasm is epithelial, mesenchymal, melanocytic, or hematopoietic in nature. Application of a screening panel to demonstrate the expression of markers of major lineages is fundamental for determination of the broad category of neoplasia. Because poorly differentiated carcinomas and in particular sarcomatoid carcinomas are known to be heterogeneous in their antigen expression, several epithelial markers in combination may be required to establish the carcinomatous nature of tumor. A diagnostic misinterpretation as a consequence of occasional aberrant or unexpected antigen expression is best avoided by using a broad panel that includes both antibodies that are anticipated to be positive and those that are expected to be negative. In this treatise, the immunohistochemical dissection of undifferentiated tumors on the basis of their morphologic features is outlined, supplemented with algorithmic immunohistochemical analysis for each morphologic category of small round cell tumors, carcinomatous tumors, sarcomatous (or sarcoma-like) tumors, and tumors with histologically overlapping features, including hematolymphoid malignancies, melanoma, and sarcomas with epithelioid appearance. The utility of several organ- or tissue-specific markers in the context of undifferentiated tumors is reviewed.

Advances in the understanding of cytogenetic and molecular abnormalities of renal neoplasms in the last decade have significantly refined the morphologic classification of these lesions, which has resulted in a [...], Context.--Recent advances of molecular biology and cytogenetics of renal cancer have resulted in the new classification of renal neoplasms and a number of subtypes are identified and emphasized. In addition, rare nonepithelial renal neoplasms are identified and characterized. Familiarity with these entities will help make the most accurate diagnosis and guide the treatment and follow-up of patients with renal neoplasm. Objective.--To review the clinicopathologic entities of renal neoplasms that are recently defined or emphasized. Their clinical, gross, microscopic, and immunohistochemical features, as well as specific cytogenetic or molecular abnormalities, are discussed. Important differential diagnoses of each entity are also briefly discussed. Data Sources.--Extensive review of published literature and our experience. Conclusions.--A number of new entities of renal neoplasms or genetically defined renal cell carcinomas have been identified or emphasized because of their unique genetic or molecular changes. Recognition of these entities becomes important as some of them have different biologic behavior and treatment strategies may be different. (Arch Pathol Lab Med. 2007;131:1234-1243)

Renal allograft failure can be caused by a large variety of diseases, most of which can only be accurately diagnosed by transplant biopsies. (1) Among them, acute rejection is both [...], * Context.--Acute antibody-mediated rejection (AMR) has emerged recently as an important cause of graft failure. Objective.--To review the pathogenetic, clinicopathologic, and diagnostic considerations of AMR. Data Sources.--Review of literature and the authors&apos; experience. Conclusions.--Acute antibody-mediated rejection is mediated by antibodies specific for donor antigens, which bind to target antigens and activate the complement system, culminating in tissue injury. The clinical manifestation of AMR is not specific, and transplant biopsy is needed for diagnosis. The glomeruli show thrombosis or neutrophils or mononuclear leukocytes in capillary lumens. The tubulointerstitial compartment shows edema, hemorrhage, necrosis, mild inflammation, and neutrophils or mononuclear leukocytes in the peritubular capillary lumens. The blood vessels show thrombosis, thrombotic microangiopathy, fibrinoid necrosis, or transmural vasculitis. Strong staining for C4d in the peritubular capillaries is characteristic. A definitive diagnosis of AMR requires (1) morphologic evidence of acute tissue injury, (2) immunopathologic evidence for antibody action, and (3) serologic evidence of circulating donor-specific antibodies. Acute antibody-mediated rejection should be suspected if some but not all 3 criteria are met. Since effective treatment is currently available, accurate and timely diagnosis of AMR is essential. (Arch Pathol Lab Med. 2007;131:1200-1208)

Osmotically relevant membrane signaling complex: association between HB-EGF, [[Beta].sub.1]-integrin, and CD9 in mTAL. Am J Physiol Cell Physiol 279: C136-C146, 2000.--The integral membrane proteins cluster of differentiation-9 (CD9), [[Beta].sub.1]-integrin, and heparin-binding epidermal growth factor-like (HB-EGF) exist in association in many cell lines and are linked to intracellular signaling mechanisms. Two of the proteins (CD9 and [[Beta].sub.1]-integrin) are induced by hypertonicity, suggesting that their related signaling processes may be relevant to osmotic stress. The validity of this hypothesis rests upon coexpression and physical association between these molecules in nephron segments that are normally exposed to high and variable ambient osmolality. In this work, we show that CD9 and [[Beta].sub.1]-integrin are induced in rat kidney medulla after dehydration. Immunohistochemistry and immunoprecipitation studies show that CD9, HB-EGF, and [[Beta].sub.1]-integrin are coexpressed and physically associated in medullary thick ascending limbs (mTAL), nephron segments that are normally exposed to high and variable extracellular osmolality. Our findings are consistent with the existence of a cluster of integral membrane proteins in mTAL that may initiate or modulate osmotically relevant signaling pathways. cluster of differentiation-9; heparin-binding epidermal growth factor; [[Beta].sub.1]-integrin; osmotic stress; thick ascending limb; kidney

Osteopontin (OPN) is a pro-and anti-inflammatory molecule that simultaneously attenuates oxidative stress. Both inflammation and oxidative stress play a role in the pathogenesis of glomerulonephritis and in the progression of kidney injury. Importantly, OPN is highly induced in nephritic kidneys. To characterize further the role of OPN in kidney injury we used OPN-/- mice in antiglomerular basement membrane reactive serum-induced immune (NTS) nephritis, an inflammatory and progressive model of kidney disease. Normal wild-type (WT) and OPN-/- mice did not show histological differences. However, nephritic kidneys from OPN-/- mice showed severe damage compared with WT mice. Glomerular proliferation, necrotizing lesions, crescent formation, and tubulointerstitial injury were significantly higher in OPN-/- mice. Macrophage infiltration was increased in the glomeruli and interstitium in OPN-/- mice, with higher expression of IL-6, CCL2, and chemokine CXCL1. In addition, collagen (Col) I, Col III, and Col IV deposition were increased in kidneys from OPN-/- mice. Elevated expression of the reactive oxygen species-generating enzyme Nox4 and blunted expression of Nrf2, a molecule that inhibits reactive oxygen species and inflammatory pathways, was observed in nephritic kidneys from OPN-/- mice. Notably, CD11b diphteria toxin receptor mice with NTS nephritis selectively depleted of macrophages and reconstituted with OPN-/- macrophages showed less kidney injury compared with mice receiving WT macrophages. These findings suggest that in global OPN-/- mice there is increased inflammation and redox imbalance that mediate kidney damage. However, absence of macrophage OPN is protective, indicating that macrophage OPN plays a role in the induction and progression of kidney injury in NTS nephritis. [ABSTRACT FROM AUTHOR]