Advances in Anatomic Pathology:
The Use of Immunohistochemistry in the Diagnosis of Metastatic Clear Cell Renal Cell Carcinoma: A Review of PAX-8, PAX-2, hKIM-1, RCCma, and CD10
Sangoi, Ankur R. MD*,†; Karamchandani, Jason MD*; Kim, Jinah MD, PhD*; Pai, Reetesh K. MD*; McKenney, Jesse K. MD*
*Department of Pathology, Stanford University Medical Center, Stanford
†Department of Pathology, El Camino Hospital, Mountain View, CA
Reprints: Ankur R. Sangoi, MD, Department of Pathology, El Camino Hospital, GC-33, Mountain View, CA 94040 (e-mail: email@example.com).
The diagnosis of metastatic clear cell renal cell carcinoma may be difficult in some cases, particularly in the small image-guided biopsies that are becoming more common. As targeted therapies for renal cell carcinoma are now standard treatment, the recognition and diagnosis of renal cell carcinoma has become even more critical. Many adjunctive immunohistochemical markers of renal epithelial lineage such as CD10 and RCCma have been proposed as aids in the diagnosis of metastatic renal cell carcinoma, but low specificities often limit their utility. More recently described markers (PAX-2, PAX-8, human kidney injury molecule-1, hepatocyte nuclear factor-1-β, and carbonic anhydrase-IX) offer the potential for greater sensitivity and specificity in this diagnostic setting; however, knowledge of their expected staining in other neoplasms and tissues is critical for appropriate use. In this review, we discuss the most widely used immunohistochemical markers of renal lineage with an emphasis on their sensitivity and specificity for metastatic clear cell renal cell carcinoma. Subsequently, we present a variety of organ-specific differential diagnostic scenarios in which metastatic clear cell renal cell carcinoma might be considered and we propose immunopanels for use in each situation.
Clear cell renal cell carcinoma (CC-RCC) remains one of the great mimickers in surgical pathology (perhaps second only to malignant melanoma). It can metastasize to virtually any body site1–3 and can have significant morphologic overlap with other nonrenal neoplasms and normal tissues.4 CC-RCC also has the propensity to metastasize years after the initial diagnosis, making its diagnostic consideration more problematic.5 As advances in image-guided biopsies make a wide variety of body sites more accessible, we have encountered an increasing number of cases in which a diagnosis of metastatic CC-RCC is being considered from an extremely small tissue sample.6–8 In this setting, adjunctive immunohistochemical studies often play a significant diagnostic role. Although there is a long history of using immunohistochemistry for the diagnosis of metastatic CC-RCC, several novel putative CC-RCC markers have become available in the past few years. Recent studies propose that these newer markers [PAX-8, PAX-2, and human kidney injury molecule-1 (hKIM-1)] are significantly more sensitive and specific for metastatic CC-RCC and should replace the older standards such as CD10 and renal cell carcinoma monoclonal antibody (RCCma).1,9 In this review, we discuss the antibodies with the most utility in the diagnosis of CC-RCC, review the nonrenal tissues known to express them, and present the spectrum of differential diagnostic scenarios that may be encountered.
PAX-8, a member of the human paired boxed gene family, was originally described as an important transcription factor in the development of thyroid and renal tumors.10 Only 1 study has evaluated PAX-8 staining in a large series of metastatic CC-RCCs, and reported high sensitivity (94%) and overall specificity (88%).1 Most studies reporting immunohistochemical expression of this marker have focused on expression in renal, thyroid, and epithelial ovarian neoplasms11–16 with infrequent reactivity reported in urothelial carcinoma.9,14,17 Two recent studies have investigated PAX-8 reactivity in pancreatic neuroendocrine tumors,18,19 and 1 study has documented frequent immunoreactivity in Merkel cell carcinoma, thymoma, and medulloblastoma/medullomyoblastoma.9
Nuclear immunoreactivity is considered positive PAX-8 staining, but staining intensity may vary substantially between cases (Fig. 1B). Interpretative caution should be used in small biopsy samples as admixed B lymphocytes show strong PAX-8 reactivity.9
Similar to PAX-8, PAX-2 is also a member of the human paired boxed gene family and a renal cell-lineage transcription factor. Both markers share coexpression in embryonal and renal tissues.10,14 Although reactivity for both markers in RCC was originally reported more than decade ago,10,20 PAX-2 has been more frequently studied as a putative marker of CC-RCC, including metastatic tumors.21–30 Of the few studies reporting PAX-2 reactivity in metastatic CC-RCC, results show moderate sensitivity (47% to 85%) and high overall specificity (90% to 97%).1,21,22,30
Nonrenal neoplasms with well-documented PAX-2 immunoreactivity include tumors of müllerian origin (eg, uterine carcinomas, ovarian surface epithelial neoplasms, and endocervical carcinomas),9,11,30–34 parathyroid tumors,9,21 epididymal tumors,21 and lobular breast carcinoma.9,32 One study has also reported PAX-2 staining in testicular yolk sac tumors and Merkel cell carcinoma.9 Variable PAX-2 reactivity has been described in some soft tissue sarcomas.9
Nuclear immunoreactivity is considered positive PAX-2 staining (Fig. 1C). Interpretative caution should be used in small biopsy samples as admixed B-lymphocytes show strong PAX-2 reactivity.9 Although both PAX-2 and PAX-8 are useful markers of CC-RCC (primary and metastatic), it is our experience that PAX-8 has superior performance, given the generally stronger staining pattern for PAX-8 and the increasingly lower sensitivity of PAX-2 in our clinical diagnostic immunohistochemistry laboratory. Although using a more concentrated dilution of anti-PAX-2 will increase sensitivity to a level comparable with PAX-8, we have earlier shown that in certain instances this reduces specificity for metastatic CC-RCC, particularly in the distinction from lesions of the adrenal cortex.35
Human Kidney Injury Molecule-1
Although most studies of hKIM-1 are in the medical renal literature given its association with proximal tubular injury/ischemia, hKIM-1 has been recently reported as a diagnostic marker of CC-RCC and ovarian clear cell carcinoma.9,36,37 Variable reactivity with this marker has also been reported in hepatocellular carcinoma (HCC), colonic adenocarcinoma, urothelial carcinoma, and germ cell tumors.9,36–39 The 2 studies specifically investigating hKIM-1 reactivity in metastatic CC-RCC show good sensitivity (78% to 92%) and high overall specificity (86% to 98%).1,37
Membranous and/or cytoplasmic reactivity is considered positive hKIM-1 staining (Fig. 1D). Although the studies reporting hKIM-1 expression were not from a commercially available source, this is currently under development and should be available in the near future (personal communication, J.V. Bonventre, MD, PhD, Boston, MA). Some antibodies that share significant homology with hKIM-1 are available (TIM-1; R&D Systems, Minneapolis, MN and anti-rat KIM-1; Immunology Consultants Laboratory, Newberg, OR), but are not yet fully evaluated in a diagnostic setting.
Renal Cell Carcinoma Monoclonal Antibody
RCCma, which is reactive to a proximal nephrogenic renal antigen, was first described as a highly sensitive (84%) and specific (83%) marker of metastatic RCC over 30 years ago.40 The initial description suggested poor diagnostic specificity with documented reactivity in 78% of mammary carcinomas, 100% of parathyroid tumors, and 50% of germ cell tumors.40 Several more recent studies have also highlighted specificity problems by showing RCCma staining in a variety of tumors.21,41 Overall specificities for metastatic RCC (either CC-RCC or unspecified type) with anti-RCCma range from 48% to 100%, and sensitivities range from 27% to 90%.21,41–43
Membranous and/or cytoplasmic reactivity is considered positive RCCma staining (Fig. 1E). In our opinion, for most differential diagnostic scenarios PAX-8, PAX-2, and hKIM-1 should replace RCCma in routine diagnostic practice.
Since the initial description of CD10 as a proximal nephron marker over 20 years ago,44 CD10 immunoreactivity in CC-RCC has been well established.45,46 Some studies have reported sensitivities for metastatic CC-RCC ranging from 83% to 100%43,47; however, the fact that CD10 immunoreactivity is seen in a wide variety of nonrenal neoplasms has been extensively reviewed and recognized.45,46,48–50
Cytoplasmic and/or membranous reactivity is considered positive CD10 staining (Fig. 1F). As in the statement for RCCma, it is our opinion that with few exceptions, PAX-8, PAX-2, and hKIM-1 should replace CD10 in routine diagnostic practice.
Carbonic Anhydrase-IX and Hepatocyte Nuclear Factor-1-β
Although the antibody carbonic anhydrase-IX (regulated by hypoxia-inducible factor-1) has been described as a sensitive marker for CC-RCC (Fig. 1G), its expression is well recognized in a wide variety of other common nonrenal neoplasms, particularly in areas associated with ischemia or necrosis.51,52
Hepatocyte nuclear factor-1-β, originally reported as a marker of ovarian clear cell carcinoma,53 has since been described with immunoreactivity in many nonrenal neoplasms with a clear cell phenotype in addition to CC-RCC (Fig. 1H).54–57 As such, these markers are not as thoroughly studied at present time, and may lack diagnostic specificity in cases where metastatic CC-RCC is in the differential diagnosis, particularly in small biopsy samples.
DIFFERENTIAL DIAGNOSTIC SCENARIOS
Metastatic Clear Cell Renal Cell Carcinoma in Carcinoma of Unknown Primary (General Comments)
Given modern imaging techniques, the possibility of a radiographically undetectable, occult primary RCC that has given rise to metastatic disease is extremely improbable. In some patients with multicystic kidneys, either from autosomal-dominant disease or dialysis, it is possible that some imaging studies may be inconclusive. However, in most cases, abdominal computed tomography studies that include the kidneys offer the most specific test for excluding a primary renal carcinoma. Using immunohistochemistry for diagnosing CC-RCC in the absence of a renal mass or lesion is ill-advised. In most situations, the use of immunohistochemistry is for the pathologic confirmation of metastatic CC-RCC in the setting of a suspicious renal mass or in a patient with prior history of CC-RCC. In rare instances, immunostains may be used to exclude the possibility that a tumor might be unrelated to a synchronous renal mass or previously treated CC-RCC. It should be remembered that metastatic RCC may present many years after nephrectomy. The diagnostic work-up in various differential diagnostic scenarios is presented in the following sections. To facilitate the use of renal epithelial markers in the work-up of carcinomas of uncertain primary, we provide a summary of lesions with known immunoreactivity for PAX-2, PAX-8, and hKIM-1 in Table 1. It cannot be overemphasized that immunohistochemistry is an adjunct to the morphologic appearance and the clinical setting. Unusual immunophenotypes and expression in unexpected tissues and neoplasms invariably occur over time with more frequent use and additional study; therefore, these immunohistochemical stains should always be interpreted within the morphologic and clinical context.
Metastatic Clear Cell Renal Cell Carcinoma Versus Adrenal Tumors
Adrenal Cortical Lesions
The frequency of metastatic CC-RCC to the adrenal gland among reported organ sites from 2 large series is 2% to 3%.1,58 Although differentiating metastatic CC-RCC from primary adrenal cortical lesions (including adrenal rests, adrenal cortical hyperplasias, and adrenal cortical adenomas/carcinomas) can be made on clinical grounds in many instances, steroid-inactive adrenal cortical lesions and cases with significant morphologic overlap (eg, cytologically bland metastatic CC-RCC, adrenal cortical lesion with marked nuclear pleomorphism) can make this distinction challenging.1,59,60 An antibody panel including pankeratin/epithelial membrane antigen (EMA; reactive in metastatic CC-RCC) and calretinin/inhibin/MelanA (reactive in adrenal cortical lesions) has been traditionally used in making this distinction. These immunohistochemical markers are not entirely specific, particularly if used in isolation or without a minimum diagnostic staining intensity threshold.1 Adrenal cortical markers may show some weak cytoplasmic staining in CC-RCC. The addition of the nuclear marker steroidogenic factor-1 (also known as adrenal 4 binding protein) to a diagnostic panel offers improved specificity for adrenal cortical lesions (100%) and may also obviate issues of nonspecific cytoplasmic staining.1 Adrenal cortical lesions have not been reported to express PAX-2, PAX-8, or hKIM-11,36,37; however, we have noted that nuclear PAX-2 expression may be seen with more concentrated antibody dilutions.35
Although the distinction of metastatic CC-RCC from pheochromocytoma can be made clinically in most instances, not all patients present symptomatically.13,61 Moreover, the so-called “clear cell variant” (lipid degeneration) of pheochromocytoma may show significant morphologic overlap with metastatic CC-RCC.62,63 As such, an antibody panel including PAX-2, PAX-8, or hKIM-1 (reactive in metastatic CC-RCC) and chromogranin (reactive in pheochromocytoma) may be useful in certain cases. Chromogranin is recommended over synaptophysin based on occasional synaptophysin reactivity in metastatic CC-RCC (up to 2%, even with >2+ diagnostic staining threshold).1
Metastatic Clear Cell Renal Cell Carcinoma Versus Breast Tumors
Summary: CC-RCC Vers...Image Tools
Given the cyclical histologic changes in the breast64 and various types of mammary clear cells (including sebaceous, apocrine, endocrine, myoepithelial, glycogen-rich, lipid-rich, and mucin-rich),65 it is not surprising that metastatic CC-RCC may show morphologic overlap with a primary breast tumor. Most studies using “putative RCC” markers in breast pathology have focused on differentiating mammary carcinoma from ovarian or thyroid neoplasms using PAX-8. Although most studies have reported no expression of PAX-8 in mammary carcinomas,11,33 weak nuclear immunoreactivity has been reported in a small subset of cases.9 Similarly, PAX-2 immunoreactivity in breast tumors (particularly lobular carcinoma) is well described.9,32,66 To date, expression of hKIM-1 has not been described in breast carcinoma.9,36,37 In addition, immunoreactivity for the most used breast-lineage markers mammaglobin, gross cystic disease fluid protein-15, and GATA3 has not been reported in CC-RCC.67,68
Given their potential for cytoplasmic clearing and infrequent immunoreactivity with typical breast markers, differentiating myoepithelial breast lesions from metastatic CC-RCC can be problematic in a subset of cases. Almost no data is available for expression of newer RCC markers in mammary myoepithelial lesions; therefore, myoepithelial markers are presently the most specific antibodies in this diagnostic scenario.
Metastatic Clear Cell Renal Cell Carcinoma Versus Lung Tumors
Summary: CC-RCC Vers...Image Tools
The lungs are the most common site of CC-RCC metastasis, comprising from 21% to 54% of metastases.1,2,58 Clear cell change can occur in primary bronchogenic squamous cell carcinoma, adenocarcinoma, or neuroendocrine tumors.69,70 Of the studies reporting hKIM-1 immunoreactivity in nonrenal tumors,9,36,37 focal, weak hKIM-1 has been reported in only 1 lung adenocarcinoma.9 PAX-2 and PAX-8 staining have not been reported in lung tumors,9,21 whereas thyroid transcription factor-1 immunoreactivity has not been reported in RCC.71,72 Importantly, the putative lung marker Napsin A can be expressed in up to one-third of CC-RCCs and should not be used in this setting.71
Other lung neoplasms that may show prominent clear cell phenotypes overlapping with CC-RCC include salivary-type tumors (most notably acinic cell carcinoma and mucoepidermoid carcinoma), clear cell (sugar) tumor, and clear cell mesothelioma.70 Only limited data for hKIM-1, PAX-2, and PAX-8 expression is available in these rarer lung tumors.9
Metastatic Clear Cell Renal Cell Carcinoma Versus Gynecologic Tract Tumors
Summary: CC-RCC Vers...Image Tools
Using immunohistochemistry to distinguish metastatic CC-RCC from neoplasms of the gynecologic tract is problematic. In this differential diagnostic category, the novel CC-RCC markers PAX-8, PAX-2, and hKIM-1 may not be as useful as the more traditional markers. Both ovarian and uterine clear cell carcinomas show strong immunoreactivity with hKIM-1, PAX-2, and PAX-89,16,21,30–33,37,39; however, CD10 is reportedly negative in most gynecologic carcinomas.49,73,74 Similarly, Aries-Stella change shows PAX-8 immunoreactivity without staining for CD10.49,75
Other gynecologic tumors containing clear cells, which may show morphologic overlap with metastatic CC-RCC, include vaginal and cervical clear cell adenocarcinomas; similarly, CD10 is also reportedly negative in these carcinomas and has been reported as useful in this distinction.49 A detailed study of the newer CC-RCC markers in these tumors has not been performed. Trophoblastic tumors, which often show a clear cell phenotype, are frequently positive for CD10 and should prompt additional serologic and immunohistochemical work-up (eg, β-human chorionic gonadotrophin).49
Metastatic Clear Cell Renal Cell Carcinoma Versus Male Reproductive Tract Tumors
Summary: CC-RCC Vers...Image Tools
Of germ cell tumors, seminoma and yolk sac tumors have the most histologic overlap with CC-RCC. Seminoma shows no immunohistochemical reactivity with the markers hKIM-1 or PAX-2,9 but infrequent staining is reported for PAX-833; PAX-2 (and rarely PAX-8) may show reactivity in yolk sac tumors and should therefore be used cautiously.9 The marker hKIM-1 can be useful in the differentiation of CC-RCC from germ cell tumors, and the newer germ cell markers OCT3/4 (seminoma) and SALL-4 (seminoma and yolk sac tumor) seem relatively specific. In the category of sex-cord stromal testicular tumors, both Leydig and Sertoli cell tumors can show lipid accumulation imparting a clear cell phenotype.76 Immunoreactivity for typical sex-cord stromal markers (steroidogenic factor-1 and inhibin) with negative staining for hKIM-1, PAX-2, and PAX-8 are useful.
Finally, papillary cystadenoma of the epididymis presents a unique dilemma as it has both morphologic (clear cell phenotype) and clinical [von Hippel-Lindau (VHL) disease association with potential for concomitant RCC] overlap with metastatic CC-RCC. A cytokeratin (CK)7-positive, CD10-negative phenotype in clear cell papillary cystadenoma is reported as useful in this distinction77,78; however, we have anecdotally encountered a similar tumor in the ovary showing reactivity for CD10 (personal observation). Importantly, PAX-2 (and probably PAX-8) is not useful in this scenario as it characteristically has strong expression in clear cell papillary cystadenoma.21 The expression of hKIM-1 in the epididymis is not known.
In the prostate, the most common malignant morphologic mimic of metastatic CC-RCC is prostatic acinar adenocarcinoma with clear cell change, particularly those of transition zone origin, with posthormonal therapy, or with a diffuse Gleason pattern 5 sheet-like growth.76 Although unlikely to be problematic in most cases, clear cell cribriform hyperplasia and adenosis (atypical adenomatous hyperplasia) are some of the most frequently encountered benign lesions with clear cytoplasm.76,79 These benign and malignant morphologic mimics of metastatic CC-RCC show negative immunoreactivity with hKIM-1, PAX-2, and PAX-8 and positive immunoreactivity for prostate-specific acid, prostate-specific acid phosphatase, and p63 (p63 staining in basal cells of benign mimics). A recent study has proposed NKX3.1 as a useful prostatic epithelial marker.80 PAX-2 staining has been reported in rare benign prostatic secretory cells within the central zone, but PAX-8 has not been fully evaluated.81
Metastatic Clear Cell Renal Cell Carcinoma Versus Other Urinary Tract Tumors
Summary: CC-RCC Vers...Image Tools
In the setting of metastatic RCC to the urinary bladder, isolated bladder metastasis in the absence of multiple organ involvement is extremely rare.82 As such, differentiating metastatic CC-RCC from a primary vesical urothelial carcinoma with clear cell features (so-called “glyocogen-rich” variant) should strongly rely on clinical findings given the infrequent, but reported immunohistochemical overlap with both hKIM-1 and PAX-8 in both of these tumors.9,14,17,83 PAX-2 may have utility in this distinction, but has not been fully studied. We have encountered a small number of invasive urothelial carcinomas of the renal pelvis showing PAX-8 and PAX-2 immunoreactivity (15 and 10%, respectively, unpublished data), although others have reported infrequent staining.84
Clear cell adenocarcinoma of the urinary bladder or urethra is another tumor showing both morphologic and immunophenotypic overlap with metastatic CC-RCC, as both express of CD10, PAX-2, and PAX-8.85,86 Diffuse strong staining with CK7 and cancer antigen-125 have been reported in clear cell adenocarcinoma,74,85–88 which would be uncommon in metastatic CC-RCC. Nevertheless, clinical (female sex predilection and lack of prior/concurrent renal mass) and other morphologic features such as associated endometriosis and/or papillary, tubulocystic, and hobnail patterns may be the most useful information in differentiating clear cell adenocarcinoma from metastatic CC-RCC.
The solid, clear cell pattern of nephrogenic adenoma (ie, the diffuse pattern) may arise anywhere along the urinary tract (including the prostatic urethra) and can be a very close mimic of metastatic CC-RCC, particularly in a patient with an uncertain history of renal neoplasia. Given the proposed renal tubular histogenesis of a subset of nephrogenic adenomas, it is not surprising that they show immunohistochemical overlap with metastatic CC-RCC with reported positivity for CD10, PAX-2, and PAX-8.85,86,89–91 To our knowledge, hKIM-1 expression in nephrogenic adenoma has not been evaluated. As such, reliance on an admixture of more typical morphologic patterns of nephrogenic adenoma (ie, papillary, tubulocystic, hobnail, and thickened basement membrane) may be the most reliable tool in the distinction from metastatic CC-RCC.
Ureteral von Brunn nests frequently show clear cell change, and anecdotally we have seen several CC-RCCs over-staged in radical cystectomy specimens based on this finding. Spread of RCC along the ureter would be highly unusual. Immunohistochemistry is typically not needed for this distinction, but von Brunn nests maintain the typical urothelial phenotype.
Metastatic Clear Cell Renal Cell Carcinoma Versus Mediastinal Tumors
Summary: CC-RCC Vers...Image Tools
Clear cell thymic carcinomas, lymphomas with clear cell phenotype, and germ cell tumors are the 3 most common neoplasms of the anterior mediastinum showing morphologic overlap with metastatic CC-RCC.63,92,93 Germ cell tumors have already been discussed in the male reproductive tract section and will not be repeated here. Given the immunohistochemical overlap between hematopoietic tumors (lymphomas and thymomas) and renal neoplasms using markers of the PAX gene family (notably PAX-2, PAX-5, and PAX-8),9,30,94 these markers may not be a useful tool in differentiation. Rather, a reliance on hKIM-1 and lineage-specific markers (CD5 for thymic tumors and CD20/CD45/CD3/CD43 for lymphomas) are helpful.
Of the posterior mediastinal tumors, neurogenic tumors (in particular paraganglioma) may show the most morphologic overlap with metastatic CC-RCC, and will be discussed in the soft tissue tumor section.
Metastatic Clear Cell Renal Cell Carcinoma Versus Head and Neck Tumors
Summary: CC-RCC Vers...Image Tools
Although the frequency of thyroid metastasis from CC-RCC among reported organ sites from a single large series is low (1%),1 it is important to recognize that several thyroid lesions, both benign (follicular adenoma) and malignant (follicular and papillary carcinoma), can be comprised of clear cells mimicking metastatic CC-RCC.63,95 Moreover, acknowledgment of the role of the PAX-8 gene in thyroid development is critical in appreciating immunohistochemical overlap in both thyroid tumors and metastatic CC-RCC.1,9–12,15,96 Immunoreactivity for PAX-2 in thyroid tumors is predominantly negative (1 case with weak staining reported),9,97 whereas hKIM-1 is reportedly negative in thyroid lesions.9,36,37
Similar to the thyroid, both benign (parathyroid adenoma, particularly “water-clear cell” variant) and malignant (parathyroid carcinoma) parathyroid neoplasms can show morphologic overlap with metastatic CC-RCC.63 Although clear cell hyperplasia may also show features reminiscent of metastatic CC-RCC, involvement of multiple glands is a helpful clinical aid in this distinction. Although both PAX-2 and PAX-8 show immunoreactivity in both the normal and neoplastic parathyroid,9,21,30 hKIM-1 staining has not been reported in the parathyroid gland.9
Metastatic CC-RCC can show morphologic overlap with several categories of primary salivary gland tumors, particularly (hyalinizing) clear cell carcinoma, epithelial-myoepithelial carcinoma, and myoepithelioma/myoepithelial carcinoma, as well as clear cell variants of mucoepidermoid carcinoma, acinic cell carcinoma, oncocytoma/oncocytic carcinoma, and sebaceous adenoma/carcinoma.98–100 Tumors with a myoepithelial component can be differentiated from metastatic CC-RCC using myoepithelial immunohistochemical markers (eg, calponin and p63).98–101 Many of these tumors can be differentiated from metastatic CC-RCC using traditional histochemistry [periodic-acid Schiff-diastase (PAS-D) in acinic cell carcinoma and mucin stain in mucoepidermoid carcinoma).95 Although very few cases have been evaluated, immunoreactivity for PAX-2, PAX-8, and hKIM-1 is negative to date in salivary gland tumors.
Squamous cell carcinoma may occasionally have abundant intracytoplasmic glycogen imparting a clear cell appearance. Typical markers of squamous cell carcinoma, such as CK5/6, high molecular weight CK, and p63 are characteristically expressed. No PAX-2, PAX-8, or hKIM-1 expression has been reported in squamous cell carcinoma.9,21
Clear cell odontogenic carcinoma is a rare carcinoma of the mandible and maxilla, which can closely mimic the histology of metastatic CC-RCC, but is most commonly found in older women. There is very limited immunohistochemical data available for these tumors. Close clinical correlation is critical to exclude a metastatic lesion.
Rare clear cell variants of calcifying epithelial odontogenic tumors (Pindborg tumors) are described. Although most are located in the mandible or maxilla, rare peripheral lesions may be seen in the anterior gingiva. There is very limited immunohistochemical information available for these tumors, but they have been shown to express p63 and CK5/6, which would aid in the distinction from metastatic CC-RCC.102 In addition, calcifying epithelial odontogenic tumor is associated with extensive amyloid deposition that can be highlighted by Congo red stains.
Ameloblastoma, which typically presents as a mass lesion in the mandible or maxilla, may have pronounced clear cell or granular features that might mimic metastatic CC-RCC. Extraosseous or peripheral ameloblastomas may also involve the gingiva or buccal mucosa. The immunophenotype of ameloblastoma is similar to the Pindborg tumor with CK5/6 and p63 expression.102 Little to no data is available regarding staining with renal markers. Recognition of other more typical patterns of ameloblastoma is most helpful in the distinction from a metastatic carcinoma.
Metastatic Clear Cell Renal Cell Carcinoma Versus Clear Cell Pancreaticobiliary Tract, Gastrointestinal Tract, and Liver Tumors
Summary: CC-RCC Vers...Image Tools
Metastatic carcinoma to the pancreas from another primary site is extremely uncommon; however, CC-RCC is one of the few known tumors, along with lung, colon, and breast carcinomas, known to metastasize to the pancreas,5,103–108 with an estimated frequency of metastasis among reported organ sites of 1%.1,58 Metastatic CC-RCC can closely mimic a primary pancreatic neoplasm, as many are also known to exhibit clear cell change. Pancreatic ductal adenocarcinoma can exhibit a clear cell or foamy gland appearance.109–112 Although primary clear cell or foamy gland adenocarcinoma of the pancreas typically maintains a tubular architecture and is often associated with areas of conventional ductal adenocarcinoma, cases with a predominantly solid growth pattern have been reported.111 clear cell and foamy gland ductal adenocarcinoma of the pancreas are positive for CK7, carcinoembryonic antigen, and MUC1 by immunohistochemistry, which are not typically immunoreactive in CC-RCC.109,111 Both clear cell and foamy gland ductal adenocarcinoma show cytoplasmic mucin positivity with mucicarmine and PAS-D, which is not seen in CC-RCC.109,112 PAX-8 reactivity has been reported in a small subset of pancreatic ductal adenocarcinomas and thus may not be useful in distinguishing these 2 entities.113,114
Clear cell change in well-differentiated neuroendocrine tumors of the pancreas has also been recognized, particularly in patients with VHL syndrome, and can also be confused for CC-RCC.115 Strong and diffuse expression for immunohistochemical neuroendocrine markers synaptophysin and chromogranin in clear cell neuroendocrine tumors should allow distinction from CC-RCC. PAX-8 and CD10 immunohistochemistry are not helpful as both characteristically label both pancreatic neuroendocrine tumors and CC-RCC.18,19,116
Clear cell solid-pseudopapillary neoplasms of the pancreas have also been reported,117 although their distinction from CC-RCC is usually not problematic given the characteristic nuclear localization of β-catenin in solid-pseudopapillary neoplasm.118,119 CD10 and PAX-8 are not helpful in the distinction of solid-pseudopapillary neoplasm from CC-RCC, as both tumors can be positive for these markers.18 Finally, serous adenomas of the pancreas characteristically have clear cytoplasm with abundant PAS-positive cytoplasmic glycogen which is diastase-sensitive, similar to CC-RCC. Serous adenomas of the pancreas lack the cytologic atypia typical of CC-RCC and are characterized by perfectly round nuclei, which are uniformly euchromatic. Immunohistochemical analysis is rarely needed to distinguish these entities and caution should be used as serous adenomas of the pancreas may show immunoreactivity for RCCma.21 Two studies have shown an absence of PAX-2 expression in pancreatic serous neoplasms.18,120
A small subset of gastric and gastroesophageal junction adenocarcinomas have been described as clear cell adenocarcinoma with most exhibiting a tubulopapillary growth pattern.121–123 Clear cell carcinomas of the stomach can be intermixed with areas with a hepatoid morphology and can also be associated with α-fetoprotein production.123,124 Similar to CC-RCC, the cytoplasmic clearing of these tumors is because of the accumulation of glycogen and thus will stain with PAS but not after diastase digestion. These tumors are positive for CK7 and carcinoembryonic antigen, and a subset may also be positive for SALL4, unlike CC-RCC.121,124 Epithelioid gastrointestinal stromal tumor (GIST) can also be considered in the differential diagnosis of CC-RCC, as both may have a “rhabdoid” or clear appearance.125 Distinction from CC-RCC is often not difficult histologically, and ancillary immunohistochemical studies for CD117 and DOG1 can help to confirm the diagnosis of GIST.126–128 Of note, a small number of GISTs can show focal immunoreactivity for CK8 and CK18 and such staining should not be interpreted as being indicative of carcinoma.129 Renal markers are not well studied in GISTs.
The frequency of metastatic CC-RCC to the liver among reported organ sites ranges from 3% to 10%.1,2,58 The differential diagnosis for hepatic neoplasms with clear cell morphology includes metastatic CC-RCC, clear cell HCC, and clear cell cholangiocarcinomas.125 Hepar-1 and arginase-1 are sensitive markers of hepatic differentiation and can typically distinguish HCC from CC-RCC.130–132 Glypican-3 is also a useful marker for HCC and is only rarely seen in RCC, most commonly in the chromophobe subtype.133 Recent data also suggests that PAX-2 and PAX-8 may be useful in distinguishing CC-HCC from CC-RCC, as only a small subset of HCC will exhibit immunoreactivity for these markers.36,134 Importantly, RCCma is not specific for CC-RCC in this setting as it often is positive in HCCs with clear cell change.21 Intrahepatic clear cell cholangiocarcinoma is a rare entity with few cases reported in the literature.135,136 Clear cell cholangiocarcinomas typically maintain a tubular architecture and are positive for CK7 and CK19, but negative for CD10 and PAX-8.9
Metastatic Clear Cell Renal Cell Carcinoma Versus Cutaneous Tumors
Summary: CC-RCC Vers...Image Tools
Metastatic carcinoma to the skin is a relatively common finding and cutaneous metastasis of RCC may occur in 3% to 11% of cases.1,58,137–139 Dermal tumors composed entirely of clear cells, however, are not common and typically show adnexal differentiation. Therefore, the main morphologic differential diagnosis of cutaneous metastatic CC-RCC includes dermal adnexal neoplasms with clear cell change and other metastatic clear cell carcinomas. As metastatic cutaneous adenocarcinomas typically maintain their characteristic primary immunohistochemical patterns, this discussion will be limited to other entities.
Adnexal lesions may show eccrine, follicular, or sebaceous differentiation. Clear cell adnexal lesions that show eccrine differentiation include hidradenoma, syringoma, eccrine carcinoma, syringoid carcinoma, and porocarcinoma.140–147 The clear cell adnexal lesions with follicular differentiation include trichilemmoma and trichilemmal carcinoma. Neoplasms with sebaceous differentiation, such as sebaceous adenoma, sebaceoma, and sebaceous carcinoma, contain distinctive EMA-positive intracytoplasmic vacuoles with lipid droplets.148–150 Primary adnexal lesions are p63 positive, in contrast to metastatic carcinomas, including CC-RCC.151–154 Recently, it was reported that combined expression of podoplanin (D2-40) and p63 permits the distinction between primary cutaneous tumors and metastatic adenocarcinomas.155,156 In addition, adnexal carcinomas lack expression of PAX-8.157
Occasionally, melanocytic lesions (balloon cell nevi and melanoma) may also mimic metastatic CC-RCC. Expression of S-100 protein or other melanocytic immunohistochemical markers is useful to assist in this distinction.
Recently, a clear cell dermal tumor present on the lower extremities of adults has been described and termed “distinctive dermal clear cell mesenchymal neoplasms.”158 These lesions morphologically mimic CC-RCC; however, the lesional cells express NKI-C3 and did not show reactivity with any melanocytic or keratinocytic markers tested.158 Dermal-based perivascular epithelioid cell tumors may also have cytoplasmic clearing that could potentially mimic CC-RCC.159 The expression of smooth muscle actin and melanocytic markers in perivascular epithelioid cell tumors should aid in this distinction.
Other entities, such as Paget disease, extramammary Paget disease, clear cell squamous cell carcinoma in situ, melanoma in situ, tricholemmal carcinoma, and sebaceous carcinoma may also show clear cell change; however, the intraepidermal location/component of these lesions typically allows distinction.
Metastatic Clear Cell Renal Cell Carcinoma Versus Bone Tumors
Summary: CC-RCC Vers...Image Tools
As metastatic carcinoma is the most common malignant bone lesion in adult patients, a variety of other carcinoma types may be encountered. Studies have reported that 9% to 25% of metastatic CC-RCC lesions involve bone.1,2,58 The comments for carcinoma of unknown primary are relevant here.
Primary Bone Tumors
Chordoma typically arises at the base of skull or in the sacrum, but may be seen anywhere in bone along the midline. In very rare instances, chordomas may be found in nonaxial locations (so-called true peripheral chordomas).160–162 Although peripheral chordomas are extraordinarily rare, they are described in multiple locations with the tibia representing the most common site.161
Chordoma can closely mimic RCC given its potentially nested or solid growth and typically clear cytoplasm. Recent studies have identified brachyury, a transcription factor involved in notochord development, that is expressed strongly in chordomas by immunohistochemistry.163 The use of this antibody has made the distinction of chordoma from CC-RCC much easier. A recent study of a large number of metastatic CC-RCCs has documented that they do not show immunoreactivity for brachyury.164 Rare chordomas may show focal PAX-8 immunoreactivity, but usually not as strongly or as diffusely as CC-RCC.164 Similarly, rare chordoma cases may also have RCCma expression,21 but CD10 expression is not typical.165
Clear cell chondrosarcoma typically occurs in the epiphyseal region of long tubular bones, typically in patients in their third or fourth decade of life; however, they have been reported in a wide spectrum of patient ages and in varying bones.166,167 Although these sarcomas have abundant clear cytoplasm, they generally have other features that are distinct from CC-RCC such as heterogeneous osteoid matrix, very well-delineated cell borders with surrounding eosinophlic material, or osteoclast-type giant cells. However, in a small biopsy, the presence of delicate capillaries forming a lobular architecture may closely mimic metastatic CC-RCC. To our knowledge, PAX-8, PAX-2, and hKIM-1 have not been studied in clear cell chondrosarcoma; therefore, the distinction is currently based predominantly on the morphologic features and the clinical/radiographic setting.
Occasional high-grade osteosarcomas may have abundant clear cytoplasm.168 Although osteosarcomas may be seen in any bone, they are most common in the metaphysis of long tubular bones, predominantly in adolescents and young adults. As with chondrosarcomas, the renal markers have not been well studied in osteosarcomas. Diagnosis depends on the clinical setting, the radiographic appearance, and the identification of irregular osteoid production by the neoplastic cells.
Adamantinoma may mimic metastatic carcinoma because it contains epithelial elements. It arises in the cortex of the tibia and fibula, and is commonly associated with a fibrous stromal component.169 Although not typical, adamantinomas may show clear cell change that could create diagnostic confusion on a small biopsy. We have seen biopsies misinterpreted as metastatic carcinoma because of biopsy crush artifact and positive CK stains. Very few published immunohistochemical studies of adamantinomas are available; however, distinction from CC-RCC is typically not difficult as the radiographic appearance is usually quite distinct.
Metastatic Clear Cell Renal Cell Carcinoma Versus Soft Tissue Tumors
Summary: CC-RCC Vers...Image Tools
Paragangliomas may mimic CC-RCC because of the nested architecture with surrounding well-formed vascular septae. These tumors typically express the neuroendocrine markers synaptophysin, chromogranin, and microtubule-associated protein-2 (MAP2).13 They may also show S-100 protein reactivity in the sustentacular cell component surrounding the nests. An absence of CK immunoreactivity also helps to exclude an epithelial process. PAX-2 is reportedly negative in paraganglioma, but RCCma staining may be observed.21
Clear cell sarcoma (melanoma of soft parts) also commonly has a nested pattern that may potentially mimic CC-RCC.170,171 Most cases have a distinctive spindled morphology with dense fibrous septa creating a nested architecture, but nested epithelioid patterns that mimic carcinoma are also seen. Despite the name, clear cell sarcoma more commonly has eosinophilic cytoplasm. Many cases also have admixed multinucleated giant cells. Immunohistochemically, clear cell sarcoma has a melanocytic phenotype with expression of S-100 protein, HMB-45, melanA, and other markers. In addition, clear cell sarcoma harbors an EWS translocation that can be identified with break-apart fluorescence in-situ hybridization (FISH) probes.172 Renal epithelial markers are not well studied in clear cell sarcoma, but we have seen cases with weak immunoreactivity for PAX-8.9
Alveolar soft part sarcoma often mimics the eosinophilic pattern of CC-RCC because of the characteristic sinusoidal vascular spaces that divide the tumor into nests.173 PAS-D stains characteristically show large intracytoplasmic crystals in alveolar soft part sarcoma.174 Diffuse nuclear overexpression for TFE3 is considered diagnostic of alveolar soft part sarcoma, but the antibody can be technically challenging to use.175 On account of this issue, some laboratories have developed a FISH test for documentation of a TFE3 rearrangement.176,177 CD10 expression has been reported in alveolar soft part sarcoma,178 but other renal lineage markers have not been well studied. Although not the focus of this review, the possibility of a TFE3/microphthalmia-associated transcription factor translocation RCC should be carefully considered when diagnosing alveolar soft part sarcoma as they may have the same translocation. This is particularly important in the presence of a renal mass.179
Many other sarcomas may have focal areas with cytoplasmic clearing that could potentially mimic a carcinoma on a small biopsy. Ewing/primitive neuroectodermal tumor (PNET) and rhabdomyosarcoma are 2 sarcomas that occasionally have abundant clear cytoplasm. Ewing/PNETs with abundant intracytoplasmic glycogen maintain their typical strong membranous immunoreactivity with CD99. A subset of cases may show CK reactivity, but the diagnosis of Ewing/PNET can usually be confirmed by testing with EWS break-apart FISH probes.180 Rhabdomyosarcoma may similarly have intracytoplasmic glycogen in some cases imparting a clear cell appearance, but documentation of myogenin and/or MyoD1 expression aids in this diagnosis.181–183 The epithelioid variant of pleomorphic liposarcoma may closely resemble a carcinoma, usually RCC or adrenal cortical carcinoma.184 The expression of CK and EMA in these epithelioid areas further complicates the distinction from carcinoma.184,185 Imaging correlation (ie, exclusion of a renal or adrenal mass) may be essential in tumors that do not show areas of more conventional pleomorphic liposarcoma.
In a large study of the renal epithelial markers, PAX-2, PAX-8, and hKIM-1 in nonrenal neoplasms and tissues, a few soft tissue sarcomas were evaluated. One pleomorphic undifferentiated sarcoma and 1 monophasic synovial sarcoma showed weak immunoreactivity for PAX-8, but no expression of PAX-2 or hKIM-1 was observed.9 Given the very limited immunoreactivity data available for the broad spectrum of sarcomas, caution should be used in the distinction of sarcomatoid RCC from a soft tissue sarcoma until the novel renal epithelial markers are more fully evaluated. Any immunophenotypic findings must be closely correlated with the clinical and radiographic context.
Metastatic Clear Cell Renal Cell Carcinoma Versus Central Nervous System Tumors
Summary: CC-RCC Vers...Image Tools
Many neoplasms of the central nervous system (CNS), such as oligodendroglioma, hemangioblastoma, germinoma, and neurocytoma are composed of cells with clear cytoplasm. Others tumors have morphologic variants featuring prominent clear cells such as clear cell meningioma and clear cell ependymoma.
Oligodendrogliomas are composed of monomorphic cells with round nuclei and delicate chromatin that frequently show perinuclear clearing.186,187 This perinuclear clearing is a processing artifact, and is not seen on frozen section.188 Unlike metastatic CC-RCC, oligodendrogliomas typically lack a pushing border, and frequently show an infiltrative growth pattern. FISH will often identify 1p/19q co-deletion.189 Glial fibrillary acid protein is positive in gliofibrillary oligodendroglial cells.190,191 MAP-2 and SOX10 are consistently positive in oligodendrogliomas,192,193 and Olig2 is also frequently expressed in oligodendrogliomas.194 CKs are not expressed in oligodendrogliomas,194 although crossreactivity is possible with other intermediate filaments.195 EMA is also not expressed in oligodendrogliomas.194
Hemangioblastomas are partially composed of stromal cells featuring clear, lipidized, and occasionally glycogenated vacuoles.187 The clear cell appearance of these stromal cells frequently raises the possibility of metastatic CC-RCC in the differential diagnosis. This consideration is of particular importance as approximately 25% to 30% of these tumors are associated with an inherited mutation of the VHL gene on 3p25 to 26, and these patients are also prone to developing renal tumors.196 To complicate matters, true collision metastatic CC-RCC to hemangioblastoma has been described.197–199 Although necrosis and mitoses are frequently present in metastatic CC-RCC, these features are typically absent in hemangioblastomas; however, the stromal cells of hemangioblastoma can show marked atypia.188 When interpreting immunohistochemical stains, it is important to evaluate only the clear stromal cells. A number of immunohistochemical stains, most prominently inhibin-α200 and D2-40,201,202 have recently been touted as useful in distinguishing hemangioblastoma from RCC. These reports have been followed by publications describing discordant results.28,203 Most recently, PAX-2 negativity, along with inhibin-α positivity has been reported to help to distinguish between these entities.28
Primary germinoma of the CNS is morphologically identical to its counterpart in the testis and ovary. Germinomas in the CNS have a predilection for the midline, particularly the pineal and pituitary/suprasellar regions.187 In the CNS, germinomas can be accompanied by vigorous lymphocytic and occasionally granulomatous inflammation. CK immunoreactivity in germinomas is typically weak and patchy,204,205 but diffuse strong CK staining may represent a component of embryonal carcinoma.190 The use of markers such as placental-like alkaline phosphatase and CD117 has generally been supplanted by the newer makers OCT3/4 and SALL4,206–208 which show nuclear staining and have increased specificity when compared with their predecessors. In other anatomic sites, PAX-8 expression has been reported in a subset of seminomas (germinomas), but PAX-2 and hKIM-1 have been negative.
Central neurocytoma is a rare tumor composed of a monotonous uniform population of small round cells featuring mild perinuclear clearing. It typically occurs in the supratentorial ventricular system of young adults (in contrast to RCC, which typically affects older patients). Unlike metastatic RCC, mitotic activity and necrosis are not generally present, although these features can be seen in atypical neurocytomas.209,210 Central neurocytomas typically show nuclear Neu-N staining,211 and strong cytoplasmic staining for MAP-2212,213 and synaptophysin.188
Clear cell meningioma is a rare variant of meningioma that typically features sheet-like growth pattern, and often lacks obvious meningothelial differentiation, whorl formation, and psammoma bodies. The tumor cells are clear as a consequence of glycogen-rich cytoplasm, and are thus PAS positive.187 Although earlier reported to be most commonly encountered in the cauda equina,187 a recent large series showed a predilection for these tumors to arise in the dura overlying the frontal lobes and posterior fossa.214 Nearly half of the 18 clear cell meningiomas in this study showed expression of carbonic anhydrase-IX, and more than a quarter of clear cell meningiomas were positive for CD10, although both of these stains were positive in fewer than 50% of cells. None of the tumors in their series were RCCma positive.214 EMA is unhelpful in distinguishing clear cell meningioma from metastatic CC-RCC, as this can be positive in both entities.188
Clear cell ependymoma is a rare variant of ependymoma that occurs most commonly in the supratentorial region in children.215 These tumors are composed of a monomorphic population of cells with the classic nuclear morphology of ependymal cells (ovoid nuclei with finely stippled chromatin), and moderate amounts of clear cytoplasm. Perivascular pseudorosettes are present, but these may be focal. These tumors are glial fibrillary acid protein positive and show the classic “dot-like” EMA positivity of ependymoma.186
Unfortunately, at present, the newer renal epithelial markers are not adequately studied in the CNS.
Summary: CC-RCC Vers...Image Tools
1. McKenney JK, Fujiwara M, Higgins JP, et al. Comparison of putative renal cell carcinoma immunohistochemical markers in primary adrenal cortical lesions and metastatic renal cell carcinoma: a tissue microarray study of 246 Cases. Mod Pathol
. 2009;22(suppl 1):182A.
2. Hoffmann NE, Gillett MD, Cheville JC, et al. Differences in organ system of distant metastasis by renal cell carcinoma subtype. J Urol. 2008;179:474–477
3. Renshaw AA, Richie JP. Subtypes of renal cell carcinoma. Different onset and sites of metastatic disease. Am J Clin Pathol. 1999;111:539–543
4. Nappi O, Mills SE, Swanson PE, et al. Clear cell tumors of unknown nature and origin: a systematic approach to diagnosis. Semin Diagn Pathol. 1997;14:164–174
5. Kassabian A, Stein J, Jabbour N, et al. Renal cell carcinoma metastatic to the pancreas: a single-institution series and review of the literature. Urology. 2000;56:211–215
6. Hughes JH, Jensen CS, Donnelly AD, et al. The role of fine-needle aspiration cytology in the evaluation of metastatic clear cell tumors. Cancer. 1999;87:380–389
7. Jhala NC, Jhala D, Eloubeidi MA, et al. Endoscopic ultrasound-guided fine-needle aspiration biopsy of the adrenal glands: analysis of 24 patients. Cancer. 2004;102:308–314
8. Sahni VA, Silverman SG. Biopsy of renal masses: when and why. Cancer Imaging. 2009;9:44–55
9. Sangoi AR, West RB, Bonventre JV, et al. Exploring the specificity of putative renal cell carcinoma markers in non-renal tissues and neoplasms from various organ systems: a tissue microarray study of 501 cases. Mod Pathol
. 2010;23(suppl 1):216A.
10. Poleev A, Fickenscher H, Mundlos S, et al. PAX8, a human paired box gene: isolation and expression in developing thyroid, kidney and Wilms' tumors. Development. 1992;116:611–623
11. Nonaka D, Tang Y, Chiriboga L, et al. Diagnostic utility of thyroid transcription factors Pax8 and TTF-2 (FoxE1) in thyroid epithelial neoplasms. Mod Pathol. 2008;21:192–200
12. Puglisi F, Cesselli D, Damante G, et al. Expression of Pax-8, p53 and bcl-2 in human benign and malignant thyroid diseases. Anticancer Res. 2000;20:311–316
13. Sangoi AR, McKenney JK. A tissue microarray-based comparative analysis of novel and traditional immunohistochemical markers in the distinction between adrenal cortical lesions and pheochromocytoma. Am J Surg Pathol. 2010;34:423–432
14. Tong GX, Yu WM, Beaubier NT, et al. Expression of PAX8 in normal and neoplastic renal tissues: an immunohistochemical study. Mod Pathol. 2009;22:1218–1227
15. Zhang P, Zuo H, Nakamura Y, et al. Immunohistochemical analysis of thyroid-specific transcription factors in thyroid tumors. Pathol Int. 2006;56:240–245
16. Bowen NJ, Logani S, Dickerson EB, et al. Emerging roles for PAX8 in ovarian cancer and endosalpingeal development. Gynecol Oncol. 2007;104:331–337
17. Pellizzari L, Puppin C, Mariuzzi L, et al. PAX8 expression in human bladder cancer. Oncol Rep. 2006;16:1015–1020
18. Sangoi AR, Ohgami RS, Pai RK, et al. PAX-8 expression reliably distinguishes pancreatic well-differentiated neuroendocrine tumors from ileal and pulmonary well-differentiated neuroendocrine tumors and pancreatic acinar cell carcinoma. Mod Pathol
. 2010. In press.
19. Long KB, Srivastava A, Hirsch MS, et al. PAX8 Expression in well-differentiated pancreatic endocrine tumors: correlation with clinicopathologic features and comparison with gastrointestinal and pulmonary carcinoid tumors. Am J Surg Pathol. 2010;34:723–729
20. Gnarra JR, Dressler GR. Expression of Pax-2 in human renal cell carcinoma and growth inhibition by antisense oligonucleotides. Cancer Res. 1995;55:4092–4098
21. Gokden N, Gokden M, Phan DC, et al. The utility of PAX-2 in distinguishing metastatic clear cell renal cell carcinoma from its morphologic mimics: an immunohistochemical study with comparison to renal cell carcinoma marker. Am J Surg Pathol. 2008;32:1462–1467
22. Gokden N, Kemp SA, Gokden M. The utility of Pax-2 as an immunohistochemical marker for renal cell carcinoma in cytopathology. Diagn Cytopathol. 2008;36:473–477
23. Gupta R, Balzer B, Picken M, et al. Diagnostic implications of transcription factor Pax 2 protein and transmembrane enzyme complex carbonic anhydrase IX immunoreactivity in adult renal epithelial neoplasms. Am J Surg Pathol. 2009;33:241–247
24. Luu VD, Boysen G, Struckmann K, et al. Loss of VHL and hypoxia provokes PAX2 up-regulation in clear cell renal cell carcinoma. Clin Cancer Res. 2009;15:3297–3304
25. Mazal PR, Stichenwirth M, Koller A, et al. Expression of aquaporins and PAX-2 compared to CD10 and cytokeratin 7 in renal neoplasms: a tissue microarray study. Mod Pathol. 2005;18:535–540
26. Memeo L, Jhang J, Assaad AM, et al. Immunohistochemical analysis for cytokeratin 7, KIT, and PAX2: value in the differential diagnosis of chromophobe cell carcinoma. Am J Clin Pathol. 2007;127:225–229
27. Ozcan A, Zhai J, Hamilton C, et al. PAX-2 in the diagnosis of primary renal tumors: immunohistochemical comparison with renal cell carcinoma marker antigen and kidney-specific cadherin. Am J Clin Pathol. 2009;131:393–404
28. Rivera AL, Takei H, Zhai J, et al. Useful immunohistochemical markers in differentiating hemangioblastoma versus metastatic renal cell carcinoma. Neuropathology. 2010 [Epub ahead of print].
29. Wasco MJ, Pu RT. Comparison of PAX-2, RCC antigen, and antiphosphorylated H2AX antibody (gamma-H2AX) in diagnosing metastatic renal cell carcinoma by fine-needle aspiration. Diagn Cytopathol. 2008;36:568–573
30. Zhai QJ, Ozcan A, Hamilton C, et al. PAX-2 expression in non-neoplastic, primary neoplastic, and metastatic neoplastic tissue: a comprehensive immunohistochemical study. Appl Immunohistochem Mol Morphol. 2010;18:323–332
31. Chivukula M, Dabbs DJ, O'Connor S, et al. PAX 2: a novel Mullerian marker for serous papillary carcinomas to differentiate from micropapillary breast carcinoma. Int J Gynecol Pathol. 2009;28:570–578
32. Muratovska A, Zhou C, He S, et al. Paired-Box genes are frequently expressed in cancer and often required for cancer cell survival. Oncogene. 2003;22:7989–7997
33. Nonaka D, Chiriboga L, Soslow RA. Expression of pax8 as a useful marker in distinguishing ovarian carcinomas from mammary carcinomas. Am J Surg Pathol. 2008;32:1566–1571
34. Tong GX, Chiriboga L, Hamele-Bena D, et al. Expression of PAX2 in papillary serous carcinoma of the ovary: immunohistochemical evidence of fallopian tube or secondary Mullerian system origin?. Mod Pathol. 2007;20:856–863
35. McKenney JK, Fujiwara M, Higgins JP, et al. A cautionary note regarding the use of PAX-2 immunohistochemistry in differentiating metastatic clear cell renal cell carcinoma from adrenal cortical lesions: a tissue microarray study of 245 cases. Mod Pathol. 2009;22(suppl 1):823
36. Han WK, Alinani A, Wu CL, et al. Human kidney injury molecule-1 is a tissue and urinary tumor marker of renal cell carcinoma. J Am Soc Nephrol. 2005;16:1126–1134
37. Lin F, Zhang PL, Yang XJ, et al. Human kidney injury molecule-1 (hKIM-1): a useful immunohistochemical marker for diagnosing renal cell carcinoma and ovarian clear cell carcinoma. Am J Surg Pathol. 2007;31:371–381
38. Lin F, Shi J, Yang XJ, et al. A useful panel of immunohistochemical markers in differentiating papillary renal cell carcinoma from papillary urothelial carcinoma. Mod Pathol. 2008;21:166A
39. Liu H, Prichard JW, Shi J, et al. The von hippel-lindau gene product (pVHL) and kidney injury molecule-1 (KIM-1) are useful diagnostic markers for identifying focal clear cell carcinoma of the uterus. Mod Pathol. 2009;22:225A
40. Yoshida SO, Imam A. Monoclonal antibody to a proximal nephrogenic renal antigen: immunohistochemical analysis of formalin-fixed, paraffin-embedded human renal cell carcinomas. Cancer Res. 1989;49:1802–1809
41. Bakshi N, Kunju LP, Giordano T, et al. Expression of renal cell carcinoma antigen (RCC) in renal epithelial and nonrenal tumors: diagnostic implications. Appl Immunohistochem Mol Morphol. 2007;15:310–315
42. McGregor DK, Khurana KK, Cao C, et al. Diagnosing primary and metastatic renal cell carcinoma: the use of the monoclonal antibody “renal cell carcinoma marker.”. Am J Surg Pathol. 2001;25:1485–1492
43. Simsir A, Chhieng D, Wei XJ, et al. Utility of CD10 and RCCma in the diagnosis of metastatic conventional renal-cell adenocarcinoma by fine-needle aspiration biopsy. Diagn Cytopathol. 2005;33:3–7
44. Holm-Nielsen P, Pallesen G. Expression of segment-specific antigens in the human nephron and in renal epithelial tumors. APMIS Suppl. 1988;4:48–55
45. Chu P, Arber DA. Paraffin-section detection of CD10 in 505 nonhematopoietic neoplasms. Frequent expression in renal cell carcinoma and endometrial stromal sarcoma. Am J Clin Pathol. 2000;113:374–382
46. Pan CC, Chen PC, Tsay SH, et al. Differential immunoprofiles of hepatocellular carcinoma, renal cell carcinoma, and adrenocortical carcinoma: a systemic immunohistochemical survey using tissue array technique. Appl Immunohistochem Mol Morphol. 2005;13:347–352
47. Yang B, Ali SZ, Rosenthal DL. CD10 facilitates the diagnosis of metastatic renal cell carcinoma from primary adrenal cortical neoplasm in adrenal fine-needle aspiration. Diagn Cytopathol. 2002;27:149–152
48. Kristiansen G, Schluns K, Yongwei Y, et al. CD10 expression in non-small cell lung cancer. Anal Cell Pathol. 2002;24:41–46
49. Ordi J, Romagosa C, Tavassoli FA, et al. CD10 expression in epithelial tissues and tumors of the gynecologic tract: a useful marker in the diagnosis of mesonephric, trophoblastic, and clear cell tumors. Am J Surg Pathol. 2003;27:178–186
50. Perna AG, Smith MJ, Krishnan B, et al. CD10 is expressed in cutaneous clear cell lesions of different histogenesis. J Cutan Pathol. 2005;32:348–351
51. Al-Ahmadie HA, Alden D, Qin LX, et al. Carbonic anhydrase IX expression in clear cell renal cell carcinoma: an immunohistochemical study comparing 2 antibodies. Am J Surg Pathol. 2008;32:377–382
52. Potter C, Harris AL. Hypoxia inducible carbonic anhydrase IX, marker of tumour hypoxia, survival pathway and therapy target. Cell Cycle. 2004;3:164–167
53. Tsuchiya A, Sakamoto M, Yasuda J, et al. Expression profiling in ovarian clear cell carcinoma: identification of hepatocyte nuclear factor-1 beta as a molecular marker and a possible molecular target for therapy of ovarian clear cell carcinoma. Am J Pathol. 2003;163:2503–2512
54. Cuff J, Huang S, Higgins JP, et al. CpG island methylation within the TCF2 promoter may enable epigenetic modulation of HNF1-beta and clear cell phenotype in ovarian clear cell carcinoma. Mod Pathol. 2009;22:210A
55. Illei PB, Epstein JI, Herawi M, et al. Hepatocyte nuclear factor-1 beta expression in clear cell adenocarcinomas of the bladder and urethra. Mod Pathol. 2010;23:197A
56. Kim L, Liao J, Zhang M, et al. Clear cell carcinoma of the pancreas: histopathologic features and a unique biomarker: hepatocyte nuclear factor-1beta. Mod Pathol. 2008;21:1075–1083
57. Yamamoto S, Tsuda H, Aida S, et al. Immunohistochemical detection of hepatocyte nuclear factor 1beta in ovarian and endometrial clear-cell adenocarcinomas and nonneoplastic endometrium. Hum Pathol. 2007;38:1074–1080
58. Saitoh H. Distant metastasis of renal adenocarcinoma. Cancer. 1981;48:1487–1491
59. Duenschede F, Bittinger F, Heintz A, et al. Malignant and unclear histological findings in incidentalomas. Eur Surg Res. 2008;40:235–238
60. Midorikawa S, Sanada H, Hashimoto S, et al. Analysis of cortisol secretion in hormonally inactive adrenocortical incidentalomas: study of in vitro steroid secretion and immunohistochemical localization of steroidogenic enzymes. Endocr J. 2001;48:167–174
61. Anagnostis P, Efstathiadou Z, Polyzos SA, et al. Long term follow-up of patients with adrenal incidentalomas a single center experience and review of the literature. Exp Clin Endocrinol Diabetes. 2009 Oct 23 [Epub ahead of print].
62. Ramsay JA, Asa SL, van Nostrand AW, et al. Lipid degeneration in pheochromocytomas mimicking adrenal cortical tumors. Am J Surg Pathol. 1987;11:480–486
63. Wick MR, Ritter JH, Humphrey PA, et al. Clear cell neoplasms of the endocrine system and thymus. Semin Diagn Pathol. 1997;14:183–202
64. Vogel PM, Georgiade NG, Fetter BF, et al. The correlation of histologic changes in the human breast with the menstrual cycle. Am J Pathol. 1981;104:23–34
65. Dina R, Eusebi V. Clear cell tumors of the breast. Semin Diagn Pathol. 1997;14:175–182
66. Silberstein GB, Dressler GR, Van Horn K. Expression of the PAX2 oncogene in human breast cancer and its role in progesterone-dependent mammary growth. Oncogene. 2002;21:1009–1016
67. Bhargava R, Beriwal S, Dabbs DJ. Mammaglobin versus GCDFP-15: an immunohistologic validation survey for sensitivity and specificity. Am J Clin Pathol. 2007;127:103–113
68. Higgins JP, Kaygusuz G, Wang L, et al. Placental S100 (S100P) and GATA3: markers for transitional epithelium and urothelial carcinoma discovered by complementary DNA microarray. Am J Surg Pathol. 2007;31:673–680
69. Gaffey MJ, Mills SE, Frierson HF Jr, et al. Pulmonary clear cell carcinoid tumor: another entity in the differential diagnosis of pulmonary clear cell neoplasia. Am J Surg Pathol. 1998;22:1020–1025
70. Gaffey MJ, Mills SE, Ritter JH. Clear cell tumors of the lower respiratory tract. Semin Diagn Pathol. 1997;14:222–232
71. Bishop JA, Sharma R, Illei PB. Napsin A and thyroid transcription factor-1 expression in carcinomas of the lung, breast, pancreas, colon, kidney, thyroid, and malignant mesothelioma. Hum Pathol. 2010;41:20–25
72. Reis-Filho JS, Carrilho C, Valenti C, et al. Is TTF1 a good immunohistochemical marker to distinguish primary from metastatic lung adenocarcinomas?. Pathol Res Pract. 2000;196:835–840
73. Cameron RI, Ashe P, O'Rourke DM, et al. A panel of immunohistochemical stains assists in the distinction between ovarian and renal clear cell carcinoma. Int J Gynecol Pathol. 2003;22:272–276
74. Vang R, Whitaker BP, Farhood AI, et al. Immunohistochemical analysis of clear cell carcinoma of the gynecologic tract. Int J Gynecol Pathol. 2001;20:252–259
75. Aguilar CE, Silva EG. New antibodies for clear cell carcinoma (Pax-8, HNF-α, vHL) are also positive in Arias-Stella reaction. Mod Pathol. 2010;23:232A
76. Humphrey PA. Clear cell neoplasms of the urinary tract and male reproductive system. Semin Diagn Pathol. 1997;14:240–252
77. Aydin H, Young RH, Ronnett BM, et al. Clear cell papillary cystadenoma of the epididymis and mesosalpinx: immunohistochemical differentiation from metastatic clear cell renal cell carcinoma. Am J Surg Pathol. 2005;29:520–523
78. Odrzywolski KJ, Mukhopadhyay S. Papillary cystadenoma of the epididymis. Arch Pathol Lab Med. 2010;134:630–633
79. Bostwick DG, Dundore PA. Clear Cell Proliferations of the Prostate: Differential Diagnosis 1997 New York Chapman and Hall Medical:39
80. Gurel B, Ali TZ, Montgomery EA, et al. NKX3.1 as a arker of prostatic origin in metastatic tumors. Am J Surg Pathol. 2010;34:1097–1105
81. Quick CM, Gokden N, Sangoi AR, et al. The distribution of PAX-2 immunoreactivity in the prostate gland, seminal vesicle, and ejaculatory duct: comparison with prostatic adenocarcinoma and discussion of prostatic zonal embryogenesis. Hum Pathol. 2010;41:1145–1149
82. Sim SJ, Ro JY, Ordonez NG, et al. Metastatic renal cell carcinoma to the bladder: a clinicopathologic and immunohistochemical study. Mod Pathol. 1999;12:351–355
83. Albadine R, Schultz L, Fajardo DA, et al. PAX-8 expression in urothelial neoplasia—an immunohistochemical study of 236 cases. Mod Pathol. 2010;23:1474A
84. Albadine R, Schultz L, Illei P, et al. PAX8 (+)/p63 (−) immunostaining pattern in renal collecting duct carcinoma (CDC): a useful immunoprofile in the differential diagnosis of CDC versus urothelial carcinoma of upper urinary tract. Am J Surg Pathol. 2010;34:965–969
85. Herawi M, Drew PA, Pan CC, et al. Clear cell adenocarcinoma of the bladder and urethra: cases diffusely mimicking nephrogenic adenoma. Hum Pathol. 2010;41:594–601
86. Tong GX, Weeden EM, Hamele-Bena D, et al. Expression of PAX8 in nephrogenic adenoma and clear cell adenocarcinoma of the lower urinary tract: evidence of related histogenesis?. Am J Surg Pathol. 2008;32:1380–1387
87. Oliva E, Amin MB, Jimenez R, et al. Clear cell carcinoma of the urinary bladder: a report and comparison of four tumors of mullerian origin and nine of probable urothelial origin with discussion of histogenesis and diagnostic problems. Am J Surg Pathol. 2002;26:190–197
88. Sun K, Huan Y, Unger PD. Clear cell adenocarcinoma of urinary bladder and urethra: another urinary tract lesion immunoreactive for P504S. Arch Pathol Lab Med. 2008;132:1417–1422
89. Fromont G, Barcat L, Gaudin J, et al. Revisiting the immunophenotype of nephrogenic adenoma. Am J Surg Pathol. 2009;33:1654–1658
90. Mazal PR, Schaufler R, Altenhuber-Muller R, et al. Derivation of nephrogenic adenomas from renal tubular cells in kidney-transplant recipients. N Engl J Med. 2002;347:653–659
91. Tong GX, Melamed J, Mansukhani M, et al. PAX2: a reliable marker for nephrogenic adenoma. Mod Pathol. 2006;19:356–363
92. McKenney JK, Heerema-McKenney A, Rouse RV. Extragonadal germ cell tumors: a review with emphasis on pathologic features, clinical prognostic variables, and differential diagnostic considerations. Adv Anat Pathol. 2007;14:69–92
93. Snover DC, Levine GD, Rosai J. Thymic carcinoma: five distinctive histological variants. Am J Surg Pathol. 1982;6:451–470
94. Morgenstern DA, Hasan F, Gibson S, et al. PAX5 expression in nonhematopoietic tissues. Reappraisal of previous studies. Am J Clin Pathol. 2010;133:407–415
95. Sindoni A, Rizzo M, Tuccari G, et al. Thyroid metastases from renal cell carcinoma: review of the literature. ScientificWorldJournal. 2010;10:590–602
96. Fabbro D, Di Loreto C, Beltrami CA, et al. Expression of thyroid-specific transcription factors TTF-1 and PAX-8 in human thyroid neoplasms. Cancer Res. 1994;54:4744–4749
97. Liles N, Hamilton G, Shen SS, et al. PAX-8 is a sensitive marker for thyroid differentiation. Comparison with PAX-2, TTF-1, and thyroglobulin. Mod Pathol. 2010;23(suppl 1):130A
98. Maiorano E, Altini M, Favia G. Clear cell tumors of the salivary glands, jaws, and oral mucosa. Semin Diagn Pathol. 1997;14:203–212
99. Said-Al-Naief N, Klein MJ. Clear cell entities of the head and neck: a selective review of clear cell tumors of the salivary glands. Head Neck Pathol. 2008;2:111–115
100. Wang B, Brandwein M, Gordon R, et al. Primary salivary clear cell tumors--a diagnostic approach: a clinicopathologic and immunohistochemical study of 20 patients with clear cell carcinoma, clear cell myoepithelial carcinoma, and epithelial-myoepithelial carcinoma. Arch Pathol Lab Med. 2002;126:676–685
101. McHugh JB, Hoschar AP, Dvorakova M, et al. p63 immunohistochemistry differentiates salivary gland oncocytoma and oncocytic carcinoma from metastatic renal cell carcinoma. Head Neck Pathol. 2007;1:123–131
102. Gratzinger D, Salama ME, Poh CF, et al. Ameloblastoma, calcifying epithelial odontogenic tumor, and glandular odontogenic cyst show a distinctive immunophenotype with some myoepithelial antigen expression. J Oral Pathol Med. 2008;37:177–184
103. Ghavamian R, Klein KA, Stephens DH, et al. Renal cell carcinoma metastatic to the pancreas: clinical and radiological features. Mayo Clin Proc. 2000;75:581–585
104. Robbins EG, Franceschi D, Barkin JS. Solitary metastatic tumors to the pancreas: a case report and review of the literature. Am J Gastroenterol. 1996;91:2414–2417
105. Sohn TA, Yeo CJ, Cameron JL, et al. Renal cell carcinoma metastatic to the pancreas: results of surgical management. J Gastrointest Surg. 2001;5:346–351
106. Stankard CE, Karl RC. The treatment of isolated pancreatic metastases from renal cell carcinoma: a surgical review. Am J Gastroenterol. 1992;87:1658–1660
107. Sweeney AD, Wu MF, Hilsenbeck SG, et al. Value of pancreatic resection for cancer metastatic to the pancreas. J Surg Res. 2009;156:189–198
108. Z'Graggen K, Fernandez-del Castillo C, Rattner DW, et al. Metastases to the pancreas and their surgical extirpation. Arch Surg. 1998;133:413–447
109. Adsay V, Logani S, Sarkar F, et al. Foamy gland pattern of pancreatic ductal adenocarcinoma: a deceptively benign-appearing variant. Am J Surg Pathol. 2000;24:493–504
110. Kanai N, Nagaki S, Tanaka T. Clear cell carcinoma of the pancreas. Acta Pathol Jpn. 1987;37:1521–1526
111. Luttges J, Vogel I, Menke M, et al. Clear cell carcinoma of the pancreas: an adenocarcinoma with ductal phenotype. Histopathology. 1998;32:444–448
112. Ray S, Lu Z, Rajendiran S. Clear cell ductal adenocarcinoma of pancreas: a case report and review of the literature. Arch Pathol Lab Med. 2004;128:693–696
113. Laury AR, Hornick JL, Piao H, et al. PAX8 is highly sensitive and specific for mullerian, renal, and thyroid neoplasms: a study of 1500 epithelial tumors. Mod Pathol. 2010;23:388A
114. Tacha D, Cheng L, Zhou D, et al. Expression of PAX8 in normal and neoplastic tissues: a comprehensive IHC analysis. Mod Pathol. 2010;23:222A
115. Hoang MP, Hruban RH, Albores-Saavedra J. Clear cell endocrine pancreatic tumor mimicking renal cell carcinoma: a distinctive neoplasm of von Hippel-Lindau disease. Am J Surg Pathol. 2001;25:602–609
116. Salla C, Konstantinou P, Chatzipantelis P. CK19 and CD10 expression in pancreatic neuroendocrine tumors diagnosed by endoscopic ultrasound-guided fine-needle aspiration cytology. Cancer Cytopathol. 2009;117:516–521
117. Albores-Saavedra J, Simpson KW, Bilello SJ. The clear cell variant of solid pseudopapillary tumor of the pancreas: a previously unrecognized pancreatic neoplasm. Am J Surg Pathol. 2006;30:1237–1242
118. Abraham SC, Klimstra DS, Wilentz RE, et al. Solid-pseudopapillary tumors of the pancreas are genetically distinct from pancreatic ductal adenocarcinomas and almost always harbor beta-catenin mutations. Am J Pathol. 2002;160:1361–1369
119. Tiemann K, Heitling U, Kosmahl M, et al. Solid pseudopapillary neoplasms of the pancreas show an interruption of the Wnt-signaling pathway and express gene products of 11q. Mod Pathol. 2007;20:955–960
120. Molina CP, Kim M, Zhai J, et al. Differentiation of serous cystic pancreatic neoplasms and metastatic renal cell carcinoma by immunohistochemistry. Mod Pathol. 2007;20:287A
121. Ghotli ZA, Serra S, Chetty R. Clear cell (glycogen rich) gastric adenocarcinoma: a distinct tubulo-papillary variant with a predilection for the cardia/gastro-oesophageal region. Pathology. 2007;39:466–469
122. Govender D, Ramdial PK, Clarke B, et al. Clear cell (glycogen-rich) gastric adenocarcinoma. Ann Diagn Pathol. 2004;8:69–73
123. Matsunou H, Konishi F, Jalal RE, et al. Alpha-fetoprotein-producing gastric carcinoma with enteroblastic differentiation. Cancer. 1994;73:534–540
124. Ushiku T, Shinozaki A, Shibahara J, et al. SALL4 represents fetal gut differentiation of gastric cancer, and is diagnostically useful in distinguishing hepatoid gastric carcinoma from hepatocellular carcinoma. Am J Surg Pathol. 2010;34:533–540
125. Ritter JH, Mills SE, Gaffey MJ, et al. Clear cell tumors of the alimentary tract and abdominal cavity. Semin Diagn Pathol. 1997;14:213–219
126. Espinosa I, Lee CH, Kim MK, et al. A novel monoclonal antibody against DOG1 is a sensitive and specific marker for gastrointestinal stromal tumors. Am J Surg Pathol. 2008;32:210–218
127. Liegl B, Hornick JL, Corless CL, et al. Monoclonal antibody DOG1.1 shows higher sensitivity than KIT in the diagnosis of gastrointestinal stromal tumors, including unusual subtypes. Am J Surg Pathol. 2009;33:437–446
128. Miettinen M, Wang ZF, Lasota J. DOG1 antibody in the differential diagnosis of gastrointestinal stromal tumors: a study of 1840 cases. Am J Surg Pathol. 2009;33:1401–1408
129. Miettinen M, Furlong M, Sarlomo-Rikala M, et al. Gastrointestinal stromal tumors, intramural leiomyomas, and leiomyosarcomas in the rectum and anus: a clinicopathologic, immunohistochemical, and molecular genetic study of 144 cases. Am J Surg Pathol. 2001;25:1121–1133
130. Fan Z, van de Rijn M, Montgomery K, et al. Hep par 1 antibody stain for the differential diagnosis of hepatocellular carcinoma: 676 tumors tested using tissue microarrays and conventional tissue sections. Mod Pathol. 2003;16:137–144
131. Lamps LW, Folpe AL. The diagnostic value of hepatocyte paraffin antibody 1 in differentiating hepatocellular neoplasms from nonhepatic tumors: a review. Adv Anat Pathol. 2003;10:39–43
132. Yan BC, Gong C, Song J, et al. Arginase-1: a new immunohistochemical marker of hepatocytes and hepatocellular neoplasms. Am J Surg Pathol. 2010;34:1147–1154
133. Kandil DH, Cooper K. Glypican-3: a novel diagnostic marker for hepatocellular carcinoma and more. Adv Anat Pathol. 2009;16:125–129
134. Mattis AN, Browne LW, Kakar S, et al. Comparison of PAX-2 and PAX-8 in distinguishing hepatocellular carcinomas with clear-cell morphology from renla cell carcinomas. Mod Pathol. 2010;23:365A
135. Haas S, Gutgemann I, Wolff M, et al. Intrahepatic clear cell cholangiocarcinoma: immunohistochemical aspects in a very rare type of cholangiocarcinoma. Am J Surg Pathol. 2007;31:902–906
136. Toriyama E, Nanashima A, Hayashi H, et al. A case of intrahepatic clear cell cholangiocarcinoma. World J Gastroenterol. 2010;16:2571–2576
137. Cuckow P, Doyle P. Renal cell carcinoma presenting in the skin. J R Soc Med. 1991;84:497–498
138. Kouroupakis D, Patsea E, Sofras F. Renal cell carcinoma metastases to the skin: a not so rare case?. Br J Urol. 1995;75:583–585
139. Mueller TJ, Wu H, Greenberg RE, et al. Cutaneous metastases from genitourinary malignancies. Urology. 2004;63:1021–1026
140. Civatte J. Clear-cell tumors of the skin: a histopathologic review. J Cutan Pathol. 1984;11:165–175
141. Furue M, Hori Y, Nakabayashi Y. Clear-cell syringoma. Association with diabetes mellitus. Am J Dermatopathol. 1984;6:131–138
142. Kitamura K, Muraki R, Tamura N. Clear cell syringoma. Cutis. 1983;32:169–172
143. Ramos D, Monteagudo C, Carda C, et al. Clear cell syringoid carcinoma: an ultrastructural and immunohistochemical study. Am J Dermatopathol. 2000;22:60–64
144. Requena L, Sarasa JL, Pique E, et al. Clear-cell porocarcinoma: another cutaneous marker of diabetes mellitus. Am J Dermatopathol. 1997;19:540–544
145. Rutten A, Requena L, Requena C. Clear-cell porocarcinoma in situ: a cytologic variant of porocarcinoma in situ. Am J Dermatopathol. 2002;24:67–71
146. Suster S. Clear cell tumors of the skin. Semin Diagn Pathol. 1996;13:40–59
147. Wong TY, Suster S, Nogita T, et al. Clear cell eccrine carcinomas of the skin: a clinicopathologic study of nine patients. Cancer. 1994;73:1631–1643
148. Heyderman E, Graham RM, Chapman DV, et al. Epithelial markers in primary skin cancer: an immunoperoxidase study of the distribution of epithelial membrane antigen (EMA) and carcinoembryonic antigen (CEA) in 65 primary skin carcinomas. Histopathology. 1984;8:423–434
149. Latham JA, Redfern CP, Thody AJ, et al. Immunohistochemical markers of human sebaceous gland differentiation. J Histochem Cytochem. 1989;37:729–734
150. Noda Y, Horike H, Watanabe Y, et al. Immunohistochemical identification of epithelial membrane antigen in sweat gland tumors by the use of a monoclonal antibody. Pathol Res Pract. 1987;182:797–804
151. Ivan D, Diwan AH, Lazar AJ, et al. The usefulness of p63 detection for differentiating primary from metastatic skin adenocarcinomas. J Cutan Pathol. 2008;35:880–881
152. Ivan D, Hafeez Diwan A, Prieto VG. Expression of p63 in primary cutaneous adnexal neoplasms and adenocarcinoma metastatic to the skin. Mod Pathol. 2005;18:137–142
153. Ivan D, Nash JW, Prieto VG, et al. Use of p63 expression in distinguishing primary and metastatic cutaneous adnexal neoplasms from metastatic adenocarcinoma to skin. J Cutan Pathol. 2007;34:474–480
154. Qureshi HS, Ormsby AH, Lee MW, et al. The diagnostic utility of p63, CK5/6, CK 7, and CK 20 in distinguishing primary cutaneous adnexal neoplasms from metastatic carcinomas. J Cutan Pathol. 2004;31:145–152
155. Liang H, Wu H, Giorgadze TA, et al. Podoplanin is a highly sensitive and specific marker to distinguish primary skin adnexal carcinomas from adenocarcinomas metastatic to skin. Am J Surg Pathol. 2007;31:304–310
156. Plaza JA, Ortega PF, Stockman DL, et al. Value of p63 and podoplanin (D2-40) immunoreactivity in the distinction between primary cutaneous tumors and adenocarcinomas metastatic to the skin: a clinicopathologic and immunohistochemical study of 79 cases. J Cutan Pathol. 2010;37:403–410
157. Fujiwara M, Taube J, Sharma M, et al. PAX8 discriminates ovarian metastases from adnexal tumors and other cutaneous metastases. J Cutan Pathol. 2010;37:938–943
158. Lazar AJF, Fletcher CDM. Distinctive dermal clear cell mesenchymal neoplasm; clinicopathologic analysis of five cases. Am J Dermatopathol. 2004;26:273–279
159. Liegl B, Hornick JL, Fletcher CD. Primary cutaneous PEComa: distinctive clear cell lesions of skin. Am J Surg Pathol. 2008;32:608–614
160. Nielsen GP, Mangham DC, Grimer RJ, et al. Chordoma periphericum: a case report. Am J Surg Pathol. 2001;25:263–267
161. O'Donnell P, Tirabosco R, Vujovic S, et al. Diagnosing an extra-axial chordoma of the proximal tibia with the help of brachyury, a molecule required for notochordal differentiation. Skeletal Radiol. 2007;36:59–65
162. Tirabosco R, Mangham DC, Rosenberg AE, et al. Brachyury expression in extra-axial skeletal and soft tissue chordomas: a marker that distinguishes chordoma from mixed tumor/myoepithelioma/parachordoma in soft tissue. Am J Surg Pathol. 2008;32:572–580
163. Vujovic S, Henderson S, Presneau N, et al. Brachyury, a crucial regulator of notochordal development, is a novel biomarker for chordomas. J Pathol. 2006;209:157–165
164. Sangoi AR, Karamchandani J, Lane B, et al. Specificity of brachyury in the distinction of chordoma from clear cell renal cell carcinoma and germ cell tumors: a study of 305 cases. Mod Pathol
. 2010. In press.
165. Al-Adnani M, Cannon SR, Flanagan AM. Chordomas do not express CD10 and renal cell carcinoma (RCC) antigen: an immunohistochemical study. Histopathology. 2005;47:535–537
166. Bjornsson J, Unni KK, Dahlin DC, et al. Clear cell chondrosarcoma of bone. Observations in 47 cases. Am J Surg Pathol. 1984;8:223–230
167. Collins MS, Koyama T, Swee RG, et al. Clear cell chondrosarcoma: radiographic, computed tomographic, and magnetic resonance findings in 34 patients with pathologic correlation. Skeletal Radiol. 2003;32:687–694
168. Povysil C, Matejovsky Z, Zidkova H. Osteosarcoma with a clear-cell component. Virchows Arch A Pathol Anat Histopathol. 1988;412:273–279
169. Keeney GL, Unni KK, Beabout JW, et al. Adamantinoma of long bones: a clinicopathologic study of 85 cases. Cancer. 1989;64:730–737
170. Chung EB, Enzinger FM. Malignant melanoma of soft parts: a reassessment of clear cell sarcoma. Am J Surg Pathol. 1983;7:405–413
171. Enzinger FM. Clear-cell sarcoma of tendons and aponeuroses: an analysis of 21 cases. Cancer. 1965;18:1163–1174
172. Curry CV, Dishop MK, Hicks MJ, et al. Clear cell sarcoma of soft tissue: diagnostic utility of fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction. J Cutan Pathol. 2008;35:411–417
173. Lieberman PH, Brennan MF, Kimmel M, et al. Alveolar soft-part sarcoma: a clinico-pathologic study of half a century. Cancer. 1989;63:1–13
174. Ladanyi M, Antonescu CR, Drobnjak M, et al. The precrystalline cytoplasmic granules of alveolar soft part sarcoma contain monocarboxylate transporter 1 and CD147. Am J Pathol. 2002;160:1215–1221
175. Argani P, Lal P, Hutchinson B, et al. Aberrant nuclear immunoreactivity for TFE3 in neoplasms with TFE3 gene fusions: a sensitive and specific immunohistochemical assay. Am J Surg Pathol. 2003;27:750–761
176. Ladanyi M, Lui MY, Antonescu CR, et al. The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25. Oncogene. 2001;20:48–57
177. Zhong M, De Angelo P, Osborne L, et al. Dual-color, break-apart FISH assay on paraffin-embedded tissues as an adjunct to diagnosis of Xp11 translocation renal cell carcinoma and alveolar soft part sarcoma. Am J Surg Pathol. 2010;34:757–766
178. Kasashima S, Minato H, Kobayashi M, et al. Alveolar soft part sarcoma of the endometrium with expression of CD10 and hormone receptors. APMIS. 2007;115:861–865
179. Argani P, Antonescu CR, Illei PB, et al. Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft part sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents. Am J Pathol. 2001;159:179–192
180. Folpe AL, Goldblum JR, Rubin BP, et al. Morphologic and immunophenotypic diversity in Ewing family tumors: a study of 66 genetically confirmed cases. Am J Surg Pathol. 2005;29:1025–1033
181. Cui S, Hano H, Harada T, et al. Evaluation of new monoclonal anti-MyoD1 and anti-myogenin antibodies for the diagnosis of rhabdomyosarcoma. Pathol Int. 1999;49:62–68
182. Folpe AL. MyoD1 and myogenin expression in human neoplasia: a review and update. Adv Anat Pathol. 2002;9:198–203
183. Kumar S, Perlman E, Harris CA, et al. Myogenin is a specific marker for rhabdomyosarcoma: an immunohistochemical study in paraffin-embedded tissues. Mod Pathol. 2000;13:988–993
184. Miettinen M, Enzinger FM. Epithelioid variant of pleomorphic liposarcoma: a study of 12 cases of a distinctive variant of high-grade liposarcoma. Mod Pathol. 1999;12:722–728
185. Gebhard S, Coindre JM, Michels JJ, et al. Pleomorphic liposarcoma: clinicopathologic, immunohistochemical, and follow-up analysis of 63 cases: a study from the French Federation of Cancer Centers Sarcoma Group. Am J Surg Pathol. 2002;26:601–616
186. Burger PC, Scheithauer BWAmerican Registry of Pathology, Armed Forces Institute of Pathology (US). Tumors of the Central Nervous System 2007 Washington, DC American Registry of Pathology in collaboration with the Armed Forces Institute of Pathology:596
187. Burger PC, Scheithauer BW, Vogel FS. Surgical Pathology of the Nervous System and its Coverings 20024th ed New York Churchill Livingstone:657
188. Vogel H. Nervous System 2009 Cambridge, New York Cambridge University Press:501
189. Perry A. Oligodendroglial neoplasms: current concepts, misconceptions, and folklore. Adv Anat Pathol. 2001;8:183–199
190. Greenfield JG, Love S, Louis DN, et al.. Greenfield's neuropathology 20088th ed London Hodder Arnold
191. Herpers MJ, Budka H. Glial fibrillary acidic protein (GFAP) in oligodendroglial tumors: gliofibrillary oligodendroglioma and transitional oligoastrocytoma as subtypes of oligodendroglioma. Acta Neuropathol. 1984;64:265–272
192. Bannykh SI, Stolt CC, Kim J, et al. Oligodendroglial-specific transcriptional factor SOX10 is ubiquitously expressed in human gliomas. J Neurooncol. 2006;76:115–127
193. Blumcke I, Becker AJ, Normann S, et al. Distinct expression pattern of microtubule-associated protein-2 in human oligodendrogliomas and glial precursor cells. J Neuropathol Exp Neurol. 2001;60:984–993
194. Ikota H, Kinjo S, Yokoo H, et al. Systematic immunohistochemical profiling of 378 brain tumors with 37 antibodies using tissue microarray technology. Acta Neuropathol. 2006;111:475–482
195. Kriho VK, Yang HY, Moskal JR, et al. Keratin expression in astrocytomas: an immunofluorescent and biochemical reassessment. Virchows Arch. 1997;431:139–147
196. Hussein MR. Central nervous system capillary haemangioblastoma: the pathologist's viewpoint. Int J Exp Pathol. 2007;88:311–324
197. Altinoz MA, Santaguida C, Guiot MC, et al. Spinal hemangioblastoma containing metastatic renal cell carcinoma in von Hippel-Lindau disease: case report and review of the literature. J Neurosurg Spine. 2005;3:495–500
198. Hamazaki S, Nakashima H, Matsumoto K, et al. Metastasis of renal cell carcinoma to central nervous system hemangioblastoma in two patients with von Hippel-Lindau disease. Pathol Int. 2001;51:948–953
199. Polydorides AD, Rosenblum MK, Edgar MA. Metastatic renal cell carcinoma to hemangioblastoma in von Hippel-Lindau disease. Arch Pathol Lab Med. 2007;131:641–645
200. Hoang MP, Amirkhan RH. Inhibin alpha distinguishes hemangioblastoma from clear cell renal cell carcinoma. Am J Surg Pathol. 2003;27:1152–1156
201. Kalof AN, Cooper K. D2-40 immunohistochemistry--so far!. Adv Anat Pathol. 2009;16:62–64
202. Roy S, Chu A, Trojanowski JQ, et al. D2-40, a novel monoclonal antibody against the M2A antigen as a marker to distinguish hemangioblastomas from renal cell carcinomas. Acta Neuropathol. 2005;109:497–502
203. Jung SM, Kuo TT. Immunoreactivity of CD10 and inhibin alpha in differentiating hemangioblastoma of central nervous system from metastatic clear cell renal cell carcinoma. Mod Pathol. 2005;18:788–794
204. Felix I, Becker LE. Intracranial germ cell tumors in children: an immunohistochemical and electron microscopic study. Pediatr Neurosurg. 1990;16:156–162
205. Ho DM, Liu HC. Primary intracranial germ cell tumor. Pathologic study of 51 patients. Cancer. 1992;70:1577–1584
206. Edgar MA, Rosenblum MK. The differential diagnosis of central nervous system tumors: a critical examination of some recent immunohistochemical applications. Arch Pathol Lab Med. 2008;132:500–509
207. Mei K, Liu A, Allan RW, et al. Diagnostic utility of SALL4 in primary germ cell tumors of the central nervous system: a study of 77 cases. Mod Pathol. 2009;22:1628–1636
208. Takei H, Bhattacharjee MB, Rivera A, et al. New immunohistochemical markers in the evaluation of central nervous system tumors: a review of 7 selected adult and pediatric brain tumors. Arch Pathol Lab Med. 2007;131:234–241
209. Kuchiki H, Kayama T, Sakurada K, et al. Two cases of atypical central neurocytomas. Brain Tumor Pathol. 2002;19:105–110
210. Soylemezoglu F, Scheithauer BW, Esteve J, et al. Atypical central neurocytoma. J Neuropathol Exp Neurol. 1997;56:551–556
211. Soylemezoglu F, Onder S, Tezel GG, et al. Neuronal nuclear antigen (NeuN): a new tool in the diagnosis of central neurocytoma. Pathol Res Pract. 2003;199:463–468
212. Hessler RB, Lopes MB, Frankfurter A, et al. Cytoskeletal immunohistochemistry of central neurocytomas. Am J Surg Pathol. 1992;16:1031–1038
213. Liu Y, Saad RS, Shen SS, et al. Diagnostic value of microtubule-associated protein-2 (MAP-2) for neuroendocrine neoplasms. Adv Anat Pathol. 2003;10:101–106
214. Prayson RA, Chamberlain WA, Angelov L. Clear cell meningioma: a clinicopathologic study of 18 tumors and examination of the use of CD10, CA9, and RCC antibodies to distinguish between clear cell meningioma and metastatic clear cell renal cell carcinoma. Appl Immunohistochem Mol Morphol. 2010;18:422–428
215. Fouladi M, Helton K, Dalton J, et al. Clear cell ependymoma: a clinicopathologic and radiographic analysis of 10 patients. Cancer. 2003;98:2232–2244
renal cell carcinoma; clear cell; metastatic; immunohistochemistry; PAX-8; PAX-2; hKIM-1; RCCma; CD10
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