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
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
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
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
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
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
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
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
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
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
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
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
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.
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