Recently Described and Emphasized Entities of Renal Neoplasms

By Shen, Steven S Truong, Luan D; Ayala, Alberto G; Ro, Jae Y

Context.-Recent advances of molecular biology and cytogenetics of renal cancer have resulted in the new classification of renal neoplasms and a number of subtypes are identified and emphasized. In addition, rare nonepithelial renal neoplasms are identified and characterized. Familiarity with these entities will help make the most accurate diagnosis and guide the treatment and follow-up of patients with renal neoplasm. Objective.-To review the clinicopathologic entities of renal neoplasms that are recently defined or emphasized. Their clinical, gross, microscopic, and immunohistochemical features, as well as specific cytogenetic or molecular abnormalities, are discussed. Important differential diagnoses of each entity are also briefly discussed.

Data Sources.-Extensive review of published literature and our experience.

Conclusions.-A number of new entities of renal neoplasms or genetically defined renal cell carcinomas have been identified or emphasized because of their unique genetic or molecular changes. Recognition of these entities becomes important as some of them have different biologic behavior and treatment strategies may be different.

(Arch Pathol Lab Med. 2007;131:1234-1243)

Advances in the understanding of cytogenetic and molecular abnormalities of renal neoplasms in the last decade have significantly refined the morphologic classification of these lesions, which has resulted in a 1997 consensus classification of renal cell neoplasms.1,2 Accurate histologic subtyping of renal tumors is important as each entity has its own biologic behavior.3- 6 In the last few years, new types of renal neoplasms have been described and a few of these are listed as specific entities in the new 2004 World Health Organization classification of renal neoplasms (Table 1).7 Furthermore, emphasis is placed on these variants because they are associated with specific cytogenetic changes or syndromes. Recognition of these morphologically or genetically unique entities then becomes important.

In this article, we review newly defined clinicopathologic entities of renal neoplasms and variants of renal cell carcinomas (RCCs) that have distinct cytogenetic and molecular changes. Gross and histologic features are described including salient immunohistochemical profiles and specific cytogenetic or molecular changes. The differential diagnosis of each entity is briefly discussed. Other miscellaneous nonepithelial renal neoplasms that have been recently recognized or emphasized are also included.

The entities herein discussed include Xp11 translocation carcinoma, mucinous tubular and spindle cell carcinoma, hybrid chromophobe RCC and oncocytoma associated with Birt-Hogg-Dube (BHD) syndrome, multilocular cystic RCC, subtypes of papillary RCC, and unclassified RCC. We also include renal neoplasms other than renal carcinoma, such as mixed epithelial and stromal renal tumors, primary renal synovial sarcomas, primitive neuroectodermal tumor (Ewing sarcoma), and epithelioid angiomyolipoma (AML) (Table 2).

RENAL CELL CARCINOMA

Xp11 Translocation Carcinoma

This is a newly defined type of RCC (World Health Organization 2004) that primarily occurs in children and young adults.7 It includes RCCs with the ASPL-TFE3 and PRCC-TFE3 gene fusions. Collectively, these tumors have been termed Xp11.2 or TFE3 translocation carcinomas.8 The gene fusion is a result of a specific translocation that involves TFE3, a member of MiTF/TFE transcription factor family. The exact incidence of Xp11 translocation carcinoma is not entirely clear. In one report, 8 (22%) of 41 carcinomas occurring in patients younger than 22 years showed translocation carcinoma morphology.9 The incidence of translocation carcinoma in adults is unclear. Although the clinical behavior of these neoplasms appears to be similar to that of adult-type RCCs, it would still be important to determine their long-term biologic behavior.

Grossly, these tumors are similar to those of adult-type RCC. Histologically, the tumors are characterized by papillary architecture and a clear cell lining. Tumor cells in ASPL-TFE3 carcinoma have abundant voluminous clear to eosinophilic cytoplasm, discrete cytoplasmic membrane, and prominent nucleoli (Figure 1, A through C). There are often psammoma bodies associated with hyaline nodules. 10 In contrast, PRCC-TFE3 RCCs show less abundant cytoplasm and less prominent psammoma bodies and hyaline nodules.

Chromosome translocation can be detected immunohistochemically by nuclear labeling for TFE3 (Figure 1, D), the fusion gene product.11 Because this technique is highly sensitive and specific, it is currently being used as a diagnostic marker for these neoplasms. Other than nuclear stain for TFE3, the tumors show similar staining characteristic of clear cell RCC; they are positive for vimentin, but, unlike adult-type RCC, they are often weakly or focally positive for pan-cytokeratin (AE1/AE3/CAM 5.2). These tumors are positive for RCC marker antigen and CD10.12

When an RCC is diagnosed in a child or young adult, pan- cytokeratin immunostain should be performed; if it is strongly and diffusely positive, a diagnosis of adult-type RCC can be made. If the tumor is negative or weakly positive and has features as described previously, TFE3 immunohistochemistry should be performed to help make a diagnosis of Xp11 translocation-associated carcinoma.

Mucinous Tubular and Spindle Carcinoma

Several recent reports have described an unusual renal tumor characterized by the presence of tubules lined by round cells, variable spindle cell component, relatively low-grade cytologic features, and mucinous or myxoid stroma. This tumor has been previously referred to as an unusual type of RCC with prominent spindle cells13 and as low-grade myxoid tumor or low-grade collecting duct carcinoma.14-17 The new 2004 World Health Organization classification on renal tumor named it mucinous tubular and spindle cell carcinoma (MTSCC).7 Mucinous tubular and spindle cell carcinoma occurs predominantly in female patients and appears to have a relatively indolent clinical behavior.13-17

Grossly, MTSCC is typically well circumscribed and frequently centered around the renal medulla (Figure 2, A). Necrosis might be seen but is uncommon. Microscopically, the tumor is composed of interconnecting tubular structures in a variable myxoid/mucinous background. The cells lining the tubules are generally medium sized with round nuclei and moderate amount of clear, amphophilic or eosinophilic cytoplasm. A spindled cell architecture on a myxoid background is variably present (Figure 2, B and C). The cells, whether round or spindle, display bland nuclear features and show no significant pleomorphism. In our experience of 12 cases, most of the tumors disclose prominent nucleoli, but the nuclei retain their uniformity.

So far, the published results on immunohistochemical studies on MTSCC are inconsistent. Most of the tumors express CK18, CK19, and epithelial membrane antigen (EMA). The staining for RCC marker antigen and CD15 (markers of proximal tubular differentiation) is variable. In a recent report using tissue microarray of 27 cases of MTSCC, Paner et al18 showed that most of the tumors are positive for alpha-methylacyl-CoA racemase (AMACR) and EMA, but only 7% and 10% express RCC marker antigen and CD10, respectively. However, positive immunoreactivity for proximal tubular markers, including CD15, RCC marker antigen, and AMACR, was observed in most tumors of our recent study, which supports the proximal tubule differentiation for MTSCC (Figure 2, D through F).19 Neuroendocrine differentiation of MTSCC has also been recently described.20,21

Ultrastructural studies of MTSCC have shown that tumor cells forming tubules have profiles resembling those of the loop of Henle or distal convoluted tubule, that is, mitochondria and loosely spaced microvilli.14 Other study, however, showed that the tumor cells contained abundant mitochondria, intracytoplasmic glycogen, and lipid, features that are more consistent with proximal tubular differentiation. 22

At least 3 studies have described the cytogenetic and molecular features of MTSCC. In a comparative genomic hybridization study of 5 such tumors by Rakozy et al,23 losses of multiple chromosomes (-1,- 4,-6,-8,-9, -13,-14,-15,-22) were found. Two other recent studies done in 3 cases showed similar losses of multiple chromosomes (-1,- 4,-6,-8,-11,-13,-14,-15,-18,-22).24,25 Gains of chromosome 7 and 17, a feature of papillary RCC, was reported in only 1 case.25 Loss of 3p, typical for clear RCC, was not seen.

The current data indicate that the lines of differentiation of MTSCC are not clear for this type of tumor, and in spite of a distinct and uniform morphology, it may actually be a heterogeneous subset of neoplasms. Although there are striking similarities of morphologic and immunohistochemical profiles to those of papillary RCC,18,19 additional immunohistochemical, ultrastructural, and genetic analysis will be necessary to further define this entity.

Hybrid Chromophobe RCC and Oncocytoma Associated With BHD Syndrome

Birt-Hogg-Dube syndrome is an autosomal dominant genodermatosis characterized by benign skin tumors on the face, neck, and upper trunk, spontaneous pneumothorax, and an increased risk of developing renal tumors. The responsible gene has been mapped to the chromosome 17p11.2, and the corresponding protein was recently identified and named folliculin.26,27 In a study of 30 patients with BHD syndrome in 19 different families,28 a total of 130 solid renal tumors were found in the specimens obtained by nephrectomies or multiple partial nephrectomies. The range of renal tumors was from 1 to 28 per specimen (average, 5.3). Multiple and bilateral tumors were noted at a slightly younger age (mean, 50.7 years) than other RCCs (mean, 55.0 years). The tumors showed varied cell types including cell- type combinations. The majority were hybrid tumors with combination of chromophobe RCC and oncocytoma (65 cases) (Figure 3, A and B). Other cell types included chromophobe RCC (44 cases), clear RCC (12 cases), oncocytoma (7 cases), and papillary RCC (2 cases). Microscopic oncocytosis was found in the renal parenchyma of most specimens (Figure 3, C). Further studies are necessary to address the incidence, pathogenesis, association with BHD syndrome, and their clinical significance. Unlike other cell-type-specific hereditary kidney cancer-related genes (ie, VHL and MET), the BHD gene appears to involve the entire spectrum of histologic types of renal tumors, suggesting that this gene has a major role in overall kidney cancer tumorigenesis.

The renal tumors associated with BHD syndrome show the same immunoprofiles as those of sporadic oncocytomas, chromophobe RCC, or other types of RCC.

Multilocular Cystic RCC

Cystic changes are frequent findings in RCC, particularly those that have clear cell morphology. However, multilocular cystic RCC (MCRCC) is a rare entity, comprising less than 3% of RCCs.29-32 This type of tumor is specifically emphasized here to differentiate it from other cystic renal lesions. It is listed as a separate histologic subtype of RCC in the recent World Health Organization classification. This tumor has indolent behavior, and metastasis has never been reported.31,33,34 Multilocular cystic RCC has a male predominance (3:1) and occurs in slightly younger adult patients (mean, 51 years; range, 20-76 years) compared with other RCCs.

Grossly, the tumor is often well circumscribed and composed of multiple, variably sized cysts containing serous to hemorrhagic fluids. The cysts range in size from 0.25 to 1.3 cm. Microscopically, the tumor is characterized by numerous cysts separated by thin septae of connective tissue. Most of the cysts are lined by a single cell layer of epithelial cells with pale to clear cytoplasm. Characteristically, there are small nests or aggregates of clear cells within the septae. The lining cells may be flattened, be attenuated, or focally display a hobnail appearance. Layering and papillation may be seen. The nuclei are usually uniform, small, and spherical with dense chromatin without prominent nucleoli (Figure 4, A and B). Solid nodules of clear cell carcinoma are not present. No necrosis is present. The wall of cysts is frequently fibrotic or edematous. Chronic inflammation and calcification can be seen within the fibrous septa.

The major differential diagnosis includes cystic nephroma, mixed epithelial and stromal tumor, and most importantly RCC with extensive necrotic and cystic changes. Cystic nephroma shares the multicystic appearance with MCRCC, but the lining is predominantly made up of plump epithelial cells often with a hobnail appearance and lacks nests of clear cells in the septae. Mixed epithelial and stromal tumor is also a multicystic lesion, but nests or aggregates of clear cells are not present. Furthermore, the stromal component at least focally resembles ovarian stroma and is positive for estrogen receptor and progesterone receptors. Renal cell carcinoma can be quite cystic, but the cystic changes are not as diffuse and sizes of cysts are not as large. In these RCCs, large solid nodules of clear cells can be easily identified and necrosis is commonly seen. In addition, tumor cell nuclei are of low grade in MCRCC.

It is important to realize that the aggregates of clear cells in MCRCC can be very focal and the multicystic component in this tumor appears to be an inherent component of the tumor rather than reactive or degenerative in nature.

Immunohistochemical stains are usually not required for the diagnosis. Similar to clear RCC, the tumor cells are positive for pan-cytokeratin, EMA, and RCC marker antigen.

Subtypes of Papillary RCC

Papillary RCC, the second most common primary renal carcinoma, is a clinically and genotypically distinct entity. Papillary RCCs account for about 10% to 15% of renal parenchymal neoplasms in most recent surgical series.3-6 It is clinically, histologically, and even genetically more heterogeneous than previously thought.

It is well recognized that the cytoplasm of papillary RCC can be basophilic, eosinophilic, or duophilic.35 Delahunt and Eble36 studied 105 papillary RCCs and divided them into 2 types. In type 1, the cells lining the papillary cores disclose scanty pale cytoplasm and the tumors frequently express cytokeratin 7. Psammoma bodies and foamy macrophages are frequently seen (Figure 5, A and B). The cells in type 2 tumors usually have voluminous eosinophilic cytoplasm, pseudostratified nuclei, and large nuclei with prominent nucleoli (Figure 5, C and D). Multivariate analysis has shown that tumor type is an independent prognostic factor of survival. It was also observed by Amin et al37 that papillary RCCs with eosinophilic cytoplasm are predominantly of high grade, but tumors with basophilic cytoplasm are of low grade. Papillary RCCs usually present at an earlier stage, and stage I papillary RCC has a better 5-year survival rate (87%-100%) than clear RCC of the same stage (65%-75%). Furthermore, the overall 5-year survival rate for papillary RCC (82%-90%) is also higher than that of clear RCC (44%- 54%). However, in a Cox proportional hazard regression model, tumornode-metastasis stage appeared to be the only significant variable.37

Recently, Yang et al38 studied the gene expression profile of 34 cases of papillary RCC, and comparative genomic microarray analysis was used to infer cytogenetic aberrations. Based on the results, they proposed 2 molecular subclasses of papillary RCC with morphologic and survival correlation. The class 1 papillary RCC (with excellent survival) consists of 3 morphologic subtypes: low- grade type 1, low-grade type 2, and mixed type 1/low-grade type 2 tumors. The class 2 papillary RCC (with poor survival) consists of high-grade type 2 tumors. Therefore, it appears that the nuclear grade but not the cytoplasmic quality or quantity is a more important prognostic factor.

Papillary RCCs are often positive for cytokeratin, the RCC marker antigen, CD10, and AMACR; they are negative for E-cadherin or Ksp- cadherin.39 In addition, most of the type 1 papillary RCCs have high expression of CK7, and most type 2 tumors express topoisomerase II alpha.38

The most frequent chromosomal changes include gains of chromosomes 7 and 17 and loss of Y chromosome. Tumors with additional chromosomal aberrations (+8, +12,+16,+20,+9p) are often associated with more aggressive behavior than those without these changes.40 Mutation of MET proto-oncogene occurs in some cases of both hereditary and sporadic papillary RCC. Papillary RCC with changes of MET proto-oncogene show type 1 histologic features. Papillary RCCs with involvement of the chromosome 1q and cancer syndrome with predisposition to cutaneous/uterine leiomyomas and leiomyosarcomas are also described.41

Unclassified RCC

This is a new subtype of RCC, introduced in 1997.1,2 It is a diagnostic category for those tumors that do not fit into any of the 4 known categories of RCC: clear cell, papillary, chromophobe, or collecting duct carcinoma. The features that might prompt assignment of a tumor to this category include apparent composites of recognized subtypes, mucin production, mixture of epithelial and stromal elements, sarcomatoid morphology without recognizable epithelial elements, and unrecognizable cell types. Because there are no well-established diagnostic criteria, the frequency of this type of RCC is quite variable, accounting for 1% to 6% of RCCs in some larger contemporary series. 3-6 The tumor tends to be heterogenous and most often is of high grade and has a poor prognosis with a 5-year disease-specific survival around 24%.5

Renal cell carcinoma with different recognizable subtypes is not infrequently seen; thus, tumors with a mixture of clear cell and papillary morphology and oncocytoma and chromophobe RCC are not uncommon. In our opinion, it is best not to categorize those tumors with a composite of low-grade recognizable epithelial types as unclassified RCC. The presence of a tumor with a mixture of oncocytoma and chromophobe RCC, particularly when multiple and occurring in younger adults, should prompt the consideration of BHD syndrome. This type of tumor probably is best categorized as chromophobe RCC with oncocytoma component as these tumors often behave favorably.

Renal cell carcinomas with mucin production are not infrequently seen in type 1 papillary RCC, collecting duct carcinoma, urothelial carcinoma, or the aforementioned MTSCC. For tumors with mixed epithelial and stromal elements, diagnostic consideration should include mixed epithelial and stromal tumor of kidney, sarcomatoid RCC, or sarcomatoid urothelial carcinoma.

We believe it is appropriate to assign tumors as unclassified RCC when the tumors are truly unrecognizable including high-grade and sarcomatoid tumors with no recognizable epithelial elements. It should not be a wastebasket and a diagnosis of convenience. Before a diagnosis of unclassified RCC is rendered, one should consider obtaining additional sections of tumor and possibly obtaining expert consultation. Immunohistochemical or cytogenetic studies may be helpful in some cases.

MISCELLANEOUS NEOPLASMS

Mixed Epithelial and Stromal Renal Tumor of Kidney The mixed epithelial and stromal tumor of the kidney (MESTK) is a rare and newly defined entity. A similar lesion was previously referred to as cystic hamartoma of the renal pelvis,42 adult type of mesoblastic nephroma,43 or cystic nephroma. The term mixed epithelial and stromal tumor of the kidney was first proposed by Michal and Syrucek. 44 Adsay et al45 published the first large series of this type of tumor with 12 cases, and later a larger series was published by Michal et al.46 The tumor occurs in adults with ages ranging from 31 to 71 years with a mean age of 56 years and has a strong female predilection with female-male ratio of 10:1.

Grossly, MESTK is often a well-circumscribed tumor with a mean size of 6 cm (range, 3-12 cm) with cystic and solid components of variable proportion.45 Microscopically, the tumor is composed of biphasic components including cysts and tubules embedded in the spindle cell stroma (Figure 6, A). The spindle cell component ranges in appearance from scarlike fibrous tissue to leiomyoma-like interlacing fascicles; usually there is a mixture of both. Cellular foci reminiscent of ovarian stroma or solitary fibrous tumor are also present (Figure 6, B and C). No blastema component is present. The epithelial elements, composed of clusters of tubules with variable lining, are found scattered within the spindle cell stroma. Focally, large cysts display a lining made up of cells with abundant eosinophilic cytoplasm that often has a hobnail appearance.

A recent case report showed a MESTK that has translocation t(1;19).47 The histogenesis of this tumor is unknown, and it has been proposed that both components of the tumor, stromal and epithelial, are neoplastic. It has also been suggested that MESTK might be the renal counterpart of similar mixed epithelial and stromal neoplasms that occurs in the biliary tract and pancreas. The latter are also characterized by cystic structures lined by epithelium, admixed with ovarian-like stroma.46

Although in most reported cases of this entity, recurrence or metastasis has not been observed, malignant transformation does rarely occur.48,49 We have recently encountered a case of MESTK displaying malignant transformation to a sarcomatoid carcinoma with heterologous components, that is, rhabdomyosarcomatous and chondrosarcomatous components (Figure 6, D).

Immunohistochemically, muscle markers (desmin and smooth muscle actin) are often diffusely and strongly positive in the spindle cells of the tumors, whereas HMB-45 and CD34 stains are negative. Estrogen receptor or progesterone receptors are frequently positive in the nuclei of spindle cells. The female preponderance of MESTK and a history of long-term estrogen replacement in female patients or long-term sex-steroid exposure in male patients, combined with the frequent expression of estrogen and progesterone receptors in the spindle cells, suggest that the steroid hormones might play a role in the evolution of these tumors.

By electron microscopy, some tubules within the tumor have features of proximal tubular epithelium, whereas other tubules have features of the thin segment of the loop of Henle. These findings have led some authors to believe that the tubules are entrapped rather than neoplastic.50

Differential diagnosis includes congenital mesoblastic nephroma, cystic nephroma, and MCRCC. Congential mesoblastic nephroma is generally a solid mass composed of spindle stromal cell components with rare entrapped renal tubules. Recent studies have shown clearly that MESTK lacks the genetic alteration of cellular congenital mesoblastic nephroma.51 There are striking similarities between cystic nephroma and MESTK in their clinical behavior, histology, and immunohistochemical profiles.52 A recent study by Antic et al53 showed that MESTK had considerable morphologic overlap with cystic nephroma and suggested that they may represent opposite ends of the spectrum of the same process. However, this interesting hypothesis remains to be investigated. Lack of aggregates of clear cells in MESTK helps differentiate it from MCRCC.

Primary Renal Synovial Sarcoma

Primary renal synovial sarcoma is a rare type of kidney tumor. Faria et al54 first described primary renal synovial sarcoma in 1999. A few dozen cases of this entity have been reported to date. Primary renal synovial sarcomas may display either a monophasic or a biphasic pattern. The average patient age is 35 years with a range of 12 to 59 years.7 This type of tumor occurs in men more often than in women with a male-female ratio of 1.7:1. The monophasic variant of primary renal synovial sarcoma is more common and tends to have a better prognosis than the biphasic variant. The presence of an SYT- SSX gene fusion resulting from the t(X;18), characteristic of synovial sarcoma, has been demonstrated by using reverse transcriptase polymerase chain reaction.55-57 Regardless of the treatment, the prognosis remains poor.

Grossly, the tumor often presents as a large solid mass (Figure 7, A), frequently associated with focal necrosis and smooth-walled cysts. Histologically, primary renal synovial sarcomas do not differ from their soft tissue counterpart. They demonstrate a solid growth pattern with intersecting fascicles of closely packed short spindle cells. Focal hypocellular myxoid areas may be present. Another component is that of hemangiopericytic pattern (Figure 7, B). Collagenous fibrosis or calcification may also be found. The neoplastic cells consist of plump spindle cells in a monophasic or biphasic pattern with minimal cytoplasm and variable numbers of mitotic figures (Figure 7, C). Cases of synovial sarcoma with rhabdoid features have been recently described (Figure 7, D).57 Cysts are commonly present and are lined with polygonal epithelial cells containing eosinophilic cytoplasm with apically oriented nuclei that create a hobnail appearance, and these cystic structures are believed to be entrapped tubules with cystic changes.

Immunohistochemical staining has been performed to help corroborate the diagnosis. The spindle cells are constantly immunoreactive for vimentin, and often immunoreactive for pan- cytokeratin, EMA, CD56, BCL2, and CD99, but typically nonimmunoreactive for smooth muscle actin, desmin, S100 protein, and CD34.55,56

The differential diagnosis of renal synovial sarcoma includes adult Wilms tumor, clear cell sarcoma of the kidney, primitive neuroectodermal tumor of the kidney, congenital mesoblastic nephroma, sarcomatoid RCC, and undifferentiated carcinoma. Based on the histologic findings and immunohistochemical profiles, the majority of these considerations are relatively easy to rule out. However, to confirm the diagnosis of renal synovial sarcoma, polymerase chain reaction testing for the detection of SYT-SSX fusion gene that results from the translocation of the SYT gene on chromosome 18 with the SSX gene on the X chromosome is required. The ETV6-NTRK3 fusion gene can be detected on polymerase chain reaction to confirm the diagnosis of congenital mesoblastic nephroma.

There is limited information on the prognosis of this entity, but some tumors have been reported to respond to chemotherapy. Treatment of primary renal synovial sarcomas involves surgery and chemotherapy including isophosphamide-containing regimens.

Primary Neuroectodermal Tumor/Ewing Sarcoma of the Kidney

This is an extremely rare primary tumor of the kidney with fewer than 100 cases reported in the literature. The mean age of patients is 27 years with a wide age range from 4 to 69 years, and the tumors appear to have a slight male predilection.7,58-60 The major prognostic factor for renal Ewing/primary neuroectodermal tumor is the stage of the tumor. Despite aggressive therapy with surgery, chemotherapy, and radiation, the prognosis remains poor.

The tumor is typically large, is well circumscribed but nonencapsulated, and frequently exceeds 10 cm. Cut sections show a grayish tan to white lobulated appearance with areas of hemorrhage and necrosis. Microscopically, the tumor is composed of sheets of relatively monotonous small, oval, round to polygonal cells with round hyperchromatic nuclei. The chromatin is often finely dispersed, and small, but not prominent, nucleoli can be seen. Cohesive lobules, rosettes, and perivascular cellular condensation may be prominent in some cases (Figure 8).

Immunohistochemical profile is the same as that of Ewing/ primitive neuroectodermal tumor of other sites. The tumor cells are typically positive for vimentin and CD99 (O13). All the reported cases have shown t(11;22)(q24;q12) translocation, resulting in the fusion transcript EWS-FLI1, which can be detected by reverse transcription polymerase chain reaction. Variant translocation of EWS with other ETS-related oncogenes has also been reported.58,61

The differential diagnosis of renal Ewing/primitive neuroectodermal tumor includes rhabdomyosarcoma, Wilms tumor, small cell neuroendocrine carcinoma, neuroblastoma, sarcomatoid RCC, and lymphoma. A proper immunohistochemical stain result and chromosomal translocation or molecular studies are necessary to make a definitive diagnosis in unusual sites such as the kidney.

Epithelioid AML

Renal epithelioid AML is a recently recognized variant of AML characterized by the proliferation of predominantly or entirely epithelioid smooth muscle cells and more aggressive behavior.62-65 At least half of the reported cases are associated with tuberous sclerosis and the rest appear to be sporadic. Malignant transformation and metastasis have been reported.66-70

Grossly, the tumor is often a large, circumscribed, and partially encapsulated mass with an average size of 9 cm ranging from 4 to 13 cm) with frequent extrarenal extension. The cut surface of tumor discloses a tan, pink, and gray appearance. Some tumors show focal necrosis and hemorrhage.

Histologically, the tumor is composed of sheets of large polygonal cells with abundant densely eosinophilic cytoplasm and a variable degree of nuclear atypia (Figure 9, A and B). Fat cells and thick-walled abnormal vessels, typical components of the conventional AML, are not prominent or are absent despite extensive sampling. Areas of necrosis, increased mitotic activity, and nuclear pleomorphism can be seen. Multinucleated giant cells and clusters of foamy histiocytes are present in some cases (Figure 9, C). The morphologies of sporadic or tuberous sclerosis-associated epithelioid AML are similar. Immunohistochemically, the tumor cells are typically positive for HMB-45 (Figure 9, D), smooth muscle actin, desmin, CD68, and Melan-A, and they are negative for S100 protein, cytokeratin, and EMA markers.

The most important differential diagnoses are RCC with granular cells, eosinophilic variant of chromophobe RCC, and adrenal cortical neoplasms. In most cases, awareness of this morphologic variant of AML and critical review of the morphologic characteristics of RCC, such as alveolar and tubulo-cystic growth pattern and features of the vascular network of each histologic subtype, will permit the correct diagnosis. Immunohistochemical stains with cytokeratin, smooth muscle actin, and HMB-45 are very helpful to confirm the diagnosis. The possibility of epithelioid AML should be considered in any renal tumor with abundant granular cytoplasm and lack of cytokeratin immunoreactivity, for which a panel of immunohistochemical stains is required. Stains for cytokeratin, inhibin, and HMB-45 will help differentiate from adrenal cortical neoplasm; however, Melan-A stains both AML and adrenal cortical neoplasms.

In summary, we have reviewed a number of recently defined entities of renal neoplasms with either unique morphologic and genetic changes or distinctive biologic significance. Familiarity with these entities allows for accurate classification and proper clinical management.

Table 1. World Health Organization Histologic Classification of Renal Tumors*

Renal cell tumors

Clear cell renal cell carcinoma

Multilocular clear cell renal cell carcinoma

Papillary renal cell carcinoma

Chromophobe renal cell carcinoma

Carcinoma of the collecting ducts of Bellini

Renal medullary carcinoma

Xp11 translocation carcinomas

Carcinoma associated with neuroblastoma

Mucinous and tubular and spindle cell carcinoma

Renal cell carcinoma, unclassified

Papillary adenoma

Oncocytoma

Metanephric tumors

Metanephric adenoma

Metanephric adenofibroma

Metanephric stromal tumors

Nephroblastic tumors

Nephrogenic rests

Nephroblastoma

Cystic partially differentiated nephroblastoma

Mesenchymal tumors

Occurring mainly in children

Clear cell sarcoma

Rhabdoid tumor

Congential mesoblastic nephroma

Ossifying renal tumor of infants

Occurring mainly in adults

Leiomyosarcoma (including renal vein)

Angiosarcoma

Rhabdomyosarcoma

Malignant fibrous histiocytoma

Hemangiopericytoma

Osteosarcoma

Angiomyolipoma

Epithelioid angiomyolipoma

Leiomyoma

Hemangioma

Lymphangioma

Juxtaglomerular cell tumor

Renomedullary interstitial cell tumor

Schwannoma

Solitary fibrous tumor

Mixed epithelial and epithelial tumors

Cystic nephroma

Mixed epithelial and stromal tumor

Synovial sarcoma

Neuroendocrine tumors

Carcinoid

Neuroendocrine carcinoma

Primitive neuroectodermal tumor

Neuroblastoma

Phaeochromocytoma

Hematopoietic and lymphoid tumors

Lymphoma

Leukemia

Plasmacytoma

Germ cell tumors

Teratoma

Choriocarcinoma

Metastatic tumors

* Adapted from Eble et al.7(p10)

Table 2. Entities Described in This Review

A. Renal cell carcinoma (RCC)

1. Xp11 translocation carcinoma

2. Mucinous tubular and spindle cell carcinoma

3. Hybrid chromophobe RCC and oncocytoma associated with Birt- Hogg-Dube syndrome

4. Multilocular clear cell RCC

5. Subtypes of papillary RCC

6. Unclassified RCC

B. Miscellaneous lesions

1. Mixed epithelial/stromal renal tumor

2. Primary renal synovial sarcoma

3. Primitive neuroectodermal tumor (Ewing sarcoma)

4. Epithelioid angiomyolipoma

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Steven S. Shen, MD, PhD; Luan D. Truong, MD; Alberto G. Ayala, MD; Jae Y. Ro, MD, PhD

Accepted for publication September 8, 2006.

From the Department of Pathology, The Methodist Hospital, Houston, Tex.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Steven S. Shen, MD, PhD, Department of Pathology, The Methodist Hospital, 6565 Fannin St, Houston, TX 77030 (e-mail: stevenshen@tmh.tmc.edu).

Copyright College of American Pathologists Aug 2007

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