Sarcomatoid and Rhabdoid Renal Cell Carcinoma Pathology

Definition of sarcomatoid renal cell carcinoma

Sarcomatoid renal cell carcinoma (SRCC) is currently defined in the 2004 World Health Organization (WHO) classification of renal tumors as any histologic type of renal cell carcinoma (RCC) containing foci of high-grade malignant spindle cells. ^[1]

Many studies have defined a tumor as SRCC if even a small amount of sarcomatoid differentiation is present, ^{[2, 3, 4, 5]} whereas other studies have excluded tumors with a sarcomatoid component of less than 20% of the tumor volume ^[6] or less than one microscopic low-power (40x) field in size. ^[7]

However, some evidence exists of increased risk associated with sarcomatoid components comprising 5-10% of total tumor volume, ^{[5, 7]} indicating that even small amounts of sarcomatoid differentiation may be clinically relevant and should be included in the pathology report.

Focal spindling due to noncohesion of tumor cells is not considered to represent sarcomatoid differentiation. ^[7] Tumors with pure sarcomatoid morphology due to overgrowth of the RCC components are classified as SRCC if evidence of epithelial differentiation can be demonstrated through immunohistochemical or ultrastructural analysis.

In cases in which the histologic subtype of the RCC component is not recognizable, the tumor is designated as unclassified RCC with sarcomatoid differentiation. ^[1]

Definition of rhabdoid renal cell carcinoma

Adult rhabdoid renal cell carcinoma (RRCC) is currently recognized in the literature as any histologic type of RCC containing foci of high-grade malignant cells with rhabdoid morphology, characterized by large eccentric vesicular nuclei, prominent nucleoli, globular eosinophilic paranuclear inclusion bodies, and abundant eosinophilic cytoplasm. ^{[8, 9, 10, 11]}

The proportion of rhabdoid components in published series of RRCC ranges from 1-90% of the total tumor volume ^{[8, 10, 11]} ; however, occasional tumors composed entirely of rhabdoid cells have been described in which no RCC component is detected despite extensive sampling. ^{[9, 12]}

RR CC was named for its morphologic resemblance to pediatric malignant rhabdoid tumor (MRT) of the kidney, which is a highly aggressive tumor characterized by cells that resemble rhabdomyoblasts and by genetic alterations involving chromosome 22, particularly the hSNF5/INI1 gene on 22q11.2. ^{[13, 14]} MRT usually arises in children younger than 3 years, and the occasional cases previously reported as adult MRT are now considered more likely to be RRCC in which rhabdoid components have overgrown the original histologic tumor type. ^[8]

Go to Renal Cell Carcinoma and Clear Cell Renal Cell Carcinoma for more complete information on these topics.

Epidemiology of sarcomatoid renal cell carcinoma

Sarcomatoid differentiation is reported in 4-32% of RCCs overall. ^{[2, 4, 6, 7]} The incidence rates according to RCC histologic subtypes are 5-13% for clear cell renal cell carcinoma (CCRCC), 2-7% for papillary RCC, 9-13% for chromophobe RCC, and 11-26% for unclassified RCC. Sarcomatoid differentiation also occurs in around 29% of carcinomas of the collecting duct of Bellini. ^{[4, 7, 15, 16]}

Histologic sources of origin for SRCC, by percentage, are as follows ^{[4, 7]} :

• CCRCC, 79-87%

• Chromophobe RCC, 7-7.5%

• Papillary RCC, 4-8%

• Unclassified RCC, 2-4%

• Collecting (Bellini) duct carcinoma, 2%

The average age at diagnosis of SRCC is 56-61 years, with male-to-female ratios ranging between 1.6:1 and 2.2:1. ^{[3, 4, 7]}

Epidemiology of rhabdoid renal cell carcinoma

Rhabdoid differentiation is found in 3-7.5% of RCCs, most commonly in CCRCC, although rare cases have been reported involving papillary RCC, chromophobe RCC, and collecting duct (Bellini duct) carcinoma.

Combined analysis of the 4 small series of RRCC published to date shows an average age of 60-64 years at diagnosis and a male-to-female ratio of 1.4:1. ^{[8, 9, 10, 11]}

Etiology of sarcomatoid renal cell carcinoma

SRCCs were originally considered to be carcinosarcomas or to be renal sarcomas in cases in which the sarcomatous component had overgrown all epithelial (carcinomatous) components. ^{[17, 18]} Then, in 1968, sarcomatoid cells were proposed to arise through transformation of malignant renal epithelial cells; thus, the term sarcomatoid RCC was introduced. ^[19]

This theory has been confirmed by genetic studies such as analysis of X-chromosome inactivation patterns, which indicated a clonal origin for both the epithelial and sarcomatoid components of CCRCCs with sarcomatoid differentiation. ^[20]

Currently, the 2004 WHO classification of renal tumors recognizes this transformation as "sarcomatoid change" or "sarcomatoid features" arising within RCC, rather than as a separate histologic entity. ^[1] Sarcomatoid differentiation usually arises within high-grade RCC, ^{[4, 7]} representing a late step in the progression of this tumor type; however, the factors leading to development of sarcomatoid differentiation are unknown.

Etiologic factors associated with development of the underlying renal cell carcinoma (RCC) are most likely similar to those described for RCC in general, which include smoking, obesity, hypertension, and hereditary genetic disorders. ^{[21, 22, 23]}

Etiology of rhabdoid renal cell carcinoma

Cells with rhabdoid differentiation arise through transformation of malignant renal epithelial cells, analogous to the process of sarcomatoid change. ^{[8, 9, 10, 11]} One study has demonstrated loss of chromosome 3p and/or mutation of the VHL gene in both the rhabdoid and clear cell components of 2 rhabdoid renal cell carcinomas (RRCCs), confirming an epithelial derivation for the rhabdoid cells. ^[9]

As both sarcomatoid renal cell carcinoma (SRCC) and rhabdoid renal cell carcinoma (RRCC) can arise from various histological types of RCC, the location of tumor origin varies according to the underlying RCC subtype. Most RCCs are believed to arise within the renal cortex, with the epithelial cells of origin proposed to be from the proximal convoluted tubule for clear cell renal cell carcinoma (CCRCC), from the proximal straight tubule for papillary RCC, and from the intercalated cells of the cortical collecting duct for chromophobe RCC. Collecting duct (Bellini duct) carcinoma arises within the renal medulla, from the principal cells of the medullary collecting duct. ^{[24, 25, 26]}

Extension into the renal sinus is the most common pathway of spread for most histologic types of RCC because the sinus is not separated from the cortical columns of Bertin by connective tissue. ^[27] Because only 13-22% of SRCCs have regional lymph node involvement, but 45-66% have distant metastasis at presentation, ^{[3, 4, 7]} most of these tumors likely invade the vasculature of the renal sinus fat, as observed for CCRCC. ^{[28, 29]}

Although 37% of RRCCs have lymph node metastases and 22% have distant metastases at presentation, ^{[8, 9, 10, 11]} the small number of these tumors studied to date does not allow any conclusions to be drawn on their pattern of spread.

Sarcomatoid renal cell carcinoma

A high proportion (86-89%) of patients with SRCC are symptomatic, mainly presenting with pain (51%) and/or hematuria (22%), ^{[3, 4]} while 13-22% of patients have regional lymph node metastases and 45-66% have distant metastases at presentation. ^{[3, 4, 7]}

Rhabdoid renal cell carcinoma

Of 37 patients with RRCC with clinical details available, 27 (73%) presented clinically with a palpable mass, 5 (14%) had flank pain, and 4 (11%) had macroscopic hematuria. Of the 27 patients assessed, 10 (37%) had lymph node metastases and 6 (22%) had distant metastases at presentation. ^{[8, 9, 10, 11]}

The differential diagnoses of sarcomatoid renal cell carcinoma (SRCC) and rhabdoid renal cell carcinoma (RRCC) are as follows:

• Hemangiopericytoma

• Leiomyoma

• Leiomyosarcoma

• Malignant rhabdoid tumor

• Pathology - Rhabdomyosarcoma

• Rhabdoid transitional cell carcinoma

• Sarcomatoid transitional cell carcinoma

• Smooth muscle-predominant angiomyolipoma

• Solitary fibrous tumor Synovial sarcoma

Gross findings of sarcomatoid renal cell carcinoma

On gross inspection, the sarcomatoid components of SRCC appear as solid gray/white areas with an invasive margin and a firm, fleshy-to-fibrous cut surface. (See the image below.) Regions of hemorrhage and necrosis are common. ^{[7, 17, 18]} Tumor sizes in published series of SRCC range from 3-25 cm, with mean diameters of 9.2-11 cm. ^{[3, 7, 30]}

Sarcomatoid renal cell carcinoma arising from a clear cell renal cell carcinoma (lower left). Clear cell areas are golden in color due to cellular lipid accumulation while sarcomatoid foci are white. Note tumor extension along the renal vein.

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Gross findings of rhabdoid renal cell carcinoma

On gross inspection, the rhabdoid components of RRCC appear as solid white areas, with a homogeneous white surface on sectioning (see the image below). ^[9] In published series, the tumor sizes range from 4-15 cm, with mean diameters of 7.5-8.8 cm. ^{[8, 10, 11]}

Rhabdoid renal cell carcinoma arising from a clear cell renal cell carcinoma. The clear cell component is golden in color with a variegated appearance due to hemorrhage, cystic change and necrosis. Rhabdoid foci are translucent white and a metastatic rhabdoid deposit is seen within the perinephric fat below the main tumor mass.

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Microscopic findings of SRCC

On microscopic examination, 2 main histologic types of sarcomatoid renal cell carcinoma (SRCC) have been described. A fibrosarcoma-like appearance is reported in 14-65% of cases, characterized by sheets of whorled or interlacing bundles of spindle cells. Alternately, 27-85% of cases resemble malignant fibrous histiocytoma characterized by spindle cells in a storiform pattern, a greater degree of nuclear pleomorphism, and occasional multinucleated osteoclast-like giant cells (see the image below). ^[7] Some tumors (3-24%) have no distinct pattern, ^[7] and a hemangiopericytomalike pattern has been described in rare cases. ^[31]

Sarcomatoid renal cell carcinoma showing a storiform growth pattern (malignant fibrous histiocytoma-like) with marked nuclear pleomorphism, occasional multi-nucleated giant cells and atypical mitoses.

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Histologic coagulative tumor necrosis is seen in 90% of SRCCs (see the image below), ^[4] while less common histologic findings include foci of myxoid stromal change and regions of chondrosarcomatous or osteosarcomatous differentiation. ^{[17, 18]}

Sarcomatoid renal cell carcinoma in a storiform pattern associated with histologic coagulative necrosis (top left).

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Regions of rhabdoid differentiation are reported in around 15% of tumors classified as SRCC. ^[32] In 61% of SRCCs, a clear demarcation exists between the sarcomatoid and RCC components (see the image below), whereas in 39%, the 2 components are intimately admixed, often showing regions of transition between them. ^[7]

A region of clear demarcation between the sarcomatoid and clear cell components of sarcomatoid renal cell carcinoma.

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In most cases, both the sarcomatoid (86-92%) and the RCC (67-95%) components of SRCC are of Fuhrman grade III or IV. ^{[4, 7, 31]} However, the poor prognosis associated with sarcomatoid differentiation is independent of the nuclear grade of either component, and the convention is to assign all SRCCs to Fuhrman grade IV. ^{[4, 7, 15, 17, 33]}

Ultrastructural analysis confirms the epithelial derivation of sarcomatoid components in SRCC, most commonly by revealing interdigitation of the spindle cells with occasional-to-multiple desmosomal junctions. Some tumors also have short segments of basal lamina and/or occasional cells with sparse microvilli. In SRCC with CCRCC components, the sarcomatoid cells can display small pools of glycogen and lipid. ^{[34, 35, 36]}

Microscopic findings of RRCC

On microscopic examination, the rhabdoid component of rhabdoid renal cell carcinoma (RRCC) is characterized by large round or polygonal cells with globular eosinophilic paranuclear inclusion bodies, large eccentric vesicular nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm (see the image below). ^{[8, 9, 10, 11]} A variable proportion of these large pleomorphic cells may lack inclusion bodies, and some have clear cytoplasm, which is due in some cases to glycogen deposits ^[9] and in other cases to coalescence of large vacuoles in the cell periphery. ^[8]

Rhabdoid renal cell carcinoma showing large pleomorphic cells with globular eosinophilic paranuclear inclusion bodies, large eccentric vesicular nuclei, prominent nucleoli and abundant eosinophilic cytoplasm. Note lymphocytic infiltrate.

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The 2 main architectural growth patterns reported are solid sheets of cells or an alveolar pattern with delicate fibrovascular septae encircling solid nests of cells. Stroma is scanty, with occasional cases showing stromal myxoid change or hyalinization.

The rhabdoid components are commonly associated with hemorrhage (39% of cases), necrosis (22%), and focal lymphocytic infiltration. A coexisting sarcomatoid component is reported in 7-50% of RRCCs, often showing transition with rhabdoid components and occasionally intermixed with the rhabdoid cells. ^{[8, 9, 10, 11]}

In most RRCCs, the rhabdoid component also shows transition with coexisting RCC components, although in some tumors, these 2 morphologic elements are distinct and separated by a fibrous capsule. ^{[9, 10]}

In rare cases, no RCC component is detected despite extensive sampling of the tumor. ^{[9, 12]} In most RRCCs (86-94%), the RCC components are of Fuhrman grade III or IV, and the rhabdoid cells are typically described as high grade. ^{[8, 11]} Given the poor prognosis associated with this form of differentiation, rhabdoid change should likely be viewed as analogous to sarcomatoid change, and all RRCCs should be assigned to Fuhrman grade IV.

Ultrastructural analysis shows that 43-50% of RRCCs have classic rhabdoid cells with eccentric nuclei displaced by paranuclear cytoplasmic condensations of intermediate filaments, often in a concentric whorled pattern. ^{[8, 10]} Although rhabdoid cells in the remaining cases do contain increased amounts of intermediate filaments, the cytoplasmic inclusion bodies visible by light microscopy are due to paranuclear aggregation of organelles that have been displaced by large vacuoles in the cell periphery. ^[8] Similar findings have been reported in some cases of pediatric MRT of the kidney, in which the vacuoles were interpreted as large dilated cisternae of endoplasmic reticulum. ^[37]

Immunohistochemistry of SRCC

Immunoreactivity for epithelial markers is common in the sarcomatoid components of SRCC, providing evidence of their epithelial derivation. Positive staining in sarcomatoid areas is most frequently obtained with cytokeratin cocktail AE1/AE3 (33-94%) and epithelial membrane antigen (50-55%), while the intermediate filament vimentin is expressed in 56-100% of cases. Despite the spindle cell morphology, immunoreactivity for muscle-specific actin is only seen in 22% of cases, and staining for desmin is almost always negative. ^{[17, 18, 38, 39]}

As expected with transformation, sarcomatoid tumor components tend to lose the staining patterns that are characteristic of their RCC components. Sarcomatoid regions of chromophobe SRCC show only patchy staining with Hales colloidal iron and are negative for expression of parvalbumin and cytokeratin 7. ^[40] Similarly, sarcomatoid regions of papillary SRCC show significantly reduced expression of AMACR compared with the RCC components. ^[41]

However, sarcomatoid components of SRCC have significantly higher expression of the Ki-67 nuclear proliferation antigen compared with the RCC components, consistent with the aggressive behavior associated with sarcomatoid differentiation. ^[6]

SRCC with a predominant sarcomatoid component can be difficult to distinguish from other spindle cell neoplasms that occur in the kidney. Distinction from true smooth muscle tumors such as leiomyoma or leiomyosarcoma is aided by extensive sampling to detect an epithelial component in SRCC or by confirmation of epithelial derivation with immunohistochemical or ultrastructural analysis. Furthermore, immunostains for desmin are positive for leiomyoma and leiomyosarcoma, but they are negative for SRCC. ^[42]

Primary renal sarcomas may have unique cytogenetics features that serve to distinguish them from SRCC, as with the characteristic t(X:18) (p11.2-q11.2) translocation demonstrated in a primary renal synovial sarcoma. ^[43] Immunostains for HMB-45 or Melan A distinguish SRCC from smooth-muscle-predominant angiomyolipomas with hypercellularity and nuclear pleomorphism, which have positive immunoreactivity for these markers. ^{[42, 44]}

Similarly, immunostains for CD34 distinguish SRCC from solitary fibrous tumor and hemangiopericytoma, which have positive reactivity for these markers. ^[42]

However, urothelial or transitional cell carcinoma (TCC) that has undergone extensive sarcomatoid change can resemble SRCC in both morphology and immunohistochemical profile. Distinction between these tumor types is possible only by identifying components of usual TCC or RCC, respectively. ^[45]

Immunohistochemistry of RRCC

Immunoreactivity for epithelial markers is common in the rhabdoid components of RRCC, providing evidence of their epithelial derivation. Rhabdoid cells have positive staining for cytokeratin cocktail AE1/AE3 in 58-75% of cases and for epithelial membrane antigen in 41-78% of cases, while the intermediate filament vimentin is expressed in 100% of cases arising from clear cell, papillary, or collecting duct RCC.

Both cytokeratin and vimentin give diffuse cytoplasmic staining with strong accentuation in the globular cytoplasmic inclusion bodies. ^{[8, 10, 11]} Vimentin staining was negative in both components of the single reported case of RRCC arising from chromophobe RCC, consistent with the fact that chromophobe RCCs do not express vimentin. ^[9] Despite their morphology, the rhabdoid cells show no evidence of myoblastic differentiation, as immunostains for the muscle markers desmin and muscle-specific actin/smooth muscle actin are negative. ^{[8, 10, 11]}

Nuclear staining for the Ki-67 nuclear proliferation antigen is significantly stronger in rhabdoid components compared with RCC components, consistent with the aggressive behavior associated with rhabdoid change. ^[10] Rhabdoid components of RRCC also more frequently show overexpression of mutant p53 tumor suppressor protein compared with the RCC components. ^[11]

The rhabdoid component of RRCC closely resembles pediatric MRT of the kidney in all aspects, including histologic appearance, immunohistochemical profile, and ultrastructural details. ^{[8, 37]} However, the median age at diagnosis for renal MRT is 11 months, with a range of newborn to 9 years, ^[37] and 84% of MRT tumors have lost expression of the hSNF5/INI protein due to genetic alterations involving chromosome 22. ^{[46, 47, 48]}

For RRCC, hSNF5/INI is expressed in the rhabdoid components, ^[49] and extensive sampling reveals a coexisting RCC component in most cases. ^[48] Identification of a typical RCC component also helps distinguish RRCC from other renal tumors that may contain rhabdoid elements, including transitional cell carcinoma and rhabdomyosarcoma. ^{[8, 37]} In the case of rhabdomyosarcoma, the malignant rhabdomyoblast cells can be differentiated by positive expression of at least one muscle marker-most commonly, desmin, myoglobin, or muscle-specific actin. ^[43]

Molecular and genetic aspects of SRCC

Little information is available on genetic alterations in SRCC. Mutations of the p53 tumor suppressor gene are reported to be more prevalent in sarcomatoid components (79%) compared with clear cell components (14%) of SRCC arising from CCRCC. ^[50]

Cytogenetic analysis of 6 tumors with predominant sarcomatoid components has revealed complex polyploid karyotypes in 5 (83%) cases, ^[51] which is consistent with the view that sarcomatoid differentiation represents an advanced (late) step in the progression of RCC. This is supported by findings of polyploid DNA indices in the sarcomatoid components of 8 SRCCs, compared with hypodiploid or hyperdiploid DNA indices in the RCC components. ^[39]

Similarly, genetic analysis by fluorescent in situ hybridization has shown polyploidy of chromosomes 1, 2, 6, 10, and 17 in the sarcomatoid components of 6 chromophobe RCCs, whereas the RCC components had either 1 (monosomy) or 2 (disomy) copies of these chromosomes. ^[40] In rare cases, cytogenetic analysis has shown alterations involving chromosome 3p in SRCC associated with CCRCC ^[52] or polysomy of chromosomes 7 and 17 in SRCC associated with papillary RCC. ^[53]

However, in most cases analyzed, SRCC does not show the underlying chromosomal changes that are characteristic of the histologic type of RCC it is derived from, suggesting that sarcomatoid change occurs more frequently in a subgroup of tumors that are genetically atypical. ^{[40, 51]}

A study by Ito et al found that sarcomatoid differentiation in RCC is associated with a high rate of chromosomal imbalances with losses of 9q, 15q, 18p/q and 22q, and gains of 1q and 8q occurring at significantly higher frequencies in comparison to non-sRCC tumors. ^[54]

Molecular and genetic aspects of RRCC

Little information is available regarding genetic alterations in RRCC. Although deletions involving the long arm of chromosome 22 (22q) are found in 80% of renal malignant rhabdoid tumors (MRTs), ^[13] they are very seldom found in the rhabdoid components of tumors with rhabdoid change, including RRCC. ^{[14, 49]}

Similarly, the hSNF5/INI1 gene on 22q11.2 is inactivated by mutation in 75% of rhabdoid MRT, ^[55] whereas loss of expression of the hSNF5/INI protein is extremely rare in tumors with rhabdoid change, including RRCC. ^[49] One study has demonstrated loss of chromosome 3p and/or mutation of the VHL gene in both the rhabdoid and clear cell components of 2 RRCCs. ^[9] Recently, rhabdoid morphology has been linked to mutations in BAP1 and PBRM1. ^[56]

Both SRCC and RRCC are currently staged according to the 2002 version of the American Joint Committee on Cancer's TNM (tumor-node-metastasis) staging system for renal tumors. ^[57]

Tumors restricted to the kidney are stratified as follows:

• T1a (4 cm or less in maximal diameter)

• T1b (greater than 4 cm but not greater than 7 cm)

• T2 (greater than 7 cm)

Tumors not restricted to the kidney are stratified as follows:

• T3a (invading adrenal gland or perinephric and/or renal sinus fat but not beyond the Gerota fascia)

• T3b (extending into the renal vein or the inferior vena cava [IVC], but below the diaphragm)

• T3c (extending into the IVC above the diaphragm or invading into the wall of the IVC)

• T4 (extension beyond the Gerota fascia)

Tumors are stratified according to regional lymph node metastasis as follows:

• NX (nodes not assessed)

• N0 (no nodal involvement)

• N1 (involvement of a single node)

• N2 (involvement of more than one node)

Finally, tumors are stratified according to distant metastasis as follows:

• MX (distant metastasis not assessed)

• M0 (no distant metastasis)

• M1 (distant metastasis present)

Treatment of metastatic SRCC with interferon and/or interleukin-2 immunotherapy gives a partial response in 33% of patients but extends median survival only from 7 months to 19 months. ^[3]

Similarly, combination chemotherapy regimens such as doxorubicin plus gemcitabine are reported to give complete or partial responses in 40% of cases, but with a median response duration of only 5 months. ^[58] A study investigating treatment of metastatic SRCC with the antiangiogenic agents sunitinib, sorafenib, or bevacizumab showed a partial response in only 19% of patients, with a mean response duration of 9 months. ^[59] Interestingly, the partial responses were limited to those patients who had SRCC arising from clear cell renal cell carcinoma (CCRCC), with less than 20% of the tumor volume comprised of sarcomatoid elements.

Little information is available regarding response of RRCC to adjuvant therapy; however, a study of metastatic RCC, including 10 cases with rhabdoid change, did not find any association between rhabdoid features and response to treatment with interleukin 2. ^[60]

Prognosis of SRCC

The 5-year cancer-specific survival rates for patients with SRCC are 15-27%, ^{[2, 4, 7]} compared with 79% for patients with clear cell renal cell carcinoma (CCRCC) showing no sarcomatoid change. ^[7] Most patients (80%) with SRCC who undergo nephrectomy for clinically localized disease subsequently present with metastatic disease. ^[3]

Multivariate analyses of RCC cases show that sarcomatoid differentiation is an independent predictor of poor prognosis even after adjustment for tumor stage, nuclear grade, and the presence of tumor necrosis or metastatic spread, all of which are also significant predictors. ^{[2, 4, 15, 33]} Some studies have found in univariate analysis that prognosis worsens as the percentage of sarcomatoid differentiation increases, particularly once it constitutes 50% or more of the tumor volume. ^{[5, 7]}

Multivariate analysis specifically of SRCC cases shows that only TNM stage conveys an independent risk of poor prognosis above that of sarcomatoid differentiation. In contrast, Fuhrman nuclear grade, tumor size, angiolymphatic invasion, percentage of sarcomatoid component, and underlying RCC subtype do not have independent predictive value. ^[7]

Prognosis of RRCC

Of 37 patients with RRCC with available follow-up, 16 (43%) died from their disease within 1 to 36 months of diagnosis, indicating that rhabdoid differentiation is associated with aggressive tumor behavior and a high mortality rate similar to that seen for sarcomatoid differentiation. ^{[8, 9, 10, 11]} Prognostic factors specific to RRCC have not yet been determined.