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- PATIENTS AND METHODS
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Unclassified RCC, a subtype of kidney cancer introduced in 1997, is a diagnostic category for those tumours that do not fit into any of the four known common categories of RCC: clear-cell, papillary, chromophobe, or collecting duct carcinoma [1–8]. According to the 2004 WHO classification of urological tumours , the features that might prompt assignment of a tumour to this category include: composites of recognized subtypes, mucin production, rare mixture of epithelial and stromal elements, pure sarcomatoid morphology without recognizable epithelial elements, and unrecognizable cell types (Table 1). The frequency of this type of RCC is quite variable, accounting for 0.7–5.7% of all RCCs in some larger contemporary series [1–17]. Studies of unclassified RCC suggest that this category is associated with unfavourable histological features and aggressive behaviour [3–8,12,13,15–17].
Table 1. Features that support assignment to unclassified RCC category in the current WHO classification of kidney tumours
|• Composites of recognized types|
|• Pure sarcomatoid morphology without recognizable epithelial elements|
|• Mucin production|
|• Rare mixtures of epithelial and stromal elements|
|• Unrecognizable cell types|
Tumours assigned to this category tend to be heterogeneous and most often are of high grade [3,4]. Although the effect of histological subtype on the prognosis of patients with RCC has been investigated among the more common histological subtypes, few series have evaluated the significance of the unclassified RCC category on RCC-specific outcomes [3–17].
The aim of the present study was to describe the clinicopathological features and specific outcomes of 56 patients with unclassified RCC meeting 2004 WHO diagnostic criteria.
- Top of page
- PATIENTS AND METHODS
- CONFLICT OF INTEREST
According to the current WHO classification of kidney cancer ,the following features define unclassified RCC: composites of recognized types; pure sarcomatoid morphology without recognizable epithelial elements; mucin production; rare mixtures of epithelial and stromal elements; and unrecognizable cell types. Unclassified RCC represents 0.7–5.7% of renal tumours, and the majority are of high grade and stage at presentation [3–17]. One study  found that the proportion of unclassified RCC did not change with increasing decade of life. Although features that might place a carcinoma in this category are defined by the current WHO classification of kidney cancer, reported data suggest differences on how these criteria are applied, resulting in a more heterogeneous group than would be expected.
Limited reported data suggest that unclassified RCC is an aggressive form of RCC, mainly because most cases are at an advanced stage at presentation [1–17]. Results based on three relatively large series support this suggestion. Zisman et al.  reported 31 patients with unclassified RCC and compared the prognostic outcome with 317 matched patients with clear-cell RCC. The incidence of unclassified RCC in that series was 2.9%, slightly lower than in the present series, where the incidence was 4.8% out of 290 consecutive cases (based on 14 cases provided by one of the participating institutions). These differences are probably related to more restrictive inclusion criteria since Zisman et al.  included only pure anaplastic, pure sarcomatoid or mixtures of both types of RCC. On follow-up, 94% of the patients with unclassified tumours had metastatic disease vs 83% with matched patients with clear-cell RCC. Unclassified carcinomas were larger tumours, had increased risk of adrenal gland involvement (25% of cases), direct invasion to adjacent organs (42%), bone (52%), regional (52%) and non-regional lymph node (41%) metastases . Unclassified histology was a significant indicator for poor prognosis on multivariate analysis . The median survival in patients with unclassified RCC was 4.3 months . Karakiewicz et al.  reviewed 85 cases of unclassified RCC to compare cancer-specific mortality in patients with unclassified RCC vs. clear-cell RCC after nephrectomy. Of the patients with unclassified RCC, 80% had Fuhrman grades III or IV vs. 37.8% for clear-cell RCC . In addition, 36.5% of patients with unclassified RCC had pathologically confirmed nodal metastases vs. 8.6% with clear-cell RCC. Finally, 54.1% of patients with unclassified RCC had distant metastases at the time of nephrectomy vs. 16.8% with clear-cell RCC. Despite these differences in the overall analyses, after matching for tumour characteristics, the unclassified RCC specific mortality rate was 1.6 times higher in matched analyses and 1.7 times higher in multivariate analyses . The studies by Zisman et al. and Karakiewicz et al.  both provide evidence supporting the hypothesis that unclassified RCC is more aggressive than matched clear-cell RCC.
By constrast, Crispen et al.  more recently reported on 38 unclassified RCCs and showed that patients were more likely to have regional lymph node involvement, higher grade, tumour necrosis and sarcomatoid differentiation as compared to patients with clear-cell RCC, but overall and cancer-specific survival were not significantly different between patients with unclassified RCC and those with clear-cell RCC in either the unmatched or matched cohorts. In their study, Crispen et al.  included RCC cases with oncoytic/eosinophilic features, pure sarcomatoid/undifferentiated epithelial tumours, or tumours with pure rhabdoid differentiation. Again, the different results of the Crispen et al.  study can be explained by the selection criteria, which were different from those used in the series by Zisman et al.  and Karakiewicz et al. . The latter two studies concluded that unclassified RCC is associated with distinct and highly aggressive biological behaviour, and poor clinical outcome; likewise, Crispen et al.  concluded that although unclassified RCC is more likely to present with advanced clinicopathological features compared with clear-cell RCC, no statistically significant differences in outcome were noted after adjusting for these features in a matched analysis.
The present study of 56 cases of unclassified RCC is different from previous large series mainly because our cases were selected by dedicated uropathologists following the diagnostic criteria reported by the 2004 WHO , and also because emphasis was placed on pathological features as prognostic predictors of disease-free and cancer-specific survival. The present study is original as it describes the pathological features that can be applied to predict prognosis on a daily basis. We showed that nuclear grade, TNM classification, tumour coagulative necrosis, tumour size, microvascular invasion [18,19] and 2004 WHO histotype are independent predictors of disease-free and cancer-specific survival in our cohort of 56 unclassified RCC cases, with tumour size and recurrence as main predictors; therefore, these histological markers could be included in nomograms to assess unclassified RCC in clinical practice [20–22]. With regard to 2004 WHO histotype, it is notable that pure sarcomatoid morphology portended a dismal prognosis in the present series.
Pathological studies on unclassified RCC are limited, with most reporting on small cases series [3,4]. Bruder et al.  reported 13 cases of unclassified RCC in a series of 41 cases of RCC in patients younger than 22 years. These tumours could not be assigned to types specified by the current WHO classification .Of these, 10 cases were grouped as unclassified not otherwise specified, including a unique RCC with prominently vacuolated cytoplasm and WT1 expression. Three additional unclassified RCCs occurred in combination with nephroblastoma. The study by Bruder et al.  adds new morphological features which, together with the WHO criteria, might place a carcinoma in the category of unclassified RCC. Pathologists must be aware of the spectrum of histological findings within unclassified RCC to ensure accurate diagnosis [3,4,8,10]. As recently suggested by Reuter , using the current WHO criteria, unclassified RCC represents a histologically and clinically heterogeneous category of tumours that does not fit neatly into any of the other well-defined categories.
In conclusion, unclassified RCC according to 2004 WHO diagnostic criteria represents a heterogeneous group of tumours whose prognosis seems to be related to histological features known to be relevant in more common forms of RCC.