Histopathological analysis of T1 renal cell carcinoma: Does presentation matter?

Objectives:Objectives: To study the differences in the clinico-pathological features of incidental and symptomatic T1 renal cell carcinoma (RCC) and to see, particularly in T1b RCC, if symptomatic presentation has adverse pathological features concerning the oncological safety of elective nephron-sparing surgery (NSS) in this subgroup. Materials and Methods: Materials and Methods: Of 278 patients who underwent radical nephrectomy for RCC from January 1995 to January 2005, 70 had tumor size up to 7 cm (T1). They were categorized as incidental or symptomatic and as T1a or T1b tumors. Clinico-pathological features were compared between incidental (IRCC) and symptomatic (SRCC) groups. Tumors were analyzed using the 1997 TNM staging and Fuhrman(cid:146)s grade. Results:Results: Of the 70 with T1 tumors, 24 had T1a (IRCC, 12 and SRCC, 12) and 46 had T1b tumors (IRCC, 27 and SRCC, 19). Clear cell was the commonest histology. In T1a cancers, though no signi (cid:222) cant difference in histopathological pattern and grade was seen between the incidental and symptomatic groups, symptomatic tumors had more papillary, mixed histopathological pattern and higher nuclear grade. Among T1b tumors, 14 had papillary and mixed histology, 12 (86%) of which were symptomatic (P= <0.0001). In T1b, 15 (79%) symptomatic had higher nuclear grade (G2-3) while 22 (81%) incidental had lower Fuhrman(cid:146)s grade (P= <0.0001). Conclusion:Conclusion: Symptomatic T1b RCCs had higher nuclear grade and papillary histology. This difference was statistically signi (cid:222) cant. This may be relevant when considering elective NSS in symptomatic T1b disease.


INTRODUCTION
Renal cell carcinoma (RCC) accounts for approximately 2% of adult malignancies and 80-85% of malignant kidney tumors. [1] With the increasing use of noninvasive imaging in those with nonspeciÞ c symptoms, more than 50% of the RCCs are detected incidentally in younger age and are now referred to as the "radiologist's tumor". [1,2] Studies have demonstrated that incidental RCCs tend to be smaller, lower-stage and with better survival outcomes as compared to symptomatic RCC. [3] Although the contributions of lead and length time bias have not been deÞ ned, others have challenged this claim. [4,5] With the evolution of nephron-sparing surgery (NSS),

Original Article Original Article
Histopathological analysis of T1 renal cell carcinoma: Does presentation matter? from the study. Patients were categorized according to their clinical presentation. Tumors diagnosed incidentally as a part of a health checkup or for evaluation of vague upper gastrointestinal symptoms comprised the incidental (IRCC) group. Patients presenting with loin pain, hematuria, weight loss, cachexia and mass formed the symptomatic (SRCC) group. Of the 70 patients, 39 (56%) and 31 (44%) were in IRCC and SRCC groups respectively.
The histopathological data was retrieved from the pathology database. Staging was based on TNM, 1997 classiÞ cation. For grading Fuhrman nuclear grade was used. Both groups were compared for clinical and pathological parameters with mean follow-up of 36 (12-108) and 60 (12-120) months in IRCC and SRCC respectively.

Statistical analysis
All the categorical variables were summarized using frequencies and percentages. SigniÞ cance was calculated using Fisher's exact test. A two tailed P-value < 0.05 was considered as statistically signiÞ cant.

Patient characteristics
The mean age in the IRCC and SRCC group was 52.6 (32-76 years) and 52.4 (21-76 years) years respectively. Female preponderance was seen in incidentally detected RCC (46%), as compared to the symptomatic group (16%). In the symptomatic group the majority presented with hematuria [ Table 1].

Tumor characteristics
Patient distribution in IRCC and SRCC is shown in Table  2. Pathological examination of operative specimen of T 1a group did not reveal a statistical difference for different histological patterns (clear cell vs. papillary and mixed; P=0.37) and grade (Grade-1 vs. Grade 2-3; P=0.09). In the T 1b group, compared to the clear cell type, papillary and mixed histological varieties were signiÞ cantly more in the SRCC than IRCC group (P <0.0001). Symptomatic T 1b RCCs had a signiÞ cantly higher grade (2-3) [ Table 3] than Grade-1 (P <0.0001).
One of the patients in SRCC T 1b had sarcomatoid variant of clear cell type. One in T 1a SRCC (8%) and two in SRCC T 1b (11%) group developed distant metastasis at 64, 34 and 48 months of follow-up respectively but none developed in the IRCC group. In SRCC T 1a and T 1b the Þ ve-year cancer-speciÞ c survival rate was 100 and 89%. While in IRCC T 1a and T 1b it was 100%. The mean follow-up in IRCC and SRCC was 36 (12-108) and 60 months (12-120 months) respectively.

DISCUSSION
Renal cell carcinoma is characterized by diverse clinical manifestations. Small, localized tumors rarely produce symptoms and for this reason the diagnosis is often delayed. Symptomatic presentation is usually a sign of advanced disease. The most common presentations are hematuria (50-60%), abdominal pain (40%), and a palpable mass in the ß ank or abdomen (30-40%). These three symptoms occur as a combination ("classic triad") in less than 10% of patients. [10] Other signs and symptoms are relatively nonspeciÞ cfever, night sweats, malaise, and weight loss. In our series hematuria was the most common presentation, which is intuitively a sign of pelvi-calycial system invasion and makes metastasis disease more possible. Several studies have demonstrated that incidental neoplasms tend to be smaller, lower stage and grade and have better survival outcomes when compared with symptomatic RCC. [3] On analyzing our results we also found that incidental tumors were lowgrade and with a favorable histology as compared to the symptomatic tumors. Licht et al., found that symptomatic renal tumors (>4 cm) treated with partial nephrectomy had a statistically signiÞ cant worse prognosis. In their series Þ ve-year cancer-speciÞ c survival rates for incidental and symptomatic RCC was 94 and 83%. [11] This prompted Patard et al., to propose a classiÞ cation based on mode of presentation (incidental or symptomatic) combined with tumor size to stratify prognosis. [12] Renshaw et al., found that papillary RCCs were more aggressive as compared to clear cell RCC. [13] In T 1a , seven patients had papillary and mixed histology, of which Þ ve were symptomatic. In T 1b , papillary and mixed histology was seen in 14 patients, of which 12 were symptomatic (P=0.0001; Table 3). Kletscher et al., have shown that multi-focality occur at a signiÞ cantly higher rate (P=0.011) with papillary and mixed histological pattern. [14] Sarcomatoid histology is no longer considered a distinct subtype of RCC. It represents a relatively rare, poorly differentiated form of RCC subtypes; seen in less than 5% of RCCs and associated with dismal prognosis. [15] In our study sarcomatoid differentiation was seen in one patient who had a symptomatic presentation.   [17] In Fuhrman's original report, the Þ ve-year survival rates for Grades 1 to 4 were 64%, 34%, 31% and 10% respectively. Nuclear grade proved to be the most signiÞ cant prognostic factor for Stage-I tumor in his series. [18] In our study, 15 in the SRCC group as compared to Þ ve in the IRCC of the T 1b had higher nuclear grade (G2,3) [ Table 3]. Fergany et al., have shown a signiÞ cant survival beneÞ t not only for smaller lesions but also for those who had incidental presentation and with lower grade. [6] Elective NSS has become standard treatment for T 1a tumors. The rate of local recurrence in partial nephrectomy varies from 0-10% [19] and reflects the fact that most patients treated in this manner had large tumors, multi-focal tumors (microscopic/macroscopic), or both. Reported overall survival of NSS is similar to that of patients with disease of similar stage (T1) when compared with radical nephrectomy. [6,8] In the era of advanced laparoscopic surgery technical success is excellent and operative morbidity and mortalities are low. [19] In contemporary series cancer-speciÞ c survival has been found to be between 95-100 %. [19] Because of these favorable results in T 1a RCCs and increased number of diagnosis at early stage of tumors, elective NSS approach has been extended to select exophytic >4-7 cm size RCCs be they symptomatic or incidental. This is in spite of large partial nephrectomy series, showing size to be the most signiÞ cant predictor of cancer-related outcome [ Table 4]. [6,7,9,11] Rational for expanding elective NSS to larger tumors include recent changes in the staging of RCC suggesting a favorable tumor-related prognosis for individuals with tumors less than 7 cm, increase in the life expectancy, incidental diagnosis at an earlier age and metachronous tumor recurrences in patients undergoing radical nephrectomy and thus increased concerns about the long-term risk of renal insufÞ ciency. Our analysis on tumors > 4 cm in size has shown that symptomatic RCCs were associated with higher nuclear grade and papillary histology; the latter is associated with multi-centricity and could account for lower disease-free survival in T 1b RCCs as reported in the literature. This data indicates that it may be a cause for concern for elective NSS in those who had symptomatic presentation.
In this context we feel that there could be a role of core needle biopsy in the management decision for symptomatic T 1b RCC. In a review by Lane et al., renal mass biopsy has a 94% overall accuracy for identifying RCC subtypes. [20] Fuhrman nuclear grade has been assessed correctly up to 83% on these biopsies. These discrepancies in grades are likely due to tumor heterogeneity, since 16-25% of renal tumors show some variability of grade. [21] Hence to enhance the yield, it is important to obtain samples from various areas of the mass. [20] In conjunction with conventional histological analysis of renal mass biopsies, using core needle biopsy (18-gauge needle) with minimal or no increase in risk of complications, [20] additional tests such as immunohistochemistry, molecular markers, fluroscent in-situ hybridization [22] and polymerase chain reaction [23] further improve the accuracy of these biopsies.

CONCLUSION
Symptomatic RCCs had a higher nuclear grade and unfavorable histology. In partial nephrectomy the main worry is of local tumor recurrence and metastasis thus affecting the disease-free survival. We have found that symptomatic T 1b RCC had an unfavorable histology and higher grade both of which are known to be associated with multi-centricity, higher recurrence rate and poor prognosis. These data indicate that NSS should be avoided in symptomatic RCCs but could be extended to select incidentally diagnosed 4-7cm-sized renal cell carcinomas.
Source of Support: Nil, Confl ict of Interest: None declared.