The Role of Percutaneous Needle Biopsy in Differentiation of Renal Tumors

Objective: The safety and accuracy of active percutaneous needle biopsy for small renal tumors have been reported. However, there have been few reports of passive biopsy for renal tumors without clear pretreatment histological characterization based on imaging studies due to the rarity of these tumors. In this study, we examined the background, accuracy, adverse events and patient prognosis associated with such biopsies. Methods: Japanese patients with renal tumors histological characteristics of which were unclear on imaging prior to treatment were enrolled in this study and analyzed retrospectively. The study population consisted of 24 renal cell carcinoma patients and 13 non-renal cell carcinoma patients. Results: Although the percentage of hypervascularity was significantly higher in clear cell renal cell carcinoma compared with the other neoplasms (P , 0.001), there were no significant differences between renal cell carcinoma and non-renal cell carcinoma with regard to hypervascularity, hydronephrosis, venous thrombus, hematuria or metastasis. The histological results in eight of nine (89%) nephrectomy patients were in accordance with those of biopsies. The median survival time of all 37 patients was 21 months and the 5-year survival rate was 31.1%. The 5-year survival rates of nephrectomy patients and non-nephrectomy patients were 75 and 0%, respectively. The overall survival of nephrectomy patients was significantly better than that of non-nephrectomy patients (P 1⁄4 0.003). Conclusions: Biopsy of renal tumors is safe and accurate regardless of the type of guidance and nephrectomy after appropriate diagnosis by biopsy contributed to longer survival.


INTRODUCTION
The incidence of renal tumors has been increasing in the USA, with 57 760 new cases and 12 980 deaths estimated in 2009 (1).Similarly, the incidence of renal tumors in Japan has also been increasing, with an estimated 4000 deaths from renal tumors in 2007.Renal cell carcinoma (RCC) is the most frequent malignancy of renal tumors and clear cell RCC (cRCC), the most common type of RCC, accounts for 75% of malignant renal tumors (2).Although most cases of RCC are diagnosed as hypervascular, encapsulated tumors with central necrosis by imaging methods, such as computed tomography (CT), differential diagnosis from other types of neoplasm, especially large urothelial carcinoma (UC) occurring in the renal pelvis, is difficult.There are differences between RCC and the other neoplasms with regard to appropriate surgical technique, and in cases with metastasis, the primary site of RCC should be resected.On the other hand, the other neoplasms generally should not be resected and should initially be treated with systemic therapy.Furthermore, the advent of molecular target therapies directed against vascular endothelial growth factor and the mammalian target of rapamycin requires diagnosis of RCC subtype (3 -7).Therefore, the histological results of renal tumors must be predicted before treatment if they cannot be confirmed by imaging.Recently, the safety and accuracy of active percutaneous needle biopsy for small renal tumors have been reported.These reports mainly spotlighted the differentiation between RCC and benign renal tumors due to prevention of unnecessary surgery, because 30% of renal tumors ,4 cm in diameter that were removed by radical or partial open nephrectomy were benign on final histological evaluation.However, such concerns are inherent in small renal tumors because the percentage of benign tumors decreased from 46.3% for those ,1 cm in diameter to 6.3% for those measuring 7 cm or more (8).There have been few report of passive biopsy for various renal tumors histological characteristics of which were unclear on imaging prior to treatment due to the rarity of these tumors.In the present study, we examined the background, accuracy, adverse events and patient prognosis of such biopsy of renal tumors.

PATIENTS
Japanese patients with renal tumors without clear pretreatment characterization based on imaging studies were enrolled in this study.All patients had undergone imageguided percutaneous needle biopsy at Kanazawa University Hospital from 1989 to 2009 and they were analyzed retrospectively.All patients were 15 years or older at the time of biopsy.The reasons for the necessity of biopsy were as follows: (i) for differentiation between RCC and UC occurring in the renal pelvis, which could not be diagnosed despite drip infusion pyelography or retrograde pyelography in addition to CT; (ii) for histological identification of inoperable hypervascular tumors with invasion to adjacent organs or multiple metastases; (iii) for histological identification of hypovascular tumors that could not be diagnosed as RCC; (iv) for histological identification of tumors unsuitable for contrast-enhanced CT.CT images of typical cRCC and representative biopsied tumors are shown in Fig. 1.All percutaneous needle biopsies were performed under CT (12 patients) or ultrasound (US) (25 patients) guidance.Before 1996, all biopsies were performed under US guidance, and after 2007, all biopsies were performed under CT guidance.Between 1997 and 2006, as a transition period from US-guided to CT-guided, nine US-guided biopsies and five CT-guided biopsies were performed.All US-guided biopsies were performed by urologists and all CT-guided biopsies were performed by radiologists.

STATISTICAL ANALYSIS
The date of surgery or biopsy was used as the start of observation.Statistical analyses were performed using commercially available software (Prism).Comparisons between two groups were performed by unpaired two-sided t-test or Fisher's exact test.The crude probability of survival was estimated using the Kaplan -Meier method.Univariate analysis of differences between patient groups was performed with the log-rank test.Statistical significance was defined as P , 0.05.

PATIENT POPULATION
Thirty-seven patients were included in the present study.Patients were divided into two groups according to the histological results: the RCC group and the non-RCC group.Although the histological results diagnosed by biopsy were used, the results of final histological evaluation were used if the patient underwent nephrectomy.Patient demographic and clinical characteristics are shown in Table 1.The numbers of RCC and non-RCC patients were 24 and 13, respectively.The median ages of the patients in the two groups were 61.5 and 69 years, respectively.The median tumor sizes determined by the largest dimension were 8.0 and 9.0 cm, respectively, and the numbers of small renal tumors defined as ,4 cm were three and one, respectively.Three patients did not undergo contrast-enhanced CT because of renal impairment, asthma and for unknown reason, respectively.Vascularity was unclear in two patients despite contrast-enhanced CT.Lymph node (LN) metastasis was defined according to the LN classification of RCC and UC, including bilateral renal hilus, abdominal para-aortic, parainferior vena cava and aortocaval regions.Although we examined whether findings on CT and hematuria allowed prediction of RCC before biopsy or surgery, there were no marked differences between RCC and non-RCC with regard to hypervascularity, hydronephrosis, venous thrombus, hematuria or metastasis.However, the percentage of hypervascularity was significantly higher in cRCC (8 of 11 patients) compared with non-cRCC (2 of 21 patients; P , 0.001).
Urine cytology was performed in 17 patients in the RCC group and 11 patients in the non-RCC group.Positive diagnosis was three and one patients, respectively.However, all three positive patients in the RCC group were misdiagnosed as UC and the patient in the non-RCC group was diagnosed as just malignant findings.

RESULTS OF BIOPSIES
The results of biopsies are shown in Table 2. Despite being the most prevalent subtype of RCC, the percentage of cRCC was only 30% in the present study.Various histological types were confirmed.Sufficient tumor sample (only normal tissue) was not extracted for histological examination in 4 of 37 patients.However, the patient with neck LN swelling was diagnosed as having papillary RCC (pRCC) by biopsy of the neck LN, and a diagnosis of angiomyolipoma was made in the patient who underwent plain CT again.Two patients underwent nephrectomy, and were diagnosed as having cRCC and hematoma, respectively.There were no significant differences between the proportions of insufficiency in CT-guided biopsy (no patients) and US-guided biopsy (four patients; P ¼ 0.2823).
Biopsies were accompanied by adverse events in four cases; hematuria occurred in two cases and continuous pain or bleeding were observed in one case each.These adverse events resolved spontaneously within 24 h.There were no significant differences between the proportions of adverse events in CT-guided biopsy (no patients) and US-guided biopsy (four patients; P ¼ 0.2823).There was no tumor seeding along the needle tract during follow-up.

RESULTS OF NEPHRECTOMY
Excluding two patients from whom sufficient amounts of tissue could not be extracted for histological examination by biopsy, nine patients underwent nephrectomy according to the results of the biopsy.The final histological results for seven of nine nephrectomy patients were completely in accordance with the histological results of biopsy.One patient diagnosed as having cRCC by biopsy was subsequently confirmed to have pRCC on final histological evaluation.The diagnosis at final histological evaluation ( pRCC) was different from the histological results of the biopsy (UC) in only one patient.

OVERALL SURVIVAL
The median survival time of all 37 patients was 21 months and the 5-year survival rate was 31.1% (Fig. 2A).The overall survival of patients who underwent nephrectomy was significantly better than that of patients who did not undergo nephrectomy (P ¼ 0.003).The 5-year survival rates of nephrectomy patients and non-nephrectomy patients were 75 and 0%, respectively.The median survival time of nonnephrectomy patients was 8 months (Fig. 2B).The median ages of nephrectomy patients and of non-nephrectomy patients were 55 years (range: 15 -65 years) and 68.

DISCUSSION
Renal tumor biopsy has become common in the evaluation of small renal tumors because imaging alone is insufficient to show the underlying aggressiveness of these lesions and more ablative therapies are available (9).On the other hand, the role of conventional percutaneous biopsy for renal tumors has been limited, and there is little general experience to date (10).In the present study, we evaluated the background, accuracy, adverse events and patient prognosis of such passive biopsy.The median tumor size was 8.3 cm and the percentage of small renal tumors defined as ,4 cm was only 11%.To our knowledge, the median tumor size in the present study is the largest reported.The percentage of cases with metastases was 65%.Accordingly, renal tumors that had to be biopsied were generally progressive.In addition, a wide range of histological results were found and the percentage of cRCC, the most common type of RCC, was only 30% in the present study, although it was 74% in a recent report (11).Hydronephrosis, which is inherent in UC, and venous thrombus, which is inherent in RCC, did not

Meta of parotid carcinoma 1
Normal tissue (insufficient) 4 RCC, renal cell carcinoma; meta, metastasis.predict UC and RCC as histological results, and hypervascularity alone strongly predicted cRCC and may allow the patient to avoid undergoing biopsy.Biopsy was non-diagnostic in 4 of 37 patients (11%) in the present study.The reported percentage of non-diagnostic biopsies was 0 -21% (12 -15).Although histological results in eight of nine nephrectomy tumors (89%) were in accordance with histological results of biopsies, the subtype of RCC was different between the histological results of biopsy and nephrectomy in one patient.It was reported that the percentage accuracy was 86.7 -100% (12 -15).The most controversial potential complication of renal tumor biopsy is the risk of tumor seeding along the needle tract.However, the overall estimated risk is ,0.01%and only six cases of seeding have been reported (10).In consideration of these results, our data were equivalent to the standard outcome regardless of type of guidance used.
Importantly, the overall survival of patients who underwent nephrectomy was significantly better than that of patients who did not undergo nephrectomy.There have been no previous reports regarding the overall survival focused on nephrectomy after biopsy.Although there was no significant difference between the median tumor size of nephrectomy patients and non-nephrectomy patients, the median age of the former was significantly younger than that of the latter and the percentage of non-nephrectomy patients who had either LN or distant metastasis was significantly higher than that of nephrectomy patients.Biopsy may effectively extract patients with metastasis who should undergo nephrectomy, such as those with RCC, and exclude non-RCC patients with metastasis, lymphoma and small cell carcinoma which are very sensitive to chemotherapy from candidates for nephrectomy.
The present study had a number of limitations.Histological grade was not considered as a prognostic variable because it was not clear in some specimens and the success of grading by percutaneous needle biopsy is controversial (16).Needles used were mostly 18 gauges with a tissue cutting tip; however, precise records were not available.Wunderlich et al. ( 17) recommended obtaining one central and one peripheral biopsy specimen from tumors smaller than 4 cm and two peripheral biopsies from larger tumors.Although at least two peripheral biopsies were obtained in all CT-guided biopsies, the precise numbers of US-guided biopsies were not available in our series.In addition, all patients were Japanese, so the distribution of RCC according to histological subtype or the percentage of RCC in renal tumors may differ in patients from other ethnic backgrounds.More importantly, this study was retrospectively analyzed with small sample size in a single institute.It may have prevented determination of the precise statistical significance.To avoid unnecessary nephrectomy of a kidney with hypovascular tumor, the usefulness of prior biopsy should be validated.Long followed-up and larger prospective studies comparing prior biopsy group to upfront nephrectomy group without biopsy in patients with hypovascular renal tumor may be needed to confirm our findings.
Finally, there were various histological results in renal tumors without clear pretreatment characterization based on imaging studies and hypervascularity may be an important predictive factor of cRCC.It was confirmed that biopsies of such tumors were safe and accurate regardless of the type of guidance used.Nephrectomy after diagnosis by biopsy might contribute to longer survival.

CONCLUSIONS
The patients who underwent biopsy for renal tumors without clear pretreatment histological characterization based on imaging studies tended to show progressive disease.Owing to the wide variety of histological results, hypovascular tumors should be biopsied actively before treatment.It was confirmed that biopsy of such tumors was safe and accurate regardless of the type of guidance used.Nephrectomy after diagnosis by biopsy might contribute to longer survival.

Figure 1 .
Figure 1.(A) A hypervascular encapsulated tumor with central necrosis consistent with cRCC was not biopsied but treated by surgery and was identified as cRCC.(B) A hypovascular tumor infiltrating the left kidney was identified as cRCC by biopsy.(C) A hypovascular tumor with calcification and hydronephrosis was associated with lung, lymph node (LN) and liver metastases and was identified as pRCC by biopsy.(D) A large hypovascular tumor with adrenal and LN metastases was identified as chromophobe RCC by biopsy.(E) A hypovascular tumor replacing the left kidney was identified as urothelial carcinoma by biopsy.(F) A hypovascular tumor replacing the right kidney with renal venous thrombus was identified as squamous cell carcinoma by biopsy.

Figure 2 .
Figure 2. (A) Kaplan -Meier analysis of the overall survival in all 37 biopsied patients.(B) Kaplan -Meier analysis of the overall survival in nephrectomy and non-nephrectomy patients.The solid line shows the overall survival of nephrectomy patients excluding two patients with insufficient biopsy samples (n ¼ 9).The broken line shows the overall survival of non-nephrectomy patients (n ¼ 26).

Table 1 .
Patient demographics and clinical characteristics RCC, renal cell carcinoma; meta, metastasis; LN, lymph node.Data in parentheses are range.

Table 2 .
Results of biopsies