Cystic Renal Cell Carcinoma, Multilocular or Cystic Necrosis

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1 J Med Sci 004;4(5): Copyright 004 JMS Shih-Ming Ou, et al. Cystic Renal Cell Carcinoma, Multilocular or Cystic Necrosis Shih-Ming Ou, Shang-Sen Lee, En Meng, Jong-Shiaw Jin, Ching-Jiunn Wu 3, Dah-Shyong Yu, Chung-Yang Yen, Sun-Yran Chang 4, and Guang-Huan Sun * Division of Urology, Department of Surgery, Department of Pathology, 3 Department of Radiology, Tri-Service General Hospital, National Defense Medical Center, 4 Military Medical Bureau, Ministry of National Defense, Taipei, Taiwan, Republic of China Background: To compare the clinical presentation, radiological features, surgical prognosis and treatment options between multilocular cystic renal cell carcinoma (MCRCC) and renal cell carcinoma (RCC) with cystic necrosis. Methods: A retrospective review was carried out to investigate the patients with RCC at the Tri-Service General Hospital during an - year period (from 993 to 003). The clinicopathologic features, radiological features, surgical procedures and follow-up outcomes were recorded. Results: Among 8 cases of RCC, 3 cases of RCC with cystic components were identified according to the pathologic files. Among them, 4 cases were MCRCC (3.3 % of all RCC cases), 4 cases were RCC with cystic necrosis and 5 cases were RCC superimposed with simple cysts. Seventy-five percent cases of MCRCC and 5 percent cases of RCC with cystic necrosis were found incidentally. Otherwise, the common symptoms were flank pain and gross hematuria. The overall mean age of MCRCC was 6.3 years whereas RCC with cystic necrosis was years. For treatment, radical and partial were done in cases respectively in the cases of MCRCC. Radical was applied in all the cases of RCC with cystic necrosis. The mean tumor size of MCRCC and RCC with cystic necrosis were cm and 8..9 cm, respectively. The clinical staging were all stage I in cases of MCRCC, whereas in stage II and in stage III in cases of RCC with cystic necrosis. For all the cases, there was no tumor or metastasis till now. The overall mean follow-up period was months. Conclusions: MCRCC represents an uncommon but distinct subtype of renal cell carcinoma that could be cured by nephron-sparing surgery. The clinical staging and nuclear grading of MCRCC is better than that of RCC with cystic necrosis. Histopathologic examination rather than radiologic differentiation is mandatory to distinguish the two diseases. Key words: multilocular, necrosis, nephron-sparing surgery, renal cell carcinoma INTRODUCTION Renal cell carcinoma (RCC) is the most common tumor of the kidney in adults, representing 3% of all adult malignancies, and 80% to 90% of all primary renal neoplasms. Multilocular cystic renal cell carcinoma (MCRCC) is a predominantly cystic lesion of kidney and an uncommon histologic subtype of conventional (clear cell) RCC with a reported incidence between % and 6% of RCC -5. RCC, known as renal adenocarcinoma, is prone to develop cystic change. According to the literatures, Received: March 5, 004; Revised: June 4, 004; Accepted: June 5, 004. * Corresponding author: Guang-Huan Sun, Division of Urology, Department of Surgery, Tri-Service General Hospital, 35, Cheng-Kung Road Section, Taipei 4, Taiwan, Republic of China. Tel : ; Fax : ; ghsun@mail.ndmctsgh.edu.tw RCC shows cystic patterns on imaging studies in 4% to 5% of the cases 6. A complex of cystic renal lesions, including multilocular cystic nephroma, RCC with cystic necrosis and MCRCC, contains different natural course and clinical prognosis. A histopathologic examination is often mandatory to delineate the benign or malignant nature. Hartman s classification was employed to categorize the RCC with cystic components. MCRCC is considered to be with low grade and low stage of malignancy and can benefit from nephron-sparing surgery 5. Meanwhile, RCC with cystic necrosis seems to be just as aggressive as ordinary RCC. We compared the clinicopathologic features and surgical prognosis in patients with MCRCC having undergone surgery to those with RCC with cystic necrosis in our institution. MATERIALS AND METHODS We reviewed the pathology files of RCC of the Tri- 63

2 Cystic renal cell carcinoma Table Clinical and pathological presentation of MCRCC and RCC with cystic necrosis Pt No. Age(yr)/Sex Clinical presentation Side/Treatment Stage Tumor size(cm) Cell type Nuclear grade Solid (%) Bosniak s classification Follow-up (month) Outcome NCRCC 3 4 Median 6.5 RCC with cystic necrosis 5 74/M Incidental Median 7/M 48/M 70/F 55/F 4/M 58/F 6/M Incidental Flank pain Incidental Incidental Gross hematuria Gross hematuria Flak pain Gross hematuria nehrectomy Right/Partial Right/Radical Left/Partial Right/Radical T3aN0M0 T3aN0M0 TN0M0 TN0M Papillary NA NA IV I NA IV III IV Loss of follow-up M: male; F: female; NA: not available Service General Hospital from Jan. 993 to Dec The clinical data and pathologic results from these patients were retrieved from the medical records. For all cases, the clinical presentation, radiological feature, histological subtype, tumor size, TNM stage, nuclear grade, surgical options as well as prognosis, were recorded. Thirteen cases of RCC with cystic components, including 4 cases of MCRCC, were reviewed and identified by pathologists. The histopathologic criteria for MCRCC employed were as follows: well-demarcated, multicystic mass; neoplastic clear tumor cells lining the cystic spaces; non-cystic part occupying 5% or less of the tumor volume 7. Hematoxylin-eosin sections were used to determine microscopically the percentage of solid component. Ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI) and renal arteriography were applied preoperatively to differentiate the cystic renal masses. By these radiologic studies, Bosniak s classification 8 was made by radiologist. Patients with familial RCC syndromes, including von Hippel-Lindau disease, were excluded. None of the patients had a history of chronic renal failure. The pathologic tumor stage was determined according to the 997 TNM classification system. The tumor nuclear grade was assessed with the grading system of 9. Tumor size was reported as the longest dimension of the lesion measured at pathologic examination. All cases of RCC with cystic components were solitary, and tissue specimens were obtained during radical or partial. Follow-up protocol was arranged with surveillance abdominal sonography and chest radiography in the interval of -month, 3-month, 6-month and -year after surgery. RESULTS Clinical Features One hundred and twenty-eight cases of RCC had been identified and undergone surgery in our institution in an -year period. Among them, 3 cases of RCC with cystic components, including 4 cases of MCRCC, 4 cases of RCC with cystic necrosis and 5 cases of RCC superimposed with simple cysts were investigated. The clinical and pathologic findings of MCRCC and RCC with cystic necrosis are summarized in Table. The mean patient age of MCRCC was 6.3 years (range 48 to 7), whereas RCC with cystic necrosis was years (range 4 to 74). The cases of MCRCC consist of men and women, whereas RCC with cystic necrosis are composed of 3 men and woman. Concerning the clinical presentation, flank pain (5 %) and incidental finding (75%) were found in the cases of MCRCC. On the other hand, gross hematuria (50%), both flank pain and gross hematuria (5%) and incidental finding (5%) were present in the cases of RCC with cystic necrosis. Imaging Studies All the cases of MCRCC and RCC with cystic necrosis received at least one diagnostic imaging modality as follows: ultrasonography, CT scan, MRI and renal arteriography. 64

3 Shih-Ming Ou, et al. Fig. (A) CT scan of MCRCC (case 3) showing lobulated, multi-septated cystic lesion over right kidney (arrow). (B) T- and (C) T-weighted MRI of MCRCC (case 4) showing a cystic lesion over inferior pole of left kidney with low signal in T and high signal in T (arrows). (D) Histological examination (original magnification x 400) of MCRCC (case 3) showing multiloculated cyst with neoplastic clear cell in the thin wall. Ultrasonography was available in 3 cases of MCRCC, in which were impressed as renal cysts whereas the remaining was suspected as angiomyolipoma. CT scans were available in 3 cases of MCRCC and lobulated, multiseptated cystic lesions of kidney were noted (Fig. A). MRI was employed in cases of MCRCC which demonstrate well-defined heterogenous cystic renal masses (Fig. B & C). Ultrasonography and CT scan were available in 3 and cases of RCC with cystic necrosis, respectively. One case of RCC with cystic necrosis revealed cystic renal lesion with heterogeneity in ultrasonography (Fig. A) and mural soft tissue nodules with contrast enhancement in CT scan (Fig. B), which resembled MCRCC in architecture. There were case of MCRCC and case of RCC with cystic necrosis receiving renal angiography in order to identify the blood supply of the cystic tumors. Neovascularity surrounding the cystic wall were found. One case of RCC with cystic necrosis in our series was initially impressed as MCRCC in the radiologic evaluation. Otherwise, Bosniak s classification was recorded in Table. Treatment In 4 cases of MCRCC, underwent radical and received partial nephrec-tomy. In 4 cases of RCC with cystic necrosis, all patients received radical. No patient received adjuvant treatment, including chemotherapy, radiotherapy and immunotherapy. Pathologic Findings All cases of MCRCC were conventional (clear cell) type with nuclear grade in 3 cases and grade in. All were clinical stage I (TN0M0). Microscopically, the cases of MCRCC show multiseptum renal cyst with epithelial lining of neoplastic clear cells (Fig. D). In the cases of RCC with cystic necrosis, 3 patients were conventional (clear cell) type and patient was chromophil (papillary cell) type. The nuclear grading was grade in case, grade in cases and grade 3 in case. The clinical staging was cases in stage II (TN0M0) and cases in stage III (T3aN0M0). Microscopically, extensive necrosis with pseudocysts formation was evident in the cases of RCC with cystic necrosis (Fig. C & D). The mean gross tumor size were cm and 8..9 cm in MCRCC and RCC with cystic necrosis, separately. The mean percentage of solid components and mean nuclear grading are approximately % and. 0.5 in the cases of MCRCC, whereas 75.9 % and in the cases of RCC with cystic necrosis. 65

4 Cystic renal cell carcinoma Fig. (A) Renal sonography of RCC with cystic necrosis (case 7) showing a cystic lesion with heterogeneity and post-acoustic enhancement. (B) CT scan of RCC with cystic necrosis (case 7) showing a cystic lesion (arrow). (C) Histological examination (original magnification x 00) and (D) Histological examination (original magnification x 400 ) of RCC with cystic necrosis (case 7) showing central necrosis with clear tumor cells arranged in sheet-like pattern. Follow-up Six patients were at regular follow-up, patient was lost after 5 years of follow-up and patient was interviewed by phone to exclude metastasis or. Patients of MCRCC were followed up for an average of months (range 6 to 46). Patients of RCC with cystic necrosis were followed up for an average of months (range 6 to 97). Neither tumor nor metastasis was noted in all cases. The overall mean followup period was months. 66 DISCUSSION In the past, the terms cystic RCC and RCC with cystic degeneration had started off controversy in the diagnosis and treatment 7. In 986, Hartman classified the possible mechanism accounting for the nature of RCC with cystic components into 4 histopathologic growth patterns 5 : intrinsic multilocular growth, intrinsic unilocular growth (cystadenocarcinoma), cystic necrosis (pseudocyst) and RCC arising from the epithelial lining in a pre-existing simple cyst. Although the prognostic difference between these subtypes had not been well-documented, MCRCC is considered to be with better prognosis, while RCC with cystic necrosis is not. According to the literature, multilocular renal cysts with a small clear cell population within the walls were first reported under the diagnosis of lymphangioma in Then in 957, RCC with cystic components and epithelial clear cells lining the cystic spaces was unveiled. It appears to be that the case reports were the earliest descriptions about MCRCC. In 98, the term multilocular cystic renal adenocarcinoma was firstly introduced and MCRCC became accepted as a subtype of clear RCC since then. Nowadays, MCRCC is considered as a rare and distinct entity, comprising approximately % to 6% of all RCC -5. In our series, the incidence of MCRCC was 3.3%, which is consistent with the previous reports. Because of the often-incidental findings of this disease, we predict that the incidence would be increased with the screening by radiologic modalities, especially ultrasonography. In the 4 cases of MCRCC we encountered, 75 percent (3 in 4 cases) was discovered incidentally, compared to 5 percent ( in 4 cases) in the cases of RCC with cystic necrosis. Fujii et al. found that all their patients with MCRCC were asymp-

5 Shih-Ming Ou, et al. tomatic and their patients with solid RCC were not 3. And Corica et al. disclosed that 83% of MCRCC patients were found incidentally 4. It is attributed to the possibility that MCRCC is slow-growing neoplasm and seldom causes necrosis or sarcomatoid changes, in which tumor size and blood clots deposition are related to the symptoms, such as flank pain and gross hematuria. Concerning the tumor size and clinical signi-ficance, we had observed larger volume in RCC with cystic necrosis compared to that in MCRCC (8..9 cm vs cm). We deduce that RCC with cystic necrosis is related to rapid tumor growth and often shows bulking tumor mass at presentation. On the contrary, MCRCC presents with slow tumor growth and seldom exceeds the T stage in size. Gender predominance of males over females of approximately 3: was noted in a large series of MCRCC 4. However, the phenomenon was not observed in our patients probably due to the limited numbers. There are 4 main histological subtypes of RCC. (Clear or granular) RCC accounts for 70% to 80% of RCC, chromophil (papillary) RCC accounts for 0% to 0% and chromophobe RCC accounts for 5%. Collecting duct RCC is rare and accounts for less than % of RCC 5. MCRCC is a variant of conventional (clear cell) RCC, characterized by well-demarcated multicystic lesions with single layer lining of neoplastic clear cells within the fibrous septum 3. Grossly, the MCRCC resembles cystic nephroma and cystic partially differentiated nephroblastoma. Calcification and osseous metaplasia occasionally occur 5,6. In general, MCRCC is classified as a variant of conventional (clear cell) RCC, and RCC with cystic necrosis is usually without obvious histological subtyping. Nuclear grading system has been adopted as prognostic factors to predict the outcome for patients with RCC. The nuclear grading system we employ here is based on s definition 7, which is a well-accepted prognostic factor and correlates with the survival 8 of RCC. In the 4 cases of MCRCC in our series, only case presented nuclear grade otherwise 3 cases were grade. Although Murad et al. had recommended that nuclear grade was a defining criterion for MCRCC 3, other investigators do not include nuclear grading as a diagnostic characteristic in MCRCC 7,4. In the cases of RCC with necrosis, the nuclear grading is obviously advanced than the cases of MCRCC (median nuclear grading vs ). We deduce that the higher nuclear grading of cystic necrosis is related to rapid tumor growth, in which pathogenesis is different from MCRCC. In the Minervini et al. s series, the survival rate showed significant difference between nuclear grade - and grade 3-4 in the T patients 9 of RCC, in which higher nuclear grading is related to gravid prognosis. In this series, we failed to show significant difference of survival rate between MCRCC and RCC with cystic necrosis. The shorter period of follow-up and limited cases should be responsible. The imaging techniques, including ultrasonography and CT scans, are often employed to differentiate cystic renal tumors. These lesions may be either benign or malignant, such as multilocular cystic nephroma (MCN) and renal cell carcinoma (RCC) with cystic components. CT scan is better than ultrasonography for the differentiation by recognizing the thick, irregular, calcified wall or neovascularity 0. The MCN is a benign tumor and conservative treatment may be indicated. In fact, the differential diagnosis of complicated renal cystic lesions, such as hemorrhagic cysts, is sometimes difficult. Even in the cases of RCC with cystic components, it seems to be impossible to distinguish a unilocular or multilocular RCC from an RCC with cystic necrosis by radiologic presentations 0. In this series, we utilized Bosniak s classification to retrospectively identify cystic renal masses. In 986, Bosniak proposed a classification system to differentiate renal cysts based on CT scan findings 8. Category I cystic masses have well-defined margins with homogenous and water-dense content. Category II cystic masses show thin septa (less than mm) with fine calcification. Category III cystic masses show more thick and irregular septa (more than mm) with thick and irregular calcifications. Category IV cystic masses have irregular thickened walls or solid elements and enhancement of cyst walls. Category I lesions are considered to be simple benign cysts and do not require further evaluation, whereas category IV cysts are presumed malignant and are the candidates for surgical excision. Category II and III cysts pose a difficulty in management because they contain features not only consistent with simple cysts but also solid renal masses. In the definition of Bosniak s classification, calcification, septation and wall thickening are associated more with malignant changes. Bosniak s classification provides a non-invasive method currently available for categorizing renal cysts. However, the relationship between prognosis and Bosniak s classification were not well established. In our series, there is no conclusive finding in Bosniak s classification to correlate the radiologic and clinical staging. Most of the RCC with cystic necrosis presented with advanced Bosniak categories. However, case of the MCRCC also presented with category IV in Bosniak s classification (Table ). Other diagnostic imaging modalities for RCC with cystic components include MRI, CT-guided cyst aspira- 67

6 Cystic renal cell carcinoma tion and angiography. The role of MRI in differentiating cystic renal mass is not conclusive. Some authors recommend it as useful to evaluate the character of the fluid inside the cyst 0. A tumor with serous fluid showed hypointensity on T-weighted images and hyperintensity on T-weighted images, while tumor with hemorrhage showed hyperintensity on both T- and T-weighted images. Cyst aspiration or biopsy is not necessary to determine the status of a suspected lesion of cystic RCC. Hayakawa et al. had reported that only 4% of 37 patients with pathologically proven cystic RCC had a preoperative finding of malignancy 6. Concerning the multilocular nature of MCRCC, sufficient pathological sampling of the neoplastic epithelial clear cell is difficult to obtain. Hence, we do not favor the diagnostic approach with renal cyst aspiration or biopsy. Otherwise, renal arteriography could be employed when renal malignancy is suspected. Generally speaking, neovascularity is suggestive of malignancy. According to the literature 0, in cases of MCRCC or RCC with cystic necrosis, neovascularity could be seen peripherally or within the tumors. Similar findings were found in our series. In general, CT scan is the best diagnostic modality to identify RCC with cystic components. However, diagnostic difficulties could be encountered between MCRCC and RCC with cystic necrosis because of the various appearances of the later. The surgical prognosis of MCRCC is extremely good. Recurrence or metastasis is rare. In the statistical survey of Eble et al., 44 patients of MCRCC received surgery and none was found to have had or metastasis in the follow-up 4. Nephron-sparing surgery has become a standard option for patients with localized RCC when it is necessary to preserve functioning renal parenchyma, and in selected patients with a small unilateral tumor and a normal contralateral kidney 3. We recommend partial for localized MCRCC because of its low potential of malignancy. Nassir et al. had reported cases that had undergone MCRCC surgery 7, in which 3 cases were treated with partial. Neither tumor nor metastasis was found in the mean follow-up of 44 months. In conclusion, MCRCC is a rare renal neoplasm with low grade and low potential of malignancy. The clinical staging and nuclear grading of MCRCC are better than that of RCC with cystic necrosis. Recognition of subtypes of RCC with cystic components may have some clinical significance on account of varied prognosis. Histopathologic rather than radiologic examination is mandatory to differentiate the MCRCC and RCC with cystic necrosis. Nephron-sparing surgery is recommended for localized MCRCC. REFERENCES. Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 00. CA J Clin 00;5: Mulders P, Bleumer I, Oosterwijk E. Tumor antigens and markers in renal cell carcinoma. Urol Clin N Am 003;30: Murad T, Komaiko W, Oyasu R, Bauer K. Multilocular cystic renal cell carcinoma. Am J Clin Pathol 99; 95: Corica FA, Iczkowski KA, Cheng L, Zincke H, Blute ML, Wendel A, Sebo TJ, Neumann R, Bostwick DG. Cystic renal cell carcinoma is cured by resection: a study of 4 cases with long-term follow-up. J Urol 999;6: Hartman DS, Davis CJ Jr, Johns T, Goldman SM. Cystic renal cell carcinoma. Urol 986;8: Hayakawa M, Hatano T, Tsuji A, Nakajima F, Ogawa Y. Patients with renal cysts associated with renal cell carcinoma and the clinical implications of cyst puncture: a study of 3 cases. Urology 996;47: Nassir A, Jollimore J, Gupta R, Bell D, Norman R. Multilocular cystic renal cell carcinoma: a series of cases and review of the literature. Urology 00;: Bosniak MA. The current radiological approach to renal cysts. Radiology 986;58: SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 98;6: Perlmann S. Uber einen Fall von Lymphangioma cysticum der Niere. Virchows Arch Pathol Anat Physiol Klin Med 98;68: Robinson GL. Perlmann s tumor of the kidney. Br J Surg 957;44: Lewis RH, Clark MA, Dobson CL, O Connell KJ. Multilocular cystic renal adenocarcinoma arising in a solitary kidney. J Urol 98;7: Fujii Y, Ajima J, Tosaka A, Sekine H, Ohya K, Kitahara S, Ohashi H, Oka K. Asymptomatic multilocular cystic renal cell carcinoma. Nippon Hinyokika Gakkai Zasshi Jap J Urol 99;83: Eble JN, Bonsib SM. Extensively cystic renal neoplasms: cystic nephroma, cystic partially differentiated nephroblastoma, multilocular cystic renal cell carcinoma, and cystic hamartoma of renal pelvis. Sem Diag Pathol 998;5: Leibovich BC, Pantuck AJ, Bui MH, Ryu-Han K, Zisman A, Figlin R, Belldegrun A. Current staging of renal cell carcinoma. Urol Clin N Am 003;30:48-68

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