Micropapillary Urothelial Carcinoma of the Upper Urinary Tract Clinicopathologic Study of Five Cases

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1 Anatomic Pathology / MICROPAPILLARY UROTHELIAL CARCINOMA Micropapillary Urothelial Carcinoma of the Upper Urinary Tract Clinicopathologic Study of Five Cases Delia Perez-Montiel, MD, 1,2 Ondrej Hes, MD, 3 Michal Michal, MD, 3 and Saul Suster, MD 1 Key Words: Micropapillary carcinoma; Urogenital tract; Urothelial carcinoma Abstract We report 5 cases of micropapillary urothelial carcinoma (MPUC) involving the renal pelvis (2), renal pelvis and ureter (2), and proximal ureter (1). The patients were 2 women and 3 men, ages 65 to 92 years (mean, 76.0 years). All tumors showed a high-grade transitional cell carcinoma component, and in 3 cases, there also were areas of in situ carcinoma. The case involving only the ureter occurred in a 65-year-old man with a history of nephrectomy 12 years previously for urothelial carcinoma of the renal pelvis. The tumor recurred in the ureteral stump. In all cases, areas displaying micropapillary architecture were observed. In 2 cases the micropapillary areas were noninvasive; in 1 case a pure invasive pattern was seen; and in 2 cases a mixed invasive and noninvasive pattern was present. All patients died of their tumors from 3 to 24 months after initial diagnosis. MPUC involving the renal pelvis and ureter is associated closely with advanced stages of disease and has highly aggressive behavior. Recognition of this growth pattern is important for prognosis and avoiding misdiagnosis with papillary renal cell carcinoma and other tumors. Micropapillary urothelial carcinoma (MPUC) is a recently described, rare variant of high-grade urothelial carcinoma. 1 In the bladder, the incidence reported in different series for this unusual variant of urothelial carcinoma is between 0.7% and 6%. 2,3 Cases involving the ureter are rare and have been presented as single case reports or as a part of secondary involvement in larger bladder cancer series. 2-4 To the best of our knowledge (with the exception of 1 case mentioned in a letter to the editor 5 ), cases of MPUC involving the renal pelvis have not been described in detail. We describe the clinicopathologic findings in 5 cases of MPUC of the renal pelvis and ureter. The clinical significance and histologic differential diagnosis of these lesions is discussed. Materials and Methods All cases coded as carcinoma of the renal pelvis were retrieved from the surgical pathology files at Ohio State University Medical Center, Columbus, between January 1968 and December 2000, and at University Hospital, Plzen, the Czech Republic, between January 1995 and December We found 155 cases of transitional cell carcinoma of the renal pelvis; from these, 4 cases with micropapillary morphologic features were identified (2.6%). Another case displaying micropapillary carcinoma involving the distal ureter in a patient who had a nephrectomy 12 years previously for urothelial carcinoma of the renal pelvis also was identified. From 6 to 13 histologic sections stained with H&E were retrieved for each case and reviewed. The diagnosis of micropapillary carcinoma was based on the identification of the characteristic histopathologic features as described for this condition by Amin et al Am J Clin Pathol 2006;126:86-92 Downloaded 86 from

2 Anatomic Pathology / ORIGINAL ARTICLE Representative paraffin blocks were available in all 5 cases for immunohistochemical stains. The cases were stained with a panel of antibodies including cytokeratin (CK)7, CK20, and polyclonal carcinoembryonic antigen (CEA). Case 5 also was stained for CD10 and vimentin. Formalin-fixed, paraffinembedded tissue sections were cut at 4 µm, dried for 1 hour at 60 C, deparaffinized in xylene, and rehydrated through graded alcohols. Antigen retrieval was performed using Target Retrieval Solution, 10 concentrate (DakoCytomation, Carpinteria, CA) for all antibodies. Endogenous peroxidase activity was quenched by immersion in absolute methanol containing 3% (vol/vol) hydrogen peroxide for 5 minutes. Immunohistochemical stains were performed by the avidin-biotin complex immunoperoxidase technique on a DAKO Autostainer (DAKO, Carpinteria, CA). Tissue sections were incubated with antibodies for CK7 (1:200 dilution; DakoCytomation), CK20 (1:200 dilution; DakoCytomation), polyclonal CEA (1:1,000 dilution; DakoCytomation), vimentin (1:200 dilution; DakoCytomation), and CD10 (1:20 dilution; Novocastra, Newcastle upon Tyne, England). Appropriate positive and negative control experiments were run concurrently for all cases. Age, sex, location, size, pathologic stage, tumor grade, presence or absence of in situ carcinoma, and percentage of micropapillary areas were recorded. Clinical follow-up for the patients was obtained from medical records. Results Clinical Features The clinical characteristics of the patients are summarized in Table 1. There were 3 men and 2 women aged 65 to 92 years (mean, 76.0 years). Two tumors were located in the left side and 3 in the right side. In 2 cases, the tumors extended into the ureter without involving the surgical resection margin. In 3 cases, an in situ component was identified in the renal pelvis. All cases were in advanced pathologic stages (stages T2-T4) at the time of diagnosis. Metastases to regional lymph nodes were documented in 2 patients at the time of surgery; in 1 patient, a bone lesion compatible with metastasis was diagnosed on radiologic studies. In all cases, the lymph node metastases also showed micropapillary features. All patients died of their tumors between 3 and 24 months after diagnosis (mean survival, 17.2 months). Gross Features Grossly, the tumors measured from 1 to 4.5 cm in greatest diameter and were described in 3 cases as polypoid, friable, and granular lesions occupying the renal pelvis with gross invasion into the kidney. A fourth tumor (case 3) was described as a small mass displaying a granular appearance at the ureterocaliceal junction of the renal pelvis in a hydronephrotic kidney. The fifth case (case 2) corresponded to a segment of distal ureter showing dilatation due to an intraluminal tumor mass that infiltrated through the wall of the organ in a patient with a history of nephrectomy 12 years previously for urothelial carcinoma of the renal pelvis. Histopathologic Findings Two morphologic patterns, invasive and noninvasive, as described by Amin et al, 1 were identified. The noninvasive pattern was seen in 2 cases; a pure invasive pattern was seen in 1 case; and the other 2 cases showed a combination of invasive and noninvasive patterns. The percentage and distribution of the micropapillary growth pattern varied among the cases. In case 1, approximately 70% of the tumor consisted of highgrade urothelial carcinoma with necrosis, and approximately 30% consisted of invasive micropapillary carcinoma Image 1. The invasive micropapillary component showed prominent lymphovascular and perineurial invasion Image 2. The micropapillary component was characterized by small nests of tightly cohesive tumor cells displaying hyperchromatic nuclei with occasional nucleoli and a scant rim of lightly eosinophilic cytoplasm. The clusters of tumor cells showed a distinctive retraction artifact from the surrounding stroma Image 3. Multiple perirenal lymph nodes showed involvement by metastatic carcinoma. The perirenal fat also showed microscopic tumor implants displaying micropapillary architecture Image 4. Table 1 Clinicopathologic Features in Five Cases of Micropapillary Urothelial Carcinoma of Upper Urinary Tract Case No./ Size Micropapillary MPC TCC Follow-up Sex/Age (y) Location (cm) Stage Type (%) ISC Grade VI Metastasis (mo) 1/F/68 Right RP 3 T4 Invasive 30 Y High Yes Local lymph nodes; DWT, 3 implants in perirenal fat 2/M/65 Right DU 1 T4 Mixed 60 NA High Yes Local lymph nodes; DWT, 22 bone 3/M/81 Left RP/DU 1 T2 Mixed 40 Y High No No DWT, 24 4/F/74 Left RP 4.5 T3 Noninvasive 30 N High No No DWT, 17 5/M/92 Right RP/DU 3 T3 Noninvasive 50 Y High Yes No DWT, 20 DU, distal ureter; DWT, died with tumor; ISC, in situ carcinoma component; MPC, micropapillary carcinoma; NA, information not available; RP, renal pelvis; TCC, transitional cell carcinoma; VI, vascular invasion. Downloaded from Am J Clin Pathol 2006;126:

3 Perez-Montiel et al / MICROPAPILLARY UROTHELIAL CARCINOMA In case 2, the tumor involved the ureter. This patient had a history of nephrectomy on the same side 12 years previously for transitional cell carcinoma of the renal pelvis. Unfortunately, the slides from the original resection were not available for review. The tumor in the ureter showed a combination of invasive and noninvasive growth patterns. The noninvasive growth pattern was characterized by delicate filiform papillae projecting into the lumen Image 5. Cells showing high-grade nuclear features and eosinophilic cytoplasm lined the papillae Image 6. The invasive component showed the characteristic retraction artifact from the surrounding stroma. Multiple small perirenal lymph nodes showed extensive replacement by metastatic micropapillary carcinoma. Both components accounted for approximately 60% of the tumor. Cases 3 and 4 showed a noninvasive micropapillary component similar to that of case 2. Case 3 showed, besides the Image 1 (Case 1) Scanning magnification showing highgrade urothelial carcinoma (right) with comedo-like areas of necrosis, merging with an invasive micropapillary component on the left (H&E, 20). Image 2 Higher magnification from Image 1 showing prominent perineurial invasion by micropapillary carcinoma (H&E, 400). Image 3 (Case 1) The micropapillary areas are composed of tight clusters of cells with hyperchromatic nuclei surrounded by eosinophilic cytoplasm. The small micropapillary tufts display distinctive clearing from the surrounding stroma resulting from retraction artifact (H&E, 400). Image 4 (Case 1) Small tumor implant is seen in perinephric fat, displaying micropapillary architecture (H&E, 40). 88 Am J Clin Pathol 2006;126:86-92 Downloaded 88 from

4 Anatomic Pathology / ORIGINAL ARTICLE noninvasive component, invasive features identical to those of case 1. The micropapillary component accounted for 40% of the tumor in case 3 and 30% of the tumor in case 4. The nonmicropapillary component in both cases consisted of highgrade invasive urothelial carcinoma with extensive areas of necrosis with infiltration to subepithelial tissue in case 3 and infiltration of the renal parenchyma in case 4; in case 4, prominent vascular invasion by the high-grade invasive component was noted. In case 5, the micropapillary pattern was present in the noninvasive component of the tumor and accounted for approximately 50% of the lesion. The micropapillary areas in this tumor were characterized by filiform processes lined by 1 or 2 rows of cells with prominent cytoplasmic oxyphilia reminiscent of a papillary renal cell carcinoma Image 7. On higher magnification, the tumor cells showed large vesicular nuclei with prominent nucleoli surrounded by abundant, deeply eosinophilic cytoplasm Image 8. The invasive component consisted of high-grade urothelial carcinoma, with diffuse infiltration of the kidney and prominent vascular invasion. Areas of in situ carcinoma could be identified in the renal pelvis Image 9. Immunohistochemical Findings Immunohistochemical studies performed in all cases showed diffuse cytoplasmic positivity of the tumor cells for CK7 Image 10. In 2 cases, there was focal and strong positive reaction for CEA, and 2 cases also were positive for CK20 Image 11 and Table 2. The tumor in case 5 showed positive staining of the tumor cells for vimentin and focal positivity for CD10. Discussion Transitional cell carcinomas of the renal pelvis are rare tumors that account for approximately 5% of all renal neoplasms. 6 The micropapillary pattern of urothelial carcinoma (MPUC) is a rare type of growth pattern originally described by Amin et al 1 that generally is associated with high-grade urothelial carcinomas. Although principally recognized in the urinary bladder, a few case reports have been described of this unusual growth pattern in other segments of the urinary tract. 3-5 MPUC has been reported to account for 0.7% to 6% of tumors of the bladder. 2,3 Besides the urinary bladder, the tumor has been reported in the ureter with the same highgrade morphologic features, except in 1 case in which a ureteral tumor was associated with grade 1 to 2 transitional cell carcinoma. 4 A single case arising in the renal pelvis was described in a letter to the editor in a patient with a hydronephrotic kidney, 5 a clinical presentation similar to 1 of our cases. That patient had metastasis to gastric mucosa and died 1 month later. 5 Two different patterns of MPUC have been described in the urinary tract. 1 The most common is the invasive pattern characterized by clusters of atypical cells with high nuclear grade that form tight micropapillary structures surrounded by clear spaces resulting from retraction artifact. The second is the noninvasive pattern composed of small, slender, fingerlike projections lined by atypical cells with or without central fibrovascular cores. 1 An admixture of both patterns or only one of them can be seen in these tumors; the proportions of the micropapillary growth pattern can vary, and the percentage of Image 5 (Case 2) Noninvasive papillary proliferation is seen projecting into the lumen of the ureter (H&E, 20). Image 6 (Case 2) Higher magnification showing an elongated papillary structure containing a fibrovascular core and lined by cells with large, hyperchromatic nuclei surrounded by eosinophilic cytoplasm (H&E, 200). Downloaded from Am J Clin Pathol 2006;126:

5 Perez-Montiel et al / MICROPAPILLARY UROTHELIAL CARCINOMA micropapillary pattern that is necessary to make this diagnosis has not been specified. Cases with as little as 10% of MPUC were included in some of the older series. 1,2,3,7 All patients in our study had tumors that showed highgrade histologic features, and most were in an advanced clinical stage. Four patients in this study died of tumor from 3 to 24 months after the diagnosis. In case 2, the patient had a history of removal of a previous renal pelvic tumor 12 years previously. The recurrence showed MPUC with high stage and aggressive behavior. This patient also died 22 months after resection. When these tumors were first described by Amin et al, 1 the authors concluded that it was important to recognize the micropapillary pattern because of its association with highgrade and advanced-stage malignancy but accepted that the series was too small for more reliable statistical results; other small series reported similar findings. 8 A few years later, Samaratunga and Khoo, 7 in a study of 20 cases of MPUC of the Image 7 (Case 5) Complex papillary proliferation occupying the lumen of the renal pelvis (H&E, 20). Image 8 Higher magnification from Image 7 showing papillary structures lined by cells with large, vesicular nuclei with prominent nucleoli and surrounded by abundant oxyphilic cytoplasm (H&E, 200). Image 9 (Case 5) A focus of in situ urothelial carcinoma is seen lining the renal pelvis adjacent to noninvasive micropapillary carcinoma (H&E, 200). Image 10 (Case 1) Invasive micropapillary carcinoma of the renal pelvis showing strong positivity for cytokeratin 7 (avidinbiotin peroxidase complex technique, 100). 90 Am J Clin Pathol 2006;126:86-92 Downloaded 90 from

6 Anatomic Pathology / ORIGINAL ARTICLE urinary bladder, confirmed the association between high grade and advanced stage and a micropapillary component and noted that the higher the proportion of micropapillary component, the worse the prognosis. This finding was corroborated in a recent series of 38 cases of MPUC of the urinary tract. 3 In the present series, MPUC accounted for 2.6% of all carcinomas of the renal pelvis. Compared with previous studies of MPUC of the urinary tract, this percentage may seem somewhat high. It must be kept in mind, however, that unlike the bladder, approximately 70% of urothelial carcinomas of the renal pelvis are of high grade, 9 accounting for the higher incidence of these tumors observed in our study. The main differential diagnosis for this tumor in the renal pelvis is papillary renal cell carcinoma, particularly type 2. Such tumors are characterized by papillae that are lined by a single or multiple layers of large cells with abundant eosinophilic cytoplasm and large, round nuclei with prominent nucleoli. The cytoplasm of the tumor cells often is oxyphilic, and the nuclei tend to be of higher grade than in type 1 papillary renal cell carcinoma. 10 Psammoma bodies, edematous papillae, and foamy macrophages in the papillary cores can be seen in papillary renal cell carcinoma but are not a feature of MPUC. 1,10 Another distinguishing feature of papillary renal cell carcinoma is that the tumors are centered within the renal parenchyma rather than arising from the renal pelvis. Because in advanced stages it may not be possible to determine with certainty whether the tumor arose in the pelvis and secondarily infiltrated the kidney or vice versa, identification of foci of conventional transitional cell carcinoma can help resolve the identity of the tumor. Extensive sampling of the pelvis, therefore, is indicated in these tumors. Immunohistochemical stains may be of limited value in this setting because renal cell carcinoma and urothelial carcinoma can express CK7, CD10, and vimentin. 8,11 One helpful marker for the diagnosis of MPUC is CK20, which can be positive in these tumors but does not react with papillary renal cell carcinoma. 12 The recently developed renal cell carcinoma antigen also can be of aid in identifying papillary renal cell carcinoma. The few reports with this antibody in urothelial carcinoma have shown a negative reaction in the cases analyzed. 13 Another differential diagnosis includes renal carcinomas associated with Xp11.2 translocation/tfe3 gene fusion. Image 11 (Case 5) Noninvasive micropapillary carcinoma of the renal pelvis showing focal positivity of the tumor cells for cytokeratin 20 (avidin-biotin peroxidase complex technique, 100). These tumors are more frequent in children and young adults and can be confused with the present lesions because of papillary architecture; however, they usually display cells with clear, voluminous cytoplasm and psammoma bodies. 14 A more remote possibility to consider in the differential diagnosis is metastasis of papillary carcinoma of the ovary or from another source. However, metastases to the kidney from epithelial malignant neoplasms are rare. Careful sampling for the identification of areas of in situ urothelial carcinoma and a good clinical history are the 2 most helpful steps for determining the correct diagnosis. The renal pelvis is another important site of urinary tract involvement by this rare variant of urothelial carcinoma. The present study confirms the aggressive nature of MPUC in the renal pelvis. These tumors are associated with advanced stages and with high-grade histologic features and should be considered in the differential diagnosis of papillary neoplasms involving the upper urinary tract. Table 2 Immunohistochemical Results in Five Cases of Micropapillary Urothelial Carcinoma of the Renal Pelvis and Distal Ureter Case No. CK7 CK20 CEA Vimentin CD , Focal ND ND 2 + +, Focal ND ND ND ND 4 + ND ND CEA, carcinoembryonic antigen; CK, cytokeratin; ND, not done. Downloaded from Am J Clin Pathol 2006;126:

7 Perez-Montiel et al / MICROPAPILLARY UROTHELIAL CARCINOMA From the Departments of Pathology, 1 Ohio State University Medical Center, Columbus; 2 Instituto Nacional de Cancerologia, Mexico City, Mexico; and 3 University Hospital, Plzen, Czech Republic. Address reprint requests to Dr Suster: Dept of Pathology, the Ohio State University, E-411 Doan Hall, University Hospital, 410 NE 10th Ave, Columbus, OH References 1. Amin MB, Ro JY, el-sharkawy T, et al. Micropapillary variant of transitional cell carcinoma of the urinary bladder: histologic pattern resembling ovarian papillary serous carcinoma. Am J Surg Pathol. 1994;18: Johansson SL, Borghede G, Holmang S. Micropapillary bladder carcinoma: a clinicopathological study of 20 cases. J Urol. 1999;161: Alvarado-Cabrero I, Sierra-Santiesteban FI, Mantilla-Morales A, et al. Micropapillary carcinoma of the urothelial tract: a clinicopathologic study of 38 cases. Ann Diagn Pathol. 2005;9: Vang R, Abrams J. A micropapillary variant of transitional cell carcinoma arising in the ureter. Arch Pathol Lab Med. 2000;124: Ribe A, Sole M, Campo E, et al. Papillary transitional cell carcinoma [letter]. Am J Surg Pathol. 1996;20: Murphy WM, Beckwith JB, Farrow GM. Tumors of the Kidney, Bladder and Related Structures. Washington, DC: Armed Forces Institute of Pathology; 1994: Atlas of Tumor Pathology; Third series, Fascicle Samaratunga H, Khoo K. Micropapillary variant of urothelial carcinoma of the urinary bladder: a clinicopathological and immunohistochemical study. Histopathology. 2004;45: Maranchie JK, Bouyounes BT, Zhang PL, et al. Clinical and pathological characteristics of micropapillary transitional cell carcinoma: a highly aggressive variant. J Urol. 2000;163: Olag S, Mazumdar M, Dalbagni G, et al. Urothelial carcinoma of the renal pelvis: a clinicopathological study of 130 cases. Am J Surg Pathol. 2004;28: Delahunt B, Eble JN. Papillary renal cell carcinoma: a clinicopathologic and immunohistochemical study of 105 tumors. Mod Pathol. 1997;10: Chu P, Arber DA. Paraffin-section detection of CD10 in 505 nonhematopoietic neoplasms: frequent expression in renal cell carcinoma and endometrial stromal sarcoma. Am J Clin Pathol. 2000;113: Skinnider BF, Folpe AL, Hennigar RA, et al. Distribution of cytokeratins and vimentin in adult renal neoplasms and normal renal tissue: potential utility of a cytokeratin antibody panel in the differential diagnosis of renal tumors. Am J Surg Pathol. 2005;29: McGregor DK, Khurana KK, Cao C, et al. Diagnosing primary and metastatic renal cell carcinoma: the use of the monoclonal antibody Renal Cell Carcinoma Marker. Am J Surg Pathol. 2001;25: Argani P, Antonescu CR, Illei PB, et al. Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft part sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents. Am J Pathol. 2001;159: Am J Clin Pathol 2006;126:86-92 Downloaded 92 from