Context.—Juxtaglomerular cell tumor is a rare renal neoplasm. Renin immunohistochemistry and electron microscopic documentation of rhomboid crystals are the primary methods of diagnosing this benign tumor.
Objectives.—In this retrospective study, we evaluated the morphologic, immunohistochemical, and ultrastructural features of 5 cases of juxtaglomerular cell tumor to determine the effectiveness of CD34 and CD117 immunohistochemistry for the diagnosis of this tumor.
Design.—We reviewed 5 cases with clinical, histologic, immunohistochemical, and ultrastructural aspects.
Results.—Three women and 2 men with a mean age of 37.8 years (range, 16–60 years) were included in this study. All patients presented with severe hypertension. All tumors were well circumscribed and ranged from 1.5 cm to 8.5 cm (mean, 4.4 cm). On light microscopic examination, we found solid sheets and nests of tumor cells with oval-to-round nuclei and eosinophilic cytoplasm. Low-power microscopic examination disclosed a hemangiopericytic vascular pattern. Immunohistochemistry results were as follows: vimentin (positive), renin (weakly positive), smooth muscle actin (focal immunoreactivity), and cytokeratin (negative). All 5 tumors were immunoreactive for CD34 and CD117. Electron microscopy revealed rhomboid crystals in the cytoplasm. Postoperatively, 4 patients were normotensive and 1 patient experienced persistent mild hypertension.
Conclusions.—Our findings indicate that immunohistochemistry for CD34 and CD117 are effective at diagnosing juxtaglomerular cell tumor. Juxtaglomerular cell tumor should be considered in the diagnosis of any renal tumors with epithelioid cells and negative initial cytokeratin immunohistochemistry.
Juxtaglomerular cell tumor (JGCT) is a rare renal tumor, first described by Robertson et al1 in 1967. To our knowledge, approximately 70 cases have been reported in the English language medical literature,2 with only 1 case being reported in Korea.3 This tumor is typically found in young adults, with a peak incidence in the second and third decades of life. Patients with JGCT experience hypertension, hyperaldosteronism, and hyperkalemia secondary to renin secretion by tumor cells,4 which are evident as rhomboid-shaped renin protogranules on electron microscopic examination.5 The immunohistochemical profile has been recently reported as immunoreactive for vimentin, focally immunoreactive for smooth muscle actin, and negative for cytokeratin. CD34 immunoreactivity has recently been reported to be a helpful marker for the diagnosis of JGCT.2,6 CD34-positive gastrointestinal tumors are often immunoreactive for CD117, and CD117 immunoreactivity has also been reported in other than gastrointestinal tumors. However, the results of CD117 immunohistochemistry in JGCT have not been reported. We report the use of CD34 and CD117 immunohistochemistry to diagnose JGCT in 5 cases.
MATERIALS AND METHODS
Four cases of JGCT were retrieved from the surgical file and consultation file of the University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea, from January 2000 to June 2004. One case was retrieved from the archives of The Methodist Hospital in Houston, Tex. Two consultation cases from the Asan Medical Center had been previously reported.3,6 Formalin-fixed, paraffin-embedded sections had been stained with hematoxylin-eosin for routine microscopic examination. Tumors were assessed for growth pattern, nuclear atypia, mitotic activity, and necrosis. Nuclear pleomorphism was defined as more than 3-fold variation in nuclear size. Mitotic activity was determined at the high-power (×400) field.
Formalin-fixed, paraffin-embedded tissue sections were available for all cases for immunohistochemical study and electron microscopic examination. Specimens were immunostained with smooth muscle actin (1:100; Dinona, Seoul, Korea), vimentin (1: 2000; Zymed, San Francisco, Calif), cytokeratin (1:100 AE1/AE3; Zymed; 1:50 MNF116; Dako, Carpinteria, Calif), HMB-45 (1:100; Dako), CD34 (1:500; Immunotech, Marseille, France), CD117 (1: 400; Dako), and renin (polyclonal antibody of rat, University of Florida, Gainesville) using a standard avidin-biotin complex technique. Slides were processed using a Benchmark autostainer (Ventana, Tucson, Ariz). Ultrastructural analysis was performed in all cases using glutaraldehyde-fixed tissue after deparaffinization of the paraffin-embedded sections.
Clinical and follow-up data were obtained from the medical records or patients' outside physicians.
Three women and 2 men were included in this study (Table 1). The mean age at the diagnosis of JGCT was 37.8 years (range, 16–60 years). Four patients (cases 2 to 5) had taken antihypertensive drugs for severe hypertension. In case 1, hypertension was diagnosed during and attributed to pregnancy. The patient remained hypertensive for 2 years after delivery, despite intermittent use of antihypertensive medication. She began to experience abdominal pain, and computed tomography of the abdomen disclosed a 6-cm renal mass. Two patients (cases 1 and 4) presented with generalized edema and one patient (case 2) with an abdominal pain. The other patient (case 3) had no symptom other than hypertension. Three patients (cases 1, 2, and 4) were treated with radical nephrectomy, and 2 patients (cases 3 and 5) with partial nephrectomy. All patients were followed up for 6 to 43 months (mean, 26 months), and no tumors recurred. One patient (case 3) continued to experience mild hypertension that was well controlled with an antihypertensive therapy, and the remaining patients were normotensive postoperatively without an antihypertensive medication.
On computed tomography, all 5 tumors were well defined and had internal foci of low attenuation. Their appearance was suspicious for renal cell carcinoma or angiomyolipoma (Figure 1).
Gross features were determined from surgical specimens in 2 cases treated at the Asan Medical Center hospital, and 1 case at The Methodist Hospital in Houston, Tex, and gross photographs in the 2 consultation cases. Four tumors were located in the right kidney and 1 in the left kidney. The tumors ranged in size from 1.5 cm to 8.5 cm (mean, 4.4 cm). All tumors were confined to the renal parenchyma and were solitary, well circumscribed, and at least partially surrounded by a fibrous capsule. The cut surfaces were whitish gray to gray-tan, granular, and soft, with areas of hemorrhage (Figure 2). No necrosis was present. Tumor involvement of the mucosa of the renal pelvis, calyces, or ureter was not seen in any case.
On microscopic examination, the tumors were well circumscribed, at least partially surrounded by a thick fibrous capsule, and composed of solid sheets of closely packed uniform round-to-polygonal cells with oval-to-round irregular nuclei, pale-to-eosinophilic cytoplasm, inconspicuous nucleoli, and ill-defined cell borders. The nuclei varied in size but did not exhibit pleomorphism (Figure 3). Mitotic activity was not identified. The vasculature was well developed; focally, it had a hemangiopericytic pattern (Figure 4). In some areas, microcystic change and interstitial hemorrhage without evidence of necrosis were present.
Immunohistochemistry was performed in all cases. The neoplastic cells of tumors had diffuse and strong immunoreactivity for vimentin and CD34 (Figure 5, a), weak immunoreactivity for renin (Figure 5, b), and focal immunoreactivity for smooth muscle actin (Figure 5, c) and CD117 (Figure 5, d), but were negative for cytokeratin and HMB-45.
Ultrastructural examination revealed polygonal tumor cells with oval-to-round nuclei and dispersed chromatin. The cytoplasm contained abundant rough endoplasmic reticula, prominent Golgi apparatuses, and a few discrete rhomboid-shaped renin protogranules (Figure 6).
Our study further confirms the unique clinical, morphologic, immunohistochemical, and ultrastructural features of JGCT. The clinicopathologic features of the previously reported 70 cases compared with those of our study are summarized in Table 2.2 Clinically, these tumors typically occur in young adults (mean age, 26.8 years), with a female predominance (female-to-male ratio, 1.5:1). Patients almost invariably are hypertensive at initial examination owing to renin secretion by the tumor. One patient in the literature was diagnosed with JGCT during pregnancy,7 which also occurred in 1 case in our series.
No recurrences of JGCT have been reported, to our knowledge, with either radical or partial nephrectomy. In our series, all patients were alive with no recurrences at last follow-up. Blood pressure had returned to normal levels postoperatively in 4 patients but not in 1 patient (case 3). Approximately 10% of previously reported patients with this tumor have remained mildly hypertensive after resection of the tumor, and, in rare cases, the condition has progressed to renal failure.2
Grossly, these tumors are well circumscribed and often encapsulated within the renal cortex. Because the morphologic features of JGCT vary, the diagnosis can be difficult when using only routine hematoxylin-eosin–stained sections in young adults, especially if clinical history of hypertension is not provided. A common pattern of JGCT is an irregular trabecular arrangement of round-to-polygonal tumor cells in loose myxoid stroma. The neoplastic cells are relatively uniform, with abundant, granular, and acidophilic cytoplasm. Nuclei are oval to round, with uniformly distributed chromatin. Mitotic features are rare to absent. Tubules and cysts can be present. A lymphocytic infiltrate may be conspicuous, particularly at the periphery of the tumor. Characteristically, there is prominent vascularity resembling hemangiopericytoma. Because of the prominent hemangiopericytic pattern in JGCT, solitary fibrous tumor and hemangiopericytoma should be included in the differential diagnosis. Because these tumors are CD34 positive, it may be difficult to distinguish JGCT from a solitary fibrous tumor or hemangiopericytoma solely on the basis of light microscopic and immunohistochemical examination. A clinical history of hypertension, immunohistochemical detection of renin, and electron microscopic findings of rhomboid crystals are diagnostic features of JGCT. Positive immunoreactivity for renin has been also found in renal cell carcinomas8 and Wilms tumors, some of which may cause hypertension9,10; therefore, one should be aware of possible association with renin immunoreactivity and hypertension in these tumors to avoid diagnostic confusion.
CD34 is known to be expressed on hematopoietic stem cells, endothelial cells, interstitial cells of Cajal, dendritic cells in dermis, mast cells, and cells around vessels and in the nerve sheaths. CD34 expression has also been well documented in vascular tumor, Kaposi sarcoma, dermatofibrosarcoma protuberans, malignant peripheral nerve sheath tumor, gastrointestinal stromal tumor, and epithelioid sarcoma. To our knowledge, Kim et al6 were the first to use CD34 immunoreactivity in JGCT; they found a strong and diffuse reaction, and, thus, determined that JGCT was another CD34-positive tumor. This observation was further supported by a recent study.2 The cases in our current study were immunoreactive for CD34, renin, and vimentin. The tumor cells were also immunoreactive for smooth muscle actin and c-Kit (CD117), but were negative for cytokeratin and HMB-45.11
We tested the tumors for CD117 immunoreactivity because many different tumors coexpress CD34 and CD117. All of the JGCTs in our study were immunoreactive for CD117, although the reactivity was focal. The surrounding tubular epithelial cells in the cortex and mast cells were used as internal positive controls in our study, as described in the previous literature.12 Some studies on c-Kit overexpression in renal neoplasms have been reported, focusing on differential diagnosis between conventional and chromophobe renal cell carcinomas.13–15 In addition, there have been recent studies on c-Kit immunoreactivity in renal angiomyolipomas,16 as well as other types of renal cell carcinomas.17,18 However, c-Kit immunoreactivity has not been reported in JGCT.
In summary, on the basis of our findings as well as the findings from the previous reports, CD34, and possibly CD117, immunoreactivity is useful in diagnosing JGCT. In cases of unusual epithelioid tumors of the kidney with negative cytokeratin immunoreactivity at the initial screening, JGCT should be considered and immunohistochemistry with CD34, in addition to vimentin and smooth muscle actin, is recommended for diagnosis. Our study demonstrated that CD117 may be a useful immunohistochemical marker, but its diagnostic effectiveness should be validated with future studies. Until then, JGCT should be diagnosed by positive immunoreactivity for renin and demonstration of characteristic renin protogranules by electron microscopic examination, in conjunction with clinical findings.
The authors have no relevant financial interest in the products or companies described in this article.
Presented in part at the 93rd Annual Meeting of the United States and Canadian Academy of Pathology, Vancouver, British Columbia, March 2004.
Reprints: Jae Y. Ro, MD, PhD, Department of Pathology, Weill Cornell University, The Methodist Hospital, 6565 Fannin, M243, Houston, TX 77030 (email@example.com)