DOI: 10.1148/rg.276075013
RadioGraphics 2007;27:1801-1807
© RSNA, 2007
Best Cases from the AFIP
Metastatic Renal Cell Carcinoma1
Shao-Pow Lin, MD, PhD,
Andrew J. Bierhals, MD, MPH, and
James S. Lewis, Jr, MD
1 From the Mallinckrodt Institute of Radiology (S.-P.L., A.J.B.) and Department of Pathology and Immunology (J.S.L.), Washington University School of Medicine, 510 S Kingshighway Blvd, St Louis, MO 63110. Received January 30, 2007; revision requested March 13 and received April 30; accepted May 9. All authors have no financial relationships to disclose.
Address correspondence to S.-P.L. (e-mail: lins{at}mir.wustl.edu).
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History
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A 59-year-old man with a history of hypertension presented with flu-like symptoms to his primary care physician. The most significant of these symptoms was a dry cough that had persisted for 1 week. Results of the patient’s physical examination, complete metabolic panel, complete blood count, and urinalysis were all normal; however, a chest radiograph depicted a pulmonary nodule. The patient subsequently underwent further imaging evaluation.
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Imaging Findings
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The initial two-view chest radiographic study demonstrated a nodule in the lingula approximately 3 cm in diameter (Fig 1). This finding was initially followed up with chest computed tomography (CT), and the results were suggestive of a primary bronchogenic carcinoma (images not available). The patient was subsequently referred to our institution for thoracic surgical consultation. Further work-up with both CT-guided percutaneous biopsy for tissue diagnosis and combined positron emission tomography/noncontrast CT (PET/CT) for staging was requested.
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Figure 1a. Posteroanterior (a) and lateral (b) radiographs of the chest in a 59-year-old man with flu-like symptoms demonstrate a lingular nodule approximately 3 cm in diameter (arrow).
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Figure 1b. Posteroanterior (a) and lateral (b) radiographs of the chest in a 59-year-old man with flu-like symptoms demonstrate a lingular nodule approximately 3 cm in diameter (arrow).
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For logistical reasons, PET/CT was performed prior to the biopsy, which was subsequently canceled. PET/CT revealed multiple small pulmonary nodules throughout both lungs in addition to the dominant nodule seen on chest radiographs. None of the nodules demonstrated increased uptake of fluorine 18 (18F) fluorodeoxyglucose (FDG). Within the abdomen there was mildly increased FDG uptake in a solid, 4-cm diameter exophytic lesion arising from the posterior cortex of the left kidney. The kidneys were otherwise normal in size and configuration with no hydronephrosis present. Nodularity was also noted in the tail of the pancreas, but with no FDG uptake (Fig 2).
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Figure 2a. (a, b) PET/CT scans do not show increased FDG uptake in either the dominant pulmonary nodule (a) or in a nodule in the pancreatic tail (b). (c) PET/CT scan obtained at a lower level shows mildly increased FDG uptake within a 4-cm-diameter lesion arising from the left kidney (arrow).
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Figure 2b. (a, b) PET/CT scans do not show increased FDG uptake in either the dominant pulmonary nodule (a) or in a nodule in the pancreatic tail (b). (c) PET/CT scan obtained at a lower level shows mildly increased FDG uptake within a 4-cm-diameter lesion arising from the left kidney (arrow).
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Figure 2c. (a, b) PET/CT scans do not show increased FDG uptake in either the dominant pulmonary nodule (a) or in a nodule in the pancreatic tail (b). (c) PET/CT scan obtained at a lower level shows mildly increased FDG uptake within a 4-cm-diameter lesion arising from the left kidney (arrow).
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Based on the PET/CT findings, which were suggestive of a primary renal cell carcinoma with distant metastases, three-phase contrast-enhanced CT of the abdomen and pelvis was performed. The left renal mass enhanced heterogeneously in a relatively arterial phase of contrast material administration, a pattern that suggested hypervascularity (Fig 3). Before the contrast media injection, the mass averaged 35 Hounsfield units (HU); it increased to 153 HU in the cortical phase and decreased slightly to 102 HU in the nephrographic phase. In addition, an approximately 2-cm, hypervascular nodule was identified in the tail of the pancreas. Its attenuation varied from 18 to 184 to 122 HU during the precontrast, cortical, and nephrographic phases of contrast enhancement, respectively. Although imaging of the lung bases was limited in this study, evaluation of the largest visualized pulmonary nodule in the right base demonstrated similar hypervascularity, with attenuation ranging from 50 to 227 to 115 HU during the three phases of enhancement (Fig 4).
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Figure 3a. Axial (a), coronal (b), and sagittal (c) CT images acquired during the cortical phase of contrast material enhancement show a left renal mass. The mass was well-defined, exophytic (appearing to arise from the cortex), and heterogeneously and avidly enhancing.
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Figure 3b. Axial (a), coronal (b), and sagittal (c) CT images acquired during the cortical phase of contrast material enhancement show a left renal mass. The mass was well-defined, exophytic (appearing to arise from the cortex), and heterogeneously and avidly enhancing.
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Figure 3c. Axial (a), coronal (b), and sagittal (c) CT images acquired during the cortical phase of contrast material enhancement show a left renal mass. The mass was well-defined, exophytic (appearing to arise from the cortex), and heterogeneously and avidly enhancing.
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Figure 4a. (a, b) Cortical (a) and nephrographic (b) phase CT images demonstrate the left renal lesion. (c, d) Cortical (arterial) phase images reveal the pancreatic tail nodule (c) and one of numerous pulmonary nodules (d). All lesions demonstrated the characteristic hypervascularity expected from clear cell renal cell carcinoma.
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Figure 4b. (a, b) Cortical (a) and nephrographic (b) phase CT images demonstrate the left renal lesion. (c, d) Cortical (arterial) phase images reveal the pancreatic tail nodule (c) and one of numerous pulmonary nodules (d). All lesions demonstrated the characteristic hypervascularity expected from clear cell renal cell carcinoma.
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Figure 4c. (a, b) Cortical (a) and nephrographic (b) phase CT images demonstrate the left renal lesion. (c, d) Cortical (arterial) phase images reveal the pancreatic tail nodule (c) and one of numerous pulmonary nodules (d). All lesions demonstrated the characteristic hypervascularity expected from clear cell renal cell carcinoma.
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Figure 4d. (a, b) Cortical (a) and nephrographic (b) phase CT images demonstrate the left renal lesion. (c, d) Cortical (arterial) phase images reveal the pancreatic tail nodule (c) and one of numerous pulmonary nodules (d). All lesions demonstrated the characteristic hypervascularity expected from clear cell renal cell carcinoma.
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Pathologic Evaluation
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Given that all of the imaging findings were consistent with the diagnosis of metastatic renal cell carcinoma, the patient underwent a laparoscopic left radical nephrectomy; the Gerota fascia was also removed. The adrenal gland was spared. Gross examination of the excised kidney revealed a raised area at the upper pole that did not involve the overlying adipose tissue. Bisection uncovered a 3.8-cm, heterogeneous yellow-red mass that extended to and bulged beneath, but did not penetrate, the renal capsule (Fig 5). The remaining renal parenchyma was light tan with normal renal pyramids and a normal collecting system. At gross inspection, the renal pelvis and associated vasculature appeared free of tumor.
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Figure 5. Gross photograph of the laparoscopically excised and bisected left kidney shows a heterogeneous, yellow-red mass in the upper pole. The mass expanded, but did not penetrate, the renal capsule.
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Microscopic evaluation showed a typical clear cell–type renal cell carcinoma (Fig 6). The tumor was well-circumscribed with a fibrous capsule and consisted of sheets of clear cells with prominent vessels in between. The tumor cells had round to oval nuclei with irregular contours and focally prominent nucleoli. Focally, tumor cells had large, hyperchromatic nuclei with multinucleated giant cells, a more eosinophilic cytoplasm, and associated areas of necrosis. These areas constituted a Fuhrman Nuclear Grade of III–IV out of IV. No vascular invasion or capsular penetration was identified, no hilar nodes were submitted or subsequently found, and the resection margins were widely free of tumor.
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Figure 6a. (a) Photomicrograph (original magnification, x4; hematoxylin-eosin [H-E] stain) demonstrates sheets of clear cells with intervening vasculature and a well-circumscribed fibrous capsule (arrows). (b, c) Higher power photomicrographs (b, original magnification, x20; H-E stain) show prominent nucleoli within the tumor cells (arrows) and (c, original magnification, x40; H-E stain) hyperchromatic nuclei with multinucleated giant cells (arrows). (d) Photomicrograph (original magnification, x10; H-E stain) also reveals areas of necrosis (N) within the tumor.
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Figure 6b. (a) Photomicrograph (original magnification, x4; hematoxylin-eosin [H-E] stain) demonstrates sheets of clear cells with intervening vasculature and a well-circumscribed fibrous capsule (arrows). (b, c) Higher power photomicrographs (b, original magnification, x20; H-E stain) show prominent nucleoli within the tumor cells (arrows) and (c, original magnification, x40; H-E stain) hyperchromatic nuclei with multinucleated giant cells (arrows). (d) Photomicrograph (original magnification, x10; H-E stain) also reveals areas of necrosis (N) within the tumor.
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Figure 6c. (a) Photomicrograph (original magnification, x4; hematoxylin-eosin [H-E] stain) demonstrates sheets of clear cells with intervening vasculature and a well-circumscribed fibrous capsule (arrows). (b, c) Higher power photomicrographs (b, original magnification, x20; H-E stain) show prominent nucleoli within the tumor cells (arrows) and (c, original magnification, x40; H-E stain) hyperchromatic nuclei with multinucleated giant cells (arrows). (d) Photomicrograph (original magnification, x10; H-E stain) also reveals areas of necrosis (N) within the tumor.
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Figure 6d. (a) Photomicrograph (original magnification, x4; hematoxylin-eosin [H-E] stain) demonstrates sheets of clear cells with intervening vasculature and a well-circumscribed fibrous capsule (arrows). (b, c) Higher power photomicrographs (b, original magnification, x20; H-E stain) show prominent nucleoli within the tumor cells (arrows) and (c, original magnification, x40; H-E stain) hyperchromatic nuclei with multinucleated giant cells (arrows). (d) Photomicrograph (original magnification, x10; H-E stain) also reveals areas of necrosis (N) within the tumor.
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Discussion
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When renal cell carcinoma manifests with its classic symptoms of hematuria or flank pain, the standard work-up generally begins with either abdominal CT or ultrasonography, followed by three-phase contrast-enhanced CT for staging and surgical planning (1). Currently, magnetic resonance (MR) imaging is generally reserved for problem solving or is used as an adjunct for surgical planning, MR angiography in particular. PET imaging is not a component of the typical evaluation for renal cell carcinoma. Given the increased utilization of cross-sectional imaging, roughly half of all renal cell carcinomas are now detected incidentally during the work-up of unrelated symptoms (1,2). In this particular case, the detection of a lung mass initiated a staging work-up with PET/CT for presumed lung cancer. Only after the primary neoplasm within the left kidney was identified was the standard evaluation with three-phase CT performed for renal cell carcinoma.
Renal cell carcinoma is by far the most common renal neoplasm; it accounts for 85% of all renal malignancies. The clear cell variety is the most common histologic subtype and accounts for 70% of renal cell carcinomas (3). These "conventional" renal cell carcinomas, as they were previously called, are believed to derive from the epithelium of the proximal convoluted tubules, hence their typical cortical location and their expansile growth. Glycogen and lipid-laden neoplastic cells give these tumors a yellowish gross coloration, with "clear cells" seen histologically after the lipids dissolve during tissue processing. Macroscopic areas of necrosis, hemorrhage, cystic changes, and calcifications result in a typically heterogeneous appearance on images. In addition, the characteristic development of a network of small sinusoid-like blood vessels imparts the classic finding of hypervascularity on contrast-enhanced images, particularly in the cortical phase of enhancement (4,5). Recent advances in the field of cancer genetics have shown that there are distinct genomic markers for the different histopathologic subtypes of renal cell carcinoma. In particular, increased microvessel density in the clear cell type is believed to be due to inactivation of tumor suppressor genes, particularly the von Hippel–Lindau gene, which results in overexpression of a number of hypoxia-inducible genes, including vascular endothelial growth factor (6). Interestingly, there is also evidence to suggest that the predilection for metastasis may be encoded in the genome of the primary neoplasm as well, with clear prognostic implications for the management of patients with localized tumor (7,8).
Unfortunately, because renal cell carcinoma tends to cause few, if any, early symptoms, only 50% of patients with clear cell renal cell carcinoma present in stage I or stage II (Table). The most common sites for metastasis are the lung, liver, lymph nodes, and bones (3,9,10). Other sites include the pancreas, adrenal gland, contralateral kidney, and brain. Although FDG PET has proved to be an invaluable tool in staging a variety of cancer types such as lung, breast, lymphoma, colorectal, and head and neck, it currently has a limited role in evaluating renal cell carcinoma. Several retrospective studies have shown that the sensitivity of conventional FDG PET (not PET/CT) is inferior to that of CT and MR imaging, despite its high specificity (and hence positive predictive value) for malignancy in the evaluation of suspicious primary or metastatic renal cell carcinoma. FDG PET surpasses the 90% sensitivity mark only for lesions at least 2 cm in diameter (10–12). Although there are studies that report sensitivity of FDG PET to be as high as 94% (13), it is generally accepted that malignancy cannot be ruled out with a negative study (14,15). Renal cell carcinomas have inconsistent FDG uptake, which may be due to hypo- or isometabolism relative to background tissues, lack of accessibility of FDG, or heterogeneity of glucose transporter expression.
Although it was not required in this case, renal cell carcinoma can also be readily detected and diagnosed with MR imaging. In general, the majority of renal cell carcinomas are isointense relative to normal kidney on both T1- and T2-weighted images (16); however, as with CT, hypervascularity increases conspicuity significantly on contrast-enhanced images. In addition, the diagnosis of clear cell–type renal cell carcinoma can be aided by the finding of microscopic fat, which causes signal loss on opposed-phase images (17).
In addition to clear cell renal cell carcinoma, papillary renal cell carcinoma—the second most common histologic subtype of the 11 described by the World Health Organization—warrants specific mention. It accounts for another 10%–15% of all renal cell carcinomas, and like the clear cell subtype, these tumors are believed to derive from the proximal convoluted tubular epithelium. The name derives from the histologic appearance of papillary growth around a fibrovascular core. In contradistinction to clear cell renal cell carcinoma, the papillary subtype has a tendency to appear homogeneous and hypovascular on contrast-enhanced images, with macroscopic necrosis, hemorrhage, cysts, and calcification typically seen only when the tumors are large (3). The remaining 15%–20% of renal cell carcinomas are divided between nine histologic subtypes. Imaging patterns worth recognizing (but which are not pathognomonic) include septated, variable-sized cysts with septal calcifications in multilocular cystic renal cell carcinoma; spokewheel enhancement in chromophobe renal cell carcinoma (possibly related to oncocytoma); and medullary-centered, infiltrative masses in collecting duct or renal medullary renal cell carcinoma (3).
In summary, renal cell carcinoma comprises a heterogeneous family of neoplasms that are not only common, but, owing to their relatively late manifestation, are often lethal. With improvements in cross-sectional imaging and increased imaging utilization, there has been an increase in frequency of detection of renal cell carcinomas and a concomitant migration toward earlier-stage lesions. When the tumor is still localized, the prognosis of patients with renal cell carcinoma is excellent, with a 5-year disease-free survival rate of 95% or better for patients with tumors with a 4-cm diameter. It is thus important for radiologists to be aware of the unique properties of this malignancy and how they appear on images from various modalities. The standard of care in these cases is partial or radical nephrectomy, either open or laparoscopic. Less invasive alternatives include radiofrequency ablation and cryotherapy; however, these approaches remain investigational (2).
The presence of distant metastatic disease at the time of diagnosis is a strong predictor of poor outcome, with a 5-year survival rate of 10%–20% (6,18). Less than 5% of metastatic renal cell carcinomas respond to chemotherapy, and the response rate to immunotherapy (interleukin-2 or interferon-
) is only 20% (19). One year after diagnosis and laparoscopic left nephrectomy, our patient is doing very well. His ongoing medical therapy consists of sunitinib (Sutent; Pfizer, New York, NY), an investigational multi-targeted tyrosine-kinase inhibitor that specifically inhibits receptors for both vascular endothelial growth factor and platelet-derived growth factor (19). Follow-up imaging has demonstrated interval decrease in the number and size of both lung and pancreatic metastases, with no evidence for recurrent or new disease.
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Acknowledgments
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The authors thank Eric Duncavage, MD, for his assistance in preparing images for case submission to the AFIP.
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Footnotes
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Abbreviations: PET/CT = positron emission tomography/computed tomography, FDG = fluorine 18 (18F) fluorodeoxyglucose
Editor’s Note.—Everyone who has taken the course in radiologic pathology at the Armed Forces Institute of Pathology (AFIP) remembers bringing beautifully illustrated cases for accession to the Institute. In recent years, the staff of the Department of Radiologic Pathology has judged the "best cases" by organ system, and recognition is given to the winners on the last day of the class. With each issue of RadioGraphics, one or more of these cases are published, written by the winning resident. Radiologic-pathologic correlation is emphasized, and the causes of the imaging signs of various diseases are illustrated.
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References
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History
Imaging Findings
