Oligometastatic Renal Cell Carcinoma With Sarcomatoid ...

Case Report

Oligometastatic Renal Cell Carcinoma With Sarcomatoid Differentiation Demonstrating Variable Imaging Phenotypes on 68Ga-PSMA and 18 F-FDG PET/CT: A Case Report and Review of the Literature David P. Nadebaum,1 Michael S. Hofman,1,2 Catherine A. Mitchell,3 Shankar Siva,2,4 Rodney J. Hicks1,2 Clinical Practice Points Sarcomatoid differentiation is observed in approxi-

Conversely, a rapidly growing pulmonary metastasis

mately 5% of renal cell carcinomas (RCCs) and is an adverse prognostic factor. The molecular imaging characteristics of sarcomatoid RCC remain largely unknown, with limited case reports describing intense uptake on 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). We present a patient with oligometastatic clear cell RCC with sarcomatoid differentiation, who had 2 subpopulations of disease with different imaging phenotypes on 68Ga-prostate-specific membrane antigen (PSMA) and 18F-FDG PET/computed tomography. A slowly growing site of local disease recurrence showed intense 68Ga-PSMA avidity and low-intensity 18 F-FDG uptake.

with confirmed sarcomatoid differentiation was intensely 18F-FDG avid, but showed near absent 68 Ga-PSMA uptake with corresponding high GLUT-1 and absent PSMA staining on immunohistochemistry. The case suggests that sarcomatoid differentiation is associated with a loss of PSMA expression from the neovasculature, with an opposing upregulation of GLUT-1 transporter expression. This ‘flip-flop’ phenomenon, in which the molecular imaging phenotype shifts as de-differentiation occurs, highlights the utility of PET to characterize heterogeneity between individual sites of metastatic disease in vivo.

Clinical Genitourinary Cancer, Vol. 16, No. 1, 1-5 ª 2017 Elsevier Inc. All rights reserved. Keywords: Fluorodeoxyglucose, Molecular imaging, Positron emission tomography, Prostate-specific membrane antigen, Renal cell carcinoma

Introduction 1

Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia 2 The Sir Peter MacCallum Department of Oncology, the University of Melbourne, Parkville, Victoria, Australia 3 Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia 4 Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia Submitted: Aug 10, 2017; Accepted: Aug 13, 2017; Epub: Aug 23, 2017 Address for correspondence: Dr Michael S. Hofman, MBBS, FRACP, FAANMS, Department of Cancer Imaging, Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, Victoria, 3000, Australia E-mail contact: [email protected]

1558-7673/$ - see frontmatter ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2017.08.009

Sarcomatoid differentiation is observed in approximately 5% of renal cell carcinomas (RCC) and is defined by the identification of high-grade spindle cells on histopathology.1 It can arise in all RCC neoplasms, including the clear cell and chrxomophobe subtypes, and can involve a variable proportion of total cell mass.2 Sarcomatoid differentiation is an adverse prognostic indicator, with a 5-year cancer-specific survival rate of 22%.2 Prognosis appears dependent on the extent of sarcomatoid differentiation, with lower percentages of sarcomatoid elements (< 20% tumor mass) being associated with more favorable long-term outcomes and possibly better response to systemic therapy.2,3

Clinical Genitourinary Cancer February 2018

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RCC Imaging Phenotype Heterogeneity Case Report The patient was a 58-year-old woman who was diagnosed with RCC during the investigation of a chronic cough, anemia, and raised inflammatory markers. Contrast-enhanced computed tomography (CT) demonstrated no definite evidence of distant metastatic disease; however, note was made of a 3-mm right upper

lobe pulmonary nodule for which imaging follow-up was recommended. The patient proceeded to right nephrectomy without complication. Histopathology demonstrated a 72-mm partially hemorrhagic/necrotic clear cell RCC (Fuhrman grade 4). On subsequent serial CT imaging, the right upper lobe pulmonary nodule increased to 19-mm diameter at 9 months post-diagnosis, with

Figure 1 Maximum Intensity Projection Images of the 18F-FDG (A) and 68Ga-PSMA (B) PET/CT Studies and Transaxial Sections Through the Enlarging Pulmonary Nodules (1, 1A, 1B) and Site of Nephrectomy Bed Recurrence (2, 2A, 2B). The Pulmonary Metastases With 100% Sarcomatoid Differentiation Showed Intense 18F-FDG Uptake (1A) But Very Low PSMA Expression (1B) on PET/CT. Conversely, the Site of Nephrectomy Bed Recurrence With Likely Low Sarcomatoid Differentiation Showed Relatively Low 18F-FDG Uptake (2A) But Intense PSMA Avidity (2B)

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Abbreviations: CT ¼ computed tomography; FDG ¼ fluorodeoxyglucose; PET ¼ positron emission tomography; PSMA ¼ prostate-specific membrane antigen.


David P. Nadebaum et al development of 2 new adjacent pulmonary nodules. In view of apparently oligometastatic disease, treatment with curative intent was contemplated. Suitable local treatment options considered included surgery, stereotactic ablative radiotherapy, and percutaneous thermal ablation. Accordingly, 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) was performed to exclude occult widespread metastatic disease. The coalescent cluster of enlarging pulmonary nodules demonstrated intense 18 F-FDG uptake (maximum standardized uptake value [SUVmax], 17.3), in addition to a focus of mild uptake (SUVmax, 4.2) identified inferior to the right nephrectomy bed (Figure 1). The latter was further evaluated with magnetic resonance imaging, which demonstrated a 3.1-cm mass infiltrating the right psoas muscle, compatible with local disease recurrence (Figure 2). 68 Ga-prostate specific membrane antigen (PSMA)-HBED-CC PET/CT was subsequently performed to further characterize this lesion (Figure 1). This demonstrated very intense 68Ga-PSMA uptake within the site of local recurrence in the nephrectomy bed (SUVmax, 16.1), but minimal 68Ga-PSMA uptake within the rapidly enlarging cluster of pulmonary nodules (SUVmax, 4.4). The contrasting imaging phenotypes were hypothesized to represent 2 discrete populations of RCC metastases, with more poorly differentiated disease suspected in the lung. This was confirmed on subsequent core lung biopsy, which demonstrated infiltration by tumor composed of malignant spindle cells, with immunophenotype compatible with a sarcomatoid RCC metastasis. Immunohistochemical staining showed near absent PSMA expression but strong GLUT-1 expression (Figure 3). The unexpected histopathologic finding prompted rereview of the patient’s original nephrectomy specimen, which in retrospect was found to have sarcomatoid components comprising up to 20% of total cell mass. This specimen was also stained, demonstrating intense PSMA expression in the primary tumor’s neovasculature but more modest GLUT-1 expression (Figure 3). The patient subsequently underwent treatment for oligometastatic disease in the context of an institutional clinical trial, which included single fraction stereotactic ablative radiotherapy (20 Gy) to the right lung metastases and external beam radiotherapy (30 Gy, 10 fractions) to the nephrectomy bed recurrence in addition to antiPD1 immunotherapy.

Discussion Molecular imaging has traditionally had a limited role in the imaging of renal cell carcinomas, with clinical practice guidelines currently recommending contrast-enhanced CT be used as the firstline investigation tool in both staging and restaging RCC.4 This is largely attributable to the variable 18F-FDG avidity of RCC, with 18 F-FDG PET demonstrating only modest sensitivity for detecting sites of metastatic disease.5 18F-FDG PET has nonetheless shown prognostic utility in RCC, with low 18F-FDG avidity being associated with more favorable clinical outcomes.6 There is also emerging evidence that 68Ga-PSMA PET/CT may also have utility in imaging RCC. Although this radiotracer was originally developed and evaluated in prostate cancer, clear-cell RCC also demonstrates very high tumor uptake owing to the expression of PSMA within tumor neovasculature.7 There is now preliminary evidence that PSMA PET/CT may have value for staging, restaging, and response assessment in RCC,8-10 with the technology possibly exhibiting higher sensitivity compared with conventional imaging.8 The molecular imaging phenotype of sarcomatoid RCC is, however, less well-established, with only limited case reports describing intense 18F-FDG uptake within sites of rapidly progressive sarcomatoid metastases on 18F-FDG PET.11,12 The 18FFDG avidity of this tumor underlies its aggressive behavior and also mirrors the imaging characteristics of sarcoma, for which the clinical role of 18F-FDG PET is well-established.13 It remains unclear, however, whether 18F-FDG avidity is seen across the spectrum of sarcomatoid RCC, particularly those with lower levels of sarcomatoid differentiation. Furthermore, to our knowledge, the imaging characteristics of sarcomatoid RCC with 68Ga-PSMA PET/CT have not been previously described. The case presented suggests the imaging phenotype of sarcomatoid RCC shifts with increasing levels of sarcomatoid differentiation. The patient’s more slow-growing site of nephrectomy bed recurrence, which had likely low levels of sarcomatoid differentiation, showed only moderate 18F-FDG uptake but relatively intense 68Ga-PSMA avidity on PET, which corresponded to significant PSMA expression throughout the primary tumor’s neovasculature on histopathology. Conversely, the rapidly growing pulmonary metastases showed intense 18F-FDG avidity and near absent 68Ga-PSMA uptake, which

Figure 2 Further Characterization of the Right Psoas Lesion on Magnetic Resonance Imaging, Which Appears Hypointense on T1 (A) and Demonstrates Intense Contrast Enhancement, Consistent With Neovascularization (B). The Lesion Shows Infiltration of the Anterior Psoas Margin, Compatible With Local Malignant Recurrence Inferior to the Right Nephrectomy Bed


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RCC Imaging Phenotype Heterogeneity Figure 3 Histopathology of the Lung Metastasis With 100% Sarcomatoid Differentiation (A and B) and the Original Nephrectomy Specimen Demonstrating Clear Cell RCC With More Limited Sarcomatoid Components (C and D), All 1003 Original Magnification. The Lung Metastasis Shows Near Absent PSMA Staining (A); However, It Demonstrates Very Intense GLUT-1 Expression (B). In Contrast, the Primary RCC Demonstrates Intense PSMA Expression in the Neovasculature (C) and Only Moderate GLUT-1 Staining (D)

Abbreviations: PSMA ¼ prostate-specific membrane antigen; RCC ¼ renal cell carcinoma.

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too mirrored the histopathologic findings (ie, upregulation of the GLUT-1 transporter and loss of PSMA expression). This case study provides yet another example of the so-called ‘flip-flop’ phenomenon, in which the molecular imaging phenotype of a malignancy changes as it de-differentiates into a more aggressive form of the disease. This phenomenon is observed in a wide range of cancers but is perhaps best recognized in thyroid and neuroendocrine malignancies, in which de-differentiation is associated with the loss of Na/iodide symporter or somatostatin receptor expression respectively, and upregulation of the GLUT-1 transporter.14,15 In addition to heralding tumor de-differentiation, 18 F-FDG avidity has important prognostic implications for disease behavior and patient outcome. The intensity of 18F-FDG uptake (ie, SUVmax) has been found to be a powerful independent prognostic factor in a range of malignancies,6,16-18 and may even be superior to histopathology as a prognostic marker in neuroendocrine tumors.17 The case study described above suggests the same principle applies for sarcomatoid RCC, which similarly loses its more typical expression of PSMA and upregulates GLUT-1 expression with increasing levels of sarcomatoid differentiation. The case also illustrates the power of PET/CT to characterize the properties of individual metastases in vivo in patients with stage IV disease. Cancer is a heterogeneous disease comprising a range of clonal subpopulations with variable collections of genetic mutations.19 As a


consequence, individual metastatic deposits can exhibit highly variable disease behavior, which is difficult to characterize on conventional imaging. Molecular imaging, however, allows the level of differentiation and aggressiveness of individual metastases to be assessed on a whole body level, enabling clinicians to identify metastases that are phenotypically discordant with the remainder of the patient’s disease. Directed biopsy of discordant sites can then be performed to further characterize disease. In the case study presented, the combination of 18F-FDG and 68Ga-PSMA PET/CT studies helped identify a site of local recurrence occult on CT, and to characterize the aggressive de-differentiated pulmonary metastases. The PET/CT information also led to the identification of the malignancy’s previously unrecognized sarcomatoid components, which has important prognostic and future management implications for the patient. In contrast to clear-cell RCC, data surrounding systemic treatment options for sarcomatoid RCC is very limited. Therefore, local extirpative or ablative therapies for limited metastatic disease maybe conceptually advantageous for this disease.

Conclusion We describe a patient with sarcomatoid RCC demonstrating a ‘flip-flop’ phenomenon on 68Ga-PSMA and 18F-FDG PET/CT. A slowly growing site of local disease recurrence with low levels of sarcomatoid differentiation showed an imaging phenotype typical of

David P. Nadebaum et al its predominant clear-cell components (ie, intense 68Ga-PSMA expression with relatively poor 18F-FDG avidity). In contrast, the rapidly progressive pulmonary metastases with 100% sarcomatoid differentiation showed loss of 68Ga-PSMA expression but intense 18 F-FDG uptake. Each imaging phenotype was corroborated by immunohistochemistry. This suggests the imaging phenotype of sarcomatoid RCC shifts as it de-differentiates into a more aggressive form, and also illustrates the power of molecular imaging to characterize individual sites of metastatic disease in vivo.

Acknowledgments This research did not receive a direct grant from funding agencies in the public, commercial, or not-for-profit sectors. Michael Hofman is supported by a Movember Clinical Trials Award awarded through the Prostate Cancer Foundation of Australia’s Research Program, and also a Clinical Fellowship Award from the Peter MacCallum Foundation. Shankar Siva is supported by a National Health and Medical Research Council Fellowship. Rodney Hicks is supported by a National Health and Medical Research Council Practitioner Fellowship.

Disclosure The authors have stated that they have no conflicts of interest.

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