To the Editors:
Kaposi sarcoma (KS) is the most common neoplasm in HIV-positive patients. It is characterized by proliferating spindle cells, angiogenesis, inflammation, and edema. The human herpes virus 8 (HHV8) is one of the most important pathogenic factors. Together with HIV, HHV8 causes the activation of numerous both preexistent and virus-specific signal transduction pathways.1 KS usually presents with skin or oral lesions. However, systemic involvement is possible, particularly in the gastrointestinal tract and respiratory system, in which case systemic treatment is warranted to prevent potentially lethal hemorrhage. Because visceral lesions can be asymptomatic and radiologic findings are highly variable,2 endoscopy and bronchoscopy are recommended for their detection.3 These techniques are, however, invasive and therefore unattractive, and a biopsy to obtain histologic samples may be fraught with complications because of a high bleeding risk. An alternative, noninvasive staging and restaging method is wanted. We evaluated the potential of FDG-PET/CT imaging and Indium-111-bevacizumabscintigraphy to detect KS lesions and examined the correlation between immunohistochemically detected vascular endothelial growth factor (VEGF) expression and the in vivo targeting of radiolabeled bevazicumab in KS. FDG-PET scanning is a widely available technique based on increased glucose utilization of malignant cells in general as a major source of energy and carbons. Bevacizumab is a humanized monoclonal antibody that selectively binds with high affinity to all isoforms of human VEGF-A.4 After radiolabeling, it can be used as a radiopharmaceutical to detect the presence of VEGF in lesions.5 The VEGF pathway is involved in the pathogenesis of KS; VEGF-A,6,7 -C,6,8 and VEGF receptor-1, -2, and -36,8 are expressed in KS lesions and several clinical trials evaluating angiogenesis inhibition as a therapeutic target in KS are ongoing (www.clinicaltrials.gov identifiers NCT00923936 and NCT00686842). Indium-111-bevacizumabscintigraphy thus depicts a disease-specific process with possible therapeutic relevance.
With approval of the Institutional Review Board of the Radboud University Nijmegen Medical Centre, 3 patients with different stages of AIDS-associated KS were recruited. First, whole-body FDG-PET/CT was performed. Subsequently, VEGF expression was scintigraphically depicted 1 week after iv injection of Indium-111-labeled bevacizumab (100 MBq In-111, 1 mg of antibody).
Immunohistochemical staining of routinely obtained tissue samples was performed with a purified mouse anti-human VEGF-A antibody (BD Pharmingen # 555036, dilution 1:50, no antigen retrieval, detected with a goat anti-mouse IgG2B:Horse Radish Peroxidase (HRP) developed with diaminobenzidine). Expression was semiquantitatively scored ranging from undetectable (-), low (±), moderate (+), high (++) to very high (+++).
The first patient was a 58-year-old man with 100 HIV-RNA copies/mL, a CD4 count of 60 cells/μL, and National Institute of Health AIDS Clinical Trial Group (ACTG) stage T1 (I1) S16 poor risk7 KS. He had palpable enlarged inguinal lymph nodes and widespread cutaneous involvement of KS, affecting all extremities, the neck, ears, trunk, and perianal region. Gastroduodenoscopy revealed lesions in the stomach suspicious for KS. FDG-PET/CT (Fig. 1) revealed multiple cutaneous lesions and cervical, mediastinal, retroperitoneal, inguinal, pararectal, and intra-abdominal extracutaneous lesions. VEGF expression as determined by immunohistochemistry varied strongly between lesions (chest skin: ++, perianal region: +++ and −, penis: focal + and lymph nodes in the left axilla: +++). Focal uptake on the In-111-bevacizumabscans was noticed in the left leg area, colocalizing with the clinically visible and PET/CT positive cutaneous KS lesions (see Figure, Supplemental Digital Content 1, http://links.lww.com/QAI/A33). The second patient, a 37-year-old woman with 50 HIV-RNA copies/mL, a CD4 count of 750 cells/μL and ACTG stage T1 (I0) S06 good risk7 KS, had cutaneous KS lesions on all extremities. At physical examination no other signs of KS were found, especially no enlarged lymph nodes. FDG-PET/CT showed multiple cutaneous lesions, lymph node involvement in both axillae and inguinal regions and extracutaneous lesions in the right iliac fossa, in the left obturator region, and near the left femoral artery and vein. The diagnosis of KS was confirmed on multiple skin biopsies. Immunohistochemical staining revealed VEGF expression varying from + to ++. In-111-bevacizumab scintigraphy showed uptake in the left leg area and both axillae. Physical examination of the third patient, who was a 44-year-old man with <40 HIV-RNA copies/mL, a CD4 count of 710 cells/μL, and ACTG stage T0 (I0) S06 good risk7 KS, revealed cutaneous KS lesions on the back, lower arms, and lower legs. Skin biopsy was consistent with KS while staining for VEGF was weak. The patient was successfully treated with highly active antiretroviral therapy and all larger lesions had been treated by radiotherapy for cosmetic reasons. No lymphadenopathy was present at clinical examination. In this patient, no focal FDG uptake nor labeled bevacizumab uptake was seen.
In the present pilot study, FDG-PET/CT was effective in detecting clinically occult KS lesions that are difficult to diagnose with standard imaging techniques in more advanced stages of KS. The lack of FDG avidity in patient 3 may be explained by a smaller size of KS lesions and previous exposure to effective KS treatment. FDG-PET/CT findings in only 2 further cases of KS have been reported in literature, with both patients having advanced disease.9,10 In both reports, previously undiscovered visceral FDG avid lesions were described, which underscores our findings. FDG avidity in lymph nodes should be interpreted with caution because it may also be caused by HIV viremia in the absence of highly active antiretroviral therapy.11
Surprisingly, given the angiogenic nature of these lesions and their superficial location, In-111-bevacizumabscintigraphy showed uptake only in a minority of lesions in the patients that were included in this study. This may be explained by actual variability in antigen expression, which was also observed by immunohistochemistry. There was, however, no congruence between immunohistochemical staining intensity and In-111-bevacizumab uptake at the various sites. Another possibility is differential accessibility of the tumor sites for bevacizumab in vivo, a phenomenon that has also been described for VEGF expression and in vivo In-111-bevacizumab targeting in colorectal livermetastases.12 In that case, it might be worthwhile to include In-111-bevacizumab imaging as a potential tool to select patients for VEGF-targeted therapy in KS. An alternative explanation for this discrepancy may, however, be found in the differential properties of the VEGF-A splice variants. Whereas VEGF-121 is freely diffusible, VEGF-189 and -206 are almost completely sequestered in the extracellular matrix, and VEGF-165 has intermediate properties.13 Because scintigraphic imaging is performed 1 week after administering labeled bevacizumab to allow clearance of nonspecific background activity, soluble isoforms of VEGF are not visualized by this technique. Whether the latter limits suitability of In-111-bevacizumabscans as a predictor for response to antiangiogenic therapy in KS remains to be elucidated.
In conclusion, FDG-PET/CT very effectively detected clinically occult KS lesions in advanced stages of KS. This technique may prove helpful in the decision to initiate cytotoxic therapy in KS patients without the need for invasive procedures. Differential uptake of In-111-bevacizumab in KS lesions provides potentially interesting information on in vivo expression and accessibility of VEGF and the possibly of evaluation of mixed responses of KS lesions to angiogenesis inhibitors. This should be explored further in a well-designed prospective clinical trial.
We thank Mrs K. Verrijp for technical assistance.
Addy van de Luijtgaarden, MD*
Andre van der Ven, MD, PhD†
William Leenders, PhD‡
Suzanne Kaal, MD*
Uta Flucke, MD‡
Wim Oyen, MD, PhD§
Winette van der Graaf, MD, PhD*
*Department of Medical Oncology, Radboud University Nijmegen Medical Centre, The Netherlands
†Departments of General Internal Medicine, Radboud University Nijmegen Medical Centre, The Netherlands
‡Department of Pathology, Radboud University Nijmegen Medical Centre, The Netherlands
§Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, The Netherlands
1. Sullivan R, Dezube BJ, Koon HB. Signal transduction targets in Kaposi's sarcoma. Curr Opin Oncol
2. Restrepo CS, Martinez S, Lemos JA, et al. Imaging manifestations of Kaposi sarcoma. Radiographics
3. Di Lorenzo G, Konstantinopoulos PA, Pantanowitz L, et al. Management of AIDS-related Kaposi's sarcoma. Lancet Oncol
4. Ferrara N, Hillan KJ, Gerber HP, et al. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov
5. Stollman TH, Scheer MG, Leenders WP, et al. Specific imaging of VEGF-A expression with radiolabeled anti-VEGF monoclonal antibody. Int J Cancer
6. Masood R, Cai J, Zheng T, et al. Vascular endothelial growth factor/vascular permeability factor is an autocrine growth factor for AIDS-Kaposi sarcoma. Proc Natl Acad Sci U S A
7. Cornali E, Zietz C, Benelli R, et al. Vascular endothelial growth factor regulates angiogenesis and vascular permeability in Kaposi's sarcoma. Am J Pathol
8. Vart RJ, Nikitenko LL, Lagos D, et al. Kaposi's sarcoma-associated herpesvirus-encoded interleukin-6 and G-protein-coupled receptor regulate angiopoietin-2 expression in lymphatic endothelial cells. Cancer Res
9. Bonardel G, Coindre JM, Gontier E, et al. Elevated FDG uptake in Kaposi sarcoma mimicking Hodgkin's lymphoma relapse. Clin Nucl Med
10. Martinez S, McAdams HP, Youens KE. Kaposi sarcoma after bilateral lung transplantation. J Thorac Imaging
11. Lucignani G, Orunesu E, Cesari M, et al. FDG-PET imaging in HIV-infected subjects: relation with therapy and immunovirological variables. Eur J Nucl Med Mol Imaging
12. Scheer MG, Stollman TH, Boerman OC, et al. Imaging liver metastases of colorectal cancer patients with radiolabelled bevacizumab: lack of correlation with VEGF-A expression. Eur J Cancer
13. Neufeld G, Cohen T, Gengrinovitch S, et al. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J