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Increased FDG avidity in lymphoid tissue associated with response to combined immune checkpoint blockade

Increased FDG avidity in lymphoid tissue associated with response to combined immune checkpoint... Background: Antibodies against programmed death 1 (PD-1) receptor and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) have transformed the systemic treatment of melanoma and many other cancers. Understanding the spectrum of benign findings and atypical response patterns seen in immune checkpoint blockade is important for accurately assessing treatment response as these immunotherapies become more widely used. Case presentation: We report a 63-year-old man with metastatic melanoma successfully treated with combination CTLA-4 and PD-1 blockade (ipilimumab and nivolumab), after non-response to pembrolizumab monotherapy. The initial impression of disease progression, based on cutaneous and PET/CT findings of increased fluoro-2-deoxy-D- glucose (FDG) uptake in benign lymphoid tissue, proved to be erroneous after assiduous review of radiographic imaging and correlative pathology. Conclusions: These findings indicate that increased FDG uptake in benign lymphoid tissue seen on PET/CT may be a surrogate marker of immune activation and treatment response. Prospective studies will be invaluable in validating immune-related radiographic findings as a prognostic biomarker of response in cancer patients being treated with immune checkpoint blockade. Keywords: Immunotherapy, Biomarker, PD-1, CTLA-4, PET/CT Abbreviations: CT, Computed tomography; CTLA-4, Cytotoxic T-lymphocyte-associated antigen 4; FDG, Fluoro- 2-deoxy-D-glucose; irRC, Immune related response criteria; PD-1, Programmed death receptor-1; PET, Positron emission tomography; RECIST, Response evaluation criteria in solid tumors; SLNB, Sentinel lymph node biopsy; SUV, Standardized uptake value; WLE, Wide local excision Background advanced, there has been increasing interest in using Melanoma is an aggressive cutaneous neoplasm. Surgical FDG avidity not only for staging and monitoring, but resection for early stage melanoma is often curative, but as apredictivebiomarker to assess prognosisand ef- metastatic disease carries a poor prognosis, highlighting fectiveness of therapy [6]. the importance of accurate staging. Whole-body positron We present a case of increased FDG uptake in lymphoid emission tomography (PET) with 2-[fluorine-18]-fluoro-2- tissue as a surrogate marker of immune activation in a pa- deoxy-D-glucose (FDG) combined with computed tomog- tient with metastatic melanoma treated with combination raphy (CT) scans demonstrate improved sensitivity and ipilimumab and nivolumab, following non-response to specificity for melanoma detection, and their utility in pembrolizumab monotherapy. Our discussion includes melanoma staging and monitoring is well established details of radiographic imaging and pathologic analyses. [1–5]. As systemic treatments for melanoma have * Correspondence: katy.tsai@ucsf.edu Case presentation Helen Diller Family Comprehensive Cancer Center, University of California, San A 63-year-old man came to the University of California, Francisco, 1600 Divisadero Street, Box 1770, San Francisco, CA 94115, USA Full list of author information is available at the end of the article San Francisco in May 2015 seeking care for his © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Tsai et al. Journal for ImmunoTherapy of Cancer (2016) 4:58 Page 2 of 5 melanoma. Review of outside medical records revealed Diagnostic dermatopathology that in August 2014, a biopsy of a left scalp lesion Punch biopsies of cutaneous chest lesions were obtained showed a non-ulcerated, 1.3 mm thick melanoma. He prior to and during immunotherapy. Immunohistochemi- subsequently underwent wide local excision (WLE) and cal staining was performed with antibodies against Melan- sentinel lymph node biopsy (SLNB). The SLNB was A (clone A103; dilution 1:200) (Dako, Carpinteria, CA). positive for a 4 mm focus of BRAF wild-type melanoma in the subcapsular region of a left cervical lymph node. Diagnostic fine needle aspiration A PET/CT scan did not show any metastatic lesions. Inguinal lymph nodes were visualized with ultrasound During his consultation at UCSF, the initial diagnosis imaging. Targets were oriented in a position that allowed of stage IIIA melanoma was confirmed. Unfortunately, sampling throughout the hypoechoic cortex. On-site in the interim he had developed new hyperpigmented smear evaluation showed adequate material. papules on his left chest. One was biopsied on 5/19/15, and pathology demonstrated features of epidermotropic Results metastatic melanoma. He was upstaged to stage IV mel- Clinical findings anoma, and on 7/1/15 was started on a clinical trial of The patient had widespread cutaneous metastases that intralesional IL-12. He had progressive lesions after were readily clinically observed though not detected 12 weeks on therapy, and on 9/15/15 was transitioned to on PET/CT. His photograph on 10/5/15, prior to standard of care pembrolizumab. He received two doses pembrolizumab, shows hyperpigmented papules scat- (10/5/15, 10/26/15) which were well tolerated, but had tered on the chest and neck (Fig. 1a). While receiving rapidly increasing size and number of hyperpigmented pembrolizumab, he developed increasing confluence papules and plaques across his chest, bilateral arms and of existing chest papules, and numerous new hyper- back. On 11/16/15 he received his first dose of combin- pigmented papules on the neck, abdomen and bilat- ation ipilimumab/nivolumab. A PET/CT scan on 11/20/ eral upper arms. His treatment was changed to 15 did not show any lesions concerning for metastasis. ipilimumab/nivolumab on 11/16/15 due to clinical He went on to receive four induction doses of ipilimu- concern for progressive disease. Upon completion of mab/nivolumab; a PET/CT scan was repeated on 2/11/ ipilimumab/nivolumab induction, clinical photographs 16 and he was transitioned to nivolumab monotherapy. were repeated on 2/23/16 (Fig. 1b). Although his ap- At this time, the patient remains on nivolumab and is pearance continued to be concerning for progression, tolerating treatment well. thereweresubtleimprovements(absenceofnew lesions, flattening papules) towards the end of the in- Methods duction period. Radiologic technique Patient’s fasting time was at least six hours. Following Radiologic findings intravenous administration of F18-FDG, CT was acquired The PET/CT on 11/20/15, four days after the first dose of from vertex to toes with intravenous contrast (Omnipaque ipilimumab/nivolumab, showed no remarkable areas of 350), followed by an emission PET scan. A rotating 3D FDG avidity (Fig. 2a). The PET/CT on 2/11/16 showed maximum intensity projection image, as well as axial, cor- hypermetabolic lymph nodes throughout multiple nodal onal, and sagittal PET images were interpreted. stations: in bilateral inguinal, iliac, and axillary lymph Fig. 1 Clinical photographs prior to and during treatment with immune checkpoint inhibition. Panel a shows a photograph of the chest from 10/5/15 prior to initiation of pembrolizumab, with numerous hyperpigmented papules and plaques scattered across the chest. Panel b shows a photograph of the chest from 2/23/16, after completing ipilimumab/nivolumab induction. There is increased confluence of existing lesions, as well as new hyperpigmented papules on the bilateral upper arms and the neck Tsai et al. Journal for ImmunoTherapy of Cancer (2016) 4:58 Page 3 of 5 the dermal melanocytes (Fig. 3b). The melanocytes in ab the dermis generally did not diminish in size with des- cent. These findings were consistent with epidermo- trophic metastatic melanoma. A punch biopsy was obtained of cutaneous lesions on the right chest on 2/18/16, which showed melanophages and fibrosis. A Melan-A immunostain confirmed that no melanocytes were present in the dermis. These features were consistent with complete regression of melanoma (Fig. 3c, d). Fine needle aspiration of bilateral inguinal lymph nodes was done on 2/17/16. Pathology yielded unre- markable small lymphocytes, without evidence of malig- nancy [7, 8] (Fig. 3e). Conclusions Monoclonal antibodies against PD-1 and CTLA-4 are approved for advanced melanoma, non-small cell lung cancer, and renal cell carcinoma, and are being investi- gated in numerous other cancers. Use of immunother- apies is poised to increase in the coming years, thus highlighting the need for clinicians to gain expertise in immunotherapeutic response patterns. Historically, the Response Evaluation Criteria in Solid Tumors (RECIST) have been the most widely accepted guidelines for defining solid tumor progres- Fig. 2 Maximum intensity projection images of two whole-body sion [9, 10]. However, atypical response patterns have 18 F-FDG PET/CT studies. Panel a shows the PETCT from 11/20/15, been demonstrated in clinical trials of ipilimumab early in the course of immunotherapy. Panel b shows the PET/CT [11] and pembrolizumab [12], and have led to the from 2/11/16, after completion of induction ipilimumab/nivolumab. development of immune-related response criteria Arrows indicate the increased metabolic glucose consumption in bilateral inguinal, iliac, axillary lymph nodes as well as the spleen, (irRC) [11]. Described patterns of atypical response, highly suggestive of immune activation or pseudoprogression, have included initial increases in the size of target lesions followed by decreases without the appearance of new lesions, and regres- sion of target lesions but with appearance of new nodes as well as in the spleen (Fig. 2b). The inguinal lesions. Benign lymphadenopathy has also been de- lymph nodes were the largest, measuring 8 mm in short scribed as a radiographic finding in melanoma pa- axis, and with increased FDG avidity (12 SUV ). There max tients treated with anti-CTLA-4 therapy, the most was initial concern for progressive disease, however the common pattern reported to be sarcoid-like and in a bilateral pattern of uptake, preservation of fatty hilum, bilateral hilar and mediastinal distribution. These and concurrent splenic hypermetabolism (8.4 SUV ) max findings were seen in a series of eight patients on combined with clinically slowed growth and flattening of anti-CTLA-4 therapy; there was no reported detail cutaneous lesions were suggestive of FDG avidity as a on FDG avidity. Interestingly, in the same series, marker of immune activation rather than progressive radiologic evidence of immune-related effects seemed disease. to correlate with response to treatment [13]. More recent efforts to identify an imaging biomarker have Pathologic findings reported an elevated spleen-to-liver SUV ratiotobe The skin biopsy on 5/19/15, prior to pembrolizumab associated with increased overall survival in meta- therapy, revealed a narrow diameter compound prolifer- static melanoma patients treated with anti-CTLA-4 ation of melanocytes (Fig. 3a). There were nests of mela- or anti-PD-1 therapy [14]. nocytes within the lower epidermis and scattered single Ourcaseisthe firstreportofFDG-aviddiffuse melanocytes in irregular pagetoid array above the basal lymphadenopathy occurring with combined CTLA-4 layer of the epidermis. There were similar melanocytes and PD-1 blockade, with correlative pathology con- in the dermis, and mitotic figures were evident among firming benign lymphadenopathy and regression of Tsai et al. Journal for ImmunoTherapy of Cancer (2016) 4:58 Page 4 of 5 Fig. 3 Punch biopsies of cutaneous lesions of the chest before (Panels a and b) and during (Panels c and d) systemic immunotherapy. Panel a shows a narrow-based compound melanocytic proliferation at low power (4×) with a few nests of melanocytes within the lower epidermis and a few melanocytes above the basal layer of the epidermis. In addition, there are nests of melanocytes within the dermis and mitotic figures are present among them. These features are consistent with metastatic melanoma. Panel b shows a high-power view (60×) of the melanocytes in the dermis, highlighting scattered dermal mitoses. Panel c shows a biopsy on treatment at low power (10×) with an area of complete regression of metastatic melanoma with dermal fibrosis and numerous melanophages. A high-power view (60×) of a Melan-A immunoperoxidase stain, shown in Panel d, does not show any labeling, confirming that there is no evidence of residual melanoma. Panel e shows the cytology smear from the inguinal node fine needle aspiration at 200×, with predominantly small unremarkable lymphocytes cutaneous metastases. The initial clinical impression Acknowledgements Not applicable. of disease progression proved to be erroneous after assiduous review of radiographic imaging and biopsy Funding results. This highlights the importance of multi- No external funding was used for the design and conduct of this report; collection, management, analysis and interpretation of data; and preparation, disciplinary evaluation of these cases, and the need review and approval of this manuscript. for more prospective work to evaluate FDG avidity of benign lymphoid tissue in a larger case series as a Availability of data and material Data sharing not applicable to this article as no datasets were generated or surrogate for clinical benefit [15]. Heightened aware- analyzed during the current study. ness of the full spectrum of benign findings and atyp- ical response patterns seen with immunotherapies will Authors’ contributions improve our care of cancer patients being treated KKT conceptualized and designed this report, analyzed and interpreted patient data, and drafted the manuscript. AID made substantial contributions with these increasingly widespread agents, and en- to the conceptualization and design of this report, and analyzed and courage further research and development of novel interpreted patient data. MHP made substantial contributions to acquisition, imaging biomarkers. analysis and interpretation of radiologic data. BML, LP and CH made Tsai et al. Journal for ImmunoTherapy of Cancer (2016) 4:58 Page 5 of 5 substantial contributions to the acquisition, analysis and interpretation Advanced Melanoma Treated With Pembrolizumab. J Clin Oncol. 2016; of dermatopathologic and cytopathologic data. APA made substantial 34(13):1510-7. contributions to the analysis and interpretation of patient data. All authors 13. Bronstein Y, Ng CS, Hwu P, Hwu W-J. Radiologic manifestations of read the draft, critically revised the draft for intellectual content, and immune-related adverse events in patients with metastatic melanoma approved the final manuscript. undergoing anti–ctla-4 antibody therapy. Am J Roentgenol. 2011;197(6): W992–1000. 14. Wong ANM, Callahan J, Beresford J, Herschtal A, Fullerton S, Milne D, et al. Competing interests Spleen to liver ratio (SLR): Novel PET imaging biomarker for prediction KKT, MHP, CH, LP, BML have no potential conflicts of interest to report. APA of overall survival after ipilimumab and anti-PD1 in patients with reports research funding from Merck, Bristol-Myers Squibb, AstraZeneca, metastatic melanoma. J Clin Oncol [Internet]. [cited 2016 Jul 1]; MedImmune, Oncosec, Novartis, and GlaxoSmithKline. AID is the recipient Available from: http://meetinglibrary.asco.org/content/163854-176. of grants from Bristol-Myers Squibb, Genentech, Merck, and Roche, as well 15. Chiou VL, Burotto M. Pseudoprogression and Immune-Related Response in as consulting fees/honoraria from Merck, and Roche. Solid Tumors. J Clin Oncol. 2015 Aug 10;JCO.2015.61.6870. Consent for publication Written informed consent for publication of clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal. Ethics approval and consent to participate Not applicable. Author details Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1600 Divisadero Street, Box 1770, San Francisco, CA 94115, USA. Department of Radiology and Biomedical Imaging, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA 94117, USA. Department of Dermatology, University of California, San Francisco, 1701 Divisadero Street, San Francisco, CA 94115, USA. Department of Pathology, University of California, San Francisco, 1600 Divisadero Street, San Francisco, CA 94115, USA. Received: 15 July 2016 Accepted: 31 August 2016 References 1. Gritters LS, Francis IR, Zasadny KR, Wahl RL. Initial assessment of positron emission tomography using 2-Fluorine-18-Fluoro-2-Deoxy-D-glucose in the imaging of malignant melanoma. J Nucl Med. 1993;34(9):1420–7. 2. Gillies RJ, Robey I, Gatenby RA. Causes and consequences of increased glucose metabolism of cancers. J Nucl Med. 2008;49 Suppl 2:24S–42S. 3. Mottaghy FM, Sunderkötter C, Schubert R, Wohlfart P, Blumstein NM, Neumaier B, et al. Direct comparison of [18 F]FDG PET/CT with PET alone and with side-by-side PET and CT in patients with malignant melanoma. Eur J Nucl Med Mol Imaging. 2007;34(9):1355–64. 4. Swetter SM, Carroll LA, Johnson DL, Segall GM. Positron emission tomography is superior to computed tomography for metastatic detection in melanoma patients. Ann Surg Oncol. 2002;9(7):646–53. 5. Rinne D, Baum RP, Hör G, Kaufmann R. Primary staging and follow-up of high risk melanoma patients with whole-body 18 F-fluorodeoxyglucose positron emission tomography. Cancer. 1998;82(9):1664–71. 6. Perng P, Marcus C, Subramaniam RM. 18 F-FDG PET/CT and Melanoma: staging, immune modulation and mutation-targeted therapy assessment, and prognosis. Am J Roentgenol. 2015;205(2):259–70. 7. Rodrigues LKE, Leong SPL, Ljung B-M, Sagebiel RW, Burnside N, Hu TW, et al. Fine needle aspiration in the diagnosis of metastatic melanoma. J Am Acad Dermatol. 2000;42(5, Part 1):735–40. Submit your next manuscript to BioMed Central 8. Hall BJ, Schmidt RL, Sharma RR, Layfield LJ. Fine-needle aspiration cytology for the diagnosis of metastatic melanoma. Am J Clin Pathol. 2013;140(5): and we will help you at every step: 635–42. • We accept pre-submission inquiries 9. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. J � Our selector tool helps you to find the most relevant journal Natl Cancer Inst. 2000;92(3):205–16. � We provide round the clock customer support 10. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. � Convenient online submission New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47. � Thorough peer review 11. Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbé C, et al. Guidelines � Inclusion in PubMed and all major indexing services for the evaluation of immune therapy activity in solid tumors: immune- � Maximum visibility for your research related response criteria. Clin Cancer Res. 2009;15(23):7412–20. 12. Hodi FS, Hwu W-J, Kefford R, Weber JS, Daud A, Hamid O, et al. Evaluation Submit your manuscript at of Immune-Related Response Criteria and RECIST v1.1 in Patients With www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal for ImmunoTherapy of Cancer Springer Journals

Increased FDG avidity in lymphoid tissue associated with response to combined immune checkpoint blockade

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Springer Journals
Copyright
Copyright © 2016 by The Author(s).
Subject
Medicine & Public Health; Oncology; Immunology
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2051-1426
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10.1186/s40425-016-0162-9
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27660712
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Abstract

Background: Antibodies against programmed death 1 (PD-1) receptor and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) have transformed the systemic treatment of melanoma and many other cancers. Understanding the spectrum of benign findings and atypical response patterns seen in immune checkpoint blockade is important for accurately assessing treatment response as these immunotherapies become more widely used. Case presentation: We report a 63-year-old man with metastatic melanoma successfully treated with combination CTLA-4 and PD-1 blockade (ipilimumab and nivolumab), after non-response to pembrolizumab monotherapy. The initial impression of disease progression, based on cutaneous and PET/CT findings of increased fluoro-2-deoxy-D- glucose (FDG) uptake in benign lymphoid tissue, proved to be erroneous after assiduous review of radiographic imaging and correlative pathology. Conclusions: These findings indicate that increased FDG uptake in benign lymphoid tissue seen on PET/CT may be a surrogate marker of immune activation and treatment response. Prospective studies will be invaluable in validating immune-related radiographic findings as a prognostic biomarker of response in cancer patients being treated with immune checkpoint blockade. Keywords: Immunotherapy, Biomarker, PD-1, CTLA-4, PET/CT Abbreviations: CT, Computed tomography; CTLA-4, Cytotoxic T-lymphocyte-associated antigen 4; FDG, Fluoro- 2-deoxy-D-glucose; irRC, Immune related response criteria; PD-1, Programmed death receptor-1; PET, Positron emission tomography; RECIST, Response evaluation criteria in solid tumors; SLNB, Sentinel lymph node biopsy; SUV, Standardized uptake value; WLE, Wide local excision Background advanced, there has been increasing interest in using Melanoma is an aggressive cutaneous neoplasm. Surgical FDG avidity not only for staging and monitoring, but resection for early stage melanoma is often curative, but as apredictivebiomarker to assess prognosisand ef- metastatic disease carries a poor prognosis, highlighting fectiveness of therapy [6]. the importance of accurate staging. Whole-body positron We present a case of increased FDG uptake in lymphoid emission tomography (PET) with 2-[fluorine-18]-fluoro-2- tissue as a surrogate marker of immune activation in a pa- deoxy-D-glucose (FDG) combined with computed tomog- tient with metastatic melanoma treated with combination raphy (CT) scans demonstrate improved sensitivity and ipilimumab and nivolumab, following non-response to specificity for melanoma detection, and their utility in pembrolizumab monotherapy. Our discussion includes melanoma staging and monitoring is well established details of radiographic imaging and pathologic analyses. [1–5]. As systemic treatments for melanoma have * Correspondence: katy.tsai@ucsf.edu Case presentation Helen Diller Family Comprehensive Cancer Center, University of California, San A 63-year-old man came to the University of California, Francisco, 1600 Divisadero Street, Box 1770, San Francisco, CA 94115, USA Full list of author information is available at the end of the article San Francisco in May 2015 seeking care for his © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Tsai et al. Journal for ImmunoTherapy of Cancer (2016) 4:58 Page 2 of 5 melanoma. Review of outside medical records revealed Diagnostic dermatopathology that in August 2014, a biopsy of a left scalp lesion Punch biopsies of cutaneous chest lesions were obtained showed a non-ulcerated, 1.3 mm thick melanoma. He prior to and during immunotherapy. Immunohistochemi- subsequently underwent wide local excision (WLE) and cal staining was performed with antibodies against Melan- sentinel lymph node biopsy (SLNB). The SLNB was A (clone A103; dilution 1:200) (Dako, Carpinteria, CA). positive for a 4 mm focus of BRAF wild-type melanoma in the subcapsular region of a left cervical lymph node. Diagnostic fine needle aspiration A PET/CT scan did not show any metastatic lesions. Inguinal lymph nodes were visualized with ultrasound During his consultation at UCSF, the initial diagnosis imaging. Targets were oriented in a position that allowed of stage IIIA melanoma was confirmed. Unfortunately, sampling throughout the hypoechoic cortex. On-site in the interim he had developed new hyperpigmented smear evaluation showed adequate material. papules on his left chest. One was biopsied on 5/19/15, and pathology demonstrated features of epidermotropic Results metastatic melanoma. He was upstaged to stage IV mel- Clinical findings anoma, and on 7/1/15 was started on a clinical trial of The patient had widespread cutaneous metastases that intralesional IL-12. He had progressive lesions after were readily clinically observed though not detected 12 weeks on therapy, and on 9/15/15 was transitioned to on PET/CT. His photograph on 10/5/15, prior to standard of care pembrolizumab. He received two doses pembrolizumab, shows hyperpigmented papules scat- (10/5/15, 10/26/15) which were well tolerated, but had tered on the chest and neck (Fig. 1a). While receiving rapidly increasing size and number of hyperpigmented pembrolizumab, he developed increasing confluence papules and plaques across his chest, bilateral arms and of existing chest papules, and numerous new hyper- back. On 11/16/15 he received his first dose of combin- pigmented papules on the neck, abdomen and bilat- ation ipilimumab/nivolumab. A PET/CT scan on 11/20/ eral upper arms. His treatment was changed to 15 did not show any lesions concerning for metastasis. ipilimumab/nivolumab on 11/16/15 due to clinical He went on to receive four induction doses of ipilimu- concern for progressive disease. Upon completion of mab/nivolumab; a PET/CT scan was repeated on 2/11/ ipilimumab/nivolumab induction, clinical photographs 16 and he was transitioned to nivolumab monotherapy. were repeated on 2/23/16 (Fig. 1b). Although his ap- At this time, the patient remains on nivolumab and is pearance continued to be concerning for progression, tolerating treatment well. thereweresubtleimprovements(absenceofnew lesions, flattening papules) towards the end of the in- Methods duction period. Radiologic technique Patient’s fasting time was at least six hours. Following Radiologic findings intravenous administration of F18-FDG, CT was acquired The PET/CT on 11/20/15, four days after the first dose of from vertex to toes with intravenous contrast (Omnipaque ipilimumab/nivolumab, showed no remarkable areas of 350), followed by an emission PET scan. A rotating 3D FDG avidity (Fig. 2a). The PET/CT on 2/11/16 showed maximum intensity projection image, as well as axial, cor- hypermetabolic lymph nodes throughout multiple nodal onal, and sagittal PET images were interpreted. stations: in bilateral inguinal, iliac, and axillary lymph Fig. 1 Clinical photographs prior to and during treatment with immune checkpoint inhibition. Panel a shows a photograph of the chest from 10/5/15 prior to initiation of pembrolizumab, with numerous hyperpigmented papules and plaques scattered across the chest. Panel b shows a photograph of the chest from 2/23/16, after completing ipilimumab/nivolumab induction. There is increased confluence of existing lesions, as well as new hyperpigmented papules on the bilateral upper arms and the neck Tsai et al. Journal for ImmunoTherapy of Cancer (2016) 4:58 Page 3 of 5 the dermal melanocytes (Fig. 3b). The melanocytes in ab the dermis generally did not diminish in size with des- cent. These findings were consistent with epidermo- trophic metastatic melanoma. A punch biopsy was obtained of cutaneous lesions on the right chest on 2/18/16, which showed melanophages and fibrosis. A Melan-A immunostain confirmed that no melanocytes were present in the dermis. These features were consistent with complete regression of melanoma (Fig. 3c, d). Fine needle aspiration of bilateral inguinal lymph nodes was done on 2/17/16. Pathology yielded unre- markable small lymphocytes, without evidence of malig- nancy [7, 8] (Fig. 3e). Conclusions Monoclonal antibodies against PD-1 and CTLA-4 are approved for advanced melanoma, non-small cell lung cancer, and renal cell carcinoma, and are being investi- gated in numerous other cancers. Use of immunother- apies is poised to increase in the coming years, thus highlighting the need for clinicians to gain expertise in immunotherapeutic response patterns. Historically, the Response Evaluation Criteria in Solid Tumors (RECIST) have been the most widely accepted guidelines for defining solid tumor progres- Fig. 2 Maximum intensity projection images of two whole-body sion [9, 10]. However, atypical response patterns have 18 F-FDG PET/CT studies. Panel a shows the PETCT from 11/20/15, been demonstrated in clinical trials of ipilimumab early in the course of immunotherapy. Panel b shows the PET/CT [11] and pembrolizumab [12], and have led to the from 2/11/16, after completion of induction ipilimumab/nivolumab. development of immune-related response criteria Arrows indicate the increased metabolic glucose consumption in bilateral inguinal, iliac, axillary lymph nodes as well as the spleen, (irRC) [11]. Described patterns of atypical response, highly suggestive of immune activation or pseudoprogression, have included initial increases in the size of target lesions followed by decreases without the appearance of new lesions, and regres- sion of target lesions but with appearance of new nodes as well as in the spleen (Fig. 2b). The inguinal lesions. Benign lymphadenopathy has also been de- lymph nodes were the largest, measuring 8 mm in short scribed as a radiographic finding in melanoma pa- axis, and with increased FDG avidity (12 SUV ). There max tients treated with anti-CTLA-4 therapy, the most was initial concern for progressive disease, however the common pattern reported to be sarcoid-like and in a bilateral pattern of uptake, preservation of fatty hilum, bilateral hilar and mediastinal distribution. These and concurrent splenic hypermetabolism (8.4 SUV ) max findings were seen in a series of eight patients on combined with clinically slowed growth and flattening of anti-CTLA-4 therapy; there was no reported detail cutaneous lesions were suggestive of FDG avidity as a on FDG avidity. Interestingly, in the same series, marker of immune activation rather than progressive radiologic evidence of immune-related effects seemed disease. to correlate with response to treatment [13]. More recent efforts to identify an imaging biomarker have Pathologic findings reported an elevated spleen-to-liver SUV ratiotobe The skin biopsy on 5/19/15, prior to pembrolizumab associated with increased overall survival in meta- therapy, revealed a narrow diameter compound prolifer- static melanoma patients treated with anti-CTLA-4 ation of melanocytes (Fig. 3a). There were nests of mela- or anti-PD-1 therapy [14]. nocytes within the lower epidermis and scattered single Ourcaseisthe firstreportofFDG-aviddiffuse melanocytes in irregular pagetoid array above the basal lymphadenopathy occurring with combined CTLA-4 layer of the epidermis. There were similar melanocytes and PD-1 blockade, with correlative pathology con- in the dermis, and mitotic figures were evident among firming benign lymphadenopathy and regression of Tsai et al. Journal for ImmunoTherapy of Cancer (2016) 4:58 Page 4 of 5 Fig. 3 Punch biopsies of cutaneous lesions of the chest before (Panels a and b) and during (Panels c and d) systemic immunotherapy. Panel a shows a narrow-based compound melanocytic proliferation at low power (4×) with a few nests of melanocytes within the lower epidermis and a few melanocytes above the basal layer of the epidermis. In addition, there are nests of melanocytes within the dermis and mitotic figures are present among them. These features are consistent with metastatic melanoma. Panel b shows a high-power view (60×) of the melanocytes in the dermis, highlighting scattered dermal mitoses. Panel c shows a biopsy on treatment at low power (10×) with an area of complete regression of metastatic melanoma with dermal fibrosis and numerous melanophages. A high-power view (60×) of a Melan-A immunoperoxidase stain, shown in Panel d, does not show any labeling, confirming that there is no evidence of residual melanoma. Panel e shows the cytology smear from the inguinal node fine needle aspiration at 200×, with predominantly small unremarkable lymphocytes cutaneous metastases. The initial clinical impression Acknowledgements Not applicable. of disease progression proved to be erroneous after assiduous review of radiographic imaging and biopsy Funding results. This highlights the importance of multi- No external funding was used for the design and conduct of this report; collection, management, analysis and interpretation of data; and preparation, disciplinary evaluation of these cases, and the need review and approval of this manuscript. for more prospective work to evaluate FDG avidity of benign lymphoid tissue in a larger case series as a Availability of data and material Data sharing not applicable to this article as no datasets were generated or surrogate for clinical benefit [15]. Heightened aware- analyzed during the current study. ness of the full spectrum of benign findings and atyp- ical response patterns seen with immunotherapies will Authors’ contributions improve our care of cancer patients being treated KKT conceptualized and designed this report, analyzed and interpreted patient data, and drafted the manuscript. AID made substantial contributions with these increasingly widespread agents, and en- to the conceptualization and design of this report, and analyzed and courage further research and development of novel interpreted patient data. MHP made substantial contributions to acquisition, imaging biomarkers. analysis and interpretation of radiologic data. BML, LP and CH made Tsai et al. Journal for ImmunoTherapy of Cancer (2016) 4:58 Page 5 of 5 substantial contributions to the acquisition, analysis and interpretation Advanced Melanoma Treated With Pembrolizumab. J Clin Oncol. 2016; of dermatopathologic and cytopathologic data. APA made substantial 34(13):1510-7. contributions to the analysis and interpretation of patient data. All authors 13. Bronstein Y, Ng CS, Hwu P, Hwu W-J. Radiologic manifestations of read the draft, critically revised the draft for intellectual content, and immune-related adverse events in patients with metastatic melanoma approved the final manuscript. undergoing anti–ctla-4 antibody therapy. Am J Roentgenol. 2011;197(6): W992–1000. 14. Wong ANM, Callahan J, Beresford J, Herschtal A, Fullerton S, Milne D, et al. Competing interests Spleen to liver ratio (SLR): Novel PET imaging biomarker for prediction KKT, MHP, CH, LP, BML have no potential conflicts of interest to report. APA of overall survival after ipilimumab and anti-PD1 in patients with reports research funding from Merck, Bristol-Myers Squibb, AstraZeneca, metastatic melanoma. J Clin Oncol [Internet]. [cited 2016 Jul 1]; MedImmune, Oncosec, Novartis, and GlaxoSmithKline. AID is the recipient Available from: http://meetinglibrary.asco.org/content/163854-176. of grants from Bristol-Myers Squibb, Genentech, Merck, and Roche, as well 15. Chiou VL, Burotto M. Pseudoprogression and Immune-Related Response in as consulting fees/honoraria from Merck, and Roche. Solid Tumors. J Clin Oncol. 2015 Aug 10;JCO.2015.61.6870. Consent for publication Written informed consent for publication of clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal. Ethics approval and consent to participate Not applicable. Author details Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1600 Divisadero Street, Box 1770, San Francisco, CA 94115, USA. Department of Radiology and Biomedical Imaging, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA 94117, USA. Department of Dermatology, University of California, San Francisco, 1701 Divisadero Street, San Francisco, CA 94115, USA. Department of Pathology, University of California, San Francisco, 1600 Divisadero Street, San Francisco, CA 94115, USA. Received: 15 July 2016 Accepted: 31 August 2016 References 1. Gritters LS, Francis IR, Zasadny KR, Wahl RL. Initial assessment of positron emission tomography using 2-Fluorine-18-Fluoro-2-Deoxy-D-glucose in the imaging of malignant melanoma. J Nucl Med. 1993;34(9):1420–7. 2. Gillies RJ, Robey I, Gatenby RA. Causes and consequences of increased glucose metabolism of cancers. J Nucl Med. 2008;49 Suppl 2:24S–42S. 3. Mottaghy FM, Sunderkötter C, Schubert R, Wohlfart P, Blumstein NM, Neumaier B, et al. Direct comparison of [18 F]FDG PET/CT with PET alone and with side-by-side PET and CT in patients with malignant melanoma. Eur J Nucl Med Mol Imaging. 2007;34(9):1355–64. 4. Swetter SM, Carroll LA, Johnson DL, Segall GM. Positron emission tomography is superior to computed tomography for metastatic detection in melanoma patients. Ann Surg Oncol. 2002;9(7):646–53. 5. Rinne D, Baum RP, Hör G, Kaufmann R. Primary staging and follow-up of high risk melanoma patients with whole-body 18 F-fluorodeoxyglucose positron emission tomography. Cancer. 1998;82(9):1664–71. 6. Perng P, Marcus C, Subramaniam RM. 18 F-FDG PET/CT and Melanoma: staging, immune modulation and mutation-targeted therapy assessment, and prognosis. Am J Roentgenol. 2015;205(2):259–70. 7. Rodrigues LKE, Leong SPL, Ljung B-M, Sagebiel RW, Burnside N, Hu TW, et al. Fine needle aspiration in the diagnosis of metastatic melanoma. J Am Acad Dermatol. 2000;42(5, Part 1):735–40. Submit your next manuscript to BioMed Central 8. Hall BJ, Schmidt RL, Sharma RR, Layfield LJ. Fine-needle aspiration cytology for the diagnosis of metastatic melanoma. Am J Clin Pathol. 2013;140(5): and we will help you at every step: 635–42. • We accept pre-submission inquiries 9. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. J � Our selector tool helps you to find the most relevant journal Natl Cancer Inst. 2000;92(3):205–16. � We provide round the clock customer support 10. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. � Convenient online submission New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47. � Thorough peer review 11. Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbé C, et al. Guidelines � Inclusion in PubMed and all major indexing services for the evaluation of immune therapy activity in solid tumors: immune- � Maximum visibility for your research related response criteria. Clin Cancer Res. 2009;15(23):7412–20. 12. Hodi FS, Hwu W-J, Kefford R, Weber JS, Daud A, Hamid O, et al. Evaluation Submit your manuscript at of Immune-Related Response Criteria and RECIST v1.1 in Patients With www.biomedcentral.com/submit

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