A case of pulmonary adenocarcinoma showing rapid progression of peritoneal dissemination after immune checkpoint inhibitor therapy

A case of pulmonary adenocarcinoma showing rapid progression of peritoneal dissemination after... Background: Immune checkpoint inhibitors are standard treatments for non-small cell lung cancer. Unique cases with paradoxical acceleration of the disease after immunotherapy have been reported. These have been described as cases of hyperprogressive disease. Case presentation: A 76-year-old man was diagnosed with pulmonary adenocarcinoma with pleural dissemination and liver and adrenal metastases. Genomic analysis revealed neither EGFR mutations nor ALK translocations. Immunohistochemical analysis revealed a programmed death-ligand 1 tumor proportion score of 23%. Chemotherapy with carboplatin, paclitaxel, and bevacizumab resulted in Grade 3 skin eruption and disease progression. Pembrolizumab was initiated as a second-line treatment. However, peritoneal dissemination and ascites developed. The patient died 2 weeks later. The autopsy revealed widespread peritoneal dissemination and an extensive hemorrhagic infarction. Conclusion: This was a rare case of hyperprogressive disease with rapid progression of peritoneal dissemination after pembrolizumab treatment. Keywords: Adenocarcinoma, Hyperprogressive disease, Immune checkpoint inhibitor, Lung cancer, Pembrolizumab, Peritoneal dissemination Background Herein, we report on a case of hyperprogressive Immune checkpoint inhibitors (ICIs) are currently disease after treatment with pembrolizumab, an ICI cur- standard treatments for non-small cell lung cancer rently used in the treatment of NSCLC. The clinical (NSCLC) [1, 2]. The unique adverse events that can course in this case was highly unusual as it exhibited arise after treatment with ICIs, including pneumonitis, rapid progression of peritoneal dissemination shortly colitis, and thyroiditis, are known as immune-related after a single administration of pembrolizumab. More- adverse events [3]. Recently, unique cases with para- over, this is one of the first reports to document hyper- doxical acceleration of the disease after immunother- progressive disease by autopsy. apy have been reported [4, 5]. These have been described as cases of hyperprogressive disease. In one Case presentation study, hyperprogressive disease was observed in 9% of A 76-year-old man with no history of smoking presented patients treated with ICIs [4]. with an abnormal shadow on chest X-ray. He had a medical history of hypertension, dyslipidemia, reflux esophagitis, and benign prostatic hyperplasia. He had * Correspondence: terasima@tdc.ac.jp mild dyspnea on exertion. Physical examination did not Department of Respiratory Medicine, Tokyo Dental College Ichikawa General reveal any abnormal findings and the results of the Hospital, 5-11-13 Sugano, Ichikawa, Chiba 272-0824, Japan Full list of author information is available at the end of the article © The Author(s). 2018 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. Shinozaki et al. BMC Cancer (2018) 18:620 Page 2 of 5 laboratory tests were within normal limits. The patient First-line chemotherapy with carboplatin (area under had an Eastern Cooperative Oncology Group perform- the curve, 6), paclitaxel (200 mg/m ), and bevacizumab ance status (ECOG PS) score of 1. Chest X-ray revealed (15 mg/kg) was initiated for pulmonary adenocarcinoma a tumor in the left hilar region and left pleural effusion. cT3N1M1c (Stage IVB). However, skin eruption devel- This was confirmed by enhanced computed tomography oped during the week following administration and (CT) scan, which showed a 40 mm tumor in the left spread to his whole body. The size of the liver metastasis lower lobe with left pleural effusion. Enhanced CT scan in the S4 region also increased from 1.0 to 1.3 cm and of the abdomen revealed liver and adrenal metastases. new liver metastases were detected (Fig. 2). The ECOG Tissue specimens obtained by bronchoscopy revealed a PS score of the patient was 1. Since the patient’s skin well-differentiated adenocarcinoma (Fig. 1a). Genomic eruption was classified as a Grade 3 adverse event (Com- analysis was performed to identify whether there were mon Terminology Criteria for Adverse Events, version any driver mutations present. This revealed that there 4.0) and the disease was progressive, treatment was were no sensitizing mutations in the epidermal growth switched to an ICI. Pembrolizumab (200 mg/body) was factor receptor (EGFR) gene, nor were there transloca- administered as a second-line treatment. Following ad- tions in the anaplastic lymphoma kinase (ALK) gene. Im- ministration, the patient began to experience a gradual munohistochemical analysis of programmed death-ligand loss of appetite and abdominal distension, followed by a 1 (PD-L1) expression using the murine 22C-3 antibody, worsening of his general condition. On Day 13 after expressed as the tumor proportion score (TPS), revealed a pembrolizumab administration, an enhanced CT scan TPS of 23% (Fig. 1b). Furthermore, there were no in- showed progression of the liver metastases (Fig. 3a). creases in the serum levels of various tumor markers. There was also a large amount of ascites and widespread peritoneal dissemination (Fig. 3b, c). These were novel findings that had not been observed prior to pembroli- zumab treatment. The patient died suddenly due to rapid progression of respiratory failure on Day 14 after pembrolizumab administration. An autopsy revealed extensive Stage IV lung adenocar- cinoma originating from the left lower lobe with metas- tases in the lungs, left pleura, liver, adrenal glands, kidneys, pancreas, stomach, small intestine, colon, bone marrow, and lymph nodes of the bilateral hilar and para-aortic lesions. Dissemination to the peritoneum (Fig. 4), omentum, and diaphragm was also documented by autopsy. Microscopic examination of the peritoneal Fig. 1 Histopathological findings of tissue specimens obtained under bronchoscopy. a Hematoxylin and eosin staining showing a Fig. 2 Enhanced computed tomography (CT) imaging. CT was well-differentiated adenocarcinoma (200× magnification). b 22C-3 performed after a single course of cytotoxic chemotherapy. The size antibody staining against programmed death-ligand 1. Tumor of the liver metastasis in the S4 region increased from 1.0 to proportion score, 23% 1.3 cm (arrow) Shinozaki et al. BMC Cancer (2018) 18:620 Page 3 of 5 Fig. 4 Macroscopic examination of the autopsy specimens revealed widespread peritoneal dissemination (arrows) Fig. 3 Enhanced computed tomography (CT) imaging. a After a single administration of pembrolizumab, the size of the liver metastasis increased from 1.3 to 1.6 cm (arrow). b and c Widespread peritoneal dissemination (arrows) and a large amount of ascites were visible after pembrolizumab treatment tissue confirmed the presence of a well-differentiated in- vasive adenocarcinoma (Fig. 5a). Immunohistochemical analysis of the peritoneal tissue revealed that the PD-L1 TPS of the tumor cells was 12% (Fig. 5b), which is simi- Fig. 5 Histopathological findings of peritoneal autopsy specimens. lar to the score for the tumor tissue obtained by bron- a Hematoxylin and eosin staining of the peritoneal tissue revealed an invasive, well-differentiated adenocarcinoma (100× magnification). choscopy. Overexpression of the MDM2 gene was not b 22C-3 antibody staining against programmed death-ligand 1. Tumor detected by immunohistochemistry. In addition to these proportion score, 12% findings, an extensive hemorrhagic infarction due to Shinozaki et al. BMC Cancer (2018) 18:620 Page 4 of 5 tumor embolism was observed in the right lung the present case ruled out the possibility of pseudopro- (Fig. 6a, b). This was recorded as the cause of death gression. Champiat et al. proposed that hyperprogressive based on the autopsy. disease should be defined as a > 2.0-fold increase in tumor growth rate after immunotherapy [4]. Kato et al. Discussion and conclusions defined hyperprogressive disease as a time-to-treatment To the best of our knowledge, this is the first case of failure of < 2 months, a > 50.0% increase in tumor bur- lung cancer with hyperprogressive disease showing rapid den, and > 2.0-fold increase in tumor growth rate [5]. In progression of peritoneal dissemination after ICI treat- our case, the scale measurable region was the liver me- ment. Moreover, this is the first case where hyperpro- tastases. The time elapsed between the 1.0 to 1.3 cm gressive disease was documented by autopsy. and 1.3 to 1.6 cm enlargement of the target lesion of Hyperprogressive disease has recently been described the liver was 51 and 19 days, respectively. The volume in cases treated with immunotherapy [4, 5]. In current doubling time before and after pembrolizumab treat- treatment strategies for advanced NSCLC, the ICI pem- ment was 45 and 21 days, respectively (volume doub- brolizumab is recommended as a first-line therapy in ling time = [(T1 − T0)·log2]/[3log(D1/D0)], where cases where the TPS is ≥50% and as a second-line ther- D1 and D0 are the diameters at T1 and T0, respectively) apy in cases where the TPS is 1–49% [1, 2]. It is critical [7]. There was a > 2.0-fold increase in tumor growth rate to determine whether the progression observed in this since tumor growth rate is the inverse of the volume case was hyperprogressive disease, pseudoprogression, doubling time (i.e., tumor growth rate = 1 / volume or natural progression, as is often observed in the ter- doubling time) [8]. minal stages of malignant diseases. ICIs are sometimes In a previous study, the median time from diagnosis of known to result in unique response patterns, such as Stage IV disease to peritoneal metastasis was 16.5 pseudoprogression [6]. However, the autopsy findings in (range, 0.6–108) months among 410 patients with metastatic NSCLC [9], which is notably longer than the 2.3 months in this case. Moreover, the time from pem- a brolizumab administration to peritoneal metastasis was just 0.4 months (13 days). The novel appearance of widespread peritoneal dissemination and a large amount of ascites within 13 days met the criteria of time-to-treatment failure of < 2 months and suggested that the clinical course of our case was much more rapid than the natural terminal course. Finally, autopsy findings revealed greater progression of the metastases than CT scan images taken 1 day prior to the patient’s death. Together, these indicate that this was a case of hyperprogressive disease. The clinical course of our case was highly unique due to the presence of widespread peritoneal dissemination. Peritoneal dissemination is a rare clinical event in lung cancer patients, with autopsy results indicating an inci- dence of 9.4–15.8% [10, 11]. It is even rarer that periton- eal dissemination develops during the clinical course. A 26-year study of 1024 lung cancer patients reported that only 12 patients (1.2%) developed clinically detectable peritoneal dissemination [12]. Another study found that in 410 patients with metastatic NSCLC, 33 pa- tients (8%) developed peritoneal dissemination and that this was highly associated with pleural dissemin- ation [9]. In our case, it is possible that pleural dissem- ination and hyperprogressive disease contributed to peritoneal dissemination. Fig. 6 Histopathological findings of autopsy specimens from the The mechanisms of hyperprogressive disease are not right lung. a Hematoxylin and eosin staining (100× magnification). yet understood. Tumor profiles and patient characteris- b Verhoeff-Van Gieson elastic staining. An extensive hemorrhagic tics are thought to be important factors. The finding that infarction due to tumor embolism was observed (arrow) the PD-L1 TPS was similar before and after the Shinozaki et al. BMC Cancer (2018) 18:620 Page 5 of 5 administration of pembrolizumab in our case was in Ethics approval and consent to participate Not applicable. agreement with the finding that hyperprogressive disease was not associated with the PD-L1 status of tumors [4]. Consent for publication Kato et al. showed that cancer patients with MDM2 Written informed consent was obtained from the patient’s family for publication of this case report and any accompanying images. gene amplification or EGFR mutations had increased rates of tumor growth after treatment with ICIs [5]. Competing interests However, in our case, EGFR was wild-type and there was The authors declare that they have no competing interests. no overexpression of the MDM2 gene. In terms of pa- tient characteristics, age > 65 years was identified as the Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in only associated factor for hyperprogressive disease [4]. published maps and institutional affiliations. Although there may be other unknown risk factors, it is likely that old age was the primary risk factor for pro- Author details Department of Respiratory Medicine, Tokyo Dental College Ichikawa General gressive disease in our case. Hospital, 5-11-13 Sugano, Ichikawa, Chiba 272-0824, Japan. Department of Our report has several limitations. Firstly, there is the Pathology and Laboratory Medicine, Tokyo Dental College Ichikawa General potential that the rapid progression seen in our patient Hospital, 5-11-13 Sugano, Ichikawa, Chiba 272-0824, Japan. was due to the natural course or intrinsic cancer biology Received: 28 January 2018 Accepted: 23 May 2018 rather than pembrolizumab therapy. In fact, the disease was chemoresistant and progressive prior to pembrolizu- References mab treatment. The widespread peritoneal dissemin- 1. Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, et al. ation, however, suggested accelerated progression after Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, pembrolizumab treatment. Secondly, the tumor growth advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387:1540–50. rate is not a standardized model for response and the 2. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. definition of hyperprogressive disease proposed by Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung Champiat et al. has not been widely accepted by the Cancer. N Engl J Med. 2016;375:1823–33. 3. Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F, Postel-Vinay S, broader oncology community [13]. In our case, the rapid et al. Immune-related adverse events with immune checkpoint blockade: a growth of the tumor was shown by a shortening of the comprehensive review. Eur J Cancer. 2016;54:139–48. doubling time of the target lesion of the liver. The 4. Champiat S, Dercle L, Ammari S, Massard C, Hollebecque A, Postel-Vinay S, et al. Hyperprogressive disease is a new pattern of progression in Cancer strength of our case is the fact that true progression was patients treated by anti-PD-1/PD-L1. Clin Cancer Res. 2017;23:1920–8. documented by autopsy and that autopsy specimens will 5. Kato S, Goodman A, Walavalkar V, Barkauskas DA, Sharabi A, Kurzrock R. be useful for elucidating the mechanisms of hyperpro- Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res. 2017;23:4242–50. gressive disease in the future. 6. Chiou VL, Burotto M. Pseudoprogression and immune-related response in In this report, we describe a case of pulmonary adeno- solid tumors. J Clin Oncol. 2015;33:3541–3. carcinoma showing rapid progression of peritoneal dis- 7. Schwartz M. A biomathematical approach to clinical tumor growth. Cancer. 1961;14:1272–94. semination soon after a single administration of 8. Mackintosh JA, Marshall HM, Yang IA, Bowman RV, Fong KM. A retrospective pembrolizumab. It is likely that old age was a risk factor study of volume doubling time in surgically resected non-small cell lung for progressive disease after ICI treatment. Clinicians cancer. Respirol. 2014;19:755–62. 9. Patil T, Aisner DL, Noonan SA, Bunn PA, Purcell WT, Carr LL, et al. Malignant should consider the possibility of hyperprogressive dis- pleural disease is highly associated with subsequent peritoneal metastasis in ease in a small subset of patients after ICI treatment. patients with stage IV non-small cell lung cancer independent of oncogene Further studies are needed to elucidate the risk factors status. Lung Cancer. 2016;96:27–32. 10. Abrams HL, Spiro R, Goldstein N. Metastases in carcinoma; analysis of 1000 and mechanisms of hyperprogressive disease following autopsied cases. Cancer. 1950;3:74–85. immunotherapy. 11. McNeill PM, Wagman LD, Neifeld JP. Small bowel metastases from primary carcinoma of the lung. Cancer. 1987;59:1486–9. Abbreviations 12. Satoh H, Ishikawa H, Yamashita YT, Kurishima K, Ohtsuka M, Sekizawa K. ALK: Anaplastic lymphoma kinase; CT: Computed tomography; ECOG PS: Eastern Peritoneal carcinomatosis in lung cancer patients. Oncol Rep. 2001;8:1305–7. Cooperative Oncology Group performance status; EGFR: Epidermal growth factor 13. Sharon E. Can an immune checkpoint inhibitor (sometimes) make things receptor; ICI: Immune checkpoint inhibitor; NSCLC: Non-small cell lung worse? Clin Cancer Res. 2017;23:1879–81. cancer; PD-L1: Programmed death-ligand 1; TPS: Tumor proportion score Availability of data and materials All data generated or analyzed during this study are included in this published article. Authors’ contributions TS contributed to treatment decisions, the collection of clinical data, data analysis, and writing the manuscript. EI, SI, TM, TN, and TT contributed to the interpretation of the clinical data and chest images. KH contributed to the autopsies, pathological examinations, and immunohistochemical analysis. All authors have read and approved the final manuscript. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Cancer Springer Journals

A case of pulmonary adenocarcinoma showing rapid progression of peritoneal dissemination after immune checkpoint inhibitor therapy

Free
5 pages
Loading next page...
 
/lp/springer_journal/a-case-of-pulmonary-adenocarcinoma-showing-rapid-progression-of-SnfAdBwenF
Publisher
BioMed Central
Copyright
Copyright © 2018 by The Author(s).
Subject
Biomedicine; Cancer Research; Oncology; Surgical Oncology; Health Promotion and Disease Prevention; Biomedicine, general; Medicine/Public Health, general
eISSN
1471-2407
D.O.I.
10.1186/s12885-018-4549-5
Publisher site
See Article on Publisher Site

Abstract

Background: Immune checkpoint inhibitors are standard treatments for non-small cell lung cancer. Unique cases with paradoxical acceleration of the disease after immunotherapy have been reported. These have been described as cases of hyperprogressive disease. Case presentation: A 76-year-old man was diagnosed with pulmonary adenocarcinoma with pleural dissemination and liver and adrenal metastases. Genomic analysis revealed neither EGFR mutations nor ALK translocations. Immunohistochemical analysis revealed a programmed death-ligand 1 tumor proportion score of 23%. Chemotherapy with carboplatin, paclitaxel, and bevacizumab resulted in Grade 3 skin eruption and disease progression. Pembrolizumab was initiated as a second-line treatment. However, peritoneal dissemination and ascites developed. The patient died 2 weeks later. The autopsy revealed widespread peritoneal dissemination and an extensive hemorrhagic infarction. Conclusion: This was a rare case of hyperprogressive disease with rapid progression of peritoneal dissemination after pembrolizumab treatment. Keywords: Adenocarcinoma, Hyperprogressive disease, Immune checkpoint inhibitor, Lung cancer, Pembrolizumab, Peritoneal dissemination Background Herein, we report on a case of hyperprogressive Immune checkpoint inhibitors (ICIs) are currently disease after treatment with pembrolizumab, an ICI cur- standard treatments for non-small cell lung cancer rently used in the treatment of NSCLC. The clinical (NSCLC) [1, 2]. The unique adverse events that can course in this case was highly unusual as it exhibited arise after treatment with ICIs, including pneumonitis, rapid progression of peritoneal dissemination shortly colitis, and thyroiditis, are known as immune-related after a single administration of pembrolizumab. More- adverse events [3]. Recently, unique cases with para- over, this is one of the first reports to document hyper- doxical acceleration of the disease after immunother- progressive disease by autopsy. apy have been reported [4, 5]. These have been described as cases of hyperprogressive disease. In one Case presentation study, hyperprogressive disease was observed in 9% of A 76-year-old man with no history of smoking presented patients treated with ICIs [4]. with an abnormal shadow on chest X-ray. He had a medical history of hypertension, dyslipidemia, reflux esophagitis, and benign prostatic hyperplasia. He had * Correspondence: terasima@tdc.ac.jp mild dyspnea on exertion. Physical examination did not Department of Respiratory Medicine, Tokyo Dental College Ichikawa General reveal any abnormal findings and the results of the Hospital, 5-11-13 Sugano, Ichikawa, Chiba 272-0824, Japan Full list of author information is available at the end of the article © The Author(s). 2018 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. Shinozaki et al. BMC Cancer (2018) 18:620 Page 2 of 5 laboratory tests were within normal limits. The patient First-line chemotherapy with carboplatin (area under had an Eastern Cooperative Oncology Group perform- the curve, 6), paclitaxel (200 mg/m ), and bevacizumab ance status (ECOG PS) score of 1. Chest X-ray revealed (15 mg/kg) was initiated for pulmonary adenocarcinoma a tumor in the left hilar region and left pleural effusion. cT3N1M1c (Stage IVB). However, skin eruption devel- This was confirmed by enhanced computed tomography oped during the week following administration and (CT) scan, which showed a 40 mm tumor in the left spread to his whole body. The size of the liver metastasis lower lobe with left pleural effusion. Enhanced CT scan in the S4 region also increased from 1.0 to 1.3 cm and of the abdomen revealed liver and adrenal metastases. new liver metastases were detected (Fig. 2). The ECOG Tissue specimens obtained by bronchoscopy revealed a PS score of the patient was 1. Since the patient’s skin well-differentiated adenocarcinoma (Fig. 1a). Genomic eruption was classified as a Grade 3 adverse event (Com- analysis was performed to identify whether there were mon Terminology Criteria for Adverse Events, version any driver mutations present. This revealed that there 4.0) and the disease was progressive, treatment was were no sensitizing mutations in the epidermal growth switched to an ICI. Pembrolizumab (200 mg/body) was factor receptor (EGFR) gene, nor were there transloca- administered as a second-line treatment. Following ad- tions in the anaplastic lymphoma kinase (ALK) gene. Im- ministration, the patient began to experience a gradual munohistochemical analysis of programmed death-ligand loss of appetite and abdominal distension, followed by a 1 (PD-L1) expression using the murine 22C-3 antibody, worsening of his general condition. On Day 13 after expressed as the tumor proportion score (TPS), revealed a pembrolizumab administration, an enhanced CT scan TPS of 23% (Fig. 1b). Furthermore, there were no in- showed progression of the liver metastases (Fig. 3a). creases in the serum levels of various tumor markers. There was also a large amount of ascites and widespread peritoneal dissemination (Fig. 3b, c). These were novel findings that had not been observed prior to pembroli- zumab treatment. The patient died suddenly due to rapid progression of respiratory failure on Day 14 after pembrolizumab administration. An autopsy revealed extensive Stage IV lung adenocar- cinoma originating from the left lower lobe with metas- tases in the lungs, left pleura, liver, adrenal glands, kidneys, pancreas, stomach, small intestine, colon, bone marrow, and lymph nodes of the bilateral hilar and para-aortic lesions. Dissemination to the peritoneum (Fig. 4), omentum, and diaphragm was also documented by autopsy. Microscopic examination of the peritoneal Fig. 1 Histopathological findings of tissue specimens obtained under bronchoscopy. a Hematoxylin and eosin staining showing a Fig. 2 Enhanced computed tomography (CT) imaging. CT was well-differentiated adenocarcinoma (200× magnification). b 22C-3 performed after a single course of cytotoxic chemotherapy. The size antibody staining against programmed death-ligand 1. Tumor of the liver metastasis in the S4 region increased from 1.0 to proportion score, 23% 1.3 cm (arrow) Shinozaki et al. BMC Cancer (2018) 18:620 Page 3 of 5 Fig. 4 Macroscopic examination of the autopsy specimens revealed widespread peritoneal dissemination (arrows) Fig. 3 Enhanced computed tomography (CT) imaging. a After a single administration of pembrolizumab, the size of the liver metastasis increased from 1.3 to 1.6 cm (arrow). b and c Widespread peritoneal dissemination (arrows) and a large amount of ascites were visible after pembrolizumab treatment tissue confirmed the presence of a well-differentiated in- vasive adenocarcinoma (Fig. 5a). Immunohistochemical analysis of the peritoneal tissue revealed that the PD-L1 TPS of the tumor cells was 12% (Fig. 5b), which is simi- Fig. 5 Histopathological findings of peritoneal autopsy specimens. lar to the score for the tumor tissue obtained by bron- a Hematoxylin and eosin staining of the peritoneal tissue revealed an invasive, well-differentiated adenocarcinoma (100× magnification). choscopy. Overexpression of the MDM2 gene was not b 22C-3 antibody staining against programmed death-ligand 1. Tumor detected by immunohistochemistry. In addition to these proportion score, 12% findings, an extensive hemorrhagic infarction due to Shinozaki et al. BMC Cancer (2018) 18:620 Page 4 of 5 tumor embolism was observed in the right lung the present case ruled out the possibility of pseudopro- (Fig. 6a, b). This was recorded as the cause of death gression. Champiat et al. proposed that hyperprogressive based on the autopsy. disease should be defined as a > 2.0-fold increase in tumor growth rate after immunotherapy [4]. Kato et al. Discussion and conclusions defined hyperprogressive disease as a time-to-treatment To the best of our knowledge, this is the first case of failure of < 2 months, a > 50.0% increase in tumor bur- lung cancer with hyperprogressive disease showing rapid den, and > 2.0-fold increase in tumor growth rate [5]. In progression of peritoneal dissemination after ICI treat- our case, the scale measurable region was the liver me- ment. Moreover, this is the first case where hyperpro- tastases. The time elapsed between the 1.0 to 1.3 cm gressive disease was documented by autopsy. and 1.3 to 1.6 cm enlargement of the target lesion of Hyperprogressive disease has recently been described the liver was 51 and 19 days, respectively. The volume in cases treated with immunotherapy [4, 5]. In current doubling time before and after pembrolizumab treat- treatment strategies for advanced NSCLC, the ICI pem- ment was 45 and 21 days, respectively (volume doub- brolizumab is recommended as a first-line therapy in ling time = [(T1 − T0)·log2]/[3log(D1/D0)], where cases where the TPS is ≥50% and as a second-line ther- D1 and D0 are the diameters at T1 and T0, respectively) apy in cases where the TPS is 1–49% [1, 2]. It is critical [7]. There was a > 2.0-fold increase in tumor growth rate to determine whether the progression observed in this since tumor growth rate is the inverse of the volume case was hyperprogressive disease, pseudoprogression, doubling time (i.e., tumor growth rate = 1 / volume or natural progression, as is often observed in the ter- doubling time) [8]. minal stages of malignant diseases. ICIs are sometimes In a previous study, the median time from diagnosis of known to result in unique response patterns, such as Stage IV disease to peritoneal metastasis was 16.5 pseudoprogression [6]. However, the autopsy findings in (range, 0.6–108) months among 410 patients with metastatic NSCLC [9], which is notably longer than the 2.3 months in this case. Moreover, the time from pem- a brolizumab administration to peritoneal metastasis was just 0.4 months (13 days). The novel appearance of widespread peritoneal dissemination and a large amount of ascites within 13 days met the criteria of time-to-treatment failure of < 2 months and suggested that the clinical course of our case was much more rapid than the natural terminal course. Finally, autopsy findings revealed greater progression of the metastases than CT scan images taken 1 day prior to the patient’s death. Together, these indicate that this was a case of hyperprogressive disease. The clinical course of our case was highly unique due to the presence of widespread peritoneal dissemination. Peritoneal dissemination is a rare clinical event in lung cancer patients, with autopsy results indicating an inci- dence of 9.4–15.8% [10, 11]. It is even rarer that periton- eal dissemination develops during the clinical course. A 26-year study of 1024 lung cancer patients reported that only 12 patients (1.2%) developed clinically detectable peritoneal dissemination [12]. Another study found that in 410 patients with metastatic NSCLC, 33 pa- tients (8%) developed peritoneal dissemination and that this was highly associated with pleural dissemin- ation [9]. In our case, it is possible that pleural dissem- ination and hyperprogressive disease contributed to peritoneal dissemination. Fig. 6 Histopathological findings of autopsy specimens from the The mechanisms of hyperprogressive disease are not right lung. a Hematoxylin and eosin staining (100× magnification). yet understood. Tumor profiles and patient characteris- b Verhoeff-Van Gieson elastic staining. An extensive hemorrhagic tics are thought to be important factors. The finding that infarction due to tumor embolism was observed (arrow) the PD-L1 TPS was similar before and after the Shinozaki et al. BMC Cancer (2018) 18:620 Page 5 of 5 administration of pembrolizumab in our case was in Ethics approval and consent to participate Not applicable. agreement with the finding that hyperprogressive disease was not associated with the PD-L1 status of tumors [4]. Consent for publication Kato et al. showed that cancer patients with MDM2 Written informed consent was obtained from the patient’s family for publication of this case report and any accompanying images. gene amplification or EGFR mutations had increased rates of tumor growth after treatment with ICIs [5]. Competing interests However, in our case, EGFR was wild-type and there was The authors declare that they have no competing interests. no overexpression of the MDM2 gene. In terms of pa- tient characteristics, age > 65 years was identified as the Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in only associated factor for hyperprogressive disease [4]. published maps and institutional affiliations. Although there may be other unknown risk factors, it is likely that old age was the primary risk factor for pro- Author details Department of Respiratory Medicine, Tokyo Dental College Ichikawa General gressive disease in our case. Hospital, 5-11-13 Sugano, Ichikawa, Chiba 272-0824, Japan. Department of Our report has several limitations. Firstly, there is the Pathology and Laboratory Medicine, Tokyo Dental College Ichikawa General potential that the rapid progression seen in our patient Hospital, 5-11-13 Sugano, Ichikawa, Chiba 272-0824, Japan. was due to the natural course or intrinsic cancer biology Received: 28 January 2018 Accepted: 23 May 2018 rather than pembrolizumab therapy. In fact, the disease was chemoresistant and progressive prior to pembrolizu- References mab treatment. The widespread peritoneal dissemin- 1. Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, et al. ation, however, suggested accelerated progression after Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, pembrolizumab treatment. Secondly, the tumor growth advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387:1540–50. rate is not a standardized model for response and the 2. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. definition of hyperprogressive disease proposed by Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung Champiat et al. has not been widely accepted by the Cancer. N Engl J Med. 2016;375:1823–33. 3. Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F, Postel-Vinay S, broader oncology community [13]. In our case, the rapid et al. Immune-related adverse events with immune checkpoint blockade: a growth of the tumor was shown by a shortening of the comprehensive review. Eur J Cancer. 2016;54:139–48. doubling time of the target lesion of the liver. The 4. Champiat S, Dercle L, Ammari S, Massard C, Hollebecque A, Postel-Vinay S, et al. Hyperprogressive disease is a new pattern of progression in Cancer strength of our case is the fact that true progression was patients treated by anti-PD-1/PD-L1. Clin Cancer Res. 2017;23:1920–8. documented by autopsy and that autopsy specimens will 5. Kato S, Goodman A, Walavalkar V, Barkauskas DA, Sharabi A, Kurzrock R. be useful for elucidating the mechanisms of hyperpro- Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res. 2017;23:4242–50. gressive disease in the future. 6. Chiou VL, Burotto M. Pseudoprogression and immune-related response in In this report, we describe a case of pulmonary adeno- solid tumors. J Clin Oncol. 2015;33:3541–3. carcinoma showing rapid progression of peritoneal dis- 7. Schwartz M. A biomathematical approach to clinical tumor growth. Cancer. 1961;14:1272–94. semination soon after a single administration of 8. Mackintosh JA, Marshall HM, Yang IA, Bowman RV, Fong KM. A retrospective pembrolizumab. It is likely that old age was a risk factor study of volume doubling time in surgically resected non-small cell lung for progressive disease after ICI treatment. Clinicians cancer. Respirol. 2014;19:755–62. 9. Patil T, Aisner DL, Noonan SA, Bunn PA, Purcell WT, Carr LL, et al. Malignant should consider the possibility of hyperprogressive dis- pleural disease is highly associated with subsequent peritoneal metastasis in ease in a small subset of patients after ICI treatment. patients with stage IV non-small cell lung cancer independent of oncogene Further studies are needed to elucidate the risk factors status. Lung Cancer. 2016;96:27–32. 10. Abrams HL, Spiro R, Goldstein N. Metastases in carcinoma; analysis of 1000 and mechanisms of hyperprogressive disease following autopsied cases. Cancer. 1950;3:74–85. immunotherapy. 11. McNeill PM, Wagman LD, Neifeld JP. Small bowel metastases from primary carcinoma of the lung. Cancer. 1987;59:1486–9. Abbreviations 12. Satoh H, Ishikawa H, Yamashita YT, Kurishima K, Ohtsuka M, Sekizawa K. ALK: Anaplastic lymphoma kinase; CT: Computed tomography; ECOG PS: Eastern Peritoneal carcinomatosis in lung cancer patients. Oncol Rep. 2001;8:1305–7. Cooperative Oncology Group performance status; EGFR: Epidermal growth factor 13. Sharon E. Can an immune checkpoint inhibitor (sometimes) make things receptor; ICI: Immune checkpoint inhibitor; NSCLC: Non-small cell lung worse? Clin Cancer Res. 2017;23:1879–81. cancer; PD-L1: Programmed death-ligand 1; TPS: Tumor proportion score Availability of data and materials All data generated or analyzed during this study are included in this published article. Authors’ contributions TS contributed to treatment decisions, the collection of clinical data, data analysis, and writing the manuscript. EI, SI, TM, TN, and TT contributed to the interpretation of the clinical data and chest images. KH contributed to the autopsies, pathological examinations, and immunohistochemical analysis. All authors have read and approved the final manuscript.

Journal

BMC CancerSpringer Journals

Published: May 31, 2018

References

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off