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Early Gastrointestinal Progression to Immunotherapy in Lung Cancer: A Report of Two Cases

Early Gastrointestinal Progression to Immunotherapy in Lung Cancer: A Report of Two Cases Hindawi Case Reports in Oncological Medicine Volume 2021, Article ID 6692538, 5 pages https://doi.org/10.1155/2021/6692538 Case Report Early Gastrointestinal Progression to Immunotherapy in Lung Cancer: A Report of Two Cases 1,2,3 2 2 2 Federica Martorana , Katia Lanzafame, Giuliana Pavone, Lucia Motta, 2 2 2 4 Gianmarco Motta, Nicola Inzerilli, Rosaria Carciotto, Giada Maria Vecchio, 4 2 4 1,2,3 Antonino Maria Zanghì, Héctor Josè Soto Parra, Gaetano Magro, and Paolo Vigneri Dept. of Clinical and Experimental Medicine, University of Catania-Catania, Via Santa Sofia, 78-95123 Catania, Sicily, Italy Division of Medical Oncology-A.O.U. Policlinico G. Rodolico-San Marco-Catania, Via Santa Sofia, 78-95123 Catania, Sicily, Italy Center of Experimental Oncology and Hematology-A.O.U. Policlinico G. Rodolico-San Marco-Catania, Via Santa Sofia, 78- 95123 Catania, Sicily, Italy Dept. of Medical and Surgical Sciences and Advanced Technology G. F. Ingrassia-A.O.U. Policlinico G. Rodolico-San Marco- Catania, Via Santa Sofia 87, 95123 Catania, Sicily, Italy Correspondence should be addressed to Federica Martorana; fede.marto.fm@gmail.com Received 23 December 2020; Revised 13 February 2021; Accepted 20 February 2021; Published 1 March 2021 Academic Editor: Jose I. Mayordomo Copyright © 2021 Federica Martorana et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Intestinal and pancreatic metastases are rare and often challenging to recognize and manage. Lung cancer patients with enteric involvement usually display poor outcomes. Hyperprogression to immunotherapy represents a concern, even though there is currently no agreement on its exact definition. Gastrointestinal hyperprogression to immune checkpoint inhibitors has not been described so far. In these cases, distinguishing disease-related symptoms from immune-related adverse events may represent a diagnostic conundrum. Here, we report two cases of non-small-cell lung cancer experiencing a rapid pancreatic and colic progression to immunotherapy, respectively. While further investigations to identify biomarkers associated with hyperprogression are warranted, clinicians should be aware of the potential unusual clinical presentations of this phenomenon. 1. Introduction of patients receiving immune checkpoint inhibitors experi- ence rapid disease evolution during treatment, a phenome- Lung cancer commonly metastasizes to the bone, contralat- non known as hyperprogression (HP) [6, 7]. To the best of eral lung, liver, adrenal glands, brain, and lymph nodes, but our knowledge, no data are available about the occurrence less frequently it spreads to other anatomic sites, including of gastrointestinal HP to immunotherapy in lung cancer. the gastrointestinal system [1, 2]. Indeed, enteric metastases Here, we report two cases of NSCLC with a rapid and have been infrequently described in patients with non- unusual pancreatic and intestinal progression during treat- small-cell lung cancer (NSCLC). Clinical presentation can ment with the anti-Programmed Death-1 (PD-1) monoclo- be either abrupt with bleeding, bowel obstruction, or perfora- nal antibody nivolumab. tion, requiring intensive care in a hospital setting, or sub- acute, with abdominal pain, progressive anaemia, or 2. Cases Presentation jaundice. Unfortunately, patients with gastrointestinal 2.1. Case#1. In December 2015, a 68-year-old Caucasian man metastases display a dismal prognosis regardless of their clin- with a 55 pack-years smoking history, chronic obstructive ical presentation [3–5]. While immunotherapy has signifi- pulmonary disease, type 2 diabetes, hypercholesterolemia, cantly improved the outcomes of stage IV NSCLC, a subset 2 Case Reports in Oncological Medicine (a) (b) (c) (d) Figure 1: MR imaging of the pancreatic head mass (a) of the larger liver metastasis (b) and of the biliary dilatation (c). CT imaging of the biliary drainage (d). and hypertension presented to the Emergency Room because Imaging (MRI) of the abdomen that showed a bulky lesion of persistent cough and haemoptysis. A whole body Com- of the pancreatic head, partially infiltrating the duodenal wall puted Tomography (CT) scan revealed a 60 mm mass in and causing visible distension of both the Wirsung and the the left lung along with several satellite nodules in the same intrahepatic biliary ducts. Moreover, multiple hepatic and lobe. Both the CT and an ensuing Positron Emission Tomog- nodal metastases emerged (Figure 1). Given these findings, raphy (PET) scan excluded the presence of distant metasta- the patient underwent percutaneous trans-hepatic cholangi- ses. Thus, in February 2016, he underwent a left ography with biliary drainage, stenting, and cytological sam- pneumonectomy with lymph nodal dissection. The pathol- pling, the latter consistent with lung cancer metastasis. Once ogy report indicated the presence of a poorly differentiated bilirubin levels normalized, he began third line chemother- squamous cell carcinoma, pT3 (main diameter 60 mm) N0 apy with weekly paclitaxel. However, in the following six (0 out of 24) M0 (stage II according to the UICC/AJCC months his clinical conditions progressively deteriorated, TNM 7th edition). From March to July 2016, he received four and in June 2017, he developed persistent fever, abdominal cycles of adjuvant cisplatin plus vinorelbine, but one month pain, anorexia, and weight loss. He therefore suspended after completing the last chemotherapy infusion, both CT active treatment and eventually died in August 2017. and PET scans showed hepatic and para-aortic nodal relapse that were confirmed by a liver biopsy. Programmed Death- 2.2. Case#2. In November 2016, a 69-year-old Caucasian Ligand 1 (PD-L1) immunohistochemical expression, male came to our attention because of the acute onset of dys- assessed on the metastatic tissue, was below 1%. Given the pnoea and haemoptysis. He was a 35-pack-year former short interval between the end of adjuvant chemotherapy smoker since 2010, and his previous medical history was notable for myocardial infarction, diabetes mellitus, bilateral and the disease relapse, in September 2016 the patient started a second line treatment with nivolumab 3 mg/kg every two glaucoma, and benign prostatic hyperplasia. A CT scan weeks. After the third administration of immunotherapy, showed a 40 × 33 mm mass in the right lung invading the he developed progressive jaundice, fever, nausea, and vomit- main bronchus, with increased metabolic activity (Standard- ing along with a rise in bilirubin, alkaline phosphatase, and ized Uptake Value (SUV) 41) at the PET scan. An ensuing bronchoscopy indicated the presence of a poorly differenti- glutamyl-transpeptidase. Because of these symptoms, ini- tially attributed to an immune-related adverse events, the ated lung adenocarcinoma for which he received four cycles patient was admitted to the oncology ward where he received of neo-adjuvant chemotherapy with cisplatin and vinorel- high-dose corticosteroids (prednisone 1 mg/kg intrave- bine, achieving a satisfactory dimensional and metabolic nously). However, in the absence of any meaningful clinical response. Thus, in April 2017, he underwent a right upper lobectomy with mediastinal node dissection. The benefit after 48 hours, he performed a Magnetic Resonance Case Reports in Oncological Medicine 3 (a) (b) Figure 2: Endoscopic imaging of lung adenocarcinoma metastasis in the splenic flexure and (a) CT imaging of left colonic wall thickening (b). pathologist’s assessment revealed a 30 mm poorly differenti- ated adenocarcinoma of the lung, Cytokeratin 7, and Thyroid Transcription Factor 1 (TTF1) positive, with involvement of the main bronchus (pT2b) and no nodal metastases (0 out of 21; stage IIB according to the UICC/AJCC TNM 7th edition). Five months after surgery the patient noticed a rapidly grow- ing subcutaneous lump in his right thigh and another one in his left axilla, both excised and histologically proven to be lung adenocarcinoma metastases. No Epidermal Growth Factor Receptor (EGFR) mutations or Anaplastic Lymphoma Kinase (ALK) translocations were detected, and immunohis- tochemical staining for PD-L1 was below 1%. Hence, in December 2017, he began first line chemotherapy with car- boplatin and pemetrexed, experiencing disease stabilization, followed by pemetrexed maintenance until April 2018, when a CT scan showed an abdominal nodal progression. At this time, the patient received second line treatment with nivolu- mab 240 mg every two weeks, from May to August 2018. However, throughout these months, he experienced progres- CK7 CK20 sively worsening fatigue and developed G1 anaemia. After the 6th nivolumab cycle, a CT scan revealed a new cerebellar Figure 3: Intestinal biopsy: normal colonic mucosa infiltrated by lesion, confirmed by MRI and treated with stereotactic radi- solid-pseudoglandolar carcinoma, positive for CK7 and negative ation therapy. The CT exam also documented extensive for intestinal differentiation markers, such as CK20 and CDX2 nodal progression and a left colonic wall thickening, further (arrows). Lung adenocarcinomas with prevalent solid pattern may investigated with a colonoscopy which revealed an ulcerated be negative for TTF-1 but often positive for CK7. On the basis of lesion in the splenic flexure histologically consistent with a the morpho-immunohistochemical data and clinical history, the diagnosis of intestinal metastasis of lung adenocarcinoma was lung adenocarcinoma metastasis (Figures 2 and 3). Thus, in made. September 2018, he underwent palliative segmental resection of the left colon, which confirmed the diagnosis of intestinal metastasis of lung adenocarcinoma (Figure 4). Upon recov- ery, he began third line chemotherapy with weekly paclitaxel of which he received only two cycles, as he developed both G2 anaemia and melena. A new colonoscopy showed cancer relapse at the site of the previous surgery, whereas a CT scan performed in January 2019 revealed nodal and hepatic progression, along with a femoral vein thrombosis. Because of the latter finding, interventional radiologists positioned an inferior vena cava filter. The patient continued best supportive care and died in August 2019. CK7 3. Discussion Figure 4: Surgical findings: the diagnosis of lung adenocarcinoma metastasis was confirmed after surgical resection. The figure shows We describe here two cases of metastatic NSCLC with intramural CK7 positive neoplasia, with a normal underlying unusual early gastrointestinal progression to the immune colonic mucosa. 4 Case Reports in Oncological Medicine checkpoint inhibitor nivolumab. Both patients were heavy histological samples. FM and LM did the literature search. smokers (i.e., >30 pack-years) presenting with a squamous PV, FM, KL, GP, and LM drafted the manuscript. All authors cell carcinoma or an adenocarcinoma, the histological vari- read and approved the final manuscript. ants most frequently associated with pancreatic and intesti- nal involvement, respectively [3, 4, 8]. However, no data are currently available concerning the EGFR, ALK, and PD-L1 References status of these tumours. Consistent with preexisting evi- [1] L. E. Quint, S. Tummala, L. J. Brisson et al., “Distribution of dence, clinical manifestations of gastrointestinal metastases distant metastases from newly diagnosed non-small cell lung were severe and led to treatment discontinuation, heavily cancer,” The Annals of Thoracic Surgery, vol. 62, no. 1, worsening the patients’ quality of life [5]. Moreover, symp- pp. 246–250, 1996. toms were difficult to recognize, and even after radiological [2] F. Y. Niu, Q. Zhou, J. J. Yang et al., “Distribution and prognosis diagnosis, a biopsy was mandatory to rule out a second syn- of uncommon metastases from non-small cell lung cancer,” chronous cancer. Although our patients received additional BMC Cancer, vol. 16, no. 1, p. 149, 2016. chemotherapy after discontinuing nivolumab, they lacked [3] N. V. Adsay, A. Andea, O. Basturk, N. Kilinc, H. Nassar, and any consistent benefit from the subsequent treatment J. D. Cheng, “Secondary tumors of the pancreas: an analysis (weekly paclitaxel). However, our patients experienced a 9- of a surgical and autopsy database and review of the literature,” month and a 12-month survival from the detection of the Virchows Archiv, vol. 444, no. 6, pp. 527–535, 2004. enteric lesions, respectively. Hence, their survival is signifi- [4] Y. Hu, N. Feit, Y. Huang, W. Xu, S. Zheng, and X. Li, “Gastro- cantly longer than the one reported in the literature (2.8 intestinal metastasis of primary lung cancer: an analysis of months) [4, 5]. 366 cases,” Oncology Letters, vol. 15, no. 6, pp. 9766–9776, To the best of our knowledge, this is the first report of gastrointestinal hyperprogression to immunotherapy in lung [5] K. R. Badipatla, N. Yadavalli, T. Vakde, M. Niazi, and H. K. cancer. Of note, Miyazawa and colleagues reported two cases Patel, “Lung cancer metastasis to the gastrointestinal system: of metastatic melanoma spreading to the small bowel and the an enigmatic occurrence,” World Journal of Gastrointestinal colon during nivolumab treatment [9]. Due to the rapid and Oncology, vol. 9, no. 3, pp. 129–134, 2017. extensive disease progression that our patients experienced, [6] H. I. Assi, A. O. Kamphorst, N. M. Moukalled, and S. S. Rama- we deemed them “hyper-progressors.” Although several lingam, “Immune checkpoint inhibitors in advanced non- studies recently provided an overview about HP, this phe- small cell lung cancer,” Cancer, vol. 124, no. 2, pp. 248–261, nomenon is still matter of debate [10–12]. However, prelim- 2018. inary evidences are emerging about potential molecular [7] R. Ferrara, L. Mezquita, M. Texier et al., “Hyperprogressive biomarkers useful in the timely identification of hyperpro- disease in patients with advanced non-small cell lung cancer gressing patients [11, 13–15]. It is crucial to promptly and treated with PD-1/PD-L1 inhibitors or with single-agent che- correctly recognize NSCLC gastrointestinal progression as motherapy,” JAMA Oncology, vol. 4, no. 11, pp. 1543–1552, this atypical metastatic spread, usually associated with subtle and equivocal symptoms, may result in diagnostic delay. In [8] G. Rossi, A. Marchioni, E. Romagnani et al., “Primary lung cancer presenting with gastrointestinal tract involvement: clin- addition, if an intestinal progression occurs during immuno- icopathologic and immunohistochemical features in a series of therapy, its clinical identification can be extremely challeng- 18 consecutive cases,” Journal of Thoracic Oncology, vol. 2, ing as it may be potentially mistaken for an immune- no. 2, pp. 115–120, 2007. related complication. The present report emphasizes the pos- [9] H. Miyazawa, T. Yanagi, Y. Yamaguchi et al., “Two cases of sibility of an unusual enteric metastatic disease in patients melanomas paradoxically metastasizing to the intestinal tract affected by NSCLC treated with immune checkpoint inhibi- during nivolumab therapy,” The Journal of Dermatology, tors. As an increasing number of patients will receive anti- vol. 44, no. 8, pp. 959–962, 2017. PD-1 or anti-PD-L1 antibodies, a concerted effort is needed [10] S. Champiat, L. Dercle, S. Ammari et al., “Hyperprogressive in order to identify biomarkers predictive of HP. disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1,” Clinical Cancer Research, Data Availability vol. 23, no. 8, pp. 1920–1928, 2017. [11] S. Kato, A. Goodman, V. Walavalkar, D. A. Barkauskas, The underlying data supporting the results of the study can A. Sharabi, and R. Kurzrock, “Hyperprogressors after immu- be found in the manuscript. notherapy: analysis of genomic alterations associated with accelerated growth rate,” Clinical Cancer Research, vol. 23, Conflicts of Interest no. 15, pp. 4242–4250, 2017. [12] E. Saâda-Bouzid, C. Defaucheux, A. Karabajakian et al., The authors declare that there is no conflict of interest “Hyperprogression during anti-PD-1/PD-L1 therapy in regarding the publication of this paper. patients with recurrent and/or metastatic head and neck squa- mous cell carcinoma,” Annals of Oncology, vol. 28, no. 7, pp. 1605–1611, 2017. Authors’ Contributions [13] D. A. Knorr and J. V. Ravetch, “Immunotherapy and hyper- FM, KL, GP, LM, GM, NI, RC, HSP, AZ, and PV participated progression: unwanted outcomes, unclear mechanism,” Clini- in the patient’s treatment. GMV and GAM reviewed the cal Cancer Research, vol. 25, no. 3, pp. 904–906, 2019. Case Reports in Oncological Medicine 5 [14] P. Vigneri, F. Martorana, L. Manzella, and S. Stella, “Bio- markers and prognostic factors for malignant pleural mesothe- lioma,” Future Oncology, vol. 11, no. 24s, pp. 29–33, 2015. [15] X. Wang, F. Wang, M. Zhong, Y. Yarden, and L. Fu, “The bio- markers of hyperprogressive disease in PD-1/PD-L1 blockage therapy,” Molecular Cancer, vol. 19, no. 1, p. 81, 2020. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Case Reports in Oncological Medicine Hindawi Publishing Corporation

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Abstract

Hindawi Case Reports in Oncological Medicine Volume 2021, Article ID 6692538, 5 pages https://doi.org/10.1155/2021/6692538 Case Report Early Gastrointestinal Progression to Immunotherapy in Lung Cancer: A Report of Two Cases 1,2,3 2 2 2 Federica Martorana , Katia Lanzafame, Giuliana Pavone, Lucia Motta, 2 2 2 4 Gianmarco Motta, Nicola Inzerilli, Rosaria Carciotto, Giada Maria Vecchio, 4 2 4 1,2,3 Antonino Maria Zanghì, Héctor Josè Soto Parra, Gaetano Magro, and Paolo Vigneri Dept. of Clinical and Experimental Medicine, University of Catania-Catania, Via Santa Sofia, 78-95123 Catania, Sicily, Italy Division of Medical Oncology-A.O.U. Policlinico G. Rodolico-San Marco-Catania, Via Santa Sofia, 78-95123 Catania, Sicily, Italy Center of Experimental Oncology and Hematology-A.O.U. Policlinico G. Rodolico-San Marco-Catania, Via Santa Sofia, 78- 95123 Catania, Sicily, Italy Dept. of Medical and Surgical Sciences and Advanced Technology G. F. Ingrassia-A.O.U. Policlinico G. Rodolico-San Marco- Catania, Via Santa Sofia 87, 95123 Catania, Sicily, Italy Correspondence should be addressed to Federica Martorana; fede.marto.fm@gmail.com Received 23 December 2020; Revised 13 February 2021; Accepted 20 February 2021; Published 1 March 2021 Academic Editor: Jose I. Mayordomo Copyright © 2021 Federica Martorana et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Intestinal and pancreatic metastases are rare and often challenging to recognize and manage. Lung cancer patients with enteric involvement usually display poor outcomes. Hyperprogression to immunotherapy represents a concern, even though there is currently no agreement on its exact definition. Gastrointestinal hyperprogression to immune checkpoint inhibitors has not been described so far. In these cases, distinguishing disease-related symptoms from immune-related adverse events may represent a diagnostic conundrum. Here, we report two cases of non-small-cell lung cancer experiencing a rapid pancreatic and colic progression to immunotherapy, respectively. While further investigations to identify biomarkers associated with hyperprogression are warranted, clinicians should be aware of the potential unusual clinical presentations of this phenomenon. 1. Introduction of patients receiving immune checkpoint inhibitors experi- ence rapid disease evolution during treatment, a phenome- Lung cancer commonly metastasizes to the bone, contralat- non known as hyperprogression (HP) [6, 7]. To the best of eral lung, liver, adrenal glands, brain, and lymph nodes, but our knowledge, no data are available about the occurrence less frequently it spreads to other anatomic sites, including of gastrointestinal HP to immunotherapy in lung cancer. the gastrointestinal system [1, 2]. Indeed, enteric metastases Here, we report two cases of NSCLC with a rapid and have been infrequently described in patients with non- unusual pancreatic and intestinal progression during treat- small-cell lung cancer (NSCLC). Clinical presentation can ment with the anti-Programmed Death-1 (PD-1) monoclo- be either abrupt with bleeding, bowel obstruction, or perfora- nal antibody nivolumab. tion, requiring intensive care in a hospital setting, or sub- acute, with abdominal pain, progressive anaemia, or 2. Cases Presentation jaundice. Unfortunately, patients with gastrointestinal 2.1. Case#1. In December 2015, a 68-year-old Caucasian man metastases display a dismal prognosis regardless of their clin- with a 55 pack-years smoking history, chronic obstructive ical presentation [3–5]. While immunotherapy has signifi- pulmonary disease, type 2 diabetes, hypercholesterolemia, cantly improved the outcomes of stage IV NSCLC, a subset 2 Case Reports in Oncological Medicine (a) (b) (c) (d) Figure 1: MR imaging of the pancreatic head mass (a) of the larger liver metastasis (b) and of the biliary dilatation (c). CT imaging of the biliary drainage (d). and hypertension presented to the Emergency Room because Imaging (MRI) of the abdomen that showed a bulky lesion of persistent cough and haemoptysis. A whole body Com- of the pancreatic head, partially infiltrating the duodenal wall puted Tomography (CT) scan revealed a 60 mm mass in and causing visible distension of both the Wirsung and the the left lung along with several satellite nodules in the same intrahepatic biliary ducts. Moreover, multiple hepatic and lobe. Both the CT and an ensuing Positron Emission Tomog- nodal metastases emerged (Figure 1). Given these findings, raphy (PET) scan excluded the presence of distant metasta- the patient underwent percutaneous trans-hepatic cholangi- ses. Thus, in February 2016, he underwent a left ography with biliary drainage, stenting, and cytological sam- pneumonectomy with lymph nodal dissection. The pathol- pling, the latter consistent with lung cancer metastasis. Once ogy report indicated the presence of a poorly differentiated bilirubin levels normalized, he began third line chemother- squamous cell carcinoma, pT3 (main diameter 60 mm) N0 apy with weekly paclitaxel. However, in the following six (0 out of 24) M0 (stage II according to the UICC/AJCC months his clinical conditions progressively deteriorated, TNM 7th edition). From March to July 2016, he received four and in June 2017, he developed persistent fever, abdominal cycles of adjuvant cisplatin plus vinorelbine, but one month pain, anorexia, and weight loss. He therefore suspended after completing the last chemotherapy infusion, both CT active treatment and eventually died in August 2017. and PET scans showed hepatic and para-aortic nodal relapse that were confirmed by a liver biopsy. Programmed Death- 2.2. Case#2. In November 2016, a 69-year-old Caucasian Ligand 1 (PD-L1) immunohistochemical expression, male came to our attention because of the acute onset of dys- assessed on the metastatic tissue, was below 1%. Given the pnoea and haemoptysis. He was a 35-pack-year former short interval between the end of adjuvant chemotherapy smoker since 2010, and his previous medical history was notable for myocardial infarction, diabetes mellitus, bilateral and the disease relapse, in September 2016 the patient started a second line treatment with nivolumab 3 mg/kg every two glaucoma, and benign prostatic hyperplasia. A CT scan weeks. After the third administration of immunotherapy, showed a 40 × 33 mm mass in the right lung invading the he developed progressive jaundice, fever, nausea, and vomit- main bronchus, with increased metabolic activity (Standard- ing along with a rise in bilirubin, alkaline phosphatase, and ized Uptake Value (SUV) 41) at the PET scan. An ensuing bronchoscopy indicated the presence of a poorly differenti- glutamyl-transpeptidase. Because of these symptoms, ini- tially attributed to an immune-related adverse events, the ated lung adenocarcinoma for which he received four cycles patient was admitted to the oncology ward where he received of neo-adjuvant chemotherapy with cisplatin and vinorel- high-dose corticosteroids (prednisone 1 mg/kg intrave- bine, achieving a satisfactory dimensional and metabolic nously). However, in the absence of any meaningful clinical response. Thus, in April 2017, he underwent a right upper lobectomy with mediastinal node dissection. The benefit after 48 hours, he performed a Magnetic Resonance Case Reports in Oncological Medicine 3 (a) (b) Figure 2: Endoscopic imaging of lung adenocarcinoma metastasis in the splenic flexure and (a) CT imaging of left colonic wall thickening (b). pathologist’s assessment revealed a 30 mm poorly differenti- ated adenocarcinoma of the lung, Cytokeratin 7, and Thyroid Transcription Factor 1 (TTF1) positive, with involvement of the main bronchus (pT2b) and no nodal metastases (0 out of 21; stage IIB according to the UICC/AJCC TNM 7th edition). Five months after surgery the patient noticed a rapidly grow- ing subcutaneous lump in his right thigh and another one in his left axilla, both excised and histologically proven to be lung adenocarcinoma metastases. No Epidermal Growth Factor Receptor (EGFR) mutations or Anaplastic Lymphoma Kinase (ALK) translocations were detected, and immunohis- tochemical staining for PD-L1 was below 1%. Hence, in December 2017, he began first line chemotherapy with car- boplatin and pemetrexed, experiencing disease stabilization, followed by pemetrexed maintenance until April 2018, when a CT scan showed an abdominal nodal progression. At this time, the patient received second line treatment with nivolu- mab 240 mg every two weeks, from May to August 2018. However, throughout these months, he experienced progres- CK7 CK20 sively worsening fatigue and developed G1 anaemia. After the 6th nivolumab cycle, a CT scan revealed a new cerebellar Figure 3: Intestinal biopsy: normal colonic mucosa infiltrated by lesion, confirmed by MRI and treated with stereotactic radi- solid-pseudoglandolar carcinoma, positive for CK7 and negative ation therapy. The CT exam also documented extensive for intestinal differentiation markers, such as CK20 and CDX2 nodal progression and a left colonic wall thickening, further (arrows). Lung adenocarcinomas with prevalent solid pattern may investigated with a colonoscopy which revealed an ulcerated be negative for TTF-1 but often positive for CK7. On the basis of lesion in the splenic flexure histologically consistent with a the morpho-immunohistochemical data and clinical history, the diagnosis of intestinal metastasis of lung adenocarcinoma was lung adenocarcinoma metastasis (Figures 2 and 3). Thus, in made. September 2018, he underwent palliative segmental resection of the left colon, which confirmed the diagnosis of intestinal metastasis of lung adenocarcinoma (Figure 4). Upon recov- ery, he began third line chemotherapy with weekly paclitaxel of which he received only two cycles, as he developed both G2 anaemia and melena. A new colonoscopy showed cancer relapse at the site of the previous surgery, whereas a CT scan performed in January 2019 revealed nodal and hepatic progression, along with a femoral vein thrombosis. Because of the latter finding, interventional radiologists positioned an inferior vena cava filter. The patient continued best supportive care and died in August 2019. CK7 3. Discussion Figure 4: Surgical findings: the diagnosis of lung adenocarcinoma metastasis was confirmed after surgical resection. The figure shows We describe here two cases of metastatic NSCLC with intramural CK7 positive neoplasia, with a normal underlying unusual early gastrointestinal progression to the immune colonic mucosa. 4 Case Reports in Oncological Medicine checkpoint inhibitor nivolumab. Both patients were heavy histological samples. FM and LM did the literature search. smokers (i.e., >30 pack-years) presenting with a squamous PV, FM, KL, GP, and LM drafted the manuscript. All authors cell carcinoma or an adenocarcinoma, the histological vari- read and approved the final manuscript. ants most frequently associated with pancreatic and intesti- nal involvement, respectively [3, 4, 8]. However, no data are currently available concerning the EGFR, ALK, and PD-L1 References status of these tumours. Consistent with preexisting evi- [1] L. E. Quint, S. Tummala, L. J. Brisson et al., “Distribution of dence, clinical manifestations of gastrointestinal metastases distant metastases from newly diagnosed non-small cell lung were severe and led to treatment discontinuation, heavily cancer,” The Annals of Thoracic Surgery, vol. 62, no. 1, worsening the patients’ quality of life [5]. Moreover, symp- pp. 246–250, 1996. toms were difficult to recognize, and even after radiological [2] F. Y. Niu, Q. Zhou, J. J. Yang et al., “Distribution and prognosis diagnosis, a biopsy was mandatory to rule out a second syn- of uncommon metastases from non-small cell lung cancer,” chronous cancer. Although our patients received additional BMC Cancer, vol. 16, no. 1, p. 149, 2016. chemotherapy after discontinuing nivolumab, they lacked [3] N. V. Adsay, A. Andea, O. Basturk, N. Kilinc, H. Nassar, and any consistent benefit from the subsequent treatment J. D. Cheng, “Secondary tumors of the pancreas: an analysis (weekly paclitaxel). However, our patients experienced a 9- of a surgical and autopsy database and review of the literature,” month and a 12-month survival from the detection of the Virchows Archiv, vol. 444, no. 6, pp. 527–535, 2004. enteric lesions, respectively. Hence, their survival is signifi- [4] Y. Hu, N. Feit, Y. Huang, W. Xu, S. Zheng, and X. Li, “Gastro- cantly longer than the one reported in the literature (2.8 intestinal metastasis of primary lung cancer: an analysis of months) [4, 5]. 366 cases,” Oncology Letters, vol. 15, no. 6, pp. 9766–9776, To the best of our knowledge, this is the first report of gastrointestinal hyperprogression to immunotherapy in lung [5] K. R. Badipatla, N. Yadavalli, T. Vakde, M. Niazi, and H. K. cancer. Of note, Miyazawa and colleagues reported two cases Patel, “Lung cancer metastasis to the gastrointestinal system: of metastatic melanoma spreading to the small bowel and the an enigmatic occurrence,” World Journal of Gastrointestinal colon during nivolumab treatment [9]. Due to the rapid and Oncology, vol. 9, no. 3, pp. 129–134, 2017. extensive disease progression that our patients experienced, [6] H. I. Assi, A. O. Kamphorst, N. M. Moukalled, and S. S. Rama- we deemed them “hyper-progressors.” Although several lingam, “Immune checkpoint inhibitors in advanced non- studies recently provided an overview about HP, this phe- small cell lung cancer,” Cancer, vol. 124, no. 2, pp. 248–261, nomenon is still matter of debate [10–12]. However, prelim- 2018. inary evidences are emerging about potential molecular [7] R. Ferrara, L. Mezquita, M. Texier et al., “Hyperprogressive biomarkers useful in the timely identification of hyperpro- disease in patients with advanced non-small cell lung cancer gressing patients [11, 13–15]. It is crucial to promptly and treated with PD-1/PD-L1 inhibitors or with single-agent che- correctly recognize NSCLC gastrointestinal progression as motherapy,” JAMA Oncology, vol. 4, no. 11, pp. 1543–1552, this atypical metastatic spread, usually associated with subtle and equivocal symptoms, may result in diagnostic delay. In [8] G. Rossi, A. Marchioni, E. Romagnani et al., “Primary lung cancer presenting with gastrointestinal tract involvement: clin- addition, if an intestinal progression occurs during immuno- icopathologic and immunohistochemical features in a series of therapy, its clinical identification can be extremely challeng- 18 consecutive cases,” Journal of Thoracic Oncology, vol. 2, ing as it may be potentially mistaken for an immune- no. 2, pp. 115–120, 2007. related complication. The present report emphasizes the pos- [9] H. Miyazawa, T. Yanagi, Y. Yamaguchi et al., “Two cases of sibility of an unusual enteric metastatic disease in patients melanomas paradoxically metastasizing to the intestinal tract affected by NSCLC treated with immune checkpoint inhibi- during nivolumab therapy,” The Journal of Dermatology, tors. As an increasing number of patients will receive anti- vol. 44, no. 8, pp. 959–962, 2017. PD-1 or anti-PD-L1 antibodies, a concerted effort is needed [10] S. Champiat, L. Dercle, S. Ammari et al., “Hyperprogressive in order to identify biomarkers predictive of HP. disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1,” Clinical Cancer Research, Data Availability vol. 23, no. 8, pp. 1920–1928, 2017. [11] S. Kato, A. Goodman, V. Walavalkar, D. A. Barkauskas, The underlying data supporting the results of the study can A. Sharabi, and R. Kurzrock, “Hyperprogressors after immu- be found in the manuscript. notherapy: analysis of genomic alterations associated with accelerated growth rate,” Clinical Cancer Research, vol. 23, Conflicts of Interest no. 15, pp. 4242–4250, 2017. [12] E. Saâda-Bouzid, C. Defaucheux, A. Karabajakian et al., The authors declare that there is no conflict of interest “Hyperprogression during anti-PD-1/PD-L1 therapy in regarding the publication of this paper. patients with recurrent and/or metastatic head and neck squa- mous cell carcinoma,” Annals of Oncology, vol. 28, no. 7, pp. 1605–1611, 2017. Authors’ Contributions [13] D. A. Knorr and J. V. Ravetch, “Immunotherapy and hyper- FM, KL, GP, LM, GM, NI, RC, HSP, AZ, and PV participated progression: unwanted outcomes, unclear mechanism,” Clini- in the patient’s treatment. GMV and GAM reviewed the cal Cancer Research, vol. 25, no. 3, pp. 904–906, 2019. Case Reports in Oncological Medicine 5 [14] P. Vigneri, F. Martorana, L. Manzella, and S. Stella, “Bio- markers and prognostic factors for malignant pleural mesothe- lioma,” Future Oncology, vol. 11, no. 24s, pp. 29–33, 2015. [15] X. Wang, F. Wang, M. Zhong, Y. Yarden, and L. Fu, “The bio- markers of hyperprogressive disease in PD-1/PD-L1 blockage therapy,” Molecular Cancer, vol. 19, no. 1, p. 81, 2020.

Journal

Case Reports in Oncological MedicineHindawi Publishing Corporation

Published: Mar 1, 2021

References