Neoplasms Arising at the CIED Pocket: A Hybrid Study Combining Case Report, Scoping Review, and Clinical Survey.

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Francesca Fortunato, Ciro Iardino, Veronica Abate, Maria D’Armiento, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7009208/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 08 Jan, 2026 Read the published version in Internal and Emergency Medicine → Version 1 posted 4 You are reading this latest preprint version Abstract Cardiac implantable electronic device (CIED) implantation is a minor surgical procedure, with a low complication incidence. Neoplasm occurrence at the CIED pocket is a rare event, and sporadic cases are reported without a comprehensive evaluation. This hybrid study aims to fill this gap through a three-part approach: a new case report, a scoping review with individual patient data (IPD) analysis, and a clinical survey. In March 2024, a male patient with a history of high-grade urothelial cancer referred to our Department with a mass at the CIED pocket. Incisional biopsy confirmed the diagnosis of high-grade urothelial carcinoma. The patient died after 4 months. Through our scoping review and IPD analysis, we collected 56 patients affected by primary neoplasms [40 (71.4%)] and metastasis [16 (28.6%)] at the CIED pocket. Among the primary neoplasms, adenocarcinoma (12; 30.0%) was most frequent in females, while sarcoma (10; 25.0%) was predominant in males. On the other hand, metastasis types were represented by breast cancer (3; 18.8%) in females, and myeloma (2; 13.3%) and melanoma (2; 13.3%) in males. The clinical survey showed data from 471 patients who underwent CIED implantation. No primary neoplasm or metastasis developed at the CIED pocket, also in subjects with history of cancer. Although rare, both primary and metastatic neoplasms may occur at the site of CIED implantation. Vigilant monitoring of CIED patients is essential, particularly when changes at the pocket site arise. Early biopsy and oncologic assessment should be considered in such cases to enable timely diagnosis and intervention. CIED cancer neoplasm metastasis Figures Figure 1 Introduction Since their introduction in the 1960s, cardiac implantable electronic devices (CIEDs), including permanent pacemakers and implantable cardioverter-defibrillators, have represented a significant breakthrough in the clinical management of patients with life-threatening cardiac arrhythmias [ 1 ]. Originally developed as large external devices, technological advancements have led to the evolution of implantable CIEDs. These are inserted into a subcutaneous pocket and connected to cardiac tissue via one or more leads (single- or dual-chambers systems). More recently, leadless CIEDs that are directly anchored to the ventricular wall have been introduced [ 2 , 3 ]. According to the 2021 cardiac pacing guidelines CIED implantation is indicated for patients with sinus node dysfunction, advanced or paroxysmal atrioventricular block, conduction disorder without atrioventricular block, and reflex syncope [ 4 ]. Approximately, 1.25 million CIEDs are implanted each year, although implantation rates vary by economic, socio-cultural, health and geographical factors [ 3 ]. CIED implantation is considered a minor surgery with a relatively low incidence of complications [ 5 ]. The most common complications, each occurring in fewer than 6% of cases, include cardiac tamponade, cardiac perforation, venous thrombosis, left ventricular leads alteration, leads dislodgment, local hematoma, pocket infection, and pneumothorax [ 3 ]. Neoplasia arising at the CIED pocket is an ultra-rare complication only sporadically reports and lacking systematic evaluation in the literature [ 6 ]. Therefore, its clinical characteristics, management strategies, and prognosis remain poorly defined. To fill this gap, this hybrid article presents 1) a new case of neoplasm arising at the CIED pocket, 2) a scoping review with individual patient data analysis (IPD) to define the clinical characteristics, treatment and outcomes of neoplasm arising at the CIED pocket, 3) a clinical survey conducted across 3 CIED Centers in Campania and Calabria, Southern Italy. Methods 1) Case report . The patient has voluntarily signed his informed consent to the publication of the case report. 2) Scoping review with IPD analysis. Data Sources and Search Strategy. The review was planned, conducted, and reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement [ 7 ] (Supplementary Fig. 1). Systematic search was performed in Medline, Google Scholar, Google book, and Cochrane Library (last conducted search April 20, 2024) using the following term: “cancer AND cardiac implantable electronic devices”, "cancer pacemaker", “neoplasm leads”, “cancer pocket”, “pacemaker metastasis”, “cancer CIED”. No language restrictions were applied. The reference lists of all identified articles were searched for additional relevant publications. Study selection. Eligible studies included case reports and case series. All articles were obtained in full text and the references were analyzed to exclude duplicate data. The predetermined inclusion criterion was cancer arising at the CIED pocket. Predetermined exclusion criterion was cancer not CIED pocket related. Data Extraction. Titles and abstracts (when available) of the studies retrieved using the described search strategy were screened independently by 2 review team members (C.I. and F.F.) to identify studies that potentially met the inclusion criteria outlined. The full text of potentially eligible studies was retrieved and independently assessed for eligibility by 3 review team members (D.R., A.V., V.A.). Studies in languages other than English, French, and Italian (i.e., Chinese, Spanish, Portuguese, German, and Japanese) were translated into English or Italian by a professional translator. Any disagreement over the eligibility of studies was resolved through discussion among all review team members. A standardized, pre-piloted form was used to extract relevant clinical data from the included studies. The extracted data included: sex, current age, age at CIED implantation, history of CIED replacement, age at diagnosis of neoplasm arising at the CIED pocket, histological diagnosis of CIED pocket neoplasm, CIED type, CIED components, CIED removal, neoplasm treatment, follow-up, death, age of death, causes of death, comorbidities including occurrence of neoplasm not-CIED pocket related. Two review team members (C.I. and F.F.) extracted data independently, and any discrepancies were resolved through discussion with D.R. When available, missing data were obtained upon request from study authors via mail. The critical appraisal of case report and case series included in the systematic review was conducted according to the Joanna Briggs Institute checklist for case series (Supplementary table 1 ) and for case reports (Supplementary table 2 ) [ 8 ]. 3) Clinical survey. From January 1st to December 31st, 2023, all patients referred to the Department of Cardiology at the University of Naples, Castrovillari Hospital (Castrovillari, Cosenza, Italy), and “Nicola Giannattasio” Hospital (Rossano, Cosenza, Italy) for PMK implantation, were enrolled in our clinical survey. A standardized pre-piloted form was used to extract relevant data from enrolled patients’ medical records. The extracted data included: sex, current age, age at CIED implantation, diseases leading to CIED implantation, history of CIED replacement, occurrence of neoplasm arising at the CIED pocket, histological diagnosis of CIED pocket neoplasm, CIED type, CIED components, CIED removal, follow-up, death, age of death, causes of death, comorbidities including occurrence of neoplasm not-CIED pocket related. Two review team members (F.F. and C.I.) extracted data independently, and any discrepancies were resolved through discussion with D.R. Statistical Analysis. All statistical Analysis were performed using the IBM SPSS (Statistical Package for Social Science), version 25 (IBM, Armonk, NY, USA). Data from study publications were extracted and included in a single database. These data were then reanalyzed and combined. The χ2 or Fisher exact test was used to evaluate differences between categorical variables or proportions. The Kolmogorov-Smirnov test was used to assess the data distribution. Data are expressed as media ± standard deviation for continuous variables with normal distribution, as median [25°-75°] for continuous variables with not-normal distribution, and as absolute number (percentages) for categorical variables [ 9 ]. All statistical tests were 2-enrolltailed. A P value < 0.05 was considered statistically significant. Result Case report. In March 2024, an 84-year-old Caucasian man (LM) was referred to the Department of Clinical Medicine and Surgery of the Federico II University in Naples, Italy, due to mass in CIED pocket, located on the left side of his chest. About a year earlier, he had been diagnosed with high-grade urothelial cancer, which infiltrated the muscle causing metastases (stage IV-Metastatic cancer, T1-T4, N1-N3, M1). [ 10 , 11 ]. Following syncopal episodes, a double chamber CIED was implanted in February 2023. On physical examination, a mass measuring 13 cm was noted at the skin level. The mass was red, firm, warm and tender to palpation (Fig. 1 A). At the time of hospital admission, the patient’s vital signs were stable: body temperature 36,5°C, blood pressure 135/80 mmHg, heart rate 65 bpm, and respiratory rate 15 breaths per minute. A computerized tomography (CT) scan revealed an oval mass with regular margins, measuring 10 cm in the axial plane and 15 cm in the cranial-caudal direction. The mass showed modest vascularization without signs of active bleeding, and was not separated from the underlying muscle, while the bone remained intact (Fig. 1 B-C-D-E). During the hospitalization, two cardiac echocardiograms were performed, revealing a jagged and mobile image in the electro-catheter at the apex of the right ventricle (2.6 x 1.6 cm). This image was difficult to distinguish from the top of the catheter (Fig. 1 G-H). Initially, vegetations were suspected, suggesting an infection. However, laboratory tests (C-reative protein, procalcitonin, leucocytes) did not indicate any infectious process, which was further confirmed by culture results. Consequently, the mass underwent incisional biopsy. Histological examination shows a high-grade cancer with a diffuse, organoid pattern composed of medium-sized cells with large atypical nuclei, pleomorphism, and central macronucleolus (Fig. 1 I). Immunohistochemical analysis of the tumor showed positivity for vimentin, cytokeratin 7, cytokeratin 8 and 18, epithelial membrane antigen, integrase Interactor 1, and beta membrane catenin. Negativity was observed for cytokeratin 5 and 6, GATA3 binding protein, chromogranin, S100, and Cd99. Histological examination of the CIED pocket revealed findings consistent with urothelial carcinoma, negative for chromogranin, synaptophysin, and anticardiolipin, but positive for pancytokeratin (Fig. 1 I). The CIED pocket mass was diagnosed as a metastasis of bladder carcinoma. Over time, the mass enlarged, ulcerated and began to bleed. He was evaluated for potential surgical removal of the mass, with possible transposition of the latissimus dorsi muscle flap. However, due to the high surgical risk, the patient was deemed inoperable and subsequently received palliative radiotherapy (5 Gy for 5 total sessions), following device deactivation. The patient died 4 months after the initial diagnosis. Scoping review with IPD analysis. As showed in the Supplementary Fig. 1, 50 studies were included in qualitative and quantitative syntheses. The case reports and the case series included in the final analysis were 45 and 5, respectively. A complete list of studies included in the systematic review with IPD analysis and their critical appraisals are reported in Supplementary Tables 1 and 2. We collected data from 56 [male: female (M: F) = 37 (66.1%): 19 (33.9%), mean age 75.7 ± 13.7 years] subjects with neoplasm at CIED pocket site, including our case report. The mean age at PMK implantation was 67.9 ± 16.3 years. Sixteen subjects had a previous history of cancer [M: F = 10 (62.5%): 6 (37.5%); mean age at cancer onset 69.8 ± 22.3 years], and 18 [M: F = 12 (66.7%): 6 (33.3%); mean age 58.4 ± 19.2 years] underwent CIED replacement pre-cancer onset. Based on histological diagnosis, neoplasm arising at the CIED pocket are classified as primary neoplasm or metastasis (Tables 1 and 2 , respectively). Table 1 Characteristics of subjects with primary neoplasm on PMK pocket N° of subjects with available data Men (27; 66.5) Women (13;32.5) p-value Age at cancer onset on CIED pocket (years) 40 76.8 ± 13.6 76.7 ± 9.5 0.97 Age at CIED implantation (years) 36 69.0 ± 18.0 68.3 ± 7.6 0.89 CIED replacement pre-cancer 10 7 (70.0) 3 (30.0) 0.59 CIED replacement post-cancer 14 10 (71.4) 4 (28.6) 0.35 Primary neoplasm 40 • Carcinoma [ 1 ] 9 (22.5) 13 (32.5) Adenocarcinoma 2 (5.1) 12(30.0) Cutaneous squamous-cell carcinoma 4 (10.0) 1 (2.5) Basal-cell carcinoma 3 (7.5) - < 0.05 • Sarcoma 10 (25.0) - • Hematological malignancy 8 (20.0) - Therapeutic approach 36 0.03 • Surgery 18 (50.0) 1 (2.8) • CHT 2 (5.6) 3 (8.3) • RT - 1 (2.8) • Surgery + CHT 2 (5.6) 3 (8.3) • Surgery + RT 1 (2.8) 2 (5.6) • Surgery + CHT + RT 1 (2.8) 1 (2.8) Follow-up (months) 23 5 [2.2–12.0] 7.0 [5.0–24.0] 0.13 Death/Alive 28 9 (32.1)/11 (39.3) 4 (14.3)/4 (14.3) 0.56 Data are expressed as media ± standard deviation for continuous variables with normal distribution at Kolmogorov-Smirnov test and median (25°-75°) for continuous variables with not-normal distribution at Kolmogorov-Smirnov test, and absolute number (percentage). CIED: implantable management device; CHT: chemotherapy; RT: radiotherapy. [ 1 ] https://training.seer.cancer.gov/disease/categories/classification.html (last accessed on June 21st, 2025) Table 2 Characteristics of subjects with metastases on PMK pocket N° of subjects with available data Men (10; 62.5) Women (6; 37.5) p-value Age at metastasis onset on CIED pocket (years) 16 68.5 ± 18.6 78.5 ± 11.9 0.26 Age at CIED implantation (years) 12 59.9 ± 22.6 71.8 ± 10.9 0.27 CIED replacement pre-metastasis 8 5 (62.5) 3 (37.5) 0.41 CIED replacement post-metastasis 7 5 (71.4) 2 (28.6) 0.64 Metastasis 15 • Breast cancer - 3 (18.8) • Sarcoma 1 (6.7) - • Basal-cell carcinoma 1 (6.7) - • Myeloma 2 (13.3) 2 (13.3) 0.01 • Lymphoma 1 (6.7) 1 (6.7) • Melanoma 2 (13.3) - • Prostate cancer 1 (6.7) - • Urothelial cancer 1 (6.7) - Therapeutic approach 15 0.89 • Surgery 5 (33.3) 2 (13.3) • CHT 2 (13.3) 1 (6.7) • Surgery + CHT 1 (6.7) 1 (6.7) • CHT + RT 1 (6.7) - • Surgery + CHT + RT 1 (6.7) 1 (6.7) Follow-up (months) 7 7.5 [1.0–24.0] 6.0 [-] 0.40 Death/Alive 11 3 (27.3)/5 (45.5) 3 (27.3)/- 0.12 Data are expressed as media ± standard deviation for continuous variables with normal distribution at Kolmogorov-Smirnov test and median (25°-75°) for continuous variables with not-normal distribution at Kolmogorov-Smirnov test, and absolute number (percentage). CIED: implantable management device; CHT: chemotherapy; RT: radiotherapy. As showed in Table 1 , primary neoplasms affected 27 (66.5%) males and 13 (32.5%) females. The distribution of different cancer types between males and female was significantly different. All females were affected by adenocarcinoma, whereas males were mainly affected by sarcoma (10; 37.0%) and haematological malignancies (8; 29.6%). The onset of primary neoplasms at the CIED pocket occurs approximately 8 years after the CIED implantation, and after neoplasm diagnosis, 15 (71.4%) males and 6 (28.6%) females underwent CIED replacement. The median follow-up was 6.0 [3.0–12.0] months and 13 [M: F = 9 (69.2%): 4 (30.8)] died during the follow-up. As showed in Table 2 , metastases were observed in 10 (62.5%) males and 6 (37.5%) females. The distribution of different metastases between males and female was significantly different. Breast cancer metastasis affected typically females (3; 18.8%), whereas males were mainly affected by myeloma (2; 13.3%) and melanoma (2; 13.3%). The onset of metastasis at the CIED pocket occurs approximately 9 years after the CIED implantation, and after metastasis occurrence, 5 (71.4%) males and 2 (28.6%) females underwent CIED replacement. The median follow-up was 6.0 [1.0–24.0] months and 6 [M: F = 3(50.0%): 3 (50.0%)] died during the follow-up. Clinical survey. We collected data from 471 [M: F = 339 (71.9%): 102 (28.1%); mean age 70.3 ± 9.8 years] patients who underwent CIED implantation. Forty-nine subjects [10.4%; F:M = 22 (43.0%): 27; (57.0%); mean age at CIED implantation 72.1 ± 10.3 years] had a history of cancer at CIED implantation. The most common cancer types was adenocarcinoma, followed by hematological malignancy, melanoma, and sarcoma. During a mean follow-up of 19.1 ± 7.4 months, 24 (5.0%) patients [M: F = 13 (53.4%): 11 (46.6%)] developed complications related to CIED implantation: 11 [45.8%; 3 men] pocket hematomas; 6 [25.0%; 3 men] pneumothoraxes; 6 [25.0%; 1 man] perforation tamponades; 1 (4.2%) hemothorax. No patient has developed neoplasm at the CIED pocket. The occurrence of complications was the same in subjects with and without history of cancer. Discussion The results of our hybrid study highlight that, although rare, primary neoplasms and metastases may represent a potential complication of CIED implantation. These cancers are more commonly observed in the elderly population, with adenocarcinoma being the most frequent type in females, and sarcoma and hematological malignancies more common in males. CIED implantation is generally a safe procedure, however, it carries some potential risks and complication both in the short and long term. Common complications include arrhythmias, infections, bleeding and hematomas, lead dislodgement or fracture, and venous thrombosis [ 12 ]. Despite the high number of CIED implantations performed each year, cases of neoplasm at the PMK pocket site remain rare in the current literature. CIED can be considered a foreign body and may trigger immune responses and potentially lead to inflammation and tissue changes [ 13 ]. Chronic inflammation is known to be linked to tumorigenesis by promoting cellular transformation, proliferation, angiogenesis, and metastasis [ 14 ]. The majority of cancers are associated with environmental factors, such as chronic infections, tobacco smoke, pollution, and lifestyle [ 15 ]. All of these contribute to chronic inflammation, that is considered a main driver of tumorigenesis. The connection between inflammation and cancer can be summarized in two main pathways: an extrinsic pathway, in which inflammation increases the risk of cancer, and an intrinsic pathway, in which genetic mutations initiate inflammation and tumor development [ 16 ]. Inflammatory mediators and cells are a part of the microenvironment of cancer. Moreover, some oncogene mutations can promote inflammation and consequently cancer progression [ 16 ]. Mechanisms involved in cancer-related inflammation also play a role in invasion and metastasis. Chemokines such as interleukin-8 (IL-8) facilitate the migration of cancer cells to distant sites [ 17 ]. Inflammatory cytokines, including tumor necrosis factor-α (TNF- α), IL-1 β, and IL-6, enhance the invasive potential of cancer cells [ 18 – 20 ]. A key regulator in this process is NF-κB, a coordinator of innate immunity and inflammatory. NF-κB acts as an endogenous promoter of cancer and metastatic by activating genes encoding inflammatory and angiogenic factors, promoting cell survival and proliferation, and increasing the cell migration and invasion [ 21 ]. Another consequence of the persistent presence of a foreign body, such as CIED, is the overproduction of growth and angiogenic factors. These factors are involved into several stages of cancer development and progression. Growth factors can stabilize oncogenic mutation and increase the population of cells susceptible to further mutations [ 22 ]. They also play a critical role in invasion and migration of cancer cells [ 23 ], for instance by inducing the loss of epithelial E-cadherin or the acquisition of N-cadherin [ 24 ]. Vascular endothelial growth factors (VEGFs), Fibroblast-growth Factors (FGFs), and Transforming growth factor-β (TGF- β) are among the main growth factors implicated in cancer initiation, progression and metastasis [ 25 ]. As our hybrid study shows, cancers developing at the CIED pocket site are a rare occurrence, and current evidence is insufficient to fully explain this phenomenon. Nevertheless, patients with CIED should be routinely monitored, and any changes in the pocket site should prompt cancer screening and appropriate treatment. CIED remains a life-saving device, especially in cancer patients by increasing their chances of undergoing treatment and improving survival outcomes. Strengths and limitations of this study are represented by its systematic review nature. Indeed, it enables the collection and synthesis of global data on an extremely rare clinical condition, the heterogenicity of the same cannot guarantee an even and consistent approach. Moreover, the available data is limited to what reported by the authors. Another limitation is represented by the uniqueness of the complication; therefore, a small number of cases have been collected. This study highlights that neoplastic transformation within CIED pocket is a rare but life-threatening complication. Despite the implementation of multimodal treatment strategies—including chemotherapy, radiotherapy, and surgery—prognosis remains poor, with a marked reduction in life expectancy. Declarations No financial interest or conflict of interest is related to the publication of this manuscript. References Al-Khatib SM (2024) Cardiac Implantable Electronic Devices. N Engl J Med 390:442-454. https://doi.org/10.1056/NEJMra2308353 Reynolds D, Duray GZ, Omar R, Soejima K, Neuzil P, Zhang S, Narasimhan C, Steinwender C, Brugada J, Lloyd M, Roberts PR, Sagi V, Hummel J, Bongiorni MG, Knops RE, Ellis CR, Gornick CC, Bernabei MA, Laager V, Stromberg K, Williams ER, Hudnall JH, Ritter P, Micra Transcatheter Pacing Study Group (2016) A Leadless Intracardiac Transcatheter Pacing System. N Engl J Med 374:533-41. https://doi.org/10.1056/NEJMoa1511643 Saleem-Talib S, Hoevenaars CPR, Molitor N, van Driel VJ, van der Heijden J, Breitenstein A, van Wessel H, van Schie MS, de Groot NMS, Ramanna H (2025) Leadless pacing: a comprehensive review. Eur Heart J 46:1979-1990. https://doi.org/10.1093/eurheartj/ehaf119 Glikson M, Nielsen JC, Kronborg MB, Michowitz Y, Auricchio A, Barbash IM, Barrabés JA, Boriani G, Braunschweig F, Brignole M, Burri H, Coats AJS, Deharo JC, Delgado V, Diller GP, Israel CW, Keren A, Knops RE, Kotecha D, Leclercq C, Merkely B, Starck C, Thylén I, Tolosana J, ESC Scientific Document Group (2021) 2021 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy. Eur Heart J 43:1651. https://doi.org/10.1093/eurheartj/ehac075 Udo EO, Zuithoff NP, van Hemel NM, de Cock CC, Hendriks T, Doevendans PA, Moons KG (2012) Incidence and predictors of short- and long-term complications in pacemaker therapy: the FOLLOWPACE study. Heart Rhythm 9:728-35. https://doi.org/10.1016/j.hrthm.2011.12.014 Moraes FCA, Dal Moro L, Pessoa FR, Passos ESDR, Campos RALS, Souza DDSM, Feio D, Rodríguez Burbano RM, Fernandes MR, Santos NPCD (2023) Malignant Neoplasms Arising in the Cardiac Pacemaker Cavity: A Systematic Review. Cancers 15:5206. https://doi.org/10.3390/cancers15215206 https:// www.bmj.com/content/372bmj.n71 (last access on June 21 st , 2025) Moola S, Munn Z, Tufanaru C, Aromataris E, Sears K, Sfetcu R, Currie M, Lisy K, Qureshi R, Mattis P, Mu P. Chapter 7: Systematic reviews of etiology and risk. In: Aromataris E, Munn Z (Editors). JBI Manual for Evidence Synthesis. JBI, 2020. Available from https://synthesismanual.jbi.global. https://doi.org/10.46658/JBIMES-20-08 Sainani KL. Dealing with non-normal data (2012) PM R 4:1001-1005. https://doi.org/10.1016/j.pmrj.2012.10.013 Rosen RD, Sapra A (2023) TNM Classification. https://www.ncbi.nlm.nih.gov/books/NBK553187 Raspollini MR, Comperat EM, Lopez-Beltran A, Montironi R, Cimadamore A, Tsuzuki T, Netto GJ (2023) News in the classification of WHO 2022 bladder tumors. Pathologica 115:32-40. https://doi.org/10.32074/1591-951X-838. Puette JA, Malek R, Ahmed I, Ellison MB (2024) Pacemaker Insertion. Treasure Island, Florida Anderson JM, Rodriguez A, Chang DT (2008) Foreign body reaction to biomaterials. Semin Immunol 20:86-100. https://doi.org/10.1016/j.smim.2007.11.004 Mantovani A (2005) Cancer: inflammation by remote control. Nature 435:752-3. https://doi.org/10.1038/435752a Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860-7. https://doi.org/10.1038/nature01322 Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436-44. https://doi.org/10.1038/nature07205 Singh N, Baby D, Rajguru JP, Patil PB, Thakkannavar SS, Pujari VB (2019) Inflammation and cancer. Ann Afr Med 18:121-126. https://doi.org/10.4103/aam.aam_56_18 Szlosarek PW, Balkwill FR (2003) Tumour necrosis factor alpha: a potential target for the therapy of solid tumours. Lancet Oncol 4:565-73. https://doi.org/10.1016/s1470-2045(03)01196-3 Voronov E, Shouval DS, Krelin Y, Cagnano E, Benharroch D, Iwakura Y, Dinarello CA, Apte RN (2003) IL-1 is required for tumor invasiveness and angiogenesis. Proc Natl Acad Sci U S A 100:2645-50. https://doi.org/10.1073/pnas.0437939100 Grivennikov S, Karin M (2008) Autocrine IL-6 signaling: a key event in tumorigenesis? Cancer Cell 13:7-9. https://doi.org/10.1016/j.ccr.2007.12.020 Balkwill F (2004) Cancer and the chemokine network. Nat Rev Cancer 4:540-50. https://doi.org/10.1038/nrc1388 Sporn MB, Todaro GJ (1980) Autocrine secretion and malignant transformation of cells. N Engl J Med 303:878-80. https://doi.org/10.1056/NEJM198010093031511 Yilmaz M, Christofori G (2009) EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev 28:15-33. https://doi.org/10.1007/s10555-008-9169-0 Nieman MT, Prudoff RS, Johnson KR, Wheelock MJ (1999) N-cadherin promotes motility in human breast cancer cells regardless of their E-cadherin expression. J Cell Biol 147:631-44. https://doi.org/10.1083/jcb.147.3.631 Witsch E, Sela M, Yarden Y (2010) Roles for growth factors in cancer progression. Physiology 25:85-101. https://doi.org/10.1152/physiol.00045.2009 Supplementary Files SupplementaryFigure1.tif SupplementaryTable1.docx SupplementaryTable2.docx Cite Share Download PDF Status: Published Journal Publication published 08 Jan, 2026 Read the published version in Internal and Emergency Medicine → Version 1 posted Reviewers agreed at journal 09 Sep, 2025 Reviewers invited by journal 11 Jul, 2025 Editor assigned by journal 02 Jul, 2025 First submitted to journal 02 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7009208","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":484159082,"identity":"b96b6495-c445-4a72-b0fb-64ee217cbc8b","order_by":0,"name":"Francesca Fortunato","email":"","orcid":"","institution":"University of Naples Federico II: Universita degli Studi di Napoli Federico II","correspondingAuthor":false,"prefix":"","firstName":"Francesca","middleName":"","lastName":"Fortunato","suffix":""},{"id":484159083,"identity":"68e1f2af-75c1-49d6-b90e-4e09511edefa","order_by":1,"name":"Ciro Iardino","email":"","orcid":"","institution":"University of Naples Federico II: Universita degli Studi di Napoli Federico II","correspondingAuthor":false,"prefix":"","firstName":"Ciro","middleName":"","lastName":"Iardino","suffix":""},{"id":484159084,"identity":"b8d340a9-75d3-4040-ab06-02e96fb02f03","order_by":2,"name":"Veronica Abate","email":"","orcid":"","institution":"University of Naples Federico II: Universita degli Studi di Napoli Federico II","correspondingAuthor":false,"prefix":"","firstName":"Veronica","middleName":"","lastName":"Abate","suffix":""},{"id":484159085,"identity":"a8160731-f728-4645-b8bc-1fec1e72c9f1","order_by":3,"name":"Maria D’Armiento","email":"","orcid":"","institution":"University of Naples Federico II: Universita degli Studi di Napoli Federico II","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"","lastName":"D’Armiento","suffix":""},{"id":484159086,"identity":"385e1628-74c6-48ca-aa20-d27edbd731a7","order_by":4,"name":"Antonio Rapacciuolo","email":"","orcid":"","institution":"University of Naples Federico II: Universita degli Studi di Napoli Federico II","correspondingAuthor":false,"prefix":"","firstName":"Antonio","middleName":"","lastName":"Rapacciuolo","suffix":""},{"id":484159087,"identity":"3ff98b36-ed42-4a2b-810a-e77c747cefbf","order_by":5,"name":"Daniele Faccenda","email":"","orcid":"","institution":"University of Naples Federico II: Universita degli Studi di Napoli Federico II","correspondingAuthor":false,"prefix":"","firstName":"Daniele","middleName":"","lastName":"Faccenda","suffix":""},{"id":484159088,"identity":"71e7163e-c8fa-4b87-873a-47ee94a6b127","order_by":6,"name":"Pietro Venetucci","email":"","orcid":"","institution":"University of Naples Federico II: Universita degli Studi di Napoli Federico II","correspondingAuthor":false,"prefix":"","firstName":"Pietro","middleName":"","lastName":"Venetucci","suffix":""},{"id":484159089,"identity":"6025a18b-c909-4424-bed5-cb4d0e5d2ad8","order_by":7,"name":"Antonio Barbato","email":"","orcid":"","institution":"University of Naples Federico II: Universita degli Studi di Napoli Federico II","correspondingAuthor":false,"prefix":"","firstName":"Antonio","middleName":"","lastName":"Barbato","suffix":""},{"id":484159090,"identity":"a35f00fb-c182-47aa-acb4-44e2a2dc2001","order_by":8,"name":"Silvana De Bonis","email":"","orcid":"","institution":"Department of Cardiology, Ospedale Ferrari, Castrovillari, Italy","correspondingAuthor":false,"prefix":"","firstName":"Silvana","middleName":"","lastName":"De Bonis","suffix":""},{"id":484159091,"identity":"fe82fc17-6b06-44bc-b7b8-4cb5f03f8840","order_by":9,"name":"Giovanni Bisignani","email":"","orcid":"","institution":"Department of Cardiology, Ferrari Hospital, Cosenza, Italy","correspondingAuthor":false,"prefix":"","firstName":"Giovanni","middleName":"","lastName":"Bisignani","suffix":""},{"id":484159092,"identity":"0106c4e1-b8af-4165-bcbe-12ee527d1324","order_by":10,"name":"ANITA VERGATTI","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+ElEQVRIiWNgGAWjYFACxgYkjoENAwMzmIFXSyNMD2PDAYM0mBb8epC0MByG24dTPf/s5vYHPxgOy5n3L37++EPB+cTt7LwHPzAU/MGpReLOwcbGHobDxjI3nhkCHXY7cWczX7IEXofdSGxs4GFIS5whcQCiZcNhHgO8WuSBWhr/MKTVz5A4/hGo5RxIi/EPfFoMgFqaeRhsEiT4e0C2HABpMcNriyFQy2wZAxvDGRI8hTPOGCQbg7RYJBgY49QidyP9wcc3FRLyEvzHN3yo+GMnu+H8GeMbH/7I4fY+xHlALJGAJJCAXR0a4D9AlLJRMApGwSgYgQAA7gdYZoLQE78AAAAASUVORK5CYII=","orcid":"https://orcid.org/0009-0009-6574-9120","institution":"University of Naples Federico II: Universita degli Studi di Napoli Federico II","correspondingAuthor":true,"prefix":"","firstName":"ANITA","middleName":"","lastName":"VERGATTI","suffix":""},{"id":484159093,"identity":"b28b325e-21ed-4c2f-9336-85a0b06da32c","order_by":11,"name":"Vincenzo Damiano","email":"","orcid":"","institution":"University of Naples Federico II: Universita degli Studi di Napoli Federico II","correspondingAuthor":false,"prefix":"","firstName":"Vincenzo","middleName":"","lastName":"Damiano","suffix":""},{"id":484159094,"identity":"10a021e9-427a-4a03-b5dc-ec21e85ee31d","order_by":12,"name":"Gianpaolo De Filippo","email":"","orcid":"","institution":"Assistance Publique- Hopitaux de Paris, Hopital Robert-Debre","correspondingAuthor":false,"prefix":"","firstName":"Gianpaolo","middleName":"","lastName":"De Filippo","suffix":""},{"id":484159095,"identity":"a19773cb-cc93-4b14-ad67-eadbce3ccf85","order_by":13,"name":"Domenico Rendina","email":"","orcid":"","institution":"University of Naples Federico II: Universita degli Studi di Napoli Federico II","correspondingAuthor":false,"prefix":"","firstName":"Domenico","middleName":"","lastName":"Rendina","suffix":""}],"badges":[],"createdAt":"2025-06-30 10:08:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7009208/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7009208/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11739-025-04251-4","type":"published","date":"2026-01-08T15:57:53+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":86780009,"identity":"b4f567b0-241c-4a49-a941-2377210ba065","added_by":"auto","created_at":"2025-07-15 13:14:55","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":294737,"visible":true,"origin":"","legend":"\u003cp\u003eFigure A: Neoplasm arising at the CIED pocket.\u003c/p\u003e\n\u003cp\u003eFigure B: Computed tomography images.\u003c/p\u003e\n\u003cp\u003eFigure C: Coronal section.\u003c/p\u003e\n\u003cp\u003eFigure D: transversal section.\u003c/p\u003e\n\u003cp\u003eFigure E: three-dimensional rotational angiography.\u003c/p\u003e\n\u003cp\u003eFigure F: Three- dimensional computed tomography reconstruction.\u003c/p\u003e\n\u003cp\u003eWhite star: device pocket neoplasm. Black star: ICD device. White arrow: device’s leads. Empty arrow: arterial circulation of the neoplasm. Arrowheads: venous circulation of the neoplasm\u003c/p\u003e\n\u003cp\u003eFigure G, H: Cardiac ultrasound examination. Apical four chamber view. White arrow: images of the vegetation on catheter.\u003c/p\u003e\n\u003cp\u003eFigure I. Hematoxylin-Eosin 10x; Device pocket neoplasm biopsy. Both samplings show high-grade neoplasm with diffuse and organoid patterns, medium-sized cells, with large atypical nuclei, pleomorphs.\u003c/p\u003e","description":"","filename":"Figure1.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7009208/v1/2f4c8eb8dcc3927a56342b19.jpg"},{"id":100069520,"identity":"954a7663-3a95-49de-9555-fefcec9ee656","added_by":"auto","created_at":"2026-01-12 16:14:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1131922,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7009208/v1/3fce6604-b651-4254-b9d4-33ae9885559c.pdf"},{"id":86780548,"identity":"187d6cc2-df99-4a79-b935-d23f89e495ca","added_by":"auto","created_at":"2025-07-15 13:22:55","extension":"tif","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":98734,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure1.tif","url":"https://assets-eu.researchsquare.com/files/rs-7009208/v1/016faf0e99044b004b6257f7.tif"},{"id":86780011,"identity":"0fbcf8c1-fbd2-41f7-86c5-6b8dcfe3632d","added_by":"auto","created_at":"2025-07-15 13:14:55","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":32576,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7009208/v1/762f241419dc4499b47c0f8a.docx"},{"id":86780015,"identity":"882192cb-4c2c-4d89-85ea-86c1a6bcb0be","added_by":"auto","created_at":"2025-07-15 13:14:55","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":18902,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable2.docx","url":"https://assets-eu.researchsquare.com/files/rs-7009208/v1/5e97ca4b02fd90b8d34f5888.docx"}],"financialInterests":"","formattedTitle":"Neoplasms Arising at the CIED Pocket: A Hybrid Study Combining Case Report, Scoping Review, and Clinical Survey.","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSince their introduction in the 1960s, cardiac implantable electronic devices (CIEDs), including permanent pacemakers and implantable cardioverter-defibrillators, have represented a significant breakthrough in the clinical management of patients with life-threatening cardiac arrhythmias [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Originally developed as large external devices, technological advancements have led to the evolution of implantable CIEDs. These are inserted into a subcutaneous pocket and connected to cardiac tissue via one or more leads (single- or dual-chambers systems). More recently, leadless CIEDs that are directly anchored to the ventricular wall have been introduced [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. According to the 2021 cardiac pacing guidelines CIED implantation is indicated for patients with sinus node dysfunction, advanced or paroxysmal atrioventricular block, conduction disorder without atrioventricular block, and reflex syncope [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Approximately, 1.25\u0026nbsp;million CIEDs are implanted each year, although implantation rates vary by economic, socio-cultural, health and geographical factors [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. CIED implantation is considered a minor surgery with a relatively low incidence of complications [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The most common complications, each occurring in fewer than 6% of cases, include cardiac tamponade, cardiac perforation, venous thrombosis, left ventricular leads alteration, leads dislodgment, local hematoma, pocket infection, and pneumothorax [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Neoplasia arising at the CIED pocket is an ultra-rare complication only sporadically reports and lacking systematic evaluation in the literature [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Therefore, its clinical characteristics, management strategies, and prognosis remain poorly defined. To fill this gap, this hybrid article presents 1) a new case of neoplasm arising at the CIED pocket, 2) a scoping review with individual patient data analysis (IPD) to define the clinical characteristics, treatment and outcomes of neoplasm arising at the CIED pocket, 3) a clinical survey conducted across 3 CIED Centers in Campania and Calabria, Southern Italy.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cb\u003e1) Case report\u003c/b\u003e. The patient has voluntarily signed his informed consent to the publication of the case report.\u003c/p\u003e\u003cp\u003e\u003cb\u003e 2) Scoping review with IPD analysis.\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eData Sources and Search Strategy.\u003c/b\u003e The review was planned, conducted, and reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] (Supplementary Fig.\u0026nbsp;1). Systematic search was performed in Medline, Google Scholar, Google book, and Cochrane Library (last conducted search April 20, 2024) using the following term: “cancer AND cardiac implantable electronic devices”, \"cancer pacemaker\", “neoplasm leads”, “cancer pocket”, “pacemaker metastasis”, “cancer CIED”. No language restrictions were applied. The reference lists of all identified articles were searched for additional relevant publications. \u003cb\u003eStudy selection.\u003c/b\u003e Eligible studies included case reports and case series. All articles were obtained in full text and the references were analyzed to exclude duplicate data. The predetermined inclusion criterion was cancer arising at the CIED pocket. Predetermined exclusion criterion was cancer not CIED pocket related. \u003cb\u003eData Extraction.\u003c/b\u003e Titles and abstracts (when available) of the studies retrieved using the described search strategy were screened independently by 2 review team members (C.I. and F.F.) to identify studies that potentially met the inclusion criteria outlined. The full text of potentially eligible studies was retrieved and independently assessed for eligibility by 3 review team members (D.R., A.V., V.A.). Studies in languages other than English, French, and Italian (i.e., Chinese, Spanish, Portuguese, German, and Japanese) were translated into English or Italian by a professional translator. Any disagreement over the eligibility of studies was resolved through discussion among all review team members. A standardized, pre-piloted form was used to extract relevant clinical data from the included studies. The extracted data included: sex, current age, age at CIED implantation, history of CIED replacement, age at diagnosis of neoplasm arising at the CIED pocket, histological diagnosis of CIED pocket neoplasm, CIED type, CIED components, CIED removal, neoplasm treatment, follow-up, death, age of death, causes of death, comorbidities including occurrence of neoplasm not-CIED pocket related. Two review team members (C.I. and F.F.) extracted data independently, and any discrepancies were resolved through discussion with D.R. When available, missing data were obtained upon request from study authors via mail. The critical appraisal of case report and case series included in the systematic review was conducted according to the Joanna Briggs Institute checklist for case series (Supplementary table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) and for case reports (Supplementary table \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cb\u003e3) Clinical survey.\u003c/b\u003e From January 1st to December 31st, 2023, all patients referred to the Department of Cardiology at the University of Naples, Castrovillari Hospital (Castrovillari, Cosenza, Italy), and “Nicola Giannattasio” Hospital (Rossano, Cosenza, Italy) for PMK implantation, were enrolled in our clinical survey. A standardized pre-piloted form was used to extract relevant data from enrolled patients’ medical records. The extracted data included: sex, current age, age at CIED implantation, diseases leading to CIED implantation, history of CIED replacement, occurrence of neoplasm arising at the CIED pocket, histological diagnosis of CIED pocket neoplasm, CIED type, CIED components, CIED removal, follow-up, death, age of death, causes of death, comorbidities including occurrence of neoplasm not-CIED pocket related. Two review team members (F.F. and C.I.) extracted data independently, and any discrepancies were resolved through discussion with D.R.\u003c/p\u003e\u003cp\u003e\u003cb\u003eStatistical Analysis.\u003c/b\u003e All statistical Analysis were performed using the IBM SPSS (Statistical Package for Social Science), version 25 (IBM, Armonk, NY, USA). Data from study publications were extracted and included in a single database. These data were then reanalyzed and combined. The χ2 or Fisher exact test was used to evaluate differences between categorical variables or proportions. The Kolmogorov-Smirnov test was used to assess the data distribution. Data are expressed as media ± standard deviation for continuous variables with normal distribution, as median [25°-75°] for continuous variables with not-normal distribution, and as absolute number (percentages) for categorical variables [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. All statistical tests were 2-enrolltailed. A P value \u0026lt; 0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Result","content":"\u003cp\u003e\u003cb\u003eCase report.\u003c/b\u003e In March 2024, an 84-year-old Caucasian man (LM) was referred to the Department of Clinical Medicine and Surgery of the Federico II University in Naples, Italy, due to mass in CIED pocket, located on the left side of his chest. About a year earlier, he had been diagnosed with high-grade urothelial cancer, which infiltrated the muscle causing metastases (stage IV-Metastatic cancer, T1-T4, N1-N3, M1). [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Following syncopal episodes, a double chamber CIED was implanted in February 2023. On physical examination, a mass measuring 13 cm was noted at the skin level. The mass was red, firm, warm and tender to palpation (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). At the time of hospital admission, the patient’s vital signs were stable: body temperature 36,5°C, blood pressure 135/80 mmHg, heart rate 65 bpm, and respiratory rate 15 breaths per minute. A computerized tomography (CT) scan revealed an oval mass with regular margins, measuring 10 cm in the axial plane and 15 cm in the cranial-caudal direction. The mass showed modest vascularization without signs of active bleeding, and was not separated from the underlying muscle, while the bone remained intact (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB-C-D-E). During the hospitalization, two cardiac echocardiograms were performed, revealing a jagged and mobile image in the electro-catheter at the apex of the right ventricle (2.6 x 1.6 cm). This image was difficult to distinguish from the top of the catheter (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eG-H). Initially, vegetations were suspected, suggesting an infection. However, laboratory tests (C-reative protein, procalcitonin, leucocytes) did not indicate any infectious process, which was further confirmed by culture results. Consequently, the mass underwent incisional biopsy. Histological examination shows a high-grade cancer with a diffuse, organoid pattern composed of medium-sized cells with large atypical nuclei, pleomorphism, and central macronucleolus (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eI). Immunohistochemical analysis of the tumor showed positivity for vimentin, cytokeratin 7, cytokeratin 8 and 18, epithelial membrane antigen, integrase Interactor 1, and beta membrane catenin. Negativity was observed for cytokeratin 5 and 6, GATA3 binding protein, chromogranin, S100, and Cd99. Histological examination of the CIED pocket revealed findings consistent with urothelial carcinoma, negative for chromogranin, synaptophysin, and anticardiolipin, but positive for pancytokeratin (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eI). The CIED pocket mass was diagnosed as a metastasis of bladder carcinoma. Over time, the mass enlarged, ulcerated and began to bleed. He was evaluated for potential surgical removal of the mass, with possible transposition of the latissimus dorsi muscle flap. However, due to the high surgical risk, the patient was deemed inoperable and subsequently received palliative radiotherapy (5 Gy for 5 total sessions), following device deactivation. The patient died 4 months after the initial diagnosis.\u003c/p\u003e\u003cp\u003e\u003cb\u003eScoping review with IPD analysis.\u003c/b\u003e As showed in the Supplementary Fig.\u0026nbsp;1, 50 studies were included in qualitative and quantitative syntheses. The case reports and the case series included in the final analysis were 45 and 5, respectively. A complete list of studies included in the systematic review with IPD analysis and their critical appraisals are reported in Supplementary Tables\u0026nbsp;1 and 2. We collected data from 56 [male: female (M: F) = 37 (66.1%): 19 (33.9%), mean age 75.7 ± 13.7 years] subjects with neoplasm at CIED pocket site, including our case report. The mean age at PMK implantation was 67.9 ± 16.3 years. Sixteen subjects had a previous history of cancer [M: F = 10 (62.5%): 6 (37.5%); mean age at cancer onset 69.8 ± 22.3 years], and 18 [M: F = 12 (66.7%): 6 (33.3%); mean age 58.4 ± 19.2 years] underwent CIED replacement pre-cancer onset. Based on histological diagnosis, neoplasm arising at the CIED pocket are classified as primary neoplasm or metastasis (Tables\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, respectively).\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCharacteristics of subjects with primary neoplasm on PMK pocket\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eN° of subjects with available data\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMen (27; 66.5)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eWomen (13;32.5)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge at cancer onset on CIED pocket (years)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e76.8 ± 13.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e76.7 ± 9.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.97\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge at CIED implantation (years)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e69.0 ± 18.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e68.3 ± 7.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.89\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCIED replacement pre-cancer\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 (70.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (30.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.59\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCIED replacement post-cancer\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10 (71.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4 (28.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.35\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePrimary neoplasm\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e• Carcinoma [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9 (22.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13 (32.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdenocarcinoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (5.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12(30.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCutaneous squamous-cell carcinoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (10.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (2.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBasal-cell carcinoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (7.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt; 0.05\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e• Sarcoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10 (25.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e• Hematological malignancy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8 (20.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTherapeutic approach\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"6\" rowspan=\"7\"\u003e\u003cp\u003e0.03\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e• Surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18 (50.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (2.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e• CHT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (5.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (8.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e• RT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (2.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e• Surgery + CHT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (5.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (8.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e• Surgery + RT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (2.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (5.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e• Surgery + CHT + RT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (2.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (2.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFollow-up (months)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 [2.2–12.0]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7.0 [5.0–24.0]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.13\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDeath/Alive\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9 (32.1)/11 (39.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4 (14.3)/4 (14.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.56\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eData are expressed as media ± standard deviation for continuous variables with normal distribution at Kolmogorov-Smirnov test and median (25°-75°) for continuous variables with not-normal distribution at Kolmogorov-Smirnov test, and absolute number (percentage). CIED: implantable management device; CHT: chemotherapy; RT: radiotherapy.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://training.seer.cancer.gov/disease/categories/classification.html\u003c/span\u003e\u003cspan address=\"https://training.seer.cancer.gov/disease/categories/classification.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (last accessed on June 21st, 2025)\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCharacteristics of subjects with metastases on PMK pocket\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eN° of subjects with available data\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMen (10; 62.5)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eWomen (6; 37.5)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge at metastasis onset on CIED pocket (years)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e68.5 ± 18.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e78.5 ± 11.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.26\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge at CIED implantation (years)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e59.9 ± 22.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e71.8 ± 10.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.27\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCIED replacement pre-metastasis\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (62.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (37.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.41\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCIED replacement post-metastasis\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (71.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (28.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.64\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMetastasis\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e• Breast cancer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (18.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e• Sarcoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (6.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e• Basal-cell carcinoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (6.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e• Myeloma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (13.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (13.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e• Lymphoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (6.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (6.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e• Melanoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (13.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e• Prostate cancer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (6.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e• Urothelial cancer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (6.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTherapeutic approach\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"5\" rowspan=\"6\"\u003e\u003cp\u003e0.89\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e• \u003cb\u003eSurgery\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (33.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (13.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e• \u003cb\u003eCHT\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (13.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (6.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e• \u003cb\u003eSurgery + CHT\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (6.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (6.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e• \u003cb\u003eCHT + RT\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (6.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e• \u003cb\u003eSurgery + CHT + RT\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (6.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (6.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFollow-up (months)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7.5 [1.0–24.0]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6.0 [-]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.40\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDeath/Alive\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (27.3)/5 (45.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (27.3)/-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.12\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eData are expressed as media ± standard deviation for continuous variables with normal distribution at Kolmogorov-Smirnov test and median (25°-75°) for continuous variables with not-normal distribution at Kolmogorov-Smirnov test, and absolute number (percentage). CIED: implantable management device; CHT: chemotherapy; RT: radiotherapy.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003cp\u003eAs showed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, primary neoplasms affected 27 (66.5%) males and 13 (32.5%) females. The distribution of different cancer types between males and female was significantly different. All females were affected by adenocarcinoma, whereas males were mainly affected by sarcoma (10; 37.0%) and haematological malignancies (8; 29.6%). The onset of primary neoplasms at the CIED pocket occurs approximately 8 years after the CIED implantation, and after neoplasm diagnosis, 15 (71.4%) males and 6 (28.6%) females underwent CIED replacement. The median follow-up was 6.0 [3.0–12.0] months and 13 [M: F = 9 (69.2%): 4 (30.8)] died during the follow-up.\u003c/p\u003e\u003cp\u003eAs showed in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, metastases were observed in 10 (62.5%) males and 6 (37.5%) females. The distribution of different metastases between males and female was significantly different. Breast cancer metastasis affected typically females (3; 18.8%), whereas males were mainly affected by myeloma (2; 13.3%) and melanoma (2; 13.3%). The onset of metastasis at the CIED pocket occurs approximately 9 years after the CIED implantation, and after metastasis occurrence, 5 (71.4%) males and 2 (28.6%) females underwent CIED replacement. The median follow-up was 6.0 [1.0–24.0] months and 6 [M: F = 3(50.0%): 3 (50.0%)] died during the follow-up.\u003c/p\u003e\u003cp\u003e\u003cb\u003eClinical survey.\u003c/b\u003e We collected data from 471 [M: F = 339 (71.9%): 102 (28.1%); mean age 70.3 ± 9.8 years] patients who underwent CIED implantation. Forty-nine subjects [10.4%; F:M = 22 (43.0%): 27; (57.0%); mean age at CIED implantation 72.1 ± 10.3 years] had a history of cancer at CIED implantation. The most common cancer types was adenocarcinoma, followed by hematological malignancy, melanoma, and sarcoma. During a mean follow-up of 19.1 ± 7.4 months, 24 (5.0%) patients [M: F = 13 (53.4%): 11 (46.6%)] developed complications related to CIED implantation: 11 [45.8%; 3 men] pocket hematomas; 6 [25.0%; 3 men] pneumothoraxes; 6 [25.0%; 1 man] perforation tamponades; 1 (4.2%) hemothorax. No patient has developed neoplasm at the CIED pocket. The occurrence of complications was the same in subjects with and without history of cancer.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe results of our hybrid study highlight that, although rare, primary neoplasms and metastases may represent a potential complication of CIED implantation. These cancers are more commonly observed in the elderly population, with adenocarcinoma being the most frequent type in females, and sarcoma and hematological malignancies more common in males.\u003c/p\u003e\u003cp\u003eCIED implantation is generally a safe procedure, however, it carries some potential risks and complication both in the short and long term. Common complications include arrhythmias, infections, bleeding and hematomas, lead dislodgement or fracture, and venous thrombosis [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Despite the high number of CIED implantations performed each year, cases of neoplasm at the PMK pocket site remain rare in the current literature.\u003c/p\u003e\u003cp\u003eCIED can be considered a foreign body and may trigger immune responses and potentially lead to inflammation and tissue changes [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Chronic inflammation is known to be linked to tumorigenesis by promoting cellular transformation, proliferation, angiogenesis, and metastasis [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The majority of cancers are associated with environmental factors, such as chronic infections, tobacco smoke, pollution, and lifestyle [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. All of these contribute to chronic inflammation, that is considered a main driver of tumorigenesis. The connection between inflammation and cancer can be summarized in two main pathways: an extrinsic pathway, in which inflammation increases the risk of cancer, and an intrinsic pathway, in which genetic mutations initiate inflammation and tumor development [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Inflammatory mediators and cells are a part of the microenvironment of cancer. Moreover, some oncogene mutations can promote inflammation and consequently cancer progression [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Mechanisms involved in cancer-related inflammation also play a role in invasion and metastasis. Chemokines such as interleukin-8 (IL-8) facilitate the migration of cancer cells to distant sites [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Inflammatory cytokines, including tumor necrosis factor-α (TNF- α), IL-1 β, and IL-6, enhance the invasive potential of cancer cells [\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. A key regulator in this process is NF-κB, a coordinator of innate immunity and inflammatory. NF-κB acts as an endogenous promoter of cancer and metastatic by activating genes encoding inflammatory and angiogenic factors, promoting cell survival and proliferation, and increasing the cell migration and invasion [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAnother consequence of the persistent presence of a foreign body, such as CIED, is the overproduction of growth and angiogenic factors. These factors are involved into several stages of cancer development and progression. Growth factors can stabilize oncogenic mutation and increase the population of cells susceptible to further mutations [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. They also play a critical role in invasion and migration of cancer cells [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], for instance by inducing the loss of epithelial E-cadherin or the acquisition of N-cadherin [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Vascular endothelial growth factors (VEGFs), Fibroblast-growth Factors (FGFs), and Transforming growth factor-β (TGF- β) are among the main growth factors implicated in cancer initiation, progression and metastasis [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAs our hybrid study shows, cancers developing at the CIED pocket site are a rare occurrence, and current evidence is insufficient to fully explain this phenomenon. Nevertheless, patients with CIED should be routinely monitored, and any changes in the pocket site should prompt cancer screening and appropriate treatment. CIED remains a life-saving device, especially in cancer patients by increasing their chances of undergoing treatment and improving survival outcomes.\u003c/p\u003e\u003cp\u003eStrengths and limitations of this study are represented by its systematic review nature. Indeed, it enables the collection and synthesis of global data on an extremely rare clinical condition, the heterogenicity of the same cannot guarantee an even and consistent approach. Moreover, the available data is limited to what reported by the authors. Another limitation is represented by the uniqueness of the complication; therefore, a small number of cases have been collected.\u003c/p\u003e\u003cp\u003eThis study highlights that neoplastic transformation within CIED pocket is a rare but life-threatening complication. Despite the implementation of multimodal treatment strategies\u0026mdash;including chemotherapy, radiotherapy, and surgery\u0026mdash;prognosis remains poor, with a marked reduction in life expectancy.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eNo financial interest or conflict of interest is related to the publication of this manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAl-Khatib SM (2024) Cardiac Implantable Electronic Devices. N Engl J Med 390:442-454. https://doi.org/10.1056/NEJMra2308353\u003c/li\u003e\n\u003cli\u003eReynolds D, Duray GZ, Omar R, Soejima K, Neuzil P, Zhang S, Narasimhan C, Steinwender C, Brugada J, Lloyd M, Roberts PR, Sagi V, Hummel J, Bongiorni MG, Knops RE, Ellis CR, Gornick CC, Bernabei MA, Laager V, Stromberg K, Williams ER, Hudnall JH, Ritter P, Micra Transcatheter Pacing Study Group (2016) A Leadless Intracardiac Transcatheter Pacing System. N Engl J Med 374:533-41. https://doi.org/10.1056/NEJMoa1511643\u003c/li\u003e\n\u003cli\u003eSaleem-Talib S, Hoevenaars CPR, Molitor N, van Driel VJ, van der Heijden J, Breitenstein A, van Wessel H, van Schie MS, de Groot NMS, Ramanna H (2025) Leadless pacing: a comprehensive review. Eur Heart J 46:1979-1990. https://doi.org/10.1093/eurheartj/ehaf119\u003c/li\u003e\n\u003cli\u003eGlikson M, Nielsen JC, Kronborg MB, Michowitz Y, Auricchio A, Barbash IM, Barrab\u0026eacute;s JA, Boriani G, Braunschweig F, Brignole M, Burri H, Coats AJS, Deharo JC, Delgado V, Diller GP, Israel CW, Keren A, Knops RE, Kotecha D, Leclercq C, Merkely B, Starck C, Thyl\u0026eacute;n I, Tolosana J, ESC Scientific Document Group (2021) 2021 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy. Eur Heart J 43:1651. https://doi.org/10.1093/eurheartj/ehac075\u003c/li\u003e\n\u003cli\u003eUdo EO, Zuithoff NP, van Hemel NM, de Cock CC, Hendriks T, Doevendans PA, Moons KG (2012) Incidence and predictors of short- and long-term complications in pacemaker therapy: the FOLLOWPACE study. Heart Rhythm 9:728-35. https://doi.org/10.1016/j.hrthm.2011.12.014\u003c/li\u003e\n\u003cli\u003eMoraes FCA, Dal Moro L, Pessoa FR, Passos ESDR, Campos RALS, Souza DDSM, Feio D, Rodr\u0026iacute;guez Burbano RM, Fernandes MR, Santos NPCD (2023) Malignant Neoplasms Arising in the Cardiac Pacemaker Cavity: A Systematic Review. Cancers 15:5206. https://doi.org/10.3390/cancers15215206\u003c/li\u003e\n\u003cli\u003ehttps:// www.bmj.com/content/372bmj.n71 (last access on June 21\u003csup\u003est\u003c/sup\u003e, 2025)\u003c/li\u003e\n\u003cli\u003eMoola S, Munn Z, Tufanaru C, Aromataris E, Sears K, Sfetcu R, Currie M, Lisy K, Qureshi R, Mattis P, Mu P. Chapter 7: Systematic reviews of etiology and risk. In: Aromataris E, Munn Z (Editors). JBI Manual for Evidence Synthesis. JBI, 2020. Available from https://synthesismanual.jbi.global. https://doi.org/10.46658/JBIMES-20-08\u003c/li\u003e\n\u003cli\u003eSainani KL. Dealing with non-normal data (2012) PM R 4:1001-1005. https://doi.org/10.1016/j.pmrj.2012.10.013\u003c/li\u003e\n\u003cli\u003eRosen RD, Sapra A (2023) TNM Classification. https://www.ncbi.nlm.nih.gov/books/NBK553187\u003c/li\u003e\n\u003cli\u003eRaspollini MR, Comperat EM, Lopez-Beltran A, Montironi R, Cimadamore A, Tsuzuki T, Netto GJ (2023) News in the classification of WHO 2022 bladder tumors. Pathologica 115:32-40. https://doi.org/10.32074/1591-951X-838.\u003c/li\u003e\n\u003cli\u003ePuette JA, Malek R, Ahmed I, Ellison MB (2024) Pacemaker Insertion. Treasure Island, Florida\u003c/li\u003e\n\u003cli\u003eAnderson JM, Rodriguez A, Chang DT (2008) Foreign body reaction to biomaterials. Semin Immunol 20:86-100. https://doi.org/10.1016/j.smim.2007.11.004\u003c/li\u003e\n\u003cli\u003eMantovani A (2005) Cancer: inflammation by remote control. Nature 435:752-3. https://doi.org/10.1038/435752a\u003c/li\u003e\n\u003cli\u003eCoussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860-7. https://doi.org/10.1038/nature01322 \u003c/li\u003e\n\u003cli\u003eMantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436-44. https://doi.org/10.1038/nature07205\u003c/li\u003e\n\u003cli\u003eSingh N, Baby D, Rajguru JP, Patil PB, Thakkannavar SS, Pujari VB (2019) Inflammation and cancer. Ann Afr Med 18:121-126. https://doi.org/10.4103/aam.aam_56_18\u003c/li\u003e\n\u003cli\u003eSzlosarek PW, Balkwill FR (2003) Tumour necrosis factor alpha: a potential target for the therapy of solid tumours. Lancet Oncol 4:565-73. https://doi.org/10.1016/s1470-2045(03)01196-3\u003c/li\u003e\n\u003cli\u003eVoronov E, Shouval DS, Krelin Y, Cagnano E, Benharroch D, Iwakura Y, Dinarello CA, Apte RN (2003) IL-1 is required for tumor invasiveness and angiogenesis. Proc Natl Acad Sci U S A 100:2645-50. https://doi.org/10.1073/pnas.0437939100\u003c/li\u003e\n\u003cli\u003eGrivennikov S, Karin M (2008) Autocrine IL-6 signaling: a key event in tumorigenesis? Cancer Cell 13:7-9. https://doi.org/10.1016/j.ccr.2007.12.020\u003c/li\u003e\n\u003cli\u003eBalkwill F (2004) Cancer and the chemokine network. Nat Rev Cancer 4:540-50. https://doi.org/10.1038/nrc1388\u003c/li\u003e\n\u003cli\u003eSporn MB, Todaro GJ (1980) Autocrine secretion and malignant transformation of cells. N Engl J Med 303:878-80. https://doi.org/10.1056/NEJM198010093031511\u003c/li\u003e\n\u003cli\u003eYilmaz M, Christofori G (2009) EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev 28:15-33. https://doi.org/10.1007/s10555-008-9169-0\u003c/li\u003e\n\u003cli\u003eNieman MT, Prudoff RS, Johnson KR, Wheelock MJ (1999) N-cadherin promotes motility in human breast cancer cells regardless of their E-cadherin expression. J Cell Biol 147:631-44. https://doi.org/10.1083/jcb.147.3.631\u003c/li\u003e\n\u003cli\u003eWitsch E, Sela M, Yarden Y (2010) Roles for growth factors in cancer progression. Physiology 25:85-101. https://doi.org/10.1152/physiol.00045.2009\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"internal-and-emergency-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"iaem","sideBox":"Learn more about [Internal and Emergency Medicine](http://link.springer.com/journal/11739)","snPcode":"11739","submissionUrl":"https://www.editorialmanager.com/iaem/default.aspx","title":"Internal and Emergency Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"CIED, cancer, neoplasm, metastasis","lastPublishedDoi":"10.21203/rs.3.rs-7009208/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7009208/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eCardiac implantable electronic device (CIED) implantation is a minor surgical procedure, with a low complication incidence. Neoplasm occurrence at the CIED pocket is a rare event, and sporadic cases are reported without a comprehensive evaluation. This hybrid study aims to fill this gap through a three-part approach: a new case report, a scoping review with individual patient data (IPD) analysis, and a clinical survey.\u003c/p\u003e\u003cp\u003eIn March 2024, a male patient with a history of high-grade urothelial cancer referred to our Department with a mass at the CIED pocket. Incisional biopsy confirmed the diagnosis of high-grade urothelial carcinoma. The patient died after 4 months.\u003c/p\u003e\u003cp\u003e Through our scoping review and IPD analysis, we collected 56 patients affected by primary neoplasms [40 (71.4%)] and metastasis [16 (28.6%)] at the CIED pocket. Among the primary neoplasms, adenocarcinoma (12; 30.0%) was most frequent in females, while sarcoma (10; 25.0%) was predominant in males. On the other hand, metastasis types were represented by breast cancer (3; 18.8%) in females, and myeloma (2; 13.3%) and melanoma (2; 13.3%) in males.\u003c/p\u003e\u003cp\u003eThe clinical survey showed data from 471 patients who underwent CIED implantation. No primary neoplasm or metastasis developed at the CIED pocket, also in subjects with history of cancer.\u003c/p\u003e\u003cp\u003eAlthough rare, both primary and metastatic neoplasms may occur at the site of CIED implantation. Vigilant monitoring of CIED patients is essential, particularly when changes at the pocket site arise. Early biopsy and oncologic assessment should be considered in such cases to enable timely diagnosis and intervention.\u003c/p\u003e","manuscriptTitle":"Neoplasms Arising at the CIED Pocket: A Hybrid Study Combining Case Report, Scoping Review, and Clinical Survey.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-15 13:14:50","doi":"10.21203/rs.3.rs-7009208/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-09-09T22:36:48+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-11T15:44:19+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-03T03:50:18+00:00","index":"","fulltext":""},{"type":"submitted","content":"Internal and Emergency Medicine","date":"2025-07-02T14:19:48+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"internal-and-emergency-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"iaem","sideBox":"Learn more about [Internal and Emergency Medicine](http://link.springer.com/journal/11739)","snPcode":"11739","submissionUrl":"https://www.editorialmanager.com/iaem/default.aspx","title":"Internal and Emergency Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"b230871e-ace7-49d7-a0e8-3b85f3793c58","owner":[],"postedDate":"July 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-12T16:07:22+00:00","versionOfRecord":{"articleIdentity":"rs-7009208","link":"https://doi.org/10.1007/s11739-025-04251-4","journal":{"identity":"internal-and-emergency-medicine","isVorOnly":false,"title":"Internal and Emergency Medicine"},"publishedOn":"2026-01-08 15:57:53","publishedOnDateReadable":"January 8th, 2026"},"versionCreatedAt":"2025-07-15 13:14:50","video":"","vorDoi":"10.1007/s11739-025-04251-4","vorDoiUrl":"https://doi.org/10.1007/s11739-025-04251-4","workflowStages":[]},"version":"v1","identity":"rs-7009208","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7009208","identity":"rs-7009208","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}