Malignant Neoplasms Arising in the Cardiac Pacemaker Cavity: A Systematic Review

Simple Summary Cancer, a complex group of diseases marked by abnormal cell proliferation and loss of physiological functions. Furthermore, tumors in the cardiac pacemaker pocket are rare and challenging medical problems, where the location of the implanted devices employed to manage heart rhythm disorders unexpectedly becomes a site for neoplasm growth. This intersection becomes even more nuanced with the rise in cardiac pacemaker (PM) implantations, a common practice globally. This study aimed to evaluate reported cases of this condition throughout the existing literature, in addition to enhancing early detection strategies and improving the management of affected patients. Abstract Cancer is the abnormal proliferation of physiologically inadequate cells. Studies have identified the cardiac pacemaker pocket as a site of rare neoplasms. To evaluate the clinical outcomes, treatment, prognosis, and individualized management of tumors originating in the cardiac pacemaker pocket, a systematic review was conducted using case reports and case series available in the PubMed/Medline, Science Direct, Cochrane Central, LILACS, and Scientific Electronic Library Online (Scielo) databases. Pacemaker pocket tumors affected patients with a mean age of 72.9 years, with a higher incidence in males (76.9%, n = 10). The average time for neoplasm development was 4.4 years (54.07 months). The most prevalent model was Medtronic (38.4%, n = 5), with titanium (83.3%) being the most common metal composition. Chemotherapy was the most performed procedure among patients (38.4%), followed by radiation therapy (38.4%) and surgical tumor resection (30.7%). Six analyzed cases (46.1%) resulted in death, and four patients (30.7%) achieved a cure. Patients with pacemakers should be routinely evaluated for the occurrence of malignant tumors at the site of device implantation.


Introduction
Cancer is a cluster of diseases characterized by the abnormal proliferation of cells, leading to the loss of their physiological functions in terms of division, growth, and lifespan [1,2].Oncogenesis involves intricate mechanisms influenced by genetic factors, environmental exposures, and individual lifestyle habits that contribute to the development of malignancy [3,4].In the United States, an estimated 2 million new cancer cases are diag-nosed annually, with 610,000 deaths attributed to the disease [5].Globally, approximately 19.3 million cases are identified each year, accompanied by 10 million deaths [6].
Cardiovascular diseases (CVDs) and cancer rank as the primary causes of global mortality [7], accounting for approximately one in six deaths worldwide [8].The correlation between anticancer therapies and alterations in left ventricular ejection function, as well as the onset of heart failure symptoms, is well documented [9].Factors such as radiotherapy and certain medications (anthracyclines, cyclophosphamide, sunitinib) [10] have been shown to induce senescence in cardiomyocytes.Consequently, this association is justified by the exacerbation of adverse cardiac remodeling due to the secretion of pro-inflammatory molecules and matrix protease degradation, which significantly impact patient prognosis [11,12].
The cardiac pacemaker (PM), on the other hand, is an electronic device utilized to regulate heart rhythm and treat electrical conduction disorders, including bradycardia, atrioventricular blocks (AVBs), left bundle branch blocks (LBBBs), right bundle branch blocks (RBBBs), and other congenital or acquired cardiovascular diseases (CVDs) [13,14].Over time, the use of pacemakers has progressively increased, and their implantation is associated with a reduced risk of cardiovascular complications such as heart failure, acute myocardial infarction, malignant arrhythmias, and even mortality [15,16].
Pacemaker implantation is progressively increasing.More than 1 million cardiac pacemakers are implanted per year worldwide, with 200,000 implantations being performed in the United States [17].Although pacemaker implantation is safe, complications such as bleeding, infection, pain, and inflammation at the incision site are present in a reduced proportion of insertion procedures [18].In rare cases, the development of malignant neoplasms around the pacemaker tissue adjacent to the pacemaker has also been described [19].
Currently, investigations regarding malignancies in the pacemaker pocket (PP) are restricted to case reports and series.Hence, this systematic review endeavored to assess, by examining reports and case series, the available evidence concerning clinical outcomes, treatment approaches, prognosis, and tailored management strategies for each case.

Protocol and Registration
This systematic review followed the 27 items described in the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) protocol [20], which assist in the construction of systematic reviews and meta-analyses.This review was registered in the Prospective International Registry of Systematic Reviews (PROSPERO) of the National Institute for Health Research under number CRD42022360240.

Eligibility Criterion
The articles included in this review were only case reports and case series in patients over 18 years of age who registered malignant neoplasms with the primary site of the pacemaker pocket.Only articles with confirmation of cancer by histopathology and/or immunohistochemistry were included in this study.Only articles in English were included in this review.
Articles from literature reviews and encyclopedias, editorials, book chapters, conference abstracts, correspondence, reviews, news, and small communications were excluded.Interventional studies involving animals or humans, and other studies that require ethical approval, must list the authority that provided approval and the corresponding ethical approval code.
Thus, we sought to answer the following question: what are the main clinical, demographic, and management-related characteristics described in cases of malignancy affecting the region covering the pacemaker implantation cavity?

Search Strategy and Data Extraction
This study used references describing cancer at the primary site in the pacemaker pocket indexed in the PubMed/Medline, SCOPUS, Web of Science, and LILACS databases.The following descriptors were used: "Cancer", "malignancy", "tumor", "malignancies", "carcinoma", "Plasmacytoma", "neoplasms", "neoplasia", "lymphoma", "adenocarcinoma", "leiomyosarcoma", "histiocytoma", "artificial pacemaker", "Resynchronization therapy", "CIED", "cardiac implantable electronic devices", "cardiac pacemaker", "cardiac pacing artificial", "implantable pacemaker", "pacemaker pocket", "pacemaker cavity", "pacemaker implantation site", "pacemaker sac".For the combination of terms in the databases, we used Boolean connectors (OR, AND).For the inclusion of additional articles, a manual search was performed in the references of the selected studies and notification alerts in the databases were activated if new titles that suited the query were published.In addition, research was also carried out using abstracts, articles, and scientific presentations from virtual meetings of the American Society of Clinical Oncology [21] and the American College of Cardiology [22].
Sources found in the databases and in the references of the articles were incorporated into the reference management software (EndNote ® , version X7, Thomson Reuters, Philadelphia, PA, USA).Duplicate articles were removed using both automated and manual methods.Subsequently, two reviewers (F.C.A.M. and F.R.P.) independently analyzed the titles and abstracts of the identified articles.In case of disagreements between the two reviewers, a third reviewer was responsible for the final decision (N.P.C.S.).
The following baseline characteristics were extracted: (

Risk of Bias in Included Studies
To assess the risk of bias in the selected articles, the Critical Assessment of the Joanna Briggs Institute (JBI) [23] for case reports was used as a tool, which consists of a checklist of eight scoring items.The evaluation was carried out by two reviewers independently (L.D.M. and R.A.L.S.C.).And in case of disagreement, a third reviewer was responsible for the final opinion (M.R.F.).Additionally, to reduce the risk of bias, all studies included in this review were published in peer-reviewed journals.
Data were tabulated in Microsoft Office Excel version 2016, and patient characteristics, tumor classification, pacemaker implantation time, clinical symptoms, laboratory and imaging tests, management, and outcome were presented descriptively.

Selection of Studies
We identified 1277 titles of which, after removing duplicates, 819 titles remained for analysis.By applying the eligibility criteria, we selected 22 articles to compose the literature review.As seen on the Figure 1.

Results of Individual Studies
Eighteen (n = 18) case reports and four (n = 4) case series were included in the systematic review .Milner et al. [29] reported an ulcerative and expansive plasmacytic lymphoma in the pacemaker pocket (PP) of a 78-year-old man from Portugal.De Mattia, Brieda, and Dametto [36] presented a case of an 87-year-old female patient with an invasive ductal carcinoma developing in the pacemaker pocket, which, along with Moruzzo et al.'s study [35], represented non-Hodgkin's lymphomas identified

Results of Individual Studies
Eighteen (n = 18) case reports and four (n = 4) case series were included in the systematic review .Milner et al. [29] reported an ulcerative and expansive plasmacytic lymphoma in the pacemaker pocket (PP) of a 78-year-old man from Portugal.De Mattia, Brieda, and Dametto [36] presented a case of an 87-year-old female patient with an invasive ductal carcinoma developing in the pacemaker pocket, which, along with Moruzzo et al.'s study [35], represented non-Hodgkin's lymphomas identified consecutively in the adjacent region of the pocket; these were the two reported Italian cases.In the UK, cases were reported by Bhandarkar, Bewu, and Taylor and Rathinam et al. [32,33], describing two adenocarcinomas and one inflammatory myofibroblastic tumor, respectively.The study from Spain conducted by González-Vela et al. in 2009 [32] described a cutaneous leiomyosarcoma in the subpectoral pouch of a 74-year-old man, and another case report published in 2013 [31] described an atypical fibroxanthoma in the PP of an 89-year-old man with four years of implantation.Rasmussen et al. [34] reported a case of papillary adenocarcinoma that developed one year after implantation in a 75-year-old man in Norway.Hamaker et al. [24] reported a 48-year-old male patient with a plasmacytoma in the PP region 16 months after implantation.The study conducted in Germany by Fraedrich et al. [37] described a malignant fibrous histiocytoma in the PP of an 82-year-old male patient three years after implantation.Hojo et al. [43] described, in their Japanese study, a case of a 29-year-old man with stage II diffuse large B-cell lymphoma that developed six years after implantation.The Slovak study by Zonca et al. [40] reported a case of invasive ductal carcinoma in the PP of a 78-year-old woman with ulcerations in the affected region.The Dutch case report by Khamooshian et al. [41] described a pleomorphic sarcoma in the PP of a 43-year-old man eight months into the third device replacement.
In the United States, six cases have been reported.In Hamaker et al. [24], a man was described who developed plasmocytoma, diagnosed 1 year and 4 months after implantation of the generator.Reyes [27] reported in his study a case of clear cell hidradenocarcinoma affecting the pacemaker region of an 88-year-old woman four years later.In the work by Herrmann, Mishra, and Greenway [25], the case of a nodular basal cell carcinoma with features of an erythematous plaque on the left pectoral under the generator was cited.Magilligan and Ishak [26] described in their study a case of an 89-year-old woman who developed a breast adenocarcinoma in the region located in the PP.Zarifi et al. [28] described a case of plasmablastic lymphoma affecting the PP of a 100-year-old male patient after a period of 10 years from implantation until the onset of symptoms, as observed in Table 1 below.

Imaging Exams
In total, 6 cases (23%) underwent CT (Table S1).Among them, one case had a mass measuring 65 × 24 mm associated with left axillary lymphadenopathy [29]; one case had a mass on the pacemaker battery measuring 6 cm in diameter [35], also with localized lymphadenopathy; and one case had a round mass measuring 8-9 cm in the left clavicular region superficial to the left pectoral muscle on the upper surface of the pacemaker [32].Furthermore, two suspected metastases were ruled out [41,42] and one was identified as highly suggestive.[38] Regarding mammography, it was performed in three cases, presenting the following results: spiculated round mass caudal to the pacemaker pocket [36], absence of abnormalities or suspicious changes in both breasts [27], and findings difficult to interpret [40].Four cases (15.3%) underwent USG, revealing a solid-looking lesion in two cases [27,41] and liquid in one case [28] A total of seven case reports (26.9%)presented in their descriptions the results of chest X-rays performed [24,26,29,33,37,42], of which two reported no visible changes [26,29], one reported the presence of soft tissue mass around the pulse generator [24], one reported a shadow in the posterobasal segment of the lung with a suspicious indication of bronchial carcinoma with enlargement [37], one reported no metastasis [42], one reported a clinically palpable mass [33], and one reported nodular bilateral round shadows typical of metastatic lesions in the lungs [38].
Another tumor that stood out after consultation was a clear cell hidradenocarcinoma mimicking the immunohistochemistry of a metastatic lobular carcinoma by presenting a positive estrogen receptor, a progesterone receptor, mammaglobin, and CK7 cytokeratin [27].Finally, the anatomopathological analysis can be highlighted, which identified invasion in different tissues in 19.2% (n = 5) of the samples [24,29,34], with one (1) in the bone marrow [29], one (1) in the right scapular region [24], and three (3) in the axillary lymph node region [19,34,38].
Radiotherapy was described in 34.61% of cases (n = 9) [24,27,32,34,38,40,41,43,44].Of the nine studies with radiotherapy, only three provided details on how the procedure was performed.The description presented by Hamaker et al. [24] in their study included the use of cobalt therapy with 2000 rads at the pacemaker site, Hojo et al. [43] reported the use of 30 Gy at the tumor site in the pacemaker pocket of a patient with AC, and Khamooshian [41] described the use of 60 Gy of adjuvant radiotherapy in the treatment.However, Reyes [27] presented a patient who refused the recommended irradiation.

Discussion
Every year, approximately 1 million pacemakers are implanted worldwide [46], with a total of 19 million in the USA over the period from 1993 to 2009.Nevertheless, only 15 cases of malignancies are described in the literature, which substantiates the infrequent occurrence of malignancies within the pacemaker pocket [28].Publications reporting and describing the appearance of tumors with a primary site in the pocket of these devices are still rare in the current medical literature.
The process of formation of malignant neoplasms around the cardiac pacemaker is still not well understood.One hypothesis would be that titanium is involved in tumor formation in this region [28,45].The wearing away and corrosion of titanium in the human body, associated with the release of metal ions in the reaction, can cause toxicity in the body due to the potential pro-inflammatory effects mediated by interleucins, tumor necrosis factor α (TNF-α), transforming growth factor β (TGF-β), and β-glucuronidase (GLU), and oxidative effects on the tissue surrounding the metal may cause apoptosis, genomic instabilities, and production of titanium-specific T-lymphocytes [45,[47][48][49][50].In addition, titanium particles in their oxidized form (TiO 2 ) are capable of inducing DNA damage, genetic mutations, DNA deletions, and formation of micronuclei indicative of chromosomal aberrations in different cell lines [45,51,52].
Another possibility is that there may be genetic factors involved in the neoplasia formation process within the pacemaker pocket.The occurrence of cancer at the site of silicone breast implantation has been linked to mutations in the JAK1/STAT3 signaling pathway and the TP53 gene, which are involved in the modulation and prevention of clonal expansion of tumor cells [53][54][55].Overexpression of the MYC gene and mutations in BRCA1/2 have also been associated with a higher likelihood of lymphomagenesis in patients following silicone implants [53,56,57].Mutations in the p53 gene have also been described in the development of oral cancer after metal implants [58,59].Currently, there is no evidence to support the presence of any specific common genetic component for the development of cancer in the pacemaker pocket among the patients described in the study.
Two other hypotheses regarding the formation of tumors in the pacemaker pocket would be chronic inflammation due to prolonged pacemaker presence and as a result of electrical stimulation [24,28].The inflammation and the electric stimulation caused by a pacemaker are linked to chronic mechanical irritation, electrochemical disbalance, and trauma, all of which contribute to the development of cancer by inducing prolonged immune activation, cellular damage, and cancer cell migration resulting from electrical activity (galvanotaxis/electrotaxis) [60][61][62].
In the current study, titanium was the main metal described in the composition of pacemakers (30.7%, n = 8) [24,26,28,30,31,43,44].Moreover, Pinchasov et al. [63] also reported in their study a series of cases of oral cancer of the squamous cell type in patients with dental implants made of titanium.For Onega et al. [64], in their meta-analysis with patients undergoing total arthroplasty who developed cancer at the implant site, there was no identification of an increased risk of cancer with the use of metal prostheses.
A study carried out with the population of Denmark observed a greater chance of developing bladder cancer and multiple myeloma in patients with a cardiac pacemaker, suggesting that the use of the device or the shared risk factors between cancer and cardiovascular diseases would be involved in the development of these tumors [65].
The presence of lymphomas was reported in 23.07% of the observed studies (n = 6) [19,28,29,35,43].A similar result was described by Kricheldorff et al. [69], who also reported the predominance of lymphoma-type cancer-more specifically, anaplastic large cell lymphoma (BIA-ALCL)-in women undergoing silicone breast implantation.BIA-ALCL is a type of non-Hodgkin's lymphoma that also originates from a silicone implant in the pectoral region of women [70].Its genesis involves factors related to immunological interaction between tissue and prosthesis, bacterial growth in the implanted site, and genetic factors [70,71].
As for tumor development time, 12 patients developed cancer within 4 years of pacemaker implantation [19,24,27,30,31,34,35,37,38,41,44], 5 patients were diagnosed in a period greater than 4 years and less than 10 years [26,36,38,40,43], and 8 developed cancer over a period of more than 10 years [19,28,29,32,33,39,42].In comparison, the International Agency for Research on Cancer (IARC) [74] described the growth of sarcomas and lymphomas at sites of orthopedic metal implants as occurring over variable periods, with cases reported between a few months and 30 years after implantation but with an average time of diagnosis that was also less than 10 years.
Chest radiography (26.9%) was the most used imaging test due to its ability to analyze the insertion of the cardiac device and identify tumors or structures adjacent to the implant [75,76], and it was also used in some patients to assess metastases [38,42], an action that is recurrent in underdeveloped countries [77].Of the patients who underwent computed tomography (26.9%) (n = 7), in four of them the exact location of the mass and its relationship with adjacent structures (pacemaker bag and muscle bundles) were verified, in addition to definition of the presence or absence of lymphadenopathy in the axillary and mediastinal chains [29,32,35,41,[78][79][80]. Finally, the third most used imaging test was USG (19.2%) due to its usefulness in observing soft tissues and differentiating the described tumors from isolated abscesses [81] and because it serves as a quick and cost-effective way to locate a lesion in relation to the pacemaker pocket [82], as seen in the studies by De Mattia [36], Khamooshian et al. [41], Zonca et al. [40], and Reyes [27].
In this systematic review, the approaches described were heterogeneous in terms of treatment, with significant differences between them.The treatment was carried out according to the specific indications of each histological type of tumor, the resources and evidence available at the time of the studies' respective publications and the clinical condition of the patients and the indications for surgery [29,32,35,41,[78][79][80], chemotherapy [33][34][35]38,40,42,44], and radiotherapy [24,32,34,38,40,41,43,44].
Primary pacemaker pocket tumors are rare.The relationship between pacemaker components and the appearance of malignancies is not yet well understood, but occurrence is probably due to coincidence [28,83].Currently, there is insufficient evidence to establish a clear link between the occurrence of pacemaker pocket tumors and a specific factor, such as genetic characteristics, pacemaker composition, or immunological processes.Due to the rarity of these tumors, there is a lack of consensus on the approach to diagnosis and treatment.More studies are needed to improve our understanding of the biology and treatment of these rare tumors.

Conclusions
Patients who have been implanted with a pacemaker should be routinely clinically evaluated for the occurrence of malignant tumors at the implantation site of these devices.

Figure 1 .
Figure 1.Diagram of the research selection flow adapted from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Figure 1 .
Figure 1.Diagram of the research selection flow adapted from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Figure 4 .
Figure 4. (A) Countries of origin of the selected publications.(B) Graphic representation of time to development of cancer in years [19,24-44].3.11.Laboratory Tests

Figure 4 .
Figure 4. (A) Countries of origin of the selected publications.(B) Graphic representation of time to development of cancer in years [19,24-44].

Table 1 .
Identification of articles included in the study.

Table 2 .
Characteristics of patients and pacemakers.