Brain tumors are a collection of neoplasms that are distinctively described based on biology, prognosis, and treatment [1]. Moreover, brain tumors are identified as intracranial neoplasms with a global prevalence of 3.5 per 100,000 population in 2022 [2]. First primary brain tumors refer to neoplasms arising from the central nervous system (CNS), and can be both benign and malignant [3]. However, a second primary tumor (SPT) refers to a separate development of another cancer that is not metastasis or a recurrence and is different from the first primary tumor (FPT) [4].

Adjuvant and neoadjuvant chemoradiotherapy are integral components of treatment algorithms for various tumors, contributing to an improved survival rate among patients. However, exposure to these therapies has been associated with the development of SPTs following the resolution of initial tumors [56]. Compared to the general population, the risk of developing SPTs has been approximately 15%–20% higher in cancer patients [78]. According to Yang et al. [9], the cumulative incidence of SPTs was reported at 14% and the probability of an SPT in FPT patients varied from 5.5% to 16% [10].

A high incidence of second primary meningiomas has also been reported among patients with initial breast and thyroid malignancies [1112]. Similarly, in patients with malignant astrocytoma, a considerably higher risk of developing SPTs has been reported compared to the general population, commonly involving salivary glands, bones, joints, and soft tissues [13]. Among patients with initial glioblastoma multiforme (GBM), a study by Kim et al. [5] revealed that 47% of SPTs were attributed to chemoradiotherapy for GBM management. In the case of GBM, SPTs primarily included leukemias, low-grade gliomas, sarcomas of the scalp, prostate cancers, bladder cancers, endometriosis adenocarcinomas, basal cell carcinomas, and renal cell carcinomas [14].

Apart from patients receiving chemoradiotherapy, the risk of SPTs has also been observed to be higher in patients aged less than or equal to 59 [51415]. Additionally, genetic abnormalities, such as isocitrate dehydrogenase mutations and platelet-derived growth factor receptor amplification, etc., also lead to an increased risk of developing second neoplasms in children with primary CNS tumors [141516].

With improvements in the prognosis of cancer patients, SPTs remain a serious health concern for patients and healthcare personnel, warranting further research in this field. However, studies have not been reported on SPTs among cancer survivors from Pakistan. To bridge this gap, this study aimed to determine the types of second primary malignancies amongst patients with brain tumors presenting at a tertiary care hospital and to assess the clinic-demographic characteristics of patients with initial brain tumors and initial extra neural tumors who subsequently developed brain tumors as SPTs.

This single-center retrospective study was conducted at the Section of Neurosurgery, Department of Surgery, Aga Khan University Hospital, Pakistan. The ethical exemption was obtained from the Institutional Ethics and Review Committee (ERC # 2021-6013-16843).

This study included all patients with histologically confirmed SPTs after primary brain tumors or brain tumors as SPTs after primary extra neural tumors between January 1, 2000 and December 31, 2020. Data were retrospectively collected from de-identified patient records. The variables recorded were patient clinicodemographics, characteristics of first and second tumors, and treatment modalities.

Descriptive statistics were presented as median, range, mean, standard deviation, and numerical percentages for patients who developed SPTs after primary brain tumors and those who developed brain tumors as SPTs following primary extra neural tumors. Categorical variables were described using frequencies and percentages. Analysis of variance was conducted to assess the association between SPTs and FPTs with a subsequent chi-square test to assess the association between categorical variables. Statistical significance was defined as p<0.05 with a confidence interval (CI) at 95%. All statistical analyses were conducted using STAT version 18.0 (StataCorp LLC) [17].

Overall, the median age at diagnosis was reported at 44.5 years. A total of 41 patients with SPTs were included in the study and most of the patients were 27 females (65.9%). Of the 41 patients, 20 patients (48.7%) developed SPTs after primary brain tumors while the remaining 21 patients (51.2%) developed brain tumors as SPTs after extra neural tumors (Table 1). The mean ages at diagnoses of FPTs as brain tumors and extra-neural tumors were comparable (45.00±7.00 and 45.00±24.00 years). The most common treatment modality was surgery (n=40, 97.6%).

According to the hospital record a total of 961 meningioma patients presented to the hospital during the years 2000–2020, hence the incidence of meningioma patients developing breast cancer as SPT is 3 out of 961 (31/10,000). Similarly, 781 pituitary adenoma patients presented to the hospital during the years 2000 to 2020, and the incidence of pituitary adenoma patients developing breast cancer as SPT is 1 out of 781 (13/10,000).

Among those who developed brain tumors as SPTs following extra-neural FPTs (n=21), breast carcinoma (n=9, 42.9%) was the commonest FPT while meningioma and pituitary adenoma predominated as SPTs 10 (47.6%) and 5 (23.8%), respectively. According to the hospital record, a total of 5,146 patients with breast cancer presented to the hospital from the year 2000 to 2020. Incidence SPTs in patients with breast cancers who develop meningiomas, pituitary adenomas, and gliomas were 6/5,146 (10/10,000), 2/5,146 (4/10,000), and 1/5,146 (2/10,000), respectively.

Among patients who developed SPTs after brain tumors group (n=20), meningioma (n=8, 40.0%) and pituitary adenoma (n=6, 30.0%) were the most prevalent FPTs while breast tumors predominated as SPTs (n=4, 20.0%) (Table 2).

However, for patients who developed brain tumors as SPTs following extra neural FPTs (n=21), breast carcinoma (n=9, 42.9%) was the commonest FPT while meningioma and pituitary adenoma predominated as SPTs 10 (47.6%) and 5 (23.8%), respectively.

Additionally, there was no significant difference in the development of breast cancer as SPT compared to other extra neural SPT among patients who had pituitary adenoma as FPT vs. other neural FPT (p=0.81) and meningioma vs. other neural FPT (p=0.11) (Table 3). Amongst patients with breast cancer vs. other extra neural FPT, there was no significant difference in the development of pituitary adenoma vs. other neural SPT (p=0.74) and meningioma vs. other neural SPT (p=0.13).

Statistical analysis showed no significant difference in age distribution across different tumor types (p=0.20). Additionally, no significant association was found between comorbidities and patient outcomes (p=0.41). However, the survival analysis revealed that patients marked as alive had a mean age of 44.5 years, whereas those marked as dead had a mean age of 57.0 years. Patients with unknown outcomes tended to be older, with a mean age of 63.0 years.

Our findings demonstrated a significant number of SPTs in patients with FPTs. Of the total 41 patients, 20 (48.7%) developed SPTs, while 51.2% had brain tumors as SPTs following extra-neural tumors, with comparable mean diagnostic ages (45 years). Among patients with brain tumors as SPTs, breast carcinoma was the most common FPT, while meningioma and pituitary adenoma were frequent brain SPTs. Incidence rates showed 31 per 10,000 for meningioma and 13 per 10,000 for pituitary adenoma patients developing breast cancer as SPT. Statistical analysis indicated no significant differences in age distribution, comorbidities, or survival outcomes by tumor type. Survival analysis showed a younger mean age for those patients who were alive (44.5 years) compared to those deceased (57.0 years) and with unknown outcomes (63.0 years).

Over the past few decades, research output has increased at a substantial rate, particularly in oncology, leading to an era where the formulation of most clinical decisions and healthcare policies is based exclusively on evidence-based data. There is a significant gap in the current literature concerning SPTs’ association with FPT in Pakistan; however, cancer’s significant disease burden makes the study more important. Studies report that Pakistan recorded 173,937 new cancer cases and 118,442 deaths in 2020 [18]. In this study, we present data on the occurrence of SPTs in brain tumor patients and the development of brain tumors as SPTs following extra neural FPTs in the Pakistani population.

Prior reports evaluating SPTs after CNS malignancies have found a substantially increased risk of SPTs in patients with pituitary adenoma treated with limited surgery and radiotherapy [19]. Similarly, studies have also discovered a statistically significant relation between breast cancer and SPT in meningioma patients [20]. Results from our study support both these associations in the Pakistani population, reporting a high occurrence of breast cancer as SPT following initial pituitary adenomas or meningiomas in our study. Meningiomas comprise most benign brain tumors and are associated with an increased survival rate, subsequently increasing the risk for the development of SPTs [21].

Conversely, the occurrence of brain tumors as SPTs following an extra neural FPT has also been previously explored. A national population-based study from Denmark reported a standardized incidence ratio (SIR) of 1.45 per 10,000 (CI: 1.14–1.82) for CNS malignancies in patients with first primary breast cancer who received radiotherapy [22]. Existing literature has also shown an association between pituitary adenoma and initial breast cancer (SIR: 1.46, CI: 0.33–5.25) [14]. Similarly, another study has reported a potential association between meningiomas and breast cancers. In some instances, meningiomas preceded breast cancers while the reverse was true in other instances [23]. These results are remarkably like the findings we observed where breast carcinoma was the most common FPT for patients who developed meningioma and pituitary adenoma as SPTs. Although CNS is a common site of metastasis for breast carcinoma, we confirmed the existence of the CNS tumor as a SPT and not metastases through histopathological reports.

Moreover, in addition to histopathological reports, gene expression profiling between first primary and SPTs has shown significant similarity. A study conducted with a Danish database comprising over 700,000 patients over the span of 28 years reported that the incidence of SPTs for the reported 27 FPTs was associated with both the genetic predisposition and diagnostic procedures [24]. Similarly, many mutations were associated with neural and non-neural tumors, associating a genetic link to a first primary and SPT [25]. IDH1 mutations were reported in 80% of secondary glioblastomas, and >80% in diffuse astrocytoma with an estimated 55% association with central chondrosarcomas and 23% with intrahepatic cholangiocarcinoma [262728]. However, there still needs to be in-depth genetic studies to draw strong correlation between FPTs and SPTs at the genetic level.

Previous studies report an average time interval between the discovery of two non-simultaneously diagnosed primary tumors of roughly 5 years [23]. Our results are consistent with previous data with a median duration between diagnoses of SPT after primary brain tumor of 6 years (interquartile range [IQR]: 12) and brain tumor after FPT of 6 years (IQR: 7). Lifestyle, environmental, host, and treatment-related factors for FPTs serve as possible etiologic factors leading to the development of SPTs. Most studies assessing the risk of SPTs in brain tumor patients or vice versa have shown an increased risk of SPTs in patients receiving radiation and chemotherapy for the first tumor [29].

Our single-center retrospective study is the first of its kind, conducted in Pakistan, exploring the association between FPTs and SPTs. Our findings demonstrated an association between FPTs and secondary primary tumors–from both neural and extra-neural perspectives–drawing relationships between the incidence of secondary tumors and different treatment modalities for the FPT. The study provides the foundation for establishing the baseline relationship, essential to studying in-depth associations and understanding causes. Moreover, given the treatment disparity and availability of advanced treatment measures in Pakistan, the study helps provide a basic population focus for SPTs and FPTs.

The occurrence of SPTs in brain tumor patients or vice versa may be a result of an amalgamation of different factors. Hence, it is imperative to study the individual factors affecting the occurrence of SPTs in the future. Replicating this study with a multicenter prospective study is warranted to allow a better understanding of SPTs in the Pakistani population.