Open Access

Occurrence of Second Primary Malignancies in Patients With Primary Optic Nerve Gliomas: A Surveillance, Epidemiology, and End Results Analysis


1University of Medicine and Health Sciences, Portland, ME, U.S.A.

2Texas Tech University Health Sciences Center – Paul L. Foster School of Medicine, El Paso, TX, U.S.A.

Cancer Diagnosis & Prognosis Nov-Dec; 1(5): 393-398 DOI: 10.21873/cdp.10052
Received 23 August 2021 | Revised 21 March 2023 | Accepted 13 October 2021
Corresponding author
Zain Hussain, UMHS, 275 7th Ave 26th floor, New York, NY 10001, U.S.A. Tel: +1 8327442189


Background/Aim: Advanced understanding of screening and therapeutic modalities acts as provision for increased survival in patients diagnosed with optic nerve gliomas. Secondary primary malignancies (SPMs) in patients diagnosed with primary optic nerve glioma (OPG) are currently an uncharacterized frontier. This US national database analysis highlights the incidences of SPMs in patients diagnosed with primary OPG. Materials and Methods: Standardized incidence ratios (SIR) and excess absolute risk (EAR) for SPMs were calculated using the SEER-specific multiple outcome analysis. 95% SIR confidence intervals were calculated with statistical significance achieved at p<0.05. Results: SPMs originating from soft tissues (including the heart) (SIR=33.23, CI=6.85-97.11; EAR=5.07), breast (SIR=4.99, CI=1.36-12.77; EAR=5.57), female breast (SIR=5.03, CI=1.37-12.89; EAR=5.58), brain (SIR=105.38, CI=65.23-161.08; EAR=36.23), cranial nerves (SIR=103.29, CI=12.51-373.12; EAR=3.45), non-lymphocytic leukemia (SIR=15.05, CI=1.82-54.37; EAR=3.25), myeloid and monocytic leukemia (SIR=16.26, CI=1.97-58.75; EAR=3.27), and Kaposi’s sarcoma (SIR=79.88, CI=2.02-445.08; EAR=1.72) demonstrated significantly increased SIR. Overall, the values for cumulative SPM (SIR=6.04, CI=4.33-8.19; EAR=59.60) highlight the overall significance in incidence of SPM in patients diagnosed with OPG. Conclusion: Clinical decision-making should reconcile enhanced propensities for development of SPM.
Keywords: Second primary malignancy, optic nerve glioma, incidence ratios

Primary optic nerve glioma, or optic pathway glioma (OPG), is the most common primary tumor of the optic nerve (1) and arises from astrocytes, a glial cell subtype found in the central nervous system (CNS) (2,3). The majority of these neoplasms present as low-grade tumors and are mostly seen in the first decade of life (1). Additionally, OPGs are strongly associated with neurofibromatosis 1 (NF1); OPGs are observed as the most common CNS tumor within this disease entity (4,5). The clinical rationale for patients diagnosed with primary OPG includes genetic screening for NF1. Diagnosis is confirmed through imaging, preferably magnetic resonance imaging (6), albeit this neoplasm may be evident through a computed tomography scan (7). Importantly, biopsy is unwarranted due to inherent and enhanced imaging sensitivity for typical pathognomonic findings of OPGs on imaging (8). The clinical course of OPGs can be volatile in children and adults due to their location and variance in histology, respectively (9-13). Currently, controversy exists regarding what the most optimal treatment regimen for OPG may be (14,15).

The occurrence of SPMs is common as they are diagnosed in one out of every 12 patients with cancer (16). A multitude of prior studies have characterized the risk of SPM development in the setting of a variety of primary cancer, including primary sites of the breast, colon, and lung (17-19). Furthermore, it was noted that more than a half of patients diagnosed with two types of cancer died due to their SPM (20). It is reported that the 5-year survival rate associated with OPG is more than 90% (21,22). While the survival rate is impressive, clinical consequences include a heightened propensity for development of a SPM (23-25). One study showed a significantly increased rate of SPM in children diagnosed with NF1 and treated for OPG with radiotherapy (26).

The number of patients diagnosed and treated for OPGs is increasing. Despite continual improvements in survival, it is important to understand the long-term complications of malignancy. To our knowledge, few studies characterize the incidence of SPM in those with first primary OPG. This retrospective cohort study aimed to analyze the occurrence and risk of SPM in patients with a diagnosis of OPG between 1992 and 2017 through The Surveillance, Epidemiology, and End Results (SEER) database.

Materials and Methods

Within the SEER system, the “Incidence-SEER Research Data, 13 Registries (excl AK), Nov 2019 Sub (1992-2017)” database was analyzed for patients diagnosed with optic nerve gliomas between January 1992 and December 2017. This retrospective cohort study filtered over 10 million patients by utilizing the search criteria “C72.3-Optic Nerve” for “Site and Morphology, Primary Site-labeled) and selecting only cancer with malignant behavior. Multiple outcome analysis was performed yielding standardized incidence ratios (SIR) for SPM, and excess absolute risk (EAR). The 95% confidence intervals for SIRs are given with statistical significance achieved at p<0.05.


Cohort analysis. Descriptive statistics of a total of 622 patients with a formal diagnosis of primary glioma originating within the optic nerve are given in Table I. Patients had a mean age ±SD of 62.20±12.52 years (range=0.5-80). Please see Table I for additional information regarding baseline demographical characteristics of this cohort.

For the majority of patients, diagnostic confirmation was obtained via radiography without microscopic confirmation (63.2%), while positive histology (32.3%), direct visualization without microscopic confirmation (1.1%), and clinical diagnosis (1.8%) were less often utilized. Nearly all cases (97.7%) were reported from hospital inpatient/outpatient services or clinics. Within the subdivision of patients acquiring a SPM, the mean age at diagnosis of primary OPG was 13.52 years of age and of SPM was 26.66 years of age.

SIR of SPM. Relative to the US national population, patients afflicted with primary OPG demonstrated a significantly increased risk for multiple SPMs. Primary malignancies originating from soft tissues (including the heart) (SIR=33.23, CI=6.85-97.11; EAR=5.07), breast (SIR=4.99, CI=1.36-12.77; EAR=5.57), brain (SIR=105.38, CI=65.23-161.08; EAR=36.23), cranial nerves (SIR=103.29, CI=12.51-373.12; EAR=3.45), non-lymphocytic leukemia (SIR=15.05, CI=1.82-54.37; EAR=3.25), myeloid and monocytic leukemia (SIR=16.26, CI=1.97-58.75; EAR=3.27), and Kaposi’s sarcoma (SIR=79.88, CI=2.02-445.08; EAR=1.72) demonstrated significantly increased SIRs as SPMs (Table II). In totality, cumulative SPM (SIR=6.04, CI=4.33-8.19; EAR=59.60) highlighted overall significance in incidence rates of SPM in patients diagnosed with OPGs.

Utilizing a large-scale population-based cancer database, this study evaluated age-adjusted SIRs of SPMs in patients with a first primary diagnosis of OPG. Analysis of baseline demographic data showed 61.7% of our population was diagnosed with primary OPG before 10 years of age, corroborating previous studies highlighting 70% of OPGs are diagnosed in the first decade of life (1,16). The overall risk of SPMs for all sites was significantly elevated in patients with primary OPGs (SIR=6.0; 95% CI=4.3-8.2) (Table II). Risk was also increased for all types of solid tumor, soft-tissue tumors (including heart), breast tumors (when considering both male and female patients, and females alone). Interestingly, brain and cranial nerve tumors had the highest SIRs (SIR=105.4, CI=66.7-157.9; and SIR=103.3, 95% CI=12.5-373.1, respectively) (Table II).

Previous studies have been limited in exploring the relationships between these primary malignancies (27). However, hypotheses describe shared embryonic etiologies to be the greatest contributing factor to the reported increase in brain and cranial nerve tumors as has been reported for various other cancer types (27-29). A multitude of mutual risk factors found in cancer of the neuroepithelium (e.g., ionizing radiation) might also contribute to the increased age-adjusted SIR for brain and cranial nerve tumors (27,30,31). Lastly, genetic mechanisms influence the association between OPGs and SPMs of the brain and cranial nerves (32). Multiple genetic syndromes (e.g., NF1 and -2), specific genotypes (i.e., glioma CpG island methylator phenotype) and certain molecular mutations (BRAF proto-oncogene - V600E mutation) are well-characterized and implicated in both OPGs and brain/cranial nerve malignancies (32-34).

Unexpectedly, our survival study discovered a high incidence of Kaposi’s sarcoma in patients with primary OPGs (SIR=79.88, CI=2.02-445.08), not previously reported as far as we are aware. One study showed that human herpesvirus-8 (HHV-8) infection modulates the proliferation of glioma stem-like cells (GSCs) in vitro (35). After establishing both HHV-8-infected glioblastoma cell and GSC lines, HHV-8 was associated with significantly higher infectivity for GSCs compared to human endothelial cells, and higher rates of cellular proliferation and lower cell death in GSCs. One proposed pathway for this is HHV-8 microRNA-accelerated phosphorylation of AKT (36).

Non-lymphocytic leukemia (SIR=15.1, CI=1.8-54.4; EAR=3.3) and myeloid and monocytic leukemia (SIR=16.3, CI=1.97-58.8; EAR=3.3) also demonstrated significantly increased incidence in our study population (Table II). Some studies have shown a strong involvement of pre-B-cell leukemia homeobox 3 (PBX3) transcription factor in gliomas and in multiple other cancer types, especially leukemia (37-40). A 2017 study elucidated how silencing PBX3 reduces proliferation of glioma cells in vitro and in vivo (38). Furthermore, how microRNA-98 attenuation of PBX3 reduces cell migration and invasion in glioma was also outlined (38). PBX3 overexpression has frequently been reported in many solid tumor types and in several hematological malignancies, serving as a promoter for cell survival, proliferation, and invasion (39). Further gene and protein expression data are needed to fully understand the relationship between optic nerve gliomas, PBX3 and the development of SPMs.

The limitations of our study are several and merit understanding before implications of the results can be considered. Firstly, the rate of SPMs may have been inflated given that metastases from the primary glioma might have been misclassified as second malignancies. Additionally, sites of increased secondary malignancies (soft tissue including of the heart, breast, and Kaposi’s sarcoma) are unlikely locations for distant metastasis of OPGs which tend not to metastasize (41). While rigorous quality control and data gathering protocols by the National Cancer Institute allow for reasonable generalizability, this comprehensive database only accounts for roughly 28% of the entire US general population. Consequently, rare SPMs of OPG such as Kaposi’s sarcoma, are possibly unaccounted for. Lastly, due to inherent limitations of the SEER database, adjustments for common cancer risk factors such as consumption of tobacco or alcohol, the presence of obesity, or of underlying genetic mutations were not made. Such unaccounted characteristics are undoubtedly associated with both primary and secondary cancer and would certainly modify the incidence of given SPMs.


This study highlights significantly increased SIRs for SPMs in patients diagnosed with OPGs in a nationally representative database via a multiple outcomes analysis. These primary cancer types include originations from the breast, CNS, cranial nerves, non-lymphocytic leukemia, myeloid and monocytic leukemias, and Kaposi’s sarcoma. Increased sensitivity in clinical diagnosis coupled with modern advancements in cancer treatment confer early detection and increased survival, leading to greater incidence of SPMs (30,31,42,43). Clinical surveillance utilizing real-time screening measures in this predisposed target population can promote longevity and health in patients diagnosed with OPGs.

Conflicts of Interest

The Authors declare that they have no competing interests.

Authors’ Contributions

Z.H. performed statistical analysis of SPMs in patients with primary optic nerve gliomas. J.K. and A.S. contributed equally to the drafting of the article. F.D. provided direction via clinical oversight and mentorship during project completion. All Authors read and approved the final article.


1 Fried I Tabori U Tihan T Reginald A & Bouffet E Optic pathway gliomas: a review. CNS Oncol. 2(2) 143 - 159 2013. PMID: 25057976. DOI: 10.2217/cns.12.47
2 Huang M Patel J & Patel BC Optic Nerve Glioma. [Updated 2020 May 4]. In: StatPearls [Internet]. Treasure Island (FL), StatPearls Publishing, 2020.. Available at: https: //
3 Dutton JJ Gliomas of the anterior visual pathway. Surv Ophthalmol. 38(5) 427 - 452 1994. PMID: 8009427. DOI: 10.1016/0039-6257(94)90173-2
4 Listernick R Charrow J Greenwald M & Mets M Natural history of optic pathway tumors in children with neurofibromatosis type 1: a longitudinal study. J Pediatr. 125(1) 63 - 66 1994. PMID: 8021787. DOI: 10.1016/s0022-3476(94)70122-9
5 Listernick R Louis DN Packer RJ & Gutmann DH Optic pathway gliomas in children with neurofibromatosis 1: consensus statement from the NF1 Optic Pathway Glioma Task Force. Ann Neurol. 41(2) 143 - 149 1997. PMID: 9029062. DOI: 10.1002/ana.410410204
6 Shapey J Danesh-Meyer HV & Kaye AH Diagnosis and management of optic nerve glioma. J Clin Neurosci. 18(12) 1585 - 1591 2011. PMID: 22071462. DOI: 10.1016/j.jocn.2011.09.003
7 Dutton JJ Optic nerve gliomas and meningiomas. Neurol Clin. 9(1) 163 - 177 1991. PMID: 2011108.
8 Wilhelm H Primary optic nerve tumours. Curr Opin Neurol. 22(1) 11 - 18 2009. PMID: 19155759. DOI: 10.1097/WCO.0b013e32831fd9f5
9 Hamilton AM Garner A Tripathi RC & Sanders MD Malignant optic nerve glioma. Report of a case with electron microscope study. Br J Ophthalmol. 57(4) 253 - 264 1973. PMID: 4707622. DOI: 10.1136/bjo.57.4.253
10 Borit A & Richardson EP Jr The biological and clinical behaviour of pilocytic astrocytomas of the optic pathways. Brain. 105(Pt 1) 161 - 187 1982. PMID: 7066671. DOI: 10.1093/brain/105.1.161
11 Rush JA Younge BR Campbell RJ & MacCarty CS Optic glioma. Long-term follow-up of 85 histopathologically verified cases. Ophthalmology. 89(11) 1213 - 1219 1982. PMID: 6818504.
12 Gibberd FB Miller TN & Morgan AD Glioblastoma of the optic chiasm. Br J Ophthalmol. 57(10) 788 - 791 1973. PMID: 4361475. DOI: 10.1136/bjo.57.10.788
13 Hoyt WF Meshel LG Lessell S Schatz NJ & Suckling RD Malignant optic glioma of adulthood. Brain. 96(1) 121 - 132 1973. PMID: 4695718. DOI: 10.1093/brain/96.1.121
14 Grill J Laithier V Rodriguez D Raquin MA Pierre-Kahn A & Kalifa C When do children with optic pathway tumours need treatment? An oncological perspective in 106 patients treated in a single centre. Eur J Pediatr. 159(9) 692 - 696 2000. PMID: 11014471. DOI: 10.1007/s004310000531
15 Fisher MJ Loguidice M Gutmann DH Listernick R Ferner RE Ullrich NJ Packer RJ Tabori U Hoffman RO Ardern-Holmes SL Hummel TR Hargrave DR Bouffet E Charrow J Bilaniuk LT Balcer LJ & Liu GT Visual outcomes in children with neurofibromatosis type 1-associated optic pathway glioma following chemotherapy: a multicenter retrospective analysis. Neuro Oncol. 14(6) 790 - 797 2012. PMID: 22474213. DOI: 10.1093/neuonc/nos076
16 Zheng X Li X Wang M Shen J Sisti G He Z Huang J Li YM Wu A & Multidisciplinary Oncology Research Collaborative Group (MORCG) Second primary malignancies among cancer patients. Ann Transl Med. 8(10) 638 2020. PMID: 32566575. DOI: 10.21037/atm-20-2059
17 Li D Weng S Zhong C Tang X Zhu N Cheng Y Xu D & Yuan Y Risk of second primary cancers among long-term survivors of breast cancer. Front Oncol. 9 1426 2020. PMID: 31998630. DOI: 10.3389/fonc.2019.01426
18 Guan X Jin Y Chen Y Jiang Z Liu Z Zhao Z Yan P Wang G & Wang X The incidence characteristics of second primary malignancy after diagnosis of primary colon and rectal cancer: a population based study. PLoS One. 10(11) e0143067 2015. PMID: 26571301. DOI: 10.1371/journal.pone.0143067
19 Barclay ME Lyratzopoulos G Walter FM Jefferies S Peake MD & Rintoul RC Incidence of second and higher order smoking-related primary cancers following lung cancer: a population-based cohort study. Thorax. 74(5) 466 - 472 2019. PMID: 30777897. DOI: 10.1136/thoraxjnl-2018-212456
20 Donin N Filson C Drakaki A Tan HJ Castillo A Kwan L Litwin M & Chamie K Risk of second primary malignancies among cancer survivors in the United States, 1992 through 2008. Cancer. 122(19) 3075 - 3086 2016. PMID: 27377470. DOI: 10.1002/cncr.30164
21 Jahraus CD & Tarbell NJ Optic pathway gliomas. Pediatr Blood Cancer. 46(5) 586 - 596 2006. PMID: 16411210. DOI: 10.1002/pbc.20655
22 Mishra MV Andrews DW Glass J Evans JJ Dicker AP Shen X & Lawrence YR Characterization and outcomes of optic nerve gliomas: a population-based analysis. J Neurooncol. 107(3) 591 - 597 2012. PMID: 22237948. DOI: 10.1007/s11060-011-0783-2
23 Davis EJ Beebe-Dimmer JL Yee CL & Cooney KA Risk of second primary tumors in men diagnosed with prostate cancer: a population-based cohort study. Cancer. 120(17) 2735 - 2741 2014. PMID: 24842808. DOI: 10.1002/cncr.28769
24 Rubino C de Vathaire F Dottorini ME Hall P Schvartz C Couette JE Dondon MG Abbas MT Langlois C & Schlumberger M Second primary malignancies in thyroid cancer patients. Br J Cancer. 89(9) 1638 - 1644 2003. PMID: 14583762. DOI: 10.1038/sj.bjc.6601319
25 Raymond JS & Hogue CJ Multiple primary tumours in women following breast cancer, 1973-2000. Br J Cancer. 94(11) 1745 - 1750 2006. PMID: 16721370. DOI: 10.1038/sj.bjc.6603172
26 Sharif S Ferner R Birch JM Gillespie JE Gattamaneni HR Baser ME & Evans DG Second primary tumors in neurofibromatosis 1 patients treated for optic glioma: substantial risks after radiotherapy. J Clin Oncol. 24(16) 2570 - 2575 2006. PMID: 16735710. DOI: 10.1200/JCO.2005.03.8349
27 Bolf EL Sprague BL & Carr FE A linkage between thyroid and breast cancer: a common etiology. Cancer Epidemiol Biomarkers Prev. 28(4) 643 - 649 2019. PMID: 30541751. DOI: 10.1158/1055-9965.EPI-18-0877
28 Papatla K Halpern MT Hernandez E Brown J Benrubi D Houck K Chu C & Rubin S Second primary anal and oropharyngeal cancers in cervical cancer survivors. Am J Obstet Gynecol. 221(5) 478.e1 - 478.e6 2019. PMID: 31128108. DOI: 10.1016/j.ajog.2019.05.025
29 Schonfeld SJ Morton LM Berrington de González A Curtis RE & Kitahara CM Risk of second primary papillary thyroid cancer among adult cancer survivors in the United States, 2000-2015. Cancer Epidemiol. 64 101664 2020. PMID: 31884334. DOI: 10.1016/j.canep.2019.101664
30 Ostrom QT Bauchet L Davis FG Deltour I Fisher JL Langer CE Pekmezci M Schwartzbaum JA Turner MC Walsh KM Wrensch MR & Barnholtz-Sloan JS The epidemiology of glioma in adults: a “state of the science” review. Neuro Oncol. 16(7) 896 - 913 2014. PMID: 24842956. DOI: 10.1093/neuonc/nou087
31 Wen PY & Kesari S Malignant gliomas in adults. N Engl J Med. 359(5) 492 - 507 2008. PMID: 18669428. DOI: 10.1056/NEJMra0708126
32 Evans DGR Salvador H Chang VY Erez A Voss SD Schneider KW Scott HS Plon SE & Tabori U Cancer and central nervous system tumor surveillance in pediatric neurofibromatosis 1. Clin Cancer Res. 23(12) e46 - e53 2017. PMID: 28620004. DOI: 10.1158/1078-0432.CCR-17-0589
33 Malta TM de Souza CF Sabedot TS Silva TC Mosella MS Kalkanis SN Snyder J Castro AVB & Noushmehr H Glioma CpG island methylator phenotype (G-CIMP): biological and clinical implications. Neuro Oncol. 20(5) 608 - 620 2018. PMID: 29036500. DOI: 10.1093/neuonc/nox183
34 Reifenberger G Wirsching HG Knobbe-Thomsen CB & Weller M Advances in the molecular genetics of gliomas - implications for classification and therapy. Nat Rev Clin Oncol. 14(7) 434 - 452 2017. PMID: 28031556. DOI: 10.1038/nrclinonc.2016.204
35 Barton NW Safai B Nielsen SL & Posner JB Neurological complications of Kaposi’s sarcomat. An analysis of 5 cases and a review of the literature. J Neurooncol. 1(4) 333 - 346 1983. PMID: 6381658. DOI: 10.1007/BF00165717
36 Jeon H Kang YH Yoo SM Park MJ Park JB Lee SH & Lee MS Kaposi’s sarcoma-associated herpesvirus infection modulates the proliferation of glioma stem-like cells. J Microbiol Biotechnol. 28(1) 165 - 174 2018. PMID: 29032648. DOI: 10.4014/jmb.1709.09001
37 Xu X Cai N Bao Z You Y Ji J & Liu N Silencing Pre-B-cell leukemia homeobox 3 decreases the proliferation of human glioma cells in vitro and in vivo. J Neurooncol. 135(3) 453 - 463 2017. PMID: 28856521. DOI: 10.1007/s11060-017-2603-9
38 Xu X Bao Z Liu Y Ji J & Liu N MicroRNA-98 Attenuates cell migration and invasion in glioma by directly targeting Pre-B cell leukemia homeobox 3. Cell Mol Neurobiol. 37(8) 1359 - 1371 2017. PMID: 28124208. DOI: 10.1007/s10571-017-0466-4
39 Morgan R & Pandha HS PBX3 in cancer. Cancers (Basel). 12(2) 431 2020. PMID: 32069812. DOI: 10.3390/cancers12020431
40 Guo H Chu Y Wang L Chen X Chen Y Cheng H Zhang L Zhou Y Yang FC Cheng T Xu M Zhang X Zhou J & Yuan W PBX3 is essential for leukemia stem cell maintenance in MLL-rearranged leukemia. Int J Cancer. 141(2) 324 - 335 2017. PMID: 28411381. DOI: 10.1002/ijc.30739
41 Gunderson LL Tepper JE & Bogart JA Clinical Radiation Oncology.. Philadelphia, PA, Elsevier Saunders.
42 Li S Yang J Shen Y Zhao X Zhang L Wang B Li P Wang Y Yi M & Yang J Clinicopathological features, survival and risk in breast cancer survivors with thyroid cancer: an analysis of the SEER database. BMC Public Health. 19(1) 1592 2019. PMID: 31783815. DOI: 10.1186/s12889-019-7947-y
43 Saltus CW Vassilev ZP Zong J Calingaert B Andrews EB Soriano-Gabarró M & Kaye JA Incidence of second primary malignancies in patients with castration-resistant prostate cancer: an observational retrospective cohort study in the United States. Prostate Cancer. 2019 4387415 2019. PMID: 30886751. DOI: 10.1155/2019/4387415