Ewing sarcoma family of tumors (ESFT) is a group of small, round blue cell tumors that arise in the bone or soft tissue. ESFT include classic Ewing sarcoma (ES) of bone, extraskeletal ES, skin tumors of the chest wall, and primitive neuroectodermal tumors (PNET) of the bone or soft tissue. About 90% of ESFT cases are characterized by the chromosome translocation t(11;22)(q24;q12) which involves the EWS/FLI-1 fusion gene and may share a common neural histogenesis [
While few risk factors for ESFT have been identified, the racial difference and specific chromosomal translocation might suggest a genetic predisposition [
The aim of this study was to review all cases of ESFT that have been reported to FDA from January 1, 1998, through December 31, 2013, and to assess any possible association with therapeutic products. (FAERS includes therapeutic agents which include drugs and also biologics.) We also conducted an extensive literature search of articles that pertained to the epidemiology of ESFT.
All case reports for drug products that included ESFT from the FDA Adverse Event Reporting System (FAERS) database were analyzed. The FAERS database, including foreign and domestic reports and all age groups, was searched for the time period, January 1, 1998, through December 31, 2013. The following Medical Dictionary for Regulatory Activities (MedDRA) search terms (MedDRA website,
Over the 16-year time period, 134 reports were retrieved with mention of ESFT. After clinical review of the narrative reports 25 cases were identified with a history of medication use prior to ESFT diagnosis, most with a history of ≥18 months. Age range was 5–68 years of age (median 24 years) (Table
Summary of FAERS reports of medication use prior to Ewing Sarcoma Family of Tumor (ESFT) diagnosis, 1997–2013. Total = 25; 13 US, 12 foreign; 16 females, 9 males. Ages 4–68 years (median age 24 years; mean 30 years). Known latency for 20 patients: 3 months–12 years (median 27 months; mean 3.2 years); 5 unknown.
Report year | Number of cases |
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1997–1999 | 1 |
2000–2004 | 6 |
2005–2009 | 9 |
2010–2013 | 9 |
Drug use | Number of cases | Patient age (yrs) | Latency |
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Immunosuppressive |
12 | 5–68 | Mean 4.2 years, median 4 years |
Growth hormone (GH) | 2 |
11, 16 | 4 months after 5 years therapy, 18 months |
Estrogen/progestin | 2 | 24, 47 | 10 months, 2.5 years |
CNS depressant | 2 | 34, 42 | 22 months, unknown |
Atypical antipsychotic | 1 | 17 | No information |
Antiepileptic | 1 | 8 | 8 years |
Antipsychotic and AED | 1 | 19 | 3 months |
ADHD | 1 | 8 | No information |
Isotretinoin | 1 | 20 | 10 months |
Statin for hyperlipidemia | 1 | 9 | >2 years |
rPTH |
1 | 49 | 1 year |
Underlying conditions | ||
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12 | Immune-related | 3 Crohn’s disease, 3 multiple sclerosis, 1 renal transplant, 1 rheumatoid arthritis, 1 nephrotic syndrome, 1 ankylosing spondylitis, 1 psoriasis vulgaris, and 1 chronic hepatitis B |
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5 | Endocrine | 2 growth disorders, 1 menopause, 1 osteoporosis, and 1 birth control (patient morbidly obese but no underlying condition reported) |
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3 | Neurologic | 1 each of narcolepsy, seizure disorder, and fibromyalgia with sciatica/neuropathic pain |
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3 | Psychiatric | 1 each of unspecified depression, psychoses, and ADHD |
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2 | Other | 1 each of familial hypercholesterolemia, acne |
Characteristics of 25 FDA case reports of pre-ESFT drug exposures.
Age/sex | Disease | latency | Site | Drug | Type | Concomitant meds | Other | |
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1 | 13 f | Crohn’s | >2 yrs | Pelvis | Infliximab | Immune | None reported | |
2 | 26 f | Crohn’s | 4 yrs | Calf | Infliximab | Immune | Mesalamine, GH | Severe Crohn’s, registry azathioprine lansoprazole |
3 | 39 m | Crohn’s | 2.5 yrs | Unknown | Infliximab | Immune | Mesalamine, Azathioprine | |
4 |
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MS | 9-10 mos | Clavicle | Interferon | Immune | Potassium | pmh: clavicle fibrodysplasia, beta-1A, FMH positive for cancer |
5 | 68 f | MS | >5 yrs | Shoulder | Interferon | Immune | No information | beta-1A |
6 | 54 f | MS | 3 mos | Brain | Natalizumab | immune | No information | |
7 |
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Ankylosing spondylitis | unknown | Unknown | Infliximab | Immune | No information | |
8 | 50 f | RA | 4 yrs | Unknown | Etanercept | Immune | No information | Canada |
9 | 20 m | Psoriasis | 6 yrs | Unknown | Infliximab | Immune | Methotrexate, cyclosporine, etanercept | Acitretin, efalizumab >6 yrs |
10 | 52 m | transplant | 8 yrs | Abdomen | Cyclosporine | Immune | steroids, azathioprine | Lliterature case [ |
11 | 65 m | Chronic hepatitis C | 12 yrs | Unknown | Peginterferon | Immune | Cholecystectomy, cirrhosis, esophageal varices alfa-2b and ribavirin | |
12 | 5 f | Nephrotic sx | 18 mos | Spine | Cyclosporine | Immune | Dipyramidole, warfarin, prednisolone, cyclosporin | |
13 | 11 f | GH def | 18 mos | Thigh | r-somatropin | Hormone | Dose 0.7 mg sq should have been 0.47 | |
14 | 16 f | GH def | Unknown | Clavicle | r-somatropin | Hormone | Patient grew 2.5 cm after GH | |
15 | 47 f | Menopause | 10 mos | Spine | Estrogen/progestin | hormone | No information | Medical history—negative |
16 | 24 f | Contraception | 2.5 yrs | Unknown | Etonogestrel | Hormone | No information | Patient wt 268 lbs, ht 66.9′′, BMI = 42 |
17 | 49 f | Osteoporosis | 4 mos | Shoulder | Teriparatide | Hormone | Other osteoporosis drugs, family history—breast cancer | |
18 | 17 m | Unspecified psychiatric condition | unknown | Unknown | Olanzapine | Psychotropic | Acetaminophen | |
19 | 19 m | Depression | 3 mos | Unknown | Olanzapine | Psychotropic | Clonazepam | Unspecified depression |
20 | 8 m | Epilepsy | 8 yrs | metastatic | Ethosuximide | Psychotropic | Clobazam, valproic acid | CNS depressant |
21 | 8 f | ADHD | Unknown | Mnknown | Methylphenidate | Psychotropic | ||
22 | 34 f | Narcolepsy | 22 mos | Unknown | Sodium oxybate | Psychotropic | None | |
23 | 42 f | Sciatica | Unknown | Unknown | Pregabalin | Psychotropic | Lisinopril for high blood pressure | Fibromyalgia, CNS depressant |
24 | 24 f | Acne | 10 mos | Unknown | Isotretinoin | Others | No information | |
25 | 9 m | High cholesterol | 23 mos | Mandible | Atorvastatin | Cholesterol Lowering | Ezetimibe | 3-year trial |
Twelve cases were treated with immunosuppressive products for a variety of conditions including 3 Crohn’s, 3 multiple sclerosis (MS), 1 renal transplant, 1 rheumatoid arthritis (RA) and 1 each of ankylosing spondylitis, psoriasis vulgaris, chronic hepatitis C genotype 1b, and nephrotic syndrome. Use of more than one immunosuppressant drug was mentioned in 6 of the 12 reports.
Three cases received growth hormone (GH) and were diagnosed with ESFT 18 months to 4 years after beginning therapy. One child was treated with somatropin for microsomia due to neurosecretory GH disorder and a second child was treated for GH deficiency. The third case was a patient with Crohn’s disease who received immunosuppressants and GH (this case is included in the 12 immunosuppressant cases above).
Three cases received other hormonal products, including parathyroid hormone, combined estrogen/progesterone, and etonogestrel implant. The one case treated with recombinant human parathyroid hormone had failed several earlier therapies for osteoporosis. The one case taking combined estrogen/medroxyprogesterone was a menopausal woman who was diagnosed with ESFT 10 months later, and the third case with the etonogestrel implant was a morbidly obese young woman (268 pounds, body mass index (BMI) = 42).
Six cases were treated with psychotropic medications, including 2 with atypical antipsychotics (1 olanzapine for unspecified condition, 1 olanzapine and antiepileptic drugs (AED), clonazepam, for depression), 1 attention deficit hyperactivity disorder (ADHD) drug, methylphenidate, 1 case taking 3 AEDs (ethosuximide, valproic acid, and clobazam), 1 case treated with sodium oxylate for narcolepsy, and 1 case treated with another AED, pregabalin, for neuropathic pain.
There were 2 additional cases that received other medications and then developed ESFT, including 1 young adult treated with isotretinoin for acne and developed ESFT 9 months later and 1 young child treated with atorvastatin for familial hypercholesterolemia.
The FAERS is a passive surveillance system that collects data on adverse events possibly related to drugs and biologics that are reported to FDA by manufacturers, user facilities, and voluntary reporters, such as health care professionals and consumers. Importantly this system may capture rare and serious events that may not be detected in clinical trials and other studies and may lead to further understanding of possible associations of drugs and other risk factors for various diseases.
While few studies have found any association of exposure to medications with ESFT, our retrospective review of FAERS reports identified 25 cases of ES that followed drug therapy for various conditions. The majority were immunosuppressive agents used to treat autoimmune disorders. Most of the other reported drugs included hormones and psychotropic medications. We also reviewed the published literature to see if our findings might be consistent with other studies and case reports.
While various other malignancies have been reported in association with each of the drugs reported in the FAERS cases, there have been few literature reports of ESFT with the use of these medications. Many of the immunosuppressant drugs and some of the psychotropic and hormonal products are labeled with warnings of increased risk for malignancy or have product labeling for carcinogenicity based on animal studies (Table
Product labeling information on carcinogenicity for medications reported in FAERS that were used pre-ESFT diagnosis (Drugs@fda)
Black box warning: | Adalimumab, azathioprine, cyclosporine, etanercept, everolimus, infliximab, teriparatide |
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Warning and precautions: | Recombinant human growth hormone or somatropin, methotrexate, estrogen/medroxyprogesterone |
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Cancer occurrence in mice or rat studies | Isotretinoin, olanzapine, atorvastatin, methylphenidate, pregabalin, valproic acid |
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No increase in tumor growth rates or metastasis in mouse xenograft transplant studies | Natalizumab |
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No carcinogenic risk detected in long-term studies: | Clozapine |
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No carcinogenic risk in animal studies conducted: | Mesalamine, etonogestrel implant, xyrem |
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No information on carcinogenicity in labeling: | Ethosuximide |
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Carcinogenicity testing not adequately addressed: | Clobazam |
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Carcinogenicity testing not done: | Interferon beta-1a, clonazepam, peginterferon alfa-2b |
While the possible carcinogenic effects would differ for all these products, it may be important that most of the drugs in our case series may affect the hypothalamus and pituitary axis causing growth and neuroendocrine disturbance.
Nine of the 25 (36%) ESFT cases had been previously treated with immunosuppressive agents for autoimmune disorders including Crohn’s disease, MS, RA, psoriasis, and ankylosing spondylitis. Three other cases receiving immunosuppressive therapy included 1 each for renal transplant, chronic hepatitis C, and nephrotic syndrome. Most were older individuals who had received immunosuppressive products two years or more prior to developing ESFT. While many of the case reports did not provide detailed information about duration of therapy and dosage, several reports indicated the use of combination or multimodal therapy with a variety of agents including cytotoxic drugs (e.g., cyclophosphamide, azathioprine, and methotrexate), antibodies and other drug and biologic products for example, interferons, TNF blockers (infliximab, etanercept, and adalimumab), also mesalamine (aminosalicylate, an anti-inflammatory), and 1 case with glucocorticoids.
While ESFT per se has not been reported in association with immunosuppressant drugs, increased exposure to immunosuppressive agents has been found to be related to other cancers [
In our case series, most reports had incomplete information with regard to dosage and what additional past therapies had been given for the underlying diseases. While most cases had latency periods over a year, 2 of the MS cases had very short latencies of 3 and 10 months. It seems likely that these may have been misdiagnoses for what was later identified to be ESFT. With ESFT, compared to other malignancies, there is frequently a long period of time after initial symptoms until a diagnosis is made. Studies have shown the mean time to be 19–37 weeks [
From a regulatory perspective, FDA classifies carcinogenic risk of drugs and biologics based on their mechanism of action and hazard identification from in vivo and in vitro nonclinical assays [
We also conducted an extensive literature search for additional cases of ESFT reported with underlying autoimmune disorders or immunosuppressive therapy. In addition to the one renal transplant case in our series which was a case report by Balakrishnan et al. [
There were three reports of ESFT following GH therapy, including two with GH deficiency and an additional case with Crohn’s disease who received both GH and immunosuppressants (included in the 12 immunosuppressant drug reports above). It remains unclear if GH is a carcinogen. Studies have conflicting results regarding any association with GH and cancer. A French population-based cohort study, The French Safety and Appropriateness of Growth Hormone treatments in Europe (SAGhE), of patients treated with recombinant GH reported an increased risk of bone cancers (
ESFT is thought to be of neural origin and while neurogenic cancers such as neuroblastoma have been reported after GH, we could find no additional literature reports of ESFT following GH. In our ESFT cases one might wonder about the possible risk factor for cancer: is it the GH or is it related to the underlying growth disorder itself?
The other therapeutic hormonal drugs prior to ESFT diagnosis in our series included progestin, combined estrogen/progestin, and parathyroid hormone in nonadolescent females. Our literature review revealed one case report of ES in a young woman four months following abortion [
It is of interest that 16 of the 25 FAERS reports involved various drugs that all have an influence or effect on the hypothalamic-pituitary axis. In particular interferons may be associated growth suppression. Some studies showed that immunosuppressive agents, such as TNF blockers (e.g., infliximab), can also affect the hypothalamic-pituitary-adrenal axis [
Epilepsy itself [
The other category of pre-ESFT therapies included psychotropic drugs. There was only 1 case of each therapy in this category. Currently, most antipsychotic drugs are not considered to increase the risk of cancer [
Few studies have closely examined drug exposures in children who later develop ESFT. Past registry, case-control studies and case series that collected data on medication use [
ESFT-related studies.
Author/publication year/age group | Number of cases | Number of controls/cohort | Findings |
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Case-control studies | |||
Buckley et al., 1998 [ |
153 | 153 | Inverse association with asthma. Looked at diseases and treatments, but not specifically medications. Earlier growth spurt and lower gain in weight and height among males but ES females no differences between cases and controls during growth spurt associations between GU anomalies and ES could not be confirmed. |
Hartley et al., 1988 [ |
43 soft tissue & bone cancers (16 ES) | 146 | Developmental anomalies in 5 ES children: 1 meningomyelocele; 1 with an absent kidney and ureter. Medications were evaluated first month of life, 1–5 months, ≥6 months and grouped as antibiotics, anticonvulsants, corticosteroids, anti-allergic, bronchodilators, decongestants, cough suppressants and expectorants, and drugs for GI disorders. |
Holly et al., 1992 [ |
43 | 193 | Agricultural exposures, overdose of medications or accidental ingestion of poisonings |
Winn et al., 1992 [ |
208 | 395 | Hernias ~6 times more than expected, (OR 5.7; 95% Cl, 1.7–19.3) and also excess of cardiac conditions which however were mostly functional heart murmurs |
Valery et al., 2003 [ |
106 | 344 | Disorders of the digestive tract, behavioral hyperactivity and disorder of male organs (hydrocele and cryptorchidism) were also more frequent in cases but were not statistically significant. Only hernia excess achieved statistical significance (OR 3.1, 95% CI 1.2–7.6). Inverse association with asthma; deficit of bone disorders in cases (mostly fractures); also less frequent family history of stomach and neuroectodermal cancers. |
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Cohort studies: case series or registries | |||
Pendergrass et al. 1984 [ |
291 | n/a | No strong association with stature |
Cope et al. 2000 [ |
306 | n/a | 13 inguinal hernias, also 14 bony anomalies, 5 undescended testes, 1 abnormal kidney, 6 duplication of ureters, Zollinger-Ellison syndrome (which is associated with pituitary tumors) |
Narod et al., 1997 [ |
396 ES (out of 20,304 cancers) | 23 (5.8% anomalies) | National Registry Britain for Childhood Tumors (NRCT) and the BC British Registry for anomalies for presence of anomalies note in this study CNS PNETs were classified with medulloblastomas not part of ES. 2 cases osteogenic imperfecta. (confirmed previous associations that McKeen et al. [ |
McKeen et al., 1983 [ |
154 (23 cases ES) | Genitourinary, musculoskeletal. 56 development anomalies, 19 GU, of 99 males, 2 with unilateral cryptorchidism, 2 hypospadias, 5 of 55 females with unilateral ureter duplications, 8 rib anomalies, 7 vertebral defects, 4 with benign bone neoplasms (2 at primary ESFT site were bone cyst and enchondroma) | |
Glass and Fraumeni 1970 [ |
146 (out of 396 childhood cancers) | Hospital series, 2 spina bifida (1 with café au lait spots), osteoid osteoma, bone cysts, cryptorchidism, varicocele, Meckel’s diverticulum, colonic polyps w/accessory spleen, congenital pulmonic stenosis, pulmonic valve 4 cusps, 1 mongolism (Down syndrome), 2 mothers of ES pts had multiple sclerosis; thyroidectomy for goiters in 2 mothers of ES pts. | |
Beyaert et al., 2013 [ |
Rib anomalies ES with high incidence of cervical ribs. 17.1% (not confirmed by other studies) | ||
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Pooled analysis and meta-analysis of studies regarding hernias in association with ESFT | |||
Valery et al. 2003 [ |
199 cases | 1,451 controls | Association with hernias, umbilical, inguinal, and congenital. The primary endpoint was development of a tumor from the Ewing’s sarcoma family. 138 patients with such a tumor and 574 controls were included in the pooled analysis, and 357 patients with these tumors and 745 controls were included in the meta-analysis. |
While our FAERS reports were submitted to FDA in association with drug use, the reported therapies were used to treat autoimmune disorders and childhood conditions that, especially if severe, might lead to growth and/or endocrine disturbance. Crohn’s disease, renal failure (especially posttransplant), psychoses, and epilepsy [
The observation of a small number of cases of an uncommon cancer occurring in association with certain exposures does not provide evidence of any causal link. This study using the FDA database has several limitations including reporting biases for cases from manufacturers as well as health care professionals and consumers. FAERS cases may be reported to FDA from postmarket surveillance studies with incomplete enrollment and reporting is dependent upon physician investigator compliance with submitting forms consistently and accurately, and whether the reported disease is related or unrelated to the therapy is subjective. Submitted reports may lack important information on the underlying disease, comorbid conditions, and prior therapies. These reports do not provide histopathologic confirmation of the cancer diagnosis. Another limitation of this study is that it is a retrospective analysis. However, epidemiological studies on patient populations also have limited value because of the long latency period for most cancers and because most studies lack sensitivity. Most studies approach bone cancers as a group without breakdown into subtypes of osteosarcoma and ESFT which are thought to have very different etiologies. Nonetheless, FAERS is the largest postmarketing drug safety database in the world maintained by a single country, containing more than 9 million reports of “drug-related” (but not necessarily causal) adverse event reports since 1969. Because of its potential comprehensiveness in capturing rare drug-associated adverse events from all over the world, the FAERS data may be useful in generating hypotheses relating to possible causes of a specific rare cancer, which later if warranted may be tested in formal and more rigorous epidemiological studies.
ESFT is known for its striking unimodal incident peak during puberty and few risk factors have been identified as to its etiology. In this present study we found ESFT cases following the use of immunosuppressant agents as well as hormonal medications. These medications as well as the reported underlying immune disorders and neuroendocrine conditions are associated with abnormal growth and hormonal disturbance. These findings may provide insight as to why this cancer has a peak incidence during adolescence. Perhaps the neuroendocrine abnormalities might even be linked to a common gene. Formal epidemiological or clinical studies should be conducted to further evaluate any possible role of neuroendocrine disturbances with these underlying conditions and drugs in the development of ESFT.
All authors are government employees of the Food and Drug Administration, HHS.
The authors have no conflict of interests to report.