Routine cancer screening in young dermatomyositis patients risks missing most occult malignancies

*Sarah Kitts¹, Avery Kundrick¹, Steven Maczuga², Nancy Olsen³, Galen Foulke²

¹Penn State College of Medicine, Hershey, PA, ²Department of Dermatology, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, ³Division of Rheumatology, Penn State Health Milton S. Hershey Medical Center, Hershey, PA

KEYWORDS: dermatomyositis, malignancy, screening

Background

The idiopathic inflammatory myopathies, including dermatomyositis (DM) and polymyositis (PM), are a group of chronic inflammatory muscle disorders characterized by progressive symmetric proximal muscle weakness. They are thought to be caused by a humoral-mediated autoimmune disease. DM, unlike PM, is associated with characteristic skin findings including Gottron’s papules, heliotrope eruption, and facial erythema. While the skin and muscle are most frequently affected, DM may also affect the joints, esophagus, and lungs.¹ Studies have found that DM affects as many as 21.42 persons per 100,000 in the United States.²

DM is strongly associated with the development of malignancy. Since the association between DM and cancer was described in 1916, numerous studies have been performed to quantify the risk.^3,4 According to a 2015 meta-analysis, which included publications from various countries worldwide, the relative risk of malignancy in DM patients is 5.50 (95% CI 4.31-7.70).⁵ The largest cohort study, which included 1,012 DM patients from Taiwan, estimated the standardized incidence ratio (SIR) for malignancy in DM patients as 5.11 (95% CI 5.01-5.22).⁶ Other studies estimate SIRs between 3.0 and 7.7 with malignancy occurring in 13.8 to 25% of DM patients.^7-16 Although females are more likely to have DM, males are more likely to develop paraneoplastic disease.^5,10,13 The risk of malignancy also increases with age.^10,12,13 Other features suggested to be predictive of malignancy include the presence of cutaneous necrosis, shawl sign, dysphagia, elevated CK, LDH, AST, or ALT, and age greater than 40 in Asian populations, or 52 in Europeans.^17-22

Previous studies have attempted to determine the period of greatest malignancy risk with respect to DM diagnosis. Madan et al. found that the risk is elevated three years prior to diagnosis of DM and five years after diagnosis, while András et al. found that risk is elevated two years before and three years after diagnosis.^23,24 Other studies have found the greatest SIRs have been reported during the first year after the diagnosis of DM.^9,10,14

The most common types of malignancy associated with DM are lung, colon, breast, and gastric.^{6,8,9,12,14,18} The risk for ovarian cancer is well established to be uniquely high, with reports of a seventeenfold increased risk over the rest of the population.^8,25 Other malignancies associated with DM include leukemia/lymphoma, thymic, cervical, bone/joint, pancreatic, prostate, testicular, and epipharyngeal cancers.^{6,8,10,12,14,18,24}

Because DM is associated with a variety of malignancies, screening DM patients is challenging. Consensus guidelines have not developed around malignancy screening in DM patients. Age-appropriate guidelines as outlined by the United States Preventive Services Task Force (USPSTF) and the American Cancer Society (ACS) (Table 1), recommended for DM patients, may not evaluate organs susceptible to malignancy in DM.^26,27 In addition, a recently published retrospective analysis of a large cohort of DM patients in the US found that most cancers diagnosed after the onset of DM were identified using blind screening modalities, rather than guidance by symptoms or age appropriate screenings, further emphasizing the need for the development of screening guidelines in this population.²⁸

This study was conducted to determine the incidence and types of malignancies in DM patients and the percentage of cancers not detected by routine age- and gender-appropriate malignancy screening in one of the largest samples of DM patients studied in the United States. We hope this research further supports the need for more rigorous screening methods in DM patients.

Materials and Methods

Data Source

Using the MarketScan® (MS) Commercial Claims and Encounters database, a retrospective cohort study from January 1, 2005 to December 31, 2015 was conducted. The database includes healthcare claims from more than 130 payers reporting healthcare utilization and expenditures, with claims from inpatient encounters, outpatient encounters and prescribed drugs, for an estimate of 150 million employees and family members per year. The database includes diagnostic codes (ICD-9), procedure codes (Current Procedural Terminology, 4th Edition (CPT-4)), dates of service, type of plan and expenditure data from 2005-2015. Patients’ ages ranged from birth to 64 years old. Individuals with Medicare or Medicaid are not included in the database. IRB approval was not necessary as all data is de-identified and therefore does not meet the definition of a human subject.

Study Design and Population

The DM cohort was formed from the MS database by identifying any patient receiving at least two separate diagnoses of DM by ICD-9 code (710.3), separated by at least six months. This technique has been previously validated by Kwa et al.²⁹ The Index Date of diagnosis was defined as the first entry of ICD-9 code 710.3 for an individual patient. Patients were included if they had at least two years of continuous enrollment before and three years after the Index Date for DM diagnosis in order to capture the period of increased malignancy risk as noted by András et el.²⁴ Any patient with any entry of ICD-9 codes for polymyositis or lupus were excluded. The control cohort was formed from the MS database by identifying patients without a history of DM. Controls were age and gender matched in a 5:1 control case ratio in order to increase the power of the study. The ICD-9 codes listed in Table 2 were used to identify specific cancers in DM and control patients. Patients with cancer prior to DM diagnosis were excluded.

Analyses

Controls were age and gender matched 5:1 with all DM cases in order to increase the power of the study. We compared the frequency and types of malignancies in patients <50 years old and those >50. Malignancies were separated by those screened for vs those not routinely screened for based on USPSTF/ACS guidelines in Table 1. The frequency of malignancy between DM cases and controls were compared using a chi-square test with odds ratios.

Results

632 total DM cases were identified across all age groups. 302 DM patients were >50 years old. 89 malignancies were identified in 44 DM patients. In 1526 controls, 222 malignancies were identified in 116 individuals. Malignancy frequency was 14.6% in DM patients compared to 7.6% in controls (p< 0.00001). 55% of malignancies in DM patients and 37.4% of malignancies in controls occurred in areas not routinely screened by ACS/USPSTF. When compared to controls, there was a statistically significant increase in DM malignancies not routinely screened (p < 0.00001). This included lymphomas, leukemias, prostate, skin, secondary, connective and soft tissue, ovarian, stomach, brain, reticulosarcoma, pancreas, liver, and neuroendocrine malignancies. (Figure 1)

330 DM patients were under 50 years old. 28 malignancies were identified in 21 DM patients. In 1,634 controls, 84 malignancies were identified in 46 individuals. Malignancy frequency was 6.4% in DM patients compared to 2.8% in controls (p=0.0010). 100% of malignancies in DM patients and 48% of malignancies in controls occurred in areas not routinely screened by ACS/USPSTF. When compared to controls, there was a statistically significant increase in DM malignancies not routinely screened (p < 0.00001). This included lymphoma, breast, ovary, kidney, secondary, endocrine, connective and soft tissue, reticulosarcoma, lymphosarcoma, brain, pancreas, stomach, prostate malignancies. (Figure 2)

Discussion

Lack of evidence-based guidelines for malignancy screening in DM represents a practice gap in both dermatology and rheumatology. Previous studies have confirmed an increased risk of malignancy in the DM population but currently there are no specific screening guidelines for DM patients. Here, we sought to determine if routine age- and gender-appropriate screening, as recommended by the USPSTF and ACS, would accurately evaluate the organs susceptible to malignancy in DM. Our results confirm that DM patients are at an increased risk of malignancy and highlight the unique risk faced by DM patients, particularly in organs not routinely evaluated. This risk is especially highlighted in patients traditionally deemed lower risk for cancer (<50 years old).

Increased age is consistently cited as the leading risk factor for developing malignancy, with risk rising more rapidly in midlife.³⁰ White, et al. notes that the cumulative risk for all cancers combined increases with age, up to age 70, then decreases slightly.³¹ In a study looking at the future of cancer incidence in the United States, researchers found that from 2010 – 2030 cancer incidence will increase by 43% with a 63% increase in older adults and an 11% increase in younger adults.³² These findings have become the basis for screening guidelines, such as those provided by the USPSTF and ACS, leading to an emphasis on screening the adult population over 50 years old. However, for DM patients, these guidelines may be inadequate.

Currently, no formal consensus exists as to the best practices for malignancy screening in DM and some argue that only age-appropriate malignancy screening is necessary, especially with increasing years since initial diagnosis.³³ Our results, however, show that age- appropriate screening misses a significant amount of malignancies in DM patients of all ages and, in patients under 50 years old, all malignancies were missed. This suggests that utilizing USPSTF and ACS guidelines for the DM population is highly likely to miss most, if not all, malignancies in DM patients, especially those under 50 years old.

Additionally, the USPSTF and ACS only recommend screening for breast, colorectal, cervical and lung cancers as there is an increased risk of these types of cancers in the general population and mechanisms exist to screen for these cancers.^26,27 Our results, however, show that the types of malignancies seen in the DM population differ vastly from the general population. In DM patients of all ages, we found an increase in lymphomas and leukemias, prostate, lung, ovarian, pancreas, liver, and neuroendocrine tumors. In patients under 50 we found an increase in lymphomas, secondary, endocrine, leukemias, pancreas, stomach, and prostate cancers. Screening tests including the prostate specific antigen (PSA) for prostate cancer, CA 19-9 and carcinoembryonic antigen (CEA) blood tests for pancreatic cancer, transvaginal ultrasound and CA-125 blood test for ovarian cancer, endoscopy and serum pepsinogen levels for stomach cancer, alpha-fetoprotein (AFP) blood tests and ultrasound for liver cancer exist but are not used in the general population as the benefits do not outweigh the risks and their sensitivities/specificities are low.^34-39 Utilization of these screening mechanisms in the DM population has not been well studied.

Researchers have looked into optimal screening mechanisms for patients with DM. In one study, Selva-O’Callaghan et al. assessed the utility of a PET scan for diagnosing occult malignancy in patients with myositis. After comparing a broad panel of gender-specific screening tests to a single PET-CT they found that the efficacy of the two screening options were comparable.⁴⁰ Other studies suggest that the co-occurrence of other risk factors such as dysphagia, skin necrosis, cutaneous vasculitis, rapid onset of DM (< 4 weeks), elevated CK, an increase in ESR and a high level of C-reactive protein increase the risk of cancer development in patients with DM.⁴¹ In a study conducted by Leatham et al., they found that malignancy in DM patients is often not associated with a specific sign or symptom and that blind screening may be more effective in diagnosing malignancy.²⁸

Myositis specific antibodies (MSA’s) can also provide insight into malignancy risk and may be utilized as a potential screening mechanism. Research has shown that patients with DM positive for anti-p155, anti-transcriptional intermediary factor 1γ (TIF-gamma) or anti-nuclear matrix protein 2 (NXP-2) antibodies have an increased risk of malignancy.^42,43 In the absence of official screening recommendations, Selva-O’Callaghan et al. suggests baseline broad screening in all DM patients, with yearly repeat screenings in TIF-1gamma and NXP-2 positive patients, as well as those without detectable MSA’s, for 3-5 years.⁴⁴ To date, there are no official recommendations as to best practices screening, but our results emphasize that consideration should be given to young patients as guidelines undergo development.

Limitations

Our study has several limitations. First, it does not distinguish blind versus targeted diagnosis of cancer. This information would better help us understand the modalities in which the malignancies were diagnosed and help to guide screening in future patients. Second, even though the sample size was large, the MarketScan® database only includes patients up to 64 years old. Additionally, no Medicare or Medicaid patients were included, therefore the actual population risk of cancer is likely underestimated, especially in those >50, and the generalizability of our study is limited. Lastly, we are unable to account for the presence or absence of multiple known risk factors, including clinical signs, MSAs, or inflammatory markers which are associated with increased risk of malignancy in DM patients.

Conclusion

Our results agree with the well-defined risk for neoplasia with DM and highlight that younger patients have a considerably higher risk of developing cancer with DM than matched controls, especially in organs not routinely screened. Development of evidence-based guidelines to optimize malignancy screening in adult DM patients of all ages is needed. We agree with previously published recommendations for baseline broad screening in all DM patients, with yearly repeat screenings in TIF-1gamma and NXP-2 positive patients, as well as those without detectable MSA’s, for 3-5 years.⁴⁴ Broad malignancy screening should include modalities for identifying cancers poorly visualized on traditional imaging, such as ovarian and prostate. Such screening should not be relegated to older patients and special attention should be given to young DM patients as guidelines undergo development. Overall, our research supports the need for future studies aimed at optimizing malignancy screening in all patients with DM.

Figure 1. Number of unscreened malignancies in DM patients and controls of >50 [controls scaled by 1/5]. Number of malignancies not routinely screened by ACS/USPSTF guidelines in DM patients and controls of >50 years old. There was a statistically significant (*) increase in the number of unscreened malignancies in DM patients when compared to age-and-gender matched controls. 55% of malignancies in DM patients occurred in organs not routinely screened. This included lymphomas, leukemias, prostate, skin, secondary, connective and soft tissue, ovarian, stomach, brain, reticulosarcoma, pancreas, liver, and neuroendocrine malignancies.

Figure 2. Number of unscreened malignancies in DM patients and controls of <50 [controls scaled by 1/5]. Number of malignancies not routinely screened by ACS/USPSTF guidelines in DM patients and controls of <50 years old. There was a statistically significant (*) increase in the number of unscreened malignancies in DM patients when compared to age-and-gender matched controls. 100% of malignancies in DM patients occurred in organs not routinely screened. This included lymphoma, breast, ovary, kidney, secondary, endocrine, connective and soft tissue, reticulosarcoma, lymphosarcoma, brain, pancreas, stomach, prostate malignancies.

Author Information

Corresponding Author

*Sarah Kitts, BS
skitts@pennstatehealth.psu.edu

Author Contributions

All author(s) have given approval to the final version of the manuscript.

Funding Sources

This research was funded by the James and Joyce Marks Educational Endowment.

Disclosures

Nancy Olsen, MD (Malinckrodt Pharmaceuticals)

Acknowledgements

Data was originally published as a research letter in the British Journal of Dermatology. Appropriate permissions were obtained to publish in The Penn State Journal of Medicine.

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