Abstract
We studied 3 patients with systemic lupus erythematosus (SLE) who developed thyroid cancer (TC). Potential risk factors for TC development was explored. Fifty-three patients with a clinical diagnosis of rheumatic diseases including SLE at our hospital between July 2014 and December 2014 were enrolled. Demographic, clinical, and laboratory findings were retrospectively compared between TC-positive and TC-negative patients. Among rheumatic diseases, lymphadenopathy/splenomegaly at treatment commencement, and lymphadenopathy/splenomegaly, painless ulcer (oral, nasal, or mucosal), and weight loss during the entire study period were precipitating factors. Lower current values of hemoglobin and methylprednisolone pulse therapy favored TC development. In 29 SLE patients, lymphadenopathy/splenomegaly at treatment commencement, lymphadenopathy/splenomegaly and weight loss during the entire study period, urinary granular casts at treatment commencement, and a lower current value of hemoglobin predisposed patients to TC. Several risk factors of TC are present in pediatric SLE. Patients with SLE should be investigated vigorously for TC with ultrasound.
Keywords: allergy/immunology, rheumatology, pulmonology, general pediatrics, infectious diseases
Introduction
A high risk of thyroid cancer (TC) in adult-onset systemic lupus erythematosus (SLE) has been reported,1,2 though a multiple-site international SLE cohort study has provided different conclusions.3 TC incidence in SLE patients in Scandinavian countries has been reported to be 0.4 to 3.4 per 105 subjects.4 We wished to ascertain the factors promoting TC in childhood-onset SLE. To achieve this goal, symptoms, laboratory findings, medication, and complications were compared between TC-positive and TC-negative patients.
Methods
Ethical Approval of the Study Protocol
The study protocol was approved by the Ethics Committee of Saitama Children’s Medical Center (Saitama, Japan; Approval Number 16).
Participants
Fifty-three patients with a clinical diagnosis of SLE, mixed connective-tissue disease (MCTD), juvenile dermatomyositis/polymyositis (DM/PM), Sjögren’s syndrome, and antisynthetase syndrome at our hospital between July and December 2014 were enrolled. Participant profiles are shown in Table 1. Diagnoses of SLE, MCTD, DM/PM, Sjögren’s syndrome, and antisynthetase syndrome are described elsewhere.5-9 Remarkably, despite careful examination, TC was observed only in patients with SLE and not in patients with other collagen-based diseases.
Table 1.
Patients’ Profile.
| Disease | Patients (Male–Female) | Age of Onset, Range (Median) | Current Age, Range (Median) |
|---|---|---|---|
| SLE | 29 (4:25) | 1-14 (12) | 13-30 (19) |
| MCTD | 7 (0:7) | 2-12 (8) | 11-36 (16) |
| DM/PM | 11 (2:9) | 3-14 (6) | 6-26 (16) |
| Sjögren’s syndrome | 4 (2:2) | 4-12 (10) | 14-22 (16) |
| Antisynthetase syndrome | 2 (1:1) | 3-5 (4) | 10-20 (15) |
| Total | 53 (9:44) | 1-14 (11) | 6-36 (17) |
Abbreviations: SLE, systemic lupus erythematosus; MCTD, mixed connective tissue disease; DM/PM, dermatomyositis/polymyositis.
Examination Items
Medical records of 53 patients were investigated retrospectively. These items were derived from the diagnostic criteria9 and severity score10 of SLE.
Symptoms at the Start of Treatment and During the Entire Study Period
The cutaneous and mucosal symptoms that we examined were “butterfly rash,” discoid lupus-like plaques, photosensitivity, painless ulcers (oral, nasal, or mucosal), hair loss, Reynaud’s phenomenon, peptic ulcers, as well as other cutaneous and mucosal conditions.
Neurological Symptoms
The neurological symptoms that we examined were convulsions, psychological symptoms, organic brain syndrome, cranial-nerve symptoms, mononeuritis multiplex, disturbance of consciousness, cerebrovascular disorders, spinal disorders, aseptic meningitis, as well as other neurological symptoms.
Musculoskeletal Symptoms
The musculoskeletal symptoms that we examined were nondestructive arthritis (more than one), muscle pain, and muscle weakness.
Cardiopulmonary Symptoms
The cardiopulmonary symptoms that we examined were pleurisy, epicarditis, interstitial pneumonia, pulmonary hypertension, pulmonary infarction, pulmonary hemorrhage, as well as other cardiopulmonary symptoms.
Renal Symptoms
The renal symptoms that we examined were rapidly progressive nephritis, renal failure (acute and chronic), nephrotic syndrome, abnormal renal biopsy, as well as other renal symptoms.
Systemic Symptoms
The systemic symptoms that we examined were fever, weight loss, lymphadenopathy, splenomegaly, easy fatigability/general malaise/weakness, and loss of appetite/nausea/vomiting.
Laboratory Data at Treatment Start and Currently
An array of laboratory data were examined: white blood cells, lymphocytes, hemoglobin, platelets, creatinine, CH50, C3, C4, C-reactive protein (CRP), serum amyloid A (SAA), erythrocyte sedimentation rate (ESR), anti-nuclear antibody (ANA; homogeneous, speckled, nucleolar, peripheral, centromere, granular, and nuclear-membrane types), anti-DNA antibody, anti-double-stranded DNA (dsDNA) IgG, anti-Smith (Sm) antibody, anti-U1 ribonucleoprotein (U1RNP) antibody, anti-Sjögren’s-syndrome-related antigen A (SSA) antibody, anti-Sjögren’s-syndrome-related antigen B (SSB) antibody, anti-cardiolipin antibody, lupus anti-coagulant, biological false-positive (BFP), hemolytic anemia, proteinuria, hematuria, urinary granular casts, thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), thyroglobulin, anti-thyroglobulin antibody, anti-thyroid peroxidase (TPO) antibody, and thyroid-stimulating hormone receptor (TSHR) antibody.
Therapy
Prednisolone was excluded from the present study because all patients received this agent. The drugs that we evaluated were mycophenolate mofetil (MMF), methyl prednisolone (mPSL) pulse therapy, azathioprine (AZA), cyclosporine A (CyA), cyclophosphamide (CYP) pulse therapy, mizoribine, methotrexate (MTX), intravenous immunoglobulin (IVIG), tacrolimus, etanercept, and adalimumab.
Current Therapy and Its Effect
We examined the effects of PSL, nonsteroidal anti-inflammatory drugs, immunosuppressive agents, mPSL pulse therapy, and CYP therapy, as well as other drugs.
Complications
The complications that we looked for specifically were infection, peptic ulcers, diabetes mellitus, hypertension, compression fractures, osteonecrosis, cerebral infarction, myocardial infarction, disseminated intravascular coagulation, as well as other types of complications.
Statistical Analyses
In the whole analysis, the item “other” (eg, other skin conditions) was excluded from final data unless more than one patient exhibited the same attribute. Patient findings contributing to TC development were compared using the χ2 test and Fisher’s exact test or nonparametric Mann-Whitney test. P values were 2-sided, and a significance of .05 was used. Statistical analyses were undertaken with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (R Foundation for Statistical Computing, Vienna, Austria).11
Methodological Quality
For methodological quality assessment, the checklist set by the Strengthening the Reporting of Observational Studies in Epidemiology12 and MOOSE guidelines13 were used.
Results
Case 1
A 24-year-old woman was diagnosed with SLE at the age of 14 years based on fever, butterfly rash, joint pain, swelling of lymph nodes in the neck, reduced numbers of blood cells, anti-nuclear antibody, anti-ds-DNA IgG antibody, anti-DNA antibody, and complement depletion. Renal biopsy was classified as IIIa.
She was treated with PSL, mPSL pulse therapy, AZA, and MMF. When she was 22 years old, she noticed swelling of the thyroid gland. She was diagnosed with papillary TC on ultrasonography. Tumor dimensions were 27 × 19 × 15 mm. After resection of the right lobe of the thyroid gland and dissection of paratracheal lymph nodes, TC did not relapse.
Case 2
Case 2 was a 22-year-old woman. At the age of 12 years, swelling of cervical lymph nodes, fever, erythema, hematuria, anti-ds-DNA IgG antibody, and hypocomplementemia led to the diagnosis of SLE. Renal biopsy was classified as IIIa.
She underwent treatment with PSL, mPSL pulse therapy, and MMF. She was rehospitalized because of relapse of enteropathy at the age of 20 years, and evaluation of the thyroid gland by ultrasound revealed TC. She was diagnosed with papillary TC and tumor dimensions were 9.8 × 9.5 × 15.7 mm. Resection of the right lobe of the thyroid gland, as well as dissection of paratracheal and peribronchial lymph nodes, was successful. Enteropathy was controlled by a combination of mPSL pulse therapy and AZA.
Case 3
Case 3 was a 14-year-old girl. When aged 14 years, she was diagnosed with SLE based on fever, butterfly rash, joint pain, anti-nuclear antibody, and cytopenia. She received PSL and mPSL pulse therapy. Thereafter, she developed lupus enteritis and was treated further with MMF. She was prescribed with mPSL pulse therapy, cyclosporine, and cyclophosphamide, but noticed a neck tumor 6 months after SLE onset. Ultrasound examination identified a tumor with intra-thyroid calcification. She was diagnosed with papillary TC, and tumor dimensions were 26 × 19 × 39 mm. Concomitant with thyroidectomy, neck lesions equivalent to TC tissue were identified and resected. Postoperatively, she has been treated with PSL without TC relapse.
TC Prevalence Among Patients With Rheumatic Disease
TC was identified exclusively in patients with SLE, but not in those with other rheumatic diseases (Table 2). However, TC prevalence was not increased compared with that for other diseases.
Table 2.
Incidence of Thyroid Cancer in Patients With Rheumatic Diseasesa.
| Thyroid Cancer (−) | Thyroid Cancer (+) | Sum | |
|---|---|---|---|
| SLE | 26 | 3 | 29 |
| MCTD | 7 | 0 | 7 |
| DM/PM | 11 | 0 | 11 |
| Sjögren’s syndrome | 4 | 0 | 4 |
| Antisynthetase syndrome | 2 | 0 | 2 |
| Total | 50 | 3 | 53 |
Abbreviations: SLE, systemic lupus erythematosus; MCTD, mixed connective tissue disease; DM/PM, dermatomyositis/polymyositis.
P = .68.
Risk Factors in Patients With Rheumatic Disease
Demographic Features
No items distinguished cancer-positive patients from cancer-free cases.
Symptoms
Lymphadenopathy/splenomegaly at the start of treatment and symptoms present during the entire period, such as lymphadenopathy/splenomegaly, painless ulcers (oral, nasal, mucosal), and weight loss, were precipitating factors for TC development (Table 3).
Table 3.
Risk Factors for the Development of Thyroid Cancer in Patients With Rheumatic Diseases.
(1) Demographic Features.
| Thyroid Cancer (−) | Thyroid Cancer (+) | P | |
|---|---|---|---|
| Age | 18.0 | 20.3 | .478 |
| Age of onset | 10.3 | 9.3 | .692 |
| Family history | 7/50 | 0/3 | .952 |
| Sex, male (%) | 0.22 | 0 | 1 |
(2) Clinical Symptoms.
| At the Start of Treatment |
Entire Period |
|||||
|---|---|---|---|---|---|---|
| Thyroid Cancer (−) | Thyroid Cancer (+) | P | Thyroid Cancer (−) | Thyroid Cancer (+) | P | |
| Butterfly rash | 29/50 | 2/3 | 1 | 31/50 | 3/3 | .242 |
| Discoid papulosis | 2/50 | 0/3 | 1 | 2/50 | 0/3 | 1 |
| Photosensitivity | 7/50 | 0/3 | 1 | 7/50 | 0/3 | 1 |
| Oral, nasal, or mucosal painless ulcer | 8/50 | 2/3 | .088 | 10/50 | 3/3 | .012 |
| Hair loss | 3/50 | 0/3 | 1 | 6/50 | 1/3 | .352 |
| Raynaud’s phenomenon | 7/50 | 0/3 | 1 | 11/50 | 0/3 | 1 |
| Peptic ulcer | 0/50 | 0/3 | 1 | 10/50 | 0/3 | 1 |
| Other skin conditions | 5/50 | 2/3 | .043 | 4/50 | 2/3 | .031 |
| Convulsion | 0/50 | 0/3 | 1 | 2/50 | 0/3 | 1 |
| Psychological symptom | 2/50 | 0/3 | 1 | 2/50 | 0/3 | 1 |
| Organic brain syndrome | 1/50 | 0/3 | 1 | 0/50 | 0/3 | 1 |
| Cranial nerve symptoms | 0/50 | 0/3 | 1 | 1/50 | 0/3 | 1 |
| Mononeuritis multiplex | 0/50 | 0/3 | 1 | 0/50 | 0/3 | 1 |
| Disturbance of consciousness | 2/50 | 0/3 | 1 | 4/50 | 0/3 | 1 |
| Cerebrovascular disorder | 0/50 | 0/3 | 1 | 0/50 | 0/3 | 1 |
| Spinal disorder | 0/50 | 0/3 | 1 | 0/50 | 0/3 | 1 |
| Aseptic meningitis | 0/50 | 0/3 | 1 | 0/50 | 0/3 | 1 |
| Other neurological symptoms | 4/50 | 0/3 | 1 | 4/50 | 0/3 | 1 |
| Nondestructive arthritis (more than two) | 20/50 | 2/3 | .258 | 19/50 | 2/3 | .555 |
| Muscle pain | 3/50 | 0/3 | .567 | 15/50 | 0/3 | .550 |
| Muscle weakness | 15/50 | 0/3 | .549 | 15/50 | 0/3 | 1 |
| Pleurisy | 1/50 | 0/3 | 1 | 2/50 | 0/3 | 1 |
| Epicarditis | 2/50 | 0/3 | 1 | 4/50 | 0/3 | 1 |
| Interstitial pneumonia | 1/50 | 0/3 | 1 | 2/50 | 0/3 | 1 |
| Pulmonary hypertension | 2/50 | 0/3 | 1 | 2/50 | 0/3 | 1 |
| Pulmonary infarction | 0/50 | 0/3 | 1 | 0/50 | 0/3 | 1 |
| Pulmonary hemorrhage | 0/50 | 0/3 | 1 | 0/50 | 0/3 | 1 |
| Other cardiopulmonary symptoms | 0/50 | 0/3 | 1 | 0/50 | 0/3 | 1 |
| Rapidly progressive nephritis | 0/50 | 0/3 | 1 | 0/50 | 0/3 | 1 |
| Acute renal failure | 0/50 | 0/3 | 1 | 0/50 | 0/3 | 1 |
| Chronic renal failure | 0/50 | 0/3 | 1 | 0/50 | 0/3 | 1 |
| Nephrotic syndrome | 0/50 | 0/3 | 1 | 0/50 | 0/3 | 1 |
| Renal biopsy abnormal | 5/6 | 2/2 | 1 | 8/12 | 2/3 | 1 |
| Other renal symptoms | 2/50 | 0/3 | 1 | 1/50 | 0/3 | 1 |
| Fever | 30/50 | 3/3 | .282 | 30/50 | 3/3 | .282 |
| Weight loss | 13/50 | 1/3 | 1 | 13/50 | 3/3 | .024 |
| Lymphadenopathy, splenomegaly | 11/50 | 3/3 | .016 | 11/50 | 3/3 | .016 |
| Easy fatigability, general malaise, weakness | 23/50 | 2/3 | .597 | 24/50 | 2/3 | .611 |
| Loss of appetite, nausea, and vomiting | 20/50 | 2/3 | .258 | 20/50 | 3/3 | .076 |
(3) Laboratory Data.
| At the Start of Treatment |
Current |
|||||
|---|---|---|---|---|---|---|
| Thyroid Cancer (−) | Thyroid Cancer (+) | P | Thyroid Cancer (−) | Thyroid Cancer (+) | P | |
| WBC (/µL) | 5392 | 4433 | .686 | 5957 | 5766 | .954 |
| Lymphocytes (/µL) | 1456 | 648 | .084 | 1402 | 1339 | .686 |
| Hb (g/dL) | 117 | 10.4 | .143 | 12.9 | 10.6 | .0393 |
| Plt (×104/µL) | 23.3 | 22.4 | 1 | 27.2 | 30.7 | .366 |
| Cre (mg/dL) | 0.42 | 0.55 | .0706 | 0.54 | 0.48 | .289 |
| CH50 (U/mL) | 32.6 | 7.0 | .211 | 36.3 | 38.8 | 1 |
| C3 (mg/dL) | 64.2 | 60.0 | .186 | 90.7 | 86 | .677 |
| C4 (mg/dL) | 11.4 | 11.0 | .367 | 19.2 | 20.3 | .531 |
| CRP (mg/dL) | 0.975 | 0.563 | .335 | 0.109 | 0.423 | .341 |
| SAA (µg/mL) | 167.5 | 226.4 | .127 | 10.15 | 28.67 | .114 |
| ESR (mm/h) | 47.1 | 68.0 | .193 | 16.42 | 23 | .901 |
| ANA (fold) | 1647 | 1493 | .658 | 605 | 40 | .524 |
| Homogeneous type | 22/43 | 1/3 | 1 | 10/26 | 1/1 | .407 |
| Speckled type | 29/44 | 2/3 | 1 | 14/26 | 1/1 | 1 |
| Nucleolar type | 1/42 | 0/3 | 1 | 0/26 | 0/1 | 1 |
| Peripheral type | 1/42 | 0/3 | 1 | 0/26 | 0/1 | 1 |
| Centromere type | 0/42 | 0/3 | 1 | 0/26 | 0/1 | 1 |
| Granular type | 0/42 | 0/3 | 1 | 1/26 | 0/1 | 1 |
| Nuclearmembrane type | 0/42 | 0/3 | 1 | 0/26 | 0/1 | 1 |
| Anti-DNA Ab (IU/mL) | 88.3 | 135.6 | .374 | 8.35 | 6.33 | .569 |
| Anti-dsDNA IgG (IU/mL) | 126.5 | 183.5 | .55 | 6.84 | 6.07 | .547 |
| Anti-Sm Ab | 18/39 | 2/2 | .232 | 12/24 | 0/3 | .537 |
| Anti-U1RNP Ab | 18/36 | 2/2 | 1 | 8/32 | 0/3 | 1 |
| Anti-SSA Ab | 23/42 | 1/3 | .591 | 20/37 | 1/3 | .596 |
| Anti-SSB Ab | 12/41 | 1/3 | 1 | 11/37 | 0/3 | .548 |
| Anti-cardiolipin Ab | 13/35 | 2/3 | .050 | 3/15 | 2/2 | .132 |
| Lupus anticoagulant | 8/34 | 0/3 | 1 | 4/16 | 0/1 | 1 |
| BFP | 0/5 | 0/1 | 1 | 0/2 | 0/0 | 1 |
| Hemolytic anemia | 1/45 | 0/2 | 1 | 0/47 | 0/3 | 1 |
| Proteinuria (mg/dL) | 10.4 | 22.0 | .103 | 5.20 | 11.8 | .483 |
| Hematuria | 5/43 | 1/3 | .056 | 1/50 | 0/3 | 1 |
| Urine granular cast | 1/43 | 2/3 | .127 | 1/50 | 0/3 | 1 |
Abbreviations: WBC, white blood cells; Hb, hemoglobin; Plt, platelet; Cre, creatinine; CH50, 50% hemolytic complement; C3, complement component 3; C4, complement component 4; CRP, C-reactive protein; SAA, serum amyloid A; ESR, erythrocyte sedimentation rate; ANA, anti-nuclear antibody; Ab, antibody; BFP, biological false positive.
(4) Therapy.
| Thyroid Cancer (−) | Thyroid Cancer (+) | P | |
|---|---|---|---|
| MMF | 36/50 | 3/3 | .557 |
| mPSL pulse | 17/50 | 3/3 | .049 |
| AZA | 17/50 | 2/3 | .290 |
| CyA | 9/50 | 1/3 | .920 |
| CYP pulse | 4/50 | 1/3 | .261 |
| Mizoribine | 14/50 | 0/3 | .557 |
| MTX | 11/50 | 0/3 | 1 |
| IVIG | 4/50 | 0/3 | 1 |
| Tacrolimus | 2/50 | 0/3 | 1 |
| Eterercept | 1/50 | 0/3 | 1 |
| Adalimab | 1/50 | 0/3 | 1 |
Abbreviations: MMF, mycophenolate mofetil; mPSL, methyl prednisolone; AZA, azathioprine; CyA, cyclosporine A; CYP, cyclophosphamide; MTX, methotrexate; IVIG, intravenous immunoglobulin.
(5) Current Therapy and Its Effect.
| Current Therapy |
Therapeutic Effect |
|||||
|---|---|---|---|---|---|---|
| Thyroid Cancer (−) | Thyroid Cancer (+) | P | Thyroid Cancer (−) | Thyroid Cancer (+) | P | |
| PSL | 44/50 | 3/3 | 1 | 44/44 | 3/3 | 1 |
| NSAID | 10/50 | 0/3 | 1 | 8/10 | 0/0 | 1 |
| Immunosuppressants | 45/50 | 2/3 | .308 | 42/42 | 2/2 | 1 |
| mPSL pulse | 1/50 | 0/3 | 1 | 1/1 | 0/0 | 1 |
| CYP pulse | 1/50 | 0/3 | 1 | 1/1 | 0/0 | 1 |
| Others | 11/50 | 2/3 | .145 | 10/11 | 1/1 | .289 |
| Maximal dose of PSL | 9.41 | 10.17 | .327 | |||
Abbreviations: PSL, prednisolone; NSAID, nonsteroidal anti-inflammatory drug; mPSL, methyl prednisolone; CYP, cyclophosphamide.
(6) Complications.
| Thyroid Cancer (−) | Thyroid Cancer (+) | P | |
|---|---|---|---|
| Infection | 9/50 | 2/3 | .105 |
| Peptic ulcer | 3/50 | 0/3 | 1 |
| Diabetes mellitus | 1/50 | 0/3 | 1 |
| Hypertension | 4/50 | 0/3 | 1 |
| Compression fracture | 3/50 | 0/3 | 1 |
| Osteonecrosis | 2/50 | 1/3 | .163 |
| Cerebral infarction | 0/50 | 0/3 | 1 |
| Myocardial infarction | 0/50 | 0/3 | 1 |
| DIC | 0/50 | 0/3 | 1 |
| Others | 11/50 | 1/3 | .545 |
Abbreviations: DIC, disseminated intravascular coagulation.
Laboratory Data
Current hemoglobin levels in cancer patients were significantly lower (P = .0393) than in those who did not have cancer.
Medication
More patients with cancer received mPSL pulse therapy than those who did not have cancer.
Current Therapy and Its Effect
No mediations used in current therapy or their effect had an impact on TC development.
Complications
Prevalence of complications between the 2 groups was not different.
Risk Factors in SLE Patients
Demographic Factors
None of the elements noted in SLE patients favored TC development (Table 4).
Table 4.
Risk Factors for the Development of Thyroid Cancer in Patients With SLE.
(1) Demographic Features.
| Thyroid Cancer (−) | Thyroid Cancer (+) | P | |
|---|---|---|---|
| Age | 18.9 | 20.3 | .617 |
| Age of onset | 10.3 | 9.3 | .692 |
| Family history | 3/19 | 0/2 | 1 |
| Sex, male (%) | 0.154 | 0 | 1 |
(2) Clinical Symptoms.
| At the Start of Treatment |
Entire Period |
|||||
|---|---|---|---|---|---|---|
| Thyroid Cancer (−) | Thyroid Cancer (+) | P | Thyroid Cancer (−) | Thyroid Cancer (+) | P | |
| Butterfly rash | 11/26 | 1/3 | 1 | 16/26 | 3/3 | .532 |
| Discoid papulosis | 1/26 | 0/3 | 1 | 1/26 | 0/3 | 1 |
| Photosensitivity | 5/26 | 0/3 | 1 | 5/26 | 0/3 | 1 |
| Oral, nasal, or mucosal painless ulcer | 8/26 | 2/3 | .267 | 9/26 | 3/3 | .062 |
| Hair loss | 1/26 | 0/3 | 1 | 4/26 | 1/3 | .446 |
| Raynaud’s phenomenon | 3/26 | 0/3 | 1 | 4/26 | 0/3 | 1 |
| Peptic ulcer | 0/26 | 0/3 | 1 | 4/26 | 0/3 | 1 |
| Other skin conditions | 3/25 | 2/3 | .0733 | 1/25 | 2/3 | .0232 |
| Convulsion | 3/26 | 0/3 | 1 | 3/26 | 0/3 | 1 |
| Psychological symptom | 3/26 | 0/3 | 1 | 3/26 | 0/3 | 1 |
| Organic brain syndrome | 1/25 | 0/3 | 1 | 1/25 | 0/3 | 1 |
| Cranial nerve symptoms | 1/25 | 0/3 | 1 | 0/25 | 0/3 | 1 |
| Mononeuritis multiplex | 1/25 | 0/3 | 1 | 0/25 | 0/3 | 1 |
| Disturbance of consciousness | 2/26 | 0/3 | 1 | 2/26 | 0/3 | 1 |
| Cerebrovascular disorder | 0/26 | 0/3 | 1 | 0/26 | 0/3 | 1 |
| Spinal disorder | 0/26 | 0/3 | 1 | 0/26 | 0/3 | 1 |
| Aseptic meningitis | 0/26 | 0/3 | 1 | 0/26 | 0/3 | 1 |
| Other neurological symptoms | 1/25 | 0/3 | 1 | 2/25 | 0/3 | 1 |
| Nondestructive arthritis (more than two) | 12/26 | 2/3 | .598 | 12/26 | 2/3 | .598 |
| Muscle pain | 2/26 | 0/3 | 1 | 5/26 | 0/3 | 1 |
| Muscle weakness | 3/26 | 0/3 | 1 | 3/26 | 0/3 | 1 |
| Pleurisy | 0/26 | 0/3 | 1 | 1/26 | 0/3 | 1 |
| Epicarditis | 1/26 | 0/3 | 1 | 3/26 | 0/3 | 1 |
| Interstitial pneumonia | 0/26 | 0/3 | 1 | 1/26 | 0/3 | 1 |
| Pulmonary hypertension | 0/26 | 0/3 | 1 | 0/26 | 0/3 | 1 |
| Pulmonary infarction | 0/26 | 0/3 | 1 | 0/26 | 0/3 | 1 |
| Pulmonary hemorrhage | 0/26 | 0/3 | 1 | 0/26 | 0/3 | 1 |
| Other cardiopulmonary symptoms | 0/25 | 0/3 | 1 | 0/25 | 0/3 | 1 |
| Rapidly progressive nephritis | 0/26 | 0/3 | 1 | 0/26 | 0/3 | 1 |
| Acute renal failure | 0/26 | 0/3 | 1 | 0/26 | 0/3 | 1 |
| Chronic renal failure | 0/26 | 0/3 | 1 | 0/26 | 0/3 | 1 |
| Nephrotic syndrome | 0/26 | 0/3 | 1 | 0/26 | 0/3 | 1 |
| Renal biopsy abnormal | 5/7 | 2/2 | 1 | 10/11 | 1/1 | 1 |
| Other renal symptoms | 1/25 | 1/3 | .206 | 2/26 | 0/3 | 1 |
| Fever | 18/25 | 3/3 | .551 | 20/26 | 3/3 | 1 |
| Weight loss | 6/26 | 1/3 | 1 | 6/26 | 3/3 | .023 |
| Lymphadenopathy, splenomegaly | 8/26 | 3/3 | .0452 | 8/26 | 3/3 | .045 |
| Easy fatigability, general malaise, weakness | 12/26 | 2/3 | .598 | 13/26 | 2/3 | 1 |
| Loss of appetite, nausea, and vomiting | 12/26 | 2/3 | .598 | 12/26 | 3/3 | .224 |
(3) Laboratory Data.
| At the Start of Treatment |
Current |
|||||
|---|---|---|---|---|---|---|
| Thyroid Cancer (−) | Thyroid Cancer (+) | P | Thyroid Cancer (−) | Thyroid Cancer (+) | P | |
| WBC (/µL) | 4276 | 4433 | .496 | 5413 | 5766 | .474 |
| Lymphocytes (/µL) | 1055 | 648 | .371 | 957 | 1339 | .092 |
| Hb (g/dL) | 11.1 | 10.4 | .333 | 12.8 | 10.6 | .0341 |
| Plt (×104/µL) | 16.7 | 22.4 | .35 | 24 | 30.7 | .112 |
| Cre (mg/dL) | 0.47 | 0.55 | .266 | 1.41 | 0.48 | .282 |
| CH50 (U/mL) | 22.1 | 7.0 | .298 | 32.8 | 38.8 | .618 |
| C3 (mg/dL) | 64.2 | 60.0 | .616 | 84.2 | 86 | .641 |
| C4 (mg/dL) | 11.4 | 11.0 | .693 | 16.1 | 20.3 | .37 |
| CRP (mg/dL) | 0.975 | 0.563 | .519 | 0.098 | 0.423 | .325 |
| SAA (µg/mL) | 167.5 | 226.4 | .229 | 10.05 | 28.67 | .146 |
| ESR (mm/h) | 47.1 | 68.0 | .334 | 16.4 | 23 | .926 |
| ANA (fold) | 1647 | 1493 | .687 | 769 | 40 | .243 |
| Homogeneous type | 15/26 | 1/3 | .573 | 8/14 | 1/1 | .243 |
| Speckled type | 19/26 | 2/3 | 1 | 12/14 | 1/1 | 1 |
| Nucleolar type | 1/26 | 0/3 | 1 | 0/14 | 0/1 | 1 |
| Peripheral type | 0/26 | 0/3 | 1 | 0/14 | 0/1 | 1 |
| Centromere type | 0/26 | 0/3 | 1 | 0/14 | 0/1 | 1 |
| Granular type | 0/26 | 0/3 | 1 | 1/14 | 0/1 | 1 |
| Nuclearmembrane type | 0/26 | 0/3 | 1 | 0/14 | 0/1 | 1 |
| Anti-DNA Ab (IU/mL) | 88.3 | 135.6 | .709 | 10.23 | 6.33 | .367 |
| Anti-dsDNA IgG (IU/mL) | 126.5 | 183.5 | .876 | 8.73 | 6.07 | .316 |
| Anti-Sm Ab | 15/22 | 2/3 | 1 | 6/22 | 0/3 | .554 |
| Anti-U1RNP Ab | 6/18 | 2/3 | 1 | 2/20 | 0/3 | 1 |
| Anti-SSA Ab | 19/24 | 1/3 | .156 | 17/23 | 1/3 | .215 |
| Anti-SSB Ab | 8/23 | 1/3 | 1 | 6/23 | 0/3 | 1 |
| Anti-cardiolipin Ab | 13/22 | 2/3 | 1 | 3/13 | 2/2 | .095 |
| Lupus anti-coagulant | 7/21 | 0/3 | .53 | 3/12 | 0/1 | 1 |
| BFP | 0/4 | 0/1 | 1 | 0/0 | 0/0 | 1 |
| Hemolytic anemia | 1/25 | 0/3 | 1 | 0/26 | 0/3 | .316 |
| Proteinuria (mg/dL) | 111 | 22.0 | .139 | 3.14 | 11.8 | .187 |
| Hematuria | 5/25 | 2/3 | .145 | 1/25 | 0/3 | 1 |
| Urine granular cast | 1/25 | 2/3 | .023 | 1/25 | 0/3 | 1 |
Abbreviations: WBC, white blood cells; Hb, hemoglobin; Plt, platelet; Cre, creatinine; CH50, 50% hemolytic complement; C3, complement component 3; C4, complement component 4; CRP, C-reactive protein; SAA, serum amyloid A; ESR, erythrocyte sedimentation rate; ANA, anti-nuclear antibody; Ab, antibody; BFP, biological false positive.
(4) Therapy.
| Thyroid Cancer (−) | Thyroid Cancer (+) | P | |
|---|---|---|---|
| MMF | 21/26 | 3/3 | 1 |
| mPSL pulse | 9/26 | 3/3 | .060 |
| AZA | 12/26 | 2/3 | .598 |
| CyA | 1/26 | 1/3 | .200 |
| CYP pulse | 2/26 | 1/3 | .298 |
| Mizoribine | 10/26 | 0/3 | .532 |
| MTX | 2/26 | 0/3 | 1 |
| IVIG | 2/26 | 0/3 | 1 |
| Tacrolimus | 2.26 | 0/3 | 1 |
| Eterercept | 0/26 | 0/3 | 1 |
| Adalimab | 0/26 | 0/3 | 1 |
Abbreviations: MMF, mycophenolate mofetil; mPSL, methyl prednisolone; AZA, azathioprine; CyA, cyclosporine A; CYP, cyclophosphamide; MTX, methotrexate; IVIG, intravenous immunoglobulin.
(5) Current Therapy and Its Effect.
| Current Therapy |
Therapeutic Effect |
|||||
|---|---|---|---|---|---|---|
| Thyroid Cancer (−) | Thyroid Cancer (+) | P | Thyroid Cancer (−) | Thyroid Cancer (+) | P | |
| PSL | 26/26 | 3/3 | 1 | 26/26 | 3/3 | .237 |
| NSAID | 6/24 | 0/3 | 1 | 5/6 | 0/0 | 1 |
| Immunosuppressants | 25/26 | 2/3 | .2 | 25/25 | 2/2 | .2 |
| mPSL pulse | 0/25 | 0/3 | 1 | |||
| CYP pulse | 0/25 | 0/3 | 1 | |||
| Others | 0/20 | 0/2 | 1 | 5/6 | 0/0 | 1 |
| Maximal dose of PSL | 6.63 | 10.17 | .237 | |||
Abbreviations: PSL, prednisolone; NSAID, nonsteroidal anti-inflammatory drug; mPSL, methyl prednisolone; CYP, cyclophosphamide.
(6) Complications.
| Thyroid Cancer (−) | Thyroid Cancer (+) | P | |
|---|---|---|---|
| Infection | 7/25 | 2/3 | .234 |
| Peptic ulcer | 0/25 | 0/3 | 1 |
| Diabetes mellitus | 0/26 | 0/3 | 1 |
| Hypertension | 3/25 | 0/3 | 1 |
| Compression fracture | 2/25 | 0/3 | 1 |
| Osteonecrosis | 2/25 | 1/3 | .293 |
| Cerebral infarction | 0/25 | 0/3 | 1 |
| Myocardial infarction | 0/25 | 0/3 | 1 |
| DIC | 0/25 | 0/3 | 1 |
| Others | 4/26 | 1/3 | .446 |
Abbreviation: DIC, disseminated intravascular coagulation.
Symptoms
Lymphadenopathy/splenomegaly at treatment commencement and lymphadenopathy/splenomegaly and weight loss during the entire period promoted TC development in SLE patients.
Laboratory Data
Urinary granular casts at the start of therapy and currently low hemoglobin levels were contributing factors to TC development.
Medications
Specific examination for SLE revealed no significant differences between patients with or without TC (Table 4).
Current Therapy and Its Effect
We did not find any items that increase the risk of TC with regard to current treatment and its effect.
Complications
Definite comorbidities that differentiate cancer patients from noncancer patients were not identified.
Thyroid Hormone and Autoantibodies
Levels of thyroid hormones (TSH, FT3, FT4) in TC patients were not different from those of cancer-free patients with regard to rheumatic diseases or specifically to SLE (Table 5). Levels of thyroglobulin and autoantibodies (eg, anti-thyroglobulin, anti-TPO, TSHR antibody) in rheumatic disease and SLE were not significantly different (Table 5).
Table 5.
Thyroid Hormone and Autoantibodies.
(1) Rheumatic Diseases.
| Thyroid cancer (−), Mean ± SD | Thyroid Cancer (+), Mean ± SD | P | |
|---|---|---|---|
| TSH (µU/mL) | 1.38 ± 1.05 | 1.30 ± 0.26 | .908 |
| FT3 (pg/mL) | 2.71 ± 0.69 | 2.50 ± 0.53 | .608 |
| FT4 (ng/dL) | 1.11 ± 0.17 | 1.01 ± 0.12 | .306 |
| Thyroglobulin (ng/mL) | 19.16 ± 12.70 | 13.53 ± 13.04 | .465 |
| Anti-thyroglobulin (IU/mL) | 16.05 ± 16.81 | 12.33 ± 2.08 | .707 |
| Anti-TPO (IU/mL) | 10.66 ± 8.40 | 10.66 ± 7.37 | .998 |
| TSHR antibody (IU/L) | 1.43 ± 7.69 | 0.50 ± 0.00 | .783 |
Abbreviations: TSH, thyroid-stimulating hormone; FT3, free triiodothyronine; FT4, free thyroxine; TPO, thyroid peroxidase; TSHR, thyroid-stimulating hormone receptor.
(2) Systemic Lupus Erythematosus.
| Thyroid cancer (−), Mean ± SD | Thyroid cancer (+), Mean ± SD | P | |
|---|---|---|---|
| TSH (µU/mL) | 1.38 ± 0.86 | 1.30 ± 0.26 | .869 |
| FT3 (pg/mL) | 2.67 ± 0.78 | 2.50 ± 0.53 | .720 |
| FT4 (ng/dL) | 1.11 ± 0.17 | 1.01 ± 0.12 | .345 |
| Thyroglobulin (ng/mL) | 19.44 ± 13.35 | 13.53 ± 13.04 | .480 |
| Anti-thyroglobulin (IU/mL) | 14.82 ± 10.07 | 12.33 ± 2.08 | .679 |
| Anti-TPO (IU/mL) | 10.87 ± 9.85 | 10.66 ± 7.37 | .973 |
| TSHR antibody (IU/L) | 2.07 ± 6.18 | 0.50 ± 0.00 | .730 |
Abbreviations: TSH, thyroid-stimulating hormone; FT3, free triiodothyronine; FT4, free thyroxine; TPO, thyroid peroxidase; TSHR, thyroid-stimulating hormone receptor.
Discussion
Similar to the report that identified AZA as a risk factor for thyroid nodules in SLE,14 we identified several risk factors that may lead to TC development. Expression of each factor may suggest that TC patients have high SLE activity because these items are associated with severe disease.10 Furthermore, mPSL pulse therapy is ubiquitous for rheumatic diseases (mainly targeting severe disease) and may contribute to the relatively high distribution among TC patients, with low distribution among cancer-free patients with rheumatic disease. We identified lymphadenopathy/splenomegaly and weight loss to be risk factors, which are systemic conditions (and not organ-specific symptoms) as defined by the severity index.10 Owing to the small sample size, rheumatic diseases as a whole were associated with more risk factors than SLE alone as a specific single disease entity.
In our investigation, thyroid immunity and thyroid hormones were compared between cancer-positive and cancer-free patients because involvement of the autoimmunity and function of the thyroid gland in cancer development has been suggested by Antonelli et al1 and Papendieck et al.15 Our data were not in accordance with their results, and we did not find a distinction in autoantibody levels or hormone levels in the thyroid gland.
With the development of medical technology, identification of thyroid tumors (including benign nodules) has become more common, and some authors recognize benign tumors as “thyroid incidentalomas.”16 However, Papendieck et al suggested a higher prevalence of TC in pediatric thyroid nodules than in adult thyroid nodules.15 Therefore, we advocate careful investigations to find occult thyroid cancers because failure to detect “true” malignant tumors of the thyroid gland may result in a poor prognosis for SLE patients who carry the potential risk factors to develop them.
Our study had limitations. We evaluated a small number of SLE patients and those with other rheumatic diseases. Using Yates’ correction, we analyzed small-sample data in the χ2 test. Moreover, we used univariate analyses instead of multivariate analyses because an extremely low prevalence of TC did not permit enrolment of sufficient numbers of affected patients (which did not allow for analyses of the confounders that favor TC development). To use logistic regression analyses to study as few as 2 confounders, ≥20 cancer-positive SLE patients are required, which corresponds to ≈200 000 cancer-free SLE patients. Understandably, further expansion of confounders requires large populations.
Conclusion
There are several risk factors for TC development in pediatric SLE. Efforts should be made to find thyroid tumors carefully and intensively and to extract various characteristics among large numbers of TC-positive SLE children to permit multivariate analyses. Our results warrant a wide range of multicenter epidemiological studies instead of the single-center investigation described here.
Author Contributions
All authors made a substantial contribution to the work presented in this article. YK and TO contributed to the concept and design, data analysis, and interpretation of data. MM, TU, SS, ES, and TT are instrumental to the data acquisition. All authors edited and approved the article as submitted.
Footnotes
Authors’ Note: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
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