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Scleroderma renal crisis and cancer Colombe Crosnier1, Aurélie Achille1, Marie Lecouffe-Desprets1, Antoine Néel1, Cécile Durant1, Christian Agard1 1

Internal Medicine Department, Hôtel-Dieu, CHU Nantes, France.

Corresponding author: Pr Christian Agard Internal Medicine Department, Hôtel-Dieu, Centre Hospitalier Universitaire de Nantes 1 place Alexis Ricordeau 44093 Nantes, France. Tel: +33 240 084 933 Fax: +33 240 083 379 E-mail: [email protected]

Abstract: We report two cases of elderly patients with diffuse systemic sclerosis (SSc) and inaugural scleroderma renal crisis (SRC). Initial exhaustive search for an underlying cancer was negative, but aggressive metastatic neoplasia was diagnosed after 1 year of follow-up. We emphasize the role of 18-FDG PET-scan to detect neoplasia in the following months after inaugural SRC in elderly.

Key words : systemic sclerosis, cancer, scleroderma renal crisis

© The Author 2018. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: [email protected]

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Scleroderma renal crisis and cancer

Systemic sclerosis (SSc) is characterized by microvascular involvement including Raynaud phenomenon (RP), dermal/other tissue fibrosis, and auto-immune markers. Systemic renal crisis (SRC) occurs in about 5% of patients, particularly in male with recent diffuse skin involvement and anti-RNA polymerase (pol) III antibodies (Ab). These latter may be associated to synchrone cancer in SSc patients [1]. Case 1: A 74-year-old woman was admitted for hypertensive encephalopathy, renal failure, and thrombotic microangiopathy. She had progressive diffuse skin sclerosis since 6 weeks, digital telangiectasia, and recent RP. Laboratory tests found antinuclear Ab (title>1/2560), anti-SSA/Ro52 and anti-RNA pol III Ab. Nailfold capillaroscopy noted numerous giant capillaries. SSc with SRC was diagnosed and treatment including angiotensin converting enzyme (ACE) inhibitors led to significant improvement. Repeated physical examinations, thoracic and abdominal (TA) CTscan, PET-scan, and mammography failed to detect any underlying cancer. However, she complained 11 months later of asthenia and abdominal pain, and a second PETscan revealed abdominal hypermetabolic mass (6 cm in diameter) with peritoneal carcinosis (figure a). Biopsy of the mass showed an undifferentiated carcinoma. Despite chemotherapy, she died 8 months after cancer diagnosis. Case 2: A 70-year-old man with a pre-existing RP was hospitalized for hypertensive encephalopathy in the context of recent-onset arthralgia and diffuse skin sclerosis. Serum creatinine was 306 µmol/L and he had antinuclear Ab 2

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(title>1/2560), but the specificities tested were all negative, including anti-centromere, -anti-topoisomerase1 (Scl-70) or -RNA pol III. Diffuse SSc with inaugural SRC was diagnosed, and the patient improved with treatment comprising ACE inhibitor, mycophenolate mofetil 2g/d and prednisone 10mg/d. Physical examination was normal, TA CT-scan found a single lung micronodule of the middle right lobe, but PET-scan was normal. One year later, he complained of costal pain with weight loss. A second PET-scan visualized high uptakes of 18 fluorodeoxyglucose of 2 lung nodules and of T9 vertebra (figure b). Biopsy led to the diagnosis of metastatic lung carcinoma, and the patient unfortunately died 4 months later. In both cases, agressive neoplasia was diagnosed 1 year after late-onset diffuse SSc with inaugural SRC. Our reports highlight the recently described notion of « synchrone » cancer to ScS [1]. Cancer is usually considered « synchrone » when its diagnosis is made between 6 months before and 12 months after the diagnosis of SSc. Different neoplasia are slightly more frequent in the SSc population, especially breast cancer, hematologic malignancies, neoplasia of the digestive tract, or gynecologic and lung cancers [2]. Most of them are « non synchrone », whereas « synchrone » cancer appears to affect a distinctive population of SSc patients aged over 60 or 70, with diffuse cutaneous form and anti-RNA pol III antibodies [1]. In such cases, a mutated form of the protein pol III may be expressed in the malignant tumor, and the production of anti-RNA pol III antibodies might reflect an antitumor immune response [3]. We assume such response might be temporary effective in controlling tumor progression, explaining that cancer might remain undetectable at the time of SSc diagnosis. However, this antitumor immune response might progressively become uneffective, leading to cancer growth within the next 12 months after SSc.

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In conclusion, patients > 70 years of age with recent SSc and inaugural SRC should be screened for neoplasia, particularly but not exclusively in anti-RNA pol III+ patients. Underlying “synchrone” cancer might be undetectable at the time of diagnosis of SSc, but within the 6 following months, a second exhaustive search for cancer, including PET-scan, should be made for its early detection.

Learning points for clinicians: Serious synchrone cancer may occur in the following year of late-onset SSc with inaugural SRC. In such patients, PET scan should be made 4-6 months after SRC diagnosis.

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References: [1] Lazzaroni MG, Cavazzana I, Colombo E, Dobrota R, Hernandez J, Hesselstrand R, et al. Malignancies in patients with anti-RNA polymerase III antibodies and systemic sclerosis: analysis of the EULAR Scleroderma Trials and Research Cohort and possible recommendations for screening. J Rheumatol 2017;44:639-47. [2] Moinzadeh P, Fonseca C, Hellmich M, Shah AA, Chighizola C, Denton CP, et al. Association of anti-RNA polymerase III autoantibodies and cancer in scleroderma. Arthritis Res Ther 2014;16:R53. [3] Joseph CG, Darrah E, Shah AA, Skora AD, Casciola-Rosen LA, Wigley FM, et al. Association of the autoimmune disease scleroderma with an immunologic response to cancer. Science 2014;343:152-7.

Each author declares no conflicts of interest.

Funding statement: none

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Legend of figures:

Figure a: PET-scan performed for patient 1 at the time of diagnosis of SRC (left), and 12 months later (right) showing occurrence of a large and high 18 FDG uptaken intraperitoneal mass, with features of peritoneal carcinosis.

Figure b: PET-scan performed for patient 2 at the time of diagnosis of SSc (left), with an isolated right lung micronodule with no 18-FDG uptake, and 15 months after the diagnosis (right), with occurrence of bone metastasis of the 9th thoracic and the 1st sacral vertebrae.

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166x157mm (72 x 72 DPI)

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155x144mm (72 x 72 DPI)

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