Case Presentation

1. Case Presentation Soniya hanif Wayne state university/ Henry Ford Medical Center

2. 61 year old gentleman • Presented at VA inpatient unit • CC: dizziness, lightheadedness and inability to swallow solid food

3. HPI: • Progressive difficulty with swallowing solid food, to the point of pain in swallowing saliva • Progressive over three months • Associated with central chest pain on swallowing • An episode of dizziness, lightheadedness, on standing up that brought him to Emergency Room • Also states worsening shortness of breath on exertion for past five months

4. Noticed initials symptoms over year back, painful pale and then blue discoloration of fingertips • Tingling and numbness of fingers: had Carpal tunnel repair • Physical therapist post surgery noted thickening and tightening of skin • Referred to Dermatology: skin biopsy of left upper chest morphea/scleroderma • Referred to Rheumatologist: started Methotrexate and low dose prednisone for scleroderma • Was discontinued: enrolled in trial as state scleroderma center for tocilizumab for diffuse systemic scleroderma • PFTs mild restrictive disease, Echo hyper dynamic EF 70%

5. ROS • Constitutional: weight loss of 9 lbs in three weeks, 20 lbs in past 5 months, skin thickening • HEENT: hoarseness for past two weeks • ENT: dysphagia and odynophagia • Respiratory: progressive dyspnea • CVS: odynophagia, lightheadedness • Neurologic: headache • MSK: Diffuse joint pains

6. PMH: • Diabetes mellitus • Hypertension • Dyslipidemia • Obstructive sleep apnea • Benign prostatic hypertrophy

7. PSH • Carpal tunnel release surgery • Lumbar fusion surgery • All: Penicillin • FH: no scleroderma or autoimmune diseases in family

8. Meds: • Acetaminophen PRN • Albuterol Inhaler, Budenoside / Formoterol inhalers, tiotropium • Folic acid • Insulin • Nifedipine, losartan • Simvastatin • Omeprazole

9. SH • Worked in transportation during his military service • Denied any exposure to pesticides, toxic chemical / agents while in service • Married, lived with wife • Former smoker: quit thirty years back, smoked 0.25 PPD/ 10 years • Would drink1-2 beers/day • No illicit drugs

10. Physical Examination • Temp: 98.4 C • Pulse: 78 • RR: 20 • BP 112/73 (95/61 on standing) • Pulse oximetry: 100%

11. General: Alert, oriented times three, no apparent distress • HEENT: EOM intact, no pallor or icterus • Neck: No lymphadenopathy • CVS: S1 S2 RRR, no murmurs • Abdominal: Soft, NT, ND, BS +, No HSM • Neuro: Strength 4/5 both shoulders, 5/5 in LE, sensation intact, reflexes +2, no focal Neurological deficits

12. Integumentary: Hands: sclerodactyly bilaterally Forearms and elbows: skin thickening up to elbows bilaterally Neck: spared Upper chest: skin thickening, Lower chest: spared Abdomen: some involvement Thighs: spared Shins/ Legs: R>L thickening Feet: thickening bilaterally (healing scar in left shin) no ulcers or telangiectasias noted

13. Investigations (in standard units) Glucose 104 Bun 15 Cr 1.5 (>>1.2) eGFR 58 Na 141 K 4.2 CL 110 HCO3 23 • WBC: 11.2 • RBC: 3.71 • HB: 11.0 • MCV 90 • Plt 175

14. CRP <0.012 Wintrobe 14 ANA: 1:640 speckled ENA detected SSA not detected SSB detected Anti-SM not detected SCL-70 not detected Anti dsDNA negative

15. Chest X-rays • No acute process • Aorta is prominent in caliber • Left mainstem bronchus appears narrowed in caliber • Follow with Chest CT advised

16. Echocardiogram • Normal LV size and function, EF 60-65% • Mild left ventricular hypertrophy • Stage 1 diastolic dysfunction • RVSP 22 mm Hg • Small circumferential pericardial effusion • No evidence of tamponade

17. Chest CT without contrast • Limited due to lack of IV contrast • Diffuse mediastinal, axillary lymphadenopathy • Deviation of the trachea to the right with a mild narrowing of the distal portion of the left mainstem bronchus • Hilar Lymphadenopathy • Pericardial effusion • Esophagus could not be separated from posterior mediastinal LAD • Small amount of right pleural effusion

19. Outside records: one years back • ESR 20 • CRP 0.6 • Hepatitis profile negative • ANA positive 1:2560 speckled • Anti RNA polymerase: positive • Centromere Ab negative • Anti RNP positive • Anti Jo1 negative

20. CT thorax with contrast • No ILD or pulmonary fibrosis • Mediastinal mass that is well defined with complex fluid internal density. Lesion is favored to represent esophageal or foregut duplication cyst. This may have mild mass effect in the esophagus. Correlate for any dysphagia.

21. Punch biopsy: left chest • There is mild hyperorthokeratosis with an underlying square shaped dermis. Prominent dermal sclerosis, thickening of collagen bundles, loss of periadnexal adipose tissue. • Diagnosis: scleroderma/ morphea

22. Biopsy: skin right lower arm • Epidermis demonstrates mild elongation of rete ridges, pigmentation of basal keratinocytes, and overlying compact orthokeratosis. Underlying dermis is fibrotic, loss of periadnexal fat. Dermal telangiectasia and sparse periadnexal inflammatory cell infiltrate is seen. • Diagnosis: dermal fibrosis, findings are most consistent with a morphea.

23. Hospital course • Orthostatic hypotension: resolved IVF • Overnight: choking sensation: respiratory distress (spO2 94% on 3 liters): airway compromised with diffuse LAD and likely aspirating own secretions • Laryngoscopy: abnormal vocal cord motion (likely due to laryngeal nerve compression) • EGD: small food bonus in mid esophagus gently pushed down, biopsy + H pylorrhi • Dysphagia screen: able to take thick liquids

24. We were concerned about scleroderma mimics at this time vs paraneoplastic syndrome

25. EBUS performed • Oncology consulted • Continue to fail dysphagia screen: aspiration with respiratory distress • Failed NGT: PEG? • Preliminary biopsy: Aggressive stage 3 diffuse large B-cell lymphoma, Non Hodgkin’s type: transferred to Cancer centre • Pulled out of tocilizumab study • Axillary excisional biopsy: Mantle Cell lymphoma: high proliferation activity

26. Started on EPOCH regimen (etoposide, prednisone, Oncovin, cyclophosphamide, hydroxydaunorubicin) • Followed by bendamustine, rituximab • Completed four cycles of chemotherapy

27. In clinic five months later… • Dysphagia improved • Dyspnea improved • Skin tightening improved (from 2-3 mRSS to 1-2 in his hands, wrists and forearms)

28. Chest CT after chemotherapy • Marked improvement in previously noted mediastinal lymphadenopathy with residual mildly enlarged subcarinallymph nodes

29. Complications • Postobstructive pneumonia • Neutropenia fever • Pericardial tamponade

30. Discussion • We describe to you a unique case posing as a diagnostic and therapeutic challenge with symptoms attributed to both scleroderma and lymphoma. • With concurrent incidence of both scleroderma and lymphoma complicating initial presentation • A unique subset of scleroderma patients with positive its of RNA polymerase 3 Ab with greater association of hematological malignancies • The only reported case where Chemotherapy of lymphoma almost completely “resolved” skin tightness • We propose greater clinical-serological surveillance for this specific population • Consider clinical response to skin in response to management of lymphoma

31. Patients with scleroderma have been noted to have increased risk of cancer compared with general population • Risk could be secondary to • Damage from scleroderma (chronic inflammation and fibrosis with resultant malignant transformation, and Barretts from chronic GERD, ILD leading to lung cancers) • Cytotoxic therapy used for management • A common inciting exposure • Genetic predisposition: increased risk of cancer in first degree relatives of Scleroderma patients

32. Conversely, cancer therapies may trigger severe Raynaud’s or lead to exaggerated fibrosis (such as Bleomycin, carboplatin, gemcitabine, paclitaxel), also checkpoint inhibitors, and by radiation. There have been reports of Scl-like skin after radiation therapy for breast cancer, also reports of Scl-like illness after the use of chemotherapy • However, a unique subset has been described with concurrent onset of scleroderma and cancer, showing mechanical association of the two phenomenon

33. In Johns Hopkins Scleroderma Center Cohort, about 22.7% of cancer diagnosis occurred within two years of first scleroderma symptom Shah AA, Hummers LK, Casciola-Rosen L, et al. Examination of autoantibody status and clinicalfeatures associated with cancer risk and cancer-associated scleroderma. Arthritis & rheumatology.2015; 67(4):1053–61. [PubMed: 25605296]

34. Shah et al at Johns Hopkins initially noted a striking temporal clustering of cancer diagnosis with the first clinical signs of scleroderma • Noted unique nucleolar expression of RNA Polymerase III in their cancerous cell not noted in patients with other scleroderma autoantibodies or in normal control • A study in Australia concluded 4.2 fold increased odd of cancer within five years of scleroderma onset in scleroderma patients with positive anti-RNP polymerase III Ab • At Johns Hopkins, a 5.08 fold increased risk of cancer within two years of scleroderma onset was found in those with positive Anti RNP III Ab, strongly associated with older age of onset of scleroderma • Temporal clustering of cancer scleroderma is described with short cancer-scleroderma interval was observed in this group

35. Paraneoplastic model of scleroderma • POLR3A gene locus for RNA Polymerase III • Mutated RNA polymerase II proteins are hypothesized to be immunogenic that initiate Anti-RNA polymerase III Ab response

37. Cancer-induced autoimmunity in a subset of patients with positive RNA polymerase III • Scleroderma may be a paraneoplastic disease • RNA polymerase III Ab is a red flag that warrants more aggressive cancer screening • In our patient, we proved that cancer therapy was effective in treating scleroderma • Only report in literature where skin tightening improved after chemotherapy for management of cancer

38. References • Shah AA, Casciola-Rosen L. Cancer and scleroderma: a paraneoplastic disease with implications for malignancy screening. Curr Opin Rheumatol. 2015;27(6):563-70. • Colaci M, Giuggioli D, Vacchi C, Ferri C. Haematological Malignancies in Systemic Sclerosis Patients: Case Reports and Review of the World Literature. Case Rep Rheumatol. 2017;2017:6230138. • Joseph CG, Darrah E, Shah AA, et al. Association of the autoimmune disease scleroderma with an immunologic response to cancer. Science. 2013;343(6167):152-7 • Shah AA, Hummers LK, Casciola-Rosen L, et al. Examination of autoantibody status and clinicalfeatures associated with cancer risk and cancer-associated scleroderma. Arthritis & rheumatology.2015; 67(4):1053–61. [PubMed: 25605296] • Shah AA, Rosen A, Hummers L, et al. Close temporal relationship between onset of cancer andscleroderma in patients with RNA polymerase I/III antibodies. Arthritis and rheumatism. 2010; 62(9):2787–95.

39. Shah AA, Rosen A, Hummers L, et al. Close temporal relationship between onset of cancer and scleroderma in patients with RNA polymerase I/III antibodies. Arthritis and rheumatism. 2010; 62(9):2787–95. • Nikpour M, Hissaria P, Byron J, et al. Prevalence, correlates and clinical usefulness of antibodies to RNA polymerase III in systemic sclerosis: a cross-sectional analysis of data from an Australian cohort. Arthritis research & therapy. 2011; 13(6):R211. [PubMed: 22189167]