Background
There are several rheumatologic disorders well-known to be associated with underlying malignancy. 1 One of these is systemic sclerosis (scleroderma), which can manifest as a paraneoplastic syndrome in some cases. 2 Here, we present the case of a patient with new-onset scleroderma found to have underlying recurrent metastatic breast cancer concerning paraneoplastic scleroderma. We discuss the signs and symptoms of paraneoplastic scleroderma and show the importance of multidisciplinary consultation and discussion to manage these complex cases.
Case presentation
A woman in her 70s with a medical history of right breast invasive ductal adenocarcinoma in remission presented as a hospital transfer for dyspnoea. She initially presented to her primary care physician several months prior with new bilateral arm and leg peripheral oedema. Diuretics were initiated without improvement. Approximately 1 month later, she reported associated new dyspnoea and generalised arthralgias. Basic metabolic panel, rheumatoid factor, anti-nuclear antibody (ANA), sedimentation rate, C-reactive protein, serum uric acid, right-hand X-ray and chest X-ray were ordered, and she was referred to cardiology, which recommended transthoracic echocardiogram, bilateral lower extremity venous ultrasound and exercise stress test. This initial work-up was notable for a reportedly normal ejection fraction, elevated right ventricular systolic pressure of 43 mm Hg, bilateral lower extremity venous insufficiency and normal stress test. Compression stockings were recommended, and diuretics were adjusted. She was referred to rheumatology for her persistent arthralgias and started on allopurinol for suspected gout.
She then had several inpatient admissions for her dyspnoea, suspected to be due to heart failure exacerbations, with multiple thoracentesis for bilateral pleural effusions showing unremarkable studies and cytology. She was noted to have a suspicion of possible scleroderma/myositis overlap syndrome; however, further evaluation was deferred to the outpatient setting. At her most recent hospital stay prior to transfer, the findings included a pericardial effusion with tamponade physiology, requiring pericardiocentesis and bilateral transudative thoracentesis with negative cytology. A nuclear bone scan showed multisite osseous lesions, and her echocardiogram showed elevated right ventricular systolic pressure with concerns for pulmonary hypertension. Her serum creatinine was elevated to 1.5 mg/dL. She reported that a bone biopsy was planned but was not yet able to be performed. She was transferred to our facility for further work-up and management. Other reported symptoms included new Raynaud’s phenomenon, chronic fatigue and unintentional weight loss of 15 pounds over several months.
20 years prior to admission, she underwent unilateral mastectomy, radiation therapy and chemotherapy with letrozole and tamoxifen for breast cancer followed by sustained remission. She had been followed by oncology up until 2013, when she was lost to follow-up. Family history was significant for breast cancer in her sister and lymphoma and renal cancer in her father. She denied any family history of autoimmune conditions. She reported no tobacco or alcohol use.
Initial vital signs were significant for blood pressure of 173/73 mm Hg, with oxygen saturation of 92% on 4 L of oxygen. She had sclerodactyly (skin tightening/thickening) and crackles throughout bilateral lung fields, with decreased breath sounds at bilateral bases.
Investigations
Initial laboratory work-up at our facility revealed a negative ANA by multiplex assay and a positive ANA by immunofluorescent assay, with a titre of 1:320 in a speckled pattern. She had otherwise normal inflammatory and autoimmune markers, including erythrocyte sedimentation, C-reactive protein, complement C3/C4, rheumatoid factor, cyclic citrullinated peptide, scleroderma antibody (anti-SCL-70) and anti-double-stranded DNA. The scleroderma panel was pending. Serum creatinine was elevated to 1.5 mg/dL. A CT chest without contrast was obtained and revealed bilateral pleural effusions, a patulous oesophagus and lesions of the left posterior fourth rib ( figure 1 ). A nuclear bone scan was obtained and revealed increased radiotracer uptake in several bones ( figure 2 ).
Differential diagnosis
Given her presentation with sclerodactyly, volume overload with concerns for pulmonary hypertension on echocardiography and a history of breast cancer with findings on the nuclear bone scan concerning osseous metastatic disease, the highest suspicion was for an underlying autoimmune process, such as scleroderma, possibly as a paraneoplastic phenomenon due to new malignancy. The differential diagnosis for her underlying malignancy included recurrent metastatic breast cancer, given her history; multiple myeloma, given her concomitant acute kidney injury and osseous lesions, though the serum kappa/lambda ratio was normal on outside laboratory studies; and metastatic disease from an unknown primary. While she was noted to have hypoattenuating liver lesions on CT, her serum alpha-fetoprotein was negative, making hepatocellular carcinoma unlikely. She reported that her most recent colonoscopy had been 7–8 years prior and was normal, so colorectal cancer was thought to be less likely. She previously had a total hysterectomy, making cervical cancer less likely.
Treatment
Rheumatology, pulmonary hypertension, pulmonology, oncology and nephrology were consulted. Captopril was initiated due to concern for scleroderma renal crisis (SRC). Repeat bilateral thoracentesis revealed transudative effusion with negative cytology. Right heart catheterisation was suggestive of group 1 pulmonary hypertension. The scleroderma panel was positive for RNA polymerase 11 (RP11 (97, ref: <11)) and RP155 (40, ref: <11). Vertebral biopsy was consistent with metastatic recurrent breast cancer.
Through multidisciplinary discussion between oncology, rheumatology, nephrology and the general medicine team, treatment with rituximab was initiated for her diffuse scleroderma syndrome. Rheumatology noted that while mycophenolate would be the first-line treatment for her skin findings, rituximab had a lower risk of progression of underlying malignancy. She received one dose of rituximab while inpatient.
Oncology discussed treatment for her oestrogen-receptor positive, progesterone-receptor negative, human epithelial growth factor receptor-positive breast cancer with docetaxel, herceptin and potentially pertuzumab. While the patient was awaiting insurance approval for inpatient chemotherapy, she developed a worsening acute kidney injury with rapidly reaccumulating pleural effusions and volume overload refractory to maximal diuresis. This was thought to be secondary to ongoing SRC, cardiorenal syndrome and thrombotic microangiopathy. In light of her worsening clinical status, palliative care was consulted. She chose to transition to supportive care, and pulmonology placed bilateral chest tubes for symptomatic relief.
Outcome and follow-up
Shortly after bilateral chest tube placement, the patient elected to pursue transfer to an inpatient hospice facility and subsequently passed away.
Discussion
The temporal relationship between the patient’s onset of sclerodactyly and her diagnosis of recurrent breast cancer, along with the presence of anti-RP antibodies, is suggestive of scleroderma as a paraneoplastic syndrome, a rare but increasingly reported phenomenon. Here, we discuss a few key aspects of the diagnosis and management of paraneoplastic scleroderma.
Our patient had several factors concerning the presence of underlying malignancy—older age of onset of scleroderma signs and symptoms (Raynaud’s phenomenon and sclerodactyly), prior history of breast cancer and constitutional symptoms, including weight loss and fatigue. Several other factors can hint towards rheumatologic conditions as a sign of occult neoplasia, including the history of exposure to carcinogens or immunotherapy, long-standing presence of particular rheumatic syndromes known to predispose to malignancy (eg, Sjogren’s syndrome, rheumatoid arthritis and systemic sclerosis), the concomitant presence of another paraneoplastic syndrome (eg, Lambert-Eaton syndrome) and positivity for certain tumour biomarkers or monoclonal antibodies. 1 Patients with advanced age of onset of scleroderma, in general, and even other rheumatologic signs or symptoms, such as Raynaud’s phenomenon, should be evaluated for the presence of occult malignancy. 2 3
Specific autoantibodies confer a higher risk of developing cancer and represent a complex interplay between autoimmunity and the host defence response to malignancy. 4 Anti-RP antibodies, which are also associated with a higher risk of developing SRC, are more frequently found in patients with systemic sclerosis and cancer than other antibodies associated with systemic sclerosis. 4 5 Furthermore, the presence of anti-RP antibodies was associated with a higher risk of developing cancer, particularly breast cancer, within 36 months of systemic sclerosis onset, supporting the theory that systemic sclerosis may present as a form of paraneoplastic syndrome. 6 The association between anti-RP III antibodies and cancer in scleroderma has been confirmed by several other studies. 2 4
Our laboratory evaluation was extensive and included the scleroderma antibody panel, ANA by multiplex and immunofluorescent assays (both ordered as the multiplex tests for a limited number of autoantibodies and thus has a lower sensitivity), cyclic citrullinated peptide and a repeat rheumatoid factor. In our case, the scleroderma antibody panel did not directly affect our patient’s course, as the positive RP11 and RP155 did not further help diagnose her underlying malignancy; however, the prognostication and management of positive scleroderma autoantibodies are increasingly undergoing investigation, with some newer recommendations to even increase screening for malignancy based on positivity. 7 The repeat rheumatoid factor and the cyclic citrullinated peptide were likely unnecessary and served as a reminder to practice high-value care.
There remains little research regarding optimal treatment for scleroderma as a paraneoplastic phenomenon, though it has been shown generally that rheumatologic disorders that present in this manner may improve with treatment of the underlying malignancy. 8 There have been cases described, however, where aggressive oncologic treatment has led to poor and fatal outcomes due to exacerbations of scleroderma. 9 In our case, the patient’s significant organ failure, poor functional status and rapid progression of her malignancy made her a poor candidate for chemotherapy. Based on shared decision-making with the patient and the consultant teams, we pursued treatment with rituximab with the hope for improvement in her skin and pulmonary symptoms.
Learning points
New-onset scleroderma in older patients may represent a sign of underlying malignancy.
A thorough history and physical examination are paramount in cases of new autoimmune disease, given the close association between rheumatologic disease presentations and occult malignancy.
Multidisciplinary discussion is essential in cases of paraneoplastic scleroderma to determine the treatment course pursued.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Consent obtained from next of kin.
References
1 Naschitz JE Rosner I Rozenbaum M et al Rheumatic syndromes: clues to occult neoplasia Semin Arthritis Rheum 1999 29 43 55 10.1016/s0049-0172(99)80037-7 10468414
2 Shah AA Casciola-Rosen L Cancer and scleroderma: a paraneoplastic disease with implications for malignancy screening Curr Opin Rheumatol 2015 27 563 70 10.1097/BOR.0000000000000222 26352736 PMC4643720
3 Madabhavi I Revannasiddaiah S Rastogi M et al Paraneoplastic Raynaud’s phenomenon manifesting before the diagnosis of lung cancer BMJ Case Rep 2012 2012 10.1136/bcr.03.2012.5985 PMC3391388 22761213
4 Fiorentino DF Casciola-Rosen L Autoantibodies and Cancer Association: the Case of Systemic Sclerosis and Dermatomyositis Clin Rev Allergy Immunol 2022 63 330 41 10.1007/s12016-022-08944-y 35593962 PMC10666558
5 Denton CP Lapadula G Mouthon L et al Renal complications and scleroderma renal crisis Rheumatology 2006 48 iii32 5 10.1093/rheumatology/ken483 19487221
6 Moinzadeh P Fonseca C Hellmich M et al Association of anti-RNA polymerase III autoantibodies and cancer in scleroderma Arthritis Res Ther 2014 16 R53 10.1186/ar4486 24524733 PMC3978927
7 Mecoli CA Casciola-Rosen L An update on autoantibodies in scleroderma Curr Opin Rheumatol 2018 30 548 53 10.1097/BOR.0000000000000550 30148799 PMC6546089
8 András C Csiki Z Ponyi A et al Paraneoplastic rheumatic syndromes Rheumatol Int 2006 26 376 82 10.1007/s00296-005-0005-3 16091919
9 Kochhar R Umbreit JN Fatal exacerbation of paraneoplastic systemic sclerosis after neoadjuvant chemotherapy in a breast cancer patient Clin Rheumatol 2004 23 269 71 10.1007/s10067-004-0875-x 15168161