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Table of Contents
Year : 2019  |  Volume : 6  |  Issue : 1  |  Page : 45-49

Paraneoplastic Systemic Sclerosis in a Patient with Metastatic Thymic Carcinoma

1 Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
2 Department of Rheumatology, National Taiwan University Hospital, Taipei, Taiwan
3 Department of Oncology, National Taiwan University Hospital, Taipei; Division of Hematology and Oncology, Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan

Date of Submission30-Jun-2018
Date of Decision18-Sep-2018
Date of Acceptance25-Sep-2018
Date of Web Publication1-Mar-2019

Correspondence Address:
Dr. Hung-Yang Kuo
Division of Hematology and Oncology, Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, No. 25, Lane 442, Sec. 1, Jingguo Road, Hsinchu 300
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JCRP.JCRP_8_18

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Thymic malignancies cause alterations in the immune system. Thymomas are known to be associated with paraneoplastic syndrome and autoimmunity, including myasthenia gravis, systemic lupus erythematosus, inappropriate antidiuretic hormone secretion, pure red cell aplasia, pernicious anemia, pemphigus, and autoimmune thyroid diseases. However, paraneoplastic syndrome has rarely been observed in patients with thymic carcinoma. The management of patients with paraneoplastic autoimmune disease is difficult, and treatment of the underlying malignancy is important. Herein, we present a case of thymic carcinoma who developed systemic sclerosis 3 years after the initial diagnosis during disease progression.

Keywords: Autoimmune, paraneoplastic syndrome, systemic sclerosis, thymic carcinoma

How to cite this article:
Chen HW, Li KJ, Kuo HY. Paraneoplastic Systemic Sclerosis in a Patient with Metastatic Thymic Carcinoma. J Cancer Res Pract 2019;6:45-9

How to cite this URL:
Chen HW, Li KJ, Kuo HY. Paraneoplastic Systemic Sclerosis in a Patient with Metastatic Thymic Carcinoma. J Cancer Res Pract [serial online] 2019 [cited 2023 Feb 3];6:45-9. Available from: https://www.ejcrp.org/text.asp?2019/6/1/45/253251

  Introduction Top

Thymoma and thymic carcinomas are thymic epithelial tumors originating in the thymus. Thymomas are relatively rare (1.5 cases/million), and thymic carcinoma, which is classified as a type C thymoma in the WHO classification system, is even rarer. Thymomas often present with locally advanced disease, and it is much less aggressive than thymic carcinoma. Thymic carcinoma is distinct from other thymomas, since thymic carcinoma has more overtly malignant cytologic characteristics (anaplasia, cellular atypia, and mitotic activity) and poor prognosis.[1]

Thymomas are associated with a variety of paraneoplastic syndromes and in particular myasthenia gravis which is found in 30% of thymoma patients.[2],[3],[4],[5] However, the incidence of paraneoplastic autoimmune syndrome is much lower among patients with thymic carcinoma.[6] In one study based on the retrospective database of the International Thymic Malignancy Interest Group, the incidence of paraneoplastic autoimmune syndrome was 5.8% in patients with thymic carcinoma, compared to 38% in patients with thymoma.[2] In another study that included 614 patients with anterior mediastinal tumors in Taiwan, 7.8% of the patients with thymic carcinoma were associated with myasthenia gravis.[7],[8] Other paraneoplastic autoimmune syndromes have rarely been described. Herein, we report a case of metastatic thymic carcinoma who developed a rare paraneoplastic autoimmune syndrome and review the associated literature.

  Case Report Top

A 61-year-old man, who was healthy except for a history of hypertension, presented with dull chest pain and breathing difficulty in November 2014. Chest plain film and computed tomography (CT) revealed a mediastinal tumor measuring 8.4 cm × 6.3 cm × 6.1 cm abutting the ascending aorta and superior vena cava, with involvement of the right upper lobe of the lung. After serial workup, the final diagnosis was thymic carcinoma, with neuroendocrine differentiation, Masaoka Stage III, cT3N0M0.

The initial treatment plan was neoadjuvant chemotherapy followed by surgical resection. He received two courses of neoadjuvant chemotherapy with cisplatin and etoposide; however, the size of the tumor did not change. He then received radiation therapy (50 Grays in 25 fractions over 35 days) to the tumor, and the tumor size decreased. He subsequently received thymectomy with right diaphragm plication through sternotomy in July 2015. The pathology report showed thymic carcinoma with pericardium invasion and positive margins. After surgery, he received adjuvant radiation therapy to the tumor bed and positive margin (36 Grays in 18 fractions over 26 days).

Liver metastasis was detected 3 months after the operation. In addition, pleural and pericardial effusions were also found while the cytology was negative. He received CT-guided radiofrequency ablation with a concomitant biopsy, and the pathology report confirmed liver metastasis of thymic carcinoma. The patient also complained of lower back numbness, and L-S spine magnetic resonance imaging revealed intradural tumors at L5 and L3–L4 levels. He subsequently received laminectomy for L3–L4 tumor resection, followed by radiation therapy to the lumbar spine tumor bed.

To control systemic progression, he was given palliative chemotherapy with cisplatin and weekly 24-h infusions of high-dose 5-fluorouracil and leucovorin. After four courses of cisplatin-based chemotherapy, CT revealed stable disease. He was thus given oral tegafur-uracil as maintenance therapy, and a follow-up CT scan revealed stable disease.

However, he complained of having a puffy face in March 2017 and generalized edema in September 2017. We gave him diuretics and albumin supplements, but the symptoms did not improve. Stiffness of his fingers and face developed in November 2017 [Figure 1] and [Figure 2], and we checked his autoimmune profile for possible autoimmune disorders. The laboratory results disclosed a high antinuclear antibody level [Table 1], and he was referred to a rheumatologist in December 2017. Although further laboratory tests including anti-Scl-70 and anti-CENP were negative, a diagnosis of cancer-associated scleroderma was made according to the clinical picture. Hydroxychloroquine, prednisolone, and colchicine were prescribed, and his condition remained stable.
Figure 1: Typical presentation of systemic sclerosis in our patient including (a and b) Skin thickening of the fingers of both the hands, extending to near the elbow joint. This was sufficient for the diagnosis of systemic sclerosis according to the 2013 ACA/EULAR classification. (c) Sclerodactyly and puffy fingers were also evident

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Figure 2: Nailfold capillaroscopy. Typical findings of nailfold capillaroscopy in systemic sclerosis patients including (a) bizarre capillaries and (b) loss of capillaries, as noted in our patient

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Table 1: Autoimmune profile

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Since malignancy was considered to be the underlying cause of autoimmunity, we resumed chemotherapy with doxorubicin (50 mg/m2), cyclophosphamide (500 mg/m2), and carboplatin (area under the curve = 3). His finger stiffness improved after chemotherapy, and we plan to give him four cycles of chemotherapy followed by oral maintenance therapy.

  Materials and Methods Top

A literature search was conducted in PubMed using the search terms: (((autoimmune[Title/Abstract]) OR paraneoplastic[Title/Abstract])) AND thymic carcinoma[Title/Abstract].

Seventy-three articles were found. We reviewed the title and abstract of every article and also reviewed the context if necessary. Reports that were not written in English were excluded from the study. Sixteen cases were identified that specifically described thymic carcinoma and paraneoplastic autoimmune diseases.[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23]

  Results Top

[Table 2] shows the previously reported cases of thymic carcinoma and paraneoplastic autoimmune disease. The median age of the reported 17 cases was 53 years (range: 11–69 years). Of note, in all but two cases (including our case), autoimmune diseases were either present before the diagnosis of the malignant disease or were diagnosed just before recurrence. Polymyositis was the most frequently reported paraneoplastic autoimmune disease associated with thymic carcinoma. Other diseases included dermatomyositis, systemic lupus erythematosus, thyroiditis, encephalitis, hepatitis, and Morvan's syndrome. There was only one reported case of scleroderma, which was also treated in our facility.[9] Various different pathologies were associated with the autoimmune diseases.
Table 2: Reported cases of thymic carcinoma with paraneoplastic autoimmune disease

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The treatment usually included steroids, and immune modulators such as intravenous immunoglobulin or disease-modifying antirheumatic drugs (azathioprine and hydroxychloroquine) were also used in some cases. In some cases, the paraneoplastic autoimmune disease was successfully treated after curative resection of the primary tumor. In two of the reported cases, systemic therapy, either parenteral chemotherapy or oral metronomic therapy, successfully controlled the autoimmune disease.[9],[22] Effective treatment of the underlying cancer appeared to successfully reverse the autoimmune process.

  Discussion Top

Autoimmune diseases have been widely reported to be related to cancer. A patient with an autoimmune disease may develop malignancy secondary to (1) target tissue damage from the autoimmune disease, (2) cytotoxic therapies used to treat aggressive manifestations, or (3) as a consequence of a defective immune system that predisposes to the development of both cancer and autoimmunity.[24] On the other hand, a patient with cancer may also develop secondary autoimmune disorders. Autoimmune diseases may be a by-product of anticancer immunity, and they can also be induced by anticancer therapy including chemotherapeutic agents and checkpoint inhibitors.[25] Paraneoplastic autoimmunity is often more severe and often presents with a broader range of clinical signs and symptoms.[5]

Systemic sclerosis, also called scleroderma, is an autoimmune disease characterized by fibrosis of the skin, internal organs, and vasculopathy. This uncommon disease is associated with high rates of morbidity and mortality. Currently, the 2013 ACA/EULAR classification is used to make a diagnosis.[26] It can be classified into two major forms: the limited form and diffuse form. Some people have typical clinical features and autoantibodies but no skin involvement, and some have overlap syndromes with other autoimmune diseases. Typical autoantibodies include anti-centromere, anti-topoisomerase I, and anti-RNA polymerase III antibodies. No medication is known to alter the disease course, and the most important focus of therapy is on the treatment of major complications (interstitial lung disease, cardiac disease, pulmonary arterial hypertension, gastrointestinal dysmotility, renal crisis, and skin/musculoskeletal complications).[27],[28]

Patients with scleroderma have an elevated risk of cancer, as indicated in two meta-analysis reports. The association is especially strong in lung, bladder, hematologic, liver, and nonmelanoma skin cancers.[29],[30] Shah and Casciola-Rosen demonstrated that patients with RNA polymerase III autoantibodies have unique nucleolar expressions of RNA polymerase III in their cancerous cells, which are not detected in patients with other scleroderma autoantibodies or in normal control tissues. The authors indicated that autoimmunity may be a by-product of anticancer immunity and further postulated that occult tumors may exist which are eradicated by antitumor immunity. Consequently, they developed an algorithm for cancer screening in patients with systemic sclerosis.[25]

Thymic malignancy is associated with autoimmune diseases; however, the incidence of paraneoplastic autoimmune disease is far higher in thymoma than in thymic carcinoma. Approximately one-third of thymoma patients have been reported to have a paraneoplastic autoimmune syndrome, with the vast majority being myasthenia gravis. In one study, paraneoplastic autoimmune syndromes were associated with a younger age, female sex, thymoma histologic type, earlier stage, and a higher rate of total thymectomy and complete resection status. The relapse-free and overall survival rates are better in patients with paraneoplastic autoimmune syndrome, implying the existence of anticancer immunity.[7]

Several theories have been proposed to explain the link between thymic epithelial malignancy and autoimmunity, including the “escape theory,” the “genetic theory,” and the “autoimmune regulator (AIRE) theory.” The “escape theory” states that in thymic malignancies where the tumor environment is disorganized, immature lymphocytes enter the affected site without passing through the thymic medulla, where self-tolerance is induced, resulting in autoimmunity. The “genetic theory” hypothesizes that genetic changes in neoplastic cells may impair normal T-cell development, thus generating self-reactive lymphocytes. The “AIRE theory” assumes that mutations of the AIRE gene, which encodes the protein that eliminates self-reactive T-cells, impairs the negative selection mechanisms of lymphocytes, and thus allows autoreactive T-cell to enter the target organ and induce autoimmunity.[5] However, these theories have yet to be validated, and further studies are warranted to explore the true mechanism.[2]

The management of paraneoplastic autoimmunity centers on treating the underlying malignancy. After successful chemotherapy or surgical excision of the tumor, subsequent improvements in autoimmunity are frequently noted. If anticancer therapy is difficult, immunosuppression is required to control the autoimmune disease. However, the clinical presentations of paraneoplastic immune-mediated diseases are often severe, and the treatment response is usually poor.[5] Moreover, immunosuppression may impair intrinsic antitumor immunity, causing a treatment dilemma.

With regard to our patient, the first-line treatment, which was given before the presentation of autoimmunity, was cisplatin with weekly infusions of high-dose 5-fluorouracil and leucovorin. This regimen is minimally toxic and has been shown to be beneficial in our facility previously.[9] After the first-line treatment, we gave him metronomic maintenance therapy, which has been shown to be effective against paraneoplastic autoimmune hepatitis.[22] After disease progression and the emergence of the autoimmune disorder, we started chemotherapy with the CAP regimen [doxorubicin (50 mg/m2), cyclophosphamide (500 mg/m2), and carboplatin (area under the curve = 3)], which is commonly used to treat thymic epithelial malignancies. Subjectively, his hand and finger stiffness improved, which may have been secondary to the effect of immunosuppression or anticancer effect of the cytotoxic medication. The disease pace of thymic carcinoma was slow, which may have indicated robust anticancer immunity.

  Conclusion Top

Thymic carcinoma with autoimmunity is rare, and the disease spectrum is broad. Although there is no consensus on optimal treatment options, treating the underlying malignancy is still the first priority. Reports on the most effective immune suppressive medication for paraneoplastic autoimmune disease are also lacking. A multidisciplinary approach may be needed to improve long-term outcomes.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

NCCN clinical practice guidelines in oncology. Thymomas and Thymic Carcinomas. (Version 2.2018). https://www.nccn.org/professionals/physician_gls/pdf/thymic.pdf. [Last accessed on 2018 Jun 20].  Back to cited text no. 1
Padda SK, Yao X, Antonicelli A, Riess JW, Shang Y, Shrager JB, et al. Paraneoplastic syndromes and thymic malignancies: An examination of the international thymic malignancy interest group retrospective database. J Thorac Oncol 2018;13:436-46.  Back to cited text no. 2
Weksler B, Lu B. Alterations of the immune system in thymic malignancies. J Thorac Oncol 2014;9:S137-42.  Back to cited text no. 3
Bernard C, Frih H, Pasquet F, Kerever S, Jamilloux Y, Tronc F, et al. Thymoma associated with autoimmune diseases: 85 cases and literature review. Autoimmun Rev 2016;15:82-92.  Back to cited text no. 4
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Inoue Y, True LD, Martins RG. Thymic carcinoma associated with paraneoplastic polymyositis. J Clin Oncol 2009;27:e33-4.  Back to cited text no. 6
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Liu HC, Hsu WH, Chen YJ, Chan YJ, Wu YC, Huang BS, et al. Primary thymic carcinoma. Ann Thorac Surg 2002;73:1076-81.  Back to cited text no. 8
Hsu CH, Yeh KH, Cheng AL. Thymic carcinoma with autoimmune syndrome: Successful treatment with weekly infusional high-dose 5-fluorouracil and leucovorin. Anticancer Res 1997;17:1331-4.  Back to cited text no. 9
Di Cataldo A, Villari L, Milone P, Miano AE, Sambataro MP, Florio G, et al. Thymic carcinoma, systemic lupus erythematosus, and hypertrophic pulmonary osteoarthropathy in an 11-year-old boy: A novel association. Pediatr Hematol Oncol 2000;17:701-6.  Back to cited text no. 10
Kastrup O, Meyring S, Diener HC. Atypical paraneoplastic brainstem encephalitis associated with anti-Ri-antibodies due to thymic carcinoma with possible clinical response to immunoglobulins. Eur Neurol 2001;45:285-7.  Back to cited text no. 11
Ances BM, Vitaliani R, Taylor RA, Liebeskind DS, Voloschin A, Houghton DJ, et al. Treatment-responsive limbic encephalitis identified by neuropil antibodies: MRI and PET correlates. Brain 2005;128:1764-77.  Back to cited text no. 12
Yoshidome Y, Hayashi S, Maruyama Y, Yoneda T, Matsuzoe D, Kawakami T, et al. Acase of mixed connective tissue disease complicated with thymic carcinoma and Hashimoto's thyroiditis. Mod Rheumatol 2007;17:63-6.  Back to cited text no. 13
Takahashi F, Tsuta K, Nagaoka T, Miyamoto H, Saito Y, Amano H, et al. Successful resection of dermatomyositis associated with thymic carcinoma: Report of a case. Surg Today 2008;38:245-8.  Back to cited text no. 14
Azuma Y, Shiga K, Ishii R, Yamaguchi T, Niwa F, Nakagawa M, et al. Polymyositis with atypical pathological features associated with thymic carcinoma. Intern Med 2009;48:163-8.  Back to cited text no. 15
Koppula BR, Pipavath S, Lewis DH. Epstein-Barr virus (EBV) associated lymphoepithelioma-like thymic carcinoma associated with paraneoplastic syndrome of polymyositis: A rare tumor with rare association. Clin Nucl Med 2009;34:686-8.  Back to cited text no. 16
Chan JC, Trendell-Smith NJ, Yeung CK. Scleromyxedema: A cutaneous paraneoplastic syndrome associated with thymic carcinoma. J Clin Oncol 2012;30:e27-9.  Back to cited text no. 17
Yamaguchi Y, Wada M, Tanji H, Kurokawa K, Kawanami T, Ohtake H, et al. Marked improvement in opsoclonus and cerebellar ataxia after the surgical removal of a squamous cell carcinoma of the thymus: A case report. J Neurol Sci 2013;325:156-9.  Back to cited text no. 18
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Kivrak Salim D, Mutlu H, Karakurt Eryilmaz M, Yalçin Musri F, Tural D, Coşkun HŞ. Metronomic maintenance chemotherapy in patients presenting with paraneoplastic autoimmune hepatitis with recurrent thymic carcinoma. J Oncol Pharm Pract 2016;22:313-5.  Back to cited text no. 22
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Shah AA, Casciola-Rosen L, Rosen A. Review: Cancer-induced autoimmunity in the rheumatic diseases. Arthritis Rheumatol 2015;67:317-26.  Back to cited text no. 24
Shah AA, Casciola-Rosen L. Cancer and scleroderma: A paraneoplastic disease with implications for malignancy screening. Curr Opin Rheumatol 2015;27:563-70.  Back to cited text no. 25
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Bonifazi M, Tramacere I, Pomponio G, Gabrielli B, Avvedimento EV, La Vecchia C, et al. Systemic sclerosis (scleroderma) and cancer risk: systematic review and meta-analysis of observational studies. Rheumatology (Oxford) 2013;52:143-54.  Back to cited text no. 29
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  [Table 1], [Table 2]


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