Paraneoplastic Arthritis in Advanced Ovarian Cancer and its Correlation with CA125 and HE4 Levels: A Case Report

Alessandra Gatti; Francesco Plotti; Roberto Montera; Corrado Terranova; Carlo De Cicco Nardone; Daniela Luvero; Federica Guzzo; Roberto Angioli

Paraneoplastic Arthritis in Advanced Ovarian Cancer and its Correlation with CA125 and HE4 Levels: A Case Report

Alessandra Gatti^*, Francesco Plotti, Roberto Montera, Corrado Terranova, Carlo De Cicco Nardone, Daniela Luvero, Federica Guzzo, Roberto Angioli

Department of Gynecology, University Campus Biomedico, Rome, Italy

*Corresponding author: Alessandra Gatti, Department of Gynecology, University Campus Biomedico, Rome, Italy

Received Date: 08 January, 2021; Accepted Date: 12 January, 2021; Published Date: 19 January, 2021

Citation: Gatti A, Plotti F, Montera R, Terranova C, Nardone CDC, et al. (2021) Paraneoplastic Arthritis in Advanced Ovarian Cancer and its Correlation with CA125 and HE4 Levels: A Case Report. Ann Case Report 6: 608. DOI: 10.29011/2574-7754.100608

Introduction

Ovarian cancer (OC) is the eighth most common cancer in women, with 313.959 new cases and 207.252 new deaths in 2020 worldwide [1]. It is frequently called the “big silent killer”, since most of the cases become symptomatic and are diagnosed in advanced stages, without any screening program being yet available. Sign and symptoms are absolutely general and vague: abdominal pain, early satiety, changes in bowel habits, abdominal pain [2], thus causing a delayed diagnosis. In extremely rare cases, ovarian cancer can only manifests through a paraneoplastic poliarthritis syndrome [3,4]. To date, only about twenty cases have been reported in literature, the first one in 1966 [5]. The median age of onset is 64 years [4].

Generally speaking, a paraneoplastic syndrome is defined as a disease, which can develop prior or concomitantly with a cancer, but is not due to the local presence of tumor cells. Usually it precedes the diagnosis of cancer by no more than two years and is mostly associated with lung and gastric tumors, while it is very rare in gynecological malignancies [6]. Symptoms are heterogeneous and include endocrine, neurological, vascular or dermatological manifestations [6-8] Endocrine manifestations should not, by definition, figure in the ovarian cancer paraneoplastic syndrome, since the ovarian tissue regularly produces hormones [8]. The most possible explanation for the paraneoplastic syndrome is an immunological alteration [9].

Concerning OC, circulating immune complexes have been discovered in patients’ serum [9]. When they deposit in the glomerulus, a nephrotic syndrome can occur [10]. In addition, several antibodies to a number of tissue antigens have been found in the blood of women affected by OC [11]. These antibodies can explain some rare and extremely unusual OC clinical manifestations, such as cerebellar degeneration or osteoarticular disorders. In fact, the antibodies against Purkinje cells, found in a patient with OC, caused a cerebellar degeneration [12,13]. Other antibodies may provoke, in women affected by OC, a polyarthritis syndrome, dermatomyositis and polymyositis [4,14,15].

This article describes a case of severe, disabling arthritis in a 60 years old patient affected by advanced serous OC. For the first time, arthritis is correlated to CA125 and HE4, the most promising biomarkers in OC, to monitor the status of the disease.

Materials and Methods

A 60 years old Caucasian woman presented at Campus Bio Medico University of Rome in March 2016 with strong, acute, hand pain (NRS 10) and stiffness, which made it difficult for her to make a fist or hold an object. The pain, arisen in January 2016, involved both arms and shoulders and was sometimes so intense that her movements were totally restricted. Because of the pain, she could not even rest during the night. She presented a deformation of her hands as well: they were edematous, shiny, stiff, white and discoloured. Metacarpophalangeal 2-5 (MCF 2-5) and proximal interphalangeal 2-5( IFP 2-5) were the most thick and painful joints. In March, her blood exams showed an hemoglobin of 8,2 gr/ dl, leucocytes 6.32 x 10⁹/L, ENA (SSA, SSB, RNP, Scl70), ACA, ANA, FR, Anti-GAD totally negative. Her Body Mass Index was 17. She had no other relevant systemic symptoms. After several investigations, she underwent an abdominal computed tomography scan, which revealed a 10 cm large abdominal mass with some peritoneal and intestine secondaries and ascitis. CA125 was 4532 UI/ml (normally <35 UI/ml), HE4 5430 pmol/L (normally <140 pmol/L). A diagnostic laparoscopy was immediately performed, confirming an advanced, metastatic, serous ovarian cystadenocarcinoma, stage IIIC. Therefore, doctors decided to initiate neoadiuvant chemotherapy with carboplatin and paclitaxel.

Progress The patient referred a clear improvement of her conditions some days after each cycle of chemotherapy, NRS 6, but then the pain and the stiffness worsened again. She tried to control her symptoms with: Fentanil 25 mcg, Duloxetine 30mg, Tetracosactide acetate 1mg, Oxycodone 10 mg and some physiotherapy. At the end of four cycles of chemotherapy, with the medications mentioned above, the pain finally ameliorated and remained stable (NRS 6), and her stiffness slightly improved in the following months. Levels of CA125 and HE4 were dosed after each cycle of chemotherapy, and showed a progressive reduction. CA125 was 4532 UI/ml at the beginning, 3903 UI/ml after the 1^st cycle, 2465 UI/ml after the 2^nd, 1875 UI/ml at the 3^rd, 987 UI/ml at the end. HE4 was 5430 pmol/L at the beginning, 4567 pmol/L after the 1^st cycle, 3980 pmol/L after the 2^nd, 2579 pmol/L at the 3^rd, 1256 pmol/L at the end. CA125 and HE4 demonstrated the tumor response to chemotherapy. Unfortunately the patient died before the already scheduled debulking surgery.

Discussion

Paraneoplastic arthritis is a rare and severe condition, which can be associated to ovarian cancer. It has also been described in a wide set of other malignancies such as leukemia, pancreatic adenocarcinoma, lung carcinoma and Hodgkin’s disease [16]. Etiology is still unclear. Some possible reasons in OC may be an autoimmune phenomenon [17], or the release of fibrosis enhancing factors, hormones or neuronal factors from tumor cells [4,18]. Bremer was the first scientist to describe a case of bilateral shoulder-hand syndrome linked to ovarian carcinoma in 1966 [5]. Medsger reported a case of polyarthritis, preceding the diagnosis of OC by 5 to 25 months, in 1982 [18]. Since then, a few more articles have shown the association between OC and paraneoplastic arthritis, for a total of about 20 cases to date [3-5,8,17-19]. The differential diagnosis includes many diseases such as rheumatoid arthritis, scleroderma and eosinophilic fascitiis [4]. The literature is unanimous in the conclusion that corticosteroid treatment has a minimal impact on the quality of life and is not able to eradicate the problem [18,19]. Literature also shows the poor prognosis of these patients [4,5,18]. Chemotherapy or debulking surgery could decrease pain and lead to a functional restoration of joints, but are never totally healing [3,19]. Hand therapy is not useful [4]. Our case is similar, since the woman demonstrated a satisfactory improvement of pain and stiffness at the end of the four cycles of neoadiuvant chemotherapy, from NRS 10 to NRS 6. Functional movements were restored, but not totally. These improvements remained stable in the following months, until her death in August 2016. Hand physiotherapy was not helpful; she declared a benefit from the painkillers she was taking.

In this article, for the first time in literature, arthritis was correlated to CA125 and HE4 levels to monitor the status of the disease. CA125 and HE4 were dosed at the beginning and after each cycle of chemotherapy. Their values showed a marked reduction, thus confirming the chemotherapy efficacy. Symptoms improved accordingly. Therefore, the paraneoplastic arthritis returned doubly useful. Firstly, the arthritis partial regression revealed the good response to chemotherapy of the underlying malignancy, taken together with the serum biomarkers CA125 and HE4. In addition, it anticipated the diagnosis of OC by 4 months, since it was the only symptom complained by the woman. It will be interesting in the future to collect other cases of paraneoplastic syndromes associated with OC, and make a correlation with the onset of the disease and with its response to treatment. For sure, women presenting the symptoms described above, who have high levels of CA125 and HE4, should be immediately screened for ovarian cancer, to get an early diagnosis and urgent treatment.