Asmussen Andreasen, Rikke

Bang, Jacob Christian

Emamifar, Amir

Jensen Hansen, Inger Marie

Møller, Michael Boe

English

Syddansk Universitets Forskerportal

       University of Southern DenmarkSevere joint pain as a manifestation of paraneoplastic rheumatic syndrome in a patient with amalignant lymphomaa case report and review of the literatureAsmussen Andreasen, Rikke; Emamifar, Amir; Bang, Jacob Christian; Møller, Michael Boe;Jensen Hansen, Inger MariePublished in:Itch & PainDOI:10.14800/ip.759Publication date:2015Document version:Final published versionCitation for pulished version (APA):Asmussen Andreasen, R., Emamifar, A., Bang, J. C., Møller, M. B., & Jensen Hansen, I. M. (2015). Severe jointpain as a manifestation of paraneoplastic rheumatic syndrome in a patient with a malignant lymphoma: a casereport and review of the literature. Itch & Pain, 2(2), Article e759. https://doi.org/10.14800/ip.759Go to publication entry in University of Southern Denmark's Research PortalTerms of useThis work is brought to you by the University of Southern Denmark.Unless otherwise specified it has been shared according to the terms for self-archiving.If no other license is stated, these terms apply:            • You may download this work for personal use only.            • You may not further distribute the material or use it for any profit-making activity or commercial gain            • You may freely distribute the URL identifying this open access versionIf you believe that this document breaches copyright please contact us providing details and we will investigate your claim.Please direct all enquiries to puresupport@bib.sdu.dkDownload date: 25. Oct. 2025Itch & Pain 2015; 2: e759. doi: 10.14800/ip.759; © 2015 by Rikke Asmussen Andreasen, et al. http://www.smartscitech.com/index.php/ip  Page 1 of 4     Severe joint pain as a manifestation of paraneoplastic rheumatic syndrome in a patient with a malignant lymphoma: A case report and review of the literature  Rikke Asmussen Andreasen1, Amir Emamifar1, Jacob Christian Bang2, Michael Boe Møller3, Inger Marie Jensen Hansen1  1Department of Rheumatology, Svendborg Hospital, Odense University Hospital, Valdemarsgade 53, DK-5700, Svendborg, Denmark 2Department of Radiology, Svendborg Hospital, Odense University Hospital, Valdemarsgade 53, DK-5700, Svendborg, Denmark 3Department of Pathology, Odense University Hospital Odense, J.B. Winsløwsvej 15, DK-5000, Odense, Denmark  Correspondence: Rikke Asmussen Andreasen E-mail: Rikke.asmussen@rsyd.dk Received: March 28, 2015 Published online: April 13, 2015   Keywords: Rheumatic Disease (RD); Paraneoplastic Syndrome (PNS); B-cell Lymphoma To cite this article: Rikke Asmussen Andreasen, et al. Severe joint pain as a manifestation of paraneoplastic rheumatic syndrome in a patient with a malignant lymphoma: A case report and review of the literature. Itch Pain 2015; 2: e759. doi: 10.14800/ip.759.  Background Rheumatic diseases (RD) and malignancies may be connected to each other in different ways. It has previously been shown, that RD can be a primary manifestation of an underlying cancer as a paraneoplastic syndrome (PNS). RD are related with increased incidence of different malignancies due to the characteristic of the disease or as a result of drug therapy, for instance immunosuppressive agents and tumor necrosis factor inhibitors [1]. Paraneoplastic rheumatic syndromes (PRS) are rheumatologic diseases that are triggered by a malignant disease. Symptoms of PRS can not be explained by the anatomical location of the tumor or metastases, and they often remit following treatment of the underlying disease [2]. The pathogenesis of PRS is complex and not fully understood. Recent research has shown that certain tumors produce hormones, peptides or cytokines that can interact with the immune system and results in various clinical manifestations of the musculoskeletal system [3]. The PNS may be the patient's primary complaint and occurs up to two years before the underlying cancer is diagnosed. Non-Hodgkin's lymphoma is often associated with rheumatic disease [1, 4].  As a result of improvement in diagnostic and therapeutic technique the number of patients with cancer and probably the incidence of PRS will increase, which can affect the clinical course and management of the disease. Management of PRS consists of treatment of underlying malignancy and standard therapy of rheumatic syndrome [2]. The purpose of this case report is to emphasize the challenging elements in the differential diagnosis within rheumatology, and to describe a newly defined group of very aggressive lymphomas, so-called double-hit lymphoma (DHL), which are characterized by cytogenetic translocation of both MYC and BCL2. We report a case history of a 63-year-old woman with hip pain as a PRS. Case report A 63-year-old woman referred to the rheumatology outpatient clinic with a history of a persistent four weeks CASE REPORT Itch & Pain 2015; 2: e759. doi: 10.14800/ip.759; © 2015 by Rikke Asmussen Andreasen, et al. http://www.smartscitech.com/index.php/ip  Page 2 of 4  right-sided hip pain. The pain was constant and severe. X-ray of the hip and pelvis were normal. Objectively, there was no sign of arthritis, except pain-related limitation of motion. Laboratory work-up showed leukocytes: 10.4 x 109 / l, platelets: 110 × 109 / l, Hb: 5.6 mmol/l, C-reactive protein: 47 mg/l (normal range: <10 mg / l), ionized calcium: 1.22 mmol/l (normal range: 1.19-1.29mmol/l), Lactate dehydrogenase (LDH): 958 U/l (normal range: 105-205) and erythrocyte sedimentation rate: 17. Immunological test values including Immunoglobulin (Ig) M, IgG and IgA were within normal limits.  Four days later she was admitted to the local hospital with a preliminary diagnosis of cholecystitis. Ultrasound of abdomen identified supracapsular process on the right kidney upper pole. CT urography demonstrated 3 pathologically enlarged lymph nodes located centrally in the retroperitoneum. A biopsy of a subcutaneous nodule was performed. Pathology results revealed aggressive medium-sized B-cell lymphoma between diffuse large B-cell lymphoma and Burkitt lymphoma (Figure 1) with high mitotic activity (starry-sky appearance). Immunohistochemical staining of tumor cells were positive for CD20, CD10, PAX5, FOX P1, MUM1, lambda, MYC, BCL2 and Ki 67 (with 100% proliferation rate) and negative for CD21, BCL6, GCET1, TdT, EBER, CD3, CD5 and kappa. Flowcytometry analysis showed 59.4% B-cells with expression of CD20, CD22, CD79b, CD24, CD19 and lambda. In addition, these cells were weakly positive for CD10. FISH technique detected translocation of MYC, BCL2, IGH and no translocation of the BCL6 gene. These findings  Table 1. Ann Arbor staging Stage I Indicates that the cancer is located in a single region, usually one lymph node and the surrounding area. Stage I often will not have outward symptoms. Stage II Indicates that the cancer is located in two separate regions, an affected lymph node or organ and a second affected area, and that both affected areas are confined to one side of the diaphragm - that is, both are above the diaphragm, or both are below the diaphragm. Stage III Indicates that the cancer has spread to both sides of the diaphragm, including one organ or area near the lymph nodes or the spleen. Stage IV Indicates diffuse or disseminated involvement of one or more extralymphatic organs, including any involvement of the liver, bone marrow, or nodular involvement of the lungs. A or B The absence of constitutional (B-type) symptoms is denoted by adding an "A" to the stage; the presence is denoted by adding a "B" to the stage. S Is used if the disease has spread to the spleen. E Is used if the disease is "extranodal" (not in the lymph nodes) or has spread from lymph nodes to adjacent tissue. X Is used if the largest deposit is >10 cm large ("bulky disease"), or whether the mediastinum is wider than 1/3 of the chest on a chest X-ray.  are diagnostic of underlying double-hit lymphoma (DHL). Staging investigations showed widespread disease with involvement of several lymph node regions, bone marrow, subcutaneous tissue and myocardium equal to Ann Arbor staging 4B [5]. (Table 1) .Intensive courses of chemotherapy with high doses of Methotrexate, Rituximab, Cyclophosphamide, Doxorubicin, Vincristine were started with supplemented high dose Prednisolone, and a month later hip pain disappeared. Patient achieved complete remission after chemotherapy, but the disease relapsed shortly after in central nervous system (Figure 2). The patient died after a total of 11 months disease. Discussion PNS is relatively rare and occurs in up to 8% of all cancer patients [2]. It is known that some rheumatological diseases are associated with increased incidence of cancer. In the literature there are underlying malignancies in 10-25% of cases with dermato-/polymyositis, and up to 90% in hypertrophic osteoarthropathy (HOA). Therefore clinicians have to pay special attention to the symptoms of the above-mentioned diseases. HOA is divided into primary/hereditary and secondary forms. The secondary form is commonly related with lung cancer, bone metastasis, nasopharyngeal carcinoma and rhabdomyosarcoma. Diagnosis of hypertrophic osteoarthropathy can be made by physical examination and radiographic evaluation. Subsequent treatment of the underlying cancer improves the condition. [1, 2]. There is an association between ovarian, lung, breast, gastrointestinal system, non-Hodgkin lymphomas, prostate  Figure 1. Subcutaneous biopsy shows diffuse infiltration of the medium-sized lymphoid cells with a high mitotic activity (A). The tumor cells expressing CD20 (B), myc (C) and BCL2 (D) [12]  Itch & Pain 2015; 2: e759. doi: 10.14800/ip.759; © 2015 by Rikke Asmussen Andreasen, et al. http://www.smartscitech.com/index.php/ip  Page 3 of 4  Table 2. Different paraneoplastic rheumatic syndromes and their association with underlying cancer Hypertrophy osteoarthropathy Lung cancer, metastasis to bone, nasopharyngeal carcinoma, rhabdomyosarcoma  Dermato-/polymyositis Ovarian, lung, breast, gastrointestinal system, non-Hodgkin lymphomas, prostate and nasopharynx (Asian population) Vasculitis Lymphoproliferative and myeloproliferative disorders Carcinomatous polyarthritis Breast, colon, lung and ovarian lymphoproliferative disorders. Palmar fasciitis Ovarian (most common), stomach, pancreas, lung and colon Reflex-sympathetic dystrophy syndrome (chronic regional pain syndrome type II) Pancoast tumor of the lung, malignancies that infiltrates the stellate ganglion or brachial plexus Erythromelalgia Myeloproliferative disorders especially Polycythemia Vera and essential trombocytosis Polymyalgia Rheumatica (PMR) Kidney, lung, colon cancer and multiple myeloma Amyloidosis Multiple myeloma, lymphomas and carcinomas Digital necrosis - Raynaud’s syndrome Solid tumors (most frequent stomach, lung, ovarian) and lymphoproliferative disorders. Remitting seronegative symmetric synovitis with pitting edema (RS3PE) Lymphoma, myelodysplastic syndrome, adenocarcinoma Multicentric reticulohistiocytosis Carcinoma of the lung, stomach, breast, cervix, colon and ovary Panniculitis Hematologic malignancies or pancreatic cancer. Lupus-like syndromes Ovarian carcinoma, hairy-cell leukemia and breast carcinoma Scleroderma-like syndrome Adenocarcinoma and carcinoid tumor Sjögren’s syndrome Lymphoproliferative disorders(non-Hodgkin’s lymphoma), lymphoma of mucosal-associated lymphoid tissue (MALT), Waldenström’s macroglobulinemia, chronic lymphocytic leukemia and multiple myeloma Rheumatoid arthritis (RA) Lymphoproliferative disorders, lung cancer Systemic lupus erythematosus (SLE) Lymphoproliferative disorders, gynecologic malignancies Systemic sclerosis Lung, breast, esophagus and skin Paget’s disease of bone Osteosarcoma (under 1%)  and nasopharynx (Asian population) malignancies and dermato-/polymyositis [1, 6]. Ovarian cancer is the most common cancer in patients diagnosed with paraneoplastic dermatomyositis [7]. The highest risk for malignancy is within the first year of disease and it decreases gradually, but the risk still remains high compared to the general population. Thorough physical examination and laboratory test can lead to a diagnosis; although definite diagnosis is based on skin or muscle biopsy. Further imaging studies such as ultrasound, mammography and PET/CT Scan are helpful to determine the underlying cancer in specific cases. Paraneoplastic dermatomyositis responds poorly to corticosteroid treatment. Treatment of the primary cancer is a mainstay and can cause symptom regression [1, 6, 7].  Vasculitis can occur as PRS especially in association with haematological cancers, but the prevalence is not exactly known (approximately 3-8%) [8]. Leukocytoclastic vasculitis is the most frequent finding in histopathological exam, which is responsible for 30-40% of all paraneoplastic vasculitis cases [8]. The etiology of paraneoplastic vasculitis is not clear. Paraneoplastic vasculitis responds poorly to conventional treatment. Other paraneoplastic rheumatic syndromes such as Raynaud's phenomenon, erythema nodosum and non-specific symptom as arthralgia, are reported less frequently in a few case reports. (Table 2) [1-4, 8]. In recent years DHL has been identified as a group of extremely aggressive B-lymphomas with often poor treatment response and consequently short survival. Patients almost always present with advanced disease with involvement of extranodal sites. Poor prognostic factor associated with double hit lymphoma include increased LDH level, involvement of central nervous system/ bone marrow and a high international prognostic index score which primarily present in most of the cases. This case report illustrates a fulminant clinical course, which is characteristic of this type of lymphoma [9-10] . Figure 2. T1-weighted coronal sequence after Gd-contrast shows a 17x12x12 mm contrast enhancing tumor in the right temporal lobe.   Itch & Pain 2015; 2: e759. doi: 10.14800/ip.759; © 2015 by Rikke Asmussen Andreasen, et al. http://www.smartscitech.com/index.php/ip  Page 4 of 4  In rheumatologic studies it may be difficult for the clinicians to differentiate between underlying malignancy and primary rheumatologic disease, because the clinical manifestations are identical. But attention should be given when there are sudden occurrence of symptoms, unusual joint involvement, atypical age at disease onset and lack of response to therapy [4, 11]. There is no consensus on when a patient with rheumatological symptoms should be screened for possible underlying cancer. It is not economically justifiable to start performing a comprehensive examination for occult cancer, where it could be PRS in every case, but it should be part of the differential diagnosis in patients showing an atypical course, since early diagnosis of PRS will increase the patient's quality of life and chance of survival. References 1. Bojinca V, Janta I. Rheumatic Diseases and Malignancies. Maedica. 2012; 7:364-371. 2. Pelosof LC, Gerber DE. Paraneoplastic Syndromes: An Approach to Diagnosis and Treatment. Mayo Clin. Proc. 2010; 85:838-854. 3. Fam AG. Paraneoplastic rheumatic syndromes. Ballieres Best Pract Res Clin Reumatol 2000; 14:515-533. 4. Nascitz JE, Rosner I,Rozenbaum M, Elias N, Yeshurun D. Cancer-Associated Rheumatic Disorders: Clue to OccultNeoplasia. Semin Arthritis Rheum 1995; 24: 231-241. 5. Armitage JO. Staging Non-Hodgkin Lymphoma. CA Cancer J Clin 2005; 55: 368-376. 6. Requena C, Alfaro A, Traves V, Nagore E, Llombart B, Serra C, et al. Paraneoplastic dermatomyositis: a study of 12 cases. Actas Dermosifiliogr. 2014; 105:675-682. 7. Wada C, Hua CN, Carney ME. Paraneoplastic Syndrome in Hawai‘i: A Case of Dermatomyositis Associated with Endometrial Cancer. Hawaii J Med Public Health 2014; 73:112-114. 8. Wong M, Grossman J, Hahn BH, La Cava A. Cutaneous vasculitis in breast cancer treated with chemotherapy. Clin Immunol 2008; 129:3-9. 9. Green TM, Young KH, Visco C, Xu-Monette ZY, Orazi A, Go RS, et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone, J Clin Oncol 2012; 30:3460-3467. 10. Kapur S, Levin MB. Transformation of Follicular Lymphoma to Double Hit B-Cell Lymphoma Causing Hypercalcemia in 69-Year-Old Female: A Case Report and Review of the Literature. Case Rep Hematol 2014; 2014:619760. 11. Racanelli V, Prete M, Minoia C, Favoino E, Perosa F. Rheumatic disorders as paraneoplastic syndromes. Autoimmun Rev. 2008; 7: 352-358. 12. Asmussen R, Møller MB, Hansen IMJ. Hip pain as a paraneoplastic rheumatic syndrome in a patient with double-hit lymphoma. Ugeskr Laeger 2014; 15; 176(25A). 

Severe joint pain as a manifestation of paraneoplastic rheumatic syndrome in a patient with a malignant lymphoma:a case report and review of the literature

       University of Southern DenmarkSevere joint pain as a manifestation of paraneoplastic rheumatic syndrome in a patient with amalignant lymphomaa case report and review of the literatureAsmussen Andreasen, Rikke; Emamifar, Amir; Bang, Jacob Christian; Møller, Michael Boe;Jensen Hansen, Inger MariePublished in:Itch & PainDOI:10.14800/ip.759Publication date:2015Document version:Final published versionCitation for pulished version (APA):Asmussen Andreasen, R., Emamifar, A., Bang, J. C., Møller, M. B., & Jensen Hansen, I. M. (2015). Severe jointpain as a manifestation of paraneoplastic rheumatic syndrome in a patient with a malignant lymphoma: a casereport and review of the literature. Itch & Pain, 2(2), Article e759. https://doi.org/10.14800/ip.759Go to publication entry in University of Southern Denmark's Research PortalTerms of useThis work is brought to you by the University of Southern Denmark.Unless otherwise specified it has been shared according to the terms for self-archiving.If no other license is stated, these terms apply:            • You may download this work for personal use only.            • You may not further distribute the material or use it for any profit-making activity or commercial gain            • You may freely distribute the URL identifying this open access versionIf you believe that this document breaches copyright please contact us providing details and we will investigate your claim.Please direct all enquiries to puresupport@bib.sdu.dkDownload date: 22. Oct. 2025Itch & Pain 2015; 2: e759. doi: 10.14800/ip.759; © 2015 by Rikke Asmussen Andreasen, et al. http://www.smartscitech.com/index.php/ip  Page 1 of 4     Severe joint pain as a manifestation of paraneoplastic rheumatic syndrome in a patient with a malignant lymphoma: A case report and review of the literature  Rikke Asmussen Andreasen1, Amir Emamifar1, Jacob Christian Bang2, Michael Boe Møller3, Inger Marie Jensen Hansen1  1Department of Rheumatology, Svendborg Hospital, Odense University Hospital, Valdemarsgade 53, DK-5700, Svendborg, Denmark 2Department of Radiology, Svendborg Hospital, Odense University Hospital, Valdemarsgade 53, DK-5700, Svendborg, Denmark 3Department of Pathology, Odense University Hospital Odense, J.B. Winsløwsvej 15, DK-5000, Odense, Denmark  Correspondence: Rikke Asmussen Andreasen E-mail: Rikke.asmussen@rsyd.dk Received: March 28, 2015 Published online: April 13, 2015   Keywords: Rheumatic Disease (RD); Paraneoplastic Syndrome (PNS); B-cell Lymphoma To cite this article: Rikke Asmussen Andreasen, et al. Severe joint pain as a manifestation of paraneoplastic rheumatic syndrome in a patient with a malignant lymphoma: A case report and review of the literature. Itch Pain 2015; 2: e759. doi: 10.14800/ip.759.  Background Rheumatic diseases (RD) and malignancies may be connected to each other in different ways. It has previously been shown, that RD can be a primary manifestation of an underlying cancer as a paraneoplastic syndrome (PNS). RD are related with increased incidence of different malignancies due to the characteristic of the disease or as a result of drug therapy, for instance immunosuppressive agents and tumor necrosis factor inhibitors [1]. Paraneoplastic rheumatic syndromes (PRS) are rheumatologic diseases that are triggered by a malignant disease. Symptoms of PRS can not be explained by the anatomical location of the tumor or metastases, and they often remit following treatment of the underlying disease [2]. The pathogenesis of PRS is complex and not fully understood. Recent research has shown that certain tumors produce hormones, peptides or cytokines that can interact with the immune system and results in various clinical manifestations of the musculoskeletal system [3]. The PNS may be the patient's primary complaint and occurs up to two years before the underlying cancer is diagnosed. Non-Hodgkin's lymphoma is often associated with rheumatic disease [1, 4].  As a result of improvement in diagnostic and therapeutic technique the number of patients with cancer and probably the incidence of PRS will increase, which can affect the clinical course and management of the disease. Management of PRS consists of treatment of underlying malignancy and standard therapy of rheumatic syndrome [2]. The purpose of this case report is to emphasize the challenging elements in the differential diagnosis within rheumatology, and to describe a newly defined group of very aggressive lymphomas, so-called double-hit lymphoma (DHL), which are characterized by cytogenetic translocation of both MYC and BCL2. We report a case history of a 63-year-old woman with hip pain as a PRS. Case report A 63-year-old woman referred to the rheumatology outpatient clinic with a history of a persistent four weeks CASE REPORT Itch & Pain 2015; 2: e759. doi: 10.14800/ip.759; © 2015 by Rikke Asmussen Andreasen, et al. http://www.smartscitech.com/index.php/ip  Page 2 of 4  right-sided hip pain. The pain was constant and severe. X-ray of the hip and pelvis were normal. Objectively, there was no sign of arthritis, except pain-related limitation of motion. Laboratory work-up showed leukocytes: 10.4 x 109 / l, platelets: 110 × 109 / l, Hb: 5.6 mmol/l, C-reactive protein: 47 mg/l (normal range: <10 mg / l), ionized calcium: 1.22 mmol/l (normal range: 1.19-1.29mmol/l), Lactate dehydrogenase (LDH): 958 U/l (normal range: 105-205) and erythrocyte sedimentation rate: 17. Immunological test values including Immunoglobulin (Ig) M, IgG and IgA were within normal limits.  Four days later she was admitted to the local hospital with a preliminary diagnosis of cholecystitis. Ultrasound of abdomen identified supracapsular process on the right kidney upper pole. CT urography demonstrated 3 pathologically enlarged lymph nodes located centrally in the retroperitoneum. A biopsy of a subcutaneous nodule was performed. Pathology results revealed aggressive medium-sized B-cell lymphoma between diffuse large B-cell lymphoma and Burkitt lymphoma (Figure 1) with high mitotic activity (starry-sky appearance). Immunohistochemical staining of tumor cells were positive for CD20, CD10, PAX5, FOX P1, MUM1, lambda, MYC, BCL2 and Ki 67 (with 100% proliferation rate) and negative for CD21, BCL6, GCET1, TdT, EBER, CD3, CD5 and kappa. Flowcytometry analysis showed 59.4% B-cells with expression of CD20, CD22, CD79b, CD24, CD19 and lambda. In addition, these cells were weakly positive for CD10. FISH technique detected translocation of MYC, BCL2, IGH and no translocation of the BCL6 gene. These findings  Table 1. Ann Arbor staging Stage I Indicates that the cancer is located in a single region, usually one lymph node and the surrounding area. Stage I often will not have outward symptoms. Stage II Indicates that the cancer is located in two separate regions, an affected lymph node or organ and a second affected area, and that both affected areas are confined to one side of the diaphragm - that is, both are above the diaphragm, or both are below the diaphragm. Stage III Indicates that the cancer has spread to both sides of the diaphragm, including one organ or area near the lymph nodes or the spleen. Stage IV Indicates diffuse or disseminated involvement of one or more extralymphatic organs, including any involvement of the liver, bone marrow, or nodular involvement of the lungs. A or B The absence of constitutional (B-type) symptoms is denoted by adding an "A" to the stage; the presence is denoted by adding a "B" to the stage. S Is used if the disease has spread to the spleen. E Is used if the disease is "extranodal" (not in the lymph nodes) or has spread from lymph nodes to adjacent tissue. X Is used if the largest deposit is >10 cm large ("bulky disease"), or whether the mediastinum is wider than 1/3 of the chest on a chest X-ray.  are diagnostic of underlying double-hit lymphoma (DHL). Staging investigations showed widespread disease with involvement of several lymph node regions, bone marrow, subcutaneous tissue and myocardium equal to Ann Arbor staging 4B [5]. (Table 1) .Intensive courses of chemotherapy with high doses of Methotrexate, Rituximab, Cyclophosphamide, Doxorubicin, Vincristine were started with supplemented high dose Prednisolone, and a month later hip pain disappeared. Patient achieved complete remission after chemotherapy, but the disease relapsed shortly after in central nervous system (Figure 2). The patient died after a total of 11 months disease. Discussion PNS is relatively rare and occurs in up to 8% of all cancer patients [2]. It is known that some rheumatological diseases are associated with increased incidence of cancer. In the literature there are underlying malignancies in 10-25% of cases with dermato-/polymyositis, and up to 90% in hypertrophic osteoarthropathy (HOA). Therefore clinicians have to pay special attention to the symptoms of the above-mentioned diseases. HOA is divided into primary/hereditary and secondary forms. The secondary form is commonly related with lung cancer, bone metastasis, nasopharyngeal carcinoma and rhabdomyosarcoma. Diagnosis of hypertrophic osteoarthropathy can be made by physical examination and radiographic evaluation. Subsequent treatment of the underlying cancer improves the condition. [1, 2]. There is an association between ovarian, lung, breast, gastrointestinal system, non-Hodgkin lymphomas, prostate  Figure 1. Subcutaneous biopsy shows diffuse infiltration of the medium-sized lymphoid cells with a high mitotic activity (A). The tumor cells expressing CD20 (B), myc (C) and BCL2 (D) [12]  Itch & Pain 2015; 2: e759. doi: 10.14800/ip.759; © 2015 by Rikke Asmussen Andreasen, et al. http://www.smartscitech.com/index.php/ip  Page 3 of 4  Table 2. Different paraneoplastic rheumatic syndromes and their association with underlying cancer Hypertrophy osteoarthropathy Lung cancer, metastasis to bone, nasopharyngeal carcinoma, rhabdomyosarcoma  Dermato-/polymyositis Ovarian, lung, breast, gastrointestinal system, non-Hodgkin lymphomas, prostate and nasopharynx (Asian population) Vasculitis Lymphoproliferative and myeloproliferative disorders Carcinomatous polyarthritis Breast, colon, lung and ovarian lymphoproliferative disorders. Palmar fasciitis Ovarian (most common), stomach, pancreas, lung and colon Reflex-sympathetic dystrophy syndrome (chronic regional pain syndrome type II) Pancoast tumor of the lung, malignancies that infiltrates the stellate ganglion or brachial plexus Erythromelalgia Myeloproliferative disorders especially Polycythemia Vera and essential trombocytosis Polymyalgia Rheumatica (PMR) Kidney, lung, colon cancer and multiple myeloma Amyloidosis Multiple myeloma, lymphomas and carcinomas Digital necrosis - Raynaud’s syndrome Solid tumors (most frequent stomach, lung, ovarian) and lymphoproliferative disorders. Remitting seronegative symmetric synovitis with pitting edema (RS3PE) Lymphoma, myelodysplastic syndrome, adenocarcinoma Multicentric reticulohistiocytosis Carcinoma of the lung, stomach, breast, cervix, colon and ovary Panniculitis Hematologic malignancies or pancreatic cancer. Lupus-like syndromes Ovarian carcinoma, hairy-cell leukemia and breast carcinoma Scleroderma-like syndrome Adenocarcinoma and carcinoid tumor Sjögren’s syndrome Lymphoproliferative disorders(non-Hodgkin’s lymphoma), lymphoma of mucosal-associated lymphoid tissue (MALT), Waldenström’s macroglobulinemia, chronic lymphocytic leukemia and multiple myeloma Rheumatoid arthritis (RA) Lymphoproliferative disorders, lung cancer Systemic lupus erythematosus (SLE) Lymphoproliferative disorders, gynecologic malignancies Systemic sclerosis Lung, breast, esophagus and skin Paget’s disease of bone Osteosarcoma (under 1%)  and nasopharynx (Asian population) malignancies and dermato-/polymyositis [1, 6]. Ovarian cancer is the most common cancer in patients diagnosed with paraneoplastic dermatomyositis [7]. The highest risk for malignancy is within the first year of disease and it decreases gradually, but the risk still remains high compared to the general population. Thorough physical examination and laboratory test can lead to a diagnosis; although definite diagnosis is based on skin or muscle biopsy. Further imaging studies such as ultrasound, mammography and PET/CT Scan are helpful to determine the underlying cancer in specific cases. Paraneoplastic dermatomyositis responds poorly to corticosteroid treatment. Treatment of the primary cancer is a mainstay and can cause symptom regression [1, 6, 7].  Vasculitis can occur as PRS especially in association with haematological cancers, but the prevalence is not exactly known (approximately 3-8%) [8]. Leukocytoclastic vasculitis is the most frequent finding in histopathological exam, which is responsible for 30-40% of all paraneoplastic vasculitis cases [8]. The etiology of paraneoplastic vasculitis is not clear. Paraneoplastic vasculitis responds poorly to conventional treatment. Other paraneoplastic rheumatic syndromes such as Raynaud's phenomenon, erythema nodosum and non-specific symptom as arthralgia, are reported less frequently in a few case reports. (Table 2) [1-4, 8]. In recent years DHL has been identified as a group of extremely aggressive B-lymphomas with often poor treatment response and consequently short survival. Patients almost always present with advanced disease with involvement of extranodal sites. Poor prognostic factor associated with double hit lymphoma include increased LDH level, involvement of central nervous system/ bone marrow and a high international prognostic index score which primarily present in most of the cases. This case report illustrates a fulminant clinical course, which is characteristic of this type of lymphoma [9-10] . Figure 2. T1-weighted coronal sequence after Gd-contrast shows a 17x12x12 mm contrast enhancing tumor in the right temporal lobe.   Itch & Pain 2015; 2: e759. doi: 10.14800/ip.759; © 2015 by Rikke Asmussen Andreasen, et al. http://www.smartscitech.com/index.php/ip  Page 4 of 4  In rheumatologic studies it may be difficult for the clinicians to differentiate between underlying malignancy and primary rheumatologic disease, because the clinical manifestations are identical. But attention should be given when there are sudden occurrence of symptoms, unusual joint involvement, atypical age at disease onset and lack of response to therapy [4, 11]. There is no consensus on when a patient with rheumatological symptoms should be screened for possible underlying cancer. It is not economically justifiable to start performing a comprehensive examination for occult cancer, where it could be PRS in every case, but it should be part of the differential diagnosis in patients showing an atypical course, since early diagnosis of PRS will increase the patient's quality of life and chance of survival. References 1. Bojinca V, Janta I. Rheumatic Diseases and Malignancies. Maedica. 2012; 7:364-371. 2. Pelosof LC, Gerber DE. Paraneoplastic Syndromes: An Approach to Diagnosis and Treatment. Mayo Clin. Proc. 2010; 85:838-854. 3. Fam AG. Paraneoplastic rheumatic syndromes. Ballieres Best Pract Res Clin Reumatol 2000; 14:515-533. 4. Nascitz JE, Rosner I,Rozenbaum M, Elias N, Yeshurun D. Cancer-Associated Rheumatic Disorders: Clue to OccultNeoplasia. Semin Arthritis Rheum 1995; 24: 231-241. 5. Armitage JO. Staging Non-Hodgkin Lymphoma. CA Cancer J Clin 2005; 55: 368-376. 6. Requena C, Alfaro A, Traves V, Nagore E, Llombart B, Serra C, et al. Paraneoplastic dermatomyositis: a study of 12 cases. Actas Dermosifiliogr. 2014; 105:675-682. 7. Wada C, Hua CN, Carney ME. Paraneoplastic Syndrome in Hawai‘i: A Case of Dermatomyositis Associated with Endometrial Cancer. Hawaii J Med Public Health 2014; 73:112-114. 8. Wong M, Grossman J, Hahn BH, La Cava A. Cutaneous vasculitis in breast cancer treated with chemotherapy. Clin Immunol 2008; 129:3-9. 9. Green TM, Young KH, Visco C, Xu-Monette ZY, Orazi A, Go RS, et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone, J Clin Oncol 2012; 30:3460-3467. 10. Kapur S, Levin MB. Transformation of Follicular Lymphoma to Double Hit B-Cell Lymphoma Causing Hypercalcemia in 69-Year-Old Female: A Case Report and Review of the Literature. Case Rep Hematol 2014; 2014:619760. 11. Racanelli V, Prete M, Minoia C, Favoino E, Perosa F. Rheumatic disorders as paraneoplastic syndromes. Autoimmun Rev. 2008; 7: 352-358. 12. Asmussen R, Møller MB, Hansen IMJ. Hip pain as a paraneoplastic rheumatic syndrome in a patient with double-hit lymphoma. Ugeskr Laeger 2014; 15; 176(25A). 

       University of Southern DenmarkSevere joint pain as a manifestation of paraneoplastic rheumatic syndrome in a patient with amalignant lymphomaa case report and review of the literatureAsmussen Andreasen, Rikke; Emamifar, Amir; Bang, Jacob Christian; Møller, Michael Boe;Jensen Hansen, Inger MariePublished in:Itch & PainDOI:10.14800/ip.759Publication date:2015Document version:Final published versionCitation for pulished version (APA):Asmussen Andreasen, R., Emamifar, A., Bang, J. C., Møller, M. B., & Jensen Hansen, I. M. (2015). Severe jointpain as a manifestation of paraneoplastic rheumatic syndrome in a patient with a malignant lymphoma: a casereport and review of the literature. Itch & Pain, 2(2), Article e759. https://doi.org/10.14800/ip.759Go to publication entry in University of Southern Denmark's Research PortalTerms of useThis work is brought to you by the University of Southern Denmark.Unless otherwise specified it has been shared according to the terms for self-archiving.If no other license is stated, these terms apply:            • You may download this work for personal use only.            • You may not further distribute the material or use it for any profit-making activity or commercial gain            • You may freely distribute the URL identifying this open access versionIf you believe that this document breaches copyright please contact us providing details and we will investigate your claim.Please direct all enquiries to puresupport@bib.sdu.dkDownload date: 20. Oct. 2025Itch & Pain 2015; 2: e759. doi: 10.14800/ip.759; © 2015 by Rikke Asmussen Andreasen, et al. http://www.smartscitech.com/index.php/ip  Page 1 of 4     Severe joint pain as a manifestation of paraneoplastic rheumatic syndrome in a patient with a malignant lymphoma: A case report and review of the literature  Rikke Asmussen Andreasen1, Amir Emamifar1, Jacob Christian Bang2, Michael Boe Møller3, Inger Marie Jensen Hansen1  1Department of Rheumatology, Svendborg Hospital, Odense University Hospital, Valdemarsgade 53, DK-5700, Svendborg, Denmark 2Department of Radiology, Svendborg Hospital, Odense University Hospital, Valdemarsgade 53, DK-5700, Svendborg, Denmark 3Department of Pathology, Odense University Hospital Odense, J.B. Winsløwsvej 15, DK-5000, Odense, Denmark  Correspondence: Rikke Asmussen Andreasen E-mail: Rikke.asmussen@rsyd.dk Received: March 28, 2015 Published online: April 13, 2015   Keywords: Rheumatic Disease (RD); Paraneoplastic Syndrome (PNS); B-cell Lymphoma To cite this article: Rikke Asmussen Andreasen, et al. Severe joint pain as a manifestation of paraneoplastic rheumatic syndrome in a patient with a malignant lymphoma: A case report and review of the literature. Itch Pain 2015; 2: e759. doi: 10.14800/ip.759.  Background Rheumatic diseases (RD) and malignancies may be connected to each other in different ways. It has previously been shown, that RD can be a primary manifestation of an underlying cancer as a paraneoplastic syndrome (PNS). RD are related with increased incidence of different malignancies due to the characteristic of the disease or as a result of drug therapy, for instance immunosuppressive agents and tumor necrosis factor inhibitors [1]. Paraneoplastic rheumatic syndromes (PRS) are rheumatologic diseases that are triggered by a malignant disease. Symptoms of PRS can not be explained by the anatomical location of the tumor or metastases, and they often remit following treatment of the underlying disease [2]. The pathogenesis of PRS is complex and not fully understood. Recent research has shown that certain tumors produce hormones, peptides or cytokines that can interact with the immune system and results in various clinical manifestations of the musculoskeletal system [3]. The PNS may be the patient's primary complaint and occurs up to two years before the underlying cancer is diagnosed. Non-Hodgkin's lymphoma is often associated with rheumatic disease [1, 4].  As a result of improvement in diagnostic and therapeutic technique the number of patients with cancer and probably the incidence of PRS will increase, which can affect the clinical course and management of the disease. Management of PRS consists of treatment of underlying malignancy and standard therapy of rheumatic syndrome [2]. The purpose of this case report is to emphasize the challenging elements in the differential diagnosis within rheumatology, and to describe a newly defined group of very aggressive lymphomas, so-called double-hit lymphoma (DHL), which are characterized by cytogenetic translocation of both MYC and BCL2. We report a case history of a 63-year-old woman with hip pain as a PRS. Case report A 63-year-old woman referred to the rheumatology outpatient clinic with a history of a persistent four weeks CASE REPORT Itch & Pain 2015; 2: e759. doi: 10.14800/ip.759; © 2015 by Rikke Asmussen Andreasen, et al. http://www.smartscitech.com/index.php/ip  Page 2 of 4  right-sided hip pain. The pain was constant and severe. X-ray of the hip and pelvis were normal. Objectively, there was no sign of arthritis, except pain-related limitation of motion. Laboratory work-up showed leukocytes: 10.4 x 109 / l, platelets: 110 × 109 / l, Hb: 5.6 mmol/l, C-reactive protein: 47 mg/l (normal range: <10 mg / l), ionized calcium: 1.22 mmol/l (normal range: 1.19-1.29mmol/l), Lactate dehydrogenase (LDH): 958 U/l (normal range: 105-205) and erythrocyte sedimentation rate: 17. Immunological test values including Immunoglobulin (Ig) M, IgG and IgA were within normal limits.  Four days later she was admitted to the local hospital with a preliminary diagnosis of cholecystitis. Ultrasound of abdomen identified supracapsular process on the right kidney upper pole. CT urography demonstrated 3 pathologically enlarged lymph nodes located centrally in the retroperitoneum. A biopsy of a subcutaneous nodule was performed. Pathology results revealed aggressive medium-sized B-cell lymphoma between diffuse large B-cell lymphoma and Burkitt lymphoma (Figure 1) with high mitotic activity (starry-sky appearance). Immunohistochemical staining of tumor cells were positive for CD20, CD10, PAX5, FOX P1, MUM1, lambda, MYC, BCL2 and Ki 67 (with 100% proliferation rate) and negative for CD21, BCL6, GCET1, TdT, EBER, CD3, CD5 and kappa. Flowcytometry analysis showed 59.4% B-cells with expression of CD20, CD22, CD79b, CD24, CD19 and lambda. In addition, these cells were weakly positive for CD10. FISH technique detected translocation of MYC, BCL2, IGH and no translocation of the BCL6 gene. These findings  Table 1. Ann Arbor staging Stage I Indicates that the cancer is located in a single region, usually one lymph node and the surrounding area. Stage I often will not have outward symptoms. Stage II Indicates that the cancer is located in two separate regions, an affected lymph node or organ and a second affected area, and that both affected areas are confined to one side of the diaphragm - that is, both are above the diaphragm, or both are below the diaphragm. Stage III Indicates that the cancer has spread to both sides of the diaphragm, including one organ or area near the lymph nodes or the spleen. Stage IV Indicates diffuse or disseminated involvement of one or more extralymphatic organs, including any involvement of the liver, bone marrow, or nodular involvement of the lungs. A or B The absence of constitutional (B-type) symptoms is denoted by adding an "A" to the stage; the presence is denoted by adding a "B" to the stage. S Is used if the disease has spread to the spleen. E Is used if the disease is "extranodal" (not in the lymph nodes) or has spread from lymph nodes to adjacent tissue. X Is used if the largest deposit is >10 cm large ("bulky disease"), or whether the mediastinum is wider than 1/3 of the chest on a chest X-ray.  are diagnostic of underlying double-hit lymphoma (DHL). Staging investigations showed widespread disease with involvement of several lymph node regions, bone marrow, subcutaneous tissue and myocardium equal to Ann Arbor staging 4B [5]. (Table 1) .Intensive courses of chemotherapy with high doses of Methotrexate, Rituximab, Cyclophosphamide, Doxorubicin, Vincristine were started with supplemented high dose Prednisolone, and a month later hip pain disappeared. Patient achieved complete remission after chemotherapy, but the disease relapsed shortly after in central nervous system (Figure 2). The patient died after a total of 11 months disease. Discussion PNS is relatively rare and occurs in up to 8% of all cancer patients [2]. It is known that some rheumatological diseases are associated with increased incidence of cancer. In the literature there are underlying malignancies in 10-25% of cases with dermato-/polymyositis, and up to 90% in hypertrophic osteoarthropathy (HOA). Therefore clinicians have to pay special attention to the symptoms of the above-mentioned diseases. HOA is divided into primary/hereditary and secondary forms. The secondary form is commonly related with lung cancer, bone metastasis, nasopharyngeal carcinoma and rhabdomyosarcoma. Diagnosis of hypertrophic osteoarthropathy can be made by physical examination and radiographic evaluation. Subsequent treatment of the underlying cancer improves the condition. [1, 2]. There is an association between ovarian, lung, breast, gastrointestinal system, non-Hodgkin lymphomas, prostate  Figure 1. Subcutaneous biopsy shows diffuse infiltration of the medium-sized lymphoid cells with a high mitotic activity (A). The tumor cells expressing CD20 (B), myc (C) and BCL2 (D) [12]  Itch & Pain 2015; 2: e759. doi: 10.14800/ip.759; © 2015 by Rikke Asmussen Andreasen, et al. http://www.smartscitech.com/index.php/ip  Page 3 of 4  Table 2. Different paraneoplastic rheumatic syndromes and their association with underlying cancer Hypertrophy osteoarthropathy Lung cancer, metastasis to bone, nasopharyngeal carcinoma, rhabdomyosarcoma  Dermato-/polymyositis Ovarian, lung, breast, gastrointestinal system, non-Hodgkin lymphomas, prostate and nasopharynx (Asian population) Vasculitis Lymphoproliferative and myeloproliferative disorders Carcinomatous polyarthritis Breast, colon, lung and ovarian lymphoproliferative disorders. Palmar fasciitis Ovarian (most common), stomach, pancreas, lung and colon Reflex-sympathetic dystrophy syndrome (chronic regional pain syndrome type II) Pancoast tumor of the lung, malignancies that infiltrates the stellate ganglion or brachial plexus Erythromelalgia Myeloproliferative disorders especially Polycythemia Vera and essential trombocytosis Polymyalgia Rheumatica (PMR) Kidney, lung, colon cancer and multiple myeloma Amyloidosis Multiple myeloma, lymphomas and carcinomas Digital necrosis - Raynaud’s syndrome Solid tumors (most frequent stomach, lung, ovarian) and lymphoproliferative disorders. Remitting seronegative symmetric synovitis with pitting edema (RS3PE) Lymphoma, myelodysplastic syndrome, adenocarcinoma Multicentric reticulohistiocytosis Carcinoma of the lung, stomach, breast, cervix, colon and ovary Panniculitis Hematologic malignancies or pancreatic cancer. Lupus-like syndromes Ovarian carcinoma, hairy-cell leukemia and breast carcinoma Scleroderma-like syndrome Adenocarcinoma and carcinoid tumor Sjögren’s syndrome Lymphoproliferative disorders(non-Hodgkin’s lymphoma), lymphoma of mucosal-associated lymphoid tissue (MALT), Waldenström’s macroglobulinemia, chronic lymphocytic leukemia and multiple myeloma Rheumatoid arthritis (RA) Lymphoproliferative disorders, lung cancer Systemic lupus erythematosus (SLE) Lymphoproliferative disorders, gynecologic malignancies Systemic sclerosis Lung, breast, esophagus and skin Paget’s disease of bone Osteosarcoma (under 1%)  and nasopharynx (Asian population) malignancies and dermato-/polymyositis [1, 6]. Ovarian cancer is the most common cancer in patients diagnosed with paraneoplastic dermatomyositis [7]. The highest risk for malignancy is within the first year of disease and it decreases gradually, but the risk still remains high compared to the general population. Thorough physical examination and laboratory test can lead to a diagnosis; although definite diagnosis is based on skin or muscle biopsy. Further imaging studies such as ultrasound, mammography and PET/CT Scan are helpful to determine the underlying cancer in specific cases. Paraneoplastic dermatomyositis responds poorly to corticosteroid treatment. Treatment of the primary cancer is a mainstay and can cause symptom regression [1, 6, 7].  Vasculitis can occur as PRS especially in association with haematological cancers, but the prevalence is not exactly known (approximately 3-8%) [8]. Leukocytoclastic vasculitis is the most frequent finding in histopathological exam, which is responsible for 30-40% of all paraneoplastic vasculitis cases [8]. The etiology of paraneoplastic vasculitis is not clear. Paraneoplastic vasculitis responds poorly to conventional treatment. Other paraneoplastic rheumatic syndromes such as Raynaud's phenomenon, erythema nodosum and non-specific symptom as arthralgia, are reported less frequently in a few case reports. (Table 2) [1-4, 8]. In recent years DHL has been identified as a group of extremely aggressive B-lymphomas with often poor treatment response and consequently short survival. Patients almost always present with advanced disease with involvement of extranodal sites. Poor prognostic factor associated with double hit lymphoma include increased LDH level, involvement of central nervous system/ bone marrow and a high international prognostic index score which primarily present in most of the cases. This case report illustrates a fulminant clinical course, which is characteristic of this type of lymphoma [9-10] . Figure 2. T1-weighted coronal sequence after Gd-contrast shows a 17x12x12 mm contrast enhancing tumor in the right temporal lobe.   Itch & Pain 2015; 2: e759. doi: 10.14800/ip.759; © 2015 by Rikke Asmussen Andreasen, et al. http://www.smartscitech.com/index.php/ip  Page 4 of 4  In rheumatologic studies it may be difficult for the clinicians to differentiate between underlying malignancy and primary rheumatologic disease, because the clinical manifestations are identical. But attention should be given when there are sudden occurrence of symptoms, unusual joint involvement, atypical age at disease onset and lack of response to therapy [4, 11]. There is no consensus on when a patient with rheumatological symptoms should be screened for possible underlying cancer. It is not economically justifiable to start performing a comprehensive examination for occult cancer, where it could be PRS in every case, but it should be part of the differential diagnosis in patients showing an atypical course, since early diagnosis of PRS will increase the patient's quality of life and chance of survival. References 1. Bojinca V, Janta I. Rheumatic Diseases and Malignancies. Maedica. 2012; 7:364-371. 2. Pelosof LC, Gerber DE. Paraneoplastic Syndromes: An Approach to Diagnosis and Treatment. Mayo Clin. Proc. 2010; 85:838-854. 3. Fam AG. Paraneoplastic rheumatic syndromes. Ballieres Best Pract Res Clin Reumatol 2000; 14:515-533. 4. Nascitz JE, Rosner I,Rozenbaum M, Elias N, Yeshurun D. Cancer-Associated Rheumatic Disorders: Clue to OccultNeoplasia. Semin Arthritis Rheum 1995; 24: 231-241. 5. Armitage JO. Staging Non-Hodgkin Lymphoma. CA Cancer J Clin 2005; 55: 368-376. 6. Requena C, Alfaro A, Traves V, Nagore E, Llombart B, Serra C, et al. Paraneoplastic dermatomyositis: a study of 12 cases. Actas Dermosifiliogr. 2014; 105:675-682. 7. Wada C, Hua CN, Carney ME. Paraneoplastic Syndrome in Hawai‘i: A Case of Dermatomyositis Associated with Endometrial Cancer. Hawaii J Med Public Health 2014; 73:112-114. 8. Wong M, Grossman J, Hahn BH, La Cava A. Cutaneous vasculitis in breast cancer treated with chemotherapy. Clin Immunol 2008; 129:3-9. 9. Green TM, Young KH, Visco C, Xu-Monette ZY, Orazi A, Go RS, et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone, J Clin Oncol 2012; 30:3460-3467. 10. Kapur S, Levin MB. Transformation of Follicular Lymphoma to Double Hit B-Cell Lymphoma Causing Hypercalcemia in 69-Year-Old Female: A Case Report and Review of the Literature. Case Rep Hematol 2014; 2014:619760. 11. Racanelli V, Prete M, Minoia C, Favoino E, Perosa F. Rheumatic disorders as paraneoplastic syndromes. Autoimmun Rev. 2008; 7: 352-358. 12. Asmussen R, Møller MB, Hansen IMJ. Hip pain as a paraneoplastic rheumatic syndrome in a patient with double-hit lymphoma. Ugeskr Laeger 2014; 15; 176(25A). 

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Severe joint pain as a manifestation of paraneoplastic rheumatic syndrome in a patient with a malignant lymphoma:a case report and review of the literature

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