Rheumatol Int (2012) 32:1485–1489 DOI 10.1007/s00296-011-2252-9
REVIEW ARTICLE
Paraneoplastic rheumatic syndromes: report of eight cases and review of literature Jinane Hakkou • Samira Rostom • Rachid Bahiri Najia Hajjaj-Hassouni
•
Received: 6 August 2011 / Accepted: 22 October 2011 / Published online: 17 November 2011 Ó Springer-Verlag 2011
Abstract Malignant neoplasms are associated with a wide variety of paraneoplastic rheumatological syndromes. The paraneoplastic nature should be based on specific criteria. We report a series of eight cases of paraneoplastic rheumatic syndromes revealing an underlying neoplasia. Our series consists of six men and two women, with a mean age of 46.1 (20–69 years). The first case is a hypertrophic osteoarthropathy of Pierre Marie that occurred in a 20-year-old man 1 month after treatment for his nasopharyngeal carcinoma; the paraclinical examinations showed lung and bone metastasis. The second case is that of a bilateral shoulder-hand syndrome revealing an invasive squamous cell carcinoma of the cervix in a 63-year-old woman. The third case involved a 69-year-old patient who had surgery 2 years ago for prostate adenocarcinoma and presented with polymyalgia rheumatica revealing bone metastasis. We also report two cases of leukemia in adults revealed by polyarthritis. The sixth observation is that of a paraneoplastic scleroderma that occurred concomitantly with prostate cancer. The seventh case of an acute arthritis showed a B lymphoma. The eighth case is that of a 52-year-old patient who presented with inflammatory arthralgias, and digital clubbing revealing a squamous cell carcinoma of the skin. Paraneoplastic rheumatism remains a rare event, but knowledge of it is essential for early diagnosis of underlying cancer. Keywords Cancer
Rheumatism Paraneoplastic syndrome
Introduction Paraneoplastic syndrome is defined by signs or symptoms related to an occult or already recognized tumour without direct anatomical relationship with it, not explained by metastasis. The responsible neoplasm is most malignant than benign. The temporal relationship between the tumor and the rheumatic symptoms is fundamental. Musculoskeletal manifestations of malignancy may coincide, follow or antedate the diagnosis of cancer, or herald its recurrence. The clinical course generally parallels that of the primary tumour, and treatment of the underlying malignancy often results in regression of the rheumatic disorder [1, 2]. Malignant neoplasms are associated with a wide variety of paraneoplastic rheumatological syndromes. We studied a series of eight patients with paraneoplastic rheumatological syndromes; in three adult patients, these syndromes revealed haematological malignancies, including two cases of leukemia, which are rarely found in the literature.
Patients and methods We report eight cases of paraneoplastic rheumatological syndromes revealing a tumour. This is a series of patients collected from the Rheumatology Department at El Ayachi Hospital between 2002 and 2009.
Results J. Hakkou (&) S. Rostom R. Bahiri N. Hajjaj-Hassouni Department of Rheumatology, El Ayachi University Hospital, Rabat-Sale, Morocco e-mail:
[email protected]
The characteristics of our series are summarized in Table 1. Our series consists of six men and two women, with a mean age of 46.8 (20–69 years). This series includes
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Table 1 Characteristics of our series Case
Age
Sex
Diagnosis delay
Paraneoplastic syndrome
Cancer
Treatment of tumour
Rheumatism out come
1
22
F
8 Months
Paraneoplastic polyarthritis
Acute lymphoblastic leukemia
Polychemotherapy
Heamatologic and rheumatologic remission
2
34
M
1 Month
Acute polyarthritis
Chronic myeloide leukemia
Polychemotherapy
Hematologic and rheumatologic remission
3
20
M
5 Months
Hypertrophic osteoarhtopathy
Pulmonary and bones metastasis of nasopharyngeal cancer
Radiotherapy
Patient’s death
4
63
F
3 Months
Bilateral shoulder hand syndrome ? inflammatory arthralgias
Squameous carcinoma of cervix
Surgery and chemotherapy
Improvement of rheumatism
5
69
M
4 Months
Polymyalgia rheumatica
Bones metastasis of prostatic adenocarcinoma
6
67
M
1 Month
Paraneoplastic scleroderma
Prostate cancer
Hormone refusing treatment
Patient’s death
7
48
M
4 Months
Paraneoplastic polyarthritis
B-cell lymphoma
Chemotherapy and surgery
Heamatologic and rheumatologic remission
8
52
M
9 Months
Inflammatory arthralgias
Squamous cell carcinoma of skin
Surgery
Improvement of rheumatism
Patient’s death
M male, F female
various presentations of paraneoplastic rheumatic syndromes with features of our cases detailed in Table 2. For all patients, a complete clinical examination, laboratory, and radiological investigations were performed to diagnose the underlying cancer.
Discussion Our series includes various presentations of paraneoplastic rheumatic syndromes, some of which are common as hypertrophic osteoarthropathy of Pierre Marie and carcinoma polyarthritis. In two patients, this rheumatic syndrome has revealed leukemia, which is rare in the literature, and that is what makes our series original. Paraneoplastic syndromes are present in approximately 10% of cancers [2]. About paraneoplastic arthritis, its incidence is high in the general population. A review of the literature, some years ago, reveals 12 cases of patients in whom the paraneoplastic nature of polyarthritis appeared likely because of a parallelism between joint manifestations and cancer [2]. The most common sites of malignancy include the lung, the digestive tract, and the prostate. These patients were often characterized by an important alteration of the general condition (7/12), high temperature up to 40°C (8/12), and an explosive onset of an unusual inflammatory arthritis.
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Recently, Morel et al. [3] collected 26 cases of paraneoplastic arthritis. There were 16 males and 10 females, with a mean age of 57.5 (range 28–85). Patients presented with symmetric polyarthritis involving wrists and hands (85%). The mean delay between the diagnosis of rheumatism and neoplasia was 3.6 months (0–21.2). Twenty patients had a solid cancer; six had haematological malignancy. Adenocarcinoma of the lungs was the most frequent type of solid cancer (60%). In our series, polyarthritis was found in three patients (3/ 8), and revealed haematological malignancies in these three cases. In our seventh case, a haematological malignancy in question was a B-cell lymphoma. The patient was a male and the distribution of arthritis was asymmetric. The patient had a poor general condition. He had a high CRP, with absence of rheumatoid factor and erosions. The delay between arthritis and the diagnosis of cancer was 4 months. These findings were consistent with the literature data [3]. Regarding the two other cases, the polyarthritis revealed leukemia [4]. In fact, generally musculoskeletal manifestations of leukemia in adults are rare. They revealed acute leukemia (AL) in 14% of cases in children and in 4% of cases in adults [5]. In our two patients, joint symptoms were represented by acute or chronic symmetric polyarthritis, affecting large and even the small joints, which are consistent with the literature data [5, 6]. However, this polyarthritis was accompanied by a tenosynovitis, which is quite
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Table 2 The clinical and laboratory characteristics of our series Case
Clinical features
Paraclinical features
1
Bilateral symmetric polyarthritis Bones pain
ESR = 85 mm/1st H, CRP = 96 mg/l, WBC = 2,1200/mm3 with lymphocytes 82%
Parotidomegaly
Platelets: 9,400/mm3, no anemia, no myelemia
Cervical lymphadenopathy Splenomegaly
2
Bilateral symmetric polyarthritis and tenosynovitis of the flexor tendons of the hand Fever 38.2°C Pale skin and mucous Hepatosplenomegaly
Myelogram: medullary invasion by blasts whose typing was lymphoblastic, phenotyping: CD3; CD7; CD1O?; CD20? Rx: microgeodic carpal bones and metacarpals heads and heterogeneous demineralization of the distal radius and ulna ESR: 102 mm/1st H, CRP: 6 mg/l, LDH: 919UI, normocytic anaemias with haemoglobin at 8.7 g/l, leucocytosis at 375.000/mm3, with 87% of neutrophil Thrombocytosis at 52,5000/mm3, 5% of metamyelocytis; 4% of myelocytis Joint aspiration of the left knee found a liquid with rate of leucocytes at 1,450/mm3, with 70% of neutrophil; absence of germ, microcrytals and abnormal cells Sternal puncture: increased myelocytis, metamyelocytis and neutrophil polymorphonuclear cells Bone marrow biopsy: medullary areas with high cellularity and hyperplasia focusing on immature cells and granulocytic series. Search of Philadelphia chromosome in the karyotype was positive
3
Bilateral symmetric polyarthritis Involvement of hip Poor general condition Edema of the extremities Vasomotor changes at hands
ESR: 65 mm/1st H, CRP: 51 mg/l, rheumatoid factor RF, ACPA and HLA B27 were negative Joint fluid of hip: paucicellular fluid with WBC \ 200/mm3 Rx of long bones: periosteal reaction (Fig. 1), RX of hands: normale TDM of nasopharynx: normal, thoracic TDM: pulmonary metastasis, Spinal MRI: spinal and iliac crest metastasis (Fig. 2)
Digital clubbing thumbs 4
5
Bilateral shoulder-hand syndrome
ESR: 81 mm/1st H, CRP at 48 mg/l
Inflammatory polyarthralgias
Pelvic exam: ectocervix was redness at the speculum
Muscle were very painful on pressure at the fourth members
Vaginal pap smear: atypical squamous cells
Temporal pulse was present
Bone scintigraphy showed locoregionale increased uptake at both shoulders and both wrists
Surgery for prostate adenocarcinoma 2 years ago
ESR: 86 mm/1st H, CRP negative, ultrasonography of shoulders: bilateral sub acromial bursitis
Inflammatory arthralgia affecting both the shoulder and hip girdles
Cervical biopsy: squamous carcinoma in situ with probably invasion
Bone scintigraphy and spinal MRI showed bones metastasis
Poor general condition, weight loss of 20 kg in 1 year Clinical examination: painful limitation of shoulders and hips 6
Followed since 4 years for prostate adenocarcinoma Raynaud’s phenomenon affecting hands and feet Dyspnoea grade 3 of NYHA score Poor general condition ? weight loss of 10 kg in 1 year Sclerosis of skin Acrocynosis of hands and feet
ESR: 21 mm/1st H, CRP: 7.3 mg/l, antinuclear antibodies positive at 1/340 with speckled fluorescence and anti SCL70 antibodies positive Pulmonary Rx: bilateral interstitial syndrome with restrictive syndrome in functional respiratory exploration Echocardiography: minimal mitral and aortic insufficiency Esogastroduodenal endoscopy and manometry: esophageal peptic ulcer and lower peristalsis and decrease of lower esophageal sphincter pressure
Digital clubbing Edema in a gloves and socks distribution 7
Bilateral asymmetric polyarthritis
ESR: 104 mm/1st H and CRP: 93 mg/l. RF: negative
Poor general condition
Under axillary lymphadenopathy biopsy: B lymphoma
Under left axillary lymphadenopathy
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Table 2 continued Case
Clinical features
Paraclinical features
8
Chronic smoking and cannabis
ESR: 65 mm/1st H and CRP: 10 mg/l
Inflammatory polyarthralgias
Ultrasonography of the swelling: subcutaneous mass with clear borders, heterogeneous and hypoechoic with variable volume
Poor general condition and weight loss of 16 kg in 1 month Painless swelling of hard consistency extending from the posterior right leg to the right buttock, of 3–4 mm of diameter, fixed to the deep plane without local inflammatory signs
Doppler examination showed significant activity especially at the periphery of the mass with reinforcements toward center Biopsy of this swelling: moderately differentiated infiltrating squamous cell carcinoma with keratinisation
Important digital clubbing ESR erythrocyte sedimentation rate, CRP C reactive protein, WBC white blood cells, RF rheumatoid factor, ACPA anti-cyclic citrullinated peptide antibodies, Rx radiographs, TDM tomodensitometry, MRI Magnetic resonance imaging
Fig. 1 Radiography of right knee (3rd case): the periosteal reaction at the right femur
Fig. 2 MRI Lumbar Spine (3rd case): bone metastasis
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unusual in chronic myeloid leukemia (CML) [7]. Bone abnormalities are rare, found radiologically in 3–8% of cases [8]. Radiographs are normal or may show osteoporosis or lytic bone lesions, predisposing pathological fractures [7]. Radiographs performed in our patient revealed a micro lacunae aspect in the carpal bones and metacarpophalangeal joints (MCP). This is an atypical aspect, since the large joints are the most usually affected in the literature [5]. Hypertrophic osteoarthropathy (HOA) is a common paraneoplastic rheumatic syndrome whose physiopathology remains complex. In above 90% of cases, it is secondary to an intrathoracic tumour: primary lung cancer (75% of cases), pleural mesothelioma, mediastinal tumours; various origins of lung metastasis (sarcomas, cancers of the ovary, breast cancer) are exceptionally concerned; very rarely, it is secondary to haematological malignancies or nasopharyngeal cancer [9]. In our case, hypertrophic osteoarthropathy of Pierre Marie revealed lung metastasis and also bone metastasis, which are exceptionally found in the literature [1, 10]. Our patient had a complete form of this syndrome. The affected joints are the joints most frequently found in the literature such as knees, ankles, hands, and wrists. Involvement of the hip is exceptional and has never been reported in the literature in this syndrome, and that is what makes our observation original. As another presentation of paraneoplastic rheumatic syndrome, we found the algodystrophy or reflex sympathetic dystrophy syndrome. It may be associated with different types of malignant tumours; in particular squamous cell lung cancer but also colon cancer, pancreas and ovary cancers, myeloid leukemia, or breast cancer [1]. The combination of shoulder-hand syndrome and inflammatory arthralgias, revealing genital cancer as shown in our case is exceptional, since only few cases have been published in the literature [11]. Concerning polymyalgia rheumatica (PMR), the study of different published series do not seem to show increased
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incidence of cancers over the general population. Indeed, in Horton’s disease, the hazard rate for developing malignancy in patients with biopsy-positive temporal arteritis was higher than in the controls; however, the general long interval between diagnosis of PMR and/or temporal arteritis and registration of malignancy (mean 6.5 years) is not consistent with a paraneoplastic mechanism [12]. In the experience of Liozon et al. [13], concurrent malignancy was found in 23 patients from a series of 250 diagnosed with temporal arteritis (TA) and followed up between 1976 and 2003. The authors concluded that there was a frequent, non-fortuitous association between TA and malignancy. The question of possible paraneoplastic process however remains open. Sheon et al. [14] reported five cases of patients whose cancer was discovered in 3 months following the occurrence of PMR. It was a blood disease, cancers of the colon, prostate, ovary, and kidney. Erythrocyte sedimentation rate was very high, as usual during the PMR and the evolution was favorable under corticosteroid therapy. For these authors, PMR associated with cancers are unusual but they can always justify a precautionary approach [14]. In our patient, the PMR was not associated with Horton’s disease. It revealed bone metastasis of prostate cancer, which is rare according to this review of the literature. Although the incidence of systemic scleroderma (SS) and neoplastic diseases increases with age, the coexistence of these two entities is unusual. The most common situation is where a neoplastic lesion occurs in a patient with SS already known. More rarely cancers can induce skin lesions similar to SS. Paraneoplastic scleroderma like syndromes occur in various clinical forms. The clinical table includes cutaneous sclerosis of fingers similar to those found in SS, which sometimes progresses to the proximal extremities and trunk. Raynaud’s phenomenon is less common [15]. The antinuclear antibodies (ANA) are more often negative than in the idiopathic SS and anticentromere antibodies (ACA), anti-topoisomerase I antibodies (anti-SCl-70) antifibrillarin and anti-RNA polymerase III are not detected in these patients [15]. Furthermore, our observation, interestingly, note that clinical and immunological changes found in idiopathic forms of SS may be present in patients with paraneoplastic scleroderma like syndrome; presence of Raynaud’s phenomenon, dyspnea, digital clubbing, acrocyanosis and positivity of ANA and anti-SCl-70 antibodies. The only atypical parameter in our case was male gender of the patient, because 80% of patients with SS were women.
Conclusion Paraneoplastic rheumatisms remain a rare event; they are dominated by hypertrophic osteoarthropathy of Pierre
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Marie. The interest of our work is to describe the features of paraneoplastic rheumatic syndromes in our series and also insist on the possibility of revelation of hematological malignancies or leukemias by polyarthritis. Whatever the mode of presentation, the awareness that cancer can cause certain non-metastatic symptoms is important for early diagnosis and treatment of an occult neoplasm. However, several issues concerning the pathogenesis remain unanswered. Further research on the nature of the association between cancer and paraneoplastic rheumatic syndromes can provide knowledge on the mechanisms for these disorders. Conflict of interest
None.
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