The paraneoplastic musculoskeletal syndrome is not uncommon but quite often missed in busy outpatient clinics because of its mimicking and masquerading nature. Careful clinical investigation and knowledge of musculoskeletal syndromes are key. This places great responsibility on doctors in diagnosing and referring the patient to the required line of treatment.

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What is paraneoplastic musculoskeletal syndrome?

Paraneoplastic manifestation can be defined as distant manifestations which are not related to metastasis or direct tumour infiltration. It can be the first manifestation of about 10% of malignancies. It is usually associated with haematological cancers, lymphoproliferative diseases and solid cancers. It can manifest concomitantly or precede the diagnosis of malignancy or its relapse. It can be mediated via hormones or cytokines from a tumour or because of humoral or cellular immune defence mechanisms against tumour cells cross-reacting with normal tissues at regions distant from the underlying malignancy. Treatment of the underlying malignancy will completely or partially abolish the rheumatological manifestation.

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Symptoms for suspicion

The usual clues of suspicion are:

1. Older age at onset
2. Atypical manifestation
3. Significant constitutional symptoms like weight loss, fever, night sweats etc.
4. Autoantibody status
5. Inadequate response or refractory to conventional treatment

Paraneoplastic rheumatological or musculoskeletal syndromes can be subclassified into:

1. Arthropathies
2. Myopathies
3. Vasculitides
4. Miscellaneous

Arthropathies associated with underlying malignancy are:

1. Carcinomatous polyarthritis
2. Remitting seronegative symmetric synovitis with pitting oedema (RS3PE)
3. Hypertrophic osteoarthropathy (HPOA)
4. Polymyalgia rheumatica
5. Amyloid associated arthritis
6. Palmar fasciitis and arthritis

Carcinomatous polyarthritis: It is characterised by rapid onset treatment-refractory oligo or polyarthritis affecting predominantly large joints. It can mimic rheumatoid arthritis. Rheumatoid factor, anti-CCP antibody or antinuclear antibody can be positive in subgroups of patients making diagnosis difficult. It is a diagnosis of exclusion and usually responds completely after treatment of malignancy.

RS3PE: It presents as bilateral swelling of hand and feet mimicking boxing glove appearance. It has a strong association with malignancy (50-60%).

HPOA: It is characterised by periosteal thickening of tubular bones like tibia, fibula, skin and nail fold thickening, clubbing, arthralgia, or arthritis. It can be primary or secondary to pulmonary, gastrointestinal, and rarely cardiac malignancies. Like other paraneoplastic conditions, it responds well to the treatment of underlying cancer. If not improved, zoledronate or pamidronate can be helpful.

Polymyalgia rheumatica: It is typically seen in age >50 years. It affects the bilateral shoulder and hip girdle. It typically responds well to low-dose corticosteroids (prednisolone <10-20 mg/day). Any atypical features should raise suspicion of underlying malignancy.

Amyloid associated arthritis: It affects large joints and surrounding periarticular tissue (e.g. shoulder pad sign of shoulder involvement). Mostly other features like racoon eyes, macroglossia, cutaneous infiltration, steroid unresponsive carpal tunnel syndrome or another organ involvement might be present concomitantly. It can be secondary to underlying malignancies.

Palmar fasciitis: Whenever elderly women present with rapid onset refractory bilateral palmar fasciitis or florid arthritis of the metacarpophalangeal and interphalangeal joint should raise a strong suspicion for underlying ovarian cancers.

Cancer-associated myopathies: They include dermatomyositis, polymyositis, amyopathic dermatomyositis. Dermatomyositis has the strongest association among all. Major risk factors include male gender, very high creatinine kinase, presence of dysphagia, antibodies like anti TIF1 gamma, anti NXP2, anti-MDA 5, low complement C4. All above-mentioned myositis diagnosis requires extensive annual cancer screening up to 3 to 5 years from diagnosis. Treatment of underlying malignancy usually improves myositis; reappearance of symptoms indicate relapse.

Vasculitis: It can be the paraneoplastic manifestation of underlying malignancies. Usually, it presents as small vessel vasculitis or middle vessel vasculitis like polyarteritis nodosa. It usually presents with palpable purpura or nodules or refractory ulcers. Rarely, it can also manifest as orchitis or mono neuritis multiplex. Cryoglobulinaemic vasculitis (type I) secondary to plasma cell or B cell neoplasms or polyarteritis nodosa can be a paraneoplastic manifestation of hairy cell leukaemia. Various solid organ malignancies like renal cell carcinoma can also manifest as small vessel vasculitis.

Scleroderma or scleroderma mimicker like scleroderma or scleromyxedema: They can be a paraneoplastic manifestation of underlying malignancy. The presence of anti-RNA polymerase III antibodies indicates a higher association with malignancy.

Tumour-induced osteomalacia or oncogenic osteomalacia: It presents as non-specific debilitating pain, impaired gait, insufficiency fractures, hypophosphatemia refractory to vitamin D correction. It is secondary to mesenchymal tumours producing fibroblast factor 23 or phosphatonin.

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Approach

Any paraneoplastic manifestations warrant evaluation for underlying malignancies and close monitoring for the evolution of clinical features. These manifestations can be concomitant or precede malignancies. Reappearance or new-onset musculoskeletal manifestation in patients with treated malignancy can be an indication of relapse.

1. Diagnostic workup can be individualised as per the clinical history, physical examination or commonly associated malignancies.
2. Workup ranges from laboratory investigations including tumour markers, autoantibodies, imaging, and histopathology.
3. Mostly, diagnosis of malignancy can be made within 2 years of paraneoplastic manifestation; hence close monitoring and annual workup for at least 3 to 5 years are recommended.

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Treatment

Treatment of underlying malignancy usually improves the paraneoplastic musculoskeletal symptom. Musculoskeletal manifestations of non-treatable malignancies should be managed with anti-rheumatic drugs and glucocorticoids.

Paraneoplastic manifestations are the varied manifestations of underlying malignancy. It can be the initial manifestation of the underlying malignancies. It can precede the diagnosis of malignancy. It is quite often missed by treating doctors due to lack of awareness or due to its masquerading nature.

Treatment of malignancy will improve the paraneoplastic manifestations. Hence, physicians or rheumatologists should be vigilant for any of the above symptoms or any atypical feature or refractoriness to conventional therapy. Any suspicions should follow a tailored approach for cancer screening as per the clinical scenario. Early diagnosis and management of underlying malignancy can abolish rheumatological symptoms and improve survival.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The author is a practising Rheumatologist from Bangalore.