Paraneoplastic Raynaud's phenomenon and Digital Ischaemia as a Presenting Feature of Underlying Malignancy
D Ashok, E Baguley
digital ischaemia, malignancy, paraneoplastic, raynaud's
D Ashok, E Baguley. Paraneoplastic Raynaud's phenomenon and Digital Ischaemia as a Presenting Feature of Underlying Malignancy. The Internet Journal of Rheumatology. 2006 Volume 3 Number 2.
Late onset Raynaud's, rapidly worsening, poses a diagnostic challenge. Rarely may it be associated with underlying malignancy. Associated autoantibody positivity may cause diagnostic delay. We describe three cases who sought treatment for Raynaud's subsequently diagnosed with malignancy, treatment of which improved the Raynaud's. We discuss the possible mechanisms.
Raynaud's phenomenon (RP) first described by Maurice Raynaud 1862 is characterised by reversible vasospasm in response to cold or emotion. In young patients it is commonly hereditary but after the second decade its onset is often linked with underlying causes particularly scleroderma and systemic lupus erythematosus. Other conditions including emboli, hemostatic abnormalities, trauma and the use of vasoconsrictive drugs may produce symptoms mimicking RP1.
Rapidly worsening RP poses a diagnostic and therapeutic challenge. Rarely may it be associated with underlying malignancy. We present three patients who presented with RP and other features of connective tissue disease where further investigations revealed undiagnosed malignancy and review possible mechanisms.
Results of the tests are summarised in table 1.
He developed digital ulceration (Figure 3) despite intravenous prostacycline, aspirin, clopidogrel and nifedipine. CT scan of chest and abdomen revealed bilateral axillary and inguinal lymphedenopathy with a marginally enlarged spleen. Lymph node biopsy showed B- cell chronic lymphocytic leukaemia (CLL), biopsy of the bone marrow did not reveal any infiltration by the CLL. He was commenced on 60 mg prednisolone. He required re admission for further prostacycline infusions and surgical debridement of the digital ulcers.
He was commenced on azathioprine 2mg/kg body weight with gradual reduction of prednisolone and regularly reviewed in the rheumatology clinic. His finger ulcers healed and he experienced no further episode of digital ischaemia after 12 months of follow up. No further treatment was deemed necessary for his CLL.
Results of the blood tests are in table 1.
Ultrasonography and biopsy of the mass in the left axilla revealed metastatic carcinoma suggestive of breast cancer. She was commenced on chemotherapy and subsequently radiotherapy. Subsequently she has had no further episodes of digital cyanosis with her Raynauds requiring minimal therapy.
Physical examination revealed mild bilateral parotid swelling, dusky hands with abnormal nail fold capillaries and synovitis affecting the proximal and distal interphalangeal joints. She was commenced on nifedipine and hydroxychloroquine and regularly reviewed in the clinic, with a presumptive diagnosis of an evolving connective tissue disease.
Results of the blood tests are shown in table 1.
Over the course of next six months she developed sore finger tips, discolouration over the knuckles and mild proximal muscle weakness with raised muscle enzyme CPK 310 (24-170). She was commenced on prednisolone 20mg per day with improvement in the symptoms.
A year after her original presentation, she was admitted with right loin discomfort and haematuria. A renal ultrasound scan showed a solid mass in the right kidney consistent with renal cell carcinoma. Further imaging revealed multiple pulmonary metastasis. She underwent right radical nephrectomy and had a good postoperative recovery with improvement of all musculoskeletal symptoms being able to stop steroids completely. She was commenced on immunotherapy for the metastatic disease without subsequent relapse of any musculoskeletal symptoms.
The association between malignancy and musculoskeletal disease is complex and intriguing. A search of the Medline database by Poszepczynska-Guigne et el1 identified 66 previously reported cases of paraneoplastic Raynaud's with two new cases in their report. The malignancies that have been associated with RP include carcinoma of the lung, stomach, colon, small intestine, pancreas uterus, ovary, kidney and maxillary antrum, myeloma melanoma, leukaemia and lymphoma (3, 4).
Unlike primary RP which predominantly affects young women, paraneoplastic RP almost equally affects both sexes at an older mean age5. The onset may be of short duration, with severe, asymmetric involvement of the digits. More than 80% of patients progress to ischemia, necrosis, pulp atrophy and gangrene. The evolution of paraneoplastic RP is similar to that of other paraneoplastic syndromes. Our first patient had short duration of symptoms, asymmetric involvement, and rapidly developed necrosis of the digits.
There are several mechanisms suggested whereby malignancy could lead to digital ischemia including sympathetic hyperactivity, cryoglobulinimia, immune –complex – induced vasospasm, vasculitis, hypercoagulable state, antiphospholipid antibodies, and marantic endocardits with embolic phenomena(6, 7). Multiple mechanisms may be involved in a case.
Arteritis of diverse etiologies has been associated with digital artery vasospasm, as well as with digital artery obstruction producing finger ischemia and finger gangrene8. The cause of the arteritis is unknown but may be related to tumour antigen – antibody complexes with subsequent complement activation in contact with the arterial wall. The induction of vasculitis by antibodies to tumour antigens has been suggested as a possible mechanism9. Digital ischaemic symptoms have been reported to improve after removal of renal carcinoma and ovarian carcinoma, with recurrence indicating relapse(9, 10). The improvement in digital symptoms following treatment of breast cancer with chemotherapy followed by radiotherapy as in our second patient and surgery for renal cancer as in our third patient may be in keeping with the suggestion that tumour antigen contributes to the pathogenesis.
The immune system plays a central role in cancer both in vigilance for atypia and in the sympomatology of cancers. A balance exists between immune response and tolerance or ignorance of tumour antigens. Dendritic cells are at the centre of this balance. Uncontrolled exponential expansion of lymphocytes and unchecked cytokine production and cytotoxic activity may lead to autoimmunity11. An understanding of these control mechanisms of immune activation has helped to optimise the design of immunotherapy intervention and cancer vaccine development(11, 12). Monoclonal antibodies to surface receptors, such as rituximab, have complex mechanisms of action leading to effective tumour regressions. Stimulation of antibody–dependent cell mediated cytotoxicity together with ability of immune complexes to allow antigen cross–presentation in dendritic cells, may contribute to their antitumor effects by a coordinated humoral and cellular response(13,14,15) . Resultant tumour cell damage and cross–presentation of antigen by host APCs (antigen presenting cell) may allow the transfer of the immunologic stimulus to cellular immune responses16 leading to trials in auto immune disease where improvement has also been observed. Cancer immunotherapy attempts to shift the balance of the immune system toward rejection of cancer. The therapeutic window may be narrow between antitumor immune response and autoimmunity, but also between response and tolerance to tumour antigens.
In conclusion Raynaud's as a presenting feature of malignancy is rare, when it does occur it tend to be severe and requires aggressive treatment. Improvement can be seen following treatment of underlying malignancy as in our two cases. An immunological mechanism has been suggested.
All three patients exhibited a rapid evolution of symptoms with markedly symptomatic RP. Even in the presence of positive auto antibodies we would suggest that malignancy is considered in patients with atypical presentations.