Abstract
Background
A paraneoplastic syndrome is observed in 5% to 10% of cancer patients. Paraneoplastic vasculitis (PV) in metastatic renal cell carcinoma (mRCC) patients has been poorly investigated.
Aims
In our case series study, we evaluated the incidence and development of PV in patients with mRCC.
Methods and results
Patients were required to have previously untreated clear‐cell or papillary mRCC and no evidence of autoimmune diseases or venous thrombosis in history. Patients had a careful examination including Doppler ultrasonography of the blood vessels and skin punch biopsy in the presence of suspicious skin rash. Sixteen (8.2%) of 196 patients were diagnosed with PV, which was manifested clinically by leukocytoclastic vasculitis on the lower extremities. Skin biopsy confirmed vasculitis. Progression‐free survival and overall survival were significantly better in patients without PV.
Conclusions
PV is not rare paraneoplastic syndrome in mRCC. Leukocytoclastic vasculitis was the most common type of PV in this study.
Keywords: paraneoplastic vasculitis, metastatic renal cell carcinoma
1. INTRODUCTION
Paraneoplastic vasculitis (PV) is a type of paraneoplastic syndromes characterized by inflammation and necrosis of the vascular wall due to autoimmune damage.1 In most cases, PV develops in patients with haemoblastoses. Less frequently, it is associated with solid tumours. The prevalence of PV in cancer patients is in the range of 0.01% to 1%, according to different data.2, 3 Metastasis‐associated PV occurs in up to 8% of all patients with advanced cancer and generally conveys a poor prognosis.4 PV in patients with advanced renal cancer has been very poorly investigated. In our prospective case series study, we evaluated the prevalence and development of PV in patients with metastatic renal cell carcinoma.
2. PATIENTS AND METHODS
The study population consisted of adults (aged 18 years and above) with previously untreated metastatic renal cell carcinoma that showed a clear‐cell or papillary component. Key eligibility criteria included the presence of measurable disease (as per the Response Evaluation Criteria in Solid Tumors (RECIST), favourable or intermediate prognosis according to the Memorial Sloan‐Kettering Cancer Center (MSKCC) criteria, and a signed informed consent. Patients were ineligible if they had evidence of autoimmune diseases or venous thrombosis in history, and previously received anticoagulants.
All patients had a general examination, which included careful skin examination by dermatologist, blood coagulation tests, a complete blood count that included a platelet count, Doppler ultrasonography of the blood vessels, and skin punch biopsy in the presence of suspicious skin rash. The staging procedure comprised a computed tomography (CT) of the chest, abdomen, and pelvis. A CT scan or magnetic resonance imaging of the brain was also to be carried out. A bone scan was also carried out in case of bone‐related symptoms. The trial was approved by the Institutional Review Board and by the Ethics Committee in each center.
The primary endpoint of this study was rate of PV before anticancer treatment. Secondary endpoints included progression‐free and overall survival. Summary statistics (mean, median, and proportion) were used to describe baseline patient characteristics, treatment patterns, and response rate. Survival times were calculated from the date of therapy initiation to the date of progression or death (progression‐free survival) and the date of death (overall survival). Survival was estimated using the Kaplan–Meier method. Cox proportional hazards regression analysis was used to relate several risk factors to survival time. All statistical analyses were carried out using IBM SPSS Statistics Base v22.0 (SPSS, Inc, Chicago, Illinois).
3. RESULTS
One hundred ninety‐six patients with metastatic renal cell carcinoma were enrolled, and 193 (98.5%) patients were analyzed. The characteristics of the analyzed patient population are presented in the Table 1.
Table 1.
Patient characteristics
| Age (years), median (range) | 58.7 (44–73) |
| Sex, N (%) | |
| Male | 161 (82) |
| Female | 35 (18) |
| ECOG PS, N (%) | |
| 0,1 | 147 (75) |
| 2,3 | 49 (25) |
| MSKCC risk factors, N (%) | |
| Favourable | 67 (34) |
| Intermediate | 108 (55) |
| Poor | 11 (6) |
| NA | 10 (5) |
| Histology, N (%) | |
| Clear‐cell RCC | 194 (99) |
| Papillary‐cell RCC | 2 (1) |
| Previous surgery, N (%) | |
| Nephrectomy | 196 (100) |
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group Performance Status; MSKCC, Memorial Sloan‐Kettering Cancer Center; NA, not available.
Sixteen of 196 patients (8.2%, 95% CI, 7.7‐8.7) were diagnosed with PV, which was manifested clinically by erythematous spots and palpable purpura (leukocytoclastic vasculitis) on the lower extremities. Some patients had urticarial plaques, vesicles, or pustules. Figures 1, 2, 3 demonstrate examples of vasculitis. Additional clinical manifestations were arthralgia and painful rash in five and six patients, respectively.
Figure 1.
Patient 1 (male, 60 years old, bone and lung metastases) with PV. PV classically presented with purpuric papules a few millimeters in diameter, predominately located on the lower legs
Figure 2.
Patient 2 (male, 49 years old, multiple metastases in lungs and lymph nodes) with PV. PV presented as palpable purpura and urticarial plaques
Figure 3.
Patient 3 (male, 71 years old, multiple metastases in lungs and liver) with PV. Clinical findings included vesicles, pustules, and urticarial papules
Doppler ultrasonography revealed acute deep vein thrombosis of lower limb in one patient at the time of examination. Other patients had no any significant features of large‐vessel vasculitis. Thrombocytosis was detected in three (19%) of 16 PV patients. Abnormal coagulation (increased fibrinogen, D‐dimer content, and fibrin monomer) was found in all patients with PV. Skin biopsy confirmed vasculitis. Necrosis with deposits of fibrin in the wall of small vessels, neutrophil infiltration, and leukocytoclasis were observed.
Vasculitis developed simultaneously with the metastatic disease in all patients. One patient had previously received prednisolone therapy. There was no relationship between PV activity and course of metastatic renal cell carcinoma. Nevertheless, patients without PV had longer progression‐free survival and overall survival. Median progression‐free survival was 8.7 (95% CI, 7.5‐9.8) months in patients who had PV and 4.5 (95% CI, 2.9‐7) months in patients without PV (P = 0.02). Median overall survival was 12.5 (95% CI, 10.7‐14.8) and 6.0 (95% CI, 4.2‐8.2) months (P < 0.001) in these groups, respectively. Moreover, after adjustment for clinical risk factors (age, sex, ECOG performance status, and MSKCC group), there was statistically significant difference between patients with and without PV in terms of the risk of disease progression (HR = 1.81, P = 0.03) and death (HR = 2.19, P = 0.01).
4. DISCUSSION
In our study, we demonstrate that PV is not the rarest paraneoplastic syndrome in metastatic renal cell carcinoma; it is observed in 8% of cases. There is no common theory of the pathogenesis of PV, but most authors favour an autoimmune mechanism of vasculitis with deposition of tumour antigen‐antibody immune complexes in the walls of blood vessels of different calibers and subsequent development of inflammation and necrosis.5, 6, 7, 8 Complement‐dependent toxicity is accompanied by cell cytotoxicity mediated by various inflammatory cells, including neutrophils. The higher prevalence of PV in patients with metastatic renal cell carcinoma could be explained by the immunogenicity of this type of tumour. It is well known that growth of renal cell carcinoma is associated with impaired autoimmune and antitumor immune response, which involves T cells, natural killer cells, dendritic cells, and macrophages.9, 10 Cross‐reactivity between the antigens of the tumour and the endothelial cell is believed to be one of the essential mechanisms of an autoimmune process; fibrin deposits are found in the vascular wall in this case. Our patients with PV had same inflammatory changes.
Leukocytoclastic vasculitis was the most common type of PV in this study. Clinically, leukocytoclastic vasculitis is manifested by erythematous spots and palpable purpura located predominantly on the lower limbs.11, 12 Patients with rapidly growing tumours may develop leukocytoclastic vasculitis with haemorrhagic bullae and ulceration.
Progression of PV was not associated with the course of the kidney cancer. Based on results of survival, we can suppose that PV could be negative prognostic factor. However, this study was not planned to evaluate prognostic role of PV. Larger trials are needed to better establish the role of PV in this subgroup of patients.
CONFLICTS OF INTEREST
The authors have no conflict of interest to report.
AUTHORS' CONTRIBUTION
All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualization, I.T., V.L., E.S., L.V.; Methodology, I.T., E.S., L.V.; Investigation, I.T., V.L., V.K., E.S., A.B., L.D.; Formal Analysis, I.T., V.L., V.K.; Resources, I.T., V.L., V.K., A.B., L.D.; Writing ‐ Original Draft, I.T.; Writing ‐ Review & Editing, I.T., V.L., V.K., E.S., A.B., L.D.; Visualization, I.T., V.K.; Supervision, E.S., L.V.; Funding Acquisition, none.
ACKNOWLEDGEMENTS
We would like to thank Dr Mikhail Laskov for excellent technical assistance.
Tsimafeyeu I, Leonenko V, Kuznetsov V, Semenkova E, Bondarenko A, Demidov L. Paraneoplastic vasculitis in patients with metastatic renal cell carcinoma. Cancer Reports. 2019;2:e1142. 10.1002/cnr2.1142
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