Accepted Manuscript Ruptured mycotic aortic aneurysm after BCG therapy Nikolaos Floros, MD, Konstantinos Meletiadis, Dr. med., Ursula Meyer, Dr. med., Ulrich Kusenack, Dr. med., Hubert Zirngibl, Prof. Dr. med., Lars Kamper, Dr. med., Patrick Haage, Prof. Dr. med., Nici Markus Dreger, Dr. med. PII:

S0890-5096(15)00488-4

DOI:

10.1016/j.avsg.2015.03.060

Reference:

AVSG 2406

To appear in:

Annals of Vascular Surgery

Received Date: 19 December 2014 Revised Date:

25 February 2015

Accepted Date: 16 March 2015

Please cite this article as: Floros N, Meletiadis K, Meyer U, Kusenack U, Zirngibl H, Kamper L, Haage P, Dreger NM, Ruptured mycotic aortic aneurysm after BCG therapy, Annals of Vascular Surgery (2015), doi: 10.1016/j.avsg.2015.03.060. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Ruptured mycotic aortic aneurysm after BCG therapy

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Nikolaos Floros, MD, [email protected]*, Konstantinos Meletiadis, Dr. med.*, Ursula Meyer, Dr. med.*, Ulrich Kusenack, Dr. med.*, Hubert Zirngibl, Prof. Dr. med., surgical center, Helios Hospital of the private university of Witten-Herdecke in Wuppertal Lars Kamper, Dr. med. °, Patrick Haage, Prof. Dr. med. °, Nici Markus Dreger, Dr. med., Department of Urology and pediatric urology, prostate center Wuppertal, Center for research in clinical medicine (ZFKM)

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*‚Bergisch vascular center‘, Clinic for vascular surgery, Helios Hospital of the private university of Witten-Herdecke in Wuppertal °Center for radiology, Clinic for Radiology, Depart ment of diagnostic and interventional radiology

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Conflict of interest: none

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Corresponding author: Nikolaos Floros, Bruederstrasse 2, 42105 Wuppertal, Germany, 004915141803020/00492028974575, [email protected]

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Abstract

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I. Purpose: To report a case of a ruptured mycotic abdominal aortic aneurysm (MAA) after intravesical Bacille Calmette Guerin (BCG) therapy due to bladder carcinoma. II. Case Report: A 57-year-old male patient was admitted to our hospital for follow-up computed tomography 14 months after transurethral resection (TUR) of a papillary carcinoma of the bladder and intravesical BCG therapy. The CT-scan revealed a ruptured mycotic abdominal aortic aneurysm and the patient underwent an endovascular repair with an aorto-bi-iliacal stent graft. III. Conclusion: A ruptured MAA is a rare but lethal complication after BCG instillation therapy. The standard therapy is the open reconstruction but according to the literature an endovascular therapy in combination with long-term antibiotics should be considered as a bridging or a definite solution. IV. Key words: ruptured mycotic aortic aneurysm, BCG therapy, endovascular repair.

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I. Introduction: MAA after BCG therapy due to bladder carcinoma is an extremely rare but lethal complication. Endovascular therapy of the ACCEPTED MANUSCRIPT ruptured aorta competes more and more often with open reconstruction because of its less invasive character. Our case report underlines the importance of considering such a lifethreatening aneurysm after BCG therapy in the past. II. Case Report: A 57-year-old male patient was diagnosed with urinary bladder carcinoma in January 2012. He underwent TUR of the bladder tumor. The histopathological examination revealed an invasive, papillary carcinoma infiltrating the superficial part of M. detrusor vesicae (pT2a). The postoperative CT scan showed no suspicious findings. The patient declined a radical cystectomy and two months later a second TUR for treatment of the residual tumor in the posterior bladder wall (pTa + pTis, G2) was necessary. The patient received a complementary therapy with intravesical BCGinstillations (2 cycles of 6 treatments each cycle). The therapy was completed in August 2012, 7 months after the first TUR. A month later he underwent a hexylaminolevulinate (HAL) photodynamic diagnosis (PDD) - assisted transurethral resection of bladder tumor (TURBT) in our hospital but there was no tumor detected in the posterior wall of the bladder. The follow-up CT scan 2 months after the BCG therapy revealed enlarged retroperitoneal lymph nodes, characterized as metastasis of bladder carcinoma (Figure 1, A). According to the literature, the most common cause of enlarged retroperitoneal lymph nodes following a TUR by pT2a carcinoma is a metastasis. If we take into consideration the rarity of this infectious complication, at the time of the examination no one suspected an infectious disease. The next follow-up CT scan 6 months after the BCG showed further enlargement of the known retroperitoneal lymph nodes with lymphadenitis para-aortal (Figure 1, B). Retrospectively, the CT scan showed an aneurysmatic dilatation of the abdominal aorta with saccular configuration just above the aortic bifurcation. The mural ring of calcification was interrupted at the level of dilatation. 12 months after the BCG, in August 2013 the patient was admitted to our emergency room with abdominal pain. The pain was localized at the lower abdomen and radiated along the left thigh. Abdominal ultrasound was inconspicuous. Biochemical parameters were within normal limits. The lumbar spine radiograph demonstrated degenerative changes. The patient was afebrile discharged with nonsteroidal antiinflammatory drugs (NSAID). The next follow-up CT scan 14 months after the BCG therapy surprisingly revealed butterflyshaped abdominal aortic aneurysm with a maximum diameter of 8.6 cm, which is reaching to the bifurcation of the aorta abdominalis and to m. ileopsoas, about 4.7 cm long. The polymerase chain reaction (PCR) was mild increased to 1, 6 mg/dl (< 0,5 mlg/dl) and the creatin kinase (CK 37°C) to 1302 U/l (< 174 U/L ). The patients temperature was 37, 5 ° C. The CK elevation can bei explained by hematoma in the m. ileopsoas and muscle cell destruction. The mild elevation of the CRP on the other hand explained by an inflammatory reaction which would be more pronounced if the patient was not taking NSAID.

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The results were associated with a covered rupture of the abdominal aorta. Considering the patient history, the rapid ACCEPTED MANUSCRIPT progression of the aneurysm and the mild infection signs we diagnosed a MAA most likely following the BCG therapy. The indication for an emergency treatment was given and after detailed explanation of the treatment options and our recommendation for an open reconstruction by MAA relying on the good condition of the patients health, on explicit request of the patient for a minimal invasive therapy an endovascular aneurysm repair (EVAR) was performed. An aorto-bi-iliacal stent graft (Zenith Flex, Cook Medical Inc., Bloomington, IN, USA) was implanted by an access through the groins (Figure 2). The patient was discharged against medical advice four days after the operation without any signs of infection.

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An additional therapy with isoniazid, rifampicin and ethambutol for at least 6 months was recommended and a follow up CT scanning in 3 months showed a regression of the hematoma and no sings of stent infection (Figure 1, D). This fact and the absence of infection signs are against the diagnosis of an abscess.

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BCG is a live attenuated strain of Mycobacterium bovis. Morales et al. first used instillation for superficial bladder cancer therapy in 1976. The use of BCG as adjuvant therapy for superficial G2T1 and G3Ta/T1 bladder carcinomas and as ablative therapy for carcinomas in situ (pTis) remains an important part of bladder cancer management. Its use decreases the number of recurrences and delays the time to first recurrence compared with TUR alone (1). BCG is used as an immunomodulator agent for malignant conditions. The instillation produces a localized inflammatory response in the bladder. The mechanism by which BCG develops its activity against tumor is unknown. There are some mechanisms that have been proposed: a. a specific immune response to BCG also stimulates non-specific immune mechanisms which destroys tumor cells, b. a specific immune response to BCG stimulates specific anti-tumor immune mechanisms (e.g. cross reaction between BCG and tumor antigens) or c. the antitumor action of BCG is caused by the general ‘toxic’ effects of inflammation (2). The recent literature suggests the role of a mononuclear cell infiltrate and the neutrophil-mediated release of tumor necrosis factor apoptosis related ligand (3). Most peri-procedural side effects are mild and self-limiting, such as bladder irritability, hematuria, low-grade fever, myalgia, malaise, prostatitis, orchitis, epididymitis. There are some serious complications that occur rare: high-grade fever (2,8%), arthritis/arthralgia (0,5%), granulomatous hepatitis, pneumonitis (0,7%), renal abscess (0,1%), leucopenia (0,1%), life-threatening sepsis (0,4%) and vascular complication such as MAA. BCGassociated aneurysms of the abdominal aorta are most common, but aneurysms of other arteries including femoral, popliteal and carotid arteries are also documented (4). 50% of mycotic aneurysms secondary to BCG instillation are ruptured and necessitate emergency surgery. Another serious complication, the

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development of an aortoenteric fistula, comes with an over 50% mortality rate (5). ACCEPTED MANUSCRIPT The mechanism that leads to a vascular damage is not clear and assuming that the routes of infection are similar to M. tuberculosis, three different mechanisms could explain an arterial infection by M. bovis: a. direct intimal colonization during a haematogenous dissemination, especially in the setting of an altered arterial wall by atherosclerosis, b. metastatic implantation of the bacteria through adventitial vasa-vasorum or c. local vascular extension of an infected site such as contiguous lymphadenitis or psoas abscess (4), as probably in our case. There are case reports with multiple mycotic aneurysms or aneurysm of the femoral artery that supports the haematogenous dissemination (3), (8), (9) and other cases that support a lymphatic spread or a direct extension from a psoas abscess. The clinical appearance varies from asymptomatic aneurysms to potentially fatal aortoenteric fistulas.

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III. Discussion: Although there are only 20 documented cases of aortoenteric fistulas the mortality of more than 50% demonstrates us that we have to be alerted. The classic triad of mycotic aneurysms with fever, abdominal pain and pulsatile mass may be present but doesn’t appear regularly. Identifying BCG on tissue samples delays diagnosis and therapy. A mycobacterial culture requires a minimum incubation period of 6-8 weeks and a minimum of 10,000 organisms per gram of tissue to obtain a positive result. The management of this severe vascular complication is difficult and demands vigilance. If we see our case retrospectiv, it is obvious that the lack of experience can lead to delay of the diagnosis or in worst case in wrong treatment. The fact that there are no guidelines due to the complicity of the case and the small number of patients makes treatment more difficult. An aortic aneurysm in a patient with a history of treatment with BCG instillation should be handled as a MAA. The therapy should be according to the literature - open reconstruction after debridement. Some authors though propose a bridging therapy with a covered stent graft and a final therapy by open reconstruction after longterm antibiotics. An exclusively endovascular therapy without another open procedure is suggested by Sörelius et al. but only in combination with long-term antibiotics and follow-up CT-scans to prevent a secondary MAA (6).

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The need of a second operation with stent graft removal and open in-situ or extraanatomical reconstruction, as suggested in the literature, should be reevaluated, in 6 months. In our case, in the first CT, 3 months after the EVAR, the size of the mass lesion of the iliopsoas was diminished. Prevention on the one hand and regarding the right surgical approach on the other are the two most important items in treating aortic aneurysm after BCG therapy. Due to the high mortality rate of aortic aneurysm or aortoenteric fistula after BCG therapy follow-up

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imaging may be warranted. But since the overall frequency of such illness still remains very low, cost-effectiveness is under discussion. ACCEPTED MANUSCRIPT Even if open reconstruction of such aneurysms should remain gold standard when less invasive endovascular approaches are feasible is part of the debate. Many patients might not even be candidates for open reconstruction and at the same time, physicians are getting more and more experienced in endovascular methods. But while the number of experts inclining towards less invasive procedures along with long-term antibiotic treatment increases, so does the number of patients.

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IV. Conclusion: Mycotic ruptured abdominal aortic aneurysm is a rare but lethal complication after BCG therapy for bladder carcinoma and requires our attention. Open reconstruction is the standard therapy but an endovascular approach in combination with antibiotics should be considered in order to long-term profit from the benefits of minimal invasive therapy.

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References

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1. Babjuk M. et al, EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2013; Eur Urol. 2013 Oct;64(4):639-53. 2. Kamphuis J.Th. et al, BCG immunotherapy: be cautious of granulomas. Disseminated BCG infection and mycotic aneurysm as late complications of intravesical BCG instillation. The Netherlands Journal of Medicine. 2001; 58:71-75. 3. Suttmann H. et al, Neutrophil granulocytes are required for effective Bacillus Calmette-Guerin immunotherapy of bladder cancer and orchestrate local immune responses. Cancer Res. 2006 Aug 15;66(16):8250-7. 4. Coscas R., MD et al, Multiple mycotic aneurysms due to Mycobacterium bovis after intravesical bacillus Calmette-Guérin therapy. Journal of Vascular Surgery. 2009; 50:1185-90. 5. Farber A. et al, Primary aortoduodenal fistula in a patient with a history of intravesical therapy by bladder cancer with bacillus Calmette-Guérin: review of primary aortoduodenal fistula without abdominal aortic aneurysm. Journal of Vascular Surgery. 2011;33:868-873. 6. Sörelius K. MD et al, Uppsala, Sweden, Endovascular repair of mycotic aortic aneurysms. J Vasc Surg 2009;50:269-74. 7. Cheng M. et al, Endovascular management of aortoduodenal fistula arising from recurrent mycotic aneurysm in an aortic stump. Ann Vasc Surg 2013; 27: 1188.e131188.e17. 8. Mizoguchi H. et al, Hyogo, Japan, Abdominal aortic aneurysmal and endovascular device infection with iliopsoas abscess caused by Mycobacterium Bovis as a complication of intravesical Bacillus Calmette-Guerin therapy. Ann Vasc Surg 2013; 27: 1186.e1-1186.e5. 9. Roylance A. et al, Aorto-enteric fistula development secondary to mycotic abdominal aortic aneurysm following intravesical bacillus Calmette-Guerin (BCG) treatment for transitional cell carcinoma of the bladder. Int J Case Rep. 2013; 4(1): 88-90. 10. Harding E. J. G. MD, Lawlor D. K. MD, London, Ontario, Canada, Ruptured mycotic abdominal aortic aneurysm secondary to Mycobacterium bovis after intravesical treatment with bacillus Calmette-Guerin. J Vasc Surg 2007; 46:131-4.

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Figure 1: A. 2 months after BCG: non-specific para-aortic lymph nodes, B. 6 months after BCG: enlarged lymph nodes, C: 14 months after BCG: butterfly-shaped abdominal aortic aneurysm with rupture and hematoma reaching to m. ileopsoas. D: 3 months after EVAR: regression of the hematoma.

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Figure 2: Intraoperative angiography after implantation of an aorto-bi-iliacal stent graft.

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Ruptured Mycotic Aortic Aneurysm after Bacille Calmette-Guerin Therapy.

To report a case of a ruptured mycotic abdominal aortic aneurysm (MAA) after intravesical Bacille Calmette-Guerin (BCG) therapy because of bladder car...
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