59 Članek prispel / Received 5. 2. 2022 Članek sprejet / Accepted 27. 9. 2022 Abstract Purpose: This study aimed to present the case of prolonged, recurrent, spon- taneous massive bleeding in a patient with five metachronous primary mali- gnancies. Case presentation: A 70-year-old male patient presented with massive hematomas in the gluteal and femo- ral regions and a 6-year history of prostatic, urethral (penile), right co- lonic, and right pulmonary carcino- ma, with a myeloproliferative disease that recently ended with lymphatic leukemia. Fasciotomies with the eva- cuation of massive hematomas were performed due to the development of compartment syndrome, which were followed by persistent recurrent bleeding. Despite several surgical Izvleček Namen: Predstavitev primera dolgo- trajne, ponavljajoče, spontane, ma- sivne krvavitve pri pacientu s petimi različnimi malignomi, nastalimi v različnih obdobjih. Prikaz primera: Predstavljamo primer 70-letnega pacienta z masiv- nimi, ponavljajočimi hematomi v zadnjičnem in stegneničnem področju z malignomom prostate, uretre (peni- sa), desne strani debelega črevesa in desnih pljuč, z mieloproliferativnim obolenjem, ki se je nedavno zaključilo z razvojem levkemije. Zaradi nastan- ka utesnitvenega sindroma sta bili nujni fasciotomiji z odstranitvijo he- matomov, po katerih se je krvavitev vztrajno ponavljala. Kljub številnim kirurškim posegom z zatlačenjem, lo- Ključne besede: masivna krvavitev, številni primarni malignomi, metahrone novotvorbe, embolizacija Key words: embolization, massive bleeding, metachronous neoplasms, multiple primary malignancies Dolgotrajne, ponavljajoče, spontane, masivne krvavitve v zadnjičnem in stegneničnem področju pri pacientu s petimi primarnimi malignomi, nastalimi v različnih obdobjih Prolonged, recurrent, spontaneous massive gluteal and femoral bleeding in a patient with five metachronous primary malignancies Avtor / Author Andrej Čretnik1,3, Pia Šumer2, Silva Breznik2 Ustanova / Institute 1Univerzitetni klinični center Maribor, Oddelek za travmatologijo, Maribor, Slovenija; 2Univerzitetni klinični center Maribor, Radiološki oddelek, Maribor, Slovenija; 3Univerza v Mariboru, Medicinska fakulteta, Katedra za kirurgijo, Maribor, Slovenija; 1University Medical Centre Maribor, Department of Traumatology, Maribor, Slovenia; 2University Medical Centre Maribor, Department for Radiology, Maribor, Slovenia; 3 University of Maribor, Faculty of Medicine, Department of surgery, Maribor, Slovenia; ACTA MEDICO-BIOTECHNICA 2022; 15 (2): 59–64 Poročilo o primeru / Case report https://doi.org/10.18690/actabiomed.244, CC BY 4.0 © 2022 Avtor(ji) / The Author(s) 60 INTRODUCTION An increase in overall life expectancy, improved cancer therapies and follow-up, and more sensitive detection modalities have allowed an increase in the reported frequency of multiple primary tumors in the range of 2%–17% (1,2). The term multiple primary malignan- cies commonly includes two large categories: if they are diagnosed simultaneously or within 6 months, they are called synchronous neoplasms, and if second- or higher- order malignancies follow at least 6 months after the previous one, they are called metachronous neoplasms (2). Massive soft-tissue hematomas can occur acutely or can be chronic, with an increase in size for more than a month after the initial hemorrhagic event (3-5). In most cases, these hematomas are associated with trauma, sur- gery, and bleeding disorders (3-7). Bleeding can be ex- acerbated by medications and can vary from single epi- sodic bleeding, which can be stopped and spontaneous- ly resolved by hemostatic mechanisms, to catastrophic bleeding, possibly with compartment syndrome or even exsanguination (4,7). Besides surgical treatment, the embolization of bleeding vessels has been proven to be successful in treating prolonged and recurrent bleeding in patients (7,8). CASE PRESENTATION A 70-year-old male patient visited the emergency de- partment due to pain in the chest and in the left lower extremity for some days, with a “hot feeling” in the hip region. kalnimi sredstvi za zaustavitev krva- vitve, kirurškimi šivi in selektivnimi embolizacijami s takojšnjo zaustavi- tvijo krvavitve je digitalna subtrakcij- ska angiografija po nekaj dneh vedno pokazala ponovitev krvavitve iz odda- ljenega povirja notranje črevnične in globoke stegnenične arterije. Testi ko- agulacije in agregacije in testi za bole- zni motenj krvavitve so bili nenehno v mejah normale. Histološke preiskave niso pokazale malignega procesa v področjih krvavitev, prav tako nismo našli ponovitve malignega procesa na kontrolnih računalniških (CT) in pozitronskih emisijskih tomografijah (PET). Zaklju~ek: Ponavljajoče krvavitve nam je uspelo zaustaviti šele s posto- pno, vse agresivnejšo, neciljno emboli- zacijo, po čemer sta se fasciotomijski rani postopno zacelili. interventions with packing, local he- mostatic agents and sutures, and se- lective embolization with immediate clinical discontinuation of bleeding, the digital subtraction angiography showed recurrent bleeding from the peripheral branches of the internal iliac and deep femoral arteries always a few days after the procedures. The coagulation and aggregation parame- ters and bleeding disorders tests were within normal ranges. The histology showed no malignancy in the affected regions, and no relapse was reported in any regions with previously ope- rated malignant diseases on control computed tomography and positron emission tomography scans. Conclusion: We could stop the bleeding only with more aggressive, nontarget gradual embolization. Sub- sequently, hemostasis was achieved, with gradual healing of incisions. Poročilo o primeru / Case report ACTA MEDICO-BIOTECHNICA 2022; 15 (2): 59–64 Naslov za dopisovanje / Correspondence Corresponding author: Andrej Čretnik M.D., Ph.D., Department of Traumatology, University Clinical Center Maribor, Ljubljanska 5, 2000 Maribor, Slovenia Phone: +386 2 321 1391, Fax: +386 2 332 4830, e-mail: andrej.cretnik@guest.arnes.si 61 anamnesis of a “hot feeling” a night before, recurrent palpable mass in the gluteal and femoral regions, and a drop in the hemoglobin level to 81 g/L. The bleeding tests, including rotational thromboelastometry, were again without abnormalities, and computer tomogra- phy angiography showed no active bleeding. Magnetic resonance imaging (MRI) was performed, showing mas- sive hematomas in the gluteal and femoral regions (Fig. 1). In the next 5 days, the hemoglobin level continuously dropped and symptoms of compartment syndrome de- veloped. Therefore, two separate fasciotomies and evac- uation of massive hematomas in the gluteal and femo- ral regions were performed, with no obvious source of bleeding found. In the following days, the drop in the hemoglobin level and hematomas were found on ul- trasonography again. Subsequently, another operative revision with packing and topical local hemostats and digital subtraction angiography (DSA) were performed. Large-caliber peripheral arteries (Fig. 2) with minor ex- travasation were found. Hence, selective peripheral em- ACTA MEDICO-BIOTECHNICA 2022; 15 (2): 59–64 Poročilo o primeru / Case report Figure 1. MRI (pelvic and femoral region, antero- posterior plane); central areas of massive hematomas in the gluteal and femoral regions are marked with ar- rows. His medical history revealed prostatic enlargement with elevated levels of prostate-specific antigen 9 years ago. The prostatic biopsy showed adenocarcinoma three years later, but the patient could not decide on the op- erative therapy. During the follow-up, a planocellular tumor of the urethra in the penile region was found on cystoscopy 2 years later. First partial and then total am- putation of the penis with neo-urethrostomy was per- formed due to disease progression. Two years later, ane- mia and, consequently, adenocarcinoma of the right colon were found. Hence, a right hemicolectomy was performed (T3, N0, M0, R0). Additional biopsy of the bone marrow was performed due to the high suspicion of myelofibrosis, which was not confirmed at that time (and a year later), but was confirmed with an additional biopsy and genetic tests 3 years later, when enlarged spleen was detected, which recently progressed to leu- kemia. With scintigraphy, planocellular carcinoma of the right lung was found a year after the adenocarci- noma of the colon. Therefore, right inferior pulmonary lobectomy was performed (T3, N0, M0, R0). During the further follow-up, positron emission tomography scans showed some reactive nodes in the thorax, but with no signs of local relapse of any malignant diseases. Therefore, chemotherapy was added to the therapy, which ended 5 months before problems in the hip re- gion occurred. The routine laboratory tests and electrocardiogram showed no abnormalities and infection. Hence, trau- matic, coronary, and thromboembolic events were ex- cluded, and the patient was discharged with symptom- atic therapy. Eight days later, a palpable mass and hematoma were confirmed in the gluteal region on ultrasonography. The hemoglobin level dropped to 84 g/L. Other rou- tine laboratory tests, including bleeding (aggregation and coagulation) tests, showed no abnormalities. Mini incision and evacuation of the gluteal hematoma, with transfusion of red blood cells and compression dress- ing, were performed. The patient was discharged 3 days later, as he reported no signs of bleeding or other prob- lems. Three days later, he returned to the clinic, with the same 62 bolization was conducted, with no bleeding found at the end of the procedure. Unfortunately, new hematomas, bleeding, and the same anamnesis of “hot feeling” recurred almost ev- ery 3–5 days. A multidisciplinary approach involving a consultation with a hematologist, an oncologist, a trans- fusiologist, a microbiologist, a pathologist, a specialist in infective diseases, and an interventional radiologist was chosen. However, the bleeding, genetic, autoim- mune, and hormonal tests, including tumor markers, showed no abnormalities. Therefore, the same therapy of repeated surgical revisions with packing and less and less selective interventional embolization with bigger and bigger coils (up to 4 mm), gelfoam, microspheres, and polyvinyl alcohol particles (up to 1200 µm) was per- formed. The bleeding in the gluteal region stopped af- ter the fourth interventional embolization. However, in the femoral region, seven procedures of embolization were needed. Aggressive, nontarget proximal emboliza- Poročilo o primeru / Case report Figure 2. DSA (femoral region, AP plane); large- caliber peripheral arteries are seen, together with extravasation and (previous) peripheral (selective) embolization with coils, gelfoam, microspheres, and polyvinyl alcohol particles. Figure 3. DSA (femoral region, AP plane); proximal nontarget embolization of deep femoral artery (marked with an arrow) is seen, together with previous proximal nontarget embolization of the internal iliac artery and more selective (periph- eral) embolization of branches with coils, gelfoam, microspheres, and polyvinyl alcohol particles. tion of the deep femoral artery with a plague of 7 mm was conducted until hemostasis was achieved (Fig. 3). Minor skin edge ischemia in the femoral region oc- curred at the end of all the procedures, which healed us- ing negative-pressure dressings in the following months. The tissue samples from the bleeding regions were sent several times for microbiologic and histologic examina- tions. A network of enlarged capillaries (and peripheral vessels) with signs of inflammation was found, with no signs of infection or malignant growth. The patient re- ceived 91 doses of red blood cells, and it took 167 days until he was discharged home. ACTA MEDICO-BIOTECHNICA 2022; 15 (2): 59–64 63 Poročilo o primeru / Case report REFERENCES 1. Vogt A, Schmid S, Heinimann K, Frick H, Herrmann C, Cerny T et al. Multiple primary tumors: challeng- es and approaches, a review. ESMO Open 2017; 2: e000172. 2. Dayer N, Fasquelle F, Salati E, Dietrich G. Multiple primary malignancies: synchronous lymphoma, pan- creatic neuroendocrine tumour and colorectal can- cer. BMJ Case rep 2021; 14: e241938. 3. 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We could not detect any traumatic event, bleeding (hematologic) disorders, coagulopathy, markers for autoimmune conditions, or medication (anticoagulant) history. No such case was reported earlier. During surgical revisions and DSA, we found a capil- lary network that continuously formed and bled, with a greater diameter of vessels, as in histologic samples. The activation and recruitment of macrophages and neutro- phils (leukocytes) in inflammation processes and under hypoxic conditions, as in compartment syndrome or due to the iatrogenic embolization of the bleeding ves- sels, contribute to the changes in vascular permeability and secretion of proangiogenic growth factors (includ- ing Fibroblast Growth Factor - FGF and Vascular En- dothelial Growth Factor - VEGF), stimulating neoan- giogenesis and changes in vascular properties (9). This mechanism is well known as tumor-induced lo- cal and systemic impacts on blood vessel function, not only in the local tumor microenvironment but also at other sites, in a patient with cancer (5,9), which might be related to patient’s bleeding problems. However, this needs further investigation. Finally, the bleeding was stopped with more aggressive, nontarget gradual embo- lization with a combination of different embolic materi- als because embolization with coils only was associated with a greater occurrence of recurrent bleeding or could cause the occlusion of nontarget vessels with coil migra- tion (8). More aggressive, nontarget embolization could successfully stop the bleeding and thus reduce the risks of massive blood loss, compartment syndrome, and ne- crosis due to massive hematomas with compression ef- fect. Necrosis with potential infection could arise due to the ischemic effect of embolization. Therefore, a mul- tidisciplinary approach with benefits outweighing the risks could be a reasonable approach in such cases. CONCLUSION The proposed multidisciplinary approach with surgical interventions, less selective embolization, and full sup- portive (replenishment) therapy was proved in our case to be effective, as hemostasis was successfully achieved with no adverse effects. ACTA MEDICO-BIOTECHNICA 2022; 15 (2): 59–64 64 8. Nolan T, Phan H, Hardy AH, Khanna P, Dong P. Bullet embolization: multidisciplinary approach by interventional radiology and surgery. Semin Inter- vent Radiol 2012; 29: 192–6. 9. Cedervall J, Dimberg A, Olsson AK. Tumor-Induced Local and Systemic Impact on Blood Vessel Func- tion. Mediators Inflamm 2015; 2015: 418290. Poročilo o primeru / Case report ACTA MEDICO-BIOTECHNICA 2022; 15 (2): 59–64