A 69-year-old man under long-term spironolactone therapy (16 years) was hospitalized with spontaneous hematoma on the trunk and extremities. Coagulation studies disclosed an acquired hemophilia that was successfully treated with human factor VIII for a few days and immunosuppressive agents for several months. Physical examination revealed bilateral gynecomastia and an upper left quadrant breast nodule. Complete staging was unremarkable. Complete left mastectomy was performed. Histopathology showed invasive ductal carcinoma, expressing positivity for estrogen and progesterone receptors. The acquired hemophilia was considered to be a paraneoplasic syndrome. The question of a linkage between long-term spironolactone therapy and breast carcinoma is discusse

Bauer, Jean

Elmiger, Hubert

Fiche, Maryse

Lamy, Olivier

Livio, FranÇoise

RERO DOC Digital Library

CASE REPORTInt J Clin Oncol (2004) 9:130–133 © The Japan Society of Clinical Oncology 2004DOI 10.1007/s10147-003-0372-2Olivier Lamy · Hubert Elmiger · Maryse FicheJean Bauer · Françoise LivioAcquired hemophilia as first manifestation of breast carcinoma in a manunder long-term spironolactone therapyReceived: March 6, 2003 / Accepted: December 8, 2003Abstract A 69-year-old man under long-term spironolac-tone therapy (16 years) was hospitalized with spontaneoushematoma on the trunk and extremities. Coagulation stud-ies disclosed an acquired hemophilia that was successfullytreated with human factor VIII for a few days and im-munosuppressive agents for several months. Physicalexamination revealed bilateral gynecomastia and an upperleft quadrant breast nodule. Complete staging was unre-markable. Complete left mastectomy was performed. His-topathology showed invasive ductal carcinoma, expressingpositivity for estrogen and progesterone receptors. Theacquired hemophilia was considered to be a paraneoplasicsyndrome. The question of a linkage between long-termspironolactone therapy and breast carcinoma is discussed.Key words Acquired hemophilia · Breast carcinoma ·SpironolactoneIntroductionAcquired hemophilia is a rare disease, considered to be aparaneoplasic syndrome in nearly 10% of cases.1 Malebreast carcinoma accounts for nearly 1% of all diagnosedbreast carcinomas.2,3 Unfortunately, male breast cancer isO. Lamy (*) · H. ElmigerService of Medicine A, Department of Internal Medicine, UniversityHospital, CHUV, BH10, CH-1011 Lausanne, SwitzerlandTel. 41.21.314.02.81; Fax 41.21.314.08.71e-mail: olivier.lamy@chuv.hospvd.chM. FicheDepartment of Pathology, University Hospital, Lausanne,SwitzerlandJ. BauerOncology Center, Department of Internal Medicine, UniversityHospital, Lausanne, SwitzerlandF. LivioDivision of Clinical Pharmacology, Department of InternalMedicine, University Hospital, Lausanne, Switzerlandoften diagnosed at a late stage because of the minimalawareness of presenting symptoms by the patient and some-times by the health-care provider. Because of this latepresentation, the overall prognosis is less favorable.2,3Spironolactone has antiandrogenic characteristics, andanimal data suggest the oncogenic potential of spironolac-tone’s metabolite. We report a very rare case of a manunder long-term spironolactone therapy who was hospital-ized for hematoma as the first manifestation of an acquiredhemophilia related to breast carcinoma.Case reportA 69-year-old man with a history of membranous nephro-pathy and moderate renal failure (creatinine clearance,50ml/min) had been on spironolactone therapy (100mg/day) for 16 years. He was known to have atrial fibrillation,hyperlipidemia, and diabetes. Co-medications includedfurosemide, digoxin, acenocoumarol, simvastatin, andglibenclamide. He was hospitalized on September 12, 2001with arthralgia and spontaneous hematoma on the trunkand extremities.At presentation, his hemoglobin level was 88g/dl, whitecell count was 17000/µl, and platelet count was 36.4  104/µl. Complete chemistry confirmed an elevated creatininelevel, at 120µmol/l (normal range, 44–106µmol/l) and re-vealed only a slight increase of total creatine kinase andlactate dehydrogenase. Urinanalysis was normal. Coagula-tion studies disclosed: prothrombin time, 130% (normalrange, 85%–125%); activated partial thromboplastin time,91 sec (normal range, 21–33 sec); fibrinogen, 5.8g/l (normalrange, 1.6–3.8g); negative fibrin monomer; D-dimer, 0.4–0.8mg/l (normal range, 0.2mg). Factor VIII was very low,at 1% (normal range, 70%–150%) and an inhibitor wasidentifiable.An acquired hemophilia was diagnosed. Fresh frozenplasma was initiated upon presentation. Once factor VIIIinhibitor was discovered, human factor VIII was started, ata dose of 200UI/kg per day. This treatment was given at a131tapered dose, according to the clinical status and the nor-malization of factor VIII values, for a period of 16 days.Immunosuppressive agents, including cyclophosphamide200mg/day and prednisone 1mg/kg per day (80mg) werestarted with human factor VIII. Considering the good bio-logical response, prednisone was decreased to 0.5mg/kg perday after 2 weeks. Results of serum protein electrophoresis;serologies for virus, including HIV, hepatitis virus, cytome-galovirus, and Epstein-Barr virus; and rheumatologic tests,including rheumatoid factor, antinuclear antibody, andantineutrophil cytoplasmic antibodies, were unremarkable.Complete examination revealed bilateral gynecomastia andan upper left quadrant breast nodule of 2  3cm. Thegynecomastia had appeared after the initiation of spirono-lactone, and had been known by the patient and his generalpractitioner for 10 years or more. No physical examinationof the gynecomastia had been made previously. The mam-mographic findings are shown in Fig. 1.An ultrasound-guided needle-core biopsy was per-formed on September 28. Histopathological analysisshowed invasive ductal carcinoma. Staging, including tho-racic, abdominal, and pelvic computed tomography (CT)scanning; bone scintigraphy; and laboratory parameters(corrected calcemia, liver function tests) was unremarkable.A mastectomy was performed on October 15, without com-plication. At gross examination, the tumor measured 1.8cm.Histologically, it was invasive ductal carcinoma with an insitu ductal carcinoma component (Fig. 2a,b). The invasivecarcinoma was organized partly in tubes (50% of tumorsurface), nuclear pleomorphism was marked, and the mi-totic count was low (six mitoses per ten high-power fields),corresponding to histoprognostic grade II according to theElston and Ellis system. The in situ component accountedfor 10% of the tumor surface, was located within the tu-moral nodule, and exhibited low nuclear grade and a cribri-form pattern. All (100%) tumor cells, in both components,expressed estrogen receptors (Fig. 2b) and progesteronereceptors. Peritumoral mammary tissue exhibited diffuseFig. 1. Mammography. Mass with irregular contours (diameter, 1.1 cm)without calcifications, at the junction of the upper and the lower outerleft quadrant of the left breastabFig. 2a,b. Invasive ductal carcinoma, histopathology. a Invasive ductalcarcinoma with minimal in situ component (right), and fibroticperitumoral mammary tissue consistent with the fibrous type of gy-necomastia (left). b Immunohistochemical staining, showing that 100%of the invasive carcinoma cells, as well as some normal duct epithelialcells (top), express estrogen receptor. a H&E, 200; b immuno-peroxidase, 400132fibrosis surrounding ducts, without significant epithelial hy-perplasia, consistent with the fibrous type of gynecomastia(Fig. 2a). Two axillary sentinel lymph nodes were analyzedon 12 sections 250µm-thick, after both hematoxylin eosinand immunohistochemical stainings, the latter using anantibody directed to cytokeratins. No tumor cells werefound by these procedures. The final pathological diagnosiswas invasive ductal carcinoma, grade II, pathological stagepT1pN0 (sn). Spironolactone was stopped and adjuvanttamoxifen started. The patient returned home on October23. Blood test results rapidly returned to normal and theimmunosuppressive therapy was stopped after 7 months.The factor VIII level was in the upper normal range andfactor VIII inhibitor was undetectable. After 2 years, thepatient remains clinically well, without clinical or biologicalrecurrence. At physical examination, the size of the rightgynecomastia has decreased and the consistency is moreadipose.DiscussionAcquired hemophilia is a rare disease caused by thedevelopment of auto-antibodies against factor VIII. Inapproximately 50% of cases, the etiology is unknown.1Autoimmune disorders account for more than 10% ofcases, paraneoplasic syndrome for 7%–15% of cases, thethird trimester of pregnancy or the postpartum period for10% of cases, adverse drug reaction for 3%–6% of cases,and various skin disorders for 2%–5% of cases.1 The treat-ment of choice for acquired hemophilia includes the use ofhuman or porcine factor VIII in patients who are bleeding,and immunosuppressive agents (corticosteroids with orwithout cyclophosphamide or chlorambucil).4,5We performed a Medline search of the literature anda review of appropriate publications to identify a linkbetween acquired hemophilia and spironolactone or breastcarcinoma. No case of association between spironolactoneand acquired hemophilia was described. Adverse drug reac-tions with penicillin, ampicillin, phenytoin, nitrofurazone,chloramphenicol, sulfa drugs, or fluoroquinolones havebeen associated with factor VIII inhibitors.1 Some case re-ports have suggested a relationship between chronic renalfailure and acquired hemophilia.6 This association was notdescribed in the review by Bossi et al.1 In our patient, theblood test results rapidly returned to norm after the immu-nosuppressive therapy was started and the left mastectomyperformed. At the same time, the magnitude of chronicrenal failure did not change. For this reason, we have notsuggested a relationship between chronic renal failure andacquired hemophilia. We identified only three other casesdescribing an association between breast cancer and ac-quired hemophilia.7–9 These three cases occurred in women.In our patient, breast carcinoma was considered to be the“primum movens”. A retrospective study of 41 patientswith cancer and acquired hemophilia revealed that in 61%of cases solid-organ tumor was the underlying diagnosis.7Prostate cancer was the most common, followed by lungcarcinoma. The most common histologic type wasadenocarcinoma.Putative risk factors for breast carcinoma in men in-cluded advanced age, Jewish ancestry, a positive family his-tory, excess exposure to female hormones (Klinefelter’ssyndrome), environmental exposure (irradiation), alcohol,and obesity.2,3 Our patient had none of these risk factors.Considering the well-known causal relationship betweenspironolactone and gynecomastia, although gynecomastia isnot recognized per se as a predisposing factor for breastcarcinoma, the question of a linkage between long-termspironolactone therapy and breast carcinoma was raisedin this case. The manifestations of spironolactone’santiandrogenic effects are various and partly dose- andtime-dependent; in men, these involve gynecomastia, de-clining libido, and impotence. Competitive antagonism onandrogenic tissue receptors by spironolactone is thought tobe the main mechanism. Weak inhibition of androgen syn-thesis and increased conversion of androgens to estrogenswere irregularly demonstrated and are probably minor.10,11Animal studies have shown an increased rate of neoplasia,including breast carcinoma, in rats on high-dosecanrenoate, another aldosterone antagonist which shares acommon metabolite (canrenone) with spironolactone.12Some cases of breast carcinoma in women under spirono-lactone therapy have been reported, but this associationmay only be fortuitous.13 Male cases have also been re-ported to the WHO database, without a proven causalrelationship.Although there is no proven association betweenspironolactone and breast malignancy, a doubt cannot beruled out, considering the antiandrogenic characteristics ofspironolactone and animal data suggesting the oncogenicpotential of spironolactone’s metabolite. As spironolactoneis now widely used, especially for cardiac failure, specialattention should be paid to its safety profile.References1. Bossi P, Cabane J, Ninet J, et al. (1998) Acquired hemophilia dueto factor VIII inhibitors in 34 patients. Am J Med 105:400–4082. Goss PE, Reid C, Pintilie M, et al. (1999) Breast carcinoma: areview of 229 patients who presented to the Princess MargaretHospital during 40 years: 1955–1996. Cancer 85:629–6393. Giordano SH, Buzdar AU, Hortobagyi GN (2002) Breast cancer inmen. Ann Intern Med 137:678–6874. Kleinman MB (2002) Anti-inhibitor coagulant complex for therescue therapy of acquired inhibitors to factor VIII: case reportand review of the literature. Haemophilia 8:694–6975. Boggio LN, Green D (2001) Acquired hemophilia. Rev Clin ExpHematol 5:389–4046. Narukawa N, Abe T, Shouno M, et al. (1999) A case of factor VIIIinhibitor-positive acquired hemophilia treated by plasmapheresis.Ther Apher 3:323–3257. Sallah S, Wan JY (2001) Inhibitors against factor VIII in patientswith cancer. Cancer 91:1067–10748. Lopez R, Mateo J, Cruz J, et al. (1995) Presentation of an acquiredfactor VIII inhibitor with a muscular haematoma mimicking a deepvenous thrombosis in a patient with breast cancer. Blood CoagulFibrinolysis 6:680–6829. Barlas AH (1986) Acquired factor VIII deficiency in an elderlywoman on tamoxifen. J Am Geriatr Soc 34:318–32013310. Corvol P, Michaud A, Menard J, et al. (1975) Antiandrogeniceffect of spironolactones: mechanism of action. Endocrinology97:52–5811. Miyatake A, Noma K, Nakao K, et al. (1978) Increased serumoestrone and oestradiol following spironolactone administration inhypertensive men. Clin Endocrinol 9:523–53312. Wagner BM (1987) Long-term toxicology studies of spironolac-tone in animals and comparison with potassium canrenoate. J DrugDev 1S2:7–1113. Loube SD, Quirk RA (1975) Breast cancer associated with admin-istration of spironolactone. Lancet 28:1428–1429

Acquired hemophilia as first manifestation of breast carcinoma in a man under long-term spironolactone therapy

http://doc.rero.ch/record/312887/files/10147_2003_Article_372.pdf

Acquired hemophilia as first manifestation of breast carcinoma in a man under long-term spironolactone therapy

Abstract

Similar works

Full text

Available Versions

RERO DOC Digital Library