Document yr1DDBna031ZVwQeLyeYD2Kx3

...... , ... ::r/j ak Ounotnieritl :(7;24(4);276-27?; :45j^^7-1^iCriticWeritiahftrnV::|^l)1btii'.- ' Peritoneal Mesothelioma in Recurrent Familial Peritonitis ) notice this material may bp funm-rTF BY COPYRIGHT I>W mTlE \1 UJS.COD& Nicola Gentilom, M.1X, Stefania Febbraro, Carlo Barone, M.D., Gianfranco Lenxmo, M.D., Giovanni Neri, M.D., Giaoftanco Zanrtoni, M.p., Arraldo Capetfi, M-D,, and Giovanni Gasbamni, m.d. ........ . A 39-year-old man had a 2-year history offatigue, weight loss, tkug-resisiantasdtea.toidtlecreasett intestinal motility During.. aiMtecence-.'fie, began : to :suffer frequent epispdfcs ! of acute benign, pertiortitisthat spontaneously: subsided at age 35. The fact that his younger brother was taki ng colchicine for the same symptoms led us to diagnose familial Mediterranean fever (FMF);The medical weikup revealedtmtfonntluckertmgof the intestinal wall with::ao; :signs of: amyloidosis. Exploratory: laparotomy revealed diffuse: peritoneal mesothelioma that proved to be unresponsive to chemotherapy. There was no his tory of asbestos exposure, It is probable that the chtonic peri toneal inflammation was responsible for the development of this tumor, although in almost all cases of FMF this phenome non causes only limited peritoneal fibrosis or. less commonly, encapsulating peritonitis. A computerized search of the litera ture indicates that this is the second report of peritoneal mesothelioma associated With FME Key Wards: . Familial . Mediterranean ^ feyer--Malignant: mesothelioma--Colchicine. ............................................... Mesothelioma is a primary tumor arising in die pleura or, less commonly, the peritonetim and pericardium. Localized form* are usually benign, whereas diffuse involvement generally indicates malignancy. The most impprtantcause of theseiumoireis asbestosexposure.and the incidence fcinong exposed populations ranges from 13% to 100% (1). Exposure to other fibers, mineral dust, various chemicals, and ionizing radiation as well as chronic serosal inflammation are also considered; to increase the risk for these tumors (2). The possibility that R(^iva::lamiaiy 30,1996. Revision seiwMamh l.9.:!996.Accefited JW)Uy:f7, tW7i;: ; ; ; : . .''Vtili . '' . : ' From, die Institute: Of Internal Medidne and Geriatrics, Institute of Geriatric Surgety, Institute of Anatomy and Patbplogy, sad Institute ot* Genetic Metficiue, Catholic University of the Sacred Heart, Rome, Italy. / A&fiejseaiftjpbiaeiice and riprint repeats td; be. NicctaGemitoni. FoUelinico A. Gemelti, Largo A. Gertjelli,.8,00168, Home, Italy.: hereditary factors are involved in the development of mesothelioma was first raised in 1985, when Lynch ct al. (3) described 11 patients with mesothelioma in four unre lated families, However, 10 of these patients had histo ries of asbestos exposure........................... We describe a 39-year-old man in whom a malignant peritoneal mesothelioma developed after a 20-year hislory of recurrent peritonitis related to familial Mediter ranean fever (FMF). patient repoht In January 1994, a: 39-year-old Italian! man of non-Jewisti ancestry was admitted to our mcdieal center with a 2-vear his tory ofdecreased appetite,: progressive weight loss, occasional diarrhea, fatigue, low-grade ftvet, and drug-resistant ascites. At -the age of 16 years, the patient had begun to suffer frequent, self-limiting bouts. of acute abdominal pain associated with Tevsfi; boiyel distehdoh,:bbstipa{ibii,!ahd:failuhS tbpass flatus. Between attacks,-he; was...oompletelyLasymptoutiitic,' -These, episodes, which generally: lasted 24 to 72 hours, continued to octhir.^ipfoxvmatel; once a pnonth until age SSeWheri theyiub-: ridedspontanep)b!ly,At:oge3?,:tHe:3^ptbms tharbrdh^itMm to our hospital began to develop. - The patient's younger brother (age 29 years in 1994) had a : history of nontaherculous pleural effusion at the: age of 20 years, . Since, then he had experienced the Same type of recurrent ' :ahdonunal: ;pain 'Wim:::demased:::intestinal::.Tnodliiy: had already undergone two laparotomies that had no effect ott bis : symptoms. In 1992 he began daily treatment with colchicine, -and.3ince.theB his acute attacks hadbeen decieasingin both fre quency and intensity. .. : :Qn. physical examination, die patient-appeared cachectic, with marked abdominal distention resulting from ascites with . ouf.oplliftrahsupeificial'veitK.:Tbe:0yef and spleen W.ere.riot enlarged, and there were no palpable lymph nodes. The heart and lungs appeared normal, ...:: Laboratory findings were as follows: total seram proteins, 5,6 gAil; scrum albumin, 2.8 gfdtt serwn iron. 16 jigfdJ; fibrinogen, : 641 ;ingfdh transferrin; 109:mg)dl; pfodifOthbin. rijne.;88%; faemb- globin. 9.7 g/dl: red Mood ceil count, 3.]6510CK_Vmm3: mean cor- 276 MESOTHELIOMA IN FAMMAl PEBITONITIS 277 pusailai< volume; SJ::femclitrr (fl); white., blood coll count, O.fsQWrtim3 balanced leukocyte formula); total lymphocytes, 672; CtM^CD8?v OA; homan immuftodcfidcncy virus, 172 negative; total urinary porphyrin, normal. A tuberculin &|cjn test was nega tive, as was serology for antigUadin antibodSe-S, endomysium anti-; bodies, and antinuclear antibody. Circulating immune complexes Were normal. ' , Paracentesis revealed exudative: ascites consisting of sterile , peritonea) fluid with polymorphic inflammatory -cells and no neoplastic cells; Rena! function was normal, and there was no albtauinuris. The xylota and sorbitol breath tests were normal. .it? with bseterial:by^rowth. St^i;cultureswere nejfMive. -: A rectal biopsy:was:inilclty posfrive for.amylciidfCongoted)- Histologic examination of multipfe biopsies of the duodenal and jejunal mucosa revealed normal villous architecture with : no signs of amyloid or pathologic cells. Results of colorectal biopsies and thepereutaneous liver biopsy were negative. : --: On abdominal sonography, the liver, spleen, and Stomach appeared normal, and there was no: poire'i hypertension. The intestinal wall was mildly ihickoned. Computed: tomography and magnetic resonance imaging confinned (he normal appear ance ofthe liver and Spleen. The thick ascitic fluid appeared to ContMniptotein;:^ ceils. The; iritestoai jneKbteriuni was eyi- dent;' and the :enSre bowel wall was.uniformly thickened with out any evidence of localised masses or pathologic Lymph nodes. On the small intestinal bariunt study, Kerckriog's folds: and intestinal lumen appeared normal, but intestinal motility was markedly decreased; and the barium reached the terminal ileum 4 hours after ingestion. Results ofthe barium enema were normal, , In light of the family history;: ifc-seetmsd fairly clear that the - ^patient'attacks between the ages, of 16 -and 35 were i mani- fostation Of FMF, but the cause of his more recent symptoms : remained obscure. Exploratory laparotomy was performed to. ; TUle otit thepiesence of intestinal amyloidosis.:. . Surgery; revealed marked, diffuse ttuckehing Of the visceral and parietal peritoneum wjdi coitDike structures (Fig. 1). Hifto-:. logic- examination of thc latter demonstrated an epithelial;neo plasm (Fig. 2) that was aegative for.periodic aciii-Suhiff/dias-. tase,. Immunohistoehehiiail: ; studies. were -negative- for caneftioembryonic -antigen and LeuMl; andpositiveforkerafm and EMA. These findings, although not specific, were' highly suggestive of mesothelioma. The patient was started on doxorubicin and platinum but died 6 month? lats:At autopsy; the tumor was essentially unchanged There-were no signs ofiDtraeabdotninal orgsn: infif ..i.ttaijpnt.or.distaDtntetastases.. . DISCUSSION Malabsorption resulting from celiac sprue or smalt bowel lymphoma with ascites was excluded by the nor-mal' -mucosal : .biopsies and sefotogifi1 markers. The patient's history and that of his brother were highly . indicative of FMF; and although there was no sign of amyloid material in the mucosal biopsies from the duo denum or jejunum, wc initially suspected that the diffuse, uniform thickening ofthe small bowel wall and markedly reduced nrotility imgbt be due to amyloid depositioftiin the external muscle layer. The surgical biopsies instead revealed a tubopapillaiy epithelial neoplasm, with immunohistoehemical features FIG; 1. Laparotomy: dthuse and massive thickening of the peritoneum, which appears lardaceena with orartge-psei suriace. The peritoneum covers the thtra-abtfominal organs and tikes the intestine, as a rigid tangle, to the posterior wall of the abdomen: Itforms cordlike structures all around the Intestinal loops, the lateral wall of the abdomen, the liver, and the spleen. pf mesothelioma, that involved both the visceral and parietal peritoneum. The extent of the abdominal involvement and the clinical evolution of the disease were more indicative of malignancy than were the histo logic findings. In the presence of asbestos exposure, the symptoms this man had been experiencing for the past 2 years (cachexia, intractable ascites, reduced intestinal motil ity), altbou^r nonspecific; would have been suggestive of peritoneal mesothelioma (4). However, neither, the patient nor his brother had been exposed to this substance or any of the oilier substances implicated in the appearanceofihistuinor. Theonlyplausibleexplanatibnforthe tumor was the patient's lorig hjstory of "benign peritoni tis," which was diagnosed as FMF, FMF is a genetic disorderofunknown causo that is snestricted to certain-Mediterranean ; populatipns;>paiticu-; 278 gentilometal " "...............'.......r FIG, 2, Histologic evaluation Shows diffuse tubopaplltery woptasm d the epithelial type.. lady the Arabs of thc Middle Essti Anatolian Turks, and Armenians. In Jewish ethnic groups, the frequency of heterozygous earners also appears tohe quite high, rang ing from approximately 3% in the Ashkenazic subgroup to 20% among (he Jews of Libya (5), Rare cases have also Been reported tn non-Jewish Italians (6). In 1961, Heller et a]. (7> suggested that FMF was : inherited as a single autosomal recessive trait. A mutant FMF gene with pleiotropic effects {known as the MBF gene) has been mapped on the short arm of chromosome 16 (8). Observadotis.suggest that there may also be a sec ond gene that causes a milder form of the disease, with autosomal dominant characteristics (9). Hie clinical presentation is usually a variable cotubinucion of two different phenotypic expressions. Type 1 FMF is primarily characterized: by recurrenV self-limiting attacks of serosalulflammationinvolving theperitoneum, pleura, and synovia. Two thirds of all patients with this type of disease, undergo unnecessary laparotomy for "acute abdomen," and surgery is; generally well tolerated but ineffective. In type 11 FMF, the major feature is inside ioos systemic deposition of AA-amyloid that is particu larly marked in the kidneys. In 90% of these patients, renal failure develops beforeage 40 years. The amyloido sis generally appears to be caused by the chronic inflam mation,: although in many cases it precedes the abdomiaal symptoms andBmyremaintheoidyraaDjfesmtionofdie disease. Forms of FMF with persistent fever as the only symptom and:no family history have also been described * (10), aiiddiagnosis is difficult in these cases, - - , For the moment, there is no specific procedure for the diagnosis, of FMF. Positive responses in the metoreminol provocation test and elevated plasma levels of dopamine B-hydroxylase were considered highly specific for FMF when the disease was thought to be caused by an inborn error of catecholamine: metabolism, but this hypothesis has now been abandoned. Israeli investigators have demonstrated a striking reduction in the in vitro pro duction of inducible tumor necrosis factor by peri pheral-bipod monohucleiir Cells during acute; FMF:4ttacks and a fivefold Increase over normal in serum tumor necrosis factor levels during asymptomatic in* tervafs {11), These findings suggest that tumor necrosis factor tuny play a role in the pathogenesis of the disease and raise the possibility of a specificdiagnostic test based on serum levels. Systemic perivascular AA-amyloid infiltration can be demonstrated in bone marrow biopsies . using an immunoperoxidase stain: and monoclonal anti* body (12). In the early 1970s, two double-blind, placebo* controlledtrials showed thatcolchicinecouldpreventthe acute attacks in FMF and reduce the incidence of renal amyloidosis by approximately two: thirds when admicis* 1 tered prophylactidally <13,14-). The drug has also been shown to reverse PMF-relatednepluotic .syndrome (15) and to preventthe recurrence of amyloid deposition after renal transplantation (16), All of the symptoms presented by our patient and his brother were typical of type I FMF, which appears to be more common among Italians than type II (unpublished observations), and there was no evi dence of: renal or Intestinal amyloidosis in either case. :fn: :the:.absence:of:previous* exposure to asbestos:or other known riskfactors, it seems probable that the: malignant peritoneal mesotheliomawas: toeresaltofchronic.irrita-: Son causedby recurrent peritonea) Lnflsjnmation. A case of malignant peritoneal mesothelioma;was described by Riddell etal. in a patient with a U-year history of rccurrent diverticulitis, and chronic infiammation was: sitspeered of contributing to the development of the tumor :: Howeveri :::fiie :]phg*terrn: effects: :.pf:. pt-fitphetil J in GtKilucnIen>l,: lW; 2S; ,V<X 4.IV97 MESOTHELIOMA IN FAMILIAL PERITONITIS m involvement ia FMF me generally limited to localized fibrosis or encapsulating peritonitis (18). Malignant outcombs are:rare,-; and there:has been only one other repeat .: thus far of mesothelioma associated with FMF (19). Hie diffuse abdominal involvement in the present cash sug gests a polyclonal origin, end the long latency is consis tent with the slow growth of this tumor. .. Several chromosomal deletions, have been found in patients with malignant mesothelioma,.including some involving chromosome 16 where the MEF gene is located (20). Although there are no data to support this hypothesis, jris possible that the MO1 also functioned as an oncogenic suppressor gene and that , a subsequent mutation might have lead to the development of the mesothelioma. Shortly after the patient's death, his brother underwent surgery for repair of a ventral hernia that had developed after a previous laparotomy. Careful exploration of the abdomen did not reveal any sign of mesothelioma. The absence of malignancy in this case is not surprising given the pleiotropic nature of thC-MEF gene, but it might also be a reflection of the 'attenuation of the inflammatory process achieved with colchicine. Nonetbelessj thepossi-. : bility that peritoneal mesothelioma will eventually develop in the younger brother* who is currently only: 32 years old, cannot bo ruled out, and he is currently being monitored by our staff. Acknowledgment: We are grateful to Miss MariairKent for : her editorial assistance in preparing this article. 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Kidney.hat t993:44;834-86. ll,EiiaarelioCA.Wo)SSM.:Goldnnecr.S,:ctakEolchidTte.UKisp)-: ' for familial Mediterranean fever: avdoiibie-blind trial: 'V Engl j . .VfeiJ:t.974;591:934-7. ' v- :: .1? :# J;.; ; 14: :Zcinsrt>,,itevacl] M, pros. M, et aL A eontrollejd triiiVdf colchicine i - rin preientnig attack of familial'Mediterranean fever, A Engl i Med . 1974i29li932r4.. : ' P' -r .'':f Jr; :.': ::15. ZemeriD^Li-yeneh A. ^gevitiiR.EeV^in::# the nephrotie syri- L drdrite by colthiciitt: in: aniyioitl6s:ii of familial Maditonanear fever. Aim-Intern Med 1992:116:426. 16. Livneli A, Zcmer D: Siegal B, el al. Golchigins prevents kidney . fri fairiilialMedilerreheffli fever. Nephron. 1992;60:418-22 . 17. Atsenrijevich UGruberg L. Rras E: et;d.:vit!.nce fpr:lu}kageiif J J" die gen* causing fimiltal Mediieireneaa fever (o.chromdWrtiS I7g ; : :iti nnn-Astikcnazi Jewish families; second lotus or type I error? Ham Gruel 1993;91;527-?4. 18. Cifttoi AO, TaayefCr BujTi.kpantdliCu 14,;.H3cspiimeeAi Adbesiye: ., amaiftKiyteliobsmiiiton caost by famiJjai:M|dtwOTiiew feVer:. the incidence and outcome. J Pedratr Surg 1995:30:577-9, 19. BariS VI, Artvihli:M, Sbdin AA &vjrdnmental meidihelionia tri Turkey Ana NYAcad Set l979f!30i423-32, : 20, Taiudii T, JhanwariSC. Siejfried JM, et l;Re0ltreM. :dele<lqns of VS:;: speciflc ehroftirepaial Sites inlp; 3p; iki; and 9p in human jnaiig- ^ 'V.:- W-^rP i - : ' .'is:;;# : ; . pw: i-s|: ^- ^ p P & M-.py : s:P V- - , , ssssisvl:, lir V. . ' w-l . y:\&. -::i . " f -ivi: " ' J- V- ,V:J- ;;S; ^ ^ ;|v ^ W 'W ^ ' . pp - -v - J J , . . - * .y- . ' - : :<PP"i ... MX' ^. : . : h. ^P PM-SP P- m >-= v-qir 9-ypP'P tiPPMPW:W-- :...'> ' . ,P;. ----- -y. v:.::. e-f - 'S-"::' '.vV :> :o ;->... . v v,x . >> ."'V' V' ' . " ". . . ' ' '' V>S S-v . . 'VjV-`7? , '