An autopsy case of rapid progressive atypical carcinoid of the lung discovered with multiple nodular shadows
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1 142 CASE REPORT An utopsy cse of rpid progressive typicl crcinoid of the lung discovered with multiple nodulr shdows Yoshio Okno*, Mmi Inym*, Nouo Htkeym*, Hiroyuki Hino*, Yoshito Iwhr*, Tokuji Motoki*, Keishi Nruse**, Yoshio Yokot***, nd Fumitk Ogushi* *Deprtments of Respirtory Medicine, nd **Deprtment of Pthology, Ntionl Hospitl Orgniztion, Kochi Hospitl, Kochi ; nd ***Yokot Clinic, Ashi-mchi, Kochi, Jpn Astrct : We report n utopsy cse of rpid progressive typicl crcinoid of the lung discovered s multiple nodulr shdows. The ptient ws n 82-yer-old mn with nonproductive cough. Both chest rdiogrphy nd computed tomogrphy reveled multiple nodules in oth the lung nd pleurl effusion. Multiple metstses to one nd liver were lso noted. Smples from the wll-side pleurl lesion were otined y videossisted thorcoscopic surgery under locl nesthesi, nd histologicl exmintion led to dignosis of typicl crcinoid. Tretment ws ineffective nd the ptient died on dy 39 fter dmission. The primry site ws identified s the lung fter utopsy. We elieve tht erly detection is crucil in the tretment of typicl crcinoid due to poor prognosis. J. Med. Invest. 55 : , Ferury, 2008 Keywords : typicl crcinoid, lung, computed tomogrphy, video-ssisted thorcoscopic surgery INTRODUCTION Crcinoid tumors comprise 1-2% of ll lung tumors (1). Although crcinoid tumors re generlly considered to represent low-grde mlignncy, n typicl vrint exists tht exhiits more virulent ehvior nd less fvorle prognosis. The first description of typicl crcinoid tumor ppered in 1944, when Engelreth-Holm descried two cses of ronchil crcinoids with typicl fetures (2). Tretment for crcinoid tumors involves complete surgicl removl, while more ggressive pproch is required in the tretment of typicl crcinoid tumors. The cse of typicl crcinoid tumor descried herein ws discovered s multiple nodulr shdows nd pleurl effusion on chest rdiogrphy, Received for puliction July 20, 2007 ; ccepted Octoer 9, Address correspondence nd reprint requests to Fumitk Ogushi, Ntionl Hospitl Orgniztion, Kochi Hospitl, Askur Nishimchi, Kochi , Jpn nd Fx : nd ws dignosed y video-ssisted thorcoscopy. Aggrvtion of the condition ws rpid nd the ptient died shortly fter dmission. Autopsy ws performed. We descrie n unusul cse of typicl crcinoid tumor of the lung nd review the relevnt literture. CASE REPORT An 82-yer-old mn ws referred to our hospitl from his locl physicin due to dry cough, dyspne nd norml chest shdows on chest rdiogrphy. He hd never smoked. On dmission to our hospitl, no normlities were identified other thn wekness of reth sounds in the left chest. Lortory lood exmintion reveled decreses in oth hemogloin nd totl protein levels (Tle 1). Erythrocyte sedimenttion rte nd levels of C- rective protein nd lctte dehydrogense were elevted. In ddition, serum levels of neuron-specific enolse (NSE), tumor mrker, were mrkedly The Journl of Medicl Investigtion Vol
2 The Journl of Medicl Investigtion Vol. 55 Ferury Tle 1. Clinicl exmintion test on dmission WBC 6900/μl Neutro 63.1% Eos. 5.1% Bso. 1.2% Mono. 6.1% Lymph. 24.5% RBC /μl H 11.9g/dl Ht 35.7% Plt /μl ESR 50mm/hour CRP 0.85mg/dl GOT 19IU/L GPT 22IU/L LDH 230IU/L T-Bil 0.46mg/dl γ-gtp 62IU/L TP 6.2g/dl BUN 20.3mg/dl Cre 0.97mg/dl N 141mEq/L K 4.40mEq/L Cl 109mEq/L NSE 57ng/ml Pro-GRP 17.4pg/ml CEA 3.3ng/ml incresed (norml : 10 ng/ml). Conversely, crcinoemryonic ntigen nd progstrin-relesing peptide levels were within norml rnges. Rdiogrphy nd computed tomogrphy (CT) of the chest reveled multiple nodules in ilterl middle nd lower loes, nd ilterl pleurl effusion (Figs. 1, 2). Multiple metstses to the one nd liver were lso noted. Although ronchoscopy ws Fig. 2, ) Chest CT on dmission, demonstrting multiple shdows in oth lung fields. Fig. 1 Chest rdiogrphy on dmission showing multiple nodules in oth lungs. performed, definitive dignosis could e identified. Specimens for histologicl exmintion were otined from the pleurl wll lesion y video-ssisted thorcoscopic surgery under locl nesthesi. Thorcoscopic findings showed multiple nodules t the pleurl surfce. Histologicl findings demonstrted tht tumor cells displyed smll, round nuclei with incresed levels of chromtin nd low nucleus/ cytoplsm (N/C) rtio. Cells displyed nested, nodulr rrngement nd numerous mitotic figures, nd intrcellulr connections were wek. Blood vessels were included diffusely inside tumors nd necrotic lesions were lso occsionlly oserved in high-power fields (Fig. 3). Immunohistochemistry reveled tht tumor cells were positive for chromogrnin A, NSE nd synptophysin (Fig. 4), nd negtive for AE 1/3, CK7, CK20, EMA, CEA nd thyroid trnscription fctor (TTF)-1 (dt not shown). MIB-I index ws 10%. Histologicl dignosis ws
3 144 Y. Okno, et l. Atypicl crcinoid of the lung c Fig. 4, ) Immunohistochemicl findings show positive stining of tumor cells for synptophysin nd chromogrnin A. d Fig. 3 -d) The specimen otined from the wll side of the pleurl lesion using thorcoscopy showed smll nuclei nd smll deep stined round nuclei with mny nucler division (), with wek intercellulr connections ut infiltrtive growth with lveolr structures contining vessels. Severl res ppered rosette-like (c). Necrotic res were identified (d). typicl crcinoid, not smll cell crcinom, sed on the following findings : tumor cells showed low N/C rtio, presence of cler, ig nuclei compred with those in smll cell crcinom, positivity for chromogrnin A, nd overly extensive synptophysin. Tendency of infiltrtion to orgns ws wek, nd cells formed clumps (Tle 2). Given the ntomicl loction of the tumor, typicl crcinoid ws dignosed. For control of pleurl effusion, locl comintion chemotherpy comprising hypotonic cispltin tretment using 250 ml distilled wter, cispltin 10 mg, OK432 10KE, nd 100 mg minocycline ws initited ccording to modifiction of the method descried y Ichinose, et l. (3). This tretment hd no effect. Disese progressed rpidly nd the ptient died on dy 17 fter initition of tretment. Autopsy ws performed, nd no lesion of typicl crcinoid could e confirmed in the digestive orgns, lthough 80% of crcinoid tumors develop in the wll of the hollow orgns of the gstrointestinl trct (4). The tumor ws thus identified s typicl crcinoid tumor rising from the lungs.
4 The Journl of Medicl Investigtion Vol. 55 Ferury Tle 2. Clinicopthologicl chrcteristics etween typicl, typicl crcinoid lrge cell neuroendocrine crcinom nd smll cell crcinom Clinicopthologicl Fetures TC AC LCNEC SCLC Mitoses Asent or rre 5to10per10HPF More thn 10 per 10 HPF (verge, 75 per 10 HPF) Unchrcteristic Frequent, usully punctte Frequent, usully infrct-like Uncommon Sometimes Frequent Necrosis Nucler,pleomorphism, hyperchromtism N/C rtio Nucleoli Nucler chromtin Histologicl grde 5-y survivl(%) Moderte Occsionl Finely grnulr Low Moderte Common Finely grnulr Intermedite Low Very commom Usully vesiculr,cn e finely grnulr More thn 10 per 10 HPF (verge, 75 per 10 HPF) Frequent, usully infrct-like Cells re usully smll, lrge pleomorphic cells re rre unless mixed SC/LC Asent or inconspicuous Finely grnulr 10-20*, 0-5** Arevitions : HPF, -power fields ; N/C, Nucler to cytoplsmic ; SC/LC, Mixed smll-cell/lrge-cell crcinom ; *Liimited disese **Extensive disese DISCUSSION Crcinoid tumors constitute pproximtely 1-2% of ll lung tumors (5). These re low-grde mlignncies tht elong to the mine precursor uptke decroxylse group of tumors. The ronchopulmonry trct hs rich nd complex complement of neuroendocrine cells (6), nd ronchil crcinoids pper to shre common neuroectoderml stem cell origin with smll cell crcinom of the lung (7). The clinicl presenttion of crcinoid tumors lrgely depends on loction nd size. Tumors usully cuse symptoms only fter growing lrge enough to restrict the irwys. Moreover, crcinoid syndrome ppers in ptients with crcinoids (7). However, the present ptient showed neither signs nor symptoms suggestive of crcinoid syndrome. Crcinoids cn e divided into typicl nd typicl types, the difference eing first defined y the histopthologicl criteri of Arrigoni, et l.nd lter modified y Trvis, et l., eventully resulting in the generlly ccepted clssifiction (8-10). Crcinoids re lmost eqully distriuted etween mles nd femles (9). Men ge of onset is pproximtely 47 yers, ut typicl crcinoid tumors occur in significntly older ptients (11-13). Although this theory is specultive, such ge differences might e due to smoking s risk fctor. Severl studies support the hypothesis tht smoking my represent risk fctor in the development of typicl crcinoid tumor (14-15), ut the present ptient ws non-smoker. In ccordnce with the clssifiction of typicl crcinoids nd typicl crcinoids on pthologicl nd clinicl grounds, moleculr studies hve lso shown differences etween typicl nd typicl crcinoids nd etween typicl crcinoids nd other neuroendocrine tumors (16-20). Bsed on these reports, normlities in tumor-suppressor genes nd oncogenes re seen more frequently in typicl thn in typicl crcinoids. Chest imging is widely recognized for detecting men lesion sizes of pproximtely 3 cm (lthough much lrger lesions re lso frequent), mostly centrlly locted, with only pproximtely one-third locted in peripherlly (21). In this cse, chest rdiogrphy showed multiple nodules in oth lungs. To the est of our knowledge, pulmonry typicl crcinoid with multiple nodules in ilterl lung fields on dignosis is very rre. Metstsis ws oserved more frequently with typicl crcinoid tumors thn for other ronchopulmonry crcinoids (22). The multiple nodules in our cse were considered pulmonry metstses of typicl crcinoid tumor. Although the primry site in this cse ws uncler, we did not identify typicl crcinoid cells in the digestive orgns, which re the most common primry orgn fter utopsy. We thus consider tht the primry orgn in this cse ws the lungs. In conclusion, we hve presented n utopsy cse of rpid progressive typicl crcinoid of the lung discovered s multiple nodulr shdows nd rre clinicl course involving no crcinoid syndrome signs. Furthermore, the outcome following chemotherpeutic tretment ws ftl. In this regrd, erly dignosis is importnt for more successful surgicl tretment. REFERENCES 1. Crter D, Eggleston JC : Tumors of the lower respirtory trct. In : Atls of Tumor Pthology,
5 146 Y. Okno, et l. Atypicl crcinoid of the lung pp , Armed Forces Institute of Pthology. Wshington D.C Arrigoni MG, Woolner LB, Berntz PE : Atypicl crcinoid tumors of the lung. J Thorc Crdiovsc Surg 64 : , Ichinose Y, Tsuchiy R, Koike Y, Ysumitsu T, Nkmur K, Td H, Yoshimur H, Mitsudomi T, Nkgw K, Yokoi K, Kto H : A premturely terminted phse III tril of intropertive intrpleurl hypotonic cispltin tretment in ptients with respectle non-smll cell lung cncer with positive pleurl lvge cytology in the incidence of crcinomtous pleuritis fter surgicl intervention. J Thorc Crdiovsc Surg 123 : 695-9, Modlin IM, Sndor A : Anlysis of 8305 cses of crcinoid tumors. Cncer 79 : , Wrren WH, Gould VE, Fer LP, Kittle CF, Memoli VA : Neuroendocrine neoplsms of the ronchopulmonry trct. J Thorc Crdiovsc Surg 89 : , Gould VE, Linnoil RI, Memoli VA, Wrren WH : Neuroendocrine components of the ronchopulmonry trit. Hyperplsi, dysplsis, nd neoplsms. L Invest 49 : , McMughn BC, Mrtini N, Bins MD : Bronchil crcinoids, review of 124 cses. J Thorc Surg 43 : 8-17, Trvis WD, Rush W, Flieder DB, Flk R, Fleming MV, Gl AA, Koss MN : Survivl nlysis of 200 pulmonry neuroendocrine tumors with clrifiction of criteri for typicl crcinoid nd its seprtion from typicl crcinoid. Am J Surg Pthol 22 : , Arrigoni MG, Woolner LB, Berntz PE : Atypicl crcinoid tumors of the lung. J Thorc Crdiovsc Surg 64 : , Trvis WD, Cory TV, Corrin B : Histopthologicl Typing of Lung nd Pleurl Tumors. 3 rd ed. Springer, Berlin, Skuldottir H, Hirsch FR, Hnsen HH, Olsen JH : Pulmonry neuroendocrine tumors : incidence nd prognosis of histologicl sutypes. A popultion-sed study in Denmrk. Lung Cncer 37 : , Filosso PL, Ren O, Donti G, Csdio C, Ruffini E, Mncuso M : Bronchil crcinoid tumors : surgicl mngement nd long-term outcome. J Thorc Crdiovsc Surg 123 : 303-9, El Jml M, Nicholson AG, Goldstrw P : The fesiility of conservtive resection for crcinoid tumors : is pneumonectomy eve necessry for uncomplicted cse? Eur J Crdiothorc Surg 18 : 301-6, Besley MB, Thunnissen FBJM, Brmill E, Hsleton P, Steele R, Hmmr SP, Coly TV, Shepprd M, Shimost Y, Koss MN, Flk R, Trvis WD : Pulmonry typicl crcinoid ; predictors of survivl in 106 cses. Hum Pthol 31 : , Ersmus JJ, McAdms HP, Ptz EF Jr, Colemn RE, Ahuj V, Goodmn PC : Evlution of primry pulmonry crcinoid tumors using FDG PET. Am J Roentgenol 170 : , Ullmnn R, Schwendel A, Klemen H, Wolf G, Petersen I, Popper HH : Unlnced chromosoml errtions in neuroendocrine lung tumors s detected y comprtive genomic hyridiztion. Hum Pthol 29 : , Gugger M, Burckhrdt E, Kppeler A, Hirsiger H, Lissue JA, Mzzucchelli L : Quntittive expression of structurl genomic ltertions in the spectrum of neuroendocrine lung crcinoms. J Pthol 196 : , Gouyer V, Gzzer S, Brmill E, Bolon I, Moro D, Perron P, Benid AL, Brmill C : Loss of heterozygosity t the RB locus correltions with loss of RB protein in primry mlignnt neuro-endocrine lung crcinoms. Int J Cncer 58 : 18-24, Przygodzki RM, Flinkelstein SD, Lnger JC, Swlsky PA, Fishck N, Bkker A, Guinee DG,KossM,TrvisWD:Anlysisofp53,Krs-2, nd C-rf-1 in pulmonry neuroendocrine tumors : correltion with histologicl sutype nd clinicl outcome. Am J Pthol 148 : , Pelosi G, Rodriques J, Vile G, Rosi J : Typicl nd typicl pulmonry crcinoid tumor overdignosed s smll-cell crcinom on iopsy specimens. A mjor pitfll in the mngement of lung cncer ptients : Am J Surg Pthol 29 : , Hge R, de l Riviere A, Seldenrijk CA, vn den Bosch MM : Updte in pulmonry crcinoid tumors : A review rticle. Ann Surg Oncol 10 : , Wrren WH, Gould VE, Fer LP, Kittle CF, Menoli VA : Neuroendocrine neoplsms of the ronchopulmonry trct. J Thorc Crdivsc Surg 89 : , 1985
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