Tumor-to-tumor metastases in Cowden s disease: an autopsy case report and review of the literature
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1 Mtsumoto et l. Dignostic Pthology (2015) 10:172 DOI /s CASE REPORT Tumor-to-tumor metstses in Cowden s disese: n utopsy cse report nd review of the literture Kren Mtsumoto, Kne Nosk, Ttsushi Shiomi, Yuki Mtsuok nd Yoshihis Umekit * Open Access Astrct Tumor-to-tumor metstsis is rre phenomenon, ut it hs een suggested to e more frequent in ptients with hereditry cncer syndrome. We report n utopsy cse of tumor-to-tumor metstsis in 75-yer-old mle. At 6 months efore his deth, the ptient complined of horseness nd dysphgi, nd clinicl whole-ody exmintions reveled dvnced lung denocrcinom (T4N2M1, Stge IV), multiple skin verrucs, gstrointestinl polyposis, goiters, nd cereellr dysplstic gngliocytom (Lhermitte-Duclos disese), while PTEN gene muttion ws detected in his serum. An mtor inhiitor hd een used to tret his lung denocrcinom, ut he developed spirtion pneumoni nd died of respirtory filure. Autopsy reveled tht the lung denocrcinom hd metstsized to cvernous hemngioms of the right tril ppendge nd liver, to cereellr dysplstic gngliocytom nd to multiple orgns such s the liver, kidney, drenl glnds nd spine. This is the first reported cse of Cowden s disese with multiple tumor-to-tumor metstses. Bckground Tumor-to-tumor metstsis (TTM) is term descriing the presence of two histologiclly distinct tumors t one loction, ech with different morphologic nd immunophenotypic fetures [1]. The most common metsttic donor neoplsms re lung cncer followed y rest cncer, while meningiom is the most common recipient of metstsis mong enign tumors, nd renl cell crcinom is the most common recipient mong mlignnt tumors [2]. It hs een suggested tht ptients with hereditry cncer syndrome my e t risk for the developing TTM [3]. Cowden s disese is hereditry cncer syndrome tht consists of multiple hmrtoms nd is ssocited with incresed risks of mlignnt neoplsms in multiple orgns. However, to our knowledge, there hs een no report descriing TTM in Cowden s disese. We report herein n extremely rre cse of Cowden s disese with multiple TTM, nd discuss the ssocition etween TTM nd hereditry cncer syndrome. * Correspondence: yume@med.tottori-u.c.jp Division of Orgn Pthology, Deprtment of Pthology, Fculty of Medicine, Tottori University, 86 Nishicho, Yongo, Tottori , Jpn Cse presenttion Clinicl presenttion A 75-yer-old Jpnese mle complined of horseness nd dysphgi. By vrious whole-ody exmintions, he ws dignosed with lung denocrcinom (T4N2M1, Stge IV). Also found were right cereellr tumor (Fig. 1 nd ), derml multiple verrucs, ppillomtosis in the mouth, goiters, nd gstrointestinl polyposis. Together these results suggested Cowden s disese. PTEN gene muttion, point muttion (TGT to CGT) t exon 5 in codon 136, ws detected in his serum. Finlly, definitive dignosis of Cowden s disese ws mde. Everolimus, n mtor inhiitor, ws used for 10 dys to tret the lung denocrcinom ut ws stopped fter spirtion pneumoni egn to develop. After severl dys, he died of respirtory filure. Pthology Gross findings Mcroscopic exmintion showed white solid nodules of mm in dimeter locted in S8, S9, nd S10 of the left lung nd in S7 nd S10 of the right lung (Fig. 2). Well-demrcted reddish nodules in the right tril ppendge (Fig. 3) nd liver (Fig. 3), nd n ill-defined 2015 Mtsumoto et l. Open Access This rticle is distriuted under the terms of the Cretive Commons Attriution 4.0 Interntionl License ( which permits unrestricted use, distriution, nd reproduction in ny medium, provided you give pproprite credit to the originl uthor(s) nd the source, provide link to the Cretive Commons license, nd indicte if chnges were mde. The Cretive Commons Pulic Domin Dediction wiver ( pplies to the dt mde ville in this rticle, unless otherwise stted.
2 Mtsumoto et l. Dignostic Pthology (2015) 10:172 Pge 2 of 5 Fig. 1 MRI findings in cereellr dysplstic gngliocytom. T1 () nd T2 () weighted mgnetic resonnce imges of the hed. A striped pttern is seen in the right hemisphere of the cereellum (rrowheds). The cererl queduct is compressed while the re of solid pttern ws negtive for TTF-1 nd Npsin A. Alveolr spces in the ilterl lungs were filed with infiltrted neutrophils. The lung cncer metstsized to the left ronchopulmonry nd medistinl lymph nodes, nd infiltrted to the chest wll directly, cusing intrthorcic dissemintion nd generlized metstsis. The histologicl findings of Cowden s disese included cereellr dysplstic gngliocytom (Lhermitte-Duclos disese), multiple derml kertosis, orl ppillomtosis, gstrointestinl polyposis nd lipomtosis, nd multiple goiters. In the cereellr dysplstic gngliocytom, infiltrtion of signetring cell nests ws found (Fig. 4). In ddition, metsttic denocrcinoms forming solid nests were found in cvernous hemngioms in the right tril ppendge (Fig. 4) lesion with striped pttern in cereellr hemisphere were noted. Histology nd immunohistochemistry All tissue smples were fixed in 10 % formlin nd emedded in prffin. Severl 4-μm sections were cut from ech prffin lock. Hemtoxylin-eosin (H.E.) nd immunohistochemicl stins were performed. Microscopic exmintion of the H.E. sections reveled lung denocrcinom including solid nodules with signet-ring cells (Fig. 2) nd cinr ptterns (Fig. 2c). Intr-nd/or extrcellulr mucin ws detected y Alcin-Blue stining (not shown). The immunohistochemicl exmintion demonstrted positivity for CK7 nd negtivity for CK20, c Fig. 2 Mcroscopic nd histologic findings of lung denocrcinom. Right lungs showing multiple solid nodules (rrowheds). Solid pttern with signet-ring cells (H.E. x200). c Acinr pttern (H.E. x200)
3 Mtsumoto et l. Dignostic Pthology (2015) 10:172 Pge 3 of 5 c Fig. 3 Mcroscopic views of tumor-to-tumor metstsis from lung denocrcinom to hemngioms of the right tril ppendge () nd liver () nd liver (Fig. 4c). The metsttic denocrcinoms showed the lmost sme morphologicl nd immunohistochemicl findings s the lung denocrcinoms: tht is, they were positive for CK7 nd negtive for CK20, TTF-1 nd Npsin A. Although the frequency of such primry lung denocrcinoms is low [4], no denocrcinom ws detected in other orgns. We therefore concluded tht ech of the metsttic denocrcinom originted from the lung. Discussion We presented n utopsy cse of ptient with Cowden s disese nd multiple TTM, nd these findings greed with previous reports tht TTM occurred more frequently in ptients with hereditry cncer syndrome [3]. To our knowledge, this is the first cse report of ptient with Cowden s disese hving multiple TTM from lung cncer to cvernous hemngioms nd cereellr dysplstic gngliocytom. Cmpell et l. [1] estlished the following criteri for the dignosis of TTM: 1) The Fig. 4 Microscopic findings of tumor-to-tumor metstsis from lung denocrcinom. Metsttic denocrcinom in cereellr dysplstic gngliocytom () (H.E. x40, inset x200). Metsttic denocrcinom in hemngiom of the right tril ppendge () nd liver (c) (H.E. x40, inset x200) presence of two or more distinct tumors must exist; 2) The presence of extrvsculr metstsis; 3) Exclusion of tumor emolism nd of collision tumors ; nd 4) Exclusion of tumors tht hve metstsized to lymphtic systems tht were lredy involved y generlized lymphtic or hemtologicl mlignncy. Pmphlett estlished three criteri for the dignosis of TTM [5]: 1) The metsttic nidus must e t lest prtilly enclosed y rim of histologiclly distinct primry tumor tissue; 2) The existence of primry crcinom must e proven; 3) The metsttic tumor must e demonstrly comptile with primry crcinom y morphologicl or immunohistochemicl methods. Our cse lmost fully met oth sets of criteri for TTM. The most frequent metsttic donor in TTM is lung cncer, followed y rest cncer [2, 6 8], while renl
4 Mtsumoto et l. Dignostic Pthology (2015) 10:172 Pge 4 of 5 cell crcinom nd meningiom hve een reported s the most common recipient tumors [2, 9]. Recipient tumors hve een considered to hve certin chrcteristics tht mke them fvorle sites of metstsis, such s hypervsculrity, high glycogen nd lipid contents, the high expression of cell dhesion molecules, nd slow growth rte [10 12]. However, it hs lso een reported tht TTM cnnot e induced y vsculr-rich environment lone [13]. Thus, it remins to e clrified why certin tumorsremorelikelythnotherstoerecipientsof TTM. In turn, Cowden s disese is PTEN hmrtom tumor syndrome cused y PTEN gene muttion. It is n utosoml-dominnt disese chrcterized y the development of multiple hmrtoms in the skin, mucos, digestive trct, rest, nd centrl nervous system, nd presents high risk for mlignnt tumors in some orgns. The pthologicl findings of the present cse fully stisfied the criteri for Cowden s disese [14]. Brest cncer, thyroid cncer, nd endometril cncer re the most common mlignnt neoplsms in Cowden s disese, nd lung denocrcinom is rre [15]. Although hemngiom ws not included in the dignostic criteri for Cowden s disese [14], the revised dignostic criteri proposed y Pilrski et l. [16] included vsculr nomlies in the minor criteri. There hve lso een some reports of complicting hemngiom in ptients with PTEN muttion [17 19]. Moreover, loss of PTEN function hs een reported to result in enhnced ngiogenesis, nd it ws suggested tht ptients with Cowden s disese my experience ccelerted growth of ny incipient tumors due to enhnced ngiogenesis [20]. Thus, we speculted tht the hemngioms in our cse my hve een cused y Cowden s disese. TTM is considered to occur more frequently in hereditry cncer syndrome ecuse symptomtic enign tumors re not treted in hereditry cncer syndrome, nd thus re t risk of ecoming recipient tumors in the long term. For exmple, hemngiolstom is rrely excised in von Hippel-Lindu (VHL) disese ecuse of its slow growth nd sence of symptoms: therefore, hemngiolstoms hve een considered to e preferred site for metstsis in VHL disese [3]. However, there hs een no report descriing TTM in Cowden s disese, even though it is lso hereditry cncer syndrome. This phenomenon remins to e fully explined. In the present cse, however, we speculted tht there were three resons for the multiple TTM. First, the ptient hd symptomtic nd longstnding neoplstic lesions such s multiple hemngioms nd cereellr dysplstic gngliocytom, which my hve ecome preferred sites for metstsizing tumors. Second, lung cncer is the most common donor neoplsm in TTM. Third, it hs een reported tht TTM could occur s results of metstsis from lung cncer with more ggressive ehvior [13], which is similr to the present cse. Conclusions To our knowledge, this is the first reported cse of Cowden s disese with multiple TTM from lung cncer to cvernous hemngioms nd cereellr dysplstic gngliocytom. TTM hs een considered rre phenomenon even though it is hereditry cncer syndrome. The results of the present utopsy cse suggest tht more cse of TTM in hereditry cncer syndrome might e reveled through creful mcroscopic exmintion nd smpling of tumors t utopsy, followed y ttentive microscopic exmintion. Consent Written informed consent ws otined from the ptient s fmily for the puliction of this cse report nd ccompnying imges. A copy of the written consent is ville for review y the Editor-in-Chief of this journl. Arevition TTM: Tumor-to-tumor metstsis. Competing interests The uthors declre tht they hve no competing interests. Authors contriutions KM nd YU conceived of the study nd drfted the mnuscript. KN prticipted in the design of the study. TS nd YM prticipted in the interprettion of the pthologicl specimen. All uthors red nd pproved the finl mnuscript. Received: 16 July 2015 Accepted: 3 Septemer 2015 References 1. Cmpell Jr LV, Gilert E, Chmerlin Jr CR, Wtne AL. Metstses of cncer to cncer. Cncer. 1968;22: Honm K, Hr K, Swi T. Tumour-to-tumour metstsis: report of two unusul utopsy cses. Virchows Arch A Pthol Ant Histopthol. 1989;416: Jrrell ST, Vortmeyer AO, Linehn WM, Oldfield EH, Lonser RR. Metstses to hemngiolstoms in von Hippel-Lindu disese. J Neurosurg. 2006;105: Ye J, Findeis-Hosey JJ, Yng Q, McMhon LA, Yo JL, Li F. Comintion of npsin A nd TTF-1 immunohistochemistry helps in differentiting primry lung denocrcinom from metsttic crcinom in the lung. Appl Immunohistochem Mol Morphol. 2011;19: Pmphlett R. Crcinom metstsis to meningiom. J Neurol Neurosurg Psychitry. 1984;47: Petrki C, Vslmtzis M, Argyrkos T, Petrki K, Strtki M, Alexopoulos C, et l. Tumor to tumor metstsis: report of two cses nd review of the literture. 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5 Mtsumoto et l. Dignostic Pthology (2015) 10:172 Pge 5 of Moody P, Murtgh K, Piduru S, Brem S, Murtgh R, Rojini AM. Tumor-totumor metstsis: pthology nd neuroimging considertions. Int Clin Exp Pthol. 2012;5: Mtsukum S, Kono T, Tkeo H, Hmkw Y, Sto K. Tumor-to-tumor metstsis from lung cncer: clinicopthologicl postmortem study. Virchows Arch. 2013;463: Uppl S, Mistry D, Cotesworth P. Cowden disese: review. Int J Clin Prct. 2007;61: Boespflug A, Courud S, Bringuier PP, Isc S, Geriniere L, Perrot E, et l. Primry lung denocrcinom occurring in PTEN relted syndrome (Cowden s disese): routine EGFR sequencing lso highlights two rre somtic muttions S7681 nd V769L. Lung Cncer. 2013;79: Pilrski R, Burt R, Kohlmn W, Pho L, Shnnon KM, Swisher E. Cowden Syndrome nd the PTEN Hmrtom Tumor Syndrome: Systemtic Review nd Revised Dignostic Criteri. J Ntl Cncer Inst. 2013;105: Be BG, Kim HJ, Lee SG, Choi JR, Hwng C, Lee JH, et l. A Novel PTEN Muttion in Koren Ptient with Cowden Syndrome nd vsculr Anomlies. Act Dermto-Venereologic. 2011;91: Slem OS, Steck WD. Cowden s disese (multiple hmrtom nd neoplsi syndrome). A cse report nd review of the English literture. J Am Acd Dermtol. 1983;8: Jenny B, Rdovnovic I, Henggell CA, Delvelle J, Rufencht D, Kelin A, et l. Assocition of multiple verterl hemngioms nd severe prpresis in ptient with PTEN hmrtom tumor syndrome. J Neurosurg. 2007;107: Hmd K, Sski T, Koni PA, Ntsui M, Kishimoto H, Sski J, et l. The PTEN/PI3K pthwy governs norml vsculr development nd tumor ngiogenesis. Genes Dev. 2005;19: Sumit your next mnuscript to BioMed Centrl nd tke full dvntge of: Convenient online sumission Thorough peer review No spce constrints or color figure chrges Immedite puliction on cceptnce Inclusion in PuMed, CAS, Scopus nd Google Scholr Reserch which is freely ville for redistriution Sumit your mnuscript t
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