Orig i nals. Gas tro in tes ti nal Stromal Tu mors. A Multicenter Ex pe ri ence *

Transcription

1 Pol J Pathol 2005, 56, 2, PL ISSN Orig i nals Katarzyna Urbañczyk 1, Janusz Limon 2, El bieta Korobowicz 3, Maria Chosia 4, Jacek Sygut 5, Danuta Karcz 6, Katarzyna Iwanik 7, Czes³aw Osuch 8, Jerzy Lasota 9, Jerzy Stachura 1 Gas tro in tes ti nal Stromal Tu mors. A Multicenter Ex pe ri ence * 1 Cha ir and De partm ent of Cli nic al and Exper ime ntal Pa thom orph ology, Col leg ium Me dic um, Ja giell oni an Univers ity, Kraków, 2 Cha ir of Ge net ics, Me dic al Univers ity, Gdañsk, 3 Cha ir and De partm ent of Cli nic al Pa thom orph ology, Me dic al Univers ity, Lu blin, 4 De partm ent of Pa thom orph ology, Fa culty of Me dic ine, Po mer ani an Me dic al Univers ity, Szcze cin, 5 De partm ent of Pa thom orph ology, Œwi êtok rzys ki On col ogy Cen ter, Kiel ce, 6 II nd Cha ir of Ge ner al Sur gery, Col leg ium Me dic um, Ja giell oni an Univers ity, Kraków, 7 Cha ir and De partm ent of Cli nic al Pa thom orph ology, Me dic al Univers ity, Poznañ, 8 I st Cha ir of Ge ner al Sur gery, Col leg ium Me dic um, Ja giell oni an Univers ity, Kraków, 9 De partm ent of Soft Ti ss ue Pa thol ogy, Ar med For ces In stit ute of Pa thol ogy, Was hingt on, DC, USA The report presents 200 cases of gastrointestinal stro - mal tu mors (GIST). The ma te rial orig i nated from six di - agnostic centers in Poland and was reclassified according to the cur rent cri te ria. Among le sions other than GISTs, 14 were iden ti fied as smooth mus cle tu mors and seven as neu ral tu mors. GISTs were lo cated in the stom ach ( % of the in ves ti gated se ries), small in tes tine ( %), colon (approximately 4.5%), abdominal cav ity, i.e. in the peri to neum and omentum (6%), and in the retroperitoneal space (2.5%). A slight pre dom i nance of women was noted (53 56%). The age of the pa tients ranged be tween 14 and 93 years of life, with the mean age of 62.4 years. In di vid u als youn ger than 45 years of age ac - counted for 10% of the group. In ten pa tients (five of them less than 45 years of life), mul ti ple tu mors were de tected, their num ber rang ing from two to less than 20; these in di - viduals constituted 5% of the entire series. Moderately and highly ag gres sive tu mors pre dom i nated. In the se ries, when mul ti ple tu mors were ex cluded, a to tal of 24 epithelioid GISTs (12%) were ob served; of this num ber, 13 were sit u ated in the stom ach, six in the small in tes tine, two in the ab dom i nal cav ity and an other two in the retro peritoneal space. Synchronic tu mors ob served in pa - tients with GISTs were seen in seven pa tients, in clud ing an adenocarcinoma of the co lon, two adenocar cinomas of the stom ach, a carcinoid tu mor of the small in tes tine, a pheochromocytoma of the retroperitoneal space, an anaplastic lym phoma and a dis sem i nated squamous cell carcinoma. In immunohistochemical reactions (CD117, CD34, SMA, S-100, DES), at ten tion was fo cused on the immunoreactivity of small GISTs, be low 2 cm in size, and of multiple tumors. Immunohistochemical reactions were equally dif fer en ti ated as to their pres ence and in ten sity in small tu mors and in highly ag gres sive le sions above 5 10 cm in size. In mul ti ple GISTs, immuno histo chemical tests strongly indicated the heterogeneity of neoplastic cells, which, nevertheless, showed no consistent association with the lo ca tion of the tu mor, its ag gres sive ness, cel - lu lar struc ture or a ten dency to form mul ti ple foci. Introduction Gas tro in tes ti nal stromal tu mors (GISTs), as well as tu - mors that de velop out side the gas tro in tes ti nal tract, in the greater omentum, intestinal mesentery, gallbladder, retro - peritoneal space or the uri nary blad der [18, 29, 35, 44, 46, 53, 55], rep re sent mesenchymal spin dle cell and/or epithe - lioid cell neoplasms with a fairly spe cific immunohisto che - mical profile, characterized by a positive reaction to the CD117 an ti gen, fre quent pos i tive re ac tion to CD34, di ver si - fied re ac tion to smooth mus cle actin (SMA), a re ac tion to * The study was supported by the grant No. 3P05C05925 from the State Committee of Scientific Research (KBN). 51

2 K. Urbañczyk et al desmin which is pos i tive only in iso lated cells, and a re ac - tion to the S-100 pro tein that is ei ther neg a tive or ex pressed in no more than 10% of cells. The histogenesis of stromal tu mors is not fully elu ci - dated, es pe cially when one in cludes tu mors sit u ated out side the gas tro in tes ti nal tract. These tu mors are be lieved to arise from the multipotential CD34+ cell, a pre cur sor cell of the GI tract that is ca pa ble of vary ing de grees of dif fer en ti a tion into the in ter sti tial Cajal cells (ICC) and smooth mus cle cells, cre at ing forms with an in ter me di ate phe no type. A pos i tive re ac tion to CD117 re sults from the ex pres sion of a transmembrane re cep tor with the ty ro sine kinase ac tiv ity, which is en coded by the KITC gene on the 4q12 chro mo some that un der nor mal con di tions binds a li gand, i.e. the stem cell fac tor (SCF). In the ma jor ity of GISTs (be tween 57 and 85%), a con tin u ous ac ti va tion of KIT is as so ci ated with a mu - ta tion in the KITC gene, while the re main ing tu mors do not manifest this mutation [21, 51]. Familial multiple GISTs result ei ther from a point mu ta tion in the KITC gene in the germ cell lines or a mu ta tion in the platelet-de rived growth fac tor re cep - tor A gene (PDGFRA) [9, 34]. A pos i tive re ac tion to CD117 is seen in var i ous types of nor mal cells, in clud ing the in ter sti tial Cajal cells of the gastrointestinal tract, submesothelial spin dle cells of the greater omentum (ICC-like cells) [53, 58], bone mar row stem cells, mast cells and epi der mal basal layer cells, me - lanocytes, as well as the ep i the lium of the mam mary ducts and sweat glands. Pathological cells, including numerous neoplastic cells, also demonstrate a positive reaction to CD117. These are re ac tive myofibroblasts, as well as neo - plas tic cells in chronic myeloid leu ke mia, mel a noma, clear cell sar coma, germ cell tu mors (seminoma/dysgerminoma) and angiosar coma [61]. In ad di tion, a fo cal and usu ally cy - to plas mic re ac tion was ob served in such tu mors as synovial sar coma, leio myosarcoma, ma lig nant schwannoma, liposar - coma, der mato fibrosarcoma protuberans, atyp i cal fibroxan - thoma, ma lig nant fibrohistio cytoma, Kaposi sar coma and ad e noid cys tic car ci noma [51, 52], as well as in child hood tu mors: neuro blastoma, nephro blastoma, Ew ing sar coma and osteosarcoma [58]. In GISTs, the pos i tive re ac tion to CD117 is ob served in mem brane and/or cy to plasm and al though it is usu ally pres ent in the ma jor ity of tu mor cells it may be ab sent in some, in fre quent cases, also when they show neg a tive re ac - tions to the re main ing an ti bod ies [32, 51, 55, 57]. Material and Methods From the ma te rial pro vided by the Chair of Patho mor - phology, Collegium Medicum, Jagiellonian Uni ver sity, Kra - ków, 162 gastrointestinal mesenchymal tumors were selected, in clud ing 79 cases col lected in the years and iden - tified through reclassification. The surgical specimens formalin-fixed, routinely processed and paraffin-embedded were stained with hematoxylin and eosin and im muno histo che - mically us ing a DAKO Immunostainer (DAKO, Den mark) and the fol low ing an ti bod ies: CD117 (c-kit) (DAKO A 4502, 1:25), CD34 (DAKO M 7165, 1:25), S-100 (DAKO Z 0311, 1:200), SMA (DAKO M 0851, 1:50) and DES (DAKO M 0760, 1:50). The con trols, mostly in ter nal, were re ac tion re - sults ob tained in the nor mal tis sues of the GI tract. In ad di tion, in an at tempt to col lect as many data on GISTs in the Pol ish pop u la tion as pos si ble, the au thors re - ceived considerable assistance from other diagnostic centers in the coun try, such as the De part ment of Clin i cal Patho - morphology, Med i cal Uni ver sity in Poznañ; De part ment of Pathomorphology, Pom er a nian Med i cal Uni ver sity in Szcze cin; De part ment of Clin i cal Pathomorphology, Med i - cal Uni ver sity in Lublin; De part ment of Tu mor Pa thol ogy, Œwiêtokrzyski On col ogy Cen ter, as well as Di vi sion of Pathomorphology, First Chair of Gen eral Sur gery, Colle - gium Medicum, Jagiellonian Uni ver sity. The pro vided ma - te rial was col lected in the years and was largely pre se lected, rep re sent ing GISTs di ag nosed in the above cen ters or tu mors sus pected of be ing GISTs. Since the spec - i mens were sent to Kraków for con sul ta tions (as slides stained with hematoxylin and eosin and/or para ffin-em - bedded spec i mens or non-stained prep a ra tions only), le - sions other than GISTs had been elim i nated. These were pre dom i nantly leiomyomas, schwannomas, mel a no mas and a sin gle case of den dritic cell sar coma, which were not in - cluded into the pre sented ma te rial. Results and Discussion 1. Ma te rial orig i nat ing from the Chair of Patho morpho - logy, Collegium Medicum, Jagiellonian Uni ver sity, Kraków The re-eval u ated tu mors from the pe riod of had been pri mar ily di ag nosed as smooth mus cle tu mors (leio - myoma, leiomyoblastoma, leiomyosarcoma) or neu ral tu mors (schwannoma, neurinoma). I. Mesenchymal tu mors other than GISTs The di ag no sis of a smooth mus cle tu mor (DES+, SMA+, CD117, CD34 ) was con firmed in 14 cases: 1) Esoph a geal tu mors: 5 leiomyomas (4 males aged years and 1 fe male aged 55 years; tu mor di am e ter of 3 8 cm), 1 leiomyosarcoma (a 44-year old fe male; tu mor dia - meter of 10 cm). 52

3 GISTs 2) Gas tric tu mors: 2 leiomyomas (a 74-year old male, tu mor di am e ter of 1 cm, and a 76-year old fe male, with two ad ja cent tu - mors, 1 cm in di am e ter). 3) Intestinal tumors: 1 leiomyoma, 14 cm in di am e ter (a 67-year old fe - male), 1 leiomyosarcoma, 6 cm in di am e ter (a 70-year old male). 4) Co lonic tu mors: 2 leiomyomas (a 69-year old male; tu mor di am e ter of 0.7 cm; a 67-year old male, no data avail able on the tu - mor size), 2 leiomyosarcomas (a 62-year old male, tu mor di am e - ter of 22 cm, and a 65-year old fe male, tu mor di am e ter of 6.5 cm). Neu ral tu mors (S-100+, SMA-, DES-, CD117-, CD34-): 1) Tu mors of the stom ach (5 pa tients): 4 fe males aged years man i fested schwannoma type tu mors (4.5 and 7 cm in di am e ter, no data avail - able in two cases), dif fuse le sions in a 60-year old male ganglioneuro - matosis. 2) Tu mors of the small in tes tine: 1 tu mor with the di am e ter of 3 cm, cor re spond ing to ma lig nant schwannoma (a 75-year old fe male). 3) Tu mors in volv ing the co lon (2 pa tients): 1 schwannoma (a 60-year old fe male; tu mor di am e ter up to 6 cm), 1 neurofibroma (a 70-year old male; tu mor di am e ter of 1 cm). Ba sic data are pre sented in the Ta ble 1. In ad di tion, the in ves ti gated se ries in cluded two in - flam ma tory pol yps of the stom ach, one cal ci fy ing fi brous pseudotumor and two cases of tumoriform, fibromatous in - flam ma tory gran u la tion tis sue (in the greater omentum and Meckel s diverticulum). In two tu mors pre vi ously iden ti fied as an epithelioid leiomyosarcoma and a ma lig nant stromal tu mor, the di ag no - sis was changed re spec tively to a non-hodg kin lym phoma (the case oc curred in the pre-immunohistochemistry time) and a ma lig nant mel a noma (CD117+). One tu mor of the stom ach, 6 cm in di am e ter (an 82-year old fe male), orig i nally iden ti fied as a leiomyo - sarcoma, ultimately escaped classification (negative reac - tions to the S-100 pro tein, SMA, DES, CD117, CD34, Leu, EMA, HMB-45); there fore, the di ag no sis of a non-spec i fied sar coma was main tained. In to tal, smooth mus cle tu mors ac counted for 18.5% of cases in the in ves ti gated se ries. Six such tu mors were sit - u ated in the esoph a gus; not a sin gle case of GIST was found among them. Leiomyomas are the most com mon mesenchymal tu - mors of the esoph a gus: they ac count for 8% of all tu mors in - volv ing this part of the GI tract, up to 2/3 of mesenchymal tu mors and more than one half of be nign le sions [27, 28, 40, 62]. Only in this seg ment of the gas tro in tes ti nal tract do they pre dom i nate over both stromal and neural tumors. Neu ral tu mors are rarely seen in the gas tro in tes ti nal tract. In the in ves ti gated ma te rial, they con sti tuted 4.9% of all cases, with five such tu mors in volv ing the stom ach. The lit er a ture on the sub ject usu ally de scribes iso lated cases, with only few larger se ries be ing re ported in fre quently [11, 54, 62]. Such tu - mors are mainly seen in adults, are more com mon in fe males and are pre dom i nantly sit u ated in the stom ach. They are en - coun tered in the esoph a gus only spo rad i cally [27, 49]. At times, they are con cur rent with von Recklinghausen dis ease [10, 16, 60]. It should be men tioned that type 1 neuro fib - romatosis is also as so ci ated with mul ti ple GISTs, es pe cially in volv ing the small in tes tine [6, 24, 36]. The re main ing 79 tu mors, com bined with 53 cases orig i - nat ing from the pe riod of , con sti tute a group of 132 gas tro in tes ti nal stromal tu mors, i.e. 81% of the orig i nal series. TABLE 1 Le iom yoma Schwannoma Malignant schwannoma Neu rof ibr oma Leiomyosarcoma Ganglioneuromatosis Total Esophagus Stomach Small intestine Colon Age Gender 7M/3F 2M/2F 5F 1F 1M 1M Diameter cm 6 22 cm 4 7 cm 3 cm 1 cm diffuse 53

4 K. Urbañczyk et al 2. Sixty-eight GISTs orig i nat ing from the ma te ri als sup plied by the above-men tioned De part ments of Patho - mor phology were in cluded into the anal y sis. II. GISTs location within the gastrointestinal tract 1. Ma te rial sup plied by the Chair of Patho morpho logy, Collegium Medicum, Jagiellonian Uni ver sity, Kraków In 83 pa tients (63.3%), GISTs were lo cated in the stom - ach. The group in cluded 33 males (mean age 62 years) and 51 fe males (mean age 63 years ). The tu mors pre dom i nantly in volved the gas tric body and the cardia. Their size ranged from 0.5 to 22 cm; in clud ing 62 cases with tu mors of 3 and more centimeters in diameter. Six patients presented with multiple tumors. Macroscopically isolated lesions of more than 1 cm in size had a dome-like form and were cov ered with slightly smooth ened mu cosa, at times show ing ul cer ation at the top. In the ma jor ity of cases, a round tu mor would ex tend in tra mu rally, more rarely it was hour-glass shaped and formed a bulge un der the serosa, was well de lin eated, its sec tion showed a zonular and lob u lar (polycyclic) struc ture and its color in frag ments sit u ated be yond the foci of hem or rhage and ne cro sis in larger le sions was cream-pink. Small tu mors with the di am e ter of cm, if they de vel oped within the muscularis propria, were usu ally ac ci den tally found on au - topsy or in stom ach spec i mens resected for other rea sons. More su per fi cially sit u ated le sions were shaped as round pol - yps with a broad base. Macroscopically, intestinal tumors were similar. Ul - cer ations were seen in large le sions, but no typ i cal cen tral crater was noted. Thirty-six stromal tu mors (27.4%) were sit u ated in the small in tes tine, in clud ing 20 in male pa tients (at the mean age of 62 years in two cases no data were avail able) and 16 in fe males (mean age, 60.3 years). Twenty-one tu mors were 3 cm or more in di am e ter (no data were avail able in six cases). In four pa tients, mul ti ple le - sions were de tected; of this num ber, it was a local disse - mination in two cases. In six in di vid u als (4.5%), the tu mor was sit u ated in the co lon; this group in cluded four males (mean age, 54 years) and two fe males (mean age, 79.5 years). The size of these tu mors ranged from 1 to12 cm, with five be ing 3 cm or more in diameter. In the re main ing six pa tients, the tu mors were sit u ated in the peri to neum (two cases, in clud ing one most likely rep - re sent ing a dis sem i nated dis ease orig i nat ing from an un - iden ti fied pri mary site), retroperitoneal space (two cases), while in the other two pa tients, the clin i cal in for ma tion on the lo ca tion of the tu mor was lim ited to a state ment in the abdominal cavity. 2. Material originating from the Departments of Pathomorphology, Medical University in Poznañ, Pomeranian Medical Uni ver sity in Szczecin, Med i cal Uni ver sity in Lublin, Department of Tumor Pathology, Œwiêtokrzyski Oncology Cen ter, and Di vi sion of Pathomorphology, First Chair of Ge - neral Sur gery, Collegium Medicum, Jagiellonian Uni ver sity Out of 68 stromal tu mors, 35 were sit u ated in the stom ach (51%), in clud ing 19 in males (mean age, 64 years) and 16 in fe males (mean age, 64.4 years). Twenty-three GISTs were de tected in the small in tes tine (33.8%) eight in men (mean age, 58.1 years) and 15 in women (mean age, 48.5 years). Three GISTs de vel oped in the co lon: two in males with the mean age of 57.5 years and one in a 56-year old fe male. The re main ing seven tu mors were sit u ated in the retroperitoneal space and within the ab dom i nal cav ity (10% of the se ries); the tu mors were seen in six fe males (mean age, 59.9 years) and in a 66-year old male. GISTs constitute the majority of the investigated gas - tro in tes ti nal mesenchymal tu mors and with the ex cep tion of the esoph a gus are pre dom i nant in par tic u lar seg ments of the GI tract. They are the most com monly seen in the stom ach, ac count ing for 48 to 84% of gas tric mesenchymal tu mors (up to 2/3 of the to tal num ber, on the av er age) [17, 20, 64, 66]. The sec ond most of ten in volved or gan is the small in tes tine, fol lowed by the anorectum, colon and eso - phagus [17, 30, 36, 66]. In this re spect, the pres ent re sults (51 63% of GISTs sit u ated in the stom ach and 27 33% in the small in tes tine) are well within the mean re ported per cent age. III. GISTs age and gen der of the pa tients 1. Ma te rial orig i nat ing from the Chair of Patho mor - phology, Collegium Medicum, Jagiellonian Uni ver sity The en tire group of pa tients showed a slight pre dom i - nance of fe males: 70 (i.e. 53.4%) women aged years and 61 men (46.5%) at the age range of years. The mean age of both male and fe male pa tients with GISTs sit u ated in the stom ach and small in tes tine was sim i - lar slightly above 60 years of age, but 16 out of 132 in di - vid u als (12.1%) were be low 45 years of life. The group of youn ger pa tients in cluded 11 women (ten cases in volv ing the stom ach and one the small in tes tine) and five men (four tu mors of the stom ach and one in volv ing the small in - tes tine), as well as five of eight cases of mul ti ple tu mors (four in volv ing the stom ach and one the small intestine). 2. Ma te rial pro vided by the De part ments of Patho mor - phology, Medical University in Poznañ, Pomeranian Medical Uni ver sity in Szczecin, Med i cal Uni ver sity in Lublin, De part - ment of Tu mor Pa thol ogy, Œwiêtokrzyski On col ogy Cen ter, and Di vi sion of Pathomorphology, First Chair of Gen eral Sur gery, Collegium Medicum, Jagiellonian Uni ver sity The pa tients in cluded 38 women (56%) aged years (mean age, 57.1 years) and 30 men (44%) in the age 54

5 GISTs range of 28 to 82 years (mean age, 61.4 years). Six in di vid u - als four males and two fe males were be low 45 years of life (8.8%); this group in cluded three pa tients with tu mors of the stom ach, two with GISTs sit u ated in the small in tes - tine and one in the retroperitoneal space. Two pa tients had mul ti ple le sions; in both cases the le sions in volved the small in tes tine and the pa tients were above 45 years of life. On di ag no sis, the ma jor ity of GIST pa tients are in their 6 th or 7 th de cade of life [7, 20, 31, 55, 59, 66]. Nev er - the less, not a sin gle age group is risk-free: GISTs are di ag - nosed in chil dren and a case of a con gen i tal GIST was de scribed [32, 65]. In gen eral, males fall to the dis ease more fre quently [20, 41, 59, 66]. And thus, al though the mean age of pa tients from our se ries does not dif fer from the an tic i - pated value, yet 12% of them were be low 45 years of life. In this sub group, as well as among the en tire se ries of patients, women predominated. IV. Assessment of tumor malignant potential To date, no uni form cri te ria have been es tab lished that would de scribe the risk of an un fa vor able course of GIST, apart from such ob vi ous clin i cal prop er ties as lo cal re cur - rent disease, infiltration of adjacent organs or metastases. Nev er the less, among prog nos tic fac tors, the size of a tu mor and the num ber of mitoses gen er ally oc cupy the lead ing po - si tion. While as sess ing the pos si ble de vel op ment of the tu - mors, the au thors used the scale pro posed by Fletcher [14], ac cord ing to which the bound ary val ues sep a rat ing low and me dium de grees of ag gres sive ness are as fol lows: tu mor di - am e ter of 5 cm and the num ber of mi totic fig ures up to 5/50 HPF. Ta ble 2 pres ents the num ber of tu mors with the pre - dicted degree of aggressiveness situated in particular seg - ments of the GI tract (the num bers are given as ag gre gates for both series). Thus, when 25 cases with the as sess ment hin dered by lack of clin i cal in for ma tion had been ex cluded, the in ves ti - gated GISTs were found to show a pre pon der ance of mod er - ately and highly ag gres sive tu mors, ac count ing for 53% of the to tal group. Mod er ately ag gres sive GISTs with met a - static po ten tial are as a mat ter of fact un pre dict able tu mors. In a pa tient of ours with a tu mor 6 cm in di am e ter metastasizing into the liver, the num ber of mitoses in the pri - mary le sion was 1/50 HPF. Such a sit u a tion has been com - monly ob served. The very histological as sess ment of tu mor ag gres sive ness in mul ti ple le sions also poses a prob lem, ex - em pli fied by the his tol ogy of fa mil ial GISTs de scribed by Maeyama as spin dle cell tu mors, show ing no mi totic ac tiv - ity, and yet of a fa tal course [34]. Pa tients with tu mors show ing high histological ag - gres sive ness con sti tuted up to 1/3 of all in di vid u als in the in - ves ti gated se ries; the re sult is com pa ra ble to or lower than val ues re ported by other au thors [26, 64]. Wang [64] di - vided 76 GISTs orig i nat ing from Chi nese pa tients into 38 be nign and 35 ma lig nant tu mors [46%]. Wang based his classification on unquestionable criteria: recurrent disease, metastases or in fil tra tion, and thus the num ber of cases with a clin i cally ma lig nant course might have been higher. The like li hood of an un fa vor able course of GIST is higher when the tu mor is sit u ated in the small in tes tine, where GISTs ac - count for more than 13% of ma lig nan cies [7, 13, 14]. In our se ries, mod er ately and highly ag gres sive tu mors ac counted for more than 55% of the small in tes tine le sions and less than 50% of the gas tric tu mors. GIST metastases are found in ap prox i mately 47% of cases, be ing pre dom i nantly seen in the liver and peri to neum, more rarely in the lungs and bones and only in fre quently in the lymph nodes [7, 12, 38, 59]. One should also bear in mind atyp i cal lo ca tion of meta - stases, such as the breast, skin or cavernous sinus [2, 23, 56]. Five-year survival rate in GISTs is approximately 54% [12]. V. Epithelioid cell and spin dle cell tu mors In both se ries (ex clud ing mul ti ple le sions), 24 epi - thelioid GISTs (12%) were noted. This group in deed in - cluded more ag gres sive tu mors (a to tal of 12 cases), but the au thors also found six le sions be long ing to the low and very low ag gres sive ness cat e gory and orig i nat ing from the stom - ach and the small in tes tine. Thir teen epithelioid cell GISTs TABLE 2 Degree of aggressiveness Stomach (119) Small intestine (59) Colon (9) Other (13) Total (200) Very low Low Moderate High Difficult to assess * *No data avail able on the tu mor size 55

6 56 K. Urbañczyk et al

7 GISTs Fig. 1. A typ i cal spin dle cell GIST. Broad, interwinding bands of cells char ac ter ized by low de gree of poly mor phism, with quite abun dant, eosinophilic cy - to plasm re sem bling a leiomyoma. HE. Fig. 2. An epithelioid cell GIST. The empty spaces in the cy to plasm, con sti tute a fairly com mon ar ti fact and may at times sug gest a car ci noma. HE. Fig. 3. Pos i tive cy to plas mic and mem bra nous immunohistochemical re ac tion to CD117 in nu mer ous GIST cells. Fig. 4. Pos i tive cy to plas mic CD117 dot-like stain ing in GIST cells (so-called Golgi-zone pat tern). Fig. 5. Pos i tive immunohistochemical re ac tion to CD34 in an epithelioid tu mor vis i ble as a rel a tively rare mem bra nous stain ing pat tern. Fig. 6. A whorl-like pat tern in a spin dle cell tu mor, em pha sized by pe riph er ally ar ranged SMA-pos i tive cells, most likely orig i nat ing from small ves sel walls. Fig. 7. Pos i tive cy to plas mic re ac tion to CD117 in scat tered, spin dle and highly elon gated GIST cells. Fig. 8. Pos i tive immunohistochemical re ac tion to CD34 seen solely in nu mer ous, small ves sels within the tu mor. This GIST is CD34-neg a tive. Fig. 9. Pos i tive immunohistochemical re ac tion to S-100 pro tein in a small num ber of GIST cells, in clud ing sev eral pleomorphic cells. Fig. 10. Con trasted, strongly CD34-pos i tive and CD34-neg a tive GIST re gions. Fig. 11. A multifocal GIST one of sev eral tu mors was a con glom er ate, the struc ture of which was em pha sized by bands of smooth mus cles (SMA+). Fig. 12. A multinodular GIST. Within the sat el lite tu mor a small neo plas tic fo cus sep a rated from the main tu mor mass the immunohistochemical re ac tion to CD34 is more in ten sive (see the right side of the pho to graph). Figs. 13 and 14. The same groups of GIST cells in perivascular spaces on the pe riph ery of mul ti ple tu mors CD34-neg a tive (Fig. 13) and CD117-pos i tive (Fig. 14). 57

8 K. Urbañczyk et al were sit u ated in the stom ach, six in the small in tes tine, two in the ab dom i nal cav ity, and an other two in the retro - peritoneal space. VI. GISTs and syn chro nous tu mors Ma te rial pro vided by the Chair of Pathomorphology, Collegium Medicum, Jagiellonian Uni ver sity In seven pa tients, other can cers de vel oped con cur - rently with GISTs; in some cases the for mer dom i nated over the clinical picture: in a 74-old male, a GIST sit u ated in the stom ach, mea sur - ing 17 cm in di am e ter and dis sem i nated within the ab - dom i nal cav ity oc curred con com i tantly with a co lonic adenocarcinoma (B2); a 57-year old male pa tient with a gas tric GIST, 18 cm in diameter, presented with a disseminated squamous cell carcinoma; a 53-year old male was di ag nosed with a co lonic GIST, 12 cm in di am e ter, and a con com i tant carcinoid tu mor sit - u ated in the small in tes tine, a 38-year old male with mul ti ple tu mors of the small in - tes tine, up to 2.5 cm in size, also showed a pheochro - mocytoma in the retroperitoneal space, two pa tients with small stromal tu mors (M/61, two GISTs, 0.5 cm each, and an other M/69, one GIST, 2 cm in di am e ter), also had adenocarcinomas of the stom ach in one of them, it was an early car ci noma, in a 55-year old fe male pa tient de ceased due to anaplastic lym phoma, the gas tric GIST mea sured 0.5 cm. It ap pears that the group of GIST pa tients that were ad di - tionally (or predominantly) burdened with another tumor was for tu nately small. Apart from in di vid u als with von Rec kling - hausen dis ease, only a sin gle case of a syn chro nous mesen - chymal tu mor sit u ated at the same site was re ported; this was a lipoma of the stom ach [3]. In ad di tion, pa tients with GISTs were also diagnosed with concomitant Burkitt s lymphoma, osteosarcoma, mel a noma, neuroblastoma, pri mary kid ney tu - mor, Car ney s triad, MEN I syn drome, co lonic adenocar - cinomas and gas tric adenocarcinomas, inclu ding a one case of col li sion tu mors [4, 5, 8, 15, 25, 33, 43, 45, 48, 63]. VII. Multiple GISTs Ma te rial orig i nat ing from the Chair of Pathomor pho - logy, Collegium Medicum, Jagiellonian University Eight pa tients pre sented with two or more con cur rent tu - mors sit u ated in tra mu rally within the same or gan. The group in cluded four males and four fe males in the age range of years (five pa tients were be low 45 years of life). The size of the le sions os cil lated be tween 0.5 and 4.5 cm, and the num ber of tu mors ranged from two to al most twenty. The stom ach was in volved in six cases, and the small in tes tine in two. In ad di tion, two pa tients were di ag nosed with syn chro - nous tu mors: an early stage can cer of the gas tric body and cardia in a 61-year old man (two GISTs, 0.5 cm in di am e ter, in the stom ach) and a pheochromocytoma of the ad re nal gland in a male pa tient aged 38 years of life (two GISTs, 2.5 cm in di - ameter, situated in the small intestine). Some le sions that mac ro scop i cally seemed to be a unity were in fact con glom er ates of smaller and larger tu mors sep a - rated by bands of nor mal smooth mus cles (Fig. 11). This type of multifocal pro lif er a tion was clearly seen in two pa tients (a 14-year old and a 20-year old fe males) with an ex ten sive in - volve ment of the stom ach, but it was also pres ent in the case of two other, par tially hyalinized tu mors of the small in tes tine, where sep a rate small, mi cro scopic foci were seen in the im - mediate vicinity (Fig. 12). With respect to their cellular structure, particular tumors ob served in a sin gle pa tient were usu ally sim i lar, al though one of the spin dle cell con glom er ates also con tained a sin gle epithelioid tu mor. Mi totic ac tiv ity in bi fo cal le sions was com - pa ra ble, while in multifocal le sions it ranged from 0 1 mi totic fig ure/50 HPF in small tu mors to 11 mitoses/50 HPF in larger ones. Thus, this group of le sions in cluded GISTs with a pre - dicted course rang ing from be nign to ma lig nant (histological assessment). Mul ti ple GISTs are mostly de scribed as a fa mil ial auto somal dom i nant dis ease with mu ta tions in volv ing the c-kit or PDGFRA genes [9, 34, 50]. In some of these pa - tients, c-kit is also ac ti vated in the mast cells and skin melanocytes (what is clin i cally man i fested as ur ti caria pigmentosa and hyperpig mentation); these in di vid u als also pres ent with dysphagia, not as so ci ated with typ i cal achalasia [22]. Mul ti ple GISTs more of ten de velop in the small in tes tine than in the stom ach, also when the pa tient has con com i tant von Recklinghausen dis ease [6, 19, 24, 34, 36, 47]. Ac cord ing to clin i cal data, the above men - tioned eight pa tients showed no skin le sions; no in for ma - tion was ei ther pro vided that would in di cate fa mil ial di sease. In one pa tient with a syn chro nous pheochro - mocytoma, tests aim ing at a pos si ble di ag no sis of Car - ney s triad had been sug gested. Our data are in com plete and at times, Car ney s triad be comes ap par ent af ter many years, yet one may sus pect that mul ti ple GISTs may also ap pear spo rad i cally. Any pre dic tions as to the course of the dis ease be come prob lem atic when we deal with small and the o ret i cally be nign tu mors that have been sur gi cally re moved in a sal vag ing pro ce dure, pro vid ing we as sume that the en tire or gan (gas tro in tes ti nal tract?) is sus cep ti ble to GIST de vel op ment. In ad di tion, as it can be ex em pli fied by one small GIST of the small in tes tine from our se ries, a tendency to wards form ing mul ti ple le sions may es cape de tec tion. Only af ter nu mer ous sec tions had been pre - 58

9 GISTs pared the fact be ing re lated to tech ni cal rather than diag - nostic is sues did the sec ond, mi cro scopic in size, but clearly de lin eated tu mor be come vis i ble. VIII. Immunoreactivity, in clud ing mul ti ple GISTs and small GISTs Ma te rial pro vided by the Chair of Pathomorphology, Collegium Medicum, Jagiellonian Uni ver sity For a long time now, di ver si fied ex pres sion of CD34, SMA and KIT (CD117) with re spect to re ac tion in ten sity and the num ber of pos i tive cells, also within a sin gle tu mor, has been em pha sized. In the group of highly ag gres sive GISTs one ex pects to find tu mors mark edly di ver si fied in the above re spects. Pos i tive re ac tions to CD34 were noted in 58% to 80% of all GISTs, while in the case of CD117, only a few tu mors tested neg a tive. There were also cases when within a sin gle sec tion CD34-neg a tive and CD117-pos i - tive zones were ob served (Figs. 13 and 14). The de scrip - tions also in cluded tu mors - al though they were sin gu lar only clas si fied as CD117-pos i tive GISTs, which showed a positive re ac tion to desmin. CD34 was more fre quently seen in GISTs of the co lon and the esoph a gus, while SMA positivity was more com mon in small intestine tumors [1, 31, 37, 42, 57, 66]. In our se ries, among 124 sin gle GISTs, three tu mors were CD117-neg a tive, in clud ing one that tested neg a tively in all the em ployed re ac tions, while two le sions were CD34-pos i tive. Pos i tive re ac tions to CD34 were pres ent in 97 (78%) cases, while con com i tant positivity to CD34 and CD117 was seen in 94 le sions. Sev en teen tu mors were only CD117-pos i tive. A strong re ac tion to SMA in more than 80% of tu mor cells was ob served in 19 le sions sit u ated in the stom ach and 11 in volv ing the small in tes tine. The pres - ent se ries did not in clude any GISTs of the esoph a gus and only a small num ber of tu mors lo cated in the small in tes tine. One of the below described tumors was desmin-positive. In sev eral highly ag gres sive GISTs, a weak re ac tion to CD117 and CD34 was noted only in sin gle fields within the le sion. We as sumed that sin gle, small and be nign tu - mors would be uni form in char ac ter; this, how ever, was not the case. In the in ves ti gated se ries, 23 tu mors were iden ti fied, which were char ac ter ized by a di am e ter be low 2 cm (be tween 0.5 and 2 cm) and con sti tuted sin gu lar, spin dle cell le sions al - most iden ti cal in HE, with out mi totic ac tiv ity. How ever, im - munohistochemistry demonstrated their high versatility, from a 0.7-cm in di am e ter GIST that was CD34-pos i tive only in 10% of the cells, to a 2-cm GIST with a pos i tive re ac tion to CD117, CD34 and SMA in 100% of the cells; both the tu mors were sit u ated in the stom ach. In an other small le sion, zones highly CD34-pos i tive were strongly con trasted with neg a tive zones (Fig. 10), while the dif fer ences as so ci ated with CD117 were slightly less pro nounced. Further investigations of this versatility can be best done in mul ti ple tu mors, and es pe cially in tu mor con glom - erates. Multifocal le sions showed marked dif fer ences in their immunoreactivity, which re sulted from the het er o ge neous character of neoplastic cells: in a 42-year old male, one tu mor of the stom ach showed a positive re ac tion to CD117 in all the cells, while the sec - ond only in 10%, while both le sions were CD34-pos i - tive in 50% of their cells; in a 14-year old and a 20-year old fe male pa tients, the in - ten sity of CD117 re ac tion was sim i lar in all the le sions, but pos i tive CD34 re ac tion ranged from 0 to 100% of the cells; in an other pa tient (a 57-year old male), two tu mors dif - fered with re spect to four re ac tions: CD117 50% pos i - tive/5% pos i tive; CD34 90% pos i tive/neg a tive; SMA neg a tive/5% pos i tive; S % pos i tive/neg a tive, while DES 50% pos i tive/50% pos i tive. In all the above four pa tients, the le sions were clas si - fied as mod er ately to highly ag gres sive. Clearly stron ger re ac tions to CD34 and CD117 were seen in tu mor cell bands that in fil trated the sur round ing tis - sues and in small tu mor foci de vel op ing in the vi cin ity of the pri mary mass. Based on the above data and the re sults re ported in the lit - er a ture, one may say that in di ag nos tic man age ment of tu mors in particular patients, the sole significance of immunohistochemical re ac tion ver sa til ity lies in the fact that it may hin der a firm diagnosis, especially in endoscopic sections and thickneedle biopsies. However, it shows no stable association with tumor location, aggressiveness, cellular structure or tendency to form multifocal le sions. Doubt lessly, such im por tant is sues as the re cruit ment of pa tients for Glivec ther apy, as sess ment of tumor resistance to treatment, detection of familial cases and concurrent neoplastic syndromes, all require genetic studies. This only em pha sizes the sig nif i cance of an early and ac - curate GIST detection in routine diagnostic management. Conclusions 1. In ves ti ga tions of GIST cell immunoreactivity are nec es - sary in dif fer en tial di ag nos tics of these le sions. This pos - tu late has been con firmed by the pres ent re sults. 2. Co-ex pres sion of SMA and CD117, dem on strated in our ma te rial in some cases in more than 80% of cells, con - firms the fact of GIST de vel op ing from pre cur sor cells differentiating to Cajal cells. 59

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