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xtragastrointestinal Stromal Tumor and Liver Transplantation:ase Report and Review

.A. Camargo, I. Boin, J.P.A. Mainnardi, M. de Lourdes, S. Ayrizono, C.S. Coy, M.I. Leonardi,. Meirelles, L.S. Leonardi, and C.A. Escanhoela

ABSTRACT

The occurrence of de novo malignant neoplasias has been shown in postransplantpatients under imunosuppression. It is the second leading cause of late death in livertransplant recipients. The greatest incidence is seen in cancers associated with chronicinfection by human papilloma virus, skin cancers, oropharyngeal, and gastrointestinal(GI) malignancies.

GI stromal tumors (GISTs) are the most common mesenchymal tumors of the GI tract.Rare cases are identified outside the GI tract are collectively known as extragastrointestinalstromal tumors (EGISTs). We present an EGIST case in a liver transplantation patient.

A 64-year-old man underwent liver transplantation because of cirrhosis (hepatitis Bvirus and alcoholism) and hepatocellular carcinoma. Histopathologic findings revealed 2trabecular hepatocellular carcinomas: a 3.5-cm-diameter lesion located at segment VIIIand another 2-cm one at segment V. Seven months later, he noticed a hardened, mobile,painless, 3-cm subcutaneous nodule in the perineum localized in the right lateral quadrant2 cm distant from the anus. A surgical resection with 1 cm margin yielded a histopathologyreport of a 5.0 � 3.0 cm spindle cell stromal tumor. The immunohistochemical profile wascompatible with a GIST, with 5 mitosis per 50 high-powered fields.

This tumor is extremely rare after liver transplantation but has shown a good outcome

up to now.

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ECURRENT AND de novo malignancies are the 2ndleading causes of late death in liver transplant recip-

ents, following age-related cardiovascular complications.1

t may reflect preexistent risk factors for cancer, greaterate of chronic viral infection, and actions of exogenousmmunosuppression. The greatest incidence of de novo

alignancies is seen in cancers associated with chronic viralnfections, skin cancers, oropharyngeal malignancy, andolorectal cancer.1

Gastrointestinal stromal tumors (GISTs) are the most com-on mesenchymal tumors of the gastrointestinal (GI) tract.2–7

ntil recently GISTs have been classified as leiomyosarcomas,eiomyoblastomas, schwannomas, or leiomyomas.4 The ex-ression of Kit protein distinguishes GISTs from true leiomyo-as, leiomyosarcomas and other stromal tumors of the GI

ract.8

Small rectal GISTs are often detected during routinerostate or gynecologic examination. According to some

uthors, such small tumors are generally clinically harmless B

2008 by Elsevier Inc. All rights reserved.60 Park Avenue South, New York, NY 10010-1710

ransplantation Proceedings, 40, 3781–3783 (2008)

esions.3,5 Rare cases identified outside the GI tract areollectively known as extragastrointestinal stromal tumorsEGIST).9,10 Recently we discovered an EGIST in a liverransplant recipient.

ASE REPORT

64-year-old man was admitted with hepatic cirrhosis due tohronic type B hepatitis and alcoholism. A computed tomographyCT) scan showed a 3.0 � 4.0 cm diameter right lobe (segmentIII) heterogeneous mass with arterial enhancement, compatibleith hepatocellular carcinoma. The alpha-fetoprotein (AFP) levelas 4.71 ng/mL (which never exceeded reference value).

From the Unit of Liver Transplantation, State University ofampinas, Campinas, Sao Paulo, Brazil.This paper was sponsored by FAPESP - São Paulo -Brasil.Address reprint requests to Ilka Boin, MD, PhD, Unit of Liver

ransplantation, State University of Campinas, Rua Aldo Oliveira

arbosa 184, Campinas, Sao Paulo 13086-030, Brazil

0041-1345/08/$–see front matterdoi:10.1016/j.transproceed.2008.04.017

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3782 CAMARGO, BOIN, MAINNARDI ET AL

He underwent orthotopic liver transplantation by the piggybackechnique in April 2005. Histopathologic findings revealed 2 tra-ecular hepatocellular carcinoma nodules: 1 moderately differen-iated with a diameter of 3.5 cm located at segment VIII (Edmond-on II) and another, well-differentiated one of 2 cm at segment Vhat had not been diagnosed previously (Fig 1).

The patient received hepatitis B immunoglobulin in the anhepatichase of the transplant and during the postoperative period. Startingn postoperative day 2, he received lamivudine 150 mg/d and began

mmunosuppression with tacrolimus (FK506; 0.1 mg/kg per day).Two months later, mycophenolate sodium (Myfortic, Novartis

harma; – 720 mg/d) was introduced because of impaired renalunction, to reduce the tacrolimus dosage (reduced to 0.05 mg/kger day). On about postoperative day 80th he underwent an

ncisional herniorrhaphy due to an incarcerated hernia. A hepaticiopsy performed during surgery revealed no signs of acute rejec-ion or viral reinfection.

Seven months posttransplantation, the patient noticed a small, painlessodule in his perineum. On digital rectal examination, a 3-cm,ardened, mobile, painless node was noticed at the right lateraluadrant, apparently outside the rectum the mucosa was normal. Itas 2 cm distant from the anus on physical examination of the perineum.Tumor markers included carcinoembryonic antigen (CEA), AFP,

rostate-specific antigen, and CA19-9, all of which were within normalimits. Because a subcutaneous nodule is an extremely rare locationor an hepatocellular carcinoma metastasis, this diagnosis was notonsidered at first. After physical examination, a chest x-ray wasormal. No further diagnostic methods were performed becauseistopathologic analysis was decided to be first step in the searchor the diagnosis. Surgical resection was feasible, so the lesion wasemoved under local anesthesia rather than to perform only aiopsy. The entire tumor was excised with 1 cm margin. Theistopathologic report revealed a 5.0 � 3.0 cm spindle cell stromalumor. Five mitoses were present per 50 high-power fields. Themmunohistochemical study revealed CD117�/CD34�/S100� fo-ally/Desmin�/1A4�, compatible with GIST (Fig 2).

Thereafter, CT showed no evidence of metastasis, lymphadenopa-hy, or any other abdominal or perineal lesion. After 20 months, at theime of writing, the patient continues asymptomatic with no evidencef GIST recurrence. Follow-up using semestral abdominal ultrasound,T, and tumor markers is ongoing. The immunosuppressive protocol

ig 1. Trabecular hepatocellular carcinoma nodule, a well-ifferentiated tumor.

emains the same as before the EGIST diagnosis. s

ISCUSSION

here are case reports of EGIST; however, there are noeferences to EGIST occurrence after liver transplantationn the English literature. The annual estimated incidence of

IST in the United States is 1–2 cases per 100,000 people,f which 20%–30% are malignant.11 GISTs occur predom-

nantly in patients � 40 years old, although some articlesave shown a mean age of about 60.5,12,13 There existsonflicting evidence on male predominance,4,9 althoughost studies indicate no gender predilection.12,13

GIST may be present throughout the GI tract from theharynx to the anus. The stomach is the most frequentlyoted site (50%–60%), followed by the small intestine20%–30%). The large bowel (5%–10%) and esophagus5%) are the least likely involved, sites.4,6,8,13 Approxi-ately 10%–30% of patients with GISTs may be completely

symptomatic, with the tumor being incidentally discovereduring radiographic studies, endoscopy, or surgery per-ormed for unrelated reasons.13

ig 2. A. Histopathologic aspect of EGIST showing splindle celltromal tumor (hematoxylin and eosin; original magnification,200). B. Immunohistochemistry study of the EGIST. Observe

trong positivity for CD-117 (c-Kit).

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EXTRAGASTROINTESTINAL STROMAL TUMOR 3783

The interstitial cell of Cajal, an intestinal pacemakerell,4,13 has been recently proposed as the origin of GISTs.athologic activation of Kit signal transduction is believed

o be a central event of GIST pathogenesis.11–14 GISTs,hich arise from the muscularis propria of the GI tract wall,

end to have an exophytic growth pattern, usually centeredutside the organ of origin.Therefore, all stromal tumors must be tested for c-kit

xpression to ensure that GISTs outside the GI tract areble to be diagnosed and treated correctly.7–10

A GIST is defined as a mesenchymal tumor with immu-ohistochemical positivity for CD117, the proto-oncogenerotein of c-Kit. Immunoreactivity with antibodies to actin,esmin, or muscle specific actin (HHF-35) defines a spec-rum of myoid differentiation, whereas S-100 immunoreac-ivity defines neural differentiation.13 Approximately 70%–0% of GISTs are also positive for CD34,4 a hematopoieticrogenitor cell antigen also present in endothelial cells andubsets of fibroblasts and many neoplasms related to theseell types.4 S-100 protein expression is relatively rare inISTs, occurring most commonly in the small intestine. Theositivity is usually focal, but is present in both cytoplasmnd nuclei, likely representing true expression of this anti-en.4,5 Positivity for desmin, the muscle-type intermediatelament protein, is rare in GISTs of all sites, but has beenbserved relatively more often among esophageal GISTs.Fletcher et al8 showed that the most common antibody

xpression is positivity for kit (CD117), CD34 (60%–70%),MA (30%–40%), and S-100 (5%), and are rarely positiveor desmin. The immunohistochemical panel for the caseeported above was totally compatible with GIST.

Surgical resection, the treatment of choice for GIST,hould be done with the intention of performing a completen bloc resection of the tumor, with avoidance of tumorupture; it is difficult or impossible to differentiate betweenenign or malignant lesions before or during operation.9–13

ide margins of resection do not seem to be necessary.16 Inddition, lymphadenectomy does not need to be performedecause lymph node metastases are rare in GISTs.9,16 Theedian survival time for completely resected GISTs is

onger than that for incompletely resected or inoperableatients.10,12,15 Adjuvant therapy appears to improve theurvival and quality of life for patients with incompleteumor resections.9,10,12,16 Fletcher et al8 proposed a defini-ion for malignant behavior of GISTs based on tumor sizend mitotic rate. Our patient had an intermediate riskumor because it was 5 cm in size and showed 5 mitosis per0 high-power fields.Rare cases of GIST have been identified outside the

ntestinal tract and are collectively known as EGISTs.16

hey show a c-kit expression and histologic appearanceimilar to those of a GIST.7–10 These tumors may beisdiagnosed owing to their unusual anatomic locations.isdiagnosis may lead to inappropriate therapy because

onventional chemotherapy and radiotherapy are not effec-ive in the treatment of GISTs, whereas imatinib mesylate

as a proven role in managing these tumors.15

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Nevertheless, Agaimy and Wunsch7 have reported 14 casesf stromal tumors initially classified as EGIST. After criticaleevaluation of surgical reports and careful search for residualuscular tissue from the gut wall in the tumor pseudocapsule,

hey concluded that most so-called EGISTs represent appar-nt GISTs that should have arisen from the outermost muscleoat, but have lost their contact to the point of origin due to anxtensive extramural growth pattern.

In conclusion, EGISTs are rare, but need to be remem-ered in the investigation of mesenchymal tumors outsidehe GI tract, because complete en bloc surgical resection ofhe tumor is the treatment of choice. Misdiagnosis may leado inappropriate therapy. Despite liver transplant recipientsaving a higher incidence of de novo tumors, GISTs arencommon in these patients.

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astrointestinal stromal tumor cases. Eur J Surg Oncol 18:1, 20063. Hiromura T, Nishioka T, Nishioka S, et al: Anorectal gastro-

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