CASE REPORT

Lymphoepithelioma-Like Carcinoma of the Stomachwith Incidental Gastrointestinal Stromal Tumor (GIST)—A RareSynchrony of Two Tumors

Aanchal Kakkar & Rakesh K. Gupta & Nihar R. Dash &

Ishrat Afshan & Vaishali Suri

# Springer Science+Business Media New York 2014

Introduction

Lymphoepithelioma-like carcinoma (LLC) of the stom-ach, also known as gastric carcinoma with lymphoidstroma, is a rare gastric tumor with an incidence of 1–4 % of all gastric carcinomas [1]. It is characterized bya prominent lymphocytic infiltrate and has been shownto be associated with Epstein-Barr virus (EBV) infectionin as many as 80 % of cases [1]. Seen more frequentlyin male and in elderly patients, this tumor occurs at thecardia and body of the stomach, where it is seen as anulcerating mass [2]. In addition, it is associated with agood outcome as compared to more common gastriccancers [3, 4]. Gastrointestinal stromal tumor (GIST) isthe most common mesenchymal tumor arising in thegastrointestinal tract, accounting for approximately 2 %of all gastrointestinal tumors, with a peak incidence inthe seventh decade of life [5, 6]. It occurs most fre-quently in the stomach and small intestine; however, itis also seen arising in the rectum, colon, esophagus, andmesentery [7]. While incidental GIST occurring in asso-ciation with primary gastric cancer is not an infrequentfinding, the association of LLC with an incidentallydetected GIST has not been reported till date.

Case Report

A 69-year-old male presented to the Department ofGastroenterology outpatient clinic with complaints ofdark-colored stools since 15 days. The patient did nothave other gastrointestinal symptoms, viz., vomiting,hematemesis, abdominal pain, or fullness after meals.On examination, pallor was present. The abdomen wassoft and no mass was palpable. Computerized tomogra-phy of the abdomen (Fig. 1a) revealed a growth in theantro-pyloric region of the stomach. No liver metastasesor omental nodules were identified. An upper gastroin-testinal endoscopic examination was performed, whichshowed a large ulcer in the antrum along the lessercurvature of the stomach, from which a biopsy wastaken. Histopathological examination showed featuresof a poorly differentiated adenocarcinoma, and a partialgastrectomy was planned. Intraoperatively, a 7-cm×8-cmulceroinfiltrative tumor was identified in the antro-pyloric region, extending up to the D1 region of theduodenum. A separate nodule measuring 0.8 cm inmaximum dimension was also identified on the serosalaspect of the anterior wall of the proximal stomach,away from the main tumor (Fig. 1b), which wascompletely excised and sent for intraoperative histopatholog-ical examination. Cryostat sections from the nodule showed atumor composed of bland-appearing, spindle-shaped cellsdisplaying minimal nuclear atypia and pleomorphism. Mito-ses and necrosis were not seen. A preliminary diagnosis ofGIST was offered. A near-total gastrectomy was performedinstead of a partial gastrectomy, with a 2-cm margin proximalto the serosal nodule and 2-cm margin distal to the gastriccarcinoma, along with resection of the perigastric, left gastric,and hepatic artery lymph nodes. The patient subsequentlyreceived four cycles of chemotherapy as well as radiotherapyand is doing well 8 months later.

N. R. DashDepartment of Gastrointestinal Surgery, All India Institute ofMedicalSciences, New Delhi 110029, India

I. AfshanDepartment of Radio-Diagnosis, All India Institute of MedicalSciences, New Delhi 110029, India

A. Kakkar :R. K. Gupta :V. Suri (*)Department of Pathology, All India Institute of Medical Sciences,New Delhi 110029, Indiae-mail: surivaishali@yahoo.co.in

J Gastrointest CancDOI 10.1007/s12029-014-9581-3

Pathological Features

On gross examination, the gastrectomy specimen measured17 cm in length and showed a crater-like ulcero-infiltrativegrowth in the antro-pyloric region. The tumor measured 6.5×6.5×3.5 cm and grossly appeared to infiltrate transmurallythrough the submucosa and muscularis propria, up to theserosa. Microscopic examination of hematoxylin- and eosin-stained sections (Fig. 2) showed a tumor with infiltrativemargins that extended from the mucosa to the serosal fat.The tumor cells were arranged in sheets and in clusters ofvarying size and were also lying singly. Individual tumor cellshad moderate amount of eosinophilic cytoplasm, indistinctcytoplasmic borders, large vesicular nuclei showing markedatypia, and prominent nucleoli. Frequent mitotic figures wereidentified. There was no definite evidence of glandular differ-entiation. A prominent inflammatory cell infiltrate was present

intermixed with the tumor cells, comprising mature lympho-cytes, plasma cells, and neutrophils. True syncytial growthpattern, tumor circumscription, restriction of thelymphoplasmacytic infiltrate to the peritumoral area, and con-nective tissue proliferation were not seen. Histochemicalstains did not reveal the presence of acidic mucin within thetumor cells. The histomorphological features favored the di-agnosis of an epithelial malignancy. However, in view of theintraoperative diagnosis of GIST, a panel of immunohisto-chemical stains was applied to rule out the remote possibilityof an epithelioid GIST. On immunohistochemistry, the tumorcells were immunopositive for pan-cytokeratin and were neg-ative for CD117 and DOG1. EBV latent membrane protein1 (LMP-1) was also negative in the tumor cells. In situhybridization (ISH) for EBV-encoded small RNA 1(EBER-1) could not be performed as it was unavailable inour laboratory. Paraffin-embedded hematoxylin- and eosin-

Fig. 1 Computerized tomography image showing a circumferentialhomogenously enhancing soft tissue thickening involving the pylorusof the stomach, with no evidence of gastric outlet obstruction or

infiltration of the adjacent omentum (a). Operative specimen showingan ulcero-infiltrative tumor and a nodule (N) at a distance away from thetumor (b)

Fig. 2 Photomicrographsshowing a lymphoepithelioma-like carcinoma infiltrating thelamina propria of the gastricmucosa; preserved gastric glandsshow dysplastic change (a; H &E, ×100); tumor cells withinterspersed inflammatory cells(b; H & E, ×200); tumor cells areimmunopositive for cytokeratin(c; ×200) while inflammatorycells are positive for leukocytecommon antigen (d; ×200)

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stained sections examined from the nodule on the anteriorwall of the proximal stomach (Fig. 3) showed a spindle celltumor of low cellularity with abundant collagenous matrixand focal calcification; no mitoses or necroses were seen. Onimmunohistochemistry, the tumor cells displayedimmunopositivity for CD117, DOG1, and CD34; pan-cytokeratin, smooth muscle actin, and S100 were negative.The hepatic artery lymph node showed metastatic carcinoma;however, the perigastric and left gastric lymph nodes were freeof tumor. Based on the histomorphological and immunohisto-chemical features, a final diagnosis of LLC with incidentallydetected GISTwas arrived at.

Discussion

LLC is a rare type of gastric carcinoma, which is also knownas gastric carcinoma with lymphoid stroma, and is commonlyassociated with EBV infection [3, 4]. A prominent lymphoidinfiltrate is seen in two variants of gastric carcinoma, viz., LLC

and medullary carcinoma, which differ in theirhistomorphological characteristics as well as pathogenesis [8].Medullary carcinoma is characterized by a syncytial pattern oftumor cells in more than 75 % of tumor area, non-infiltratingborders, and mainly peritumoral lymphoplasmacytic infiltra-tion [8]. LLC, on the other hand, is characterized by tumor cellsarranged singly or in small clusters with a pseudosyncytialpattern, dense intratumoral inflammatory cell infiltrate, andinfiltrating borders [8]. Microalveolar, thin trabecular, andprimitive tubular arrangements of tumor cells have also beendescribed [3]. While medullary carcinoma is frequently asso-ciated with microsatellite instability (MSI) [4], LLC is usuallyassociated with EBV infection, which can be demonstrated byISH for EBER [8]. Grogg and colleagues described the role ofEBV and MSI in the pathogenesis of gastric carcinomas withlymphoid-rich stroma and found these two pathogenetic mech-anisms to be mutually exclusive [9]. The distincthistomorphological features also recapitulate separate pathoge-netic mechanisms in these two entities. Studies havedemonstrated that EBV LMP-1 protein expression may

Fig. 3 Photomicrographsshowing a gastrointestinal tumorcomposed of spindle-shaped cellsin a collagenous matrix (a; ×100);tumor cells have elongated nucleiwith tapering ends and lackpleomorphism or mitoses (b;×400); immunopositivity forDOG1(c; ×100) and CD117 (d;×100) in tumor cells; and smoothmuscle actin (e; ×100) andcytokeratin are negative (f; ×100)

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be absent in EBV-associated gastric carcinomas in whichEBER was detected by ISH [10, 11]. Thus, negative immuno-histochemical results with LMP-1, as in our case, should not beinterpreted as absence of EBV infection in these tumors.Watanabe et al. reported that patients with LLC have a prog-nostic advantage as compared to other gastric carcinomas [12].They established the role of infiltrating lymphocytes as a hostdefense mechanism against tumor cells and demonstrated thatpatient outcome is directly proportional to the number of infil-trating lymphocytes. Nakamura et al. demonstrated that LLC inthe stomach have a survival advantage irrespective of EBVstatus and concluded that infiltrating lymphocytes play a criti-cal role in the improved prognosis of these tumors [13].

GIST is the most common mesenchymal neoplasm seen inthe gastrointestinal tract with a predilection for the stomach,which may be incidentally detected or symptomatic [14]. Theincidence of incidental synchronous GIST in gastrectomy spec-imens for gastric cancer in published literature is highly vari-able, ranging from less than 1 to 35%, as it is determined by thegeographic region, mode of surgery, anatomic location of thetumor, number of histological sections examined, and the de-tection method [14–17]. The average size of incidental GISTsranges from 0.2–3 cm, and a predilection for the upper part ofstomach and gastro-esophageal junction has been noted [14].The malignant potential of GISTs is determined by tumor sizeand the number of mitoses [18]. Considering the small size ofincidental GISTs in various reports, their malignant potential isusually low [14]. The recommended management for theseincidentally detected tumors is en bloc removal along with thegastric carcinoma where possible, and no detrimental effect onthe outcome of the primary gastric malignancy has been notedto date. However, one concern is that the extent of surgicalresection may be extended in order to achieve an adequatemargin of resection around both tumors, as with our patient.This could possibly lead to difficulties in construction of agastric conduit [14]. However, leaving the GIST behind in thegastric stump may lead to misdiagnosis as a recurrence of theprimary gastric malignancy at a later date. In order to avoidsubjecting the patient to unnecessary additional therapy, thealternative of resecting the GIST seems more feasible.

Conclusion

LLC is a rare variant of gastric cancer with characteristichistomorphology, is frequently associated with EBV infection,and has a better prognosis in comparison to more commongastric carcinomas. Incidental detection of GIST in associationwith primary gastric cancer is not an unusual finding; however,this is the first report of GIST occurring synchronously withLLC. Although detection of incidental GISTs may alter thesurgical procedure, it usually does not alter overall prognosis,which depends on the gastric carcinoma. Knowledge of the

coexistence of these two entities is essential for pathologists aswell as surgeons to avoid mistaking a small incidental GIST asmetastasis from the primary gastric carcinoma.

Conflict of Interest The authors declare that they have no conflict ofinterest.

Funding None declared.

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