Keratin-positive Gastrointestinal Stromal Tumor of the Stomach Mimicking Gastric Carcinoma: Diagnosis Confirmed by c-kit Mutation Analysis : Diagnostic Molecular Pathology

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00019606-200812000-00009ReportDiagnostic Molecular PathologyDiagnostic Molecular Pathology© 2008 Lippincott Williams & Wilkins, Inc.17December 2008 p 241-244Keratin-positive Gastrointestinal Stromal Tumor of the Stomach Mimicking Gastric Carcinoma: Diagnosis Confirmed by c-kit Mutation AnalysisCase ReportLippai, Norbert MD*; Füle, Tibor PhD†; Németh, Tamás MD*; Benedek, György MD‡; Mályi, Imre MD§; Pádi, Éva MD∥; Sápi, Zoltán MD, PhD†Departments of *Pathology‡Surgery§Gastroenterology∥Oncology, Bajcsy Zsilinszky Hospital†1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, HungaryReprints: Zoltán Sápi, MD, PhD, Üllői út 26, 1085 Budapest, Hungary (e-mail: [email protected]).AbstractIn routine practice, gastrointestinal stromal tumor (GIST) can usually be identified with relative ease on the basis of a rather simple immunohistochemical panel besides its characteristic morphology. Still, serious differential diagnostic problems may arise because of the heterogeneity of these tumors in both morphologic appearance and clinical behavior. In our case, we present a metastatic, ulcerative, hemorrhagic GIST with epithelioid appearance, which displayed diffuse pan cytokeratin (AE1/AE3) positivity beside CD117 expression. As carcinomas may also be CD117-positive, definitive diagnosis was confirmed by the detection of a hexanucleotide deletion in the exon 11 of c-kit. This case demonstrates that although gastric carcinoma more commonly ulcerates or causes hemorrhage than GIST, keratin-positive GIST should also be considered from a differential diagnostic point of view. In these cases, c-kit mutation analysis may be necessary.The current definition of gastrointestinal stromal tumor (GIST) collects mesenchymal neoplasms typically originating from the gastrointestinal tract, consisting of spindle, epithelioid or mixed phenotype (spindle/epithelioid) cells, and expressing KIT protein (CD117). With the use of routine immunhistochemical markers, the diagnosis of GIST suggested by the morphologic picture can usually be unequivocally confirmed or excluded, as these tumors are practically always CD117 positive (2% to 8% may be negative). CD34 expression occurs in 60% to 70% of cases, whereas α-smooth muscle actin positivity is observed in 30% to 40% and S-100 in 5%. On the other hand, desmin and epitheloid markers such as cytokeratins (CKs) are regularly negative.1–3 Below we describe a gastric GIST with epithelioid appearance, which infiltrated and ulcerated the stomach, caused gastrointestinal bleeding and had multiple liver metastasis and peritoneal dissemination. Remarkably, tumor cells displayed the extremely rare coexpression of CD117 and pan-CK.CASE AND PATHOLOGIC FINDINGSIn December 2006, a 45-year-old woman was admitted to our gastroenterology department with undefined abdominal pain, inappetence, and hematemesis. She had a medical history of chronic alcohol abuse. Urgent gastroscopy revealed a 3-to 4-mm large, smooth-surfaced polypoid mass in the cardia, and an erosive ulcer was seen on the posterior wall of the subcardial region, which involved both the lesser and greater curvatures and extended to the fundus. The origin of bleeding was localized by acid hematine absorbance on the base of the ulcer. Other significant alterations were not found. Several biopsies were performed from the ulcerated area. By histology, besides fragments of ulcerated stomach, a single small portion of solid tumor was identified, which appeared as a proliferation of anaplastic epithelioid cells. No tubular formation was seen, but mitotic activity was high and necrosis was found in the tumor. In some places minimal PAS-negative, myxoidlike stroma were also found. The morphologic picture suggested undifferentiated carcinoma or high-grade non-Hodgkin lymphoma; thus immunohistochemistry was performed to confirm either epithelial or lymphoid origin. The tumor cells showed diffuse positivity with CK AE1/AE3 (1:50, Dako, Carpinteria, USA), whereas leukocyte common antigen (LCA) (1:50, Dako) was negative; therefore, anaplastic carcinoma was considered (Figs. 1A, B, D). In the meantime, abdominal ultrasonography revealed multiple liver and lymph node metastases; however, because of the bleeding of the tumor, explorative laparotomy was carried out, which confirmed inoperability with peritoneal carcinosis. For histologic examination, biopsy was taken from the peritoneal metastasis. The morphologic picture in most places showed a well-circumcised, solid anaplastic pattern that was almost identical to the pattern of gastric biopsy, whereas in other parts some more spindled cells also appeared. Considering the morphologic picture and the fact that further immunostaining proved Vimentin (1:100, Dako), CD34 (1:20, Dako), and CD117 (1:20, Novocastra, Newcastle, UK) positivity, the tumor was diagnosed as GIST (Fig. 1C). Besides this, the metastatic tumor exhibited the same strong keratin positivity as the biopsy material, whereas desmin (1:100, Dako), α-smooth muscle actin (1:150, Dako), chromogranin (1:50, Dako), and S-100 (1.1000, Dako) were negative. To confirm the diagnosis and to determine the therapeutic level, c-kit analysis was performed. Molecular analysis of the tumor DNA revealed a mutation in the c-kit gene, which turned out to be a hexanucleotide deletion at the position 75687 to 75692 of exon 11. The result of the analysis of c-kit mutation confirmed the diagnosis of metastatic GIST and determined the dose of therapy. The patient was transferred to the Oncology department by the Gastro-oncology team for optimal management. The patient is under treatment from February 2007 (imatinib mesylat, with the initial dose of 400 mg/d), and no further surgical intervention was performed after biopsies. Six months later, a remarkable tumor regression has been observed and the patient is in a good physical and psychologic condition.JOURNAL/dimp/04.03/00019606-200812000-00009/figure1-9/v/2021-02-17T195958Z/r/image-jpeg A, Fragments of ulcerated stomach with 1 fraction of solid tumor in the left part of the picture. Hematoxylin and eosin staining, ×40. B, Proliferation of anaplastic epithelioid tumor cells; mitotic forms are visible in the inset. Hematoxylin and eosin staining, ×200; inset ×400. C and D, Strong cytoplasmic CD117 and keratin AE1/AE3 positivity of tumor cells; (C), ×200 and (D), ×100.GENETIC FINDINGSThe KIT mutation status of the patient was analyzed by direct sequencing of the c-kit gene. DNA was extracted from formalin-fixed, paraffin-embedded tissue sections according to the standard salting-out method. The primer sequences and the polymerase chain reaction conditions have been previously described by Penzel et al.4 Polymerase chain reaction products were directly sequenced on an ABI Prism 310 Genetic Analyzer (Applied Biosystems, Foster City, CA) using the BigDye Terminator v.3.1 kit (Applied Biosystems) according to the manufacturer's instructions. Molecular analysis revealed an AGGTTG hexanucleotide deletion in the exon 11 of c-kit (position 75687 to 75692). This mutation results in the exchange of 3 original amino acids at positions 558 to 560 to a single aberrant amino acid in the KIT protein (Ex11 KVV558-560del-insI) (Fig. 2).JOURNAL/dimp/04.03/00019606-200812000-00009/figure2-9/v/2021-02-17T195958Z/r/image-jpeg Electropherograms of forward (A) and reverse (B) sequence of c-kit exon 11 from the patient's tumor tissue. Arrows show the starting point of the sequence shifting. Mutation was identified as AGGTTG hexanucleotid deletion. (Reverse sequence is in reverse complement view.)DISCUSSIONErosive ulcer of the gastric wall is most frequently caused by peptic ulceration, but the second most frequent cause is gastric cancer, especially in the fundus. In everyday routine practice, the biopsy easily reveals the nature of the lesion if it is a more or less differentiated adenocarcinoma. This is not the case when the tumor is anaplastic, because the consideration of both undifferentiated carcinoma and high-grade malignant lymphoma is necessary. Immunohistochemistry for pan-CK and LCA is usually sufficient to distinguish between the 2 entities, with strong keratin positivity indicating carcinoma and LCA positivity speaking for lymphoma. So it happened in our case too: strong keratin positivity in the first gastric biopsy suggested the diagnosis of undifferentiated carcinoma, and it was only the second biopsy from the metastasis that called to our attention the fact that we were holding something different, namely, of an overtly malignant epithelioid GIST in hand.Today, we already know that GIST is the most common mesenchymal neoplasm of the digestive tract. The disease is clinicopathologically well characterized. CD117 reaction gives a positive result in more than 90% of the cases of GIST. In these tumors, gain-of-function mutations of c-kit (the gene of a type III tyrosine kinase protein) can be recognized in approximately 75% to 80%, whereas 20% to 25% of GIST cases are negative.1 On the genetic level, the c-kit–negative tumors form heterogeneous groups. One subset contains intact (wild-type) c-kit gene and the abnormal kinase function is believed to be due to platelet-derived growth factor receptor α-polypeptide (PDGFRA) mutation in approximately 8% of the cases.3 For reasons not entirely understood, KIT mutant tumors seem to respond very well to imatinib mesylat (Glivec) therapy, whereas most of the PDGFRA mutants fail to respond.1 Currently, a new marker called DOG1 has been reported to be expressed in 97.8% of GIST, irrespective of the mutation status of c-kit or PDGFRA, but this is not yet widely used in routine practice.5On the basis of its morphologic picture, GIST can be divided into 3 groups: spindle, epithelioid, or mixed (spindle/epithelioid) cell variants. Still, because of the variable cellular morphology and a broad range of growth patterns, serious differential diagnostic problems can arise. Pure morphologic examination can easily lead to misdiagnosis and confusion of GIST with smooth muscle tumors, desmoid, neural or neuroendocrine neoplasms or, as in our case, with anaplastic carcinoma. Very recently, a CK-positive metastatic GIST was described by Rossi et al,6 which had been previously diagnosed as gastric epithelioid angiosarcoma. They found strong AE1/AE3 keratin positivity as it was in our case. Though in a few previous reports (Nga et al7: cytokeratin-positive pleural metastatic GIST that had been suspected to be lung carcinoma, and Miettinen et al8: 2 CK18-positive cases from 57 anorectal GIST) keratin positivity was detected, this was restricted to CAM 5.2 and CK-8 and CK-18, and the authors failed to find broader keratin positivity such as AE1/AE3, which is more generally used in routine practice.From a differential diagnostic point of view it is interesting that some carcinomas, especially neuroendocrine carcinomas of the lung and the gastrointestinal tract, can be CD117 positive9–11 without displaying canonical mutations at hot spots in the c-kit gene.9,10,12 Because neuroendocrine carcinomas may show strong keratin positivity with neuroendocrine markers (chromogranin, synaptophysin, CD56) appearing only focally, it can be very important to distinguish them from a poorly differentiated epithelioid GIST by using CD34 antibody and/or justifying the KIT or PDGFRA mutation. In our case, we found a genetic alteration involving the codons 558 to 560, the position most frequently affected by deletion or point mutation in the c-kit gene in GIST.13Immunohistochemical examinations have an important role not only in the establishment of diagnosis but also in the targeted treatment and clinical characterization of GIST, as suggested by Fletcher et al.14 However, our case instructs us that sometimes routine stains may prove insufficient, and in these cases mutation analysis of c-kit is the method of choice to resolve the diagnostic dilemma, and—as in our case—to confirm a very rare variant of GIST that is CK-positive and shows a CK and CD117 coexpression.In conclusion, pathologists should be aware that GIST in extremely rare cases expresses CK. Unless this possibility is taken into account, such an irregular finding might easily lead to misdiagnosis, especially when working with small endoscopic biopsies.Moreover, as our case represents, genetic analysis may be important, not only from a therapeutic point of view but also for the establishment of the proper diagnosis.REFERENCES1. Rubin BP, Heinrich MC, Corless CL. Gastrointestinal stromal tumour. Lancet. 2007;369:1731–1741.[Context Link][CrossRef][Medline Link]2. Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol. 2005;29:52–68.[Context Link][Full Text][CrossRef][Medline Link]3. Dow N, Giblen G, Sobin LH, et al. Gastrointestinal stromal tumors: differential diagnosis. Semin Diagn Pathol. 2006;23:111–119.[Context Link][CrossRef][Medline Link]4. Penzel R, Aulmann S, Moock M, et al. 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Text]00000478-200109000-0000200019606-200812000-0000900000475_2001_25_1121_miettinen_immunohistochemical_|00019606-200812000-00009#xpointer(id(citation_FROM_JRF_ID_d4555e557_citationRF_FLOATING))|11065213||ovftdb|SL00000475200125112111065213citation_FROM_JRF_ID_d4555e557_citationRF_FLOATING[CrossRef]10.1097%2F00000478-200109000-0000200019606-200812000-0000900000475_2001_25_1121_miettinen_immunohistochemical_|00019606-200812000-00009#xpointer(id(citation_FROM_JRF_ID_d4555e557_citationRF_FLOATING))|11065405||ovftdb|SL00000475200125112111065405citation_FROM_JRF_ID_d4555e557_citationRF_FLOATING[Medline Link]1168857100019606-200812000-0000900043746_2004_10_8214_tamborini_phosphorylated_|00019606-200812000-00009#xpointer(id(citation_FROM_JRF_ID_d4555e591_citationRF_FLOATING))|11065405||ovftdb|SL00043746200410821411065405citation_FROM_JRF_ID_d4555e591_citationRF_FLOATING[Medline Link]15623596 A, Fragments of ulcerated stomach with 1 fraction of solid tumor in the left part of the picture. Hematoxylin and eosin staining, ×40. B, Proliferation of anaplastic epithelioid tumor cells; mitotic forms are visible in the inset. Hematoxylin and eosin staining, ×200; inset ×400. C and D, Strong cytoplasmic CD117 and keratin AE1/AE3 positivity of tumor cells; (C), ×200 and (D), ×100. Electropherograms of forward (A) and reverse (B) sequence of c-kit exon 11 from the patient's tumor tissue. Arrows show the starting point of the sequence shifting. Mutation was identified as AGGTTG hexanucleotid deletion. (Reverse sequence is in reverse complement view.)Keratin-positive Gastrointestinal Stromal Tumor of the Stomach Mimicking Gastric Carcinoma: Diagnosis Confirmed by c-kit Mutation AnalysisLippai Norbert MD; Füle, Tibor PhD; Németh, Tamás MD; Benedek, György MD; Mályi, Imre MD; Pádi, Éva MD; Sápi, Zoltán MD, PhDCase ReportCase Report417p 241-244

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