ORIGINAL ARTICLE

Gastrointestinal Stromal Tumors of the Stomach in Children and Young Adults

A Clinicopathologic, Immunohistochemical, and Molecular Genetic Study of 44 Cases With Long-Term Follow-Up and Review of the Literature
Markku Miettinen, MD,* Jerzy Lasota, MD,* and Leslie H. Sobin, MD

Abstract: Gastrointestinal stromal tumors (GISTs), specic KIT- or

PDFGRA-signaling driven mesenchymal tumors, are rare in children and young adults, and their clinicopathologic and molecular genetic prole is incompletely understood. In this study, we analyzed 44 gastric GISTs occurring by the age of 21 years. There were 32 females and 12 males, youngest of whom were a 5-year-old boy and an 8-year-old girl. All but 1 of 25 patients under the age of 16 were girls. The patients most commonly received medical attention because of chronic, insidious gastrointestinal bleeding with anemia, less commonly with acute GI bleeding. Only 1 patient had Carney triad with pulmonary chondroma. None of the patients had family members with GIST. The tumors measured from 1.5 to 24 cm (median, 5.6 cm). A total of 21 tumors with specied location were in the antrum and 8 were in the gastric body. Histologically, 26 tumors were composed of epithelioid cells, 12 of spindle cells, and 6 of combination thereof. Mitotic activity varied form 0 to 65/50 HPF (median, 5/50). All but one of the 24 tumors tested were KIT-positive, and 20 were CD34positive. Eleven patients developed liver or abdominal metastases, and 6 of them died of tumor surviving 5.5 to 35.5 years (median, 16 years) after the rst surgery; three of these tumors had a low mitotic activity and size ,10 cm. Twenty-one patients were alive with no evidence for disease 7 to 41 years (median, 17 years) after the rst surgery. None of the 13 tumors examined (7 of them 8- to 16-year-old females) had KIT exon 9, 11, 13, or 17 or PDGFRA exon 12 or 18 mutation as typically seen in adult GISTs. Gastric GISTs in children have mainly epithelioid morphology, often occur in antrum, and have a somewhat unpredictable but slow course of disease. Their pathogenesis may differ from that of adult GISTs because no KIT or PDGFRA mutations were found; connection with Carney triad seems infrequent despite demographic and histologic similarities.

Key Words: gastrointestinal stromal tumor, stomach, child, prognosis, KIT, PDGFRA, mutation (Am J Surg Pathol 2005;29:13731381)

astric stromal tumors (GISTs), the specic KIT-positive and KIT- or PDGFRA-driven mesenchymal tumors of the GI tract, typically occur in older adults and comprise approximately 60% of all GISTs of all sites.37 These tumors seem to be very rare in children and young adults and are mostly reported in the English literature as single cases and small series with scant data on long-term follow-up.4,6,10,11,1315,2022,25,26,30,33,34,36,4244,4749,5254 Some of those tumors were reported as gastrointestinal autonomic nerve tumors (GANTs) currently understood as variants of GIST, based on similar KIT expression and KIT mutations,31 and others as gastric leiomyomas, leiomyoblastomas, and leiomyosarcomas. Some GISTs in children and young adults occur in connection with Carney triad or GIST paraganglioma syndrome, of which a large series was published, including approximately 45 patients 20 years old or younger and showing a relatively indolent course of disease with commonly persisting disease.7,8 A majority of adult GISTs have gain-of-function mutations in KIT or PDGFRA, two closely related receptor tyrosine kinases.16,17,24,27,46 However, there is little information on mutation status in GISTs at young age with only 1 case reported and found to be KIT mutation negative.33 In this study, we present a clinicopathologic, immunohistochemical, and molecular genetic analysis of 44 gastric GISTs in children and young adults, all but one of which occurred outside the setting of Carney triad/GIST paraganglioma syndrome.

From the Departments of *Soft Tissue Pathology and Hepatic and Gastrointestinal Pathology, Armed Forces Institute of Pathology, Washington, DC. The opinions and assertions contained herein are the expressed views of the authors and are not to be construed as ofcial or reecting the views of the Departments of the Army or Defense. Reprints: Markku Miettinen, MD, Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, 6825 16th Street NW, Bldg 54, Rm G090, Washington, DC 20306-6000 (e-mail: miettinen@ap.osd.mil). Copyright 2005 by Lippincott Williams & Wilkins

MATERIALS AND METHODS Case Material

All cases coded as gastric smooth muscle or stromal tumors (including any alternative designation) submitted from the United States or Canada during 1970 to 1996 (n = 1877) were retrieved. Of these 1877 tumors, 55 occurred at or under the age of 21 years. Forty-four tumors were histologically

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classied as GISTs and included in this study. The classication was based on the known histologic spectrum of KITpositive gastric GISTs with spindle cell or epithelioid features, and with one exception, on KIT positivity. Based on reclassication, 11 tumors were excluded: 4 inammatory myobroblastic tumors, 1 desmoid, 1 small round cell desmoplastic tumor, 3 benign mesenchymal tumors not further classied, and 2 unclassied sarcomas. There were no true leiomyomas, leiomyosarcomas, or schwannomas. Clinical data were reviewed from the records, and follow-up information was obtained from the hospital records, tumor registries, primary care physicians, patients, or in some cases from family members, according to the institutional review board approval. For the purpose of clinicopathologic comparison, the gastric GISTs were divided into eight groups based on tumor maximum diameter and mitotic activity per 50 high power elds (HPFs), as previously detailed.40 The groups were dened as follows: group 1, tumors 2 cm or less in diameter with 5 or fewer mitoses per 50 HPF; group 2, tumors larger than 2 cm and not over 5 cm, with 5 or fewer mitoses per 50 HPF; group 3a, tumors larger than 5 cm and not over 10 cm, with 5 or fewer mitoses per 50 HPF; group 3b, tumors larger than 10 cm, with 5 or fewer mitoses per 50 HPF; group 4, tumors 2 cm or smaller and with more than 5 mitoses per 50 HPF; group 5, tumors larger than 2 cm and not over 5 cm and with more than 5 mitoses per 50 HPF; group 6a, tumors larger than 5 cm and not over 10 cm with more than 5 mitoses per 50 HPF; group 6b, tumors larger than 10 cm with more than 5 mitoses per 50 HPF.

Louis, MO, 1:50 no pretreatment); desmin, clone D33 (Dako 1:50, heat-induced epitope retrieval by EDTA buffer); S-100 protein, polyclonal (Dako, 1:1600, no pretreatment). The primary antibodies were incubated 1 hour at room temperature. The detection was performed using the Envision non-avidin-biotin based polymer system (Dako) with diaminobenzidine as the chromogen.

Molecular Genetics
DNAwas extracted from formalin-xed, parafn-embedded tissue in 13 cases. Sequences of KIT exon 9, 11, 13, 17 and PDGFRA exon 12 and 18 were PCR-amplied and analyzed as previously described.2729

RESULTS
A total of 44 patients with GISTs of age of 21 or under were identied among 1782 patients with gastric GISTs (2.6%). There were 32 females and 12 males with age range 5 to 21 years (median and mean, 14.5 years). Only 2 patients were younger than 10 years: a 5-year-old boy and an 8-year-old girl. All but 1 patient under age 16 were female. The age and sex distribution is shown in Figure 1.

Clinical Features
The clinicopathologic features are summarized in Table 1. A great majority of patients with known clinical history (35 of 37 patients, 95%) presented with gastrointestinal bleeding. This was most commonly insidious leading to anemia and related symptoms such as syncope and weakness. Six patients were specied to have hematemesis and 5 had melena, and 3 patients had both. One patient had upper abdominal discomfort and another was diagnosed umbilical hernia caused by tumor. One patient had Carney triad. She had a gastric epithelioid GIST rst excised at the age of 12 years and had surgery for pulmonary chondroma 3 years later. The details of this patient were reported previously.40 None of the patients had evidence for paraganglioma, neurobromatosis type I, or familial GIST; the information was based in addition to documents, interview of 19 patients or family members.

Analysis of Histologic Parameters

A total of 1 to 26 hematoxylin and eosin-stained slides (median, 7 slides) were reviewed of each case. Mitotic gures were counted in 50 elds by searching the most mitotically active areas or until 100 mitoses were found. The total area of the 50 elds measured 5.3 mm2. The mitosis counting as well as enumeration of histologic features was performed blindly without knowing tumor outcome. The tumors were subclassied and histologic features enumerated as previously reported.40 By cell type, the tumors were divided into spindle, epithelioid, or combination types. By subtype, the spindle cell tumors were divided into sclerosing, palisaded- vacuolated, hypercellular, and sarcomatous ones, and the epithelioid tumors were divided into sclerosing, discohesive, hypercellular, and sarcomatous subtypes. The following additional parameters were recorded in all cases: nuclear atypia, presence of coagulative or liquefactive necrosis, mucosal invasion, calcication, organoid pattern, nuclear palisading, and cytoplasmic vacuolization.

Immunohistochemistry
All tumors with available parafn blocks or unstained slides were evaluated. The primary antibodies, sources, dilutions, and pretreatments were the following: CD34, clone QBEND/10, Biogenex, San Ramon, CA 1:40, Sigma protease VIII for 2 minutes; KIT (CD117), polyclonal antibody A4502, 1:200 (Dako, Carpinteria, CA) with heat-induced epitope retrieval by EDTA buffer; smooth muscle actin, clone 1A3 (Sigma, St.

FIGURE 1. Age and sex distribution of 44 gastric GISTs in children and young adults. Pale = males; dark = females. q 2005 Lippincott Williams & Wilkins

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TABLE 1. Clinicopathologic Features of the 44 Children and Young Adults With a Gastric GIST
Patient No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 Age (yr) 5 8 10 10 10 10 11 11 11 11 11 12 12 12 12 13 13 14 14 14 14 14 14 15 15 16 16 16 17 17 17 18 18 18 19 19 19 19 19 19 20 21 21 21 Sex M F F F F F F F F F F F F F F F F F F F F F F F F F M M M M M F F M F F F M M M M F F M Size (cm) 14.5 8 5 5.7 .10 ND 3 5 5 6 7 2.7 5 6 8.5 4.3 .10 3.5 4.5 6 6 7 9 3.5 24 1.5 4 8 2.7 4 5 3.5 5.5 ND 1.5 6.5 12 3.8 5 6 7 3.5 7 7 Location Anterior wall LC LC LC Cardia, posterior wall Antrum Antrum, LC Antrum, posterior wall Antrum, near LC LC Antrum, LC Distal LC Fundus, LC, post wall Distal, GC LC Upper body LC Antrum, posterior wall Antrum, LC Antrum Antrum, fundus, multiple Distal stomach Antrum Antrum, LC Antrum, LC Antrum, LC Distal, posterior wall Cardia, posterior wall Antrum Antrum, anterior wall Posterior wall Distal body Fundus Antrum GC, anterior Antrum Body Mid-body Mitoses/ 50 HPF 0 18 10 3 8 14 (met) 16 0 3 37 16 6 18 2 7 4 11 2 7 4 1 1 6 6 65 1 9 2 6 2 30 3 2 7 4 16 3 0 15 12 3 0 13 2 Cell Type E E E E E E E/S E E S E S E E E S E E E E/S E E/S S E/S E E S E S E S E/S S E E S E E S E S S E/S E Prognostic Group 3b 6a 5 3a 6b 5 2 2 6a 6a 5 5 3b 6a 2 6b 2 5 3a 3a 3a 6a 5 6b 5 3a 5 2 5 2 3a 2 6a 3b 2 5 6a 3a 2 6a 3a multiple Recurrences/Metastases (yrs from onset) Abdominal mets, 18 Follow-Up (yrs) 18 8.6 29.4 35.5 Outcome AWD ANED ANED DOD

Gastric recurrence, 13, gastrectomy Liver mets, duration unknown

7 Liver mets, 4.5 5.6

ANED DOD

Gastric recurrences, 9 and 30, total gastrectomy Liver mets, 4.5 Liver mets, at presentation Liver mets, time of diagnosis unknown Liver mets, 14

41.2 8.9 6.5 20.4 28 13 20.7 21.5 27.5 8.1

ANED AWD AWD DOD DOD ANED ANED ANED AWD ANED ANED DOD ANED DOD AWD ANED ANED

Liver mets, 7

Abdominal and liver mets, 4

11 10.8 23.3 11.3 17.3 31.2

Liver mets, 22 Liver mets, 11

12.2 17.5 16.6 29.3 14.7 34.2 7.4 10.1 17.3

ANED ANED ANED ANED ANED ANED ANED ANED ANED

LC, lesser curvature; GC, great curvature; ANED, alive with no evidence of disease; AWD, alive with disease; DOD, dead of disease; mets, metastases.

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A majority of the tumors with specied location occurred in the antrum (n = 21). Eight tumors were known to occur in the gastric body (3 in fundus, 2 in cardia, and 3 elsewhere). At least 2 patients had multiple tumors: 1 (patient no. 24, Table 1) had two tumors: one in the antrum and another in the fundus, and another (patient no. 44, Table 1) had multiple tumor nodules in gastric body. In addition, four tumors were grossly multinodular, probably representing a single tumor in one region of the stomach. The types of primary operation varied from simple local excision (n = 4) to total gastrectomy (n = 1). Most common was partial gastrectomy, usually antrectomy (n = 12), followed by wedge resection (n = 11). Seven patients had subtotal gastrectomy. Two patients underwent total gastrectomy upon gastric recurrence 15 and 30 years after the primary tumor.

Molecular Genetics
All 13 tumors analyzed (7 of them 8- to 16-year-old girls) showed wild-type sequences of KIT exons 9, 11, 13, and 17, and wild-type sequences of PDGFRA exons 12 and 18.

Follow-Up
The data are summarized in Table 1. Follow-up information was available of 32 patients. A total of 21 patients were alive with no evidence of disease with median follow-up of 17 years (range, 741 years). Five patients were alive with liver metastasis with median follow-up time of 14 years (range, 9 22 years). Six patients died of disease (liver metastases) with median survival of 16 years (range, 5.535.5 years).

DISCUSSION
Gastric GISTs are rare in children and encompass a spectrum of clinically benign and malignant tumors. Most commonly gastrointestinal cancer in children represents a lymphoma. However, two studies3,36 found that 2 of 3 and 2 of 8 gastric malignancies, respectively, were sarcomas, probably representing GISTs in the current classication. Patients at or under the age 16 represent 1.4% and those under the age of 21 years represent 2.5% of all gastric GIST patients in our series; it is possible that this number overstates the frequency of childhood tumors because of consultation bias; a similar frequency was found in an older AFIP series on gastric epithelioid GISTs.1 However, two recent series of 76 and 108 gastric GISTs did not include any children.50,51 In the AFIP series of GISTs of other sites, only 1 of 132 rectal and 1 of 156 duodenal GISTs (,1%) occurred in patients at or under the age of 21 year indicating that intestinal GISTs are much less common than the gastric ones at young age.38,39 Based on our series and previously published cases (summarized and referenced in Table 2), a majority of gastric GISTs below the age of 16 years occurs in girls; in our series all but 1 of the patients were female. This suggests a developmentally related sex difference, with the occurrence in males being essentially restricted to postpubertal age. According to our ndings, GISTs at young age are not associated with NF1 or familial occurrence, neither of which was encountered among the 44 patients in this study. Only 1 patient in our series has evidence of Carney triad, suggesting that this syndrome is not associated with the majority of GISTs of early onset; among the 38 previously published cases, 7 (18%) had Carney triad (Table 2). Nevertheless, there is close demographic similarity in the pediatric gastric GIST patients with or without signs or Carney triad, suggesting that these groups may be related. Certain clinicopathologic features were associated with childhood GISTs in this series: epithelioid cytology with high cellularity, and location in the antrum in a majority of cases; of all gastric GISTs only 29% occurred in the antrum.40 Previously reported childhood gastric GISTs also had epithelioid cytology in a majority of cases, and antrum and pylorus were common locations (cited in Table 2). Although GISTs in general are known to have KIT or PDGFRA activating mutations with an overall high frequency, none of the 11 subjects in this study had such mutations. This strongly suggests that the pathogenesis of GIST in young age
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Pathology
Selected pathologic features are shown in Table 1. The tumor size varied form 1.5 cm to 24 cm (median, 6 cm). In 4 cases, the size of the primary tumor was not available, but two of these tumors were known to be over 10 cm. Representative images are shown in Figure 2. Histologically, the majority of the tumors (26 of 44, 76%) had purely or predominantly epithelioid morphology; 6 of these cases had focal spindle cell areas. The epithelioid tumors varied from moderately to highly cellular and were most commonly subclassied as hypercellular (n = 18) based on densely packed cells yet lacking sarcomatous features by low-mitotic rate; 4 epithelioid tumors were overtly sarcomatous with high mitotic activity, 3 sclerosing, and 1 of discohesive subtype. Twelve tumors had purely or predominantly spindle cell pattern, and 4 of these cases had focal epithelioid cytology. The spindle cell tumors were subtyped as sclerosing (n = 2), palisading-vacuolated (n = 4), hypercellular (n = 3), and sarcomatous (n = 3). Six tumors contained mixed epithelioid and spindle cell components and did not t into subclassication. The mitotic rate varied from 0/50 to 65/50 HPFs (median 6/50 HPFs). Typical feature in these tumors were muscle invasion between gastric smooth muscle bers (34 cases); this often created a plexiform growth pattern with alternating areas of tumor and normal smooth muscle. Perinuclear vacuolization was also typical, seen in 30 cases. Seven epithelioid tumors had well or partially developed organoid pattern (Fig. 2A) and 7 spindle cell tumors but none of the epithelioid tumors showed nuclear palisading resembling that commonly seen in schwannoma (Fig. 2E). Coagulative necrosis (2 cases) and mucosal invasion (1 case) were rare ndings, but foci of liquefactive necrosis often seen in adult GISTs were not present. None of the tumors had calcication. Lymph nodes were negative in all 8 cases in which nodes were sampled. Immunohistochemically, all but one of the 24 cases tested for KIT (CD117) were positive (96%) typically showing strong pan-cytoplasmic staining highlighting the tumoral elements from brovascular background (Fig. 2G, H). CD34 was present in 21 of 25 cases (84%), typically extensively (Fig. 2I), but smooth muscle actin (Fig. 2J), desmin, and S-100 protein in none of the 24 cases tested.

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FIGURE 2. Typical examples of gastric GISTs in children in young adults. A, Epithelioid GIST with an organoid pattern with supercial resemblance to paraganglioma. B, Hypercellular epithelioid GIST with pseudorosettes. C, Hypercellular epithelioid GIST with a focal trabecular pattern. D, Sarcomatous epithelioid GIST with a significant mitotic activity. E, Spindle cell GIST of palisading vacuolized subtype. F, Hypercellular spindle cell GIST. G, Strongly KIT-positive gastric GIST. H, Strongly KIT-positive gastric GIST. I, Strongly CD34-positive gastric GIST. J, All tumors were negative for smooth muscle actin.

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TABLE 2. Summary of 38 Previously Published Cases of Gastric GISTs/GANTs in Children and Young Adults
Case No. 1 2 3 5 6 7 8 9 10 11 12 13 14 18 15 16 17 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 Case No. 1 2 3 5 6 7 8 9 10 11 12 13 14 18 Age (yr) 3.5 4 7 9 10 10 10 10 10 11 11 11 11.5 11.7 11 11 12 13 13 13 13 13 14 14 15 15 15 15 15 16 16 16 16 17 17 17 19 Cell Type S E E E E/S S E/S S E E S/E Sex F M F F F F F F M F F F F F M M F F F F F M F F F F F M M F F F M F F F F KIT + + Diagnosed as GANT Diagnosed as GANT + Diagnosed as GANT + + Tumor Size (cm) 3 5.7 3 4.8 3 4.3 434 Large 8 3 5 (rec) Multiple, ad 2 cm 8 5.5 3 3.4 3 1.5 6.5 3 5.5 3 3 8.5 18.5 3 16 3 11 11.0 5.5 3 2.5 4.5 12 3 10 12 3 9 3 6 13 3 4.5 Large 3.8 Huge, .15 8 cm+, multiple nodules 8.0 Large, multinodular 10 0.52.7, multiple nodules 16 cm, multiple 9.0 32 3 24 3 15 0.25 multiple nodules 15 3 8, multiple nodules 5.0 83837 7 cm (estimated) Multiple Comment Location Fundus Antrum, posterior wall Distal stomach Posterior wall, LC LC Fundus, posterior Antrum, anterior wall LC GC Body and antrum LC LC Near pylorus, GC LC Antrum, posterior wall Antrum, LC Near cardia, antrum Pylorus Body, posterior wall Antrum, LC Pylorus Body and antrum Fundus, body, duodenum Midbody to pylorus, LC Distal stomach LC Follow-Up (yr) 1 yr 0.5 8.5 1.3 8.7 18.0 1.6 1.5 18.0 12.7 4.3 Outcome DOD, liver mets AWD, liver mets* ANED, rec at 8 yr ANED ANED ANED ANED ANED AWD, liver mets ANED ANED, with treated liver mets Mitoses/HPF 0/50 ,2/HPF Easily found 5/10 ND 0/50 2/10 30/50 15/10 7/50 8/50 25/50 1/10 5-6/50 rare 28/10 ,5/50 0/50 14/50 2/50 ,1/50 1/25 4/50 250/50 ,1/20 3/10 4/50 1/50 Reference 54 13 47 13 13 30 22 36, 53 15 22 15 21 10 20

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TABLE 2. (continued ) Summary of 38 Previously Published Cases of Gastric GISTs/GANTs in Children and Young Adults
Case No. 15 16 17 19 20 21 22 23 24 25 26 27 28 29 30 31 32 Cell Type S S E E S/E E E S E S E E/S KIT Comment Follow-Up (yr) 0.5 2.0 7.0 Diagnosed as GANT 0.7 1.0 1.2 6.0 27.0 0.8 1.5 5.0 1.3 2.5 9 Outcome DOD, abdominal and liver mets ANED AWD, liver mets AWD, peritoneal implants at 5 yr ANED ANED AWD, liver mets AWD, liver mets AWD, liver mets ANED, abdominal rec/mets at 9, 16, 20, 25 yr AWD, liver mets ANED ANED ANED* ANED ANED Reference 36, 53 34 33 54 22 42 54 4 26 54 44 25 14 26 10 43 11

Monozygotic twin had retroperitoneal paraganglioma

Also pulmonary chondroma

Also mediastinal paraganglioma + Also mediastinal paraganglioma Also pulmonary chondroma and mediastinal paraganglioma Diagnosed as GANT Features of GANT, Also retroperitoneal paraganglioma Survivor of a neuroblastoma at the age of 5 mo Also retroperitoneal paraganglioma Also 3 para-aortic paragangliomas

33 34

9.0 0.7

ANED, recurrence, with LN involvement at 3 and 5 yr ANED

22 49, 52

35 36 37 38

E E

1.1

ANED

21 6

48 6

LC, lesser curvature; GC, greater curvature; mets, metastases; rec, recurrence; ANED, alive with no evidence of disease; AWD, alive with disease; DOD, dead of disease. *Patient has received imatinib mesylate for treatment. In some cases, age has been rounded to the closest year.

groups may differ from that in adults. Previously another subgroup of GISTs, those occurring in neurobromatosis 1 patients, has been reported to be negative for KIT and PDFGRA mutations.23 Recently, one gastric GIST in an adult with Carney triad12 and another, pediatric one without it33 were also found negative for KIT and PDGFRA mutations. If the KIT/PDGFRA mutation negativity applies to Carney triad-associated GISTs in general, pediatric gastric GISTs with or without Carney triad may have a similar pathogenesis, possibly involving alternative mode of KIT activation than the type of mutations typically seen in GISTs. More studies are needed to understand the pathogenesis of pediatric gastric GISTs. The occurrence of GISTs at young age raises the question whether this could be linked with familial disease. However, none of our patients, including 19 patients who were interviewed, had evidence of GISTs in other family members. Also, there are many differences between pediatric and reported
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familial GISTs. The latter manifest in adult age (age range in 23 patients with reported details, 1871 years; median, 45 years), and are always associated with constitutional KIT or PDGFRA mutation.2,5,9,18,19,32,35,41,45 In two studies, occurrence in children of the affected families was specically excluded, in 1 case by CT scan.2,32 No KIT or PDGFRA mutations were detected in pediatric GISTs, indicating a different pathogenesis. Prognostically, gastric GISTs in children are heterogeneous. A majority of these tumors are clinically indolent with an excellent long-term prognosis, based on our cases with variably long follow-up and previously published cases with mostly limited follow-up (Table 2). Treatable recurrences are not uncommon and may reect initial insufcient excision or multifocal disease escaping surgical detection at the outset. In our series 11 of 32 patients with follow-up developed liver metastases, and 6 patients died during the follow-up. Most of the patients who developed metastases were in unfavorable

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TABLE 3. Prognosis of 30 GISTs in Children and Young Adults by Prognostic Groups in Comparison With 1055 Gastric GIST Patients
Patients With Metastases of All in the Group (%) Prognostic Group and Denition 2 3A 3B 5 6A 6B (#5 cm, #5/50 HPF) (5 # 10 cm, #5/50 HPF) (.10 cm, #5/50 HPF) (.2 # 5 cm, .5/50 HPF) (.5 # 10 cm, .5/50 HPF) (.10 cm, .5/50 HPF) Children and Young Adults 1/6 2/7 1/2 1/7 3/5 2/3 (17%) (28%) (50%) (14%) (60%) (67%) All Gastric GIST Patients 6/320 8/229 17/140 16/99 52/96 89/108 (2%) (3%) (12%) (16%) (54%) (82%)

Note: Only cases with follow-up and dened tumor size are included.

categories with high mitotic rate, large tumor size, or both. However, 3 of 13 patients with gastric GISTs with favorable parameters associated with only 2% to 3% mortality in gastric GIST patients in general40 developed metastasis (Table 3). This may suggest that GISTs in young age are somewhat unpredictable and may behave more aggressively than those in adults, as the comparison with our collective data on gastric GISTs shows. REFERENCES
1. Appelman HD, Helwig EB. Gastric epithelioid leiomyoma and leiomyosarcoma (leiomyoblastoma). Cancer. 1976;38:708728. 2. Beghini A, Tibiletti M, Roversi G, et al. Germline mutation in the juxtamembrane domain of the Kit gene in a family with gastrointestinal stromal tumors and urticaria pigmentosa. Cancer. 2001;92:657662. 3. Bethel CAI, Bhattacharyya, Hutchinson C, et al. Alimentary tract malignancies in children. J Pediatr Surg. 1997;32:10041009. 4. Boccon-Gibod L, Boman F, Boudjemaa S, et al. Separate occurrence of extra-adrenal paraganglioma and gastrointestinal stromal tumor in monozygotic twins: probable familial Carney syndrome. Pediatr Dev Pathol. 2004;7:380384. 5. Carballo M, Roig I, Aguilar F, et al. Novel c-KIT germline mutation in a family with gastrointestinal stromal tumors and cutaneous hyperpigmentation. Am J Med Genet. 2005;132:361364. 6. Carney JA, Sheps SG, Go VL, et al. The triad of gastric leiomyosarcoma, functioning extra-adrenal paraganglioma and pulmonary chondroma. N Engl J Med. 1977;296:517518. 7. Carney JA. Gastric stromal sarcoma, pulmonary chondroma, and extraadrenal paraganglioma (Carney triad): natural history, adrenocortical component, and possible familial occurrence. Mayo Clin Proc. 1999;74: 543552. 8. Carney JA, Stratakis CA. Familial paraganglioma and gastric stromal sarcoma: a new syndrome distinct from the Carney triad. Am J Med Genet. 2002;108:132139. 9. Chompret A, Kannengiesser C, Barrois M, et al. PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor. Gastroenterology. 2004;126:318321. 10. Cypriano MS, Jenkins JJ, Pappo AS, et al. Pediatric gastrointestinal stromal tumors and leiomyosarcoma. Cancer. 2004;101:3950. 11. de Castro FJ, Olsen WR, Littler ER. Gastric leiomyoblastoma in an adolescent. Am J Surg. 1972;123:614616. 12. Diment J, Tamborini E, Casali P, et al. Carney triad: case report and molecular analysis of gastric tumor. Hum Pathol. 2005;36:112116. 13. Durham MM, Gow KW, Shehata BM, et al. Gastrointestinal stromal tumors arising from the stomach: a report of three children. J Pediatr Surg. 2004;39:14951499. 14. Grace MP, Batist G, Grace WR, et al. Aorticopulmonary paranganglioma and gastric leiomyoblastoma in a young woman. Am J Med. 1981;70: 12881292.

15. Haider N, Kader M, McDermott M, et al. Gastric stromal tumors in children. Pediatr Blood Cancer. 2004;42:186189. 16. Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299:708710. 17. Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279:577580. 18. Hirota S, Nishida T, Isozaki K, et al. Familial gastrointestinal stromal tumors associated with dysphagia and novel type germline mutation of KIT gene. Gastroenterology. 2002;122:14931499. 19. Isozaki K, Terris B, Belghiti J, et al. Germline-activating mutation in the kinase domain of KIT gene in familial gastrointestinal stromal tumors. Am J Pathol. 2000;157:15811585. 20. Johnson H, Hutter JJ Jr, Paplanus SH. Leiomyosarcoma of the stomach: results of surgery and chemotherapy in an eleven-year-old girl with liver metastases. Med Pediatr Oncol. 1980;8:137142. 21. Johnston DL, Olson JM, Benjamin DR. Gastrointestinal stromal tumor in a patient with previous neuroblastoma. J Pediatr Hematol Oncol. 2001; 23:255256. 22. Kerr JZ, Hicks MJ, Nuchtern JG, et al. Gastrointestinal autonomic nerve tumors in the pediatric population: a report of four cases and review of the literature. Cancer. 1999;85:220230. 23. Kinoshita K, Hirota S, Isozaki K, et al. Absence of c-kit gene mutations in gastrointestinal stromal tumours from neurobromatosis type 1 patients. J Pathol. 2004;202:8085. 24. Kitamura Y, Hirota S, Nishida T. Molecular pathology of c-kit protooncogene and development of gastrointestinal stromal tumors. Ann Chir Gynaecol. 1998;87:282286. 25. Kodet R, Snajdauf J, Smelhaus V. Gastrointestinal autonomic nerve tumor: a case report with electron microscopic and immunohistochemical analysis and review of the literature. Pediatr Pathol. 1994;14:10051016. 26. Lack EE. Leiomyosarcomas in childhood: a clinical and pathologic study of 10 cases. Pediatr Pathol. 1986;6:181197. 27. Lasota J, Jasinski M, Sarlomo-Rikala M, et al. C-kit mutations occur preferentially in malignant vs. benign gastrointestinal stromal tumors and do not occur in leiomyomas and leiomyosarcomas. Am J Pathol. 1999; 154:5360. 28. Lasota J, Wozniak A, Sarlomo-Rikala M, et al. Mutations in exons 9 and 13 of KIT gene are rare events in gastrointestinal stromal tumors: a study of two hundred cases. Am J Pathol. 2000;157:10911095. 29. Lasota J, Dansonka-Mieszkowska A, Sobin LH, et al. A great majority of GISTs with PDGFRA mutations represents gastric tumors of no or low malignant potential. Lab Invest. 2004;84:874883. 30. Lauwers GY, Erlandson RA, Casper ES, et al. Gastrointestinal autonomic nerve tumors: a clinicopathological, immunohistochemical, and ultrastructural study of 12 cases. Am J Surg Pathol. 1993;17:887897. 31. Lee JR, Joshi V, Grifn JW Jr, et al. Gastrointestinal autonomic nerve tumor: immunohistochemical and molecular identity with gastrointestinal stromal tumor. Am J Surg Pathol. 2001;25:979987. 32. Li FP, Fletcher JA, Heinrich MC, et al. Familial gastrointestinal stromal tumor syndrome: phenotypic and molecular features in a kindred. J Clin Oncol. 2005;23:27352743. 33. Li P, Wei J, West AB, et al. Epithelioid gastrointestinal stromal tumor of stomach with liver metastases in a 12-year old girl: aspiration cytology and molecular study. Pediatr Dev Pathol. 2002;5:386394. 34. Luzzatto C, Calligioni A, Candiani F, et al. Gastric leiomyoblastoma in childhood: a case report and review of the literature. Z Kinderchir. 1989; 44:373376. 35. Maeyama H, Hidaka E, Ota H, et al. Familial gastrointestinal stromal tumor with hyperpigmentation associated with a germline mutation of the c-kit gene. Gastroenterology. 2001;120:210215. 36. Mahour GH, Isaacs H Jr, Chang L. Primary malignant tumors of the stomach in children. Pediatr Surg. 1980;15:603608. 37. Miettinen M, Lasota J. Gastrointestinal stromal tumors: denition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis. Virchows Arch. 2001;438:112. 38. Miettinen M, Sarlomo-Rikala M, Sobin LH, et al. Gastrointestinal stromal tumors of the rectum: a clinicopathologic, immunohistochemical and molecular genetic study of 144 cases. Am J Surg Pathol. 2001;25:11211133. 39. Miettinen M, Kopczynski J, Maklouf HR, et al. Gastrointestinal stromal tumors, intramural leiomyomas and leiomyosarcomas in the duodenum: a clinicopathologic, immunohistochemical and molecular genetic study of 167 cases. Am J Surg Pathol. 2003;27:625641.

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40. Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic studies of 1765 cases with long-term follow-up. Am J Surg Pathol. 2005;29:5268. 41. Nishida T, Hirota S, Taniguchi M, et al. Familial gastrointestinal stromal tumours with germline mutation of the KIT gene. Nat Genet. 1998;19: 323324. 42. Oguzkurt P, Akcoren Z, Sonocak ME, et al. A huge gastric stromal tumor in a 13-year-old girl. Turk J Pediatr. 2002;44:6568. 43. Perez-Atayde AR, Shamberger RC, Kozakewich HW. Neuroectodermal differentiation of the gastrointestinal tumors in the Carney triad: an ultrastructural and immunohistochemical study. Am J Surg Pathol. 1993; 17:706714. 44. Persson S, Kindblom LG, Angervall L, et al. Metastasizing gastric epithelioid leiomyosarcomas (leiomyoblaastomas) in young individuals with long-term survival. Cancer. 1992;70:721732. 45. Robson ME, Glogowski E, Sommer G, et al. Pleomorphic characteristics of a germ-line KIT mutation in a large kindred with gastrointestinal stromal tumors, hyperpigmentation, and dysphagia. Clin Cancer Res. 2004;10: 12501254. 46. Rubin BP, Singer S, Tsao C, et al. KIT activation is ubiquitous feature of gastrointestinal stromal tumors. Cancer Res. 2001;61:81188121.

47. Schmitt EL, Heidelberger KP. Gastric leiomyoblastoma in a child. J Can Assoc Radiol. 1976;27:115117. 48. Stout AP. Bizarre smooth muscle tumors of the stomach. Cancer. 1962;15: 400409. 49. Tortella BJ, Matthews JB, Antonioli DA, et al. Gastric autonomic nerve (GAN) tumor and extra-adrenal paraganglioma in Carneys triad: a common origin. Ann Surg. 1987;205:221225. 50. Trupiano JK, Stewart RE, Misick C, et al. Gastric stromal tumors: a clinicopathologic study of 77 cases with correlation of features with nonaggressive and aggressive behaviors. Am J Surg Pathol. 2002;26:705 714. 51. Wong NACS, Young R, Malcolmson RDG, et al. Prognostic indicators for gastrointestinal stromal tumours: a clinicopathological and immunohistochemical study of 108 resected cases of the stomach. Histopathology. 2003;43:118126. 52. Walker P, Dvorak AM. Gastrointestinal autonomic nerve tumor: ultrastructural evidence for a newly recognized entity. Arch Pathol Lab Med. 1986;110:309316. 53. Wurlitzer FP, Mares AJ, Isaacs H Jr, et al. Smooth muscle tumors of the stomach in childhood and adolescence. J Pediatr Surg. 1973;8:421427. 54. Yannopoulos K, Stout AP. Smooth muscle tumors in children. Cancer. 1962;15:958971.

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