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Sweden 1969–1991. Acta Ophthalmol (Copenh) 1992;70:289–

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predictive factors for development of recurrence and metastasis

in conjunctival melanoma: A review of 68 cases. Br J Ophthalmol

1993;77:624–630.

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exenteration in 95 cases of primary conjunctival malignant

melanoma. Br J Ophthalmol 1994;78:252–259.

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value of clinical and histopathological parameters in conjunctival

melanomas: A retrospective study. Br J Ophthalmol 2002;86:163–

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Surg Oncol 1993;19:985–990.

Treatment of Wild-Type Gastrointestinal Stromal Tumor (WT-GIST)With Imatinib and Sunitinib

MatthewMurray, MB, BChir,1* Helen Hatcher, MB, BChir, PhD,1,4 Flora Jessop, BSc(Hons), MBChB,2 DeniseWilliams, MB, BCh,1

Nicholas Carroll, MB, BChir,3 Ramesh Bulusu, MBBS, MD,1 and Ian Judson, MD4

INTRODUCTION

Gastrointestinal stromal tumors (GISTs) are rare, accounting for

0.1–0.3% of all gastrointestinal cancers and 5% of all soft tissue

sarcomas in adults [1]. The incidence in children is exceptional with

less than 30 sporadic cases reported. The majority of pediatric

GISTs occur in adolescent females and are of gastric origin [2,3]. In

contrast to adults, lymph node metastasis is common but overall

prognosis is much better in pediatric disease [3]. Themajority of adult

GIST cases (83.6–88.2%) have activating mutations in the KIT gene,

which codes for the KIT receptor tyrosine kinase. These mutations

We report a rare case of advanced, metastatic gastrointestinalstromal tumor (GIST) in a young female. Molecular analysis of thetumor revealed wild-type (WT) KIT and platelet derived growthfactor receptor alpha (PDGFRA) gene status with no mutations

characteristic of adult GIST. Despite this she had clinical benefit andevidence of radiological response to sequential treatment with thetyrosine kinase inhibitors imatinib and sunitinib. Pediatr BloodCancer 2008;50:386–388. � 2007 Wiley-Liss, Inc.

Key words: gastrointestinal stromal tumors; imatinib; sunitinib; KIT; PDGFRA; pediatric

——————This article contains Supplementary Material available at http://www.

interscience.wiley.com/jpages/1545-5009/suppmat.

1Oncology Department, Addenbrooke’s Hospital, Cambridge, UK;2Department of Histopathology, Addenbrooke’s Hospital, Cambridge,

UK; 3Department of Radiology, Addenbrooke’s Hospital, Cambridge,

UK; 4Sarcoma Unit, Royal Marsden Hospital, Sutton, London, UK

*Correspondence to: Matthew Murray, Pediatric Oncology Department,

Box 181, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ,

UK. E-mail: mjm16@cam.ac.uk

Received 22 March 2007; Accepted 20 June 2007

� 2007 Wiley-Liss, Inc.DOI 10.1002/pbc.21312

386 Brief Reports

result in constitutive activation of the receptor, resulting in down-

stream signals for cell survival and proliferation, in the absence of

ligand binding and receptor dimerization. The majority of GISTs

express CD117 (the immunohistochemical marker for KIT) irre-

spective of whether the gene is mutated or not. PDGFRA mutations

account for a further 2.6–4.7% of cases while the remaining 7.1–

13.8%areWT for either receptor [4,5]. Such tumorsmust be drivenby

othermolecular alterations, the nature of which is currently unknown.

Most pediatric GISTs areWT, with only two sporadic cases published

with mutations (one in KIT, one in PDGFRA) [6,7]. In adults these

mutations and their exonic location accurately predict response to

the tyrosine kinase inhibitor (TKI) imatinib, which targets the

ATP binding site of KIT and PDGFRA resulting in inhibition of

downstream signaling and cell growth [4,5]. Overall response to

imatinib in terms of objective remission and disease stabilization

approaches 90% in adult patients [8], although in diseasewithout such

mutations imatinib is less efficacious. A progression-free survival

advantage has been reported for high-dose imatinib (800 mg vs.

400 mg/day) in adults with advanced GIST associated with exon 9

mutations in KIT [5]. Another TKI, sunitinib, also targets PDGFRA

and KIT but additionally inhibits vascular endothelial growth

receptors (VEGFR) and is now licensed for second line therapy in

GISTs unresponsive to imatinib [9]. The response of pediatricGIST to

these agents is not well documented.

CASE REPORT

A 15-year-old female presented with a 3-week history of pallor,

lethargy and 2 days shortness of breath on exertion. Pastmedical and

family history was unremarkable. Positive findings on examination

were pallor and epigastric tenderness; nomasses were palpable. She

had a severe hypochromic microcytic anemia with hemoglobin of

3.9 g/L, corrected by blood transfusion and iron therapy. Fecal

occult blood tests were positive. Barium meal demonstrated large

multilobular masses arising from the greater curvature of the

stomach; endoscopy showed that these were submucosal in nature.

CT scanning confirmed the above findings (Fig. 1) and identified no

metastases. Laparotomy was performed and biopsies showed a

spindle cell tumor with a mitotic count of 1–2 per 10 high power

fields. Immunohistochemistry revealed KIT (CD117), CD34 and

smooth muscle actin positivity, but S100, desmin and keratin were

negative, consistent with a GIST (Supplemental Fig. 1). Mutation

analysis of KIT and PDGFRAwas negative.

Imatinib was begun (400 mg/day) with resultant reduction in

transfusion requirements. Follow-up CT scans showed minimal

change in size of her abdominal disease, although the lesions were

more heterogeneous and cystic suggesting a response (Fig. 1) [10].

Deterioration in clinical condition, with increased abdominal pain,

nausea, and lethargy, occurred 18 months into treatment. CT scan

revealed no evidence of tumor progression, but FDG-PET

demonstrated marked uptake within the pelvis, inguinal region

and three lesions in the liver, in addition to the primary site,

consistent with metastatic disease. She was referred for a second

opinion and her imatinib dose increased to 800 mg/day. An FDG-

PET scan performed 4 months later showed no reduction in uptake.

However, she remained clinically and radiologically stable at this

higher dose for a total of 4 years, after which she developed

abdominal disease progression onCT scan. Second line therapywas

begun with sunitinib and resulted in lesion density reduction

followed by further disease stabilization on CT scan, but with

frequent episodes of gastrointestinal blood loss.

DISCUSSION

Primary surgery is advocated in adults with GIST but, in

pediatric patients, gastrectomy has profound consequences for

future quality of life and nutrition. We would therefore advocate

multidisciplinary pretreatment discussion of such cases to ensure

most appropriate management. Where surgical resection is not

feasible, or in the case of metastatic disease, imatinib treatment

should be initiated [8].

Our patient had disease characterized by nomutations, typical of

the pediatric form of GIST, but responded to therapy with both

imatinib and sunitinib. In adults, clinical and radiological response

to imatinib inWT GIST is significantly worse than in those patients

with mutations [4,5]. Furthermore, a phase II trial of sunitinib in

adults with imatinib-refractory GIST reported a clinical benefit rate

(i.e., those with complete and partial remission as well as patients

experiencing more than 6 months of disease stabilization) of 56%

with WT tumors, indicating that sunitinib may be more effective

than imatinib for this patient group [11]. Responses have also been

reported with sunitinib in pediatric WT GIST refractory to imatinib

[12]. In contrast to adults, WT disease is far more likely in pediatric

cases, with only twomutations described [6,7], suggesting pediatric

GISTs are a separate clinicopathological and molecular subset with

a predilection for females and WT genotype [2,3].

Choi et al. [13] have demonstrated that in patients with

metastatic GIST treated with imatinib, tumor reduction is often

small, with a mean decrease in size of just 13%. Tumor density

measurement, however, provides a reliable quantitative means of

monitoring response in this patient group. They conclude that the

one-dimensional criteria ofRECISTalone [14] should not be used to

assess disease response; instead a reduction in size and/or tumor

density should be employed [10]. Using these updated criteria our

patient responded to sequential imatinib and sunitinib therapy.

Initial tumor density reduction was followed by a period of

meaningful disease stabilization.

In summary, we describe a pediatric patient with GIST and WT

KIT and PDGFRA status demonstrating clinical benefit and disease

stabilization using imatinib and sunitinib. Further studies with

sunitinib and other receptor TKIs in pediatric GIST are required in

order to determine the optimum systemic therapy for these patients.

Pediatr Blood Cancer DOI 10.1002/pbc

Fig. 1. Abdominal CT at presentation demonstrates a large multi-

lobular tumor arising from the stomach. The mean density of the tumor

is 79HounsfieldUnits (A). After 10months of imatinib therapy there is a

significant tumor density reduction to 52HounsfieldUnits accompanied

by a small decrease in tumor size (B).

Brief Reports 387

ACKNOWLEDGMENT

The authors would like to thank Dr. Maria Debiec-Rychter,

Department of Human Genetics, Catholic University of Leuven,

Leuven, Belgium for kindly providing the mutational analysis for

our patient.

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1. Miettinen M, Lasota J. Gastrointestinal stromal tumors-definition,

clinical, histological, immunohistochemical, and molecular

genetic features and differential diagnosis. Virchows Arch 2001;

438:1–12.

2. Miettinen M, Lasota J, Sobin LH. 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. Am J Surg

Pathol 2005;29:1373–1381.

3. Prakash S, Sarran L, Socci N, et al. Gastrointestinal stromal tumors

in children and young adults: A clinicopathologic, molecular, and

genomic study of 15 cases and review of the literature. J Pediatr

Hematol Oncol 2005;27:179–187.

4. HeinrichMC,Corless CL,Demetri GD, et al. Kinasemutations and

imatinib response in patients with metastatic gastrointestinal

stromal tumor. J Clin Oncol 2003;21:4342–4349.

5. Debiec-Rychter M, Sciot R, Le Cesne A, et al. KIT mutations and

dose selection for imatinib in patients with advanced gastrointest-

inal stromal tumours. Eur J Cancer 2006;42:1093–1103.

6. Price VE, Zielenska M, Chilton-MacNeill S, et al. Clinical and

molecular characteristics of pediatric gastrointestinal stromal

tumors (GISTs). Pediatr Blood Cancer 2005;45:20–24.

7. Kuroiwa M, Hiwatari M, Hirato J, et al. Advanced-stage

gastrointestinal stromal tumor treated with imatinib in a 12-year-

old girl with a unique mutation of PDGFRA. J Pediatr Surg

2005;40:1798–1801.

8. Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in

gastrointestinal stromal tumours with high-dose imatinib: Rando-

mised trial. Lancet 2004;364:1127–1134.

9. Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and

safety of sunitinib in patients with advanced gastrointestinal

stromal tumour after failure of imatinib: A randomised controlled

trial. Lancet 2006;368:1329–1338.

10. Choi H, Charnsangavej C, Faria SC, et al. Correlation of computed

tomography and positron emission tomography in patients with

metastatic gastrointestinal stromal tumor treated at a single

institution with imatinib mesylate: Proposal of new computed

tomography response criteria. J Clin Oncol 2007;25:1753–1759.

11. HeinrichMC,Maki RG, Corless CL, et al. Sunitinib (SU) response

in imatinib-resistant (IM-R) GIST correlates with KIT and

PDGFRAmutation status. Proc Am Soc Clin Oncol 2006;24:520s.

12. Janeway KA, Matthews DC, Butrynski JE, et al. Sunitinib

treatment of pediatric metastatic GIST after failure of imatinib.

Proc Am Soc Clin Oncol 2006;24:18s.

13. Choi H, Charnsangavej C, de Castro Faria S, et al. CTevaluation of

the response of gastrointestinal stromal tumors after imatinib

mesylate treatment: A quantitative analysis correlated with FDG

PET findings. Am J Roentgenol 2004;183:1619–1628.

14. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to

evaluate the response to treatment in solid tumors. European

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Cancer Institute of the United States, National Cancer Institute of

Canada. J Natl Cancer Inst 2000;92:205–216.

Sister Mary Joseph’s Nodule as Presenting Sign of a DesmoplasticSmall Round Cell Tumor

Leslie Doros, MD,1 Sue C. Kaste, DO,2,3,4 and Carlos Rodriguez-Galindo, MD1,4*

INTRODUCTION

Sister Mary Joseph’s nodule, representing metastatic cancer to

the umbilicus, can present as the first sign of an advanced intra-

abdominal malignancy. It is a rare entity often carrying a poor

prognosis. Cutaneous metastases occur in only 1–9% of individuals

[1]; of those, only 10% represent metastases to the umbilicus and

have in general been limited to documentation in the adult

population. The first report of neoplastic involvement of the

umbilicus was described by Walshe in 1846 who noted two cases

in the autopsy examinations of 9,118 individuals with cancer [2,3].

Since then, the presence of umbilical metastases has been well

described as the presenting sign of intra-abdominal malignancies in

adults. However, this is an extremely rare presentation in children

Umbilical metastases, also named Sister Mary Joseph’s nodules,are well documented in the adult population and most oftenrepresent an underlying intra-abdominal malignancy, usually acarcinoma of gastrointestinal or gynecologic origin. They areindicative of widespread abdominal disease and are associated witha poor prognosis. An extensive review of the literature reveals onlytwo such presentations in the pediatric population. A 14-year-old

male presented with an umbilical mass, which was found to be ametastatic lesion of a desmoplastic small round cell tumor (DSRCT)of the abdomen. The diagnosis of an intra-abdominal malignancy,most commonly a DSRCT, should be considered in the presence ofan umbilical mass in a child. Pediatr Blood Cancer 2008;50:388–390. � 2006 Wiley-Liss, Inc.

Key words: desmoplastic small round cell tumor; Sister Mary Joseph node; umbilical metastases

——————1Department of Pediatrics, University of Tennessee Health Sciences

Center, Memphis, Tennessee; 2Department of Radiology, University of

Tennessee Health Sciences Center, Memphis, Tennessee; 3Department

of Radiological Sciences, St. Jude Children’s Research Hospital,

Memphis, Tennessee; 4Department of Hematology-Oncology, St. Jude

Children’s Research Hospital, Memphis, Tennessee

Grant sponsor: National Institutes of Health; Grant numbers:

CA-21765, CA-71907; Grant sponsor: American Lebanese Syrian

Associated Charities (ALSAC).

*Correspondence to: Carlos Rodriguez-Galindo, Department of

Hematology-Oncology, St. Jude Children’s Research Hospital, 332

N. Lauderdale, Memphis 38105, TN.

E-mail: Carlos.Rodriguez-Galindo@stjude.org

Received 6 March 2006; Accepted 2 May 2006

� 2006 Wiley-Liss, Inc.DOI 10.1002/pbc.20915

388 Brief Reports