Characteristics of aggressive fibromatosis in children.pdf

Annals of Diagnostic Paediatric PathologyOfficial Journal of the Polish Paediatric Pathology Society

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Annals of Diagnostic Paediatric PathologyOfficial Journal of the Polish Paediatric Pathology Society

and Section of Oncological Surgery of Polish Association of Paediatric Surgeons

VVoolluummee 1111 NNuummbbeerr 11––22 SSuummmmeerr 22000077

CCOONNTTEENNTTSS

Ataxia telangiectasia: clinical manifestation and diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . 5Barbara Pietrucha, Edyta Heropolitañska-Pliszka, Bo¿ena Cukrowska, Ewa Bernatowska

Characteristics of aggressive fibromatosis in children – review of the literatureand epidemiological study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9Krzysztof Bronowicki, Jan Godziñski

Pheochromocytoma in children and adolescents based on Polish Pheochromocytoma Registry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15Mariola Peczkowska, Andrzej Januszewicz, Barbara Jarz¹b, Hartmut Neumann, Agata Kubaszek, Hanna Janaszek-Sitkowska, Mieczys³aw Litwin, Jolanta Antoniewicz, Ewa Aksamit-Bia³oszewska, El¿bieta Ros³onowska, Aleksander Prejbisz, Magdalena Januszewicz, Ilona Micha³owska, Jaros³aw Æwik³a, Mariusz Furmanek, Jerzy Walecki

Langerhan’s cell histiocytosis with tuberculosis: a rare combination diagnosed on FNAC . 21Sanjay Kumar, Charu Batra, Sant Prakash Kataria, Brijbala Arora, Gajender Singh, Kamal NayanRattan, Simmi Ratan

Unusual case of small bowel obstruction: Impacted jelly candy in Meckel’s diverticulum . 25Andrzej Zaj¹c, Wojciech Górecki, Adam Bysiek

First Polish report on laparoscopic nephrectomy in Wilms’ tumor . . . . . . . . . . . . . . . . . . . 27Piotr Czauderna, Marcin £osin, Teresa Stachowicz-Stencel, Ewa Bieñ

Asymptomatic gastric duplication mimicking suprarenal gland tumor in a 7 years old boy 29Adam Bysiek, Andrzej Zaj¹c, £ukasz Wyrobek, Pawe³ Bysiek, Joanna Pa³ka

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Introduction

Ataxia telangiectasia (AT; MIM # 208900) is a rare autoso-mal recessive disorder caused by mutation in the ATM genefor Ataxia-Telangiectasia Mutated. Hallmarks of the diseasecomprise progressive cerebellar ataxia, oculocutaneous te-langiectasiae, variable humoral and cellular deficiency, chro-mosomal instability, increased risk of cancer and radiationsensitivity (12). Epidemiologists estimate the frequency ofAT as 1 in 40 000 to 100 000 live births. However, it is be-lieved that many children with AT, particularly those whodie at young age, have been never properly diagnosed. The-refore, this disease may actually be much more common. Theresponsible gene ATM, maps to chromosome 11q22-23 (15),and contains 66 exons (8). The ATM product is a large (370-kd) serine/threonine kinase, with a phosphaditiloinositol 3-kinase (Pi3K) domain, which localizes mainly to nuclei(lymphocytes, fibroblasts, germ cells) and is involved in thecellular responses to DNA double strain breaks, damage-in-duced cell-cycle checkpoints (15). In cytoplasm ATM regu-lates redox state concerning especially neurons (9). Over 400

mutations have been identified to date which occur througho-ut the entire gene (10). No curative strategy for this diseaseexist nowadays, however extensive work is being carried outin laboratories worldwide.

Clinical manifestation

AT is one of a group of autosomal recessive cerebellar ata-xias. The most debilitating feature of this disorder is the pro-gressive neurodegeneration due to loss of Purkinje cells inthe cerebellum and malfunction of other neuronal cells. Thepresence of early onset cerebellar ataxia with oculocutaneoustelangiectasiae permits diagnosis of AT. Ataxia of both up-per and lower limbs develops usually by the age of 2 years.This clinical diagnosis becomes most apparent after age 10years, when other symptoms such as dysarthric speech, ocu-lomotor apraxia and choreoathetosis are fully expressed (2).By teenage most patients require a wheelchair for mobility.However, AT diagnosis may become problematic before theappearance of telangiectasiae or when the characteristic neu-rological impairment is mild or delayed. Most patients begin

Annals of Diagnostic Paediatric Pathology 2007, 11(1–2):5–8© Copyright by Polish Paediatric Pathology Society Annals of

DiagnosticPaediatricPathology

Address for correspondence

Barbara Pietrucha, MD, PhD tel. +48 22 815 72 13Department of Immunology e-mail: [email protected] Children’s Memorial Health Institute, Warsaw, PolandAleja Dzieci Polskich 2004-734 Warsaw

Ataxia telangiectasia: clinical manifestation and diagnosis

Barbara Pietrucha1, Edyta Heropolitañska-Pliszka1, Bo¿ena Cukrowska2, Ewa Bernatowska1

1 Department of Immunology2 Department of PathologyThe Children’s Memorial Health InstituteWarsaw, Poland

Abstract

Ataxia-telangiectasia (AT) is an autosomal recessive disease that coexist with progressive cerebellar ataxia,immunodeficiency, sinopulmonary infections, skin disorders, including oculocutaneus telangiectasiae,cancer susceptibility, radiosensitivity and early aging. AT is caused by mutations of the ATM gene.Laboratory findings include elevated alphaprotein, cerebellar atrophy on MRI, translocations involvingchromosomes 7 and 14, absence or dysfunction of the ATM protein, radiosensitivity in CSA. Patients withAT present with an undetectable intracellular ATM protein level or absence of catalytic activity. Accordingto last reports increased radiosensitivity together with ATM protein absence confirm the diagnosis of AT.ATM gene is very large and searching for mutations is time-consuming and expensive.

Key words: ataxia telangiectasia, ATM protein, CSA, radiosensitivity

to have difficulty walking at the end of the first year of lifeand are wheelchair-bound by the teenage years (13). Howe-ver, some patients are not recognized to have AT until the se-cond decade of life. In young infants the diagnosis may beelusive and easily confused with mild cereblar palsy, acuteinfectious, or episodic ataxia, ataxia with oculomotor apra-xia or other rare genetic or mitochondrial diseases (1).

One of the main hallmarks of AT – telangiectasiae ap-pear most noticeably on the bulbar conjunctiva several yearsafter onset of neurological symptoms (Fig. 1). They are no-ted, usually in the eyes, in almost all patients by age 10 years.Frequent sinopulmonary infections are observed in approxi-mately one-third of AT patients (6). They often precede neu-rological complications and immunodeficiency is the main,but not the only, etiology for lung disease in AT. Malignan-cy occurs frequently in patients with AT. They are said to ha-ve 100 fold higher risk of cancer than the general population.One in the three AT patients will develop a malignancy at so-me time during their lives (5). The 85% of cancers are lym-phoid, either leukaemia or lymphoma, which are characteri-stic for younger patients. Whereas older patients tend to de-velop also malignant solid tumors such as stomach, breast,liver or ovarian cancer (5). An occasional AT patient mayfirst develop cancer, before a diagnosis of AT is suspected.Patients with AT and their cultured cells are unusually sen-sitive to x-ray (17). Consequently, the therapy of malignan-cies is complicated by the fact of conventional doses of ra-diation therapy as well as chemotherapy with radiomimeticagents.

AT children if evaluated properly are not retarded inmental skills. The prognosis for individuals with AT is po-or, however some patients live to forties or even fifties. Tre-atment has focused on slowing the progress of the neurode-generation; devising approaches for treatment of tumourswhile minimizing side effects and treatment with immuno-globulin for the immunodeficiency. Additionally, since it se-ems likely that oxidative stress may contribute to the neuro-degeneration in AT, potential therapies based on the use ofantioxidants offer some hope.

Diagnosis

The clinical diagnosis of AT used to be based on progressivecerebellar ataxia of early onset and then development of ocu-locutaneous telangiectasia. Serum level of alpha fetal protein(AFP) is a useful tool to diagnose AT especially in youngchildren. Elevated serum levels of AFP are found in 95% ofpatients (7). However false-positive findings are seen in chil-dren under age 2 years, whose levels remain slightly elevatedfrom neonatal period. There are also some rare condition ofhereditary persistence of elevated AFP and association withsome malignancies (8). So each time the serum AFP level iselevated, AT should be taken into consideration.

Dysgammaglobulinemia, decreased cellular immuneresponse and peripheral lymphopenia are on one hand thesupportive findings but on the other a variable feature of ATpatients. Most patients demonstrate immunoglobulin defi-ciencies involving IgA (in 60%–70%), IgE (in 80%) and IgGespecially IgG2 (in 80%) and IgG4 subclasses. One possibleexplanation for this variation is that different ATM mutationsmay have differing effects on immune gene rearrangementsor cell survival (9). Due to humoral immunodeficiency andsino-pulmonary infections, 20% to 25% of patients with A-T require regular immunoglobulin replacement therapy. Se-rum IgM levels are highly variable, may change during dise-ase progression. Hyper-IgM is seen in approximately1%–2% of patients with AT worldwide and appears to be dueto a polyclonal rather than a monoclonal gammopathy (14).In patients with AT hyper-IgM may represent an efficient orthwarted immunologic response to an infectious agent. Re-sponses to polysaccharides antigen are reduced in almost allpatients. The number of circulating T lymphocytes is usual-ly reduced, gamma/delta T-cell levels are usually elevated,probably reflecting a maturation defect in this pathway. Bcells are normal or slightly elevated with poor in vitro re-sponse to mitogens.

Magnetic resonance imaging (MRI) of the cerebellumshows atrophy usually by age 10. Karyotyping reveals cha-racteristic chromosomal aberrations, such as t (7; 14), trans-locations and telomeric fusion and increased rate of telome-ric shortening (17).

Much progress has been made in the early diagnosissince the ATM gene was cloned in 1995 (8). As mentionedabove, AT cells are hypersensitive to ionizing radiation. Thecolony survival assay (CSA) is the only measure of radiosen-sitivity that has been validated for clinical use. It measuresthe survival fraction of Epstein-Barr virus-transformed lym-phoblastoid cell lines (LCLs) established from patient sam-ples, following exposure to 1 Gray gamma radiation. Survi-val fractions for classical AT usually score below 21%, si-gnifying radiosensitivity; a normal response to irradiation(IR) is > 36%. The CSA identifies radiosensitivity in appro-ximately 90% of patients with A-T (16) (Fig. 2)

European Society for Immunodeficiency Disorders(ESID) created diagnostic criteria for clinicians for better re-cognizing of AT. They are divided into three categories: de-finitive possible, and probable (Table 1). Possible and pro-

6

Fig. 1. Ocular telangiectasiae in AT patient

bable categories comprise clinical features as cerebellar ata-xia and ocular or facial telangiectasia together with labora-tory tests like: serum IgA at least 2 SD below normal for age,AFP at least 2 SD above normal for age and increased radia-tion induced chromosomal breakage in cultured cells.

AT cells are typically deficient of ATM protein dueto null mutations in both copies of the ATM gene. This cha-racteristic has recently been validated as a diagnostic crite-rion for identifying AT (12). Western blot of nuclear lysatesfrom AT cells is a semi-quantitative measurement of ATMprotein, with > 98% sensitivity and specificity. The immu-noblotting is not practical for testing samples from young in-fants unless LCLs are first established. When they are stu-died, lack of ATM protein is noted in >95% of patients withAT (3). The lack of detectable ATM protein levels by immu-noblotting analysis and the abnormal CSA results offerstrong support for a clinical diagnosis of AT. Very smallamounts of ATM protein are seen in some patients. Equally,there is 1% of AT patients with normal amounts of ATMprotein, which is functionally impaired. Here, we can analy-ze of the many substrates of ATM kinase activity to deter-mine whether the expected serine or threonine residues havebeen phosphorylated. Assays of PI-3 kinase activity can beused (3). More than 400 mutations in the ATM gene have be-en described in AT patients (10). The reported AT mutationsare evenly distributed throughout the gene, affecting everycoding exon (4). The majority of AT patients carry uniquemutations. Most patients present a classic form of AT resul-ting from the presence of two truncating mutations, leading

to total loss of the ATM protein (11). These facts, taken to-gether with the large size of the ATM gene, make the scre-ening for mutations expensive and labor intensive with theuse of currently available methods. On the other hand futu-re treatment strategies vary, depending on type of mutation.They are focused on restoring ATM protein function with theuse of compounds such as aminoglycosides which have thepotential to read through premature termination codons (7).Further research is done on curing splicing mutations.

Acknowledgement

The study was supported by the project of Children’s Memo-rial Health Institute S100/2006.

7

References

1. Cabana MD, Crawford TO, Winkelste-in JA, et al (1998) Consequences of thedelayed diagnosis of ataxia-telangiecta-sia. Pediatrics 102: 98–100

2. Chun HH, Gatti RA (2004) Ataxia-Te-langiectasia, an evolving phenotype.DNA Repair 3: 1187–1196

3. Chun HH, Sun X, Nahas SA, et al(2003) Improved diagnostic testing forataxia-telangiectasia by immunoblot-ting of nuclear lisates for ATM proteinexpression and PI-3 kinase activity.Mol Genet Metab 80: 437–439

4. Concannon P, Gatti RA (1997) Diversi-ty of ATM gene mutations detected inpatients with ataxia-telangiectasia.Hum Mutat 10: 100–107

5. Gatti RA (1998) The genetic basis ofhuman cancers in ataxia-telangiectasia.In: Vogelstein B, Kinzler KW (Eds)New York, McGraw-Hill, pp 275–300

6. Gatti RA (2001) Ataxia-Telangiectasia.In: Scriver CR, Beaudet AL, Sly WS,Valle D (Eds) The metabolic and mole-cular basis of inherited disease, NewYork, Mc Graw-Hill, pp 705–725

Fig. 2. Colony Survival Assay (CSA)

DefinitiveMale or female patient with either increased radiationinduced chromosomal breakage in cultured cells, orprogressive cerebellar ataxia, who has disabling mutationson both alleles of ATM.

ProbableMale or female patient with progressive cerebellar ataxiaand three out of the following four findings:! ocular or facial telangiectasia! serum IgA at least 2 SD below normal for age! alpha fetoprotein at least 2 SD above normal for age! increased radiation induced chromosomal breakage in

cultured cells

PossibleMale or female patient with progressive cerebellar ataxiaand at least one of the following four findings:! ocular or facial telangiectasia! serum IgA at least 2 SD below normal for age! alpha fetoprotein more than 2 SD above normal for age! increased chromosomal breakage after exposure to

irradiation

Table 1

ESID criteria of AT syndrome

7. Lai CH, Chun HH, Nahas SA, Gatti RAet al (2004) Correction of ATM genefunction by aminoglycoside-induced re-ad-through of premature terminationcodons. PNAS 101: 15676–15681

8. Lange E, Borresen AL, Chen X, Ches-sa L, Chiplunkar S, Concannon P, et al(1995) Localization of an ataxia-telan-giectasia gene to approximately 500-kbinterval on chromosome 11q23: linkageanalysis of 176 families by an interna-tional consortium. Am J Hum Genet 57:112–119

9. Lavin MF, Concannon P, Gatti RA(1999) Eight International Workshopon Ataxia-Telangiectasia (ATW8).Cancer Res 59: 3845–3849.

10. Mitui M, Campbell C, Couintinho G,Gatti RA et al (2003) Independent mu-tational events are rare in the ATM ge-ne: haplotype pre-screening enhancesmutation detection rate. Hum Mutat 22:43–50

11. Mitui M, Bernatowska E, Pietrucha B,Gatti RA et al. (2005) ATM gene foun-der haplotypes and associated muta-tions in polish families with Ataxia-Te-langiectasia. Ann of Hum Genet 69:657–664

12. Perlman S, Becker-Catania S, Gatti RA(2003) Ataxia-Telangiectasia: Diagno-sis and Treatment. Semin in PediatrNeur 10: 173–182

13. Regueiro JR, Porras O, Lavin M, GattiRA (2000) Ataxia-Telangiectasia.A primary immunodeficiency revisited.Immunol Allergy Clinics North Ameri-ca 20: 177–206

14. Sanal O, Ersoy F, Tezcan I, Gogus S(1991) Ataxia-telangiectasia presentingas hyper IgM syndrome. In: ChapelHM, Levinsky RJ, Webster ADB, (Eds)Progress in immune deficiency III.Royal Society of Medicine 173:303–304

15. Savitsky K, Sfez S, Tagle DA, Ziv Y,Sartiel A, Collins FS, et al (1995) Thecomplete sequence of the coding regionof the ATM gene reveals similarity tocell cycle regulators in different spe-cies. Hum Mol Genet 4: 2025–2032

16. Sun X, Becker-Catania S, Chun HH,Gatti RA et al (2002) Early diagnosis ofataxia-teleangiectasia using radiosensi-tivity testing. Jour of Pediatrics 140:724-731

17. Uhrhammer N, Bay JO, Bignon YJ(1998) Seventh International Workshopon Ataxia-Telangiectasia. Cancer Res58: 3490–3495

8

Introduction

Fibrous tumours of infancy and childhood vary from benignto malignant. Aggressive fibromatosis is classified into theborderline group of these tumours.

Aggressive fibromatosis is fibroproliferative processwith tendency to infiltrate the surrounding tissue. The infil-tration may be locally uncontrollable and destructive, espe-cially regarding vessels, nerves and other vital structures.These tumours do not metastasize but tend to recur after in-complete excision [38, 77]. The recurrence rate ranges for 27to 75% [11, 20, 26-30, 50, 70, 71].

The term aggressive fibromatosis is often employedto emphasize its locally aggressive behaviour [38, 77]. In theliterature, the names deep fibromatosis and desmoid tumo-urs are also attributed to that pathology [38, 52, 77].

This kind of tumour was first described by MacFar-lane in 1832 [47] and the term desmoid (derived from theGreek desmos meaning band or tendon-like) was used byMüller in 1838 [52].

According to the WHO classification, aggressive fi-bromatosis is located in the group of deep fibromatoses. Lo-gically, the deep fibromatoses do not originate from the sub-cutaneous tissue or the skin, although these structures maybe involved secondarily. These tumours develop within the

deep soft tissues and are divided, on the basis of anatomic lo-cation, into arising in the abdominal wall (abdominal fibro-matosis or abdominal desmoid), in the abdominal cavity andpelvis (pelvic fibromatosis, mesenteric fibromatosis, and re-troperitoneal fibromatosis) and outside the abdomen and ab-dominal cavity (extra-abdominal fibromatosis or extra-abdo-minal desmoid) [38, 77].

Aetiology

The aetiology of aggressive fibromatosis still remains enig-matic. An antecedent history of trauma and inflammatory re-action are factors responsible for development of tumours re-ported in several studies. There are cases of aggressive fibro-matosis developed within postsurgial scars [16, 34, 49, 62,77].

Currently it is generally accepted, that aggressive fi-bromatosis is clonal process and is not the result of an in-flammatory response. This is also the argument to classifyaggressive fibromatosis as neoplasm [2, 46].

Deregulation of intracellular beta-catenin level seemsto be very important in pathogenesis of this disease. Beta-ca-tenin is protein which acts in altering nuclear transcriptionand is also an important mediator in a signaling system, ter-med Wnt in humans. Mutations in the APC (adenomatous




Krzysztof Bronowicki, MD, PhD phone: +48 71 7890231Department of Paediatric Surgery fax: +48 71 7890156Marciniak-Hospital e-mail: [email protected] 11650-420 Wroc³aw, Poland

Characteristics of aggressive fibromatosis in children – review of the literature and epidemiological study

Krzysztof Bronowicki, Jan Godziñski

Department of Paediatric SurgeryMarciniak−HospitalWrocław, Poland

Abstract

Aggressive fibromatosis in children is rare, locally destructive proliferative process with a strong tendencyfor recurrence. Clinical, pathological and therapeutic heterogenity of this disease implies difficulties inunderstanding the behaviour of aggressive fibromatosis especially in paediatric patients. This reviewpresents clinical and pathological features of aggressive fibromatosis in children and current trends in thetreatment of this disease.

Key words: aggressive fibromatosis, deep fibromatosis, desmoid tumours

polyposis coli) gene (5q21-q22) and beta-catenin gene(3p22-p21.3) are responsible for elevated level of beta-cate-nin, which increases tumour cell proliferation. There isa strong correlation between development of desmoid tumo-urs and FAP (familial adenomatous polyposis) and Gardner’ssyndrome. That may implicate a common genetic defect [3,8, 33, 51, 76].

Epidemiology

Aggressive fibromatosis is rare disease with incidence of 2–4per million inhabitants per year. The five-year survival rateis over 90%. The mortality is very low and it is related tocompression and obstruction of vital structures and organs[14, 38, 40, 58, 59, 77]. In rare cases tumour can spontane-ously diminish and disappear [15, 37, 77].

It is still common opinion that characteristic of ag-gressive fibromatosis in adults does not differ from that inchildren. Review of published paediatric series and authors’experience suggest that characteristics and behaviour of ag-gressive fibromatosis in childhood markedly differs fromthat in adults. Some authors suggest that the age under 18 isresponsible for higher risk of local recurrence; however, theage factor is not of further value under the age of eighteen[5, 10, 11, 20].

In contrast to adults, aggressive fibromatosis in chil-dren is more frequent in boys than in girls (62,2% vs. 37,8%respectively) and locates predominantly in limbs (50%), thenin head and neck (29,3) and trunk (20,7%) [10, 11, 20, 26-30, 38, 77]. In adults prevails female gender and localizationin abdominal wall (49%; post pregnancy desmoid). Theextra- (43%) and intra-abdominal localizations (8%) are lessfrequent [16, 38, 58, 71, 75, 77]. Sometimes tumours are dia-gnosed in foetus or directly after birth. In 5 to 8% of cases,the disease can occur as multicentric form [4, 13, 20, 23, 49].

Most of the literature data do not confirm in childrenany relationship between gender of patients and tendency todevelop local recurrences [5, 10, 11, 20, 35, 50]. Regardingthe tumour site, the recurrence rate seems highest for extre-mities (73%) and lowest in trunk (23,5%) [5, 6, 11, 32, 59,61]. In majority of studies, the size of the tumour has not pre-dictive value for local recurrence [5, 6, 7, 11, 20, 50].

Pathologic findings

In microscopic examination, the lesions are poorlycircumscribed and infiltrate surrounding tissue, usually ske-letal muscle [38, 64, 77]. Tumours consist of elongated, uni-form, spindle-shaped fibroblasts and myofibroblasts looselysurrounded and separated from one another by abundant col-lagen, with little or no cell-to-cell contact. Apart from colla-gen bundles, the cells can be seen in myxoid matrix. The cel-lularity of those tumours varies considerably from low to mo-derate. The cells lack the pleomorphic, atypical orhyperchromatic nuclei typical for malignancy. Mitotic figu-res are difficult to find and very rarely surpass 5 mitotic fi-gures per 10 high-power fields (HPF). When the mitotic ac-

tivity is greater than 10 per 10 high-power fields the possi-bility of sarcoma should be considered. Arteries within thelesions are characteristically thick-walled, some of them ap-pear slit-like. Microhemorrhages and focal collections oflymphocytes, especially at the periphery of the lesions areobserved in some cases. In rare instances, calcification, me-taplastic bone or cartilage can be found within the tumours[38, 64, 77]. Immunohistochemically, the spindle cells stainwith vimentin, desmin, Ki-67 antibodies and beta-catenin.Negative reaction is usually observed with monoclonal anti-bodies CD-34, c-kit, EMA (epithelial membrane antigen)and protein S-100 [8, 12, 38, 51, 64, 77].

The differential diagnosis of aggressive fibromatosistakes into account benign fibrous and malignant prolifera-tions. On one hand, the lesion can resemble fibrosarcoma,myxofibrosarcoma, liposarcoma or GIST (gastrointestinalstromal tumour) and on the other hand the superficial palmarand plantar fibromatosis, reactive fibrosis, desmoplastic fi-broma, nodular fascitis, normal cellular fibrous tissue or scar[38, 51, 77].

In pathological examination, diagnostic criteria pre-dicting behaviour of aggressive fibromatosis were not preci-sely defined. There are opinions that only microscopic evi-dence of tumour at resection margins is the factor which isresponsible for higher tendency to locally recur [10, 35, 50].Some authors add to predictive factors the presence of areasof necrosis and inflammation within the tumour and mitoticindex of 5 or more per 10 high-power fields [5]. It was noti-ced that tumours presenting with a large number of small, sli-t-like blood vessels and with plump, stellate-shaped cells ormyxomatous foci showed a higher recurrence rate than le-sions without these features [64, 65, 78].

Imaging of aggressive fibromatosis

Number of imaging techiniques help in determining the po-ssibility of surgical resection of desmoid tumours and in de-ciding whether adjuvant therapy is necessary [1, 17, 21, 24,39, 55, 60, 67, 73, 77].

X-ray pictures usually show a soft tissue, poorly de-fined mass which may cause local erosion, periosteal reac-tion, deformation, or bowing of bone [17, 39, 60, 77]. Sono-graphic examination is nonspecific. Some tumours may beheterogeneous and of variable echogenicity. The solid le-sions are often homogeneous and hypoechogenic [17, 73].Computed tomography (CT) scans of aggressive fibormato-sis show usually lesions which may be hypoattenuating rela-tive to skeletal muscle but are typically isoattenuating oreven hyperattenuating. After injection of iodinated contrastmaterial most lesions demonstrate various enhancements [24,39]. On MR imaging aggressive fibromatosis have high si-gnal intensity on T2-weighted images. Areas of high signalintensity on T2-weighted images correspond to variable gra-des of cellularity, collagenization, or myxoid change [1, 21,39, 60, 67].

In single cases is proposed the use of scintigraphy andpositron emission tomography (PET) [25, 63].

10

Strategies of treatment

Surgical treatment still remains the basic type of therapy inaggressive fibromatosis [5, 6, 10, 11, 18, 19, 20, 26-30, 35,43, 50, 71, 72, 74]. According to the Enneking classificationmicroscopic margin status system is an important prognosticfactor. Four types of surgical margins basing on the relation-ship of the surgical margin to the tumour and its reactive zo-ne are defined: intralesional (within lesion), marginal (withinreactive zone), wide (intracompartimental en block with cuffof normal tissue) and radical (extracompartimental en blocwith entire compartment). Wide or radical excision with cle-ar microscopic margin seems most effective treatment of ag-gressive fibromatosis [5, 6, 10, 11, 18-20, 26-30, 35, 43, 50,71, 72]

In case of incomplete surgery, when the potentialmorbidity of a second operation is high, the use of adjuvantradiotherapy dosed from 50 to 60 Gy should be considered[6, 7, 11, 20, 31, 66, 69, 74].

In paediatric patients with gross residual disease andwith recurrent tumours, some authors advocate chemothera-py with Methotrexat (MTX) and Vinblastin (VBL) or VAC(vincristin, actinomycin D, cyclophosphamide) [9, 11, 29,30, 36, 41, 54, 56, 57, 67, 68, 74].

Some authors mention the use of antiestrogens like to-remifene and testolactone or nonsteroidal anti-inflammatorydrugs (indomethacine, suldinac) [9, 23, 36, 41, 42, 69, 74].

In Poland the scheme of treatment of aggressive fibro-matosis in children was prepared on the basis of experiencegained in centres gathered in Polish Paediatric Solid Tumo-urs Study Group, on the basis of data from literature and sug-

gestions from other therapeutic protocols (mainly CWS- Co-operative Weichteilsarkom Studie) [11, 26-30, 74].

When the resection of tumour is marginal and the lo-cation is difficult for further surgery, or possible relapse co-uld alter functions of the vitally important structures, the pre-sent treatment suggestions propose the use of radiotherapy inpatients over the age of 5, and chemotherapy (MTX-VBL for6 months) under the age of 5. Preoperative chemotherapywith MTX-VBL is advocated when the tumour is impossibleto remove without mutilation. If the tumour fails to respondto MTX-VBL after 4-month of treatment, the schedule ofchemotherapy can be change into VAC. This scheme may al-so be the first treatment in case of the need of rapid decom-pression of the vitally important structures [11, 26-30].

When the tumour does not respond to that therapy, anexperimental treatment (Interferon alpha, isolated limb per-fusion with tumour necrosis factor and Melfalan, retinoicacid, hyperthermia, Glivec) or mutilating surgery are to beconsidered. In selected patients from this group, adequatemay be the “wait – and – see” policy [11, 22, 26, 32, 36, 44,45, 48, 53, 70, 74].

Summary

Aggressive fibromatosis in children have different characte-ristic and behaviour than in adults. Tumours locate predomi-nantly in limbs and are more frequent in boys. Clearence ofsurgical margins and localisation are significant clinical pro-gnostic factors. These specific features suggest introducinga common and clear defined protocol of treatment of paedia-tric aggressive fibromatosis.

11

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Mariola Peczkowska, MD, PhD phone: 022 34 34 338Department of Hypertension fax: 022 34 34 517Institute of Cardiology e-mail: [email protected] 04-628 WarsawAlpejska 42

Pheochromocytoma in children and adolescents based on Polish Pheochromocytoma Registry

Mariola Peczkowska1, Andrzej Januszewicz1, Barbara Jarz¹b3, Hartmut Neumann4, Agata Kubaszek1, Hanna Janaszek-Sitkowska1, Mieczys³aw Litwin5, Jolanta Antoniewicz5, Ewa Aksamit-Bialoszewska6, El¿bieta Ros³onowska7, Aleksander Prejbisz1, Magdalena Januszewicz8, Ilona Micha³owska2, Jaros³aw Æwik³a9, Mariusz Furmanek9, Jerzy Walecki9

1 Department of Hypertension2 Department of RadiologyInstitute of Cardiology Warsaw, Poland

3 Nuclear Medicine and Endocrine Oncology DepartmentMaria Sklodowska−Curie Memorial Institute Gliwice, Poland

4 Medizinische UniversitatsklinikAbteilung IV Freiburg, Germany

5 Department of Nephrology, Kidney Transplantation andArterial HypertensionThe Children's Memorial Health Institute Warsaw, Poland

6 Endocrinology and Diabetology WardGeneral District Hospital Olsztyn, Poland

7 Department of EndocrinologyCentre for Postgraduate Medical Education Warsaw, Poland

8 II Department of Clinical RadiologyMedical Academy in Warsaw Poland

9 Department of RadiologyCentral Clinical Hospital of the Ministry of Internal Affairs and Administration Warsaw, Poland

Abstract

Pheochromocytomas and paragangliomas occur as sporadic tumors or in a familial context. It has been shownthat approximately 25% of patients with pheochromocytoma and paraganglioma carry germline mutations inone of 4 susceptibility genes. Peripheral blood from unrelated, registry patients with pheochromocytoma wastested for mutations of RET, VHL, SDHD, and SDHB. Clinical data at first presentation and follow-up wereevaluated. Among 136 patients (93 female and 43 male, 68,4% and 31,6% respectively; mean age, 45±14years) who presented with pheochromocytoma, 34 (24,8%) were found to have mutations. Younger age,multifocal tumors, and extra-adrenal tumors were significantly associated with the presence of a mutation.There were 16 patients with pheochromocytoma under 20 years of age (9 female and 7 male, mean age15,9±4,6 years, age range 5-20 years). Among them, we identified 15 patients with germ-line mutations (94percent); 1 had M918T mutation of RET proto-oncogene resulting in MEN 2B syndrome, 6 had mutations ofVHL gene, 5 mutations of SDHD gene, and 3 mutations of SDHB gene. Only two patients had positive familyhistory at presentation. One fourth of patients with pheochromocytoma are carriers of mutations. Incidenceof hereditary syndromes in patients under 20 years is 94%. Paraganglioma – pheochromocytoma syndromeresulting from SDHD or SDHB gene mutations (PGL1 and PGL4 syndrome, respectively) seems to be mostcommon hereditary syndrome in Polish population of patients with pheochromocytoma under 20 years of age.Second major hereditary syndrome in this group was von Hippel-Lindau disease.

Key words: Hereditary syndromes, paraganglioma, pheochromocytoma

Introduction

Pheochromocytomas are rare tumors of the adrenal glandthat arise from chromaffin cells in the adrenal medulla.Paragangliomas arise from extra – adrenal chromaffincells and can originate in either the sympathetic nervoussystem or parasympathetic ganglia. Paragangliomas that ari-se from sympathetic nervous system occur most frequentlyin the retroperitoneum and are traditio-nally termed extra – adrenal pheochro-mocytoma. Paragangliomas have beenbroadly categorized into two groups:those in the head and neck region withcarotid body as the major site and tho-se located elsewhere, with adrenal me-dulla as the major site. Tumors in thehead and neck are anatomically associa-ted with parasympathetic nervous sys-tem and are located close to the majorarteries and nerves, whereas the adrenalmedulla and other paraganglia belowneck and head are closer associatedwith the sympathetic nervous system.Parasympathetic tumors are usuallypresent as an asymptomatic slow gro-wing mass, lacking endocrine activity,whereas sympathetic tumors are hormo-nally active and secret excess amount ofcatecholamines. Pheochromocytomasand paragangliomas occur as sporadictumors or may be associated with here-ditary syndromes [2]. Several geneticsyndromes are known to be associatedwith increased risk for pheochromocy-toma, including von Hippel – Lindau(VHL) syndrome, multiple endocrineneoplasia typ 2 (MEN 2) and neurofi-bromatosis type 1 (NF1), occurring asa result of germline mutations in VHL,RET, or NF1 genes, respectively. Morerecently, nuclear genes encoding mito-chondrial complex II subunit proteinshave been associated with the develop-ment of pheochromocytomas and para-gangliomas and newly discovered para-ganglioma/pheochromocytoma syndro-me (PPS) was added to the list ofhereditary syndrome in pheochromocy-toma and paraganglioma. Neumann etal. showed that close to 24% of patientswith pheochromocytomas and paragan-gliomas carry a germline mutation [8].This was confirmed by Amar et al. whoeven found 27% carrying germline mu-tations [1]. Therefore, the historicallyestablished rule of tens’, stating that ap-proximately 10% of pheochromocyto-

mas are hereditary, 10% are malignant, 10% are bilateral,10% are extra-adrenal, 10% are not associated with hyper-tension and 10% occur in children, is no longer valid con-cerning genetics. Molecular medicine makes it possible todifferentiate sporadic from hereditary disease, which willaffect medical management not only for the patient but al-so for the family. Familial syndromes of pheochromocyto-ma are presented in Table 1.

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Table 1

Familial pheochromocytomas

Syndrome and prevalence Gene Gene locusof pheochromocytomas

Multiple endocrine neoplasia Type 2A Ret-protooncogene 10q11.2(30–60%)

Medullary thyroid carcinoma

Pheochromocytoma

Hyperparathyroidism

Multiple endocrine neoplasia Type 2B Ret-protooncogene 10q11.2(MEN2B) (30-60%)

Medullary thyroid carcinoma

Pheochromocytoma

Marfanoid habitus

Skeletal deformation

Mucosal neuromas

Ganglioneuromatosis of the intestinal tract

Von Hippel-Lindau disesase (VHL) VHL-tumor 3p25-26(15–20%) type 2 suppressor gene

A: Retinal and CNS

haemangioblastomas

Pheochromocytomas

Endolymphatic sac tumors

Epididymal cystadenomas

B: As in VHL type 2A +renal cell cysts and carcinomas

As in VHL type 2A + pancreatic neoplasmas and cysts

C: Pheochromocytomas only

Neurofibromatosis type 1 (NF1) NF-1-gene 1 7q11.2(3–5%)

Multiple fibromas on skin

Cafe au lait spots

Lisch nodules of the iris

Pheochromocytoma-paraganglioma SDHB-gene 1p35-36syndrome (PGL, 70-80%) SDHD-gene 11q21-23

Head and neck tumors

Extra – adrenal and adrenal pheochromocytomas

In the present study, we analyzed the known suscep-tibility genes for pheochromocytoma – VHL, RET, SDHD,and SDHB – in a large, unselected series of patients collec-ted in Polish Registry of Pheochromocytoma who presentedwith this tumor in order to classify them as having eithersporadic or hereditary disease. In addition, we analyzed he-reditary syndrome prevalence and clinical characteristic inyoung pheochromocytoma patients under 20 years of age.

Material and methods

The population based registry for pheochromocytoma wasconducted in Poland. Patients were recruited from thirty fi-ve centres and clinical, radiological and demographical datawas collected. One hundred thirty-six consecutive, unrelatedpatients with histologically confirmed pheochromocytomafrom whom blood-leukocyte DNA was available were enrol-led. All patients provided written or oral informed consent.For classification we used term paraganglioma for tumors oflocation in the head and neck area whereas those of adrenal,extraadrenal abdominal and thoracic location were namedpheochromocytomas.

All eight exons of SDHB, all four exons of SDHD, allthree exons of VHL, and exons 10, 11, and 13 through 16 ofRET were examined by analysis of single-strand conforma-tion polymorphisms and direct sequencing, as previously de-scribed [5].

Missense mutations were diagnosed if the DNA va-riants were absent in 100 healthy controls. All molecular exa-minations were performed in Department of Nephrology andHypertension, Albert Ludwigs University, Freiburg, Germany.

Results

A total of 136 patients (93 female and 43 male, 68,4% and31,6% respectively; mean age, 45±14 years) with pheochro-mocytoma were enrolled in the study. We identified 34 pa-tients with deleterious germ-line mutations (24,8%). Only3 patients had family history at the presentation. Among the34 patients with mutations, 32% had mutations of RET, 18%had germ-line mutations of VHL, 12% had clinical signs ofNF1 syndrome, and 18 and 21% presented mutations of twonewly identified genes, SDHD and SDHB.

The age at the onset of symptoms was statistically lo-wer in all carriers of mutations than in patients with spora-dic disease. Multiple, extra – adrenal, and bilateral adrenalpheochromocytomas as well as recurrences of the diseasewere statistically more frequent among patients with muta-tions than among patients without mutations. Incidence ofmalignant pheochromocytoma did not differ between studygroups (Table 2).

The most frequent symptom of the disease was hyper-tension (86%), then palpitations (67%), sweating (56%), he-adache (40%), blanching of the skin (40%), severe cardiova-scular complications (myocardial infarction, stroke, severearrhythmia, etc.) (7,4%). Asymptomatic clinical course wasobserved in 8,8% of patients (Table 3).

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Table 2

Comparison between hereditary pheochromocytoma andsporadic pheochromocytoma groups

Hereditary Sporadic p

Age (years) 34,3±13,2 48,7±13,4 p<0,0001Multiple 17 of 34 4 of 102 p<0,0001

[50%] [3,9%]Extra-adrenal 8 of 43 6 of 102 p<0,0001

[23,6%] [5.9%]Bilateral adrenal 10 of 34 2 of 102 p<0,0001

[29,4%] [2%]Recurrence 10 of 34 0 of 102 p<0,0001

[29,4%]Malignant 4 of 34 4 of 102 NS

[11,8%] [3,9%]

Table 3

Major symptoms in pheochromocytoma

Symptoms Frequency

Hypertension 86%Palpitations 67%Sweating 56%Headache 40%Blanching of the skin 40%Severe cardio-vascular complications 7,4%Asymptomatic 8,8%

Then we analyzed the subgroup of 16 patients withpheochromocytoma under 20 years of age (9 female and7 male, mean age 15,9±4,6 years, age range 5–20 years).Among them, we identified 15 patients with germ-line mu-tations (94 percent); 1 had M918T mutation of RET pro-to-oncogene resulting in MEN 2B syndrome, 6 had mu-tations of VHL gene, 5 mutations of SDHD gene, and3 mutations of SDHB gene. Only two patients had positivefamily history at presentation. Paraganglioma – pheochromo-cytoma syndrome resulting from SDHD or SDHB gene mu-tations (PGL1 and PGL4 syndrome, respectively) seems tobe most common hereditary syndrome in Polish population.Second major hereditary syndrome in this group was vonHippel-Lindau disease. Type of mutations is presented inTable 5.

In group with hereditary syndromes, multiple phe-ochromocytomas were observed in 12 patients (80%), extra– adrenal in 7 patients (47%) and bilateral adrenal tumors oc-curred in 6 patients (40%). Thoracic pheochromocytomaswere found in 2 patients with SDHD gene mutations. Multi-ple or extra – adrenal or bilateral adrenal pheochromcytomaswere found in 13 patients (87%). Recurrence of the diseaseoccurred in 5 patients (33%). We did not observe malignantpheochromocytoma in this group. Several additional tumor

types were diagnosed in participating patients. A medullarythyroid carcinoma was present in one patient with MEN 2Bsyndrome. Renal cell carcinoma (RCC) occurred in two pa-tients – in SDHB mutation carrier and in patient with vonHippel – Lindau disease. Pancreatic islet tumors and ha-emangioblastoma of IV brain ventricle were found in patientwith VHL. In the cohort presented here, there were also tworeports of multiple head and neck paraganglioma in SDHDgene mutation carriers [Table 4].

inted out, that extra – adrenal and/or multiple pheochromo-cytomas as well as young age at presentation may be stri-king features of hereditary disease [9]. Interestingly, 91% ofprobands found to have hereditary disease with the use ofmolecular testing had no associated signs and symptoms atpresentation. Only three (9%) of them had positive familyhistory at presentation. A partial explanation for the highfrequency of hereditary pheochromocytoma without familyhistory of disease might include spontaneous mutation inone of the susceptibility genes, decreased penetrance, andmaternal imprinting [9]. In our registry, spontaneous muta-tions in one of four susceptibility genes occurred in two pa-tients with hereditary von Hippel–Lindau disease, one withMEN 2B syndrome, one with SDHD gene mutation and onewith SDHB mutation (Table 5).

Today, more than 200 different VHL mutations havebeen identified which appear to be equally distributed thro-ughout the gene. De novo mutations at hypermutable sequ-ences result in most of the recurrent mutations. In large Ger-man registry of von Hippel–Lindau disease, frequency ofspontaneous mutation in VHL is thirteen percent of all cases[9, 10]. In MEN 2B syndrome, which is the most distinct andaggressive of the MEN 2 variants, de novo mutations are ve-ry often and reach fifty percent [12]. A little is known aboutspontaneous mutations in SDHD and SDHB genes becausethey are newly identified genes.

Penetrance is known to be relatively high (approxima-tely 70 percent by the age of 70) among patients with MEN-2 and von Hippel–Lindau disease, overall [9, 10]. Benn et al.reported a statistically significant age-related penetrance dif-ference for SDHB and SDHD mutation carriers. By age 30yr, 29% of SDHB mutation carriers and 48% of SDHD mu-tation carriers were diagnosed with paraganglioma; by age40 yr, 45% of SDHB mutation carriers and 73% of SDHDmutation carriers were diagnosed with paraganglioma [3,13]. As discussed by authors, SDHD and SDHB mutationshave an age-related penetrance, and the lifetime risk of de-veloping paraganglioma (s)/pheochromocytoma (s) appro-aches 100% by age 70 yr [3, 13].

In patients with SDHD mutations, penetrance de-pends on whether the individual inherited the mutation fromthe mother or the father [11, 13]. The disease is not manife-sted when the mutation is inherited from the mother, but ishighly penetrant when inherited from the father. This pheno-menon is known as maternal imprinting.

Overall, therefore, pheochromocytomas in patientswithout family histories are due to spontaneous mutations,decreased penetrance, or maternal imprinting, although othercauses such as gene–gene interactions and gene–enviro-nment interactions may be possible. Genetic testing can bea powerful aid to the identification of a syndrome in such ca-ses. Since disease is likely to develop in virtually all patientswith a family specific mutation, it seems reasonable to sub-ject such patients to lifelong surveillance.

This report highlights the value of genetic testing foraffected patients and at-risk asymptomatic family members.Genetic testing should be considered in all patients with pa-

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Table 4

Clinical characteristic of patients with hereditary syndromesof pheochromocytoma

Characteristics of pheochromocytoma patients withhereditary syndromes under 20 years of age

Multiple tumors – 12 patients (80%)

Extra – adrenal tumors – 7 patients (47%)

Bilateral adrenal tumors – 6 patients (40%)

Thoracic localization of tumors – 2 patients (13%) – only inSDHD gene mutations

Recurrence of the disease – 5 patients (33%)

Malignant – 0

Associated tumors: ! Renal cell carcinoma – 2 patients: VHL and SDHB! Pancreatic islet tumors – 1 patient – VHL! haemangioblastoma of IV brain ventricle! Multiple head and neck paraganglioma – 2 patients –

SDHD! Medullary thyroid carcinoma – 1 patient – MEN 2B

Multiple or extraadrenal or bilateral adrenal pheochromocy-toma – 13 patients (87%)

Discussion

Our clinical and molecular evaluation of 136 unrela-ted patients who presented with pheochromocytoma reve-aled that 34 patients (24,8%) had a hereditary predispositionto von Hippel–Lindau disease, MEN-2, neurofibromatosistype 1, or the syndromes associated with pheochromocyto-ma and paraganglioma. Among the 34 patients with muta-tions, 32% had mutations of RET, 18% had germ-line mu-tations of VHL, 12 percent had clinical signs of NF1 syn-drome, and 18 and 21% had mutations of two newlyidentified genes, SDHD and SDHB. Patients with heredita-ry syndromes were younger that those with sporadic diseaseand multiple and extraadrenal tumors were more frequentin this group. Our results are consistent with other popula-tion-based studies [2, 4, 7, 8, 9]. In our registry almost onehalf of patients with hereditary pheochromocytoma was un-der 20 years of age. We can state that 87% of all multifocal(including bilateral tumors) and extra – adrenal tumors inpatients with onset of the disease at the age of 20 years oryounger were found to be hereditary. All these findings po-

raganglioma and/or pheochromocytoma [6, 9, 13]. Familialpheochromocytoma/paraganglioma is inherited in an autoso-mal dominant manner; thus, an affected person has a 50%chance of passing the mutation on to each child.

The surveillance strategy for a germline mutation-po-sitive asymptomatic patient should include: annual historyand physical examination by a clinician experienced withpheochromocytoma and paraganglioma; annual biochemical

testing, e. g. 24-h urine for metanephrines and catecholami-nes and computed tomography or magnetic resonance ima-ging every 2 yr taking into consideration the tumour loca-tions typically associated with the mutated gene [6, 13]. Gi-ven the observation that children of female SDHD mutationcarriers do not manifest the disease when the mutation hasbeen inherited, rigorous clinical surveillance is probably notwarranted for these offspring.

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Table 5

Germ-line mutations in the four genes detected in the series of patients with pheochromocytoma under 20 years of age

Independent cases Gene Exon cDNA nucleotide Amino-acid change Mutation type Family history

1. SDHB 3 402 C>T R90X Stopcodon hereditary2. 6 721 G>A C196Y Missense unknown3. 6 847-50delTCTC F238frameshift Frameshift spontaneous 4. SDHD 1 33 C>A C11X Stopcodon spontaneous5. 1 33 C>A C11X Stopcodon hereditary6. 1 33 C>A C11X Stopcodon unknown7. 1 33 C>A C11X Stopcodon hereditary8. 1 33 C>A C11X Stopcodon hereditary9. VHL 3 712 C>T A167Y Missense spontaneous10. 3 764 T>A L184H Missense unknown11. 1 451A>G S80G Missense hereditary12. 1 451A>G S80G Missense hereditary13. 1 451A>G S80G Missense hereditary14. 1 404G>C R64P Missense spontaneous15. RET 16 918 ATG>ACG M918T Missense spontaneous

References

1. Amar L, Bertherat J, Baudin E, et al(2005) Genetic testing in pheochromo-cytoma or functional paraganglioma. JClin Oncol 23: 8812–8818

2. Baysal BE, Ferrell RE, Willett-BrozickJE, et al (2000) Mutations in SDHD,a mitochondrial complex II gene, in he-reditary paraganglioma. Science 287:848–851

3. al (2006) Clinical presentation and pe-netrance of pheochromocytoma/para-ganglioma syndromes. J Clin Endocri-nol Metab 91 (3): 827–836

4. Elder EE, Elder G, Larsson C (2005)Pheochromocytoma and functional pa-raganglioma syndrome: No longer the10% tumor. J Surg Oncol 89: 193–201

5. Gimm O, Armanios M, Dziema H,Neumann HPH, Eng C (2000) Somaticand occult germ-line mutations inSDHD, a mitochondrial complex II ge-ne, in nonfamilial pheochromocytoma.Cancer Res 60: 6822–6825

6. Grupa robocza PTNT (2006) ZaleceniaPolskiego Towarzystwa NadcisnieniaTetniczego dotyczace diagnostyki i le-czenia pheochromocytoma. Nadcisnie-nie Tetnicze 76–78 (in Polish)

7. Januszewicz W, Wocial B, Sznajder-man M, Januszewicz A (2000) Guzchromochlonny. Wydawnictwo Lekar-skie PZWL, Warszawa (in Polish)

8. Jarzab B (2004) Dziedziczne uwarun-kowania guzow chromochlonnych. In:Nadcisnienie tetnicze. Red. Janusze-wicz A, Januszewicz W, Szczepanska--Sadowska E, Sznajderman M. Medy-cyna Praktyczna, Krakow (in Polish)

9. Neumann HP, Bausch B, McWhinneySR, et al (2002) Germ-line mutations innonsyndromic pheochromocytoma. NEngl J Med 346: 1459–1466

10. Neumann HP, Berger DP, Sigmund G,et al. (1993) Pheochromocytomas, mul-tiple endocrine neoplasia type 2, andvon Hippel-Lindau disease. N Engl JMed 329: 1531–1538

11. Neumann HPH, Pawlu C, PeczkowskaM, et al. (2004) Distinct clinical featu-res of paraganglioma syndromes asso-ciated with SDHB and SDHD gene mu-tations. JAMA 292: 943–951

12. Peczkowska M, Januszewicz A (2005)Multiple endocrine neoplasia type 2.Familial Cancer 4: 25–36

13. Young WF, Abboud AL (2006) Para-ganglioma – All in the family J Clin En-docrinol Metab 91: 790–792

Introduction

Langerhan’s cell histiocytosis (LCH) is a proliferative disor-der of the histiocytes which is characterized by heterogene-ous clinical manifestations with an unpredictable clinical co-urse [6]. The estimated incidence of this disease in childrenis 1-5 cases per million each year [2]. The etiopathogenesisof LCH is still not certain but an infectious etiology either asa promoter or initiator of the disease has been proposed be-cause of expression of HHV-6 and EBV in some cases [4].An immunological and clonal proliferation etiology has alsobeen suggested in literatures [6]. The lesion is characterizedby proliferation of Langerhan’s cell (LC), a special type ofhistiocytes of dendritic origin [8]. The term “HistiocytosisX” proposed by Lichenstein in 1953, is composed of threedisease complexes, i. e. Letterer Siwe syndrome, HandSchuller Christian disease and eosinophilic granuloma [3].The clinical spectrum of LCH is wide ranging from poten-tially lethal leukemia like disorder to solitary lytic lesion ofthe bone [7]. The disease can affect any organ system at oneor multiple sites or can be multisystemic. LCH can manifest

as unifocal or present as a multifocal unisystem or multifo-cal multisystem (disseminated) disease. Even though the cli-nical and radiological features can be suggestive of LCH, thedefinitive diagnosis is morphologic which can be confirmedwith electron microscopy or immunochemistry [8].

Case report

Eighteen months old child presented with difficulty in bre-athing and with loss of weight since two months. On exami-nation multiple matted lymph nodes of varying size werepresent on both sides of the neck. Patient had a past historyof an irregular short course of antitubercular drugs, whichwas stopped fifteen days prior to admission. Hematologicalinvestigations did not reveal any significant change exceptanemia. X-ray chest revealed a non homogenous opacity inthe left hilar region. Ultrasonography abdomen showed mildhepatosplenomegaly without any enlarged para aortic or me-senteric group of lymph nodes. Fine needle aspiration cyto-logy (FNAC) from the cervical lymph node revealed cellu-lar smears comprising of a predominant population of singly




Katarzyna Iwanicka Phone: +48 22 815 70 15Department of Pathology E-mail: [email protected] Children’s Memorial Health InstituteAl. Dzieci Polskich 2004-736 Warsaw, Poland

Langerhan’s cell histiocytosis with tuberculosis: a rare combination diagnosed on FNAC

Sanjay Kumar1, Charu Batra1, Sant Prakash Kataria1, Brijbala Arora1, Gajender Singh, Kamal NayanRattan2, Simmi Ratan2

1 Departments of Pathology and Pediatric SurgeryMedical Enclave,PGIMS, India

2 Departments of Pathology and Pediatric SurgeryPostgraduate Institute of Medical Sciences, India

Abstract

Langerhan’s cell histiocytosis is a disease spectrum characterized by proliferation of histiocytes in variousbody tissues with variable, often unpredictable clinical behavior. The problem in diagnosis of such lesionsis complicated by the presence of other associated diseases. We describe a case of 18 months old childpresenting with cervical lymphadenopathy which using fine needle aspiration cytology was diagnosed asLangerhan’s cell histiocytosis with associated tuberculosis.

Key words: Cytology, Langerhan’s cell histiocytosis, tuberculosis

scattered large atypical cells. These cells had moderate toabundant pale blue cytoplasm and round to oval nucleus sho-wing nuclear grooving with “coffee bean” appearance. A fewbi and multinucleated cells were also seen in the smears. Lar-ge numbers of eosinophils, moderate population of neutro-phils along with lymphoid cells in varying stages of matura-tion were noted in the background (Fig. 1). An additional fin-ding was the presence of few epithelioid cell granulomas(Fig. 2) and occasional Langerhan’s type of giant cells. ZiehlNeelsen staining revealed numerous acid fast bacilli. A cy-tological diagnosis of Langerhan’s cell histiocytosis with as-sociated tuberculosis was offered. Histopathological exami-nation of the lymph node confirmed the diagnosis (Fig. 3).The diagnosis of Langerhan’s cell histiocytosis with tuber-culosis was further confirmed on immunohistochemistrywhich was performed at a tertiary care institute. Patient wastreated with a combination of antitubercular drugs along withchemotherapy.

Discussion

Langerhan’s cell histiocytosis is a clinical syndrome whishwas previously designated as histiocytosis X, eosinophilicgranuloma, Letterer Siwe disease, Hand Schuller Christiansyndrome, Hashimoto Pritzker syndrome, Self-healing histio-cytosis, pure cutaneous histiocytosis, Langerhan’s cell granu-lomatosis, type II histiocytosis and a generic term non lipidreticuloendotheliosis [4]. It is characterized by proliferation ofabnormal and clonal Langerhan’s cells in one or more bodyorgans such as skin, bone, lymph node, lung, liver, spleen andbone marrow. The disease can persist at any age, though it ismore common in infancy and early childhood. LCH remainsa rare, diverse enigmatic collection of clinical syndromes. Pa-tients can experience spontaneous remissions and exacerba-tions. Subjects with a localized disease have a good progno-sis [6]. Poor prognosis can be associated with certain featu-res like young age at presentation, hepatosplenomegaly, andthrombocytopenia and polyostotic bone disease [5].

Primary LCH is documented to occur in any of thebody systems with a dominant involvement of osseous andpulmonary system. However involvement of skin, pituitary,hypothalamus and lymph node were relatively unusual forprimary LCH. In such a case, the true primary disease sitemay be in bone or lung which may have regressed spontane-ously [4].

LCH has also been associated with certain other dise-ased conditions. The most frequently associated neoplasmswere adenocarcinoma and small cell carcinoma of lung.Other diseases associated were acute and chronic myeloidleukemia, non-Hodgkin’s lymphoma, carcinoma prostate,carcinoma breast and adenomas of parathyroid and pancre-as. Immune deregulation has been proposed as a predispo-sing factor for these associated secondary conditions [4]. Ra-rely, LCH has been reported to be associated with chronic in-fectious disease like tuberculosis [1, 9]. Reviewing theliterature, we identified only two published cases of LCHwith tuberculosis. However, in both the reported cases, LCH

22

Fig. 1. Cytology smear showing Langerhan’s cells, multinucleate cells, feweosinophils and lymphocytes (Giemsa Stain; 400X)

Fig. 3. Histopathological section showing sheets of Langerhan’s cell witheosinophils in the lymph node (Hematoxylin & Eosin stain; 400X)

Fig. 2. Cytology smear showing epitheloid cell granuloma (Giemsa Stain;400X)

was associated with pulmonary tuberculosis in young adults.The reason of this association of LCH with tuberculosis isobscure, but in both these cases a history of smoking has be-en observed.

In 1987, the Writing Group of Histiocyte Society sug-gested that a definite diagnosis of LCH can be confirmed on-ly when the histo/cytomorphology of the lesion was suppor-ted by findings of Birbeck granules on electron microscopyor by demonstration of CD1a or S-100 protein antigen [8].Immunohistochemical reactivity for these antigens or ultra-structural demonstration of Birbeck granules help in clin-ching a final diagnosis, but should not be considered as exc-lusive diagnostic criteria for LCH, because they have also be-en reported in other disease processes. Careful attention tomorphological features along with clinical and radiologicaldata is more importance in establishing the diagnosis of LCH[5]. In appropriate clinical setting, a typical cytomorphologi-cal picture can be used alone as a definite proof of LCH priorto treatment [8].

The characteristic cytomorphologic feature consistsof a mixture of abundant, predominantly dissociated Langer-han’s cells accompanied by numerous eosinophils, variablenumber of neutrophils, lymphocytes, macrophages andbi/multinucleated cells [8]. Presence of necrosis, ill formed

granulomas and variation in the population of other cell ty-pes make the picture less recognizable. The differential dia-gnosis include non-neoplastic conditions like parasitic infec-tions with granuloma formation, tuberculosis and Kimura’sdisease and neoplasms associated with eosinophilia likeHodgkin disease, peripheral T-cell lymphoma and metasta-tic carcinoma. The problem in diagnosis is compounded withthe presence of associated disease especially tuberculosiswhich is quite rare. In our case too, presence of epithelioidcell granulomas associated with LC’s, eosinophils, neutro-phils and lymphocytes caused a diagnostic dilemma. Howe-ver, presence of acid fast bacilli and associated atypical LC’shelped in reaching a provisional diagnosis of LCH with tu-berculosis which was subsequently confirmed on histopatho-logy and immunohistochemistry. To the best of our knowled-ge, there is no case report of LCH associated with tubercu-losis diagnosed on cytology in the literature.

LCH can be recognized in a cytological smear whenaccompanied by the appropriate clinical setting but the pro-blem is complicated with the presence of associated disor-ders. Thus, it should always be kept in mind that Langerhan’scell histiocytosis and tuberculosis may exist as a concomitantdisorder in the same patient in countries where incidence oftuberculosis is quite high.

23

References

1. Arai T, Inoue Y, Yamamoto S, et al(2005) Incipient stage of pulmonaryLangerhans-cell histiocytosis complica-ted with pulmonary tuberculosis wasexamined by high resolution computedtomography. Respir Med 99: 1188–1190

2. Cochrane LA, Prince M, Clarke K(2003) Langerhan’s cell histiocytosis inthe paediatric population: presentationand treatment of head and neck manife-stations. J Otolaryngol 32 (1): 33–37

3. Goldsmith AJ, Myssiorek D, Valderra-ma E, Patel M (1993) Unifocal Langer-han’s Cell Histiocytosis (EosinophilicGranuloma) of the Petrous Apex. ArchOtolaryngol Head Neck Surg119:113–116

4. Howarth DM, Gilchrist GS, Mullan BP,Wiseman GA, Edmonson JH, Schom-berg PJ (1999) Langerhans cell histio-cytosis: Diagnosis, natural history, ma-nagement and outcome. Cancer 85:2278–2290

5. Klipatrick SE, Wenger DE, GilchristGS, Shives TC, Wollan PC, Unni KK(1995) Langerhan’s Cell Histiocytosis(Histiocytosis X) of Bone. A clinicopa-thological analysis of 263 pediatric andadult cases. Cancer 76 (12): 2471–2484

6. Kumary PK, Priyakumari P, ChellamVG, James FV, Nair KM (1999) Lan-gerhans cell histiocytosis in childrenless than 2 years of age. Indian Pediatr36 (1): 29–36

7. Plasschaert F, Craig C, Bell R, ColeWG, Wunder JS, Alman BA (2002)Eiosinophilic granulomas. A differentbehaviour in children than in adults. JBone Joint Surg Br 84 (6): 870–872.

8. Pohar-Marinsek Z, Us-Krasovek M(1996) Cytomorphology of Langerhanscell histiocytosis. Acta Cytol 40 (6):1257–1264

9. Okutan O, Kartaloglu Z, Ilvan A, DenizO, Silit E, Gorur R (2006) Active pul-monary tuberculosis in a patient withLangerhans’ cell histiocytosis. SaudiMed J 27 (3): 447–448

Introduction

Food ileus is usually seen in adult, often psychiatric patients.Initially, it develops as recurrent bowel obstruction (phyto-bezoar, bile stones, coproliths), progressing with time to fullobstruction, or severe food ileus after abundant consumptionof substances that are difficult to digest (mushrooms, nuts)[1-3, 5-7].

In some patients Mecel’s diverticulum may be a star-ting point to capture residual parts of food.

Case Report

We present a 5-year old girl with no prior medical and sur-gical history, who ingested a large amount of jelly candies(“gummy bears” presented on Fig. 1) over a period of twodays. She was brought to the emergency room withsymptoms of abdominal pain, vomiting and obstipation. Onphysical examination she was showing signs of ileus and de-hydratation. Her abdomen was distended and tender to pal-pation with small bowel movements on ascultation. Labola-

tory tests presented little change in electrolyte concentration.The white blood cell count was significantly elevated:39 000/mm3. Abdominal X-ray revealed a distended loop ofthe small bowel with multiple fluid levels, what was consi-stent with complete small bowel obstruction.

At exploratory laparotomy the point of obstructionappeared to be multiple impacted jelly candies obstructing




Adam Bysiek MD. phone: +48 12 658 02 32Department of Pediatric Surgery fax: +48 12 658 13 25Jagiellonian University, Collegium Medicum e-mail: [email protected] Children’s Hospital30-663 Krakow, ul. Wielicka 265

Unusual case of small bowel obstruction: Impacted jelly candy in Meckel’s diverticulum

Andrzej Zaj¹c, Wojciech Górecki, Adam Bysiek

Department of Pediatric SurgeryDepartment of RadiologyJagiellonian University, Collegium MedicumPolish−American Children's HospitalKrakow, Poland

Abstract

The incidence of food ileus in children is extremely low. We present a case of a complete small bowel ob-struction concomitant with Meckel’s diverticulum; the obstruction developed after abundant consumptionof jelly candies (“gummy bears”). The ileus had to be resolved through laparotomy. Such a case of smallbowel obstruction has not been reported in pediatric literature.

Key words: child food ileus, jelly candy overconsumption, obturative obstruction

Fig. 1. A view of jelly candies (“gummi bears”)

the small bowel at the level of the detected Meckel’s diver-ticulum. We observed the ileum completely filled with soft,jelly mass over a segment 40 cm in length. The Meckel’s di-verticulum was partially filled. Through the intestinal wallwe could palpate numerous harder objects in the jelly mass,which were not completely digested “gummi bears”. Foreignbody-like structures obstructing the small bowel were passedinto the cecum. A portion of the obstructing material wasmilked into a wide-based Meckel’s divericlum, which wasresected at its base using an intestinal stapler. The residualmass was pushed to the cecum. The child’s recovery wasuneventful and she was discharged on the fifth postoperati-ve day, tolerating normal food. A pathology report confirmedthat the obstructing particles represented jelly candies.

Discussion

Obturative obstruction occurs when a foreign body or partsof food passing through the bowel block the intestinal lumen.The blockage usually develops at the narrowest point in thesmall intestine (distal ileum) or at the coexisting Meckel’s di-

verticulum. Gallstone ileus, bezoars, food-ileus are typicallyobserved in patients over the age of 65 year [4, 8]. Many ofthem are mentally disturbed [3].

Food ileus in childhood is seen extremaly rarely. Thisis our first experience in an institution handling a large volu-me of patients annually. After X-ray examination of the abdo-men, we suspected a simple mechanical obstruction seconda-ry to adhesions or Meckel’s diverticulum. Not completely di-gested “gummi bears” found intra operatively at the distal partof the ileum suggest, that the child must have swallowed who-le jelly candies. We interviewed her parents after surgery. Thegirl had received 3 packets of jelly candies (450 grams) andprobably had eaten them all at one time. Based on this reportwe suggest that bowel obstruction due to impaction of jelly-li-ke candies poses a real risk in pediatric population.

Conclusion

We caution both the parents and food industry that overcon-sumption of jelly candies can produce a foreign body-likeimpaction resulting in complete bowel obstruction.

26

References

1. Gerber P (1989) Mushroom ileus wi-thout previous intestinal obstruction.Schweiz Med Wochenschr 119:1479–81

2. Hammann HJ (1977) Coprolith-ileus ofthe small intestine. Fortschr Med 95:64–66

3. Hitosugi M, Kitamura O, Takatsu A, etal. (1998) Autopsy case of duodenal ob-struction from impacted mushroom. JGastroenterol 33: 562–565

4. Kurtz RJ, Heimann TM, Kurtz AB(1983) Gallstone ileus: a diagnosticproblem. Am J Surg 146: 314–317

5. Kux M, Fuchsjager N, Baraka A (1986)Food-induced ileus associated with in-traperitoneal adhesions. Dtsch MedWochenschr 111: 1277–1280

6. Mosca F, Alongi G, Sciuto G, et al(1989) Food ileus caused by a phytobe-zoar of the small intestine. MinervaChir 44: 1395–1400

7. Robinson FW (1966) Intestinal obstruc-tion due to food (peanut ileus): case re-port. Am Surg 32: 405–406

8. Shocker E, Simon SA (1982) Small bo-wel obstruction due to enterolith (bez-oar) formed in a duodenal diverticulum:a case report and review of the literatu-re. Am J Gastroenterol 77: 621–624

Introduction

Wilms’ tumor is the most common malignant renal tumor inchildren and since it accounts for 6% of all pediatric cancers,it is one of the most common solid tumors in children. Withmedian age at initial presentation of 3,5 years, it is typicallyfound in early childhood, it may also occur in older children,however almost 98% cases are detected before the 7-th yearof life [1].

Treatment is multimodal combining chemotherapy,radiotherapy and surgery. Open nephrectomy used to be con-sidered the golden standard in Wilms’ tumors, however re-cent developments in minimally invasive surgery (MIS) ma-ke us questioning its possible application in the treatment ofthis malignancy. Minimally invasive surgery is widely used,especially in pediatric nephrectomies for benign renal condi-tions [9], but use of this method in renal malignancies in chil-dren is still very controversial. There are only few reports onapplications of this procedure in Wilms’ tumor. Authors pre-sent case report of successful laparoscopic nephrectomy in22-month-old child [2, 3].

Case report

Twenty two-months-old girl was admitted to hospitalbecause of incidentally found right retroperitoneal mass. Dia-

gnosis was confirmed by Computer Tomography (CT)which showed a 95 x 57 x 60 mm tumor spreading from ri-ght kidney. No lymph nodes involvement and distant meta-stasis were found. Child started preoperative chemotherapyaccording to SIOP 2001 protocol and received four coursesof vincristine and dactinomycin. After four weeks of chemo-therapy shrinkage of tumor to 3 cm of diameter was obse-rved. Patient was qualified to surgery and decision on per-formance of laparoscopic nephrectomy was undertaken. Thechild was placed in a 30-degree supine position with right--sided elevated. First 10 mm open trockar was inserted byopen technique. Abdominal pneumoperitoneum was thencreated with CO2 to pressure of 12 mmHg and two additio-nal ports were put, one in supraumbilical region under xy-phoid appendix for 10mm trockar and one for 5mm trockaron the right side of umbilicus (Fig. 1). Mobilization of theleft colon and the caecum allowed exposing the right kidneyand its hilum. Tumor mass was identified in the lower poleof kidney. Renal vein and artery were identified, ligated with2.0 absorbable suture, additionally clipped and transsected.The kidney was dissected “en-block” from the surroundingtissues and after sectioning of the ureter with Ligasure devi-ce, the specimen was removed via small incision in the rightlower abdomen. Normal sized pericaval lymph nodes werebiopsied and sent for histological evaluation. Blood loss du-ring surgery was approximately 40 ml and no blood transfu-




Marcin £osin phone: (58) 302 3031 w. 190, 501 735 345 Department of Surgery and Urology for Children and Adolescents E-mail: [email protected] Medical University of Gdañsk Nowe Ogrody 1-6, 80-803 Gdañsk

First Polish report on laparoscopic nephrectomy in Wilms’ tumor

Piotr Czauderna1, Marcin £osin1, Teresa Stachowicz-Stencel2, Ewa Bieñ2

1 Department of Surgery and Urology for Children and Adolescents2 Department of Hematology, Endocrinology and Pediatric OncologyMedical University of Gdańsk

Abstract

Wilms’ tumor is the most common malignant renal tumor in pediatric population and it’s one of the mostcommon solid tumors in children. Treatment is multimodal combining chemotherapy, radiotherapy andsurgery. Open nephrectomy is golden standard for surgical approach to this malignancy. While minimallyinvasive is widely used in benign renal conditions there are only few reports on applications of thisprocedure in Wilms’ tumor. Authors present first Polish report on laparoscopic nephrectomy in this tumor.

Key words: laparoscopic, nephrectomy, Wilms’ tumor

sion was required during the surgery and in postoperative pe-riod. Operation time was 120 minutes. Postoperative coursewas uneventful and child was dismissed from hospital after3 days. Histological evaluation of specimen confirmed dia-gnosis of the stage I nephroblastoma of intermediate histolo-gy confined to the kidney. No lymph nodes involment wasobserved in microscopic examination.

Discussion

Multimodal treatment of Wilms’ tumor with overall survivalrate around 90% is a classical example of effective moderntreatment. Such results are mostly achieved due to up-to-datechemotherapy combined with surgery. In most cases opennephrectomy is the treatment of choice [5]. However this ra-dical approach is usually associated with severe postoperati-

ve pain, big scares and prolonged hospital stay. For this re-ason a search for an alternative method of surgical treatmentseems to be justified.

The initial adult laparoscopic nephrectomy was per-formed in 1990 by Clayman et al. [7], first pediatric appro-ach to laparoscopic nephrectomy was done in 1992 by Koy-le et al [4]. Laparoscopic nephroureterectomy was describedby Figenshau in 1992 [6]. Results of initial minimally inva-sive surgery (MIS) approach to Wilms’ tumor was publishedin 2004 by Duarte and Denes [3] and followed by the sameauthors in 2006 [2].

In some pediatric malignancies, especially in neuro-blastoma, minimally invasive surgery (MIS) is being takeninto consideration as an alternative to open surgery and re-sults gained with MIS are comparable to standard open tech-nique [8]. Laparoscopic nephrectomy is widely acceptablemethod in children’s benign renal diseases. Visualisation ofrenal hilum, vessels and ureter is excellent. In Wilms’ tumorcases dissection of kidney with a confined, small tumor sho-uldn’t bring too many technical problems to a properly tra-ined surgeon, cause operative technique is similar to thoseused in benign renal diseases. In our case, blond loss was mi-nimal and operative time was acceptable, too, however wehave to admit that surgery lasted longer than the standardopen technique.

It has to be mentioned that nowadays there is a trendtowards nephron sparing surgery in small size, peripherallylocated Wilms’ tumors instead of classical open nephrecto-my. However even this attitude does not preclude the use ofminimally invasive approach. Using MIS in carefully selec-ted Wilms’ tumor cases seems to be justified, however col-lection of the further clinical experience is necessary.

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Fig.1. Localizations of the ports

References

1. Breslow N, Olhan A, Beckwith JB,Green DM (1993) Epidemiology ofWilms’ tumor. Med Ped Oncol 21:172–81

2. Duarte RJ, Denes FT, Cristofani LM, etal (2006) Further experience with lapa-roscopic nephrectomy for Wilms’ tu-mor after chemotherapy. BJU Int 98(1): 155–159

3. Duarte RJ, Denes FT, Cristofani LM, etal (2004) Laparoscopic nephrectomyfor Wilms’ tumor after chemotherapy:initial experience, J Urol; 155, pp1180–1185

4. Ehrlich RM, Gershmann A, Mee S, et al(1992) Laparoscopic nephrectomy ina child: expanding horizons for laparo-scopy in pediatric urology. J Endourol,6: 463

5. Fingeshau RS, Clayman RV, Kerbl K,et al (1994) Laparoscopic nephrourete-ronephrectomy in the child: initial casereport. J Urol 151: 740–741

6. Kalapurakal JA, Dome JS, Perlman EJ,Maloglowkin M (2004) Management ofWilms’ tumour: current practice and fu-ture goals. Lancet Oncol 5 (1): 37–46

7. Kerbl K, Clayman RV, et al (1993) La-paroscopic nephroureterectomy: evalu-ation of first clinical series. Eur Urol23: 431–436

8. Sailhamer E, Jackson CC, Vogel AM,et al (2003) Minimally invasive surge-ry for pediatric solid neoplasms. AmSurg 69: 566–568

9. Smaldone MC, Sweeney DD, Ost MC,Docimo SG (2007) Laparoscopy in pe-diatric urology: present status. 100 (1):143–150

Introduction

Duplications of the alimentary tract are rare congenital anoma-lies. The term “alimentary tract duplication” was popularizedin 1930s by Ladd who proposed unifying previously used de-scriptive terms such as enterogenous cysts, giant diverticula,unusual Meckel’s diverticulum, ileal and jejunal duplex. It canoccur in any part of the digestive tract, anywhere from mouthto anus [6, 9, 10, 11, 14]. Most, but not all lesions are attachedto gastrointestinal tract. Gastric duplications represent 4–8%of all alimentary tract duplications [10, 11]. They usually be-come symptomatic before second year of age. The most com-mon symptom at presentation is nonbilious vomiting. Also ga-strointestinal hemorrhage is frequently seen. Other accompa-nying symptoms include acute abdominal pain, anorexia,failure to thrive and mass in the epigastric area. Most of themare localised on the greater curvature, but are also known thecases of antral localization causing gastric outlet obstruction.We present rare case of asymptomatic gastric duplication in7 years old boy, mimicking suprarenal gland tumor.

Case report

A 7 years old boy referred to Pediatric Department of ourhospital with suspicion of left suprarenal gland tumor. Cy-stic mass was diagnosed on routinely ultrasound done be-cause of enuresis. CT scans showed cystic structure aboveleft kidney (left suprarenal gland incidentaloma). Endocri-ne diagnostics revealed only mild elevated aldosteron serumlevel.

Laparotomy was performed and we found normal leftsuprarenal gland in the typical localization. Spleen and co-lon did not show any abnormalites also. Then we opened ga-strocolic ligament and revealed gastric duplication (multicy-stic structure attached to the posterior wall of the stomachat the fundus (Fig. 1). Cystic duplication after opening sho-wed small retentional cysts inside (Fig. 2). Because of com-mon but intact muscular layer of the stomach and duplica-tion, the cyst has been opened and removed without openingof gastric wall (Fig. 3). The postoperative course was une-ventful.




Adam Bysiek MD. phone: +48 12 658 02 32Department of Pediatric Surgery fax: +48 12 658 13 25Jagiellonian University, Collegium Medicum e-mail: [email protected] Children’s Hospital30-663 Krakow, ul. Wielicka 265

Asymptomatic gastric duplication mimicking suprarenal gland tumor in a 7 years old boy

Adam Bysiek1, Andrzej Zaj¹c1, £ukasz Wyrobek2, Pawe³ Bysiek1, Joanna Pa³ka1

1 Department of Pediatric Surgery2 Department of RadiologyJagiellonian University, Collegium MedicumPolish−American Children's HospitalKrakow, Poland

Abstract

A case of gastric duplication in a 7-years old boy, mimicking left suprarenal gland tumor is presented.Cystic mass has been diagnosed on routinely done abdominal ultrasound. Patient was asymptomatic andendocrine check-up did not reveal any significant hormonal abnormalities. Intraoperatively gastricduplication cyst was found in typical localization on the greater curvature and totally excised. We discusssome surgical aspects of gastric duplications.

Key words: diagnostic imaging, gastric duplication, suprarenal tumor

tubular shaped structure communicating with proximal partof the digestive tract. Lesion’s wall is formed by smooth mu-scle, the inner layer is lined with epithelial cells. Multipletheories try to explain embryologic cause of duplications ofthe intestinal tract. Until now any simple theory could not doit completely, so it is possible, that combination of the diffe-rent factors may be critical. Some authors postulated failedrecanalisation of the solid primitive gut, others proposed di-vertcular theory, at last others have suggested environmen-tal factors.

From all intestinal tract duplications, gastric duplica-tions are relatively rare, but most of them are usually symp-tomatic in the first 2 years of life. Leading symptoms are vo-miting, malnutrition and failure to thrive, even acute life thre-atening hemorrhage has been also reported [1, 7]. Gastricduplications may be isolated structure (observed in majorityof cases) or may communicate with gastric lumen. Occasio-nally they present narrow tract passing through diaphragmand connecting with mediastinal broncho-enteric cyst or sim-ply with lung [8]. From histological point of view duplica-tion is a part of stomach or gut wall, so is representing mo-re or less excretional activity.

Also ectopic pancreatic tissue may be involved, cau-sing early ulceration with bleeding or perforation. When themucosal layer of duplication mostly consists of mucinouscells and duplication is isolated, dominating symptom is epi-gastric mass and may appear later in childhood or even inadulthood [5, 12, 13, 15]. Ultrasound is usually the first stu-dy and completed with CT or MRI is sufficient to establishthe diagnosis. Typically gastric duplication occurs on thegreater curvature of the stomach close to pancreas, left su-prarenal gland and spleen. Because of localization it may beconsidered as pathology of such organs. Duplication cyst fil-led with homogenous fluid can be similar to a cystic lesionof pancreas or suprarenal gland. There are few cases in theliterature of duplication mimicking pancreatic pseudocyst[2, 3].

In the presented patent, who was completely asymp-tomatic, routinely done abdominal ultrasound for assessmentof urinary tract revealed cystic lesion located retroperitone-al above the left kidney. CT scan confirmed multicystic cha-racter of the lesion and the diagnosis of left suprarenal glandincidentaloma was established. We planned to extend radio-logical diagnostic, but patients family was not cooperativeand angio-MRI failed.

Clinical policy regarding hormonal non-active supra-renal gland incidentaloma in adults is well defined, but tac-tic in children is still unequivocal. It is advised surgical tre-atment, because of higher risk of malignancy in children.Either a laparoscopic or an open proceeding may be pefor-med because both have demonstrated to be safe and equallyuseful to identify and completely excise of the gastric dupli-cation [4].

30

Fig. 1. Gastric duplication localized on posterior wall of the stomach, ari-sing close to fundus

Fig. 2. Small retentional cysts visible inside duplication

Fig. 3. Completely removed duplication cyst. Intact gastric wall, only ellip-tical serosa defect where duplication cyst was attached to the stomach

Discussion

Duplications of the alimentary tract are rare congenital ano-malies. They can form a cyst containing chyle and mucus or

References

1. Barlev DM, Weinberg G (2004) Acutegastrointestinal hemorrhage in infancyfrom gastric duplication: imaging fin-dings. Emerg Radiol 10 (4): 204–206

2. D’Journo XB, Moutardier V, Turrini O,Guiramand J, Lelong B, Pesenti C,Monges G, Giovannini M, Delpero JR(2004) Gastric duplication in an adultmimicking mucinous cystadenoma ofthe pancreas. J Clin Pathol. 57 (11):1215–1218

3. Davies S, Morris-Stiff G, Lewis MH(2007) Gastric duplication cyst mimic-king a pancreatic pseudocyst in a pa-tient with chronic pancreatitis Int J Surg18 (in press)

4. Ford WD, Guelfand M, Lopez PJ, Fur-ness ME (2004) Laparoscopic excisionof a gastric duplication cyst detected onantenatal ultrasound scan. J PediatrSurg 39 (10): e8–e10

5. Hlouschek V, Domagk D, Naehrig J,Siewert JR, Domschke W (2005) Ga-stric duplication cyst: a rare endosono-graphic finding in an adult. Scand J Ga-stroenterol 40 (9): 1129–1131

6. Ildstad ST, Tollerud DJ, Weiss RG, Ry-an DP; McGowan MA, Martin LW(1988) Duplication of the alimentarytract. Clinical characteristics, prefferedtreatment and associated malforma-tions. Ann Surg 208: 194–199

7. Master V, Woods RH, Morris LL, Fre-eman J (2004) Gastric duplication cystcausing gastric outlet obstruction Pe-diatr Radiol 34 (7): 574–576

8. Menon P, Rao KL, Saxena AK. (2004)Duplication cyst of the stomach presen-ting as hemoptysis. Eur J Pediatr Surg14 (6): 429–431

9. Pinter AB, Schubert W, Szemledy F,Gobel P, Schafer J, Kustos G (1992)Alimentary tract duplications in infantsand children. Eur J Pediatr Surg 2 (1):8–12

10. Puligandla PS, Nguyen LT, St-Vil D,Flageole H, Bensoussan AL, NguyenVH, Laberge JM (2003) Gastrointesti-nal duplications. J Pediatr Surg 38 (5):740–744

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