Surgery For Endocrinological Diseases and Malformations in Childhood
Surgery For Endocrinological Diseases and Malformations in Childhood
Surgery For Endocrinological Diseases and Malformations in Childhood
Volume 26
Co-founding Editor:
P. P. Rickham
Editors:
T. A. Angerpointner
M. W. L. Gauderer . W. Ch. Hecker
J. Prevot . L. Spitz
U. G. Stauffer . P. Wurnig
Surgery
for Endocrinological Diseases
and Malformations
in Childhood
Volume Editors
M. W. L. Gauderer and T. A. Angerpointner
With 45 Figures
and 33 Tables
Springer-Verlag
Berlin Heidelberg New York
London Paris Tokyo
Hong Kong Barcelona
Budapest
MICHAEL W. L. GAUDERER, MD
Rainbow Babies and Childrens Hospital
2074 Abington Road
Cleveland, OH 44106, USA
MICHAEL W. L. GAUDERER, MD
Cleveland, Ohio, USA
Contents
Pheochromocytoma in Childhood.
E. W. FONKALSRUD. With 1 Figure . . . . . . . 103
You will find the addresses at the beginning of the respective contribution
Angerpointner, T. A. 21 Ladurner, D. 15
Bako, G. 31 Linder, R. 84
Balazs, G. 31,41 Lukacs, G. 41
Boros, P. 41 Mengel, W. 92
Britsch, E. 21 Muller, E. 76
Csaky, G. 31,41 Nieder, M.L. 124
Cutz, E. 60 Otten, A. 84
Deindl, C. 96 Rauh, V. 28
Dobroschke, J. 84 Reimers, C. 28
Dohrmann, P. 92 Riccabona, G. 15
Ehrlich, R. M. 60 Ross, A.J. 48
Filler, R.M. 60 Schneider, K. 1
Fonkalsrud, E. W. 103 Schwabel, M. G. 112
Gauderer, M. W. L. 124 Splieth, J. 92
Hecker, W. Ch. 21 Stauffer, U. G. 112
Hacht, B. 28 Szabo, J. 31
Ilyes, I. 31,41 Weinberg, M.J. 60
Kalman, K. 31 Wesson, D. E. 60
Knorr, D. 21 Willberg, B. 76
Kujath, H. P. 28
Sonographic Imaging of the Thyroid in Children
K. Schneider
Summary
Zusammenfassung
L'echographie it haute resolution, d'une extreme precision, est employee de plus en plus fre-
quemment pour obtenir des images des affections thyroidiennes chez les enfants. En conse-
quence, I'importance de la scintigraphie decline rapidement. L'anatomie et la morphologie echo-
graphique de la glande tyhroide (resultats normaux, variantes) chez les nouveaux-nes et les
enfants sont decrites. On presente des exemples d'affections thyroidiennes et les algorithmes qui
y correspondent en echographie.
Introdnction
Rontgenabteilung der Kinderklinik der Universitat, Dr. von Haunersches Kinderspital, Lind-
wurmstraBe 4, D-8000 Miinchen 2 (W), FRG.
Embryology
Anatomy
The thyroid is composed of two lobes which are connected across the midline by
the isthmus (Fig. 1). On transverse sections the lobes are pear- or wedge-shaped.
The isthmus lies in front of the larynx and upper trachea and is often very thin.
The lobes extend upwards on both sides of the larynx and occasionally down
along the trachea to the jugular fossa. On longitudinal sagittal or lateral sections
they have an oval disk- or barlike shape (see Fig. 5). The common carotid arteries
and internal jugular veins are located at the lateral edges of the two thyroid lobes
(see Fig. 1). The left common carotid artery is occasionally found behind the
lateral margin of the left lobe. The cervical esophagus is either in the midline be-
hind the trachea or partially to the left. The thyroid is bordered posteriorly in the
midline by the cervical spine, the longus colli and scalene muscles, anteriorly by
the sternohyoid and sternothyroid, and laterally by the sternocleidomastoid mus-
LC
Fig. I. Anatomy of the neck. Transverse section through the thyroid at the level of the first tracheal
ring. I, Isthmus; T, trachea; RL, right lobe; LL, left lobe of the thyroid; E, esophagus; LCA, left
carotid artery; LJV, left jugular vein; P, platysma, SM, SH, ST, OM, SC, and LC, sternocleido-
mastoid, sternohyoid, sternothyroid, omohyoid, scalene and longus colli muscles; VC, vertebral
column
Sonographic Imaging of the Thyroid in Children 3
cles. The parathyroids are closely situated at the posterior surfaces of the thyroid
lobes.
Fig.2. Imaging of the thyroid. Transverse section at the height of the isthmus. The dashed line
shows the section level
Fig. 3. Imaging of the thyroid. Sagittal longitudinal section through the right lobe
4 K. Schneider
The size of the gland in relation to body weight is three to four times greater in the
newborn period than in later life [8]. After infancy, the ratio of thyroid volume to
body surface remains constant at about 5.0 [8]. The parenchymal echogenicity of
the newborn's thyroid is a little lower than in later childhood (Fig. 4). In school-
age children or adolescents, the pattern of the thyroid tissue changes to a very
bright parenchymal echogenicity - the typical adult pattern (Fig. 5).
The thyroid volumes are age dependent (Fig. 6). The daily iodine intake is the
single most effective variable related to thyroid growth in children and adults. In
countries with high iodine intake, such as Sweden, the thyroid volumes of school
children and adults are considerably smaller than in the Federal Republic of Ger-
many [6]. In the FRG the thyroid volumes of children with normal thyroid func-
tion are not significantly different from one region to another [6, 8, 9].
Fig. 5. Normal thyroid in a 14-year-old girl. Transverse (left) and longitudinal section (right)
through the left lobe. Crosses, length, depth
,::;-
E
.:=
<l!
E
;;)
-0
Fig. 6. Thyroid volumes (in cm 3) of >
healthy infants and children in
FRG. Normal values for girls and
boys [8]
2 3 7 11 15
Age (years)
Based on morphology, thyroid pathology can be classified into two main groups
by sonography: (a) the size of the thyroid may be abnormal (Table 1); (b) the
parenchymal echogenicity can be altered by pathological conditions (Table 2).
These changes may affect the whole gland (diffuse pattern) or only a part of it
6 K. Schneider
(focal pattern). Changes in shape or size and an abnormal echogenic pattern can
coexist in the individual case.
Fig. 7. Hypoplasia of the thyroid in a 24-year-old patient who suffered from hypothyroidism from
birth. Very small thyroid with normal shape and slightly increased parenchymal echogenicity.
Total volume was 3.1 cm 3 . Transverse (left) and longitudinal section (right) through the left lobe
Sonographic Imaging of the Thyroid in Children 7
Fig. 9. Endemic goitre caused by iodine deficiency in a 14-year-old girl. Diffusely enlarged
thyroid. Transverse (left) and longitudinal section (right). Crosses, width of the right lobe
8 K. Schneider
come so massive that its lower portions extend into the mediastinum (Fig. 9).
These substernal portions extending into the thoracic inlet can be demonstrated in
children by sonography, because the ossification of the sternum is not complete
until about the age of 12 (Fig. 10). With increasing age, often multinodular adeno-
matous parenchymal changes accompany simple homogeneous hypertrophy.
Another cause of thyroid enlargement is inflammation. The most common
form of thyroiditis in childhood is Hashimoto's thyroiditis, which belongs to the
group of autoimmune thyroid diseases [5]. The parenchymal changes during the
acute stage are characterized by diffuse decrease of parenchymal echogenicity
[1,11, 13]. The parenchymal pattern is especially inhomogeneous throughout
the gland. However, in about 10% of patients with this form of thyroiditis only
a general enlargement with no apparent change of echogenicity [11]. In some
other cases, focal alteration in echogenicity in a diffusely enlarged gland can be
demonstrated (Fig. 11). Associated enlarged cervical lymph nodes are a frequent
finding [7]. Histologically, there is a heavy lymphocyte and plasma cell infiltration
of the interstitial tissue of the gland. Similar sonographic changes, and sometimes
a more marked diffuse hypoechogenicity, are seen in Graves' disease [1, 11].
In some patients acute Hashimoto's thyroiditis may be associated with hyper-
thyroidism (Fig. 12). However, during the course of the illness the thyroid often
decreases in size, and at the same time the parenchymal echogenicity increases in
many patients [11, 13]. These sonographic changes are frequently associated with
the development of hypothyroidism.
Another form of inflammation is the subacute thyroiditis de Quervain, which
in the English-language literature is named 'focal thyroiditis'. The entity is pre-
sumably a viral disease of the thyroid which is characterized by a diffuse enlarge-
ment of the gland with wandering focal infiltrations of the glandular tissue [11].
Both phenomena (enlargement and focal parenchymal changes) can easily be
demonstrated by serial sonography [11]. Characteristic histological signs for this
variant of thyroiditis are: granulomas, giant cell reaction, tissue infiltration with
lymphocytes and plasma cells.
Cysts in the thyroid can be very easily diagnosed sonographically (Fig. 13). These
cysts are rarely true epithelial cysts. In most cases, these cysts represent degenera-
tive changes in adenomatous nodular goitre. These cysts may contain colloid
fluid, yellow fluid (old blood), fresh blood or infected material (suppurative
thyroiditis) [11]. Some cysts may have a thickened wall, irregulars contour and/or
calcifications within their walls.
The most frequent solitary solid lesion is the echo genic nodule, which is also
called adenomatous nodule. More often, however, the whole organ may consist of
adenomatous nodules of nearly equal size. In the early stages of nodular develop-
ment, computed sonography can demonstrate these multinodular changes, even
though the glandular tissue appears homogeneous in conventional sonography
(Fig. 14). In more advanced cases, the adenomatous alteration of the thyroid is
evident. Most of these nodules are echogenic, a few hypo echoic (Fig. 15). In addi-
tion small calcifications of some nodules can also be seen.
10 K. Schneider
Fig.14. Goitre with adenomatous changes in a 15-year-old girl. Transverse section shows mul-
tiple hyperechogenic nodes (large arrows) and very small hypo echoic areas (small arrows).
Crosses, measurement of width, length and depth of the right lobe
Fig. 17. Recurrent thyroid carcinoma in a 24-year-old woman operated on at the age of 11 years.
Lobulated hypoechoic mass in transverse (left) and longitudinal (right) sections indicated by cros-
ses. Enlarged lymph node (arrowheads). Fine calcifications within the tumour (curved arrows).
RCA, anteriorly displaced right carotid artery; LCA, left carotid artery
12 K. Schneider
cases have been reported with CT, the resolution of computed sonography is
higher, multiplanar section planes are available, biopsy can be guided in question-
able cases and no contrast medium is needed. Recently, high-resolution sono-
graphy was proposed as the imaging method of choice for the primary evaluation
and even for the follow-up evaluation of patients with thyroid carcinoma [16].
Sonography
/ \
~ ~
~
1123-,131-
Scintigraphy
solitary multi- MRI
nodular
Fig. IS. Algorithm for investigation of nodular thyroid enlargement. FNA, Fine-needle aspira-
tion; CT, computed tomography; MRI; magnetic resonance imaging
Sonographic Imaging of the Thyroid in Children 13
positive negative
\ I
;; l~hY~
1" ;-
Diffuse Thyroiditis Focal Graves' Endemic
Goitre
REPEAT
Sonography
Fig. 19. Algorithm for investigation
of diffuse thyroid enlargement.
FNA, Fine-needle aspiration FNA STOP
trapping tumour with widespread metastases; then, iodine 131 isotope studies
should be performed. Of mere academic interest is the use of radio nuclide studies
for the evaluation of neonatal hypothyroidism. Scintigraphy is the best method to
demonstrate a hypoplastic lingual thyroid [1,12].
A thyroid nodule should be first imaged with sonography, because the evalua-
tion of morphology of the lesion is critical (Fig. 18). No further imaging is neces-
sary for simple cysts. Multiple echogenic nodules in an otherwise homogeneously
enlarged thyroid gland are characteristic for multinodular adenomatous goitre.
No further diagnostic workup is indicated.
When a single solid hyperechoic or hypo echoic area or nodule is found sono-
graphically, 123I-scintigraphy and fine-needle aspiration should subsequently be
performed. If the aspirate is clearly malignant or not conclusive [17], then surgery
is needed. Patients with a high risk for thyroid malignancy should have early sur-
gical evaluation [10]. High-risk disorders are: multiple endocrine neoplasia syn-
drome, mucosa neuroma syndrome, and prior irradiation of the neck [10].
Fine-needle aspiration is extremely helpful in the diagnosis of focal or atypical
forms of thyroiditis [10, 11]. However, in most patients with thyroiditis, thyroid
antibodies are positive (Fig. 19); fine-needle aspiration is therefore not needed in
the majority of cases.
14 K. Schneider: Sonographic Imaging of the Thyroid in Children
References
Summary
The treatment of juvenile struma is the domain of the pediatrician, and operations are rarely
necessary, even in struma-endemic regions. An absolute indication for surgery is diagnosed or
suspected struma maligna; relative indications are hyperthyroidism and euthyroid goiter. The
operative procedure in benign thyroid diseases is based on the pathogenesis; a tissue-saving tech-
nique is mandatory to prevent postoperative hypothyroidism. Therapeutic strategy in malignant
diseases, i.e., the radicality of surgical and postoperative management, depends, as in adults, on
the prognostic relevance of variable parameters.
Zusammenfassung
Die Therapie der juvenilen Struma ist eine Domane des J;'adiaters, die Operation eine Seltenheit,
selbst in Endemiegebieten. Absolute Operationsindikationen bestehen bei Struma maligna und
bei Malignitatsverdacht, relative bei Hyperthyreose und bei euthyreotem Kropf. Die operative
Taktik bei gutartigen Erkrankungen beruht auf dem Verstandnis der Pathogenese, zur Vermei-
dung postoperativer Hypothyreosen ist besonders parenchymschonendes Vorgehen angezeigt.
Die therapeutische Strategie bei bosartigen Erkrankungen, d. h. das AusmaB der Radikalitat der
operativen und der postoperativen Behandlung, stutzt sich, wie beim Erwachsenen, auf die pro-
gnostische Relevanz der vorhandenen EinfluBgroBen.
Resume
Alors que Ie pediatre traite tres souvent les thyro'idites juveniles, les interventions chirurgicales
restent rares, meme dans les regions ou cette affection est endemique. L'intervention chirurgicale
est indiquee imperativement dans les cas de cancer de la thyro'ide et de struma malign a eventu-
ellement dans les cas d'hyperthyro'idie et de goitre euthyro'idique. La technique operatoire dans
les cas benins est guidee par des considerations pathogeniques; elle doit preserver Ie plus possible
les tissus pour eviter une hypothyreose postoperatoire. La strategie therapeutique, c'est-a-dire
Ie fait de pratiquer une intervention radicale ou non et Ie traitement postoperatoire, depend,
comme chez les patients adultes, de I'importance relative, pour Ie prognostic, de parametres
variables.
lUniv. Doz. Dr. D. Ladurner, II. Universitats-Klinik fur Chirurgie, AnichstraBe 35, A-6020
Innsbruck, Austria.
2Prof. Dr. G. Riccabona, Universitats-Klinik flir Nuklearmedizin, AnichstraBe 35, A-6020
Innsbruck, Austria.
Introduction
Hyperthyroidism
Euthyroid Struma
New insights into the pathogenesis of common struma also provide new thera-
peutic pathways [5]. Identification of immunogenic growth factors in the serum of
patients with goiter and the ability of the thyroid follicle cells to proliferate auto-
nomously make it clear why many goiters continue to grow despite thyroxine sub-
18 D.Ladurner and G.Riccabona
stitution; why, in struma-endemic countries such as Austria, only about half of the
goiters can be explained by iodine deficiency [6]; and why goiters occur even after
correction of iodine deficiency, as in Switzerland [4].
With these new insights in mind, the following therapeutic procedure is recom-
mended in cases of juvenile struma: Primary thyroxine substitution; if the goiter
diminishes thereafter, the classical TSH-regulated iodine deficiency mechanism
must be assumed for the development of goiter. If the struma continues to grow
under thyroxine substitution, it can be deduced that thyroid-stimulating immuno-
globulins or autonomous processes are responsible for struma growth. In this
case, surgical treatment is unavoidable.
Criteria for the extent of resection of juvenile struma are, above all, impend-
ing hypothyroidism and struma recurrence. The surgeon should use the following
strategy:
Struma maligna
The incidence of thyroid cancer in childhood is low. Schauer [17] estimates one
childhood case among 100 thyroid cancers. Young and Gloeckler-Ries calculate
a rate of 1.8 per million white inhabitants in the USA, based on a study by the
National Cancer Institute [23]. However, 5 of our 11 patients who underwent
struma operations had thyroid cancer.
It must be emphasized in this context that every nodular goiter in children
must be carefully investigated. For instance, at the Mayo Clinic, 35% of the oper-
ated solitary nodular goiters in children were malignant [9]. Every thyroid nodule
that develops under therapy or causes local symptoms and every struma with sus-
pect findings obtained by ultrasound, scintigraphy, or cytology must be clarified
surgically. This means, for children as well, a regular operation with complete
excision of the nodule, and not just a biopsy.
The predominance of the papillary form of thyroid cancer with primary in-
vasion of the lymph nodes in our patients is in accordance with reports in the liter-
ature (Table 3). Lymph node metastases are frequently the first and only symp-
tom of thyroid cancer: Joppich et al. [10] found this to be true in 28% and Harness
et al. [7] in 63% of their patients. In the latter series, the average time between
first symptoms and final diagnosis was more than 2 years, in single cases even
more than 5 years.
In spite of this unfavorable starting position, the prognosis of thyroid car-
cinoma in children is generally considered promising. Tubiana et al. [20] reported
a 20-year-survival rate of 88%, and Buckwalter et al. [2] reported only one death
among 68 patients after a follow-up of up to 30 years. Likewise, all our patients
are alive and tumor free after follow-ups of up to 14 years. Nevertheless, death
due to thyroid cancer can occur as late as decades after surgery [20]. Criteria for
the radicality of surgery or of therapeutic strategy in general are the prognostic
factors worked out by multivariate studies [3, 12,20]. Our studies [11] showed the
following parameters to be prognostically important for papillary carcinoma, the
predominating tumor form in children (Table 4): age, TNM stage, and special
his to morphological criteria such as blood vessel avulsions and colloid content.
Based on these insights, we are of the opinion that a mere lobectomy on the tumor
side is adequate in the rare childhood thyroid carcinoma without remote meta-
stases or unfavorable prognostic factors. If the cervical lymph nodes are affected
- the most common finding in children - additional subtotal, contralateral
strumectomy with removal of the cervical lymph nodes is the method of choice.
References
1. Berchtold R (1983) Juvenile Struma. In: Steiner H, Galvan G (eds) Die Therapie der
Schilddriisenerkrankungen - Kritisches und Neues. 2. Internationales Schilddriisensym-
posium Salzburg. 18-19 Nov 1983
2. Buckwalter JA, Gurll NJ, Thomas CG (1981) Cancer of the thyroid in youth. World J Surg
5: 15-25
20 D. Ladurner and G. Riccabona: Surgical Aspects of Diseases of the Thyroid Gland
3. Byar DP, Green SB, Dor P, Williams D, Colon J, van Gilse HA, Mayer M, Sylvester RJ,
van Glabbeke M (1979) A prognostic index for thyroid carcinoma. A study of the
E.O.R.T.C. thyroid cancer cooperative group. Eur J Cancer 15: 1033-1041
4. Eberhard H, Eigenmann F, Scharer K, Biirgi H (1983) Auswirkungen der verbesserten
Kropfprophylaxe mit jodiertem Kochsalz auf den Jodstoffwechsel in der Schweiz. Schweiz
Med Wochenschr 113: 24-27
5. Gerber H, Peter HJ, Ramelli F, Miloni E, Konig MP, Studer H, Berchtold R, Gemsenjager
E (1983) Autonomie und Heterogenitat der Follikel in der euthyreoten und hyperthyreoten
menschlichen Knotenstruma: die Losung alter Ratsel? Schweiz Med Wochenschr 113: 1178-
1187
6. Grubeck-Loebenstein B, Kletter K, Kiss A, Vierhapper H, Waldhausl W (1982) Endemische
Struma in Osterreich. 1st Jodmangel die prim are Kropfursache? Schweiz Med Wochenschr
112: 1526-1530
7. Harness JK, Thompson NW, Nishiyama RH (1971) Childhood thyroid carcinoma. Arch Surg
102: 278-284
8. Hayles AB, Kennedy RLJ, Woolner LB, Black BM (1956) Nodular lesions of the thyroid
gland in children. J Clin Endocrinol Metab 16: 1580-1594
9. Hayles AB (1972) Problems of childhood Graves' disease. Mayo Clin Proc 47: 850-853
10. Joppich I, Roher HD, Hecker WCh, Knorr D, Daum R (1983) Thyroid carcinoma in child-
hood. Prog Pediatr Surg 16: 23-28
11. Ladurner D, Seeber G, Hofstlidter F (1984) Das papillare Schilddriisenkarzinom - Prognose
und prognostische Faktoren. Langenbecks Arch Chir 363: 43-55
12. Ladurner D, Seeber G, Hofstlidter F, Zechmann W (1985) Das differenzierte Schilddriisen-
karzinom. Klinik, Prognose, therapeutische Uberlegungen. Dtsch Med Wochenschr 110:
333-338
13. Oberdisse K (1980) Die Hyperthyreose. In: Oberdisse K, Klein E, Reinwein D (eds) Die
Krankheiten der Schilddriise. 2nd edn. Thieme, Stuttgart, p 189
14. Osterreichisches Statistisches Zentralamt (1982) SchilddriisenvergroBerungen bei Schulkin-
dern 1978179. In: Osterreichisches Bundesinstitut flir Gesundheitswesen (ed). Schilddriise
und Vollsalz
15. Platzer S, Riccabona G, Fill H, Ladurner D, Glatzl J, De Sanso G, Brambati-Testori 0,
Costa A (1975) Notes of endemic goitre and cretinism in the upper Isarco valley. J Nuc1 Bioi
Med 19: 65-72
16. Riccabona G, Glatzl J, Platzer S, Fill H, Ehlich P, Obendorf L (1981) Gibt es noch eine
Kropfendemie bei Osterreichs Jugend? Padiatr Padol 16: 189-194
17. Schauer A (1984) Pathogenese und pathologische Anatomie. In: Becker HD, Heinze HG
(eds) Maligne Schilddriisentumoren. Springer, Berlin Heidelberg New York, p 2
18. Scriba PC, Beckers C, Biirgi H, Escobar Del Rey F, Gembicki M, Koutras DA, Lamberg
BA, Langer P, Lazarus JH, Querido A, Thilly C, Vigneri R (1985) Goitre and iodine defi-
ciency in Europe. Report fo the Subcommittee for the Study of Endemic Goitre and Iodine
Deficiency of the European Thyroid Association. Lancet 1: 1289-1293
19. Steiner H, Zimmermann G (1978) Die Epidemiologie der endemischen Struma unter Jod-
salzprophylaxe. Wien Med Wochenschr 128: 476-479
20. Tubiana M, Schlumberger M, Rougier Ph, Laplanche A, Benhamou E, Gardet P, Caillou B,
Travagli JP, Parmentier C (1985) Long-term results and prognostic factors in patients with
differentiated thyroid carcinoma. Cancer 55: 794-804
21. Vaidya VA, Bongiovanni AM, Parks JS, Tenore A, Kirkland RT (1974) Twenty-two years'
experience in the medical management of juvenile thyrotoxicosis. Pediatrics 54: 565-570
22. Winship T, Rosvoll RV (1961) Childhood thyroid carcinoma. Cancer 14:734-743
23. Young JL, Gloeckler Ries L, Silverberg E, Horm JW, Miller RW (1986) Cancer incidence,
survival, and mortality for children younger than age 15 years. Cancer 58: 598-602
Surgery for Benign and Malignant Diseases
of the Thyroid Gland in Childhood
T.A. Angerpointner 1, E. Britsch\ D. Knorr2, and W. Ch.Hecker l
Summary
From 1970 to 1986, 51 children and adolescents aged 5-18 years were operated on for diseases of
the thyroid gland, among them 42 with benign diseases Quvenile goiter 21, adenoma 17, Graves'
disease 3, Hashimoto's thyroiditis 1) and nine with malignancies (papillary carcinoma 4, follicular
carcinoma 3, medullary carcinoma 1, anaplastic carcinoma 1). In benign entities, females were
three times as often affected as males, whereas both sexes were equally affected in malignancies.
Positive family histories were found in 23.3% of the children with adenomas and in 71.4% of the
children with juvenile goiters. Subtotal strumectomy was carried out in 30 instances and enculea-
tion in 12. Iodized salt and L-thyroxine were given postoperatively as recurrence prophylaxis.
Recurrence was seen in two children (4.8%) who had no recurrence prophylaxis.
Symptoms in children with malignancies were palpable cervical lymph nodes and solitary
nodes in the thyroid gland. Total thyroidectomy was done in all instances, followed by radio-
iodine treatment in eight cases and cobalt 60 irradiation in one case. Two children died, of diffuse
metastases and irradiation fibrosis of the lung respectively.
The peculiarities of diseases of the thyroid gland in childhood that require surgery are dis-
cussed.
Zusammenfassung
Von 1970 bis 1986 wurden 51 Kinder und Jugendliche im Alter von 5-18 Jahren wegen Schild-
driisenerkrankungen operiert, darunter 42 mit benignen Schilddriisenerkrankungen Quvenile
Struma 21, Adenome 17, Basedow-Struma 3, Hashimoto-Thyreoiditis 1) and 9 mit Malignomen
(papilUire Karzinome 4, follikuHire Karzinome 3, medulUires Karzinom 1, undifferenziertes
Karzinom 1). Bei den benignen Erkrankungen waren Madchen 3mal haufiger betroffen als Jun-
gen, bei den Malignomen war die Geschlechtsverteilung gleich. Eine positive Familienanamnese
fand sich bei 23,3 % der Kinder mit Adenomen und bei 71 ,4 % der Kinder mit juveniler Struma;
30mal wurde eine subtotale Strumektomie und 12mal eine Enukleation durchgefiihrt. Jodiertes
Speisesalz und L-Thyroxin wurden zur postoperativen Rezidivprophylaxe gegeben. Bei 2 Kin-
dem, die keine Rezidivprophylaxe durchgefiihrt hatten, kam es zum Strumarezidiv (4,8%).
Erstsymptome bei Kindem mit Schilddriisenmalignomen waren tastbare Halslymphknoten
und Solitarknoten in der Schilddriise. Totale Thyreoidektomien wurden in allen Fallen vorge-
nommen. 8 Kinder wurden postoperativ mit Radiojod behandelt, und bei einem Kind wurde eine
6oCo-Bestrahlung durchgefiihrt. 2 Kinder starben an diffuser Metastasierung bzw. Strahlenfi-
brose der Lunge.
Die Besonderheiten der chirurgischen Schilddriisenerkrankungen im Kindesalter werden dis-
kutiert.
1 Pediatric Surgical Clinic and 2 Pediatric Clinic, Dr. von Haunersches Kinderspital of the Univer-
sity of Munich, LindwurrnstraBe 4, D-8000 Munich 2 (W) FRG.
Entre 1970 et 1986, 51 enfants et adolescents, ages de 5 a 18 ans ont ete operes pour une affection
de la glande thyro'ide; 42d'entre eux presentaient des affections benignes (goitre juvenile: 21;
adenome: 17; maladie de Basedow: 3; thyro'idite de Hashimoto: 1) et 9 des affections malignes
(carcinome papillaire: 4; carcinome folliculaire: 3; carcinome medulaire: 1; carcinome ana-
plasique: 1). Dans les cas benins, il y avait trois fois plus de patientes que de patients alors que
les deux sexes etaient representes dans la meme proportion dans les cas malins. Dans 23.3% des
cas d'adenomes et 71.4% des cas de goitres juveniles on note une predisposition familiale. Dans
30 cas, on pratiqua une strumectomie subtotale et dans 12 cas une enucleation. On administra du
sel iode et de la thyroxine L(?) apres I'intervention pour eviter une recurrence. II y eut recurrence
dans Ie cas de deux enfants qui avaient ignore les mesures prophylactiques.
Les sympt6mes des affections malignes etaient les nodules Iymphatiques cervicaux et les
nodules solitaires de la glande thyro'ide. Dans tous les cas, une thyroldectomie tot ale a ete pra-
tiquee, suivie d'un traitement a I'iode radioactif dans 8 cas et d'irradiation au cobalt 60 dans un
cas. Deux enfants sont decedes a la suite de metastases diffuses dans un cas et a une fibrose pul-
monaire due a I'irradiation dans l'autre cas.
Suit une discussion sur les affections de la thyrolde relevant de la chirurgie des enfants.
Introduction
The juvenile goiter is of extraordinary size (struma grade III) and sufficient re-
gression with conservative treatment cannot be expected
Tracheal and esophageal stenosis or venous blockage occurs
There is a retrosternal struma
Conservative treatment of even a minor goiter remains unsuccessful for 2 or
more years
The TSH-thyroid axis is disrupted (autonomous adenoma)
Thyroid cancer is suspected
We present and discuss our patients with pediatric thyroid diseases who were sur-
gically treated during the past two decades.
Surgery for Benign and Malignant Diseases of the Thyroid Gland in Childhood 23
Patients
From 1970 through 1986, 51 children and adolescents aged 5-18 years were opera-
ted on for thyroid diseases at the Pediatric Surgical Clinic, Dr. von Haunersches
Kinderspital, of the University of Munich, 42 of them with benign and nine with
malignant entities.
Benign Diseases
Disease Patients
n Female Male Sex ratio Positive
family history
Total 42 31 11 2.8: 1
24 T. A. Angerpointner et al.
Thyroid Cancer
Nine of the 52 children had to undergo surgery for thyroid cancer. Pathohistolog-
ical examination revealed papillary carcinoma in four cases, follicular carcinoma
in three cases, medullary (C-cell cancer) in one case and anaplastic carcinoma in
the remaining case. The child with C-ce11 cancer suffered from the multiple endo-
crine neoplasia syndrome (MEN type IIb). Sex ratio was equal, with five girls and
four boys (Table 2).
First symptoms in children with thyroid cancer were enlarged cervical lymph
nodes and solitary nodules in the thyroid gland. Anamnestically, there was no
preceding irradiation of the neck or the mediastinum. All children underwent
total thyroidectomy in order not to endanger the relatively good prognosis in this
age group by a less radical procedure. Total thyroidectomy was performed
primarily in six cases and as a second-look procedure in the remaining three cases
when the diagnosis was finally established by pathohistological examination. The
affected cervical lymph nodes were surgically removed in seven cases, but no rad-
ical neck dissection was carried out.
Three of the nine children developed postoperative complications (paralysis of
the recurrent nerve, Horner's syndrome, hypocalcemia). All children received
substitution therapy with thyroid hormones postoperatively. Eight children un-
derwent postoperative radioiodine treatment at a dose of 100-150 mCi for 1
month following surgery. One child with anaplastic carcinoma received 60Co ir-
radiation of the neck, axilla and mediastinum. This child died 2 months post-
operatively of diffuse metastases including the myocardium. Another child with
follicular carcinoma died 5 months postoperatively of lung fibrosis and irradiation
pneumonitis. Thus, the survival rate in our series was 77.8 % .
Papillary carcinoma 4 3
Follicular carcinoma 3 1 2
Medullary carcinoma (C-cell)
Anaplastic carcinoma
Total 9 5 4 2 (22.2%)
Surgery for Benign and Malignant Diseases of the Thyroid Gland in Childhood 25
Discussion
Iodine deficiency is the etiologic agent for juvenile struma, effecting an increase
in TSH [6, 24]. Surgery is indicated for juvenile struma if compression signs occur
or if conservative treatment remains unsuccessful for a longer period of time. The
Federal Republic of Germany is a struma-endemic country with a marked north-
south gradient, the incidence being 4% in Schleswig-Holstein and 32% in Bavaria
[16]. In the USA, in contrast, the incidence of juvenile struma is 1.8 % [2].
The pronounced female predominance of up to 4.5: 1 [14, 15, 17] was con-
firmed in our series. We have also found a very distinct hereditary component,
with a positive family history of juvenile struma in 71 % and of adenoma in 24% .
Thus, exogenic and endogenic (hereditary) factors cooperate in the etiology of
benign thyroid diseases in children and adolescents. Lindinger and Sitzmann [16]
reported a struma incidence of 40% in the offspring if one parent had a struma
and of 64% if both parents were affected.
Sufficiently iodized table salt available for everybody is very desirable for gen-
eral prophylaxis in struma-endemic areas. In Switzerland, Austria, and Finland,
the struma incidence was lowered to 3% by table salt iodization [14, 24, 25]. In the
Federal Republic of Germany, sufficiently iodized table salt (100 Jlg iodine per 5 g
salt) has been available since 1982 [24], but its use is still voluntary.
Since the same etiologic factors remain active postoperatively, the necessity of
postoperative recurrence prophylaxis with L-thyroxine and iodized table salt is
generally accepted [3, 4, 7, 15,23,26]. The principle is depression of the TSH
axis. Prior to the introduction of postoperative recurrence prophylaxis, the re-
currence rate was 60% secondary to subtotal strumectomy [3]. Today, postopera-
tive struma recurrence is reported to be from 1.2% up to 10%, with a mean inci-
dence of 5% [3,7,15,23,26], which is in good accordance with our recurrence
rate of 4.8%. Most authors, however, emphasize that the majority of recurrences
are seen in patients who disregard the prophylactic treatment, as was the case with
our two patients who developed struma relapse postoperatively. Bartels et al. [3]
stressed that after 2 years only 60% of patients take their prophylaxis regularly.
Permanent prophylaxis with L-thyroxine and iodized table salt securely prevents
struma relapse.
Thyroid autonomy is the excess production of thyroid hormones without hypo-
physeal influence via TSH regulation. The treatment of choice is surgery, with
enucleation of the adenoma if it is sufficiently demarcated against the surrounding
tissue. If this is not the case, subtotal strumectomy has to be carried out [7, 11, 17,
20, 23, 27]. We gave recurrence prophylaxis also after surgery for thyroid
adenoma. Since the etiology of adenoma is still not completely clear, no general
agreement on postoperative recurrence prophylaxis exists in the literature.
However, the fact that one of our patients with an adenoma who did not take L-
thyroxine postoperatively developed a relapse is a hint at the usefulness of post-
operative recurrence prophylaxis also in adenoma. We are of the opinion that in
a struma-endemic region the depression of the TSH axis may also prevent a
relapse of an adenoma.
26 T. A. Angerpointner et al.
Conclusion
The variety of thyroid disorders in childhood and adolescence, both benign and
malignant, requires a very consistent therapeutic regime because of the special
tasks of the thyroid gland in this age-group. Close cooperation between pediatri-
cians, pediatric endocrinologists and pediatric surgeons is mandatory to ensure a
good to excellent prognosis in benign as well as in malignant diseases.
Surgery for Benign and Malignant Diseases of the Thyroid Gland in Childhood 27
References
1. Anger K, Feine U (1983) Thyroid carcinoma in childhood. Prog Pediatr Surg 16: 39-42
2. Balazs G, Lukacs G, Csaky G, Boros P, Ilyes J (1986) Splitergebnisse kindlicher Schild-
driisenkarzinome. Presented at the 5th ACE Meeting, Hamburg, Sept 19/20
3. Bartels H, Erdt E, Haluszczynski I (1982) Sind Rezidive nach Resektionen benigner
Schilddriisenerkrankungen vermeidbar? Fortschr Med 82: 1108-1110
4. Benker G (1986) Diagnostik und Therapiekontrolle bei M. Basedow. Therapiewoche 36:
1724-1730
5. Bindewald H, Raue F, Merkle P (1983) The diagnosis and therapy of medullary thyroid car-
°
cinoma in childhood. Prog Pediatr Surg 16: 43-46
6. Butenandt (1983) Die Therapie endokriner Erkrankungen im Kindes- und Jugendlichen-
alter. Fortschr Med 101: 667-669
7. Csaky G, Balazs G, Bako G, Ilyes J, Kalman K, Szabo J (1986) Splitresultate der im Kindes-
alter durchgefiihrten Schilddriisenoperationen wegen Hyperthyreose. Presented at the 5th
ACE Meeting, Hamburg, Sept 19/20
8. Herzog B (1983) Thyroid gland diseases and tumors - surgical aspects. Prog Pediatr Surg
16: 15-22
9. Joppich I, Roher HD, Hecker WC, Knorr D, Daum R (1980) Besonderheiten des Schild-
driisenkarzinomes im Kindesalter. KEn Padiatr 192: 436-439
10. Joppich I, Roher HD, Hecker WC, Knorr D, Daum R (1983) Thyroid carcinoma in child-
hood. Prog Pediatr Surg 16: 23-27
11. Joseph K (1986) Thyreoidale Autonomie. Therapiewoche 36: 1711-1723
12. Kaiser P, Wurnig P (1980) Seltene Erkrankungen der kindlichen Schilddriise. Z Kinderchir
30: 112-114
13. Klein E, Blaeser W (1969) Die Therapie der juvenilen Struma. Dtsch Med Wochenschr
94: 609-611
14. Ladurner D, Riccabona G (1986) Schilddriisenerkrankungen im Kindesalter aus chirur-
gischer Sicht. Presented at the 5th ACE Meeting, Hamburg, Sept 19/20
15. Langenbach J (1986) Zehn Jahre Schilddriisenchirurgie. Therapiewoche 36: 2336-2342
16. Lindinger A, Sitzmann C (1978) Die juvenile Struma. Kinderarzt 9 :277-281
17. Niillen H, Sailer R, Miiller E (1979) Chirurgie der Schilddriise im Kindesalter. Kinderarzt
10: 1129-1134
18. Pfister-Goedeke L, Stauffer UG (1983) Thyroid carcinoma in childhood. Prog Pediatr Surg
16:29-37
19. Pohl P (1983) Schilddriisenchirurgie. In: Heberer G, Ki:ile W, Tscherne H (eds) Chirurgie.
Springer, Berlin Heidelberg New York, pp 440-448
20. Rauh V, Kujath HP, Reimers C, Wicht B (1989) Indikation, operative Therapie und
Nachsorge bei der kindlichen Hyperthyreose. Presented at the 5th ACE Meeting, Hamburg,
Sept 19/20
21. Ravitch MM (1979) The thyroid. In: Ravitch MM, Welch KJ, Benson CD, Aberdeen E,
Randolph JG (eds) Pediatric surgery .. Yearbook Med Publ Mediat, Chicago, pp 348-364
22. Reiter EO, Root AW, Rettig K (1981) Childhood thyromegaly: recent developments. J
Pediatr 99 : 507 - 518
23. Roher H-D (1987) Endokrine Chirurgie. Thieme, Stuttgart, pp 1-35
24. Scriba PC (1983) Pathophysiologie der blanden Struma und Jodsalzprophylaxe. Therapie-
woche 32: 29-34
25. Wiebei J (1981) Die sogenannte euthyreote Struma im Kindes- und Jugendlichenalter. Kin-
derarzt 12: 1411-1413
26. Waag K-L, Hanisch E, Kollmann F, Wons T, Wenisch H (1988) Erfahrung mit der operati-
ven Therapie von Schilddriisenerkrankungen im Kindesalter. Z Kinderchir 43: 232-235
27. Zabransky S (1983) Seltene Schilddriisenerkrankungen im Kindesalter. Therapiewoche
33:61-72
Indications, Surgical Treatment and After-Care
in Juvenile Hyperthyroidism
V. Rauh l , H.P. Kujath l , C. Reimers2 , and B. Hocht l
Summary
Between 1974 and 1985, 12 children and adolescents aged 10-18 years were operated on for
immunogenic hyperthyroidism resistant to medical treatment. Bilateral, subtotal strumectomies
were carried out, leaving a remnant of 2-3 g of thyroid tissue in place. There were no immediate
postoperative complications. Hyperthyroidism recurred in two instances. During the same time,
26 children and adolescents up to 18 years of age underwent surgery for autonomous adenoma.
Enucleation is the method of choice in adenoma, but is not always possible.
Zusammeufassuug
Von 1974 bis 1985 wurden 12 Kinder und Heranwachsende im Alter von 10-18 Jahren wegen ei-
ner therapieresistenten Hyperthyreose operiert. Dabei wurde eine bilaterale, subtotale Strum-
ektomie mit einem Schilddrtisenrest von 2-3 g durchgeftihrt. Unmittelbare postoperative Kom-
plikationen wurden nicht beobachtet. Zu einem Hyperthyreoserezidiv kam es in 2 Fallen. 1m
gleichen Zeitraum wurden 26 Kinder und Jugendliche bis 18 Jahre wegen eines autonomen Ade-
noms operiert. Die Enukleation ist das Verfahren der Wahl, jedoch nicht immer durchftihrbar.
Resume
Entre 1974 et 1985, 12 enfants et adolescents ages de 10 it 18 ans ont ete open~s pour hyperthy-
reose immunogenetiques resistant au traitement medical. Des strumectomies bilaterales et sub-
totales ont ete pratiquees, laissant en place un reste de 2 it 3 g de tissu thyroidien. II n'y a pas eu
de complications postoperatoires. Dans deux cas, il y a eu recurrence de l'hyperthyreose. Au
cours de la meme periode, 26 enfants et adolescents (age maximum: 18 ans) ont subi une inter-
vention chirurgicale pour adenome autonome. Si I'enucleation reste la methode de choix, elle
n'est malheureusement pas toujours possible.
therapies do not compete with each other, but rather have their own clear indica-
tions:
References
Summary
The authors report on the complex follow-up of 60 patients operated on for hyperthyroidism in
childhood, on average 13.7 years after surgery. In 16.7% of the patients manifest hypo-
thyroidism, in 45% subclinical hypothyroidism was found; 30% of the patients were euthyroid,
and manifest hyperthyroidism recurred in 8.3%. Autonomous adenomas were enucleated in two
children and three young adults.
Severe disorders in thyroid function developed especially after the surgery of diffuse toxic
goiters accompanied by ophthalmopathy. The disorders of humoral and cellular immunity were
detected most frequently in recurrent manifest hyperthyroidism. There was no case where
ophthalmopathy progressed after the operation.
In the offspring of the operated patients the incidence of hyperthyroidism was not increased
in childhood. The authors call attention to the importance of postoperative follow-up and
hormone treatment.
Zusammenfassung
Es wird iiber die Ergebnisse von Nachuntersuchungen bei 60 Patienten berichtet, die wegen einer
Hyperthyreose operiert worden waren. Die Untersuchungen fanden im Durchschnitt 13,7 Jahre
nach der Operation statt. Bei 16,7% wurde eine manifeste und bei 45 % eine subklinische Hypo-
thyreose gefunden, wogegen 30 % der Patienten euthyreot waren und 8,3 % eine manifeste
Hyperthyreose aufwiesen. Autonome Adenome wurden bei 2 Kindem und 3 jungen Erwachse-
nen enukleiert.
Schwere StCirungen der Schilddriisenfunktion traten v.a. nach Operationen diffuser, toxi-
scher Strumen mit begleitender Ophthalmopathie auf. Storungen der humoralen und zellularen
Immunitat wurden meist bei rezidivierender manifester Hyperthyreose gefunden. In keinem Fall
kam es postoperativ zur Progredienz der Ophthalmopathie.
Bei den Kindem der operierten Patienten war die Haufigkeit einer Hyperthyreose gegeniiber
anderen Kindem nicht erhoht. Es wird nachdriicklich auf die Notwendigkeit der postoperativen
Nachuntersuchungen und der Hormonsubstitution hingewiesen.
Les auteurs ont suivi, de fa~on tres complexe, pendant une moyenne de 13,7 ans apres l'opera-
tion 60 patients ayant subi durant leur enfance une intervention chirurgicale pour hyperthyroidie.
Chez 16,7% des patients on note une hypothyroidie manifeste, une hypothyroidie subclinique
chez 45%, une euthyroidie chez 30%, une recurrence d'hyperthyroidie manifeste chez 8,3%. On
a pratique I'enucleation d'un adenome autonome chez deux enfants et trois jeunes adultes.
Des troubles graves de la fonction thyroidienne sont apparus surtout apres I'ablation chir-
urgicale de goitres diffus toxiques accompagnes d'ophtalmopathie. Les troubles de l'immunite
humorale et cellulaire sont plus frequents dans les cas de recurrence d'une hyperthyroidie mani-
feste. Apres !'intervention on ne constate aucun cas d'evolution de I'ophtalmopathie.
Chez les enfants des patients ayant subi une intervention, on ne constate pas, durant
I'enfance, une augmentation de la frequence de l'hyperthyroidie. Les auteurs insistent sur
I'importance du suivi postoperatoire et du traitement hormonal.
Introduction
At the First Clinic of Surgery of the University Medical School of Debrecen be-
tween 1951 and 1980, 68 operations were performed on patients under 18 years
of age for hyperthyroidism. In the 1950s, for the establishment of the diagnosis we
used, besides the clinical picture, the basal metabolic test, serum cholesterol and
PBI determinations; later 131 1 uptake, thyroid scan, and suppression tests; and in
the last 15 years of the period under discussion thyroid hormone assay and TRH-
TSH test.
The thyroid lobes that were diffusely or nodularly transformed on both sides
were subtotally resected after preparation with antithyroid drugs and Lugol's
solution, and 6-10 g of thyroid tissue was retained. Autonomous adenomas were
enucleated. The patients who underwent postoperative thyroid hormone treat-
ment stopped taking the medicine 2 weeks before the follow-up examination.
Of the 68 operated patients, 60 were re-examined in 1984, an average of 13.7
years after surgery. During the re-examination the following tests were performed
on the patients' sera: T4-RIA (our own laboratory, norm 55-155 nmol/l), T3-RIA
(our own laboratory, norm 1.6-3.4 nmol/l) and T3 uptake (our own laboratory,
norm 0.85-1.15). In addition, TRH-Ioading tests were performed with the i.v.
Late Results of Thyroid Surgery for Hyperthyroidism Performed in Childhood 33
Results
9
!
~
fl.
Table 2. Thyroid function of patients operated on for hyperthyroidism: immunological assay data at follow-up according to diagnosis at surgery
(n = 9) 1 1 4 2 4 1 1
Hyperfunctional diffuse goitre
~~
A: without ophthalmopathy 2 10 1 2 6 2 2 1 g
(n = 19)
B: with ophthalmopathy 7 1 2 3 13 1 2 2 3 3 1 1 34 3
Total (n = 60) 10 1 1 2 3 27 2 5 5 4 18 3 2 3 5 3 2
(16.7%) (45%) (30%) (8.3%)
DOT-IBA, Dot-immunobinding-assay + (positive), +- (uncertain positive); IF, indirect immunofluorescence: Tg+ (anti-thyroglobulin antibody:
positive), Mi+ (anti-microsome antibody: positive)
if
'"t;j
S·
I
~
g
8.
v.>
Vl
36 G. Csaky et al.
Discussion
The histological structure of the thyroid gland of children differs greatly from that
of adults: for example, autonomous adenoma, hardly occurs in children and
hyperfunctional nodular goitre is also much less frequent [21]. The appearance
and course of some symptoms of hyperthyroidism are also different: there is a pre-
ponderance of lesions of the nervous system; on the other hand, ophthalmopathy
is milder and has a better prognosis. The possibilities of therapy are also different,
since radioiodine treatment is counterindicated in the opinion of a number of
authors.
The majority of authors agree that in childhood hyperthyroidism can be
treated successfully in 30%-60% of cases with antithyroid drugs [3,14].
Nevertheless, the aim that the child become euthyroid in the shortest possible
time with long-lasting results can be achieved in the rest of the cases only by surgi-
cal methods.
Abe and associates [1], also taking into account the previously published data,
reported on 11 cases of childhood autonomous thyroid adenomas and found it
characteristic that there was no connection between the size of the thyroid
nodules of the children and the onset of their hyperthyroidism. Since the solitary
nodule in childhood raises the suspicion of carcinoma, and this suspicion is not
ruled out even by existing hyperthyroidism, in the treatment of autonomous
adenoma enucleation is indicated. Among our patients with autonomous adenoma,
the lesion of the two 13-year-old girls can be regarded as childhood disorders,
whereas the autonomous adenoma in the three 17-year-old patients is rather to be
evaluated as disease in early adulthood.
Whereas Saxena et al. [25], in the histopathological examination of 70 children
with hyperthyroidism, found no more than four nodular disorders, Maenpaa und
Kuusi [19] observed multinodular lesions in 11 cases of 40 in Finland. For their
treatment hardly anything but surgery is recommended, since for nodular lesions
lasting remission cannot be attained with antithyroid drugs. In the development of
nodular goitre in our patients iodine deficiency may have played a role, our area
being an endemic goitre district. In the course of the investigations on humoral
immunity, in a striking way, several pathological cases were observed. This is
38 G. Csaky et al.
and hormone treatment. Regular checking of the patient's thyroid function seems
to be necessary until the end of the patient's life. Thyroid hormone substitution is
obligatory in manifest and subclinical hypothyroidism, whereas there are different
opinions on hormone therapy in a euthyroid state [8, 16].
There are observations to suggest [7, 13] that both Graves' disease and
Hashimoto's thyroiditis can occur in an accumulative way in a family. On the basis
of our results we have established only that in the offspring of parents operated on
in childhood for hyperthyroidism no higher rate of juvenile thyroid hyperfunction
was found.
Abbreviations
References
12. Freitas JE, Swanson DP, Gross MD, Sisson JC (1979) Iodine-131: optimal therapy for hyper-
thyroidism in children and adolescents? J Nucl Med 20: 847 -850
13. Friedman JM, Fialkow PJ (1978) The genetics of Graves' disease. Clin Endocrinol Metab
7:47-65
14. Hothem AL, Thomas CG Jr, Van Wyk JJ (1978) Selection of treatment in the management
of thyrotoxicosis in childhood and adolescence. Ann Surg 187: 593-598
15. Islam MN, Briones-Urbino R, Bak6 Gy, Farid NR (1983) Both TSH and thyroid-stimulating
antibody of Graves' disease bind to an Mr 197000 holoreceptor. Endocrinology 113: 436-438
16. Junginger T, Kogel H, Winkelmann W (1981) Nachsorge nach operativer Behandlung der
Hyperthyreose. In: Rothmund M, Ktimmerle F (eds) Fortschritte der endokrinologischen
Chirurgie. Thieme, Stuttgart
17. Kalman K, Fazakas S, Erdei I, Leavey A (1976) Leukocyte migration inhibition in vitro in
untreated and methimazole-treated patients with Graves' disease. Acta Med Acad Sci Hung
33:327-332
18. Kalman K, Erdei I, Sandor P, Fazakas S, Leavey A (1978) Leukocyte migration test for the
study of immune reactivity in cases of Graves' disease associated with infiltrative ophthalmo-
pathy. Acta Med Acad Sci Hung 35: 94-34
19. Maenpaa J, Kuusi A (1980) Childhood hyperthyroidism. Acta Paediatr Scand 69: 137-142
20. McClintock JC, Frawky TF, Holden JHP (1956) Hyperthyroidism in children: observations
in 50 treated cases, including an evaluation of endorine factors. J Clin Endocrinol16: 62-85
21. Mtihlendahl KE, Helge H (1978) Hyperthyreose im Kindesalter. 2. Klinik und Therapie.
Padiatr Prax 20: 601-616
22. Perzik SL (1976) The place of total thyroidecotmy in the management of 909 patients with
thyroid disease. Am J Surg 132: 480-483
23. Roitt I, Doniach D (1969) Immunfluorescent tests for the detection of antibodies. In: WHO
manual of autoimmune serology. Geneva
24. Safa AM, Schumacher OP, Rodriguez-Antunez A (1975) Long-arm follow-up results in chil-
dren and adolescents treated with radioactive iodine (131 I) for hyperthyroidism. N Engl J
Med 292: 167-171
25. Saxena KM, Crawford JD, Talbot NB (1964) Childhood thyrotoxicosis: a long-term perspec-
tive. Br Med J 2: 1153-1158
26. Schatz H (1981) Die Bedeutung der Bestimmung von Schilddrusenantikarpern und der
HLA-Typisierung ftir die Prognose der Hyperthyreose. Med Welt 32: 649-652
27. Schatz H, Federlin K (1979) Diagnostik von Immunvergangen bei Schilddrtisenerkran-
kungen und deren klinische Bedeutung. Med Welt 30: 614-618
28. Szab6 J, Leavey A (1980) Thyroid antibodies in Graves' disease. An immunofluorescence
study. Acta Med Acad Sci Hung 40: 91-97
29. Thompson NW, Dunn EL, Freitas JE, Sisson JC, Coran AG, Nishiyama RH (1977) Surgical
treatment of thyrotoxicosis in children and adolescents. J Pediatr Surg 12: 1009-1017
30. Werner SC (1977) Modification of the classification of the eye changes of Graves' disease: re-
commendations of the ad hoc committee of the American Thyroid Association. J Clin En-
docrinol Metab 44: 203-204
31. Wesley JR, Buckingham BA, Gahr JA, Isaacs HJr, Kogut MD, Weitzman JJ (1977) Surgical
treatment of hyperthyroidism in children. Surg Gynecol Obstet 145: 343-346
32. Young RJ, Sherwood MB, Simpson JG, Nicol AG, Michie W, Becks JS (1976) Histometry
of lymphoid infiltrate in the thyroid of primary thyrotoxicosis patients. J Clin Pathol29: 398-
402
Late Prognosis
of Childhood and Juvenile Thyroid Carcinomas
G. Bahlzs\ G. Lukacs l , G. Csaky\ P. Boros2, and I. Ilyes 3
Summary
The authors report on the biological properties and late prognosis of 16 children and juvenile
patients operated on during the past 24 years for thyroid tumour who underwent regular follow-
up. The clinical and morphological characteristics of the carcinomas are described, together with
the late immune response of the patients undergoing complex treatment. The study is also con-
cerned with the characteristics of the DNA content of the tumorous cell nuclei, the pregnancy
success rate of the operated patients and the thyroid function of the children born.
Zusammenfassung
Es wird tiber die biologischen Eigenheiten und die Spatprognose bei 16 Kindem und Jugend-
lichen berichtet, die wegen eines Schilddrtisenkarzinoms operiert und regelmaBig nachuntersucht
worden waren. Klinische und morphologische Charakteristika der Karzinome sowie die spate
Immunantwort der Patienten, die einer komplexen Behandlung unterzogen wurden, werden
beschrieben. Die vorliegende Untersuchung befaBt sich ebenfalls mit dem DNS-Gehalt der
Tumorzellkerne, der Schwangerschaftserfolgsrate der operierten Patientinnen und der Schild-
driisenfunktion ihrer Kinder.
Resume
Les auteurs rapportent les particularites biologiques et les prognostics actuels de 16 enfants et
adolescents ayant subi une intervention chirurgicale pour tumeur thyroidienne au cours des 24
dernieres annees et qui ont ete suivis de fa90n reguliere. Ils decrivent les caracteristiques cliniques
et morphologiques des carcinomes ainsi que la reponse immunologique recente des patients
soumis it un traitement complexe. Cette etude traite aussi des caracteristiques de la teneur
en ADN du noyau de la cellule tumorale, de la proportion de grossesses reussies des patientes
operees et de la fonction thyroidienne de leurs enfants.
Results
Tumour size is important in view of early diagnosis and radical surgical treatment.
It should be noted that of all diagnostic methods we regard as most specific the
method of preoperative aspiration and intraoperative imprint cytology. The
carcinomas were localized intrathyroidally in all our patients: seven of them
belonged to group T1 and nine to T2; thus, none of the tumours adhered to the
adjacent cervical organs (Table 1).
Metastasis formation is also characteristic. In ten patients the first clinical
symptom was regional lymph node, and in one distant metastasis imitating a
miliary pulmonary lesion, which led to the correct diagnosis after preliminary
biopsy and histological examination. In the other five cases the indication for
surgery was the solitary nodule palpable in the thyroid.
pMO pM1
15 1 = 16
Late Prognosis of Childhood and Juvenile Thyroid Carcinomas 43
~ ~IP IP
IF
IP
_ 16 c0 19701 IP
~ 13 :g 1972 §I ~~~~~~3) P
:g
Cl.
16 ~Cl.
1972"'1
t::
~~~~~~31 P
Q) 17 0 1974 EI~~~~~3 P
L Q)
: 14::: 19741 P
o 13 '0 19791 IP
~ 15 Q) 19791 )P
« -
12~19801 1M
14 1982~ F
16 1984§ P
Fig. 1. Survival of the children P=Papillary
operated on for thyroid carcinoma 17 198513 P
F =Follicular
1962-1986 12 19861 P M=Medullar
44 G.Bahizs et al.
data for the interpretation of special biological properties. It is well known that
one form of anti-tumour defence of the human organism is the anti-tumour T-cell-
mediated immune response. We have studied the T-cell sensibilization of the
patients by parallel application of two methods: leucocyte adhesion inhibition
15
10 P
(1 )
15
0
Lf"I
c" 10 F
(1 )
~
~ 5
.....0
'"ro
CJI
+-
0
2c
c
'"u'- 15
'"
c..
10 M
(1 )
(LAI) and the leucocyte migration test (LMT). The antigen was prepared from
papillary thyroid tumour tissue.
According to our results, about half of the patients showed sensibilization
against thyroid tumour antigen both with LAI and LMT for a long time - 8-10
years - after the operation (Table 3). Thus, it was not possible to detect factors
that would inhibit the sensibilization of T-cells against tumour antigens in the sera
of the patients.
Cytochemical tests were performed on the surgically removed tissue in three
cases: the DNA content of the cell nuclei was determined by cytofluorimetry.
Whereas the relative DNA content of normal thyroid epithelial cells is identical
with the diploid (2c) value, in all forms of malignant tumours a considerable ele-
vation is encountered with aneuploid cell distribution (Fig. 2). Similar conclusions
have been drawn by other authors [3, 6].
At different times after the complex treatment, three of our patients became
pregnant. After uneventful pregnancies, these patients delivered five live-born
mature neonates, with weights above 3000 g (Table 4). During and after their
pregnancies the mothers were given substitution therapy. The thyroid state of the
neonates and small children was normal. No hypothyroidism or factitial hyper-
thyroidism has so far occurred.
The somatic development of the children born proved to be normal, their per-
centual values for weight and length fell within the normal range. On physical
examination no case of goitre was found in any of them. To evaluate their thyroid
function the T3U test was performed; the T4 and TSH concentrations were deter-
mined with the RIA method, and from the T3U and T4-RIA values the so-called
free T4 index (FT4I) was calculated (Table 5). Both the individual and average
values fell within the normal range. The titres of thyroglobulin and microsomal
antibodies were also determined: titres 1: 16 or higher were not encountered.
Discussion
Few reports have so far been published on the biological properties and long
follow-up of childhood thyroid carcinomas [5, 7-10]. Interestingly, anaplastic
cancer hardly occurs at this age, and medullary carcinoma is also considered rare
[14]. In our material of 400 patients with thyroid carcinoma, the proportion of
anaplastic tumours is 20%. No such tumour has been seen among the cases of
childhood carcinoma. The favourable prognosis of childhood thyroid carcinomas
can be attributed mainly to slow tumour growth, intrathyroidal localization, its
mostly papillary structure, the rarity of recurrence of primary tumour and the
benign metastases. These patients do not show general tumorous symptoms.
Their development corresponds to that of their age group; with regard to work
capacity they are citizens of full value. This is why, together with Rohrer [15], we
consider the less radical surgical solution justified.
It is worthy of note that the patients who have undergone complex treatment
show, for a long time after the operation, sensibilization against thyroid tumour
antigen. Therefore, it is recommended that the immunological tests be repeated
at certain intervals - every 0.5-1 year - since it can be assumed that decrease in
the reactivity of the T -cells may predict the progress of the tumour.
The treated and regularly followed up patient can, with full responsibility and
a fair prognosis, take on the task of founding a family. The general development
of the children born and their thyroid function do not seem to be influenced by the
earlier disease of the mother.
References
1. Balazs Gy, Banfi J, Peter F (1974) Biologische Eigenschaften des kindlichen und juvenilen
Schilddrusenkrebses. Z Kinderchir 14: 366-373
2. Balazs Gy, Csaky G, Lukacs G, Banfi J, Peter F, Krajczar G (1979) Biologische Eigenschaf-
ten des kindlichen und juvenilen Schilddrusenkrebses. Erfahrungen von 17 Jahren bei 11
Patienten. Z Kinderchir 28: 225-232
3. Bengtsson A, Malmaeus J, Grimelius L, Johansson H, Ponten J, Rastad J, Akerstrom G
(1984) Measurement of nuclear DNA content in thyroid diagnosis. World J Surg 8: 481-486
4. Boros P, Csaky, G, Balazs Gy, Szegedi Gy (1986) Zellularimmunologische Untersuchungen
beim kindlichen und juvenilen Schilddriisenkrebs. Zentralbl Chir 111 : 1179-1182
5. Bretzel RG, Schatz M (1985) Prognostische Faktoren beim Schilddriisenkarzinom. Zentralbl
Chir 110:1304-1314
Late Prognosis of Childhood and Juvenile Thyroid Carcinomas 47
Summary
Zusammenfassung
Operationen der Nebenschilddriise bei Kindem sind selten. Spontan auftretende Hille von
Hyperparathyreoidismus beruhen fast immer auf der Erkrankung einer einzelnen Driise. Es sol1-
ten jedoch bei der Operation alle 4 Nebenschilddriisenkorperchen identifiziert werden. Bei den
meisten anderen Hillen, wo der Chirurg bei Siiuglingen oder Kindem eine Parathyroidektomie
durchfiihren muB,liegt in der Regel eine Erkrankung mehrerer Driisen anstatt nur einer VOL Da-
her muB der Chirurg ein klares Konzept der Behandlung von Kindem mit Erkrankungen mehre-
rer Nebenschilddriisenkorperchen haben. Es wird die Auffassung vertreten, daB die Technik der
Nebenschilddriisenautotransplantation den chirurgischen Erfordemissen bei Kindem mit fami-
liiirem Hyperparathyreoidismus inklusive der multiplen endokrinen Neoplasien entspricht. Diese
Technik ist ebenfalls die Methode der Wahl bei Patienten mit neonatal em Hyperparathyreoidis-
mus sowie bei Kindem mit sekundiirem und tertiiirem Hyperparathyreoidismus. Der Chirurg,
der Explorationen der Halsregion vomimmt, sollte mit der Diagnostik von Nebenschilddriisen-
erkrankungen vertraut sein. Es soll auf das Krankheitsbild der familiiiren hypokalziurischen
Hyperkalziiimie geachtet werden, da diese Patienten hochstwahrscheinlich von einer Parathyro-
idektomie nicht profitieren werden.
Resume
L'ablation chirurgicale des glandes parathyroYdes chez les enfants est rare. Les cas d'hyperpara-
thyroYdie survenue spontanement sont presque toujours dus a une affection d'une seule glande;
il faudra malgre tout toujours verifier les quatre glandes. Dans la plupart des cas pout lesquels
une parathyroYdectomie s'impose, il y a affection multiple des glandes. II faut donc que Ie chir-
urgien ait mis en place un plan therapeutique logique pour Ie traitement des enfants present ant
des troubles parathyroYdien dus ades affections glandulaires multiples. A notre avis, la technique
d'autotransplantation parathyroYdienne repond parfaitement aux besoins des enfants de familles
ou les cas d'hyperparathyroYdie sont frequents, y compris les neoplasies endocrines multiples.
Pour nons ce traitement s'impose absolument dans Ie cas de patients present ant une hyperpara-
thyroYdie neonatale primaire et reste aussi Ie traitement de choix des hyperparathyroYdies secon-
daires et tertiaires. Le chirurgien se doit de connaitre parfaitement la methode de diagnostic des
troubles parathyroYdiens quand il examine Ie cou des enfants et de prendre en consideration une
possibilite d'hypercalcemie hypocalciurique familiale qui risquerait fort de compromettre les
resultats de la parathyroYdectomie.
Introduction
Pathophysiology
tion from the skeleton. Additionally, through interaction with vitamin D and its
metabolites, an indirect effect of parathyroid hormone exists at the gut level via
vitamin D-mediated absorption of calcium. Parathyroid hormone also influences
the concentration of phosphate in the extracellular fluid via its phosphaturic
action upon the kidney.
In primary states of hyperparathyroidism, regardless of whether one or mul-
tiple glands are involved, the physical and biochemical findings are explained by
idiopathic glandular overactivity. This differs from states of secondary hyper-
parathyroidism, where the hypersecretion of parathyroid hormone is a compensa-
tory reaction following the chronic tendency toward hypocalcemia due to prob-
lems such as the impaired formation of 1,25 dihydroxy vitamin D, so it is impor-
tant to know whether the specific type of parathyroid disorder is primary or sec-
ondary when dealing with any child with hyperparathyroidism and whether it is
due to the overactivity of a single or multiple glands.
Diagnosis
ploration. The value of their application in the routine evaluation of the child with
primary hyperparathyroidism has yet to be established.
Specific aids in the diagnosis of many of the individual parathyroid syndromes,
as well as the differential diagnosis, are covered in the discussions of these en-
tities.
Clinical Disorders
tags are placed directly adjacent to each of the normal glands. Despite the fact
that in this population virtually all patients will have a single enlarged gland, we
believe that it is important to have identified all four glands before removing the
adenoma, and, of course, frozen section confirmation is mandatory. The indi-
vidual surgeon's experience and expertise dictate whether biopsies should be
obtained of the "normal" glands; however, at the very least, their gross identifica-
tion is mandatory.
Postoperatively, these patients may have a precipitous fall in their serum cal-
cium, so serum calcium levels should be monitored until they are found to have
become stable. It is our preference not to treat this relative hypocalcemia unless
the patient becomes specifically symptomatic.
Familial Hyperparathyroidism
are clearly enlarged whereas others may appear to be normal. Furthermore, all
glands must be identified and biopsied, as it is not at all uncommon for a "normal"
sized gland to have hyperplastic changes clearly demonstrable upon microscopic
examination.
Many have employed and utilized the technique of 31h-gland parathyroidec-
tomy in the management of four-gland disease. This spares a total of 30-50mg of
parathyroid tissue. Although success has been reported with this technique, there
are high rates of complications of recurrent or persistent hyperparathyroidism in
this population. Indeed, as many as 30%-50% of these patients have required
neck reexploration. Such procedures are technically more difficult than are initial
neck explorations and are associated with a far greater risk of recurrent laryngeal
nerve damage as well as prolonged permanent hypoparathyroidism [23-26].
These concerns led to the introduction, in 1976, of the application of parathyroid
autotransplantation for these patients [27]. This technique was developed as a
more effective means of dealing with patients with four-gland disease, which is so
often present in this population. Following identification and removal of all four
glands, one is divided into slivers of 1-2 mm which are implanted into the volar
aspect of the non dominant forearm marked with individual nonabsorbable
sutures. Postoperatively, once the patient is symptomatically hypocalcemic,
calcium and vitamin D are administered until graft function occurs - usually in
10-21 days [4, 28]. The success of the technique has been well documented and
can be successfully accomplished in almost all patients with no appreciable in-
cidence of late graft failure. Recurrence of hypercalcemia in familial hyper-
parathyroid patients is a difficult problem and occurs with this technique, too, but
it is far more safely and easily managed with graft removal from the forearm than
with neck reexploration, which is historically both hazardous and unsuccessful
[29]. Our approach to patients with MEA type II who have no biochemical evi-
dence of hyperparathyroidism, and in patients with MEA type lIB, has been that
of total thyroidectomy for their medullary carcinoma with preservation of the
parathyroid glands. We feel that if a total thyroidectomy cannot be performed
without jeopardizing the blood supply to the parathyroids, as is so often the case,
the parathyroids should be transplanted into the sternocleidomastoid muscle,
where they will function well. It is more important to accomplish the complete
thyroidectomy than it is to preserve the blood supply to the parathyroids in this
disorder, and the decision to transplant into the sternocleidomastoid muscle
should be made. On the basis of the fact that MEA type IIA patients seem to
have less "severe" parathyroid disease with a lower likelihood of recurrence, it
has been recommended that consideration be given to excision of the enlarged
parathyroid glands only, and that the patient not undergo an empiric 3 1/2-gland
parathyroidectomy or parathyroid autotransplant. It must be emphasized that, in
our view, there must be unequivocal histologic proof of normal parathyroid gland
anatomy before any consideration is given to employing this approach. As always,
individual consideration of each patient and each surgeon's training and expertise
are of paramount importance when designing the appropriate operative proce-
dure for any of these patients.
Parathyroid Surgery in Children 55
This is a rare and interesting disorder; at the time of our recent review, we found
29 cases reported in the world literature [30]. Neonatal primary hyperpara-
thyroidism uniformly presents within the first 3 months of life, usually at or
shortly following birth. The histologic finding in 100% of afflicted neonates is
hyperplasia of all four parathyroid glands. The predominant symptoms include
hypotonicity, respiratory distress, failure to thrive, constipation, anorexia, irri-
tability, lethargy, and polyuria. These babies often have impressive roentgeno-
grams demonstrating pathologic fractures as well as subperiosteal bone resorption
and osteoporosis. Although Goldman and Smith, in 1936, first recognized that
hyperparathyroidism could be familial, it was not proven until 1964, when Hill-
man et al. described neonatal primary hyperparathyroidism in two siblings born to
first-cousin parents [12, 31]. Since that time, it has become apparent that this
phenotpye can be inherited in an autosomal recessive fashion, and in our review
we found that approximately half of the affected infants reported had a familial
tendency toward hyperparathyroidism.
The differential diagnosis of neonatal hyperparathyroidism includes such dis-
orders as neonatal hyperparathyroidism associated with maternal hypoparathy-
roidism, idiopathic infantile hypercalcemia, subcutaneous fat necrosis, and blue
diaper syndrome [32-35]. Additionally, cases of hypercalcemia due to mesoblas-
tic nephroma have also been reported; the pathogenesis of the hypercalcemia in
these infants was felt to be prostaglandin E-related [36]. Whereas hypercalcemia
has frequently been reported as a sequela of cancer in adults, this is one of the few
instances where hypercalcemia (other than due to bone metastases) occurs in
infants with a malignancy. The serum calcium returns to normal following man-
agement of the mesoblastic nephroma.
Infants with neonatal primary hyperparathyroidism often seem to display a
clinical and biochemical phenotype similar to those with the FHH syndrome.
Their disease, however, is an exception to the usual benign nature of FHH which
is typically detected later in life, as afflicted babies are usually critically ill.
As medical management of neonatal primary hyperparathyroidism resulted in
near certain death, the severe nature of the illness in infants presenting with this
condition led to the recommendation for urgent parathyroidectomy. Subtotal 31/2-
gland parathyroidectomy was initially performed, but this, too, was found to be
unacceptable due to the almost uniform recurrence of disease. Whereas total
parathyroidectomy was later employed, it led to the need for lifelong replacement
of calcium and vitamin D, which is a difficult management problem. Due to a
basic dissatisfaction with these therapeutic options, we and two other groups have
utilized total parathyroidectomy with parathyroid autotransplantation when con-
fronted with neonates with this disorder [30, 37, 38]. All of the children have
responded successfully to this approach and have done well, leading us to recom-
mend total parathyroidectomy with parathyroid autotransplantation for the rare
neonate with primary hyperparathyroidism. A neonate of an FHH kindred is
reported for whom the illness was substantially less devastating than for most
56 A. J. Ross, III
Secondary Hyperparathyroidism
Tertiary Hyperparathyroidism
Parathyroid Allotransplantation
Of all indications for parathyroid surgery in children, those for parathyroid allo-
transplantation are the most uncommon. Some years ago it was believed that
parathyroid was an immunologically privileged tissue. This hypothesis was never
conclusively demonstrated and this has not been our experience clinically; we
have reported on a patient who had the rapid concurrent rejection of both his
renal and parathyroid allotransplants after 30 months of function [41]. Currently,
we feel that, at least in man, parathyroid tissue is not privileged immunologically,
and it seems that the pharmacologic immunosupression which would be required
for successful allotransplantation likely presents a potentially greater risk of mor-
bidity than the vitamin D and oral calcium replacement therapy required. On
the other hand, in the rarely encountered situation where hypoparathyroidism is
refractory to pharmacologic management, consideration should be given to para-
thyroid allotransplantation in the appropriately immunosuppressed host utilizing
a "match" of maximal tissue histocompatibility. For patients with DeGeorge's
syndrome, a disease characterized by absence of the pharyngeal pouch derivatives
(parathyroid and thymus), allotransplantation of the parathyroid glands could
theoretically be accomplished without immunosuppression. The other coincident
findings in such patients - for example, severe cardiac disease - have not en-
abled this hypothesis to be well tested in man.
References
1. Alveryd A (1968) Parathyroid glands in thyroid surgery. Acta Chir Scand [Suppl]389: 1-120
2. Akerstrom G, Malmaers J, Bergstrom R (1984) Surgical anatomy of human parathyroid
glands. Surgery 95: 14-21
3. Palmer FJ, Nelson JC, Bacchus H (1974) The chloride-phosphate ratio in hypercalcemia.
Ann Intern Med 80: 200-204
4. Wells SA Jr, Leight GS, Ross AJ III (1980) Primary hyperparathyroidism. In: Ravitch MM,
Steichen FM (eds) Current problems in surgery, vol 17. Yearbook Medical, Chicago, pp 397-
464
58 A.J.Ross, III
30. Ross Al III, Cooper A, Attie MF, Bishop HC (1986) Primary hyperparathyroidism in in-
fancy. 1 Pediatr Surg 21 :493-499
31. Hillman DA, Scriver CR, Pedvis S, et al (1964) Neonatal familial primary hyperpara-
thyroidism. N Engl 1 Med 270: 483-490
32. Landing BH, Kamoshita S (1970) Congenital hyperparathyroidism secondary to maternal
hypoparathyroidism. 1 Pediatr 77: 842-847
33. Forbes GB, Bryson MF, Manning 1, et al (1972) Impaired calcium homeostasis in the infan-
tile hypercalcemic syndrome. Acta Paediatr Scand 61: 305-309
34. Norwood-Galloway A, Lebwohl M, Phelps RG, Raucher H (1987) Sucutaneous fat necrosis
of the newborn with hypercalcemia. 1 Am Acad Dermatol 16: 435-439
35. Drummond KN, Michael AF, Ulstrom RA, et al (1964) The blue diaper syndrome: familial
hypercalcemia with nephrocalcinosis and indicanuria. Am 1 Med 37: 928-948
36. Vido L, Carli M, Rizzoni G, Calo L, Dalla Palma P, Parenti A, Fusco F (1986) Congen-
ital mesoblastic nephroma with hypercalcemia: pathogenetic role of prostaglandins. Am 1
Pediatr Hematol Oncol 8: 149-152
37. Cooper L, Wertheimer 1, Levey R, Brown E, Leboff M, Wilkinson R, Anast CS (1986)
Severe primary hyperparathyroidism in a neonate with two hypercalcemic parents: manage-
ment with parathyroidectomy and heterotopic autotransplantation. Pediatrics 78: 263-268
38. Lutz P, Kane 0, Pfersdorff A, Seiller F, Sauvage P, Levy 1M (1986) Neonatal primary hyper-
parathyroidism: total parathyroidectomy with autotransplantation of cryopreserved para-
thyroid tissue. Acta Paediatr Scand 75: 179-182
39. Page LA, Haddow IE (1987) Self-limited neonatal hyperparathyroidism in familial hypo-
calciuric hypercalcemia. 1 Pediatr 111: 261-264
40. Kinder BK, Rasmussen H (1985) New applications of total parathyroidectomy and auto-
transplantation: use in proximal renal tubular dysfunction. World 1 Surg 9: 156-164
41. Ross Al III, Dale IK, Gunnells IC, Wells SA Ir (1979) Parathyroid transplantation: fate of
a long-term allograft in man. Surgery 85 : 382-384
Current Status of Pancreatectomy
for Persistent Idiopathic Neonatal Hypoglycemia
Due to Islet Cell Dysplasia
R.M. Fillerl, M.J. Weinberg4, E. Cutz 2 , D. E. Wesson!, and R. M. Ehrlich 3
Summary
Zusammenfassung
Es wird eine Serie von 18 Kindem mit persistierender, idiopathischer neonataler Hypoglykamie
(PIN H) vorgestellt. Konservative und chirurgische Behandlungen werden detailliert beschrie-
ben. Bei allen Kindem, die operiert wurden, hatte die konservative Behandlung versagt. Diese
Patienten wurden in 2 Gruppen eingeteilt: 1) 85%-Pankreatektomie unter Zuriicklassung des
Processus uncinatus und 2) 95%-Pankreatektomie unter Zuriicklassung eines schmalen Saumes
von Pankreasgewebe entlang Duodenum und Ductus choledochus. Die Milz wurde in allen Fal-
len erhalten; 2 Kinder aus Gruppe 1 muBten sich einer weiteren Pankreasresektion unterziehen
und gelangten somit in Gruppe 2. Seit 1981 wird nur noch die 95 %-Pankreatektomie durchge-
fiihrt. Nur 1 Patient benotigte Insulin flir 3 Wochen nach der Operation. Histopathologie und Im-
munhistochemie ergaben eine Inselzelldysplasie und Inselzellkemhypertrophie in der Mehrzahl
der Falle. 35 % hatten eine fokale Adenomatose. Eine bessere Kontrolle der Hypoglykamien
wird durch die prim are 95%-Pankreatektomie erreicht, und deshalb wird die 95 %-Pankreatekto-
mie als primare Operation zur Behandlung der PINH empfohlen.
Resume
Les auteurs pn:\sentent une serie de 18 enfants atteints d' hypoglycemie idiopathique neonatale
persistante. Le traitement, tant medical que chirurgical est decrit en details. Dans le cas de tous
1 Department of Surgery,
2 Department of Pathology, and
JDepartment of Endocrinology, Hospital for Sick Children Toronto, Ontario, Canada.
4 University of Toronto, Toronto, Ontario, Canada.
les patients ayant subi une intervention chirurgicale, Ie traitement medical avait echoue. Ces
patients ont ete repartis en deux groupes: 1) pancreatectomie 11 85%, laissant en place Ie pro-
cessus uncinatus pancreatis et 2) pancreatectomie 11 95% laissant en place une etroite bordure de
tissu pancreatique Ie long du duodenum et du canal choledoque. La rate est restee en place dans
tous les cas. Deux des enfants du groupe 1 ont dfi subir une nouvelle resection du pancreas,
I'hypoglycemie persistant, passant ainsi dans Ie groupe 2 des pancreatectomies 11 95%. Depuis
1981, ce type d'intervention fut d'ailleurs Ie seul 11 etre utilise. Un seul patient eut besoin d'une
administration d'insuline durant les trois semaines suivant I'intervention. Dans la majorite des
cas, I'examen histopathologique et immunohistochimique revela une dysplasie des Hots et une
hypertrophie de leurs noyaux. 35% des patients presentaient une adenomatose focale. Le trait-
ment de choix de I'hypoglycemie reste donc la pancreatectomie a 95% qui doit etre Ie premier
geste therapeutique pour Ie traitement de I' hypoglycemie idiopathique neonatale persistante.
Introduction
Between 1977 and 1989, 18 children with PINH were seen (Table 1). Some of the
data from the first ten patients have been analyzed and reported previously [1, 9].
We include them in this report, since our current management is based on the
results of the management of those patients, and follow-up data will be presented.
There were 15 females and 3 males. Eight were neonates, and the others pre-
sented between 2 months and 11 months of age. Twelve presented with seizures,
one with irritability, one with blackout spells and four were asymptomatic. All pa-
tients were examined yearly, and growth parameters were measured, verbal and
motor skills were assessed and blood sugar levels were evaluated.
Medical Management
Surgical Management
All patients subjected to surgery had failed medical management. The patients
were divided retrospectively into two groups according to their initial operation.
Group 1 was treated by 85% pancreatectomy, leaving the uncinate process in situ
(Fig. la). Group 2 had a 95% pancreatectomy, leaving a small rim of pancreatic
tissue along the duodenum and common bile duct (Fig. Ib). The spleen was pre-
served in all cases, either by ligation of the pancreatic branches of the splenic ves-
sels or by mass ligation of the splenic artery (12 cases). In the latter situation the
splenic blood flow was from the short gastric vessels. Radionuclide spleen scans
were performed on all patients within 6 weeks of surgery and demonstrated nor-
mal splenic function in all.
Group I: 85% pancreatectomy. As noted in Table 1, cases 1-5 had 85% pan-
createctomy. One patient suffered severe neurological impairment. This was due
to poor preoperative blood sugar control and delay in instituting surgery. She was
normoglycemic postoperatively and died of pneumonia at age 3. Two of the five
children required a further resection and were converted to a 95% pancreatec-
64 R. M. Filler et al.
Group II: 95% pancreatectomy. Because of the relatively high incidence of failure
with lesser resections we have employed 95% pancreatectomy as the first surgical
procedure since 1981. To date 13 children have had 95% pancreatectomy. The
postoperative complications in this group included one mild would infection and
one patient with persistent obstruction of the common bile duct, eventually requiring
choledochoduodenostomy. Only one patient required insulin, which was discon-
tinued 3 weeks postoperatively. All these patients were well at the most recent follow-
up although case 12 had not been followed because the family resides outside of
Canada. The 95% resection failed to control hypoglycemia in three children. One
child had persistent hypoglycemia on the operating table and a near total pan-
createctomy was performed (case 13). Similarly, a second child had recurrent hypo-
glycemia and a near total pancreatectomy was necessary (case 11) 10 months after
the primary procedure. One child (case 12) required diazoxide postoperatively.
Pathology
Gross Findings
The pathological findings are summarized in Table 2 and Fig. 2. On gross exami-
nation, most resected pancreata showed no obvious abnormalities. However, in
three patients a single whitish-tan nodule « 1.0 cm) was identified either during
surgery or later by the pathologist. In two cases the nodule was located on the sur-
face of the pancreas, and in one case a 0.2-cm nodule embedded within the paren-
chyma was found after serial sectioning of the specimen. On microscopic exami-
nation, the nodule in each case was composed of islet cells mixed with exocrine
elements, forming an area of focal adenomatosis (see Fig. Sa).
100 (17)
(16)
80
60
%
Fig. 2. Distribution of pathology findings in 18
40
patients with persistent idiopathic neonatal hypo-
glycemia. Numbers in parentheses represent num-
20 bers of patients. lCD, Islet cell dysplasia;
NH, nuclear hypertrophy; FA, focal adenomatosis;
0 DA, diffuse adenomatosis
ICD
Current Status of Pancreatectomy for Persistent Idiopathic Neonatal Hypoglycemia 67
b
Fig. 3. a Low-magnification view of a section from patient 18, showing well-preserved exocrine
tissue and several irregular islets of Langerhans (pale areas) in a routine H & E stain. x 25.
b Similar field as in a, but immunostained with an antibody against insulin. Islet cells (darkly
stained) show positive reaction, with "ragged" islet shape and distribution, i.e., poorly defined
clusters. This abnormal distribution of islets is not apparent on a routine section. x 63
68 R. M. Filler et al.
Fig. 4. Higher magnification of islet cells with large, irregular "dysplastic" nuclei, an additional
feature of islet cell dysplasia (case 11). H & E, x 225
islet formation, (b) an increase in single and small endocrine cell clusters random-
ly distributed throughout exocrine tissue, (c) irregular islet cell contour ("ragged"
islets) and (d) islet cell nuclear hypertrophy. Although it is not known whether
these abnormalities are the basis for hypoglycemia, these lesions were found in
the majority of cases and were not observed in the normal postnatal pancreas.
Considerable variation in the extent and degree of these changes was noted be-
tween individual cases as well as within the same pancreas. In our series, diffuse
abnormal distribution of islets was seen in the majority of cases (94%), with the
exception of a single patient (case 10) in whom the endocrine pancreas appeared
histologically normal.
Islet cell nuclear hypertrophy as evidenced by large polyploid nuclei (2-6
times greater than normal) is another distinctive feature of ICD (Fig. 4). In our
Current Status of Pancreatectomy for Persistent Idiopathic Neonatal Hypoglycemia 69
b
Fig. 5. a Area of focal adenomatosis (case 7) with closely packed aggregates of insulin-producing
B cells. Immunostaining for insulin, x 63. b Section adjacent to that in a, immunostained for
glucagon showing x-cells at the periphery of B-cell aggregates, as in normal islets. x 63
70 R. M. Filler et al.
series, islet cell nuclear hypertrophy was observed in 88% of cases, although the
number and distribution of islet cells with large nuclei varied between cases (see
Table 2 and Fig. 2). While in some cases only occasional cells with large nuclei
were observed in a few islets, in others this change involved the majority of islets.
The predominant islet cells with hypertrophic nuclei appear to be insulin-produc-
ing B cells (Fig. 4), but occasional somatostatin-immunopositive D cells have been
shown to exhibit a similar change [10, 11]. On the other hand, glucagon-producing
A cells do not appear to be affected. The presence of nuclear hypertrophy is
generally considered a sign of cell hypertrophy and hyperfunction. In the case of
islet cell dysplasia, this change most likely reflects hypersecretion of insulin and
points to B cells as being the main abnormal element involved in this disorder.
Furthermore, the finding of hypertrophic islet cell nuclei is a useful diagnostic
marker of lCD, which is easily detected even on routinely stained sections
(Fig. 4).
Adenomatosis
The term adenomatosis refers to localized or diffuse proliferation of islet cells
which form a grossly and/or microscopically identifiable lesion (usually < 1 cm in
diameter). Microscopically, this lesion consists of a mixture of endocrine and
exocrine elements, including ductal and acinar structures. Focal adenomatosis
(microadenomatosis) is distinguished from a true adenoma by its heterogeneous
cell population, that of a true adenoma being made up exclusively of a single cell
type (e.g., a true insulinoma is composed of B cells only). In our series, six of 17
patients (35%) were found to have focal adenomatosis and two patients (12%)
had a diffuse lesion (see Table 2; Fig. 2). The notable features include areas of
neoformation of islets from ductal elements and the presence of acinar cells be-
tween the mass of endocrine cells (Fig. 5). The islet cells, however, maintain their
usual organization and arrangement, including peripheral placement of A and D
cells; i.e. a nodule of focal adenomatosis is composed of a cluster of well-defined
islets (Fig. 5). In cases with diffuse adenomatosis, the same changes as described
for the localized form a affect a large portion of the pancreas.
Focal adenomatosis and diffuse adenomatosis are considered to be the most
advanced lesions in the spectrum of islet cell dysplasia [10, 12, 13]. The practical
implication is that cases with diffuse disorganization of islets without adenomatosis
may potentially be amenable to nonsurgical treatment and may resolve as the
infant grows older, whereas for focal or diffuse adenomatosis surgical resection
remains the treatment of choice.
Discussion
Morphological changes in the endocrine pancreas of infants with PINH have been
the subject of several recent studies and reviews [10-14]. Systematic immuno-
histochemical studies, combined with electron microscopy, revealed several new
Current Status of Pancreatectomy for Persistent Idiopathic Neonatal Hypoglycemia 71
findings, leading to revision of previous notions of the underlying islet cell ab-
normalities. A revised terminology, together with new pathologic criteria for mor-
phological diagnosis of this disorder, has emerged. The previous term "nesidio-
blastosis" (neoformation of islets) has been replaced by "islet cell dysplasia", to
highlight specific pathologic features and to differentiate them from normal
developmental changes [10, 14]. The term islet cell dysplasia (endocrine cell dys-
plasia, nesidiodysplasia) encompasses a wide range of lesions which can be en-
countered singly or in combination, including diffuse abnormal distribution and
disorganization of islets, islet cell and islet hypertrophy and diffuse or focal prolif-
eration of islet cells (adenomatosis) [10, 12, 13]. Thus, while there is no general
agreement on terminology, it is widely acknowledged that this rather uniform
clinical entity is associated with heterogeneous pathologic changes. It is also be-
coming more evident that abnormal regulation of insulin secretion rather than
true neoplasia is the underlying abnormality.
The degree and duration of hypoglycemia tolerated by the CNS without per-
manent neurologic sequelae appear to very widely. Some infants can withstand
numerous episodes without significant deficit, while others with borderline hypo-
glycemia sustain severe deficits early in their course [15]. One factor that probably
influences the susceptibility of the CNS to hypoglycemia is the availability of alter-
native substrates such as ketone bodies, which the brain can use when glucose is
scarce. When hypoglycemia is associated with a relative hyperinsulinemia the
levels of insulin inhibit lipolysis and prevent the formation of ketone bodies. As a
result, infants with this cause of hypoglycemia are more apt to develop permanent
neurologic deficits than those with ketotic hypoglycemia.
Since 1934, when Graham and Hartman [17] resected 80% -90% of the pan-
creas in a l-year-old child with hypoglycemia, surgery has gained an increasingly
important place in the therapy of hypoglycemia secondary to various pancreatic
disorders [18]. As recently as 17 years ago, persistent neonatal hypoglycemia was
associated with neurologic and developmental morbidity in more than 50% of
cases [15], regardless of the extent of pancreatic resection. Thomas et al. [16]
reviewed 66 patients with intractable hypoglycemia and found that the delay
between diagnosis and surgery had been shorter in those with normal mental
development than in those with retarded postoperative and mental development.
The mean delay in patients with normal postoperative development was 6 months
compared with 10 months in patients with retardation, but the difference was not
statistically significant. The rather long delays before surgery may explain why the
overall incidence of mental retardation in the Thomas series was 52% .
When a pancreatectomy is undertaken, splenectomy is not advised. The in-
creased incidence of sepsis following splenectomy in infants and children is well
known, and the same procedure when accompanied by PINH seems to carry an
even greater risk. A review of 19 cases where spenectomy was undertaken dis-
closed seven patients (37%) who suffered infectious complications, with four
cases of overwhelming postsplenectomy sepsis reported [19]. An 85%-95%
pancreatic resection can be carefully performed with all pancreatic tributaries of
the splenic artery and vein ligated, thus preserving normal splenic perfusion.
72 R. M. Filler et a\.
Alternatively, the main splenic vessels may be ligated with careful preservation of
the short gastric vessels, which will maintain splenic viability.
Early reports of idiopathic neonatal hypoglycemia suggested that a subtotal re-
section of approximately 75% (to the level of the superior mesenteric artery)
should be performed [20, 21]. More recent evidence indicates that more extensive
resection is necessary to eliminate hypoglycemia and decrease the high failure rate
with neurologic sequelae following the traditional operation [1, 15, 18].
Clearly, if a discrete adenoma is found, then it must be removed. However, in
almost all cases no gross lesion is seen, and a decision must be made as to how
extensive a resection should be done [1]. The extent of pancreatectomy required
to achieve the euglycemic state has been debated. Preoperatively, the clinical
presentation, serum glucose and insulin levels, and the response to diazoxide are
of no predictive value as to the cause of hyperinsulinism [8]. Microscopic exami-
nation of frozen biopsy material obtained during the operative procedure when
the pancreas is grossly normal is generally inadequate to define the underlying
pathologic process [8]. Thus, the decision about the extent of resection is a
difficult one, and the surgeon must be guided solely by his or her philosophy and
experience [8].
Martin et al. [19] reviewed the complete literature in 1984, which consisted of
181 cases. In the group that underwent less than 80% pancreatectomy, almost half
of the patients required additional medical therapy to control persistent or re-
current hypoglycemia. In addition, one quarter required further pancreatectomy
because of persistent symptoms refractory to medical therapy [22-51]. These data
encouraged most surgeons to pursue a more aggressive initial surgical approach to
this condition. When 85%-95% pancreatectomy has been performed, control of
hypoglycemia has improved markedly. Of 63 cases reported in the literature, re-
operation was required in only 8%, and only 20% required additional medical
treatment [3, 19, 23, 29, 37,45, 52-60]. Diabetes was not a significant complica-
tion.
We have previously reviewed our own experience, and in a small consecutive
series we have compared pancreatectomy in the treatment of this disease [1, 9].
These results are reviewed earlier in this paper. Since there was no difference in
operative morbidity, mortality or long-term results (given that two of the five pa-
tients initially undergoing 85% pancreatectomy subsequently had more extensive
resections) and because there is better control of hypoglycemia with more exten-
sive resection, we now recommend 95% pancreatectomy as the initial procedure
of choice for these patients.
References
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Current Status of Pancreatectomy for Persistent Idiopathic Neonatal Hypoglycemia 73
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7. Vance JE, Stoll RW, Kitabchi AE, Williams RH, Wood FC Jr (1969) Nesidioblastosis in fa-
milial endocrine adenomatosis. JAMA 207: 1679-1682
8. Moosa AR, Baker L, Lavell-Jones M (1987) Hypoglycemic syndrome in infancy and child-
hood: a surgeon's perspective. West J Med 146: 585-588
9. Jacobs DG, Haka-Ikse K, Wesson DE, Filler RM, Sherwood G (1986) Growth and develop-
ment in patients operated on for islet cell dysplasia. J Pediatr Surg 21 (12) : 1184-1189
10. Jaffe R, Hashida Y, Yunis EJ (1980) Pancreatic pathology in hyperinsulinemic hypoglycemia
of infancy. Lab Invest 42: 356-365
11. Drut R. Drut RM (1987) An immunohistochemical study of islet cells with macronuclei in
infancy. Pediatr Pathol 7: 585-591
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of the pancreas. In: Falkner S, Hakanson R, Sundler F (eds) Evolution and tumor pathology
of the neuroendocrine system. Elsevier Science, Amsterdam, pp 349-370
13. Kloppel G, Sajons I, Schulte H, Nizze H, Andermatt HJ, Heitz PHU (1986) Focal and
diffuse nesidioblastosis and persistent hyperinsulinemic hypoglycemia: a morphologic analy-
sis of 12 patients. Pathologe 7: 266-275
14. Gould VE, Memoli VA, Dardi LE, Gould NS (1983) Nesidiodysplasia and nesidioblastosis
of infancy: structural and functional correlations with the syndrome of hyperinsulinemic
hypoglycemia. Pediatr Patholl: 7-31
15. Harken AH, Filler AM, Avruskin TW, Crigler SF (1971) The role of total pancreatectomy
in the treatment of unremitting hypoglycemia of infancy. J Pediatr Surg 6: 284-289
16. Thoms CG jr, Underwood LE, Carney CN, Dolcourt JL, Whitt JJ (1977) Neonatal and
infantile hypoglycemia due to insulin excess: new aspects of diagnosis and surgical manage-
ment. Ann Surg 185: 505-517
17. Graham EA, Hartmann AF (1934) Subtotal resection of pancreas for hypoglycemia. Surg
Gynecol Obstet 59: 474-479
18. Kramer JL, Bell MJ, DeSchryer K, Bower RL Ternberg JL, White NH (1982) Clinical and
histologic indications for extensive pancreatic resection in nesidioblastosis. Am 1 Surg 143:
116-119
19. Martin LW, Ryckman FC, Sheldon CA (1984) Experience with 95% pancreatectomy and
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20. Hamilton JP, Baker L, Kaye R, et al (1967) Subtotal pancreatectomy in the management of
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evidence of nesidioblastosis on the pancreas. Arch Dis Child 51: 528-531
48. Habbick BF, Cram RW, Miller KR (1977) Neonatal hypoglycemia resulting from islet cell
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50. Kramer lL, Bell Ml, DeSchryver K, et al (1982) Clinical and histologic indications for exten-
sive pancreatic resection in nesidioblastosis. Am 1 Surg 143: 116-119
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Current Status of Pancreatectomy for Persistent Idiopathic Neonatal Hypoglycemia 75
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Surgery for Nesidioblastosis -
Indications, Treatment and Results
B. Willberg 1 and E. Miillert
Summary
Nesidioblastosis is a life-threatening form of hypoglycemia that starts during the neonatal period
in most cases and is caused by hyperinsulinism. Its diagnostic criteria are an extremely high
demand for carbohydrates (more than 15 g/kg/day), an inadequately high plasma insulin level,
and an inhibited production of ketone bodies. This acute, life-threatening hypoglycemia requires
immediate intensive-care treatment. The most important aim of continuous therapy is the pre-
vention of irreversible brain damage. This cannot be reliably avoided by conservative treatment
(increased carbohydrate supply, diazoxide administration). Therefore, surgical treatment con-
sisting in subtotal pancreatectomy is becoming increasingly important. The reduction of hor-
mone-producing tissue resolves hyperinsulinism and apparently enables the onset of physio-
logical regulatory mechanisms. Surgical strategy and results in 12 children who underwent sur-
gery for nesidioblastosis are described.
Zusammenfassung
Resume
La nesidioblastose est une forme tres dangereuse d'hypoglycemie, survenant Ie plus souvent
durant la peri ode neonatale et causee par une hyperinsulinie. Le critere diagnostique est un besoin
extremement eleve en hydrates de carbone (plus de 15 g/kg/jour). un taux d'insuline trop eleve
dans Ie plasma et une inhibition de la production de cetones. L'hypoglycemie aigue, extreme-
ment dangereuse, exige une traitement immediat et intensif. Le but majeur de la therapeutique
continue est de prevenir un dommage cerebral irreversible. Le traitement conservateur (augmen-
tation de ['apport en hydrates de carbone, administration de diazoxide) n'est pas une garantie
suffisante. Le traitement chirurgical, donc la pancreatectomie subtotale, prend de plus en plus
d'importance. La reduction des tissus producteurs d'hormones resoud Ie probleme de l'hyper-
insulinie et met en place des mecanismes regulateurs physiologiques. La strategie chirurgicale
et les resultats obtenus dans Ie cas de 12 enfants ayant subi une intervention chirurgicale pour ne-
sidioblastose sont alors rapportes.
Introduction
Clinical Picture
irreversible brain damage with general retardation and cerebral convulsions is the
consequence. This is probably due to a decrease or lack of ketone bodies, which
are essential for brain development.
Carcassone et al. [3] differentiated between the more common infant type of
nesidioblastosis and a childhood type which does not become manifest until several
months of age. Laboratory data and prognosis are similar to those for the infant
type. The reasons for the late manifestation remain unknown. It may represent a
milder form temporarily compensated by alimentary influences. It must be kept in
mind that hypoglycemia as low as 30 mg% serum glucose may remain asymptoma-
tic in infants [3].
In some cases spontaneous interruption of hypoglycemic states between the
first and fourth year of life is observed. There are no prognostic criteria that
allow an estimation of when and whether the endocrine pancreatic function
normalizes.
Diagnosis
The following criteria are important for the diagnosis of insulin-induced hypo-
glycemia in infants and children:
Treatment
Due to the high standard of pediatric intensive care, the treatment of life-
threatening hypoglycemia is generally successful. It comprises high-dose paren-
teral glucose administration with serum glucose monitoring every 15 min and, if
necessary, administration of somatostatin at an average dose of a 250 Jlg/l. 73 m 2
body surface per hour [12].
Long-term therapy of nesidioblastosis is far more problematic; its central aim
is to avoid irreversible brain damage. Medical treatment of recurrent hypo-
glycemia alone, usually with diazoxide, is normally insufficient.
Surgery for Nesidioblastosis - Indications, Treatment and Results 79
Surgery
Our Series
From 1976 to 1985, 12 infants and children underwent subtotal pancreatectomy for
nesidioblastosis at the Department of Pediatric Surgery of the University of Dussel-
dorf. Ten patients were followed up for 9 months to 10 years postoperatively.
Siblings suffering from hypoglycemia were observed in three instances. Two of
them have died; the third sibling still has episodes of hypoglycemia at the age of
15 years and is mentally retarded.
Nine children presented with symptoms (cyanosis, apneic spells, hypotonia,
tremors, tonic-clonic convulsions) immediately after delivery; three children fell
ill at the ages of 4,6, and 7 months respectively.
Relative hyperinsulinism was shown in all cases. The compensatory carbo-
hydrate requirement was between 18 and 31 g/kg/day. Only one of the ten chil-
dren who received diazoxide prior to surgery was asymptomatic at operation on
the 13th day. All other children presented with symptomatic hypoglycemia de-
spite administration of high-dose carbohydrates and diazoxide.
Preoperatively, serum glucose was stabilized by administration of somatostat-
in for a maximum of 5 days in five instances. Two infants, operated on at the 16th
and 26th day of life respectively, were treated exclusively with somatostatin.
Five children presented preoperatively with marked, two with severe, psycho-
motor retardation. Four of these children required anticonvulsant therapy. Only
one of the children, whose development corresponded to its age, required anti-
convulsants (Table 1).
Four infants underwent subtotal pancreatectomy during the first 4 weeks of
life. Only three children were operated on beyond the first year of life, at 16, 31,
and 40 months respectively. Technically, surgical reduction of hormone-producing
pancreatic tissue was carried out as a four-fifths resection in two cases and as a
seven-eighths resection in the remaining cases. Pathohistological, immunocyto-
chemical, and electron-microscopical examinations confirmed the preoperative
diagnosis in all cases.
Intraoperative complications included accidental lesion of the splenic vein in
three instances; it was reconstructed in one case and ligated in the other two. The
spleen was preserved in every case. The remaining part of the pancreas was closed
using prolene-U sutures and additional Z sutures without additional ligation of
the pancreatic duct. No leakage was observed.
Postoperative surgical problems occurred only once, in the form of mechanical
ileus which necessitated relaparotomy 5 months following pancreatectomy. Dur-
ing the same session a hiatal hernia was repaired by means of a fundoplication.
The pancreatic remnant was unsuspicious. Because of postoperative sepsis in four
children, probably due to the central venous catheters, routine antibiotic therapy
was conducted for 10 days.
Ten children required insulin for 1-76 days postoperatively for transitory
hyperglycemia. None of the children, however, developed insulin-dependent
diabetes mellitus. Five of the children have a borderline or pathological glucose
tolerance. Insufficiency of the exocrine pancreas was not observed in any case.
Surgery for Nesidioblastosis - Indications, Treatment and Results 81
Table 1. Time of onset, conservative preoperative treatment, preoperative state, and age at
operation of 12 children with nesidioblastosis
After the end of insulin dependence, four children exhibited normal serum
glucose levels. Recurrent hypoglycemia was corrected by increasing carbohydrate
intake in three cases and required temporary diazoxide medication in another
four. In contrast to the preoperative course, diazoxide was successful in three
cases and failed in one. In this child, however, serum glucose levels normalized
spontaneously after a few months. The longest diazoxide dependence (12 months)
was in a child who had undergone resection of only four-fifths of the pancreas.
Pancreatectomy was unsuccessful in a boy already heavily retarded prior to sur-
gery at 31 months of age who suffered from severe, recurrent hypoglycemia up to
his 7th year, despite diazoxide medication.
The long-term results correlate closely with preoperative conditions as far as
general development is concerned. Seven of eight children who were normally de-
veloped preoperatively showed age-corresponding development postoperatively
as well. One child with slight retardation preoperatively made up for delayed
development postoperatively. However, severe retardation and already manifest
seizures did not improve by operation, even if serum glucose levels were normal
after surgery (Table 2).
Discussion
should be as small as feasible, but should render a secure closure of the stump. In
our opinion, primary total pancreatectomy is not indicated. Considering the
favorable results of subtotal pancreatectomy, a permanent, insulin-dependent
diabetes is not justifiable a priori. Only in cases where normalization of glucose
metabolism cannot be achieved by subtotal resection or by medical therapy may
total pancreatectomy be indicated as the ultima ratio [6, 11].
References
1. Aynsly-Green A, Polak JM, Bloom SR, Gough MH, Keeling J, Ashcroft SJH, Turner RC,
Baum JD (1981) Nesidioblastosis of the pancreas: definition of the syndrome and the man-
agement of the severe neonatal hyperinsulinaemic hypoglycaemia. Arch Dis Child 56: 496-
508
2. Bremer HJ (1983) Metabolisch bedingte Notfallsituationen des Neugeborenen. Monatsschr
Kinderheilkd 131: 317-320
3. Carcass one M, De Larue A, Le Tourneau IN (1983) Surgical treatment of organic pancreatic
hypoglycemia in the pediatric age. J Pediatr Surg 18: 75-79
4. Haberland R, Wil\berg B, Holschneider AM, Engelskirchen R, Gharib M (1988) Chirurgie
des endokrinen Pankreas. Z Kinderchir 43: 273-280
5. Laidlaw GF (1938) Nesidioblastoma, the islet tumor of the pancreas. Am J Pathol14: 125-
134
6. Martin LW, Ryckman FC, Sheldon CA (1984) Experience with 95% pancreatectomy and
splenic salvage for neonatal nesidioblastosis. Ann Surg 200: 355-362
7. Miiller E (1985) 14. International. Symposium der Osterreichischen Gesellschaft fiir Kinder-
chirurgie. Obergurgl, 28-30 January
8. Rahier J, Hilt K, Miintefering H, Becker K, Gepts W, Falkmer S (1984) The basic structural
lesion of the persistent neonatal hypo glycaemia with hyperinsulinism: deficiency of pancrea-
tic D cells or hyperactivity of B cells? Diabetologia 26: 282-289
9. Saul W, Willberg B, Bremer HJ (1984) Die chirurgische Therapie der Nesidioblastose. Z
Kinderchir 39 : 96-98
10. Schiller M, Krausz M, Meyer S, Lijovetzky G, Landau H (1980) Neonatal hyperinsulinismus
- surgical and pathologic considerations. J Pediatr Surg 15: 16-20
11. Simmons PS, Telander RL, Carney JA, Wold JE, Haymond MW (1984) Surgical manage-
ment of hyperinsulinemic hypoglycemia in children. Arch Surg 19: 520-525
12. Wendel U, Kardorff C, Dorittke P, Bremer HJ (1985) Somatostatin zur Notfallbehandlung
bei persistierenden Hypoglykamien aufgrund eines Hyperinsulinismus (Nesidioblastose des
Pankreas). Monatsschr Kinderheilkd 133: 527-531
Surgical Treatment of Nesidioblastosis in Childhood
J. Dobroschke 1 , R. Linder2, and A. Otten3
Summary
A review of the literature on the surgical treatment of nesidioblastosis in childhood was made to
answer the following questions: age at operation, surgical procedure, pathohistological findings,
incidence of recurrence and its treatment, as well as mortality. Primary subtotal pancreatectomy
appears to be the method of choice. It should be performed as early as possible following exact
diagnosis. Total pancreatectomy is reserved for treatment of a recurrence.
Zusammenfassung
Eine Literaturubersicht zur chirurgischen Behandlung der kindlichen Nesidioblastose soUte Klar-
heit zu folgenden Fragen schaffen: Alter bei Operation, Operationstechnik, pathohistologische
Befunde, Haufigkeit und Behandlung von Rezidiven und Letalitat. Als Methode der Wahl beim
Ersteingriff wird die subtotale Pankreatektomie angesehen. Diese soli nach exakter Diagnostik
so fruh wie moglich erfolgen. Die tot ale Pankreatektomie ist der Behandlung eines Rezidives
vorbehalten.
Une etude de la litterature sur Ie traitement chirurgical de la nesidioblastose des enfants devait
repondre aux questions suivantes: age lors de I'operation, technique chirurgicale, resultats histo-
pathologiques, frequence des recurrences, traitement et lethalite. II en ressort que la pancreat-
ectomie primaire subtotale est la methode de choix. EI\e doit etre pratiquee aussit6t que possible
apres l'etablissement du diagnostic. La pancreatectomie tot ale sera reservee au traitement d'une
recurrence.
Introduction
1 Krankenhaus der Barmherzigen Bruder, PrufeningerstraSe 86, D-8400 Regensburg (W), FRG.
2Klinik fur Aligemein- und Thoraxchirurgie am Zentrum flir Chirurgie, Anasthesiologie und
Urologie and
3Zentrum flir Kinderheilkunde, Justus-Liebig-Universitat GieSen, KlinikstraBe 29, D-6300
GieSen (W), FRG.
when choosing the best treatment in a given case. From the literature that has
appeared in the past 5 years we have collected a group of comparable cases [1,2,
4-11]. The important points were age at operation, surgical procedure, patho-
histological findings, and incidence, treatment and mortality of recurrence.
Age at Operation
The decision to operate is made in close cooperation with a skilled pediatric endo-
crinologist. Likewise, the time of surgery should be fixed with the endocrino-
logist. Both the indication and the date for surgery are usually clear when the
diagnosis has been made. In most instances this takes place within the first 2
months of life, at our institution in the third week (Table 1). Most infants who
were operated on later had undergone examinations at other clinics for cerebro-
organic diseases, similar to adult hyperinsulinism. If hypoglycemic states are
recognized only after 1 year or later, one should consider a solitary adenoma in
particular.
Surgical Procedure
Up to 2 months 28
2-6 months 13
6-12 months 4
Over 12 months 6
86 J. Dobroschke et a1.
Procedure No. of
patients
Fig. 2. Operative technique; mobilization of the pancreas with preservation of the spleen. Tail of
pancreas is lifted off and splenic vessels are dissected
Surgical Treatment of Nesidioblastosis in Childhood 87
Pathohistological Findings
Findings No. of
patients
Multifocal proliferation 46
Focal adenomatosis
Adenoma 3
Multifocal proliferation plus adenoma 2
Surgical Treatment of Nesidioblastosis in Childhood 89
Subtotal pancreatectomy
150 300
125 250
post-op 100 200
75 150
50 100
25 50
o 0
G.F. OS G.J.
1978 1980 1984 mg% ng/ml
Fig. 5. Pre- and postoperative levels of serum glucose and insulin in three children with nesidio-
blastosis treated at the Surgical Clinic of the University of GieBen
development has been normal without insulin substitution. Only during the first
6 postoperative months was substitution with exocrine pancreatic enzymes neces-
sary.
By means of collagenase digestion, microfragments of Langerhans islets were
extracted from the resection specimen of the child who was operated (Fig. 6).
0>
ui
-;
~ Op.
w
-;
I
co
'"
2 3 I. 5 6 7 8 9 10 11 12
Wochen
Fig. 7. Insulin requirement of a 45-year-old diabetic prior to and following islet cell transplanta-
tion. f.E. tgl, IU daily
Surgical Treatment of Nesidioblastosis in Childhood 91
These were injected for treatment of diabetes into the spleen of a 45-year-old
diabetic patient who had undergone kidney transplantation 4 weeks earlier
[3]. Four weeks later, at least a partial effect of the transplant was seen. For a
further 6 weeks, this patient required only half of the insulin dose which had been
necessary preoperatively (Fig. 7). However, his insulin requirement increased
again thereafter. The transplanted Langerhans islets fell victim to either rejection
or fibrosis.
To summarize, it can be stated that subtotal pancreatectomy is the method of
choice for treatment of nesidioblastosis in childhood. The operation should be
carried out as soon as possible after establishment of the diagnosis. Total pan-
createctomy should be reserved for the treatment of recurrence.
References
1. Aynsley-Green A, Polak JM, Bloom SR, Gouch MH, Keeling J, Ashcroft SJH, Turner RC,
Baum JD (1981) Nesidioblastasis of the pancreas: definition of the syndrome and the man-
agement of the severe neonatal hyperinsulinaemic hypo glycaemia. Arch Dis Child 56: 496-
508
2. Bindewald H, Heinze E, Merkle P (1982) Chirurgische Therapie der Nesidioblastosis im
Kindesalter. Langenbecks Arch Chir 356: 299-302
3. Dobroschke J, Schwemmle K, Langhoff G, Bretzel RG (1983) Allotransplantation of
neonatal pancreas-microfragments in man. Horm Metab Res [Suppl]13 : 91-93
4. Gough MH (1984) The surgical treatment of hyperinsulinism in infancy and childhood. Br J
Surg 71 : 75-78
5. Jeschke R, Romen W, Thanner F, Niggemeyer H (1978) Zum Krankheitsbild der diffusen,
nesidioblastischen Inselhyperplasie im Neugebarenen- und Sauglingsalter. Klin Padiatr 191 :
403-411
6. Kramer JL, Bell MJ, DeSchryver K, Bower RJ, Ternberg JL, White NH (1981) Clinical and
histologic indications for extensive pancreatic resection in nesidioblastosis. AQm J Surg 143:
116-119
7. Landau H, Perlman M, Meyer S, Isacsohn M, Krausz M, Mayan H, Lijovetzky G, Schiller
M (1982) Persistent neonatal hypoglycemia due to hyperinsulinism: medical aspects. Pedia-
trics 70: 440-446
8. Lloyd RV, Caceres V, Warner TFCS, Gilbert EF (1981) Islet cell adenomatosis. A report of
two cases and review of the literature. Arch Pathal Lab Med 105: 198-202
9. Moazam F, Rodgers BM, Talbert JL, Rosenbloom AL (1982) Near-total pancreatectomy in
persistent infantile hypoglycemia. Arch Surg 117: 1151-1154
10. Rahier J, Fait K, Milntefering H, Becker K, Gepts W, Falkmer S (1984) The basic structural
lesion of persistent neonatal hypo glycaemia with hyperinsulinism: deficiency of pancreatic D
cells or hyperactivity of B cells? Diabetologia 26: 282-289
11. Tiipke B, Menzel K, Kasper JM (1985) Nesidioblastose - eine seltene Ursache kongenitaler
persistierender Hyperglykamien. Kinderarztl Prax 53: 291-295
Total Pancreatectomy in a Case of Nesidioblastosis
Due to Persisting Hyperinsulinism
Following Subtotal Pancreatectomy
P. Dohrmann, W.Mengel, and J. Splieth
Summary
Zusammenfassung
Bei einem 6410 g schweren Neugeborenen persistierte eine Hypoglykamie mit Hyperinsulinismus
trotz hochdosierter Diazoxid- und Glukagonbehandlung sowie Glukoseinfusionen und Somato-
statininfusion. Nachdem laborchemisch die Diagnose einer Nesidioblastose gestellt wurde,
erfolgte primar die subtotale Pankreasresektion. Bei anhaltenden therapieresistenten Hypoglyk-
amien erfolgte 6 Wochen spater die tot ale Pankreatektomie unter Erhaltung des Duodenums und
des Ductus choledochus. Das nunmehr 63/4 Jahre alte Kind hat sich unter Insulin- und Pankreon-
substitution altersentsprechend normal entwickelt.
Resume
Chez un nouveau-ne pesant 6410 g, on constatait une hypoglycemie persistante et une hyper-
insulinie en depit de I'administration it hautes doses de diazoxide et de glucagon et de perfusions
de glucose et de somatostatine. Les resultats de l'examen en laboratoire ayant confirme Ie
diagnostic de nesidioblastose, l'enfant subit d'abord une pancreatectomie subtotale puis, six
semaines plus tard, une pancreatectomie totale, conservant Ie duodenum et Ie canal choledoque
car I'hypoglycemie resistait au traitement. Cet enfant, qui a maintenant 6 ans et 9 mois, est traite
avec une substitution d'insuline et de pancreatine, et sa croissance et son developpement sont
normaux pour son age.
Introduction
Department of General Surgery, Pediatric Surgery, Arnold-Heller StraBe 7, D-2300 Kiel1 (W),
FRG.
nounced proliferation of B cells which are spread diffusely over the entire pan-
creas [2, 5, 7]. A clinical sign during the first days of life is severe hypoglycemia
that can hardly be influenced by drugs. This results in an increased spasmophilia,
which causes infantile brain damage if treated inadequately.
Persisting uncontrollable hypoglycemia and demonstrated hyperinsulinism are
indications for surgical intervention. A subtotal pancreatectomy preserving only a
narrow pancreatic rest on the duodenal C is the procedure of choice. In a case of
persisting resistance to therapy a total pancreatectomy is necessary, and when
performing this operation it is possible to preserve the duodenum and the
choledochus. Based on a case of ours, these aspects are presented and reported
in the following.
Case Report
The little girl we treated is the second child of a healthy mother. The infant, de-
livered by cesarean section, had a birth weight of 6410 g and measured 60 cm in
length (Fig. 1). Pronounced adiposity and hypertrichosis were evident; the infant
also suffered from cardiac insufficiency. Apnea and a convulsive fit with a blood-
sugar value below lOmg/dl occurred shortly after delivery. The further develop-
ment was characterized by therapy-resistant hypoglycemia which persisted despite
glucose infusion rates of up to 10 mg/kg body wt.lmin and the additional adminis-
tration of prednisone and diazoxide. Since the laboratory findings (insulin-glucose
quotient, lacking suppression of insulin in the epinephrine test, somatostatin test)
were indicative of nesidioblastosis, surgery was decided upon at the age of 6
weeks.
A subtotal pancreatectomy was performed at first, leaving only an extremely
narrow parenchymal rest in the duodenal C. The postoperative course was un-
complicated. After initial, short-term attacks of hyperglycemia, the condition de-
veloped once again on the 10th day. The maximum utilization of conservative
treatment was unsuccessful; even high doses of somatostatin did not satisfactorily
control the hypoglycemia. Thus, it proved necessary to perform a relaparotomy
and to remove the remaining parenchyma as in a total pancreatectomy. It was
possible to resect the remaining pancreatic tissue while preserving the duodenum
and the bile duct. The postoperative course once again was uncomplicated. As
had been expected, diabetes mellitus developed, requiring a daily insulin dose of
0.2 units/kg.
The histological findings confirmed the nesidioblastosis, with a pronounced
multiplication of the B cells, an islet cell proliferation from epithelial cells along
the efferent ducts, and a slight polymorphism and hypochromasia of the nuclei.
During the further development the cardiac insufficiency returned to normal and
both adiposity and hirsutism regressed. Convulsive fits were no longer observed.
By now, the patient is 6 years and 9 months of age (Fig. 2)and has had regular
check-ups. The child receives pancreatic enzymes and insulin, and her somatic-
psychosomatic development is normal.
94 P. Dohrmann et al.
Fig. 2. The same child at 6 years and 9 months after total pan-
createctomy
Discussion
References
1. Dobroschke J, Linder R, Otten A (1986) Chirurgische Behandlung der kindlichen Nesidio-
blastose. Arbeitsgemeinschaft Chirurgische Endokrinologie 5th Symposium, 19-20 Sept,
Hamburg
2. Dutrillaux MC, Hollande E, Roze C (1979) Occurrence and cytodifferentiation of muco-
polysaccharide-secreting cells in the pancreas of children with nesidioblastosis. Virchows
Arch [B]30: 195-208
3. Goudswaard WB, Zwiestra RP, Houthoff HJ, Rouwe C, Kootstra G (1984) Surgical treat-
ment of organic hyperinsulinism in infancy. Surgical procedure in the absence of a demon-
strable insulinoma and a peroperative diagnosis of nesidioblastosis. Z Kinderchir 39: 91-95
4. Harken AH, Filler RM, AvRuskin TW, Crigler JF (1971) The role of "total" pancreatectomy
in the treatment of unremitting hypoglycemia of infancy. J Pediatr Surg 6: 284-289
5. Kltippel G (1981) Spezielle pathologische Anatomie. Pathologie der endokrinen Organe.
Springer, Berlin Heidelberg New York, pp 618-728
6. Morger R (1983) Surgical operations on pancreas in malignant disease in children. In: Rick-
ham PP, Hecker WCh, Prevot J (eds) Progress in pediatric surgery. Endocrine disorders and
tumors in children, vol 16. Urban & Schwarzenberg, Baltimore, pp 63-70
7. Schwarz SS, Rich BH, Lucky AW, Straus FH, Gonen B, Wolfsdorf J, Thorb FW, Burrington
JD, Madden JD, Rubenstein A, Rosenfield AH (1979) Familial nesidioblastosis: severe
neonatal hypoglycemia in two families. J Pediatr 95 :44-53
8. Thomas CG, Underwood LE, Carney CN, Dolcourt JL, Whitt JJ (1977) Neonatal and infan-
tile hypoglycemia due to insulin excess: new aspects of diagnosis and surgical management.
Ann Surg 185:506-517
9. Willberg B (1986) Kindliche Nesidioblastose - Chirurgische Therapie. Arbeitsgemeinschaft
Chirurgische Endokrinologie 5th Symposium, 19-20 Sept, Hamburg
10. Zuppinger K (1983) Disorders of the endocrine pancreas. In: Rickham PP, Hecker WCh,
Prevot J (eds) Progress in pediatric surgery. Endocrine disorders and tumors in children, vol
16. Urban and Schwarzenberg, Baltimore, pp 51-61
Pancreatic Head Tumor in a Child
C.Deindl
Summary
A 13-year-old girl with pancreatic head tumor required a pancreatoduodenectomy (Whipple pro-
cedure). Pathohistological examination disclosed a pancreatic apudoma. The characteristics of
this very rare tumor, its symptoms and treatment are described.
Zusammeufassung
Es wird tiber ein 13jahriges Madchen mit einem Pankreaskopftumor berichtet, der eine Duo-
denopankreatektomie (Whipple-Operation) erforderlich machte. Die pathohistologische Unter-
suchung ergab ein Apudom des Pankreas. Die Charakteristika dieses sehr seltenen Tumors sowie
Symptome und Behandlung werden beschrieben.
Resume
Une fillette de 13 ans present ant une tumeur de la tete du pancreas a subi une pancreatectomie
et duodenectomie associee (operation de Whipple). L'examen histopathologique revel a un
apudome pancreatique. Les caracteristiques de cette tumeur extremement rare, les symptomes et
Ie traitement sont decrits.
Pediatric Surgical Clinic (Dir. Prof. Dr. 1. Joppich), Dr. von Haunersches Kinderspital of the
University of Munich, LindwurmstraBe 4, D-8000 Munich 2 (W), FRG.
duodenal wall. The common bile duct was not involved and resection borders
were tumor free. Microscopically, tumor nodules with follicular structure but
without cell atypia or mitosis were found (Fig. 3). The edges of the tumor con-
tained normal exocrine pancreatic tissue and a pseudocapsule. A destructive in-
filtration of surrounding tissues was not shown.
Immunohistological investigations disclosed a faint antibody reaction against
somatostatin, the tumor thus representing a somatostatinoma. Somatostatinomas
typically do not cause clinical symptoms [19]. Immunohistological reactions with
gastrin, serotonin, pancreatic polypeptides, insulin and glucagon were negative.
Electron microscopy revealed numerous intracellular granules.
Thus, this endocrine pancreatic head tumor was a so-called pancreatic
apudoma, or carcinoid [11, 20]. The origin of the tumor is the APUD cells (amine
precursor uptake and decarboxylation cells), first described by Pearse in 1968
[21]. Apudomas are very rare, with a postmortem incidence under 1% [10]. There
98 C.Deindl
References
26. Roher HD, Branscheid D (1986) Multiple endokrine Neoplasien - MEN Typ I und II - in
klinischer Erscheinung, diagnostischer und chirurgisch-therapeutischer Strategie. Chirurg
57:533-540
27. Rothmund M, Riickert K, Beyer J (1986) Insulinome und seltene endokrine Pankreastumo-
reno Chirurg 55: 541-551
28. Silverman A, Roy CC (1983) Pancreastumor. In: Silverman A, Roy Cc. Pediatric clinical
gastroenterology, 3rd edn. Mosby, St. Louis, pp 490-493
29. Wilander E, Sundstrom C, Meurling S, Grotte G (1976) A highly differentiated exocrine
pancreatic tumor in a young boy. Acta Paediatr Scand 65: 769-772
30. Wood SM, Polak JM, Polak SR (1983) Gastrointestinal endocrine tumors. In: Hodgson HJ,
Bloom SR, (eds) Gastrointestinal and hepatobiliary cancer. Chapman Hall, London, pp 207
Pheochromocytoma in Childhood
E. W. Fonkalsrud
Summary
Zusammenfassung
Phaochromozytome sind bei Kindem seltene Tumoren und sind flir nur 1 % der Hypertoniefalle
in dieser Altersgruppe verantwortlich. Bei Kindem liegen haufig bilaterale, multiple oder extra-
adrenale Tumoren vor, die zudem selten maligne sind. Praoperativ verabreichte a- und ~
Blocker haben die Komplikationsrate betrachtlich gesenkt. Die transabdominelle Resektion wird
empfohlen wegen der haufigen extra adrenal en Lokalisation und Multizentrizitat bei Kindem.
Die Operationsletalitat des Phaochromozytoms im Kinderalter liegt derzeit unter 3 % .
Resume
Le pheochromocytome est une tumeur rare chez les enfants, responsable de 1% des cas d'hyper-
tension a cet age. Les enfants presentent un certain nombre de tumeurs bilaterales, multiples ou
situees hors de la glande surrenale et peu de tumerus malignes. L'administration d' alpha- et de
betabloquants avant I'operation reduit considerablement les complications. II est recommande de
pratiquer une resection transabdominale car Ie siege est souvent hors de la glande surrenale et la
tumeur, multifocale chez les enfants. La mortalite due a la resection des pheochromocytomes
chez les enfants a I'heure actuelle de mains de 3%.
Introduction
Although Frankel [1], in 1886, reported the first case of a hypertensive syndrome
with retinitis and bilateral adrenal tumors in an 18-year-old girl, it was not until
1922 that a clear relation between paroxysmal hypertension and adrenal medul-
lary tumors was established by Labbe et al. [2]. In 1912, Pick [3] named the tumor
for its predominant cell, the pheochromocyte.
Division of Pediatric Surgery, UCLA School of Medicine, Los Angeles, CA 90024, USA.
Symptoms
The average age at the onset of signs and symptoms in children is 9.5 years.
Tumors arising in the adrenal medulla produce both epinephrine and norepi-
nephrine, whereas most extra-adrenal pheochromocytomas produce only nor-
epinephrine. The catecholamines released by the tumors may directly or indi-
rectly activate that alpha- and/or beta-adrenergic receptors, resulting in apprehen-
sion, hypertension, tachycardia, diaphoresis, evidence of increased metabolism,
constipation, gastrointestinal bleeding, and other symptoms. A functioning
pheochromocytoma usually causes sustained hypertension in children, in contrast
to adults, who generally have paroxysmal elevations of blood pressure. Episodes
of tachycardia, systolic hypertension, and arrhythmias reflect the muscular beta-
receptor effects of epinephrine secretion, whereas bradycardia and diastolic
hypertension are evidence of increased peripheral vasoconstriction by alpha-
receptors from circulating norepinephrine. A contracted vascular system often re-
sults, owing to decreased plasma volume, reduced red cell mass, and occasionally,
orthostatic hypotension [10]. Norepinephrine is predominantly alpha in effect,
whereas epinephrine elicits a mixture of alpha and beta actions. The majority of
childhood pheochromocytomas contain, but do not secrete, substantial quantities
of dopamine, which is primarily a beta-stimulator. The relative proportions of
norepinephrine and epinephrine may influence the signs and symptoms produced
by pheochromocytomas [11]. In general, higher levels of norepinephrine are en-
countered in most childhood tumors, possibly reflecting a higher incidence of
extra-adrenal pheochromocytomas, which do not possess the capacity for methy-
lation of norepinephrine.
The onset of symptoms in children is often rapid, with diaphoresis unrelated to
environmental temperature, usually preceded by pallor. Throbbing headaches
Pheochromocytoma in Childhood 105
with flushing may occur, and hands may show a puffy redness, cyanosis, and mott-
ling. Elevated body temperature, dilated pupils, and heat intolerance may be-
come evident. Weight loss is common, despite a ravenous appetite. Occasionally,
substernal, precordial, abdominal, lumbar, or femoral pain may be present as a
constant or colicky symptom. Epistaxis, hematemesis, melena, nausea and vomit-
ing may be associated with abdominal pain, which may simulate or actually be
caused by colitis or appendicitis [12]. Partial intestinal obstruction may stem from
fecal impaction. Polyuria, polydipsia, microscopic hematuria, and glycosuria with
elevated fasting blood sugar levels are typical of pheochromocytoma in children
and adults. Convulsions and coma may occasionally result from hypertensive
encephalopathy, and vision may be blurred by hypertensive retinitis. Despite
these alarming symptoms, sudden death due to pheochromocytoma is uncommon
in childhood. Peripheral vasoconstriction, bradycardia, and sweating characterize
the alpha effects, while the beta effects include tachycardia, increased cardiac
contractile force, bronchodilatation, and peripheral vasodilatation with lowered
diastolic blood pressure.
Hypertension from pheochromocytomas may be differentiated from that due
to coarctation of the aorta by the presence of bounding femoral pulses in pheo-
chromocytoma. Many renal lesions, including intrinsic and extrinsic tumors, uni-
lateral and bilateral pyelonephritis, glomerulonephritis, and renal artery stenosis
may be associated with hypertension in childhood. Urinalysis, renal function
studies, MRI scan, and arteriography can, in most cases, distinguish these condi-
tions from pheochromocytoma. Other causes of hypertension in childhood that
should be differentiated from pheochromocytoma are hyperthyroidism, adreno-
genital syndrome, Cushing's syndrome, acrodynia, brain tumor, lead poisoning
and essential hypertension. In children with paroxysmal hypertension, the diag-
nosis of familial autonomic dysfunction (Riley-Day syndrome) should be ruled
out.
Approximately 10% of childhood pheochromocytomas are familial, four times
the frequency in adults. This familial occurrence has been noted in a variety of
syndromes that are attributed to genetic derangements of neural crest derivatives.
The common cell origin of a number of endocrine tumors was regarded by Pearse
as a part of the neuroendocrine group; on the basis of the function of the cells, he
termed these "APUD tumors" (amine precursor uptake and decarboxylation)
[13]. These cells are believed to be totipotential, migratory, and capable of secret-
ing a variety of polypeptide hormones [14].
Sipple's syndrome, multiple endocrine adenomatosis II (MEA II), and mul-
tiple endocrine neoplasia (MEN II) are genetic disorders involving multifocal
tumor formation in the system of polypeptide-secreting cells. Their expressions
can include pheochromocytoma, medullary carcinoma of the thyroid, parathyroid
hyperplasia or tumors, and multiple mucosal neuromas [14]. The neuroma associ-
ated with Sipple's syndrome develops primarily in the lip and is a true neuroma
rather than the nerve sheath tumor that characterizes Recklinghausen's disease.
Patients whose disease complex is characterized by medullary carcinoma of the
thyroid, by pheochromocytoma, by multiple mucosal neuroma of the lips, tongue
106 E. W. Fonkalsrud
and upper eyelids, and by pathognomonic facies are subclassified as MEA lIb
[15]. These patients also commonly have a marfanoid habitus. The only true clin-
ical overlap with Recklinghausen's neurofibromatosis is the association of pheo-
chromocytoma, usually bilateral.
Adrenal medullary hyperplasia has been documented as a probable precursor
of pheochromocytoma in the MEA II syndrome [16]. Serum calcitonin determina-
tions have been used for screening potential MEA II patients for medullary
thyroid cancers. In occult cases, the pentagastrin-stimulation test of calcitonin
secretion may prove more reliable [11]. The association of pheochromocytoma
with parathyroid hyperplasia or adenomas in the MEA II syndrome may be
secondary or compensatory in nature, representing reactive stimulation of the
parathyroid to maintain normal calcium concentrations in response to the calcium-
lowering effects of calcitonin.
Approximately 4% of patients with pheochromocytomas have accompanying
neurocutaneous syndromes, including Recklinghausen's disease, tuberous sclero-
sis, Sturge-Weber syndrome, and von Rippel-Lindau disease [15]. The 12% inci-
dence of other anomalies in such children's families (hydrocephalus, neurofibromas,
ganglioneuromas, megacolon megaureter, cryptorchidism) suggests a genetic trait
having characteristics of a malformation syndrome. The incidence of pheo-
chromocytoma is increased in patients suffering from congenital heart disease.
Diagnostic studies
Fig.I. Left renal arteriogram showing arterial circulation to large left adrenal pheochromo-
cytoma
tensive patient. The phentolamine (Regitine) test is useful only in patients with
sustained hypertension and should rarely be used. A positive result produces a
25-35 mmHg fall of pressure within 5-10 min after intravenous injection of 5 mg
Regitine.
During the past few years, direct chemical methods of measuring catechol-
amine levels and metabolites in plasma have largely replaced the indirect phar-
macologic tests. Catecholamine secretion is initiated by acetylcholine released
from neurons that embrace the secretory cell. After a brief period of activity in
the circulation, these catecholamines are reduced by oxidation to 3-methoxy,
4-hydroxy-mandelic acid (VMA). Only 2%-4% of norepinephrine and epi-
nephrine is excreted directly into the urine, whereas more than one third of the
total secreted catecholamine appears as VMA and one half is excreted as free or
conjugated metanephrines [18]. A direct linear relation between the rate of uri-
nary excretion of VMA and the size of a pheochromocytoma has been reported
[19]. Because of their higher concentrations, urinary assays for the metabolites of
the epinephrine or norepinephrine has proved easier and more reliable. A pheo-
chromocytoma may be localized by determining catecholamine levels in blood
samples obtained at various levels in the inferior vena cava when not identified by
MRI studies.
The most commonly used diagnostic tests in children are 24-h collections of
urine for free catecholamines, VMA, and metanephrines. For screening pur-
108 E. W. Fonkalsrud
poses, overnight urine collection can be used. The catecholamine quantities are
modified by the amount of creatinine in the sample. When the total catechol-
amine level is normal, epinephrine-norepinephrine fractionation has proved
highly reliable [20]. An increased epinephrine fraction (> 20%) may help in iden-
tifying a pheochromocytoma. Although VMA assays are widely available, they
are subject to interference from various medications and dietary components.
Assays of urinary catecholamines and VMA have been associated with an approx-
imate 25% incidence of false-negative findings, whereas such results occurred in
only 4% of metanephrine determinations. Measurement of urinary homovanillic
acid (HVA), the major end product of dopamine metabolism, may help to diag-
nose malignant dopamine-secreting pheochromocytomas. Patients with neuro-
blastoma characteristically secrete high levels of dopamine metabolites.
Measurement of plasma catecholamines by radioisotope enzyme assay may be
more effective than either 24-h urinary VMA or metanephrine determinations
[21]. Patients must remain supine while blood samples are obtained; nonetheless,
the catecholamine assay offers the major advantage of obviating 24-h urine collec-
tion, which can be difficult in young children.
Plasma renin activity may increase in approximately 70% of patients with
pheochromocytomas, possibly leading to an erroneous diagnosis of renal artery
stenosis in children.
Treatment
to avoid flooding the circulation with excess catecholamines. The tumor is usually
encapsulated and may have small remnants of normal adrenal tissue contiguous
with it. The entire adrenal gland should be removed. Pheochromocytomas rarely
adhere to the kidney, so that a concomitant nephrectomy is seldom required.
Clear visualization and exploration of the contralateral adrenal gland is manda-
tory for all children because of the high incidence of bilateral tumors. When the
adrenal veins are divided and the pheochromocytoma is removed, hypotension
usually ensues, requiring a norepinephrine infusion for varying periods of time,
ranging up to several days. The reduced blood volume resulting from long-term
catecholamine secretion should be corrected by appropriate transfusions of
plasma, albumin, blood, or electrolyte solutions, as indicated. Adrenocortical in-
sufficiency is unlikely if the major portion of one adrenal gland is left in place. If
both adrenals are removed, or if the remaining gland is atrophic, intravenous
hydrocortisone should be given promptly.
In the occasional child the blood pressure may not return to a normal level for
several days after tumor removal. In our clinical experience with resection of
pheochromocytomas in 17 children, when blood pressure failed to normalize with-
in 2-3 weeks, or when hypertension returned, a second tumor was often found.
Hypertension due to a second pheochromocytoma is apt to occur within 5 years
subsequent to removal of the initial tumor. Children who undergo resection of the
pheochromocytoma should have follow-up examinations at least twice annually,
including measurement of blood pressure and urine catecholamine determina-
tions. The progeny and siblings of patients with pheochromocytoma should also
be periodically evaluated for hypertension because of the high familial incidence.
Although malignancy of pheochromocytomas is approximately 10% in adults,
it is uncommon in children and is usually diagnosed by the finding of distant non-
functioning metastases. On the basis of its histology, it is difficult to predict
whether a pheochromocytoma in a child will behave as a malignant tumor, since
pleomorphism and lymphatic, vascular, and capsular invasion are frequently evi-
dent. A combination of local excision, radiation, chemotherapy, and antiadren-
ergic agents has provided symptomatic palliation for many years in these rare
patients. Complete cure is difficult to achieve.
References
1. Frankel F (1986) Ein Fall von doppelseitigen, vollig latent verlaufenen Nebennierentumor
und gleichzeitiger Nephritis mit Veranderungen am Circulationsapparat und Retinitis. Arch
Pathol Anat 103: 244-249
2. Labbe M, Tinel J, Doumer A (1922) Crises solaires et hypertension paroxysmique en rapport
avec une tumeur surrenale. Bull Soc Med Hop Paris 46: 982-987
3. Pick L (1912) Das Ganglioma Embryonale Sympathicum. Klin Wochenschr 19: 16-22
4. Kremer DN (1936) Medullary tumor of the adrenal glands. Arch Intern Med 57: 999-1005
5. Stackpole RH, Melicow MM, Uson SC (1963) Pheochromocytoma in children: report of nine
cases with follow-up studies. J Pediatr Surg 63: 314-319
6. Kvale WF, Roth GM, Manager WM, et al (1957) Present-day diagnosis and treatment of
pheochromocytoma. JAMA 164: 854-860
Pheochromocytoma in Childhood 111
7. Hume DM (1960) Pheochromocytoma in the adult and in the child. Am J Surg 99 :458-466
8. Bloom DA, Fonkalsrud EW (1974) Surgical management of pheochromocytoma in children.
J Pediatr Surg 9: 179-184
9. Gibbs MK, Carney JA, Hayles AB, et al (1977) Simultaneous adrenal and cerivcal pheo-
chromocytomas in childhood. Ann Surg 185 :273-278
10. Brunjes J, Johns VJ Jr, Crane MD (1960) Pheochromocytoma: postoperative shock and
blood volume. N Engl J Med 262: 393-397
11. Dibbins A W, Wiener ES (1973) Retroperitoneal tumors in children. CUIT Probl Surg 10
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Surgical Treatment of Ovarian Tumors in Childhood
M. G. Schwobel and U. G. Stauffer
Summary
From 1971 to 1988,45 girls aged 1 week to 17 years were treated for a total of 46 solid and cystic
tumors of the ovaries. Pathohistological examination revealed epithelial tumors in eight cases, a
tumor originating from the ovarian stroma in one case, germinal tumors in 17 cases, 15 functional
ovarian cysts, and five paraovarian cysts. The stroma tumor and four of the 17 germinal tumors
were malignant. Surgical treatment for solid tumors consisted generally of a unilateral salpingo-
oophorectomy, but in operations for cystic tumors as well, vital ovarian tissue could only rarely
be preserved. Functional ovarian cysts were excised if they were larger than 5 cm. Subsequent to
excision of malignant tumors, chemotherapy with cisplatin, vincristine and bleomycin was per-
formed. On follow-up, all patients with benign lesions were well. One of the girls with malignan-
cies died and another is undergoing chemotherapy for tumor recurrence in the contralateral
ovary.
Zusammenfassung
Von 1971 bis 1988 wurden 45 Madchen im Alter von 1 Woche bis 17 lahren wegen 46 solider oder
zystischer Ovarialtumoren behandelt. Es handelte sich urn 8 epitheliale Tumoren, einen yom
gonadalen Stroma ausgehenden Tumor, 17 Keimzelltumoren, 15 funktionelle Ovarialzysten und
5 Paraovarialzysten. Der Stromatumor und 4 der Keimzelltumoren waren maligne.
Die chirurgische Therapie der soliden Tumoren bestand in der Regel aus der unilateralen
Salpingo-Oophorektomie. Aber auch bei der Operation zystischer Tumoren konnte nur selten
vitales Ovargewebe erhalten werden. Funktionelle Ovarialzysten wurden operiert, wenn sie grb-
Ber als 5 cm waren.
Nach der Resektion maligner Tumoren wurde eine Chemotherapie mit Cisplatin, Vincristin
und Bleomycin angeschlossen. Die Patientinnen mit benign en Lasionen sind bei der Nachkon-
trolle alle beschwerdefrei. Von den Madchen mit malignen Tumoren ist eines gestorben und ein
zweites steht wegen eines Rezidivs im Gegenovar unter Chemotherapie.
Entre 1971 et 1988 nous avons traite 45 fillettes agees de 1 semaine a 17 ans pour 46 tumeurs
ovariennes soli des ou kystiques. II s'agissait de 8 tumeurs epitheliales, d'une tumeur proven ant
d'un stroma gonadique, de 17 tumeurs des cellules germinatives, de 15 kystes ovariens fonction-
nels et de 5 kystes parovariens. La tumeur du stroma et 4 des tumeurs des cellules germinatives
etaient malignes.
Le traitement chirurgical des tumeurs solides consistait en regie generale en une salpingo-
ovarectomie (oophorectomie). Lors de la resection de tumeurs kystiques, il n'etait que rarement
Pediatric Surgical Clinic, University Children's Hospital of Zurich, SteinwiesstraBe 75, CH-8032
Zurich, Switzerland.
possible de conserver du tissu ovarien vital. Les kystes ovarien ont ete operes quand leur taille
depassait 5 cm.
Apres la resection des tumeurs malignes, il y eut une chimiotherapie au cis-platinum, it la vin-
cristine et it la bleomycine. Les patients n'ayant que des lesions benignes ne presentaient plus
aucun symptome au contole ulterieur. Une des fillettes ayant une tumeur maligne est decedee et
une autre subit une chimiotherapie pour une recidive dans I'autre ovaire.
Introduction
Patients
o Malignant
25 12221 Benign 3
~ 20
0
E
.2 15
'0
0
z 10
n= 46
8
lfl
c
."! 6
0
0..
'0 L.
0
z
2
Fig. 2. Age at operation of 46 patients
0 with ovarian tumors 1971-1988
0 5 10 15
Age (years)
formed during the first year of life in only two cases. There is a minor peak
between the 6th and 8th year of life, due to a prevalence of benign ovarian
teratomas in this age group. The number of patients rises steeply after menarche
because of an increase of ovarian cysts.
Eighteen girls suffered from solid or mainly solid ovarian tumors, five of which
were malignant. Nearly two thirds of the pathological entities were cystic lesions.
The pathohistological findings in our cases are summarized in Table 2.
Acute abdominal pain was the leading symptom in more than half of the girls
with ovarian and paraovarian cysts. A palpable mass, on the other hand, predomi-
nated in girls with ovarian teratomas and cystadenomas [1]. Premature thelarche
combined with vaginal discharge occurred in only two girls with ovarian cysts.
These two ovarian cysts, one malignant ovarian teratoma, and two yolk sac tu-
mors were endocrine active.
Surgical Treatment of Ovarian Tumors in Childhood 115
Epithelial Tumors
The only epithelial tumors occurring in our patients were cystadenomas and
cystadenofibromas. Eight girls between 5 and 16 years were thus affected. Re-
markably, the tumor site was the right ovary in seven cases. In all but one case,
the cystic part predominated, containing up to 2.51 fluid. Numerous small cysts
and interstitial fibrosis were found in the remaining case, pathohistologically cor-
responding to a cystadenofibroma. In two cases the cysts could be enucleated
from the remaining ovary, and the organ was thus preserved. In the other cases
ovarian tissue had entirely disappeared because of the pressure exerted by the
cyst. This was confirmed histologically.
Although the adenocarcinoma is the most common ovarian tumor in mature
women, particularly after menopause, carcinomas of the ovaries practically never
occur in childhood and there were none in our patients. Likewise, no ovarian
carcinomas in women under 20 years of age were reported to the registry of the
workshop of the Swiss Gynecological Hospitals (1983-1986) [3]. Cronen and
Nagaraj [7] described only one girl with a cystadenocarcinoma among 30 patients
with ovarian tumors. Ehren et al. [6] found only one cystadenocarcinoma in 63
children with ovarian tumors; this girl already had liver metastases and died 12
days following surgery.
The granulosa cell tumors and Sertoli-Leydig cell tumors belong to this group.
Combinations with germinal tumors and undifferentiated tumors are very rare
[19]. Granulosa cell tumors appear typically in young adults, and we have not seen
a case with this tumor type at our hospital during the past 18 years. These tumors
are frequently endocrine active and exhibit a relatively benign course. There-
fore, unilateral salpingo-oophorectomy is generally sufficient [2]. Vassal et al.
[34] reported on 15 girls with granulosa cell tumors whom they had treated
116 M. G. Schwtibel and U. G. Stauffer
over a period of 19 years. Eleven of the patients are free of recurrence an average
of 6 years following surgery. In four cases where the tumors had primarily in-
vaded the surrounding structures the patients developed recurrences, and all have
died.
We have recently seen a case of a bilateral, malignant, undifferenciated
stroma cell tumor. The medical course will be briefly described. The 12.5-year-old
girl was repeatedly seen at our outpatient department for familial gigantism dur-
ing the year prior to her hospitalization. The last examination, 3 months prior to
the acute onset of illness, had not revealed any pathological findings. Endocrino-
logical examinations had not been performed. The onset of menarche was at the
age of 11 years, 10 months. During summer vacation in Italy the girl had to be
hospitalized for acute dyspnea. Clinical examinations revealed bilateral pneu-
monia, bilateral pleural effusions, and ascites. After 1 week without clinical im-
provement she was flown back to Switzerland. Shortly after admission to our hos-
pital she had to be intubated and artificially ventilated. Further diagnosis dis-
closed bilateral ovarian tumors with metastases in the retroperitoneum, lungs,
pleura, base and vault of the skull, and bone marrow. The alpha-fetoprotein
(AFP) was normal, but beta-human-chorionic gonadotropin (HCG), at 31 lUll,
was slightly increased (normal range, 0-5 lUll). A bilateral ovariectomy was car-
ried out. The right ovary weighed 470 g, the left 300 g. Chemotherapy with actino-
mycin D, cyclophosphamide and vincristine was started subsequent to surgery.
There was no response, and the girl died on the tenth postoperative day of multi-
organ failure. Pathohistological examination revealed a parvicellular stroma cell
tumor. Electron-microscopical and immunohistochemical examinations showed a
neuroectodermal tumor.
Germinal Tumors
Teratomas
Fifteen girls aged 2-16 years were operated on for ovarian teratomas. The weight
of the tumors ranged from 60 to 2800 g; there was no prevalence of the left or right
side. Treatment consisted of a unilateral ovariectomy in 14 patients and enuclea-
tion of a predominantly cystic teratoma with preservation of the ovary in the
remaining patient. Two teratomas were malignant. The medical histories of these
two patients are described here in brief.
T. M., 12 years, 3 months. The patient became aware of an increase in her abdom-
inal circumference 4 weeks prior to hospitalization. Except for a feeling of pres-
sure, she had no other symptoms. Clinical examination revealed a huge palpable
mass extending from the xiphoid process to the symphysis and into both flanks. A
tumor weighing 2800 g and originating from the right ovary was removed in toto
by laparotomy via a lower transverse approach. Histologically, the tumor was
found to be a malignant teratoma, limited to the organ itself. There was no evi-
Surgical Treatment of Ovarian Tumors in Childhood 117
dence of local or remote metastases. The girl is doing well 7 years following the
operation and subsequent chemotherapy with vincristine, actinomycin D, and
cyclophosphamide.
B. c., 6 years, 1 month. The girl underwent laparotomy at a district hospital at the
age of 6 years and 1 month for acute abdominal pain and suspected acute appen-
dicitis. A tumor originating from the right ovary was found and subtotally re-
moved. Peritoneal metastases were already present. Subsequent to surgery, ir-
radiation therapy with a total dose of 3000 rads was carried out. However, the girl
developed a recurrent tumor 5 months following surgery and was transferred to
our hospital. The AFP was normal, but the beta-HeG, at 10600 lUll, was mark-
edly elevated prior to surgery. On laparotomy, the recurrent tumor weighing
750 g was removed. Radical tumor excision was again impossible. Further tumor
growth could be prevented by means of chemotherapy with cyclophosphamide
and vincristine combined with intra-abdominal implantation of radio gold. The
woman is free of recurrence today, 18 years after the first operation, and can be
regarded as cured. Remarkably, menarche took place and further development
was entirely normal. She is taking contraceptives, as a child is not desired so far.
Larger series also report malignancy in Vs to 1/6 of all teratomas [5, 15, 20, 32].
Billmire and Grosfeld [4] reported on ovarian teratomas in 15 patients they had
seen between 1960 and 1984, of which 11 were benign and four malignant. Only
one of the malignant tumors could be excised in toto; the patient was symptom
free at follow-up. The remaining malignant teratomas not radically removable
metastasized rapidly, and all patients died.
Dysgerminoma
According to La Vecchia et al. [20] and Breen and Maxson [5], dysgerminomas
are five times as frequent as teratomas. Nevertheless, we saw no patient with a
dysgerminoma between 1971 and 1988. Steck [31] summarized all patients with
ovarian tumors treated at our hospital from 1934 to 1954. Among those 19 patients,
one girl had a dysgerminoma. This tumor is histologically identical and embryo-
logically equivalent to the testicular seminoma. Five to twenty percent of dys-
germinomas occur bilaterally [5]. Since the prognosis depends largely on tumor
stage at the primary operation, standardized surgical procedures and peritoneal
lavage for intraoperative cytological sampling are necessary [33]. Weinblatt and
Ortega [35] recommend a unilateral salpingo-oophorectomy for a stage-IA tumor
according to FlGO [12] and a bilateral salpingo-oophorectomy with hysterectomy
for stage IB. Only if the tumor extends beyond the organ borders is chemotherapy
given subsequent to surgery. Although the dysgerminoma is the only ovarian
tumor really sensitive to radiotherapy, irradiation was applied as the primary
treatment in only two of nine patients by these authors. If the tumor does not ex-
tend beyond the organ borders, cure can be expected in over 90% of cases [10].
118 M. G. Schwabe! and U. G. Stauffer
In large series the endodermal sinus tumor appears as the third most common
ovarian tumor [5, 20]. The age peak is at around 20 years, but it has also been ob-
served in young children. Rapid invasion of the pelvic organs and early metastasis
render this tumor highly malignant. In the series of Kurman and Norris [18], only
13% of the patients survived longer than 3 years. We saw two girls with endo-
dermal sinus tumors during the period under discussion.
s. S.,7 years, 2 months. The girl had suffered from diffuse abdominal pain and
dysuria for 1 week before hospitalization. Urinalysis was normal. Symptomatic
therapy did not improve the girl's condition. She was admitted to the hospital be-
cause of a palpable mass the size of a child's head in the lower abdomen. Ultra-
sound and CT increased the suspicion of a malignant tumor originating from the
ovaries or the uterus, but the primarily affected organ could not be exactly
specified. On laparotomy a 350-g tumor was found, originating from the left ovary
and adhering to the bladder wall. It was excised in toto, together with the bladder
wall. Pathohistological examination revealed an endodermal sinus tumor. The
bladder wall was tumor free, and the tumor was classified as stage 1. Postoperative
chemotherapy with vincristine, actinomycin D, and cyclophosphamide was car-
ried out. An increase of serum AFP to 1968 IU/ml (normal range up to 20IU/ml)
was diagnosed 9 months after salpingo-oophorectomy. Radiology disclosed a
tumor recurrence in the uterus and right ovary. Relaparotomy disclosed
peritoneal carcinosis as well, and a right-sided salpingo-oophorectomy and hyster-
ectomy was performed. Postoperative chemotherapy consisted of cisplatin,
bleomycin, and vinblastine. AFP dropped to normal postoperatively and remains
normal 4 months following surgery.
M. M., 15 years, 6 months. The girl complained of diffuse abdominal pain and a
feeling of pressure 1 month prior to hospitalization. When she could no longer
close her trousers, she went to see a physician, who diagnosed ascites and sent her
to the hospital. Clinical and radiological examinations revealed ascites, a right-
sided pleural effusion, and a vaginally and rectally clearly palpable tumor in the
lower abdomen. At 3353 IU/ml (normal up to 20 IU/ml) serum AFP was markedly
elevated, the beta-RCG at 6 lUll (normal up to 5 lUll) slightly elevated. On
laparotomy, 51 of ascitic fluid was aspirated and the tumor, originating from the
right ovary, was removed. The left ovary was macroscopically and histologically
tumor free. Likewise, no malignant cells were found in the ascitic fluid. The girl
recovered quickly and the ascites and pleural effusion did not reappear. Serum
AFP and beta-RCG levels were normal 1 month following surgery. Today, 4
months after the operation, the girl is undergoing chemotherapy with carboplatin,
vinblastine, and bleomycin. She is radiologically and clinically without evidence of
a recurrence.
Surgical Treatment of Ovarian Tumors in Childhood 119
Tumor-like Lesions
Functional Cysts
Follicular and corpus luteum cysts are regarded as functional cysts. Whereas cor-
pus luteum cysts occur only in sexually mature girls, follicular cysts are seen in any
age-group. We subdivided our patients into three age-groups, namely neonatal,
childhood up to puberty, and post-menarche.
Neonatal
Two infant girls belonged to this group. R. C. was delivered via cesarean section
in the 27th gestational week because of pre-term labor and was immediately intu-
bated for 27 hours thereafter. Prematurity problems were overcome during the
next several weeks. Apneic spells were treated with theophylline. At the age of
4 months, 2 weeks after term, an endocrinological examination was performed for
grossly feminized external genitalia and vaginal discharge. The estrogens were
markedly elevated (E2 380pglml; E3 180pg/ml). Abdominal ultrasound disclosed
a large cyst in the right adnexa. On subsequent laparotomy, the cyst, which had
destroyed the ovarian tissue, was removed and small cysts were enucleated from
the left ovary. Pathohistological examination disclosed follicular cysts on the right
as well as on the left side. The external genitalia normalized entirely postopera-
tively. However, the E2 and E3 remained slightly elevated even 6 months after
operation.
Antenatal ultrasound performed in the 39th gestational week revealed an
intra-abdominal cyst 8 X 9 cm in the girl R. M., 1 week prior to delivery. Post-
natally, there was a fist-sized palpable mass in the right lower and middle ab-
domen of the otherwise healthy baby. At laparotomy performed on the 4th day of
life, a 360 twisted ovarian cyst was found. The right fallopian tube was infarcted
0
cecum. All these cysts were observed in term babies and were endocrine inactive.
Sedin et al. [29] published reports of four girls delivered before the 30th gesta-
tional week in whom estradiol-producing ovarian cysts were found 1-4 weeks be-
fore term. One of these cysts was surgically removed, two disappeared spontane-
ously, and two were treated with medroxyprogesterone acetate (one was on the
contralateral ovary of the girl who was operated on). Measurements of serum LH
and FSH levels after LHRH stimulation showed autonomous estradiol production
by the cysts. Our patient R. c., who was also born prior to the 30th gestational
week, likewise exhibited autonomous estradiol production by the ovarian cysts.
Moreover, the patients of Sedin et al. and our patient have in common that all
received theophylline for apneic spells. However, nothing is found in the litera-
ture with regard to induction of ovarian cysts by theophylline. Hormone-produc-
ing ovarian cysts appear predominantly in term girls with diabetic mothers [13].
There is no general agreement in the literature so far about the best therapeu-
tic procedure for ovarian cysts. Whereas some authors [9, 28,36] recommend ex-
cision of any diagnosed cyst to avoid complications such as torsion or damage to
the bowels, others prefer conservative observation [11, 29]. An argument for the
conservative attitude is frequent bilateral appearance of the cysts and frequent
spontaneous healing during the first year of life. Treatment with medroxyproges-
terone acetate, as recommended by Sedin et al. [29] is indicated for hormone-
producing cysts only.
As a rule, we observe endocrine-inactive symptom-free cysts primarily, and
we excise only cysts that grow rapidly or that have a primary diameter of more
than 5 cm. We have no experience with laparoscopic puncture of the cysts.
Childhood up to Puberty
Two girls with endocrine-active follicular cysts belonged to this group; their med-
ical histories are described here in brief. The girl F. K. was hospitalized at 5 years
and 9 months of age for vaginal hemorrhage. Clinical examination revealed
slightly feminized external genitalia and markedly enlarged breasts. A vaginal
smear showed estrogen-stimulated epithelial cells. E2 was elevated, at 36 pmolJl.
Autonomous ovarian estrogen production could be deduced from the missing
increase of LH and FHS following LHRH stimulation. Ultrasonographically and
radiologically, a cystic tumor was found in the left pelvis; it could not be un-
equivocally appointed to the left ovary. On laparotomy, an ovarian cyst measur-
ing 6 cm in diameter was found. No ovarian tissue was visible macroscopically, so
the cyst was removed in toto. The right ovary appeared macroscopically normal.
Pathohistological examination disclosed a follicular cyst. Serum estradiol levels
(E2, 3 pmol/l) dropped to normal within 1 week after surgery.
The girl R. S. was admitted to hospital at the age of 3.5 years because of an en-
larged clitoris. Serum estrogens were normal. However, serum testosterone and
dehydroepiandrostenone were clearly elevated. Laparoscopy revealed several
small cysts in both ovaries. These were removed during subsequent laparotomy,
but the ovaries were preserved. Pathohistological examination revealed follicular
Surgical Treatment of Ovarian Tumors in Childhood 121
Post-menarche
Eleven of the 15 girls with follicular cysts (75%) belonged to this age-group.
Acute abdominal pain led to hospitalization in all cases. It is not surprising that
acute appendicitis was usually the suspected diagnosis, because ten ovarian cysts
were located on the right side. No cyst exhibited autonomous hormone produc-
tion. Follicular cysts which contained up to 200 ml fluid were surgically enucleated
and the ovarian tissue was sutured. Like Scheye et al. [26], we recommend exci-
sion of cysts larger than 5 cm, also because of the differential diagnosis of a
granulosa cell tumor, which is not so rare in this age-group.
Paraovarian Cysts
Paraovarian cysts originate from the epoophoron and are located in the meso-
salpinx. Although they do not stem from ovarian tissue, they are mentioned here
because they occur close to the ovary. Our five girls were 11-16 years of age and
post menarche. Ultrasonographically and radiologically, paraovarian cysts were
indistinguishable from ovarian follicular cysts. On laparotomy, the largest para-
ovarian cyst contained as much as 21 of fluid. The cysts were enucleated from the
mesosalpinx in such a way that the fallopian tube and ovary were not damaged.
All patients are well postoperatively without evidence of recurrence.
122 M. G. Schwabel and U. G. Stauffer
Conclusion
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Recent Developments
in the Management of Neuroblastoma
M. L. Nieder and M. W. L. Gauderer
Summary
Neuroblastoma was first described in 1864 by Virchow [44]. For the next 100 years, the primary
approach to these patients was predominantly surgical resection. With the advent of multimodal
adjuvant treatments using chemotherapy and irradiation in the 1950s and 1960s, coordination of
multi specialty therapeutic interventions became important. By the late 1970s, effective neo-
adjuvant chemotherapeutic regimens enabled some inoperable tumors to be completely removed
at the time of "second look" procedures. In the 1980s, advances in tumor biology and imaging
gave new insight and novel prognostic indicators which helped determine the course of therapy.
In the 1990s, treating poor risk patients with extremely high dose chemotherapy, irradiation, and
allogeneic or autologous bone marrow rescue with or without surgical resection may finally im-
prove the survival of these children.
Zusammenfassung
Das Neuroblastom wurde erstmalig im Jahr 1864 von Virchow beschrieben. Wahrend der nach-
sten hundert Jahre wurde die chirurgische Resektion als alleinige Therapie der Wahl davon be-
troffenen Patienten angesehen. Mit der Entwicklung multimodaler, adjuvanter Therapiemetho-
den wie Bestrahlung oder Chemotherapie in den 50er und 60er Jahren gewann die Koordination
interdisziplinarer Behandlungskonzepte immer mehr an Bedeutung. Seit den spaten 70er Jahren
ermoglichen effektive adjuvante Chemotherapieprotokolle die komplette Entfernung urspriing-
lich inoperabler Tumoren in einer "second-look-Operation". In den 80er Jahren ergaben Fort-
schritte in der Tumorbiologie sowie der Tumordarstellung neue Gesichtspunkte und neue pro-
gnostische Marker, die zur Festlegung des Therapieverlaufs beitrugen. In den 90er Jahren wird
moglicherweise die Behandlung von Patienten mit schlechter Prognose durch extrem hohe
Chemotherapie, Bestrahlung oder allogene bzw. auto loge Knochenmarkstransplantation mit
oder ohne chirurgische Intervention endlich zu einer Verbesserung der Heilungschancen fiihren.
Resume
Le neuroblastome a ete decrit pour la premiere fois en 1864 par Virchow. Au siecle suivant, Ie
traitement de choix consistait, dans la grande majorite des cas, en une resection chirurgicale. Des
therapeutiques d'appoint telles que chimiotherapie et radiotherapie ayant fait leur apparition
pendant les annees 50 et 60, il est devenu indispensable de bien coordonner ces therapeutiques
relevant de specialisations multiples. Vers la fin des annees 70, la chimiotherapie adjuvante per-
mit de faire disparaitre certaines tumeurs par une intervention dite de "second look" inoperables
it l'origine. Durant les annees 80, les progres realises en biologie et en imagerie dans Ie domaine
des tumeurs perrnirent de determiner de nouveaux facteurs donnant la possibilite de prevoir
l'evolution et l'issue de la maladie et d'en organiser Ie traitement en consequence. Au cours des
annees 90, il sera peut-etre possible de prolonger la survie des enfants ayant un pronostic tres
defavorable en ayant recours a la chimiotherapie it dose tres elevee, ala radiotherapie, a la trans-
plantation autologue ou allogenique de moelle osseuse, avec ou sans resection chirurgicale.
Introduction
Neuroblastoma affects young children and comprises almost 50% of the malig-
nancies among infants [7]. It is the third most common solid tumor in children
aged 1-15 years and is usually widespread at the time of diagnosis [29]. In more
than 50% of cases, the abdomen is the site of the primary tumor [29]. Because the
tumor is of neural crest origin, primary sites have been reported in every location
which has sympathetic nerve innervation [33]. Though prognosis was once solely
linked to age and stage of disease, recent advances in molecular biology have
afforded a better understanding of the biologic basis of this disease.
Pathologic Diagnosis
Biologic Characteristics
be related to the aggressive nature of those tumors which lack dopamine beta-
hydroxylase (and hence cannot produce VMA from HVA).
Cytogenetic studies of actual neuroblastoma tissue specimens have revealed
chromosomal abnormalities in approximately 80% of cases [4]. Most of these ab-
normalities involve the short arm of chromosome 1 [6]. Interestingly, unlike the
majority of solid tumors which affect adults, tumor cell hyperdiploidy (increased
DNA content) has been associated with a better prognosis [18, 32]. Results of
neuroblastoma tumor cell cycle analysis (proliferative activity) suggest that more
rapidly dividing tumors may portend a worse prognosis [10]. In addition to tumor
cell kinetics, Northern and Southern blotting techniques have revealed that
patients with poor prognosis neuroblastoma have increased numbers of the N-myc
oncogene in the tumor genome as well as excess N-myc messenger RNA (mRNA)
in tumor cells [38, 39].
The oncogene N-myc is normally found on chromosome 2, but is translocated
to chromosome 1 and amplified in some cases of neuroblastoma. N-myc is
amplified (increased numbers of gene copies) or overexpressed (increased mRNA
or N-myc protein) in half the patients with stage III or IV disease [39]. Patients
with stage I, II, or IVS disease rarely show tumor cell N-myc amplification or
over expression [8, 39]. N-myc amplification studies are important components of
the evaluation of a child with neuroblastoma. The prognostic significance of N-
myc gene copy number has been recognized and these results are now being used
as part of the eligibility criteria in Children's Cancer Study Group neuroblastoma
studies (CCSG study 3881).
Other prognostic indicators include serum ferritin values (elevated in some
poor-prognosis patients), serum neuron-specific enolase (elevated in some poor-
prognosis patients), age and stage of the patient at diagnosis, and location of the
tumor [29, 30]. Though multivariate analysis has determined that most of these
biochemical aberrations may not be independently significant, biochemical mark-
ers do prove useful when following the clinical status and progress of treatment in
these children.
An especially favorable prognosis is conferred upon those two percent of pa-
tients who present with ataxia and opsomyoclonus accompanying their neuroblas-
toma [1, 3, 9]. Unfortunately, the neurological sequelae often persist even when
the child is free of disease. In addition to those patients who present with opso-
myoclonus, those few patients with ganglioneuroblastoma and diarrhea caused by
secretion of vasoactive intestinal polypeptides also have a favorable outcome [11,
13,28]. In contrast to the patients with opsomyoclonus, children with diarrhea be-
come asymptomatic after the tumor is removed.
Tumor Imaging
imaging (MRI) as a distinct modality within radiology has led to better studies of
certain organs and soft tissue. Advances in nuclear medicine made meta-iodo-
benzylguanidine (MIBG) scanning an important diagnostic tool in many centers
[27,36]. Though still experimental, immunolocalization of neuroblastoma using
radiolabeled monoclonal antibodies and gamma scanning began in the 1980's and
is being used in some centers today [7, 20]. MIBG and monoclonal antibody-
mediated nuclear scanning can identify some small tumors which go unnoticed on
CT, MRI, or conventional nuclear medicine scans. Localization of small residual
tumors is now possible and can help determine which children are candidates for
further surgical procedures.
Surgical Management
Operative techniques and anesthesia have improved significantly over the past
several decades, Therefore, localized tumors should be removed in an attempt to
eliminate all gross disease. In those cases where less than 90% of the tumor can
be resected, only a biopsy should be performed. Those patients with residual dis-
ease will undergo chemotherapy in an attempt to substantially reduce the size of
the tumor.
Patients with residual disease whose tumor responds favorably to chemother-
apy are good candidates for aggressive "second look" surgical procedures [16, 24].
The removal of all gross tumor prior to consolidation, maintenance, or ablative
chemotherapy and radiotherapy is thought to enhance the possibility of prolonged
disease-free survival [24].
Supportive Care
Beside the technological strides made over the past 20 years, supportive care tech-
niques have improved the quality of life for children with cancer. Insertion of cen-
tral venous access devices has minimized the possibility of chemotherapy extra-
vasation as well as making treatment and diagnostic sessions less uncomfortable
[19]. The ease of vascular access has eliminated the single greatest cause of fear in
these children undergoing cancer treatment. The medical and nursing expertise in
dealing with critically ill children has ripened and pediatric intensive care units
now provide outstanding care. The improved outcome of many patients with
neuroblastoma is related not only to nuances in therapy but also to a better under-
standing of the well-being of the whole child. The cooperation between physi-
cians, nurses, child life specialists, psychologists, and social workers has resulted
in excellent comprehensive treatment for children and their families.
Patients
From January, 1975 to December, 1989, 100 children with neuroblastoma were
treated at Rainbow Babies' and Children's Hospital in Cleveland, Ohio. The ini-
128 M. L. Nieder and M. W. L. Gauderer
tial staging data on these patients were similar to hose reported in other large
studies and within the CCSG: stage I, 14%; stage II, 15%; stage III, 18%; stage
IV, 41 %; stage IV-S, 12%. During this period, the children were treated with a
variety of multiagent chemotherapeutic regimens. Those patients with advanced
or relapsed disease were enrolled in pilot studies using high-dose chemotherapy
and bone marrow rescue. Because of the variation in treatment over the years, it
is not feasible to report outcome data even on this large group of patients.
Treatment
Stage Criteria
Stage Criteria
chemical and molecular biological analysis. If such analysis is not readily avail-
able, a portion of the tumor should be quickly frozen for future testing.
Presently, the staging of neuroblastoma is based on two different systems
(Tables 1,2). The St. Jude Children's Research Hospital staging method adopted
by the Pediatric Oncology Group (POG) is dependent upon surgical-pathologic
criteria, while the Evans staging method used by the CCSG relies on physical ex-
amination, imaging studies, and bone marrow aspirationlbiopsy [14, 26]. In the
future, a staging system encompassing both clinical and molecular biology para-
meters will be more useful. Regardless of the staging system, the following
guidelines should be considered when treating patients with neuroblastoma:
A gross total surgical resection should be attempted. As in all initial surgical pro-
cedures in patients suspected of having neuroblastoma, excision of adjacent
organs is not indicated. However, if a para-aortic primary tumor invades the renal
vessels, radical nephrectomy may be performed. If the primary tumor cannot be
completely removed, surgical debulking should be attempted only if 90% -95% of
the mass can be excised.
Those patients with complete resections and negative lymph nodes are not
candidates for chemotherapy or radiotherapy. If the entire tumor was not resec-
ted or if pathological examination demonstrates lymph node spread, further ther-
apy may be recommended. However, Matthay and colleagues [34] reported that
chemotherapy and/or radiotherapy in stage II patients did not improve survival.
To identify a subgroup of stage II patients who might benefit from additional
treatment, N-myc amplification results are being used in some studies as the
determining factor for further chemotherapy (CCSG 3881). In other settings,
these children have received local radiotherapy or short-term multi agent chemo-
therapy [22].
The care of patients with localized metastatic disease (e.g., involved lymph nodes)
has garnered controversy over the past decade. In the Evans staging system, these
patients are classified as either stage III or IV-S (special). The approach to these
children has been age-related, since younger children historically have fared bet-
ter [29, 30]. Young infants with abdominal primary tumors may have respiratory
distress, and a resection of the tumor mass may have immediate therapeutic
value. Even if the tumor cannot be resected, biopsy alone followed by insertion of
an abdominal wall extender (patch or silo) may be beneficial [15]. Though surgical
resection of the primary tumor may have been achieved, extensive procedures to
remove all areas of metastases should not be employed. In patients presenting
with the syndrome of ataxia and opsomyoclonus, excellent outcomes are achieved
with surgical resection alone [1, 3].
130 M. L. Nieder and M. W. L. Gauderer
Some infants with stage IV -S or stage CID disease receive chemotherapy with
or without radiotherapy [22]. While some of these babies had spontaneous regres-
sion of their disease, those that did usually had small primary tumors and no bone
marrow involvement [15]. There is evidence to suggest that infants whose tumor
exhibits no N-myc amplification will do well without either chemotherapy or
radiotherapy, and the current CCSG study recommends no therapy for these
patients (CCSG study 3881). In this study, infants in this group whose tumor cells
have N-myc amplification will receive multi agent chemotherapy. Other strategy
groups recommend a short course of chemotherapy with limited agents, and addi-
tional drugs such as cis-platinum should be used only if remission is not achieved
early [22].
The treatment of older children with limited metastatic disease (e.g., lymph
nodes) should include chemotherapy with or without radiotherapy. In some
aggressive protocols, radiotherapy is reserved as a local control measure in
patients with unresectable disease after chemotherapy. Since investigators have
reported a poor outcome in patients with tumor cell N-myc amplification, those
patients should receive extensive chemotherapy [6, 38, 39]. Additional treatment
with high dose chemotherapy and bone marrow rescue should be considered in
those individuals with N-myc amplification within the tumor cells [40].
In the majority of these cases, the diagnosis can be made by bone marrow aspira-
tion and urinary catecholamine elevation. However, it is extremely important to
obtain an adequate specimen for tumor cell studies, and a tissue biopsy may be
necessary to achieve this. There are very few cases where an extensive primary
surgical procedure can be justified in cases of widespread metastatic disease. Chil-
dren with evidence of metastatic disease should have a primary surgical debulking
only if the diagnosis cannot be confirmed by a less invasive procedure.
All such patients receive multi agent chemotherapy with the intent of signifi-
cantly decreasing the size of the primary tumor and alleviating metastatic spread.
Children who enjoy a good response to chemotherapy are then ideal candidates
for delayed surgical procedures. The goal of delayed surgical intervention is to
assess the effect of therapy and remove any gross residual disease [16,24]. Follow-
ing this, further chemotherapy, radiotherapy, or high dose chemotherapy with
bone marrow rescue may be used. A few institutions are studying the therapeutic
efficacy of cytotoxic agents linked to neuroblastoma-seeking monoclonal anti-
bodies in an effort to eliminate minimal residual disease [7]. This is used in addi-
tion to systemic chemotherapy.
Discussion
Until recently, the survival of children with widespread neuroblastoma had not
changed since the early 1960s. Although a multimodal approach had been coordi-
Recent Developments in the Management of Neuroblastoma 131
tals and centers with pediatric oncology expertise. The children's hospital in the
1990s also provides comprehensive psychosocial support to patients and their
families which cannot be given elsewhere. Such support is of equal importance to
medical care in the treatment of these children. Finally, our knowledge of the
pathophysiology of this disease will grow only when patients are enrolled in
groupwide studies, receive standardized treatment, and are managed by a com-
passionate team approach.
Illustrative Case
Fig. 2. Computed tomogram of the upper abdomen demonstrating the massive size of the par-
tially calcified tumor. Because of the tumor size and location, it was initially assessed as being un-
resectable
Fig. 4. Computed tomography 9 months after gross total resection reveals no evidence of residual
disease. Both kidneys appear normal and demonstrate appropriate excretion of contrast material
upper abdomen with destruction of a portion of her left 12th rib (Figs. 1-3).
Although it was felt that resection could not be accomplished, the child was pre-
pared for either biopsy only or complete resection. Reexamination of the anes-
thetized child revealed some tumor mobility. A small incision was initially made
and after resectability could be demonstrated, the incision was extended trans-
versely across the upper abdomen. Gross total tumor resection was achieved after
a prolonged surgical procedure. Bone marrow examinations were normal. After
recovering from surgery, the patient received 11 cycles of multiagent chemother-
apy in the next year using cis-platinum, cyclophosphamide, etoposide, and
doxorubicin. Nine months after her initial diagnosis, her abdominal CT scan
showed no evidence of disease (Fig. 4). Her initial serum ferritin and tumor N-
myc studies were not elevated. She has been off chemotherapy for 9 months and
continues to be free of disease.
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SUbject Index
cyst(s) familial
- corpus luteum, ovarian 113, 119 - endocrine adenomatosis 61
- dermoid, ovarian 115 - endocrinopathies 53
- follicular 113, 119, 121 - hyperparathyroidism 52ff.
- - endocrine-active 121 - hypocalciuric hypercalcemia (FHH) 53
- functional, ovarian 115, 119 fat necrosis, subcutaneous, hyperpara-
- ovarian 113, 114 thyroidism 55
- paraovarian 113-115,121 fetal islet cell formation, nesidioblastosis 92
FHH, familial hypocalciuric hypercalcemia
DeGeorge's syndrome 57 53
dermoid cyst, ovarian 115 follicular
dextrose, hypertonic, PINH 63 - adenoma, thyroid gland 11
diazoxide - cysts 119, 121
- nesidioblastosis 78 FSH levels, ovarian cysts 120
- PINH 63,65
DNA content, thyroid carcinoma 42 gastrinoma
dopamine, pheochromocytoma 108 - gastrointestinal tract 99, 100
drugs - pancreas 99
- antithyroid 32, 37 gastrointestinal tract, endocrine tumors 99
- thyrostatic 28, 29 gastrojejunostomy, pancreatic head tumor 98
duodenopancratectomy (Whipple procedure) germinal tumors, ovarian 113, 116
96 - and stroma tumors, mixed 113
dysgerminoma, ovarian 113, 117 glucagon, PINH 63
glucagonoma
embryology, thyroid gland 2 - gastrointestinal tract 99, 100
endocrine - pancreas 99
- adenomatosis, familial 61 glucose administration, nesidioblastosis 78
- - multiple, types I and II 52 goitre/goiter (see also thyroid gland) 5-7, 11
- neoplasia, multiple (MEN), pancreatic - adenomatous changes 10
head tumor 98 - diffuse toxic 34
- - syndrome, multiple (MEN), type lIb 24 - hyperfunctional diffuse 35
- ophthalmopathy 29,38 - - multinodular 35
- tumors, gastrointestinal tract 99 - hyperthyroid 37
- - pancreas 99 - juvenile 22
endocrine-active tumors, gastrointestinal tract, - multinodular toxic 34
clinical symptoms 100 - nodular 22, 38
endocrinopathies - recurrence 36
- familial 53 gonadoblastoma, ovarian 113
- spontaneous primary hyperparathyroidism 52 gonadotropin, beta-hum an-chorionic (beta-
endodermal sinus tumor, ovarian (Yolk Sac) HCG), ovarian tumors 116-118
113-115,118 granulosa cell tumor
enucleation - ovarian 113
- nesidioblastosis 89 - - stroma 115
- ovarian tumors 116 Graves' disease 29,38,39, 51
- thyroid carcinoma 37 - thyroid gland 6,9, 16,23
epinephrine, pheochromocytoma 104, 107
epithelial tumors, ovarian 113, 115 Hashimoto's
estradiol production, ovarian cysts 120 - disease 38
estrogens, ovarian cysts 119 - thyroiditis 23,39
ethyroidism 34, 35 HCG (human-chorionic gonadotropin)
euglycemia, PINH 63 - beta-HCG, ovarian tumors 116-118
euthyroid - paraovarian cysts 122
- nudular goiter 16 von Hippel-Lindau disease, pheochromo-
- struma 17 cytoma 106
Evans staging system, neuroblastoma 128 homovannilic acid (HVA)
Subject Index 139
irradiation - hyperparathyroidism 54
- 60CO iradiation, thyroid gland 24 - pheochromocytoma 105, 106
- cobalt, thyroid carcinoma 43 - syndrome, pheochromocytoma 106
islet cell/islets MEN (multiple endocrine neoplasia)
- adenoma, nesidioblastosis 79 - pancreatic head tumor 98
- adenomatosis, PINH 70 - type lIb 24
- dysplasia, PINH 61, 65, 66, 68 MEN II (multiple endocrine neoplasia II),
- formation, fetal, nesidioblastosis 92 pheochromocytoma 105
- Langerhans, PINH 66, 90 mesoblastic nephroma, hyperparathyroidism
- nuclear hypertrophy, PINH 68,70 55
- proliferation, nesidioblastosis 93 metabolig test, basal 32
- transplantation, insulin requirement 90 metastasis
isolitary nodule 37 - thyroid carcinoma 42, 44
- - formation 42
jejunum - thyroid gland 6
- cholecystojejunostomy, pancreatic head migration index, thyroid gland 33
tumor 98 monoclonal antibodies, neuroblastoma 125
- gastrojejunostomy, pancreatic head tumor multinodular lesion 37
98 multiple endocrine neoplasia syndrome (see
- pancreaticojejunostomy, pancreatic head MEN)
tumor 98
juvenile N-myc
- goiter 22 - messenger RNA, neuroblastoma 125
- hyperplasia, thyroid gland 22 - oncogene, neuroblastoma 125
- hypertyhroidism 28 neck surgery, exploratory, spontaneous
- struma 16, 25 primary hyperparathyroidism 51
neonatal
LAI (leucocyte adhesion inhibition), thyroid - hyperparathyroidism 53
carcinoma 44 - hypoglycemia 61
Langerhans, islets, PINH 66, 90 - primary hyperparathyroidism 55
laryngeal nerve damage 54 nesidioblastosis 76ff.
leucocyte - adenoma 88
- adhesion inhibition (LAI), thyroid - clinical picture 77
carcinoma 42-44 - diagnosis 78
- migration test, thyroid carcinoma 36, - focal adenomatosis 88
42,43,45 - incidence of recurrence 88
LH levels, ovarian cysts 120 - multifocal proliferation 88
LHRH stimulation, ovarian cysts 120 - - plus adenoma 88
lingual thyroid (dystrophy of the thyroid - neonatal hypoglycemia 61
gland) 5 - pathohistological findings 88
lipoid cell tumor, ovarian 113 - surgery 79-82,84ff.
lobectomy 42 - - age at operation 81,85
L-thyroxine 23-25, 29 - - indications 76
Lugol's solution 32 - - conservative preoperative treatment 81
lymph node - - pancreatectomy, left-sided 86,88,89
- matastasis 43 - - pancreatectomy, near total 87, 94
- regional 42 - - pancreatectomy, subtotal 79-81,
lymphocytic thyroiditis 38 85-89
- chronic 29 - - pancreatectomy, subtotal 92ff.
- - pancreatectomy, total 86-89, 92ff.
malign struma 19 - - preoperative state 81
malignant lymphoma, ovarian tumors 113 - - surgical procedure 85, 86
maternal hypoparathyroidism 55 - - time for onset 81
MEA II (multiple endocrine adenomatosis - results 76
syndrom II) - treatment 76
Subject Index 141
Volume 25
T.A.Angerpointner, University of Munich (Ed.)
Operative Technique
in Neonates
and Infants
1990. VIII, 141 pp. 77 figs., some in color. 34 tabs.
Hardcover DM 176,- ISBN 3-540-51057-5
Volume 24 Volume 21
J. Yokoyama, Keio University, Tokyo; P. Wurnig, Vienna (Ed.)
T. A. Angerpointner, University of
Munich (Eds.)
Trachea and Lung Surgery
in Childhood
Constipation 1987. X, 147 pp. 75 figs.
and Fecal Incontinence Hardcover DM l36,-
and Motility Disturbances ISBN 3-540-17232-7
of the Gut
Volume 20
1989. X, 235 pp. 113 figs. 62 tabs. P.P.Rickham, Zurich (Ed.)
Hardcover DM 198,-
ISBN 3-540-508l3-9 Historical Aspects
of Pediatric Surgery
1986. x, 285 pp. 119 figs. Hardcover
Volume 23 DM 240,- ISBN 3-540-15960-6
L. Spitz, London; P. Wurnig, Vienna;
T.A.Angerpointner, University of Volume 19
Munich (Eds.) P. Wurnig, Vienna (Ed.)
Surgery in Solitary Kidney Long-gap Esophageal
and Corrections of Urinary Atresia Prenatal Diagnosis
Transport Disturbances of Congenital Malformations
1989. VIII, 205 pp. l36 figs. 1986. XII, 205 pp. 86 figs. Hardcover
34 tabs. Hardcover DM 198,- DM 180,- ISBN 3-540-15881-2
ISBN 3-540-50485-0
Volume 22
L. Spitz, London; P. Wurnig, Vienna;
T. A. Angerpointner, University of
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Pediatric Surgical Oncology
1989. VIII, 180 pp. 78 figs.
44 tabs. Hardcover DM 178,-
ISBN 3-540-17769-8