First report of ectopic ACTH syndrome and PTHrP-induced hypercalcemia due to a hepatoblastoma in a child

Article (PDF Available)inEuropean Journal of Endocrinology 162(4):813-8 · April 2010with19 Reads
DOI: 10.1530/EJE-09-0961 · Source: PubMed
Abstract
Only occasionally, endocrine-active tumors develop directly from hepatic tissue, and may lead to paraneoplastic syndromes (PNS). PNS mostly accompany malignancy of adulthood and are exceedingly rare in children. A girl aged 6 years and 9 months presented with a 2-month history of rapidly progressive weight gain, abdominal distension, and polyuria/pollakiuria accompanied by short episodes of abdominal pain. She showed the typical clinical features of Cushing's syndrome and a huge hepatic mass. An abdominal computed tomography (CT) scan revealed a large liver tumor. Blood glucose and serum calcium were greatly elevated. Case report describing the causative relationship of the clinical findings. Physical examination; ultrasound of the abdomen; CT scan of the abdomen and the chest; conventional X-rays; routine hematology; blood chemistry and multiple parameters of calcium and phosphorus metabolism; multisteroid analysis in serum and urine; adrenocortical stimulation and suppression tests; histopathological assessment of the resected tumor; immunohistochemistry for ACTH, beta-endorphin, corticotrophin-releasing hormone (CRH), and PTH-related peptide (PTHrP); electron microscopy of tumor cells; ACTH and CRH extraction from the tumor tissue; and clinical follow-up for more than 20 years. Giant hepatoblastoma (HB; approximately 1000 ml volume) of the right lobe of the liver with combined ectopic ACTH syndrome and PTHrP-induced tumor-associated hypercalcemia. Wide local excision and polychemotherapy led to complete reversal of the paraneoplastic phenotype. This is the first report of an endocrine-active HB causing both Cushing's syndrome and PTHrP-related 'humoral hypercalcemia of malignancy'. This information should be added to the well-known beta-human chorionic gonadotropin-related paraneoplastic effects of HB in children.
CASE REPORT
First report of ectopic ACTH syndrome and PTHrP-induced
hypercalcemia due to a hepatoblastoma in a child
Thomas G P Grunewald
1,2
, Irene von Luettichau
1
, Ulrich Welsch
3
, Helmuth-Gu
¨
nther Do¨rr
4
, Frank Ho¨pner
5
,
Kalman Kovacs
6
, Stefan Burdach
1,2
and Wolfgang Rabl
1
1
Department of Pediatrics, Klinikum rechts der Isar, Technische Universita¨t Mu¨nchen, Ko¨lner Platz 1, D-80804 Munich, Germany,
2
Laboratory of
Functional Genomics and Transplantation Biology, Children’s Cancer Research Center, Pediatric Oncology and Roman Herzog Comprehensive Cancer Center,
Klinikum rechts der Isar, Technische Universita¨t Mu¨nchen, Ko¨lner Platz 1, D-80804 Munich, Germany,
3
Anatomical Institute, Ludwig Maximilians
University Munich, Pettenkoferstrasse 11, D-80336 Munich, Germany,
4
University Hospital for Children and Adolescents,
Friedrich-Alexander-University of Erlangen, Loschgestraße 15, D-91054 Erlangen, Germany,
5
Department of Pediatric Surgery, Klinikum Schwabing,
Ko¨lner Platz 1, D-80804 Munich, Germany and
6
Division of Pathology, Department of Laboratory Medicine, St Michael’s Hospital, 30 Bond Street,
Toronto, Ontario, Canada M5B 1W8
(Correspondence should be addressed to W Rabl; Email: wolfgang.rabl@lrz.tum.de)
Abstract
Context: Only occasionally, endocrine-active tumors develop directly from hepatic tissue, and may lead
to paraneoplastic syndromes (PNS). PNS mostly accompany malignancy of adulthood and are
exceedingly rare in children.
Patient: A girl aged 6 years and 9 months presented with a 2-month history of rapidly progressive
weight gain, abdominal distension, and polyuria/pollakiuria accompanied by short episodes of
abdominal pain. She showed the typical clinical features of Cushing’s syndrome and a huge hepatic
mass. An abdominal computed tomography (CT) scan revealed a large liver tumor. Blood glucose and
serum calcium were greatly elevated.
Design and objective: Case report describing the causative relationship of the clinical findings.
Methods: Physical examination; ultrasound of the abdomen; CT scan of the abdomen and the chest;
conventional X-rays; routine hematology; blood chemistry and multiple parameters of calcium and
phosphorus metabolism; multisteroid analysis in serum and urine; adrenocortical stimulation and
suppression tests; histopathological assessment of the resected tumor; immunohistochemistry for
ACTH, b-endorphin, corticotrophin-releasing hormone (CRH), and PTH-related peptide (PTHrP);
electron microscopy of tumor cells; ACTH and CRH extraction from the tumor tissue; and clinical
follow-up for more than 20 years.
Results: Giant hepatoblastoma (HB; w1000 ml volume) of the right lobe of the liver with combined
ectopic ACTH syndrome and PTHrP-induced tumor-associated hypercalcemia. Wide local excision and
polychemotherapy led to complete reversal of the paraneoplastic phenotype.
Conclusions: This is the first report of an endocrine-active HB causing both Cushing’s syndrome and
PTHrP-related ‘humoral hypercalcemia of malignancy’. This information should be added to the well-
known b-human chorionic gonadotropin-related paraneoplastic effects of HB in children.
European Journal of Endocrinology 162 813–818
Case report
The case
A girl aged 6 years and 9 months (height: 115.5 cm
(z-score K0.87); weight: 23.8 kg (z-score 0.42); body
mass index (BMI): 18.1 kg/m
2
(z-score 1.24); breast
and pubic hair development Tanner stage 1) of healthy
Caucasian parents was referred to our endocrine clinic
because of polyuria/pollakiuria and episodes of mild
abdominal pain. Within the last 2 months, she had
experienced a remarkable change in her facial features,
weight gain, and abdominal distension. Otherwise, her
own as well as her family history was essentially
negative. On physical examination, she presented with the
typical signs of Cushing’s syndrome including a ‘moon
face’, a buffalo hump, central obesity, and hirsutism most
prominent at the lower back. She also had a protruding
abdomen due to a huge abdominal mass (Fig. 1).
Her blood pressure was elevated at 160/120 mmHg,
and blood glucose amounted to 365 mg/dl. A computed
tomography (CT) scan and an ultrasound of the
abdomen revealed a giant liver tumor of the right lobe
of the liver with a volume of w1000 ml (Fig. 2A) and
bilateral nephrocalcinosis (Fig. 2B). Excretion of serum
calcium and urinary calcium was markedly elevated.
European Journal of Endocrinology (2010) 162 813–818 ISSN 0804-4643
q 2010 European Society of Endocrinology DOI: 10.1530/EJE-09-0961
Online version via www.eje-online.org
Plasma ACTH was elevated ranging from 184 to
819 pg/ml (normal 15–50), and was unresponsive to
either CRH stimulation or dexamethasone suppression
(2 and 8 mg), suggesting ectopic ACTH production. Serum
corticotropin-releasing hormone (CRH) was undetectable.
All urinary steroids, except for tetrahydroaldosterone, were
greatly elevated. By contrast, serum multisteroid
analysis revealed high levels of cortisol, cortisone,
corticosterone, and DHEAS, whereas progestins
(progesterone and 17a-OH-progesterone) and miner-
alocorticoids (11-deoxycorticosterone and aldosterone)
were normal (Table 1).
Figure 1 Representative images of the patient.
(A) Two months before admission to hospital;
(B) one month before admission; (C and D) on
admission to hospital: the patient shows the
classical phenotype of Cushing’s syndrome;
(E) hirsutism of the back and neck; (F) 12
months after surgical resection of the tumor.
Authors have obtained informed written consent
for use of patient’s images.
Figure 2 CT scan and ultrasound of the
abdomen and conventional X-rays of the
spinal column. (A) Abdominal CT scan
revealed a large tumor in the right lobe of
the liver. (B) Ultrasound of the kidneys showed
bilateral nephrocalcinosis (the right kidney
is depicted). (C) Conventional X-rays
demonstrated severe demineralization leading
to deformation of the vertebra.
814 T G P Grunewald and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2010) 162
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Corrected serum calcium was 14.2 mg/dl (normal:
8.4–10.6) and phosphate was 2.2 mg/dl (normal:
4.0–7.0). Calcitriol (1,25-(OH)
2
D
3
) was slightly
elevated and urinary cAMP was massively elevated,
whereas phosphate reabsorption was decreased. Serum
parathyroid hormone (PTH 44–68), calcidiol (25-
(OH)D
3
), alkaline phosphatase, osteocalcin, and urinary
hydroxyproline (Pro-OH) were normal, and intact PTH
was suppressed, suggesting the presence of a PTH-like
factor distinct from PTH (Table 2). Conventional
X-rays of the spinal column demonstrated significant
demineralization of the skeleton (Fig. 2C). There was no
evidence of metastases on routine staging. a-fetoprotein
and b-human chorionic gonadotropin (b-hCG) levels in
serum were normal. The tumor was surgically removed,
and was proven to be a hepatoblastoma (HB) by
histology. Hormone extraction from the tumor mass
yielded 8.3 ng/ml ACTH and 0.04 ng/ml CRH. Initial
immunohistochemical staining was positive for ACTH,
b-endorphin, and traces of CRH, but negative for
a-fetoprotein. Retrospectively, after successful cloning
of PTH-related peptide (PTHrP) in 1987, PTHrP could
also be detected by secondary immunohistochemical
analysis in preserved tissue of the tumor. Multiple
hormone granules were observed in individual tumor
cells by electron microscopy (Fig. 3). Postoperatively,
serum ACTH, calcium, blood glucose, and blood
pressure rapidly reverted to normal. In addition to
surgery, the girl also received adjuvant polychemo-
therapy. Four months later, basal as well as CRH- and
insulin tolerance test-stimulated ACTH and cortisol
levels were normal. Accordingly, the signs of Cushing’s
syndrome disappeared, and the bilateral nephrocalci-
nosis dissolved within several months. We have followed
the girl for more than two decades. The patient is
doing physically well and shows no signs of relapse
or metastasis.
Discussion of diagnosis
Paraneoplastic syndromes (PNS) are commonly associ-
ated with certain tumor entities. Virtually any cancer
may result in PNS, but in some tumors such as small cell
lung cancer, gynecologic cancers (breast and ovarian),
thymoma, and plasma cell tumors, PNS are more
frequently encountered. PNS can arise either from
hormone-producing tumors or from auto-reactive
antibodies induced by antigenic mimicry of tumor-
associated antigens (1). Only rarely do endocrine-active
tumors develop directly from hepatic tissue (2).
However, the most common ectopic hormone produced
in HB is b-hCG, resulting in paraneoplastic pseudo-
precocious puberty mainly in boys (‘virilizing HB’) (3)
Table 1 Serum and urinary steroid hormones before surgery.
Value Reference
Serum
Aldosterone 0.064 0.18–0.69
Progesterone 0.069 0.08–0.89
11-Deoxycorticosterone 0.25 !0.03–0.37
17a-OH-progesterone 0.61 !0.03–0.84
11-Deoxycortisol 1.33 0.16–1.70
Corticosterone 12.9 !0.05–6.45
Cortisone 28.9 7.0–27.0
Cortisol 673.5 39.8–136.0
DHEAS 1150 !500
Urine
Aet 1016 0–71
11-OH-AN 2643 25–223
11-OH-Aet 3253 0–119
PT 5286 34–278
P
5
T 1016 0–142
THE 25 416 138–1559
THA 406 22–489
THB 1016 0–216
a-THB 1016 38–568
THF 39 039 17–715
a-THF 5896 47–1416
a-CL 3253 91–390
b-CL, b-C 7929 26–380
a-C 4473 22–168
THS 3049 0–427
a-THS 609 0–229
Cortisol 1829 !100
6b-OH-cortisol 4879 !100
20a-OH-cortisol 1016 !100
6a-OH-b-CL 1016 !100
1b-OH-b-CL 2236 0–158
THE/THF 0.65 1.5–7.0
THF/a-THF 6.62 0.5–3.5
Reference values are age adjusted, and elevated values are marked in bold
font. Serum values are given in ng/ml, and urine values in mg/24 h. Analyses
were performed as described previously (30). Aet, aetiocholanolone;
11-OH-AN, 11-hydroxyandrosterone; 11-OH-Aet, 11-hydroxyetiochola-
nolone; PT, pregnanetriol; P
5
T, pregnenetriol; THE, tetrahydrocortisone;
THA, tetrahydro-11-dehydrocorticosterone; THB, tetrahydrocorticosterone;
aTHB, allotetrahydrocorticosterone; THF, tetrahydrocortisol; aTHF,
allotetrahydrocortisol; a-C, a-cortol; a-CL, a-cortolone; b-CL, b-cortolone;
b-C, b-cortol; THS, tetrahydro-11-deoxycortisol; aTHS, allotetrahydro-11-
deoxycortisol.
Table 2 Serum and urinary calcium/phosphate parameters before
surgery.
Value Reference
Serum
Ca (mg/dl) 14.2 8.4–10.6
P (mg/dl) 2.2 4–7
AP (U/l) 319 200–600
Osteocalcin (ng/ml) 6.4 7–15
PTH (44–68) (pmol/l) 51 30–90
PTH (intact) (pg/ml) !12 12–55
bioPTH (ng/ml) 30 1–19
Calcidiol (ng/ml) 14.7 10–50
Calcitriol (pg/ml) 61 20–40
Urine
Ca/Cr (mg/mg) 760 6–174
cAMP (nmol/dlGF) 6.7 1.6–4.9
TRP (%) 71.4 80–95
TmPO4/GFR (mg/dl) 1.6 4.5–6.8
Pro-OH/Cr (mg/mg) 107 60–160
Reference values are age adjusted, and abnormal values are marked in bold
font. TRP, tubular reabsorption of phosphate; TmPO4/GFR, renal threshold
phosphate concentration; Pro-OH/Cr, hydroxyproline.
ACTH syndrome and PTHrP-induced hypercalcemia 815EUROPEAN JOURNAL OF ENDOCRINOLOGY (2010) 162
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and very rarely in a forme fruste in girls (4). In our case,
b-hCG production could not be demonstrated. Often,
symptoms of PNS are the rst signs of an otherwise
occult tumor, prompting the patients to seek medical
attention. Cushing’s syndrome results from prolonged
exposure to excessive amounts of glucocorticoids. Non-
iatrogenic Cushing’s syndrome can be related to
excessive ACTH production from the pituitary gland,
ectopic ACTH secretion by a non-pituitary tumor, or
excessive autonomous secretion of cortisol from a
hyperfunctioning adrenocortical tumor. Ectopic ACTH
production by a non-pituitary tumor is the cause of
non-iatrogenic Cushing’s syndrome in w10% of all
cases in adults (5), but it is exceedingly rare in children
(6). To our knowledge, a ‘liver tumor’ has been reported
only once as a cause of ectopic ACTH production in
children (7). In another single case, ‘humoral hyper-
calcemia of malignancy’ (HHM) due to a HB has been
observed. However, definitive pathological diagnosis
and/or identification of the hormones are not available
(8). Our case report is the first of combined ectopic
ACTH syndrome and PTHrP-induced tumor-associated
hypercalcemia in a child with HB.
Hypercalcemia complicating malignancy is a serious
and frequent occurrence in adults, but it is extremely
rare in children (9). The polypeptide PTHrP was
discovered 1 year after admission of the patient to our
hospital (10). Kemp et al. showed PTHrP to have a much
stronger activity than PTH in 1987 (11). In the same
year, PTHrP was found to be the cause of HHM (10, 12).
Surprisingly, serum calcitriol was elevated in our
patient (Table 2), whereas PTHrP generally suppresses
calcitriol synthesis in HHM. However, rarely PTHrP-
induced HHM is associated with increased calcitriol
levels, and recent work has shown that short-term
exposure to very high doses of PTHrP can also induce
renal calcitriol synthesis, which may only decline after
long-lasting exposure to PTHrP (13). Thus, we assume
that either PTHrP levels were unusually excessive in our
patient and/or time of exposure was insufficient to
suppress calcitriol production.
Histologically, the HB of our case was partially
composed of typical HB cells and mesenchymal cells of
an embryonic hepatoma (also known as infantile
sarcoma) as assessed by local and reference path-
ologists. This biphenotypic tumor was subsequently
classified as HB of the mixed type. HBs are the most
common liver cancers of childhood with w 90%
occurring within the first 5 years of life (14).In
particular, HBs with low expression of a-fetoprotein, like
in this case, belong to a more undifferentiated subtype
with a worse prognosis (15).
Morphologically, HB is classified into different pat-
terns, including the frequent fetal pattern that evokes
the prenatal fetal liver with sheets of uniform, cuboidal
cells showing low mitotic activity; the more immature
embryonic type characterized by higher cell density,
enlarged nuclei, and frequent mitosis; macrotrabecular
patterns evoking hepatocellular carcinoma (HCC);
and small cell undifferentiated pattern, suggesting that
HB may arise from a primitive, uncommitted progenitor
cell (16). Accordingly, HB is divided into molecular
subclasses by liver differentiation stages that rely entirely
on tumor transcriptional profiling (17).
HBs are embryo- or fetal-like liver cancers displaying
a stem cell-like phenotype, which is often observed in a
wide variety of liver cancers (17, 18). A salient feature
of immature HB is the characteristic interplay of
stemness and high proliferation found in aggressive
tumors (19). To date, it is not definitively clear if
HB is directly derived from infant hepatic stem cells
Figure 3 Surgical specimen and light and electron microscopy
of tumor cells. (A) In situ image of the giant tumor. The tumor mass
had a volume of w1000 ml and a weight of 1.5 kg. (B) Macroscopic
section of the large tumor (arrow). (C) H&E staining of the HB
(magnification 100!). (D) Strong immunohistochemical staining
positivity of ACTH (brown) of many tumor cells (magnification
100!). (E) Strong staining positivity of PTHrP (brown) in some
restiform like tumor cells by immunohistochemistry (magnification
100!). (F) Low-power electron micrograph of HB epithelial cells,
forming irregular strands separated by a loose connective tissue
matrix. Note irregularly shaped nuclei with highly uncondensed
chromatin, and well-developed rough endoplasmic reticulum typical
for increased protein synthesis (magnification 1100!). (G and H)
Small groups of roundish, oval and rod-shaped dense core granules
are noted in some of the cytoplasmic processes of the HB cells,
which are likely to be hormone-containing granules (arrows;
magnification 2300! and 10 000! respectively).
816 T G P Grunewald and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2010) 162
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(the hepatoblasts) through arrest of maturation or from
mature hepatic cells, which resemble a hepatoblast-like
phenotype upon reactivation of a conserved transcrip-
tional stemness program, through the process of de-
differentiation (18, 20). Indeed, liver cancer stem cells
have been isolated from human hepatoma cell lines,
primary HCC, and blood of HCC patients, supporting the
notion that some HCC subtypes are derived from hepatic
progenitors (17, 21, 22). Blockage of tumor stemness
may allow differentiation into a large cohort of
differentiated tissues as seen in other solid pediatric
malignancies (23, 24). Moreover, infant hepatic stem
cells (also called hepatoblasts) physiologically divide
asymmetrically and give rise to both a differentiated and
a stem cell-like daughter cell (18). Thus, it is tempting to
speculate that in the biphenotypic HB reported in this
case study, some tumor (stem) cells aberrantly differ-
entiated in hormone-producing cells upon yet unknown
stimuli through asymmetric cell division (25).
Ontologically, hepatoblasts and endocrine-active
pancreatic progenitor cells descend from the same
stem cells of the ventral endoderm, and specific
evolutionarily conserved inductive signals promote
differentiation into liver cells or pancreatic cells
(extensively reviewed by Zaret et al. 2008 (26)). The
plasticity of differentiation into endocrine cells may be
conserved also in tumors derived from hepatoblasts
the infant hepatic stem cells.
Consistent with this hypothesis, sporadic childhood
pancreatic islet cell tumors rarely produce ACTH (27).
Since recent evidence suggests that stemness is rather
a state than a fate (23, 24, 28), our case could suggest
a clinical correlate for tumors partially phenocopying
differentiated cells upon inductive micro-environmental
imprinting. In accordance, the well-defined multiple
histopathological and molecular stages of HB differen-
tiation, which reflect genetically and/or epigenetically
programmed loss of stemness signature, may be
intimately contextualized in developmental stages of
the embryonic, fetal, or infant liver harboring the
hepatic cancer stem cell (16, 17, 21, 22, 29).
Treatment and management
Due to the severe symptoms of hypercortisolism, the
marked hypercalcemia, which was unresponsive to a
short treatment trial with calcitonin, and the uncertain
response to chemotherapy, the local expert panel decided
on the primary resection of the tumor. Accordingly, the
giant liver tumor was completely removed through
resection of the whole right lobe of the liver. The tumor
had a weight of 1.5 kg, and histologically proved to be a
HB. Surgery turned out to be very challenging and lasted
for 9 h. Intra-operatively, the patient needed resuscita-
tion due to breakdown of circulation and cardiac arrest.
The critical episode lasted for 3 min. Perioperatively,
pharmacological doses of hydrocortisone were adminis-
tered to avoid relative hypocortisolism after removal of
the ACTH-producing HB. Postoperatively, the patient
needed artificial ventilation, but could be extubated
successfully after 5 days. In the following 3 months,
we treated the patient with a combined adjuvant
chemotherapy based on cisplatin, etoposide, adriblas-
tina, and ifosfamide, which was tolerated without severe
complications. One year after surgery, the girl developed
symptomatic complex-partial seizures, clonal stutter,
prominent deficiencies of coordination, and a more left-
sided hemiparesis. A brain CT scan revealed mild brain
atrophy probably as a result of brain hypoxia during
resuscitation. On several follow-up electroencephalo-
graphy (EEG) examinations, dysrhythmic groups and
diffuse sharp waves were detected, especially while the
patient was asleep, which were absent in routine EEG
before surgery. Seizures could be controlled and
prevented partially through therapy with carbamaze-
pine and valproic acid, but the girl experienced severe
learning difficulties in adolescence due to residual
mental handicap. To date, the patient is 29 years old
(height: 156 cm (z-score K1.13); weight: 70 kg (z-score
0.96); BMI: 28.8 kg/m
2
(z-score 1.41); breast and pubic
hair development Tanner stage 5; regular menses) and
physically well, and has regularly attended our out-
patient clinic for follow-up for more than two decades.
Presently, there is no evidence of relapse and/or
metastasis, and laboratory parameters are normal.
Conclusion
To our knowledge, this is the first report of an
endocrine-active HB leading to combined PNS of
Cushing’s syndrome and PTHrP-related HHM. This
information should be added to the well-known b-hCG-
related PNS effects of HB in children.
Declaration of interest
The authors declare that there is no conflict of interest that could be
perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any agency in the
public, commercial, or not-for-profit sector.
Author contribution statement
T Grunewald drafted and wrote the paper, designed the figures and the
tables. I von Luettichau and S Burdach provided oncological guidance
and corrected the paper. U Welsch performed ultrastructural analysis
of the tumor by electron microscopy. H-G Do¨rr performed serum
steroid analyses, F Ho¨pner performed the surgery, and K Kovacs
delivered the immunohistochemistry and the histology slides. W Rabl
was responsible for the initial diagnostic work-up, provided endo-
crinologic guidance throughout the patient’s care, and helped with
the final draft of the paper. All authors approved the nal manuscript.
ACTH syndrome and PTHrP-induced hypercalcemia
817EUROPEAN JOURNAL OF ENDOCRINOLOGY (2010) 162
www.eje-online.org
Acknowledgements
We are very grateful to Dr Klaus Kruse for analysis of serum and
urinary calcium/phosphate parameters, to Dr Otto-Albrecht Mu
¨
ller for
ACTH and CRH extraction from the tumor tissue, to Dr Janos Homoki
for the urinary steroid analysis, to Dr Franz Prantl for the histological
diagnosis, Dr Helmut Hahn for the X-ray, ultrasound and CT images,
and to Dr Stephan Mu
¨
ller-Weihrich for the initial oncological care of
the patient.
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    • "Likewise, ectopic βHCG production can cause precocious puberty in boys (virilizing HB) or a forme fruste in females [62]. A case of hormonally active HB causing both ectopic ACTH syndrome and PTH-related peptide-induced hypercalcemia has also been reported [63]. Although these paraneoplastic syndromes are not frequently linked to HB, they underscore the importance of considering these oncofetal proteins as tumor-associated rather than tumor-specific, and the diverse presentations that can pose diagnostic and therapeutic challenges in HB. "
    [Show abstract] [Hide abstract] ABSTRACT: Childhood cancer is the leading cause of death by disease among U.S. children between infancy and age 15. Despite successes in treating solid tumors such as Wilms tumor, disappointments in the outcomes of high-risk solid tumors like neuroblastoma have precipitated efforts towards the early and accurate detection of these malignancies. This review summarizes available solid tumor serum biomarkers with a special focus on mediastinal and abdominal cancers in children.
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    • "Angiogenic mimicry complements tumor-induced angiogenesis as a form of tumor metaplasia [29,75], a process that also applies to other forms of trans-differentiation (e.g. hormone production), which may present clinically as a paraneoplastic syndrome [76]. "
    [Show abstract] [Hide abstract] ABSTRACT: Compelling evidence broadens our understanding of tumors as highly heterogeneous populations derived from one common progenitor. In this review we portray various stages of tumorigenesis, tumor progression, self-seeding and metastasis in analogy to the superorganisms of insect societies to exemplify the highly complex architecture of a neoplasm as a system of functional "castes." Accordingly, we propose a model in which clonal expansion and cumulative acquisition of genetic alterations produce tumor compartments each equipped with distinct traits and thus distinct functions that cooperate to establish clinically apparent tumors. This functional compartment model also suggests mechanisms for the self-construction of tumor stem cell niches. Thus, thinking of a tumor as a superorganism will provide systemic insight into its functional compartmentalization and may even have clinical implications.
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  • [Show abstract] [Hide abstract] ABSTRACT: Ectopic ACTH syndrome (EAS) in youngsters has seldom been reported and is poorly known. We conducted a multicenter retrospective study involving 18 French tertiary hospitals. Cases of EAS presenting Cushing's syndrome before the age of 20 during the period from 1985 to 2008 were analyzed. Ten patients aged 14 to 20 yr were identified and compared to 20 age-matched patients with Cushing's disease diagnosed during the same period. Etiologies, clinical, biochemical and radiological features, prognosis, and treatment were described. Seven patients had well-differentiated neuroendocrine tumors (five bronchial carcinoids, one mediastinal lymph node, and one thymic), one had a poorly differentiated thymic carcinoma, one had a pleural Ewing's sarcoma, and one had a liver nested stromal epithelial tumor. At presentation, seven tumors were identified with computed tomography scanning and somatostatin receptor scintigraphy, and one with fluoro-18-L-dihydroxyphenylalanine positron emission tomography scan. Two carcinoids were occult and were identified during follow-up. Cushing's syndrome was more intense in EAS, but the clinical and biological spectrum overlapped with that of Cushing's disease. No dynamic test achieved 100% accuracy, whereas petrosal sinus sampling provided correct diagnosis in all patients tested. Medical treatment of hypercortisolism was successful in six of the eight patients with whom it was attempted, and bilateral adrenalectomy had to be performed in only two cases. Prognosis was good; nine patients with curative resection of the tumor were alive and cured (median follow-up, 6.5 yr), whereas one patient died. EAS in youngsters displays many similarities to that described in adults. The diagnostic and therapeutic algorithms recommended in adults can be used in this population.
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